WO2015148863A2

WO2015148863A2 - Crispr/cas-related methods and compositions for treating sickle cell disease

Info

Publication number: WO2015148863A2
Application number: PCT/US2015/022856
Authority: WO
Inventors: Ari E. FRIEDLAND; Morgan L. MAEDER; G. Grant Welstead; David A. Bumcrot; Cecilia COTTA-RAMUSINO
Original assignee: Editas Medicine, Inc.
Priority date: 2014-03-26
Filing date: 2015-03-26
Publication date: 2015-10-01
Also published as: EP3122880A2; EP3981876A1; US20170314015A1; US20230026726A1; EP3122880B1; WO2015148863A3; US11242525B2

Abstract

CRISPR/CAS-related compositions and methods for treatment of Sickle Cell Disease (SCD) are disclosed.

Description

CRISPR/CAS-RELATED METHODS AND COMPOSITIONS FOR TREATING

SICKLE CELL DISEASE

REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of U.S. Provisional Application No.

61/970,588, filed March 26, 2014, and U.S. Provisional Application No. 62/084,487, filed November 25, 2014, the contents of each of which are hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

The invention relates to CRISPR/CAS-related methods and components for editing of a target nucleic acid sequence, or modulating expression of a target nucleic acid sequence, and applications thereof in connection with Sickle Cell Disease (SCD).

BACKGROUND

Sickle Cell Disease (SCD), also known as Sickle Cell Anemia (SCA), is a common inherited hematologic disease. It affects 80,000-90,000 people in the United States. It is common in people of African descent and in Hispanic- Americans with the prevalence of SCD being 1 in 500 and 1 in 1,000, respectively.

SCD is caused by a mutation in the beta-globin (HBB) gene. HBB is located on chromosome 11 within the HBB gene cluster, which includes genes encoding the delta globin chain, A gamma chain, G gamma chain. The alpha-globin gene is located on chromosome 16. A point mutation (e.g., GAG GTG) results in the substitution of valine for glutamic acid at amino acid position 6 in exon 1 of the HBB gene. Beta hemoglobin chains with this mutation are expressed as HbS. The disease is inherited in an autosomal recessive manner, so that only patients with two HbS alleles have SCD. Subjects who have sickle cell trait (are heterozygous for HbS) only display a phenotype if they are severely dehydrated or oxygen deprived.

Normal adult hemoglobin (Hb) is composed of a tetramer made from two alpha-globin chains and two beta-globin chains. In SCD, the valine at position 6 of the beta-chain is hydrophobic and causes a change in conformation of the beta-globin protein when it is not bound to oxygen. HbS is more likely to polymerize and leads to the characteristic sickle shaped red blood cells (RBCs) found in SCD.

Sickle shape RBCs cause multiple manifestations of disease, which include, e.g., anemia, sickle cell crises, vaso-occlusive crises, aplastic crises and acute chest syndrome. The disease has varous manifestations, e.g., vaso-occlusive crisis, splenic sequestration crisis and anemia. Subjects may also suffer from acute chest crisis and infarcts of extremities, end organs and central nervous system. Treatment includes, e.g., hydration, transfusion and analgesics.

Treatment of SCD also includes, e.g., the use of hydroxyurea, supplementation with folic acid, and penicillin prophylaxis during childhood. Bone marrow transplants have been demonstrated to cure SCD.

Thus, there remains a need for additional methods and compositions that can be used to treat SCD.

SUMMARY OF THE INVENTION

Methods and compositions discussed herein, provide for the treatment and prevention of

Sickle Cell Disease (SCD), also known as Sickle Cell Anemia (SCA). SCD is an inherited hematologic disease.

In healthy individuals, two beta-globin molecules pair with two alpha-globin molecules to form normal hemoglobin (Hb). In SCD, mutations in the beta-globin (HBB) gene, e.g., a point mutation (GAG→ GTG) that results in the substitution of valine for glutamic acid at amino acid position 6 of the beta-globin molecule, cause production of sickle hemoglobin (HbS). HbS is more likely to polymerize and leads to the characteristic sickle shaped red blood cells (RBCs). Sickle shaped RBCs give rise to multiple manifestations of disease, such as, anemia, sickle cell crises, vaso-occlusive crises, aplastic crises and acute chest syndrome. Alpha-globin can also pair with fetal hemoglobin (HbF), which significantly moderates the severe anemia and other symptoms of SCD. However, the expression of HbF is negatively regulated by the BCL11A gene product.

Methods and compositions disclosed herein provide a number of approaches for treating SCD. As is discussed in more detail below, methods described herein provide for treating SCD by correcting a target position in the HBB gene to provide corrected, or functional, e.g., wild type, beta-globin. Methods and compositions discussed herein can be used to treat or prevent SCD by altering the BCLllA gene (also known as B-cell CLL/lymphoma 11A, BCL11A-L, BCL11A-S, BCL11A-XL, CTIP1, HBFQTL5 and ZNF). BCLllA encodes a zinc-finger protein that is involved in the regulation of globin gene expression. By altering the BCLllA gene (e.g., one or both alleles of the BCLllA gene), the levels of gamma globin can be increased. Gamma globin can replace beta globin in the hemoglobin complex and effectively carry oxygen to tissues, thereby ameliorating SCD disease phenotypes.

In one aspect, methods and compositions discussed herein, provide for the correction of the underlying genetic cause of SCD, e.g., the correction of a mutation at a target position in the HBB gene, e.g., correction of a mutation at amino acid position 6, e.g., an E6V substitution in the HBB gene.

Mutations in the HBB gene (also known as beta- globin and CD113t-C) have been shown to cause SCD. Mutations leading to SCD can be described based on their target positions in the HBB gene. In an embodiment, the target position is E6, e.g., E6V, in the HBB gene.

"SCD target point position", as used herein, refers to a target position in the HBB gene, typically a single nucleotide, which, if mutated, can result in a protein having a mutant amino acid and give rise to SCD. In an embodiment, the SCD target position is the target position at which a change can give rise to an E6 mutant protein, e.g., a protein having an E6V substitution.

While much of the disclosure herein is presented in the context of the mutation in the HBB gene that gives rise to an E6 mutant protein (e.g., E6V mutant protein), the methods and compositions herein are broadly applicable to any mutation, e.g., a point mutation or a deletion, in the HBB gene that gives rise to SCD.

While not wishing to be bound by theory, it is believed that, in an embodiment, a mutation at an SCD target point position in the HBB gene is corrected, e.g., by homology directed repair (HDR), as described herein.

In one aspect, methods and compositions discussed herein may be used to alter the

BCLllA gene to treat or prevent SCD, by targeting the BCLllA gene, e.g., coding or non-coding regions of the BCLllA gene. Altering the BCLllA gene herein refers to reducing or eliminating (1) BCLllA gene expression, (2) BCLllA protein function, or (3) the level of BCLllA protein. In an embodiment, the coding region (e.g., an early coding region) of the BCLllA gene is targeted for alteration. In an embodiment, a non-coding sequence (e.g., an enhancer region, a promoter region, an intron, 5'UTR, 3'UTR, or polyadenylation signal) is targeted for alteration.

In an embodiment, the method provides an alteration that comprises disrupting the BCLllA gene by the insertion or deletion of one or more nucleotides mediated by Cas9 (e.g., enzymatically active Cas9 (eaCas9), e.g., Cas9 nuclease or Cas9 nickase) as described below. This type of alteration is also referred to as "knocking out" the BCLllA gene.

In another embodiment, the method provides an alteration that does not comprise nucleotide insertion or deletion in the BCLllA gene and is mediated by enzymatically inactive Cas9 (eiCas9) or an eiCas9-fusion protein, as described below. This type of alteration is also referred to as "knocking down" the BCLllA gene.

In an embodiment, the methods and compositions discussed herein may be used to alter the BCLllA gene to treat or prevent SCD by knocking out one or both alleles of the BCLllA gene. In an embodiment, the coding region (e.g., an early coding region) of the BCLllA gene, is targeted to alter the gene. In an embodiment, a non-coding region of the BCLllA gene (e.g., an enhancer region, a promoter region, an intron, 5' UTR, 3'UTR, polyadenylation signal) is targeted to alter the gene. In an embodiment, an enhancer (e.g., a tissue-specific enhancer, e.g., a myeloid enhancer, e.g., an erythroid enhancer) is targeted to alter the gene. BCLllA erythroid enhancer comprises an approximatel2.4 kb fragment of BCLllA intron2, located between approximate +52.0 to +64.4 kilobases (kb) from the Transcription Start Site (TSS+52kb to TSS+64.4kb, see Fig. 10). It's also referred to herein as chromosome 2 location 60,716,189- 60,728,612 (according to UCSC Genome Browser hg 19 human genome assembly). Three deoxyribonuclese I hypersensitive sites (DHSs), TSS+62kb, TSS+58kb and TSS+55kb are located in this region. Deoxyribonuclease I sensitivity is a marker for gene regulatory elements. While not wishing to be bound by theory, it's believed that deleting the ehancer region (e.g.,

TSS+52kb to TSS+64.4kb) may reduce or eliminate BCLllA expression in erythroid precursors which leads to gamma globin derepression while sparing BCLllA expression in nonerythoroid lineages. In an embodiment, the method provides an alteration that comprises a deletion of the enhancer region (e.g., a tissue-specific enhancer, e.g., a myleloid enhancer, e.g., an erythroid enhancer) or a protion of the region resulting in disruption of one or more DNase 1- hypersensitivie sites (DHS). In an embodiment, the method provides an alteration that comprises an insertion or deletion of one or more nucleotides. As described herein, in an embodiment, a targeted knockout approach is mediated by non-homologous end joining (NHEJ) using a CRISPR/Cas system comprising an enzymatically active Cas9 (eaCas9). In an embodiment, a targeted knockout approach alters the BCLllA gene. In an embodiment, a targeted knockout approach reduces or eliminates expression of functional BCLllA gene product. In an

embodiment, targeting affects one or both alleles of the BCLllA gene. In an embodiment, an enhancer disruption approach reduces or eliminates expression of functional BCLllA gene product in the erythroid lineage.

"SCD target knockout position", as used herein, refers to a position in the BCLllA gene, which if altered, e.g., disrupted by insertion or deletion of one or more nucleotides, e.g., by NHEJ-mediated alteration, results in reduction or elimination of expression of functional BCLllA gene product. In an embodiment, the position is in the BCLllA coding region, e.g., an early coding region. In an embodiment, the position is in the BCLllA non-coding region, e.g., an enhancer region.

In an embodiment, methods and compositions discussed herein, provide for altering (e.g., knocking out) the BCLllA gene. In an embodiment, knocking out the BCLllA gene herein refers to (1) insertion or deletion (e.g., NHEJ-mediated insertion or deletion) of one or more nucleotides in close proximity to or within the early coding region of the BCLllA gene, or (2) deletion (e.g., NHEJ-mediated deletion) of a genomic sequence including the erythroid enhancer of the BCLllA gene,

In an embodiment, the SCD target knockout position is altered by genome editing using the CRISPR/Cas9 system. The SCD target knockout position may be targeted by cleaving with either a single nuclease or dual nickases, e.g., to induce insertion or deletion (e.g., NHEJ- mediated insertion or deletion) of one or more nucleotides in close proximity to or within the early coding region of the SCD target knockout position or to delete (e.g., mediated by NHEJ) a genomic sequence including the erythroid enhancer of the BCLllA gene.

In an embodiment, the methods and compositions described herein introduce one or more breaks in close proximity to or within the early coding region in at least one allele of the BCLllA gene. In an embodiment, a single strand break is introduced in close proximity to or within the early coding region in at least one allele of the BCLllA gene. In an embodiment, the single strand break will be accompanied by an additional single strand break, positioned by a second gRNA molecule.

In an embodiment, a double strand break is introduced in close proximity to or within the early coding region in at least one allele of the BCLllA gene. In an embodiment, a double strand break will be accompanied by an additional single strand break positioned by a second gRNA molecule. In an embodiment, a double strand break will be accompanied by two additional single strand breaks positioned by a second gRNA molecule and a third gRNA molecule.

In an embodiment, a pair of single strand breaks is introduced in close proximity to or within the early coding region in at least one allele of the BCLllA gene. In an embodiment, the pair of single strand breaks will be accompanied by an additional double strand break, positioned by a third gRNA molecule. In an embodiment, the pair of single strand breaks will be accompanied by an additional pair of single strand breaks positioned by a third gRNA molecule and a fourth gRNA molecule.

In an embodiment, two double strand breaks are introduced to flank the erythroid enhancer at the in the BCLllA gene (one 5' and the other one 3' to the erythroid enhancer) to remove (e.g., delete) the genomic sequence including the erythroid enhancer. It is contemplated herein that in an embodiment the deletion of the genomic sequence including the erythroid enhancer is mediated by NHEJ. In an embodiment, the breaks (i.e., the two double strand breaks) are positioned to avoid unwanted deletion of certain elements, such as endogenous splice sites. The breaks, i.e., two double strand breaks, can be positioned upstream and downstream of the erythroid enhancer, as discussed herein.

In an embodiment, two sets of breaks (e.g., one double strand break and a pair of single strand breaks) are introduced to flank the erythroid enhancer in the BCLllA gene (one set 5' and the other set 3' to the erythroid enhancer) to remove (e.g., delete) the genomic sequence including the erythroid enhancer. It is contemplated herein that in an embodiment the deletion of the genomic sequence including the erythroid enhancer is mediated by NHEJ. In an

embodiment, the breaks (i.e., the double strand break and the pair of single strand breaks) are positioned to avoid unwanted deletion of certain chromosome elements, such as endogenous splice sites. The breaks, e.g., the double strand break and the pair of single strand breaks, can be positioned upstream and downstream of the erythroid enhancer, as discussed herein. In an embodiment, two sets of breaks (e.g., two pairs of single strand breaks) are introduced to flank the erythroid enhancer at the SCD target position in the BCLllA gene (one set 5' and the other set 3' to the erythroid enhancer) to remove (e.g., delete) the genomic sequence including the erythroid enhancer. It is contemplated herein that in an embodiment the deletion of the genomic sequence including the erythroid enhancer is mediated by NHEJ. In an embodiment, the breaks (i.e., the two pairs of single strand breaks) are positioned to avoid unwanted deletion of certain chromosome elements, such as endogenous splice sites. The breaks, e.g., the two pairs of single strand breaks, can be positioned upstream and downstream of the erythroid enhancer, as discussed herein.

In an embodiment, the methods and compositions discussed herein may be used to alter the BCLllA gene to treat or prevent SCD by knocking down one or both alleles of the BCLllA gene. In one embodiment, the coding region of the BCLllA gene, is targeted to alter the gene. In another embodiment, a non-coding region (e.g., an enhancer region, a promoter region, an intron, 5' UTR, 3'UTR, polyadenylation signal) of the BCLllA gene is targeted to alter the gene. In an embodiment, the promoter region of the BCLllA gene is targeted to knock down the expression of the BCLllA gene. A targeted knockdown approach alters, e.g., reduces or eliminates the expression of the BCLllA gene. As described herein, in an embodiment, a targeted knockdown is mediated by targeting an enzymatically inactive Cas9 (eiCas9) or an eiCas9 fused to a transcription repressor domain or chromatin modifying protein to alter transcription, e.g., to block, reduce, or decrease transcription, of the BCLllA gene.

"SCD target knockdown position", as used herein, refers to a position, e.g., in the

BCLllA gene, which if targeted by an eiCas9 or an eiCas9 fusion described herein, results in reduction or elimination of expression of functional BCLllA gene product. In an embodiment, transcription is reduced or eliminated. In an embodiment, the position is in the BCLllA promoter sequence. In an embodiment, a position in the promoter sequence of the BCLllA gene is targeted by an enzymatically inactive Cas9 (eiCas9) or an eiCas9-fusion protein, as described herein.

In an embodiment, one or more gRNA molecule comprising a targeting domain configured to target an enzymatically inactive Cas9 (eiCas9) or an eiCas9 fusion protein (e.g., an eiCas9 fused to a transcription repressor domain), sufficiently close to a SCD target knockdown position to reduce, decrease or repress expression of the BCLllA gene. "SCD target position", as used herein, refers to any of an SCD target point position, SCD target knockout position, or SCD target knockdown position, as described herein.

In one aspect, disclosed herein is a gRNA molecule, e.g., an isolated or non-naturally occurring gRNA molecule, comprising a targeting domain which is complementary with a target domain from the HBB gene or BCL11A gene.

When two or more gRNAs are used to position two or more cleavage events, e.g., double strand or single strand breaks, in a target nucleic acid, it is contemplated that the two or more cleavage events may be made by the same or different Cas9 proteins. For example, when two gRNAs are used to position two double strand breaks, a single Cas9 nuclease may be used to create both double strand breaks. When two or more gRNAs are used to position two or more single stranded breaks (single strand breaks), a single Cas9 nickase may be used to create the two or more single strand breaks. When two or more gRNAs are used to position at least one double strand break and at least one single strand break, two Cas9 proteins may be used, e.g., one Cas9 nuclease and one Cas9 nickase. It is contemplated that when two or more Cas9 proteins are used that the two or more Cas9 proteins may be delivered sequentially to control specificity of a double strand versus a single strand break at the desired position in the target nucleic acid.

In an embodiment, the targeting domain of the first gRNA molecule and the targeting domain of the second gRNA molecule hybridize to the target domain through complementary base pairing to opposite strands of the target nucleic acid molecule. In an embodiment, the gRNA molecule and the second gRNA molecule are configured such that the PAMs are oriented outward.

In an embodiment, the targeting domain of a gRNA molecule is configured to avoid unwanted target chromosome elements, such as repeat elements, e.g., an Alu repeat, or the endogenous splice sites, in the target domain. The gRNA molecule may be a first, second, third and/or fourth gRNA molecule.

In an embodiment, the targeting domain of a gRNA molecule is configured to position a cleavage event sufficiently far from a preselected nucleotide, e.g., the nucleotide of a coding region, such that the nucleotide is not altered. In an embodiment, the targeting domain of a gRNA molecule is configured to position an intronic cleavage event sufficiently far from an intron/exon border, or naturally occurring splice signal, to avoid alteration of the exonic sequence or unwanted splicing events. The gRNA molecule may be a first, second, third and/or fourth gRNA molecule, as described herein.

In an embodiment, a point mutation in the HBB gene, e.g., at E6, e.g., E6V, is targeted, e.g., for correction. In an embodiment, the targeting domain of a gRNA molecule comprises a sequence that is the same as, or differs by no more than 1, 2, 3, 4, or 5 nucleotides from, a targeting domain sequence from any one of Tables 1A-1D. In an embodiment, the targeting domain is selected from those in Tables 1A-1D. For example, in an embodiment, the targeting domain is:

AAGGUGAACGUGGAUGAAGU (SEQ ID NO: 387);

GUAACGGCAGACUUCUCCUC (SEQ ID NO: 388);

GUGAACGUGGAUGAAGU (SEQ ID NO: 389); or

ACGGCAGACUUCUCCUC (SEQ ID NO: 390). In an embodiment, when the SCD target point position is E6, e.g., E6V, and two gRNAs are used to position two breaks, e.g., two single stranded breaks, in the target nucleic acid sequence, the targeting domain of each guide RNA is selected from one of Tables 1A-1D.

In an embodiment, a point mutation in the HBB gene, e.g., at E6, e.g., E6V, is targeted, e.g., for correction. In an embodiment, the targeting domain of a gRNA molecule comprises a sequence that is the same as, or differs by no more than 1, 2, 3, 4, or 5 nucleotides from, a targeting domain sequence from any one of Tables 13A-13D. In an embodiment, the targeting domain is selected from those in Tables 13A-13D. For example, in an embodiment, the targeting domain is:

GGUGCACCUGACUCCUG (SEQ ID NO: 6803); or

GUAACGGCAGACUUCUCCAC (SEQ ID NO: 6804). In an embodiment, when the SCD target point position is E6, e.g., E6V, and two gRNAs are used to position two breaks, e.g., two single stranded breaks, in the target nucleic acid sequence, the targeting domain of each guide RNA is selected from one of Tables 13A-13D.

In an embodiment, a point mutation in the HBB gene, e.g., at E6, e.g., E6V, is targeted, e.g., for correction. In an embodiment, the targeting domain of a gRNA molecule comprises a sequence that is the same as, or differs by no more than 1, 2, 3, 4, or 5 nucleotides from, a targeting domain sequence from any one of Tables 14A-14C. In an embodiment, the targeting domain is selected from those in Tables 14A-14C. In an embodiment, when the SCD target point position is E6, e.g., E6V, and two gRNAs are used to position two breaks, e.g., two single stranded breaks, in the target nucleic acid sequence, each guide RNA is selected from one of Tables 14A-14C.

In an embodiment, a point mutation in the HBB gene, e.g., at E6, e.g., E6V, is targeted, e.g., for correction. In an embodiment, the targeting domain of a gRNA molecule comprises a sequence that is the same as, or differs by no more than 1, 2, 3, 4, or 5 nucleotides from, a targeting domain sequence from any one of Tables 24A-24D. In an embodiment, the targeting domain is selected from those in Tables 24A-24D.

In an embodiment, when the SCD target point position is E6, e.g., E6V, and two gRNAs are used to position two breaks, e.g., two single stranded breaks, in the target nucleic acid sequence, the targeting domain of each guide RNA is selected from one of Tables 24A-24D.

In an embodiment, a point mutation in the HBB gene, e.g., at E6, e.g., E6V, is targeted, e.g., for correction. In an embodiment, the targeting domain of a gRNA molecule comprises a sequence that is the same as, or differs by no more than 1, 2, 3, 4, or 5 nucleotides from, a targeting domain sequence from any one of Tables 25A-25B. In an embodiment, the targeting domain is selected from those in Tables 25A-25B.

In an embodiment, when the SCD target point position is E6, e.g., E6V, and two gRNAs are used to position two breaks, e.g., two single stranded breaks, in the target nucleic acid sequence, the targeting domain of each guide RNA is selected from one of Tables 25A-25B.

In an embodiment, a point mutation in the HBB gene, e.g., at E6, e.g., E6V, is targeted, e.g., for correction. In an embodiment, the targeting domain of a gRNA molecule comprises a sequence that is the same as, or differs by no more than 1, 2, 3, 4, or 5 nucleotides from, a targeting domain sequence from Table 26. In an embodiment, the targeting domain is selected from those in Table 26.

In an embodiment, when the SCD target point position is E6, e.g., E6V, and two gRNAs are used to position two breaks, e.g., two single stranded breaks, in the target nucleic acid sequence, the targeting domain of each guide RNA is selected from Table 26. In another embodiment, a position in the coding region, e.g., the early coding region, of the BCLllA gene is targeted, e.g., for knockout. In an embodiment, the targeting domain comprises a sequence that is the same as, or differs by no more than 1, 2, 3, 4, or 5 nucleotides from, a targeting domain sequence from any one of Tables 2A-2F. In an embodiment, the targeting domain is selected from those in Tables 2A-2F. In another embodiment, the targeting domain is:

UGGCAUCCAGGUCACGCCAG (SEQ ID NO: 486);

GAUGCUUUUUUCAUCUCGAU (SEQ ID NO: 487);

GCAUCCAAUCCCGUGGAGGU (SEQ ID NO: 488);

UUUUCAUCUCGAUUGGUGAA (SEQ ID NO: 489);

CCAGAUGAACUUCCCAUUGG (SEQ ID NO: 490);

AGGAGGUCAUGAUCCCCUUC (SEQ ID NO: 491);

CAUCCAGGUCACGCCAG (SEQ ID NO: 492);

GCUUUUUUCAUCUCGAU (SEQ ID NO: 493);

UCCAAUCCCGUGGAGGU (SEQ ID NO: 494);

UCAUCUCGAUUGGUGAA (SEQ ID NO: 495);

GAUGAACUUCCCAUUGG (SEQ ID NO: 496); or

AGGUCAUGAUCCCCUUC (SEQ ID NO: 497).

In an embodiment, when the SCD target knockout position is the BCL11A coding region, e.g., early coding region, and more than one gRNA is used to position breaks, e.g., two single stranded breaks or two double stranded breaks, or a combination of single strand and double strand breaks, e.g., to create one or more indels, in the target nucleic acid sequence, the targeting domain of each guide RNA is selected from one of Tables 2A-2F.

In another embodiment, a position in the coding region, e.g., the early coding region, of the BCL11A gene is targeted, e.g., for knockout. In an embodiment, the targeting domain comprises a sequence that is the same as, or differs by no more than 1, 2, 3, 4, or 5 nucleotides from, a targeting domain sequence from any one of Table 4A-4E. In an embodiment, the targeting domain is selected from those in Table 4A-4E. In another embodiment, the targeting domain is:

GAGCUCCAUGUGCAGAACGA (SEQ ID NO: 3073);

GAGCUCCCAACGGGCCG (SEQ ID NO: 3074);

GAGUGCAGAAUAUGCCCCGC (SEQ ID NO: 3075);

GAUAAACAAUCGUCAUCCUC (SEQ ID NO: 3076);

GAUGCCAACCUCCACGGGAU (SEQ ID NO: 3077);

GCAGAAUAUGCCCCGCA (SEQ ID NO: 3078);

GCAUCCAAUCCCGUGGAGGU (SEQ ID NO: 3079);

GCCAACCUCCACGGGAU (SEQ ID NO: 3080);

GCUCCCAACGGGCCGUGGUC (SEQ ID NO: 3081); or

GGAGCUCUAAUCCCCACGCC (SEQ ID NO: 3082). In an embodiment, when the SCD target knockout position is the BCL11A coding region, e.g., early coding region, and more than one gRNA is used to position breaks, e.g., two single strand breaks or two double strand breaks, or a combination of single strand and double strand breaks, e.g., to create one or more indels, in the target nucleic acid sequence, the targeting domain of each guide RNA is selected from one of Table 4A-4E.

In another embodiment, a position in the coding region, e.g., the early coding region, of the BCL11A gene is targeted, e.g., for knockout. In an embodiment, the targeting domain comprises a sequence that is the same as, or differs by no more than 1, 2, 3, 4, or 5 nucleotides from, a targeting domain sequence from any one of Table 5A-5E. In an embodiment, the targeting domain is selected from those in Table 5A-5E.

In an embodiment, when the SCD target knockout position is the BCL11A coding region, e.g., early coding region, and more than one gRNA is used to position breaks, e.g., two single strand breaks or two double strand breaks, or a combination of single strand and double strand breaks, e.g., to create one or more indels, in the target nucleic acid sequence, the targeting domain of each guide RNA is selected from one of Table 5A-5E.

In another embodiment, a position in the coding region, e.g., the early coding region, of the BCL11A gene is targeted, e.g., for knockout. In an embodiment, the targeting domain comprises a sequence that is the same as, or differs by no more than 1, 2, 3, 4, or 5 nucleotides from, a targeting domain sequence from any one of Table 6A-6B. In an embodiment, the targeting domain is selected from those in Table 6A-6B.

In an embodiment, when the SCD target knockout position is the BCL11A coding region, e.g., early coding region, and more than one gRNA is used to position breaks, e.g., two single strand breaks or two double strand breaks, or a combination of single strand and double strand breaks, e.g., to create one or more indels, in the target nucleic acid sequence, the targeting domain of each guide RNA is selected from one of Table 6A-6B.

In another embodiment, a position in the coding region, e.g., the early coding region, of the BCL11A gene is targeted, e.g., for knockout. In an embodiment, the targeting domain comprises a sequence that is the same as, or differs by no more than 1, 2, 3, 4, or 5 nucleotides from, a targeting domain sequence from any one of Table 15A-15D. In an embodiment, the targeting domain is selected from those in Table 15A-15D. In an embodiment, when the SCD target knockout position is the BCL11A coding region, e.g., early coding region, and more than one gRNA is used to position breaks, e.g., two single strand breaks or two double strand breaks, or a combination of single strand and double strand breaks, e.g., to create one or more indels, in the target nucleic acid sequence, the targeting domain of each guide RNA is selected from one of Table 15A-15D.

In another embodiment, a position in the coding region, e.g., the early coding region, of the BCL11A gene is targeted, e.g., for knockout. In an embodiment, the targeting domain comprises a sequence that is the same as, or differs by no more than 1, 2, 3, 4, or 5 nucleotides from, a targeting domain sequence from any one of Table 16A-16E. In an embodiment, the targeting domain is selected from those in Table 16A-16E.

In an embodiment, when the SCD target knockout position is the BCL11A coding region, e.g., early coding region, and more than one gRNA is used to position breaks, e.g., two single strand breaks or two double strand breaks, or a combination of single strand and double strand breaks, e.g., to create one or more indels, in the target nucleic acid sequence, the targeting domain of each guide RNA is selected from one of Table 16A-16E.

In another embodiment, a position in the coding region, e.g., the early coding region, of the BCL11A gene is targeted, e.g., for knockout. In an embodiment, the targeting domain comprises a sequence that is the same as, or differs by no more than 1, 2, 3, 4, or 5 nucleotides from, a targeting domain sequence from any one of Table 17A-17B. In an embodiment, the targeting domain is selected from those in Table 17A-17B.

In an embodiment, when the SCD target knockout position is the BCL11A coding region, e.g., early coding region, and more than one gRNA is used to position breaks, e.g., two single strand breaks or two double strand breaks, or a combination of single strand and double strand breaks, e.g., to create one or more indels, in the target nucleic acid sequence, the targeting domain of each guide RNA is selected from one of Table 17A-17B.

In another embodiment, a position in the non-coding region, e.g., the enhancer region, of the BCL11A gene is targeted, e.g., for knockout. In an embodiment, the targeting domain comprises a sequence that is the same as, or differs by no more than 1, 2, 3, 4, or 5 nucleotides from, a targeting domain sequence from any one of Tables 7A-7D. In an embodiment, the targeting domain is selected from those in Tables 7A-7D. In another embodiment, the targeting domain is: GAAAAUACUUACUGUACUGC (SEQ ID NO: 4835);

GAAAGCAGUGUAAGGCU (SEQ ID NO: 4836);

GGCUGUUUUGGAAUGUAGAG (SEQ ID NO: 4837); or

GUGCUACUUAUACAAUUCAC (SEQ ID NO: 4838).

In an embodiment, when the SCD target knockout position is the non-coding region, e.g., the enhancer region, of the BCL11A gene, and more than one gRNA is used to position breaks, e.g., two single strand breaks or two double strand breaks, or a combination of single strand and double strand breaks, e.g., to create a deletion, in the target nucleic acid sequence, the targeting domain of each guide RNA is selected from one of Table 7A-7D.

In another embodiment, a position in the non-coding region, e.g., the enhancer region, of the BCL11A gene is targeted, e.g., for knockout. In an embodiment, the targeting domain comprises a sequence that is the same as, or differs by no more than 1, 2, 3, 4, or 5 nucleotides from, a targeting domain sequence from any one of Tables 8A-8D. In an embodiment, the targeting domain is selected from those in Tables 8A-8D.

In an embodiment, when the SCD target knockout position is the non-coding region, e.g., the enhancer region, of the BCL11A gene, and more than one gRNA is used to position breaks, e.g., two single strand breaks or two double strand breaks, or a combination of single strand and double strand breaks, e.g., to create a deletion, in the target nucleic acid sequence, the targeting domain of each guide RNA is selected from one of Table 8A-8D.

In another embodiment, a position in the non-coding region, e.g., the enhancer region, of the BCL11A gene is targeted, e.g., for knockout. In an embodiment, the targeting domain comprises a sequence that is the same as, or differs by no more than 1, 2, 3, 4, or 5 nucleotides from, a targeting domain sequence from Table 9. In an embodiment, the targeting domain is selected from those in Table 9.

In an embodiment, when the SCD target knockout position is the non-coding region, e.g., the enhancer region, of the BCL11A gene, and more than one gRNA is used to position breaks, e.g., two single strand breaks or two double strand breaks, or a combination of single strand and double strand breaks, e.g., to create a deletion, in the target nucleic acid sequence, the targeting domain of each guide RNA is selected from one of Table 9.

In another embodiment, a position in the non-coding region, e.g., the enhancer region, of the BCL11A gene is targeted, e.g., for knockout. In an embodiment, the targeting domain comprises a sequence that is the same as, or differs by no more than 1, 2, 3, 4, or 5 nucleotides from, a targeting domain sequence from any one of Tables 21A-21E. In an embodiment, the targeting domain is selected from those in Tables 21A-21E. In an embodiment, when the SCD target knockout position is the non-coding region, e.g., the enhancer region, of the BCLllA gene, and more than one gRNA is used to position breaks, e.g., two single strand breaks or two double strand breaks, or a combination of single strand and double strand breaks, e.g., to create a deletion, in the target nucleic acid sequence, the targeting domain of each guide RNA is selected from one of Table 21A-21E.

In another embodiment, a position in the non-coding region, e.g., the enhancer region, of the BCLllA gene is targeted, e.g., for knockout. In an embodiment, the targeting domain comprises a sequence that is the same as, or differs by no more than 1, 2, 3, 4, or 5 nucleotides from, a targeting domain sequence from any one of Tables 22A-22E. In an embodiment, the targeting domain is selected from those in Tables 22A-22E. In an embodiment, when the SCD target knockout position is the non-coding region, e.g., the enhancer region, of the BCLllA gene, and more than one gRNA is used to position breaks, e.g., two single strand breaks or two double strand breaks, or a combination of single strand and double strand breaks, e.g., to create a deletion, in the target nucleic acid sequence, the targeting domain of each guide RNA is selected from one of Table 22A-22E.

In another embodiment, a position in the non-coding region, e.g., the enhancer region, of the BCLllA gene is targeted, e.g., for knockout. In an embodiment, the targeting domain comprises a sequence that is the same as, or differs by no more than 1, 2, 3, 4, or 5 nucleotides from, a targeting domain sequence from any one of Tables 23A-23C. In an embodiment, the targeting domain is selected from those in Tables 23A-23C.

In an embodiment, when the SCD target knockout position is the non-coding region, e.g., the enhancer region, of the BCLllA gene, and more than one gRNA is used to position breaks, e.g., two single strand breaks or two double strand breaks, or a combination of single strand and double strand breaks, e.g., to create a deletion, in the target nucleic acid sequence, the targeting domain of each guide RNA is selected from one of Table 23A-23C.

In an embodiment, the targeting domain of the gRNA molecule is configured to target an enzymatically inactive Cas9 (eiCas9) or an eiCas9 fusion protein (e.g., an eiCas9 fused to a transcription repressor domain), sufficiently close to an SCD knockdown target position to reduce, decrease or repress expression of the BCLllA gene. In an embodiment, the targeting domain is configured to target the promoter region of the BCL11A gene to block transcription initiation, binding of one or more transcription enhancers or activators, and/or RNA polymerase.

One or more gRNA may be used to target an eiCas9 to the promoter region of the BCL11A gene.

In an embodiment, when the BCL11A promoter region is targeted, e.g., for knockdown, the targeting domain can comprise a sequence that is the same as, or differs by no more than 1, 2,

3, 4, or 5 nucleotides from, a targeting domain sequence from any one of Tables 3A-3C. In an embodiment, the targeting domain is selected from those in Tables 3A-3C.

In an embodiment, when the SCD target knockdown position is the BCL11A promoter region and more than one gRNA is used to position an eiCas9 or an eiCas9-fusion protein (e.g., an eiCas9-transcription repressor domain fusion protein), in the target nucleic acid sequence, the targeting domain of each guide RNA is selected from one of Tables 3A-3C.

3, 4, or 5 nucleotides from, a targeting domain sequence from any one of Tables 10A-10D. In an embodiment, the targeting domain is selected from those in Tables 10A-10D. In another embodiment, the targeting domain is:

GACGACGGCUCGGUUCACAU (SEQ ID NO: 4981);

GACGCCAGACGCGGCCCCCG (SEQ ID NO: 4982);

GCCUUGCUUGCGGCGAGACA (SEQ ID NO: 4983);

GGCUCCGCGGACGCCAGACG (SEQ ID NO: 4984);

GACGGCUCGGUUCACAU (SEQ ID NO: 4985);

GCCGCGUCUGGCGUCCG (SEQ ID NO: 4986); or

GCGGGCGGACGACGGCU (SEQ ID NO: 4987).

In an embodiment, when the SCD target knockdown position is the BCL11A promoter region and more than one gRNA is used to position an eiCas9 or an eiCas9-fusion protein (e.g., an eiCas9-transcription repressor domain fusion protein), in the target nucleic acid sequence, each guide RNA is selected from one of Tables 10A-10D.

In an embodiment, when the BCL11A promoter region is targeted, e.g., for knockdown, the targeting domain can comprise a sequence that is the same as, or differs by no more than 1, 2, 3, 4, or 5 nucleotides from, a targeting domain sequence from any one of Tables 11A-11D. In an embodiment, the targeting domain is selected from those in Tables 11A-11D.

In an embodiment, when the SCD target knockdown position is the BCL11A promoter region and more than one gRNA is used to position an eiCas9 or an eiCas9-fusion protein (e.g., an eiCas9-transcription repressor domain fusion protein), in the target nucleic acid sequence, each guide RNA is selected from one of Tables 11A-11D.

In an embodiment, when the BCL11A promoter region is targeted, e.g., for knockdown, the targeting domain can comprise a sequence that is the same as, or differs by no more than 1, 2, 3, 4, or 5 nucleotides from, a targeting domain sequence from Table 12. In an embodiment, the targeting domain is selected from those in Table 12.

In an embodiment, when the SCD target knockdown position is the BCL11A promoter region and more than one gRNA is used to position an eiCas9 or an eiCas9-fusion protein (e.g., an eiCas9-transcription repressor domain fusion protein), in the target nucleic acid sequence, each guide RNA is selected from Table 12.

In an embodiment, when the BCL11A promoter region is targeted, e.g., for knockdown, the targeting domain can comprise a sequence that is the same as, or differs by no more than 1, 2, 3, 4, or 5 nucleotides from, a targeting domain sequence from any one of Tables 18A-18C. In an embodiment, the targeting domain is selected from those in Tables 18A-18C.

In an embodiment, when the SCD target knockdown position is the BCL11A promoter region and more than one gRNA is used to position an eiCas9 or an eiCas9-fusion protein (e.g., an eiCas9-transcription repressor domain fusion protein), in the target nucleic acid sequence, each guide RNA is selected from one of Tables 18A-18C.

In an embodiment, when the BCL11A promoter region is targeted, e.g., for knockdown, the targeting domain can comprise a sequence that is the same as, or differs by no more than 1, 2, 3, 4, or 5 nucleotides from, a targeting domain sequence from any one of Tables 19A-19E. In an embodiment, the targeting domain is selected from those in Tables 19A-19E.

In an embodiment, when the SCD target knockdown position is the BCL11A promoter region and more than one gRNA is used to position an eiCas9 or an eiCas9-fusion protein (e.g., an eiCas9-transcription repressor domain fusion protein), in the target nucleic acid sequence, each guide RNA is selected from one of Tables 19A-19E.

In an embodiment, when the BCL11A promoter region is targeted, e.g., for knockdown, the targeting domain can comprise a sequence that is the same as, or differs by no more than 1, 2, 3, 4, or 5 nucleotides from, a targeting domain sequence from any one of Tables 20A-20C. In an embodiment, the targeting domain is selected from those in Tables 20A-20C. In an embodiment, when the SCD target knockdown position is the BCL11A promoter region and more than one gRNA is used to position an eiCas9 or an eiCas9-fusion protein (e.g., an eiCas9-transcription repressor domain fusion protein), in the target nucleic acid sequence, each guide RNA is selected from one of Tables 20A-20C.

In an embodiment, the targeting domain comprises a sequence that is the same as, or differs by no more than 1, 2, 3, 4, or 5 nucleotides from, a targeting domain sequence selected from any one of Tables 1A-1D, 2A-2F, 3A-3C, 4A-4E, 5A-5E, 6A-6B, 7A-7D, 8A-8D, 9, 10A- 10D, 11A-11D, 12, 13A-13D, 14A-14C, 15A-15D, 16A-16E, 17A-17B, 18A-18C, 19A-19E, 20A-20C, 21A-21E, 22A-22E, 23A-23C, 24A-24D, 25A-25B, 26, or 31. In an embodiment, the targeting domain is selected from those in Tables 1A-1D, 2A-2F, 3A-3C, 4A-4E, 5A-5E, 6A- 6B, 7A-7D, 8A-8D, 9, 10A-10D, 11A-11D, 12, 13A-13D, 14A-14C, 15A-15D, 16A-16E, 17A- 17B, 18A-18C, 19A-19E, 20A-20C, 21A-21E, 22A-22E, 23A-23C, 24A-24D, 25A-25B, 26, or 31.

In an embodiment, the targeting domain which is complementary with the BCL11A gene is 16 nucleotides or more in length. In an embodiment, the targeting domain is 16 nucleotides in length. In an embodiment, the targeting domain is 17 nucleotides in length. In another embodiment, the targeting domain is 18 nucleotides in length. In still another embodiment, the targeting domain is 19 nucleotides in length. In still another embodiment, the targeting domain is 20 nucleotides in length. In still another embodiment, the targeting domain is 21 nucleotides in length. In still another embodiment, the targeting domain is 22 nucleotides in length. In still another embodiment, the targeting domain is 23 nucleotides in length. In still another embodiment, the targeting domain is 24 nucleotides in length. In still another embodiment, the targeting domain is 25 nucleotides in length. In still another embodiment, the targeting domain is 26 nucleotides in length.

In an embodiment, the targeting domain comprises 16 nucleotides.

In an embodiment, the targeting domain comprises 17 nucleotides.

In an embodiment, the targeting domain comprises 18 nucleotides.

In an embodiment, the targeting domain comprises 19 nucleotides.

In an embodiment, the targeting domain comprises 20 nucleotides.

In an embodiment, the targeting domain comprises 21 nucleotides.

In an embodiment, the targeting domain comprises 22 nucleotides. In an embodiment, the targeting domain comprises 23 nucleotides.

In an embodiment, the targeting domain comprises 24 nucleotides.

In an embodiment, the targeting domain comprises 25 nucleotides.

In an embodiment, the targeting domain comprises 26 nucleotides.

In an embodiment, the gRNA, e.g., a gRNA comprising a targeting domain, which is complementary with the HBB gene or BCL11A gene, is a modular gRNA. In another embodiment, the gRNA is a unimolecular or chimeric gRNA.

HBB gRNA as described herein may comprise from 5' to 3' : a targeting domain (comprising a "core domain", and optionally a "secondary domain"); a first complementarity domain; a linking domain; a second complementarity domain; a proximal domain; and a tail domain. In an embodiment, the proximal domain and tail domain are taken together as a single domain.

In an embodiment, a gRNA comprises a linking domain of no more than 25 nucleotides in length; a proximal and tail domain, that taken together, are at least 20 nucleotides in length; and a targeting domain equal to or greater than 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26 nucleotides in length.

In another embodiment, a gRNA comprises a linking domain of no more than 25 nucleotides in length; a proximal and tail domain, that taken together, are at least 25 nucleotides in length; and a targeting domain equal to or greater than 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26 nucleotides in length.

In another embodiment, a gRNA comprises a linking domain of no more than 25 nucleotides in length; a proximal and tail domain, that taken together, are at least 30 nucleotides in length; and a targeting domain equal to or greater than 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26 nucleotides in length.

In another embodiment, a gRNA comprises a linking domain of no more than 25 nucleotides in length; a proximal and tail domain, that taken together, are at least 40 nucleotides in length; and a targeting domain equal to or greater than 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26 nucleotides in length.

A cleavage event, e.g., a double strand or single strand break, is generated by a Cas9 molecule. The Cas9 molecule may be an enzymatically active Cas9 (eaCas9) molecule, e.g., an eaCas9 molecule that forms a double strand break in a target nucleic acid or an eaCas9 molecule forms a single strand break in a target nucleic acid (e.g., a nickase molecule). Alternatively, in an embodiment, the Cas9 molecule may be an enzymatically inactive Cas9 (eiCas9) molecule or a modified eiCas9 molecule, e.g., the eiCas9 molecule is fused to Kriippel- associated box (KRAB) to generate an eiCas9-KRAB fusion protein molecule.

In an embodiment, the eaCas9 molecule catalyzes a double strand break.

In an embodiment, the eaCas9 molecule comprises HNH-like domain cleavage activity but has no, or no significant, N-terminal RuvC-like domain cleavage activity. In this case, the eaCas9 molecule is an HNH-like domain nickase, e.g., the eaCas9 molecule comprises a mutation at D10, e.g., D10A. In another embodiment, the eaCas9 molecule comprises N- terminal RuvC-like domain cleavage activity but has no, or no significant, HNH-like domain cleavage activity. In an embodiment, the eaCas9 molecule is an N-terminal RuvC-like domain nickase, e.g., the eaCas9 molecule comprises a mutation at H840, e.g., H840A. In an embodiment, the eaCas9 molecule is an N-terminal RuvC-like domain nickase, e.g., the eaCas9 molecule comprises a mutation at N863, e.g., N863A.

In an embodiment, a single strand break is formed in the strand of the target nucleic acid to which the targeting domain of said gRNA is complementary. In another embodiment, a single strand break is formed in the strand of the target nucleic acid other than the strand to which the targeting domain of said gRNA is complementary.

In another aspect, disclosed herein is a nucleic acid, e.g., an isolated or non-naturally occurring nucleic acid, e.g., DNA, that comprises (a) a sequence that encodes a gRNA molecule comprising a targeting domain that is complementary with a target domain, e.g., with an SCD target position, in the HBB gene or BCL11A gene as disclosed herein.

In an embodiment, the nucleic acid encodes a gRNA molecule, e.g., a first gRNA molecule, comprising a targeting domain configured to provide a cleavage event, e.g., a double strand break or a single strand break, sufficiently close to an SCD target position in the HBB gene or BCL11A gene to allow alteration, e.g., alteration associated with HDR or NHEJ, of the an SCD target position in the HBB gene or BCL11A gene.

In an embodiment, the nucleic acid encodes a gRNA molecule, e.g., a first gRNA molecule, comprising a targeting domain configured to target an enzymatically inactive Cas9 (eiCas9) or an eiCas9 fusion protein (e.g., an eiCas9 fused to a transcription repressor domain), sufficiently close to an SCD knockdown target position to reduce, decrease or repress expression of the BCL11A gene.

In an embodiment, the nucleic acid encodes a gRNA molecule, e.g., the first gRNA molecule, comprising a targeting domain comprising a sequence that is the same as, or differs by no more than 1, 2, 3, 4, or 5 nucleotides from, a targeting domain sequence from any one of Tables 1A-1D, 2A-2F, 3A-3C, 4A-4E, 5A-5E, 6A-6B, 7A-7D, 8A-8D, 9, 10A-10D, 11A-11D, 12, 13A-13D, 14A-14C, 15A-15D, 16A-16E, 17A-17B, 18A-18C, 19A-19E, 20A-20C, 21A- 21E, 22A-22E, 23A-23C, 24A-24D, 25A-25B, 26, or 31. In an embodiment, the nucleic acid encodes a gRNA molecule comprising a targeting domain is selected from those in Tables 1A- ID, 2A-2F, 3A-3C, 4A-4E, 5A-5E, 6A-6B, 7A-7D, 8A-8D, 9, 10A-10D, 11A-11D, 12, 13A- 13D, 14A-14C, 15A-15D, 16A-16E, 17A-17B, 18A-18C, 19A-19E, 20A-20C, 21A-21E, 22A- 22E, 23A-23C, 24A-24D, 25A-25B, 26, or 31.

In an embodiment, the nucleic acid encodes a modular gRNA, e.g., one or more nucleic acids encode a modular gRNA. In another embodiment, the nucleic acid encodes a chimeric gRNA. The nucleic acid may encode a gRNA, e.g., the first gRNA molecule, comprising a targeting domain comprising 16 nucleotides or more in length. In one embodiment, the nucleic acid encodes a gRNA, e.g., the first gRNA molecule, comprising a targeting domain that is 16 nucleotides in length. In another embodiment, the nucleic acid encodes a gRNA, e.g., the first gRNA molecule, comprising a targeting domain that is 17 nucleotides in length. In still another embodiment, the nucleic acid encodes a gRNA, e.g., the first gRNA molecule, comprising a targeting domain that is 18 nucleotides in length. In still another embodiment, the nucleic acid encodes a gRNA, e.g., the first gRNA molecule, comprising a targeting domain that is 19 nucleotides in length. In still another embodiment, the nucleic acid encodes a gRNA, e.g., the first gRNA molecule, comprising a targeting domain that is 20 nucleotides in length. In still another embodiment, the nucleic acid encodes a gRNA, e.g., the first gRNA molecule, comprising a targeting domain that is 21 nucleotides in length. In still another embodiment, the nucleic acid encodes a gRNA, e.g., the first gRNA molecule, comprising a targeting domain that is 22 nucleotides in length. In still another embodiment, the nucleic acid encodes a gRNA, e.g., the first gRNA molecule, comprising a targeting domain that is 23 nucleotides in length. In still another embodiment, the nucleic acid encodes a gRNA, e.g., the first gRNA molecule, comprising a targeting domain that is 24 nucleotides in length. In still another embodiment, the nucleic acid encodes a gRNA, e.g., the first gRNA molecule, comprising a targeting domain that is 25 nucleotides in length. In still another embodiment, the nucleic acid encodes a gRNA, e.g., the first gRNA molecule, comprising a targeting domain that is 26 nucleotides in length.

In an embodiment, the targeting domain comprises 16 nucleotides.

In an embodiment, the targeting domain comprises 17 nucleotides.

In an embodiment, the targeting domain comprises 18 nucleotides.

In an embodiment, the targeting domain comprises 19 nucleotides.

In an embodiment, the targeting domain comprises 20 nucleotides.

In an embodiment, the targeting domain comprises 21 nucleotides.

In an embodiment, the targeting domain comprises 22 nucleotides.

In an embodiment, the targeting domain comprises 23 nucleotides.

In an embodiment, the targeting domain comprises 24 nucleotides.

In an embodiment, the targeting domain comprises 25 nucleotides.

In an embodiment, the targeting domain comprises 26 nucleotides.

In an embodiment, a nucleic acid encodes a gRNA comprising from 5' to 3'

domain (comprising a "core domain", and optionally a "secondary domain"); a first

complementarity domain; a linking domain; a second complementarity domain; a proximal domain; and a tail domain. In an embodiment, the proximal domain and tail domain are taken together as a single domain.

In an embodiment, a nucleic acid encodes a gRNA e.g., the first gRNA molecule, comprising a linking domain of no more than 25 nucleotides in length; a proximal and tail domain, that taken together, are at least 20 nucleotides in length; and a targeting domain equal to or greater than 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26 nucleotides in length.

In an embodiment, a nucleic acid encodes a gRNA e.g., the first gRNA molecule, comprising a linking domain of no more than 25 nucleotides in length; a proximal and tail domain, that taken together, are at least 30 nucleotides in length; and a targeting domain equal to or greater than 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26 nucleotides in length.

In an embodiment, a nucleic acid encodes a gRNA e.g., the first gRNA molecule, comprising a linking domain of no more than 25 nucleotides in length; a proximal and tail domain, that taken together, are at least 30 nucleotides in length; and a targeting domain equal to or greater than 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26 nucleotides in length. In an embodiment, a nucleic acid encodes a gRNA comprising e.g., the first gRNA molecule, a linking domain of no more than 25 nucleotides in length; a proximal and tail domain, that taken together, are at least 40 nucleotides in length; and a targeting domain equal to or greater than 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26 nucleotides in length.

In an embodiment, a nucleic acid comprises (a) a sequence that encodes a gRNA molecule e.g., the first gRNA molecule, comprising a targeting domain that is complementary with a target domain in the HBB gene or BCLllA gene as disclosed herein, and further comprising (b) a sequence that encodes a Cas9 molecule.

The Cas9 molecule may be an enzymatically active Cas9 (eaCas9) molecule, e.g., an eaCas9 molecule that forms a double strand break in a target nucleic acid or an eaCas9 molecule forms a single strand break in a target nucleic acid (e.g., a nickase molecule). Alternatively, in an embodiment, the Cas9 molecule may be an enzymatically inactive Cas9 (eiCas9) molecule or a modified eiCas9 molecule, e.g., the eiCas9 molecule is fused to Kriippel- associated box (KRAB) to generate an eiCas9-KRAB fusion protein molecule.

A nucleic acid disclosed herein may comprise (a) a sequence that encodes a gRNA molecule comprising a targeting domain that is complementary with a target domain in the HBB gene or BCLllA gene as disclosed herein; (b) a sequence that encodes a Cas9 molecule; and further comprises (c)(i) a sequence that encodes a second gRNA molecule described herein having a targeting domain that is complementary to a second target domain of the HBB gene or BCLllA gene, and optionally, (c)(ii) a sequence that encodes a third gRNA molecule described herein having a targeting domain that is complementary to a third target domain of the HBB gene or BCLllA gene; and optionally, (c)(iii) a sequence that encodes a fourth gRNA molecule described herein having a targeting domain that is complementary to a fourth target domain of the HBB gene or BCLllA gene.

In an embodiment, a nucleic acid encodes a second gRNA molecule comprising a targeting domain configured to provide a cleavage event, e.g., a double strand break or a single strand break, sufficiently close to an SCD target position in the HBB gene or BCLllA gene, to allow alteration, e.g., alteration associated with HDR or NHEJ, of an SCD target position in the HBB gene or BCLllA gene, either alone or in combination with the break positioned by said first gRNA molecule. In an embodiment, the nucleic acid encodes a second gRNA molecule comprising a targeting domain configured to target an enzymatically inactive Cas9 (eiCas9) or an eiCas9 fusion protein (e.g., an eiCas9 fused to a transcription repressor domain), sufficiently close to an SCD knockdown target position to reduce, decrease or repress expression of the BCL11A gene.

In an embodiment, a nucleic acid encodes a third gRNA molecule comprising a targeting domain configured to provide a cleavage event, e.g., a double strand break or a single strand break, sufficiently close to an SCD target position in the HBB gene or BCL11A gene to allow alteration, e.g., alteration associated with HDR or NHEJ, of an SCD target position in the HBB gene or BCL11A gene, either alone or in combination with the break positioned by the first and/or second gRNA molecule.

In an embodiment, the nucleic acid encodes a third gRNA molecule comprising a targeting domain configured to target an enzymatically inactive Cas9 (eiCas9) or an eiCas9 fusion protein (e.g., an eiCas9 fused to a transcription repressor domain), sufficiently close to an SCD knockdown target position to reduce, decrease or repress expression of the BCL11A gene.

In an embodiment, a nucleic acid encodes a fourth gRNA molecule comprising a targeting domain configured to provide a cleavage event, e.g., a double strand break or a single strand break, sufficiently close to an SCD target position in the HBB gene or BCL11A gene to allow alteration, e.g., alteration associated with HDR or NHEJ, of an SCD target position in the HBB gene or BCL11A gene, either alone or in combination with the break positioned by the first gRNA molecule, the second gRNA molecule and/or the third gRNA molecule.

In an embodiment, the nucleic acid encodes a fourth gRNA molecule comprising a targeting domain configured to target an enzymatically inactive Cas9 (eiCas9) or an eiCas9 fusion protein (e.g., an eiCas9 fused to a transcription repressor domain), sufficiently close to an SCD knockdown target position to reduce, decrease or repress expression of the BCL11A gene.

In an embodiment, the nucleic acid encodes a second gRNA molecule. The second gRNA is selected to target the same SCD target position as the first gRNA molecule. Optionally, the nucleic acid may encode a third gRNA, and further optionally, the nucleic acid may encode a fourth gRNA molecule. The third gRNA molecule and the fourth gRNA molecule are selected to target the same SCD target position as the first and/or second gRNA molecules.

In an embodiment, the nucleic acid encodes a second gRNA molecule comprising a targeting domain comprising a sequence that is the same as, or differs by no more than 1, 2, 3, 4, or 5 nucleotides from, a targeting domain sequence from one of Tables 1A-1D, 2A-2F, 3A-3C, 4A-4E, 5A-5E, 6A-6B, 7A-7D, 8A-8D, 9, 10A-10D, 11A-11D, 12, 13A-13D, 14A-14C, 15A- 15D, 16A-16E, 17A-17B, 18A-18C, 19A-19E, 20A-20C, 21A-21E, 22A-22E, 23A-23C, 24A- 24D, 25A-25B, 26, or 31. In an embodiment, the nucleic acid encodes a second gRNA molecule comprising a targeting domain selected from those in Tables 1A-1D, 2A-2F, 3A-3C, 4A-4E, 5A-5E, 6A-6B, 7A-7D, 8A-8D, 9, 10A-10D, 11A-11D, 12, 13A-13D, 14A-14C, 15A-15D, 16A- 16E, 17A-17B, 18A-18C, 19A-19E, 20A-20C, 21A-21E, 22A-22E, 23A-23C, 24A-24D, 25A- 25B, 26, or 31. In an embodiment, when a third or fourth gRNA molecule are present, the third and fourth gRNA molecules may independently comprise a targeting domain comprising a sequence that is the same as, or differs by no more than 1, 2, 3, 4, or 5 nucleotides from, a targeting domain sequence from one of Tables 1A-1D, 2A-2F, 3A-3C, 4A-4E, 5A-5E, 6A-6B, 7A-7D, 8A-8D, 9, 10A-10D, 11A-11D, 12, 13A-13D, 14A-14C, 15A-15D, 16A-16E, 17A-17B, 18A-18C, 19A-19E, 20A-20C, 21A-21E, 22A-22E, 23A-23C, 24A-24D, 25A-25B, 26, or 31. In a further embodiment, when a third or fourth gRNA molecule are present, the third and fourth gRNA molecules may independently comprise a targeting domain selected from those in Tables 1A-1D, 2A-2F, 3A-3C, 4A-4E, 5A-5E, 6A-6B, 7A-7D, 8A-8D, 9, 10A-10D, 11A-11D, 12, 13A-13D, 14A-14C, 15A-15D, 16A-16E, 17A-17B, 18A-18C, 19A-19E, 20A-20C, 21A-21E, 22A-22E, 23A-23C, 24A-24D, 25A-25B, 26, or 31.

In an embodiment, the nucleic acid encodes a second gRNA which is a modular gRNA, e.g., wherein one or more nucleic acid molecules encode a modular gRNA. In another embodiment, the nucleic acid encoding a second gRNA is a chimeric gRNA. In another embodiment, when a nucleic acid encodes a third or fourth gRNA, the third and/or fourth gRNA may be a modular gRNA or a chimeric gRNA. When multiple gRNAs are used, any

combination of modular or chimeric gRNAs may be used.

A nucleic acid may encode a second, a third, and/or a fourth gRNA comprising a targeting domain comprising 16 nucleotides or more in length. In an embodiment, the nucleic acid encodes a second gRNA comprising a targeting domain that is 16 nucleotides in length. In another embodiment, the nucleic acid encodes a second gRNA comprising a targeting domain that is 17 nucleotides in length. In still another embodiment, the nucleic acid encodes a second gRNA comprising a targeting domain that is 18 nucleotides in length. In still another embodiment, the nucleic acid encodes a second gRNA comprising a targeting domain that is 19 nucleotides in length. In still another embodiment, the nucleic acid encodes a second gRNA comprising a targeting domain that is 20 nucleotides in length. In still another embodiment, the nucleic acid encodes a second gRNA comprising a targeting domain that is 21 nucleotides in length. In still another embodiment, the nucleic acid encodes a second gRNA comprising a targeting domain that is 22 nucleotides in length. In still another embodiment, the nucleic acid encodes a second gRNA comprising a targeting domain that is 23 nucleotides in length. In still another embodiment, the nucleic acid encodes a second gRNA comprising a targeting domain that is 24 nucleotides in length. In still another embodiment, the nucleic acid encodes a second gRNA comprising a targeting domain that is 25 nucleotides in length. In still another embodiment, the nucleic acid encodes a second gRNA comprising a targeting domain that is 26 nucleotides in length.

In an embodiment, the targeting domain comprises 16 nucleotides.

In an embodiment, the targeting domain comprises 17 nucleotides.

In an embodiment, the targeting domain comprises 18 nucleotides.

In an embodiment, the targeting domain comprises 19 nucleotides.

In an embodiment, the targeting domain comprises 20 nucleotides.

In an embodiment, the targeting domain comprises 21 nucleotides.

In an embodiment, the targeting domain comprises 22 nucleotides.

In an embodiment, the targeting domain comprises 23 nucleotides.

In an embodiment, the targeting domain comprises 24 nucleotides.

In an embodiment, the targeting domain comprises 25 nucleotides.

In an embodiment, the targeting domain comprises 26 nucleotides.

In an embodiment, a nucleic acid encodes a second, a third, and/or a fourth gRNA comprising from 5' to 3' : a targeting domain (comprising a "core domain", and optionally a "secondary domain"); a first complementarity domain; a linking domain; a second

complementarity domain; a proximal domain; and a tail domain. In an embodiment, the proximal domain and tail domain are taken together as a single domain.

In an embodiment, a nucleic acid encodes a second, a third, and/or a fourth gRNA comprising a linking domain of no more than 25 nucleotides in length; a proximal and tail domain, that taken together, are at least 20 nucleotides in length; and a targeting domain equal to or greater than 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26 nucleotides in length. In an embodiment, a nucleic acid encodes a second, a third, and/or a fourth gRNA comprising a linking domain of no more than 25 nucleotides in length; a proximal and tail domain, that taken together, are at least 30 nucleotides in length; and a targeting domain equal to or greater than 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26 nucleotides in length.

In an embodiment, a nucleic acid encodes a second, a third, and/or a fourth gRNA comprising a linking domain of no more than 25 nucleotides in length; a proximal and tail domain, that taken together, are at least 35 nucleotides in length; and a targeting domain equal to or greater than 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26 nucleotides in length.

In an embodiment, a nucleic acid encodes a second, a third, and/or a fourth gRNA comprising a linking domain of no more than 25 nucleotides in length; a proximal and tail domain, that taken together, are at least 40 nucleotides in length; and a targeting domain equal to or greater than 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26 nucleotides in length.

In an embodiment, when the HBB gene is corrected, e.g., by HDR, the nucleic acid encodes (a) a sequence that encodes a gRNA molecule comprising a targeting domain that is complementary with a target domain in the HBB gene as disclosed herein; (b) a sequence that encodes a Cas9 molecule; optionally, (c)(i) a sequence that encodes a second gRNA molecule described herein having a targeting domain that is complementary to a second target domain of the HBB gene, and further optionally, (c)(ii) a sequence that encodes a third gRNA molecule described herein having a targeting domain that is complementary to a third target domain of the HBB gene; and still further optionally, (c)(iii) a sequence that encodes a fourth gRNA molecule described herein having a targeting domain that is complementary to a fourth target domain of the HBB gene; and further may comprise (d) a template nucleic acid (in an embodiment where an exogenous template is used).

In an embodiment, a mutation in the HBB gene is corrected, e.g., by HDR, using an exogenously provided template nucleic acid.

In an embodiment, the template nucleic acid is a single stranded nucleic acid. In another embodiment, the template nucleic acid is a double stranded nucleic acid. In an embodiment, the template nucleic acid comprises a nucleotide sequence, e.g., of one or more nucleotides, that will be added to or will template a change in the target nucleic acid. In another embodiment, the template nucleic acid comprises a nucleotide sequence that may be used to modify the target position. In another embodiment, the template nucleic acid comprises a nucleotide sequence, e.g., of one or more nucleotides, that corresponds to wild type sequence of the target nucleic acid, e.g., of the target position.

The template nucleic acid may comprise a replacement sequence, e.g., a replacement sequence from the Table 27. In an embodiment, the template nucleic acid comprises a 5' homology arm, e.g., a 5' homology arm from Table 27. In another embodiment, the template nucleic acid comprises a 3' homology arm, e.g., a 3' homology arm from Table 27.

In another embodiment, a mutation in the HBB gene is corrected, e.g., by HDR, without using an exogenously provided template nucleic acid. While not wishing to be bound by theory, it is believed that an endogenous region of homology can mediate HDR-based correction. In an embodiment, alteration of the target sequence occurs by HDR with an endogenous genomic donor sequence. In an embodiment, the endogenous genomic donor sequence is located on the same chromosome as the target sequence. In another embodiment, the endogenous genomic donor sequence is located on a different chromosome from the target sequence. In an embodiment, the endogenous genomic donor sequence comprises one or more nucleotides derived from the HBD gene. Mutations in the HBB gene that can be corrected (e.g., altered) by HDR with an endogenous genomic donor sequence include, e.g., a point mutation at E6, e.g., E6V.

As described above, a nucleic acid may comprise (a) a sequence encoding a gRNA molecule comprising a targeting domain that is complementary with a target domain in the HBB gene or BCL11A gene, and (b) a sequence encoding a Cas9 molecule.

In an embodiment, (a) and (b) are present on the same nucleic acid molecule, e.g., the same vector, e.g., the same viral vector, e.g., the same adeno-associated virus (AAV) vector. In an embodiment, the nucleic acid molecule is an AAV vector. Exemplary AAV vectors that may be used in any of the described compositions and methods include an AAV2 vector, a modified AAV2 vector, an AAV3 vector, a modified AAV3 vector, an AAV6 vector, a modified AAV6 vector, an AAV8 vector and an AAV9 vector.

In another embodiment, (a) is present on a first nucleic acid molecule, e.g. a first vector, e.g., a first viral vector, e.g., a first AAV vector; and (b) is present on a second nucleic acid molecule, e.g., a second vector, e.g., a second vector, e.g., a second AAV vector. The first and second nucleic acid molecules may be AAV vectors. In another embodiment, the nucleic acid may further comprise (c) a sequence that encodes a second, third and/or fourth gRNA molecule as described herein. In an embodiment, the nucleic acid comprises (a), (b) and (c). Each of (a) and (c) may be present on the same nucleic acid molecule, e.g., the same vector, e.g., the same viral vector, e.g., the same adeno- associated virus (AAV) vector. In an embodiment, the nucleic acid molecule is an AAV vector.

In another embodiment, (a) and (c) are on different vectors. For example, (a) may be present on a first nucleic acid molecule, e.g. a first vector, e.g., a first viral vector, e.g., a first AAV vector; and (c) may be present on a second nucleic acid molecule, e.g., a second vector, e.g., a second vector, e.g., a second AAV vector. In an embodiment, the first and second nucleic acid molecules are AAV vectors.

In another embodiment, each of (a), (b), and (c) are present on the same nucleic acid molecule, e.g., the same vector, e.g., the same viral vector, e.g., an AAV vector. In an embodiment, the nucleic acid molecule is an AAV vector. In an alternate embodiment, one of (a), (b), and (c) is encoded on a first nucleic acid molecule, e.g., a first vector, e.g., a first viral vector, e.g., a first AAV vector; and a second and third of (a), (b), and (c) is encoded on a second nucleic acid molecule, e.g., a second vector, e.g., a second vector, e.g., a second AAV vector. The first and second nucleic acid molecule may be AAV vectors.

In an embodiment, (a) is present on a first nucleic acid molecule, e.g., a first vector, e.g., a first viral vector, a first AAV vector; and (b) and (c) are present on a second nucleic acid molecule, e.g., a second vector, e.g., a second vector, e.g., a second AAV vector. The first and second nucleic acid molecule may be AAV vectors.

In another embodiment, (b) is present on a first nucleic acid molecule, e.g., a first vector, e.g., a first viral vector, e.g., a first AAV vector; and (a) and (c) are present on a second nucleic acid molecule, e.g., a second vector, e.g., a second vector, e.g., a second AAV vector. The first and second nucleic acid molecule may be AAV vectors.

In another embodiment, (c) is present on a first nucleic acid molecule, e.g., a first vector, e.g., a first viral vector, e.g., a first AAV vector; and (b) and (a) are present on a second nucleic acid molecule, e.g., a second vector, e.g., a second vector, e.g., a second AAV vector. The first and second nucleic acid molecule may be AAV vectors.

In another embodiment, each of (a), (b) and (c) are present on different nucleic acid molecules, e.g., different vectors, e.g., different viral vectors, e.g., different AAV vector. For example, (a) may be on a first nucleic acid molecule, (b) on a second nucleic acid molecule, and (c) on a third nucleic acid molecule. The first, second and third nucleic acid molecule may be AAV vectors.

In another embodiment, when a third and/or fourth gRNA molecule are present, each of (a), (b), (c)(i), (c)(ii) and (c)(iii) may be present on the same nucleic acid molecule, e.g., the same vector, e.g., the same viral vector, e.g., an AAV vector. In an embodiment, the nucleic acid molecule is an AAV vector. In an alternate embodiment, each of (a), (b), (c)(i), (c)(ii) and

(c) (iii) may be present on the different nucleic acid molecules, e.g., different vectors, e.g., the different viral vectors, e.g., different AAV vectors. In further embodiments, each of (a), (b), (c)(i), (c)(ii) and (c)(iii) may be present on more than one nucleic acid molecule, but fewer than five nucleic acid molecules, e.g., AAV vectors.

In another embodiment, when (d) a template nucleic acid is present, each of (a), (b), and

(d) may be present on the same nucleic acid molecule, e.g., the same vector, e.g., the same viral vector, e.g., an AAV vector. In an embodiment, the nucleic acid molecule is an AAV vector. In an alternate embodiment, each of (a), (b), and (d) may be present on the different nucleic acid molecules, e.g., different vectors, e.g., the different viral vectors, e.g., different AAV vectors. In further embodiments, each of (a), (b), and (d) may be present on more than one nucleic acid molecule, but fewer than three nucleic acid molecules, e.g., AAV vectors.

In another embodiment, when (d) a template nucleic acid is present, each of (a), (b), (c)(i) and (d) may be present on the same nucleic acid molecule, e.g., the same vector, e.g., the same viral vector, e.g., an AAV vector. In an embodiment, the nucleic acid molecule is an AAV vector. In an alternate embodiment, each of (a), (b), (c)(i) and (d) may be present on the different nucleic acid molecules, e.g., different vectors, e.g., the different viral vectors, e.g., different AAV vectors. In further embodiments, each of (a), (b), (c)(i) and (d) may be present on more than one nucleic acid molecule, but fewer than four nucleic acid molecules, e.g., AAV vectors.

In another embodiment, when (d) a template nucleic acid is present, each of (a), (b), (c)(i), (c)(ii) and (d) may be present on the same nucleic acid molecule, e.g., the same vector, e.g., the same viral vector, e.g., an AAV vector. In an embodiment, the nucleic acid molecule is an AAV vector. In an alternate embodiment, each of (a), (b), (c)(i), (c)(ii) and (d) may be present on the different nucleic acid molecules, e.g., different vectors, e.g., the different viral vectors, e.g., different AAV vectors. In further embodiments, each of (a), (b), (c)(i), (c)(ii) and (d) may be present on more than one nucleic acid molecule, but fewer than five nucleic acid molecules, e.g., AAV vectors.

In another embodiment, when (d) a template nucleic acid is present, each of (a), (b), (c)(i), (c)(ii), (c)(iii) and (d) may be present on the same nucleic acid molecule, e.g., the same vector, e.g., the same viral vector, e.g., an AAV vector. In an embodiment, the nucleic acid molecule is an AAV vector. In an alternate embodiment, each of (a), (b), (c)(i), (c)(ii), (c)(iii) and (d) may be present on the different nucleic acid molecules, e.g., different vectors, e.g., the different viral vectors, e.g., different AAV vectors. In further embodiments, each of (a), (b), (c)(i), (c)(ii), (c)(iii) and (d) may be present on more than one nucleic acid molecule, but fewer than six nucleic acid molecules, e.g., AAV vectors.

The nucleic acids described herein may comprise a promoter operably linked to the sequence that encodes the gRNA molecule of (a), e.g., a promoter described herein. The nucleic acid may further comprise a second promoter operably linked to the sequence that encodes the second, third and/or fourth gRNA molecule of (c), e.g., a promoter described herein. The promoter and second promoter differ from one another. In an embodiment, the promoter and second promoter are the same.

The nucleic acids described herein may further comprise a promoter operably linked to the sequence that encodes the Cas9 molecule of (b), e.g., a promoter described herein.

In another aspect, disclosed herein is a composition comprising (a) a gRNA molecule comprising a targeting domain that is complementary with a target domain in the HBB gene or BCL11A gene, as described herein. The composition of (a) may further comprise (b) a Cas9 molecule, e.g., a Cas9 molecule as described herein. A composition of (a) and (b) may further comprise (c) a second, third and/or fourth gRNA molecule, e.g., a second, third and/or fourth gRNA molecule described herein. A composition of (a), (b) and (c) may further comprise (d) a template nucleic acid (in an embodiment where an exogenous template is used). In an embodiment, the composition is a pharmaceutical composition. The Compositions described herein, e.g., pharmaceutical compositions described herein, can be used in treating SCD in a subject, e.g., in accordance with a method disclosed herein.

In another aspect, disclosed herein is a method of altering a cell, e.g., altering the structure, e.g., altering the sequence, of a target nucleic acid of a cell, comprising contacting said cell with: (a) a gRNA that targets the HBB gene or BCL11A gene, e.g., a gRNA as described herein; (b) a Cas9 molecule, e.g., a Cas9 molecule as described herein; and optionally, (c) a second, third and/or fourth gRNA that targets HBB gene or BCL11A gene, e.g., a gRNA; and optionally, (d) a template nucleic acid, as described herein.

In an embodiment, the method comprises contacting said cell with (a) and (b).

In an embodiment, the method comprises contacting said cell with (a), (b), and (c).

In an embodiment, the method comprises contacting said cell with (a), (b), (c) and (d).

In an embodiment, the gRNA targets the HBB gene and no exogenous template nucleic acid is contacted with the cell.

The gRNA of (a) and optionally (c) may be selected from any of Tables 1A-1D, 2A-2F,

3A-3C, 4A-4E, 5A-5E, 6A-6B, 7A-7D, 8A-8D, 9, 10A-10D, 11A-11D, 12, 13A-13D, 14A-14C, 15A-15D, 16A-16E, 17A-17B, 18A-18C, 19A-19E, 20A-20C, 21A-21E, 22A-22E, 23A-23C, 24A-24D, 25A-25B, 26, or 31, or a gRNA that differs by no more than 1, 2, 3, 4, or 5 nucleotides from, a targeting domain sequence from any of Tables 1A-1D, 2A-2F, 3A-3C, 4A-4E, 5A-5E, 6A-6B, 7A-7D, 8A-8D, 9, 10A-10D, 11A-11D, 12, 13A-13D, 14A-14C, 15A-15D, 16A-16E, 17A-17B, 18A-18C, 19A-19E, 20A-20C, 21A-21E, 22A-22E, 23A-23C, 24A-24D, 25A-25B, 26, or 31.

In an embodiment, the method comprises contacting a cell from a subject suffering from or likely to develop SCD. The cell may be from a subject having a mutation at an SCD target position in the HBB gene or a subject which would benefit from having a mutation at an SCD target position in the BCL11A gene.

In an embodiment, the cell being contacted in the disclosed method is an erythroid cell. The contacting may be performed ex vivo and the contacted cell may be returned to the subject's body after the contacting step. In another embodiment, the contacting step may be performed in vivo.

In an embodiment, the method of altering a cell as described herein comprises acquiring knowledge of the sequence at an SCD target position in said cell, prior to the contacting step. Acquiring knowledge of the sequence at an SCD target position in the cell may be by sequencing the HBB gene or BCL11A gene, or a portion of the HBB gene or BCL11A gene.

In an embodiment, the contacting step of the method comprises contacting the cell with a nucleic acid, e.g., a vector, e.g., an AAV vector, that expresses at least one of (a), (b), and (c). In an embodiment, the contacting step of the method comprises contacting the cell with a nucleic acid, e.g., a vector, e.g., an AAV vector, that expresses each of (a), (b), and (c). In another embodiment, the contacting step of the method comprises delivering to the cell a Cas9 molecule of (b) and a nucleic acid which encodes a gRNA (a) and optionally, a second gRNA (c)(i) (and further optionally, a third gRNA (c)(iv) and/or fourth gRNA (c)(iii).

In an embodiment, the contacting step of the method comprises contacting the cell with a nucleic acid, e.g., a vector, e.g., an AAV vector, that expresses at least one of (a), (b), (c) and (d). In an embodiment, the contacting step of the method comprises contacting the cell with a nucleic acid, e.g., a vector, e.g., an AAV vector, that expresses each of (a), (b), and (c). In another embodiment, the contacting step of the method comprises delivering to the cell a Cas9 molecule of (b), a nucleic acid which encodes a gRNA of (a) and a template nucleic acid of (d), and optionally, a second gRNA (c)(i) (and further optionally, a third gRNA (c)(iv) and/or fourth gRNA (c)(iii).

In an embodiment, contacting comprises contacting the cell with a nucleic acid, e.g., a vector, e.g., an AAV vector, e.g., an AAV2 vector, a modified AAV2 vector, an AAV3 vector, a modified AAV3 vector, an AAV6 vector, a modified AAV6 vector, an AAV8 vector or an AAV9 vector.

In an embodiment, contacting comprises delivering to the cell a Cas9 molecule of (b), as a protein or an mRNA, and a nucleic acid which encodes (a) and optionally a second, third and/or fourth gRNA of (c).

In an embodiment, contacting comprises delivering to the cell a Cas9 molecule of (b), as a protein or an mRNA, said gRNA of (a), as an RNA, and optionally said second, third and/or fourth gRNA of (c), as an RNA.

In an embodiment, contacting comprises delivering to the cell a gRNA of (a) as an RNA, optionally said second, third and/or fourth gRNA of (c) as an RNA, and a nucleic acid that encodes the Cas9 molecule of (b).

In another aspect, disclosed herein is a method of treating or preventing a subject suffering from or likely to develop SCD, e.g., altering the structure, e.g., sequence, of a target nucleic acid of the subject, comprising contacting the subject (or a cell from the subject) with:

(a) a gRNA that targets the HBB gene or BCL11A gene, e.g., a gRNA disclosed herein;

(b) a Cas9 molecule, e.g., a Cas9 molecule disclosed herein; and optionally, (c)(i) a second gRNA that targets the HBB gene or BCL11A gene, e.g., a second gRNA disclosed herein, and

further optionally, (c)(ii) a third gRNA, and still further optionally, (c)(iii) a fourth gRNA that target the HBB gene or BCL11A gene, e.g., a third and fourth gRNA disclosed herein.

The method of treating a subject may further comprise contacting the subject (or a cell from the subject) with (d) a template nucleic acid (in an embodiment where an exogenous template is used), e.g., a template nucleic acid disclosed herein.

In an embodiment, a template nucleic acid is used when the method of treating a subject uses HDR to alter the sequence of the target nucleic acid of the subject. In an embodiment, the gRNA targets the HBB gene and no exogenous template nucleic acid is contacted with the subject (or a cell from the subject).

In an embodiment, contacting comprises contacting with (a) and (b).

In an embodiment, contacting comprises contacting with (a), (b), and (c)(i).

In an embodiment, contacting comprises contacting with (a), (b), (c)(i) and (c)(ii).

In an embodiment, contacting comprises contacting with (a), (b), (c)(i), (c)(ii) and (c)(iii).

In an embodiment, contacting comprises contacting with (a), (b), (c)(i) and (d).

In an embodiment, contacting comprises contacting with (a), (b), (c)(i), (c)(ii) and (d).

In an embodiment, contacting comprises contacting with (a), (b), (c)(i), (c)(ii), (c)(iii) and

(d).

The gRNA of (a) or (c) (e.g., (c)(i), (c)(ii), or (c)(iii) may be selected from any of Tables 1A-1D, 2A-2F, 3A-3C, 4A-4E, 5A-5E, 6A-6B, 7A-7D, 8A-8D, 9, 10A-10D, 11A-11D, 12, 13A-13D, 14A-14C, 15A-15D, 16A-16E, 17A-17B, 18A-18C, 19A-19E, 20A-20C, 21A-21E, 22A-22E, 23A-23C, 24A-24D, 25A-25B, 26, or 31, or a gRNA that differs by no more than 1, 2, 3, 4, or 5 nucleotides from, a targeting domain sequence from any of Tables 1A-1D, 2A-2F, 3A- 3C, 4A-4E, 5A-5E, 6A-6B, 7A-7D, 8A-8D, 9, 10A-10D, 11A-11D, 12, 13A-13D, 14A-14C, 15A-15D, 16A-16E, 17A-17B, 18A-18C, 19A-19E, 20A-20C, 21A-21E, 22A-22E, 23A-23C, 24A-24D, 25A-25B, 26, or 31.

In an embodiment, the method comprises acquiring knowledge of the sequence (e.g., a mutation) of an SCD target position in said subject. In an embodiment, the method comprises acquiring knowledge of the sequence (e.g., a mutation) of an SCD target position in said subject by sequencing the HBB gene or BCL11A gene or a portion of the HBB gene or BCL11A gene.

In an embodiment, the method comprises correcting a mutation at an SCD target position in the HBB gene.

In an embodiment, the method comprises correcting a mutation at an SCD target position in the HBB gene by HDR.

In an embodiment, the method comprises introducing a mutation at an SCD target position in the BCL11A gene.

In an embodiment, the method comprises introducing a mutation at an SCD target position in the BCL11A gene by NHEJ.

When the method comprises correcting the mutation at an SCD target position by HDR, a Cas9 of (b), at least one guide RNA, e.g., a guide RNA of (a) and a template nucleic acid of (d) are included in the contacting step.

In an embodiment, a cell of the subject is contacted ex vivo with (a), (b), (d) and optionally (c)(i), further optionally (c)(ii), and still further optionally (c)(iii). In an embodiment, said cell is returned to the subject's body.

In an embodiment, a cell of the subject is contacted is in vivo with (a), (b) (d) and optionally (c)(i), further optionally (c)(ii), and still further optionally (c)(iii).

In an embodiment, the cell of the subject is contacted in vivo by intravenous delivery of

(a), (b), (d) and optionally (c)(i), further optionally (c)(ii), and still further optionally (c)(iii).

In an embodiment, the cell of the subject is contacted in vivo by intramuscular delivery of

(a) , (b), (d) and optionally (c)(i), further optionally (c)(ii), and still further optionally (c)(iii).

In an embodiment, the cell of the subject is contacted in vivo by subcutaneous delivery of (a), (b), (d) and optionally (c)(i), further optionally (c)(ii), and still further optionally (c)(iii).

In an embodiment, the cell of the subject is contacted in vivo by intra-bone marrow (IBM) delivery of (a), (b), (d) and optionally (c)(i), further optionally (c)(ii), and still further optionally (c)(iii).

In an embodiment, contacting comprises contacting the subject with a nucleic acid, e.g., a vector, e.g., an AAV vector, described herein, e.g., a nucleic acid that encodes at least one of (a),

(b) , (d) and optionally (c)(i), further optionally (c)(ii), and still further optionally (c)(iii). In an embodiment, contacting comprises delivering to said subject said Cas9 molecule of

(b) , as a protein or mRNA, and a nucleic acid which encodes (a), a nucleic acid of (d) and optionally (c)(i), further optionally (c)(ii), and still further optionally (c)(iii).

In an embodiment, contacting comprises delivering to the subject the Cas9 molecule of (b), as a protein or mRNA, the gRNA of (a), as an RNA, a nucleic acid of (d) and optionally the second, third and/or fourth gRNA of (c), as an RNA.

In an embodiment, contacting comprises delivering to the subject the gRNA of (a), as an RNA, optionally said second, third and/or fourth gRNA of (c), as an RNA, a nucleic acid that encodes the Cas9 molecule of (b), and a nucleic acid of (d).

When the method comprises (1) introducing a mutation at an SCD target position by

NHEJ or (2) knocking down expression of the BCL11A gene by targeting the promoter region, a Cas9 of (b) and at least one guide RNA, e.g., a guide RNA of (a) are included in the contacting step.

In an embodiment, a cell of the subject is contacted ex vivo with (a), (b) and optionally (c)(i), further optionally (c)(ii), and still further optionally (c)(iii). In an embodiment, said cell is returned to the subject's body.

In an embodiment, a populations of cells from a subject is contacted ex vivo with (a), (b) and optionally (c) to correct the E6V mutation in the HBB gene and a second population of cells from the subject is contacted ex vivo with (a), (b) and optionally (c) to introduce a mutation in the BCL11A gene to knockout the BCL11A gene. A mixture of the two cell populations may be returned to the subject's body to treat or prevent SCD.

In an embodiment, a cell of the subject is contacted is in vivo with (a), (b) and optionally

(c) (i), further optionally (c)(ii), and still further optionally (c)(iii). In an embodiment, the cell of the subject is contacted in vivo by intravenous delivery of (a), (b) and optionally (c)(i), further optionally (c)(ii), and still further optionally (c)(iii). In an embodiment, the cell of the subject is contacted in vivo by intramuscular delivery of (a), (b) and optionally (c)(i), further optionally (c)(ii), and still further optionally (c)(iii). In an embodiment, the cell of the subject is contacted in vivo by subcutaneous delivery of (a), (b) and optionally (c)(i), further optionally (c)(ii), and still further optionally (c)(iii). In an embodiment, the cell of the subject is contacted in vivo by intra-bone marrow (IBM) delivery of (a), (b) and optionally (c)(i), further optionally (c)(ii), and still further optionally (c)(iii). In an embodiment, contacting comprises contacting the subject with a nucleic acid, e.g., a vector, e.g., an AAV vector, described herein, e.g., a nucleic acid that encodes at least one of (a), (b), and optionally (c)(i), further optionally (c)(ii), and still further optionally (c)(iii).

In an embodiment, contacting comprises delivering to said subject said Cas9 molecule of (b), as a protein or mRNA, and a nucleic acid which encodes (a) and optionally (c)(i), further optionally (c)(ii), and still further optionally (c)(iii).

In an embodiment, contacting comprises delivering to the subject the Cas9 molecule of (b), as a protein or mRNA, the gRNA of (a), as an RNA, and optionally the second, third and/or fourth gRNA of (c), as an RNA.

In an embodiment, contacting comprises delivering to the subject the gRNA of (a), as an

RNA, optionally said second, third and/or fourth gRNA of (c), as an RNA, and a nucleic acid that encodes the Cas9 molecule of (b).

In another aspect, disclosed herein is a reaction mixture comprising a gRNA, a nucleic acid, or a composition described herein, and a cell, e.g., a cell from a subject having, or likely to develop SCD, or a subject having a mutation at an SCD target position in the HBB gene, or a cell from a subject which would benefit from having a mutation at an SCD target position in the BCL11A gene.

In another aspect, disclosed herein is a kit comprising, (a) gRNA molecule described herein, or nucleic acid that encodes the gRNA, and one or more of the following:

(b) a Cas9 molecule, e.g., a Cas9 molecule described herein, or a nucleic acid or mRNA that encodes the Cas9;

(c)(i) a second gRNA molecule, e.g., a second gRNA molecule described herein or a nucleic acid that encodes (c)(i);

(c)(ii) a third gRNA molecule, e.g., a second gRNA molecule described herein or a nucleic acid that encodes (c)(ii);

(c) (iii) a fourth gRNA molecule, e.g., a second gRNA molecule described herein or a nucleic acid that encodes (c)(iii);

(d) a template nucleic acid (in an embodiment where an exogenous template is used), e.g., a template nucleic acid described herein.

In an embodiment, the kit comprises nucleic acid, e.g., an AAV vector, that encodes one or more of (a), (b), (c)(i), (c)(ii), (c)(iii) and (d). In an aspect, the disclosure features a gRNA molecule, referred to herein as a governing gRNA molecule, comprising a targeting domain which is complementary to a target domain on a nucleic acid that encodes a component of the CRISPR/Cas system introduced into a cell or subject. In an embodiment, the governing gRNA molecule targets a nucleic acid that encodes a Cas9 molecule or a nucleic acid that encodes a target gene gRNA molecule. In an embodiment, the governing gRNA comprises a targeting domain that is complementary to a target domain in a sequence that encodes a Cas9 component, e.g., a Cas9 molecule or target gene gRNA molecule. In an embodiment, the target domain is designed with, or has, minimal homology to other nucleic acid sequences in the cell, e.g., to minimize off-target cleavage. For example, the targeting domain on the governing gRNA can be selected to reduce or minimize off-target effects. In an embodiment, a target domain for a governing gRNA can be disposed in the control or coding region of a Cas9 molecule or disposed between a control region and a transcribed region. In an embodiment, a target domain for a governing gRNA can be disposed in the control or coding region of a target gene gRNA molecule or disposed between a control region and a transcribed region for a target gene gRNA. While not wishing to be bound by theory, it is believed that altering, e.g., inactivating, a nucleic acid that encodes a Cas9 molecule or a nucleic acid that encodes a target gene gRNA molecule can be effected by cleavage of the targeted nucleic acid sequence or by binding of a Cas9 molecule/governing gRNA molecule complex to the targeted nucleic acid sequence.

The compositions, reaction mixtures and kits, as disclosed herein, can also include a governing gRNA molecule, e.g., a governing gRNA molecule disclosed herein.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

Headings, including numeric and alphabetical headings and subheadings, are for organization and presentation and are not intended to be limiting. Other features and advantages of the invention will be apparent from the detailed description, drawings, and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

Figs. 1A-1I are representations of several exemplary gRNAs.

Fig. 1A depicts a modular gRNA molecule derived in part (or modeled on a sequence in part) from Streptococcus pyogenes (S. pyogenes) as a duplexed structure (SEQ ID NOS: 42 and 43, respectively, in order of appearance);

Fig. IB depicts a unimolecular (or chimeric) gRNA molecule derived in part from S. pyogenes as a duplexed structure (SEQ ID NO: 44);

Fig. 1C depicts a unimolecular gRNA molecule derived in part from S. pyogenes as a duplexed structure (SEQ ID NO: 45);

Fig. ID depicts a unimolecular gRNA molecule derived in part from S. pyogenes as a duplexed structure (SEQ ID NO: 46);

Fig. IE depicts a unimolecular gRNA molecule derived in part from S. pyogenes as a duplexed structure (SEQ ID NO: 47);

Fig. IF depicts a modular gRNA molecule derived in part from Streptococcus thermophilus (S. thermophilus) as a duplexed structure (SEQ ID NOS: 48 and 49, respectively, in order of appearance);

Fig. 1G depicts an alignment of modular gRNA molecules of S. pyogenes and S.

thermophilus (SEQ ID NOS: 50-53, respectively, in order of appearance).

Figs. 1H-1I depicts additional exemplary structures of unimolecular gRNA molecules. Fig. 1H shows an exemplary structure of a unimolecular gRNA molecule derived in part from S. pyogenes as a duplexed structure (SEQ ID NO: 45).

Fig. II shows an exemplary structure of a unimolecular gRNA molecule derived in part from S. aureus as a duplexed structure (SEQ ID NO: 40).

Figs. 2A-2G depict an alignment of Cas9 sequences from Chylinski et al. (RNA Biol. 2013; 10(5): 726-737). The N-terminal RuvC-like domain is boxed and indicated with a "Y". The other two RuvC-like domains are boxed and indicated with a "B". The HNH-like domain is boxed and indicated by a "G". Sm: S. mutans (SEQ ID NO: 1); Sp: S. pyogenes (SEQ ID NO: 2); St: S. thermophilus (SEQ ID NO: 3); Li: L. innocua (SEQ ID NO: 4). Motif: this is a motif based on the four sequences: residues conserved in all four sequences are indicated by single letter amino acid abbreviation; "*" indicates any amino acid found in the corresponding position of any of the four sequences; and "-" indicates any amino acid, e.g., any of the 20 naturally occurring amino acids, or absent.

Figs. 3A-3B show an alignment of the N-terminal RuvC-like domain from the Cas9 molecules disclosed in Chylinski et al (SEQ ID NOS: 54-103, respectively, in order of appearance). The last line of Fig. 3B identifies 4 highly conserved residues.

Figs. 4A-4B show an alignment of the N-terminal RuvC-like domain from the Cas9 molecules disclosed in Chylinski et al. with sequence outliers removed (SEQ ID NOS: 104-177, respectively, in order of appearance). The last line of Fig. 4B identifies 3 highly conserved residues.

Figs. 5A-5C show an alignment of the HNH-like domain from the Cas9 molecules disclosed in Chylinski et al (SEQ ID NOS: 178-252, respectively, in order of appearance). The last line of Fig. 5C identifies conserved residues.

Figs. 6A-6B show an alignment of the HNH-like domain from the Cas9 molecules disclosed in Chylinski et al. with sequence outliers removed (SEQ ID NOS: 253-302, respectively, in order of appearance). The last line of Fig. 6B identifies 3 highly conserved residues.

Figs. 7A-7B depict an alignment of Cas9 sequences from S. pyogenes and Neisseria meningitidis (N. meningitidis). The N-terminal RuvC-like domain is boxed and indicated with a "Y". The other two RuvC-like domains are boxed and indicated with a "B". The HNH-like domain is boxed and indicated with a "G". Sp: S. pyogenes; Nm: N. meningitidis. Motif: this is a motif based on the two sequences: residues conserved in both sequences are indicated by a single amino acid designation; "*" indicates any amino acid found in the corresponding position of any of the two sequences; "-" indicates any amino acid, e.g., any of the 20 naturally occurring amino acids, and "-" indicates any amino acid, e.g., any of the 20 naturally occurring amino acids, or absent.

Fig. 8 shows a nucleic acid sequence encoding Cas9 of N. meningitidis (SEQ ID NO: 303). Sequence indicated by an "R" is an SV40 NLS; sequence indicated as "G" is an HA tag; and sequence indicated by an "O" is a synthetic NLS sequence; the remaining (unmarked) sequence is the open reading frame (ORF). Figs. 9A and 9B are schematic representations of the domain organization of S. pyogenes Cas 9. Fig. 9A shows the organization of the Cas9 domains, including amino acid positions, in reference to the two lobes of Cas9 (recognition (REC) and nuclease (NUC) lobes). Fig. 9B shows the percent homology of each domain across 83 Cas9 orthologs.

Fig. 10 shows chromosome 2 location (according to UCSC Genome Browser hg 19 human genome assembly) that corresponds to BCLllA intron 2. Three erythroid DHSs are labled as distance in kilobases from BCLllA TSS (+62, +58 and +55). BCLllA transcription is from right to left.

Fig. 11 depicts the efficiency of NHEJ mediated by a Cas9 molecule and exemplary gRNA molecules targeting three different regions of the BCLllA locus.

Figs. 12A-12B depict detected deletion events resulting from co-transfection of exemplary gRNA molecules, BCL11A-2983W and BCL11A-2981W.

Fig. 12A depicts schematic of DNA sequence recognized by BCL11 A-2983W and BCL11A-2981W, which flanks the putative erythroid enhancer elements.

Fig. 12B depicts sequenced deletion events from the TOPO cloning of the PCR using primers that flank the enhancer region. A product is obtained when a deletion event has taken place.

Figs. 13A-13B depicts detected deletion events resulting from co-transfection of the exemplary gRNA molecules, BCL11A-2995W and BCL11A-2984W.

Fig. 13A depicts Schematic of DNA sequence recognized by BCL11 A-2995W and

BCL11 A-2984W, which flanks the putative erythroid enhancer elements.

Fig. 13B depicts sequenced deletion events from the TOPO cloning of the PCR using primers that flank the enhancer region. A product is obtained when a deletion event has taken place.

Fig. 14 depicts a scheme of the pair 8/15 of gRNAs surrounding the sickle mutation in combination with a Cas9 nickase (DIOA or N863A). The nickases are shown as the grey ovals.

Fig. 15 depicts the percentages of total editing event after a wildtype Cas9 or a Cas9 nickase (DIOA or N863A). A preprentation of at least three independent experiments for each condition is shown.

Fig. 16A depicts the frequency of deletions a wildtype Cas9 or a Cas9 nickase (DIOA or

N863A). A representation of at least 3 independent experiments for each condition is shown. Fig. 16B depicts the frequency distribution of the length of deletions using a wildtype Cas9 and gRNA 8 (similar results have been obtained with gRNA 15).

Fig. 16C depicts the frequency distribution of the length of deletions using a Cas9 nickase (DIOA) with gRNAs 8/15 (similar results have been obtained using Cas9 N863A).

Fig. 17A depicts the frequency of gene conversion a wildtype Cas9 or a Cas9 nickase

(DIOA or N863A).

Fig. 17B shows a scheme representing the region of similarity between the HBB and HBD loci.

Fig. 18 depicts the frequency of different lengths of HBD sequences that were incorporated into the HBB locus.

Fig. 19A depicts the frequency of insertions using a wildtype Cas9 or a Cas9 nickase (DIOA or N863A). A representation of at least three independent experiments for each condition is shown.

Fig. 19B depicts examples of common reads observed in U20S cells electroporated with plasmid encoding Cas9 N863 and gRNA 8/15 pair. The HBB reference is shown on the top.

Fig. 20A is a schematic representation of the donor template.

Fig. 20B depicts the frequency of HDR using a wildtype Cas9 or a Cas9 nickase (DIOA or N863A).

Fig. 20C depicts different forms of nonors and there contribution to HDR.

Fig. 21 depicts genome editing of the HBB locus in bone marrow leukemia K562 hematopoietic cells after electroporation of Cas9 protein complexed to HBB gRNAs 8 and 15 (RNP) or Cas9 mRNA co-delivered with HBB gRNAs 8 and 15 (RNA).

DETAILED DESCRIPTION

Definitions

"Alt-HDR" or "alternative HDR", or alternative homology-directed repair, as used herein, refers to the process of repairing DNA damage using a homologous nucleic acid (e.g., an endogenous homologous sequence, e.g., a sister chromatid, or an exogenous nucleic acid, e.g., a template nucleic acid). Alt-HDR is distinct from canonical HDR in that the process utilizes different pathways from canonical HDR, and can be inhibited by the canonical HDR mediators, RAD51 and BRCA2. Also, alt-HDR uses a single- stranded or nicked homologous nucleic acid for repair of the break.

"Canonical HDR", or canonical homology-directed repair, as used herein, refers to the process of repairing DNA damage using a homologous nucleic acid (e.g., an endogenous homologous sequence, e.g., a sister chromatid, or an exogenous nucleic acid, e.g., a template nucleic acid). Canonical HDR typically acts when there has been significant resection at the double strand break, forming at least one single stranded portion of DNA. In a normal cell, HDR typically involves a series of steps such as recognition of the break, stabilization of the break, resection, stabilization of single stranded DNA, formation of a DNA crossover intermediate, resolution of the crossover intermediate, and ligation. The process requires RAD51 and BRCA2, and the homologous nucleic acid is typically double-stranded.

Unless indicated otherwise, the term "HDR" as used herein encompasses canonical HDR and alt-HDR.

"Domain", as used herein, is used to describe segments of a protein or nucleic acid.

Unless otherwise indicated, a domain is not required to have any specific functional property.

Calculations of homology or sequence identity between two sequences (the terms are used interchangeably herein) are performed as follows. The sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). The optimal alignment is determined as the best score using the GAP program in the GCG software package with a Blossum 62 scoring matrix with a gap penalty of 12, a gap extend penalty of 4, and a frame shift gap penalty of 5. The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences.

"Governing gRNA molecule", as used herein, refers to a gRNA molecule that comprises a targeting domain that is complementary to a target domain on a nucleic acid that comprises a sequence that encodes a component of the CRISPR/Cas system that is introduced into a cell or subject. A governing gRNA does not target an endogenous cell or subject sequence. In an embodiment, a governing gRNA molecule comprises a targeting domain that is complementary with a target sequence on: (a) a nucleic acid that encodes a Cas9 molecule; (b) a nucleic acid that encodes a gRNA which comprises a targeting domain that targets the HBB or BCL11A gene (a target gene gRNA); or on more than one nucleic acid that encodes a CRISPR/Cas component, e.g., both (a) and (b). In an embodiment, a nucleic acid molecule that encodes a CRISPR/Cas component, e.g., that encodes a Cas9 molecule or a target gene gRNA, comprises more than one target domain that is complementary with a governing gRNA targeting domain. While not wishing to be bound by theory, it is believed that a governing gRNA molecule complexes with a Cas9 molecule and results in Cas9 mediated inactivation of the targeted nucleic acid, e.g., by cleavage or by binding to the nucleic acid, and results in cessation or reduction of the production of a CRISPR/Cas system component. In an embodiment, the Cas9 molecule forms two complexes: a complex comprising a Cas9 molecule with a target gene gRNA, which complex will alter the HBB or BCL11A gene; and a complex comprising a Cas9 molecule with a governing gRNA molecule, which complex will act to prevent further production of a

CRISPR/Cas system component, e.g., a Cas9 molecule or a target gene gRNA molecule. In an embodiment, a governing gRNA molecule/Cas9 molecule complex binds to or promotes cleavage of a control region sequence, e.g., a promoter, operably linked to a sequence that encodes a Cas9 molecule, a sequence that encodes a transcribed region, an exon, or an intron, for the Cas9 molecule. In an embodiment, a governing gRNA molecule/Cas9 molecule complex binds to or promotes cleavage of a control region sequence, e.g., a promoter, operably linked to a gRNA molecule, or a sequence that encodes the gRNA molecule. In an embodiment, the governing gRNA, e.g., a Cas9-targeting governing gRNA molecule, or a target gene gRNA- targeting governing gRNA molecule, limits the effect of the Cas9 molecule/target gene gRNA molecule complex-mediated gene targeting. In an embodiment, a governing gRNA places temporal, level of expression, or other limits, on activity of the Cas9 molecule/target gene gRNA molecule complex. In an embodiment, a governing gRNA reduces off-target or other unwanted activity. In an embodiment, a governing gRNA molecule inhibits, e.g., entirely or substantially entirely inhibits, the production of a component of the Cas9 system and thereby limits, or governs, its activity.

"Modulator", as used herein, refers to an entity, e.g., a drug, that can alter the activity

(e.g., enzymatic activity, transcriptional activity, or translational activity), amount, distribution, or structure of a subject molecule or genetic sequence. In an embodiment, modulation comprises cleavage, e.g., breaking of a covalent or non-covalent bond, or the forming of a covalent or non- covalent bond, e.g., the attachment of a moiety, to the subject molecule. In an embodiment, a modulator alters the, three dimensional, secondary, tertiary, or quaternary structure, of a subject molecule. A modulator can increase, decrease, initiate, or eliminate a subject activity.

"Large molecule", as used herein, refers to a molecule having a molecular weight of at least 2, 3, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 kD. Large molecules include proteins, polypeptides, nucleic acids, biologies, and carbohydrates.

A "polypeptide", as used herein, refers to a polymer of amino acids having less than 100 amino acid residues. In an embodiment, it has less than 50, 20, or 10 amino acid residues.

"Non-homologous end joining" or "NHEJ", as used herein, refers to ligation mediated repair and/or non-template mediated repair including canonical NHEJ (cNHEJ), alternative NHEJ (altNHEJ), microhomology-mediated end joining (MMEJ), single-strand annealing (SSA), and synthesis-dependent microhomology-mediated end joining (SD-MMEJ).

A "reference molecule", e.g., a reference Cas9 molecule or reference gRNA, as used herein, refers to a molecule to which a subject molecule, e.g., a subject Cas9 molecule of subject gRNA molecule, e.g., a modified or candidate Cas9 molecule is compared. For example, a Cas9 molecule can be characterized as having no more than 10% of the nuclease activity of a reference Cas9 molecule. Examples of reference Cas9 molecules include naturally occurring unmodified Cas9 molecules, e.g., a naturally occurring Cas9 molecule such as a Cas9 molecule of S.

pyogenes, S. aureus or S. thermophilus. In an embodiment, the reference Cas9 molecule is the naturally occurring Cas9 molecule having the closest sequence identity or homology with the Cas9 molecule to which it is being compared. In an embodiment, the reference Cas9 molecule is a sequence, e.g., a naturally occurring or known sequence, which is the parental form on which a change, e.g., a mutation has been made.

"Replacement", or "replaced", as used herein with reference to a modification of a molecule does not require a process limitation but merely indicates that the replacement entity is present.

"Small molecule", as used herein, refers to a compound having a molecular weight less than about 2 kD, e.g., less than about 2 kD, less than about 1.5 kD, less than about 1 kD, or less than about 0.75 kD. "Subject", as used herein, may mean either a human or non-human animal. The term includes, but is not limited to, mammals (e.g., humans, other primates, pigs, rodents (e.g., mice and rats or hamsters), rabbits, guinea pigs, cows, horses, cats, dogs, sheep, and goats). In an embodiment, the subject is a human. In another embodiment, the subject is poultry.

"Treat", "treating" and "treatment", as used herein, mean the treatment of a disease in a mammal, e.g., in a human, including (a) inhibiting the disease, i.e., arresting or preventing its development; (b) relieving the disease, i.e., causing regression of the disease state; and (c) curing the disease.

"Prevent", "preventing" and "prevention", as used herein, means the prevention of a disease in a mammal, e.g., in a human, including (a) avoiding or precluding the disease; (2) affecting the predisposition toward the disease, e.g., preventing at least one symptom of the disease or to delay onset of at least one symptom of the disease.

"X" as used herein in the context of an amino acid sequence, refers to any amino acid (e.g., any of the twenty natural amino acids) unless otherwise specified.

Methods of repairing mutation(s) in the HBB gene

One approach to treat or prevent SCD is to repair (i.e., correct) one or more mutations in the HBB gene, e.g., by HDR. In this approach, mutant HBB allele(s) are corrected and restored to wild type state. While not wishing to be bound by theory, it is believed that correction of the glutamic acid to valine substitution at amino acid 6 in the beta-globin gene restores wild type beta-globin production within erythroid cells. The method described herein can be performed in all cell types. Beta-globin is expressed in cells of erythroid cell lineage. In an embodiment, an erythroid cell is targeted.

In an embodiment, one HBB allele is repaired in the subject. In another embodiment, both HBB alleles are repaired in the subject. In either situation, the subject can be cured of disease. As the disease only displays a phenotype when both alleles are mutated, repair of a single allele is adequate for a cure.

In one aspect, methods and compositions discussed herein, provide for the correction of the underlying genetic cause of SCD, e.g., the correction of a mutation at a target position in the HBB gene, e.g., correction of a mutation at amino acid position 6, e.g., an E6V substitution in the HBB gene. In an embodiment, the method provides for the correction of a mutation at a target position in the HBB gene, e.g., correction of a mutation at amino acid position 6, e.g., an E6V substitution in the HBB gene. As described herein, in one embodiment, the method comprises the introduction of one or more breaks (e.g., single strand breaks or double strand breaks) sufficiently close to (e.g., either 5' or 3' to) the target position in the HBB gene, e.g., E6V.

In an embodiment, the targeting domain of the gRNA molecule is configured to provide a cleavage event, e.g., a double strand break or a single strand break, sufficiently close to (e.g., either 5' or 3' to) the target position in the HBB gene, e.g., E6V to allow correction, e.g., an alteration in the HBB gene, e.g., an alternation associated with HDR. In an embodiment, the targeting domain is configured such that a cleavage event, e.g., a double strand or single strand break, is positioned within 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450 or 500 nucleotides of a the target position in the HBB gene, e.g., E6V. The break, e.g., a double strand or single strand break, can be positioned upstream or downstream of the target position in the HBB gene, e.g., E6V.

In an embodiment, a second, third and/or fourth gRNA molecule is configured to provide a cleavage event, e.g., a double strand break or a single strand break, sufficiently close to (e.g., either 5' or 3' to) the target position in the HBB gene, e.g., E6V to allow correction, e.g., an alteration associated with HDR in the HBB gene. In an embodiment, the targeting domain is configured such that a cleavage event, e.g., a double strand or single strand break, is positioned within 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300,

350, 400, 450 or 500 nucleotides of a the target position in the HBB gene, e.g., E6V. The break, e.g., a double strand or single strand break, can be positioned upstream or downstream of the target position in the HBB gene, e.g., E6V.

In an embodiment, a single strand break is accompanied by an additional single strand break, positioned by a second, third and/or fourth gRNA molecule, as discussed below. For example, The targeting domains bind configured such that a cleavage event, e.g., the two single strand breaks, are positioned within 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450 or 500 nucleotides of the target position in the HBB gene, e.g., E6V. In an embodiment, the first and second gRNA molecules are configured such, that when guiding a Cas9 nickase, a single strand break will be accompanied by an additional single strand break, positioned by a second gRNA, sufficiently close to one another to result in an alteration of the target position in the HBB gene, e.g., E6V. In an embodiment, the first and second gRNA molecules are configured such that a single strand break positioned by said second gRNA is within 10, 20, 30, 40, or 50 nucleotides of the break positioned by said first gRNA molecule, e.g., when the Cas9 is a nickase. In an embodiment, the two gRNA molecules are configured to position cuts at the same position, or within a few nucleotides of one another, on different strands, e.g., essentially mimicking a double strand break.

In an embodiment, a double strand break can be accompanied by an additional double strand break, positioned by a second, third and/or fourth gRNA molecule, as is discussed below. For example, the targeting domain of a first gRNA molecule is configured such that a double strand break is positioned upstream of the target position in the HBB gene, e.g., E6V, e.g., within 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450 or 500 nucleotides of the target position; and the targeting domain of a second gRNA molecule is configured such that a double strand break is positioned downstream the target position in the HBB gene, e.g., E6V, e.g., within 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450 or 500 nucleotides of the target position.

In an embodiment, a double strand break can be accompanied by two additional single strand breaks, positioned by a second gRNA molecule and a third gRNA molecule. For example, the targeting domain of a first gRNA molecule is configured such that a double strand break is positioned upstream of the target position in the HBB gene, e.g., E6V, e.g., within 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450 or 500 nucleotides of the target position; and the targeting domains of a second and third gRNA molecule are configured such that two single strand breaks are positioned downstream of the target position in the HBB gene, e.g., E6V, e.g., within 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450 or 500 nucleotides of the target position. In an embodiment, the targeting domain of the first, second and third gRNA molecules are configured such that a cleavage event, e.g., a double strand or single strand break, is positioned, independently for each of the gRNA molecules.

In an embodiment, a first and second single strand breaks can be accompanied by two additional single strand breaks positioned by a third gRNA molecule and a fourth gRNA molecule. For example, the targeting domain of a first and second gRNA molecule are configured such that two single strand breaks are positioned upstream of the target position in the HBB gene, e.g., E6V, e.g., within 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450 or 500 nucleotides of the target position in the HBB gene, e.g., E6V; and the targeting domains of a third and fourth gRNA molecule are configured such that two single strand breaks are positioned downstream of the target position in the HBB gene, e.g., E6V, e.g., within 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450 or 500 nucleotides of the target position in the HBB gene, e.g., E6V.

In an embodiment, a mutation in the HBB gene, e.g., E6V is corrected using an exogenously provided template nucleic acid, e.g., by HDR. In another embodiment, a mutation in the HBB gene, e.g., E6V is corrected without using an exogenously provided template nucleic acid, e.g., by HDR. In an embodiment, alteration of the target sequence occurs with an endogenous genomic donor sequence, e.g., by HDR. In an embodiment, the endogenous genomic donor sequence comprises one or more nucleotides derived from the HBD gene. In an embodiment, a mutation in the HBB gene, e.g., E6V is corrected by an endogenous genomic donor sequence (e.g, an HBD gene). In an embodiment, an eaCas9 molecule, e.g., an eaCas9 molecule described herein, is used. In an embodiment, the eaCas9 molecule comprises HNH- like domain cleavage activity but has no, or no significant, N-terminal RuvC-like domain cleavage activity. In an embodiment, the eaCas9 molecule is an HNH-like domain nickase. In an embodiment, the eaCas9 molecule comprises a mutation at D10 (e.g., D10A). In an embodiment, the eaCas9 molecule comprises N-terminal RuvC-like domain cleavage activity but has no, or no significant, HNH-like domain cleavage activity. In an embodiment, the eaCas9 molecule is an N-terminal RuvC-like domain nickase. In an embodiment, the eaCas9 molecule comprises a mutation at H840 (e.g., H840A) or N863 (e.g., N863A). Methods of Altering BCL11A

One approach to increase the expression of HbF involves identification of genes whose products play a role in the regulation of globin gene expression. One such gene is BCL11A. It plays a role in the regulation of γ globin expression. It was first identified because of its role in lymphocyte development. BCL11A encodes a zinc finger protein that is thought to be involved in the stage specific regulation of γ globin expression. The BCL11A gene product is expressed in adult erythroid precursor cells and down-regulation of its expression leads to an increase in γ globin expression. In addition, it appears that the splicing of the BCL11A mRNA is developmentally regulated. In embryonic cells, it appears that the shorter BCL11A mRNA variants, known as BCL11A-S and BCL11A-XS are primary expressed, while in adult cells, the longer BCL11A-L and BCL11A-XL mRNA variants are predominantly expressed. See, Sankaran et al (2008) Science 322 p. 1839. The BCL11A protein appears to interact with the β globin locus to alter its conformation and thus its expression at different developmental stages. Thus, if BCL11A expression is altered e.g., disrupted (e.g., reduced or eliminated), it results in the elevation of γ globin and HbF production.

Disclosed herein are methods for altering the SCD target position in the BCL11A gene. Altering the SCD target position is achieved, e.g., by:

(1) knocking out the BCL11A gene:

(a) insertion or deletion (e.g., NHEJ-mediated insertion or deletion) of one or more nucleotides in close proximity to or within the early coding region of the BCL11A gene, or

(b) deletion (e.g., NHEJ-mediated deletion) of a genomic sequence including the erythroid enhancer of the BCL11A gene, or

(2) knocking down the BCL11A gene mediated by enzymatically inactive Cas9 (eiCas9) molecule or an eiCas9-fusion protein by targeting the promoter region of the gene.

All approaches give rise to alteration of the BCL11A gene.

In one embodiment, methods described herein introduce one or more breaks near the early coding region in at least one allele of the BCL11A gene. In another embodiment, methods described herein introduce two or more breaks to flank the erythroid enhancer of SCD target knockout position. The two or more breaks remove (e.g., delete) genomic sequence including the erythorid enhancer. In another embodiment, methods described herein comprises knocking down the BCL11A gene mediated by enzymatically inactive Cas9 (eiCas9) molecule or an eiCas9- fusion protein by targeting the promoter region of SCD target knockdown position. All methods described herein result in alteration of the BCL11A gene. NHEJ-mediated introduction of an indel in close proximity to or within the early coding region of the SCD knockout position

In an embodiment, the method comprises introducing a NHEJ-mediated insertion or deletion of one more nucleotides in close proximity to the SCD target knockout position (e.g., the early coding region) of the BCL11A gene. As described herein, in one embodiment, the method comprises the introduction of one or more breaks (e.g., single strand breaks or double strand breaks) sufficiently close to (e.g., either 5' or 3' to) the early coding region of the SCD target knockout position, such that the break-induced indel could be reasonably expected to span the SCD target knockout position (e.g., the early coding region). While not wishing to be bound by theory, it is believed that NHEJ-mediated repair of the break(s) allows for the NHEJ-mediated introduction of an indel in close proximity to within the early coding region of the SCD target knockout position.

In an embodiment, the targeting domain of the gRNA molecule is configured to provide a cleavage event, e.g., a double strand break or a single strand break, sufficiently close to the early coding region in the BCL11A gene to allow alteration, e.g., alteration associated with NHEJ in the BCL11A gene. In an embodiment, the targeting domain is configured such that a cleavage event, e.g., a double strand or single strand break, is positioned within 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450 or 500 nucleotides of a SCD target knockout position. The break, e.g., a double strand or single strand break, can be positioned upstream or downstream of a SCD target knockout position in the BCL11A gene.

In an embodiment, a second gRNA molecule comprising a second targeting domain is configured to provide a cleavage event, e.g., a double strand break or a single strand break, sufficiently close to the early coding region in the BCL11A gene, to allow alteration, e.g., alteration associated with NHEJ in the BCL11A gene, either alone or in combination with the break positioned by said first gRNA molecule. In an embodiment, the targeting domains of the first and second gRNA molecules are configured such that a cleavage event, e.g., a double strand or single strand break, is positioned, independently for each of the gRNA molecules, within 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450 or 500 nucleotides of the target position. In an embodiment, the breaks, e.g., double strand or single strand breaks, are positioned on both sides of a nucleotide of a SCD target knockout position in the BCL11A gene. In an embodiment, the breaks, e.g., double strand or single strand breaks, are positioned on one side, e.g., upstream or downstream, of a nucleotide of a SCD target knockout position in the BCLllA gene.

In an embodiment, a single strand break is accompanied by an additional single strand break, positioned by a second gRNA molecule, as discussed below. For example, The targeting domains bind configured such that a cleavage event, e.g., the two single strand breaks, are positioned within 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450 or 500 nucleotides of the early coding region in the BCLllA gene. In an embodiment, the first and second gRNA molecules are configured such, that when guiding a Cas9 nickase, a single strand break will be accompanied by an additional single strand break, positioned by a second gRNA, sufficiently close to one another to result in alteration of the early coding region in the BCLllA gene. In an embodiment, the first and second gRNA molecules are configured such that a single strand break positioned by said second gRNA is within 10, 20, 30, 40, or 50 nucleotides of the break positioned by said first gRNA molecule, e.g., when the Cas9 is a nickase. In an embodiment, the two gRNA molecules are configured to position cuts at the same position, or within a few nucleotides of one another, on different strands, e.g., essentially mimicking a double strand break.

In an embodiment, a double strand break can be accompanied by an additional double strand break, positioned by a second gRNA molecule, as is discussed below. For example, the targeting domain of a first gRNA molecule is configured such that a double strand break is positioned upstream of the early coding region in the BCLllA gene, e.g., within 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450 or 500 nucleotides of the target position; and the targeting domain of a second gRNA molecule is configured such that a double strand break is positioned downstream of the early coding region in the BCLllA gene, e.g., within 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450 or 500 nucleotides of the target position.

In an embodiment, a double strand break can be accompanied by two additional single strand breaks, positioned by a second gRNA molecule and a third gRNA molecule. For example, the targeting domain of a first gRNA molecule is configured such that a double strand break is positioned upstream of the early coding region in the BCLllA gene, e.g., within 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450 or 500 nucleotides of the target position; and the targeting domains of a second and third gRNA molecule are configured such that two single strand breaks are positioned downstream of the early coding region in the BCL11A gene, e.g., within 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450 or 500 nucleotides of the target position. In an embodiment, the targeting domain of the first, second and third gRNA molecules are configured such that a cleavage event, e.g., a double strand or single strand break, is positioned, independently for each of the gRNA molecules.

In an embodiment, a first and second single strand breaks can be accompanied by two additional single strand breaks positioned by a third gRNA molecule and a fourth gRNA molecule. For example, the targeting domain of a first and second gRNA molecule are configured such that two single strand breaks are positioned upstream of the early coding region in the BCL11A gene, e.g., within 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450 or 500 nucleotides of the early coding region in the BCL11A gene; and the targeting domains of a third and fourth gRNA molecule are configured such that two single strand breaks are positioned downstream of a SCD target knockout position in the early coding region in the BCL11A gene, e.g., within 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450 or 500 nucleotides of the early coding region in the BCL11A gene.

NHEJ-mediated deletion of the erythroid enhancer at the SCD target position

In an embodiment, the method comprises introducing a NHEJ-mediated deletion of a genomic sequence including the erythroid enhancer. As described herein, in one embodiment, the method comprises the introduction of two double strand breaks— one 5' and the other 3' to (i.e., flanking) the SCD target position (e.g., the erythroid enhancer). Two gRNAs, e.g., unimolecular (or chimeric) or modular gRNA molecules, are configured to position the two double strand breaks on opposite sides of the SCD target knockdown position (e.g., the erythroid enhancer) in the BCL11A gene. In an embodiment, the first double strand break is positioned upstream of the the erythroid enhancer within intron 2 (e.g., between TSS+0.75kb to

TSS+52.0kb), and the second double strand break is positioned downstream of the the erythroid enhancer within intron 2 (e.g., between TSS+64.4kb to TSS+84.7kb) (see Fig. 10). In an embodiment, the two double strand breaks are positioned to remove a portion of the erythroid enhancer resulting in disruption of one or more DHSs. In an embodiment, the breaks (i.e., the two double strand breaks) are positioned to avoid unwanted target chromosome elements, such as repeat elements, e.g., an Alu repeat, or the endogenous splice sites.

The first double strand break may be positioned as follows:

(1) upstream of the 5' end of the erythroid enhancer in intron 2 (e.g., between TSS+0.75kb to TSS+52.0kb), or

(2) within the erythroid enhancer provided that a portion of the erythroid enhancer is removed resulting in disruption of one or more DHSs (e.g., between TSS+52.0kb to TSS+64.4kb),

and the second double strand break to be paired with the first double strand break may be positioned as follows:

(1) downstream the 3' end of the erythroid enhancer in intron 2 (e.g., between TSS+64.4kb to TSS+84.7kb), or

(2) within the erythroid enhancer provided that a portion of the erythroid

enhancer is removed resulting in disruption of one or more DHSs (e.g., between TSS+52.0kb to TSS+64.4kb).

For example, the first double strand break may be positioned in the BCLllA gene:

(1) between TSS+0.75kb to TSS+lOkb,

(2) between TSS+lOkb to TSS+20kb,

(3) between TSS+20kb to TSS+30kb,

(4) between TSS+30kb to TSS+40kb,

(5) between TSS+40kb to TSS+45kb,

(6) between TSS+45kb to TSS+47.5kb,

(7) between TSS+47.5kb to TSS+50kb,

(8) between TSS+50kb to TSS+51kb,

(9) between TSS+5 lkb to TSS+51. lkb,

(10) between TSS+51. lkb to TSS+51.2kb,

(11) between TSS+51.2kb to TSS+51.3kb,

(12) between TSS+51.3kb to TSS+51.4kb,

(13) between TSS+51.4kb to TSS+51.5kb,

(14) between TSS+51.5kb to TSS+51.6kb,

(15) between TSS+51.6kb to TSS+51.7kb, (16) between TSS+51.7kb to TSS+51.8kb,

(17) between TSS+51.8kb to TSS+51.9kb,

(18) between TSS+51.9kb to TSS+52kb,

(19) between TSS+52kb to TSS+53kb,

(20) between TSS+53kb to TSS+54kb,

(21) between TSS+54kb to TSS+55kb,

(22) between TSS+55kb to TSS+56kb,

(23) between TSS+56kb to TSS+57kb,

(24) between TSS+57kb to TSS+58kb,

(25) between TSS+58kb to TSS+59kb,

(26) between TSS+59kb to TSS+60kb,

(27) between TSS+60kb to TSS+61kb,

(28) between TSS+61kb to TSS+62kb,

(29) between TSS+62kb to TSS+63kb,

(30) between TSS+63kb to TSS+64kb, or

(31) between TSS+64kb to TSS+64.4kb,

and the second double strand break to be paired with the first double strand break may be positioned in the BCL11A gene:

(1) between TSS+52kb to TSS+53kb,

(2) between TSS+53kb to TSS+54kb,

(3) between TSS+54kb to TSS+55kb,

(4) between TSS+55kb to TSS+56kb,

(5) between TSS+56kb to TSS+57kb,

(6) between TSS+57kb to TSS+58kb,

(7) between TSS+58kb to TSS+59kb,

(8) between TSS+59kb to TSS+60kb,

(9) between TSS+60kb to TSS+61kb,

(10) between TSS+61kb to TSS+62kb,

(11) between TSS+62kb to TSS+63kb,

(12) between TSS+63kb to TSS+64kb,

(13) between TSS+64kb to TSS+64.4kb, (14) between TSS+64.4kb to TSS+65kb,

(15) between TSS+65kb to TSS+65.1kb,

(16) between TSS+65.1kb to TSS+65.2kb,

(17) between TSS+65.2kb to TSS+65.3kb,

(18) between TSS+65.3kb to TSS+65.4kb,

(19) between TSS+65.4kb to TSS+65.5kb,

(20) between TSS+65.5kb to TSS+65.7kb,

(21) between TSS+65.7kb to TSS+65.8kb,

(22) between TSS+65.8kb to TSS+65.9kb,

(23) between TSS+65.9kb to TSS+66kb,

(24) between TSS+66kb to TSS+67kb,

(25) between TSS+67kb to TSS+68kb,

(26) between TSS+68kb to TSS+69kb,

(27) between TSS+69kb to TSS+70kb,

(28) between TSS+70kb to TSS+75kb,

(29) between TSS+75kb to TSS+80kb, or

(30) between TSS+80kb to TSS+84.4kb.

While not wishing to be bound by theory, it is believed that the two double strand breaks allow for NHEJ-mediated deletion of erythroid enhancer in the BCL11A gene.

In an embodiment, the method comprises introducing a NHEJ-mediated deletion of a genomic sequence including the erythroid enhancer. As described herein, in one embodiment, the method comprises the introduction of two sets of breaks (e.g., one double strand break and a pair of single strand breaks)— one 5' and the other 3' to (i.e., flanking) the SCD target position (e.g., the erythroid enhancer). Two gRNAs, e.g., unimolecular (or chimeric) or modular gRNA molecules, are configured to position the two sets of breaks (either the double strand break or the pair of single strand breaks) on opposite sides of the SCD target knockdown position (e.g., the erythroid enhancer) in the BCL11A gene. In an embodiment, the first set of breaks (either the double strand break or the pair of single strand breaks) is positioned upstream of the the erythroid enhancer within intron 2 (e.g., between TSS+0.75kb to TSS+52.0kb), and the second set of breaks (either the double strand break or the pair of single strand breaks) is positioned downstream of the the erythroid enhancer within intron 2 (e.g., between TSS+64.4kb to TSS+84.7kb) (see Fig. 10). In an embodiment, the two sets of breaks (either the double strand break or the pair of single strand breaks) are positioned to remove a portion of the erythroid enhancer resulting in disruption of one or more DHSs. In an embodiment, the breaks (i.e., the two sets of breaks (either the double strand break or the pair of single strand breaks)) are positioned to avoid unwanted target chromosome elements, such as repeat elements, e.g., an Alu repeat, or the endogenous splice sites.

The first set of breaks (either the double strand break or the pair of single strand breaks) may be positioned as follows:

(2) within the erythroid enhancer provided that a portion of the erythroid enhancer is removed resulting in disruption of one or more DHSs (e.g., between

TSS+52.0kb to TSS+64.4kb),

and the second set of breaks (either the double strand break or the pair of single strand breaks) to be paired with the first set of breaks (either the double strand break or the pair of single strand breaks) may be positioned as follows:

(2) within the erythroid enhancer provided that a portion of the erythroid

For example, the first set of breaks (either the double strand break or the pair of single strand breaks) may be positioned in the BCL11A gene:

(1) between TSS+0.75kb to TSS+lOkb,

(2) between TSS+lOkb to TSS+20kb,

(3) between TSS+20kb to TSS+30kb,

(4) between TSS+30kb to TSS+40kb,

(5) between TSS+40kb to TSS+45kb,

(6) between TSS+45kb to TSS+47.5kb,

(7) between TSS+47.5kb to TSS+50kb,

(8) between TSS+50kb to TSS+51kb, 9) between TSS+51kb to TSS+51.1kb,

(10) between TSS+51.1kb to TSS+51.2kb,

(11) between TSS+51.2kb to TSS+51.3kb,

(12) between TSS+51.3kb to TSS+51.4kb,

(13) between TSS+51.4kb to TSS+51.5kb,

(14) between TSS+51.5kb to TSS+51.6kb,

(15) between TSS+51.6kb to TSS+51.7kb,

(16) between TSS+51.7kb to TSS+51.8kb,

(17) between TSS+51.8kb to TSS+51.9kb,

(18) between TSS+51.9kb to TSS+52kb,

(19) between TSS+52kb to TSS+53kb,

(20) between TSS+53kb to TSS+54kb,

(21) between TSS+54kb to TSS+55kb,

(22) between TSS+55kb to TSS+56kb,

(23) between TSS+56kb to TSS+57kb,

(24) between TSS+57kb to TSS+58kb,

(25) between TSS+58kb to TSS+59kb,

(26) between TSS+59kb to TSS+60kb,

(27) between TSS+60kb to TSS+61kb,

(28) between TSS+61kb to TSS+62kb,

(29) between TSS+62kb to TSS+63kb,

(30) between TSS+63kb to TSS+64kb, or

(31) between TSS+64kb to TSS+64.4kb,

and the second set of breaks (either the double strand break or the pair of single strand breaks) to be paired with the first set of breaks (either the double strand break or the pair of single strand breaks)may be positioned in the BCLllA gene:

(1) between TSS+52kb to TSS+53kb,

(2) between TSS+53kb to TSS+54kb,

(3) between TSS+54kb to TSS+55kb,

(4) between TSS+55kb to TSS+56kb,

(5) between TSS+56kb to TSS+57kb, 6) between TSS+57kb to TSS+58kb,

7) between TSS+58kb to TSS+59kb,

8) between TSS+59kb to TSS+60kb,

9) between TSS+60kb to TSS+61kb,

(10) between TSS+61kb to TSS+62kb,

(11) between TSS+62kb to TSS+63kb,

(12) between TSS+63kb to TSS+64kb,

(13) between TSS+64kb to TSS+64.4kb,

(14) between TSS+64.4kb to TSS+65kb,

(15) between TSS+65kb to TSS+65.1kb,

(16) between TSS+65.1kb to TSS+65.2kb,

(17) between TSS+65.2kb to TSS+65.3kb,

(18) between TSS+65.3kb to TSS+65.4kb,

(19) between TSS+65.4kb to TSS+65.5kb,

(20) between TSS+65.5kb to TSS+65.7kb,

(21) between TSS+65.7kb to TSS+65.8kb,

(22) between TSS+65.8kb to TSS+65.9kb,

(23) between TSS+65.9kb to TSS+66kb,

(24) between TSS+66kb to TSS+67kb,

(25) between TSS+67kb to TSS+68kb,

(26) between TSS+68kb to TSS+69kb,

(27) between TSS+69kb to TSS+70kb,

(28) between TSS+70kb to TSS+75kb,

(29) between TSS+75kb to TSS+80kb, or

(30) between TSS+80kb to TSS+84.4kb.

While not wishing to be bound by theory, it is believed that the two sets of breaks (either the double strand break or the pair of single strand breaks) allow for NHEJ-mediated deletion of erythroid enhancer in the BCL11A gene.

In an embodiment, the method comprises introducing a NHEJ-mediated deletion of a genomic sequence including the erythroid enhancer. As described herein, in one embodiment, the method comprises the introduction of two sets of breaks (e.g., two pairs of single strand breaks)— one 5' and the other 3' to (i.e., flanking) the SCD target position (e.g., the erythroid enhancer). Two gRNAs, e.g., unimolecular (or chimeric) or modular gRNA molecules, are configured to position the two sets of breaks on opposite sides of the SCD target knockdown position (e.g., the erythroid enhancer) in the BCLllA gene. In an embodiment, the first set of breaks (i.e., the first pair of single strand breaks) is positioned upstream of the the erythroid enhancer within intron 2 (e.g., between TSS+0.75kb to TSS+52.0kb), and the second set of breaks (i.e., the second pair of single strand breaks) is positioned downstream of the the erythroid enhancer within intron 2 (e.g., between TSS+64.4kb to TSS+84.7kb) (see Fig. 10). In an embodiment, the two sets of breaks (e.g., two pairs of single strand breaks)) are positioned to remove a portion of the erythroid enhancer resulting in disruption of one or more DHSs. In an embodiment, the breaks (i.e., the two pairs of single strand breaks) are positioned to avoid unwanted target chromosome elements, such as repeat elements, e.g., an Alu repeat, or the endogenous splice sites.

The first pair of single strand breaks may be positioned as follows:

TSS+52.0kb to TSS+64.4kb),

and the second pair of single strand breaks to be paired with the first pair of single strand breaks may be positioned as follows:

(2) within the erythroid enhancer provided that a portion of the erythroid

For example, the pair of single strand breaks may be positioned in the BCLllA gene: (1) between TSS+0.75kb to TSS+lOkb,

(2) between TSS+lOkb to TSS+20kb,

(3) between TSS+20kb to TSS+30kb, 4) between TSS+30kb to TSS+40kb,

5) between TSS+40kb to TSS+45kb,

6) between TSS+45kb to TSS+47.5kb,

7) between TSS+47.5kb to TSS+50kb,

8) between TSS+50kb to TSS+51kb,

9) between TSS+51kb to TSS+51.1kb,

(10) between TSS+51.1kb to TSS+51.2kb,

(11) between TSS+51.2kb to TSS+51.3kb,

(12) between TSS+51.3kb to TSS+51.4kb,

(13) between TSS+51.4kb to TSS+51.5kb,

(14) between TSS+51.5kb to TSS+51.6kb,

(15) between TSS+51.6kb to TSS+51.7kb,

(16) between TSS+51.7kb to TSS+51.8kb,

(17) between TSS+51.8kb to TSS+51.9kb,

(18) between TSS+51.9kb to TSS+52kb,

(19) between TSS+52kb to TSS+53kb,

(20) between TSS+53kb to TSS+54kb,

(21) between TSS+54kb to TSS+55kb,

(22) between TSS+55kb to TSS+56kb,

(23) between TSS+56kb to TSS+57kb,

(24) between TSS+57kb to TSS+58kb,

(25) between TSS+58kb to TSS+59kb,

(26) between TSS+59kb to TSS+60kb,

(27) between TSS+60kb to TSS+61kb,

(28) between TSS+61kb to TSS+62kb,

(29) between TSS+62kb to TSS+63kb,

(30) between TSS+63kb to TSS+64kb, or

(31) between TSS+64kb to TSS+64.4kb,

and the second pair of single strand breaks to be paired with the first pair of single strand breaks may be positioned in the BCL11A gene:

(1) between TSS+52kb to TSS+53kb, 2) between TSS+53kb to TSS+54kb,

3) between TSS+54kb to TSS+55kb,

4) between TSS+55kb to TSS+56kb,

5) between TSS+56kb to TSS+57kb,

6) between TSS+57kb to TSS+58kb,

7) between TSS+58kb to TSS+59kb,

8) between TSS+59kb to TSS+60kb,

9) between TSS+60kb to TSS+61kb,

(10) between TSS+61kb to TSS+62kb,

(11) between TSS+62kb to TSS+63kb,

(12) between TSS+63kb to TSS+64kb,

(13) between TSS+64kb to TSS+64.4kb,

(14) between TSS+64.4kb to TSS+65kb,

(15) between TSS+65kb to TSS+65.1kb,

(16) between TSS+65.1kb to TSS+65.2kb,

(17) between TSS+65.2kb to TSS+65.3kb,

(18) between TSS+65.3kb to TSS+65.4kb,

(19) between TSS+65.4kb to TSS+65.5kb,

(20) between TSS+65.5kb to TSS+65.7kb,

(21) between TSS+65.7kb to TSS+65.8kb,

(22) between TSS+65.8kb to TSS+65.9kb,

(23) between TSS+65.9kb to TSS+66kb,

(24) between TSS+66kb to TSS+67kb,

(25) between TSS+67kb to TSS+68kb,

(26) between TSS+68kb to TSS+69kb,

(27) between TSS+69kb to TSS+70kb,

(28) between TSS+70kb to TSS+75kb,

(29) between TSS+75kb to TSS+80kb, or

(30) between TSS+80kb to TSS+84.4kb. While not wishing to be bound by theory, it is believed that the two sets of breaks (e.g., the two pair of single strand breaks) allow for NHEJ-mediated deletion of erythroid enhancer in the BCLllA gene.

Knocking down the BCLllA gene mediated by an enzymatically inactive Cas9 (eiCas9) molecule or an eiCas9-fusion protein by targeting the promoter region of the gene.

A targeted knockdown approach reduces or eliminates expression of functional BCLllA gene product. As described herein, a targeted knockdown is mediated by targeting an enzymatically inactive Cas9 (eiCas9) molecule or an eiCas9 fused to a transcription repressor domain or chromatin modifying protein to alter transcription, e.g., to block, reduce, or decrease transcription, of the BCLllA gene. In an embodiment, one or more eiCas9s may be used to block binding of one or more endogenous transcription factors. In another embodiment, an eiCas9 can be fused to a chromatin modifying protein. Altering chromatin status can result in decreased expression of the target gene. One or more eiCas9s fused to one or more chromatin modifying proteins may be used to alter chromatin status.

Methods and compositions discussed herein may be used to alter the expression of the BCLllA gene to treat or prevent SCD by targeting a promoter region of the BCLllA gene. In an embodiment, the promoter region, e.g., at least 2 kb, at least 1.5 kb, at least 1.0 kb, or at least 0.5 kb upstream or downstream of the TSS is targeted to knockdown expression of the BCLllA gene. In an embodiment, the methods and compositions discussed herein may be used to knock down the BCLllA gene to treat or prevent SCD by targeting 0.5 kb upstream or downstream of the TSS. A targeted knockdown approach reduces or eliminates expression of functional BCLllA gene product. As described herein, a targeted knockdown is mediated by targeting an enzymatically inactive Cas9 (eiCas9) molecule or an eiCas9 fused to a transcription repressor domain or chromatin modifying protein to alter transcription, e.g., to block, reduce, or decrease transcription, of the BCLllA gene.

Methods to Treat or Prevent Sickle Cell Disease (SCD)

Disclosed herein are the approaches to treat or prevent SCD, using the compositions and methods described herein. One approach to treat or prevent SCD is to repair (i.e., correct) one or more mutations in the HBB gene, e.g., by HDR. In this approach, mutant HBB allele(s) are corrected and restored to wild type state. While not wishing to be bound by theory, it is believed that correction of the glutamic acid to valine substitution at amino acid 6 in the beta-globin gene restores wild type beta-globin production within erythroid cells. The method described herein can be performed in all cell types. Beta-globin is expressed in cells of erythroid cell lineage. In an embodiment, an erythroid cell is targeted.

In an embodiment, one HBB allele is repaired in the subject. In another embodiment, both HBB alleles are repaired in the subject. In either situation, the subjects can be cured of disease. As the disease only displays a phenotype when both alleles are mutated, repair of a single allele is adequate for a cure.

In one approach, the BCL11A gene is targeted as a targeted knockout or knockdown, e.g., to increase expression of fetal hemoglobin.

While not wishing to be bound by theory, it is considered that increasing levels of fetal hemoglobin (HbF) in subjects with SCD may ameliorate disease. Fetal hemoglobin can replace beta hemoglobin in the hemoglobin complex, form adequate tetramers with alpha hemoglobin, and effectively carry oxygen to tissues. Subjects with beta- thalassemia who express higher levels of fetal hemoglobin have been found to have a less severe phenotype. Hydroxyurea, often used in the treatment of beta-thalassemia, may exert its mechanism of action via increasing levels of HbF production.

In an embodiment, knockout or knockdown of the BCL11A gene increases fetal hemoglobin levels in beta-thalassemia subjects and improves phenotype and/or reduces or prevents disease progression. BCL11A is a zinc-finger repressor that is involved in the regulation of fetal hemoglobin and acts to repress the synthesis of fetal hemoglobin. Knockout of the BCL11A gene in erythroid cells induces increased fetal hemoglobin (HbF) synthesis and increased HbF can result in more effective oxygen carrying capacity in subjects with beta- thalassemia (HbF will form tetramers with hemoglobin alpha).

In an embodiment, the BCL11A knockout or knockdown is targeted specifically to cells of the erythroid lineage. BCL11A knockout in erythroid cells has been found in in vitro studies to have no effect on erythroid growth, maturation and function. In an embodiment, erythroid cells are preferentially targeted, e.g., at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the targeted cells are erythroid cells. For example, in the case of in vivo delivery, erythroid cells are preferentially targeted, and if cells are treated ex vivo and returned to the subject, erythroid cells are preferentially modified.

In an embodiment, the methods described herein result in increased fetal hemoglobin synthesis in beta thalassemia subjects, thereby improving disease phenotype in subjects with

SCD. For example, subjects with beta thalassemia major will suffer from less severe anemia and will need fewer blood transfusions. They will therefore have fewer complications arising from transfusions and chelation therapy. In an embodiment, the method described herein increases fetal hemoglobin synthesis and improves the oxygen carrying capacity of erythroid cells. For example, subjects are expected to demonstrate decreased rates of extramedullary erythropoiesis and decreased erythroid hypertrophy within the bone marrow compared to a subject who has not received the therapy. In an embodiment, the method described herein results in reduction of bone fractures, bone abnormalities, splenomegaly, and thrombosis compared to a subject who has not received the therapy.

Knockdown or knockout of one or both BCL11A alleles may be performed prior to disease onset or after disease onset, but preferably early in the disease course.

In an embodiment, the method comprises initiating treatment of a subject prior to disease onset.

In an embodiment, the method comprises initiating treatment of a subject after disease onset.

In an embodiment, the method comprises initiating treatment of a subject well after disease onset, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 24, 36, 48 or more months after onset of SCD. While not wishing to be bound by theory it is believed that this treatment may be effective if subjects present well into the course of illness.

In an embodiment, the method comprises initiating treatment of a subject in an advanced stage of disease.

Overall, initiation of treatment for subjects at all stages of disease is expected to prevent negative consequences of disease and be of benefit to subjects.

In an embodiment, the method comprises initiating treatment of a subject prior to disease expression. In an embodiment, the method comprises initiating treatment of a subject in an early stage of disease, e.g., when a subject has tested positive for beta-thalassemia mutations but has no signs or symptoms associated with beta-thalassemia major, minor or intermedia.

In an embodiment, the method comprises initiating treatment of a subject at the appearance of microcytic anemia, e.g., in an infant, child, adult or young adult.

In an embodiment, the method comprises initiating treatment of a subject who is transfusion-dependent.

In an embodiment, the method comprises initiating treatment of a subject who has tested positive for a mutation in a beta globin gene.

In an embodiment, the method comprises initiating treatment at the appearance of any one or more of the following findings associated or consistent with beta-thalassemia major or beta-thalassemia minor: anemia, diarrhea, fever, failure to thrive, frontal bossing, broken long bones, hepatomegaly, splenomegaly, thrombosis, pulmonary embolus, stroke, leg ulcer, cardiomyopathy, cardiac arrhythmia, and evidence of extramedullary erythropoiesis.

In an embodiment, a cell is treated, e.g., ex vivo. In an embodiment, an ex vivo treated cell is returned to a subject.

In an embodiment, allogenic or autologous bone marrow or erythroid cells are treated ex vivo. In an embodiment, an ex vivo treated allogenic or autologous bone marrow or erythroid cells are administered to the subject. In an embodiment, an erythroid cell, e.g., an autologous erythroid cell, is treated ex vivo and returned to the subject. In an embodiment, an autologous stem cell, is treated ex vivo and returned to the subject. In an embodiment, the modified HSCs are administered to the patient following no myeloablative pre-conditioning. In an embodiment, the modified HSCs are administered to the patient following mild myeloablative preconditioning such that following engraftment, some of the hematopoietic cells are devied from the modified HSCs. In other aspects, the HSCs are administered after full myeloablation such that following engraftment, 100% of the hematopoietic cells are derived from the modified HSCs.

In an embodiment, the method comprises delivery of a gRNA molecule and Cas9 molecule by intravenous injection, intramuscular injection, subcutaneous injection, or intra-bone marrow (IBM) injection.

In an embodiment, the method comprises delivery of a gRNA molecule and/or a Cas9 molecule by an AAV. In an embodiment, the method comprises delivery of a gRNA molecule and/or a Cas9 molecule by a lentivirus. In an embodiment, the method comprises delivery of a gRNA molecule and/or a Cas9 molecule by a nanoparticle. In an embodiment, the method comprises delivery of a gRNA molecule by a parvovirus, e.g., a modified parvovirus specifically designed to target bone marrow cells and/or CD4 cells. In an embodiment, two or more gRNA molecules (e.g., a second, third or fourth gRNA molecules) are delivered.

I. gRNA Molecules

A gRNA molecule, as that term is used herein, refers to a nucleic acid that promotes the specific targeting or homing of a gRNA molecule/Cas9 molecule complex to a target nucleic acid. gRNA molecules can be unimolecular (having a single RNA molecule), sometimes referred to herein as "chimeric" gRNAs, or modular (comprising more than one, and typically two, separate RNA molecules). A gRNA molecule comprises a number of domains. The gRNA molecule domains are described in more detail below.

Several exemplary gRNA structures, with domains indicated thereon, are provided in Figs. 1A-1G. While not wishing to be bound by theory, in an embodiment, with regard to the three dimensional form, or intra- or inter-strand interactions of an active form of a gRNA, regions of high complementarity are sometimes shown as duplexes in Figs. 1A-1G and other depictions provided herein.

In an embodiment, a unimolecular, or chimeric, gRNA comprises, preferably from 5' to

3':

a targeting domain (which is complementary to a target nucleic acid in the HBB gene or BCL11A gene, e.g., a targeting domain from any of Tables 1A-1D, 2A- 2F, 3A-3C, 4A-4E, 5A-5E, 6A-6B, 7A-7D, 8A-8D, 9, 10A-10D, 11A-11D, 12, 13A-13D, 14A-14C, 15A-15D, 16A-16E, 17A-17B, 18A-18C, 19A-19E, 20A- 20C, 21A-21E, 22A-22E, 23A-23C, 24A-24D, 25A-25B, 26, or 31; a first complementarity domain;

a linking domain;

a second complementarity domain (which is complementary to the first

complementarity domain);

a proximal domain; and

optionally, a tail domain. In an embodiment, a modular gRNA comprises:

a first strand comprising, preferably from 5' to 3' ;

a targeting domain (which is complementary to a target nucleic acid in the HBB gene or BCL11A gene, e.g., a targeting domain from Tables 1A-1D, 2A-2F, 3A-3C, 4A- 4E, 5A-5E, 6A-6B, 7A-7D, 8A-8D, 9, 10A-10D, 11A-11D, 12, 13A-13D, 14A-14C, 15A-15D, 16A-16E, 17A-17B, 18A-18C, 19A-19E, 20A-20C, 21A-21E, 22A-22E, 23A-23C, 24A-24D, 25A-25B, 26, or 31; and

a first complementarity domain; and

a second strand, comprising, preferably from 5' to 3':

optionally, a 5' extension domain;

a second complementarity domain;

a proximal domain; and

optionally, a tail domain.

The domains are discussed briefly below.

The Targeting Domain

Figs. 1A-1G provide examples of the placement of targeting domains.

The targeting domain comprises a nucleotide sequence that is complementary, e.g., at least 80, 85, 90, or 95% complementary, e.g., fully complementary, to the target sequence on the target nucleic acid. The targeting domain is part of an RNA molecule and will therefore comprise the base uracil (U), while any DNA encoding the gRNA molecule will comprise the base thymine (T). While not wishing to be bound by theory, in an embodiment, it is believed that the complementarity of the targeting domain with the target sequence contributes to specificity of the interaction of the gRNA molecule/Cas9 molecule complex with a target nucleic acid. It is understood that in a targeting domain and target sequence pair, the uracil bases in the targeting domain will pair with the adenine bases in the target sequence. In an embodiment, the target domain itself comprises in the 5' to 3' direction, an optional secondary domain, and a core domain. In an embodiment, the core domain is fully complementary with the target sequence. In an embodiment, the targeting domain is 5 to 50 nucleotides in length. The strand of the target nucleic acid with which the targeting domain is complementary is referred to herein as the complementary strand. Some or all of the nucleotides of the domain can have a modification, e.g., a modification found in Section VIII herein

In an embodiment, the targeting domain is 16 nucleotides in length.

In an embodiment, the targeting domain is 17 nucleotides in length.

In an embodiment, the targeting domain is 18 nucleotides in length.

In an embodiment, the targeting domain is 19 nucleotides in length.

In an embodiment, the targeting domain is 20 nucleotides in length.

In an embodiment, the targeting domain is 21 nucleotides in length.

In an embodiment, the targeting domain is 22 nucleotides in length.

In an embodiment, the targeting domain is 23 nucleotides in length.

In an embodiment, the targeting domain is 24 nucleotides in length.

In an embodiment, the targeting domain is 25 nucleotides in length.

In an embodiment, the targeting domain is 26 nucleotides in length.

In an embodiment, the targeting domain comprises 16 nucleotides.

In an embodiment, the targeting domain comprises 17 nucleotides.

In an embodiment, the targeting domain comprises 18 nucleotides.

In an embodiment, the targeting domain comprises 19 nucleotides.

In an embodiment, the targeting domain comprises 20 nucleotides.

In an embodiment, the targeting domain comprises 21 nucleotides.

In an embodiment, the targeting domain comprises 22 nucleotides.

In an embodiment, the targeting domain comprises 23 nucleotides.

In an embodiment, the targeting domain comprises 24 nucleotides.

In an embodiment, the targeting domain comprises 25 nucleotides.

In an embodiment, the targeting domain comprises 26 nucleotides.

Targeting domains are discussed in more detail below. The First Complementarity Domain

Figs. 1A-1G provide examples of first complementarity domains. The first complementarity domain is complementary with the second complementarity domain, and in an embodiment, has sufficient complementarity to the second complementarity domain to form a duplexed region under at least some physiological conditions. In an embodiment, the first complementarity domain is 5 to 30 nucleotides in length. In an

embodiment, the first complementarity domain is 5 to 25 nucleotides in length. In an

embodiment, the first complementary domain is 7 to 25 nucleotides in length. In an

embodiment, the first complementary domain is 7 to 22 nucleotides in length. In an

embodiment, the first complementary domain is 7 to 18 nucleotides in length. In an

embodiment, the first complementary domain is 7 to 15 nucleotides in length. In an

embodiment, the first complementary domain is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleotides in length.

In an embodiment, the first complementarity domain comprises 3 subdomains, which, in the 5' to 3' direction are: a 5' subdomain, a central subdomain, and a 3' subdomain. In an embodiment, the 5' subdomain is 4 to 9, e.g., 4, 5, 6, 7, 8 or 9 nucleotides in length. In an embodiment, the central subdomain is 1, 2, or 3, e.g., 1, nucleotide in length. In an embodiment, the 3' subdomain is 3 to 25, e.g., 4 to 22, 4 to 18, or 4 to 10, or 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleotides in length.

The first complementarity domain can share homology with, or be derived from, a naturally occurring first complementarity domain. In an embodiment, it has at least 50% homology with a first complementarity domain disclosed herein, e.g., an S. pyogenes, S. aureus or S. thermophilus, first complementarity domain.

Some or all of the nucleotides of the domain can have a modification, e.g., a modification found in Section VIII herein.

First complementarity domains are discussed in more detail below.

The Linking Domain

Figs. 1A-1G provide examples of linking domains.

A linking domain serves to link the first complementarity domain with the second complementarity domain of a unimolecular gRNA. The linking domain can link the first and second complementarity domains covalently or non-covalently. In an embodiment, the linkage is covalent. In an embodiment, the linking domain covalently couples the first and second complementarity domains, see, e.g., Figs. IB-IE. In an embodiment, the linking domain is, or comprises, a covalent bond interposed between the first complementarity domain and the second complementarity domain. Typically the linking domain comprises one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides.

In modular gRNA molecules the two molecules are associated by virtue of the

hybridization of the complementarity domains see e.g., Fig. 1A.

A wide variety of linking domains are suitable for use in unimolecular gRNA molecules. Linking domains can consist of a covalent bond, or be as short as one or a few nucleotides, e.g., 1, 2, 3, 4, or 5 nucleotides in length. In an embodiment, a linking domain is 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, or 25 or more nucleotides in length. In an embodiment, a linking domain is 2 to 50, 2 to 40, 2 to 30, 2 to 20, 2 to 10, or 2 to 5 nucleotides in length. In an embodiment, a linking domain shares homology with, or is derived from, a naturally occurring sequence, e.g., the sequence of a tracrRNA that is 5' to the second complementarity domain. In an embodiment, the linking domain has at least 50% homology with a linking domain disclosed herein.

Linking domains are discussed in more detail below.

The 5' Extension Domain

In an embodiment, a modular gRNA can comprise additional sequence, 5' to the second complementarity domain, referred to herein as the 5' extension domain, see, e.g., Fig. 1A. In an embodiment, the 5' extension domain is, 2 to 10, 2 to 9, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4 nucleotides in length. In an embodiment, the 5' extension domain is 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more nucleotides in length.

The Second Complementarity Domain

Figs. 1A-1G provides examples of second complementarity domains.

The second complementarity domain is complementary with the first complementarity domain, and in an embodiment, has sufficient complementarity to the second complementarity domain to form a duplexed region under at least some physiological conditions. In an

embodiment, e.g., as shown in Figs. 1A-1B, the second complementarity domain can include sequence that lacks complementarity with the first complementarity domain, e.g., sequence that loops out from the duplexed region.

In an embodiment, the second complementarity domain is 5 to 27 nucleotides in length. In an embodiment, it is longer than the first complementarity region. In an embodiment the second complementary domain is 7 to 27 nucleotides in length. In an embodiment, the second complementary domain is 7 to 25 nucleotides in length. In an embodiment, the second complementary domain is 7 to 20 nucleotides in length. In an embodiment, the second complementary domain is 7 to 17 nucleotides in length. In an embodiment, the complementary domain is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26 nucleotides in length.

In an embodiment, the second complementarity domain comprises 3 subdomains, which, in the 5' to 3' direction are: a 5' subdomain, a central subdomain, and a 3' subdomain. In an embodiment, the 5' subdomain is 3 to 25, e.g., 4 to 22, 4 tol8, or 4 to 10, or 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleotides in length. In an embodiment, the central subdomain is 1, 2, 3, 4 or 5, e.g., 3, nucleotides in length. In an embodiment, the 3' subdomain is 4 to 9, e.g., 4, 5, 6, 7, 8 or 9 nucleotides in length.

In an embodiment, the 5' subdomain and the 3' subdomain of the first complementarity domain, are respectively, complementary, e.g., fully complementary, with the 3' subdomain and the 5' subdomain of the second complementarity domain.

The second complementarity domain can share homology with or be derived from a naturally occurring second complementarity domain. In an embodiment, it has at least 50% homology with a second complementarity domain disclosed herein, e.g., an S. pyogenes, S.

aureus or S. thermophilus, first complementarity domain.

A Proximal domain

Figs. 1A-1G provide examples of proximal domains.

In an embodiment, the proximal domain is 5 to 20 nucleotides in length. In an embodiment, the proximal domain can share homology with or be derived from a naturally occurring proximal domain. In an embodiment, it has at least 50% homology with a proximal domain disclosed herein, e.g., an S. pyogenes, S. aureus or S. thermophilus, proximal domain.

Some or all of the nucleotides of the domain can have a modification, e.g., modification found in Section VIII herein.

A Tail Domain

Figs. 1A-1G provide examples of tail domains.

As can be seen by inspection of the tail domains in Figs. 1A-1E, a broad spectrum of tail domains are suitable for use in gRNA molecules. In an embodiment, the tail domain is 0 (absent), 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides in length. In embodiment, the tail domain nucleotides are from or share homology with sequence from the 5' end of a naturally occurring tail domain, see e.g., panels 4a or 5a of Fig. ID or Fig. IE. In an embodiment, the tail domain includes sequences that are complementary to each other and which, under at least some physiological conditions, form a duplexed region.

In an embodiment, the tail domain is absent or is 1 to 50 nucleotides in length. In an embodiment, the tail domain can share homology with or be derived from a naturally occurring proximal tail domain. In an embodiment, it has at least 50% homology with a tail domain disclosed herein, e.g., an S. pyogenes, S. aureus or S. thermophilus, tail domain.

In an embodiment, the tail domain includes nucleotides at the 3' end that are related to the method of in vitro or in vivo transcription. When a T7 promoter is used for in vitro transcription of the gRNA, these nucleotides may be any nucleotides present before the 3' end of the DNA template. When a U6 promoter is used for in vivo transcription, these nucleotides may be the sequence UUUUUU. When alternate pol-III promoters are used, these nucleotides may be various numbers or uracil bases or may include alternate bases.

The domains of gRNA molecules are described in more detail below.

The Targeting Domain

The "targeting domain" of the gRNA is complementary to the "target domain" on the target nucleic acid. The strand of the target nucleic acid comprising the nucleotide sequence complementary to the core domain of the gRNA is referred to herein as the "complementary strand" of the target nucleic acid. Guidance on the selection of targeting domains can be found, e.g., in Fu Y et al., Nat Biotechnol 2014 (doi: 10.1038/nbt.2808) and Sternberg SH et al., Nature 2014 (doi: 10.1038/naturel3011).

In an embodiment, the targeting domain is 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26 nucleotides in length.

In an embodiment, the targeting domain is 16 nucleotides in length.

In an embodiment, the targeting domain is 17 nucleotides in length.

In an embodiment, the targeting domain is 18 nucleotides in length.

In an embodiment, the targeting domain is 19 nucleotides in length.

In an embodiment, the targeting domain is 20 nucleotides in length.

In an embodiment, the targeting domain is 21 nucleotides in length.

In an embodiment, the targeting domain is 22 nucleotides in length.

In an embodiment, the targeting domain is 23 nucleotides in length.

In an embodiment, the targeting domain is 24 nucleotides in length.

In an embodiment, the targeting domain is 25 nucleotides in length.

In an embodiment, the targeting domain is 26 nucleotides in length.

In an embodiment, the targeting domain comprises 16 nucleotides.

In an embodiment, the targeting domain comprises 17 nucleotides.

In an embodiment, the targeting domain comprises 18 nucleotides.

In an embodiment, the targeting domain comprises 19 nucleotides.

In an embodiment, the targeting domain comprises 20 nucleotides.

In an embodiment, the targeting domain comprises 21 nucleotides.

In an embodiment, the targeting domain comprises 22 nucleotides.

In an embodiment, the targeting domain comprises 23 nucleotides.

In an embodiment, the targeting domain comprises 24 nucleotides.

In an embodiment, the targeting domain comprises 25 nucleotides.

In an embodiment, the targeting domain comprises 26 nucleotides.

In an embodiment, the targeting domain is 10 +/-5, 20+/-5, 30+/-5, 40+/-5, 50+/-5, 60+/- 5, 70+/-5, 80+/-5, 90+/-5, or 100+/-5 nucleotides, in length.

In an embodiment, the targeting domain is 20+/-5 nucleotides in length.

In an embodiment, the targeting domain is 20+/- 10, 30+/- 10, 40+/- 10, 50+/- 10, 60+/- 10,

70+/- 10, 80+/- 10, 90+/- 10, or 100+/- 10 nucleotides, in length. In an embodiment, the targeting domain is 30+/- 10 nucleotides in length.

In an embodiment, the targeting domain is 10 to 100, 10 to 90, 10 to 80, 10 to 70, 10 to 60, 10 to 50, 10 to 40, 10 to 30, 10 to 20 or 10 to 15 nucleotides in length.

In another embodiment, the targeting domain is 20 to 100, 20 to 90, 20 to 80, 20 to 70, 20 to 60, 20 to 50, 20 to 40, 20 to 30, or 20 to 25 nucleotides in length.

Typically the targeting domain has full complementarity with the target sequence. In an embodiment the targeting domain has or includes 1, 2, 3, 4, 5, 6, 7 or 8 nucleotides that are not complementary with the corresponding nucleotide of the targeting domain.

In an embodiment, the target domain includes 1, 2, 3, 4 or 5 nucleotides that are complementary with the corresponding nucleotide of the targeting domain within 5 nucleotides of its 5' end. In an embodiment, the target domain includes 1, 2, 3, 4 or 5 nucleotides that are complementary with the corresponding nucleotide of the targeting domain within 5 nucleotides of its 3' end.

In an embodiment, the target domain includes 1, 2, 3, or 4 nucleotides that are not complementary with the corresponding nucleotide of the targeting domain within 5 nucleotides of its 5' end. In an embodiment, the target domain includes 1, 2, 3, or 4 nucleotides that are not complementary with the corresponding nucleotide of the targeting domain within 5 nucleotides of its 3' end.

In an embodiment, the degree of complementarity, together with other properties of the gRNA, is sufficient to allow targeting of a Cas9 molecule to the target nucleic acid.

In an embodiment, the targeting domain comprises two consecutive nucleotides that are not complementary to the target domain ("non-complementary nucleotides"), e.g., two consecutive noncomplementary nucleotides that are within 5 nucleotides of the 5' end of the targeting domain, within 5 nucleotides of the 3' end of the targeting domain, or more than 5 nucleotides away from one or both ends of the targeting domain.

In an embodiment, no two consecutive nucleotides within 5 nucleotides of the 5' end of the targeting domain, within 5 nucleotides of the 3' end of the targeting domain, or within a region that is more than 5 nucleotides away from one or both ends of the targeting domain, are not complementary to the targeting domain.

In an embodiment, there are no noncomplementary nucleotides within 5 nucleotides of the 5' end of the targeting domain, within 5 nucleotides of the 3' end of the targeting domain, or within a region that is more than 5 nucleotides away from one or both ends of the targeting domain.

In an embodiment, the targeting domain nucleotides do not comprise modifications, e.g., modifications of the type provided in Section VIII. However, in an embodiment, the targeting domain comprises one or more modifications, e.g., modifications that it render it less susceptible to degradation or more bio-compatible, e.g., less immunogenic. By way of example, the backbone of the targeting domain can be modified with a phosphorothioate, or other

modification from Section VIII. In an embodiment, a nucleotide of the targeting domain can comprise a 2' modification (e.g., a modification at the 2' position on ribose), e.g., a 2- acetylation, e.g., a 2' methylation, or other modification(s) from Section VIII.

In an embodiment, the targeting domain includes 1, 2, 3, 4, 5, 6, 7 or 8 or more modifications. In an embodiment, the targeting domain includes 1, 2, 3, or 4 modifications within 5 nucleotides of its 5' end. In an embodiment, the targeting domain comprises as many as 1, 2, 3, or 4 modifications within 5 nucleotides of its 3' end.

In an embodiment, the targeting domain comprises modifications at two consecutive nucleotides, e.g., two consecutive nucleotides that are within 5 nucleotides of the 5' end of the targeting domain, within 5 nucleotides of the 3' end of the targeting domain, or more than 5 nucleotides away from one or both ends of the targeting domain.

In an embodiment, no two consecutive nucleotides are modified within 5 nucleotides of the 5' end of the targeting domain, within 5 nucleotides of the 3' end of the targeting domain, or within a region that is more than 5 nucleotides away from one or both ends of the targeting domain. In an embodiment, no nucleotide is modified within 5 nucleotides of the 5' end of the targeting domain, within 5 nucleotides of the 3' end of the targeting domain, or within a region that is more than 5 nucleotides away from one or both ends of the targeting domain.

Modifications in the targeting domain can be selected to not interfere with targeting efficacy, which can be evaluated by testing a candidate modification in the system described in Section IV. gRNAs having a candidate targeting domain having a selected length, sequence, degree of complementarity, or degree of modification, can be evaluated in a system in Section IV. The candidate targeting domain can be placed, either alone, or with one or more other candidate changes in a gRNA molecule/Cas9 molecule system known to be functional with a selected target and evaluated. In an embodiment, all of the modified nucleotides are complementary to and capable of hybridizing to corresponding nucleotides present in the target domain. In another embodiment,

1, 2, 3, 4, 5, 6, 7 or 8 or more modified nucleotides are not complementary to or capable of hybridizing to corresponding nucleotides present in the target domain.

In an embodiment, the targeting domain comprises, preferably in the 5'→3' direction: a secondary domain and a core domain. These domains are discussed in more detail below.

The Core Domain and Secondary Domain of the Targeting Domain

The "core domain" of the targeting domain is complementary to the "core domain target" on the target nucleic acid. In an embodiment, the core domain comprises about 8 to about 13 nucleotides from the 3' end of the targeting domain (e.g., the most 3' 8 to 13 nucleotides of the targeting domain).

In an embodiment, the core domain and targeting domain, are independently, 6 +1-2, 1+1-

2, 8+/-2, 9+1-2, 10+/-2, 11+/-2, 12+/-2, 13+/-2, 14+/-2, 15+/-2, or 16+-2, nucleotides in length.

In an embodiment, the core domain and targeting domain, are independently, 10+/-2 nucleotides in length.

In an embodiment, the core domain and targeting domain, are independently, 10+/-4 nucleotides in length.

In an embodiment, the core domain and targeting domain are independently 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 nucleotides in length.

In an embodiment, the core domain and targeting domain are independently 3 to 20, 4 to 20, 5 to 20, 6 to 20, 7 to 20, 8 to 20, 9 to 20 10 to 20 or 15 to 20 nucleotides in length.

In an embodiment, the core domain and targeting domain are independently 3 to 15, e.g., 6 to 15, 7 to 14, 7 to 13, 6 to 12, 7 to 12, 7 to 11, 7 to 10, 8 to 14, 8 to 13, 8 to 12, 8 to 11, 8 to 10 or 8 to 9 nucleotides in length.

The core domain is complementary with the core domain target. Typically the core domain has exact complementarity with the core domain target. In an embodiment, the core domain can have 1, 2, 3, 4 or 5 nucleotides that are not complementary with the corresponding nucleotide of the core domain. In an embodiment, the degree of complementarity, together with other properties of the gRNA, is sufficient to allow targeting of a Cas9 molecule to the target nucleic acid.

The "secondary domain" of the targeting domain of the gRNA is complementary to the "secondary domain target" of the target nucleic acid.

In an embodiment, the secondary domain is positioned 5' to the core domain.

In an embodiment, the secondary domain is absent or optional.

In an embodiment, if the targeting domain is 26 nucleotides in length and the core domain (counted from the 3' end of the targeting domain) is 8 to 13 nucleotides in length, the secondary domain is 12 to 17 nucleotides in length.

In an embodiment, if the targeting domain is 25 nucleotides in length and the core domain (counted from the 3' end of the targeting domain) is 8 to 13 nucleotides in length, the secondary domain is 12 to 17 nucleotides in length.

In an embodiment, if the targeting domain is 24 nucleotides in length and the core domain (counted from the 3' end of the targeting domain) is 8 to 13 nucleotides in length, the secondary domain is 11 to 16 nucleotides in length.

In an embodiment, if the targeting domain is 23 nucleotides in length and the core domain (counted from the 3' end of the targeting domain) is 8 to 13 nucleotides in length, the secondary domain is 10 to 15 nucleotides in length.

In an embodiment, if the targeting domain is 22 nucleotides in length and the core domain (counted from the 3' end of the targeting domain) is 8 to 13 nucleotides in length, the secondary domain is 9 to 14 nucleotides in length.

In an embodiment, if the targeting domain is 21 nucleotides in length and the core domain (counted from the 3' end of the targeting domain) is 8 to 13 nucleotides in length, the secondary domain is 8 to 13 nucleotides in length.

In an embodiment, if the targeting domain is 20 nucleotides in length and the core domain (counted from the 3' end of the targeting domain) is 8 to 13 nucleotides in length, the secondary domain is 7 to 12 nucleotides in length.

In an embodiment, if the targeting domain is 19 nucleotides in length and the core domain (counted from the 3' end of the targeting domain) is 8 to 13 nucleotides in length, the secondary domain is 6 to 11 nucleotides in length. In an embodiment, if the targeting domain is 18 nucleotides in length and the core domain (counted from the 3' end of the targeting domain) is 8 to 13 nucleotides in length, the secondary domain is 5 to 10 nucleotides in length.

In an embodiment, if the targeting domain is 17 nucleotides in length and the core domain (counted from the 3' end of the targeting domain) is 8 to 13 nucleotides in length, the secondary domain is 4 to 9 nucleotides in length.

In an embodiment, if the targeting domain is 16 nucleotides in length and the core domain (counted from the 3' end of the targeting domain) is 8 to 13 nucleotides in length, the secondary domain is 3 to 8 nucleotides in length.

In an embodiment, the secondary domain is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or

15 nucleotides in length.

The secondary domain is complementary with the secondary domain target. Typically the secondary domain has exact complementarity with the secondary domain target. In an embodiment the secondary domain can have 1, 2, 3, 4 or 5 nucleotides that are not

complementary with the corresponding nucleotide of the secondary domain. In an embodiment, the degree of complementarity, together with other properties of the gRNA, is sufficient to allow targeting of a Cas9 molecule to the target nucleic acid.

In an embodiment, the core domain nucleotides do not comprise modifications, e.g., modifications of the type provided in Section VIII. However, in an embodiment, the core domain comprises one or more modifications, e.g., modifications that it render it less susceptible to degradation or more bio-compatible, e.g., less immunogenic. By way of example, the backbone of the core domain can be modified with a phosphorothioate, or other modification(s) from Section VIII. In an embodiment a nucleotide of the core domain can comprise a 2' modification (e.g., a modification at the 2' position on ribose), e.g., a 2-acetylation, e.g., a 2' methylation, or other modification(s) from Section VIII. Typically, a core domain will contain no more than 1, 2, or 3 modifications.

Modifications in the core domain can be selected to not interfere with targeting efficacy, which can be evaluated by testing a candidate modification in the system described in Section IV. gRNAs having a candidate core domain having a selected length, sequence, degree of complementarity, or degree of modification, can be evaluated in the system described at Section IV. The candidate core domain can be placed, either alone, or with one or more other candidate changes in a gRNA molecule/Cas9 molecule system known to be functional with a selected target and evaluated.

In an embodiment, the secondary domain nucleotides do not comprise modifications, e.g., modifications of the type provided in Section VIII. However, in an embodiment, the secondary domain comprises one or more modifications, e.g., modifications that render it less susceptible to degradation or more bio-compatible, e.g., less immunogenic. By way of example, the backbone of the secondary domain can be modified with a phosphorothioate, or other modification(s) from Section VIII. In an embodiment a nucleotide of the secondary domain can comprise a 2' modification (e.g., a modification at the 2' position on ribose), e.g., a 2-acetylation, e.g., a 2' methylation, or other modification from Section VIII. Typically, a secondary domain will contain no more than 1, 2, or 3 modifications.

Modifications in the secondary domain can be selected to not interfere with targeting efficacy, which can be evaluated by testing a candidate modification in the system described in Section IV. gRNAs having a candidate secondary domain having a selected length, sequence, degree of complementarity, or degree of modification, can be evaluated in the system described at Section IV. The candidate secondary domain can be placed, either alone, or with one or more other candidate changes in a gRNA molecule/Cas9 molecule system known to be functional with a selected target and evaluated.

In an embodiment, (1) the degree of complementarity between the core domain and its target, and (2) the degree of complementarity between the secondary domain and its target, may differ. In an embodiment, (1) may be greater than (2). In an embodiment, (1) may be less than (2). In an embodiment, (1) and (2) are the same, e.g., each may be completely complementary with its target.

In an embodiment, (1) the number of modifications (e.g., modifications from Section VIII) of the nucleotides of the core domain and (2) the number of modification (e.g.,

modifications from Section VIII) of the nucleotides of the secondary domain, may differ. In an embodiment, (1) may be less than (2). In an embodiment, (1) may be greater than (2). In an embodiment, (1) and (2) may be the same, e.g., each may be free of modifications. The First and Second Complementarity Domains

The first complementarity domain is complementary with the second complementarity domain.

Typically the first domain does not have exact complementarity with the second complementarity domain target. In an embodiment, the first complementarity domain can have 1, 2, 3, 4 or 5 nucleotides that are not complementary with the corresponding nucleotide of the second complementarity domain. In an embodiment, 1, 2, 3, 4, 5 or 6, e.g., 3 nucleotides, will not pair in the duplex, and, e.g., form a non-duplexed or looped-out region. In an embodiment, an unpaired, or loop-out, region, e.g., a loop-out of 3 nucleotides, is present on the second complementarity domain. In an embodiment, the unpaired region begins 1, 2, 3, 4, 5, or 6, e.g., 4, nucleotides from the 5' end of the second complementarity domain.

In an embodiment, the first and second complementarity domains are:

independently, 6 +1-2, 1+1-2, 8+/-2, 9+1-2, 10+/-2, 11+/-2, 12+/-2, 13+/-2, 14+/-2, 15+/-2,

16+/-2, 17+/-2, 18+/-2, 19+/-2, or 20+/-2, 21+/-2, 22+/-2, 23+/-2, or 24+/-2 nucleotides in length;

independently, 6, 7, 8, 9, 10, 11, 12, 13, 14, 14, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26, nucleotides in length; or

independently, 5 to 24, 5 to 23, 5 to 22, 5 to 21, 5 to 20, 7 to 18, 9 to 16, or 10 to 14 nucleotides in length.

In an embodiment, the second complementarity domain is longer than the first complementarity domain, e.g., 2, 3, 4, 5, or 6, e.g., 6, nucleotides longer.

In an embodiment, the first and second complementary domains, independently, do not comprise modifications, e.g., modifications of the type provided in Section VIII.

In an embodiment, the first and second complementary domains, independently, comprise one or more modifications, e.g., modifications that the render the domain less susceptible to degradation or more bio-compatible, e.g., less immunogenic. By way of example, the backbone of the domain can be modified with a phosphorothioate, or other modification(s) from Section VIII. In an embodiment a nucleotide of the domain can comprise a 2' modification (e.g., a modification at the 2' position on ribose), e.g., a 2-acetylation, e.g., a 2' methylation, or other modification(s) from Section VIII.

In an embodiment, the first and second complementary domains, independently, include 1, 2, 3, 4, 5, 6, 7 or 8 or more modifications. In an embodiment, the first and second

complementary domains, independently, include 1, 2, 3, or 4 modifications within 5 nucleotides of its 5' end. In an embodiment, the first and second complementary domains, independently, include as many as 1, 2, 3, or 4 modifications within 5 nucleotides of its 3' end.

In an embodiment, the first and second complementary domains, independently, include modifications at two consecutive nucleotides, e.g., two consecutive nucleotides that are within 5 nucleotides of the 5' end of the domain, within 5 nucleotides of the 3' end of the domain, or more than 5 nucleotides away from one or both ends of the domain. In an embodiment, the first and second complementary domains, independently, include no two consecutive nucleotides that are modified, within 5 nucleotides of the 5' end of the domain, within 5 nucleotides of the 3' end of the domain, or within a region that is more than 5 nucleotides away from one or both ends of the domain. In an embodiment, the first and second complementary domains, independently, include no nucleotide that is modified within 5 nucleotides of the 5' end of the domain, within 5 nucleotides of the 3' end of the domain, or within a region that is more than 5 nucleotides away from one or both ends of the domain.

Modifications in a complementarity domain can be selected to not interfere with targeting efficacy, which can be evaluated by testing a candidate modification in the system described in Section IV. gRNAs having a candidate complementarity domain having a selected length, sequence, degree of complementarity, or degree of modification, can be evaluated in the system described in Section IV. The candidate complementarity domain can be placed, either alone, or with one or more other candidate changes in a gRNA molecule/Cas9 molecule system known to be functional with a selected target and evaluated.

In an embodiment, the first complementarity domain has at least 60, 70, 80, 85%, 90% or 95% homology with, or differs by no more than 1, 2, 3, 4, 5, or 6 nucleotides from, a reference first complementarity domain, e.g., a naturally occurring, e.g., an S. pyogenes, S. aureus or S. thermophilus, first complementarity domain, or a first complementarity domain described herein, e.g., from Figs. 1A-1G. In an embodiment, the second complementarity domain has at least 60, 70, 80, 85%, 90%, or 95% homology with, or differs by no more than 1, 2, 3, 4, 5, or 6 nucleotides from, a reference second complementarity domain, e.g., a naturally occurring, e.g., an S. pyogenes, S. aureus or S. thermophilus, second complementarity domain, or a second complementarity domain described herein, e.g., from Figs. 1A-1G.

The duplexed region formed by first and second complementarity domains is typically 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22 base pairs in length (excluding any looped out or unpaired nucleotides).

In an embodiment, the first and second complementarity domains, when duplexed, comprise 11 paired nucleotides, for example, in the gRNA sequence (one paired strand underlined, one bolded):

NNNNNNNNNNNNNNNNNNNNGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGG CUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGC (SEQ ID NO: 5).

In an embodiment, the first and second complementarity domains, when duplexed, comprise 15 paired nucleotides, for example in the gRNA sequence (one paired strand underlined, one bolded):

NNNNNNNNNNNNNNNNNNNNGUUUUAGAGCUAUGCUGAAAAGCAUAGCAAGUUA AAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGC (SEQ ID NO: 27).

In an embodiment the first and second complementarity domains, when duplexed, comprise 16 paired nucleotides, for example in the gRNA sequence (one paired strand underlined, one bolded):

NNNNNNNNNNNNNNNNNNNNGUUUUAGAGCUAUGCUGGAAACAGCAUAGCAAGU UAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGC

(SEQ ID NO: 28).

In an embodiment the first and second complementarity domains, when duplexed, comprise 21 paired nucleotides, for example in the gRNA sequence (one paired strand underlined, one bolded):

NNNNNNNNNNNNNNNNNNNNGUUUUAGAGCUAUGCUGUUUUGGAAACAAAACAG CAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGA GUCGGUGC (SEQ ID NO: 29). In an embodiment, nucleotides are exchanged to remove poly-U tracts, for example in the gRNA sequences (exchanged nucleotides underlined):

NNNNNNNNNNNNNNNNNNNNGUAUUAGAGCUAGAAAUAGCAAGUUAAUAUAAGG CUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGC (SEQ ID NO: 30); NNNNNNNNNNNNNNNNNNNNGUUUAAGAGCUAGAAAUAGCAAGUUUAAAUAAGG CUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGC (SEQ ID NO: 31); or NNNNNNNNNNNNNNNNNNNNGUAUUAGAGCUAUGCUGUAUUGGAAACAAUACAG CAUAGCAAGUUAAUAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGA GUCGGUGC (SEQ ID NO: 32).

The 5' Extension Domain

In an embodiment, a modular gRNA can comprise additional sequence, 5' to the second complementarity domain. In an embodiment, the 5' extension domain is 2 to 10, 2 to 9, 2 to 8, 2 to 7, 2 to 6, 2 to 5, or 2 to 4 nucleotides in length. In an embodiment, the 5' extension domain is 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more nucleotides in length.

In an embodiment, the 5' extension domain nucleotides do not comprise modifications, e.g., modifications of the type provided in Section VIII. However, in an embodiment, the 5' extension domain comprises one or more modifications, e.g., modifications that it render it less susceptible to degradation or more bio-compatible, e.g., less immunogenic. By way of example, the backbone of the 5' extension domain can be modified with a phosphorothioate, or other modification(s) from Section VIII. In an embodiment, a nucleotide of the 5' extension domain can comprise a 2' modification (e.g., a modification at the 2' position on ribose), e.g., a 2- acetylation, e.g., a 2' methylation, or other modification(s) from Section VIII.

In an embodiment, the 5' extension domain can comprise as many as 1, 2, 3, 4, 5, 6, 7 or 8 modifications. In an embodiment, the 5' extension domain comprises as many as 1, 2, 3, or 4 modifications within 5 nucleotides of its 5' end, e.g., in a modular gRNA molecule. In an embodiment, the 5' extension domain comprises as many as 1, 2, 3, or 4 modifications within 5 nucleotides of its 3' end, e.g., in a modular gRNA molecule.

In an embodiment, the 5' extension domain comprises modifications at two consecutive nucleotides, e.g., two consecutive nucleotides that are within 5 nucleotides of the 5' end of the 5' extension domain, within 5 nucleotides of the 3' end of the 5' extension domain, or more than 5 nucleotides away from one or both ends of the 5' extension domain. In an embodiment, no two consecutive nucleotides are modified within 5 nucleotides of the 5' end of the 5' extension domain, within 5 nucleotides of the 3' end of the 5' extension domain, or within a region that is more than 5 nucleotides away from one or both ends of the 5' extension domain. In an embodiment, no nucleotide is modified within 5 nucleotides of the 5' end of the 5' extension domain, within 5 nucleotides of the 3' end of the 5' extension domain, or within a region that is more than 5 nucleotides away from one or both ends of the 5' extension domain.

Modifications in the 5' extension domain can be selected so as to not interfere with gRNA molecule efficacy, which can be evaluated by testing a candidate modification in the system described in Section IV. gRNAs having a candidate 5' extension domain having a selected length, sequence, degree of complementarity, or degree of modification, can be evaluated in the system described at Section IV. The candidate 5' extension domain can be placed, either alone, or with one or more other candidate changes in a gRNA molecule/Cas9 molecule system known to be functional with a selected target and evaluated.

In an embodiment, the 5' extension domain has at least 60, 70, 80, 85, 90 or 95% homology with, or differs by no more than 1, 2, 3, 4, 5, or 6 nucleotides from, a reference 5' extension domain, e.g., a naturally occurring, e.g., an S. pyogenes, S. aureus or S. thermophilus, 5' extension domain, or a 5' extension domain described herein, e.g., from Figs. 1A-1G. The Linking Domain

In a unimolecular gRNA molecule the linking domain is disposed between the first and second complementarity domains. In a modular gRNA molecule, the two molecules are associated with one another by the complementarity domains.

In an embodiment, the linking domain is 10 +/-5, 20+/-5, 30+/-5, 40+/-5, 50+/-5, 60+/-5, 70+/-5, 80+/-5, 90+/-5, or 100+/-5 nucleotides, in length.

In an embodiment, the linking domain is 20+/- 10, 30+/- 10, 40+/- 10, 50+/- 10, 60+/- 10, 70+/- 10, 80+/- 10, 90+/- 10, or 100+/- 10 nucleotides, in length.

In an embodiment, the linking domain is 10 to 100, 10 to 90, 10 to 80, 10 to 70, 10 to 60, 10 to 50, 10 to 40, 10 to 30, 10 to 20 or 10 to 15 nucleotides in length.

In another embodiment, the linking domain is 20 to 100, 20 to 90, 20 to 80, 20 to 70, 20 to 60, 20 to 50, 20 to 40, 20 to 30, or 20 to 25 nucleotides in length. In an embodiment, the linking domain is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 17, 18, 19, or 20 nucleotides in length.

In and embodiment, the linking domain is a covalent bond.

In an embodiment, the linking domain comprises a duplexed region, typically adjacent to or within 1, 2, or 3 nucleotides of the 3' end of the first complementarity domain and/or the 5- end of the second complementarity domain. In an embodiment, the duplexed region can be 20+/-10 base pairs in length. In an embodiment, the duplexed region can be 10+/-5, 15+/-5, 20+/-5, or 30+/-5 base pairs in length. In an embodiment, the duplexed region can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 base pairs in length.

Typically the sequences forming the duplexed region have exact complementarity with one another, though in an embodiment as many as 1, 2, 3, 4, 5, 6, 7 or 8 nucleotides are not complementary with the corresponding nucleotides.

In an embodiment, the linking domain nucleotides do not comprise modifications, e.g., modifications of the type provided in Section VIII. However, in an embodiment, the linking domain comprises one or more modifications, e.g., modifications that it render it less susceptible to degradation or more bio-compatible, e.g., less immunogenic. By way of example, the backbone of the linking domain can be modified with a phosphorothioate, or other

modification(s) from Section VIII. In an embodiment a nucleotide of the linking domain can comprise a 2' modification (e.g., a modification at the 2' position on ribose), e.g., a 2- acetylation, e.g., a 2' methylation, or other modification(s) from Section VIII. In an embodiment, the linking domain can comprise as many as 1, 2, 3, 4, 5, 6, 7 or 8 modifications.

Modifications in a linking domain can be selected so as to not interfere with targeting efficacy, which can be evaluated by testing a candidate modification in the system described in Section IV. gRNAs having a candidate linking domain having a selected length, sequence, degree of complementarity, or degree of modification, can be evaluated a system described in Section IV. A candidate linking domain can be placed, either alone, or with one or more other candidate changes in a gRNA molecule/Cas9 molecule system known to be functional with a selected target and evaluated.

In an embodiment, the linking domain has at least 60, 70, 80, 85, 90 or 95% homology with, or differs by no more than 1, 2, 3, 4, 5 ,or 6 nucleotides from, a reference linking domain, e.g., a linking domain described herein, e.g., from Figs. 1A-1G. The Proximal Domain

In an embodiment, the proximal domain is 6 +1-2, 1+1-2, 8+/-2, 9+1-2, 10+/-2, 11+/-2, 12+/-2, 13+/-2, 14+/-2, 14+/-2, 16+/-2, 17+/-2, 18+/-2, 19+/-2, or 20+/-2 nucleotides in length.

In an embodiment, the proximal domain is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 21, 22, 23, 24, 25 or 26 nucleotides in length.

In an embodiment, the proximal domain is 5 to 20, 7, to 18, 9 to 16, or 10 to 14 nucleotides in length.

In an embodiment, the proximal domain nucleotides do not comprise modifications, e.g., modifications of the type provided in Section VIII. However, in an embodiment, the proximal domain comprises one or more modifications, e.g., modifications that it render it less susceptible to degradation or more bio-compatible, e.g., less immunogenic. By way of example, the backbone of the proximal domain can be modified with a phosphorothioate, or other

modification(s) from Section VIII. In an embodiment a nucleotide of the proximal domain can comprise a 2' modification (e.g., a modification at the 2' position on ribose), e.g., a 2- acetylation, e.g., a 2' methylation, or other modification(s) from Section VIII.

In an embodiment, the proximal domain can comprise as many as 1, 2, 3, 4, 5, 6, 7 or 8 modifications. In an embodiment, the proximal domain comprises as many as 1, 2, 3, or 4 modifications within 5 nucleotides of its 5' end, e.g., in a modular gRNA molecule. In an embodiment, the target domain comprises as many as 1, 2, 3, or 4 modifications within 5 nucleotides of its 3' end, e.g., in a modular gRNA molecule.

In an embodiment, the proximal domain comprises modifications at two consecutive nucleotides, e.g., two consecutive nucleotides that are within 5 nucleotides of the 5' end of the proximal domain, within 5 nucleotides of the 3' end of the proximal domain, or more than 5 nucleotides away from one or both ends of the proximal domain. In an embodiment, no two consecutive nucleotides are modified within 5 nucleotides of the 5' end of the proximal domain, within 5 nucleotides of the 3' end of the proximal domain, or within a region that is more than 5 nucleotides away from one or both ends of the proximal domain. In an embodiment, no nucleotide is modified within 5 nucleotides of the 5' end of the proximal domain, within 5 nucleotides of the 3' end of the proximal domain, or within a region that is more than 5 nucleotides away from one or both ends of the proximal domain. Modifications in the proximal domain can be selected so as to not interfere with gRNA molecule efficacy, which can be evaluated by testing a candidate modification in the system described in Section IV. gRNAs having a candidate proximal domain having a selected length, sequence, degree of complementarity, or degree of modification, can be evaluated in the system described at Section IV. The candidate proximal domain can be placed, either alone, or with one or more other candidate changes in a gRNA molecule/Cas9 molecule system known to be functional with a selected target and evaluated.

In an embodiment, the proximal domain has at least 60, 70, 80, 85 90 or 95% homology with, or differs by no more than 1, 2, 3, 4, 5, or 6 nucleotides from, a reference proximal domain, e.g., a naturally occurring, e.g., an S. pyogenes, S. aureus or S. thermophilus, proximal domain, or a proximal domain described herein, e.g., from Figs. 1A-1G.

The Tail Domain

In an embodiment, the tail domain is 10 +/-5, 20+/-5, 30+/-5, 40+/-5, 50+/-5, 60+/-5, 70+/-5, 80+/-5, 90+/-5, or 100+/-5 nucleotides, in length.

In an embodiment, the tail domain is 20+/-5 nucleotides in length.

In an embodiment, the tail domain is 20+/- 10, 30+/- 10, 40+/- 10, 50+/- 10, 60+/- 10, 70+/- 10, 80+/- 10, 90+/- 10, or 100+/- 10 nucleotides, in length.

In an embodiment, the tail domain is 25+/- 10 nucleotides in length.

In an embodiment, the tail domain is 10 to 100, 10 to 90, 10 to 80, 10 to 70, 10 to 60, 10 to 50, 10 to 40, 10 to 30, 10 to 20 or 10 to 15 nucleotides in length.

In another embodiment, the tail domain is 20 to 100, 20 to 90, 20 to 80, 20 to 70, 20 to 60, 20 to 50, 20 to 40, 20 to 30, or 20 to 25 nucleotides in length.

In an embodiment, the tail domain is 1 to 20, 1 to 15, 1 to 10, or 1 to 5 nucleotides in length.

In an embodiment, the tail domain nucleotides do not comprise modifications, e.g., modifications of the type provided in Section VIII. However, in an embodiment, the tail domain comprises one or more modifications, e.g., modifications that it render it less susceptible to degradation or more bio-compatible, e.g., less immunogenic. By way of example, the backbone of the tail domain can be modified with a phosphorothioate, or other modification(s) from

Section VIII. In an embodiment a nucleotide of the tail domain can comprise a 2' modification (e.g., a modification at the 2' position on ribose), e.g., a 2-acetylation, e.g., a 2' methylation, or other modification(s) from Section VIII.

In an embodiment, the tail domain can have as many as 1, 2, 3, 4, 5, 6, 7 or 8

modifications. In an embodiment, the target domain comprises as many as 1, 2, 3, or 4 modifications within 5 nucleotides of its 5' end. In an embodiment, the target domain comprises as many as 1, 2, 3, or 4 modifications within 5 nucleotides of its 3' end.

In an embodiment, the tail domain comprises a tail duplex domain, which can form a tail duplexed region. In an embodiment, the tail duplexed region can be 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 base pairs in length. In an embodiment, a further single stranded domain, exists 3' to the tail duplexed domain. In an embodiment, this domain is 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides in length. In an embodiment it is 4 to 6 nucleotides in length.

In an embodiment, the tail domain has at least 60, 70, 80, or 90% homology with, or differs by no more than 1, 2, 3, 4, 5 ,or 6 nucleotides from, a reference tail domain, e.g., a naturally occurring, e.g., an S. pyogenes, S. aureus or S. thermophilus, tail domain, or a tail domain described herein, e.g., from Figs. 1A-1G.

In an embodiment, the proximal and tail domain, taken together comprise the following sequences:

AAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCU (SEQ ID NO: 33), or

AAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGGUGC (SEQ ID NO: 34), or

AAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCGGAUC (SEQ ID NO: 35), or

AAGGCUAGUCCGUUAUCAACUUGAAAAAGUG (SEQ ID NO: 36), or

AAGGCUAGUCCGUUAUCA (SEQ ID NO: 37), or

AAGGCUAGUCCG (SEQ ID NO: 38).

In an embodiment, the tail domain comprises the 3' sequence UUUUUU, e.g., if a U6 promoter is used for transcription.

In an embodiment, the tail domain comprises the 3' sequence UUUU, e.g., if an HI promoter is used for transcription.

In an embodiment, tail domain comprises variable numbers of 3' Us depending, e.g., on the termination signal of the pol-III promoter used. In an embodiment, the tail domain comprises variable 3' sequence derived from the DNA template if a T7 promoter is used.

In an embodiment, the tail domain comprises variable 3' sequence derived from the DNA template, e.g., if in vitro transcription is used to generate the RNA molecule.

In an embodiment, the tail domain comprises variable 3' sequence derived from the DNA template, e., if a pol-II promoter is used to drive transcription.

Modifications in the tail domain can be selected to not interfere with targeting efficacy, which can be evaluated by testing a candidate modification in the system described in Section IV. gRNAs having a candidate tail domain having a selected length, sequence, degree of complementarity, or degree of modification, can be evaluated in the system described in Section IV. The candidate tail domain can be placed, either alone, or with one or more other candidate changes in a gRNA molecule/Cas9 molecule system known to be functional with a selected target and evaluated.

In an embodiment, the tail domain comprises modifications at two consecutive nucleotides, e.g., two consecutive nucleotides that are within 5 nucleotides of the 5' end of the tail domain, within 5 nucleotides of the 3' end of the tail domain, or more than 5 nucleotides away from one or both ends of the tail domain. In an embodiment, no two consecutive nucleotides are modified within 5 nucleotides of the 5' end of the tail domain, within 5 nucleotides of the 3' end of the tail domain, or within a region that is more than 5 nucleotides away from one or both ends of the tail domain. In an embodiment, no nucleotide is modified within 5 nucleotides of the 5' end of the tail domain, within 5 nucleotides of the 3' end of the tail domain, or within a region that is more than 5 nucleotides away from one or both ends of the tail domain.

In an embodiment a gRNA has the following structure:

5' [targeting domain] -[first complementarity domain] -[linking domain] -[second complementarity domain] -[proximal domain] -[tail domain] -3'

wherein, the targeting domain comprises a core domain and optionally a secondary domain, and is 10 to 50 nucleotides in length;

the first complementarity domain is 5 to 25 nucleotides in length and, In an embodiment has at least 50, 60, 70, 80, 85, 90 or 95% homology with a reference first complementarity domain disclosed herein; the linking domain is 1 to 5 nucleotides in length;

the second complementarity domain is 5 to 27 nucleotides in length and, in an embodiment has at least 50, 60, 70, 80, 85, 90 or 95% homology with a reference second complementarity domain disclosed herein;

the proximal domain is 5 to 20 nucleotides in length and, in an embodiment has at least 50, 60, 70, 80, 85, 90 or 95% homology with a reference proximal domain disclosed herein; and the tail domain is absent or a nucleotide sequence is 1 to 50 nucleotides in length and, in an embodiment has at least 50, 60, 70, 80, 85, 90 or 95% homology with a reference tail domain disclosed herein.

Exemplary Chimeric gRNAs

3':

a targeting domain (which is complementary to a target nucleic acid);

a first complementarity domain, e.g., comprising 15, 16, 17, 18, 19, 20, 21, 22,

23, 24, 25, or 26 nucleotides;

a linking domain;

a second complementarity domain (which is complementary to the first complementarity domain);

a proximal domain; and

a tail domain,

wherein,

(a) the proximal and tail domain, when taken together, comprise

at least 15, 18, 20, 25, 30, 31, 35, 40, 45, 49, 50, or 53 nucleotides;

(b) there are at least 15, 18, 20, 25, 30, 31, 35, 40, 45, 49, 50, or 53 nucleotides 3' to the last nucleotide of the second complementarity domain; or

(c) there are at least 16, 19, 21, 26, 31, 32, 36, 41, 46, 50, 51, or 54 nucleotides 3' to the last nucleotide of the second complementarity domain that is complementary to its corresponding nucleotide of the first complementarity domain. In an embodiment, the sequence from (a), (b), or (c), has at least 60, 75, 80, 85, 90, 95, or 99% homology with the corresponding sequence of a naturally occurring gRNA, or with a gRNA described herein.

In an embodiment, the proximal and tail domain, when taken together, comprise at least 15, 18, 20, 25, 30, 31, 35, 40, 45, 49, 50, or 53 nucleotides.

In an embodiment, there are at least 15, 18, 20, 25, 30, 31, 35, 40, 45, 49, 50, or 53 nucleotides 3' to the last nucleotide of the second complementarity domain.

In an embodiment, there are at least 16, 19, 21, 26, 31, 32, 36, 41, 46, 50, 51, or 54 nucleotides 3' to the last nucleotide of the second complementarity domain that is

complementary to its corresponding nucleotide of the first complementarity domain.

In an embodiment, the targeting domain comprises, has, or consists of, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26 nucleotides (e.g., 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26 nucleotides in length.

In an embodiment, the targeting domain comprises, has, or consists of, 16 nucleotides

(e.g., 16 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 16 nucleotides in length.

In an embodiment, the targeting domain comprises, has, or consists of, 17 nucleotides (e.g., 17 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 17 nucleotides in length.

In an embodiment, the targeting domain comprises, has, or consists of, 18 nucleotides (e.g., 18 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 18 nucleotides in length.

In an embodiment, the targeting domain comprises, has, or consists of, 19 nucleotides (e.g., 19 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 19 nucleotides in length.

In an embodiment, the targeting domain comprises, has, or consists of, 20 nucleotides (e.g., 20 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 20 nucleotides in length. In an embodiment, the targeting domain comprises, has, or consists of, 21 nucleotides (e.g., 21 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 21 nucleotides in length.

In an embodiment, the targeting domain comprises, has, or consists of, 22 nucleotides (e.g., 22 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 22 nucleotides in length.

In an embodiment, the targeting domain comprises, has, or consists of, 23 nucleotides (e.g., 23 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 23 nucleotides in length.

In an embodiment, the targeting domain comprises, has, or consists of, 24 nucleotides

(e.g., 24 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 24 nucleotides in length.

In an embodiment, the targeting domain comprises, has, or consists of, 25 nucleotides (e.g., 25 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 25 nucleotides in length.

In an embodiment, the targeting domain comprises, has, or consists of, 26 nucleotides (e.g., 26 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 26 nucleotides in length.

In an embodiment, the targeting domain comprises, has, or consists of, 16 nucleotides (e.g., 16 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 16 nucleotides in length; and the proximal and tail domain, when taken together, comprise at least 15, 18, 20, 25, 30, 31, 35, 40, 45, 49, 50, or 53 nucleotides.

In an embodiment, the targeting domain comprises, has, or consists of, 16 nucleotides (e.g., 16 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 16 nucleotides in length; and there are at least 15, 18, 20, 25, 30, 31, 35, 40, 45, 49, 50, or 53 nucleotides 3' to the last nucleotide of the second complementarity domain.

In an embodiment, the targeting domain comprises, has, or consists of, 16 nucleotides (e.g., 16 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 16 nucleotides in length; and there are at least 16, 19, 21, 26, 31, 32, 36, 41, 46, 50, 51, or 54 nucleotides 3' to the last nucleotide of the second complementarity domain that is complementary to its corresponding nucleotide of the first complementarity domain. In an embodiment, the targeting domain comprises, has, or consists of, 17 nucleotides (e.g., 17 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 17 nucleotides in length; and the proximal and tail domain, when taken together, comprise at least 15, 18, 20, 25, 30, 31, 35, 40, 45, 49, 50, or 53 nucleotides.

In an embodiment, the targeting domain comprises, has, or consists of, 17 nucleotides

(e.g., 17 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 17 nucleotides in length; and there are at least 15, 18, 20, 25, 30, 31, 35, 40,

45, 49, 50, or 53 nucleotides 3' to the last nucleotide of the second complementarity domain.

In an embodiment, the targeting domain comprises, has, or consists of, 17 nucleotides (e.g., 17 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 17 nucleotides in length; and there are at least 16, 19, 21, 26, 31, 32, 36, 41,

46, 50, 51, or 54 nucleotides 3' to the last nucleotide of the second complementarity domain that is complementary to its corresponding nucleotide of the first complementarity domain.

In an embodiment, the targeting domain comprises, has, or consists of, 18 nucleotides (e.g., 18 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 18 nucleotides in length; and the proximal and tail domain, when taken together, comprise at leastl5, 18, 20, 25, 30, 31, 35, 40, 45, 49, 50, or 53 nucleotides.

In an embodiment, the targeting domain comprises, has, or consists of, 18 nucleotides (e.g., 18 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 18 nucleotides in length; and there are at least 15, 18, 20, 25, 30, 31, 35, 40, 45, 49, 50, or 53 nucleotides 3' to the last nucleotide of the second complementarity domain.

In an embodiment, the targeting domain comprises, has, or consists of, 18 nucleotides (e.g., 18 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 18 nucleotides in length; and there are at least 16, 19, 21, 26, 31, 32, 36, 41, 46, 50, 51, or 54 nucleotides 3' to the last nucleotide of the second complementarity domain that is complementary to its corresponding nucleotide of the first complementarity domain.

In an embodiment, the targeting domain comprises, has, or consists of, 19 nucleotides (e.g., 19 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 19 nucleotides in length; and the proximal and tail domain, when taken together, comprise at least 15, 18, 20, 25, 30, 31, 35, 40, 45, 49, 50, or 53 nucleotides. In an embodiment, the targeting domain comprises, has, or consists of, 19 nucleotides (e.g., 19 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 19 nucleotides in length; and there are at least 15, 18, 20, 25, 30, 31, 35, 40,

In an embodiment, the targeting domain comprises, has, or consists of, 19 nucleotides

(e.g., 19 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 19 nucleotides in length; and there are at least 16, 19, 21, 26, 31, 32, 36, 41,

In an embodiment, the targeting domain comprises, has, or consists of, 20 nucleotides

(e.g., 20 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 20 nucleotides in length; and the proximal and tail domain, when taken together, comprise at least 15, 18, 20, 25, 30, 31, 35, 40, 45, 49, 50, or 53 nucleotides.

In an embodiment, the targeting domain comprises, has, or consists of, 20 nucleotides (e.g., 20 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 20 nucleotides in length; and there are at least 15, 18, 20, 25, 30, 31, 35, 40,

In an embodiment, the targeting domain comprises, has, or consists of, 20 nucleotides (e.g., 20 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 20 nucleotides in length; and there are at least 16, 19, 21, 26, 31, 32, 36, 41,

In an embodiment, the targeting domain comprises, has, or consists of, 21 nucleotides (e.g., 21 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 21 nucleotides in length; and the proximal and tail domain, when taken together, comprise at least 15, 18, 20, 25, 30, 31, 35, 40, 45, 49, 50, or 53 nucleotides.

In an embodiment, the targeting domain comprises, has, or consists of, 21 nucleotides (e.g., 21 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 21 nucleotides in length; and there are at least 15, 18, 20, 25, 30, 31, 35, 40, 45, 49, 50, or 53 nucleotides 3' to the last nucleotide of the second complementarity domain. In an embodiment, the targeting domain comprises, has, or consists of, 21 nucleotides (e.g., 21 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 21 nucleotides in length; and there are at least 16, 19, 21, 26, 31, 32, 36, 41, 46, 50, 51, or 54 nucleotides 3' to the last nucleotide of the second complementarity domain that is complementary to its corresponding nucleotide of the first complementarity domain.

In an embodiment, the targeting domain comprises, has, or consists of, 22 nucleotides (e.g., 22 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 22 nucleotides in length; and the proximal and tail domain, when taken together, comprise at least 15, 18, 20, 25, 30, 31, 35, 40, 45, 49, 50, or 53 nucleotides.

In an embodiment, the targeting domain comprises, has, or consists of, 22 nucleotides

(e.g., 22 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 22 nucleotides in length; and there are at least 15, 18, 20, 25, 30, 31, 35, 40,

In an embodiment, the targeting domain comprises, has, or consists of, 22 nucleotides (e.g., 22 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 22 nucleotides in length; and there are at least 16, 19, 21, 26, 31, 32, 36, 41,

In an embodiment, the targeting domain comprises, has, or consists of, 23 nucleotides (e.g., 23 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 23 nucleotides in length; and the proximal and tail domain, when taken together, comprise at least 15, 18, 20, 25, 30, 31, 35, 40, 45, 49, 50, or 53 nucleotides.

In an embodiment, the targeting domain comprises, has, or consists of, 23 nucleotides (e.g., 23 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 23 nucleotides in length; and there are at least 15, 18, 20, 25, 30, 31, 35, 40, 45, 49, 50, or 53 nucleotides 3' to the last nucleotide of the second complementarity domain.

In an embodiment, the targeting domain comprises, has, or consists of, 23 nucleotides (e.g., 23 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 23 nucleotides in length; and there are at least 16, 19, 21, 26, 31, 32, 36, 41, 46, 50, 51, or 54 nucleotides 3' to the last nucleotide of the second complementarity domain that is complementary to its corresponding nucleotide of the first complementarity domain. In an embodiment, the targeting domain comprises, has, or consists of, 24 nucleotides (e.g., 24 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 24 nucleotides in length; and the proximal and tail domain, when taken together, comprise at least 15, 18, 20, 25, 30, 31, 35, 40, 45, 49, 50, or 53 nucleotides.

(e.g., 24 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 24 nucleotides in length; and there are at least 15, 18, 20, 25, 30, 31, 35, 40,

In an embodiment, the targeting domain comprises, has, or consists of, 24 nucleotides (e.g., 24 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 24 nucleotides in length; and there are at least 16, 19, 21, 26, 31, 32, 36, 41,

In an embodiment, the targeting domain comprises, has, or consists of, 25 nucleotides (e.g., 25 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 25 nucleotides in length; and the proximal and tail domain, when taken together, comprise at least 15, 18, 20, 25, 30, 31, 35, 40, 45, 49, 50, or 53 nucleotides.

In an embodiment, the targeting domain comprises, has, or consists of, 25 nucleotides (e.g., 25 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 25 nucleotides in length; and there are at least 15, 18, 20, 25, 30, 31, 35, 40, 45, 49, 50, or 53 nucleotides 3' to the last nucleotide of the second complementarity domain.

In an embodiment, the targeting domain comprises, has, or consists of, 25 nucleotides (e.g., 25 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 25 nucleotides in length; and there are at least 16, 19, 21, 26, 31, 32, 36, 41, 46, 50, 51, or 54 nucleotides 3' to the last nucleotide of the second complementarity domain that is complementary to its corresponding nucleotide of the first complementarity domain.

In an embodiment, the targeting domain comprises, has, or consists of, 26 nucleotides (e.g., 26 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 26 nucleotides in length; and the proximal and tail domain, when taken together, comprise at least 15, 18, 20, 25, 30, 31, 35, 40, 45, 49, 50, or 53 nucleotides. In an embodiment, the targeting domain comprises, has, or consists of, 26 nucleotides (e.g., 26 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 26 nucleotides in length; and there are at least 15, 18, 20, 25, 30, 31, 35, 40,

In an embodiment, the targeting domain comprises, has, or consists of, 26 nucleotides

(e.g., 26 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 26 nucleotides in length; and there are at least 16, 19, 21, 26, 31, 32, 36, 41,

In an embodiment, the unimolecular, or chimeric, gRNA molecule (comprising a targeting domain, a first complementary domain, a linking domain, a second complementary domain, a proximal domain and, optionally, a tail domain) comprises the following sequence in which the targeting domain is depicted as 20 Ns but could be any sequence and range in length from 16 to 26 nucleotides and in which the gRNA sequence is followed by 6 Us, which serve as a termination signal for the U6 promoter, but which could be either absent or fewer in number: NNNNNNNNNNNNNNNNNNNNGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGG CUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUUUUUU (SEQ ID NO: 45). In an embodiment, the unimolecular, or chimeric, gRNA molecule is a S. pyogenes gRNA molecule.

In some embodiments, the unimolecular, or chimeric, gRNA molecule (comprising a targeting domain, a first complementary domain, a linking domain, a second complementary domain, a proximal domain and, optionally, a tail domain) comprises the following sequence in which the targeting domain is depicted as 20 Ns but could be any sequence and range in length from 16 to 26 nucleotides and in which the gRNA sequence is followed by 6 Us, which serve as a termination signal for the U6 promoter, but which could be either absent or fewer in number: NNNNNNNNNNNNNNNNNNNNGUUUUAGUACUCUGGAAACAGAAUCUACUAAAAC AAGGCAAAAUGCCGUGUUUAUCUCGUCAACUUGUUGGCGAGAUUUUUU (SEQ ID NO: 40). In an embodiment, the unimolecular, or chimeric, gRNA molecule is a S. aureus gRNA molecule.

The sequences and structures of exemplary chimeric gRNAs are also shown in Figs. 1H-

II. Exemplary Modular gRNAs

In an embodiment, a modular gRNA comprises:

a first strand comprising, preferably from 5' to 3' ;

a targeting domain, e.g., comprising 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,

25, or 26 nucleotides;

a first complementarity domain; and

a second strand, comprising, preferably from 5' to 3':

optionally a 5' extension domain;

a second complementarity domain;

a proximal domain; and

a tail domain,

wherein:

(a) the proximal and tail domain, when taken together, comprise

at least 15, 18, 20, 25, 30, 31, 35, 40, 45, 49, 50, or 53 nucleotides;

(c) there are at least 16, 19, 21, 26, 31, 32, 36, 41, 46, 50, 51, or 54 nucleotides 3' to the last nucleotide of the second complementarity domain that is complementary to its corresponding nucleotide of the first complementarity domain.

In an embodiment, the sequence from (a), (b), or (c), has at least 60, 75, 80, 85, 90, 95, or 99% homology with the corresponding sequence of a naturally occurring gRNA, or with a gRNA described herein.

In an embodiment, the proximal and tail domain, when taken together, comprise at least

15, 18, 20, 25, 30, 31, 35, 40, 45, 49, 50, or 53 nucleotides.

complementary to its corresponding nucleotide of the first complementarity domain. In an embodiment, the targeting domain comprises, has, or consists of, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26 nucleotides (e.g., 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26 nucleotides in length. In an embodiment, the targeting domain comprises, has, or consists of, 16 nucleotides (e.g., 16 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 16 nucleotides in length.

In an embodiment, the targeting domain has, or consists of, 17 nucleotides (e.g., 17 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 17 nucleotides in length.

In an embodiment, the targeting domain has, or consists of, 18 nucleotides (e.g., 18 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 18 nucleotides in length.

In an embodiment, the targeting domain comprises, has, or consists of, 20 nucleotides (e.g., 20 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 20 nucleotides in length.

In an embodiment, the targeting domain comprises, has, or consists of, 21 nucleotides (e.g., 21 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 21 nucleotides in length.

In an embodiment, the targeting domain comprises, has, or consists of, 23 nucleotides

(e.g., 23 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 23 nucleotides in length.

In an embodiment, the targeting domain comprises, has, or consists of, 24 nucleotides (e.g., 24 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 24 nucleotides in length. In an embodiment, the targeting domain comprises, has, or consists of, 25 nucleotides (e.g., 25 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 5 nucleotides in length.

In an embodiment, the targeting domain comprises, has, or consists of, 16 nucleotides (e.g., 16 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 16 nucleotides in length; and there are at least 15, 18, 20, 25, 30, 31, 35, 40,

(e.g., 16 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 16 nucleotides in length; and there are at least 16, 19, 21, 26, 31, 32, 36, 41,

In an embodiment, the targeting domain has, or consists of, 17 nucleotides (e.g., 17 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 17 nucleotides in length; and the proximal and tail domain, when taken together, comprise at least 15, 18, 20, 25, 30, 31, 35, 40, 45, 49, 50, or 53 nucleotides.

In an embodiment, the targeting domain has, or consists of, 17 nucleotides (e.g., 17 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 17 nucleotides in length; and there are at least 15, 18, 20, 25, 30, 31, 35, 40, 45, 49, 50, or 53 nucleotides 3' to the last nucleotide of the second complementarity domain.

In an embodiment, the targeting domain has, or consists of, 17 nucleotides (e.g., 17 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 17 nucleotides in length; and there are at least 16, 19, 21, 26, 31, 32, 36, 41, 46, 50, 51, or 54 nucleotides 3' to the last nucleotide of the second complementarity domain that is complementary to its corresponding nucleotide of the first complementarity domain.

In an embodiment, the targeting domain has, or consists of, 18 nucleotides (e.g., 18 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 18 nucleotides in length; and the proximal and tail domain, when taken together, comprise at least 15, 18, 20, 25, 30, 31, 35, 40, 45, 49, 50, or 53 nucleotides.

In an embodiment, the targeting domain has, or consists of, 18 nucleotides (e.g., 18 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 18 nucleotides in length; and there are at least 15, 18, 20, 25, 30, 31, 35, 40, 45, 49, 50, or 53 nucleotides 3' to the last nucleotide of the second complementarity domain.

In an embodiment, the targeting domain has, or consists of, 18 nucleotides (e.g., 18 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 18 nucleotides in length; and there are at least 16, 19, 21, 26, 31, 32, 36, 41, 46, 50, 51, or 54 nucleotides 3' to the last nucleotide of the second complementarity domain that is complementary to its corresponding nucleotide of the first complementarity domain.

In an embodiment, the targeting domain comprises, has, or consists of, 19 nucleotides (e.g., 19 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 19 nucleotides in length; and the proximal and tail domain, when taken together, comprise at least 15, 18, 20, 25, 30, 31, 35, 40, 45, 49, 50, or 53 nucleotides.

(e.g., 19 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 19 nucleotides in length; and there are at least 15, 18, 20, 25, 30, 31, 35, 40,

In an embodiment, the targeting domain comprises, has, or consists of, 19 nucleotides (e.g., 19 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 19 nucleotides in length; and there are at least 16, 19, 21, 26, 31, 32, 36, 41,

In an embodiment, the targeting domain comprises, has, or consists of, 20 nucleotides (e.g., 20 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 20 nucleotides in length; and the proximal and tail domain, when taken together, comprise at least 15, 18, 20, 25, 30, 31, 35, 40, 45, 49, 50, or 53 nucleotides.

In an embodiment, the targeting domain comprises, has, or consists of, 20 nucleotides (e.g., 20 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 20 nucleotides in length; and there are at least 15, 18, 20, 25, 30, 31, 35, 40, 45, 49, 50, or 53 nucleotides 3' to the last nucleotide of the second complementarity domain.

In an embodiment, the targeting domain comprises, has, or consists of, 20 nucleotides (e.g., 20 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 20 nucleotides in length; and there are at least 16, 19, 21, 26, 31, 32, 36, 41, 46, 50, 51, or 54 nucleotides 3' to the last nucleotide of the second complementarity domain that is complementary to its corresponding nucleotide of the first complementarity domain.

In an embodiment, the targeting domain comprises, has, or consists of, 21 nucleotides (e.g., 21 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 21 nucleotides in length; and there are at least 15, 18, 20, 25, 30, 31, 35, 40,

In an embodiment, the targeting domain comprises, has, or consists of, 21 nucleotides

(e.g., 21 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 21 nucleotides in length; and there are at least 16, 19, 21, 26, 31, 32, 36, 41,

(e.g., 22 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 22 nucleotides in length; and the proximal and tail domain, when taken together, comprise at least 15, 18, 20, 25, 30, 31, 35, 40, 45, 49, 50, or 53 nucleotides.

In an embodiment, the targeting domain comprises, has, or consists of, 22 nucleotides (e.g., 22 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 22 nucleotides in length; and there are at least 15, 18, 20, 25, 30, 31, 35, 40,

In an embodiment, the targeting domain comprises, has, or consists of, 23 nucleotides (e.g., 23 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 23 nucleotides in length; and there are at least 16, 19, 21, 26, 31, 32, 36, 41, 46, 50, 51, or 54 nucleotides 3' to the last nucleotide of the second complementarity domain that is complementary to its corresponding nucleotide of the first complementarity domain.

In an embodiment, the targeting domain comprises, has, or consists of, 24 nucleotides (e.g., 24 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 24 nucleotides in length; and the proximal and tail domain, when taken together, comprise at least 15, 18, 20, 25, 30, 31, 35, 40, 45, 49, 50, or 53 nucleotides.

(e.g., 24 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 24 nucleotides in length; and there are at least 15, 18, 20, 25, 30, 31, 35, 40, 45, 49, 50, or 53 nucleotides 3' to the last nucleotide of the second complementarity domain.

In an embodiment, the targeting domain comprises, has, or consists of, 24 nucleotides (e.g., 24 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 24 nucleotides in length; and there are at least 16, 19, 21, 26, 31, 32, 36, 41, 46, 50, 51, or 54 nucleotides 3' to the last nucleotide of the second complementarity domain that is complementary to its corresponding nucleotide of the first complementarity domain.

In an embodiment, the targeting domain comprises, has, or consists of, 26 nucleotides (e.g., 26 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 26 nucleotides in length; and the proximal and tail domain, when taken together, comprise at least 15, 18, 20, 25, 30, 31, 35, 40, 45, 49, 50, or 53 nucleotides.

(e.g., 26 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 26 nucleotides in length; and there are at least 15, 18, 20, 25, 30, 31, 35, 40,

In an embodiment, the targeting domain comprises, has, or consists of, 26 nucleotides (e.g., 26 consecutive nucleotides) having complementarity with the target domain, e.g., the targeting domain is 26 nucleotides in length; and there are at least 16, 19, 21, 26, 31, 32, 36, 41,

46, 50, 51, or 54 nucleotides 3' to the last nucleotide of the second complementarity domain that is complementary to its corresponding nucleotide of the first complementarity domain. II. Methods for Designing gRNAs

Methods for designing gRNAs are described herein, including methods for selecting, designing and validating target domains. Exemplary targeting domains are also provided herein. Targeting Domains discussed herein can be incorporated into the gRNAs described herein.

Methods for selection and validation of target sequences as well as off-target analyses are described, e.g., in Mali et al., 2013 Science 339(6121): 823-826; Hsu et al. Nat Biotechnol, 31(9): 827-32; Fu et al., 2014 Nat Biotechnol, doi: 10.1038/nbt.2808. PubMed PMID: 24463574; Heigwer et al., 2014 Nat Methods l l(2): 122-3. doi: 10.1038/nmeth.2812. PubMed PMID:

24481216; Bae et al., 2014 Bioinformatics PubMed PMID: 24463181; Xiao A et al., 2014 Bioinformatics PubMed PMID: 24389662.

For example, a software tool can be used to optimize the choice of gRNA within a user's target sequence, e.g., to minimize total off-target activity across the genome. Off target activity may be other than cleavage. For each possible gRNA choice using S. pyogenes Cas9, software tools can identify all potential off-target sequences (preceding either NAG or NGG PAMs) across the genome that contain up to a certain number (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of mismatched base-pairs. The cleavage efficiency at each off-target sequence can be predicted, e.g., using an experimentally-derived weighting scheme. Each possible gRNA can then ranked according to its total predicted off-target cleavage; the top-ranked gRNAs represent those that are likely to have the greatest on-target and the least off-target cleavage. Other functions, e.g., automated reagent design for gRNA vector construction, primer design for the on-target

Surveyor assay, and primer design for high-throughput detection and quantification of off -target cleavage via next-generation sequencing, can also be included in the tool. Candidate gRNA molecules can be evaluated by art-known methods or as described in Section IV herein.

Guide RNAs (gRNAs) for use with S. pyogenes, S. aureus and N. meningitidis Cas9s were identified using a DNA sequence searching algorithm. Guide RNA design was carried out using a custom guide RNA design software based on the public tool cas-offinder (reference:Cas- OFFinder: a fast and versatile algorithm that searches for potential off-target sites of Cas9 RNA- guided endonucleases., Bioinformatics. 2014 Feb 17. Bae S, Park J, Kim JS. PMID:24463181). Said custom guide RNA design software scores guides after calculating their genomewide off- target propensity. Typically matches ranging from perfect matches to 7 mismatches are considered for guides ranging in length from 17 to 24. Once the off-target sites are computationally determined , an aggregate score is calculated for each guide and summarized in a tabular output using a web-interface. In addition to identifying potential gRNA sites adjacent to PAM sequences, the software also identifies all PAM adjacent sequences that differ by 1, 2, 3 or more nucleotides from the selected gRNA sites. Genomic DNA sequence for each gene was obtained from the UCSC Genome browser and sequences were screened for repeat elements using the publically available RepeatMasker program. RepeatMasker searches input DNA sequences for repeated elements and regions of low complexity. The output is a detailed annotation of the repeats present in a given query sequence.

Following identification, gRNAs were ranked into tiers based on their distance to the target site, their orthogonality or presence of a 5' G (based on identification of close matches in the human genome containing a relavant PAM (e.g., in the case of S. pyogenes, a NGG PAM, in the case of S. aureus, a NNGRRT or NNGRRV PAM, and in the case of N. meningitidis, a NNNNGATT or NNNNGCTT PAM). Orthogonality refers to the number of sequences in the human genome that contain a minimum number of mismatches to the target sequence. A "high level of orthogonality" or "good orthogonality" may, for example, refer to 20-mer gRNAs that have no identical sequences in the human genome besides the intended target, nor any sequences that contain one or two mismatches in the target sequence. Targeting domains with good orthogonality are selected to minimize off-target DNA cleavage.

As an example, for S. pyogenes and N. meningitidis targets, 17-mer, or 20-mer gRNAs were designed. As another example, for S. aureus targets, 18-mer, 19-mer, 20-mer, 21-mer, 22- mer, 23-mer and 24-mer gRNAs were designed. Tarteting domains, disclosed herein, may comprise the 17-mer described in Tables 1A-1D, 2A-2F, 3A-3C, 4A-4E, 5A-5E, 6A-6B, 7A- 7D, 8A-8D, 9, 10A-10D, 11A-11D, 12, 13A-13D, 14A-14C, 15A-15D, 16A-16E, 17A-17B, 18A-18C, 19A-19E, 20A-20C, 21A-21E, 22A-22E, 23A-23C, 24A-24D, 25A-25B, 26, or 31, e.g., the targeting domains of 18 or more nucleotides may comprise the 17-mer gRNAs described in Tables 1A-1D, 2A-2F, 3A-3C, 4A-4E, 5A-5E, 6A-6B, 7A-7D, 8A-8D, 9, 10A-10D, 11A- 11D, 12, 13A-13D, 14A-14C, 15A-15D, 16A-16E, 17A-17B, 18A-18C, 19A-19E, 20A-20C, 21A-21E, 22A-22E, 23A-23C, 24A-24D, 25A-25B, 26, or 31. Tarteting domains, disclosed herein, may comprises the 18-mer described in Tables 1A-1D, 2A-2F, 3A-3C, 4A-4E, 5A-5E, 6A-6B, 7A-7D, 8A-8D, 9, 10A-10D, 11A-11D, 12, 13A-13D, 14A-14C, 15A-15D, 16A-16E, 17A-17B, 18A-18C, 19A-19E, 20A-20C, 21A-21E, 22A-22E, 23A-23C, 24A-24D, 25A-25B, 26, or 31, e.g., the targeting domains of 19 or more nucleotides may comprise the 18-mer gRNAs described in Tables 1A-1D, 2A-2F, 3A-3C, 4A-4E, 5A-5E, 6A-6B, 7A-7D, 8A-8D, 9, 10A-10D, 11A-11D, 12, 13A-13D, 14A-14C, 15A-15D, 16A-16E, 17A-17B, 18A-18C, 19A- 19E, 20A-20C, 21A-21E, 22A-22E, 23A-23C, 24A-24D, 25A-25B, 26, or 31. Tarteting domains, disclosed herein, may comprises the 19-mer described in Tables 1A-1D, 2A-2F, 3A- 3C, 4A-4E, 5A-5E, 6A-6B, 7A-7D, 8A-8D, 9, 10A-10D, 11A-11D, 12, 13A-13D, 14A-14C, 15A-15D, 16A-16E, 17A-17B, 18A-18C, 19A-19E, 20A-20C, 21A-21E, 22A-22E, 23A-23C, 24A-24D, 25A-25B, 26, or 31, e.g., the targeting domains of 20 or more nucleotides may comprise the 19-mer gRNAs described in Tables 1A-1D, 2A-2F, 3A-3C, 4A-4E, 5A-5E, 6A- 6B, 7A-7D, 8A-8D, 9, 10A-10D, 11A-11D, 12, 13A-13D, 14A-14C, 15A-15D, 16A-16E, 17A- 17B, 18A-18C, 19A-19E, 20A-20C, 21A-21E, 22A-22E, 23A-23C, 24A-24D, 25A-25B, 26, or 31. Tarteting domains, disclosed herein, may comprises the 20-mer gRNAs described in Tables 1A-1D, 2A-2F, 3A-3C, 4A-4E, 5A-5E, 6A-6B, 7A-7D, 8A-8D, 9, 10A-10D, 11A-11D, 12, 13A-13D, 14A-14C, 15A-15D, 16A-16E, 17A-17B, 18A-18C, 19A-19E, 20A-20C, 21A-21E, 22A-22E, 23A-23C, 24A-24D, 25A-25B, 26, or 31, e.g., the targeting domains of 21 or more nucleotides may comprise the 20-mer gRNAs described in Tables 1A-1D, 2A-2F, 3A-3C, 4A- 4E, 5A-5E, 6A-6B, 7A-7D, 8A-8D, 9, 10A-10D, 11A-11D, 12, 13A-13D, 14A-14C, 15A-15D, 16A-16E, 17A-17B, 18A-18C, 19A-19E, 20A-20C, 21A-21E, 22A-22E, 23A-23C, 24A-24D, 25A-25B, 26, or 31. Tarteting domains, disclosed herein, may comprises the 21-mer described in Tables 1A-1D, 2A-2F, 3A-3C, 4A-4E, 5A-5E, 6A-6B, 7A-7D, 8A-8D, 9, 10A-10D, 11A-11D, 12, 13A-13D, 14A-14C, 15A-15D, 16A-16E, 17A-17B, 18A-18C, 19A-19E, 20A-20C, 21A- 21E, 22A-22E, 23A-23C, 24A-24D, 25A-25B, 26, or 31, e.g., the targeting domains of 22 or more nucleotides may comprise the 21-mer gRNAs described in Tables 1A-1D, 2A-2F, 3A-3C, 4A-4E, 5A-5E, 6A-6B, 7A-7D, 8A-8D, 9, 10A-10D, 11A-11D, 12, 13A-13D, 14A-14C, 15A- 15D, 16A-16E, 17A-17B, 18A-18C, 19A-19E, 20A-20C, 21A-21E, 22A-22E, 23A-23C, 24A- 24D, 25A-25B, 26, or 31. Tarteting domains, disclosed herein, may comprises the 22-mer described in Tables 1A-1D, 2A-2F, 3A-3C, 4A-4E, 5A-5E, 6A-6B, 7A-7D, 8A-8D, 9, 10A- 10D, 11A-11D, 12, 13A-13D, 14A-14C, 15A-15D, 16A-16E, 17A-17B, 18A-18C, 19A-19E, 20A-20C, 21A-21E, 22A-22E, 23A-23C, 24A-24D, 25A-25B, 26, or 31, e.g., the targeting domains of 23 or more nucleotides may comprise the 22-mer gRNAs described in Tables 1A- 1D, 2A-2F, 3A-3C, 4A-4E, 5A-5E, 6A-6B, 7A-7D, 8A-8D, 9, 10A-10D, 11A-11D, 12, 13A- 13D, 14A-14C, 15A-15D, 16A-16E, 17A-17B, 18A-18C, 19A-19E, 20A-20C, 21A-21E, 22A- 22E, 23A-23C, 24A-24D, 25A-25B, 26, or 31. Tarteting domains, disclosed herein, may comprises the 23-mer described in Tables 1A-1D, 2A-2F, 3A-3C, 4A-4E, 5A-5E, 6A-6B, 7A- 7D, 8A-8D, 9, 10A-10D, 11A-11D, 12, 13A-13D, 14A-14C, 15A-15D, 16A-16E, 17A-17B, 18A-18C, 19A-19E, 20A-20C, 21A-21E, 22A-22E, 23A-23C, 24A-24D, 25A-25B, 26, or 31,e.g., the targeting domains of 24 or more nucleotides may comprise the 23-mer gRNAs described in Tables 1A-1D, 2A-2F, 3A-3C, 4A-4E, 5A-5E, 6A-6B, 7A-7D, 8A-8D, 9, 10A- 10D, 11A-11D, 12, 13A-13D, 14A-14C, 15A-15D, 16A-16E, 17A-17B, 18A-18C, 19A-19E, 20A-20C, 21A-21E, 22A-22E, 23A-23C, 24A-24D, 25A-25B, 26, or 31. Tarteting domains, disclosed herein, may comprises the 24-mer described in Tables 1A-1D, 2A-2F, 3A-3C, 4A-4E, 5A-5E, 6A-6B, 7A-7D, 8A-8D, 9, 10A-10D, 11A-11D, 12, 13A-13D, 14A-14C, 15A-15D, 16A- 16E, 17A-17B, 18A-18C, 19A-19E, 20A-20C, 21A-21E, 22A-22E, 23A-23C, 24A-24D, 25A- 25B, 26, or 31, e.g., the targeting domains of 25 or more nucleotides may comprise the 24-mer gRNAs described in Tables 1A-1D, 2A-2F, 3A-3C, 4A-4E, 5A-5E, 6A-6B, 7A-7D, 8A-8D, 9, 10A-10D, 11A-11D, 12, 13A-13D, 14A-14C, 15A-15D, 16A-16E, 17A-17B, 18A-18C, 19A- 19E, 20A-20C, 21A-21E, 22A-22E, 23A-23C, 24A-24D, 25A-25B, 26, or 31.

gRNAs were identified for both single-gRNA nuclease cleavage and for a dual-gRNA paired "nickase" strategy. Criteria for selecting gRNAs and the determination for which gRNAs can be used for the dual-gRNA paired "nickase" strategy is based on two considerations:

1. gRNA pairs should be oriented on the DNA such that PAMs are facing out and

cutting with the D10A Cas9 nickase will result in 5' overhangs.

2. An assumption that cleaving with dual nickase pairs will result in deletion of the entire intervening sequence at a reasonable frequency. However, cleaving with dual nickase pairs can also result in indel mutations at the site of only one of the gRNAs. Candidate pair members can be tested for how efficiently they remove the entire sequence versus causing indel mutations at the site of one gRNA.

The targeting domains discussed herein can be incorporated into the gRNAs described herein. Strategies to identify gRNAs for S. pyogenes, S. Aureus, and N. meningitidis to correct a mutation in the HBB gene

gRNAs were designed for use with S. pyogenes, and S. aureus Cas9 enzymes to target the E6V mutation in the HBB gene. As an example, three strategies were utilized to identify gRNAs for use with S. pyogenes, S. aureus and N. meningitidis Cas9 enzymes.

In one strategy, the gRNAs were identified and ranked into 3 tiers for S. pyogenes

(Tables 1A-1C). The targeting domains for tier 1 gRNA molecules for use with the S. pyogenes Cas9 to target the E6V mutation in the HBB gene were selected based on (1) a reasonable distance to the target position, and (2) a high level of orthogonality. Tier 2 gRNAs were selected based on (1), a reasonable distance to the target position, and (2) presence of a 5'G. Tier 3 used the same distance restriction, but removed the requirement of good orthogonality and the

5'G. Note that tiers are non-inclusive (each gRNA is listed only once). gRNAs for use with the S. aureus (Table ID J, Cas9s were identified manually by scanning genomic DNA sequence for the presence of PAM sequences. These gRNAs were not separated into tiers, but were listed in a single list.

In a second strategy, the gRNAs were identified and ranked into 4 tiers for S. pyogenes (Tables 13A-13D) and 5 tiers for S. aureus (Tables 14A-14C). The targeting domain for tier 1 gRNA molecules to use with S. pyogenes Cas9 were selected based on (1) a short distance to the target position, e.g., within lOObp upstream and lOObp downstream of the mutation, (2) a high level of orthogonality, and (3) the presence of a 5' G. For selection of tier 2 gRNAs, a short distance and high orthogonality were required but the presence of a 5'G was not required. Tier 3 uses the same distance restriction and the requirement for a 5'G, but removes the requirement of good orthogonality. Tier 4 uses the same distance restriction but removes the requirement of good orthogonality and the 5'G. The targeting domain for tier 1 gRNA molecules to use with S. aureus Cas9 were selected based on (1) a short distance to the target position, e.g., within lOObp upstream and lOObp downstream of the mutation, (2) a high level of orthogonality, and (3) the presence of a 5' G. For selection of tier 2 gRNAs, a short distance and high orthogonality were required but the presence of a 5'G was not required. Tier 3 uses the same distance restriction and the requirement for a 5'G, but removes the requirement of good orthogonality. Tier 4 uses the same distance restriction but removes the requirement of good orthogonality and the 5'G.

Tier 5 is selected based on (1) a short distance to the target position, e.g., within lOObp upstream and lOObp downstream of the mutation and (2) PAM is NNGRRV. Note that tiers are non- inclusive (each gRNA is listed only once for the strategy). In certain instances, no gRNA was identified based on the criteria of the particular tier. In some instances, there are no

corresponding exemplary gRNAs in certain tiers.

In a third strategy, the gRNAs were identified and ranked into 3 tiers for S. pyogenes

(Tables 24A-24D), 4 tiers for S. aureus (Tables 25A-25B) and 3 tiers for N. meningitidis

(Tables 26). The targeting domain for tier 1 gRNA molecules to use with S. pyogenes Cas9 were selected based on (1) distance to the target position, e.g., within 200bp upstream and 200bp downstream of the mutation and (2) a high level of orthogonality. The targeting domain for tier 2 gRNA molecules to use with S. pyogenes Cas9 were selected based on (1) distance to the target position, e.g., within 200bp upstream and 200bp downstream of the mutation and (2) the presence of a 5'G. The targeting domain for tier 3 gRNA molecules to use with S. pyogenes Cas9 were selected based on distance to the target position, e.g., within 200bp upstream and 200bp downstream of the mutation. The targeting domain for tier 1 gRNA molecules to use with S. aureus Cas9 were selected based on (1) distance to the target position, e.g., within 200bp upstream and 200bp downstream of the mutation, (2) a high level of orthogonality and (3) PAM is NNGRRT. The targeting domain for tier 2 gRNA molecules to use with S. aureus Cas9 were selected based on (1) distance to the target position, e.g., within 200bp upstream and 200bp downstream of the mutation, (2) the presence of a 5'G, and (3) PAM is NNGRRT. The targeting domain for tier 3 gRNA molecules to use with S. aureus Cas9 were selected based on (1) distance to the target position, e.g., within 200bp upstream and 200bp downstream of the mutation and (2) PAM is NNGRRT. The targeting domain for tier 4 gRNA molecules to use with S. aureus Cas9 were selected based on (1) distance to the target position, e.g., within 200bp upstream and 200bp downstream of the mutation and (2) PAM is NNGRRV. The targeting domain for tier 1 gRNA molecules to use with N. meningitidis Cas9 were selected based on (1) distance to the target position, e.g., within 200bp upstream and 200bp downstream of the mutation and (2) a high level of orthogonality. The targeting domain for tier 2 gRNA molecules to use with N. meningitidis Cas9 were selected based on (1) distance to the target position, e.g., within 200bp upstream and 200bp downstream of the mutation and (2) the presence of a 5'G. The targeting domain for tier 3 gRNA molecules to use with N. meningitidis Cas9 were selected based on distance to the target position, e.g., within 200bp upstream and 200bp downstream of the mutation.

In an embodiment, dual targeting (e.g., dual nicking) is used to create two nicks on opposite DNA strands by using S. pyogenes, S. aureus and N. meningitidis Cas9 nickases with two targeting domains that are complementary to opposite DNA strands, e.g., a gRNA comprising any minus strand targeting domain may be paired any gRNA comprising a plus strand targeting domain provided that the two gRNAs are oriented on the DNA such that PAMs face outward and the distance between the 5' ends of the gRNAs is 0-50bp. Exemplary nickase pairs including selecting a targeting domain from Group A and a second targeting domain from Group B in Table 24D (for S. pyogenes). It is contemplated herein that in an embodiment a targeting domain of Group A can be combined with any of the targeting domains of Group B in Table 24D (for S. pyogenes). For example, HBB-9, HBB-20can be combined with HBB-11, HBB-39. Strategies to identify gRNAs for S. pyogenes, S. Aureus, and N. meningitidis to knock out the BCL11 A gene

gRNAs were designed for use with S. pyogenes, S. aureus and N. meningitidis Cas9 enzymes to induce an insertion or deletion of one or more nucleotides mediated by NHEJ in close proximity to or within the early coding region. As an example, three strategies were utilized to identify gRNAs for use with S. pyogenes, S. aureus and N. meningitidis Cas9 enzymes.

In onestrategy, the gRNAs were identified and ranked into 4 tires for S. pyogenes (Tables 2A-2D). The targeting domains for tier 1 gRNA molecules for use with the S. pyogenes Cas9 to knockout the BCL11A gene were selected based on (1) a reasonable distance to the target position, and (2) a high level of orthogonality. Tier 2 gRNAs were selected based on (1), a reasonable distance to the target position, and (2) presence of a 5'G. Tier 3 used the same distance restriction, but removed the requirement of good orthogonality and the 5'G. Tier 4 only required the presence in the coding sequence. Note that tiers are non-inclusive (each gRNA is listed only once). gRNAs for use with the S. aureus (Table 2E), and N. meningitidis (Table 2FJ Cas9s were identified manually by scanning genomic DNA sequence for the presence of PAM sequences. These gRNAs were not separated into tiers, but were listed in a single list. Note that tiers are non-inclusive (each gRNA is listed only once for the strategy). In certain instances, no gRNA was identified based on the criteria of the particular tier.

In a second strategy, the gRNAs were identified and ranked into 5 tiers for S. pyogenes (Tables 4A-4E), and S. aureus (Tables 5A-5E); and 2 tiers for N. meningitidis (Tables 6A-6B). For S. pyogenes, and S. aureus, the targeting domain for tier 1 gRNA molecules were selected based on (1) distance to a target site (e.g., start codon), e.g., within 500bp (e.g., downstream) of the target site (e.g., start codon), (2) a high level of orthogonality and (3) the presence of 5'G. The targeting domain for tier 2 gRNA molecules were selected based on (1) distance to a target site (e.g., start codon), e.g., within 500bp (e.g., downstream) of the target site (e.g., start codon) and (2) a high level of orthogonality. The targeting domain for tier 3 gRNA molecules were selected based on (1) distance to a target site (e.g., start codon), e.g., within 500bp (e.g., downstream) of the target site (e.g., start codon) and (2) the presence of 5'G. The targeting domain for tier 4 gRNA molecules were selected based on distance to a target site (e.g., start codon), e.g., within 500bp (e.g., downstream) of the target site (e.g., start codon). The targeting domain for tier 5 gRNA molecules were selected based on distance to the target site (e.g., start codon), e.g., within reminder of the coding sequence, e.g., downstream of the first 500bp of coding sequence (e.g., anywhere from +500 (relative to the start codon) to the stop codon). For N. meningitidis, the targeting domain for tier 1 gRNA molecules were selected based on (1) distance to a target site (e.g., start codon), e.g., within 500bp (e.g., downstream) of the target site (e.g., start codon). The targeting domain for tier 2 gRNA molecules were selected based on distance to the target site (e.g., start codon), e.g., within reminder of the coding sequence, e.g., downstream of the first 500bp of coding sequence (e.g., anywhere from +500 (relative to the start codon) to the stop codon). Note that tiers are non-inclusive (each gRNA is listed only once for the strategy). In certain instances, no gRNA was identified based on the criteria of the particular tier.

In a third strategy, the gRNAs were identified and ranked into 3 tiers for S. pyogenes (Tables 15A-15D), and N. meningitidis (Tables 17A-17B); and 5 tiers for S. aureus (Tables 16A-16D). The targeting domain to be used with S. pyogenes Cas9 enzymes for tier 1 gRNA molecules were selected based on (1) distance to a target site (e.g., start codon), e.g., within 500bp (e.g., downstream) of the target site (e.g., start codon) and (2) a high level of

orthogonality. The targeting domain to be used with S. pyogenes Cas9 enzymes for tier 2 gRNA molecules were selected based on (1) distance to the target site (e.g., start codon), e.g., within 500bp (e.g., downstream) of the target site (e.g., start codon). The targeting domain to be used with S. pyogenes Cas9 enzymes for tier 3 gRNA molecules were selected based on distance to the target site (e.g., start codon), e.g., within reminder of the coding sequence, e.g., downstream of the first 500bp of coding sequence (e.g., anywhere from +500 (relative to the start codon) to the stop codon). The gRNAs were identified and ranked into 5 tiers for S. aureus, when the relevant PAM was NNGRRT or NNGRRV. The targeting domain to be used with S. aureus Cas9 enzymes for tier 1 gRNA molecules were selected based on (1) distance to the target site (e.g., start codon), e.g., within 500bp (e.g., downstream) of the target site (e.g., start codon), (2) a high level of orthogonality, and (3) PAM is NNGRRT. The targeting domain to be used with S. aureus Cas9 enzymes for tier 2 gRNA molecules were selected based on (1) distance to the target site (e.g., start codon), e.g., within 500bp (e.g., downstream) of the target site (e.g., start codon), and (2) PAM is NNGRRT. The targeting domain to be used with S. aureus Cas9 enzymes for tier 3 gRNA molecules were selected based on (1) distance to a the target site (e.g., start codon) mutation, e.g., within 500bp (e.g., downstream) of the target site (e.g., start codon), and (2) PAM is NNGRRV. The targeting domain to be used with S. aureus Cas9 enzymes for tier 4 gRNA molecules were selected based on (1) distance to the target site (e.g., start codon), e.g., within reminder of the coding sequence, e.g., downstream of the first 500bp of coding sequence (e.g., anywhere from +500 (relative to the start codon) to the stop codon), and (2) PAM is NNGRRT. The targeting domain to be used with S. aureus Cas9 enzymes for tier 5 gRNA molecules were selected based on (1) distance to the target site (e.g., start codon), e.g., within reminder of the coding sequence, e.g., downstream of the first 500bp of coding sequence (e.g., anywhere from +500 (relative to the start codon) to the stop codon), and (2) PAM is NNGRRV. The gRNAs were identified and ranked into 3 tiers for N. meningitidis. The targeting domain to be used with N. meningitidis Cas9 enzymes for tier 1 gRNA molecules were selected based on (1) distance to the target site, e.g., within 500bp (e.g., downstream) of the target site (e.g., start codon) and (2) a high level of orthogonality. The targeting domain to be used with N.

meningitidis Cas9 enzymes for tier 2 gRNA molecules were selected based on (1) distance to the target site (e.g., start codon), e.g., within 500bp (e.g., downstream) of the target site (e.g., start codon). The targeting domain to be used with N. meningitidis Cas9 enzymes for tier 3 gRNA molecules were selected based on distance to the target site (e.g., start codon), e.g., within reminder of the coding sequence, e.g., downstream of the first 500bp of coding sequence (e.g., anywhere from +500 (relative to the start codon) to the stop codon). Note that tiers are non- inclusive (each gRNA is listed only once for the strategy). In certain instances, no gRNA was identified based on the criteria of the particular tier.

In an embodiment, when a single gRNA molecule is used to target a Cas9 nickase to create a single strand break in close proximity to the BCLl 1A target position, e.g., the gRNA is used to target either upstream of (e.g., within 500 bp, e.g., within 200 bp upstream of the BCLl 1 A target position), or downstream of (e.g., within 500 bp, e.g., within 200 bp downstream of the BCLl 1A target position) in the BCL11A gene.

In an embodiment, when a single gRNA molecule is used to target a Cas9 nuclease to create a double strand break to in close proximity to the BCLl 1 A target position, e.g., the gRNA is used to target either upstream of (e.g., within 500 bp, e.g., within 200 bp upstream of the BCLl 1 A target position), or downstream of (e.g., within 500 bp, e.g., within 200 bp downstream of the BCLl 1A target position) in the BCL11A gene.

In an embodiment, dual targeting is used to create two double strand breaks to in closeproximity to the mutation, e.g., the gRNA is used to target either upstream of (e.g., within 500 bp, e.g., within 200 bp upstream of the BCLl 1A target position), or downstream of (e.g., within 500 bp, e.g., within 200 bp downstream of the BCLl 1A target position) in the BCL11A gene. In an embodiment, the first and second gRNAs are used to target two Cas9 nucleases to flank, e.g., the first of gRNA is used to target upstream of (e.g., within 500 bp, e.g., within 200 bp upstream of the BCLl 1 A target position), and the second gRNA is used to target downstream of (e.g., within 500 bp, e.g., within 200 bp downstream of the BCLl 1 A target position) in the BCLl 1 A gene.

In an embodiment, dual targeting is used to create a double strand break and a pair of single strand breaks to delete a genomic sequence including the BCLl 1 A target position. In an embodiment, the first, second and third gRNAs are used to target one Cas9 nuclease and two Cas9 nickases to flank, e.g., the first gRNA that will be used with the Cas9 nuclease is used to target upstream of (e.g., within 500 bp, e.g., within 200 bp upstream of the BCLl 1A target position) or downstream of (e.g., within 500 bp, e.g., within 200 bp downstream of the BCLl 1A target position), and the second and third gRNAs that will be used with the Cas9 nickase pair are used to target the opposite side of the mutation (e.g., within 200 bp upstream or downstream of the BCLl 1A target position) in the BCL11A gene.

In an embodiment, when four gRNAs (e.g., two pairs) are used to target four Cas9 nickases to create four single strand breaks to delete genomic sequence including the mutation, the first pair and second pair of gRNAs are used to target four Cas9 nickases to flank, e.g., the first pair of gRNAs are used to target upstream of (e.g., within 500 bp, e.g., within 200 bp upstream of the BCLl 1 A target position), and the second pair of gRNAs are used to target downstream of (e.g., within 500 bp, e.g., within 200 bp downstream of the BCLl 1A target position) in the BCLl 1 A gene.

In an embodiment, dual targeting (e.g., dual nicking) is used to create two nicks on opposite DNA strands by using S. pyogenes, S. aureus and N. meningitidis Cas9 nickases with two targeting domains that are complementary to opposite DNA strands, e.g., a gRNA

comprising any minus strand targeting domain may be paired any gRNA comprising a plus strand targeting domain provided that the two gRNAs are oriented on the DNA such that PAMs face outward and the distance between the 5' ends of the gRNAs is 0-50bp. Exemplary nickase pairs including selecting a targeting domain from Group A and a second targeting domain from Group B, or including selecting a targeting domain from Group C and a second targeting domain from Group D in Table 15D (for S. pyogenes). It is contemplated herein that in an embodiment a targeting domain of Group A can be combined with any of the targeting domains of Group B; in an embodiment a targeting domain of Group C can be combined with any of the targeting domains of Group D in Table 15D (for S. pyogenes). For example, BCLl 1A-5355 or BCLl 1 A- 5380 can be combined with BCLl 1A-5321 or BCLl 1A-5416; or BCLl 1A-5333, BCLl 1A-5354, or BCLl lA-5329 can be combined with BCLl lA-5367 or BCLl lA-5341. Strategies to identify gRNAs for S. pyogenes, S. Aureus, and N. meningitidis to knock down the BCLl 1 A gene

gRNAs were designed for use with S. pyogenes, S. aureus and N. meningitidis one or more Cas9 molecules, e.g., enzymatically inactive Cas9 (eiCas9) molecules or Cas9 fusion proteins (e.g., an eiCas9 fused to a transcription repressor domain or chromatin modifying protein to alter (e.g., to block, reduce, or decrease) the transcription of the BCLl 1 A gene. As an example, three strategies were utilized to identify gRNAs for use with S. pyogenes, S. aureus and N. meningitidis one or more Cas9 molecules.

In one strategy, the targeting domains for gRNA molecules to knockdown the BCL11A gene were desgined to target the lkb of sequence 3' of the start codon. They were listed in a single list for S. pyogenes (Table 3A), S. aureus (Table 3B) and N. meningitidis (Table 3CJ.

In a second strategy, the gRNAs were identified and ranked into 4 tiers for S. pyogenes (Tables 10A-10D), and S. aureus (Tables 11A-11D). The gRNAs were identified and listed in a single list for N. meningitidis (Table 12). For S. pyogenes, and S. aureus, the targeting domain for tier 1 gRNA molecules were selected based on (1) distance to a target site (e.g., a

transcription start site), e.g., within 500bp (e.g., upstream or downstream) of the target site (e.g., the transcription start site) , (2) a high level of orthogonality and (3) the presence of 5'G. The targeting domain for tier 2 gRNA molecules were selected based on (1) distance to a target site (e.g., the transcription start site), e.g., within 500bp (e.g., upstream or downstream) of the target site (e.g., the transcription start site) and (2) a high level of orthogonality. The targeting domain for tier 3 gRNA molecules were selected based on (1) distance to a target site (e.g., the transcription start site), e.g., within 500bp (e.g., upstream or downstream) of the target site (e.g., the transcription start site) and (2) the presence of 5'G. The targeting domain for tier 4 gRNA molecules were selected based on distance to a target site (e.g., the transcription start site), e.g., within 500bp (e.g., upstream or downstream) of the target site (e.g., the transcription start site).

In a third strategy, gRNAs were designed for use with S. pyogenes, S. aureus and N. meningitidis Cas9 molecules. The gRNAs were identified and ranked into 3 tiers for S. pyogenes (Tables 18A-18C). The targeting domain to be used with S. pyogenes Cas9 enzymes for tier 1 gRNA molecules were selected based on (1) distance to a target site (e.g., the transcription start site), e.g., within 500bp (e.g., upstream or downstream) of the target site (e.g., the transcription start site) and (2) a high level of orthogonality. The targeting domain to be used with S.

pyogenes Cas9 enzymes for tier 2 gRNA molecules were selected based on (1) distance to the target site (e.g., the transcription start site), e.g., within 500bp (e.g., upstream or downstream) of the target site (e.g., the transcription start site). The targeting domain to be used with S. pyogenes Cas9 enzymes for tier 3 gRNA molecules were selected based on distance to the target site (e.g., the transcription start site), e.g., within the additional 500 bp upstream and downstream of the transcription start site (i.e., extending to 1 kb upstream and downstream of the transcription start site. The gRNAs were identified and ranked into 5 tiers for S. aureus, when the relevant PAM was NNGRRT or NNGRRV (Tables 19A-19B). The targeting domain to be used with S. aureus Cas9 enzymes for tier 1 gRNA molecules were selected based on (1) distance to the target site (e.g., the transcription start site), e.g., within 500bp (e.g., upstream or downstream) of the target site (e.g., the transcription start site), (2) a high level of orthogonality, and (3) PAM is NNGRRT. The targeting domain to be used with S. aureus Cas9 enzymes for tier 2 gRNA molecules were selected based on (1) distance to the target site (e.g., the transcription start site), e.g., within 500bp (e.g., upstream or downstream) of the target site (e.g., the transcription start site), and (2) PAM is NNGRRT. The targeting domain to be used with S. aureus Cas9 enzymes for tier 3 gRNA molecules were selected based on (1) distance to a target site (e.g., the transcription start site), e.g., within 500bp (e.g., upstream or downstream) of the target site (e.g., the transcription start site), and (2) PAM is NNGRRV. The targeting domain to be used with S. aureus Cas9 enzymes for tier 4 gRNA molecules were selected based on (1) distance to the target site (e.g., the transcription start site), e.g., within the additional 500 bp upstream and downstream of the transcription start site (i.e., extending to 1 kb upstream and downstream of the transcription start site, and (2) PAM is NNGRRT. The targeting domain to be used with S. aureus Cas9 enzymes for tier 5 gRNA molecules were selected based on (1) distance to the target site (e.g., the transcription start site), e.g., within the additional 500 bp upstream and downstream of the transcription start site (i.e., extending to 1 kb upstream and downstream of the transcription start site, and (2) PAM is NNGRRV. The gRNAs were identified and ranked into 3 tiers for N.

meningitidis (Tables 20A-20C). The targeting domain to be used with N. meningitidis Cas9 enzymes for tier 1 gRNA molecules were selected based on (1) distance to a target site (e.g., the transcription start site), e.g., within 500bp (e.g., upstream or downstream) of the target site (e.g., the transcription start site) and (2) a high level of orthogonality. The targeting domain to be used with N. meningitidis Cas9 enzymes for tier 2 gRNA molecules were selected based on (1) distance to the target site (e.g., the transcription start site), e.g., within 500bp (e.g., upstream or downstream) of the target site (e.g., the transcription start site). The targeting domain to be used with N. meningitidis Cas9 enzymes for tier 3 gRNA molecules were selected based on distance to the target site (e.g., the transcription start site), e.g., within the additional 500 bp upstream and downstream of the transcription start site (i.e., extending to 1 kb upstream and downstream of the transcription start site. Note that tiers are non-inclusive (each gRNA is listed only once for the strategy). In certain instances, no gRNA was identified based on the criteria of the particular tier.

Strategies to identify gRNAs for S. pyogenes, S. Aureus, and N. meningitidis to remove (e.g., delete) the enhancer region the BCL11A gene

gRNAs were designed for use with S. pyogenes, S. aureus and N. meningitidis Cas9 enzymes to remove (e.g., delete) the enhancer region in the BCL11A gene. As an example, two strategies were utilized to identify gRNAs for use with S. pyogenes, S. aureus and N.

meningitidis one or more Cas9 molecules.

In an strategy, the gRNAs were identified and ranked into 4 tiers for S. pyogenes (Tables

7A-7D) and for S. aureus (Tables 8A-8D). The gRNAs were identified and listed in a single list for N. meningitidis (Table 9). The targeting domains for tier 1 gRNA molecules for use with the S. pyogenes, S. aureus Cas9 were selected based on (1) a reasonable distance to the target position, e.g., within a region 5' (51.5 to 51.7kb downstream of transcription start site, TSS) or 3' (65.1 to 65.3kb downstream of TSS), (2) a high level of orthogonality and (3) presence of a

5'G. For selection of tier 2 gRNAs, reasonable distance and high orthogonality were required but the presence of a 5'G was not required. Tier 3 uses the same distance restriction and the requirement for a 5'G, but removes the requirement of good orthogonality. Tier 4 uses the same distance restriction but removes the requirement of good orthogonality and the 5'G. Note that tiers are non-inclusive (each gRNA is listed only once for the strategy). In certain instances, no gRNA was identified based on the criteria of the particular tier.

In a second strategy, gRNAs were designed for use with S. pyogenes, S. aureus and N. meningitidis Cas9 molecules. The gRNAs were identified and ranked into 4 tiers for S. pyogenes (Tables 21A-21E). The targeting domain to be used with S. pyogenes Cas9 enzymes for tier 1 gRNA molecules were selected based on (1) within a region 5' (51.5 to 51.7kb downstream of TSS) or 3' (65.1 to 65.3kb downstream of TSS), (2) a high level of orthogonality and (3) presence of 5'G. The targeting domain to be used with S. pyogenes Cas9 enzymes for tier 2 gRNA molecules were selected based on (1) within a region 5' (51.5 to 51.7kb downstream of TSS) or 3' (65.1 to 65.3kb downstream of TSS) and (2) a high level of orthogonality. The targeting domain to be used with S. pyogenes Cas9 enzymes for tier 3 gRNA molecules were selected based on (1) within a region 5' (51.5 to 51.7kb downstream of TSS) or 3' (65.1 to 65.3kb downstream of TSS) and (2) presence of 5'G. The targeting domain to be used with S. pyogenes Cas9 enzymes for tier 4 gRNA molecules were selected based on within a region 5' (51.5 to 51.7kb downstream of TSS) or 3' (65.1 to 65.3kb downstream of TSS). The gRNAs were identified and ranked into 5 tiers for S. aureus, when the relevant PAM was NNGRRT or NNGRRV (Tables 22A-22E). The targeting domain to be used with S. aureus Cas9 enzymes for tier 1 gRNA molecules were selected based on (1) within a region 5' (51.5 to 51.7kb downstream of TSS) or 3' (65.1 to 65.3kb downstream of TSS), (2) a high level of orthogonality, (3) ) presence of 5'G and (4) PAM is NNGRRT. The targeting domain to be used with S. aureus Cas9 enzymes for tier 2 gRNA molecules were selected based on (1) within a region 5' (51.5 to 51.7kb downstream of TSS) or 3' (65.1 to 65.3kb downstream of TSS), (2) a high level of orthogonality, and (3) PAM is NNGRRT. The targeting domain to be used with S. aureus Cas9 enzymes for tier 3 gRNA molecules were selected based on (1) within a region 5' (51.5 to 51.7kb downstream of TSS) or 3' (65.1 to 65.3kb downstream of TSS), (2) presence of 5'G and (3) PAM is NNGRRT. The targeting domain to be used with S. aureus Cas9 enzymes for tier 4 gRNA molecules were selected based on (1) within a region 5' (51.5 to 51.7kb downstream of TSS) or 3' (65.1 to 65.3kb downstream of TSS), and (2) PAM is NNGRRT. The targeting domain to be used with S. aureus Cas9 enzymes for tier 5 gRNA molecules were selected based on (1) within a region 5' (51.5 to 51.7kb downstream of TSS) or 3' (65.1 to 65.3kb downstream of TSS), and (2) PAM is NNGRRV. The gRNAs were identified and ranked into 3 tiers for N. meningitidis (Tables 23A-23C). The targeting domain to be used with N. meningitidis Cas9 enzymes for tier 1 gRNA molecules were selected based on (1) within a region 5' (51.5 to 51.7kb downstream of TSS) or 3' (65.1 to 65.3kb downstream of TSS), (2) a high level of orthogonality and (3) presence of 5'G. The targeting domain to be used with N. meningitidis Cas9 enzymes for tier 2 gRNA molecules were selected based on (1) within a region 5' (51.5 to 51.7kb downstream of TSS) or 3' (65.1 to 65.3kb downstream of TSS) and (2) a high level of orthogonality. The targeting domain to be used with N. meningitidis Cas9 enzymes for tier 3 gRNA molecules were selected based on (1) within a region 5' (51.5 to 51.7kb downstream of TSS) or 3' (65.1 to 65.3kb downstream of TSS) and (2) presence of 5'G. The targeting domain to be used with N. meningitidis Cas9 enzymes for tier 4 gRNA molecules were selected based on within a region 5' (51.5 to 51.7kb downstream of TSS) or 3' (65.1 to 65.3kb downstream of TSS). Note that tiers are non-inclusive (each gRNA is listed only once for the strategy). In certain instances, no gRNA was identified based on the criteria of the particular tier.

In an embodiment, dual targeting (e.g., dual nicking) is used to create two nicks on opposite DNA strands by using S. pyogenes, S. aureus and N. meningitidis Cas9 nickases with two targeting domains that are complementary to opposite DNA strands, e.g., a gRNA comprising any minus strand targeting domain may be paired any gRNA comprising a plus strand targeting domain provided that the two gRNAs are oriented on the DNA such that PAMs face outward and the distance between the 5' ends of the gRNAs is 0-50bp. Exemplary nickase pairs including selecting a targeting domain from Group A and a second targeting domain from Group B, or including selecting a targeting domain from Group C and a second targeting domain from Group D in Table 20E (for S. pyogenes). It is contemplated herein that in an embodiment a targeting domain of Group A can be combined with any of the targeting domains of Group B; in an embodiment a targeting domain of Group C can be combined with any of the targeting domains of Group D in Table 20E (for S. pyogenes). For example, BCL11A-13271 or

BCLl lA-13264 can be combined with BCLl lA-13276; or BCLl lA-13262 or BCLl lA-13282 can be combined with BCLl lA-13290 or BCLl lA-13280.

In an embodiment, two or more (e.g., three or four) gRNA molecules are used with one Cas9 molecule. In another embodiment, when two or more (e.g., three or four) gRNAs are used with two or more Cas9 molecules, at least one Cas9 molecule is from a different species than the other Cas9 molecule(s). For example, when two gRNA molecules are used with two Cas9 molecules, one Cas9 molecule can be from one species and the other Cas9 molecule can be from a different species. Both Cas9 species are used to generate a single or double-strand break, as desired.

Any of the targeting domains in the tables described herein can be used with a Cas9 nickase molecule to generate a single strand break.

Any of the targeting domains in the tables described herein can be used with a Cas9 nuclease molecule to generate a double strand break.

When two gRNAs designed for use to target two Cas9 molecules, one Cas9 can be one species, the second Cas9 can be from a different species. Both Cas9 species are used to generate a single or double-strand break, as desired. It is contemplated herein that any upstream gRNA described herein may be paired with any downstream gRNA described herein. When an upstream gRNA designed for use with one species of Cas9 is paired with a downstream gRNA designed for use from a different species of Cas9, both Cas9 species are used to generate a single or double-strand break, as desired.

Exemplary Targeting Domains

Table 1A provides exemplary targeting domains for the E6V target site in the HBB gene selected according to the first tier parameters, and are selected based on the close proximity and orientation to mutation and orthogonality in the human genome. In an embodiment, the targeting domain is the exact complement of the target domain. Any of the targeting domains in the table can be used with a Cas9 molecule (e.g., a S. pyogenes Cas9 molecule) that gives double stranded cleavage. Any of the targeting domains in the table can be used with a Cas9 (e.g., a S. pyogenes Cas9 nickase) molecule to generate a single strand break. In an embodiment, dual targeting is used to create two nicks on opposite DNA strands by using Cas9 nickases (e.g., a S. pyogenes Cas9 nickase) with two targeting domains that are complementary to opposite DNA strands, e.g., a gRNA comprising any minus strand targeting domain may be paired any gRNA comprising a plus strand targeting domain provided that the two gRNAs are oriented on the DNA such that PAMs face outward and the distance between the 5' ends of the gRNAs is 0-50bp. When selecting gRNAs for use in a nickase pair, one gRNA targets a domain in the complementary strand and the second gRNA targets a domain in the non-complementary strand, e.g., a gRNA comprising any minus strand targeting domain may be paired any gRNA comprising a plus strand targeting domain targeting ths same target position. In an embodiment, two 20-mer guide RNAs are used to target two Cas9 nucleases (e.g., two S. pyogenes Cas9 nucleases) or two Cas9 nickases (e.g., two S. pyogenes Cas9 nickases), e.g., HBB-S and HBB-25 are used. In an embodiment, two 17-mer RNAs are used to target two Cas9 nucleases or two Cas9 nickases, e.g.,

HBB-35 and HBB-53 are used.

Table 1A

HBB-35 - GUGAACGUGGAUGAAG U 17 389

H BB-53 + ACGGCAGACU UCUCCU C 17 390

Table IB provides exemplary targeting domains for the E6V target site in the HBB gene selected according to the second tier parameters and are selected based on the presence of a 5' G and reasonable proximity to mutation. In an embodiment, the targeting domain is the exact complement of the target domain. Any of the targeting domains in the table can be used with a S. pyogenes Cas9 molecule that gives double stranded cleavage. Any of the targeting domains in the table can be used with S. pyogenes single- stranded break nucleases (nickases). In an embodiment, dual targeting is used to create two nicks. When selecting gRNAs for use in a nickase pair, one gRNA targets a domain in the complementary strand and the second gRNA targets a domain in the non-complementary strand, e.g., a gRNA comprising any minus strand targeting domain may be paired any gRNA comprising a plus strand targeting domain targeting ths same target position.

Table IB

Table 1C provides exemplary targeting domains for the E6V target site in the HBB gene selected according to the third tier parameters and are selected based on reasonable proximity to mutation. In an embodiment, the targeting domain is the exact complement of the target domain. Any of the targeting domains in the table can be used with a S. pyogenes Cas9 molecule that gives double stranded cleavage. Any of the targeting domains in the table can be used with S. pyogenes single- stranded break nucleases (nickases). In an embodiment, dual targeting is used to create two nicks. When selecting gRNAs for use in a nickase pair, one gRNA targets a domain in the complementary strand and the second gRNA targets a domain in the non- complementary strand, e.g., a gRNA comprising any minus strand targeting domain may be paired any gRNA comprising a plus strand targeting domain targeting ths same target position. Table 1C

HBB-49 + UGAUACCAACCUGCCCA 17 433

HBB-27 + UGCACCAUGGUGUCUGUUUG 20 434

HBB-31 - UGCCGUUACUGCCCUGU 17 435

HBB-42 - UGGGCAGGUUGGUAUCA 17 436

HBB-16 - UGG U AU CAAGG U U ACAAG AC 20 437

HBB-14 - UGGUGAGGCCCUGGGCAGGU 20 438

HBB-18 - UUAAGGAGACCAAUAGAAAC 20 439

HBB-48 + UUGAUACCAACCUGCCC 17 440

HBB-13 - UUGGUGGUGAGGCCCUGGGC 20 441

Table ID provides exemplary targeting domains for the E6V target site in the HBB gene selected based on close proximity to mutation. In an embodiment, the targeting domain is the exact complement of the target domain. Any of the targeting domains in the table can be used with a S. aureus Cas9 molecule that gives double stranded cleavage. Any of the targeting domains in the table can be used with S. aureus single- stranded break nucleases (nickases). In an embodiment, dual targeting is used to create two nicks. When selecting gRNAs for use in a nickase pair, one gRNA targets a domain in the complementary strand and the second gRNA targets a domain in the non-complementary strand, e.g., a gRNA comprising any minus strand targeting domain may be paired any gRNA comprising a plus strand targeting domain targeting ths same target position.

Table ID

HBB-71 - CAUGGUGCAUCUGACUC 20 457

HBB-72 - UGGUGCAUCUGACUCCU 17 458

HBB-73 - GGUGCAUCUGACUCCUG 17 459

HBB-74 - UGCAUCUGACUCCUGAG 17 460

HBB-75 - UCUGCCGUUACUGCCCU 17 461

HBB-76 - CUGCCGUUACUGCCCUG 17 462

HBB-77 - CUGCCCUGUGGGGCAAG 17 463

HBB-78 - UGUGGGGCAAGGUGAAC 17 464

HBB-79 - GGGCAAGGUGAACGUGG 17 465

HBB-80 - CGUGGAUGAAGUUGGUG 17 466

HBB-81 - AAGUUGGUGGUGAGGCC 17 467

HBB-82 - GG U U ACAAG ACAGG U U U 17 468

HBB-83 - G U U ACAAG ACAGG U U U A 17 469

HBB-84 - AGG U U U AAGG AG ACCAA 17 470

HBB-85 - AAGGAGACCAAUAGAAA 17 471

HBB-86 + GCUAGUGAACACAGUUGUGU 20 472

HBB-87 + GUGUCUGUUUGAGGUUGCUA 20 473

HBB-88 + AGAUGCACCAUGGUGUCUGU 20 474

HBB-89 + GUAACGGCAGACUUCUCCUC 20 475

HBB-90 + AGUAACGGCAGACUUCUCCU 20 476

HBB-91 + UCCACGUUCACCUUGCCCCA 20 477

HBB-92 + AACCUUGAUACCAACCUGCC 20 478

HBB-93 + AGUGAACACAGUUGUGU 17 479

HBB-94 + UCUGUUUGAGGUUGCUA 17 480

HBB-95 + UGCACCAUGGUGUCUGU 17 481

HBB-96 + ACGGCAGACUUCUCCUC 17 482

HBB-97 + AACGGCAGACUUCUCCU 17 483

HBB-98 + ACGUUCACCUUGCCCCA 17 484

HBB-99 + CUUGAUACCAACCUGCC 17 485

Table 2 A provides exemplary targeting domains for knocking out the BCL11A gene selected according to first tier parameters, and are selected based on close proximity to start of the coding sequence and orthogonality in the human genome. In an embodiment, the targeting domain is the exact complement of the target domain. Any of the targeting domains in the table can be used with a S. pyogenes Cas9 molecule that gives double stranded cleavage. Any of the targeting domains in the table can be used with a S. pyogenes Cas9 single- stranded break nucleases (nickases). In an embodiment, dual targeting is used to create two nicks. When selecting gRNAs for use in a nickase pair, one gRNA targets a domain in the complementary strand and the second gRNA targets a domain in the non-complementary strand, e.g., a gRNA comprising any minus strand targeting domain may be paired any gRNA comprising a plus strand targeting domain targeting ths same target position. In an embodiment, two 20-mer guide RNAs are used to target two S. pyogenes Cas9 nucleases or two S. pyogenes Cas9 nickases, e.g., BCLllA-31 and BCL1 J4-40, BCLllA-30 and BCLllA-42, or BCLllA-24 and BCLllA-53 are used. In an embodiment, two 17-mer RNAs are used to target two Cas9 nucleases or two Cas9 nickases, e.g., BCL11A-19 and BCLUA-90, BCLllA-ΊΊ and BCLUA-92, or BCL11A-1\ and BCLUA-103 are used.

Table 2A

Table 2B provides exemplary targeting domains for knocking out the BCL11A gene selected according to the second tier parameters and are selected based on close proximity to start of the coding sequence and presence of a 5' G. In an embodiment, the targeting domain is the exact complement of the target domain. Any of the targeting domains in the table can be used with a S. pyogenes Cas9 molecule that gives double stranded cleavage. Any of the targeting domains in the table can be used with a S. pyogenes Cas9 single-stranded break nucleases

(nickases). In an embodiment, dual targeting is used to create two nicks. When selecting gRNAs for use in a nickase pair, one gRNA targets a domain in the complementary strand and the second gRNA targets a domain in the non-complementary strand, e.g., a gRNA comprising any minus strand targeting domain may be paired any gRNA comprising a plus strand targeting domain targeting ths same target position. Table 2B

Table 2C provides exemplary targeting domains for knocking out the BCLllA gene selected according to the third tier parameters and are selected based on close proximity to start of the coding sequence. In an embodiment, the targeting domain is the exact complement of the target domain. Any of the targeting domains in the table can be used with a S. pyogenes Cas9 molecule that gives double stranded cleavage. Any of the targeting domains in the table can be used with a S. pyogenes Cas9 single- stranded break nucleases (nickases). In an embodiment, dual targeting is used to create two nicks. When selecting gRNAs for use in a nickase pair, one gRNA targets a domain in the complementary strand and the second gRNA targets a domain in the non-complementary strand, e.g., a gRNA comprising any minus strand targeting domain may be paired any gRNA comprising a plus strand targeting domain targeting ths same target position.

Table 2C

BCLllA-134 + CACUCAUCCCAGGCGUG 17 557

BCLllA-139 + CAGAACGAGGGGAGGAG 17 558

BCLllA-69 - CAGAUGAACUUCCCAUU 17 559

BCLllA-96 + CAGCUUUUUCUAAGCAG 17 560

BCLllA-86 + CAUCCUCUGGCGUGACC 17 561

BCLllA-93 + CAUCUCGAUUGGUGAAG 17 562

BCLllA-100 + CAUCUGGCACUGCCCAC 17 563

BCLllA-66 - CAUGACCUCCUCACCUG 17 564

BCLllA-99 + CCAAUGGGAAGUUCAUC 17 565

BCLllA-46 + CCACAGCUU UUUCUAAGCAG 20 566

BCLllA-62 - CCAGACCACGGCCCGUU 17 567

BCLllA-68 - CCAGAUGAACUUCCCAU 17 568

BCLllA-8 - CCAGCACUUAAGCAAAC 17 569

BCLllA-107 + CCCAACGGGCCGUGGUC 17 570

BCLllA-7 - CCCAGCACUUAAGCAAA 17 571

BCLllA-49 + CCCCCAAUGGGAAGUUCAUC 20 572

BCLllA-55 + CCCCUUCUGGAGCUCCCAAC 20 573

BCLllA-18 - CCCGUUGGGAGCUCCAGAAG 20 574

BCLllA-9 + CCCGUUUGCU UAAGUGC 17 575

BCLllA-63 - CCGUUGGGAGCUCCAGA 17 576

BCLllA-10 + CCGUUUGCUUAAGUGCU 17 577

BCLllA-27 - CCUCUGCUUAGAAAAAGCUG 20 578

BCLllA-104 + CCUUCUGGAGCUCCCAA 17 579

BCLllA-36 + CGUCAUCCUCUGGCGUGACC 20 580

BCLllA-78 - CGUGGAGGUUGGCAUCC 17 581

BCLllA-64 - CGUUGGGAGCUCCAGAA 17 582

BCLllA-11 + CGUUUGCU UAAGUGCUG 17 583

BCLllA-84 + CUAUGUGUUCCUGUUUG 17 584

BCLllA-136 + CUCCAUGUGCAGAACGA 17 585

BCLllA-128 - CUCUAAUCCCCACGCCU 17 586

BCLllA-118 + CUGCACUCAUCCCAGGCGUG 20 587

BCLllA-74 - CUGCUUAGAAAAAGCUG 17 588

BCLllA-56 + CUGGAGCUCCCAACGGGCCG 20 589

BCLllA-87 + CUGGAUGCCAACCUCCA 17 590

BCLllA-105 + CUUCUGGAGCUCCCAAC 17 591

BCLllA-124 - UAAACUUCUGCACUGGA 17 592

BCLllA-98 + UAAGAAUGUCCCCCAAU 17 593

BCLllA-34 - UAGAGGAAUUUGCCCCAAAC 20 594

BCLllA-131 + UAUUCUGCACUCAUCCC 17 595

BCLllA-137 + U CCAU G U G C AG AACG AG 17 596

BCLllA-122 + UCCAUGUGCAGAACGAGGGG 20 597

BCLllA-126 - UCCCCUCGUUCUGCACA 17 598 BCLllA-54 + UCCCCUUCUGGAGCUCCCAA 20 599

BCLllA-31 - UCCCGUGGAGGUUGGCAUCC 20 600

BCLllA-5 + UCCCGU UUGCUUAAGUGCUG 20 601

BCLllA-110 - UCCUCCCCUCGUUCUGCACA 20 602

BCLllA-94 + UCGAUUGGUGAAGGGGA 17 603

BCLllA-45 + UCGAUUGGUGAAGGGGAAGG 20 604

BCLllA-117 + UCUGCACUCAUCCCAGGCGU 20 605

BCLllA-51 + UCUGGCACUGCCCACAGGUG 20 606

BCLllA-59 + UCUGUAAGAAUGGCUUCAAG 20 607

BCLllA-14 - UGAACCAGACCACGGCCCGU 20 608

BCLllA-132 + UGCACUCAUCCCAGGCG 17 609

BCLllA-129 - UGCAGAAUAUGCCCCGC 17 610

BCLllA-22 - UGCCAGAUGAACUUCCCAUU 20 611

BCLllA-82 + UGCUAUGUGUUCCUGUU 17 612

BCLllA-88 + UGGAUGCCAACCUCCAC 17 613

BCLllA-58 + UGGUUCAUCAUCUGUAAGAA 20 614

BCLllA-33 - UGU UUAUCAACGUCAUCUAG 20 615

BCLllA-80 - UUAUCAACGUCAUCUAG 17 616

BCLllA-25 - UUAUUUUUAUCGAGCACAAA 20 617

BCLllA-108 + U UCAUCAUCUGUAAGAA 17 618

BCLllA-91 + UUCAUCUCGAUUGGUGA 17 619

BCLllA-4 + UUCCCGUU UGCUUAAGUGCU 20 620

BCLllA-116 + U UCUGCACUCAUCCCAGGCG 20 621

BCLllA-43 + UUUCAUCUCGAUUGGUGAAG 20 622

BCLllA-72 - UU UUUAUCGAGCACAAA 17 623

BCLllA-41 + UU UUUCAUCUCGAUUGGUGA 20 624

Table 2D provides exemplary targeting domains for knocking out the BCL11A gene selected according to the fourth tier parameters and are selected based on presence in the coding sequence. In an embodiment, the targeting domain is the exact complement of the target domain. Any of the targeting domains in the table can be used with a S. pyogenes Cas9 molecule that gives double stranded cleavage. Any of the targeting domains in the table can be used with a S. pyogenes Cas9 single- stranded break nucleases (nickases). In an embodiment, dual targeting is used to create two nicks. When selecting gRNAs for use in a nickase pair, one gRNA targets a domain in the complementary strand and the second gRNA targets a domain in the non- complementary strand, e.g., a gRNA comprising any minus strand targeting domain may be paired any gRNA comprising a plus strand targeting domain targeting ths same target position. Table 2D 4th Tier

DNA Target Site SEQ ID gRNA Name Targeting domain

Strand Length NO

BCLllA-140 - AACAGCCAUUCACCAGUGCA 20 625

BCLllA-141 - CAACACGCACAGAACACUCA 20 626

BCLllA-142 - AUCUACUUAGAAAGCGAACA 20 627

BCLllA-143 - ACGGAAGUCCCCUGACCCCG 20 628

BCLllA-144 - CGGAAGUCCCCUGACCCCGC 20 629

BCLllA-145 - AGUCCCCUGACCCCGCGGGU 20 630

BCLllA-146 - CCGCGGGUUGGUAUCCCUUC 20 631

BCLllA-147 - GUUGGUAUCCCUUCAGGACU 20 632

BCLllA-148 - CCUUCCCAGCCACCUCUCCA 20 633

BCLllA-149 - CUUCCCAGCCACCUCUCCAU 20 634

BCLllA-150 - UUUAACCUGCUAAGAAUACC 20 635

BCLllA-151 - ACCAGGAUCAGUAUCGAGAG 20 636

BCLllA-152 - UCAGUAUCGAGAGAGGCUUC 20 637

BCLllA-153 - AUCGAGAGAGGCUUCCGGCC 20 638

BCLllA-154 - GAGGCUUCCGGCCUGGCAGA 20 639

BCLllA-155 - AGGCUUCCGGCCUGGCAGAA 20 640

BCLllA-156 - UCCACCACCGAGACAUCACU 20 641

BCLllA-157 - CCCCCACCGCAUAGAGCGCC 20 642

BCLllA-158 - CCCCACCGCAUAGAGCGCCU 20 643

BCLllA-159 - CCCACCGCAUAGAGCGCCUG 20 644

BCLllA-160 - CCACCGCAUAGAGCGCCUGG 20 645

BCLllA-161 - CCGCAUAGAGCGCCUGGGGG 20 646

BCLllA-162 - GCGCCUGGGGGCGGAAGAGA 20 647

BCLllA-163 - GGGGGCGGAAGAGAUGGCCC 20 648

BCLllA-164 - AUCACCCGAGUGCCUUUGAC 20 649

BCLllA-165 - UCACCCGAGUGCCUUUGACA 20 650

BCLllA-166 - GUGCCUUUGACAGGGUGCUG 20 651

BCLllA-167 - GGUGCUGCGGUUGAAUCCAA 20 652

BCLllA-168 - GCGGUUGAAUCCAAUGGCUA 20 653

BCLllA-169 - GGCUAUGGAGCCUCCCGCCA 20 654

BCLllA-170 - CUCCCGCCAUGGAUUUCUCU 20 655

BCLllA-171 - CUCUAGGAGACUUAGAGAGC 20 656

BCLllA-172 - AGGAGACUUAGAGAGCUGGC 20 657

BCLllA-173 - GGAGACUUAGAGAGCUGGCA 20 658

BCLllA-174 - UCUAGCCCACCGCUGUCCCC 20 659

BCLllA-175 - GCCCACCGCUGUCCCCAGGC 20 660

BCLllA-176 - GCCGGCCCAGCCCUAUGCAA 20 661

BCLllA-177 - UUACUGCAACCAUUCCAGCC 20 662

BCLllA-178 - AGGUAGCAAGCCGCCCUUCC 20 663 BCLllA-179 - CCCUCCUCCCUCCCAGCCCC 20 664

BCLllA-180 - UCCAAGUCAUGCGAGUUCUG 20 665

BCLllA-181 - GUUCAAAUUUCAGAGCAACC 20 666

BCLllA-182 - CAAAUUUCAGAGCAACCUGG 20 667

BCLllA-183 - AGAGCAACCUGGUGGUGCAC 20 668

BCLllA-184 - GGUGCACCGGCGCAGCCACA 20 669

BCLllA-185 - GUGCACCGGCGCAGCCACAC 20 670

BCLllA-186 - GUGCGACCACGCGUGCACCC 20 671

BCLllA-187 - GCACAAAUCGUCCCCCAUGA 20 672

BCLllA-188 - AUGACGGUCAAGUCCGACGA 20 673

BCLllA-189 - UCUCUCCACCGCCAGCUCCC 20 674

BCLllA-190 - ACCGCCAGCUCCCCGGAACC 20 675

BCLllA-191 - GGAACCCGGCACCAGCGACU 20 676

BCLllA-192 - ACCCGGCACCAGCGACUUGG 20 677

BCLllA-193 - CCCGGCACCAGCGACUUGGU 20 678

BCLllA-194 - CAG CAG CG CG C U CAAG U CCG 20 679

BCLllA-195 - CAGCGCGCUCAAGUCCGUGG 20 680

BCLllA-196 - GAACGACCCCAACCUGAUCC 20 681

BCLllA-197 - CCCAACCUGAUCCCGGAGAA 20 682

BCLllA-198 - CCAACCUGAUCCCGGAGAAC 20 683

BCLllA-199 - CAACCUGAUCCCGGAGAACG 20 684

BCLllA-200 - GAUCCCGGAGAACGGGGACG 20 685

BCLllA-201 - CCCGGAGAACGGGGACGAGG 20 686

BCLllA-202 - GAACGGGGACGAGGAGGAAG 20 687

BCLllA-203 - CGGGGACGAGGAGGAAGAGG 20 688

BCLllA-204 - GGAGGAAGAGGAGGACGACG 20 689

BCLllA-205 - AGAGGAGGACGACGAGGAAG 20 690

BCLllA-206 - CGACGAGGAAGAGGAAGAAG 20 691

BCLllA-207 - CGAGGAAGAGGAAGAAGAGG 20 692

BCLllA-208 - AGAGGAAGAAGAGGAGGAAG 20 693

BCLllA-209 - GGAAGAAGAGGAGGAAGAGG 20 694

BCLllA-210 - AGAAGAGGAGGAAGAGGAGG 20 695

BCLllA-211 - AGAGGAGGAAGAGGAGGAGG 20 696

BCLllA-212 + UCCUCCUCGUCCCCGUUCUC 20 697

BCLllA-213 + CCUCCUCGUCCCCGUUCUCC 20 698

BCLllA-214 + CGUCCCCGUUCUCCGGGAUC 20 699

BCLllA-215 + CCCGUUCUCCGGGAUCAGGU 20 700

BCLllA-216 + CCGUUCUCCGGGAUCAGGUU 20 701

BCLllA-217 + CGUUCUCCGGGAUCAGGUUG 20 702

BCLllA-218 + GUCGUUCUCGCUCUUGAACU 20 703

BCLllA-219 + GCUCUUGAACUUGGCCACCA 20 704

BCLllA-220 + CACGGACUUGAGCGCGCUGC 20 705 BCLllA-221 + GGCGCUGCCCACCAAGUCGC 20 706

BCLllA-222 + GCCCACCAAGUCGCUGGUGC 20 707

BCLllA-223 + CCCACCAAGUCGCUGGUGCC 20 708

BCLllA-224 + AAGUCGCUGGUGCCGGGUUC 20 709

BCLllA-225 + AGUCGCUGGUGCCGGGUUCC 20 710

BCLllA-226 + GUCGCUGGUGCCGGGU UCCG 20 711

BCLllA-227 + GGUGCCGGGUUCCGGGGAGC 20 712

BCLllA-228 + GCCGGGUUCCGGGGAGCUGG 20 713

BCLllA-229 + GGGU UCCGGGGAGCUGGCGG 20 714

BCLllA-230 + GGCGGUGGAGAGACCGUCGU 20 715

BCLllA-231 + GUCGUCGGACUUGACCGUCA 20 716

BCLllA-232 + UCGUCGGACUUGACCGUCAU 20 717

BCLllA-233 + CGUCGGACU UGACCGUCAUG 20 718

BCLllA-234 + GUCGGACUUGACCGUCAUGG 20 719

BCLllA-235 + UGUGCAUGUGCGUCUUCAUG 20 720

BCLllA-236 + CAUGUGGCGCUUCAGCU UGC 20 721

BCLllA-237 + GGCGCUUCAGCUUGCUGGCC 20 722

BCLllA-238 + GCGCUUCAGCUUGCUGGCCU 20 723

BCLllA-239 + UGCUGGCCUGGGUGCACGCG 20 724

BCLllA-240 + GGGUGCACGCGUGGUCGCAC 20 725

BCLllA-241 + GUCGCACAGGU UGCACU UGU 20 726

BCLllA-242 + UCGCACAGGUUGCACUUGUA 20 727

BCLllA-243 + UGUAGGGCUUCUCGCCCGUG 20 728

BCLllA-244 + UCUCGCCCGUGUGGCUGCGC 20 729

BCLllA-245 + GGCUGCGCCGGUGCACCACC 20 730

BCLllA-246 + GCCGCAGAACUCGCAUGACU 20 731

BCLllA-247 + UCGCAUGACU UGGACU UGAC 20 732

BCLllA-248 + CGCAUGACUUGGACUUGACC 20 733

BCLllA-249 + GCAUGACUUGGACUUGACCG 20 734

BCLllA-250 + CAUGACUUGGACUUGACCGG 20 735

BCLllA-251 + ACUUGGACUUGACCGGGGGC 20 736

BCLllA-252 + CUUGGACUUGACCGGGGGCU 20 737

BCLllA-253 + GGACUUGACCGGGGGCUGGG 20 738

BCLllA-254 + GACU UGACCGGGGGCUGGGA 20 739

BCLllA-255 + UUGACCGGGGGCUGGGAGGG 20 740

BCLllA-256 + ACCGGGGGCUGGGAGGGAGG 20 741

BCLllA-257 + CCGGGGGCUGGGAGGGAGGA 20 742

BCLllA-258 + CGGGGGCUGGGAGGGAGGAG 20 743

BCLllA-259 + GGGCUGGGAGGGAGGAGGGG 20 744

BCLllA-260 + GGAGGAGGGGCGGAUUGCAG 20 745

BCLllA-261 + GGAGGGGCGGAUUGCAGAGG 20 746

BCLllA-262 + GAGGGGCGGAUUGCAGAGGA 20 747 BCLllA-263 + GGGCGGAUUGCAGAGGAGGG 20 748

BCLllA-264 + GGCGGAUUGCAGAGGAGGGA 20 749

BCLllA-265 + GCGGAUUGCAGAGGAGGGAG 20 750

BCLllA-266 + CGGAUUGCAGAGGAGGGAGG 20 751

BCLllA-267 + GGAUUGCAGAGGAGGGAGGG 20 752

BCLllA-268 + GAUUGCAGAGGAGGGAGGGG 20 753

BCLllA-269 + GAGGGAGGGGGGGCGUCGCC 20 754

BCLllA-270 + GAGGGGGGGCGUCGCCAGGA 20 755

BCLllA-271 + AGGGGGGGCGUCGCCAGGAA 20 756

BCLllA-272 + GGGGGCGUCGCCAGGAAGGG 20 757

BCLllA-273 + AGGAAGGGCGGCUUGCUACC 20 758

BCLllA-274 + AGGGCGGCUUGCUACCUGGC 20 759

BCLllA-275 + GGCUUGCUACCUGGCUGGAA 20 760

BCLllA-276 + GGUUGCAGUAACCUUUGCAU 20 761

BCLllA-277 + GU UGCAGUAACCUUUGCAUA 20 762

BCLllA-278 + CAGUAACCUUUGCAUAGGGC 20 763

BCLllA-279 + AGUAACCUUUGCAUAGGGCU 20 764

BCLllA-280 + ACCUU UGCAUAGGGCUGGGC 20 765

BCLllA-281 + UGCAUAGGGCUGGGCCGGCC 20 766

BCLllA-282 + GCAUAGGGCUGGGCCGGCCU 20 767

BCLllA-283 + CAUAGGGCUGGGCCGGCCUG 20 768

BCLllA-284 + CUGGGCCGGCCUGGGGACAG 20 769

BCLllA-285 + GGCCGGCCUGGGGACAGCGG 20 770

BCLllA-286 + GCCGGCCUGGGGACAGCGGU 20 771

BCLllA-287 + AAGUCUCCUAGAGAAAUCCA 20 772

BCLllA-288 + UCUCCUAGAGAAAUCCAUGG 20 773

BCLllA-289 + CUCCUAGAGAAAUCCAUGGC 20 774

BCLllA-290 + CUAGAGAAAUCCAUGGCGGG 20 775

BCLllA-291 + GCGGGAGGCUCCAUAGCCAU 20 776

BCLllA-292 + CAACCGCAGCACCCUGUCAA 20 111

BCLllA-293 + AGCACCCUG UCAAAGGCACU 20 778

BCLllA-294 + GCACCCUGUCAAAGGCACUC 20 779

BCLllA-295 + UGUCAAAGGCACUCGGGUGA 20 780

BCLllA-296 + GUCAAAGGCACUCGGGUGAU 20 781

BCLllA-297 + AAAGGCACUCGGGUGAUGGG 20 782

BCLllA-298 + CACUCGGGUGAUGGGUGGCC 20 783

BCLllA-299 + ACUCGGGUGAUGGGUGGCCA 20 784

BCLllA-300 + GGGCCAUCUCUUCCGCCCCC 20 785

BCLllA-301 + CCGCCCCCAGGCGCUCUAUG 20 786

BCLllA-302 + CCCCCAGGCGCUCUAUGCGG 20 787

BCLllA-303 + CCCCAGGCGCUCUAUGCGGU 20 788

BCLllA-304 + CCCAGGCGCUCUAUGCGGUG 20 789 BCLllA-305 + CCAGGCGCUCUAUGCGGUGG 20 790

BCLllA-306 + UGGGGGUCCAAGUGAUGUCU 20 791

BCLllA-307 + GGGUCCAAGUGAUGUCUCGG 20 792

BCLllA-308 + UCCAAGUGAUGUCUCGGUGG 20 793

BCLllA-309 + GUCUCGGUGGUGGACUAAAC 20 794

BCLllA-310 + UCUCGGUGGUGGACUAAACA 20 795

BCLllA-311 + CUCGGUGGUGGACUAAACAG 20 796

BCLllA-312 + UCGGUGGUGGACUAAACAGG 20 797

BCLllA-313 + CGGUGGUGGACUAAACAGGG 20 798

BCLllA-314 + GGUGGUGGACUAAACAGGGG 20 799

BCLllA-315 + UGGACUAAACAGGGGGGGAG 20 800

BCLllA-316 + GGACUAAACAGGGGGGGAGU 20 801

BCLllA-317 + CUAAACAGGGGGGGAGUGGG 20 802

BCLllA-318 + GUGGAAAGCGCCCUUCUGCC 20 803

BCLllA-319 + AAAGCGCCCUUCUGCCAGGC 20 804

BCLllA-320 + GCCUCUCUCGAUACUGAUCC 20 805

BCLllA-321 + CUGAUCCUGGUAUUCU UAGC 20 806

BCLllA-322 + UGGUAUUCUUAGCAGGUUAA 20 807

BCLllA-323 + GGUAUUCUUAGCAGGUUAAA 20 808

BCLllA-324 + GUAUUCUUAGCAGGUUAAAG 20 809

BCLllA-325 + UGUCUGCAAUAUGAAUCCCA 20 810

BCLllA-326 + GCAAUAUGAAUCCCAUGGAG 20 811

BCLllA-327 + AUAUGAAUCCCAUGGAGAGG 20 812

BCLllA-328 + GAAUCCCAUGGAGAGGUGGC 20 813

BCLllA-329 + AAUCCCAUGGAGAGGUGGCU 20 814

BCLllA-330 + CCAUGGAGAGGUGGCUGGGA 20 815

BCLllA-331 + CAUUCUGCACCUAGUCCUGA 20 816

BCLllA-332 + AUUCUGCACCUAGUCCUGAA 20 817

BCLllA-333 + CCUGAAGGGAUACCAACCCG 20 818

BCLllA-334 + CUGAAGGGAUACCAACCCGC 20 819

BCLllA-335 + UGAAGGGAUACCAACCCGCG 20 820

BCLllA-336 + GGAUACCAACCCGCGGGGUC 20 821

BCLllA-337 + GAUACCAACCCGCGGGGUCA 20 822

BCLllA-338 + AUACCAACCCGCGGGGUCAG 20 823

BCLllA-339 + U UGCAAGAGAAACCAUGCAC 20 824

BCLllA-340 + AGAAACCAUGCACUGGUGAA 20 825

BCLllA-341 + AGUUGUACAUGUGUAGCUGC 20 826

BCLllA-342 + GUUGUACAUGUGUAGCUGCU 20 827

BCLllA-343 - AGCCAUUCACCAGUGCA 17 828

BCLllA-344 - CACGCACAGAACACUCA 17 829

BCLllA-345 - UACUUAGAAAGCGAACA 17 830

BCLllA-346 - GAAGUCCCCUGACCCCG 17 831 BCLllA-347 - AAGUCCCCUGACCCCGC 17 832

BCLllA-348 - CCCCUGACCCCGCGGGU 17 833

BCLllA-349 - CGGGUUGGUAUCCCUUC 17 834

BCLllA-350 - GGUAUCCCUUCAGGACU 17 835

BCLllA-351 - UCCCAGCCACCUCUCCA 17 836

BCLllA-352 - CCCAGCCACCUCUCCAU 17 837

BCLllA-353 - AACCUGCUAAGAAUACC 17 838

BCLllA-354 - AGGAUCAGUAUCGAGAG 17 839

BCLllA-355 - GUAUCGAGAGAGGCUUC 17 840

BCLllA-356 - GAGAGAGGCUUCCGGCC 17 841

BCLllA-357 - GCUUCCGGCCUGGCAGA 17 842

BCLllA-358 - CUUCCGGCCUGGCAGAA 17 843

BCLllA-359 - ACCACCGAGACAUCACU 17 844

BCLllA-360 - CCACCGCAUAGAGCGCC 17 845

BCLllA-361 - CACCGCAUAGAGCGCCU 17 846

BCLllA-362 - ACCGCAUAGAGCGCCUG 17 847

BCLllA-363 - CCGCAUAGAGCGCCUGG 17 848

BCLllA-364 - CAUAGAGCGCCUGGGGG 17 849

BCLllA-365 - CCUGGGGGCGGAAGAGA 17 850

BCLllA-366 - GGCGGAAGAGAUGGCCC 17 851

BCLllA-367 - ACCCGAGUGCCUUUGAC 17 852

BCLllA-368 - CCCGAGUGCCUUUGACA 17 853

BCLllA-369 - CCUUUGACAGGGUGCUG 17 854

BCLllA-370 - GCUGCGGUUGAAUCCAA 17 855

BCLllA-371 - GUUGAAUCCAAUGGCUA 17 856

BCLllA-372 - UAUGGAGCCUCCCGCCA 17 857

BCLllA-373 - CCGCCAUGGAUUUCUCU 17 858

BCLllA-374 - UAGGAGACUUAGAGAGC 17 859

BCLllA-375 - AGACUUAGAGAGCUGGC 17 860

BCLllA-376 - GACUUAGAGAGCUGGCA 17 861

BCLllA-377 - AGCCCACCGCUGUCCCC 17 862

BCLllA-378 - CACCGCUGUCCCCAGGC 17 863

BCLllA-379 - GGCCCAGCCCUAUGCAA 17 864

BCLllA-380 - CUGCAACCAUUCCAGCC 17 865

BCLllA-381 - UAGCAAGCCGCCCUUCC 17 866

BCLllA-382 - UCCUCCCUCCCAGCCCC 17 867

BCLllA-383 - AAGUCAUGCGAGUUCUG 17 868

BCLllA-384 - CAAAUUUCAGAGCAACC 17 869

BCLllA-385 - AUUUCAGAGCAACCUGG 17 870

BCLllA-386 - GCAACCUGGUGGUGCAC 17 871

BCLllA-387 - GCACCGGCGCAGCCACA 17 872

BCLllA-388 - CACCGGCGCAGCCACAC 17 873 BCLllA-389 - CGACCACGCGUGCACCC 17 874

BCLllA-390 - CAAAUCGUCCCCCAUGA 17 875

BCLllA-391 - ACGGUCAAGUCCGACGA 17 876

BCLllA-392 - CUCCACCGCCAGCUCCC 17 877

BCLllA-393 - GCCAGCUCCCCGGAACC 17 878

BCLllA-394 - ACCCGGCACCAGCGACU 17 879

BCLllA-395 - CGGCACCAGCGACUUGG 17 880

BCLllA-396 - GGCACCAGCGACU UGGU 17 881

BCLllA-397 - CAGCGCGCUCAAGUCCG 17 882

BCLllA-398 - CGCGCUCAAGUCCGUGG 17 883

BCLllA-399 - CGACCCCAACCUGAUCC 17 884

BCLllA-400 - AACCUGAUCCCGGAGAA 17 885

BCLllA-401 - ACCUGAUCCCGGAGAAC 17 886

BCLllA-402 - CCUGAUCCCGGAGAACG 17 887

BCLllA-403 - CCCGGAGAACGGGGACG 17 888

BCLllA-404 - GGAGAACGGGGACGAGG 17 889

BCLllA-405 - CGGGGACGAGGAGGAAG 17 890

BCLllA-406 - GGACGAGGAGGAAGAGG 17 891

BCLllA-407 - GGAAGAGGAGGACGACG 17 892

BCLllA-408 - GGAGGACGACGAGGAAG 17 893

BCLllA-409 - CGAGGAAGAGGAAGAAG 17 894

BCLllA-410 - GGAAGAGGAAGAAGAGG 17 895

BCLllA-411 - GGAAGAAGAGGAGGAAG 17 896

BCLllA-412 - AGAAGAGGAGGAAGAGG 17 897

BCLllA-413 - AGAGGAGGAAGAGGAGG 17 898

BCLllA-414 - GGAGGAAGAGGAGGAGG 17 899

BCLllA-415 + UCCUCGUCCCCGUUCUC 17 900

BCLllA-416 + CCUCGUCCCCGUUCUCC 17 901

BCLllA-417 + CCCCGUUCUCCGGGAUC 17 902

BCLllA-418 + GU UCUCCGGGAUCAGGU 17 903

BCLllA-419 + UUCUCCGGGAUCAGGU U 17 904

BCLllA-420 + UCUCCGGGAUCAGGUUG 17 905

BCLllA-421 + GU UCUCGCUCUUGAACU 17 906

BCLllA-422 + CUUGAACUUGGCCACCA 17 907

BCLllA-423 + GGACU UGAGCGCGCUGC 17 908

BCLllA-424 + GCUGCCCACCAAGUCGC 17 909

BCLllA-425 + CACCAAGUCGCUGGUGC 17 910

BCLllA-426 + ACCAAGUCGCUGGUGCC 17 911

BCLllA-427 + UCGCUGGUGCCGGGUUC 17 912

BCLllA-428 + CGCUGGUGCCGGGUUCC 17 913

BCLllA-429 + GCUGGUGCCGGGUUCCG 17 914

BCLllA-430 + GCCGGGUUCCGGGGAGC 17 915 BCLllA-431 + GGGU UCCGGGGAGCUGG 17 916

BCLllA-432 + U UCCGGGGAGCUGGCGG 17 917

BCLllA-433 + GGUGGAGAGACCGUCGU 17 918

BCLllA-434 + GUCGGACUUGACCGUCA 17 919

BCLllA-435 + UCGGACUUGACCGUCAU 17 920

BCLllA-436 + CGGACUUGACCGUCAUG 17 921

BCLllA-437 + GGACUUGACCGUCAUGG 17 922

BCLllA-438 + GCAUGUGCGUCUUCAUG 17 923

BCLllA-439 + GUGGCGCU UCAGCUUGC 17 924

BCLllA-440 + GCUUCAGCUUGCUGGCC 17 925

BCLllA-441 + CUUCAGCUUGCUGGCCU 17 926

BCLllA-442 + UGGCCUGGGUGCACGCG 17 927

BCLllA-443 + UGCACGCGUGGUCGCAC 17 928

BCLllA-444 + GCACAGGUUGCACUUGU 17 929

BCLllA-445 + CACAGGUUGCACUUGUA 17 930

BCLllA-446 + AGGGCUUCUCGCCCGUG 17 931

BCLllA-447 + CGCCCGUGUGGCUGCGC 17 932

BCLllA-448 + UGCGCCGGUGCACCACC 17 933

BCLllA-449 + GCAGAACUCGCAUGACU 17 934

BCLllA-450 + CAUGACUUGGACUUGAC 17 935

BCLllA-451 + AUGACUUGGACUUGACC 17 936

BCLllA-452 + UGACUUGGACUUGACCG 17 937

BCLllA-453 + GACU UGGACUUGACCGG 17 938

BCLllA-454 + UGGACUUGACCGGGGGC 17 939

BCLllA-455 + GGACUUGACCGGGGGCU 17 940

BCLllA-456 + CUUGACCGGGGGCUGGG 17 941

BCLllA-457 + UUGACCGGGGGCUGGGA 17 942

BCLllA-458 + ACCGGGGGCUGGGAGGG 17 943

BCLllA-459 + GGGGGCUGGGAGGGAGG 17 944

BCLllA-460 + GGGGCUGGGAGGGAGGA 17 945

BCLllA-461 + GGGCUGGGAGGGAGGAG 17 946

BCLllA-462 + CUGGGAGGGAGGAGGGG 17 947

BCLllA-463 + GGAGGGGCGGAUUGCAG 17 948

BCLllA-464 + GGGGCGGAUUGCAGAGG 17 949

BCLllA-465 + GGGCGGAUUGCAGAGGA 17 950

BCLllA-466 + CGGAUUGCAGAGGAGGG 17 951

BCLllA-467 + GGAUUGCAGAGGAGGGA 17 952

BCLllA-468 + GAUUGCAGAGGAGGGAG 17 953

BCLllA-469 + AUUGCAGAGGAGGGAGG 17 954

BCLllA-470 + UUGCAGAGGAGGGAGGG 17 955

BCLllA-471 + UGCAGAGGAGGGAGGGG 17 956

BCLllA-472 + GGAGGGGGGGCGUCGCC 17 957 BCLllA-473 + GGGGGGCGUCGCCAGGA 17 958

BCLllA-474 + GGGGGCGUCGCCAGGAA 17 959

BCLllA-475 + GGCGUCGCCAGGAAGGG 17 960

BCLllA-476 + AAGGGCGGCUUGCUACC 17 961

BCLllA-477 + GCGGCUUGCUACCUGGC 17 962

BCLllA-478 + U UGCUACCUGGCUGGAA 17 963

BCLllA-479 + UGCAGUAACCUU UGCAU 17 964

BCLllA-480 + GCAGUAACCUUUGCAUA 17 965

BCLllA-481 + UAACCUUUGCAUAGGGC 17 966

BCLllA-482 + AACCU UUGCAUAGGGCU 17 967

BCLllA-483 + U UUGCAUAGGGCUGGGC 17 968

BCLllA-484 + AUAGGGCUGGGCCGGCC 17 969

BCLllA-485 + UAGGGCUGGGCCGGCCU 17 970

BCLllA-486 + AGGGCUGGGCCGGCCUG 17 971

BCLllA-487 + GGCCGGCCUGGGGACAG 17 972

BCLllA-488 + CGGCCUGGGGACAGCGG 17 973

BCLllA-489 + GGCCUGGGGACAGCGGU 17 974

BCLllA-490 + UCUCCUAGAGAAAUCCA 17 975

BCLllA-491 + CCUAGAGAAAUCCAUGG 17 976

BCLllA-492 + CUAGAGAAAUCCAUGGC 17 977

BCLllA-493 + GAGAAAUCCAUGGCGGG 17 978

BCLllA-494 + GGAGGCUCCAUAGCCAU 17 979

BCLllA-495 + CCGCAGCACCCUGUCAA 17 980

BCLllA-496 + ACCCUGUCAAAGGCACU 17 981

BCLllA-497 + CCCUGUCAAAGGCACUC 17 982

BCLllA-498 + CAAAGGCACUCGGGUGA 17 983

BCLllA-499 + AAAGGCACUCGGGUGAU 17 984

BCLllA-500 + GGCACUCGGGUGAUGGG 17 985

BCLllA-501 + UCGGGUGAUGGGUGGCC 17 986

BCLllA-502 + CGGGUGAUGGGUGGCCA 17 987

BCLllA-503 + CCAUCUCU UCCGCCCCC 17 988

BCLllA-504 + CCCCCAGGCGCUCUAUG 17 989

BCLllA-505 + CCAGGCGCUCUAUGCGG 17 990

BCLllA-506 + CAGGCGCUCUAUGCGGU 17 991

BCLllA-507 + AGGCGCUCUAUGCGGUG 17 992

BCLllA-508 + GGCGCUCUAUGCGGUGG 17 993

BCLllA-509 + GGGUCCAAGUGAUGUCU 17 994

BCLllA-510 + UCCAAGUGAUGUCUCGG 17 995

BCLllA-511 + AAGUGAUGUCUCGGUGG 17 996

BCLllA-512 + UCGGUGGUGGACUAAAC 17 997

BCLllA-513 + CGGUGGUGGACUAAACA 17 998

BCLllA-514 + GGUGGUGGACUAAACAG 17 999 BCLllA-515 + GUGGUGGACUAAACAGG 17 1000

BCLllA-516 + UGGUGGACUAAACAGGG 17 1001

BCLllA-517 + GGUGGACUAAACAGGGG 17 1002

BCLllA-518 + ACUAAACAGGGGGGGAG 17 1003

BCLllA-519 + CUAAACAGGGGGGGAGU 17 1004

BCLllA-520 + AACAGGGGGGGAGUGGG 17 1005

BCLllA-521 + GAAAGCGCCCUUCUGCC 17 1006

BCLllA-522 + GCGCCCUUCUGCCAGGC 17 1007

BCLllA-523 + UCUCUCGAUACUGAUCC 17 1008

BCLllA-524 + AUCCUGGUAUUCUUAGC 17 1009

BCLllA-525 + UAUUCUUAGCAGGUUAA 17 1010

BCLllA-526 + AUUCUUAGCAGGUUAAA 17 1011

BCLllA-527 + UUCUUAGCAGGUUAAAG 17 1012

BCLllA-528 + CUGCAAUAUGAAUCCCA 17 1013

BCLllA-529 + AUAUGAAUCCCAUGGAG 17 1014

BCLllA-530 + UGAAUCCCAUGGAGAGG 17 1015

BCLllA-531 + UCCCAUGGAGAGGUGGC 17 1016

BCLllA-532 + CCCAUGGAGAGGUGGCU 17 1017

BCLllA-533 + UGGAGAGGUGGCUGGGA 17 1018

BCLllA-534 + UCUGCACCUAGUCCUGA 17 1019

BCLllA-535 + CUGCACCUAGUCCUGAA 17 1020

BCLllA-536 + GAAGGGAUACCAACCCG 17 1021

BCLllA-537 + AAGGGAUACCAACCCGC 17 1022

BCLllA-538 + AGGGAUACCAACCCGCG 17 1023

BCLllA-539 + UACCAACCCGCGGGGUC 17 1024

BCLllA-540 + ACCAACCCGCGGGGUCA 17 1025

BCLllA-541 + CCAACCCGCGGGGUCAG 17 1026

BCLllA-542 + CAAGAGAAACCAUGCAC 17 1027

BCLllA-543 + AACCAUGCACUGGUGAA 17 1028

BCLllA-544 + UGUACAUGUGUAGCUGC 17 1029

BCLllA-545 + GUACAUGUGUAGCUGCU 17 1030

BCLllA-546 - AGAGGAGGAGGAGGAGCUGA 20 1031

BCLllA-547 - AGGAGCUGACGGAGAGCGAG 20 1032

BCLllA-548 - GGAGCUGACGGAGAGCGAGA 20 1033

BCLllA-549 - GCUGACGGAGAGCGAGAGGG 20 1034

BCLllA-550 - GAGAGCGAGAGGGUGGACUA 20 1035

BCLllA-551 - GAGAGGGUGGACUACGGCUU 20 1036

BCLllA-552 - AGAGGGUGGACUACGGCUUC 20 1037

BCLllA-553 - CUACGGCU UCGGGCUGAGCC 20 1038

BCLllA-554 - CGGCUUCGGGCUGAGCCUGG 20 1039

BCLllA-555 - CUUCGGGCUGAGCCUGGAGG 20 1040

BCLllA-556 - GCCACCACGAGAACAGCUCG 20 1041 BCLllA-557 - CCACCACGAGAACAGCUCGC 20 1042

BCLllA-558 - CACCACGAGAACAGCUCGCG 20 1043

BCLllA-559 - CGAGAACAGCUCGCGGGGCG 20 1044

BCLllA-560 - CAGCUCGCGGGGCGCGGUCG 20 1045

BCLllA-561 - AGCUCGCGGGGCGCGGUCGU 20 1046

BCLllA-562 - GCGGGGCGCGGUCGUGGGCG 20 1047

BCLllA-563 - CGGGGCGCGGUCGUGGGCGU 20 1048

BCLllA-564 - CGCCCUGCCCGACGUCAUGC 20 1049

BCLllA-565 - GCCCUGCCCGACGUCAUGCA 20 1050

BCLllA-566 - GCCCGACGUCAUGCAGGGCA 20 1051

BCLllA-567 - CUCCAUGCAGCACUUCAGCG 20 1052

BCLllA-568 - CUUCAGCGAGGCCUUCCACC 20 1053

BCLllA-569 - CGAGGCCUUCCACCAGGUCC 20 1054

BCLllA-570 - GAGGCCUUCCACCAGGUCCU 20 1055

BCLllA-571 - CUGGGCGAGAAGCAUAAGCG 20 1056

BCLllA-572 - GAAGCAUAAGCGCGGCCACC 20 1057

BCLllA-573 - UAAGCGCGGCCACCUGGCCG 20 1058

BCLllA-574 - CGGCCACCUGGCCGAGGCCG 20 1059

BCLllA-575 - GGCCACCUGGCCGAGGCCGA 20 1060

BCLllA-576 - UGGCCGAGGCCGAGGGCCAC 20 1061

BCLllA-577 - GGCCGAGGCCGAGGGCCACA 20 1062

BCLllA-578 - GGACACUUGCGACGAAGACU 20 1063

BCLllA-579 - CACUUGCGACGAAGACUCGG 20 1064

BCLllA-580 - UGCGACGAAGACUCGGUGGC 20 1065

BCLllA-581 - AGACUCGGUGGCCGGCGAGU 20 1066

BCLllA-582 - GAGUCGGACCGCAUAGACGA 20 1067

BCLllA-583 - AUAGACGAUGGCACUGUUAA 20 1068

BCLllA-584 - GAUGGCACUGUUAAUGGCCG 20 1069

BCLllA-585 - UAAUGGCCGCGGCUGCUCCC 20 1070

BCLllA-586 - AAUGGCCGCGGCUGCUCCCC 20 1071

BCLllA-587 - CGGCUGCUCCCCGGGCGAGU 20 1072

BCLllA-588 - CUCCCCGGGCGAGUCGGCCU 20 1073

BCLllA-589 - UCCCCGGGCGAGUCGGCCUC 20 1074

BCLllA-590 - CCCCGGGCGAGUCGGCCUCG 20 1075

BCLllA-591 - CCCGGGCGAGUCGGCCUCGG 20 1076

BCLllA-592 - CCGGGCGAGUCGGCCUCGGG 20 1077

BCLllA-593 - CCUGUCCAAAAAGCUGCUGC 20 1078

BCLllA-594 - CUGUCCAAAAAGCUGCUGCU 20 1079

BCLllA-595 - UAAGCGCAUCAAGCUCGAGA 20 1080

BCLllA-596 - GAAGGAGUUCGACCUGCCCC 20 1081

BCLllA-597 - CCCGGCCGCGAUGCCCAACA 20 1082

BCLllA-598 - CGGAGAACGUGUACUCGCAG 20 1083 BCLllA-599 - GUGUACUCGCAGUGGCUCGC 20 1084

BCLllA-600 - GCAGUGGCUCGCCGGCUACG 20 1085

BCLllA-601 - UCGCCGGCUACGCGGCCUCC 20 1086

BCLllA-602 - AAAGAUCCCUUCCUUAGCUU 20 1087

BCLllA-603 - AUCGCCUUUUGCCUCCUCGU 20 1088

BCLllA-604 - CUCCUCGUCGGAGCACUCCU 20 1089

BCLllA-605 - UCGGAGCACUCCUCGGAGAA 20 1090

BCLllA-606 - CGGAGCACUCCUCGGAGAAC 20 1091

BCLllA-607 - UUGCGCUUCUCCACACCGCC 20 1092

BCLllA-608 - UGCGCUUCUCCACACCGCCC 20 1093

BCLllA-609 - GCGCUUCUCCACACCGCCCG 20 1094

BCLllA-610 - CUCCACACCGCCCGGGGAGC 20 1095

BCLllA-611 - ACACCGCCCGGGGAGCUGGA 20 1096

BCLllA-612 - CCGCCCGGGGAGCUGGACGG 20 1097

BCLllA-613 - CGCCCGGGGAGCUGGACGGA 20 1098

BCLllA-614 - GGAGCUGGACGGAGGGAUCU 20 1099

BCLllA-615 - GAGCUGGACGGAGGGAUCUC 20 1100

BCLllA-616 - AGCUGGACGGAGGGAUCUCG 20 1101

BCLllA-617 - GGAGGGAUCUCGGGGCGCAG 20 1102

BCLllA-618 - GAUCUCGGGGCGCAGCGGCA 20 1103

BCLllA-619 - AUCUCGGGGCGCAGCGGCAC 20 1104

BCLllA-620 - GGGCGCAGCGGCACGGGAAG 20 1105

BCLllA-621 - CGCAGCGGCACGGGAAGUGG 20 1106

BCLllA-622 - GCAGCGGCACGGGAAGUGGA 20 1107

BCLllA-623 - GGGAGCACGCCCCAUAUUAG 20 1108

BCLllA-624 - CACGCCCCAUAUUAGUGGUC 20 1109

BCLllA-625 - ACGCCCCAUAUUAGUGGUCC 20 1110

BCLllA-626 - CCAUAUUAGUGGUCCGGGCC 20 1111

BCLllA-627 - CAUAUUAGUGGUCCGGGCCC 20 1112

BCLllA-628 - UUAGUGGUCCGGGCCCGGGC 20 1113

BCLllA-629 - GGGCAGGCCCAGCUCAAAAG 20 1114

BCLllA-630 - GGCAGGCCCAGCUCAAAAGA 20 1115

BCLllA-631 + GCGUCUGCCCUCUUUUGAGC 20 1116

BCLllA-632 + CGUCUGCCCUCUUUUGAGCU 20 1117

BCLllA-633 + UCUUUUGAGCUGGGCCUGCC 20 1118

BCLllA-634 + CUUUUGAGCUGGGCCUGCCC 20 1119

BCLllA-635 + GAGCUGGGCCUGCCCGGGCC 20 1120

BCLllA-636 + CCGGGCCCGGACCACUAAUA 20 1121

BCLllA-637 + CGGGCCCGGACCACUAAUAU 20 1122

BCLllA-638 + GGGCCCGGACCACUAAUAUG 20 1123

BCLllA-639 + GAUCCCUCCGUCCAGCUCCC 20 1124

BCLllA-640 + AUCCCUCCGUCCAGCUCCCC 20 1125 BCLllA-641 + CCUCCGUCCAGCUCCCCGGG 20 1126

BCLllA-642 + GUCCAGCUCCCCGGGCGGUG 20 1127

BCLllA-643 + GCGCAAACUCCCGU UCUCCG 20 1128

BCLllA-644 + CUCCGAGGAGUGCUCCGACG 20 1129

BCLllA-645 + CGAGGAGUGCUCCGACGAGG 20 1130

BCLllA-646 + UGCUCCGACGAGGAGGCAAA 20 1131

BCLllA-647 + GGAGGCAAAAGGCGAUUGUC 20 1132

BCLllA-648 + GUCUGGAGUCUCCGAAGCUA 20 1133

BCLllA-649 + GGAGUCUCCGAAGCUAAGGA 20 1134

BCLllA-650 + GAGUCUCCGAAGCUAAGGAA 20 1135

BCLllA-651 + GAAGGGAUCUUUGAGCUGCC 20 1136

BCLllA-652 + GGGAUCUUUGAGCUGCCUGG 20 1137

BCLllA-653 + CUGCCUGGAGGCCGCGUAGC 20 1138

BCLllA-654 + CGAGUACACGUUCUCCGUGU 20 1139

BCLllA-655 + GAGUACACGUUCUCCGUGUU 20 1140

BCLllA-656 + GUUCUCCGUGUUGGGCAUCG 20 1141

BCLllA-657 + UCCGUGUUGGGCAUCGCGGC 20 1142

BCLllA-658 + CCGUGUUGGGCAUCGCGGCC 20 1143

BCLllA-659 + CGUGUUGGGCAUCGCGGCCG 20 1144

BCLllA-660 + GUGUUGGGCAUCGCGGCCGG 20 1145

BCLllA-661 + UGGGCAUCGCGGCCGGGGGC 20 1146

BCLllA-662 + GAGCU UGAUGCGCUUAGAGA 20 1147

BCLllA-663 + AGCU UGAUGCGCUUAGAGAA 20 1148

BCLllA-664 + GCUUGAUGCGCUUAGAGAAG 20 1149

BCLllA-665 + AGAGAAGGGGCUCAGCGAGC 20 1150

BCLllA-666 + GAGAAGGGGCUCAGCGAGCU 20 1151

BCLllA-667 + AGAAGGGGCUCAGCGAGCUG 20 1152

BCLllA-668 + GCUGCCCAGCAGCAGCU UUU 20 1153

BCLllA-669 + CCAGCAGCAGCUUUUUGGAC 20 1154

BCLllA-670 + CUUUUUGGACAGGCCCCCCG 20 1155

BCLllA-671 + CCCCCCGAGGCCGACUCGCC 20 1156

BCLllA-672 + CCCCCGAGGCCGACUCGCCC 20 1157

BCLllA-673 + CCCCGAGGCCGACUCGCCCG 20 1158

BCLllA-674 + ACUCGCCCGGGGAGCAGCCG 20 1159

BCLllA-675 + UAACAGUGCCAUCGUCUAUG 20 1160

BCLllA-676 + GUCUAUGCGGUCCGACUCGC 20 1161

BCLllA-677 + CUUCGUCGCAAGUGUCCCUG 20 1162

BCLllA-678 + GCAAGUGUCCCUGUGGCCCU 20 1163

BCLllA-679 + GUCCCUGUGGCCCUCGGCCU 20 1164

BCLllA-680 + UGUGGCCCUCGGCCUCGGCC 20 1165

BCLllA-681 + GGCCCUCGGCCUCGGCCAGG 20 1166

BCLllA-682 + CGCGCUUAUGCUUCUCGCCC 20 1167 BCLllA-683 + UAUGCUUCUCGCCCAGGACC 20 1168

BCLllA-684 + GCUUCUCGCCCAGGACCUGG 20 1169

BCLllA-685 + CUCGCCCAGGACCUGGUGGA 20 1170

BCLllA-686 + GGCCUCGCUGAAGUGCUGCA 20 1171

BCLllA-687 + CACCAUGCCCUGCAUGACGU 20 1172

BCLllA-688 + ACCAUGCCCUGCAUGACGUC 20 1173

BCLllA-689 + UGCCCUGCAUGACGUCGGGC 20 1174

BCLllA-690 + GCCCUGCAUGACGUCGGGCA 20 1175

BCLllA-691 + GCAUGACGUCGGGCAGGGCG 20 1176

BCLllA-692 + CGCCCCGCGAGCUGUUCUCG 20 1177

BCLllA-693 + CCCGCGAGCUGUUCUCGUGG 20 1178

BCLllA-694 + CGUGGUGGCGCGCCGCCUCC 20 1179

BCLllA-695 - GGAGGAAGAGGAGGAGG 17 1180

BCLllA-696 - GGAGGAGGAGGAGCUGA 17 1181

BCLllA-697 - AGCUGACGGAGAGCGAG 17 1182

BCLllA-698 - GCUGACGGAGAGCGAGA 17 1183

BCLllA-699 - GACGGAGAGCGAGAGGG 17 1184

BCLllA-700 - AGCGAGAGGGUGGACUA 17 1185

BCLllA-701 - AGGGUGGACUACGGCUU 17 1186

BCLllA-702 - GGGUGGACUACGGCUUC 17 1187

BCLllA-703 - CGGCUUCGGGCUGAGCC 17 1188

BCLllA-704 - CUUCGGGCUGAGCCUGG 17 1189

BCLllA-705 - CGGGCUGAGCCUGGAGG 17 1190

BCLllA-706 - ACCACGAGAACAGCUCG 17 1191

BCLllA-707 - CCACGAGAACAGCUCGC 17 1192

BCLllA-708 - CACGAGAACAGCUCGCG 17 1193

BCLllA-709 - GAACAGCUCGCGGGGCG 17 1194

BCLllA-710 - CUCGCGGGGCGCGGUCG 17 1195

BCLllA-711 - UCGCGGGGCGCGGUCGU 17 1196

BCLllA-712 - GGGCGCGGUCGUGGGCG 17 1197

BCLllA-713 - GGCGCGGUCGUGGGCGU 17 1198

BCLllA-714 - CCUGCCCGACGUCAUGC 17 1199

BCLllA-715 - CUGCCCGACGUCAUGCA 17 1200

BCLllA-716 - CGACGUCAUGCAGGGCA 17 1201

BCLllA-717 - CAUGCAGCACUUCAGCG 17 1202

BCLllA-718 - CAGCGAGGCCUUCCACC 17 1203

BCLllA-719 - GGCCUUCCACCAGGUCC 17 1204

BCLllA-720 - GCCUUCCACCAGGUCCU 17 1205

BCLllA-721 - GGCGAGAAGCAUAAGCG 17 1206

BCLllA-722 - GCAUAAGCGCGGCCACC 17 1207

BCLllA-723 - GCGCGGCCACCUGGCCG 17 1208

BCLllA-724 - CCACCUGGCCGAGGCCG 17 1209 BCLllA-725 - CACCUGGCCGAGGCCGA 17 1210

BCLllA-726 - CCGAGGCCGAGGGCCAC 17 1211

BCLllA-727 - CGAGGCCGAGGGCCACA 17 1212

BCLllA-728 - CACUUGCGACGAAGACU 17 1213

BCLllA-729 - UUGCGACGAAGACUCGG 17 1214

BCLllA-730 - GACGAAGACUCGGUGGC 17 1215

BCLllA-731 - CUCGGUGGCCGGCGAGU 17 1216

BCLllA-732 - UCGGACCGCAUAGACGA 17 1217

BCLllA-733 - GACGAUGGCACUGUUAA 17 1218

BCLllA-734 - GGCACUGUUAAUGGCCG 17 1219

BCLllA-735 - UGGCCGCGGCUGCUCCC 17 1220

BCLllA-736 - GGCCGCGGCUGCUCCCC 17 1221

BCLllA-737 - CUGCUCCCCGGGCGAGU 17 1222

BCLllA-738 - CCCGGGCGAGUCGGCCU 17 1223

BCLllA-739 - CCGGGCGAGUCGGCCUC 17 1224

BCLllA-740 - CGGGCGAGUCGGCCUCG 17 1225

BCLllA-741 - GGGCGAGUCGGCCUCGG 17 1226

BCLllA-742 - GGCGAGUCGGCCUCGGG 17 1227

BCLllA-743 - GUCCAAAAAGCUGCUGC 17 1228

BCLllA-744 - UCCAAAAAGCUGCUGCU 17 1229

BCLllA-745 - GCGCAUCAAGCUCGAGA 17 1230

BCLllA-746 - GGAGUUCGACCUGCCCC 17 1231

BCLllA-747 - GGCCGCGAUGCCCAACA 17 1232

BCLllA-748 - AGAACGUGUACUCGCAG 17 1233

BCLllA-749 - UACUCGCAGUGGCUCGC 17 1234

BCLllA-750 - GUGGCUCGCCGGCUACG 17 1235

BCLllA-751 - CCGGCUACGCGGCCUCC 17 1236

BCLllA-752 - GAUCCCUUCCUUAGCUU 17 1237

BCLllA-753 - GCCUUUUGCCUCCUCGU 17 1238

BCLllA-754 - CUCGUCGGAGCACUCCU 17 1239

BCLllA-755 - GAGCACUCCUCGGAGAA 17 1240

BCLllA-756 - AGCACUCCUCGGAGAAC 17 1241

BCLllA-757 - CGCUUCUCCACACCGCC 17 1242

BCLllA-758 - GCUUCUCCACACCGCCC 17 1243

BCLllA-759 - CUUCUCCACACCGCCCG 17 1244

BCLllA-760 - CACACCGCCCGGGGAGC 17 1245

BCLllA-761 - CCGCCCGGGGAGCUGGA 17 1246

BCLllA-762 - CCCGGGGAGCUGGACGG 17 1247

BCLllA-763 - CCGGGGAGCUGGACGGA 17 1248

BCLllA-764 - GCUGGACGGAGGGAUCU 17 1249

BCLllA-765 - CUGGACGGAGGGAUCUC 17 1250

BCLllA-766 - UGGACGGAGGGAUCUCG 17 1251 BCLllA-767 - GGGAUCUCGGGGCGCAG 17 1252

BCLllA-768 - CUCGGGGCGCAGCGGCA 17 1253

BCLllA-769 - UCGGGGCGCAGCGGCAC 17 1254

BCLllA-770 - CGCAGCGGCACGGGAAG 17 1255

BCLllA-771 - AGCGGCACGGGAAGUGG 17 1256

BCLllA-772 - GCGGCACGGGAAGUGGA 17 1257

BCLllA-773 - AGCACGCCCCAUAUUAG 17 1258

BCLllA-774 - GCCCCAUAU UAGUGGUC 17 1259

BCLllA-775 - CCCCAUAU UAGUGGUCC 17 1260

BCLllA-776 - UAUUAGUGGUCCGGGCC 17 1261

BCLllA-777 - AU UAGUGGUCCGGGCCC 17 1262

BCLllA-778 - GUGGUCCGGGCCCGGGC 17 1263

BCLllA-779 - CAGGCCCAGCUCAAAAG 17 1264

BCLllA-780 - AGGCCCAGCUCAAAAGA 17 1265

BCLllA-781 + UCUGCCCUCU UUUGAGC 17 1266

BCLllA-782 + CUGCCCUCUU UUGAGCU 17 1267

BCLllA-783 + UUUGAGCUGGGCCUGCC 17 1268

BCLllA-784 + UUGAGCUGGGCCUGCCC 17 1269

BCLllA-785 + CUGGGCCUGCCCGGGCC 17 1270

BCLllA-786 + GGCCCGGACCACUAAUA 17 1271

BCLllA-787 + GCCCGGACCACUAAUAU 17 1272

BCLllA-788 + CCCGGACCACUAAUAUG 17 1273

BCLllA-789 + CCCUCCGUCCAGCUCCC 17 1274

BCLllA-790 + CCUCCGUCCAGCUCCCC 17 1275

BCLllA-791 + CCGUCCAGCUCCCCGGG 17 1276

BCLllA-792 + CAGCUCCCCGGGCGGUG 17 1277

BCLllA-793 + CAAACUCCCGUUCUCCG 17 1278

BCLllA-794 + CGAGGAGUGCUCCGACG 17 1279

BCLllA-795 + GGAGUGCUCCGACGAGG 17 1280

BCLllA-796 + UCCGACGAGGAGGCAAA 17 1281

BCLllA-797 + GGCAAAAGGCGAUUGUC 17 1282

BCLllA-798 + UGGAGUCUCCGAAGCUA 17 1283

BCLllA-799 + GUCUCCGAAGCUAAGGA 17 1284

BCLllA-800 + UCUCCGAAGCUAAGGAA 17 1285

BCLllA-801 + GGGAUCUUUGAGCUGCC 17 1286

BCLllA-802 + AUCUUUGAGCUGCCUGG 17 1287

BCLllA-803 + CCUGGAGGCCGCGUAGC 17 1288

BCLllA-804 + GUACACGUUCUCCGUGU 17 1289

BCLllA-805 + UACACGUUCUCCGUGUU 17 1290

BCLllA-806 + CUCCGUGUUGGGCAUCG 17 1291

BCLllA-807 + GUGUUGGGCAUCGCGGC 17 1292

BCLllA-808 + UGUUGGGCAUCGCGGCC 17 1293 BCLllA-809 + GUUGGGCAUCGCGGCCG 17 1294

BCLllA-810 + U UGGGCAUCGCGGCCGG 17 1295

BCLllA-811 + GCAUCGCGGCCGGGGGC 17 1296

BCLllA-812 + CUUGAUGCGCUUAGAGA 17 1297

BCLllA-813 + UUGAUGCGCUUAGAGAA 17 1298

BCLllA-814 + UGAUGCGCUUAGAGAAG 17 1299

BCLllA-815 + GAAGGGGCUCAGCGAGC 17 1300

BCLllA-816 + AAGGGGCUCAGCGAGCU 17 1301

BCLllA-817 + AGGGGCUCAGCGAGCUG 17 1302

BCLllA-818 + GCCCAGCAGCAGCUUU U 17 1303

BCLllA-819 + GCAGCAGCU UUUUGGAC 17 1304

BCLllA-820 + UUUGGACAGGCCCCCCG 17 1305

BCLllA-821 + CCCGAGGCCGACUCGCC 17 1306

BCLllA-822 + CCGAGGCCGACUCGCCC 17 1307

BCLllA-823 + CGAGGCCGACUCGCCCG 17 1308

BCLllA-824 + CGCCCGGGGAGCAGCCG 17 1309

BCLllA-825 + CAGUGCCAUCGUCUAUG 17 1310

BCLllA-826 + UAUGCGGUCCGACUCGC 17 1311

BCLllA-827 + CGUCGCAAGUGUCCCUG 17 1312

BCLllA-828 + AGUGUCCCUGUGGCCCU 17 1313

BCLllA-829 + CCUGUGGCCCUCGGCCU 17 1314

BCLllA-830 + GGCCCUCGGCCUCGGCC 17 1315

BCLllA-831 + CCUCGGCCUCGGCCAGG 17 1316

BCLllA-832 + GCUUAUGCU UCUCGCCC 17 1317

BCLllA-833 + GCUUCUCGCCCAGGACC 17 1318

BCLllA-834 + UCUCGCCCAGGACCUGG 17 1319

BCLllA-835 + GCCCAGGACCUGGUGGA 17 1320

BCLllA-836 + CUCGCUGAAGUGCUGCA 17 1321

BCLllA-837 + CAUGCCCUGCAUGACGU 17 1322

BCLllA-838 + AUGCCCUGCAUGACGUC 17 1323

BCLllA-839 + CCUGCAUGACGUCGGGC 17 1324

BCLllA-840 + CUGCAUGACGUCGGGCA 17 1325

BCLllA-841 + UGACGUCGGGCAGGGCG 17 1326

BCLllA-842 + CCCGCGAGCUGUUCUCG 17 1327

BCLllA-843 + GCGAGCUGUUCUCGUGG 17 1328

BCLllA-844 + GGUGGCGCGCCGCCUCC 17 1329

BCLllA-845 - CCCAGAGAGCUCAAGAUGUG 20 1330

BCLllA-846 - UCAAGAUGUGUGGCAGUUUU 20 1331

BCLllA-847 - GAUGUGUGGCAGUU UUCGGA 20 1332

BCLllA-848 + GCCACACAUCUUGAGCUCUC 20 1333

BCLllA-849 + CCACACAUCU UGAGCUCUCU 20 1334

BCLllA-850 + UCUCUGGGUACUACGCCGAA 20 1335 BCLllA-851 + CUCUGGGUACUACGCCGAAU 20 1336

BCLllA-852 + UCUGGGUACUACGCCGAAUG 20 1337

BCLllA-853 + CUGGGUACUACGCCGAAUGG 20 1338

BCLllA-854 - CUUCACACACCCCCAUU 17 1339

BCLllA-855 - AGAGAGCUCAAGAUGUG 17 1340

BCLllA-856 - AGAUGUGUGGCAGUUU U 17 1341

BCLllA-857 - GUGUGGCAGUUU UCGGA 17 1342

BCLllA-858 + ACACAUCUUGAGCUCUC 17 1343

BCLllA-859 + CACAUCUUGAGCUCUCU 17 1344

BCLllA-860 + CUGGGUACUACGCCGAA 17 1345

BCLllA-861 + UGGGUACUACGCCGAAU 17 1346

BCLllA-862 + GGGUACUACGCCGAAUG 17 1347

BCLllA-863 + GGUACUACGCCGAAUGG 17 1348

Table 2E provides exemplary targeting domains for knocking out the BCL11A gene. In an embodiment, the targeting domain is the exact complement of the target domain. Any of the targeting domains in the table can be used with a S. aureus Cas9 molecule that gives double stranded cleavage. Any of the targeting domains in the table can be used with a S. aureus Cas9 single- stranded break nucleases (nickases). In an embodiment, dual targeting is used to create two nicks. When selecting gRNAs for use in a nickase pair, one gRNA targets a domain in the complementary strand and the second gRNA targets a domain in the non-complementary strand, e.g., a gRNA comprising any minus strand targeting domain may be paired any gRNA comprising a plus strand targeting domain targeting ths same target position.

Table 2E

BCLllA-875 + UCCCGUUUGCUUAAGUG 17 1360

BCLllA-876 - UGAAGCCAUUCUUACAGAUG 20 1361

BCLllA-877 - AUGAACCAGACCACGGCCCG 20 1362

BCLllA-878 - UGAACCAGACCACGGCCCGU 20 1363

BCLllA-879 - G AACCAG ACCACGG CCCG U U 20 1364

BCLllA-880 - CCACGGCCCGUUGGGAGCUC 20 1365

BCLllA-881 - CGGCCCGUUGGGAGCUCCAG 20 1366

BCLllA-882 - GGCCCGUUGGGAGCUCCAGA 20 1367

BCLllA-883 - GCCCGUUGGGAGCUCCAGAA 20 1368

BCLllA-884 - GGAUCAUGACCUCCUCACCU 20 1369

BCLllA-885 - UCACCUGUGGGCAGUGCCAG 20 1370

BCLllA-886 - AGUGCCAGAUGAACUUCCCA 20 1371

BCLllA-887 - GUGCCAGAUGAACUUCCCAU 20 1372

BCLllA-888 - UGCCAGAUGAACUUCCCAUU 20 1373

BCLllA-889 - GCCAGAUGAACUUCCCAUUG 20 1374

BCLllA-890 - GGGGGACAUUCUUAUUUUUA 20 1375

BCLllA-891 - CUUAUUUUUAUCGAGCACAA 20 1376

BCLllA-892 - UUAUUUUUAUCGAGCACAAA 20 1377

BCLllA-893 - AUGCAAUGGCAGCCUCUGCU 20 1378

BCLllA-894 - GCCUCUGCUUAGAAAAAGCU 20 1379

BCLllA-895 - GCCACCUUCCCCUUCACCAA 20 1380

BCLllA-896 - CUUCCCCUUCACCAAUCGAG 20 1381

BCLllA-897 - UGAAAAAAGCAUCCAAUCCC 20 1382

BCLllA-898 - G A A A A A AG C A U C C A A U C C CG 20 1383

BCLllA-899 - GGUUGGCAUCCAGGUCACGC 20 1384

BCLllA-900 - UUGGCAUCCAGGUCACGCCA 20 1385

BCLllA-901 - GAUUGUUUAUCAACGUCAUC 20 1386

BCLllA-902 - UUGUUUAUCAACGUCAUCUA 20 1387

BCLllA-903 - UGUUUAUCAACGUCAUCUAG 20 1388

BCLllA-904 - CUAGAGGAAUUUGCCCCAAA 20 1389

BCLllA-905 - UAGAGGAAUUUGCCCCAAAC 20 1390

BCLllA-906 - AGCCAUUCUUACAGAUG 17 1391

BCLllA-907 - AACCAGACCACGGCCCG 17 1392

BCLllA-908 - ACCAGACCACGGCCCGU 17 1393

BCLllA-909 - CCAGACCACGGCCCGUU 17 1394

BCLllA-910 - CGGCCCGUUGGGAGCUC 17 1395

BCLllA-911 - CCCGUUGGGAGCUCCAG 17 1396

BCLllA-912 - CCGUUGGGAGCUCCAGA 17 1397

BCLllA-913 - CGUUGGGAGCUCCAGAA 17 1398

BCLllA-914 - UCAUGACCUCCUCACCU 17 1399

BCLllA-915 - CCUGUGGGCAGUGCCAG 17 1400

BCLllA-916 - GCCAGAUGAACUUCCCA 17 1401 BCLllA-917 - CCAGAUGAACUUCCCAU 17 1402

BCLllA-918 - CAGAUGAACUUCCCAUU 17 1403

BCLllA-919 - AGAUGAACUUCCCAU UG 17 1404

BCLllA-920 - GGACAUUCUUAUUUUUA 17 1405

BCLllA-921 - AU U U U U AU CG AGCACAA 17 1406

BCLllA-922 - UU UUUAUCGAGCACAAA 17 1407

BCLllA-923 - CAAUGGCAGCCUCUGCU 17 1408

BCLllA-924 - UCUGCU UAGAAAAAGCU 17 1409

BCLllA-925 - ACCUUCCCCUUCACCAA 17 1410

BCLllA-926 - CCCCUUCACCAAUCGAG 17 1411

BCLllA-927 - AAAAAGCAUCCAAUCCC 17 1412

BCLllA-928 - AAAAGCAUCCAAUCCCG 17 1413

BCLllA-929 - UGGCAUCCAGGUCACGC 17 1414

BCLllA-930 - GCAUCCAGGUCACGCCA 17 1415

BCLllA-931 - UGU UUAUCAACGUCAUC 17 1416

BCLllA-932 - UU UAUCAACGUCAUCUA 17 1417

BCLllA-933 - UUAUCAACGUCAUCUAG 17 1418

BCLllA-934 - GAGGAAUUUGCCCCAAA 17 1419

BCLllA-935 - AGGAAUUUGCCCCAAAC 17 1420

BCLllA-936 + UCAUCUGUAAGAAUGGCUUC 20 1421

BCLllA-937 + UGGUCUGGU UCAUCAUCUGU 20 1422

BCLllA-938 + AUCCCCUUCUGGAGCUCCCA 20 1423

BCLllA-939 + AGGAGGUCAUGAUCCCCUUC 20 1424

BCLllA-940 + GAGGAGGUCAUGAUCCCCUU 20 1425

BCLllA-941 + UCUGGCACUGCCCACAGGUG 20 1426

BCLllA-942 + AUCUGGCACUGCCCACAGGU 20 1427

BCLllA-943 + UCAUCUGGCACUGCCCACAG 20 1428

BCLllA-944 + AAAUAAGAAUGUCCCCCAAU 20 1429

BCLllA-945 + AAAAUAAGAAUGUCCCCCAA 20 1430

BCLllA-946 + AAAAAUAAGAAUGUCCCCCA 20 1431

BCLllA-947 + CGUUUGUGCUCGAUAAAAAU 20 1432

BCLllA-948 + UAUCCACAGCUUUUUCUAAG 20 1433

BCLllA-949 + UUUCAUCUCGAUUGGUGAAG 20 1434

BCLllA-950 + UUUUCAUCUCGAUUGGUGAA 20 1435

BCLllA-951 + U UUUUCAUCUCGAUUGGUGA 20 1436

BCLllA-952 + UUUUUUCAUCUCGAUUGGUG 20 1437

BCLllA-953 + UGCUUUUU UCAUCUCGAUUG 20 1438

BCLllA-954 + GGAUGCCAACCUCCACGGGA 20 1439

BCLllA-955 + GACCUGGAUGCCAACCUCCA 20 1440

BCLllA-956 + UGACCUGGAUGCCAACCUCC 20 1441

BCLllA-957 + UCGUCAUCCUCUGGCGUGAC 20 1442

BCLllA-958 + CUGCUAUGUGUUCCUGUUUG 20 1443 BCLllA-959 + CUGCUAUGUGUUCCUGUUUG 20 1444

BCLllA-960 + UCUGUAAGAAUGGCUUC 17 1445

BCLllA-961 + UCUGGUUCAUCAUCUGU 17 1446

BCLllA-962 + CCCUUCUGGAGCUCCCA 17 1447

BCLllA-963 + AGGUCAUGAUCCCCUUC 17 1448

BCLllA-964 + GAGGUCAUGAUCCCCUU 17 1449

BCLllA-965 + GGCACUGCCCACAGGUG 17 1450

BCLllA-966 + UGGCACUGCCCACAGGU 17 1451

BCLllA-967 + UCUGGCACUGCCCACAG 17 1452

BCLllA-968 + UAAGAAUGUCCCCCAAU 17 1453

BCLllA-969 + AUAAGAAUGUCCCCCAA 17 1454

BCLllA-970 + AAUAAGAAUGUCCCCCA 17 1455

BCLllA-971 + UUGUGCUCGAUAAAAAU 17 1456

BCLllA-972 + CCACAGCUU UUUCUAAG 17 1457

BCLllA-973 + CAUCUCGAUUGGUGAAG 17 1458

BCLllA-974 + UCAUCUCGAU UGGUGAA 17 1459

BCLllA-975 + U UCAUCUCGAUUGGUGA 17 1460

BCLllA-976 + UUUCAUCUCGAUUGGUG 17 1461

BCLllA-977 + U UUUUUCAUCUCGAUUG 17 1462

BCLllA-978 + UGCCAACCUCCACGGGA 17 1463

BCLllA-979 + CUGGAUGCCAACCUCCA 17 1464

BCLllA-980 + CCUGGAUGCCAACCUCC 17 1465

BCLllA-981 + UCAUCCUCUGGCGUGAC 17 1466

BCLllA-982 + UGCUAUGUGUUCCUGUU 17 1467

BCLllA-983 + CUGCUAUGUGUUCCUGU 17 1468

BCLllA-984 - CUCCUCCCCUCGU UCUGCAC 20 1469

BCLllA-985 - UCCUCCCCUCGUUCUGCACA 20 1470

BCLllA-986 - UGGAGCUCUAAUCCCCACGC 20 1471

BCLllA-987 - GGAGCUCUAAUCCCCACGCC 20 1472

BCLllA-988 - CUCUAAUCCCCACGCCUGGG 20 1473

BCLllA-989 - CCCCACGCCUGGGAUGAGUG 20 1474

BCLllA-990 - UGAGUGCAGAAUAUGCCCCG 20 1475

BCLllA-991 - CUCCCCUCGUUCUGCAC 17 1476

BCLllA-992 - UCCCCUCGUUCUGCACA 17 1477

BCLllA-993 - AGCUCUAAUCCCCACGC 17 1478

BCLllA-994 - GCUCUAAUCCCCACGCC 17 1479

BCLllA-995 - UAAUCCCCACGCCUGGG 17 1480

BCLllA-996 - CACGCCUGGGAUGAGUG 17 1481

BCLllA-997 - GUGCAGAAUAUGCCCCG 17 1482

BCLllA-998 + GAGGAGAGGCCCCUCCAGUG 20 1483

BCLllA-999 + CAUGUGCAGAACGAGGGGAG 20 1484

BCLllA-1000 + UCCAUGUGCAGAACGAGGGG 20 1485 BCLllA-1001 + CUCCAUGUGCAGAACGAGGG 20 1486

BCLllA-1002 + AGCUCCAUGUGCAGAACGAG 20 1487

BCLllA-1003 + GAGCUCCAUGUGCAGAACGA 20 1488

BCLllA-1004 + AGAGCUCCAUGUGCAGAACG 20 1489

BCLllA-1005 + UAGAGCUCCAUGUGCAGAAC 20 1490

BCLllA-1006 + AUUAGAGCUCCAUGUGCAGA 20 1491

BCLllA-1007 + GGGGAUUAGAGCUCCAUGUG 20 1492

BCLllA-1008 + CUCAUCCCAGGCGUGGGGAU 20 1493

BCLllA-1009 + UCUGCACUCAUCCCAGGCGU 20 1494

BCLllA-1010 + U UCUGCACUCAUCCCAGGCG 20 1495

BCLllA-1011 + AUUCUGCACUCAUCCCAGGC 20 1496

BCLllA-1012 + GAGAGGCCCCUCCAGUG 17 1497

BCLllA-1013 + GUGCAGAACGAGGGGAG 17 1498

BCLllA-1014 + AUGUGCAGAACGAGGGG 17 1499

BCLllA-1015 + CAUGUGCAGAACGAGGG 17 1500

BCLllA-1016 + UCCAUGUGCAGAACGAG 17 1501

BCLllA-1017 + CUCCAUGUGCAGAACGA 17 1502

BCLllA-1018 + GCUCCAUGUGCAGAACG 17 1503

BCLllA-1019 + AGCUCCAUGUGCAGAAC 17 1504

BCLllA-1020 + AGAGCUCCAUGUGCAGA 17 1505

BCLllA-1021 + GAUUAGAGCUCCAUGUG 17 1506

BCLllA-1022 + AUCCCAGGCGUGGGGAU 17 1507

BCLllA-1023 + GCACUCAUCCCAGGCGU 17 1508

BCLllA-1024 + UGCACUCAUCCCAGGCG 17 1509

BCLllA-1025 + CUGCACUCAUCCCAGGC 17 1510

BCLllA-1026 - GGUUUCUCUUGCAACACGCA 20 1511

BCLllA-1027 - GCAACACGCACAGAACACUC 20 1512

BCLllA-1028 - GCACAGAACACUCAUGGAUU 20 1513

BCLllA-1029 - UCAUGGAUUAAGAAUCUACU 20 1514

BCLllA-1030 - AU U AAG AAU CU ACU U AG AAA 20 1515

BCLllA-1031 - AAUCUACUUAGAAAGCGAAC 20 1516

BCLllA-1032 - AUCUACUUAGAAAGCGAACA 20 1517

BCLllA-1033 - CACGGAAGUCCCCUGACCCC 20 1518

BCLllA-1034 - CCCGCGGGUUGGUAUCCCUU 20 1519

BCLllA-1035 - UAUCCCUUCAGGACUAGGUG 20 1520

BCLllA-1036 - UCCUUCCCAGCCACCUCUCC 20 1521

BCLllA-1037 - CCUUCCCAGCCACCUCUCCA 20 1522

BCLllA-1038 - AAUAACCCCUUUAACCUGCU 20 1523

BCLllA-1039 - CUUUAACCUGCUAAGAAUAC 20 1524

BCLllA-1040 - UAAGAAUACCAGGAUCAGUA 20 1525

BCLllA-1041 - AGAAUACCAGGAUCAGUAUC 20 1526

BCLllA-1042 - AAUACCAGGAUCAGUAUCGA 20 1527 BCLllA-1043 - GAGAGAGGCUUCCGGCCUGG 20 1528

BCLllA-1044 - AGAGGCUUCCGGCCUGGCAG 20 1529

BCLllA-1045 - CCCCCCUGUUUAGUCCACCA 20 1530

BCLllA-1046 - GUCCACCACCGAGACAUCAC 20 1531

BCLllA-1047 - UCACUUGGACCCCCACCGCA 20 1532

BCLllA-1048 - ACCCCCACCGCAUAGAGCGC 20 1533

BCLllA-1049 - CCCCCACCGCAUAGAGCGCC 20 1534

BCLllA-1050 - CCCCACCGCAUAGAGCGCCU 20 1535

BCLllA-1051 - ACCGCAUAGAGCGCCUGGGG 20 1536

BCLllA-1052 - CCGCAUAGAGCGCCUGGGGG 20 1537

BCLllA-1053 - CAUAGAGCGCCUGGGGGCGG 20 1538

BCLllA-1054 - UGGCCCUGGCCACCCAUCAC 20 1539

BCLllA-1055 - CAUCACCCGAGUGCCUUUGA 20 1540

BCLllA-1056 - CCUUUGACAGGGUGCUGCGG 20 1541

BCLllA-1057 - UGCGGUUGAAUCCAAUGGCU 20 1542

BCLllA-1058 - GCGGUUGAAUCCAAUGGCUA 20 1543

BCLllA-1059 - UGGCUAUGGAGCCUCCCGCC 20 1544

BCLllA-1060 - CCUCCCGCCAUGGAUUUCUC 20 1545

BCLllA-1061 - CUCCCGCCAUGGAUUUCUCU 20 1546

BCLllA-1062 - AUGGAUUUCUCUAGGAGACU 20 1547

BCLllA-1063 - GGAUUUCUCUAGGAGACUUA 20 1548

BCLllA-1064 - UAGGAGACUUAGAGAGCUGG 20 1549

BCLllA-1065 - AGGAGACUUAGAGAGCUGGC 20 1550

BCLllA-1066 - GGAGACUUAGAGAGCUGGCA 20 1551

BCLllA-1067 - CCCGGUCAAGUCCAAGUCAU 20 1552

BCLllA-1068 - GCGGCAAGACGUUCAAAUUU 20 1553

BCLllA-1069 - UGGUGCACCGGCGCAGCCAC 20 1554

BCLllA-1070 - GCACCGGCGCAGCCACACGG 20 1555

BCLllA-1071 - ACCGGCGCAGCCACACGGGC 20 1556

BCLllA-1072 - CGUGCACCCAGGCCAGCAAG 20 1557

BCLllA-1073 - CCAGCAAGCUGAAGCGCCAC 20 1558

BCLllA-1074 - GUCUCUCCACCGCCAGCUCC 20 1559

BCLllA-1075 - UCUCUCCACCGCCAGCUCCC 20 1560

BCLllA-1076 - AACCCGGCACCAGCGACUUG 20 1561

BCLllA-1077 - AGUCCGUGGUGGCCAAGUUC 20 1562

BCLllA-1078 - CGUGGUGGCCAAGUUCAAGA 20 1563

BCLllA-1079 - UGGUGGCCAAGUUCAAGAGC 20 1564

BCLllA-1080 - AGAACGACCCCAACCUGAUC 20 1565

BCLllA-1081 - GAACGACCCCAACCUGAUCC 20 1566

BCLllA-1082 - ACGACCCCAACCUGAUCCCG 20 1567

BCLllA-1083 - CCCCAACCUGAUCCCGGAGA 20 1568

BCLllA-1084 - CCCAACCUGAUCCCGGAGAA 20 1569 BCLllA-1085 - CCAACCUGAUCCCGGAGAAC 20 1570

BCLllA-1086 - CCUGAUCCCGGAGAACGGGG 20 1571

BCLllA-1087 - UGAUCCCGGAGAACGGGGAC 20 1572

BCLllA-1088 - GAUCCCGGAGAACGGGGACG 20 1573

BCLllA-1089 - UCCCGGAGAACGGGGACGAG 20 1574

BCLllA-1090 - CCCGGAGAACGGGGACGAGG 20 1575

BCLllA-1091 - GGAGAACGGGGACGAGGAGG 20 1576

BCLllA-1092 - AGAACGGGGACGAGGAGGAA 20 1577

BCLllA-1093 - GAACGGGGACGAGGAGGAAG 20 1578

BCLllA-1094 - ACGGGGACGAGGAGGAAGAG 20 1579

BCLllA-1095 - CGAGGAGGAAGAGGAGGACG 20 1580

BCLllA-1096 - AGGAGGAAGAGGAGGACGAC 20 1581

BCLllA-1097 - GGAGGAAGAGGAGGACGACG 20 1582

BCLllA-1098 - GGAAGAGGAGGACGACGAGG 20 1583

BCLllA-1099 - AAGAGGAGGACGACGAGGAA 20 1584

BCLllA-1100 - AGAGGAGGACGACGAGGAAG 20 1585

BCLllA-1101 - GGAGGACGACGAGGAAGAGG 20 1586

BCLllA-1102 - GGACGACGAGGAAGAGGAAG 20 1587

BCLllA-1103 - ACGACGAGGAAGAGGAAGAA 20 1588

BCLllA-1104 - CGACGAGGAAGAGGAAGAAG 20 1589

BCLllA-1105 - ACGAGGAAGAGGAAGAAGAG 20 1590

BCLllA-1106 - CGAGGAAGAGGAAGAAGAGG 20 1591

BCLllA-1107 - GGAAGAGGAAGAAGAGGAGG 20 1592

BCLllA-1108 - AAGAGGAAGAAGAGGAGGAA 20 1593

BCLllA-1109 - AGAGGAAGAAGAGGAGGAAG 20 1594

BCLllA-1110 - AGGAAGAAGAGGAGGAAGAG 20 1595

BCLllA-1111 - GGAAGAAGAGGAGGAAGAGG 20 1596

BCLllA-1112 - AAGAAGAGGAGGAAGAGGAG 20 1597

BCLllA-1113 - AGAAGAGGAGGAAGAGGAGG 20 1598

BCLllA-1114 - AAGAGGAGGAAGAGGAGGAG 20 1599

BCLllA-1115 - AGAGGAGGAAGAGGAGGAGG 20 1600

BCLllA-1116 - AAGAGGAGGAGGAGGAGCUG 20 1601

BCLllA-1117 - AGAGGAGGAGGAGGAGCUGA 20 1602

BCLllA-1118 - AGGAGGAGGAGGAGCUGACG 20 1603

BCLllA-1119 - GGAGGAGGAGCUGACGGAGA 20 1604

BCLllA-1120 - AGGAGGAGCUGACGGAGAGC 20 1605

BCLllA-1121 - GAGGAGCUGACGGAGAGCGA 20 1606

BCLllA-1122 - AGCUGACGGAGAGCGAGAGG 20 1607

BCLllA-1123 - CGAGAGGGUGGACUACGGCU 20 1608

BCLllA-1124 - GGGUGGACUACGGCUUCGGG 20 1609

BCLllA-1125 - ACUACGGCUUCGGGCUGAGC 20 1610

BCLllA-1126 - CUACGGCUUCGGGCUGAGCC 20 1611 BCLllA-1127 - CCUGGAGGCGGCGCGCCACC 20 1612

BCLllA-1128 - UGGAGGCGGCGCGCCACCAC 20 1613

BCLllA-1129 - CGCCACCACGAGAACAGCUC 20 1614

BCLllA-1130 - GCCACCACGAGAACAGCUCG 20 1615

BCLllA-1131 - ACAGCUCGCGGGGCGCGGUC 20 1616

BCLllA-1132 - CGCGGGGCGCGGUCGUGGGC 20 1617

BCLllA-1133 - CGCGGUCGUGGGCGUGGGCG 20 1618

BCLllA-1134 - CGGUCGUGGGCGUGGGCGAC 20 1619

BCLllA-1135 - GCGCCCUGCCCGACGUCAUG 20 1620

BCLllA-1136 - CAGCUCCAUGCAGCACUUCA 20 1621

BCLllA-1137 - GCGAGGCCUUCCACCAGGUC 20 1622

BCLllA-1138 - GGCCUUCCACCAGGUCCUGG 20 1623

BCLllA-1139 - CCUUCCACCAGGUCCUGGGC 20 1624

BCLllA-1140 - GCAUAAGCGCGGCCACCUGG 20 1625

BCLllA-1141 - GCGCGGCCACCUGGCCGAGG 20 1626

BCLllA-1142 - GCGGCCACCUGGCCGAGGCC 20 1627

BCLllA-1143 - CUGGCCGAGGCCGAGGGCCA 20 1628

BCLllA-1144 - UGGCCGAGGCCGAGGGCCAC 20 1629

BCLllA-1145 - GGGCCACAGGGACACUUGCG 20 1630

BCLllA-1146 - CGACGAAGACUCGGUGGCCG 20 1631

BCLllA-1147 - AAGACUCGGUGGCCGGCGAG 20 1632

BCLllA-1148 - UUAAUGGCCGCGGCUGCUCC 20 1633

BCLllA-1149 - UGGCCGCGGCUGCUCCCCGG 20 1634

BCLllA-1150 - GCUCCCCGGGCGAGUCGGCC 20 1635

BCLllA-1151 - CUCCCCGGGCGAGUCGGCCU 20 1636

BCLllA-1152 - UCCCCGGGCGAGUCGGCCUC 20 1637

BCLllA-1153 - CCCCGGGCGAGUCGGCCUCG 20 1638

BCLllA-1154 - GCCUGUCCAAAAAGCUGCUG 20 1639

BCLllA-1155 - UGCUGGGCAGCCCCAGCUCG 20 1640

BCLllA-1156 - CUUCUCUAAGCGCAUCAAGC 20 1641

BCLllA-1157 - UCUCUAAGCGCAUCAAGCUC 20 1642

BCLllA-1158 - CUAAGCGCAUCAAGCUCGAG 20 1643

BCLllA-1159 - UAAGCGCAUCAAGCUCGAGA 20 1644

BCLllA-1160 - CCCCGGCCGCGAUGCCCAAC 20 1645

BCLllA-1161 - CCCGGCCGCGAUGCCCAACA 20 1646

BCLllA-1162 - CGGCCGCGAUGCCCAACACG 20 1647

BCLllA-1163 - CAAAGAUCCCUUCCUUAGCU 20 1648

BCLllA-1164 - AAAGAUCCCUUCCUUAGCUU 20 1649

BCLllA-1165 - AAUCGCCUUUUGCCUCCUCG 20 1650

BCLllA-1166 - AUCGCCUUUUGCCUCCUCGU 20 1651

BCLllA-1167 - CCUCCUCGUCGGAGCACUCC 20 1652

BCLllA-1168 - CUCCUCGUCGGAGCACUCCU 20 1653 BCLllA-1169 - CCUCGUCGGAGCACUCCUCG 20 1654

BCLllA-1170 - GUCGGAGCACUCCUCGGAGA 20 1655

BCLllA-1171 - UCGGAGCACUCCUCGGAGAA 20 1656

BCLllA-1172 - CGGAGCACUCCUCGGAGAAC 20 1657

BCLllA-1173 - UUUGCGCUUCUCCACACCGC 20 1658

BCLllA-1174 - UUGCGCUUCUCCACACCGCC 20 1659

BCLllA-1175 - UGCGCUUCUCCACACCGCCC 20 1660

BCLllA-1176 - GCGCUUCUCCACACCGCCCG 20 1661

BCLllA-1177 - UCUCCACACCGCCCGGGGAG 20 1662

BCLllA-1178 - CACACCGCCCGGGGAGCUGG 20 1663

BCLllA-1179 - ACACCGCCCGGGGAGCUGGA 20 1664

BCLllA-1180 - ACCGCCCGGGGAGCUGGACG 20 1665

BCLllA-1181 - CCGCCCGGGGAGCUGGACGG 20 1666

BCLllA-1182 - GGGAGCUGGACGGAGGGAUC 20 1667

BCLllA-1183 - GGAGCUGGACGGAGGGAUCU 20 1668

BCLllA-1184 - GGAUCUCGGGGCGCAGCGGC 20 1669

BCLllA-1185 - GAUCUCGGGGCGCAGCGGCA 20 1670

BCLllA-1186 - AUCUCGGGGCGCAGCGGCAC 20 1671

BCLllA-1187 - GGGGCGCAGCGGCACGGGAA 20 1672

BCLllA-1188 - GGGCGCAGCGGCACGGGAAG 20 1673

BCLllA-1189 - GCGCAGCGGCACGGGAAGUG 20 1674

BCLllA-1190 - CGCAGCGGCACGGGAAGUGG 20 1675

BCLllA-1191 - GCAGCGGCACGGGAAGUGGA 20 1676

BCLllA-1192 - GCACGCCCCAUAUUAGUGGU 20 1677

BCLllA-1193 - CCCAUAUUAGUGGUCCGGGC 20 1678

BCLllA-1194 - CCCGGGCAGGCCCAGCUCAA 20 1679

BCLllA-1195 - CGGGCAGGCCCAGCU C A A A A 20 1680

BCLllA-1196 - UUCUCUUGCAACACGCA 17 1681

BCLllA-1197 - ACACGCACAGAACACUC 17 1682

BCLllA-1198 - CAGAACACUCAUGGAUU 17 1683

BCLllA-1199 - UGGAUUAAGAAUCUACU 17 1684

BCLllA-1200 - AAGAAUCUACUUAGAAA 17 1685

BCLllA-1201 - CUACUUAGAAAGCGAAC 17 1686

BCLllA-1202 - UACUUAGAAAGCGAACA 17 1687

BCLllA-1203 - GGAAGUCCCCUGACCCC 17 1688

BCLllA-1204 - GCGGGUUGGUAUCCCUU 17 1689

BCLllA-1205 - CCCUUCAGGACUAGGUG 17 1690

BCLllA-1206 - UUCCCAGCCACCUCUCC 17 1691

BCLllA-1207 - UCCCAGCCACCUCUCCA 17 1692

BCLllA-1208 - AACCCCUUUAACCUGCU 17 1693

BCLllA-1209 - UAACCUGCUAAGAAUAC 17 1694

BCLllA-1210 - GAAUACCAGGAUCAGUA 17 1695 BCLllA-1211 - AUACCAGGAUCAGUAUC 17 1696

BCLllA-1212 - ACCAGGAUCAGUAUCGA 17 1697

BCLllA-1213 - AGAGGCUUCCGGCCUGG 17 1698

BCLllA-1214 - GGCUUCCGGCCUGGCAG 17 1699

BCLllA-1215 - CCCUGUUUAGUCCACCA 17 1700

BCLllA-1216 - CACCACCGAGACAUCAC 17 1701

BCLllA-1217 - CUUGGACCCCCACCGCA 17 1702

BCLllA-1218 - CCCACCGCAUAGAGCGC 17 1703

BCLllA-1219 - CCACCGCAUAGAGCGCC 17 1704

BCLllA-1220 - CACCGCAUAGAGCGCCU 17 1705

BCLllA-1221 - GCAUAGAGCGCCUGGGG 17 1706

BCLllA-1222 - CAUAGAGCGCCUGGGGG 17 1707

BCLllA-1223 - AGAGCGCCUGGGGGCGG 17 1708

BCLllA-1224 - CCCUGGCCACCCAUCAC 17 1709

BCLllA-1225 - CACCCGAGUGCCUUUGA 17 1710

BCLllA-1226 - UUGACAGGGUGCUGCGG 17 1711

BCLllA-1227 - GGUUGAAUCCAAUGGCU 17 1712

BCLllA-1228 - GUUGAAUCCAAUGGCUA 17 1713

BCLllA-1229 - CUAUGGAGCCUCCCGCC 17 1714

BCLllA-1230 - CCCGCCAUGGAUUUCUC 17 1715

BCLllA-1231 - CCGCCAUGGAUUUCUCU 17 1716

BCLllA-1232 - GAUUUCUCUAGGAGACU 17 1717

BCLllA-1233 - UUUCUCUAGGAGACUUA 17 1718

BCLllA-1234 - GAGACUUAGAGAGCUGG 17 1719

BCLllA-1235 - AGACUUAGAGAGCUGGC 17 1720

BCLllA-1236 - GACUUAGAGAGCUGGCA 17 1721

BCLllA-1237 - GGUCAAGUCCAAGUCAU 17 1722

BCLllA-1238 - GCAAGACG U U CAAAU U U 17 1723

BCLllA-1239 - UGCACCGGCGCAGCCAC 17 1724

BCLllA-1240 - CCGGCGCAGCCACACGG 17 1725

BCLllA-1241 - GGCGCAGCCACACGGGC 17 1726

BCLllA-1242 - GCACCCAGGCCAGCAAG 17 1727

BCLllA-1243 - GCAAGCUGAAGCGCCAC 17 1728

BCLllA-1244 - UCUCCACCGCCAGCUCC 17 1729

BCLllA-1245 - CUCCACCGCCAGCUCCC 17 1730

BCLllA-1246 - CCGGCACCAGCGACUUG 17 1731

BCLllA-1247 - CCGUGGUGGCCAAGUUC 17 1732

BCLllA-1248 - GGUGGCCAAGUUCAAGA 17 1733

BCLllA-1249 - UGGCCAAG U U CAAG AG C 17 1734

BCLllA-1250 - ACGACCCCAACCUGAUC 17 1735

BCLllA-1251 - CGACCCCAACCUGAUCC 17 1736

BCLllA-1252 - ACCCCAACCUGAUCCCG 17 1737 BCLllA-1253 - CAACCUGAUCCCGGAGA 17 1738

BCLllA-1254 - AACCUGAUCCCGGAGAA 17 1739

BCLllA-1255 - ACCUGAUCCCGGAGAAC 17 1740

BCLllA-1256 - GAUCCCGGAGAACGGGG 17 1741

BCLllA-1257 - UCCCGGAGAACGGGGAC 17 1742

BCLllA-1258 - CCCGGAGAACGGGGACG 17 1743

BCLllA-1259 - CGGAGAACGGGGACGAG 17 1744

BCLllA-1260 - GGAGAACGGGGACGAGG 17 1745

BCLllA-1261 - GAACGGGGACGAGGAGG 17 1746

BCLllA-1262 - ACGGGGACGAGGAGGAA 17 1747

BCLllA-1263 - CGGGGACGAGGAGGAAG 17 1748

BCLllA-1264 - GGGACGAGGAGGAAGAG 17 1749

BCLllA-1265 - GGAGGAAGAGGAGGACG 17 1750

BCLllA-1266 - AGGAAGAGGAGGACGAC 17 1751

BCLllA-1267 - GGAAGAGGAGGACGACG 17 1752

BCLllA-1268 - AGAGGAGGACGACGAGG 17 1753

BCLllA-1269 - AGGAGGACGACGAGGAA 17 1754

BCLllA-1270 - GGAGGACGACGAGGAAG 17 1755

BCLllA-1271 - GGACGACGAGGAAGAGG 17 1756

BCLllA-1272 - CGACGAGGAAGAGGAAG 17 1757

BCLllA-1273 - ACGAGGAAGAGGAAGAA 17 1758

BCLllA-1274 - CGAGGAAGAGGAAGAAG 17 1759

BCLllA-1275 - AGGAAGAGGAAGAAGAG 17 1760

BCLllA-1276 - GGAAGAGGAAGAAGAGG 17 1761

BCLllA-1277 - AGAGGAAGAAGAGGAGG 17 1762

BCLllA-1278 - AGGAAGAAGAGGAGGAA 17 1763

BCLllA-1279 - GGAAGAAGAGGAGGAAG 17 1764

BCLllA-1280 - AAGAAGAGGAGGAAGAG 17 1765

BCLllA-1281 - AGAAGAGGAGGAAGAGG 17 1766

BCLllA-1282 - AAGAGGAGGAAGAGGAG 17 1767

BCLllA-1283 - AGAGGAGGAAGAGGAGG 17 1768

BCLllA-1284 - AGGAGGAAGAGGAGGAG 17 1769

BCLllA-1285 - GGAGGAAGAGGAGGAGG 17 1770

BCLllA-1286 - AGGAGGAGGAGGAGCUG 17 1771

BCLllA-1287 - GGAGGAGGAGGAGCUGA 17 1772

BCLllA-1288 - AGGAGGAGGAGCUGACG 17 1773

BCLllA-1289 - GGAGGAGCUGACGGAGA 17 1774

BCLllA-1290 - AGGAGCUGACGGAGAGC 17 1775

BCLllA-1291 - GAGCUGACGGAGAGCGA 17 1776

BCLllA-1292 - UGACGGAGAGCGAGAGG 17 1777

BCLllA-1293 - GAGGGUGGACUACGGCU 17 1778

BCLllA-1294 - UGGACUACGGCUUCGGG 17 1779 BCLllA-1295 - ACGGCUUCGGGCUGAGC 17 1780

BCLllA-1296 - CGGCUUCGGGCUGAGCC 17 1781

BCLllA-1297 - GGAGGCGGCGCGCCACC 17 1782

BCLllA-1298 - AGGCGGCGCGCCACCAC 17 1783

BCLllA-1299 - CACCACG AG AACAG CU C 17 1784

BCLllA-1300 - ACCACGAGAACAGCUCG 17 1785

BCLllA-1301 - GCUCGCGGGGCGCGGUC 17 1786

BCLllA-1302 - GGGGCGCGGUCGUGGGC 17 1787

BCLllA-1303 - GGUCGUGGGCGUGGGCG 17 1788

BCLllA-1304 - UCGUGGGCGUGGGCGAC 17 1789

BCLllA-1305 - CCCUGCCCGACGUCAUG 17 1790

BCLllA-1306 - CUCCAUGCAGCACUUCA 17 1791

BCLllA-1307 - AGGCCUUCCACCAGGUC 17 1792

BCLllA-1308 - CUUCCACCAGGUCCUGG 17 1793

BCLllA-1309 - UCCACCAGGUCCUGGGC 17 1794

BCLllA-1310 - UAAGCGCGGCCACCUGG 17 1795

BCLllA-1311 - CGGCCACCUGGCCGAGG 17 1796

BCLllA-1312 - GCCACCUGGCCGAGGCC 17 1797

BCLllA-1313 - GCCGAGGCCGAGGGCCA 17 1798

BCLllA-1314 - CCGAGGCCGAGGGCCAC 17 1799

BCLllA-1315 - CCACAGGGACACUUGCG 17 1800

BCLllA-1316 - CGAAGACUCGGUGGCCG 17 1801

BCLllA-1317 - ACUCGGUGGCCGGCGAG 17 1802

BCLllA-1318 - AUGGCCGCGGCUGCUCC 17 1803

BCLllA-1319 - CCGCGGCUGCUCCCCGG 17 1804

BCLllA-1320 - CCCCGGGCGAGUCGGCC 17 1805

BCLllA-1321 - CCCGGGCGAGUCGGCCU 17 1806

BCLllA-1322 - CCGGGCGAGUCGGCCUC 17 1807

BCLllA-1323 - CGGGCGAGUCGGCCUCG 17 1808

BCLllA-1324 - UGUCCAAAAAGCUGCUG 17 1809

BCLllA-1325 - UGGGCAGCCCCAGCUCG 17 1810

BCLllA-1326 - CUCUAAGCGCAUCAAGC 17 1811

BCLllA-1327 - CUAAGCGCAUCAAGCUC 17 1812

BCLllA-1328 - AGCGCAUCAAGCUCGAG 17 1813

BCLllA-1329 - GCGCAUCAAGCUCGAGA 17 1814

BCLllA-1330 - CGGCCGCGAUGCCCAAC 17 1815

BCLllA-1331 - GGCCGCGAUGCCCAACA 17 1816

BCLllA-1332 - CCGCGAUGCCCAACACG 17 1817

BCLllA-1333 - AGAUCCCUUCCUUAGCU 17 1818

BCLllA-1334 - GAUCCCUUCCUUAGCUU 17 1819

BCLllA-1335 - CGCCUUUUGCCUCCUCG 17 1820

BCLllA-1336 - GCCUUUUGCCUCCUCGU 17 1821 BCLllA-1337 - CCUCGUCGGAGCACUCC 17 1822

BCLllA-1338 - CUCGUCGGAGCACUCCU 17 1823

BCLllA-1339 - CGUCGGAGCACUCCUCG 17 1824

BCLllA-1340 - GGAGCACUCCUCGGAGA 17 1825

BCLllA-1341 - GAGCACUCCUCGGAGAA 17 1826

BCLllA-1342 - AGCACUCCUCGGAGAAC 17 1827

BCLllA-1343 - GCGCUUCUCCACACCGC 17 1828

BCLllA-1344 - CGCUUCUCCACACCGCC 17 1829

BCLllA-1345 - GCUUCUCCACACCGCCC 17 1830

BCLllA-1346 - CUUCUCCACACCGCCCG 17 1831

BCLllA-1347 - CCACACCGCCCGGGGAG 17 1832

BCLllA-1348 - ACCGCCCGGGGAGCUGG 17 1833

BCLllA-1349 - CCGCCCGGGGAGCUGGA 17 1834

BCLllA-1350 - GCCCGGGGAGCUGGACG 17 1835

BCLllA-1351 - CCCGGGGAGCUGGACGG 17 1836

BCLllA-1352 - AGCUGGACGGAGGGAUC 17 1837

BCLllA-1353 - GCUGGACGGAGGGAUCU 17 1838

BCLllA-1354 - UCUCGGGGCGCAGCGGC 17 1839

BCLllA-1355 - CUCGGGGCGCAGCGGCA 17 1840

BCLllA-1356 - UCGGGGCGCAGCGGCAC 17 1841

BCLllA-1357 - GCGCAGCGGCACGGGAA 17 1842

BCLllA-1358 - CGCAGCGGCACGGGAAG 17 1843

BCLllA-1359 - CAGCGGCACGGGAAGUG 17 1844

BCLllA-1360 - AGCGGCACGGGAAGUGG 17 1845

BCLllA-1361 - GCGGCACGGGAAGUGGA 17 1846

BCLllA-1362 - CGCCCCAUAU UAGUGGU 17 1847

BCLllA-1363 - AUAUUAGUGGUCCGGGC 17 1848

BCLllA-1364 - GGGCAGGCCCAGCUCAA 17 1849

BCLllA-1365 - GCAGGCCCAGCU C A A A A 17 1850

BCLllA-1366 + AAGUUGUACAUGUGUAGCUG 20 1851

BCLllA-1367 + GCAAGAGAAACCAUGCACUG 20 1852

BCLllA-1368 + GUGUUCUGUGCGUGU UGCAA 20 1853

BCLllA-1369 + GAGUGUUCUGUGCGUGUUGC 20 1854

BCLllA-1370 + UCUAAGUAGAUUCUUAAUCC 20 1855

BCLllA-1371 + GAUACCAACCCGCGGGGUCA 20 1856

BCLllA-1372 + GGAUACCAACCCGCGGGGUC 20 1857

BCLllA-1373 + GGGAUACCAACCCGCGGGGU 20 1858

BCLllA-1374 + CCUGAAGGGAUACCAACCCG 20 1859

BCLllA-1375 + UCCUGAAGGGAUACCAACCC 20 1860

BCLllA-1376 + CAUUCUGCACCUAGUCCUGA 20 1861

BCLllA-1377 + ACAUUCUGCACCUAGUCCUG 20 1862

BCLllA-1378 + AGGACAUUCUGCACCUAGUC 20 1863 BCLllA-1379 + CCCAUGGAGAGGUGGCUGGG 20 1864

BCLllA-1380 + AAUCCCAUGGAGAGGUGGCU 20 1865

BCLllA-1381 + GAAUCCCAUGGAGAGGUGGC 20 1866

BCLllA-1382 + UGAAUCCCAUGGAGAGGUGG 20 1867

BCLllA-1383 + UCUGCAAUAUGAAUCCCAUG 20 1868

BCLllA-1384 + UGUCUGCAAUAUGAAUCCCA 20 1869

BCLllA-1385 + U UGUCUGCAAUAUGAAUCCC 20 1870

BCLllA-1386 + AAGGGGUUAUUGUCUGCAAU 20 1871

BCLllA-1387 + UGGUAUUCUUAGCAGGUUAA 20 1872

BCLllA-1388 + CUGGUAUUCUUAGCAGGUUA 20 1873

BCLllA-1389 + AAAGCGCCCUUCUGCCAGGC 20 1874

BCLllA-1390 + GAAAGCGCCCUUCUGCCAGG 20 1875

BCLllA-1391 + CUAAACAGGGGGGGAGUGGG 20 1876

BCLllA-1392 + ACUAAACAGGGGGGGAGUGG 20 1877

BCLllA-1393 + GUGGACUAAACAGGGGGGGA 20 1878

BCLllA-1394 + GGUGGUGGACUAAACAGGGG 20 1879

BCLllA-1395 + CGGUGGUGGACUAAACAGGG 20 1880

BCLllA-1396 + UCGGUGGUGGACUAAACAGG 20 1881

BCLllA-1397 + CUCGGUGGUGGACUAAACAG 20 1882

BCLllA-1398 + UCUCGGUGGUGGACUAAACA 20 1883

BCLllA-1399 + GUCUCGGUGGUGGACUAAAC 20 1884

BCLllA-1400 + UGUCUCGGUGGUGGACUAAA 20 1885

BCLllA-1401 + GUCCAAGUGAUGUCUCGGUG 20 1886

BCLllA-1402 + CCCCAGGCGCUCUAUGCGGU 20 1887

BCLllA-1403 + CCCCCAGGCGCUCUAUGCGG 20 1888

BCLllA-1404 + GCCCCCAGGCGCUCUAUGCG 20 1889

BCLllA-1405 + GCACUCGGGUGAUGGGUGGC 20 1890

BCLllA-1406 + CUGUCAAAGGCACUCGGGUG 20 1891

BCLllA-1407 + C AG CACCCUGU CAAAG G CAC 20 1892

BCLllA-1408 + GGCGGGAGGCUCCAUAGCCA 20 1893

BCLllA-1409 + CUCCUAGAGAAAUCCAUGGC 20 1894

BCLllA-1410 + UCUCCUAGAGAAAUCCAUGG 20 1895

BCLllA-1411 + GUCUCCUAGAGAAAUCCAUG 20 1896

BCLllA-1412 + CCAGCUCUCUAAGUCUCCUA 20 1897

BCLllA-1413 + UGCCAGCUCUCUAAGUCUCC 20 1898

BCLllA-1414 + GGGCCGGCCUGGGGACAGCG 20 1899

BCLllA-1415 + GCAUAGGGCUGGGCCGGCCU 20 1900

BCLllA-1416 + UGCAUAGGGCUGGGCCGGCC 20 1901

BCLllA-1417 + U UGCAUAGGGCUGGGCCGGC 20 1902

BCLllA-1418 + GCAGUAACCUUUGCAUAGGG 20 1903

BCLllA-1419 + UGGUUGCAGUAACCUU UGCA 20 1904

BCLllA-1420 + AGGGCGGCUUGCUACCUGGC 20 1905 BCLllA-1421 + AAGGGCGGCUUGCUACCUGG 20 1906

BCLllA-1422 + GGAGGGGGGGCGUCGCCAGG 20 1907

BCLllA-1423 + GAGGGAGGGGGGGCGUCGCC 20 1908

BCLllA-1424 + GGAGGGAGGGGGGGCGUCGC 20 1909

BCLllA-1425 + CGGAUUGCAGAGGAGGGAGG 20 1910

BCLllA-1426 + GCGGAUUGCAGAGGAGGGAG 20 1911

BCLllA-1427 + GGCGGAUUGCAGAGGAGGGA 20 1912

BCLllA-1428 + GGGCGGAUUGCAGAGGAGGG 20 1913

BCLllA-1429 + GGGGCGGAUUGCAGAGGAGG 20 1914

BCLllA-1430 + GAGGGGCGGAUUGCAGAGGA 20 1915

BCLllA-1431 + GGAGGGGCGGAUUGCAGAGG 20 1916

BCLllA-1432 + AGGAGGGGCGGAUUGCAGAG 20 1917

BCLllA-1433 + GGAGGAGGGGCGGAUUGCAG 20 1918

BCLllA-1434 + GGGAGGAGGGGCGGAUUGCA 20 1919

BCLllA-1435 + GAGGGAGGAGGGGCGGAUUG 20 1920

BCLllA-1436 + GGGGCUGGGAGGGAGGAGGG 20 1921

BCLllA-1437 + ACCGGGGGCUGGGAGGGAGG 20 1922

BCLllA-1438 + GACCGGGGGCUGGGAGGGAG 20 1923

BCLllA-1439 + UUGACCGGGGGCUGGGAGGG 20 1924

BCLllA-1440 + CUUGACCGGGGGCUGGGAGG 20 1925

BCLllA-1441 + GACUUGACCGGGGGCUGGGA 20 1926

BCLllA-1442 + GGACUUGACCGGGGGCUGGG 20 1927

BCLllA-1443 + UGGACUUGACCGGGGGCUGG 20 1928

BCLllA-1444 + CUUGGACUUGACCGGGGGCU 20 1929

BCLllA-1445 + ACUUGGACUUGACCGGGGGC 20 1930

BCLllA-1446 + GACUUGGACUUGACCGGGGG 20 1931

BCLllA-1447 + CGCAUGACUUGGACUUGACC 20 1932

BCLllA-1448 + UCGCAUGACU UGGACU UGAC 20 1933

BCLllA-1449 + CUCGCAUGACUUGGACUUGA 20 1934

BCLllA-1450 + UGCCGCAGAACUCGCAUGAC 20 1935

BCLllA-1451 + GAAAUUUGAACGUCUUGCCG 20 1936

BCLllA-1452 + CCACCAGGU UGCUCUGAAAU 20 1937

BCLllA-1453 + CGGUGCACCACCAGGUUGCU 20 1938

BCLllA-1454 + GGUCGCACAGGUUGCACUUG 20 1939

BCLllA-1455 + UGGCGCU UCAGCUUGCUGGC 20 1940

BCLllA-1456 + CGUCGGACU UGACCGUCAUG 20 1941

BCLllA-1457 + UCGUCGGACUUGACCGUCAU 20 1942

BCLllA-1458 + GUCGUCGGACUUGACCGUCA 20 1943

BCLllA-1459 + CGUCGUCGGACUUGACCGUC 20 1944

BCLllA-1460 + UGGCGGUGGAGAGACCGUCG 20 1945

BCLllA-1461 + GU UCCGGGGAGCUGGCGGUG 20 1946

BCLllA-1462 + GGGUUCCGGGGAGCUGGCGG 20 1947 BCLllA-1463 + CGGGU UCCGGGGAGCUGGCG 20 1948

BCLllA-1464 + GUCGCUGGUGCCGGGU UCCG 20 1949

BCLllA-1465 + AGUCGCUGGUGCCGGGUUCC 20 1950

BCLllA-1466 + AAGUCGCUGGUGCCGGGUUC 20 1951

BCLllA-1467 + CAAGUCGCUGGUGCCGGGUU 20 1952

BCLllA-1468 + UGCCCACCAAGUCGCUGGUG 20 1953

BCLllA-1469 + UGAACUUGGCCACCACGGAC 20 1954

BCLllA-1470 + CGCUCU UGAACUUGGCCACC 20 1955

BCLllA-1471 + GGUUGGGGUCGUUCUCGCUC 20 1956

BCLllA-1472 + CCCGUUCUCCGGGAUCAGGU 20 1957

BCLllA-1473 + CCCCGUUCUCCGGGAUCAGG 20 1958

BCLllA-1474 + UCCUCCUCGUCCCCGUUCUC 20 1959

BCLllA-1475 + UUCCUCCUCGUCCCCGUUCU 20 1960

BCLllA-1476 + GCGCCGCCUCCAGGCUCAGC 20 1961

BCLllA-1477 + CACGCCCACGACCGCGCCCC 20 1962

BCLllA-1478 + AUGCCCUGCAUGACGUCGGG 20 1963

BCLllA-1479 + GCACCAUGCCCUGCAUGACG 20 1964

BCLllA-1480 + CGCUGAAGUGCUGCAUGGAG 20 1965

BCLllA-1481 + GGCCUCGCUGAAGUGCUGCA 20 1966

BCLllA-1482 + AGGCCUCGCUGAAGUGCUGC 20 1967

BCLllA-1483 + GGACCUGGUGGAAGGCCUCG 20 1968

BCLllA-1484 + GCUUCUCGCCCAGGACCUGG 20 1969

BCLllA-1485 + UGCUUCUCGCCCAGGACCUG 20 1970

BCLllA-1486 + CCGCGCUUAUGCU UCUCGCC 20 1971

BCLllA-1487 + GCGGUCCGACUCGCCGGCCA 20 1972

BCLllA-1488 + CCCCGAGGCCGACUCGCCCG 20 1973

BCLllA-1489 + CCCCCGAGGCCGACUCGCCC 20 1974

BCLllA-1490 + CCCCCCGAGGCCGACUCGCC 20 1975

BCLllA-1491 + GCCCCCCGAGGCCGACUCGC 20 1976

BCLllA-1492 + CAGCUUUUUGGACAGGCCCC 20 1977

BCLllA-1493 + GGCUGCCCAGCAGCAGCUUU 20 1978

BCLllA-1494 + AGAGAAGGGGCUCAGCGAGC 20 1979

BCLllA-1495 + UAGAGAAGGGGCUCAGCGAG 20 1980

BCLllA-1496 + GCGCUUAGAGAAGGGGCUCA 20 1981

BCLllA-1497 + GAGCUUGAUGCGCUUAGAGA 20 1982

BCLllA-1498 + CGAGCU UGAUGCGCUUAGAG 20 1983

BCLllA-1499 + UCUCGAGCUUGAUGCGCUUA 20 1984

BCLllA-1500 + CUUCUCGAGCUUGAUGCGCU 20 1985

BCLllA-1501 + GGGGCAGGUCGAACUCCUUC 20 1986

BCLllA-1502 + GCAUCGCGGCCGGGGGCAGG 20 1987

BCLllA-1503 + CCGUGUUGGGCAUCGCGGCC 20 1988

BCLllA-1504 + UCCGUGUUGGGCAUCGCGGC 20 1989 BCLllA-1505 + CUCCGUGUUGGGCAUCGCGG 20 1990

BCLllA-1506 + GCGAGUACACGUUCUCCGUG 20 1991

BCLllA-1507 + CGCGUAGCCGGCGAGCCACU 20 1992

BCLllA-1508 + GCCUGGAGGCCGCGUAGCCG 20 1993

BCLllA-1509 + GAAGGGAUCUUUGAGCUGCC 20 1994

BCLllA-1510 + GGAAGGGAUCUUUGAGCUGC 20 1995

BCLllA-1511 + CGAAGCUAAGGAAGGGAUCU 20 1996

BCLllA-1512 + GGAGUCUCCGAAGCUAAGGA 20 1997

BCLllA-1513 + UGGAGUCUCCGAAGCUAAGG 20 1998

BCLllA-1514 + GUCUGGAGUCUCCGAAGCUA 20 1999

BCLllA-1515 + UGUCUGGAGUCUCCGAAGCU 20 2000

BCLllA-1516 + AAGGCGAUUGUCUGGAGUCU 20 2001

BCLllA-1517 + GGAGGCAAAAGGCGAUUGUC 20 2002

BCLllA-1518 + AGGAGGCAAAAGGCGAUUGU 20 2003

BCLllA-1519 + CUCCGAGGAGUGCUCCGACG 20 2004

BCLllA-1520 + UCUCCGAGGAGUGCUCCGAC 20 2005

BCLllA-1521 + GUUCUCCGAGGAGUGCUCCG 20 2006

BCLllA-1522 + GCGCAAACUCCCGUUCUCCG 20 2007

BCLllA-1523 + AGCGCAAACUCCCGUUCUCC 20 2008

BCLllA-1524 + GAAGCGCAAACUCCCGUUCU 20 2009

BCLllA-1525 + CCAGCUCCCCGGGCGGUGUG 20 2010

BCLllA-1526 + GUCCAGCUCCCCGGGCGGUG 20 2011

BCLllA-1527 + CGUCCAGCUCCCCGGGCGGU 20 2012

BCLllA-1528 + AGAUCCCUCCGUCCAGCUCC 20 2013

BCLllA-1529 + ACUUCCCGUGCCGCUGCGCC 20 2014

BCLllA-1530 + CCGGGCCCGGACCACUAAUA 20 2015

BCLllA-1531 + CCCGGGCCCGGACCACUAAU 20 2016

BCLllA-1532 + UGAGCUGGGCCUGCCCGGGC 20 2017

BCLllA-1533 + CUCU UUUGAGCUGGGCCUGC 20 2018

BCLllA-1534 + UGCGUCUGCCCUCUUU UGAG 20 2019

BCLllA-1535 + GUCGCUGCGUCUGCCCUCUU 20 2020

BCLllA-1536 + UUGUACAUGUGUAGCUG 17 2021

BCLllA-1537 + AGAGAAACCAUGCACUG 17 2022

BCLllA-1538 + UUCUGUGCGUGUUGCAA 17 2023

BCLllA-1539 + UGUUCUGUGCGUGUUGC 17 2024

BCLllA-1540 + AAGUAGAUUCUUAAUCC 17 2025

BCLllA-1541 + ACCAACCCGCGGGGUCA 17 2026

BCLllA-1542 + UACCAACCCGCGGGGUC 17 2027

BCLllA-1543 + AUACCAACCCGCGGGGU 17 2028

BCLllA-1544 + GAAGGGAUACCAACCCG 17 2029

BCLllA-1545 + UGAAGGGAUACCAACCC 17 2030

BCLllA-1546 + UCUGCACCUAGUCCUGA 17 2031 BCLllA-1547 + U UCUGCACCUAGUCCUG 17 2032

BCLllA-1548 + ACAUUCUGCACCUAGUC 17 2033

BCLllA-1549 + AUGGAGAGGUGGCUGGG 17 2034

BCLllA-1550 + CCCAUGGAGAGGUGGCU 17 2035

BCLllA-1551 + UCCCAUGGAGAGGUGGC 17 2036

BCLllA-1552 + AUCCCAUGGAGAGGUGG 17 2037

BCLllA-1553 + GCAAUAUGAAUCCCAUG 17 2038

BCLllA-1554 + CUGCAAUAUGAAUCCCA 17 2039

BCLllA-1555 + UCUGCAAUAUGAAUCCC 17 2040

BCLllA-1556 + GGGUUAUUGUCUGCAAU 17 2041

BCLllA-1557 + UAUUCUUAGCAGGUUAA 17 2042

BCLllA-1558 + GUAUUCUUAGCAGGUUA 17 2043

BCLllA-1559 + GCGCCCUUCUGCCAGGC 17 2044

BCLllA-1560 + AGCGCCCUUCUGCCAGG 17 2045

BCLllA-1561 + AACAGGGGGGGAGUGGG 17 2046

BCLllA-1562 + AAACAGGGGGGGAGUGG 17 2047

BCLllA-1563 + GACUAAACAGGGGGGGA 17 2048

BCLllA-1564 + GGUGGACUAAACAGGGG 17 2049

BCLllA-1565 + UGGUGGACUAAACAGGG 17 2050

BCLllA-1566 + GUGGUGGACUAAACAGG 17 2051

BCLllA-1567 + GGUGGUGGACUAAACAG 17 2052

BCLllA-1568 + CGGUGGUGGACUAAACA 17 2053

BCLllA-1569 + UCGGUGGUGGACUAAAC 17 2054

BCLllA-1570 + CUCGGUGGUGGACUAAA 17 2055

BCLllA-1571 + CAAGUGAUGUCUCGGUG 17 2056

BCLllA-1572 + CAGGCGCUCUAUGCGGU 17 2057

BCLllA-1573 + CCAGGCGCUCUAUGCGG 17 2058

BCLllA-1574 + CCCAGGCGCUCUAUGCG 17 2059

BCLllA-1575 + CUCGGGUGAUGGGUGGC 17 2060

BCLllA-1576 + UCAAAGGCACUCGGGUG 17 2061

BCLllA-1577 + CACCCUGUCAAAGGCAC 17 2062

BCLllA-1578 + GGGAGGCUCCAUAGCCA 17 2063

BCLllA-1579 + CUAGAGAAAUCCAUGGC 17 2064

BCLllA-1580 + CCUAGAGAAAUCCAUGG 17 2065

BCLllA-1581 + UCCUAGAGAAAUCCAUG 17 2066

BCLllA-1582 + GCUCUCUAAGUCUCCUA 17 2067

BCLllA-1583 + CAGCUCUCUAAGUCUCC 17 2068

BCLllA-1584 + CCGGCCUGGGGACAGCG 17 2069

BCLllA-1585 + UAGGGCUGGGCCGGCCU 17 2070

BCLllA-1586 + AUAGGGCUGGGCCGGCC 17 2071

BCLllA-1587 + CAUAGGGCUGGGCCGGC 17 2072

BCLllA-1588 + GUAACCUUUGCAUAGGG 17 2073 BCLllA-1589 + U UGCAGUAACCU UUGCA 17 2074

BCLllA-1590 + GCGGCUUGCUACCUGGC 17 2075

BCLllA-1591 + GGCGGCU UGCUACCUGG 17 2076

BCLllA-1592 + GGGGGGGCGUCGCCAGG 17 2077

BCLllA-1593 + GGAGGGGGGGCGUCGCC 17 2078

BCLllA-1594 + GGGAGGGGGGGCGUCGC 17 2079

BCLllA-1595 + AUUGCAGAGGAGGGAGG 17 2080

BCLllA-1596 + GAUUGCAGAGGAGGGAG 17 2081

BCLllA-1597 + GGAUUGCAGAGGAGGGA 17 2082

BCLllA-1598 + CGGAUUGCAGAGGAGGG 17 2083

BCLllA-1599 + GCGGAUUGCAGAGGAGG 17 2084

BCLllA-1600 + GGGCGGAUUGCAGAGGA 17 2085

BCLllA-1601 + GGGGCGGAUUGCAGAGG 17 2086

BCLllA-1602 + AGGGGCGGAUUGCAGAG 17 2087

BCLllA-1603 + GGAGGGGCGGAUUGCAG 17 2088

BCLllA-1604 + AGGAGGGGCGGAUUGCA 17 2089

BCLllA-1605 + GGAGGAGGGGCGGAUUG 17 2090

BCLllA-1606 + GCUGGGAGGGAGGAGGG 17 2091

BCLllA-1607 + GGGGGCUGGGAGGGAGG 17 2092

BCLllA-1608 + CGGGGGCUGGGAGGGAG 17 2093

BCLllA-1609 + ACCGGGGGCUGGGAGGG 17 2094

BCLllA-1610 + GACCGGGGGCUGGGAGG 17 2095

BCLllA-1611 + UUGACCGGGGGCUGGGA 17 2096

BCLllA-1612 + CUUGACCGGGGGCUGGG 17 2097

BCLllA-1613 + ACUUGACCGGGGGCUGG 17 2098

BCLllA-1614 + GGACUUGACCGGGGGCU 17 2099

BCLllA-1615 + UGGACUUGACCGGGGGC 17 2100

BCLllA-1616 + UUGGACUUGACCGGGGG 17 2101

BCLllA-1617 + AUGACUUGGACUUGACC 17 2102

BCLllA-1618 + CAUGACUUGGACUUGAC 17 2103

BCLllA-1619 + GCAUGACUUGGACUUGA 17 2104

BCLllA-1620 + CGCAGAACUCGCAUGAC 17 2105

BCLllA-1621 + AUUUGAACGUCUUGCCG 17 2106

BCLllA-1622 + CCAGGU UGCUCUGAAAU 17 2107

BCLllA-1623 + UGCACCACCAGGUUGCU 17 2108

BCLllA-1624 + CGCACAGGUUGCACUUG 17 2109

BCLllA-1625 + CGCUUCAGCUUGCUGGC 17 2110

BCLllA-1626 + CGGACUUGACCGUCAUG 17 2111

BCLllA-1627 + UCGGACUUGACCGUCAU 17 2112

BCLllA-1628 + GUCGGACUUGACCGUCA 17 2113

BCLllA-1629 + CGUCGGACU UGACCGUC 17 2114

BCLllA-1630 + CGGUGGAGAGACCGUCG 17 2115 BCLllA-1631 + CCGGGGAGCUGGCGGUG 17 2116

BCLllA-1632 + U UCCGGGGAGCUGGCGG 17 2117

BCLllA-1633 + GUUCCGGGGAGCUGGCG 17 2118

BCLllA-1634 + GCUGGUGCCGGGUUCCG 17 2119

BCLllA-1635 + CGCUGGUGCCGGGUUCC 17 2120

BCLllA-1636 + UCGCUGGUGCCGGGUUC 17 2121

BCLllA-1637 + GUCGCUGGUGCCGGGUU 17 2122

BCLllA-1638 + CCACCAAGUCGCUGGUG 17 2123

BCLllA-1639 + ACU UGGCCACCACGGAC 17 2124

BCLllA-1640 + UCU UGAACUUGGCCACC 17 2125

BCLllA-1641 + UGGGGUCGUUCUCGCUC 17 2126

BCLllA-1642 + GU UCUCCGGGAUCAGGU 17 2127

BCLllA-1643 + CGU UCUCCGGGAUCAGG 17 2128

BCLllA-1644 + UCCUCGUCCCCGUUCUC 17 2129

BCLllA-1645 + CUCCUCGUCCCCGU UCU 17 2130

BCLllA-1646 + CCGCCUCCAGGCUCAGC 17 2131

BCLllA-1647 + GCCCACGACCGCGCCCC 17 2132

BCLllA-1648 + CCCUGCAUGACGUCGGG 17 2133

BCLllA-1649 + CCAUGCCCUGCAUGACG 17 2134

BCLllA-1650 + UGAAGUGCUGCAUGGAG 17 2135

BCLllA-1651 + CUCGCUGAAGUGCUGCA 17 2136

BCLllA-1652 + CCUCGCUGAAGUGCUGC 17 2137

BCLllA-1653 + CCUGGUGGAAGGCCUCG 17 2138

BCLllA-1654 + UCUCGCCCAGGACCUGG 17 2139

BCLllA-1655 + U UCUCGCCCAGGACCUG 17 2140

BCLllA-1656 + CGCUUAUGCUUCUCGCC 17 2141

BCLllA-1657 + GUCCGACUCGCCGGCCA 17 2142

BCLllA-1658 + CGAGGCCGACUCGCCCG 17 2143

BCLllA-1659 + CCGAGGCCGACUCGCCC 17 2144

BCLllA-1660 + CCCGAGGCCGACUCGCC 17 2145

BCLllA-1661 + CCCCGAGGCCGACUCGC 17 2146

BCLllA-1662 + CUU UUUGGACAGGCCCC 17 2147

BCLllA-1663 + UGCCCAGCAGCAGCUU U 17 2148

BCLllA-1664 + GAAGGGGCUCAGCGAGC 17 2149

BCLllA-1665 + AGAAGGGGCUCAGCGAG 17 2150

BCLllA-1666 + CUUAGAGAAGGGGCUCA 17 2151

BCLllA-1667 + CUUGAUGCGCUUAGAGA 17 2152

BCLllA-1668 + GCUUGAUGCGCUUAGAG 17 2153

BCLllA-1669 + CGAGCU UGAUGCGCUUA 17 2154

BCLllA-1670 + CUCGAGCU UGAUGCGCU 17 2155

BCLllA-1671 + GCAGGUCGAACUCCUUC 17 2156

BCLllA-1672 + UCGCGGCCGGGGGCAGG 17 2157 BCLllA-1673 + UGUUGGGCAUCGCGGCC 17 2158

BCLllA-1674 + GUGUUGGGCAUCGCGGC 17 2159

BCLllA-1675 + CGUGUUGGGCAUCGCGG 17 2160

BCLllA-1676 + AGUACACGUUCUCCGUG 17 2161

BCLllA-1677 + GUAGCCGGCGAGCCACU 17 2162

BCLllA-1678 + UGGAGGCCGCGUAGCCG 17 2163

BCLllA-1679 + GGGAUCUUUGAGCUGCC 17 2164

BCLllA-1680 + AGGGAUCUUUGAGCUGC 17 2165

BCLllA-1681 + AGCUAAGGAAGGGAUCU 17 2166

BCLllA-1682 + GUCUCCGAAGCUAAGGA 17 2167

BCLllA-1683 + AGUCUCCGAAGCUAAGG 17 2168

BCLllA-1684 + UGGAGUCUCCGAAGCUA 17 2169

BCLllA-1685 + CUGGAGUCUCCGAAGCU 17 2170

BCLllA-1686 + GCGAUUGUCUGGAGUCU 17 2171

BCLllA-1687 + GGCAAAAGGCGAUUGUC 17 2172

BCLllA-1688 + AGGCAAAAGGCGAUUGU 17 2173

BCLllA-1689 + CGAGGAGUGCUCCGACG 17 2174

BCLllA-1690 + CCGAGGAGUGCUCCGAC 17 2175

BCLllA-1691 + CUCCGAGGAGUGCUCCG 17 2176

BCLllA-1692 + CAAACUCCCGUUCUCCG 17 2177

BCLllA-1693 + GCAAACUCCCGUUCUCC 17 2178

BCLllA-1694 + GCGCAAACUCCCGUUCU 17 2179

BCLllA-1695 + GCUCCCCGGGCGGUGUG 17 2180

BCLllA-1696 + CAGCUCCCCGGGCGGUG 17 2181

BCLllA-1697 + CCAGCUCCCCGGGCGGU 17 2182

BCLllA-1698 + UCCCUCCGUCCAGCUCC 17 2183

BCLllA-1699 + UCCCGUGCCGCUGCGCC 17 2184

BCLllA-1700 + GGCCCGGACCACUAAUA 17 2185

BCLllA-1701 + GGGCCCGGACCACUAAU 17 2186

BCLllA-1702 + GCUGGGCCUGCCCGGGC 17 2187

BCLllA-1703 + U UUUGAGCUGGGCCUGC 17 2188

BCLllA-1704 + GUCUGCCCUCU UUUGAG 17 2189

BCLllA-1705 + GCUGCGUCUGCCCUCU U 17 2190

BCLllA-1706 - CCCCCAUUCGGCGUAGUACC 20 2191

BCLllA-1707 - CCCAUUCGGCGUAGUACCCA 20 2192

BCLllA-1708 - CUCAAGAUGUGUGGCAGUUU 20 2193

BCLllA-1709 - AGAUGUGUGGCAGUUU UCGG 20 2194

BCLllA-1710 - GAUGUGUGGCAGUU UUCGGA 20 2195

BCLllA-1711 - GGCAGUUUUCGGAUGGAAGC 20 2196

BCLllA-1712 - CAGUUUUCGGAUGGAAGCUC 20 2197

BCLllA-1713 - CCAUUCGGCGUAGUACC 17 2198

BCLllA-1714 - AUUCGGCGUAGUACCCA 17 2199 BCLllA-1715 - AAGAUGUGUGGCAGUUU 17 2200

BCLllA-1716 - UGUGUGGCAGUUUUCGG 17 2201

BCLllA-1717 - GUGUGGCAGUUU UCGGA 17 2202

BCLllA-1718 - AGUUUUCGGAUGGAAGC 17 2203

BCLllA-1719 - U UUUCGGAUGGAAGCUC 17 2204

BCLllA-1720 + ACGCCGAAUGGGGGUGUGUG 20 2205

BCLllA-1721 + ACUACGCCGAAUGGGGGUGU 20 2206

BCLllA-1722 + CUCUGGGUACUACGCCGAAU 20 2207

BCLllA-1723 + UCUCUGGGUACUACGCCGAA 20 2208

BCLllA-1724 + CUCUCUGGGUACUACGCCGA 20 2209

BCLllA-1725 + UGAGCUCUCUGGGUACUACG 20 2210

BCLllA-1726 + UGCCACACAUCUUGAGCUCU 20 2211

BCLllA-1727 + UCCGAAAACUGCCACACAUC 20 2212

BCLllA-1728 + AAGGGCUCUCGAGCUUCCAU 20 2213

BCLllA-1729 + CCGAAUGGGGGUGUGUG 17 2214

BCLllA-1730 + ACGCCGAAUGGGGGUGU 17 2215

BCLllA-1731 + UGGGUACUACGCCGAAU 17 2216

BCLllA-1732 + CUGGGUACUACGCCGAA 17 2217

BCLllA-1733 + UCUGGGUACUACGCCGA 17 2218

BCLllA-1734 + GCUCUCUGGGUACUACG 17 2219

BCLllA-1735 + CACACAUCUUGAGCUCU 17 2220

BCLllA-1736 + G AAAACUG CCACACAU C 17 2221

BCLllA-1737 + GGCUCUCGAGCUUCCAU 17 2222

Table 2F provides exemplary targeting domains for knocking out the BCL11A gene. In an embodiment, the targeting domain is the exact complement of the target domain. Any of the targeting domains in the table can be used with an N. meningitidis Cas9 molecule that gives double stranded cleavage. Any of the targeting domains in the table can be used with an N. meningitidis Cas9 single- stranded break nucleases (nickases). In an embodiment, dual targeting is used to create two nicks. When selecting gRNAs for use in a nickase pair, one gRNA targets a domain in the complementary strand and the second gRNA targets a domain in the non- complementary strand, e.g., a gRNA comprising any minus strand targeting domain may be paired any gRNA comprising a plus strand targeting domain targeting ths same target position. Table 2F

BCLllA-1739 - UGCAACACGCACAGAACACU 20 2224

BCLllA-1740 - UCCUUCCCAGCCACCUCUCC 20 2225

BCLllA-1741 - AUGGCUAUGGAGCCUCCCGC 20 2226

BCLllA-1742 - CAGGUCACGCCAGAGGA 17 2227

BCLllA-1743 - AACACG CACAG AACACU 17 2228

BCLllA-1744 - UUCCCAGCCACCUCUCC 17 2229

BCLllA-1745 - GCUAUGGAGCCUCCCGC 17 2230

BCLllA-1746 + UGAAAAAAGCAUCCAAUCCC 20 2231

BCLllA-1747 + GGAGGUUGGCAUCCAGGUCA 20 2232

BCLllA-1748 + CGCCUGGGAUGAGUGCAGAA 20 2233

BCLllA-1749 + UAGAAAGCGAACACGGAAGU 20 2234

BCLllA-1750 + GGCUAUGGAGCCUCCCGCCA 20 2235

BCLllA-1751 + CCUCCUCCCUCCCAGCCCCC 20 2236

BCLllA-1752 + CCCAUGACGGUCAAGUCCGA 20 2237

BCLllA-1753 + UUUGCCUCCUCGUCGGAGCA 20 2238

BCLllA-1754 + UGAAAAAAGCAUCCAAU 17 2239

BCLllA-1755 + GGAGGUUGGCAUCCAGG 17 2240

BCLllA-1756 + CGCCUGGGAUGAGUGCA 17 2241

BCLllA-1757 + UAGAAAGCGAACACGGA 17 2242

BCLllA-1758 + GGCUAUGGAGCCUCCCG 17 2243

BCLllA-1759 + CCUCCUCCCUCCCAGCC 17 2244

BCLllA-1760 + CCCAUGACGGUCAAGUC 17 2245

BCLllA-1761 + U UUGCCUCCUCGUCGGA 17 2246

Table 3A provides exemplary targeting domains for repressing (i.e., knocking down or decreasing) expression of the BCLllA gene. In an embodiment, the targeting domain is the exact complement of the target domain. Any of the targeting domains in the table can be used with a S. pyogenes eiCas9 molecule to cause a steric block at the promoter region to block transcription resulting in the repression of the BCLllA gene. Alternatively, any of the targeting domains in the table can be used with a S. pyogenes eiCas9 fused to a transcriptional repressor to decrease transcription and therefore downregulate gene expression.

Table 3A

BCLllA-1766 - GCCUCUGAGGUUCGGUCGGG 20 2251

BCLllA-1767 - CCUCUGAGGUUCGGUCGGGA 20 2252

BCLllA-1768 - CUCUGAGGUUCGGUCGGGAG 20 2253

BCLllA-1769 - UGAGGUUCGGUCGGGAGGGG 20 2254

BCLllA-1770 - GAGGUUCGGUCGGGAGGGGA 20 2255

BCLllA-1771 - CGGUCGGGAGGGGAGGGCAG 20 2256

BCLllA-1772 - GGGGAGGGCAGCGGCAACCC 20 2257

BCLllA-1773 - GAGGGCAGCGGCAACCCAGG 20 2258

BCLllA-1774 - CAACCCAGGAGGCAGCAGUC 20 2259

BCLllA-1775 - AACCCAGGAGGCAGCAGUCC 20 2260

BCLllA-1776 - CUCCCUCUCCCGCGUGCCCC 20 2261

BCLllA-1777 - CCCCCGGCCGCCUCCUCCCC 20 2262

BCLllA-1778 - CGGCCCUAGCUCCUGCCCUU 20 2263

BCLllA-1779 - CCCUAGCUCCUGCCCUUCGG 20 2264

BCLllA-1780 - UAGCUCCUGCCCUUCGGCGG 20 2265

BCLllA-1781 - CUCCUGCCCUUCGGCGGCGG 20 2266

BCLllA-1782 - CUGCCCUUCGGCGGCGGCGG 20 2267

BCLllA-1783 - CCCUUCGGCGGCGGCGGCGG 20 2268

BCLllA-1784 - UUCGGCGGCGGCGGCGGCGG 20 2269

BCLllA-1785 - CGGCGGCGGCGGCGGCGGCG 20 2270

BCLllA-1786 - GGCGGCGGCGGCGGCGGCGC 20 2271

BCLllA-1787 - GGCGGCGGCGGCGGCGCGGG 20 2272

BCLllA-1788 - GCGGCGGCGGCGGCGCGGGA 20 2273

BCLllA-1789 - GGCGCGGGAGGGCAAGCGCG 20 2274

BCLllA-1790 - GGAGGGCAAGCGCGAGGAGC 20 2275

BCLllA-1791 - GCGCGAGGAGCCGGCACAAA 20 2276

BCLllA-1792 - GGAGCCGGCACAAAAGGCAG 20 2277

BCLllA-1793 - GAGCCGGCACAAAAGGCAGC 20 2278

BCLllA-1794 - GCGGGACAAACACCCACCUC 20 2279

BCLllA-1795 - GACAAACACCCACCUCUGGC 20 2280

BCLllA-1796 - CCACCUCUGGCCGGAACAAA 20 2281

BCLllA-1797 - CCUCUGGCCGGAACAAAAGG 20 2282

BCLllA-1798 - GGAACAAAAGGCGGCAGUGC 20 2283

BCLllA-1799 - GCCGCGUCUCCCGUCCUUCC 20 2284

BCLllA-1800 - UCCCGUCCUUCCCGGUCCCA 20 2285

BCLllA-1801 - CACGGCUCUCCCCGUCGCCG 20 2286

BCLllA-1802 - CGGCCCCUCUCCCGACUCCG 20 2287

BCLllA-1803 - UCUCCCGACUCCGCGGACUC 20 2288

BCLllA-1804 - CUCCGCGGACUCAGGAGCGC 20 2289

BCLllA-1805 - UCCGCGGACUCAGGAGCGCC 20 2290

BCLllA-1806 - CCGCGGACUCAGGAGCGCCG 20 2291

BCLllA-1807 - CGCGGACUCAGGAGCGCCGG 20 2292 BCLllA-1808 - GUGCCACUUUCUCACUAUUG 20 2293

BCLllA-1809 - UGCCACUUUCUCACUAUUGU 20 2294

BCLllA-1810 - GCCACUUUCUCACUAUUGUG 20 2295

BCLllA-1811 - ACACUUGACCGUGAGCGCGC 20 2296

BCLllA-1812 - AGUCUCACCUCUUUUCUCCC 20 2297

BCLllA-1813 - GUCUCACCUCUUUUCUCCCC 20 2298

BCLllA-1814 - CCUACCCCCCCAUUUUCUUA 20 2299

BCLllA-1815 - CCCCAUUUUCUUACGGUGAG 20 2300

BCLllA-1816 - CCCAUUUUCUUACGGUGAGU 20 2301

BCLllA-1817 - CCCCACCAGCUCCCACCCCC 20 2302

BCLllA-1818 - UGUUCAUUAUUUUGCAAAAC 20 2303

BCLllA-1819 - UCAUUAUUUUGCAAAACUGG 20 2304

BCLllA-1820 - CAUUAUUUUGCAAAACUGGC 20 2305

BCLllA-1821 - AUUAUUUUGCAAAACUGGCG 20 2306

BCLllA-1822 - AUUUUGCAAAACUGGCGGGG 20 2307

BCLllA-1823 - UUUUGCAAAACUGGCGGGGC 20 2308

BCLllA-1824 - UUUGCAAAACUGGCGGGGCG 20 2309

BCLllA-1825 - UUGCAAAACUGGCGGGGCGG 20 2310

BCLllA-1826 - UGCAAAACUGGCGGGGCGGG 20 2311

BCLllA-1827 - GCAAAACUGGCGGGGCGGGG 20 2312

BCLllA-1828 - CAAAACUGGCGGGGCGGGGG 20 2313

BCLllA-1829 - CUGGCGGGGCGGGGGGGGAG 20 2314

BCLllA-1830 - U U U CG A A A AG AG AAA U A A AG 20 2315

BCLllA-1831 - CGAAAAGAGAAAUAAAGCGG 20 2316

BCLllA-1832 - AGAGAAAUAAAGCGGCGGAA 20 2317

BCLllA-1833 - GAAAUAAAGCGGCGGAAAGG 20 2318

BCLllA-1834 - AGCGGCGGAAAGGAGGAAAG 20 2319

BCLllA-1835 - GGCGGAAAGGAGGAAAGAGG 20 2320

BCLllA-1836 - UAAAAU U AAAU AAAAU U AAA 20 2321

BCLllA-1837 - CUGUCUCAAAAGUGCAUACA 20 2322

BCLllA-1838 - CAAAAGUGCAUACACGGCAA 20 2323

BCLllA-1839 - UACACGGCAAUGGUUCCAGA 20 2324

BCLllA-1840 - ACACGGCAAUGGUUCCAGAU 20 2325

BCLllA-1841 - CAAUGGUUCCAGAUGGGAUG 20 2326

BCLllA-1842 - AAUGGUUCCAGAUGGGAUGA 20 2327

BCLllA-1843 - AUCUCUUUUACCUCGACUCU 20 2328

BCLllA-1844 - UCUUUUACCUCGACUCUCGG 20 2329

BCLllA-1845 - AUAAUUAUUAUUACUAUUAU 20 2330

BCLllA-1846 - UAAUUAUUAUUACUAUUAUU 20 2331

BCLllA-1847 + UAAUAAUCACGAGAGCGCGC 20 2332

BCLllA-1848 + CAGGACUAGAAGCAAAAGCG 20 2333

BCLllA-1849 + AGGACUAGAAGCAAAAGCGA 20 2334 BCLllA-1850 + GGACUAGAAGCAAAAGCGAG 20 2335

BCLllA-1851 + GACUAGAAGCAAAAGCGAGG 20 2336

BCLllA-1852 + AGCAAAAGCGAGGGGGAGAG 20 2337

BCLllA-1853 + GCAAAAGCGAGGGGGAGAGA 20 2338

BCLllA-1854 + CAAAAGCGAGGGGGAGAGAG 20 2339

BCLllA-1855 + AGAAAAACCUCCGAGAGUCG 20 2340

BCLllA-1856 + AGUCGAGGUAAAAGAGAUAA 20 2341

BCLllA-1857 + GUCGAGGUAAAAGAGAUAAA 20 2342

BCLllA-1858 + U CG AGG U AAAAG AG AU AAAG 20 2343

BCLllA-1859 + CG AGG U AAAAG AG AUAAAGG 20 2344

BCLllA-1860 + GAAAAAACCCUCAUCCCAUC 20 2345

BCLllA-1861 + CUUUAUUUCUCUUUUCGAAA 20 2346

BCLllA-1862 + CAAAAUAAUGAACAAUGCUA 20 2347

BCLllA-1863 + GAACAACUCACAUGCAAACC 20 2348

BCLllA-1864 + AACAACUCACAUGCAAACCU 20 2349

BCLllA-1865 + ACAACUCACAUGCAAACCUG 20 2350

BCLllA-1866 + CAACUCACAUGCAAACCUGG 20 2351

BCLllA-1867 + CUCACAUGCAAACCUGGGGG 20 2352

BCLllA-1868 + UCACAUGCAAACCUGGGGGU 20 2353

BCLllA-1869 + GCAAACCUGGGGGUGGGAGC 20 2354

BCLllA-1870 + AACCUGGGGGUGGGAGCUGG 20 2355

BCLllA-1871 + ACCUGGGGGUGGGAGCUGGU 20 2356

BCLllA-1872 + CCUGGGGGUGGGAGCUGGUG 20 2357

BCLllA-1873 + GGGUGGGAGCUGGUGGGGAA 20 2358

BCLllA-1874 + GGUGGGAGCUGGUGGGGAAA 20 2359

BCLllA-1875 + GGGAGCUGGUGGGGAAAGGG 20 2360

BCLllA-1876 + U CCCACU CACCG U AAG AAAA 20 2361

BCLllA-1877 + CCCACU CACCG U AAG AAAAU 20 2362

BCLllA-1878 + CCACUCACCGUAAGAAAAUG 20 2363

BCLllA-1879 + CACU CACCG U AAG AAAAUGG 20 2364

BCLllA-1880 + ACU CACCG U AAG AAAAU GGG 20 2365

BCLllA-1881 + CUCACCGUAAGAAAAUGGGG 20 2366

BCLllA-1882 + CCGUAAGAAAAUGGGGGGGU 20 2367

BCLllA-1883 + CGUAAGAAAAUGGGGGGGUA 20 2368

BCLllA-1884 + AAGAAAAUGGGGGGGUAGGG 20 2369

BCLllA-1885 + AGAAAAUGGGGGGGUAGGGA 20 2370

BCLllA-1886 + CAAGUCUAAAAAACGAUUCC 20 2371

BCLllA-1887 + AAGUCUAAAAAACGAUUCCC 20 2372

BCLllA-1888 + AGUCUAAAAAACGAUUCCCG 20 2373

BCLllA-1889 + ACGAUUCCCGGGGAGAAAAG 20 2374

BCLllA-1890 + GGGGAGAAAAGAGGUGAGAC 20 2375

BCLllA-1891 + AAAGAGGUGAGACUGGCUUU 20 2376 BCLllA-1892 + UUUGGACACCAGCGCGCUCA 20 2377

BCLllA-1893 + GCUCACGGUCAAGUGUGCAG 20 2378

BCLllA-1894 + CUCACGGUCAAGUGUGCAGC 20 2379

BCLllA-1895 + ACGGUCAAGUGUGCAGCGGG 20 2380

BCLllA-1896 + UCCCCACAAUAGUGAGAAAG 20 2381

BCLllA-1897 + AUAGUGAGAAAGUGGCACUG 20 2382

BCLllA-1898 + GAGAAAGUGGCACUGUGGAA 20 2383

BCLllA-1899 + AGAAAGUGGCACUGUGGAAA 20 2384

BCLllA-1900 + GAAAGUGGCACUGUGGAAAG 20 2385

BCLllA-1901 + GCACUGUGGAAAGGGGCCCC 20 2386

BCLllA-1902 + CCCCGGCGCUCCUGAGUCCG 20 2387

BCLllA-1903 + CGCUCCUGAGUCCGCGGAGU 20 2388

BCLllA-1904 + GCUCCUGAGUCCGCGGAGUC 20 2389

BCLllA-1905 + UGAGUCCGCGGAGUCGGGAG 20 2390

BCLllA-1906 + GAGUCCGCGGAGUCGGGAGA 20 2391

BCLllA-1907 + AGUCCGCGGAGUCGGGAGAG 20 2392

BCLllA-1908 + CGGAGUCGGGAGAGGGGCCG 20 2393

BCLllA-1909 + CGGGAGAGGGGCCGCGGCGA 20 2394

BCLllA-1910 + GGGAGAGGGGCCGCGGCGAC 20 2395

BCLllA-1911 + GGAGAGGGGCCGCGGCGACG 20 2396

BCLllA-1912 + CGCGGCGACGGGGAGAGCCG 20 2397

BCLllA-1913 + GCGGCGACGGGGAGAGCCGU 20 2398

BCLllA-1914 + GACGGGGAGAGCCGUGGGAC 20 2399

BCLllA-1915 + ACGGGGAGAGCCGUGGGACC 20 2400

BCLllA-1916 + GGAGAGCCGUGGGACCGGGA 20 2401

BCLllA-1917 + AGCCGUGGGACCGGGAAGGA 20 2402

BCLllA-1918 + GCCGUGGGACCGGGAAGGAC 20 2403

BCLllA-1919 + ACCGGGAAGGACGGGAGACG 20 2404

BCLllA-1920 + GGAAGGACGGGAGACGCGGC 20 2405

BCLllA-1921 + GGCACUGCCGCCUUUUGUUC 20 2406

BCLllA-1922 + CCGCCUUUUGUUCCGGCCAG 20 2407

BCLllA-1923 + CCUU UUGUUCCGGCCAGAGG 20 2408

BCLllA-1924 + CUUUUGUUCCGGCCAGAGGU 20 2409

BCLllA-1925 + UGUCCCGCUGCCUUUUGUGC 20 2410

BCLllA-1926 + GCCGCCGCCGCCGCCGCCGA 20 2411

BCLllA-1927 + CCGCCGCCGCCGCCGCCGAA 20 2412

BCLllA-1928 + CGCCGCCGCCGCCGAAGGGC 20 2413

BCLllA-1929 + GCCGCCGAAGGGCAGGAGCU 20 2414

BCLllA-1930 + CCGCCGAAGGGCAGGAGCUA 20 2415

BCLllA-1931 + CGAAGGGCAGGAGCUAGGGC 20 2416

BCLllA-1932 + GAAGGGCAGGAGCUAGGGCC 20 2417

BCLllA-1933 + AAGGGCAGGAGCUAGGGCCG 20 2418 BCLllA-1934 + AGGGCAGGAGCUAGGGCCGG 20 2419

BCLllA-1935 + GCAGGAGCUAGGGCCGGGGG 20 2420

BCLllA-1936 + GGAGCUAGGGCCGGGGGAGG 20 2421

BCLllA-1937 + GCUAGGGCCGGGGGAGGAGG 20 2422

BCLllA-1938 + GGGCCGGGGGAGGAGGCGGC 20 2423

BCLllA-1939 + GGCCGGGGGAGGAGGCGGCC 20 2424

BCLllA-1940 + GCCGGGGGAGGAGGCGGCCG 20 2425

BCLllA-1941 + CCGGGGGAGGAGGCGGCCGG 20 2426

BCLllA-1942 + AGGAGGCGGCCGGGGGCACG 20 2427

BCLllA-1943 + GGAGGCGGCCGGGGGCACGC 20 2428

BCLllA-1944 + CGGCCGGGGGCACGCGGGAG 20 2429

BCLllA-1945 + GGCCGGGGGCACGCGGGAGA 20 2430

BCLllA-1946 + CGGGGGCACGCGGGAGAGGG 20 2431

BCLllA-1947 + GGGGGCACGCGGGAGAGGGA 20 2432

BCLllA-1948 + GGCACGCGGGAGAGGGAGGG 20 2433

BCLllA-1949 + GCACGCGGGAGAGGGAGGGA 20 2434

BCLllA-1950 + GGAGAGGGAGGGAGGGAGCC 20 2435

BCLllA-1951 + GAGCCCGGACUGCUGCCUCC 20 2436

BCLllA-1952 + AGCCCGGACUGCUGCCUCCU 20 2437

BCLllA-1953 + CCCUCCCGACCGAACCUCAG 20 2438

BCLllA-1954 + ACCGAACCUCAGAGGCAGCA 20 2439

BCLllA-1955 + AGAGGCAGCAAGGAGAAGAC 20 2440

BCLllA-1956 + AAAAUAAAAUAAAUAAAACA 20 2441

BCLllA-1957 - UCUCCU UGCUGCCUCUG 17 2442

BCLllA-1958 - UUGCUGCCUCUGAGGUU 17 2443

BCLllA-1959 - UGCCUCUGAGGUUCGGU 17 2444

BCLllA-1960 - GCCUCUGAGGUUCGGUC 17 2445

BCLllA-1961 - UCUGAGGUUCGGUCGGG 17 2446

BCLllA-1962 - CUGAGGUUCGGUCGGGA 17 2447

BCLllA-1963 - UGAGGUUCGGUCGGGAG 17 2448

BCLllA-1964 - GGU UCGGUCGGGAGGGG 17 2449

BCLllA-1965 - GUUCGGUCGGGAGGGGA 17 2450

BCLllA-1966 - UCGGGAGGGGAGGGCAG 17 2451

BCLllA-1967 - GAGGGCAGCGGCAACCC 17 2452

BCLllA-1968 - GGCAGCGGCAACCCAGG 17 2453

BCLllA-1969 - CCCAGGAGGCAGCAGUC 17 2454

BCLllA-1970 - CCAGGAGGCAGCAGUCC 17 2455

BCLllA-1971 - CCUCUCCCGCGUGCCCC 17 2456

BCLllA-1972 - CCGGCCGCCUCCUCCCC 17 2457

BCLllA-1973 - CCCUAGCUCCUGCCCUU 17 2458

BCLllA-1974 - UAGCUCCUGCCCUUCGG 17 2459

BCLllA-1975 - CUCCUGCCCUUCGGCGG 17 2460 BCLllA-1976 - CUGCCCUUCGGCGGCGG 17 2461

BCLllA-1977 - CCCUUCGGCGGCGGCGG 17 2462

BCLllA-1978 - UUCGGCGGCGGCGGCGG 17 2463

BCLllA-1979 - GGCGGCGGCGGCGGCGG 17 2464

BCLllA-1980 - CGGCGGCGGCGGCGGCG 17 2465

BCLllA-1981 - GGCGGCGGCGGCGGCGC 17 2466

BCLllA-1982 - GGCGGCGGCGGCGCGGG 17 2467

BCLllA-1983 - GCGGCGGCGGCGCGGGA 17 2468

BCLllA-1984 - GCGGGAGGGCAAGCGCG 17 2469

BCLllA-1985 - GGGCAAGCGCGAGGAGC 17 2470

BCLllA-1986 - CGAGGAGCCGGCACAAA 17 2471

BCLllA-1987 - GCCGGCACAAAAGGCAG 17 2472

BCLllA-1988 - CCGGCACAAAAGGCAGC 17 2473

BCLllA-1989 - GGACAAACACCCACCUC 17 2474

BCLllA-1990 - AAACACCCACCUCUGGC 17 2475

BCLllA-1991 - CCUCUGGCCGGAACAAA 17 2476

BCLllA-1992 - C U GG CCG G A ACAAAAG G 17 2477

BCLllA-1993 - A C A A A AG GCGGCAGUGC 17 2478

BCLllA-1994 - GCGUCUCCCGUCCUUCC 17 2479

BCLllA-1995 - CGUCCUUCCCGGUCCCA 17 2480

BCLllA-1996 - GGCUCUCCCCGUCGCCG 17 2481

BCLllA-1997 - CCCCUCUCCCGACUCCG 17 2482

BCLllA-1998 - CCCGACUCCGCGGACUC 17 2483

BCLllA-1999 - CGCGGACUCAGGAGCGC 17 2484

BCLllA-2000 - GCGGACUCAGGAGCGCC 17 2485

BCLllA-2001 - CGGACUCAGGAGCGCCG 17 2486

BCLllA-2002 - GGACUCAGGAGCGCCGG 17 2487

BCLllA-2003 - CCACUUUCUCACUAUUG 17 2488

BCLllA-2004 - CACUUUCUCACUAUUGU 17 2489

BCLllA-2005 - ACUUUCUCACUAUUGUG 17 2490

BCLllA-2006 - CUUGACCGUGAGCGCGC 17 2491

BCLllA-2007 - CUCACCUCUUUUCUCCC 17 2492

BCLllA-2008 - UCACCUCUUUUCUCCCC 17 2493

BCLllA-2009 - ACCCCCCCAUUUUCUUA 17 2494

BCLllA-2010 - CAUUUUCUUACGGUGAG 17 2495

BCLllA-2011 - AUUUUCUUACGGUGAGU 17 2496

BCLllA-2012 - CACCAGCUCCCACCCCC 17 2497

BCLllA-2013 - U CAU U AU U U UG CAAAAC 17 2498

BCLllA-2014 - UUAUUUUGCAAAACUGG 17 2499

BCLllA-2015 - UAUUUUGCAAAACUGGC 17 2500

BCLllA-2016 - AUUUUGCAAAACUGGCG 17 2501

BCLllA-2017 - UUGCAAAACUGGCGGGG 17 2502 BCLllA-2018 - UGCAAAACUGGCGGGGC 17 2503

BCLllA-2019 - GCAAAACUGGCGGGGCG 17 2504

BCLllA-2020 - CAAAACUGGCGGGGCGG 17 2505

BCLllA-2021 - AAAACUGGCGGGGCGGG 17 2506

BCLllA-2022 - AAACUGGCGGGGCGGGG 17 2507

BCLllA-2023 - AACUGGCGGGGCGGGGG 17 2508

BCLllA-2024 - GCGGGGCGGGGGGGGAG 17 2509

BCLllA-2025 - CGAAAAGAGAAAUAAAG 17 2510

BCLllA-2026 - A A AG AG A A A U A A AG CG G 17 2511

BCLllA-2027 - GAAAUAAAGCGGCGGAA 17 2512

BCLllA-2028 - AUAAAGCGGCGGAAAGG 17 2513

BCLllA-2029 - GGCGGAAAGGAGGAAAG 17 2514

BCLllA-2030 - GGAAAGGAGGAAAGAGG 17 2515

BCLllA-2031 - AAU U AAAU AAAAU U AAA 17 2516

BCLllA-2032 - U C U C A A A AG U G C A U AC A 17 2517

BCLllA-2033 - AAGUGCAUACACGGCAA 17 2518

BCLllA-2034 - ACGGCAAUGGUUCCAGA 17 2519

BCLllA-2035 - CGGCAAUGGUUCCAGAU 17 2520

BCLllA-2036 - UGGUUCCAGAUGGGAUG 17 2521

BCLllA-2037 - GGUUCCAGAUGGGAUGA 17 2522

BCLllA-2038 - UCU UUUACCUCGACUCU 17 2523

BCLllA-2039 - U UUACCUCGACUCUCGG 17 2524

BCLllA-2040 - AUUAUUAUUACUAUUAU 17 2525

BCLllA-2041 - UUAUUAUUACUAUUAUU 17 2526

BCLllA-2042 + UAAUCACGAGAGCGCGC 17 2527

BCLllA-2043 + G ACU AG AAG CAAAAG CG 17 2528

BCLllA-2044 + ACU AG AAG CAAAAG CG A 17 2529

BCLllA-2045 + CUAGAAGCAAAAGCGAG 17 2530

BCLllA-2046 + UAGAAGCAAAAGCGAGG 17 2531

BCLllA-2047 + AAAAGCGAGGGGGAGAG 17 2532

BCLllA-2048 + AAAGCGAGGGGGAGAGA 17 2533

BCLllA-2049 + AAGCGAGGGGGAGAGAG 17 2534

BCLllA-2050 + AAAACCU CCG AG AG U CG 17 2535

BCLllA-2051 + CG AGG U AAAAG AG AU AA 17 2536

BCLllA-2052 + G AG G U A A A AG AG A U AAA 17 2537

BCLllA-2053 + AGG U AAAAG AG AU AAAG 17 2538

BCLllA-2054 + GGU AAAAG AGAUAAAGG 17 2539

BCLllA-2055 + AAAACCCUCAUCCCAUC 17 2540

BCLllA-2056 + UAUUUCUCUUUUCGAAA 17 2541

BCLllA-2057 + AAUAAUGAACAAUGCUA 17 2542

BCLllA-2058 + CAACUCACAUGCAAACC 17 2543

BCLllA-2059 + AAC U CAC AU G CAAACCU 17 2544 BCLllA-2060 + ACUCACAUGCAAACCUG 17 2545

BCLllA-2061 + CUCACAUGCAAACCUGG 17 2546

BCLllA-2062 + ACAUGCAAACCUGGGGG 17 2547

BCLllA-2063 + CAUGCAAACCUGGGGGU 17 2548

BCLllA-2064 + AACCUGGGGGUGGGAGC 17 2549

BCLllA-2065 + CUGGGGGUGGGAGCUGG 17 2550

BCLllA-2066 + UGGGGGUGGGAGCUGGU 17 2551

BCLllA-2067 + GGGGGUGGGAGCUGGUG 17 2552

BCLllA-2068 + UGGGAGCUGGUGGGGAA 17 2553

BCLllA-2069 + GGGAGCUGGUGGGGAAA 17 2554

BCLllA-2070 + AGCUGGUGGGGAAAGGG 17 2555

BCLllA-2071 + CAC U CACCG U AAGAAAA 17 2556

BCLllA-2072 + ACUCACCGUAAGAAAAU 17 2557

BCLllA-2073 + CUCACCGUAAGAAAAUG 17 2558

BCLllA-2074 + UCACCGUAAGAAAAUGG 17 2559

BCLllA-2075 + CACCG UAAGAAAAUGGG 17 2560

BCLllA-2076 + ACCGUAAGAAAAUGGGG 17 2561

BCLllA-2077 + UAAGAAAAUGGGGGGGU 17 2562

BCLllA-2078 + AAGAAAAUGGGGGGGUA 17 2563

BCLllA-2079 + AAAAUGGGGGGGUAGGG 17 2564

BCLllA-2080 + AAAUGGGGGGGUAGGGA 17 2565

BCLllA-2081 + GUCUAAAAAACGAUUCC 17 2566

BCLllA-2082 + U CU AAAAAACG AU U CCC 17 2567

BCLllA-2083 + CUAAAAAACGAUUCCCG 17 2568

BCLllA-2084 + AUUCCCGGGGAGAAAAG 17 2569

BCLllA-2085 + GAGAAAAGAGGUGAGAC 17 2570

BCLllA-2086 + GAGGUGAGACUGGCU UU 17 2571

BCLllA-2087 + GGACACCAGCGCGCUCA 17 2572

BCLllA-2088 + CACGGU CA AG U G U G CAG 17 2573

BCLllA-2089 + ACGGUCAAGUGUGCAGC 17 2574

BCLllA-2090 + GUCAAGUGUGCAGCGGG 17 2575

BCLllA-2091 + CCACAAUAGUGAGAAAG 17 2576

BCLllA-2092 + GUGAGAAAGUGGCACUG 17 2577

BCLllA-2093 + AAAGUGGCACUGUGGAA 17 2578

BCLllA-2094 + AAGUGGCACUGUGGAAA 17 2579

BCLllA-2095 + AGUGGCACUGUGGAAAG 17 2580

BCLllA-2096 + CUGUGGAAAGGGGCCCC 17 2581

BCLllA-2097 + CGGCGCUCCUGAGUCCG 17 2582

BCLllA-2098 + UCCUGAGUCCGCGGAGU 17 2583

BCLllA-2099 + CCUGAGUCCGCGGAGUC 17 2584

BCLllA-2100 + GUCCGCGGAGUCGGGAG 17 2585

BCLllA-2101 + UCCGCGGAGUCGGGAGA 17 2586 BCLllA-2102 + CCGCGGAGUCGGGAGAG 17 2587

BCLllA-2103 + AGUCGGGAGAGGGGCCG 17 2588

BCLllA-2104 + GAGAGGGGCCGCGGCGA 17 2589

BCLllA-2105 + AGAGGGGCCGCGGCGAC 17 2590

BCLllA-2106 + GAGGGGCCGCGGCGACG 17 2591

BCLllA-2107 + GGCGACGGGGAGAGCCG 17 2592

BCLllA-2108 + GCGACGGGGAGAGCCGU 17 2593

BCLllA-2109 + GGGGAGAGCCGUGGGAC 17 2594

BCLllA-2110 + GGGAGAGCCGUGGGACC 17 2595

BCLllA-2111 + GAGCCGUGGGACCGGGA 17 2596

BCLllA-2112 + CGUGGGACCGGGAAGGA 17 2597

BCLllA-2113 + GUGGGACCGGGAAGGAC 17 2598

BCLllA-2114 + GGGAAGGACGGGAGACG 17 2599

BCLllA-2115 + AGGACGGGAGACGCGGC 17 2600

BCLllA-2116 + ACUGCCGCCUUUUGUUC 17 2601

BCLllA-2117 + CCUU UUGUUCCGGCCAG 17 2602

BCLllA-2118 + UUUGUUCCGGCCAGAGG 17 2603

BCLllA-2119 + UUGUUCCGGCCAGAGGU 17 2604

BCLllA-2120 + CCCGCUGCCUUUUGUGC 17 2605

BCLllA-2121 + GCCGCCGCCGCCGCCGA 17 2606

BCLllA-2122 + CCGCCGCCGCCGCCGAA 17 2607

BCLllA-2123 + CGCCGCCGCCGAAGGGC 17 2608

BCLllA-2124 + GCCGAAGGGCAGGAGCU 17 2609

BCLllA-2125 + CCGAAGGGCAGGAGCUA 17 2610

BCLllA-2126 + AGGGCAGGAGCUAGGGC 17 2611

BCLllA-2127 + GGGCAGGAGCUAGGGCC 17 2612

BCLllA-2128 + GGCAGGAGCUAGGGCCG 17 2613

BCLllA-2129 + GCAGGAGCUAGGGCCGG 17 2614

BCLllA-2130 + GGAGCUAGGGCCGGGGG 17 2615

BCLllA-2131 + GCUAGGGCCGGGGGAGG 17 2616

BCLllA-2132 + AGGGCCGGGGGAGGAGG 17 2617

BCLllA-2133 + CCGGGGGAGGAGGCGGC 17 2618

BCLllA-2134 + CGGGGGAGGAGGCGGCC 17 2619

BCLllA-2135 + GGGGGAGGAGGCGGCCG 17 2620

BCLllA-2136 + GGGGAGGAGGCGGCCGG 17 2621

BCLllA-2137 + AGGCGGCCGGGGGCACG 17 2622

BCLllA-2138 + GGCGGCCGGGGGCACGC 17 2623

BCLllA-2139 + CCGGGGGCACGCGGGAG 17 2624

BCLllA-2140 + CGGGGGCACGCGGGAGA 17 2625

BCLllA-2141 + GGGCACGCGGGAGAGGG 17 2626

BCLllA-2142 + GGCACGCGGGAGAGGGA 17 2627

BCLllA-2143 + ACGCGGGAGAGGGAGGG 17 2628 BCLllA-2144 + CGCGGGAGAGGGAGGGA 17 2629

BCLllA-2145 + GAGGGAGGGAGGGAGCC 17 2630

BCLllA-2146 + CCCGGACUGCUGCCUCC 17 2631

BCLllA-2147 + CCGGACUGCUGCCUCCU 17 2632

BCLllA-2148 + UCCCGACCGAACCUCAG 17 2633

BCLllA-2149 + G AACCU CAG AGG CAG CA 17 2634

BCLllA-2150 + G G CAG CAAG G AG AAG AC 17 2635

BCLllA-2151 + AUAAAAUAAAUAAAACA 17 2636

Table 3B provides exemplary targeting domains for repressing (i.e., knocking down or decreasing) expression of the BCLllA gene. Any of the targeting domains in the table can be used with a S. aureus eiCas9 molecule to cause a steric block in the promoter region to block transcription elongation resulting in the repression of the BCLllA gene. Any of the targeting domains in the table can be used with a S. aureus eiCas9 fused to a transcriptional repressor to decrease transcription and therefore downregulate gene expression.

Table 3B

BCLllA-2172 - GGAGCCGGCACAAAAGGCAG 20 2657

BCLllA-2173 - GGACAAACACCCACCUCUGG 20 2658

BCLllA-2174 - GACAAACACCCACCUCUGGC 20 2659

BCLllA-2175 - GCGGCCCCUCUCCCGACUCC 20 2660

BCLllA-2176 - CUCUCCCGACUCCGCGGACU 20 2661

BCLllA-2177 - UCUCCCGACUCCGCGGACUC 20 2662

BCLllA-2178 - ACUCCGCGGACUCAGGAGCG 20 2663

BCLllA-2179 - CUCCGCGGACUCAGGAGCGC 20 2664

BCLllA-2180 - UCCGCGGACUCAGGAGCGCC 20 2665

BCLllA-2181 - AGUGCCACUUUCUCACUAUU 20 2666

BCLllA-2182 - GUGCCACUUUCUCACUAUUG 20 2667

BCLllA-2183 - UGCCACUUUCUCACUAUUGU 20 2668

BCLllA-2184 - CUCCCGCUGCACACUUGACC 20 2669

BCLllA-2185 - CAGUCUCACCUCUUUUCUCC 20 2670

BCLllA-2186 - AGUCUCACCUCUUUUCUCCC 20 2671

BCLllA-2187 - GUCUCACCUCUUUUCUCCCC 20 2672

BCLllA-2188 - UACCCCCCCAUUUUCUUACG 20 2673

BCLllA-2189 - CCCCCAUUUUCUUACGGUGA 20 2674

BCLllA-2190 - CCCCAUUUUCUUACGGUGAG 20 2675

BCLllA-2191 - CCCAUUUUCUUACGGUGAGU 20 2676

BCLllA-2192 - UCCCACCCCCAGGUUUGCAU 20 2677

BCLllA-2193 - UUCAUUAUUUUGCAAAACUG 20 2678

BCLllA-2194 - UCAUUAUUUUGCAAAACUGG 20 2679

BCLllA-2195 - UAUUUUGCAAAACUGGCGGG 20 2680

BCLllA-2196 - AUUUUGCAAAACUGGCGGGG 20 2681

BCLllA-2197 - UUUUGCAAAACUGGCGGGGC 20 2682

BCLllA-2198 - UUUGCAAAACUGGCGGGGCG 20 2683

BCLllA-2199 - UUGCAAAACUGGCGGGGCGG 20 2684

BCLllA-2200 - UGCAAAACUGGCGGGGCGGG 20 2685

BCLllA-2201 - GCAAAACUGGCGGGGCGGGG 20 2686

BCLllA-2202 - CAAAACUGGCGGGGCGGGGG 20 2687

BCLllA-2203 - ACUGGCGGGGCGGGGGGGGA 20 2688

BCLllA-2204 - CUGGCGGGGCGGGGGGGGAG 20 2689

BCLllA-2205 - UGGAAUCAUUGCAUUCCUUU 20 2690

BCLllA-2206 - UCAUUGCAUUCCUUUUCGAA 20 2691

BCLllA-2207 - AUUGCAUUCCUUUUCGAAAA 20 2692

BCLllA-2208 - UCGAAAAGAGAAAUAAAGCG 20 2693

BCLllA-2209 - CGAAAAGAGAAAUAAAGCGG 20 2694

BCLllA-2210 - AAGAGAAAUAAAGCGGCGGA 20 2695

BCLllA-2211 - AGAGAAAUAAAGCGGCGGAA 20 2696

BCLllA-2212 - AGAAAUAAAGCGGCGGAAAG 20 2697

BCLllA-2213 - GAAAUAAAGCGGCGGAAAGG 20 2698 BCLllA-2214 - UAAAGCGGCGGAAAGGAGGA 20 2699

BCLllA-2215 - AAGCGGCGG A A AG G AG G AAA 20 2700

BCLllA-2216 - AGCGGCGGAAAGGAGGAAAG 20 2701

BCLllA-2217 - CGGCGGAAAGGAGGAAAGAG 20 2702

BCLllA-2218 - GGCGGAAAGGAGGAAAGAGG 20 2703

BCLllA-2219 - AUACACGGCAAUGGUUCCAG 20 2704

BCLllA-2220 - UACACGGCAAUGGUUCCAGA 20 2705

BCLllA-2221 - CGGCAAUGGUUCCAGAUGGG 20 2706

BCLllA-2222 - GCAAUGGUUCCAGAUGGGAU 20 2707

BCLllA-2223 - UAUCUCUUUUACCUCGACUC 20 2708

BCLllA-2224 - AUCUCUUUUACCUCGACUCU 20 2709

BCLllA-2225 - GACUCUCGGAGGUUUUUCUC 20 2710

BCLllA-2226 - AAUAAUUAUUAUUACUAUUA 20 2711

BCLllA-2227 - ACUAUUAUUGGGUUACUUAC 20 2712

BCLllA-2228 - UAUUAUUGGGUUACUUACGC 20 2713

BCLllA-2229 - UCUUCUCCUUGCUGCCU 17 2714

BCLllA-2230 - CUGCCUCUGAGGUUCGG 17 2715

BCLllA-2231 - UGCCUCUGAGGUUCGGU 17 2716

BCLllA-2232 - GCCUCUGAGGUUCGGUC 17 2717

BCLllA-2233 - CUCUGAGGUUCGGUCGG 17 2718

BCLllA-2234 - UCUGAGGUUCGGUCGGG 17 2719

BCLllA-2235 - CUGAGGUUCGGUCGGGA 17 2720

BCLllA-2236 - UGAGGUUCGGUCGGGAG 17 2721

BCLllA-2237 - AGGUUCGGUCGGGAGGG 17 2722

BCLllA-2238 - GGAGGGCAGCGGCAACC 17 2723

BCLllA-2239 - GAGGGCAGCGGCAACCC 17 2724

BCLllA-2240 - ACCCAGGAGGCAGCAGU 17 2725

BCLllA-2241 - GCGGCGGCGGCGGCGGC 17 2726

BCLllA-2242 - CGGCGGCGGCGGCGGCG 17 2727

BCLllA-2243 - GGCGGCGGCGGCGGCGC 17 2728

BCLllA-2244 - CGGCGGCGGCGGCGCGG 17 2729

BCLllA-2245 - GGCGCGGGAGGGCAAGC 17 2730

BCLllA-2246 - CGCGGGAGGGCAAGCGC 17 2731

BCLllA-2247 - GCGGGAGGGCAAGCGCG 17 2732

BCLllA-2248 - AG CCGG CAC AAAAG G C A 17 2733

BCLllA-2249 - GCCGGCACAAAAGGCAG 17 2734

BCLllA-2250 - CAAACACCCACCUCUGG 17 2735

BCLllA-2251 - AAACACCCACCUCUGGC 17 2736

BCLllA-2252 - GCCCCUCUCCCGACUCC 17 2737

BCLllA-2253 - UCCCGACUCCGCGGACU 17 2738

BCLllA-2254 - CCCGACUCCGCGGACUC 17 2739

BCLllA-2255 - CCGCGGACUCAGGAGCG 17 2740 BCLllA-2256 - CGCGGACUCAGGAGCGC 17 2741

BCLllA-2257 - GCGGACUCAGGAGCGCC 17 2742

BCLllA-2258 - GCCACUUUCUCACUAUU 17 2743

BCLllA-2259 - CCACUUUCUCACUAUUG 17 2744

BCLllA-2260 - CACUUUCUCACUAUUGU 17 2745

BCLllA-2261 - CCGCUGCACACUUGACC 17 2746

BCLllA-2262 - UCUCACCUCUUUUCUCC 17 2747

BCLllA-2263 - CUCACCUCUUUUCUCCC 17 2748

BCLllA-2264 - UCACCUCUUUUCUCCCC 17 2749

BCLllA-2265 - CCCCCCAUUUUCUUACG 17 2750

BCLllA-2266 - CCAUUUUCUUACGGUGA 17 2751

BCLllA-2267 - CAUUUUCUUACGGUGAG 17 2752

BCLllA-2268 - AUUUUCUUACGGUGAGU 17 2753

BCLllA-2269 - CACCCCCAGGUUUGCAU 17 2754

BCLllA-2270 - AUUAUUUUGCAAAACUG 17 2755

BCLllA-2271 - UUAUUUUGCAAAACUGG 17 2756

BCLllA-2272 - UUUGCAAAACUGGCGGG 17 2757

BCLllA-2273 - UUGCAAAACUGGCGGGG 17 2758

BCLllA-2274 - UGCAAAACUGGCGGGGC 17 2759

BCLllA-2275 - GCAAAACUGGCGGGGCG 17 2760

BCLllA-2276 - CAAAACUGGCGGGGCGG 17 2761

BCLllA-2277 - AAAACUGGCGGGGCGGG 17 2762

BCLllA-2278 - AAACUGGCGGGGCGGGG 17 2763

BCLllA-2279 - AACUGGCGGGGCGGGGG 17 2764

BCLllA-2280 - GGCGGGGCGGGGGGGGA 17 2765

BCLllA-2281 - GCGGGGCGGGGGGGGAG 17 2766

BCLllA-2282 - AAUCAUUGCAUUCCUUU 17 2767

BCLllA-2283 - UUGCAUUCCUUUUCGAA 17 2768

BCLllA-2284 - GCAUUCCUUUU CGAAAA 17 2769

BCLllA-2285 - AAAAGAGAAAUAAAGCG 17 2770

BCLllA-2286 - A A AG AG A A A U A A AG CG G 17 2771

BCLllA-2287 - AGAAAUAAAGCGGCGGA 17 2772

BCLllA-2288 - GAAAUAAAGCGGCGGAA 17 2773

BCLllA-2289 - A A U A A AG CG G CG G A A AG 17 2774

BCLllA-2290 - AUAAAGCGGCGGAAAGG 17 2775

BCLllA-2291 - AGCGGCGGAAAGGAGGA 17 2776

BCLllA-2292 - CGGCGGAAAGGAGGAAA 17 2777

BCLllA-2293 - GGCGGAAAGGAGGAAAG 17 2778

BCLllA-2294 - CGGAAAGGAGGAAAGAG 17 2779

BCLllA-2295 - GGAAAGGAGGAAAGAGG 17 2780

BCLllA-2296 - CACGGCAAUGGUUCCAG 17 2781

BCLllA-2297 - ACGGCAAUGGUUCCAGA 17 2782 BCLllA-2298 - CAAUGGUUCCAGAUGGG 17 2783

BCLllA-2299 - AUGGUUCCAGAUGGGAU 17 2784

BCLllA-2300 - CUCUUUUACCUCGACUC 17 2785

BCLllA-2301 - UCU UUUACCUCGACUCU 17 2786

BCLllA-2302 - UCUCGGAGGU UUUUCUC 17 2787

BCLllA-2303 - AAUUAUUAUUACUAUUA 17 2788

BCLllA-2304 - AUUAUUGGGUUACU UAC 17 2789

BCLllA-2305 - UAUUGGGUUACUUACGC 17 2790

BCLllA-2306 + CG AACCU CAG AGG CAG CAAG 20 2791

BCLllA-2307 + ACCGAACCUCAGAGGCAGCA 20 2792

BCLllA-2308 + GACCGAACCUCAGAGGCAGC 20 2793

BCLllA-2309 + CUCCCCUCCCGACCGAACCU 20 2794

BCLllA-2310 + CCGCUGCCCUCCCCUCCCGA 20 2795

BCLllA-2311 + GGAGCCCGGACUGCUGCCUC 20 2796

BCLllA-2312 + GGGAGAGGGAGGGAGGGAGC 20 2797

BCLllA-2313 + GCACGCGGGAGAGGGAGGGA 20 2798

BCLllA-2314 + GGCACGCGGGAGAGGGAGGG 20 2799

BCLllA-2315 + GGGCACGCGGGAGAGGGAGG 20 2800

BCLllA-2316 + GGGGGCACGCGGGAGAGGGA 20 2801

BCLllA-2317 + CGGGGGCACGCGGGAGAGGG 20 2802

BCLllA-2318 + CCGGGGGCACGCGGGAGAGG 20 2803

BCLllA-2319 + GGCCGGGGGCACGCGGGAGA 20 2804

BCLllA-2320 + CGGCCGGGGGCACGCGGGAG 20 2805

BCLllA-2321 + GCGGCCGGGGGCACGCGGGA 20 2806

BCLllA-2322 + AGGCGGCCGGGGGCACGCGG 20 2807

BCLllA-2323 + GGAGGCGGCCGGGGGCACGC 20 2808

BCLllA-2324 + AGGAGGCGGCCGGGGGCACG 20 2809

BCLllA-2325 + GAGGAGGCGGCCGGGGGCAC 20 2810

BCLllA-2326 + GGCCGGGGGAGGAGGCGGCC 20 2811

BCLllA-2327 + GGGCCGGGGGAGGAGGCGGC 20 2812

BCLllA-2328 + AGGGCCGGGGGAGGAGGCGG 20 2813

BCLllA-2329 + GCAGGAGCUAGGGCCGGGGG 20 2814

BCLllA-2330 + GGCAGGAGCUAGGGCCGGGG 20 2815

BCLllA-2331 + AGGGCAGGAGCUAGGGCCGG 20 2816

BCLllA-2332 + AAGGGCAGGAGCUAGGGCCG 20 2817

BCLllA-2333 + GAAGGGCAGGAGCUAGGGCC 20 2818

BCLllA-2334 + CGAAGGGCAGGAGCUAGGGC 20 2819

BCLllA-2335 + CCGAAGGGCAGGAGCUAGGG 20 2820

BCLllA-2336 + CGCCGCCGAAGGGCAGGAGC 20 2821

BCLllA-2337 + CGCCGCCGCCGCCGAAGGGC 20 2822

BCLllA-2338 + CCGCCGCCGCCGCCGAAGGG 20 2823

BCLllA-2339 + CGCCGCCGCCGCCGCCGCCG 20 2824 BCLllA-2340 + CGCCGCCGCCGCCGCCGCCG 20 2825

BCLllA-2341 + GCCUUUUGUUCCGGCCAGAG 20 2826

BCLllA-2342 + CUGCCGCCUUU UGUUCCGGC 20 2827

BCLllA-2343 + GCCGUGGGACCGGGAAGGAC 20 2828

BCLllA-2344 + AGCCGUGGGACCGGGAAGGA 20 2829

BCLllA-2345 + GAGCCGUGGGACCGGGAAGG 20 2830

BCLllA-2346 + GGGAGAGCCGUGGGACCGGG 20 2831

BCLllA-2347 + ACGGGGAGAGCCGUGGGACC 20 2832

BCLllA-2348 + GACGGGGAGAGCCGUGGGAC 20 2833

BCLllA-2349 + CGACGGGGAGAGCCGUGGGA 20 2834

BCLllA-2350 + CGCGGCGACGGGGAGAGCCG 20 2835

BCLllA-2351 + CCGCGGCGACGGGGAGAGCC 20 2836

BCLllA-2352 + AGAGGGGCCGCGGCGACGGG 20 2837

BCLllA-2353 + GGAGAGGGGCCGCGGCGACG 20 2838

BCLllA-2354 + GGGAGAGGGGCCGCGGCGAC 20 2839

BCLllA-2355 + CGGGAGAGGGGCCGCGGCGA 20 2840

BCLllA-2356 + UCGGGAGAGGGGCCGCGGCG 20 2841

BCLllA-2357 + UGAGUCCGCGGAGUCGGGAG 20 2842

BCLllA-2358 + CUGAGUCCGCGGAGUCGGGA 20 2843

BCLllA-2359 + UCCUGAGUCCGCGGAGUCGG 20 2844

BCLllA-2360 + GCUCCUGAGUCCGCGGAGUC 20 2845

BCLllA-2361 + CGCUCCUGAGUCCGCGGAGU 20 2846

BCLllA-2362 + GCGCUCCUGAGUCCGCGGAG 20 2847

BCLllA-2363 + CCCCGGCGCUCCUGAGUCCG 20 2848

BCLllA-2364 + CCCCCGGCGCUCCUGAGUCC 20 2849

BCLllA-2365 + GAAAGGGGCCCCCGGCGCUC 20 2850

BCLllA-2366 + GAGAAAGUGGCACUGUGGAA 20 2851

BCLllA-2367 + UGAGAAAGUGGCACUGUGGA 20 2852

BCLllA-2368 + AUAGUGAGAAAGUGGCACUG 20 2853

BCLllA-2369 + AAUAGUGAGAAAGUGGCACU 20 2854

BCLllA-2370 + GUAGUCAUCCCCACAAUAGU 20 2855

BCLllA-2371 + AAGUAGUCAUCCCCACAAUA 20 2856

BCLllA-2372 + ACGGUCAAGUGUGCAGCGGG 20 2857

BCLllA-2373 + CACGGUCAAGUGUGCAGCGG 20 2858

BCLllA-2374 + CUCACGGUCAAGUGUGCAGC 20 2859

BCLllA-2375 + GCUCACGGUCAAGUGUGCAG 20 2860

BCLllA-2376 + CGCUCACGGUCAAGUGUGCA 20 2861

BCLllA-2377 + AAAAGAGGUGAGACUGGCUU 20 2862

BCLllA-2378 + GAUUCCCGGGGAGAAAAGAG 20 2863

BCLllA-2379 + AAAACGAUUCCCGGGGAGAA 20 2864

BCLllA-2380 + UCUAAAAAACGAUUCCCGGG 20 2865

BCLllA-2381 + AGUCUAAAAAACGAUUCCCG 20 2866 BCLllA-2382 + AAGUCUAAAAAACGAUUCCC 20 2867

BCLllA-2383 + CAAGUCUAAAAAACGAUUCC 20 2868

BCLllA-2384 + ACAAGUCUAAAAAACGAUUC 20 2869

BCLllA-2385 + AAUGGGGGGGUAGGGAGGGA 20 2870

BCLllA-2386 + AGAAAAUGGGGGGGUAGGGA 20 2871

BCLllA-2387 + AAGAAAAUGGGGGGGUAGGG 20 2872

BCLllA-2388 + UAAGAAAAUGGGGGGGUAGG 20 2873

BCLllA-2389 + CGUAAGAAAAUGGGGGGGUA 20 2874

BCLllA-2390 + CCGUAAGAAAAUGGGGGGGU 20 2875

BCLllA-2391 + ACCGUAAGAAAAUGGGGGGG 20 2876

BCLllA-2392 + CACU CACCG U AAG AAAAUGG 20 2877

BCLllA-2393 + CCACUCACCGUAAGAAAAUG 20 2878

BCLllA-2394 + CCCACU CACCG U AAG AAAAU 20 2879

BCLllA-2395 + U CCCACU CACCG U AAG AAAA 20 2880

BCLllA-2396 + U UCCCACUCACCGUAAGAAA 20 2881

BCLllA-2397 + GGUUGCUUCCCACUCACCGU 20 2882

BCLllA-2398 + GGUGGGAGCUGGUGGGGAAA 20 2883

BCLllA-2399 + GGGUGGGAGCUGGUGGGGAA 20 2884

BCLllA-2400 + GGGGUGGGAGCUGGUGGGGA 20 2885

BCLllA-2401 + CCUGGGGGUGGGAGCUGGUG 20 2886

BCLllA-2402 + ACCUGGGGGUGGGAGCUGGU 20 2887

BCLllA-2403 + AACCUGGGGGUGGGAGCUGG 20 2888

BCLllA-2404 + AAACCUGGGGGUGGGAGCUG 20 2889

BCLllA-2405 + UCACAUGCAAACCUGGGGGU 20 2890

BCLllA-2406 + CUCACAUGCAAACCUGGGGG 20 2891

BCLllA-2407 + ACUCACAUGCAAACCUGGGG 20 2892

BCLllA-2408 + AACAACUCACAUGCAAACCU 20 2893

BCLllA-2409 + GAACAACUCACAUGCAAACC 20 2894

BCLllA-2410 + CGAACAACUCACAUGCAAAC 20 2895

BCLllA-2411 + UAAUGAACAAUGCUAAGGUU 20 2896

BCLllA-2412 + CCCGCCAGUUUUGCAAAAUA 20 2897

BCLllA-2413 + CUUUAUUUCUCUUUUCGAAA 20 2898

BCLllA-2414 + GCU UUAUUUCUCUU UUCGAA 20 2899

BCLllA-2415 + CCGCCGCUUUAUUUCUCUUU 20 2900

BCLllA-2416 + CCAU UGCCGUGUAUGCACUU 20 2901

BCLllA-2417 + GAAAAAACCCUCAUCCCAUC 20 2902

BCLllA-2418 + GGAAAAAACCCUCAUCCCAU 20 2903

BCLllA-2419 + CG AGG U AAAAG AG AU AAAGG 20 2904

BCLllA-2420 + U CG AGG U AAAAG AG AU AAAG 20 2905

BCLllA-2421 + GUCGAGGUAAAAGAGAUAAA 20 2906

BCLllA-2422 + AGUCGAGGUAAAAGAGAUAA 20 2907

BCLllA-2423 + GAGUCGAGGUAAAAGAGAUA 20 2908 BCLllA-2424 + ACCUCCGAGAGUCGAGGUAA 20 2909

BCLllA-2425 + ACGAGAAAAACCUCCGAGAG 20 2910

BCLllA-2426 + UUUUCACGAGAAAAACCUCC 20 2911

BCLllA-2427 + AU U U U U CACG AG AAAAACCU 20 2912

BCLllA-2428 + UGCAUUUUUAAAUUUU UCAC 20 2913

BCLllA-2429 + CAUGCAUUUUUAAAUU UUUC 20 2914

BCLllA-2430 + AGCAAAAGCGAGGGGGAGAG 20 2915

BCLllA-2431 + AAGCAAAAGCGAGGGGGAGA 20 2916

BCLllA-2432 + AGAAGCAAAAGCGAGGGGGA 20 2917

BCLllA-2433 + CUAGAAGCAAAAGCGAGGGG 20 2918

BCLllA-2434 + GACUAGAAGCAAAAGCGAGG 20 2919

BCLllA-2435 + GGACUAGAAGCAAAAGCGAG 20 2920

BCLllA-2436 + AGGACUAGAAGCAAAAGCGA 20 2921

BCLllA-2437 + CAGGACUAGAAGCAAAAGCG 20 2922

BCLllA-2438 + G C AG G AC U AG AAG CAAA AG C 20 2923

BCLllA-2439 + GCGCAGGACUAGAAGCAAAA 20 2924

BCLllA-2440 + AU CACG AG AG CG CG CAGG AC 20 2925

BCLllA-2441 + U UAAUAAUCACGAGAGCGCG 20 2926

BCLllA-2442 + U AAU AAU U AU U AAU AAU CAC 20 2927

BCLllA-2443 + AAUAAUAAUUAUUAAUAAUC 20 2928

BCLllA-2444 + ACCUCAGAGGCAGCAAG 17 2929

BCLllA-2445 + G AACCU CAG AGG CAG CA 17 2930

BCLllA-2446 + CGAACCUCAGAGGCAGC 17 2931

BCLllA-2447 + CCCUCCCGACCGAACCU 17 2932

BCLllA-2448 + CUGCCCUCCCCUCCCGA 17 2933

BCLllA-2449 + GCCCGGACUGCUGCCUC 17 2934

BCLllA-2450 + AGAGGGAGGGAGGGAGC 17 2935

BCLllA-2451 + CGCGGGAGAGGGAGGGA 17 2936

BCLllA-2452 + ACGCGGGAGAGGGAGGG 17 2937

BCLllA-2453 + CACGCGGGAGAGGGAGG 17 2938

BCLllA-2454 + GGCACGCGGGAGAGGGA 17 2939

BCLllA-2455 + GGGCACGCGGGAGAGGG 17 2940

BCLllA-2456 + GGGGCACGCGGGAGAGG 17 2941

BCLllA-2457 + CGGGGGCACGCGGGAGA 17 2942

BCLllA-2458 + CCGGGGGCACGCGGGAG 17 2943

BCLllA-2459 + GCCGGGGGCACGCGGGA 17 2944

BCLllA-2460 + CGGCCGGGGGCACGCGG 17 2945

BCLllA-2461 + GGCGGCCGGGGGCACGC 17 2946

BCLllA-2462 + AGGCGGCCGGGGGCACG 17 2947

BCLllA-2463 + GAGGCGGCCGGGGGCAC 17 2948

BCLllA-2464 + CGGGGGAGGAGGCGGCC 17 2949

BCLllA-2465 + CCGGGGGAGGAGGCGGC 17 2950 BCLllA-2466 + GCCGGGGGAGGAGGCGG 17 2951

BCLllA-2467 + GGAGCUAGGGCCGGGGG 17 2952

BCLllA-2468 + AGGAGCUAGGGCCGGGG 17 2953

BCLllA-2469 + GCAGGAGCUAGGGCCGG 17 2954

BCLllA-2470 + GGCAGGAGCUAGGGCCG 17 2955

BCLllA-2471 + GGGCAGGAGCUAGGGCC 17 2956

BCLllA-2472 + AGGGCAGGAGCUAGGGC 17 2957

BCLllA-2473 + AAGGGCAGGAGCUAGGG 17 2958

BCLllA-2474 + CGCCGAAGGGCAGGAGC 17 2959

BCLllA-2475 + CGCCGCCGCCGAAGGGC 17 2960

BCLllA-2476 + CCGCCGCCGCCGAAGGG 17 2961

BCLllA-2477 + CGCCGCCGCCGCCGCCG 17 2962

BCLllA-2478 + CGCCGCCGCCGCCGCCG 17 2963

BCLllA-2479 + UUUUGUUCCGGCCAGAG 17 2964

BCLllA-2480 + CCGCCUUU UGUUCCGGC 17 2965

BCLllA-2481 + GUGGGACCGGGAAGGAC 17 2966

BCLllA-2482 + CGUGGGACCGGGAAGGA 17 2967

BCLllA-2483 + CCGUGGGACCGGGAAGG 17 2968

BCLllA-2484 + AGAGCCGUGGGACCGGG 17 2969

BCLllA-2485 + GGGAGAGCCGUGGGACC 17 2970

BCLllA-2486 + GGGGAGAGCCGUGGGAC 17 2971

BCLllA-2487 + CGGGGAGAGCCGUGGGA 17 2972

BCLllA-2488 + GGCGACGGGGAGAGCCG 17 2973

BCLllA-2489 + CGGCGACGGGGAGAGCC 17 2974

BCLllA-2490 + GGGGCCGCGGCGACGGG 17 2975

BCLllA-2491 + GAGGGGCCGCGGCGACG 17 2976

BCLllA-2492 + AGAGGGGCCGCGGCGAC 17 2977

BCLllA-2493 + GAGAGGGGCCGCGGCGA 17 2978

BCLllA-2494 + GGAGAGGGGCCGCGGCG 17 2979

BCLllA-2495 + GUCCGCGGAGUCGGGAG 17 2980

BCLllA-2496 + AGUCCGCGGAGUCGGGA 17 2981

BCLllA-2497 + UGAGUCCGCGGAGUCGG 17 2982

BCLllA-2498 + CCUGAGUCCGCGGAGUC 17 2983

BCLllA-2499 + UCCUGAGUCCGCGGAGU 17 2984

BCLllA-2500 + CUCCUGAGUCCGCGGAG 17 2985

BCLllA-2501 + CGGCGCUCCUGAGUCCG 17 2986

BCLllA-2502 + CCGGCGCUCCUGAGUCC 17 2987

BCLllA-2503 + AGGGGCCCCCGGCGCUC 17 2988

BCLllA-2504 + AAAGUGGCACUGUGGAA 17 2989

BCLllA-2505 + GAAAGUGGCACUGUGGA 17 2990

BCLllA-2506 + GUGAGAAAGUGGCACUG 17 2991

BCLllA-2507 + AG U G AG AAAG U G G C AC U 17 2992 BCLllA-2508 + GUCAUCCCCACAAUAGU 17 2993

BCLllA-2509 + UAGUCAUCCCCACAAUA 17 2994

BCLllA-2510 + GUCAAGUGUGCAGCGGG 17 2995

BCLllA-2511 + GGUCAAGUGUGCAGCGG 17 2996

BCLllA-2512 + ACGGUCAAGUGUGCAGC 17 2997

BCLllA-2513 + CACGGU CA AG U G U G CAG 17 2998

BCLllA-2514 + UCACGGUCAAGUGUGCA 17 2999

BCLllA-2515 + AGAGGUGAGACUGGCUU 17 3000

BCLllA-2516 + UCCCGGGGAGAAAAGAG 17 3001

BCLllA-2517 + ACGAUUCCCGGGGAGAA 17 3002

BCLllA-2518 + AAAAAACGAUUCCCGGG 17 3003

BCLllA-2519 + CUAAAAAACGAUUCCCG 17 3004

BCLllA-2520 + U CU AAAAAACG AU U CCC 17 3005

BCLllA-2521 + GUCUAAAAAACGAUUCC 17 3006

BCLllA-2522 + AGUCUAAAAAACGAUUC 17 3007

BCLllA-2523 + GGGGGGGUAGGGAGGGA 17 3008

BCLllA-2524 + AAAUGGGGGGGUAGGGA 17 3009

BCLllA-2525 + AAAAUGGGGGGGUAGGG 17 3010

BCLllA-2526 + GAAAAUGGGGGGGUAGG 17 3011

BCLllA-2527 + AAGAAAAUGGGGGGGUA 17 3012

BCLllA-2528 + UAAGAAAAUGGGGGGGU 17 3013

BCLllA-2529 + GUAAGAAAAUGGGGGGG 17 3014

BCLllA-2530 + UCACCGUAAGAAAAUGG 17 3015

BCLllA-2531 + CUCACCGUAAGAAAAUG 17 3016

BCLllA-2532 + ACUCACCGUAAGAAAAU 17 3017

BCLllA-2533 + CAC U CACCG U AAGAAAA 17 3018

BCLllA-2534 + CCACUCACCGUAAGAAA 17 3019

BCLllA-2535 + UGCUUCCCACUCACCGU 17 3020

BCLllA-2536 + GGGAGCUGGUGGGGAAA 17 3021

BCLllA-2537 + UGGGAGCUGGUGGGGAA 17 3022

BCLllA-2538 + GUGGGAGCUGGUGGGGA 17 3023

BCLllA-2539 + GGGGGUGGGAGCUGGUG 17 3024

BCLllA-2540 + UGGGGGUGGGAGCUGGU 17 3025

BCLllA-2541 + CUGGGGGUGGGAGCUGG 17 3026

BCLllA-2542 + CCUGGGGGUGGGAGCUG 17 3027

BCLllA-2543 + CAUGCAAACCUGGGGGU 17 3028

BCLllA-2544 + ACAUGCAAACCUGGGGG 17 3029

BCLllA-2545 + CACAUGCAAACCUGGGG 17 3030

BCLllA-2546 + AAC U CAC AU G CAAACCU 17 3031

BCLllA-2547 + CAACUCACAUGCAAACC 17 3032

BCLllA-2548 + ACAACUCACAUGCAAAC 17 3033

BCLllA-2549 + UGAACAAUGCUAAGGUU 17 3034 BCLllA-2550 + GCCAGUUUUGCAAAAUA 17 3035

BCLllA-2551 + UAUUUCUCUUUUCGAAA 17 3036

BCLllA-2552 + U UAUUUCUCUUUUCGAA 17 3037

BCLllA-2553 + CCGCUUUAUUUCUCUU U 17 3038

BCLllA-2554 + U UGCCGUGUAUGCACU U 17 3039

BCLllA-2555 + AAAACCCUCAUCCCAUC 17 3040

BCLllA-2556 + AAAAACCCUCAUCCCAU 17 3041

BCLllA-2557 + G G U A A A AG AG A U A A AG G 17 3042

BCLllA-2558 + AGG U AAAAG AG AU AAAG 17 3043

BCLllA-2559 + G AG G U A A A AG AG A U AAA 17 3044

BCLllA-2560 + CG AGG U AAAAG AG AU AA 17 3045

BCLllA-2561 + UCGAGGUAAAAGAGAUA 17 3046

BCLllA-2562 + UCCGAGAGUCGAGGUAA 17 3047

BCLllA-2563 + AGAAAAACCUCCGAGAG 17 3048

BCLllA-2564 + UCACGAGAAAAACCUCC 17 3049

BCLllA-2565 + U U U CACG AG AAAAACCU 17 3050

BCLllA-2566 + AUUUUUAAAUUUUUCAC 17 3051

BCLllA-2567 + GCAUUUUUAAAUUUUUC 17 3052

BCLllA-2568 + AAAAGCGAGGGGGAGAG 17 3053

BCLllA-2569 + CAAAAGCGAGGGGGAGA 17 3054

BCLllA-2570 + AG C A A A AG CGAGGGGGA 17 3055

BCLllA-2571 + G A AG C AAAAG CG AG GG G 17 3056

BCLllA-2572 + UAGAAGCAAAAGCGAGG 17 3057

BCLllA-2573 + CUAGAAGCAAAAGCGAG 17 3058

BCLllA-2574 + ACU AG AAG CAAAAG CG A 17 3059

BCLllA-2575 + G ACU AG AAG CAAAAG CG 17 3060

BCLllA-2576 + GGACUAGAAG CAAAAG C 17 3061

BCLllA-2577 + CAGGACUAGAAG C A A A A 17 3062

BCLllA-2578 + ACGAGAGCGCGCAGGAC 17 3063

BCLllA-2579 + AUAAUCACGAGAGCGCG 17 3064

BCLllA-2580 + U AAU U AU U AAU AAU CAC 17 3065

BCLllA-2581 + AAUAAUUAUUAAUAAUC 17 3066

Table 3C provides exemplary targeting domains for repressing (i.e., knocking down or decreasing) expression of the BCLllA gene. Any of the targeting domains in the table can be used with an N. meningitidis eiCas9 molecule to cause a steric block in the promoter region to block transcription elongation resulting in the repression of the BCLllA gene. Any of the targeting domains in the table can be used with an N. meningitidis eiCas9 fused to a transcriptional repressor to decrease transcription and therefore downregulate gene expression. Table 3C

Table 4A provides exemplary targeting domains for knocking out the BCLllA gene by targeting the early coding sequence the BCLllA gene selected according to first tier parameters. The targeting domains bind within first 500bp of coding sequence downstream of start codon, good orthogonality, start with G. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. pyogenes Cas9 molecule that generates a double strand break (Cas9 nuclease) or a single-strand break (Cas9 nickase). In an embodiment, dual targeting is used to create two double strand breaks to remove the enhancer region in the BCLllA gene, e.g., the first gRNA is used to target upstream (i.e., 5') of the enhancer region in the BCLllA gene and the second gRNA is used to target downstream (i.e., 3') of the enhancer region in the BCLllA gene.

Any of the targeting domains in the table can be used with a S. pyogenes Cas9 (nickase) molecule to generate a single strand break. In an embodiment, dual targeting is used to create two nicks on opposite DNA strands by using S. pyogenes Cas9 nickases with two targeting domains that are complementary to opposite DNA strands, e.g., a gRNA comprising any minus strand targeting domain may be paired any gRNA comprising a plus strand targeting domain provided that the two gRNAs are oriented on the DNA such that PAMs face outward and the distance between the 5' ends of the gRNAs is 0-50bp. Exemplary gRNA pairs are: BCL11A- 2607 and BCL11 A-2593, BCL11 A-2607 and BCL11 A-2598, BCL11 A-264 and BCL11 A-2593, BCL11A-2614 and BCL11 A-2598, BCL11A-2589 and BCL11A-2664, BCL11A-2589 and BCLl lA-2666, BCLl lA-2596 and BCLl lA-2664, BCLl lA-2596 and BCLl lA-2666,

BCLl lA-2603 and BCLl lA-2664, of BCLl lA-2603 and BCLl lA-2666.

In an embodiment, four gRNAs (e.g., two pairs) are used to target four Cas9 nickases to create four nicks to remove the enhancer region in the BCLllA gene, e.g., the first pair of gRNAs are used to target upstream (i.e., 5') of the enhancer region in the BCLllA gene and the second pair of gRNAs are used to target downstream (i.e., 3') of the enhancer region in the BCLllA gene. For example, gRNA pairs that target upstream (i.e., 5') of the enhancer region in the BCLllA gene (e.g., 2607 and BCLl lA-2593, BCLl lA-2607 and BCLl lA-2598, BCL11A- 264 and BCLl 1A-2593, or BCLl 1A-2614 and BCLl 1A-2598) can be paired with gRNA pairs that target downstream (i.e., 3') of the enhancer region in the BCLllA gene (e.g., BCLl 1A-2589 and BCLl 1A-2664, BCLl 1A-2589 and BCLl 1 A-2666, BCLl 1A-2596 and BCLl 1A-2664, BCLl lA-2596 and BCLl 1 A-2666, BCLl lA-2603 and BCLl lA-2664, of BCLl lA-2603 and BCLl lA-2666).

Table 4A

Table 4B provides exemplary targeting domains for knocking out the BCLllA gene by targeting the early coding sequence the BCLllA gene selected according to second tier parameters. The targeting domains bind within first 500bp of coding sequence downstream of start codon, good orthogonality, and do not start with G. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. pyogenes Cas9 molecule that generates a double strand break (Cas9 nuclease) or a single-strand break (Cas9 nickase). In an embodiment, dual targeting is used to create two double strand breaks to remove the enhancer region in the BCLllA gene, e.g., the first gRNA is used to target upstream (i.e., 5') of the enhancer region in the BCLllA gene and the second gRNA is used to target downstream (i.e., 3') of the enhancer region in the BCLllA gene.

Any of the targeting domains in the table can be used with a S. pyogenes Cas9 (nickase) molecule to generate a single strand break. In an embodiment, dual targeting is used to create two nicks on opposite DNA strands by using S. pyogenes Cas9 nickases with two targeting domains that are complementary to opposite DNA strands, e.g., a gRNA comprising any minus strand targeting domain may be paired any gRNA comprising a plus strand targeting domain provided that the two gRNAs are oriented on the DNA such that PAMs face outward and the distance between the 5' ends of the gRNAs is 0-50bp.

In an embodiment, four gRNAs (e.g., two pairs) are used to target four Cas9 nickases to create four nicks to remove the enhancer region in the BCLllA gene, e.g., the first pair of gRNAs are used to target upstream (i.e., 5') of the enhancer region in the BCLllA gene and the second pair of gRNAs are used to target downstream (i.e., 3') of the enhancer region in the BCLllA gene.

Table 4B

Table 4C provides exemplary targeting domains for knocking out the BCL11A gene by targeting the early coding sequence the BCL11A gene selected according to third tier parameters. The targeting domains bind within first 500bp of coding sequence downstream of start codon and start with G. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. pyogenes Cas9 molecule that generates a double strand break (Cas9 nuclease) or a single- strand break (Cas9 nickase). In an embodiment, dual targeting is used to create two double strand breaks to remove the enhancer region in the BCL11A gene, e.g., the first gRNA is used to target upstream (i.e., 5') of the enhancer region in the BCL11A gene and the second gRNA is used to target downstream (i.e., 3') of the enhancer region in the BCL11A gene.

In an embodiment, four gRNAs (e.g., two pairs) are used to target four Cas9 nickases to create four nicks to remove the enhancer region in the BCL11A gene, e.g., the first pair of gRNAs are used to target upstream (i.e., 5') of the enhancer region in the BCL11A gene and the second pair of gRNAs are used to target downstream (i.e., 3') of the enhancer region in the BCL11A gene.

Table 4C

BCLllA-2622 + GAUGCUUUUUUCAUCUCGAU 20 3107

BCLllA-2623 + GCACUCAUCCCAGGCGU 17 3108

BCLllA-2624 + GCAUAUUCUGCACUCAUCCC 20 3109

BCLllA-2625 - GCCAGAUGAACUUCCCAUUG 20 3110

BCLllA-2626 - GCCCGUUGGGAGCUCCAGAA 20 3111

BCLllA-2627 + GCUAUGUGUUCCUGU UU 17 3112

BCLllA-2628 + GCUCCAUGUGCAGAACG 17 3113

BCLllA-2629 - GCUCUAAUCCCCACGCC 17 3114

BCLllA-2630 + GCUGGGGUUUGCCU UGCUUG 20 3115

BCLllA-2631 + GCUUUUUUCAUCUCGAU 17 3116

BCLllA-2632 + GGCACUGCCCACAGGUG 17 3117

BCLllA-2633 + GGCACUGCCCACAGGUGAGG 20 3118

BCLllA-2634 - GGCCCGU UGGGAGCUCCAGA 20 3119

BCLllA-2635 + GGGGUUUGCCUUGCUUG 17 3120

BCLllA-2636 + GUAAGAAUGGCUUCAAG 17 3121

BCLllA-2637 + GUGCAGAACGAGGGGAGGAG 20 3122

BCLllA-2638 - GUGCCAGAUGAACUUCCCAU 20 3123

BCLllA-2639 + GUUCAUCUGGCACUGCCCAC 20 3124

BCLllA-2640 - GU UGGGAGCUCCAGAAG 17 3125

Table 4D provides exemplary targeting domains for knocking out the BCL11A gene by targeting the early coding sequence the BCL11A gene selected according to forth tier parameters. The targeting domains bind within first 500bp of coding sequence downstream of start codon and do not start with G. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. pyogenes Cas9 molecule that generates a double strand break (Cas9 nuclease) or a single-strand break (Cas9 nickase). In an embodiment, dual targeting is used to create two double strand breaks to remove the enhancer region in the BCL11A gene, e.g., the first gRNA is used to target upstream (i.e., 5') of the enhancer region in the BCL11A gene and the second gRNA is used to target downstream (i.e., 3') of the enhancer region in the BCL11A gene.

Table 4D

BCLllA-2669 - CACAAACGGAAACAAUGCAA 20 3154

BCLllA-2670 + CACUCAUCCCAGGCGUG 17 3155

BCLllA-2671 + CAGAACGAGGGGAGGAG 17 3156

BCLllA-2672 - CAGAUGAACUUCCCAUU 17 3157

BCLllA-2673 + CAGCUUUUUCUAAGCAG 17 3158

BCLllA-2674 - CAUCCAGGUCACGCCAG 17 3159

BCLllA-2675 + CAUCUCGAUUGGUGAAG 17 3160

BCLllA-2676 + CAUCUGGCACUGCCCAC 17 3161

BCLllA-2677 - CAUGACCUCCUCACCUG 17 3162

BCLllA-2678 + CCAAUGGGAAGUUCAUC 17 3163

BCLllA-2679 + CCACAGCUU UUUCUAAGCAG 20 3164

BCLllA-2680 - CCAGACCACGGCCCGUU 17 3165

BCLllA-2681 - CCAGAUGAACUUCCCAU 17 3166

BCLllA-2682 - CCAGAUGAACUUCCCAU UGG 20 3167

BCLllA-2683 - CC AG C ACU U AAG CAAAC 17 3168

BCLllA-2684 - CCCAG CAC U U AAG C AAA 17 3169

BCLllA-2685 + CCCCUUCUGGAGCUCCCAAC 20 3170

BCLllA-2686 - CCCGUUGGGAGCUCCAGAAG 20 3171

BCLllA-2687 - CCGUUGGGAGCUCCAGA 17 3172

BCLllA-2688 + CCGUUUGCUUAAGUGCU 17 3173

BCLllA-2689 - CCUCUGCUUAGAAAAAGCUG 20 3174

BCLllA-2690 + CCUUCUGGAGCUCCCAA 17 3175

BCLllA-2691 - CGUGGAGGUUGGCAUCC 17 3176

BCLllA-2692 - CGUUGGGAGCUCCAGAA 17 3177

BCLllA-2693 + CGUUUGCU UAAGUGCUG 17 3178

BCLllA-2694 + CUAUGUGUUCCUGUUUG 17 3179

BCLllA-2695 + CUCCAUGUGCAGAACGA 17 3180

BCLllA-2696 - CUCUAAUCCCCACGCCU 17 3181

BCLllA-2697 + CUGCACUCAUCCCAGGCGUG 20 3182

BCLllA-2698 + CUGCUAUGUGUUCCUGUUUG 20 3183

BCLllA-2699 - CUGCUUAGAAAAAGCUG 17 3184

BCLllA-2700 + CUGGAGCUCCCAACGGGCCG 20 3185

BCLllA-2701 + CUGGAUGCCAACCUCCA 17 3186

BCLllA-2702 + CUUCUGGAGCUCCCAAC 17 3187

BCLllA-2703 - UAAACUUCUGCACUGGA 17 3188

BCLllA-2704 + UAAGAAUGUCCCCCAAU 17 3189

BCLllA-2705 - UAGAGGAAUUUGCCCCAAAC 20 3190

BCLllA-2706 + UAUUCUGCACUCAUCCC 17 3191

BCLllA-2707 + UCCAUGUGCAGAACGAG 17 3192

BCLllA-2708 + UCCAUGUGCAGAACGAGGGG 20 3193

BCLllA-2709 - UCCCCUCGUUCUGCACA 17 3194

BCLllA-2710 + UCCCCUUCUGGAGCUCCCAA 20 3195 BCLllA-2711 - UCCCGUGGAGGUUGGCAUCC 20 3196

BCLllA-2712 - UCCUCCCCUCGUUCUGCACA 20 3197

BCLllA-2713 + UCGAUUGGUGAAGGGGA 17 3198

BCLllA-2714 + UCGAUUGGUGAAGGGGAAGG 20 3199

BCLllA-2715 + UCUGCACUCAUCCCAGGCGU 20 3200

BCLllA-2716 + UCUGGCACUGCCCACAGGUG 20 3201

BCLllA-2717 + UCUGUAAGAAUGGCUUCAAG 20 3202

BCLllA-2718 + UGCACUCAUCCCAGGCG 17 3203

BCLllA-2719 - UGCCAGAUGAACUUCCCAUU 20 3204

BCLllA-2720 + UGCUAUGUGUUCCUGUU 17 3205

BCLllA-2721 + UGGAUGCCAACCUCCAC 17 3206

BCLllA-2722 + UGGUUCAUCAUCUGUAAGAA 20 3207

BCLllA-2723 - UGUUUAUCAACGUCAUCUAG 20 3208

BCLllA-2724 - UUAUUUUUAUCGAGCACAAA 20 3209

BCLllA-2725 + U UCAUCAUCUGUAAGAA 17 3210

BCLllA-2726 + UUCCCGU UUGCUUAAGUGCU 20 3211

BCLllA-2727 + U UCUGCACUCAUCCCAGGCG 20 3212

BCLllA-2728 + UUUCAUCUCGAUUGGUGAAG 20 3213

BCLllA-2729 + UUUUCAUCUCGAUUGGUGAA 20 3214

BCLllA-2730 - U UUUUAUCGAGCACAAA 17 3215

BCLllA-2731 + U UUUUCAUCUCGAUUGGUGA 20 3216

Table 4E provides exemplary targeting domains for knocking out the BCLllA gene by targeting the early coding sequence the BCLllA gene selected according to fifth tier parameters. The targeting domains outside the first 500bp of coding sequence downstream of start codon. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. pyogenes Cas9 molecule that generates a double strand break (Cas9 nuclease) or a single-strand break (Cas9 nickase). In an embodiment, dual targeting is used to create two double strand breaks to remove the enhancer region in the BCLllA gene, e.g., the first gRNA is used to target upstream (i.e., 5') of the enhancer region in the BCLllA gene and the second gRNA is used to target downstream (i.e., 3') of the enhancer region in the BCLllA gene.

Table 4E

BCLllA-2760 - CACUUGCGACGAAGACU 17 3245

BCLllA-2761 - CGGGUUGGUAUCCCU UC 17 3246

BCLllA-2762 - CUCGUCGGAGCACUCCU 17 3247

BCLllA-2763 + CCCGGACCACUAAUAUG 17 3248

BCLllA-2764 + UCGGUGGUGGACUAAAC 17 3249

BCLllA-2765 + CAGGCGCUCUAUGCGGU 17 3250

BCLllA-2766 + AAGGGAUACCAACCCGC 17 3251

BCLllA-2767 + GGCGCUCUAUGCGGUGG 17 3252

BCLllA-2768 - CCACCGCAUAGAGCGCC 17 3253

BCLllA-2769 - UACUCGCAGUGGCUCGC 17 3254

BCLllA-2770 - CGGGCGAGUCGGCCUCG 17 3255

BCLllA-2771 + UACACGUUCUCCGUGUU 17 3256

BCLllA-2772 - AGCACGCCCCAUAUUAG 17 3257

BCLllA-2773 + GAAGGGAUACCAACCCG 17 3258

BCLllA-2774 + U UGGGCAUCGCGGCCGG 17 3259

BCLllA-2775 - CCGGGCGAGUCGGCCUC 17 3260

BCLllA-2776 + GGUGGAGAGACCGUCGU 17 3261

BCLllA-2777 + GUUGGGCAUCGCGGCCG 17 3262

BCLllA-2778 - AGAACGUGUACUCGCAG 17 3263

BCLllA-2779 + ACCAACCCGCGGGGUCA 17 3264

BCLllA-2780 - CACGAGAACAGCUCGCG 17 3265

BCLllA-2781 - UAUUAGUGGUCCGGGCC 17 3266

BCLllA-2782 + CGUCGCAAGUGUCCCUG 17 3267

BCLllA-2783 + CCCGCGAGCUGU UCUCG 17 3268

BCLllA-2784 + UGCGCCGGUGCACCACC 17 3269

BCLllA-2785 - CUGCCCGACGUCAUGCA 17 3270

BCLllA-2786 - GACGAAGACUCGGUGGC 17 3271

BCLllA-2787 - CCUGCCCGACGUCAUGC 17 3272

BCLllA-2788 + AAGGGCGGCUUGCUACC 17 3273

BCLllA-2789 - GGGUGGACUACGGCUUC 17 3274

BCLllA-2790 + UCGCUGGUGCCGGGUUC 17 3275

BCLllA-2791 - GGCGAGAAGCAUAAGCG 17 3276

BCLllA-2792 + GGACUUGAGCGCGCUGC 17 3277

BCLllA-2793 - CUCGGUGGCCGGCGAGU 17 3278

BCLllA-2794 + CCCGAGGCCGACUCGCC 17 3279

BCLllA-2795 - CCCGGGCGAGUCGGCCU 17 3280

BCLllA-2796 - CCGCAUAGAGCGCCUGG 17 3281

BCLllA-2797 + UGUUGGGCAUCGCGGCC 17 3282

BCLllA-2798 + GUGUUGGGCAUCGCGGC 17 3283

BCLllA-2799 + UCUCUCGAUACUGAUCC 17 3284

BCLllA-2800 - ACCCGAGUGCCUUUGAC 17 3285

BCLllA-2801 + UCCGACGAGGAGGCAAA 17 3286 BCLllA-2802 - ACCCGGCACCAGCGACU 17 3287

BCLllA-2803 + CCCCGUUCUCCGGGAUC 17 3288

BCLllA-2804 + CCGAGGCCGACUCGCCC 17 3289

BCLllA-2805 - CCCCAUAU UAGUGGUCC 17 3290

BCLllA-2806 + GACUUGGACUUGACCGG 17 3291

BCLllA-2807 - GCCCCAUAU UAGUGGUC 17 3292

BCLllA-2808 - AGGGUGGACUACGGCUU 17 3293

BCLllA-2809 - CAAAUCGUCCCCCAUGA 17 3294

BCLllA-2810 - CGACGUCAUGCAGGGCA 17 3295

BCLllA-2811 - GGCCGCGAUGCCCAACA 17 3296

BCLllA-2812 + CCAGGCGCUCUAUGCGG 17 3297

BCLllA-2813 - CCUGAUCCCGGAGAACG 17 3298

BCLllA-2814 + CCAACCCGCGGGGUCAG 17 3299

BCLllA-2815 - GGCGAGUCGGCCUCGGG 17 3300

BCLllA-2816 + GGCAAAAGGCGAUUGUC 17 3301

BCLllA-2817 + UUUGGACAGGCCCCCCG 17 3302

BCLllA-2818 + GCGGCUUGCUACCUGGC 17 3303

BCLllA-2819 + GGACUUGACCGUCAUGG 17 3304

BCLllA-2820 + GGAGUGCUCCGACGAGG 17 3305

BCLllA-2821 - AUUAGUGGUCCGGGCCC 17 3306

BCLllA-2822 - CCACGAGAACAGCUCGC 17 3307

BCLllA-2823 - GUAUCGAGAGAGGCUUC 17 3308

BCLllA-2824 + CUCCGUGUUGGGCAUCG 17 3309

BCLllA-2825 + CAAACUCCCGUUCUCCG 17 3310

BCLllA-2826 - ACCUGAUCCCGGAGAAC 17 3311

BCLllA-2827 - GGCACUGUUAAUGGCCG 17 3312

BCLllA-2828 + UUCUCCGGGAUCAGGU U 17 3313

BCLllA-2829 - UAUGGAGCCUCCCGCCA 17 3314

BCLllA-2830 + CUUGAUGCGCUUAGAGA 17 3315

BCLllA-2831 - UAGCAAGCCGCCCU UCC 17 3316

BCLllA-2832 - CCGGCUACGCGGCCUCC 17 3317

BCLllA-2833 + UCCAAGUGAUGUCUCGG 17 3318

BCLllA-2834 - GAACAGCUCGCGGGGCG 17 3319

BCLllA-2835 - GCUGCGGU UGAAUCCAA 17 3320

BCLllA-2836 + UGACUUGGACUUGACCG 17 3321

BCLllA-2837 - CCCGGAGAACGGGGACG 17 3322

BCLllA-2838 + GUGGCGCU UCAGCUUGC 17 3323

BCLllA-2839 + GU UCUCCGGGAUCAGGU 17 3324

BCLllA-2840 + CAGUGCCAUCGUCUAUG 17 3325

BCLllA-2841 + UCUCCGGGAUCAGGUUG 17 3326

BCLllA-2842 - GACGAUGGCACUGUUAA 17 3327

BCLllA-2843 - CUGCUCCCCGGGCGAGU 17 3328 BCLllA-2844 + CGGUGGUGGACUAAACA 17 3329

BCLllA-2845 - CUCGCGGGGCGCGGUCG 17 3330

BCLllA-2846 + AUGCCCUGCAUGACGUC 17 3331

BCLllA-2847 + UGGACUUGACCGGGGGC 17 3332

BCLllA-2848 - ACCACCGAGACAUCACU 17 3333

BCLllA-2849 - GGAGUUCGACCUGCCCC 17 3334

BCLllA-2850 + CCUGCAUGACGUCGGGC 17 3335

BCLllA-2851 + CUGCAUGACGUCGGGCA 17 3336

BCLllA-2852 - AGGAUCAGUAUCGAGAG 17 3337

BCLllA-2853 + GGACUUGACCGGGGGCU 17 3338

BCLllA-2854 + AAAGGCACUCGGGUGAU 17 3339

BCLllA-2855 - UGGACGGAGGGAUCUCG 17 3340

BCLllA-2856 + CCCCCAGGCGCUCUAUG 17 3341

BCLllA-2857 - CCGCCAUGGAUUUCUCU 17 3342

BCLllA-2858 - GGCGCGGUCGUGGGCGU 17 3343

BCLllA-2859 - AACCUGAUCCCGGAGAA 17 3344

BCLllA-2860 + CAUGCCCUGCAUGACGU 17 3345

BCLllA-2861 + CGCUGGUGCCGGGUUCC 17 3346

BCLllA-2862 + CCUGGAGGCCGCGUAGC 17 3347

BCLllA-2863 - CCCCUGACCCCGCGGGU 17 3348

BCLllA-2864 + GCUUAUGCU UCUCGCCC 17 3349

BCLllA-2865 - AAGUCAUGCGAGUUCUG 17 3350

BCLllA-2866 + CACCAAGUCGCUGGUGC 17 3351

BCLllA-2867 - CCCGAGUGCCUUUGACA 17 3352

BCLllA-2868 + CAUGACUUGGACUUGAC 17 3353

BCLllA-2869 - CGACCCCAACCUGAUCC 17 3354

BCLllA-2870 + ACCAAGUCGCUGGUGCC 17 3355

BCLllA-2871 + AAGUGAUGUCUCGGUGG 17 3356

BCLllA-2872 - CUUCUCCACACCGCCCG 17 3357

BCLllA-2873 + UGGAGUCUCCGAAGCUA 17 3358

BCLllA-2874 - CGCUUCUCCACACCGCC 17 3359

BCLllA-2875 + GCUGGUGCCGGGUUCCG 17 3360

BCLllA-2876 - CGCAGCGGCACGGGAAG 17 3361

BCLllA-2877 + GCAUCGCGGCCGGGGGC 17 3362

BCLllA-2878 - GAGCACUCCUCGGAGAA 17 3363

BCLllA-2879 + GGGGGGCGUCGCCAGGA 17 3364

BCLllA-2880 + GAAAGCGCCCUUCUGCC 17 3365

BCLllA-2881 - CUGGACGGAGGGAUCUC 17 3366

BCLllA-2882 - CGGCUUCGGGCUGAGCC 17 3367

BCLllA-2883 + GGGGGCGUCGCCAGGAA 17 3368

BCLllA-2884 + UAACCUUUGCAUAGGGC 17 3369

BCLllA-2885 - GGGCGAGUCGGCCUCGG 17 3370 BCLllA-2886 - CACACCGCCCGGGGAGC 17 3371

BCLllA-2887 - GGGAUCUCGGGGCGCAG 17 3372

BCLllA-2888 + CUCGCUGAAGUGCUGCA 17 3373

BCLllA-2889 - UCGGGGCGCAGCGGCAC 17 3374

BCLllA-2890 - AAGUCCCCUGACCCCGC 17 3375

BCLllA-2891 - GCCUUU UGCCUCCUCGU 17 3376

BCLllA-2892 - CACCUGGCCGAGGCCGA 17 3377

BCLllA-2893 - GGUAUCCCUUCAGGACU 17 3378

BCLllA-2894 + GUGGUGGACUAAACAGG 17 3379

BCLllA-2895 + GCGAGCUGUUCUCGUGG 17 3380

BCLllA-2896 - AGCACUCCUCGGAGAAC 17 3381

BCLllA-2897 - CAUGCAGCACU UCAGCG 17 3382

BCLllA-2898 + UGGCCUGGGUGCACGCG 17 3383

BCLllA-2899 - AGCGAGAGGGUGGACUA 17 3384

BCLllA-2900 + GCACAGGUUGCACUUGU 17 3385

BCLllA-2901 + GAGAAAUCCAUGGCGGG 17 3386

BCLllA-2902 + GCAGAACUCGCAUGACU 17 3387

BCLllA-2903 + UCUCCGAAGCUAAGGAA 17 3388

BCLllA-2904 + UGACGUCGGGCAGGGCG 17 3389

BCLllA-2905 + GGGUCCAAGUGAUGUCU 17 3390

BCLllA-2906 - GCAACCUGGUGGUGCAC 17 3391

BCLllA-2907 + GGUGGCGCGCCGCCUCC 17 3392

BCLllA-2908 + GCUGCCCACCAAGUCGC 17 3393

BCLllA-2909 + GU UCUCGCUCUUGAACU 17 3394

BCLllA-2910 + CCGCAGCACCCUGUCAA 17 3395

BCLllA-2911 - GAAGUCCCCUGACCCCG 17 3396

BCLllA-2912 - GCGCGGCCACCUGGCCG 17 3397

BCLllA-2913 + GGCGUCGCCAGGAAGGG 17 3398

BCLllA-2914 - GUUGAAUCCAAUGGCUA 17 3399

BCLllA-2915 - CUCGGGGCGCAGCGGCA 17 3400

BCLllA-2916 - CCGAGGCCGAGGGCCAC 17 3401

BCLllA-2917 + CUAAACAGGGGGGGAGU 17 3402

BCLllA-2918 - GCGGCACGGGAAGUGGA 17 3403

BCLllA-2919 + CACAGGUUGCACUUGUA 17 3404

BCLllA-2920 - CAGCGAGGCCU UCCACC 17 3405

BCLllA-2921 - AACCUGCUAAGAAUACC 17 3406

BCLllA-2922 + AUCCUGGUAUUCUUAGC 17 3407

BCLllA-2923 + GGUGGUGGACUAAACAG 17 3408

BCLllA-2924 - CGAGGCCGAGGGCCACA 17 3409

BCLllA-2925 + GUACAUGUGUAGCUGCU 17 3410

BCLllA-2926 + UUGAUGCGCUUAGAGAA 17 3411

BCLllA-2927 + UCCUCGUCCCCGUUCUC 17 3412 BCLllA-2928 + AUGACUUGGACUUGACC 17 3413

BCLllA-2929 + GUCUCCGAAGCUAAGGA 17 3414

BCLllA-2930 + GGUGGACUAAACAGGGG 17 3415

BCLllA-2931 + GCAUGUGCGUCUUCAUG 17 3416

BCLllA-2932 + GGCACUCGGGUGAUGGG 17 3417

BCLllA-2933 + AUAGGGCUGGGCCGGCC 17 3418

BCLllA-2934 + CCGUCCAGCUCCCCGGG 17 3419

BCLllA-2935 + GCAGUAACCUUUGCAUA 17 3420

BCLllA-2936 - GAUCCCU UCCUUAGCUU 17 3421

BCLllA-2937 + AAGGGGCUCAGCGAGCU 17 3422

BCLllA-2938 - AGCUGACGGAGAGCGAG 17 3423

BCLllA-2939 - UCGCGGGGCGCGGUCGU 17 3424

BCLllA-2940 - AGCGGCACGGGAAGUGG 17 3425

BCLllA-2941 + CAAAGGCACUCGGGUGA 17 3426

BCLllA-2942 + CUGCACCUAGUCCUGAA 17 3427

BCLllA-2943 - GCUGGACGGAGGGAUCU 17 3428

BCLllA-2944 + CCCUGUCAAAGGCACUC 17 3429

BCLllA-2945 + AACCUUUGCAUAGGGCU 17 3430

BCLllA-2946 + CGCCCGGGGAGCAGCCG 17 3431

BCLllA-2947 + UGGUGGACUAAACAGGG 17 3432

BCLllA-2948 - GGCCCAGCCCUAUGCAA 17 3433

BCLllA-2949 + CCUCGUCCCCGUUCUCC 17 3434

BCLllA-2950 - GCCAGCUCCCCGGAACC 17 3435

BCLllA-2951 + GCCGGGUUCCGGGGAGC 17 3436

BCLllA-2952 + UGCAGUAACCUU UGCAU 17 3437

BCLllA-2953 + GCU UCUCGCCCAGGACC 17 3438

BCLllA-2954 - CCGCCCGGGGAGCUGGA 17 3439

BCLllA-2955 - CCGGGGAGCUGGACGGA 17 3440

BCLllA-2956 - CUUCCGGCCUGGCAGAA 17 3441

BCLllA-2957 + CCUAGAGAAAUCCAUGG 17 3442

BCLllA-2958 + GGAGGGGGGGCGUCGCC 17 3443

BCLllA-2959 - UACUUAGAAAGCGAACA 17 3444

BCLllA-2960 + GGAGGCUCCAUAGCCAU 17 3445

BCLllA-2961 + ACACAUCUUGAGCUCUC 17 3446

BCLllA-2962 - GGCACCAGCGACU UGGU 17 3447

BCLllA-2963 + GGGAUCUUUGAGCUGCC 17 3448

BCLllA-2964 + GCAGCAGCUUUUUGGAC 17 3449

BCLllA-2965 + CUGCAAUAUGAAUCCCA 17 3450

BCLllA-2966 + UCUGCACCUAGUCCUGA 17 3451

BCLllA-2967 + GAAGGGGCUCAGCGAGC 17 3452

BCLllA-2968 + U UCCGGGGAGCUGGCGG 17 3453

BCLllA-2969 - GCACCGGCGCAGCCACA 17 3454 BCLllA-2970 + AUAUGAAUCCCAUGGAG 17 3455

BCLllA-2971 - GUGGUCCGGGCCCGGGC 17 3456

BCLllA-2972 - CUUCACACACCCCCAU U 17 3457

BCLllA-2973 - GUCCAAAAAGCUGCUGC 17 3458

BCLllA-2974 - CGGCACCAGCGACU UGG 17 3459

BCLllA-2975 - GCUUCUCCACACCGCCC 17 3460

BCLllA-2976 + CGCCCGUGUGGCUGCGC 17 3461

BCLllA-2977 - CACGCACAGAACACUCA 17 3462

BCLllA-2978 + UGUACAUGUGUAGCUGC 17 3463

BCLllA-2979 - CACCGGCGCAGCCACAC 17 3464

BCLllA-2980 + U UGCUACCUGGCUGGAA 17 3465

BCLllA-2981 + ACCCUGUCAAAGGCACU 17 3466

BCLllA-2982 - CCACCUGGCCGAGGCCG 17 3467

BCLllA-2983 + GGGCGGAUUGCAGAGGA 17 3468

BCLllA-2984 + CUAGAGAAAUCCAUGGC 17 3469

BCLllA-2985 - GGCGGAAGAGAUGGCCC 17 3470

BCLllA-2986 + GGGGCGGAUUGCAGAGG 17 3471

BCLllA-2987 - GUGUGGCAGUUU UCGGA 17 3472

BCLllA-2988 - GAGAGAGGCUUCCGGCC 17 3473

BCLllA-2989 + CGGGUGAUGGGUGGCCA 17 3474

BCLllA-2990 - CCCGGGGAGCUGGACGG 17 3475

BCLllA-2991 - UAGGAGACUUAGAGAGC 17 3476

BCLllA-2992 + CACAUCUUGAGCUCUCU 17 3477

BCLllA-2993 + CCUCGGCCUCGGCCAGG 17 3478

BCLllA-2994 - GGCCUUCCACCAGG UCC 17 3479

BCLllA-2995 + UCUCGCCCAGGACCUGG 17 3480

BCLllA-2996 + UCUGCCCUCU UUUGAGC 17 3481

BCLllA-2997 + ACUAAACAGGGGGGGAG 17 3482

BCLllA-2998 + CUUGACCGGGGGCUGGG 17 3483

BCLllA-2999 + UUGACCGGGGGCUGGGA 17 3484

BCLllA-3000 - AGACUUAGAGAGCUGGC 17 3485

BCLllA-3001 - AGCCCACCGCUGUCCCC 17 3486

BCLllA-3002 - AGCCAUUCACCAGUGCA 17 3487

BCLllA-3003 - GCUUCCGGCCUGGCAGA 17 3488

BCLllA-3004 - GACUUAGAGAGCUGGCA 17 3489

BCLllA-3005 - AGGCCCAGCUCAAAAGA 17 3490

BCLllA-3006 + UCGGGUGAUGGGUGGCC 17 3491

BCLllA-3007 + CAAGAGAAACCAUGCAC 17 3492

BCLllA-3008 + AUCUUUGAGCUGCCUGG 17 3493

BCLllA-3009 + UAUUCUUAGCAGGUUAA 17 3494

BCLllA-3010 + CUGCCCUCUU UUGAGCU 17 3495

BCLllA-3011 + CCAUCUCU UCCGCCCCC 17 3496 BCLllA-3012 - UGGCCGCGGCUGCUCCC 17 3497

BCLllA-3013 + CCUGUGGCCCUCGGCCU 17 3498

BCLllA-3014 + CAGCUCCCCGGGCGGUG 17 3499

BCLllA-3015 + U UUGCAUAGGGCUGGGC 17 3500

BCLllA-3016 + GGCCCUCGGCCUCGGCC 17 3501

BCLllA-3017 - GCUGACGGAGAGCGAGA 17 3502

BCLllA-3018 - AGAUGUGUGGCAGUUU U 17 3503

BCLllA-3019 + AUUCUUAGCAGGUUAAA 17 3504

BCLllA-3020 + UCUCCUAGAGAAAUCCA 17 3505

BCLllA-3021 - CCUUUGACAGGGUGCUG 17 3506

BCLllA-3022 + GGAGGGGCGGAUUGCAG 17 3507

BCLllA-3023 + UUCUUAGCAGGUUAAAG 17 3508

BCLllA-3024 + CGGAUUGCAGAGGAGGG 17 3509

BCLllA-3025 + UUUGAGCUGGGCCUGCC 17 3510

BCLllA-3026 + CUUCAGCUUGCUGGCCU 17 3511

BCLllA-3027 + CUUGAACUUGGCCACCA 17 3512

BCLllA-3028 - CUGCAACCAUUCCAGCC 17 3513

BCLllA-3029 - CAUAGAGCGCCUGGGGG 17 3514

BCLllA-3030 - GGGCGCGGUCGUGGGCG 17 3515

BCLllA-3031 + UCCCAUGGAGAGGUGGC 17 3516

BCLllA-3032 - GGCCGCGGCUGCUCCCC 17 3517

BCLllA-3033 - AUUUCAGAGCAACCUGG 17 3518

BCLllA-3034 - GCCUUCCACCAGGUCCU 17 3519

BCLllA-3035 + UGAAUCCCAUGGAGAGG 17 3520

BCLllA-3036 + UUGAGCUGGGCCUGCCC 17 3521

BCLllA-3037 + AGGGGCUCAGCGAGCUG 17 3522

BCLllA-3038 + AGGGCUUCUCGCCCGUG 17 3523

BCLllA-3039 - CACCGCUGUCCCCAGGC 17 3524

BCLllA-3040 - CAAAUUUCAGAGCAACC 17 3525

BCLllA-3041 - AGAGAGCUCAAGAUGUG 17 3526

BCLllA-3042 + AACCAUGCACUGGUGAA 17 3527

BCLllA-3043 + CCUCCGUCCAGCUCCCC 17 3528

BCLllA-3044 + AGUGUCCCUGUGGCCCU 17 3529

BCLllA-3045 + CCCUCCGUCCAGCUCCC 17 3530

BCLllA-3046 + GGCCUGGGGACAGCGGU 17 3531

BCLllA-3047 + GCCCAGCAGCAGCUUU U 17 3532

BCLllA-3048 - CAGGCCCAGCUCAAAAG 17 3533

BCLllA-3049 - CUUCGGGCUGAGCCUGG 17 3534

BCLllA-3050 + CCCAUGGAGAGGUGGCU 17 3535

BCLllA-3051 - CCCAGCCACCUCUCCAU 17 3536

BCLllA-3052 + GGGUUCCGGGGAGCUGG 17 3537

BCLllA-3053 + UAGGGCUGGGCCGGCCU 17 3538 BCLllA-3054 - CCUGGGGGCGGAAGAGA 17 3539

BCLllA-3055 + GCCCAGGACCUGGUGGA 17 3540

BCLllA-3056 - CGGGCUGAGCCUGGAGG 17 3541

BCLllA-3057 - ACCACGAGAACAGCUCG 17 3542

BCLllA-3058 + CGGCCUGGGGACAGCGG 17 3543

BCLllA-3059 - UCCAAAAAGCUGCUGCU 17 3544

BCLllA-3060 + GCGCCCUUCUGCCAGGC 17 3545

BCLllA-3061 - UCCCAGCCACCUCUCCA 17 3546

BCLllA-3062 - CUCCACCGCCAGCUCCC 17 3547

BCLllA-3063 + CUGGGCCUGCCCGGGCC 17 3548

BCLllA-3064 + AGGGCUGGGCCGGCCUG 17 3549

BCLllA-3065 + AACAGGGGGGGAGUGGG 17 3550

BCLllA-3066 - GGAGAACGGGGACGAGG 17 3551

BCLllA-3067 + UGAUGCGCUUAGAGAAG 17 3552

BCLllA-3068 + GGAUUGCAGAGGAGGGA 17 3553

BCLllA-3069 + GGCCGGCCUGGGGACAG 17 3554

BCLllA-3070 + GAUUGCAGAGGAGGGAG 17 3555

BCLllA-3071 + AUUGCAGAGGAGGGAGG 17 3556

BCLllA-3072 + ACCGGGGGCUGGGAGGG 17 3557

BCLllA-3073 + UGGAGAGGUGGCUGGGA 17 3558

BCLllA-3074 + UUGCAGAGGAGGGAGGG 17 3559

BCLllA-3075 - CGGGGACGAGGAGGAAG 17 3560

BCLllA-3076 - GACGGAGAGCGAGAGGG 17 3561

BCLllA-3077 - UCCUCCCUCCCAGCCCC 17 3562

BCLllA-3078 + GCU UCAGCUUGCUGGCC 17 3563

BCLllA-3079 + UGCAGAGGAGGGAGGGG 17 3564

BCLllA-3080 + GGGCUGGGAGGGAGGAG 17 3565

BCLllA-3081 - GGAAGAGGAGGACGACG 17 3566

BCLllA-3082 + GGGGCUGGGAGGGAGGA 17 3567

BCLllA-3083 - GGAGGACGACGAGGAAG 17 3568

BCLllA-3084 - GGAGGAGGAGGAGCUGA 17 3569

BCLllA-3085 + GGGGGCUGGGAGGGAGG 17 3570

BCLllA-3086 + CUGGGAGGGAGGAGGGG 17 3571

BCLllA-3087 - CGAGGAAGAGGAAGAAG 17 3572

BCLllA-3088 - GGACGAGGAGGAAGAGG 17 3573

BCLllA-3089 - GGAAGAAGAGGAGGAAG 17 3574

BCLllA-3090 - GGAAGAGGAAGAAGAGG 17 3575

BCLllA-3091 - AGAAGAGGAGGAAGAGG 17 3576

BCLllA-3092 - AGAGGAGGAAGAGGAGG 17 3577

BCLllA-3093 - GGAGGAAGAGGAGGAGG 17 3578

BCLllA-3094 + GUCUAUGCGGUCCGACUCGC 20 3579

BCLllA-3095 + UCGUCGGACUUGACCGUCAU 20 3580 BCLllA-3096 + CGUCGGACU UGACCGUCAUG 20 3581

BCLllA-3097 - AUGACGGUCAAGUCCGACGA 20 3582

BCLllA-3098 - GAGUCGGACCGCAUAGACGA 20 3583

BCLllA-3099 + CGGGCCCGGACCACUAAUAU 20 3584

BCLllA-3100 + GUCGUCGGACUUGACCGUCA 20 3585

BCLllA-3101 + CUCUGGGUACUACGCCGAAU 20 3586

BCLllA-3102 + CUGGGUACUACGCCGAAUGG 20 3587

BCLllA-3103 + CCGGGCCCGGACCACUAAUA 20 3588

BCLllA-3104 - CCGCGGGUUGGUAUCCCUUC 20 3589

BCLllA-3105 + UCUGGGUACUACGCCGAAUG 20 3590

BCLllA-3106 + GGAUACCAACCCGCGGGGUC 20 3591

BCLllA-3107 - ACGCCCCAUAUUAGUGGUCC 20 3592

BCLllA-3108 - CACUUGCGACGAAGACUCGG 20 3593

BCLllA-3109 + UCUCUGGGUACUACGCCGAA 20 3594

BCLllA-3110 - UAAGCGCAUCAAGCUCGAGA 20 3595

BCLllA-3111 - UGCGACGAAGACUCGGUGGC 20 3596

BCLllA-3112 + CGCGCUUAUGCUUCUCGCCC 20 3597

BCLllA-3113 + UGAAGGGAUACCAACCCGCG 20 3598

BCLllA-3114 + GGGCCCGGACCACUAAUAUG 20 3599

BCLllA-3115 + CGUGUUGGGCAUCGCGGCCG 20 3600

BCLllA-3116 + UCCGUGUUGGGCAUCGCGGC 20 3601

BCLllA-3117 + GUCGGACUUGACCGUCAUGG 20 3602

BCLllA-3118 + GCGCAAACUCCCGUUCUCCG 20 3603

BCLllA-3119 + CUCCGAGGAGUGCUCCGACG 20 3604

BCLllA-3120 + CACGGACUUGAGCGCGCUGC 20 3605

BCLllA-3121 - CACGCCCCAUAU UAGUGGUC 20 3606

BCLllA-3122 + GAUACCAACCCGCGGGGUCA 20 3607

BCLllA-3123 - CAGCGCGCUCAAGUCCGUGG 20 3608

BCLllA-3124 + GGGUGCACGCGUGGUCGCAC 20 3609

BCLllA-3125 - GAAGCAUAAGCGCGGCCACC 20 3610

BCLllA-3126 - GUGCGACCACGCGUGCACCC 20 3611

BCLllA-3127 + GAGUACACGUUCUCCGUGUU 20 3612

BCLllA-3128 + GUCUCGGUGGUGGACUAAAC 20 3613

BCLllA-3129 + CCGUUCUCCGGGAUCAGGUU 20 3614

BCLllA-3130 + CGAGUACACGUUCUCCGUGU 20 3615

BCLllA-3131 - CGGAGAACGUGUACUCGCAG 20 3616

BCLllA-3132 - GGGAGCACGCCCCAUAU UAG 20 3617

BCLllA-3133 - CCAUAUUAGUGGUCCGGGCC 20 3618

BCLllA-3134 + GCCGCAGAACUCGCAUGACU 20 3619

BCLllA-3135 + CGCCCCGCGAGCUGUUCUCG 20 3620

BCLllA-3136 - GCAGUGGCUCGCCGGCUACG 20 3621

BCLllA-3137 - CAUAUUAGUGGUCCGGGCCC 20 3622 BCLllA-3138 + CUGAAGGGAUACCAACCCGC 20 3623

BCLllA-3139 + AUACCAACCCGCGGGGUCAG 20 3624

BCLllA-3140 - CAG CAG CG CG C U CA AG U CCG 20 3625

BCLllA-3141 + CGUCCCCGUUCUCCGGGAUC 20 3626

BCLllA-3142 - CACCACGAGAACAGCUCGCG 20 3627

BCLllA-3143 - GCGGU UGAAUCCAAUGGCUA 20 3628

BCLllA-3144 - GGACACUUGCGACGAAGACU 20 3629

BCLllA-3145 + GUGUUGGGCAUCGCGGCCGG 20 3630

BCLllA-3146 + CUUCGUCGCAAGUGUCCCUG 20 3631

BCLllA-3147 + CCCCAGGCGCUCUAUGCGGU 20 3632

BCLllA-3148 + CCGUGUUGGGCAUCGCGGCC 20 3633

BCLllA-3149 + CGUUCUCCGGGAUCAGGUUG 20 3634

BCLllA-3150 + GCCUCUCUCGAUACUGAUCC 20 3635

BCLllA-3151 + UCGCAUGACU UGGACU UGAC 20 3636

BCLllA-3152 - AUCACCCGAGUGCCUUUGAC 20 3637

BCLllA-3153 - UAAGCGCGGCCACCUGGCCG 20 3638

BCLllA-3154 - GCACAAAUCGUCCCCCAUGA 20 3639

BCLllA-3155 - CGCCCUGCCCGACGUCAUGC 20 3640

BCLllA-3156 - CAACCUGAUCCCGGAGAACG 20 3641

BCLllA-3157 - CGGAGCACUCCUCGGAGAAC 20 3642

BCLllA-3158 - AGACUCGGUGGCCGGCGAGU 20 3643

BCLllA-3159 + GGCGGUGGAGAGACCGUCGU 20 3644

BCLllA-3160 - GUGUACUCGCAGUGGCUCGC 20 3645

BCLllA-3161 - UCGGAGCACUCCUCGGAGAA 20 3646

BCLllA-3162 - CCCGGCCGCGAUGCCCAACA 20 3647

BCLllA-3163 + CCCGUUCUCCGGGAUCAGGU 20 3648

BCLllA-3164 + UCGGUGGUGGACUAAACAGG 20 3649

BCLllA-3165 + CCUGAAGGGAUACCAACCCG 20 3650

BCLllA-3166 + GUCGUUCUCGCUCUUGAACU 20 3651

BCLllA-3167 - CCCCACCGCAUAGAGCGCCU 20 3652

BCLllA-3168 + GUCGCUGGUGCCGGGU UCCG 20 3653

BCLllA-3169 - CGAGAACAGCUCGCGGGGCG 20 3654

BCLllA-3170 + CGCAUGACUUGGACUUGACC 20 3655

BCLllA-3171 - CCCACCGCAUAGAGCGCCUG 20 3656

BCLllA-3172 + AAGUCGCUGGUGCCGGGUUC 20 3657

BCLllA-3173 + CGAGGAGUGCUCCGACGAGG 20 3658

BCLllA-3174 - UCCCCGGGCGAGUCGGCCUC 20 3659

BCLllA-3175 - CUCCCCGGGCGAGUCGGCCU 20 3660

BCLllA-3176 + CAUGACUUGGACUUGACCGG 20 3661

BCLllA-3177 - AGCUCGCGGGGCGCGGUCGU 20 3662

BCLllA-3178 + UGCUCCGACGAGGAGGCAAA 20 3663

BCLllA-3179 + CUUUUUGGACAGGCCCCCCG 20 3664 BCLllA-3180 - CUACGGCU UCGGGCUGAGCC 20 3665

BCLllA-3181 - CCCCGGGCGAGUCGGCCUCG 20 3666

BCLllA-3182 + UAACAGUGCCAUCGUCUAUG 20 3667

BCLllA-3183 - CUCCUCGUCGGAGCACUCCU 20 3668

BCLllA-3184 - CCCGGCACCAGCGACUUGGU 20 3669

BCLllA-3185 - GCGCUUCUCCACACCGCCCG 20 3670

BCLllA-3186 + CUCGGUGGUGGACUAAACAG 20 3671

BCLllA-3187 - CCCCCACCGCAUAGAGCGCC 20 3672

BCLllA-3188 - GAUCCCGGAGAACGGGGACG 20 3673

BCLllA-3189 + CCAGGCGCUCUAUGCGGUGG 20 3674

BCLllA-3190 - U UAGUGGUCCGGGCCCGGGC 20 3675

BCLllA-3191 + CCCAGGCGCUCUAUGCGGUG 20 3676

BCLllA-3192 - CGGCUGCUCCCCGGGCGAGU 20 3677

BCLllA-3193 - UCGCCGGCUACGCGGCCUCC 20 3678

BCLllA-3194 - AUCGAGAGAGGCUUCCGGCC 20 3679

BCLllA-3195 + GGGUCCAAGUGAUGUCUCGG 20 3680

BCLllA-3196 - AUCGCCU UUUGCCUCCUCGU 20 3681

BCLllA-3197 - AUCUCGGGGCGCAGCGGCAC 20 3682

BCLllA-3198 + CGGUGGUGGACUAAACAGGG 20 3683

BCLllA-3199 - GAUGGCACUGUUAAUGGCCG 20 3684

BCLllA-3200 + UGCCCUGCAUGACGUCGGGC 20 3685

BCLllA-3201 + UCUCGGUGGUGGACUAAACA 20 3686

BCLllA-3202 - AGAGGGUGGACUACGGCUUC 20 3687

BCLllA-3203 + CCCCGAGGCCGACUCGCCCG 20 3688

BCLllA-3204 - GAUCUCGGGGCGCAGCGGCA 20 3689

BCLllA-3205 - ACGGAAGUCCCCUGACCCCG 20 3690

BCLllA-3206 + ACUCGCCCGGGGAGCAGCCG 20 3691

BCLllA-3207 - U UGCGCUUCUCCACACCGCC 20 3692

BCLllA-3208 - GGAACCCGGCACCAGCGACU 20 3693

BCLllA-3209 + GCAUGACUUGGACUUGACCG 20 3694

BCLllA-3210 - UAAUGGCCGCGGCUGCUCCC 20 3695

BCLllA-3211 - CCGGGCGAGUCGGCCUCGGG 20 3696

BCLllA-3212 + GUCAAAGGCACUCGGGUGAU 20 3697

BCLllA-3213 - GGUGCUGCGGUUGAAUCCAA 20 3698

BCLllA-3214 - CUGGGCGAGAAGCAUAAGCG 20 3699

BCLllA-3215 + ACUUGGACUUGACCGGGGGC 20 3700

BCLllA-3216 + CCCCCCGAGGCCGACUCGCC 20 3701

BCLllA-3217 - CCACCGCAUAGAGCGCCUGG 20 3702

BCLllA-3218 + AGUCGCUGGUGCCGGGUUCC 20 3703

BCLllA-3219 + UCGCACAGGUUGCACUUGUA 20 3704

BCLllA-3220 + GCCCUGCAUGACGUCGGGCA 20 3705

BCLllA-3221 + CCGCCCCCAGGCGCUCUAUG 20 3706 BCLllA-3222 - GCCCUGCCCGACGUCAUGCA 20 3707

BCLllA-3223 + GUCGCACAGGU UGCACU UGU 20 3708

BCLllA-3224 - AGGUAGCAAGCCGCCCUUCC 20 3709

BCLllA-3225 - CCAACCUGAUCCCGGAGAAC 20 3710

BCLllA-3226 + AGGAAGGGCGGCUUGCUACC 20 3711

BCLllA-3227 - GAAGGAGUUCGACCUGCCCC 20 3712

BCLllA-3228 + CUUGGACUUGACCGGGGGCU 20 3713

BCLllA-3229 - GAGAGGGUGGACUACGGCUU 20 3714

BCLllA-3230 - UCCAAGUCAUGCGAGUUCUG 20 3715

BCLllA-3231 - ACCCGGCACCAGCGACUUGG 20 3716

BCLllA-3232 + CCCCCAGGCGCUCUAUGCGG 20 3717

BCLllA-3233 + GCGUCUGCCCUCUUUUGAGC 20 3718

BCLllA-3234 - GCCCGACGUCAUGCAGGGCA 20 3719

BCLllA-3235 + GAGCUUGAUGCGCUUAGAGA 20 3720

BCLllA-3236 - CAGCUCGCGGGGCGCGGUCG 20 3721

BCLllA-3237 + CGUGGUGGCGCGCCGCCUCC 20 3722

BCLllA-3238 - UCACCCGAGUGCCU UUGACA 20 3723

BCLllA-3239 - GAACGACCCCAACCUGAUCC 20 3724

BCLllA-3240 + CAACCGCAGCACCCUG UCAA 20 3725

BCLllA-3241 + UCCAAGUGAUGUCUCGGUGG 20 3726

BCLllA-3242 + GUUCUCCGUGUUGGGCAUCG 20 3727

BCLllA-3243 - CGGAAGUCCCCUGACCCCGC 20 3728

BCLllA-3244 + UAUGCUUCUCGCCCAGGACC 20 3729

BCLllA-3245 - AGCUGGACGGAGGGAUCUCG 20 3730

BCLllA-3246 + GGCUGCGCCGGUGCACCACC 20 3731

BCLllA-3247 - GU UGGUAUCCCUUCAGGACU 20 3732

BCLllA-3248 - AUAGACGAUGGCACUGU UAA 20 3733

BCLllA-3249 - CUCCCGCCAUGGAU UUCUCU 20 3734

BCLllA-3250 - ACCAGGAUCAGUAUCGAGAG 20 3735

BCLllA-3251 - AGUCCCCUGACCCCGCGGGU 20 3736

BCLllA-3252 + GUCUGGAGUCUCCGAAGCUA 20 3737

BCLllA-3253 - GCCGGCCCAGCCCUAUGCAA 20 3738

BCLllA-3254 - GAUGUGUGGCAGUU UUCGGA 20 3739

BCLllA-3255 + CUAGAGAAAUCCAUGGCGGG 20 3740

BCLllA-3256 + GGCGCUGCCCACCAAGUCGC 20 3741

BCLllA-3257 - CCCGGGCGAGUCGGCCUCGG 20 3742

BCLllA-3258 - ACACCGCCCGGGGAGCUGGA 20 3743

BCLllA-3259 + CAGUAACCUUUGCAUAGGGC 20 3744

BCLllA-3260 - UCAGUAUCGAGAGAGGCUUC 20 3745

BCLllA-3261 + GCAUGACGUCGGGCAGGGCG 20 3746

BCLllA-3262 - CCGCAUAGAGCGCCUGGGGG 20 3747

BCLllA-3263 + CCCCCGAGGCCGACUCGCCC 20 3748 BCLllA-3264 + AGGGCGGCUUGCUACCUGGC 20 3749

BCLllA-3265 + GCACCCUGUCAAAGGCACUC 20 3750

BCLllA-3266 + CUGAUCCUGGUAUUCU UAGC 20 3751

BCLllA-3267 + CAUGUGGCGCUUCAGCU UGC 20 3752

BCLllA-3268 + CCCACCAAGUCGCUGGUGCC 20 3753

BCLllA-3269 + GGAGGCAAAAGGCGAUUGUC 20 3754

BCLllA-3270 - CCCAACCUGAUCCCGGAGAA 20 3755

BCLllA-3271 + GAGUCUCCGAAGCUAAGGAA 20 3756

BCLllA-3272 - GGCUAUGGAGCCUCCCGCCA 20 3757

BCLllA-3273 + CGUCUGCCCUCUUUUGAGCU 20 3758

BCLllA-3274 - CGCCCGGGGAGCUGGACGGA 20 3759

BCLllA-3275 + AGUAACCUUUGCAUAGGGCU 20 3760

BCLllA-3276 - UCCACCACCGAGACAUCACU 20 3761

BCLllA-3277 + GGUUGCAGUAACCUUUGCAU 20 3762

BCLllA-3278 + GCAAUAUGAAUCCCAUGGAG 20 3763

BCLllA-3279 + ACCAUGCCCUGCAUGACGUC 20 3764

BCLllA-3280 + GGCCUCGCUGAAGUGCUGCA 20 3765

BCLllA-3281 - AGAGCAACCUGGUGGUGCAC 20 3766

BCLllA-3282 + GCCCACCAAGUCGCUGGUGC 20 3767

BCLllA-3283 + UGUCAAAGGCACUCGGGUGA 20 3768

BCLllA-3284 + AGCUUGAUGCGCUUAGAGAA 20 3769

BCLllA-3285 + AGGGGGGGCGUCGCCAGGAA 20 3770

BCLllA-3286 + GUGGAAAGCGCCCUUCUGCC 20 3771

BCLllA-3287 + UGGGGGUCCAAGUGAUGUCU 20 3772

BCLllA-3288 - CUCCAUGCAGCACUUCAGCG 20 3773

BCLllA-3289 + GCGCUUCAGCUUGCUGGCCU 20 3774

BCLllA-3290 - CUUCAGCGAGGCCUUCCACC 20 3775

BCLllA-3291 + GGAGUCUCCGAAGCUAAGGA 20 3776

BCLllA-3292 + CACUCGGGUGAUGGGUGGCC 20 3777

BCLllA-3293 - UGCGCUUCUCCACACCGCCC 20 3778

BCLllA-3294 + GGUGGUGGACUAAACAGGGG 20 3779

BCLllA-3295 - CGAGGCCUUCCACCAGGUCC 20 3780

BCLllA-3296 - AAUGGCCGCGGCUGCUCCCC 20 3781

BCLllA-3297 + GUUGUACAUGUGUAGCUGCU 20 3782

BCLllA-3298 - GUUCUUCACACACCCCCAUU 20 3783

BCLllA-3299 - CGCAGCGGCACGGGAAGUGG 20 3784

BCLllA-3300 + GCGGGAGGCUCCAUAGCCAU 20 3785

BCLllA-3301 - GGUGCACCGGCGCAGCCACA 20 3786

BCLllA-3302 - CUCCACACCGCCCGGGGAGC 20 3787

BCLllA-3303 + AAAGCGCCCUUCUGCCAGGC 20 3788

BCLllA-3304 + ACUCGGGUGAUGGGUGGCCA 20 3789

BCLllA-3305 + CUGCCUGGAGGCCGCGUAGC 20 3790 BCLllA-3306 + GUCCAGCUCCCCGGGCGGUG 20 3791

BCLllA-3307 - GAGCUGGACGGAGGGAUCUC 20 3792

BCLllA-3308 - UCUAGCCCACCGCUGUCCCC 20 3793

BCLllA-3309 + AGUUGUACAUGUGUAGCUGC 20 3794

BCLllA-3310 + AUUCUGCACCUAGUCCUGAA 20 3795

BCLllA-3311 - CCACCACGAGAACAGCUCGC 20 3796

BCLllA-3312 + CUCCUAGAGAAAUCCAUGGC 20 3797

BCLllA-3313 - U UUAACCUGCUAAGAAUACC 20 3798

BCLllA-3314 + GGACUAAACAGGGGGGGAGU 20 3799

BCLllA-3315 - GGCCACCUGGCCGAGGCCGA 20 3800

BCLllA-3316 + GGCUUGCUACCUGGCUGGAA 20 3801

BCLllA-3317 + CAUUCUGCACCUAGUCCUGA 20 3802

BCLllA-3318 + UGCUGGCCUGGGUGCACGCG 20 3803

BCLllA-3319 + UGUGGCCCUCGGCCUCGGCC 20 3804

BCLllA-3320 - CCGCCCGGGGAGCUGGACGG 20 3805

BCLllA-3321 - UGGCCGAGGCCGAGGGCCAC 20 3806

BCLllA-3322 + UGGGCAUCGCGGCCGGGGGC 20 3807

BCLllA-3323 + UCUCCUAGAGAAAUCCAUGG 20 3808

BCLllA-3324 + GGGCCAUCUCUUCCGCCCCC 20 3809

BCLllA-3325 + GU UGCAGUAACCUUUGCAUA 20 3810

BCLllA-3326 + AAAGGCACUCGGGUGAUGGG 20 3811

BCLllA-3327 + GAAGGGAUCUUUGAGCUGCC 20 3812

BCLllA-3328 + GCCACACAUCUUGAGCUCUC 20 3813

BCLllA-3329 - GGAGGGAUCUCGGGGCGCAG 20 3814

BCLllA-3330 - CCCGGAGAACGGGGACGAGG 20 3815

BCLllA-3331 + UGCAUAGGGCUGGGCCGGCC 20 3816

BCLllA-3332 - CGGGGCGCGGUCGUGGGCGU 20 3817

BCLllA-3333 + GAGGGGGGGCGUCGCCAGGA 20 3818

BCLllA-3334 - ACCGCCAGCUCCCCGGAACC 20 3819

BCLllA-3335 + GGUAUUCUUAGCAGGUUAAA 20 3820

BCLllA-3336 - AGGCUUCCGGCCUGGCAGAA 20 3821

BCLllA-3337 + GAUCCCUCCGUCCAGCUCCC 20 3822

BCLllA-3338 + UGGUAUUCUUAGCAGGUUAA 20 3823

BCLllA-3339 - AUCUACUUAGAAAGCGAACA 20 3824

BCLllA-3340 - CGGCCACCUGGCCGAGGCCG 20 3825

BCLllA-3341 - CAACACGCACAGAACACUCA 20 3826

BCLllA-3342 + GCCGGCCUGGGGACAGCGGU 20 3827

BCLllA-3343 - GCCACCACGAGAACAGCUCG 20 3828

BCLllA-3344 + GUAUUCUUAGCAGGUUAAAG 20 3829

BCLllA-3345 - CUCUAGGAGACUUAGAGAGC 20 3830

BCLllA-3346 - AACAGCCAUUCACCAGUGCA 20 3831

BCLllA-3347 + U UGCAAGAGAAACCAUGCAC 20 3832 BCLllA-3348 + GACUUGACCGGGGGCUGGGA 20 3833

BCLllA-3349 + ACCU UUGCAUAGGGCUGGGC 20 3834

BCLllA-3350 + UCUUUUGAGCUGGGCCUGCC 20 3835

BCLllA-3351 - GAGGCCU UCCACCAGGUCCU 20 3836

BCLllA-3352 + CUUUUGAGCUGGGCCUGCCC 20 3837

BCLllA-3353 + GGGAUCUUUGAGCUGCCUGG 20 3838

BCLllA-3354 - GGGCAGGCCCAGCUCAAAAG 20 3839

BCLllA-3355 + AGCACCCUGUCAAAGGCACU 20 3840

BCLllA-3356 + UGGACUAAACAGGGGGGGAG 20 3841

BCLllA-3357 + GCUCUUGAACUUGGCCACCA 20 3842

BCLllA-3358 + GAAUCCCAUGGAGAGGUGGC 20 3843

BCLllA-3359 - GUGCACCGGCGCAGCCACAC 20 3844

BCLllA-3360 - AAAGAUCCCUUCCUUAGCUU 20 3845

BCLllA-3361 + UGUCUGCAAUAUGAAUCCCA 20 3846

BCLllA-3362 - GGCAGGCCCAGCUCAAAAGA 20 3847

BCLllA-3363 + CCUCCGUCCAGCUCCCCGGG 20 3848

BCLllA-3364 - CUGUCCAAAAAGCUGCUGCU 20 3849

BCLllA-3365 + GCUUGAUGCGCUUAGAGAAG 20 3850

BCLllA-3366 - CGGCUUCGGGCUGAGCCUGG 20 3851

BCLllA-3367 + CACCAUGCCCUGCAUGACGU 20 3852

BCLllA-3368 - UCAAGAUGUGUGGCAGUUUU 20 3853

BCLllA-3369 - GUUCAAAUUUCAGAGCAACC 20 3854

BCLllA-3370 + GAGAAGGGGCUCAGCGAGCU 20 3855

BCLllA-3371 - GCAGCGGCACGGGAAGUGGA 20 3856

BCLllA-3372 + AAGUCUCCUAGAGAAAUCCA 20 3857

BCLllA-3373 + GGUGCCGGGUUCCGGGGAGC 20 3858

BCLllA-3374 - CCUGUCCAAAAAGCUGCUGC 20 3859

BCLllA-3375 + AUAUGAAUCCCAUGGAGAGG 20 3860

BCLllA-3376 - GGGCGCAGCGGCACGGGAAG 20 3861

BCLllA-3377 - GGCCGAGGCCGAGGGCCACA 20 3862

BCLllA-3378 + GCAAGUGUCCCUGUGGCCCU 20 3863

BCLllA-3379 + GGACUUGACCGGGGGCUGGG 20 3864

BCLllA-3380 + GCUUCUCGCCCAGGACCUGG 20 3865

BCLllA-3381 - GCGCCUGGGGGCGGAAGAGA 20 3866

BCLllA-3382 + GUCCCUGUGGCCCUCGGCCU 20 3867

BCLllA-3383 + AUCCCUCCGUCCAGCUCCCC 20 3868

BCLllA-3384 - GUGCCU UUGACAGGGUGCUG 20 3869

BCLllA-3385 - CCCAGAGAGCUCAAGAUGUG 20 3870

BCLllA-3386 + GGCCCUCGGCCUCGGCCAGG 20 3871

BCLllA-3387 - GAGAGCGAGAGGGUGGACUA 20 3872

BCLllA-3388 + GGGGGCGUCGCCAGGAAGGG 20 3873

BCLllA-3389 + AGAGAAGGGGCUCAGCGAGC 20 3874 BCLllA-3390 + CCACACAUCUUGAGCUCUCU 20 3875

BCLllA-3391 + GCUGCCCAGCAGCAGCUUUU 20 3876

BCLllA-3392 - GGAGCUGGACGGAGGGAUCU 20 3877

BCLllA-3393 - GGGGGCGGAAGAGAUGGCCC 20 3878

BCLllA-3394 - AGGAGACUUAGAGAGCUGGC 20 3879

BCLllA-3395 - GAGGCUUCCGGCCUGGCAGA 20 3880

BCLllA-3396 + AAUCCCAUGGAGAGGUGGCU 20 3881

BCLllA-3397 + UGUGCAUGUGCGUCUUCAUG 20 3882

BCLllA-3398 + CUCGCCCAGGACCUGGUGGA 20 3883

BCLllA-3399 + UCCUCCUCGUCCCCGUUCUC 20 3884

BCLllA-3400 + AGAAACCAUGCACUGGUGAA 20 3885

BCLllA-3401 - CUUCGGGCUGAGCCUGGAGG 20 3886

BCLllA-3402 + GCCGGGU UCCGGGGAGCUGG 20 3887

BCLllA-3403 + AGAAGGGGCUCAGCGAGCUG 20 3888

BCLllA-3404 + CUAAACAGGGGGGGAGUGGG 20 3889

BCLllA-3405 - CAAAUUUCAGAGCAACCUGG 20 3890

BCLllA-3406 + GAGGGAGGGGGGGCGUCGCC 20 3891

BCLllA-3407 + CCUCCUCGUCCCCGUUCUCC 20 3892

BCLllA-3408 + CCAGCAGCAGCUUUUUGGAC 20 3893

BCLllA-3409 - GCCCACCGCUGUCCCCAGGC 20 3894

BCLllA-3410 - GGAGACUUAGAGAGCUGGCA 20 3895

BCLllA-3411 - AGGAGCUGACGGAGAGCGAG 20 3896

BCLllA-3412 + GAGGGGCGGAUUGCAGAGGA 20 3897

BCLllA-3413 + CAUAGGGCUGGGCCGGCCUG 20 3898

BCLllA-3414 + GGCGGAUUGCAGAGGAGGGA 20 3899

BCLllA-3415 + GGAGGGGCGGAUUGCAGAGG 20 3900

BCLllA-3416 - U UACUGCAACCAUUCCAGCC 20 3901

BCLllA-3417 + GCAUAGGGCUGGGCCGGCCU 20 3902

BCLllA-3418 + GGGCGGAUUGCAGAGGAGGG 20 3903

BCLllA-3419 + GGGUUCCGGGGAGCUGGCGG 20 3904

BCLllA-3420 + UCUCGCCCGUGUGGCUGCGC 20 3905

BCLllA-3421 - CUUCCCAGCCACCUCUCCAU 20 3906

BCLllA-3422 - GCUGACGGAGAGCGAGAGGG 20 3907

BCLllA-3423 + GCGGAUUGCAGAGGAGGGAG 20 3908

BCLllA-3424 - GGAGCUGACGGAGAGCGAGA 20 3909

BCLllA-3425 - UCUCUCCACCGCCAGCUCCC 20 3910

BCLllA-3426 + UUGACCGGGGGCUGGGAGGG 20 3911

BCLllA-3427 + CGGAUUGCAGAGGAGGGAGG 20 3912

BCLllA-3428 - GCGGGGCGCGGUCGUGGGCG 20 3913

BCLllA-3429 + GAGCUGGGCCUGCCCGGGCC 20 3914

BCLllA-3430 + CUGGGCCGGCCUGGGGACAG 20 3915

BCLllA-3431 + UGUAGGGCUUCUCGCCCGUG 20 3916 BCLllA-3432 + CCAUGGAGAGGUGGCUGGGA 20 3917

BCLllA-3433 + GGAGGAGGGGCGGAUUGCAG 20 3918

BCLllA-3434 - CCUUCCCAGCCACCUCUCCA 20 3919

BCLllA-3435 + CCCGCGAGCUGUUCUCGUGG 20 3920

BCLllA-3436 + GAUUGCAGAGGAGGGAGGGG 20 3921

BCLllA-3437 + GGCCGGCCUGGGGACAGCGG 20 3922

BCLllA-3438 + GGAUUGCAGAGGAGGGAGGG 20 3923

BCLllA-3439 + ACCGGGGGCUGGGAGGGAGG 20 3924

BCLllA-3440 + CCGGGGGCUGGGAGGGAGGA 20 3925

BCLllA-3441 - GAACGGGGACGAGGAGGAAG 20 3926

BCLllA-3442 - CCCUCCUCCCUCCCAGCCCC 20 3927

BCLllA-3443 + CGGGGGCUGGGAGGGAGGAG 20 3928

BCLllA-3444 + GGCGCUUCAGCUUGCUGGCC 20 3929

BCLllA-3445 - CGGGGACGAGGAGGAAGAGG 20 3930

BCLllA-3446 - AGAGGAGGAGGAGGAGCUGA 20 3931

BCLllA-3447 + GGGCUGGGAGGGAGGAGGGG 20 3932

BCLllA-3448 - AGAGGAGGACGACGAGGAAG 20 3933

BCLllA-3449 - CGACGAGGAAGAGGAAGAAG 20 3934

BCLllA-3450 - GGAGGAAGAGGAGGACGACG 20 3935

BCLllA-3451 - CGAGGAAGAGGAAGAAGAGG 20 3936

BCLllA-3452 - GGAAGAAGAGGAGGAAGAGG 20 3937

BCLllA-3453 - AGAGGAAGAAGAGGAGGAAG 20 3938

BCLllA-3454 - AGAAGAGGAGGAAGAGGAGG 20 3939

BCLllA-3455 - AGAGGAGGAAGAGGAGGAGG 20 3940

Table 5A provides exemplary targeting domains for knocking out the BCL11A gene by targeting the early coding sequence the BCL11A gene selected according to first tier parameters. The targeting domains bind within first 500bp of coding sequence downstream of start codon, good orthogonality, start with G. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. aureus Cas9 molecule that generates a double strand break (Cas9 nuclease) or a single-strand break (Cas9 nickase). In an embodiment, dual targeting is used to create two double strand breaks to remove the enhancer region in the BCL11A gene, e.g., the first gRNA is used to target upstream (i.e., 5') of the enhancer region in the BCL11A gene and the second gRNA is used to target downstream (i.e., 3') of the enhancer region in the BCL11A gene.

Any of the targeting domains in the table can be used with a S. aureus Cas9 (nickase) molecule to generate a single strand break. In an embodiment, dual targeting is used to create two nicks on opposite DNA strands by using S. aureus Cas9 nickases with two targeting domains that are complementary to opposite DNA strands, e.g., a gRNA comprising any minus strand targeting domain may be paired any gRNA comprising a plus strand targeting domain provided that the two gRNAs are oriented on the DNA such that PAMs face outward and the distance between the 5' ends of the gRNAs is 0-50bp.

Table 5A

Table 5B provides exemplary targeting domains for knocking out the BCL11A gene by targeting the early coding sequence the BCL11A gene selected according to second tier parameters. The targeting domains bind within first 500bp of coding sequence downstream of start codon, good orthogonality, and do not start with G. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. aureus Cas9 molecule that generates a double strand break (Cas9 nuclease) or a single-strand break (Cas9 nickase). In an embodiment, dual targeting is used to create two double strand breaks to remove the enhancer region in the BCL11A gene, e.g., the first gRNA is used to target upstream (i.e., 5') of the enhancer region in the BCL11A gene and the second gRNA is used to target downstream (i.e., 3') of the enhancer region in the BCL11A gene.

Table 5B

Table 5C provides exemplary targeting domains for knocking out the BCL11A gene by targeting the early coding sequence the BCL11A gene selected according to third tier parameters. The targeting domains bind within first 500bp of coding sequence downstream of start codon and start with G. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. aureus Cas9 molecule that generates a double strand break (Cas9 nuclease) or a single- strand break (Cas9 nickase). In an embodiment, dual targeting is used to create two double strand breaks to remove the enhancer region in the BCL11A gene, e.g., the first gRNA is used to target upstream (i.e., 5') of the enhancer region in the BCL11A gene and the second gRNA is used to target downstream (i.e., 3') of the enhancer region in the BCL11A gene.

Table 5C

BCLllA-3496 - GCCACCUUCCCCUUCACCAA 20 3981

BCLllA-3497 - GCCAGAUGAACUUCCCA 17 3982

BCLllA-3498 - GCCAGAUGAACUUCCCAUUG 20 3983

BCLllA-3499 - GCCCGUUGGGAGCUCCAGAA 20 3984

BCLllA-3500 - GCCUCUGCUUAGAAAAAGCU 20 3985

BCLllA-3501 + GCUCCAUGUGCAGAACG 17 3986

BCLllA-3502 - GCUCUAAUCCCCACGCC 17 3987

BCLllA-3503 - GGACAUUCUUAUUUUUA 17 3988

BCLllA-3504 - GGAGCUCUAAUCCCCACGCC 20 3989

BCLllA-3505 - GGAUCAUGACCUCCUCACCU 20 3990

BCLllA-3506 + GGAUGCCAACCUCCACGGGA 20 3991

BCLllA-3507 + GGCACUGCCCACAGGUG 17 3992

BCLllA-3508 - GGCCCGU UGGGAGCUCCAGA 20 3993

BCLllA-3509 - GGGGGACAUUCUUAUUUUUA 20 3994

BCLllA-3510 - GGUUGGCAUCCAGGUCACGC 20 3995

BCLllA-3511 + GGUUUGCCUUGCUUGCG 17 3996

BCLllA-3512 + GUGCAGAACGAGGGGAG 17 3997

BCLllA-3513 - GUGCCAGAUGAACUUCCCAU 20 3998

Table 5D provides exemplary targeting domains for knocking out the BCL11A gene by targeting the early coding sequence the BCL11A gene selected according to forth tier parameters. The targeting domains bind within first 500bp of coding sequence downstream of start codon and do not start with G. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. aureus Cas9 molecule that generates a double strand break (Cas9 nuclease) or a single-strand break (Cas9 nickase). In an embodiment, dual targeting is used to create two double strand breaks to remove the enhancer region in the BCL11A gene, e.g., the first gRNA is used to target upstream (i.e., 5') of the enhancer region in the BCL11A gene and the second gRNA is used to target downstream (i.e., 3') of the enhancer region in the BCL11A gene.

Any of the targeting domains in the table can be used with a S. aureus Cas9 (nickase) molecule to generate a single strand break. In an embodiment, dual targeting is used to create two nicks on opposite DNA strands by using S. aureus Cas9 nickases with two targeting domains that are complementary to opposite DNA strands, e.g., a gRNA comprising any minus strand targeting domain may be paired any gRNA comprising a plus strand targeting domain provided that the two gRNAs are oriented on the DNA such that PAMs face outward and the distance between the 5' ends of the gRNAs is 0-50bp. In an embodiment, four gRNAs (e.g., two pairs) are used to target four Cas9 nickases to create four nicks to remove the enhancer region in the BCLllA gene, e.g., the first pair of gRNAs are used to target upstream (i.e., 5') of the enhancer region in the BCLllA gene and the second pair of gRNAs are used to target downstream (i.e., 3') of the enhancer region in the BCLllA gene.

Table 5D

BCLllA-3545 - CACGCCUGGGAUGAGUG 17 4030

BCLllA-3546 - CAGAUGAACUUCCCAUU 17 4031

BCLllA-3547 + CAUCUCGAUUGGUGAAG 17 4032

BCLllA-3548 + CAUGUGCAGAACGAGGG 17 4033

BCLllA-3549 + CAUGUGCAGAACGAGGGGAG 20 4034

BCLllA-3550 + CCACAGCU UUUUCUAAG 17 4035

BCLllA-3551 - CCACGGCCCGUUGGGAGCUC 20 4036

BCLllA-3552 - CCAGAUGAACUUCCCAU 17 4037

BCLllA-3553 - CC AG C ACU U AAG CAAAC 17 4038

BCLllA-3554 - CCCAG CAC U U AAG C AAA 17 4039

BCLllA-3555 - CCCCACGCCUGGGAUGAGUG 20 4040

BCLllA-3556 - CCCCAGCACUUAAGCAA 17 4041

BCLllA-3557 - CCCCUUCACCAAUCGAG 17 4042

BCLllA-3558 - CCCGUUGGGAGCUCCAG 17 4043

BCLllA-3559 + CCCUUCUGGAGCUCCCA 17 4044

BCLllA-3560 - CCGUUGGGAGCUCCAGA 17 4045

BCLllA-3561 - CCUGUGGGCAGUGCCAG 17 4046

BCLllA-3562 - CGGCCCGUUGGGAGCUC 17 4047

BCLllA-3563 - CGGCCCGUUGGGAGCUCCAG 20 4048

BCLllA-3564 - CGUUGGGAGCUCCAGAA 17 4049

BCLllA-3565 + CGUUUGUGCUCGAUAAAAAU 20 4050

BCLllA-3566 - CUAGAGGAAUUUGCCCCAAA 20 4051

BCLllA-3567 + CUCAUCCCAGGCGUGGGGAU 20 4052

BCLllA-3568 + CUCCAUGUGCAGAACGA 17 4053

BCLllA-3569 + CUCCAUGUGCAGAACGAGGG 20 4054

BCLllA-3570 - CUCCCCUCGUUCUGCAC 17 4055

BCLllA-3571 - CUCCUCCCCUCGU UCUGCAC 20 4056

BCLllA-3572 - CUCUAAUCCCCACGCCUGGG 20 4057

BCLllA-3573 + CUGCACUCAUCCCAGGC 17 4058

BCLllA-3574 - CUUAUUUUUAUCGAGCACAA 20 4059

BCLllA-3575 - CUUCCCCUUCACCAAUCGAG 20 4060

BCLllA-3576 + UAAGAAUGUCCCCCAAU 17 4061

BCLllA-3577 - UAAUCCCCACGCCUGGG 17 4062

BCLllA-3578 + UAGAGCUCCAUGUGCAGAAC 20 4063

BCLllA-3579 - UAGAGGAAUUUGCCCCAAAC 20 4064

BCLllA-3580 + UAUCCACAGCUUUUUCUAAG 20 4065

BCLllA-3581 - UCACCUGUGGGCAGUGCCAG 20 4066

BCLllA-3582 + UCAUCUCGAU UGGUGAA 17 4067

BCLllA-3583 + UCAUCUGGCACUGCCCACAG 20 4068

BCLllA-3584 + UCAUCUGUAAGAAUGGCUUC 20 4069

BCLllA-3585 - UCAUGACCUCCUCACCU 17 4070

BCLllA-3586 + UCCAUGUGCAGAACGAG 17 4071 BCLllA-3587 + UCCAUGUGCAGAACGAGGGG 20 4072

BCLllA-3588 - UCCCCUCGUUCUGCACA 17 4073

BCLllA-3589 - UCCUCCCCUCGUUCUGCACA 20 4074

BCLllA-3590 - UCUGCU UAGAAAAAGCU 17 4075

BCLllA-3591 + UCUGGCACUGCCCACAG 17 4076

BCLllA-3592 + UCUGGCACUGCCCACAGGUG 20 4077

BCLllA-3593 + UCUGUAAGAAUGGCUUC 17 4078

BCLllA-3594 - UGAAAAAAGCAUCCAAUCCC 20 4079

BCLllA-3595 - UGAAGCCAUUCU UACAGAUG 20 4080

BCLllA-3596 + UGCCAACCUCCACGGGA 17 4081

BCLllA-3597 - UGCCAGAUGAACUUCCCAUU 20 4082

BCLllA-3598 + UGCUUUUU UCAUCUCGAUUG 20 4083

BCLllA-3599 - UGGAGCUCUAAUCCCCACGC 20 4084

BCLllA-3600 + UGGCACUGCCCACAGGU 17 4085

BCLllA-3601 - UGGCAUCCAGGUCACGC 17 4086

BCLllA-3602 + UGGGGUUUGCCUUGCUUGCG 20 4087

BCLllA-3603 - UUAUUUUUAUCGAGCACAAA 20 4088

BCLllA-3604 + U UCAUCUCGAUUGGUGA 17 4089

BCLllA-3605 - UUGGCAUCCAGGUCACGCCA 20 4090

BCLllA-3606 + UUGUGCUCGAUAAAAAU 17 4091

BCLllA-3607 + UUUCAUCUCGAUUGGUG 17 4092

BCLllA-3608 + UUUCAUCUCGAUUGGUGAAG 20 4093

BCLllA-3609 + UUUUCAUCUCGAUUGGUGAA 20 4094

BCLllA-3610 - U UUUUAUCGAGCACAAA 17 4095

BCLllA-3611 + U UUUUCAUCUCGAUUGGUGA 20 4096

BCLllA-3612 + U UUUUUCAUCUCGAUUG 17 4097

BCLllA-3613 + UUUUUUCAUCUCGAUUGGUG 20 4098

Table 5E provides exemplary targeting domains for knocking out the BCLllA gene by targeting the early coding sequence the BCLllA gene selected according to fifth tier parameters. The targeting domains target outside the first 500bp of coding sequence downstream of start codon. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. aureus Cas9 molecule that generates a double strand break (Cas9 nuclease) or a single- strand break (Cas9 nickase). In an embodiment, dual targeting is used to create two double strand breaks to remove the enhancer region in the BCLllA gene, e.g., the first gRNA is used to target upstream (i.e., 5') of the enhancer region in the BCLllA gene and the second gRNA is used to target downstream (i.e., 3') of the enhancer region in the BCLllA gene. Any of the targeting domains in the table can be used with a S. aureus Cas9 (nickase) molecule to generate a single strand break. In an embodiment, dual targeting is used to create two nicks on opposite DNA strands by using S. aureus Cas9 nickases with two targeting domains that are complementary to opposite DNA strands, e.g., a gRNA comprising any minus strand targeting domain may be paired any gRNA comprising a plus strand targeting domain provided that the two gRNAs are oriented on the DNA such that PAMs face outward and the distance between the 5' ends of the gRNAs is 0-50bp.

Table 5E

BCLllA-3636 + UGCCGCAGAACUCGCAUGAC 20 4121

BCLllA-3637 + GAUACCAACCCGCGGGGUCA 20 4122

BCLllA-3638 + GGAUACCAACCCGCGGGGUC 20 4123

BCLllA-3639 + GGGAUACCAACCCGCGGGGU 20 4124

BCLllA-3640 - CCCCCACCGCAUAGAGCGCC 20 4125

BCLllA-3641 + GGUUGGGGUCGUUCUCGCUC 20 4126

BCLllA-3642 - GCACGCCCCAUAUUAGUGGU 20 4127

BCLllA-3643 - UAAGCGCAUCAAGCUCGAGA 20 4128

BCLllA-3644 + GUUCUCCGAGGAGUGCUCCG 20 4129

BCLllA-3645 + UCUCGAGCUUGAUGCGCUUA 20 4130

BCLllA-3646 - CUAAGCGCAUCAAGCUCGAG 20 4131

BCLllA-3647 - GUCGGAGCACUCCUCGGAGA 20 4132

BCLllA-3648 - UGGCCGCGGCUGCUCCCCGG 20 4133

BCLllA-3649 - CCCCACCGCAUAGAGCGCCU 20 4134

BCLllA-3650 + CCUGAAGGGAUACCAACCCG 20 4135

BCLllA-3651 - GCGCUUCUCCACACCGCCCG 20 4136

BCLllA-3652 - GCGCCCUGCCCGACGUCAUG 20 4137

BCLllA-3653 - AACCCGGCACCAGCGACU UG 20 4138

BCLllA-3654 + CUCUGGGUACUACGCCGAAU 20 4139

BCLllA-3655 + CCCGUUCUCCGGGAUCAGGU 20 4140

BCLllA-3656 - GAACGACCCCAACCUGAUCC 20 4141

BCLllA-3657 + ACGCCGAAUGGGGGUGUGUG 20 4142

BCLllA-3658 + GUCGCUGGUGCCGGGU UCCG 20 4143

BCLllA-3659 - CCCCGGGCGAGUCGGCCUCG 20 4144

BCLllA-3660 + CGGUGCACCACCAGGUUGCU 20 4145

BCLllA-3661 - GUCCACCACCGAGACAUCAC 20 4146

BCLllA-3662 - UUAAUGGCCGCGGCUGCUCC 20 4147

BCLllA-3663 + CUCUCUGGGUACUACGCCGA 20 4148

BCLllA-3664 + GCGCAAACUCCCGUUCUCCG 20 4149

BCLllA-3665 + CCCGGGCCCGGACCACUAAU 20 4150

BCLllA-3666 + GCCCCCAGGCGCUCUAUGCG 20 4151

BCLllA-3667 - AUCGCCU UUUGCCUCCUCGU 20 4152

BCLllA-3668 - CCUCGUCGGAGCACUCCUCG 20 4153

BCLllA-3669 + GAGCUUGAUGCGCUUAGAGA 20 4154

BCLllA-3670 + CCCCGUUCUCCGGGAUCAGG 20 4155

BCLllA-3671 - CGGCCGCGAUGCCCAACACG 20 4156

BCLllA-3672 + GCCCCCCGAGGCCGACUCGC 20 4157

BCLllA-3673 - CCCGGCCGCGAUGCCCAACA 20 4158

BCLllA-3674 - CUCCUCGUCGGAGCACUCCU 20 4159

BCLllA-3675 + GUCUCGGUGGUGGACUAAAC 20 4160

BCLllA-3676 + CCCCAGGCGCUCUAUGCGGU 20 4161

BCLllA-3677 + GGUCGCACAGGUUGCACUUG 20 4162 BCLllA-3678 + AGUCGCUGGUGCCGGGUUCC 20 4163

BCLllA-3679 - CCCGGUCAAGUCCAAGUCAU 20 4164

BCLllA-3680 - AGAACGACCCCAACCUGAUC 20 4165

BCLllA-3681 + UCCGUGUUGGGCAUCGCGGC 20 4166

BCLllA-3682 - CCUCCUCGUCGGAGCACUCC 20 4167

BCLllA-3683 - UCACU UGGACCCCCACCGCA 20 4168

BCLllA-3684 - CCCAACCUGAUCCCGGAGAA 20 4169

BCLllA-3685 - ACUACGGCUUCGGGCUGAGC 20 4170

BCLllA-3686 - U UUGCGCUUCUCCACACCGC 20 4171

BCLllA-3687 + AAGUCGCUGGUGCCGGGUUC 20 4172

BCLllA-3688 - CCCCAACCUGAUCCCGGAGA 20 4173

BCLllA-3689 - AAGACUCGGUGGCCGGCGAG 20 4174

BCLllA-3690 - GCGCGGCCACCUGGCCGAGG 20 4175

BCLllA-3691 - AAUCGCCUUU UGCCUCCUCG 20 4176

BCLllA-3692 - ACGACCCCAACCUGAUCCCG 20 4177

BCLllA-3693 - GAUCCCGGAGAACGGGGACG 20 4178

BCLllA-3694 + GGGGCAGGUCGAACUCCUUC 20 4179

BCLllA-3695 - UGGCUAUGGAGCCUCCCGCC 20 4180

BCLllA-3696 + CCCCCAGGCGCUCUAUGCGG 20 4181

BCLllA-3697 - GCGGU UGAAUCCAAUGGCUA 20 4182

BCLllA-3698 - CUACGGCU UCGGGCUGAGCC 20 4183

BCLllA-3699 - ACAGCUCGCGGGGCGCGGUC 20 4184

BCLllA-3700 - CCCCCCUGU UUAGUCCACCA 20 4185

BCLllA-3701 + CGCAUGACUUGGACUUGACC 20 4186

BCLllA-3702 - CACGGAAGUCCCCUGACCCC 20 4187

BCLllA-3703 - CCUCCCGCCAUGGAU UUCUC 20 4188

BCLllA-3704 + UCUCGGUGGUGGACUAAACA 20 4189

BCLllA-3705 + UGAACUUGGCCACCACGGAC 20 4190

BCLllA-3706 - CUUCUCUAAGCGCAUCAAGC 20 4191

BCLllA-3707 + AGCGCAAACUCCCGUUCUCC 20 4192

BCLllA-3708 + UCGGUGGUGGACUAAACAGG 20 4193

BCLllA-3709 - CGCCACCACGAGAACAGCUC 20 4194

BCLllA-3710 - CUCCCGCCAUGGAU UUCUCU 20 4195

BCLllA-3711 + CGAGCU UGAUGCGCUUAGAG 20 4196

BCLllA-3712 + AUGCCCUGCAUGACGUCGGG 20 4197

BCLllA-3713 - UCUCUAAGCGCAUCAAGCUC 20 4198

BCLllA-3714 + GUCCAAGUGAUGUCUCGGUG 20 4199

BCLllA-3715 + CCCCCGAGGCCGACUCGCCC 20 4200

BCLllA-3716 + CCCCGAGGCCGACUCGCCCG 20 4201

BCLllA-3717 + GAAAUUUGAACGUCUUGCCG 20 4202

BCLllA-3718 + GUCGCUGCGUCUGCCCUCUU 20 4203

BCLllA-3719 - UGGAGGCGGCGCGCCACCAC 20 4204 BCLllA-3720 + CUUCUCGAGCUUGAUGCGCU 20 4205

BCLllA-3721 + GAAGCGCAAACUCCCGUUCU 20 4206

BCLllA-3722 - GAGAGAGGCUUCCGGCCUGG 20 4207

BCLllA-3723 - UCCCCGGGCGAGUCGGCCUC 20 4208

BCLllA-3724 + CAAGUCGCUGGUGCCGGGUU 20 4209

BCLllA-3725 - CAUAGAGCGCCUGGGGGCGG 20 4210

BCLllA-3726 + CUCGGUGGUGGACUAAACAG 20 4211

BCLllA-3727 + CCCCCCGAGGCCGACUCGCC 20 4212

BCLllA-3728 - GGUUUCUCUUGCAACACGCA 20 4213

BCLllA-3729 + ACUUGGACUUGACCGGGGGC 20 4214

BCLllA-3730 - UGAUCCCGGAGAACGGGGAC 20 4215

BCLllA-3731 + UGUCUGGAGUCUCCGAAGCU 20 4216

BCLllA-3732 - AUGGAUUUCUCUAGGAGACU 20 4217

BCLllA-3733 - UGCGGUUGAAUCCAAUGGCU 20 4218

BCLllA-3734 - CUCCCCGGGCGAGUCGGCCU 20 4219

BCLllA-3735 - CCUGAUCCCGGAGAACGGGG 20 4220

BCLllA-3736 + UGUCUCGGUGGUGGACUAAA 20 4221

BCLllA-3737 + CGGUGGUGGACUAAACAGGG 20 4222

BCLllA-3738 + UGCCCACCAAGUCGCUGGUG 20 4223

BCLllA-3739 - CGUGGUGGCCAAGUUCAAGA 20 4224

BCLllA-3740 - CAUCACCCGAGUGCCUUUGA 20 4225

BCLllA-3741 - GCGGCAAGACGUUCAAAUUU 20 4226

BCLllA-3742 + AAGGGCUCUCGAGCUUCCAU 20 4227

BCLllA-3743 + GUCUGGAGUCUCCGAAGCUA 20 4228

BCLllA-3744 - CCCCGGCCGCGAUGCCCAAC 20 4229

BCLllA-3745 + CUGUCAAAGGCACUCGGGUG 20 4230

BCLllA-3746 + CUUGGACUUGACCGGGGGCU 20 4231

BCLllA-3747 + GACUUGGACUUGACCGGGGG 20 4232

BCLllA-3748 + UGCGUCUGCCCUCUUU UGAG 20 4233

BCLllA-3749 + GGAGGCAAAAGGCGAUUGUC 20 4234

BCLllA-3750 - GCAACACGCACAGAACACUC 20 4235

BCLllA-3751 + GCAGUAACCUUUGCAUAGGG 20 4236

BCLllA-3752 - UGGUGCACCGGCGCAGCCAC 20 4237

BCLllA-3753 - UGGUGGCCAAGUUCAAGAGC 20 4238

BCLllA-3754 - GCAUAAGCGCGGCCACCUGG 20 4239

BCLllA-3755 + U UGCAUAGGGCUGGGCCGGC 20 4240

BCLllA-3756 - CCAACCUGAUCCCGGAGAAC 20 4241

BCLllA-3757 - AGAUGUGUGGCAGUUU UCGG 20 4242

BCLllA-3758 - CAGUUUUCGGAUGGAAGCUC 20 4243

BCLllA-3759 - GCUCCCCGGGCGAGUCGGCC 20 4244

BCLllA-3760 - GGGUGGACUACGGCUUCGGG 20 4245

BCLllA-3761 - UAUCCCUUCAGGACUAGGUG 20 4246 BCLllA-3762 - AUCUCGGGGCGCAGCGGCAC 20 4247

BCLllA-3763 + CGCUCU UGAACUUGGCCACC 20 4248

BCLllA-3764 - GCACCGGCGCAGCCACACGG 20 4249

BCLllA-3765 + GCUUCUCGCCCAGGACCUGG 20 4250

BCLllA-3766 - UCCCGGAGAACGGGGACGAG 20 4251

BCLllA-3767 + C AG CACCCUGU CAAAG G CAC 20 4252

BCLllA-3768 + CAUUCUGCACCUAGUCCUGA 20 4253

BCLllA-3769 - CUUUAACCUGCUAAGAAUAC 20 4254

BCLllA-3770 - GUCUCUCCACCGCCAGCUCC 20 4255

BCLllA-3771 - UCUCUCCACCGCCAGCUCCC 20 4256

BCLllA-3772 + UGCUUCUCGCCCAGGACCUG 20 4257

BCLllA-3773 + GCGCCGCCUCCAGGCUCAGC 20 4258

BCLllA-3774 + AGAUCCCUCCGUCCAGCUCC 20 4259

BCLllA-3775 - CGAGAGGGUGGACUACGGCU 20 4260

BCLllA-3776 + CGUCCAGCUCCCCGGGCGGU 20 4261

BCLllA-3777 + CCAGCUCUCUAAGUCUCCUA 20 4262

BCLllA-3778 + UCGCAUGACU UGGACU UGAC 20 4263

BCLllA-3779 + GCACCAUGCCCUGCAUGACG 20 4264

BCLllA-3780 + AAGGCGAUUGUCUGGAGUCU 20 4265

BCLllA-3781 + GCCUGGAGGCCGCGUAGCCG 20 4266

BCLllA-3782 - GCGGCCACCUGGCCGAGGCC 20 4267

BCLllA-3783 - AGAAUACCAGGAUCAGUAUC 20 4268

BCLllA-3784 - GAUGUGUGGCAGUU UUCGGA 20 4269

BCLllA-3785 - UCUCCACACCGCCCGGGGAG 20 4270

BCLllA-3786 - CCUGGAGGCGGCGCGCCACC 20 4271

BCLllA-3787 + CUGGUAUUCUUAGCAGGUUA 20 4272

BCLllA-3788 + UAGAGAAGGGGCUCAGCGAG 20 4273

BCLllA-3789 + GAGUGUUCUGUGCGUGUUGC 20 4274

BCLllA-3790 - AAUAACCCCUUUAACCUGCU 20 4275

BCLllA-3791 + AAAGCGCCCUUCUGCCAGGC 20 4276

BCLllA-3792 + GUCCAGCUCCCCGGGCGGUG 20 4277

BCLllA-3793 + AAGGGCGGCUUGCUACCUGG 20 4278

BCLllA-3794 + GAAAGCGCCCUUCUGCCAGG 20 4279

BCLllA-3795 + AGGGCGGCUUGCUACCUGGC 20 4280

BCLllA-3796 - CGCGGGGCGCGGUCGUGGGC 20 4281

BCLllA-3797 - GCGAGGCCU UCCACCAGGUC 20 4282

BCLllA-3798 + ACUUCCCGUGCCGCUGCGCC 20 4283

BCLllA-3799 - GCACAGAACACUCAUGGAUU 20 4284

BCLllA-3800 + CCAGCUCCCCGGGCGGUGUG 20 4285

BCLllA-3801 - ACCGCCCGGGGAGCUGGACG 20 4286

BCLllA-3802 + UGGUUGCAGUAACCUU UGCA 20 4287

BCLllA-3803 - AGGAGACUUAGAGAGCUGGC 20 4288 BCLllA-3804 - ACCGGCGCAGCCACACGGGC 20 4289

BCLllA-3805 + ACAUUCUGCACCUAGUCCUG 20 4290

BCLllA-3806 + GUGUUCUGUGCGUGU UGCAA 20 4291

BCLllA-3807 - UGGCCCUGGCCACCCAUCAC 20 4292

BCLllA-3808 + UGCAUAGGGCUGGGCCGGCC 20 4293

BCLllA-3809 - AAUACCAGGAUCAGUAUCGA 20 4294

BCLllA-3810 + UCCUGAAGGGAUACCAACCC 20 4295

BCLllA-3811 + CUCCUAGAGAAAUCCAUGGC 20 4296

BCLllA-3812 + UGGCGGUGGAGAGACCGUCG 20 4297

BCLllA-3813 - GGAUUUCUCUAGGAGACUUA 20 4298

BCLllA-3814 + CUCGCAUGACUUGGACUUGA 20 4299

BCLllA-3815 - GAUCUCGGGGCGCAGCGGCA 20 4300

BCLllA-3816 + GGUGGUGGACUAAACAGGGG 20 4301

BCLllA-3817 + AGGCCUCGCUGAAGUGCUGC 20 4302

BCLllA-3818 + CCACCAGGU UGCUCUGAAAU 20 4303

BCLllA-3819 - ACCGCAUAGAGCGCCUGGGG 20 4304

BCLllA-3820 - CCAGCAAGCUGAAGCGCCAC 20 4305

BCLllA-3821 + GGCCUCGCUGAAGUGCUGCA 20 4306

BCLllA-3822 - CGUGCACCCAGGCCAGCAAG 20 4307

BCLllA-3823 + GGCGGGAGGCUCCAUAGCCA 20 4308

BCLllA-3824 + AGGAGGCAAAAGGCGAUUGU 20 4309

BCLllA-3825 - AAAGAUCCCUUCCUUAGCUU 20 4310

BCLllA-3826 + GGAGUCUCCGAAGCUAAGGA 20 4311

BCLllA-3827 + GCGCUUAGAGAAGGGGCUCA 20 4312

BCLllA-3828 + CAGCUUUUUGGACAGGCCCC 20 4313

BCLllA-3829 + GCACUCGGGUGAUGGGUGGC 20 4314

BCLllA-3830 + CACGCCCACGACCGCGCCCC 20 4315

BCLllA-3831 + AAGUUGUACAUGUGUAGCUG 20 4316

BCLllA-3832 - AGUCCGUGGUGGCCAAGUUC 20 4317

BCLllA-3833 - CCCGGAGAACGGGGACGAGG 20 4318

BCLllA-3834 - CGGGCAGGCCCAGCU C A A A A 20 4319

BCLllA-3835 + UGGUAUUCUUAGCAGGUUAA 20 4320

BCLllA-3836 + U UGUCUGCAAUAUGAAUCCC 20 4321

BCLllA-3837 + GUCUCCUAGAGAAAUCCAUG 20 4322

BCLllA-3838 + UGGACUUGACCGGGGGCUGG 20 4323

BCLllA-3839 + UGGAGUCUCCGAAGCUAAGG 20 4324

BCLllA-3840 + UGAGCUGGGCCUGCCCGGGC 20 4325

BCLllA-3841 - CAAAGAUCCCUUCCUUAGCU 20 4326

BCLllA-3842 + UGCCACACAUCUUGAGCUCU 20 4327

BCLllA-3843 - CCGCCCGGGGAGCUGGACGG 20 4328

BCLllA-3844 + AGAGAAGGGGCUCAGCGAGC 20 4329

BCLllA-3845 - GGAGACUUAGAGAGCUGGCA 20 4330 BCLllA-3846 + GAAUCCCAUGGAGAGGUGGC 20 4331

BCLllA-3847 + CGCUGAAGUGCUGCAUGGAG 20 4332

BCLllA-3848 + AGGACAUUCUGCACCUAGUC 20 4333

BCLllA-3849 + AAUCCCAUGGAGAGGUGGCU 20 4334

BCLllA-3850 + UGAGCUCUCUGGGUACUACG 20 4335

BCLllA-3851 - GGGCCACAGGGACACUUGCG 20 4336

BCLllA-3852 - UAGGAGACUUAGAGAGCUGG 20 4337

BCLllA-3853 - CCUUUGACAGGGUGCUGCGG 20 4338

BCLllA-3854 - UGGCCGAGGCCGAGGGCCAC 20 4339

BCLllA-3855 + GGAAGGGAUCUUUGAGCUGC 20 4340

BCLllA-3856 + UCUAAGUAGAUUCUUAAUCC 20 4341

BCLllA-3857 - GGGGCGCAGCGGCACGGGAA 20 4342

BCLllA-3858 - CUGGCCGAGGCCGAGGGCCA 20 4343

BCLllA-3859 - CUCAAGAUGUGUGGCAGUUU 20 4344

BCLllA-3860 + CGAAGCUAAGGAAGGGAUCU 20 4345

BCLllA-3861 + UGCCAGCUCUCUAAGUCUCC 20 4346

BCLllA-3862 + UCUCCUAGAGAAAUCCAUGG 20 4347

BCLllA-3863 - GCCACCACGAGAACAGCUCG 20 4348

BCLllA-3864 + UCUGCAAUAUGAAUCCCAUG 20 4349

BCLllA-3865 - CAGCUCCAUGCAGCACUUCA 20 4350

BCLllA-3866 - GCCUGUCCAAAAAGCUGCUG 20 4351

BCLllA-3867 - UAAGAAUACCAGGAUCAGUA 20 4352

BCLllA-3868 - GGAUCUCGGGGCGCAGCGGC 20 4353

BCLllA-3869 - GGCAGUUUUCGGAUGGAAGC 20 4354

BCLllA-3870 - CGGUCGUGGGCGUGGGCGAC 20 4355

BCLllA-3871 + GCAUCGCGGCCGGGGGCAGG 20 4356

BCLllA-3872 - AAUCUACUUAGAAAGCGAAC 20 4357

BCLllA-3873 + AAGGGGUUAUUGUCUGCAAU 20 4358

BCLllA-3874 + GGACUUGACCGGGGGCUGGG 20 4359

BCLllA-3875 - UCAUGGAUUAAGAAUCUACU 20 4360

BCLllA-3876 - AGAGGCUUCCGGCCUGGCAG 20 4361

BCLllA-3877 - GGCCUUCCACCAGGUCCUGG 20 4362

BCLllA-3878 + UGGCGCU UCAGCUUGCUGGC 20 4363

BCLllA-3879 - CCGCAUAGAGCGCCUGGGGG 20 4364

BCLllA-3880 + GGACCUGGUGGAAGGCCUCG 20 4365

BCLllA-3881 - CCUUCCACCAGGUCCUGGGC 20 4366

BCLllA-3882 + UGUCUGCAAUAUGAAUCCCA 20 4367

BCLllA-3883 - GGAGCUGGACGGAGGGAUCU 20 4368

BCLllA-3884 + GACUUGACCGGGGGCUGGGA 20 4369

BCLllA-3885 - UCCUUCCCAGCCACCUCUCC 20 4370

BCLllA-3886 + CUCU UUUGAGCUGGGCCUGC 20 4371

BCLllA-3887 - UGCGCUUCUCCACACCGCCC 20 4372 BCLllA-3888 + GCAAGAGAAACCAUGCACUG 20 4373

BCLllA-3889 - GGGAGCUGGACGGAGGGAUC 20 4374

BCLllA-3890 + GU UCCGGGGAGCUGGCGGUG 20 4375

BCLllA-3891 + UGAAUCCCAUGGAGAGGUGG 20 4376

BCLllA-3892 + CGGGU UCCGGGGAGCUGGCG 20 4377

BCLllA-3893 + GUGGACUAAACAGGGGGGGA 20 4378

BCLllA-3894 + GGCUGCCCAGCAGCAGCUUU 20 4379

BCLllA-3895 + GAAGGGAUCUUUGAGCUGCC 20 4380

BCLllA-3896 - CCUUCCCAGCCACCUCUCCA 20 4381

BCLllA-3897 - GCGCAGCGGCACGGGAAGUG 20 4382

BCLllA-3898 + GGGUUCCGGGGAGCUGGCGG 20 4383

BCLllA-3899 + UCCUCCUCGUCCCCGUUCUC 20 4384

BCLllA-3900 - GCAGCGGCACGGGAAGUGGA 20 4385

BCLllA-3901 - UGCUGGGCAGCCCCAGCUCG 20 4386

BCLllA-3902 - GGGCGCAGCGGCACGGGAAG 20 4387

BCLllA-3903 - ACACCGCCCGGGGAGCUGGA 20 4388

BCLllA-3904 + CCCAUGGAGAGGUGGCUGGG 20 4389

BCLllA-3905 + UUCCUCCUCGUCCCCGUUCU 20 4390

BCLllA-3906 - AUCUACUUAGAAAGCGAACA 20 4391

BCLllA-3907 - CCCGGGCAGGCCCAGCUCAA 20 4392

BCLllA-3908 - CACACCGCCCGGGGAGCUGG 20 4393

BCLllA-3909 + ACUAAACAGGGGGGGAGUGG 20 4394

BCLllA-3910 + GACCGGGGGCUGGGAGGGAG 20 4395

BCLllA-3911 + GGGCCGGCCUGGGGACAGCG 20 4396

BCLllA-3912 + GCAUAGGGCUGGGCCGGCCU 20 4397

BCLllA-3913 - AU U AAG AAU CU ACU U AG AAA 20 4398

BCLllA-3914 + CUAAACAGGGGGGGAGUGGG 20 4399

BCLllA-3915 + UUGACCGGGGGCUGGGAGGG 20 4400

BCLllA-3916 - CGCGGUCGUGGGCGUGGGCG 20 4401

BCLllA-3917 + GAGGGAGGGGGGGCGUCGCC 20 4402

BCLllA-3918 - GGAGAACGGGGACGAGGAGG 20 4403

BCLllA-3919 + CUUGACCGGGGGCUGGGAGG 20 4404

BCLllA-3920 + GGAGGGAGGGGGGGCGUCGC 20 4405

BCLllA-3921 + ACCGGGGGCUGGGAGGGAGG 20 4406

BCLllA-3922 - CGCAGCGGCACGGGAAGUGG 20 4407

BCLllA-3923 + GCGGAUUGCAGAGGAGGGAG 20 4408

BCLllA-3924 + GGAGGGGGGGCGUCGCCAGG 20 4409

BCLllA-3925 + GGCGGAUUGCAGAGGAGGGA 20 4410

BCLllA-3926 + GAGGGGCGGAUUGCAGAGGA 20 4411

BCLllA-3927 + GGGGCGGAUUGCAGAGGAGG 20 4412

BCLllA-3928 - GAGGAGCUGACGGAGAGCGA 20 4413

BCLllA-3929 + UCCGAAAACUGCCACACAUC 20 4414 BCLllA-3930 + CGGAUUGCAGAGGAGGGAGG 20 4415

BCLllA-3931 + GGAGGGGCGGAUUGCAGAGG 20 4416

BCLllA-3932 + GGGCGGAUUGCAGAGGAGGG 20 4417

BCLllA-3933 + AGGAGGGGCGGAUUGCAGAG 20 4418

BCLllA-3934 - AGAACGGGGACGAGGAGGAA 20 4419

BCLllA-3935 + GAGGGAGGAGGGGCGGAUUG 20 4420

BCLllA-3936 - UUGCGCUUCUCCACACCGCC 20 4421

BCLllA-3937 - AGCUGACGGAGAGCGAGAGG 20 4422

BCLllA-3938 - AGGAGGAGCUGACGGAGAGC 20 4423

BCLllA-3939 + GGGGCUGGGAGGGAGGAGGG 20 4424

BCLllA-3940 + GGGAGGAGGGGCGGAUUGCA 20 4425

BCLllA-3941 + CCGUGUUGGGCAUCGCGGCC 20 4426

BCLllA-3942 - GAACGGGGACGAGGAGGAAG 20 4427

BCLllA-3943 + GGAGGAGGGGCGGAUUGCAG 20 4428

BCLllA-3944 - GGAGGAGGAGCUGACGGAGA 20 4429

BCLllA-3945 - ACGGGGACGAGGAGGAAGAG 20 4430

BCLllA-3946 - AGGAGGAGGAGGAGCUGACG 20 4431

BCLllA-3947 - ACGACGAGGAAGAGGAAGAA 20 4432

BCLllA-3948 - ACGAGGAAGAGGAAGAAGAG 20 4433

BCLllA-3949 - AGGAGGAAGAGGAGGACGAC 20 4434

BCLllA-3950 - AAGAGGAGGACGACGAGGAA 20 4435

BCLllA-3951 - AGAGGAGGAGGAGGAGCUGA 20 4436

BCLllA-3952 - GGAGGAAGAGGAGGACGACG 20 4437

BCLllA-3953 - CGAGGAGGAAGAGGAGGACG 20 4438

BCLllA-3954 - CGAGGAAGAGGAAGAAGAGG 20 4439

BCLllA-3955 - AAGAGGAGGAGGAGGAGCUG 20 4440

BCLllA-3956 - CGACGAGGAAGAGGAAGAAG 20 4441

BCLllA-3957 - GGAGGACGACGAGGAAGAGG 20 4442

BCLllA-3958 - AGAGGAGGACGACGAGGAAG 20 4443

BCLllA-3959 - GGACGACGAGGAAGAGGAAG 20 4444

BCLllA-3960 - GGAAGAGGAGGACGACGAGG 20 4445

BCLllA-3961 - AGGAAGAAGAGGAGGAAGAG 20 4446

BCLllA-3962 - AAGAGGAAGAAGAGGAGGAA 20 4447

BCLllA-3963 - GGAAGAGGAAGAAGAGGAGG 20 4448

BCLllA-3964 - AAGAAGAGGAGGAAGAGGAG 20 4449

BCLllA-3965 - AAGAGGAGGAAGAGGAGGAG 20 4450

BCLllA-3966 - AGAGGAAGAAGAGGAGGAAG 20 4451

BCLllA-3967 - GGAAGAAGAGGAGGAAGAGG 20 4452

BCLllA-3968 - AGAAGAGGAGGAAGAGGAGG 20 4453

BCLllA-3969 - AGAGGAGGAAGAGGAGGAGG 20 4454

BCLllA-3970 + UCGGACUUGACCGUCAU 17 4455

BCLllA-3971 + GUCGGACUUGACCGUCA 17 4456 BCLllA-3972 + CGUCGGACU UGACCGUC 17 4457

BCLllA-3973 + CGGACUUGACCGUCAUG 17 4458

BCLllA-3974 - AUAUUAGUGGUCCGGGC 17 4459

BCLllA-3975 + GUCCGACUCGCCGGCCA 17 4460

BCLllA-3976 + CGAGGAGUGCUCCGACG 17 4461

BCLllA-3977 - CCAUUCGGCGUAGUACC 17 4462

BCLllA-3978 + CCGAGGAGUGCUCCGAC 17 4463

BCLllA-3979 - GCGGGUUGGUAUCCCUU 17 4464

BCLllA-3980 + AGUACACGUUCUCCGUG 17 4465

BCLllA-3981 - AUUCGGCGUAGUACCCA 17 4466

BCLllA-3982 + CGUGUUGGGCAUCGCGG 17 4467

BCLllA-3983 + CGCUUAUGCUUCUCGCC 17 4468

BCLllA-3984 - CGAAGACUCGGUGGCCG 17 4469

BCLllA-3985 - CCCACCGCAUAGAGCGC 17 4470

BCLllA-3986 + ACGCCGAAUGGGGGUGU 17 4471

BCLllA-3987 + GGCCCGGACCACUAAUA 17 4472

BCLllA-3988 + GUAGCCGGCGAGCCACU 17 4473

BCLllA-3989 - GAGCACUCCUCGGAGAA 17 4474

BCLllA-3990 - AGCACUCCUCGGAGAAC 17 4475

BCLllA-3991 + CUGGGUACUACGCCGAA 17 4476

BCLllA-3992 + CGCAGAACUCGCAUGAC 17 4477

BCLllA-3993 + ACCAACCCGCGGGGUCA 17 4478

BCLllA-3994 + UACCAACCCGCGGGGUC 17 4479

BCLllA-3995 + AUACCAACCCGCGGGGU 17 4480

BCLllA-3996 - CCACCGCAUAGAGCGCC 17 4481

BCLllA-3997 + UGGGGUCGUUCUCGCUC 17 4482

BCLllA-3998 - CGCCCCAUAU UAGUGGU 17 4483

BCLllA-3999 - GCGCAUCAAGCUCGAGA 17 4484

BCLllA-4000 + CUCCGAGGAGUGCUCCG 17 4485

BCLllA-4001 + CGAGCU UGAUGCGCUUA 17 4486

BCLllA-4002 - AGCGCAUCAAGCUCGAG 17 4487

BCLllA-4003 - GGAGCACUCCUCGGAGA 17 4488

BCLllA-4004 - CCGCGGCUGCUCCCCGG 17 4489

BCLllA-4005 - CACCGCAUAGAGCGCCU 17 4490

BCLllA-4006 + GAAGGGAUACCAACCCG 17 4491

BCLllA-4007 - CUUCUCCACACCGCCCG 17 4492

BCLllA-4008 - CCCUGCCCGACGUCAUG 17 4493

BCLllA-4009 - CCGGCACCAGCGACU UG 17 4494

BCLllA-4010 + UGGGUACUACGCCGAAU 17 4495

BCLllA-4011 + GU UCUCCGGGAUCAGGU 17 4496

BCLllA-4012 - CGACCCCAACCUGAUCC 17 4497

BCLllA-4013 + CCGAAUGGGGGUGUGUG 17 4498 BCLllA-4014 + GCUGGUGCCGGGUUCCG 17 4499

BCLllA-4015 - CGGGCGAGUCGGCCUCG 17 4500

BCLllA-4016 + UGCACCACCAGGUUGCU 17 4501

BCLllA-4017 - CACCACCGAGACAUCAC 17 4502

BCLllA-4018 - AUGGCCGCGGCUGCUCC 17 4503

BCLllA-4019 + UCUGGGUACUACGCCGA 17 4504

BCLllA-4020 + CAAACUCCCGUUCUCCG 17 4505

BCLllA-4021 + GGGCCCGGACCACUAAU 17 4506

BCLllA-4022 + CCCAGGCGCUCUAUGCG 17 4507

BCLllA-4023 - GCCUUU UGCCUCCUCGU 17 4508

BCLllA-4024 - CGUCGGAGCACUCCUCG 17 4509

BCLllA-4025 + CUUGAUGCGCUUAGAGA 17 4510

BCLllA-4026 + CGU UCUCCGGGAUCAGG 17 4511

BCLllA-4027 - CCGCGAUGCCCAACACG 17 4512

BCLllA-4028 + CCCCGAGGCCGACUCGC 17 4513

BCLllA-4029 - GGCCGCGAUGCCCAACA 17 4514

BCLllA-4030 - CUCGUCGGAGCACUCCU 17 4515

BCLllA-4031 + UCGGUGGUGGACUAAAC 17 4516

BCLllA-4032 + CAGGCGCUCUAUGCGGU 17 4517

BCLllA-4033 + CGCACAGGUUGCACUUG 17 4518

BCLllA-4034 + CGCUGGUGCCGGGUUCC 17 4519

BCLllA-4035 - GGUCAAGUCCAAGUCAU 17 4520

BCLllA-4036 - ACGACCCCAACCUGAUC 17 4521

BCLllA-4037 + GUGUUGGGCAUCGCGGC 17 4522

BCLllA-4038 - CCUCGUCGGAGCACUCC 17 4523

BCLllA-4039 - CUUGGACCCCCACCGCA 17 4524

BCLllA-4040 - AACCUGAUCCCGGAGAA 17 4525

BCLllA-4041 - ACGGCUUCGGGCUGAGC 17 4526

BCLllA-4042 - GCGCUUCUCCACACCGC 17 4527

BCLllA-4043 + UCGCUGGUGCCGGGUUC 17 4528

BCLllA-4044 - CAACCUGAUCCCGGAGA 17 4529

BCLllA-4045 - ACUCGGUGGCCGGCGAG 17 4530

BCLllA-4046 - CGGCCACCUGGCCGAGG 17 4531

BCLllA-4047 - CGCCUUU UGCCUCCUCG 17 4532

BCLllA-4048 - ACCCCAACCUGAUCCCG 17 4533

BCLllA-4049 - CCCGGAGAACGGGGACG 17 4534

BCLllA-4050 + GCAGGUCGAACUCCUUC 17 4535

BCLllA-4051 - CUAUGGAGCCUCCCGCC 17 4536

BCLllA-4052 + CCAGGCGCUCUAUGCGG 17 4537

BCLllA-4053 - GUUGAAUCCAAUGGCUA 17 4538

BCLllA-4054 - CGGCUUCGGGCUGAGCC 17 4539

BCLllA-4055 - GCUCGCGGGGCGCGGUC 17 4540 BCLllA-4056 - CCCUGU UUAGUCCACCA 17 4541

BCLllA-4057 + AUGACUUGGACUUGACC 17 4542

BCLllA-4058 - GGAAGUCCCCUGACCCC 17 4543

BCLllA-4059 - CCCGCCAUGGAUUUCUC 17 4544

BCLllA-4060 + CGGUGGUGGACUAAACA 17 4545

BCLllA-4061 + ACU UGGCCACCACGGAC 17 4546

BCLllA-4062 - CUCUAAGCGCAUCAAGC 17 4547

BCLllA-4063 + GCAAACUCCCGUUCUCC 17 4548

BCLllA-4064 + GUGGUGGACUAAACAGG 17 4549

BCLllA-4065 - CACCACG AG AACAG CU C 17 4550

BCLllA-4066 - CCGCCAUGGAUUUCUCU 17 4551

BCLllA-4067 + GCUUGAUGCGCUUAGAG 17 4552

BCLllA-4068 + CCCUGCAUGACGUCGGG 17 4553

BCLllA-4069 - CUAAGCGCAUCAAGCUC 17 4554

BCLllA-4070 + CAAGUGAUGUCUCGGUG 17 4555

BCLllA-4071 + CCGAGGCCGACUCGCCC 17 4556

BCLllA-4072 + CGAGGCCGACUCGCCCG 17 4557

BCLllA-4073 + AUUUGAACGUCUUGCCG 17 4558

BCLllA-4074 + GCUGCGUCUGCCCUCU U 17 4559

BCLllA-4075 - AGGCGGCGCGCCACCAC 17 4560

BCLllA-4076 + CUCGAGCU UGAUGCGCU 17 4561

BCLllA-4077 + GCGCAAACUCCCGUUCU 17 4562

BCLllA-4078 - AGAGGCUUCCGGCCUGG 17 4563

BCLllA-4079 - CCGGGCGAGUCGGCCUC 17 4564

BCLllA-4080 + GUCGCUGGUGCCGGGUU 17 4565

BCLllA-4081 - AGAGCGCCUGGGGGCGG 17 4566

BCLllA-4082 + GGUGGUGGACUAAACAG 17 4567

BCLllA-4083 + CCCGAGGCCGACUCGCC 17 4568

BCLllA-4084 - U UCUCUUGCAACACGCA 17 4569

BCLllA-4085 + UGGACUUGACCGGGGGC 17 4570

BCLllA-4086 - UCCCGGAGAACGGGGAC 17 4571

BCLllA-4087 + CUGGAGUCUCCGAAGCU 17 4572

BCLllA-4088 - GAUUUCUCUAGGAGACU 17 4573

BCLllA-4089 - GGUUGAAUCCAAUGGCU 17 4574

BCLllA-4090 - CCCGGGCGAGUCGGCCU 17 4575

BCLllA-4091 - GAUCCCGGAGAACGGGG 17 4576

BCLllA-4092 + CUCGGUGGUGGACUAAA 17 4577

BCLllA-4093 + UGGUGGACUAAACAGGG 17 4578

BCLllA-4094 + CCACCAAGUCGCUGGUG 17 4579

BCLllA-4095 - GGUGGCCAAGUUCAAGA 17 4580

BCLllA-4096 - CACCCGAGUGCCUU UGA 17 4581

BCLllA-4097 - GCAAGACG U U CAAAU U U 17 4582 BCLllA-4098 + GGCUCUCGAGCUUCCAU 17 4583

BCLllA-4099 + UGGAGUCUCCGAAGCUA 17 4584

BCLllA-4100 - CGGCCGCGAUGCCCAAC 17 4585

BCLllA-4101 + UCAAAGGCACUCGGGUG 17 4586

BCLllA-4102 + GGACUUGACCGGGGGCU 17 4587

BCLllA-4103 + UUGGACUUGACCGGGGG 17 4588

BCLllA-4104 + GUCUGCCCUCU UUUGAG 17 4589

BCLllA-4105 + GGCAAAAGGCGAUUGUC 17 4590

BCLllA-4106 - ACACGCACAGAACACUC 17 4591

BCLllA-4107 + GUAACCUUUGCAUAGGG 17 4592

BCLllA-4108 - UGCACCGGCGCAGCCAC 17 4593

BCLllA-4109 - UGGCCAAG U U CAAG AG C 17 4594

BCLllA-4110 - UAAGCGCGGCCACCUGG 17 4595

BCLllA-4111 + CAUAGGGCUGGGCCGGC 17 4596

BCLllA-4112 - ACCUGAUCCCGGAGAAC 17 4597

BCLllA-4113 - UGUGUGGCAGUUUUCGG 17 4598

BCLllA-4114 - U UUUCGGAUGGAAGCUC 17 4599

BCLllA-4115 - CCCCGGGCGAGUCGGCC 17 4600

BCLllA-4116 - UGGACUACGGCUUCGGG 17 4601

BCLllA-4117 - CCCUUCAGGACUAGGUG 17 4602

BCLllA-4118 - UCGGGGCGCAGCGGCAC 17 4603

BCLllA-4119 + UCU UGAACUUGGCCACC 17 4604

BCLllA-4120 - CCGGCGCAGCCACACGG 17 4605

BCLllA-4121 + UCUCGCCCAGGACCUGG 17 4606

BCLllA-4122 - CGGAGAACGGGGACGAG 17 4607

BCLllA-4123 + CACCCUGUCAAAGGCAC 17 4608

BCLllA-4124 + UCUGCACCUAGUCCUGA 17 4609

BCLllA-4125 - UAACCUGCUAAGAAUAC 17 4610

BCLllA-4126 - UCUCCACCGCCAGCUCC 17 4611

BCLllA-4127 - CUCCACCGCCAGCUCCC 17 4612

BCLllA-4128 + U UCUCGCCCAGGACCUG 17 4613

BCLllA-4129 + CCGCCUCCAGGCUCAGC 17 4614

BCLllA-4130 + UCCCUCCGUCCAGCUCC 17 4615

BCLllA-4131 - GAGGGUGGACUACGGCU 17 4616

BCLllA-4132 + CCAGCUCCCCGGGCGGU 17 4617

BCLllA-4133 + GCUCUCUAAGUCUCCUA 17 4618

BCLllA-4134 + CAUGACUUGGACUUGAC 17 4619

BCLllA-4135 + CCAUGCCCUGCAUGACG 17 4620

BCLllA-4136 + GCGAUUGUCUGGAGUCU 17 4621

BCLllA-4137 + UGGAGGCCGCGUAGCCG 17 4622

BCLllA-4138 - GCCACCUGGCCGAGGCC 17 4623

BCLllA-4139 - AUACCAGGAUCAGUAUC 17 4624 BCLllA-4140 - GUGUGGCAGUUU UCGGA 17 4625

BCLllA-4141 - CCACACCGCCCGGGGAG 17 4626

BCLllA-4142 - GGAGGCGGCGCGCCACC 17 4627

BCLllA-4143 + GUAUUCUUAGCAGGUUA 17 4628

BCLllA-4144 + AGAAGGGGCUCAGCGAG 17 4629

BCLllA-4145 + UGUUCUGUGCGUGUUGC 17 4630

BCLllA-4146 - AACCCCUU UAACCUGCU 17 4631

BCLllA-4147 + GCGCCCUUCUGCCAGGC 17 4632

BCLllA-4148 + CAGCUCCCCGGGCGGUG 17 4633

BCLllA-4149 + GGCGGCU UGCUACCUGG 17 4634

BCLllA-4150 + AGCGCCCUUCUGCCAGG 17 4635

BCLllA-4151 + GCGGCUUGCUACCUGGC 17 4636

BCLllA-4152 - GGGGCGCGGUCGUGGGC 17 4637

BCLllA-4153 - AGGCCUUCCACCAGGUC 17 4638

BCLllA-4154 + UCCCGUGCCGCUGCGCC 17 4639

BCLllA-4155 - CAGAACACUCAUGGAUU 17 4640

BCLllA-4156 + GCUCCCCGGGCGGUGUG 17 4641

BCLllA-4157 - GCCCGGGGAGCUGGACG 17 4642

BCLllA-4158 + U UGCAGUAACCU UUGCA 17 4643

BCLllA-4159 - AGACUUAGAGAGCUGGC 17 4644

BCLllA-4160 - GGCGCAGCCACACGGGC 17 4645

BCLllA-4161 + U UCUGCACCUAGUCCUG 17 4646

BCLllA-4162 + UUCUGUGCGUGUUGCAA 17 4647

BCLllA-4163 - CCCUGGCCACCCAUCAC 17 4648

BCLllA-4164 + AUAGGGCUGGGCCGGCC 17 4649

BCLllA-4165 - ACCAGGAUCAGUAUCGA 17 4650

BCLllA-4166 + UGAAGGGAUACCAACCC 17 4651

BCLllA-4167 + CUAGAGAAAUCCAUGGC 17 4652

BCLllA-4168 + CGGUGGAGAGACCGUCG 17 4653

BCLllA-4169 - U UUCUCUAGGAGACUUA 17 4654

BCLllA-4170 + GCAUGACUUGGACUUGA 17 4655

BCLllA-4171 - CUCGGGGCGCAGCGGCA 17 4656

BCLllA-4172 + GGUGGACUAAACAGGGG 17 4657

BCLllA-4173 + CCUCGCUGAAGUGCUGC 17 4658

BCLllA-4174 + CCAGGU UGCUCUGAAAU 17 4659

BCLllA-4175 - GCAUAGAGCGCCUGGGG 17 4660

BCLllA-4176 - GCAAGCUGAAGCGCCAC 17 4661

BCLllA-4177 + CUCGCUGAAGUGCUGCA 17 4662

BCLllA-4178 - GCACCCAGGCCAGCAAG 17 4663

BCLllA-4179 + GGGAGGCUCCAUAGCCA 17 4664

BCLllA-4180 + AGGCAAAAGGCGAUUGU 17 4665

BCLllA-4181 - GAUCCCU UCCUUAGCUU 17 4666 BCLllA-4182 + GUCUCCGAAGCUAAGGA 17 4667

BCLllA-4183 + CUUAGAGAAGGGGCUCA 17 4668

BCLllA-4184 + CUU UUUGGACAGGCCCC 17 4669

BCLllA-4185 + CUCGGGUGAUGGGUGGC 17 4670

BCLllA-4186 + GCCCACGACCGCGCCCC 17 4671

BCLllA-4187 + UUGUACAUGUGUAGCUG 17 4672

BCLllA-4188 - CCGUGGUGGCCAAGUUC 17 4673

BCLllA-4189 - GGAGAACGGGGACGAGG 17 4674

BCLllA-4190 - GCAGGCCCAGCU C A A A A 17 4675

BCLllA-4191 + UAUUCUUAGCAGGUUAA 17 4676

BCLllA-4192 + UCUGCAAUAUGAAUCCC 17 4677

BCLllA-4193 + UCCUAGAGAAAUCCAUG 17 4678

BCLllA-4194 + ACUUGACCGGGGGCUGG 17 4679

BCLllA-4195 + AGUCUCCGAAGCUAAGG 17 4680

BCLllA-4196 + GCUGGGCCUGCCCGGGC 17 4681

BCLllA-4197 - AGAUCCCUUCCUUAGCU 17 4682

BCLllA-4198 + CACACAUCUUGAGCUCU 17 4683

BCLllA-4199 - CCCGGGGAGCUGGACGG 17 4684

BCLllA-4200 + GAAGGGGCUCAGCGAGC 17 4685

BCLllA-4201 - GACUUAGAGAGCUGGCA 17 4686

BCLllA-4202 + UCCCAUGGAGAGGUGGC 17 4687

BCLllA-4203 + UGAAGUGCUGCAUGGAG 17 4688

BCLllA-4204 + ACAUUCUGCACCUAGUC 17 4689

BCLllA-4205 + CCCAUGGAGAGGUGGCU 17 4690

BCLllA-4206 + GCUCUCUGGGUACUACG 17 4691

BCLllA-4207 - CCACAGGGACACUUGCG 17 4692

BCLllA-4208 - GAGACUUAGAGAGCUGG 17 4693

BCLllA-4209 - UUGACAGGGUGCUGCGG 17 4694

BCLllA-4210 - CCGAGGCCGAGGGCCAC 17 4695

BCLllA-4211 + AGGGAUCUUUGAGCUGC 17 4696

BCLllA-4212 + AAGUAGAUUCUUAAUCC 17 4697

BCLllA-4213 - GCGCAGCGGCACGGGAA 17 4698

BCLllA-4214 - GCCGAGGCCGAGGGCCA 17 4699

BCLllA-4215 - AAGAUGUGUGGCAGUUU 17 4700

BCLllA-4216 + AGCUAAGGAAGGGAUCU 17 4701

BCLllA-4217 + CAGCUCUCUAAGUCUCC 17 4702

BCLllA-4218 + CCUAGAGAAAUCCAUGG 17 4703

BCLllA-4219 - ACCACGAGAACAGCUCG 17 4704

BCLllA-4220 + GCAAUAUGAAUCCCAUG 17 4705

BCLllA-4221 - CUCCAUGCAGCACUUCA 17 4706

BCLllA-4222 - UGUCCAAAAAGCUGCUG 17 4707

BCLllA-4223 - GAAUACCAGGAUCAGUA 17 4708 BCLllA-4224 - UCUCGGGGCGCAGCGGC 17 4709

BCLllA-4225 - AGUUUUCGGAUGGAAGC 17 4710

BCLllA-4226 - UCGUGGGCGUGGGCGAC 17 4711

BCLllA-4227 + UCGCGGCCGGGGGCAGG 17 4712

BCLllA-4228 - CUACUUAGAAAGCGAAC 17 4713

BCLllA-4229 + GGGUUAUUGUCUGCAAU 17 4714

BCLllA-4230 + CUUGACCGGGGGCUGGG 17 4715

BCLllA-4231 - UGGAUUAAGAAUCUACU 17 4716

BCLllA-4232 - GGCUUCCGGCCUGGCAG 17 4717

BCLllA-4233 - CUUCCACCAGGUCCUGG 17 4718

BCLllA-4234 + CGCUUCAGCUUGCUGGC 17 4719

BCLllA-4235 - CAUAGAGCGCCUGGGGG 17 4720

BCLllA-4236 + CCUGGUGGAAGGCCUCG 17 4721

BCLllA-4237 - UCCACCAGGUCCUGGGC 17 4722

BCLllA-4238 + CUGCAAUAUGAAUCCCA 17 4723

BCLllA-4239 - GCUGGACGGAGGGAUCU 17 4724

BCLllA-4240 + UUGACCGGGGGCUGGGA 17 4725

BCLllA-4241 - UUCCCAGCCACCUCUCC 17 4726

BCLllA-4242 + U UUUGAGCUGGGCCUGC 17 4727

BCLllA-4243 - GCUUCUCCACACCGCCC 17 4728

BCLllA-4244 + AGAGAAACCAUGCACUG 17 4729

BCLllA-4245 - AGCUGGACGGAGGGAUC 17 4730

BCLllA-4246 + CCGGGGAGCUGGCGGUG 17 4731

BCLllA-4247 + AUCCCAUGGAGAGGUGG 17 4732

BCLllA-4248 + GUUCCGGGGAGCUGGCG 17 4733

BCLllA-4249 + GACUAAACAGGGGGGGA 17 4734

BCLllA-4250 + UGCCCAGCAGCAGCUU U 17 4735

BCLllA-4251 + GGGAUCUUUGAGCUGCC 17 4736

BCLllA-4252 - UCCCAGCCACCUCUCCA 17 4737

BCLllA-4253 - CAGCGGCACGGGAAGUG 17 4738

BCLllA-4254 + U UCCGGGGAGCUGGCGG 17 4739

BCLllA-4255 + UCCUCGUCCCCGUUCUC 17 4740

BCLllA-4256 - GCGGCACGGGAAGUGGA 17 4741

BCLllA-4257 - UGGGCAGCCCCAGCUCG 17 4742

BCLllA-4258 - CGCAGCGGCACGGGAAG 17 4743

BCLllA-4259 - CCGCCCGGGGAGCUGGA 17 4744

BCLllA-4260 + AUGGAGAGGUGGCUGGG 17 4745

BCLllA-4261 + CUCCUCGUCCCCGU UCU 17 4746

BCLllA-4262 - UACUUAGAAAGCGAACA 17 4747

BCLllA-4263 - GGGCAGGCCCAGCUCAA 17 4748

BCLllA-4264 - ACCGCCCGGGGAGCUGG 17 4749

BCLllA-4265 + AAACAGGGGGGGAGUGG 17 4750 BCLllA-4266 + CGGGGGCUGGGAGGGAG 17 4751

BCLllA-4267 + CCGGCCUGGGGACAGCG 17 4752

BCLllA-4268 + UAGGGCUGGGCCGGCCU 17 4753

BCLllA-4269 - AAGAAUCUACUUAGAAA 17 4754

BCLllA-4270 + AACAGGGGGGGAGUGGG 17 4755

BCLllA-4271 + ACCGGGGGCUGGGAGGG 17 4756

BCLllA-4272 - GGUCGUGGGCGUGGGCG 17 4757

BCLllA-4273 + GGAGGGGGGGCGUCGCC 17 4758

BCLllA-4274 - GAACGGGGACGAGGAGG 17 4759

BCLllA-4275 + GACCGGGGGCUGGGAGG 17 4760

BCLllA-4276 + GGGAGGGGGGGCGUCGC 17 4761

BCLllA-4277 + GGGGGCUGGGAGGGAGG 17 4762

BCLllA-4278 - AGCGGCACGGGAAGUGG 17 4763

BCLllA-4279 + GAUUGCAGAGGAGGGAG 17 4764

BCLllA-4280 + GGGGGGGCGUCGCCAGG 17 4765

BCLllA-4281 + GGAUUGCAGAGGAGGGA 17 4766

BCLllA-4282 + GGGCGGAUUGCAGAGGA 17 4767

BCLllA-4283 + GCGGAUUGCAGAGGAGG 17 4768

BCLllA-4284 - GAGCUGACGGAGAGCGA 17 4769

BCLllA-4285 + G AAAACUG CCACACAU C 17 4770

BCLllA-4286 + AUUGCAGAGGAGGGAGG 17 4771

BCLllA-4287 + GGGGCGGAUUGCAGAGG 17 4772

BCLllA-4288 + CGGAUUGCAGAGGAGGG 17 4773

BCLllA-4289 + AGGGGCGGAUUGCAGAG 17 4774

BCLllA-4290 - ACGGGGACGAGGAGGAA 17 4775

BCLllA-4291 + GGAGGAGGGGCGGAUUG 17 4776

BCLllA-4292 - CGCUUCUCCACACCGCC 17 4777

BCLllA-4293 - UGACGGAGAGCGAGAGG 17 4778

BCLllA-4294 - AGGAGCUGACGGAGAGC 17 4779

BCLllA-4295 + GCUGGGAGGGAGGAGGG 17 4780

BCLllA-4296 + AGGAGGGGCGGAUUGCA 17 4781

BCLllA-4297 + UGUUGGGCAUCGCGGCC 17 4782

BCLllA-4298 - CGGGGACGAGGAGGAAG 17 4783

BCLllA-4299 + GGAGGGGCGGAUUGCAG 17 4784

BCLllA-4300 - GGAGGAGCUGACGGAGA 17 4785

BCLllA-4301 - GGGACGAGGAGGAAGAG 17 4786

BCLllA-4302 - AGGAGGAGGAGCUGACG 17 4787

BCLllA-4303 - ACGAGGAAGAGGAAGAA 17 4788

BCLllA-4304 - AGGAAGAGGAAGAAGAG 17 4789

BCLllA-4305 - AGGAAGAGGAGGACGAC 17 4790

BCLllA-4306 - AGGAGGACGACGAGGAA 17 4791

BCLllA-4307 - GGAGGAGGAGGAGCUGA 17 4792 BCLllA-4308 - GGAAGAGGAGGACGACG 17 4793

BCLllA-4309 - GGAGGAAGAGGAGGACG 17 4794

BCLllA-4310 - GGAAGAGGAAGAAGAGG 17 4795

BCLllA-4311 - AGGAGGAGGAGGAGCUG 17 4796

BCLllA-4312 - CGAGGAAGAGGAAGAAG 17 4797

BCLllA-4313 - GGACGACGAGGAAGAGG 17 4798

BCLllA-4314 - GGAGGACGACGAGGAAG 17 4799

BCLllA-4315 - CGACGAGGAAGAGGAAG 17 4800

BCLllA-4316 - AGAGGAGGACGACGAGG 17 4801

BCLllA-4317 - AAGAAGAGGAGGAAGAG 17 4802

BCLllA-4318 - AGGAAGAAGAGGAGGAA 17 4803

BCLllA-4319 - AGAGGAAGAAGAGGAGG 17 4804

BCLllA-4320 - AAGAGGAGGAAGAGGAG 17 4805

BCLllA-4321 - AGGAGGAAGAGGAGGAG 17 4806

BCLllA-4322 - GGAAGAAGAGGAGGAAG 17 4807

BCLllA-4323 - AGAAGAGGAGGAAGAGG 17 4808

BCLllA-4324 - AGAGGAGGAAGAGGAGG 17 4809

BCLllA-4325 - GGAGGAAGAGGAGGAGG 17 4810

Table 6A provides exemplary targeting domains for knocking out the BCLllA gene by targeting the early coding sequence the BCLllA gene selected according to first tier parameters. The targeting domains bind within first 500bp of coding sequence downstream of start codon, good orthogonality, start with G. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a N. meningitidis Cas9 molecule that generates a double strand break (Cas9 nuclease) or a single-strand break (Cas9 nickase). In an embodiment, dual targeting is used to create two double strand breaks to remove the enhancer region in the BCLllA gene, e.g., the first gRNA is used to target upstream (i.e., 5') of the enhancer region in the BCLllA gene and the second gRNA is used to target downstream (i.e., 3') of the enhancer region in the BCLllA gene.

Any of the targeting domains in the table can be used with a N. meningitidis Cas9 (nickase) molecule to generate a single strand break. In an embodiment, dual targeting is used to create two nicks on opposite DNA strands by using N. meningitidis Cas9 nickases with two targeting domains that are complementary to opposite DNA strands, e.g., a gRNA comprising any minus strand targeting domain may be paired any gRNA comprising a plus strand targeting domain provided that the two gRNAs are oriented on the DNA such that PAMs face outward and the distance between the 5' ends of the gRNAs is 0-50bp. In an embodiment, four gRNAs (e.g., two pairs) are used to target four Cas9 nickases to create four nicks to remove the enhancer region in the BCLllA gene, e.g., the first pair of gRNAs are used to target upstream (i.e., 5') of the enhancer region in the BCLllA gene and the second pair of gRNAs are used to target downstream (i.e., 3') of the enhancer region in the BCLllA gene.

Table 6A

Table 6B provides exemplary targeting domains for knocking out the BCLllA gene by targeting the early coding sequence the BCLllA gene. The targeting domains target outside the first 500bp of coding sequence downstream of start codon. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a N. meningitidis Cas9 molecule that generates a double strand break (Cas9 nuclease) or a single- strand break (Cas9 nickase). In an embodiment, dual targeting is used to create two double strand breaks to remove the enhancer region in the BCLllA gene, e.g., the first gRNA is used to target upstream (i.e., 5') of the enhancer region in the BCLllA gene and the second gRNA is used to target downstream (i.e., 3') of the enhancer region in the BCLllA gene.

Any of the targeting domains in the table can be used with a N. meningitidis Cas9 (nickase) molecule to generate a single strand break. In an embodiment, dual targeting is used to create two nicks on opposite DNA strands by using N. meningitidis Cas9 nickases with two targeting domains that are complementary to opposite DNA strands, e.g., a gRNA comprising any minus strand targeting domain may be paired any gRNA comprising a plus strand targeting domain provided that the two gRNAs are oriented on the DNA such that PAMs face outward and the distance between the 5' ends of the gRNAs is 0-50bp.

Table 6B

Table 7A provides exemplary targeting domains for removing (e.g., deleting) the enhancer region in the BCL11A gene selected according to first tier parameters. The targeting domains bind within a region 5' (51.5 to 51.7kb downstream of transcription start site, TSS) or 3' (65.1 to 65.3kb downstream of TSS) of enhancer, good orthogonality, starts with G. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. pyogenes Cas9 molecule that generates a double strand break (Cas9 nuclease) or a single-strand break (Cas9 nickase). In an embodiment, dual targeting is used to create two double strand breaks to remove the enhancer region in the BCLllA gene, e.g., the first gRNA is used to target upstream (i.e., 5') of the enhancer region in the BCLllA gene and the second gRNA is used to target downstream (i.e., 3') of the enhancer region in the BCLllA gene.

Any of the targeting domains in the table can be used with a S. pyogenes Cas9 (nickase) molecule to generate a single strand break. In an embodiment, dual targeting is used to create two nicks on opposite DNA strands by using S. pyogenes Cas9 nickases with two targeting domains that are complementary to opposite DNA strands, e.g., a gRNA comprising any minus strand targeting domain may be paired any gRNA comprising a plus strand targeting domain provided that the two gRNAs are oriented on the DNA such that PAMs face outward and the distance between the 5' ends of the gRNAs is 0-50bp. Exemplary gRNA pairs are: BCL11 A- 5210 and BCLl lA-5204, BCLl lA-5211 and BCLl lA-5204, BCLl lA-5172 and BCLl lA- 5176, BCLl lA-5172 and BCLl lA-5186, BCLl lA-5179 and BCLl lA-5176, or BCLl lA-5179 and BCLl lA-5186.

In an embodiment, four gRNAs (e.g., two pairs) are used to target four Cas9 nickases to create four nicks to remove the enhancer region in the BCLllA gene, e.g., the first pair of gRNAs are used to target upstream (i.e., 5') of the enhancer region in the BCLllA gene and the second pair of gRNAs are used to target downstream (i.e., 3') of the enhancer region in the BCLllA gene. For example, gRNA pairs that target upstream (i.e., 5') of the enhancer region in the BCLllA gene (e.g., BCLl lA-5210 and BCLl lA-5204, or BCLl lA-5211 and BCLHA- 5204) can be paired with gRNA pairs that target downstream (i.e., 3') of the enhancer region in the BCLllA gene (e.g., BCLl lA-5172 and BCLl lA-5176, BCLl lA-5172 and BCLl lA-5186, BCLl lA-5179 and BCLl lA-5176, or BCLl lA-5179 and BCLl lA-5186).

Table 7A

Table 7B provides exemplary targeting domains for removing (e.g., deleting) the enhancer region in the BCLllA gene selected according to second tier parameters. The targeting domains bind within a region 5' (51.5 to 51.7kb downstream of transcription start site, TSS) or 3' (65.1 to 65.3kb downstream of TSS) of enhancer, good orthogonality, and do not start with G. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. pyogenes Cas9 molecule that generates a double strand break (Cas9 nuclease) or a single-strand break (Cas9 nickase). In an embodiment, dual targeting is used to create two double strand breaks to remove the enhancer region in the BCLllA gene, e.g., the first gRNA is used to target upstream (i.e., 5') of the enhancer region in the BCLllA gene and the second gRNA is used to target downstream (i.e., 3') of the enhancer region in the BCLllA gene.

Any of the targeting domains in the table can be used with a S. pyogenes Cas9 (nickase) molecule to generate a single strand break. In an embodiment, dual targeting is used to create two nicks on opposite DNA strands by using S. pyogenes Cas9 nickases with two targeting domains that are complementary to opposite DNA strands, e.g., a gRNA comprising any minus strand targeting domain may be paired any gRNA comprising a plus strand targeting domain provided that the two gRNAs are oriented on the DNA such that PAMs face outward and the distance between the 5' ends of the gRNAs is 0-50bp.The table provides exemplary targeting domains for removing (e.g., deleting) the enhancer region in the BCLllA gene selected according to first tier parameters. The targeting domains bind within a region 5' (51.5 to 51.7kb downstream of transcription start site, TSS) or 3' (65.1 to 65.3kb downstream of TSS) of enhancer, good orthogonality, starts with G. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. pyogenes Cas9 molecule that generates a double strand break (Cas9 nuclease) or a single-strand break (Cas9 nickase). In an embodiment, dual targeting is used to create two double strand breaks to remove the enhancer region in the BCLllA gene, e.g., the first gRNA is used to target upstream (i.e., 5') of the enhancer region in the BCLllA gene and the second gRNA is used to target downstream (i.e., 3') of the enhancer region in the BCLllA gene.

Table 7B

Table 7C provides exemplary targeting domains for removing (e.g., deleting) the enhancer region in the BCL11A gene selected according to third tier parameters. The targeting domains bind within a region 5' (51.5 to 51.7kb downstream of transcription start site, TSS) or 3' (65.1 to 65.3kb downstream of TSS) of enhancer and start with G. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. pyogenes Cas9 molecule that generates a double strand break (Cas9 nuclease) or a single- strand break (Cas9 nickase). In an

embodiment, dual targeting is used to create two double strand breaks to remove the enhancer region in the BCLllA gene, e.g., the first gRNA is used to target upstream (i.e., 5') of the enhancer region in the BCLllA gene and the second gRNA is used to target downstream (i.e., 3') of the enhancer region in the BCLllA gene.

Any of the targeting domains in the table can be used with a S. pyogenes Cas9 (nickase) molecule to generate a single strand break. In an embodiment, dual targeting is used to create two nicks on opposite DNA strands by using S. pyogenes Cas9 nickases with two targeting domains that are complementary to opposite DNA strands, e.g., a gRNA comprising any minus strand targeting domain may be paired any gRNA comprising a plus strand targeting domain provided that the two gRNAs are oriented on the DNA such that PAMs face outward and the distance between the 5' ends of the gRNAs is 0-50bp. The table provides exemplary targeting domains for removing (e.g., deleting) the enhancer region in the BCLllA gene selected according to first tier parameters. The targeting domains bind within a region 5' (51.5 to 51.7kb downstream of transcription start site, TSS) or 3' (65.1 to 65.3kb downstream of TSS) of enhancer, good orthogonality, starts with G. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. pyogenes Cas9 molecule that generates a double strand break (Cas9 nuclease) or a single-strand break (Cas9 nickase). In an embodiment, dual targeting is used to create two double strand breaks to remove the enhancer region in the BCLllA gene, e.g., the first gRNA is used to target upstream (i.e., 5') of the enhancer region in the BCLllA gene and the second gRNA is used to target downstream (i.e., 3') of the enhancer region in the BCLllA gene.

Any of the targeting domains in the table can be used with a S. pyogenes Cas9 (nickase) molecule to generate a single strand break. In an embodiment, dual targeting is used to create two nicks on opposite DNA strands by using S. pyogenes Cas9 nickases with two targeting domains that are complementary to opposite DNA strands, e.g., a gRNA comprising any minus strand targeting domain may be paired any gRNA comprising a plus strand targeting domain provided that the two gRNAs are oriented on the DNA such that PAMs face outward and the distance between the 5' ends of the gRNAs is 0-50bp. In an embodiment, four gRNAs (e.g., two pairs) are used to target four Cas9 nickases to create four nicks to remove the enhancer region in the BCLllA gene, e.g., the first pair of gRNAs are used to target upstream (i.e., 5') of the enhancer region in the BCLllA gene and the second pair of gRNAs are used to target downstream (i.e., 3') of the enhancer region in the BCLllA gene.

Table 7C

Table 7D provides exemplary targeting domains for removing (e.g., deleting) the enhancer region in the BCLllA gene selected according to forth tier parameters. The targeting domains bind within a region 5' (51.5 to 51.7kb downstream of transcription start site, TSS) or 3' (65.1 to 65.3kb downstream of TSS) of enhancer and do not start with G. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. pyogenes Cas9 molecule that generates a double strand break (Cas9 nuclease) or a single-strand break (Cas9 nickase). In an embodiment, dual targeting is used to create two double strand breaks to remove the enhancer region in the BCLllA gene, e.g., the first gRNA is used to target upstream (i.e., 5') of the enhancer region in the BCLllA gene and the second gRNA is used to target downstream (i.e., 3') of the enhancer region in the BCLllA gene.

Any of the targeting domains in the table can be used with a S. pyogenes Cas9 (nickase) molecule to generate a single strand break. In an embodiment, dual targeting is used to create two nicks on opposite DNA strands by using S. pyogenes Cas9 nickases with two targeting domains that are complementary to opposite DNA strands, e.g., a gRNA comprising any minus strand targeting domain may be paired any gRNA comprising a plus strand targeting domain provided that the two gRNAs are oriented on the DNA such that PAMs face outward and the distance between the 5' ends of the gRNAs is 0-50bp. The table provides exemplary targeting domains for removing (e.g., deleting) the enhancer region in the BCL11A gene selected according to first tier parameters. The targeting domains bind within a region 5' (51.5 to 51.7kb downstream of transcription start site, TSS) or 3' (65.1 to 65.3kb downstream of TSS) of enhancer, good orthogonality, starts with G. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. pyogenes Cas9 molecule that generates a double strand break (Cas9 nuclease) or a single-strand break (Cas9 nickase). In an embodiment, dual targeting is used to create two double strand breaks to remove the enhancer region in the BCL11A gene, e.g., the first gRNA is used to target upstream (i.e., 5') of the enhancer region in the BCL11A gene and the second gRNA is used to target downstream (i.e., 3') of the enhancer region in the BCL11A gene.

Table 7D

BCLllA-5203 - AG AAAG CAG U GUAAG G C 17 5' 4866

BCLllA-5204 - AGAAUAAAAGGCUGUUU 17 5' 4867

BCLllA-5205 - AGUAAAAUAAUUAGAAUAAA 20 5' 4868

BCLllA-5206 - AGUAAGUAUUUUCUUUCAUU 20 3' 4869

BCLllA-5207 - AGUAUUUUCUUUCAUUG 17 3' 4870

BCLllA-5208 - AUUAAGAAAGCAGUGUA 17 5' 4871

BCLllA-5209 - AU U AG AAU AAAAGG CUG U U U 20 5' 4872

BCLllA-5210 + AUUAUUUUACUAGUGAAUUA 20 5' 4873

BCLllA-5211 + AUUUUACUAGUGAAUUA 17 5' 4874

BCLllA-5212 + CACAU AAAAAU U UAAGA 17 5' 4875

BCLllA-5213 - CAGUAAGUAUUUUCU UUCAU 20 3' 4876

BCLllA-5214 + CU CACAU AAAAAU U U AAG AC 20 5' 4877

BCLllA-5215 - UAAGUAUUUUCUUUCAU 17 3' 4878

BCLllA-5216 - UAAGUAUUUUCUUUCAUUGG 20 3' 4879

BCLllA-5217 - UAUUUACAGCCAUAACA 17 3' 4880

BCLllA-5218 + U CU CACAU AAAAAU U UAAGA 20 5' 4881

BCLllA-5219 - UGGAAUGUAGAGAGGCAGAG 20 5' 4882

BCLllA-5220 - UGUUUUGGAAUGUAGAG 17 5' 4883

BCLllA-5221 - U U A AG A A AG CAGUGUAAGGC 20 5' 4884

BCLllA-5222 - U UGGAAUGUAGAGAGGCAGA 20 5' 4885

BCLllA-5223 - UUUGGAAUGUAGAGAGGCAG 20 5' 4886

Table 8A provides exemplary targeting domains for removing (e.g., deleting) the enhancer region in the BCLllA gene selected according to first tier parameters. The targeting domains bind within a region 5' (51.5 to 51.7kb downstream of transcription start site, TSS) or 3' (65.1 to 65.3kb downstream of TSS) of enhancer, good orthogonality, starts with G. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. aureus Cas9 molecule that generates a double strand break (Cas9 nuclease) or a single- strand break (Cas9 nickase). In an embodiment, dual targeting is used to create two double strand breaks to remove the enhancer region in the BCLllA gene, e.g., the first gRNA is used to target upstream (i.e., 5') of the enhancer region in the BCLllA gene and the second gRNA is used to target downstream (i.e., 3') of the enhancer region in the BCLllA gene.

Table 8A

Table 8B provides exemplary targeting domains for removing (e.g., deleting) the enhancer region in the BCLllA gene selected according to second tier parameters. The targeting domains bind within a region 5' (51.5 to 51.7kb downstream of transcription start site, TSS) or 3' (65.1 to 65.3kb downstream of TSS) of enhancer, good orthogonality, and do not start with G. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. aureus Cas9 molecule that generates a double strand break (Cas9 nuclease) or a single- strand break (Cas9 nickase). In an embodiment, dual targeting is used to create two double strand breaks to remove the enhancer region in the BCLllA gene, e.g., the first gRNA is used to target upstream (i.e., 5') of the enhancer region in the BCLllA gene and the second gRNA is used to target downstream (i.e., 3') of the enhancer region in the BCLllA gene.

Any of the targeting domains in the table can be used with a S. aureus Cas9 (nickase) molecule to generate a single strand break. In an embodiment, dual targeting is used to create two nicks on opposite DNA strands by using S. aureus Cas9 nickases with two targeting domains that are complementary to opposite DNA strands, e.g., a gRNA comprising any minus strand targeting domain may be paired any gRNA comprising a plus strand targeting domain provided that the two gRNAs are oriented on the DNA such that PAMs face outward and the distance between the 5' ends of the gRNAs is 0-50bp. The table provides exemplary targeting domains for removing (e.g., deleting) the enhancer region in the BCL11A gene selected according to first tier parameters. The targeting domains bind within a region 5' (51.5 to 51.7kb downstream of transcription start site, TSS) or 3' (65.1 to 65.3kb downstream of TSS) of enhancer, good orthogonality, starts with G. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. aureus Cas9 molecule that generates a double strand break (Cas9 nuclease) or a single-strand break (Cas9 nickase). In an embodiment, dual targeting is used to create two double strand breaks to remove the enhancer region in the BCL11A gene, e.g., the first gRNA is used to target upstream (i.e., 5') of the enhancer region in the BCL11A gene and the second gRNA is used to target downstream (i.e., 3') of the enhancer region in the BCL11A gene.

Table 8B

BCLllA-5231 - AGCACACUGCUGUAAUU 17 5' 4894

BCLllA-5232 + AGUGCUACUUAUACAAUUCA 20 3' 4895

BCLllA-5233 + AUAGUUUGCUUCCCCCA 17 3' 4896

BCLllA-5234 - AUGAGCACACUGCUGUAAUU 20 5' 4897

BCLllA-5235 - CAAACU AU U UACAGCCAUAA 20 3' 4898

BCLllA-5236 - CAGCCAUAACAGGGUU UCCA 20 3' 4899

BCLllA-5237 - CCAU AACAGGG U U U CCA 17 3' 4900

BCLllA-5238 + CUACUUAUACAAUUCAC 17 3' 4901

BCLllA-5239 - CUU UGGCUAUUGAUACUGAU 20 3' 4902

BCLllA-5240 + UAAAUAGUUUGCUUCCCCCA 20 3' 4903

BCLllA-5241 + UAGUUUGCUUCCCCCAAUGA 20 3' 4904

BCLllA-5242 - UGCAACACAAGUUGUGUAGA 20 5' 4905

BCLllA-5243 - UGGAAUGUAGAGAGGCA 17 5' 4906

BCLllA-5244 - UGGCUAUUGAUACUGAU 17 3' 4907

BCLllA-5245 + UUUGCUUCCCCCAAUGA 17 3' 4908

BCLllA-5246 - U UUUGGAAUGUAGAGAGGCA 20 5' 4909

Table 8C provides exemplary targeting domains for removing (e.g., deleting) the enhancer region in the BCL11A gene selected according to third tier parameters. The targeting domains bind within a region 5' (51.5 to 51.7kb downstream of transcription start site, TSS) or 3' (65.1 to 65.3kb downstream of TSS) of enhancer and start with G. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. aureus Cas9 molecule that generates a double strand break (Cas9 nuclease) or a single-strand break (Cas9 nickase). In an embodiment, dual targeting is used to create two double strand breaks to remove the enhancer region in the BCL11A gene, e.g., the first gRNA is used to target upstream (i.e., 5') of the enhancer region in the BCL11A gene and the second gRNA is used to target downstream (i.e., 3') of the enhancer region in the BCL11A gene.

Table 8C

BCLllA-5253 - GUAAGUAUUUUCUUUCA 17 3' 4916

BCLllA-5254 - GUAAGUAUUUUCUUUCAUUG 20 3' 4917

BCLllA-5255 - GUAUUUUCUU UCAUUGG 17 3' 4918

Table 8D provides exemplary targeting domains for removing (e.g., deleting) the enhancer region in the BCLllA gene selected according to forth tier parameters. The targeting domains bind within a region 5' (51.5 to 51.7kb downstream of transcription start site, TSS) or 3' (65.1 to 65.3kb downstream of TSS) of enhancer and do not start with G. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. aureus Cas9 molecule that generates a double strand break (Cas9 nuclease) or a single-strand break (Cas9 nickase). In an embodiment, dual targeting is used to create two double strand breaks to remove the enhancer region in the BCLllA gene, e.g., the first gRNA is used to target upstream (i.e., 5') of the enhancer region in the BCLllA gene and the second gRNA is used to target downstream (i.e., 3') of the enhancer region in the BCLllA gene.

Any of the targeting domains in the table can be used with a S. aureus Cas9 (nickase) molecule to generate a single strand break. In an embodiment, dual targeting is used to create two nicks on opposite DNA strands by using S. aureus Cas9 nickases with two targeting domains that are complementary to opposite DNA strands, e.g., a gRNA comprising any minus strand targeting domain may be paired any gRNA comprising a plus strand targeting domain provided that the two gRNAs are oriented on the DNA such that PAMs face outward and the distance between the 5' ends of the gRNAs is 0-50bp. The table provides exemplary targeting domains for removing (e.g., deleting) the enhancer region in the BCLllA gene selected according to first tier parameters. The targeting domains bind within a region 5' (51.5 to 51.7kb downstream of transcription start site, TSS) or 3' (65.1 to 65.3kb downstream of TSS) of enhancer, good orthogonality, starts with G. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. aureus Cas9 molecule that generates a double strand break (Cas9 nuclease) or a single-strand break (Cas9 nickase). In an embodiment, dual targeting is used to create two double strand breaks to remove the enhancer region in the BCLllA gene, e.g., the first gRNA is used to target upstream (i.e., 5') of the enhancer region in the BCLllA gene and the second gRNA is used to target downstream (i.e., 3') of the enhancer region in the BCL11A gene.

Table 8D

BCLllA-5274 + ACAU AAAAAU U U AAG AC 17 5' 4937

BCLllA-5275 + ACUUUCUAGUU UUGCUUAAC 20 3' 4938

BCLllA-5276 + AGAAAAUACUUACUGUACUG 20 3' 4939

BCLllA-5277 - AGAAUAAAAGGCUGUUU 17 5' 4940

BCLllA-5278 - AGCAAAACU AG AAAG U U U U A 20 3' 4941

BCLllA-5279 - AGUAAGUAUUUUCUUUCAUU 20 3' 4942

BCLllA-5280 - AGUAUUUUCUUUCAUUG 17 3' 4943

BCLllA-5281 - AGUGAAUUGUAUAAGUAGCA 20 3' 4944

BCLllA-5282 + AUACUUACUGUACUGCA 17 3' 4945

BCLllA-5283 + AUCUCACAU A A A A A U U U A AG 20 5' 4946

BCLllA-5284 - AUUAAGAAAGCAGUGUAAGG 20 5' 4947

BCLllA-5285 - AU U AG AAU AAAAGG CUG U U U 20 5' 4948

BCLllA-5286 + AUUAUUUUACUAGUGAAUUA 20 5' 4949

BCLllA-5287 + AU U U AAG ACGGG AAAAC 17 5' 4950

BCLllA-5288 + AUUUUACUAGUGAAUUA 17 5' 4951

BCLllA-5289 - AUUUUCAUGUUAAGCAAAAC 20 3' 4952

BCLllA-5290 + CACAU AAAAAU U U AAG A 17 5' 4953

BCLllA-5291 - CAGUAAGUAUUUUCU UUCAU 20 3' 4954

BCLllA-5292 - CCGUCU UAAAUUUUUAU 17 5' 4955

BCLllA-5293 + CU CACAU AAAAAU U U AAG AC 20 5' 4956

BCLllA-5294 - UAAAAGGCUGUUUUGGAAUG 20 5' 4957

BCLllA-5295 - UAAGUAUUUUCUUUCAU 17 3' 4958

BCLllA-5296 - UAAGUAUUUUCUUUCAUUGG 20 3' 4959

BCLllA-5297 - U AAU U CACU AG U AAAAU AAU 20 5' 4960

BCLllA-5298 + UACUUACUGUACUGCAG 17 3' 4961

BCLllA-5299 - UAGAAUAAAAGGCUGUU 17 5' 4962

BCLllA-5300 + UAUUUUACUAGUGAAUU 17 5' 4963

BCLllA-5301 + U CACAU AAAAAU U U AAG 17 5' 4964

BCLllA-5302 + U CU CACAU AAAAAU U U AAG A 20 5' 4965

BCLllA-5303 + UGUUUCAUUU UUUGCUGACA 20 3' 4966

BCLllA-5304 - UGUUUUGGAAUGUAGAGAGG 20 5' 4967

BCLllA-5305 - U UAAAUUUUUAUGUGAG 17 5' 4968

BCLllA-5306 + U UAUUCUAAUUAUUU UACUA 20 5' 4969

BCLllA-5307 - U U CACU AG U AAAAU AAU 17 5' 4970

BCLllA-5308 - U UCAUGUUAAG C A A A AC 17 3' 4971

BCLllA-5309 + UUCAUUUUUUGCUGACA 17 3' 4972

BCLllA-5310 - UUCCCGUCUUAAAUUU UUAU 20 5' 4973

BCLllA-5311 + UUCUAAUUAUUUUACUA 17 5' 4974

BCLllA-5312 + UUCUAGUUUUGCUUAAC 17 3' 4975

BCLllA-5313 - UUCUGUGUCAGCAAAAA 17 3' 4976

BCLllA-5314 - U UUGGAAUGUAGAGAGG 17 5' 4977

BCLllA-5315 - UUUGGAAUGUAGAGAGGCAG 20 5' 4978 Table 9 provides exemplary targeting domains for removing (e.g., deleting) the enhancer region in the BCL11A gene selected according to first tier parameters. The targeting domains bind within a region 5' (51.5 to 51.7kb downstream of transcription start site, TSS) or 3' (65.1 to 65.3kb downstream of TSS) of enhancer, good orthogonality, starts with G. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a N. meningitidis Cas9 molecule that generates a double strand break (Cas9 nuclease) or a single-strand break (Cas9 nickase). In an embodiment, dual targeting is used to create two double strand breaks to remove the enhancer region in the BCL11A gene, e.g., the first gRNA is used to target upstream (i.e., 5') of the enhancer region in the BCL11A gene and the second gRNA is used to target downstream (i.e., 3') of the enhancer region in the BCL11A gene.

Table 9

Table 10A provides exemplary targeting domains for knocking down expression of the BCL11A gene according to first tier parameters. The targeting domains bind between 500bp upstream and 500bp downstream of transcription start site, good orthogonality, starts with G. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. pyogenes eiCas9 molecule to cause a steric block at the target region, e.g., between 500bp upstream and 500bp downstream of transcription start site to block transcription resulting in the repression of the BCL11A gene. Alternatively, any of the targeting domains in the table can be used with a S. pyogenes eiCas9 fused to a transcriptional repressor to decrease transcription and therefore downregulate gene expression.

Table 10A

Table 10B provides exemplary targeting domains for knocking down expression of the BCL11A gene according to second tier parameters. The targeting domains bind between 500bp upstream and 500bp downstream of transcription start site, good orthogonality and do not start with G. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. pyogenes eiCas9 molecule to cause a steric block at the target region, e.g., between 500bp upstream and 500bp downstream of transcription start site to block transcription resulting in the repression of the BCL11A gene. Alternatively, any of the targeting domains in the table can be used with a S. pyogenes eiCas9 fused to a transcriptional repressor to decrease transcription and therefore downregulate gene expression.

Table 10B

DNA Target Site SEQ ID gRNA Name Targeting Domain

Strand Length NO

BCLllA-4357 + ACACGGCAAUGGUUCCAGAU 20 4988

BCLllA-4358 - ACCAUGUCUCGCCGCAAGCA 20 4989

BCLllA-4359 + ACGACGGCUCGGUUCACAUC 20 4990

BCLllA-4360 + AUUCCCGUUUGCU UAAGUGC 20 4991

BCLllA-4361 - CAUUUUAGAGUCCGCGUGUG 20 4992

BCLllA-4362 + CGGACGCCAGACGCGGCCCC 20 4993

BCLllA-4363 + CGGUUCACAUCGGGAGAGCC 20 4994

BCLllA-4364 - CUCCUGACGU UCAAGUUCGC 20 4995

BCLllA-4365 - UAAUAAUCACGAGAGCGCGC 20 4996

BCLllA-4366 - UCCUGACGUUCAAGUUCGCA 20 4997

BCLllA-4367 + UCGGUUCACAUCGGGAGAGC 20 4998

BCLllA-4368 + UCU UUUACCUCGACUCUCGG 20 4999

BCLllA-4369 + UGCUUGCGGCGAGACAUGGU 20 5000

BCLllA-4370 - UUUAGAGUCCGCGUGUGUGG 20 5001

BCLllA-4371 + ACGGCUCGGUUCACAUC 17 5002

BCLllA-4372 - AUGUCUCGCCGCAAGCA 17 5003

BCLllA-4373 - CUGACGUUCAAGUUCGC 17 5004

BCLllA-4374 - UAAUCACGAGAGCGCGC 17 5005

BCLllA-4375 + UCCGCGGACGCCAGACG 17 5006

BCLllA-4376 - U G ACG U U CAAG U U CG CA 17 5007

BCLllA-4377 - U UAGAGUCCGCGUGUGU 17 5008

BCLllA-4378 + UUGCGGCGAGACAUGGU 17 5009

BCLllA-4379 + U UGCUUGCGGCGAGACA 17 5010

BCLllA-4380 + U UUACCUCGACUCUCGG 17 5011

BCLllA-4381 - U UUAGAGUCCGCGUGUG 17 5012

Table IOC provides exemplary targeting domains for knocking down expression of the BCL11A gene according to third tier parameters. The targeting domains bind between 500bp upstream and 500bp downstream of transcription start site and start with G. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. pyogenes eiCas9 molecule to cause a steric block at the target region, e.g., between 500bp upstream and 500bp downstream of transcription start site to block transcription resulting in the repression of the BCL11A gene. Alternatively, any of the targeting domains in the table can be used with a S. pyogenes eiCas9 fused to a transcriptional repressor to decrease transcription and therefore downregulate gene expression. Table IOC

BCLllA-4420 - GCACUUGAACUUGCAGCUCA 20 5051

BCLllA-4421 + GCAGGGAAGAUGAAUUG 17 5052

BCLllA-4422 + GCAGGGCGAGCAGGAGAGAA 20 5053

BCLllA-4423 + GCAGGGGUGGGAGGAAA 17 5054

BCLllA-4424 + GCAGGGGUGGGAGGAAAGGG 20 5055

BCLllA-4425 + GCCAAUGGCCAGUGCGGGGA 20 5056

BCLllA-4426 - GCCACCCCUUUCUUCUCUCC 20 5057

BCLllA-4427 + GCCAGACGCGGCCCCCG 17 5058

BCLllA-4428 - GCCCCAGCGCCCCCUCCCCU 20 5059

BCLllA-4429 + GCCCCCGGGGGAGGGGC 17 5060

BCLllA-4430 - GCCCGCCCCUCCCCCGG 17 5061

BCLllA-4431 + GCCGAGGGGAGGGGGCGCUG 20 5062

BCLllA-4432 + GCCGCGGCGGUGGCGUGGCC 20 5063

BCLllA-4433 + GCCGGGAGAGAAGAAAG 17 5064

BCLllA-4434 + GCCGGGAGAGAAGAAAGGGG 20 5065

BCLllA-4435 + GCGAGACAUGGUGGGCUGCG 20 5066

BCLllA-4436 + GCGCAGGGAAGAUGAAUUGU 20 5067

BCLllA-4437 + GCGCCGCGGCGGUGGCG 17 5068

BCLllA-4438 - GCGCUCGCUGCGGCCAC 17 5069

BCLllA-4439 + GCGGCCCCCGGGGGAGGGGC 20 5070

BCLllA-4440 - GCGGCGCUCGCUGCGGCCAC 20 5071

BCLllA-4441 + GCGGCGGCGGCGGCGGC 17 5072

BCLllA-4442 + GCGGCGGCGGCGGCGGCGGC 20 5073

BCLllA-4443 + GCGGCGGCGGCGGCGGCGGG 20 5074

BCLllA-4444 + GCGGCGGCGGCGGCGGG 17 5075

BCLllA-4445 + GCGGCGGGCGGACGACGGCU 20 5076

BCLllA-4446 + GCGGCGGUGGCGUGGCC 17 5077

BCLllA-4447 + GCGGGCGGCGGCGGCGG 17 5078

BCLllA-4448 + GCGGGCGGCGGCGGCGGCGG 20 5079

BCLllA-4449 + GCGGGGAGGGGGAGGUG 17 5080

BCLllA-4450 + GCGUGGCCGGGAGAGAAGAA 20 5081

BCLllA-4451 + GCUCCCCCCCACACACG 17 5082

BCLllA-4452 + GCUGGGGUUUGCCU UGCUUG 20 5083

BCLllA-4453 + GGACAAGCCAAUGGCCAGUG 20 5084

BCLllA-4454 + GGACACACAUCAGGGGC 17 5085

BCLllA-4455 + GGACAGAGACACACAAAACA 20 5086

BCLllA-4456 + GGACGCCAGACGCGGCCCCC 20 5087

BCLllA-4457 - GGACUAGAAGCAAAAGCGAG 20 5088

BCLllA-4458 + GGAGAGAAGAAAGGGGUGGC 20 5089

BCLllA-4459 + GGAGAGAAGGGGAGGAGGGA 20 5090

BCLllA-4460 + GGAGAGCCGGGUUAGAAAGA 20 5091

BCLllA-4461 + GGAGGGGCGGGCCGAGGGGA 20 5092 BCLllA-4462 + GGAGGGGGAGGUGCGGGGCG 20 5093

BCLllA-4463 + GGAGGGGGCGCUGGGGCCGC 20 5094

BCLllA-4464 + GGCAGGGCGAGCAGGAGAGA 20 5095

BCLllA-4465 + GGCAGGGGUGGGAGGAA 17 5096

BCLllA-4466 - GGCCACUGG UGAGCCCG 17 5097

BCLllA-4467 + GGCCCCCGGGGGAGGGG 17 5098

BCLllA-4468 - GGCCCGCCCCUCCCCCG 17 5099

BCLllA-4469 + GGCCGAGGGGAGGGGGCGCU 20 5100

BCLllA-4470 + GGCCGCAGCGAGCGCCG 17 5101

BCLllA-4471 + GGCCGCAGCGAGCGCCGCGG 20 5102

BCLllA-4472 + GGCCGCGGGCUCACCAG 17 5103

BCLllA-4473 + GGCCGGGAGAGAAGAAA 17 5104

BCLllA-4474 + GGCGAGACAUGGUGGGCUGC 20 5105

BCLllA-4475 + GGCGAGCAGGAGAGAAG 17 5106

BCLllA-4476 + GGCGAGCAGGAGAGAAGGGG 20 5107

BCLllA-4477 + GGCGCAGGGAAGAUGAAUUG 20 5108

BCLllA-4478 + GGCGGCGGCGGCGGCGG 17 5109

BCLllA-4479 + GGCGGCGGCGGCGGCGGCGG 20 5110

BCLllA-4480 + GGCGGGCCGAGGGGAGG 17 5111

BCLllA-4481 + GGCUGCGGGGCGGGCGG 17 5112

BCLllA-4482 + GGCUGCGGGGCGGGCGGCGG 20 5113

BCLllA-4483 + GGGAGAGAAGAAAGGGG 17 5114

BCLllA-4484 + GGGAGGAAAGGGUGGGG 17 5115

BCLllA-4485 + GGGAGGGGCGGGCCGAG 17 5116

BCLllA-4486 + GGGAGGGGCGGGCCGAGGGG 20 5117

BCLllA-4487 + GGGAGGGGGAGGUGCGGGGC 20 5118

BCLllA-4488 + GGGAGGGGGCGCUGGGGCCG 20 5119

BCLllA-4489 + GGGAGGUGCGGGGCGGG 17 5120

BCLllA-4490 + GGGCCGAGGGGAGGGGGCGC 20 5121

BCLllA-4491 + GGGCGAGCAGGAGAGAA 17 5122

BCLllA-4492 + GGGCGGGCCGAGGGGAG 17 5123

BCLllA-4493 + GGGGAAGCUCACACCAA 17 5124

BCLllA-4494 + GGGGAGGGGCGGGCCGA 17 5125

BCLllA-4495 + GGGGAGGGGGAGGUGCG 17 5126

BCLllA-4496 + GGGGAGGGGGAGGUGCGGGG 20 5127

BCLllA-4497 + GGGGAGGUGCGGGGCGG 17 5128

BCLllA-4498 - GGGGCCGCGUCUGGCGUCCG 20 5129

BCLllA-4499 + GGGGCGGGCCGAGGGGA 17 5130

BCLllA-4500 + GGGGCGGGCGGCGGCGG 17 5131

BCLllA-4501 + GGGGCGGGCGGCGGCGGCGG 20 5132

BCLllA-4502 + GGGGGAGGGGCGGGCCG 17 5133

BCLllA-4503 + GGGGGAGGUGCGGGGCG 17 5134 BCLllA-4504 + GGGGGCGCUGGGGCCGC 17 5135

BCLllA-4505 + GGGGUGGCAGGGGUGGG 17 5136

BCLllA-4506 + GGGGUGGGAGGAAAGGG 17 5137

BCLllA-4507 + GGGGUGGGAGGAAAGGGUGG 20 5138

BCLllA-4508 + GGGGUUUGCCUUGCUUG 17 5139

BCLllA-4509 + GGGUGGGAGGAAAGGGU 17 5140

BCLllA-4510 + GGGUGGGAGGAAAGGGUGGG 20 5141

BCLllA-4511 - G G U A A A AG AG A U A A AG G 17 5142

BCLllA-4512 + GGUGGCAGGGGUGGGAGGAA 20 5143

BCLllA-4513 + GGUGGGAGGAAAGGGUG 17 5144

BCLllA-4514 + GGUGGGAGGAAAGGGUGGGG 20 5145

BCLllA-4515 + GGUUCCAGAUGGGAUGA 17 5146

BCLllA-4516 - GUAUUAUUUCUAAUUUAUUU 20 5147

BCLllA-4517 - GUCGAGGU A A A AG AG A U AAA 20 5148

BCLllA-4518 + GUGCGGGGAGGGGGAGGUGC 20 5149

BCLllA-4519 + GUGCGGGGCGGGGGGCUCCG 20 5150

BCLllA-4520 + GUGGCAGGGGUGGGAGGAAA 20 5151

BCLllA-4521 + GUGGCCGGGAGAGAAGAAAG 20 5152

BCLllA-4522 + GUGGGAGGAAAGGGUGG 17 5153

BCLllA-4523 + GUGGGCUGCGGGGCGGG 17 5154

BCLllA-4524 + GUGGGCUGCGGGGCGGGCGG 20 5155

BCLllA-4525 - GUGUGUGGGGGGGAGCA 17 5156

Table 10D provides exemplary targeting domains for knocking down expression of the BCLllA gene according to forth tier parameters. The targeting domains bind between 500bp upstream and 500bp downstream of transcription start site and do not start with G. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. pyogenes eiCas9 molecule to cause a steric block at the target region, e.g., between 500bp upstream and 500bp downstream of transcription start site to block transcription resulting in the repression of the BCLllA gene. Alternatively, any of the targeting domains in the table can be used with a S. pyogenes eiCas9 fused to a transcriptional repressor to decrease transcription and therefore downregulate gene expression.

Table 10D

BCLllA-4527 + AAAAAAAAAAAAAAAAAAGA 20 5158

BCLllA-4528 + AAAAAAAAAAAAAAAAG 17 5159

BCLllA-4529 + AAAAAAAAAAAAAAAGA 17 5160

BCLllA-4530 + AAAACAUGGGCAGGGCGAGC 20 5161

BCLllA-4531 - AAAACCCUCAUCCCAUC 17 5162

BCLllA-4532 - AAAACCU CCG AG AG U CG 17 5163

BCLllA-4533 - AAAAGCGAGGGGGAGAG 17 5164

BCLllA-4534 - AAAGCGAGGGGGAGAGA 17 5165

BCLllA-4535 + AAAGGGGUGGCAGGGGU 17 5166

BCLllA-4536 + AAAGGGGUGGCAGGGGUGGG 20 5167

BCLllA-4537 + AAAUAAUACAAAGAUGGCGC 20 5168

BCLllA-4538 - AACCCCAGCACUUAAGCAAA 20 5169

BCLllA-4539 + AACGUCAGGAGUCUGGA 17 5170

BCLllA-4540 + AAGAAAGGGGUGGCAGGGGU 20 5171

BCLllA-4541 + AAGAGACCAGGACAAGCCAA 20 5172

BCLllA-4542 + AAGCCAAUGGCCAGUGC 17 5173

BCLllA-4543 - AAGCGAGGGGGAGAGAG 17 5174

BCLllA-4544 + AAGUGCAUACACGGCAA 17 5175

BCLllA-4545 + AAUAAUACAAAGAUGGCGCA 20 5176

BCLllA-4546 + AAUACAAAGAUGGCGCA 17 5177

BCLllA-4547 + AAUGGACACACAUCAGGGGC 20 5178

BCLllA-4548 + AAUGGCCAGUGCGGGGA 17 5179

BCLllA-4549 + AAUGGUUCCAGAUGGGAUGA 20 5180

BCLllA-4550 + AAU U AAAU AAAAU U AAA 17 5181

BCLllA-4551 + AAU U AG AAAU AAU ACAAAG A 20 5182

BCLllA-4552 - AAUUUAUUUUGGAUGUCAAA 20 5183

BCLllA-4553 + ACAAGCCAAUGGCCAGUGCG 20 5184

BCLllA-4554 + ACACACAAAACAUGGGC 17 5185

BCLllA-4555 + ACACCAAUGGACACACAUCA 20 5186

BCLllA-4556 + ACAUGGGCAGGGCGAGC 17 5187

BCLllA-4557 + ACCAAUGGACACACAUC 17 5188

BCLllA-4558 - ACCCCAGCACUUAAGCAAAC 20 5189

BCLllA-4559 - ACCCCUU UCU UCUCUCC 17 5190

BCLllA-4560 + ACGCCAGACGCGGCCCC 17 5191

BCLllA-4561 + ACGCCAGACGCGGCCCCCGG 20 5192

BCLllA-4562 + ACGCGGCCCCCGGGGGA 17 5193

BCLllA-4563 + ACGGCAAUGGUUCCAGA 17 5194

BCLllA-4564 - ACU AG AAG CAAAAG CG A 17 5195

BCLllA-4565 - ACUGAUGAAGAUAUUUUCUC 20 5196

BCLllA-4566 - ACU UGAACUUGCAGCUC 17 5197

BCLllA-4567 - ACU UGAACUUGCAGCUCAGG 20 5198

BCLllA-4568 - AGAAAAACCUCCGAGAGUCG 20 5199 BCLllA-4569 + AGAAGAAAGGGGUGGCA 17 5200

BCLllA-4570 + AGAAGGGGAGGAGGGAA 17 5201

BCLllA-4571 + AGACACACAAAACAUGGGCA 20 5202

BCLllA-4572 + AGACAUGGUGGGCUGCG 17 5203

BCLllA-4573 + AGACAUGGUGGGCUGCGGGG 20 5204

BCLllA-4574 + AGACCAGGACAAGCCAA 17 5205

BCLllA-4575 + AGACGCGGCCCCCGGGGGAG 20 5206

BCLllA-4576 + AGAGAAGAAAGGGGUGGCAG 20 5207

BCLllA-4577 + AGAGAAGGGGAGGAGGGAAG 20 5208

BCLllA-4578 + AGAGACACACAAAACAU 17 5209

BCLllA-4579 + AGAGAGAAGAGAGAUAG 17 5210

BCLllA-4580 + AGAGAGAGAAGAGAGAUAGA 20 5211

BCLllA-4581 + AGAGAGAGAGAUGAAAAAAA 20 5212

BCLllA-4582 - AGAGUCCGCGUGUGUGG 17 5213

BCLllA-4583 - AGCAAAAGCGAGGGGGAGAG 20 5214

BCLllA-4584 + AGCAGGAGAGAAGGGGAGGA 20 5215

BCLllA-4585 + AGCCAAUGGCCAGUGCG 17 5216

BCLllA-4586 + AGCCAAUGGCCAGUGCGGGG 20 5217

BCLllA-4587 - AGCCCCUGAUGUGUGUCCAU 20 5218

BCLllA-4588 + AGCGAGCGCCGCGGCGG 17 5219

BCLllA-4589 + AG C U G C A AG U U C A AG U G 17 5220

BCLllA-4590 - AGGACUAGAAGCAAAAGCGA 20 5221

BCLllA-4591 + AGGAGAGAAGGGGAGGA 17 5222

BCLllA-4592 + AGGGCGAGCAGGAGAGA 17 5223

BCLllA-4593 + AGGGGCGGGCCGAGGGG 17 5224

BCLllA-4594 + AGGGGCGGGCCGAGGGGAGG 20 5225

BCLllA-4595 + AGGGGGAGGUGCGGGGC 17 5226

BCLllA-4596 + AGGGGGAGGUGCGGGGCGGG 20 5227

BCLllA-4597 + AGGGGGCGCUGGGGCCG 17 5228

BCLllA-4598 + AGGGGUGGGAGGAAAGGGUG 20 5229

BCLllA-4599 - AGG U AAAAG AG AU AAAG 17 5230

BCLllA-4600 - AGUCCGCGUGUGUGGGG 17 5231

BCLllA-4601 - AGUCGAGGUAAAAGAGAUAA 20 5232

BCLllA-4602 + AGUGCGGGGAGGGGGAGGUG 20 5233

BCLllA-4603 + AGUGGCCGCAGCGAGCGCCG 20 5234

BCLllA-4604 + AUAAUUAUUAUUACUAUUAU 20 5235

BCLllA-4605 + AUCUCUUU UACCUCGACUCU 20 5236

BCLllA-4606 + AUGGCCAGUGCGGGGAG 17 5237

BCLllA-4607 + AUGGUGGGCUGCGGGGC 17 5238

BCLllA-4608 + AUGGUGGGCUGCGGGGCGGG 20 5239

BCLllA-4609 + AUUAUUAUUACUAUUAU 17 5240

BCLllA-4610 - AUUUUAGAGUCCGCGUGUGU 20 5241 BCLllA-4611 - CAAAAGCGAGGGGGAGAGAG 20 5242

BCLllA-4612 + CAAAAGUGCAUACACGGCAA 20 5243

BCLllA-4613 + CAAGCCAAUGGCCAGUG 17 5244

BCLllA-4614 + CAAUGGACACACAUCAG 17 5245

BCLllA-4615 + CAAUGGCCAGUGCGGGG 17 5246

BCLllA-4616 + CAAUGGCCAGUGCGGGGAGG 20 5247

BCLllA-4617 + CAAUGGUUCCAGAUGGGAUG 20 5248

BCLllA-4618 + CACACAAAACAUGGGCA 17 5249

BCLllA-4619 + CACACCAAUGGACACACAUC 20 5250

BCLllA-4620 + CACCAAUGGACACACAUCAG 20 5251

BCLllA-4621 - CACCGCCGCGGCGCUCGCUG 20 5252

BCLllA-4622 - CACUGGCCAUUGGCUUGUCC 20 5253

BCLllA-4623 - CACUUGAACUUGCAGCUCAG 20 5254

BCLllA-4624 + CAGACGCGGCCCCCGGGGGA 20 5255

BCLllA-4625 + CAGAGACACACAAAACA 17 5256

BCLllA-4626 - CAGGACUAGAAGCAAAAGCG 20 5257

BCLllA-4627 + CAGGAGAGAAGGGGAGG 17 5258

BCLllA-4628 + CAGGGAAGAUGAAUUGU 17 5259

BCLllA-4629 + CAGGGCGAGCAGGAGAGAAG 20 5260

BCLllA-4630 + CAGGGGUGGGAGGAAAGGGU 20 5261

BCLllA-4631 + CAUGGUGGGCUGCGGGG 17 5262

BCLllA-4632 + CCAAUGGACACACAUCA 17 5263

BCLllA-4633 + CCAAUGGCCAGUGCGGGGAG 20 5264

BCLllA-4634 + CCAGACGCGGCCCCCGG 17 5265

BCLllA-4635 + CCAGACGCGGCCCCCGGGGG 20 5266

BCLllA-4636 - CC AG C ACU U AAG CAAAC 17 5267

BCLllA-4637 - CCAGCGCCCCCUCCCCU 17 5268

BCLllA-4638 + CCAGUGCGGGGAGGGGG 17 5269

BCLllA-4639 - CCCAG CAC U U AAG C AAA 17 5270

BCLllA-4640 - CCCCCGGGGGCCGCGUC 17 5271

BCLllA-4641 - CCCCUCCCCGCACUGGCCAU 20 5272

BCLllA-4642 + CCCGGGGGAGGGGCGGGCCG 20 5273

BCLllA-4643 + CCCGUUUGCUUAAGUGC 17 5274

BCLllA-4644 - CCCUCGGCCCGCCCCUCCCC 20 5275

BCLllA-4645 - CCCUGAUGUGUGUCCAU 17 5276

BCLllA-4646 + CCGAGGGGAGGGGGCGC 17 5277

BCLllA-4647 - CCGCGUGUGUGGGGGGGAGC 20 5278

BCLllA-4648 + CCGGGGGAGGGGCGGGCCGA 20 5279

BCLllA-4649 + CCGUUUGCUUAAGUGCU 17 5280

BCLllA-4650 - CCUCCCCCGGGGGCCGCGUC 20 5281

BCLllA-4651 - CCUCCCCCUCCCCGCAC 17 5282

BCLllA-4652 - CCUCGGCCCGCCCCUCCCCC 20 5283 BCLllA-4653 + CCUGCUCCCCCCCACACACG 20 5284

BCLllA-4654 + CGAGACAUGGUGGGCUG 17 5285

BCLllA-4655 + CGAGCGCCGCGGCGGUGGCG 20 5286

BCLllA-4656 + CGAGGGGAGGGGGCGCU 17 5287

BCLllA-4657 - CGAGGUAAAAGAGAUAA 17 5288

BCLllA-4658 - CGAGGUAAAAGAGAUAAAGG 20 5289

BCLllA-4659 - CGCACUUGAACUUGCAGCUC 20 5290

BCLllA-4660 + CGCAGCGAGCGCCGCGG 17 5291

BCLllA-4661 + CGCAGCGAGCGCCGCGGCGG 20 5292

BCLllA-4662 + CGCCAGACGCGGCCCCC 17 5293

BCLllA-4663 - CGCCGCGGCGCUCGCUG 17 5294

BCLllA-4664 + CGCCGCGGCGGUGGCGUGGC 20 5295

BCLllA-4665 + CGCGGCCCCCGGGGGAG 17 5296

BCLllA-4666 + CGCGGCCCCCGGGGGAGGGG 20 5297

BCLllA-4667 + CGCGGCGGUGGCGUGGC 17 5298

BCLllA-4668 - CGCGUGUGUGGGGGGGAGCA 20 5299

BCLllA-4669 + CGGCAAUGGUUCCAGAU 17 5300

BCLllA-4670 - CGGCCACGCCACCGCCG 17 5301

BCLllA-4671 - CGGCCCGCCCCUCCCCC 17 5302

BCLllA-4672 + CGGCGAGACAUGGUGGGCUG 20 5303

BCLllA-4673 + CGGCGGCGGCGGGCGGACGA 20 5304

BCLllA-4674 + CGGCGGCGGGCGGACGA 17 5305

BCLllA-4675 + CGGGGAGGGGGAGGUGC 17 5306

BCLllA-4676 + CGGGGCGGGGGGCUCCG 17 5307

BCLllA-4677 + CGGGGGAGGGGCGGGCCGAG 20 5308

BCLllA-4678 + CGUGGCCGGGAGAGAAGAAA 20 5309

BCLllA-4679 - CGUGUGUGGGGGGGAGC 17 5310

BCLllA-4680 + CGUUUGCU UAAGUGCUG 17 5311

BCLllA-4681 - CUAGAAGCAAAAGCGAG 17 5312

BCLllA-4682 - CUCCCCGCACUGGCCAU 17 5313

BCLllA-4683 - CUCGGCCCGCCCCUCCCCCG 20 5314

BCLllA-4684 + CUGAGCUGCAAGU UCAAGUG 20 5315

BCLllA-4685 + CUGCGAACUUGAACGUC 17 5316

BCLllA-4686 + CUGGACAUGAAAAAGAGACC 20 5317

BCLllA-4687 + CUGUCUCAAAAGUGCAUACA 20 5318

BCLllA-4688 + CUUGAACGUCAGGAGUC 17 5319

BCLllA-4689 - CUUGAACUUGCAGCUCA 17 5320

BCLllA-4690 - CUUGAACUUGCAGCUCAGGG 20 5321

BCLllA-4691 + CUUGCGGCGAGACAUGG 17 5322

BCLllA-4692 + GU UCACAUCGGGAGAGC 17 5323

BCLllA-4693 + UAAUACAAAGAUGGCGC 17 5324

BCLllA-4694 + UAAUUAUUAUUACUAUUAUU 20 5325 BCLllA-4695 + UACACGGCAAUGGUUCCAGA 20 5326

BCLllA-4696 + U AG AAA U A A U AC A A AG A 17 5327

BCLllA-4697 - UAGAAGCAAAAGCGAGG 17 5328

BCLllA-4698 - UAGAGUCCGCGUGUGUG 17 5329

BCLllA-4699 - UAGAGUCCGCGUGUGUGGGG 20 5330

BCLllA-4700 - UCCCGGCCACGCCACCGCCG 20 5331

BCLllA-4701 + UCCCGU UUGCUUAAGUGCUG 20 5332

BCLllA-4702 + UCCCUGCGAACUUGAACGUC 20 5333

BCLllA-4703 - U CG AGG U AAAAG AG AU AAAG 20 5334

BCLllA-4704 - UCGGCCCGCCCCUCCCC 17 5335

BCLllA-4705 - UCGGCCCGCCCCUCCCCCGG 20 5336

BCLllA-4706 + U C U C A A A AG U G C A U AC A 17 5337

BCLllA-4707 - UCUCCU UCUUUCUAACC 17 5338

BCLllA-4708 + UCU UUUACCUCGACUCU 17 5339

BCLllA-4709 - UGAACUUGCAGCUCAGG 17 5340

BCLllA-4710 - UGCGGCCACUGGUGAGCCCG 20 5341

BCLllA-4711 + UGCGGGGAGGGGGAGGUGCG 20 5342

BCLllA-4712 + UGCGGGGCGGGCGGCGG 17 5343

BCLllA-4713 + UGCGGGGCGGGCGGCGGCGG 20 5344

BCLllA-4714 - UGCUUAAAAAAAAGCCAUGA 20 5345

BCLllA-4715 + UGGCCAGUGCGGGGAGG 17 5346

BCLllA-4716 + UGGCCAGUGCGGGGAGGGGG 20 5347

BCLllA-4717 - UGGCCAUUGGCUUGUCC 17 5348

BCLllA-4718 + UGGCCGGGAGAGAAGAA 17 5349

BCLllA-4719 + UGGGAGGAAAGGGUGGG 17 5350

BCLllA-4720 + UGGGGCCGCGGGCUCACCAG 20 5351

BCLllA-4721 + UGGUUCCAGAUGGGAUG 17 5352

BCLllA-4722 - UUAAAAAAAAGCCAUGA 17 5353

BCLllA-4723 - UUAGAGUCCGCGUGUGUGGG 20 5354

BCLllA-4724 + UUAUUAUUACUAUUAUU 17 5355

BCLllA-4725 - U UAUUUCUAAUUUAU UU 17 5356

BCLllA-4726 - UUAUUUUGGAUGUCAAA 17 5357

BCLllA-4727 + U UCACAUCGGGAGAGCC 17 5358

BCLllA-4728 + UUCCCGU UUGCUUAAGUGCU 20 5359

BCLllA-4729 + UUGAACGUCAGGAGUCUGGA 20 5360

BCLllA-4730 - U UGAACUUGCAGCUCAG 17 5361

BCLllA-4731 + UUGCUUGCGGCGAGACAUGG 20 5362

BCLllA-4732 + UUGUGGGAGAGCCGUCA 17 5363

BCLllA-4733 - U UUUAGAGUCCGCGUGUGUG 20 5364

Table 11A provides exemplary targeting domains for knocking down expression of the BCLllA gene according to first tier parameters. The targeting domains bind between 500bp upstream and 500bp downstream of transcription start site, good orthogonality, starts with G. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. aureus eiCas9 molecule to cause a steric block at the target region, e.g., between 500bp upstream and 500bp downstream of transcription start site to block transcription resulting in the repression of the BCL11A gene. Alternatively, any of the targeting domains in the table can be used with a S. aureus eiCas9 fused to a transcriptional repressor to decrease transcription and therefore downregulate gene expression.

Table 11A

Table 11B provides exemplary targeting domains for knocking down expression of the BCL11A gene according to second tier parameters. The targeting domains bind between 500bp upstream and 500bp downstream of transcription start site, good orthogonality and do not start with G. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. aureus eiCas9 molecule to cause a steric block at the target region, e.g., between 500bp upstream and 500bp downstream of transcription start site to block transcription resulting in the repression of the BCL11A gene. Alternatively, any of the targeting domains in the table can be used with a S. aureus eiCas9 fused to a transcriptional repressor to decrease transcription and therefore downregulate gene expression. Table 11B

Table 11C provides exemplary targeting domains for knocking down expression of the BCL11A gene according to third tier parameters. The targeting domains bind between 500bp upstream and 500bp downstream of transcription start site and start with G. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. aureus eiCas9 molecule to cause a steric block at the target region, e.g., between 500bp upstream and 500bp downstream of transcription start site to block transcription resulting in the repression of the BCL11A gene. Alternatively, any of the targeting domains in the table can be used with a S. aureus eiCas9 fused to a transcriptional repressor to decrease transcription and therefore downregulate gene expression.

Table 11C

BCLllA-4765 + GAACGUCAGGAGUCUGG 17 6396

BCLllA-4766 + GAAGAAAGGGGUGGCAGGGG 20 6397

BCLllA-4767 + GAAGAGAGAUAGAGGGA 17 6398

BCLllA-4768 - G A AG C AAAAG CG AG GG G 17 6399

BCLllA-4769 + GAAGGGGAGGAGGGAAG 17 6400

BCLllA-4770 + GACAAGCCAAUGGCCAGUGC 20 6401

BCLllA-4771 + GACACACAAAACAUGGG 17 6402

BCLllA-4772 + GACGCCAGACGCGGCCC 17 6403

BCLllA-4773 + GACGCCAGACGCGGCCCCCG 20 6404

BCLllA-4774 + GACGCGGCCCCCGGGGG 17 6405

BCLllA-4775 - G ACU AG AAG CAAAAG CG 17 6406

BCLllA-4776 - GACUAGAAGCAAAAGCGAGG 20 6407

BCLllA-4777 + GACUCUCGGAGGUUUU UCUC 20 6408

BCLllA-4778 + GAGAAGAAAGGGGUGGC 17 6409

BCLllA-4779 + GAGAAGAGAGAUAGAGG 17 6410

BCLllA-4780 + GAGAAGGGGAGGAGGGA 17 6411

BCLllA-4781 + GAGACAUGGUGGGCUGCGGG 20 6412

BCLllA-4782 + GAGAGAAGAGAGAUAGA 17 6413

BCLllA-4783 + GAGAGAAGGGGAGGAGGGAA 20 6414

BCLllA-4784 + GAGAGAGAAGAGAGAUA 17 6415

BCLllA-4785 + GAGAGAGAGAAGAGAGA 17 6416

BCLllA-4786 + GAGAGAGAGAAGAGAGAUAG 20 6417

BCLllA-4787 + GAGAGAGAGAGAGAGAG 17 6418

BCLllA-4788 + GAGAGAUAGAGGGAGAGAGA 20 6419

BCLllA-4789 + GAGAUAGAGGGAGAGAGAGA 20 6420

BCLllA-4790 + GAGCAGGAGAGAAGGGG 17 6421

BCLllA-4791 + GAGCAGGAGAGAAGGGGAGG 20 6422

BCLllA-4792 + GAGCCGGGUUAGAAAGA 17 6423

BCLllA-4793 + G AG C U G C AAG U U C AAG U 17 6424

BCLllA-4794 + GAGGGAGAGAGAGAGAA 17 6425

BCLllA-4795 + GAGGGGCGGGCCGAGGG 17 6426

BCLllA-4796 + GAGGGGGAGGUGCGGGG 17 6427

BCLllA-4797 + GAGGGGGCGCUGGGGCC 17 6428

BCLllA-4798 - G AG G U AAAAG AG A U AAA 17 6429

BCLllA-4799 - GAGUCCGCG UGUGUGGG 17 6430

BCLllA-4800 - GAGUCGAGGUAAAAGAGAUA 20 6431

BCLllA-4801 + GAUAGAGGGAGAGAGAGAGA 20 6432

BCLllA-4802 - GAUGAAGAUAUUUUCUC 17 6433

BCLllA-4803 - GAUGUCAAAAGGCACUG 17 6434

BCLllA-4804 - GAUGUGUGUCCAUUGGU 17 6435

BCLllA-4805 + GCAAUGGUUCCAGAUGGGAU 20 6436

BCLllA-4806 - GCACUUGAACUUGCAGCUCA 20 6437 BCLllA-4807 - G C AG G AC U AG AAG CAAA AG C 20 6438

BCLllA-4808 + GCAGGAGAGAAGGGGAG 17 6439

BCLllA-4809 + GCAGGGAAGAUGAAUUG 17 6440

BCLllA-4810 + GCAGGGAAGAUGAAUUGUGG 20 6441

BCLllA-4811 + GCAGGGCGAGCAGGAGAGAA 20 6442

BCLllA-4812 + GCAGGGGUGGGAGGAAAGGG 20 6443

BCLllA-4813 - GCAU UUUUAAAUUUUUC 17 6444

BCLllA-4814 + GCCAAUGGCCAGUGCGGGGA 20 6445

BCLllA-4815 + GCCAGACGCGGCCCCCG 17 6446

BCLllA-4816 + GCCAGACGCGGCCCCCGGGG 20 6447

BCLllA-4817 + GCCCCCGGGGGAGGGGCGGG 20 6448

BCLllA-4818 + GCCGAGGGGAGGGGGCG 17 6449

BCLllA-4819 + GCCGCGGCGGUGGCGUGGCC 20 6450

BCLllA-4820 - GCCGCGUCUGGCGUCCG 17 6451

BCLllA-4821 + GCGAGACAUGGUGGGCU 17 6452

BCLllA-4822 - GCGCAGGACUAGAAGCAAAA 20 6453

BCLllA-4823 + GCGCAGGGAAGAUGAAUUGU 20 6454

BCLllA-4824 + GCGCCGCGGCGGUGGCGUGG 20 6455

BCLllA-4825 + GCGGACGCCAGACGCGGCCC 20 6456

BCLllA-4826 + GCGGCGAGACAUGGUGGGCU 20 6457

BCLllA-4827 + GCGGCGGUGGCGUGGCC 17 6458

BCLllA-4828 + GCGGGGAGGGGGAGGUG 17 6459

BCLllA-4829 + GCGGGGCGGGGGGCUCC 17 6460

BCLllA-4830 + GCGUGGCCGGGAGAGAAGAA 20 6461

BCLllA-4831 - GCGUGUGUGGGGGGGAG 17 6462

BCLllA-4832 + GCUCACCAGUGGCCGCA 17 6463

BCLllA-4833 - GCUCGCUGCGGCCACUG 17 6464

BCLllA-4834 + GCUGGACAUGAAAAAGAGAC 20 6465

BCLllA-4835 + GCUUGCGGCGAGACAUG 17 6466

BCLllA-4836 - GGAAAAAACCCUCAUCCCAU 20 6467

BCLllA-4837 + GGAAGGGGAAGCUCACACCA 20 6468

BCLllA-4838 + GGACAAGCCAAUGGCCAGUG 20 6469

BCLllA-4839 + GGACAUGAAAAAGAGAC 17 6470

BCLllA-4840 + GGACGCCAGACGCGGCCCCC 20 6471

BCLllA-4841 - GGACUAGAAG CAAA AG C 17 6472

BCLllA-4842 - GGACUAGAAGCAAAAGCGAG 20 6473

BCLllA-4843 + GGAGAGAAGAAAGGGGUGGC 20 6474

BCLllA-4844 + GGAGAGAAGGGGAGGAGGGA 20 6475

BCLllA-4845 + GGAGAGAGAGAGAAGAGAGA 20 6476

BCLllA-4846 + GGAGAGCCGGGUUAGAAAGA 20 6477

BCLllA-4847 + GGAGGGGCGGGCCGAGGGGA 20 6478

BCLllA-4848 + GGAGGGGGAGGUGCGGG 17 6479 BCLllA-4849 + GGAGGGGGAGGUGCGGGGCG 20 6480

BCLllA-4850 + GGCAGGGCGAGCAGGAGAGA 20 6481

BCLllA-4851 + GGCAGGGGUGGGAGGAAAGG 20 6482

BCLllA-4852 - GGCCGCGUCUGGCGUCC 17 6483

BCLllA-4853 + GGCGAGCAGGAGAGAAG 17 6484

BCLllA-4854 + GGCGAGCAGGAGAGAAGGGG 20 6485

BCLllA-4855 + GGCGCAGGGAAGAUGAAUUG 20 6486

BCLllA-4856 - GGCGCUCGCUGCGGCCACUG 20 6487

BCLllA-4857 + GGCGGCGGCGGCGGCGG 17 6488

BCLllA-4858 + GGCGGCGGCGGCGGCGGCGG 20 6489

BCLllA-4859 + GGCGGUGGCGUGGCCGG 17 6490

BCLllA-4860 + GGCGUGGCCGGGAGAGAAGA 20 6491

BCLllA-4861 + GGGAAGAUGAAUUGUGG 17 6492

BCLllA-4862 + GGGAGAGAAGAAAGGGGUGG 20 6493

BCLllA-4863 + GGGAGAGCCGGGUUAGA 17 6494

BCLllA-4864 + GGGAGAGCCGGGUUAGAAAG 20 6495

BCLllA-4865 + GGGAGGAAAGGGUGGGG 17 6496

BCLllA-4866 + GGGAGGGGCGGGCCGAG 17 6497

BCLllA-4867 + GGGAGGGGCGGGCCGAGGGG 20 6498

BCLllA-4868 + GGGAGGGGGAGGUGCGGGGC 20 6499

BCLllA-4869 + GGGCAGGGCGAGCAGGA 17 6500

BCLllA-4870 + GGGCAGGGCGAGCAGGAGAG 20 6501

BCLllA-4871 + GGGCCGAGGGGAGGGGGCGC 20 6502

BCLllA-4872 + GGGCGAGCAGGAGAGAA 17 6503

BCLllA-4873 + GGGCGAGCAGGAGAGAAGGG 20 6504

BCLllA-4874 + GGGGAGGGGCGGGCCGA 17 6505

BCLllA-4875 + GGGGAGGGGCGGGCCGAGGG 20 6506

BCLllA-4876 + GGGGAGGGGGAGGUGCGGGG 20 6507

BCLllA-4877 + GGGGAGGGGGCGCUGGGGCC 20 6508

BCLllA-4878 - GGGGCCGCGUCUGGCGUCCG 20 6509

BCLllA-4879 + GGGGCGGGCCGAGGGGA 17 6510

BCLllA-4880 + GGGGGAGGGGCGGGCCG 17 6511

BCLllA-4881 + GGGGGAGGUGCGGGGCG 17 6512

BCLllA-4882 - GGGGGCCGCGUCUGGCGUCC 20 6513

BCLllA-4883 + GGGGUGGCAGGGGUGGG 17 6514

BCLllA-4884 + GGGGUGGGAGGAAAGGG 17 6515

BCLllA-4885 + GGGGUGGGAGGAAAGGGUGG 20 6516

BCLllA-4886 + GGGUGGCAGGGGUGGGAGGA 20 6517

BCLllA-4887 + GGGUGGGAGGAAAGGGU 17 6518

BCLllA-4888 + GGGUGGGAGGAAAGGGUGGG 20 6519

BCLllA-4889 - G G U A A A AG AG A U A A AG G 17 6520

BCLllA-4890 + GGUGCGGGGCGGGGGGCUCC 20 6521 BCLllA-4891 + GGUGGGAGGAAAGGGUG 17 6522

BCLllA-4892 + GGUGGGAGGAAAGGGUGGGG 20 6523

BCLllA-4893 + GG U U AG AAAG AAGG AG ACU C 20 6524

BCLllA-4894 + GGUUUGCCUUGCUUGCG 17 6525

BCLllA-4895 - GUCGAGGU A A A AG AG A U AAA 20 6526

BCLllA-4896 + GUGGCCGGGAGAGAAGA 17 6527

BCLllA-4897 + GUGGGAGGAAAGGGUGG 17 6528

Table 11D provides exemplary targeting domains for knocking down expression of the BCLllA gene according to forth tier parameters. The targeting domains bind between 500bp upstream and 500bp downstream of transcription start site and do not start with G. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. aureus eiCas9 molecule to cause a steric block at the target region, e.g., between 500bp upstream and 500bp downstream of transcription start site to block transcription resulting in the repression of the BCLllA gene. Alternatively, any of the targeting domains in the table can be used with a S. aureus eiCas9 fused to a transcriptional repressor to decrease transcription and therefore downregulate gene expression.

Table 11D

BCLllA-4914 - AAAAACCCUCAUCCCAU 17 6545

BCLllA-4915 + AAAAAGAGGGAGAGAGA 17 6546

BCLllA-4916 + AAAAAGAGGGAGAGAGAGAG 20 6547

BCLllA-4917 + AAAACAUGGGCAGGGCGAGC 20 6548

BCLllA-4918 - AAAACCCUCAUCCCAUC 17 6549

BCLllA-4919 - AAAAGCGAGGGGGAGAG 17 6550

BCLllA-4920 - AAACCCCAGCACUUAAGCAA 20 6551

BCLllA-4921 + AAAGAGGGAGAGAGAGAGAA 20 6552

BCLllA-4922 + AAAGGGGUGGCAGGGGU 17 6553

BCLllA-4923 + AAAGGGGUGGCAGGGGUGGG 20 6554

BCLllA-4924 + AAAUAAUACAAAGAUGGCGC 20 6555

BCLllA-4925 + AAAUGGCAAAAGCCCCC 17 6556

BCLllA-4926 + AACAUGGGCAGGGCGAG 17 6557

BCLllA-4927 + AACAUGGGCAGGGCGAGCAG 20 6558

BCLllA-4928 - AACCCCAGCACUUAAGCAAA 20 6559

BCLllA-4929 - AACCCGGCUCUCCCGAU 17 6560

BCLllA-4930 + AAGAAAGGGGUGGCAGGGGU 20 6561

BCLllA-4931 + AAGAGAGAUAGAGGGAGAGA 20 6562

BCLllA-4932 + AAGAGGGAGAGAGAGAG 17 6563

BCLllA-4933 + AAGAUGGCGCAGGGAAG 17 6564

BCLllA-4934 - AAGCAAAAGCGAGGGGGAGA 20 6565

BCLllA-4935 + AAGCCAAUGGCCAGUGC 17 6566

BCLllA-4936 + AAGCCAAUGGCCAGUGCGGG 20 6567

BCLllA-4937 - AAUAAUAAUUAUUAAUAAUC 20 6568

BCLllA-4938 + AAUAAUACAAAGAUGGCGCA 20 6569

BCLllA-4939 - AAUAAUUAUUAAUAAUC 17 6570

BCLllA-4940 + AAUAAUUAUUAUUACUAUUA 20 6571

BCLllA-4941 + AAUACAAAGAUGGCGCA 17 6572

BCLllA-4942 + AAUGGCCAGUGCGGGGA 17 6573

BCLllA-4943 + AAUUAUUAUUACUAUUA 17 6574

BCLllA-4944 + AAUUCCCGUUUGCUUAAGUG 20 6575

BCLllA-4945 + ACAAAGAUGGCGCAGGGAAG 20 6576

BCLllA-4946 + ACAAGCCAAUGGCCAGU 17 6577

BCLllA-4947 + ACAAGCCAAUGGCCAGUGCG 20 6578

BCLllA-4948 + ACACACAAAACAUGGGCAGG 20 6579

BCLllA-4949 + ACACACAUCAGGGGCUGGAC 20 6580

BCLllA-4950 + ACAGAGACACACAAAAC 17 6581

BCLllA-4951 + ACAUGGGCAGGGCGAGC 17 6582

BCLllA-4952 + ACAUGGUGGGCUGCGGG 17 6583

BCLllA-4953 + ACCAAUGGACACACAUC 17 6584

BCLllA-4954 - ACCCCAGCACUUAAGCAAAC 20 6585

BCLllA-4955 - ACCUCCGAGAGUCGAGGUAA 20 6586 BCLllA-4956 - ACGAGAAAAACCUCCGAGAG 20 6587

BCLllA-4957 + ACGCCAGACGCGGCCCC 17 6588

BCLllA-4958 + ACGCCAGACGCGGCCCCCGG 20 6589

BCLllA-4959 + ACGCGGCCCCCGGGGGAGGG 20 6590

BCLllA-4960 + ACGGCAAUGGUUCCAGA 17 6591

BCLllA-4961 + ACGUCAGGAGUCUGGAUGGA 20 6592

BCLllA-4962 - ACU AG AAG CAAAAG CG A 17 6593

BCLllA-4963 + ACUAUUAUUGGGUUACUUAC 20 6594

BCLllA-4964 - ACUCCUGACGUUCAAGUUCG 20 6595

BCLllA-4965 - ACUGAUGAAGAUAUUUUCUC 20 6596

BCLllA-4966 + ACU UGAACGUCAGGAGU 17 6597

BCLllA-4967 - ACU UGAACUUGCAGCUC 17 6598

BCLllA-4968 - AGAAAAACCUCCGAGAG 17 6599

BCLllA-4969 + AGAAAGGGGUGGCAGGG 17 6600

BCLllA-4970 + AGAAGAAAGGGGUGGCAGGG 20 6601

BCLllA-4971 + AGAAGAGAGAUAGAGGGAGA 20 6602

BCLllA-4972 - AGAAGCAAAAGCGAGGGGGA 20 6603

BCLllA-4973 + AGAAGGGGAGGAGGGAA 17 6604

BCLllA-4974 + AGACGCGGCCCCCGGGG 17 6605

BCLllA-4975 + AGAGAAGAAAGGGGUGG 17 6606

BCLllA-4976 + AGAGAAGAGAGAUAGAGGGA 20 6607

BCLllA-4977 + AGAGAAGGGGAGGAGGG 17 6608

BCLllA-4978 + AGAGAAGGGGAGGAGGGAAG 20 6609

BCLllA-4979 + AGAGACACACAAAACAUGGG 20 6610

BCLllA-4980 + AGAGAGAAGAGAGAUAG 17 6611

BCLllA-4981 + AGAGAGAAGAGAGAUAGAGG 20 6612

BCLllA-4982 + AGAGAGAGAAGAGAGAUAGA 20 6613

BCLllA-4983 + AGAGAGAGAGAAGAGAGAUA 20 6614

BCLllA-4984 + AGAGAGAUAGAGGGAGA 17 6615

BCLllA-4985 + AGAGAUAGAGGGAGAGA 17 6616

BCLllA-4986 + AGAGCCGGGUUAGAAAG 17 6617

BCLllA-4987 + AGAGGGAGAGAGAGAGA 17 6618

BCLllA-4988 - AGAGUCCGCGUGUGUGG 17 6619

BCLllA-4989 + AGAUAGAGGGAGAGAGA 17 6620

BCLllA-4990 - AG CAAAAG CGAGGGGGA 17 6621

BCLllA-4991 - AGCAAAAGCGAGGGGGAGAG 20 6622

BCLllA-4992 + AGCAGGAGAGAAGGGGAGGA 20 6623

BCLllA-4993 + AGCCAAUGGCCAGUGCG 17 6624

BCLllA-4994 + AGCCAAUGGCCAGUGCGGGG 20 6625

BCLllA-4995 + AGGACAAGCCAAUGGCCAGU 20 6626

BCLllA-4996 - AGGACUAGAAGCAAAAGCGA 20 6627

BCLllA-4997 + AGGAGAGAAGGGGAGGA 17 6628 BCLllA-4998 + AGGAGAGAAGGGGAGGAGGG 20 6629

BCLllA-4999 + AGGGAGAGAGAGAGAGAGAG 20 6630

BCLllA-5000 + AGGGCGAGCAGGAGAGA 17 6631

BCLllA-5001 + AGGGGAAGCUCACACCA 17 6632

BCLllA-5002 + AGGGGCGGGCCGAGGGG 17 6633

BCLllA-5003 + AGGGGCUGGACAUGAAA 17 6634

BCLllA-5004 + AGGGGGAGGUGCGGGGC 17 6635

BCLllA-5005 + AGGGGUGGCAGGGGUGG 17 6636

BCLllA-5006 + AGGGGUGGGAGGAAAGG 17 6637

BCLllA-5007 + AGGGGUGGGAGGAAAGGGUG 20 6638

BCLllA-5008 - AGG U AAAAG AG AU AAAG 17 6639

BCLllA-5009 - AGUCCGCGUGUGUGGGG 17 6640

BCLllA-5010 - AGUCGAGGUAAAAGAGAUAA 20 6641

BCLllA-5011 + AGUGCGGGGAGGGGGAGGUG 20 6642

BCLllA-5012 + AUAAUACAAAGAUGGCG 17 6643

BCLllA-5013 - AUAAUCACGAGAGCGCG 17 6644

BCLllA-5014 + AUACACGGCAAUGGUUCCAG 20 6645

BCLllA-5015 + AUAGAGGGAGAGAGAGA 17 6646

BCLllA-5016 + AUCAGGGGCUGGACAUGAAA 20 6647

BCLllA-5017 + AUCGGGAGAGCCGGGUUAGA 20 6648

BCLllA-5018 + AUCUCUUU UACCUCGACUCU 20 6649

BCLllA-5019 + AUGGCCAGUGCGGGGAG 17 6650

BCLllA-5020 + AUGGGCAGGGCGAGCAG 17 6651

BCLllA-5021 + AUGGUUCCAGAUGGGAU 17 6652

BCLllA-5022 + AUUAUUGGGUUACU UAC 17 6653

BCLllA-5023 - AUUAUUUCUAAUUUAUU 17 6654

BCLllA-5024 + AUUCCCGUUUGCU UAAGUGC 20 6655

BCLllA-5025 - AUUUUAGAGUCCGCGUGUGU 20 6656

BCLllA-5026 - AUUUUUAAAUUUUUCAC 17 6657

BCLllA-5027 - AU U U U U CACG AG AAAAACCU 20 6658

BCLllA-5028 + CAAAACAUGGGCAGGGCGAG 20 6659

BCLllA-5029 - CAAAAGCGAGGGGGAGA 17 6660

BCLllA-5030 + CAAGCCAAUGGCCAGUG 17 6661

BCLllA-5031 + CAAUGGACACACAUCAGGGG 20 6662

BCLllA-5032 + CAAUGGCCAGUGCGGGG 17 6663

BCLllA-5033 + CAAUGGCCAGUGCGGGGAGG 20 6664

BCLllA-5034 + CAAUGGUUCCAGAUGGG 17 6665

BCLllA-5035 + CACAAAACAUGGGCAGG 17 6666

BCLllA-5036 + CACACCAAUGGACACACAUC 20 6667

BCLllA-5037 + CACACGCGGACUCUAAA 17 6668

BCLllA-5038 + CACAUCAGGGGCUGGAC 17 6669

BCLllA-5039 + CACCAAUGGACACACAU 17 6670 BCLllA-5040 + CACGGCAAUGGUUCCAG 17 6671

BCLllA-5041 - CACUGAUGAAGAUAUU UUCU 20 6672

BCLllA-5042 - CACUUGAACUUGCAGCU 17 6673

BCLllA-5043 - CACUUGAACUUGCAGCUCAG 20 6674

BCLllA-5044 - CAGGACUAGAAG C A A A A 17 6675

BCLllA-5045 - CAGGACUAGAAGCAAAAGCG 20 6676

BCLllA-5046 + CAGGAGAGAAGGGGAGG 17 6677

BCLllA-5047 + CAGGGAAGAUGAAUUGU 17 6678

BCLllA-5048 + CAGGGCGAGCAGGAGAG 17 6679

BCLllA-5049 + CAGGGCGAGCAGGAGAGAAG 20 6680

BCLllA-5050 + CAGGGGUGGGAGGAAAGGGU 20 6681

BCLllA-5051 + CAGUGCGGGGAGGGGGAGGU 20 6682

BCLllA-5052 - CAUGCAUUUUUAAAUU UUUC 20 6683

BCLllA-5053 + CAUGGGCAGGGCGAGCAGGA 20 6684

BCLllA-5054 - CAUUUUAGAGUCCGCGUGUG 20 6685

BCLllA-5055 + CCAAUGGCCAGUGCGGG 17 6686

BCLllA-5056 + CCAAUGGCCAGUGCGGGGAG 20 6687

BCLllA-5057 + CCACACACGCGGACUCUAAA 20 6688

BCLllA-5058 + CCAGACGCGGCCCCCGG 17 6689

BCLllA-5059 + CCAGACGCGGCCCCCGGGGG 20 6690

BCLllA-5060 - CC AG C ACU U AAG CAAAC 17 6691

BCLllA-5061 - CCAUUGCCGUGUAUGCACUU 20 6692

BCLllA-5062 - CCCAG CAC U U AAG C AAA 17 6693

BCLllA-5063 - CCCCAGCACUUAAGCAA 17 6694

BCLllA-5064 + CCCCGGGGGAGGGGCGGGCC 20 6695

BCLllA-5065 - CCCCUCGGCCCGCCCCUCCC 20 6696

BCLllA-5066 + CCCGGGGGAGGGGCGGG 17 6697

BCLllA-5067 + CCCGGGGGAGGGGCGGGCCG 20 6698

BCLllA-5068 + CCCGUUUGCUUAAGUGC 17 6699

BCLllA-5069 - CCCUCGGCCCGCCCCUCCCC 20 6700

BCLllA-5070 + CCCUGCUCCCCCCCACACAC 20 6701

BCLllA-5071 + CCGAGGGGAGGGGGCGC 17 6702

BCLllA-5072 - CCGCACUUGAACUUGCAGCU 20 6703

BCLllA-5073 + CCGCGGCGGUGGCGUGG 17 6704

BCLllA-5074 + CCGGGGGAGGGGCGGGCCGA 20 6705

BCLllA-5075 - CCUCGGCCCGCCCCUCCCCC 20 6706

BCLllA-5076 - CCUGACGU UCAAGUUCG 17 6707

BCLllA-5077 + CCUGAGCUG CAAG U U CA AG U 20 6708

BCLllA-5078 - CCUGAUGUGUGUCCAUUGGU 20 6709

BCLllA-5079 + CGAACUUGAACGUCAGGAGU 20 6710

BCLllA-5080 + CGAGACAUGGUGGGCUG 17 6711

BCLllA-5081 + CGAGCAGGAGAGAAGGG 17 6712 BCLllA-5082 + CGAGCAGGAGAGAAGGGGAG 20 6713

BCLllA-5083 - CGAGGUAAAAGAGAUAA 17 6714

BCLllA-5084 - CGAGGUAAAAGAGAUAAAGG 20 6715

BCLllA-5085 - CGCACUUGAACUUGCAGCUC 20 6716

BCLllA-5086 + CGCAGGGAAGAUGAAU U 17 6717

BCLllA-5087 + CGCCAGACGCGGCCCCC 17 6718

BCLllA-5088 + CGCCGCGGCGGUGGCGUGGC 20 6719

BCLllA-5089 + CGCGGCGGUGGCGUGGC 17 6720

BCLllA-5090 + CGCGGCGGUGGCGUGGCCGG 20 6721

BCLllA-5091 + CGGACGCCAGACGCGGCCCC 20 6722

BCLllA-5092 + CGGCAAUGGUUCCAGAUGGG 20 6723

BCLllA-5093 + CGGCCCCCGGGGGAGGG 17 6724

BCLllA-5094 - CGGCCCGCCCCUCCCCC 17 6725

BCLllA-5095 + CGGCGAGACAUGGUGGGCUG 20 6726

BCLllA-5096 + CGGCGGCGGCGGCGGCG 17 6727

BCLllA-5097 + CGGCGGCGGCGGCGGCGGCG 20 6728

BCLllA-5098 + CGGCGGUGGCGUGGCCGGGA 20 6729

BCLllA-5099 + CGGGCCGAGGGGAGGGGGCG 20 6730

BCLllA-5100 + CGGGCUCACCAGUGGCCGCA 20 6731

BCLllA-5101 + CGGGGAGGGGGAGGUGCGGG 20 6732

BCLllA-5102 + CGGGGGAGGGGCGGGCC 17 6733

BCLllA-5103 + CGGGGGAGGGGCGGGCCGAG 20 6734

BCLllA-5104 + CGGUGGCGUGGCCGGGA 17 6735

BCLllA-5105 + CGGUGGCGUGGCCGGGAGAG 20 6736

BCLllA-5106 - CUAGAAGCAAAAGCGAG 17 6737

BCLllA-5107 - CUAGAAGCAAAAGCGAGGGG 20 6738

BCLllA-5108 - CUCCUGACGU UCAAGUUCGC 20 6739

BCLllA-5109 - CUCGGCCCGCCCCUCCC 17 6740

BCLllA-5110 + CUCUUUUACCUCGACUC 17 6741

BCLllA-5111 - CUGACGUUCAAGUUCGC 17 6742

BCLllA-5112 + CUUGAACGUCAGGAGUCUGG 20 6743

BCLllA-5113 - CUUGAACUUGCAGCUCA 17 6744

BCLllA-5114 + CUUGCUUGCGGCGAGACAUG 20 6745

BCLllA-5115 - U AAU AAU U AU U AAU AAU CAC 20 6746

BCLllA-5116 + UAAUACAAAGAUGGCGC 17 6747

BCLllA-5117 - U AAU U AU U AAU AAU CAC 17 6748

BCLllA-5118 + UACACGGCAAUGGUUCCAGA 20 6749

BCLllA-5119 + UAGAAAGAAGGAGACUC 17 6750

BCLllA-5120 - UAGAAGCAAAAGCGAGG 17 6751

BCLllA-5121 - UAGAGUCCGCGUGUGUG 17 6752

BCLllA-5122 - UAGAGUCCGCGUGUGUGGGG 20 6753

BCLllA-5123 + UAUCUCUU UUACCUCGACUC 20 6754 BCLllA-5124 + UAUUAUUGGGUUACUUACGC 20 6755

BCLllA-5125 + UAUUGGGUUACUUACGC 17 6756

BCLllA-5126 + UCACACCAAUGGACACACAU 20 6757

BCLllA-5127 - UCACGAGAAAAACCUCC 17 6758

BCLllA-5128 + UCAGGAGUCUGGAUGGA 17 6759

BCLllA-5129 - UCAUUUUAGAGUCCGCGUGU 20 6760

BCLllA-5130 + UCCCGU UUGCUUAAGUG 17 6761

BCLllA-5131 - UCCGAGAGUCGAGGUAA 17 6762

BCLllA-5132 - UCCGCGUGUGUGGGGGGGAG 20 6763

BCLllA-5133 - UCGAGGUAAAAGAGAUA 17 6764

BCLllA-5134 - U CG AGG U AAAAG AG AU AAAG 20 6765

BCLllA-5135 - UCGGCCCGCCCCUCCCC 17 6766

BCLllA-5136 - UCUAACCCGGCUCUCCCGAU 20 6767

BCLllA-5137 + UCUCGGAGGU UUUUCUC 17 6768

BCLllA-5138 + UCU UUUACCUCGACUCU 17 6769

BCLllA-5139 + UGACAUCCAAAAUAAAU 17 6770

BCLllA-5140 - UGAUGAAGAUAUUUUCU 17 6771

BCLllA-5141 - UGCAUUUUUAAAUUUU UCAC 20 6772

BCLllA-5142 + UGCGGGGAGGGGGAGGU 17 6773

BCLllA-5143 + UGCUCCCCCCCACACAC 17 6774

BCLllA-5144 + UGGACACACAUCAGGGG 17 6775

BCLllA-5145 + UGGACAGAGACACACAAAAC 20 6776

BCLllA-5146 + UGGCAGGGGUGGGAGGA 17 6777

BCLllA-5147 + UGGCCAGUGCGGGGAGG 17 6778

BCLllA-5148 + UGGCCGGGAGAGAAGAA 17 6779

BCLllA-5149 + UGGCGCAGGGAAGAUGAAUU 20 6780

BCLllA-5150 + UGGCGUGGCCGGGAGAG 17 6781

BCLllA-5151 + UGGGAGGAAAGGGUGGG 17 6782

BCLllA-5152 + UGGGGUUUGCCUUGCUUGCG 20 6783

BCLllA-5153 - UGUAUUAUUUCUAAU UUAUU 20 6784

BCLllA-5154 - U UAAUAAUCACGAGAGCGCG 20 6785

BCLllA-5155 + UUAGAAAGAAGGAGACUCCA 20 6786

BCLllA-5156 - U UAGAGUCCGCGUGUGU 17 6787

BCLllA-5157 - UUAGAGUCCGCGUGUGUGGG 20 6788

BCLllA-5158 - U UGAACUUGCAGCUCAG 17 6789

BCLllA-5159 - U UGCCGUGUAUGCACU U 17 6790

BCLllA-5160 - U UGGAUGUCAAAAGGCACUG 20 6791

BCLllA-5161 - U UUAGAGUCCGCGUGUG 17 6792

BCLllA-5162 - UUUAGAGUCCGCGUGUGUGG 20 6793

BCLllA-5163 - U U U CACG AG AAAAACCU 17 6794

BCLllA-5164 - UUUUAGAGUCCGCGUGU 17 6795

BCLllA-5165 - U UUUAGAGUCCGCGUGUGUG 20 6796 BCLllA-5166 - UUUUCACGAGAAAAACCUCC 20 6797

BCLllA-5167 + U U U UG ACAU CCAAAAU AAAU 20 6798

Table 12 provides exemplary targeting domains for knocking down expression of the BCL11A gene. The targeting domains bind between 500bp upstream and 500bp downstream of transcription start site. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a N. meningitidismeningitidis eiCas9 molecule to cause a steric block at the target region, e.g., between 500bp upstream and 500bp downstream of transcription start site to block transcription resulting in the repression of the BCL11A gene. Alternatively, any of the targeting domains in the table can be used with a N. meningitidismeningitidis eiCas9 fused to a

transcriptional repressor to decrease transcription and therefore downregulate gene expression. Table 12

Table 13A provides exemplary targeting domains for the E6V target site in the HBB gene selected according to the first tier parameters. The targeting domains bind within lOObp upstream and lOObp downstream of the target position, good orthogonality and start with G. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. pyogenes Cas9 molecule that generates a double strand break (Cas9 nuclease) or a single-strand break (Cas9 nickase).

Any of the targeting domains in the table can be used with a S. pyogenes Cas9 (nickase) molecule to generate a single strand break. In an embodiment, dual targeting is used to create two nicks on opposite DNA strands by using S. pyogenes Cas9 nickases with two targeting domains that are complementary to opposite DNA strands, e.g., a gRNA comprising any minus strand targeting domain may be paired any gRNA comprising a plus strand targeting domain provided that the two gRNAs are oriented on the DNA such that PAMs face outward and the distance between the 5' ends of the gRNAs is 0-50bp. Exemplary gRNA pairs are: HBB-9 and HBB-11, HBB-9 and HBB-39, HBB-20 and HBB-11 and HBB-20 and HBB-39.

Table 13A

Table 13B provides exemplary targeting domains for the E6V target site in the HBB gene selected according to the second tier parameters. The targeting domains bind within lOObp upstream and lOObp downstream of the target position, good orthogonality and do not start with G. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. pyogenes Cas9 molecule that generates a double strand break (Cas9 nuclease) or a single-strand break (Cas9 nickase).

Table 13B

Table 13C provides exemplary targeting domains for the E6V target site in the HBB gene selected according to the third tier parameters. The targeting domains bind within lOObp upstream and lOObp downstream of the target position, and start with G. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. pyogenes Cas9 molecule that generates a double strand break (Cas9 nuclease) or a single-strand break (Cas9 nickase).

Table 13C

Table 13D provides exemplary targeting domains for the E6V target site in the HBB gene selected according to the fourth tier parameters. The targeting domains bind within lOObp upstream and lOObp downstream of the target position, and do not start with G. It is

contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. pyogenes Cas9 molecule that generates a double strand break (Cas9 nuclease) or a single-strand break (Cas9 nickase).

Table 13D

HBB-47 - UGCCGU UACUGCCCUG U 17 6849

H BB-48 - UGGGCAGG U UGG UAUCA 17 6850

H BB-49 - UGG U AU CAAGG U U ACAAG AC 20 6851

H BB-50 - UGG UGAGGCCCUGGGCAGGU 20 6852

H BB-51 + U UGAUACCAACCUGCCC 17 6853

H BB-52 - U UGG UGG UGAGGCCCUGGGC 20 6854

Table 14A provides exemplary targeting domains for the E6V target site in the HBB gene selected according to the first tier parameters. The targeting domains bind within lOObp upstream and lOObp downstream of the target position, good orthogonality and start with G. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. aureus Cas9 molecule that generates a double strand break (Cas9 nuclease) or a single-strand break (Cas9 nickase).

Any of the targeting domains in the table can be used with a S. aureus Cas9 (nickase) molecule to generate a single strand break. In an embodiment, dual targeting is used to create two nicks on opposite DNA strands by using S. aureus Cas9 nickases with two targeting domains that are complementary to opposite DNA strands, e.g., a gRNA comprising any minus strand targeting domain may be paired any gRNA comprising a plus strand targeting domain provided that the two gRNAs are oriented on the DNA such that PAMs face outward and the distance between the 5' ends of the gRNAs is 0-50bp. Exemplary gRNA pairs are: HBB-9 and HBB-11, HBB-9 and HBB-39, HBB-20 and HBB-11 and HBB-20 and HBB-39.

Table 14A

Table 14B provides exemplary targeting domains for the E6V target site in the HBB gene selected according to the second tier parameters. The targeting domains bind within lOObp upstream and lOObp downstream of the target position, good orthogonality and do not start with G. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. aureus Cas9 molecule that generates a double strand break (Cas9 nuclease) or a single-strand break (Cas9 nickase).

Table 14B

Table 14C provides exemplary targeting domains for the E6V target site in the HBB gene selected according to the fifth tier parameters. The targeting domains bind within lOObp upstream and lOObp downstream of the target position and PAM is NNGRRV. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. aureus Cas9 molecule that generates a double strand break (Cas9 nuclease) or a single-strand break (Cas9 nickase).

Table 14C

HBB-56 - AAGUCUGCCGU UACUGCCCU 20 6858

HBB-57 + AACCUUGAUACCAACCUGCC 20 6859

HBB-58 + UCCACGU UCACCUUGCCCCA 20 6860

HBB-59 + GCUAGUGAACACAGUUGUGU 20 6861

HBB-60 - CCAUGGUGCACCUGACUCCU 20 6862

HBB-61 - CAUGGUGCACCUGACUCCUG 20 6863

HBB-62 + AGGUGCACCAUGGUGUCUGU 20 6864

HBB-63 - UGGUGCACCUGACUCCUGUG 20 6865

HBB-64 - GAACGUGGAUGAAGUUGGUG 20 6866

HBB-65 - UUACUGCCCUGUGGGGCAAG 20 6867

HBB-66 + GUGUCUGUU UGAGGUUGCUA 20 6868

HBB-67 - GUGGGGCAAGGUGAACGUGG 20 6869

HBB-68 - AUGAAGUUGGUGGUGAGGCC 20 6870

HBB-69 + AGUAACGGCAGACUUCUCCA 20 6871

Table 15A provides exemplary targeting domains for knocking out the BCL11A gene selected according to the first tier parameters. The targeting domains bind within the first 500 bp of the coding sequence (e.g., within 500 bp downstream from the start codon) and have a high level of orthogonality. It is contemplated herein that in an embodiment the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. pyogenes Cas9 molecule that generates a double stranded break (Cas9 nuclease) or a single- stranded break (Cas9 nickase).

Table 15A

BCLllA-5331 - CAUCCAGGUCACGCCAG 17 6885

BCLllA-5332 - UUAUCAACGUCAUCUAG 17 6886

BCLllA-5333 + GAGCUCCCAACGGGCCG 17 6887

BCLllA-5334 + UGCACUCAUCCCAGGCG 17 6888

BCLllA-5335 + AGACAUGGUGGGCUGCG 17 6889

BCLllA-5336 + CGU UUGCUUAAGUGCUG 17 6890

BCLllA-5337 + GCU UUUUUCAUCUCGAU 17 6891

BCLllA-5338 + CCGUU UGCUUAAGUGCU 17 6892

BCLllA-5339 - UCCAAUCCCGUGGAGGU 17 6893

BCLllA-5340 + U UGCGGCGAGACAUGGU 17 6894

BCLllA-5341 - AUGACCUCCUCACCUGU 17 6895

BCLllA-5342 - U UAUUUUUAUCGAGCACAAA 20 6896

BCLllA-5343 + UCCCCUUCUGGAGCUCCCAA 20 6897

BCLllA-5344 + U UUUCAUCUCGAUUGGUGAA 20 6898

BCLllA-5345 + GCCUUGCU UGCGGCGAGACA 20 6899

BCLllA-5346 - ACCAUGUCUCGCCGCAAGCA 20 6900

BCLllA-5347 + GAGCUCCAUGUGCAGAACGA 20 6901

BCLllA-5348 - UCACAGAUAAACUUCUGCAC 20 6902

BCLllA-5349 + CGUCAUCCUCUGGCGUGACC 20 6903

BCLllA-5350 - GGAGCUCUAAUCCCCACGCC 20 6904

BCLllA-5351 - UCCCGUGGAGGUUGGCAUCC 20 6905

BCLllA-5352 + AUUCCCGU UUGCUUAAGUGC 20 6906

BCLllA-5353 + CCCCCAAUGGGAAGUUCAUC 20 6907

BCLllA-5354 + GCUCCCAACGGGCCGUGGUC 20 6908

BCLllA-5355 + U UUCAUCUCGAUUGGUGAAG 20 6909

BCLllA-5356 - UGUUUAUCAACGUCAUCUAG 20 6910

BCLllA-5357 + AGAGCUCCAUGUGCAGAACG 20 6911

BCLllA-5358 - GAAAAAAGCAUCCAAUCCCG 20 6912

BCLllA-5359 + GCGAGACAUGGUGGGCUGCG 20 6913

BCLllA-5360 - CAGAUAAACUUCUGCACUGG 20 6914

BCLllA-5361 + CGGCGAGACAUGGUGGGCUG 20 6915

BCLllA-5362 + CUGCACUCAUCCCAGGCGUG 20 6916

BCLllA-5363 - UGAACCAGACCACGGCCCGU 20 6917

BCLllA-5364 - GCAUCCAAUCCCGUGGAGGU 20 6918

BCLllA-5365 + UGCUUGCGGCGAGACAUGGU 20 6919

BCLllA-5366 + UCAAGAGGCUCGGCUGUGGU 20 6920

BCLllA-5367 - AUCAUGACCUCCUCACCUGU 20 6921

Table 15B provides exemplary targeting domains for knocking out the BCLllA gene selected according to the second tier parameters. The targeting domains bind within the first 500 bp of the coding sequence (e.g., within 500 bp downstream from the start codon). It is contemplated herein that in an embodiment the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. pyogenes Cas9 molecule that generates a double stranded break (Cas9 nuclease) or a single- stranded break (Cas9 nickase).

Table 15B

BCLllA-5400 - GUUGGGAGCUCCAGAAG 17 6954

BCLllA-5401 + CAGCU UUUUCUAAGCAG 17 6955

BCLllA-5402 + UCCAUGUGCAGAACGAG 17 6956

BCLllA-2671 + CAGAACGAGGGGAGGAG 17 6957

BCLllA-5403 - AAACUUCUGCACUGGAG 17 6958

BCLllA-5404 + GCUCCAUGUGCAGAACG 17 6959

BCLllA-5405 - AAAAGCAUCCAAUCCCG 17 6960

BCLllA-5406 + CUUACAAAUACCCUGCG 17 6961

BCLllA-5407 + AUUGGUGAAGGGGAAGG 17 6962

BCLllA-5408 + ACUGCCCACAGGUGAGG 17 6963

BCLllA-4500 + GGGGCGGGCGGCGGCGG 17 6964

BCLllA-5409 + UGCGGGGCGGGCGGCGG 17 6965

BCLllA-5410 + GGCUGCGGGGCGGGCGG 17 6966

BCLllA-5411 + GUGGGCUGCGGGGCGGG 17 6967

BCLllA-5412 + AUGUGCAGAACGAGGGG 17 6968

BCLllA-5413 + CAUGGUGGGCUGCGGGG 17 6969

BCLllA-5414 + CUUGCGGCGAGACAUGG 17 6970

BCLllA-5415 - AUAAACUUCUGCACUGG 17 6971

BCLllA-5416 - AGCAUCCAAUCCCGUGG 17 6972

BCLllA-5417 - GAUGAACUUCCCAUUGG 17 6973

BCLllA-5418 - CAUGACCUCCUCACCUG 17 6974

BCLllA-5419 + AACUUACAAAUACCCUG 17 6975

BCLllA-5420 - CUGCUUAGAAAAAGCUG 17 6976

BCLllA-5421 + UUCAAGAGGCUCGGCUG 17 6977

BCLllA-5422 + CGAGACAUGGUGGGCUG 17 6978

BCLllA-5423 + CACUCAUCCCAGGCGUG 17 6979

BCLllA-5424 + GGCACUGCCCACAGGUG 17 6980

BCLllA-5425 - AGAUGAACUUCCCAUUG 17 6981

BCLllA-5426 + GGGGUUUGCCUUGCUUG 17 6982

BCLllA-5427 + CUAUGUGUUCCUGUU UG 17 6983

BCLllA-5428 + UAAGAAUGUCCCCCAAU 17 6984

BCLllA-5429 - CCAGAUGAACUUCCCAU 17 6985

BCLllA-5430 + GCCAACCUCCACGGGAU 17 6986

BCLllA-5431 + AUUAUUAUUACUAUUAU 17 6987

BCLllA-5432 - CUCUAAUCCCCACGCCU 17 6988

BCLllA-5433 + AAUGGCUUCAAGAGGCU 17 6989

BCLllA-5434 + GUACAUGUGUAGCUGCU 17 6990

BCLllA-5435 - ACCAGACCACGGCCCGU 17 6991

BCLllA-5436 + GCACUCAUCCCAGGCGU 17 6992

BCLllA-5437 + AGAGGCUCGGCUGUGGU 17 6993

BCLllA-5438 - CAGAUGAACUUCCCAUU 17 6994

BCLllA-5439 + U UAUUAUUACUAUUAU U 17 6995 BCLllA-5440 - CCAGACCACGGCCCGUU 17 6996

BCLllA-5441 + UGCUAUGUGUUCCUGU U 17 6997

BCLllA-5442 + GCUAUGUGUUCCUGUU U 17 6998

BCLllA-5443 - AACCCCAGCACU UAAGCAAA 20 6999

BCLllA-5444 + AAAAUAAGAAUGUCCCCCAA 20 7000

BCLllA-5445 - C ACAA ACG G AAAC AAU G CAA 20 7001

BCLllA-5446 + UGGUUCAUCAUCUGUAAGAA 20 7002

BCLllA-5447 - GCCCGUUGGGAGCUCCAGAA 20 7003

BCLllA-5448 - UCCUCCCCUCGUUCUGCACA 20 7004

BCLllA-5449 - ACAGAUGAUGAACCAGACCA 20 7005

BCLllA-5450 + GACCUGGAUGCCAACCUCCA 20 7006

BCLllA-5451 - U AG C AG G U AAA U G AG A AG C A 20 7007

BCLllA-5452 - AGUGCAGAAUAUGCCCCGCA 20 7008

BCLllA-5453 - GGCCCGUUGGGAGCUCCAGA 20 7009

BCLllA-5454 + AUCUCGAUUGGUGAAGGGGA 20 7010

BCLllA-5455 - AGAUAAACUUCUGCACUGGA 20 7011

BCLllA-5456 + UUUUUCAUCUCGAUUGGUGA 20 7012

BCLllA-5457 - UAGAGGAAUUUGCCCCAAAC 20 7013

BCLllA-5458 - ACCCCAGCACUUAAGCAAAC 20 7014

BCLllA-5459 + CCCCU UCUGGAGCUCCCAAC 20 7015

BCLllA-5460 + GU UCAUCUGGCACUGCCCAC 20 7016

BCLllA-5461 + ACCUGGAUGCCAACCUCCAC 20 7017

BCLllA-5462 + GCAUAUUCUGCACUCAUCCC 20 7018

BCLllA-5463 - CCCAAACAGGAACACAUAGC 20 7019

BCLllA-5464 - GAGUGCAGAAUAUGCCCCGC 20 7020

BCLllA-5465 + GACAUGGUGGGCUGCGGGGC 20 7021

BCLllA-5466 + UCAACUUACAAAUACCCUGC 20 7022

BCLllA-5467 + AGUUGUACAUGUGUAGCUGC 20 7023

BCLllA-5468 + GGCGAGACAUGGUGGGCUGC 20 7024

BCLllA-5469 - UUGGUGUUGUAU UAUUUUGC 20 7025

BCLllA-5470 + GAUAAACAAUCGUCAUCCUC 20 7026

BCLllA-5471 + AGGAGGUCAUGAUCCCCUUC 20 7027

BCLllA-5472 + UCUGUAAGAAUGGCUUCAAG 20 7028

BCLllA-5473 - CCCGUUGGGAGCUCCAGAAG 20 7029

BCLllA-5474 - UGGCAUCCAGGUCACGCCAG 20 7030

BCLllA-5475 + CCACAG CU U U U U CU AAG CAG 20 7031

BCLllA-5476 + AGCUCCAUGUGCAGAACGAG 20 7032

BCLllA-5477 + GUGCAGAACGAGGGGAGGAG 20 7033

BCLllA-5478 - GAUAAACUUCUGCACUGGAG 20 7034

BCLllA-5479 + CUGGAGCUCCCAACGGGCCG 20 7035

BCLllA-5480 + UUCUGCACUCAUCCCAGGCG 20 7036

BCLllA-5481 + CAACUUACAAAUACCCUGCG 20 7037 BCLllA-5482 + UCGAUUGGUGAAGGGGAAGG 20 7038

BCLllA-5483 + GGCACUGCCCACAGGUGAGG 20 7039

BCLllA-5484 + UGCGGGGCGGGCGGCGGCGG 20 7040

BCLllA-5485 + GGCUGCGGGGCGGGCGGCGG 20 7041

BCLllA-5486 + GUGGGCUGCGGGGCGGGCGG 20 7042

BCLllA-5487 + AUGGUGGGCUGCGGGGCGGG 20 7043

BCLllA-5488 + UCCAUGUGCAGAACGAGGGG 20 7044

BCLllA-5489 + AGACAUGGUGGGCUGCGGGG 20 7045

BCLllA-5490 + U UGCUUGCGGCGAGACAUGG 20 7046

BCLllA-5491 - AAAAGCAUCCAAUCCCGUGG 20 7047

BCLllA-5492 - CCAGAUGAACUUCCCAUUGG 20 7048

BCLllA-5493 - GAUCAUGACCUCCUCACCUG 20 7049

BCLllA-5494 + CUCAACUUACAAAUACCCUG 20 7050

BCLllA-5495 - CCUCUGCUUAGAAAAAGCUG 20 7051

BCLllA-5496 + GGCU UCAAGAGGCUCGGCUG 20 7052

BCLllA-5497 + UCCCGUU UGCUUAAGUGCUG 20 7053

BCLllA-5498 + UCUGGCACUGCCCACAGGUG 20 7054

BCLllA-5499 - GCCAGAUGAACUUCCCAUUG 20 7055

BCLllA-5500 + GCUGGGGUUUGCCUUGCUUG 20 7056

BCLllA-5501 + CUGCUAUGUGUUCCUGUUUG 20 7057

BCLllA-5502 + AAAUAAGAAUGUCCCCCAAU 20 7058

BCLllA-5503 - GUGCCAGAUGAACUUCCCAU 20 7059

BCLllA-5504 + GAUGCUUUUU UCAUCUCGAU 20 7060

BCLllA-5505 + GAUGCCAACCUCCACGGGAU 20 7061

BCLllA-5506 - GAGCUCUAAUCCCCACGCCU 20 7062

BCLllA-5507 + AAGAAUGGCUUCAAGAGGCU 20 7063

BCLllA-5508 + GU UGUACAUGUGUAGCUGCU 20 7064

BCLllA-5509 + U UCCCGUUUGCU UAAGUGCU 20 7065

BCLllA-5510 + UCUGCACUCAUCCCAGGCGU 20 7066

BCLllA-5511 - UGCCAGAUGAACUUCCCAUU 20 7067

BCLllA-5512 - G AACCAG ACCACGG CCCG U U 20 7068

BCLllA-5513 + ACCUGCUAUGUGUUCCUGUU 20 7069

BCLllA-5514 + CCUGCUAUGUGUUCCUGUUU 20 7070

Table 15C provides exemplary targeting domains for knocking out the BCL11A gene selected according to the third tier parameters. The targeting domains fall in the coding sequence of the gene, downstream of the first 500bp of coding sequence (e.g., anywhere from +500 (relative to the start codon) to the stop codon of the gene). It is contemplated herein that in an embodiment the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. pyogenes Cas9 molecule that generates a double stranded break (Cas9 nuclease) or a single- stranded break (Cas9 nickase).

Table 15C

BCLllA-5548 - CUGCCCGACGUCAUGCA 17 7106

BCLllA-5549 + CUCGCUGAAGUGCUGCA 17 7107

BCLllA-5550 - AG CCA U U CACC AG U G CA 17 7108

BCLllA-5551 - CACG CAC AG AACAC U C A 17 7109

BCLllA-5552 + GUCGGACUUGACCGUCA 17 7110

BCLllA-5553 + ACCAACCCGCGGGGUCA 17 7111

BCLllA-5554 - AGGCCCAGCUCAAAAGA 17 7112

BCLllA-5555 - GCUUCCGGCCUGGCAGA 17 7113

BCLllA-5556 - CCUGGGGGCGGAAGAGA 17 7114

BCLllA-5557 + CUUGAUGCGCUUAGAGA 17 7115

BCLllA-5558 - GCUGACGGAGAGCGAGA 17 7116

BCLllA-5559 - GCGCAUCAAGCUCGAGA 17 7117

BCLllA-5560 - UCGGACCGCAUAGACGA 17 7118

BCLllA-5561 - ACGGUCAAGUCCGACGA 17 7119

BCLllA-5562 - CACCUGGCCGAGGCCGA 17 7120

BCLllA-5563 + GUCUCCGAAGCUAAGGA 17 7121

BCLllA-5564 + GGGGGGCGUCGCCAGGA 17 7122

BCLllA-5565 + AGGUUGGAGACAGAGGA 17 7123

BCLllA-5566 + GGGCGGAUUGCAGAGGA 17 7124

BCLllA-5567 + GGGGCUGGGAGGGAGGA 17 7125

BCLllA-5568 - CCGGGGAGCUGGACGGA 17 7126

BCLllA-5569 - GUGUGGCAGUUUUCGGA 17 7127

BCLllA-5570 + GGAUUGCAGAGGAGGGA 17 7128

BCLllA-5571 + UUGACCGGGGGCUGGGA 17 7129

BCLllA-5572 + UGGAGAGGUGGCUGGGA 17 7130

BCLllA-5573 - CCGCCCGGGGAGCUGGA 17 7131

BCLllA-5574 - GCGGCACGGGAAGUGGA 17 7132

BCLllA-5575 + GCCCAGGACCUGGUGGA 17 7133

BCLllA-5576 - CAAAUCGUCCCCCAUGA 17 7134

BCLllA-5577 + UCUGCACCUAGUCCUGA 17 7135

BCLllA-5578 - GGAGGAGGAGGAGCUGA 17 7136

BCLllA-5579 + CAAAGGCACUCGGGUGA 17 7137

BCLllA-5580 + GGCCCGGACCACUAAUA 17 7138

BCLllA-5581 + GCAGUAACCUUUGCAUA 17 7139

BCLllA-5582 - AGCGAGAGGGUGGACUA 17 7140

BCLllA-5583 + UGGAGUCUCCGAAGCUA 17 7141

BCLllA-5584 - GUUGAAUCCAAUGGCUA 17 7142

BCLllA-5585 + CACAGGUUGCACUUGUA 17 7143

BCLllA-5586 + AAUUUUCUCAGAACU UA 17 7144

BCLllA-5587 + UCGGUGGUGGACUAAAC 17 7145

BCLllA-5588 - ACCUGAUCCCGGAGAAC 17 7146

BCLllA-5589 - AGCACUCCUCGGAGAAC 17 7147 BCLllA-2979 - CACCGGCGCAGCCACAC 17 7148

BCLllA-2916 - CCGAGGCCGAGGGCCAC 17 7149

BCLllA-5590 + UGCACGCGUGGUCGCAC 17 7150

BCLllA-5591 - UCGGGGCGCAGCGGCAC 17 7151

BCLllA-5592 + CAAGAGAAACCAUGCAC 17 7152

BCLllA-5593 - GCAACCUGGUGGUGCAC 17 7153

BCLllA-5594 + GCAGCAGCUUU UUGGAC 17 7154

BCLllA-5595 + CAUGACUUGGACUUGAC 17 7155

BCLllA-5596 - ACCCGAGUGCCU UUGAC 17 7156

BCLllA-5597 - CAAAUUUCAGAGCAACC 17 7157

BCLllA-5598 - GCCAGCUCCCCGGAACC 17 7158

BCLllA-5599 + UGCGCCGGUGCACCACC 17 7159

BCLllA-5600 - GCAUAAGCGCGGCCACC 17 7160

BCLllA-5601 - CAGCGAGGCCUUCCACC 17 7161

BCLllA-5602 + GCUUCUCGCCCAGGACC 17 7162

BCLllA-5603 + AUGACUUGGACUUGACC 17 7163

BCLllA-5604 - AACCUGCUAAGAAUACC 17 7164

BCLllA-5605 + AAGGGCGGCUUGCUACC 17 7165

BCLllA-5606 - CGACCACGCGUGCACCC 17 7166

BCLllA-5607 - GAAAAU U UG AAG CCCCC 17 7167

BCLllA-5608 + CCAUCUCU UCCGCCCCC 17 7168

BCLllA-5609 - UCCUCCCUCCCAGCCCC 17 7169

BCLllA-5610 - GGAGUUCGACCUGCCCC 17 7170

BCLllA-5611 + CCUCCGUCCAGCUCCCC 17 7171

BCLllA-5612 - GGCCGCGGCUGCUCCCC 17 7172

BCLllA-5613 - AGCCCACCGCUGUCCCC 17 7173

BCLllA-5614 - GCUUCUCCACACCGCCC 17 7174

BCLllA-5615 + CCGAGGCCGACUCGCCC 17 7175

BCLllA-5616 + GCU UAUGCUUCUCGCCC 17 7176

BCLllA-5617 - AUUAGUGGUCCGGGCCC 17 7177

BCLllA-5618 - GGCGGAAGAGAUGGCCC 17 7178

BCLllA-5619 + U UGAGCUGGGCCUGCCC 17 7179

BCLllA-5620 - CUCCACCGCCAGCUCCC 17 7180

BCLllA-5621 + CCCUCCGUCCAGCUCCC 17 7181

BCLllA-5622 - UGGCCGCGGCUGCUCCC 17 7182

BCLllA-5623 - CUGCAACCAUUCCAGCC 17 7183

BCLllA-5624 - CGGCUUCGGGCUGAGCC 17 7184

BCLllA-5625 - CGCUUCUCCACACCGCC 17 7185

BCLllA-5626 - CCACCGCAUAGAGCGCC 17 7186

BCLllA-5627 + CCCGAGGCCGACUCGCC 17 7187

BCLllA-5628 + GGAGGGGGGGCGUCGCC 17 7188

BCLllA-5629 + AUAGGGCUGGGCCGGCC 17 7189 BCLllA-5630 - GAGAGAGGCUUCCGGCC 17 7190

BCLllA-5631 + UGUUGGGCAUCGCGGCC 17 7191

BCLllA-5632 + GGCCCUCGGCCUCGGCC 17 7192

BCLllA-5633 + CUGGGCCUGCCCGGGCC 17 7193

BCLllA-5634 - UAUUAGUGGUCCGGGCC 17 7194

BCLllA-5635 + GCU UCAGCUUGCUGGCC 17 7195

BCLllA-5636 + UCGGGUGAUGGGUGGCC 17 7196

BCLllA-5637 + UUUGAGCUGGGCCUGCC 17 7197

BCLllA-5638 + GGGAUCUUUGAGCUGCC 17 7198

BCLllA-5639 + GAAAGCGCCCUUCUGCC 17 7199

BCLllA-5640 + ACCAAGUCGCUGGUGCC 17 7200

BCLllA-5641 + UCUCUCGAUACUGAUCC 17 7201

BCLllA-5642 - CGACCCCAACCUGAUCC 17 7202

BCLllA-5643 + GGUGGCGCGCCGCCUCC 17 7203

BCLllA-5644 - CCGGCUACGCGGCCUCC 17 7204

BCLllA-5645 + CCUCGUCCCCGUUCUCC 17 7205

BCLllA-5646 - GGCCUUCCACCAGGUCC 17 7206

BCLllA-5647 - CCCCAUAU UAGUGGUCC 17 7207

BCLllA-5648 - UAGCAAGCCGCCCU UCC 17 7208

BCLllA-5649 + CGCUGGUGCCGGGUUCC 17 7209

BCLllA-5650 - UAGGAGACUUAGAGAGC 17 7210

BCLllA-5651 + GAAGGGGCUCAGCGAGC 17 7211

BCLllA-2886 - CACACCGCCCGGGGAGC 17 7212

BCLllA-5652 + GCCGGGU UCCGGGGAGC 17 7213

BCLllA-5653 + UCUGCCCUCU UUUGAGC 17 7214

BCLllA-5654 + CCUGGAGGCCGCGUAGC 17 7215

BCLllA-5655 + AUCCUGGUAUUCUUAGC 17 7216

BCLllA-5656 + AAGGGAUACCAACCCGC 17 7217

BCLllA-5657 - AAGUCCCCUGACCCCGC 17 7218

BCLllA-5658 + CGCCCGUGUGGCUGCGC 17 7219

BCLllA-5659 + UAUGCGGUCCGACUCGC 17 7220

BCLllA-5660 - CCACGAGAACAGCUCGC 17 7221

BCLllA-5661 - UACUCGCAGUGGCUCGC 17 7222

BCLllA-5662 + GCUGCCCACCAAGUCGC 17 7223

BCLllA-5663 - CACCGCUGUCCCCAGGC 17 7224

BCLllA-5664 + GCGCCCUUCUGCCAGGC 17 7225

BCLllA-5665 + GUGUUGGGCAUCGCGGC 17 7226

BCLllA-5666 + UAACCUUUGCAUAGGGC 17 7227

BCLllA-5667 - GUGGUCCGGGCCCGGGC 17 7228

BCLllA-5668 + CCUGCAUGACGUCGGGC 17 7229

BCLllA-5669 + UGGACUUGACCGGGGGC 17 7230

BCLllA-5670 + GCAUCGCGGCCGGGGGC 17 7231 BCLllA-5671 + U UUGCAUAGGGCUGGGC 17 7232

BCLllA-5672 + CUAGAGAAAUCCAUGGC 17 7233

BCLllA-5673 + GCGGCUUGCUACCUGGC 17 7234

BCLllA-5674 - AGACUUAGAGAGCUGGC 17 7235

BCLllA-5675 + UCCCAUGGAGAGGUGGC 17 7236

BCLllA-5676 - GACGAAGACUCGGUGGC 17 7237

BCLllA-5677 - CCUGCCCGACGUCAUGC 17 7238

BCLllA-5394 + UGUACAUGUGUAGCUGC 17 7239

BCLllA-5678 + GGACUUGAGCGCGCUGC 17 7240

BCLllA-5679 - GUCCAAAAAGCUGCUGC 17 7241

BCLllA-5680 + CACCAAGUCGCUGGUGC 17 7242

BCLllA-5681 + GUGGCGCU UCAGCUUGC 17 7243

BCLllA-5682 + CCCCGUUCUCCGGGAUC 17 7244

BCLllA-5683 + CCCUGUCAAAGGCACUC 17 7245

BCLllA-5684 - CCGGGCGAGUCGGCCUC 17 7246

BCLllA-5685 - CUGGACGGAGGGAUCUC 17 7247

BCLllA-5686 + ACACAUCUUGAGCUCUC 17 7248

BCLllA-5687 + UCCUCGUCCCCGUUCUC 17 7249

BCLllA-5688 + AUGCCCUGCAUGACGUC 17 7250

BCLllA-5689 + UACCAACCCGCGGGGUC 17 7251

BCLllA-5690 - GCCCCAUAU UAGUGGUC 17 7252

BCLllA-5691 + GGCAAAAGGCGAUUGUC 17 7253

BCLllA-5692 - CGGGU UGGUAUCCCUUC 17 7254

BCLllA-5693 - GUAUCGAGAGAGGCUUC 17 7255

BCLllA-5694 - GGGUGGACUACGGCUUC 17 7256

BCLllA-5695 + UCGCUGGUGCCGGGUUC 17 7257

BCLllA-5696 - CAGGCCCAGCUCAAAAG 17 7258

BCLllA-5697 + GUGAAGAACCUAGAAAG 17 7259

BCLllA-5698 + U UCUUAGCAGGU UAAAG 17 7260

BCLllA-3087 - CGAGGAAGAGGAAGAAG 17 7261

BCLllA-5699 + UGAUGCGCUUAGAGAAG 17 7262

BCLllA-3083 - GGAGGACGACGAGGAAG 17 7263

BCLllA-3089 - GGAAGAAGAGGAGGAAG 17 7264

BCLllA-3075 - CGGGGACGAGGAGGAAG 17 7265

BCLllA-2876 - CGCAGCGGCACGGGAAG 17 7266

BCLllA-5700 + GGUGGUGGACUAAACAG 17 7267

BCLllA-5701 + A A AG AG G U UGG AG ACAG 17 7268

BCLllA-5702 + GGCCGGCCUGGGGACAG 17 7269

BCLllA-5703 - AAAUUUGAAGCCCCCAG 17 7270

BCLllA-5704 - GGGAUCUCGGGGCGCAG 17 7271

BCLllA-5705 - AGAACGUGUACUCGCAG 17 7272

BCLllA-5706 + GGAGGGGCGGAUUGCAG 17 7273 BCLllA-5707 + CCAACCCGCGGGGUCAG 17 7274

BCLllA-5708 - AGGAUCAGUAUCGAGAG 17 7275

BCLllA-5709 - AGCUGACGGAGAGCGAG 17 7276

BCLllA-5710 + GGUUGGAGACAGAGGAG 17 7277

BCLllA-5711 + GGGCUGGGAGGGAGGAG 17 7278

BCLllA-5712 + GAUUGCAGAGGAGGGAG 17 7279

BCLllA-5713 + ACUAAACAGGGGGGGAG 17 7280

BCLllA-5714 + AUAUGAAUCCCAUGGAG 17 7281

BCLllA-5715 - AGCACGCCCCAUAUUAG 17 7282

BCLllA-5716 - CCUGAUCCCGGAGAACG 17 7283

BCLllA-3081 - GGAAGAGGAGGACGACG 17 7284

BCLllA-5717 + CGAGGAGUGCUCCGACG 17 7285

BCLllA-2837 - CCCGGAGAACGGGGACG 17 7286

BCLllA-5718 - GUGGCUCGCCGGCUACG 17 7287

BCLllA-5719 + UGACUUGGACUUGACCG 17 7288

BCLllA-5720 + GAAGGGAUACCAACCCG 17 7289

BCLllA-5721 - GAAGUCCCCUGACCCCG 17 7290

BCLllA-5722 + U UUGGACAGGCCCCCCG 17 7291

BCLllA-5723 - CUUCUCCACACCGCCCG 17 7292

BCLllA-5724 + CGAGGCCGACUCGCCCG 17 7293

BCLllA-2946 + CGCCCGGGGAGCAGCCG 17 7294

BCLllA-5725 - CCACCUGGCCGAGGCCG 17 7295

BCLllA-5726 + GUUGGGCAUCGCGGCCG 17 7296

BCLllA-5727 - GGCACUGUUAAUGGCCG 17 7297

BCLllA-5728 - GCGCGGCCACCUGGCCG 17 7298

BCLllA-5729 + CAAACUCCCGUUCUCCG 17 7299

BCLllA-5730 - CAGCGCGCUCAAGUCCG 17 7300

BCLllA-5731 + GCUGGUGCCGGGUUCCG 17 7301

BCLllA-5732 - GGCGAGAAGCAUAAGCG 17 7302

BCLllA-5733 - CAUGCAGCACU UCAGCG 17 7303

BCLllA-5734 + UGGCCUGGGUGCACGCG 17 7304

BCLllA-5735 + AGGGAUACCAACCCGCG 17 7305

BCLllA-5736 - CACGAGAACAGCUCGCG 17 7306

BCLllA-5737 + UGACGUCGGGCAGGGCG 17 7307

BCLllA-5738 - GAACAGCUCGCGGGGCG 17 7308

BCLllA-5739 - GGGCGCGGUCGUGGGCG 17 7309

BCLllA-5740 + CUCCGUGUUGGGCAUCG 17 7310

BCLllA-5741 - CGGGCGAGUCGGCCUCG 17 7311

BCLllA-5742 - ACCACGAGAACAGCUCG 17 7312

BCLllA-5743 - UGGACGGAGGGAUCUCG 17 7313

BCLllA-5744 + CCCGCGAGCUGUUCUCG 17 7314

BCLllA-5745 - CUCGCGGGGCGCGGUCG 17 7315 BCLllA-5746 + GUGGUGGACUAAACAGG 17 7316

BCLllA-5747 + CCUCGGCCUCGGCCAGG 17 7317

BCLllA-3090 - GGAAGAGGAAGAAGAGG 17 7318

BCLllA-3091 - AGAAGAGGAGGAAGAGG 17 7319

BCLllA-3088 - GGACGAGGAGGAAGAGG 17 7320

BCLllA-5748 + GAGGUUGGAGACAGAGG 17 7321

BCLllA-5749 + GGGGCGGAUUGCAGAGG 17 7322

BCLllA-5750 + UGAAUCCCAUGGAGAGG 17 7323

BCLllA-5751 + GGAGUGCUCCGACGAGG 17 7324

BCLllA-3066 - GGAGAACGGGGACGAGG 17 7325

BCLllA-3092 - AGAGGAGGAAGAGGAGG 17 7326

BCLllA-5752 + GU UGGAGACAGAGGAGG 17 7327

BCLllA-3093 - GGAGGAAGAGGAGGAGG 17 7328

BCLllA-5753 + AUUGCAGAGGAGGGAGG 17 7329

BCLllA-5754 + GGGGGCUGGGAGGGAGG 17 7330

BCLllA-5755 - CGGGCUGAGCCUGGAGG 17 7331

BCLllA-5756 - CCCGGGGAGCUGGACGG 17 7332

BCLllA-5757 + GACUUGGACUUGACCGG 17 7333

BCLllA-5758 + U UGGGCAUCGCGGCCGG 17 7334

BCLllA-5759 + CGGCCUGGGGACAGCGG 17 7335

BCLllA-5760 + UUCCGGGGAGCUGGCGG 17 7336

BCLllA-5761 + CCAGGCGCUCUAUGCGG 17 7337

BCLllA-5762 - UUGCGACGAAGACUCGG 17 7338

BCLllA-5763 - GGGCGAGUCGGCCUCGG 17 7339

BCLllA-5764 + UCCAAGUGAUGUCUCGG 17 7340

BCLllA-5765 + GGCGUCGCCAGGAAGGG 17 7341

BCLllA-5766 + UGGUGGACUAAACAGGG 17 7342

BCLllA-3076 - GACGGAGAGCGAGAGGG 17 7343

BCLllA-5767 + CGGAUUGCAGAGGAGGG 17 7344

BCLllA-5768 + UUGCAGAGGAGGGAGGG 17 7345

BCLllA-5769 + ACCGGGGGCUGGGAGGG 17 7346

BCLllA-5770 + CCGUCCAGCUCCCCGGG 17 7347

BCLllA-5771 + GAGAAAUCCAUGGCGGG 17 7348

BCLllA-5772 - GGCGAGUCGGCCUCGGG 17 7349

BCLllA-5773 + GGUGGACUAAACAGGGG 17 7350

BCLllA-5774 - UUUGAAGCCCCCAGGGG 17 7351

BCLllA-5775 + CUGGGAGGGAGGAGGGG 17 7352

BCLllA-5776 + UGCAGAGGAGGGAGGGG 17 7353

BCLllA-5777 - CAUAGAGCGCCUGGGGG 17 7354

BCLllA-5778 - AGCCCCCAGGGGUGGGG 17 7355

BCLllA-5779 + GGCACUCGGGUGAUGGG 17 7356

BCLllA-5780 + CUUGACCGGGGGCUGGG 17 7357 BCLllA-5781 + AACAGGGGGGGAGUGGG 17 7358

BCLllA-5782 + GGUACUACGCCGAAUGG 17 7359

BCLllA-5783 + CCUAGAGAAAUCCAUGG 17 7360

BCLllA-5784 + GGACUUGACCGUCAUGG 17 7361

BCLllA-5785 - AUUUCAGAGCAACCUGG 17 7362

BCLllA-5786 + UCUCGCCCAGGACCUGG 17 7363

BCLllA-5787 - CUUCGGGCUGAGCCUGG 17 7364

BCLllA-5788 - CCGCAUAGAGCGCCUGG 17 7365

BCLllA-5789 + AUCUUUGAGCUGCCUGG 17 7366

BCLllA-5790 + GGGUUCCGGGGAGCUGG 17 7367

BCLllA-5791 - AGCGGCACGGGAAGUGG 17 7368

BCLllA-5792 - CGCGCUCAAGUCCGUGG 17 7369

BCLllA-5793 + GCGAGCUGUUCUCGUGG 17 7370

BCLllA-5794 + GGCGCUCUAUGCGGUGG 17 7371

BCLllA-5795 + AAGUGAUGUCUCGGUGG 17 7372

BCLllA-5796 - CGGCACCAGCGACU UGG 17 7373

BCLllA-5797 + GGGUACUACGCCGAAUG 17 7374

BCLllA-5798 + CGGACUUGACCGUCAUG 17 7375

BCLllA-5799 + GCAUGUGCGUCUUCAUG 17 7376

BCLllA-5800 + CCCGGACCACUAAUAUG 17 7377

BCLllA-5801 + CCCCCAGGCGCUCUAUG 17 7378

BCLllA-5802 + CAGUGCCAUCGUCUAUG 17 7379

BCLllA-5803 - GACACUUGUGAGUACUG 17 7380

BCLllA-5804 + CGUCGCAAGUGUCCCUG 17 7381

BCLllA-5805 - ACCGCAUAGAGCGCCUG 17 7382

BCLllA-5806 + AGGGCUGGGCCGGCCUG 17 7383

BCLllA-5807 + AGGGGCUCAGCGAGCUG 17 7384

BCLllA-5808 - CCUUUGACAGGGUGCUG 17 7385

BCLllA-5809 - AAGUCAUGCGAGUUCUG 17 7386

BCLllA-5810 + AGGGCUUCUCGCCCGUG 17 7387

BCLllA-5811 + CAGCUCCCCGGGCGGUG 17 7388

BCLllA-5812 + AGGCGCUCUAUGCGGUG 17 7389

BCLllA-5813 - UGAAGCCCCCAGGGGUG 17 7390

BCLllA-5814 - AGAGAGCUCAAGAUGUG 17 7391

BCLllA-5815 + UCUCCGGGAUCAGGUUG 17 7392

BCLllA-5816 + UGGGUACUACGCCGAAU 17 7393

BCLllA-5817 + GGAGGCUCCAUAGCCAU 17 7394

BCLllA-5818 - CCCAGCCACCUCUCCAU 17 7395

BCLllA-5819 + UGCAGUAACCUUUGCAU 17 7396

BCLllA-5820 + UCGGACUUGACCGUCAU 17 7397

BCLllA-5821 + AAAGGCACUCGGGUGAU 17 7398

BCLllA-5822 + GCCCGGACCACUAAUAU 17 7399 BCLllA-5823 + GUUCUCGCUCUUGAACU 17 7400

BCLllA-5824 + ACCCUGUCAAAGGCACU 17 7401

BCLllA-5825 - ACCACCGAGACAUCACU 17 7402

BCLllA-5826 - CACUUGCGACGAAGACU 17 7403

BCLllA-5827 - ACCCGGCACCAGCGACU 17 7404

BCLllA-5828 - GGUAUCCCUUCAGGACU 17 7405

BCLllA-5829 + GCAGAACUCGCAUGACU 17 7406

BCLllA-5830 + AGUGUCCCUGUGGCCCU 17 7407

BCLllA-5831 - CACCGCAUAGAGCGCCU 17 7408

BCLllA-5832 + UAGGGCUGGGCCGGCCU 17 7409

BCLllA-5833 + CCUGUGGCCCUCGGCCU 17 7410

BCLllA-5834 - CCCGGGCGAGUCGGCCU 17 7411

BCLllA-5835 + CUUCAGCU UGCUGGCCU 17 7412

BCLllA-5836 - CUCGUCGGAGCACUCCU 17 7413

BCLllA-5837 - GCCUUCCACCAGGUCCU 17 7414

BCLllA-5838 + AAGGGGCUCAGCGAGCU 17 7415

BCLllA-5839 + CUGCCCUCUU UUGAGCU 17 7416

BCLllA-5840 + AACCUUUGCAUAGGGCU 17 7417

BCLllA-5841 + GGACUUGACCGGGGGCU 17 7418

BCLllA-5842 + CCCAUGGAGAGGUGGCU 17 7419

BCLllA-5434 + GUACAUGUGUAGCUGCU 17 7420

BCLllA-5843 - UCCAAAAAGCUGCUGCU 17 7421

BCLllA-5844 - GCUGGACGGAGGGAUCU 17 7422

BCLllA-5845 + CACAUCUUGAGCUCUCU 17 7423

BCLllA-5846 - CCGCCAUGGAUUUCUCU 17 7424

BCLllA-5847 + GGGUCCAAGUGAUGUCU 17 7425

BCLllA-5848 - GUCUCCAACCUCUUUCU 17 7426

BCLllA-5849 - CUCGGUGGCCGGCGAGU 17 7427

BCLllA-5850 - CUGCUCCCCGGGCGAGU 17 7428

BCLllA-5851 + CUAAACAGGGGGGGAGU 17 7429

BCLllA-5852 + CAUGCCCUGCAUGACGU 17 7430

BCLllA-5853 - GGCGCGGUCGUGGGCGU 17 7431

BCLllA-5854 - GCCUUU UGCCUCCUCGU 17 7432

BCLllA-5855 + GGUGGAGAGACCGUCGU 17 7433

BCLllA-5856 - UCGCGGGGCGCGGUCGU 17 7434

BCLllA-5857 + GU UCUCCGGGAUCAGGU 17 7435

BCLllA-5858 + AGAACCUAGAAAGAGGU 17 7436

BCLllA-5859 + GGCCUGGGGACAGCGGU 17 7437

BCLllA-5860 + CAGGCGCUCUAUGCGGU 17 7438

BCLllA-5861 - CCCCUGACCCCGCGGGU 17 7439

BCLllA-5862 - UUGAAGCCCCCAGGGGU 17 7440

BCLllA-5863 - GGCACCAGCGACUUGGU 17 7441 BCLllA-5864 - ACACUUGUGAGUACUGU 17 7442

BCLllA-5865 + GUACACGUUCUCCGUGU 17 7443

BCLllA-5866 + GCACAGGUUGCACUUGU 17 7444

BCLllA-5867 - CUUCACACACCCCCAU U 17 7445

BCLllA-5868 - GAUCCCUUCCUUAGCUU 17 7446

BCLllA-5869 - AGGGUGGACUACGGCUU 17 7447

BCLllA-5870 + U UCUCCGGGAUCAGGUU 17 7448

BCLllA-5871 + UACACGUUCUCCGUGUU 17 7449

BCLllA-5872 + GCCCAGCAGCAGCU UUU 17 7450

BCLllA-5873 - AGAUGUGUGGCAGUUU U 17 7451

BCLllA-5874 + UGCUCCGACGAGGAGGCAAA 20 7452

BCLllA-5875 + GGUAUUCUUAGCAGGU UAAA 20 7453

BCLllA-5876 - GGUGCUGCGGUUGAAUCCAA 20 7454

BCLllA-5877 - GCCGGCCCAGCCCUAUGCAA 20 7455

BCLllA-5878 + CAACCGCAGCACCCUGUCAA 20 7456

BCLllA-5879 - AGGCUUCCGGCCUGGCAGAA 20 7457

BCLllA-5880 + AGCUUGAUGCGCUUAGAGAA 20 7458

BCLllA-5881 - CCCAACCUGAUCCCGGAGAA 20 7459

BCLllA-5882 - UCGGAGCACUCCUCGGAGAA 20 7460

BCLllA-5883 + UCUCUGGGUACUACGCCGAA 20 7461

BCLllA-5884 + GAGUCUCCGAAGCUAAGGAA 20 7462

BCLllA-5885 + AGGGGGGGCGUCGCCAGGAA 20 7463

BCLllA-5886 + GGCU UGCUACCUGGCUGGAA 20 7464

BCLllA-5887 + AUUCUGCACCUAGUCCUGAA 20 7465

BCLllA-5888 + AGAAACCAUGCACUGGUGAA 20 7466

BCLllA-5889 + CAAAUUUUCUCAGAACUUAA 20 7467

BCLllA-5890 + UGGUAUUCUUAGCAGGUUAA 20 7468

BCLllA-5891 - AUAGACGAUGGCACUGUUAA 20 7469

BCLllA-5892 + UCUCGGUGGUGGACUAAACA 20 7470

BCLllA-5893 - CCCGGCCGCGAUGCCCAACA 20 7471

BCLllA-5894 - AUCUACUUAGAAAGCGAACA 20 7472

BCLllA-5895 - GGUGCACCGGCGCAGCCACA 20 7473

BCLllA-3377 - GGCCGAGGCCGAGGGCCACA 20 7474

BCLllA-5896 - UCACCCGAGUGCCU UUGACA 20 7475

BCLllA-5897 + GCUCUUGAACUUGGCCACCA 20 7476

BCLllA-5898 - GAGAAAAUUUGAAGCCCCCA 20 7477

BCLllA-5899 + UGUCUGCAAUAUGAAUCCCA 20 7478

BCLllA-5900 - GGCUAUGGAGCCUCCCGCCA 20 7479

BCLllA-5901 + ACUCGGGUGAUGGGUGGCCA 20 7480

BCLllA-5902 + AAGUCUCCUAGAGAAAUCCA 20 7481

BCLllA-5903 - CCUUCCCAGCCACCUCUCCA 20 7482

BCLllA-5904 - GAUCUCGGGGCGCAGCGGCA 20 7483 BCLllA-5905 - GCCCGACGUCAUGCAGGGCA 20 7484

BCLllA-5906 + GCCCUGCAUGACGUCGGGCA 20 7485

BCLllA-5907 - GGAGACUUAGAGAGCUGGCA 20 7486

BCLllA-5908 - GCCCUGCCCGACGUCAUGCA 20 7487

BCLllA-5909 + GGCCUCGCUGAAGUGCUGCA 20 7488

BCLllA-5910 - AACAGCCAUUCACCAGUGCA 20 7489

BCLllA-5911 - CAACACG CAC AG AAC AC U CA 20 7490

BCLllA-5912 + GUCGUCGGACUUGACCGUCA 20 7491

BCLllA-5913 + GAUACCAACCCGCGGGGUCA 20 7492

BCLllA-5914 - GGCAGGCCCAGCUCAAAAGA 20 7493

BCLllA-5915 - GAGGCUUCCGGCCUGGCAGA 20 7494

BCLllA-5916 - GCGCCUGGGGGCGGAAGAGA 20 7495

BCLllA-5917 + GAGCUUGAUGCGCUUAGAGA 20 7496

BCLllA-5918 - GGAGCUGACGGAGAGCGAGA 20 7497

BCLllA-5919 - UAAGCGCAUCAAGCUCGAGA 20 7498

BCLllA-5920 - GAGUCGGACCGCAUAGACGA 20 7499

BCLllA-5921 - AUGACGGUCAAGUCCGACGA 20 7500

BCLllA-5922 - GGCCACCUGGCCGAGGCCGA 20 7501

BCLllA-5923 + GGAGUCUCCGAAGCUAAGGA 20 7502

BCLllA-5924 + GAGGGGGGGCGUCGCCAGGA 20 7503

BCLllA-5925 + AAGAGGUUGGAGACAGAGGA 20 7504

BCLllA-5926 + GAGGGGCGGAUUGCAGAGGA 20 7505

BCLllA-5927 + CCGGGGGCUGGGAGGGAGGA 20 7506

BCLllA-5928 - CGCCCGGGGAGCUGGACGGA 20 7507

BCLllA-5929 - GAUGUGUGGCAGUU UUCGGA 20 7508

BCLllA-5930 + GGCGGAUUGCAGAGGAGGGA 20 7509

BCLllA-5931 + GACUUGACCGGGGGCUGGGA 20 7510

BCLllA-5932 + CCAUGGAGAGGUGGCUGGGA 20 7511

BCLllA-5933 - ACACCGCCCGGGGAGCUGGA 20 7512

BCLllA-5934 - GCAGCGGCACGGGAAGUGGA 20 7513

BCLllA-5935 + CUCGCCCAGGACCUGGUGGA 20 7514

BCLllA-5936 - GCACAAAUCGUCCCCCAUGA 20 7515

BCLllA-5937 + CAU UCUGCACCUAGUCCUGA 20 7516

BCLllA-5938 - AGAGGAGGAGGAGGAGCUGA 20 7517

BCLllA-5939 + UGUCAAAGGCACUCGGGUGA 20 7518

BCLllA-5940 + CCGGGCCCGGACCACUAAUA 20 7519

BCLllA-5941 + GU UGCAGUAACCUUUGCAUA 20 7520

BCLllA-5942 - GAGAGCGAGAGGGUGGACUA 20 7521

BCLllA-5943 + GUCUGGAGUCUCCGAAGCUA 20 7522

BCLllA-5944 - GCGGU UGAAUCCAAUGGCUA 20 7523

BCLllA-5945 + UCGCACAGGUUGCACUUGUA 20 7524

BCLllA-5946 + UCAAAUUUUCUCAGAACUUA 20 7525 BCLllA-5947 + GUCUCGGUGGUGGACUAAAC 20 7526

BCLllA-5948 - CCAACCUGAUCCCGGAGAAC 20 7527

BCLllA-5949 - CGGAGCACUCCUCGGAGAAC 20 7528

BCLllA-5950 - GUGCACCGGCGCAGCCACAC 20 7529

BCLllA-5951 - UGGCCGAGGCCGAGGGCCAC 20 7530

BCLllA-5952 + GGGUGCACGCGUGGUCGCAC 20 7531

BCLllA-5953 - AUCUCGGGGCGCAGCGGCAC 20 7532

BCLllA-5954 + UUGCAAGAGAAACCAUGCAC 20 7533

BCLllA-5955 - AGAGCAACCUGGUGGUGCAC 20 7534

BCLllA-5956 + CCAGCAGCAGCU UUUUGGAC 20 7535

BCLllA-5957 + UCGCAUGACU UGGACU UGAC 20 7536

BCLllA-5958 - AUCACCCGAGUGCCUUUGAC 20 7537

BCLllA-5959 - GUUCAAAUUUCAGAGCAACC 20 7538

BCLllA-5960 - ACCGCCAGCUCCCCGGAACC 20 7539

BCLllA-5961 + GGCUGCGCCGGUGCACCACC 20 7540

BCLllA-5962 - GAAGCAUAAGCGCGGCCACC 20 7541

BCLllA-5963 - CUUCAGCGAGGCCUUCCACC 20 7542

BCLllA-5964 + UAUGCUUCUCGCCCAGGACC 20 7543

BCLllA-5965 + CGCAUGACUUGGACUUGACC 20 7544

BCLllA-5966 - UUUAACCUGCUAAGAAUACC 20 7545

BCLllA-5967 + AGGAAGGGCGGCUUGCUACC 20 7546

BCLllA-5968 - GUGCGACCACGCGUGCACCC 20 7547

BCLllA-5969 - UGAGAAAAUUUGAAGCCCCC 20 7548

BCLllA-5970 + GGGCCAUCUCUUCCGCCCCC 20 7549

BCLllA-5971 - CCCUCCUCCCUCCCAGCCCC 20 7550

BCLllA-5972 - GAAGGAGUUCGACCUGCCCC 20 7551

BCLllA-5973 + AUCCCUCCGUCCAGCUCCCC 20 7552

BCLllA-5974 - AAUGGCCGCGGCUGCUCCCC 20 7553

BCLllA-5975 - UCUAGCCCACCGCUGUCCCC 20 7554

BCLllA-5976 - UGCGCUUCUCCACACCGCCC 20 7555

BCLllA-5977 + CCCCCGAGGCCGACUCGCCC 20 7556

BCLllA-5978 + CGCGCUUAUGCUUCUCGCCC 20 7557

BCLllA-5979 - CAUAUUAGUGGUCCGGGCCC 20 7558

BCLllA-5980 - GGGGGCGGAAGAGAUGGCCC 20 7559

BCLllA-5981 + CUU UUGAGCUGGGCCUGCCC 20 7560

BCLllA-5982 - UCUCUCCACCGCCAGCUCCC 20 7561

BCLllA-5983 + GAUCCCUCCGUCCAGCUCCC 20 7562

BCLllA-5984 - UAAUGGCCGCGGCUGCUCCC 20 7563

BCLllA-5985 - UUACUGCAACCAUUCCAGCC 20 7564

BCLllA-5986 - CUACGGCU UCGGGCUGAGCC 20 7565

BCLllA-5987 - UUGCGCUUCUCCACACCGCC 20 7566

BCLllA-5988 - CCCCCACCGCAUAGAGCGCC 20 7567 BCLllA-5989 + CCCCCCGAGGCCGACUCGCC 20 7568

BCLllA-5990 + GAGGGAGGGGGGGCGUCGCC 20 7569

BCLllA-5991 + UGCAUAGGGCUGGGCCGGCC 20 7570

BCLllA-5992 - AUCGAGAGAGGCUUCCGGCC 20 7571

BCLllA-5993 + CCGUGU UGGGCAUCGCGGCC 20 7572

BCLllA-5994 + UGUGGCCCUCGGCCUCGGCC 20 7573

BCLllA-5995 + GAGCUGGGCCUGCCCGGGCC 20 7574

BCLllA-5996 - CCAUAUUAGUGGUCCGGGCC 20 7575

BCLllA-5997 + GGCGCUUCAGCUUGCUGGCC 20 7576

BCLllA-5998 + CACUCGGGUGAUGGGUGGCC 20 7577

BCLllA-5999 + UCUUUUGAGCUGGGCCUGCC 20 7578

BCLllA-6000 + GAAGGGAUCUUUGAGCUGCC 20 7579

BCLllA-6001 + GUGGAAAGCGCCCUUCUGCC 20 7580

BCLllA-6002 + CCCACCAAGUCGCUGGUGCC 20 7581

BCLllA-6003 + GCCUCUCUCGAUACUGAUCC 20 7582

BCLllA-6004 - GAACGACCCCAACCUGAUCC 20 7583

BCLllA-6005 + CGUGGUGGCGCGCCGCCUCC 20 7584

BCLllA-6006 - UCGCCGGCUACGCGGCCUCC 20 7585

BCLllA-6007 + CCUCCUCGUCCCCGUUCUCC 20 7586

BCLllA-6008 - CGAGGCCUUCCACCAGGUCC 20 7587

BCLllA-6009 - ACGCCCCAUAUUAGUGGUCC 20 7588

BCLllA-6010 - AGGUAGCAAGCCGCCCUUCC 20 7589

BCLllA-6011 + AGUCGCUGGUGCCGGGUUCC 20 7590

BCLllA-6012 - CUCUAGGAGACU UAGAGAGC 20 7591

BCLllA-6013 + AGAGAAGGGGCUCAGCGAGC 20 7592

BCLllA-6014 - CUCCACACCGCCCGGGGAGC 20 7593

BCLllA-6015 + GGUGCCGGGUUCCGGGGAGC 20 7594

BCLllA-6016 + GCGUCUGCCCUCU UUUGAGC 20 7595

BCLllA-6017 + CUGCCUGGAGGCCGCGUAGC 20 7596

BCLllA-6018 + CUGAUCCUGGUAUUCUUAGC 20 7597

BCLllA-6019 + CUGAAGGGAUACCAACCCGC 20 7598

BCLllA-6020 - CGGAAGUCCCCUGACCCCGC 20 7599

BCLllA-6021 + UCUCGCCCGUGUGGCUGCGC 20 7600

BCLllA-6022 + GUCUAUGCGGUCCGACUCGC 20 7601

BCLllA-6023 - CCACCACGAGAACAGCUCGC 20 7602

BCLllA-6024 - GUGUACUCGCAGUGGCUCGC 20 7603

BCLllA-6025 + GGCGCUGCCCACCAAGUCGC 20 7604

BCLllA-6026 - GCCCACCGCUGUCCCCAGGC 20 7605

BCLllA-6027 + AAAGCGCCCUUCUGCCAGGC 20 7606

BCLllA-6028 + UCCGUGUUGGGCAUCGCGGC 20 7607

BCLllA-6029 + CAGUAACCUUUGCAUAGGGC 20 7608

BCLllA-6030 - UUAGUGGUCCGGGCCCGGGC 20 7609 BCLllA-6031 + UGCCCUGCAUGACGUCGGGC 20 7610

BCLllA-6032 + ACUUGGACUUGACCGGGGGC 20 7611

BCLllA-6033 + UGGGCAUCGCGGCCGGGGGC 20 7612

BCLllA-6034 + ACCUUUGCAUAGGGCUGGGC 20 7613

BCLllA-6035 + CUCCUAGAGAAAUCCAUGGC 20 7614

BCLllA-6036 + AGGGCGGCUUGCUACCUGGC 20 7615

BCLllA-6037 - AGGAGACUUAGAGAGCUGGC 20 7616

BCLllA-6038 + GAAUCCCAUGGAGAGGUGGC 20 7617

BCLllA-6039 - UGCGACGAAGACUCGGUGGC 20 7618

BCLllA-6040 - CGCCCUGCCCGACGUCAUGC 20 7619

BCLllA-5467 + AGUUGUACAUGUGUAGCUGC 20 7620

BCLllA-6041 + CACGGACUUGAGCGCGCUGC 20 7621

BCLllA-6042 - CCUGUCCAAAAAGCUGCUGC 20 7622

BCLllA-6043 + GCCCACCAAGUCGCUGGUGC 20 7623

BCLllA-6044 + CAUGUGGCGCUUCAGCU UGC 20 7624

BCLllA-6045 + CGUCCCCGUUCUCCGGGAUC 20 7625

BCLllA-6046 + GCACCCUGUCAAAGGCACUC 20 7626

BCLllA-6047 - UCCCCGGGCGAGUCGGCCUC 20 7627

BCLllA-6048 - GAGCUGGACGGAGGGAUCUC 20 7628

BCLllA-6049 + GCCACACAUCUUGAGCUCUC 20 7629

BCLllA-6050 + UCCUCCUCGUCCCCGUUCUC 20 7630

BCLllA-6051 + ACCAUGCCCUGCAUGACGUC 20 7631

BCLllA-6052 + GGAUACCAACCCGCGGGGUC 20 7632

BCLllA-6053 - CACGCCCCAUAU UAGUGGUC 20 7633

BCLllA-6054 + GGAGGCAAAAGGCGAU UGUC 20 7634

BCLllA-6055 - CCGCGGGUUGGUAUCCCUUC 20 7635

BCLllA-6056 - UCAGUAUCGAGAGAGGCUUC 20 7636

BCLllA-6057 - AGAGGGUGGACUACGGCUUC 20 7637

BCLllA-6058 + AAGUCGCUGGUGCCGGGUUC 20 7638

BCLllA-6059 - GGGCAGGCCCAGCUCAAAAG 20 7639

BCLllA-6060 + UGUGUGAAGAACCUAGAAAG 20 7640

BCLllA-6061 + GUAUUCUUAGCAGGUUAAAG 20 7641

BCLllA-3449 - CGACGAGGAAGAGGAAGAAG 20 7642

BCLllA-6062 + GCUUGAUGCGCUUAGAGAAG 20 7643

BCLllA-3448 - AGAGGAGGACGACGAGGAAG 20 7644

BCLllA-3453 - AGAGGAAGAAGAGGAGGAAG 20 7645

BCLllA-3441 - GAACGGGGACGAGGAGGAAG 20 7646

BCLllA-3376 - GGGCGCAGCGGCACGGGAAG 20 7647

BCLllA-6063 + CUCGGUGGUGGACUAAACAG 20 7648

BCLllA-6064 + UAGAAAGAGGUUGGAGACAG 20 7649

BCLllA-6065 + CUGGGCCGGCCUGGGGACAG 20 7650

BCLllA-6066 - AGAAAAUUUGAAGCCCCCAG 20 7651 BCLllA-6067 - GGAGGGAUCUCGGGGCGCAG 20 7652

BCLllA-6068 - CGGAGAACGUGUACUCGCAG 20 7653

BCLllA-6069 + GGAGGAGGGGCGGAUUGCAG 20 7654

BCLllA-6070 + AUACCAACCCGCGGGGUCAG 20 7655

BCLllA-6071 - ACCAGGAUCAGUAUCGAGAG 20 7656

BCLllA-6072 - AGGAGCUGACGGAGAGCGAG 20 7657

BCLllA-6073 + AGAGGUUGGAGACAGAGGAG 20 7658

BCLllA-6074 + CGGGGGCUGGGAGGGAGGAG 20 7659

BCLllA-6075 + GCGGAUUGCAGAGGAGGGAG 20 7660

BCLllA-6076 + UGGACUAAACAGGGGGGGAG 20 7661

BCLllA-6077 + GCAAUAUGAAUCCCAUGGAG 20 7662

BCLllA-6078 - GGGAGCACGCCCCAUAU UAG 20 7663

BCLllA-6079 - CAACCUGAUCCCGGAGAACG 20 7664

BCLllA-3450 - GGAGGAAGAGGAGGACGACG 20 7665

BCLllA-6080 + CUCCGAGGAGUGCUCCGACG 20 7666

BCLllA-6081 - GAUCCCGGAGAACGGGGACG 20 7667

BCLllA-6082 - GCAGUGGCUCGCCGGCUACG 20 7668

BCLllA-6083 + GCAUGACUUGGACUUGACCG 20 7669

BCLllA-6084 + CCUGAAGGGAUACCAACCCG 20 7670

BCLllA-6085 - ACGGAAGUCCCCUGACCCCG 20 7671

BCLllA-6086 + CUU UUUGGACAGGCCCCCCG 20 7672

BCLllA-6087 - GCGCUUCUCCACACCGCCCG 20 7673

BCLllA-6088 + CCCCGAGGCCGACUCGCCCG 20 7674

BCLllA-6089 + ACUCGCCCGGGGAGCAGCCG 20 7675

BCLllA-6090 - CGGCCACCUGGCCGAGGCCG 20 7676

BCLllA-6091 + CGUGUUGGGCAUCGCGGCCG 20 7677

BCLllA-6092 - GAUGGCACUGUUAAUGGCCG 20 7678

BCLllA-6093 - UAAGCGCGGCCACCUGGCCG 20 7679

BCLllA-6094 + GCGCAAACUCCCGUUCUCCG 20 7680

BCLllA-6095 - CAGCAGCGCGCUCAAGUCCG 20 7681

BCLllA-6096 + GUCGCUGGUGCCGGGUUCCG 20 7682

BCLllA-6097 - CUGGGCGAGAAGCAUAAGCG 20 7683

BCLllA-6098 - CUCCAUGCAGCACUUCAGCG 20 7684

BCLllA-6099 + UGCUGGCCUGGGUGCACGCG 20 7685

BCLllA-6100 + UGAAGGGAUACCAACCCGCG 20 7686

BCLllA-6101 - CACCACGAGAACAGCUCGCG 20 7687

BCLllA-6102 + GCAUGACGUCGGGCAGGGCG 20 7688

BCLllA-6103 - CGAGAACAGCUCGCGGGGCG 20 7689

BCLllA-6104 - GCGGGGCGCGGUCGUGGGCG 20 7690

BCLllA-6105 + GU UCUCCGUGUUGGGCAUCG 20 7691

BCLllA-6106 - CCCCGGGCGAGUCGGCCUCG 20 7692

BCLllA-6107 - GCCACCACGAGAACAGCUCG 20 7693 BCLllA-6108 - AGCUGGACGGAGGGAUCUCG 20 7694

BCLllA-6109 + CGCCCCGCGAGCUGUUCUCG 20 7695

BCLllA-6110 - CAGCUCGCGGGGCGCGGUCG 20 7696

BCLllA-6111 + UCGGUGGUGGACUAAACAGG 20 7697

BCLllA-6112 + GGCCCUCGGCCUCGGCCAGG 20 7698

BCLllA-3451 - CGAGGAAGAGGAAGAAGAGG 20 7699

BCLllA-3452 - GGAAGAAGAGGAGGAAGAGG 20 7700

BCLllA-3445 - CGGGGACGAGGAGGAAGAGG 20 7701

BCLllA-6113 + AAAGAGGUUGGAGACAGAGG 20 7702

BCLllA-6114 + GGAGGGGCGGAUUGCAGAGG 20 7703

BCLllA-6115 + AUAUGAAUCCCAUGGAGAGG 20 7704

BCLllA-6116 + CGAGGAGUGCUCCGACGAGG 20 7705

BCLllA-3330 - CCCGGAGAACGGGGACGAGG 20 7706

BCLllA-3454 - AGAAGAGGAGGAAGAGGAGG 20 7707

BCLllA-6117 + GAGGUUGGAGACAGAGGAGG 20 7708

BCLllA-3455 - AGAGGAGGAAGAGGAGGAGG 20 7709

BCLllA-6118 + CGGAUUGCAGAGGAGGGAGG 20 7710

BCLllA-6119 + ACCGGGGGCUGGGAGGGAGG 20 7711

BCLllA-6120 - CUUCGGGCUGAGCCUGGAGG 20 7712

BCLllA-6121 - CCGCCCGGGGAGCUGGACGG 20 7713

BCLllA-6122 + CAUGACUUGGACUUGACCGG 20 7714

BCLllA-6123 + GUGUUGGGCAUCGCGGCCGG 20 7715

BCLllA-6124 + GGCCGGCCUGGGGACAGCGG 20 7716

BCLllA-6125 + GGGUUCCGGGGAGCUGGCGG 20 7717

BCLllA-6126 + CCCCCAGGCGCUCUAUGCGG 20 7718

BCLllA-6127 - CACUUGCGACGAAGACUCGG 20 7719

BCLllA-6128 - CCCGGGCGAGUCGGCCUCGG 20 7720

BCLllA-6129 + GGGUCCAAGUGAUGUCUCGG 20 7721

BCLllA-6130 + GGGGGCGUCGCCAGGAAGGG 20 7722

BCLllA-6131 + CGGUGGUGGACUAAACAGGG 20 7723

BCLllA-6132 - GCUGACGGAGAGCGAGAGGG 20 7724

BCLllA-6133 + GGGCGGAUUGCAGAGGAGGG 20 7725

BCLllA-6134 + GGAUUGCAGAGGAGGGAGGG 20 7726

BCLllA-6135 + U UGACCGGGGGCUGGGAGGG 20 7727

BCLllA-6136 + CCUCCGUCCAGCUCCCCGGG 20 7728

BCLllA-6137 + CUAGAGAAAUCCAUGGCGGG 20 7729

BCLllA-6138 - CCGGGCGAGUCGGCCUCGGG 20 7730

BCLllA-6139 + GGUGGUGGACUAAACAGGGG 20 7731

BCLllA-6140 - AAAUUUGAAGCCCCCAGGGG 20 7732

BCLllA-6141 + GGGCUGGGAGGGAGGAGGGG 20 7733

BCLllA-6142 + GAUUGCAGAGGAGGGAGGGG 20 7734

BCLllA-6143 - CCGCAUAGAGCGCCUGGGGG 20 7735 BCLllA-6144 - UGAAGCCCCCAGGGGUGGGG 20 7736

BCLllA-6145 + AAAGGCACUCGGGUGAUGGG 20 7737

BCLllA-6146 + GGACUUGACCGGGGGCUGGG 20 7738

BCLllA-6147 + CUAAACAGGGGGGGAGUGGG 20 7739

BCLllA-6148 + CUGGGUACUACGCCGAAUGG 20 7740

BCLllA-6149 + UCUCCUAGAGAAAUCCAUGG 20 7741

BCLllA-6150 + GUCGGACUUGACCGUCAUGG 20 7742

BCLllA-6151 - CAAAUUUCAGAGCAACCUGG 20 7743

BCLllA-6152 + GCU UCUCGCCCAGGACCUGG 20 7744

BCLllA-6153 - CGGCUUCGGGCUGAGCCUGG 20 7745

BCLllA-6154 - CCACCGCAUAGAGCGCCUGG 20 7746

BCLllA-6155 + GGGAUCUUUGAGCUGCCUGG 20 7747

BCLllA-6156 + GCCGGGUUCCGGGGAGCUGG 20 7748

BCLllA-6157 - CGCAGCGGCACGGGAAGUGG 20 7749

BCLllA-6158 - CAGCGCGCUCAAGUCCGUGG 20 7750

BCLllA-6159 + CCCGCGAGCUGU UCUCGUGG 20 7751

BCLllA-6160 + CCAGGCGCUCUAUGCGGUGG 20 7752

BCLllA-6161 + UCCAAGUGAUGUCUCGGUGG 20 7753

BCLllA-6162 - ACCCGGCACCAGCGACU UGG 20 7754

BCLllA-6163 + UCUGGGUACUACGCCGAAUG 20 7755

BCLllA-6164 + CGUCGGACUUGACCGUCAUG 20 7756

BCLllA-6165 + UGUGCAUGUGCGUCUUCAUG 20 7757

BCLllA-6166 + GGGCCCGGACCACUAAUAUG 20 7758

BCLllA-6167 + CCGCCCCCAGGCGCUCUAUG 20 7759

BCLllA-6168 + UAACAGUGCCAUCGUCUAUG 20 7760

BCLllA-6169 - AGCGACACUUGUGAGUACUG 20 7761

BCLllA-6170 + CUUCGUCGCAAGUGUCCCUG 20 7762

BCLllA-6171 - CCCACCGCAUAGAGCGCCUG 20 7763

BCLllA-6172 + CAUAGGGCUGGGCCGGCCUG 20 7764

BCLllA-6173 + AGAAGGGGCUCAGCGAGCUG 20 7765

BCLllA-6174 - GUGCCUUUGACAGGGUGCUG 20 7766

BCLllA-6175 - UCCAAGUCAUGCGAGUUCUG 20 7767

BCLllA-6176 + UGUAGGGCUUCUCGCCCGUG 20 7768

BCLllA-6177 + GUCCAGCUCCCCGGGCGGUG 20 7769

BCLllA-6178 + CCCAGGCGCUCUAUGCGGUG 20 7770

BCLllA-6179 - AUUUGAAGCCCCCAGGGGUG 20 7771

BCLllA-6180 - CCCAGAGAGCUCAAGAUGUG 20 7772

BCLllA-6181 + CGU UCUCCGGGAUCAGGUUG 20 7773

BCLllA-6182 + CUCUGGGUACUACGCCGAAU 20 7774

BCLllA-6183 + GCGGGAGGCUCCAUAGCCAU 20 7775

BCLllA-6184 - CUUCCCAGCCACCUCUCCAU 20 7776

BCLllA-6185 + GGU UGCAGUAACCUUUGCAU 20 7777 BCLllA-6186 + UCGUCGGACUUGACCGUCAU 20 7778

BCLllA-6187 + GUCAAAGGCACUCGGGUGAU 20 7779

BCLllA-6188 + CGGGCCCGGACCACUAAUAU 20 7780

BCLllA-6189 + GUCGUUCUCGCUCUUGAACU 20 7781

BCLllA-6190 + AGCACCCUGUCAAAGGCACU 20 7782

BCLllA-6191 - UCCACCACCGAGACAUCACU 20 7783

BCLllA-6192 - GGACACUUGCGACGAAGACU 20 7784

BCLllA-6193 - GGAACCCGGCACCAGCGACU 20 7785

BCLllA-6194 - GU UGGUAUCCCUUCAGGACU 20 7786

BCLllA-6195 + GCCGCAGAACUCGCAUGACU 20 7787

BCLllA-6196 + GCAAGUGUCCCUGUGGCCCU 20 7788

BCLllA-6197 - CCCCACCGCAUAGAGCGCCU 20 7789

BCLllA-6198 + GCAUAGGGCUGGGCCGGCCU 20 7790

BCLllA-6199 + GUCCCUGUGGCCCUCGGCCU 20 7791

BCLllA-6200 - CUCCCCGGGCGAGUCGGCCU 20 7792

BCLllA-6201 + GCGCUUCAGCUUGCUGGCCU 20 7793

BCLllA-6202 - CUCCUCGUCGGAGCACUCCU 20 7794

BCLllA-6203 - GAGGCCU UCCACCAGGUCCU 20 7795

BCLllA-6204 + GAGAAGGGGCUCAGCGAGCU 20 7796

BCLllA-6205 + CGUCUGCCCUCUU UUGAGCU 20 7797

BCLllA-6206 + AGUAACCUUUGCAUAGGGCU 20 7798

BCLllA-6207 + CUUGGACUUGACCGGGGGCU 20 7799

BCLllA-6208 + AAUCCCAUGGAGAGGUGGCU 20 7800

BCLllA-5508 + GUUGUACAUGUGUAGCUGCU 20 7801

BCLllA-6209 - CUGUCCAAAAAGCUGCUGCU 20 7802

BCLllA-6210 - GGAGCUGGACGGAGGGAUCU 20 7803

BCLllA-6211 + CCACACAUCUUGAGCUCUCU 20 7804

BCLllA-6212 - CUCCCGCCAUGGAU UUCUCU 20 7805

BCLllA-6213 + UGGGGGUCCAAGUGAUGUCU 20 7806

BCLllA-6214 - UCUGUCUCCAACCUCUU UCU 20 7807

BCLllA-6215 - AGACUCGGUGGCCGGCGAGU 20 7808

BCLllA-6216 - CGGCUGCUCCCCGGGCGAGU 20 7809

BCLllA-6217 + GGACUAAACAGGGGGGGAGU 20 7810

BCLllA-6218 + CACCAUGCCCUGCAUGACGU 20 7811

BCLllA-6219 - CGGGGCGCGGUCGUGGGCGU 20 7812

BCLllA-6220 - AUCGCCUU UUGCCUCCUCGU 20 7813

BCLllA-6221 + GGCGGUGGAGAGACCGUCGU 20 7814

BCLllA-6222 - AGCUCGCGGGGCGCGGUCGU 20 7815

BCLllA-6223 + CCCGUUCUCCGGGAUCAGGU 20 7816

BCLllA-6224 + UGAAGAACCUAGAAAGAGGU 20 7817

BCLllA-6225 + GCCGGCCUGGGGACAGCGGU 20 7818

BCLllA-6226 + CCCCAGGCGCUCUAUGCGGU 20 7819 BCLllA-6227 - AGUCCCCUGACCCCGCGGGU 20 7820

BCLllA-6228 - AAUUUGAAGCCCCCAGGGGU 20 7821

BCLllA-6229 - CCCGGCACCAGCGACUUGGU 20 7822

BCLllA-6230 - GCGACACU UGUGAGUACUGU 20 7823

BCLllA-6231 + CGAGUACACGUUCUCCGUGU 20 7824

BCLllA-6232 + GUCGCACAGGUUGCACUUGU 20 7825

BCLllA-6233 - GU UCUUCACACACCCCCAUU 20 7826

BCLllA-6234 - AAAGAUCCCUUCCUUAGCUU 20 7827

BCLllA-6235 - GAGAGGGUGGACUACGGCUU 20 7828

BCLllA-6236 + CCGUUCUCCGGGAUCAGGUU 20 7829

BCLllA-6237 + GAGUACACGUUCUCCGUGUU 20 7830

BCLllA-6238 + GCUGCCCAGCAGCAGCU UUU 20 7831

BCLllA-6239 - UCAAGAUGUGUGGCAGUUUU 20 7832

Table 15D provides targeting domains for knocking out the BCL11A gene by dual targeting (e.g., dual single strand cleavages). In an embodiment, dual targeting (e.g., dual nicking) is used to create two nicks on opposite DNA strands by using S. pyogenes Cas9 nickases with two targeting domains that are complementary to opposite DNA strands, e.g., a gRNA comprising any minus strand targeting domain may be paired any gRNA comprising a plus strand targeting domain provided that the two gRNAs are oriented on the DNA such that PAMs face outward and the distance between the 5' ends of the gRNAs is 0-50bp. Exemplary nickase pairs include a targeting domain from Group A and a second targeting domain from Group B, or include a targeting domain from Group C and a second targeting domain from

Group D. It is contemplated herein that in an embodiment a targeting domain of Group A can be combined with any of the targeting domains of Group B; in an embodiment a targeting domain of Group C can be combined with any of the targeting domains of Group D. Exemplary gRNA pairs to be used with S. pyogenes Cas9 are shown in Table 15D, e.g., BCL11A-5355 or

BCL11A-5380 can be combined with BCL11A-5321 or BCL11A-5416; or BCL11A-5333, BCLl lA-5354, or BCLl lA-5329 can be combined with BCLl lA-5367 or BCLl lA-5341. Table 15D

Table 16A provides exemplary targeting domains for knocking out the BCL11A gene selected according to the first tier parameters. The targeting domains bind within the first 500 bp of the coding sequence (e.g., within 500 bp downstream from the start codon) and have a high level of orthogonality, and the PAM is NNGRRT. It is contemplated herein that in an

embodiment the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. aureus Cas9 molecule that generates a double stranded break (Cas9 nuclease) or a single- stranded break (Cas9 nickase).

Table 16A

BCLllA-6266 + U UCCCGUUUGCU UAAGUGC 19 7859

BCLllA-5352 + AUUCCCGU UUGCUUAAGUGC 20 7860

BCLllA-6267 + AAUUCCCGUUUGCUUAAGUGC 21 7861

BCLllA-6268 + GAAUUCCCGUUUGCUUAAGUGC 22 7862

BCLllA-6269 + AGAAUUCCCGUU UGCUUAAGUGC 23 7863

BCLllA-6270 + GAGAAUUCCCGUUUGCUUAAGUGC 24 7864

BCLllA-6271 + U UUGUGCUCGAUAAAAAU 18 7865

BCLllA-6272 + GU UUGUGCUCGAUAAAAAU 19 7866

BCLllA-6273 + CGU UUGUGCUCGAUAAAAAU 20 7867

BCLllA-6274 + CCGUU UGUGCUCGAUAAAAAU 21 7868

BCLllA-6275 + UCCGU UUGUGCUCGAUAAAAAU 22 7869

BCLllA-6276 + UUCCGUUUGUGCUCGAUAAAAAU 23 7870

BCLllA-6277 + UUUCCGUUUGUGCUCGAUAAAAAU 24 7871

BCLllA-6278 + UGCACUCAUCCCAGGCGU 18 7872

BCLllA-6279 + CUGCACUCAUCCCAGGCGU 19 7873

BCLllA-5510 + UCUGCACUCAUCCCAGGCGU 20 7874

BCLllA-6280 + UUCUGCACUCAUCCCAGGCGU 21 7875

BCLllA-6281 + AUUCUGCACUCAUCCCAGGCGU 22 7876

BCLllA-6282 + UAUUCUGCACUCAUCCCAGGCGU 23 7877

BCLllA-6283 + AUAUUCUGCACUCAUCCCAGGCGU 24 7878

BCLllA-6284 + GUCUGGUUCAUCAUCUGU 18 7879

BCLllA-6285 + GGUCUGGUUCAUCAUCUGU 19 7880

BCLllA-6286 + UGGUCUGGUUCAUCAUCUGU 20 7881

BCLllA-6287 + GUGGUCUGGUUCAUCAUCUGU 21 7882

BCLllA-6288 + CGUGGUCUGGUUCAUCAUCUGU 22 7883

BCLllA-6289 + CCGUGGUCUGGUUCAUCAUCUGU 23 7884

BCLllA-6290 + GCCGUGGUCUGGUUCAUCAUCUGU 24 7885

BCLllA-6291 - CCGUUGGGAGCUCCAGAA 18 7886

BCLllA-6292 - CCCGUUGGGAGCUCCAGAA 19 7887

BCLllA-5447 - GCCCGUUGGGAGCUCCAGAA 20 7888

BCLllA-6293 - GGCCCGU UGGGAGCUCCAGAA 21 7889

BCLllA-6294 - CGGCCCGUUGGGAGCUCCAGAA 22 7890

BCLllA-6295 - ACGGCCCGUUGGGAGCUCCAGAA 23 7891

BCLllA-6296 - CACGGCCCGUUGGGAGCUCCAGAA 24 7892

BCLllA-6297 - GGCAUCCAGGUCACGCCA 18 7893

BCLllA-6298 - UGGCAUCCAGGUCACGCCA 19 7894

BCLllA-6299 - U UGGCAUCCAGGUCACGCCA 20 7895

BCLllA-6300 - GUUGGCAUCCAGGUCACGCCA 21 7896

BCLllA-6301 - GGUUGGCAUCCAGGUCACGCCA 22 7897

BCLllA-6302 - AGGUUGGCAUCCAGGUCACGCCA 23 7898

BCLllA-6303 - GAGGUUGGCAUCCAGGUCACGCCA 24 7899

BCLllA-6304 - AACCCCAGCACUUAAGCAAAC 21 7900 BCLllA-6305 - AAACCCCAGCACUUAAGCAAAC 22 7901

BCLllA-6306 - CAAACCCCAGCACUUAAGCAAAC 23 7902

BCLllA-6307 - G CAA ACCCCAG CAC U UAAG CAAAC 24 7903

BCLllA-6308 - AGCUCUAAUCCCCACGCC 18 7904

BCLllA-6309 - GAGCUCUAAUCCCCACGCC 19 7905

BCLllA-5350 - GGAGCUCUAAUCCCCACGCC 20 7906

BCLllA-6310 - UGGAGCUCUAAUCCCCACGCC 21 7907

BCLllA-6311 - AUGGAGCUCUAAUCCCCACGCC 22 7908

BCLllA-6312 - CAUGGAGCUCUAAUCCCCACGCC 23 7909

BCLllA-6313 - ACAUGGAGCUCUAAUCCCCACGCC 24 7910

BCLllA-6314 - UUUAUCAACGUCAUCUAG 18 7911

BCLllA-6315 - GUUUAUCAACGUCAUCUAG 19 7912

BCLllA-5356 - UGUUUAUCAACGUCAUCUAG 20 7913

BCLllA-6316 - UUGUUUAUCAACGUCAUCUAG 21 7914

BCLllA-6317 - AUUGUUUAUCAACGUCAUCUAG 22 7915

BCLllA-6318 - GAUUGUUUAUCAACGUCAUCUAG 23 7916

BCLllA-6319 - CGAUUGUUUAUCAACGUCAUCUAG 24 7917

BCLllA-6320 - AGUGCAGAAUAUGCCCCG 18 7918

BCLllA-6321 - GAGUGCAGAAUAUGCCCCG 19 7919

BCLllA-6322 - UGAGUGCAGAAUAUGCCCCG 20 7920

BCLllA-6323 - AUGAGUGCAGAAUAUGCCCCG 21 7921

BCLllA-6324 - GAUGAGUGCAGAAUAUGCCCCG 22 7922

BCLllA-6325 - GGAUGAGUGCAGAAUAUGCCCCG 23 7923

BCLllA-6326 - GGGAUGAGUGCAGAAUAUGCCCCG 24 7924

BCLllA-6327 - CUAAUCCCCACGCCUGGG 18 7925

BCLllA-6328 - UCUAAUCCCCACGCCUGGG 19 7926

BCLllA-6329 - CUCUAAUCCCCACGCCUGGG 20 7927

BCLllA-6330 - GCUCUAAUCCCCACGCCUGGG 21 7928

BCLllA-6331 - AGCUCUAAUCCCCACGCCUGGG 22 7929

BCLllA-6332 - GAGCUCUAAUCCCCACGCCUGGG 23 7930

BCLllA-6333 - GGAGCUCUAAUCCCCACGCCUGGG 24 7931

BCLllA-6334 - CCACGCCUGGGAUGAGUG 18 7932

BCLllA-6335 - CCCACGCCUGGGAUGAGUG 19 7933

BCLllA-6336 - CCCCACGCCUGGGAUGAGUG 20 7934

BCLllA-6337 - UCCCCACGCCUGGGAUGAGUG 21 7935

BCLllA-6338 - AUCCCCACGCCUGGGAUGAGUG 22 7936

BCLllA-6339 - AAUCCCCACGCCUGGGAUGAGUG 23 7937

BCLllA-6340 - UAAUCCCCACGCCUGGGAUGAGUG 24 7938

BCLllA-6341 - CUCUGCUUAGAAAAAGCU 18 7939

BCLllA-6342 - CCUCUGCUUAGAAAAAGCU 19 7940

BCLllA-6343 - GCCUCUGCUUAGAAAAAGCU 20 7941

BCLllA-6344 - AGCCUCUGCUUAGAAAAAGCU 21 7942 BCLllA-6345 - CAGCCUCUGCUUAGAAAAAGCU 22 7943

BCLllA-6346 - GCAGCCUCUGCUUAGAAAAAGCU 23 7944

BCLllA-6347 - GGCAGCCUCUGCU UAGAAAAAGCU 24 7945

Table 16B provides exemplary targeting domains for knocking out the BCL11A gene selected according to the second tier parameters. The targeting domains bind within the first 500 bp of the coding sequence (e.g., within 500 bp downstream from the start codon), and the PAM is NNGRRT. It is contemplated herein that in an embodiment the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. aureus Cas9 molecule that generates a double stranded break (Cas9 nuclease) or a single- stranded break (Cas9 nickase).

Table 16B

Table 16C provides exemplary targeting domains for knocking out the BCL11A gene selected according to the third tier parameters. The targeting domains bind within the first 500 bp of the coding sequence (e.g., within 500 bp downstream from the start codon), and the PAM is NNGRRV. It is contemplated herein that in an embodiment the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. aureus Cas9 molecule that generates a double stranded break (Cas9 nuclease) or a single- stranded break (Cas9 nickase).

Table 16C

BCLllA-6354 + AAAAAUAAGAAUGUCCCCCAA 21 7955

BCLllA-6355 + UAAAAAUAAGAAUGUCCCCCAA 22 7956

BCLllA-6356 + AUAAAAAUAAGAAUGUCCCCCAA 23 7957

BCLllA-6357 + GAUAAAAAUAAGAAUGUCCCCCAA 24 7958

BCLllA-6358 + U UCAUCUCGAUUGGUGAA 18 7959

BCLllA-6359 + U UUCAUCUCGAUUGGUGAA 19 7960

BCLllA-5344 + U UUUCAUCUCGAUUGGUGAA 20 7961

BCLllA-6360 + U UUUUCAUCUCGAUUGGUGAA 21 7962

BCLllA-6361 + U UUUUUCAUCUCGAUUGGUGAA 22 7963

BCLllA-6362 + CUU UUUUCAUCUCGAUUGGUGAA 23 7964

BCLllA-6363 + GCUUUUUUCAUCUCGAUUGGUGAA 24 7965

BCLllA-6364 + AAAUAAGAAUGUCCCCCA 18 7966

BCLllA-6365 + AAAAUAAGAAUGUCCCCCA 19 7967

BCLllA-6366 + AAAAAUAAGAAUGUCCCCCA 20 7968

BCLllA-6367 + UAAAAAUAAGAAUGUCCCCCA 21 7969

BCLllA-6368 + AUAAAAAUAAGAAUGUCCCCCA 22 7970

BCLllA-6369 + GAUAAAAAUAAGAAUGUCCCCCA 23 7971

BCLllA-6370 + CGAUAAAAAUAAGAAUGUCCCCCA 24 7972

BCLllA-6371 + CCCCUUCUGGAGCUCCCA 18 7973

BCLllA-6372 + UCCCCUUCUGGAGCUCCCA 19 7974

BCLllA-6373 + AUCCCCU UCUGGAGCUCCCA 20 7975

BCLllA-6374 + GAUCCCCUUCUGGAGCUCCCA 21 7976

BCLllA-6375 + UGAUCCCCUUCUGGAGCUCCCA 22 7977

BCLllA-6376 + AUGAUCCCCUUCUGGAGCUCCCA 23 7978

BCLllA-6377 + CAUGAUCCCCUUCUGGAGCUCCCA 24 7979

BCLllA-6378 + UAGAGCUCCAUGUGCAGA 18 7980

BCLllA-6379 + UUAGAGCUCCAUGUGCAGA 19 7981

BCLllA-6380 + AUUAGAGCUCCAUGUGCAGA 20 7982

BCLllA-6381 + GAUUAGAGCUCCAUGUGCAGA 21 7983

BCLllA-6382 + GGAUUAGAGCUCCAUGUGCAGA 22 7984

BCLllA-6383 + GGGAUUAGAGCUCCAUGUGCAGA 23 7985

BCLllA-6384 + GGGGAUUAGAGCUCCAUGUGCAGA 24 7986

BCLllA-6385 + GCUCCAUGUGCAGAACGA 18 7987

BCLllA-6386 + AGCUCCAUGUGCAGAACGA 19 7988

BCLllA-5347 + GAGCUCCAUGUGCAGAACGA 20 7989

BCLllA-6387 + AGAGCUCCAUGUGCAGAACGA 21 7990

BCLllA-6388 + UAGAGCUCCAUGUGCAGAACGA 22 7991

BCLllA-6389 + UUAGAGCUCCAUGUGCAGAACGA 23 7992

BCLllA-6390 + AUUAGAGCUCCAUGUGCAGAACGA 24 7993

BCLllA-6391 + UUUCAUCUCGAUUGGUGA 18 7994

BCLllA-6392 + UUUUCAUCUCGAUUGGUGA 19 7995

BCLllA-5456 + UUUUUCAUCUCGAUUGGUGA 20 7996 BCLllA-6393 + UUUUUUCAUCUCGAUUGGUGA 21 7997

BCLllA-6394 + CUUUUUUCAUCUCGAU UGGUGA 22 7998

BCLllA-6395 + GCU UUUUUCAUCUCGAUUGGUGA 23 7999

BCLllA-6396 + UGCUUUUUUCAUCUCGAUUGGUGA 24

8000

BCLllA-6397 + GCAGAAGUUUAUCUGUGA 18 8001

BCLllA-6398 + UGCAGAAGUUUAUCUGUGA 19 8002

BCLllA-6399 + GUGCAGAAGUUUAUCUGUGA 20 8003

BCLllA-6400 + AGUGCAGAAGUUUAUCUGUGA 21 8004

BCLllA-6401 + CAGUGCAGAAGUUUAUCUGUGA 22 8005

BCLllA-6402 + CCAGUGCAGAAGUUUAUCUGUGA 23 8006

BCLllA-6403 + UCCAGUGCAGAAGUU UAUCUGUGA 24 8007

BCLllA-6404 + GAGCUCCAUGUGCAGAAC 18 8008

BCLllA-6405 + AGAGCUCCAUGUGCAGAAC 19 8009

BCLllA-6406 + UAGAGCUCCAUGUGCAGAAC 20 8010

BCLllA-6407 + UUAGAGCUCCAUGUGCAGAAC 21 8011

BCLllA-6408 + AUUAGAGCUCCAUGUGCAGAAC 22 8012

BCLllA-6409 + GAUUAGAGCUCCAUGUGCAGAAC 23 8013

BCLllA-6410 + GGAUUAGAGCUCCAUGUGCAGAAC 24 8014

BCLllA-6411 + UAUUAUUGGGUUACUUAC 18 8015

BCLllA-6412 + CUAUUAUUGGGUUACU UAC 19 8016

BCLllA-6413 + ACUAUUAUUGGGUUACUUAC 20 8017

BCLllA-6414 + UACUAUUAUUGGGUUACUUAC 21 8018

BCLllA-6415 + U UACUAUUAUUGGGUUACUUAC 22 8019

BCLllA-6416 + AUUACUAUUAUUGGGU UACUUAC 23 8020

BCLllA-6417 + UAUUACUAUUAUUGGGUUACUUAC 24 8021

BCLllA-6418 + ACCUGGAUGCCAACCUCC 18 8022

BCLllA-6419 + GACCUGGAUGCCAACCUCC 19 8023

BCLllA-6420 + UGACCUGGAUGCCAACCUCC 20 8024

BCLllA-6421 + GUGACCUGGAUGCCAACCUCC 21 8025

BCLllA-6422 + CGUGACCUGGAUGCCAACCUCC 22 8026

BCLllA-6423 + GCGUGACCUGGAUGCCAACCUCC 23 8027

BCLllA-6424 + GGCGUGACCUGGAUGCCAACCUCC 24 8028

BCLllA-6425 + UCUGCACUCAUCCCAGGC 18 8029

BCLllA-6426 + UUCUGCACUCAUCCCAGGC 19 8030

BCLllA-6427 + AUUCUGCACUCAUCCCAGGC 20 8031

BCLllA-6428 + UAUUCUGCACUCAUCCCAGGC 21 8032

BCLllA-6429 + AUAUUCUGCACUCAUCCCAGGC 22 8033

BCLllA-6430 + CAUAUUCUGCACUCAUCCCAGGC 23 8034

BCLllA-6431 + GCAUAUUCUGCACUCAUCCCAGGC 24 8035

BCLllA-6432 + GAGGUCAUGAUCCCCUUC 18 8036

BCLllA-6433 + GGAGGUCAUGAUCCCCU UC 19 8037 BCLllA-5471 + AGGAGGUCAUGAUCCCCUUC 20 8038

BCLllA-6434 + GAGGAGGUCAUGAUCCCCUUC 21 8039

BCLllA-6435 + UGAGGAGGUCAUGAUCCCCUUC 22 8040

BCLllA-6436 + GUGAGGAGGUCAUGAUCCCCUUC 23 8041

BCLllA-6437 + GGUGAGGAGGUCAUGAUCCCCUUC 24 8042

BCLllA-6438 + AUCUGUAAGAAUGGCU UC 18 8043

BCLllA-6439 + CAUCUGUAAGAAUGGCUUC 19 8044

BCLllA-6440 + UCAUCUGUAAGAAUGGCUUC 20 8045

BCLllA-6441 + AUCAUCUGUAAGAAUGGCUUC 21 8046

BCLllA-6442 + CAUCAUCUGUAAGAAUGGCUUC 22 8047

BCLllA-6443 + UCAUCAUCUGUAAGAAUGGCUUC 23 8048

BCLllA-6444 + UUCAUCAUCUGUAAGAAUGGCUUC 24 8049

BCLllA-6445 + UCAUCUCGAUUGGUGAAG 18 8050

BCLllA-6446 + U UCAUCUCGAUUGGUGAAG 19 8051

BCLllA-5355 + U UUCAUCUCGAUUGGUGAAG 20 8052

BCLllA-6447 + U UUUCAUCUCGAUUGGUGAAG 21 8053

BCLllA-6448 + U UUUUCAUCUCGAUUGGUGAAG 22 8054

BCLllA-6449 + U UUUUUCAUCUCGAUUGGUGAAG 23 8055

BCLllA-6450 + CUU UUUUCAUCUCGAUUGGUGAAG 24 8056

BCLllA-6451 + UCCACAGCU UUUUCUAAG 18 8057

BCLllA-6452 + AUCCACAGCUUUUUCUAAG 19 8058

BCLllA-6453 + UAUCCACAGCU UUUUCUAAG 20 8059

BCLllA-6454 + U UAUCCACAGCUUUUUCUAAG 21 8060

BCLllA-6455 + CUUAUCCACAGCUUUU UCUAAG 22 8061

BCLllA-6456 + GCU UAUCCACAGCUUUU UCUAAG 23 8062

BCLllA-6457 + GGCU UAUCCACAGCUUUUUCUAAG 24 8063

BCLllA-6458 + AUCUGGCACUGCCCACAG 18 8064

BCLllA-6459 + CAUCUGGCACUGCCCACAG 19 8065

BCLllA-6460 + UCAUCUGGCACUGCCCACAG 20 8066

BCLllA-6461 + UUCAUCUGGCACUGCCCACAG 21 8067

BCLllA-6462 + GU UCAUCUGGCACUGCCCACAG 22 8068

BCLllA-6463 + AGUUCAUCUGGCACUGCCCACAG 23 8069

BCLllA-6464 + AAGUUCAUCUGGCACUGCCCACAG 24 8070

BCLllA-6465 + CUCCAUGUGCAGAACGAG 18 8071

BCLllA-6466 + GCUCCAUGUGCAGAACGAG 19 8072

BCLllA-5476 + AGCUCCAUGUGCAGAACGAG 20 8073

BCLllA-6467 + GAGCUCCAUGUGCAGAACGAG 21 8074

BCLllA-6468 + AGAGCUCCAUGUGCAGAACGAG 22 8075

BCLllA-6469 + UAGAGCUCCAUGUGCAGAACGAG 23 8076

BCLllA-6470 + UUAGAGCUCCAUGUGCAGAACGAG 24 8077

BCLllA-6471 + UGUGCAGAACGAGGGGAG 18 8078

BCLllA-6472 + AUGUGCAGAACGAGGGGAG 19 8079 BCLllA-6473 + CAUGUGCAGAACGAGGGGAG 20 8080

BCLllA-6474 + CCAUGUGCAGAACGAGGGGAG 21 8081

BCLllA-6475 + UCCAUGUGCAGAACGAGGGGAG 22 8082

BCLllA-6476 + CUCCAUGUGCAGAACGAGGGGAG 23 8083

BCLllA-6477 + GCUCCAUGUGCAGAACGAGGGGAG 24 8084

BCLllA-6478 + AGCUCCAUGUGCAGAACG 18 8085

BCLllA-6479 + GAGCUCCAUGUGCAGAACG 19 8086

BCLllA-5357 + AGAGCUCCAUGUGCAGAACG 20 8087

BCLllA-6480 + UAGAGCUCCAUGUGCAGAACG 21 8088

BCLllA-6481 + U UAGAGCUCCAUGUGCAGAACG 22 8089

BCLllA-6482 + AUUAGAGCUCCAUGUGCAGAACG 23 8090

BCLllA-6483 + GAUUAGAGCUCCAUGUGCAGAACG 24 8091

BCLllA-6484 + CUGCACUCAUCCCAGGCG 18 8092

BCLllA-6485 + UCUGCACUCAUCCCAGGCG 19 8093

BCLllA-5480 + UUCUGCACUCAUCCCAGGCG 20 8094

BCLllA-6486 + AUUCUGCACUCAUCCCAGGCG 21 8095

BCLllA-6487 + UAUUCUGCACUCAUCCCAGGCG 22 8096

BCLllA-6488 + AUAUUCUGCACUCAUCCCAGGCG 23 8097

BCLllA-6489 + CAUAUUCUGCACUCAUCCCAGGCG 24 8098

BCLllA-6490 + GGGUUUGCCUUGCU UGCG 18 8099

BCLllA-6491 + GGGGUUUGCCUUGCUUGCG 19 8100

BCLllA-6492 + UGGGGUUUGCCUUGCU UGCG 20 8101

BCLllA-6493 + CUGGGGUUUGCCUUGCUUGCG 21 8102

BCLllA-6494 + GCUGGGGUUUGCCUUGCUUGCG 22 8103

BCLllA-6495 + UGCUGGGGUUUGCCUUGCUUGCG 23 8104

BCLllA-6496 + GUGCUGGGGUUUGCCU UGCUUGCG 24 8105

BCLllA-6497 + CCAUGUGCAGAACGAGGG 18 8106

BCLllA-6498 + UCCAUGUGCAGAACGAGGG 19 8107

BCLllA-6499 + CUCCAUGUGCAGAACGAGGG 20 8108

BCLllA-6500 + GCUCCAUGUGCAGAACGAGGG 21 8109

BCLllA-6501 + AGCUCCAUGUGCAGAACGAGGG 22 8110

BCLllA-6502 + GAGCUCCAUGUGCAGAACGAGGG 23 8111

BCLllA-6503 + AGAGCUCCAUGUGCAGAACGAGGG 24 8112

BCLllA-6504 + GACAUGGUGGGCUGCGGG 18 8113

BCLllA-6505 + AGACAUGGUGGGCUGCGGG 19 8114

BCLllA-6506 + GAGACAUGGUGGGCUGCGGG 20 8115

BCLllA-6507 + CGAGACAUGGUGGGCUGCGGG 21 8116

BCLllA-6508 + GCGAGACAUGGUGGGCUGCGGG 22 8117

BCLllA-6509 + GGCGAGACAUGGUGGGCUGCGGG 23 8118

BCLllA-6510 + CGGCGAGACAUGGUGGGCUGCGGG 24 8119

BCLllA-6511 + CAUGUGCAGAACGAGGGG 18 8120

BCLllA-6512 + CCAUGUGCAGAACGAGGGG 19 8121 BCLllA-5488 + UCCAUGUGCAGAACGAGGGG 20 8122

BCLllA-6513 + CUCCAUGUGCAGAACGAGGGG 21 8123

BCLllA-6514 + GCUCCAUGUGCAGAACGAGGGG 22 8124

BCLllA-6515 + AGCUCCAUGUGCAGAACGAGGGG 23 8125

BCLllA-6516 + GAGCUCCAUGUGCAGAACGAGGGG 24 8126

BCLllA-6517 + CAAGAGGCUCGGCUGUGG 18 8127

BCLllA-6518 + UCAAGAGGCUCGGCUGUGG 19 8128

BCLllA-6519 + U UCAAGAGGCUCGGCUGUGG 20 8129

BCLllA-6520 + CUUCAAGAGGCUCGGCUGUGG 21 8130

BCLllA-6521 + GCU UCAAGAGGCUCGGCUGUGG 22 8131

BCLllA-6522 + GGCUUCAAGAGGCUCGGCUGUGG 23 8132

BCLllA-6523 + UGGCUUCAAGAGGCUCGGCUGUGG 24 8133

BCLllA-6524 + UGCUUGCGGCGAGACAUG 18 8134

BCLllA-6525 + U UGCUUGCGGCGAGACAUG 19 8135

BCLllA-6526 + CUUGCUUGCGGCGAGACAUG 20 8136

BCLllA-6527 + CCUUGCUUGCGGCGAGACAUG 21 8137

BCLllA-6528 + GCCUUGCUUGCGGCGAGACAUG 22 8138

BCLllA-6529 + UGCCU UGCUUGCGGCGAGACAUG 23 8139

BCLllA-6530 + UUGCCUUGCUUGCGGCGAGACAUG 24 8140

BCLllA-6531 + CAACUUACAAAUACCCUG 18 8141

BCLllA-6532 + UCAACUUACAAAUACCCUG 19 8142

BCLllA-5494 + CUCAACUUACAAAUACCCUG 20 8143

BCLllA-6533 + GCUCAACUUACAAAUACCCUG 21 8144

BCLllA-6534 + GGCUCAACUUACAAAUACCCUG 22 8145

BCLllA-6535 + AGGCUCAACUUACAAAUACCCUG 23 8146

BCLllA-6536 + AAGGCUCAACUUACAAAUACCCUG 24 8147

BCLllA-6537 + GUUGUACAUGUGUAGCUG 18 8148

BCLllA-6538 + AGUUGUACAUGUGUAGCUG 19 8149

BCLllA-6539 + AAGUUGUACAUGUGUAGCUG 20 8150

BCLllA-6540 + CAAGUUGUACAUGUGUAGCUG 21 8151

BCLllA-6541 + GCAAGUUGUACAUGUGUAGCUG 22 8152

BCLllA-6542 + UGCAAGUUGUACAUGUGUAGCUG 23 8153

BCLllA-6543 + U UGCAAGUUGUACAUGUGUAGCUG 24 8154

BCLllA-6544 + GCGAGACAUGGUGGGCUG 18 8155

BCLllA-6545 + GGCGAGACAUGGUGGGCUG 19 8156

BCLllA-5361 + CGGCGAGACAUGGUGGGCUG 20 8157

BCLllA-6546 + GCGGCGAGACAUGGUGGGCUG 21 8158

BCLllA-6547 + UGCGGCGAGACAUGGUGGGCUG 22 8159

BCLllA-6548 + UUGCGGCGAGACAUGGUGGGCUG 23 8160

BCLllA-6549 + CUUGCGGCGAGACAUGGUGGGCUG 24 8161

BCLllA-6550 + UUCCCGU UUGCUUAAGUG 18 8162

BCLllA-6551 + AUUCCCGUUUGCU UAAGUG 19 8163 BCLllA-6552 + AAUUCCCGUU UGCUUAAGUG 20 8164

BCLllA-6553 + GAAUUCCCGU UUGCUUAAGUG 21 8165

BCLllA-6554 + AGAAUUCCCGUUUGCU UAAGUG 22 8166

BCLllA-6555 + GAGAAUUCCCGU UUGCUUAAGUG 23 8167

BCLllA-6556 + CGAGAAUUCCCGUUUGCUUAAGUG 24 8168

BCLllA-6557 + GGAGAGGCCCCUCCAGUG 18 8169

BCLllA-6558 + AGGAGAGGCCCCUCCAGUG 19 8170

BCLllA-6559 + GAGGAGAGGCCCCUCCAGUG 20 8171

BCLllA-6560 + GGAGGAGAGGCCCCUCCAGUG 21 8172

BCLllA-6561 + GGGAGGAGAGGCCCCUCCAGUG 22 8173

BCLllA-6562 + GGGGAGGAGAGGCCCCUCCAGUG 23 8174

BCLllA-6563 + AGGGGAGGAGAGGCCCCUCCAGUG 24 8175

BCLllA-6564 + UGGCACUGCCCACAGGUG 18 8176

BCLllA-6565 + CUGGCACUGCCCACAGGUG 19 8177

BCLllA-5498 + UCUGGCACUGCCCACAGGUG 20 8178

BCLllA-6566 + AUCUGGCACUGCCCACAGGUG 21 8179

BCLllA-6567 + CAUCUGGCACUGCCCACAGGUG 22 8180

BCLllA-6568 + UCAUCUGGCACUGCCCACAGGUG 23 8181

BCLllA-6569 + U UCAUCUGGCACUGCCCACAGGUG 24 8182

BCLllA-6570 + U UUUCAUCUCGAUUGGUG 18 8183

BCLllA-6571 + U UUUUCAUCUCGAUUGGUG 19 8184

BCLllA-6572 + U UUUUUCAUCUCGAUUGGUG 20 8185

BCLllA-6573 + CUUUUUUCAUCUCGAU UGGUG 21 8186

BCLllA-6574 + GCUUUUUUCAUCUCGAUUGGUG 22 8187

BCLllA-6575 + UGCUUUUU UCAUCUCGAUUGGUG 23 8188

BCLllA-6576 + AUGCUUUUUUCAUCUCGAUUGGUG 24 8189

BCLllA-6577 + GGAUUAGAGCUCCAUGUG 18 8190

BCLllA-6578 + GGGAUUAGAGCUCCAUGUG 19 8191

BCLllA-6579 + GGGGAUUAGAGCUCCAUGUG 20 8192

BCLllA-6580 + UGGGGAUUAGAGCUCCAUGUG 21 8193

BCLllA-6581 + GUGGGGAUUAGAGCUCCAUGUG 22 8194

BCLllA-6582 + CGUGGGGAUUAGAGCUCCAUGUG 23 8195

BCLllA-6583 + GCGUGGGGAUUAGAGCUCCAUGUG 24 8196

BCLllA-6584 + CUUUUUUCAUCUCGAU UG 18 8197

BCLllA-6585 + GCU UUUUUCAUCUCGAUUG 19 8198

BCLllA-6586 + UGCUUUUUUCAUCUCGAUUG 20 8199

BCLllA-6587 + AUGCUUUUUUCAUCUCGAUUG 21 8200

BCLllA-6588 + GAUGCUUUUU UCAUCUCGAUUG 22 8201

BCLllA-6589 + GGAUGCUUUUUUCAUCUCGAUUG 23 8202

BCLllA-6590 + UGGAUGCUUUUUUCAUCUCGAUUG 24 8203

BCLllA-6591 + GAGGCUCGGCUGUGGU UG 18 8204

BCLllA-6592 + AGAGGCUCGGCUGUGGUUG 19 8205 BCLllA-6593 + AAGAGGCUCGGCUGUGGUUG 20 8206

BCLllA-6594 + CAAGAGGCUCGGCUGUGGUUG 21 8207

BCLllA-6595 + UCAAGAGGCUCGGCUGUGGUUG 22 8208

BCLllA-6596 + U UCAAGAGGCUCGGCUGUGGUUG 23 8209

BCLllA-6597 + CUUCAAGAGGCUCGGCUGUGGUUG 24 8210

BCLllA-6598 + AUAAGAAUGUCCCCCAAU 18 8211

BCLllA-6599 + AAUAAGAAUGUCCCCCAAU 19 8212

BCLllA-5502 + AAAUAAGAAUGUCCCCCAAU 20 8213

BCLllA-6600 + AAAAUAAGAAUGUCCCCCAAU 21 8214

BCLllA-6601 + AAAAAUAAGAAUGUCCCCCAAU 22 8215

BCLllA-6602 + UAAAAAUAAGAAUGUCCCCCAAU 23 8216

BCLllA-6603 + AUAAAAAUAAGAAUGUCCCCCAAU 24 8217

BCLllA-6604 + CAUCCCAGGCGUGGGGAU 18 8218

BCLllA-6605 + UCAUCCCAGGCGUGGGGAU 19 8219

BCLllA-6606 + CUCAUCCCAGGCGUGGGGAU 20 8220

BCLllA-6607 + ACUCAUCCCAGGCGUGGGGAU 21 8221

BCLllA-6608 + CACUCAUCCCAGGCGUGGGGAU 22 8222

BCLllA-6609 + GCACUCAUCCCAGGCGUGGGGAU 23 8223

BCLllA-6610 + UGCACUCAUCCCAGGCGUGGGGAU 24 8224

BCLllA-6611 + UCAACUUACAAAUACCCU 18 8225

BCLllA-6612 + CUCAACUUACAAAUACCCU 19 8226

BCLllA-6613 + GCUCAACUUACAAAUACCCU 20 8227

BCLllA-6614 + GGCUCAACUUACAAAUACCCU 21 8228

BCLllA-6615 + AGGCUCAACUUACAAAUACCCU 22 8229

BCLllA-6616 + AAGGCUCAACUUACAAAUACCCU 23 8230

BCLllA-6617 + UAAGGCUCAACUUACAAAUACCCU 24 8231

BCLllA-6618 + GGCGAGACAUGGUGGGCU 18 8232

BCLllA-6619 + CGGCGAGACAUGGUGGGCU 19 8233

BCLllA-6620 + GCGGCGAGACAUGGUGGGCU 20 8234

BCLllA-6621 + UGCGGCGAGACAUGGUGGGCU 21 8235

BCLllA-6622 + UUGCGGCGAGACAUGGUGGGCU 22 8236

BCLllA-6623 + CUUGCGGCGAGACAUGGUGGGCU 23 8237

BCLllA-6624 + GCUUGCGGCGAGACAUGGUGGGCU 24 8238

BCLllA-6625 + CAGUGCAGAAGUUUAUCU 18 8239

BCLllA-6626 + CCAGUGCAGAAGUUUAUCU 19 8240

BCLllA-6627 + UCCAGUGCAGAAGUU UAUCU 20 8241

BCLllA-6628 + CUCCAGUGCAGAAGUUUAUCU 21 8242

BCLllA-6629 + CCUCCAGUGCAGAAGUU UAUCU 22 8243

BCLllA-6630 + CCCUCCAGUGCAGAAGU UUAUCU 23 8244

BCLllA-6631 + CCCCUCCAGUGCAGAAGUUUAUCU 24 8245

BCLllA-6632 + CUGGCACUGCCCACAGGU 18 8246

BCLllA-6633 + UCUGGCACUGCCCACAGGU 19 8247 BCLllA-6634 + AUCUGGCACUGCCCACAGGU 20 8248

BCLllA-6635 + CAUCUGGCACUGCCCACAGGU 21 8249

BCLllA-6636 + UCAUCUGGCACUGCCCACAGGU 22 8250

BCLllA-6637 + UUCAUCUGGCACUGCCCACAGGU 23 8251

BCLllA-6638 + GU UCAUCUGGCACUGCCCACAGGU 24 8252

BCLllA-6639 + AAGAGGCUCGGCUGUGGU 18 8253

BCLllA-6640 + CAAGAGGCUCGGCUGUGGU 19 8254

BCLllA-5366 + UCAAGAGGCUCGGCUGUGGU 20 8255

BCLllA-6641 + U UCAAGAGGCUCGGCUGUGGU 21 8256

BCLllA-6642 + CUUCAAGAGGCUCGGCUGUGGU 22 8257

BCLllA-6643 + GCU UCAAGAGGCUCGGCUGUGGU 23 8258

BCLllA-6644 + GGCUUCAAGAGGCUCGGCUGUGGU 24 8259

BCLllA-6645 + CCUGCUAUGUGUUCCUGU 18 8260

BCLllA-6646 + ACCUGCUAUGUGUUCCUGU 19 8261

BCLllA-6647 + UACCUGCUAUGUGUUCCUGU 20 8262

BCLllA-6648 + U UACCUGCUAUGUGUUCCUGU 21 8263

BCLllA-6649 + U UUACCUGCUAUGUGU UCCUGU 22 8264

BCLllA-6650 + AUUUACCUGCUAUGUGUUCCUGU 23 8265

BCLllA-6651 + CAU UUACCUGCUAUGUGUUCCUGU 24 8266

BCLllA-6652 + GGAGGUCAUGAUCCCCU U 18 8267

BCLllA-6653 + AGGAGGUCAUGAUCCCCUU 19 8268

BCLllA-6654 + GAGGAGGUCAUGAUCCCCUU 20 8269

BCLllA-6655 + UGAGGAGGUCAUGAUCCCCUU 21 8270

BCLllA-6656 + GUGAGGAGGUCAUGAUCCCCU U 22 8271

BCLllA-6657 + GGUGAGGAGGUCAUGAUCCCCUU 23 8272

BCLllA-6658 + AGGUGAGGAGGUCAUGAUCCCCU U 24 8273

BCLllA-6659 + CUGCUAUGUGUUCCUGUU 18 8274

BCLllA-6660 + CCUGCUAUGUGUUCCUGUU 19 8275

BCLllA-5513 + ACCUGCUAUGUGUUCCUGUU 20 8276

BCLllA-6661 + UACCUGCUAUGUGUUCCUGUU 21 8277

BCLllA-6662 + U UACCUGCUAUGUGUUCCUGUU 22 8278

BCLllA-6663 + U UUACCUGCUAUGUGU UCCUGUU 23 8279

BCLllA-6664 + AUUUACCUGCUAUGUGUUCCUGUU 24 8280

BCLllA-6665 - AUUUUUAUCGAGCACAAA 18 8281

BCLllA-6666 - UAUUUUUAUCGAGCACAAA 19 8282

BCLllA-5342 - U UAUUUUUAUCGAGCACAAA 20 8283

BCLllA-6667 - CUUAUUUUUAUCGAGCACAAA 21 8284

BCLllA-6668 - UCU UAUUUUUAUCGAGCACAAA 22 8285

BCLllA-6669 - UUCUUAUUUU U AU CG AGCACAAA 23 8286

BCLllA-6670 - AUUCUUAUUUU UAUCGAGCACAAA 24 8287

BCLllA-6671 - AGAGGAAUUUGCCCCAAA 18 8288

BCLllA-6672 - UAGAGGAAUUUGCCCCAAA 19 8289 BCLllA-6673 - CUAGAGGAAUUUGCCCCAAA 20 8290

BCLllA-6674 - UCUAGAGGAAUUUGCCCCAAA 21 8291

BCLllA-6675 - AUCUAGAGGAAUUUGCCCCAAA 22 8292

BCLllA-6676 - CAUCUAGAGGAAUUUGCCCCAAA 23 8293

BCLllA-6677 - UCAUCUAGAGGAAUUUGCCCCAAA 24 8294

BCLllA-6678 - CCCCAGCACUUAAGCAAA 18 8295

BCLllA-6679 - ACCCCAGCACUUAAGCAAA 19 8296

BCLllA-5443 - AACCCCAGCACUUAAGCAAA 20 8297

BCLllA-6680 - AAACCCCAGCACUUAAGCAAA 21 8298

BCLllA-6681 - CAAACCCCAGCACUUAAGCAAA 22 8299

BCLllA-6682 - GCAAACCCCAGCACUUAAGCAAA 23 8300

BCLllA-6683 - GGCAAACCCCAGCACUUAAGCAAA 24 8301

BCLllA-6684 - UAUUUUUAUCGAGCACAA 18 8302

BCLllA-6685 - UUAUUUUUAUCGAGCACAA 19 8303

BCLllA-6686 - CUUAUUUUUAUCGAGCACAA 20 8304

BCLllA-6687 - UCUUAUUUUUAUCGAGCACAA 21 8305

BCLllA-6688 - UUCUUAUUUUUAUCGAGCACAA 22 8306

BCLllA-6689 - AUUCUUAUUUUUAUCGAGCACAA 23 8307

BCLllA-6690 - CAUUCUUAUUUUUAUCGAGCACAA 24 8308

BCLllA-6691 - CACCUUCCCCUUCACCAA 18 8309

BCLllA-6692 - CCACCUUCCCCUUCACCAA 19 8310

BCLllA-6693 - GCCACCUUCCCCUUCACCAA 20 8311

BCLllA-6694 - AG CCACCU U CCCCU U CACCAA 21 8312

BCLllA-6695 - AAGCCACCUUCCCCUUCACCAA 22 8313

BCLllA-6696 - UAAGCCACCUUCCCCUUCACCAA 23 8314

BCLllA-6697 - AUAAGCCACCUUCCCCUUCACCAA 24 8315

BCLllA-6698 - ACCCCAGCACUUAAGCAA 18 8316

BCLllA-6699 - AACCCCAGCACUUAAGCAA 19 8317

BCLllA-6700 - AAACCCCAGCACUUAAGCAA 20 8318

BCLllA-6701 - CAAACCCCAGCACUUAAGCAA 21 8319

BCLllA-6702 - GCAAACCCCAGCACUUAAGCAA 22 8320

BCLllA-6703 - G G C A A AC CC C AG C A C U U A AG C A A 23 8321

BCLllA-6704 - AG G CA AACCCC AG CAC U UAAG CAA 24 8322

BCLllA-6705 - GGAACACAUAGCAGGUAA 18 8323

BCLllA-6706 - AGGAACACAUAGCAGGUAA 19 8324

BCLllA-6707 - CAGGAACACAUAGCAGGUAA 20 8325

BCLllA-6708 - ACAGGAACACAUAGCAGGUAA 21 8326

BCLllA-6709 - AACAGGAACACAUAGCAGGUAA 22 8327

BCLllA-6710 - AAA CAGGAACACAUAGCAGGUAA 23 8328

BCLllA-6711 - CAAACAGGAACACAUAGCAGGUAA 24 8329

BCLllA-6712 - CUCCCCUCGUUCUGCACA 18 8330

BCLllA-6713 - CCUCCCCUCGUUCUGCACA 19 8331 BCLllA-5448 - UCCUCCCCUCGUUCUGCACA 20 8332

BCLllA-6714 - CUCCUCCCCUCGUUCUGCACA 21 8333

BCLllA-6715 - UCUCCUCCCCUCGUUCUGCACA 22 8334

BCLllA-6716 - CUCUCCUCCCCUCGUUCUGCACA 23 8335

BCLllA-6717 - CCUCUCCUCCCCUCGUUCUGCACA 24 8336

BCLllA-6718 - UGCCAGAUGAACUUCCCA 18 8337

BCLllA-6719 - GUGCCAGAUGAACUUCCCA 19 8338

BCLllA-6720 - AGUGCCAGAUGAACUUCCCA 20 8339

BCLllA-6721 - CAGUGCCAGAUGAACUUCCCA 21 8340

BCLllA-6722 - GCAGUGCCAGAUGAACUUCCCA 22 8341

BCLllA-6723 - GGCAGUGCCAGAUGAACUUCCCA 23 8342

BCLllA-6724 - GGGCAGUGCCAGAUGAACUUCCCA 24 8343

BCLllA-6725 - G C AG G U AAA UGAGAAGCA 18 8344

BCLllA-6726 - AG C AG G U AAA U G AG A AG C A 19 8345

BCLllA-5451 - U AG C AG G U AAA U G AG A AG C A 20 8346

BCLllA-6727 - AUAGCAGGUAAAUGAGAAGCA 21 8347

BCLllA-6728 - CAUAGCAGGU AAA U GAG A AG C A 22 8348

BCLllA-6729 - ACAUAGCAGGUAAAUGAGAAGCA 23 8349

BCLllA-6730 - CACAUAGCAGGUAAAUGAGAAGCA 24 8350

BCLllA-6731 - CACAGAUAAACUUCUGCA 18 8351

BCLllA-6732 - UCACAGAUAAACUUCUGCA 19 8352

BCLllA-6733 - UUCACAGAUAAACUUCUGCA 20 8353

BCLllA-6734 - UUUCACAGAUAAACUUCUGCA 21 8354

BCLllA-6735 - CUUUCACAGAUAAACUUCUGCA 22 8355

BCLllA-6736 - UCUUUCACAGAUAAACUUCUGCA 23 8356

BCLllA-6737 - UUCUUUCACAGAUAAACUUCUGCA 24 8357

BCLllA-6738 - CCCGUUGGGAGCUCCAGA 18 8358

BCLllA-6739 - GCCCGUUGGGAGCUCCAGA 19 8359

BCLllA-5453 - GGCCCGUUGGGAGCUCCAGA 20 8360

BCLllA-6740 - CGGCCCGUUGGGAGCUCCAGA 21 8361

BCLllA-6741 - ACGGCCCGUUGGGAGCUCCAGA 22 8362

BCLllA-6742 - CACGGCCCGUUGGGAGCUCCAGA 23 8363

BCLllA-6743 - CCACGGCCCGUUGGGAGCUCCAGA 24 8364

BCLllA-6744 - GUUUAUCAACGUCAUCUA 18 8365

BCLllA-6745 - UGUUUAUCAACGUCAUCUA 19 8366

BCLllA-6746 - UUGUUUAUCAACGUCAUCUA 20 8367

BCLllA-6747 - AUUGUUUAUCAACGUCAUCUA 21 8368

BCLllA-6748 - GAUUGUUUAUCAACGUCAUCUA 22 8369

BCLllA-6749 - CGAUUGUUUAUCAACGUCAUCUA 23 8370

BCLllA-6750 - ACGAUUGUUUAUCAACGUCAUCUA 24 8371

BCLllA-6751 - GGGACAUUCUUAUUUUUA 18 8372

BCLllA-6752 - GGGGACAUUCUUAUUUUUA 19 8373 BCLllA-6753 - GGGGGACAUUCUUAUUUUUA 20 8374

BCLllA-6754 - UGGGGGACAUUCUUAUUUUUA 21 8375

BCLllA-6755 - UUGGGGGACAUUCUUAUUUUUA 22 8376

BCLllA-6756 - AUUGGGGGACAUUCUUAUUUUUA 23 8377

BCLllA-6757 - CAUUGGGGGACAUUCUUAUUUUUA 24 8378

BCLllA-6758 - GAGGAAUUUGCCCCAAAC 18 8379

BCLllA-6759 - AGAGGAAUUUGCCCCAAAC 19 8380

BCLllA-5457 - UAGAGGAAUUUGCCCCAAAC 20 8381

BCLllA-6760 - CUAGAGGAAUUUGCCCCAAAC 21 8382

BCLllA-6761 - UCUAGAGGAAUUUGCCCCAAAC 22 8383

BCLllA-6762 - AUCUAGAGGAAUUUGCCCCAAAC 23 8384

BCLllA-6763 - CAUCUAGAGGAAUUUGCCCCAAAC 24 8385

BCLllA-6764 - ACAGAUAAACUUCUGCAC 18 8386

BCLllA-6765 - CACAGAUAAACUUCUGCAC 19 8387

BCLllA-5348 - UCACAGAUAAACUUCUGCAC 20 8388

BCLllA-6766 - UUCACAGAUAAACUUCUGCAC 21 8389

BCLllA-6767 - UUUCACAGAUAAACUUCUGCAC 22 8390

BCLllA-6768 - CUUUCACAGAUAAACUUCUGCAC 23 8391

BCLllA-6769 - UCUUUCACAGAUAAACUUCUGCAC 24 8392

BCLllA-6770 - CCUCCCCUCGUUCUGCAC 18 8393

BCLllA-6771 - UCCUCCCCUCGUUCUGCAC 19 8394

BCLllA-6772 - CUCCUCCCCUCGUUCUGCAC 20 8395

BCLllA-6773 - UCUCCUCCCCUCGUUCUGCAC 21 8396

BCLllA-6774 - CUCUCCUCCCCUCGUUCUGCAC 22 8397

BCLllA-6775 - CCUCUCCUCCCCUCGUUCUGCAC 23 8398

BCLllA-6776 - GCCUCUCCUCCCCUCGUUCUGCAC 24 8399

BCLllA-6777 - AAAAAAGCAUCCAAUCCC 18 8400

BCLllA-6778 - G A A A A A AG C A U C C A A U C C C 19 8401

BCLllA-6779 - UGAAAAAAGCAUCCAAUCCC 20 8402

BCLllA-6780 - AUGAAAAAAGCAUCCAAUCCC 21 8403

BCLllA-6781 - G A U G A A A A A AG CAUCCAAUCCC 22 8404

BCLllA-6782 - AGAUGAAAAAAGCAUCCAAUCCC 23 8405

BCLllA-6783 - GAGAUGAAAAAAGCAUCCAAUCCC 24 8406

BCLllA-6784 - AGCAGGUAAAUGAGAAGC 18 8407

BCLllA-6785 - UAGCAGGUAAAUGAGAAGC 19 8408

BCLllA-6786 - AUAGCAGGUAAAUGAGAAGC 20 8409

BCLllA-6787 - CAUAGCAGGUAAAUGAGAAGC 21 8410

BCLllA-6788 - ACAUAGCAGGU AAA U G AG A AG C 22 8411

BCLllA-6789 - CACAUAGCAGGU AAA U G AG A AG C 23 8412

BCLllA-6790 - ACACAUAGCAGGUAAAUGAGAAGC 24 8413

BCLllA-6791 - GAGCUCUAAUCCCCACGC 18 8414

BCLllA-6792 - GGAGCUCUAAUCCCCACGC 19 8415 BCLllA-6793 - UGGAGCUCUAAUCCCCACGC 20 8416

BCLllA-6794 - AUGGAGCUCUAAUCCCCACGC 21 8417

BCLllA-6795 - CAUGGAGCUCUAAUCCCCACGC 22 8418

BCLllA-6796 - ACAUGGAGCUCUAAUCCCCACGC 23 8419

BCLllA-6797 - CACAUGGAGCUCUAAUCCCCACGC 24 8420

BCLllA-6798 - UUGGCAUCCAGGUCACGC 18 8421

BCLllA-6799 - GUUGGCAUCCAGGUCACGC 19 8422

BCLllA-6800 - GGUUGGCAUCCAGGUCACGC 20 8423

BCLllA-6801 - AGGUUGGCAUCCAGGUCACGC 21 8424

BCLllA-6802 - GAGGUUGGCAUCCAGGUCACGC 22 8425

BCLllA-6803 - GGAGGUUGGCAUCCAGGUCACGC 23 8426

BCLllA-6804 - UGGAGGUUGGCAUCCAGGUCACGC 24 8427

BCLllA-6805 - UUGUUUAUCAACGUCAUC 18 8428

BCLllA-6806 - AUUGUUUAUCAACGUCAUC 19 8429

BCLllA-6807 - GAUUGUUUAUCAACGUCAUC 20 8430

BCLllA-6808 - CGAUUGUUUAUCAACGUCAUC 21 8431

BCLllA-6809 - ACGAUUGUUUAUCAACGUCAUC 22 8432

BCLllA-6810 - GACGAUUGUUUAUCAACGUCAUC 23 8433

BCLllA-6811 - UGACGAUUGUUUAUCAACGUCAUC 24 8434

BCLllA-6812 - CAACCACAGCCGAGCCUC 18 8435

BCLllA-6813 - CCAACCACAGCCGAGCCUC 19 8436

BCLllA-6814 - UCCAACCACAGCCGAGCCUC 20 8437

BCLllA-6815 - CUCCAACCACAGCCGAGCCUC 21 8438

BCLllA-6816 - UCUCCAACCACAGCCGAGCCUC 22 8439

BCLllA-6817 - UUCUCCAACCACAGCCGAGCCUC 23 8440

BCLllA-6818 - UUUCUCCAACCACAGCCGAGCCUC 24 8441

BCLllA-6819 - ACGGCCCGUUGGGAGCUC 18 8442

BCLllA-6820 - CACGGCCCGUUGGGAGCUC 19 8443

BCLllA-6821 - CCACGGCCCGUUGGGAGCUC 20 8444

BCLllA-6822 - ACCACGGCCCGUUGGGAGCUC 21 8445

BCLllA-6823 - GACCACGGCCCGUUGGGAGCUC 22 8446

BCLllA-6824 - AGACCACGGCCCGUUGGGAGCUC 23 8447

BCLllA-6825 - CAGACCACGGCCCGUUGGGAGCUC 24 8448

BCLllA-6826 - AUUAUUUUGCAGGUAAAG 18 8449

BCLllA-6827 - UAUUAUUUUGCAGGUAAAG 19 8450

BCLllA-6828 - GU AUUAUUUUGCAGGUAAAG 20 8451

BCLllA-6829 - UGUAUUAUUUUGCAGGUAAAG 21 8452

BCLllA-6830 - UUGUAUUAUUUUGCAGGUAAAG 22 8453

BCLllA-6831 - GUUGUAUUAUUUUGCAGGUAAAG 23 8454

BCLllA-6832 - UGUUGUAUUAUUUUGCAGGUAAAG 24 8455

BCLllA-6833 - AGGUAAAUGAGAAGCAAG 18 8456

BCLllA-6834 - C AG G U AAA UGAGAAGCAAG 19 8457 BCLllA-6835 - GCAGGUAAAUGAGAAGCAAG 20 8458

BCLllA-6836 - AG C AG G U AAA U G AG A AG C A AG 21 8459

BCLllA-6837 - U AG C AG G U AAA U G AG A AG C A AG 22 8460

BCLllA-6838 - AUAGCAGGUAAAUGAGAAGCAAG 23 8461

BCLllA-6839 - CAUAGCAGGUAAAUGAGAAGCAAG 24 8462

BCLllA-6840 - CCGCAGGGUAUUUGUAAG 18 8463

BCLllA-6841 - CCCGCAGGGUAUUUGUAAG 19 8464

BCLllA-6842 - CCCCGCAGGGUAUUUGUAAG 20 8465

BCLllA-6843 - GCCCCGCAGGGUAUUUGUAAG 21 8466

BCLllA-6844 - UGCCCCGCAGGGUAUUUGUAAG 22 8467

BCLllA-6845 - AUGCCCCGCAGGGUAUUUGUAAG 23 8468

BCLllA-6846 - UAUGCCCCGCAGGGUAUUUGUAAG 24 8469

BCLllA-6847 - UUGUUUCU CCAACCACAG 18 8470

BCLllA-6848 - UUUGUUUCUCCAACCACAG 19 8471

BCLllA-6849 - UUUUGUUUCUCCAACCACAG 20 8472

BCLllA-6850 - CUUUUGUUUCUCCAACCACAG 21 8473

BCLllA-6851 - GCUUUUGUUUCUCCAACCACAG 22 8474

BCLllA-6852 - UGCUUUUGUUUCUCCAACCACAG 23 8475

BCLllA-6853 - GUGCUUUUGUUUCUCCAACCACAG 24 8476

BCLllA-6854 - ACCUGUGGGCAGUGCCAG 18 8477

BCLllA-6855 - CACCUGUGGGCAGUGCCAG 19 8478

BCLllA-6856 - UCACCUGUGGGCAGUGCCAG 20 8479

BCLllA-6857 - CUCACCUGUGGGCAGUGCCAG 21 8480

BCLllA-6858 - CCUCACCUGUGGGCAGUGCCAG 22 8481

BCLllA-6859 - UCCUCACCUGUGGGCAGUGCCAG 23 8482

BCLllA-6860 - CUCCUCACCUGUGGGCAGUGCCAG 24 8483

BCLllA-6861 - GCCCGUUGGGAGCUCCAG 18 8484

BCLllA-6862 - GGCCCGUUGGGAGCUCCAG 19 8485

BCLllA-6863 - CGGCCCGUUGGGAGCUCCAG 20 8486

BCLllA-6864 - ACGGCCCGUUGGGAGCUCCAG 21 8487

BCLllA-6865 - CACGGCCCGUUGGGAGCUCCAG 22 8488

BCLllA-6866 - CCACGGCCCGUUGGGAGCUCCAG 23 8489

BCLllA-6867 - ACCACGGCCCGUUGGGAGCUCCAG 24 8490

BCLllA-6868 - UCCCCUUCACCAAUCGAG 18 8491

BCLllA-6869 - UUCCCCUUCACCAAUCGAG 19 8492

BCLllA-6870 - CUUCCCCUUCACCAAUCGAG 20 8493

BCLllA-6871 - CCUUCCCCUUCACCAAUCGAG 21 8494

BCLllA-6872 - ACCUUCCCCUUCACCAAUCGAG 22 8495

BCLllA-6873 - CACCU U CCCCU U CACCAAU CG AG 23 8496

BCLllA-6874 - CCACCUUCCCCUUCACCAAUCGAG 24 8497

BCLllA-6875 - GAACCAGACCACGGCCCG 18 8498

BCLllA-6876 - UGAACCAGACCACGGCCCG 19 8499 BCLllA-6877 - AUGAACCAGACCACGGCCCG 20 8500

BCLllA-6878 - GAUGAACCAGACCACGGCCCG 21 8501

BCLllA-6879 - UGAUGAACCAGACCACGGCCCG 22 8502

BCLllA-6880 - AUGAUGAACCAGACCACGGCCCG 23 8503

BCLllA-6881 - GAUGAUGAACCAGACCACGGCCCG 24 8504

BCLllA-6882 - AAAAAGCAUCCAAUCCCG 18 8505

BCLllA-6883 - A A A A A AG C A U C C A A U C C CG 19 8506

BCLllA-5358 - GAAAAAAGCAUCCAAUCCCG 20 8507

BCLllA-6884 - UGAAAAAAGCAUCCAAUCCCG 21 8508

BCLllA-6885 - AUGAAAAAAGCAUCCAAUCCCG 22 8509

BCLllA-6886 - GAUGAAAAAAGCAUCCAAUCCCG 23 8510

BCLllA-6887 - AGAUGAAAAAAGCAUCCAAUCCCG 24 8511

BCLllA-6888 - GAUAAACUUCUGCACUGG 18 8512

BCLllA-6889 - AGAUAAACUUCUGCACUGG 19 8513

BCLllA-5360 - CAGAUAAACUUCUGCACUGG 20 8514

BCLllA-6890 - ACAGAUAAACUUCUGCACUGG 21 8515

BCLllA-6891 - CACAGAUAAACUUCUGCACUGG 22 8516

BCLllA-6892 - UCA CAGAUAAACUUCUGCACUGG 23 8517

BCLllA-6893 - UUCACAGAUAAACUUCUGCACUGG 24 8518

BCLllA-6894 - AAGCCAUUCUUACAGAUG 18 8519

BCLllA-6895 - GAAGCCAUUCUUACAGAUG 19 8520

BCLllA-6896 - UGAAGCCAUUCUUACAGAUG 20 8521

BCLllA-6897 - UUGAAGCCAUUCUUACAGAUG 21 8522

BCLllA-6898 - CUUGAAGCCAUUCUUACAGAUG 22 8523

BCLllA-6899 - UCUUGAAGCCAUUCUUACAGAUG 23 8524

BCLllA-6900 - CUCUUGAAGCCAUUCUUACAGAUG 24 8525

BCLllA-6901 - AGAUAAACUUCUGCACUG 18 8526

BCLllA-6902 - CAGAUAAACUUCUGCACUG 19 8527

BCLllA-6903 - ACAGAUAAACUUCUGCACUG 20 8528

BCLllA-6904 - CACAGAUAAACUUCUGCACUG 21 8529

BCLllA-6905 - UCACAGAUAAACUUCUGCACUG 22 8530

BCLllA-6906 - UUCACAGAUAAACUUCUGCACUG 23 8531

BCLllA-6907 - UUUCACAGAUAAACUUCUGCACUG 24 8532

BCLllA-6908 - CAGAUGAACUUCCCAUUG 18 8533

BCLllA-6909 - CCAGAUGAACUUCCCAUUG 19 8534

BCLllA-5499 - GCCAGAUGAACUUCCCAUUG 20 8535

BCLllA-6910 - UGCCAGAUGAACUUCCCAUUG 21 8536

BCLllA-6911 - GUGCCAGAUGAACUUCCCAUUG 22 8537

BCLllA-6912 - AGUGCCAGAUGAACUUCCCAUUG 23 8538

BCLllA-6913 - CAGUGCCAGAUGAACUUCCCAUUG 24 8539

BCLllA-6914 - AACACAUAGCAGGUAAAU 18 8540

BCLllA-6915 - GAACACAUAGCAGGUAAAU 19 8541 BCLllA-6916 - GGAACACAUAGCAGGUAAAU 20 8542

BCLllA-6917 - AGGAACACAUAGCAGGUAAAU 21 8543

BCLllA-6918 - CAGGAACACAUAGCAGGUAAAU 22 8544

BCLllA-6919 - ACAGGAACACAUAGCAGGUAAAU 23 8545

BCLllA-6920 - AACAGGAACACAUAGCAGGUAAAU 24 8546

BCLllA-6921 - GCCAGAUGAACUUCCCAU 18 8547

BCLllA-6922 - UGCCAGAUGAACUUCCCAU 19 8548

BCLllA-5503 - GUGCCAGAUGAACUUCCCAU 20 8549

BCLllA-6923 - AGUGCCAGAUGAACUUCCCAU 21 8550

BCLllA-6924 - CAGUGCCAGAUGAACUUCCCAU 22 8551

BCLllA-6925 - GCAGUGCCAGAUGAACUUCCCAU 23 8552

BCLllA-6926 - GGCAGUGCCAGAUGAACUUCCCAU 24 8553

BCLllA-6927 - AUCAUGACCUCCUCACCU 18 8554

BCLllA-6928 - GAUCAUGACCUCCUCACCU 19 8555

BCLllA-6929 - GGAUCAUGACCUCCUCACCU 20 8556

BCLllA-6930 - GGGAUCAUGACCUCCUCACCU 21 8557

BCLllA-6931 - GGGGAUCAUGACCUCCUCACCU 22 8558

BCLllA-6932 - AGGGGAUCAUGACCUCCUCACCU 23 8559

BCLllA-6933 - AAGGGGAUCAUGACCUCCUCACCU 24 8560

BCLllA-6934 - GCAAUGGCAGCCUCUGCU 18 8561

BCLllA-6935 - UGCAAUGGCAGCCUCUGCU 19 8562

BCLllA-6936 - AUGCAAUGGCAGCCUCUGCU 20 8563

BCLllA-6937 - AAUGCAAUGGCAGCCUCUGCU 21 8564

BCLllA-6938 - CAAUGCAAUGGCAGCCUCUGCU 22 8565

BCLllA-6939 - ACAAUGCAAUGGCAGCCUCUGCU 23 8566

BCLllA-6940 - AACAAUGCAAUGGCAGCCUCUGCU 24 8567

BCLllA-6941 - AACCAGACCACGGCCCGU 18 8568

BCLllA-6942 - GAACCAGACCACGGCCCGU 19 8569

BCLllA-5363 - UGAACCAGACCACGGCCCGU 20 8570

BCLllA-6943 - AUGAACCAGACCACGGCCCGU 21 8571

BCLllA-6944 - GAUGAACCAGACCACGGCCCGU 22 8572

BCLllA-6945 - UGAUGAACCAGACCACGGCCCGU 23 8573

BCLllA-6946 - AUGAUGAACCAGACCACGGCCCGU 24 8574

BCLllA-6947 - CCAGAUGAACUUCCCAUU 18 8575

BCLllA-6948 - GCCAGAUGAACUUCCCAUU 19 8576

BCLllA-5511 - UGCCAGAUGAACUUCCCAUU 20 8577

BCLllA-6949 - GUGCCAGAUGAACUUCCCAUU 21 8578

BCLllA-6950 - AGUGCCAGAUGAACUUCCCAUU 22 8579

BCLllA-6951 - CAGUGCCAGAUGAACUUCCCAUU 23 8580

BCLllA-6952 - GCAGUGCCAGAUGAACUUCCCAUU 24 8581

BCLllA-6953 - ACCAG ACCACGG CCCG U U 18 8582

BCLllA-6954 - AACCAGACCACGGCCCGUU 19 8583 BCLllA-5512 - G AACCAG ACCACGG CCCG U U 20 8584

BCLllA-6955 - UGAACCAGACCACGGCCCGUU 21 8585

BCLllA-6956 - AUGAACCAGACCACGGCCCGUU 22 8586

BCLllA-6957 - GAUGAACCAGACCACGGCCCGUU 23 8587

BCLllA-6958 - UGAUGAACCAGACCACGGCCCGUU 24 8588

Table 16D provides exemplary targeting domains for knocking out the BCL11A gene selected according to the fourth tier parameters. The targeting domains fall in the coding sequence of the gene, downstream of the first 500bp of coding sequence (e.g., anywhere from +500 (relative to the start codon) to the stop codon of the gene), and the PAM is NNGRRT. It is contemplated herein that in an embodiment the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. aureus Cas9 molecule that generates a double stranded break (Cas9 nuclease) or a single- stranded break (Cas9 nickase).

Table 16D

BCLllA-6979 + AGUCUCCGAAGCUAAGGA 18 8610

BCLllA-6980 + GAGUCUCCGAAGCUAAGGA 19 8611

BCLllA-5923 + GGAGUCUCCGAAGCUAAGGA 20 8612

BCLllA-6981 + UGGAGUCUCCGAAGCUAAGGA 21 8613

BCLllA-6982 + CUGGAGUCUCCGAAGCUAAGGA 22 8614

BCLllA-6983 + UCUGGAGUCUCCGAAGCUAAGGA 23 8615

BCLllA-6984 + GUCUGGAGUCUCCGAAGCUAAGGA 24 8616

BCLllA-6985 + GGACUAAACAGGGGGGGA 18 8617

BCLllA-6986 + UGGACUAAACAGGGGGGGA 19 8618

BCLllA-6987 + GUGGACUAAACAGGGGGGGA 20 8619

BCLllA-6988 + GGUGGACUAAACAGGGGGGGA 21 8620

BCLllA-6989 + UGGUGGACUAAACAGGGGGGGA 22 8621

BCLllA-6990 + GUGGUGGACUAAACAGGGGGGGA 23 8622

BCLllA-6991 + GGUGGUGGACUAAACAGGGGGGGA 24 8623

BCLllA-6992 + UUCUGCACCUAGUCCUGA 18 8624

BCLllA-6993 + AUUCUGCACCUAGUCCUGA 19 8625

BCLllA-5937 + CAUUCUGCACCUAGUCCUGA 20 8626

BCLllA-6994 + ACAUUCUGCACCUAGUCCUGA 21 8627

BCLllA-6995 + GACAUUCUGCACCUAGUCCUGA 22 8628

BCLllA-6996 + GGACAUUCUGCACCUAGUCCUGA 23 8629

BCLllA-6997 + AGGACAUUCUGCACCUAGUCCUGA 24 8630

BCLllA-6998 + GCACCCUGUCAAAGGCAC 18 8631

BCLllA-6999 + AGCACCCUGUCAAAGGCAC 19 8632

BCLllA-7000 + C AG CACCCUGU CAAAG G CAC 20 8633

BCLllA-7001 + GCAGCACCCUGUCAAAGGCAC 21 8634

BCLllA-7002 + CGCAGCACCCUGUCAAAGGCAC 22 8635

BCLllA-7003 + CCGCAGCACCCUGUCAAAGGCAC 23 8636

BCLllA-7004 + ACCGCAGCACCCUGUCAAAGGCAC 24 8637

BCLllA-7005 + UAAGUAGAUUCUUAAUCC 18 8638

BCLllA-7006 + CUAAGUAGAUUCUUAAUCC 19 8639

BCLllA-7007 + UCUAAGUAGAUUCUUAAUCC 20 8640

BCLllA-7008 + UUCUAAGUAGAUUCU UAAUCC 21 8641

BCLllA-7009 + UUUCUAAGUAGAUUCUUAAUCC 22 8642

BCLllA-7010 + CUUUCUAAGUAGAUUCUUAAUCC 23 8643

BCLllA-7011 + GCUUUCUAAGUAGAUUCUUAAUCC 24 8644

BCLllA-7012 + GGCGGCUUGCUACCUGGC 18 8645

BCLllA-7013 + GGGCGGCUUGCUACCUGGC 19 8646

BCLllA-6036 + AGGGCGGCUUGCUACCUGGC 20 8647

BCLllA-7014 + AAGGGCGGCUUGCUACCUGGC 21 8648

BCLllA-7015 + GAAGGGCGGCUUGCUACCUGGC 22 8649

BCLllA-7016 + GGAAGGGCGGCUUGCUACCUGGC 23 8650

BCLllA-7017 + AGGAAGGGCGGCUUGCUACCUGGC 24 8651 BCLllA-7018 + GCGCUUCAGCUUGCUGGC 18 8652

BCLllA-7019 + GGCGCUUCAGCUUGCUGGC 19 8653

BCLllA-7020 + UGGCGCU UCAGCUUGCUGGC 20 8654

BCLllA-7021 + GUGGCGCU UCAGCUUGCUGGC 21 8655

BCLllA-7022 + UGUGGCGCUUCAGCU UGCUGGC 22 8656

BCLllA-7023 + AUGUGGCGCU UCAGCU UGCUGGC 23 8657

BCLllA-7024 + CAUGUGGCGCUUCAGCUUGCUGGC 24 8658

BCLllA-7025 + CUCCUCGUCCCCGUUCUC 18 8659

BCLllA-7026 + CCUCCUCGUCCCCGUUCUC 19 8660

BCLllA-6050 + UCCUCCUCGUCCCCGUUCUC 20 8661

BCLllA-7027 + U UCCUCCUCGUCCCCGU UCUC 21 8662

BCLllA-7028 + CUUCCUCCUCGUCCCCGUUCUC 22 8663

BCLllA-7029 + UCUUCCUCCUCGUCCCCGU UCUC 23 8664

BCLllA-7030 + CUCUUCCUCCUCGUCCCCGUUCUC 24 8665

BCLllA-7031 + AGGCAAAAGGCGAUUGUC 18 8666

BCLllA-7032 + GAGGCAAAAGGCGAUUGUC 19 8667

BCLllA-6054 + GGAGGCAAAAGGCGAUUGUC 20 8668

BCLllA-7033 + AGGAGGCAAAAGGCGAU UGUC 21 8669

BCLllA-7034 + GAGGAGGCAAAAGGCGAUUGUC 22 8670

BCLllA-7035 + CGAGGAGGCAAAAGGCGAUUGUC 23 8671

BCLllA-7036 + ACGAGGAGGCAAAAGGCGAUUGUC 24 8672

BCLllA-7037 + AGCUCUCUGGGUACUACG 18 8673

BCLllA-7038 + GAGCUCUCUGGGUACUACG 19 8674

BCLllA-7039 + UGAGCUCUCUGGGUACUACG 20 8675

BCLllA-7040 + UUGAGCUCUCUGGGUACUACG 21 8676

BCLllA-7041 + CUUGAGCUCUCUGGGUACUACG 22 8677

BCLllA-7042 + UCUUGAGCUCUCUGGGUACUACG 23 8678

BCLllA-7043 + AUCUUGAGCUCUCUGGGUACUACG 24 8679

BCLllA-7044 + UGAAGGGAUACCAACCCG 18 8680

BCLllA-7045 + CUGAAGGGAUACCAACCCG 19 8681

BCLllA-6084 + CCUGAAGGGAUACCAACCCG 20 8682

BCLllA-7046 + UCCUGAAGGGAUACCAACCCG 21 8683

BCLllA-7047 + GUCCUGAAGGGAUACCAACCCG 22 8684

BCLllA-7048 + AGUCCUGAAGGGAUACCAACCCG 23 8685

BCLllA-7049 + UAGUCCUGAAGGGAUACCAACCCG 24 8686

BCLllA-7050 + GCAAACUCCCGUUCUCCG 18 8687

BCLllA-7051 + CGCAAACUCCCGUUCUCCG 19 8688

BCLllA-6094 + GCGCAAACUCCCGUUCUCCG 20 8689

BCLllA-7052 + AGCGCAAACUCCCGUUCUCCG 21 8690

BCLllA-7053 + AAGCGCAAACUCCCGUUCUCCG 22 8691

BCLllA-7054 + GAAGCGCAAACUCCCGUUCUCCG 23 8692

BCLllA-7055 + AGAAGCGCAAACUCCCGUUCUCCG 24 8693 BCLllA-7056 + GGCUGGGAGGGAGGAGGG 18 8694

BCLllA-7057 + GGGCUGGGAGGGAGGAGGG 19 8695

BCLllA-7058 + GGGGCUGGGAGGGAGGAGGG 20 8696

BCLllA-7059 + GGGGGCUGGGAGGGAGGAGGG 21 8697

BCLllA-7060 + CGGGGGCUGGGAGGGAGGAGGG 22 8698

BCLllA-7061 + CCGGGGGCUGGGAGGGAGGAGGG 23 8699

BCLllA-7062 + ACCGGGGGCUGGGAGGGAGGAGGG 24 8700

BCLllA-7063 + UGGUGGACUAAACAGGGG 18 8701

BCLllA-7064 + GUGGUGGACUAAACAGGGG 19 8702

BCLllA-6139 + GGUGGUGGACUAAACAGGGG 20 8703

BCLllA-7065 + CGGUGGUGGACUAAACAGGGG 21 8704

BCLllA-7066 + UCGGUGGUGGACUAAACAGGGG 22 8705

BCLllA-7067 + CUCGGUGGUGGACUAAACAGGGG 23 8706

BCLllA-7068 + UCUCGGUGGUGGACUAAACAGGGG 24 8707

BCLllA-7069 + AAGAGAAACCAUGCACUG 18 8708

BCLllA-7070 + CAAGAGAAACCAUGCACUG 19 8709

BCLllA-7071 + GCAAGAGAAACCAUGCACUG 20 8710

BCLllA-7072 + UGCAAGAGAAACCAUGCACUG 21 8711

BCLllA-7073 + U UGCAAGAGAAACCAUGCACUG 22 8712

BCLllA-7074 + G U U G C AAG AG AAACC AU G CAC U G 23 8713

BCLllA-7075 + U G U U G C AAG AG AAACC AU G CAC U G 24 8714

BCLllA-7076 + GUCAAAGGCACUCGGGUG 18 8715

BCLllA-7077 + UGUCAAAGGCACUCGGGUG 19 8716

BCLllA-7078 + CUGUCAAAGGCACUCGGGUG 20 8717

BCLllA-7079 + CCUGUCAAAGGCACUCGGGUG 21 8718

BCLllA-7080 + CCCUGUCAAAGGCACUCGGGUG 22 8719

BCLllA-7081 + ACCCUGUCAAAGGCACUCGGGUG 23 8720

BCLllA-7082 + CACCCUGUCAAAGGCACUCGGGUG 24 8721

BCLllA-7083 + CCCACCAAGUCGCUGGUG 18 8722

BCLllA-7084 + GCCCACCAAGUCGCUGGUG 19 8723

BCLllA-7085 + UGCCCACCAAGUCGCUGGUG 20 8724

BCLllA-7086 + CUGCCCACCAAGUCGCUGGUG 21 8725

BCLllA-7087 + GCUGCCCACCAAGUCGCUGGUG 22 8726

BCLllA-7088 + CGCUGCCCACCAAGUCGCUGGUG 23 8727

BCLllA-7089 + GCGCUGCCCACCAAGUCGCUGGUG 24 8728

BCLllA-7090 + GGGGUUAUUGUCUGCAAU 18 8729

BCLllA-7091 + AGGGGUUAUUGUCUGCAAU 19 8730

BCLllA-7092 + AAGGGGUUAUUGUCUGCAAU 20 8731

BCLllA-7093 + AAAGGGGUUAUUGUCUGCAAU 21 8732

BCLllA-7094 + UAAAGGGGUUAUUGUCUGCAAU 22 8733

BCLllA-7095 + U UAAAGGGGUUAUUGUCUGCAAU 23 8734 BCLllA-7096 + GU UAAAGGGGUUAUUGUCUGCAAU 24

8735

BCLllA-7097 + CUGGGUACUACGCCGAAU 18 8736

BCLllA-7098 + UCUGGGUACUACGCCGAAU 19 8737

BCLllA-6182 + CUCUGGGUACUACGCCGAAU 20 8738

BCLllA-7099 + UCUCUGGGUACUACGCCGAAU 21 8739

BCLllA-7100 + CUCUCUGGGUACUACGCCGAAU 22 8740

BCLllA-7101 + GCUCUCUGGGUACUACGCCGAAU 23 8741

BCLllA-7102 + AGCUCUCUGGGUACUACGCCGAAU 24 8742

BCLllA-7103 + CGUAGCCGGCGAGCCACU 18 8743

BCLllA-7104 + GCGUAGCCGGCGAGCCACU 19 8744

BCLllA-7105 + CGCGUAGCCGGCGAGCCACU 20 8745

BCLllA-7106 + CCGCGUAGCCGGCGAGCCACU 21 8746

BCLllA-7107 + GCCGCGUAGCCGGCGAGCCACU 22 8747

BCLllA-7108 + GGCCGCGUAGCCGGCGAGCCACU 23 8748

BCLllA-7109 + AGGCCGCGUAGCCGGCGAGCCACU 24 8749

BCLllA-7110 + CCACACAUCUUGAGCUCU 18 8750

BCLllA-7111 + GCCACACAUCUUGAGCUCU 19 8751

BCLllA-7112 + UGCCACACAUCUUGAGCUCU 20 8752

BCLllA-7113 + CUGCCACACAUCUUGAGCUCU 21 8753

BCLllA-7114 + ACUGCCACACAUCUUGAGCUCU 22 8754

BCLllA-7115 + AACUGCCACACAUCUUGAGCUCU 23 8755

BCLllA-7116 + AAACUGCCACACAUCUUGAGCUCU 24 8756

BCLllA-7117 + CGU UCUCCGGGAUCAGGU 18 8757

BCLllA-7118 + CCGUUCUCCGGGAUCAGGU 19 8758

BCLllA-6223 + CCCGUUCUCCGGGAUCAGGU 20 8759

BCLllA-7119 + CCCCGUUCUCCGGGAUCAGGU 21 8760

BCLllA-7120 + UCCCCGUUCUCCGGGAUCAGGU 22 8761

BCLllA-7121 + GUCCCCGUUCUCCGGGAUCAGGU 23 8762

BCLllA-7122 + CGUCCCCGUUCUCCGGGAUCAGGU 24 8763

BCLllA-7123 + CCAGGCGCUCUAUGCGGU 18 8764

BCLllA-7124 + CCCAGGCGCUCUAUGCGGU 19 8765

BCLllA-6226 + CCCCAGGCGCUCUAUGCGGU 20 8766

BCLllA-7125 + CCCCCAGGCGCUCUAUGCGGU 21 8767

BCLllA-7126 + GCCCCCAGGCGCUCUAUGCGGU 22 8768

BCLllA-7127 + CGCCCCCAGGCGCUCUAUGCGGU 23 8769

BCLllA-7128 + CCGCCCCCAGGCGCUCUAUGCGGU 24 8770

BCLllA-7129 - U UCCCAGCCACCUCUCCA 18 8771

BCLllA-7130 - CUUCCCAGCCACCUCUCCA 19 8772

BCLllA-5903 - CCUUCCCAGCCACCUCUCCA 20 8773

BCLllA-7131 - UCCUUCCCAGCCACCUCUCCA 21 8774

BCLllA-7132 - GUCCUUCCCAGCCACCUCUCCA 22 8775 BCLllA-7133 - UGUCCUUCCCAGCCACCUCUCCA 23 8776

BCLllA-7134 - AUGUCCUUCCCAGCCACCUCUCCA 24 8777

BCLllA-7135 - AGCGCAUCAAGCUCGAGA 18 8778

BCLllA-7136 - AAGCGCAUCAAGCUCGAGA 19 8779

BCLllA-5919 - UAAGCGCAUCAAGCUCGAGA 20 8780

BCLllA-7137 - CUAAGCGCAUCAAGCUCGAGA 21 8781

BCLllA-7138 - UCU AAGCGCAUCAAGCUCGAGA 22 8782

BCLllA-7139 - CUCUAAGCGCAUCAAGCUCGAGA 23 8783

BCLllA-7140 - UCUCUAAGCGCAUCAAGCUCGAGA 24 8784

BCLllA-7141 - GGAGCUGACGGAGAGCGA 18 8785

BCLllA-7142 - AGGAGCUGACGGAGAGCGA 19 8786

BCLllA-7143 - GAGGAGCUGACGGAGAGCGA 20 8787

BCLllA-7144 - GGAGGAGCUGACGGAGAGCGA 21 8788

BCLllA-7145 - AGGAGGAGCUGACGGAGAGCGA 22 8789

BCLllA-7146 - GAGGAGGAGCUGACGGAGAGCGA 23 8790

BCLllA-7147 - GGAGGAGGAGCUGACGGAGAGCGA 24 8791

BCLllA-7148 - UCACCCGAGUGCCUUUGA 18 8792

BCLllA-7149 - AUCACCCGAGUGCCUUUGA 19 8793

BCLllA-7150 - CAUCACCCGAGUGCCUUUGA 20 8794

BCLllA-7151 - CCAUCACCCGAGUGCCUUUGA 21 8795

BCLllA-7152 - CCCAUCACCCGAGUGCCUUUGA 22 8796

BCLllA-7153 - ACCCAUCACCCGAGUGCCUUUGA 23 8797

BCLllA-7154 - CACCCAUCACCCGAGUGCCUUUGA 24 8798

BCLllA-7155 - GAGCACUCCUCGGAGAAC 18 8799

BCLllA-7156 - GGAGCACUCCUCGGAGAAC 19 8800

BCLllA-5949 - CGGAGCACUCCUCGGAGAAC 20 8801

BCLllA-7157 - UCGGAGCACUCCUCGGAGAAC 21 8802

BCLllA-7158 - GUCGGAGCACUCCUCGGAGAAC 22 8803

BCLllA-7159 - CGUCGGAGCACUCCUCGGAGAAC 23 8804

BCLllA-7160 - UCGUCGGAGCACUCCUCGGAGAAC 24 8805

BCLllA-7161 - GCCCUGGCCACCCAUCAC 18 8806

BCLllA-7162 - GGCCCUGGCCACCCAUCAC 19 8807

BCLllA-7163 - UGGCCCUGGCCACCCAUCAC 20 8808

BCLllA-7164 - AUGGCCCUGGCCACCCAUCAC 21 8809

BCLllA-7165 - GAUGGCCCUGGCCACCCAUCAC 22 8810

BCLllA-7166 - AGAUGGCCCUGGCCACCCAUCAC 23 8811

BCLllA-7167 - GAGAUGGCCCUGGCCACCCAUCAC 24 8812

BCLllA-7168 - UUAACCUGCUAAGAAUAC 18 8813

BCLllA-7169 - UUUAACCUGCUAAGAAUAC 19 8814

BCLllA-7170 - CUUUAACCUGCUAAGAAUAC 20 8815

BCLllA-7171 - CCUUUAACCUGCUAAGAAUAC 21 8816

BCLllA-7172 - CCCUUUAACCUGCUAAGAAUAC 22 8817 BCLllA-7173 - CCCCUUUAACCUGCUAAGAAUAC 23 8818

BCLllA-7174 - ACCCCUUUAACCUGCUAAGAAUAC 24 8819

BCLllA-7175 - CGGAAGUCCCCUGACCCC 18 8820

BCLllA-7176 - ACGGAAGUCCCCUGACCCC 19 8821

BCLllA-7177 - CACGGAAGUCCCCUGACCCC 20 8822

BCLllA-7178 - ACACGGAAGUCCCCUGACCCC 21 8823

BCLllA-7179 - AACACGGAAGUCCCCUGACCCC 22 8824

BCLllA-7180 - GAACACGGAAGUCCCCUGACCCC 23 8825

BCLllA-7181 - CGAACACGGAAGUCCCCUGACCCC 24 8826

BCLllA-7182 - AG AAAAU U UG AAG CCCCC 18 8827

BCLllA-7183 - GAGAAAAUUUGAAGCCCCC 19 8828

BCLllA-5969 - UGAGAAAAUUUGAAGCCCCC 20 8829

BCLllA-7184 - CUGAGAAAAUUUGAAGCCCCC 21 8830

BCLllA-7185 - UCUGAGAAAAUUUGAAGCCCCC 22 8831

BCLllA-7186 - UUCUGAGAAAAUUUGAAGCCCCC 23 8832

BCLllA-7187 - GUUCUGAGAAAAUUUGAAGCCCCC 24 8833

BCLllA-7188 - GCUAUGGAGCCUCCCGCC 18 8834

BCLllA-7189 - GGCUAUGGAGCCUCCCGCC 19 8835

BCLllA-7190 - UGGCUAUGGAGCCUCCCGCC 20 8836

BCLllA-7191 - AUGGCUAUGGAGCCUCCCGCC 21 8837

BCLllA-7192 - AAUGGCUAUGGAGCCUCCCGCC 22 8838

BCLllA-7193 - CAAUGGCUAUGGAGCCUCCCGCC 23 8839

BCLllA-7194 - CCAAUGGCUAUGGAGCCUCCCGCC 24 8840

BCLllA-7195 - AACACGCACAGAACACUC 18 8841

BCLllA-7196 - CAACACG CAC AG AAC AC U C 19 8842

BCLllA-7197 - GCAACACGCACAGAACACUC 20 8843

BCLllA-7198 - UGCAACACGCACAGAACACUC 21 8844

BCLllA-7199 - UUGCAACACGCACAGAACACUC 22 8845

BCLllA-7200 - CU U G CAACACG CAC AG A ACAC U C 23 8846

BCLllA-7201 - UCU UGCAACACGCACAGAACACUC 24 8847

BCLllA-7202 - ACGAAGACUCGGUGGCCG 18 8848

BCLllA-7203 - GACGAAGACUCGGUGGCCG 19 8849

BCLllA-7204 - CGACGAAGACUCGGUGGCCG 20 8850

BCLllA-7205 - GCGACGAAGACUCGGUGGCCG 21 8851

BCLllA-7206 - UGCGACGAAGACUCGGUGGCCG 22 8852

BCLllA-7207 - UUGCGACGAAGACUCGGUGGCCG 23 8853

BCLllA-7208 - CUUGCGACGAAGACUCGGUGGCCG 24 8854

BCLllA-7209 - GCCCGGGGAGCUGGACGG 18 8855

BCLllA-7210 - CGCCCGGGGAGCUGGACGG 19 8856

BCLllA-6121 - CCGCCCGGGGAGCUGGACGG 20 8857

BCLllA-7211 - ACCGCCCGGGGAGCUGGACGG 21 8858

BCLllA-7212 - CACCGCCCGGGGAGCUGGACGG 22 8859 BCLllA-7213 - ACACCGCCCGGGGAGCUGGACGG 23 8860

BCLllA-7214 - CACACCGCCCGGGGAGCUGGACGG 24 8861

BCLllA-7215 - GCCGCGGCUGCUCCCCGG 18 8862

BCLllA-7216 - GGCCGCGGCUGCUCCCCGG 19 8863

BCLllA-7217 - UGGCCGCGGCUGCUCCCCGG 20 8864

BCLllA-7218 - AUGGCCGCGGCUGCUCCCCGG 21 8865

BCLllA-7219 - AAUGGCCGCGGCUGCUCCCCGG 22 8866

BCLllA-7220 - UAAUGGCCGCGGCUGCUCCCCGG 23 8867

BCLllA-7221 - UUAAUGGCCGCGGCUGCUCCCCGG 24 8868

BCLllA-7222 - UUUGACAGGGUGCUGCGG 18 8869

BCLllA-7223 - CUUUGACAGGGUGCUGCGG 19 8870

BCLllA-7224 - CCUUUGACAGGGUGCUGCGG 20 8871

BCLllA-7225 - GCCUUUGACAGGGUGCUGCGG 21 8872

BCLllA-7226 - UGCCUUUGACAGGGUGCUGCGG 22 8873

BCLllA-7227 - GUGCCUUUGACAGGGUGCUGCGG 23 8874

BCLllA-7228 - AGUGCCUUUGACAGGGUGCUGCGG 24 8875

BCLllA-7229 - AUUUGAAGCCCCCAGGGG 18 8876

BCLllA-7230 - AAUUUGAAGCCCCCAGGGG 19 8877

BCLllA-6140 - AAAUUUGAAGCCCCCAGGGG 20 8878

BCLllA-7231 - AAAAUUUGAAGCCCCCAGGGG 21 8879

BCLllA-7232 - GAAAAUUUGAAGCCCCCAGGGG 22 8880

BCLllA-7233 - AGAAAAUUUGAAGCCCCCAGGGG 23 8881

BCLllA-7234 - GAGAAAAUUUGAAGCCCCCAGGGG 24 8882

BCLllA-7235 - UCCCUUCAGGACUAGGUG 18 8883

BCLllA-7236 - AUCCCUUCAGGACUAGGUG 19 8884

BCLllA-7237 - UAUCCCUUCAGGACUAGGUG 20 8885

BCLllA-7238 - GUAUCCCUUCAGGACUAGGUG 21 8886

BCLllA-7239 - GGUAUCCCUUCAGGACUAGGUG 22 8887

BCLllA-7240 - UGGUAUCCCUUCAGGACUAGGUG 23 8888

BCLllA-7241 - UUGGUAUCCCUUCAGGACUAGGUG 24 8889

BCLllA-7242 - CG G U C A AG U C C A AG U C A U 18 8890

BCLllA-7243 - CCGGUCAAGUCCAAGUCAU 19 8891

BCLllA-7244 - CCCGGUCAAGUCCAAGUCAU 20 8892

BCLllA-7245 - CCCCGGUCAAGUCCAAGUCAU 21 8893

BCLllA-7246 - CCCCCGGUCAAGUCCAAGUCAU 22 8894

BCLllA-7247 - GCCCCCGGUCAAGUCCAAGUCAU 23 8895

BCLllA-7248 - AGCCCCCGG U CAAG U CCAAG U CAU 24 8896

BCLllA-7249 - UAACCCCUUUAACCUGCU 18 8897

BCLllA-7250 - AUAACCCCUUUAACCUGCU 19 8898

BCLllA-7251 - AAUAACCCCUUUAACCUGCU 20 8899

BCLllA-7252 - CAAUAACCCCUUUAACCUGCU 21 8900

BCLllA-7253 - ACAAUAACCCCUUUAACCUGCU 22 8901 BCLllA-7254 - GACAAUAACCCCUUUAACCUGCU 23 8902

BCLllA-7255 - AGACAAUAACCCCUU UAACCUGCU 24 8903

BCLllA-7256 - ACAGAACACUCAUGGAUU 18 8904

BCLllA-7257 - CACAGAACACUCAUGGAUU 19 8905

BCLllA-7258 - GCACAGAACACUCAUGGAUU 20 8906

BCLllA-7259 - CGCACAGAACACUCAUGGAUU 21 8907

BCLllA-7260 - ACGCACAGAACACUCAUGGAUU 22 8908

BCLllA-7261 - CACGCACAGAACACUCAUGGAUU 23 8909

BCLllA-7262 - ACACGCACAGAACACUCAUGGAUU 24 8910

BCLllA-7263 - GCAGACGCAGCGACACU U 18 8911

BCLllA-7264 - GGCAGACGCAGCGACACUU 19 8912

BCLllA-7265 - GGGCAGACGCAGCGACACUU 20 8913

BCLllA-7266 - AGGGCAGACGCAGCGACACUU 21 8914

BCLllA-7267 - GAGGGCAGACGCAGCGACACUU 22 8915

BCLllA-7268 - AGAGGGCAGACGCAGCGACACUU 23 8916

BCLllA-7269 - AAGAGGGCAGACGCAGCGACACUU 24 8917

BCLllA-7270 - CAAGAUGUGUGGCAGU UU 18 8918

BCLllA-7271 - UCAAGAUGUGUGGCAGUUU 19 8919

BCLllA-7272 - CUCAAGAUGUGUGGCAGUUU 20 8920

BCLllA-7273 - GCUCAAGAUGUGUGGCAGUUU 21 8921

BCLllA-7274 - AGCUCAAGAUGUGUGGCAGUUU 22 8922

BCLllA-7275 - GAGCUCAAGAUGUGUGGCAGUUU 23 8923

BCLllA-7276 - AGAGCUCAAGAUGUGUGGCAGUUU 24 8924

Table 16E provides exemplary targeting domains for knocking out the BCL11A gene selected according to the fifth tier parameters. The targeting domains fall in the coding sequence of the gene, downstream of the first 500bp of coding sequence (e.g., anywhere from +500 (relative to the start codon) to the stop codon of the gene), and the PAM is NNGRRV. It is contemplated herein that in an embodiment the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. aureus Cas9 molecule that generates a double stranded break (Cas9 nuclease) or a single- stranded break (Cas9 nickase).

Table 16E

BCLllA-7280 + AUGUCUCGGUGGUGGACUAAA 21 8928

BCLllA-7281 + GAUGUCUCGGUGGUGGACUAAA 22 8929

BCLllA-7282 + UGAUGUCUCGGUGGUGGACUAAA 23 8930

BCLllA-7283 + GUGAUGUCUCGGUGGUGGACUAAA 24 8931

BCLllA-7284 + GU UCUGUGCGUGUUGCAA 18 8932

BCLllA-7285 + UGUUCUGUGCGUGUUGCAA 19 8933

BCLllA-7286 + GUGUUCUGUGCGUGU UGCAA 20 8934

BCLllA-7287 + AGUGUUCUGUGCGUGUUGCAA 21 8935

BCLllA-7288 + GAGUGUUCUGUGCGUGUUGCAA 22 8936

BCLllA-7289 + UGAGUGUUCUGUGCGUGUUGCAA 23 8937

BCLllA-7290 + AUGAGUGUUCUGUGCGUGUUGCAA 24 8938

BCLllA-7291 + UCUGGGUACUACGCCGAA 18 8939

BCLllA-7292 + CUCUGGGUACUACGCCGAA 19 8940

BCLllA-5883 + UCUCUGGGUACUACGCCGAA 20 8941

BCLllA-7293 + CUCUCUGGGUACUACGCCGAA 21 8942

BCLllA-7294 + GCUCUCUGGGUACUACGCCGAA 22 8943

BCLllA-7295 + AGCUCUCUGGGUACUACGCCGAA 23 8944

BCLllA-7296 + GAGCUCUCUGGGUACUACGCCGAA 24 8945

BCLllA-7297 + UCGGUGGUGGACUAAACA 18 8946

BCLllA-7298 + CUCGGUGGUGGACUAAACA 19 8947

BCLllA-5892 + UCUCGGUGGUGGACUAAACA 20 8948

BCLllA-7299 + GUCUCGGUGGUGGACUAAACA 21 8949

BCLllA-7300 + UGUCUCGGUGGUGGACUAAACA 22 8950

BCLllA-7301 + AUGUCUCGGUGGUGGACUAAA CA 23 8951

BCLllA-7302 + GAUGUCUCGGUGGUGGACUAAACA 24 8952

BCLllA-7303 + AG AAAG AGG U UGG AG ACA 18 8953

BCLllA-7304 + UAGAAAGAGGUUGGAGACA 19 8954

BCLllA-7305 + CU AG AAAG AGG U UGG AG ACA 20 8955

BCLllA-7306 + CCUAGAAAGAGGUUGGAGACA 21 8956

BCLllA-7307 + ACCUAGAAAGAGGUUGGAGACA 22 8957

BCLllA-7308 + AACCUAGAAAGAGGUUGGAGACA 23 8958

BCLllA-7309 + GAACCUAGAAAGAGGUUGGAGACA 24 8959

BCLllA-7310 + UCUGCAAUAUGAAUCCCA 18 8960

BCLllA-7311 + GUCUGCAAUAUGAAUCCCA 19 8961

BCLllA-5899 + UGUCUGCAAUAUGAAUCCCA 20 8962

BCLllA-7312 + UUGUCUGCAAUAUGAAUCCCA 21 8963

BCLllA-7313 + AUUGUCUGCAAUAUGAAUCCCA 22 8964

BCLllA-7314 + UAUUGUCUGCAAUAUGAAUCCCA 23 8965

BCLllA-7315 + U UAUUGUCUGCAAUAUGAAUCCCA 24 8966

BCLllA-7316 + CCUCGCUGAAGUGCUGCA 18 8967

BCLllA-7317 + GCCUCGCUGAAGUGCUGCA 19 8968

BCLllA-5909 + GGCCUCGCUGAAGUGCUGCA 20 8969 BCLllA-7318 + AGGCCUCGCUGAAGUGCUGCA 21 8970

BCLllA-7319 + AAGGCCUCGCUGAAGUGCUGCA 22 8971

BCLllA-7320 + GAAGGCCUCGCUGAAGUGCUGCA 23 8972

BCLllA-7321 + GGAAGGCCUCGCUGAAGUGCUGCA 24 8973

BCLllA-7322 + GAGGAGGGGCGGAUUGCA 18 8974

BCLllA-7323 + GGAGGAGGGGCGGAUUGCA 19 8975

BCLllA-7324 + GGGAGGAGGGGCGGAUUGCA 20 8976

BCLllA-7325 + AGGGAGGAGGGGCGGAUUGCA 21 8977

BCLllA-7326 + GAGGGAGGAGGGGCGGAUUGCA 22 8978

BCLllA-7327 + GGAGGGAGGAGGGGCGGAUUGCA 23 8979

BCLllA-7328 + GGGAGGGAGGAGGGGCGGAUUGCA 24 8980

BCLllA-7329 + GUUGCAGUAACCUUUGCA 18 8981

BCLllA-7330 + GGUUGCAGUAACCUUUGCA 19 8982

BCLllA-7331 + UGGUUGCAGUAACCUU UGCA 20 8983

BCLllA-7332 + AUGGUUGCAGUAACCU UUGCA 21 8984

BCLllA-7333 + AAUGGUUGCAGUAACCUUUGCA 22 8985

BCLllA-7334 + GAAUGGUUGCAGUAACCUUUGCA 23 8986

BCLllA-7335 + GGAAUGGUUGCAGUAACCUUUGCA 24 8987

BCLllA-7336 + GCU UAGAGAAGGGGCUCA 18 8988

BCLllA-7337 + CGCUUAGAGAAGGGGCUCA 19 8989

BCLllA-7338 + GCGCUUAGAGAAGGGGCUCA 20 8990

BCLllA-7339 + UGCGCUUAGAGAAGGGGCUCA 21 8991

BCLllA-7340 + AUGCGCUUAGAGAAGGGGCUCA 22 8992

BCLllA-7341 + GAUGCGCUUAGAGAAGGGGCUCA 23 8993

BCLllA-7342 + UGAUGCGCUUAGAGAAGGGGCUCA 24 8994

BCLllA-7343 + CGUCGGACUUGACCGUCA 18 8995

BCLllA-7344 + UCGUCGGACUUGACCGUCA 19 8996

BCLllA-5912 + GUCGUCGGACUUGACCGUCA 20 8997

BCLllA-7345 + CGUCGUCGGACUUGACCGUCA 21 8998

BCLllA-7346 + CCGUCGUCGGACU UGACCGUCA 22 8999

BCLllA-7347 + ACCGUCGUCGGACUUGACCGUCA 23 9000

BCLllA-7348 + GACCGUCGUCGGACUUGACCGUCA 24 9001

BCLllA-7349 + UACCAACCCGCGGGGUCA 18 9002

BCLllA-7350 + AUACCAACCCGCGGGGUCA 19 9003

BCLllA-5913 + GAUACCAACCCGCGGGGUCA 20 9004

BCLllA-7351 + GGAUACCAACCCGCGGGGUCA 21 9005

BCLllA-7352 + GGGAUACCAACCCGCGGGGUCA 22 9006

BCLllA-7353 + AGGGAUACCAACCCGCGGGGUCA 23 9007

BCLllA-7354 + AAGGGAUACCAACCCGCGGGGUCA 24 9008

BCLllA-7355 + GCU UGAUGCGCUUAGAGA 18 9009

BCLllA-7356 + AGCUUGAUGCGCUUAGAGA 19 9010

BCLllA-5917 + GAGCUUGAUGCGCUUAGAGA 20 9011 BCLllA-7357 + CGAGCUUGAUGCGCUUAGAGA 21 9012

BCLllA-7358 + UCGAGCUUGAUGCGCU UAGAGA 22 9013

BCLllA-7359 + CUCGAGCU UGAUGCGCUUAGAGA 23 9014

BCLllA-7360 + UCUCGAGCUUGAUGCGCUUAGAGA 24 9015

BCLllA-7361 + CUAGAAAGAGGUUGGAGA 18 9016

BCLllA-7362 + CCUAGAAAGAGGUUGGAGA 19 9017

BCLllA-7363 + ACCUAGAAAGAGGUUGGAGA 20 9018

BCLllA-7364 + AACCUAGAAAGAGGUUGGAGA 21 9019

BCLllA-7365 + GAACCUAGAAAGAGGUUGGAGA 22 9020

BCLllA-7366 + AGAACCUAGAAAGAGGUUGGAGA 23 9021

BCLllA-7367 + AAGAACCUAGAAAGAGGUUGGAGA 24 9022

BCLllA-7368 + GUGUGUGAAGAACCUAGA 18 9023

BCLllA-7369 + GGUGUGUGAAGAACCUAGA 19 9024

BCLllA-7370 + GGGUGUGUGAAGAACCUAGA 20 9025

BCLllA-7371 + GGGGUGUGUGAAGAACCUAGA 21 9026

BCLllA-7372 + GGGGGUGUGUGAAGAACCUAGA 22 9027

BCLllA-7373 + UGGGGGUGUGUGAAGAACCUAGA 23 9028

BCLllA-7374 + AUGGGGGUGUGUGAAGAACCUAGA 24 9029

BCLllA-7375 + CUCUGGGUACUACGCCGA 18 9030

BCLllA-7376 + UCUCUGGGUACUACGCCGA 19 9031

BCLllA-7377 + CUCUCUGGGUACUACGCCGA 20 9032

BCLllA-7378 + GCUCUCUGGGUACUACGCCGA 21 9033

BCLllA-7379 + AGCUCUCUGGGUACUACGCCGA 22 9034

BCLllA-7380 + GAGCUCUCUGGGUACUACGCCGA 23 9035

BCLllA-7381 + UGAGCUCUCUGGGUACUACGCCGA 24 9036

BCLllA-7382 + GAGGUUGGAGACAGAGGA 18 9037

BCLllA-7383 + AGAGGUUGGAGACAGAGGA 19 9038

BCLllA-5925 + AAGAGGUUGGAGACAGAGGA 20 9039

BCLllA-7384 + AAAGAGGUUGGAGACAGAGGA 21 9040

BCLllA-7385 + GAAAGAGGUUGGAGACAGAGGA 22 9041

BCLllA-7386 + AGAAAGAGGUUGGAGACAGAGGA 23 9042

BCLllA-7387 + UAGAAAGAGGUUGGAGACAGAGGA 24 9043

BCLllA-7388 + GGGGCGGAUUGCAGAGGA 18 9044

BCLllA-7389 + AGGGGCGGAUUGCAGAGGA 19 9045

BCLllA-5926 + GAGGGGCGGAUUGCAGAGGA 20 9046

BCLllA-7390 + GGAGGGGCGGAUUGCAGAGGA 21 9047

BCLllA-7391 + AGGAGGGGCGGAUUGCAGAGGA 22 9048

BCLllA-7392 + GAGGAGGGGCGGAUUGCAGAGGA 23 9049

BCLllA-7393 + GGAGGAGGGGCGGAUUGCAGAGGA 24 9050

BCLllA-7394 + CGGAUUGCAGAGGAGGGA 18 9051

BCLllA-7395 + GCGGAUUGCAGAGGAGGGA 19 9052

BCLllA-5930 + GGCGGAUUGCAGAGGAGGGA 20 9053 BCLllA-7396 + GGGCGGAUUGCAGAGGAGGGA 21 9054

BCLllA-7397 + GGGGCGGAUUGCAGAGGAGGGA 22 9055

BCLllA-7398 + AGGGGCGGAUUGCAGAGGAGGGA 23 9056

BCLllA-7399 + GAGGGGCGGAUUGCAGAGGAGGGA 24 9057

BCLllA-7400 + CUUGACCGGGGGCUGGGA 18 9058

BCLllA-7401 + ACUUGACCGGGGGCUGGGA 19 9059

BCLllA-5931 + GACUUGACCGGGGGCUGGGA 20 9060

BCLllA-7402 + GGACUUGACCGGGGGCUGGGA 21 9061

BCLllA-7403 + UGGACUUGACCGGGGGCUGGGA 22 9062

BCLllA-7404 + U UGGACUUGACCGGGGGCUGGGA 23 9063

BCLllA-7405 + CUUGGACUUGACCGGGGGCUGGGA 24 9064

BCLllA-7406 + CGCAUGACUUGGACUUGA 18 9065

BCLllA-7407 + UCGCAUGACUUGGACUUGA 19 9066

BCLllA-7408 + CUCGCAUGACUUGGACUUGA 20 9067

BCLllA-7409 + ACUCGCAUGACUUGGACUUGA 21 9068

BCLllA-7410 + AACUCGCAUGACUUGGACUUGA 22 9069

BCLllA-7411 + GAACUCGCAUGACUUGGACUUGA 23 9070

BCLllA-7412 + AGAACUCGCAUGACUUGGACUUGA 24 9071

BCLllA-7413 + GGGCCCGGACCACUAAUA 18 9072

BCLllA-7414 + CGGGCCCGGACCACUAAUA 19 9073

BCLllA-5940 + CCGGGCCCGGACCACUAAUA 20 9074

BCLllA-7415 + CCCGGGCCCGGACCACUAAUA 21 9075

BCLllA-7416 + GCCCGGGCCCGGACCACUAAUA 22 9076

BCLllA-7417 + UGCCCGGGCCCGGACCACUAAUA 23 9077

BCLllA-7418 + CUGCCCGGGCCCGGACCACUAAUA 24 9078

BCLllA-7419 + AGCUCUCUAAGUCUCCUA 18 9079

BCLllA-7420 + CAGCUCUCUAAGUCUCCUA 19 9080

BCLllA-7421 + CCAGCUCUCUAAGUCUCCUA 20 9081

BCLllA-7422 + GCCAGCUCUCUAAGUCUCCUA 21 9082

BCLllA-7423 + UGCCAGCUCUCUAAGUCUCCUA 22 9083

BCLllA-7424 + CUGCCAGCUCUCUAAGUCUCCUA 23 9084

BCLllA-7425 + CCUGCCAGCUCUCUAAGUCUCCUA 24 9085

BCLllA-7426 + CUGGAGUCUCCGAAGCUA 18 9086

BCLllA-7427 + UCUGGAGUCUCCGAAGCUA 19 9087

BCLllA-5943 + GUCUGGAGUCUCCGAAGCUA 20 9088

BCLllA-7428 + UGUCUGGAGUCUCCGAAGCUA 21 9089

BCLllA-7429 + U UGUCUGGAGUCUCCGAAGCUA 22 9090

BCLllA-7430 + AUUGUCUGGAGUCUCCGAAGCUA 23 9091

BCLllA-7431 + GAUUGUCUGGAGUCUCCGAAGCUA 24 9092

BCLllA-7432 + UCGAGCUUGAUGCGCUUA 18 9093

BCLllA-7433 + CUCGAGCU UGAUGCGCU UA 19 9094

BCLllA-7434 + UCUCGAGCUUGAUGCGCUUA 20 9095 BCLllA-7435 + UUCUCGAGCUUGAUGCGCUUA 21 9096

BCLllA-7436 + CUUCUCGAGCUUGAUGCGCUUA 22 9097

BCLllA-7437 + CCUUCUCGAGCUUGAUGCGCUUA 23 9098

BCLllA-7438 + UCCUUCUCGAGCU UGAUGCGCUUA 24 9099

BCLllA-7439 + GGUAUUCUUAGCAGGUUA 18 9100

BCLllA-7440 + UGGUAUUCUUAGCAGGUUA 19 9101

BCLllA-7441 + CUGGUAUUCUUAGCAGGUUA 20 9102

BCLllA-7442 + CCUGGUAUUCUUAGCAGGUUA 21 9103

BCLllA-7443 + UCCUGGUAU UCUUAGCAGGUUA 22 9104

BCLllA-7444 + AUCCUGGUAUUCUUAGCAGGUUA 23 9105

BCLllA-7445 + GAUCCUGGUAUUCUUAGCAGGUUA 24 9106

BCLllA-7446 + CUCGGUGGUGGACUAAAC 18 9107

BCLllA-7447 + UCUCGGUGGUGGACUAAAC 19 9108

BCLllA-5947 + GUCUCGGUGGUGGACUAAAC 20 9109

BCLllA-7448 + UGUCUCGGUGGUGGACUAAAC 21 9110

BCLllA-7449 + AUGUCUCGGUGGUGGACUAAAC 22 9111

BCLllA-7450 + GAUGUCUCGGUGGUGGACUAAAC 23 9112

BCLllA-7451 + UGAUGUCUCGGUGGUGGACUAAAC 24 9113

BCLllA-7452 + UCCGAGGAGUGCUCCGAC 18 9114

BCLllA-7453 + CUCCGAGGAGUGCUCCGAC 19 9115

BCLllA-7454 + UCUCCGAGGAGUGCUCCGAC 20 9116

BCLllA-7455 + U UCUCCGAGGAGUGCUCCGAC 21 9117

BCLllA-7456 + GU UCUCCGAGGAGUGCUCCGAC 22 9118

BCLllA-7457 + CGU UCUCCGAGGAGUGCUCCGAC 23 9119

BCLllA-7458 + CCGUUCUCCGAGGAGUGCUCCGAC 24 9120

BCLllA-7459 + AACUUGGCCACCACGGAC 18 9121

BCLllA-7460 + GAACUUGGCCACCACGGAC 19 9122

BCLllA-7461 + UGAACUUGGCCACCACGGAC 20 9123

BCLllA-7462 + U UGAACUUGGCCACCACGGAC 21 9124

BCLllA-7463 + CUUGAACUUGGCCACCACGGAC 22 9125

BCLllA-7464 + UCU UGAACUUGGCCACCACGGAC 23 9126

BCLllA-7465 + CUCU UGAACUUGGCCACCACGGAC 24 9127

BCLllA-7466 + CCGCAGAACUCGCAUGAC 18 9128

BCLllA-7467 + GCCGCAGAACUCGCAUGAC 19 9129

BCLllA-7468 + UGCCGCAGAACUCGCAUGAC 20 9130

BCLllA-7469 + U UGCCGCAGAACUCGCAUGAC 21 9131

BCLllA-7470 + CUUGCCGCAGAACUCGCAUGAC 22 9132

BCLllA-7471 + UCU UGCCGCAGAACUCGCAUGAC 23 9133

BCLllA-7472 + GUCUUGCCGCAGAACUCGCAUGAC 24 9134

BCLllA-7473 + GCAUGACUUGGACUUGAC 18 9135

BCLllA-7474 + CGCAUGACUUGGACUUGAC 19 9136

BCLllA-5957 + UCGCAUGACU UGGACU UGAC 20 9137 BCLllA-7475 + CUCGCAUGACUUGGACUUGAC 21 9138

BCLllA-7476 + ACUCGCAUGACUUGGACUUGAC 22 9139

BCLllA-7477 + AACUCGCAUGACU UGGACUUGAC 23 9140

BCLllA-7478 + GAACUCGCAUGACUUGGACUUGAC 24 9141

BCLllA-7479 + GGGGGUGUGUGAAGAACC 18 9142

BCLllA-7480 + UGGGGGUGUGUGAAGAACC 19 9143

BCLllA-7481 + AUGGGGGUGUGUGAAGAACC 20 9144

BCLllA-7482 + AAUGGGGGUGUGUGAAGAACC 21 9145

BCLllA-7483 + GAAUGGGGGUGUGUGAAGAACC 22 9146

BCLllA-7484 + CGAAUGGGGGUGUGUGAAGAACC 23 9147

BCLllA-7485 + CCGAAUGGGGGUGUGUGAAGAACC 24 9148

BCLllA-7486 + CUCUUGAACU UGGCCACC 18 9149

BCLllA-7487 + GCUCU UGAACUUGGCCACC 19 9150

BCLllA-7488 + CGCUCU UGAACUUGGCCACC 20 9151

BCLllA-7489 + UCGCUCUUGAACUUGGCCACC 21 9152

BCLllA-7490 + CUCGCUCU UGAACUUGGCCACC 22 9153

BCLllA-7491 + UCUCGCUCUUGAACUUGGCCACC 23 9154

BCLllA-7492 + U UCUCGCUCUUGAACUUGGCCACC 24 9155

BCLllA-7493 + CAUGACUUGGACUUGACC 18 9156

BCLllA-7494 + GCAUGACUUGGACUUGACC 19 9157

BCLllA-5965 + CGCAUGACUUGGACUUGACC 20 9158

BCLllA-7495 + UCGCAUGACUUGGACUUGACC 21 9159

BCLllA-7496 + CUCGCAUGACUUGGACU UGACC 22 9160

BCLllA-7497 + ACUCGCAUGACUUGGACUUGACC 23 9161

BCLllA-7498 + AACUCGCAUGACU UGGACUUGACC 24 9162

BCLllA-7499 + CUGAAGGGAUACCAACCC 18 9163

BCLllA-7500 + CCUGAAGGGAUACCAACCC 19 9164

BCLllA-7501 + UCCUGAAGGGAUACCAACCC 20 9165

BCLllA-7502 + GUCCUGAAGGGAUACCAACCC 21 9166

BCLllA-7503 + AGUCCUGAAGGGAUACCAACCC 22 9167

BCLllA-7504 + UAGUCCUGAAGGGAUACCAACCC 23 9168

BCLllA-7505 + CUAGUCCUGAAGGGAUACCAACCC 24 9169

BCLllA-7506 + CGCCCACGACCGCGCCCC 18 9170

BCLllA-7507 + ACGCCCACGACCGCGCCCC 19 9171

BCLllA-3830 + CACGCCCACGACCGCGCCCC 20 9172

BCLllA-7508 + CCACGCCCACGACCGCGCCCC 21 9173

BCLllA-7509 + CCCACGCCCACGACCGCGCCCC 22 9174

BCLllA-7510 + GCCCACGCCCACGACCGCGCCCC 23 9175

BCLllA-7511 + CGCCCACGCCCACGACCGCGCCCC 24 9176

BCLllA-7512 + GCUUUUUGGACAGGCCCC 18 9177

BCLllA-7513 + AGCUUUUUGGACAGGCCCC 19 9178

BCLllA-7514 + CAGCUUUUUGGACAGGCCCC 20 9179 BCLllA-7515 + GCAGCU UUUUGGACAGGCCCC 21 9180

BCLllA-7516 + AGCAGCUUUUUGGACAGGCCCC 22 9181

BCLllA-7517 + CAGCAGCUUUUUGGACAGGCCCC 23 9182

BCLllA-7518 + GCAGCAGCUUU UUGGACAGGCCCC 24 9183

BCLllA-7519 + CCCGAGGCCGACUCGCCC 18 9184

BCLllA-7520 + CCCCGAGGCCGACUCGCCC 19 9185

BCLllA-5977 + CCCCCGAGGCCGACUCGCCC 20 9186

BCLllA-7521 + CCCCCCGAGGCCGACUCGCCC 21 9187

BCLllA-7522 + GCCCCCCGAGGCCGACUCGCCC 22 9188

BCLllA-7523 + GGCCCCCCGAGGCCGACUCGCCC 23 9189

BCLllA-7524 + AGGCCCCCCGAGGCCGACUCGCCC 24 9190

BCLllA-7525 + GUCUGCAAUAUGAAUCCC 18 9191

BCLllA-7526 + UGUCUGCAAUAUGAAUCCC 19 9192

BCLllA-7527 + U UGUCUGCAAUAUGAAUCCC 20 9193

BCLllA-7528 + AUUGUCUGCAAUAUGAAUCCC 21 9194

BCLllA-7529 + UAUUGUCUGCAAUAUGAAUCCC 22 9195

BCLllA-7530 + UUAUUGUCUGCAAUAUGAAUCCC 23 9196

BCLllA-7531 + GU UAUUGUCUGCAAUAUGAAUCCC 24 9197

BCLllA-7532 + UUCCCGUGCCGCUGCGCC 18 9198

BCLllA-7533 + CUUCCCGUGCCGCUGCGCC 19 9199

BCLllA-7534 + ACUUCCCGUGCCGCUGCGCC 20 9200

BCLllA-7535 + CACUUCCCGUGCCGCUGCGCC 21 9201

BCLllA-7536 + CCACUUCCCGUGCCGCUGCGCC 22 9202

BCLllA-7537 + UCCACUUCCCGUGCCGCUGCGCC 23 9203

BCLllA-7538 + CUCCACUUCCCGUGCCGCUGCGCC 24 9204

BCLllA-7539 + CCCCGAGGCCGACUCGCC 18 9205

BCLllA-7540 + CCCCCGAGGCCGACUCGCC 19 9206

BCLllA-5989 + CCCCCCGAGGCCGACUCGCC 20 9207

BCLllA-7541 + GCCCCCCGAGGCCGACUCGCC 21 9208

BCLllA-7542 + GGCCCCCCGAGGCCGACUCGCC 22 9209

BCLllA-7543 + AGGCCCCCCGAGGCCGACUCGCC 23 9210

BCLllA-7544 + CAGGCCCCCCGAGGCCGACUCGCC 24 9211

BCLllA-7545 + GCGCUUAUGCUUCUCGCC 18 9212

BCLllA-7546 + CGCGCUUAUGCUUCUCGCC 19 9213

BCLllA-7547 + CCGCGCUUAUGCU UCUCGCC 20 9214

BCLllA-7548 + GCCGCGCUUAUGCUUCUCGCC 21 9215

BCLllA-7549 + GGCCGCGCUUAUGCUUCUCGCC 22 9216

BCLllA-7550 + UGGCCGCGCUUAUGCUUCUCGCC 23 9217

BCLllA-7551 + GUGGCCGCGCUUAUGCUUCUCGCC 24 9218

BCLllA-7552 + GGGAGGGGGGGCGUCGCC 18 9219

BCLllA-7553 + AGGGAGGGGGGGCGUCGCC 19 9220

BCLllA-5990 + GAGGGAGGGGGGGCGUCGCC 20 9221 BCLllA-7554 + GGAGGGAGGGGGGGCGUCGCC 21 9222

BCLllA-7555 + AGGAGGGAGGGGGGGCGUCGCC 22 9223

BCLllA-7556 + GAGGAGGGAGGGGGGGCGUCGCC 23 9224

BCLllA-7557 + AGAGGAGGGAGGGGGGGCGUCGCC 24 9225

BCLllA-7558 + CAUAGGGCUGGGCCGGCC 18 9226

BCLllA-7559 + GCAUAGGGCUGGGCCGGCC 19 9227

BCLllA-5991 + UGCAUAGGGCUGGGCCGGCC 20 9228

BCLllA-7560 + UUGCAUAGGGCUGGGCCGGCC 21 9229

BCLllA-7561 + UUUGCAUAGGGCUGGGCCGGCC 22 9230

BCLllA-7562 + CUUUGCAUAGGGCUGGGCCGGCC 23 9231

BCLllA-7563 + CCUU UGCAUAGGGCUGGGCCGGCC 24 9232

BCLllA-7564 + GUGUUGGGCAUCGCGGCC 18 9233

BCLllA-7565 + CGUGUUGGGCAUCGCGGCC 19 9234

BCLllA-5993 + CCGUGUUGGGCAUCGCGGCC 20 9235

BCLllA-7566 + UCCGUGUUGGGCAUCGCGGCC 21 9236

BCLllA-7567 + CUCCGUGU UGGGCAUCGCGGCC 22 9237

BCLllA-7568 + UCUCCGUGUUGGGCAUCGCGGCC 23 9238

BCLllA-7569 + U UCUCCGUGUUGGGCAUCGCGGCC 24 9239

BCLllA-7570 + AGGGAUCUUUGAGCUGCC 18 9240

BCLllA-7571 + AAGGGAUCUUUGAGCUGCC 19 9241

BCLllA-6000 + GAAGGGAUCUUUGAGCUGCC 20 9242

BCLllA-7572 + GGAAGGGAUCUUUGAGCUGCC 21 9243

BCLllA-7573 + AGGAAGGGAUCUUUGAGCUGCC 22 9244

BCLllA-7574 + AAGGAAGGGAUCUUUGAGCUGCC 23 9245

BCLllA-7575 + UAAGGAAGGGAUCUUUGAGCUGCC 24 9246

BCLllA-7576 + AUCCCUCCGUCCAGCUCC 18 9247

BCLllA-7577 + GAUCCCUCCGUCCAGCUCC 19 9248

BCLllA-7578 + AGAUCCCUCCGUCCAGCUCC 20 9249

BCLllA-7579 + GAGAUCCCUCCGUCCAGCUCC 21 9250

BCLllA-7580 + CGAGAUCCCUCCGUCCAGCUCC 22 9251

BCLllA-7581 + CCGAGAUCCCUCCGUCCAGCUCC 23 9252

BCLllA-7582 + CCCGAGAUCCCUCCGUCCAGCUCC 24 9253

BCLllA-7583 + CCAGCUCUCUAAGUCUCC 18 9254

BCLllA-7584 + GCCAGCUCUCUAAGUCUCC 19 9255

BCLllA-7585 + UGCCAGCUCUCUAAGUCUCC 20 9256

BCLllA-7586 + CUGCCAGCUCUCUAAGUCUCC 21 9257

BCLllA-7587 + CCUGCCAGCUCUCUAAGUCUCC 22 9258

BCLllA-7588 + CCCUGCCAGCUCUCUAAGUCUCC 23 9259

BCLllA-7589 + UCCCUGCCAGCUCUCUAAGUCUCC 24 9260

BCLllA-7590 + CGCAAACUCCCGUUCUCC 18 9261

BCLllA-7591 + GCGCAAACUCCCGUUCUCC 19 9262

BCLllA-7592 + AGCGCAAACUCCCGUUCUCC 20 9263 BCLllA-7593 + AAGCGCAAACUCCCGUUCUCC 21 9264

BCLllA-7594 + GAAGCGCAAACUCCCGU UCUCC 22 9265

BCLllA-7595 + AGAAGCGCAAACUCCCGUUCUCC 23 9266

BCLllA-7596 + GAGAAGCGCAAACUCCCGUUCUCC 24 9267

BCLllA-7597 + UCGCUGGUGCCGGGUUCC 18 9268

BCLllA-7598 + GUCGCUGGUGCCGGGUUCC 19 9269

BCLllA-6011 + AGUCGCUGGUGCCGGGUUCC 20 9270

BCLllA-7599 + AAGUCGCUGGUGCCGGGUUCC 21 9271

BCLllA-7600 + CAAGUCGCUGGUGCCGGGUUCC 22 9272

BCLllA-7601 + CCAAGUCGCUGGUGCCGGGUUCC 23 9273

BCLllA-7602 + ACCAAGUCGCUGGUGCCGGGUUCC 24 9274

BCLllA-7603 + GCCGCCUCCAGGCUCAGC 18 9275

BCLllA-7604 + CGCCGCCUCCAGGCUCAGC 19 9276

BCLllA-7605 + GCGCCGCCUCCAGGCUCAGC 20 9277

BCLllA-7606 + CGCGCCGCCUCCAGGCUCAGC 21 9278

BCLllA-7607 + GCGCGCCGCCUCCAGGCUCAGC 22 9279

BCLllA-7608 + GGCGCGCCGCCUCCAGGCUCAGC 23 9280

BCLllA-7609 + UGGCGCGCCGCCUCCAGGCUCAGC 24 9281

BCLllA-7610 + AGAAGGGGCUCAGCGAGC 18 9282

BCLllA-7611 + GAGAAGGGGCUCAGCGAGC 19 9283

BCLllA-6013 + AGAGAAGGGGCUCAGCGAGC 20 9284

BCLllA-7612 + UAGAGAAGGGGCUCAGCGAGC 21 9285

BCLllA-7613 + UUAGAGAAGGGGCUCAGCGAGC 22 9286

BCLllA-7614 + CUUAGAGAAGGGGCUCAGCGAGC 23 9287

BCLllA-7615 + GCUUAGAGAAGGGGCUCAGCGAGC 24 9288

BCLllA-7616 + CCCCCGAGGCCGACUCGC 18 9289

BCLllA-7617 + CCCCCCGAGGCCGACUCGC 19 9290

BCLllA-7618 + GCCCCCCGAGGCCGACUCGC 20 9291

BCLllA-7619 + GGCCCCCCGAGGCCGACUCGC 21 9292

BCLllA-7620 + AGGCCCCCCGAGGCCGACUCGC 22 9293

BCLllA-7621 + CAGGCCCCCCGAGGCCGACUCGC 23 9294

BCLllA-7622 + ACAGGCCCCCCGAGGCCGACUCGC 24 9295

BCLllA-7623 + AGGGAGGGGGGGCGUCGC 18 9296

BCLllA-7624 + GAGGGAGGGGGGGCGUCGC 19 9297

BCLllA-7625 + GGAGGGAGGGGGGGCGUCGC 20 9298

BCLllA-7626 + AGGAGGGAGGGGGGGCGUCGC 21 9299

BCLllA-7627 + GAGGAGGGAGGGGGGGCGUCGC 22 9300

BCLllA-7628 + AGAGGAGGGAGGGGGGGCGUCGC 23 9301

BCLllA-7629 + CAGAGGAGGGAGGGGGGGCGUCGC 24 9302

BCLllA-7630 + AGCGCCCUUCUGCCAGGC 18 9303

BCLllA-7631 + AAGCGCCCU UCUGCCAGGC 19 9304

BCLllA-6027 + AAAGCGCCCUUCUGCCAGGC 20 9305 BCLllA-7632 + GAAAGCGCCCUUCUGCCAGGC 21 9306

BCLllA-7633 + GGAAAGCGCCCU UCUGCCAGGC 22 9307

BCLllA-7634 + UGGAAAGCGCCCUUCUGCCAGGC 23 9308

BCLllA-7635 + GUGGAAAGCGCCCUUCUGCCAGGC 24 9309

BCLllA-7636 + GCAUAGGGCUGGGCCGGC 18 9310

BCLllA-7637 + UGCAUAGGGCUGGGCCGGC 19 9311

BCLllA-7638 + U UGCAUAGGGCUGGGCCGGC 20 9312

BCLllA-7639 + U UUGCAUAGGGCUGGGCCGGC 21 9313

BCLllA-7640 + CUU UGCAUAGGGCUGGGCCGGC 22 9314

BCLllA-7641 + CCUUUGCAUAGGGCUGGGCCGGC 23 9315

BCLllA-7642 + ACCU UUGCAUAGGGCUGGGCCGGC 24 9316

BCLllA-7643 + CGUGUUGGGCAUCGCGGC 18 9317

BCLllA-7644 + CCGUGU UGGGCAUCGCGGC 19 9318

BCLllA-6028 + UCCGUGUUGGGCAUCGCGGC 20 9319

BCLllA-7645 + CUCCGUGUUGGGCAUCGCGGC 21 9320

BCLllA-7646 + UCUCCGUGUUGGGCAUCGCGGC 22 9321

BCLllA-7647 + UUCUCCGUGUUGGGCAUCGCGGC 23 9322

BCLllA-7648 + GU UCUCCGUGUUGGGCAUCGCGGC 24 9323

BCLllA-7649 + AGCUGGGCCUGCCCGGGC 18 9324

BCLllA-7650 + GAGCUGGGCCUGCCCGGGC 19 9325

BCLllA-7651 + UGAGCUGGGCCUGCCCGGGC 20 9326

BCLllA-7652 + UUGAGCUGGGCCUGCCCGGGC 21 9327

BCLllA-7653 + UUUGAGCUGGGCCUGCCCGGGC 22 9328

BCLllA-7654 + UUUUGAGCUGGGCCUGCCCGGGC 23 9329

BCLllA-7655 + CUUUUGAGCUGGGCCUGCCCGGGC 24 9330

BCLllA-7656 + U UGGACUUGACCGGGGGC 18 9331

BCLllA-7657 + CUUGGACUUGACCGGGGGC 19 9332

BCLllA-6032 + ACUUGGACUUGACCGGGGGC 20 9333

BCLllA-7658 + GACUUGGACUUGACCGGGGGC 21 9334

BCLllA-7659 + UGACUUGGACUUGACCGGGGGC 22 9335

BCLllA-7660 + AUGACUUGGACUUGACCGGGGGC 23 9336

BCLllA-7661 + CAUGACUUGGACUUGACCGGGGGC 24 9337

BCLllA-7662 + CCUAGAGAAAUCCAUGGC 18 9338

BCLllA-7663 + UCCUAGAGAAAUCCAUGGC 19 9339

BCLllA-6035 + CUCCUAGAGAAAUCCAUGGC 20 9340

BCLllA-7664 + UCUCCUAGAGAAAUCCAUGGC 21 9341

BCLllA-7665 + GUCUCCUAGAGAAAUCCAUGGC 22 9342

BCLllA-7666 + AGUCUCCUAGAGAAAUCCAUGGC 23 9343

BCLllA-7667 + AAGUCUCCUAGAGAAAUCCAUGGC 24 9344

BCLllA-7668 + AUCCCAUGGAGAGGUGGC 18 9345

BCLllA-7669 + AAUCCCAUGGAGAGGUGGC 19 9346

BCLllA-6038 + GAAUCCCAUGGAGAGGUGGC 20 9347 BCLllA-7670 + UGAAUCCCAUGGAGAGGUGGC 21 9348

BCLllA-7671 + AUGAAUCCCAUGGAGAGGUGGC 22 9349

BCLllA-7672 + UAUGAAUCCCAUGGAGAGGUGGC 23 9350

BCLllA-7673 + AUAUGAAUCCCAUGGAGAGGUGGC 24 9351

BCLllA-7674 + ACUCGGGUGAUGGGUGGC 18 9352

BCLllA-7675 + CACUCGGGUGAUGGGUGGC 19 9353

BCLllA-7676 + GCACUCGGGUGAUGGGUGGC 20 9354

BCLllA-7677 + GGCACUCGGGUGAUGGGUGGC 21 9355

BCLllA-7678 + AGGCACUCGGGUGAUGGGUGGC 22 9356

BCLllA-7679 + AAGGCACUCGGGUGAUGGGUGGC 23 9357

BCLllA-7680 + AAAGGCACUCGGGUGAUGGGUGGC 24 9358

BCLllA-7681 + CUU UUGAGCUGGGCCUGC 18 9359

BCLllA-7682 + UCU UUUGAGCUGGGCCUGC 19 9360

BCLllA-7683 + CUCU UUUGAGCUGGGCCUGC 20 9361

BCLllA-7684 + CCUCUU UUGAGCUGGGCCUGC 21 9362

BCLllA-7685 + CCCUCUUU UGAGCUGGGCCUGC 22 9363

BCLllA-7686 + GCCCUCUU UUGAGCUGGGCCUGC 23 9364

BCLllA-7687 + UGCCCUCUUUUGAGCUGGGCCUGC 24 9365

BCLllA-7688 + AAGGGAUCUUUGAGCUGC 18 9366

BCLllA-7689 + GAAGGGAUCUUUGAGCUGC 19 9367

BCLllA-7690 + GGAAGGGAUCUUUGAGCUGC 20 9368

BCLllA-7691 + AGGAAGGGAUCUUUGAGCUGC 21 9369

BCLllA-7692 + AAGGAAGGGAUCUUUGAGCUGC 22 9370

BCLllA-7693 + UAAGGAAGGGAUCUUUGAGCUGC 23 9371

BCLllA-7694 + CUAAGGAAGGGAUCUU UGAGCUGC 24 9372

BCLllA-7695 + GCCUCGCUGAAGUGCUGC 18 9373

BCLllA-7696 + GGCCUCGCUGAAGUGCUGC 19 9374

BCLllA-7697 + AGGCCUCGCUGAAGUGCUGC 20 9375

BCLllA-7698 + AAGGCCUCGCUGAAGUGCUGC 21 9376

BCLllA-7699 + GAAGGCCUCGCUGAAGUGCUGC 22 9377

BCLllA-7700 + GGAAGGCCUCGCUGAAGUGCUGC 23 9378

BCLllA-7701 + UGGAAGGCCUCGCUGAAGUGCUGC 24 9379

BCLllA-7702 + GUGUUCUGUGCGUGU UGC 18 9380

BCLllA-7703 + AGUGUUCUGUGCGUGUUGC 19 9381

BCLllA-7704 + GAGUGUUCUGUGCGUGUUGC 20 9382

BCLllA-7705 + UGAGUGUUCUGUGCGUGUUGC 21 9383

BCLllA-7706 + AUGAGUGUUCUGUGCGUGUUGC 22 9384

BCLllA-7707 + CAUGAGUGUUCUGUGCGUGUUGC 23 9385

BCLllA-7708 + CCAUGAGUGUUCUGUGCGUGUUGC 24 9386

BCLllA-7709 + CGAAAACUGCCACACAUC 18 9387

BCLllA-7710 + CCGAAAACUGCCACACAUC 19 9388

BCLllA-7711 + UCCGAAAACUGCCACACAUC 20 9389 BCLllA-7712 + AUCCGAAAACUGCCACACAUC 21 9390

BCLllA-7713 + CAUCCGAAAACUGCCACACAUC 22 9391

BCLllA-7714 + CCAUCCGAAAACUGCCACACAUC 23 9392

BCLllA-7715 + UCCAUCCGAAAACUGCCACACAUC 24 9393

BCLllA-7716 + U UGGGGUCGUUCUCGCUC 18 9394

BCLllA-7717 + GUUGGGGUCGUUCUCGCUC 19 9395

BCLllA-7718 + GGUUGGGGUCGUUCUCGCUC 20 9396

BCLllA-7719 + AGGUUGGGGUCGUUCUCGCUC 21 9397

BCLllA-7720 + CAGGUUGGGGUCGUUCUCGCUC 22 9398

BCLllA-7721 + UCAGGUUGGGGUCGUUCUCGCUC 23 9399

BCLllA-7722 + AUCAGGUUGGGGUCGUUCUCGCUC 24 9400

BCLllA-7723 + CUCAGAACUUAAGGGCUC 18 9401

BCLllA-7724 + UCUCAGAACUUAAGGGCUC 19 9402

BCLllA-7725 + UUCUCAGAACUUAAGGGCUC 20 9403

BCLllA-7726 + UUUCUCAGAACU UAAGGGCUC 21 9404

BCLllA-7727 + U UUUCUCAGAACUUAAGGGCUC 22 9405

BCLllA-7728 + AUUUUCUCAGAACUUAAGGGCUC 23 9406

BCLllA-7729 + AAUUUUCUCAGAACU UAAGGGCUC 24 9407

BCLllA-7730 + GACAUUCUGCACCUAGUC 18 9408

BCLllA-7731 + GGACAUUCUGCACCUAGUC 19 9409

BCLllA-7732 + AGGACAUUCUGCACCUAGUC 20 9410

BCLllA-7733 + AAGGACAUUCUGCACCUAGUC 21 9411

BCLllA-7734 + GAAGGACAUUCUGCACCUAGUC 22 9412

BCLllA-7735 + GGAAGGACAUUCUGCACCUAGUC 23 9413

BCLllA-7736 + GGGAAGGACAUUCUGCACCUAGUC 24 9414

BCLllA-7737 + UCGUCGGACUUGACCGUC 18 9415

BCLllA-7738 + GUCGUCGGACUUGACCGUC 19 9416

BCLllA-7739 + CGUCGUCGGACUUGACCGUC 20 9417

BCLllA-7740 + CCGUCGUCGGACUUGACCGUC 21 9418

BCLllA-7741 + ACCGUCGUCGGACUUGACCGUC 22 9419

BCLllA-7742 + GACCGUCGUCGGACUUGACCGUC 23 9420

BCLllA-7743 + AGACCGUCGUCGGACUUGACCGUC 24 9421

BCLllA-7744 + AUACCAACCCGCGGGGUC 18 9422

BCLllA-7745 + GAUACCAACCCGCGGGGUC 19 9423

BCLllA-6052 + GGAUACCAACCCGCGGGGUC 20 9424

BCLllA-7746 + GGGAUACCAACCCGCGGGGUC 21 9425

BCLllA-7747 + AGGGAUACCAACCCGCGGGGUC 22 9426

BCLllA-7748 + AAGGGAUACCAACCCGCGGGGUC 23 9427

BCLllA-7749 + GAAGGGAUACCAACCCGCGGGGUC 24 9428

BCLllA-7750 + GGCAGGUCGAACUCCUUC 18 9429

BCLllA-7751 + GGGCAGGUCGAACUCCU UC 19 9430

BCLllA-7752 + GGGGCAGGUCGAACUCCUUC 20 9431 BCLllA-7753 + GGGGGCAGGUCGAACUCCUUC 21 9432

BCLllA-7754 + CGGGGGCAGGUCGAACUCCUUC 22 9433

BCLllA-7755 + CCGGGGGCAGG UCGAACUCCUUC 23 9434

BCLllA-7756 + GCCGGGGGCAGGUCGAACUCCUUC 24 9435

BCLllA-7757 + GUCGCUGGUGCCGGGU UC 18 9436

BCLllA-7758 + AGUCGCUGGUGCCGGGUUC 19 9437

BCLllA-6058 + AAGUCGCUGGUGCCGGGUUC 20 9438

BCLllA-7759 + CAAGUCGCUGGUGCCGGGUUC 21 9439

BCLllA-7760 + CCAAGUCGCUGGUGCCGGGUUC 22 9440

BCLllA-7761 + ACCAAGUCGCUGGUGCCGGGUUC 23 9441

BCLllA-7762 + CACCAAGUCGCUGGUGCCGGGUUC 24 9442

BCLllA-7763 + CGGUGGUGGACUAAACAG 18 9443

BCLllA-7764 + UCGGUGGUGGACUAAACAG 19 9444

BCLllA-6063 + CUCGGUGGUGGACUAAACAG 20 9445

BCLllA-7765 + UCUCGGUGGUGGACUAAACAG 21 9446

BCLllA-7766 + GUCUCGGUGGUGGACUAAACAG 22 9447

BCLllA-7767 + UGUCUCGGUGGUGGACUAAACAG 23 9448

BCLllA-7768 + AUGUCUCGGUGGUGGACUAAACAG 24 9449

BCLllA-7769 + G AAAG AGG U UGG AG ACAG 18 9450

BCLllA-7770 + AGAAAGAGGUUGGAGACAG 19 9451

BCLllA-6064 + UAGAAAGAGGUUGGAGACAG 20 9452

BCLllA-7771 + CUAGAAAGAGGUUGGAGACAG 21 9453

BCLllA-7772 + CCUAGAAAGAGGUUGGAGACAG 22 9454

BCLllA-7773 + ACCU AGAAAGAGGUUGGAGACAG 23 9455

BCLllA-7774 + AACCUAGAAAGAGGUUGGAGACAG 24 9456

BCLllA-7775 + AGGAGGGGCGGAUUGCAG 18 9457

BCLllA-7776 + GAGGAGGGGCGGAUUGCAG 19 9458

BCLllA-6069 + GGAGGAGGGGCGGAUUGCAG 20 9459

BCLllA-7777 + GGGAGGAGGGGCGGAUUGCAG 21 9460

BCLllA-7778 + AGGGAGGAGGGGCGGAUUGCAG 22 9461

BCLllA-7779 + GAGGGAGGAGGGGCGGAUUGCAG 23 9462

BCLllA-7780 + GGAGGGAGGAGGGGCGGAUUGCAG 24 9463

BCLllA-7781 + AAGAGGUUGGAGACAGAG 18 9464

BCLllA-7782 + AAAG AGG U UGG AG ACAG AG 19 9465

BCLllA-7783 + GAAAGAGGUUGGAGACAGAG 20 9466

BCLllA-7784 + AG AAAG AGG U UGG AG ACAG AG 21 9467

BCLllA-7785 + UAGAAAGAGGUUGGAGACAGAG 22 9468

BCLllA-7786 + CU AG AAAG AGG U UGG AG ACAG AG 23 9469

BCLllA-7787 + CCUAGAAAGAGGUUGGAGACAGAG 24 9470

BCLllA-7788 + GAGGGGCGGAUUGCAGAG 18 9471

BCLllA-7789 + GGAGGGGCGGAUUGCAGAG 19 9472

BCLllA-7790 + AGGAGGGGCGGAUUGCAGAG 20 9473 BCLllA-7791 + GAGGAGGGGCGGAUUGCAGAG 21 9474

BCLllA-7792 + GGAGGAGGGGCGGAUUGCAGAG 22 9475

BCLllA-7793 + GGGAGGAGGGGCGGAUUGCAGAG 23 9476

BCLllA-7794 + AGGGAGGAGGGGCGGAUUGCAGAG 24 9477

BCLllA-7795 + AGCUUGAUGCGCUUAGAG 18 9478

BCLllA-7796 + GAGCUUGAUGCGCUUAGAG 19 9479

BCLllA-7797 + CGAGCU UGAUGCGCUUAGAG 20 9480

BCLllA-7798 + UCGAGCUUGAUGCGCUUAGAG 21 9481

BCLllA-7799 + CUCGAGCU UGAUGCGCU UAGAG 22 9482

BCLllA-7800 + UCUCGAGCUUGAUGCGCUUAGAG 23 9483

BCLllA-7801 + UUCUCGAGCUUGAUGCGCUUAGAG 24 9484

BCLllA-7802 + GAGAAGGGGCUCAGCGAG 18 9485

BCLllA-7803 + AGAGAAGGGGCUCAGCGAG 19 9486

BCLllA-7804 + UAGAGAAGGGGCUCAGCGAG 20 9487

BCLllA-7805 + U UAGAGAAGGGGCUCAGCGAG 21 9488

BCLllA-7806 + CUU AGAGAAGGGGCUCAGCGAG 22 9489

BCLllA-7807 + GCUUAGAGAAGGGGCUCAGCGAG 23 9490

BCLllA-7808 + CGCUU AGAGAAGGGGCUCAGCGAG 24 9491

BCLllA-7809 + GGAUUGCAGAGGAGGGAG 18 9492

BCLllA-7810 + CGGAUUGCAGAGGAGGGAG 19 9493

BCLllA-6075 + GCGGAUUGCAGAGGAGGGAG 20 9494

BCLllA-7811 + GGCGGAUUGCAGAGGAGGGAG 21 9495

BCLllA-7812 + GGGCGGAUUGCAGAGGAGGGAG 22 9496

BCLllA-7813 + GGGGCGGAUUGCAGAGGAGGGAG 23 9497

BCLllA-7814 + AGGGGCGGAUUGCAGAGGAGGGAG 24 9498

BCLllA-7815 + CCGGGGGCUGGGAGGGAG 18 9499

BCLllA-7816 + ACCGGGGGCUGGGAGGGAG 19 9500

BCLllA-7817 + GACCGGGGGCUGGGAGGGAG 20 9501

BCLllA-7818 + UGACCGGGGGCUGGGAGGGAG 21 9502

BCLllA-7819 + U UGACCGGGGGCUGGGAGGGAG 22 9503

BCLllA-7820 + CUUGACCGGGGGCUGGGAGGGAG 23 9504

BCLllA-7821 + ACU UGACCGGGGGCUGGGAGGGAG 24 9505

BCLllA-7822 + CUGAAGUGCUGCAUGGAG 18 9506

BCLllA-7823 + GCUGAAGUGCUGCAUGGAG 19 9507

BCLllA-7824 + CGCUGAAGUGCUGCAUGGAG 20 9508

BCLllA-7825 + UCGCUGAAGUGCUGCAUGGAG 21 9509

BCLllA-7826 + CUCGCUGAAGUGCUGCAUGGAG 22 9510

BCLllA-7827 + CCUCGCUGAAGUGCUGCAUGGAG 23 9511

BCLllA-7828 + GCCUCGCUGAAGUGCUGCAUGGAG 24 9512

BCLllA-7829 + CGUCUGCCCUCUU UUGAG 18 9513

BCLllA-7830 + GCGUCUGCCCUCUUUUGAG 19 9514

BCLllA-7831 + UGCGUCUGCCCUCUUU UGAG 20 9515 BCLllA-7832 + CUGCGUCUGCCCUCU UUUGAG 21 9516

BCLllA-7833 + GCUGCGUCUGCCCUCU UUUGAG 22 9517

BCLllA-7834 + CGCUGCGUCUGCCCUCU UUUGAG 23 9518

BCLllA-7835 + UCGCUGCGUCUGCCCUCUUUUGAG 24 9519

BCLllA-7836 + CCGAGGAGUGCUCCGACG 18 9520

BCLllA-7837 + UCCGAGGAGUGCUCCGACG 19 9521

BCLllA-6080 + CUCCGAGGAGUGCUCCGACG 20 9522

BCLllA-7838 + UCUCCGAGGAGUGCUCCGACG 21 9523

BCLllA-7839 + U UCUCCGAGGAGUGCUCCGACG 22 9524

BCLllA-7840 + GU UCUCCGAGGAGUGCUCCGACG 23 9525

BCLllA-7841 + CGU UCUCCGAGGAGUGCUCCGACG 24 9526

BCLllA-7842 + ACCAUGCCCUGCAUGACG 18 9527

BCLllA-7843 + CACCAUGCCCUGCAUGACG 19 9528

BCLllA-7844 + GCACCAUGCCCUGCAUGACG 20 9529

BCLllA-7845 + AGCACCAUGCCCUGCAUGACG 21 9530

BCLllA-7846 + GAGCACCAUGCCCUGCAUGACG 22 9531

BCLllA-7847 + UGAGCACCAUGCCCUGCAUGACG 23 9532

BCLllA-7848 + CUGAGCACCAUGCCCUGCAUGACG 24 9533

BCLllA-7849 + CCGAGGCCGACUCGCCCG 18 9534

BCLllA-7850 + CCCGAGGCCGACUCGCCCG 19 9535

BCLllA-6088 + CCCCGAGGCCGACUCGCCCG 20 9536

BCLllA-7851 + CCCCCGAGGCCGACUCGCCCG 21 9537

BCLllA-7852 + CCCCCCGAGGCCGACUCGCCCG 22 9538

BCLllA-7853 + GCCCCCCGAGGCCGACUCGCCCG 23 9539

BCLllA-7854 + GGCCCCCCGAGGCCGACUCGCCCG 24 9540

BCLllA-7855 + CUGGAGGCCGCGUAGCCG 18 9541

BCLllA-7856 + CCUGGAGGCCGCGUAGCCG 19 9542

BCLllA-7857 + GCCUGGAGGCCGCGUAGCCG 20 9543

BCLllA-7858 + UGCCUGGAGGCCGCGUAGCCG 21 9544

BCLllA-7859 + CUGCCUGGAGGCCGCGUAGCCG 22 9545

BCLllA-7860 + GCUGCCUGGAGGCCGCGUAGCCG 23 9546

BCLllA-7861 + AGCUGCCUGGAGGCCGCGUAGCCG 24 9547

BCLllA-7862 + AAUUUGAACGUCUUGCCG 18 9548

BCLllA-7863 + AAAUUUGAACGUCUUGCCG 19 9549

BCLllA-7864 + GAAAUUUGAACGUCUUGCCG 20 9550

BCLllA-7865 + UGAAAUUUGAACGUCU UGCCG 21 9551

BCLllA-7866 + CUGAAAUUUGAACGUCUUGCCG 22 9552

BCLllA-7867 + UCUGAAAUUUGAACGUCUUGCCG 23 9553

BCLllA-7868 + CUCUGAAAUUUGAACGUCUUGCCG 24 9554

BCLllA-7869 + UCUCCGAGGAGUGCUCCG 18 9555

BCLllA-7870 + U UCUCCGAGGAGUGCUCCG 19 9556

BCLllA-7871 + GUUCUCCGAGGAGUGCUCCG 20 9557 BCLllA-7872 + CGUUCUCCGAGGAGUGCUCCG 21 9558

BCLllA-7873 + CCGUUCUCCGAGGAGUGCUCCG 22 9559

BCLllA-7874 + CCCGUUCUCCGAGGAGUGCUCCG 23 9560

BCLllA-7875 + UCCCGU UCUCCGAGGAGUGCUCCG 24 9561

BCLllA-7876 + CGCUGGUGCCGGGU UCCG 18 9562

BCLllA-7877 + UCGCUGGUGCCGGGUUCCG 19 9563

BCLllA-6096 + GUCGCUGGUGCCGGGU UCCG 20 9564

BCLllA-7878 + AGUCGCUGGUGCCGGGUUCCG 21 9565

BCLllA-7879 + AAGUCGCUGGUGCCGGGUUCCG 22 9566

BCLllA-7880 + CAAGUCGCUGGUGCCGGGUUCCG 23 9567

BCLllA-7881 + CCAAGUCGCUGGUGCCGGGUUCCG 24 9568

BCLllA-7882 + GCCGGCCUGGGGACAGCG 18 9569

BCLllA-7883 + GGCCGGCCUGGGGACAGCG 19 9570

BCLllA-7884 + GGGCCGGCCUGGGGACAGCG 20 9571

BCLllA-7885 + UGGGCCGGCCUGGGGACAGCG 21 9572

BCLllA-7886 + CUGGGCCGGCCUGGGGACAGCG 22 9573

BCLllA-7887 + GCUGGGCCGGCCUGGGGACAGCG 23 9574

BCLllA-7888 + GGCUGGGCCGGCCUGGGGACAGCG 24 9575

BCLllA-7889 + GGU UCCGGGGAGCUGGCG 18 9576

BCLllA-7890 + GGGUUCCGGGGAGCUGGCG 19 9577

BCLllA-7891 + CGGGU UCCGGGGAGCUGGCG 20 9578

BCLllA-7892 + CCGGGUUCCGGGGAGCUGGCG 21 9579

BCLllA-7893 + GCCGGGUUCCGGGGAGCUGGCG 22 9580

BCLllA-7894 + UGCCGGGUUCCGGGGAGCUGGCG 23 9581

BCLllA-7895 + GUGCCGGGU UCCGGGGAGCUGGCG 24 9582

BCLllA-7896 + CCCCAGGCGCUCUAUGCG 18 9583

BCLllA-7897 + CCCCCAGGCGCUCUAUGCG 19 9584

BCLllA-7898 + GCCCCCAGGCGCUCUAUGCG 20 9585

BCLllA-7899 + CGCCCCCAGGCGCUCUAUGCG 21 9586

BCLllA-7900 + CCGCCCCCAGGCGCUCUAUGCG 22 9587

BCLllA-7901 + UCCGCCCCCAGGCGCUCUAUGCG 23 9588

BCLllA-7902 + U UCCGCCCCCAGGCGCUCUAUGCG 24 9589

BCLllA-7903 + ACCUGGUGGAAGGCCUCG 18 9590

BCLllA-7904 + GACCUGGUGGAAGGCCUCG 19 9591

BCLllA-7905 + GGACCUGGUGGAAGGCCUCG 20 9592

BCLllA-7906 + AGGACCUGGUGGAAGGCCUCG 21 9593

BCLllA-7907 + CAGGACCUGGUGGAAGGCCUCG 22 9594

BCLllA-7908 + CCAGGACCUGGUGGAAGGCCUCG 23 9595

BCLllA-7909 + CCCAGGACCUGGUGGAAGGCCUCG 24 9596

BCLllA-7910 + GCGGUGGAGAGACCGUCG 18 9597

BCLllA-7911 + GGCGGUGGAGAGACCGUCG 19 9598

BCLllA-7912 + UGGCGGUGGAGAGACCGUCG 20 9599 BCLllA-7913 + CUGGCGGUGGAGAGACCGUCG 21 9600

BCLllA-7914 + GCUGGCGGUGGAGAGACCGUCG 22 9601

BCLllA-7915 + AGCUGGCGGUGGAGAGACCGUCG 23 9602

BCLllA-7916 + GAGCUGGCGGUGGAGAGACCGUCG 24 9603

BCLllA-7917 + GAGUCUCCGAAGCUAAGG 18 9604

BCLllA-7918 + GGAGUCUCCGAAGCUAAGG 19 9605

BCLllA-7919 + UGGAGUCUCCGAAGCUAAGG 20 9606

BCLllA-7920 + CUGGAGUCUCCGAAGCUAAGG 21 9607

BCLllA-7921 + UCUGGAGUCUCCGAAGCUAAGG 22 9608

BCLllA-7922 + GUCUGGAGUCUCCGAAGCUAAGG 23 9609

BCLllA-7923 + UGUCUGGAGUCUCCGAAGCUAAGG 24 9610

BCLllA-7924 + GGUGGUGGACUAAACAGG 18 9611

BCLllA-7925 + CGGUGGUGGACUAAACAGG 19 9612

BCLllA-6111 + UCGGUGGUGGACUAAACAGG 20 9613

BCLllA-7926 + CUCGGUGGUGGACUAAACAGG 21 9614

BCLllA-7927 + UCUCGGUGGUGGACUAAACAGG 22 9615

BCLllA-7928 + GUCUCGGUGGUGGACUAAACAGG 23 9616

BCLllA-7929 + UGUCUCGGUGGUGGACUAAACAGG 24 9617

BCLllA-7930 + AGGGGGGGCGUCGCCAGG 18 9618

BCLllA-7931 + GAGGGGGGGCGUCGCCAGG 19 9619

BCLllA-7932 + GGAGGGGGGGCGUCGCCAGG 20 9620

BCLllA-7933 + GGGAGGGGGGGCGUCGCCAGG 21 9621

BCLllA-7934 + AGGGAGGGGGGGCGUCGCCAGG 22 9622

BCLllA-7935 + GAGGGAGGGGGGGCGUCGCCAGG 23 9623

BCLllA-7936 + GGAGGGAGGGGGGGCGUCGCCAGG 24 9624

BCLllA-7937 + AAGCGCCCU UCUGCCAGG 18 9625

BCLllA-7938 + AAAGCGCCCUUCUGCCAGG 19 9626

BCLllA-7939 + GAAAGCGCCCUUCUGCCAGG 20 9627

BCLllA-7940 + GGAAAGCGCCCUUCUGCCAGG 21 9628

BCLllA-7941 + UGGAAAGCGCCCUUCUGCCAGG 22 9629

BCLllA-7942 + GUGGAAAGCGCCCUUCUGCCAGG 23 9630

BCLllA-7943 + GGUGGAAAGCGCCCUUCUGCCAGG 24 9631

BCLllA-7944 + AUCGCGGCCGGGGGCAGG 18 9632

BCLllA-7945 + CAUCGCGGCCGGGGGCAGG 19 9633

BCLllA-7946 + GCAUCGCGGCCGGGGGCAGG 20 9634

BCLllA-7947 + GGCAUCGCGGCCGGGGGCAGG 21 9635

BCLllA-7948 + GGGCAUCGCGGCCGGGGGCAGG 22 9636

BCLllA-7949 + UGGGCAUCGCGGCCGGGGGCAGG 23 9637

BCLllA-7950 + UUGGGCAUCGCGGCCGGGGGCAGG 24 9638

BCLllA-7951 + CCGUUCUCCGGGAUCAGG 18 9639

BCLllA-7952 + CCCGUUCUCCGGGAUCAGG 19 9640

BCLllA-7953 + CCCCGUUCUCCGGGAUCAGG 20 9641 BCLllA-7954 + UCCCCGUUCUCCGGGAUCAGG 21 9642

BCLllA-7955 + GUCCCCGUUCUCCGGGAUCAGG 22 9643

BCLllA-7956 + CGUCCCCGUUCUCCGGGAUCAGG 23 9644

BCLllA-7957 + UCGUCCCCGUUCUCCGGGAUCAGG 24 9645

BCLllA-7958 + GAAGAACCUAGAAAGAGG 18 9646

BCLllA-7959 + UGAAGAACCUAGAAAGAGG 19 9647

BCLllA-7960 + GUGAAGAACCUAGAAAGAGG 20 9648

BCLllA-7961 + UG UGAAGAACCUAGAAAGAGG 21 9649

BCLllA-7962 + GUGUGAAGAACCUAGAAAGAGG 22 9650

BCLllA-7963 + UGUGUGAAGAACCUAGAAAGAGG 23 9651

BCLllA-7964 + GUGUGUGAAGAACCUAGAAAGAGG 24 9652

BCLllA-7965 + AGAGGUUGGAGACAGAGG 18 9653

BCLllA-7966 + AAGAGGUUGGAGACAGAGG 19 9654

BCLllA-6113 + AAAGAGGUUGGAGACAGAGG 20 9655

BCLllA-7967 + GAAAGAGGUUGGAGACAGAGG 21 9656

BCLllA-7968 + AGAAAGAGGUUGGAGACAGAGG 22 9657

BCLllA-7969 + UAGAAAGAGGUUGGAGACAGAGG 23 9658

BCLllA-7970 + CUAGAAAGAGGUUGGAGACAGAGG 24 9659

BCLllA-7971 + AGGGGCGGAUUGCAGAGG 18 9660

BCLllA-7972 + GAGGGGCGGAUUGCAGAGG 19 9661

BCLllA-6114 + GGAGGGGCGGAUUGCAGAGG 20 9662

BCLllA-7973 + AGGAGGGGCGGAUUGCAGAGG 21 9663

BCLllA-7974 + GAGGAGGGGCGGAUUGCAGAGG 22 9664

BCLllA-7975 + GGAGGAGGGGCGGAUUGCAGAGG 23 9665

BCLllA-7976 + GGGAGGAGGGGCGGAUUGCAGAGG 24 9666

BCLllA-7977 + GGCGGAUUGCAGAGGAGG 18 9667

BCLllA-7978 + GGGCGGAUUGCAGAGGAGG 19 9668

BCLllA-7979 + GGGGCGGAUUGCAGAGGAGG 20 9669

BCLllA-7980 + AGGGGCGGAUUGCAGAGGAGG 21 9670

BCLllA-7981 + GAGGGGCGGAUUGCAGAGGAGG 22 9671

BCLllA-7982 + GGAGGGGCGGAUUGCAGAGGAGG 23 9672

BCLllA-7983 + AGGAGGGGCGGAUUGCAGAGGAGG 24 9673

BCLllA-7984 + GAUUGCAGAGGAGGGAGG 18 9674

BCLllA-7985 + GGAUUGCAGAGGAGGGAGG 19 9675

BCLllA-6118 + CGGAUUGCAGAGGAGGGAGG 20 9676

BCLllA-7986 + GCGGAUUGCAGAGGAGGGAGG 21 9677

BCLllA-7987 + GGCGGAUUGCAGAGGAGGGAGG 22 9678

BCLllA-7988 + GGGCGGAUUGCAGAGGAGGGAGG 23 9679

BCLllA-7989 + GGGGCGGAUUGCAGAGGAGGGAGG 24 9680

BCLllA-7990 + CGGGGGCUGGGAGGGAGG 18 9681

BCLllA-7991 + CCGGGGGCUGGGAGGGAGG 19 9682

BCLllA-6119 + ACCGGGGGCUGGGAGGGAGG 20 9683 BCLllA-7992 + GACCGGGGGCUGGGAGGGAGG 21 9684

BCLllA-7993 + UGACCGGGGGCUGGGAGGGAGG 22 9685

BCLllA-7994 + UUGACCGGGGGCUGGGAGGGAGG 23 9686

BCLllA-7995 + CUUGACCGGGGGCUGGGAGGGAGG 24 9687

BCLllA-7996 + UGACCGGGGGCUGGGAGG 18 9688

BCLllA-7997 + U UGACCGGGGGCUGGGAGG 19 9689

BCLllA-7998 + CUUGACCGGGGGCUGGGAGG 20 9690

BCLllA-7999 + ACU UGACCGGGGGCUGGGAGG 21 9691

BCLllA-8000 + GACUUGACCGGGGGCUGGGAGG 22 9692

BCLllA-8001 + GGACUUGACCGGGGGCUGGGAGG 23 9693

BCLllA-8002 + UGGACUUGACCGGGGGCUGGGAGG 24 9694

BCLllA-8003 + CCGUGU UGGGCAUCGCGG 18 9695

BCLllA-8004 + UCCGUGUUGGGCAUCGCGG 19 9696

BCLllA-8005 + CUCCGUGUUGGGCAUCGCGG 20 9697

BCLllA-8006 + UCUCCGUGUUGGGCAUCGCGG 21 9698

BCLllA-8007 + UUCUCCGUGUUGGGCAUCGCGG 22 9699

BCLllA-8008 + GUUCUCCGUGUUGGGCAUCGCGG 23 9700

BCLllA-8009 + CGUUCUCCGUGU UGGGCAUCGCGG 24 9701

BCLllA-8010 + GUUCCGGGGAGCUGGCGG 18 9702

BCLllA-8011 + GGU UCCGGGGAGCUGGCGG 19 9703

BCLllA-6125 + GGGUUCCGGGGAGCUGGCGG 20 9704

BCLllA-8012 + CGGGU UCCGGGGAGCUGGCGG 21 9705

BCLllA-8013 + CCGGGUUCCGGGGAGCUGGCGG 22 9706

BCLllA-8014 + GCCGGGU UCCGGGGAGCUGGCGG 23 9707

BCLllA-8015 + UGCCGGGUUCCGGGGAGCUGGCGG 24 9708

BCLllA-8016 + CCCAGGCGCUCUAUGCGG 18 9709

BCLllA-8017 + CCCCAGGCGCUCUAUGCGG 19 9710

BCLllA-6126 + CCCCCAGGCGCUCUAUGCGG 20 9711

BCLllA-8018 + GCCCCCAGGCGCUCUAUGCGG 21 9712

BCLllA-8019 + CGCCCCCAGGCGCUCUAUGCGG 22 9713

BCLllA-8020 + CCGCCCCCAGGCGCUCUAUGCGG 23 9714

BCLllA-8021 + UCCGCCCCCAGGCGCUCUAUGCGG 24 9715

BCLllA-8022 + GUGGUGGACUAAACAGGG 18 9716

BCLllA-8023 + GGUGGUGGACUAAACAGGG 19 9717

BCLllA-6131 + CGGUGGUGGACUAAACAGGG 20 9718

BCLllA-8024 + UCGGUGGUGGACUAAACAGGG 21 9719

BCLllA-8025 + CUCGGUGGUGGACUAAACAGGG 22 9720

BCLllA-8026 + UCUCGGUGGUGGACUAAACAGGG 23 9721

BCLllA-8027 + GUCUCGGUGGUGGACUAAACAGGG 24 9722

BCLllA-8028 + GCGGAUUGCAGAGGAGGG 18 9723

BCLllA-8029 + GGCGGAUUGCAGAGGAGGG 19 9724

BCLllA-6133 + GGGCGGAUUGCAGAGGAGGG 20 9725 BCLllA-8030 + GGGGCGGAUUGCAGAGGAGGG 21 9726

BCLllA-8031 + AGGGGCGGAUUGCAGAGGAGGG 22 9727

BCLllA-8032 + GAGGGGCGGAUUGCAGAGGAGGG 23 9728

BCLllA-8033 + GGAGGGGCGGAUUGCAGAGGAGGG 24 9729

BCLllA-8034 + GACCGGGGGCUGGGAGGG 18 9730

BCLllA-8035 + UGACCGGGGGCUGGGAGGG 19 9731

BCLllA-6135 + UUGACCGGGGGCUGGGAGGG 20 9732

BCLllA-8036 + CUUGACCGGGGGCUGGGAGGG 21 9733

BCLllA-8037 + ACU UGACCGGGGGCUGGGAGGG 22 9734

BCLllA-8038 + GACUUGACCGGGGGCUGGGAGGG 23 9735

BCLllA-8039 + GGACUUGACCGGGGGCUGGGAGGG 24 9736

BCLllA-8040 + AGUAACCUUUGCAUAGGG 18 9737

BCLllA-8041 + CAGUAACCUUUGCAUAGGG 19 9738

BCLllA-8042 + GCAGUAACCUUUGCAUAGGG 20 9739

BCLllA-8043 + UGCAGUAACCUU UGCAUAGGG 21 9740

BCLllA-8044 + U UGCAGUAACCU UUGCAUAGGG 22 9741

BCLllA-8045 + GU UGCAGUAACCUUUGCAUAGGG 23 9742

BCLllA-8046 + GGUUGCAGUAACCUUUGCAUAGGG 24 9743

BCLllA-8047 + GCCCUGCAUGACGUCGGG 18 9744

BCLllA-8048 + UGCCCUGCAUGACGUCGGG 19 9745

BCLllA-8049 + AUGCCCUGCAUGACGUCGGG 20 9746

BCLllA-8050 + CAUGCCCUGCAUGACGUCGGG 21 9747

BCLllA-8051 + CCAUGCCCUGCAUGACGUCGGG 22 9748

BCLllA-8052 + ACCAUGCCCUGCAUGACGUCGGG 23 9749

BCLllA-8053 + CACCAUGCCCUGCAUGACGUCGGG 24 9750

BCLllA-8054 + CUUGGACUUGACCGGGGG 18 9751

BCLllA-8055 + ACU UGGACUUGACCGGGGG 19 9752

BCLllA-8056 + GACUUGGACUUGACCGGGGG 20 9753

BCLllA-8057 + UGACUUGGACUUGACCGGGGG 21 9754

BCLllA-8058 + AUGACUUGGACUUGACCGGGGG 22 9755

BCLllA-8059 + CAUGACUUGGACUUGACCGGGGG 23 9756

BCLllA-8060 + GCAUGACUUGGACUUGACCGGGGG 24 9757

BCLllA-8061 + ACU UGACCGGGGGCUGGG 18 9758

BCLllA-8062 + GACUUGACCGGGGGCUGGG 19 9759

BCLllA-6146 + GGACUUGACCGGGGGCUGGG 20 9760

BCLllA-8063 + UGGACUUGACCGGGGGCUGGG 21 9761

BCLllA-8064 + UUGGACUUGACCGGGGGCUGGG 22 9762

BCLllA-8065 + CUUGGACUUGACCGGGGGCUGGG 23 9763

BCLllA-8066 + ACUUGGACUUGACCGGGGGCUGGG 24 9764

BCLllA-8067 + CAUGGAGAGGUGGCUGGG 18 9765

BCLllA-8068 + CCAUGGAGAGGUGGCUGGG 19 9766

BCLllA-8069 + CCCAUGGAGAGGUGGCUGGG 20 9767 BCLllA-8070 + UCCCAUGGAGAGGUGGCUGGG 21 9768

BCLllA-8071 + AUCCCAUGGAGAGGUGGCUGGG 22 9769

BCLllA-8072 + AAUCCCAUGGAGAGGUGGCUGGG 23 9770

BCLllA-8073 + GAAUCCCAUGGAGAGGUGGCUGGG 24 9771

BCLllA-8074 + AAACAGGGGGGGAGUGGG 18 9772

BCLllA-8075 + UAAACAGGGGGGGAGUGGG 19 9773

BCLllA-6147 + CUAAACAGGGGGGGAGUGGG 20 9774

BCLllA-8076 + ACU AAACAGGGGGGGAGUGGG 21 9775

BCLllA-8077 + GACUAAACAGGGGGGGAGUGGG 22 9776

BCLllA-8078 + GGACUAAACAGGGGGGGAGUGGG 23 9777

BCLllA-8079 + UGGACUAAACAGGGGGGGAGUGGG 24 9778

BCLllA-8080 + UCCUAGAGAAAUCCAUGG 18 9779

BCLllA-8081 + CUCCUAGAGAAAUCCAUGG 19 9780

BCLllA-6149 + UCUCCUAGAGAAAUCCAUGG 20 9781

BCLllA-8082 + GUCUCCUAGAGAAAUCCAUGG 21 9782

BCLllA-8083 + AGUCUCCUAGAGAAAUCCAUGG 22 9783

BCLllA-8084 + AAGUCUCCUAGAGAAAUCCAUGG 23 9784

BCLllA-8085 + UAAGUCUCCUAGAGAAAUCCAUGG 24 9785

BCLllA-8086 + UUCUCGCCCAGGACCUGG 18 9786

BCLllA-8087 + CUUCUCGCCCAGGACCUGG 19 9787

BCLllA-6152 + GCUUCUCGCCCAGGACCUGG 20 9788

BCLllA-8088 + UGCUUCUCGCCCAGGACCUGG 21 9789

BCLllA-8089 + AUGCUUCUCGCCCAGGACCUGG 22 9790

BCLllA-8090 + UAUGCUUCUCGCCCAGGACCUGG 23 9791

BCLllA-8091 + UUAUGCUUCUCGCCCAGGACCUGG 24 9792

BCLllA-8092 + GGGCGGCUUGCUACCUGG 18 9793

BCLllA-8093 + AGGGCGGCUUGCUACCUGG 19 9794

BCLllA-8094 + AAGGGCGGCUUGCUACCUGG 20 9795

BCLllA-8095 + GAAGGGCGGCUUGCUACCUGG 21 9796

BCLllA-8096 + GGAAGGGCGGCUUGCUACCUGG 22 9797

BCLllA-8097 + AGGAAGGGCGGCUUGCUACCUGG 23 9798

BCLllA-8098 + CAGGAAGGGCGGCUUGCUACCUGG 24 9799

BCLllA-8099 + GACUUGACCGGGGGCUGG 18 9800

BCLllA-8100 + GGACUUGACCGGGGGCUGG 19 9801

BCLllA-8101 + UGGACUUGACCGGGGGCUGG 20 9802

BCLllA-8102 + UUGGACUUGACCGGGGGCUGG 21 9803

BCLllA-8103 + CUUGGACUUGACCGGGGGCUGG 22 9804

BCLllA-8104 + ACU UGGACUUGACCGGGGGCUGG 23 9805

BCLllA-8105 + GACUUGGACUUGACCGGGGGCUGG 24 9806

BCLllA-8106 + UAAACAGGGGGGGAGUGG 18 9807

BCLllA-8107 + CUAAACAGGGGGGGAGUGG 19 9808

BCLllA-8108 + ACUAAACAGGGGGGGAGUGG 20 9809 BCLllA-8109 + GACUAAACAGGGGGGGAGUGG 21 9810

BCLllA-8110 + GGACUAAACAGGGGGGGAGUGG 22 9811

BCLllA-8111 + UGGACUAAACAGGGGGGGAGUGG 23 9812

BCLllA-8112 + GUGGACUAAACAGGGGGGGAGUGG 24 9813

BCLllA-8113 + AAUCCCAUGGAGAGGUGG 18 9814

BCLllA-8114 + GAAUCCCAUGGAGAGGUGG 19 9815

BCLllA-8115 + UGAAUCCCAUGGAGAGGUGG 20 9816

BCLllA-8116 + AUGAAUCCCAUGGAGAGGUGG 21 9817

BCLllA-8117 + UAUGAAUCCCAUGGAGAGGUGG 22 9818

BCLllA-8118 + AUAUGAAUCCCAUGGAGAGGUGG 23 9819

BCLllA-8119 + AAUAUGAAUCCCAUGGAGAGGUGG 24 9820

BCLllA-8120 + UGCAAUAUGAAUCCCAUG 18 9821

BCLllA-8121 + CUGCAAUAUGAAUCCCAUG 19 9822

BCLllA-8122 + UCUGCAAUAUGAAUCCCAUG 20 9823

BCLllA-8123 + GUCUGCAAUAUGAAUCCCAUG 21 9824

BCLllA-8124 + UGUCUGCAAUAUGAAUCCCAUG 22 9825

BCLllA-8125 + U UGUCUGCAAUAUGAAUCCCAUG 23 9826

BCLllA-8126 + AUUGUCUGCAAUAUGAAUCCCAUG 24 9827

BCLllA-8127 + CUCCUAGAGAAAUCCAUG 18 9828

BCLllA-8128 + UCUCCUAGAGAAAUCCAUG 19 9829

BCLllA-8129 + GUCUCCUAGAGAAAUCCAUG 20 9830

BCLllA-8130 + AGUCUCCUAGAGAAAUCCAUG 21 9831

BCLllA-8131 + AAGUCUCCUAGAGAAAUCCAUG 22 9832

BCLllA-8132 + UAAGUCUCCUAGAGAAAUCCAUG 23 9833

BCLllA-8133 + CUAAGUCUCCUAGAGAAAUCCAUG 24 9834

BCLllA-8134 + UCGGACUUGACCGUCAUG 18 9835

BCLllA-8135 + GUCGGACUUGACCGUCAUG 19 9836

BCLllA-6164 + CGUCGGACU UGACCGUCAUG 20 9837

BCLllA-8136 + UCGUCGGACUUGACCGUCAUG 21 9838

BCLllA-8137 + GUCGUCGGACUUGACCGUCAUG 22 9839

BCLllA-8138 + CGUCGUCGGACUUGACCGUCAUG 23 9840

BCLllA-8139 + CCGUCGUCGGACUUGACCGUCAUG 24 9841

BCLllA-8140 + CUUCUCGCCCAGGACCUG 18 9842

BCLllA-8141 + GCU UCUCGCCCAGGACCUG 19 9843

BCLllA-8142 + UGCUUCUCGCCCAGGACCUG 20 9844

BCLllA-8143 + AUGCUUCUCGCCCAGGACCUG 21 9845

BCLllA-8144 + UAUGCUUCUCGCCCAGGACCUG 22 9846

BCLllA-8145 + UUAUGCUUCUCGCCCAGGACCUG 23 9847

BCLllA-8146 + CUUAUGCUUCUCGCCCAGGACCUG 24 9848

BCLllA-8147 + AUUCUGCACCUAGUCCUG 18 9849

BCLllA-8148 + CAU UCUGCACCUAGUCCUG 19 9850

BCLllA-8149 + ACAUUCUGCACCUAGUCCUG 20 9851 BCLllA-8150 + GACAUUCUGCACCUAGUCCUG 21 9852

BCLllA-8151 + GGACAUUCUGCACCUAGUCCUG 22 9853

BCLllA-8152 + AGGACAUUCUGCACCUAGUCCUG 23 9854

BCLllA-8153 + AAGGACAUUCUGCACCUAGUCCUG 24 9855

BCLllA-6537 + GU UGUACAUGUGUAGCUG 18 9856

BCLllA-6538 + AGUUGUACAUGUGUAGCUG 19 9857

BCLllA-6539 + AAGUUGUACAUGUGUAGCUG 20 9858

BCLllA-6540 + CAAGUUGUACAUGUGUAGCUG 21 9859

BCLllA-6541 + GCAAGUUGUACAUGUGUAGCUG 22 9860

BCLllA-6542 + UGCAAGUUGUACAUGUGUAGCUG 23 9861

BCLllA-6543 + UUGCAAGUUGUACAUGUGUAGCUG 24 9862

BCLllA-8154 + GAGUACACGUUCUCCGUG 18 9863

BCLllA-8155 + CGAGUACACGUUCUCCGUG 19 9864

BCLllA-8156 + GCGAGUACACGUUCUCCGUG 20 9865

BCLllA-8157 + UGCGAGUACACGUUCUCCGUG 21 9866

BCLllA-8158 + CUGCGAGUACACGUUCUCCGUG 22 9867

BCLllA-8159 + ACUGCGAGUACACGUUCUCCGUG 23 9868

BCLllA-8160 + CACUGCGAGUACACGUUCUCCGUG 24 9869

BCLllA-8161 + CCAGCUCCCCGGGCGGUG 18 9870

BCLllA-8162 + UCCAGCUCCCCGGGCGGUG 19 9871

BCLllA-6177 + GUCCAGCUCCCCGGGCGGUG 20 9872

BCLllA-8163 + CGUCCAGCUCCCCGGGCGGUG 21 9873

BCLllA-8164 + CCGUCCAGCUCCCCGGGCGGUG 22 9874

BCLllA-8165 + UCCGUCCAGCUCCCCGGGCGGUG 23 9875

BCLllA-8166 + CUCCGUCCAGCUCCCCGGGCGGUG 24 9876

BCLllA-8167 + UCCGGGGAGCUGGCGGUG 18 9877

BCLllA-8168 + U UCCGGGGAGCUGGCGGUG 19 9878

BCLllA-8169 + GU UCCGGGGAGCUGGCGGUG 20 9879

BCLllA-8170 + GGUUCCGGGGAGCUGGCGGUG 21 9880

BCLllA-8171 + GGGUUCCGGGGAGCUGGCGGUG 22 9881

BCLllA-8172 + CGGGUUCCGGGGAGCUGGCGGUG 23 9882

BCLllA-8173 + CCGGGUUCCGGGGAGCUGGCGGUG 24 9883

BCLllA-8174 + CCAAGUGAUGUCUCGGUG 18 9884

BCLllA-8175 + UCCAAGUGAUGUCUCGGUG 19 9885

BCLllA-8176 + GUCCAAGUGAUGUCUCGGUG 20 9886

BCLllA-8177 + GGUCCAAGUGAUGUCUCGGUG 21 9887

BCLllA-8178 + GGGUCCAAGUGAUGUCUCGGUG 22 9888

BCLllA-8179 + GGGGUCCAAGUGAUGUCUCGGUG 23 9889

BCLllA-8180 + GGGGGUCCAAGUGAUGUCUCGGUG 24 9890

BCLllA-8181 + AGCUCCCCGGGCGGUGUG 18 9891

BCLllA-8182 + CAGCUCCCCGGGCGGUGUG 19 9892

BCLllA-8183 + CCAGCUCCCCGGGCGGUGUG 20 9893 BCLllA-8184 + UCCAGCUCCCCGGGCGGUGUG 21 9894

BCLllA-8185 + GUCCAGCUCCCCGGGCGGUGUG 22 9895

BCLllA-8186 + CGUCCAGCUCCCCGGGCGGUGUG 23 9896

BCLllA-8187 + CCGUCCAGCUCCCCGGGCGGUGUG 24 9897

BCLllA-8188 + GCCGAAUGGGGGUGUGUG 18 9898

BCLllA-8189 + CGCCGAAUGGGGGUGUGUG 19 9899

BCLllA-8190 + ACGCCGAAUGGGGGUGUGUG 20 9900

BCLllA-8191 + UACGCCGAAUGGGGGUGUGUG 21 9901

BCLllA-8192 + CUACGCCGAAUGGGGGUGUGUG 22 9902

BCLllA-8193 + ACU ACGCCGAAUGGGGGUGUGUG 23 9903

BCLllA-8194 + UACUACGCCGAAUGGGGGUGUGUG 24 9904

BCLllA-8195 + GGGAGGAGGGGCGGAU UG 18 9905

BCLllA-8196 + AGGGAGGAGGGGCGGAUUG 19 9906

BCLllA-8197 + GAGGGAGGAGGGGCGGAUUG 20 9907

BCLllA-8198 + GGAGGGAGGAGGGGCGGAUUG 21 9908

BCLllA-8199 + GGGAGGGAGGAGGGGCGGAUUG 22 9909

BCLllA-8200 + UGGGAGGGAGGAGGGGCGGAUUG 23 9910

BCLllA-8201 + CUGGGAGGGAGGAGGGGCGGAUUG 24 9911

BCLllA-8202 + UCGCACAGGUUGCACUUG 18 9912

BCLllA-8203 + GUCGCACAGGU UGCACU UG 19 9913

BCLllA-8204 + GGUCGCACAGGUUGCACUUG 20 9914

BCLllA-8205 + UGGUCGCACAGGUUGCACUUG 21 9915

BCLllA-8206 + GUGGUCGCACAGGUUGCACUUG 22 9916

BCLllA-8207 + CGUGGUCGCACAGGUUGCACUUG 23 9917

BCLllA-8208 + GCGUGGUCGCACAGGUUGCACUUG 24 9918

BCLllA-8209 + ACCAGGUUGCUCUGAAAU 18 9919

BCLllA-8210 + CACCAGGUUGCUCUGAAAU 19 9920

BCLllA-8211 + CCACCAGGU UGCUCUGAAAU 20 9921

BCLllA-8212 + ACCACCAGGUUGCUCUGAAAU 21 9922

BCLllA-8213 + CACCACCAGGU UGCUCUGAAAU 22 9923

BCLllA-8214 + GCACCACCAGGU UGCUCUGAAAU 23 9924

BCLllA-8215 + UGCACCACCAGGUUGCUCUGAAAU 24 9925

BCLllA-8216 + CGGGCCCGGACCACUAAU 18 9926

BCLllA-8217 + CCGGGCCCGGACCACUAAU 19 9927

BCLllA-8218 + CCCGGGCCCGGACCACUAAU 20 9928

BCLllA-8219 + GCCCGGGCCCGGACCACUAAU 21 9929

BCLllA-8220 + UGCCCGGGCCCGGACCACUAAU 22 9930

BCLllA-8221 + CUGCCCGGGCCCGGACCACUAAU 23 9931

BCLllA-8222 + CCUGCCCGGGCCCGGACCACUAAU 24 9932

BCLllA-8223 + GGGCUCUCGAGCUUCCAU 18 9933

BCLllA-8224 + AGGGCUCUCGAGCUUCCAU 19 9934

BCLllA-8225 + AAGGGCUCUCGAGCUUCCAU 20 9935 BCLllA-8226 + UAAGGGCUCUCGAGCUUCCAU 21 9936

BCLllA-8227 + UUAAGGGCUCUCGAGCU UCCAU 22 9937

BCLllA-8228 + CUUAAGGGCUCUCGAGCUUCCAU 23 9938

BCLllA-8229 + ACUUAAGGGCUCUCGAGCUUCCAU 24 9939

BCLllA-8230 + GUCGGACUUGACCGUCAU 18 9940

BCLllA-8231 + CGUCGGACUUGACCGUCAU 19 9941

BCLllA-6186 + UCGUCGGACUUGACCGUCAU 20 9942

BCLllA-8232 + GUCGUCGGACUUGACCGUCAU 21 9943

BCLllA-8233 + CGUCGUCGGACUUGACCGUCAU 22 9944

BCLllA-8234 + CCGUCGUCGGACU UGACCGUCAU 23 9945

BCLllA-8235 + ACCGUCGUCGGACUUGACCGUCAU 24 9946

BCLllA-8236 + AUAGGGCUGGGCCGGCCU 18 9947

BCLllA-8237 + CAUAGGGCUGGGCCGGCCU 19 9948

BCLllA-6198 + GCAUAGGGCUGGGCCGGCCU 20 9949

BCLllA-8238 + UGCAUAGGGCUGGGCCGGCCU 21 9950

BCLllA-8239 + UUGCAUAGGGCUGGGCCGGCCU 22 9951

BCLllA-8240 + UUUGCAUAGGGCUGGGCCGGCCU 23 9952

BCLllA-8241 + CUUUGCAUAGGGCUGGGCCGGCCU 24 9953

BCLllA-8242 + UCUGGAGUCUCCGAAGCU 18 9954

BCLllA-8243 + GUCUGGAGUCUCCGAAGCU 19 9955

BCLllA-8244 + UGUCUGGAGUCUCCGAAGCU 20 9956

BCLllA-8245 + UUGUCUGGAGUCUCCGAAGCU 21 9957

BCLllA-8246 + AUUGUCUGGAGUCUCCGAAGCU 22 9958

BCLllA-8247 + GAUUGUCUGGAGUCUCCGAAGCU 23 9959

BCLllA-8248 + CGAUUGUCUGGAGUCUCCGAAGCU 24 9960

BCLllA-8249 + UCUCGAGCUUGAUGCGCU 18 9961

BCLllA-8250 + U UCUCGAGCUUGAUGCGCU 19 9962

BCLllA-8251 + CUUCUCGAGCUUGAUGCGCU 20 9963

BCLllA-8252 + CCUUCUCGAGCUUGAUGCGCU 21 9964

BCLllA-8253 + UCCU UCUCGAGCUUGAUGCGCU 22 9965

BCLllA-8254 + CUCCUUCUCGAGCUUGAUGCGCU 23 9966

BCLllA-8255 + ACUCCU UCUCGAGCUUGAUGCGCU 24 9967

BCLllA-8256 + UGGACUUGACCGGGGGCU 18 9968

BCLllA-8257 + U UGGACUUGACCGGGGGCU 19 9969

BCLllA-6207 + CUUGGACUUGACCGGGGGCU 20 9970

BCLllA-8258 + ACUUGGACUUGACCGGGGGCU 21 9971

BCLllA-8259 + GACUUGGACUUGACCGGGGGCU 22 9972

BCLllA-8260 + UGACUUGGACUUGACCGGGGGCU 23 9973

BCLllA-8261 + AUGACUUGGACUUGACCGGGGGCU 24 9974

BCLllA-8262 + UCCCAUGGAGAGGUGGCU 18 9975

BCLllA-8263 + AUCCCAUGGAGAGGUGGCU 19 9976

BCLllA-6208 + AAUCCCAUGGAGAGGUGGCU 20 9977 BCLllA-8264 + GAAUCCCAUGGAGAGGUGGCU 21 9978

BCLllA-8265 + UGAAUCCCAUGGAGAGGUGGCU 22 9979

BCLllA-8266 + AUGAAUCCCAUGGAGAGGUGGCU 23 9980

BCLllA-8267 + UAUGAAUCCCAUGGAGAGGUGGCU 24 9981

BCLllA-8268 + GUGCACCACCAGGUUGCU 18 9982

BCLllA-8269 + GGUGCACCACCAGGUUGCU 19 9983

BCLllA-8270 + CGGUGCACCACCAGGUUGCU 20 9984

BCLllA-8271 + CCGGUGCACCACCAGGU UGCU 21 9985

BCLllA-8272 + GCCGGUGCACCACCAGGUUGCU 22 9986

BCLllA-8273 + CGCCGGUGCACCACCAGGU UGCU 23 9987

BCLllA-8274 + GCGCCGGUGCACCACCAGGU UGCU 24 9988

BCLllA-8275 + AAGCUAAGGAAGGGAUCU 18 9989

BCLllA-8276 + GAAGCUAAGGAAGGGAUCU 19 9990

BCLllA-8277 + CGAAGCUAAGGAAGGGAUCU 20 9991

BCLllA-8278 + CCGAAGCUAAGGAAGGGAUCU 21 9992

BCLllA-8279 + UCCGAAGCUAAGGAAGGGAUCU 22 9993

BCLllA-8280 + CUCCGAAGCUAAGGAAGGGAUCU 23 9994

BCLllA-8281 + UCUCCGAAGCUAAGGAAGGGAUCU 24 9995

BCLllA-8282 + GGCGAUUGUCUGGAGUCU 18 9996

BCLllA-8283 + AGGCGAUUGUCUGGAGUCU 19 9997

BCLllA-8284 + AAGGCGAUUGUCUGGAGUCU 20 9998

BCLllA-8285 + AAAGGCGAUUGUCUGGAGUCU 21 9999

BCLllA-8286 + AAAAGGCGAUUGUCUGGAGUCU 22 10000

BCLllA-8287 + CAAAAGGCGAUUGUCUGGAGUCU 23 10001

BCLllA-8288 + GCAAAAGGCGAUUGUCUGGAGUCU 24 10002

BCLllA-8289 + CCUCCUCGUCCCCGUUCU 18 10003

BCLllA-8290 + UCCUCCUCGUCCCCGUUCU 19 10004

BCLllA-8291 + UUCCUCCUCGUCCCCGUUCU 20 10005

BCLllA-8292 + CUUCCUCCUCGUCCCCGUUCU 21 10006

BCLllA-8293 + UCUUCCUCCUCGUCCCCGU UCU 22 10007

BCLllA-8294 + CUCU UCCUCCUCGUCCCCGUUCU 23 10008

BCLllA-8295 + CCUCUUCCUCCUCGUCCCCGUUCU 24 10009

BCLllA-8296 + AGCGCAAACUCCCGUUCU 18 10010

BCLllA-8297 + AAGCGCAAACUCCCGUUCU 19 10011

BCLllA-8298 + GAAGCGCAAACUCCCGUUCU 20 10012

BCLllA-8299 + AGAAGCGCAAACUCCCGUUCU 21 10013

BCLllA-8300 + GAGAAGCGCAAACUCCCGUUCU 22 10014

BCLllA-8301 + GGAGAAGCGCAAACUCCCGUUCU 23 10015

BCLllA-8302 + UGGAGAAGCGCAAACUCCCGUUCU 24 10016

BCLllA-8303 + GGGGGCU UCAAAUU UUCU 18 10017

BCLllA-8304 + UGGGGGCUUCAAAUUUUCU 19 10018

BCLllA-8305 + CUGGGGGCUUCAAAUUUUCU 20 10019 BCLllA-8306 + CCUGGGGGCU UCAAAUU UUCU 21 10020

BCLllA-8307 + CCCUGGGGGCUUCAAAUUUUCU 22 10021

BCLllA-8308 + CCCCUGGGGGCUUCAAAUUUUCU 23 10022

BCLllA-8309 + ACCCCUGGGGGCU UCAAAUUUUCU 24 10023

BCLllA-8310 + AAGAACCUAGAAAGAGGU 18 10024

BCLllA-8311 + GAAGAACCUAGAAAGAGGU 19 10025

BCLllA-6224 + UGAAGAACCUAGAAAGAGGU 20 10026

BCLllA-8312 + GUGAAGAACCUAGAAAGAGGU 21 10027

BCLllA-8313 + UG UGAAGAACCUAGAAAGAGGU 22 10028

BCLllA-8314 + GUGUGAAGAACCUAGAAAGAGGU 23 10029

BCLllA-8315 + UGUGUGAAGAACCUAGAAAGAGGU 24 10030

BCLllA-8316 + UCCAGCUCCCCGGGCGGU 18 10031

BCLllA-8317 + GUCCAGCUCCCCGGGCGGU 19 10032

BCLllA-8318 + CGUCCAGCUCCCCGGGCGGU 20 10033

BCLllA-8319 + CCGUCCAGCUCCCCGGGCGGU 21 10034

BCLllA-8320 + UCCGUCCAGCUCCCCGGGCGGU 22 10035

BCLllA-8321 + CUCCGUCCAGCUCCCCGGGCGGU 23 10036

BCLllA-8322 + CCUCCGUCCAGCUCCCCGGGCGGU 24 10037

BCLllA-8323 + GAUACCAACCCGCGGGGU 18 10038

BCLllA-8324 + GGAUACCAACCCGCGGGGU 19 10039

BCLllA-8325 + GGGAUACCAACCCGCGGGGU 20 10040

BCLllA-8326 + AGGGAUACCAACCCGCGGGGU 21 10041

BCLllA-8327 + AAGGGAUACCAACCCGCGGGGU 22 10042

BCLllA-8328 + GAAGGGAUACCAACCCGCGGGGU 23 10043

BCLllA-8329 + UGAAGGGAUACCAACCCGCGGGGU 24 10044

BCLllA-8330 + UACGCCGAAUGGGGGUGU 18 10045

BCLllA-8331 + CUACGCCGAAUGGGGGUGU 19 10046

BCLllA-8332 + ACUACGCCGAAUGGGGGUGU 20 10047

BCLllA-8333 + UACUACGCCGAAUGGGGGUGU 21 10048

BCLllA-8334 + GUACUACGCCGAAUGGGGGUGU 22 10049

BCLllA-8335 + GGUACUACGCCGAAUGGGGGUGU 23 10050

BCLllA-8336 + GGGUACUACGCCGAAUGGGGGUGU 24 10051

BCLllA-8337 + GAGGCAAAAGGCGAUUGU 18 10052

BCLllA-8338 + GGAGGCAAAAGGCGAU UGU 19 10053

BCLllA-8339 + AGGAGGCAAAAGGCGAUUGU 20 10054

BCLllA-8340 + GAGGAGGCAAAAGGCGAUUGU 21 10055

BCLllA-8341 + CGAGGAGGCAAAAGGCGAUUGU 22 10056

BCLllA-8342 + ACGAGGAGGCAAAAGGCGAUUGU 23 10057

BCLllA-8343 + GACGAGGAGGCAAAAGGCGAUUGU 24 10058

BCLllA-8344 + CAAAUUUUCUCAGAACU U 18 10059

BCLllA-8345 + UCAAAUUUUCUCAGAACUU 19 10060

BCLllA-8346 + UUCAAAUUUUCUCAGAACUU 20 10061 BCLllA-8347 + CUUCAAAUUUUCUCAGAACUU 21 10062

BCLllA-8348 + GCUUCAAAUUUUCUCAGAACUU 22 10063

BCLllA-8349 + GGCU UCAAAUUUUCUCAGAACUU 23 10064

BCLllA-8350 + GGGCUUCAAAUUUUCUCAGAACUU 24 10065

BCLllA-8351 + CGCUGCGUCUGCCCUCU U 18 10066

BCLllA-8352 + UCGCUGCGUCUGCCCUCUU 19 10067

BCLllA-8353 + GUCGCUGCGUCUGCCCUCUU 20 10068

BCLllA-8354 + UGUCGCUGCGUCUGCCCUCUU 21 10069

BCLllA-8355 + GUGUCGCUGCGUCUGCCCUCUU 22 10070

BCLllA-8356 + AGUGUCGCUGCGUCUGCCCUCUU 23 10071

BCLllA-8357 + AAGUGUCGCUGCGUCUGCCCUCUU 24 10072

BCLllA-8358 + AGUCGCUGGUGCCGGGUU 18 10073

BCLllA-8359 + AAGUCGCUGGUGCCGGGUU 19 10074

BCLllA-8360 + CAAGUCGCUGGUGCCGGGUU 20 10075

BCLllA-8361 + CCAAGUCGCUGGUGCCGGGUU 21 10076

BCLllA-8362 + ACCAAGUCGCUGGUGCCGGGUU 22 10077

BCLllA-8363 + CACCAAGUCGCUGGUGCCGGGUU 23 10078

BCLllA-8364 + CCACCAAGUCGCUGGUGCCGGGUU 24 10079

BCLllA-8365 + CUGCCCAGCAGCAGCU UU 18 10080

BCLllA-8366 + GCUGCCCAGCAGCAGCUUU 19 10081

BCLllA-8367 + GGCUGCCCAGCAGCAGCUUU 20 10082

BCLllA-8368 + GGGCUGCCCAGCAGCAGCUUU 21 10083

BCLllA-8369 + GGGGCUGCCCAGCAGCAGCUUU 22 10084

BCLllA-8370 + UGGGGCUGCCCAGCAGCAGCUUU 23 10085

BCLllA-8371 + CUGGGGCUGCCCAGCAGCAGCUUU 24 10086

BCLllA-8372 - GGCAGGCCCAGCU C A A A A 18 10087

BCLllA-8373 - GGGCAGGCCCAGCUCAAAA 19 10088

BCLllA-8374 - CGGGCAGGCCCAGCU C A A A A 20 10089

BCLllA-8375 - CCGGGCAGGCCCAGCUCAAAA 21 10090

BCLllA-8376 - CCCGGGCAGGCCCAGCUCAAAA 22 10091

BCLllA-8377 - GCCCGGGCAGGCCCAGCUCAAAA 23 10092

BCLllA-8378 - GGCCCGGGCAGGCCCAGCUCAAAA 24 10093

BCLllA-8379 - UAAGAAUCUACUUAGAAA 18 10094

BCLllA-8380 - U UAAGAAUCUACUUAGAAA 19 10095

BCLllA-8381 - AU U AAG AAU CU ACU U AG AAA 20 10096

BCLllA-8382 - GAUUAAGAAUCUACUUAGAAA 21 10097

BCLllA-8383 - GGAUUAAGAAUCUACU UAGAAA 22 10098

BCLllA-8384 - UGGAUUAAGAAUCUACUUAGAAA 23 10099

BCLllA-8385 - AUGGAUUAAGAAUCUACUUAGAAA 24 10100

BCLllA-8386 - CGGGCAGGCCCAGCUCAA 18 10101

BCLllA-8387 - CCGGGCAGGCCCAGCUCAA 19 10102

BCLllA-8388 - CCCGGGCAGGCCCAGCUCAA 20 10103 BCLllA-8389 - GCCCGGGCAGGCCCAGCUCAA 21 10104

BCLllA-8390 - GGCCCGGGCAGGCCCAGCUCAA 22 10105

BCLllA-8391 - GGGCCCGGGCAGGCCCAGCUCAA 23 10106

BCLllA-8392 - CGGGCCCGGGCAGGCCCAGCUCAA 24 10107

BCLllA-8393 - GACGAGGAAGAGGAAGAA 18 10108

BCLllA-8394 - CGACGAGGAAGAGGAAGAA 19 10109

BCLllA-3947 - ACGACGAGGAAGAGGAAGAA 20 10110

BCLllA-8395 - GACGACGAGGAAGAGGAAGAA 21 10111

BCLllA-8396 - GGACGACGAGGAAGAGGAAGAA 22 10112

BCLllA-8397 - AGGACGACGAGGAAGAGGAAGAA 23 10113

BCLllA-8398 - GAGGACGACGAGGAAGAGGAAGAA 24 10114

BCLllA-8399 - CAACCUGAUCCCGGAGAA 18 10115

BCLllA-8400 - CCAACCUGAUCCCGGAGAA 19 10116

BCLllA-5881 - CCCAACCUGAUCCCGGAGAA 20 10117

BCLllA-8401 - CCCCAACCUGAUCCCGGAGAA 21 10118

BCLllA-8402 - ACCCCAACCUGAUCCCGGAGAA 22 10119

BCLllA-8403 - GACCCCAACCUGAUCCCGGAGAA 23 10120

BCLllA-8404 - CGACCCCAACCUGAUCCCGGAGAA 24 10121

BCLllA-8405 - GGAGCACUCCUCGGAGAA 18 10122

BCLllA-8406 - CGGAGCACUCCUCGGAGAA 19 10123

BCLllA-5882 - UCGGAGCACUCCUCGGAGAA 20 10124

BCLllA-8407 - GUCGGAGCACUCCUCGGAGAA 21 10125

BCLllA-8408 - CGUCGGAGCACUCCUCGGAGAA 22 10126

BCLllA-8409 - UCGUCGGAGCACUCCUCGGAGAA 23 10127

BCLllA-8410 - CUCGUCGGAGCACUCCUCGGAGAA 24 10128

BCLllA-8411 - GAGGAGGACGACGAGGAA 18 10129

BCLllA-8412 - AGAGGAGGACGACGAGGAA 19 10130

BCLllA-3950 - AAGAGGAGGACGACGAGGAA 20 10131

BCLllA-8413 - GAAGAGGAGGACGACGAGGAA 21 10132

BCLllA-8414 - GGAAGAGGAGGACGACGAGGAA 22 10133

BCLllA-8415 - AGGAAGAGGAGGACGACGAGGAA 23 10134

BCLllA-8416 - GAGGAAGAGGAGGACGACGAGGAA 24 10135

BCLllA-8417 - GAGGAAGAAGAGGAGGAA 18 10136

BCLllA-8418 - AGAGGAAGAAGAGGAGGAA 19 10137

BCLllA-3962 - AAGAGGAAGAAGAGGAGGAA 20 10138

BCLllA-8419 - GAAGAGGAAGAAGAGGAGGAA 21 10139

BCLllA-8420 - GGAAGAGGAAGAAGAGGAGGAA 22 10140

BCLllA-8421 - AGGAAGAGGAAGAAGAGGAGGAA 23 10141

BCLllA-8422 - GAGGAAGAGGAAGAAGAGGAGGAA 24 10142

BCLllA-8423 - AACGGGGACGAGGAGGAA 18 10143

BCLllA-8424 - GAACGGGGACGAGGAGGAA 19 10144

BCLllA-3934 - AGAACGGGGACGAGGAGGAA 20 10145 BCLllA-8425 - GAGAACGGGGACGAGGAGGAA 21 10146

BCLllA-8426 - GGAGAACGGGGACGAGGAGGAA 22 10147

BCLllA-8427 - CGGAGAACGGGGACGAGGAGGAA 23 10148

BCLllA-8428 - CCGGAGAACGGGGACGAGGAGGAA 24 10149

BCLllA-8429 - GGCGCAGCGGCACGGGAA 18 10150

BCLllA-8430 - GGGCGCAGCGGCACGGGAA 19 10151

BCLllA-3857 - GGGGCGCAGCGGCACGGGAA 20 10152

BCLllA-8431 - CGGGGCGCAGCGGCACGGGAA 21 10153

BCLllA-8432 - UCGGGGCGCAGCGGCACGGGAA 22 10154

BCLllA-8433 - CUCGGGGCGCAGCGGCACGGGAA 23 10155

BCLllA-8434 - UCUCGGGGCGCAGCGGCACGGGAA 24 10156

BCLllA-8435 - CGGCCGCGAUGCCCAACA 18 10157

BCLllA-8436 - CCGGCCGCGAUGCCCAACA 19 10158

BCLllA-5893 - CCCGGCCGCGAUGCCCAACA 20 10159

BCLllA-8437 - CCCCGGCCGCGAUGCCCAACA 21 10160

BCLllA-8438 - CCCCCGGCCGCGAUGCCCAACA 22 10161

BCLllA-8439 - GCCCCCGGCCGCGAUGCCCAACA 23 10162

BCLllA-8440 - UGCCCCCGGCCGCGAUGCCCAACA 24 10163

BCLllA-8441 - CUACUUAGAAAGCGAACA 18 10164

BCLllA-8442 - U CU ACU U AG AAAG CG AACA 19 10165

BCLllA-5894 - AUCUACUUAGAAAGCGAACA 20 10166

BCLllA-8443 - AAUCUACUUAGAAAGCGAACA 21 10167

BCLllA-8444 - GAAUCUACUUAGAAAGCGAACA 22 10168

BCLllA-8445 - AGAAUCUACUUAGAAAGCGAACA 23 10169

BCLllA-8446 - AAGAAUCUACUUAGAAAGCGAACA 24 10170

BCLllA-8447 - CCCCUGUUUAGUCCACCA 18 10171

BCLllA-8448 - CCCCCUGUUUAGUCCACCA 19 10172

BCLllA-8449 - CCCCCCUGUUUAGUCCACCA 20 10173

BCLllA-8450 - CCCCCCCUGUUUAGUCCACCA 21 10174

BCLllA-8451 - UCCCCCCCUGUUUAGUCCACCA 22 10175

BCLllA-8452 - CUCCCCCCCUGUUUAGUCCACCA 23 10176

BCLllA-8453 - ACUCCCCCCCUGUUUAGUCCACCA 24 10177

BCLllA-8454 - CAUUCGGCGUAGUACCCA 18 10178

BCLllA-8455 - CCAUUCGGCGUAGUACCCA 19 10179

BCLllA-8456 - CCCAUUCGGCGUAGUACCCA 20 10180

BCLllA-8457 - CCCCAUUCGGCGUAGUACCCA 21 10181

BCLllA-8458 - CCCCCAUUCGGCGUAGUACCCA 22 10182

BCLllA-8459 - ACCCCCAUUCGGCGUAGUACCCA 23 10183

BCLllA-8460 - CACCCCCAUUCGGCGUAGUACCCA 24 10184

BCLllA-8461 - GGCCGAGGCCGAGGGCCA 18 10185

BCLllA-8462 - UGGCCGAGGCCGAGGGCCA 19 10186

BCLllA-8463 - CUGGCCGAGGCCGAGGGCCA 20 10187 BCLllA-8464 - CCUGGCCGAGGCCGAGGGCCA 21 10188

BCLllA-8465 - ACCUGGCCGAGGCCGAGGGCCA 22 10189

BCLllA-8466 - CACCUGGCCGAGGCCGAGGGCCA 23 10190

BCLllA-8467 - CCACCUGGCCGAGGCCGAGGGCCA 24 10191

BCLllA-8468 - UUUCUCUUGCAACACGCA 18 10192

BCLllA-8469 - GUUUCUCUUGCAACACGCA 19 10193

BCLllA-8470 - GGUUUCUCUUGCAACACGCA 20 10194

BCLllA-8471 - UGGUUUCUCUUGCAACACGCA 21 10195

BCLllA-8472 - AUGGUUUCUCUUGCAACACGCA 22 10196

BCLllA-8473 - CAUGGUUUCUCUUGCAACACGCA 23 10197

BCLllA-8474 - GCAUGGUUUCUCUUGCAACACGCA 24 10198

BCLllA-8475 - ACU UGG ACCCCCACCGCA 18 10199

BCLllA-8476 - CACUUGGACCCCCACCGCA 19 10200

BCLllA-8477 - UCACUUGGACCCCCACCGCA 20 10201

BCLllA-8478 - AUCACUUGGACCCCCACCGCA 21 10202

BCLllA-8479 - CAUCACUUGGACCCCCACCGCA 22 10203

BCLllA-8480 - ACAUCACUUGGACCCCCACCGCA 23 10204

BCLllA-8481 - GACAUCACUUGGACCCCCACCGCA 24 10205

BCLllA-8482 - UCUCGGGGCGCAGCGGCA 18 10206

BCLllA-8483 - AUCUCGGGGCGCAGCGGCA 19 10207

BCLllA-5904 - GAUCUCGGGGCGCAGCGGCA 20 10208

BCLllA-8484 - GGAUCUCGGGGCGCAGCGGCA 21 10209

BCLllA-8485 - GGGAUCUCGGGGCGCAGCGGCA 22 10210

BCLllA-8486 - AGGGAUCUCGGGGCGCAGCGGCA 23 10211

BCLllA-8487 - GAGGGAUCUCGGGGCGCAGCGGCA 24 10212

BCLllA-8488 - AGACUUAGAGAGCUGGCA 18 10213

BCLllA-8489 - GAGACUUAGAGAGCUGGCA 19 10214

BCLllA-5907 - GGAGACUUAGAGAGCUGGCA 20 10215

BCLllA-8490 - AGGAGACUUAGAGAGCUGGCA 21 10216

BCLllA-8491 - UAGGAGACUUAGAGAGCUGGCA 22 10217

BCLllA-8492 - CUAGGAGACUUAGAGAGCUGGCA 23 10218

BCLllA-8493 - UCUAGGAGACUUAGAGAGCUGGCA 24 10219

BCLllA-8494 - GCUCCAUGCAGCACUUCA 18 10220

BCLllA-8495 - AGCUCCAUGCAGCACUUCA 19 10221

BCLllA-8496 - CAGCUCCAUGCAGCACUUCA 20 10222

BCLllA-8497 - UCAGCUCCAUGCAGCACUUCA 21 10223

BCLllA-8498 - CUCAGCUCCAUGCAGCACUUCA 22 10224

BCLllA-8499 - GCUCAGCUCCAUGCAGCACUUCA 23 10225

BCLllA-8500 - UGCUCAGCUCCAUGCAGCACUUCA 24 10226

BCLllA-8501 - UGGUGGCCAAGUUCAAGA 18 10227

BCLllA-8502 - G U GG UGG CCAAG U U CAAGA 19 10228

BCLllA-8503 - CGUGGUGGCCAAGUUCAAGA 20 10229 BCLllA-8504 - CCGUGGUGGCCAAGUUCAAGA 21 10230

BCLllA-8505 - UCCGUGGUGGCCAAGUUCAAGA 22 10231

BCLllA-8506 - GUCCGUGGUGGCCAAGUUCAAGA 23 10232

BCLllA-8507 - AGUCCGUGGUGGCCAAGUUCAAGA 24 10233

BCLllA-8508 - AGGAGGAGCUGACGGAGA 18 10234

BCLllA-8509 - GAGGAGGAGCUGACGGAGA 19 10235

BCLllA-8510 - GGAGGAGGAGCUGACGGAGA 20 10236

BCLllA-8511 - AGGAGGAGGAGCUGACGGAGA 21 10237

BCLllA-8512 - GAGGAGGAGGAGCUGACGGAGA 22 10238

BCLllA-8513 - GGAGGAGGAGGAGCUGACGGAGA 23 10239

BCLllA-8514 - AGGAGGAGGAGGAGCUGACGGAGA 24 10240

BCLllA-8515 - CCAACCUGAUCCCGGAGA 18 10241

BCLllA-8516 - CCCAACCUGAUCCCGGAGA 19 10242

BCLllA-8517 - CCCCAACCUGAUCCCGGAGA 20 10243

BCLllA-8518 - ACCCCAACCUGAUCCCGGAGA 21 10244

BCLllA-8519 - GACCCCAACCUGAUCCCGGAGA 22 10245

BCLllA-8520 - CGACCCCAACCUGAUCCCGGAGA 23 10246

BCLllA-8521 - ACGACCCCAACCUGAUCCCGGAGA 24 10247

BCLllA-8522 - CGGAGCACUCCUCGGAGA 18 10248

BCLllA-8523 - UCGGAGCACUCCUCGGAGA 19 10249

BCLllA-8524 - GUCGGAGCACUCCUCGGAGA 20 10250

BCLllA-8525 - CGUCGGAGCACUCCUCGGAGA 21 10251

BCLllA-8526 - UCGUCGGAGCACUCCUCGGAGA 22 10252

BCLllA-8527 - CUCGUCGGAGCACUCCUCGGAGA 23 10253

BCLllA-8528 - CCUCGUCGGAGCACUCCUCGGAGA 24 10254

BCLllA-8529 - UACCAGGAUCAGUAUCGA 18 10255

BCLllA-8530 - AUACCAGGAUCAGUAUCGA 19 10256

BCLllA-8531 - AAUACCAGGAUCAGUAUCGA 20 10257

BCLllA-8532 - GAAUACCAGGAUCAGUAUCGA 21 10258

BCLllA-8533 - AGAAUACCAGGAUCAGUAUCGA 22 10259

BCLllA-8534 - AAGAAUACCAGGAUCAGUAUCGA 23 10260

BCLllA-8535 - UAAGAAUACCAGGAUCAGUAUCGA 24 10261

BCLllA-8536 - UGUGUGGCAGUUUUCGGA 18 10262

BCLllA-8537 - AUGUGUGGCAGUUUUCGGA 19 10263

BCLllA-5929 - GAUGUGUGGCAGUUUUCGGA 20 10264

BCLllA-8538 - AGAUGUGUGGCAGUUUUCGGA 21 10265

BCLllA-8539 - AAGAUGUGUGGCAGUUUUCGGA 22 10266

BCLllA-8540 - CAAGAUGUGUGGCAGUUUUCGGA 23 10267

BCLllA-8541 - UCAAGAUGUGUGGCAGUUUUCGGA 24 10268

BCLllA-8542 - ACCGCCCGGGGAGCUGGA 18 10269

BCLllA-8543 - CACCGCCCGGGGAGCUGGA 19 10270

BCLllA-5933 - ACACCGCCCGGGGAGCUGGA 20 10271 BCLllA-8544 - CACACCGCCCGGGGAGCUGGA 21 10272

BCLllA-8545 - CCACACCGCCCGGGGAGCUGGA 22 10273

BCLllA-8546 - UCCACACCGCCCGGGGAGCUGGA 23 10274

BCLllA-8547 - CUCCACACCGCCCGGGGAGCUGGA 24 10275

BCLllA-8548 - AGCGGCACGGGAAGUGGA 18 10276

BCLllA-8549 - CAGCGGCACGGGAAGUGGA 19 10277

BCLllA-5934 - GCAGCGGCACGGGAAGUGGA 20 10278

BCLllA-8550 - CGCAGCGGCACGGGAAGUGGA 21 10279

BCLllA-8551 - GCGCAGCGGCACGGGAAGUGGA 22 10280

BCLllA-8552 - GGCGCAGCGGCACGGGAAGUGGA 23 10281

BCLllA-8553 - GGGCGCAGCGGCACGGGAAGUGGA 24 10282

BCLllA-8554 - AGGAGGAGGAGGAGCUGA 18 10283

BCLllA-8555 - GAGGAGGAGGAGGAGCUGA 19 10284

BCLllA-5938 - AGAGGAGGAGGAGGAGCUGA 20 10285

BCLllA-8556 - AAGAGGAGGAGGAGGAGCUGA 21 10286

BCLllA-8557 - GAAGAGGAGGAGGAGGAGCUGA 22 10287

BCLllA-8558 - GGAAGAGGAGGAGGAGGAGCUGA 23 10288

BCLllA-8559 - AGGAAGAGGAGGAGGAGGAGCUGA 24 10289

BCLllA-8560 - GGUUGAAUCCAAUGGCUA 18 10290

BCLllA-8561 - CGGUUGAAUCCAAUGGCUA 19 10291

BCLllA-5944 - GCGGUUGAAUCCAAUGGCUA 20 10292

BCLllA-8562 - UGCGGUUGAAUCCAAUGGCUA 21 10293

BCLllA-8563 - CUGCGGUUGAAUCCAAUGGCUA 22 10294

BCLllA-8564 - GCUGCGGUUGAAUCCAAUGGCUA 23 10295

BCLllA-8565 - UGCUGCGGUUGAAUCCAAUGGCUA 24 10296

BCLllA-8566 - AGAAUACCAGGAUCAGUA 18 10297

BCLllA-8567 - AAGAAUACCAGGAUCAGUA 19 10298

BCLllA-8568 - UAAGAAUACCAGGAUCAGUA 20 10299

BCLllA-8569 - CUAAGAAUACCAGGAUCAGUA 21 10300

BCLllA-8570 - G CU AAG AAU ACCAGG AU CAG U A 22 10301

BCLllA-8571 - UGCU AAGAAUACCAGGAUCAGUA 23 10302

BCLllA-8572 - CUGCUAAGAAUACCAGGAUCAGUA 24 10303

BCLllA-8573 - AUUUCUCUAGGAGACUUA 18 10304

BCLllA-8574 - GAUUUCUCUAGGAGACUUA 19 10305

BCLllA-8575 - GGAUUUCUCUAGGAGACUUA 20 10306

BCLllA-8576 - UGGAUUUCUCUAGGAGACUUA 21 10307

BCLllA-8577 - AUGGAUUUCUCUAGGAGACUUA 22 10308

BCLllA-8578 - CAUGGAUUUCUCUAGGAGACUUA 23 10309

BCLllA-8579 - CCAUGGAUUUCUCUAGGAGACUUA 24 10310

BCLllA-8580 - CCGGCCGCGAUGCCCAAC 18 10311

BCLllA-8581 - CCCGGCCGCGAUGCCCAAC 19 10312

BCLllA-8582 - CCCCGGCCGCGAUGCCCAAC 20 10313 BCLllA-8583 - CCCCCGGCCGCGAUGCCCAAC 21 10314

BCLllA-8584 - GCCCCCGGCCGCGAUGCCCAAC 22 10315

BCLllA-8585 - UGCCCCCGGCCGCGAUGCCCAAC 23 10316

BCLllA-8586 - CUGCCCCCGGCCGCGAUGCCCAAC 24 10317

BCLllA-8587 - AACCUGAUCCCGGAGAAC 18 10318

BCLllA-8588 - CAACCUGAUCCCGGAGAAC 19 10319

BCLllA-5948 - CCAACCUGAUCCCGGAGAAC 20 10320

BCLllA-8589 - CCCAACCUGAUCCCGGAGAAC 21 10321

BCLllA-8590 - CCCCAACCUGAUCCCGGAGAAC 22 10322

BCLllA-8591 - ACCCCAACCUGAUCCCGGAGAAC 23 10323

BCLllA-8592 - GACCCCAACCUGAUCCCGGAGAAC 24 10324

BCLllA-8593 - UCUACUUAGAAAGCGAAC 18 10325

BCLllA-8594 - AUCUACUUAGAAAGCGAAC 19 10326

BCLllA-8595 - AAUCUACUUAGAAAGCGAAC 20 10327

BCLllA-8596 - GAAUCUACUUAGAAAGCGAAC 21 10328

BCLllA-8597 - AGAAUCUACUUAGAAAGCGAAC 22 10329

BCLllA-8598 - AAGAAUCUACUUAGAAAGCGAAC 23 10330

BCLllA-8599 - UAAGAAUCUACUUAGAAAGCGAAC 24 10331

BCLllA-8600 - GAGGCGGCGCGCCACCAC 18 10332

BCLllA-8601 - GGAGGCGGCGCGCCACCAC 19 10333

BCLllA-8602 - UGGAGGCGGCGCGCCACCAC 20 10334

BCLllA-8603 - CUGGAGGCGGCGCGCCACCAC 21 10335

BCLllA-8604 - CCUGGAGGCGGCGCGCCACCAC 22 10336

BCLllA-8605 - GCCUGGAGGCGGCGCGCCACCAC 23 10337

BCLllA-8606 - AGCCUGGAGGCGGCGCGCCACCAC 24 10338

BCLllA-8607 - GUGCACCGGCGCAGCCAC 18 10339

BCLllA-8608 - GGUGCACCGGCGCAGCCAC 19 10340

BCLllA-8609 - UGGUGCACCGGCGCAGCCAC 20 10341

BCLllA-8610 - GUGGUGCACCGGCGCAGCCAC 21 10342

BCLllA-8611 - GGUGGUGCACCGGCGCAGCCAC 22 10343

BCLllA-8612 - UGGUGGUGCACCGGCGCAGCCAC 23 10344

BCLllA-8613 - CUGGUGGUGCACCGGCGCAGCCAC 24 10345

BCLllA-8614 - AG CA AG C UGAAG CG CCAC 18 10346

BCLllA-8615 - CAG CA AG C UGAAG CG CC AC 19 10347

BCLllA-8616 - CCAGCAAGCUGAAGCGCCAC 20 10348

BCLllA-8617 - GCCAGCAAGCUGAAGCGCCAC 21 10349

BCLllA-8618 - GG CCAGCAAG CU G AAG CGCCAC 22 10350

BCLllA-8619 - AG G CC AG CAAG CU G AAG CG CC AC 23 10351

BCLllA-8620 - CAGGCCAGCAAGCUGAAGCGCCAC 24 10352

BCLllA-8621 - GCCGAGGCCGAGGGCCAC 18 10353

BCLllA-8622 - GGCCGAGGCCGAGGGCCAC 19 10354

BCLllA-5951 - UGGCCGAGGCCGAGGGCCAC 20 10355 BCLllA-8623 - CUGGCCGAGGCCGAGGGCCAC 21 10356

BCLllA-8624 - CCUGGCCGAGGCCGAGGGCCAC 22 10357

BCLllA-8625 - ACCUGGCCGAGGCCGAGGGCCAC 23 10358

BCLllA-8626 - CACCUGGCCGAGGCCGAGGGCCAC 24 10359

BCLllA-8627 - CUCGGGGCGCAGCGGCAC 18 10360

BCLllA-8628 - UCUCGGGGCGCAGCGGCAC 19 10361

BCLllA-5953 - AUCUCGGGGCGCAGCGGCAC 20 10362

BCLllA-8629 - GAUCUCGGGGCGCAGCGGCAC 21 10363

BCLllA-8630 - GGAUCUCGGGGCGCAGCGGCAC 22 10364

BCLllA-8631 - GGGAUCUCGGGGCGCAGCGGCAC 23 10365

BCLllA-8632 - AGGGAUCUCGGGGCGCAGCGGCAC 24 10366

BCLllA-8633 - CCACCACCGAGACAUCAC 18 10367

BCLllA-8634 - UCCACCACCGAGACAUCAC 19 10368

BCLllA-8635 - GUCCACCACCGAGACAUCAC 20 10369

BCLllA-8636 - AGUCCACCACCGAGACAUCAC 21 10370

BCLllA-8637 - UAGUCCACCACCGAGACAUCAC 22 10371

BCLllA-8638 - UUAGUCCACCACCGAGACAUCAC 23 10372

BCLllA-8639 - UUUAGUCCACCACCGAGACAUCAC 24 10373

BCLllA-8640 - GAGGAAGAGGAGGACGAC 18 10374

BCLllA-8641 - GGAGGAAGAGGAGGACGAC 19 10375

BCLllA-3949 - AGGAGGAAGAGGAGGACGAC 20 10376

BCLllA-8642 - GAGGAGGAAGAGGAGGACGAC 21 10377

BCLllA-8643 - CGAGGAGGAAGAGGAGGACGAC 22 10378

BCLllA-8644 - ACGAGGAGGAAGAGGAGGACGAC 23 10379

BCLllA-8645 - GACGAGGAGGAAGAGGAGGACGAC 24 10380

BCLllA-8646 - GUCGUGGGCGUGGGCGAC 18 10381

BCLllA-8647 - GGUCGUGGGCGUGGGCGAC 19 10382

BCLllA-8648 - CGGUCGUGGGCGUGGGCGAC 20 10383

BCLllA-8649 - GCGGUCGUGGGCGUGGGCGAC 21 10384

BCLllA-8650 - CGCGGUCGUGGGCGUGGGCGAC 22 10385

BCLllA-8651 - GCGCGGUCGUGGGCGUGGGCGAC 23 10386

BCLllA-8652 - GGCGCGGUCGUGGGCGUGGGCGAC 24 10387

BCLllA-8653 - AUCCCGGAGAACGGGGAC 18 10388

BCLllA-8654 - GAUCCCGGAGAACGGGGAC 19 10389

BCLllA-8655 - UGAUCCCGGAGAACGGGGAC 20 10390

BCLllA-8656 - CUGAUCCCGGAGAACGGGGAC 21 10391

BCLllA-8657 - CCUGAUCCCGGAGAACGGGGAC 22 10392

BCLllA-8658 - ACCUGAUCCCGGAGAACGGGGAC 23 10393

BCLllA-8659 - AACCUGAUCCCGGAGAACGGGGAC 24 10394

BCLllA-8660 - UGGAGGCGGCGCGCCACC 18 10395

BCLllA-8661 - CUGGAGGCGGCGCGCCACC 19 10396

BCLllA-8662 - CCUGGAGGCGGCGCGCCACC 20 10397 BCLllA-8663 - GCCUGGAGGCGGCGCGCCACC 21 10398

BCLllA-8664 - AGCCUGGAGGCGGCGCGCCACC 22 10399

BCLllA-8665 - GAGCCUGGAGGCGGCGCGCCACC 23 10400

BCLllA-8666 - UGAGCCUGGAGGCGGCGCGCCACC 24 10401

BCLllA-8667 - CCCAUUCGGCGUAGUACC 18 10402

BCLllA-8668 - CCCCAUUCGGCGUAGUACC 19 10403

BCLllA-8669 - CCCCCAUUCGGCGUAGUACC 20 10404

BCLllA-8670 - ACCCCCAUUCGGCGUAGUACC 21 10405

BCLllA-8671 - CACCCCCAUUCGGCGUAGUACC 22 10406

BCLllA-8672 - ACACCCCCAUUCGGCGUAGUACC 23 10407

BCLllA-8673 - CACACCCCCAUUCGGCGUAGUACC 24 10408

BCLllA-8674 - G AG AAAAU U UG AAG CCCC 18 10409

BCLllA-8675 - UGAGAAAAUUUGAAGCCCC 19 10410

BCLllA-8676 - CUGAGAAAAUUUGAAGCCCC 20 10411

BCLllA-8677 - UCUGAGAAAAUUUGAAGCCCC 21 10412

BCLllA-8678 - UUCUGAGAAAAUUUGAAGCCCC 22 10413

BCLllA-8679 - GU UCUGAGAAAAUUUGAAGCCCC 23 10414

BCLllA-8680 - AGUUCUGAGAAAAUUUGAAGCCCC 24 10415

BCLllA-8681 - CGCUUCUCCACACCGCCC 18 10416

BCLllA-8682 - GCGCUUCUCCACACCGCCC 19 10417

BCLllA-5976 - UGCGCUUCUCCACACCGCCC 20 10418

BCLllA-8683 - UUGCGCUUCUCCACACCGCCC 21 10419

BCLllA-8684 - UUUGCGCUUCUCCACACCGCCC 22 10420

BCLllA-8685 - GUUUGCGCUUCUCCACACCGCCC 23 10421

BCLllA-8686 - AGUUUGCGCUUCUCCACACCGCCC 24 10422

BCLllA-8687 - UCUCCACCGCCAGCUCCC 18 10423

BCLllA-8688 - CUCUCCACCGCCAGCUCCC 19 10424

BCLllA-5982 - UCUCUCCACCGCCAGCUCCC 20 10425

BCLllA-8689 - GUCUCUCCACCGCCAGCUCCC 21 10426

BCLllA-8690 - GGUCUCUCCACCGCCAGCUCCC 22 10427

BCLllA-8691 - CGGUCUCUCCACCGCCAGCUCCC 23 10428

BCLllA-8692 - ACGGUCUCUCCACCGCCAGCUCCC 24 10429

BCLllA-8693 - ACGGCUUCGGGCUGAGCC 18 10430

BCLllA-8694 - UACGGCUUCGGGCUGAGCC 19 10431

BCLllA-5986 - CUACGGCUUCGGGCUGAGCC 20 10432

BCLllA-8695 - ACUACGGCUUCGGGCUGAGCC 21 10433

BCLllA-8696 - GACUACGGCUUCGGGCUGAGCC 22 10434

BCLllA-8697 - GGACUACGGCUUCGGGCUGAGCC 23 10435

BCLllA-8698 - UGGACUACGGCUUCGGGCUGAGCC 24 10436

BCLllA-8699 - GCGCUUCUCCACACCGCC 18 10437

BCLllA-8700 - UGCGCUUCUCCACACCGCC 19 10438

BCLllA-5987 - UUGCGCUUCUCCACACCGCC 20 10439 BCLllA-8701 - UUUGCGCUUCUCCACACCGCC 21 10440

BCLllA-8702 - GUUUGCGCUUCUCCACACCGCC 22 10441

BCLllA-8703 - AGUUUGCGCUUCUCCACACCGCC 23 10442

BCLllA-8704 - GAGUUUGCGCUUCUCCACACCGCC 24 10443

BCLllA-8705 - CCCACCGCAUAGAGCGCC 18 10444

BCLllA-8706 - CCCCACCGCAUAGAGCGCC 19 10445

BCLllA-5988 - CCCCCACCGCAUAGAGCGCC 20 10446

BCLllA-8707 - ACCCCCACCGCAUAGAGCGCC 21 10447

BCLllA-8708 - GACCCCCACCGCAUAGAGCGCC 22 10448

BCLllA-8709 - GGACCCCCACCGCAUAGAGCGCC 23 10449

BCLllA-8710 - UGGACCCCCACCGCAUAGAGCGCC 24 10450

BCLllA-8711 - GGCCACCUGGCCGAGGCC 18 10451

BCLllA-8712 - CGGCCACCUGGCCGAGGCC 19 10452

BCLllA-8713 - GCGGCCACCUGGCCGAGGCC 20 10453

BCLllA-8714 - CGCGGCCACCUGGCCGAGGCC 21 10454

BCLllA-8715 - GCGCGGCCACCUGGCCGAGGCC 22 10455

BCLllA-8716 - AGCGCGGCCACCUGGCCGAGGCC 23 10456

BCLllA-8717 - AAGCGCGGCCACCUGGCCGAGGCC 24 10457

BCLllA-8718 - UCCCCGGGCGAGUCGGCC 18 10458

BCLllA-8719 - CUCCCCGGGCGAGUCGGCC 19 10459

BCLllA-8720 - GCUCCCCGGGCGAGUCGGCC 20 10460

BCLllA-8721 - UGCUCCCCGGGCGAGUCGGCC 21 10461

BCLllA-8722 - CUGCUCCCCGGGCGAGUCGGCC 22 10462

BCLllA-8723 - GCUGCUCCCCGGGCGAGUCGGCC 23 10463

BCLllA-8724 - GGCUGCUCCCCGGGCGAGUCGGCC 24 10464

BCLllA-8725 - ACGACCCCAACCUGAUCC 18 10465

BCLllA-8726 - AACGACCCCAACCUGAUCC 19 10466

BCLllA-6004 - GAACGACCCCAACCUGAUCC 20 10467

BCLllA-8727 - AGAACGACCCCAACCUGAUCC 21 10468

BCLllA-8728 - GAGAACGACCCCAACCUGAUCC 22 10469

BCLllA-8729 - CGAGAACGACCCCAACCUGAUCC 23 10470

BCLllA-8730 - GCGAGAACGACCCCAACCUGAUCC 24 10471

BCLllA-8731 - UCCUCGUCGGAGCACUCC 18 10472

BCLllA-8732 - CUCCUCGUCGGAGCACUCC 19 10473

BCLllA-8733 - CCUCCUCGUCGGAGCACUCC 20 10474

BCLllA-8734 - GCCUCCUCGUCGGAGCACUCC 21 10475

BCLllA-8735 - UGCCUCCUCGUCGGAGCACUCC 22 10476

BCLllA-8736 - UUGCCUCCUCGUCGGAGCACUCC 23 10477

BCLllA-8737 - UUUGCCUCCUCGUCGGAGCACUCC 24 10478

BCLllA-8738 - CUCUCCACCGCCAGCUCC 18 10479

BCLllA-8739 - UCUCUCCACCGCCAGCUCC 19 10480

BCLllA-8740 - GUCUCUCCACCGCCAGCUCC 20 10481 BCLllA-8741 - GGUCUCUCCACCGCCAGCUCC 21 10482

BCLllA-8742 - CGGUCUCUCCACCGCCAGCUCC 22 10483

BCLllA-8743 - ACGGUCUCUCCACCGCCAGCUCC 23 10484

BCLllA-8744 - GACGGUCUCUCCACCGCCAGCUCC 24 10485

BCLllA-8745 - AAUGGCCGCGGCUGCUCC 18 10486

BCLllA-8746 - UAAUGGCCGCGGCUGCUCC 19 10487

BCLllA-8747 - UUAAUGGCCGCGGCUGCUCC 20 10488

BCLllA-8748 - GUUAAUGGCCGCGGCUGCUCC 21 10489

BCLllA-8749 - UGUUAAUGGCCGCGGCUGCUCC 22 10490

BCLllA-8750 - CUGUUAAUGGCCGCGGCUGCUCC 23 10491

BCLllA-8751 - ACUGUUAAUGGCCGCGGCUGCUCC 24 10492

BCLllA-8752 - CUUCCCAGCCACCUCUCC 18 10493

BCLllA-8753 - CCUUCCCAGCCACCUCUCC 19 10494

BCLllA-8754 - UCCUUCCCAGCCACCUCUCC 20 10495

BCLllA-8755 - GUCCUUCCCAGCCACCUCUCC 21 10496

BCLllA-8756 - UGUCCUUCCCAGCCACCUCUCC 22 10497

BCLllA-8757 - AUGUCCUUCCCAGCCACCUCUCC 23 10498

BCLllA-8758 - AAUGUCCUUCCCAGCCACCUCUCC 24 10499

BCLllA-8759 - UCUCUAAGCGCAUCAAGC 18 10500

BCLllA-8760 - UUCUCUAAGCGCAUCAAGC 19 10501

BCLllA-8761 - CUUCUCUAAGCGCAUCAAGC 20 10502

BCLllA-8762 - CCUUCUCUAAGCGCAUCAAGC 21 10503

BCLllA-8763 - CCCUUCUCUAAGCGCAUCAAGC 22 10504

BCLllA-8764 - CCCCUUCUCUAAGCGCAUCAAGC 23 10505

BCLllA-8765 - GCCCCUUCUCUAAGCGCAUCAAGC 24 10506

BCLllA-8766 - CAGUUUUCGGAUGGAAGC 18 10507

BCLllA-8767 - GCAGUUUUCGGAUGGAAGC 19 10508

BCLllA-8768 - GGCAGUUUUCGGAUGGAAGC 20 10509

BCLllA-8769 - UGGCAGUUUUCGGAUGGAAGC 21 10510

BCLllA-8770 - GUGGCAGUUUUCGGAUGGAAGC 22 10511

BCLllA-8771 - UGUGGCAGUUUUCGGAUGGAAGC 23 10512

BCLllA-8772 - GUGUGGCAGUUUUCGGAUGGAAGC 24 10513

BCLllA-8773 - GUGGCCAAGUUCAAGAGC 18 10514

BCLllA-8774 - GGUGGCCAAGUUCAAGAGC 19 10515

BCLllA-8775 - UGGUGGCCAAGUUCAAGAGC 20 10516

BCLllA-8776 - G UGGUGGCCAAG U U CAAG AG C 21 10517

BCLllA-8777 - CGUGGUGGCCAAGUUCAAGAGC 22 10518

BCLllA-8778 - CCGUGGUGGCCAAGUUCAAGAGC 23 10519

BCLllA-8779 - UCCGUGGUGGCCAAGUUCAAGAGC 24 10520

BCLllA-8780 - GAGGAGCUGACGGAGAGC 18 10521

BCLllA-8781 - GGAGGAGCUGACGGAGAGC 19 10522

BCLllA-8782 - AGGAGGAGCUGACGGAGAGC 20 10523 BCLllA-8783 - GAGGAGGAGCUGACGGAGAGC 21 10524

BCLllA-8784 - GGAGGAGGAGCUGACGGAGAGC 22 10525

BCLllA-8785 - AGGAGGAGGAGCUGACGGAGAGC 23 10526

BCLllA-8786 - GAGGAGGAGGAGCUGACGGAGAGC 24 10527

BCLllA-8787 - UACGGCUUCGGGCUGAGC 18 10528

BCLllA-8788 - CUACGGCUUCGGGCUGAGC 19 10529

BCLllA-8789 - ACUACGGCUUCGGGCUGAGC 20 10530

BCLllA-8790 - GACUACGGCUUCGGGCUGAGC 21 10531

BCLllA-8791 - GGACUACGGCUUCGGGCUGAGC 22 10532

BCLllA-8792 - UGGACUACGGCUUCGGGCUGAGC 23 10533

BCLllA-8793 - GUGGACUACGGCUUCGGGCUGAGC 24 10534

BCLllA-8794 - UGCGCUUCUCCACACCGC 18 10535

BCLllA-8795 - UUGCGCUUCUCCACACCGC 19 10536

BCLllA-8796 - UUUGCGCUUCUCCACACCGC 20 10537

BCLllA-8797 - GUUUGCGCUUCUCCACACCGC 21 10538

BCLllA-8798 - AGUUUGCGCUUCUCCACACCGC 22 10539

BCLllA-8799 - GAGUUUGCGCUUCUCCACACCGC 23 10540

BCLllA-8800 - GGAGUUUGCGCUUCUCCACACCGC 24 10541

BCLllA-8801 - CCCCACCGCAUAGAGCGC 18 10542

BCLllA-8802 - CCCCCACCGCAUAGAGCGC 19 10543

BCLllA-8803 - ACCCCCACCGCAUAGAGCGC 20 10544

BCLllA-8804 - GACCCCCACCGCAUAGAGCGC 21 10545

BCLllA-8805 - GGACCCCCACCGCAUAGAGCGC 22 10546

BCLllA-8806 - UGGACCCCCACCGCAUAGAGCGC 23 10547

BCLllA-8807 - UUGGACCCCCACCGCAUAGAGCGC 24 10548

BCLllA-8808 - AUCUCGGGGCGCAGCGGC 18 10549

BCLllA-8809 - GAUCUCGGGGCGCAGCGGC 19 10550

BCLllA-8810 - GGAUCUCGGGGCGCAGCGGC 20 10551

BCLllA-8811 - GGGAUCUCGGGGCGCAGCGGC 21 10552

BCLllA-8812 - AGGGAUCUCGGGGCGCAGCGGC 22 10553

BCLllA-8813 - GAGGGAUCUCGGGGCGCAGCGGC 23 10554

BCLllA-8814 - GGAGGGAUCUCGGGGCGCAGCGGC 24 10555

BCLllA-8815 - CGGCGCAGCCACACGGGC 18 10556

BCLllA-8816 - CCGGCGCAGCCACACGGGC 19 10557

BCLllA-3804 - ACCGGCGCAGCCACACGGGC 20 10558

BCLllA-8817 - CACCGGCGCAGCCACACGGGC 21 10559

BCLllA-8818 - GCACCGGCGCAGCCACACGGGC 22 10560

BCLllA-8819 - UGCACCGGCGCAGCCACACGGGC 23 10561

BCLllA-8820 - GUGCACCGGCGCAGCCACACGGGC 24 10562

BCLllA-8821 - CAUAUUAGUGGUCCGGGC 18 10563

BCLllA-8822 - CCAUAUUAGUGGUCCGGGC 19 10564

BCLllA-8823 - CCCAUAUUAGUGGUCCGGGC 20 10565 BCLllA-8824 - CCCCAUAUUAGUGGUCCGGGC 21 10566

BCLllA-8825 - GCCCCAUAUUAGUGGUCCGGGC 22 10567

BCLllA-8826 - CGCCCCAUAUUAGUGGUCCGGGC 23 10568

BCLllA-8827 - ACGCCCCAUAUUAGUGGUCCGGGC 24 10569

BCLllA-8828 - UUCCACCAGGUCCUGGGC 18 10570

BCLllA-8829 - CUUCCACCAGGUCCUGGGC 19 10571

BCLllA-8830 - CCUUCCACCAGGUCCUGGGC 20 10572

BCLllA-8831 - GCCUUCCACCAGGUCCUGGGC 21 10573

BCLllA-8832 - GGCCUUCCACCAGGUCCUGGGC 22 10574

BCLllA-8833 - AGGCCUUCCACCAGGUCCUGGGC 23 10575

BCLllA-8834 - GAGGCCUUCCACCAGGUCCUGGGC 24 10576

BCLllA-8835 - CGGGGCGCGGUCGUGGGC 18 10577

BCLllA-8836 - GCGGGGCGCGGUCGUGGGC 19 10578

BCLllA-8837 - CGCGGGGCGCGGUCGUGGGC 20 10579

BCLllA-8838 - UCGCGGGGCGCGGUCGUGGGC 21 10580

BCLllA-8839 - CUCGCGGGGCGCGGUCGUGGGC 22 10581

BCLllA-8840 - GCUCGCGGGGCGCGGUCGUGGGC 23 10582

BCLllA-8841 - AGCUCGCGGGGCGCGGUCGUGGGC 24 10583

BCLllA-8842 - GAGACUUAGAGAGCUGGC 18 10584

BCLllA-8843 - GGAGACUUAGAGAGCUGGC 19 10585

BCLllA-6037 - AGGAGACUUAGAGAGCUGGC 20 10586

BCLllA-8844 - UAGGAGACUUAGAGAGCUGGC 21 10587

BCLllA-8845 - CUAGGAGACUUAGAGAGCUGGC 22 10588

BCLllA-8846 - UCUAGGAGACUUAGAGAGCUGGC 23 10589

BCLllA-8847 - CUCUAGGAGACUUAGAGAGCUGGC 24 10590

BCLllA-8848 - GAGCUGGACGGAGGGAUC 18 10591

BCLllA-8849 - GGAGCUGGACGGAGGGAUC 19 10592

BCLllA-8850 - GGGAGCUGGACGGAGGGAUC 20 10593

BCLllA-8851 - GGGGAGCUGGACGGAGGGAUC 21 10594

BCLllA-8852 - CGGGGAGCUGGACGGAGGGAUC 22 10595

BCLllA-8853 - CCGGGGAGCUGGACGGAGGGAUC 23 10596

BCLllA-8854 - CCCGGGGAGCUGGACGGAGGGAUC 24 10597

BCLllA-8855 - AACGACCCCAACCUGAUC 18 10598

BCLllA-8856 - GAACGACCCCAACCUGAUC 19 10599

BCLllA-8857 - AGAACGACCCCAACCUGAUC 20 10600

BCLllA-8858 - GAGAACGACCCCAACCUGAUC 21 10601

BCLllA-8859 - CGAGAACGACCCCAACCUGAUC 22 10602

BCLllA-8860 - GCGAGAACGACCCCAACCUGAUC 23 10603

BCLllA-8861 - AGCGAGAACGACCCCAACCUGAUC 24 10604

BCLllA-8862 - AAUACCAGGAUCAGUAUC 18 10605

BCLllA-8863 - GAAUACCAGGAUCAGUAUC 19 10606

BCLllA-8864 - AGAAUACCAGGAUCAGUAUC 20 10607 BCLllA-8865 - AAGAAUACCAGGAUCAGUAUC 21 10608

BCLllA-8866 - UAAGAAUACCAGGAUCAGUAUC 22 10609

BCLllA-8867 - CUAAGAAUACCAGGAUCAGUAUC 23 10610

BCLllA-8868 - GCUAAGAAUACCAGGAUCAGUAUC 24 10611

BCLllA-8869 - CCCGGGCGAGUCGGCCUC 18 10612

BCLllA-8870 - CCCCGGGCGAGUCGGCCUC 19 10613

BCLllA-6047 - UCCCCGGGCGAGUCGGCCUC 20 10614

BCLllA-8871 - CUCCCCGGGCGAGUCGGCCUC 21 10615

BCLllA-8872 - GCUCCCCGGGCGAGUCGGCCUC 22 10616

BCLllA-8873 - UGCUCCCCGGGCGAGUCGGCCUC 23 10617

BCLllA-8874 - CUGCUCCCCGGGCGAGUCGGCCUC 24 10618

BCLllA-8875 - UCUAAGCGCAUCAAGCUC 18 10619

BCLllA-8876 - CUCUAAGCGCAUCAAGCUC 19 10620

BCLllA-8877 - UCUCUAAGCGCAUCAAGCUC 20 10621

BCLllA-8878 - UUCUCUAAGCGCAUCAAGCUC 21 10622

BCLllA-8879 - CUUCUCUAAGCGCAUCAAGCUC 22 10623

BCLllA-8880 - CCUUCUCUAAGCGCAUCAAGCUC 23 10624

BCLllA-8881 - CCCUUCUCUAAGCGCAUCAAGCUC 24 10625

BCLllA-8882 - GUUUUCGGAUGGAAGCUC 18 10626

BCLllA-8883 - AGUUUUCGGAUGGAAGCUC 19 10627

BCLllA-8884 - CAGUUUUCGGAUGGAAGCUC 20 10628

BCLllA-8885 - GCAGUUUUCGGAUGGAAGCUC 21 10629

BCLllA-8886 - GGCAGUUUUCGGAUGGAAGCUC 22 10630

BCLllA-8887 - UGGCAGUUUUCGGAUGGAAGCUC 23 10631

BCLllA-8888 - GUGGCAGUUUUCGGAUGGAAGCUC 24 10632

BCLllA-8889 - CCACCACGAGAACAGCUC 18 10633

BCLllA-8890 - GCCACCACGAGAACAGCUC 19 10634

BCLllA-8891 - CGCCACCACGAGAACAGCUC 20 10635

BCLllA-8892 - GCGCCACCACGAGAACAGCUC 21 10636

BCLllA-8893 - CGCGCCACCACGAGAACAGCUC 22 10637

BCLllA-8894 - GCGCGCCACCACGAGAACAGCUC 23 10638

BCLllA-8895 - GGCGCGCCACCACGAGAACAGCUC 24 10639

BCLllA-8896 - UCCCGCCAUGGAUUUCUC 18 10640

BCLllA-8897 - CUCCCGCCAUGGAUUUCUC 19 10641

BCLllA-8898 - CCUCCCGCCAUGGAUUUCUC 20 10642

BCLllA-8899 - GCCUCCCGCCAUGGAUUUCUC 21 10643

BCLllA-8900 - AGCCUCCCGCCAUGGAUUUCUC 22 10644

BCLllA-8901 - GAGCCUCCCGCCAUGGAUUUCUC 23 10645

BCLllA-8902 - GGAGCCUCCCGCCAUGGAUUUCUC 24 10646

BCLllA-8903 - GAGGCCUUCCACCAGGUC 18 10647

BCLllA-8904 - CGAGGCCUUCCACCAGGUC 19 10648

BCLllA-8905 - GCGAGGCCUUCCACCAGGUC 20 10649 BCLllA-8906 - AGCGAGGCCUUCCACCAGGUC 21 10650

BCLllA-8907 - CAGCGAGGCCUUCCACCAGGUC 22 10651

BCLllA-8908 - UCAGCGAGGCCUUCCACCAGGUC 23 10652

BCLllA-8909 - UUCAGCGAGGCCUUCCACCAGGUC 24 10653

BCLllA-8910 - AGCUCGCGGGGCGCGGUC 18 10654

BCLllA-8911 - CAGCUCGCGGGGCGCGGUC 19 10655

BCLllA-8912 - ACAGCUCGCGGGGCGCGGUC 20 10656

BCLllA-8913 - AACAGCUCGCGGGGCGCGGUC 21 10657

BCLllA-8914 - GAACAGCUCGCGGGGCGCGGUC 22 10658

BCLllA-8915 - AGAA CAGCUCGCGGGGCGCGGUC 23 10659

BCLllA-8916 - GAGAACAGCUCGCGGGGCGCGGUC 24 10660

BCLllA-8917 - UACUGUGGGAAAGUCUUC 18 10661

BCLllA-8918 - GUACUGUGGGAAAGUCUUC 19 10662

BCLllA-8919 - AGUACUGUGGGAAAGUCUUC 20 10663

BCLllA-8920 - GAGUACUGUGGGAAAGUCUUC 21 10664

BCLllA-8921 - UGAGUACUGUGGGAAAGUCUUC 22 10665

BCLllA-8922 - GUGAGUACUGUGGGAAAGUCUUC 23 10666

BCLllA-8923 - UGUGAGUACUGUGGGAAAGUCUUC 24 10667

BCLllA-8924 - UCCGUGGUGGCCAAGUUC 18 10668

BCLllA-8925 - GUCCGUGGUGGCCAAGUUC 19 10669

BCLllA-8926 - AGUCCGUGGUGGCCAAGUUC 20 10670

BCLllA-8927 - AAGUCCGUGGUGGCCAAGUUC 21 10671

BCLllA-8928 - CAAGUCCGUGGUGGCCAAGUUC 22 10672

BCLllA-8929 - UCAAGUCCGUGGUGGCCAAGUUC 23 10673

BCLllA-8930 - CUCAAGUCCGUGGUGGCCAAGUUC 24 10674

BCLllA-6826 - AUUAUUUUGCAGGUAAAG 18 10675

BCLllA-6827 - UAUUAUUUUGCAGGUAAAG 19 10676

BCLllA-6828 - GUAUUAUUUUGCAGGUAAAG 20 10677

BCLllA-8931 - U GCACCCAGG CCAG CAAG 18 10678

BCLllA-8932 - GUGCACCCAGGCCAGCAAG 19 10679

BCLllA-8933 - CGUGCACCCAGGCCAGCAAG 20 10680

BCLllA-8934 - GCGUGCACCCAGGCCAGCAAG 21 10681

BCLllA-8935 - CGCGUGCACCCAGGCCAGCAAG 22 10682

BCLllA-8936 - ACG CG U G CACCC AG G CC AG CAAG 23 10683

BCLllA-8937 - CACG CG UG CACCCAGG CCAGCAAG 24 10684

BCLllA-8938 - ACGAGGAAGAGGAAGAAG 18 10685

BCLllA-8939 - GACGAGGAAGAGGAAGAAG 19 10686

BCLllA-3449 - CGACGAGGAAGAGGAAGAAG 20 10687

BCLllA-8940 - ACGACGAGGAAGAGGAAGAAG 21 10688

BCLllA-8941 - GACGACGAGGAAGAGGAAGAAG 22 10689

BCLllA-8942 - GGACGACGAGGAAGAGGAAGAAG 23 10690

BCLllA-8943 - AGGACGACGAGGAAGAGGAAGAAG 24 10691 BCLllA-8944 - ACGACGAGGAAGAGGAAG 18 10692

BCLllA-8945 - GACGACGAGGAAGAGGAAG 19 10693

BCLllA-3959 - GGACGACGAGGAAGAGGAAG 20 10694

BCLllA-8946 - AGGACGACGAGGAAGAGGAAG 21 10695

BCLllA-8947 - GAGGACGACGAGGAAGAGGAAG 22 10696

BCLllA-8948 - GGAGGACGACGAGGAAGAGGAAG 23 10697

BCLllA-8949 - AGGAGGACGACGAGGAAGAGGAAG 24 10698

BCLllA-8950 - AGGAGGACGACGAGGAAG 18 10699

BCLllA-8951 - GAGGAGGACGACGAGGAAG 19 10700

BCLllA-3448 - AGAGGAGGACGACGAGGAAG 20 10701

BCLllA-8952 - AAGAGGAGGACGACGAGGAAG 21 10702

BCLllA-8953 - GAAGAGGAGGACGACGAGGAAG 22 10703

BCLllA-8954 - GGAAGAGGAGGACGACGAGGAAG 23 10704

BCLllA-8955 - AGGAAGAGGAGGACGACGAGGAAG 24 10705

BCLllA-8956 - AGGAAGAAGAGGAGGAAG 18 10706

BCLllA-8957 - GAGGAAGAAGAGGAGGAAG 19 10707

BCLllA-3453 - AGAGGAAGAAGAGGAGGAAG 20 10708

BCLllA-8958 - AAGAGGAAGAAGAGGAGGAAG 21 10709

BCLllA-8959 - GAAGAGGAAGAAGAGGAGGAAG 22 10710

BCLllA-8960 - GGAAGAGGAAGAAGAGGAGGAAG 23 10711

BCLllA-8961 - AGGAAGAGGAAGAAGAGGAGGAAG 24 10712

BCLllA-8962 - ACGGGGACGAGGAGGAAG 18 10713

BCLllA-8963 - AACGGGGACGAGGAGGAAG 19 10714

BCLllA-3441 - GAACGGGGACGAGGAGGAAG 20 10715

BCLllA-8964 - AGAACGGGGACGAGGAGGAAG 21 10716

BCLllA-8965 - GAGAACGGGGACGAGGAGGAAG 22 10717

BCLllA-8966 - GGAGAACGGGGACGAGGAGGAAG 23 10718

BCLllA-8967 - CGGAGAACGGGGACGAGGAGGAAG 24 10719

BCLllA-8968 - GCGCAGCGGCACGGGAAG 18 10720

BCLllA-8969 - GGCGCAGCGGCACGGGAAG 19 10721

BCLllA-3376 - GGGCGCAGCGGCACGGGAAG 20 10722

BCLllA-8970 - GGGGCGCAGCGGCACGGGAAG 21 10723

BCLllA-8971 - CGGGGCGCAGCGGCACGGGAAG 22 10724

BCLllA-8972 - UCGGGGCGCAGCGGCACGGGAAG 23 10725

BCLllA-8973 - CUCGGGGCGCAGCGGCACGGGAAG 24 10726

BCLllA-8974 - AGGCUUCCGGCCUGGCAG 18 10727

BCLllA-8975 - GAGGCUUCCGGCCUGGCAG 19 10728

BCLllA-8976 - AGAGGCUUCCGGCCUGGCAG 20 10729

BCLllA-8977 - GAGAGGCUUCCGGCCUGGCAG 21 10730

BCLllA-8978 - AGAGAGGCUUCCGGCCUGGCAG 22 10731

BCLllA-8979 - GAGAGAGGCUUCCGGCCUGGCAG 23 10732

BCLllA-8980 - CGAGAGAGGCUUCCGGCCUGGCAG 24 10733 BCLllA-8981 - GAGGAAGAGGAAGAAGAG 18 10734

BCLllA-8982 - CGAGGAAGAGGAAGAAGAG 19 10735

BCLllA-3948 - ACGAGGAAGAGGAAGAAGAG 20 10736

BCLllA-8983 - GACGAGGAAGAGGAAGAAGAG 21 10737

BCLllA-8984 - CGACGAGGAAGAGGAAGAAGAG 22 10738

BCLllA-8985 - ACGACGAGGAAGAGGAAGAAGAG 23 10739

BCLllA-8986 - GACGACGAGGAAGAGGAAGAAGAG 24 10740

BCLllA-8987 - GAAGAAGAGGAGGAAGAG 18 10741

BCLllA-8988 - GGAAGAAGAGGAGGAAGAG 19 10742

BCLllA-3961 - AGGAAGAAGAGGAGGAAGAG 20 10743

BCLllA-8989 - GAGGAAGAAGAGGAGGAAGAG 21 10744

BCLllA-8990 - AGAGGAAGAAGAGGAGGAAGAG 22 10745

BCLllA-8991 - AAGAGGAAGAAGAGGAGGAAGAG 23 10746

BCLllA-8992 - GAAGAGGAAGAAGAGGAGGAAGAG 24 10747

BCLllA-8993 - GGGGACGAGGAGGAAGAG 18 10748

BCLllA-8994 - CGGGGACGAGGAGGAAGAG 19 10749

BCLllA-3945 - ACGGGGACGAGGAGGAAGAG 20 10750

BCLllA-8995 - AACGGGGACGAGGAGGAAGAG 21 10751

BCLllA-8996 - GAACGGGGACGAGGAGGAAGAG 22 10752

BCLllA-8997 - AGAACGGGGACGAGGAGGAAGAG 23 10753

BCLllA-8998 - GAGAACGGGGACGAGGAGGAAGAG 24 10754

BCLllA-8999 - CCGGAGAACGGGGACGAG 18 10755

BCLllA-9000 - CCCGGAGAACGGGGACGAG 19 10756

BCLllA-9001 - UCCCGGAGAACGGGGACGAG 20 10757

BCLllA-9002 - AUCCCGGAGAACGGGGACGAG 21 10758

BCLllA-9003 - GAUCCCGGAGAACGGGGACGAG 22 10759

BCLllA-9004 - UGAUCCCGGAGAACGGGGACGAG 23 10760

BCLllA-9005 - CUGAUCCCGGAGAACGGGGACGAG 24 10761

BCLllA-9006 - GACUCGGUGGCCGGCGAG 18 10762

BCLllA-9007 - AGACUCGGUGGCCGGCGAG 19 10763

BCLllA-9008 - AAGACUCGGUGGCCGGCGAG 20 10764

BCLllA-9009 - GAAGACUCGGUGGCCGGCGAG 21 10765

BCLllA-9010 - CGAAGACUCGGUGGCCGGCGAG 22 10766

BCLllA-9011 - ACGAAGACUCGGUGGCCGGCGAG 23 10767

BCLllA-9012 - GACGAAGACUCGGUGGCCGGCGAG 24 10768

BCLllA-9013 - AAGCGCAUCAAGCUCGAG 18 10769

BCLllA-9014 - UAAGCGCAUCAAGCUCGAG 19 10770

BCLllA-9015 - CUAAGCGCAUCAAGCUCGAG 20 10771

BCLllA-9016 - UCU AAGCGCAUCAAGCUCGAG 21 10772

BCLllA-9017 - CUCUAAGCGCAUCAAGCUCGAG 22 10773

BCLllA-9018 - UCUCUAAGCGCAUCAAGCUCGAG 23 10774

BCLllA-9019 - UUCUCUAAGCGCAUCAAGCUCGAG 24 10775 BCLllA-9020 - GAAGAGGAGGAAGAGGAG 18 10776

BCLllA-9021 - AGAAGAGGAGGAAGAGGAG 19 10777

BCLllA-3964 - AAGAAGAGGAGGAAGAGGAG 20 10778

BCLllA-9022 - GAAGAAGAGGAGGAAGAGGAG 21 10779

BCLllA-9023 - GGAAGAAGAGGAGGAAGAGGAG 22 10780

BCLllA-9024 - AGGAAGAAGAGGAGGAAGAGGAG 23 10781

BCLllA-9025 - GAGGAAGAAGAGGAGGAAGAGGAG 24 10782

BCLllA-9026 - GAGGAGGAAGAGGAGGAG 18 10783

BCLllA-9027 - AGAGGAGGAAGAGGAGGAG 19 10784

BCLllA-3965 - AAGAGGAGGAAGAGGAGGAG 20 10785

BCLllA-9028 - GAAGAGGAGGAAGAGGAGGAG 21 10786

BCLllA-9029 - AGAAGAGGAGGAAGAGGAGGAG 22 10787

BCLllA-9030 - AAGAAGAGGAGGAAGAGGAGGAG 23 10788

BCLllA-9031 - GAAGAAGAGGAGGAAGAGGAGGAG 24 10789

BCLllA-9032 - UCCACACCGCCCGGGGAG 18 10790

BCLllA-9033 - CUCCACACCGCCCGGGGAG 19 10791

BCLllA-9034 - UCUCCACACCGCCCGGGGAG 20 10792

BCLllA-9035 - UUCUCCACACCGCCCGGGGAG 21 10793

BCLllA-9036 - CUUCUCCACACCGCCCGGGGAG 22 10794

BCLllA-9037 - GCUUCUCCACACCGCCCGGGGAG 23 10795

BCLllA-9038 - CGCUUCUCCACACCGCCCGGGGAG 24 10796

BCLllA-9039 - GCCGCGAUGCCCAACACG 18 10797

BCLllA-9040 - GGCCGCGAUGCCCAACACG 19 10798

BCLllA-9041 - CGGCCGCGAUGCCCAACACG 20 10799

BCLllA-9042 - CCGGCCGCGAUGCCCAACACG 21 10800

BCLllA-9043 - CCCGGCCGCGAUGCCCAACACG 22 10801

BCLllA-9044 - CCCCGGCCGCGAUGCCCAACACG 23 10802

BCLllA-9045 - CCCCCGGCCGCGAUGCCCAACACG 24 10803

BCLllA-9046 - AGGAAGAGGAGGACGACG 18 10804

BCLllA-9047 - GAGGAAGAGGAGGACGACG 19 10805

BCLllA-3450 - GGAGGAAGAGGAGGACGACG 20 10806

BCLllA-9048 - AGGAGGAAGAGGAGGACGACG 21 10807

BCLllA-9049 - GAGGAGGAAGAGGAGGACGACG 22 10808

BCLllA-9050 - CGAGGAGGAAGAGGAGGACGACG 23 10809

BCLllA-9051 - ACGAGGAGGAAGAGGAGGACGACG 24 10810

BCLllA-9052 - AGGAGGAAGAGGAGGACG 18 10811

BCLllA-9053 - GAGGAGGAAGAGGAGGACG 19 10812

BCLllA-3953 - CGAGGAGGAAGAGGAGGACG 20 10813

BCLllA-9054 - ACGAGGAGGAAGAGGAGGACG 21 10814

BCLllA-9055 - GACGAGGAGGAAGAGGAGGACG 22 10815

BCLllA-9056 - GGACGAGGAGGAAGAGGAGGACG 23 10816

BCLllA-9057 - GGGACGAGGAGGAAGAGGAGGACG 24 10817 BCLllA-9058 - UCCCGGAGAACGGGGACG 18 10818

BCLllA-9059 - AUCCCGGAGAACGGGGACG 19 10819

BCLllA-6081 - GAUCCCGGAGAACGGGGACG 20 10820

BCLllA-9060 - UGAUCCCGGAGAACGGGGACG 21 10821

BCLllA-9061 - CUGAUCCCGGAGAACGGGGACG 22 10822

BCLllA-9062 - CCUGAUCCCGGAGAACGGGGACG 23 10823

BCLllA-9063 - ACCUGAUCCCGGAGAACGGGGACG 24 10824

BCLllA-9064 - CGCCCGGGGAGCUGGACG 18 10825

BCLllA-9065 - CCGCCCGGGGAGCUGGACG 19 10826

BCLllA-9066 - ACCGCCCGGGGAGCUGGACG 20 10827

BCLllA-9067 - CACCGCCCGGGGAGCUGGACG 21 10828

BCLllA-9068 - ACACCGCCCGGGGAGCUGGACG 22 10829

BCLllA-9069 - CACACCGCCCGGGGAGCUGGACG 23 10830

BCLllA-9070 - CCACACCGCCCGGGGAGCUGGACG 24 10831

BCLllA-9071 - GAGGAGGAGGAGCUGACG 18 10832

BCLllA-9072 - GGAGGAGGAGGAGCUGACG 19 10833

BCLllA-9073 - AGGAGGAGGAGGAGCUGACG 20 10834

BCLllA-9074 - GAGGAGGAGGAGGAGCUGACG 21 10835

BCLllA-9075 - AGAGGAGGAGGAGGAGCUGACG 22 10836

BCLllA-9076 - AAGAGGAGGAGGAGGAGCUGACG 23 10837

BCLllA-9077 - GAAGAGGAGGAGGAGGAGCUGACG 24 10838

BCLllA-9078 - GCUUCUCCACACCGCCCG 18 10839

BCLllA-9079 - CGCUUCUCCACACCGCCCG 19 10840

BCLllA-6087 - GCGCUUCUCCACACCGCCCG 20 10841

BCLllA-9080 - UGCGCUUCUCCACACCGCCCG 21 10842

BCLllA-9081 - UUGCGCUUCUCCACACCGCCCG 22 10843

BCLllA-9082 - UUUGCGCUUCUCCACACCGCCCG 23 10844

BCLllA-9083 - GUUUGCGCUUCUCCACACCGCCCG 24 10845

BCLllA-9084 - GACCCCAACCUGAUCCCG 18 10846

BCLllA-9085 - CGACCCCAACCUGAUCCCG 19 10847

BCLllA-9086 - ACGACCCCAACCUGAUCCCG 20 10848

BCLllA-9087 - AACGACCCCAACCUGAUCCCG 21 10849

BCLllA-9088 - GAACGACCCCAACCUGAUCCCG 22 10850

BCLllA-9089 - AGAACGACCCCAACCUGAUCCCG 23 10851

BCLllA-9090 - GAGAACGACCCCAACCUGAUCCCG 24 10852

BCLllA-9091 - CGGUCGUGGGCGUGGGCG 18 10853

BCLllA-9092 - GCGGUCGUGGGCGUGGGCG 19 10854

BCLllA-9093 - CGCGGUCGUGGGCGUGGGCG 20 10855

BCLllA-9094 - GCGCGGUCGUGGGCGUGGGCG 21 10856

BCLllA-9095 - GGCGCGGUCGUGGGCGUGGGCG 22 10857

BCLllA-9096 - GGGCGCGGUCGUGGGCGUGGGCG 23 10858

BCLllA-9097 - GGGGCGCGGUCGUGGGCGUGGGCG 24 10859 BCLllA-9098 - GCCACAGGGACACUUGCG 18 10860

BCLllA-9099 - GGCCACAGGGACACUUGCG 19 10861

BCLllA-9100 - GGGCCACAGGGACACUUGCG 20 10862

BCLllA-9101 - AGGGCCACAGGGACACUUGCG 21 10863

BCLllA-9102 - GAGGGCCACAGGGACACUUGCG 22 10864

BCLllA-9103 - CGAGGGCCACAGGGACACUUGCG 23 10865

BCLllA-9104 - CCGAGGGCCACAGGGACACUUGCG 24 10866

BCLllA-9105 - CCGGGCGAGUCGGCCUCG 18 10867

BCLllA-9106 - CCCGGGCGAGUCGGCCUCG 19 10868

BCLllA-6106 - CCCCGGGCGAGUCGGCCUCG 20 10869

BCLllA-9107 - UCCCCGGGCGAGUCGGCCUCG 21 10870

BCLllA-9108 - CUCCCCGGGCGAGUCGGCCUCG 22 10871

BCLllA-9109 - GCUCCCCGGGCGAGUCGGCCUCG 23 10872

BCLllA-9110 - UGCUCCCCGGGCGAGUCGGCCUCG 24 10873

BCLllA-9111 - UCGUCGGAGCACUCCUCG 18 10874

BCLllA-9112 - CUCGUCGGAGCACUCCUCG 19 10875

BCLllA-9113 - CCUCGUCGGAGCACUCCUCG 20 10876

BCLllA-9114 - UCCUCGUCGGAGCACUCCUCG 21 10877

BCLllA-9115 - CUCCUCGUCGGAGCACUCCUCG 22 10878

BCLllA-9116 - CCUCCUCGUCGGAGCACUCCUCG 23 10879

BCLllA-9117 - GCCUCCUCGUCGGAGCACUCCUCG 24 10880

BCLllA-9118 - UCGCCUUUUGCCUCCUCG 18 10881

BCLllA-9119 - AUCGCCUUUUGCCUCCUCG 19 10882

BCLllA-9120 - AAUCGCCUUUUGCCUCCUCG 20 10883

BCLllA-9121 - CAAUCGCCUUUUGCCUCCUCG 21 10884

BCLllA-9122 - ACAAUCGCCUUUUGCCUCCUCG 22 10885

BCLllA-9123 - GACAAUCGCCUUUUGCCUCCUCG 23 10886

BCLllA-9124 - AGACAAUCGCCUUUUGCCUCCUCG 24 10887

BCLllA-9125 - CACCACGAGAACAGCUCG 18 10888

BCLllA-9126 - CCACCACGAGAACAGCUCG 19 10889

BCLllA-6107 - GCCACCACGAGAACAGCUCG 20 10890

BCLllA-9127 - CGCCACCACGAGAACAGCUCG 21 10891

BCLllA-9128 - GCGCCACCACGAGAACAGCUCG 22 10892

BCLllA-9129 - CGCGCCACCACGAGAACAGCUCG 23 10893

BCLllA-9130 - GCGCGCCACCACGAGAACAGCUCG 24 10894

BCLllA-9131 - CUGGGCAGCCCCAGCUCG 18 10895

BCLllA-9132 - GCUGGGCAGCCCCAGCUCG 19 10896

BCLllA-9133 - UGCUGGGCAGCCCCAGCUCG 20 10897

BCLllA-9134 - CUGCUGGGCAGCCCCAGCUCG 21 10898

BCLllA-9135 - GCUGCUGGGCAGCCCCAGCUCG 22 10899

BCLllA-9136 - UGCUGCUGGGCAGCCCCAGCUCG 23 10900

BCLllA-9137 - CUGCUGCUGGGCAGCCCCAGCUCG 24 10901 BCLllA-9138 - AGGAAGAGGAAGAAGAGG 18 10902

BCLllA-9139 - GAGGAAGAGGAAGAAGAGG 19 10903

BCLllA-3451 - CGAGGAAGAGGAAGAAGAGG 20 10904

BCLllA-9140 - ACGAGGAAGAGGAAGAAGAGG 21 10905

BCLllA-9141 - GACGAGGAAGAGGAAGAAGAGG 22 10906

BCLllA-9142 - CGACGAGGAAGAGGAAGAAGAGG 23 10907

BCLllA-9143 - ACGACGAGGAAGAGGAAGAAGAGG 24 10908

BCLllA-9144 - AGGACGACGAGGAAGAGG 18 10909

BCLllA-9145 - GAGGACGACGAGGAAGAGG 19 10910

BCLllA-3957 - GGAGGACGACGAGGAAGAGG 20 10911

BCLllA-9146 - AGGAGGACGACGAGGAAGAGG 21 10912

BCLllA-9147 - GAGGAGGACGACGAGGAAGAGG 22 10913

BCLllA-9148 - AGAGGAGGACGACGAGGAAGAGG 23 10914

BCLllA-9149 - AAGAGGAGGACGACGAGGAAGAGG 24 10915

BCLllA-9150 - AAGAAGAGGAGGAAGAGG 18 10916

BCLllA-9151 - GAAGAAGAGGAGGAAGAGG 19 10917

BCLllA-3452 - GGAAGAAGAGGAGGAAGAGG 20 10918

BCLllA-9152 - AGGAAGAAGAGGAGGAAGAGG 21 10919

BCLllA-9153 - GAGGAAGAAGAGGAGGAAGAGG 22 10920

BCLllA-9154 - AGAGGAAGAAGAGGAGGAAGAGG 23 10921

BCLllA-9155 - AAGAGGAAGAAGAGGAGGAAGAGG 24 10922

BCLllA-9156 - CUGACGGAGAGCGAGAGG 18 10923

BCLllA-9157 - GCUGACGGAGAGCGAGAGG 19 10924

BCLllA-9158 - AGCUGACGGAGAGCGAGAGG 20 10925

BCLllA-9159 - GAGCUGACGGAGAGCGAGAGG 21 10926

BCLllA-9160 - GGAGCUGACGGAGAGCGAGAGG 22 10927

BCLllA-9161 - AGGAGCUGACGGAGAGCGAGAGG 23 10928

BCLllA-9162 - GAGGAGCUGACGGAGAGCGAGAGG 24 10929

BCLllA-9163 - AAGAGGAGGACGACGAGG 18 10930

BCLllA-9164 - GAAGAGGAGGACGACGAGG 19 10931

BCLllA-3960 - GGAAGAGGAGGACGACGAGG 20 10932

BCLllA-9165 - AGGAAGAGGAGGACGACGAGG 21 10933

BCLllA-9166 - GAGGAAGAGGAGGACGACGAGG 22 10934

BCLllA-9167 - GGAGGAAGAGGAGGACGACGAGG 23 10935

BCLllA-9168 - AGGAGGAAGAGGAGGACGACGAGG 24 10936

BCLllA-9169 - CGGAGAACGGGGACGAGG 18 10937

BCLllA-9170 - CCGGAGAACGGGGACGAGG 19 10938

BCLllA-3330 - CCCGGAGAACGGGGACGAGG 20 10939

BCLllA-9171 - UCCCGGAGAACGGGGACGAGG 21 10940

BCLllA-9172 - AUCCCGGAGAACGGGGACGAGG 22 10941

BCLllA-9173 - GAUCCCGGAGAACGGGGACGAGG 23 10942

BCLllA-9174 - UGAUCCCGGAGAACGGGGACGAGG 24 10943 BCLllA-9175 - GCGGCCACCUGGCCGAGG 18 10944

BCLllA-9176 - CGCGGCCACCUGGCCGAGG 19 10945

BCLllA-9177 - GCGCGGCCACCUGGCCGAGG 20 10946

BCLllA-9178 - AGCGCGGCCACCUGGCCGAGG 21 10947

BCLllA-9179 - AAGCGCGGCCACCUGGCCGAGG 22 10948

BCLllA-9180 - UAAGCGCGGCCACCUGGCCGAGG 23 10949

BCLllA-9181 - AUAAGCGCGGCCACCUGGCCGAGG 24 10950

BCLllA-9182 - AAGAGGAAGAAGAGGAGG 18 10951

BCLllA-9183 - GAAGAGGAAGAAGAGGAGG 19 10952

BCLllA-3963 - GGAAGAGGAAGAAGAGGAGG 20 10953

BCLllA-9184 - AGGAAGAGGAAGAAGAGGAGG 21 10954

BCLllA-9185 - GAGGAAGAGGAAGAAGAGGAGG 22 10955

BCLllA-9186 - CGAGGAAGAGGAAGAAGAGGAGG 23 10956

BCLllA-9187 - ACGAGGAAGAGGAAGAAGAGGAGG 24 10957

BCLllA-9188 - AAGAGGAGGAAGAGGAGG 18 10958

BCLllA-9189 - GAAGAGGAGGAAGAGGAGG 19 10959

BCLllA-3454 - AGAAGAGGAGGAAGAGGAGG 20 10960

BCLllA-9190 - AAG AAG AG G AG G AAG AG G AG G 21 10961

BCLllA-9191 - GAAGAAGAGGAGGAAGAGGAGG 22 10962

BCLllA-9192 - GGAAGAAGAGGAGGAAGAGGAGG 23 10963

BCLllA-9193 - AGGAAGAAGAGGAGGAAGAGGAGG 24 10964

BCLllA-9194 - AGAACGGGGACGAGGAGG 18 10965

BCLllA-9195 - GAGAACGGGGACGAGGAGG 19 10966

BCLllA-3918 - GGAGAACGGGGACGAGGAGG 20 10967

BCLllA-9196 - CGGAGAACGGGGACGAGGAGG 21 10968

BCLllA-9197 - CCGGAGAACGGGGACGAGGAGG 22 10969

BCLllA-9198 - CCCGGAGAACGGGGACGAGGAGG 23 10970

BCLllA-9199 - UCCCGGAGAACGGGGACGAGGAGG 24 10971

BCLllA-9200 - AGGAGGAAGAGGAGGAGG 18 10972

BCLllA-9201 - GAGGAGGAAGAGGAGGAGG 19 10973

BCLllA-3455 - AGAGGAGGAAGAGGAGGAGG 20 10974

BCLllA-9202 - AAGAGGAGGAAGAGGAGGAGG 21 10975

BCLllA-9203 - GAAGAGGAGGAAGAGGAGGAGG 22 10976

BCLllA-9204 - AGAAGAGGAGGAAGAGGAGGAGG 23 10977

BCLllA-9205 - AAGAAGAGGAGGAAGAGGAGGAGG 24 10978

BCLllA-9206 - ACCGGCGCAGCCACACGG 18 10979

BCLllA-9207 - CACCGGCGCAGCCACACGG 19 10980

BCLllA-3764 - GCACCGGCGCAGCCACACGG 20 10981

BCLllA-9208 - UGCACCGGCGCAGCCACACGG 21 10982

BCLllA-9209 - GUGCACCGGCGCAGCCACACGG 22 10983

BCLllA-9210 - GGUGCACCGGCGCAGCCACACGG 23 10984

BCLllA-9211 - UGGUGCACCGGCGCAGCCACACGG 24 10985 BCLllA-9212 - UAGAGCGCCUGGGGGCGG 18 10986

BCLllA-9213 - AUAGAGCGCCUGGGGGCGG 19 10987

BCLllA-9214 - CAUAGAGCGCCUGGGGGCGG 20 10988

BCLllA-9215 - GCAUAGAGCGCCUGGGGGCGG 21 10989

BCLllA-9216 - CGCAUAGAGCGCCUGGGGGCGG 22 10990

BCLllA-9217 - CCGCAUAGAGCGCCUGGGGGCGG 23 10991

BCLllA-9218 - ACCGCAUAGAGCGCCUGGGGGCGG 24 10992

BCLllA-9219 - AUGUGUGGCAGUUUUCGG 18 10993

BCLllA-9220 - GAUGUGUGGCAGUUUUCGG 19 10994

BCLllA-9221 - AGAUGUGUGGCAGUUUUCGG 20 10995

BCLllA-9222 - AAGAUGUGUGGCAGUUUUCGG 21 10996

BCLllA-9223 - CAAGAUGUGUGGCAGUUUUCGG 22 10997

BCLllA-9224 - UCAAGAUGUGUGGCAGUUUUCGG 23 10998

BCLllA-9225 - CUCAAGAUGUGUGGCAGUUUUCGG 24 10999

BCLllA-9226 - AAUUUGAAGCCCCCAGGG 18 11000

BCLllA-9227 - AAAUUUGAAGCCCCCAGGG 19 11001

BCLllA-9228 - AAAAUUUGAAGCCCCCAGGG 20 11002

BCLllA-9229 - GAAAAUUUGAAGCCCCCAGGG 21 11003

BCLllA-9230 - AGAAAAUUUGAAGCCCCCAGGG 22 11004

BCLllA-9231 - GAGAAAAUUUGAAGCCCCCAGGG 23 11005

BCLllA-9232 - UGAGAAAAUUUGAAGCCCCCAGGG 24 11006

BCLllA-9233 - GUGGACUACGGCUUCGGG 18 11007

BCLllA-9234 - GGUGGACUACGGCUUCGGG 19 11008

BCLllA-9235 - GGGUGGACUACGGCUUCGGG 20 11009

BCLllA-9236 - AGGGUGGACUACGGCUUCGGG 21 11010

BCLllA-9237 - GAGGGUGGACUACGGCUUCGGG 22 11011

BCLllA-9238 - AGAGGGUGGACUACGGCUUCGGG 23 11012

BCLllA-9239 - GAGAGGGUGGACUACGGCUUCGGG 24 11013

BCLllA-9240 - UGAUCCCGGAGAACGGGG 18 11014

BCLllA-9241 - CUGAUCCCGGAGAACGGGG 19 11015

BCLllA-9242 - CCUGAUCCCGGAGAACGGGG 20 11016

BCLllA-9243 - ACCUGAUCCCGGAGAACGGGG 21 11017

BCLllA-9244 - AACCUGAUCCCGGAGAACGGGG 22 11018

BCLllA-9245 - CAACCUGAUCCCGGAGAACGGGG 23 11019

BCLllA-9246 - CCAACCUGAUCCCGGAGAACGGGG 24 11020

BCLllA-9247 - GCAUAGAGCGCCUGGGGG 18 11021

BCLllA-9248 - CGCAUAGAGCGCCUGGGGG 19 11022

BCLllA-6143 - CCGCAUAGAGCGCCUGGGGG 20 11023

BCLllA-9249 - ACCGCAUAGAGCGCCUGGGGG 21 11024

BCLllA-9250 - CACCGCAUAGAGCGCCUGGGGG 22 11025

BCLllA-9251 - CCACCGCAUAGAGCGCCUGGGGG 23 11026

BCLllA-9252 - CCCACCGCAUAGAGCGCCUGGGGG 24 11027 BCLllA-9253 - CGCAUAGAGCGCCUGGGG 18 11028

BCLllA-9254 - CCGCAUAGAGCGCCUGGGG 19 11029

BCLllA-9255 - ACCGCAUAGAGCGCCUGGGG 20 11030

BCLllA-9256 - CACCGCAUAGAGCGCCUGGGG 21 11031

BCLllA-9257 - CCACCGCAUAGAGCGCCUGGGG 22 11032

BCLllA-9258 - CCCACCGCAUAGAGCGCCUGGGG 23 11033

BCLllA-9259 - CCCCACCGCAUAGAGCGCCUGGGG 24 11034

BCLllA-9260 - AUAAGCGCGGCCACCUGG 18 11035

BCLllA-9261 - CAUAAGCGCGGCCACCUGG 19 11036

BCLllA-9262 - GCAUAAGCGCGGCCACCUGG 20 11037

BCLllA-9263 - AGCAUAAGCGCGGCCACCUGG 21 11038

BCLllA-9264 - AAGCAUAAGCGCGGCCACCUGG 22 11039

BCLllA-9265 - GAAGCAUAAGCGCGGCCACCUGG 23 11040

BCLllA-9266 - AGAAGCAUAAGCGCGGCCACCUGG 24 11041

BCLllA-9267 - GAGAGGCUUCCGGCCUGG 18 11042

BCLllA-9268 - AGAGAGGCUUCCGGCCUGG 19 11043

BCLllA-9269 - GAGAGAGGCUUCCGGCCUGG 20 11044

BCLllA-9270 - CGAGAGAGGCUUCCGGCCUGG 21 11045

BCLllA-9271 - UCGAGAGAGGCUUCCGGCCUGG 22 11046

BCLllA-9272 - AUCGAGAGAGGCUUCCGGCCUGG 23 11047

BCLllA-9273 - UAUCGAGAGAGGCUUCCGGCCUGG 24 11048

BCLllA-9274 - CCUUCCACCAGGUCCUGG 18 11049

BCLllA-9275 - GCCUUCCACCAGGUCCUGG 19 11050

BCLllA-9276 - GGCCUUCCACCAGGUCCUGG 20 11051

BCLllA-9277 - AGGCCUUCCACCAGGUCCUGG 21 11052

BCLllA-9278 - GAGGCCUUCCACCAGGUCCUGG 22 11053

BCLllA-9279 - CGAGGCCUUCCACCAGGUCCUGG 23 11054

BCLllA-9280 - GCGAGGCCUUCCACCAGGUCCUGG 24 11055

BCLllA-9281 - GGAGACUUAGAGAGCUGG 18 11056

BCLllA-9282 - AGGAGACUUAGAGAGCUGG 19 11057

BCLllA-9283 - UAGGAGACUUAGAGAGCUGG 20 11058

BCLllA-9284 - CUAGGAGACUUAGAGAGCUGG 21 11059

BCLllA-9285 - UCU AGGAGACUUAGAGAGCUGG 22 11060

BCLllA-9286 - CUCUAGGAGACUUAGAGAGCUGG 23 11061

BCLllA-9287 - UCUCUAGGAGACUUAGAGAGCUGG 24 11062

BCLllA-9288 - CACCGCCCGGGGAGCUGG 18 11063

BCLllA-9289 - ACACCGCCCGGGGAGCUGG 19 11064

BCLllA-9290 - CACACCGCCCGGGGAGCUGG 20 11065

BCLllA-9291 - CCACACCGCCCGGGGAGCUGG 21 11066

BCLllA-9292 - UCCACACCGCCCGGGGAGCUGG 22 11067

BCLllA-9293 - CUCCACACCGCCCGGGGAGCUGG 23 11068

BCLllA-9294 - UCUCCA CACCGCCCGGGGAGCUGG 24 11069 BCLllA-9295 - CAGCGGCACGGGAAGUGG 18 11070

BCLllA-9296 - GCAGCGGCACGGGAAGUGG 19 11071

BCLllA-6157 - CGCAGCGGCACGGGAAGUGG 20 11072

BCLllA-9297 - GCGCAGCGGCACGGGAAGUGG 21 11073

BCLllA-9298 - GGCGCAGCGGCACGGGAAGUGG 22 11074

BCLllA-9299 - GGGCGCAGCGGCACGGGAAGUGG 23 11075

BCLllA-9300 - GGGGCGCAGCGGCACGGGAAGUGG 24 11076

BCLllA-9301 - GCCCUGCCCGACGUCAUG 18 11077

BCLllA-9302 - CGCCCUGCCCGACGUCAUG 19 11078

BCLllA-9303 - GCGCCCUGCCCGACGUCAUG 20 11079

BCLllA-9304 - CGCGCCCUGCCCGACGUCAUG 21 11080

BCLllA-9305 - CCGCGCCCUGCCCGACGUCAUG 22 11081

BCLllA-9306 - GCCGCGCCCUGCCCGACGUCAUG 23 11082

BCLllA-9307 - AGCCGCGCCCUGCCCGACGUCAUG 24 11083

BCLllA-9308 - CGACACUUGUGAGUACUG 18 11084

BCLllA-9309 - GCGACACUUGUGAGUACUG 19 11085

BCLllA-6169 - AGCGACACUUGUGAGUACUG 20 11086

BCLllA-9310 - CAGCGACACUUGUGAGUACUG 21 11087

BCLllA-9311 - GCAGCGACACUUGUGAGUACUG 22 11088

BCLllA-9312 - CGCAGCGACACUUGUGAGUACUG 23 11089

BCLllA-9313 - ACGCAGCGACACUUGUGAGUACUG 24 11090

BCLllA-9314 - GAGGAGGAGGAGGAGCUG 18 11091

BCLllA-9315 - AGAGGAGGAGGAGGAGCUG 19 11092

BCLllA-9316 - AAGAGGAGGAGGAGGAGCUG 20 11093

BCLllA-9317 - GAAGAGGAGGAGGAGGAGCUG 21 11094

BCLllA-9318 - GGAAGAGGAGGAGGAGGAGCUG 22 11095

BCLllA-9319 - AGGAAGAGGAGGAGGAGGAGCUG 23 11096

BCLllA-9320 - GAGGAAGAGGAGGAGGAGGAGCUG 24 11097

BCLllA-9321 - CUGUCCAAAAAGCUGCUG 18 11098

BCLllA-9322 - CCUGUCCAAAAAGCUGCUG 19 11099

BCLllA-9323 - GCCUGUCCAAAAAGCUGCUG 20 11100

BCLllA-9324 - GGCCUGUCCAAAAAGCUGCUG 21 11101

BCLllA-9325 - GGGCCUGUCCAAAAAGCUGCUG 22 11102

BCLllA-9326 - GGGGCCUGUCCAAAAAGCUGCUG 23 11103

BCLllA-9327 - GGGGGCCUGUCCAAAAAGCUGCUG 24 11104

BCLllA-9328 - GCAGCGGCACGGGAAGUG 18 11105

BCLllA-9329 - CGCAGCGGCACGGGAAGUG 19 11106

BCLllA-9330 - GCGCAGCGGCACGGGAAGUG 20 11107

BCLllA-9331 - GGCGCAGCGGCACGGGAAGUG 21 11108

BCLllA-9332 - GGGCGCAGCGGCACGGGAAGUG 22 11109

BCLllA-9333 - GGGGCGCAGCGGCACGGGAAGUG 23 11110

BCLllA-9334 - CGGGGCGCAGCGGCACGGGAAGUG 24 11111 BCLllA-9335 - CCCGGCACCAGCGACUUG 18 11112

BCLllA-9336 - ACCCGGCACCAGCGACUUG 19 11113

BCLllA-9337 - AACCCGGCACCAGCGACUUG 20 11114

BCLllA-9338 - GAACCCGGCACCAGCGACUUG 21 11115

BCLllA-9339 - GGAACCCGGCACCAGCGACUUG 22 11116

BCLllA-9340 - CGGAACCCGGCACCAGCGACUUG 23 11117

BCLllA-9341 - CCGGAACCCGGCACCAGCGACUUG 24 11118

BCLllA-9342 - CUUAAGUUCUGAGAAAAU 18 11119

BCLllA-9343 - CCUUAAGUUCUGAGAAAAU 19 11120

BCLllA-9344 - CCCU U AAG U U CUG AG AAAAU 20 11121

BCLllA-9345 - GCCCUUAAGUUCUGAGAAAAU 21 11122

BCLllA-9346 - AGCCCUUAAGUUCUGAGAAAAU 22 11123

BCLllA-9347 - GAGCCCUUAAGUUCUGAGAAAAU 23 11124

BCLllA-9348 - AG AG CCCU U AAG U U CUG AG AAAAU 24 11125

BCLllA-9349 - GGAUUUCUCUAGGAGACU 18 11126

BCLllA-9350 - UGGAUUUCUCUAGGAGACU 19 11127

BCLllA-9351 - AUGGAUUUCUCUAGGAGACU 20 11128

BCLllA-9352 - CAUGGAUUUCUCUAGGAGACU 21 11129

BCLllA-9353 - CCAUGGAUUUCUCUAGGAGACU 22 11130

BCLllA-9354 - GCCAUGGAUUUCUCUAGGAGACU 23 11131

BCLllA-9355 - CGCCAUGGAUUUCUCUAGGAGACU 24 11132

BCLllA-9356 - AUGGAUUAAGAAUCUACU 18 11133

BCLllA-9357 - CAUGGAUUAAGAAUCUACU 19 11134

BCLllA-9358 - UCAUGGAUUAAGAAUCUACU 20 11135

BCLllA-9359 - CUCAUGGAUUAAGAAUCUACU 21 11136

BCLllA-9360 - ACUCAUGGAUUAAGAAUCUACU 22 11137

BCLllA-9361 - CACUCAUGGAUUAAGAAUCUACU 23 11138

BCLllA-9362 - ACACUCAUGGAUUAAGAAUCUACU 24 11139

BCLllA-9363 - GCGACACUUGUGAGUACU 18 11140

BCLllA-9364 - AGCGACACUUGUGAGUACU 19 11141

BCLllA-9365 - CAGCGACACUUGUGAGUACU 20 11142

BCLllA-9366 - GCAGCGACACUUGUGAGUACU 21 11143

BCLllA-9367 - CGCAGCGACACUUGUGAGUACU 22 11144

BCLllA-9368 - ACGCAGCGACACUUGUGAGUACU 23 11145

BCLllA-9369 - GACGCAGCGACACUUGUGAGUACU 24 11146

BCLllA-9370 - CCACCGCAUAGAGCGCCU 18 11147

BCLllA-9371 - CCCACCGCAUAGAGCGCCU 19 11148

BCLllA-6197 - CCCCACCGCAUAGAGCGCCU 20 11149

BCLllA-9372 - CCCCCACCGCAUAGAGCGCCU 21 11150

BCLllA-9373 - ACCCCCACCGCAUAGAGCGCCU 22 11151

BCLllA-9374 - GACCCCCACCGCAUAGAGCGCCU 23 11152

BCLllA-9375 - GGACCCCCACCGCAUAGAGCGCCU 24 11153 BCLllA-9376 - CCCCGGGCGAGUCGGCCU 18 11154

BCLllA-9377 - UCCCCGGGCGAGUCGGCCU 19 11155

BCLllA-6200 - CUCCCCGGGCGAGUCGGCCU 20 11156

BCLllA-9378 - GCUCCCCGGGCGAGUCGGCCU 21 11157

BCLllA-9379 - UGCUCCCCGGGCGAGUCGGCCU 22 11158

BCLllA-9380 - CUGCUCCCCGGGCGAGUCGGCCU 23 11159

BCLllA-9381 - GCUGCUCCCCGGGCGAGUCGGCCU 24 11160

BCLllA-9382 - CCUCGUCGGAGCACUCCU 18 11161

BCLllA-9383 - UCCUCGUCGGAGCACUCCU 19 11162

BCLllA-6202 - CUCCUCGUCGGAGCACUCCU 20 11163

BCLllA-9384 - CCUCCUCGUCGGAGCACUCCU 21 11164

BCLllA-9385 - GCCUCCUCGUCGGAGCACUCCU 22 11165

BCLllA-9386 - UGCCUCCUCGUCGGAGCACUCCU 23 11166

BCLllA-9387 - UUGCCUCCUCGUCGGAGCACUCCU 24 11167

BCLllA-9388 - AAGAUCCCUUCCUUAGCU 18 11168

BCLllA-9389 - AAAGAUCCCUUCCUUAGCU 19 11169

BCLllA-9390 - CAAAGAUCCCUUCCUUAGCU 20 11170

BCLllA-9391 - UCAAAGAUCCCUUCCUUAGCU 21 11171

BCLllA-9392 - CUCAAAGAUCCCUUCCUUAGCU 22 11172

BCLllA-9393 - GCUCAAAGAUCCCUUCCUUAGCU 23 11173

BCLllA-9394 - AGCUCAAAGAUCCCUUCCUUAGCU 24 11174

BCLllA-9395 - AGAGGGUGGACUACGGCU 18 11175

BCLllA-9396 - GAGAGGGUGGACUACGGCU 19 11176

BCLllA-9397 - CGAGAGGGUGGACUACGGCU 20 11177

BCLllA-9398 - GCGAGAGGGUGGACUACGGCU 21 11178

BCLllA-9399 - AGCGAGAGGGUGGACUACGGCU 22 11179

BCLllA-9400 - GAGCGAGAGGGUGGACUACGGCU 23 11180

BCLllA-9401 - AGAGCGAGAGGGUGGACUACGGCU 24 11181

BCLllA-9402 - CGGUUGAAUCCAAUGGCU 18 11182

BCLllA-9403 - GCGGUUGAAUCCAAUGGCU 19 11183

BCLllA-9404 - UGCGGUUGAAUCCAAUGGCU 20 11184

BCLllA-9405 - CUGCGGUUGAAUCCAAUGGCU 21 11185

BCLllA-9406 - GCUGCGGUUGAAUCCAAUGGCU 22 11186

BCLllA-9407 - UGCUGCGGUUGAAUCCAAUGGCU 23 11187

BCLllA-9408 - GUGCUGCGGUUGAAUCCAAUGGCU 24 11188

BCLllA-9409 - AGCUGGACGGAGGGAUCU 18 11189

BCLllA-9410 - GAGCUGGACGGAGGGAUCU 19 11190

BCLllA-6210 - GGAGCUGGACGGAGGGAUCU 20 11191

BCLllA-9411 - GGGAGCUGGACGGAGGGAUCU 21 11192

BCLllA-9412 - GGGGAGCUGGACGGAGGGAUCU 22 11193

BCLllA-9413 - CGGGGAGCUGGACGGAGGGAUCU 23 11194

BCLllA-9414 - CCGGGGAGCUGGACGGAGGGAUCU 24 11195 BCLllA-9415 - CCCGCCAUGGAUUUCUCU 18 11196

BCLllA-9416 - UCCCGCCAUGGAUUUCUCU 19 11197

BCLllA-6212 - CUCCCGCCAUGGAUUUCUCU 20 11198

BCLllA-9417 - CCUCCCGCCAUGGAUUUCUCU 21 11199

BCLllA-9418 - GCCUCCCGCCAUGGAUUUCUCU 22 11200

BCLllA-9419 - AGCCUCCCGCCAUGGAUUUCUCU 23 11201

BCLllA-9420 - GAGCCUCCCGCCAUGGAUUUCUCU 24 11202

BCLllA-9421 - CGAGAGCCCUUAAGUUCU 18 11203

BCLllA-9422 - UCGAGAGCCCUUAAGUUCU 19 11204

BCLllA-9423 - CUCGAGAGCCCUUAAGUUCU 20 11205

BCLllA-9424 - GCUCGAGAGCCCUUAAGUUCU 21 11206

BCLllA-9425 - AGCUCGAGAGCCCUUAAGUUCU 22 11207

BCLllA-9426 - AAGCUCGAGAGCCCUUAAGUUCU 23 11208

BCLllA-9427 - GAAGCUCGAGAGCCCUUAAGUUCU 24 11209

BCLllA-9428 - CGCCUUUUGCCUCCUCGU 18 11210

BCLllA-9429 - UCGCCUUUUGCCUCCUCGU 19 11211

BCLllA-6220 - AUCGCCUUUUGCCUCCUCGU 20 11212

BCLllA-9430 - AAUCGCCUUUUGCCUCCUCGU 21 11213

BCLllA-9431 - CAAUCGCCUUUUGCCUCCUCGU 22 11214

BCLllA-9432 - ACAAUCGCCUUUUGCCUCCUCGU 23 11215

BCLllA-9433 - GACAAUCGCCUUUUGCCUCCUCGU 24 11216

BCLllA-9434 - ACGCCCCAUAUUAGUGGU 18 11217

BCLllA-9435 - CACGCCCCAUAUUAGUGGU 19 11218

BCLllA-9436 - GCACGCCCCAUAUUAGUGGU 20 11219

BCLllA-9437 - AGCACGCCCCAUAUUAGUGGU 21 11220

BCLllA-9438 - GAGCACGCCCCAUAUUAGUGGU 22 11221

BCLllA-9439 - GGAGCACGCCCCAUAUUAGUGGU 23 11222

BCLllA-9440 - GGGAGCACGCCCCAUAUUAGUGGU 24 11223

BCLllA-9441 - GACACUUGUGAGUACUGU 18 11224

BCLllA-9442 - CGACACUUGUGAGUACUGU 19 11225

BCLllA-6230 - GCGACACUUGUGAGUACUGU 20 11226

BCLllA-9443 - AGCGACACUUGUGAGUACUGU 21 11227

BCLllA-9444 - CAGCGACACUUGUGAGUACUGU 22 11228

BCLllA-9445 - GCAGCGACACUUGUGAGUACUGU 23 11229

BCLllA-9446 - CGCAGCGACACUUGUGAGUACUGU 24 11230

BCLllA-9447 - CGCGGGUUGGUAUCCCUU 18 11231

BCLllA-9448 - CCGCGGGUUGGUAUCCCUU 19 11232

BCLllA-9449 - CCCGCGGGUUGGUAUCCCUU 20 11233

BCLllA-9450 - CCCCGCGGGUUGGUAUCCCUU 21 11234

BCLllA-9451 - ACCCCGCGGGUUGGUAUCCCUU 22 11235

BCLllA-9452 - GACCCCGCGGGUUGGUAUCCCUU 23 11236

BCLllA-9453 - UGACCCCGCGGGUUGGUAUCCCUU 24 11237 BCLllA-9454 - AGAUCCCUUCCUUAGCU U 18 11238

BCLllA-9455 - AAGAUCCCUUCCUUAGCUU 19 11239

BCLllA-6234 - AAAGAUCCCUUCCUUAGCUU 20 11240

BCLllA-9456 - CAAAGAUCCCUUCCUUAGCUU 21 11241

BCLllA-9457 - UCAAAGAUCCCU UCCUUAGCUU 22 11242

BCLllA-9458 - CUCAAAGAUCCCUUCCU UAGCUU 23 11243

BCLllA-9459 - GCUCAAAGAUCCCUUCCUUAGCUU 24 11244

BCLllA-9460 - CUCGAGAGCCCUUAAGUU 18 11245

BCLllA-9461 - GCUCGAGAGCCCU UAAGUU 19 11246

BCLllA-9462 - AGCUCGAGAGCCCUUAAGUU 20 11247

BCLllA-9463 - AAGCUCGAGAGCCCUUAAGUU 21 11248

BCLllA-9464 - GAAGCUCGAGAGCCCUUAAGUU 22 11249

BCLllA-9465 - GGAAGCUCGAGAGCCCU UAAGUU 23 11250

BCLllA-9466 - UGGAAGCUCGAGAGCCCUUAAGUU 24 11251

BCLllA-9467 - GGCAAGACGUUCAAAUUU 18 11252

BCLllA-9468 - CGGCAAGACGUUCAAAUUU 19 11253

BCLllA-9469 - GCGGCAAGACGUUCAAAUUU 20 11254

BCLllA-9470 - UGCGGCAAGACG U U CAAAU U U 21 11255

BCLllA-9471 - CUGCGGCAAGACGUUCAAAUUU 22 11256

BCLllA-9472 - UCUGCGGCAAGACGUUCAAAUUU 23 11257

BCLllA-9473 - U UCUGCGGCAAGACGUUCAAAUUU 24 11258

Table 17A provides exemplary targeting domains for knocking out the BCL11A gene selected according to the first tier parameters. The targeting domains bind within the first 500 bp of the coding sequence (e.g., within 500 bp downstream from the start codon) and have a high level of orthogonality. It is contemplated herein that in an embodiment the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a N. meningitidis Cas9 molecule that generates a double stranded break (Cas9 nuclease) or a single- stranded break (Cas9 nickase).

Table 17A

BCLllA-9480 + GGGGAAGGUGGCUUAUC 17 11265

BCLllA-9481 + GGUUCAUCAUCUGUAAG 17 11266

BCLllA-5334 + UGCACUCAUCCCAGGCG 17 11267

BCLllA-9482 + UUAAGUGCUGGGGUUUG 17 11268

BCLllA-9483 + CCAACCUCCACGGGAU U 17 11269

BCLllA-9484 + UCUCGAUUGGUGAAGGGGAA 20 11270

BCLllA-9485 + GGGAUUGGAUGCUUUU UUCA 20 11271

BCLllA-9486 - AUCCAGGUCACGCCAGAGGA 20 11272

BCLllA-9487 + U UACUUACGCGAGAAUUCCC 20 11273

BCLllA-6420 + UGACCUGGAUGCCAACCUCC 20 11274

BCLllA-9488 - GGAAACAAUGCAAUGGCAGC 20 11275

BCLllA-9489 + GAAGGGGAAGGUGGCU UAUC 20 11276

BCLllA-9490 + UCUGGUUCAUCAUCUGUAAG 20 11277

BCLllA-5480 + U UCUGCACUCAUCCCAGGCG 20 11278

BCLllA-9491 + UGCUUAAGUGCUGGGGUUUG 20 11279

BCLllA-9492 + AUGCCAACCUCCACGGGAUU 20 11280

Table 17B provides exemplary targeting domains for knocking out the BCL11A gene selected according to the third tier parameters. The targeting domains fall in the coding sequence of the gene, downstream of the first 500bp of coding sequence (e.g., anywhere from +500 (relative to the start codon) to the stop codon of the gene). It is contemplated herein that in an embodiment the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a N. meningitidis Cas9 molecule that generates a double stranded break (Cas9 nuclease) or a single- stranded break (Cas9 nickase).

Table 17B

BCLllA-9501 + U CAGAACU UAAGGGCU C 17 11291

BCLllA-9502 - AGCUCAAAGAUCCCUUC 17 11292

BCLllA-9503 + GCAGGUCGAACUCCUUC 17 11293

BCLllA-9504 + GGGGCGUCGCCAGGAAG 17 11294

BCLllA-9505 - CCAGGAUCAGUAUCGAG 17 11295

BCLllA-9506 + GGCUGGGAGGGAGGAGG 17 11296

BCLllA-9507 + GACUUGACCGUCAUGGG 17 11297

BCLllA-9508 + CGGCCUCGGCCAGGUGG 17 11298

BCLllA-5799 + GCAUGUGCGUCUUCAUG 17 11299

BCLllA-9509 + CGCACAGGUUGCACUUG 17 11300

BCLllA-9510 + ACUCCU UCUCGAGCUUG 17 11301

BCLllA-9511 - AACACG CACAG AACACU 17 11302

BCLllA-9512 - CCUCGGAGAACGGGAGU 17 11303

BCLllA-9513 + GGUCAGGGGACUUCCGU 17 11304

BCLllA-5874 + UGCUCCGACGAGGAGGCAAA 20 11305

BCLllA-5879 - AGGCU UCCGGCCUGGCAGAA 20 11306

BCLllA-9514 + ACUUCCGUGUUCGCUUUCUA 20 11307

BCLllA-9515 - CGGAGAGCGAGAGGGUGGAC 20 11308

BCLllA-9516 + UGGCGGGAGGCUCCAUAGCC 20 11309

BCLllA-8754 - UCCUUCCCAGCCACCUCUCC 20 11310

BCLllA-9517 + GCGAGCUGGGGCUGCCCAGC 20 11311

BCLllA-9518 - AUGGCUAUGGAGCCUCCCGC 20 11312

BCLllA-9519 + CCUCGGCCAGGUGGCCGCGC 20 11313

BCLllA-9520 + UGUGCGUCUUCAUGUGGCGC 20 11314

BCLllA-7725 + UUCUCAGAACUUAAGGGCUC 20 11315

BCLllA-9521 - GGCAGCUCAAAGAUCCCUUC 20 11316

BCLllA-7752 + GGGGCAGGUCGAACUCCUUC 20 11317

BCLllA-9522 + GGGGGGGCGUCGCCAGGAAG 20 11318

BCLllA-9523 - AUACCAGGAUCAGUAUCGAG 20 11319

BCLllA-9524 + GGGGGCUGGGAGGGAGGAGG 20 11320

BCLllA-9525 + UCGGACUUGACCGUCAUGGG 20 11321

BCLllA-9526 + CCUCGGCCUCGGCCAGGUGG 20 11322

BCLllA-6165 + UGUGCAUGUGCGUCUUCAUG 20 11323

BCLllA-8204 + GGUCGCACAGGU UGCACUUG 20 11324

BCLllA-9527 + CGAACUCCU UCUCGAGCUUG 20 11325

BCLllA-9528 - UGCAACACGCACAGAACACU 20 11326

BCLllA-9529 - ACUCCUCGGAGAACGGGAGU 20 11327

BCLllA-9530 + CGGGGUCAGGGGACUUCCGU 20 11328

Table 18A provides exemplary targeting domains for knocking down the BCLllA gene selected according to the first tier parameters. The targeting domains bind within 500 bp (e.g., upstream or downstream) of a transcription start site (TSS) and have a high level of orthogonality. It is contemplated herein that in an embodiment the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. pyogenes eiCas9 molecule or eiCas9 fusion protein (e.g., an eiCas9 fused to a transcription repressor domain) to alter the BCLl 1 A gene (e.g., reduce or eliminate BCLl 1A gene expression, BCLl 1A protein function, or the level of BCLl 1A protein). One or more gRNA may be used to target an eiCas9 to the promoter region of the BCLl 1 A gene.

Table 18A

BCLllA-9553 + GCGGGCGGACGACGGCU 17 11357

BCLllA-5338 + CCGUU UGCUUAAGUGCU 17 11358

BCLllA-5340 + U UGCGGCGAGACAUGGU 17 11359

BCLllA-9554 + CGUGGCCGGGAGAGAAGAAA 20 11360

BCLllA-5345 + GCCUUGCU UGCGGCGAGACA 20 11361

BCLllA-5346 - ACCAUGUCUCGCCGCAAGCA 20 11362

BCLllA-9555 - UCCUGACGUUCAAGUUCGCA 20 11363

BCLllA-9556 + ACACCAAUGGACACACAUCA 20 11364

BCLllA-9557 + UACACGGCAAUGGUUCCAGA 20 11365

BCLllA-9558 + GCCAAUGGCCAGUGCGGGGA 20 11366

BCLllA-9559 + AAUGGUUCCAGAUGGGAUGA 20 11367

BCLllA-9560 - GAGUCUCCUUCUUUCUAACC 20 11368

BCLllA-9561 + CGGU UCACAUCGGGAGAGCC 20 11369

BCLllA-9562 + UCGGUUCACAUCGGGAGAGC 20 11370

BCLllA-9563 - CCGCGUGUGUGGGGGGGAGC 20 11371

BCLllA-9564 - UAAUAAUCACGAGAGCGCGC 20 11372

BCLllA-9565 + AAAUAAUACAAAGAUGGCGC 20 11373

BCLllA-9566 - CUCCUGACGUUCAAGUUCGC 20 11374

BCLllA-9567 + GAGACACACAAAACAUGGGC 20 11375

BCLllA-5352 + AUUCCCGU UUGCUUAAGUGC 20 11376

BCLllA-9568 + ACGACGGCUCGGUUCACAUC 20 11377

BCLllA-9569 - CGCACUUGAACUUGCAGCUC 20 11378

BCLllA-9570 + UCCCUGCGAACUUGAACGUC 20 11379

BCLllA-9571 - U CG AG G U A A A AG AG A U A A AG 20 11380

BCLllA-9572 + CCAAUGGCCAGUGCGGGGAG 20 11381

BCLllA-4351 + GACGCCAGACGCGGCCCCCG 20 11382

BCLllA-9573 - UGCGGCCACUGGUGAGCCCG 20 11383

BCLllA-9574 - GGGGCCGCGUCUGGCGUCCG 20 11384

BCLllA-5359 + GCGAGACAUGGUGGGCUGCG 20 11385

BCLllA-9575 - AG AAAAACCU CCG AG AG U CG 20 11386

BCLllA-4561 + ACGCCAGACGCGGCCCCCGG 20 11387

BCLllA-9576 + UCUUUUACCUCGACUCUCGG 20 11388

BCLllA-9577 - UAGAGUCCGCGUGUGUGGGG 20 11389

BCLllA-9578 - U UUAGAGUCCGCGUGUGUGG 20 11390

BCLllA-9579 + CAAUGGUUCCAGAUGGGAUG 20 11391

BCLllA-5361 + CGGCGAGACAUGGUGGGCUG 20 11392

BCLllA-9580 + CUGAGCUGCAAGUUCAAGUG 20 11393

BCLllA-9581 - CAU UUUAGAGUCCGCGUGUG 20 11394

BCLllA-9582 + GACGACGGCUCGGUUCACAU 20 11395

BCLllA-9583 - AGCCCCUGAUGUGUGUCCAU 20 11396

BCLllA-9584 + GCGGCGGGCGGACGACGGCU 20 11397

BCLllA-9585 + AUCUCUUUUACCUCGACUCU 20 11398 BCLllA-5365 + UGCUUGCGGCGAGACAUGGU 20 11399

BCLllA-9586 - AUUUUAGAGUCCGCGUGUGU 20 11400

Table 18B provides exemplary targeting domains for knocking down the BCLl 1 A gene selected according to the second tier parameters. The targeting domains bind within 500 bp (e.g., upstream or downstream) of a transcription start site (TSS). It is contemplated herein that in an embodiment the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. pyogenes eiCas9 molecule or eiCas9 fusion protein (e.g., an eiCas9 fused to a transcription repressor domain) to alter the BCLl 1 A gene (e.g., reduce or eliminate BCLl 1A gene expression, BCLl 1A protein function, or the level of BCLl 1 A protein). One or more gRNA may be used to target an eiCas9 to the promoter region of the BCLl 1A gene.

Table 18B

BCLllA-4529 + AAAAAAAAAAAAAAAGA 17 11423

BCLllA-9603 + U AG AAA U A A U AC A A AG A 17 11424

BCLllA-9604 + GAGCCGGGUUAGAAAGA 17 11425

BCLllA-4592 + AGGGCGAGCAGGAGAGA 17 11426

BCLllA-4534 - AAAGCGAGGGGGAGAGA 17 11427

BCLllA-9605 + GAGAGAAGAGAGAUAGA 17 11428

BCLllA-4674 + CGGCGGCGGGCGGACGA 17 11429

BCLllA-4494 + GGGGAGGGGCGGGCCGA 17 11430

BCLllA-9606 - ACU AG AAG CAAAAG CG A 17 11431

BCLllA-4591 + AGGAGAGAAGGGGAGGA 17 11432

BCLllA-4399 + GAGAAGGGGAGGAGGGA 17 11433

BCLllA-4499 + GGGGCGGGCCGAGGGGA 17 11434

BCLllA-9607 + AAUGGCCAGUGCGGGGA 17 11435

BCLllA-4562 + ACGCGGCCCCCGGGGGA 17 11436

BCLllA-9608 + AACGUCAGGAGUCUGGA 17 11437

BCLllA-9609 - UUAAAAAAAAGCCAUGA 17 11438

BCLllA-9610 + GGUUCCAGAUGGGAUGA 17 11439

BCLllA-5383 - CC AG C ACU U AAG CAAAC 17 11440

BCLllA-9611 - CCUCCCCCUCCCCGCAC 17 11441

BCLllA-9612 - UCUCCUUCUUUCUAACC 17 11442

BCLllA-9613 + GACAUGAAAAAGAGACC 17 11443

BCLllA-4662 + CGCCAGACGCGGCCCCC 17 11444

BCLllA-9614 - CGGCCCGCCCCUCCCCC 17 11445

BCLllA-9615 - UCGGCCCGCCCCUCCCC 17 11446

BCLllA-9616 + GCGGCGGUGGCGUGGCC 17 11447

BCLllA-9617 - ACCCCUUUCUUCUCUCC 17 11448

BCLllA-9618 - UGGCCAUUGGCUUGUCC 17 11449

BCLllA-9619 + ACAUGGGCAGGGCGAGC 17 11450

BCLllA-9620 - CGUGUGUGGGGGGGAGC 17 11451

BCLllA-9621 + GGGGGCGCUGGGGCCGC 17 11452

BCLllA-4646 + CCGAGGGGAGGGGGCGC 17 11453

BCLllA-9622 + UAAUACAAAGAUGGCGC 17 11454

BCLllA-4441 + GCGGCGGCGGCGGCGGC 17 11455

BCLllA-9623 + GGACACACAUCAGGGGC 17 11456

BCLllA-4429 + GCCCCCGGGGGAGGGGC 17 11457

BCLllA-5392 + AUGGUGGGCUGCGGGGC 17 11458

BCLllA-9624 + AGGGGGAGGUGCGGGGC 17 11459

BCLllA-9625 + ACACACAAAACAUGGGC 17 11460

BCLllA-9626 + CGCGGCGGUGGCGUGGC 17 11461

BCLllA-9627 + GAGAAGAAAGGGGUGGC 17 11462

BCLllA-5395 + GAGACAUGGUGGGCUGC 17 11463

BCLllA-9628 + AAGCCAAUGGCCAGUGC 17 11464 BCLllA-9629 + CGGGGAGGGGGAGGUGC 17 11465

BCLllA-9630 + ACCAAUGGACACACAUC 17 11466

BCLllA-9631 - AAAACCCUCAUCCCAUC 17 11467

BCLllA-9632 - ACUUGAACUUGCAGCUC 17 11468

BCLllA-9633 - GAUGAAGAUAUUUUCUC 17 11469

BCLllA-4528 + AAAAAAAAAAAAAAAAG 17 11470

BCLllA-4433 + GCCGGGAGAGAAGAAAG 17 11471

BCLllA-9634 - AGG U AAAAG AG AU AAAG 17 11472

BCLllA-4475 + GGCGAGCAGGAGAGAAG 17 11473

BCLllA-4389 + GAAGGGGAGGAGGGAAG 17 11474

BCLllA-9635 + GGCCGCGGGCUCACCAG 17 11475

BCLllA-9636 + G A AG AAAG GG G U G G C AG 17 11476

BCLllA-9637 + CAAUGGACACACAUCAG 17 11477

BCLllA-9638 - UUGAACUUGCAGCUCAG 17 11478

BCLllA-4543 - AAGCGAGGGGGAGAGAG 17 11479

BCLllA-4533 - AAAAGCGAGGGGGAGAG 17 11480

BCLllA-4485 + GGGAGGGGCGGGCCGAG 17 11481

BCLllA-9639 - CUAGAAGCAAAAGCGAG 17 11482

BCLllA-4492 + GGGCGGGCCGAGGGGAG 17 11483

BCLllA-9640 + AUGGCCAGUGCGGGGAG 17 11484

BCLllA-4665 + CGCGGCCCCCGGGGGAG 17 11485

BCLllA-9641 + AGAGAGAAGAGAGAUAG 17 11486

BCLllA-9642 + GCUCCCCCCCACACACG 17 11487

BCLllA-4427 + GCCAGACGCGGCCCCCG 17 11488

BCLllA-9643 - GGCCCGCCCCUCCCCCG 17 11489

BCLllA-9644 - GGCCACUGGUGAGCCCG 17 11490

BCLllA-4670 - CGGCCACGCCACCGCCG 17 11491

BCLllA-4470 + GGCCGCAGCGAGCGCCG 17 11492

BCLllA-4502 + GGGGGAGGGGCGGGCCG 17 11493

BCLllA-9645 + AGGGGGCGCUGGGGCCG 17 11494

BCLllA-9646 + CGGGGCGGGGGGCUCCG 17 11495

BCLllA-9647 - GCCGCGUCUGGCGUCCG 17 11496

BCLllA-9648 + GGGGGAGGUGCGGGGCG 17 11497

BCLllA-9649 + GCGCCGCGGCGGUGGCG 17 11498

BCLllA-9650 + AGCCAAUGGCCAGUGCG 17 11499

BCLllA-9651 + GGGGAGGGGGAGGUGCG 17 11500

BCLllA-9652 - GGU AAAAG AGAUAAAGG 17 11501

BCLllA-9653 - UGAACUUGCAGCUCAGG 17 11502

BCLllA-9654 - UAGAAGCAAAAGCGAGG 17 11503

BCLllA-4627 + CAGGAGAGAAGGGGAGG 17 11504

BCLllA-4480 + GGCGGGCCGAGGGGAGG 17 11505

BCLllA-9655 + UGGCCAGUGCGGGGAGG 17 11506 BCLllA-4634 + CCAGACGCGGCCCCCGG 17 11507

BCLllA-9656 - GCCCGCCCCUCCCCCGG 17 11508

BCLllA-4660 + CGCAGCGAGCGCCGCGG 17 11509

BCLllA-4588 + AGCGAGCGCCGCGGCGG 17 11510

BCLllA-4478 + GGCGGCGGCGGCGGCGG 17 11511

BCLllA-4447 + GCGGGCGGCGGCGGCGG 17 11512

BCLllA-4500 + GGGGCGGGCGGCGGCGG 17 11513

BCLllA-5409 + UGCGGGGCGGGCGGCGG 17 11514

BCLllA-5410 + GGCUGCGGGGCGGGCGG 17 11515

BCLllA-9657 + GGGGAGGUGCGGGGCGG 17 11516

BCLllA-9658 + GGGGUGGGAGGAAAGGG 17 11517

BCLllA-9659 - GAACUUGCAGCUCAGGG 17 11518

BCLllA-4444 + GCGGCGGCGGCGGCGGG 17 11519

BCLllA-5411 + GUGGGCUGCGGGGCGGG 17 11520

BCLllA-9660 + GGGAGGUGCGGGGCGGG 17 11521

BCLllA-4483 + GGGAGAGAAGAAAGGGG 17 11522

BCLllA-4407 + GAGCAGGAGAGAAGGGG 17 11523

BCLllA-9661 + GAAAGGGGUGGCAGGGG 17 11524

BCLllA-4593 + AGGGGCGGGCCGAGGGG 17 11525

BCLllA-4467 + GGCCCCCGGGGGAGGGG 17 11526

BCLllA-5413 + CAUGGUGGGCUGCGGGG 17 11527

BCLllA-9662 + CAAUGGCCAGUGCGGGG 17 11528

BCLllA-9663 + GAGGGGGAGGUGCGGGG 17 11529

BCLllA-9664 + CCAGUGCGGGGAGGGGG 17 11530

BCLllA-4395 + GACGCGGCCCCCGGGGG 17 11531

BCLllA-9665 + GGGAGGAAAGGGUGGGG 17 11532

BCLllA-9666 + UGGGAGGAAAGGGUGGG 17 11533

BCLllA-9667 + GGGGUGGCAGGGGUGGG 17 11534

BCLllA-9668 - GAGUCCGCGUGUGUGGG 17 11535

BCLllA-5414 + CUUGCGGCGAGACAUGG 17 11536

BCLllA-9669 + GUGGGAGGAAAGGGUGG 17 11537

BCLllA-9670 - AGAGUCCGCGUGUGUGG 17 11538

BCLllA-9671 + UGGUUCCAGAUGGGAUG 17 11539

BCLllA-9672 + GAGGGGAGGGGGCGCUG 17 11540

BCLllA-9673 - CGCCGCGGCGCUCGCUG 17 11541

BCLllA-5422 + CGAGACAUGGUGGGCUG 17 11542

BCLllA-9674 + AG C U G C A AG U U C A AG U G 17 11543

BCLllA-9675 + CAAGCCAAUGGCCAGUG 17 11544

BCLllA-9676 + GCGGGGAGGGGGAGGUG 17 11545

BCLllA-9677 + GGUGGGAGGAAAGGGUG 17 11546

BCLllA-9678 - UUUAGAGUCCGCGUGUG 17 11547

BCLllA-9679 + GCAGGGAAGAUGAAUUG 17 11548 BCLllA-5426 + GGGGUUUGCCUUGCUUG 17 11549

BCLllA-9680 + AGAGACACACAAAACAU 17 11550

BCLllA-9681 - CCCUGAUGUGUGUCCAU 17 11551

BCLllA-5431 + AUUAUUAUUACUAUUAU 17 11552

BCLllA-9682 - CCAGCGCCCCCUCCCCU 17 11553

BCLllA-9683 + CGAGGGGAGGGGGCGCU 17 11554

BCLllA-9684 + UCU UUUACCUCGACUCU 17 11555

BCLllA-9685 + GGGUGGGAGGAAAGGGU 17 11556

BCLllA-9686 + AAAGGGGUGGCAGGGGU 17 11557

BCLllA-9687 - U UAGAGUCCGCGUGUGU 17 11558

BCLllA-9688 + CAGGGAAGAUGAAUUGU 17 11559

BCLllA-5439 + UUAUUAUUACUAUUAUU 17 11560

BCLllA-9689 - U UAUUUCUAAUUUAU UU 17 11561

BCLllA-9690 + AGAGAGAGAGAUGAAAAAAA 20 11562

BCLllA-5443 - AACCCCAGCACUUAAGCAAA 20 11563

BCLllA-9691 - AAUUUAUUUUGGAUGUCAAA 20 11564

BCLllA-9692 + GUGGCAGGGGUGGGAGGAAA 20 11565

BCLllA-9693 - GUCGAGGU A A A AG AG A U AAA 20 11566

BCLllA-9694 + UAAAAU U AAAU AAAAU U AAA 20 11567

BCLllA-9695 + GAAGGGGAAGCUCACACCAA 20 11568

BCLllA-4541 + AAGAGACCAGGACAAGCCAA 20 11569

BCLllA-9696 + CAAAAGUGCAUACACGGCAA 20 11570

BCLllA-9697 + GCGUGGCCGGGAGAGAAGAA 20 11571

BCLllA-4422 + GCAGGGCGAGCAGGAGAGAA 20 11572

BCLllA-9698 + GGUGGCAGGGGUGGGAGGAA 20 11573

BCLllA-4404 + GAGAGAAGGGGAGGAGGGAA 20 11574

BCLllA-9699 - AGUCGAGGUAAAAGAGAUAA 20 11575

BCLllA-4455 + GGACAGAGACACACAAAACA 20 11576

BCLllA-9700 + CUGUCUCAAAAGUGCAUACA 20 11577

BCLllA-9701 - CGCGUGUGUGGGGGGGAGCA 20 11578

BCLllA-9702 + AAUAAUACAAAGAUGGCGCA 20 11579

BCLllA-9703 + AGACACACAAAACAUGGGCA 20 11580

BCLllA-9704 + G AG AG A AG A A AG G G G U G G C A 20 11581

BCLllA-9705 - GCACUUGAACUUGCAGCUCA 20 11582

BCLllA-9706 + GAAUUGUGGGAGAGCCGUCA 20 11583

BCLllA-4527 + AAAAAAAAAAAAAAAAAAGA 20 11584

BCLllA-9707 + AAU U AG AAAU AAU ACAAAG A 20 11585

BCLllA-9708 + GGAGAGCCGGGUUAGAAAGA 20 11586

BCLllA-4464 + GGCAGGGCGAGCAGGAGAGA 20 11587

BCLllA-4418 - GCAAAAGCGAGGGGGAGAGA 20 11588

BCLllA-9709 + AGAGAGAGAAGAGAGAUAGA 20 11589

BCLllA-4673 + CGGCGGCGGCGGGCGGACGA 20 11590 BCLllA-4648 + CCGGGGGAGGGGCGGGCCGA 20 11591

BCLllA-9710 - AGGACUAGAAGCAAAAGCGA 20 11592

BCLllA-4584 + AGCAGGAGAGAAGGGGAGGA 20 11593

BCLllA-4459 + GGAGAGAAGGGGAGGAGGGA 20 11594

BCLllA-4461 + GGAGGGGCGGGCCGAGGGGA 20 11595

BCLllA-4624 + CAGACGCGGCCCCCGGGGGA 20 11596

BCLllA-9711 + UUGAACGUCAGGAGUCUGGA 20 11597

BCLllA-9712 - UGCUUAAAAAAAAGCCAUGA 20 11598

BCLllA-5458 - ACCCCAGCACUUAAGCAAAC 20 11599

BCLllA-9713 - GCGGCGCUCGCUGCGGCCAC 20 11600

BCLllA-9714 - GCACCUCCCCCUCCCCGCAC 20 11601

BCLllA-9715 + CUGGACAUGAAAAAGAGACC 20 11602

BCLllA-4456 + GGACGCCAGACGCGGCCCCC 20 11603

BCLllA-9716 - CCUCGGCCCGCCCCUCCCCC 20 11604

BCLllA-4362 + CGGACGCCAGACGCGGCCCC 20 11605

BCLllA-9717 - CCCUCGGCCCGCCCCUCCCC 20 11606

BCLllA-9718 + GCCGCGGCGGUGGCGUGGCC 20 11607

BCLllA-9719 - GCCACCCCUUUCUUCUCUCC 20 11608

BCLllA-9720 - CACUGGCCAUUGGCUUGUCC 20 11609

BCLllA-9721 + AAAACAUGGGCAGGGCGAGC 20 11610

BCLllA-9722 + GGAGGGGGCGCUGGGGCCGC 20 11611

BCLllA-4490 + GGGCCGAGGGGAGGGGGCGC 20 11612

BCLllA-4442 + GCGGCGGCGGCGGCGGCGGC 20 11613

BCLllA-9723 + AAUGGACACACAUCAGGGGC 20 11614

BCLllA-4439 + GCGGCCCCCGGGGGAGGGGC 20 11615

BCLllA-5465 + GACAUGGUGGGCUGCGGGGC 20 11616

BCLllA-9724 + GGGAGGGGGAGGUGCGGGGC 20 11617

BCLllA-9725 + CGCCGCGGCGGUGGCGUGGC 20 11618

BCLllA-9726 + GGAGAGAAGAAAGGGGUGGC 20 11619

BCLllA-5468 + GGCGAGACAUGGUGGGCUGC 20 11620

BCLllA-9727 + GACAAGCCAAUGGCCAGUGC 20 11621

BCLllA-9728 + GUGCGGGGAGGGGGAGGUGC 20 11622

BCLllA-9729 + CACACCAAUGGACACACAUC 20 11623

BCLllA-9730 - GAAAAAACCCUCAUCCCAUC 20 11624

BCLllA-9731 - ACUGAUGAAGAUAUUUUCUC 20 11625

BCLllA-9732 + GAACUUGAACGUCAGGAGUC 20 11626

BCLllA-9733 - CCUCCCCCGGGGGCCGCGUC 20 11627

BCLllA-4526 + AAAAAAAAAAAAAAAAAAAG 20 11628

BCLllA-9734 + GUGGCCGGGAGAGAAGAAAG 20 11629

BCLllA-4629 + CAGGGCGAGCAGGAGAGAAG 20 11630

BCLllA-4577 + AGAGAAGGGGAGGAGGGAAG 20 11631

BCLllA-9735 + UGGGGCCGCGGGCUCACCAG 20 11632 BCLllA-9736 + AGAGAAGAAAGGGGUGGCAG 20 11633

BCLllA-9737 + CACCAAUGGACACACAUCAG 20 11634

BCLllA-9738 - CACUUGAACUUGCAGCUCAG 20 11635

BCLllA-4611 - CAAAAGCGAGGGGGAGAGAG 20 11636

BCLllA-4583 - AGCAAAAGCGAGGGGGAGAG 20 11637

BCLllA-4677 + CGGGGGAGGGGCGGGCCGAG 20 11638

BCLllA-9739 - GGACUAGAAGCAAAAGCGAG 20 11639

BCLllA-4411 + GAGGGGCGGGCCGAGGGGAG 20 11640

BCLllA-4575 + AGACGCGGCCCCCGGGGGAG 20 11641

BCLllA-9740 + GAGAGAGAGAAGAGAGAUAG 20 11642

BCLllA-9741 + CCUGCUCCCCCCCACACACG 20 11643

BCLllA-9742 + GGCUCCGCGGACGCCAGACG 20 11644

BCLllA-9743 - CUCGGCCCGCCCCUCCCCCG 20 11645

BCLllA-9744 - UCCCGGCCACGCCACCGCCG 20 11646

BCLllA-9745 + AGUGGCCGCAGCGAGCGCCG 20 11647

BCLllA-4642 + CCCGGGGGAGGGGCGGGCCG 20 11648

BCLllA-9746 + GGGAGGGGGCGCUGGGGCCG 20 11649

BCLllA-9747 + GUGCGGGGCGGGGGGCUCCG 20 11650

BCLllA-9748 - CAGGACUAGAAGCAAAAGCG 20 11651

BCLllA-9749 + GGAGGGGGAGGUGCGGGGCG 20 11652

BCLllA-9750 + CGAGCGCCGCGGCGGUGGCG 20 11653

BCLllA-9751 + ACAAGCCAAUGGCCAGUGCG 20 11654

BCLllA-9752 + UGCGGGGAGGGGGAGGUGCG 20 11655

BCLllA-9753 - CGAGGUAAAAGAGAUAAAGG 20 11656

BCLllA-9754 - ACU UGAACUUGCAGCUCAGG 20 11657

BCLllA-9755 - GACUAGAAGCAAAAGCGAGG 20 11658

BCLllA-4408 + GAGCAGGAGAGAAGGGGAGG 20 11659

BCLllA-4594 + AGGGGCGGGCCGAGGGGAGG 20 11660

BCLllA-9756 + CAAUGGCCAGUGCGGGGAGG 20 11661

BCLllA-9757 - UCGGCCCGCCCCUCCCCCGG 20 11662

BCLllA-4471 + GGCCGCAGCGAGCGCCGCGG 20 11663

BCLllA-4661 + CGCAGCGAGCGCCGCGGCGG 20 11664

BCLllA-4479 + GGCGGCGGCGGCGGCGGCGG 20 11665

BCLllA-4448 + GCGGGCGGCGGCGGCGGCGG 20 11666

BCLllA-4501 + GGGGCGGGCGGCGGCGGCGG 20 11667

BCLllA-5484 + UGCGGGGCGGGCGGCGGCGG 20 11668

BCLllA-5485 + GGCUGCGGGGCGGGCGGCGG 20 11669

BCLllA-5486 + GUGGGCUGCGGGGCGGGCGG 20 11670

BCLllA-9758 + GAGGGGGAGGUGCGGGGCGG 20 11671

BCLllA-9759 + GCAGGGGUGGGAGGAAAGGG 20 11672

BCLllA-9760 - CUUGAACUUGCAGCUCAGGG 20 11673

BCLllA-4443 + GCGGCGGCGGCGGCGGCGGG 20 11674 BCLllA-5487 + AUGGUGGGCUGCGGGGCGGG 20 11675

BCLllA-9761 + AGGGGGAGGUGCGGGGCGGG 20 11676

BCLllA-4434 + GCCGGGAGAGAAGAAAGGGG 20 11677

BCLllA-4476 + GGCGAGCAGGAGAGAAGGGG 20 11678

BCLllA-9762 + GAAGAAAGGGGUGGCAGGGG 20 11679

BCLllA-4486 + GGGAGGGGCGGGCCGAGGGG 20 11680

BCLllA-4666 + CGCGGCCCCCGGGGGAGGGG 20 11681

BCLllA-5489 + AGACAUGGUGGGCUGCGGGG 20 11682

BCLllA-9763 + AGCCAAUGGCCAGUGCGGGG 20 11683

BCLllA-9764 + GGGGAGGGGGAGGUGCGGGG 20 11684

BCLllA-9765 + UGGCCAGUGCGGGGAGGGGG 20 11685

BCLllA-4635 + CCAGACGCGGCCCCCGGGGG 20 11686

BCLllA-9766 + GGUGGGAGGAAAGGGUGGGG 20 11687

BCLllA-9767 + GGGUGGGAGGAAAGGGUGGG 20 11688

BCLllA-9768 + AAAGGGGUGGCAGGGGUGGG 20 11689

BCLllA-9769 - UUAGAGUCCGCGUGUGUGGG 20 11690

BCLllA-5490 + UUGCUUGCGGCGAGACAUGG 20 11691

BCLllA-9770 + GGGGUGGGAGGAAAGGGUGG 20 11692

BCLllA-9771 + GCCGAGGGGAGGGGGCGCUG 20 11693

BCLllA-9772 - CACCGCCGCGGCGCUCGCUG 20 11694

BCLllA-5497 + UCCCGU UUGCUUAAGUGCUG 20 11695

BCLllA-9773 + GGACAAGCCAAUGGCCAGUG 20 11696

BCLllA-9774 + AGUGCGGGGAGGGGGAGGUG 20 11697

BCLllA-9775 + AGGGGUGGGAGGAAAGGGUG 20 11698

BCLllA-9776 - U UUUAGAGUCCGCGUGUGUG 20 11699

BCLllA-9777 + GGCGCAGGGAAGAUGAAUUG 20 11700

BCLllA-5500 + GCUGGGGUUUGCCU UGCUUG 20 11701

BCLllA-9778 + GACAGAGACACACAAAACAU 20 11702

BCLllA-9779 - CCCCUCCCCGCACUGGCCAU 20 11703

BCLllA-9780 + ACACGGCAAUGGUUCCAGAU 20 11704

BCLllA-9781 + AUAAUUAUUAUUACUAUUAU 20 11705

BCLllA-9782 - GCCCCAGCGCCCCCUCCCCU 20 11706

BCLllA-9783 + GGCCGAGGGGAGGGGGCGCU 20 11707

BCLllA-5509 + UUCCCGU UUGCUUAAGUGCU 20 11708

BCLllA-9784 + CAGGGGUGGGAGGAAAGGGU 20 11709

BCLllA-9785 + AAGAAAGGGGUGGCAGGGGU 20 11710

BCLllA-9786 + GCGCAGGGAAGAUGAAUUGU 20 11711

BCLllA-9787 + UAAUUAUUAUUACUAUUAUU 20 11712

BCLllA-9788 - GUAUUAUUUCUAAUU UAUUU 20 11713

Table 18C provides exemplary targeting domains for knocking down the BCLllA gene selected according to the third tier parameters. The targeting domains binds within the additional 500 bp (e.g., upstream or downstream) of a transcription start site (TSS), e.g., extending to lkb upstream and downstream of a TSS. It is contemplated herein that in an embodiment the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. pyogenes eiCas9 molecule or eiCas9 fusion protein (e.g., an eiCas9 fused to a transcription repressor domain) to alter the BCLl 1 A gene (e.g., reduce or eliminate BCLl 1A gene expression, BCLl 1A protein function, or the level of BCLl 1A protein). One or more gRNA may be used to target an eiCas9 to the promoter region of the BCLl 1 A gene.

Table 18C

BCLllA-9816 - CGCGGCGGCGGCGGGGA 17 11742

BCLllA-9817 + GGCGAGGGGAGGUGGGA 17 11743

BCLllA-9818 + UCCAGCCUAAGUUUGGA 17 11744

BCLllA-9819 - AAUAAUGAACAAUGCUA 17 11745

BCLllA-9820 - GGAAGUGGGUGUGCGUA 17 11746

BCLllA-9821 - AAGAAAAUGGGGGGGUA 17 11747

BCLllA-9822 + ACCCCCCCAUUUUCUUA 17 11748

BCLllA-9823 + UCAUUAUUUUGCAAAAC 17 11749

BCLllA-9824 + AUAGAGCGAGAGUGCAC 17 11750

BCLllA-9825 - GAGAAAAGAGGUGAGAC 17 11751

BCLllA-9826 - AGAGGGGCCGCGGCGAC 17 11752

BCLllA-9827 - GUGGGACCGGGAAGGAC 17 11753

BCLllA-9828 + AAGGCCGAGCCAGGGAC 17 11754

BCLllA-9829 + GCCUGGAAAGAGGGGAC 17 11755

BCLllA-9830 - GGGGAGAGCCGUGGGAC 17 11756

BCLllA-9831 - CAACUCACAUGCAAACC 17 11757

BCLllA-9832 + UAGAGCGAGAGUGCACC 17 11758

BCLllA-9833 + AGGCCGAGCCAGGGACC 17 11759

BCLllA-9834 + CCUGGAAAGAGGGGACC 17 11760

BCLllA-9835 - GGGAGAGCCGUGGGACC 17 11761

BCLllA-9836 - CCGGGAGCAACUCUACC 17 11762

BCLllA-9837 + CACCAGCUCCCACCCCC 17 11763

BCLllA-9838 + CGGGAGGCUGCAGCCCC 17 11764

BCLllA-9839 - GCUUUUACUUCGGCCCC 17 11765

BCLllA-9840 - CUGUGGAAAGGGGCCCC 17 11766

BCLllA-9841 + UCACCUCUUUUCUCCCC 17 11767

BCLllA-9842 - CCGCGCUUCCCCAGCCC 17 11768

BCLllA-9843 + CCGGGAGGCUGCAGCCC 17 11769

BCLllA-9844 - GGGGCGCCCUCGGGCCC 17 11770

BCLllA-9845 - CGCCGCCUGCCUCUCCC 17 11771

BCLllA-9846 + CUCACCUCUUUUCUCCC 17 11772

BCLllA-9847 - UCUAAAAAACGAUUCCC 17 11773

BCLllA-9848 + GCGGGCGGAGGGAAGCC 17 11774

BCLllA-9849 - CCCGCGCUUCCCCAGCC 17 11775

BCLllA-9850 + GCCCCCAAGGCCGAGCC 17 11776

BCLllA-9851 + CCCCGCGUGUGGACGCC 17 11777

BCLllA-9852 + GCGGACUCAGGAGCGCC 17 11778

BCLllA-9853 + GGCAGGCGGCGCAGGCC 17 11779

BCLllA-9854 + CAGGAGCCCGCGCGGCC 17 11780

BCLllA-9855 - CCGGGGCUGCAGCCUCC 17 11781

BCLllA-9856 - CAGGCCGCGCGGGCUCC 17 11782

BCLllA-9857 + CCAGGUAGAGUUGCUCC 17 11783 BCLllA-9858 + GCAGCGCCCAAGUCUCC 17 11784

BCLllA-9859 - UACGGAGGAGGGUGUCC 17 11785

BCLllA-9860 - GUCUAAAAAACGAUUCC 17 11786

BCLllA-9861 + GCGUCUCCCGUCCUUCC 17 11787

BCLllA-9862 - CCCGGUCCCCUCUUUCC 17 11788

BCLllA-9863 + AGUUACAGCUCCGCAGC 17 11789

BCLllA-9864 + CCGG CAC AAAAG G C AG C 17 11790

BCLllA-9865 - ACGGUCAAGUGUGCAGC 17 11791

BCLllA-9866 + GGGCAAGCGCGAGGAGC 17 11792

BCLllA-9620 - CGUGUGUGGGGGGGAGC 17 11793

BCLllA-9867 - AACCUGGGGGUGGGAGC 17 11794

BCLllA-9868 - CCCUGGCGUCCACACGC 17 11795

BCLllA-9869 - UUCCCGAGCGCAGCCGC 17 11796

BCLllA-9870 + CCGGGCUGGGGAAGCGC 17 11797

BCLllA-9871 + CGCGGACUCAGGAGCGC 17 11798

BCLllA-9872 - CUCUUUCCAGGCCGCGC 17 11799

BCLllA-9873 + CUUGACCGUGAGCGCGC 17 11800

BCLllA-9874 + GGAGAGGCAGGCGGCGC 17 11801

BCLllA-9875 + AGGCAGGCGGCGCAGGC 17 11802

BCLllA-9876 + GGGGACCGGGGAGAGGC 17 11803

BCLllA-9877 - GCCCUCCAAACUUAGGC 17 11804

BCLllA-9878 - AGGACGGGAGACGCGGC 17 11805

BCLllA-9879 - GCGAGCGCGGCGGCGGC 17 11806

BCLllA-9880 + AGGCUGCAGCCCCGGGC 17 11807

BCLllA-9881 + UGCAAAACUGGCGGGGC 17 11808

BCLllA-9882 + UAUUUUGCAAAACUGGC 17 11809

BCLllA-9883 + AAACACCCACCUCUGGC 17 11810

BCLllA-9884 + UAAGUUUGGAGGGCUGC 17 11811

BCLllA-9885 + AC A A A AG GCGGCAGUGC 17 11812

BCLllA-9886 - CCCGCUGCCUUUUGUGC 17 11813

BCLllA-9887 + CCCGACUCCGCGGACUC 17 11814

BCLllA-9888 + GGACAAACACCCACCUC 17 11815

BCLllA-9889 - GCCUUGGGGGCGCCCUC 17 11816

BCLllA-9890 - UUUGCUGUCCUCUCCUC 17 11817

BCLllA-9891 + AGCCCGCGGCUGCGCUC 17 11818

BCLllA-9892 - AGCGCAGCCGCGGGCUC 17 11819

BCLllA-9893 - CCUGAGUCCGCGGAGUC 17 11820

BCLllA-9894 + UUGGAGGGCUGCGGGUC 17 11821

BCLllA-9895 - GUACGGAGGAGGGUGUC 17 11822

BCLllA-9896 - GCUCAGCUCUCAACUUC 17 11823

BCLllA-9897 - CUUGGGCGCUGCCCUUC 17 11824

BCLllA-9898 - ACUGCCGCCUUUUGUUC 17 11825 BCLllA-9899 - AUUCCCGGGGAGAAAAG 17 11826

BCLllA-9900 - CCACAAUAGUGAGAAAG 17 11827

BCLllA-9901 + GGCGGAAAGGAGGAAAG 17 11828

BCLllA-9902 + CCGCGCGGCCUGGAAAG 17 11829

BCLllA-9903 - AGUGGCACUGUGGAAAG 17 11830

BCLllA-9904 + CG A A A AG AG A A A U A A AG 17 11831

BCLllA-9905 - GCGGCGGGGAGGGGAAG 17 11832

BCLllA-9906 + CCGCGUGUGGACGCCAG 17 11833

BCLllA-9907 - CCUUUUGUUCCGGCCAG 17 11834

BCLllA-9908 + AAGUUACAGCUCCGCAG 17 11835

BCLllA-9909 + G CCGG CAC AAAAG G C AG 17 11836

BCLllA-9910 - C ACG G U CAAG U G U G C AG 17 11837

BCLllA-9911 + GCGCGGCCUGGAAAGAG 17 11838

BCLllA-9912 - CCGCGGAGUCGGGAGAG 17 11839

BCLllA-9913 + GCUCCGCAGCGGGCGAG 17 11840

BCLllA-9914 + AAACUUUGCCCGAGGAG 17 11841

BCLllA-9915 - GUCCGCGGAGUCGGGAG 17 11842

BCLllA-9916 + AAGAGGGGACCGGGGAG 17 11843

BCLllA-9917 - GCGGCGGCGGCGGGGAG 17 11844

BCLllA-9918 + GCGGGGCGGGGGGGGAG 17 11845

BCLllA-9919 + CAUUUUCUUACGGUGAG 17 11846

BCLllA-9920 + GGGAGCGCACGGCAACG 17 11847

BCLllA-9642 + GCUCCCCCCCACACACG 17 11848

BCLllA-9921 - CCCCUGGCGUCCACACG 17 11849

BCLllA-9922 - GGGAAGGACGGGAGACG 17 11850

BCLllA-9923 - GAGGGGCCGCGGCGACG 17 11851

BCLllA-9924 + CUGGAAAGAGGGGACCG 17 11852

BCLllA-9925 - CGCGCUUCCCCAGCCCG 17 11853

BCLllA-9926 + UAAAAGCCCCGAGCCCG 17 11854

BCLllA-9927 + GCGCAGGCCGGGGCCCG 17 11855

BCLllA-9928 + UCGGGAAACUUUGCCCG 17 11856

BCLllA-9929 - CUAAAAAACGAUUCCCG 17 11857

BCLllA-9930 - UUUCCCGAGCGCAGCCG 17 11858

BCLllA-9931 - GGCGACGGGGAGAGCCG 17 11859

BCLllA-9932 + CGGACUCAGGAGCGCCG 17 11860

BCLllA-9933 + GGCUCUCCCCGUCGCCG 17 11861

BCLllA-9934 + GCAGGCGGCGCAGGCCG 17 11862

BCLllA-9935 - AGUCGGGAGAGGGGCCG 17 11863

BCLllA-9936 + CCCCUCUCCCGACUCCG 17 11864

BCLllA-9937 - CGGCGCUCCUGAGUCCG 17 11865

BCLllA-9938 + CCCGGGCUGGGGAAGCG 17 11866

BCLllA-9939 - CACGCGGGGAGCGAGCG 17 11867 BCLllA-9940 - CCUGGCGUCCACACGCG 17 11868

BCLllA-9941 + GUCUCCAGGAGCCCGCG 17 11869

BCLllA-9942 - CCUCUUUCCAGGCCGCG 17 11870

BCLllA-9943 + GCGGGAGGGCAAGCGCG 17 11871

BCLllA-9944 - CGAGCGCGGCGGCGGCG 17 11872

BCLllA-9945 + CAGCUCCGCAGCGGGCG 17 11873

BCLllA-9946 + GCAAAACUGGCGGGGCG 17 11874

BCLllA-9947 + AUUUUGCAAAACUGGCG 17 11875

BCLllA-9948 - GCGCAGCCGCGGGCUCG 17 11876

BCLllA-9949 + CUGGCCGGAACAAAAGG 17 11877

BCLllA-9950 + A U A A AG CG G CG G A A AG G 17 11878

BCLllA-9951 + GACCGGGGAGAGGCAGG 17 11879

BCLllA-9952 + GGAAAGGAGGAAAGAGG 17 11880

BCLllA-9953 - UUUGUUCCGGCCAGAGG 17 11881

BCLllA-9954 - GGGUGUGCGUACGGAGG 17 11882

BCLllA-9955 + CAGCGGGCGAGGGGAGG 17 11883

BCLllA-9956 - AGUGGGUGUGCGUACGG 17 11884

BCLllA-9957 + GGACUCAGGAGCGCCGG 17 11885

BCLllA-9958 + AAAGAGAAAUAAAGCGG 17 11886

BCLllA-9959 - GCGGGGAGCGAGCGCGG 17 11887

BCLllA-9960 - GGGAGCGAGCGCGGCGG 17 11888

BCLllA-9961 - AGCGAGCGCGGCGGCGG 17 11889

BCLllA-9962 + UGGGGAAGCGCGGGCGG 17 11890

BCLllA-9963 + CAAAACUGGCGGGGCGG 17 11891

BCLllA-9964 - AGCUGGUGGGGAAAGGG 17 11892

BCLllA-9965 - AAAAUGGGGGGGUAGGG 17 11893

BCLllA-9966 + AGCGAGAGUGCACCGGG 17 11894

BCLllA-9967 - GUCAAGUGUGCAGCGGG 17 11895

BCLllA-9968 + GGCUGGGGAAGCGCGGG 17 11896

BCLllA-9969 + AAAACUGGCGGGGCGGG 17 11897

BCLllA-9970 + CCGCAGCGGGCGAGGGG 17 11898

BCLllA-9971 - GCGCGGCGGCGGCGGGG 17 11899

BCLllA-9972 + AAACUGGCGGGGCGGGG 17 11900

BCLllA-9973 + UUGCAAAACUGGCGGGG 17 11901

BCLllA-9974 + AACUGGCGGGGCGGGGG 17 11902

BCLllA-9975 - ACAUGCAAACCUGGGGG 17 11903

BCLllA-9976 - ACCGUAAGAAAAUGGGG 17 11904

BCLllA-9548 - AGUCCGCGUGUGUGGGG 17 11905

BCLllA-9977 - CACCGUAAGAAAAUGGG 17 11906

BCLllA-9978 + GGGCGAGGGGAGGUGGG 17 11907

BCLllA-9668 - GAGUCCGCGUGUGUGGG 17 11908

BCLllA-9979 - U C A CCG U A AG A A A A U G G 17 11909 BCLllA-9980 + UUAUUUUGCAAAACUGG 17 11910

BCLllA-9981 - CUCACAUGCAAACCUGG 17 11911

BCLllA-9982 - CUGGGGGUGGGAGCUGG 17 11912

BCLllA-9670 - AGAGUCCGCGUGUGUGG 17 11913

BCLllA-9983 - GCGGAGCUGUAACUUGG 17 11914

BCLllA-9984 - CCCUGGCUCGGCCUUGG 17 11915

BCLllA-9985 + AUCCAGCCUAAGUUUGG 17 11916

BCLllA-9986 - CUCACCGUAAGAAAAUG 17 11917

BCLllA-9987 - GUGAGAAAGUGGCACUG 17 11918

BCLllA-9988 - ACUCACAUGCAAACCUG 17 11919

BCLllA-9989 - CCUCCCCUCGCCCGCUG 17 11920

BCLllA-9990 + CUAAGUUUGGAGGGCUG 17 11921

BCLllA-9991 + GCUGCAGCCCCGGGCUG 17 11922

BCLllA-9992 + CGCUCGCUCCCCGCGUG 17 11923

BCLllA-9993 - GGGGGUGGGAGCUGGUG 17 11924

BCLllA-9678 - UUUAGAGUCCGCGUGUG 17 11925

BCLllA-9549 - UAGAGUCCGCGUGUGUG 17 11926

BCLllA-9994 + ACUUUCUCACUAUUGUG 17 11927

BCLllA-9995 + CCACUUUCUCACUAUUG 17 11928

BCLllA-9996 - UCCCUGGCUCGGCCUUG 17 11929

BCLllA-9997 - ACUCACCGUAAGAAAAU 17 11930

BCLllA-9998 - GCUGCGGAGCUGUAACU 17 11931

BCLllA-9999 - GCGGGCUCCUGGAGACU 17 11932

BCLllA-10000 - AACUCACAUGCAAACCU 17 11933

BCLllA-10001 - GGCCUUGGGGGCGCCCU 17 11934

BCLllA-10002 - GGUCCCUGGCUCGGCCU 17 11935

BCLllA-10003 - CUUUGCUGUCCUCUCCU 17 11936

BCLllA-10004 + GAGCCCGCGGCUGCGCU 17 11937

BCLllA-10005 + GGCUGCAGCCCCGGGCU 17 11938

BCLllA-10006 - GAGCGCAGCCGCGGGCU 17 11939

BCLllA-10007 - CGGCGGGGAGGGGAAGU 17 11940

BCLllA-10008 - UCCUGAGUCCGCGGAGU 17 11941

BCLllA-10009 + AUUUUCUUACGGUGAGU 17 11942

BCLllA-10010 - GCGACGGGGAGAGCCGU 17 11943

BCLllA-10011 - UUGUUCCGGCCAGAGGU 17 11944

BCLllA-10012 + AGCGGGCGAGGGGAGGU 17 11945

BCLllA-10013 - UAAGAAAAUGGGGGGGU 17 11946

BCLllA-10014 - CAUGCAAACCUGGGGGU 17 11947

BCLllA-10015 - UGGGGGUGGGAGCUGGU 17 11948

BCLllA-9687 - UUAGAGUCCGCGUGUGU 17 11949

BCLllA-10016 + CACUUUCUCACUAUUGU 17 11950

BCLllA-10017 - CGCAGCCCUCCAAACUU 17 11951 BCLllA-10018 - GGCUCAGCUCUCAACUU 17 11952

BCLllA-10019 - CGGGCUCCUGGAGACU U 17 11953

BCLllA-10020 - GCUCGGGGCUUUUACU U 17 11954

BCLllA-10021 - GUCCCUGGCUCGGCCUU 17 11955

BCLllA-10022 + GGAAUCCAGCCUAAGUU 17 11956

BCLllA-10023 - GAGGUGAGACUGGCUU U 17 11957

BCLllA-10024 - UCCCACUCACCGUAAGAAAA 20 11958

BCLllA-10025 + CCACCUCUGGCCGGAACAAA 20 11959

BCLllA-10026 + GCGCGAGGAGCCGGCACAAA 20 11960

BCLllA-10027 - CUU UAUUUCUCUUU UCGAAA 20 11961

BCLllA-10028 - GGUGGGAGCUGGUGGGGAAA 20 11962

BCLllA-10029 - AGAAAGUGGCACUGUGGAAA 20 11963

BCLllA-10030 + GGAGGGCUGCGGGUCCGGAA 20 11964

BCLllA-10031 + AGAGAAAUAAAGCGGCGGAA 20 11965

BCLllA-10032 - GGGUGGGAGCUGGUGGGGAA 20 11966

BCLllA-10033 - GAGAAAGUGGCACUGUGGAA 20 11967

BCLllA-10034 + GGGGCCCGAGGGCGCCCCCA 20 11968

BCLllA-10035 + UCCCGUCCUUCCCGGUCCCA 20 11969

BCLllA-10036 + GCGCCCCCAAGGCCGAGCCA 20 11970

BCLllA-10037 + CUCCCCGCGUGUGGACGCCA 20 11971

BCLllA-9701 - CGCGUGUGUGGGGGGGAGCA 20 11972

BCLllA-10038 + GGGAGGUGGGAGGGAGCGCA 20 11973

BCLllA-10039 - U UUGGACACCAGCGCGCUCA 20 11974

BCLllA-10040 + GCCCGCGCGGCCUGGAAAGA 20 11975

BCLllA-10041 - GAGUCCGCGGAGUCGGGAGA 20 11976

BCLllA-10042 + CGGCGCAGGCCGGGGCCCGA 20 11977

BCLllA-10043 - CGGGAGAGGGGCCGCGGCGA 20 11978

BCLllA-10044 + UACAGCUCCGCAGCGGGCGA 20 11979

BCLllA-10045 - AGCCGUGGGACCGGGAAGGA 20 11980

BCLllA-10046 - GUGGGUGUGCGUACGGAGGA 20 11981

BCLllA-10047 + UGGAGGGCUGCGGGUCCGGA 20 11982

BCLllA-10048 + GCUGGGGAAGCGCGGGCGGA 20 11983

BCLllA-10049 - AGAAAAUGGGGGGGUAGGGA 20 11984

BCLllA-10050 - GGAGAGCCGUGGGACCGGGA 20 11985

BCLllA-10051 - GAGCGCGGCGGCGGCGGGGA 20 11986

BCLllA-10052 + GCGGGCGAGGGGAGGUGGGA 20 11987

BCLllA-10053 + GAAUCCAGCCUAAGU UUGGA 20 11988

BCLllA-10054 - CAAAAUAAUGAACAAUGCUA 20 11989

BCLllA-10055 - AGGGGAAGUGGGUGUGCGUA 20 11990

BCLllA-10056 - CGUAAGAAAAUGGGGGGGUA 20 11991

BCLllA-10057 + CCUACCCCCCCAUUUUCUUA 20 11992

BCLllA-10058 + UGUUCAUUAUUU UGCAAAAC 20 11993 BCLllA-10059 + AAAAUAGAGCGAGAGUGCAC 20 11994

BCLllA-10060 - GGGGAGAAAAGAGGUGAGAC 20 11995

BCLllA-10061 - GGGAGAGGGGCCGCGGCGAC 20 11996

BCLllA-10062 - GCCGUGGGACCGGGAAGGAC 20 11997

BCLllA-10063 + CCCAAGGCCGAGCCAGGGAC 20 11998

BCLllA-10064 + GCGGCCUGGAAAGAGGGGAC 20 11999

BCLllA-10065 - GACGGGGAGAGCCGUGGGAC 20 12000

BCLllA-10066 - GAACAACUCACAUGCAAACC 20 12001

BCLllA-10067 + AAAUAGAGCGAGAGUGCACC 20 12002

BCLllA-10068 + CCAAGGCCGAGCCAGGGACC 20 12003

BCLllA-10069 + CGGCCUGGAAAGAGGGGACC 20 12004

BCLllA-10070 - ACGGGGAGAGCCGUGGGACC 20 12005

BCLllA-10071 - UGUCCGGGAGCAACUCUACC 20 12006

BCLllA-10072 + CCCCACCAGCUCCCACCCCC 20 12007

BCLllA-10073 + CACCGGGAGGCUGCAGCCCC 20 12008

BCLllA-10074 - GGGGCU UUUACUUCGGCCCC 20 12009

BCLllA-10075 - GCACUGUGGAAAGGGGCCCC 20 12010

BCLllA-10076 + GUCUCACCUCUU UUCUCCCC 20 12011

BCLllA-10077 - CGCCCGCGCU UCCCCAGCCC 20 12012

BCLllA-10078 + GCACCGGGAGGCUGCAGCCC 20 12013

BCLllA-10079 - UUGGGGGCGCCCUCGGGCCC 20 12014

BCLllA-10080 - CUGCGCCGCCUGCCUCUCCC 20 12015

BCLllA-10081 + AGUCUCACCUCUUU UCUCCC 20 12016

BCLllA-10082 - AAGUCUAAAAAACGAUUCCC 20 12017

BCLllA-10083 + AGCGCGGGCGGAGGGAAGCC 20 12018

BCLllA-10084 - CCGCCCGCGCUUCCCCAGCC 20 12019

BCLllA-10085 + GGCGCCCCCAAGGCCGAGCC 20 12020

BCLllA-10086 + GCUCCCCGCGUGUGGACGCC 20 12021

BCLllA-10087 + UCCGCGGACUCAGGAGCGCC 20 12022

BCLllA-10088 + AGAGGCAGGCGGCGCAGGCC 20 12023

BCLllA-10089 + CUCCAGGAGCCCGCGCGGCC 20 12024

BCLllA-10090 - AGCCCGGGGCUGCAGCCUCC 20 12025

BCLllA-10091 - U UCCAGGCCGCGCGGGCUCC 20 12026

BCLllA-10092 + AAGCCAGGUAGAGUUGCUCC 20 12027

BCLllA-10093 + AGGGCAGCGCCCAAGUCUCC 20 12028

BCLllA-10094 - GCGUACGGAGGAGGGUGUCC 20 12029

BCLllA-10095 - CAAGUCUAAAAAACGAUUCC 20 12030

BCLllA-10096 + GCCGCGUCUCCCGUCCU UCC 20 12031

BCLllA-10097 - CUCCCCGGUCCCCUCUU UCC 20 12032

BCLllA-10098 + CCAAGUUACAGCUCCGCAGC 20 12033

BCLllA-10099 + GAGCCGGCA C A A A AG G C AG C 20 12034

BCLllA-10100 - CUCACGGUCAAGUGUGCAGC 20 12035 BCLllA-10101 + GGAGGGCAAGCGCGAGGAGC 20 12036

BCLllA-9563 - CCGCGUGUGUGGGGGGGAGC 20 12037

BCLllA-10102 - GCAAACCUGGGGGUGGGAGC 20 12038

BCLllA-10103 - GGCCCCUGGCGUCCACACGC 20 12039

BCLllA-10104 - AGUUUCCCGAGCGCAGCCGC 20 12040

BCLllA-10105 + GCCCCGGGCUGGGGAAGCGC 20 12041

BCLllA-10106 + CUCCGCGGACUCAGGAGCGC 20 12042

BCLllA-10107 - CCCCUCUUUCCAGGCCGCGC 20 12043

BCLllA-10108 + ACACUUGACCGUGAGCGCGC 20 12044

BCLllA-10109 + CGGGGAGAGGCAGGCGGCGC 20 12045

BCLllA-10110 + GAGAGGCAGGCGGCGCAGGC 20 12046

BCLllA-10111 + AGAGGGGACCGGGGAGAGGC 20 12047

BCLllA-10112 - GCAGCCCUCCAAACUUAGGC 20 12048

BCLllA-10113 - GGAAGGACGGGAGACGCGGC 20 12049

BCLllA-10114 - GGAGCGAGCGCGGCGGCGGC 20 12050

BCLllA-10115 + GGGAGGCUGCAGCCCCGGGC 20 12051

BCLllA-10116 + U UUUGCAAAACUGGCGGGGC 20 12052

BCLllA-10117 + CAUUAUUUUGCAAAACUGGC 20 12053

BCLllA-10118 + GACAAACACCCACCUCUGGC 20 12054

BCLllA-10119 + GCCUAAGUUUGGAGGGCUGC 20 12055

BCLllA-10120 + GGAACAAAAGGCGGCAGUGC 20 12056

BCLllA-10121 - UGUCCCGCUGCCU UUUGUGC 20 12057

BCLllA-10122 + UCUCCCGACUCCGCGGACUC 20 12058

BCLllA-10123 + GCGGGACAAACACCCACCUC 20 12059

BCLllA-10124 - UCGGCCUUGGGGGCGCCCUC 20 12060

BCLllA-10125 - UUCUUUGCUGUCCUCUCCUC 20 12061

BCLllA-10126 + CCGAGCCCGCGGCUGCGCUC 20 12062

BCLllA-10127 - CCGAGCGCAGCCGCGGGCUC 20 12063

BCLllA-10128 - GCUCCUGAGUCCGCGGAGUC 20 12064

BCLllA-10129 + AGUUUGGAGGGCUGCGGGUC 20 12065

BCLllA-10130 - UGCGUACGGAGGAGGGUGUC 20 12066

BCLllA-10131 - GAGGCUCAGCUCUCAACUUC 20 12067

BCLllA-10132 - AGACUUGGGCGCUGCCCUUC 20 12068

BCLllA-10133 - GGCACUGCCGCCUU UUGUUC 20 12069

BCLllA-10134 - ACGAUUCCCGGGGAGAAAAG 20 12070

BCLllA-10135 - UCCCCACAAUAGUGAGAAAG 20 12071

BCLllA-10136 + AGCGGCGGAAAGGAGGAAAG 20 12072

BCLllA-10137 + AGCCCGCGCGGCCUGGAAAG 20 12073

BCLllA-10138 - GAAAGUGGCACUGUGGAAAG 20 12074

BCLllA-10139 + U U U CG AAAAG AG AAAU AAAG 20 12075

BCLllA-10140 - GCGGCGGCGGGGAGGGGAAG 20 12076

BCLllA-10141 + UCCCCGCGUGUGGACGCCAG 20 12077 BCLllA-10142 - CCGCCUUU UGUUCCGGCCAG 20 12078

BCLllA-10143 + UCCAAGUUACAGCUCCGCAG 20 12079

BCLllA-10144 + GGAGCCGGCA C A A A AG G C AG 20 12080

BCLllA-10145 - GCUCACGGUCAAGUGUGCAG 20 12081

BCLllA-10146 + CCCGCGCGGCCUGGAAAGAG 20 12082

BCLllA-10147 - AGUCCGCGGAGUCGGGAGAG 20 12083

BCLllA-10148 + ACAGCUCCGCAGCGGGCGAG 20 12084

BCLllA-10149 + GGGAAACUUUGCCCGAGGAG 20 12085

BCLllA-10150 - UGAGUCCGCGGAGUCGGGAG 20 12086

BCLllA-10151 + GGAAAGAGGGGACCGGGGAG 20 12087

BCLllA-10152 - AGCGCGGCGGCGGCGGGGAG 20 12088

BCLllA-10153 + CUGGCGGGGCGGGGGGGGAG 20 12089

BCLllA-10154 + CCCCAUU UUCUUACGGUGAG 20 12090

BCLllA-10155 + GGAGGGAGCGCACGGCAACG 20 12091

BCLllA-9741 + CCUGCUCCCCCCCACACACG 20 12092

BCLllA-10156 - CGGCCCCUGGCGUCCACACG 20 12093

BCLllA-10157 - ACCGGGAAGGACGGGAGACG 20 12094

BCLllA-10158 - GGAGAGGGGCCGCGGCGACG 20 12095

BCLllA-10159 + GGCCUGGAAAGAGGGGACCG 20 12096

BCLllA-10160 - GCCCGCGCUUCCCCAGCCCG 20 12097

BCLllA-10161 + AAGUAAAAGCCCCGAGCCCG 20 12098

BCLllA-10162 + GCGGCGCAGGCCGGGGCCCG 20 12099

BCLllA-10163 + CGCUCGGGAAACUUUGCCCG 20 12100

BCLllA-10164 - AGUCUAAAAAACGAUUCCCG 20 12101

BCLllA-10165 - AAGUUUCCCGAGCGCAGCCG 20 12102

BCLllA-10166 - CGCGGCGACGGGGAGAGCCG 20 12103

BCLllA-10167 + CCGCGGACUCAGGAGCGCCG 20 12104

BCLllA-10168 + CACGGCUCUCCCCGUCGCCG 20 12105

BCLllA-10169 + GAGGCAGGCGGCGCAGGCCG 20 12106

BCLllA-10170 - CGGAGUCGGGAGAGGGGCCG 20 12107

BCLllA-10171 + CGGCCCCUCUCCCGACUCCG 20 12108

BCLllA-10172 - CCCCGGCGCUCCUGAGUCCG 20 12109

BCLllA-10173 + AGCCCCGGGCUGGGGAAGCG 20 12110

BCLllA-10174 - CCACACGCGGGGAGCGAGCG 20 12111

BCLllA-10175 - GCCCCUGGCGUCCACACGCG 20 12112

BCLllA-10176 + CAAGUCUCCAGGAGCCCGCG 20 12113

BCLllA-10177 - UCCCCUCUU UCCAGGCCGCG 20 12114

BCLllA-10178 + GGCGCGGGAGGGCAAGCGCG 20 12115

BCLllA-10179 - GAGCGAGCGCGGCGGCGGCG 20 12116

BCLllA-10180 + U UACAGCUCCGCAGCGGGCG 20 12117

BCLllA-10181 + UUUGCAAAACUGGCGGGGCG 20 12118

BCLllA-10182 + AUUAUUUUGCAAAACUGGCG 20 12119 BCLllA-10183 - CGAGCGCAGCCGCGGGCUCG 20 12120

BCLllA-10184 + CCUCUGGCCGGAACAAAAGG 20 12121

BCLllA-10185 + G AAA U A A AG CG G CG G A A AG G 20 12122

BCLllA-10186 + GGGGACCGGGGAGAGGCAGG 20 12123

BCLllA-10187 + GGCGGAAAGGAGGAAAGAGG 20 12124

BCLllA-10188 - CCUUUUGUUCCGGCCAGAGG 20 12125

BCLllA-10189 - AGUGGGUGUGCGUACGGAGG 20 12126

BCLllA-10190 + CCGCAGCGGGCGAGGGGAGG 20 12127

BCLllA-10191 - GGAAGUGGGUGUGCGUACGG 20 12128

BCLllA-10192 + CGCGGACUCAGGAGCGCCGG 20 12129

BCLllA-10193 + CGAAAAGAGAAAUAAAGCGG 20 12130

BCLllA-10194 - CACGCGGGGAGCGAGCGCGG 20 12131

BCLllA-10195 - GCGGGGAGCGAGCGCGGCGG 20 12132

BCLllA-10196 - GGGAGCGAGCGCGGCGGCGG 20 12133

BCLllA-10197 + GGCUGGGGAAGCGCGGGCGG 20 12134

BCLllA-10198 + U UGCAAAACUGGCGGGGCGG 20 12135

BCLllA-10199 - GGGAGCUGGUGGGGAAAGGG 20 12136

BCLllA-10200 - AAGAAAAUGGGGGGGUAGGG 20 12137

BCLllA-10201 + UAGAGCGAGAGUGCACCGGG 20 12138

BCLllA-10202 - ACGGUCAAGUGUGCAGCGGG 20 12139

BCLllA-10203 + CCGGGCUGGGGAAGCGCGGG 20 12140

BCLllA-10204 + UGCAAAACUGGCGGGGCGGG 20 12141

BCLllA-10205 + GCUCCGCAGCGGGCGAGGGG 20 12142

BCLllA-10206 - CGAGCGCGGCGGCGGCGGGG 20 12143

BCLllA-10207 + GCAAAACUGGCGGGGCGGGG 20 12144

BCLllA-10208 + AUUUUGCAAAACUGGCGGGG 20 12145

BCLllA-10209 + CAAAACUGGCGGGGCGGGGG 20 12146

BCLllA-10210 - CUCACAUGCAAACCUGGGGG 20 12147

BCLllA-10211 - CUCACCGUAAGAAAAUGGGG 20 12148

BCLllA-9577 - UAGAGUCCGCGUGUGUGGGG 20 12149

BCLllA-10212 - ACUCACCGUAAGAAAAUGGG 20 12150

BCLllA-10213 + AGCGGGCGAGGGGAGGUGGG 20 12151

BCLllA-9769 - U UAGAGUCCGCGUGUGUGGG 20 12152

BCLllA-10214 - CACUCACCGUAAGAAAAUGG 20 12153

BCLllA-10215 + UCAUUAUUUUGCAAAACUGG 20 12154

BCLllA-10216 - CAACUCACAUGCAAACCUGG 20 12155

BCLllA-10217 - AACCUGGGGGUGGGAGCUGG 20 12156

BCLllA-9578 - U UUAGAGUCCGCGUGUGUGG 20 12157

BCLllA-10218 - GCUGCGGAGCUGUAACU UGG 20 12158

BCLllA-10219 - GGUCCCUGGCUCGGCCU UGG 20 12159

BCLllA-10220 + GGAAUCCAGCCUAAGU UUGG 20 12160

BCLllA-10221 - CCACUCACCGUAAGAAAAUG 20 12161 BCLllA-10222 - AUAGUGAGAAAGUGGCACUG 20 12162

BCLllA-10223 - ACAACUCACAUGCAAACCUG 20 12163

BCLllA-10224 - CCACCUCCCCUCGCCCGCUG 20 12164

BCLllA-10225 + AGCCUAAGUUUGGAGGGCUG 20 12165

BCLllA-10226 + GAGGCUGCAGCCCCGGGCUG 20 12166

BCLllA-10227 + CCGCGCUCGCUCCCCGCGUG 20 12167

BCLllA-10228 - CCUGGGGGUGGGAGCUGGUG 20 12168

BCLllA-9581 - CAU UUUAGAGUCCGCGUGUG 20 12169

BCLllA-9776 - UUUUAGAGUCCGCGUGUGUG 20 12170

BCLllA-10229 + GCCACU UUCUCACUAUUGUG 20 12171

BCLllA-10230 + GUGCCACU UUCUCACUAUUG 20 12172

BCLllA-10231 - CGGUCCCUGGCUCGGCCUUG 20 12173

BCLllA-10232 - CCCACUCACCGUAAGAAAAU 20 12174

BCLllA-10233 - CCCGCUGCGGAGCUGUAACU 20 12175

BCLllA-10234 - CGCGCGGGCUCCUGGAGACU 20 12176

BCLllA-10235 - AACAACUCACAUGCAAACCU 20 12177

BCLllA-10236 - CUCGGCCUUGGGGGCGCCCU 20 12178

BCLllA-10237 - CCCGGUCCCUGGCUCGGCCU 20 12179

BCLllA-10238 - U UUCUUUGCUGUCCUCUCCU 20 12180

BCLllA-10239 + CCCGAGCCCGCGGCUGCGCU 20 12181

BCLllA-10240 + GGAGGCUGCAGCCCCGGGCU 20 12182

BCLllA-10241 - CCCGAGCGCAGCCGCGGGCU 20 12183

BCLllA-10242 - CGGCGGCGGGGAGGGGAAGU 20 12184

BCLllA-10243 - CGCUCCUGAGUCCGCGGAGU 20 12185

BCLllA-10244 + CCCAUU UUCUUACGGUGAGU 20 12186

BCLllA-10245 - GCGGCGACGGGGAGAGCCGU 20 12187

BCLllA-10246 - CUU UUGUUCCGGCCAGAGGU 20 12188

BCLllA-10247 + CGCAGCGGGCGAGGGGAGGU 20 12189

BCLllA-10248 - CCGUAAGAAAAUGGGGGGGU 20 12190

BCLllA-10249 - UCACAUGCAAACCUGGGGGU 20 12191

BCLllA-10250 - ACCUGGGGGUGGGAGCUGGU 20 12192

BCLllA-9586 - AUUUUAGAGUCCGCGUGUGU 20 12193

BCLllA-10251 + UGCCACUUUCUCACUAU UGU 20 12194

BCLllA-10252 - ACCCGCAGCCCUCCAAACUU 20 12195

BCLllA-10253 - GGAGGCUCAGCUCUCAACUU 20 12196

BCLllA-10254 - GCGCGGGCUCCUGGAGACUU 20 12197

BCLllA-10255 - CGGGCUCGGGGCU UUUACUU 20 12198

BCLllA-10256 - CCGGUCCCUGGCUCGGCCUU 20 12199

BCLllA-10257 + CGCGGAAUCCAGCCUAAGUU 20 12200

BCLllA-10258 - AAAGAGGUGAGACUGGCUUU 20 12201 Table 19A provides exemplary targeting domains for knocking down the BCLl 1 A gene selected according to the first tier parameters. The targeting domains bind within 500 bp (e.g., upstream or downstream) of a transcription start site (TSS) and have a high level of

orthogonality, and the PAM is NNGRRT. It is contemplated herein that in an embodiment the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. aureus eiCas9 molecule or eiCas9 fusion protein (e.g., an eiCas9 fused to a transcription repressor domain) to alter the BCLl 1 A gene (e.g., reduce or eliminate BCLl 1 A gene expression, BCLl 1 A protein function, or the level of BCLl 1 A protein). One or more gRNA may be used to target an eiCas9 to the promoter region of the BCLl 1 A gene.

Table 19A

BCLllA-5352 + AUUCCCGU UUGCUUAAGUGC 20 12226

BCLllA-6267 + AAUUCCCGUUUGCUUAAGUGC 21 12227

BCLllA-6268 + GAAUUCCCGUUUGCUUAAGUGC 22 12228

BCLllA-6269 + AGAAUUCCCGUU UGCUUAAGUGC 23 12229

BCLllA-6270 + GAGAAUUCCCGUUUGCUUAAGUGC 24 12230

BCLllA-10273 + CCUGCGAACUUGAACGUC 18 12231

BCLllA-10274 + CCCUGCGAACUUGAACGUC 19 12232

BCLllA-9570 + UCCCUGCGAACUUGAACGUC 20 12233

BCLllA-10275 + GUCCCUGCGAACUUGAACGUC 21 12234

BCLllA-10276 + CGUCCCUGCGAACU UGAACGUC 22 12235

BCLllA-10277 + ACGUCCCUGCGAACUUGAACGUC 23 12236

BCLllA-10278 + GACGUCCCUGCGAACU UGAACGUC 24 12237

BCLllA-10279 + UACAAAGAUGGCGCAGGGAAG 21 12238

BCLllA-10280 + AUACAAAGAUGGCGCAGGGAAG 22 12239

BCLllA-10281 + AAUACAAAGAUGGCGCAGGGAAG 23 12240

BCLllA-10282 + UAAUACAAAGAUGGCGCAGGGAAG 24 12241

BCLllA-10283 + CGGU UCACAUCGGGAGAG 18 12242

BCLllA-10284 + UCGGUUCACAUCGGGAGAG 19 12243

BCLllA-10285 + CUCGGU UCACAUCGGGAGAG 20 12244

BCLllA-10286 + GCUCGGUUCACAUCGGGAGAG 21 12245

BCLllA-10287 + GGCUCGGU UCACAUCGGGAGAG 22 12246

BCLllA-10288 + CGGCUCGGU UCACAUCGGGAGAG 23 12247

BCLllA-10289 + ACGGCUCGGUUCACAUCGGGAGAG 24 12248

BCLllA-10290 + AAUGGUUCCAGAUGGGAU 18 12249

BCLllA-10291 + CAAUGGUUCCAGAUGGGAU 19 12250

BCLllA-10292 + GCAAUGGUUCCAGAUGGGAU 20 12251

BCLllA-10293 + GGCAAUGGUUCCAGAUGGGAU 21 12252

BCLllA-10294 + CGGCAAUGGUUCCAGAUGGGAU 22 12253

BCLllA-10295 + ACGGCAAUGGUUCCAGAUGGGAU 23 12254

BCLllA-10296 + CACGGCAAUGGUUCCAGAUGGGAU 24 12255

BCLllA-10297 + AACUUGAACGUCAGGAGU 18 12256

BCLllA-10298 + GAACUUGAACGUCAGGAGU 19 12257

BCLllA-10299 + CGAACUUGAACG U CAGG AG U 20 12258

BCLllA-10300 + GCGAACUUGAACGUCAGGAGU 21 12259

BCLllA-10301 + UGCGAACUUGAACGUCAGGAGU 22 12260

BCLllA-10302 + CUGCGAACUUGAACGUCAGGAGU 23 12261

BCLllA-10303 + CCUGCGAACUUGAACGUCAGGAGU 24 12262

BCLllA-6304 - AACCCCAGCACUUAAGCAAAC 21 12263

BCLllA-6305 - AAACCCCAGCACUUAAGCAAAC 22 12264

BCLllA-6306 - CAAACCCCAGCACUUAAGCAAAC 23 12265

BCLllA-6307 - G CAA ACCCCAG CAC U UAAG CAAAC 24 12266

BCLllA-10304 - AAGCAAAAGCGAGGGGGAGAG 21 12267 BCLllA-10305 - GAAGCAAAAGCGAGGGGGAGAG 22 12268

BCLllA-10306 - AGAAGCAAAAGCGAGGGGGAGAG 23 12269

BCLllA-10307 - UAGAAGCAAAAGCGAGGGGGAGAG 24 12270

Table 19B provides exemplary targeting domains for knocking down the BCLl 1 A gene selected according to the second tier parameters. The targeting domains bind within 500 bp (e.g., upstream or downstream) of a transcription start site (TSS), and PAM is NNGRRT. It is contemplated herein that in an embodiment the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. aureus eiCas9 molecule or eiCas9 fusion protein (e.g., an eiCas9 fused to a transcription repressor domain) to alter the BCLl 1 A gene (e.g., reduce or eliminate BCLl 1 A gene expression, BCLl 1A protein function, or the level of BCLl 1A protein). One or more gRNA may be used to target an eiCas9 to the promoter region of the BCLl 1A gene.

Table 19B

BCLllA-10326 + AAAGAUGGCGCAGGGAAG 18 12291

BCLllA-10327 + CAAAGAUGGCGCAGGGAAG 19 12292

BCLllA-10328 + ACAAAGAUGGCGCAGGGAAG 20 12293

BCLllA-6350 - CCCAGCACUUAAGCAAAC 18 12294

BCLllA-6351 - CCCCAGCACUUAAGCAAAC 19 12295

BCLllA-5458 - ACCCCAGCACUUAAGCAAAC 20 12296

BCLllA-10329 - UUCACGAGAAAAACCUCC 18 12297

BCLllA-10330 - U U U CACG AG AAAAACCU CC 19 12298

BCLllA-10331 - UUUUCACGAGAAAAACCUCC 20 12299

BCLllA-10332 - UUUUUCACGAGAAAAACCUCC 21 12300

BCLllA-10333 - AUUUUUCACGAGAAAAACCUCC 22 12301

BCLllA-10334 - AAU U U U U CACG AG AAAAACCU CC 23 12302

BCLllA-10335 - AAAU U U U U CACG AG AAAAACCU CC 24 12303

BCLllA-10336 - UGAUGAAGAUAUUUUCUC 18 12304

BCLllA-10337 - CUGAUGAAGAUAUUUUCUC 19 12305

BCLllA-9731 - ACUGAUGAAGAUAUUUUCUC 20 12306

BCLllA-10338 - CACUGAUGAAGAUAUUUUCUC 21 12307

BCLllA-10339 - GCACUGAUGAAGAUAUUUUCUC 22 12308

BCLllA-10340 - GGCACUGAUGAAGAUAUUUUCUC 23 12309

BCLllA-10341 - AGGCACUGAUGAAGAUAUUUUCUC 24 12310

BCLllA-10342 - CAAAAGCGAGGGGGAGAG 18 12311

BCLllA-10343 - GCAAAAGCGAGGGGGAGAG 19 12312

BCLllA-4583 - AGCAAAAGCGAGGGGGAGAG 20 12313

BCLllA-10344 - UAUUAUUUCUAAUUUAUU 18 12314

BCLllA-10345 - GUAUUAUUUCUAAUU UAUU 19 12315

BCLllA-10346 - UGUAUUAUUUCUAAU UUAUU 20 12316

BCLllA-10347 - U UGUAUUAUUUCUAAU UUAUU 21 12317

BCLllA-10348 - U UUGUAUUAUUUCUAAUUUAUU 22 12318

BCLllA-10349 - CUUUGUAUUAUUUCUAAUUUAUU 23 12319

BCLllA-10350 - UCUUUGUAUUAUUUCUAAUUUAUU 24 12320

BCLllA-10351 - UUGAAUAAUCUUUCAUUU 18 12321

BCLllA-10352 - UUUGAAUAAUCUUUCAUUU 19 12322

BCLllA-10353 - U UUUGAAUAAUCUUUCAUUU 20 12323

BCLllA-10354 - U UUUUGAAUAAUCUUUCAUUU 21 12324

BCLllA-10355 - U UUUUUGAAUAAUCUU UCAUUU 22 12325

BCLllA-10356 - CUU UUUUGAAUAAUCU UUCAUUU 23 12326

BCLllA-10357 - UCU UUUUUGAAUAAUCUUUCAUUU 24 12327

Table 19C provides exemplary targeting domains for knocking down the BCLllA gene selected according to the third tier parameters. The targeting domains bind within 500 bp (e.g., upstream or downstream) of a transcription start site (TSS), and the PAM is NNGRRV. It is contemplated herein that in an embodiment the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. aureus eiCas9 molecule or eiCas9 fusion protein (e.g., an eiCas9 fused to a transcription repressor domain) to alter the BCLl 1 A gene (e.g., reduce or eliminate BCLl 1 A gene expression, BCLl 1A protein function, or the level of BCLl 1A protein). One or more gRNA may be used

Table 19C

BCLllA-4422 + GCAGGGCGAGCAGGAGAGAA 20 12358

BCLllA-10386 + GGCAGGGCGAGCAGGAGAGAA 21 12359

BCLllA-10387 + GGGCAGGGCGAGCAGGAGAGAA 22 12360

BCLllA-10388 + UGGGCAGGGCGAGCAGGAGAGAA 23 12361

BCLllA-10389 + AUGGGCAGGGCGAGCAGGAGAGAA 24 12362

BCLllA-10390 + GAGAAGGGGAGGAGGGAA 18 12363

BCLllA-10391 + AGAGAAGGGGAGGAGGGAA 19 12364

BCLllA-4404 + GAGAGAAGGGGAGGAGGGAA 20 12365

BCLllA-10392 + GGAGAGAAGGGGAGGAGGGAA 21 12366

BCLllA-10393 + AGGAGAGAAGGGGAGGAGGGAA 22 12367

BCLllA-10394 + CAGGAGAGAAGGGGAGGAGGGAA 23 12368

BCLllA-10395 + GCAGGAGAGAAGGGGAGGAGGGAA 24 12369

BCLllA-10396 + ACGACGGCUCGGUUCACA 18 12370

BCLllA-10397 + GACGACGGCUCGGUUCACA 19 12371

BCLllA-10398 + GGACGACGGCUCGGUUCACA 20 12372

BCLllA-10399 + CGGACGACGGCUCGGUUCACA 21 12373

BCLllA-10400 + GCGGACGACGGCUCGGUUCACA 22 12374

BCLllA-10401 + GGCGGACGACGGCUCGGUUCACA 23 12375

BCLllA-10402 + GGGCGGACGACGGCUCGGUUCACA 24 12376

BCLllA-10403 + AAGGGGAAGCUCACACCA 18 12377

BCLllA-10404 + GAAGGGGAAGCUCACACCA 19 12378

BCLllA-10405 + GGAAGGGGAAGCUCACACCA 20 12379

BCLllA-10406 + GGGAAGGGGAAGCUCACACCA 21 12380

BCLllA-10407 + AGGGAAGGGGAAGCUCACACCA 22 12381

BCLllA-10408 + GAGGGAAGGGGAAGCUCACACCA 23 12382

BCLllA-10409 + GGAGGGAAGGGGAAGCUCACACCA 24 12383

BCLllA-10410 + AGAAAGAAGGAGACUCCA 18 12384

BCLllA-10411 + UAGAAAGAAGGAGACUCCA 19 12385

BCLllA-10412 + U UAGAAAGAAGGAGACUCCA 20 12386

BCLllA-10413 + G U U AG AAAG AAGG AG ACU CCA 21 12387

BCLllA-10414 + GGUUAGAAAGAAGGAGACUCCA 22 12388

BCLllA-10415 + GGGUUAGAAAGAAGGAGACUCCA 23 12389

BCLllA-10416 + CGGGUUAGAAAGAAGGAGACUCCA 24 12390

BCLllA-10417 + GGCUCACCAGUGGCCGCA 18 12391

BCLllA-10418 + GGGCUCACCAGUGGCCGCA 19 12392

BCLllA-10419 + CGGGCUCACCAGUGGCCGCA 20 12393

BCLllA-10420 + GCGGGCUCACCAGUGGCCGCA 21 12394

BCLllA-10421 + CGCGGGCUCACCAGUGGCCGCA 22 12395

BCLllA-10422 + CCGCGGGCUCACCAGUGGCCGCA 23 12396

BCLllA-10423 + GCCGCGGGCUCACCAGUGGCCGCA 24 12397

BCLllA-10424 + UAAUACAAAGAUGGCGCA 18 12398

BCLllA-10425 + AUAAUACAAAGAUGGCGCA 19 12399 BCLllA-9702 + AAUAAUACAAAGAUGGCGCA 20 12400

BCLllA-10426 + A A A U A A U AC A A AG A U G G CG C A 21 12401

BCLllA-10427 + GAAAUAAUACAAAGAUGGCGCA 22 12402

BCLllA-10428 + AG AAA U A A U AC A A AG A U G G CG C A 23 12403

BCLllA-10429 + UAGAAAUAAUACAAAGAUGGCGCA 24 12404

BCLllA-10430 + AAAAAAAAAAAAAAAAGA 18 12405

BCLllA-10431 + AAAAAAAAAAAAAAAAAGA 19 12406

BCLllA-4527 + A A A A A A A A A A A A AAA A AAG A 20 12407

BCLllA-10432 + AAAAAAAAAAAAAAAAAAAGA 21 12408

BCLllA-10433 + A A A A A A A A A A A A A A A A AAA AG A 22 12409

BCLllA-10434 + A A A A A A A A A A A A A A A A AAA A AG A 23 12410

BCLllA-10435 + AAAAAAAAAAAAAAAAAAAAAAGA 24 12411

BCLllA-10436 + AGAGCCGGGUUAGAAAGA 18 12412

BCLllA-10437 + GAGAGCCGGGUUAGAAAGA 19 12413

BCLllA-9708 + GGAGAGCCGGGUUAGAAAGA 20 12414

BCLllA-10438 + GGGAGAGCCGGGUUAGAAAGA 21 12415

BCLllA-10439 + CGGGAGAGCCGGGUUAGAAAGA 22 12416

BCLllA-10440 + U CGGG AG AG CCGGGU U AG AAAG A 23 12417

BCLllA-10441 + AUCGGGAGAGCCGGGU UAGAAAGA 24 12418

BCLllA-10442 + CGUGGCCGGGAGAGAAGA 18 12419

BCLllA-10443 + GCGUGGCCGGGAGAGAAGA 19 12420

BCLllA-10444 + GGCGUGGCCGGGAGAGAAGA 20 12421

BCLllA-10445 + UGGCGUGGCCGGGAGAGAAGA 21 12422

BCLllA-10446 + GUGGCGUGGCCGGGAGAGAAGA 22 12423

BCLllA-10447 + GGUGGCGUGGCCGGGAGAGAAGA 23 12424

BCLllA-10448 + CGGUGGCGUGGCCGGGAGAGAAGA 24 12425

BCLllA-10449 + AGAGAGAGAGAAGAGAGA 18 12426

BCLllA-10450 + GAGAGAGAGAGAAGAGAGA 19 12427

BCLllA-4845 + GGAGAGAGAGAGAAGAGAGA 20 12428

BCLllA-10451 + GGGAGAGAGAGAGAAGAGAGA 21 12429

BCLllA-10452 + AGGGAGAGAGAGAGAAGAGAGA 22 12430

BCLllA-10453 + GAGGGAGAGAGAGAGAAGAGAGA 23 12431

BCLllA-10454 + AGAGGGAGAGAGAGAGAAGAGAGA 24 12432

BCLllA-10455 + UAGAGGGAGAGAGAGAGA 18 12433

BCLllA-10456 + AUAGAGGGAGAGAGAGAGA 19 12434

BCLllA-10457 + GAUAGAGGGAGAGAGAGAGA 20 12435

BCLllA-10458 + AGAUAGAGGGAGAGAGAGAGA 21 12436

BCLllA-10459 + GAGAUAGAGGGAGAGAGAGAGA 22 12437

BCLllA-10460 + AGAGAUAGAGGGAGAGAGAGAGA 23 12438

BCLllA-10461 + GAGAGAUAGAGGGAGAGAGAGAGA 24 12439

BCLllA-10462 + GAUAGAGGGAGAGAGAGA 18 12440

BCLllA-10463 + AGAUAGAGGGAGAGAGAGA 19 12441 BCLllA-10464 + GAGAUAGAGGGAGAGAGAGA 20 12442

BCLllA-10465 + AGAGAUAGAGGGAGAGAGAGA 21 12443

BCLllA-10466 + GAGAGAUAGAGGGAGAGAGAGA 22 12444

BCLllA-10467 + AGAGAGAUAGAGGGAGAGAGAGA 23 12445

BCLllA-10468 + AAGAGAGAUAGAGGGAGAGAGAGA 24 12446

BCLllA-10469 + AAAAAAGAGGGAGAGAGA 18 12447

BCLllA-10470 + AAAAAAAGAGGGAGAGAGA 19 12448

BCLllA-4911 + AAAAAAAAGAGGGAGAGAGA 20 12449

BCLllA-10471 + A A A A A A A A AG AGGGAGAGAGA 21 12450

BCLllA-10472 + AAAAAAAAAAGAGGGAGAGAGA 22 12451

BCLllA-10473 + AAAAAAAAAAAGAGGGAGAGAGA 23 12452

BCLllA-10474 + A A A A A A AAA A AAG AGGGAGAGAGA 24 12453

BCLllA-10475 + GAGAUAGAGGGAGAGAGA 18 12454

BCLllA-10476 + AGAGAUAGAGGGAGAGAGA 19 12455

BCLllA-10477 + GAGAGAUAGAGGGAGAGAGA 20 12456

BCLllA-10478 + AGAGAGAUAGAGGGAGAGAGA 21 12457

BCLllA-10479 + AAGAGAGAUAGAGGGAGAGAGA 22 12458

BCLllA-10480 + GAAGAGAGAUAGAGGGAGAGAGA 23 12459

BCLllA-10481 + AGAAGAGAGAUAGAGGGAGAGAGA 24 12460

BCLllA-10482 + CAGGGCGAGCAGGAGAGA 18 12461

BCLllA-10483 + GCAGGGCGAGCAGGAGAGA 19 12462

BCLllA-4464 + GGCAGGGCGAGCAGGAGAGA 20 12463

BCLllA-10484 + GGGCAGGGCGAGCAGGAGAGA 21 12464

BCLllA-10485 + UGGGCAGGGCGAGCAGGAGAGA 22 12465

BCLllA-10486 + AUGGGCAGGGCGAGCAGGAGAGA 23 12466

BCLllA-10487 + CAUGGGCAGGGCGAGCAGGAGAGA 24 12467

BCLllA-10488 + AAAAAAAAGAGGGAGAGA 18 12468

BCLllA-10489 + A A A A A A A A AG AGGGAGAGA 19 12469

BCLllA-4909 + AAAAAAAAAAGAGGGAGAGA 20 12470

BCLllA-10490 + A A A A A A A A A A AG AG G G AG AG A 21 12471

BCLllA-10491 + A A A A A A A A A A AAG AGGGAGAGA 22 12472

BCLllA-10492 + A A A A A A A A A AAA AG AGGGAGAGA 23 12473

BCLllA-10493 + AAAAAAAAAAAAAAGAGGGAGAGA 24 12474

BCLllA-10494 + GAGAGAUAGAGGGAGAGA 18 12475

BCLllA-10495 + AGAGAGAUAGAGGGAGAGA 19 12476

BCLllA-10496 + AAGAGAGAUAGAGGGAGAGA 20 12477

BCLllA-10497 + GAAGAGAGAUAGAGGGAGAGA 21 12478

BCLllA-10498 + AGAAGAGAGAUAGAGGGAGAGA 22 12479

BCLllA-10499 + GAGAAGAGAGAUAGAGGGAGAGA 23 12480

BCLllA-10500 + AGAGAAGAGAGAUAGAGGGAGAGA 24 12481

BCLllA-10501 + AAAAAAAAAAGAGGGAGA 18 12482

BCLllA-10502 + AAAAAAAAAAAGAGGGAGA 19 12483 BCLllA-4907 + AAAAAAAAAAAAGAGGGAGA 20 12484

BCLllA-10503 + A A A A A A A A A AAA AG AG G G AG A 21 12485

BCLllA-10504 + AAAAAAAAAAAAAAGAGGGAGA 22 12486

BCLllA-10505 + A A A A A A A A A A AAA A AG AG G G AG A 23 12487

BCLllA-10506 + AAAAAAAAAAAAAAAAGAGGGAGA 24 12488

BCLllA-10507 + AAGAGAGAUAGAGGGAGA 18 12489

BCLllA-10508 + GAAGAGAGAUAGAGGGAGA 19 12490

BCLllA-10509 + AGAAGAGAGAUAGAGGGAGA 20 12491

BCLllA-10510 + GAGAAGAGAGAUAGAGGGAGA 21 12492

BCLllA-10511 + AGAGAAGAGAGAUAGAGGGAGA 22 12493

BCLllA-10512 + GAGAGAAGAGAGAUAGAGGGAGA 23 12494

BCLllA-10513 + AGAGAGAAGAGAGAUAGAGGGAGA 24 12495

BCLllA-10514 + AGAGAGAAGAGAGAUAGA 18 12496

BCLllA-10515 + GAGAGAGAAGAGAGAUAGA 19 12497

BCLllA-9709 + AGAGAGAGAAGAGAGAUAGA 20 12498

BCLllA-10516 + GAGAGAGAGAAGAGAGAUAGA 21 12499

BCLllA-10517 + AGAGAGAGAGAAGAGAGAUAGA 22 12500

BCLllA-10518 + GAGAGAGAGAGAAGAGAGAUAGA 23 12501

BCLllA-10519 + GGAGAGAGAGAGAAGAGAGAUAGA 24 12502

BCLllA-10520 + CGGGAGAGCCGGGUUAGA 18 12503

BCLllA-10521 + UCGGGAGAGCCGGGUUAGA 19 12504

BCLllA-10522 + AUCGGGAGAGCCGGGUUAGA 20 12505

BCLllA-10523 + CAUCGGGAGAGCCGGGUUAGA 21 12506

BCLllA-10524 + ACAUCGGGAGAGCCGGGUUAGA 22 12507

BCLllA-10525 + CACAUCGGGAGAGCCGGGUUAGA 23 12508

BCLllA-10526 + UCACAUCGGGAGAGCCGGGUUAGA 24 12509

BCLllA-10527 + GGGGGAGGGGCGGGCCGA 18 12510

BCLllA-10528 + CGGGGGAGGGGCGGGCCGA 19 12511

BCLllA-4648 + CCGGGGGAGGGGCGGGCCGA 20 12512

BCLllA-10529 + CCCGGGGGAGGGGCGGGCCGA 21 12513

BCLllA-10530 + CCCCGGGGGAGGGGCGGGCCGA 22 12514

BCLllA-10531 + CCCCCGGGGGAGGGGCGGGCCGA 23 12515

BCLllA-10532 + GCCCCCGGGGGAGGGGCGGGCCGA 24 12516

BCLllA-10533 + UGGGCAGGGCGAGCAGGA 18 12517

BCLllA-10534 + AUGGGCAGGGCGAGCAGGA 19 12518

BCLllA-10535 + CAUGGGCAGGGCGAGCAGGA 20 12519

BCLllA-10536 + ACAUGGGCAGGGCGAGCAGGA 21 12520

BCLllA-10537 + AACAUGGGCAGGGCGAGCAGGA 22 12521

BCLllA-10538 + AAACAUGGGCAGGGCGAGCAGGA 23 12522

BCLllA-10539 + AAAACAUGGGCAGGGCGAGCAGGA 24 12523

BCLllA-10540 + CAGGAGAGAAGGGGAGGA 18 12524

BCLllA-10541 + GCAGGAGAGAAGGGGAGGA 19 12525 BCLllA-4584 + AGCAGGAGAGAAGGGGAGGA 20 12526

BCLllA-10542 + GAGCAGGAGAGAAGGGGAGGA 21 12527

BCLllA-10543 + CGAGCAGGAGAGAAGGGGAGGA 22 12528

BCLllA-10544 + GCGAGCAGGAGAGAAGGGGAGGA 23 12529

BCLllA-10545 + GGCGAGCAGGAGAGAAGGGGAGGA 24 12530

BCLllA-10546 + A A A A A A A A A A A AG AG G G A 18 12531

BCLllA-10547 + AAAAAAAAAAAAAGAGGGA 19 12532

BCLllA-4905 + A A A A A A A A A A AAA AG AG G G A 20 12533

BCLllA-10548 + AAAAAAAAAAAAAAAGAGGGA 21 12534

BCLllA-10549 + A A A A A A A A A A AAA A A AG AG G G A 22 12535

BCLllA-10550 + AAAAAAAAAAAAAAAAAGAGGGA 23 12536

BCLllA-10551 + A A A A A A A A A A AAA A A A A AG AG G G A 24 12537

BCLllA-10552 + AGAAGAGAGAUAGAGGGA 18 12538

BCLllA-10553 + GAGAAGAGAGAUAGAGGGA 19 12539

BCLllA-10554 + AGAGAAGAGAGAUAGAGGGA 20 12540

BCLllA-10555 + GAGAGAAGAGAGAUAGAGGGA 21 12541

BCLllA-10556 + AGAGAGAAGAGAGAUAGAGGGA 22 12542

BCLllA-10557 + GAGAGAGAAGAGAGAUAGAGGGA 23 12543

BCLllA-10558 + AGAGAGAGAAGAGAGAUAGAGGGA 24 12544

BCLllA-10559 + AGAGAAGGGGAGGAGGGA 18 12545

BCLllA-10560 + GAGAGAAGGGGAGGAGGGA 19 12546

BCLllA-4459 + GGAGAGAAGGGGAGGAGGGA 20 12547

BCLllA-10561 + AGGAGAGAAGGGGAGGAGGGA 21 12548

BCLllA-10562 + CAGGAGAGAAGGGGAGGAGGGA 22 12549

BCLllA-10563 + GCAGGAGAGAAGGGGAGGAGGGA 23 12550

BCLllA-10564 + AGCAGGAGAGAAGGGGAGGAGGGA 24 12551

BCLllA-10565 + GCGGUGGCGUGGCCGGGA 18 12552

BCLllA-10566 + GGCGGUGGCGUGGCCGGGA 19 12553

BCLllA-10567 + CGGCGGUGGCGUGGCCGGGA 20 12554

BCLllA-10568 + GCGGCGGUGGCGUGGCCGGGA 21 12555

BCLllA-10569 + CGCGGCGGUGGCGUGGCCGGGA 22 12556

BCLllA-10570 + CCGCGGCGGUGGCGUGGCCGGGA 23 12557

BCLllA-10571 + GCCGCGGCGGUGGCGUGGCCGGGA 24 12558

BCLllA-10572 + AGGGGCGGGCCGAGGGGA 18 12559

BCLllA-10573 + GAGGGGCGGGCCGAGGGGA 19 12560

BCLllA-4461 + GGAGGGGCGGGCCGAGGGGA 20 12561

BCLllA-10574 + GGGAGGGGCGGGCCGAGGGGA 21 12562

BCLllA-10575 + GGGGAGGGGCGGGCCGAGGGGA 22 12563

BCLllA-10576 + GGGGGAGGGGCGGGCCGAGGGGA 23 12564

BCLllA-10577 + CGGGGGAGGGGCGGGCCGAGGGGA 24 12565

BCLllA-10578 + CAAUGGCCAGUGCGGGGA 18 12566

BCLllA-10579 + CCAAUGGCCAGUGCGGGGA 19 12567 BCLllA-9558 + GCCAAUGGCCAGUGCGGGGA 20 12568

BCLllA-10580 + AGCCAAUGGCCAGUGCGGGGA 21 12569

BCLllA-10581 + AAGCCAAUGGCCAGUGCGGGGA 22 12570

BCLllA-10582 + CAAGCCAAUGGCCAGUGCGGGGA 23 12571

BCLllA-10583 + ACAAGCCAAUGGCCAGUGCGGGGA 24 12572

BCLllA-10584 + GUCAGGAGUCUGGAUGGA 18 12573

BCLllA-10585 + CGUCAGGAGUCUGGAUGGA 19 12574

BCLllA-10586 + ACGUCAGGAGUCUGGAUGGA 20 12575

BCLllA-10587 + AACGUCAGGAGUCUGGAUGGA 21 12576

BCLllA-10588 + GAACGUCAGGAGUCUGGAUGGA 22 12577

BCLllA-10589 + UGAACGUCAGGAGUCUGGAUGGA 23 12578

BCLllA-10590 + UUGAACGUCAGGAGUCUGGAUGGA 24 12579

BCLllA-10591 + AGAGAGAGAAGAGAGAUA 18 12580

BCLllA-10592 + GAGAGAGAGAAGAGAGAUA 19 12581

BCLllA-10593 + AGAGAGAGAGAAGAGAGAUA 20 12582

BCLllA-10594 + GAGAGAGAGAGAAGAGAGAUA 21 12583

BCLllA-10595 + GGAGAGAGAGAGAAGAGAGAUA 22 12584

BCLllA-10596 + GGGAGAGAGAGAGAAGAGAGAUA 23 12585

BCLllA-10597 + AGGGAGAGAGAGAGAAGAGAGAUA 24 12586

BCLllA-10598 + GACAGAGACACACAAAAC 18 12587

BCLllA-10599 + GGACAGAGACACACAAAAC 19 12588

BCLllA-10600 + UGGACAGAGACACACAAAAC 20 12589

BCLllA-10601 + AUGGACAGAGACACACAAAAC 21 12590

BCLllA-10602 + GAUGGACAGAGACACACAAAAC 22 12591

BCLllA-10603 + GGAUGGACAGAGACACACAAAAC 23 12592

BCLllA-10604 + UGGAUGGACAGAGACACACAAAAC 24 12593

BCLllA-10605 + CGUGACGUCCCUGCGAAC 18 12594

BCLllA-10606 + ACGUGACGUCCCUGCGAAC 19 12595

BCLllA-10607 + GACGUGACGUCCCUGCGAAC 20 12596

BCLllA-10608 + GGACGUGACGUCCCUGCGAAC 21 12597

BCLllA-10609 + CGGACGUGACGUCCCUGCGAAC 22 12598

BCLllA-10610 + GCGGACGUGACGUCCCUGCGAAC 23 12599

BCLllA-10611 + UGCGGACGUGACGUCCCUGCGAAC 24 12600

BCLllA-10612 + CUGCUCCCCCCCACACAC 18 12601

BCLllA-10613 + CCUGCUCCCCCCCACACAC 19 12602

BCLllA-10614 + CCCUGCUCCCCCCCACACAC 20 12603

BCLllA-10615 + GCCCUGCUCCCCCCCACACAC 21 12604

BCLllA-10616 + CGCCCUGCUCCCCCCCACACAC 22 12605

BCLllA-10617 + GCGCCCUGCUCCCCCCCACACAC 23 12606

BCLllA-10618 + UGCGCCCUGCUCCCCCCCACACAC 24 12607

BCLllA-10619 + UGGACAUGAAAAAGAGAC 18 12608

BCLllA-10620 + CUGGACAUGAAAAAGAGAC 19 12609 BCLllA-10621 + GCUGGACAUGAAAAAGAGAC 20 12610

BCLllA-10622 + GGCUGGACAUGAAAAAGAGAC 21 12611

BCLllA-10623 + GGGCUGGACAUGAAAAAGAGAC 22 12612

BCLllA-10624 + GGGGCUGGACAUGAAAAAGAGAC 23 12613

BCLllA-10625 + AGGGGCUGGACAUGAAAAAGAGAC 24 12614

BCLllA-10626 + ACACAUCAGGGGCUGGAC 18 12615

BCLllA-10627 + CACACAUCAGGGGCUGGAC 19 12616

BCLllA-10628 + ACACACAUCAGGGGCUGGAC 20 12617

BCLllA-10629 + GACACACAUCAGGGGCUGGAC 21 12618

BCLllA-10630 + GGACACACAUCAGGGGCUGGAC 22 12619

BCLllA-10631 + UGGACACACAUCAGGGGCUGGAC 23 12620

BCLllA-10632 + AUGGACACACAUCAGGGGCUGGAC 24 12621

BCLllA-6411 + UAUUAUUGGGUUACUUAC 18 12622

BCLllA-6412 + CUAUUAUUGGGUUACUUAC 19 12623

BCLllA-6413 + ACUAUUAUUGGGUUACUUAC 20 12624

BCLllA-6414 + UACUAUUAUUGGGU UACUUAC 21 12625

BCLllA-6415 + U UACUAUUAUUGGGUUACUUAC 22 12626

BCLllA-6416 + AUUACUAUUAUUGGGUUACUUAC 23 12627

BCLllA-6417 + UAUUACUAUUAUUGGGUUACUUAC 24 12628

BCLllA-10633 + A A A A U G G C A A A AG C CC C C 18 12629

BCLllA-10634 + A A A A A U G G C A A A AG C CC C C 19 12630

BCLllA-10635 + AAAAAAUGGCAAAAGCCCCC 20 12631

BCLllA-10636 + AAAAAAAUGGCAAAAGCCCCC 21 12632

BCLllA-10637 + GAAAAAAAUGGCAAAAGCCCCC 22 12633

BCLllA-10638 + UGAAAAAAAUGGCAAAAGCCCCC 23 12634

BCLllA-10639 + AUGAAAAAAAUGGCAAAAGCCCCC 24 12635

BCLllA-10640 + ACGCCAGACGCGGCCCCC 18 12636

BCLllA-10641 + GACGCCAGACGCGGCCCCC 19 12637

BCLllA-4456 + GGACGCCAGACGCGGCCCCC 20 12638

BCLllA-10642 + CGGACGCCAGACGCGGCCCCC 21 12639

BCLllA-10643 + GCGGACGCCAGACGCGGCCCCC 22 12640

BCLllA-10644 + CGCGGACGCCAGACGCGGCCCCC 23 12641

BCLllA-10645 + CCGCGGACGCCAGACGCGGCCCCC 24 12642

BCLllA-10646 + GACGCCAGACGCGGCCCC 18 12643

BCLllA-10647 + GGACGCCAGACGCGGCCCC 19 12644

BCLllA-4362 + CGGACGCCAGACGCGGCCCC 20 12645

BCLllA-10648 + GCGGACGCCAGACGCGGCCCC 21 12646

BCLllA-10649 + CGCGGACGCCAGACGCGGCCCC 22 12647

BCLllA-10650 + CCGCGGACGCCAGACGCGGCCCC 23 12648

BCLllA-10651 + UCCGCGGACGCCAGACGCGGCCCC 24 12649

BCLllA-10652 + GGACGCCAGACGCGGCCC 18 12650

BCLllA-10653 + CGGACGCCAGACGCGGCCC 19 12651 BCLllA-4825 + GCGGACGCCAGACGCGGCCC 20 12652

BCLllA-10654 + CG CGGACG CCAGACG CGGCCC 21 12653

BCLllA-10655 + CCGCGGACGCCAGACGCGGCCC 22 12654

BCLllA-10656 + UCCGCGGACGCCAGACGCGGCCC 23 12655

BCLllA-10657 + CUCCGCGGACGCCAGACGCGGCCC 24 12656

BCLllA-10658 + CCGGGGGAGGGGCGGGCC 18 12657

BCLllA-10659 + CCCGGGGGAGGGGCGGGCC 19 12658

BCLllA-5064 + CCCCGGGGGAGGGGCGGGCC 20 12659

BCLllA-10660 + CCCCCGGGGGAGGGGCGGGCC 21 12660

BCLllA-10661 + GCCCCCGGGGGAGGGGCGGGCC 22 12661

BCLllA-10662 + GGCCCCCGGGGGAGGGGCGGGCC 23 12662

BCLllA-10663 + CGGCCCCCGGGGGAGGGGCGGGCC 24 12663

BCLllA-10664 + GGAGGGGGCGCUGGGGCC 18 12664

BCLllA-10665 + GGGAGGGGGCGCUGGGGCC 19 12665

BCLllA-10666 + GGGGAGGGGGCGCUGGGGCC 20 12666

BCLllA-10667 + AGGGGAGGGGGCGCUGGGGCC 21 12667

BCLllA-10668 + GAGGGGAGGGGGCGCUGGGGCC 22 12668

BCLllA-10669 + CGAGGGGAGGGGGCGCUGGGGCC 23 12669

BCLllA-10670 + CCGAGGGGAGGGGGCGCUGGGGCC 24 12670

BCLllA-10671 + CGCGGCGGUGGCGUGGCC 18 12671

BCLllA-10672 + CCGCGGCGGUGGCGUGGCC 19 12672

BCLllA-9718 + GCCGCGGCGGUGGCGUGGCC 20 12673

BCLllA-10673 + CGCCGCGGCGGUGGCGUGGCC 21 12674

BCLllA-10674 + GCGCCGCGGCGGUGGCGUGGCC 22 12675

BCLllA-10675 + AGCGCCGCGGCGGUGGCGUGGCC 23 12676

BCLllA-10676 + GAGCGCCGCGGCGGUGGCGUGGCC 24 12677

BCLllA-10677 + UGCGGGGCGGGGGGCUCC 18 12678

BCLllA-10678 + GUGCGGGGCGGGGGGCUCC 19 12679

BCLllA-10679 + GGUGCGGGGCGGGGGGCUCC 20 12680

BCLllA-10680 + AGGUGCGGGGCGGGGGGCUCC 21 12681

BCLllA-10681 + GAGGUGCGGGGCGGGGGGCUCC 22 12682

BCLllA-10682 + GGAGGUGCGGGGCGGGGGGCUCC 23 12683

BCLllA-10683 + GGGAGGUGCGGGGCGGGGGGCUCC 24 12684

BCLllA-10684 + AACAUGGGCAGGGCGAGC 18 12685

BCLllA-10685 + AAACAUGGGCAGGGCGAGC 19 12686

BCLllA-9721 + AAAACAUGGGCAGGGCGAGC 20 12687

BCLllA-10686 + CAAAACAUGGGCAGGGCGAGC 21 12688

BCLllA-10687 + ACAAAACAUGGGCAGGGCGAGC 22 12689

BCLllA-10688 + CA CAAAACAUGGGCAGGGCGAGC 23 12690

BCLllA-10689 + ACACAAAACAUGGGCAGGGCGAGC 24 12691

BCLllA-10690 + GCCGAGGGGAGGGGGCGC 18 12692

BCLllA-10691 + GGCCGAGGGGAGGGGGCGC 19 12693 BCLllA-4490 + GGGCCGAGGGGAGGGGGCGC 20 12694

BCLllA-10692 + CGGGCCGAGGGGAGGGGGCGC 21 12695

BCLllA-10693 + GCGGGCCGAGGGGAGGGGGCGC 22 12696

BCLllA-10694 + GGCGGGCCGAGGGGAGGGGGCGC 23 12697

BCLllA-10695 + GGGCGGGCCGAGGGGAGGGGGCGC 24 12698

BCLllA-10696 + AUAAUACAAAGAUGGCGC 18 12699

BCLllA-10697 + AAUAAUACAAAGAUGGCGC 19 12700

BCLllA-9565 + AAAUAAUACAAAGAUGGCGC 20 12701

BCLllA-10698 + GAAAUAAUACAAAGAUGGCGC 21 12702

BCLllA-10699 + AGAAAUAAUACAAAGAUGGCGC 22 12703

BCLllA-10700 + UAGAAAUAAUACAAAGAUGGCGC 23 12704

BCLllA-10701 + U UAGAAAUAAUACAAAGAUGGCGC 24 12705

BCLllA-10702 + GAGGGGGAGGUGCGGGGC 18 12706

BCLllA-10703 + GGAGGGGGAGGUGCGGGGC 19 12707

BCLllA-9724 + GGGAGGGGGAGGUGCGGGGC 20 12708

BCLllA-10704 + GGGGAGGGGGAGGUGCGGGGC 21 12709

BCLllA-10705 + CGGGGAGGGGGAGGUGCGGGGC 22 12710

BCLllA-10706 + GCGGGGAGGGGGAGGUGCGGGGC 23 12711

BCLllA-10707 + UGCGGGGAGGGGGAGGUGCGGGGC 24 12712

BCLllA-10708 + CCGCGGCGGUGGCGUGGC 18 12713

BCLllA-10709 + GCCGCGGCGGUGGCGUGGC 19 12714

BCLllA-9725 + CGCCGCGGCGGUGGCGUGGC 20 12715

BCLllA-10710 + GCGCCGCGGCGGUGGCGUGGC 21 12716

BCLllA-10711 + AGCGCCGCGGCGGUGGCGUGGC 22 12717

BCLllA-10712 + GAGCGCCGCGGCGGUGGCGUGGC 23 12718

BCLllA-10713 + CGAGCGCCGCGGCGGUGGCGUGGC 24 12719

BCLllA-10714 + CAAGCCAAUGGCCAGUGC 18 12720

BCLllA-10715 + ACAAGCCAAUGGCCAGUGC 19 12721

BCLllA-9727 + GACAAGCCAAUGGCCAGUGC 20 12722

BCLllA-10716 + GGACAAGCCAAUGGCCAGUGC 21 12723

BCLllA-10717 + AGGACAAGCCAAUGGCCAGUGC 22 12724

BCLllA-10718 + CAGGACAAGCCAAUGGCCAGUGC 23 12725

BCLllA-10719 + C C AG G AC A AG CCAAUGGCCAGUGC 24 12726

BCLllA-10720 + CACCAAUGGACACACAUC 18 12727

BCLllA-10721 + ACACCAAUGGACACACAUC 19 12728

BCLllA-9729 + CACACCAAUGGACACACAUC 20 12729

BCLllA-10722 + UCACACCAAUGGACACACAUC 21 12730

BCLllA-10723 + CUCA CACCAAUGGACACACAUC 22 12731

BCLllA-10724 + GCUCACACCAAUGGACACACAUC 23 12732

BCLllA-10725 + AGCUCACACCAAUGGACACACAUC 24 12733

BCLllA-10726 + GACGGCUCGGUUCACAUC 18 12734

BCLllA-10727 + CGACGGCUCGGUUCACAUC 19 12735 BCLllA-9568 + ACGACGGCUCGGUUCACAUC 20 12736

BCLllA-10728 + GACGACGGCUCGGUUCACAUC 21 12737

BCLllA-10729 + GGACGACGGCUCGGUUCACAUC 22 12738

BCLllA-10730 + CGGACGACGGCUCGGUUCACAUC 23 12739

BCLllA-10731 + GCGGACGACGGCUCGGU UCACAUC 24 12740

BCLllA-10732 + U UAGAAAGAAGGAGACUC 18 12741

BCLllA-10733 + G U U AG AAAG AAGG AG ACU C 19 12742

BCLllA-10734 + GGUUAGAAAGAAGGAGACUC 20 12743

BCLllA-10735 + GGGUUAGAAAGAAGGAGACUC 21 12744

BCLllA-10736 + CGGGUUAGAAAGAAGGAGACUC 22 12745

BCLllA-10737 + CCGGGUUAGAAAGAAGGAGACUC 23 12746

BCLllA-10738 + GCCGGGU UAGAAAGAAGGAGACUC 24 12747

BCLllA-10739 + UCUCUUUUACCUCGACUC 18 12748

BCLllA-10740 + AUCUCUUU UACCUCGACUC 19 12749

BCLllA-10741 + UAUCUCUU UUACCUCGACUC 20 12750

BCLllA-10742 + UUAUCUCU UUUACCUCGACUC 21 12751

BCLllA-10743 + UUUAUCUCUUUUACCUCGACUC 22 12752

BCLllA-10744 + CUUUAUCUCUUUUACCUCGACUC 23 12753

BCLllA-10745 + CCUU UAUCUCUUU UACCUCGACUC 24 12754

BCLllA-10746 + CUCUCGGAGGUUUUUCUC 18 12755

BCLllA-10747 + ACUCUCGGAGGUUUUUCUC 19 12756

BCLllA-10748 + GACUCUCGGAGGUUUUUCUC 20 12757

BCLllA-10749 + CGACUCUCGGAGGUUU UUCUC 21 12758

BCLllA-10750 + UCGACUCUCGGAGGUU UUUCUC 22 12759

BCLllA-10751 + CUCGACUCUCGGAGGU UUUUCUC 23 12760

BCLllA-10752 + CCUCGACUCUCGGAGGUUUUUCUC 24 12761

BCLllA-10753 + AAAAAAAAAAAAAAAAAG 18 12762

BCLllA-10754 + AAAAAAAAAAAAAAAAAAG 19 12763

BCLllA-4526 + AAAAAAAAAAAAAAAAAAAG 20 12764

BCLllA-10755 + AAAAAAAAAAAAAAAAAAAAG 21 12765

BCLllA-10756 + AAAAAAAAAAAAAAAAAAAAAG 22 12766

BCLllA-10757 + AAAAAAAAAAAAAAAAAAAAAAG 23 12767

BCLllA-10758 + AAAAAAAAAAAAAAAAAAAAAAAG 24 12768

BCLllA-10759 + GAGAGCCGGGUUAGAAAG 18 12769

BCLllA-10760 + GGAGAGCCGGGUUAGAAAG 19 12770

BCLllA-10761 + GGGAGAGCCGGGUUAGAAAG 20 12771

BCLllA-10762 + CGGGAGAGCCGGGUUAGAAAG 21 12772

BCLllA-10763 + UCGGGAGAGCCGGGUUAGAAAG 22 12773

BCLllA-10764 + AUCGGGAGAGCCGGGUUAGAAAG 23 12774

BCLllA-10765 + CAUCGGGAGAGCCGGGU UAGAAAG 24 12775

BCLllA-10766 + GGGCGAGCAGGAGAGAAG 18 12776

BCLllA-10767 + AGGGCGAGCAGGAGAGAAG 19 12777 BCLllA-4629 + CAGGGCGAGCAGGAGAGAAG 20 12778

BCLllA-10768 + GCAGGGCGAGCAGGAGAGAAG 21 12779

BCLllA-10769 + GGCAGGGCGAGCAGGAGAGAAG 22 12780

BCLllA-10770 + GGGCAGGGCGAGCAGGAGAGAAG 23 12781

BCLllA-10771 + UGGGCAGGGCGAGCAGGAGAGAAG 24 12782

BCLllA-10772 + AGAAGGGGAGGAGGGAAG 18 12783

BCLllA-10773 + GAGAAGGGGAGGAGGGAAG 19 12784

BCLllA-4577 + AGAGAAGGGGAGGAGGGAAG 20 12785

BCLllA-10774 + GAGAGAAGGGGAGGAGGGAAG 21 12786

BCLllA-10775 + GGAGAGAAGGGGAGGAGGGAAG 22 12787

BCLllA-10776 + AGGAGAGAAGGGGAGGAGGGAAG 23 12788

BCLllA-10777 + CAGGAGAGAAGGGGAGGAGGGAAG 24 12789

BCLllA-10778 + ACACGGCAAUGGUUCCAG 18 12790

BCLllA-10779 + UACACGGCAAUGGUUCCAG 19 12791

BCLllA-10780 + AUACACGGCAAUGGUUCCAG 20 12792

BCLllA-10781 + CAUACACGGCAAUGGU UCCAG 21 12793

BCLllA-10782 + GCAUACACGGCAAUGGU UCCAG 22 12794

BCLllA-10783 + UGCAUACACGGCAAUGGUUCCAG 23 12795

BCLllA-10784 + GUGCAUACACGGCAAUGGUUCCAG 24 12796

BCLllA-10785 + CAUGGGCAGGGCGAGCAG 18 12797

BCLllA-10786 + ACAUGGGCAGGGCGAGCAG 19 12798

BCLllA-10787 + AACAUGGGCAGGGCGAGCAG 20 12799

BCLllA-10788 + AAA CAUGGGCAGGGCGAGCAG 21 12800

BCLllA-10789 + AAAACAUGGGCAGGGCGAGCAG 22 12801

BCLllA-10790 + CAAAACAUGGGCAGGGCGAGCAG 23 12802

BCLllA-10791 + ACAAAA CAUGGGCAGGGCGAGCAG 24 12803

BCLllA-10792 + GGAGAGAGAGAGAGAGAG 18 12804

BCLllA-10793 + GGGAGAGAGAGAGAGAGAG 19 12805

BCLllA-4999 + AGGGAGAGAGAGAGAGAGAG 20 12806

BCLllA-10794 + GAGGGAGAGAGAGAGAGAGAG 21 12807

BCLllA-10795 + AGAGGGAGAGAGAGAGAGAGAG 22 12808

BCLllA-10796 + UAGAGGGAGAGAGAGAGAGAGAG 23 12809

BCLllA-10797 + AUAGAGGGAGAGAGAGAGAGAGAG 24 12810

BCLllA-10798 + AAAGAGGGAGAGAGAGAG 18 12811

BCLllA-10799 + AAAAGAGGGAGAGAGAGAG 19 12812

BCLllA-4916 + AAAAAGAGGGAGAGAGAGAG 20 12813

BCLllA-10800 + AAAAAAGAGGGAGAGAGAGAG 21 12814

BCLllA-10801 + AAAAAAAGAGGGAGAGAGAGAG 22 12815

BCLllA-10802 + AAAAAAAAGAGGGAGAGAGAGAG 23 12816

BCLllA-10803 + AAAAAAAAAGAGGGAGAGAGAGAG 24 12817

BCLllA-10804 + GCAGGGCGAGCAGGAGAG 18 12818

BCLllA-10805 + GGCAGGGCGAGCAGGAGAG 19 12819 BCLllA-4870 + GGGCAGGGCGAGCAGGAGAG 20 12820

BCLllA-10806 + UGGGCAGGGCGAGCAGGAGAG 21 12821

BCLllA-10807 + AUGGGCAGGGCGAGCAGGAGAG 22 12822

BCLllA-10808 + CAUGGGCAGGGCGAGCAGGAGAG 23 12823

BCLllA-10809 + ACAUGGGCAGGGCGAGCAGGAGAG 24 12824

BCLllA-10810 + GUGGCGUGGCCGGGAGAG 18 12825

BCLllA-10811 + GGUGGCGUGGCCGGGAGAG 19 12826

BCLllA-10812 + CGGUGGCGUGGCCGGGAGAG 20 12827

BCLllA-10813 + GCGGUGGCGUGGCCGGGAGAG 21 12828

BCLllA-10814 + GGCGGUGGCGUGGCCGGGAGAG 22 12829

BCLllA-10815 + CGGCGGUGGCGUGGCCGGGAGAG 23 12830

BCLllA-10816 + GCGGCGGUGGCGUGGCCGGGAGAG 24 12831

BCLllA-10817 + GGGGAGGGGCGGGCCGAG 18 12832

BCLllA-10818 + GGGGGAGGGGCGGGCCGAG 19 12833

BCLllA-4677 + CGGGGGAGGGGCGGGCCGAG 20 12834

BCLllA-10819 + CCGGGGGAGGGGCGGGCCGAG 21 12835

BCLllA-10820 + CCCGGGGGAGGGGCGGGCCGAG 22 12836

BCLllA-10821 + CCCCGGGGGAGGGGCGGGCCGAG 23 12837

BCLllA-10822 + CCCCCGGGGGAGGGGCGGGCCGAG 24 12838

BCLllA-10823 + AAACAUGGGCAGGGCGAG 18 12839

BCLllA-10824 + A A A AC A UGGGCAGGGCGAG 19 12840

BCLllA-10825 + CAAAACAUGGGCAGGGCGAG 20 12841

BCLllA-10826 + ACAAAACAUGGGCAGGGCGAG 21 12842

BCLllA-10827 + C ACA AAACAU G GG CAG G G CG AG 22 12843

BCLllA-10828 + ACACAAAACAUGGGCAGGGCGAG 23 12844

BCLllA-10829 + CACA CAAAACAUGGGCAGGGCGAG 24 12845

BCLllA-10830 + AGCAGGAGAGAAGGGGAG 18 12846

BCLllA-10831 + GAGCAGGAGAGAAGGGGAG 19 12847

BCLllA-5082 + CGAGCAGGAGAGAAGGGGAG 20 12848

BCLllA-10832 + GCGAGCAGGAGAGAAGGGGAG 21 12849

BCLllA-10833 + GGCGAGCAGGAGAGAAGGGGAG 22 12850

BCLllA-10834 + GGGCGAGCAGGAGAGAAGGGGAG 23 12851

BCLllA-10835 + AGGGCGAGCAGGAGAGAAGGGGAG 24 12852

BCLllA-10836 + AAUGGCCAGUGCGGGGAG 18 12853

BCLllA-10837 + CAAUGGCCAGUGCGGGGAG 19 12854

BCLllA-9572 + CCAAUGGCCAGUGCGGGGAG 20 12855

BCLllA-10838 + GCCAAUGGCCAGUGCGGGGAG 21 12856

BCLllA-10839 + AGCCAAUGGCCAGUGCGGGGAG 22 12857

BCLllA-10840 + AAGCCAAUGGCCAGUGCGGGGAG 23 12858

BCLllA-10841 + CAAGCCAAUGGCCAGUGCGGGGAG 24 12859

BCLllA-10842 + GAGAGAGAAGAGAGAUAG 18 12860

BCLllA-10843 + AGAGAGAGAAGAGAGAUAG 19 12861 BCLllA-9740 + GAGAGAGAGAAGAGAGAUAG 20 12862

BCLllA-10844 + AGAGAGAGAGAAGAGAGAUAG 21 12863

BCLllA-10845 + GAGAGAGAGAGAAGAGAGAUAG 22 12864

BCLllA-10846 + GGAGAGAGAGAGAAGAGAGAUAG 23 12865

BCLllA-10847 + GGGAGAGAGAGAGAAGAGAGAUAG 24 12866

BCLllA-10848 + CGCCAGACGCGGCCCCCG 18 12867

BCLllA-10849 + ACGCCAGACGCGGCCCCCG 19 12868

BCLllA-4351 + GACGCCAGACGCGGCCCCCG 20 12869

BCLllA-10850 + GGACGCCAGACGCGGCCCCCG 21 12870

BCLllA-10851 + CGGACGCCAGACGCGGCCCCCG 22 12871

BCLllA-10852 + GCGGACGCCAGACGCGGCCCCCG 23 12872

BCLllA-10853 + CGCGGACGCCAGACGCGGCCCCCG 24 12873

BCLllA-10854 + CGGGGGAGGGGCGGGCCG 18 12874

BCLllA-10855 + CCGGGGGAGGGGCGGGCCG 19 12875

BCLllA-4642 + CCCGGGGGAGGGGCGGGCCG 20 12876

BCLllA-10856 + CCCCGGGGGAGGGGCGGGCCG 21 12877

BCLllA-10857 + CCCCCGGGGGAGGGGCGGGCCG 22 12878

BCLllA-10858 + GCCCCCGGGGGAGGGGCGGGCCG 23 12879

BCLllA-10859 + GGCCCCCGGGGGAGGGGCGGGCCG 24 12880

BCLllA-10860 + GCGGCGGCGGCGGCGGCG 18 12881

BCLllA-10861 + GGCGGCGGCGGCGGCGGCG 19 12882

BCLllA-5097 + CGGCGGCGGCGGCGGCGGCG 20 12883

BCLllA-10862 + GCGGCGGCGGCGGCGGCGGCG 21 12884

BCLllA-10863 + GGCGGCGGCGGCGGCGGCGGCG 22 12885

BCLllA-10864 + CGGCGGCGGCGGCGGCGGCGGCG 23 12886

BCLllA-10865 + GCGGCGGCGGCGGCGGCGGCGGCG 24 12887

BCLllA-10866 + AGGGGGAGGUGCGGGGCG 18 12888

BCLllA-10867 + GAGGGGGAGGUGCGGGGCG 19 12889

BCLllA-9749 + GGAGGGGGAGGUGCGGGGCG 20 12890

BCLllA-10868 + GGGAGGGGGAGGUGCGGGGCG 21 12891

BCLllA-10869 + GGGGAGGGGGAGGUGCGGGGCG 22 12892

BCLllA-10870 + CGGGGAGGGGGAGGUGCGGGGCG 23 12893

BCLllA-10871 + GCGGGGAGGGGGAGGUGCGGGGCG 24 12894

BCLllA-10872 + GGCCGAGGGGAGGGGGCG 18 12895

BCLllA-10873 + GGGCCGAGGGGAGGGGGCG 19 12896

BCLllA-5099 + CGGGCCGAGGGGAGGGGGCG 20 12897

BCLllA-10874 + GCGGGCCGAGGGGAGGGGGCG 21 12898

BCLllA-10875 + GGCGGGCCGAGGGGAGGGGGCG 22 12899

BCLllA-10876 + GGGCGGGCCGAGGGGAGGGGGCG 23 12900

BCLllA-10877 + GGGGCGGGCCGAGGGGAGGGGGCG 24 12901

BCLllA-10878 + AAUAAUACAAAGAUGGCG 18 12902

BCLllA-10879 + A A A U A A U AC A A AG A U G G CG 19 12903 BCLllA-10880 + GAAAUAAUACAAAGAUGGCG 20 12904

BCLllA-10881 + AG AAA U A A U AC A A AG A U G G CG 21 12905

BCLllA-10882 + UAGAAAUAAUACAAAGAUGGCG 22 12906

BCLllA-10883 + UUAGAAAUAAUACAAAGAUGGCG 23 12907

BCLllA-10884 + AUUAGAAAUAAUACAAAGAUGGCG 24 12908

BCLllA-10885 + AAGCCAAUGGCCAGUGCG 18 12909

BCLllA-10886 + CAAGCCAAUGGCCAGUGCG 19 12910

BCLllA-9751 + ACAAGCCAAUGGCCAGUGCG 20 12911

BCLllA-10887 + GACAAGCCAAUGGCCAGUGCG 21 12912

BCLllA-10888 + GGACAAGCCAAUGGCCAGUGCG 22 12913

BCLllA-10889 + AGGACAAGCCAAUGGCCAGUGCG 23 12914

BCLllA-10890 + CAGGACAAGCCAAUGGCCAGUGCG 24 12915

BCLllA-6490 + GGGUUUGCCUUGCUUGCG 18 12916

BCLllA-6491 + GGGGUUUGCCUUGCUUGCG 19 12917

BCLllA-6492 + UGGGGUUUGCCUUGCUUGCG 20 12918

BCLllA-6493 + CUGGGGUUUGCCUUGCUUGCG 21 12919

BCLllA-6494 + GCUGGGGUUUGCCU UGCUUGCG 22 12920

BCLllA-6495 + UGCUGGGGUU UGCCUUGCUUGCG 23 12921

BCLllA-6496 + GUGCUGGGGUUUGCCU UGCUUGCG 24 12922

BCLllA-10891 + CAGGGGUGGGAGGAAAGG 18 12923

BCLllA-10892 + GCAGGGGUGGGAGGAAAGG 19 12924

BCLllA-10893 + GGCAGGGGUGGGAGGAAAGG 20 12925

BCLllA-10894 + UGGCAGGGGUGGGAGGAAAGG 21 12926

BCLllA-10895 + GUGGCAGGGGUGGGAGGAAAGG 22 12927

BCLllA-10896 + GGUGGCAGGGGUGGGAGGAAAGG 23 12928

BCLllA-10897 + GGGUGGCAGGGGUGGGAGGAAAGG 24 12929

BCLllA-10898 + ACACAAAACAUGGGCAGG 18 12930

BCLllA-10899 + CACACAAAACAUGGGCAGG 19 12931

BCLllA-10900 + ACACACAAAACAUGGGCAGG 20 12932

BCLllA-10901 + GACACACAAAACAUGGGCAGG 21 12933

BCLllA-10902 + AGACACACAAAACAUGGGCAGG 22 12934

BCLllA-10903 + GAGACACACAAAACAUGGGCAGG 23 12935

BCLllA-10904 + AGAGACACACAAAACAUGGGCAGG 24 12936

BCLllA-10905 + A A A A A A A A A A AAA AG AG G 18 12937

BCLllA-10906 + AAAAAAAAAAAAAAAGAGG 19 12938

BCLllA-4903 + A AAAAAAAAAAAAAAAG AG G 20 12939

BCLllA-10907 + A A A A A A A A A A A A A A A A AG AG G 21 12940

BCLllA-10908 + A AAAAAAAAAAAAAAAAAG AG G 22 12941

BCLllA-10909 + A A A A A A A A A A A A A A A AAA AG AG G 23 12942

BCLllA-10910 + A AAAAAAAAAAAAAAAAAAAG AG G 24 12943

BCLllA-10911 + AGAGAAGAGAGAUAGAGG 18 12944

BCLllA-10912 + GAGAGAAGAGAGAUAGAGG 19 12945 BCLllA-10913 + AGAGAGAAGAGAGAUAGAGG 20 12946

BCLllA-10914 + GAGAGAGAAGAGAGAUAGAGG 21 12947

BCLllA-10915 + AGAGAGAGAAGAGAGAUAGAGG 22 12948

BCLllA-10916 + GAGAGAGAGAAGAGAGAUAGAGG 23 12949

BCLllA-10917 + AGAGAGAGAGAAGAGAGAUAGAGG 24 12950

BCLllA-10918 + GCAGGAGAGAAGGGGAGG 18 12951

BCLllA-10919 + AGCAGGAGAGAAGGGGAGG 19 12952

BCLllA-4408 + GAGCAGGAGAGAAGGGGAGG 20 12953

BCLllA-10920 + CGAGCAGGAGAGAAGGGGAGG 21 12954

BCLllA-10921 + GCGAGCAGGAGAGAAGGGGAGG 22 12955

BCLllA-10922 + GGCGAGCAGGAGAGAAGGGGAGG 23 12956

BCLllA-10923 + GGGCGAGCAGGAGAGAAGGGGAGG 24 12957

BCLllA-10924 + AUGGCCAGUGCGGGGAGG 18 12958

BCLllA-10925 + AAUGGCCAGUGCGGGGAGG 19 12959

BCLllA-9756 + CAAUGGCCAGUGCGGGGAGG 20 12960

BCLllA-10926 + CCAAUGGCCAGUGCGGGGAGG 21 12961

BCLllA-10927 + GCCAAUGGCCAGUGCGGGGAGG 22 12962

BCLllA-10928 + AGCCAAUGGCCAGUGCGGGGAGG 23 12963

BCLllA-10929 + AAGCCAAUGGCCAGUGCGGGGAGG 24 12964

BCLllA-10930 + GCCAGACGCGGCCCCCGG 18 12965

BCLllA-10931 + CGCCAGACGCGGCCCCCGG 19 12966

BCLllA-4561 + ACGCCAGACGCGGCCCCCGG 20 12967

BCLllA-10932 + GACGCCAGACGCGGCCCCCGG 21 12968

BCLllA-10933 + GGACGCCAGACGCGGCCCCCGG 22 12969

BCLllA-10934 + CGGACGCCAGACGCGGCCCCCGG 23 12970

BCLllA-10935 + GCGGACGCCAGACGCGGCCCCCGG 24 12971

BCLllA-10936 + CGGCGGUGGCGUGGCCGG 18 12972

BCLllA-10937 + GCGGCGGUGGCGUGGCCGG 19 12973

BCLllA-10938 + CGCGGCGGUGGCGUGGCCGG 20 12974

BCLllA-10939 + CCGCGGCGGUGGCGUGGCCGG 21 12975

BCLllA-10940 + GCCGCGGCGGUGGCGUGGCCGG 22 12976

BCLllA-10941 + CGCCGCGGCGGUGGCGUGGCCGG 23 12977

BCLllA-10942 + GCGCCGCGGCGGUGGCGUGGCCGG 24 12978

BCLllA-10943 + CGGCGGCGGCGGCGGCGG 18 12979

BCLllA-10944 + GCGGCGGCGGCGGCGGCGG 19 12980

BCLllA-4479 + GGCGGCGGCGGCGGCGGCGG 20 12981

BCLllA-10945 + CGGCGGCGGCGGCGGCGGCGG 21 12982

BCLllA-10946 + GCGGCGGCGGCGGCGGCGGCGG 22 12983

BCLllA-10947 + GGCGGCGGCGGCGGCGGCGGCGG 23 12984

BCLllA-10948 + CGGCGGCGGCGGCGGCGGCGGCGG 24 12985

BCLllA-10949 + CGGCUCGGUUCACAUCGG 18 12986

BCLllA-10950 + ACGGCUCGGUUCACAUCGG 19 12987 BCLllA-10951 + GACGGCUCGGUUCACAUCGG 20 12988

BCLllA-10952 + CGACGGCUCGGUUCACAUCGG 21 12989

BCLllA-10953 + ACGACGGCUCGGUUCACAUCGG 22 12990

BCLllA-10954 + GACGACGGCUCGGUUCACAUCGG 23 12991

BCLllA-10955 + GGACGACGGCUCGGUUCACAUCGG 24 12992

BCLllA-10956 + AGGGGUGGGAGGAAAGGG 18 12993

BCLllA-10957 + CAGGGGUGGGAGGAAAGGG 19 12994

BCLllA-9759 + GCAGGGGUGGGAGGAAAGGG 20 12995

BCLllA-10958 + GGCAGGGGUGGGAGGAAAGGG 21 12996

BCLllA-10959 + UGGCAGGGGUGGGAGGAAAGGG 22 12997

BCLllA-10960 + GUGGCAGGGGUGGGAGGAAAGGG 23 12998

BCLllA-10961 + GGUGGCAGGGGUGGGAGGAAAGGG 24 12999

BCLllA-10962 + GCGAGCAGGAGAGAAGGG 18 13000

BCLllA-10963 + GGCGAGCAGGAGAGAAGGG 19 13001

BCLllA-4873 + GGGCGAGCAGGAGAGAAGGG 20 13002

BCLllA-10964 + AGGGCGAGCAGGAGAGAAGGG 21 13003

BCLllA-10965 + CAGGGCGAGCAGGAGAGAAGGG 22 13004

BCLllA-10966 + GCAGGGCGAGCAGGAGAGAAGGG 23 13005

BCLllA-10967 + GGCAGGGCGAGCAGGAGAGAAGGG 24 13006

BCLllA-10968 + AAGAAAGGGGUGGCAGGG 18 13007

BCLllA-10969 + GAAGAAAGGGGUGGCAGGG 19 13008

BCLllA-10970 + AGAAGAAAGGGGUGGCAGGG 20 13009

BCLllA-10971 + GAGAAGAAAGGGGUGGCAGGG 21 13010

BCLllA-10972 + AGAGAAGAAAGGGGUGGCAGGG 22 13011

BCLllA-10973 + GAGAGAAGAAAGGGGUGGCAGGG 23 13012

BCLllA-10974 + GGAGAGAAGAAAGGGGUGGCAGGG 24 13013

BCLllA-10975 + GGAGGGGCGGGCCGAGGG 18 13014

BCLllA-10976 + GGGAGGGGCGGGCCGAGGG 19 13015

BCLllA-4875 + GGGGAGGGGCGGGCCGAGGG 20 13016

BCLllA-10977 + GGGGGAGGGGCGGGCCGAGGG 21 13017

BCLllA-10978 + CGGGGGAGGGGCGGGCCGAGGG 22 13018

BCLllA-10979 + CCGGGGGAGGGGCGGGCCGAGGG 23 13019

BCLllA-10980 + CCCGGGGGAGGGGCGGGCCGAGGG 24 13020

BCLllA-10981 + GAGAGAAGGGGAGGAGGG 18 13021

BCLllA-10982 + GGAGAGAAGGGGAGGAGGG 19 13022

BCLllA-4998 + AGGAGAGAAGGGGAGGAGGG 20 13023

BCLllA-10983 + CAGGAGAGAAGGGGAGGAGGG 21 13024

BCLllA-10984 + GCAGGAGAGAAGGGGAGGAGGG 22 13025

BCLllA-10985 + AGCAGGAGAGAAGGGGAGGAGGG 23 13026

BCLllA-10986 + GAGCAGGAGAGAAGGGGAGGAGGG 24 13027

BCLllA-10987 + GCGGCCCCCGGGGGAGGG 18 13028

BCLllA-10988 + CGCGGCCCCCGGGGGAGGG 19 13029 BCLllA-4959 + ACGCGGCCCCCGGGGGAGGG 20 13030

BCLllA-10989 + GACGCGGCCCCCGGGGGAGGG 21 13031

BCLllA-10990 + AGACGCGGCCCCCGGGGGAGGG 22 13032

BCLllA-10991 + CAGACGCGGCCCCCGGGGGAGGG 23 13033

BCLllA-10992 + CCAGACGCGGCCCCCGGGGGAGGG 24 13034

BCLllA-10993 + CCCCGGGGGAGGGGCGGG 18 13035

BCLllA-10994 + CCCCCGGGGGAGGGGCGGG 19 13036

BCLllA-4817 + GCCCCCGGGGGAGGGGCGGG 20 13037

BCLllA-10995 + GGCCCCCGGGGGAGGGGCGGG 21 13038

BCLllA-10996 + CGGCCCCCGGGGGAGGGGCGGG 22 13039

BCLllA-10997 + GCGGCCCCCGGGGGAGGGGCGGG 23 13040

BCLllA-10998 + CGCGGCCCCCGGGGGAGGGGCGGG 24 13041

BCLllA-6504 + GACAUGGUGGGCUGCGGG 18 13042

BCLllA-6505 + AGACAUGGUGGGCUGCGGG 19 13043

BCLllA-6506 + GAGACAUGGUGGGCUGCGGG 20 13044

BCLllA-6507 + CGAGACAUGGUGGGCUGCGGG 21 13045

BCLllA-6508 + GCGAGACAUGGUGGGCUGCGGG 22 13046

BCLllA-6509 + GGCGAGACAUGGUGGGCUGCGGG 23 13047

BCLllA-6510 + CGGCGAGACAUGGUGGGCUGCGGG 24 13048

BCLllA-10999 + GCCAAUGGCCAGUGCGGG 18 13049

BCLllA-11000 + AGCCAAUGGCCAGUGCGGG 19 13050

BCLllA-11001 + AAGCCAAUGGCCAGUGCGGG 20 13051

BCLllA-11002 + CAAGCCAAUGGCCAGUGCGGG 21 13052

BCLllA-11003 + ACAAGCCAAUGGCCAGUGCGGG 22 13053

BCLllA-11004 + GACAAGCCAAUGGCCAGUGCGGG 23 13054

BCLllA-11005 + GGACAAGCCAAUGGCCAGUGCGGG 24 13055

BCLllA-11006 + GGGAGGGGGAGGUGCGGG 18 13056

BCLllA-11007 + GGGGAGGGGGAGGUGCGGG 19 13057

BCLllA-11008 + CGGGGAGGGGGAGGUGCGGG 20 13058

BCLllA-11009 + GCGGGGAGGGGGAGGUGCGGG 21 13059

BCLllA-11010 + UGCGGGGAGGGGGAGGUGCGGG 22 13060

BCLllA-11011 + GUGCGGGGAGGGGGAGGUGCGGG 23 13061

BCLllA-11012 + AGUGCGGGGAGGGGGAGGUGCGGG 24 13062

BCLllA-11013 + CGAGCAGGAGAGAAGGGG 18 13063

BCLllA-11014 + GCGAGCAGGAGAGAAGGGG 19 13064

BCLllA-4476 + GGCGAGCAGGAGAGAAGGGG 20 13065

BCLllA-11015 + GGGCGAGCAGGAGAGAAGGGG 21 13066

BCLllA-11016 + AGGGCGAGCAGGAGAGAAGGGG 22 13067

BCLllA-11017 + CAGGGCGAGCAGGAGAGAAGGGG 23 13068

BCLllA-11018 + GCAGGGCGAGCAGGAGAGAAGGGG 24 13069

BCLllA-11019 + AGAAAGGGGUGGCAGGGG 18 13070

BCLllA-11020 + AAGAAAGGGGUGGCAGGGG 19 13071 BCLllA-9762 + GAAGAAAGGGGUGGCAGGGG 20 13072

BCLllA-11021 + AGAAGAAAGGGGUGGCAGGGG 21 13073

BCLllA-11022 + GAGAAGAAAGGGGUGGCAGGGG 22 13074

BCLllA-11023 + AGAGAAGAAAGGGGUGGCAGGGG 23 13075

BCLllA-11024 + GAGAGAAGAAAGGGGUGGCAGGGG 24 13076

BCLllA-11025 + AUGGACACACAUCAGGGG 18 13077

BCLllA-11026 + AAUGGACACACAUCAGGGG 19 13078

BCLllA-11027 + CAAUGGACACACAUCAGGGG 20 13079

BCLllA-11028 + CCAAUGGACACACAUCAGGGG 21 13080

BCLllA-11029 + ACCAAUGGACACACAUCAGGGG 22 13081

BCLllA-11030 + CACCAAUGGACACACAUCAGGGG 23 13082

BCLllA-11031 + ACACCAAUGGACACACAUCAGGGG 24 13083

BCLllA-11032 + GAGGGGCGGGCCGAGGGG 18 13084

BCLllA-11033 + GGAGGGGCGGGCCGAGGGG 19 13085

BCLllA-4486 + GGGAGGGGCGGGCCGAGGGG 20 13086

BCLllA-11034 + GGGGAGGGGCGGGCCGAGGGG 21 13087

BCLllA-11035 + GGGGGAGGGGCGGGCCGAGGGG 22 13088

BCLllA-11036 + CGGGGGAGGGGCGGGCCGAGGGG 23 13089

BCLllA-11037 + CCGGGGGAGGGGCGGGCCGAGGGG 24 13090

BCLllA-11038 + CAGACGCGGCCCCCGGGG 18 13091

BCLllA-11039 + CCAGACGCGGCCCCCGGGG 19 13092

BCLllA-4816 + GCCAGACGCGGCCCCCGGGG 20 13093

BCLllA-11040 + CGCCAGACGCGGCCCCCGGGG 21 13094

BCLllA-11041 + ACGCCAGACGCGGCCCCCGGGG 22 13095

BCLllA-11042 + GACGCCAGACGCGGCCCCCGGGG 23 13096

BCLllA-11043 + GGACGCCAGACGCGGCCCCCGGGG 24 13097

BCLllA-11044 + CCAAUGGCCAGUGCGGGG 18 13098

BCLllA-11045 + GCCAAUGGCCAGUGCGGGG 19 13099

BCLllA-9763 + AGCCAAUGGCCAGUGCGGGG 20 13100

BCLllA-11046 + AAGCCAAUGGCCAGUGCGGGG 21 13101

BCLllA-11047 + CAAGCCAAUGGCCAGUGCGGGG 22 13102

BCLllA-11048 + ACAAGCCAAUGGCCAGUGCGGGG 23 13103

BCLllA-11049 + GACAAGCCAAUGGCCAGUGCGGGG 24 13104

BCLllA-11050 + GGAGGGGGAGGUGCGGGG 18 13105

BCLllA-11051 + GGGAGGGGGAGGUGCGGGG 19 13106

BCLllA-9764 + GGGGAGGGGGAGGUGCGGGG 20 13107

BCLllA-11052 + CGGGGAGGGGGAGGUGCGGGG 21 13108

BCLllA-11053 + GCGGGGAGGGGGAGGUGCGGGG 22 13109

BCLllA-11054 + UGCGGGGAGGGGGAGGUGCGGGG 23 13110

BCLllA-11055 + GUGCGGGGAGGGGGAGGUGCGGGG 24 13111

BCLllA-11056 + AGACGCGGCCCCCGGGGG 18 13112

BCLllA-11057 + CAGACGCGGCCCCCGGGGG 19 13113 BCLllA-4635 + CCAGACGCGGCCCCCGGGGG 20 13114

BCLllA-11058 + GCCAGACGCGGCCCCCGGGGG 21 13115

BCLllA-11059 + CGCCAGACGCGGCCCCCGGGGG 22 13116

BCLllA-11060 + ACGCCAGACGCGGCCCCCGGGGG 23 13117

BCLllA-11061 + GACGCCAGACGCGGCCCCCGGGGG 24 13118

BCLllA-11062 + UGGGAGGAAAGGGUGGGG 18 13119

BCLllA-11063 + GUGGGAGGAAAGGGUGGGG 19 13120

BCLllA-9766 + GGUGGGAGGAAAGGGUGGGG 20 13121

BCLllA-11064 + GGGUGGGAGGAAAGGGUGGGG 21 13122

BCLllA-11065 + GGGGUGGGAGGAAAGGGUGGGG 22 13123

BCLllA-11066 + AGGGGUGGGAGGAAAGGGUGGGG 23 13124

BCLllA-11067 + CAGGGGUGGGAGGAAAGGGUGGGG 24 13125

BCLllA-11068 + AGACACACAAAACAUGGG 18 13126

BCLllA-11069 + GAGACACACAAAACAUGGG 19 13127

BCLllA-11070 + AGAGACACACAAAACAUGGG 20 13128

BCLllA-11071 + CAGAGACACACAAAACAUGGG 21 13129

BCLllA-11072 + ACAGAGACACACAAAACAUGGG 22 13130

BCLllA-11073 + GACAGAGACACACAAAACAUGGG 23 13131

BCLllA-11074 + GGACAGAGACACACAAAACAUGGG 24 13132

BCLllA-11075 + GCAAUGGUUCCAGAUGGG 18 13133

BCLllA-11076 + GGCAAUGGUUCCAGAUGGG 19 13134

BCLllA-11077 + CGGCAAUGGUUCCAGAUGGG 20 13135

BCLllA-11078 + ACGGCAAUGGUUCCAGAUGGG 21 13136

BCLllA-11079 + CACGGCAAUGGUUCCAGAUGGG 22 13137

BCLllA-11080 + ACACGGCAAUGGUUCCAGAUGGG 23 13138

BCLllA-11081 + UACACGGCAAUGGUUCCAGAUGGG 24 13139

BCLllA-11082 + GUGGGAGGAAAGGGUGGG 18 13140

BCLllA-11083 + GGUGGGAGGAAAGGGUGGG 19 13141

BCLllA-9767 + GGGUGGGAGGAAAGGGUGGG 20 13142

BCLllA-11084 + GGGGUGGGAGGAAAGGGUGGG 21 13143

BCLllA-11085 + AGGGGUGGGAGGAAAGGGUGGG 22 13144

BCLllA-11086 + CAGGGGUGGGAGGAAAGGGUGGG 23 13145

BCLllA-11087 + GCAGGGGUGGGAGGAAAGGGUGGG 24 13146

BCLllA-11088 + AGGGGUGGCAGGGGUGGG 18 13147

BCLllA-11089 + AAGGGGUGGCAGGGGUGGG 19 13148

BCLllA-9768 + AAAGGGGUGGCAGGGGUGGG 20 13149

BCLllA-11090 + GAAAGGGGUGGCAGGGGUGGG 21 13150

BCLllA-11091 + AGAAAGGGGUGGCAGGGGUGGG 22 13151

BCLllA-11092 + AAGAAAGGGGUGGCAGGGGUGGG 23 13152

BCLllA-11093 + GAAGAAAGGGGUGGCAGGGGUGGG 24 13153

BCLllA-11094 + UGAACGUCAGGAGUCUGG 18 13154

BCLllA-11095 + UUGAACGUCAGGAGUCUGG 19 13155 BCLllA-11096 + CUUGAACGUCAGGAGUCUGG 20 13156

BCLllA-11097 + ACUUGAACGUCAGGAGUCUGG 21 13157

BCLllA-11098 + AACUUGAACGUCAGGAGUCUGG 22 13158

BCLllA-11099 + GAACUUGAACGUCAGGAGUCUGG 23 13159

BCLllA-11100 + CGAACUUGAACGUCAGGAGUCUGG 24 13160

BCLllA-11101 + GCCGCGGCGGUGGCGUGG 18 13161

BCLllA-11102 + CGCCGCGGCGGUGGCGUGG 19 13162

BCLllA-11103 + GCGCCGCGGCGGUGGCGUGG 20 13163

BCLllA-11104 + AGCGCCGCGGCGGUGGCGUGG 21 13164

BCLllA-11105 + GAGCGCCGCGGCGGUGGCGUGG 22 13165

BCLllA-11106 + CGAGCGCCGCGGCGGUGGCGUGG 23 13166

BCLllA-11107 + GCGAGCGCCGCGGCGGUGGCGUGG 24 13167

BCLllA-11108 + GGUGGGAGGAAAGGGUGG 18 13168

BCLllA-11109 + GGGUGGGAGGAAAGGGUGG 19 13169

BCLllA-9770 + GGGGUGGGAGGAAAGGGUGG 20 13170

BCLllA-11110 + AGGGGUGGGAGGAAAGGGUGG 21 13171

BCLllA-11111 + CAGGGGUGGGAGGAAAGGGUGG 22 13172

BCLllA-11112 + GCAGGGGUGGGAGGAAAGGGUGG 23 13173

BCLllA-11113 + GGCAGGGGUGGGAGGAAAGGGUGG 24 13174

BCLllA-11114 + GAGAGAAGAAAGGGGUGG 18 13175

BCLllA-11115 + GGAGAGAAGAAAGGGGUGG 19 13176

BCLllA-11116 + GGGAGAGAAGAAAGGGGUGG 20 13177

BCLllA-11117 + CGGGAGAGAAGAAAGGGGUGG 21 13178

BCLllA-11118 + CCGGGAGAGAAGAAAGGGGUGG 22 13179

BCLllA-11119 + GCCGGGAGAGAAGAAAGGGGUGG 23 13180

BCLllA-11120 + GGCCGGGAGAGAAGAAAGGGGUGG 24 13181

BCLllA-11121 + AAGGGGUGGCAGGGGUGG 18 13182

BCLllA-11122 + AAAGGGGUGGCAGGGGUGG 19 13183

BCLllA-11123 + GAAAGGGGUGGCAGGGGUGG 20 13184

BCLllA-11124 + AGAAAGGGGUGGCAGGGGUGG 21 13185

BCLllA-11125 + AAGAAAGGGGUGGCAGGGGUGG 22 13186

BCLllA-11126 + GAAGAAAGGGGUGGCAGGGGUGG 23 13187

BCLllA-11127 + AGAAGAAAGGGGUGGCAGGGGUGG 24 13188

BCLllA-11128 + AGGGAAGAUGAAUUGUGG 18 13189

BCLllA-11129 + CAGGGAAGAUGAAUUGUGG 19 13190

BCLllA-11130 + GCAGGGAAGAUGAAUUGUGG 20 13191

BCLllA-11131 + CGCAGGGAAGAUGAAUUGUGG 21 13192

BCLllA-11132 + GCGCAGGGAAGAUGAAUUGUGG 22 13193

BCLllA-11133 + GGCGCAGGGAAGAUGAAUUGUGG 23 13194

BCLllA-11134 + UGGCGCAGGGAAGAUGAAUUGUGG 24 13195

BCLllA-6524 + UGCUUGCGGCGAGACAUG 18 13196

BCLllA-6525 + UUGCUUGCGGCGAGACAUG 19 13197 BCLllA-6526 + CUUGCUUGCGGCGAGACAUG 20 13198

BCLllA-6527 + CCUUGCU UGCGGCGAGACAUG 21 13199

BCLllA-6528 + GCCUUGCUUGCGGCGAGACAUG 22 13200

BCLllA-6529 + UGCCU UGCUUGCGGCGAGACAUG 23 13201

BCLllA-6530 + UUGCCUUGCUUGCGGCGAGACAUG 24 13202

BCLllA-6544 + GCGAGACAUGGUGGGCUG 18 13203

BCLllA-6545 + GGCGAGACAUGGUGGGCUG 19 13204

BCLllA-5361 + CGGCGAGACAUGGUGGGCUG 20 13205

BCLllA-6546 + GCGGCGAGACAUGGUGGGCUG 21 13206

BCLllA-6547 + UGCGGCGAGACAUGGUGGGCUG 22 13207

BCLllA-6548 + U UGCGGCGAGACAUGGUGGGCUG 23 13208

BCLllA-6549 + CUUGCGGCGAGACAUGGUGGGCUG 24 13209

BCLllA-6550 + U UCCCGUUUGCU UAAGUG 18 13210

BCLllA-6551 + AUUCCCGU UUGCUUAAGUG 19 13211

BCLllA-6552 + AAUUCCCGUUUGCUUAAGUG 20 13212

BCLllA-6553 + GAAUUCCCGU UUGCUUAAGUG 21 13213

BCLllA-6554 + AGAAUUCCCGUUUGCU UAAGUG 22 13214

BCLllA-6555 + GAGAAUUCCCGUUUGCUUAAGUG 23 13215

BCLllA-6556 + CGAGAAUUCCCGUUUGCUUAAGUG 24 13216

BCLllA-11135 + ACAAGCCAAUGGCCAGUG 18 13217

BCLllA-11136 + GACAAGCCAAUGGCCAGUG 19 13218

BCLllA-9773 + GGACAAGCCAAUGGCCAGUG 20 13219

BCLllA-11137 + AGGACAAGCCAAUGGCCAGUG 21 13220

BCLllA-11138 + CAGGACAAGCCAAUGGCCAGUG 22 13221

BCLllA-11139 + CCAGGACAAGCCAAUGGCCAGUG 23 13222

BCLllA-11140 + ACCAGGACAAGCCAAUGGCCAGUG 24 13223

BCLllA-11141 + UGCGGGGAGGGGGAGGUG 18 13224

BCLllA-11142 + GUGCGGGGAGGGGGAGGUG 19 13225

BCLllA-9774 + AGUGCGGGGAGGGGGAGGUG 20 13226

BCLllA-11143 + CAGUGCGGGGAGGGGGAGGUG 21 13227

BCLllA-11144 + CCAGUGCGGGGAGGGGGAGGUG 22 13228

BCLllA-11145 + GCCAGUGCGGGGAGGGGGAGGUG 23 13229

BCLllA-11146 + GGCCAGUGCGGGGAGGGGGAGGUG 24 13230

BCLllA-11147 + GGGUGGGAGGAAAGGGUG 18 13231

BCLllA-11148 + GGGGUGGGAGGAAAGGGUG 19 13232

BCLllA-9775 + AGGGGUGGGAGGAAAGGGUG 20 13233

BCLllA-11149 + CAGGGGUGGGAGGAAAGGGUG 21 13234

BCLllA-11150 + GCAGGGGUGGGAGGAAAGGGUG 22 13235

BCLllA-11151 + GGCAGGGGUGGGAGGAAAGGGUG 23 13236

BCLllA-11152 + UGGCAGGGGUGGGAGGAAAGGGUG 24 13237

BCLllA-11153 + CGCAGGGAAGAUGAAU UG 18 13238

BCLllA-11154 + GCGCAGGGAAGAUGAAUUG 19 13239 BCLllA-9777 + GGCGCAGGGAAGAUGAAUUG 20 13240

BCLllA-11155 + UGGCGCAGGGAAGAUGAAUUG 21 13241

BCLllA-11156 + AUGGCGCAGGGAAGAUGAAUUG 22 13242

BCLllA-11157 + GAUGGCGCAGGGAAGAUGAAUUG 23 13243

BCLllA-11158 + AGAUGGCGCAGGGAAGAUGAAUUG 24 13244

BCLllA-11159 + U UGACAUCCAAAAUAAAU 18 13245

BCLllA-11160 + U UUGACAUCCAAAAUAAAU 19 13246

BCLllA-11161 + U U UUGACAUCCAAAAUAAAU 20 13247

BCLllA-11162 + CU UUUGACAUCCAAAAUAAAU 21 13248

BCLllA-11163 + CCUUUUGACAUCCAAAAUAAAU 22 13249

BCLllA-11164 + GCCUU UUGACAUCCAAAAUAAAU 23 13250

BCLllA-11165 + UGCCU UUUGACAUCCAAAAUAAAU 24 13251

BCLllA-11166 + ACACCAAUGGACACACAU 18 13252

BCLllA-11167 + CACACCAAUGGACACACAU 19 13253

BCLllA-11168 + UCACACCAAUGGACACACAU 20 13254

BCLllA-11169 + CU CACACCAAUGGACACACAU 21 13255

BCLllA-11170 + GCUCACACCAAUGGACACACAU 22 13256

BCLllA-11171 + AGCUCACACCAAUGGACACACAU 23 13257

BCLllA-11172 + AAGCUCACACCAAUGGACACACAU 24 13258

BCLllA-11173 + CGACGGCUCGGUUCACAU 18 13259

BCLllA-11174 + ACGACGGCUCGGUUCACAU 19 13260

BCLllA-9582 + GACGACGGCUCGGUUCACAU 20 13261

BCLllA-11175 + GGACGACGGCUCGGUUCACAU 21 13262

BCLllA-11176 + CGGACGACGGCUCGGUUCACAU 22 13263

BCLllA-11177 + GCGGACGACGGCUCGGUUCACAU 23 13264

BCLllA-11178 + GGCGGACGACGGCUCGGUUCACAU 24 13265

BCLllA-11179 + UGCGGACGUGACGUCCCU 18 13266

BCLllA-11180 + GUGCGGACGUGACGUCCCU 19 13267

BCLllA-11181 + AGUGCGGACGUGACGUCCCU 20 13268

BCLllA-11182 + AAGUGCGGACGUGACGUCCCU 21 13269

BCLllA-11183 + CAAGUGCGGACGUGACGUCCCU 22 13270

BCLllA-11184 + UCAAGUGCGGACGUGACGUCCCU 23 13271

BCLllA-11185 + UUCAAGUGCGGACGUGACGUCCCU 24 13272

BCLllA-6618 + GGCGAGACAUGGUGGGCU 18 13273

BCLllA-6619 + CGGCGAGACAUGGUGGGCU 19 13274

BCLllA-6620 + GCGGCGAGACAUGGUGGGCU 20 13275

BCLllA-6621 + UGCGGCGAGACAUGGUGGGCU 21 13276

BCLllA-6622 + UUGCGGCGAGACAUGGUGGGCU 22 13277

BCLllA-6623 + CUUGCGGCGAGACAUGGUGGGCU 23 13278

BCLllA-6624 + GCUUGCGGCGAGACAUGGUGGGCU 24 13279

BCLllA-11186 + CUCU UUUACCUCGACUCU 18 13280

BCLllA-11187 + UCUCUUUUACCUCGACUCU 19 13281 BCLllA-9585 + AUCUCUUU UACCUCGACUCU 20 13282

BCLllA-11188 + UAUCUCUU UUACCUCGACUCU 21 13283

BCLllA-11189 + UUAUCUCU UUUACCUCGACUCU 22 13284

BCLllA-11190 + UUUAUCUCUUUUACCUCGACUCU 23 13285

BCLllA-11191 + CUUUAUCUCUUUUACCUCGACUCU 24 13286

BCLllA-11192 + U G AG CU G CAAG U U CAAG U 18 13287

BCLllA-11193 + CUGAGCUGCAAGUUCAAGU 19 13288

BCLllA-11194 + CCUGAGCUGCAAGUUCAAGU 20 13289

BCLllA-11195 + CCCUGAGCUGCAAGUUCAAGU 21 13290

BCLllA-11196 + CCCCUGAGCUGCAAGUUCAAGU 22 13291

BCLllA-11197 + CCCCCUGAGCUGCAAGUUCAAGU 23 13292

BCLllA-11198 + CCCCCCUGAGCUGCAAGUUCAAGU 24 13293

BCLllA-11199 + GACAAGCCAAUGGCCAGU 18 13294

BCLllA-11200 + GGACAAGCCAAUGGCCAGU 19 13295

BCLllA-11201 + AGGACAAGCCAAUGGCCAGU 20 13296

BCLllA-11202 + CAGGACAAGCCAAUGGCCAGU 21 13297

BCLllA-11203 + CCAGGACAAGCCAAUGGCCAGU 22 13298

BCLllA-11204 + ACCAGGACAAGCCAAUGGCCAGU 23 13299

BCLllA-11205 + GACCAGGACAAGCCAAUGGCCAGU 24 13300

BCLllA-11206 + CCCUGCGAACUUGAACGU 18 13301

BCLllA-11207 + UCCCUGCGAACUUGAACGU 19 13302

BCLllA-11208 + GUCCCUGCGAACUUGAACGU 20 13303

BCLllA-11209 + CGUCCCUGCGAACUUGAACGU 21 13304

BCLllA-11210 + ACGUCCCUGCGAACUUGAACGU 22 13305

BCLllA-11211 + GACGUCCCUGCGAACU UGAACGU 23 13306

BCLllA-11212 + UGACGUCCCUGCGAACU UGAACGU 24 13307

BCLllA-11213 + GUGCGGGGAGGGGGAGGU 18 13308

BCLllA-11214 + AGUGCGGGGAGGGGGAGGU 19 13309

BCLllA-11215 + CAGUGCGGGGAGGGGGAGGU 20 13310

BCLllA-11216 + CCAGUGCGGGGAGGGGGAGGU 21 13311

BCLllA-11217 + GCCAGUGCGGGGAGGGGGAGGU 22 13312

BCLllA-11218 + GGCCAGUGCGGGGAGGGGGAGGU 23 13313

BCLllA-11219 + UGGCCAGUGCGGGGAGGGGGAGGU 24 13314

BCLllA-11220 + GGGGUGGGAGGAAAGGGU 18 13315

BCLllA-11221 + AGGGGUGGGAGGAAAGGGU 19 13316

BCLllA-9784 + CAGGGGUGGGAGGAAAGGGU 20 13317

BCLllA-11222 + GCAGGGGUGGGAGGAAAGGGU 21 13318

BCLllA-11223 + GGCAGGGGUGGGAGGAAAGGGU 22 13319

BCLllA-11224 + UGGCAGGGGUGGGAGGAAAGGGU 23 13320

BCLllA-11225 + GUGGCAGGGGUGGGAGGAAAGGGU 24 13321

BCLllA-11226 + ACAUCGGGAGAGCCGGGU 18 13322

BCLllA-11227 + CACAUCGGGAGAGCCGGGU 19 13323 BCLllA-11228 + UCACAUCGGGAGAGCCGGGU 20 13324

BCLllA-11229 + UUCACAUCGGGAGAGCCGGGU 21 13325

BCLllA-11230 + GUUCACAUCGGGAGAGCCGGGU 22 13326

BCLllA-11231 + GGUUCACAUCGGGAGAGCCGGGU 23 13327

BCLllA-11232 + CGGU UCACAUCGGGAGAGCCGGGU 24 13328

BCLllA-11233 + GAAAGGGGUGGCAGGGGU 18 13329

BCLllA-11234 + AGAAAGGGGUGGCAGGGGU 19 13330

BCLllA-9785 + AAGAAAGGGGUGGCAGGGGU 20 13331

BCLllA-11235 + GAAGAAAGGGGUGGCAGGGGU 21 13332

BCLllA-11236 + AGAAGAAAGGGGUGGCAGGGGU 22 13333

BCLllA-11237 + GAGAAGAAAGGGGUGGCAGGGGU 23 13334

BCLllA-11238 + AGAGAAGAAAGGGGUGGCAGGGGU 24 13335

BCLllA-11239 + GCAGGGAAGAUGAAUUGU 18 13336

BCLllA-11240 + CGCAGGGAAGAUGAAU UGU 19 13337

BCLllA-9786 + GCGCAGGGAAGAUGAAUUGU 20 13338

BCLllA-11241 + GGCGCAGGGAAGAUGAAUUGU 21 13339

BCLllA-11242 + UGGCGCAGGGAAGAUGAAUUGU 22 13340

BCLllA-11243 + AUGGCGCAGGGAAGAUGAAUUGU 23 13341

BCLllA-11244 + GAUGGCGCAGGGAAGAUGAAUUGU 24 13342

BCLllA-11245 + GCGCAGGGAAGAUGAAUU 18 13343

BCLllA-11246 + GGCGCAGGGAAGAUGAAUU 19 13344

BCLllA-11247 + UGGCGCAGGGAAGAUGAAUU 20 13345

BCLllA-11248 + AUGGCGCAGGGAAGAUGAAUU 21 13346

BCLllA-11249 + GAUGGCGCAGGGAAGAUGAAUU 22 13347

BCLllA-11250 + AGAUGGCGCAGGGAAGAUGAAUU 23 13348

BCLllA-11251 + AAGAUGGCGCAGGGAAGAUGAAUU 24 13349

BCLllA-11252 - GCAGGACUAGAAGCAAAA 18 13350

BCLllA-11253 - CGCAGGACUAGAAGCAAAA 19 13351

BCLllA-11254 - GCGCAGGACUAGAAG C A A A A 20 13352

BCLllA-11255 - CGCGCAGGACUAGAAGCAAAA 21 13353

BCLllA-11256 - G CG CG CAG G AC U AG AAG CAAAA 22 13354

BCLllA-11257 - AGCGCGCAGGACUAGAAG CAAAA 23 13355

BCLllA-11258 - GAGCGCGCAGGACUAGAAGCAAAA 24 13356

BCLllA-6678 - CCCCAGCACUUAAGCAAA 18 13357

BCLllA-6679 - ACCCCAGCACUUAAGCAAA 19 13358

BCLllA-5443 - AACCCCAGCACU UAAGCAAA 20 13359

BCLllA-6680 - AAACCCCAGCACUUAAGCAAA 21 13360

BCLllA-6681 - CAAACCCCAGCACU UAAGCAAA 22 13361

BCLllA-6682 - GCAAACCCCAGCACUUAAGCAAA 23 13362

BCLllA-6683 - GGCAAACCCCAGCACUUAAGCAAA 24 13363

BCLllA-11259 - CG AG G U A A A AG AG A U AAA 18 13364

BCLllA-11260 - U CG AG G U A A A AG AG A U AAA 19 13365 BCLllA-9693 - G U CG AGG U AAAAG AG AU AAA 20 13366

BCLllA-11261 - AGUCGAGGUAAAAGAGAUAAA 21 13367

BCLllA-11262 - GAGUCGAGGUAAAAGAGAUAAA 22 13368

BCLllA-11263 - AG AG U CG AGG U AAAAG AG AU AAA 23 13369

BCLllA-11264 - GAGAGUCGAGGUAAAAGAGAUAAA 24 13370

BCLllA-6698 - ACCCCAGCACUUAAGCAA 18 13371

BCLllA-6699 - AACCCCAGCACUUAAGCAA 19 13372

BCLllA-6700 - AAACCCCAGCACUUAAGCAA 20 13373

BCLllA-6701 - CAAACCCCAGCACUUAAGCAA 21 13374

BCLllA-6702 - GCAAACCCCAGCACUUAAGCAA 22 13375

BCLllA-6703 - GGCAAACCCCAGCACUUAAGCAA 23 13376

BCLllA-6704 - AGGCAAACCCCAGCACUUAAGCAA 24 13377

BCLllA-11265 - CGGCUCUCCCGAUGUGAA 18 13378

BCLllA-11266 - CCGGCUCUCCCGAUGUGAA 19 13379

BCLllA-11267 - CCCGGCUCUCCCGAUGUGAA 20 13380

BCLllA-11268 - ACCCGGCUCUCCCGAUGUGAA 21 13381

BCLllA-11269 - AACCCGGCUCUCCCGAUGUGAA 22 13382

BCLllA-11270 - UAACCCGGCUCUCCCGAUGUGAA 23 13383

BCLllA-11271 - CUAACCCGGCUCUCCCGAUGUGAA 24 13384

BCLllA-11272 - U CG AGG U AAAAG AG AU AA 18 13385

BCLllA-11273 - GUCGAGGU AAAAG AG A U A A 19 13386

BCLllA-9699 - AG U CG AGG U AAAAG AG AU AA 20 13387

BCLllA-11274 - G AG U CG AGG U AAAAG AG AU AA 21 13388

BCLllA-11275 - AGAGUCGAGGUAAAAGAGAUAA 22 13389

BCLllA-11276 - GAG AG U CG AGG U AAAAG AG AU AA 23 13390

BCLllA-11277 - CG AG AG U CG AGG U AAAAG AG AU AA 24 13391

BCLllA-11278 - CUCCGAGAGUCGAGGUAA 18 13392

BCLllA-11279 - CCUCCGAGAGUCGAGGUAA 19 13393

BCLllA-11280 - ACCUCCGAGAGUCGAGGUAA 20 13394

BCLllA-11281 - AACCUCCGAGAGUCGAGGUAA 21 13395

BCLllA-11282 - AAACCUCCGAGAGUCGAGGUAA 22 13396

BCLllA-11283 - AAAACCUCCGAGAGUCGAGGUAA 23 13397

BCLllA-11284 - AAAAACCUCCGAGAGUCGAGGUAA 24 13398

BCLllA-11285 - ACUUGAACUUGCAGCUCA 18 13399

BCLllA-11286 - CACUUGAACUUGCAGCUCA 19 13400

BCLllA-9705 - GCACUUGAACUUGCAGCUCA 20 13401

BCLllA-11287 - CGCACUUGAACUUGCAGCUCA 21 13402

BCLllA-11288 - CCGCACUUGAACUUGCAGCUCA 22 13403

BCLllA-11289 - UCCGCACUUGAACUUGCAGCUCA 23 13404

BCLllA-11290 - GUCCGCACUUGAACUUGCAGCUCA 24 13405

BCLllA-11291 - GCAAAAGCGAGGGGGAGA 18 13406

BCLllA-11292 - AGCAAAAGCGAGGGGGAGA 19 13407 BCLllA-4934 - A AG C A A A AG CGAGGGGGAGA 20 13408

BCLllA-11293 - G A AG C A A A AG CGAGGGGGAGA 21 13409

BCLllA-11294 - AGAAGCAAAAGCGAGGGGGAGA 22 13410

BCLllA-11295 - UAGAAGCAAAAGCGAGGGGGAGA 23 13411

BCLllA-11296 - CUAGAAGCAAAAGCGAGGGGGAGA 24 13412

BCLllA-11297 - GACUAGAAGCAAAAGCGA 18 13413

BCLllA-11298 - GGACUAGAAGCAAAAGCGA 19 13414

BCLllA-9710 - AGGACUAGAAGCAAAAGCGA 20 13415

BCLllA-11299 - CAGGACUAGAAGCAAAAGCGA 21 13416

BCLllA-11300 - GCAGGACUAGAAG C A A A AG CG A 22 13417

BCLllA-11301 - CGCAGGACUAGAAGCAAAAGCGA 23 13418

BCLllA-11302 - GCGCAGGACUAGAAGCAAAAGCGA 24 13419

BCLllA-11303 - AAGCAAAAGCGAGGGGGA 18 13420

BCLllA-11304 - G A AG C A A A AG CGAGGGGGA 19 13421

BCLllA-4972 - AGAAGCAAAAGCGAGGGGGA 20 13422

BCLllA-11305 - UAGAAGCAAAAGCGAGGGGGA 21 13423

BCLllA-11306 - CUAGAAGCAAAAGCGAGGGGGA 22 13424

BCLllA-11307 - ACUAGAAGCAAAAGCGAGGGGGA 23 13425

BCLllA-11308 - GACUAGAAGCAAAAGCGAGGGGGA 24 13426

BCLllA-11309 - G U CG AGG U AAAAG AG AU A 18 13427

BCLllA-11310 - AGUCGAGGUAAAAGAGAUA 19 13428

BCLllA-11311 - GAGUCGAGGUAAAAGAGAUA 20 13429

BCLllA-11312 - AG AG U CG AGG U AAAAG AG AU A 21 13430

BCLllA-11313 - GAGAGUCGAGGUAAAAGAGAUA 22 13431

BCLllA-11314 - CGAGAGUCGAGGUAAAAGAGAUA 23 13432

BCLllA-11315 - CCG AG AG U CG AGG U AAAAG AG AU A 24 13433

BCLllA-11316 - GGGACGUCACGUCCGCAC 18 13434

BCLllA-11317 - AGGGACGUCACGUCCGCAC 19 13435

BCLllA-11318 - CAGGGACGUCACGUCCGCAC 20 13436

BCLllA-11319 - GCAGGGACGUCACGUCCGCAC 21 13437

BCLllA-11320 - CGCAGGGACGUCACGUCCGCAC 22 13438

BCLllA-11321 - U CG CAGGGACG U CACG U CCG CAC 23 13439

BCLllA-11322 - U U CG CAGGGACG U CACG U CCG CAC 24 13440

BCLllA-11323 - AUAAUUAUUAAUAAUCAC 18 13441

BCLllA-11324 - AAUAAUUAUUAAUAAUCAC 19 13442

BCLllA-11325 - UAAUAAUUAUUAAUAAUCAC 20 13443

BCLllA-11326 - AUAAUAAUUAUUAAUAAUCAC 21 13444

BCLllA-11327 - AAUAAUAAUUAUUAAUAAUCAC 22 13445

BCLllA-11328 - UAAUAAUAAUUAUUAAUAAUCAC 23 13446

BCLllA-11329 - GUAAUAAUAAUUAUUAAUAAUCAC 24 13447

BCLllA-11330 - CAUUUUUAAAUUUUUCAC 18 13448

BCLllA-11331 - GCAUUUUUAAAUUUUUCAC 19 13449 BCLllA-11332 - UGCAUUUUUAAAUUUUUCAC 20 13450

BCLllA-11333 - AUGCAUUUUUAAAUUUUUCAC 21 13451

BCLllA-11334 - CAUGCAUUUUUAAAUUUUUCAC 22 13452

BCLllA-11335 - GCAUGCAUUUUUAAAUUUUUCAC 23 13453

BCLllA-11336 - UGCAUGCAUUUUUAAAUUUUUCAC 24 13454

BCLllA-11337 - CACGAGAGCGCGCAGGAC 18 13455

BCLllA-11338 - UCACGAGAGCGCGCAGGAC 19 13456

BCLllA-11339 - AUCACGAGAGCGCGCAGGAC 20 13457

BCLllA-11340 - AAUCACGAGAGCGCGCAGGAC 21 13458

BCLllA-11341 - U AAU CACG AG AG CG CG CAGG AC 22 13459

BCLllA-11342 - AUAAUCACGAGAGCGCGCAGGAC 23 13460

BCLllA-11343 - AAUAAUCACGAGAGCGCGCAGGAC 24 13461

BCLllA-11344 - UCGGCCCGCCCCUCCCCC 18 13462

BCLllA-11345 - CUCGGCCCGCCCCUCCCCC 19 13463

BCLllA-9716 - CCUCGGCCCGCCCCUCCCCC 20 13464

BCLllA-11346 - CCCUCGGCCCGCCCCUCCCCC 21 13465

BCLllA-11347 - CCCCUCGGCCCGCCCCUCCCCC 22 13466

BCLllA-11348 - UCCCCUCGGCCCGCCCCUCCCCC 23 13467

BCLllA-11349 - CUCCCCUCGGCCCGCCCCUCCCCC 24 13468

BCLllA-11350 - CUCGGCCCGCCCCUCCCC 18 13469

BCLllA-11351 - CCUCGGCCCGCCCCUCCCC 19 13470

BCLllA-9717 - CCCUCGGCCCGCCCCUCCCC 20 13471

BCLllA-11352 - CCCCUCGGCCCGCCCCUCCCC 21 13472

BCLllA-11353 - UCCCCUCGGCCCGCCCCUCCCC 22 13473

BCLllA-11354 - CUCCCCUCGGCCCGCCCCUCCCC 23 13474

BCLllA-11355 - CCUCCCCUCGGCCCGCCCCUCCCC 24 13475

BCLllA-11356 - CCUCGGCCCGCCCCUCCC 18 13476

BCLllA-11357 - CCCUCGGCCCGCCCCUCCC 19 13477

BCLllA-11358 - CCCCUCGGCCCGCCCCUCCC 20 13478

BCLllA-11359 - UCCCCUCGGCCCGCCCCUCCC 21 13479

BCLllA-11360 - CUCCCCUCGGCCCGCCCCUCCC 22 13480

BCLllA-11361 - CCUCCCCUCGGCCCGCCCCUCCC 23 13481

BCLllA-11362 - CCCUCCCCUCGGCCCGCCCCUCCC 24 13482

BCLllA-11363 - GGGCCGCGUCUGGCGUCC 18 13483

BCLllA-11364 - GGGGCCGCGUCUGGCGUCC 19 13484

BCLllA-11365 - GGGGGCCGCGUCUGGCGUCC 20 13485

BCLllA-11366 - CGGGGGCCGCGUCUGGCGUCC 21 13486

BCLllA-11367 - CCGGGGGCCGCGUCUGGCGUCC 22 13487

BCLllA-11368 - CCCGGGGGCCGCGUCUGGCGUCC 23 13488

BCLllA-11369 - CCCCGGGGGCCGCGUCUGGCGUCC 24 13489

BCLllA-11370 - AG G AC U AG AAG CAAAAG C 18 13490

BCLllA-11371 - C AG G AC U AG AAG CAAAAG C 19 13491 BCLllA-11372 - GCAGGACUAGAAGCAAAAGC 20 13492

BCLllA-11373 - CGCAGGACUAGAAGCAAAAGC 21 13493

BCLllA-11374 - GCGCAGGACUAGAAGCAAAAGC 22 13494

BCLllA-11375 - CGCGCAGGACUAGAAG CAAAAG C 23 13495

BCLllA-11376 - G CG CG CAG G AC U AG AAG CAAAAG C 24 13496

BCLllA-11377 - CCUGACGUUCAAGUUCGC 18 13497

BCLllA-11378 - UCCUGACGUUCAAGUUCGC 19 13498

BCLllA-9566 - CUCCUGACGUUCAAGUUCGC 20 13499

BCLllA-11379 - ACUCCUGACGUUCAAGUUCGC 21 13500

BCLllA-11380 - GACUCCUGACGUUCAAGUUCGC 22 13501

BCLllA-11381 - AGACUCCUGACGUUCAAGUUCGC 23 13502

BCLllA-11382 - CAGACUCCUGACGUUCAAGUUCGC 24 13503

BCLllA-11383 - UAAUAAUUAUUAAUAAUC 18 13504

BCLllA-11384 - AUAAUAAUUAUUAAUAAUC 19 13505

BCLllA-11385 - AAUAAUAAUUAUUAAUAAUC 20 13506

BCLllA-11386 - UAAUAAUAAUUAUUAAUAAUC 21 13507

BCLllA-11387 - GUAAUAAUAAUUAUUAAUAAUC 22 13508

BCLllA-11388 - AGUAAUAAUAAUUAUUAAUAAUC 23 13509

BCLllA-11389 - UAGUAAUAAUAAUUAUUAAUAAUC 24 13510

BCLllA-11390 - AAAAACCCUCAUCCCAUC 18 13511

BCLllA-11391 - AAAAAACCCUCAUCCCAUC 19 13512

BCLllA-9730 - GAAAAAACCCUCAUCCCAUC 20 13513

BCLllA-11392 - GGAAAAAACCCUCAUCCCAUC 21 13514

BCLllA-11393 - GGGAAAAAACCCUCAUCCCAUC 22 13515

BCLllA-11394 - GGGGAAAAAACCCUCAUCCCAUC 23 13516

BCLllA-11395 - GGGGGAAAAAACCCUCAUCCCAUC 24 13517

BCLllA-11396 - CACUUGAACUUGCAGCUC 18 13518

BCLllA-11397 - GCACUUGAACUUGCAGCUC 19 13519

BCLllA-9569 - CGCACUUGAACUUGCAGCUC 20 13520

BCLllA-11398 - CCGCACUUGAACUUGCAGCUC 21 13521

BCLllA-11399 - UCCGCACUUGAACUUGCAGCUC 22 13522

BCLllA-11400 - GUCCGCACUUGAACUUGCAGCUC 23 13523

BCLllA-11401 - CGUCCGCACUUGAACUUGCAGCUC 24 13524

BCLllA-11402 - UGCAUUUUUAAAUUUUUC 18 13525

BCLllA-11403 - AUGCAUUUUUAAAUUUUUC 19 13526

BCLllA-11404 - CAUGCAUUUUUAAAUUUUUC 20 13527

BCLllA-11405 - GCAUGCAUUUUUAAAUUUUUC 21 13528

BCLllA-11406 - UGCAUGCAUUUUUAAAUUUUUC 22 13529

BCLllA-11407 - GUGCAUGCAUUUUUAAAUUUUUC 23 13530

BCLllA-11408 - UGUGCAUGCAUUUUUAAAUUUUUC 24 13531

BCLllA-11409 - G AG G U A A A AG AG A U A A AG 18 13532

BCLllA-11410 - CG AG G U A A A AG AG A U A A AG 19 13533 BCLllA-9571 - U CG AG G U AAAAG AG A U AAAG 20 13534

BCLllA-11411 - GUCGAGGU AAAAG AG A U AAAG 21 13535

BCLllA-11412 - AG U CG AGG U AAAAG AG AU AAAG 22 13536

BCLllA-11413 - GAGUCGAGGUAAAAGAGAUAAAG 23 13537

BCLllA-11414 - AG AG U CG AGG U AAAAG AG AU AAAG 24 13538

BCLllA-11415 - CUUGAACUUGCAGCUCAG 18 13539

BCLllA-11416 - ACUUGAACUUGCAGCUCAG 19 13540

BCLllA-9738 - CACUUGAACUUGCAGCUCAG 20 13541

BCLllA-11417 - GCACUUGAACUUGCAGCUCAG 21 13542

BCLllA-11418 - CGCACUUGAACUUGCAGCUCAG 22 13543

BCLllA-11419 - CCGCACUUGAACUUGCAGCUCAG 23 13544

BCLllA-11420 - UCCGCACUUGAACUUGCAGCUCAG 24 13545

BCLllA-11421 - GAGAAAAACCUCCGAGAG 18 13546

BCLllA-11422 - CGAGAAAAACCUCCGAGAG 19 13547

BCLllA-11423 - ACGAGAAAAACCUCCGAGAG 20 13548

BCLllA-11424 - CACGAGAAAAACCUCCGAGAG 21 13549

BCLllA-11425 - UCACGAGAAAAACCUCCGAGAG 22 13550

BCLllA-11426 - UUCACGAGAAAAACCUCCGAGAG 23 13551

BCLllA-11427 - UUUCACGAGAAAAACCUCCGAGAG 24 13552

BCLllA-11428 - ACU AG AAG CAAAAG CG AG 18 13553

BCLllA-11429 - GACUAGAAGCAAAAGCGAG 19 13554

BCLllA-9739 - GGACUAGAAGCAAAAGCGAG 20 13555

BCLllA-11430 - AGGACUAGAAGCAAAAGCGAG 21 13556

BCLllA-11431 - CAGGACUAGAAGCAAAAGCGAG 22 13557

BCLllA-11432 - GCAGGACUAGAAGCAAAAGCGAG 23 13558

BCLllA-11433 - CGCAGGACUAGAAGCAAAAGCGAG 24 13559

BCLllA-11434 - CGCGUGUGUGGGGGGGAG 18 13560

BCLllA-11435 - CCGCGUGUGUGGGGGGGAG 19 13561

BCLllA-11436 - UCCGCGUGUGUGGGGGGGAG 20 13562

BCLllA-11437 - GUCCGCGUGUGUGGGGGGGAG 21 13563

BCLllA-11438 - AGUCCGCGUGUGUGGGGGGGAG 22 13564

BCLllA-11439 - GAGUCCGCGUGUGUGGGGGGGAG 23 13565

BCLllA-11440 - AGAGUCCGCGUGUGUGGGGGGGAG 24 13566

BCLllA-11441 - GGCCGCGUCUGGCGUCCG 18 13567

BCLllA-11442 - GGGCCGCGUCUGGCGUCCG 19 13568

BCLllA-9574 - GGGGCCGCGUCUGGCGUCCG 20 13569

BCLllA-11443 - GGGGGCCGCGUCUGGCGUCCG 21 13570

BCLllA-11444 - CGGGGGCCGCGUCUGGCGUCCG 22 13571

BCLllA-11445 - CCGGGGGCCGCGUCUGGCGUCCG 23 13572

BCLllA-11446 - CCCGGGGGCCGCGUCUGGCGUCCG 24 13573

BCLllA-11447 - GGACUAGAAGCAAAAGCG 18 13574

BCLllA-11448 - AG G AC U AG AAG CAAAAG CG 19 13575 BCLllA-9748 - CAGGACUAGAAGCAAAAGCG 20 13576

BCLllA-11449 - G C AG G AC U AG AAG CAAA AG CG 21 13577

BCLllA-11450 - CGCAGGACUAGAAGCAAAAGCG 22 13578

BCLllA-11451 - GCGCAGGACUAGAAGCAAAAGCG 23 13579

BCLllA-11452 - CGCGCAGGACUAGAAGCAAAAGCG 24 13580

BCLllA-11453 - AAUAAUCACGAGAGCGCG 18 13581

BCLllA-11454 - UAAUAAUCACGAGAGCGCG 19 13582

BCLllA-11455 - UUAAUAAUCACGAGAGCGCG 20 13583

BCLllA-11456 - AUUAAUAAUCACGAGAGCGCG 21 13584

BCLllA-11457 - UAUUAAUAAUCACGAGAGCGCG 22 13585

BCLllA-11458 - UUAUUAAUAAUCACGAGAGCGCG 23 13586

BCLllA-11459 - AUUAUUAAUAAUCACGAGAGCGCG 24 13587

BCLllA-11460 - UCCUGACGUUCAAGUUCG 18 13588

BCLllA-11461 - CUCCUGACGUUCAAGUUCG 19 13589

BCLllA-11462 - ACUCCUGACGUUCAAGUUCG 20 13590

BCLllA-11463 - GACUCCUGACGUUCAAGUUCG 21 13591

BCLllA-11464 - AGACUCCUGACGUUCAAGUUCG 22 13592

BCLllA-11465 - CAGACUCCUGACGUUCAAGUUCG 23 13593

BCLllA-11466 - CCAGACUCCUGACGUUCAAGUUCG 24 13594

BCLllA-11467 - AGG U AAAAG AG AU AAAGG 18 13595

BCLllA-11468 - G AGG U AAAAG AG AU AAAGG 19 13596

BCLllA-9753 - CGAGGUAAAAGAGAU AAAGG 20 13597

BCLllA-11469 - U CG AGG U AAAAG AG AU AAAGG 21 13598

BCLllA-11470 - GUCGAGGUAAAAGAGAUAAAGG 22 13599

BCLllA-11471 - AG U CG AGG U AAAAG AG AU AAAGG 23 13600

BCLllA-11472 - G AG U CG AGG U AAAAG AG AU AAAGG 24 13601

BCLllA-11473 - CUAGAAGCAAAAGCGAGG 18 13602

BCLllA-11474 - ACUAGAAGCAAAAGCGAGG 19 13603

BCLllA-9755 - GACUAGAAGCAAAAGCGAGG 20 13604

BCLllA-11475 - GGACUAGAAGCAAAAGCGAGG 21 13605

BCLllA-11476 - AGGACUAGAAGCAAAAGCGAGG 22 13606

BCLllA-11477 - CAGGACUAGAAGCAAAAGCGAGG 23 13607

BCLllA-11478 - GCAGGACUAGAAGCAAAAGCGAGG 24 13608

BCLllA-11479 - AGAAGCAAAAGCGAGGGG 18 13609

BCLllA-11480 - U AG A AG CAAA AG CG AG G G G 19 13610

BCLllA-11481 - CUAGAAGCAAAAGCGAGGGG 20 13611

BCLllA-11482 - ACUAGAAGCAAAAGCGAGGGG 21 13612

BCLllA-11483 - GACUAGAAG CAAA AG CG AG G G G 22 13613

BCLllA-11484 - GGACUAGAAGCAAAAGCGAGGGG 23 13614

BCLllA-11485 - AGGACUAGAAGCAAAAGCGAGGGG 24 13615

BCLllA-11486 - GAGUCCGCGUGUGUGGGG 18 13616

BCLllA-11487 - AGAGUCCGCGUGUGUGGGG 19 13617 BCLllA-9577 - UAGAGUCCGCGUGUGUGGGG 20 13618

BCLllA-11488 - UUAGAGUCCGCGUGUGUGGGG 21 13619

BCLllA-11489 - UUUAGAGUCCGCGUGUGUGGGG 22 13620

BCLllA-11490 - UUUUAGAGUCCGCGUGUGUGGGG 23 13621

BCLllA-11491 - AUUUUAGAGUCCGCGUGUGUGGGG 24 13622

BCLllA-11492 - AGAGUCCGCGUGUGUGGG 18 13623

BCLllA-11493 - UAGAGUCCGCGUGUGUGGG 19 13624

BCLllA-9769 - UUAGAGUCCGCGUGUGUGGG 20 13625

BCLllA-11494 - UUUAGAGUCCGCGUGUGUGGG 21 13626

BCLllA-11495 - UUUUAGAGUCCGCGUGUGUGGG 22 13627

BCLllA-11496 - AUUUUAGAGUCCGCGUGUGUGGG 23 13628

BCLllA-11497 - CAUUUUAGAGUCCGCGUGUGUGGG 24 13629

BCLllA-11498 - UAGAGUCCGCGUGUGUGG 18 13630

BCLllA-11499 - UUAGAGUCCGCGUGUGUGG 19 13631

BCLllA-9578 - UUUAGAGUCCGCGUGUGUGG 20 13632

BCLllA-11500 - UUUUAGAGUCCGCGUGUGUGG 21 13633

BCLllA-11501 - AUUUUAGAGUCCGCGUGUGUGG 22 13634

BCLllA-11502 - CAUUUUAGAGUCCGCGUGUGUGG 23 13635

BCLllA-11503 - UCAUUUUAGAGUCCGCGUGUGUGG 24 13636

BCLllA-11504 - CGCUCGCUGCGGCCACUG 18 13637

BCLllA-11505 - GCGCUCGCUGCGGCCACUG 19 13638

BCLllA-11506 - GGCGCUCGCUGCGGCCACUG 20 13639

BCLllA-11507 - CGGCGCUCGCUGCGGCCACUG 21 13640

BCLllA-11508 - GCGGCGCUCGCUGCGGCCACUG 22 13641

BCLllA-11509 - CGCGGCGCUCGCUGCGGCCACUG 23 13642

BCLllA-11510 - CCGCGGCGCUCGCUGCGGCCACUG 24 13643

BCLllA-11511 - GGAUGUCAAAAGGCACUG 18 13644

BCLllA-11512 - UGGAUGUCAAAAGGCACUG 19 13645

BCLllA-11513 - UUGGAUGUCAAAAGGCACUG 20 13646

BCLllA-11514 - UUUGGAUGUCAAAAGGCACUG 21 13647

BCLllA-11515 - UUUUGGAUGUCAAAAGGCACUG 22 13648

BCLllA-11516 - AUUUUGGAUGUCAAAAGGCACUG 23 13649

BCLllA-11517 - UAUUUUGGAUGUCAAAAGGCACUG 24 13650

BCLllA-11518 - UUUUAGAGUCCGCGUGUG 18 13651

BCLllA-11519 - AUUUUAGAGUCCGCGUGUG 19 13652

BCLllA-9581 - CAUUUUAGAGUCCGCGUGUG 20 13653

BCLllA-11520 - UCAUUUUAGAGUCCGCGUGUG 21 13654

BCLllA-11521 - UUCAUUUUAGAGUCCGCGUGUG 22 13655

BCLllA-11522 - UUUCAUUUUAGAGUCCGCGUGUG 23 13656

BCLllA-11523 - CUUUCAUUUUAGAGUCCGCGUGUG 24 13657

BCLllA-11524 - UUAGAGUCCGCGUGUGUG 18 13658

BCLllA-11525 - UUUAGAGUCCGCGUGUGUG 19 13659 BCLllA-9776 - UUUUAGAGUCCGCGUGUGUG 20 13660

BCLllA-11526 - AUUUUAGAGUCCGCGUGUGUG 21 13661

BCLllA-11527 - CAUUUUAGAGUCCGCGUGUGUG 22 13662

BCLllA-11528 - UCAUUUUAGAGUCCGCGUGUGUG 23 13663

BCLllA-11529 - UUCAUUUUAGAGUCCGCGUGUGUG 24 13664

BCLllA-11530 - AAAAAACCCUCAUCCCAU 18 13665

BCLllA-11531 - GAAAAAACCCUCAUCCCAU 19 13666

BCLllA-11532 - GGAAAAAACCCUCAUCCCAU 20 13667

BCLllA-11533 - GGGAAAAAACCCUCAUCCCAU 21 13668

BCLllA-11534 - GGGGAAAAAACCCUCAUCCCAU 22 13669

BCLllA-11535 - GGGGGAAAAAACCCUCAUCCCAU 23 13670

BCLllA-11536 - AGGGGGAAAAAACCCUCAUCCCAU 24 13671

BCLllA-11537 - UAACCCGGCUCUCCCGAU 18 13672

BCLllA-11538 - CUAACCCGGCUCUCCCGAU 19 13673

BCLllA-11539 - UCUAACCCGGCUCUCCCGAU 20 13674

BCLllA-11540 - UUCUAACCCGGCUCUCCCGAU 21 13675

BCLllA-11541 - UUUCUAACCCGGCUCUCCCGAU 22 13676

BCLllA-11542 - CUUUCUAACCCGGCUCUCCCGAU 23 13677

BCLllA-11543 - UCUUUCUAACCCGGCUCUCCCGAU 24 13678

BCLllA-11544 - U U U U CACG AG AAAAACCU 18 13679

BCLllA-11545 - U U U U U CACG AG AAAAACCU 19 13680

BCLllA-11546 - AU U U U U CACG AG AAAAACCU 20 13681

BCLllA-11547 - AAU U U U U CACG AG AAAAACCU 21 13682

BCLllA-11548 - AAAU U U U U CACG AG AAAAACCU 22 13683

BCLllA-11549 - U AAAU U U U U CACG AG AAAAACCU 23 13684

BCLllA-11550 - U U AAAU U U U U CACG AG AAAAACCU 24 13685

BCLllA-11551 - GCACUUGAACUUGCAGCU 18 13686

BCLllA-11552 - CGCACUUGAACUUGCAGCU 19 13687

BCLllA-11553 - CCGCACUUGAACUUGCAGCU 20 13688

BCLllA-11554 - UCCGCACUUGAACUUGCAGCU 21 13689

BCLllA-11555 - GUCCGCACUUGAACUUGCAGCU 22 13690

BCLllA-11556 - CGUCCGCACUUGAACUUGCAGCU 23 13691

BCLllA-11557 - ACGUCCGCACUUGAACUUGCAGCU 24 13692

BCLllA-11558 - CUGAUGAAGAUAUUUUCU 18 13693

BCLllA-11559 - ACUGAUGAAGAUAUUUUCU 19 13694

BCLllA-11560 - CACUGAUGAAGAUAUUUUCU 20 13695

BCLllA-11561 - GCACUGAUGAAGAUAUUUUCU 21 13696

BCLllA-11562 - GGCACUGAUGAAGAUAUUUUCU 22 13697

BCLllA-11563 - AGGCACUGAUGAAGAUAUUUUCU 23 13698

BCLllA-11564 - AAGGCACUGAUGAAGAUAUUUUCU 24 13699

BCLllA-11565 - UGAUGUGUGUCCAUUGGU 18 13700

BCLllA-11566 - CUGAUGUGUGUCCAUUGGU 19 13701 BCLllA-11567 - CCUGAUGUGUGUCCAU UGGU 20 13702

BCLllA-11568 - CCCUGAUGUGUGUCCAUUGGU 21 13703

BCLllA-11569 - CCCCUGAUGUGUGUCCAUUGGU 22 13704

BCLllA-11570 - GCCCCUGAUGUGUGUCCAUUGGU 23 13705

BCLllA-11571 - AGCCCCUGAUGUGUGUCCAUUGGU 24 13706

BCLllA-11572 - AUUUUAGAGUCCGCGUGU 18 13707

BCLllA-11573 - CAU UUUAGAGUCCGCGUGU 19 13708

BCLllA-11574 - UCAUUUUAGAGUCCGCGUGU 20 13709

BCLllA-11575 - UUCAUUUUAGAGUCCGCGUGU 21 13710

BCLllA-11576 - UUUCAUUUUAGAGUCCGCGUGU 22 13711

BCLllA-11577 - CUUUCAUUUUAGAGUCCGCGUGU 23 13712

BCLllA-11578 - UCUUUCAUUUUAGAGUCCGCGUGU 24 13713

BCLllA-11579 - UUUAGAGUCCGCGUGUGU 18 13714

BCLllA-11580 - UUUUAGAGUCCGCGUGUGU 19 13715

BCLllA-9586 - AUUUUAGAGUCCGCGUGUGU 20 13716

BCLllA-11581 - CAU UUUAGAGUCCGCGUGUGU 21 13717

BCLllA-11582 - UCAUUUUAGAGUCCGCGUGUGU 22 13718

BCLllA-11583 - UUCAUUUUAGAGUCCGCGUGUGU 23 13719

BCLllA-11584 - UUUCAUUUUAGAGUCCGCGUGUGU 24 13720

BCLllA-11585 - AUUGCCGUGUAUGCACUU 18 13721

BCLllA-11586 - CAUUGCCGUGUAUGCACUU 19 13722

BCLllA-11587 - CCAUUGCCGUGUAUGCACUU 20 13723

BCLllA-11588 - ACCAUUGCCGUGUAUGCACUU 21 13724

BCLllA-11589 - AACCAUUGCCGUGUAUGCACUU 22 13725

BCLllA-11590 - GAACCAUUGCCGUGUAUGCACUU 23 13726

BCLllA-11591 - GGAACCAUUGCCGUGUAUGCACUU 24 13727

Table 19D provides exemplary targeting domains for knocking down the BCLl 1 A gene selected according to the fourth tier parameters. The targeting domains bind within the additional 500 bp (e.g., upstream or downstream) of a transcription start site (TSS), e.g., extending to lkb upstream and downstream of a TSS, and the PAM is NNGRRT. It is contemplated herein that in an embodiment the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. aureus eiCas9 molecule or eiCas9 fusion protein (e.g., an eiCas9 fused to a transcription repressor domain) to alter the BCLl 1 A gene (e.g., reduce or eliminate BCLl 1A gene expression, BCLl 1A protein function, or the level of BCLl 1A protein). One or more gRNA may be used to target an eiCas9 to the promoter region of the BCLl 1 A gene. Table 19D

BCLllA-11627 + CGCGGGCGGAGGGAAGCCAGG 21 13766

BCLllA-11628 + GCGCGGGCGGAGGGAAGCCAGG 22 13767

BCLllA-11629 + AGCGCGGGCGGAGGGAAGCCAGG 23 13768

BCLllA-11630 + AAGCGCGGGCGGAGGGAAGCCAGG 24 13769

BCLllA-11631 + CGGAAAGGAGGAAAGAGG 18 13770

BCLllA-11632 + GCGGAAAGGAGGAAAGAGG 19 13771

BCLllA-10187 + GGCGGAAAGGAGGAAAGAGG 20 13772

BCLllA-11633 + CGGCGGAAAGGAGGAAAGAGG 21 13773

BCLllA-11634 + GCGGCGGAAAGGAGGAAAGAGG 22 13774

BCLllA-11635 + AGCGGCGGAAAGGAGGAAAGAGG 23 13775

BCLllA-11636 + A AG CGG CG G AAAG GAG G AAAG AG G 24 13776

BCLllA-11637 + AAACUGGCGGGGCGGGGG 18 13777

BCLllA-11638 + AAAACUGGCGGGGCGGGGG 19 13778

BCLllA-10209 + CAAAACUGGCGGGGCGGGGG 20 13779

BCLllA-11639 + GCAAAACUGGCGGGGCGGGGG 21 13780

BCLllA-11640 + UGCAAAACUGGCGGGGCGGGGG 22 13781

BCLllA-11641 + U UGCAAAACUGGCGGGGCGGGGG 23 13782

BCLllA-11642 + U UUGCAAAACUGGCGGGGCGGGGG 24 13783

BCLllA-11643 + CCACCCCCAGGU UUGCAU 18 13784

BCLllA-11644 + CCCACCCCCAGGUUUGCAU 19 13785

BCLllA-11645 + UCCCACCCCCAGGUU UGCAU 20 13786

BCLllA-11646 + CUCCCACCCCCAGGUUUGCAU 21 13787

BCLllA-11647 + GCUCCCACCCCCAGGUUUGCAU 22 13788

BCLllA-11648 + AGCUCCCACCCCCAGGU UUGCAU 23 13789

BCLllA-11649 + CAGCUCCCACCCCCAGGUU UGCAU 24 13790

BCLllA-11650 + GCCUAAGUUUGGAGGGCU 18 13791

BCLllA-11651 + AGCCUAAGUUUGGAGGGCU 19 13792

BCLllA-11652 + CAGCCUAAGUUUGGAGGGCU 20 13793

BCLllA-11653 + CCAGCCUAAGU UUGGAGGGCU 21 13794

BCLllA-11654 + UCCAGCCUAAGUUUGGAGGGCU 22 13795

BCLllA-11655 + AUCCAGCCUAAGUUUGGAGGGCU 23 13796

BCLllA-11656 + AAUCCAGCCUAAGUU UGGAGGGCU 24 13797

BCLllA-11657 + CCACUUUCUCACUAUUGU 18 13798

BCLllA-11658 + GCCACUUUCUCACUAUUGU 19 13799

BCLllA-10251 + UGCCACUU UCUCACUAUUGU 20 13800

BCLllA-11659 + GUGCCACUUUCUCACUAUUGU 21 13801

BCLllA-11660 + AGUGCCACUU UCUCACUAUUGU 22 13802

BCLllA-11661 + CAGUGCCACUUUCUCACUAUUGU 23 13803

BCLllA-11662 + ACAGUGCCACU UUCUCACUAUUGU 24 13804

BCLllA-11663 - UUAUUUCUCUUUUCGAAA 18 13805

BCLllA-11664 - UUUAUUUCUCUUUUCGAAA 19 13806

BCLllA-10027 - CUUUAUUUCUCUUUUCGAAA 20 13807 BCLllA-11665 - GCUUUAUUUCUCUUUUCGAAA 21 13808

BCLllA-11666 - CGCUUUAUUUCUCUUUUCGAAA 22 13809

BCLllA-11667 - CCGCUUUAUUUCUCUUUUCGAAA 23 13810

BCLllA-11668 - GCCGCUUUAUUUCUCUUUUCGAAA 24 13811

BCLllA-11669 - CGGCGGCGGGGAGGGGAA 18 13812

BCLllA-11670 - GCGGCGGCGGGGAGGGGAA 19 13813

BCLllA-11671 - GGCGGCGGCGGGGAGGGGAA 20 13814

BCLllA-11672 - CGGCGGCGGCGGGGAGGGGAA 21 13815

BCLllA-11673 - GCGGCGGCGGCGGGGAGGGGAA 22 13816

BCLllA-11674 - CGCGGCGGCGGCGGGGAGGGGAA 23 13817

BCLllA-11675 - GCGCGGCGGCGGCGGGGAGGGGAA 24 13818

BCLllA-11676 - UGGGGGGGUAGGGAGGGA 18 13819

BCLllA-11677 - AUGGGGGGGUAGGGAGGGA 19 13820

BCLllA-11678 - AAUGGGGGGGUAGGGAGGGA 20 13821

BCLllA-11679 - AAAUGGGGGGGUAGGGAGGGA 21 13822

BCLllA-11680 - AAAAUGGGGGGGUAGGGAGGGA 22 13823

BCLllA-11681 - GAAAAUGGGGGGGUAGGGAGGGA 23 13824

BCLllA-11682 - AGAAAAUGGGGGGGUAGGGAGGGA 24 13825

BCLllA-11683 - AAAAUGGGGGGGUAGGGA 18 13826

BCLllA-11684 - GAAAAUGGGGGGGUAGGGA 19 13827

BCLllA-10049 - AGAAAAUGGGGGGGUAGGGA 20 13828

BCLllA-11685 - AAGAAAAUGGGGGGGUAGGGA 21 13829

BCLllA-11686 - UAAGAAAAUGGGGGGGUAGGGA 22 13830

BCLllA-11687 - GU AAGAAAAUGGGGGGGUAGGGA 23 13831

BCLllA-11688 - CGUAAGAAAAUGGGGGGGUAGGGA 24 13832

BCLllA-11689 - AAGGGGCCCCCGGCGCUC 18 13833

BCLllA-11690 - AAAGGGGCCCCCGGCGCUC 19 13834

BCLllA-11691 - GAAAGGGGCCCCCGGCGCUC 20 13835

BCLllA-11692 - GGAAAGGGGCCCCCGGCGCUC 21 13836

BCLllA-11693 - UGGAAAGGGGCCCCCGGCGCUC 22 13837

BCLllA-11694 - GUGGAAAGGGGCCCCCGGCGCUC 23 13838

BCLllA-11695 - UGUGGAAAGGGGCCCCCGGCGCUC 24 13839

BCLllA-11696 - CUUUUGUUCCGGCCAGAG 18 13840

BCLllA-11697 - CCUUUUGUUCCGGCCAGAG 19 13841

BCLllA-11698 - GCCUUUUGUUCCGGCCAGAG 20 13842

BCLllA-11699 - CGCCUUUUGUUCCGGCCAGAG 21 13843

BCLllA-11700 - CCGCCUUUUGUUCCGGCCAGAG 22 13844

BCLllA-11701 - GCCGCCUUUUGUUCCGGCCAGAG 23 13845

BCLllA-11702 - UGCCGCCUUUUGUUCCGGCCAGAG 24 13846

BCLllA-11703 - GUGGGUGUGCGUACGGAG 18 13847

BCLllA-11704 - AGUGGGUGUGCGUACGGAG 19 13848

BCLllA-11705 - AAGUGGGUGUGCGUACGGAG 20 13849 BCLllA-11706 - GAAGUGGGUGUGCGUACGGAG 21 13850

BCLllA-11707 - GGAAGUGGGUGUGCGUACGGAG 22 13851

BCLllA-11708 - GGGAAGUGGGUGUGCGUACGGAG 23 13852

BCLllA-11709 - GGGGAAGUGGGUGUGCGUACGGAG 24 13853

BCLllA-11710 - CCGGCGCUCCUGAGUCCG 18 13854

BCLllA-11711 - CCCGGCGCUCCUGAGUCCG 19 13855

BCLllA-10172 - CCCCGGCGCUCCUGAGUCCG 20 13856

BCLllA-11712 - CCCCCGGCGCUCCUGAGUCCG 21 13857

BCLllA-11713 - GCCCCCGGCGCUCCUGAGUCCG 22 13858

BCLllA-11714 - GGCCCCCGGCGCUCCUGAGUCCG 23 13859

BCLllA-11715 - GGGCCCCCGGCGCUCCUGAGUCCG 24 13860

BCLllA-11716 - CAGCCCUCCAAACUUAGG 18 13861

BCLllA-11717 - GCAGCCCUCCAAACUUAGG 19 13862

BCLllA-11718 - CGCAGCCCUCCAAACUUAGG 20 13863

BCLllA-11719 - CCGCAGCCCUCCAAACUUAGG 21 13864

BCLllA-11720 - CCCGCAGCCCUCCAAACUUAGG 22 13865

BCLllA-11721 - ACCCGCAGCCCUCCAAACUUAGG 23 13866

BCLllA-11722 - GACCCGCAGCCCUCCAAACUUAGG 24 13867

BCLllA-11723 - CUCACCGUAAGAAAAUGG 18 13868

BCLllA-11724 - ACU CACCG UAAGAAAAUGG 19 13869

BCLllA-10214 - CACU CACCG UAAGAAAAUGG 20 13870

BCLllA-11725 - CCACUCACCGUAAGAAAAUGG 21 13871

BCLllA-11726 - CCCACUCACCGUAAGAAAAUGG 22 13872

BCLllA-11727 - UCCCACUCACCGUAAGAAAAUGG 23 13873

BCLllA-11728 - UUCCCACUCACCGUAAGAAAAUGG 24 13874

BCLllA-11729 - GAGGCUCAGCUCUCAACU 18 13875

BCLllA-11730 - GGAGGCUCAGCUCUCAACU 19 13876

BCLllA-11731 - UGGAGGCUCAGCUCUCAACU 20 13877

BCLllA-11732 - UUGGAGGCUCAGCUCUCAACU 21 13878

BCLllA-11733 - CUUGGAGGCUCAGCUCUCAACU 22 13879

BCLllA-11734 - ACUUGGAGGCUCAGCUCUCAACU 23 13880

BCLllA-11735 - AACUUGGAGGCUCAGCUCUCAACU 24 13881

BCLllA-11736 - CAACUCACAUGCAAACCU 18 13882

BCLllA-11737 - ACAACUCACAUGCAAACCU 19 13883

BCLllA-10235 - AACAACUCACAUGCAAACCU 20 13884

BCLllA-11738 - GAACAACUCACAUGCAAACCU 21 13885

BCLllA-11739 - CGAACAACUCACAUGCAAACCU 22 13886

BCLllA-11740 - GCGAACAACUCACAUGCAAACCU 23 13887

BCLllA-11741 - UGCGAACAACUCACAUGCAAACCU 24 13888

BCLllA-10351 - UUGAAUAAUCUUUCAUUU 18 13889

BCLllA-10352 - UUUGAAUAAUCUUUCAUUU 19 13890

BCLllA-10353 - UUUUGAAUAAUCUUUCAUUU 20 13891 BCLllA-10354 - U UUUUGAAUAAUCUUUCAUUU 21 13892

BCLllA-10355 - U UUUUUGAAUAAUCUU UCAUUU 22 13893

BCLllA-10356 - CUUUUUUGAAUAAUCUUUCAUUU 23 13894

BCLllA-10357 - UCUUUUUUGAAUAAUCUUUCAUUU 24 13895

BCLllA-11742 - GCUCUAUUU UUUUCUUUU 18 13896

BCLllA-11743 - CGCUCUAU UUUUUUCUUUU 19 13897

BCLllA-11744 - UCGCUCUAUUUUUUUCUUUU 20 13898

BCLllA-11745 - CUCGCUCUAUUUUUUUCUUUU 21 13899

BCLllA-11746 - UCUCGCUCUAUUUUUU UCUUUU 22 13900

BCLllA-11747 - CUCUCGCUCUAU UUUUUUCUUUU 23 13901

BCLllA-11748 - ACUCUCGCUCUAUUUUU UUCUUUU 24 13902

Table 19E provides exemplary targeting domains for knocking down the BCLl 1 A gene selected according to the fifth tier parameters. The targeting domains bind within the additional 500 bp (e.g., upstream or downstream) of a transcription start site (TSS), e.g., extending to lkb upstream and downstream of a TSS, and the PAM is NNGRRV. It is contemplated herein that in an embodiment the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. aureus eiCas9 molecule or eiCas9 fusion protein (e.g., an eiCas9 fused to a transcription repressor domain) to alter the BCLl 1 A gene (e.g., reduce or eliminate BCLl 1A gene expression, BCLl 1A protein function, or the level of BCLl 1A protein). One or more gRNA may be used to target an eiCas9 to the promoter region of the BCLl 1 A gene.

Table 19E

BCLllA-11760 + U AAAAUG AAAG AU U AU U CAAAA 22 13914

BCLllA-11761 + CUAAAAUGAAAGAUUAUUCAAAA 23 13915

BCLllA-11762 + UCUAAAAUGAAAGAUUAUUCAAAA 24 13916

BCLllA-11763 + UGCAUUCCUUUUCGAAAA 18 13917

BCLllA-11764 + U UGCAUUCCUUUUCGAAAA 19 13918

BCLllA-11765 + AUUGCAUUCCUUUUCGAAAA 20 13919

BCLllA-11766 + CAUUGCAUUCCUUUUCGAAAA 21 13920

BCLllA-11767 + UCAUUGCAUUCCUUU UCGAAAA 22 13921

BCLllA-11768 + AUCAUUGCAUUCCUUUUCGAAAA 23 13922

BCLllA-11769 + AAUCAUUGCAUUCCUUU UCGAAAA 24 13923

BCLllA-11770 + GCGGCGGAAAGGAGGAAA 18 13924

BCLllA-11771 + AGCGGCGG AAAG G AG G AAA 19 13925

BCLllA-11772 + AAGCGGCGGAAAGGAGGAAA 20 13926

BCLllA-11773 + AAAG CG G CG G AAAG G AG G AAA 21 13927

BCLllA-11774 + U AAAG CG G CG G AAAG G AG G A A A 22 13928

BCLllA-11775 + A U A A AG CG G CG G A A AG G AG G AAA 23 13929

BCLllA-11776 + AAUAAAGCGGCGGAAAGGAGGAAA 24 13930

BCLllA-11777 + GCCCGCGCGGCCUGGAAA 18 13931

BCLllA-11778 + AGCCCGCGCGGCCUGGAAA 19 13932

BCLllA-11779 + GAGCCCGCGCGGCCUGGAAA 20 13933

BCLllA-11780 + GGAGCCCGCGCGGCCUGGAAA 21 13934

BCLllA-11781 + AGGAGCCCGCGCGGCCUGGAAA 22 13935

BCLllA-11782 + CAGGAGCCCGCGCGGCCUGGAAA 23 13936

BCLllA-11783 + CCAGGAGCCCGCGCGGCCUGGAAA 24 13937

BCLllA-10371 + ACACACGCGGACUCUAAA 18 13938

BCLllA-10372 + CACACACGCGGACUCUAAA 19 13939

BCLllA-10373 + CCACACACGCGGACUCUAAA 20 13940

BCLllA-10374 + CCCACACACGCGGACUCUAAA 21 13941

BCLllA-10375 + CCCCACACACGCGGACUCUAAA 22 13942

BCLllA-10376 + CCCCCACACACGCGGACUCUAAA 23 13943

BCLllA-10377 + CCCCCCACACACGCGGACUCUAAA 24 13944

BCLllA-11784 + AUUGCAUUCCUUUUCGAA 18 13945

BCLllA-11785 + CAUUGCAUUCCUUUUCGAA 19 13946

BCLllA-11786 + UCAUUGCAUUCCUUU UCGAA 20 13947

BCLllA-11787 + AUCAUUGCAUUCCUUUUCGAA 21 13948

BCLllA-11788 + AAUCAUUGCAUUCCUUU UCGAA 22 13949

BCLllA-11789 + GAAUCAUUGCAUUCCUU UUCGAA 23 13950

BCLllA-11790 + GGAAUCAUUGCAUUCCUUUUCGAA 24 13951

BCLllA-11791 + AGAAAUAAAGCGGCGGAA 18 13952

BCLllA-11792 + GAGAAAUAAAGCGGCGGAA 19 13953

BCLllA-10031 + AGAGAAAUAAAGCGGCGGAA 20 13954

BCLllA-11793 + AAGAGAAAUAAAGCGGCGGAA 21 13955 BCLllA-11794 + AAAGAGAAAUAAAGCGGCGGAA 22 13956

BCLllA-11795 + AAAAGAGAAAUAAAGCGGCGGAA 23 13957

BCLllA-11796 + GAAAAGAGAAAUAAAGCGGCGGAA 24 13958

BCLllA-11797 + CCCGAGGAGAGGACAGCA 18 13959

BCLllA-11798 + GCCCGAGGAGAGGACAGCA 19 13960

BCLllA-11799 + UGCCCGAGGAGAGGACAGCA 20 13961

BCLllA-11800 + U UGCCCGAGGAGAGGACAGCA 21 13962

BCLllA-11801 + U UUGCCCGAGGAGAGGACAGCA 22 13963

BCLllA-11802 + CUUUGCCCGAGGAGAGGACAGCA 23 13964

BCLllA-11803 + ACUUUGCCCGAGGAGAGGACAGCA 24 13965

BCLllA-11804 + CCAAG U UACAGCU CCG CA 18 13966

BCLllA-11805 + UCCAAGUUACAGCUCCGCA 19 13967

BCLllA-11806 + CUCCAAGUUACAGCUCCGCA 20 13968

BCLllA-11807 + CCUCCAAGU UACAGCUCCGCA 21 13969

BCLllA-11808 + GCCUCCAAGUUACAGCUCCGCA 22 13970

BCLllA-11809 + AGCCUCCAAGUUACAGCUCCGCA 23 13971

BCLllA-11810 + GAGCCUCCAAGUUACAGCUCCGCA 24 13972

BCLllA-11811 + GAGCCGGCA C A A A AG G C A 18 13973

BCLllA-11812 + GG AG CCGG CACAAAAGG CA 19 13974

BCLllA-11813 + AGGAGCCGGCACAAAAGGCA 20 13975

BCLllA-11814 + GAGGAGCCGGCACAAAAGGCA 21 13976

BCLllA-11815 + CGAGGAGCCGGCACAAAAGGCA 22 13977

BCLllA-11816 + G CG AGG AG CCGG CACAAAAGG CA 23 13978

BCLllA-11817 + CGCGAGGAGCCGGCACAAAAGGCA 24 13979

BCLllA-11818 + AAAUAGAGCGAGAGUGCA 18 13980

BCLllA-11819 + AAAAUAGAGCGAGAGUGCA 19 13981

BCLllA-11820 + AAAAAUAGAGCGAGAGUGCA 20 13982

BCLllA-11821 + AAAAAAUAGAGCGAGAGUGCA 21 13983

BCLllA-11822 + AAAAAAAU AG AG CG AG AG UG CA 22 13984

BCLllA-11823 + G A A A A A A A UAGAGCGAGAGUGCA 23 13985

BCLllA-11824 + AGAAAAAAAUAGAGCGAGAGUGCA 24 13986

BCLllA-11825 + CCGCGCGGCCUGGAAAGA 18 13987

BCLllA-11826 + CCCGCGCGGCCUGGAAAGA 19 13988

BCLllA-10040 + GCCCGCGCGGCCUGGAAAGA 20 13989

BCLllA-11827 + AGCCCGCGCGGCCUGGAAAGA 21 13990

BCLllA-11828 + GAGCCCGCGCGGCCUGGAAAGA 22 13991

BCLllA-11829 + GGAGCCCGCGCGGCCUGGAAAGA 23 13992

BCLllA-11830 + AGGAGCCCGCGCGGCCUGGAAAGA 24 13993

BCLllA-11831 + A A A A A AG A A A A AAA U AG A 18 13994

BCLllA-11832 + CAAAAAAGAAAAAAAUAGA 19 13995

BCLllA-11833 + U CAAAAAAGAAAAAAAUAGA 20 13996

BCLllA-11834 + U U CAAAAAAGAAAAAAAUAGA 21 13997 BCLllA-11835 + A U U C A A A A A AG A A A A A A A U AG A 22 13998

BCLllA-11836 + U A U U C A A A A A AG A A A A A A A U AG A 23 13999

BCLllA-11837 + U UAUUCAAAAAAGAAAAAAAUAGA 24 14000

BCLllA-11838 + CAGCUCCGCAGCGGGCGA 18 14001

BCLllA-11839 + ACAGCUCCGCAGCGGGCGA 19 14002

BCLllA-10044 + UACAGCUCCGCAGCGGGCGA 20 14003

BCLllA-11840 + UUACAGCUCCGCAGCGGGCGA 21 14004

BCLllA-11841 + GUUACAGCUCCGCAGCGGGCGA 22 14005

BCLllA-11842 + AGUUACAGCUCCGCAGCGGGCGA 23 14006

BCLllA-11843 + AAGUUACAGCUCCGCAGCGGGCGA 24 14007

BCLllA-11844 + GGAAACUUUGCCCGAGGA 18 14008

BCLllA-11845 + GGGAAACUUUGCCCGAGGA 19 14009

BCLllA-11846 + CGGGAAACUUUGCCCGAGGA 20 14010

BCLllA-11847 + UCGGGAAACUUUGCCCGAGGA 21 14011

BCLllA-11848 + CUCGGGAAACUUUGCCCGAGGA 22 14012

BCLllA-11849 + GCUCGGGAAACUUUGCCCGAGGA 23 14013

BCLllA-11850 + CGCUCGGGAAACUUUGCCCGAGGA 24 14014

BCLllA-11851 + AAGCGGCGGAAAGGAGGA 18 14015

BCLllA-11852 + A A AG CG G CG G A A AG G AG G A 19 14016

BCLllA-11853 + UAAAGCGGCGGAAAGGAGGA 20 14017

BCLllA-11854 + AUAAAGCGGCGGAAAGGAGGA 21 14018

BCLllA-11855 + AAUAAAGCGGCGGAAAGGAGGA 22 14019

BCLllA-11856 + AAAUAAAGCGGCGGAAAGGAGGA 23 14020

BCLllA-11857 + GAAAUAAAGCGGCGGAAAGGAGGA 24 14021

BCLllA-11858 + GAGAAAUAAAGCGGCGGA 18 14022

BCLllA-11859 + AGAGAAAUAAAGCGGCGGA 19 14023

BCLllA-11860 + AAGAGAAAUAAAGCGGCGGA 20 14024

BCLllA-11861 + AAAGAGAAAUAAAGCGGCGGA 21 14025

BCLllA-11862 + A A A AG AG A A A U A A AG CG G CG G A 22 14026

BCLllA-11863 + G A A A AG AG AAA U A A AG CG G CG G A 23 14027

BCLllA-11864 + CGAAAAGAGAAAUAAAGCGGCGGA 24 14028

BCLllA-11865 + UGGGGAAGCGCGGGCGGA 18 14029

BCLllA-11866 + CUGGGGAAGCGCGGGCGGA 19 14030

BCLllA-10048 + GCUGGGGAAGCGCGGGCGGA 20 14031

BCLllA-11867 + GGCUGGGGAAGCGCGGGCGGA 21 14032

BCLllA-11868 + GGGCUGGGGAAGCGCGGGCGGA 22 14033

BCLllA-11869 + CGGGCUGGGGAAGCGCGGGCGGA 23 14034

BCLllA-11870 + CCGGGCUGGGGAAGCGCGGGCGGA 24 14035

BCLllA-11871 + CCAAGGCCGAGCCAGGGA 18 14036

BCLllA-11872 + CCCAAGGCCGAGCCAGGGA 19 14037

BCLllA-11873 + CCCCAAGGCCGAGCCAGGGA 20 14038

BCLllA-11874 + CCCCCAAGGCCGAGCCAGGGA 21 14039 BCLllA-11875 + GCCCCCAAGGCCGAGCCAGGGA 22 14040

BCLllA-11876 + CGCCCCCAAGGCCGAGCCAGGGA 23 14041

BCLllA-11877 + GCGCCCCCAAGGCCGAGCCAGGGA 24 14042

BCLllA-11878 + CGGCCUGGAAAGAGGGGA 18 14043

BCLllA-11879 + GCGGCCUGGAAAGAGGGGA 19 14044

BCLllA-11880 + CGCGGCCUGGAAAGAGGGGA 20 14045

BCLllA-11881 + GCGCGGCCUGGAAAGAGGGGA 21 14046

BCLllA-11882 + CGCGCGGCCUGGAAAGAGGGGA 22 14047

BCLllA-11883 + CCGCGCGGCCUGGAAAGAGGGGA 23 14048

BCLllA-11884 + CCCGCGCGGCCUGGAAAGAGGGGA 24 14049

BCLllA-11885 + UGGCGGGGCGGGGGGGGA 18 14050

BCLllA-11886 + CUGGCGGGGCGGGGGGGGA 19 14051

BCLllA-11887 + ACUGGCGGGGCGGGGGGGGA 20 14052

BCLllA-11888 + AACUGGCGGGGCGGGGGGGGA 21 14053

BCLllA-11889 + AAACUGGCGGGGCGGGGGGGGA 22 14054

BCLllA-11890 + AAAACUGGCGGGGCGGGGGGGGA 23 14055

BCLllA-11891 + CAAAACUGGCGGGGCGGGGGGGGA 24 14056

BCLllA-11892 + GGGCGAGGGGAGGUGGGA 18 14057

BCLllA-11893 + CGGGCGAGGGGAGGUGGGA 19 14058

BCLllA-10052 + GCGGGCGAGGGGAGGUGGGA 20 14059

BCLllA-11894 + AGCGGGCGAGGGGAGGUGGGA 21 14060

BCLllA-11895 + CAGCGGGCGAGGGGAGGUGGGA 22 14061

BCLllA-11896 + GCAGCGGGCGAGGGGAGGUGGGA 23 14062

BCLllA-11897 + CGCAGCGGGCGAGGGGAGGUGGGA 24 14063

BCLllA-11898 + GAGCCCGCGCGGCCUGGA 18 14064

BCLllA-11899 + GGAGCCCGCGCGGCCUGGA 19 14065

BCLllA-11900 + AGGAGCCCGCGCGGCCUGGA 20 14066

BCLllA-11901 + CAGGAGCCCGCGCGGCCUGGA 21 14067

BCLllA-11902 + CCAGGAGCCCGCGCGGCCUGGA 22 14068

BCLllA-11903 + UCCAGGAGCCCGCGCGGCCUGGA 23 14069

BCLllA-11904 + CUCCAGGAGCCCGCGCGGCCUGGA 24 14070

BCLllA-11905 + CCCAUUUUCUUACGGUGA 18 14071

BCLllA-11906 + CCCCAUU UUCUUACGGUGA 19 14072

BCLllA-11907 + CCCCCAUUUUCUUACGGUGA 20 14073

BCLllA-11908 + CCCCCCAUUUUCUUACGGUGA 21 14074

BCLllA-11909 + CCCCCCCAUU UUCU UACGGUGA 22 14075

BCLllA-11910 + ACCCCCCCAUUU UCUUACGGUGA 23 14076

BCLllA-11911 + UACCCCCCCAUU UUCUUACGGUGA 24 14077

BCLllA-11912 + GAGGGAGCGCACGGCAAC 18 14078

BCLllA-11913 + GGAGGGAGCGCACGGCAAC 19 14079

BCLllA-11914 + GGGAGGGAGCGCACGGCAAC 20 14080

BCLllA-11915 + UGGGAGGGAGCGCACGGCAAC 21 14081 BCLllA-11916 + GUGGGAGGGAGCGCACGGCAAC 22 14082

BCLllA-11917 + GGUGGGAGGGAGCGCACGGCAAC 23 14083

BCLllA-11918 + AGGUGGGAGGGAGCGCACGGCAAC 24 14084

BCLllA-10612 + CUGCUCCCCCCCACACAC 18 14085

BCLllA-10613 + CCUGCUCCCCCCCACACAC 19 14086

BCLllA-10614 + CCCUGCUCCCCCCCACACAC 20 14087

BCLllA-10615 + GCCCUGCUCCCCCCCACACAC 21 14088

BCLllA-10616 + CGCCCUGCUCCCCCCCACACAC 22 14089

BCLllA-10617 + GCGCCCUGCUCCCCCCCACACAC 23 14090

BCLllA-10618 + UGCGCCCUGCUCCCCCCCACACAC 24 14091

BCLllA-11919 + AAUAGAGCGAGAGUGCAC 18 14092

BCLllA-11920 + AAAUAGAGCGAGAGUGCAC 19 14093

BCLllA-10059 + AAAAUAGAGCGAGAGUGCAC 20 14094

BCLllA-11921 + AAAAAUAGAGCGAGAGUGCAC 21 14095

BCLllA-11922 + AAAAAAUAGAGCGAGAGUGCAC 22 14096

BCLllA-11923 + AAAAAAAUAGAGCGAGAGUGCAC 23 14097

BCLllA-11924 + GAAAAAAAUAGAGCGAGAGUGCAC 24 14098

BCLllA-11925 + ACAGCAAAGAAAAAUCAC 18 14099

BCLllA-11926 + GACAGCAAAGAAAAAUCAC 19 14100

BCLllA-11927 + GGACAGCAAAGAAAAAUCAC 20 14101

BCLllA-11928 + AG G AC AG CAAAG AAAAAU CAC 21 14102

BCLllA-11929 + GAGGACAGCAAAGAAAAAUCAC 22 14103

BCLllA-11930 + AGAGGACAG CAAAG AAAAAU CAC 23 14104

BCLllA-11931 + GAGAGGACAGCAAAGAAAAAUCAC 24 14105

BCLllA-11932 + CAAGGCCGAGCCAGGGAC 18 14106

BCLllA-11933 + CCAAGGCCGAGCCAGGGAC 19 14107

BCLllA-10063 + CCCAAGGCCGAGCCAGGGAC 20 14108

BCLllA-11934 + CCCCAAGGCCGAGCCAGGGAC 21 14109

BCLllA-11935 + CCCCCAAGGCCGAGCCAGGGAC 22 14110

BCLllA-11936 + GCCCCCAAGGCCGAGCCAGGGAC 23 14111

BCLllA-11937 + CGCCCCCAAGGCCGAGCCAGGGAC 24 14112

BCLllA-11938 + GGCCUGGAAAGAGGGGAC 18 14113

BCLllA-11939 + CGGCCUGGAAAGAGGGGAC 19 14114

BCLllA-10064 + GCGGCCUGGAAAGAGGGGAC 20 14115

BCLllA-11940 + CGCGGCCUGGAAAGAGGGGAC 21 14116

BCLllA-11941 + GCGCGGCCUGGAAAGAGGGGAC 22 14117

BCLllA-11942 + CGCGCGGCCUGGAAAGAGGGGAC 23 14118

BCLllA-11943 + CCGCGCGGCCUGGAAAGAGGGGAC 24 14119

BCLllA-11944 + AUAGAGCGAGAGUGCACC 18 14120

BCLllA-11945 + AAUAGAGCGAGAGUGCACC 19 14121

BCLllA-10067 + AAAUAGAGCGAGAGUGCACC 20 14122

BCLllA-11946 + AAAAUAGAGCGAGAGUGCACC 21 14123 BCLllA-11947 + AAAAAUAGAGCGAGAGUGCACC 22 14124

BCLllA-11948 + AAAAAAUAGAGCGAGAGUGCACC 23 14125

BCLllA-11949 + AAAAAAAUAGAGCGAGAGUGCACC 24 14126

BCLllA-11950 + AAGGCCGAGCCAGGGACC 18 14127

BCLllA-11951 + CAAGGCCGAGCCAGGGACC 19 14128

BCLllA-10068 + CCAAGGCCGAGCCAGGGACC 20 14129

BCLllA-11952 + CCCAAGGCCGAGCCAGGGACC 21 14130

BCLllA-11953 + CCCCAAGGCCGAGCCAGGGACC 22 14131

BCLllA-11954 + CCCCCAAGGCCGAGCCAGGGACC 23 14132

BCLllA-11955 + GCCCCCAAGGCCGAGCCAGGGACC 24 14133

BCLllA-11956 + GCCUGGAAAGAGGGGACC 18 14134

BCLllA-11957 + GGCCUGGAAAGAGGGGACC 19 14135

BCLllA-10069 + CGGCCUGGAAAGAGGGGACC 20 14136

BCLllA-11958 + GCGGCCUGGAAAGAGGGGACC 21 14137

BCLllA-11959 + CGCGGCCUGGAAAGAGGGGACC 22 14138

BCLllA-11960 + GCGCGGCCUGGAAAGAGGGGACC 23 14139

BCLllA-11961 + CGCGCGGCCUGGAAAGAGGGGACC 24 14140

BCLllA-11962 + CCCGCUGCACACUUGACC 18 14141

BCLllA-11963 + UCCCGCUGCACACUUGACC 19 14142

BCLllA-11964 + CUCCCGCUGCACACUUGACC 20 14143

BCLllA-11965 + CCUCCCGCUGCACACUUGACC 21 14144

BCLllA-11966 + UCCUCCCGCUGCACACU UGACC 22 14145

BCLllA-11967 + UUCCUCCCGCUGCACACUUGACC 23 14146

BCLllA-11968 + UUUCCUCCCGCUGCACACUUGACC 24 14147

BCLllA-11969 + CGGCGCAGGCCGGGGCCC 18 14148

BCLllA-11970 + GCGGCGCAGGCCGGGGCCC 19 14149

BCLllA-11971 + GGCGGCGCAGGCCGGGGCCC 20 14150

BCLllA-11972 + AGGCGGCGCAGGCCGGGGCCC 21 14151

BCLllA-11973 + CAGGCGGCGCAGGCCGGGGCCC 22 14152

BCLllA-11974 + GCAGGCGGCGCAGGCCGGGGCCC 23 14153

BCLllA-11975 + GGCAGGCGGCGCAGGCCGGGGCCC 24 14154

BCLllA-11976 + GCUCGGGAAACUUUGCCC 18 14155

BCLllA-11977 + CGCUCGGGAAACUUUGCCC 19 14156

BCLllA-11978 + GCGCUCGGGAAACUUUGCCC 20 14157

BCLllA-11979 + UGCGCUCGGGAAACUUUGCCC 21 14158

BCLllA-11980 + CUGCGCUCGGGAAACUU UGCCC 22 14159

BCLllA-11981 + GCUGCGCUCGGGAAACU UUGCCC 23 14160

BCLllA-11982 + GGCUGCGCUCGGGAAACUUUGCCC 24 14161

BCLllA-11983 + UCUCACCUCUUUUCUCCC 18 14162

BCLllA-11984 + GUCUCACCUCUU UUCUCCC 19 14163

BCLllA-10081 + AGUCUCACCUCUUU UCUCCC 20 14164

BCLllA-11985 + CAGUCUCACCUCU UUUCUCCC 21 14165 BCLllA-11986 + CCAGUCUCACCUCUUUUCUCCC 22 14166

BCLllA-11987 + GCCAGUCUCACCUCUUUUCUCCC 23 14167

BCLllA-11988 + AGCCAGUCUCACCUCUU UUCUCCC 24 14168

BCLllA-11989 + GGGGCCGAAGUAAAAGCC 18 14169

BCLllA-11990 + AGGGGCCGAAGUAAAAGCC 19 14170

BCLllA-11991 + CAGGGGCCGAAGUAAAAGCC 20 14171

BCLllA-11992 + CCAGGGGCCGAAGUAAAAGCC 21 14172

BCLllA-11993 + G CCAG G GG CCG A AG U AAAAG CC 22 14173

BCLllA-11994 + CGCCAGGGGCCGAAGUAAAAGCC 23 14174

BCLllA-11995 + ACGCCAGGGGCCGAAGUAAAAGCC 24 14175

BCLllA-11996 + CACCGGGAGGCUGCAGCC 18 14176

BCLllA-11997 + GCACCGGGAGGCUGCAGCC 19 14177

BCLllA-11998 + UGCACCGGGAGGCUGCAGCC 20 14178

BCLllA-11999 + GUGCACCGGGAGGCUGCAGCC 21 14179

BCLllA-12000 + AGUGCACCGGGAGGCUGCAGCC 22 14180

BCLllA-12001 + GAGUGCACCGGGAGGCUGCAGCC 23 14181

BCLllA-12002 + AGAGUGCACCGGGAGGCUGCAGCC 24 14182

BCLllA-12003 + CGCCCCCAAGGCCGAGCC 18 14183

BCLllA-12004 + GCGCCCCCAAGGCCGAGCC 19 14184

BCLllA-10085 + GGCGCCCCCAAGGCCGAGCC 20 14185

BCLllA-12005 + GGGCGCCCCCAAGGCCGAGCC 21 14186

BCLllA-12006 + AGGGCGCCCCCAAGGCCGAGCC 22 14187

BCLllA-12007 + GAGGGCGCCCCCAAGGCCGAGCC 23 14188

BCLllA-12008 + CGAGGGCGCCCCCAAGGCCGAGCC 24 14189

BCLllA-12009 + UCCCCGCGUGUGGACGCC 18 14190

BCLllA-12010 + CUCCCCGCGUGUGGACGCC 19 14191

BCLllA-10086 + GCUCCCCGCGUGUGGACGCC 20 14192

BCLllA-12011 + CGCUCCCCGCGUGUGGACGCC 21 14193

BCLllA-12012 + UCGCUCCCCGCGUGUGGACGCC 22 14194

BCLllA-12013 + CUCGCUCCCCGCGUGUGGACGCC 23 14195

BCLllA-12014 + GCUCGCUCCCCGCGUGUGGACGCC 24 14196

BCLllA-12015 + CGCGGACUCAGGAGCGCC 18 14197

BCLllA-12016 + CCGCGGACUCAGGAGCGCC 19 14198

BCLllA-10087 + UCCGCGGACUCAGGAGCGCC 20 14199

BCLllA-12017 + CUCCGCGGACUCAGGAGCGCC 21 14200

BCLllA-12018 + ACUCCGCGGACUCAGGAGCGCC 22 14201

BCLllA-12019 + GACUCCGCGGACUCAGGAGCGCC 23 14202

BCLllA-12020 + CGACUCCGCGGACUCAGGAGCGCC 24 14203

BCLllA-12021 + CCAGGAGCCCGCGCGGCC 18 14204

BCLllA-12022 + UCCAGGAGCCCGCGCGGCC 19 14205

BCLllA-10089 + CUCCAGGAGCCCGCGCGGCC 20 14206

BCLllA-12023 + UCUCCAGGAGCCCGCGCGGCC 21 14207 BCLllA-12024 + GUCUCCAGGAGCCCGCGCGGCC 22 14208

BCLllA-12025 + AGUCUCCAGGAGCCCGCGCGGCC 23 14209

BCLllA-12026 + AAGUCUCCAGGAGCCCGCGCGGCC 24 14210

BCLllA-12027 + GGCCCCUCUCCCGACUCC 18 14211

BCLllA-12028 + CGGCCCCUCUCCCGACUCC 19 14212

BCLllA-12029 + GCGGCCCCUCUCCCGACUCC 20 14213

BCLllA-12030 + CGCGGCCCCUCUCCCGACUCC 21 14214

BCLllA-12031 + CCGCGGCCCCUCUCCCGACUCC 22 14215

BCLllA-12032 + GCCGCGGCCCCUCUCCCGACUCC 23 14216

BCLllA-12033 + CGCCGCGGCCCCUCUCCCGACUCC 24 14217

BCLllA-12034 + GGCAGCGCCCAAGUCUCC 18 14218

BCLllA-12035 + GGGCAGCGCCCAAGUCUCC 19 14219

BCLllA-10093 + AGGGCAGCGCCCAAGUCUCC 20 14220

BCLllA-12036 + AAGGGCAGCGCCCAAGUCUCC 21 14221

BCLllA-12037 + GAAGGGCAGCGCCCAAGUCUCC 22 14222

BCLllA-12038 + GGAAGGGCAGCGCCCAAGUCUCC 23 14223

BCLllA-12039 + CGGAAGGGCAGCGCCCAAGUCUCC 24 14224

BCLllA-12040 + GUCUCACCUCUUUUCUCC 18 14225

BCLllA-12041 + AGUCUCACCUCUUU UCUCC 19 14226

BCLllA-12042 + CAGUCUCACCUCUUUUCUCC 20 14227

BCLllA-12043 + CCAGUCUCACCUCUUUUCUCC 21 14228

BCLllA-12044 + GCCAGUCUCACCUCUUU UCUCC 22 14229

BCLllA-12045 + AGCCAGUCUCACCUCUUUUCUCC 23 14230

BCLllA-12046 + AAGCCAGUCUCACCUCUUUUCUCC 24 14231

BCLllA-12047 + CGGCGCGGGAGGGCAAGC 18 14232

BCLllA-12048 + GCGGCGCGGGAGGGCAAGC 19 14233

BCLllA-12049 + GGCGGCGCGGGAGGGCAAGC 20 14234

BCLllA-12050 + GCCCCGGGCUGGGGAAGC 18 14235

BCLllA-12051 + AGCCCCGGGCUGGGGAAGC 19 14236

BCLllA-12052 + CAGCCCCGGGCUGGGGAAGC 20 14237

BCLllA-12053 + GCAGCCCCGGGCUGGGGAAGC 21 14238

BCLllA-12054 + UGCAGCCCCGGGCUGGGGAAGC 22 14239

BCLllA-12055 + CUGCAGCCCCGGGCUGGGGAAGC 23 14240

BCLllA-12056 + GCUGCAGCCCCGGGCUGGGGAAGC 24 14241

BCLllA-12057 + GCGCCCCCAAGGCCGAGC 18 14242

BCLllA-12058 + GGCGCCCCCAAGGCCGAGC 19 14243

BCLllA-12059 + GGGCGCCCCCAAGGCCGAGC 20 14244

BCLllA-12060 + AGGGCGCCCCCAAGGCCGAGC 21 14245

BCLllA-12061 + GAGGGCGCCCCCAAGGCCGAGC 22 14246

BCLllA-12062 + CGAGGGCGCCCCCAAGGCCGAGC 23 14247

BCLllA-12063 + CCGAGGGCGCCCCCAAGGCCGAGC 24 14248

BCLllA-12064 + CUCCCCGCGUGUGGACGC 18 14249 BCLllA-12065 + GCUCCCCGCGUGUGGACGC 19 14250

BCLllA-12066 + CGCUCCCCGCGUGUGGACGC 20 14251

BCLllA-12067 + UCGCUCCCCGCGUGUGGACGC 21 14252

BCLllA-12068 + CUCGCUCCCCGCGUGUGGACGC 22 14253

BCLllA-12069 + GCUCGCUCCCCGCGUGUGGACGC 23 14254

BCLllA-12070 + CGCUCGCUCCCCGCGUGUGGACGC 24 14255

BCLllA-12071 + GCGCGGGAGGGCAAGCGC 18 14256

BCLllA-12072 + GGCGCGGGAGGGCAAGCGC 19 14257

BCLllA-12073 + CGGCGCGGGAGGGCAAGCGC 20 14258

BCLllA-12074 + CCGCGGACUCAGGAGCGC 18 14259

BCLllA-12075 + UCCGCGGACUCAGGAGCGC 19 14260

BCLllA-10106 + CUCCGCGGACUCAGGAGCGC 20 14261

BCLllA-12076 + ACUCCGCGGACUCAGGAGCGC 21 14262

BCLllA-12077 + GACUCCGCGGACUCAGGAGCGC 22 14263

BCLllA-12078 + CGACUCCGCGGACUCAGGAGCGC 23 14264

BCLllA-12079 + CCGACUCCGCGGACUCAGGAGCGC 24 14265

BCLllA-12080 + CCGAGCCCGCGGCUGCGC 18 14266

BCLllA-12081 + CCCGAGCCCGCGGCUGCGC 19 14267

BCLllA-12082 + CCCCGAGCCCGCGGCUGCGC 20 14268

BCLllA-12083 + GCCCCGAGCCCGCGGCUGCGC 21 14269

BCLllA-12084 + AGCCCCGAGCCCGCGGCUGCGC 22 14270

BCLllA-12085 + AAGCCCCGAGCCCGCGGCUGCGC 23 14271

BCLllA-12086 + AAAGCCCCGAGCCCGCGGCUGCGC 24 14272

BCLllA-12087 + GAGGCAGGCGGCGCAGGC 18 14273

BCLllA-12088 + AGAGGCAGGCGGCGCAGGC 19 14274

BCLllA-10110 + GAGAGGCAGGCGGCGCAGGC 20 14275

BCLllA-12089 + GGAGAGGCAGGCGGCGCAGGC 21 14276

BCLllA-12090 + GGGAGAGGCAGGCGGCGCAGGC 22 14277

BCLllA-12091 + GGGGAGAGGCAGGCGGCGCAGGC 23 14278

BCLllA-12092 + CGGGGAGAGGCAGGCGGCGCAGGC 24 14279

BCLllA-12093 + UCCAGGAGCCCGCGCGGC 18 14280

BCLllA-12094 + CUCCAGGAGCCCGCGCGGC 19 14281

BCLllA-12095 + UCUCCAGGAGCCCGCGCGGC 20 14282

BCLllA-12096 + GUCUCCAGGAGCCCGCGCGGC 21 14283

BCLllA-12097 + AGUCUCCAGGAGCCCGCGCGGC 22 14284

BCLllA-12098 + AAGUCUCCAGGAGCCCGCGCGGC 23 14285

BCLllA-12099 + CAAGUCUCCAGGAGCCCGCGCGGC 24 14286

BCLllA-12100 + GAGGCUGCAGCCCCGGGC 18 14287

BCLllA-12101 + GGAGGCUGCAGCCCCGGGC 19 14288

BCLllA-10115 + GGGAGGCUGCAGCCCCGGGC 20 14289

BCLllA-12102 + CGGGAGGCUGCAGCCCCGGGC 21 14290

BCLllA-12103 + CCGGGAGGCUGCAGCCCCGGGC 22 14291 BCLllA-12104 + ACCGGGAGGCUGCAGCCCCGGGC 23 14292

BCLllA-12105 + CACCGGGAGGCUGCAGCCCCGGGC 24 14293

BCLllA-12106 + UACAGCUCCGCAGCGGGC 18 14294

BCLllA-12107 + UUACAGCUCCGCAGCGGGC 19 14295

BCLllA-12108 + GUUACAGCUCCGCAGCGGGC 20 14296

BCLllA-12109 + AGUUACAGCUCCGCAGCGGGC 21 14297

BCLllA-12110 + AAGUUACAGCUCCGCAGCGGGC 22 14298

BCLllA-12111 + CAAGUUACAGCUCCGCAGCGGGC 23 14299

BCLllA-12112 + CCAAGUUACAGCUCCGCAGCGGGC 24 14300

BCLllA-12113 + GGCGGCGCAGGCCGGGGC 18 14301

BCLllA-12114 + AGGCGGCGCAGGCCGGGGC 19 14302

BCLllA-12115 + CAGGCGGCGCAGGCCGGGGC 20 14303

BCLllA-12116 + GCAGGCGGCGCAGGCCGGGGC 21 14304

BCLllA-12117 + GGCAGGCGGCGCAGGCCGGGGC 22 14305

BCLllA-12118 + AGGCAGGCGGCGCAGGCCGGGGC 23 14306

BCLllA-12119 + GAGGCAGGCGGCGCAGGCCGGGGC 24 14307

BCLllA-12120 + UUGCAAAACUGGCGGGGC 18 14308

BCLllA-12121 + U UUGCAAAACUGGCGGGGC 19 14309

BCLllA-10116 + U UUUGCAAAACUGGCGGGGC 20 14310

BCLllA-12122 + AUUUUGCAAAACUGGCGGGGC 21 14311

BCLllA-12123 + UAUUUUGCAAAACUGGCGGGGC 22 14312

BCLllA-12124 + UUAUUUUGCAAAACUGGCGGGGC 23 14313

BCLllA-12125 + AUUAUUUUGCAAAACUGGCGGGGC 24 14314

BCLllA-12126 + CAAACACCCACCUCUGGC 18 14315

BCLllA-12127 + ACAAACACCCACCUCUGGC 19 14316

BCLllA-10118 + GACAAACACCCACCUCUGGC 20 14317

BCLllA-12128 + GGACAAACACCCACCUCUGGC 21 14318

BCLllA-12129 + GGGACAAACACCCACCUCUGGC 22 14319

BCLllA-12130 + CGGGACAAACACCCACCUCUGGC 23 14320

BCLllA-12131 + GCGGGACAAACACCCACCUCUGGC 24 14321

BCLllA-12132 + GCGCUCGGGAAACUUUGC 18 14322

BCLllA-12133 + UGCGCUCGGGAAACUUUGC 19 14323

BCLllA-12134 + CUGCGCUCGGGAAACUUUGC 20 14324

BCLllA-12135 + GCUGCGCUCGGGAAACUUUGC 21 14325

BCLllA-12136 + GGCUGCGCUCGGGAAACUUUGC 22 14326

BCLllA-12137 + CGGCUGCGCUCGGGAAACUUUGC 23 14327

BCLllA-12138 + GCGGCUGCGCUCGGGAAACUUUGC 24 14328

BCLllA-12139 + UCCCGACUCCGCGGACUC 18 14329

BCLllA-12140 + CUCCCGACUCCGCGGACUC 19 14330

BCLllA-10122 + UCUCCCGACUCCGCGGACUC 20 14331

BCLllA-12141 + CUCUCCCGACUCCGCGGACUC 21 14332

BCLllA-12142 + CCUCUCCCGACUCCGCGGACUC 22 14333 BCLllA-12143 + CCCUCUCCCGACUCCGCGGACUC 23 14334

BCLllA-12144 + CCCCUCUCCCGACUCCGCGGACUC 24 14335

BCLllA-12145 + GAGCCCGCGGCUGCGCUC 18 14336

BCLllA-12146 + CGAGCCCGCGGCUGCGCUC 19 14337

BCLllA-10126 + CCGAGCCCGCGGCUGCGCUC 20 14338

BCLllA-12147 + CCCGAGCCCGCGGCUGCGCUC 21 14339

BCLllA-12148 + CCCCGAGCCCGCGGCUGCGCUC 22 14340

BCLllA-12149 + GCCCCGAGCCCGCGGCUGCGCUC 23 14341

BCLllA-12150 + AGCCCCGAGCCCGCGGCUGCGCUC 24 14342

BCLllA-12151 + AGCCAGGUAGAGUUGCUC 18 14343

BCLllA-12152 + AAGCCAGGUAGAGUUGCUC 19 14344

BCLllA-12153 + GAAGCCAGGUAGAGUUGCUC 20 14345

BCLllA-12154 + GGAAGCCAGGUAGAGU UGCUC 21 14346

BCLllA-12155 + GGGAAGCCAGGUAGAGUUGCUC 22 14347

BCLllA-12156 + AGGGAAGCCAGGUAGAGUUGCUC 23 14348

BCLllA-12157 + GAGGGAAGCCAGGUAGAGUUGCUC 24 14349

BCLllA-12158 + GGGCAGCGCCCAAGUCUC 18 14350

BCLllA-12159 + AGGGCAGCGCCCAAGUCUC 19 14351

BCLllA-12160 + AAGGGCAGCGCCCAAGUCUC 20 14352

BCLllA-12161 + GAAGGGCAGCGCCCAAGUCUC 21 14353

BCLllA-12162 + GGAAGGGCAGCGCCCAAGUCUC 22 14354

BCLllA-12163 + CGGAAGGGCAGCGCCCAAGUCUC 23 14355

BCLllA-12164 + CCGGAAGGGCAGCGCCCAAGUCUC 24 14356

BCLllA-12165 + UUUGGAGGGCUGCGGGUC 18 14357

BCLllA-12166 + GUUUGGAGGGCUGCGGGUC 19 14358

BCLllA-10129 + AGUUUGGAGGGCUGCGGGUC 20 14359

BCLllA-12167 + AAGUUUGGAGGGCUGCGGGUC 21 14360

BCLllA-12168 + UAAGUUUGGAGGGCUGCGGGUC 22 14361

BCLllA-12169 + CUAAGUUUGGAGGGCUGCGGGUC 23 14362

BCLllA-12170 + CCUAAGUUUGGAGGGCUGCGGGUC 24 14363

BCLllA-12171 + CGGCGGAAAGGAGGAAAG 18 14364

BCLllA-12172 + GCGGCGGAAAGGAGGAAAG 19 14365

BCLllA-10136 + AGCGGCGGAAAGGAGGAAAG 20 14366

BCLllA-12173 + AAGCGGCGGAAAGGAGGAAAG 21 14367

BCLllA-12174 + A AAG CGG CG G AAAG G AG G AAAG 22 14368

BCLllA-12175 + U A A AG CG G CG G A A AG G AG G A A AG 23 14369

BCLllA-12176 + AUAAAGCGGCGGAAAGGAGGAAAG 24 14370

BCLllA-12177 + AAA U AAAG CG G CG G AAAG 18 14371

BCLllA-12178 + GAAAUAAAGCGGCGGAAAG 19 14372

BCLllA-12179 + AGAAAUAAAGCGGCGGAAAG 20 14373

BCLllA-12180 + GAG AAA U A A AG CG G CGG AAAG 21 14374

BCLllA-12181 + AGAGAAAUAAAGCGGCGGAAAG 22 14375 BCLllA-12182 + AAG AG A A A U A A AG CG G CG G A A AG 23 14376

BCLllA-12183 + AAAGAGAAAUAAAGCGGCGGAAAG 24 14377

BCLllA-12184 + CCCGCGCGGCCUGGAAAG 18 14378

BCLllA-12185 + GCCCGCGCGGCCUGGAAAG 19 14379

BCLllA-10137 + AGCCCGCGCGGCCUGGAAAG 20 14380

BCLllA-12186 + GAGCCCGCGCGGCCUGGAAAG 21 14381

BCLllA-12187 + GGAGCCCGCGCGGCCUGGAAAG 22 14382

BCLllA-12188 + AGGAGCCCGCGCGGCCUGGAAAG 23 14383

BCLllA-12189 + CAGGAGCCCGCGCGGCCUGGAAAG 24 14384

BCLllA-12190 + AAG AAAAAU CACCCG AAG 18 14385

BCLllA-12191 + AAAG AAAAAU CACCCG AAG 19 14386

BCLllA-12192 + CAAAG AAAAAU CACCCG AAG 20 14387

BCLllA-12193 + GCAAAG AAAAAU CACCCG AAG 21 14388

BCLllA-12194 + AG CAAAG AAAAAU CACCCG AAG 22 14389

BCLllA-12195 + CAG CAAAG AAAAAU CACCCG AAG 23 14390

BCLllA-12196 + ACAGCAAAGAAAAAUCACCCGAAG 24 14391

BCLllA-12197 + AG CCG G CACA AAAGG CAG 18 14392

BCLllA-12198 + GAGCCGGCA C A A A AG G C AG 19 14393

BCLllA-10144 + GGAGCCGGCA C A A A AG G C AG 20 14394

BCLllA-12199 + AG GAG CCGG CAC AAAAG G CAG 21 14395

BCLllA-12200 + GAGGAGCCGG C AC A AAAG G CAG 22 14396

BCLllA-12201 + CG AG G AG CCGG C ACAAAAG G CAG 23 14397

BCLllA-12202 + GCGAGGAGCCGGCACAAAAGGCAG 24 14398

BCLllA-12203 + GCGGAAAGGAGGAAAGAG 18 14399

BCLllA-12204 + GGCGGAAAGGAGGAAAGAG 19 14400

BCLllA-12205 + CGGCGGAAAGGAGGAAAGAG 20 14401

BCLllA-12206 + GCGGCGGAAAGGAGGAAAGAG 21 14402

BCLllA-12207 + AGCGGCGGAAAGGAGGAAAGAG 22 14403

BCLllA-12208 + A AG CGG CG G AAAG G AG G AAAG AG 23 14404

BCLllA-12209 + AAAGCGGCGGAAAGGAGGAAAGAG 24 14405

BCLllA-12210 + AUCACCCGAAGUUGAGAG 18 14406

BCLllA-12211 + AAUCACCCGAAGUUGAGAG 19 14407

BCLllA-12212 + AAAU CACCCG AAG U UG AG AG 20 14408

BCLllA-12213 + AAAAUCACCCGAAGUUGAGAG 21 14409

BCLllA-12214 + AAAAAU CACCCG AAG U UG AG AG 22 14410

BCLllA-12215 + GAAAAAUCACCCGAAGU UGAGAG 23 14411

BCLllA-12216 + AG AAAAAU CACCCG AAG U UG AG AG 24 14412

BCLllA-12217 + CGGGAAACUUUGCCCGAG 18 14413

BCLllA-12218 + UCGGGAAACUUUGCCCGAG 19 14414

BCLllA-12219 + CUCGGGAAACUUUGCCCGAG 20 14415

BCLllA-12220 + GCUCGGGAAACUUUGCCCGAG 21 14416

BCLllA-12221 + CGCUCGGGAAACUUUGCCCGAG 22 14417 BCLllA-12222 + GCGCUCGGGAAACUUUGCCCGAG 23 14418

BCLllA-12223 + UGCGCUCGGGAAACUUUGCCCGAG 24 14419

BCLllA-12224 + AGCUCCGCAGCGGGCGAG 18 14420

BCLllA-12225 + CAGCUCCGCAGCGGGCGAG 19 14421

BCLllA-10148 + ACAGCUCCGCAGCGGGCGAG 20 14422

BCLllA-12226 + UACAGCUCCGCAGCGGGCGAG 21 14423

BCLllA-12227 + UUACAGCUCCGCAGCGGGCGAG 22 14424

BCLllA-12228 + GUUACAGCUCCGCAGCGGGCGAG 23 14425

BCLllA-12229 + AGUUACAGCUCCGCAGCGGGCGAG 24 14426

BCLllA-12230 + CGCAGCGGGCGAGGGGAG 18 14427

BCLllA-12231 + CCGCAGCGGGCGAGGGGAG 19 14428

BCLllA-12232 + UCCGCAGCGGGCGAGGGGAG 20 14429

BCLllA-12233 + CUCCGCAGCGGGCGAGGGGAG 21 14430

BCLllA-12234 + GCUCCGCAGCGGGCGAGGGGAG 22 14431

BCLllA-12235 + AGCUCCGCAGCGGGCGAGGGGAG 23 14432

BCLllA-12236 + CAGCUCCGCAGCGGGCGAGGGGAG 24 14433

BCLllA-12237 + CCAU UUUCUUACGGUGAG 18 14434

BCLllA-12238 + CCCAUU UUCUUACGGUGAG 19 14435

BCLllA-10154 + CCCCAUU UUCUUACGGUGAG 20 14436

BCLllA-12239 + CCCCCAUUU UCUUACGGUGAG 21 14437

BCLllA-12240 + CCCCCCAUUUUCUUACGGUGAG 22 14438

BCLllA-12241 + CCCCCCCAUU UUCU UACGGUGAG 23 14439

BCLllA-12242 + ACCCCCCCAUUU UCUUACGGUGAG 24 14440

BCLllA-12243 + CCUGGAAAGAGGGGACCG 18 14441

BCLllA-12244 + GCCUGGAAAGAGGGGACCG 19 14442

BCLllA-10159 + GGCCUGGAAAGAGGGGACCG 20 14443

BCLllA-12245 + CGGCCUGGAAAGAGGGGACCG 21 14444

BCLllA-12246 + GCGGCCUGGAAAGAGGGGACCG 22 14445

BCLllA-12247 + CGCGGCCUGGAAAGAGGGGACCG 23 14446

BCLllA-12248 + GCGCGGCCUGGAAAGAGGGGACCG 24 14447

BCLllA-12249 + CUCGGGAAACUU UGCCCG 18 14448

BCLllA-12250 + GCUCGGGAAACUU UGCCCG 19 14449

BCLllA-10163 + CGCUCGGGAAACUUUGCCCG 20 14450

BCLllA-12251 + GCGCUCGGGAAACUUUGCCCG 21 14451

BCLllA-12252 + UGCGCUCGGGAAACUUUGCCCG 22 14452

BCLllA-12253 + CUGCGCUCGGGAAACUUUGCCCG 23 14453

BCLllA-12254 + GCUGCGCUCGGGAAACU UUGCCCG 24 14454

BCLllA-12255 + G A A A AG AG AAA U A A AG CG 18 14455

BCLllA-12256 + CGAAAAGAGAAAUAAAGCG 19 14456

BCLllA-12257 + U CG A A A AG AG AAA U A A AG CG 20 14457

BCLllA-12258 + U UCGAAAAGAGAAAUAAAGCG 21 14458

BCLllA-12259 + U UUCGAAAAGAGAAAUAAAGCG 22 14459 BCLllA-12260 + U U U U CG AAAAG AG AAAU AAAGCG 23 14460

BCLllA-12261 + CU UUUCGAAAAGAGAAAUAAAGCG 24 14461

BCLllA-12262 + UCCGCGGACUCAGGAGCG 18 14462

BCLllA-12263 + CUCCGCGGACUCAGGAGCG 19 14463

BCLllA-12264 + ACUCCGCGGACUCAGGAGCG 20 14464

BCLllA-12265 + GACUCCGCGGACUCAGGAGCG 21 14465

BCLllA-12266 + CGACUCCGCGGACUCAGGAGCG 22 14466

BCLllA-12267 + CCGACUCCGCGGACUCAGGAGCG 23 14467

BCLllA-12268 + CCCGACUCCGCGGACUCAGGAGCG 24 14468

BCLllA-12269 + CGCGGGAGGGCAAGCGCG 18 14469

BCLllA-12270 + GCGCGGGAGGGCAAGCGCG 19 14470

BCLllA-10178 + GGCGCGGGAGGGCAAGCGCG 20 14471

BCLllA-12271 + ACAGCUCCGCAGCGGGCG 18 14472

BCLllA-12272 + UACAGCUCCGCAGCGGGCG 19 14473

BCLllA-10180 + UUACAGCUCCGCAGCGGGCG 20 14474

BCLllA-12273 + GUUACAGCUCCGCAGCGGGCG 21 14475

BCLllA-12274 + AGUUACAGCUCCGCAGCGGGCG 22 14476

BCLllA-12275 + AAGUUACAGCUCCGCAGCGGGCG 23 14477

BCLllA-12276 + CAAGUUACAGCUCCGCAGCGGGCG 24 14478

BCLllA-12277 + GCUGGGGAAGCGCGGGCG 18 14479

BCLllA-12278 + GGCUGGGGAAGCGCGGGCG 19 14480

BCLllA-12279 + GGGCUGGGGAAGCGCGGGCG 20 14481

BCLllA-12280 + CGGGCUGGGGAAGCGCGGGCG 21 14482

BCLllA-12281 + CCGGGCUGGGGAAGCGCGGGCG 22 14483

BCLllA-12282 + CCCGGGCUGGGGAAGCGCGGGCG 23 14484

BCLllA-12283 + CCCCGGGCUGGGGAAGCGCGGGCG 24 14485

BCLllA-12284 + UGCAAAACUGGCGGGGCG 18 14486

BCLllA-12285 + UUGCAAAACUGGCGGGGCG 19 14487

BCLllA-10181 + U UUGCAAAACUGGCGGGGCG 20 14488

BCLllA-12286 + U UUUGCAAAACUGGCGGGGCG 21 14489

BCLllA-12287 + AUUUUGCAAAACUGGCGGGGCG 22 14490

BCLllA-12288 + UAUUUUGCAAAACUGGCGGGGCG 23 14491

BCLllA-12289 + U UAUUUUGCAAAACUGGCGGGGCG 24 14492

BCLllA-12290 + AAUAAAGCGGCGGAAAGG 18 14493

BCLllA-12291 + AAA U A A AG CG G CG G A A AG G 19 14494

BCLllA-10185 + G AAA U A A AG CG G CG G A A AG G 20 14495

BCLllA-12292 + AGAAAUAAAGCGGCGGAAAGG 21 14496

BCLllA-12293 + G AG A A A U A A AG CG G CG G A A AG G 22 14497

BCLllA-12294 + AGAGAAAUAAAGCGGCGGAAAGG 23 14498

BCLllA-12295 + AAGAGAAAUAAAGCGGCGGAAAGG 24 14499

BCLllA-12296 + CCGAGGGCGCCCCCAAGG 18 14500

BCLllA-12297 + CCCGAGGGCGCCCCCAAGG 19 14501 BCLllA-12298 + GCCCGAGGGCGCCCCCAAGG 20 14502

BCLllA-12299 + GGCCCGAGGGCGCCCCCAAGG 21 14503

BCLllA-12300 + GGGCCCGAGGGCGCCCCCAAGG 22 14504

BCLllA-12301 + GGGGCCCGAGGGCGCCCCCAAGG 23 14505

BCLllA-12302 + CGGGGCCCGAGGGCGCCCCCAAGG 24 14506

BCLllA-12303 + AGAGGCAGGCGGCGCAGG 18 14507

BCLllA-12304 + GAGAGGCAGGCGGCGCAGG 19 14508

BCLllA-12305 + GGAGAGGCAGGCGGCGCAGG 20 14509

BCLllA-12306 + GGGAGAGGCAGGCGGCGCAGG 21 14510

BCLllA-12307 + GGGGAGAGGCAGGCGGCGCAGG 22 14511

BCLllA-12308 + CGGGGAGAGGCAGGCGGCGCAGG 23 14512

BCLllA-12309 + CCGGGGAGAGGCAGGCGGCGCAGG 24 14513

BCLllA-12310 + GCAGCGGGCGAGGGGAGG 18 14514

BCLllA-12311 + CGCAGCGGGCGAGGGGAGG 19 14515

BCLllA-10190 + CCGCAGCGGGCGAGGGGAGG 20 14516

BCLllA-12312 + UCCGCAGCGGGCGAGGGGAGG 21 14517

BCLllA-12313 + CUCCGCAGCGGGCGAGGGGAGG 22 14518

BCLllA-12314 + GCUCCGCAGCGGGCGAGGGGAGG 23 14519

BCLllA-12315 + AGCUCCGCAGCGGGCGAGGGGAGG 24 14520

BCLllA-12316 + GGAGGGCUGCGGGUCCGG 18 14521

BCLllA-12317 + UGGAGGGCUGCGGGUCCGG 19 14522

BCLllA-12318 + UUGGAGGGCUGCGGGUCCGG 20 14523

BCLllA-12319 + UUUGGAGGGCUGCGGGUCCGG 21 14524

BCLllA-12320 + GUUUGGAGGGCUGCGGGUCCGG 22 14525

BCLllA-12321 + AGUUUGGAGGGCUGCGGGUCCGG 23 14526

BCLllA-12322 + AAGUUUGGAGGGCUGCGGGUCCGG 24 14527

BCLllA-12323 + AAAAG AG AAAU AAAG CGG 18 14528

BCLllA-12324 + G AAAAG AG AAAU AAAG CGG 19 14529

BCLllA-10193 + CGAAAAGAGAAAUAAAGCGG 20 14530

BCLllA-12325 + UCGAAAAGAGAAAUAAAGCGG 21 14531

BCLllA-12326 + UUCGAAAAGAGAAAUAAAGCGG 22 14532

BCLllA-12327 + UUUCGAAAAGAGAAAUAAAGCGG 23 14533

BCLllA-12328 + U U U U CG AAAAG AG AAAU AAAG CGG 24 14534

BCLllA-12329 + GUUACAGCUCCGCAGCGG 18 14535

BCLllA-12330 + AGUUACAGCUCCGCAGCGG 19 14536

BCLllA-12331 + AAGUUACAGCUCCGCAGCGG 20 14537

BCLllA-12332 + CAAGUUACAGCUCCGCAGCGG 21 14538

BCLllA-12333 + CCAAGUUACAGCUCCGCAGCGG 22 14539

BCLllA-12334 + UCCAAGUUACAGCUCCGCAGCGG 23 14540

BCLllA-12335 + CUCCAAGUUACAGCUCCGCAGCGG 24 14541

BCLllA-12336 + CGGGCUGGGGAAGCGCGG 18 14542

BCLllA-12337 + CCGGGCUGGGGAAGCGCGG 19 14543 BCLllA-12338 + CCCGGGCUGGGGAAGCGCGG 20 14544

BCLllA-12339 + CCCCGGGCUGGGGAAGCGCGG 21 14545

BCLllA-12340 + GCCCCGGGCUGGGGAAGCGCGG 22 14546

BCLllA-12341 + AGCCCCGGGCUGGGGAAGCGCGG 23 14547

BCLllA-12342 + CAGCCCCGGGCUGGGGAAGCGCGG 24 14548

BCLllA-12343 + CUGGGGAAGCGCGGGCGG 18 14549

BCLllA-12344 + GCUGGGGAAGCGCGGGCGG 19 14550

BCLllA-10197 + GGCUGGGGAAGCGCGGGCGG 20 14551

BCLllA-12345 + GGGCUGGGGAAGCGCGGGCGG 21 14552

BCLllA-12346 + CGGGCUGGGGAAGCGCGGGCGG 22 14553

BCLllA-12347 + CCGGGCUGGGGAAGCGCGGGCGG 23 14554

BCLllA-12348 + CCCGGGCUGGGGAAGCGCGGGCGG 24 14555

BCLllA-12349 + GCAAAACUGGCGGGGCGG 18 14556

BCLllA-12350 + UGCAAAACUGGCGGGGCGG 19 14557

BCLllA-10198 + UUGCAAAACUGGCGGGGCGG 20 14558

BCLllA-12351 + UUUGCAAAACUGGCGGGGCGG 21 14559

BCLllA-12352 + UUUUGCAAAACUGGCGGGGCGG 22 14560

BCLllA-12353 + AUUUUGCAAAACUGGCGGGGCGG 23 14561

BCLllA-12354 + UAUUUUGCAAAACUGGCGGGGCGG 24 14562

BCLllA-12355 + UGGAAAGAGGGGACCGGG 18 14563

BCLllA-12356 + CUGGAAAGAGGGGACCGGG 19 14564

BCLllA-12357 + CCUGGAAAGAGGGGACCGGG 20 14565

BCLllA-12358 + GCCUGGAAAGAGGGGACCGGG 21 14566

BCLllA-12359 + GGCCUGGAAAGAGGGGACCGGG 22 14567

BCLllA-12360 + CGGCCUGGAAAGAGGGGACCGGG 23 14568

BCLllA-12361 + GCGGCCUGGAAAGAGGGGACCGGG 24 14569

BCLllA-12362 + GGAGGCUGCAGCCCCGGG 18 14570

BCLllA-12363 + GGGAGGCUGCAGCCCCGGG 19 14571

BCLllA-12364 + CGGGAGGCUGCAGCCCCGGG 20 14572

BCLllA-12365 + CCGGGAGGCUGCAGCCCCGGG 21 14573

BCLllA-12366 + ACCGGGAGGCUGCAGCCCCGGG 22 14574

BCLllA-12367 + CACCGGGAGGCUGCAGCCCCGGG 23 14575

BCLllA-12368 + GCACCGGGAGGCUGCAGCCCCGGG 24 14576

BCLllA-12369 + GGGCUGGGGAAGCGCGGG 18 14577

BCLllA-12370 + CGGGCUGGGGAAGCGCGGG 19 14578

BCLllA-10203 + CCGGGCUGGGGAAGCGCGGG 20 14579

BCLllA-12371 + CCCGGGCUGGGGAAGCGCGGG 21 14580

BCLllA-12372 + CCCCGGGCUGGGGAAGCGCGGG 22 14581

BCLllA-12373 + GCCCCGGGCUGGGGAAGCGCGGG 23 14582

BCLllA-12374 + AGCCCCGGGCUGGGGAAGCGCGGG 24 14583

BCLllA-12375 + CAAAACUGGCGGGGCGGG 18 14584

BCLllA-12376 + GCAAAACUGGCGGGGCGGG 19 14585 BCLllA-10204 + UGCAAAACUGGCGGGGCGGG 20 14586

BCLllA-12377 + U UGCAAAACUGGCGGGGCGGG 21 14587

BCLllA-12378 + UUUGCAAAACUGGCGGGGCGGG 22 14588

BCLllA-12379 + UUUUGCAAAACUGGCGGGGCGGG 23 14589

BCLllA-12380 + AUUUUGCAAAACUGGCGGGGCGGG 24 14590

BCLllA-12381 + U UUUGCAAAACUGGCGGG 18 14591

BCLllA-12382 + AUUUUGCAAAACUGGCGGG 19 14592

BCLllA-12383 + UAUUUUGCAAAACUGGCGGG 20 14593

BCLllA-12384 + UUAUUUUGCAAAACUGGCGGG 21 14594

BCLllA-12385 + AUUAUUUUGCAAAACUGGCGGG 22 14595

BCLllA-12386 + CAUUAUUUUGCAAAACUGGCGGG 23 14596

BCLllA-12387 + UCAUUAUUUUGCAAAACUGGCGGG 24 14597

BCLllA-12388 + GCGUGUGGACGCCAGGGG 18 14598

BCLllA-12389 + CGCGUGUGGACGCCAGGGG 19 14599

BCLllA-12390 + CCGCGUGUGGACGCCAGGGG 20 14600

BCLllA-12391 + CCCGCGUGUGGACGCCAGGGG 21 14601

BCLllA-12392 + CCCCGCGUGUGGACGCCAGGGG 22 14602

BCLllA-12393 + UCCCCGCGUGUGGACGCCAGGGG 23 14603

BCLllA-12394 + CUCCCCGCGUGUGGACGCCAGGGG 24 14604

BCLllA-12395 + AAAACUGGCGGGGCGGGG 18 14605

BCLllA-12396 + CAAAACUGGCGGGGCGGGG 19 14606

BCLllA-10207 + GCAAAACUGGCGGGGCGGGG 20 14607

BCLllA-12397 + UGCAAAACUGGCGGGGCGGGG 21 14608

BCLllA-12398 + U UGCAAAACUGGCGGGGCGGGG 22 14609

BCLllA-12399 + U UUGCAAAACUGGCGGGGCGGGG 23 14610

BCLllA-12400 + U UUUGCAAAACUGGCGGGGCGGGG 24 14611

BCLllA-12401 + UUUGCAAAACUGGCGGGG 18 14612

BCLllA-12402 + UUUUGCAAAACUGGCGGGG 19 14613

BCLllA-10208 + AUUUUGCAAAACUGGCGGGG 20 14614

BCLllA-12403 + UAUUUUGCAAAACUGGCGGGG 21 14615

BCLllA-12404 + U UAUUUUGCAAAACUGGCGGGG 22 14616

BCLllA-12405 + AUUAUUUUGCAAAACUGGCGGGG 23 14617

BCLllA-12406 + CAUUAUUUUGCAAAACUGGCGGGG 24 14618

BCLllA-12407 + CGGGCGAGGGGAGGUGGG 18 14619

BCLllA-12408 + GCGGGCGAGGGGAGGUGGG 19 14620

BCLllA-10213 + AGCGGGCGAGGGGAGGUGGG 20 14621

BCLllA-12409 + CAGCGGGCGAGGGGAGGUGGG 21 14622

BCLllA-12410 + GCAGCGGGCGAGGGGAGGUGGG 22 14623

BCLllA-12411 + CGCAGCGGGCGAGGGGAGGUGGG 23 14624

BCLllA-12412 + CCGCAGCGGGCGAGGGGAGGUGGG 24 14625

BCLllA-12413 + AUUAUUUUGCAAAACUGG 18 14626

BCLllA-12414 + CAUUAUUUUGCAAAACUGG 19 14627 BCLllA-10215 + UCAUUAUUUUGCAAAACUGG 20 14628

BCLllA-12415 + UUCAUUAUUUUGCAAAACUGG 21 14629

BCLllA-12416 + GUUCAUUAUUUUGCAAAACUGG 22 14630

BCLllA-12417 + UGUUCAUUAUUU UGCAAAACUGG 23 14631

BCLllA-12418 + UUGUUCAUUAUU UUGCAAAACUGG 24 14632

BCLllA-12419 + ACAAACACCCACCUCUGG 18 14633

BCLllA-12420 + GACAAACACCCACCUCUGG 19 14634

BCLllA-12421 + GGACAAACACCCACCUCUGG 20 14635

BCLllA-12422 + GGGACAAACACCCACCUCUGG 21 14636

BCLllA-12423 + CGGGACAAACACCCACCUCUGG 22 14637

BCLllA-12424 + GCGGGACAAACACCCACCUCUGG 23 14638

BCLllA-12425 + AGCGGGACAAACACCCACCUCUGG 24 14639

BCLllA-12426 + GCGGGCGAGGGGAGGUGG 18 14640

BCLllA-12427 + AGCGGGCGAGGGGAGGUGG 19 14641

BCLllA-12428 + CAGCGGGCGAGGGGAGGUGG 20 14642

BCLllA-12429 + GCAGCGGGCGAGGGGAGGUGG 21 14643

BCLllA-12430 + CGCAGCGGGCGAGGGGAGGUGG 22 14644

BCLllA-12431 + CCGCAGCGGGCGAGGGGAGGUGG 23 14645

BCLllA-12432 + UCCGCAGCGGGCGAGGGGAGGUGG 24 14646

BCLllA-12433 + CAUUAUUUUGCAAAACUG 18 14647

BCLllA-12434 + UCAUUAUUUUGCAAAACUG 19 14648

BCLllA-12435 + UUCAUUAUUUUGCAAAACUG 20 14649

BCLllA-12436 + GUUCAUUAUUUUGCAAAACUG 21 14650

BCLllA-12437 + UGUUCAUUAUUU UGCAAAACUG 22 14651

BCLllA-12438 + UUGUUCAUUAUU UUGCAAAACUG 23 14652

BCLllA-12439 + AUUGUUCAUUAUUUUGCAAAACUG 24 14653

BCLllA-12440 + GGCUGCAGCCCCGGGCUG 18 14654

BCLllA-12441 + AGGCUGCAGCCCCGGGCUG 19 14655

BCLllA-10226 + GAGGCUGCAGCCCCGGGCUG 20 14656

BCLllA-12442 + GGAGGCUGCAGCCCCGGGCUG 21 14657

BCLllA-12443 + GGGAGGCUGCAGCCCCGGGCUG 22 14658

BCLllA-12444 + CGGGAGGCUGCAGCCCCGGGCUG 23 14659

BCLllA-12445 + CCGGGAGGCUGCAGCCCCGGGCUG 24 14660

BCLllA-12446 + GCCACUUUCUCACUAUUG 18 14661

BCLllA-12447 + UGCCACUU UCUCACUAUUG 19 14662

BCLllA-10230 + GUGCCACU UUCUCACUAUUG 20 14663

BCLllA-12448 + AGUGCCACUUUCUCACUAUUG 21 14664

BCLllA-12449 + CAGUGCCACUUUCUCACUAUUG 22 14665

BCLllA-12450 + ACAGUGCCACU UUCUCACUAUUG 23 14666

BCLllA-12451 + CACAGUGCCACUUUCUCACUAUUG 24 14667

BCLllA-12452 + GAAUCCAGCCUAAGU UUG 18 14668

BCLllA-12453 + GGAAUCCAGCCUAAGUU UG 19 14669 BCLllA-12454 + CGGAAUCCAGCCUAAGUUUG 20 14670

BCLllA-12455 + GCGGAAUCCAGCCUAAGUUUG 21 14671

BCLllA-12456 + CGCGGAAUCCAGCCUAAGUUUG 22 14672

BCLllA-12457 + ACGCGGAAUCCAGCCUAAGUUUG 23 14673

BCLllA-12458 + AACGCGGAAUCCAGCCUAAGUUUG 24 14674

BCLllA-12459 + CUCCCGACUCCGCGGACU 18 14675

BCLllA-12460 + UCUCCCGACUCCGCGGACU 19 14676

BCLllA-12461 + CUCUCCCGACUCCGCGGACU 20 14677

BCLllA-12462 + CCUCUCCCGACUCCGCGGACU 21 14678

BCLllA-12463 + CCCUCUCCCGACUCCGCGGACU 22 14679

BCLllA-12464 + CCCCUCUCCCGACUCCGCGGACU 23 14680

BCLllA-12465 + GCCCCUCUCCCGACUCCGCGGACU 24 14681

BCLllA-12466 + CGAGCCCGCGGCUGCGCU 18 14682

BCLllA-12467 + CCGAGCCCGCGGCUGCGCU 19 14683

BCLllA-10239 + CCCGAGCCCGCGGCUGCGCU 20 14684

BCLllA-12468 + CCCCGAGCCCGCGGCUGCGCU 21 14685

BCLllA-12469 + GCCCCGAGCCCGCGGCUGCGCU 22 14686

BCLllA-12470 + AGCCCCGAGCCCGCGGCUGCGCU 23 14687

BCLllA-12471 + AAGCCCCGAGCCCGCGGCUGCGCU 24 14688

BCLllA-12472 + AGGCUGCAGCCCCGGGCU 18 14689

BCLllA-12473 + GAGGCUGCAGCCCCGGGCU 19 14690

BCLllA-10240 + GGAGGCUGCAGCCCCGGGCU 20 14691

BCLllA-12474 + GGGAGGCUGCAGCCCCGGGCU 21 14692

BCLllA-12475 + CGGGAGGCUGCAGCCCCGGGCU 22 14693

BCLllA-12476 + CCGGGAGGCUGCAGCCCCGGGCU 23 14694

BCLllA-12477 + ACCGGGAGGCUGCAGCCCCGGGCU 24 14695

BCLllA-12478 + GCGGAAUCCAGCCUAAGU 18 14696

BCLllA-12479 + CGCGGAAUCCAGCCUAAGU 19 14697

BCLllA-12480 + ACGCGGAAUCCAGCCUAAGU 20 14698

BCLllA-12481 + AACGCGGAAUCCAGCCUAAGU 21 14699

BCLllA-12482 + CAACGCGGAAUCCAGCCUAAGU 22 14700

BCLllA-12483 + GCAACGCGGAAUCCAGCCUAAGU 23 14701

BCLllA-12484 + GGCAACGCGGAAUCCAGCCUAAGU 24 14702

BCLllA-12485 + CAUUUUCUUACGGUGAGU 18 14703

BCLllA-12486 + CCAU UUUCUUACGGUGAGU 19 14704

BCLllA-10244 + CCCAUU UUCUUACGGUGAGU 20 14705

BCLllA-12487 + CCCCAUU UUCUUACGGUGAGU 21 14706

BCLllA-12488 + CCCCCAUUU UCUUACGGUGAGU 22 14707

BCLllA-12489 + CCCCCCAUUUUCUUACGGUGAGU 23 14708

BCLllA-12490 + CCCCCCCAUU UUCU UACGGUGAGU 24 14709

BCLllA-12491 + CGCGCUCGCUCCCCGCGU 18 14710

BCLllA-12492 + CCGCGCUCGCUCCCCGCGU 19 14711 BCLllA-12493 + GCCGCGCUCGCUCCCCGCGU 20 14712

BCLllA-12494 + CGCCGCGCUCGCUCCCCGCGU 21 14713

BCLllA-12495 + CCGCCGCGCUCGCUCCCCGCGU 22 14714

BCLllA-12496 + GCCGCCGCGCUCGCUCCCCGCGU 23 14715

BCLllA-12497 + CGCCGCCGCGCUCGCUCCCCGCGU 24 14716

BCLllA-12498 + CAGCGGGCGAGGGGAGGU 18 14717

BCLllA-12499 + GCAGCGGGCGAGGGGAGGU 19 14718

BCLllA-10247 + CGCAGCGGGCGAGGGGAGGU 20 14719

BCLllA-12500 + CCGCAGCGGGCGAGGGGAGGU 21 14720

BCLllA-12501 + UCCGCAGCGGGCGAGGGGAGGU 22 14721

BCLllA-12502 + CUCCGCAGCGGGCGAGGGGAGGU 23 14722

BCLllA-12503 + GCUCCGCAGCGGGCGAGGGGAGGU 24 14723

BCLllA-12504 + GUUUGGAGGGCUGCGGGU 18 14724

BCLllA-12505 + AGUUUGGAGGGCUGCGGGU 19 14725

BCLllA-12506 + AAGUUUGGAGGGCUGCGGGU 20 14726

BCLllA-12507 + UAAGUUUGGAGGGCUGCGGGU 21 14727

BCLllA-12508 + CU AAGUUUGGAGGGCUGCGGGU 22 14728

BCLllA-12509 + CCUAAGUUUGGAGGGCUGCGGGU 23 14729

BCLllA-12510 + GCCUAAGUUUGGAGGGCUGCGGGU 24 14730

BCLllA-12511 + UGCCACUU UCUCACUAUU 18 14731

BCLllA-12512 + GUGCCACUUUCUCACUAUU 19 14732

BCLllA-12513 + AGUGCCACUU UCUCACUAUU 20 14733

BCLllA-12514 + CAGUGCCACUUUCUCACUAUU 21 14734

BCLllA-12515 + ACAGUGCCACU UUCUCACUAUU 22 14735

BCLllA-12516 + CACAGUGCCACUUUCUCACUAUU 23 14736

BCLllA-12517 + CCACAGUGCCACUUUCUCACUAUU 24 14737

BCLllA-12518 + G AAAAAU CACCCG AAG U U 18 14738

BCLllA-12519 + AG AAAAAU CACCCG AAG U U 19 14739

BCLllA-12520 + AAG AAAAAU CACCCG AAG U U 20 14740

BCLllA-12521 + AAAG AAAAAU CACCCG AAG UU 21 14741

BCLllA-12522 + CAAAG AAAAAU CACCCG AAG U U 22 14742

BCLllA-12523 + G CAAAG AAAAAU CACCCG AAG UU 23 14743

BCLllA-12524 + AGCAAAGAAAAAUCACCCGAAGUU 24 14744

BCLllA-12525 + CGGAAUCCAGCCUAAGU U 18 14745

BCLllA-12526 + GCGGAAUCCAGCCUAAGUU 19 14746

BCLllA-10257 + CGCGGAAUCCAGCCUAAGUU 20 14747

BCLllA-12527 + ACGCGGAAUCCAGCCUAAGUU 21 14748

BCLllA-12528 + AACGCGGAAUCCAGCCUAAGUU 22 14749

BCLllA-12529 + CAACGCGGAAUCCAGCCUAAGUU 23 14750

BCLllA-12530 + GCAACGCGGAAUCCAGCCUAAGUU 24 14751

BCLllA-12531 + GAAUCAUUGCAUUCCUU U 18 14752

BCLllA-12532 + GGAAUCAUUGCAUUCCUUU 19 14753 BCLllA-12533 + UGGAAUCAUUGCAUUCCUUU 20 14754

BCLllA-12534 + GUGGAAUCAUUGCAUUCCUUU 21 14755

BCLllA-12535 + AGUGGAAUCAUUGCAUUCCUUU 22 14756

BCLllA-12536 + GAGUGGAAUCAUUGCAUUCCUUU 23 14757

BCLllA-12537 + GGAGUGGAAUCAUUGCAUUCCUUU 24 14758

BCLllA-12538 - CCACUCACCGUAAGAAAA 18 14759

BCLllA-12539 - CCCACU CACCG UAAGAAAA 19 14760

BCLllA-10024 - U CCCACU CACCG UAAGAAAA 20 14761

BCLllA-12540 - UUCCCACUCACCGUAAGAAAA 21 14762

BCLllA-12541 - CUUCCCACUCACCGUAAGAAAA 22 14763

BCLllA-12542 - GCUUCCCACUCACCGUAAGAAAA 23 14764

BCLllA-12543 - UGCUUCCCACUCACCGUAAGAAAA 24 14765

BCLllA-12544 - CCCACUCACCGUAAGAAA 18 14766

BCLllA-12545 - UCCCACUCACCGUAAGAAA 19 14767

BCLllA-12546 - U U CCCACU CACCG U AAG AAA 20 14768

BCLllA-12547 - CU U CCCACU CACCG U AAG AAA 21 14769

BCLllA-12548 - GCUUCCCACUCACCGUAAGAAA 22 14770

BCLllA-12549 - UGCUUCCCACUCACCGUAAGAAA 23 14771

BCLllA-12550 - UUGCUUCCCACUCACCGUAAGAAA 24 14772

BCLllA-12551 - UGGGAGCUGGUGGGGAAA 18 14773

BCLllA-12552 - GUGGGAGCUGGUGGGGAAA 19 14774

BCLllA-10028 - GGUGGGAGCUGGUGGGGAAA 20 14775

BCLllA-12553 - GGGUGGGAGCUGGUGGGGAAA 21 14776

BCLllA-12554 - GGGGUGGGAGCUGGUGGGGAAA 22 14777

BCLllA-12555 - GGGGGUGGGAGCUGGUGGGGAAA 23 14778

BCLllA-12556 - UGGGGGUGGGAGCUGGUGGGGAAA 24 14779

BCLllA-12557 - AACGAUUCCCGGGGAGAA 18 14780

BCLllA-12558 - AAACGAUUCCCGGGGAGAA 19 14781

BCLllA-12559 - AAAACGAUUCCCGGGGAGAA 20 14782

BCLllA-12560 - AAAAACGAUUCCCGGGGAGAA 21 14783

BCLllA-12561 - AAAAAACGAUUCCCGGGGAGAA 22 14784

BCLllA-12562 - UAAAAAACGAUUCCCGGGGAGAA 23 14785

BCLllA-12563 - CUAAAAAACGAUUCCCGGGGAGAA 24 14786

BCLllA-12564 - UUUAUUUCUCUUUUCGAA 18 14787

BCLllA-12565 - CUUUAUUUCUCUUUUCGAA 19 14788

BCLllA-12566 - GCUUUAUUUCUCUUUUCGAA 20 14789

BCLllA-12567 - CGCUUUAUUUCUCUUUUCGAA 21 14790

BCLllA-12568 - CCGCUUUAUUUCUCUUUUCGAA 22 14791

BCLllA-12569 - GCCGCUUUAUUUCUCUUUUCGAA 23 14792

BCLllA-12570 - CGCCGCUUUAUUUCUCUUUUCGAA 24 14793

BCLllA-12571 - GUGGGAGCUGGUGGGGAA 18 14794

BCLllA-12572 - GGUGGGAGCUGGUGGGGAA 19 14795 BCLllA-10032 - GGGUGGGAGCUGGUGGGGAA 20 14796

BCLllA-12573 - GGGGUGGGAGCUGGUGGGGAA 21 14797

BCLllA-12574 - GGGGGUGGGAGCUGGUGGGGAA 22 14798

BCLllA-12575 - UGGGGGUGGGAGCUGGUGGGGAA 23 14799

BCLllA-12576 - CUGGGGGUGGGAGCUGGUGGGGAA 24 14800

BCLllA-12577 - GAAAGUGGCACUGUGGAA 18 14801

BCLllA-12578 - AGAAAGUGGCACUGUGGAA 19 14802

BCLllA-10033 - GAGAAAGUGGCACUGUGGAA 20 14803

BCLllA-12579 - UGAGAAAGUGGCACUGUGGAA 21 14804

BCLllA-12580 - GUGAGAAAGUGGCACUGUGGAA 22 14805

BCLllA-12581 - AGUGAGAAAGUGGCACUGUGGAA 23 14806

BCLllA-12582 - UAGUGAGAAAGUGGCACUGUGGAA 24 14807

BCLllA-12583 - CUCACGGUCAAGUGUGCA 18 14808

BCLllA-12584 - GCUCACGGUCAAGUGUGCA 19 14809

BCLllA-12585 - CGCUCACGGUCAAGUGUGCA 20 14810

BCLllA-12586 - GCGCUCACGGUCAAGUGUGCA 21 14811

BCLllA-12587 - CGCGCUCACGGUCAAGUGUGCA 22 14812

BCLllA-12588 - GCGCGCUCACGGUCAAGUGUGCA 23 14813

BCLllA-12589 - AGCGCGCUCACGGUCAAGUGUGCA 24 14814

BCLllA-12590 - GGAGAGGGGCCGCGGCGA 18 14815

BCLllA-12591 - GGGAGAGGGGCCGCGGCGA 19 14816

BCLllA-10043 - CGGGAGAGGGGCCGCGGCGA 20 14817

BCLllA-12592 - UCGGGAGAGGGGCCGCGGCGA 21 14818

BCLllA-12593 - GUCGGGAGAGGGGCCGCGGCGA 22 14819

BCLllA-12594 - AGUCGGGAGAGGGGCCGCGGCGA 23 14820

BCLllA-12595 - GAGUCGGGAGAGGGGCCGCGGCGA 24 14821

BCLllA-12596 - CCGUGGGACCGGGAAGGA 18 14822

BCLllA-12597 - GCCGUGGGACCGGGAAGGA 19 14823

BCLllA-10045 - AGCCGUGGGACCGGGAAGGA 20 14824

BCLllA-12598 - GAGCCGUGGGACCGGGAAGGA 21 14825

BCLllA-12599 - AGAGCCGUGGGACCGGGAAGGA 22 14826

BCLllA-12600 - GAGAGCCGUGGGACCGGGAAGGA 23 14827

BCLllA-12601 - GGAGAGCCGUGGGACCGGGAAGGA 24 14828

BCLllA-12602 - GAGUCCGCGGAGUCGGGA 18 14829

BCLllA-12603 - UGAGUCCGCGGAGUCGGGA 19 14830

BCLllA-12604 - CUGAGUCCGCGGAGUCGGGA 20 14831

BCLllA-12605 - CCUGAGUCCGCGGAGUCGGGA 21 14832

BCLllA-12606 - UCCUGAGUCCGCGGAGUCGGGA 22 14833

BCLllA-12607 - CUCCUGAGUCCGCGGAGUCGGGA 23 14834

BCLllA-12608 - GCUCCUGAGUCCGCGGAGUCGGGA 24 14835

BCLllA-12609 - GGCGUCCACACGCGGGGA 18 14836

BCLllA-12610 - UGGCGUCCACACGCGGGGA 19 14837 BCLllA-12611 - CUGGCGUCCACACGCGGGGA 20 14838

BCLllA-12612 - CCUGGCGUCCACACGCGGGGA 21 14839

BCLllA-12613 - CCCUGGCGUCCACACGCGGGGA 22 14840

BCLllA-12614 - CCCCUGGCGUCCACACGCGGGGA 23 14841

BCLllA-12615 - GCCCCUGGCGUCCACACGCGGGGA 24 14842

BCLllA-12616 - GCGCGGCGGCGGCGGGGA 18 14843

BCLllA-12617 - AGCGCGGCGGCGGCGGGGA 19 14844

BCLllA-10051 - GAGCGCGGCGGCGGCGGGGA 20 14845

BCLllA-12618 - CGAGCGCGGCGGCGGCGGGGA 21 14846

BCLllA-12619 - GCGAGCGCGGCGGCGGCGGGGA 22 14847

BCLllA-12620 - AGCGAGCGCGGCGGCGGCGGGGA 23 14848

BCLllA-12621 - GAGCGAGCGCGGCGGCGGCGGGGA 24 14849

BCLllA-12622 - GGUGGGAGCUGGUGGGGA 18 14850

BCLllA-12623 - GGGUGGGAGCUGGUGGGGA 19 14851

BCLllA-12624 - GGGGUGGGAGCUGGUGGGGA 20 14852

BCLllA-12625 - GGGGGUGGGAGCUGGUGGGGA 21 14853

BCLllA-12626 - UGGGGGUGGGAGCUGGUGGGGA 22 14854

BCLllA-12627 - CUGGGGGUGGGAGCUGGUGGGGA 23 14855

BCLllA-12628 - CCUGGGGGUGGGAGCUGGUGGGGA 24 14856

BCLllA-12629 - ACGGGGAGAGCCGUGGGA 18 14857

BCLllA-12630 - GACGGGGAGAGCCGUGGGA 19 14858

BCLllA-12631 - CGACGGGGAGAGCCGUGGGA 20 14859

BCLllA-12632 - GCGACGGGGAGAGCCGUGGGA 21 14860

BCLllA-12633 - GGCGACGGGGAGAGCCGUGGGA 22 14861

BCLllA-12634 - CGGCGACGGGGAGAGCCGUGGGA 23 14862

BCLllA-12635 - GCGGCGACGGGGAGAGCCGUGGGA 24 14863

BCLllA-12636 - AGAAAGUGGCACUGUGGA 18 14864

BCLllA-12637 - GAGAAAGUGGCACUGUGGA 19 14865

BCLllA-12638 - UGAGAAAGUGGCACUGUGGA 20 14866

BCLllA-12639 - GUGAGAAAGUGGCACUGUGGA 21 14867

BCLllA-12640 - AGUGAGAAAGUGGCACUGUGGA 22 14868

BCLllA-12641 - UAGUGAGAAAGUGGCACUGUGGA 23 14869

BCLllA-12642 - AUAGUGAGAAAGUGGCACUGUGGA 24 14870

BCLllA-12643 - CGCCAGUUUUGCAAAAUA 18 14871

BCLllA-12644 - CCGCCAGUUUUGCAAAAUA 19 14872

BCLllA-12645 - CCCGCCAGUUUUGCAAAAUA 20 14873

BCLllA-12646 - CCCCGCCAGUUUUGCAAAAUA 21 14874

BCLllA-12647 - GCCCCGCCAGUUUUGCAAAAUA 22 14875

BCLllA-12648 - CGCCCCGCCAGUUUUGCAAAAUA 23 14876

BCLllA-12649 - CCGCCCCGCCAGUUUUGCAAAAUA 24 14877

BCLllA-12650 - GUAGUCAUCCCCACAAUA 18 14878

BCLllA-12651 - AGUAGUCAUCCCCACAAUA 19 14879 BCLllA-12652 - AAGUAGUCAUCCCCACAAUA 20 14880

BCLllA-12653 - AAAGUAGUCAUCCCCACAAUA 21 14881

BCLllA-12654 - GAAAGUAGUCAUCCCCACAAUA 22 14882

BCLllA-12655 - GGAAAGUAGUCAUCCCCACAAUA 23 14883

BCLllA-12656 - AGGAAAGUAGUCAUCCCCACAAUA 24 14884

BCLllA-12657 - GGGAAGUGGGUGUGCGUA 18 14885

BCLllA-12658 - GGGGAAGUGGGUGUGCGUA 19 14886

BCLllA-10055 - AGGGGAAGUGGGUGUGCGUA 20 14887

BCLllA-12659 - GAGGGGAAGUGGGUGUGCGUA 21 14888

BCLllA-12660 - GGAGGGGAAGUGGGUGUGCGUA 22 14889

BCLllA-12661 - GGGAGGGGAAGUGGGUGUGCGUA 23 14890

BCLllA-12662 - GGGGAGGGGAAGUGGGUGUGCGUA 24 14891

BCLllA-12663 - UAAGAAAAUGGGGGGGUA 18 14892

BCLllA-12664 - GUAAGAAAAUGGGGGGGUA 19 14893

BCLllA-10056 - CGUAAGAAAAUGGGGGGGUA 20 14894

BCLllA-12665 - CCGUAAGAAAAUGGGGGGGUA 21 14895

BCLllA-12666 - ACCGUAAGAAAAUGGGGGGGUA 22 14896

BCLllA-12667 - CACCGUAAGAAAAUGGGGGGGUA 23 14897

BCLllA-12668 - UCACCGUAAGAAAAUGGGGGGGUA 24 14898

BCLllA-12669 - A ACAAC U CAC AU G CAAAC 18 14899

BCLllA-12670 - GAACAACUCACAUGCAAAC 19 14900

BCLllA-12671 - CGAACAACUCACAUGCAAAC 20 14901

BCLllA-12672 - GCGAACAACUCACAUGCAAAC 21 14902

BCLllA-12673 - UGCGAACAACUCACAUGCAAAC 22 14903

BCLllA-12674 - UUGCGAACAACUCACAUGCAAAC 23 14904

BCLllA-12675 - G U U G CG AACAAC U C ACA U G CAAAC 24 14905

BCLllA-12676 - CCGCUGCGGAGCUGUAAC 18 14906

BCLllA-12677 - CCCGCUGCGGAGCUGUAAC 19 14907

BCLllA-12678 - GCCCGCUGCGGAGCUGUAAC 20 14908

BCLllA-12679 - CGCCCGCUGCGGAGCUGUAAC 21 14909

BCLllA-12680 - UCGCCCGCUGCGGAGCUGUAAC 22 14910

BCLllA-12681 - CUCGCCCGCUGCGGAGCUGUAAC 23 14911

BCLllA-12682 - CCUCGCCCGCUGCGGAGCUGUAAC 24 14912

BCLllA-12683 - GGCCCCUGGCGUCCACAC 18 14913

BCLllA-12684 - CGGCCCCUGGCGUCCACAC 19 14914

BCLllA-12685 - UCGGCCCCUGGCGUCCACAC 20 14915

BCLllA-12686 - UUCGGCCCCUGGCGUCCACAC 21 14916

BCLllA-12687 - CUUCGGCCCCUGGCGUCCACAC 22 14917

BCLllA-12688 - ACUUCGGCCCCUGGCGUCCACAC 23 14918

BCLllA-12689 - UACUUCGGCCCCUGGCGUCCACAC 24 14919

BCLllA-12690 - GCGCGGGCUCCUGGAGAC 18 14920

BCLllA-12691 - CGCGCGGGCUCCUGGAGAC 19 14921 BCLllA-12692 - CCGCGCGGGCUCCUGGAGAC 20 14922

BCLllA-12693 - GCCGCGCGGGCUCCUGGAGAC 21 14923

BCLllA-12694 - GGCCGCGCGGGCUCCUGGAGAC 22 14924

BCLllA-12695 - AGGCCGCGCGGGCUCCUGGAGAC 23 14925

BCLllA-12696 - CAGGCCGCGCGGGCUCCUGGAGAC 24 14926

BCLllA-12697 - GAGAGGGGCCGCGGCGAC 18 14927

BCLllA-12698 - GGAGAGGGGCCGCGGCGAC 19 14928

BCLllA-10061 - GGGAGAGGGGCCGCGGCGAC 20 14929

BCLllA-12699 - CGGGAGAGGGGCCGCGGCGAC 21 14930

BCLllA-12700 - UCGGGAGAGGGGCCGCGGCGAC 22 14931

BCLllA-12701 - GUCGGGAGAGGGGCCGCGGCGAC 23 14932

BCLllA-12702 - AGUCGGGAGAGGGGCCGCGGCGAC 24 14933

BCLllA-12703 - CGUGGGACCGGGAAGGAC 18 14934

BCLllA-12704 - CCGUGGGACCGGGAAGGAC 19 14935

BCLllA-10062 - GCCGUGGGACCGGGAAGGAC 20 14936

BCLllA-12705 - AGCCGUGGGACCGGGAAGGAC 21 14937

BCLllA-12706 - GAGCCGUGGGACCGGGAAGGAC 22 14938

BCLllA-12707 - AGAGCCGUGGGACCGGGAAGGAC 23 14939

BCLllA-12708 - GAGAGCCGUGGGACCGGGAAGGAC 24 14940

BCLllA-12709 - CGGGGAGAGCCGUGGGAC 18 14941

BCLllA-12710 - ACGGGGAGAGCCGUGGGAC 19 14942

BCLllA-10065 - GACGGGGAGAGCCGUGGGAC 20 14943

BCLllA-12711 - CGACGGGGAGAGCCGUGGGAC 21 14944

BCLllA-12712 - GCGACGGGGAGAGCCGUGGGAC 22 14945

BCLllA-12713 - GGCGACGGGGAGAGCCGUGGGAC 23 14946

BCLllA-12714 - CGGCGACGGGGAGAGCCGUGGGAC 24 14947

BCLllA-12715 - ACAACUCACAUGCAAACC 18 14948

BCLllA-12716 - AACAACUCACAUGCAAACC 19 14949

BCLllA-10066 - GAACAACUCACAUGCAAACC 20 14950

BCLllA-12717 - CGAACAACUCACAUGCAAACC 21 14951

BCLllA-12718 - GCGAACAACUCACAUGCAAACC 22 14952

BCLllA-12719 - U G CG AACAAC U CAC AU G CAAACC 23 14953

BCLllA-12720 - UUGCGAACAACUCACAUGCAAACC 24 14954

BCLllA-12721 - GGGGAGAGCCGUGGGACC 18 14955

BCLllA-12722 - CGGGGAGAGCCGUGGGACC 19 14956

BCLllA-10070 - ACGGGGAGAGCCGUGGGACC 20 14957

BCLllA-12723 - GACGGGGAGAGCCGUGGGACC 21 14958

BCLllA-12724 - CGACGGGGAGAGCCGUGGGACC 22 14959

BCLllA-12725 - GCGACGGGGAGAGCCGUGGGACC 23 14960

BCLllA-12726 - GGCGACGGGGAGAGCCGUGGGACC 24 14961

BCLllA-12727 - UCGGCCUUGGGGGCGCCC 18 14962

BCLllA-12728 - CUCGGCCUUGGGGGCGCCC 19 14963 BCLllA-12729 - GCUCGGCCUUGGGGGCGCCC 20 14964

BCLllA-12730 - GGCUCGGCCUUGGGGGCGCCC 21 14965

BCLllA-12731 - UGGCUCGGCCUUGGGGGCGCCC 22 14966

BCLllA-12732 - CUGGCUCGGCCUUGGGGGCGCCC 23 14967

BCLllA-12733 - CCUGGCUCGGCCUUGGGGGCGCCC 24 14968

BCLllA-12734 - GUCUAAAAAACGAUUCCC 18 14969

BCLllA-12735 - AGUCUAAAAAACGAUUCCC 19 14970

BCLllA-10082 - AAGUCUAAAAAACGAUUCCC 20 14971

BCLllA-12736 - CAAGUCUAAAAAACGAUUCCC 21 14972

BCLllA-12737 - ACAAGUCUAAAAAACGAUUCCC 22 14973

BCLllA-12738 - UACAAGUCUAAAAAACGAUUCCC 23 14974

BCLllA-12739 - GUACAAGUCUAAAAAACGAUUCCC 24 14975

BCLllA-12740 - GCCCGCGCUUCCCCAGCC 18 14976

BCLllA-12741 - CGCCCGCGCUUCCCCAGCC 19 14977

BCLllA-10084 - CCGCCCGCGCUUCCCCAGCC 20 14978

BCLllA-12742 - UCCGCCCGCGCUUCCCCAGCC 21 14979

BCLllA-12743 - CUCCGCCCGCGCUUCCCCAGCC 22 14980

BCLllA-12744 - CCUCCGCCCGCGCUUCCCCAGCC 23 14981

BCLllA-12745 - CCCUCCGCCCGCGCUUCCCCAGCC 24 14982

BCLllA-12746 - AGUUUCCCGAGCGCAGCC 18 14983

BCLllA-12747 - AAGUUUCCCGAGCGCAGCC 19 14984

BCLllA-12748 - A AAG UUUCCCGAG CG C AG CC 20 14985

BCLllA-12749 - CAAAG U U U CCCG AG CG CAGCC 21 14986

BCLllA-12750 - GCAAAGUUUCCCGAGCGCAGCC 22 14987

BCLllA-12751 - GGCAAAGUUUCCCGAGCGCAGCC 23 14988

BCLllA-12752 - GGGCAAAGUUUCCCGAGCGCAGCC 24 14989

BCLllA-12753 - GCGGCGACGGGGAGAGCC 18 14990

BCLllA-12754 - CGCGGCGACGGGGAGAGCC 19 14991

BCLllA-12755 - CCGCGGCGACGGGGAGAGCC 20 14992

BCLllA-12756 - GCCGCGGCGACGGGGAGAGCC 21 14993

BCLllA-12757 - GGCCGCGGCGACGGGGAGAGCC 22 14994

BCLllA-12758 - GGGCCGCGGCGACGGGGAGAGCC 23 14995

BCLllA-12759 - GGGGCCGCGGCGACGGGGAGAGCC 24 14996

BCLllA-12760 - CCGGUCCCUGGCUCGGCC 18 14997

BCLllA-12761 - CCCGGUCCCUGGCUCGGCC 19 14998

BCLllA-12762 - UCCCGGUCCCUGGCUCGGCC 20 14999

BCLllA-12763 - CCAGGCCGCGCGGGCUCC 18 15000

BCLllA-12764 - UCCAGGCCGCGCGGGCUCC 19 15001

BCLllA-10091 - UUCCAGGCCGCGCGGGCUCC 20 15002

BCLllA-12765 - UUUCCAGGCCGCGCGGGCUCC 21 15003

BCLllA-12766 - CUUUCCAGGCCGCGCGGGCUCC 22 15004

BCLllA-12767 - UCUUUCCAGGCCGCGCGGGCUCC 23 15005 BCLllA-12768 - CUCUUUCCAGGCCGCGCGGGCUCC 24 15006

BCLllA-12769 - UUCUUUGCUGUCCUCUCC 18 15007

BCLllA-12770 - UUUCUUUGCUGUCCUCUCC 19 15008

BCLllA-12771 - UUUUCUUUGCUGUCCUCUCC 20 15009

BCLllA-12772 - UUUUUCUUUGCUGUCCUCUCC 21 15010

BCLllA-12773 - AUUUUUCUUUGCUGUCCUCUCC 22 15011

BCLllA-12774 - GAUUUUUCUUUGCUGUCCUCUCC 23 15012

BCLllA-12775 - UGAUUUUUCUUUGCUGUCCUCUCC 24 15013

BCLllA-12776 - CCCGGCGCUCCUGAGUCC 18 15014

BCLllA-12777 - CCCCGGCGCUCCUGAGUCC 19 15015

BCLllA-12778 - CCCCCGGCGCUCCUGAGUCC 20 15016

BCLllA-12779 - GCCCCCGGCGCUCCUGAGUCC 21 15017

BCLllA-12780 - GGCCCCCGGCGCUCCUGAGUCC 22 15018

BCLllA-12781 - GGGCCCCCGGCGCUCCUGAGUCC 23 15019

BCLllA-12782 - GGGGCCCCCGGCGCUCCUGAGUCC 24 15020

BCLllA-12783 - GUACGGAGGAGGGUGUCC 18 15021

BCLllA-12784 - CGUACGGAGGAGGGUGUCC 19 15022

BCLllA-10094 - GCGUACGGAGGAGGGUGUCC 20 15023

BCLllA-12785 - UGCGUACGGAGGAGGGUGUCC 21 15024

BCLllA-12786 - GUGCGUACGGAGGAGGGUGUCC 22 15025

BCLllA-12787 - UGUGCGUACGGAGGAGGGUGUCC 23 15026

BCLllA-12788 - GUGUGCGUACGGAGGAGGGUGUCC 24 15027

BCLllA-12789 - AGUCUAAAAAACGAUUCC 18 15028

BCLllA-12790 - AAGUCU AAAAAACG AUUCC 19 15029

BCLllA-10095 - CAAGUCUAAAAAACGAUUCC 20 15030

BCLllA-12791 - ACAAG UCU AAAAAACG AUUCC 21 15031

BCLllA-12792 - UACAAGUCUAAAAAACGAUUCC 22 15032

BCLllA-12793 - GUACAAGUCUAAAAAACGAUUCC 23 15033

BCLllA-12794 - AG U ACAAG U CU AAAAAACG AU U CC 24 15034

BCLllA-12795 - CGCCCGCGCUUCCCCAGC 18 15035

BCLllA-12796 - CCGCCCGCGCUUCCCCAGC 19 15036

BCLllA-12797 - UCCGCCCGCGCUUCCCCAGC 20 15037

BCLllA-12798 - CUCCGCCCGCGCUUCCCCAGC 21 15038

BCLllA-12799 - CCUCCGCCCGCGCUUCCCCAGC 22 15039

BCLllA-12800 - CCCUCCGCCCGCGCUUCCCCAGC 23 15040

BCLllA-12801 - UCCCUCCGCCCGCGCUUCCCCAGC 24 15041

BCLllA-12802 - CACGGU CA AG U G U G CAG C 18 15042

BCLllA-12803 - UCACGGUCAAGUGUGCAGC 19 15043

BCLllA-10100 - CUCACGGUCAAGUGUGCAGC 20 15044

BCLllA-12804 - GCUCACGGUCAAGUGUGCAGC 21 15045

BCLllA-12805 - CGCUCACGGUCAAGUGUGCAGC 22 15046

BCLllA-12806 - GCGCUCACGGUCAAGUGUGCAGC 23 15047 BCLllA-12807 - CGCGCUCACGGUCAAGUGUGCAGC 24 15048

BCLllA-12808 - CCCCUGGCGUCCACACGC 18 15049

BCLllA-12809 - GCCCCUGGCGUCCACACGC 19 15050

BCLllA-10103 - GGCCCCUGGCGUCCACACGC 20 15051

BCLllA-12810 - CGGCCCCUGGCGUCCACACGC 21 15052

BCLllA-12811 - UCGGCCCCUGGCGUCCACACGC 22 15053

BCLllA-12812 - UUCGGCCCCUGGCGUCCACACGC 23 15054

BCLllA-12813 - CUUCGGCCCCUGGCGUCCACACGC 24 15055

BCLllA-12814 - CCCCUCUUUCCAGGCCGC 18 15056

BCLllA-12815 - UCCCCUCUUUCCAGGCCGC 19 15057

BCLllA-12816 - GUCCCCUCUUUCCAGGCCGC 20 15058

BCLllA-12817 - GGUCCCCUCUUUCCAGGCCGC 21 15059

BCLllA-12818 - CGGUCCCCUCUUUCCAGGCCGC 22 15060

BCLllA-12819 - CCGGUCCCCUCUUUCCAGGCCGC 23 15061

BCLllA-12820 - CCCGGUCCCCUCUUUCCAGGCCGC 24 15062

BCLllA-12821 - GCCGCCUUUUGUUCCGGC 18 15063

BCLllA-12822 - UGCCGCCUUUUGUUCCGGC 19 15064

BCLllA-12823 - CUGCCGCCUUUUGUUCCGGC 20 15065

BCLllA-12824 - ACUGCCGCCUUUUGUUCCGGC 21 15066

BCLllA-12825 - CACUGCCGCCUUUUGUUCCGGC 22 15067

BCLllA-12826 - GCACUGCCGCCUUUUGUUCCGGC 23 15068

BCLllA-12827 - GGCACUGCCGCCUUUUGUUCCGGC 24 15069

BCLllA-12828 - AGCGAGCGCGGCGGCGGC 18 15070

BCLllA-12829 - GAGCGAGCGCGGCGGCGGC 19 15071

BCLllA-10114 - GGAGCGAGCGCGGCGGCGGC 20 15072

BCLllA-12830 - GGGAGCGAGCGCGGCGGCGGC 21 15073

BCLllA-12831 - GGGGAGCGAGCGCGGCGGCGGC 22 15074

BCLllA-12832 - CGGGGAGCGAGCGCGGCGGCGGC 23 15075

BCLllA-12833 - GCGGGGAGCGAGCGCGGCGGCGGC 24 15076

BCLllA-12834 - CCGAGCGCAGCCGCGGGC 18 15077

BCLllA-12835 - CCCGAGCGCAGCCGCGGGC 19 15078

BCLllA-12836 - UCCCGAGCGCAGCCGCGGGC 20 15079

BCLllA-12837 - UUCCCGAGCGCAGCCGCGGGC 21 15080

BCLllA-12838 - UUUCCCGAGCGCAGCCGCGGGC 22 15081

BCLllA-12839 - GUUUCCCGAGCGCAGCCGCGGGC 23 15082

BCLllA-12840 - AG U U U CCCG AG CG CAG CCG CGGG C 24 15083

BCLllA-12841 - UCCAGGCCGCGCGGGCUC 18 15084

BCLllA-12842 - UUCCAGGCCGCGCGGGCUC 19 15085

BCLllA-12843 - UUUCCAGGCCGCGCGGGCUC 20 15086

BCLllA-12844 - CUUUCCAGGCCGCGCGGGCUC 21 15087

BCLllA-12845 - UCUUUCCAGGCCGCGCGGGCUC 22 15088

BCLllA-12846 - CUCUUUCCAGGCCGCGCGGGCUC 23 15089 BCLllA-12847 - CCUCUUUCCAGGCCGCGCGGGCUC 24 15090

BCLllA-12848 - UCCUGAGUCCGCGGAGUC 18 15091

BCLllA-12849 - CUCCUGAGUCCGCGGAGUC 19 15092

BCLllA-10128 - GCUCCUGAGUCCGCGGAGUC 20 15093

BCLllA-12850 - CGCUCCUGAGUCCGCGGAGUC 21 15094

BCLllA-12851 - GCGCUCCUGAGUCCGCGGAGUC 22 15095

BCLllA-12852 - GGCGCUCCUGAGUCCGCGGAGUC 23 15096

BCLllA-12853 - CGGCGCUCCUGAGUCCGCGGAGUC 24 15097

BCLllA-12854 - CGUACGGAGGAGGGUGUC 18 15098

BCLllA-12855 - GCGUACGGAGGAGGGUGUC 19 15099

BCLllA-10130 - UGCGUACGGAGGAGGGUGUC 20 15100

BCLllA-12856 - GUGCGUACGGAGGAGGGUGUC 21 15101

BCLllA-12857 - UGUGCGUACGGAGGAGGGUGUC 22 15102

BCLllA-12858 - GUGUGCGUACGGAGGAGGGUGUC 23 15103

BCLllA-12859 - GGUGUGCGUACGGAGGAGGGUGUC 24 15104

BCLllA-12860 - A AG U C U AAAAAACG A U U C 18 15105

BCLllA-12861 - CAAGUCU AAAAAACG AUUC 19 15106

BCLllA-12862 - ACAAG UCU AAAAAACG AUUC 20 15107

BCLllA-12863 - UACAAGUCUAAAAAACGAUUC 21 15108

BCLllA-12864 - GUACAAGUCUAAAAAACGAUUC 22 15109

BCLllA-12865 - AGUACAAGUCUAAAAAACGAUUC 23 15110

BCLllA-12866 - GAG U ACAAG U CU AAAAAACG AU U C 24 15111

BCLllA-12867 - CUCCUCGGGCAAAGUUUC 18 15112

BCLllA-12868 - UCUCCUCGGGCAAAGUUUC 19 15113

BCLllA-12869 - CUCUCCUCGGGCAAAGUUUC 20 15114

BCLllA-12870 - CCUCUCCUCGGGCAAAGUUUC 21 15115

BCLllA-12871 - UCCUCUCCUCGGGCAAAGUUUC 22 15116

BCLllA-12872 - GUCCUCUCCUCGGGCAAAGUUUC 23 15117

BCLllA-12873 - UGUCCUCUCCUCGGGCAAAGUUUC 24 15118

BCLllA-12874 - UCACGGU CAAG U G U G C AG 18 15119

BCLllA-12875 - CUCACGGUCAAGUGUGCAG 19 15120

BCLllA-10145 - GCUCACGGUCAAGUGUGCAG 20 15121

BCLllA-12876 - CGCUCACGGUCAAGUGUGCAG 21 15122

BCLllA-12877 - GCGCUCACGGUCAAGUGUGCAG 22 15123

BCLllA-12878 - CG CG CU CACGG U CAAG U G U G CAG 23 15124

BCLllA-12879 - GCGCGCUCACGGUCAAGUGUGCAG 24 15125

BCLllA-12880 - UUCCCGGGGAGAAAAGAG 18 15126

BCLllA-12881 - AUUCCCGGGGAGAAAAGAG 19 15127

BCLllA-12882 - GAUUCCCGGGGAGAAAAGAG 20 15128

BCLllA-12883 - CGAUUCCCGGGGAGAAAAGAG 21 15129

BCLllA-12884 - ACGAUUCCCGGGGAGAAAAGAG 22 15130

BCLllA-12885 - AACGAUUCCCGGGGAGAAAAGAG 23 15131 BCLllA-12886 - AAACGAUUCCCGGGGAGAAAAGAG 24 15132

BCLllA-12887 - GCUCCUGAGUCCGCGGAG 18 15133

BCLllA-12888 - CGCUCCUGAGUCCGCGGAG 19 15134

BCLllA-12889 - GCGCUCCUGAGUCCGCGGAG 20 15135

BCLllA-12890 - GGCGCUCCUGAGUCCGCGGAG 21 15136

BCLllA-12891 - CGGCGCUCCUGAGUCCGCGGAG 22 15137

BCLllA-12892 - CCGGCGCUCCUGAGUCCGCGGAG 23 15138

BCLllA-12893 - CCCGGCGCUCCUGAGUCCGCGGAG 24 15139

BCLllA-12894 - AGUCCGCGGAGUCGGGAG 18 15140

BCLllA-12895 - GAGUCCGCGGAGUCGGGAG 19 15141

BCLllA-10150 - UGAGUCCGCGGAGUCGGGAG 20 15142

BCLllA-12896 - CUGAGUCCGCGGAGUCGGGAG 21 15143

BCLllA-12897 - CCUGAGUCCGCGGAGUCGGGAG 22 15144

BCLllA-12898 - UCCUGAGUCCGCGGAGUCGGGAG 23 15145

BCLllA-12899 - CUCCUGAGUCCGCGGAGUCGGGAG 24 15146

BCLllA-12900 - CGCGGCGGCGGCGGGGAG 18 15147

BCLllA-12901 - GCGCGGCGGCGGCGGGGAG 19 15148

BCLllA-10152 - AGCGCGGCGGCGGCGGGGAG 20 15149

BCLllA-12902 - GAGCGCGGCGGCGGCGGGGAG 21 15150

BCLllA-12903 - CGAGCGCGGCGGCGGCGGGGAG 22 15151

BCLllA-12904 - GCGAGCGCGGCGGCGGCGGGGAG 23 15152

BCLllA-12905 - AGCGAGCGCGGCGGCGGCGGGGAG 24 15153

BCLllA-11434 - CGCGUGUGUGGGGGGGAG 18 15154

BCLllA-11435 - CCGCGUGUGUGGGGGGGAG 19 15155

BCLllA-11436 - UCCGCGUGUGUGGGGGGGAG 20 15156

BCLllA-11437 - GUCCGCGUGUGUGGGGGGGAG 21 15157

BCLllA-11438 - AGUCCGCGUGUGUGGGGGGGAG 22 15158

BCLllA-11439 - GAGUCCGCGUGUGUGGGGGGGAG 23 15159

BCLllA-11440 - AGAGUCCGCGUGUGUGGGGGGGAG 24 15160

BCLllA-12906 - GCCCCUGGCGUCCACACG 18 15161

BCLllA-12907 - GGCCCCUGGCGUCCACACG 19 15162

BCLllA-10156 - CGGCCCCUGGCGUCCACACG 20 15163

BCLllA-12908 - UCGGCCCCUGGCGUCCACACG 21 15164

BCLllA-12909 - UUCGGCCCCUGGCGUCCACACG 22 15165

BCLllA-12910 - CUUCGGCCCCUGGCGUCCACACG 23 15166

BCLllA-12911 - ACUUCGGCCCCUGGCGUCCACACG 24 15167

BCLllA-12912 - AGAGGGGCCGCGGCGACG 18 15168

BCLllA-12913 - GAGAGGGGCCGCGGCGACG 19 15169

BCLllA-10158 - GGAGAGGGGCCGCGGCGACG 20 15170

BCLllA-12914 - GGGAGAGGGGCCGCGGCGACG 21 15171

BCLllA-12915 - CGGGAGAGGGGCCGCGGCGACG 22 15172

BCLllA-12916 - UCGGGAGAGGGGCCGCGGCGACG 23 15173 BCLllA-12917 - GUCGGGAGAGGGGCCGCGGCGACG 24 15174

BCLllA-12918 - GAAGUGGGUGUGCGUACG 18 15175

BCLllA-12919 - GGAAGUGGGUGUGCGUACG 19 15176

BCLllA-12920 - GGGAAGUGGGUGUGCGUACG 20 15177

BCLllA-12921 - GGGGAAGUGGGUGUGCGUACG 21 15178

BCLllA-12922 - AGGGGAAGUGGGUGUGCGUACG 22 15179

BCLllA-12923 - GAGGGGAAGUGGGUGUGCGUACG 23 15180

BCLllA-12924 - GGAGGGGAAGUGGGUGUGCGUACG 24 15181

BCLllA-12925 - UCUAAAAAACGAUUCCCG 18 15182

BCLllA-12926 - GUCUAAAAAACGAUUCCCG 19 15183

BCLllA-10164 - AGUCUAAAAAACGAUUCCCG 20 15184

BCLllA-12927 - AAG UCUAAAAAACGAUUCCCG 21 15185

BCLllA-12928 - CAAGUCUAAAAAACGAUUCCCG 22 15186

BCLllA-12929 - ACAAG UCUAAAAAACGAUUCCCG 23 15187

BCLllA-12930 - UACAAGUCUAAAAAACGAUUCCCG 24 15188

BCLllA-12931 - CGGCGACGGGGAGAGCCG 18 15189

BCLllA-12932 - GCGGCGACGGGGAGAGCCG 19 15190

BCLllA-10166 - CGCGGCGACGGGGAGAGCCG 20 15191

BCLllA-12933 - CCGCGGCGACGGGGAGAGCCG 21 15192

BCLllA-12934 - GCCGCGGCGACGGGGAGAGCCG 22 15193

BCLllA-12935 - GGCCGCGGCGACGGGGAGAGCCG 23 15194

BCLllA-12936 - GGGCCGCGGCGACGGGGAGAGCCG 24 15195

BCLllA-12937 - CCCUGGCGUCCACACGCG 18 15196

BCLllA-12938 - CCCCUGGCGUCCACACGCG 19 15197

BCLllA-10175 - GCCCCUGGCGUCCACACGCG 20 15198

BCLllA-12939 - GGCCCCUGGCGUCCACACGCG 21 15199

BCLllA-12940 - CGGCCCCUGGCGUCCACACGCG 22 15200

BCLllA-12941 - UCGGCCCCUGGCGUCCACACGCG 23 15201

BCLllA-12942 - UUCGGCCCCUGGCGUCCACACGCG 24 15202

BCLllA-12943 - GGGAGAGGGGCCGCGGCG 18 15203

BCLllA-12944 - CGGGAGAGGGGCCGCGGCG 19 15204

BCLllA-12945 - UCGGGAGAGGGGCCGCGGCG 20 15205

BCLllA-12946 - GUCGGGAGAGGGGCCGCGGCG 21 15206

BCLllA-12947 - AGUCGGGAGAGGGGCCGCGGCG 22 15207

BCLllA-12948 - GAGUCGGGAGAGGGGCCGCGGCG 23 15208

BCLllA-12949 - GGAGUCGGGAGAGGGGCCGCGGCG 24 15209

BCLllA-12950 - GGAGCGAGCGCGGCGGCG 18 15210

BCLllA-12951 - GGGAGCGAGCGCGGCGGCG 19 15211

BCLllA-12952 - GGGGAGCGAGCGCGGCGGCG 20 15212

BCLllA-12953 - CGGGGAGCGAGCGCGGCGGCG 21 15213

BCLllA-12954 - GCGGGGAGCGAGCGCGGCGGCG 22 15214

BCLllA-12955 - CGCGGGGAGCGAGCGCGGCGGCG 23 15215 BCLllA-12956 - ACGCGGGGAGCGAGCGCGGCGGCG 24 15216

BCLllA-12957 - GCGAGCGCGGCGGCGGCG 18 15217

BCLllA-12958 - AGCGAGCGCGGCGGCGGCG 19 15218

BCLllA-10179 - GAGCGAGCGCGGCGGCGGCG 20 15219

BCLllA-12959 - GGAGCGAGCGCGGCGGCGGCG 21 15220

BCLllA-12960 - GGGAGCGAGCGCGGCGGCGGCG 22 15221

BCLllA-12961 - GGGGAGCGAGCGCGGCGGCGGCG 23 15222

BCLllA-12962 - CGGGGAGCGAGCGCGGCGGCGGCG 24 15223

BCLllA-12963 - GCCGUGGGACCGGGAAGG 18 15224

BCLllA-12964 - AGCCGUGGGACCGGGAAGG 19 15225

BCLllA-12965 - GAGCCGUGGGACCGGGAAGG 20 15226

BCLllA-12966 - AGAGCCGUGGGACCGGGAAGG 21 15227

BCLllA-12967 - GAGAGCCGUGGGACCGGGAAGG 22 15228

BCLllA-12968 - GGAGAGCCGUGGGACCGGGAAGG 23 15229

BCLllA-12969 - GGGAGAGCCGUGGGACCGGGAAGG 24 15230

BCLllA-12970 - AGAAAAUGGGGGGGUAGG 18 15231

BCLllA-12971 - AAGAAAAUGGGGGGGUAGG 19 15232

BCLllA-12972 - UAAGAAAAUGGGGGGGUAGG 20 15233

BCLllA-12973 - GUAAGAAAAUGGGGGGGUAGG 21 15234

BCLllA-12974 - CGUAAGAAAAUGGGGGGGUAGG 22 15235

BCLllA-12975 - CCGUAAGAAAAUGGGGGGGUAGG 23 15236

BCLllA-12976 - ACCGUAAGAAAAUGGGGGGGUAGG 24 15237

BCLllA-12977 - AAGUGGGUGUGCGUACGG 18 15238

BCLllA-12978 - GAAGUGGGUGUGCGUACGG 19 15239

BCLllA-10191 - GGAAGUGGGUGUGCGUACGG 20 15240

BCLllA-12979 - GGGAAGUGGGUGUGCGUACGG 21 15241

BCLllA-12980 - GGGGAAGUGGGUGUGCGUACGG 22 15242

BCLllA-12981 - AGGGGAAGUGGGUGUGCGUACGG 23 15243

BCLllA-12982 - GAGGGGAAGUGGGUGUGCGUACGG 24 15244

BCLllA-12983 - CGGUCAAGUGUGCAGCGG 18 15245

BCLllA-12984 - ACGGUCAAGUGUGCAGCGG 19 15246

BCLllA-12985 - CACGGUCAAGUGUGCAGCGG 20 15247

BCLllA-12986 - UCACGGUCAAGUGUGCAGCGG 21 15248

BCLllA-12987 - CUCACGGUCAAGUGUGCAGCGG 22 15249

BCLllA-12988 - GCUCACGGUCAAGUGUGCAGCGG 23 15250

BCLllA-12989 - CGCUCACGGUCAAGUGUGCAGCGG 24 15251

BCLllA-12990 - GAGCGAGCGCGGCGGCGG 18 15252

BCLllA-12991 - GGAGCGAGCGCGGCGGCGG 19 15253

BCLllA-10196 - GGGAGCGAGCGCGGCGGCGG 20 15254

BCLllA-12992 - GGGGAGCGAGCGCGGCGGCGG 21 15255

BCLllA-12993 - CGGGGAGCGAGCGCGGCGGCGG 22 15256

BCLllA-12994 - GCGGGGAGCGAGCGCGGCGGCGG 23 15257 BCLllA-12995 - CGCGGGGAGCGAGCGCGGCGGCGG 24 15258

BCLllA-12996 - CUGAGUCCGCGGAGUCGG 18 15259

BCLllA-12997 - CCUGAGUCCGCGGAGUCGG 19 15260

BCLllA-12998 - UCCUGAGUCCGCGGAGUCGG 20 15261

BCLllA-12999 - CUCCUGAGUCCGCGGAGUCGG 21 15262

BCLllA-13000 - GCUCCUGAGUCCGCGGAGUCGG 22 15263

BCLllA-13001 - CGCUCCUGAGUCCGCGGAGUCGG 23 15264

BCLllA-13002 - GCGCUCCUGAGUCCGCGGAGUCGG 24 15265

BCLllA-13003 - GAAAAUGGGGGGGUAGGG 18 15266

BCLllA-13004 - AGAAAAUGGGGGGGUAGGG 19 15267

BCLllA-10200 - AAGAAAAUGGGGGGGUAGGG 20 15268

BCLllA-13005 - UAAGAAAAUGGGGGGGUAGGG 21 15269

BCLllA-13006 - GU AAGAAAAUGGGGGGGUAGGG 22 15270

BCLllA-13007 - CGUAAGAAAAUGGGGGGGUAGGG 23 15271

BCLllA-13008 - CCGUAAGAAAAUGGGGGGGUAGGG 24 15272

BCLllA-13009 - AGGGGCCGCGGCGACGGG 18 15273

BCLllA-13010 - GAGGGGCCGCGGCGACGGG 19 15274

BCLllA-13011 - AGAGGGGCCGCGGCGACGGG 20 15275

BCLllA-13012 - GAGAGGGGCCGCGGCGACGGG 21 15276

BCLllA-13013 - GGAGAGGGGCCGCGGCGACGGG 22 15277

BCLllA-13014 - GGGAGAGGGGCCGCGGCGACGGG 23 15278

BCLllA-13015 - CGGGAGAGGGGCCGCGGCGACGGG 24 15279

BCLllA-13016 - GAGAGCCGUGGGACCGGG 18 15280

BCLllA-13017 - GGAGAGCCGUGGGACCGGG 19 15281

BCLllA-13018 - GGGAGAGCCGUGGGACCGGG 20 15282

BCLllA-13019 - GGGGAGAGCCGUGGGACCGGG 21 15283

BCLllA-13020 - CGGGGAGAGCCGUGGGACCGGG 22 15284

BCLllA-13021 - ACGGGGAGAGCCGUGGGACCGGG 23 15285

BCLllA-13022 - GACGGGGAGAGCCGUGGGACCGGG 24 15286

BCLllA-13023 - UAAAAAACGAUUCCCGGG 18 15287

BCLllA-13024 - CUAAAAAACGAUUCCCGGG 19 15288

BCLllA-13025 - U CU AAAAAACG AU U CCCGGG 20 15289

BCLllA-13026 - GUCUAAAAAACGAUUCCCGGG 21 15290

BCLllA-13027 - AGUCUAAAAAACGAUUCCCGGG 22 15291

BCLllA-13028 - A AG U C U AAAAAACG AUUCCCGGG 23 15292

BCLllA-13029 - CAAGUCUAAAAAACGAUUCCCGGG 24 15293

BCLllA-13030 - GGUCAAGUGUGCAGCGGG 18 15294

BCLllA-13031 - CGGUCAAGUGUGCAGCGGG 19 15295

BCLllA-10202 - ACGGUCAAGUGUGCAGCGGG 20 15296

BCLllA-13032 - CACGGUCAAGUGUGCAGCGGG 21 15297

BCLllA-13033 - UCACGGUCAAGUGUGCAGCGGG 22 15298

BCLllA-13034 - CUCACGGUCAAGUGUGCAGCGGG 23 15299 BCLllA-13035 - GCUCACGGUCAAGUGUGCAGCGGG 24 15300

BCLllA-13036 - GAGCGCGGCGGCGGCGGG 18 15301

BCLllA-13037 - CGAGCGCGGCGGCGGCGGG 19 15302

BCLllA-13038 - GCGAGCGCGGCGGCGGCGGG 20 15303

BCLllA-13039 - AGCGAGCGCGGCGGCGGCGGG 21 15304

BCLllA-13040 - GAGCGAGCGCGGCGGCGGCGGG 22 15305

BCLllA-13041 - GGAGCGAGCGCGGCGGCGGCGGG 23 15306

BCLllA-13042 - GGGAGCGAGCGCGGCGGCGGCGGG 24 15307

BCLllA-13043 - AGCGCGGCGGCGGCGGGG 18 15308

BCLllA-13044 - GAGCGCGGCGGCGGCGGGG 19 15309

BCLllA-10206 - CGAGCGCGGCGGCGGCGGGG 20 15310

BCLllA-13045 - GCGAGCGCGGCGGCGGCGGGG 21 15311

BCLllA-13046 - AGCGAGCGCGGCGGCGGCGGGG 22 15312

BCLllA-13047 - GAGCGAGCGCGGCGGCGGCGGGG 23 15313

BCLllA-13048 - GGAGCGAGCGCGGCGGCGGCGGGG 24 15314

BCLllA-13049 - CGUAAGAAAAUGGGGGGG 18 15315

BCLllA-13050 - CCGUAAGAAAAUGGGGGGG 19 15316

BCLllA-13051 - ACCGUAAGAAAAUGGGGGGG 20 15317

BCLllA-13052 - CACCGUAAGAAAAUGGGGGGG 21 15318

BCLllA-13053 - UCACCGUAAGAAAAUGGGGGGG 22 15319

BCLllA-13054 - CUCACCGUAAGAAAAUGGGGGGG 23 15320

BCLllA-13055 - ACUCACCGUAAGAAAAUGGGGGGG 24 15321

BCLllA-13056 - CACAUGCAAACCUGGGGG 18 15322

BCLllA-13057 - UCACAUGCAAACCUGGGGG 19 15323

BCLllA-10210 - CUCACAUGCAAACCUGGGGG 20 15324

BCLllA-13058 - ACUCACAUGCAAACCUGGGGG 21 15325

BCLllA-13059 - AACUCACAUGCAAACCUGGGGG 22 15326

BCLllA-13060 - CAACUCACAUGCAAACCUGGGGG 23 15327

BCLllA-13061 - ACAACUCACAUGCAAACCUGGGGG 24 15328

BCLllA-13062 - UCACAUGCAAACCUGGGG 18 15329

BCLllA-13063 - CUCACAUGCAAACCUGGGG 19 15330

BCLllA-13064 - ACUCACAUGCAAACCUGGGG 20 15331

BCLllA-13065 - AACUCACAUGCAAACCUGGGG 21 15332

BCLllA-13066 - CAACUCACAUGCAAACCUGGGG 22 15333

BCLllA-13067 - ACAACUCACAUGCAAACCUGGGG 23 15334

BCLllA-13068 - AACAACUCACAUGCAAACCUGGGG 24 15335

BCLllA-11486 - GAGUCCGCGUGUGUGGGG 18 15336

BCLllA-11487 - AGAGUCCGCGUGUGUGGGG 19 15337

BCLllA-9577 - UAGAGUCCGCGUGUGUGGGG 20 15338

BCLllA-11488 - UUAGAGUCCGCGUGUGUGGGG 21 15339

BCLllA-11489 - UUUAGAGUCCGCGUGUGUGGGG 22 15340

BCLllA-11490 - UUUUAGAGUCCGCGUGUGUGGGG 23 15341 BCLllA-11491 - AUUUUAGAGUCCGCGUGUGUGGGG 24 15342

BCLllA-11492 - AGAGUCCGCGUGUGUGGG 18 15343

BCLllA-11493 - UAGAGUCCGCGUGUGUGGG 19 15344

BCLllA-9769 - UUAGAGUCCGCGUGUGUGGG 20 15345

BCLllA-11494 - UUUAGAGUCCGCGUGUGUGGG 21 15346

BCLllA-11495 - UUUUAGAGUCCGCGUGUGUGGG 22 15347

BCLllA-11496 - AUUUUAGAGUCCGCGUGUGUGGG 23 15348

BCLllA-11497 - CAUUUUAGAGUCCGCGUGUGUGGG 24 15349

BCLllA-13069 - CCUGGGGGUGGGAGCUGG 18 15350

BCLllA-13070 - ACCUGGGGGUGGGAGCUGG 19 15351

BCLllA-10217 - AACCUGGGGGUGGGAGCUGG 20 15352

BCLllA-13071 - AAACCUGGGGGUGGGAGCUGG 21 15353

BCLllA-13072 - CAAACCUGGGGGUGGGAGCUGG 22 15354

BCLllA-13073 - GCAAACCUGGGGGUGGGAGCUGG 23 15355

BCLllA-13074 - UGCAAACCUGGGGGUGGGAGCUGG 24 15356

BCLllA-11498 - UAGAGUCCGCGUGUGUGG 18 15357

BCLllA-11499 - UUAGAGUCCGCGUGUGUGG 19 15358

BCLllA-9578 - UUUAGAGUCCGCGUGUGUGG 20 15359

BCLllA-11500 - UUUUAGAGUCCGCGUGUGUGG 21 15360

BCLllA-11501 - AUUUUAGAGUCCGCGUGUGUGG 22 15361

BCLllA-11502 - CAUUUUAGAGUCCGCGUGUGUGG 23 15362

BCLllA-11503 - UCAUUUUAGAGUCCGCGUGUGUGG 24 15363

BCLllA-13075 - ACU CACCG UAAGAAAAUG 18 15364

BCLllA-13076 - CACU CACCG UAAGAAAAUG 19 15365

BCLllA-10221 - CCACUCACCGUAAGAAAAUG 20 15366

BCLllA-13077 - CCCACUCACCGUAAGAAAAUG 21 15367

BCLllA-13078 - UCCCACUCACCGUAAGAAAAUG 22 15368

BCLllA-13079 - UUCCCACUCACCGUAAGAAAAUG 23 15369

BCLllA-13080 - CU U CCCACU CACCG UAAGAAAAUG 24 15370

BCLllA-13081 - AGUGAGAAAGUGGCACUG 18 15371

BCLllA-13082 - UAGUGAGAAAGUGGCACUG 19 15372

BCLllA-10222 - AUAGUGAGAAAGUGGCACUG 20 15373

BCLllA-13083 - AAUAGUGAGAAAGUGGCACUG 21 15374

BCLllA-13084 - CAAUAGUGAGAAAGUGGCACUG 22 15375

BCLllA-13085 - ACAAUAGUGAGAAAGUGGCACUG 23 15376

BCLllA-13086 - CACAAUAGUGAGAAAGUGGCACUG 24 15377

BCLllA-13087 - ACCUGGGGGUGGGAGCUG 18 15378

BCLllA-13088 - AACCUGGGGGUGGGAGCUG 19 15379

BCLllA-13089 - AAACCUGGGGGUGGGAGCUG 20 15380

BCLllA-13090 - CAAACCUGGGGGUGGGAGCUG 21 15381

BCLllA-13091 - GCAAACCUGGGGGUGGGAGCUG 22 15382

BCLllA-13092 - UGCAAACCUGGGGGUGGGAGCUG 23 15383 BCLllA-13093 - AUGCAAACCUGGGGGUGGGAGCUG 24 15384

BCLllA-13094 - ACCUCCCCUCGCCCGCUG 18 15385

BCLllA-13095 - CACCUCCCCUCGCCCGCUG 19 15386

BCLllA-10224 - CCACCUCCCCUCGCCCGCUG 20 15387

BCLllA-13096 - CCCACCUCCCCUCGCCCGCUG 21 15388

BCLllA-13097 - UCCCACCUCCCCUCGCCCGCUG 22 15389

BCLllA-13098 - CUCCCACCUCCCCUCGCCCGCUG 23 15390

BCLllA-13099 - CCUCCCACCUCCCCUCGCCCGCUG 24 15391

BCLllA-13100 - UGGGGGUGGGAGCUGGUG 18 15392

BCLllA-13101 - CUGGGGGUGGGAGCUGGUG 19 15393

BCLllA-10228 - CCUGGGGGUGGGAGCUGGUG 20 15394

BCLllA-13102 - ACCUGGGGGUGGGAGCUGGUG 21 15395

BCLllA-13103 - AACCUGGGGGUGGGAGCUGGUG 22 15396

BCLllA-13104 - AAACCUGGGGGUGGGAGCUGGUG 23 15397

BCLllA-13105 - CAAACCUGGGGGUGGGAGCUGGUG 24 15398

BCLllA-11518 - UUUUAGAGUCCGCGUGUG 18 15399

BCLllA-11519 - AUUUUAGAGUCCGCGUGUG 19 15400

BCLllA-9581 - CAUUUUAGAGUCCGCGUGUG 20 15401

BCLllA-11520 - UCAUUUUAGAGUCCGCGUGUG 21 15402

BCLllA-11521 - UUCAUUUUAGAGUCCGCGUGUG 22 15403

BCLllA-11522 - UUUCAUUUUAGAGUCCGCGUGUG 23 15404

BCLllA-11523 - CUUUCAUUUUAGAGUCCGCGUGUG 24 15405

BCLllA-11524 - UUAGAGUCCGCGUGUGUG 18 15406

BCLllA-11525 - UUUAGAGUCCGCGUGUGUG 19 15407

BCLllA-9776 - UUUUAGAGUCCGCGUGUGUG 20 15408

BCLllA-11526 - AUUUUAGAGUCCGCGUGUGUG 21 15409

BCLllA-11527 - CAUUUUAGAGUCCGCGUGUGUG 22 15410

BCLllA-11528 - UCAUUUUAGAGUCCGCGUGUGUG 23 15411

BCLllA-11529 - UUCAUUUUAGAGUCCGCGUGUGUG 24 15412

BCLllA-13106 - CACU CACCG UAAGAAAAU 18 15413

BCLllA-13107 - CCACUCACCGUAAGAAAAU 19 15414

BCLllA-10232 - CCCACU CACCG UAAGAAAAU 20 15415

BCLllA-13108 - U CCCACU CACCG UAAGAAAAU 21 15416

BCLllA-13109 - UUCCCACUCACCGUAAGAAAAU 22 15417

BCLllA-13110 - CUUCCCACUCACCGUAAGAAAAU 23 15418

BCLllA-13111 - GCUUCCCACUCACCGUAAGAAAAU 24 15419

BCLllA-13112 - CGCUGCGGAGCUGUAACU 18 15420

BCLllA-13113 - CCGCUGCGGAGCUGUAACU 19 15421

BCLllA-10233 - CCCGCUGCGGAGCUGUAACU 20 15422

BCLllA-13114 - GCCCGCUGCGGAGCUGUAACU 21 15423

BCLllA-13115 - CGCCCGCUGCGGAGCUGUAACU 22 15424

BCLllA-13116 - UCGCCCGCUGCGGAGCUGUAACU 23 15425 BCLllA-13117 - CUCGCCCGCUGCGGAGCUGUAACU 24 15426

BCLllA-13118 - UAGUGAGAAAGUGGCACU 18 15427

BCLllA-13119 - AUAGUGAGAAAGUGGCACU 19 15428

BCLllA-13120 - AAUAGUGAGAAAGUGGCACU 20 15429

BCLllA-13121 - CAAUAGUGAGAAAGUGGCACU 21 15430

BCLllA-13122 - ACAAUAGUGAGAAAGUGGCACU 22 15431

BCLllA-13123 - CACAAUAGUGAGAAAGUGGCACU 23 15432

BCLllA-13124 - CCACAAUAGUGAGAAAGUGGCACU 24 15433

BCLllA-13125 - CGGUCCCUGGCUCGGCCU 18 15434

BCLllA-13126 - CCGGUCCCUGGCUCGGCCU 19 15435

BCLllA-10237 - CCCGGUCCCUGGCUCGGCCU 20 15436

BCLllA-13127 - CACCUCCCCUCGCCCGCU 18 15437

BCLllA-13128 - CCACCUCCCCUCGCCCGCU 19 15438

BCLllA-13129 - CCCACCUCCCCUCGCCCGCU 20 15439

BCLllA-13130 - UCCCACCUCCCCUCGCCCGCU 21 15440

BCLllA-13131 - CUCCCACCUCCCCUCGCCCGCU 22 15441

BCLllA-13132 - CCUCCCACCUCCCCUCGCCCGCU 23 15442

BCLllA-13133 - CCCUCCCACCUCCCCUCGCCCGCU 24 15443

BCLllA-13134 - CGAGCGCAGCCGCGGGCU 18 15444

BCLllA-13135 - CCGAGCGCAGCCGCGGGCU 19 15445

BCLllA-10241 - CCCGAGCGCAGCCGCGGGCU 20 15446

BCLllA-13136 - UCCCGAGCGCAGCCGCGGGCU 21 15447

BCLllA-13137 - UUCCCGAGCGCAGCCGCGGGCU 22 15448

BCLllA-13138 - UUUCCCGAGCGCAGCCGCGGGCU 23 15449

BCLllA-13139 - GUUUCCCGAGCGCAGCCGCGGGCU 24 15450

BCLllA-13140 - CUCCUGAGUCCGCGGAGU 18 15451

BCLllA-13141 - GCUCCUGAGUCCGCGGAGU 19 15452

BCLllA-10243 - CGCUCCUGAGUCCGCGGAGU 20 15453

BCLllA-13142 - GCGCUCCUGAGUCCGCGGAGU 21 15454

BCLllA-13143 - GGCGCUCCUGAGUCCGCGGAGU 22 15455

BCLllA-13144 - CGGCGCUCCUGAGUCCGCGGAGU 23 15456

BCLllA-13145 - CCGGCGCUCCUGAGUCCGCGGAGU 24 15457

BCLllA-13146 - AGUCAUCCCCACAAUAGU 18 15458

BCLllA-13147 - UAGUCAUCCCCACAAUAGU 19 15459

BCLllA-13148 - GUAGUCAUCCCCACAAUAGU 20 15460

BCLllA-13149 - AGUAGUCAUCCCCACAAUAGU 21 15461

BCLllA-13150 - AAGUAGUCAUCCCCACAAUAGU 22 15462

BCLllA-13151 - AAAGUAGUCAUCCCCACAAUAGU 23 15463

BCLllA-13152 - GAAAGUAGUCAUCCCCACAAUAGU 24 15464

BCLllA-13153 - UUGCUUCCCACUCACCGU 18 15465

BCLllA-13154 - GUUGCUUCCCACUCACCGU 19 15466

BCLllA-13155 - GGUUGCUUCCCACUCACCGU 20 15467 BCLllA-13156 - AGGUUGCUUCCCACUCACCGU 21 15468

BCLllA-13157 - GAGGUUGCUUCCCACUCACCGU 22 15469

BCLllA-13158 - GGAGGUUGCUUCCCACUCACCGU 23 15470

BCLllA-13159 - GGGAGGUUGCUUCCCACUCACCGU 24 15471

BCLllA-13160 - GGGGAAGUGGGUGUGCGU 18 15472

BCLllA-13161 - AGGGGAAGUGGGUGUGCGU 19 15473

BCLllA-13162 - GAGGGGAAGUGGGUGUGCGU 20 15474

BCLllA-13163 - GGAGGGGAAGUGGGUGUGCGU 21 15475

BCLllA-13164 - GGGAGGGGAAGUGGGUGUGCGU 22 15476

BCLllA-13165 - GGGGAGGGGAAGUGGGUGUGCGU 23 15477

BCLllA-13166 - CGGGGAGGGGAAGUGGGUGUGCGU 24 15478

BCLllA-13167 - GUAAGAAAAUGGGGGGGU 18 15479

BCLllA-13168 - CGUAAGAAAAUGGGGGGGU 19 15480

BCLllA-10248 - CCGUAAGAAAAUGGGGGGGU 20 15481

BCLllA-13169 - ACCGUAAGAAAAUGGGGGGGU 21 15482

BCLllA-13170 - CACCGUAAGAAAAUGGGGGGGU 22 15483

BCLllA-13171 - UCACCGUAAGAAAAUGGGGGGGU 23 15484

BCLllA-13172 - CUCACCGUAAGAAAAUGGGGGGGU 24 15485

BCLllA-13173 - ACAUGCAAACCUGGGGGU 18 15486

BCLllA-13174 - CACAUGCAAACCUGGGGGU 19 15487

BCLllA-10249 - UCACAUGCAAACCUGGGGGU 20 15488

BCLllA-13175 - CUCACAUGCAAACCUGGGGGU 21 15489

BCLllA-13176 - ACUCACAUGCAAACCUGGGGGU 22 15490

BCLllA-13177 - AACUCACAUGCAAACCUGGGGGU 23 15491

BCLllA-13178 - CAACUCACAUGCAAACCUGGGGGU 24 15492

BCLllA-13179 - CUGGGGGUGGGAGCUGGU 18 15493

BCLllA-13180 - CCUGGGGGUGGGAGCUGGU 19 15494

BCLllA-10250 - ACCUGGGGGUGGGAGCUGGU 20 15495

BCLllA-13181 - AACCUGGGGGUGGGAGCUGGU 21 15496

BCLllA-13182 - AAACCUGGGGGUGGGAGCUGGU 22 15497

BCLllA-13183 - CAAACCUGGGGGUGGGAGCUGGU 23 15498

BCLllA-13184 - GCAAACCUGGGGGUGGGAGCUGGU 24 15499

BCLllA-11572 - AUUUUAGAGUCCGCGUGU 18 15500

BCLllA-11573 - CAUUUUAGAGUCCGCGUGU 19 15501

BCLllA-11574 - UCAUUUUAGAGUCCGCGUGU 20 15502

BCLllA-11575 - UUCAUUUUAGAGUCCGCGUGU 21 15503

BCLllA-11576 - UUUCAUUUUAGAGUCCGCGUGU 22 15504

BCLllA-11577 - CUUUCAUUUUAGAGUCCGCGUGU 23 15505

BCLllA-11578 - UCUUUCAUUUUAGAGUCCGCGUGU 24 15506

BCLllA-13185 - GCGUACGGAGGAGGGUGU 18 15507

BCLllA-13186 - UGCGUACGGAGGAGGGUGU 19 15508

BCLllA-13187 - GUGCGUACGGAGGAGGGUGU 20 15509 BCLllA-13188 - UGUGCGUACGGAGGAGGGUGU 21 15510

BCLllA-13189 - GUGUGCGUACGGAGGAGGGUGU 22 15511

BCLllA-13190 - GGUGUGCGUACGGAGGAGGGUGU 23 15512

BCLllA-13191 - GGGUGUGCGUACGGAGGAGGGUGU 24 15513

BCLllA-11579 - UUUAGAGUCCGCGUGUGU 18 15514

BCLllA-11580 - UUUUAGAGUCCGCGUGUGU 19 15515

BCLllA-9586 - AUUUUAGAGUCCGCGUGUGU 20 15516

BCLllA-11581 - CAUUUUAGAGUCCGCGUGUGU 21 15517

BCLllA-11582 - UCAUUUUAGAGUCCGCGUGUGU 22 15518

BCLllA-11583 - UUCAUUUUAGAGUCCGCGUGUGU 23 15519

BCLllA-11584 - UUUCAUUUUAGAGUCCGCGUGUGU 24 15520

BCLllA-13192 - GACUUGGGCGCUGCCCUU 18 15521

BCLllA-13193 - AGACUUGGGCGCUGCCCUU 19 15522

BCLllA-13194 - GAGACUUGGGCGCUGCCCUU 20 15523

BCLllA-13195 - GGAGACUUGGGCGCUGCCCUU 21 15524

BCLllA-13196 - UGGAGACUUGGGCGCUGCCCUU 22 15525

BCLllA-13197 - CUGGAGACUUGGGCGCUGCCCUU 23 15526

BCLllA-13198 - CCUGGAGACUUGGGCGCUGCCCUU 24 15527

BCLllA-13199 - GGUCCCUGGCUCGGCCUU 18 15528

BCLllA-13200 - CGGUCCCUGGCUCGGCCUU 19 15529

BCLllA-10256 - CCGGUCCCUGGCUCGGCCUU 20 15530

BCLllA-13201 - AAGAGGUGAGACUGGCUU 18 15531

BCLllA-13202 - AAAGAGGUGAGACUGGCUU 19 15532

BCLllA-13203 - AAAAGAGGUGAGACUGGCUU 20 15533

BCLllA-13204 - GAAAAGAGGUGAGACUGGCUU 21 15534

BCLllA-13205 - AGAAAAGAGGUGAGACUGGCUU 22 15535

BCLllA-13206 - GAGAAAAGAGGUGAGACUGGCUU 23 15536

BCLllA-13207 - GGAGAAAAGAGGUGAGACUGGCUU 24 15537

BCLllA-13208 - AUGAACAAUGCUAAGGUU 18 15538

BCLllA-13209 - AAUGAACAAUGCUAAGGUU 19 15539

BCLllA-13210 - UAAUGAACAAUGCUAAGGUU 20 15540

BCLllA-13211 - AUAAUGAACAAUGCUAAGGUU 21 15541

BCLllA-13212 - AAUAAUGAACAAUGCUAAGGUU 22 15542

BCLllA-13213 - AAAUAAUGAACAAUGCUAAGGUU 23 15543

BCLllA-13214 - AAAAUAAUGAACAAUGCUAAGGUU 24 15544

BCLllA-13215 - GCCGCUUUAUUUCUCUUU 18 15545

BCLllA-13216 - CGCCGCUUUAUUUCUCUUU 19 15546

BCLllA-13217 - CCGCCGCUUUAUUUCUCUUU 20 15547

BCLllA-13218 - UCCGCCGCUUUAUUUCUCUUU 21 15548

BCLllA-13219 - UUCCGCCGCUUUAUUUCUCUUU 22 15549

BCLllA-13220 - UUUCCGCCGCUUUAUUUCUCUUU 23 15550

BCLllA-13221 - CUUUCCGCCGCUUUAUUUCUCUUU 24 15551 Table 20A provides exemplary targeting domains for knocking down the BCLl 1 A gene selected according to the first tier parameters. The targeting domains bind within 500 bp (e.g., upstream or downstream) of a transcription start site (TSS) and have a high level of

orthogonality. It is contemplated herein that in an embodiment the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a N. meningitidis eiCas9 molecule or eiCas9 fusion protein (e.g., an eiCas9 fused to a transcription repressor domain) to alter the BCLl 1 A gene (e.g., reduce or eliminate BCLl 1 A gene expression, BCLl 1 A protein function, or the level of BCLl 1 A protein). One or more gRNA may be used to target an eiCas9 to the promoter region of the BCLl 1 A gene.

Table 20A

Table 20B provides exemplary targeting domains for knocking down the BCLl 1 A gene selected according to the second tier parameters. The targeting domains bind within 500 bp (e.g. upstream or downstream) of a transcription start site (TSS). It is contemplated herein that in an embodiment the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a N. meningitidis eiCas9 molecule or eiCas9 fusion protein (e.g., an eiCas9 fused to a transcription repressor domain) to alter the BCLl 1 A gene (e.g., reduce or eliminate BCLl 1A gene expression, BCLl 1A protein function, or the level of BCLl 1 A protein). One or more gRNA may be used to target an eiCas9 to the promoter region of the BCLl 1 A gene.

Table 20B

Table 20C provides exemplary targeting domains for knocking down the BCLl 1 A gene selected according to the third tier parameters. The targeting domains bind within the additional 500 bp (e.g., upstream or downstream) of a transcription start site (TSS), e.g., extending to lkb upstream and downstream of a TSS. It is contemplated herein that in an embodiment the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a N. meningitidis eiCas9 molecule or eiCas9 fusion protein (e.g., an eiCas9 fused to a transcription repressor domain) to alter the BCLl 1 A gene (e.g., reduce or eliminate BCLl 1A gene expression, BCLl 1A protein function, or the level of BCLl 1A protein). One or more gRNA may be used to target an eiCas9 to the promoter region of the BCLl 1 A gene.

Table 20C

BCLllA-13243 - GGGAGAAAAGAGGUGAG 17 15581

BCLllA-13244 - CAGCCCUCCAAACUUAG 17 15582

BCLllA-13245 - C U U U U CGAAAAGGAAUG 17 15583

BCLllA-13225 + CACGCGGACUCUAAAAU 17 15584

BCLllA-10006 - GAGCGCAGCCGCGGGCU 17 15585

BCLllA-13246 - GGAGUGAGUACAAGUCUAAA 20 15586

BCLllA-13247 - GGAGCUGGUGGGGAAAGGGA 20 15587

BCLllA-13248 - GGUGUCCGGGAGCAACUCUA 20 15588

BCLllA-13249 - CUGCCU UUUGUGCCGGCUCC 20 15589

BCLllA-13250 - UCUACCUGGCUUCCCUCCGC 20 15590

BCLllA-10131 - GAGGCUCAGCUCUCAACUUC 20 15591

BCLllA-13251 - UCCUCCUCU UUCCUCCUUUC 20 15592

BCLllA-13252 - CCGGGGAGAAAAGAGGUGAG 20 15593

BCLllA-13253 - CCGCAGCCCUCCAAACU UAG 20 15594

BCLllA-13254 - UCUCUUU UCGAAAAGGAAUG 20 15595

BCLllA-13235 + ACACACGCGGACUCUAAAAU 20 15596

BCLllA-10241 - CCCGAGCGCAGCCGCGGGCU 20 15597

Table 21A provides exemplary targeting domains for removing (e.g., deleting) the enhancer region of the BCL11 A gene selected according to the first tier parameters. The targeting domains bind within a region 5' (51.5 to 51.7kb downstream of TSS) or 3' (65.1 to 65.3kb downstream of TSS), and have a high level of orthogonality and starts with 5'G. It is contemplated herein that in an embodiment the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. pyogenes Cas9 molecule that generates a double stranded break (Cas9 nuclease) or a single- stranded break (Cas9 nickase).

Table 21 A

Table 21B provides exemplary targeting domains for removing (e.g., deleting) the enhancer region of the BCL11 A gene selected according to the second tier parameters. The targeting domains bind within a region 5' (51.5 to 51.7kb downstream of TSS) or 3' (65.1 to 65.3kb downstream of TSS) and have a high level of orthogonality. It is contemplated herein that in an embodiment the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. pyogenes Cas9 molecule that generates a double stranded break (Cas9 nuclease) or a single- stranded break (Cas9 nickase).

Table 21B

BCLllA-13288 + AAAAUACUUACUGUACUGCA 20 3' 15631

BCLllA-13289 + AUUCACUGGAAACCCUGUUA 20 3' 15632

BCLllA-13290 - AAACUAUUUACAGCCAUAAC 20 3' 15633

BCLllA-13291 + AAAUACUUACUGUACUGCAG 20 3' 15634

BCLllA-13292 + UACUGUACUGCAGGGGAAUU 20 3' 15635

BCLllA-13293 - U UAGGCUGUUUUUGGAUCUU 20 3' 15636

BCLllA-13294 - CAGUGGCUUUAGGCUGUUUU 20 3' 15637

Table 21C provides exemplary targeting domains for removing (e.g., deleting) the enhancer region of the BCL11 A gene selected according to the third tier parameters. The targeting domains bind within a region 5' (51.5 to 51.7kb downstream of TSS) or 3' (65.1 to 65.3kb downstream of TSS) and starts with 5'G. It is contemplated herein that in an

embodiment the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. pyogenes Cas9 molecule that generates a double stranded break (Cas9 nuclease) or a single- stranded break (Cas9 nickase). Table 21C

Table 21D provides exemplary targeting domains for removing (e.g., deleting) the enhancer region of the BCL11 A gene selected according to the fourth tier parameters. The targeting domains bind within a region 5' (51.5 to 51.7kb downstream of TSS) or 3' (65.1 to 65.3kb downstream of TSS). It is contemplated herein that in an embodiment the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. pyogenes Cas9 molecule that generates a double stranded break (Cas9 nuclease) or a single- stranded break (Cas9 nickase).

Table 21D

BCLllA-13299 - AAAAUAAU U AG AAU AAA 17 5' 15642

BCLllA-13300 + CACAU AAAAAU U UAAGA 17 5' 15643

BCLllA-13301 + ACAU AAAAAU U U AAG AC 17 5' 15644

BCLllA-13302 - UGUAAGGCUGGGCGCAG 17 5' 15645

BCLllA-13303 - AAUGUAGAGAGGCAGAG 17 5' 15646

BCLllA-13304 - AGAAUAAAAGGCUGUUU 17 5' 15647

BCLllA-13305 - AGUAAAAUAAUUAGAAUAAA 20 5' 15648

BCLllA-13306 - U U A AG A A AG CAGUGUAAGGC 20 5' 15649

BCLllA-13307 - CAGUGUAAGGCUGGGCGCAG 20 5' 15650

BCLllA-13308 - UUUGGAAUGUAGAGAGGCAG 20 5' 15651

BCLllA-13309 - UGGAAUGUAGAGAGGCAGAG 20 5' 15652

BCLllA-13310 - AGUAUUUUCUUUCAUUG 17 3' 15653

BCLllA-13311 - UAAGUAUUUUCUUUCAU 17 3' 15654

BCLllA-13312 - AAGUAUUUUCUUUCAUU 17 3' 15655

BCLllA-13313 - UAAGUAUUUUCUUUCAUUGG 20 3' 15656

BCLllA-13314 - CAGUAAGUAUUUUCU UUCAU 20 3' 15657

BCLllA-13315 - AGUAAGUAUUUUCUUUCAUU 20 3' 15658

Table 21E provides targeting domains for removing (e.g., deleting) the enhancer region of the BCLl 1A gene by dual targeting (e.g., dual double strand cleavage). It is contemplated herein that an upstream gRNA can be paired with a downstream gRNA to guide Cas9 nuclease pairs. Exemplary nickase pairs include a targeting domain from Group A and a second targeting domain from Group B, or include a targeting domain from Group C and a second targeting domain from Group D. It is contemplated herein that in an embodiment a targeting domain of Group A can be combined with any of the targeting domains of Group B; in an embodiment a targeting domain of Group C can be combined with any of the targeting domains of Group D. For example, BCLl lA-13271 or BCLl lA-13264 can be combined with BCLl lA-13276; or BCLl 1A-13262 or BCLl 1A-13282 can be combined with BCLl 1A-13290 or BCLl 1 A-13280.

Table 21E

Table 22A provides exemplary targeting domains for removing (e.g., deleting) the enhancer region of the BCL11 A gene selected according to the first tier parameters. The targeting domains bind within a region 5' (51.5 to 51.7kb downstream of TSS) or 3' (65.1 to 65.3kb downstream of TSS), have a high level of orthogonality, and start with 5'G. The PAM is NNGRRT. It is contemplated herein that in an embodiment the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. aureus Cas9 molecule that generates a double stranded break (Cas9 nuclease) or a single- stranded break (Cas9 nickase).

Table 22A

Table 22B provides exemplary targeting domains for removing (e.g., deleting) the enhancer region of the BCL11 A gene selected according to the second tier parameters. The targeting domains bind within a region 5' (51.5 to 51.7kb downstream of TSS) or 3' (65.1 to 65.3kb downstream of TSS), and have a high level of orthogonality. The PAM is NNGRRT. It is contemplated herein that in an embodiment the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. aureus Cas9 molecule that generates a double stranded break (Cas9 nuclease) or a single- stranded break (Cas9 nickase). Table 22B

BCLllA-13365 - U U U ACAGCCAU AACAGGG U U U CCA 24 3' 15708

BCLllA-13366 - UGAAUUGUAUAAGUAGCA 18 3' 15709

BCLllA-13367 - AGUGAAUUGUAUAAGUAGCA 20 3' 15710

BCLllA-13368 - CAGUGAAUUGUAUAAGUAGCA 21 3' 15711

BCLllA-13369 - CCAGUGAAUUGUAUAAGUAGCA 22 3' 15712

BCLllA-13370 - UCCAGUGAAUUGUAUAAGUAGCA 23 3' 15713

BCLllA-13371 - UUCCAGUGAAUUGUAUAAGUAGCA 24 3' 15714

BCLllA-13372 - CAAAACU AG AAAG U U U U A 18 3' 15715

BCLllA-13373 - AGCAAAACU AG AAAG U U U U A 20 3' 15716

BCLllA-13374 - AGUGGCUUUAGGCUGUUU 18 3' 15717

BCLllA-13375 - CAGUGGCUUUAGGCUGUUU 19 3' 15718

BCLllA-13376 - AGCAGUGGCUUUAGGCUGUUU 21 3' 15719

BCLllA-13377 - UAGCAGUGGCUUUAGGCUGUUU 22 3' 15720

Table 22C provides exemplary targeting domains for removing (e.g., deleting) the enhancer region of the BCL11 A gene selected according to the third tier parameters. The targeting domains bind within a region 5' (51.5 to 51.7kb downstream of TSS) or 3' (65.1 to 65.3kb downstream of TSS), and start with 5'G. The PAM is NNGRRT. It is contemplated herein that in an embodiment the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. aureus Cas9 molecule that generates a double stranded break (Cas9 nuclease) or a single- stranded break (Cas9 nickase).

Table 22C

Table 22D provides exemplary targeting domains for removing (e.g., deleting) the enhancer region of the BCL11 A gene selected according to the second tier parameters. The targeting domains bind within a region 5' (51.5 to 51.7kb downstream of TSS) or 3' (65.1 to 65.3kb downstream of TSS), and the PAM is NNGRRT. It is contemplated herein that in an embodiment the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. aureus Cas9 molecule that generates a double stranded break (Cas9 nuclease) or a single- stranded break (Cas9 nickase). Table 22D

Table 22E provides exemplary targeting domains for removing (e.g., deleting) the enhancer region of the BCL11 A gene selected according to the third tier parameters. The targeting domains bind within a region 5' (51.5 to 51.7kb downstream of TSS) or 3' (65.1 to 65.3kb downstream of TSS), and the PAM is NNGRRV. It is contemplated herein that in an embodiment the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. aureus Cas9 molecule that generates a double stranded break (Cas9 nuclease) or a single- stranded break (Cas9 nickase). Table 22E

BCLllA-13398 + CAUAAAAAUUUAAGACGGGAAAA 23 5' 15741

BCLllA-13399 + ACAU AAAAAU U U AAG ACGGG AAAA 24 5' 15742

BCLllA-13400 + U CACAU AAAAAU U U AAG A 18 5' 15743

BCLllA-13401 + CU CACAU AAAAAU U U AAG A 19 5' 15744

BCLllA-13402 + U CU CACAU AAAAAU U U AAG A 20 5' 15745

BCLllA-13403 + AUCUCACAUAAAAAUUUAAGA 21 5' 15746

BCLllA-13404 + CAUCUCACAU A A A A A U U U A AG A 22 5' 15747

BCLllA-13405 + U CAU CU CACAU AAAAAU U U AAG A 23 5' 15748

BCLllA-13406 + CU CAU CU CACAU AAAAAU U U AAG A 24 5' 15749

BCLllA-13407 + AAUU U AAG ACGGG AAAAC 18 5' 15750

BCLllA-13408 + AAAU U U AAG ACGGG AAAAC 19 5' 15751

BCLllA-13409 + AAAAU U U AAG ACGGG AAAAC 20 5' 15752

BCLllA-13410 + AAAAAU U U AAG ACGGG AAAAC 21 5' 15753

BCLllA-13411 + UAAAAAUUUAAGACGGGAAAAC 22 5' 15754

BCLllA-13412 + AU AAAAAU U U AAG ACGGG AAAAC 23 5' 15755

BCLllA-13413 + CAUAAAAAUUUAAGACGGGAAAAC 24 5' 15756

BCLllA-13414 + CACAU AAAAAU U U AAG AC 18 5' 15757

BCLllA-13415 + U CACAU AAAAAU U U AAG AC 19 5' 15758

BCLllA-13416 + CU CACAU AAAAAU U U AAG AC 20 5' 15759

BCLllA-13417 + UCUCACAUAAAAAUUUAAGAC 21 5' 15760

BCLllA-13418 + AUCUCACAUAAAAAUUUAAGAC 22 5' 15761

BCLllA-13419 + CAUCUCACAU A A A A A U U U A AG AC 23 5' 15762

BCLllA-13420 + U CAU CU CACAU AAAAAU U U AAG AC 24 5' 15763

BCLllA-13421 + CU CACAU AAAAAU U U AAG 18 5' 15764

BCLllA-13422 + U C U C AC A U A A A A A U U U A AG 19 5' 15765

BCLllA-13423 + AUCUCACAU A A A A A U U U A AG 20 5' 15766

BCLllA-13424 + C A U C U C AC A U A A A A A U U U A AG 21 5' 15767

BCLllA-13425 + U CAU CU CACAU AAAAAU UU AAG 22 5' 15768

BCLllA-13426 + CU CAU CU CACAU AAAAAU U U AAG 23 5' 15769

BCLllA-13427 + GCUCAUCUCACAUAAAAAUUUAAG 24 5' 15770

BCLllA-13428 + CAACUUGUGUUGCACUAG 18 5' 15771

BCLllA-13429 + ACAACUUGUGUUGCACUAG 19 5' 15772

BCLllA-13430 + CA CAACUUGUGUUGCACUAG 20 5' 15773

BCLllA-13431 + ACACAACUUGUGUUGCACUAG 21 5' 15774

BCLllA-13432 + UACACAACUUGUGU UGCACUAG 22 5' 15775

BCLllA-13433 + CUACACAACUUGUGUUGCACUAG 23 5' 15776

BCLllA-13434 + UCUACACAACUUGUGUUGCACUAG 24 5' 15777

BCLllA-13435 + AACAGGAAGAUGCAUUCU 18 5' 15778

BCLllA-13436 + AAACAGGAAGAUGCAUUCU 19 5' 15779

BCLllA-13437 + AAAACAGGAAGAUGCAUUCU 20 5' 15780

BCLllA-13438 + GAAAACAGGAAGAUGCAUUCU 21 5' 15781

BCLllA-13439 + GGAAAACAGGAAGAUGCAUUCU 22 5' 15782 BCLllA-13440 + GGGAAAACAGGAAGAUGCAUUCU 23 5' 15783

BCLllA-13441 + CG G G A A A AC AG GAAGAUGCAUUCU 24 5' 15784

BCLllA-13442 + U UAUUUUACUAGUGAAUU 18 5' 15785

BCLllA-13443 + AUUAUUUUACUAGUGAAUU 19 5' 15786

BCLllA-13444 + AAUUAUUUUACUAGUGAAUU 20 5' 15787

BCLllA-13445 + UAAUUAUUUUACUAGUGAAUU 21 5' 15788

BCLllA-13446 + CUAAUUAUUUUACUAGUGAAUU 22 5' 15789

BCLllA-13447 + UCUAAUUAUUUUACUAGUGAAUU 23 5' 15790

BCLllA-13448 + UUCUAAUUAUUUUACUAGUGAAUU 24 5' 15791

BCLllA-13449 + AAAACAGGAAGAUGCAUU 18 5' 15792

BCLllA-13450 + GAAAACAGGAAGAUGCAUU 19 5' 15793

BCLllA-13451 + GG AAAACAGGAAGAUGCAUU 20 5' 15794

BCLllA-13452 + GGGAAAACAGGAAGAUGCAUU 21 5' 15795

BCLllA-13453 + CGGGAAAACAGGAAGAUGCAUU 22 5' 15796

BCLllA-13454 + ACGGGAAAACAGGAAGAUGCAUU 23 5' 15797

BCLllA-13455 + GACGGG AAAACAGGAAGAUGCAUU 24 5' 15798

BCLllA-13456 - U UGGAAUGUAGAGAGGCA 18 5' 15799

BCLllA-13457 - U UUGGAAUGUAGAGAGGCA 19 5' 15800

BCLllA-13458 - U UUUGGAAUGUAGAGAGGCA 20 5' 15801

BCLllA-13459 - GUUUUGGAAUGUAGAGAGGCA 21 5' 15802

BCLllA-13460 - UGUUUUGGAAUGUAGAGAGGCA 22 5' 15803

BCLllA-13461 - CUGUUUUGGAAUGUAGAGAGGCA 23 5' 15804

BCLllA-13462 - GCUGUUUUGGAAUGUAGAGAGGCA 24 5' 15805

BCLllA-13463 - CAACACAAGUUGUGUAGA 18 5' 15806

BCLllA-13464 - GCAACACAAGUUGUGUAGA 19 5' 15807

BCLllA-13465 - UGCAACACAAGUUGUGUAGA 20 5' 15808

BCLllA-13466 - G U G C AACAC AAG UUGUGUAGA 21 5' 15809

BCLllA-13467 - AGUGCAACACAAGUUGUGUAGA 22 5' 15810

BCLllA-13468 - U AG U G C A AC AC A AG UUGUGUAGA 23 5' 15811

BCLllA-13469 - C U AG U G C AACAC AAG UUGUGUAGA 24 5' 15812

BCLllA-13470 - AGGCUGUUUUGGAAUGUA 18 5' 15813

BCLllA-13471 - AAGGCUGUUUUGGAAUGUA 19 5' 15814

BCLllA-13472 - AAAGGCUGUUUUGGAAUGUA 20 5' 15815

BCLllA-13473 - AAAAGGCUGUUUUGGAAUGUA 21 5' 15816

BCLllA-13474 - UAAAAGGCUGUUUUGGAAUGUA 22 5' 15817

BCLllA-13475 - AUAAAAGGCUGUUUUGGAAUGUA 23 5' 15818

BCLllA-13476 - AAUAAAAGGCUGUUUUGGAAUGUA 24 5' 15819

BCLllA-13477 - UGGAAUGUAGAGAGGCAG 18 5' 15820

BCLllA-13478 - U UGGAAUGUAGAGAGGCAG 19 5' 15821

BCLllA-13479 - U UUGGAAUGUAGAGAGGCAG 20 5' 15822

BCLllA-13480 - U UUUGGAAUGUAGAGAGGCAG 21 5' 15823

BCLllA-13481 - GU UUUGGAAUGUAGAGAGGCAG 22 5' 15824 BCLllA-13482 - UGUUUUGGAAUGUAGAGAGGCAG 23 5' 15825

BCLllA-13483 - CUGUUUUGGAAUGUAGAGAGGCAG 24 5' 15826

BCLllA-13484 - CUUAAAUUUUUAUGUGAG 18 5' 15827

BCLllA-13485 - UCUUAAAUUUUUAUGUGAG 19 5' 15828

BCLllA-13486 - GUCUUAAAUUUUUAUGUGAG 20 5' 15829

BCLllA-13487 - CGUCUUAAAUUUUUAUGUGAG 21 5' 15830

BCLllA-13488 - CCGUCUUAAAUUUUUAUGUGAG 22 5' 15831

BCLllA-13489 - CCCGUCUUAAAUUUUUAUGUGAG 23 5' 15832

BCLllA-13490 - UCCCGUCUUAAAUUUUUAUGUGAG 24 5' 15833

BCLllA-13491 - U A AG A A AG C AG U G U A AG G 18 5' 15834

BCLllA-13492 - U U A AG A A AG C AG U G U A AG G 19 5' 15835

BCLllA-13493 - AUUAAGAAAGCAGUGUAAGG 20 5' 15836

BCLllA-13494 - A A U U A AG A A AG C AG U G U A AG G 21 5' 15837

BCLllA-13495 - U A A U U A AG A A AG C AG U G U A AG G 22 5' 15838

BCLllA-13496 - GUAAU U AAG AAAGCAG UG U AAGG 23 5' 15839

BCLllA-13497 - U G U A A U U A AG A A AG CAGUGUAAGG 24 5' 15840

BCLllA-13498 - UUUUGGAAUGUAGAGAGG 18 5' 15841

BCLllA-13499 - GUUUUGGAAUGUAGAGAGG 19 5' 15842

BCLllA-13500 - UGUUUUGGAAUGUAGAGAGG 20 5' 15843

BCLllA-13501 - CUGUUUUGGAAUGUAGAGAGG 21 5' 15844

BCLllA-13502 - GCUGUUUUGGAAUGUAGAGAGG 22 5' 15845

BCLllA-13503 - GGCUGUUUUGGAAUGUAGAGAGG 23 5' 15846

BCLllA-13504 - AGGCUGUUUUGGAAUGUAGAGAGG 24 5' 15847

BCLllA-13505 - AAAGGCUGUUUUGGAAUG 18 5' 15848

BCLllA-13506 - AAAAGGCUGUUUUGGAAUG 19 5' 15849

BCLllA-13507 - UAAAAGGCUGUUUUGGAAUG 20 5' 15850

BCLllA-13508 - AUAAAAGGCUGUUUUGGAAUG 21 5' 15851

BCLllA-13509 - AAUAAAAGGCUGUUUUGGAAUG 22 5' 15852

BCLllA-13510 - GAAUAAAAGGCUGUUUUGGAAUG 23 5' 15853

BCLllA-13511 - AGAAUAAAAGGCUGUUUUGGAAUG 24 5' 15854

BCLllA-13512 - AG U G CAAC ACAAG U U G U G 18 5' 15855

BCLllA-13513 - U AG U G CAAC ACAAG U U G U G 19 5' 15856

BCLllA-13514 - CUAGUGCAACACAAGUUGUG 20 5' 15857

BCLllA-13515 - CCUAGUGCAACACAAGUUGUG 21 5' 15858

BCLllA-13516 - ACCUAGUGCAACACAAGUUGUG 22 5' 15859

BCLllA-13517 - CACCUAGUGCAACACAAGUUGUG 23 5' 15860

BCLllA-13518 - UCACCUAGUGCAACACAAGUUGUG 24 5' 15861

BCLllA-13519 - CCCGUCUUAAAUUUUUAU 18 5' 15862

BCLllA-13520 - UCCCGUCUUAAAUUUUUAU 19 5' 15863

BCLllA-13521 - UUCCCGUCUUAAAUUUUUAU 20 5' 15864

BCLllA-13522 - UUUCCCGUCUUAAAUUUUUAU 21 5' 15865

BCLllA-13523 - UUUUCCCGUCUUAAAUUUUUAU 22 5' 15866 BCLllA-13524 - GU UUUCCCGUCUUAAAUUUUUAU 23 5' 15867

BCLllA-13525 - UGUUUUCCCGUCUUAAAUUUUUAU 24 5' 15868

BCLllA-13526 - GAGCACACUGCUGUAAUU 18 5' 15869

BCLllA-13527 - UGAGCACACUGCUGUAAUU 19 5' 15870

BCLllA-13528 - AUGAGCACACUGCUGUAAUU 20 5' 15871

BCLllA-13529 - GAUGAGCACACUGCUGUAAUU 21 5' 15872

BCLllA-13530 - AGAUGAGCACACUGCUGUAAUU 22 5' 15873

BCLllA-13531 - GAGAUGAGCACACUGCUGUAAUU 23 5' 15874

BCLllA-13532 - UGAGAUGAGCACACUGCUGUAAUU 24 5' 15875

BCLllA-13533 - U UAGAAUAAAAGGCUGUU 18 5' 15876

BCLllA-13534 - AU U AG AAU AAAAGG CUG U U 19 5' 15877

BCLllA-13535 - AAUUAGAAUAAAAGGCUGUU 20 5' 15878

BCLllA-13536 - U AAU U AG AAU AAAAGG CUG U U 21 5' 15879

BCLllA-13537 - AUAAUUAGAAUAAAAGGCUGUU 22 5' 15880

BCLllA-13538 - AAU AAU U AG AAU AAAAGG CUG U U 23 5' 15881

BCLllA-13539 - AAAUAAUUAGAAUAAAAGGCUGUU 24 5' 15882

BCLllA-13540 + UUUCAUUUUUUGCUGACA 18 3' 15883

BCLllA-13541 + GUUUCAUUUU UUGCUGACA 19 3' 15884

BCLllA-13542 + UGUUUCAUUU UUUGCUGACA 20 3' 15885

BCLllA-13543 + UUGUUUCAUU UUUUGCUGACA 21 3' 15886

BCLllA-13544 + UUUGUUUCAU UUUUUGCUGACA 22 3' 15887

BCLllA-13545 + UUUUGUUUCAUUUUUUGCUGACA 23 3' 15888

BCLllA-13546 + UUUUUGUUUCAUUUUUUGCUGACA 24 3' 15889

BCLllA-13547 + AAUAGUUUGCUUCCCCCA 18 3' 15890

BCLllA-13548 + AAAUAGUUUGCUUCCCCCA 19 3' 15891

BCLllA-13549 + UAAAUAGUUUGCUUCCCCCA 20 3' 15892

BCLllA-13550 + GUAAAUAGUUUGCUUCCCCCA 21 3' 15893

BCLllA-13551 + UGUAAAUAGUUUGCUUCCCCCA 22 3' 15894

BCLllA-13552 + CUGUAAAUAGUUUGCUUCCCCCA 23 3' 15895

BCLllA-13553 + GCUGUAAAUAGUUUGCUUCCCCCA 24 3' 15896

BCLllA-13554 + AAUACUUACUGUACUGCA 18 3' 15897

BCLllA-13555 + AAAUACUUACUGUACUGCA 19 3' 15898

BCLllA-13556 + AAAAUACUUACUGUACUGCA 20 3' 15899

BCLllA-13557 + GAAAAUACUUACUGUACUGCA 21 3' 15900

BCLllA-13558 + AGAAAAUACUUACUGUACUGCA 22 3' 15901

BCLllA-13559 + AAGAAAAUACUUACUGUACUGCA 23 3' 15902

BCLllA-13560 + AAAGAAAAUACUUACUGUACUGCA 24 3' 15903

BCLllA-13561 + UGCUACUUAUACAAU UCA 18 3' 15904

BCLllA-13562 + GUGCUACUUAUACAAUUCA 19 3' 15905

BCLllA-13563 + AGUGCUACUUAUACAAUUCA 20 3' 15906

BCLllA-13564 + CAGUGCUACUUAUACAAUUCA 21 3' 15907

BCLllA-13565 + UCAGUGCUACUUAUACAAUUCA 22 3' 15908 BCLllA-13566 + CUCAGUGCUACUUAUACAAUUCA 23 3' 15909

BCLllA-13567 + ACUCAGUGCUACUUAUACAAUUCA 24 3' 15910

BCLllA-13568 + GUUUGCUUCCCCCAAUGA 18 3' 15911

BCLllA-13569 + AGUUUGCUUCCCCCAAUGA 19 3' 15912

BCLllA-13570 + UAGUUUGCUUCCCCCAAUGA 20 3' 15913

BCLllA-13571 + AUAGUUUGCUUCCCCCAAUGA 21 3' 15914

BCLllA-13572 + AAUAGUUUGCUUCCCCCAAUGA 22 3' 15915

BCLllA-13573 + AAAUAGUUUGCUUCCCCCAAUGA 23 3' 15916

BCLllA-13574 + UAAAUAGUUUGCUUCCCCCAAUGA 24 3' 15917

BCLllA-13575 + UUUCUAGUUU UGCUUAAC 18 3' 15918

BCLllA-13576 + CUUUCUAGU UUUGCUUAAC 19 3' 15919

BCLllA-13577 + ACUUUCUAGUUUUGCU UAAC 20 3' 15920

BCLllA-13578 + AACUUUCUAGUUU UGCUUAAC 21 3' 15921

BCLllA-13579 + AAACUUUCUAGUUUUGCUUAAC 22 3' 15922

BCLllA-13580 + AAAACUUUCUAGUUUUGCUUAAC 23 3' 15923

BCLllA-13581 + UAAAACUUUCUAGUUU UGCUUAAC 24 3' 15924

BCLllA-13582 + GCUACUUAUACAAUUCAC 18 3' 15925

BCLllA-13583 + UGCUACUUAUACAAUUCAC 19 3' 15926

BCLllA-13584 + GUGCUACUUAUACAAUUCAC 20 3' 15927

BCLllA-13585 + AGUGCUACUUAUACAAU UCAC 21 3' 15928

BCLllA-13586 + CAGUGCUACUUAUACAAUUCAC 22 3' 15929

BCLllA-13587 + UCAGUGCUACUUAUACAAUUCAC 23 3' 15930

BCLllA-13588 + CUCAGUGCUACUUAUACAAUUCAC 24 3' 15931

BCLllA-13589 + AAAUACUUACUGUACUGC 18 3' 15932

BCLllA-13590 + AAAAUACUUACUGUACUGC 19 3' 15933

BCLllA-13591 + GAAAAUACUUACUGUACUGC 20 3' 15934

BCLllA-13592 + AGAAAAUACUUACUGUACUGC 21 3' 15935

BCLllA-13593 + AAGAAAAUACUUACUGUACUGC 22 3' 15936

BCLllA-13594 + AAAGAAAAUACUUACUGUACUGC 23 3' 15937

BCLllA-13595 + GAAAGAAAAUACUUACUGUACUGC 24 3' 15938

BCLllA-13596 + AAAAUACUUACUGUACUG 18 3' 15939

BCLllA-13597 + GAAAAUACUUACUGUACUG 19 3' 15940

BCLllA-13598 + AGAAAAUACUUACUGUACUG 20 3' 15941

BCLllA-13599 + AAGAAAAUACUUACUGUACUG 21 3' 15942

BCLllA-13600 + AAAGAAAAUACUUACUGUACUG 22 3' 15943

BCLllA-13601 + GAAAGAAAAUACUUACUGUACUG 23 3' 15944

BCLllA-13602 + UGAAAGAAAAUACUUACUGUACUG 24 3' 15945

BCLllA-13603 - GU UCUGUGUCAG C A A A A A 18 3' 15946

BCLllA-13604 - AGUUCUGUGUCAGCAAAAA 19 3' 15947

BCLllA-13605 - GAGUUCUGUGUCAGCAAAAA 20 3' 15948

BCLllA-13606 - UGAGUUCUGUGUCAGCAAAAA 21 3' 15949

BCLllA-13607 - CUGAGUUCUGUGUCAGCAAAAA 22 3' 15950 BCLllA-13608 - ACUGAGUUCUGUGU CAG C AAAAA 23 3' 15951

BCLllA-13609 - CACUGAGUUCUGUGU CAG C AAAAA 24 3' 15952

BCLllA-13610 - AGUAAGUAUUUUCUUUCA 18 3' 15953

BCLllA-13611 - CAGUAAGUAUUUUCUUUCA 19 3' 15954

BCLllA-13612 - ACAGUAAGUAUUUUCUUUCA 20 3' 15955

BCLllA-13613 - UACAGUAAGUAUUUUCUUUCA 21 3' 15956

BCLllA-13614 - GUACAGUAAGUAUUUUCUUUCA 22 3' 15957

BCLllA-13615 - AGUACAGUAAGUAUUUUCUUUCA 23 3' 15958

BCLllA-13616 - CAGUACAGUAAGUAUUUUCUUUCA 24 3' 15959

BCLllA-13617 - UUUCAUGUUAAGCAAAAC 18 3' 15960

BCLllA-13618 - UUUUCAUGUUAAGCAAAAC 19 3' 15961

BCLllA-13619 - AUUUUCAUGUUAAGCAAAAC 20 3' 15962

BCLllA-13620 - UAUUUUCAUGUUAAGCAAAAC 21 3' 15963

BCLllA-13621 - UUAUUUUCAUGUUAAGCAAAAC 22 3' 15964

BCLllA-13622 - AUUAUUUUCAUGU U AAGCAAAAC 23 3' 15965

BCLllA-13623 - UAUUAUUUUCAUGUUAAGCAAAAC 24 3' 15966

BCLllA-13624 - AGUAUUUUCUUUCAUUGG 18 3' 15967

BCLllA-13625 - AAGUAUUUUCUUUCAUUGG 19 3' 15968

BCLllA-13626 - UAAGUAUUUUCUUUCAUUGG 20 3' 15969

BCLllA-13627 - GUAAGUAUUUUCUUUCAUUGG 21 3' 15970

BCLllA-13628 - AGUAAGUAUUUUCUUUCAUUGG 22 3' 15971

BCLllA-13629 - CAGUAAGUAUUUUCUUUCAUUGG 23 3' 15972

BCLllA-13630 - ACAGUAAGUAUUUUCUUUCAUUGG 24 3' 15973

BCLllA-13631 - AAGUAUUUUCUUUCAUUG 18 3' 15974

BCLllA-13632 - UAAGUAUUUUCUUUCAUUG 19 3' 15975

BCLllA-13633 - GUAAGUAUUUUCUUUCAUUG 20 3' 15976

BCLllA-13634 - AGUAAGUAUUUUCUUUCAUUG 21 3' 15977

BCLllA-13635 - CAGUAAGUAUUUUCUUUCAUUG 22 3' 15978

BCLllA-13636 - ACAGUAAGUAUUUUCUUUCAUUG 23 3' 15979

BCLllA-13637 - UACAGUAAGUAUUUUCUUUCAUUG 24 3' 15980

BCLllA-13638 - GUAAGUAUUUUCUUUCAU 18 3' 15981

BCLllA-13639 - AGUAAGUAUUUUCUUUCAU 19 3' 15982

BCLllA-13640 - CAGUAAGUAUUUUCUUUCAU 20 3' 15983

BCLllA-13641 - ACAGUAAGUAUUUUCUUUCAU 21 3' 15984

BCLllA-13642 - UACAGUAAGUAUUUUCUUUCAU 22 3' 15985

BCLllA-13643 - GUACAGUAAGUAUUUUCUUUCAU 23 3' 15986

BCLllA-13644 - AGUACAGUAAGUAUUUUCUUUCAU 24 3' 15987

BCLllA-13645 - UUGGCUAUUGAUACUGAU 18 3' 15988

BCLllA-13646 - UUUGGCUAUUGAUACUGAU 19 3' 15989

BCLllA-13647 - CUUUGGCUAUUGAUACUGAU 20 3' 15990

BCLllA-13648 - UCUUUGGCUAUUGAUACUGAU 21 3' 15991

BCLllA-13649 - AUCUUUGGCUAUUGAUACUGAU 22 3' 15992 BCLllA-13650 - GAUCUUUGGCUAUUGAUACUGAU 23 3' 15993

BCLllA-13651 - GGAUCUUUGGCUAUUGAUACUGAU 24 3' 15994

BCLllA-13652 - UAAGUAUUUUCUUUCAUU 18 3' 15995

BCLllA-13653 - GUAAGUAUUUUCUU UCAUU 19 3' 15996

BCLllA-13654 - AGUAAGUAUUUUCUUUCAUU 20 3' 15997

BCLllA-13655 - CAGUAAGUAUUUUCUU UCAUU 21 3' 15998

BCLllA-13656 - ACAGUAAGUAUUUUCUUUCAUU 22 3' 15999

BCLllA-13657 - UACAGUAAGUAUUUUCUUUCAUU 23 3' 16000

BCLllA-13658 - GUACAGUAAGUAUUUUCUUUCAUU 24 3' 16001

Table 23A provides exemplary targeting domains for removing (e.g., deleting) the enhancer region of the BCL11 A gene selected according to the first tier parameters. The targeting domains bind within a region 5' (51.5 to 51.7kb downstream of TSS) or 3' (65.1 to 65.3kb downstream of TSS), have a high level of orthogonality, and start with 5'G. It is contemplated herein that in an embodiment the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a N. meningitidis Cas9 molecule that generates a double stranded break (Cas9 nuclease) or a single- stranded break (Cas9 nickase).

Table 23A

Table 23B provides exemplary targeting domains for removing (e.g., deleting) the enhancer region of the BCL11 A gene selected according to the second tier parameters. The targeting domains bind within a region 5' (51.5 to 51.7kb downstream of TSS) or 3' (65.1 to 65.3kb downstream of TSS) and have a high level of orthogonality. It is contemplated herein that in an embodiment the targeting domain hybridizes to the target domain through

complementary base pairing. Any of the targeting domains in the table can be used with a N. meningitidis Cas9 molecule that generates a double stranded break (Cas9 nuclease) or a single- stranded break (Cas9 nickase).

Table 23B

Strand Site NO:

Length

BCLllA-13660 + UCGGUAAAACUUUCUAG 17 3' 16003

BCLllA-13661 - UUUGGAUCUUUGGCUAUUGA 20 3' 16004

BCLllA-13662 + CCCUGU UAUGGCUGUAAAUA 20 3' 16005

BCLllA-13663 + AAUUCGGUAAAACUUUCUAG 20 3' 16006

Table 23C provides exemplary targeting domains for removing (e.g., deleting) the enhancer region of the BCL11 A gene selected according to the fourth tier parameters. The targeting domains bind within a region 5' (51.5 to 51.7kb downstream of TSS) or 3' (65.1 to 65.3kb downstream of TSS). It is contemplated herein that in an embodiment the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a N. meningitidis Cas9 molecule that generates a double stranded break (Cas9 nuclease) or a single- stranded break (Cas9 nickase).

Table 23C

Table 24A provides exemplary targeting domains for correcting a mutation (e.g., E6V) in the HBB gene selected according to the first tier parameters. The targeting domains bind within 200 bp to a mutation (e.g., E6V) and have a high level of orthogonality. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. pyogenes Cas9 molecule that generates a double strand break (Cas9 nuclease) or a single-strand break (Cas9 nickase). Table 24A

HBB-71 - GU UACAAGACAGGUUUA 17 16014

HBB-72 - AGGAGACCAAUAGAAAC 17 16015

HBB-37 + CGUUCACCUUGCCCCAC 17 16016

HBB-3 + ACGGCAGACUUCUCCAC 17 16017

HBB-41 - U AU CAAGG U U ACAAG AC 17 16018

HBB-73 + ACU UUUAUGCCCAGCCC 17 16019

HBB-74 - GGCUGGGCAUAAAAGUC 17 16020

HBB-4 + ACUUCUCCACAGGAGUC 17 16021

HBB-75 - AAUAGAAACUGGGCAUG 17 16022

HBB-38 - CUGCCGUUACUGCCCUG 17 16023

HBB-13 - GGAUGAAGUUGGUGGUG 17 16024

HBB-12 - GCCGUUACUGCCCUGUG 17 16025

HBB-76 + ACAUGCCCAGUUUCUAU 17 16026

HBB-77 - GGAGACCAAUAGAAACU 17 16027

HBB-15 - GUGAACGUGGAUGAAGU 17 16028

HBB-47 - UGCCGUUACUGCCCUGU 17 16029

HBB-39 + CUUGCCCCACAGGGCAGUAA 20 16030

HBB-30 + CACGUUCACCUUGCCCCACA 20 16031

HBB-7 + CACAGGAGUCAGGUGCACCA 20 16032

HBB-78 - AGCAGGGAGGGCAGGAGCCA 20 16033

HBB-36 - CGUUACUGCCCUGUGGGGCA 20 16034

HBB-79 - AGGGCUGGGCAUAAAAGUCA 20 16035

HBB-22 + A AG C A A A U G U A AG C A A U AG A 20 16036

HBB-80 - AAGGU U ACAAG ACAGG U U U A 20 16037

HBB-81 - UUAAGGAGACCAAUAGAAAC 20 16038

HBB-2 + GUAACGGCAGACUUCUCCAC 20 16039

HBB-49 - UGGUAUCAAGGUUACAAGAC 20 16040

HBB-82 + CUGACU UUUAUGCCCAGCCC 20 16041

HBB-43 - UGAAGUUGGUGGUGAGGCCC 20 16042

HBB-83 - GAGCAGGGAGGGCAGGAGCC 20 16043

HBB-84 - CAGGGCUGGGCAUAAAAGUC 20 16044

HBB-8 + CAGACUUCUCCACAGGAGUC 20 16045

HBB-16 - GUGAACGUGGAUGAAGUUGG 20 16046

HBB-85 - ACCAAUAGAAACUGGGCAUG 20 16047

HBB-27 - AGUCUGCCGUUACUGCCCUG 20 16048

HBB-35 - CGUGGAUGAAGUUGGUGGUG 20 16049

HBB-42 - UCUGCCGUUACUGCCCUGUG 20 16050

HBB-86 - UAAGGAGACCAAUAGAAACU 20 16051

HBB-9 - GAAGUUGGUGGUGAGGCCCU 20 16052

HBB-87 - GGAGGGCAGGAGCCAGGGCU 20 16053

HBB-23 - AAGGUGAACGUGGAUGAAGU 20 16054

HBB-14 - GUCUGCCGU UACUGCCCUGU 20 16055 Table 24B provides exemplary targeting domains for correcting a mutation (e.g., E6V) in the HBB gene selected according to the second tier parameters. The targeting domains bind within 200 bp to a mutation (e.g., E6V) and start with a 5'G. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. pyogenes Cas9 molecule that generates a double strand break (Cas9 nuclease) or a single-strand break (Cas9 nickase).

Table 24B

Table 24C provides exemplary targeting domains for correcting a mutation (e.g., E6V) in the HBB gene selected according to the third tier parameters. The targeting domains bind within 200 bp to a mutation (e.g., E6V). It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. pyogenes Cas9 molecule that generates a double strand break (Cas9 nuclease) or a single-strand break (Cas9 nickase).

Table 24C

H BB-51 + U UGAUACCAACCUGCCC 17 16070

H BB-91 - CAGGGAGGGCAGGAGCC 17 16071

H BB-92 - AGGGCAGGAGCCAGGGC 17 16072

H BB-21 - AACG UGGAUGAAG U UGG 17 16073

H BB-24 + ACCAUGG UGUCUG U U UG 17 16074

H BB-44 - UGAGGCCCUGGGCAGG U 17 16075

H BB-34 + CCU UGAUACCAACCUGCCCA 20 16076

H BB-32 - CCCUGGGCAGG U UGGUAUCA 20 16077

H BB-31 + CCACG U U CACCU U GCCCCAC 20 16078

H BB-26 + ACCU UGAUACCAACCUGCCC 20 16079

H BB-52 - U UGGUGGUGAGGCCCUGGGC 20 16080

H BB-33 - CCUG UGGGGCAAGGUGAACG 20 16081

H BB-6 - CAUGG UGCACCUGACUCCUG 20 16082

H BB-46 + UGCACCAUGG UG UCUG U U UG 20 16083

H BB-50 - UGG UGAGGCCCUGGGCAGG U 20 16084

Table 24D provides targeting domains for correcting a mutation (e.g., E6V) in the HBB gene by dual targeting (e.g., dual single strand cleavages). In an embodiment, dual targeting (e.g., dual nicking) is used to create two nicks on opposite DNA strands by using S. pyogenes Cas9 nickases with two targeting domains that are complementary to opposite DNA strands, e.g., a gRNA comprising any minus strand targeting domain may be paired any gRNA comprising a plus strand targeting domain provided that the two gRNAs are oriented on the DNA such that PAMs face outward and the distance between the 5' ends of the gRNAs is 0-50bp. Exemplary nickase pairs include a targeting domain from Group A and a second targeting domain from Group B in Table 24D (for S. pyogenes). It is contemplated herein that in an embodiment a targeting domain of Group A can be combined with any of the targeting domains of Group B in Table 24D (for S. pyogenes). For example, HBB-9 or HBB-20 can be combined with HBB-11 or HBB-39.

Table 24D

Table 25A provides exemplary targeting domains for correcting a mutation (e.g., E6V) in the HBB gene selected according to the first tier parameters. The targeting domains bind within 200 bp to a mutation (e.g., E6V), and have a high level of orthogonality. The PAM is NNGRRT. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. pyogenes Cas9 molecule that generates a double strand break (Cas9 nuclease) or a single-strand break (Cas9 nickase).

Table 25A

Table 25B provides exemplary targeting domains for correcting a mutation (e.g., E6V) the HBB gene selected according to the fourth tier parameters. The targeting domains bind within 200 bp to a mutation (e.g., E6V), and the PAM is NNGRRV. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a S. pyogenes Cas9 molecule that generates a double strand break (Cas9 nuclease) or a single- strand break (Cas9 nickase).

Table 25B

HBB-109 + CAUCCACGUUCACCUUGCCCCA 22 16103

HBB-110 + UCAUCCACGUUCACCUUGCCCCA 23 16104

HBB-111 + UUCAUCCACGUUCACCUUGCCCCA 24 16105

HBB-112 + UAACGGCAGACUUCUCCA 18 16106

HBB-113 + GUAACGGCAGACUUCUCCA 19 16107

HBB-69 + AGUAACGGCAGACUUCUCCA 20 16108

HBB-114 + CAGUAACGGCAGACUUCUCCA 21 16109

HBB-115 + GCAGUAACGGCAGACUUCUCCA 22 16110

HBB-116 + GGCAGUAACGGCAGACUUCUCCA 23 16111

HBB-117 + GGGCAGUAACGGCAGACUUCUCCA 24 16112

HBB-118 + GUCUGUUUGAGGUUGCUA 18 16113

HBB-119 + UGUCUGUUUGAGGUUGCUA 19 16114

HBB-66 + GUGUCUGUUUGAGGUUGCUA 20 16115

HBB-120 + GGUGUCUGUUUGAGGUUGCUA 21 16116

HBB-121 + UGGUGUCUGUUUGAGGUUGCUA 22 16117

HBB-122 + AUGGUGUCUGUUUGAGGUUGCUA 23 16118

HBB-123 + CAUGGUGUCUGUUUGAGGUUGCUA 24 16119

HBB-124 + CCUUGAUACCAACCUGCC 18 16120

HBB-125 + ACCUUGAUACCAACCUGCC 19 16121

HBB-57 + AACCUUGAUACCAACCUGCC 20 16122

HBB-126 + UAACCUUGAUACCAACCUGCC 21 16123

HBB-127 + GUAACCUUGAUACCAACCUGCC 22 16124

HBB-128 + UGUAACCUUGAUACCAACCUGCC 23 16125

HBB-129 + UUGUAACCUUGAUACCAACCUGCC 24 16126

HBB-130 + GUGCACCAUGGUGUCUGU 18 16127

HBB-131 + GGUGCACCAUGGUGUCUGU 19 16128

HBB-62 + AGGUGCACCAUGGUGUCUGU 20 16129

HBB-132 + CAGGUGCACCAUGGUGUCUGU 21 16130

HBB-133 + UCAGGUGCACCAUGGUGUCUGU 22 16131

HBB-134 + GUCAGGUGCACCAUGGUGUCUGU 23 16132

HBB-135 + AGUCAGGUGCACCAUGGUGUCUGU 24 16133

HBB-136 + UAGUGAACACAGUUGUGU 18 16134

HBB-137 + CUAGUGAACACAGUUGUGU 19 16135

HBB-59 + GCUAGUGAACACAGUUGUGU 20 16136

HBB-138 + UGCUAGUGAACACAGUUGUGU 21 16137

HBB-139 + UUGCUAGUGAACACAGUUGUGU 22 16138

HBB-140 + GUUGCUAGUGAACACAGUUGUGU 23 16139

HBB-141 + GGUUGCUAGUGAACACAGUUGUGU 24 16140

HBB-142 - UAAGGAGACCAAUAGAAA 18 16141

HBB-143 - UUAAGGAGACCAAUAGAAA 19 16142

HBB-144 - U U UAAGGAGACCAAUAGAAA 20 16143

HBB-145 - GU UUAAGGAGACCAAUAGAAA 21 16144 HBB-146 - GG U U U AAGG AG ACCAAU AG AAA 22 16145

HBB-147 - AGG U U U AAGG AG ACCAAU AG AAA 23 16146

HBB-148 - CAGG U U U AAGG AG ACCAAU AG AAA 24 16147

HBB-149 - CAGGUUUAAGGAGACCAA 18 16148

HBB-150 - ACAGGUUUAAGGAGACCAA 19 16149

HBB-151 - GACAGGUUUAAGGAGACCAA 20 16150

HBB-152 - AG ACAGG U U U AAGG AG ACCAA 21 16151

HBB-153 - AAGACAGGUUUAAGGAGACCAA 22 16152

HBB-154 - CAAGACAGGUUUAAGGAGACCAA 23 16153

HBB-155 - ACAAG ACAGG U U U AAGG AG ACCAA 24 16154

HBB-156 - GG U U ACAAG ACAGG U U U A 18 16155

HBB-157 - AGG U U ACAAG ACAGG U U U A 19 16156

HBB-80 - AAGG U U ACAAG ACAGG U U U A 20 16157

HBB-158 - CAAGG U U ACAAG ACAGG U U U A 21 16158

HBB-159 - UCAAGGUUACAAGACAGGUUUA 22 16159

HBB-160 - AU CAAGG U U ACAAG ACAGG U U U A 23 16160

HBB-161 - U AU CAAGG U U ACAAG ACAGG U U U A 24 16161

HBB-162 - GAAGUUGGUGGUGAGGCC 18 16162

HBB-163 - UGAAGUUGGUGGUGAGGCC 19 16163

HBB-68 - AUGAAGUUGGUGGUGAGGCC 20 16164

HBB-164 - GAUGAAGUUGGUGGUGAGGCC 21 16165

HBB-165 - GGAUGAAGUUGGUGGUGAGGCC 22 16166

HBB-166 - UGGAUGAAGUUGGUGGUGAGGCC 23 16167

HBB-167 - GUGGAUGAAGUUGGUGGUGAGGCC 24 16168

HBB-168 - ACUGCCCUGUGGGGCAAG 18 16169

HBB-169 - UACUGCCCUGUGGGGCAAG 19 16170

HBB-65 - UUACUGCCCUGUGGGGCAAG 20 16171

HBB-170 - GU UACUGCCCUGUGGGGCAAG 21 16172

HBB-171 - CGUUACUGCCCUGUGGGGCAAG 22 16173

HBB-172 - CCGUUACUGCCCUGUGGGGCAAG 23 16174

HBB-173 - GCCGUUACUGCCCUGUGGGGCAAG 24 16175

HBB-174 - GGAGGGCAGGAGCCAGGG 18 16176

HBB-175 - GGGAGGGCAGGAGCCAGGG 19 16177

HBB-176 - AGGGAGGGCAGGAGCCAGGG 20 16178

HBB-177 - CAGGGAGGGCAGGAGCCAGGG 21 16179

HBB-178 - GCAGGGAGGGCAGGAGCCAGGG 22 16180

HBB-179 - AGCAGGGAGGGCAGGAGCCAGGG 23 16181

HBB-180 - GAGCAGGGAGGGCAGGAGCCAGGG 24 16182

HBB-181 - UGGGCAUAAAAGUCAGGG 18 16183

HBB-182 - CUGGGCAUAAAAGUCAGGG 19 16184

HBB-183 - GCUGGGCAUAAAAGUCAGGG 20 16185

HBB-184 - GGCUGGGCAUAAAAGUCAGGG 21 16186 HBB-185 - GGGCUGGGCAUAAAAGUCAGGG 22 16187

HBB-186 - AGGGCUGGGCAUAAAAGUCAGGG 23 16188

HBB-187 - CAGGGCUGGGCAUAAAAGUCAGGG 24 16189

HBB-188 - GGGGCAAGGUGAACGUGG 18 16190

HBB-189 - UGGGGCAAGGUGAACGUGG 19 16191

HBB-67 - GUGGGGCAAGGUGAACGUGG 20 16192

HBB-190 - UGUGGGGCAAGGUGAACGUGG 21 16193

HBB-191 - CUGUGGGGCAAGGUGAACGUGG 22 16194

HBB-192 - CCUGUGGGGCAAGGUGAACGUGG 23 16195

HBB-193 - CCCUGUGGGGCAAGGUGAACGUGG 24 16196

HBB-194 - UCUGCCGUUACUGCCCUG 18 16197

HBB-195 - GUCUGCCGUUACUGCCCUG 19 16198

HBB-27 - AGUCUGCCGUUACUGCCCUG 20 16199

HBB-196 - AAGUCUGCCGUUACUGCCCUG 21 16200

HBB-197 - GAAGUCUGCCGUUACUGCCCUG 22 16201

HBB-198 - AGAAGUCUGCCGUUACUGCCCUG 23 16202

HBB-199 - GAGAAGUCUGCCGUUACUGCCCUG 24 16203

HBB-200 - UGGUGCACCUGACUCCUG 18 16204

HBB-201 - AUGGUGCACCUGACUCCUG 19 16205

HBB-6 - CAUGGUGCACCUGACUCCUG 20 16206

HBB-202 - CCAUGGUGCACCUGACUCCUG 21 16207

HBB-203 - ACCAUGGUGCACCUGACUCCUG 22 16208

HBB-204 - CACCAUGGUGCACCUGACUCCUG 23 16209

HBB-205 - ACACCAUGGUGCACCUGACUCCUG 24 16210

HBB-206 - ACGUGGAUGAAGUUGGUG 18 16211

HBB-207 - AACGUGGAUGAAGUUGGUG 19 16212

HBB-64 - GAACGUGGAUGAAGUUGGUG 20 16213

HBB-208 - UGAACGUGGAUGAAGUUGGUG 21 16214

HBB-209 - GUGAACGUGGAUGAAGUUGGUG 22 16215

HBB-210 - GGUGAACGUGGAUGAAGUUGGUG 23 16216

HBB-211 - AGGUGAACGUGGAUGAAGUUGGUG 24 16217

HBB-212 - GUGCACCUGACUCCUGUG 18 16218

HBB-213 - GGUGCACCUGACUCCUGUG 19 16219

HBB-63 - UGGUGCACCUGACUCCUGUG 20 16220

HBB-214 - AUGGUGCACCUGACUCCUGUG 21 16221

HBB-215 - CAUGGUGCACCUGACUCCUGUG 22 16222

HBB-216 - CCAUGGUGCACCUGACUCCUGUG 23 16223

HBB-217 - ACCAUGGUGCACCUGACUCCUGUG 24 16224

HBB-218 - GUCUGCCGUUACUGCCCU 18 16225

HBB-219 - AGUCUGCCGUUACUGCCCU 19 16226

HBB-56 - AAGUCUGCCGUUACUGCCCU 20 16227

HBB-220 - GAAGUCUGCCGUUACUGCCCU 21 16228 HBB-221 - AGAAGUCUGCCGUUACUGCCCU 22 16229

HBB-222 - GAGAAGUCUGCCGUUACUGCCCU 23 16230

HBB-223 - GGAGAAGUCUGCCGUUACUGCCCU 24 16231

HBB-224 - AUGGUGCACCUGACUCCU 18 16232

HBB-225 - CAUGGUGCACCUGACUCCU 19 16233

HBB-60 - CCAUGGUGCACCUGACUCCU 20 16234

HBB-226 - ACCAUGGUGCACCUGACUCCU 21 16235

HBB-227 - CACCAUGGUGCACCUGACUCCU 22 16236

HBB-228 - ACACCAUGGUGCACCUGACUCCU 23 16237

HBB-229 - GACACCAUGGUGCACCUGACUCCU 24 16238

HBB-230 - AGGGCUGGGCAUAAAAGU 18 16239

HBB-231 - CAGGGCUGGGCAUAAAAGU 19 16240

HBB-232 - CCAGGGCUGGGCAUAAAAGU 20 16241

HBB-233 - GCCAGGGCUGGGCAUAAAAGU 21 16242

HBB-234 - AGCCAGGGCUGGGCAUAAAAGU 22 16243

HBB-235 - GAGCCAGGGCUGGGCAUAAAAGU 23 16244

HBB-236 - GGAGCCAGGGCUGGGCAUAAAAGU 24 16245

HBB-237 - AGG U U ACAAG ACAGG U U U 18 16246

HBB-238 - AAGG U U ACAAG ACAGG U U U 19 16247

HBB-239 - CAAGG U U ACAAG ACAGG U U U 20 16248

HBB-240 - U CAAGG U U ACAAG ACAGG U U U 21 16249

HBB-241 - A U CAAG G U U AC AAG AC AG G U U U 22 16250

HBB-242 - U A U CAAG G U U AC AAG AC AG G U U U 23 16251

HBB-243 - G U AU CAAGG U U ACAAG ACAGG U U U 24 16252

Table 26 provides exemplary targeting domains for correcting a mutation (e.g., E6V) in the HBB gene selected according to the first tier parameters. The targeting domains bind within 200 bp to a mutation (e.g., E6V) and have a high level of orthogonality. It is contemplated herein that the targeting domain hybridizes to the target domain through complementary base pairing. Any of the targeting domains in the table can be used with a N. meningitidis Cas9 molecule that generates a double strand break (Cas9 nuclease) or a single-strand break (Cas9 nickase).

Table 26

H BB-247 - AAAGUCAGGGCAGAGCCAUC 20 16256

III. Cas9 Molecules

Cas9 molecules of a variety of species can be used in the methods and compositions described herein. While the S. pyogenes, S. aureus, and S. thermophilus Cas9 molecules are the subject of much of the disclosure herein, Cas9 molecules of, derived from, or based on the Cas9 proteins of other species listed herein can be used as well. In other words, while the much of the description herein uses S. pyogenes and S. thermophilus Cas9 molecules, Cas9 molecules from the other species can replace them, e.g., Staphylococcus aureus and Neisseria meningitidis Cas9 molecules. Additional Cas9 species include: Acidovorax avenae, Actinobacillus

pleuropneumoniae, Actinobacillus succinogenes, Actinobacillus suis, Actinomyces sp., cycliphilus denitrificans, Aminomonas paucivorans, Bacillus cereus, Bacillus smithii, Bacillus thuringiensis, Bacteroides sp., Blastopirellula marina, Bradyrhizobium sp., Brevibacillus laterosporus, Campylobacter coli, Campylobacter jejuni, Campylobacter lari, Candidatus Puniceispirillum, Clostridium cellulolyticum, Clostridium perfringens, Corynebacterium accolens, Corynebacterium diphtheria, Corynebacterium matruchotii, Dinoroseobacter shibae, Eubacterium dolichum, gamma proteobacterium, Gluconacetobacter diazotrophicus,

Haemophilus parainfluenzae, Haemophilus sputorum, Helicobacter canadensis, Helicobacter cinaedi, Helicobacter mustelae, Ilyobacter polytropus, Kingella kingae, Lactobacillus crispatus, Listeria ivanovii, Listeria monocytogenes, Listeriaceae bacterium, Methylocystis sp.,

Methylosinus trichosporium, Mobiluncus mulieris, Neisseria bacilliformis, Neisseria cinerea, Neisseria flavescens, Neisseria lactamica, Neisseria sp., Neisseria wadsworthii, Nitrosomonas sp., Parvibaculum lavamentivorans, Pasteur ella multocida, Phascolarctobacterium

succinatutens, Ralstonia syzygii, Rhodopseudomonas palustris, Rhodovulum sp., Simonsiella muelleri, Sphingomonas sp., Sporolactobacillus vineae, Staphylococcus lugdunensis,

Streptococcus sp., Subdoligranulum sp., Tistrella mobilis, Treponema sp., or Verminephrobacter eiseniae.

A Cas9 molecule, or Cas9 polypeptide, as that term is used herein, refers to a molecule or a polypeptide that can interact with a guide RNA (gRNA) molecule and, in concert with the gRNA molecule, localizes to a site which comprises a target domain, and in an embodiment, a PAM sequence. Cas9 molecule and Cas9 polypeptide, as those terms are used herein, refer to naturally occurring Cas9 molecules and to engineered, altered, or modified Cas9 molecules or Cas9 polypeptides that differ, e.g., by at least one amino acid residue, from a reference sequence, e.g., the most similar naturally occurring Cas9 molecule or a sequence of Table 28.

Cas9 Domains

Crystal structures have been determined for two different naturally occurring bacterial Cas9 molecules (Jinek et al., Science, 343(6176): 1247997, 2014) and for S. pyogenes Cas9 with a guide RNA (e.g., a synthetic fusion of crRNA and tracrRNA) (Nishimasu et al., Cell, 156:935- 949, 2014; and Anders et al., Nature, 2014, doi: 10.1038/naturel3579).

A naturally occurring Cas9 molecule comprises two lobes: a recognition (REC) lobe and a nuclease (NUC) lobe; each of which further comprise domains described herein. Figs. 9A-9B provide a schematic of the organization of important Cas9 domains in the primary structure. The domain nomenclature and the numbering of the amino acid residues encompassed by each domain used throughout this disclosure is as described in Nishimasu et al. The numbering of the amino acid residues is with reference to Cas9 from S. pyogenes.

The REC lobe comprises the arginine-rich bridge helix (BH), the RECl domain, and the REC2 domain. The REC lobe does not share structural similarity with other known proteins, indicating that it is a Cas9-specific functional domain. The BH domain is a long a helix and arginine rich region and comprises amino acids 60-93 of the sequence of S. pyogenes Cas9. The RECl domain is important for recognition of the repeat: anti-repeat duplex, e.g., of a gRNA or a tracrRNA, and is therefore critical for Cas9 activity by recognizing the target sequence. The RECl domain comprises two RECl motifs at amino acids 94 to 179 and 308 to 717 of the sequence of S. pyogenes Cas9. These two RECl domains, though separated by the REC2 domain in the linear primary structure, assemble in the tertiary structure to form the RECl domain. The REC2 domain, or parts thereof, may also play a role in the recognition of the repeat: anti-repeat duplex. The REC2 domain comprises amino acids 180-307 of the sequence of S. pyogenes Cas9.

The NUC lobe comprises the RuvC domain, the HNH domain, and the PAM-interacting (PI) domain. The RuvC domain shares structural similarity to retroviral integrase superfamily members and cleaves a single strand, e.g., the non-complementary strand of the target nucleic acid molecule. The RuvC domain is assembled from the three split RuvC motifs (RuvC I, RuvCII, and RuvCIII, which are often commonly referred to in the art as RuvCI domain, or N- terminal RuvC domain, RuvCII domain, and RuvCIII domain) at amino acids 1-59, 718-769, and 909-1098, respectively, of the sequence of S. pyogenes Cas9. Similar to the REC1 domain, the three RuvC motifs are linearly separated by other domains in the primary structure, however in the tertiary structure, the three RuvC motifs assemble and form the RuvC domain. The HNH domain shares structural similarity with HNH endonucleases, and cleaves a single strand, e.g., the complementary strand of the target nucleic acid molecule. The HNH domain lies between the RuvC II- III motifs and comprises amino acids 775-908 of the sequence of S. pyogenes Cas9. The PI domain interacts with the PAM of the target nucleic acid molecule, and comprises amino acids 1099-1368 of the sequence of S. pyogenes Cas9.

A RuvC-like domain and an HNH-like domain

In an embodiment, a Cas9 molecule or Cas9 polypeptide comprises an HNH-like domain and a RuvC-like domain. In an embodiment, cleavage activity is dependent on a RuvC-like domain and an HNH-like domain. A Cas9 molecule or Cas9 polypeptide, e.g., an eaCas9 molecule or eaCas9 polypeptide, can comprise one or more of the following domains: a RuvC- like domain and an HNH-like domain. In an embodiment, a Cas9 molecule or Cas9 polypeptide is an eaCas9 molecule or eaCas9 polypeptide and the eaCas9 molecule or eaCas9 polypeptide comprises a RuvC-like domain, e.g., a RuvC-like domain described below, and/or an HNH-like domain, e.g., an HNH-like domain described below.

RuvC-like domains

In an embodiment, a RuvC-like domain cleaves, a single strand, e.g., the non- complementary strand of the target nucleic acid molecule. The Cas9 molecule or Cas9 polypeptide can include more than one RuvC-like domain (e.g., one, two, three or more RuvC- like domains). In an embodiment, a RuvC-like domain is at least 5, 6, 7, 8 amino acids in length but not more than 20, 19, 18, 17, 16 or 15 amino acids in length. In an embodiment, the Cas9 molecule or Cas9 polypeptide comprises an N-terminal RuvC-like domain of about 10 to 20 amino acids, e.g., about 15 amino acids in length.

N-terminal RuvC-like domains Some naturally occurring Cas9 molecules comprise more than one RuvC-like domain with cleavage being dependent on the N-terminal RuvC-like domain. Accordingly, Cas9 molecules or Cas9 polypeptide can comprise an N-terminal RuvC-like domain. Exemplary N- terminal RuvC-like domains are described below.

In an embodiment, an eaCas9 molecule or eaCas9 polypeptide comprises an N-terminal

RuvC-like domain comprising an amino acid sequence of formula I:

D-X1-G-X2-X3-X4-X5-G-X6-X7-X8-X9 (SEQ ID NO: 8),

wherein,

XI is selected from I, V, M, L and T (e.g., selected from I, V, and L);

X2 is selected from T, I, V, S, N, Y, E and L (e.g., selected from T, V, and I);

X3 is selected from N, S, G, A, D, T, R, M and F (e.g., A or N);

X4 is selected from S, Y, N and F (e.g., S);

X5 is selected from V, I, L, C, T and F (e.g., selected from V, I and L);

X6 is selected from W, F, V, Y, S and L (e.g., W);

X7 is selected from A, S, C, V and G (e.g., selected from A and S);

X8 is selected from V, I, L, A, M and H (e.g., selected from V, I, M and L); and

X9 is selected from any amino acid or is absent (e.g., selected from T, V, I, L, Δ, F, S, A, Y, M and R, or, e.g., selected from T, V, I, L and Δ).

In an embodiment, the N-terminal RuvC-like domain differs from a sequence of SEQ ID NO:8, by as many as 1 but no more than 2, 3, 4, or 5 residues.

In embodiment, the N-terminal RuvC-like domain is cleavage competent.

In embodiment, the N-terminal RuvC-like domain is cleavage incompetent.

In an embodiment, a eaCas9 molecule or eaCas9 polypeptide comprises an N-terminal RuvC-like domain comprising an amino acid sequence of formula II:

D-X1-G-X2-X3-S-X5-G-X6-X7-X8-X9, (SEQ ID NO: 9),

wherein

XI is selected from I, V, M, L and T (e.g., selected from I, V, and L);

X3 is selected from N, S, G, A, D, T, R, M and F (e.g., A or N);

X5 is selected from V, I, L, C, T and F (e.g., selected from V, I and L);

X6 is selected from W, F, V, Y, S and L (e.g., W); X7 is selected from A, S, C, V and G (e.g., selected from A and S);

X9 is selected from any amino acid or is absent (e.g., selected from T, V, I, L, Δ, F, S, A, Y, M and R or selected from e.g., T, V, I, L and Δ).

In an embodiment, the N-terminal RuvC-like domain differs from a sequence of SEQ ID

NO:9 by as many as 1 but no more than 2, 3, 4, or 5 residues.

In an embodiment, the N-terminal RuvC-like domain comprises an amino acid sequence of formula III:

D-I-G-X2-X3-S-V-G-W-A-X8-X9 (SEQ ID NO: 10),

wherein

X3 is selected from N, S, G, A, D, T, R, M and F (e.g., A or N);

In an embodiment, the N-terminal RuvC-like domain differs from a sequence of SEQ ID NO: 10 by as many as 1 but no more than, 2, 3, 4, or 5 residues.

D-I-G-T-N-S-V-G-W-A-V-X (SEQ ID NO: 11),

wherein

X is a non-polar alkyl amino acid or a hydroxyl amino acid, e.g., X is selected from V, I, L and T (e.g., the eaCas9 molecule can comprise an N-terminal RuvC-like domain shown in Figs. 2A-2G (is depicted as Y)).

NO: 11 by as many as 1 but no more than, 2, 3, 4, or 5 residues.

In an embodiment, the N-terminal RuvC-like domain differs from a sequence of an N- terminal RuvC like domain disclosed herein, e.g., in Figs. 3A-3B or Figs. 7A-7B, as many as 1 but no more than 2, 3, 4, or 5 residues. In an embodiment, 1, 2, 3 or all of the highly conserved residues identified in Figs. 3A-3B or Figs. 7A-7B are present. In an embodiment, the N-terminal RuvC-like domain differs from a sequence of an N- terminal RuvC-like domain disclosed herein, e.g., in Figs. 4A-4B or Figs. 7A-7B, as many as 1 but no more than 2, 3, 4, or 5 residues. In an embodiment, 1, 2, or all of the highly conserved residues identified in Figs. 4A-4B or Figs. 7A-7B are present.

Additional RuvC-like domains

In addition to the N-terminal RuvC-like domain, the Cas9 molecule or Cas9 polypeptide, e.g., an eaCas9 molecule or eaCas9 polypeptide, can comprise one or more additional RuvC-like domains. In an embodiment, the Cas9 molecule or Cas9 polypeptide can comprise two additional RuvC-like domains. Preferably, the additional RuvC-like domain is at least 5 amino acids in length and, e.g., less than 15 amino acids in length, e.g., 5 to 10 amino acids in length, e.g., 8 amino acids in length.

An additional RuvC-like domain can comprise an amino acid sequence:

I-X1-X2-E-X3-A-R-E (SEQ ID NO: 12), wherein

XI is V or H,

X2 is I, L or V (e.g., I or V); and

X3 is M or T.

In an embodiment, the additional RuvC-like domain comprises the amino acid sequence: I-V-X2-E-M-A-R-E (SEQ ID NO: 13), wherein

X2 is I, L or V (e.g., I or V) (e.g., the eaCas9 molecule or eaCas9 polypeptide can comprise an additional RuvC-like domain shown in Fig. 2A-2G or Figs. 7A-7B (depicted as B)).

An additional RuvC-like domain can comprise an amino acid sequence:

H-H-A-X1-D-A-X2-X3 (SEQ ID NO: 14), wherein

XI is H or L;

X2 is R or V; and

X3 is E or V.

In an embodiment, the additional RuvC-like domain comprises the amino acid sequence: H-H-A-H-D-A-Y-L (SEQ ID NO: 15).

In an embodiment, the additional RuvC-like domain differs from a sequence of SEQ ID NO: 12, 13, 14 or 15 by as many as 1 but no more than 2, 3, 4, or 5 residues. In some embodiments, the sequence flanking the N-terminal RuvC-like domain is a sequences of formula V:

K-X1'-Y-X2'-X3'-X4'-Z-T-D-X9'-Y, (SEQ ID NO: 16).

wherein

Χ is selected from K and P,

X2' is selected from V, L, I, and F (e.g., V, I and L);

X3' is selected from G, A and S (e.g., G),

X4' is selected from L, I, V and F (e.g., L);

X9' is selected from D, E, N and Q; and

Z is an N-terminal RuvC-like domain, e.g., as described above.

HNH-like domains

In an embodiment, an HNH-like domain cleaves a single stranded complementary domain, e.g., a complementary strand of a double stranded nucleic acid molecule. In an embodiment, an HNH-like domain is at least 15, 20, 25 amino acids in length but not more than 40, 35 or 30 amino acids in length, e.g., 20 to 35 amino acids in length, e.g., 25 to 30 amino acids in length. Exemplary HNH-like domains are described below.

In an embodiment, an eaCas9 molecule or eaCas9 polypeptide comprises an HNH-like domain having an amino acid sequence of formula VI:

X 1 -X2-X3-H-X4-X5-P-X6-X7-X8-X9-X 10-X 11 -X 12-X 13-X 14-X 15-N-X 16-X 17-X 18- X19-X20-X21-X22-X23-N (SEQ ID NO: 17), wherein

XI is selected from D, E, Q and N (e.g., D and E);

X2 is selected from L, I, R, Q, V, M and K;

X3 is selected from D and E;

X4 is selected from I, V, T, A and L (e.g., A, I and V);

X5 is selected from V, Y, I, L, F and W (e.g., V, I and L);

X6 is selected from Q, H, R, K, Y, I, L, F and W;

X7 is selected from S, A, D, T and K (e.g., S and A);

X8 is selected from F, L, V, K, Y, M, I, R, A, E, D and Q (e.g., F);

X9 is selected from L, R, T, I, V, S, C, Y, K, F and G;

X10 is selected from K, Q, Y, T, F, L, W, M, A, E, G, and S; XI 1 is selected from D, S, N, R, L and T (e.g., D);

X12 is selected from D, N and S;

X13 is selected from S, A, T, G and R (e.g., S);

X14 is selected from I, L, F, S, R, Y, Q, W, D, K and H (e.g., I, L and F);

X15 is selected from D, S, I, N, E, A, H, F, L, Q, M, G, Y and V;

X16 is selected from K, L, R, M, T and F (e.g., L, R and K);

X17 is selected from V, L, I, A and T;

X18 is selected from L, I, V and A (e.g., L and I);

X19 is selected from T, V, C, E, S and A (e.g., T and V);

X20 is selected from R, F, T, W, E, L, N, C, K, V, S, Q, I, Y, H and A;

X21 is selected from S, P, R, K, N, A, H, Q, G and L;

X22 is selected from D, G, T, N, S, K, A, I, E, L, Q, R and Y; and

X23 is selected from K, V, A, E, Y, I, C, L, S, T, G, K, M, D and F.

In an embodiment, a HNH-like domain differs from a sequence of SEQ ID NO: 17 by at least one but no more than, 2, 3, 4, or 5 residues.

In an embodiment, the HNH-like domain is cleavage competent.

In an embodiment, the HNH-like domain is cleavage incompetent.

In an embodiment, an eaCas9 molecule or eaCas9 polypeptide comprises an HNH-like domain comprising an amino acid sequence of formula VII:

X 1 -X2-X3-H-X4-X5-P-X6-S-X8-X9-X 10-D-D-S-X 14-X 15-N-K- V-L-X 19-X20-X21 -

X22-X23-N (SEQ ID NO: 18),

wherein

XI is selected from D and E;

X2 is selected from L, I, R, Q, V, M and K;

X3 is selected from D and E;

X4 is selected from I, V, T, A and L (e.g., A, I and V);

X5 is selected from V, Y, I, L, F and W (e.g., V, I and L);

X6 is selected from Q, H, R, K, Y, I, L, F and W;

X8 is selected from F, L, V, K, Y, M, I, R, A, E, D and Q (e.g., F);

X9 is selected from L, R, T, I, V, S, C, Y, K, F and G;

X10 is selected from K, Q, Y, T, F, L, W, M, A, E, G, and S; X14 is selected from I, L, F, S, R, Y, Q, W, D, K and H (e.g., I, L and F);

X15 is selected from D, S, I, N, E, A, H, F, L, Q, M, G, Y and V;

X19 is selected from T, V, C, E, S and A (e.g., T and V);

X20 is selected from R, F, T, W, E, L, N, C, K, V, S, Q, I, Y, H and A;

X21 is selected from S, P, R, K, N, A, H, Q, G and L;

X22 is selected from D, G, T, N, S, K, A, I, E, L, Q, R and Y; and

X23 is selected from K, V, A, E, Y, I, C, L, S, T, G, K, M, D and F.

In an embodiment, the HNH-like domain differs from a sequence of SEQ ID NO: 18 by 1, 2, 3, 4, or 5 residues.

X 1 - V-X3-H-I- V-P-X6-S-X8-X9-X 10-D-D-S-X 14-X 15-N-K- V-L-T-X20-X21 -X22-X23- N (SEQ ID NO: 19),

wherein

XI is selected from D and E;

X3 is selected from D and E;

X6 is selected from Q, H, R, K, Y, I, L and W;

X8 is selected from F, L, V, K, Y, M, I, R, A, E, D and Q (e.g., F);

X9 is selected from L, R, T, I, V, S, C, Y, K, F and G;

X10 is selected from K, Q, Y, T, F, L, W, M, A, E, G, and S;

X14 is selected from I, L, F, S, R, Y, Q, W, D, K and H (e.g., I, L and F);

X15 is selected from D, S, I, N, E, A, H, F, L, Q, M, G, Y and V;

X20 is selected from R, F, T, W, E, L, N, C, K, V, S, Q, I, Y, H and A;

X21 is selected from S, P, R, K, N, A, H, Q, G and L;

X22 is selected from D, G, T, N, S, K, A, I, E, L, Q, R and Y; and

X23 is selected from K, V, A, E, Y, I, C, L, S, T, G, K, M, D and F.

In an embodiment, the HNH-like domain differs from a sequence of SEQ ID NO: 19 by 1, 2, 3, 4, or 5 residues.

In an embodiment, an eaCas9 molecule or eaCas9 polypeptide comprises an HNH-like domain having an amino acid sequence of formula VIII: D-X2-D-H-I-X5-P-Q-X7-F-X9-X 10-D-X 12-S-I-D-N-X 16- V-L-X 19-X20-S-X22-X23-N (SEQ ID NO:20),

wherein

X2 is selected from I and V;

X5 is selected from I and V;

X7 is selected from A and S;

X9 is selected from I and L;

X10 is selected from K and T;

X12 is selected from D and N;

X16 is selected from R, K and L; X19 is selected from T and V;

X20 is selected from S and R;

X22 is selected from K, D and A; and

X23 is selected from E, K, G and N (e.g., the eaCas9 molecule or eaCas9 polypeptide can comprise an HNH-like domain as described herein).

In an embodiment, the HNH-like domain differs from a sequence of SEQ ID NO: 20 by as many as 1 but no more than 2, 3, 4, or 5 residues.

In an embodiment, an eaCas9 molecule or eaCas9 polypeptide comprises the amino acid sequence of formula IX:

L- Y- Y-L-Q-N-G-X 1 ' -D-M- Y-X2' -X3 ' -X4' -X5 ' -L-D-I— X6' -X7 ' -L-S-X8 ' - Y-Z-N-R- X9'-K-X10'-D-X11'-V-P (SEQ ID NO: 21),

wherein

Χ is selected from K and R;

X2' is selected from V and T;

X3' is selected from G and D;

X4' is selected from E, Q and D;

X5' is selected from E and D;

X6' is selected from D, N and H;

X7' is selected from Y, R and N;

X8' is selected from Q, D and N; X9' is selected from G and E;

X10' is selected from S and G;

XI 1 ' is selected from D and N; and Z is an HNH-like domain, e.g., as described above.

In an embodiment, the eaCas9 molecule or eaCas9 polypeptide comprises an amino acid sequence that differs from a sequence of SEQ ID NO:21 by as many as 1 but no more than 2, 3, 4, or 5 residues.

In an embodiment, the HNH-like domain differs from a sequence of an HNH-like domain disclosed herein, e.g., in Figs. 5A-5C or Figs. 7A-7B, as many as 1 but no more than 2, 3, 4, or 5 residues. In an embodiment, 1 or both of the highly conserved residues identified in Figs. 5A- 5C or Figs. 7A-7B are present.

In an embodiment, the HNH -like domain differs from a sequence of an HNH-like domain disclosed herein, e.g., in Figs. 6A-6B or Figs. 7A-7B, as many as 1 but no more than 2, 3, 4, or 5 residues. In an embodiment, 1, 2, all 3 of the highly conserved residues identified in Figs. 6A-6B or Figs. 7A-7B are present.

Cas9 Activities

Nuclease and Helicase Activities

In an embodiment, the Cas9 molecule or Cas9 polypeptide is capable of cleaving a target nucleic acid molecule. Typically wild type Cas9 molecules cleave both strands of a target nucleic acid molecule. Cas9 molecules and Cas9 polypeptides can be engineered to alter nuclease cleavage (or other properties), e.g., to provide a Cas9 molecule or Cas9 peolypeptide which is a nickase, or which lacks the ability to cleave target nucleic acid. A Cas9 molecule or Cas9 polypeptide that is capable of cleaving a target nucleic acid molecule is referred to herein as an eaCas9 (an enzymatically active Cas9) molecule or eaCas9 polypeptide.

In an embodiment, an eaCas9 molecule or eaCas9 polypeptide comprises one or more of the following enzymatic activities:

a nickase activity, i.e., the ability to cleave a single strand, e.g., the non-complementary strand or the complementary strand, of a nucleic acid molecule;

a double stranded nuclease activity, i.e., the ability to cleave both strands of a double stranded nucleic acid and create a double stranded break, which in an embodiment is the presence of two nickase activities;

an endonuclease activity;

an exonuclease activity; and a helicase activity, i.e., the ability to unwind the helical structure of a double stranded nucleic acid.

In an embodiment, an enzymatically active or an eaCas9 molecule or eaCas9 polypeptide cleaves both DNA strands and results in a double stranded break. In an embodiment, an eaCas9 molecule or eaCas9 polypeptide cleaves only one strand, e.g., the strand to which the gRNA hybridizes to, or the strand complementary to the strand the gRNA hybridizes with. In an embodiment, an eaCas9 molecule or eaCas9 polypeptide comprises cleavage activity associated with an HNH domain. In an embodiment, an eaCas9 molecule or eaCas9 polypeptide comprises cleavage activity associated with a RuvC domain. In an embodiment, an eaCas9 molecule or eaCas9 polypeptide comprises cleavage activity associated with an HNH domain and cleavage activity associated with a RuvC domain. In an embodiment, an eaCas9 molecule or eaCas9 polypeptide comprises an active, or cleavage competent, HNH domain and an inactive, or cleavage incompetent, RuvC domain. In an embodiment, an eaCas9 molecule or eaCas9 polypeptide comprises an inactive, or cleavage incompetent, HNH domain and an active, or cleavage competent, RuvC domain.

Some Cas9 molecules or Cas9 polypeptides have the ability to interact with a gRNA molecule, and in conjunction with the gRNA molecule localize to a core target domain, but are incapable of cleaving the target nucleic acid, or incapable of cleaving at efficient rates. Cas9 molecules having no, or no substantial, cleavage activity are referred to herein as an eiCas9 molecule or eiCas9 polypeptide. For example, an eiCas9 molecule or eiCas9 polypeptide can lack cleavage activity or have substantially less, e.g., less than 20, 10, 5, 1 or 0.1 % of the cleavage activity of a reference Cas9 molecule or eiCas9 polypeptide, as measured by an assay described herein. Targeting And PAMs

A Cas9 molecule or Cas9 polypeptide, is a polypeptide that can interact with a guide RNA (gRNA) molecule and, in concert with the gRNA molecule, localizes to a site which comprises a target domain, and in an embodiment, a PAM sequence.

In an embodiment, the ability of an eaCas9 molecule or eaCas9 polypeptide to interact with and cleave a target nucleic acid is PAM sequence dependent. A PAM sequence is a sequence in the target nucleic acid. In an embodiment, cleavage of the target nucleic acid occurs upstream from the PAM sequence. EaCas9 molecules from different bacterial species can recognize different sequence motifs (e.g., PAM sequences). In an embodiment, an eaCas9 molecule of S. pyogenes recognizes the sequence motif NGG and directs cleavage of a target nucleic acid sequence 1 to 10, e.g., 3 to 5, base pairs upstream from that sequence. See, e.g., Mali et al., SCIENCE 2013; 339(6121): 823-826. In an embodiment, an eaCas9 molecule of S. thermophilus recognizes the sequence motif NGGNG (SEQ ID NO.: 90) and/or NNAGAAW (W = A or T) (SEQ ID NO.: 91) and directs cleavage of a target nucleic acid sequence 1 to 10, e.g., 3 to 5, base pairs upstream from these sequences. See, e.g., Horvath et al. , SCIENCE 2010;

327(5962): 167-170, and Deveau et al , J BACTERIOL 2008; 190(4): 1390- 1400. In an

embodiment, an eaCas9 molecule of S. mutans recognizes the sequence motif NGG and/or

NAAR (R = A or G) (SEQ ID NO.: 92) and directs cleavage of a target nucleic acid sequence 1 to 10, e.g., 3 to 5 base pairs, upstream from this sequence. See, e.g., Deveau et al , J BACTERIOL 2008; 190(4): 1390-1400. In an embodiment, an eaCas9 molecule of S. aureus recognizes the sequence motif NNGRR (R = A or G) (SEQ ID NO.: 93) and directs cleavage of a target nucleic acid sequence 1 to 10, e.g., 3 to 5, base pairs upstream from that sequence. In an embodiment, an eaCas9 molecule of S. aureus recognizes the sequence motif NNGRRN (R = A or G) and directs cleavage of a target nucleic acid sequence 1 to 10, e.g., 3 to 5, base pairs upstream from that sequence. In an embodiment, an eaCas9 molecule of S. aureus recognizes the sequence motif NNGRRT (R = A or G) and directs cleavage of a target nucleic acid sequence 1 to 10, e.g., 3 to 5, base pairs upstream from that sequence. In an embodiment, an eaCas9 molecule of S. aureus recognizes the sequence motif NNGRRV (R = A or G) (SEQ ID NO.: ) and directs cleavage of a target nucleic acid sequence 1 to 10, e.g., 3 to 5, base pairs upstream from that sequence. In an embodiment, an eaCas9 molecule of N. meningitidis recognizes the sequence motif NNNNGATT (SEQ ID NO.: 94) or NNNGCTT (R = A or G) (SEQ ID NO: 95) and directs cleavage of a target nucleic acid sequence 1 to 10, e.g., 3 to 5, base pairs upstream from that sequence. See, e.g., Hou et al., PNAS 2013; 110(39): 15644- 15649. The ability of a Cas9 molecule to recognize a PAM sequence can be determined, e.g., using a transformation assay described in Jinek et al. , SCIENCE 2012, 337:816. In the aforementioned embodiments, N can be any nucleotide residue, e.g., any of A, G, C or T.

As is discussed herein, Cas9 molecules can be engineered to alter the PAM specificity of the Cas9 molecule. Exemplary naturally occurring Cas9 molecules are described in Chylinski et ah, RNA BIOLOGY 2013 10:5, 727-737. Such Cas9 molecules include Cas9 molecules of a cluster 1 bacterial family, cluster 2 bacterial family, cluster 3 bacterial family, cluster 4 bacterial family, cluster 5 bacterial family, cluster 6 bacterial family, a cluster 7 bacterial family, a cluster 8 bacterial family, a cluster 9 bacterial family, a cluster 10 bacterial family, a cluster 11 bacterial family, a cluster 12 bacterial family, a cluster 13 bacterial family, a cluster 14 bacterial family, a cluster 15 bacterial family, a cluster 16 bacterial family, a cluster 17 bacterial family, a cluster 18 bacterial family, a cluster 19 bacterial family, a cluster 20 bacterial family, a cluster 21 bacterial family, a cluster 22 bacterial family, a cluster 23 bacterial family, a cluster 24 bacterial family, a cluster 25 bacterial family, a cluster 26 bacterial family, a cluster 27 bacterial family, a cluster 28 bacterial family, a cluster 29 bacterial family, a cluster 30 bacterial family, a cluster 31 bacterial family, a cluster 32 bacterial family, a cluster 33 bacterial family, a cluster 34 bacterial family, a cluster 35 bacterial family, a cluster 36 bacterial family, a cluster 37 bacterial family, a cluster 38 bacterial family, a cluster 39 bacterial family, a cluster 40 bacterial family, a cluster 41 bacterial family, a cluster 42 bacterial family, a cluster 43 bacterial family, a cluster 44 bacterial family, a cluster 45 bacterial family, a cluster 46 bacterial family, a cluster 47 bacterial family, a cluster 48 bacterial family, a cluster 49 bacterial family, a cluster 50 bacterial family, a cluster 51 bacterial family, a cluster 52 bacterial family, a cluster 53 bacterial family, a cluster 54 bacterial family, a cluster 55 bacterial family, a cluster 56 bacterial family, a cluster 57 bacterial family, a cluster 58 bacterial family, a cluster 59 bacterial family, a cluster 60 bacterial family, a cluster 61 bacterial family, a cluster 62 bacterial family, a cluster 63 bacterial family, a cluster 64 bacterial family, a cluster 65 bacterial family, a cluster 66 bacterial family, a cluster 67 bacterial family, a cluster 68 bacterial family, a cluster 69 bacterial family, a cluster 70 bacterial family, a cluster 71 bacterial family, a cluster 72 bacterial family, a cluster 73 bacterial family, a cluster 74 bacterial family, a cluster 75 bacterial family, a cluster 76 bacterial family, a cluster 77 bacterial family, or a cluster 78 bacterial family.

Exemplary naturally occurring Cas9 molecules include a Cas9 molecule of a cluster 1 bacterial family. Examples include a Cas9 molecule of: S. pyogenes (e.g., strain SF370, MGAS10270, MGAS10750, MGAS2096, MGAS315, MGAS5005, MGAS6180, MGAS9429, NZ131 and SSI-1), S. thermophilus (e.g., strain LMD-9), S. pseudoporcinus (e.g., strain SPIN 20026), S. mutans (e.g., strain UA159, NN2025), S. macacae (e.g., strain NCTC11558), S.

gallolyticus (e.g., strain UCN34, ATCC BAA-2069), S. equines (e.g., strain ATCC 9812, MGCS 124), S. dysdalactiae (e.g., strain GGS 124), S. bovis (e.g., strain ATCC 700338), S. anginosus (e.g., strain F0211), S. agalactiae (e.g., strain NEM316, A909), Listeria monocytogenes (e.g., strain F6854), Listeria innocua (L. innocua, e.g., strain Clipl l262), Enterococcus italicus (e.g., strain DSM 15952), or Enterococcus faecium (e.g., strain 1,231,408). Additional exemplary Cas9 molecules are a Cas9 molecule of Neisseria meningitidis (Hou et al., PNAS Early Edition 2013, 1-6 and a S. aureus cas9 molecule.

In an embodiment, a Cas9 molecule or Cas9 polypeptide, e.g., an eaCas9 molecule or eaCas9 polypeptide, comprises an amino acid sequence:

having 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% homology with;

differs at no more than, 2, 5, 10, 15, 20, 30, or 40% of the amino acid residues when compared with;

differs by at least 1, 2, 5, 10 or 20 amino acids, but by no more than 100, 80, 70, 60, 50,

40 or 30 amino acids from; or

is identical to any Cas9 molecule sequence described herein, or a naturally occurring Cas9 molecule sequence, e.g., a Cas9 molecule from a species listed herein or described in Chylinski et al., RNA BIOLOGY 2013 10:5, 727-737; Hou et al., PNAS Early Edition 2013, 1-6; SEQ ID NO: 1-4. In an embodiment, the Cas9 molecule or Cas9 polypeptide comprises one or more of the following activities: a nickase activity; a double stranded cleavage activity (e.g., an endonuclease and/or exonuclease activity); a helicase activity; or the ability, together with a gRNA molecule, to localize to a target nucleic acid.

In an embodiment, a Cas9 molecule or Cas9 polypeptide comprises any of the amino acid sequence of the consensus sequence of Figs. 2A-2G, wherein "*" indicates any amino acid found in the corresponding position in the amino acid sequence of a Cas9 molecule of S. pyogenes, S. thermophilus, S. mutans and L. innocua, and "-" indicates any amino acid. In an embodiment, a Cas9 molecule or Cas9 polypeptide differs from the sequence of the consensus sequence disclosed in Figs. 2A-2G by at least 1, but no more than 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid residues. In an embodiment, a Cas9 molecule or Cas9 polypeptide comprises the amino acid sequence of SEQ ID NO:7 of Figs. 7A-7B, wherein "*" indicates any amino acid found in the corresponding position in the amino acid sequence of a Cas9 molecule of S. pyogenes, or N. meningitidis, "-" indicates any amino acid, and "-" indicates any amino acid or absent. In an embodiment, a Cas9 molecule or Cas9 polypeptide differs from the sequence of SEQ ID NO:6 or 7 disclosed in Figs. 7A-7B by at least 1, but no more than 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid residues.

A comparison of the sequence of a number of Cas9 molecules indicate that certain regions are conserved. These are identified below as:

region 1 ( residuesl to 180, or in the case of region l'residues 120 to 180)

region 2 ( residues360 to 480);

region 3 ( residues 660 to 720);

region 4 ( residues 817 to 900); and

region 5 ( residues 900 to 960);

In an embodiment, a Cas9 molecule or Cas9 polypeptide comprises regions 1-5, together with sufficient additional Cas9 molecule sequence to provide a biologically active molecule, e.g., a Cas9 molecule having at least one activity described herein. In an embodiment, each of regions 1-5, independently, have 50%, 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% homology with the corresponding residues of a Cas9 molecule or Cas9 polypeptide described herein, e.g., a sequence from Figs. 2A-2G or from Figs. 7A-7B.

In an embodiment, a Cas9 molecule or Cas9 polypeptide, e.g., an eaCas9 molecule or eaCas9 polypeptide, comprises an amino acid sequence referred to as region 1 :

having 50%, 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% homology with amino acids 1-180 (the numbering is according to the motif sequence in Fig. 2; 52% of residues in the four Cas9 sequences in Figs. 2A-2G are conserved) of the amino acid sequence of Cas9 of S. pyogenes;

differs by at least 1, 2, 5, 10 or 20 amino acids but by no more than 90, 80, 70, 60, 50, 40 or 30 amino acids from amino acids 1-180 of the amino acid sequence of Cas9 of S. pyogenes, S. thermophilus, S. mutans or Listeria innocua; or

is identical to 1-180 of the amino acid sequence of Cas9 of S. pyogenes, S. thermophilus, S. mutans or L. innocua.

In an embodiment, a Cas9 molecule or Cas9 polypeptide, e.g., an eaCas9 molecule or eaCas9 polypeptide, comprises an amino acid sequence referred to as region 1 ' : having 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% homology with amino acids 120-180 (55% of residues in the four Cas9 sequences in Fig. 2 are conserved) of the amino acid sequence of Cas9 of S. pyogenes, S. thermophilus, S. mutans or L. innocua;

differs by at least 1, 2, or 5 amino acids but by no more than 35, 30, 25, 20 or 10 amino acids from amino acids 120-180 of the amino acid sequence of Cas9 of S. pyogenes, S.

thermophilus, S. mutans or L. innocua ; or

is identical to 120-180 of the amino acid sequence of Cas9 of S. pyogenes, S.

thermophilus, S. mutans or L. innocua.

In an embodiment, a Cas9 molecule or Cas9 polypeptide, e.g., an eaCas9 molecule or eaCas9 polypeptide, comprises an amino acid sequence referred to as region 2:

having 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% homology with amino acids 360-480 (52% of residues in the four Cas9 sequences in Fig. 2 are conserved) of the amino acid sequence of Cas9 of S. pyogenes, S. thermophilus, S. mutans or L. innocua;

differs by at least 1, 2, or 5 amino acids but by no more than 35, 30, 25, 20 or 10 amino acids from amino acids 360-480 of the amino acid sequence of Cas9 of S. pyogenes, S.

thermophilus, S. mutans or L. innocua; or

is identical to 360-480 of the amino acid sequence of Cas9 of S. pyogenes, S.

thermophilus, S. mutans or L. innocua.

In an embodiment, a Cas9 molecule or Cas9 polypeptide, e.g., an eaCas9 molecule or eaCas9 polypeptide, comprises an amino acid sequence referred to as region 3:

having 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% homology with amino acids 660-720 (56% of residues in the four Cas9 sequences in Fig. 2 are conserved) of the amino acid sequence of Cas9 of S. pyogenes, S. thermophilus, S. mutans or L. innocua;

differs by at least 1, 2, or 5 amino acids but by no more than 35, 30, 25, 20 or 10 amino acids from amino acids 660-720 of the amino acid sequence of Cas9 of S. pyogenes, S.

thermophilus, S. mutans or L. innocua; or

is identical to 660-720 of the amino acid sequence of Cas9 of S. pyogenes, S.

thermophilus, S. mutans or L. innocua. In an embodiment, a Cas9 molecule or Cas9 polypeptide, e.g., an eaCas9 molecule or eaCas9 polypeptide, comprises an amino acid sequence referred to as region 4:

having 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% homology with amino acids 817-900 (55% of residues in the four Cas9 sequences in Figs. 2A-2G are conserved) of the amino acid sequence of Cas9 of S. pyogenes, S. thermophilus, S. mutans or L. innocua;

differs by at least 1, 2, or 5 amino acids but by no more than 35, 30, 25, 20 or 10 amino acids from amino acids 817-900 of the amino acid sequence of Cas9 of S. pyogenes, S.

thermophilus, S. mutans or L. innocua; or

is identical to 817-900 of the amino acid sequence of Cas9 of S. pyogenes, S.

thermophilus, S. mutans or L. innocua.

In an embodiment, a Cas9 molecule or Cas9 polypeptide, e.g., an eaCas9 molecule or eaCas9 polypeptide, comprises an amino acid sequence referred to as region 5:

having 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% homology with amino acids 900-960 (60% of residues in the four Cas9 sequences in Figs. 2A-2G are conserved) of the amino acid sequence of Cas9 of S. pyogenes, S. thermophilus, S. mutans or L. innocua;

differs by at least 1, 2, or 5 amino acids but by no more than 35, 30, 25, 20 or 10 amino acids from amino acids 900-960 of the amino acid sequence of Cas9 of S. pyogenes, S.

thermophilus, S. mutans or L. innocua; or

is identical to 900-960 of the amino acid sequence of Cas9 of S. pyogenes, S.

thermophilus, S. mutans or L. innocua.

Engineered Or Altered Cas9 Molecules And Cas9 Polypeptides

Cas9 molecules and Cas9 polypeptides described herein, e.g., naturally occurring Cas9 molecules, can possess any of a number of properties, including: nuclease activity (e.g., endonuclease and/or exonuclease activity); helicase activity; the ability to associate functionally with a gRNA molecule; and the ability to target (or localize to) a site on a nucleic acid (e.g., PAM recognition and specificity). In an embodiment, a Cas9 molecule or Cas9 polypeptide can include all or a subset of these properties. In a typical embodiment, a Cas9 molecule or Cas9 polypeptide has the ability to interact with a gRNA molecule and, in concert with the gRNA molecule, localize to a site in a nucleic acid. Other activities, e.g., PAM specificity, cleavage activity, or helicase activity can vary more widely in Cas9 molecules and Cas9 polypeptides.

Cas9 molecules include engineered Cas9 molecules and engineered Cas9 polypeptides (engineered, as used in this context, means merely that the Cas9 molecule or Cas9 polypeptide differs from a reference sequences, and implies no process or origin limitation). An engineered Cas9 molecule or Cas9 polypeptide can comprise altered enzymatic properties, e.g., altered nuclease activity, (as compared with a naturally occurring or other reference Cas9 molecule) or altered helicase activity. As discussed herein, an engineered Cas9 molecule or Cas9 polypeptide can have nickase activity (as opposed to double strand nuclease activity). In an embodiment an engineered Cas9 molecule or Cas9 polypeptide can have an alteration that alters its size, e.g., a deletion of amino acid sequence that reduces its size, e.g., without significant effect on one or more, or any Cas9 activity. In an embodiment, an engineered Cas9 molecule or Cas9 polypeptide can comprise an alteration that affects PAM recognition. E.g., an engineered Cas9 molecule can be altered to recognize a PAM sequence other than that recognized by the endogenous wild-type PI domain. In an embodiment a Cas9 molecule or Cas9 polypeptide can differ in sequence from a naturally occurring Cas9 molecule but not have significant alteration in one or more Cas9 activities.

Cas9 molecules or Cas9 polypeptides with desired properties can be made in a number of ways, e.g., by alteration of a parental, e.g., naturally occurring, Cas9 molecules or Cas9 polypeptides, to provide an altered Cas9 molecule or Cas9 polypeptide having a desired property. For example, one or more mutations or differences relative to a parental Cas9 molecule, e.g., a naturally occurring or engineered Cas9 molecule, can be introduced. Such mutations and differences comprise: substitutions (e.g., conservative substitutions or

substitutions of non-essential amino acids); insertions; or deletions. In an embodiment, a Cas9 molecule or Cas9 polypeptide can comprises one or more mutations or differences, e.g., at least 1, 2, 3, 4, 5, 10, 15, 20, 30, 40 or 50 mutations but less than 200, 100, or 80 mutations relative to a reference, e.g., a parental, Cas9 molecule.

In an embodiment, a mutation or mutations do not have a substantial effect on a Cas9 activity, e.g. a Cas9 activity described herein. In an embodiment, a mutation or mutations have a substantial effect on a Cas9 activity, e.g. a Cas9 activity described herein. Non-Cleaving and Modified-Cleavage Cas9 Molecules and Cas9 Polypeptides In an embodiment, a Cas9 molecule or Cas9 polypeptide comprises a cleavage property that differs from naturally occurring Cas9 molecules, e.g., that differs from the naturally occurring Cas9 molecule having the closest homology. For example, a Cas9 molecule or Cas9 polypeptide can differ from naturally occurring Cas9 molecules, e.g., a Cas9 molecule of S. pyogenes, as follows: its ability to modulate, e.g., decreased or increased, cleavage of a double stranded nucleic acid (endonuclease and/or exonuclease activity), e.g., as compared to a naturally occurring Cas9 molecule (e.g., a Cas9 molecule of S. pyogenes); its ability to modulate, e.g., decreased or increased, cleavage of a single strand of a nucleic acid, e.g., a non-complementary strand of a nucleic acid molecule or a complementary strand of a nucleic acid molecule (nickase activity) , e.g., as compared to a naturally occurring Cas9 molecule (e.g., a Cas9 molecule of S. pyogenes); or the ability to cleave a nucleic acid molecule, e.g., a double stranded or single stranded nucleic acid molecule, can be eliminated.

Modified Cleavage eaCas9 Molecules and eaCas9 Polypeptides

In an embodiment, an eaCas9 molecule or eaCas9 polypeptide comprises one or more of the following activities: cleavage activity associated with an N-terminal RuvC-like domain; cleavage activity associated with an HNH-like domain; cleavage activity associated with an HNH-like domain and cleavage activity associated with an N-terminal RuvC-like domain.

In an embodiment, an eaCas9 molecule or eaCas9 polypeptide comprises an active, or cleavage competent, HNH-like domain (e.g., an HNH-like domain described herein, e.g., SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20 or SEQ ID NO: 21) and an inactive, or cleavage incompetent, N-terminal RuvC-like domain. An exemplary inactive, or cleavage incompetent N-terminal RuvC-like domain can have a mutation of an aspartic acid in an N-terminal RuvC-like domain, e.g., an aspartic acid at position 9 of the consensus sequence disclosed in Figs. 2A-2G or an aspartic acid at position 10 of SEQ ID NO: 7, e.g., can be substituted with an alanine. In an embodiment, the eaCas9 molecule or eaCas9 polypeptide differs from wild type in the N-terminal RuvC-like domain and does not cleave the target nucleic acid, or cleaves with significantly less efficiency, e.g., less than 20, 10, 5, 1 or .1 % of the cleavage activity of a reference Cas9 molecule, e.g., as measured by an assay described herein. The reference Cas9 molecule can by a naturally occurring unmodified Cas9 molecule, e.g., a naturally occurring Cas9 molecule such as a Cas9 molecule of S. pyogenes, or S. thermophilus . In an embodiment, the reference Cas9 molecule is the naturally occurring Cas9 molecule having the closest sequence identity or homology.

In an embodiment, an eaCas9 molecule or eaCas9 polypeptide comprises an inactive, or cleavage incompetent, HNH domain and an active, or cleavage competent, N-terminal RuvC-like domain (e.g., a RuvC-like domain described herein, e.g., SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, or SEQ ID NO: 16). Exemplary inactive, or cleavage incompetent HNH-like domains can have a mutation at one or more of: a histidine in an HNH-like domain, e.g., a histidine shown at position 856 of the consensus sequence disclosed in Figs. 2A-2G, e.g., can be substituted with an alanine; and one or more asparagines in an HNH-like domain, e.g., an asparagine shown at position 870 of the consensus sequence disclosed in Figs. 2A-2G and/or at position 879 of the consensus sequence disclosed in Figs. 2A-2G, e.g., can be substituted with an alanine. In an embodiment, the eaCas9 differs from wild type in the HNH-like domain and does not cleave the target nucleic acid, or cleaves with significantly less efficiency, e.g., less than 20, 10, 5, 1 or 0.1% of the cleavage activity of a reference Cas9 molecule, e.g., as measured by an assay described herein. The reference Cas9 molecule can by a naturally occurring unmodified Cas9 molecule, e.g., a naturally occurring Cas9 molecule such as a Cas9 molecule of S. pyogenes, or S. thermophilus. In an embodiment, the reference Cas9 molecule is the naturally occurring Cas9 molecule having the closest sequence identity or homology.

Alterations in the Ability to Cleave One or Both Strands of a Target Nucleic Acid

In an embodiment, exemplary Cas9 activities comprise one or more of PAM specificity, cleavage activity, and helicase activity. A mutation(s) can be present, e.g., in: one or more RuvC domains, e.g., an N-terminal RuvC domain; an HNH domain; a region outside the RuvC domains and the HNH domain. In an embodiment, a mutation(s) is present in a RuvC domain. In an embodiment, a mutation(s) is present in an HNH domain. In an embodiment, mutations are present in both a RuvC domain and an HNH domain. Exemplary mutations that may be made in the RuvC domain or HNH domain with reference to the S. pyogenes sequence include: D10A, E762A, H840A, N854A, N863A and/or D986A.

In an embodiment, a Cas9 molecule is an eiCas9 molecule comprising one or more differences in a RuvC domain and/or in an HNH domain as compared to a reference Cas9 molecule, and the eiCas9 molecule does not cleave a nucleic acid, or cleaves with significantly less efficiency than does wildype, e.g., when compared with wild type in a cleavage assay, e.g., as described herein, cuts with less than 50, 25, 10, or 1% of a reference Cas9 molecule, as measured by an assay described herein.

Whether or not a particular sequence, e.g., a substitution, may affect one or more activity, such as targeting activity, cleavage activity, etc, can be evaluated or predicted, e.g., by evaluating whether the mutation is conservative. In an embodiment, a "non-essential" amino acid residue, as used in the context of a Cas9 molecule, is a residue that can be altered from the wild-type sequence of a Cas9 molecule, e.g., a naturally occurring Cas9 molecule, e.g., an eaCas9 molecule, without abolishing or more preferably, without substantially altering a Cas9 activity (e.g., cleavage activity), whereas changing an "essential" amino acid residue results in a substantial loss of activity (e.g., cleavage activity).

In an embodiment, a Cas9 molecule comprises a cleavage property that differs from naturally occurring Cas9 molecules, e.g., that differs from the naturally occurring Cas9 molecule having the closest homology. For example, a Cas9 molecule can differ from naturally occurring Cas9 molecules, e.g., a Cas9 molecule of S aureus, S. pyogenes, or C. jejuni as follows: its ability to modulate, e.g., decreased or increased, cleavage of a double stranded break

(endonuclease and/or exonuclease activity), e.g., as compared to a naturally occurring Cas9 molecule (e.g., a Cas9 molecule of S aureus, S. pyogenes, or C. jejuni); its ability to modulate, e.g., decreased or increased, cleavage of a single strand of a nucleic acid, e.g., a non- complimentary strand of a nucleic acid molecule or a complementary strand of a nucleic acid molecule (nickase activity), e.g., as compared to a naturally occurring Cas9 molecule (e.g., a Cas9 molecule of S aureus, S. pyogenes, or C. jejuni); or the ability to cleave a nucleic acid molecule, e.g., a double stranded or single stranded nucleic acid molecule, can be eliminated.

In an embodiment, the altered Cas9 molecule is an eaCas9 molecule comprising one or more of the following activities: cleavage activity associated with a RuvC domain; cleavage activity associated with an HNH domain; cleavage activity associated with an HNH domain and cleavage activity associated with a RuvC domain.

In an embodiment, the altered Cas9 molecule is an eiCas9 molecule which does not cleave a nucleic acid molecule (either double stranded or single stranded nucleic acid molecules) or cleaves a nucleic acid molecule with significantly less efficiency, e.g., less than 20, 10, 5, 1 or

0.1% of the cleavage activity of a reference Cas9 molecule, e.g., as measured by an assay described herein. The reference Cas9 molecule can be a naturally occurring unmodified Cas9 molecule, e.g., a naturally occurring Cas9 molecule such as a Cas9 molecule of S. pyogenes, S. thermophilus, S. aureus, C. jejuni or N. meningitidis. In an embodiment, the reference Cas9 molecule is the naturally occurring Cas9 molecule having the closest sequence identity or homology. In an embodiment, the eiCas9 molecule lacks substantial cleavage activity associated with a RuvC domain and cleavage activity associated with an HNH domain.

In an embodiment, the altered Cas9 molecule or Cas9 polypeptide is an eaCas9 molecule or eaCas9 polypeptide comprising the fixed amino acid residues of S. pyogenes shown in the consensus sequence disclosed in Figs. 2A-2G, and has one or more amino acids that differ from the amino acid sequence of S. pyogenes (e.g., has a substitution) at one or more residue (e.g., 2,

3, 5, 10, 15, 20, 30, 50, 70, 80, 90, 100, 200 amino acid residues) represented by an "-" in the consensus sequence disclosed in Figs. 2A-2G or SEQ ID NO: 7.

In an embodiment, the altered Cas9 molecule or Cas9 polypeptide comprises a sequence in which:

the sequence corresponding to the fixed sequence of the consensus sequence disclosed in Figs. 2A-2G differs at no more than 1, 2, 3, 4, 5, 10, 15, or 20% of the fixed residues in the consensus sequence disclosed in Figs. 2A-2G;

the sequence corresponding to the residues identified by "*" in the consensus sequence disclosed in Figs. 2A-2G differ at no more than 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, or 40% of the "*" residues from the corresponding sequence of naturally occurring Cas9 molecule, e.g., an S. pyogenes Cas9 molecule; and,

the sequence corresponding to the residues identified by "-" in the consensus sequence disclosed in Figs. 2A-2G differ at no more than 5, 10, 15, 20, 25, 30, 35, 40, 45, 55, or 60% of the "-" residues from the corresponding sequence of naturally occurring Cas9 molecule, e.g., an S. pyogenes Cas9 molecule. In an embodiment, the altered Cas9 molecule or Cas9 polypeptide is an eaCas9 molecule or eaCas9 polypeptide comprising the fixed amino acid residues of S. thermophilus shown in the consensus sequence disclosed in Figs. 2A-2G, and has one or more amino acids that differ from the amino acid sequence of S. thermophilus (e.g., has a substitution) at one or more residue (e.g., 2, 3, 5, 10, 15, 20, 30, 50, 70, 80, 90, 100, 200 amino acid residues) represented by an "-" in the consensus sequence disclosed in Figs. 2A-2G. In an embodiment

the sequence corresponding to the residues identified by "*" in the consensus sequence disclosed in Figs. 2A-2G differ at no more than 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, or 40% of the "*" residues from the corresponding sequence of naturally occurring Cas9 molecule, e.g., an S. thermophilus Cas9 molecule; and,

the sequence corresponding to the residues identified by "-" in the consensus sequence disclosed in Figs. 2A-2G differ at no more than 5, 10, 15, 20, 25, 30, 35, 40, 45, 55, or 60% of the "-" residues from the corresponding sequence of naturally occurring Cas9 molecule, e.g., an S. thermophilus Cas9 molecule.

In an embodiment, the altered Cas9 molecule or Cas9 polypeptide is an eaCas9 molecule or eaCas9 polypeptide comprising the fixed amino acid residues of S. mutans shown in the consensus sequence disclosed in Figs. 2A-2G, and has one or more amino acids that differ from the amino acid sequence of S. mutans (e.g., has a substitution) at one or more residue (e.g., 2, 3, 5, 10, 15, 20, 30, 50, 70, 80, 90, 100, 200 amino acid residues) represented by an "-" in the consensus sequence disclosed in Figs. 2A-2G.

the sequence corresponding to the fixed sequence of the consensus sequence disclosed in Figs. 2A-2G differs at no more than 1, 2, 3, 4, 5, 10, 15, or 20% of the fixed residues in the consensus sequence disclosed in Figs. 2A-2G; the sequence corresponding to the residues identified by "*" in the consensus sequence disclosed in Figs. 2A-2G differ at no more than 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, or 40% of the "*" residues from the corresponding sequence of naturally occurring Cas9 molecule, e.g., an S. mutans Cas9 molecule; and,

the sequence corresponding to the residues identified by "-" in the consensus sequence disclosed in Figs. 2A-2G differ at no more than 5, 10, 15, 20, 25, 30, 35, 40, 45, 55, or 60% of the "-" residues from the corresponding sequence of naturally occurring Cas9 molecule, e.g., an S. mutans Cas9 molecule.

In an embodiment, the altered Cas9 molecule or Cas9 polypeptide is an eaCas9 molecule or eaCas9 polypeptide comprising the fixed amino acid residues of L. innocula shown in the consensus sequence disclosed in Figs. 2A-2G, and has one or more amino acids that differ from the amino acid sequence of L. innocula (e.g., has a substitution) at one or more residue (e.g., 2, 3, 5, 10, 15, 20, 30, 50, 70, 80, 90, 100, 200 amino acid residues) represented by an "-"in the consensus sequence disclosed in Figs. 2A-2G.

the sequence corresponding to the fixed sequence of the consensus sequence disclosed in

Figs. 2A-2G differs at no more than 1, 2, 3, 4, 5, 10, 15, or 20% of the fixed residues in the consensus sequence disclosed in Figs. 2A-2G;

the sequence corresponding to the residues identified by "*" in the consensus sequence disclosed in Figs. 2A-2G differ at no more than 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, or 40% of the

"*" residues from the corresponding sequence of naturally occurring Cas9 molecule, e.g., an L. innocula Cas9 molecule; and,

the sequence corresponding to the residues identified by "-" in the consensus sequence disclosed in Figs. 2A-2G differ at no more than 5, 10, 15, 20, 25, 30, 35, 40, 45, 55, or 60% of the "-" residues from the corresponding sequence of naturally occurring Cas9 molecule, e.g., an

L. innocula Cas9 molecule.

In an embodiment, the altered Cas9 molecule or Cas9 polypeptide, e.g., an eaCas9 molecule or eaCas9 polypeptide, can be a fusion, e.g., of two of more different Cas9 molecules, e.g., of two or more naturally occurring Cas9 molecules of different species. For example, a fragment of a naturally occurring Cas9 molecule of one species can be fused to a fragment of a Cas9 molecule of a second species. As an example, a fragment of a Cas9 molecule of S.

pyogenes comprising an N-terminal RuvC-like domain can be fused to a fragment of Cas9 molecule of a species other than S. pyogenes (e.g., S. thermophilus) comprising an HNH-like domain.

Cas9 Molecules and Cas9 Polypeptides with Altered PAM Recognition or No PAM Recognition

Naturally occurring Cas9 molecules can recognize specific PAM sequences, for example the PAM recognition sequences described above for, e.g., S. pyogenes, S. thermophilus, S.

mutans, S. aureus and N. meningitidis.

In an embodiment, a Cas9 molecule or Cas9 polypeptide has the same PAM specificities as a naturally occurring Cas9 molecule. In an embodiment, a Cas9 molecule or Cas9

polypeptide has a PAM specificity not associated with a naturally occurring Cas9 molecule, or a PAM specificity not associated with the naturally occurring Cas9 molecule to which it has the closest sequence homology. For example, a naturally occurring Cas9 molecule can be altered, e.g., to alter PAM recognition, e.g., to alter the PAM sequence that the Cas9 molecule or Cas9 polypeptide recognizes to decrease off target sites and/or improve specificity; or eliminate a PAM recognition requirement. In an embodiment, a Cas9 molecule or Cas9 polypeptide can be altered, e.g., to increase length of PAM recognition sequence and/or improve Cas9 specificity to high level of identity (e.g., 98%, 99% or 100% match between gRNA and a PAM sequence), e.g., to decrease off target sites and increase specificity. In an embodiment, the length of the PAM recognition sequence is at least 4, 5, 6, 7, 8, 9, 10 or 15 amino acids in length. In an embodiment, the Cas9 specificity requires at least 90%, 95%, 96%, 97%, 98%, 99% or more homology between the gRNA and the PAM sequence. Cas9 molecules or Cas9 polypeptides that recognize different PAM sequences and/or have reduced off-target activity can be generated using directed evolution. Exemplary methods and systems that can be used for directed evolution of Cas9 molecules are described, e.g., in Esvelt et al. Nature 2011, 472(7344): 499- 503. Candidate Cas9 molecules can be evaluated, e.g., by methods described in Section IV.

Alterations of the PI domain, which mediates PAM recognition are discussed below. Synthetic Cas9 Molecules and Cas9 Polypeptides with Altered PI Domains Current genome-editing methods are limited in the diversity of target sequences that can be targeted by the PAM sequence that is recognized by the Cas9 molecule utilized. A synthetic Cas9 molecule (or Syn-Cas9 molecule), or synthetic Cas9 polypeptide (or syn-Cas9

polypeptide), as that term is used herein, refers to a Cas9 molecule or Cas9 polypeptide that comprises a Cas9 core domain from one bacterial species and a functional altered PI domain, i.e., a PI domain other than that naturally associated with the Cas9 core domain, e.g., from a different bacterial species.

In an embodiment, the altered PI domain recognizes a PAM sequence that is different from the PAM sequence recognized by the naturally- occurring Cas9 from which the Cas9 core domain is derived. In an embodiment, the altered PI domain recognizes the same PAM sequence recognized by the naturally- occurring Cas9 from which the Cas9 core domain is derived, but with different affinity or specificity. A Syn-Cas9 molecule or Syn-Cas9 polypetide can be, respectively, a Syn-eaCas9 molecule or Syn-eaCas9 polypeptide or a Syn-eiCas9 molecule Syn- eiCas9 polypeptide.

An exemplary Syn-Cas9 molecule Syn-Cas9 polypetide comprises:

a) a Cas9 core domain, e.g., a Cas9 core domain from Table 28 or 29, e.g., a S. aureus, S. pyogenes, or C. jejuni Cas9 core domain; and

b) an altered PI domain from a species X Cas9 sequence selected from Tables 31 and 32. In an embodiment, the RKR motif (the PAM binding motif) of said altered PI domain comprises: differences at 1, 2, or 3 amino acid residues; a difference in amino acid sequence at the first, second, or third position; differences in amino acid sequence at the first and second positions, the first and third positions, or the second and third positions; as compared with the sequence of the RKR motif of the native or endogenous PI domain associated with the Cas9 core domain.

In an embodiment, the Cas9 core domain comprises the Cas9 core domain from a species X Cas9 from Table 28 and said altered PI domain comprises a PI domain from a species Y Cas9 from Table 28.

In an embodiment, the RKR motif of the species X Cas9 is other than the RKR motif of the species Y Cas9. In an embodiment, the RKR motif of the altered PI domain is selected from XXY, XNG, and XNQ.

In an embodiment, the altered PI domain has at least 60, 70, 80, 90, 95, or 100% homology with the amino acid sequence of a naturally occurring PI domain of said species Y from Table 28.

In an embodiment, the altered PI domain differs by no more than 50, 40, 30, 25, 20, 15, 10, 5, 4, 3, 2, or 1 amino acid residue from the amino acid sequence of a naturally occurring PI domain of said second species from Table 28.

In an embodiment, the Cas9 core domain comprises a S. aureus core domain and altered PI domain comprises: an A. denitrificans PI domain; a C. jejuni PI domain; a H. mustelae PI domain; or an altered PI domain of species X PI domain, wherein species X is selected from

Table 32.

In an embodiment, the Cas9 core domain comprises a S. pyogenes core domain and the altered PI domain comprises: an A. denitrificans PI domain; a C. jejuni PI domain; a H. mustelae PI domain; or an altered PI domain of species X PI domain, wherein species X is selected from Table 32.

In an embodiment, the Cas9 core domain comprises a C. jejuni core domain and the altered PI domain comprises: an A. denitrificans PI domain; a H. mustelae PI domain; or an altered PI domain of species X PI domain, wherein species X is selected from Table 32.

In an embodiment, the Cas9 molecule further comprises a linker disposed between said

Cas9 core domain and said altered PI domain.

In an embodiment, the linker comprises: a linker described elsewhere herein disposed between the Cas9 core domain and the heterologous PI domain. Suitable linkers are further described in Section V.

Exemplary altered PI domains for use in Syn-Cas9 molecules are described in Tables 31 and 32. The sequences for the 83 Cas9 orthologs referenced in Tables 31 and 32 are provided in Table 28. Table 30 provides the Cas9 orthologs with known PAM sequences and the corresponding RKR motif.

In an embodiment, a Syn-Cas9 molecule may also be size- optimized, e.g., the Syn-Cas9 molecule comprises one or more deletions, and optionally one or more linkers disposed between the amino acid residues flanking the deletions. In an embodiment, a Syn-Cas9 molecule comprises a REC deletion.

Size-Optimized Cas9 Molecules

Engineered Cas9 molecules and engineered Cas9 polypeptides described herein include a

Cas9 molecule or Cas9 polypeptide comprising a deletion that reduces the size of the molecule while still retaining desired Cas9 properties, e.g., essentially native conformation, Cas9 nuclease activity, and/or target nucleic acid molecule recognition. Provided herein are Cas9 molecules or Cas9 polypeptides comprising one or more deletions and optionally one or more linkers, wherein a linker is disposed between the amino acid residues that flank the deletion. Methods for identifying suitable deletions in a reference Cas9 molecule, methods for generating Cas9 molecules with a deletion and a linker, and methods for using such Cas9 molecules will be apparent to one of ordinary skill in the art upon review of this document.

A Cas9 molecule, e.g., a S. aureus, S. pyogenes, or C. jejuni, Cas9 molecule, having a deletion is smaller, e.g., has reduced number of amino acids, than the corresponding naturally- occurring Cas9 molecule. The smaller size of the Cas9 molecules allows increased flexibility for delivery methods, and thereby increases utility for genome-editing. A Cas9 molecule can comprise one or more deletions that do not substantially affect or decrease the activity of the resultant Cas9 molecules described herein. Activities that are retained in the Cas9 molecules comprising a deletion as described herein include one or more of the following:

a nickase activity, i.e., the ability to cleave a single strand, e.g., the non-complementary strand or the complementary strand, of a nucleic acid molecule; a double stranded nuclease activity, i.e., the ability to cleave both strands of a double stranded nucleic acid and create a double stranded break, which in an embodiment is the presence of two nickase activities;

an endonuclease activity;

an exonuclease activity;

a helicase activity, i.e., the ability to unwind the helical structure of a double stranded nucleic acid;

and recognition activity of a nucleic acid molecule, e.g., a target nucleic acid or a gRNA. Activity of the Cas9 molecules described herein can be assessed using the activity assays described herein or in the art. Identifying regions suitable for deletion

Suitable regions of Cas9 molecules for deletion can be identified by a variety of methods. Naturally- occurring orthologous Cas9 molecules from various bacterial species, e.g., any one of those listed in Table 28, can be modeled onto the crystal structure of S. pyogenes Cas9

(Nishimasu et al., Cell, 156:935-949, 2014) to examine the level of conservation across the selected Cas9 orthologs with respect to the three-dimensional conformation of the protein. Less conserved or unconserved regions that are spatially located distant from regions involved in Cas9 activity, e.g., interface with the target nucleic acid molecule and/or gRNA, represent regions or domains are candidates for deletion without substantially affecting or decreasing Cas9 activity.

REC-Optimized Cas9 Molecules

A REC-optimized Cas9 molecule, as that term is used herein, refers to a Cas9 molecule that comprises a deletion in one or both of the REC2 domain and the REI_CT domain (collectively a REC deletion), wherein the deletion comprises at least 10% of the amino acid residues in the cognate domain. A REC-optimized Cas9 molecule can be an eaCas9 molecule or an eiCas9 molecule. An exemplary REC-optimizedCas9 molecule comprises:

a) a deletion selected from:

i) a REC2 deletion;

ii) a REC I_CT deletion; or

iii) a REC 1 SU_B deletion.

Optionally, a linker is disposed between the amino acid residues that flank the deletion. In an embodiment a Cas9 molecule includes only one deletion, or only two deletions. A Cas9 molecule can comprise a REC2 deletion and a REC I_CT deletion. A Cas9 molecule can comprise a REC2 deletion and a REC 1 _SUB deletion.

Generally, the deletion will contain at least 10% of the amino acids in the cognate domain, e.g., a REC2 deletion will include at least 10% of the amino acids in the REC2 domain.

A deletion can comprise: at least 10, 20, 30, 40, 50, 60, 70, 80, or 90% of the amino acid residues of its cognate domain; all of the amino acid residues of its cognate domain; an amino acid residue outside its cognate domain; a plurality of amino acid residues outside its cognate domain; the amino acid residue immediately N terminal to its cognate domain; the amino acid residue immediately C terminal to its cognate domain; the amino acid residue immediately N terminal to its cognate and the amino acid residue immediately C terminal to its cognate domain; a plurality of, e.g., up to 5, 10, 15, or 20, amino acid residues N terminal to its cognate domain; a plurality of, e.g., up to 5, 10, 15, or 20, amino acid residues C terminal to its cognate domain; a plurality of, e.g., up to 5, 10, 15, or 20, amino acid residues N terminal to to its cognate domain and a plurality of e.g., up to 5, 10, 15, or 20, amino acid residues C terminal to its cognate domain.

In an embodiment, a deletion does not extend beyond: its cognate domain; the N terminal amino acid residue of its cognate domain; the C terminal amino acid residue of its cognate domain.

A REC-optimized Cas9 molecule can include a linker disposed between the amino acid residues that flank the deletion. Suitable linkers for use between the amino acid resides that flank a REC deletion in a REC-optimized Cas9 molecule is disclosed in Section V.

In an embodiment a REC-optimized Cas9 molecule comprises an amino acid sequence that, other than any REC deletion and associated linker, has at least 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 99, or 100% homology with the amino acid sequence of a naturally occurring Cas 9, e.g., a Cas9 molecule described in Table 28, e.g., a S. aureus Cas9 molecule, a S. pyogenes Cas9 molecule, or a C. jejuni Cas9 molecule.

In an embodiment, a a REC-optimized Cas9 molecule comprises an amino acid sequence that, other than any REC deletion and associated linker, differs by no more than 1, 2, 3, 4, 5, 6, 7,

8, 9, 10, 15, 20, or 25, amino acid residues from the amino acid sequence of a naturally occurring Cas 9, e.g., a Cas9 molecule described in Table 28, e.g., a S. aureus Cas9 molecule, a S. pyogenes Cas9 molecule, or a C. jejuni Cas9 molecule.

In an embodiment, a REC-optimized Cas9 molecule comprises an amino acid sequence that, other than any REC deletion and associate linker, differs by no more than 1, 2, 3, 4, 5, 6, 7, 8,

9, 10, 15, 20, or 25% of the, amino acid residues from the amino acid sequence of a naturally occurring Cas 9, e.g., a Cas9 molecule described in Table 28, e.g., a S. aureus Cas9 molecule, a S. pyogenes Cas9 molecule, or a C. jejuni Cas9 molecule.

For sequence comparison, typically one sequence acts as a reference sequence, to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are entered into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. Default program parameters can be used, or alternative parameters can be designated. The sequence comparison algorithm then calculates the percent sequence identities for the test sequences relative to the reference sequence, based on the program parameters. Methods of alignment of sequences for comparison are well known in the art. Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith and Waterman, (1970) Adv. Appl. Math. 2:482c, by the homology alignment algorithm of Needleman and Wunsch, (1970) J. Mol. Biol. 48:443, by the search for similarity method of Pearson and Lipman, (1988) Proc. Nat'l. Acad. Sci. USA 85:2444, by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, WI), or by manual alignment and visual inspection (see, e.g., Brent et al., (2003) Current Protocols in Molecular Biology).

Two examples of algorithms that are suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al., (1977) Nuc. Acids Res. 25:3389-3402; and Altschul et al., (1990) J. Mol. Biol. 215:403-410, respectively. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information.

The percent identity between two amino acid sequences can also be determined using the algorithm of E. Meyers and W. Miller, (1988) Comput. Appl. Biosci. 4: 11-17) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. In addition, the percent identity between two amino acid sequences can be determined using the Needleman and Wunsch (1970) J. Mol. Biol.

48:444-453) algorithm which has been incorporated into the GAP program in the GCG software package (available at www.gcg.com), using either a Blossom 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6.

Sequence information for exemplary REC deletions are provided for 83 naturally- occurring Cas9 orthologs in Table 28. The amino acid sequences of exemplary Cas9 molecules from different bacterial species are shown below.

Table 28. Amino Acid Sequence of Cas9 Orthologs

BAA- 1640 318

gil304438954lreflZP_07398877.1

Acidaminococcus sp. D21 SEQ ID NO: 167 306 140 511 591 75 511 591 75 gil227824983lreflZP_03989815.1 319

Lactobacillus farciminis KCTC SEQ ID NO: 171 310 140 542 621 85 542 621 85

3681 320

gil336394882lreflZP_08576281.1

Streptococcus sanguinis SK49 SEQ ID NO: 185 324 140 411 490 85 411 490 85 gil422884106lreflZP_l 6930555.1 321

Coprococcus catus GD-7 SEQ ID NO: 172 310 139 556 634 76 556 634 76 gil291520705lemblCBK78998.1 l 322

Streptococcus mutans UA159 SEQ ID NO: 176 314 139 392 470 84 392 470 84 gil24379809lreflNP_721764.11 323

Streptococcus pyogenes Ml SEQ ID NO: 176 314 139 523 600 82 523 600 82

GAS 324

gill3622193lgblAAK33936.1 l

Streptococcus thermophilus SEQ ID NO: 176 314 139 481 558 81 481 558 81 LMD-9 325

gil 1 16628213 Iref 1 YP_820832.11

Fusobacteriumnucleatum SEQ ID NO: 171 308 138 537 614 76 537 614 76 ATCC49256 326

gil34762592lreflZP_00143587.1 l

Planococcus antarcticus DSM SEQ ID NO: 162 299 138 538 614 94 538 614 94

14505 327

gil389815359lreflZP_10206685.1

Treponema denticola ATCC SEQ ID NO: 169 305 137 524 600 81 524 600 81

35405 328

gil42525843lreflNP_970941.11

Solobacterium moorei F0204 SEQ ID NO: 179 314 136 544 619 77 544 619 77 gil320528778lreflZP_08029929.1 329

Staphylococcus SEQ ID NO: 164 299 136 531 606 92 531 606 92 pseudintermedius ED99 330

gil323463801 lgblADX75954.11

Flavobacterium branchiophilum SEQ ID NO: 162 286 125 538 613 63 538 613 63

FL-15 331

gil347536497lreflYP_004843922

.1

Ignavibacterium album JCM SEQ ID NO: 223 329 107 357 432 90 357 432 90

16511 332

gil38581 1609lreflYP_005848005

.1

Bergeyella zoohelcum ATCC SEQ ID NO: 165 261 97 529 604 56 529 604 56

43767 333

gi 1423317190lref IZP_ 17295095.1

Nitrobacter hamburgensis X14 SEQ ID NO: 169 253 85 536 611 48 536 611 48 gil92109262lrefl YP_571550.11 334

Odoribacter laneus YIT 12061 SEQ ID NO: 164 242 79 535 610 63 535 610 63 gil374384763lreflZP_09642280.1 335

Legionella pneumophila str. SEQ ID NO: 164 239 76 402 476 67 402 476 67

Paris 336

gil54296138lreflYP_122507.1 l Bacteroides sp. 20 3 SEQ ID NO: 198 269 72 530 604 83 530 604 83 gi 130131 1869 Iref IZP_07217791.1 337

Akkermansia muciniphila ATCC SEQ ID NO: 136 202 67 348 418 62 348 418 62

BAA-835 338

gill87736489lreflYP_001878601

Prevotella sp. C561 SEQ ID NO: 184 250 67 357 425 78 357 425 78 gil345885718lreflZP_08837074.1 339

Wolinella succinogenes DSM SEQ ID NO: 157 218 36 401 468 60 401 468 60

1740 340

gil34557932lreflNP_907747.11

Alicyclobacillus hesperidum SEQ ID NO: 142 196 55 416 482 61 416 482 61 URH17-3-68 341

gil403744858lreflZP_10953934.1

Caenispirillum salinarum AK4 SEQ ID NO: 161 214 54 330 393 68 330 393 68 gil427429481 lreflZP_l 891951 1.1 342

Eubacterium rectale ATCC SEQ ID NO: 133 185 53 322 384 60 322 384 60 33656 343

gil238924075lreflYP_002937591

.1

Mycoplasma synoviae 53 SEQ ID NO: 187 239 53 319 381 80 319 381 80 gil71894592lref 1 YP_278700.11 344

Porphyromonas sp. oral taxon SEQ ID NO: 150 202 53 309 371 60 309 371 60 279 str. F0450 345

gil402847315 Iref IZP_10895610.1

Streptococcus thermophilus SEQ ID NO: 127 178 139 424 486 81 424 486 81 LMD-9 346

gil 1 16627542lref 1 YP_820161.11

Roseburia inulinivorans DSM SEQ ID NO: 154 204 51 318 380 69 318 380 69

16841 347

gil225377804lreflZP_03755025.1

Methylosinus trichosporium SEQ ID NO: 144 193 50 426 488 64 426 488 64

OB3b 348

gil296446027lreflZP_06887976.1

Ruminococcus albus 8 SEQ ID NO: 139 187 49 351 412 55 351 412 55 gil325677756lreflZP_08157403.1 349

Bifidobacterium longum SEQ ID NO: 183 230 48 370 431 44 370 431 44 DJO10A 350

gill89440764lreflYP_001955845

Enterococcus faecalis TX0012 SEQ ID NO: 123 170 48 327 387 60 327 387 60 gil315149830lgblEFT93846.11 351

Mycoplasma mobile 163K SEQ ID NO: 179 226 48 314 374 79 314 374 79 gil47458868lreflYP_015730.1 l 352

Actinomyces coleocanis DSM SEQ ID NO: 147 193 47 358 418 40 358 418 40

15436 353

gil227494853lreflZP_03925169.1

Dinoroseobacter shibae DFL 12 SEQ ID NO: 138 184 47 338 398 48 338 398 48 gil 159042956lref 1 YP_001531750 354

.1 Actinomyces sp. oral taxon 180 SEQ ID NO: 183 228 46 349 409 40 349 409 40 str. F0310 355

gil315605738lreflZP_07880770.1

Alcanivorax sp. Wl 1-5 SEQ ID NO: 139 183 45 344 404 61 344 404 61 gil407803669lreflZP_l 1 150502.1 356

Aminomonas paucivorans DSM SEQ ID NO: 134 178 45 341 401 63 341 401 63

12260 357

gi 1312879015 Iref IZP_07738815.1

Mycoplasma canis PG 14 SEQ ID NO: 139 183 45 319 379 76 319 379 76 gil384393286lgblEIE39736.11 358

Lactobacillus coryniformis SEQ ID NO: 141 184 44 328 387 61 328 387 61 KCTC 3535 359

gil336393381 lreflZP_08574780.1

Elusimicrobium minutum Peil91 SEQ ID NO: 177 219 43 322 381 47 322 381 47 gill87250660lreflYP_001875142 360

.1

Neisseria meningitidis Z2491 SEQ ID NO: 147 189 43 360 419 61 360 419 61 gil218767588lreflYP_002342100 361

.1

Pasteurella multocida str. Pm70 SEQ ID NO: 139 181 43 319 378 61 319 378 61 gill5602992lreflNP_246064.11 362

Rhodovulum sp. PH10 SEQ ID NO: 141 183 43 319 378 48 319 378 48 gil402849997lreflZP_10898214.1 363

Eubacterium dolichum DSM SEQ ID NO: 131 172 42 303 361 59 303 361 59

3991 364

gill60915782lreflZP_02077990.1

Nitratifractor salsuginis DSM SEQ ID NO: 143 184 42 347 404 61 347 404 61

16511 365

gil319957206lreflYP_004168469

.1

Rhodospirillum rubrum ATCC SEQ ID NO: 139 180 42 314 371 55 314 371 55

1 1 170 366

gil83591793 Irefl YP_425545.11

Clostridium cellulolyticum H10 SEQ ID NO: 137 176 40 320 376 61 320 376 61 gil220930482lreflYP_002507391 367

.1

Helicobacter mustelae 12198 SEQ ID NO: 148 187 40 298 354 48 298 354 48 gi 1291276265 Iref 1 YP_003516037 368

.1

Ilyobacter polytropus DSM 2926 SEQ ID NO: 134 173 40 462 517 63 462 517 63 gil310780384lref 1 YP_003968716 369

.1

Sphaerochaeta globus str. Buddy SEQ ID NO: 163 202 40 335 389 45 335 389 45 gil325972003lreflYP_004248194 370

.1

Staphylococcus lugdunensis SEQ ID NO: 128 167 40 337 391 57 337 391 57 M23590 371

gil315659848lreflZP_07912707.1

Treponema sp. JC4 SEQ ID NO: 144 183 40 328 382 63 328 382 63 gil384109266lreflZP_10010146.1 372

uncultured delta proteobacterium SEQ ID NO: 154 193 40 313 365 55 313 365 55 HF0070 07E19 373 gi 1297182908 Igb 1 ADI 19058.11

Alicycliphilus denitrificans K601 SEQ ID NO: 140 178 39 317 366 48 317 366 48 gil330822845lreflYP_004386148 374

.1

Azospirillum sp. B510 SEQ ID NO: 205 243 39 342 389 46 342 389 46 gil288957741 lreflYP_003448082 375

.1

Bradyrhizobium sp. BTAil SEQ ID NO: 143 181 39 323 370 48 323 370 48 gill48255343lreflYP_001239928 376

.1

Parvibaculum lavamentivorans SEQ ID NO: 138 176 39 327 374 58 327 374 58

DS-1 377

gill54250555lreflYP_001411379

.1

Prevotella timonensis CRIS 5C- SEQ ID NO: 170 208 39 328 375 61 328 375 61

B l 378

gil282880052lreflZP_06288774.1

Bacillus smithii 7 3 47FAA SEQ ID NO: 134 171 38 401 448 63 401 448 63 gil365156657lreflZP_09352959.1 379

Cand. Puniceispirillum marinum SEQ ID NO: 135 172 38 344 391 53 344 391 53

IMCC1322 380

gil29408611 l lreflYP_003552871

.1

Barnesiella intestinihominis YIT SEQ ID NO: 140 176 37 371 417 60 371 417 60

11860 381

gi|404487228lreflZP_l 1022414.1

Ralstonia syzygii R24 SEQ ID NO: 140 176 37 395 440 50 395 440 50 gil344171927lemblCCA84553.1 l 382

Wolinella succinogenes DSM SEQ ID NO: 145 180 36 348 392 60 348 392 60

1740 383

gil34557790lreflNP_907605.11

Mycoplasma gallisepticum str. F SEQ ID NO: 144 177 34 373 416 71 373 416 71 gi 128493171 Olgb IADC31648.11 384

Acidothermus cellulolyticus 1 IB SEQ ID NO: 150 182 33 341 380 58 341 380 58 gill l7929158lreflYP_873709.1 l 385

Mycoplasma ovipneumoniae SEQ ID NO: 156 184 29 381 420 62 381 420 62

SCOl 386

gil363542550lreflZP_09312133.1

Table 29. Amino Acid Sequence of Cas9 Core Domains

Table 30. Identified PAM sequences and corresponding RKR motifs.

PI domains are provided in Tables 31 and 32.

Table 31. Altered PI Domains

Table 32. Other Altered PI Domains

Flavobacterium branchiophilum FL-15 1182 1473 292 KQK

Prevotella timonensis CRIS 5C-B1 957 1218 262 KQQ

Methylosinus trichosporium OB3b 830 1082 253 KRP

Prevotella sp. C561 1099 1424 326 KRY

Mycoplasma gallisepticum str. F 911 1269 359 KTA

Lactobacillus rhamnosus GG 1077 1363 287 KYG

Wolinella succinogenes DSM 1740 811 1059 249 LPN

Streptococcus thermophilus LMD-9 1099 1388 290 MLA

Treponema denticola ATCC 35405 1092 1395 304 NDS

Bergeyella zoohelcum ATCC 43767 1098 1415 318 NEK

Veillonella atypica ACS-134-V-Col7a 1107 1398 292 NGF

Neisseria meningitidis Z2491 835 1082 248 NHN

Ignavibacterium album JCM 16511 1296 1688 393 NKK

Ruminococcus albus 8 853 1156 304 NNF

Streptococcus thermophilus LMD-9 811 1121 311 N K

Barnesiella intestinihominis YIT 11860 871 1153 283 NPV

Azospirillum sp. B510 911 1168 258 PFH

Rhodospirillum rubrum ATCC 11170 863 1173 311 PRG

Planococcus antarcticus DSM 14505 1087 1333 247 PYY

Staphylococcus pseudintermedius ED99 1073 1334 262 QIV

Alcanivorax sp. Wl l-5 843 1113 271 RIE

Bradyrhizobium sp. BTAil 811 1064 254 RIY

Streptococcus pyogenes Ml GAS 1099 1368 270 RKR

Streptococcus mutans UA159 1078 1345 268 RKR

Streptococcus Pyogenes 1099 1368 270 RKR

Bacteroides sp. 20 3 1147 1517 371 RNI

S. aureus 772 1053 282 RNK

Solobacterium moorei F0204 1062 1327 266 RSG

Finegoldia magna ATCC 29328 1081 1348 268 RTE uncultured delta proteobacterium HF0070 07E19 770 1011 242 SGG

Acidaminococcus sp. D21 1064 1358 295 SIG

Eubacterium rectale ATCC 33656 824 1114 291 SKK

Caenispirillum salinarum AK4 1048 1442 395 SLV

Acidothermus cellulolyticus 11B 830 1138 309 SPS

Catenibacterium mitsuokai DSM 15897 1068 1329 262 SPT

Parvibaculum lavamentivorans DS-1 827 1037 211 TGN

Staphylococcus lugdunensis M23590 772 1054 283 TKK

Streptococcus sanguinis SK49 1123 1421 299 TRM

Elusimicrobium minutum Peil91 910 1195 286 TTG Nitrobacter hamburgensis X14 914 1166 253 VAY

Mycoplasma synoviae 53 991 1314 324 VGF

Sphaerochaeta globus str. Buddy 877 1179 303 VKG

Ilyobacter polytropus DSM 2926 837 1092 256 VNG

Rhodovulum sp. PH10 821 1059 239 VPY

Bifidobacterium longum DJO10A 904 1187 284 VRK

Amino acid sequences described in Table 28:

SEQ ID NO: 304

MKRNYILGLDIGITSVGYGI IDYETRDVIDAGVRLFKEANVENNEGRRSKRGARRLKRRRRHRI QRVKKLLFDYNLLTDHSELSGINPYEARVKGLSQKLSEEEFSAALLHLAKRRGVHNVNEVEEDT GNELSTKEQI SRNSKALEEKYVAELQLERLKKDGEVRGS INRFKTSDYVKEAKQLLKVQKAYHQ LDQSFIDTYIDLLETRRTYYEGPGEGSPFGWKDIKEWYEMLMGHCTYFPEELRSVKYAYNADLY NALNDLNNLVITRDENEKLEYYEKFQI IENVFKQKKKPTLKQIAKEILVNEEDIKGYRVTSTGK PEFTNLKVYHDIKDITARKEI IENAELLDQIAKILTIYQSSEDIQEELTNLNSELTQEEIEQIS NLKGYTGTHNLSLKAINLILDELWHTNDNQIAIFNRLKLVPKKVDLSQQKEIPTTLVDDFILSP VVKRSFIQS IKVINAI IKKYGLPNDI I IELAREKNSKDAQKMINEMQKRNRQTNERIEEI IRTT GKENAKYLIEKIKLHDMQEGKCLYSLEAIPLEDLLNNPFNYEVDHI IPRSVSFDNSFNNKVLVK QEENSKKGNRTPFQYLSSSDSKI SYETFKKHILNLAKGKGRI SKTKKEYLLEERDINRFSVQKD FINRNLVDTRYATRGLMNLLRSYFRVNNLDVKVKS INGGFTSFLRRKWKFKKERNKGYKHHAED ALI IA ADFIFKEWKKLDKAKKVMENQMFEEKQAESMPEIETEQEYKEIFITPHQIKHIKDFKD YKYSHRVDKKPNRELINDTLYSTRKDDKGNTLIVNNLNGLYDKDNDKLKKLINKSPEKLLMYHH DPQTYQKLKLIMEQYGDEKNPLYKYYEETGNYLTKYSKKDNGPVIKKIKYYGNKLNAHLDITDD YPNSRNKVVKLSLKPYRFDVYLDNGVYKFVTVKNLDVIKKENYYEVNSKCYEEAKKLKKISNQA EFIASFYNNDLIKINGELYRVIGVNNDLLNRIEVNMIDITYREYLENMNDKRPPRI IKTIASKT QS IKKYSTDILGNLYEVKSKKHPQI IKKG

SEQ ID NO: 305

MDKKYS IGLDIGTNSVGWAVITDEYKVPSKKFKVLGNTDRHS IKKNLIGALLFDSGETAEATRL KRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIVDEVAY HEKYPTIYHLRKKLVDSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQLVQTY NQLFEENPINASGVDAKAILSARLSKSRRLENLIAQLPGEKKNGLFGNLIALSLGLTPNFKSNF DLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAILLSDILRVNTEITKAPLSAS MIKRYDEHHQDLTLLKALVRQQLPEKYKEIFFDQSKNGYAGYIDGGASQEEFYKFIKPILEKMD GTEELLVKLNREDLLRKQRTFDNGS IPHQIHLGELHAILRRQEDFYPFLKDNREKIEKILTFRI PYYVGPLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQSFIERMTNFDKNLPNEKVLPKHS LLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRKVTVKQLKEDYFKKIECFD SVEI SGVEDRFNASLGTYHDLLKI IKDKDFLDNEENEDILEDIVLTLTLFEDREMIEERLKTYA HLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSGKTILDFLKSDGFANRNFMQLIHDDSLTF KEDIQKAQVSGQGDSLHEHIANLAGSPAIKKGILQTVKVVDELVKVMGRHKPENIVIEMARENQ TTQKGQKNSRERMKRIEEGIKELGSQILKEHPVENTQLQNEKLYLYYLQNGRDMYVDQELDINR LSDYDVDHIVPQSFLKDDS IDNKVLTRSDKNRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQRK FDNLTKAERGGLSELDKAGFIKRQLVETRQITKHVAQILDSRMNTKYDENDKLIREVKVITLKS KLVSDFRKDFQFYKVREINNYHHAHDAYLNAVVGTALIKKYPKLESEFVYGDYKVYDVRKMIAK SEQEIGKATAKYFFYSNIMNFFKTEITLANGEIRKRPLIETNGETGEIVWDKGRDFATVRKVLS MPQV IVKKTEVQTGGFSKES ILPKRNSDKLIARKKDWDPKKYGGFDSPTVAYSVLVVAKVEKG KSKKLKSVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLI IKLPKYSLFELENGRKRMLAS AGELQKGNELALPSKYVNFLYLASHYEKLKGSPEDNEQKQLFVEQHKHYLDEI IEQI SEFSKRV ILADANLDKVLSAYNKHRDKPIREQAE I IHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLD ATLIHQS ITGLYETRIDLSQLGGD

SEQ ID NO: 306

MARILAFDIGI SS IGWAFSENDELKDCGVRIFTKVENPKTGESLALPRRLARSARKRLARRKAR LNHLKHLIANEFKLNYEDYQSFDESLAKAYKGSLI SPYELRFRALNELLSKQDFARVILHIAKR RGYDDIKNSDDKEKGAILKAIKQNEEKLANYQSVGEYLYKEYFQKFKENSKEFTNVRNKKESYE RCIAQSFLKDELKLIFKKQREFGFSFSKKFEEEVLSVAFYKRALKDFSHLVGNCSFFTDEKRAP KNSPLAFMFVALTRI INLLNNLKNTEGILYTKDDLNALLNEVLKNGTLTYKQTKKLLGLSDDYE FKGEKGTYFIEFKKYKEFIKALGEHNLSQDDLNEIAKDITLIKDEIKLKKALAKYDLNQNQIDS LSKLEFKDHL I SFKALKLVTPLMLEGKKYDEACNELNLKVAINEDKKDFLPAFNETYYKDEVT NPVVLRAIKEYRKVLNALLKKYGKVHKINIELAREVGKNHSQRAKIEKEQNENYKAKKDAELEC EKLGLKINSKNILKLRLFKEQKEFCAYSGEKIKI SDLQDEKMLEIDHIYPYSRSFDDSYMNKVL VFTKQNQEKLNQTPFEAFGNDSAKWQKIEVLAKNLPTKKQKRILDKNYKDKEQKNFKDRNLNDT RYIARLVLNYTKDYLDFLPLSDDENTKLNDTQKGSKVHVEAKSGMLTSALRHTWGFSAKDRNNH LHHAIDAVI IAYANNS IVKAFSDFKKEQESNSAELYAKKI SELDYKNKRKFFEPFSGFRQKVLD KIDEIFVSKPERKKPSGALHEETFRKEEEFYQSYGGKEGVLKALELGKIRKVNGKIVKNGDMFR VDIFKHKKTNKFYAVPIYTMDFALKVLPNKAVARSKKGEIKDWILMDENYEFCFSLYKDSLILI QTKDMQEPEFVYY AFTSSTVSLIVSKHDNKFETLSKNQKILFKNANEKEVIAKS IGIQNLKVF EKYIVSALGEVTKAEFRQREDFKK

SEQ ID NO: 307

MKRILGLDLGTNS IGWALVNEAENKDERSS IVKLGVRVNPLTVDELTNFEKGKS ITTNADRTLK RGMRRNLQRYKLRRETLTEVLKEHKLITEDTILSENGNRTTFETYRLRAKAVTEEI SLEEFARV LLMINKKRGYKSSRKAKGVEEGTLIDGMDIARELYNNNLTPGELCLQLLDAGKKFLPDFYRSDL QNELDRIWEKQKEYYPEILTDVLKEELRGKKRDAVWAICAKYFVWKENYTEWNKEKGKTEQQER EHKLEGIYSKRKRDEAKRENLQWRVNGLKEKLSLEQLVIVFQEMNTQINNSSGYLGAI SDRSKE LYFNKQTVGQYQMEMLDKNPNASLRNMVFYRQDYLDEFNMLWEKQAVYHKELTEELKKEIRDI I IFYQRRLKSQKGLIGFCEFESRQIEVDIDGKKKIKTVGNRVI SRSSPLFQEFKIWQILNNIEVT VVGKKRKRRKLKENYSALFEELNDAEQLELNGSRRLCQEEKELLAQELFIRDKMTKSEVLKLLF DNPQELDLNFKTIDGNKTGYALFQAYSKMIEMSGHEPVDFKKPVEKVVEYIKAVFDLLNWNTDI LGFNSNEELDNQPYYKLWHLLYSFEGDNTPTGNGRLIQKMTELYGFEKEYATILANVSFQDDYG SLSAKAIHKILPHLKEGNRYDVACVYAGYRHSESSLTREEIANKVLKDRLMLLPKNSLHNPVVE KILNQMVNVINVI IDIYGKPDEIRVELARELKKNAKEREELTKS IAQTTKAHEEYKTLLQTEFG LTNVSRTDILRYKLYKELESCGYKTLYSNTYI SREKLFSKEFDIEHI IPQARLFDDSFSNKTLE ARSVNIEKGNKTAYDFVKEKFGESGADNSLEHYLNNIEDLFKSGKI SKTKYNKLKMAEQDIPDG FIERDLRNTQYIAKKALSMLNEI SHRVVATSGSVTDKLREDWQLIDVMKELNWEKYKALGLVEY FEDRDGRQIGRIKDWTKRNDHRHHAMDALTVAFTKDVFIQYFNNKNASLDPNANEHAIKNKYFQ NGRAIAPMPLREFRAEAKKHLENTLI S IKAKNKVITGNINKTRKKGGVNKNMQQTPRGQLHLET IYGSGKQYLTKEEKVNASFDMRKIGTVSKSAYRDALLKRLYENDNDPKKAFAGKNSLDKQPIWL DKEQMRKVPEKVKIVTLEAIYTIRKEI SPDLKVDKVIDVGVRKILIDRLNEYGNDAKKAFSNLD KNPIWLNKEKGI S IKRVTI SGI SNAQSLHVKKDKDGKPILDENGRNIPVDFVNTGNNHHVAVYY RPVIDKRGQLVVDEAGNPKYELEEVVVSFFEAVTRANLGLPI IDKDYKTTEGWQFLFSMKQNEY FVFPNEKTGFNPKEIDLLDVENYGLISPNLFRVQKFSLKNYVFRHHLETTIKDTSSILRGITWI DFRSSKGLDTIVKVRVNHIGQIVSVGEY

SEQ ID NO: 308

MSRKNYVDDYAI SLDIGNASVGWSAFTPNYRLVRAKGHELIGVRLFDPADTAESRRMARTTRRR YSRRRWRLRLLDALFDQALSEIDPSFLARRKYSWVHPDDENNADCWYGSVLFDSNEQDKRFYEK YPTIYHLRKALMEDDSQHDIREIYLAIHHMVKYRGNFLVEGTLESSNAFKEDELLKLLGRITRY EMSEGEQNSDIEQDDENKLVAPANGQLADALCATRGSRSMRVDNALEALSAVNDLSREQRAIVK AIFAGLEGNKLDLAKIFVSKEFSSENKKILGIYFNKSDYEEKCVQIVDSGLLDDEEREFLDRMQ GQYNAIALKQLLGRSTSVSDSKCASYDAHRANWNLIKLQLRTKENEKDINENYGILVGWKIDSG QRKSVRGESAYENMRKKANVFFKKMIETSDLSETDKNRLIHDIEEDKLFPIQRDSDNGVIPHQL HQNELKQI IKKQGKYYPFLLDAFEKDGKQINKIEGLLTFRVPYFVGPLVVPEDLQKSDNSENHW MVRKKKGEITPWNFDEMVDKDASGRKFIERLVGTDSYLLGEPTLPKNSLLYQEYEVLNELNNVR LSVRTGNHWNDKRRMRLGREEKTLLCQRLFMKGQTVTKRTAENLLRKEYGRTYELSGLSDESKF TSSLSTYGKMCRIFGEKYVNEHRDLMEKIVELQTVFEDKETLLHQLRQLEGI SEADCALLVNTH YTGWGRLSRKLLTTKAGECKI SDDFAPRKHS I IEIMRAEDRNLMEI ITDKQLGFSDWIEQENLG AENGSSLMEVVDDLRVSPKVKRGI IQS IRLIDDI SKAVGKRPSRIFLELADDIQPSGRTI SRKS RLQDLYRNANLGKEFKGIADELNACSDKDLQDDRLFLYYTQLGKDMYTGEELDLDRLSSAYDID HI IPQAVTQNDS IDNRVLVARAENARKTDSFTYMPQIADRMRNFWQILLDNGLI SRVKFERLTR QNEFSEREKERFVQRSLVETRQIMKNVATLMRQRYGNSAAVIGLNAELTKEMHRYLGFSHKNRD INDYHHAQDALCVGIAGQFAANRGFFADGEVSDGAQNSYNQYLRDYLRGYREKLSAEDRKQGRA FGFIVGSMRSQDEQKRVNPRTGEVVWSEEDKDYLRKVMNYRKMLVTQKVGDDFGALYDETRYAA TDPKGIKGIPFDGAKQDTSLYGGFSSAKPAYAVLIESKGKTRLVNVTMQEYSLLGDRPSDDELR KVLAKKKSEYAKANILLRHVPKMQLIRYGGGLMVIKSAGELNNAQQLWLPYEEYCYFDDLSQGK GSLEKDDLKKLLDS ILGSVQCLYPWHRFTEEELADLHVAFDKLPEDEKKNVITGIVSALHADAK TANLS IVGMTGSWRRMNNKSGYTFSDEDEFIFQSPSGLFEKRVTVGELKRKAKKEVNSKYRTNE KRLPTLSGASQP

SEQ ID NO: 309

METQTSNQLITSHLKDYPKQDYFVGLDIGTNSVGWAVTNTSYELLKFHSHKMWGSRLFEEGESA VTRRGFRSMRRRLERRKLRLKLLEELFADAMAQVDSTFFIRLHESKYHYEDKTTGHSSKHILFI DEDYTDQDYFTEYPTIYHLRKDLMENGTDDIRKLFLAVHHILKYRGNFLYEGATFNSNAFTFED VLKQALVNITFNCFDTNSAI SS I SNILMESGKTKSDKAKAIERLVDTYTVFDEVNTPDKPQKEQ VKEDKKTLKAFANLVLGLSANLIDLFGSVEDIDDDLKKLQIVGDTYDEKRDELAKVWGDEIHI I DDCKSVYDAI ILMS IKEPGLTI SQSKVKAFDKHKEDLVILKSLLKLDRNVYNEMFKSDKKGLHN YVHYIKQGRTEETSCSREDFYKYTKKIVEGLADSKDKEYILNEIELQTLLPLQRIKDNGVIPYQ LHLEELKVILDKCGPKFPFLHTVSDGFSVTEKLIKMLEFRIPYYVGPLNTHHNIDNGGFSWAVR KQAGRVTPWNFEEKIDREKSAAAFIKNLTNKCTYLFGEDVLPKSSLLYSEFMLLNELNNVRIDG KALAQGVKQHLIDSIFKQDHKKMTKNRIELFLKDNNYITKKHKPEITGLDGEIKNDLTSYRDMV RILGNNFDVSMAEDI ITDITIFGESKKMLRQTLRNKFGSQLNDETIKKLSKLRYRDWGRLSKKL LKGIDGCDKAGNGAPKTI IELMRNDSYNLMEILGDKFSFMECIEEENAKLAQGQVVNPHDI IDE LALSPAVKRAVWQALRIVDEVAHIKKALPSRIFVEVARTNKSEKKKKDSRQKRLSDLYSAIKKD DVLQSGLQDKEFGALKSGLANYDDAALRSKKLYLYYTQMGRCAYTGNI IDLNQLNTDNYDIDHI YPRSLTKDDSFDNLVLCERTANAKKSDIYPIDNRIQTKQKPFWAFLKHQGLI SERKYERLTRIA PLTADDLSGFIARQLVETNQSVKATTTLLRRLYPDIDVVFVKAENVSDFRHNNNFIKVRSLNHH HHAKDAYLNIVVGNVYHEKFTRNFRLFFKKNGANRTYNLAKMFNYDVICTNAQDGKAWDVKTSM NTVKKMMASNDVRVTRRLLEQSGALADATIYKASVAAKAKDGAYIGMKTKYSVFADVTKYGGMT KIKNAYS I IVQYTGKKGEEIKEIVPLPIYLINRNATDIELIDYVKSVIPKAKDI S IKYRKLCIN QLVKVNGFYYYLGGKTNDKIYIDNAIELVVPHDIATYIKLLDKYDLLRKENKTLKASS ITTS IY INTSTVVSLNKVGIDVFDYFMSKLRTPLYMKMKGNKVDELSSTGRSKFIKMTLEEQS IYLLEV LNLLTNSKTTFDVKPLGITGSRSTIGVKIHNLDEFKI INES ITGLYSNEVTIV

SEQ ID NO: 310

MTKLNQPYGIGLDIGSNS IGFAVVDANSHLLRLKGETAIGARLFREGQSAADRRGSRTTRRRLS RTRWRLSFLRDFFAPHITKIDPDFFLRQKYSEI SPKDKDRFKYEKRLFNDRTDAEFYEDYPSMY HLRLHLMTHTHKADPREIFLAIHHILKSRGHFLTPGAAKDFNTDKVDLEDIFPALTEAYAQVYP DLELTFDLAKADDFKAKLLDEQATPSDTQKALVNLLLSSDGEKEIVKKRKQVLTEFAKAITGLK TKFNLALGTEVDEADASNWQFSMGQLDDKWSNIETSMTDQGTEIFEQIQELYRARLLNGIVPAG MSLSQAKVADYGQHKEDLELFKTYLKKLNDHELAKTIRGLYDRYINGDDAKPFLREDFVKALTK EVTAHPNEVSEQLLNRMGQANFMLKQRTKANGAIPIQLQQRELDQI IANQSKYYDWLAAPNPVE AHRWKMPYQLDELLNFHIPYYVGPLITPKQQAESGENVFAWMVRKDPSGNITPYNFDEKVDREA SANTFIQRMKTTDTYLIGEDVLPKQSLLYQKYEVLNELNNVRINNECLGTDQKQRLIREVFERH SSVTIKQVADNLVAHGDFARRPEIRGLADEKRFLSSLSTYHQLKEILHEAIDDPTKLLDIENI I TWSTVFEDHTIFETKLAEIEWLDPKKINELSGIRYRGWGQFSRKLLDGLKLGNGHTVIQELMLS NHNLMQILADETLKETMTELNQDKLKTDDIEDVINDAYTSPSNKKALRQVLRVVEDIKHAANGQ DPSWLFIETADGTGTAGKRTQSRQKQIQTVYANAAQELIDSAVRGELEDKIADKASFTDRLVLY FMQGGRDIYTGAPLNIDQLSHYDIDHILPQSLIKDDSLDNRVLVNATINREKNNVFASTLFAGK MKATWRKWHEAGLI SGRKLRNLMLRPDEIDKFAKGFVARQLVETRQI IKLTEQIAAAQYPNTKI IAVKAGLSHQLREELDFPKNRDVNHYHHAFDAFLAARIGTYLLKRYPKLAPFFTYGEFAKVDVK KFREFNFIGALTHAKK I IAKDTGEIVWDKERDIRELDRIYNFKRMLITHEVYFETADLFKQTI YAAKDSKERGGSKQLIPKKQGYPTQVYGGYTQESGSYNALVRVAEADTTAYQVIKI SAQNASKI ASANLKSREKGKQLLNEIVVKQLAKRRKNWKPSANSFKIVIPRFGMGTLFQNAKYGLFMVNSDT YYRNYQELWLSRENQKLLKKLFS IKYEKTQMNHDALQVYKAI IDQVEKFFKLYDINQFRAKLSD AIERFEKLPINTDGNKIGKTETLRQILIGLQANGTRSNVKNLGIKTDLGLLQVGSGIKLDKDTQ IVYQSPSGLFKRRIPLADL

SEQ ID NO: 311

MTKEYYLGLDVGTNSVGWAVTDSQYNLCKFKKKDMWGIRLFESANTAKDRRLQRGNRRRLERKK QRIDLLQEIFSPEICKIDPTFFIRLNESRLHLEDKSNDFKYPLFIEKDYSDIEYYKEFPTIFHL RKHLIESEEKQDIRLIYLALHNI IKTRGHFLIDGDLQSAKQLRPILDTFLLSLQEEQNLSVSLS ENQKDEYEEILKNRS IAKSEKVKKLKNLFEI SDELEKEEKKAQSAVIENFCKFIVGNKGDVCKF LRVSKEELEIDSFSFSEGKYEDDIVKNLEEKVPEKVYLFEQMKAMYDWNILVDILETEEYI SFA KVKQYEKHKTNLRLLRDI ILKYCTKDEYNRMFNDEKEAGSYTAYVGKLKKNNKKYWIEKKRNPE EFYKSLGKLLDKIEPLKEDLEVLTMMIEECKNHTLLPIQKNKDNGVIPHQVHEVELKKILENAK KYYSFLTETDKDGYSVVQKIES IFRFRIPYYVGPLSTRHQEKGSNVWMVRKPGREDRIYPWNME EI IDFEKSNENFITRMTNKCTYLIGEDVLPKHSLLYSKYMVLNELNNVKVRGKKLPTSLKQKVF EDLFENKSKVTGKNLLEYLQIQDKDIQIDDLSGFDKDFKTSLKSYLDFKKQIFGEEIEKES IQN MIEDI IKWITIYGNDKEMLKRVIRANYSNQLTEEQMKKITGFQYSGWGNFSKMFLKGI SGSDVS TGETFDI ITAMWETDNNLMQILSKKFTFMDNVEDFNSGKVGKIDKITYDSTVKEMFLSPENKRA VWQTIQVAEEIKKVMGCEPKKIFIEMARGGEKVKKRTKSRKAQLLELYAACEEDCRELIKEIED RDERDFNSMKLFLYYTQFGKCMYSGDDIDINELIRGNSKWDRDHIYPQSKIKDDS IDNLVLVNK TYNAKKSNELLSEDIQKKMHSFWLSLLNKKLITKSKYDRLTRKGDFTDEELSGFIARQLVETRQ STKAIADIFKQIYSSEVVYVKSSLVSDFRKKPLNYLKSRRVNDYHHAKDAYLNIVVGNVYNKKF TSNPIQWMKKNRDTNYSLNKVFEHDVVINGEVIWEKCTYHEDTNTYDGGTLDRIRKIVERDNIL YTEYAYCEKGELFNATIQNKNGNSTVSLKKGLDVKKYGGYFSANTSYFSLIEFEDKKGDRARHI IGVPIYIANMLEHSPSAFLEYCEQKGYQNVRILVEKIKKNSLLI INGYPLRIRGENEVDTSFKR AIQLKLDQKNYELVRNIEKFLEKYVEKKGNYPIDENRDHITHEKMNQLYEVLLSKMKKFNKKGM ADPSDRIEKSKPKFIKLEDLIDKINVINKMLNLLRCDNDTKADLSLIELPKNAGSFVVKKNTIG KSKI ILVNQSVTGLYENRREL

SEQ ID NO: 312

MARDYSVGLDIGTSSVGWAAIDNKYHLIRAKSKNLIGVRLFDSAVTAEKRRGYRTTRRRLSRRH WRLRLLNDIFAGPLTDFGDENFLARLKYSWVHPQDQSNQAHFAAGLLFDSKEQDKDFYRKYPTI YHLRLALMNDDQKHDLREVYLAIHHLVKYRGHFLIEGDVKADSAFDVHTFADAIQRYAESNNSD ENLLGKIDEKKLSAALTDKHGSKSQRAETAETAFDILDLQSKKQIQAILKSVVGNQANLMAIFG LDSSAI SKDEQKNYKFSFDDADIDEKIADSEALLSDTEFEFLCDLKAAFDGLTLKMLLGDDKTV SAAMVRRFNEHQKDWEYIKSHIRNAKNAGNGLYEKSKKFDGINAAYLALQSDNEDDRKKAKKIF QDEI SSADIPDDVKADFLKKIDDDQFLPIQRTKNNGTIPHQLHRNELEQI IEKQGIYYPFLKDT YQENSHELNKITALINFRVPYYVGPLVEEEQKIADDGKNIPDPTNHWMVRKSNDTITPWNLSQV VDLDKSGRRFIERLTGTDTYLIGEPTLPKNSLLYQKFDVLQELNNIRVSGRRLDIRAKQDAFEH LFKVQKTVSATNLKDFLVQAGYI SEDTQIEGLADVNGKNFN ALTTYNYLVSVLGREFVENPSN EELLEEITELQTVFEDKKVLRRQLDQLDGLSDHNREKLSRKHYTGWGRI SKKLLTTKIVQNADK IDNQTFDVPRMNQS I IDTLYNTKMNLMEI IN AEDDFGVRAWIDKQNTTDGDEQDVYSLIDELA GPKEIKRGIVQSFRILDDITKAVGYAPKRVYLEFARKTQESHLTNSRKNQLSTLLKNAGLSELV TQVSQYDAAALQNDRLYLYFLQQGKDMYSGEKLNLDNLSNYDIDHI IPQAYTKDNSLDNRVLVS NITNRRKSDSSNYLPALIDKMRPFWSVLSKQGLLSKHKFANLTRTRDFDDMEKERFIARSLVET RQIIKNVASLIDSHFGGETKAVAIRSSLTADMRRYVDIPKNRDINDYHHAFDALLFSTVGQYTE NSGLMKKGQLSDSAGNQYNRYIKEWIHAARLNAQSQRVNPFGFVVGSMRNAAPGKLNPETGEIT PEENADWS IADLDYLHKVMNFRKITVTRRLKDQKGQLYDESRYPSVLHDAKSKAS INFDKHKPV DLYGGFSSAKPAYAALIKFKNKFRLVNVLRQWTYSDKNSEDYILEQIRGKYPKAEMVLSHIPYG QLVKKDGALVTI SSATELHNFEQLWLPLADYKLINTLLKTKEDNLVDILHNRLDLPEMTIESAF YKAFDS ILSFAFNRYALHQNALVKLQAHRDDFNALNYEDKQQTLERILDALHASPASSDLKKIN LSSGFGRLFSPSHFTLADTDEFIFQSVTGLFSTQKTVAQLYQETK

SEQ ID NO: 313

MVYDVGLDIGTGSVGWVALDENGKLARAKGKNLVGVRLFDTAQTAADRRGFRTTRRRLSRRKWR LRLLDELFSAEINEIDSSFFQRLKYSYVHPKDEENKAHYYGGYLFPTEEETKKFHRSYPTIYHL RQELMAQPNKRFDIREIYLAIHHLVKYRGHFLSSQEKITIGSTYNPEDLANAIEVYADEKGLSW ELNNPEQLTEI I SGEAGYGLNKSMKADEALKLFEFDNNQDKVAIKTLLAGLTGNQIDFAKLFGK DISDKDEAKLWKLKLDDEALEEKSQTILSQLTDEEIELFHAVVQAYDGFVLIGLLNGADSVSAA MVQLYDQHREDRKLLKSLAQKAGLKHKRFSEIYEQLALATDEATIKNGI STARELVEESNLSKE VKEDTLRRLDENEFLPKQRTKANSVIPHQLHLAELQKILQNQGQYYPFLLDTFEKEDGQDNKIE ELLRFRIPYYVGPLVTKKDVEHAGGDADNHWVERNEGFEKSRVTPWNFDKVFNRDKAARDFIER LTGNDTYLIGEKTLPQNSLRYQLFTVLNELNNVRVNGKKFDSKTKADLINDLFKARKTVSLSAL KDYLKAQGKGDVTITGLADESKFNSSLSSYNDLKKTFDAEYLENEDNQETLEKI IEIQTVFEDS KIASRELSKLPLDDDQVKKLSQTHYTGWGRLSEKLLDSKI IDERGQKVS ILDKLKSTSQNFMS I INNDKYGVQAWITEQNTGSSKLTFDEKVNELTTSPANKRGIKQSFAVLNDIKKAMKEEPRRVYL EFAREDQTSVRSVPRYNQLKEKYQSKSLSEEAKVLKKTLDGNKNKMSDDRYFLYFQQQGKDMYT GRPINFERLSQDYDIDHI IPQAFTKDDSLDNRVLVSRPENARKSDSFAYTDEVQKQDGSLWTSL LKSGFINRKKYERLTKAGKYLDGQKTGFIARQLVETRQI IKNVASLIEGEYENSKAVAIRSEIT ADMRLLVGIKKHREINSFHHAFDALLITAAGQYMQNRYPDRDSTNVYNEFDRYTNDYLKNLRQL SSRDEVRRLKSFGFVVGTMRKGNEDWSEENTSYLRKVMMFKNILTTKKTEKDRGPLNKETIFSP KSGKKLIPLNSKRSDTALYGGYSNVYSAYMTLVRANGKNLLIKIPI S IANQIEVGNLKINDYIV NNPAIKKFEKILI SKLPLGQLVNEDGNLIYLASNEYRHNAKQLWLSTTDADKIAS I SENSSDEE LLEAYDILTSENVKNRFPFFKKDIDKLSQVRDEFLDSDKRIAVIQTILRGLQIDAAYQAPVKI I SKKVSDWHKLQQSGGIKLSDNSEMIYQSATGIFETRVKI SDLL

SEQ ID NO: 314

IVDYCIGLDLGTGSVGWAVVDMNHRLMKRNGKHLWGSRLFSNAETAANRRASRS IRRRYNKRRE RIRLLRAILQDMVLEKDPTFFIRLEHTSFLDEEDKAKYLGTDYKDNYNLFIDEDFNDYTYYHKY PTIYHLRKALCESTEKADPRLIYLALHHIVKYRGNFLYEGQKFNMDASNIEDKLSDIFTQFTSF NNIPYEDDEKKNLEILEILKKPLSKKAKVDEVMTLIAPEKDYKSAFKELVTGIAGNKMNVTKMI LCEPIKQGDSEIKLKFSDSNYDDQFSEVEKDLGEYVEFVDALHNVYSWVELQTIMGATHTDNAS I SEAMVSRYNKHHDDLKLLKDCIKNNVPNKYFDMFRNDSEKSKGYYNYINRPSKAPVDEFYKYV KKCIEKVDTPEAKQILNDIELENFLLKQNSRTNGSVPYQMQLDEMIKI IDNQAEYYPILKEKRE QLLS ILTFRIPYYFGPLNETSEHAWIKRLEGKENQRILPWNYQDIVDVDATAEGFIKRMRSYCT YFPDEEVLPKNSLIVSKYEVYNELNKIRVDDKLLEVDVKNDIYNELFMKNKTVTEKKLKNWLVN NQCCSKDAEIKGFQKENQFSTSLTPWIDFTNIFGKIDQSNFDLIENI IYDLTVFEDKKIMKRRL KKKYALPDDKVKQILKLKYKDWSRLSKKLLDGIVADNRFGSSVTVLDVLEMSRLNLMEI INDKD LGYAQMIEEATSCPEDGKFTYEEVERLAGSPALKRGIWQSLQIVEEITKVMKCRPKYIYIEFER SEEAKERTESKIKKLENVYKDLDEQTKKEYKSVLEELKGFDNTKKI SSDSLFLYFTQLGKCMYS GKKLDIDSLDKYQIDHIVPQSLVKDDSFDNRVLVVPSENQRKLDDLVVPFDIRDKMYRFWKLLF DHELI SPKKFYSLIKTEYTERDEERFINRQLVETRQITKNVTQI IEDHYSTTKVAAIRANLSHE FRVKNHIYKNRDINDYHHAHDAYIVALIGGFMRDRYPNMHDSKAVYSEYMKMFRKNKNDQKRWK DGFVINSMNYPYEVDGKLIWNPDLINEIKKCFYYKDCYCTTKLDQKSGQLFNLTVLSNDAHADK GVTKAVVPVNKNRSDVHKYGGFSGLQYTIVAIEGQKKKGKKTELVKKI SGVPLHLKAAS INEKI NYIEEKEGLSDVRI IKDNIPVNQMIEMDGGEYLLTSPTEYVNARQLVLNEKQCALIADIYNAIY KQDYDNLDDILMIQLYIELTNKMKVLYPAYRGIAEKFESMNENYVVI SKEEKANI IKQMLIVMH RGPQNGNIVYDDFKI SDRIGRLKTKNHNLNNIVFI SQSPTGIYTKKYKL

SEQ ID NO: 315

MKSEKKYYIGLDVGTNSVGWAVTDEFYNILRAKGKDLWGVRLFEKADTAANTRIFRSGRRRNDR KGMRLQILREIFEDEIKKVDKDFYDRLDESKFWAEDKKVSGKYSLFNDKNFSDKQYFEKFPTIF HLRKYLMEEHGKVDIRYYFLAINQMMKRRGHFLIDGQI SHVTDDKPLKEQLILLINDLLKIELE EELMDS IFEILADVNEKRTDKKNNLKELIKGQDFNKQEGNILNS IFES IVTGKAKIKNI I SDED ILEKIKEDNKEDFVLTGDSYEENLQYFEEVLQENITLFNTLKSTYDFLILQS ILKGKSTLSDAQ VERYDEHKKDLEILKKVIKKYDEDGKLFKQVFKEDNGNGYVSYIGYYLNKNKKITAKKKI SNIE FTKYVKGILEKQCDCEDEDVKYLLGKIEQENFLLKQI SS INSVIPHQIHLFELDKILENLAKNY PSFNNKKEEFTKIEKIRKTFTFRIPYYVGPLNDYHKNNGGNAWIFRNKGEKIRPWNFEKIVDLH KSEEEFIKRMLNQCTYLPEETVLPKSS ILYSEYMVLNELNNLRINGKPLDTDVKLKLIEELFKK KTKVTLKS IRDYMVRNNFADKEDFDNSEKNLEIASNMKSYIDFNNILEDKFDVEMVEDLIEKIT IHTGNKKLLKKYIEETYPDLSSSQIQKI INLKYKDWGRLSRKLLDGIKGTKKETEKTDTVINFL RNSSDNLMQI IGSQNYSFNEYIDKLRKKYIPQEI SYEVVENLYVSPSVKKMIWQVIRVTEEITK VMGYDPDKIFIEMAKSEEEKKTTI SRKNKLLDLYKAIKKDERDSQYEKLLTGLNKLDDSDLRSR KLYLYYTQMGRDMYTGEKIDLDKLFDSTHYDKDHI IPQSMKKDDS I INNLVLVNKNANQTTKGN IYPVPSS IRNNPKIYNYWKYLMEKEFI SKEKYNRLIRNTPLTNEELGGFINRQLVETRQSTKAI KELFEKFYQKSKI IPVKASLASDLRKDMNTLKSREVNDLHHAHDAFLNIVAGDVWNREFTSNPI NYVKENREGDKVKYSLSKDFTRPRKSKGKVIWTPEKGRKLIVDTLNKPSVLI SNESHVKKGELF NATIAGKKDYKKGKIYLPLKKDDRLQDVSKYGGYKAINGAFFFLVEHTKSKKRIRS IELFPLHL LSKFYEDKNTVLDYAINVLQLQDPKI I IDKINYRTEI I IDNFSYLISTKSNDGSITVKPNEQMY WRVDEI SNLKKIENKYKKDAILTEEDRKIMESYIDKIYQQFKAGKYKNRRTTDTI IEKYEI IDL DTLDNKQLYQLLVAFI SLSYKTSNNAVDFTVIGLGTECGKPRITNLPDNTYLVYKS ITGIYEKR IRIK

SEQ ID NO: 316

MKLRGIEDDYS IGLDMGTSSVGWAVTDERGTLAHFKRKPTWGSRLFREAQTAAVARMPRGQRRR YVRRRWRLDLLQKLFEQQMEQADPDFFIRLRQSRLLRDDRAEEHADYRWPLFNDCKFTERDYYQ RFPTIYHVRSWLMETDEQADIRLIYLALHNIVKHRGNFLREGQSLSAKSARPDEALNHLRETLR VWSSERGFECS IADNGS ILAMLTHPDLSPSDRRKKIAPLFDVKSDDAAADKKLGIALAGAVIGL KTEFKNIFGDFPCEDSS IYLSNDEAVDAVRSACPDDCAELFDRLCEVYSAYVLQGLLSYAPGQT I SANMVEKYRRYGEDLALLKKLVKIYAPDQYRMFFSGATYPGTGIYDAAQARGYTKYNLGPKKS EYKPSESMQYDDFRKAVEKLFAKTDARADERYRMMMDRFDKQQFLRRLKTSDNGS IYHQLHLEE LKAIVENQGRFYPFLKRDADKLVSLVSFRIPYYVGPLSTRNARTDQHGENRFAWSERKPGMQDE PIFPWNWES I IDRSKSAEKFILRMTGMCTYLQQEPVLPKSSLLYEEFCVLNELNGAHWS IDGDD EHRFDAADREGI IEELFRRKRTVSYGDVAGWMERERNQIGAHVCGGQGEKGFESKLGSYIFFCK DVFKVERLEQSDYPMIERI ILWNTLFEDRKILSQRLKEEYGSRLSAEQIKTICKKRFTGWGRLS EKFLTGITVQVDEDSVS IMDVLREGCPVSGKRGRAMVMMEILRDEELGFQKKVDDFNRAFFAEN AQALGVNELPGSPAVRRSLNQS IRIVDEIAS IAGKAPANIFIEVTRDEDPKKKGRRTKRRYNDL KDALEAFKKEDPELWRELCETAPNDMDERLSLYFMQRGKCLYSGRAIDIHQLSNAGIYEVDHI I PRTYVKDDSLENKALVYREENQRKTDMLLIDPEIRRRMSGYWRMLHEAKLIGDKKFRNLLRSRI DDKALKGFIARQLVETGQMVKLVRSLLEARYPETNI I SVKAS I SHDLRTAAELVKCREANDFHH AHDAFLACRVGLFIQKRHPCVYENPIGLSQVVRNYVRQQADIFKRCRTIPGSSGFIVNSFMTSG FDKETGEIFKDDWDAEAEVEGIRRSLNFRQCFI SRMPFEDHGVFWDATIYSPRAKKTAALPLKQ GLNPSRYGSFSREQFAYFFIYKARNPRKEQTLFEFAQVPVRLSAQIRQDENALERYARELAKDQ GLEFIRIERSKILKNQLIEIDGDRLCITGKEEVRNACELAFAQDEMRVIRMLVSEKPVSRECVI SLFNRILLHGDQASRRLSKQLKLALLSEAFSEASDNVQRNVVLGLIAIFNGSTNMVNLSDIGGS KFAGNVRIKYKKELASPKVNVHLIDQSVTGMFERRTKIGL

SEQ ID NO: 317

MENKQYYIGLDVGTNSVGWAVTDTSYNLLRAKGKDMWGARLFEKANTAAERRTKRTSRRRSERE KARKAMLKELFADEINRVDPSFFIRLEESKFFLDDRSENNRQRYTLFNDATFTDKDYYEKYKTI FHLRSALINSDEKFDVRLVFLAILNLFSHRGHFLNASLKGDGDIQGMDVFYNDLVESCEYFEIE LPRITNIDNFEKILSQKGKSRTKILEELSEELS I SKKDKSKYNLIKLI SGLEASVVELYNIEDI QDENKKIKIGFRESDYEESSLKVKEI IGDEYFDLVERAKSVHDMGLLSNI IGNSKYLCEARVEA YENHHKDLLKIKELLKKYDKKAYNDMFRKMTDKNYSAYVGSVNSNIAKERRSVDKRKIEDLYKY IEDTALKNIPDDNKDKIEILEKIKLGEFLKKQLTASNGVIPNQLQSRELRAILKKAENYLPFLK EKGEKNLTVSEMI IQLFEFQIPYYVGPLDKNPKKDNKANSWAKIKQGGRILPWNFEDKVDVKGS RKEFIEKMVRKCTYI SDEHTLPKQSLLYEKFMVLNEINNIKIDGEKI SVEAKQKIYNDLFVKGK KVSQKDIKKELI SLNIMDKDSVLSGTDTVCNAYLSS IGKFTGVFKEEINKQS IVDMIEDI IFLK TVYGDEKRFVKEEIVEKYGDEIDKDKIKRILGFKFSNWGNLSKSFLELEGADVGTGEVRS HQS LWETNFNLMELLSSRFTYMDELEKRVKKLEKPLSEWTIEDLDDMYLSSPVKRMIWQSMKIVDEI QTVIGYAPKRIFVEMTRSEGEKVRTKSRKDRLKELYNGIKEDSKQWVKELDSKDESYFRSKKMY LYYLQKGRCMYSGEVIELDKLMDDNLYDIDHIYPRSFVKDDSLDNLVLVKKEINNRKQNDPITP QIQASCQGFWKILHDQGFMSNEKYSRLTRKTQEFSDEEKLSFINRQIVETGQATKCMAQILQKS MGEDVDVVFSKARLVSEFRHKFELFKSRLINDFHHANDAYLNIVVGNSYFVKFTRNPANFIKDA RKNPDNPVYKYHMDRFFERDVKSKSEVAWIGQSEGNSGTIVIVKKTMAKNSPLITKKVEEGHGS ITKETIVGVKEIKFGRNKVEKADKTPKKPNLQAYRPIKTSDERLC ILRYGGRTS I S I SGYCLV EYVKKRKTIRSLEAIPVYLGRKDSLSEEKLLNYFRYNLNDGGKDSVSDIRLCLPFI STNSLVKI DGYLYYLGGKNDDRIQLYNAYQLKMKKEEVEYIRKIEKAVSMSKFDEIDREKNPVLTEEKNIEL YNKIQDKFENTVFSKRMSLVKYNKKDLSFGDFLKNKKSKFEEIDLEKQCKVLY I IFNLSNLKE VDLSDIGGSKSTGKCRCKKNITNYKEFKLIQQS ITGLYSCEKDLMTI

SEQ ID NO: 318

MKNLKEYYIGLDIGTASVGWAVTDESYNIPKFNGKKMWGVRLFDDAKTAEERRTQRGSRRRLNR RKERINLLQDLFATEI SKVDPNFFLRLDNSDLYREDKDEKLKSKYTLFNDKDFKDRDYHKKYPT IHHLIMDLIEDEGKKDIRLLYLACHYLLKNRGHFIFEGQKFDTKNSFDKS INDLKIHLRDEY I DLEFNNEDLIEI ITDTTLNKTNKKKELKNIVGDTKFLKAI SAIMIGSSQKLVDLFEDGEFEETT VKSVDFSTTAFDDKYSEYEEALGDTI SLLNILKS IYDSS ILENLLKDADKSKDGNKYI SKAFVK KFNKHGKDLKTLKRI IKKYLPSEYA IFRNKS INDNYVAYTKS ITSNKRTKASKFTKQEDFYK FIKKHLDTIKETKLNSSENEDLKLIDEMLTDIEFKTFIPKLKSSDNGVIPYQLKLMELKKILDN QSKYYDFLNESDEYGTVKDKVES IMEFRIPYYVGPLNPDSKYAWIKRENTKITPWNFKDIVDLD SSREEFIDRLIGRCTYLKEEKVLPKASLIYNEFMVLNELNNLKLNEFLITEEMKKAIFEELFKT KKKVTLKAVSNLLKKEFNLTGDILLSGTDGDFKQGLNSYIDFKNI IGDKVDRDDYRIKIEEI IK LIVLYEDDKTYLKKKIKSAYKNDFTDDEIKKIAALNYKDWGRLSKRFLTGIEGVDKTTGEKGS I IYFMREYNLNLMELMSGHYTFTEEVEKLNPVENRELCYEMVDELYLSPSVKRMLWQSLRVVDEI KRIIGKDPKKIFIEMARAKEAKNSRKESRKNKLLEFYKFGKKAFINEIGEERYNYLLNEINSEE ESKFRWDNLYLYYTQLGRCMYSLEPIDLADLKSN IYDQDHIYPKSKIYDDSLENRVLVKKNLN HEKGNQYPIPEKVLNKNAYGFWKILFDKGLIGQKKYTRLTRRTPFEERELAEFIERQIVETRQA TKETANLLK ICQDSEIVYSKAENASRFRQEFDI IKCRTVNDLHHMHDAYL IVVGNVYNTKFT KNPLNFIKDKDNVRSYNLENMFKYDVVRGSYTAWIADDSEGNVKAATIKKVKRELEGKNYRFTR MSYIGTGGLYDQNLMRKGKGQIPQKENTNKSNIEKYGGYNKASSAYFALIESDGKAGRERTLET IPIMVYNQEKYGNTEAVDKYLKDNLELQDPKILKDKIKINSLIKLDGFLYNIKGKTGDSLSIAG SVQLIVNKEEQKLIKKMDKFLVKKKDNKDIKVTSFD IKEEELIKLYKTLSDKLNNGIYSNKRN NQAKNI SEALDKFKEI S IEEKIDVLNQI ILLFQSYNNGCNLKS IGLSAKTGVVFIPKKLNYKEC KLINQSITGLFENEVDLLNL

SEQ ID NO: 319

MGKMYYLGLDIGTNSVGYAVTDPSYHLLKFKGEPMWGAHVFAAGNQSAERRSFRTSRRRLDRRQ QRVKLVQEIFAPVI SPIDPRFFIRLHESALWRDDVAETDKHIFFNDPTYTDKEYYSDYPTIHHL IVDLMESSEKHDPRLVYLAVAWLVAHRGHFLNEVDKDNIGDVLSFDAFYPEFLAFLSDNGVSPW VCESKALQATLLSRNSVNDKYKALKSLIFGSQKPEDNFDANI SEDGLIQLLAGKKVKVNKLFPQ ESNDASFTLNDKEDAIEEILGTLTPDECEWIAHIRRLFDWAIMKHALKDGRTI SESKVKLYEQH HHDLTQLKYFVKTYLAKEYDDIFRNVDSETTKNYVAYSYHVKEVKGTLPKNKATQEEFCKYVLG KVKNIECSEADKVDFDEMIQRLTDNSFMPKQVSGENRVIPYQLYYYELKTILNKAASYLPFLTQ CGKDAI SNQDKLLS IMTFRIPYFVGPLRKDNSEHAWLERKAGKIYPWNFNDKVDLDKSEEAFIR RMTNTCTYYPGEDVLPLDSLIYEKFMILNEINNIRIDGYPI SVDVKQQVFGLFEKKRRVTVKDI QNLLLSLGALDKHGKLTGIDTTIHSNYNTYHHFKSLMERGVLTRDDVERIVERMTYSDDTKRVR LWLNNNYGTLTADDVKHI SRLRKHDFGRLSKMFLTGLKGVHKETGERAS ILDFMWNTNDNLMQL LSECYTFSDEITKLQEAYYAKAQLSLNDFLDSMYI SNAVKRPIYRTLAVVNDIRKACGTAPKRI FIEMARDGESKKKRSVTRREQIKNLYRS IRKDFQQEVDFLEKILENKSDGQLQSDALYLYFAQL GRDMYTGDPIKLEHIKDQSFYNIDHIYPQSMVKDDSLDNKVLVQSEINGEKSSRYPLDAAIRNK MKPLWDAYYNHGLI SLKKYQRLTRSTPFTDDEKWDFINRQLVETRQSTKALAILLKRKFPDTEI VYSKAGLSSDFRHEFGLVKSRNINDLHHAKDAFLAIVTGNVYHERFNRRWFMVNQPYSVKTKTL FTHS IKNGNFVAWNGEEDLGRIVKMLKQNKNTIHFTRFSFDRKEGLFDIQPLKASTGLVPRKAG LDVVKYGGYDKSTAAYYLLVRFTLEDKKTQHKLMMIPVEGLYKARIDHDKEFLTDYAQTTI SEI LQKDKQKVI IMFPMGTRHIKLNSMI S IDGFYLS IGGKSSKGKSVLCHAMVPLIVPHKIECYIK AMESFARKFKENNKLRIVEKFDKITVEDNLNLYELFLQKLQHNPYNKFFSTQFDVLTNGRSTFT KLSPEEQVQTLLNILS IFKTCRSSGCDLKS INGSAQAARIMI SADLTGLSKKYSDIRLVEQSAS GLFVSKSQNLLEYL

SEQ ID NO: 320

MTKKEQPYNIGLDIGTSSVGWAVTNDNYDLLNIKKKNLWGVRLFEEAQTAKETRLNRSTRRRYR RRKNRINWLNEIFSEELAKTDPSFLIRLQNSWVSKKDPDRKRDKYNLFIDGPYTDKEYYREFPT IFHLRKELILNKDKADIRLIYLALH ILKYRGNFTYEHQKF I SNLNNNLSKELIELNQQLIKY DI SFPDDCDWNHI SDILIGRGNATQKSSNILKDFTLDKETKKLLKEVINLILGNVAHLNTIFKT SLTKDEEKLNFSGKDIESKLDDLDS ILDDDQFTVLDAANRIYSTITLNEILNGESYFSMAKVNQ YENHAIDLCKLRDMWHTTKNEEAVEQSRQAYDDYINKPKYGTKELYTSLKKFLKVALPTNLAKE AEEKI SKGTYLVKPRNSENGVVPYQLNKIEMEKI IDNQSQYYPFLKENKEKLLS ILSFRIPYYV GPLQSAEKNPFAWMERKSNGHARPWNFDEIVDREKSSNKFIRRMTVTDSYLVGEPVLPKNSLIY QRYEVLNELN IRITENLKTNPIGSRLTVETKQRIYNELFKKYKKVTVKKLTKWLIAQGYYKNP ILIGLSQKDEFNSTLTTYLDMKKIFGSSFMEDNKNYDQIEELIEWLTIFEDKQILNEKLHSSKY SYTPDQIKKI SNMRYKGWGRLSKKILMDITTETNTPQLLQLSNYS ILDLMWATNNNFI S IMSND KYDFKNYIENHNLNKNEDQNI SDLVNDIHVSPALKRGITQS IKIVQEIVKFMGHAPKHIFIEVT RETKKSEITTSREKRIKRLQSKLLNKANDFKPQLREYLVPNKKIQEELKKHKNDLSSERIMLYF LQNGKSLYSEESLNINKLSDYQVDHILPRTYIPDDSLENKALVLAKENQRKADDLLLNSNVIDR NLERWTYMLNNNMIGLKKFKNLTRRVITDKDKLGFIHRQLVQTSQMVKGVANILDNMYKNQGTT CIQARANLSTAFRKALSGQDDTYHFKHPELVKNRNVNDFHHAQDAYLASFLGTYRLRRFPTNEM LLMNGEYNKFYGQVKELYSKKKKLPDSRKNGFI I SPLVNGTTQYDRNTGEI IWNVGFRDKILKI FNYHQCNVTRKTEIKTGQFYDQTIYSPKNPKYKKLIAQKKDMDPNIYGGFSGDNKSSITIVKID NNKIKPVAIPIRLINDLKDKKTLQNWLEENVKHKKS IQI IKNNVPIGQI IYSKKVGLLSLNSDR EVANRQQLILPPEHSALLRLLQIPDEDLDQILAFYDKNILVEILQELITKMKKFYPFYKGEREF LIANIENFNQATTSEKVNSLEELITLLHANSTSAHLIFNNIEKKAFGRKTHGLTLNNTDFIYQS VTGLYETRIHIE

SEQ ID NO: 321

MTKFNKNYS IGLDIGVSSVGYAVVTEDYRVPAFKFKVLGNTEKEKIKKNLIGSTTFVSAQPAKG TRVFRVNRRRIDRRNHRITYLRDIFQKEIEKVDKNFYRRLDESFRVLGDKSEDLQIKQPFFGDK ELETAYHKKYPTIYHLRKHLADADKNSPVADIREVYMAI SHILKYRGHFLTLDKINPNNINMQN SWIDFIESCQEVFDLEI SDESKNIADIFKSSENRQEKVKKILPYFQQELLKKDKS IFKQLLQLL FGLKTKFKDCFELEEEPDLNFSKENYDENLENFLGSLEEDFSDVFAKLKVLRDTILLSGMLTYT GATHARFSATMVERYEEHRKDLQRFKFFIKQNLSEQDYLDIFGRKTQNGFDVDKETKGYVGYIT NKMVLTNPQKQKTIQQNFYDYI SGKITGIEGAEYFLNKI SDGTFLRKLRTSDNGAIPNQIHAYE LEKI IERQGKDYPFLLENKDKLLS ILTFKIPYYVGPLAKGSNSRFAWIKRATSSDILDDNDEDT RNGKIRPWNYQKLINMDETRDAFITNLIGNDI ILLNEKVLPKRSLIYEEVMLQNELTRVKYKDK YGKAHFFDSELRQNI INGLFKNNSKRVNAKSLIKYLSDNHKDLNAIEIVSGVEKGKSFNSTLKT YNDLKTIFSEELLDSEIYQKELEEI IKVITVFDDKKSIKNYLTKFFGHLEILDEEKINQLSKLR YSGWGRYSAKLLLDIRDEDTGFNLLQFLRNDEENRNLTKLI SDNTLSFEPKIKDIQSKSTIEDD IFDEIKKLAGSPAIKRGILNS IKIVDELVQI IGYPPHNIVIEMARENMTTEEGQKKAKTRKTKL ESALKNIENSLLENGKVPHSDEQLQSEKLYLYYLQNGKDMYTLDKTGSPAPLYLDQLDQYEVDH I IPYSFLPIDS IDNKVLTHRENNQQKLNNIPDKETVANMKPFWEKLYNAKLI SQTKYQRLTTSE RTPDGVLTESMKAGFIERQLVETRQI IKHVARILDNRFSDTKI ITLKSQLITNFRNTFHIAKIR ELNDYHHAHDAYLAVVVGQTLLKVYPKLAPELIYGHHAHFNRHEENKATLRKHLYS IMRFFNN PDSKVSKDIWDCNRDLPI IKDVIYNSQINFVKRTMIKKGAFYNQNPVGKFNKQLAANNRYPLKT KALCLDTS IYGGYGPMNSALS I I I IAERFNEKKGKIETVKEFHDIFI IDYEKFNNNPFQFLNDT SENGFLKKNNINRVLGFYRIPKYSLMQKIDGTRMLFESKSNLHKATQFKLTKTQNELFFHMKRL LTKSNLMDLKSKSAIKESQNFILKHKEEFD I SNQLSAFSQKMLGNTTSLKNLIKGYNERKIKE IDIRDETIKYFYDNFIKMFSFVKSGAPKDINDFFDNKCTVARMRPKPDKKLLNATLIHQS ITGL YETRIDLSKLGED

SEQ ID NO: 322

MKQEYFLGLDMGTGSLGWAVTDSTYQVMRKHGKALWGTRLFESASTAEERRMFRTARRRLDRRN WRIQVLQEIFSEEI SKVDPGFFLRMKESKYYPEDKRDAEGNCPELPYALFVDDNYTDKNYHKDY PTIYHLRKMLMETTEIPDIRLVYLVLHHMMKHRGHFLLSGDI SQIKEFKSTFEQLIQNIQDEEL EWHI SLDDAAIQFVEHVLKDRNLTRSTKKSRLIKQLNAKSACEKAILNLLSGGTVKLSDIFNNK ELDESERPKVSFADSGYDDYIGIVEAELAEQYYI IASAKAVYDWSVLVEILGNSVS I SEAKIKV YQKHQADLKTLKKIVRQYMTKEDYKRVFVDTEEKLNNYSAYIGMTKKNGKKVDLKSKQCTQADF YDFLKKNVIKVIDHKEITQEIESEIEKENFLPKQVTKDNGVIPYQVHDYELKKILDNLGTRMPF IKENAEKIQQLFEFRIPYYVGPLNRVDDGKDGKFTWSVRKSDARIYPWNFTEVIDVEASAEKFI RRMTNKCTYLVGEDVLPKDSLVYSKFMVLNELNNLRLNGEKI SVELKQRIYEELFCKYRKVTRK KLERYLVIEGIAKKGVEITGIDGDFKASLTAYHDFKERLTDVQLSQRAKEAIVLNVVLFGDDKK LLKQRLSKMYPNLTTGQLKGICSLSYQGWGRLSKTFLEEITVPAPGTGEVWNIMTALWQTNDNL MQLLSRNYGFTNEVEEFNTLKKETDLSYKTVDELYVSPAVKRQIWQTLKVVKEIQKVMGNAPKR VFVEMAREKQEGKRSDSRKKQLVELYRACKNEERDWITELNAQSDQQLRSDKLFLYYIQKGRCM YSGETIQLDELWDNTKYDIDHIYPQSKTMDDSLNNRVLVKKNYNAIKSDTYPLSLDIQKKMMSF WKMLQQQGFITKEKYVRLVRSDELSADELAGFIERQIVETRQSTKAVATILKEALPDTEIVYVK AGNVSNFRQTYELLKVREMNDLHHAKDAYLNIVVGNAYFVKFTKNAAWFIRNNPGRSYNLKRMF EFDIERSGEIAWKAGNKGS IVTVKKVMQKN ILVTRKAYEVKGGLFDQQIMKKGKGQVPIKGND ERLADIEKYGGYNKAAGTYFMLVKSLDKKGKEIRTIEFVPLYLKNQIEINHESAIQYLAQERGL NSPEILLSKIKIDTLFKVDGFKMWLSGRTGNQLIFKGANQLILSHQEAAILKGVVKYVNRKNEN KDAKLSERDGMTEEKLLQLYDTFLDKLSNTVYS IRLSAQIKTLTEKRAKFIGLSNEDQCIVLNE ILHMFQCQSGSANLKLIGGPGSAGILVMNN ITACKQI SVINQSPTGIYEKEIDLIKL

SEQ ID NO: 323

MKKPYS IGLDIGTNSVGWAVVTDDYKVPAKKMKVLGNTDKSHIEKNLLGALLFDSGNTAEDRRL KRTARRRYTRRRNRILYLQEIFSEEMGKVDDSFFHRLEDSFLVTEDKRGERHPIFGNLEEEVKY HENFPTIYHLRQYLADNPEKVDLRLVYLALAHI IKFRGHFLIEGKFDTRNNDVQRLFQEFLAVY DNTFENSSLQEQNVQVEEILTDKI SKSAKKDRVLKLFPNEKSNGRFAEFLKLIVGNQADFKKHF ELEEKAPLQFSKDTYEEELEVLLAQIGDNYAELFLSAKKLYDS ILLSGILTVTDVGTKAPLSAS MIQRYNEHQMDLAQLKQFIRQKLSDKYNEVFSDVSKDGYAGYIDGKTNQEAFYKYLKGLLNKIE GSGYFLDKIEREDFLRKQRTFDNGS IPHQIHLQEMRAI IRRQAEFYPFLADNQDRIEKLLTFRI PYYVGPLARGKSDFAWLSRKSADKITPWNFDEIVDKESSAEAFINRMTNYDLYLPNQKVLPKHS LLYEKFTVYNELTKVKYKTEQGKTAFFDANMKQEIFDGVFKVYRKVTKDKLMDFLEKEFDEFRI VDLTGLDKENKVFNASYGTYHDLCKILDKDFLDNSKNEKILEDIVLTLTLFEDREMIRKRLENY SDLLTKEQVKKLERRHYTGWGRLSAELIHGIRNKESRKTILDYLIDDGNSNRNFMQLINDDALS FKEEIAKAQVIGETDNLNQVVSDIAGSPAIKKGILQSLKIVDELVKIMGHQPENIVVEMARENQ FTNQGRRNSQQRLKGLTDS IKEFGSQILKEHPVENSQLQNDRLFLYYLQNGRDMYTGEELDIDY LSQYDIDHI IPQAFIKDNS IDNRVLTSSKENRGKSDDVPSKDVVRKMKSYWSKLLSAKLITQRK FDNLTKAERGGLTDDDKAGFIKRQLVETRQITKHVARILDERFNTETDENNKKIRQVKIVTLKS NLVSNFRKEFELYKVREINDYHHAHDAYLNAVIGKALLGVYPQLEPEFVYGDYPHFHGHKENKA TAKKFFYS IMNFFKKDDVRTDKNGEI IWKKDEHI S IKKVLSYPQV IVKKVEEQTGGFSKES ILPKGNSDKLIPRKTKKFYWDTKKYGGFDSPIVAYS ILVIADIEKGKSKKLKTVKALVGVTIME KMTFERDPVAFLERKGYRNVQEE I IKLPKYSLFKLENGRKRLLASARELQKGNEIVLPNHLGT LLYHAKNIHKVDEPKHLDYVDKHKDEFKELLDVVSNFSKKYTLAEGNLEKIKELYAQNNGEDLK ELASSFINLLTFTAIGAPATFKFFDKNIDRKRYTSTTEILNATLIHQSITGLYETRIDLNKLGG D

SEQ ID NO: 324

SEQ ID NO: 325

MTKPYS IGLDIGTNSVGWAVTTDNYKVPSKKMKVLGNTSKKYIKKNLLGVLLFDSGITAEGRRL KRTARRRYTRRRNRILYLQEIFSTEMATLDDAFFQRLDDSFLVPDDKRDSKYPIFGNLVEEKAY HDEFPTIYHLRKYLADSTKKADLRLVYLALAHMIKYRGHFLIEGEFNSKNNDIQKNFQDFLDTY NAIFESDLSLENSKQLEEIVKDKI SKLEKKDRILKLFPGEKNSGIFSEFLKLIVGNQADFRKCF NLDEKASLHFSKESYDEDLETLLGYIGDDYSDVFLKAKKLYDAILLSGFLTVTDNETEAPLSSA MIKRYNEHKEDLALLKEYIRNI SLKTYNEVFKDDTKNGYAGYIDGKTNQEDFYVYLKKLLAEFE GADYFLEKIDREDFLRKQRTFDNGS IPYQIHLQEMRAILDKQAKFYPFLAKNKERIEKILTFRI PYYVGPLARGNSDFAWS IRKRNEKITPWNFEDVIDKESSAEAFINRMTSFDLYLPEEKVLPKHS LLYETFNVYNELTKVRFIAESMRDYQFLDSKQKKDIVRLYFKDKRKVTDKDI IEYLHAIYGYDG IELKGIEKQFNSSLSTYHDLLNI INDKEFLDDSSNEAI IEEI IHTLTIFEDREMIKQRLSKFEN IFDKSVLKKLSRRHYTGWGKLSAKLINGIRDEKSGNTILDYLIDDGI SNRNFMQLIHDDALSFK KKIQKAQI IGDEDKGNIKEVVKSLPGSPAIKKGILQS IKIVDELVKVMGGRKPES IVVEMAREN QYTNQGKSNSQQRLKRLEKSLKELGSKILKENIPAKLSKIDNNALQNDRLYLYYLQNGKDMYTG DDLDIDRLSNYDIDHI IPQAFLKDNS IDNKVLVSSASNRGKSDDVPSLEVVKKRKTFWYQLLKS KLISQRKFDNLTKAERGGLSPEDKAGFIQRQLVETRQITKHVARLLDEKFNNKKDENNRAVRTV KIITLKSTLVSQFRKDFELYKVREINDFHHAHDAYLNAVVASALLKKYPKLEPEFVYGDYPKYN SFRERKSATEKVYFYS IM IFKKS I SLADGRVIERPLIEVNEETGESVWNKESDLATVRRVLS YPQVNVVKKVEEQNHGLDRGKPKGLFNANLSSKPKPNSNENLVGAKEYLDPKKYGGYAGISNSF TVLVKGTIEKGAKKKITNVLEFQGI S ILDRINYRKDKLNFLLEKGYKDIELI IELPKYSLFELS DGSRRMLAS ILSTNNKRGEIHKGNQIFLSQKFVKLLYHAKRI SNTINENHRKYVENHKKEFEEL FYYILEFNENYVGAKKNGKLLNSAFQSWQNHS IDELCSSFIGPTGSERKGLFELTSRGSAADFE FLGVKIPRYRDYTPSSLLKDATLIHQSVTGLYETRIDLAKLGEG

SEQ ID NO: 326

MKKQKFSDYYLGFDIGTNSVGWCVTDLDYNVLRFNKKDMWGSRLFDEAKTAAERRVQRNSRRRL KRRKWRLNLLEEIFSDEIMKIDSNFFRRLKESSLWLEDKNSKEKFTLFNDDNYKDYDFYKQYPT IFHLRDELIKNPEKKDIRLIYLALHS IFKSRGHFLFEGQNLKEIKNFETLYNNLI SFLEDNGIN KS IDKD IEKLEKI ICDSGKGLKDKEKEFKGIFNSDKQLVAIFKLSVGSSVSLNDLFDTDEYKK EEVEKEKI SFREQIYEDDKPIYYS ILGEKIELLDIAKSFYDFMVLNNILSDSNYI SEAKVKLYE EHKKDLKNLKYI IRKYNKENYDKLFKDKNENNYPAYIGLNKEKDKKEVVEKSRLKIDDLIKVIK GYLPKPERIEEKDKTIFNEILNKIELKTILPKQRI SDNGTLPYQIHEVELEKILENQSKYYDFL NYEENGVSTKDKLLKTFKFRIPYYVGPLNSYHKDKGGNSWIVRKEEGKILPWNFEQKVDIEKSA EEFIKRMTNKCTYLNGEDVIPKDSFLYSEYI ILNELNKVQVNDEFLNEENKRKI IDELFKENKK VSEKKFKEYLLVNQIANRTVELKGIKDSFNSNYVSYIKFKDIFGEKLNLDIYKEI SEKS ILWKC LYGDDKKIFEKKIKNEYGDILNKDEIKKINSFKFNTWGRLSEKLLTGIEFINLETGECYSSVME ALRRTNYNLMELLSSKFTLQES IDNENKEMNEVSYRDLIEESYVSPSLKRAILQTLKIYEEIKK ITGRVPKKVFIEMARGGDESMKNKKIPARQEQLKKLYDSCGNDIANFS IDIKEMKNSLSSYDNN SLRQKKLYLYYLQFGKCMYTGREIDLDRLLQNNDTYDIDHIYPRSKVIKDDSFDNLVLVLKNEN AEKSNEYPVKKEIQEKMKSFWRFLKEKNFI SDEKYKRLTGKDDFELRGFMARQLVNVRQTTKEV GKILQQIEPEIKIVYSKAEIASSFREMFDFIKVRELNDTHHAKDAYLNIVAGNVYNTKFTEKPY RYLQEIKENYDVKKIYNYDIKNAWDKENSLEIVKKNMEKNTV ITRFIKEEKGELFNLNPIKKG ETSNEI I S IKPKLYDGKDNKLNEKYGYYTSLKAAYFIYVEHEKKNKKVKTFERITRIDSTLIKN EKNLIKYLVSQKKLLNPKI IKKIYKEQTLI IDSYPYTFTGVDSNKKVELKNKKQLYLEKKYEQI LKNALKFVEDNQGETEENYKFIYLKKRNNNEKNETIDAVKERY IEFNEMYDKFLEKLSSKDYK NYINNKLYTNFLNSKEKFKKLKLWEKSLILREFLKIFNKNTYGKYEIKDSQTKEKLFSFPEDTG RIRLGQSSLGNNKELLEESVTGLFVKKIKL

SEQ ID NO: 327

MKNYTIGLDIGVASVGWVCIDENYKILNYNNRHAFGVHEFESAESAAGRRLKRGMRRRYNRRKK RLQLLQSLFDSYITDSGFFSKTDSQHFWKNNNEFENRSLTEVLSSLRISSRKYPTIYHLRSDLI ESNKKMDLRLVYLALHNLVKYRGHFLQEGNWSEAASAEGMDDQLLELVTRYAELENLSPLDLSE SQWKAAETLLLNRNLTKTDQSKELTAMFGKEYEPFCKLVAGLGVSLHQLFPSSEQALAYKETKT KVQLSNENVEEVMELLLEEESALLEAVQPFYQQVVLYELLKGETYVAKAKVSAFKQYQKDMASL KNLLDKTFGEKVYRSYFI SDKNSQREYQKSHKVEVLCKLDQFNKEAKFAETFYKDLKKLLEDKS KTS IGTTEKDEMLRI IKAIDSNQFLQKQKGIQNAAIPHQNSLYEAEKILRNQQAHYPFITTEWI EKVKQILAFRIPYYIGPLVKDTTQSPFSWVERKGDAPITPWNFDEQIDKAASAEAFI SRMRKTC TYLKGQEVLPKSSLTYERFEVLNELNGIQLRTTGAESDFRHRLSYEMKCWI IDNVFKQYKTVST KRLLQELKKSPYADELYDEHTGEIKEVFGTQKENAFATSLSGYI SMKS ILGAVVDDNPAMTEEL IYWIAVFEDREILHLKIQEKYPS ITDVQRQKLALVKLPGWGRFSRLLIDGLPLDEQGQSVLDHM EQYSSVFMEVLKNKGFGLEKKIQKMNQHQVDGTKKIRYEDIEELAGSPALKRGIWRSVKIVEEL VSIFGEPANIVLEVAREDGEKKRTKSRKDQWEELTKTTLKNDPDLKSFIGEIKSQGDQRFNEQR FWLYVTQQGKCLYTGKALDIQNLSMYEVDHILPQNFVKDDSLDNLALVMPEANQRKNQVGQNKM PLEI IEANQQYAMRTLWERLHELKLI SSGKLGRLKKPSFDEVDKDKFIARQLVETRQI IKHVRD LLDERFSKSDIHLVKAGIVSKFRRFSEIPKIRDYNNKHHAMDALFAAALIQS ILGKYGKNFLAF DLSKKDRQKQWRSVKGSNKEFFLFKNFGNLRLQSPVTGEEVSGVEYMKHVYFELPWQTTKMTQT GDGMFYKES IFSPKVKQAKYVSPKTEKFVHDEVKNHS ICLVEFTFMKKEKEVQETKFIDLKVIE HHQFLKEPESQLAKFLAEKETNSPI IHARI IRTIPKYQKIWIEHFPYYFI STRELHNARQFEI S YELMEKVKQLSERSSVEELKIVFGLLIDQMNDNYPIYTKSS IQDRVQKFVDTQLYDFKSFEIGF EELKKAVAANAQRSDTFGSRI SKKPKPEEVAIGYES ITGLKYRKPRSVVGTKR

SEQ ID NO: 328

MKKEIKDYFLGLDVGTGSVGWAVTDTDYKLLKANRKDLWGMRCFETAETAEVRRLHRGARRRIE RRKKRIKLLQELFSQEIAKTDEGFFQRMKESPFYAEDKTILQENTLFNDKDFADKTYHKAYPTI NHLIKAWIENKVKPDPRLLYLACH I IKKRGHFLFEGDFDSENQFDTS IQALFEYLREDMEVDI DADSQKVKEILKDSSLKNSEKQSRLNKILGLKPSDKQKKAITNLI SGNKINFADLYDNPDLKDA EKNS I SFSKDDFDALSDDLAS ILGDSFELLLKAKAVYNCSVLSKVIGDEQYLSFAKVKIYEKHK TDLTKLKNVIKKHFPKDYKKVFGYNKNEKNNNNYSGYVGVCKTKSKKLI INNSVNQEDFYKFLK TILSAKSEIKEVNDILTEIETGTFLPKQI SKSNAEIPYQLRKMELEKILSNAEKHFSFLKQKDE KGLSHSEKI IMLLTFKIPYYIGPINDNHKKFFPDRCWVVKKEKSPSGKTTPWNFFDHIDKEKTA EAFITSRTNFCTYLVGESVLPKSSLLYSEYTVLNEINNLQI I IDGK ICDIKLKQKIYEDLFKK YKKITQKQISTFIKHEGICNKTDEVI ILGIDKECTSSLKSYIELK IFGKQVDEISTKNMLEEI IRWATIYDEGEGKTILKTKIKAEYGKYCSDEQIKKILNLKFSGWGRLSRKFLETVTSEMPGFSE PVNI ITAMRETQNNLMELLSSEFTFTENIKKINSGFEDAEKQFSYDGLVKPLFLSPSVKKMLWQ TLKLVKEISHITQAPPKKIFIEMAKGAELEPARTKTRLKILQDLYNNCKNDADAFSSEIKDLSG KIENEDNLRLRSDKLYLYYTQLGKCMYCGKPIEIGHVFDTSNYDIDHIYPQSKIKDDS I SNRVL VCSSCNKNKEDKYPLKSEIQSKQRGFWNFLQRNNFI SLEKLNRLTRATPI SDDETAKFIARQLV ETRQATKVAAKVLEKMFPETKIVYSKAETVSMFRNKFDIVKCREINDFHHAHDAYLNIVVGNVY NTKFTNNPWNFIKEKRDNPKIADTYNYYKVFDYDVKRNNITAWEKGKTI ITVKDMLKRNTPIYT RQAACKKGELFNQTIMKKGLGQHPLKKEGPFS I SKYGGYNKVSAAYYTLIEYEEKGNKIRSLE TIPLYLVKDIQKDQDVLKSYLTDLLGKKEFKILVPKIKINSLLKINGFPCHITGKTNDSFLLRP AVQFCCSNNEVLYFKKI IRFSEIRSQREKIGKTI SPYEDLSFRSYIKENLWKKTKNDEIGEKEF YDLLQKKNLEIYDMLLTKHKDTIYKKRPNSATIDILVKGKEKFKSLI IENQFEVILEILKLFSA TRNVSDLQHIGGSKYSGVAKIGNKI SSLDNCILIYQS ITGIFEKRIDLLKV

SEQ ID NO: 329

MEGQMKNNGNNLQQGNYYLGLDVGTSSVGWAVTDTDYNVLKFRGKSMWGARLFDEASTAEERRT HRGNRRRLARRKYRLLLLEQLFEKEIRKIDDNFFVRLHESNLWADDKSKPSKFLLFNDTNFTDK DYLKKYPTIYHLRSDLIHNSTEHDIRLVFLALHHLIKYRGHFIYDNSANGDVKTLDEAVSDFEE YLNENDIEFNIENKKEFINVLSDKHLTKKEKKI SLKKLYGDITDSENINI SVLIEMLSGSS I SL SNLFKDIEFDGKQNLSLDSDIEETLNDVVDILGDNIDLLIHAKEVYDIAVLTSSLGKHKYLCDA KVELFEKNKKDLMILKKYIKKNHPEDYKKIFSSPTEKKNYAAYSQTNSKNVCSQEEFCLFIKPY IRDMVKSENEDEVRIAKEVEDKSFLTKLKGTNNSVVPYQIHERELNQILKNIVAYLPFMNDEQE DI SVVDKIKLIFKFKIPYYVGPLNTKSTRSWVYRSDEKIYPWNFSNVIDLDKTAHEFMNRLIGR CTYTNDPVLPMDSLLYSKYNVLNEINPIKVNGKAIPVEVKQAIYTDLFENSKKKVTRKS IYIYL LKNGYIEKEDIVSGIDIEIKSKLKSHHDFTQIVQENKCTPEEIERI IKGILVYSDDKSMLRRWL KN IKGLSENDVKYLAKLNYKEWGRLSKTLLTDIYTINPEDGEACS ILDIMWNTNATLMEILSN EKYQFKQ IENYKAENYDEKQNLHEELDDMYI SPAARRS IWQALRIVDEIVDIKKSAPKKIFIE MAREKKSAMKKKRTESRKDTLLELYKSCKSQADGFYDEELFEKLSNESNSRLRRDQLYLYYTQM GRSMYTGKRIDFDKLINDKNTYDIDHIYPRSKIKDDS ITNRVLVEKDINGEKTDIYPI SEDIRQ KMQPFWKILKEKGLINEEKYKRLTRNYELTDEELSSFVARQLVETQQSTKALATLLKKEYPSAK IVYSKAGNVSEFRNRKDKELPKFREINDLHHAKDAYLNIVVGNVYDTKFTEKFFNNIRNENYSL KRVFDFSVPGAWDAKGSTFNTIKKYMAKNNPI IAFAPYEVKGELFDQQIVPKGKGQFPIKQGKD IEKYGGYNKLSSAFLFAVEYKGKKARERSLETVYIKDVELYLQDPIKYCESVLGLKEPQI IKPK ILMGSLFS INNKKLVVTGRSGKQYVCHHIYQLS INDEDSQYLK IAKYLQEEPDG IERQ ILN ITSVN IKLFDVLCTKFNSNTYEI ILNSLKNDVNEGREKFSELDILEQC ILLQLLKAFKCNRE SSNLEKLNNKKQAGVIVIPHLFTKCSVFKVIHQS ITGLFEKEMDLLK

SEQ ID NO: 330

MGRKPYILSLDIGTGSVGYACMDKGFNVLKYHDKDALGVYLFDGALTAQERRQFRTSRRRKNRR IKRLGLLQELLAPLVQNPNFYQFQRQFAWKNDNMDFKNKSLSEVLSFLGYESKKYPTIYHLQEA LLLKDEKFDPELIYMALYHLVKYRGHFLFDHLKIENLTNNDNMHDFVELIETYENLNNIKLNLD YEKTKVIYEILKDNEMTKNDRAKRVKNMEKKLEQFS IMLLGLKFNEGKLFNHADNAEELKGANQ SHTFADNYEENLTPFLTVEQSEFIERANKIYLSLTLQDILKGKKSMAMSKVAAYDKFRNELKQV KDIVYKADSTRTQFKKIFVSSKKSLKQYDATPNDQTFSSLCLFDQYLIRPKKQYSLLIKELKKI IPQDSELYFEAENDTLLKVLNTTDNAS IPMQINLYEAETILRNQQKYHAEITDEMIEKVLSLIQ FRIPYYVGPLVNDHTASKFGWMERKSNES IKPWNFDEVVDRSKSATQFIRRMTNKCSYLINEDV LPKNSLLYQEMEVLNELNATQIRLQTDPKNRKYRMMPQIKLFAVEHIFKKYKTVSHSKFLEIML NSNHRENFMNHGEKLS IFGTQDDKKFASKLSSYQDMTKIFGDIEGKRAQIEEI IQWITIFEDKK ILVQKLKECYPELTSKQINQLKKLNYSGWGRLSEKLLTHAYQGHS I IELLRHSDENFMEILTND VYGFQNFIKEENQVQSNKIQHQDIANLTTSPALKKGIWSTIKLVRELTS IFGEPEKI IMEFATE DQQKGKKQKSRKQLWDD IKKNKLKSVDEYKYI IDVANKLNNEQLQQEKLWLYLSQNGKCMYSG QS IDLDALLSPNATKHYEVDHIFPRSFIKDDS IDNKVLVIKKMNQTKGDQVPLQFIQQPYERIA YWKSLNKAGLI SDSKLHKLMKPEFTAMDKEGFIQRQLVETRQI SVHVRDFLKEEYPNTKVIPMK AKMVSEFRKKFDIPKIRQMNDAHHAIDAYLNGVVYHGAQLAYPNVDLFDFNFKWEKVREKWKAL GEFNTKQKSRELFFFKKLEKMEVSQGERLI SKIKLDMNHFKINYSRKLA IPQQFYNQTAVSPK TAELKYESNKSNEVVYKGLTPYQTYVVAIKSVNKKGKEKMEYQMIDHYVFDFYKFQNGNEKELA LYLAQRENKDEVLDAQIVYSLNKGDLLYINNHPCYFVSRKEVINAKQFELTVEQQLSLYNVMNN KETNVEKLLIEYDFIAEKVINEYHHYLNSKLKEKRVRTFFSESNQTHEDFIKALDELFKVVTAS ATRSDKIGSRKNSMTHRAFLGKGKDVKIAYTS I SGLKTTKPKSLFKLAESRNEL

SEQ ID NO: 331

MAKILGLDLGTNS IGWAVVERENIDFSLIDKGVRIFSEGVKSEKGIESSRAAERTGYRSARKIK YRRKLRKYETLKVLSLNRMCPLS IEEVEEWKKSGFKDYPLNPEFLKWLSTDEESNVNPYFFRDR ASKHKVSLFELGRAFYHIAQRRGFLSNRLDQSAEGILEEHCPKIEAIVEDLI S IDEI STNITDY FFETGILDSNEKNGYAKDLDEGDKKLVSLYKSLLAILKKNESDFENCKSEI IERLNKKDVLGKV KGKIKDI SQAMLDGNYKTLGQYFYSLYSKEKIRNQYTSREEHYLSEFITICKVQGIDQINEEEK INEKKFDGLAKDLYKAIFFQRPLKSQKGLIGKCSFEKSKSRCAI SHPDFEEYRMWTYLNTIKIG TQSDKKLRFLTQDEKLKLVPKFYRKNDFNFDVLAKELIEKGSSFGFYKSSKKNDFFYWFNYKPT DTVAACQVAASLKNAIGEDWKTKSFKYQTINSNKEQVSRTVDYKDLWHLLTVATSDVYLYEFAI DKLGLDEKNAKAFSKTKLKKDFASLSLSAINKILPYLKEGLLYSHAVFVANIENIVDENIWKDE KQRDYIKTQI SEI IENYTLEKSRFEI INGLLKEYKSENEDGKRVYYSKEAEQSFENDLKKKLVL FYKSNEIENKEQQETIFNELLPIFIQQLKDYEFIKIQRLDQKVLIFLKGKNETGQIFCTEEKGT AEEKEKKIKNRLKKLYHPSDIEKFKKKI IKDEFGNEKIVLGSPLTPS IKNPMAMRALHQLRKVL NALILEGQIDEKTI IHIEMARELNDANKRKGIQDYQNDNKKFREDAIKEIKKLYFEDCKKEVEP TEDDILRYQLWMEQNRSEIYEEGKNI S ICDI IGSNPAYDIEHTIPRSRSQDNSQMNKTLCSQRF NREVKKQSMPIELNNHLEILPRIAHWKEEADNLTREIEI I SRS IKAAATKEIKDKKIRRRHYLT LKRDYLQGKYDRFIWEEPKVGFKNSQIPDTGI ITKYAQAYLKSYFKKVESVKGGMVAEFRKIWG IQESFIDENGMKHYKVKDRSKHTHHTIDAITIACMTKEKYDVLAHAWTLEDQQNKKEARS I IEA SKPWKTFKEDLLKIEEEILVSHYTPDNVKKQAKKIVRVRGKKQFVAEVERDVNGKAVPKKAASG KTIYKLDGEGKKLPRLQQGDTIRGSLHQDS IYGAIKNPLNTDEIKYVIRKDLES IKGSDVES IV DEVVKEKIKEAIANKVLLLSSNAQQKNKLVGTVWMNEEKRIAINKVRIYANSVKNPLHIKEHSL LSKSKHVHKQKVYGQNDENYAMAIYELDGKRDFELI IFNLAKLIKQGQGFYPLHKKKEIKGKI VFVPIEKRNKRDVVLKRGQQVVFYDKEVENPKDI SEIVDFKGRIYI IEGLS IQRIVRPSGKVDE YGVIMLRYFKEARKADDIKQDNFKPDGVFKLGENKPTRKMNHQFTAFVEGIDFKVLPSGKFEKI

SEQ ID NO: 332

MEFKKVLGLDIGTNS IGCALLSLPKS IQDYGKGGRLEWLTSRVIPLDADYMKAFIDGKNGLPQV ITPAGKRRQKRGSRRLKHRYKLRRSRLIRVFKTLNWLPEDFPLDNPKRIKETI STEGKFSFRI S DYVPI SDESYREFYREFGYPENEIEQVIEEINFRRKTKGKNKNPMIKLLPEDWVVYYLRKKALI KPTTKEELIRI IYLFNQRRGFKSSRKDLTETAILDYDEFAKRLAEKEKYSAENYETKFVS ITKV KEVVELKTDGRKGKKRFKVILEDSRIEPYEIERKEKPDWEGKEYTFLVTQKLEKGKFKQNKPDL PKEEDWALCTTALDNRMGSKHPGEFFFDELLKAFKEKRGYKIRQYPVNRWRYKKELEFIWTKQC QLNPELNNL INKEILRKLATVLYPSQSKFFGPKIKEFENSDVLHI I SEDI IYYQRDLKSQKSL I SECRYEKRKGIDGEIYGLKCIPKSSPLYQEFRIWQDIH IKVIRKESEVNGKKKI IDETQLY INENIKEKLFELFNSKDSLSEKDILELI SLNI INSGIKI SKKEEETTHRINLFANRKELKGNET KSRYRKVFKKLGFDGEYILNHPSKLNRLWHSDYSNDYADKEKTEKS ILSSLGWKNRNGKWEKSK NYDVFNLPLEVAKAIANLPPLKKEYGSYSALAIRKMLVVMRDGKYWQHPDQIAKDQENTSLMLF DKNLIQLTNNQRKVLNKYLLTLAEVQKRSTLIKQKLNEIEHNPYKLELVSDQDLEKQVLKSFLE KKNESDYLKGLKTYQAGYLIYGKHSEKDVPIVNSPDELGEYIRKKLPNNSLRNPIVEQVIRETI FIVRDVWKSFGI IDEIHIELGRELKNNSEERKKTSESQEKNFQEKERARKLLKELLNSSNFEHY DENGNKIFSSFTVNPNPDSPLDIEKFRIWKNQSGLTDEELNKKLKDEKIPTEIEVKKYILWLTQ KCRSPYTGKI IPLSKLFDSNVYEIEHI IPRSKMKNDSTNNLVICELGVNKAKGDRLAANFI SES NGKCKFGEVEYTLLKYGDYLQYCKDTFKYQKAKYKNLLATEPPEDFIERQINDTRYIGRKLAEL LTPVVKDSKNI IFTIGS ITSELKITWGLNGVWKDILRPRFKRLES I INKKLIFQDEDDPNKYHF DLS INPQLDKEGLKRLDHRHHALDATI IAATTREHVRYLNSLNAADNDEEKREYFLSLCNHKIR DFKLPWENFTSEVKSKLLSCVVSYKESKPILSDPFNKYLKWEYKNGKWQKVFAIQIKNDRWKAV RRSMFKEPIGTVWIKKIKEVSLKEAIKIQAIWEEVKNDPVRKKKEKYIYDDYAQKVIAKIVQEL GLSSSMRKQDDEKLNKFINEAKVSAGVNKNLNTTNKTIYNLEGRFYEKIKVAEYVLYKAKRMPL NKKEYIEKLSLQKMFNDLPNFILEKS ILDNYPEILKELESDNKYI IEPHKKNNPVNRLLLEHIL EYHNNPKEAFSTEGLEKLNKKAINKIGKPIKYITRLDGDINEEEIFRGAVFETDKGSNVYFVMY ENNQTKDREFLKPNPS I SVLKAIEHKNKIDFFAPNRLGFSRI ILSPGDLVYVPTNDQYVLIKDN SSNETI INWDDNEFI SNRIYQVKKFTGNSCYFLKNDIASLILSYSASNGVGEFGSQNI SEYSVD DPPIRIKDVCIKIRVDRLGNVRPL

SEQ ID NO: 333

MKHILGLDLGTNS IGWALIERNIEEKYGKI IGMGSRIVPMGAELSKFEQGQAQTKNADRRTNRG ARRLNKRYKQRRNKLIYILQKLDMLPSQIKLKEDFSDPNKIDKITILPI SKKQEQLTAFDLVSL RVKALTEKVGLEDLGKI IYKYNQLRGYAGGSLEPEKEDIFDEEQSKDKKNKSFIAFSKIVFLGE PQEEIFKNKKLNRRAI IVETEEGNFEGSTFLENIKVGDSLELLINISASKSGDTITIKLPNKTN WRKKME IENQLKEKSKEMGREFYI SEFLLELLKENRWAKIRNNTILRARYESEFEAIWNEQVK HYPFLENLDKKTLIEIVSFIFPGEKESQKKYRELGLEKGLKYI IKNQVVFYQRELKDQSHLI SD CRYEPNEKAIAKSHPVFQEYKVWEQINKLIVNTKIEAGTNRKGEKKYKYIDRPIPTALKEWIFE ELQNKKEITFSAIFKKLKAEFDLREGIDFLNGMSPKDKLKGNETKLQLQKSLGELWDVLGLDSI NRQIELW ILYNEKGNEYDLTSDRTSKVLEFINKYGN IVDDNAEETAIRI SKIKFARAYSSLS LKAVERILPLVRAGKYFNNDFSQQLQSKILKLLNENVEDPFAKAAQTYLDNNQSVLSEGGVGNS IATILVYDKHTAKEYSHDELYKSYKEINLLKQGDLRNPLVEQI INEALVLIRDIWKNYGIKPNE IRVELARDLKNSAKERATIHKRNKDNQTINNKIKETLVKNKKELSLANIEKVKLWEAQRHLSPY TGQPIPLSDLFDKEKYDVDHI IPI SRYFDDSFTNKVI SEKSVNQEKANRTAMEYFEVGSLKYS I FTKEQFIAHVNEYFSGVKRKNLLATS IPEDPVQRQIKDTQYIAIRVKEELNKIVGNENVKTTTG SITDYLRNHWGLTDKFKLLLKERYEALLESEKFLEAEYDNYKKDFDSRKKEYEEKEVLFEEQEL TREEFIKEYKENYIRYKKNKLI IKGWSKRIDHRHHAIDALIVACTEPAHIKRLNDLNKVLQDWL VEHKSEFMPNFEGSNSELLEEILSLPENERTEIFTQIEKFRAIEMPWKGFPEQVEQKLKEI I I S HKPKDKLLLQYNKAGDRQIKLRGQLHEGTLYGI SQGKEAYRIPLTKFGGSKFATEK IQKIVSP FLSGFIANHLKEYNNKKEEAFSAEGIMDLNNKLAQYRNEKGELKPHTPI STVKIYYKDPSKNKK KKDEEDLSLQKLDREKAFNEKLYVKTGDNYLFAVLEGEIKTKKTSQIKRLYDI I SFFDATNFLK EEFRNAPDKKTFDKDLLFRQYFEERNKAKLLFTLKQGDFVYLPNENEEVILDKESPLYNQYWGD LKERGK IYVVQKFSKKQIYFIKHTIADI IKKDVEFGSQNCYETVEGRS IKENCFKLEIDRLGN IVKVIKR

SEQ ID NO: 334

MHVEIDFPHFSRGDSHLAMNKNEILRGSSVLYRLGLDLGSNSLGWFVTHLEKRGDRHEPVALGP GGVRIFPDGRDPQSGTSNAVDRRMARGARKRRDRFVERRKELIAALIKYNLLPDDARERRALEV LDPYALRKTALTDTLPAHHVGRALFHLNQRRGFQSNRKTDSKQSEDGAIKQAASRLATDKGNET LGVFFADMHLRKSYEDRQTAIRAELVRLGKDHLTGNARKKIWAKVRKRLFGDEVLPRADAPHGV RARATITGTKASYDYYPTRDMLRDEFNAIWAGQSAHHATITDEARTEIEHI IFYQRPLKPAIVG KCTLDPATRPFKEDPEGYRAPWSHPLAQRFRILSEARNLEIRDTGKGSRRLTKEQSDLVVAALL ANREVKFDKLRTLLKLPAEARFNLESDRRAALDGDQTAARLSDKKGFNKAWRGFPPERQIAIVA RLEETEDENELIAWLEKECALDGAAAARVANTTLPDGHCRLGLRAIKKIVPIMQDGLDEDGVAG AGYHIAAKRAGYDHAKLPTGEQLGRLPYYGQWLQDAVVGSGDARDQKEKQYGQFPNPTVHIGLG QLRRVVNDLIDKYGPPTEI S IEFTRALKLSEQQKAERQREQRRNQDKNKARAEELAKFGRPANP RNLLKMRLWEELAHDPLDRKCVYTGEQI S IERLLSDEVDIDHILPVAMTLDDSPANKI ICMRYA NRHKRKQTPSEAFGSSPTLQGHRYNWDDIAARATGLPRNKRWRFDANAREEFDKRGGFLARQLN ETGWLARLAKQYLGAVTDPNQIWVVPGRLTSMLRGKWGLNGLLPSDNYAGVQDKAEEFLASTDD MEFSGVKNRADHRHHAIDGLVTALTDRSLLWKMANAYDEEHEKFVIEPPWPTMRDDLKAALEKM VVSHKPDHGIEGKLHEDSAYGFVKPLDATGLKEEEAGNLVYRKAIESLNENEVDRIRDIQLRTI VRDHVNVEKTKGVALADALRQLQAPSDDYPQFKHGLRHVRILKKEKGDYLVPIANRASGVAYKA YSAGENFCVEVFETAGGKWDGEAVRRFDANKKNAGPKIAHAPQWRDANEGAKLVMRIHKGDLIR LDHEGRARIMVVHRLDAAAGRFKLADHNETGNLDKRHATNNDIDPFRWLMASYNTLKKLAAVPV RVDELGRVWRVMPN

SEQ ID NO: 335

METTLGIDLGTNS IGLALVDQEEHQILYSGVRIFPEGINKDTIGLGEKEESRNATRRAKRQMRR QYFRKKLRKAKLLELLIAYDMCPLKPEDVRRWKNWDKQQKSTVRQFPDTPAFREWLKQNPYELR KQAVTEDVTRPELGRILYQMIQRRGFLSSRKGKEEGKIFTGKDRMVGIDETRKNLQKQTLGAYL YDIAPKNGEKYRFRTERVRARYTLRDMYIREFEI IWQRQAGHLGLAHEQATRKKNIFLEGSATN VRNSKLITHLQAKYGRGHVLIEDTRITVTFQLPLKEVLGGKIEIEEEQLKFKSNESVLFWQRPL RSQKSLLSKCVFEGRNFYDPVHQKWI IAGPTPAPLSHPEFEEFRAYQFIN I IYGKNEHLTAIQ REAVFELMCTESKDFNFEKIPKHLKLFEKFNFDDTTKVPACTTI SQLRKLFPHPVWEEKREEIW HCFYFYDDNTLLFEKLQKDYALQTNDLEKIKKIRLSESYGNVSLKAIRRINPYLKKGYAYSTAV LLGGIRNSFGKRFEYFKEYEPEIEKAVCRILKEKNAEGEVIRKIKDYLVHNRFGFAKNDRAFQK LYHHSQAITTQAQKERLPETGNLRNPIVQQGLNELRRTVNKLLATCREKYGPSFKFDHIHVEMG RELRSSKTEREKQSRQIRENEKKNEAAKVKLAEYGLKAYRDNIQKYLLYKEIEEKGGTVCCPYT GKTLNI SHTLGSDNSVQIEHI IPYS I SLDDSLANKTLCDATFNREKGELTPYDFYQKDPSPEKW GASSWEEIEDRAFRLLPYAKAQRFIRRKPQESNEFI SRQLNDTRYI SKKAVEYLSAICSDVKAF PGQLTAELRHLWGLNNILQSAPDITFPLPVSATENHREYYVITNEQNEVIRLFPKQGETPRTEK GELLLTGEVERKVFRCKGMQEFQTDVSDGKYWRRIKLSSSVTWSPLFAPKPI SADGQIVLKGRI EKGVFVCNQLKQKLKTGLPDGSYWI SLPVI SQTFKEGESVNNSKLTSQQVQLFGRVREGIFRCH NYQCPASGADGNFWCTLDTDTAQPAFTPIKNAPPGVGGGQI ILTGDVDDKGIFHADDDLHYELP ASLPKGKYYGIFTVESCDPTLIPIELSAPKTSKGENLIEGNIWVDEHTGEVRFDPKKNREDQRH HAIDAIVIALSSQSLFQRLSTYNARRENKKRGLDSTEHFPSPWPGFAQDVRQSVVPLLVSYKQN PKTLCKI SKTLYKDGKKIHSCGNAVRGQLHKETVYGQRTAPGATEKSYHIRKDIRELKTSKHIG KVVDITIRQMLLKHLQENYHIDITQEFNIPSNAFFKEGVYRIFLPNKHGEPVPIKKIRMKEELG NAERLKD INQYVNPRNNHHVMIYQDADGNLKEEIVSFWSVIERQNQGQPIYQLPREGR IVS I LQINDTFLIGLKEEEPEVYRNDLSTLSKHLYRVQKLSGMYYTFRHHLASTLNNEREEFRIQSLE AWKRANPVKVQIDEIGRITFLNGPLC

SEQ ID NO: 336

MESSQILSPIGIDLGGKFTGVCLSHLEAFAELPNHANTKYSVILIDHNNFQLSQAQRRATRHRV RNKKRNQFVKRVALQLFQHILSRDLNAKEETALCHYLNNRGYTYVDTDLDEYIKDETTINLLKE LLPSESEHNFIDWFLQKMQSSEFRKILVSKVEEKKDDKELKNAVKNIKNFITGFEKNSVEGHRH RKVYFENIKSDITKDNQLDS IKKKIPSVCLSNLLGHLSNLQWKNLHRYLAKNPKQFDEQTFGNE FLRMLKNFRHLKGSQESLAVRNLIQQLEQSQDYI S ILEKTPPEITIPPYEARTNTGMEKDQSLL LNPEKLNNLYPNWRNLIPGI IDAHPFLEKDLEHTKLRDRKRI I SPSKQDEKRDSYILQRYLDLN KKIDKFKIKKQLSFLGQGKQLPANLIETQKEMETHFNSSLVSVLIQIASAYNKEREDAAQGIWF DNAFSLCELSNINPPRKQKILPLLVGAILSEDFINNKDKWAKFKIFWNTHKIGRTSLKSKCKEI EEARKNSGNAFKIDYEEALNHPEHSNNKALIKI IQTIPDI IQAIQSHLGHNDSQALIYHNPFSL SQLYTILETKRDGFHKNCVAVTCENYWRSQKTEIDPEI SYASRLPADSVRPFDGVLARMMQRLA YEIAMAKWEQIKHIPDNSSLLIPIYLEQNRFEFEESFKKIKGSSSDKTLEQAIEKQNIQWEEKF QRI INASM ICPYKGAS IGGQGEIDHIYPRSLSKKHFGVIFNSEVNLIYCSSQGNREKKEEHYL LEHLSPLYLKHQFGTDNVSDIKNFI SQNVA IKKYI SFHLLTPEQQKAARHALFLDYDDEAFKT ITKFLMSQQKARVNGTQKFLGKQIMEFLSTLADSKQLQLEFS IKQITAEEVHDHRELLSKQEPK LVKSRQQSFPSHAIDATLTMS IGLKEFPQFSQELDNSWFINHLMPDEVHLNPVRSKEKYNKP I SSTPLFKDSLYAERFIPVWVKGETFAIGFSEKDLFEIKPSNKEKLFTLLKTYSTKNPGESLQEL QAKSKAKWLYFPINKTLALEFLHHYFHKEIVTPDDTTVCHFINSLRYYTKKES ITVKILKEPMP VLSVKFESSKKNVLGSFKHTIALPATKDWERLFNHPNFLALKANPAPNPKEFNEFIRKYFLSDN NPNSDIPNNGHNIKPQKHKAVRKVFSLPVIPGNAGTMMRIRRKDNKGQPLYQLQTIDDTPSMGI QINEDRLVKQEVLMDAYKTRNLSTIDGINNSEGQAYATFDNWLTLPVSTFKPEI IKLEMKPHSK TRRYIRITQSLADFIKTIDEALMIKPSDS IDDPLNMPNEIVCKNKLFGNELKPRDGKMKIVSTG KIVTYEFESDSTPQWIQTLYVTQLKKQP

SEQ ID NO: 337

MKKIVGLDLGTNS IGWALINAYINKEHLYGIEACGSRI IPMDAAILGNFDKGNS I SQTADRTSY RGIRRLRERHLLRRERLHRILDLLGFLPKHYSDSLNRYGKFLNDIECKLPWVKDETGSYKFIFQ ESFKEMLANFTEHHPILIANNKKVPYDWTIYYLRKKALTQKI SKEELAWILLNFNQKRGYYQLR GEEEETPNKLVEYYSLKVEKVEDSGERKGKDTWYNVHLENGMIYRRTS IPLDWEGKTKEFIVT TDLEADGSPKKDKEG IKRSFRAPKDDDWTLIKKKTEADIDKIKMTVGAYIYDTLLQKPDQKIR GKLVRTIERKYYKNELYQILKTQSEFHEELRDKQLYIACLNELYPNNEPRRNS I STRDFCHLFI EDI IFYQRPLKSKKSLIDNCPYEENRYIDKESGEIKHAS IKCIAKSHPLYQEFRLWQFIVNLRI YRKETDVDVTQELLPTEADYVTLFEWLNEKKEIDQKAFFKYPPFGFKKTTSNYRWNYVEDKPYP CNETHAQI IARLGKAHIPKAFLSKEKEETLWHILYS IEDKQEIEKALHSFANKNNLSEEFIEQF KNFPPFKKEYGSYSAKAIKKLLPLMRMGKYWS IE IDNGTRIRINKI IDGEYDE IRERVRQKA INLTDITHFRALPLWLACYLVYDRHSEVKDIVKWKTPKDIDLYLKSFKQHSLRNPIVEQVITET LRTVRDIWQQVGHIDEIHIELGREMKNPADKRARMSQQMIKNENTNLRIKALLTEFLNPEFGIE NVRPYSPSQQDLLRIYEEGVLNS ILELPEDIGI ILGKFNQTDTLKRPTRSEILRYKLWLEQKYR SPYTGEMIPLSKLFTPAYEIEHI IPQSRYFDDSLSNKVICESEINKLKDRSLGYEFIKNHHGEK VELAFDKPVEVLSVEAYEKLVHESYSHNRSKMKKLLMEDIPDQFIERQLNDSRYI SKVVKSLLS IVREENEQEAI SKNVIPCTGGITDRLKKDWGINDVWNKIVLPRFIRLNELTESTRFTS INTNN TMIPSMPLELQKGFNKKRIDHRHHAMDAI I IACANR IVNYLNNVSASKNTKITRRDLQTLLCH KDKTDNNGNYKWVIDKPWETFTQDTLTALQKITVSFKQNLRVINKTTNHYQHYENGKKIVSNQS KGDSWAIRKSMHKETVHGEVNLRMIKTVSFNEALKKPQAIVEMDLKKKILAMLELGYDTKRIKN YFEENKDTWQDINPSKIKVYYFTKETKDRYFAVRKPIDTSFDKKKIKES ITDTGIQQIMLRHLE TKDNDPTLAFSPDGIDEMNRNILILNKGKKHQPIYKVRVYEKAEKFTVGQKGNKRTKFVEAAKG TNLFFAIYETEEIDKDTKKVIRKRSYSTIPLNVVIERQKQGLSSAPEDENGNLPKYILSPNDLV YVPTQEEINKGEVVMPIDRDRIYKMVDSSGITANFIPASTANLIFALPKATAEIYCNGENCIQN EYGIGSPQSKNQKAITGEMVKEICFPIKVDRLGNI IQVGSCILTN

SEQ ID NO: 338

MSRSLTFSFDIGYAS IGWAVIASASHDDADPSVCGCGTVLFPKDDCQAFKRREYRRLRR IRSR RVRIERIGRLLVQAQI ITPEMKETSGHPAPFYLASEALKGHRTLAPIELWHVLRWYAHNRGYDN NASWSNSLSEDGGNGEDTERVKHAQDLMDKHGTATMAETICRELKLEEGKADAPMEVSTPAYKN LNTAFPRLIVEKEVRRILELSAPLIPGLTAEI IELIAQHHPLTTEQRGVLLQHGIKLARRYRGS LLFGQLIPRFDNRI I SRCPVTWAQVYEAELKKGNSEQSARERAEKLSKVPTANCPEFYEYRMAR ILC IRADGEPLSAEIRRELMNQARQEGKLTKASLEKAI SSRLGKETETNVSNYFTLHPDSEEA LYLNPAVEVLQRSGIGQILSPSVYRIAANRLRRGKSVTPNYLLNLLKSRGESGEALEKKIEKES KKKEADYADTPLKPKYATGRAPYARTVLKKVVEEILDGEDPTRPARGEAHPDGELKAHDGCLYC LLDTDSSVNQHQKERRLDTMTNNHLVRHRMLILDRLLKDLIQDFADGQKDRI SRVCVEVGKELT TFSAMDSKKIQRELTLRQKSHTDAVNRLKRKLPGKALSANLIRKCRIAMDMNWTCPFTGATYGD HELENLELEHIVPHSFRQSNALSSLVLTWPGVNRMKGQRTGYDFVEQEQENPVPDKPNLHICSL NNYRELVEKLDDKKGHEDDRRRKKKRKALLMVRGLSHKHQSQNHEAMKEIGMTEGMMTQSSHLM KLACKS IKTSLPDAHIDMIPGAVTAEVRKAWDVFGVFKELCPEAADPDSGKILKENLRSLTHLH HALDACVLGLIPYI IPAHHNGLLRRVLAMRRIPEKLIPQVRPVANQRHYVLNDDGRMMLRDLSA SLKENIREQLMEQRVIQHVPADMGGALLKETMQRVLSVDGSGEDAMVSLSKKKDGKKEKNQVKA SKLVGVFPEGPSKLKALKAAIEIDGNYGVALDPKPVVIRHIKVFKRIMALKEQNGGKPVRILKK GMLIHLTSSKDPKHAGVWRIES IQDSKGGVKLDLQRAHCAVPKNKTHECNWREVDLI SLLKKYQ MKRYPTSYTGTPR

SEQ ID NO: 339

MTQKVLGLDLGTNS IGSAVRNLDLSDDLQWQLEFFSSDIFRSSVNKESNGREYSLAAQRSAHRR SRGLNEVRRRRLWATLNLLIKHGFCPMSSESLMRWCTYDKRKGLFREYPIDDKDFNAWILLDFN GDGRPDYSSPYQLRRELVTRQFDFEQPIERYKLGRALYHIAQHRGFKSSKGETLSQQETNSKPS STDEIPDVAGAMKASEEKLSKGLSTYMKEHNLLTVGAAFAQLEDEGVRVRNNNDYRAIRSQFQH EIETIFKFQQGLSVESELYERLI SEKKNVGTIFYKRPLRSQRGNVGKCTLERSKPRCAIGHPLF EKFRAWTLINNIKVRMSVDTLDEQLPMKLRLDLYNECFLAFVRTEFKFEDIRKYLEKRLGIHFS YNDKTINYKDSTSVAGCPITARFRKMLGEEWESFRVEGQKERQAHSKNNI SFHRVSYS IEDIWH FCYDAEEPEAVLAFAQETLRLERKKAEELVRIWSAMPQGYAMLSQKAIRNINKILMLGLKYSDA VILAKVPELVDVSDEELLS IAKDYYLVEAQVNYDKRINS IVNGLIAKYKSVSEEYRFADHNYEY LLDESDEKDI IRQIENSLGARRWSLMDANEQTDILQKVRDRYQDFFRSHERKFVESPKLGESFE NYLTKKFPMVEREQWKKLYHPSQITIYRPVSVGKDRSVLRLGNPDIGAIKNPTVLRVLNTLRRR VNQLLDDGVI SPDETRVVVETARELNDANRKWALDTYNRIRHDENEKIKKILEEFYPKRDGI ST DDIDKARYVIDQREVDYFTGSKTYNKDIKKYKFWLEQGGQCMYTGRTINLSNLFDPNAFDIEHT IPESLSFDSSDMNLTLCDAHYNRFIKKNHIPTDMPNYDKAITIDGKEYPAITSQLQRWVERVER LNRNVEYWKGQARRAQNKDRKDQCMREMHLWKMELEYWKKKLERFTVTEVTDGFKNSQLVDTRV ITRHAVLYLKS IFPHVDVQRGDVTAKFRKILGIQSVDEKKDRSLHSHHAIDATTLTI IPVSAKR DRMLELFAKIEEINKMLSFSGSEDRTGLIQELEGLKNKLQMEVKVCRIGHNVSEIGTFINDNII VNHHIKNQALTPVRRRLRKKGYIVGGVDNPRWQTGDALRGEIHKASYYGAITQFAKDDEGKVLM KEGRPQVNPTIKFVIRRELKYKKSAADSGFASWDDLGKAIVDKELFALMKGQFPAETSFKDACE QGIYMIKKGKNGMPDIKLHHIRHVRCEAPQSGLKIKEQTYKSEKEYKRYFYAAVGDLYAMCCYT NGKIREFRIYSLYDVSCHRKSDIEDIPEFITDKKGNRLMLDYKLRTGDMILLYKDNPAELYDLD NVNLSRRLYKINRFESQSNLVLMTHHLSTSKERGRSLGKTVDYQNLPES IRSSVKSLNFLIMGE NRDFVIKNGKI IFNHR

SEQ ID NO: 340

MLVSPI SVDLGGKNTGFFSFTDSLDNSQSGTVIYDESFVLSQVGRRSKRHSKRNNLRNKLVKRL FLLILQEHHGLS IDVLPDEIRGLFNKRGYTYAGFELDEKKKDALESDTLKEFLSEKLQS IDRDS DVEDFLNQIASNAESFKDYKKGFEAVFASATHSPNKKLELKDELKSEYGENAKELLAGLRVTKE ILDEFDKQENQGNLPRAKYFEELGEYIATNEKVKSFFDSNSLKLTDMTKLIG I SNYQLKELRR YFNDKEMEKGDIWIPNKLHKITERFVRSWHPKNDADRQRRAELMKDLKSKEIMELLTTTEPVMT IPPYDDMNNRGAVKCQTLRLNEEYLDKHLPNWRDIAKRLNHGKFNDDLADSTVKGYSEDSTLLH RLLDTSKEIDIYELRGKKPNELLVKTLGQSDANRLYGFAQNYYELIRQKVRAGIWVPVKNKDDS LNLEDNSNMLKRCNHNPPHKKNQIHNLVAGILGVKLDEAKFAEFEKELWSAKVGNKKLSAYCKN IEELRKTHGNTFKIDIEELRKKDPAELSKEEKAKLRLTDDVILNEWSQKIANFFDIDDKHRQRF NNLFSMAQLHTVIDTPRSGFSSTCKRCTAENRFRSETAFYNDETGEFHKKATATCQRLPADTQR PFSGKIERYIDKLGYELAKIKAKELEGMEAKEIKVPI ILEQNAFEYEESLRKSKTGSNDRVINS KKDRDGKKLAKAKENAEDRLKDKDKRIKAFSSGICPYCGDTIGDDGEIDHILPRSHTLKIYGTV FNPEGNLIYVHQKCNQAKADS IYKLSDIKAGVSAQWIEEQVANIKGYKTFSVLSAEQQKAFRYA LFLQNDNEAYKKVVDWLRTDQSARVNGTQKYLAKKIQEKLTKMLPNKHLSFEFILADATEVSEL RRQYARQNPLLAKAEKQAPSSHAIDAVMAFVARYQKVFKDGTPPNADEVAKLAMLDSWNPASNE PLTKGLSTNQKIEKMIKSGDYGQKNMREVFGKS IFGENAIGERYKPIVVQEGGYYIGYPATVKK GYELKNCKVVTSKNDIAKLEKI IKNQDLI SLKENQYIKIFS INKQTI SELSNRYFNMNYKNLVE RDKEIVGLLEFIVENCRYYTKKVDVKFAPKYIHETKYPFYDDWRRFDEAWRYLQENQNKTSSKD RFVIDKSSLNEYYQPDKNEYKLDVDTQPIWDDFCRWYFLDRYKTANDKKS IRIKARKTFSLLAE SGVQGKVFRAKRKIPTGYAYQALPMDNNVIAGDYANILLEANSKTLSLVPKSGI S IEKQLDKKL DVIKKTDVRGLAIDNNSFFNADFDTHGIRLIVENTSVKVGNFPI SAIDKSAKRMIFRALFEKEK GKRKKKTTI SFKESGPVQDYLKVFLKKIVKIQLRTDGS I S IVVRKNAADFTLSFRSEHIQKLL K

SEQ ID NO: 341 MAYRLGLDIGITSVGWAVVALEKDESGLKPVRIQDLGVRIFDKAEDSKTGASLALPRREARSAR RRTRRRRHRLWRVKRLLEQHGILSMEQIEALYAQRTSSPDVYALRVAGLDRCLIAEEIARVLIH IAHRRGFQSNRKSEIKDSDAGKLLKAVQENENLMQSKGYRTVAEMLVSEATKTDAEGKLVHGKK HGYVSNVRNKAGEYRHTVSRQAIVDEVRKIFAAQRALGNDVMSEELEDSYLKILCSQRNFDDGP GGDSPYGHGSVSPDGVRQS IYERMVGSCTFETGEKRAPRSSYSFERFQLLTKVVNLRIYRQQED GGRYPCELTQTERARVIDCAYEQTKITYGKLRKLLDMKDTESFAGLTYGLNRSRNKTEDTVFVE MKFYHEVRKALQRAGVFIQDLS IETLDQIGWILSVWKSDDNRRKKLSTLGLSDNVIEELLPLNG SKFGHLSLKAIRKILPFLEDGYSYDVACELAGYQFQGKTEYVKQRLLPPLGEGEVTNPVVRRAL SQAIKVVNAVIRKHGSPES IHIELARELSKNLDERRKIEKAQKENQKNNEQIKDEIREILGSAH VTGRDIVKYKLFKQQQEFCMYSGEKLDVTRLFEPGYAEVDHI IPYGI SFDDSYDNKVLVKTEQN RQKGNRTPLEYLRDKPEQKAKFIALVES IPLSQKKKNHLLMDKRAIDLEQEGFRERNLSDTRYI TRALMNHIQAWLLFDETASTRSKRVVCVNGAVTAYMRARWGLTKDRDAGDKHHAADAVVVACIG DSLIQRVTKYDKFKRNALADRNRYVQQVSKSEGITQYVDKETGEVFTWESFDERKFLPNEPLEP WPFFRDELLARLSDDPSKNIRAIGLLTYSETEQIDPIFVSRMPTRKVTGAAHKETIRSPRIVKV DDNKGTEIQVVVSKVALTELKLTKDGEIKDYFRPEDDPRLYNTLRERLVQFGGDAKAAFKEPVY KI SKDGSVRTPVRKVKIQEKLTLGVPVHGGRGIAENGGMVRIDVFAKGGKYYFVPIYVADVLKR ELPNRLATAHKPYSEWRVVDDSYQFKFSLYPNDAVMIKPSREVDITYKDRKEPVGCRIMYFVSA NIASAS I SLRTHDNSGELEGLGIQGLEVFEKYVVGPLGDTHPVYKERRMPFRVERKMN

SEQ ID NO: 342

MPVLSPLSPNAAQGRRRWSLALDIGEGS IGWAVAEVDAEGRVLQLTGTGVTLFPSAWSNENGTY VAHGAADRAVRGQQQRHDSRRRRLAGLARLCAPVLERSPEDLKDLTRTPPKADPRAIFFLRADA ARRPLDGPELFRVLHHMAAHRGIRLAELQEVDPPPESDADDAAPAATEDEDGTRRAAADERAFR RLMAEHMHRHGTQPTCGEIMAGRLRETPAGAQPVTRARDGLRVGGGVAVPTRALIEQEFDAIRA IQAPRHPDLPWDSLRRLVLDQAPIAVPPATPCLFLEELRRRGETFQGRTITREAIDRGLTVDPL IQALRIRETVGNLRLHERITEPDGRQRYVPRAMPELGLSHGELTAPERDTLVRALMHDPDGLAA KDGRIPYTRLRKLIGYDNSPVCFAQERDTSGGGITVNPTDPLMARWIDGWVDLPLKARSLYVRD VVARGADSAALARLLAEGAHGVPPVAAAAVPAATAAILESDIMQPGRYSVCPWAAEAILDAWAN APTEGFYDVTRGLFGFAPGEIVLEDLRRARGALLAHLPRTMAAARTPNRAAQQRGPLPAYESVI PSQLITSLRRAHKGRAADWSAADPEERNPFLRTWTGNAATDHILNQVRKTANEVITKYGNRRGW DPLPSRITVELAREAKHGVIRRNEIAKENRENEGRRKKESAALDTFCQDNTVSWQAGGLPKERA ALRLRLAQRQEFFCPYCAERPKLRATDLFSPAETEIDHVIERRMGGDGPDNLVLAHKDCNNAKG KKTPHEHAGDLLDSPALAALWQGWRKENADRLKGKGHKARTPREDKDFMDRVGWRFEEDARAKA EENQERRGRRMLHDTARATRLARLYLAAAVMPEDPAEIGAPPVETPPSPEDPTGYTAIYRTI SR VQPVNGSVTHMLRQRLLQRDKNRDYQTHHAEDACLLLLAGPAVVQAFNTEAAQHGADAPDDRPV DLMPTSDAYHQQRRARALGRVPLATVDAALADIVMPESDRQDPETGRVHWRLTRAGRGLKRRID DLTRNCVILSRPRRPSETGTPGALHNATHYGRREITVDGRTDTVVTQRMNARDLVALLDNAKIV PAARLDAAAPGDTILKEICTEIADRHDRVVDPEGTHARRWI SARLAALVPAHAEAVARDIAELA DLDALADADRTPEQEARRSALRQSPYLGRAI SAKKADGRARAREQEILTRALLDPHWGPRGLRH LIMREARAPSLVRIRANKTDAFGRPVPDAAVWVKTDGNAVSQLWRLTSVVTDDGRRIPLPKPIE KRIEI SNLEYARLNGLDEGAGVTGNNAPPRPLRQDIDRLTPLWRDHGTAPGGYLGTAVGELEDK ARSALRGKAMRQTLTDAGITAEAGWRLDSEGAVCDLEVAKGDTVKKDGKTYKVGVITQGIFGMP VDAAGSAPRTPEDCEKFEEQYGIKPWKAKGIPLA

SEQ ID NO: 343

MNYTEKEKLFMKYILALDIGIASVGWAILDKESETVIEAGSNIFPEASAADNQLRRDMRGAKRN NRRLKTRINDFIKLWENNNLSIPQFKSTEIVGLKVRAITEEITLDELYLILYSYLKHRGISYLE DALDDTVSGSSAYANGLKLNAKELETHYPCEIQQERLNTIGKYRGQSQI INENGEVLDLSNVFT IGAYRKEIQRVFEIQKKYHPELTDEFCDGYMLIFNRKRKYYEGPGNEKSRTDYGRFTTKLDANG NYITEDNIFEKLIGKCSVYPDELRAAAASYTAQEYNVLNDLNNLTINGRKLEENEKHEIVERIK SSNTINMRKI I SDCMGENIDDFAGARIDKSGKEIFHKFEVYNKMRKALLEIGIDI SNYSREELD EIGYIMTINTDKEAMMEAFQKSWIDLSDDVKQCLINMRKTNGALFNKWQSFSLKIMNELIPEMY AQPKEQMTLLTEMGVTKGTQEEFAGLKYIPVDVVSEDIFNPVVRRSVRI SFKILNAVLKKYKAL DTIVIEMPRDRNSEEQKKRINDSQKLNEKEMEYIEKKLAVTYGIKLSPSDFSSQKQLSLKLKLW NEQDGICLYSGKTIDPNDI INNPQLFEIDHI IPRS I SFDDARSNKVLVYRSENQKKGNQTPYYY LTHSHSEWSFEQYKATVMNLSKKKEYAI SRKKIQNLLYSEDITKMDVLKGFINR INDTSYASR LVLNTIQNFFMANEADTKVKVIKGSYTHQMRCNLKLDKNRDESYSHHAVDAMLIGYSELGYEAY HKLQGEFIDFETGEILRKDMWDENMSDEVYADYLYGKKWANIRNEVVKAEKNVKYWHYVMRKSN RGLCNQTIRGTREYDGKQYKINKLDIRTKEGIKVFAKLAFSKKDSDRERLLVYLNDRRTFDDLC KIYEDYSDAANPFVQYEKETGDI IRKYSKKHNGPRIDKLKYKDGEVGACIDI SHKYGFEKGSKK VILESLVPYRMDVYYKEENHSYYLVGVKQSDIKFEKGRNVIDEEAYARILVNEKMIQPGQSRAD LENLGFKFKLSFYKNDI IEYEKDGKIYTERLVSRTMPKQRNYIETKPIDKAKFEKQNLVGLGKT KFIKKYRYDILGNKYSCSEEKFTSFC

SEQ ID NO: 344

MLRLYCANNLVLNNVQNLWKYLLLLIFDKKI IFLFKIKVILIRRYMENNNKEKIVIGFDLGVAS VGWS IVNAETKEVIDLGVRLFSEPEKADYRRAKRTTRRLLRRKKFKREKFHKLILKNAEIFGLQ SRNEILNVYKDQSSKYRNILKLKINALKEEIKPSELVWILRDYLQNRGYFYKNEKLTDEFVSNS FPSKKLHEHYEKYGFFRGSVKLDNKLDNKKDKAKEKDEEEESDAKKESEELIFSNKQWINEIVK VFENQSYLTESFKEEYLKLFNYVRPFNKGPGSKNSRTAYGVFSTDIDPETNKFKDYSNIWDKTI GKCSLFEEEIRAPKNLPSALIFNLQNEICTIKNEFTEFKNWWLNAEQKSEILKFVFTELFNWKD KKYSDKKFNKNLQDKIKKYLLNFALENFNLNEEILKNRDLENDTVLGLKGVKYYEKSNATADAA LEFSSLKPLYVFIKFLKEKKLDLNYLLGLENTEILYFLDS IYLAI SYSSDLKERNEWFKKLLKE LYPKIKNNNLEI IENVEDIFEITDQEKFESFSKTHSLSREAFNHI IPLLLSNNEGKNYESLKHS NEELKKRTEKAELKAQQNQKYLKDNFLKEALVPLSVKTSVLQAIKIFNQI IKNFGKKYEI SQVV IEMARELTKPNLEKLLNNATNSNIKILKEKLDQTEKFDDFTKKKFIDKIENSVVFRNKLFLWFE QDRKDPYTQLDIKINEIEDETEIDHVIPYSKSADDSWFNKLLVKKSTNQLKKNKTVWEYYQNES DPEAKWNKFVAWAKRIYLVQKSDKESKDNSEKNS IFKNKKPNLKFK ITKKLFDPYKDLGFLAR NLNDTRYATKVFRDQLNNYSKHHSKDDENKLFKVVCMNGS ITSFLRKSMWRKNEEQVYRFNFWK KDRDQFFHHAVDAS I IAIFSLLTKTLYNKLRVYESYDVQRREDGVYLINKETGEVKKADKDYWK DQHNFLKIRENAIEIKNVLNNVDFQNQVRYSRKANTKLNTQLFNETLYGVKEFENNFYKLEKVN LFSRKDLRKFILEDLNEESEKNKKNENGSRKRILTEKYIVDEILQILENEEFKDSKSDINALNK YMDSLPSKFSEFFSQDFINKCKKENSLILTFDAIKHNDPKKVIKIKNLKFFREDATLKNKQAVH KDSKNQIKSFYESYKCVGFIWLKNKNDLEES IFVPINSRVIHFGDKDKDIFDFDSYNKEKLLNE INLKRPENKKFNS INEIEFVKFVKPGALLLNFENQQIYYI STLESSSLRAKIKLLNKMDKGKAV SMKKITNPDEYKI IEHVNPLGINLNWTKKLENNN

SEQ ID NO: 345

MLMSKHVLGLDLGVGS IGWCLIALDAQGDPAEILGMGSRVVPLNNATKAIEAFNAGAAFTASQE RTARRTMRRGFARYQLRRYRLRRELEKVGMLPDAALIQLPLLELWELRERAATAGRRLTLPELG RVLCHINQKRGYRHVKSDAAAIVGDEGEKKKDSNSAYLAGIRANDEKLQAEHKTVGQYFAEQLR QNQSESPTGGI SYRIKDQIFSRQCYIDEYDQIMAVQRVHYPDILTDEFIRMLRDEVIFMQRPLK SCKHLVSLCEFEKQERVMRVQQDDGKGGWQLVERRVKFGPKVAPKSSPLFQLCCIYEAVNNIRL TRPNGSPCDITPEERAKIVAHLQSSASLSFAALKKLLKEKALIADQLTSKSGLKGNSTRVALAS ALQPYPQYHHLLDMELETRMMTVQLTDEETGEVTEREVAVVTDSYVRKPLYRLWHILYS IEERE AMRRALITQLGMKEEDLDGGLLDQLYRLDFVKPGYGNKSAKFICKLLPQLQQGLGYSEACAAVG YRHSNSPTSEEITERTLLEKIPLLQRNELRQPLVEKILNQMINLVNALKAEYGIDEVRVELARE LKMSREERERMARNNKDREERNKGVAAKIRECGLYPTKPRIQKYMLWKEAGRQCLYCGRS IEEE QCLREGGMEVEHI IPKSVLYDDSYGNKTCACRRCNKEKGNRTALEYIRAKGREAEYMKRINDLL KEKKI SYSKHQRLRWLKEDIPSDFLERQLRLTQYI SRQAMAILQQGIRRVSASEGGVTARLRSL WGYGKILHTLNLDRYDSMGETERVSREGEATEELHITNWSKRMDHRHHAIDALVVACTRQSYIQ RLNRLSSEFGREDKKKEDQEAQEQQATETGRLSNLERWLTQRPHFSVRTVSDKVAEILI SYRPG QRVVTRGRNIYRKKMADGREVSCVQRGVLVPRGELMEASFYGKILSQGRVRIVKRYPLHDLKGE VVDPHLRELITTYNQELKSREKGAPIPPLCLDKDKKQEVRSVRCYAKTLSLDKAIPMCFDEKGE PTAFVKSASNHHLALYRTPKGKLVES IVTFWDAVDRARYGIPLVITHPREVMEQVLQRGDIPEQ VLSLLPPSDWVFVDSLQQDEMVVIGLSDEELQRALEAQNYRKI SEHLYRVQKMSSSYYVFRYHL ETSVADDKNTSGRIPKFHRVQSLKAYEERNIRKVRVDLLGRISLL

SEQ ID NO: 346

MSDLVLGLDIGIGSVGVGILNKVTGEI IHKNSRIFPAAQAENNLVRRTNRQGRRLARRKKHRRV RLNRLFEESGLITDFTKI S INLNPYQLRVKGLTDELSNEELFIALKNMVKHRGI SYLDDASDDG NSSVGDYAQIVKENSKQLETKTPGQIQLERYQTYGQLRGDFTVEKDGKKHRLINVFPTSAYRSE ALRILQTQQEFNPQITDEFINRYLEILTGKRKYYHGPGNEKSRTDYGRYRTSGETLDNIFGILI GKCTFYPDEFRAAKASYTAQEFNLLNDLNNLTVPTETKKLSKEQKNQI INYVKNEKAMGPAKLF KYIAKLLSCDVADIKGYRIDKSGKAEIHTFEAYRKMKTLETLDIEQMDRETLDKLAYVLTLNTE REGIQEALEHEFADGSFSQKQVDELVQFRKANSS IFGKGWHNFSVKLMMELIPELYETSEEQMT ILTRLGKQKTTSSSNKTKYIDEKLLTEEIYNPVVAKSVRQAIKIVNAAIKEYGDFDNIVIEMAR ETNEDDEKKAIQKIQKANKDEKDAAMLKAANQYNGKAELPHSVFHGHKQLATKIRLWHQQGERC LYTGKTI S IHDLINNSNQFEVDHILPLS ITFDDSLANKVLVYATANQEKGQRTPYQALDSMDDA WSFRELKAFVRESKTLSNKKKEYLLTEEDI SKFDVRKKFIERNLVDTRYASRVVLNALQEHFRA HKIDTKVSVVRGQFTSQLRRHWGIEKTRDTYHHHAVDALI IAASSQLNLWKKQKNTLVSYSEDQ LLDIETGELI SDDEYKESVFKAPYQHFVDTLKSKEFEDS ILFSYQVDSKFNRKI SDATIYATRQ AKVGKDKADETYVLGKIKDIYTQDGYDAFMKIYKKDKSKFLMYRHDPQTFEKVIEPILENYPNK QINEKGKEVPCNPFLKYKEEHGYIRKYSKKGNGPEIKSLKYYDSKLGNHIDITPKDSNNKVVLQ SVSPWRADVYFNKTTGKYEILGLKYADLQFEKGTGTYKI SQEKYNDIKKKEGVDSDSEFKFTLY KNDLLLVKDTETKEQQLFRFLSRTMPKQKHYVELKPYDKQKFEGGEALIKVLGNVANSGQCKKG LGKSNI S IYKVRTDVLGNQHI IKNEGDKPKLDF

SEQ ID NO: 347

MNAEHGKEGLLIMEENFQYRIGLDIGITSVGWAVLQNNSQDEPVRITDLGVRIFDVAENPKNGD ALAAPRRDARTTRRRLRRRRHRLERIKFLLQENGLIEMDSFMERYYKGNLPDVYQLRYEGLDRK LKDEELAQVLIHIAKHRGFRSTRKAETKEKEGGAVLKATTENQKIMQEKGYRTVGEMLYLDEAF HTECLWNEKGYVLTPRNRPDDYKHTILRSMLVEEVHAIFAAQRAHGNQKATEGLEEAYVEIMTS QRSFDMGPGLQPDGKPSPYAMEGFGDRVGKCTFEKDEYRAPKATYTAELFVALQKINHTKLIDE FGTGRFFSEEERKTI IGLLLSSKELKYGTIRKKLNIDPSLKFNSLNYSAKKEGETEEERVLDTE KAKFASMFWTYEYSKCLKDRTEEMPVGEKADLFDRIGEILTAYKNDDSRSSRLKELGLSGEEID GLLDLSPAKYQRVSLKAMRKMQPYLEDGLIYDKACEAAGYDFRALNDGNKKHLLKGEEINAIVN DITNPVVKRSVSQTIKVINAI IQKYGSPQAVNIELAREMSKNFQDRTNLEKEMKKRQQENERAK QQI IELGKQNPTGQDILKYRLWNDQGGYCLYSGKKIPLEELFDGGYDIDHILPYS ITFDDSYRN KVLVTAQENRQKGNRTPYEYFGADEKRWEDYEASVRLLVRDYKKQQKLLKKNFTEEERKEFKER NLNDTKYITRVVYNMIRQNLELEPFNHPEKKKQVWAVNGAVTSYLRKRWGLMQKDRSTDRHHAM DAVVIACCTDGMIHKI SRYMQGRELAYSRNFKFPDEETGEILNRDNFTREQWDEKFGVKVPLPW NSFRDELDIRLLNEDPKNFLLTHADVQRELDYPGWMYGEEESPIEEGRYINYIRPLFVSRMPNH KVTGSAHDATIRSARDYETRGVVITKVPLTDLKLNKDNEIEGYYDKDSDRLLYQALVRQLLLHG NDGKKAFAEDFHKPKADGTEGPVVRKVKIEKKQTSGVMVRGGTGIAANGEMVRIDVFRENGKYY FVPVYTADVVRKVLPNRAATHTKPYSEWRVMDDANFVFSLYSRDLIHVKSKKDIKTNLVNGGLL LQKEIFAYYTGADIATAS IAGFANDSNFKFRGLGIQSLEIFEKCQVDILGNI SVVRHENRQEFH

SEQ ID NO: 348

MRVLGLDAGIASLGWALIEIEESNRGELSQGTI IGAGTWMFDAPEEKTQAGAKLKSEQRRTFRG QRRVVRRRRQRMNEVRRILHSHGLLPSSDRDALKQPGLDPWRIRAEALDRLLGPVELAVALGHI ARHRGFKSNSKGAKTNDPADDTSKMKRAVNETREKLARFGSAAKMLVEDESFVLRQTPTKNGAS EIVRRFRNREGDYSRSLLRDDLAAEMRALFTAQARFQSAIATADLQTAFTKAAFFQRPLQDSEK LVGPCPFEVDEKRAPKRGYSFELFRFLSRLNHVTLRDGKQERTLTRDELALAAADFGAAAKVSF TALRKKLKLPETTVFVGVKADEESKLDVVARSGKAAEGTARLRSVIVDALGELAWGALLCSPEK LDKIAEVI SFRSDIGRI SEGLAQAGCNAPLVDALTAAASDGRFDPFTGAGHI SSKAARNILSGL RQGMTYDKACCAADYDHTASRERGAFDVGGHGREALKRILQEERI SRELVGSPTARKALIES IK QVKAIVERYGVPDRIHVELARDVGKS IEEREEITRGIEKRNRQKDKLRGLFEKEVGRPPQDGAR GKEELLRFELWSEQMGRCLYTDDYI SPSQLVATDDAVQVDHILPWSRFADDSYANKTLCMAKAN QDKKGRTPYEWFKAEKTDTEWDAFIVRVEALADMKGFKKRNYKLRNAEEAAAKFRNRNLNDTRW ACRLLAEALKQLYPKGEKDKDGKERRRVFSRPGALTDRLRRAWGLQWMKKSTKGDRIPDDRHHA LDAIVIAATTESLLQRATREVQEIEDKGLHYDLVKNVTPPWPGFREQAVEAVEKVFVARAERRR ARGKAHDATIRHIAVREGEQRVYERRKVAELKLADLDRVKDAERNARLIEKLRNWIEAGSPKDD PPLSPKGDPIFKVRLVTKSKVNIALDTGNPKRPGTVDRGEMARVDVFRKASKKGKYEYYLVPIY PHDIATMKTPPIRAVQAYKPEDEWPEMDSSYEFCWSLVPMTYLQVI SSKGEIFEGYYRGMNRSV GAIQLSAHSNSSDVVQGIGARTLTEFKKFNVDRFGRKHEVERELRTWRGETWRGKAYI

SEQ ID NO: 349

MGNYYLGLDVGIGS IGWAVINIEKKRIEDFNVRIFKSGEIQEKNRNSRASQQCRRSRGLRRLYR RKSHRKLRLKNYLS I IGLTTSEKIDYYYETADNNVIQLRNKGLSEKLTPEEIAACLIHICNNRG YKDFYEVNVEDIEDPDERNEYKEEHDS IVLI SNLMNEGGYCTPAEMICNCREFDEPNSVYRKFH NSAASKNHYLITRHMLVKEVDLILENQSKYYGILDDKTIAKIKDI IFAQRDFEIGPGKNERFRR FTGYLDS IGKCQFFKDQERGSRFTVIADIYAFVNVLSQYTYTNNRGESVFDTSFANDLINSALK NGSMDKRELKAIAKSYHIDI SDKNSDTSLTKCFKYIKVVKPLFEKYGYDWDKLIENYTDTDNNV LNRIGIVLSQAQTPKRRREKLKALNIGLDDGLINELTKLKLSGTANVSYKYMQGS IEAFCEGDL YGKYQAKFNKEIPDIDENAKPQKLPPFKNEDDCEFFKNPVVFRS INETRKLINAI IDKYGYPAA VNIETADELNKTFEDRAIDTKRNNDNQKENDRIVKEI IECIKCDEVHARHLIEKYKLWEAQEGK CLYSGETITKEDMLRDKDKLFEVDHIVPYSLILDNTINNKALVYAEENQKKGQRTPLMYMNEAQ AADYRVRVNTMFKSKKCSKKKYQYLMLPDLNDQELLGGWRSRNLNDTRYICKYLVNYLRKNLRF DRSYESSDEDDLKIRDHYRVFPVKSRFTSMFRRWWLNEKTWGRYDKAELKKLTYLDHAADAI I I ANCRPEYVVLAGEKLKLNKMYHQAGKRITPEYEQSKKACIDNLYKLFRMDRRTAEKLLSGHGRL TPI IPNLSEEVDKRLWDKNIYEQFWKDDKDKKSCEELYRENVASLYKGDPKFASSLSMPVI SLK PDHKYRGTITGEEAIRVKEIDGKLIKLKRKSISEITAESINSIYTDDKILIDSLKTIFEQADYK DVGDYLKKTNQHFFTTSSGKRVNKVTVIEKVPSRWLRKEIDDNNFSLLNDSSYYCIELYKDSKG DNNLQGIAMSDIVHDRKTKKLYLKPDFNYPDDYYTHVMYIFPGDYLRIKSTSKKSGEQLKFEGY FI SVKNVNENSFRFI SDNKPCAKDKRVS ITKKDIVIKLAVDLMGKVQGENNGKGI SCGEPLSLL KEKN SEQ ID NO: 350

MLSRQLLGASHLARPVSYSYNVQDNDVHCSYGERCFMRGKRYRIGIDVGLNSVGLAAVEVSDEN SPVRLLNAQSVIHDGGVDPQKNKEAITRKNMSGVARRTRRMRRRKRERLHKLDMLLGKFGYPVI EPESLDKPFEEWHVRAELATRYIEDDELRRES I S IALRHMARHRGWRNPYRQVDSLI SDNPYSK QYGELKEKAKAYNDDATAAEEESTPAQLVVAMLDAGYAEAPRLRWRTGSKKPDAEGYLPVRLMQ EDNANELKQIFRVQRVPADEWKPLFRSVFYAVSPKGSAEQRVGQDPLAPEQARALKASLAFQEY RIANVITNLRIKDASAELRKLTVDEKQS IYDQLVSPSSEDITWSDLCDFLGFKRSQLKGVGSLT EDGEERI SSRPPRLTSVQRIYESDNKIRKPLVAWWKSASDNEHEAMIRLLSNTVDIDKVREDVA YASAIEFIDGLDDDALTKLDSVDLPSGRAAYSVETLQKLTRQMLTTDDDLHEARKTLFNVTDSW RPPADPIGEPLGNPSVDRVLKNVNRYLMNCQQRWGNPVSVNIEHVRSSFSSVAFARKDKREYEK NNEKRS IFRSSLSEQLRADEQMEKVRESDLRRLEAIQRQNGQCLYCGRTITFRTCEMDHIVPRK GVGSTNTRTNFAAVCAECNRMKSNTPFAIWARSEDAQTRGVSLAEAKKRVTMFTFNPKSYAPRE VKAFKQAVIARLQQTEDDAAIDNRS IESVAWMADELHRRIDWYFNAKQYVNSAS IDDAEAETMK TTVSVFQGRVTASARRAAGIEGKIHFIGQQSKTRLDRRHHAVDASVIAMMNTAAAQTLMERESL RESQRLIGLMPGERSWKEYPYEGTSRYESFHLWLDNMDVLLELLNDALDNDRIAVMQSQRYVLG NSIAHDATIHPLEKVPLGSAMSADLIRRASTPALWCALTRLPDYDEKEGLPEDSHREIRVHDTR YSADDEMGFFASQAAQIAVQEGSADIGSAIHHARVYRCWKTNAKGVRKYFYGMIRVFQTDLLRA CHDDLFTVPLPPQS I SMRYGEPRVVQALQSGNAQYLGSLVVGDEIEMDFSSLDVDGQIGEYLQF FSQFSGGNLAWKHWVVDGFFNQTQLRIRPRYLAAEGLAKAFSDDVVPDGVQKIVTKQGWLPPVN TASKTAVRIVRRNAFGEPRLSSAHHMPCSWQWRHE

SEQ ID NO: 351

MYS IGLDLGI SSVGWSVIDERTGNVIDLGVRLFSAKNSEKNLERRTNRGGRRLIRRKTNRLKDA KKILAAVGFYEDKSLKNSCPYQLRVKGLTEPLSRGEIYKVTLHILKKRGI SYLDEVDTEAAKES QDYKEQVRKNAQLLTKYTPGQIQLQRLKENNRVKTGINAQGNYQLNVFKVSAYANELATILKTQ QAFYPNELTDDWIALFVQPGIAEEAGLIYRKRPYYHGPGNEANNSPYGRWSDFQKTGEPATNIF DKLIGKDFQGELRASGLSLSAQQYNLLNDLTNLKIDGEVPLSSEQKEYILTELMTKEFTRFGVN DVVKLLGVKKERLSGWRLDKKGKPEIHTLKGYRNWRKIFAEAGIDLATLPTETIDCLAKVLTLN TEREGIENTLAFELPELSESVKLLVLDRYKELSQS I STQSWHRFSLKTLHLLIPELMNATSEQN TLLEQFQLKSDVRKRYSEYKKLPTKDVLAEIYNPTVNKTVSQAFKVIDALLVKYGKEQIRYITI EMPRDDNEEDEKKRIKELHAKNSQRKNDSQSYFMQKSGWSQEKFQTTIQKNRRFLAKLLYYYEQ DGICAYTGLPI SPELLVSDSTEIDHI IPI S I SLDDS INNKVLVLSKANQVKGQQTPYDAWMDGS FKKINGKFSNWDDYQKWVESRHFSHKKENNLLETRNIFDSEQVEKFLARNLNDTRYASRLVLNT LQSFFTNQETKVRVVNGSFTHTLRKKWGADLDKTRETHHHHAVDATLCAVTSFVKVSRYHYAVK EETGEKVMREIDFETGEIVNEMSYWEFKKSKKYERKTYQVKWPNFREQLKPVNLHPRIKFSHQV DRKANRKLSDATIYSVREKTEVKTLKSGKQKITTDEYTIGKIKDIYTLDGWEAFKKKQDKLLMK DLDEKTYERLLS IAETTPDFQEVEEKNGKVKRVKRSPFAVYCEENDIPAIQKYAKKNNGPLIRS LKYYDGKLNKHINITKDSQGRPVEKTKNGRKVTLQSLKPYRYDIYQDLETKAYYTVQLYYSDLR FVEGKYGITEKEYMKKVAEQTKGQVVRFCFSLQKNDGLEIEWKDSQRYDVRFYNFQSANS INFK GLEQEMMPAENQFKQKPYNNGAINLNIAKYGKEGKKLRKFNTDILGKKHYLFYEKEPKNI IK

SEQ ID NO: 352

MYFYKNKENKLNKKVVLGLDLGIASVGWCLTDI SQKEDNKFPI ILHGVRLFETVDDSDDKLLNE TRRKKRGQRRRNRRLFTRKRDFIKYLIDNNI IELEFDKNPKILVRNFIEKYINPFSKNLELKYK SVTNLPIGFHNLRKAAINEKYKLDKSELIVLLYFYLSLRGAFFDNPEDTKSKEMNKNEIEIFDK NES IKNAEFPIDKI IEFYKI SGKIRSTINLKFGHQDYLKEIKQVFEKQNIDFMNYEKFAMEEKS FFSRIRNYSEGPGNEKSFSKYGLYANENGNPELI INEKGQKIYTKIFKTLWESKIGKCSYDKKL YRAPKNSFSAKVFDITNKLTDWKHKNEYI SERLKRKILLSRFLNKDSKSAVEKILKEE IKFEN LSEIAYNKDDNKINLPI INAYHSLTTIFKKHLINFENYLI SNENDLSKLMSFYKQQSEKLFVPN EKGSYEINQNNNVLHIFDAISNILNKFSTIQDRIRILEGYFEFSNLKKDVKSSEIYSEIAKLRE FSGTSSLSFGAYYKFIPNLISEGSKNYSTISYEEKALQNQKNNFSHSNLFEKTWVEDLIASPTV KRSLRQTMNLLKEIFKYSEKNNLEIEKIVVEVTRSSNNKHERKKIEGINKYRKEKYEELKKVYD LPNENTTLLKKLWLLRQQQGYDAYSLRKIEANDVINKPWNYDIDHIVPRS I SFDDSFSNLVIVN KLDNAKKSNDLSAKQFIEKIYGIEKLKEAKENWGNWYLRNANGKAFNDKGKFIKLYTIDNLDEF DNSDFINRNLSDTSYITNALVNHLTFSNSKYKYSVVSVNGKQTSNLRNQIAFVGIKNNKETERE WKRPEGFKSINSNDFLIREEGKNDVKDDVLIKDRSFNGHHAEDAYFITI ISQYFRSFKRIERLN VNYRKETRELDDLEKNNIKFKEKASFDNFLLINALDELNEKLNQMRFSRMVITKKNTQLFNETL YSGKYDKGKNTIKKVEKLNLLDNRTDKIKKIEEFFDEDKLKENELTKLHIFNHDKNLYETLKII WNEVKIEIKNKNLNEKNYFKYFVNKKLQEGKI SFNEWVPILDNDFKI IRKIRYIKFSSEEKETD EI IFSQSNFLKIDQRQNFSFHNTLYWVQIWVYKNQKDQYCFI S IDARNSKFEKDEIKINYEKLK TQKEKLQI INEEPILKINKGDLFENEEKELFYIVGRDEKPQKLEIKYILGKKIKDQKQIQKPVK KYFPNWKKVNLTYMGEIFKK

SEQ ID NO: 353

MDNKNYRIGIDVGLNS IGFCAVEVDQHDTPLGFLNLSVYRHDAGIDPNGKKTNTTRLAMSGVAR RTRRLFRKRKRRLAALDRFIEAQGWTLPDHADYKDPYTPWLVRAELAQTPIRDENDLHEKLAIA VRHIARHRGWRSPWVPVRSLHVEQPPSDQYLALKERVEAKTLLQMPEGATPAEMVVALDLSVDV NLRPKNREKTDTRPENKKPGFLGGKLMQSDNANELRKIAKIQGLDDALLRELIELVFAADSPKG ASGELVGYDVLPGQHGKRRAEKAHPAFQRYRIAS IVSNLRIRHLGSGADERLDVETQKRVFEYL LNAKPTADITWSDVAEEIGVERNLLMGTATQTADGERASAKPPVDVTNVAFATCKIKPLKEWWL NADYEARCVMVSALSHAEKLTEGTAAEVEVAEFLQNLSDEDNEKLDSFSLPIGRAAYSVDSLER LTKRMIENGEDLFEARVNEFGVSEDWRPPAEPIGARVGNPAVDRVLKAVNRYLMAAEAEWGAPL SV IEHVREGFI SKRQAVEIDRENQKRYQRNQAVRSQIADHINATSGVRGSDVTRYLAIQRQNG ECLYCGTAITFVNSEMDHIVPRAGLGSTNTRDNLVATCERCNKSKSNKPFAVWAAECGIPGVSV AEALKRVDFWIADGFASSKEHRELQKGVKDRLKRKVSDPEIDNRSMESVAWMARELAHRVQYYF DEKHTGTKVRVFRGSLTSAARKASGFESRVNFIGGNGKTRLDRRHHAMDAATVAMLRNSVAKTL VLRGNIRASERAIGAAETWKSFRGENVADRQIFESWSENMRVLVEKFNLALYNDEVS IFSSLRL QLGNGKAHDDTITKLQMHKVGDAWSLTEIDRASTPALWCALTRQPDFTWKDGLPANEDRTIIVN GTHYGPLDKVGIFGKAAASLLVRGGSVDIGSAIHHARIYRIAGKKPTYGMVRVFAPDLLRYRNE DLFNVELPPQSVSMRYAEPKVREAIREGKAEYLGWLVVGDELLLDLSSETSGQIAELQQDFPGT THWTVAGFFSPSRLRLRPVYLAQEGLGEDVSEGSKS I IAGQGWRPAVNKVFGSAMPEVIRRDGL GRKRRFSYSGLPVSWQG

SEQ ID NO: 354

MRLGLDIGTSS IGWWLYETDGAGSDARITGVVDGGVRIFSDGRDPKSGASLAVDRRAARAMRRR RDRYLRRRATLMKVLAETGLMPADPAEAKALEALDPFALRAAGLDEPLPLPHLGRALFHLNQRR GFKSNRKTDRGDNESGKIKDATARLDMEMMANGARTYGEFLHKRRQKATDPRHVPSVRTRLSIA NRGGPDGKEEAGYDFYPDRRHLEEEFHKLWAAQGAHHPELTETLRDLLFEKIFFQRPLKEPEVG LCLFSGHHGVPPKDPRLPKAHPLTQRRVLYETVNQLRVTADGREARPLTREERDQVIHALDNKK PTKSLSSMVLKLPALAKVLKLRDGERFTLETGVRDAIACDPLRASPAHPDRFGPRWS ILDADAQ WEVI SRIRRVQSDAEHAALVDWLTEAHGLDRAHAEATAHAPLPDGYGRLGLTATTRILYQLTAD VVTYADAVKACGWHHSDGRTGECFDRLPYYGEVLERHVIPGSYHPDDDDITRFGRITNPTVHIG LNQLRRLVNRI IETHGKPHQIVVELARDLKKSEEQKRADIKRIRDTTEAAKKRSEKLEELEIED NGRNRMLLRLWEDLNPDDAMRRFCPYTGTRI SAAMIFDGSCDVDHILPYSRTLDDSFPNRTLCL REANRQKRNQTPWQAWGDTPHWHAIAANLKNLPENKRWRFAPDAMTRFEGENGFLDRALKDTQY LARI SRSYLDTLFTKGGHVWVVPGRFTEMLRRHWGLNSLLSDAGRGAVKAKNRTDHRHHAIDAA VIAATDPGLLNRI SRAAGQGEAAGQSAELIARDTPPPWEGFRDDLRVRLDRI IVSHRADHGRID HAARKQGRDSTAGQLHQETAYS IVDDIHVASRTDLLSLKPAQLLDEPGRSGQVRDPQLRKALRV ATGGKTGKDFENALRYFASKPGPYQAIRRVRI IKPLQAQARVPVPAQDPIKAYQGGSNHLFEIW RLPDGEIEAQVITSFEAHTLEGEKRPHPAAKRLLRVHKGDMVALERDGRRVVGHVQKMDIANGL FIVPHNEANADTRNNDKSDPFKWIQIGARPAIASGIRRVSVDEIGRLRDGGTRPI

SEQ ID NO: 355

MLHCIAVIRVPPSEEPGFFETHADSCALCHHGCMTYAANDKAIRYRVGIDVGLRS IGFCAVEVD DEDHPIRILNSVVHVHDAGTGGPGETESLRKRSGVAARARRRGRAEKQRLKKLDVLLEELGWGV SSNELLDSHAPWHIRKRLVSEYIEDETERRQCLSVAMAHIARHRGWRNSFSKVDTLLLEQAPSD RMQGLKERVEDRTGLQFSEEVTQGELVATLLEHDGDVTIRGFVRKGGKATKVHGVLEGKYMQSD LVAELRQICRTQRVSETTFEKLVLS IFHSKEPAPSAARQRERVGLDELQLALDPAAKQPRAERA HPAFQKFKVVATLANMRIREQSAGERSLTSEELNRVARYLLNHTESESPTWDDVARKLEVPRHR LRGSSRASLETGGGLTYPPVDDTTVRVMSAEVDWLADWWDCANDESRGHMIDAI SNGCGSEPDD VEDEEVNELI SSATAEDMLKLELLAKKLPSGRVAYSLKTLREVTAAILETGDDLSQAITRLYGV DPGWVPTPAPIEAPVGNPSVDRVLKQVARWLKFASKRWGVPQTVNIEHTREGLKSASLLEEERE RWERFEARREIRQKEMYKRLGI SGPFRRSDQVRYEILDLQDCACLYCGNEINFQTFEVDHI IPR VDASSDSRRTNLAAVCHSCNSAKGGLAFGQWVKRGDCPSGVSLENAIKRVRSWSKDRLGLTEKA MGKRKSEVI SRLKTEMPYEEFDGRSMESVAWMAIELKKRIEGYFNSDRPEGCAAVQVNAYSGRL TACARRAAHVDKRVRLIRLKGDDGHHKNRFDRRNHAMDALVIALMTPAIARTIAVREDRREAQQ LTRAFESWKNFLGSEERMQDRWESWIGDVEYACDRLNELIDADKIPVTENLRLRNSGKLHADQP ESLKKARRGSKRPRPQRYVLGDALPADVINRVTDPGLWTALVRAPGFDSQLGLPADLNRGLKLR GKRI SADFPIDYFPTDSPALAVQGGYVGLEFHHARLYRI IGPKEKVKYALLRVCAIDLCGIDCD DLFEVELKPSS I SMRTADAKLKEAMGNGSAKQIGWLVLGDEIQIDPTKFPKQS IGKFLKECGPV SSWRVSALDTPSKITLKPRLLSNEPLLKTSRVGGHESDLVVAECVEKIMKKTGWVVEINALCQS GLIRVIRRNALGEVRTSPKSGLPI SLNLR

SEQ ID NO: 356

MRYRVGLDLGTASVGAAVFSMDEQGNPMELIWHYERLFSEPLVPDMGQLKPKKAARRLARQQRR QIDRRASRLRRIAIVSRRLGIAPGRNDSGVHGNDVPTLRAMAVNERIELGQLRAVLLRMGKKRG YGGTFKAVRKVGEAGEVASGASRLEEEMVALASVQNKDSVTVGEYLAARVEHGLPSKLKVAANN EYYAPEYALFRQYLGLPAIKGRPDCLPNMYALRHQIEHEFERIWATQSQFHDVMKDHGVKEEIR NAIFFQRPLKSPADKVGRCSLQTNLPRAPRAQIAAQNFRIEKQMADLRWGMGRRAEMLNDHQKA VIRELLNQQKELSFRKIYKELERAGCPGPEGKGLNMDRAALGGRDDLSGNTTLAAWRKLGLEDR WQELDEVTQIQVINFLADLGSPEQLDTDDWSCRFMGKNGRPRNFSDEFVAFMNELRMTDGFDRL SKMGFEGGRSSYS IKALKALTEWMIAPHWRETPETHRVDEEAAIRECYPESLATPAQGGRQSKL EPPPLTGNEVVDVALRQVRHTINMMIDDLGSVPAQIVVEMAREMKGGVTRRNDIEKQNKRFASE RKKAAQS IEENGKTPTPARILRYQLWIEQGHQCPYCESNI SLEQALSGAYTNFEHILPRTLTQI GRKRSELVLAHRECNDEKGNRTPYQAFGHDDRRWRIVEQRANALPKKSSRKTRLLLLKDFEGEA LTDES IDEFADRQLHESSWLAKVTTQWLSSLGSDVYVSRGSLTAELRRRWGLDTVIPQVRFESG MPVVDEEGAEITPEEFEKFRLQWEGHRVTREMRTDRRPDKRIDHRHHLVDAIVTALTSRSLYQQ YAKAWKVADEKQRHGRVDVKVELPMPILTIRDIALEAVRSVRI SHKPDRYPDGRFFEATAYGIA QRLDERSGEKVDWLVSRKSLTDLAPEKKS IDVDKVRANI SRIVGEAIRLHI SNIFEKRVSKGMT PQQALREPIEFQGNILRKVRCFYSKADDCVRIEHSSRRGHHYKMLLNDGFAYMEVPCKEGILYG VPNLVRPSEAVGIKRAPESGDFIRFYKGDTVKNIKTGRVYTIKQILGDGGGKLILTPVTETKPA DLLSAKWGRLKVGGRNIHLLRLCAE

SEQ ID NO: 357

MIGEHVRGGCLFDDHWTPNWGAFRLPNTVRTFTKAENPKDGSSLAEPRRQARGLRRRLRRKTQR LEDLRRLLAKEGVLSLSDLETLFRETPAKDPYQLRAEGLDRPLSFPEWVRVLYHITKHRGFQSN RRNPVEDGQERSRQEEEGKLLSGVGENERLLREGGYRTAGEMLARDPKFQDHRRNRAGDYSHTL SRSLLLEEARRLFQSQRTLGNPHASSNLEEAFLHLVAFQNPFASGEDIRNKAGHCSLEPDQIRA PRRSASAETFMLLQKTGNLRLIHRRTGEERPLTDKEREQIHLLAWKQEKVTHKTLRRHLEIPEE WLFTGLPYHRSGDKAEEKLFVHLAGIHEIRKALDKGPDPAVWDTLRSRRDLLDS IADTLTFYKN EDEILPRLESLGLSPENARALAPLSFSGTAHLSLSALGKLLPHLEEGKSYTQARADAGYAAPPP DRHPKLPPLEEADWRNPVVFRALTQTRKVVNALVRRYGPPWCIHLETARELSQPAKVRRRIETE QQANEKKKQQAEREFLDIVGTAPGPGDLLKMRLWREQGGFCPYCEEYLNPTRLAEPGYAEMDHI LPYSRSLDNGWHNRVLVHGKDNRDKGNRTPFEAFGGDTARWDRLVAWVQASHLSAPKKRNLLRE DFGEEAERELKDRNLTDTRFITKTAATLLRDRLTFHPEAPKDPVMTLNGRLTAFLRKQWGLHKN RKNGDLHHALDAAVLAVASRSFVYRLSSHNAAWGELPRGREAENGFSLPYPAFRSEVLARLCPT REEILLRLDQGGVGYDEAFRNGLRPVFVSRAPSRRLRGKAHMETLRSPKWKDHPEGPRTASRIP LKDLNLEKLERMVGKDRDRKLYEALRERLAAFGGNGKKAFVAPFRKPCRSGEGPLVRSLRIFDS GYSGVELRDGGEVYAVADHESMVRVDVYAKKNRFYLVPVYVADVARGIVKNRAIVAHKSEEEWD LVDGSFDFRFSLFPGDLVEIEKKDGAYLGYYKSCHRGDGRLLLDRHDRMPRESDCGTFYVSTRK DVLSMSKYQVDPLGEIRLVGSEKPPFVL

SEQ ID NO: 358

MEKKRKVTLGFDLGIASVGWAIVDSETNQVYKLGSRLFDAPDTNLERRTQRGTRRLLRRRKYRN QKFYNLVKRTEVFGLSSREAIENRFRELS IKYPNI IELKTKALSQEVCPDEIAWILHDYLKNRG YFYDEKETKEDFDQQTVESMPSYKLNEFYKKYGYFKGALSQPTESEMKDNKDLKEAFFFDFSNK EWLKEINYFFNVQKNILSETFIEEFKKIFSFTRDI SKGPGSDNMPSPYGIFGEFGDNGQGGRYE HIWDKNIGKCS IFTNEQRAPKYLPSALIFNFLNELANIRLYSTDKKNIQPLWKLSSVDKLNILL NLFNLPI SEKKKKLTSTNINDIVKKES IKS IMI SVEDIDMIKDEWAGKEPNVYGVGLSGLNIEE SAKENKFKFQDLKILNVLINLLDNVGIKFEFKDRNDI IKNLELLDNLYLFLIYQKESNNKDSS I DLFIAKNESLNIENLKLKLKEFLLGAGNEFENHNSKTHSLSKKAIDEILPKLLDNNEGWNLEAI KNYDEEIKSQIEDNSSLMAKQDKKYLNDNFLKDAILPPNVKVTFQQAILIFNKI IQKFSKDFEI DKVVIELAREMTQDQENDALKGIAKAQKSKKSLVEERLEANNIDKSVFNDKYEKLIYKIFLWI S QDFKDPYTGAQI SVNEIVNNKVEIDHI IPYSLCFDDSSANKVLVHKQSNQEKSNSLPYEYIKQG HSGWNWDEFTKYVKRVFVNNVDS ILSKKERLKKSENLLTASYDGYDKLGFLARNLNDTRYATIL FRDQLNNYAEHHLIDNKKMFKVIAMNGAVTSFIRKNMSYDNKLRLKDRSDFSHHAYDAAI IALF SNKTKTLYNLIDPSLNGI I SKRSEGYWVIEDRYTGEIKELKKEDWTS IKNNVQARKIAKEIEEY LIDLDDEVFFSRKTKRKTNRQLYNETIYGIATKTDEDGITNYYKKEKFS ILDDKDIYLRLLRER EKFVINQSNPEVIDQI IEI IESYGKENNIPSRDEAINIKYTKNKINYNLYLKQYMRSLTKSLDQ FSEEFINQMIANKTFVLYNPTKNTTRKIKFLRLVNDVKINDIRKNQVINKFNGKNNEPKAFYEN INSLGAIVFKNSANNFKTLS INTQIAIFGDKNWDIEDFKTYNMEKIEKYKEIYGIDKTYNFHSF IFPGTILLDKQNKEFYYI SS IQTVRDI IEIKFLNKIEFKDENKNQDTSKTPKRLMFGIKS IMNN YEQVDI SPFGINKKIFE

SEQ ID NO: 359

MGYRIGLDVGITSTGYAVLKTDKNGLPYKILTLDSVIYPRAENPQTGASLAEPRRIKRGLRRRT RRTKFRKQRTQQLFIHSGLLSKPEIEQILATPQAKYSVYELRVAGLDRRLTNSELFRVLYFFIG HRGFKSNRKAELNPENEADKKQMGQLLNS IEEIRKAIAEKGYRTVGELYLKDPKYNDHKRNKGY IDGYLSTPNRQMLVDEIKQILDKQRELGNEKLTDEFYATYLLGDENRAGIFQAQRDFDEGPGAG PYAGDQIKKMVGKDIFEPTEDRAAKATYTFQYFNLLQKMTSLNYQNTTGDTWHTLNGLDRQAII DAVFAKAEKPTKTYKPTDFGELRKLLKLPDDARFNLVNYGSLQTQKEIETVEKKTRFVDFKAYH DLVKVLPEEMWQSRQLLDHIGTALTLYSSDKRRRRYFAEELNLPAELIEKLLPLNFSKFGHLS I KSMQNI IPYLEMGQVYSEATTNTGYDFRKKQI SKDTIREEITNPVVRRAVTKTIKIVEQI IRRY GKPDGI IELARELGRNFKERGDIQKRQDKNRQTNDKIAAELTELGIPVNGQ I IRYKLHKEQN GVDPYTGDQIPFERAFSEGYEVDHI IPYS I SWDDSYTNKVLTSAKCNREKGNRIPMVYLANNEQ RLNALT IAD I IRNSRKRQKLLKQKLSDEELKDWKQR INDTRFITRVLYNYFRQAIEFNPEL EKKQRVLPLNGEVTSKIRSRWGFLKVREDGDLHHAIDATVIAAITPKFIQQVTKYSQHQEVKNN QALWHDAEIKDAEYAAEAQRMDADLFNKIFNGFPLPWPEFLDELLARI SDNPVEMMKSRSWNTY TPIEIAKLKPVFVVRLANHKI SGPAHLDTIRSAKLFDEKGIVLSRVS ITKLKINKKGQVATGDG IYDPENSNNGDKVVYSAIRQALEAHNGSGELAFPDGYLEYVDHGTKKLVRKVRVAKKVSLPVRL KNKAAADNGSMVRIDVFNTGKKFVFVPIYIKDTVEQVLPNKAIARGKSLWYQITESDQFCFSLY PGDMVHIESKTGIKPKYSNKENNTSVVPIKNFYGYFDGADIATAS ILVRAHDSSYTARS IGIAG LLKFEKYQVDYFGRYHKVHEKKRQLFVKRDE

SEQ ID NO: 360

MQKNINTKQNHIYIKQAQKIKEKLGDKPYRIGLDLGVGS IGFAIVSMEENDGNVLLPKEI IMVG SRIFKASAGAADRKLSRGQRNNHRHTRERMRYLWKVLAEQKLALPVPADLDRKENSSEGETSAK RFLGDVLQKDIYELRVKSLDERLSLQELGYVLYHIAGHRGSSAIRTFENDSEEAQKENTENKKI AG IKRLMAKKNYRTYGEYLYKEFFENKEKHKREKI SNAANNHKFSPTRDLVIKEAEAILKKQA GKDGFHKELTEEYIEKLTKAIGYESEKLIPESGFCPYLKDEKRLPASHKLNEERRLWETLNNAR YSDPIVDIVTGEITGYYEKQFTKEQKQKLFDYLLTGSELTPAQTKKLLGLKNTNFEDI ILQGRD KKAQKIKGYKLIKLESMPFWARLSEAQQDSFLYDWNSCPDEKLLTEKLSNEYHLTEEEIDNAFN EIVLSSSYAPLGKSAMLI ILEKIKNDLSYTEAVEEALKEGKLTKEKQAIKDRLPYYGAVLQEST QKI IAKGFSPQFKDKGYKTPHTNKYELEYGRIANPVVHQTLNELRKLVNEI IDILGKKPCEIGL ETARELKKSAEDRSKLSREQNDNESNRNRIYEIYIRPQQQVI ITRRENPRNYILKFELLEEQKS QCPFCGGQI SPNDI INNQADIEHLFPIAESEDNGRNNLVI SHSACNADKAKRSPWAAFASAAKD SKYDYNRILSNVKE IPHKAWRFNQGAFEKFIENKPMAARFKTDNSYI SKVAHKYLACLFEKPN IICVKGSLTAQLRMAWGLQGLMIPFAKQLITEKESESFNKDVNSNKKIRLDNRHHALDAIVIAY ASRGYGNLLNKMAGKDYKINYSERNWLSKILLPPNNIVWENIDADLESFESSVKTALKNAFISV KHDHSDNGELVKGTMYKIFYSERGYTLTTYKKLSALKLTDPQKKKTPKDFLETALLKFKGRESE MKNEKIKSAIENNKRLFDVIQDNLEKAKKLLEEENEKSKAEGKKEKNINDAS IYQKAI SLSGDK YVQLSKKEPGKFFAI SKPTPTTTGYGYDTGDSLCVDLYYDNKGKLCGEI IRKIDAQQKNPLKYK EQGFTLFERIYGGDILEVDFDIHSDKNSFRNNTGSAPENRVFIKVGTFTEITNNNIQIWFGNI I KSTGGQDDSFTINSMQQYNPRKLILSSCGFIKYRSPILKNKEG

SEQ ID NO: 361

MAAFKPNPINYILGLDIGIASVGWAMVEIDEDENPICLIDLGVRVFERAEVPKTGDSLAMARRL ARSVRRLTRRRAHRLLRARRLLKREGVLQAADFDENGLIKSLPNTPWQLRAAALDRKLTPLEWS AVLLHLIKHRGYLSQRKNEGETADKELGALLKGVADNAHALQTGDFRTPAELALNKFEKESGHI RNQRGDYSHTFSRKDLQAELILLFEKQKEFGNPHVSGGLKEGIETLLMTQRPALSGDAVQKMLG HCTFEPAEPKAAKNTYTAERFIWLTKLNNLRILEQGSERPLTDTERATLMDEPYRKSKLTYAQA RKLLGLEDTAFFKGLRYGKDNAEASTLMEMKAYHAI SRALEKEGLKDKKSPLNLSPELQDEIGT AFSLFKTDEDITGRLKDRIQPEILEALLKHI SFDKFVQI SLKALRRIVPLMEQGKRYDEACAEI YGDHYGKKNTEEKIYLPPIPADEIRNPVVLRALSQARKVINGVVRRYGSPARIHIETAREVGKS FKDRKEIEKRQEENRKDREKAAAKFREYFPNFVGEPKSKDILKLRLYEQQHGKCLYSGKEINLG RLNEKGYVEIDHALPFSRTWDDSFNNKVLVLGSENQNKGNQTPYEYFNGKDNSREWQEFKARVE TSRFPRSKKQRILLQKFDEDGFKERNLNDTRYVNRFLCQFVADRMRLTGKGKKRVFASNGQITN LLRGFWGLRKVRAENDRHHALDAVVVACSTVAMQQKITRFVRYKEMNAFDGKTIDKETGEVLHQ KTHFPQPWEFFAQEVMIRVFGKPDGKPEFEEADTPEKLRTLLAEKLSSRPEAVHEYVTPLFVSR APNRKMSGQGHMETVKSAKRLDEGVSVLRVPLTQLKLKDLEKMVNREREPKLYEALKARLEAHK DDPAKAFAEPFYKYDKAGNRTQQVKAVRVEQVQKTGVWVRNHNGIADNATMVRVDVFEKGDKYY LVPIYSWQVAKGILPDRAVVQGKDEEDWQLIDDSFNFKFSLHPNDLVEVITKKARMFGYFASCH RGTGNINIRIHDLDHKIGKNGILEGIGVKTALSFQKYQIDELGKEIRPCRLKKRPPVR

SEQ ID NO: 362

MQTTNLSYILGLDLGIASVGWAVVEINENEDPIGLIDVGVRIFERAEVPKTGESLALSRRLARS TRRLIRRRAHRLLLAKRFLKREGILSTIDLEKGLPNQAWELRVAGLERRLSAIEWGAVLLHLIK HRGYLSKRKNESQTNNKELGALLSGVAQNHQLLQSDDYRTPAELALKKFAKEEGHIRNQRGAYT HTFNRLDLLAELNLLFAQQHQFGNPHCKEHIQQYMTELLMWQKPALSGEAILKMLGKCTHEKNE FKAAKHTYSAERFVWLTKLNNLRILEDGAERALNEEERQLLINHPYEKSKLTYAQVRKLLGLSE QAIFKHLRYSKENAESATFMELKAWHAIRKALENQGLKDTWQDLAKKPDLLDEIGTAFSLYKTD EDIQQYLTNKVPNSVINALLVSLNFDKFIELSLKSLRKILPLMEQGKRYDQACREIYGHHYGEA NQKTSQLLPAIPAQEIRNPVVLRTLSQARKVINAI IRQYGSPARVHIETGRELGKSFKERREIQ KQQEDNRTKRESAVQKFKELFSDFSSEPKSKDILKFRLYEQQHGKCLYSGKEINIHRLNEKGYV EIDHALPFSRTWDDSFNNKVLVLASENQNKGNQTPYEWLQGKINSERWKNFVALVLGSQCSAAK KQRLLTQVIDDNKFIDRNLNDTRYIARFLSNYIQENLLLVGKNKKNVFTPNGQITALLRSRWGL IKARENNNRHHALDAIVVACATPSMQQKITRFIRFKEVHPYKIENRYEMVDQESGEI I SPHFPE PWAYFRQEVNIRVFDNHPDTVLKEMLPDRPQANHQFVQPLFVSRAPTRKMSGQGHMETIKSAKR LAEGI SVLRIPLTQLKPNLLENMVNKEREPALYAGLKARLAEFNQDPAKAFATPFYKQGGQQVK AIRVEQVQKSGVLVRENNGVADNAS IVRTDVFIKNNKFFLVPIYTWQVAKGILPNKAIVAHKNE DEWEEMDEGAKFKFSLFPNDLVELKTKKEYFFGYYIGLDRATG I SLKEHDGEI SKGKDGVYRV GVKLALSFEKYQVDELGKNRQICRPQQRQPVR

SEQ ID NO: 363

MGIRFAFDLGTNS IGWAVWRTGPGVFGEDTAASLDGSGVLIFKDGRNPKDGQSLATMRRVPRQS RKRRDRFVLRRRDLLAALRKAGLFPVDVEEGRRLAATDPYHLRAKALDESLTPHEMGRVIFHLN QRRGFRSNRKADRQDREKGKIAEGSKRLAETLAATNCRTLGEFLWSRHRGTPRTRSPTRIRMEG EGAKALYAFYPTREMVRAEFERLWTAQSRFAPDLLTPERHEEIAGILFRQRDLAPPKIGCCTFE PSERRLPRALPSVEARGIYERLAHLRITTGPVSDRGLTRPERDVLASALLAGKSLTFKAVRKTL KILPHALVNFEEAGEKGLDGALTAKLLSKPDHYGAAWHGLSFAEKDTFVGKLLDEADEERLIRR LVTENRLSEDAARRCAS IPLADGYGRLGRTANTEILAALVEETDETGTVVTYAEAVRRAGERTG RNWHHSDERDGVILDRLPYYGEILQRHVVPGSGEPEEKNEAARWGRLANPTVHIGLNQLRKVVN RLIAAHGRPDQIVVELARELKLNREQKERLDRENRKNREENERRTAILAEHGQRDTAENKIRLR LFEEQARANAGIALCPYTGRAIGIAELFTSEVEIDHILPVSLTLDDSLANRVLCRREANREKRR QTPFQAFGATPAWNDIVARAAKLPPNKRWRFDPAALERFEREGGFLGRQLNETKYLSRLAKIYL GKICDPDRVYVTPGTLTGLLRARWGLNS ILSDSNFKNRSDHRHHAVDAVVIGVLTRGMIQRIAH DAARAEDQDLDRVFRDVPVPFEDFRDHVRERVSTITVAVKPEHGKGGALHEDTSYGLVPDTDPN AALGNLVVRKPIRSLTAGEVDRVRDRALRARLGALAAPFRDESGRVRDAKGLAQALEAFGAENG IRRVRILKPDASVVTIADRRTGVPYRAVAPGENHHVDIVQMRDGSWRGFAASVFEVNRPGWRPE WEVKKLGGKLVMRLHKGDMVELSDKDGQRRVKVVQQIEI SANRVRLSPHNDGGKLQDRHADADD PFRWDLATIPLLKDRGCVAVRVDPIGVVTLRRSNV SEQ ID NO: 364

MMEVFMGRLVLGLDIGITSVGFGI IDLDESEIVDYGVRLFKEGTAAENETRRTKRGGRRLKRRR VTRREDMLHLLKQAGI I STSFHPLNNPYDVRVKGLNERLNGEELATALLHLCKHRGSSVETIED DEAKAKEAGETKKVLSMNDQLLKSGKYVCEIQKERLRTNGHIRGHENNFKTRAYVDEAFQILSH QDLSNELKSAI ITI I SRKRMYYDGPGGPLSPTPYGRYTYFGQKEPIDLIEKMRGKCSLFPNEPR APKLAYSAELFNLLNDLNNLS IEGEKLTSEQKAMILKIVHEKGKITPKQLAKEVGVSLEQIRGF RIDTKGSPLLSELTGYKMIREVLEKSNDEHLEDHVFYDEIAEILTKTKDIEGRKKQI SELSSDL NEESVHQLAGLTKFTAYHSLSFKALRLINEEMLKTELNQMQS ITLFGLKQNNELSVKGMK IQA DDTAILSPVAKRAQRETFKVVNRLREIYGEFDS IVVEMAREKNSEEQRKAIRERQKFFEMRNKQ VADI IGDDRKINAKLREKLVLYQEQDGKTAYSLEPIDLKLLIDDPNAYEVDHI IPI S I SLDDS I TNKVLVTHRENQEKGNLTPI SAFVKGRFTKGSLAQYKAYCLKLKEK IKTNKGYRKKVEQYLLN ENDIYKYDIQKEFINRNLVDTSYASRVVLNTLTTYFKQNEIPTKVFTVKGSLTNAFRRKINLKK DRDEDYGHHAIDALI IASMPKMRLLSTIFSRYKIEDIYDESTGEVFSSGDDSMYYDDRYFAFIA SLKAIKVRKFSHKIDTKPNRSVADETIYSTRVIDGKEKVVKKYKDIYDPKFTALAEDILNNAYQ EKYLMALHDPQTFDQIVKVVNYYFEEMSKSEKYFTKDKKGRIKI SGMNPLSLYRDEHGMLKKYS KKGDGPAITQMKYFDGVLGNHIDI SAHYQVRDKKVVLQQI SPYRTDFYYSKENGYKFVTIRYKD VRWSEKKKKYVIDQQDYAMKKAEKKIDDTYEFQFSMHRDELIGITKAEGEALIYPDETWHNFNF FFHAGETPEILKFTATNNDKSNKIEVKPIHCYCKMRLMPTI SKKIVRIDKYATDVVGNLYKVKK NTLKFEFD

SEQ ID NO: 365

MKKILGVDLGITSFGYAILQETGKDLYRCLDNSVVMRNNPYDEKSGESSQS IRSTQKSMRRLIE KRKKRIRCVAQTMERYGILDYSETMKINDPKNNPIKNRWQLRAVDAWKRPLSPQELFAIFAHMA KHRGYKS IATEDLIYELELELGLNDPEKESEKKADERRQVYNALRHLEELRKKYGGETIAQTIH RAVEAGDLRSYRNHDDYEKMIRREDIEEEIEKVLLRQAELGALGLPEEQVSELIDELKACITDQ EMPTIDESLFGKCTFYKDELAAPAYSYLYDLYRLYKKLADLNIDGYEVTQEDREKVIEWVEKKI AQGKNLKKITHKDLRKILGLAPEQKIFGVEDERIVKGKKEPRTFVPFFFLADIAKFKELFASIQ KHPDALQIFRELAEILQRSKTPQEALDRLRALMAGKGIDTDDRELLELFKNKRSGTRELSHRYI LEALPLFLEGYDEKEVQRILGFDDREDYSRYPKSLRHLHLREGNLFEKEENPINNHAVKSLASW ALGLIADLSWRYGPFDEI ILETTRDALPEKIRKEIDKAMREREKALDKI IGKYKKEFPS IDKRL ARKIQLWERQKGLDLYSGKVINLSQLLDGSADIEHIVPQSLGGLSTDYNTIVTLKSVNAAKGNR LPGDWLAGNPDYRERIGMLSEKGLIDWKKRKNLLAQSLDEIYTENTHSKGIRATSYLEALVAQV LKRYYPFPDPELRKNGIGVRMIPGKVTSKTRSLLGIKSKSRETNFHHAEDALILSTLTRGWQNR LHRMLRDNYGKSEAELKELWKKYMPHIEGLTLADYIDEAFRRFMSKGEESLFYRDMFDTIRS I S YWVDKKPLSASSHKETVYSSRHEVPTLRKNILEAFDSLNVIKDRHKLTTEEFMKRYDKEIRQKL WLHRIGNTNDESYRAVEERATQIAQILTRYQLMDAQNDKEIDEKFQQALKELITSPIEVTGKLL RKMRFVYDKLNAMQIDRGLVETDKNMLGIHI SKGPNEKLIFRRMDVNNAHELQKERSGILCYLN EMLFIFNKKGLIHYGCLRSYLEKGQGSKYIALFNPRFPANPKAQPSKFTSDSKIKQVGIGSATG I IKAHLDLDGHVRSYEVFGTLPEGS IEWFKEESGYGRVEDDPHH

SEQ ID NO: 366

MRPIEPWILGLDIGTDSLGWAVFSCEEKGPPTAKELLGGGVRLFDSGRDAKDHTSRQAERGAFR RARRQTRTWPWRRDRLIALFQAAGLTPPAAETRQIALALRREAVSRPLAPDALWAALLHLAHHR GFRSNRIDKRERAAAKALAKAKPAKATAKATAPAKEADDEAGFWEGAEAALRQRMAASGAPTVG ALLADDLDRGQPVRMRYNQSDRDGVVAPTRALIAEELAEIVARQSSAYPGLDWPAVTRLVLDQR PLRSKGAGPCAFLPGEDRALRALPTVQDFI IRQTLANLRLPSTSADEPRPLTDEEHAKALALLS TARFVEWPALRRALGLKRGVKFTAETERNGAKQAARGTAGNLTEAILAPLIPGWSGWDLDRKDR VFSDLWAARQDRSALLALIGDPRGPTRVTEDETAEAVADAIQIVLPTGRASLSAKAARAIAQAM APGIGYDEAVTLALGLHHSHRPRQERLARLPYYAAALPDVGLDGDPVGPPPAEDDGAAAEAYYG RIG I SVHIALNETRKIVNALLHRHGPILRLVMVETTRELKAGADERKRMIAEQAERERENAEI DVELRKSDRWMANARERRQRVRLARRQNNLCPYTSTPIGHADLLGDAYDIDHVIPLARGGRDSL DNMVLCQSDANKTKGDKTPWEAFHDKPGWIAQRDDFLARLDPQTAKALAWRFADDAGERVARKS AEDEDQGFLPRQLTDTGYIARVALRYLSLVTNEPNAVVATNGRLTGLLRLAWDITPGPAPRDLL PTPRDALRDDTAARRFLDGLTPPPLAKAVEGAVQARLAALGRSRVADAGLADALGLTLASLGGG GKNRADHRHHFIDAAMIAVTTRGLINQINQASGAGRILDLRKWPRTNFEPPYPTFRAEVMKQWD HIHPS IRPAHRDGGSLHAATVFGVRNRPDARVLVQRKPVEKLFLDANAKPLPADKIAEI IDGFA SPRMAKRFKALLARYQAAHPEVPPALAALAVARDPAFGPRGMTANTVIAGRSDGDGEDAGLITP FRANPKAAVRTMGNAVYEVWEIQVKGRPRWTHRVLTRFDRTQPAPPPPPENARLVMRLRRGDLV YWPLESGDRLFLVKKMAVDGRLALWPARLATGKATALYAQLSCPNINLNGDQGYCVQSAEGIRK EKIRTTSCTALGRLRLSKKAT

SEQ ID NO: 367

MKYTLGLDVGIASVGWAVIDKDNNKI IDLGVRCFDKAEESKTGESLATARRIARGMRRRI SRRS QRLRLVKKLFVQYEI IKDSSEFNRIFDTSRDGWKDPWELRYNALSRILKPYELVQVLTHITKRR GFKSNRKEDLSTTKEGVVITS IKNNSEMLRTKNYRTIGEMIFMETPENSNKRNKVDEYIHTIAR EDLLNEIKYIFS IQRKLGSPFVTEKLEHDFLNIWEFQRPFASGDS ILSKVGKCTLLKEELRAPT SCYTSEYFGLLQS INNLVLVEDNNTLTLNNDQRAKI IEYAHFKNEIKYSEIRKLLDIEPEILFK AHNLTHKNPSGNNESKKFYEMKSYHKLKSTLPTDIWGKLHSNKESLDNLFYCLTVYKNDNEIKD YLQANNLDYLIEYIAKLPTFNKFKHLSLVAMKRI IPFMEKGYKYSDACNMAELDFTGSSKLEKC NKLTVEPI IENVTNPVVIRALTQARKVINAI IQKYGLPYMV IELAREAGMTRQDRDNLKKEHE NNRKAREKI SDLIRQNGRVASGLDILKWRLWEDQGGRCAYSGKPIPVCDLLNDSLTQIDHIYPY SRSMDDSYMNKVLVLTDENQNKRSYTPYEVWGSTEKWEDFEARIYSMHLPQSKEKRLLNRNFIT KDLDSFI SRNLNDTRYI SRFLKNYIESYLQFSNDSPKSCVVCVNGQCTAQLRSRWGLNKNREES DLHHALDAAVIACADRKI IKEITNYYNERENHNYKVKYPLPWHSFRQDLMETLAGVFI SRAPRR KITGPAHDETIRSPKHFNKGLTSVKIPLTTVTLEKLETMVKNTKGGI SDKAVYNVLKNRLIEHN NKPLKAFAEKIYKPLKNGTNGAI IRS IRVETPSYTGVFRNEGKGI SDNSLMVRVDVFKKKDKYY LVPIYVAHMIKKELPSKAIVPLKPESQWELIDSTHEFLFSLYQNDYLVIKTKKGITEGYYRSCH RGTGSLSLMPHFANNKNVKIDIGVRTAI S IEKYNVDILGNKS IVKGEPRRGMEKYNSFKSN

SEQ ID NO: 368

MIRTLGIDIGIAS IGWAVIEGEYTDKGLENKEIVASGVRVFTKAENPKNKESLALPRTLARSAR RRNARKKGRIQQVKHYLSKALGLDLECFVQGEKLATLFQTSKDFLSPWELRERALYRVLDKEEL ARVILHIAKRRGYDDITYGVEDNDSGKIKKAIAENSKRIKEEQCKTIGEMMYKLYFQKSLNVRN KKESYNRCVGRSELREELKTIFQIQQELKSPWVNEELIYKLLGNPDAQSKQEREGLIFYQRPLK GFGDKIGKCSHIKKGENSPYRACKHAPSAEEFVALTKS INFLKNLTNRHGLCFSQEDMCVYLGK ILQEAQKNEKGLTYSKLKLLLDLPSDFEFLGLDYSGKNPEKAVFLSLPSTFKLNKITQDRKTQD KIANILGANKDWEAILKELESLQLSKEQIQTIKDAKLNFSKHINLSLEALYHLLPLMREGKRYD EGVEILQERGIFSKPQPKNRQLLPPLSELAKEESYFDIPNPVLRRALSEFRKVVNALLEKYGGF HYFHIELTRDVCKAKSARMQLEKINKKNKSENDAASQLLEVLGLPNTYNNRLKCKLWKQQEEYC LYSGEKITIDHLKDQRALQIDHAFPLSRSLDDSQSNKVLCLTSSNQEKSNKTPYEWLGSDEKKW DMYVGRVYSSNFSPSKKRKLTQKNFKERNEEDFLARNLVDTGYIGRVTKEYIKHSLSFLPLPDG KKEHIRI I SGSMTSTMRSFWGVQEKNRDHHLHHAQDAI I IACIEPSMIQKYTTYLKDKETHRLK SHQKAQILREGDHKLSLRWPMSNFKDKIQES IQNI IPSHHVSHKVTGELHQETVRTKEFYYQAF GGEEGVKKALKFGKIREINQGIVDNGAMVRVDIFKSKDKGKFYAVPIYTYDFAIGKLPNKAIVQ GKKNGI IKDWLEMDENYEFCFSLFKNDCIKIQTKEMQEAVLAIYKSTNSAKATIELEHLSKYAL KNEDEEKMFTDTDKEKNKTMTRESCGIQGLKVFQKVKLSVLGEVLEHKPRNRQNIALKTTPKHV

SEQ ID NO: 369

MKYS IGLDIGIASVGWSVINKDKERIEDMGVRIFQKAENPKDGSSLASSRREKRGSRRRNRRKK HRLDRIK ILCESGLVKKNEIEKIYKNAYLKSPWELRAKSLEAKI SNKEIAQILLHIAKRRGFK SFRKTDRNADDTGKLLSGIQENKKIMEEKGYLTIGDMVAKDPKFNTHVRNKAGSYLFSFSRKLL EDEVRKIQAKQKELGNTHFTDDVLEKYIEVFNSQRNFDEGPSKPSPYYSEIGQIAKMIGNCTFE SSEKRTAKNTWSGERFVFLQKLNNFRIVGLSGKRPLTEEERDIVEKEVYLKKEVRYEKLRKILY LKEEERFGDLNYSKDEKQDKKTEKTKFISLIGNYTIKKLNLSEKLKSEIEEDKSKLDKI IEILT FNKSDKTIESNLKKLELSREDIEILLSEEFSGTLNLSLKAIKKILPYLEKGLSYNEACEKADYD YKNNGIKFKRGELLPVVDKDLIANPVVLRAI SQTRKVVNAI IRKYGTPHTIHVEVARDLAKSYD DRQTI IKENKKRELENEKTKKFI SEEFGIKNVKGKLLLKYRLYQEQEGRCAYSRKELSLSEVIL DESMTDIDHI IPYSRSMDDSYSNKVLVLSGENRKKSNLLPKEYFDRQGRDWDTFVLNVKAMKIH PRKKSNLLKEKFTREDNKDWKSRALNDTRYI SRFVANYLENALEYRDDSPKKRVFMIPGQLTAQ LRARWRLNKVRENGDLHHALDAAVVAVTDQKAINNI SNI SRYKELKNCKDVIPS IEYHADEETG EVYFEEVKDTRFPMPWSGFDLELQKRLESENPREEFYNLLSDKRYLGWFNYEEGFIEKLRPVFV SRMPNRGVKGQAHQETIRSSKKI SNQIAVSKKPLNS IKLKDLEKMQGRDTDRKLYEALKNRLEE YDDKPEKAFAEPFYKPTNSGKRGPLVRGIKVEEKQNVGVYVNGGQASNGSMVRIDVFRKNGKFY TVPIYVHQTLLKELPNRAINGKPYKDWDLIDGSFEFLYSFYPNDLIEIEFGKSKS IKNDNKLTK TEIPEVNLSEVLGYYRGMDTSTGAATIDTQDGKIQMRIGIKTVKNIKKYQVDVLGNVYKVKREK RQTF

SEQ ID NO: 370

MSKKVSRRYEEQAQEICQRLGSRPYS IGLDLGVGS IGVAVAAYDPIKKQPSDLVFVSSRIFIPS TGAAERRQKRGQRNSLRHRANRLKFLWKLLAERNLMLSYSEQDVPDPARLRFEDAVVRANPYEL RLKGLNEQLTLSELGYALYHIANHRGSSSVRTFLDEEKSSDDKKLEEQQAMTEQLAKEKGI STF IEVLTAFNTNGLIGYRNSESVKSKGVPVPTRDI I SNEIDVLLQTQKQFYQEILSDEYCDRIVSA ILFENEKIVPEAGCCPYFPDEKKLPRCHFLNEERRLWEAINNARIKMPMQEGAAKRYQSASFSD EQRHILFHIARSGTDITPKLVQKEFPALKTS I IVLQGKEKAIQKIAGFRFRRLEEKSFWKRLSE EQKDDFFSAWTNTPDDKRLSKYLMKHLLLTENEVVDALKTVSLIGDYGPIGKTATQLLMKHLED GLTYTEALERGMETGEFQELSVWEQQSLLPYYGQILTGSTQALMGKYWHSAFKEKRDSEGFFKP NTNSDEEKYGRIANPVVHQTLNELRKLMNELITILGAKPQEITVELARELKVGAEKREDI IKQQ TKQEKEAVLAYSKYCEPNNLDKRYIERFRLLEDQAFVCPYCLEHI SVADIAAGRADVDHIFPRD DTADNSYGNKVVAHRQCNDIKGKRTPYAAFSNTSAWGPIMHYLDETPGMWRKRRKFETNEEEYA KYLQSKGFVSRFESDNSYIAKAAKEYLRCLFNPNNVTAVGSLKGMETS ILRKAWNLQGIDDLLG SRHWSKDADTSPTMRKNRDDNRHHGLDAIVALYCSRSLVQMINTMSEQGKRAVEIEAMIPIPGY ASEPNLSFEAQRELFRKKILEFMDLHAFVSMKTDNDANGALLKDTVYS ILGADTQGEDLVFVVK KKIKDIGVKIGDYEEVASAIRGRITDKQPKWYPMEMKDKIEQLQSKNEAALQKYKESLVQAAAV LEESNRKLIESGKKPIQLSEKTI SKKALELVGGYYYLI SNNKRTKTFVVKEPSNEVKGFAFDTG SNLCLDFYHDAQGKLCGEI IRKIQAMNPSYKPAYMKQGYSLYVRLYQGDVCELRASDLTEAESN LAKTTHVRLPNAKPGRTFVI I ITFTEMGSGYQIYFSNLAKSKKGQDTSFTLTTIKNYDVRKVQL SSAGLVRYVSPLLVDKIEKDEVALCGE

SEQ ID NO: 371 MNQKFILGLDIGITSVGYGLIDYETKNI IDAGVRLFPEANVENNEGRRSKRGSRRLKRRRIHRL ERVKKLLEDYNLLDQSQIPQSTNPYAIRVKGLSEALSKDELVIALLHIAKRRGIHKIDVIDSND DVGNELSTKEQLNKNSKLLKDKFVCQIQLERMNEGQVRGEKNRFKTADI IKEI IQLLNVQKNFH QLDENFINKYIELVEMRREYFEGPGKGSPYGWEGDPKAWYETLMGHCTYFPDELRSVKYAYSAD LFNALNDLNNLVIQRDGLSKLEYHEKYHI IENVFKQKKKPTLKQIANEINVNPEDIKGYRITKS GKPQFTEFKLYHDLKSVLFDQS ILENEDVLDQIAEILTIYQDKDS IKSKLTELDILLNEEDKEN IAQLTGYTGTHRLSLKCIRLVLEEQWYSSRNQMEIFTHLNIKPKKINLTAANKIPKAMIDEFIL SPVVKRTFGQAINLINKI IEKYGVPEDI I IELARENNSKDKQKFINEMQKKNENTRKRINEI IG KYGNQNAKRLVEKIRLHDEQEGKCLYSLES IPLEDLLNNPNHYEVDHI IPRSVSFDNSYHNKVL VKQSENSKKSNLTPYQYFNSGKSKLSYNQFKQHILNLSKSQDRI SKKKKEYLLEERDINKFEVQ KEFINRNLVDTRYATRELTNYLKAYFSANNMNVKVKTINGSFTDYLRKVWKFKKERNHGYKHHA EDALI IA ADFLFKENKKLKAVNSVLEKPEIESKQLDIQVDSEDNYSEMFI IPKQVQDIKDFRN FKYSHRVDKKPNRQLINDTLYSTRKKDNSTYIVQTIKDIYAKDNTTLKKQFDKSPEKFLMYQHD PRTFEKLEVIMKQYANEKNPLAKYHEETGEYLTKYSKKNNGPIVKSLKYIGNKLGSHLDVTHQF KSSTKKLVKLS IKPYRFDVYLTDKGYKFITI SYLDVLKKDNYYYIPEQKYDKLKLGKAIDKNAK FIASFYKNDLIKLDGEIYKI IGVNSDTRNMIELDLPDIRYKEYCELN IKGEPRIKKTIGKKVN SIEKLTTDVLGNVFTNTQYTKPQLLFKRGN

SEQ ID NO: 372

MIMKLEKWRLGLDLGTNS IGWSVFSLDKDNSVQDLIDMGVRIFSDGRDPKTKEPLAVARRTARS QRKLIYRRKLRRKQVFKFLQEQGLFPKTKEECMTLKSLNPYELRIKALDEKLEPYELGRALFNL AVRRGFKSNRKDGSREEVSEKKSPDEIKTQADMQTHLEKAIKENGCRTITEFLYKNQGENGGIR FAPGRMTYYPTRKMYEEEFNLIRSKQEKYYPQVDWDDIYKAIFYQRPLKPQQRGYCIYENDKER TFKAMPCSQKLRILQDIGNLAYYEGGSKKRVELNDNQDKVLYELLNSKDKVTFDQMRKALCLAD SNSFNLEENRDFLIGNPTAVKMRSKNRFGKLWDEIPLEEQDLI IETI ITADEDDAVYEVIKKYD LTQEQRDFIVKNTILQSGTSMLCKEVSEKLVKRLEEIADLKYHEAVESLGYKFADQTVEKYDLL PYYGKVLPGSTMEIDLSAPETNPEKHYGKI SNPTVHVALNQTRVVV ALIKEYGKPSQIAIELS RDLKNNVEKKAEIARKQNQRAKENIAINDTI SALYHTAFPGKSFYPNRNDRMKYRLWSELGLGN KCIYCGKGI SGAELFTKEIEIEHILPFSRTLLDAESNLTVAHSSCNAFKAERSPFEAFGTNPSG YSWQEI IQRANQLKNTSKKNKFSPNAMDSFEKDSSFIARQLSDNQYIAKAALRYLKCLVENPSD VWTTNGSMTKLLRDKWEMDS ILCRKFTEKEVALLGLKPEQIGNYKKNRFDHRHHAIDAVVIGLT DRSMVQKLATKNSHKGNRIEIPEFPILRSDLIEKVKNIVVSFKPDHGAEGKLSKETLLGKIKLH GKETFVCRENIVSLSEKNLDDIVDEIKSKVKDYVAKHKGQKIEAVLSDFSKENGIKKVRCVNRV QTPIEITSGKI SRYLSPEDYFAAVIWEIPGEKKTFKAQYIRRNEVEKNSKGLNVVKPAVLENGK PHPAAKQVCLLHKDDYLEFSDKGKMYFCRIAGYAATNNKLDIRPVYAVSYCADWINSTNETMLT GYWKPTPTQNWVSVNVLFDKQKARLVTVSPIGRVFRK

SEQ ID NO: 373

MSSKAIDSLEQLDLFKPQEYTLGLDLGIKS IGWAILSGERIANAGVYLFETAEELNSTGNKLI S KAAERGRKRRIRRMLDRKARRGRHIRYLLEREGLPTDELEEVVVHQSNRTLWDVRAEAVERKLT KQELAAVLFHLVRHRGYFPNTKKLPPDDESDSADEEQGKINRATSRLREELKASDCKTIGQFLA QNRDRQRNREGDYSNLMARKLVFEEALQILAFQRKQGHELSKDFEKTYLDVLMGQRSGRSPKLG NCSLIPSELRAPSSAPSTEWFKFLQNLGNLQI SNAYREEWS IDAPRRAQI IDACSQRSTSSYWQ IRRDFQIPDEYRFNLVNYERRDPDVDLQEYLQQQERKTLANFRNWKQLEKI IGTGHPIQTLDEA ARLITLIKDDEKLSDQLADLLPEASDKAITQLCELDFTTAAKI SLEAMYRILPHMNQGMGFFDA CQQESLPEIGVPPAGDRVPPFDEMYNPVVNRVLSQSRKLINAVIDEYGMPAKIRVELARDLGKG RELRERIKLDQLDKSKQNDQRAEDFRAEFQQAPRGDQSLRYRLWKEQNCTCPYSGRMIPVNSVL SEDTQIDHILPI SQSFDNSLSNKVLCFTEENAQKSNRTPFEYLDAADFQRLEAI SGNWPEAKRN KLLHKSFGKVAEEWKSRALNDTRYLTSALADHLRHHLPDSKIQTVNGRITGYLRKQWGLEKDRD KHTHHAVDAIVVACTTPAIVQQVTLYHQDIRRYKKLGEKRPTPWPETFRQDVLDVEEEIFITRQ PKKVSGGIQTKDTLRKHRSKPDRQRVALTKVKLADLERLVEKDASNRNLYEHLKQCLEESGDQP TKAFKAPFYMPSGPEAKQRPILSKVTLLREKPEPPKQLTELSGGRRYDSMAQGRLDIYRYKPGG KRKDEYRVVLQRMIDLMRGEENVHVFQKGVPYDQGPEIEQNYTFLFSLYFDDLVEFQRSADSEV IRGYYRTFNIANGQLKI STYLEGRQDFDFFGANRLAHFAKVQVNLLGKVIK

SEQ ID NO: 374

MRSLRYRLALDLGSTSLGWALFRLDACNRPTAVIKAGVRIFSDGRNPKDGSSLAVTRRAARAMR RRRDRLLKRKTRMQAKLVEHGFFPADAGKRKALEQLNPYALRAKGLQEALLPGEFARALFHINQ RRGFKSNRKTDKKDNDSGVLKKAIGQLRQQMAEQGSRTVGEYLWTRLQQGQGVRARYREKPYTT EEGKKRIDKSYDLYIDRAMIEQEFDALWAAQAAFNPTLFHEAARADLKDTLLHQRPLRPVKPGR CTLLPEEERAPLALPSTQRFRIHQEVNHLRLLDENLREVALTLAQRDAVVTALETKAKLSFEQI RKLLKLSGSVQFNLEDAKRTELKGNATSAALARKELFGAAWSGFDEALQDEIVWQLVTEEGEGA LIAWLQTHTGVDEARAQAIVDVSLPEGYGNLSRKALARIVPALRAAVITYDKAVQAAGFDHHSQ LGFEYDASEVEDLVHPETGEIRSVFKQLPYYGKALQRHVAFGSGKPEDPDEKRYGKIANPTVHI GLNQVRMVVNALIRRYGRPTEVVIELARDLKQSREQKVEAQRRQADNQRRNARIRRS IAEVLGI GEERVRGSDIQKWICWEELSFDAADRRCPYSGVQI SAAMLLSDEVEVEHILPFSKTLDDSLNNR TVAMRQANRIKRNRTPWDARAEFEAQGWSYEDILQRAERMPLRKRYRFAPDGYERWLGDDKDFL ARALNDTRYLSRVAAEYLRLVCPGTRVIPGQLTALLRGKFGLNDVLGLDGEKNRNDHRHHAVDA CVIGVTDQGLMQRFATASAQARGDGLTRLVDGMPMPWPTYRDHVERAVRHIWVSHRPDHGFEGA MMEETSYGIRKDGS IKQRRKADGSAGREI SNLIRIHEATQPLRHGVSADGQPLAYKGYVGGSNY CIEITVNDKGKWEGEVI STFRAYGVVRAGGMGRLRNPHEGQNGRKLIMRLVIGDSVRLEVDGAE RTMRIVKI SGSNGQIFMAPIHEANVDARNTDKQDAFTYTSKYAGSLQKAKTRRVTI SPIGEVRD PGFKG

SEQ ID NO: 375

MARPAFRAPRREHVNGWTPDPHRI SKPFFILVSWHLLSRVVIDSSSGCFPGTSRDHTDKFAEWE CAVQPYRLSFDLGTNS IGWGLLNLDRQGKPREIRALGSRIFSDGRDPQDKASLAVARRLARQMR RRRDRYLTRRTRLMGALVRFGLMPADPAARKRLEVAVDPYLARERATRERLEPFEIGRALFHLN QRRGYKPVRTATKPDEEAGKVKEAVERLEAAIAAAGAPTLGAWFAWRKTRGETLRARLAGKGKE AAYPFYPARRMLEAEFDTLWAEQARHHPDLLTAEAREILRHRIFHQRPLKPPPVGRCTLYPDDG RAPRALPSAQRLRLFQELASLRVIHLDLSERPLTPAERDRIVAFVQGRPPKAGRKPGKVQKSVP FEKLRGLLELPPGTGFSLESDKRPELLGDETGARIAPAFGPGWTALPLEEQDALVELLLTEAEP ERAIAALTARWALDEATAAKLAGATLPDFHGRYGRRAVAELLPVLERETRGDPDGRVRPIRLDE AVKLLRGGKDHSDFSREGALLDALPYYGAVLERHVAFGTGNPADPEEKRVGRVANPTVHIALNQ LRHLVNAILARHGRPEEIVIELARDLKRSAEDRRREDKRQADNQKRNEERKRLILSLGERPTPR NLLKLRLWEEQGPVENRRCPYSGETI SMRMLLSEQVDIDHILPFSVSLDDSAANKVVCLREANR IKRNRSPWEAFGHDSERWAGILARAEALPKNKRWRFAPDALEKLEGEGGLRARHLNDTRHLSRL AVEYLRCVCPKVRVSPGRLTALLRRRWGIDAILAEADGPPPEVPAETLDPSPAEKNRADHRHHA LDAVVIGCIDRSMVQRVQLAAASAEREAAAREDNIRRVLEGFKEEPWDGFRAELERRARTIVVS HRPEHGIGGALHKETAYGPVDPPEEGFNLVVRKPIDGLSKDEINSVRDPRLRRALIDRLAIRRR DANDPATALAKAAEDLAAQPASRGIRRVRVLKKESNPIRVEHGGNPSGPRSGGPFHKLLLAGEV HHVDVALRADGRRWVGHWVTLFEAHGGRGADGAAAPPRLGDGERFLMRLHKGDCLKLEHKGRVR VMQVVKLEPSSNSVVVVEPHQVKTDRSKHVKI SCDQLRARGARRVTVDPLGRVRVHAPGARVGI GGDAGRTAMEPAEDIS SEQ ID NO: 376

MKRTSLRAYRLGVDLGANSLGWFVVWLDDHGQPEGLGPGGVRIFPDGRNPQSKQSNAAGRRLAR SARRRRDRYLQRRGKLMGLLVKHGLMPADEPARKRLECLDPYGLRAKALDEVLPLHHVGRALFH LNQRRGLFANRAIEQGDKDASAIKAAAGRLQTSMQACGARTLGEFLNRRHQLRATVRARSPVGG DVQARYEFYPTRAMVDAEFEAIWAAQAPHHPTMTAEAHDTIREAIFSQRAMKRPS IGKCSLDPA TSQDDVDGFRCAWSHPLAQRFRIWQDVRNLAVVETGPTSSRLGKEDQDKVARALLQTDQLSFDE IRGLLGLPSDARFNLESDRRDHLKGDATGAILSARRHFGPAWHDRSLDRQIDIVALLESALDEA AIIASLGTTHSLDEAAAQRALSALLPDGYCRLGLRAIKRVLPLMEAGRTYAEAASAAGYDHALL PGGKLSPTGYLPYYGQWLQNDVVGSDDERDTNERRWGRLPNPTVHIGIGQLRRVVNELIRWHGP PAEITVELTRDLKLSPRRLAELEREQAENQRKNDKRTSLLRKLGLPASTHNLLKLRLWDEQGDV ASECPYTGEAIGLERLVSDDVDIDHLIPFS I SWDDSAANKVVCMRYANREKGNRTPFEAFGHRQ GRPYDWADIAERAARLPRGKRWRFGPGARAQFEELGDFQARLLNETSWLARVAKQYLAAVTHPH RIHVLPGRLTALLRATWELNDLLPGSDDRAAKSRKDHRHHAIDALVAALTDQALLRRMANAHDD TRRKIEVLLPWPTFRIDLETRLKAMLVSHKPDHGLQARLHEDTAYGTVEHPETEDGANLVYRKT FVDI SEKEIDRIRDRRLRDLVRAHVAGERQQGKTLKAAVLSFAQRRDIAGHPNGIRHVRLTKS I KPDYLVPIRDKAGRIYKSYNAGENAFVDILQAESGRWIARATTVFQANQANESHDAPAAQPIMR VFKGDMLRIDHAGAEKFVKIVRLSPSNNLLYLVEHHQAGVFQTRHDDPEDSFRWLFASFDKLRE WNAELVRIDTLGQPWRRKRGLETGSEDATRIGWTRPKKWP

SEQ ID NO: 377

MERIFGFDIGTTS IGFSVIDYSSTQSAGNIQRLGVRIFPEARDPDGTPLNQQRRQKRMMRRQLR RRRIRRKALNETLHEAGFLPAYGSADWPVVMADEPYELRRRGLEEGLSAYEFGRAIYHLAQHRH FKGRELEESDTPDPDVDDEKEAANERAATLKALKNEQTTLGAWLARRPPSDRKRGIHAHRNVVA EEFERLWEVQSKFHPALKSEEMRARI SDTIFAQRPVFWRKNTLGECRFMPGEPLCPKGSWLSQQ RRMLEKLNNLAIAGGNARPLDAEERDAILSKLQQQASMSWPGVRSALKALYKQRGEPGAEKSLK FNLELGGESKLLGNALEAKLADMFGPDWPAHPRKQEIRHAVHERLWAADYGETPDKKRVI ILSE KDRKAHREAAANSFVADFGITGEQAAQLQALKLPTGWEPYS IPALNLFLAELEKGERFGALVNG PDWEGWRRTNFPHRNQPTGEILDKLPSPASKEERERI SQLRNPTVVRTQNELRKVVNNLIGLYG KPDRIRIEVGRDVGKSKREREEIQSGIRRNEKQRKKATEDLIKNGIANPSRDDVEKWILWKEGQ ERCPYTGDQIGFNALFREGRYEVEHIWPRSRSFDNSPRNKTLCRKDVNIEKGNRMPFEAFGHDE DRWSAIQIRLQGMVSAKGGTGMSPGKVKRFLAKTMPEDFAARQLNDTRYAAKQILAQLKRLWPD MGPEAPVKVEAVTGQVTAQLRKLWTLNNILADDGEKTRADHRHHAIDALTVACTHPGMTNKLSR YWQLRDDPRAEKPALTPPWDTIRADAEKAVSEIVVSHRVRKKVSGPLHKETTYGDTGTDIKTKS GTYRQFVTRKKIESLSKGELDEIRDPRIKEIVAAHVAGRGGDPKKAFPPYPCVSPGGPEIRKVR LTSKQQLNLMAQTGNGYADLGSNHHIAIYRLPDGKADFEIVSLFDASRRLAQRNPIVQRTRADG ASFVMSLAAGEAIMIPEGSKKGIWIVQGVWASGQVVLERDTDADHSTTTRPMPNPILKDDAKKV SIDPIGRVRPSND

SEQ ID NO: 378

MNKRILGLDTGTNSLGWAVVDWDEHAQSYELIKYGDVIFQEGVKIEKGIESSKAAERSGYKAIR KQYFRRRLRKIQVLKVLVKYHLCPYLSDDDLRQWHLQKQYPKSDELMLWQRTSDEEGKNPYYDR HRCLHEKLDLTVEADRYTLGRALYHLTQRRGFLSNRLDTSADNKEDGVVKSGI SQLSTEMEEAG CEYLGDYFYKLYDAQGNKVRIRQRYTDRNKHYQHEFDAICEKQELSSELIEDLQRAIFFQLPLK SQRHGVGRCTFERGKPRCADSHPDYEEFRMLCFVNNIQVKGPHDLELRPLTYEEREKIEPLFFR KSKPNFDFEDIAKALAGKKNYAWIHDKEERAYKFNYRMTQGVPGCPTIAQLKS IFGDDWKTGIA ETYTLIQKKNGSKSLQEMVDDVWNVLYSFSSVEKLKEFAHHKLQLDEESAEKFAKIKLSHSFAA LSLKAIRKFLPFLRKGMYYTHASFFANIPTIVGKEIWNKEQNRKYIMENVGELVFNYQPKHREV QGTIEMLIKDFLANNFELPAGATDKLYHPSMIETYPNAQRNEFGILQLGSPRTNAIRNPMAMRS LHILRRVVNQLLKES I IDENTEVHVEYARELNDANKRRAIADRQKEQDKQHKKYGDEIRKLYKE ETGKDIEPTQTDVLKFQLWEEQNHHCLYTGEQIGITDFIGSNPKFDIEHTIPQSVGGDSTQMNL TLCDNRFNREVKKAKLPTELANHEEILTRIEPWKNKYEQLVKERDKQRTFAGMDKAVKDIRIQK RHKLQMEIDYWRGKYERFTMTEVPEGFSRRQGTGIGLI SRYAGLYLKSLFHQADSRNKSNVYVV KGVATAEFRKMWGLQSEYEKKCRDNHSHHCMDAITIACIGKREYDLMAEYYRMEETFKQGRGSK PKFSKPWATFTEDVL IYKNLLVVHDTPNNMPKHTKKYVQTS IGKVLAQGDTARGSLHLDTYYG AIERDGEIRYVVRRPLSSFTKPEELENIVDETVKRTIKEAIADKNFKQAIAEPIYMNEEKGILI KKVRCFAKSVKQPINIRQHRDLSKKEYKQQYHVMNENNYLLAIYEGLVKNKVVREFEIVSYIEA AKYYKRSQDRNIFSS IVPTHSTKYGLPLKTKLLMGQLVLMFEENPDEIQVDNTKDLVKRLYKVV GIEKDGRIKFKYHQEARKEGLPIFSTPYKNNDDYAPIFRQS INNINILVDGIDFTIDILGKVTL KE

SEQ ID NO: 379

MNYKMGLDIGIASVGWAVINLDLKRIEDLGVRIFDKAEHPQNGESLALPRRIARSARRRLRRRK HRLERIRRLLVSENVLTKEEMNLLFKQKKQIDVWQLRVDALERKLNNDELARVLLHLAKRRGFK SNRKSERNSKESSEFLKNIEENQS ILAQYRSVGEMIVKDSKFAYHKRNKLDSYSNMIARDDLER EIKLIFEKQREFNNPVCTERLEEKYLNIWSSQRPFASKEDIEKKVGFCTFEPKEKRAPKATYTF QSFIVWEHINKLRLVSPDETRALTEIERNLLYKQAFSKNKMTYYDIRKLLNLSDDIHFKGLLYD PKSSLKQIENIRFLELDSYHKIRKCIENVYGKDGIRMFNETDIDTFGYALTIFKDDEDIVAYLQ NEYITKNGKRVSNLANKVYDKSLIDELLNLSFSKFAHLSMKAIR ILPYMEQGEIYSKACELAG YNFTGPKKKEKALLLPVIPNIANPVVMRALTQSRKVVNAI IKKYGSPVS IHIELARDLSHSFDE RKKIQKDQTENRKKNETAIKQLIEYELTKNPTGLDIVKFKLWSEQQGRCMYSLKPIELERLLEP GYVEVDHILPYSRSLDDSYANKVLVLTKENREKGNHTPVEYLGLGSERWKKFEKFVLANKQFSK KKKQNLLRLRYEETEEKEFKERNLNDTRYI SKFFANFIKEHLKFADGDGGQKVYTINGKITAHL RSRWDFNKNREESDLHHAVDAVIVACATQGMIKKITEFYKAREQNKESAKKKEPIFPQPWPHFA DELKARLSKFPQES IEAFALGNYDRKKLESLRPVFVSRMPKRSVTGAAHQETLRRCVGIDEQSG KIQTAVKTKLSDIKLDKDGHFPMYQKESDPRTYEAIRQRLLEHNNDPKKAFQEPLYKPKKNGEP GPVIRTVKI IDTKNKVVHLDGSKTVAYNS IVRTDVFEKDGKYYCVPVYTMDIMKGTLPNKAIE ANKPYSEWKEMTEEYTFQFSLFPNDLVRIVLPREKTIKTSTNEEI I IKDIFAYYKTIDSATGGL ELI SHDRNFSLRGVGSKTLKRFEKYQVDVLG IHKVKGEKRVGLAAPTNQKKGKTVDSLQSVSD

SEQ ID NO: 380

MRRLGLDLGTNS IGWCLLDLGDDGEPVS IFRTGARIFSDGRDPKSLGSLKATRREARLTRRRRD RFIQRQKNLINALVKYGLMPADEIQRQALAYKDPYPIRKKALDEAIDPYEMGRAIFHINQRRGF KSNRKSADNEAGVVKQS IADLEMKLGEAGARTIGEFLADRQATNDTVRARRLSGTNALYEFYPD RYMLEQEFDTLWAKQAAFNPSLYIEAARERLKEIVFFQRKLKPQEVGRCIFLSDEDRI SKALPS FQRFRIYQELSNLAWIDHDGVAHRITASLALRDHLFDELEHKKKLTFKAMRAILRKQGVVDYPV GFNLESDNRDHLIGNLTSCIMRDAKKMIGSAWDRLDEEEQDSFILMLQDDQKGDDEVRS ILTQQ YGLSDDVAEDCLDVRLPDGHGSLSKKAIDRILPVLRDQGLIYYDAVKEAGLGEANLYDPYAALS DKLDYYGKALAGHVMGASGKFEDSDEKRYGTI SNPTVHIALNQVRAVVNELIRLHGKPDEVVIE IGRDLPMGADGKRELERFQKEGRAKNERARDELKKLGHIDSRESRQKFQLWEQLAKEPVDRCCP FTGKMMS I SDLFSDKVEIEHLLPFSLTLDDSMANKTVCFRQANRDKGNRAPFDAFGNSPAGYDW QEILGRSQNLPYAKRWRFLPDAMKRFEADGGFLERQLNDTRYI SRYTTEYI STI IPKNKIWVVT GRLTSLLRGFWGLNS ILRGHNTDDGTPAKKSRDDHRHHAIDAIVVGMTSRGLLQKVSKAARRSE DLDLTRLFEGRIDPWDGFRDEVKKHIDAI IVSHRPRKKSQGALHNDTAYGIVEHAENGASTVVH RVPITSLGKQSDIEKVRDPLIKSALLNETAGLSGKSFENAVQKWCADNS IKSLRIVETVS I IPI TDKEGVAYKGYKGDGNAYMDIYQDPTSSKWKGEIVSRFDANQKGFIPSWQSQFPTARLIMRLRI NDLLKLQDGEIEEIYRVQRLSGSKILMAPHTEANVDARDRDKNDTFKLTSKSPGKLQSASARKV HISPTGLIREG

SEQ ID NO: 381

MK ILGLDLGLSS IGWSVIRENSEEQELVAMGSRVVSLTAAELSSFTQGNGVS INSQRTQKRTQ RKGYDRYQLRRTLLRNKLDTLGMLPDDSLSYLPKLQLWGLRAKAVTQRIELNELGRVLLHLNQK RGYKS IKSDFSGDKKITDYVKTVKTRYDELKEMRLTIGELFFRRLTENAFFRCKEQVYPRQAYV EEFDCIMNCQRKFYPDILTDETIRCIRDEI IYYQRPLKSCKYLVSRCEFEKRFYLNAAGKKTEA GPKVSPRTSPLFQVCRLWES IN IVVKDRRNEIVFI SAEQRAALFDFLNTHEKLKGSDLLKLLG LSKTYGYRLGEQFKTGIQGNKTRVEIERALGNYPDKKRLLQFNLQEESSSMVNTETGEI IPMI S LSFEQEPLYRLWHVLYS IDDREQLQSVLRQKFGIDDDEVLERLSAIDLVKAGFGNKSSKAIRRI LPFLQLGMNYAEACEAAGYNHSNNYTKAENEARALLDRLPAIKKNELRQPVVEKILNQMVNVVN ALMEKYGRFDEIRVELARELKQSKEERSNTYKS INKNQRENEQIAKRIVEYGVPTRSRIQKYKM WEESKHCCIYCGQPVDVGDFLRGFDVEVEHI IPKSLYFDDSFANKVCSCRSCNKEKNNRTAYDY MKSKGEKALSDYVERVNTMYTNNQI SKTKWQNLLTPVDKI S IDFIDRQLRESQYIARKAKEILT SICYNVTATSGSVTSFLRHVWGWDTVLHDLNFDRYKKVGLTEVIEVNHRGSVIRREQIKDWSKR FDHRHHAIDALTIACTKQAYIQRLNNLRAEEGPDFNKMSLERYIQSQPHFSVAQVREAVDRILV SFRAGKRAVTPGKRYIRKNRKRI SVQSVLIPRGALSEESVYGVIHVWEKDEQGHVIQKQRAVMK YPITS INREMLDKEKVVDKRIHRILSGRLAQYNDNPKEAFAKPVYIDKECRIPIRTVRCFAKPA INTLVPLKKDDKGNPVAWVNPGNNHHVAIYRDEDGKYKERTVTFWEAVDRCRVGIPAIVTQPDT IWD ILQRNDI SENVLESLPDVKWQFVLSLQQNEMFILGMNEEDYRYAMDQQDYALLNKYLYRV QKLSKSDYSFRYHTETSVEDKYDGKPNLKLSMQMGKLKRVS IKSLLGLNPHKVHI SVLGEIKEI S

SEQ ID NO: 382

MAEKQHRWGLDIGTNS IGWAVIALIEGRPAGLVATGSRIFSDGRNPKDGSSLAVERRGPRQMRR RRDRYLRRRDRFMQALINVGLMPGDAAARKALVTENPYVLRQRGLDQALTLPEFGRALFHLNQR RGFQSNRKTDRATAKESGKVKNAIAAFRAGMGNARTVGEALARRLEDGRPVRARMVGQGKDEHY ELYIAREWIAQEFDALWASQQRFHAEVLADAARDRLRAILLFQRKLLPVPVGKCFLEPNQPRVA AALPSAQRFRLMQELNHLRVMTLADKRERPLSFQERNDLLAQLVARPKCGFDMLRKIVFGANKE AYRFTIESERRKELKGCDTAAKLAKVNALGTRWQALSLDEQDRLVCLLLDGENDAVLADALREH YGLTDAQIDTLLGLSFEDGHMRLGRSALLRVLDALESGRDEQGLPLSYDKAVVAAGYPAHTADL ENGERDALPYYGELLWRYTQDAPTAKNDAERKFGKIANPTVHIGLNQLRKLVNALIQRYGKPAQ IVVELARNLKAGLEEKERIKKQQTANLERNERIRQKLQDAGVPDNRENRLRMRLFEELGQGNGL GTPCIYSGRQI SLQRLFSNDVQVDHILPFSKTLDDSFANKVLAQHDANRYKGNRGPFEAFGANR DGYAWDDIRARAAVLPRNKRNRFAETAMQDWLHNETDFLARQLTDTAYLSRVARQYLTAICSKD DVYVSPGRLTAMLRAKWGLNRVLDGVMEEQGRPAVKNRDDHRHHAIDAVVIGATDRAMLQQVAT LAARAREQDAERLIGDMPTPWPNFLEDVRAAVARCVVSHKPDHGPEGGLHNDTAYGIVAGPFED GRYRVRHRVSLFDLKPGDLSNVRCDAPLQAELEPIFEQDDARAREVALTALAERYRQRKVWLEE LMSVLPIRPRGEDGKTLPDSAPYKAYKGDSNYCYELFINERGRWDGELI STFRANQAAYRRFRN DPARFRRYTAGGRPLLMRLCINDYIAVGTAAERTIFRVVKMSENKITLAEHFEGGTLKQRDADK DDPFKYLTKSPGALRDLGARRIFVDLIGRVLDPGIKGD

SEQ ID NO: 383 MIERILGVDLGI SSLGWAIVEYDKDDEAANRI IDCGVRLFTAAETPKKKESPNKARREARGIRR VLNRRRVRMNMIKKLFLRAGLIQDVDLDGEGGMFYSKANRADVWELRHDGLYRLLKGDELARVL IHIAKHRGYKFIGDDEADEESGKVKKAGVVLRQNFEAAGCRTVGEWLWRERGANGKKRNKHGDY EI S IHRDLLVEEVEAIFVAQQEMRSTIATDALKAAYREIAFFVRPMQRIEKMVGHCTYFPEERR APKSAPTAEKFIAI SKFFSTVI IDNEGWEQKI IERKTLEELLDFAVSREKVEFRHLRKFLDLSD NEIFKGLHYKGKPKTAKKREATLFDPNEPTELEFDKVEAEKKAWI SLRGAAKLREALGNEFYGR FVALGKHADEATKILTYYKDEGQKRRELTKLPLEAEMVERLVKIGFSDFLKLSLKAIRDILPAM ESGARYDEAVLMLGVPHKEKSAILPPLNKTDIDILNPTVIRAFAQFRKVANALVRKYGAFDRVH FELAREINTKGEIEDIKESQRKNEKERKEAADWIAETSFQVPLTRKNILKKRLYIQQDGRCAYT GDVIELERLFDEGYCEIDHILPRSRSADDSFANKVLCLARANQQKTDRTPYEWFGHDAARWNAF ETRTSAPSNRVRTGKGKIDRLLKKNFDENSEMAFKDRNLNDTRYMARAIKTYCEQYWVFKNSHT KAPVQVRSGKLTSVLRYQWGLESKDRESHTHHAVDAI I IAFSTQGMVQKLSEYYRFKETHREKE RPKLAVPLANFRDAVEEATRIENTETVKEGVEVKRLLI SRPPRARVTGQAHEQTAKPYPRIKQV KNKKKWRLAPIDEEKFESFKADRVASANQKNFYETSTIPRVDVYHKKGKFHLVPIYLHEMVLNE LPNLSLGTNPEAMDENFFKFS IFKDDLI S IQTQGTPKKPAKI IMGYFKNMHGANMVLSS INNSP CEGFTCTPVSMDKKHKDKCKLCPEENRIAGRCLQGFLDYWSQEGLRPPRKEFECDQGVKFALDV KKYQIDPLGYYYEVKQEKRLGTIPQMRSAKKLVKK

SEQ ID NO: 384

MNNS IKSKPEVTIGLDLGVGSVGWAIVDNET I IHHLGSRLFSQAKTAEDRRSFRGVRRLIRRR KYKLKRFVNLIWKYNSYFGFKNKEDILNNYQEQQKLHNTVLNLKSEALNAKIDPKALSWILHDY LKNRGHFYEDNRDFNVYPTKELAKYFDKYGYYKGI IDSKEDNDNKLEEELTKYKFSNKHWLEEV KKVLSNQTGLPEKFKEEYESLFSYVRNYSEGPGS INSVSPYGIYHLDEKEGKVVQKYN IWDKT IGKCNIFPDEYRAPKNSPIAMIFNEINELSTIRSYS IYLTGWFINQEFKKAYLNKLLDLLIKTN GEKPIDARQFKKLREETIAES IGKETLKDVENEEKLEKEDHKWKLKGLKLNTNGKIQYNDLSSL AKFVHKLKQHLKLDFLLEDQYATLDKINFLQSLFVYLGKHLRYSNRVDSANLKEFSDSNKLFER ILQKQKDGLFKLFEQTDKDDEKILAQTHSLSTKAMLLAITRMTNLDNDEDNQKNNDKGWNFEAI KNFDQKFIDITKKNNNLSLKQNKRYLDDRFINDAILSPGVKRILREATKVFNAILKQFSEEYDV TKVVIELARELSEEKELENTKNYKKLIKKNGDKI SEGLKALGI SEDEIKDILKSPTKSYKFLLW LQQDHIDPYSLKEIAFDDIFTKTEKFEIDHI IPYS I SFDDSSSNKLLVLAESNQAKSNQTPYEF ISSGNAGIKWEDYEAYCRKFKDGDSSLLDSTQRSKKFAKMMKTDTSSKYDIGFLARNLNDTRYA TIVFRDALEDYANNHLVEDKPMFKVVCINGSVTSFLRKNFDDSSYAKKDRDK IHHAVDAS IIS IFSNETKTLFNQLTQFADYKLFKNTDGSWKKIDPKTGVVTEVTDENWKQIRVRNQVSEIAKVIE KYIQDS IERKARYSRKIENKT I SLFNDTVYSAKKVGYEDQIKRKNLKTLDIHESAKENKNSK VKRQFVYRKLVNVSLLNNDKLADLFAEKEDILMYRANPWVINLAEQIFNEYTENKKIKSQNVFE KYMLDLTKEFPEKFSEFLVKSMLRNKTAI IYDDKK IVHRIKRLKMLSSELKENKLSNVI IRSK NQSGTKLSYQDTINSLALMIMRS IDPTAKKQYIRVPLNTLNLHLGDHDFDLHNMDAYLKKPKFV KYLKANEIGDEYKPWRVLTSGTLLIHKKDKKLMYISSFQNLNDVIEIKNLIETEYKENDDSDSK KKKKANRFLMTLSTILNDYILLDAKDNFDILGLSKNRIDEILNSKLGLDKIVK

SEQ ID NO: 385

MGGSEVGTVPVTWRLGVDVGERS IGLAAVSYEEDKPKEILAAVSWIHDGGVGDERSGASRLALR GMARRARRLRRFRRARLRDLDMLLSELGWTPLPDKNVSPVDAWLARKRLAEEYVVDETERRRLL GYAVSHMARHRGWRNPWTTIKDLKNLPQPSDSWERTRESLEARYSVSLEPGTVGQWAGYLLQRA PGIRLNPTQQSAGRRAELSNATAFETRLRQEDVLWELRCIADVQGLPEDVVSNVIDAVFCQKRP SVPAERIGRDPLDPSQLRASRACLEFQEYRIVAAVANLRIRDGSGSRPLSLEERNAVIEALLAQ TERSLTWSDIALEILKLPNESDLTSVPEEDGPSSLAYSQFAPFDETSARIAEFIAKNRRKIPTF AQWWQEQDRTSRSDLVAALADNS IAGEEEQELLVHLPDAELEALEGLALPSGRVAYSRLTLSGL TRVMRDDGVDVHNARKTCFGVDDNWRPPLPALHEATGHPVVDRNLAILRKFLSSATMRWGPPQS IVVELARGASESRERQAEEEAARRAHRKANDRIRAELRASGLSDPSPADLVRARLLELYDCHCM YCGAPI SWENSELDHIVPRTDGGSNRHENLAITCGACNKEKGRRPFASWAETSNRVQLRDVIDR VQKLKYSGNMYWTRDEFSRYKKSVVARLKRRTSDPEVIQS IESTGYAAVALRDRLLSYGEKNGV AQVAVFRGGVTAEARRWLDI S IERLFSRVAIFAQSTSTKRLDRRHHAVDAVVLTTLTPGVAKTL ADARSRRVSAEFWRRPSDVNRHSTEEPQSPAYRQWKESCSGLGDLLI STAARDS IAVAAPLRLR PTGALHEETLRAFSEHTVGAAWKGAELRRIVEPEVYAAFLALTDPGGRFLKVSPSEDVLPADEN RHIVLSDRVLGPRDRVKLFPDDRGS IRVRGGAAYIASFHHARVFRWGSSHSPSFALLRVSLADL AVAGLLRDGVDVFTAELPPWTPAWRYAS IALVKAVESGDAKQVGWLVPGDELDFGPEGVTTAAG DLSMFLKYFPERHWVVTGFEDDKRINLKPAFLSAEQAEVLRTERSDRPDTLTEAGEILAQFFPR CWRATVAKVLCHPGLTVIRRTALGQPRWRRGHLPYSWRPWSADPWSGGTP

SEQ ID NO: 386

MHNKKNITIGFDLGIAS IGWAI IDSTTSKILDWGTRTFEERKTANERRAFRSTRRNIRRKAYRN QRFINLILKYKDLFELKNI SDIQRANKKDTENYEKI I SFFTEIYKKCAAKHS ILEVKVKALDS KIEKLDLIWILHDYLENRGFFYDLEEENVADKYEGIEHPS ILLYDFFKKNGFFKSNSS IPKDLG GYSFSNLQWVNEIKKLFEVQEINPEFSEKFLNLFTSVRDYAKGPGSEHSASEYGIFQKDEKGKV FKKYDNIWDKTIGKCSFFVEENRSPVNYPSYEIFNLLNQLINLSTDLKTTNKKIWQLSSNDRNE LLDELLKVKEKAKI I S I SLKKNEIKKI ILKDFGFEKSDIDDQDTIEGRKI IKEEPTTKLEVTKH LLATIYSHSSDSNWININNILEFLPYLDAICI ILDREKSRGQDEVLKKLTEKNIFEVLKIDREK QLDFVKS IFSNTKFNFKKIGNFSLKAIREFLPKMFEQNKNSEYLKWKDEEIRRKWEEQKSKLGK TDKKTKYLNPRIFQDEI I SPGTKNTFEQAVLVLNQI IKKYSKENI IDAI I IESPREKNDKKTIE EIKKRNKKGKGKTLEKLFQILNLENKGYKLSDLETKPAKLLDRLRFYHQQDGIDLYTLDKINID QLINGSQKYEIEHI IPYSMSYDNSQANKILTEKAENLKKGKLIASEYIKRNGDEFYNKYYEKAK ELFINKYKKNKKLDSYVDLDEDSAKNRFRFLTLQDYDEFQVEFLARNLNDTRYSTKLFYHALVE HFENNEFFTYIDENSSKHKVKI STIKGHVTKYFRAKPVQKNNGPNENLNNNKPEKIEKNRENNE HHAVDAAIVAI IGNKNPQIANLLTLADNKTDKKFLLHDENYKE IETGELVKIPKFEVDKLAKV EDLKKI IQEKYEEAKKHTAIKFSRKTRTILNGGLSDETLYGFKYDEKEDKYFKI IKKKLVTSKN EELKKYFENPFGKKADGKSEYTVLMAQSHLSEFNKLKEIFEKYNGFSNKTGNAFVEYMNDLALK EPTLKAEIESAKSVEKLLYYNFKPSDQFTYHDNINNKSFKRFYKNIRI IEYKS IPIKFKILSKH DGGKSFKDTLFSLYSLVYKVYENGKESYKS IPVTSQMRNFGIDEFDFLDENLYNKEKLDIYKSD FAKPIPVNCKPVFVLKKGS ILKKKSLDIDDFKETKETEEGNYYFI STI SKRFNRDTAYGLKPLK LSVVKPVAEPSTNPIFKEYIPIHLDELGNEYPVKIKEHTDDEKLMCTIK

Nucleic Acids Encoding Cas9 Molecules

Nucleic acids encoding the Cas9 molecules or Cas9 polypeptides, e.g., an eaCas9 molecule or eaCas9 polypeptides are provided herein.

Exemplary nucleic acids encoding Cas9 molecules or Cas9 polypeptides are described in Cong et al., SCIENCE 2013, 399(6121):819-823; Wang et al., CELL 2013, 153(4):910-918; Mali et al., SCIENCE 2013, 399(6121):823-826; Jinek et al., SCIENCE 2012, 337(6096):816-821. Another exemplary nucleic acid encoding a Cas9 molecule or Cas9 polypeptide is shown in Fig. 8. In an embodiment, a nucleic acid encoding a Cas9 molecule or Cas9 polypeptide can be a synthetic nucleic acid sequence. For example, the synthetic nucleic acid molecule can be chemically modified, e.g., as described in Section VIII. In an embodiment, the Cas9 mRNA has one or more (e.g., all of the following properties: it is capped, polyadenylated, substituted with 5- methylcytidine and/or pseudouridine.

In addition, or alternatively, the synthetic nucleic acid sequence can be codon optimized, e.g., at least one non-common codon or less-common codon has been replaced by a common codon. For example, the synthetic nucleic acid can direct the synthesis of an optimized messenger mRNA, e.g., optimized for expression in a mammalian expression system, e.g., described herein.

In addition, or alternatively, a nucleic acid encoding a Cas9 molecule or Cas9

polypeptide may comprise a nuclear localization sequence (NLS). Nuclear localization sequences are known in the art.

Provided below is an exemplary codon optimized nucleic acid sequence encoding a Cas9 molecule of S. pyogenes.

ATGGATAAAA AGTACAGCAT CGGGCTGGAC ATCGGTACAA ACTCAGTGGG GTGGGCCGTG ATTACGGACG AGTACAAGGT ACCCTCCAAA AAATTTAAAG TGCTGGGTAA CACGGACAGA CACTCTATAA AGAAAAATCT TATTGGAGCC TTGCTGTTCG ACTCAGGCGA GACAGCCGAA GCCACAAGGT TGAAGCGGAC CGCCAGGAGG CGGTATACCA GGAGAAAGAA CCGCATATGC TACCTGCAAG AAATCTTCAG TAACGAGATG GCAAAGGTTG ACGATAGCTT TTTCCATCGC CTGGAAGAAT CCTTTCTTGT TGAGGAAGAC AAGAAGCACG AACGGCACCC CATCTTTGGC AATATTGTCG ACGAAGTGGC ATATCACGAA AAGTACCCGA CTATCTACCA CCTCAGGAAG AAGCTGGTGG ACTCTACCGA TAAGGCGGAC CTCAGACTTA TTTATTTGGC ACTCGCCCAC AT GAT T AAA T TTAGAGGACA TTTCTTGATC GAGGGCGACC TGAACCCGGA CAACAGTGAC GTCGATAAGC TGTTCATCCA ACTTGTGCAG ACCTACAATC AACTGTTCGA AGAAAACCCT ATAAATGCTT CAGGAGTCGA CGCTAAAGCA ATCCTGTCCG CGCGCCTCTC AAAATCTAGA AGACTTGAGA ATCTGATTGC TCAGTTGCCC GGGGAAAAGA AAAATGGATT GTTTGGCAAC CTGATCGCCC TCAGTCTCGG ACTGACCCCA AATTTCAAAA GTAACTTCGA CCTGGCCGAA GACGCTAAGC TCCAGCTGTC CAAGGACACA TACGATGACG ACCTCGACAA TCTGCTGGCC CAGATTGGGG ATCAGTACGC CGATCTCTTT TTGGCAGCAA AGAACCTGTC CGACGCCATC CTGTTGAGCG ATATCTTGAG AGTGAACACC GAAATTACTA AAGCACCCCT TAGCGCATCT ATGATCAAGC GGTACGACGA GCATCATCAG GATCTGACCC TGCTGAAGGC TCTTGTGAGG CAACAGCTCC CCGAAAAATA CAAGGAAATC TTCTTTGACC AGAGCAAAAA CGGCTACGCT GGCTATATAG ATGGTGGGGC CAGTCAGGAG GAATTCTATA AATTCATCAA GCCCATTCTC GAGAAAATGG ACGGCACAGA GGAGTTGCTG GTCAAACTTA ACAGGGAGGA CCTGCTGCGG AAGCAGCGGA CCTTTGACAA CGGGTCTATC CCCCACCAGA TTCATCTGGG CGAACTGCAC GCAATCCTGA GGAGGCAGGA GGATTTTTAT CCTTTTCTTA AAGATAACCG CGAGAAAATA GAAAAGATTC TTACATTCAG GATCCCGTAC TACGTGGGAC CTCTCGCCCG GGGCAATTCA CGGTTTGCCT GGATGACAAG GAAGTCAGAG GAGACTATTA CACCTTGGAA CTTCGAAGAA GTGGTGGACA AGGGTGCATC TGCCCAGTCT TTCATCGAGC GGATGACAAA TTTTGACAAG AACCTCCCTA ATGAGAAGGT GCTGCCCAAA CATTCTCTGC TCTACGAGTA CTTTACCGTC TACAATGAAC TGACTAAAGT CAAGTACGTC ACCGAGGGAA TGAGGAAGCC GGCATTCCTT AGTGGAGAAC AGAAGAAGGC GATTGTAGAC CTGTTGTTCA AGACCAACAG GAAGGTGACT GTGAAGCAAC TTAAAGAAGA CTACTTTAAG AAGATCGAAT GTTTTGACAG TGTGGAAATT TCAGGGGTTG AAGACCGCTT CAATGCGTCA TTGGGGACTT ACCATGATCT TCTCAAGATC ATAAAGGACA AAGACTTCCT GGACAACGAA GAAAATGAGG ATATTCTCGA AGACATCGTC CTCACCCTGA CCCTGTTCGA AGACAGGGAA ATGATAGAAG AGCGCTTGAA AACCTATGCC CACCTCTTCG ACGATAAAGT TATGAAGCAG CTGAAGCGCA GGAGATACAC AGGATGGGGA AGATTGTCAA GGAAGCTGAT CAATGGAATT AGGGATAAAC AGAGTGGCAA GACCATACTG GATTTCCTCA AATCTGATGG CTTCGCCAAT AGGAACTTCA TGCAACTGAT TCACGATGAC TCTCTTACCT TCAAGGAGGA CATTCAAAAG GCTCAGGTGA GCGGGCAGGG AGACTCCCTT CATGAACACA TCGCGAATTT GGCAGGTTCC CCCGCTATTA AAAAGGGCAT CCTTCAAACT GTCAAGGTGG TGGATGAATT GGTCAAGGTA ATGGGCAGAC ATAAGCCAGA AAATATTGTG ATCGAGATGG CCCGCGAAAA CCAGACCACA CAGAAGGGCC AGAAAAATAG TAGAGAGCGG ATGAAGAGGA TCGAGGAGGG CATCAAAGAG CTGGGATCTC AGATTCTCAA AGAACACCCC GTAGAAAACA CACAGCTGCA GAACGAAAAA TTGTACTTGT ACTATCTGCA GAACGGCAGA GACATGTACG TCGACCAAGA ACTTGATATT AATAGACTGT CCGACTATGA CGTAGACCAT ATCGTGCCCC AGTCCTTCCT GAAGGACGAC TCCATTGATA ACAAAGTCTT GACAAGAAGC GACAAGAACA GGGGTAAAAG TGATAATGTG CCTAGCGAGG AGGTGGTGAA AAAAATGAAG AACTACTGGC GACAGCTGCT TAATGCAAAG CTCATTACAC AACGGAAGTT CGATAATCTG ACGAAAGCAG AGAGAGGTGG CTTGTCTGAG TTGGACAAGG CAGGGTTTAT TAAGCGGCAG CTGGTGGAAA CTAGGCAGAT CACAAAGCAC GTGGCGCAGA TTTTGGACAG CCGGATGAAC ACAAAATACG ACGAAAATGA TAAACTGATA CGAGAGGTCA AAGTTATCAC GCTGAAAAGC AAGCTGGTGT CCGATTTTCG GAAAGACTTC CAGTTCTACA AAGTTCGCGA GATTAATAAC TACCATCATG CTCACGATGC GTACCTGAAC GCTGTTGTCG GGACCGCCTT GATAAAGAAG TACCCAAAGC TGGAATCCGA GTTCGTATAC GGGGATTACA AAGTGTACGA TGTGAGGAAA ATGATAGCCA AGTCCGAGCA GGAGATTGGA AAGGCCACAG CTAAGTACTT CTTTTATTCT AACATCATGA ATTTTTTTAA GACGGAAATT ACCCTGGCCA ACGGAGAGAT CAGAAAGCGG CCCCTTATAG AGACAAATGG TGAAACAGGT GAAATCGTCT GGGATAAGGG CAGGGATTTC GCTACTGTGA GGAAGGTGCT GAGTATGCCA CAGGTAAATA TCGTGAAAAA AACCGAAGTA CAGACCGGAG GATTTTCCAA GGAAAGCATT TTGCCTAAAA GAAACTCAGA CAAGCTCATC GCCCGCAAGA AAGATTGGGA CCCTAAGAAA TACGGGGGAT TTGACTCACC CACCGTAGCC TATTCTGTGC TGGTGGTAGC TAAGGTGGAA AAAGGAAAGT CTAAGAAGCT GAAGTCCGTG AAGGAACTCT TGGGAATCAC TATCATGGAA AGATCATCCT TTGAAAAGAA CCCTATCGAT TTCCTGGAGG

CTAAGGGTTA CAAGGAGGTC AAGAAAGACC TCATCATTAA ACTGCCAAAA

TACTCTCTCT TCGAGCTGGA AAATGGCAGG AAGAGAATGT TGGCCAGCGC

CGGAGAGCTG CAAAAGGGAA ACGAGCTTGC TCTGCCCTCC AAATATGTTA

ATTTTCTCTA TCTCGCTTCC CACTATGAAA AGCTGAAAGG GTCTCCCGAA

GATAACGAGC AGAAGCAGCT GTTCGTCGAA CAGCACAAGC ACTATCTGGA

TGAAATAATC GAACAAATAA GCGAGTTCAG CAAAAGGGTT ATCCTGGCGG

ATGCTAATTT GGACAAAGTA CTGTCTGCTT ATAACAAGCA CCGGGATAAG

CCTATTAGGG AACAAGCCGA GAATATAATT CACCTCTTTA CACTCACGAA

TCTCGGAGCC CCCGCCGCCT TCAAATACTT TGATACGACT ATCGACCGGA

AACGGTATAC CAGTACCAAA GAGGTCCTCG ATGCCACCCT CATCCACCAG

TCAATTACTG GCCTGTACGA AACACGGATC GACCTCTCTC AACTGGGCGG

CGACTAG

(SEQ ID NO: 22)

Provided below is the corresponding amino acid sequence of a S. pyogenes Cas9 molecule.

MDKKYS IGLDIGTNSVGWAVITDEYKVPSKKFKVLGNTDRHS IKKNLIGALLFDSGETAEATRL KRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIVDEVAY HEKYPTIYHLRKKLVDSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQLVQTY NQLFEENPINASGVDAKAILSARLSKSRRLENLIAQLPGEKKNGLFGNLIALSLGLTPNFKSNF DLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAILLSDILRVNTEITKAPLSAS MIKRYDEHHQDLTLLKALVRQQLPEKYKEIFFDQSKNGYAGYIDGGASQEEFYKFIKPILEKMD GTEELLVKLNREDLLRKQRTFDNGS IPHQIHLGELHAILRRQEDFYPFLKDNREKIEKILTFRI PYYVGPLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQSFIERMTNFDKNLPNEKVLPKHS LLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRKVTVKQLKEDYFKKIECFD SVEI SGVEDRFNASLGTYHDLLKI IKDKDFLDNEENEDILEDIVLTLTLFEDREMIEERLKTYA HLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSGKTILDFLKSDGFANRNFMQLIHDDSLTF KEDIQKAQVSGQGDSLHEHIANLAGSPAIKKGILQTVKVVDELVKVMGRHKPENIVIEMARENQ TTQKGQKNSRERMKRIEEGIKELGSQILKEHPVENTQLQNEKLYLYYLQNGRDMYVDQELDINR LSDYDVDHIVPQSFLKDDS IDNKVLTRSDKNRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQRK FDNLTKAERGGLSELDKAGFIKRQLVETRQITKHVAQILDSRMNTKYDENDKLIREVKVITLKS KLVSDFRKDFQFYKVREINNYHHAHDAYLNAVVGTALIKKYPKLESEFVYGDYKVYDVRKMIAK SEQEIGKATAKYFFYSNIMNFFKTEITLANGEIRKRPLIETNGETGEIVWDKGRDFATVRKVLS MPQV IVKKTEVQTGGFSKES ILPKRNSDKLIARKKDWDPKKYGGFDSPTVAYSVLVVAKVEKG KSKKLKSVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLI IKLPKYSLFELENGRKRMLAS AGELQKGNELALPSKYVNFLYLASHYEKLKGSPEDNEQKQLFVEQHKHYLDEI IEQI SEFSKRV ILADANLDKVLSAYNKHRDKPIREQAE I IHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLD ATLIHQS ITGLYETRIDLSQLGGD*

(SEQ ID NO: 23)

Provided below is an exemplary codon optimized nucleic acid sequence encoding a Cas9 molecule of N. meningitidis. ATGGCCGCCT TCAAGCCCAACCCCATCAACTACATCCTGGGCCTGGACATCGGCATCGCCAGCG TGGGCTGGGCCATGGTGGAGATCGACGAGGACGAGAACCCCATCTGCCTGATCGACCTGGGTGT GCGCGTGT TCGAGCGCGCTGAGGTGCCCAAGACTGGTGACAGTCTGGCTATGGCTCGCCGGCT T GCTCGCTCTGT TCGGCGCCT TACTCGCCGGCGCGCTCACCGCCT TCTGCGCGCTCGCCGCCTGC TGAAGCGCGAGGGTGTGCTGCAGGCTGCCGACT TCGACGAGAACGGCCTGATCAAGAGCCTGCC CAACACTCCT TGGCAGCTGCGCGCTGCCGCTCTGGACCGCAAGCTGACTCCTCTGGAGTGGAGC GCCGTGCTGCTGCACCTGATCAAGCACCGCGGCTACCTGAGCCAGCGCAAGAACGAGGGCGAGA CCGCCGACAAGGAGCTGGGTGCTCTGCTGAAGGGCGTGGCCGACAACGCCCACGCCCTGCAGAC TGGTGACT TCCGCACTCCTGCTGAGCTGGCCCTGAACAAGT TCGAGAAGGAGAGCGGCCACATC CGCAACCAGCGCGGCGACTACAGCCACACCT TCAGCCGCAAGGACCTGCAGGCCGAGCTGATCC TGCTGT TCGAGAAGCAGAAGGAGT TCGGCAACCCCCACGTGAGCGGCGGCCTGAAGGAGGGCAT CGAGACCCTGCTGATGACCCAGCGCCCCGCCCTGAGCGGCGACGCCGTGCAGAAGATGCTGGGC CACTGCACCT TCGAGCCAGCCGAGCCCAAGGCCGCCAAGAACACCTACACCGCCGAGCGCT TCA TCTGGCTGACCAAGCTGAACAACCTGCGCATCCTGGAGCAGGGCAGCGAGCGCCCCCTGACCGA CACCGAGCGCGCCACCCTGATGGACGAGCCCTACCGCAAGAGCAAGCTGACCTACGCCCAGGCC CGCAAGCTGCTGGGTCTGGAGGACACCGCCT TCT TCAAGGGCCTGCGCTACGGCAAGGACAACG CCGAGGCCAGCACCCTGATGGAGATGAAGGCCTACCACGCCATCAGCCGCGCCCTGGAGAAGGA GGGCCTGAAGGACAAGAAGAGTCCTCTGAACCTGAGCCCCGAGCTGCAGGACGAGATCGGCACC GCCT TCAGCCTGT TCAAGACCGACGAGGACATCACCGGCCGCCTGAAGGACCGCATCCAGCCCG AGATCCTGGAGGCCCTGCTGAAGCACATCAGCT TCGACAAGT TCGTGCAGATCAGCCTGAAGGC CCTGCGCCGCATCGTGCCCCTGATGGAGCAGGGCAAGCGCTACGACGAGGCCTGCGCCGAGATC TACGGCGACCACTACGGCAAGAAGAACACCGAGGAGAAGATCTACCTGCCTCCTATCCCCGCCG ACGAGATCCGCAACCCCGTGGTGCTGCGCGCCCTGAGCCAGGCCCGCAAGGTGATCAACGGCGT GGTGCGCCGCTACGGCAGCCCCGCCCGCATCCACATCGAGACCGCCCGCGAGGTGGGCAAGAGC T TCAAGGACCGCAAGGAGATCGAGAAGCGCCAGGAGGAGAACCGCAAGGACCGCGAGAAGGCCG CCGCCAAGT TCCGCGAGTACT TCCCCAACT TCGTGGGCGAGCCCAAGAGCAAGGACATCCTGAA GCTGCGCCTGTACGAGCAGCAGCACGGCAAGTGCCTGTACAGCGGCAAGGAGATCAACCTGGGC CGCCTGAACGAGAAGGGCTACGTGGAGATCGACCACGCCCTGCCCT TCAGCCGCACCTGGGACG ACAGCT TCAACAACAAGGTGCTGGTGCTGGGCAGCGAGAACCAGAACAAGGGCAACCAGACCCC CTACGAGTACT TCAACGGCAAGGACAACAGCCGCGAGTGGCAGGAGT TCAAGGCCCGCGTGGAG ACCAGCCGCT TCCCCCGCAGCAAGAAGCAGCGCATCCTGCTGCAGAAGT TCGACGAGGACGGCT TCAAGGAGCGCAACCTGAACGACACCCGCTACGTGAACCGCT TCCTGTGCCAGT TCGTGGCCGA CCGCATGCGCCTGACCGGCAAGGGCAAGAAGCGCGTGT TCGCCAGCAACGGCCAGATCACCAAC CTGCTGCGCGGCT TCTGGGGCCTGCGCAAGGTGCGCGCCGAGAACGACCGCCACCACGCCCTGG ACGCCGTGGTGGTGGCCTGCAGCACCGTGGCCATGCAGCAGAAGATCACCCGCT TCGTGCGCTA CAAGGAGATGAACGCCT TCGACGGTAAAACCATCGACAAGGAGACCGGCGAGGTGCTGCACCAG AAGACCCACT TCCCCCAGCCCTGGGAGT TCT TCGCCCAGGAGGTGATGATCCGCGTGT TCGGCA AGCCCGACGGCAAGCCCGAGT TCGAGGAGGCCGACACCCCCGAGAAGCTGCGCACCCTGCTGGC CGAGAAGCTGAGCAGCCGCCCTGAGGCCGTGCACGAGTACGTGACTCCTCTGT TCGTGAGCCGC GCCCCCAACCGCAAGATGAGCGGTCAGGGTCACATGGAGACCGTGAAGAGCGCCAAGCGCCTGG ACGAGGGCGTGAGCGTGCTGCGCGTGCCCCTGACCCAGCTGAAGCTGAAGGACCTGGAGAAGAT GGTGAACCGCGAGCGCGAGCCCAAGCTGTACGAGGCCCTGAAGGCCCGCCTGGAGGCCCACAAG GACGACCCCGCCAAGGCCT TCGCCGAGCCCT TCTACAAGTACGACAAGGCCGGCAACCGCACCC AGCAGGTGAAGGCCGTGCGCGTGGAGCAGGTGCAGAAGACCGGCGTGTGGGTGCGCAACCACAA CGGCATCGCCGACAACGCCACCATGGTGCGCGTGGACGTGT TCGAGAAGGGCGACAAGTACTAC CTGGTGCCCATCTACAGCTGGCAGGTGGCCAAGGGCATCCTGCCCGACCGCGCCGTGGTGCAGG GCAAGGACGAGGAGGACTGGCAGCTGATCGACGACAGCT TCAACT TCAAGT TCAGCCTGCACCC CAACGACCTGGTGGAGGTGATCACCAAGAAGGCCCGCATGTTCGGCTACTTCGCCAGCTGCCAC

CGCGGCACCGGCAACATCAACATCCGCATCCACGACCTGGACCACAAGATCGGCAAGAACGGCA

TCCTGGAGGGCATCGGCGTGAAGACCGCCCTGAGCTTCCAGAAGTACCAGATCGACGAGCTGGG

CAAGGAGATCCGCCCCTGCCGCCTGAAGAAGCGCCCTCCTGTGCGCTAA

(SEQ ID NO: 24)

Provided below is the corresponding amino acid sequence of a N. meningitidis Cas9 molecule.

MAAFKPNPINYILGLDIGIASVGWAMVEIDEDENPICLIDLGVRVFERAEVPKTGDSLAMARRL ARSVRRLTRRRAHRLLRARRLLKREGVLQAADFDENGLIKSLPNTPWQLRAAALDRKLTPLEWS AVLLHLIKHRGYLSQRKNEGETADKELGALLKGVADNAHALQTGDFRTPAELALNKFEKESGHI RNQRGDYSHTFSRKDLQAELILLFEKQKEFGNPHVSGGLKEGIETLLMTQRPALSGDAVQKMLG HCTFEPAEPKAAKNTYTAERFIWLTKLNNLRILEQGSERPLTDTERATLMDEPYRKSKLTYAQA RKLLGLEDTAFFKGLRYGKDNAEASTLMEMKAYHAI SRALEKEGLKDKKSPLNLSPELQDEIGT AFSLFKTDEDITGRLKDRIQPEILEALLKHI SFDKFVQI SLKALRRIVPLMEQGKRYDEACAEI YGDHYGKKNTEEKIYLPPIPADEIRNPVVLRALSQARKVINGVVRRYGSPARIHIETAREVGKS FKDRKEIEKRQEENRKDREKAAAKFREYFPNFVGEPKSKDILKLRLYEQQHGKCLYSGKEINLG RLNEKGYVEIDHALPFSRTWDDSFNNKVLVLGSENQNKGNQTPYEYFNGKDNSREWQEFKARVE TSRFPRSKKQRILLQKFDEDGFKERNLNDTRYVNRFLCQFVADRMRLTGKGKKRVFASNGQITN LLRGFWGLRKVRAENDRHHALDAVVVACSTVAMQQKITRFVRYKEMNAFDGKTIDKETGEVLHQ KTHFPQPWEFFAQEVMIRVFGKPDGKPEFEEADTPEKLRTLLAEKLSSRPEAVHEYVTPLFVSR APNRKMSGQGHMETVKSAKRLDEGVSVLRVPLTQLKLKDLEKMVNREREPKLYEALKARLEAHK DDPAKAFAEPFYKYDKAGNRTQQVKAVRVEQVQKTGVWVRNHNGIADNATMVRVDVFEKGDKYY LVPIYSWQVAKGILPDRAVVQGKDEEDWQLIDDSFNFKFSLHPNDLVEVITKKARMFGYFASCH RGTGNINIRIHDLDHKIGKNGILEGIGVKTALSFQKYQIDELGKEIRPCRLKKRPPVR* (SEQ ID NO: 25)

Provided below is an amino acid sequence of a S. aureus Cas9 molecule.

MKRNYILGLDIGITSVGYGI IDYETRDVIDAGVRLFKEANVENNEGRRSKRGARRLKRRRRHRI QRVKKLLFDYNLLTDHSELSGINPYEARVKGLSQKLSEEEFSAALLHLAKRRGVHNVNEVEEDT GNELSTKEQI SRNSKALEEKYVAELQLERLKKDGEVRGS INRFKTSDYVKEAKQLLKVQKAYHQ LDQSFIDTYIDLLETRRTYYEGPGEGSPFGWKDIKEWYEMLMGHCTYFPEELRSVKYAYNADLY NALNDLNNLVITRDENEKLEYYEKFQI IENVFKQKKKPTLKQIAKEILVNEEDIKGYRVTSTGK PEFTNLKVYHDIKDITARKEI IENAELLDQIAKILTIYQSSEDIQEELTNLNSELTQEEIEQIS NLKGYTGTHNLSLKAINLILDELWHTNDNQIAIFNRLKLVPKKVDLSQQKEIPTTLVDDFILSP VVKRSFIQS IKVINAI IKKYGLPNDI I IELAREKNSKDAQKMINEMQKRNRQTNERIEEI IRTT GKENAKYLIEKIKLHDMQEGKCLYSLEAIPLEDLLNNPFNYEVDHI IPRSVSFDNSFNNKVLVK QEENSKKGNRTPFQYLSSSDSKI SYETFKKHILNLAKGKGRI SKTKKEYLLEERDINRFSVQKD FINRNLVDTRYATRGLMNLLRSYFRVNNLDVKVKS INGGFTSFLRRKWKFKKERNKGYKHHAED ALI IANADFIFKEWKKLDKAKKVMENQMFEEKQAESMPEIETEQEYKEIFITPHQIKHIKDFKD YKYSHRVDKKPNRELINDTLYSTRKDDKGNTLIVNNLNGLYDKDNDKLKKLINKSPEKLLMYHH DPQTYQKLKLIMEQYGDEKNPLYKYYEETGNYLTKYSKKDNGPVIKKIKYYGNKLNAHLDITDD YPNSRNKVVKLSLKPYRFDVYLDNGVYKFVTVKNLDVIKKENYYEVNSKCYEEAKKLKKI SNQA EFIASFYNNDLIKINGELYRVIGVNNDLLNRIEVNMIDITYREYLENMNDKRPPRI IKTIASKT QS IKKYSTDILGNLYEVKSKKHPQI IKKG*

(SEQ ID NO: 26)

Provided below is an exemplary codon optimized nucleic acid sequence encoding a Cas9 molecule of S. aureus Cas9.

ATGAAAAGGAACTACATTCTGGGGCTGGACATCGGGATTACAAGCGTGGGGTATGGGATTATTG ACTATGAAACAAGGGACGTGATCGACGCAGGCGTCAGACTGTTCAAGGAGGCCAACGTGGAAAA CAATGAGGGACGGAGAAGCAAGAGGGGAGCCAGGCGCCTGAAACGACGGAGAAGGCACAGAATC CAGAGGGTGAAGAAACTGCTGTTCGATTACAACCTGCTGACCGACCATTCTGAGCTGAGTGGAA TTAATCCTTATGAAGCCAGGGTGAAAGGCCTGAGTCAGAAGCTGTCAGAGGAAGAGTTTTCCGC AGCTCTGCTGCACCTGGCTAAGCGCCGAGGAGTGCATAACGTCAATGAGGTGGAAGAGGACACC GGCAACGAGCTGTCTACAAAGGAACAGATCTCACGCAATAGCAAAGCTCTGGAAGAGAAGTATG TCGCAGAGCTGCAGCTGGAACGGCTGAAGAAAGATGGCGAGGTGAGAGGGTCAATTAATAGGTT CAAGACAAGCGACTACGTCAAAGAAGCCAAGCAGCTGCTGAAAGTGCAGAAGGCTTACCACCAG CTGGATCAGAGCTTCATCGATACTTATATCGACCTGCTGGAGACTCGGAGAACCTACTATGAGG GACCAGGAGAAGGGAGCCCCTTCGGATGGAAAGACATCAAGGAATGGTACGAGATGCTGATGGG ACATTGCACCTATTTTCCAGAAGAGCTGAGAAGCGTCAAGTACGCTTATAACGCAGATCTGTAC AACGCCCTGAATGACCTGAACAACCTGGTCATCACCAGGGATGAAAACGAGAAACTGGAATACT ATGAGAAGTTCCAGATCATCGAAAACGTGTTTAAGCAGAAGAAAAAGCCTACACTGAAACAGAT TGCTAAGGAGATCCTGGTCAACGAAGAGGACATCAAGGGCTACCGGGTGACAAGCACTGGAAAA CCAGAGTTCACCAATCTGAAAGTGTATCACGATATTAAGGACATCACAGCACGGAAAGAAATCA TTGAGAACGCCGAACTGCTGGATCAGATTGCTAAGATCCTGACTATCTACCAGAGCTCCGAGGA CATCCAGGAAGAGCTGACTAACCTGAACAGCGAGCTGACCCAGGAAGAGATCGAACAGATTAGT AATCTGAAGGGGTACACCGGAACACACAACCTGTCCCTGAAAGCTATCAATCTGATTCTGGATG AGCTGTGGCATACAAACGACAATCAGATTGCAATCTTTAACCGGCTGAAGCTGGTCCCAAAAAA GGTGGACCTGAGTCAGCAGAAAGAGATCCCAACCACACTGGTGGACGATTTCATTCTGTCACCC GTGGTCAAGCGGAGCTTCATCCAGAGCATCAAAGTGATCAACGCCATCATCAAGAAGTACGGCC TGCCCAATGATATCATTATCGAGCTGGCTAGGGAGAAGAACAGCAAGGACGCACAGAAGATGAT CAATGAGATGCAGAAACGAAACCGGCAGACCAATGAACGCATTGAAGAGATTATCCGAACTACC GGGAAAGAGAACGCAAAGTACCTGATTGAAAAAATCAAGCTGCACGATATGCAGGAGGGAAAGT GTCTGTATTCTCTGGAGGCCATCCCCCTGGAGGACCTGCTGAACAATCCATTCAACTACGAGGT CGATCATATTATCCCCAGAAGCGTGTCCTTCGACAATTCCTTTAACAACAAGGTGCTGGTCAAG CAGGAAGAGAACTCTAAAAAGGGCAATAGGACTCCTTTCCAGTACCTGTCTAGTTCAGATTCCA AGATCTCTTACGAAACCTTTAAAAAGCACATTCTGAATCTGGCCAAAGGAAAGGGCCGCATCAG CAAGACCAAAAAGGAGTACCTGCTGGAAGAGCGGGACATCAACAGATTCTCCGTCCAGAAGGAT TTTATTAACCGGAATCTGGTGGACACAAGATACGCTACTCGCGGCCTGATGAATCTGCTGCGAT CCTATTTCCGGGTGAACAATCTGGATGTGAAAGTCAAGTCCATCAACGGCGGGTTCACATCTTT TCTGAGGCGCAAATGGAAGTTTAAAAAGGAGCGCAACAAAGGGTACAAGCACCATGCCGAAGAT GCTCTGATTATCGCAAATGCCGACTTCATCTTTAAGGAGTGGAAAAAGCTGGACAAAGCCAAGA AAGTGATGGAGAACCAGATGTTCGAAGAGAAGCAGGCCGAATCTATGCCCGAAATCGAGACAGA ACAGGAGTACAAGGAGATTTTCATCACTCCTCACCAGATCAAGCATATCAAGGATTTCAAGGAC TACAAGTACTCTCACCGGGTGGATAAAAAGCCCAACAGAGAGCTGATCAATGACACCCTGTATA GTACAAGAAAAGACGATAAGGGGAATACCCTGATTGTGAACAATCTGAACGGACTGTACGACAA AGATAATGACAAGCTGAAAAAGCTGATCAACAAAAGTCCCGAGAAGCTGCTGATGTACCACCAT GATCCTCAGACATATCAGAAACTGAAGCTGATTATGGAGCAGTACGGCGACGAGAAGAACCCAC TGTATAAGTACTATGAAGAGACTGGGAACTACCTGACCAAGTATAGCAAAAAGGATAATGGCCC CGTGATCAAGAAGATCAAGTACTATGGGAACAAGCTGAATGCCCATCTGGACATCACAGACGAT TACCCTAACAGTCGCAACAAGGTGGTCAAGCTGTCACTGAAGCCATACAGATTCGATGTCTATC TGGACAACGGCGTGTATAAATTTGTGACTGTCAAGAATCTGGATGTCATCAAAAAGGAGAACTA CTATGAAGTGAATAGCAAGTGCTACGAAGAGGCTAAAAAGCTGAAAAAGATTAGCAACCAGGCA GAGTTCATCGCCTCCTTTTACAACAACGACCTGATTAAGATCAATGGCGAACTGTATAGGGTCA TCGGGGTGAACAATGATCTGCTGAACCGCATTGAAGTGAATATGATTGACATCACTTACCGAGA GTATCTGGAAAACATGAATGATAAGCGCCCCCCTCGAATTATCAAAACAATTGCCTCTAAGACT CAGAGTATCAAAAAGTACTCAACCGACATTCTGGGAAACCTGTATGAGGTGAAGAGCAAAAAGC ACCCTCAGATTATCAAAAAGGGC

(SEQ ID NO: 39)

If any of the above Cas9 sequences are fused with a peptide or polypeptide at the C- terminus, it is understood that the stop codon will be removed.

Other Cas Molecules and Cas Polypeptides

Various types of Cas molecules or Cas polypeptides can be used to practice the inventions disclosed herein. In some embodiments, Cas molecules of Type II Cas systems are used. In other embodiments, Cas molecules of other Cas systems are used. For example, Type I or Type III Cas molecules may be used. Exemplary Cas molecules (and Cas systems) are described, e.g., in Haft et al, PLoS COMPUTATIONAL BIOLOGY 2005, 1(6): e60 and Makarova et al, NATURE REVIEW MICROBIOLOGY 2011, 9:467-477, the contents of both references are incorporated herein by reference in their entirety. Exemplary Cas molecules (and Cas systems) are also shown in Table 33.

Table 33: Cas Systems

Gene System type Name from Structure of Families (and Representatives name* or subtype Haft ei a/.^§ encoded protein superfamily) of

(PDB encoded

accessions)¹ protein

cas4 • Subtype I-A cas4 and csal NA COG1468 APE1239 and BH0340

• Subtype I-B

• Subtype I-C

• Subtype I-D

• Subtype II- B

cas5 • Subtype I-A cas5a, cas5d, 3KG4 COG1688 APE1234, BH0337,

• Subtype I-B cas5e, cas5h, (RAMP) devS and ygcl

• Subtype I-C cas5p, cas5t

• Subtype I-E and cmx5

cas6 • Subtype I-A cas6 and cmx6 3I4H COG1583 and PF1131 and slr7014

• Subtype I-B COG5551

• Subtype I-D (RAMP)

• Subtype III- Α· Subtype

III-B

cas6e • Subtype I-E cse3 1WJ9 (RAMP) ygcH

cas6f • Subtype I-F csy4 2XLJ (RAMP) yl727

cas7 • Subtype I-A csal, csd2, NA COG 1857 and devR and ygcJ

• Subtype I-B cse4, csh2, COG3649

• Subtype I-C cspl and cst2 (RAMP)

• Subtype I-E

cas8al • Subtype I- cmxl, cstl, NA BH0338-like LA3191 and

A** csx8, csx 13 PG2018

and CXXC- CXXC

cas8a2 • Subtype I- csa4 and csx9 NA PH0918 AF0070, AF1873,

A** MJ0385, PF0637,

PH0918 and SSO1401 cas8b • Subtype I- cshl and NA BH0338-like MTH1090 and

B« TM1802 TM1802 cas8c • Subtype I- csdl and cspl NA BH0338-like BH0338

C**

cas9 • Type II** csnl and csxl2 NA COG3513 FTN_0757 and

SPyl046 cas 10 • Type III** cmr2, csml NA COG1353 MTH326, Rv2823c and csxll and TM1794 caslOd • Subtype I- csc3 NA COG1353 slr7011

D**

csyl • Subtype I- csyl NA yl724-like yl724

F**

csy2 • Subtype I-F csy2 NA (RAMP) y!725 Table 33: Cas Systems

Gene System type Name from Structure of Families (and Representatives name* or subtype Hatt et al encoded protein superfamily) of

(PDB encoded

accessions)¹ protein

csy3 • Subtype I-F csy3 NA (RAMP) yl726

csel • Subtype I- csel NA YgcL-like ygcL

E«

cse2 • Subtype I-E cse2 2ZCA YgcK-like ygcK

cscl • Subtype I-D cscl NA alrl563-like alrl563

(RAMP)

csc2 • Subtype I-D cscl and csc2 NA COG1337 slr7012

(RAMP)

csa5 • Subtype I-A csa5 NA AF1870 AF1870, MJ0380,

PF0643 and SS01398 csn2 • Subtype II- csn2 NA SPyl049-like SPyl049

A

csm.2 • Subtype III- csm.2 NA COG1421 MTH1081 and

A« SERP2460 csm.3 • Subtype III- csc2 and csm.3 NA COG1337 MTH1080 and

A (RAMP) SERP2459 csm.4 • Subtype III- csm4 NA COG 1567 MTH1079 and

A (RAMP) SERP2458 csm5 • Subtype III- csm5 NA COG1332 MTH1078 and

A (RAMP) SERP2457 csm.6 • Subtype III- APE2256 and 2WTE COG1517 APE2256 and

A csm6 SS01445 cmrl • Subtype Hi- cmrl NA COG 1367 PF1130

fi (RAMP)

cmr3 • Subtype Hi- cmr3 NA COG 1769 PF1128

fi (RAMP)

cmr4 • Subtype Hi- cmr4 NA COG1336 PF1126

fi (RAMP)

cmr5 • Subtype III- cmr5 2ZOP and 20EB COG3337 MTH324 and PF1125

B«

cmr6 • Subtype Hi- cmr6 NA COG 1604 PF1124

fi (RAMP)

csbl • Subtype I-U GSU0053 NA (RAMP) Balac_1306 and

GSU0053 csb2 • Subtype I- NA NA (RAMP) Balac_1305 and

U GSU0054 csb3 • Subtype I-U NA NA (RAMP) Balac_1303 csx 17 • Subtype I-U NA NA NA Btus_2683 csx 14 • Subtype I-U NA NA NA GSU0052 Table 33: Cas Systems

(PDB encoded

accessions)¹ protein

csx 10 • Subtype I-U csx 10 NA (RAMP) Caur_2274 csx 16 • Subtype III- VVA1548 NA NA VVA1548

U

csaX • Subtype III- csaX NA NA SS01438

U

csx3 • Subtype III- csx3 NA NA AF1864

U

csxl • Subtype III- csa3, csxl, lXMX and 2171 COG1517 and MJ1666, NE0113,

U csx2, DXTHG, COG4006 PF1127 and TM1812

NE0113 and

TIGR02710

csx 15 • Unknown NA NA TTE2665 TTE2665 csfl • Type U csfl NA NA AFE_1038 csfl • Type U csfl NA (RAMP) AFE_1039 csf3 • Type U csf3 NA (RAMP) AFE_1040 csf4 • Type U csf4 NA NA AFE_1037

IV. Functional Analysis of Candidate Molecules

Candidate Cas9 molecules, candidate gRNA molecules, candidate Cas9 molecule/gRNA molecule complexes, can be evaluated by art-known methods or as described herein. For example, exemplary methods for evaluating the endonuclease activity of Cas9 molecule are described, e.g., in Jinek et al, SCIENCE 2012, 337(6096):816-821.

Binding and Cleavage Assay: Testing the endonuclease activity of Cas9 molecule

The ability of a Cas9 molecule/gRNA molecule complex to bind to and cleave a target nucleic acid can be evaluated in a plasmid cleavage assay. In this assay, synthetic or in vitro- transcribed gRNA molecule is pre-annealed prior to the reaction by heating to 95 °C and slowly cooling down to room temperature. Native or restriction digest-linearized plasmid DNA (300 ng (~8 nM)) is incubated for 60 min at 37°C with purified Cas9 protein molecule (50-500 nM) and gRNA (50-500 nM, 1: 1) in a Cas9 plasmid cleavage buffer (20 mM HEPES pH 7.5, 150 mM KC1, 0.5 mM DTT, 0.1 mM EDTA) with or without 10 mM MgCl₂. The reactions are stopped with 5X DNA loading buffer (30% glycerol, 1.2% SDS, 250 mM EDTA), resolved by a 0.8 or 1% agarose gel electrophoresis and visualized by ethidium bromide staining. The resulting cleavage products indicate whether the Cas9 molecule cleaves both DNA strands, or only one of the two strands. For example, linear DNA products indicate the cleavage of both DNA strands. Nicked open circular products indicate that only one of the two strands is cleaved.

Alternatively, the ability of a Cas9 molecule/gRNA molecule complex to bind to and cleave a target nucleic acid can be evaluated in an oligonucleotide DNA cleavage assay. In this assay, DNA oligonucleotides (10 pmol) are radiolabeled by incubating with 5 units T4 polynucleotide kinase and -3-6 pmol (-20-40 mCi) [γ-32Ρ]-ΑΤΡ in IX T4 polynucleotide kinase reaction buffer at 37°C for 30 min, in a 50 μΐ_^ reaction. After heat inactivation (65°C for 20 min), reactions are purified through a column to remove unincorporated label. Duplex substrates (100 nM) are generated by annealing labeled oligonucleotides with equimolar amounts of unlabeled complementary oligonucleotide at 95 °C for 3 min, followed by slow cooling to room temperature. For cleavage assays, gRNA molecules are annealed by heating to 95°C for 30 s, followed by slow cooling to room temperature. Cas9 (500 nM final concentration) is pre- incubated with the annealed gRNA molecules (500 nM) in cleavage assay buffer (20 mM

HEPES pH 7.5, 100 mM KC1, 5 mM MgC12, 1 mM DTT, 5% glycerol) in a total volume of 9 μΐ. Reactions are initiated by the addition of 1 μΐ target DNA (10 nM) and incubated for 1 h at 37°C. Reactions are quenched by the addition of 20 μΐ of loading dye (5 mM EDTA, 0.025% SDS, 5% glycerol in formamide) and heated to 95°C for 5 min. Cleavage products are resolved on 12% denaturing polyacrylamide gels containing 7 M urea and visualized by phosphorimaging. The resulting cleavage products indicate that whether the complementary strand, the non- complementary strand, or both, are cleaved.

One or both of these assays can be used to evaluate the suitability of a candidate gRNA molecule or candidate Cas9 molecule.

Binding Assay: Testing the binding of Cas9 molecule to target DNA

Exemplary methods for evaluating the binding of Cas9 molecule to target DNA are described, e.g., in Jinek et al, SCIENCE 2012; 337(6096):816-821.

For example, in an electrophoretic mobility shift assay, target DNA duplexes are formed by mixing of each strand (10 nmol) in deionized water, heating to 95 °C for 3 min and slow cooling to room temperature. All DNAs are purified on 8% native gels containing IX TBE.

DNA bands are visualized by UV shadowing, excised, and eluted by soaking gel pieces in DEPC-treated H₂0. Eluted DNA is ethanol precipitated and dissolved in DEPC-treated H₂0. DNA samples are 5' end labeled with [γ-32Ρ]-ΑΤΡ using T4 polynucleotide kinase for 30 min at 37°C. Polynucleotide kinase is heat denatured at 65°C for 20 min, and unincorporated radiolabel is removed using a column. Binding assays are performed in buffer containing 20 mM HEPES pH 7.5, 100 mM KC1, 5 mM MgCl₂, 1 mM DTT and 10% glycerol in a total volume of 10 μΐ. Cas9 protein molecule is programmed with equimolar amounts of pre-annealed gRNA molecule and titrated from 100 pM to 1 μΜ. Radiolabeled DNA is added to a final concentration of 20 pM. Samples are incubated for 1 h at 37°C and resolved at 4°C on an 8% native polyacrylamide gel containing IX TBE and 5 mM MgCl₂. Gels are dried and DNA visualized by

pho sphorimaging .

Differential Scanning Flourimetry (DSF)

The thermostability of Cas9-gRNA ribonucleoprotein (RNP) complexes can be measured via DSF. This technique measures the thermostability of a protein, which can increase under favorable conditions such as the addition of a binding RNA molecule, e.g., a gRNA.

The assay is performed using two different protocols, one to test the best stoichiometric ratio of gRNA:Cas9 protein and another to determine the best solution conditions for RNP formation.

To determine the best solution to form RNP complexes, a 2uM solution of Cas9 in water+10x SYPRO Orange® (Life Techonologies cat#S-6650) and dispensed into a 384 well plate. An equimolar amount of gRNA diluted in solutions with varied pH and salt is then added. After incubating at room temperature for lO'and brief centrifugation to remove any bubbles,a Bio-Rad CFX384™ Real-Time System CI 000 Touch™ Thermal Cycler with the Bio-Rad CFX Manager software is used to run a gradient from 20°C to 90°C with a 1° increase in temperature every 10 seconds.

The second assay consists of mixing various concentrations of gRNA with 2uM Cas9 in optimal buffer from assay 1 above and incubating at RT for 10' in a 384 well plate. An equal volume of optimal buffer + lOx SYPRO Orange® (Life Techonologies cat#S-6650) is added and the plate sealed with Microseal® B adhesive (MSB-1001). Following brief centrifugation to remove any bubbles, a Bio-Rad CFX384™ Real-Time System CIOOO Touch™ Thermal Cycler with the Bio-Rad CFX Manager software is used to run a gradient from 20°C to 90°C with a 1° increase in temperature every 10 seconds.

V. Genome Editing Approaches

Mutations in the HBB gene may be corrected using one of the approaches discussed herein. In an embodiment, a mutation in the HBB gene is corrected by homology directed repair (HDR) using an exogenously provided template nucleic acid (see Section V. l). In another embodiment, a mutation in the HBB gene is corrected by homology directed repair without using an exogenously provided template nucleic acid (see Section V. l).

Also described herein are methods for targeted knockout of one or both alleles of the BCL11A gene using NHEJ (see Section V.2). In another embodiment, methods are provided for targeted knockdown of the BCL11A gene (see Section V.3).

V.l HDR Repair and Template Nucleic Acids

As described herein, nuclease-induced homology directed repair (HDR) can be used to alter a target sequence and correct (e.g., repair or edit) a mutation in the genome. While not wishing to be bound by theory, it is believed that alteration of the target sequence occurs by homology-directed repair (HDR) with an exogenously provided donor template or template nucleic acid. For example, the donor template or the template nucleic acid provides for alteration of the target sequence. It is contemplated that a plasmid donor can be used as a template for homologous recombination. It is further contemplated that a single stranded donor template can be used as a template for alteration of the target sequence by alternate methods of homology directed repair (e.g., single strand annealing) between the target sequence and the donor template. Donor template-effected alteration of a target sequence depends on cleavage by a Cas9 molecule. Cleavage by Cas9 can comprise a double strand break or two single strand breaks.As described herein, nuclease-induced homology directed repair (HDR) can be used to alter a target sequence and correct (e.g., repair or edit) a mutation in the genome without the use of an exogenously provided donor template or template nucleic acid. While not wishing to be bound by theory, it is believed that alteration of the target sequence occurs by homology-directed repair (HDR) with endogenous genomic donor sequence. For example, the endogenous genomic donor sequence provides for alteration of the target sequence. It is contemplated that in an embodiment the endogenous genomic donor sequence is located on the same chromosome as the target sequence. It is further contemplated that in another embodiment the endogenous genomic donor sequence is located on a different chromosome from the target sequence. In an

embodiment, the endogenous genomic donor sequence comprises one or more nucleotides derived from the HBD gene. Alteration of a target sequence by endogenous genomic donor sequence depends on cleavage by a Cas9 molecule. Cleavage by Cas9 can comprise a double strand break or two single strand breaks.

Mutations that can be corrected by HDR using a template nucleic acid, or using endogenous genomic donor sequence, include point mutations. In an embodiment, a point mutation can be corrected by either a single double-strand break or two single strand breaks. In an embodiment, a point mutation can be corrected by (1) a single double- strand break, (2) two single strand breaks, (3) two double stranded breaks with a break occurring on each side of the target position, (4) one double stranded break and two single strand breaks with the double strand break and two single strand breaks occurring on each side of the target position (5) four single stranded breaks with a pair of single stranded breaks occurring on each side of the target position, or (6) one single stranded break.

In an embodiment where a single-stranded template nucleic acid is used, the target position can be altered by alternative HDR.

Donor template-effected alteration of a target position depends on cleavage by a Cas9 molecule. Cleavage by Cas9 can comprise a nick, a double strand break, or two single strand breaks, e.g., one on each strand of the target nucleic acid. After introduction of the breaks on the target nucleic acid, resection occurs at the break ends resulting in single stranded overhanging DNA regions.

In canonical HDR, a double- stranded donor template is introduced, comprising homologous sequence to the target nucleic acid that will either be directly incorporated into the target nucleic acid or used as a template to correct the sequence of the target nucleic acid. After resection at the break, repair can progress by different pathways, e.g., by the double Holliday junction model (or double strand break repair, DSBR, pathway) or the synthesis-dependent strand annealing (SDSA) pathway. In the double Holliday junction model, strand invasion by the two single stranded overhangs of the target nucleic acid to the homologous sequences in the donor template occurs, resulting in the formation of an intermediate with two Holliday junctions. The junctions migrate as new DNA is synthesized from the ends of the invading strand to fill the gap resulting from the resection. The end of the newly synthesized DNA is ligated to the resected end, and the junctions are resolved, resulting in the correction of the target nucleic acid, e.g., incorporation of the correct sequence of the donor template at the corresponding target position. Crossover with the donor template may occur upon resolution of the junctions. In the SDSA pathway, only one single stranded overhang invades the donor template and new DNA is synthesized from the end of the invading strand to fill the gap resulting from resection. The newly synthesized DNA then anneals to the remaining single stranded overhang, new DNA is synthesized to fill in the gap, and the strands are ligated to produce the corrected DNA duplex.

In alternative HDR, a single strand donor template, e.g., template nucleic acid, is introduced. A nick, single strand break, or double strand break at the target nucleic acid, for altering a desired target position, is mediated by a Cas9 molecule, e.g., described herein, and resection at the break occurs to reveal single stranded overhangs. Incorporation of the sequence of the template nucleic acid to correct or alter the target position of the target nucleic acid typically occurs by the SDSA pathway, as described above.

Methods of promoting HDR pathways, e.g., canonical HDR or alt- HDR, are described herein in Section VI.

Additional details on template nucleic acids are provided in Section IV entitled

"Template nucleic acids" in International Application PCT/US2014/057905.

Mutations in the HBB gene that can be corrected (e.g., altered) by HDR with a template nucleic acid or with endogenous genomic donor sequence include, e.g., point mutation at E6, e.g., E6V.

Double strand break mediated correction

In an embodiment, double strand cleavage is effected by a Cas9 molecule having cleavage activity associated with an HNH-like domain and cleavage activity associated with a RuvC-like domain, e.g., an N-terminal RuvC-like domain, e.g., a wild type Cas9. Such embodiments require only a single gRNA.

Single strand break mediated correction

In some embodiments, one single strand break, or nick, is effected by a Cas9 molecule having nickase activity, e.g., a Cas9 nickase as described herein. A nicked target nucleic acid can be a substrate for alt-HDR. In other embodiments, two single strand breaks, or nicks, are effected by a Cas9 molecule having nickase activity, e.g., cleavage activity associated with an HNH-like domain or cleavage activity associated with an N-terminal RuvC-like domain. Such embodiments usually require two gRNAs, one for placement of each single strand break. In an embodiment, the Cas9 molecule having nickase activity cleaves the strand to which the gRNA hybridizes, but not the strand that is complementary to the strand to which the gRNA hybridizes. In an embodiment, the Cas9 molecule having nickase activity does not cleave the strand to which the gRNA hybridizes, but rather cleaves the strand that is complementary to the strand to which the gRNA hybridizes.

In an embodiment, the nickase has HNH activity, e.g., a Cas9 molecule having the RuvC activity inactivated, e.g., a Cas9 molecule having a mutation at D10, e.g., the D10A mutation. D10A inactivates RuvC; therefore, the Cas9 nickase has (only) HNH activity and will cut on the strand to which the gRNA hybridizes (e.g., the complementary strand, which does not have the NGG PAM on it). In other embodiments, a Cas9 molecule having an H840, e.g., an H840A, mutation can be used as a nickase. H840A inactivates HNH; therefore, the Cas9 nickase has (only) RuvC activity and cuts on the non-complementary strand (e.g., the strand that has the NGG PAM and whose sequence is identical to the gRNA). In other embodiments, a Cas9 molecule having an N863 mutation, e.g., the N863A mutation, mutation can be used as a nickase. N863A inactivates HNH therefore the Cas9 nickase has (only) RuvC activity and cuts on the non-complementary strand (the strand that has the NGG PAM and whose sequence is identical to the gRNA).

In an embodiment, in which a nickase and two gRNAs are used to position two single strand nicks, one nick is on the + strand and one nick is on the - strand of the target nucleic acid. The PAMs can be outwardly facing. The gRNAs can be selected such that the gRNAs are separated by, from about 0-50, 0-100, or 0-200 nucleotides. In an embodiment, there is no overlap between the target sequences that are complementary to the targeting domains of the two gRNAs. In an embodiment, the gRNAs do not overlap and are separated by as much as 50, 100, or 200 nucleotides. In an embodiment, the use of two gRNAs can increase specificity, e.g., by decreasing off-target binding (Ran et al., Cell 2013; 154(6): 1380-1389).

In an embodiment, a single nick can be used to induce HDR, e.g., alt-HDR. It is contemplated herein that a single nick can be used to increase the ratio of HR to NHEJ at a given cleavage site. In an embodiment, a single strand break is formed in the strand of the target nucleic acid to which the targeting domain of said gRNA is complementary. In another embodiment, a single strand break is formed in the strand of the target nucleic acid other than the strand to which the targeting domain of said gRNA is complementary.

Placement of double strand or single strand breaks relative to the target position

The double strand break or single strand break in one of the strands should be sufficiently close to target position such that an alteration is produced in the desired region, e.g., correction of a mutation occurs. In an embodiment, the distance is not more than 50, 100, 200, 300, 350 or 400 nucleotides. While not wishing to be bound by theory, in some embodiments, it is believed that the break should be sufficiently close to target position such that the target position is within the region that is subject to exonuclease-mediated removal during end resection. If the distance between the target position and a break is too great, the mutation or other sequence desired to be altered may not be included in the end resection and, therefore, may not be corrected, as donor sequence, either exogenously provided donor sequence or endogenous genomic donor sequence, in some embodiments is only used to correct sequence within the end resection region.

In an embodiment, the targeting domain is configured such that a cleavage event, e.g., a double strand or single strand break, is positioned within 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150 or 200 nucleotides of the region desired to be altered, e.g., a mutation. The break, e.g., a double strand or single strand break, can be positioned upstream or downstream of the region desired to be altered, e.g., a mutation. In some embodiments, a break is positioned within the region desired to be altered, e.g., within a region defined by at least two mutant nucleotides. In some embodiments, a break is positioned immediately adjacent to the region desired to be altered, e.g., immediately upstream or downstream of a mutation.

In an embodiment, a single strand break is accompanied by an additional single strand break, positioned by a second gRNA molecule, as discussed below. For example, the targeting domains bind configured such that a cleavage event, e.g., the two single strand breaks, are positioned within 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150 or 200 nucleotides of a target position. In an embodiment, the first and second gRNA molecules are configured such, that when guiding a Cas9 nickase, a single strand break will be accompanied by an additional single strand break, positioned by a second gRNA, sufficiently close to one another to result in alteration of the desired region. In an embodiment, the first and second gRNA molecules are configured such that a single strand break positioned by said second gRNA is within 10, 20, 30, 40, or 50 nucleotides of the break positioned by said first gRNA molecule, e.g., when the Cas9 is a nickase. In an embodiment, the two gRNA molecules are configured to position cuts at the same position, or within a few nucleotides of one another, on different strands, e.g., essentially mimicking a double strand break.

In an embodiment, in which a gRNA (unimolecular (or chimeric) or modular gRNA) and Cas9 nuclease induce a double strand break for the purpose of inducing HDR-mediated correction, the cleavage site is between 0-200 bp (e.g., 0-175, 0 to 150, 0 to 125, 0 to 100, 0 to 75, 0 to 50, 0 to 25, 25 to 200, 25 to 175, 25 to 150, 25 to 125, 25 to 100, 25 to 75, 25 to 50, 50 to 200, 50 to 175, 50 to 150, 50 to 125, 50 to 100, 50 to 75, 75 to 200, 75 to 175, 75 to 150, 75 to 125, 75 to 100 bp) away from the target position. In an embodiment, the cleavage site is between 0-100 bp (e.g., 0 to 75, 0 to 50, 0 to 25, 25 to 100, 25 to 75, 25 to 50, 50 to 100, 50 to 75 or 75 to 100 bp) away from the target position.

In embodiments, one can promote HDR by using nickases to generate a break with overhangs. While not wishing to be bound by theory, the single stranded nature of the overhangs can enhance the cell's likelihood of repairing the break by HDR as opposed to, e.g., NHEJ. Specifically, in some embodiments, HDR is promoted by selecting a first gRNA that targets a first nickase to a first target sequence, and a second gRNA that targets a second nickase to a second target sequence which is on the opposite DNA strand from the first target sequence and offset from the first nick.

Placement of a first break and a second break relative to each other

In an embodiment, a double strand break can be accompanied by an additional double strand break, positioned by a second gRNA molecule, as is discussed below. In an embodiment, a double strand break can be accompanied by two additional single strand breaks, positioned by a second gRNA molecule and a third gRNA molecule.

In an embodiment, a first and second single strand breaks can be accompanied by two additional single strand breaks positioned by a third gRNA molecule and a fourth gRNA molecule.

When two or more gRNAs are used to position two or more cleavage events, e.g., double strand or single strand breaks, in a target nucleic acid, it is contemplated that the two or more cleavage events may be made by the same or different Cas9 proteins. For example, when two gRNAs are used to position two double stranded breaks, a single Cas9 nuclease may be used to create both double stranded breaks. When two or more gRNAs are used to position two or more single stranded breaks (nicks), a single Cas9 nickase may be used to create the two or more nicks. When two or more gRNAs are used to position at least one double stranded break and at least one single stranded break, two Cas9 proteins may be used, e.g., one Cas9 nuclease and one Cas9 nickase. It is contemplated that when two or more Cas9 proteins are used that the two or more Cas9 proteins may be delivered sequentially to control specificity of a double stranded versus a single stranded break at the desired position in the target nucleic acid.

In some embodiments, the targeting domain of the first gRNA molecule and the targeting domain of the second gRNA molecules are complementary to opposite strands of the target nucleic acid molecule. In some embodiments, the gRNA molecule and the second gRNA molecule are configured such that the PAMs are oriented outward.

In certain embodiments, two gRNA are selected to direct Cas9-mediated cleavage at two positions that are a preselected distance from each other. In embodiments, the two points of cleavage are on opposite strands of the target nucleic acid. In some embodiments, the two cleavage points form a blunt ended break, and in other embodiments, they are offset so that the DNA ends comprise one or two overhangs (e.g., one or more 5' overhangs and/or one or more 3' overhangs). In some embodiments, each cleavage event is a nick. In embodiments, the nicks are close enough together that they form a break that is recognized by the double stranded break machinery (as opposed to being recognized by, e.g., the SSBr machinery). In embodiments, the nicks are far enough apart that they create an overhang that is a substrate for HDR, i.e., the placement of the breaks mimics a DNA substrate that has experienced some resection. For instance, in some embodiments the nicks are spaced to create an overhang that is a substrate for processive resection. In some embodiments, the two breaks are spaced within 25-65 nucleotides of each other. The two breaks may be, e.g., about 25, 30, 35, 40, 45, 50, 55, 60 or 65 nucleotides of each other. The two breaks may be, e.g., at least about 25, 30, 35, 40, 45, 50, 55, 60 or 65 nucleotides of each other. The two breaks may be, e.g., at most about 30, 35, 40, 45, 50, 55, 60 or 65 nucleotides of each other. In embodiments, the two breaks are about 25-30, 30-35, 35-40, 40-45, 45-50, 50-55, 55-60, or 60-65 nucleotides of each other.

In some embodiments, the break that mimics a resected break comprises a 3' overhang (e.g., generated by a DSB and a nick, where the nick leaves a 3' overhang), a 5' overhang (e.g., generated by a DSB and a nick, where the nick leaves a 5' overhang), a 3' and a 5' overhang (e.g., generated by three cuts), two 3' overhangs (e.g., generated by two nicks that are offset from each other), or two 5' overhangs (e.g., generated by two nicks that are offset from each other).

In an embodiment, in which two gRNAs (independently, unimolecular (or chimeric) or modular gRNA) complexing with Cas9 nickases induce two single strand breaks for the purpose of inducing HDR-mediated correction, the closer nick is between 0-200 bp (e.g., 0-175, 0 to 150, 0 to 125, 0 to 100, 0 to 75, 0 to 50, 0 to 25, 25 to 200, 25 to 175, 25 to 150, 25 to 125, 25 to 100, 25 to 75, 25 to 50, 50 to 200, 50 to 175, 50 to 150, 50 to 125, 50 to 100, 50 to 75, 75 to 200, 75 to 175, 75 to 150, 75 to 125, 75 to 100 bp) away from the target position and the two nicks will ideally be within 25-65 bp of each other (e.g., 25 to 50, 25 to 45, 25 to 40, 25 to 35, 25 to 30, 30 to 55, 30 to 50, 30 to 45, 30 to 40, 30 to 35, 35 to 55, 35 to 50, 35 to 45, 35 to 40, 40 to 55, 40 to 50, 40 to 45 bp, 45 to 50 bp, 50 to 55 bp, 55 to 60 bp, 60 to 65 bp) and no more than 100 bp away from each other (e.g., no more than 90, 80, 70, 60, 50, 40, 30, 20, 10 or 5 bp away from each other). In an embodiment, the cleavage site is between 0-100 bp (e.g., 0 to 75, 0 to 50, 0 to 25, 25 to 100, 25 to 75, 25 to 50, 50 to 100, 50 to 75 or 75 to 100 bp) away from the target position.

In one embodiment, two gRNAs, e.g., independently, unimolecular (or chimeric) or modular gRNA, are configured to position a double-strand break on both sides of a target position. In an alternate embodiment, three gRNAs, e.g., independently, unimolecular (or chimeric) or modular gRNA, are configured to position a double strand break (i.e., one gRNA complexes with a cas9 nuclease) and two single strand breaks or paired single stranded breaks (i.e., two gRNAs complex with Cas9 nickases) on either side of the target position. In another embodiment, four gRNAs, e.g., independently, unimolecular (or chimeric) or modular gRNA, are configured to generate two pairs of single stranded breaks (i.e., two pairs of two gRNAs complex with Cas9 nickases) on either side of the target position. The double strand break(s) or the closer of the two single strand nicks in a pair will ideally be within 0-500 bp of the target position (e.g., no more than 450, 400, 350, 300, 250, 200, 150, 100, 50 or 25 bp from the target position). When nickases are used, the two nicks in a pair are, in embodiments, within 25-65 bp of each other (e.g., between 25 to 55, 25 to 50, 25 to 45, 25 to 40, 25 to 35, 25 to 30, 50 to 55, 45 to 55, 40 to 55, 35 to 55, 30 to 55, 30 to 50, 35 to 50, 40 to 50 , 45 to 50, 35 to 45, 40 to 45 bp, 45 to 50 bp, 50 to 55 bp, 55 to 60 bp, or 60 to 65 bp) and no more than 100 bp away from each other (e.g., no more than 90, 80, 70, 60, 50, 40, 30, 20 or 10 bp).

When two gRNAs are used to target Cas9 molecules to breaks, different combinations of Cas9 molecules are envisioned. In some embodiments, a first gRNA is used to target a first Cas9 molecule to a first target position, and a second gRNA is used to target a second Cas9 molecule to a second target position. In some embodiments, the first Cas9 molecule creates a nick on the first strand of the target nucleic acid, and the second Cas9 molecule creates a nick on the opposite strand, resulting in a double stranded break (e.g., a blunt ended cut or a cut with overhangs).

Different combinations of nickases can be chosen to target one single stranded break to one strand and a second single stranded break to the opposite strand. When choosing a combination, one can take into account that there are nickases having one active RuvC-like domain, and nickases having one active HNH domain. In an embodiment, a RuvC-like domain cleaves the non-complementary strand of the target nucleic acid molecule. In an embodiment, an HNH-like domain cleaves a single stranded complementary domain, e.g., a complementary strand of a double stranded nucleic acid molecule. Generally, if both Cas9 molecules have the same active domain (e.g., both have an active RuvC domain or both have an active HNH domain), one will choose two gRNAs that bind to opposite strands of the target. In more detail, in some embodiments, a first gRNA is complementary with a first strand of the target nucleic acid and binds a nickase having an active RuvC-like domain and causes that nickase to cleave the strand that is non-complementary to that first gRNA, i.e., a second strand of the target nucleic acid; and a second gRNA is complementary with a second strand of the target nucleic acid and binds a nickase having an active RuvC-like domain and causes that nickase to cleave the strand that is non-complementary to that second gRNA, i.e., the first strand of the target nucleic acid. Conversely, in some embodiments, a first gRNA is complementary with a first strand of the target nucleic acid and binds a nickase having an active HNH domain and causes that nickase to cleave the strand that is complementary to that first gRNA, i.e., a first strand of the target nucleic acid; and a second gRNA is complementary with a second strand of the target nucleic acid and binds a nickase having an active HNH domain and causes that nickase to cleave the strand that is complementary to that second gRNA, i.e., the second strand of the target nucleic acid. In another arrangement, if one Cas9 molecule has an active RuvC-like domain and the other Cas9 molecule has an active HNH domain, the gRNAs for both Cas9 molecules can be

complementary to the same strand of the target nucleic acid, so that the Cas9 molecule with the active RuvC-like domain will cleave the non-complementary strand and the Cas9 molecule with the HNH domain will cleave the complementary strand, resulting in a double stranded break.

Length of the homology arms of the donor template

The homology arm should extend at least as far as the region in which end resection may occur, e.g., in order to allow the resected single stranded overhang to find a complementary region within the donor template. The overall length could be limited by parameters such as plasmid size or viral packaging limits. In an embodiment, a homology arm does not extend into repeated elements, e.g., Alu repeats or LINE repeats.

Exemplary homology arm lengths include at least 50, 100, 250, 500, 750, 1000, 2000, 3000, 4000, or 5000 nucleotides. In some embodiments, the homology arm length is 50-100, 100-250, 250-500, 500-750, 750-1000, 1000-2000, 2000-3000, 3000-4000, or 4000-5000 nucleotides.

Target position, as used herein, refers to a site on a target nucleic acid (e.g., the chromosome) that is modified by a Cas9 molecule-dependent process. For example, the target position can be a modified Cas9 molecule cleavage of the target nucleic acid and template nucleic acid directed modification, e.g., correction, of the target position. In an embodiment, a target position can be a site between two nucleotides, e.g., adjacent nucleotides, on the target nucleic acid into which one or more nucleotides is added. The target position may comprise one or more nucleotides that are altered, e.g., corrected, by a template nucleic acid. In an

embodiment, the target position is within a target sequence (e.g., the sequence to which the gRNA binds). In an embodiment, a target position is upstream or downstream of a target sequence (e.g., the sequence to which the gRNA binds).

A template nucleic acid, as that term is used herein, refers to a nucleic acid sequence which can be used in conjunction with a Cas9 molecule and a gRNA molecule to alter the structure of a target position. In an embodiment, the target nucleic acid is modified to have the some or all of the sequence of the template nucleic acid, typically at or near cleavage site(s). In an embodiment, the template nucleic acid is single stranded. In an alternate embodiment, the template nucleic acid is double stranded. In an embodiment, the template nucleic acid is DNA, e.g., double stranded DNA. In an alternate embodiment, the template nucleic acid is single stranded DNA. In an embodiment, the template nucleic acid is encoded on the same vector backbone, e.g. AAV genome, plasmid DNA, as the Cas9 and gRNA. In an embodiment, the template nucleic acid is excised from a vector backbone in vivo, e.g., it is flanked by gRNA recognition sequences. In an embodiment, the template nucleic acid comprises endogenous genomic sequence

In an embodiment, the template nucleic acid alters the structure of the target position by participating in a homology directed repair event. In an embodiment, the template nucleic acid alters the sequence of the target position. In an embodiment, the template nucleic acid results in the incorporation of a modified, or non-naturally occurring base into the target nucleic acid.

Typically, the template sequence undergoes a breakage mediated or catalyzed recombination with the target sequence. In an embodiment, the template nucleic acid includes sequence that corresponds to a site on the target sequence that is cleaved by an eaCas9 mediated cleavage event. In an embodiment, the template nucleic acid includes sequence that corresponds to both, a first site on the target sequence that is cleaved in a first Cas9 mediated event, and a second site on the target sequence that is cleaved in a second Cas9 mediated event.

In an embodiment, the template nucleic acid can include sequence which results in an alteration in the coding sequence of a translated sequence, e.g., one which results in the substitution of one amino acid for another in a protein product, e.g., transforming a mutant allele into a wild type allele, transforming a wild type allele into a mutant allele, and/or introducing a stop codon, insertion of an amino acid residue, deletion of an amino acid residue, or a nonsense mutation. In other embodiments, the template nucleic acid can include sequence which results in an alteration in a non-coding sequence, e.g., an alteration in an exon or in a 5' or 3' non-translated or non-transcribed region. Such alterations include an alteration in a control element, e.g., a promoter, enhancer, and an alteration in a cis-acting or trans-acting control element.

A template nucleic acid having homology with a target position in the HBB gene can be used to alter the structure of a target sequence. The template sequence can be used to alter an unwanted structure, e.g., an unwanted or mutant nucleotide.

A template nucleic acid typically comprises the following components:

[5' homology arm] -[replacement sequence] -[3' homology arm].

The homology arms provide for recombination into the chromosome, thus replacing the undesired element, e.g., a mutation or signature, with the replacement sequence. In an embodiment, the homology arms flank the most distal cleavage sites.

In an embodiment, the 3' end of the 5' homology arm is the position next to the 5' end of the replacement sequence. In an embodiment, the 5' homology arm can extend at least 10, 20, 30, 40, 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1500, 2000, 3000, 4000, or 5000 nucleotides 5' from the 5' end of the replacement sequence.

In an embodiment, the 5' end of the 3' homology arm is the position next to the 3' end of the replacement sequence. In an embodiment, the 3' homology arm can extend at least 10, 20, 30, 40, 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1500, 2000, 3000, 4000, or 5000 nucleotides 3' from the 3' end of the replacement sequence.

In an embodiment, to correct a mutation, the homology arms, e.g., the 5' and 3' homology arms, may each comprise about 1000 base pairs (bp) of sequence flanking the most distal gRNAs (e.g., lOOObp of sequence on either side of the mutation).

It is contemplated herein that one or both homology arms may be shortened to avoid including certain sequence repeat elements, e.g., Alu repeats or LINE elements. For example, a 5' homology arm may be shortened to avoid a sequence repeat element. In other embodiments, a 3' homology arm may be shortened to avoid a sequence repeat element. In some embodiments, both the 5' and the 3' homology arms may be shortened to avoid including certain sequence repeat elements. It is contemplated herein that template nucleic acids for correcting a mutation may be designed for use as a single- stranded oligonucleotide, e.g., a single- stranded

oligodeoxynucleotide (ssODN). When using a ssODN, 5' and 3' homology arms may range up to about 200 base pairs (bp) in length, e.g., at least 25, 50, 75, 100, 125, 150, 175, or 200 bp in length. Longer homology arms are also contemplated for ssODNs as improvements in oligonucleotide synthesis continue to be made. In some embodiments, a longer homology arm is made by a method other than chemical synthesis, e.g., by denaturing a long double stranded nucleic acid and purifying one of the strands, e.g., by affinity for a strand- specific sequence anchored to a solid substrate.

While not wishing to be bound by theory, in some embodiments alt-HDR proceeds more efficiently when the template nucleic acid has extended homology 5' to the nick (i.e., in the 5' direction of the nicked strand). Accordingly, in some embodiments, the template nucleic acid has a longer homology arm and a shorter homology arm, wherein the longer homology arm can anneal 5' of the nick. In some embodiments, the arm that can anneal 5' to the nick is at least 25, 50, 75, 100, 125, 150, 175, or 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1500, 2000, 3000, 4000, or 5000 nucleotides from the nick or the 5' or 3' end of the replacement sequence. In some embodiemtns, the arm that can anneal 5' to the nick is at least 10%, 20%, 30%, 40%, or 50% longer than the arm that can anneal 3' to the nick. In some embodiments, the arm that can anneal 5' to the nick is at least 2x, 3x, 4x, or 5x longer than the arm that can anneal 3' to the nick. Depending on whether a ssDNA template can anneal to the intact strand or the nicked strand, the homology arm that anneals 5' to the nick may be at the 5' end of the ssDNA template or the 3' end of the ssDNA template, respectively.

Similarly, in some embodiments, the template nucleic acid has a 5' homology arm, a replacement sequence, and a 3' homology arm, such that the template nucleic acid has extended homology to the 5' of the nick. For example, the 5' homology arm and 3' homology arm may be substantially the same length, but the replacement sequence may extend farther 5' of the nick than 3' of the nick. In some embodiments, the replacement sequence extends at least 10%, 20%, 30%, 40%, 50%, 2x, 3x, 4x, or 5x further to the 5' end of the nick than the 3' end of the nick. While not wishing to be bound by theory, in some embodiments alt-HDR proceeds more efficiently when the template nucleic acid is centered on the nick. Accordingly, in some embodiments, the template nucleic acid has two homology arms that are essentially the same size. For instance, the first homology arm of a template nucleic acid may have a length that is within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the second homology arm of the template nucleic acid.

Similarly, in some embodiments, the template nucleic acid has a 5' homology arm, a replacement sequence, and a 3' homology arm, such that the template nucleic acid extends substantially the same distance on either side of the nick. For example, the homology arms may have different lengths, but the replacement sequence may be selected to compensate for this. For example, the replacement sequence may extend further 5' from the nick than it does 3' of the nick, but the homology arm 5' of the nick is shorter than the homology arm 3' of the nick, to compensate. The converse is also possible, e.g., that the replacement sequence may extend further 3' from the nick than it does 5' of the nick, but the homology arm 3' of the nick is shorter than the homology arm 5' of the nick, to compensate.

Exemplary arrangements of linear nucleic acid template systems

In an embodiment, the nucleic acid template system is double stranded. In an

embodiment, the nucleic acid template system is single stranded. In an embodiment, the nucleic acid template system comprises a single stranded portion and a double stranded portion. In an embodiment, the template nucleic acid comprises about 50 to 100, e.g., 55 to 95, 60 to 90, 65 to 85, or 70 to 80, base pairs, homology on either side of the nick and/or replacement sequence. In an embodiment, the template nucleic acid comprises about 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 base pairs homology 5' of the nick or replacement sequence, 3' of the nick or replacement sequence, or both 5' and 3' of the nick or replacement sequences.

In an embodiment, the template nucleic acid comprises about 150 to 200, e.g., 155 to 195, 160 to 190, 165 to 185, or 170 to 180, base pairs homology 3' of the nick and/or

replacement sequence. In an embodiment, the template nucleic acid comprises about 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 200 base pairs homology 3' of the nick or replacement sequence. In an embodiment, the template nucleic acid comprises less than about 100, 90, 80, 70, 60, 50, 40, 30, 20, 15, or 10 base pairs homology 5' of the nick or replacement sequence.

In an embodiment, the template nucleic acid comprises about 150 to 200, e.g., 155 to 195, 160 to 190, 165 to 185, or 170 to 180, base pairs homology 5' of the nick and/or

replacement sequence. In an embodiment, the template nucleic acid comprises about 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 200 base pairs homology 5' of the nick or replacement sequence. In an embodiment, the template nucleic acid comprises less than about 100, 90, 80, 70, 60, 50, 40, 30, 20, 15, or 10 base pairs homology 3' of the nick or replacement sequence.

Exemplary Template Nucleic Acids

In an embodiment, the template nucleic acid is a single stranded nucleic acid. In another embodiment, the template nucleic acid is a double stranded nucleic acid. In some embodiments, the template nucleic acid comprises a nucleotide sequence, e.g., of one or more nucleotides, that will be added to or will template a change in the target nucleic acid. In other embodiments, the template nucleic acid comprises a nucleotide sequence that may be used to modify the target position. In other embodiments, the template nucleic acid comprises a nucleotide sequence, e.g., of one or more nucleotides, that corresponds to wild type sequence of the target nucleic acid, e.g., of the target position.

The template nucleic acid may comprise a replacement sequence. In some embodiments, the template nucleic acid comprises a 5' homology arm. In other embodiments, the template nucleic acid comprises a 3' homology arm.

In embodiments, the template nucleic acid is linear double stranded DNA. The length may be, e.g., about 150-200 base pairs, e.g., about 150, 160, 170, 180, 190, or 200 base pairs. The length may be, e.g., at least 150, 160, 170, 180, 190, or 200 base pairs. In some

embodiments, the length is no greater than 150, 160, 170, 180, 190, or 200 base pairs. In some embodiments, a double stranded template nucleic acid has a length of about 160 base pairs, e.g., about 155-165, 150-170, 140-180, 130-190, 120-200, 110-210, 100-220, 90-230, or 80-240 base pairs.

The template nucleic acid can be linear single stranded DNA. In embodiments, the template nucleic acid is (i) linear single stranded DNA that can anneal to the nicked strand of the target nucleic acid, (ii) linear single stranded DNA that can anneal to the intact strand of the target nucleic acid, (iii) linear single stranded DNA that can anneal to the transcribed strand of the target nucleic acid, (iv) linear single stranded DNA that can anneal to the non-transcribed strand of the target nucleic acid, or more than one of the preceding. The length may be, e.g., about 150-200 nucleotides, e.g., about 150, 160, 170, 180, 190, or 200 nucleotides. The length may be, e.g., at least 150, 160, 170, 180, 190, or 200 nucleotides. In some embodiments, the length is no greater than 150, 160, 170, 180, 190, or 200 nucleotides. In some embodiments, a single stranded template nucleic acid has a length of about 160 nucleotides, e.g., about 155-165, 150-170, 140-180, 130-190, 120-200, 110-210, 100-220, 90-230, or 80-240 nucleotides.

In some embodiments, the template nucleic acid is circular double stranded DNA, e.g., a plasmid. In some embodiments, the template nucleic acid comprises about 500 to 1000 base pairs of homology on either side of the replacement sequence and/or the nick. In some embodiments, the template nucleic acid comprises about 300, 400, 500, 600, 700, 800, 900, 1000, 1500, or 2000 base pairs of homology 5' of the nick or replacement sequence, 3' of the nick or replacement sequence, or both 5' and 3' of the nick or replacement sequence. In some embodiments, the template nucleic acid comprises at least 300, 400, 500, 600, 700, 800, 900, 1000, 1500, or 2000 base pairs of homology 5' of the nick or replacement sequence, 3' of the nick or replacement sequence, or both 5' and 3' of the nick or replacement sequence. In some embodiments, the template nucleic acid comprises no more than 300, 400, 500, 600, 700, 800, 900, 1000, 1500, or 2000 base pairs of homology 5' of the nick or replacement sequence, 3' of the nick or replacement sequence, or both 5' and 3' of the nick or replacement sequence.

In some embodiments, the template nucleic acid is an adenovirus vector, e.g., an AAV vector, e.g., a ssDNA molecule of a length and sequence that allows it to be packaged in an AAV capsid. The vector may be, e.g., less than 5 kb and may contain an ITR sequence that promotes packaging into the capsid. The vector may be integration-deficient. In some embodiments, the template nucleic acid comprises about 150 to 1000 nucleotides of homology on either side of the replacement sequence and/or the nick. In some embodiments, the template nucleic acid comprises about 100, 150, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1500, or 2000 nucleotides 5' of the nick or replacement sequence, 3' of the nick or replacement sequence, or both 5' and 3' of the nick or replacement sequence. In some embodiments, the template nucleic acid comprises at least 100, 150, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1500, or 2000 nucleotides 5' of the nick or replacement sequence, 3' of the nick or replacement sequence, or both 5' and 3' of the nick or replacement sequence. In some embodiments, the template nucleic acid comprises at most 100, 150, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1500, or 2000 nucleotides 5' of the nick or replacement sequence, 3' of the nick or replacement sequence, or both 5' and 3' of the nick or replacement sequence. In some embodiments, the template nucleic acid is a lentiviral vector, e.g., an IDLV (integration deficiency lentivirus). In some embodiments, the template nucleic acid comprises about 500 to 1000 base pairs of homology on either side of the replacement sequence and/or the nick. In some embodiments, the template nucleic acid comprises about 300, 400, 500, 600, 700, 800, 900, 1000, 1500, or 2000 base pairs of homology 5' of the nick or replacement sequence, 3' of the nick or replacement sequence, or both 5' and 3' of the nick or replacement sequence. In some embodiments, the template nucleic acid comprises at least 300, 400, 500, 600, 700, 800, 900, 1000, 1500, or 2000 base pairs of homology 5' of the nick or replacement sequence, 3' of the nick or replacement sequence, or both 5' and 3' of the nick or replacement sequence. In some embodiments, the template nucleic acid comprises no more than 300, 400, 500, 600, 700, 800, 900, 1000, 1500, or 2000 base pairs of homology 5' of the nick or replacement sequence, 3' of the nick or replacement sequence, or both 5' and 3' of the nick or replacement sequence.

In many embodiments, the template nucleic acid comprises one or more mutations, e.g., silent mutations, that prevent Cas9 from recognizing and cleaving the template nucleic acid. The template nucleic acid may comprise, e.g., at least 1, 2, 3, 4, 5, 10, 20, or 30 silent mutations relative to the corresponding sequence in the genome of the cell to be altered. In embodiments, the template nucleic acid comprises at most 2, 3, 4, 5, 10, 20, 30, or 50 silent mutations relative to the corresponding sequence in the genome of the cell to be altered.

Typically, the template sequence undergoes a breakage mediated or catalyzed

recombination with the target sequence. In an embodiment, the template nucleic acid includes sequence that corresponds to a site on the target sequence that is cleaved by an eaCas9 mediated cleavage event. In an embodiment, the template nucleic acid includes sequence that corresponds to both, a first site on the target sequence that is cleaved in a first Cas9 mediated event, and a second site on the target sequence that is cleaved in a second Cas9 mediated event.

In an embodiment, the template nucleic acid can include sequence which results in an alteration in the coding sequence of a translated sequence, e.g., one which results in the substitution of one amino acid for another in a protein product, e.g., transforming a mutant allele into a wild type allele, transforming a wild type allele into a mutant allele, and/or introducing a stop codon, insertion of an amino acid residue, deletion of an amino acid residue, or a nonsense mutation.

In other embodiments, the template nucleic acid can include sequence which results in an alteration in a non-coding sequence, e.g., an alteration in an exon or in a 5' or 3' non-translated or non-transcribed region. Such alterations include an alteration in a control element, e.g., a promoter, enhancer, and an alteration in a cis-acting or trans-acting control element.

A template nucleic acid having homology with a target position can be used to alter the structure of a target sequence. The template sequence can be used to alter an unwanted structure, e.g., an unwanted or mutant nucleotide.

Exemplary template nucleic acids (also referred to herein as donor constructs) to correction a mutation, e.g., at E6, e.g., E6V, in the HBB gene, are provided.

Suitable sequence for the 5' homology arm can be selected from (e.g., includes a portion of) or include the following sequence:

ATAGGAACTTGAATCAAGGAAATGATTTTAAAACGCAGTATTCTTAGTGGACTAGA

GGAAAAAAATAATCTGAGCCAAGTAGAAGACCTTTTCCCCTCCTACCCCTACTTTCT

AAGTCACAGAGGCTTTTTGTTCCCCCAGACACTCTTGCAGATTAGTCCAGGCAGAAA

CAGTTAGATGTCCCCAGTTAACCTCCTATTTGACACCACTGATTACCCCATTGATAGT

CACACTTTGGGTTGTAAGTGACTTTTTATTTATTTGTATTTTTGACTGCATTAAGAGG

TCTCTAGTTTTTTATCTCTTGTTTCCCAAAACCTAATAAGTAACTAATGCACAGAGCA

CATTGATTTGTATTTATTCTATTTTTAGACATAATTTATTAGCATGCATGAGCAAATT

AAGAAAAACAACAACAAATGAATGCATATATATGTATATGTATGTGTGTATATATAC

ACACATATATATATATATTTTTTCTTTTCTTACCAGAAGGTTTTAATCCAAATAAGGA

GAAGATATGCTTAGAACCGAGGTAGAGTTTTCATCCATTCTGTCCTGTAAGTATTTT

GCATATTCTGGAGACGCAGGAAGAGATCCATCTACATATCCCAAAGCTGAATTATG

GTAGACAAAACTCTTCCACTTTTAGTGCATCAACTTCTTATTTGTGTAATAAGAAAAT

TGGGAAAACGATCTTCAATATGCTTACCAAGCTGTGATTCCAAATATTACGTAAATA

CACTTGCAAAGGAGGATGTTTTTAGTAGCAATTTGTACTGATGGTATGGGGCCAAGA

GATATATCTTAGAGGGAGGGCTGAGGGTTTGAAGTCCAACTCCTAAGCCAGTGCCA

GAAGAGCCAAGGACAGGTACGGCTGTCATCACTTAGACCTCACCCTGTGGAGCCAC

ACCCTAGGGTTGGCCAATCTACTCCCAGGAGCAGGGAGGGCAGGAGCCAGGGCTGG GCATAAAAGTCAGGGCAGAGCCATCTATTGCTTACATTTGCTTCTGACACAACTGTG

TTCACTAGCAACCTCAAACAGACACCATGGTGCATCTGACTCCTG

SEQ ID NO: 16257 (5Ή arm)

Suitable sequence for the 3' homology arm can be selected from (e.g., includes a portion of) or include the following sequence:

GGAGAAGTCTGCCGTTACTGCCCTGTGGGGCAAGGTGAACGTGGATGAAGTTGGTG GTGAGGCCCTGGGCAGGTTGGTATCAAGGTTACAAGACAGGTTTAAGGAGACCAAT AGAAACTGGGCATGTGGAGACAGAGAAGACTCTTGGGTTTCTGATAGGCACTGACT CTCTCTGCCTATTGGTCTATTTTCCCACCCTTAGGCTGCTGGTGGTCTACCCTTGGAC CCAGAGGTTCTTTGAGTCCTTTGGGGATCTGTCCACTCCTGATGCTGTTATGGGCAAC CCTAAGGTGAAGGCTCATGGCAAGAAAGTGCTCGGTGCCTTTAGTGATGGCCTGGCT CACCTGGACAACCTCAAGGGCACCTTTGCCACACTGAGTGAGCTGCACTGTGACAA GCTGCACGTGGATCCTGAGAACTTCAGGGTGAGTCTATGGGACGCTTGATGTTTTCT TTCCCCTTCTTTTCTATGGTTAAGTTCATGTCATAGGAAGGGGATAAGTAACAGGGT ACAGTTTAGAATGGGAAACAGACGAATGATTGCATCAGTGTGGAAGTCTCAGGATC GTTTTAGTTTCTTTTATTTGCTGTTCATAACAATTGTTTTCTTTTGTTTAATTCTTGCTT TCTTTTTTTTTCTTCTCCGCAATTTTTACTATTATACTTAATGCCTTAACATTGTGTAT AACAAAAGGAAATATCTCTGAGATACATTAAGTAACTTAAAAAAAAACTTTACACA GTCTGCCTAGTACATTACTATTTGGAATATATGTGTGCTTATTTGCATATTCATAATC TCCCTACTTTATTTTCTTTTATTTTTAATTGATACATAATCATTATACATATTTATGGG TTAAAGTGTAATGTTTTAATATGTGTACACATATTGACCAAATCAGGGTAATTTTGC ATTTGTAATTTTAAAAAATGCTTTCTTCTTTTAATATACTTTTTTGTTTATCTTATTTCT AATACTTTCCCTAATCTCTTTCTTTCAGGGCAATAATGATACAATGTATCATGCCTCT TTGCACCATTCTAAAGAATAACAGTGATAATTTCTGGGTTAAGGCAATAGCAATATC TCTGCATATAAATATTTCTGCATATAAATTGTAACTG SEQ ID NO: 16258 (3Ή arm)

In an embodiment, the replacement sequence comprises or consists of an adenine (A) residue to correct the amino acid sequence to a glutamic acid (E) residue.

In an embodiment, to correct a mutation, e.g., at E6, e.g., E6V, in the HBB gene, the homology arms, e.g., the 5' and 3' homology arms, may each comprise about 1000 base pairs (bp) of sequence flanking the most distal gRNAs (e.g., 1100 bp of sequence on either side of the mutation). The 5' homology arm is shown as bold sequence, codon 6 is shown as underlined sequence, the inserted base to correct the mutation at E6, e.g., E6V, is shown as boxed sequence, and the 3' homology arm is shown as no emphasis sequence.

ATAGGAACTTGAATCAAGGAAATGATTTTAAAACGCAGTATTCTTAGTGGACTA

GAGGAAAAAAATAATCTGAGCCAAGTAGAAGACCTTTTCCCCTCCTACCCCTAC

TTTCTAAGTCACAGAGGCTTTTTGTTCCCCCAGACACTCTTGCAGATTAGTCCA

GGCAGAAACAGTTAGATGTCCCCAGTTAACCTCCTATTTGACACCACTGATTAC

CCCATTGATAGTCACACTTTGGGTTGTAAGTGACTTTTTATTTATTTGTATTTTT

GACTGCATTAAGAGGTCTCTAGTTTTTTATCTCTTGTTTCCCAAAACCTAATAA

GTAACTAATGCACAGAGCACATTGATTTGTATTTATTCTATTTTTAGACATAATT

TATTAGCATGCATGAGCAAATTAAGAAAAACAACAACAAATGAATGCATATATA

TGTATATGTATGTGTGTATATATACACACATATATATATATATTTTTTCTTTTCT

TACCAGAAGGTTTTAATCCAAATAAGGAGAAGATATGCTTAGAACCGAGGTAG

AGTTTTCATCCATTCTGTCCTGTAAGTATTTTGCATATTCTGGAGACGCAGGAA

GAGATCCATCTACATATCCCAAAGCTGAATTATGGTAGACAAAACTCTTCCACT

TTTAGTGCATCAACTTCTTATTTGTGTAATAAGAAAATTGGGAAAACGATCTTC

AATATGCTTACCAAGCTGTGATTCCAAATATTACGTAAATACACTTGCAAAGGA

GGATGTTTTTAGTAGCAATTTGTACTGATGGTATGGGGCCAAGAGATATATCTT

AGAGGGAGGGCTGAGGGTTTGAAGTCCAACTCCTAAGCCAGTGCCAGAAGAGC

CAAGGACAGGTACGGCTGTCATCACTTAGACCTCACCCTGTGGAGCCACACCC

TAGGGTTGGCCAATCTACTCCCAGGAGCAGGGAGGGCAGGAGCCAGGGCTGG

GCATAAAAGTCAGGGCAGAGCCATCTATTGCTTACATTTGCTTCTGACACAACT

GTGTTCACTAGCAACCTCAAACAGACACCATGGTGCATCTGACTCCTGgGGAGA

AGTCTGCCGTTACTGCCCTGTGGGGCAAGGTGAACGTGGATGAAGTTGGTGGTGAG

GCCCTGGGCAGGTTGGTATCAAGGTTACAAGACAGGTTTAAGGAGACCAATAGAAA

CTGGGCATGTGGAGACAGAGAAGACTCTTGGGTTTCTGATAGGCACTGACTCTCTCT

GCCTATTGGTCTATTTTCCCACCCTTAGGCTGCTGGTGGTCTACCCTTGGACCCAGAG

GTTCTTTGAGTCCTTTGGGGATCTGTCCACTCCTGATGCTGTTATGGGCAACCCTAAG

GTGAAGGCTCATGGCAAGAAAGTGCTCGGTGCCTTTAGTGATGGCCTGGCTCACCTG

GACAACCTCAAGGGCACCTTTGCCACACTGAGTGAGCTGCACTGTGACAAGCTGCA

CGTGGATCCTGAGAACTTCAGGGTGAGTCTATGGGACGCTTGATGTTTTCTTTCCCCT TCTTTTCTATGGTTAAGTTCATGTCATAGGAAGGGGATAAGTAACAGGGTACAGTTT AGAATGGGAAACAGACGAATGATTGCATCAGTGTGGAAGTCTCAGGATCGTTTTAG TTTCTTTTATTTGCTGTTCATAACAATTGTTTTCTTTTGTTTAATTCTTGCTTTCTTTTT TTTTCTTCTCCGCAATTTTTACTATTATACTTAATGCCTTAACATTGTGTATAACAAA AGGAAATATCTCTGAGATACATTAAGTAACTTAAAAAAAAACTTTACACAGTCTGCC TAGTACATTACTATTTGGAATATATGTGTGCTTATTTGCATATTCATAATCTCCCTAC TTTATTTTCTTTTATTTTTAATTGATACATAATCATTATACATATTTATGGGTTAAAGT GTAATGTTTTAATATGTGTACACATATTGACCAAATCAGGGTAATTTTGCATTTGTAA TTTTAAAAAATGCTTTCTTCTTTTAATATACTTTTTTGTTTATCTTATTTCTAATACTTT CCCTAATCTCTTTCTTTCAGGGCAATAATGATACAATGTATCATGCCTCTTTGCACCA TTCTAAAGAATAACAGTGATAATTTCTGGGTTAAGGCAATAGCAATATCTCTGCATA TAAATATTTCTGCATATAAATTGTAACTG (Template Construct 1; SEQ ID NO: 16259) As described below in Table 27, shorter homology arms, e.g., 5' and/or 3' homology arms may be used.

It is contemplated herein that one or both homology arms may be shortened to avoid including certain sequence repeat elements, e.g., Alu repeats, LINE elements. For example, a 5' homology arm may be shortened to avoid a sequence repeat element. In another embodiment, a 3' homology arm may be shortened to avoid a sequence repeat element. In an embodiment, both the 5' and the 3' homology arms may be shortened to avoid including certain sequence repeat elements.

It is contemplated herein that template nucleic acids for correcting a mutation may designed for use as a single- stranded oligonucleotide (ssODN). When using a ssODN, 5' and 3' homology arms may range up to about 200 base pairs (bp) in length, e.g., at least 25, 50, 75, 100, 125, 150, 175, or 200 bp in length. Longer homology arms are also contemplated for ssODNs as improvements in oligonucleotide synthesis continue to be made.

In an embodiment, an ssODN may be used to correct a mutation, e.g., E6V in the HBB gene. For example, the ssODN may include 50 bp 5' and 3' homology arms as shown below. The 5' homology arm is shown as bold sequence, codon 6 is shown as underlined sequence, the inserted base to correct the E6V mutation is shown as boxed sequence, and the 3' homology arm is shown as no emphasis sequence. ACTGTGTTCACTAGCAACCTCAAACAGACACCATGGTGCATCTGACTCCT

G0GGAGAAGTCTGCCGTTACTGCCCTGTGGGGCAAGGTGAACGTGGATGAAGT (Template Construct 2; SEQ ID NO: 16260)

Silent mutations in donor construct

It is contemplated herein that Cas9 could potentially cleave donor constructs either prior to or following homology directed repair (e.g., homologous recombination), resulting in a possible non-homologous-end-joining event and further DNA sequence mutation at the chromosomal locus of interest. Therefore, to avoid cleavage of the donor sequence before and/or after Cas9-mediated homology directed repair, alternate versions of the donor sequence may be used where silent mutations are introduced. These silent mutations may disrupt Cas9 binding and cleavage, but not disrupt the amino acid sequence of the repaired gene. For example, mutations may include those made to a donor sequence to repair the HBB gene, the mutant form of which can cause Sickle Cell Disease. If gRNA HBB-6 with the 20-base target sequence CGUUACUGCCCUGUGGGGCA is used to insert a donor sequence including

CTCCTGAGGAGAAGTCTGC|CGTTACTGCCCTGTGGGGCA|AGgGTGAACGTGGA

TGAAGT (SEQ ID NO: 16297), where the italic A is the base being corrected and the bracketed bases are those that match the guide RNA, the donor sequence may be changed to

CTCCTGAGGAGAAGTCTGCCGTTACTGCCCTGTGGGGCAAGaTGAACGTGGAT

GAAGT (SEQ ID NO: 16298), where the lowercase a has been changed from a G (lower case g in sequence ID xxx) at that position so that codon 15 still codes for the amino acid Arginine but the PAM sequence AGG has been modified to AGA to reduce or eliminate Cas9 cleavage at that locus.

Table 27 below provides exemplary template nucleic acids. In an embodiment, the template nucleic acid includes the 5' homology arm and the 3' homology arm of a row from Table 27. In another embodiment, a 5' homology arm from the first column can be combined with a 3' homology arm from Table 27. In each embodiment, a combination of the 5' and 3' homology arms include a replacement sequence, e.g., an adenine (A) residue.

Table 27

5' homology arm (the number of Replacement 3' homology arm (the number of nucleotides from SEQ ID NO: 5Ή, Sequence=A nucleotides from SEQ ID NO: 3Ή, beginning at the 3' end of SEQ ID beginning at the 5' end of SEQ ID NO: 5Ή) NO: 3Ή)

10 or more 10 or more

20 or more 20 or more

50 or more 50 or more

100 or more 100 or more

150 or more 150 or more

200 or more 200 or more

250 or more 250 or more

300 or more 300 or more

350 or more 350 or more

400 or more 400 or more

450 or more 450 or more

500 or more 500 or more

550 or more 550 or more

600 or more 600 or more

650 or more 650 or more

700 or more 700 or more

750 or more 750 or more

800 or more 800 or more

850 or more 850 or more

900 or more 900 or more

1000 or more 1000 or more

1100 or more 1100 or more

1200 or more 1200 or more

1300 or more 1300 or more

1400 or more 1400 or more

1500 or more 1500 or more

1600 or more 1600 or more 1700 or more 1700 or more

1800 or more 1800 or more

1900 or more 1900 or more

1200 or more 1200 or more

At least 50 but not long enough to At least 50 but not long enough to include a repeated element. include a repeated element.

At least 100 but not long enough to At least 100 but not long enough to include a repeated element. include a repeated element.

At least 150 but not long enough to At least 150 but not long enough to include a repeated element. include a repeated element.

5 to 100 nucleotides 5 to 100 nucleotides

10 to 150 nucleotides 10 to 150 nucleotides

20 to 150 nucleotides 20 to 150 nucleotides

Template Construct No. 1

Template Construct No. 2

V.2 NHEJ Approaches for Gene Targeting

As described herein, nuclease-induced non-homologous end-joining (NHEJ) can be used to target gene-specific knockouts. Nuclease-induced NHEJ can also be used to remove (e.g., delete) sequences in a gene of interest.

While not wishing to be bound by theory, it is believed that, in an embodiment, the genomic alterations associated with the methods described herein rely on nuclease-induced NHEJ and the error-prone nature of the NHEJ repair pathway. NHEJ repairs a double-strand break in the DNA by joining together the two ends; however, generally, the original sequence is restored only if two compatible ends, exactly as they were formed by the double-strand break, are perfectly ligated. The DNA ends of the double-strand break are frequently the subject of enzymatic processing, resulting in the addition or removal of nucleotides, at one or both strands, prior to rejoining of the ends. This results in the presence of insertion and/or deletion (indel) mutations in the DNA sequence at the site of the NHEJ repair. Two-thirds of these mutations typically alter the reading frame and, therefore, produce a non-functional protein. Additionally, mutations that maintain the reading frame, but which insert or delete a significant amount of sequence, can destroy functionality of the protein. This is locus dependent as mutations in critical functional domains are likely less tolerable than mutations in non-critical regions of the protein.

The indel mutations generated by NHEJ are unpredictable in nature; however, at a given break site certain indel sequences are favored and are over represented in the population, likely due to small regions of microhomology. The lengths of deletions can vary widely; most commonly in the 1-50 bp range, but they can reach greater than 100-200 bp. Insertions tend to be shorter and often include short duplications of the sequence immediately surrounding the break site. However, it is possible to obtain large insertions, and in these cases, the inserted sequence has often been traced to other regions of the genome or to plasmid DNA present in the cells.

Because NHEJ is a mutagenic process, it can also be used to delete small sequence motifs (e.g., motifs less than or equal to 50 nucleotides in length) as long as the generation of a specific final sequence is not required. If a double- strand break is targeted near to a target sequence, the deletion mutations caused by the NHEJ repair often span, and therefore remove, the unwanted nucleotides. For the deletion of larger DNA segments, introducing two double-strand breaks, one on each side of the sequence, can result in NHEJ between the ends with removal of the entire intervening sequence. In this way, DNA segments as large as several hundred kilobases can be deleted. Both of these approaches can be used to delete specific DNA sequences; however, the error-prone nature of NHEJ may still produce indel mutations at the site of repair.

Both double strand cleaving eaCas9 molecules and single strand, or nickase, eaCas9 molecules can be used in the methods and compositions described herein to generate NHEJ- mediated indels. NHEJ-mediated indels targeted to the the gene, e.g., a coding region, e.g., an early coding region of a gene, of interest can be used to knockout (i.e., eliminate expression of) a gene of interest. For example, early coding region of a gene of interest includes sequence immediately following a start codon, within a first exon of the coding sequence, or within 500 bp of the start codon (e.g., less than 500, 450, 400, 350, 300, 250, 200, 150, 100 or 50 bp).

In an embodiment, in which a gRNA and Cas9 nuclease generate a double strand break for the purpose of inducing NHEJ-mediated indels, a gRNA, e.g., a unimolecular (or chimeric) or modular gRNA molecule, is configured to position one double-strand break in close proximity to a nucleotide of the target position. In an embodiment, the cleavage site is between 0-30 bp away from the target position (e.g., less than 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 bp from the target position).

In an embodiment, in which two gRNAs complexing with Cas9 nickases induce two single strand breaks for the purpose of inducing NHEJ-mediated indels, two gRNAs, e.g., independently, unimolecular (or chimeric) or modular gRNA, are configured to position two single-strand breaks to provide for NHEJ repair a nucleotide of the target position. In an embodiment, the gRNAs are configured to position cuts at the same position, or within a few nucleotides of one another, on different strands, essentially mimicking a double strand break. In an embodiment, the closer nick is between 0-30 bp away from the target position (e.g., less than 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 bp from the target position), and the two nicks are within 25-55 bp of each other (e.g., between 25 to 50, 25 to 45, 25 to 40, 25 to 35, 25 to 30, 50 to 55, 45 to 55, 40 to 55, 35 to 55, 30 to 55, 30 to 50, 35 to 50, 40 to 50 , 45 to 50, 35 to 45, or 40 to 45 bp) and no more than 100 bp away from each other (e.g., no more than 90, 80, 70, 60, 50, 40, 30, 20 or 10 bp). In an embodiment, the gRNAs are configured to place a single strand break on either side of a nucleotide of the target position.

Both double strand cleaving eaCas9 molecules and single strand, or nickase, eaCas9 molecules can be used in the methods and compositions described herein to generate breaks both sides of a target position. Double strand or paired single strand breaks may be generated on both sides of a target position to remove the nucleic acid sequence between the two cuts (e.g., the region between the two breaks in deleted). In one embodiment, two gRNAs, e.g.,

independently, unimolecular (or chimeric) or modular gRNA, are configured to position a double-strand break on both sides of a target position. In an alternate embodiment, three gRNAs, e.g., independently, unimolecular (or chimeric) or modular gRNA, are configured to position a double strand break (i.e., one gRNA complexes with a cas9 nuclease) and two single strand breaks or paired single strand breaks (i.e., two gRNAs complex with Cas9 nickases) on either side of the target position. In another embodiment, four gRNAs, e.g., independently,

unimolecular (or chimeric) or modular gRNA, are configured to generate two pairs of single strand breaks (i.e., two pairs of two gRNAs complex with Cas9 nickases) on either side of the target position. The double strand break(s) or the closer of the two single strand nicks in a pair will ideally be within 0-500 bp of the target position (e.g., no more than 450, 400, 350, 300, 250, 200, 150, 100, 50 or 25 bp from the target position). When nickases are used, the two nicks in a pair are within 25-55 bp of each other (e.g., between 25 to 50, 25 to 45, 25 to 40, 25 to 35, 25 to 30, 50 to 55, 45 to 55, 40 to 55, 35 to 55, 30 to 55, 30 to 50, 35 to 50, 40 to 50 , 45 to 50, 35 to 45, or 40 to 45 bp) and no more than 100 bp away from each other (e.g., no more than 90, 80, 70, 60, 50, 40, 30, 20 or 10 bp).

V.3 Targeted Knockdown

Unlike CRISPR/Cas-mediated gene knockout, which permanently eliminates expression by mutating the gene at the DNA level, CRISPR/Cas knockdown allows for temporary reduction of gene expression through the use of artificial transcription factors. Mutating key residues in both DNA cleavage domains of the Cas9 protein (e.g. the DIOA and H840A mutations) results in the generation of a catalytically inactive Cas9 (eiCas9 which is also known as dead Cas9 or dCas9) molecule. A catalytically inactive Cas9 complexes with a gRNA and localizes to the DNA sequence specified by that gRNA's targeting domain, however, it does not cleave the target DNA. Fusion of the dCas9 to an effector domain, e.g., a transcription repression domain, enables recruitment of the effector to any DNA site specified by the gRNA. Although an enxymatically inactive (eiCas9) Cas9 molecule itself can block transcription when recruited to early regions in the coding sequence, more robust repression can be achieved by fusing a transcriptional repression domain (for example KRAB, SID or ERD) to the Cas9 and recruiting it to the target knockdown position, e.g., within lOOObp of sequence 3' of the start codon or within 500 bp of a promoter region 5' of the start codon of a gene. It is likely that targeting DNAsel hypersensitive sites (DHSs) of the promoter may yield more efficient gene repression or activation because these regions are more likely to be accessible to the Cas9 protein and are also more likely to harbor sites for endogenous transcription factors. Especially for gene repression, it is contemplated herein that blocking the binding site of an endogenous transcription factor would aid in downregulating gene expression. In an embodiment, one or more eiCas9 molecules may be used to block binding of one or more endogenous transcription factors. In another embodiment, an eiCas9 molecule can be fused to a chromatin modifying protein. Altering chromatin status can result in decreased expression of the target gene. One or more eiCas9 molecules fused to one or more chromatin modifying proteins may be used to alter chromatin status. In an embodiment, a gRNA molecule can be targeted to a known transcription response elements (e.g., promoters, enhancers, etc.), a known upstream activating sequences (UAS), and/or sequences of unknown or known function that are suspected of being able to control expression of the target DNA.

CRISPR/Cas-mediated gene knockdown can be used to reduce expression of an unwanted allele or transcript. Contemplated herein are scenarios wherein permanent destruction of the gene is not ideal. In these scenarios, site-specific repression may be used to temporarily reduce or eliminate expression. It is also contemplated herein that the off-target effects of a Cas- repressor may be less severe than those of a Cas-nuclease as a nuclease can cleave any DNA sequence and cause mutations whereas a Cas-repressor may only have an effect if it targets the promoter region of an actively transcribed gene. However, while nuclease-mediated knockout is permanent, repression may only persist as long as the Cas-repressor is present in the cells. Once the repressor is no longer present, it is likely that endogenous transcription factors and gene regulatory elements would restore expression to its natural state.

V.4 Single- Strand Annealing

Single strand annealing (SSA) is another DNA repair process that repairs a double-strand break between two repeat sequences present in a target nucleic acid. Repeat sequences utilized by the SSA pathway are generally greater than 30 nucleotides in length. Resection at the break ends occurs to reveal repeat sequences on both strands of the target nucleic acid. After resection, single strand overhangs containing the repeat sequences are coated with RPA protein to prevent the repeats sequences from inappropriate annealing, e.g., to themselves. RAD52 binds to and each of the repeat sequences on the overhangs and aligns the sequences to enable the annealing of the complementary repeat sequences. After annealing, the single-strand flaps of the overhangs are cleaved. New DNA synthesis fills in any gaps, and ligation restores the DNA duplex. As a result of the processing, the DNA sequence between the two repeats is deleted. The length of the deletion can depend on many factors including the location of the two repeats utilized, and the pathway or processivity of the resection.

In contrast to HDR pathways, SSA does not require a template nucleic acid to alter or correct a target nucleic acid sequence. Instead, the complementary repeat sequence is utilized. V. 5 Other DNA Repair Pathways

SSBR (single strand break repair)

Single- stranded breaks (SSB) in the genome are repaired by the SSBR pathway, which is a distinct mechanism from the DSB repair mechanisms discussed above. The SSBR pathway has four major stages: SSB detection, DNA end processing, DNA gap filling, and DNA ligation. A more detailed explanation is given in Caldecott, Nature Reviews Genetics 9, 619-631 (August 2008), and a summary is given here.

In the first stage, when a SSB forms, PARP1 and/or PARP2 recognize the break and recruit repair machinery. The binding and activity of PARP1 at DNA breaks is transient and it seems to accelerate SSBr by promoting the focal accumulation or stability of SSBr protein complexes at the lesion. Arguably the most important of these SSBr proteins is XRCC1, which functions as a molecular scaffold that interacts with, stabilizes, and stimulates multiple enzymatic components of the SSBr process including the protein responsible for cleaning the DNA 3' and 5' ends. For instance, XRCC1 interacts with several proteins (DNA polymerase beta, PNK, and three nucleases, APE1, APTX, and APLF) that promote end processing. APE1 has endonuclease activity. APLF exhibits endonuclease and 3' to 5' exonuclease activities. APTX has endonuclease and 3' to 5' exonuclease activity.

This end processing is an important stage of SSBR since the 3'- and/or 5 '-termini of most, if not all, SSBs are 'damaged'. End processing generally involves restoring a damaged 3'- end to a hydroxylated state and and/or a damaged 5' end to a phosphate moiety, so that the ends become ligation-competent. Enzymes that can process damaged 3' termini include PNKP, APE1, and TDP1. Enzymes that can process damaged 5' termini include PNKP, DNA polymerase beta, and APTX. LIG3 (DNA ligase III) can also participate in end processing. Once the ends are cleaned, gap filling can occur.

At the DNA gap filling stage, the proteins typically present are PARP1, DNA polymerase beta, XRCC1, FEN1 (flap endonculease 1), DNA polymerase delta/epsilon, PCNA, and LIG1. There are two ways of gap filling, the short patch repair and the long patch repair. Short patch repair involves the insertion of a single nucleotide that is missing. At some SSBs, "gap filling" might continue displacing two or more nucleotides (displacement of up to 12 bases have been reported). FEN1 is an endonuclease that removes the displaced 5'-residues. Multiple DNA polymerases, including Pol β , are involved in the repair of SSBs, with the choice of DNA polymerase influenced by the source and type of SSB.

In the fourth stage, a DNA ligase such as LIGl (Ligase I) or LIG3 (Ligase III) catalyzes joining of the ends. Short patch repair uses Ligase III and long patch repair uses Ligase I.

Sometimes, SSBR is replication-coupled. This pathway can involve one or more of CtIP, MRN, ERCCl, and FENl. Additional factors that may promote SSBR include: aPARP, PARP1, PARP2, PARG, XRCC1, DNA polymerase b, DNA polymerase d, DNA polymerase e, PCNA, LIGl, PNK, PNKP, APEl, APTX, APLF, TDPl, LIG3, FENl, CtIP, MRN, and ERCCl.

MMR (mismatch repair)

Cells contain three excision repair pathways: MMR, BER, and NER. The excision repair pathways hace a common feature in that they typically recognize a lesion on one strand of the DNA, then exo/endonucleaseases remove the lesion and leave a 1-30 nucleotide gap that is sub- sequentially filled in by DNA polymerase and finally sealed with ligase. A more complete picture is given in Li, Cell Research (2008) 18:85-98, and a summary is provided here.

Mismatch repair (MMR) operates on mispaired DNA bases.

The MSH2/6 or MSH2/3 complexes both have ATPases activity that plays an important role in mismatch recognition and the initiation of repair. MSH2/6 preferentially recognizes base- base mismatches and identifies mispairs of 1 or 2 nucleotides, while MSH2/3 preferentially recognizes larger ID mispairs.

hMLHl heterodimerizes with hPMS2 to form hMutL which possesses an ATPase activity and is important for multiple steps of MMR. It possesses a PCNA/replication factor C (RFC)-dependent endonuclease activity which plays an important role in 3 ' nick-directed MMR involving EXOl. (EXOl is a participant in both HR and MMR.) It regulates termination of mismatch-provoked excision. Ligase I is the relevant ligase for this pathway. Additional factors that may promote MMR include: EXOl, MSH2, MSH3, MSH6, MLH1, PMS2, MLH3, DNA Pol d, RPA, HMGB1, RFC, and DNA ligase I.

Base excision repair (BER)

The base excision repair (BER) pathway is active throughout the cell cycle; it is responsible primarily for removing small, non-helix-distorting base lesions from the genome. In contrast, the related Nucleotide Excision Repair pathway (discussed in the next section) repairs bulky helix-distorting lesions. A more detailed explanation is given in Caldecott, Nature Reviews Genetics 9, 619-631 (August 2008), and a summary is given here.

Upon DNA base damage, base excision repair (BER) is initiated and the process can be simplified into five major steps: (a) removal of the damaged DNA base; (b) incision of the subsequent a basic site; (c) clean-up of the DNA ends; (d) insertion of the correct nucleotide into the repair gap; and (e) ligation of the remaining nick in the DNA backbone. These last steps are similar to the SSBR.

In the first step, a damage- specific DNA glycosylase excises the damaged base through cleavage of the N-glycosidic bond linking the base to the sugar phosphate backbone. Then AP endonuclease-1 (APE1) or bifunctional DNA glycosylases with an associated lyase activity incised the phosphodiester backbone to create a DNA single strand break (SSB). The third step of BER involves cleaning-up of the DNA ends. The fourth step in BER is conducted by Pol β that adds a new complementary nucleotide into the repair gap and in the final step

XRCCl/Ligase III seals the remaining nick in the DNA backbone. This completes the short- patch BER pathway in which the majority (-80%) of damaged DNA bases are repaired.

However, if the 5⁷ -ends in step 3 are resistant to end processing activity, following one nucleotide insertion by Pol β there is then a polymerase switch to the replicative DNA polymerases, Pol δ/ε, which then add -2-8 more nucleotides into the DNA repair gap. This creates a 5 ' -flap structure, which is recognized and excised by flap endonuclease-1 (FEN-1) in association with the processivity factor proliferating cell nuclear antigen (PCNA). DNA ligase I then seals the remaining nick in the DNA backbone and completes long-patch BER. Additional factors that may promote the BER pathway include: DNA glycosylase, APE1, Polb, Pold, Pole, XRCC1, Ligase III, FEN-1, PCNA, RECQL4, WRN, MYH, PNKP, and APTX.

Nucleotide excision repair (NER)

Nucleotide excision repair (NER) is an important excision mechanism that removes bulky helix-distorting lesions from DNA. Additional details about NER are given in Marteijn et al., Nature Reviews Molecular Cell Biology 15, 465-481 (2014), and a summary is given here. NER a broad pathway encompassing two smaller pathways: global genomic NER (GG-NER) and transcription coupled repair NER (TC-NER). GG-NER and TC-NER use different factors for recognizing DNA damage. However, they utilize the same machinery for lesion incision, repair, and ligation.

Once damage is recognized, the cell removes a short single- stranded DNA segment that contains the lesion. Endonucleases XPF/ERCC1 and XPG (encoded by ERCC5) remove the lesion by cutting the damaged strand on either side of the lesion, resulting in a single-strand gap of 22-30 nucleotides. Next, the cell performs DNA gap filling synthesis and ligation. Involved in this process are: PCNA, RFC, DNA Pol δ, DNA Pol ε or DNA Pol κ, and DNA ligase I or XRCCl/Ligase III. Replicating cells tend to use DNA pol ε and DNA ligase I, while non- replicating cells tend to use DNA Pol δ, DNA Pol κ, and the XRCC1/ Ligase III complex to perform the ligation step.

NER can involve the following factors: XPA-G, POLH, XPF, ERCC1, XPA-G, and LIG1. Transcription-coupled NER (TC-NER) can involve the following factors: CSA, CSB, XPB, XPD, XPG, ERCC1, and TTDA. Additional factors that may promote the NER repair pathway include XPA-G, POLH, XPF, ERCC1, XPA-G, LIG1, CSA, CSB, XPA, XPB, XPC, XPD, XPF, XPG, TTDA, UVSSA, USP7, CETN2, RAD23B, UV-DDB, CAK subcomplex, RPA, and PCNA.

Interstrand Crosslink (ICL)

A dedicated pathway called the ICL repair pathway repairs interstrand crosslinks.

Interstrand crosslinks, or covalent crosslinks between bases in different DNA strand, can occur during replication or transcription. ICL repair involves the coordination of multiple repair processes, in particular, nucleolytic activity, translesion synthesis (TLS), and HDR. Nucleases are recruited to excise the ICL on either side of the crosslinked bases, while TLS and HDR are coordinated to repair the cut strands. ICL repair can involve the following factors:

endonucleases, e.g., XPF and RAD51C, endonucleases such as RAD51, translesion polymerases, e.g., DNA polymerase zeta and Revl), and the Fanconi anemia (FA) proteins, e.g., FancJ.

Other pathways

Several other DNA repair pathways exist in mammals.

Translesion synthesis (TLS) is a pathway for repairing a single stranded break left after a defective replication event and involves translesion polymerases, e.g., DNA pol and Revl.. Error-free postreplication repair (PRR) is another pathway for repairing a single stranded break left after a defective replication event.

V.6 Examples of gRNAs in Genome Editing Methods

gRNA molecules as described herein can be used with Cas9 molecules that generate a double strand break or a single strand break to alter the sequence of a target nucleic acid, e.g., a target position or target genetic signature. gRNA molecules useful in these methods are described below.

In an embodiment, the gRNA, e.g., a chimeric gRNA, is configured such that it comprises one or more of the following properties;

a) it can position, e.g., when targeting a Cas9 molecule that makes double strand breaks, a double strand break (i) within 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 nucleotides of a target position, or (ii) sufficiently close that the target position is within the region of end resection;

b) it has a targeting domain of at least 16 nucleotides, e.g., a targeting domain of (i) 16, (ii), 17, (iii) 18, (iv) 19, (v) 20, (vi) 21, (vii) 22, (viii) 23, (ix) 24, (x) 25, or (xi) 26 nucleotides; and

c)

(i) the proximal and tail domain, when taken together, comprise at least 15, 18, 20, 25, 30, 31, 35, 40, 45, 49, 50, or 53 nucleotides, e.g., at least 15, 18, 20, 25, 30, 31, 35, 40, 45, 49, 50, or 53 nucleotides from a naturally occurring S.

pyogenes, S. thermophilus, S. aureus, or N. meningitidis tail and proximal domain, or a sequence that differs by no more than 1, 2, 3, 4, 5; 6, 7, 8, 9 or 10 nucleotides therefrom;

(ii) there are at least 15, 18, 20, 25, 30, 31, 35, 40, 45, 49, 50, or 53 nucleotides 3' to the last nucleotide of the second complementarity domain, e.g., at least 15, 18, 20, 25, 30, 31, 35, 40, 45, 49, 50, or 53 nucleotides from the corresponding sequence of a naturally occurring S. pyogenes, S. thermophilus, S. aureus, or N. meningitidis gRNA, or a sequence that differs by no more than 1, 2, 3, 4, 5; 6, 7, 8, 9 or 10 nucleotides therefrom; (iii) there are at least 16, 19, 21, 26, 31, 32, 36, 41, 46, 50, 51, or 54 nucleotides 3' to the last nucleotide of the second complementarity domain that is complementary to its corresponding nucleotide of the first complementarity domain, e.g., at least 16, 19, 21, 26, 31, 32, 36, 41, 46, 50, 51, or 54 nucleotides from the corresponding sequence of a naturally occurring S. pyogenes, S.

thermophilus , S. aureus, or N. meningitidis gRNA, or a sequence that differs by no more than 1, 2, 3, 4, 5; 6, 7, 8, 9 or 10 nucleotides therefrom;

(iv) the tail domain is at least 10, 15, 20, 25, 30, 35 or 40 nucleotides in length, e.g., it comprises at least 10, 15, 20, 25, 30, 35 or 40 nucleotides from a naturally occurring S. pyogenes, S. thermophilus, S. aureus, or N. meningitidis tail domain, or a sequence that differs by no more than 1, 2, 3, 4, 5; 6, 7, 8, 9 or 10 nucleotides therefrom; or

(v) the tail domain comprises 15, 20, 25, 30, 35, 40 nucleotides or all of the corresponding portions of a naturally occurring tail domain, e.g., a naturally occurring S. pyogenes, S. thermophilus, S. aureus, or N. meningitidis tail domain.

In an embodiment, the gRNA is configured such that it comprises properties: a and b(i).

In an embodiment, the gRNA is configured such that it comprises properties: a and b(ii).

In an embodiment, the gRNA is configured such that it comprises properties: a and b(iii).

In an embodiment, the gRNA is configured such that it comprises properties: a and b(iv).

In an embodiment, the gRNA is configured such that it comprises properties: a and b(v).

In an embodiment, the gRNA is configured such that it comprises properties: a and b(vi).

In an embodiment, the gRNA is configured such that it comprises properties: a and b(vii).

In an embodiment, the gRNA is configured such that it comprises properties: a and b(viii).

In an embodiment, the gRNA is configured such that it comprises properties: a and b(ix).

In an embodiment, the gRNA is configured such that it comprises properties: a and b(x).

In an embodiment, the gRNA is configured such that it comprises properties: a and b(xi).

In an embodiment, the gRNA is configured such that it comprises properties: a and c.

In an embodiment, the gRNA is configured such that in comprises properties: a, b, and c.

In an embodiment, the gRNA is configured such that in comprises properties: a(i), b(i), n an embodiment, the gRNA is configured such that in comprises properties: a(i), b(i), and c(ii

n an embodiment, the gRNA is configured such that in comprises properties: a(i), b(ii), and c(i)

n an embodiment, the gRNA is configured such that in comprises properties: a(i), b(ii), and c(ii

n an embodiment, the gRNA is configured such that in comprises properties: a(i), b(iii), and c(i)

n an embodiment, the gRNA is configured such that in comprises properties: a(i), b(iii), and c(ii

n an embodiment, the gRNA is configured such that in comprises properties: a(i), b(iv), and c(i)

n an embodiment, the gRNA is configured such that in comprises properties: a(i), b(iv), and c(ii

n an embodiment, the gRNA is configured such that in comprises properties: a(i), b(v), and c(i)

n an embodiment, the gRNA is configured such that in comprises properties: a(i), b(v), and c(ii

n an embodiment, the gRNA is configured such that in comprises properties: a(i), b(vi), and c(i)

n an embodiment, the gRNA is configured such that in comprises properties: a(i), b(vi), and c(ii

n an embodiment, the gRNA is configured such that in comprises properties: a(i), b(vii), and c(i)

n an embodiment, the gRNA is configured such that in comprises properties: a(i), b(vii), and c(ii

n an embodiment, the gRNA is configured such that in comprises properties: a(i), b(viii), and c(i)

n an embodiment, the gRNA is configured such that in comprises properties: a(i), b(viii), and c(ii In an embodiment, the gRNA is configured such that in comprises properties: a(i), b(ix), and c(i).

In an embodiment, the gRNA is configured such that in comprises properties: a(i), b(ix), and c(ii).

In an embodiment, the gRNA is configured such that in comprises properties: a(i), b(x), and c(i).

In an embodiment, the gRNA is configured such that in comprises properties: a(i), b(x), and c(ii).

In an embodiment, the gRNA is configured such that in comprises properties: a(i), b(xi), and c(i).

In an embodiment, the gRNA is configured such that in comprises properties: a(i), b(xi), and c(ii).

a) one or both of the gRNAs can position, e.g., when targeting a Cas9 molecule that makes single strand breaks, a single strand break within (i) 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 nucleotides of a target position, or (ii) sufficiently close that the target position is within the region of end resection;

b) one or both have a targeting domain of at least 16 nucleotides, e.g., a targeting domain of (i) 16, (ii), 17, (iii) 18, (iv) 19, (v) 20, (vi) 21, (vii) 22, (viii) 23, (ix) 24, (x) 25, or (xi) 26 nucleotides; and

c)

(ii) there are at least 15, 18, 20, 25, 30, 31, 35, 40, 45, 49, 50, or 53 nucleotides 3' to the last nucleotide of the second complementarity domain, e.g., at least 15, 18, 20, 25, 30, 31, 35, 40, 45, 49, 50, or 53 nucleotides from the corresponding sequence of a naturally occurring S. pyogenes, S. thermophilus, S. aureus, or N. meningitidis gRNA, or a sequence that differs by no more than 1, 2, 3, 4, 5; 6, 7, 8, 9 or 10 nucleotides therefrom;

(iii) there are at least 16, 19, 21, 26, 31, 32, 36, 41, 46, 50, 51, or 54 nucleotides 3' to the last nucleotide of the second complementarity domain that is complementary to its corresponding nucleotide of the first complementarity domain, e.g., at least 16, 19, 21, 26, 31, 32, 36, 41, 46, 50, 51, or 54 nucleotides from the corresponding sequence of a naturally occurring S. pyogenes, S.

thermophilus, S. aureus, or N. meningitidis gRNA, or a sequence that differs by no more than 1, 2, 3, 4, 5; 6, 7, 8, 9 or 10 nucleotides therefrom;

In an embodiment, the gRNA is configured such that it comprises properties: a and c. In an embodiment, the gRNA is configured such that in comprises properties: a, b, and c. In an embodiment, the gRNA is configured such that in comprises properties: a(i), b(i), and c(i).

In an embodiment, the gRNA is configured such that in comprises properties: a(i), b(i), and c(ii).

In an embodiment, the gRNA is configured such that in comprises properties: a(i), b(ii), and c(i).

In an embodiment, the gRNA is configured such that in comprises properties: a(i), b(ii), and c(ii).

In an embodiment, the gRNA is configured such that in comprises properties: a(i), b(iii), and c(i).

In an embodiment, the gRNA is configured such that in comprises properties: a(i), b(iii), and c(ii).

In an embodiment, the gRNA is configured such that in comprises properties: a(i), b(iv), and c(i).

In an embodiment, the gRNA is configured such that in comprises properties: a(i), b(iv), and c(ii).

In an embodiment, the gRNA is configured such that in comprises properties: a(i), b(v), and c(i).

In an embodiment, the gRNA is configured such that in comprises properties: a(i), b(v), and c(ii).

In an embodiment, the gRNA is configured such that in comprises properties: a(i), b(vi), and c(i).

In an embodiment, the gRNA is configured such that in comprises properties: a(i), b(vi), and c(ii).

In an embodiment, the gRNA is configured such that in comprises properties: a(i), b(vii), and c(i).

In an embodiment, the gRNA is configured such that in comprises properties: a(i), b(vii), and c(ii).

In an embodiment, the gRNA is configured such that in comprises properties: a(i), b(viii), and c(i). In an embodiment, the gRNA is configured such that in comprises properties: a(i), b(viii), and c(ii).

In an embodiment, the gRNA is configured such that in comprises properties: a(i), b(ix), and c(i).

In an embodiment, the gRNA is used with a Cas9 nickase molecule having HNH activity, e.g., a Cas9 molecule having the RuvC activity inactivated, e.g., a Cas9 molecule having a mutation at D10, e.g., the D10A mutation.

In an embodiment, the gRNA is used with a Cas9 nickase molecule having RuvC activity, e.g., a Cas9 molecule having the HNH activity inactivated, e.g., a Cas9 molecule having a mutation at 840, e.g., the H840A.

In an embodiment, the gRNAs are used with a Cas9 nickase molecule having RuvC activity, e.g., a Cas9 molecule having the HNH activity inactivated, e.g., a Cas9 molecule having a mutation at N863, e.g., the N863A mutation.

In an embodiment, a pair of gRNAs, e.g., a pair of chimeric gRNAs, comprising a first and a second gRNA, is configured such that they comprises one or more of the following properties;

a) one or both of the gRNAs can position, e.g., when targeting a Cas9 molecule that makes single strand breaks, a single strand break within (i) 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 nucleotides of a target position, or (ii) sufficiently close that the target position is within the region of end resection; b) one or both have a targeting domain of at least 16 nucleotides, e.g., a targeting domain of (i) 16, (ii), 17, (iii) 18, (iv) 19, (v) 20, (vi) 21, (vii) 22, (viii) 23, (ix) 24, (x) 25, or (xi) 26 nucleotides;

c) for one or both:

(iv) the tail domain is at least 10, 15, 20, 25, 30, 35 or 40 nucleotides in length, e.g., it comprises at least 10, 15, 20, 25, 30, 35 or 40 nucleotides from a naturally occurring S. pyogenes, S. thermophilus, S. aureus, or N. meningitidis tail domain; or, or a sequence that differs by no more than 1, 2, 3, 4, 5; 6, 7, 8, 9 or 10 nucleotides therefrom; or

(v) the tail domain comprises 15, 20, 25, 30, 35, 40 nucleotides or all of the corresponding portions of a naturally occurring tail domain, e.g., a naturally occurring S. pyogenes, S. thermophilus, S. aureus, or N. meningitidis tail domain; d) the gRNAs are configured such that, when hybridized to target nucleic acid, they are separated by 0-50, 0-100, 0-200, at least 10, at least 20, at least 30 or at least 50 nucleotides; e) the breaks made by the first gRNA and second gRNA are on different strands; and f) the PAMs are facing outwards.

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a and b(i).

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a and b(ii).

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a and b(iii).

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a and b(iv).

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a and b(v).

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a and b(vi).

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a and b(vii).

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a and b(viii).

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a and b(ix).

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a and b(x).

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a and b(xi).

In an embodiment, one or both of the gRNAs configured such that it comprises properties: a and c.

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a, b, and c. In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(i), and c(i).

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(i), and c(ii).

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(i), c, and d.

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(i), c, and e.

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(i), c, d, and e.

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(ii), and c(i).

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(ii), and c(ii).

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(ii), c, and d.

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(ii), c, and e.

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(ii), c, d, and e.

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(iii), and c(i).

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(iii), and c(ii).

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(iii), c, and d.

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(iii), c, and e.

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(iii), c, d, and e. In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(iv), and c(i).

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(iv), and c(ii).

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(iv), c, and d.

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(iv), c, and e.

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(iv), c, d, and e.

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(v), and c(i).

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(v), and c(ii).

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(v), c, and d.

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(v), c, and e.

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(v), c, d, and e.

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(vi), and c(i).

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(vi), and c(ii).

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(vi), c, and d.

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(vi), c, and e.

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(vi), c, d, and e. In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(vii), and c(i).

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(vii), and c(ii).

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(vii), c, and d.

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(vii), c, and e.

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(vii), c, d, and e.

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(viii), and c(i).

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(viii), and c(ii).

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(viii), c, and d.

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(viii), c, and e.

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(viii), c, d, and e.

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(ix), and c(i).

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(ix), and c(ii).

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(ix), c, and d.

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(ix), c, and e.

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(ix), c, d, and e. In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(x), and c(i).

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(x), and c(ii).

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(x), c, and d.

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(x), c, and e.

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(x), c, d, and e.

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(xi), and c(i).

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(xi), and c(ii).

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(xi), c, and d.

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(xi), c, and e.

In an embodiment, one or both of the gRNAs is configured such that it comprises properties: a(i), b(xi), c, d, and e.

In an embodiment, the gRNAs are used with a Cas9 nickase molecule having HNH activity, e.g., a Cas9 molecule having the RuvC activity inactivated, e.g., a Cas9 molecule having a mutation at D 10, e.g., the D10A mutation.

In an embodiment, the gRNAs are used with a Cas9 nickase molecule having RuvC activity, e.g., a Cas9 molecule having the HNH activity inactivated, e.g., a Cas9 molecule having a mutation at H840, e.g., the H840A mutation.

In an embodiment, the gRNAs are used with a Cas9 nickase molecule having RuvC activity, e.g., a Cas9 molecule having the HNH activity inactivated, e.g., a Cas9 molecule having a mutation at N863, e.g., the N863A mutation. VI. Target Cells

Cas9 molecules and gRNA molecules, e.g., a Cas9 molecule/gRNA molecule complex, can be used to manipulate a cell, e.g., to edit a target nucleic acid, in a wide variety of cells.

In an embodiment, a cell is manipulated by editing (e.g., inducing a mutation in) the HBB and/or BCLllA target genes, e.g., as described herein. In an embodiment, the expression of the HBB and/or BCLllA target genes is modulated, e.g., in vivo. In another embodiment, the expression of the HBB and/or BCLllA target genes is modulated, e.g., ex vivo.

The Cas9 and gRNA molecules described herein can be delivered to a target cell. In an embodiment, the target cell is a circulating blood cell, e.g., a reticulocyte, a myeloid progenitor cell, or a hematopoietic stem cell. In an embodiment, the target cell is a bone marrow cell (e.g., a myeloid progenitor cell, an erythroid progenitor cell, a hematopoietic stem cell, or a mesenchymal stem cell). In an embodiment, the target cell is a myeloid progenitor cell (e.g. a common myeloid progenitor (CMP) cell). In an embodiment, the target cell is an erythroid progenitor cell (e.g. a megakaryocyte erythroid progenitor (MEP) cell). In an embodiment, the target cell is a hematopoietic stem cell (e.g. a long term hematopoietic stem cell (LT-HSC), a short term hematopoietic stem cell (ST-HSC), a multipotent progenitor (MPP) cell, a lineage restricted progenitor (LRP) cell).

In an embodiment, the target cell is manipulated ex vivo by editing (e.g., inducing a mutation in) the HBB and/or BCLllA target genes and/or modulating the expression of the HBB and/or BCLllA target genes, and administered to the subject. Sources of target cells for ex vivo manipulation may include, by way of example, the subject's blood, the subject's cord blood, or the subject's bone marrow. Sources of target cells for ex vivo manipulation may also include, by way of example, heterologous donor blood, cord blood, or bone marrow.

In an embodiment, a myeloid progenitor cell is removed from the subject, manipulated ex vivo as described above, and the myeloid progenitor cell is returned to the subject. In an embodiment, an erythroid progenitor cell is removed from the subject, manipulated ex vivo as described above, and the erythroid progenitor cell is returned to the subject. In an embodiment, a hematopoietic stem cell is removed from the subject, manipulated ex vivo as described above, and the hematopoietic stem cell is returned to the subject. In an embodiment, a CD34+ hematopoietic stem cell is removed from the subject, manipulated ex vivo as described above, and the CD34+ hematopoietic stem cell is returned to the subject. A suitable cell can also include a stem cell such as, by way of example, an embryonic stem cell, an induced pluripotent stem cell, a hematopoietic stem cell, a neuronal stem cell and a mesenchymal stem cell. In an embodiment, the cell is an induced pluripotent stem (iPS) cell or a cell derived from an iPS cell, e.g., an iPS cell generated from the subject, modified to induce a mutation and differentiated into a clinically relevant cell such as a myeloid progenitor cell, an erythroid progenitor cell or a hematopoietic stem cell. In an embodiment, AAV is used to transduce the target cells, e.g., the target cells described herein.

Cells produced by the methods described herein may be used immediately. Alternatively, the cells may be frozen (e.g., in liquid nitrogen) and stored for later use. The cells will usually be frozen in 10% dimehtylsulfoxide (DMSO), 50% serum, 40% buffered medium, or some other such solution as is commonly used in the art to preserve cells at such freezing temperature and thawed in such a manner as commonly known in the art for thawing frozen cultured cells.

VII. Delivery, Formulations and Routes of Administration

The components, e.g., a Cas9 molecule and gRNA molecule (e.g., a Cas9

molecule/gRNA molecule complex), and a donor template nucleic acid, can be delivered or formulated in a variety of forms, see, e.g., Tables 34-35. In an embodiment, one Cas9 molecule and two or more (e.g., 2, 3, 4, or more) different gRNA molecules are delivered, e.g., by an AAV vector. In an embodiment, the sequence encoding the Cas9 molecule and the sequence(s) encoding the two or more (e.g., 2, 3, 4, or more) different gRNA molecules are present on the same nucleic acid molecule, e.g., an AAV vector. When a Cas9 or gRNA component is encoded as DNA for delivery, the DNA will typically but not necessarily include a control region, e.g., comprising a promoter, to effect expression. Useful promoters for Cas9 molecule sequences include CMV, EFS, EF-la, MSCV, PGK, CAG promoters. In an embodiment, the promoter is a constitutive promoter. In another embodiment, the promoter is a tissue specific promoter.

Useful promoters for gRNAs include HI, 7SK, tRNA, and U6 promoters. Promoters with similar or dissimilar strengths can be selected to tune the expression of components. Sequences encoding a Cas9 molecule can comprise a nuclear localization signal (NLS), e.g., an SV40 NLS. In an embodiment, the sequence encoding a Cas9 molecule comprises at least two nuclear localization signals. In an embodiment a promoter for a Cas9 molecule or a gRNA molecule can be, independently, inducible, tissue specific, or cell specific. Table 34 provides examples of how the components can be formulated, delivered, or administered.

Table 34

vitro transcribed or synthesized RNA. In this embodiment, the donor template is provided as a DNA molecule.

mRNA DNA DNA In this embodiment, a Cas9 molecule, typically an eaCas9 molecule, is translated from in vitro transcribed mRNA, and a gRNA is transcribed from DNA. In this embodiment, the donor template is provided as a separate DNA molecule. mRNA DNA In this embodiment, a Cas9 molecule, typically an eaCas9 molecule, is translated from in vitro transcribed mRNA, and a gRNA is transcribed from DNA. In this embodiment, the donor template is provided on the same DNA molecule that encodes the gRNA.

Protein DNA DNA In this embodiment, a Cas9 molecule, typically an eaCas9 molecule, is provided as a protein, and a gRNA is transcribed from DNA. In this embodiment, the donor template is provided as a separate DNA molecule.

Protein DNA In this embodiment, a Cas9 molecule, typically an eaCas9 molecule, is provided as a protein, and a gRNA is transcribed from DNA. In this embodiment, the donor template is provided on the same DNA molecule that encodes the gRNA.

Protein RNA DNA In this embodiment, an eaCas9 molecule is

provided as a protein, and a gRNA is provided as transcribed or synthesized RNA. In this embodiment, the donor template is provided as a DNA molecule.

Table 35 summarizes various delivery methods for the components of a Cas system, e.g., the Cas9 molecule component and the gRNA molecule component, as described herein.

Table 35

Viral Retrovirus NO Stable YES RNA

Lentivirus YES Stable YES/NO with RNA

modifications

Adenovirus YES Transient NO DNA

Adeno- YES Stable NO DNA Associated

Virus (AAV)

Vaccinia Virus YES Very NO DNA

Transient

Herpes Simplex YES Stable NO DNA Virus

Non-Viral Cationic YES Transient Depends on Nucleic Acids

Liposomes what is and Proteins

delivered

Polymeric YES Transient Depends on Nucleic Acids Nanoparticles what is and Proteins

delivered

Biological Attenuated YES Transient NO Nucleic Acids Non-Viral Bacteria

Delivery Engineered YES Transient NO Nucleic Acids Vehicles Bacteriophages

Mammalian YES Transient NO Nucleic Acids

Virus-like

Particles

Biological YES Transient NO Nucleic Acids liposomes:

Erythrocyte

Ghosts and

Exosomes

DNA-based Delivery of a Cas9 molecule and/or one or more gRNA molecule and/or a donor template

Nucleic acids (e.g., DNA) encoding a Cas9 molecule (e.g., an eaCas9 molecule), a gRNA molecule, a donor template nucleic acid, or any combination (e.g., two or all) thereof, can be administered to subjects or delivered into cells by art-known methods or as described herein. For example, Cas9-encoding and/or gRNA-encoding DNA, as well as donor template nucleic acids, can be delivered, e.g., by vectors (e.g., viral or non-viral vectors), non-vector based methods (e.g., using naked DNA or DNA complexes), or a combination thereof. Donor template molecules can be administered to subjects or delivered into cells by art-known methods or as described herein. For example, donor template molecules can be delivered, e.g., by vectors (e.g., viral or non-viral vectors), non-vector based methods (e.g., using naked DNA or DNA

complexes), or a combination thereof.

Nucleic acids (e.g., DNA) encoding Cas9 molecules (e.g., eaCas9 molecules) and/or gRNA molecules can be conjugated to molecules to promote uptake by the target cells (e.g., the target cells describe herein). Donor template molecules can be conjugated to molecules to promote uptake by the target cells (e.g., the target cells describe herein).

In an embodiment, the Cas9- and/or gRNA-encoding DNA is delivered by a vector (e.g., viral vector/virus or plasmid).

A vector can comprise a sequence that encodes a Cas9 molecule and/or a gRNA molecule. A vector can also comprise a sequence encoding a signal peptide (e.g., for nuclear localization, nucleolar localization, mitochondrial localization), fused, e.g., to a Cas9 molecule sequence. For example, ae vector can comprise a nuclear localization sequence (e.g., from SV40) fused to the sequence encoding the Cas9 molecule.

One or more regulatory/control elements, e.g., a promoter, an enhancer, an intron, a polyadenylation signal, a Kozak consensus sequence, internal ribosome entry sites (IRES), a 2A sequence, and splice acceptor or donor can be included in the vectors. In an embodiment, the promoter is recognized by RNA polymerase II (e.g., a CMV promoter). In another embodiment, the promoter is recognized by RNA polymerase III (e.g., a U6 promoter). In an embodiment, the promoter is a regulated promoter (e.g., inducible promoter). In another embodiment, the promoter is a constitutive promoter. In an embodiment, the promoter is a tissue specific promoter. In an embodiment, the promoter is a viral promoter. In another embodiment, the promoter is a non-viral promoter.

In an embodiment, the vector or delivery vehicle is a viral vector (e.g., for generation of recombinant viruses). In an embodiment, the virus is a DNA virus (e.g., dsDNA or ssDNA virus). In another embodiment, the virus is an RNA virus (e.g., an ssRNA virus). Exemplary viral vectors/viruses include, e.g., retroviruses, lentiviruses, adenovirus, adeno-associated virus (AAV), vaccinia viruses, poxviruses, and herpes simplex viruses.

In an embodiment, the virus infects dividing cells. In another embodiment, the virus infects non-dividing cells. In an embodiment, the virus infects both dividing and non-dividing cells. In an embodiment, the virus can integrate into the host genome. In an embodiment, the virus is engineered to have reduced immunity, e.g., in human. In an embodiment, the virus is replication-competent. In another embodiment, the virus is replication-defective, e.g., having one or more coding regions for the genes necessary for additional rounds of virion replication and/or packaging replaced with other genes or deleted. In an embodiment, the virus causes transient expression of the Cas9 molecule and/or the gRNA molecule. In another embodiment, the virus causes long-lasting, e.g., at least 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 9 months, 1 year, 2 years, or permanent expression, of the Cas9 molecule and/or the gRNA molecule. The packaging capacity of the viruses may vary, e.g., from at least about 4 kb to at least about 30 kb, e.g., at least about 5 kb, 10 kb, 15 kb, 20 kb, 25 kb, 30 kb, 35 kb, 40 kb, 45 kb, or 50 kb.

In an embodiment, the viral vector recognizes a specific cell type or tissue. For example the viral vector can be pseudotyped with a different/alternative viral envelope glycoprotein; engineered with a cell type-specific receptor (e.g., genetic modification(s) of one or more viral envelope glycoproteins to incorporate a targeting ligand such as a peptide ligand, a single chain antibody, or a growth factor); and/or engineered to have a molecular bridge with dual specificities with one end recognizing a viral glycoprotein and the other end recognizing a moiety of the target cell surface (e.g., a ligand-receptor, monoclonal antibody, avidin-biotin and chemical conjugation).

Exemplary viral vectors/viruses include, e.g., retroviruses, lentiviruses, adenovirus, adeno-associated virus (AAV), vaccinia viruses, poxviruses, and herpes simplex viruses.

In an embodiment, the Cas9- and/or gRNA-encoding nucleic acid sequence is delivered by a recombinant retrovirus. In an embodiment, the donor template nucleic acid is delivered by recombinant retrovirus. In an embodiment, the retrovirus (e.g., Moloney murine leukemia virus comprises a reverse transcriptase, e.g., that allows integration into the host genome. In an embodiment, the retrovirus is replication-competent. In another embodiment, the retrovirus is replication-defective, e.g., having one of more coding regions for the genes necessary for additional rounds of virion replication and packaging replaced with other genes, or deleted.

In an embodiment, the Cas9- and/or gRNA-encoding nucleic acid sequence is delivered by a recombinant lentivirus. In an embodiment, the donor template nucleic acid is delivered by recombinant lentivirus. For example, the lentivirus is replication-defective, e.g., does not comprise one or more genes required for viral replication. In an embodiment, the Cas9- and/or gRNA-encoding DNA is delivered by a recombinant adenovirus. In an embodiment, the donor template nucleic acid is delivered by a recombinant adenovirus. In an embodiment, the adenovirus is engineered to have reduced immunity in human.

In an embodiment, the Cas9- and/or gRNA-encoding DNA is delivered by a recombinant AAV. In an embodiment, the donor template nucleic acid is delivered by a recombinant AAV. In some embodiments, the AAV does not incorporate its geneome into that of a host cell, e.g., a target cell as describe herein. In an embodiment, the AAV can incorporate its genome into that of a host cell, e.g., a target cell as described herein. In an embodiment, the AAV is a self- complementary adeno-associated virus (scAAV), e.g., a scAAV that packages both strands which anneal together to form double stranded DNA. AAV serotypes that may be used in the disclosed methods, include AAV1, AAV2, modified AAV2 (e.g., modifications at Y444F, Y500F, Y730F and/or S662V), AAV3, modified AAV3 (e.g., modifications at Y705F, Y731F and/or T492V), AAV4, AAV5, AAV6, modified AAV6 (e.g., modifications at S663V and/or T492V), AAV8, AAV 8.2, AAV9, AAV rh 10, and pseudotyped AAV, such as AAV2/8, AAV2/5 and AAV2/6 can also be used in the disclosed methods.

In an embodiment, an AAV capsid that can be used in the methods described herein is a capsid sequence from serotype AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV.rh8, AAV.rhlO, AAV.rh32/33, AAV.rh43, AAV.rh64Rl, or AAV7m8.

In an embodiment, the Cas9- and/or gRNA-encoding DNA is delivered in a re- engineered AAV capsid, e.g., with 50% or greater, e.g., 60% or greater, 70% or greater, 80% or greater, 90% or greater, or 95% or greater, sequence homology with a capsid sequence from serotypes AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV.rh8, AAV.rhl0, AAV.rh32/33, AAV.rh43, or AAV.rh64Rl.

In an embodiment, the Cas9- and/or gRNA-encoding DNA is delivered by a chimeric AAV capsid. In an embodiment, the donor template nucleic acid is delivered by a chimeric AAV capsid. Exemplary chimeric AAV capsids include, but are not limited to, AAV9il, AAV2i8, AAV-DJ, AAV2G9, AAV2i8G9, or AAV8G9.

In an embodiment, the AAV is a self-complementary adeno-associated virus (scAAV), e.g., a scAAV that packages both strands which anneal together to form double stranded DNA. In an embodiment, the Cas9- and/or gRNA-encoding DNA is delivered by a hybrid virus, e.g., a hybrid of one or more of the viruses described herein. In an embodiment, the hybrid virus is hybrid of an AAV (e.g., of any AAV serotype), with a Bocavirus, B19 virus, porcine AAV, goose AAV, feline AAV, canine AAV, or MVM.

A Packaging cell is used to form a virus particle that is capable of infecting a target cell. Such a cell includes a 293 cell, which can package adenovirus, and a ψ2 cell or a PA317 cell, which can package retrovirus. A viral vector used in gene therapy is usually generated by a producer cell line that packages a nucleic acid vector into a viral particle. The vector typically contains the minimal viral sequences required for packaging and subsequent integration into a host or target cell (if applicable), with other viral sequences being replaced by an expression cassette encoding the protein to be expressed, eg. Cas9. For example, an AAV vector used in gene therapy typically only possesses inverted terminal repeat (ITR) sequences from the AAV genome which are required for packaging and gene expression in the host or target cell. The missing viral functions can be supplied in trans by the packaging cell line and/or plasmid containing E2A, E4, and VA genes from adenovirus, and plasmid encoding Rep and Cap genes from AAV, as described in "Triple Transfection Protocol." Henceforth, the viral DNA is packaged in a cell line, which contains a helper plasmid encoding the other AAV genes, namely rep and cap, but lacking ITR sequences. In embodiment, the viral DNA is packaged in a producer cell line, which contains El A and/or E1B genes from adenovirus. The cell line is also infected with adenovirus as a helper. The helper virus (e.g., adenovirus or HSV) or helper plasmid promotes replication of the AAV vector and expression of AAV genes from the helper plasmid with ITRs. The helper plasmid is not packaged in significant amounts due to a lack of ITR sequences. Contamination with adenovirus can be reduced by, e.g., heat treatment to which adenovirus is more sensitive than AAV.

In an embodiment, the viral vector has the ability of cell type and/or tissue type recognition. For example, the viral vector can be pseudotyped with a different/alternative viral envelope glycoprotein; engineered with a cell type-specific receptor (e.g., geneticmodification of the viral envelope glycoproteins to incorporate targeting ligands such as a peptide ligand, a single chain antibodie, a growth factor); and/or engineered to have a molecular bridge with dual specificities with one end recognizing a viral glycoprotein and the other end recognizing a moiety of the target cell surface (e.g., ligand-receptor, monoclonal antibody, avidin-biotin and chemical conjugation).

In an embodiment, the viral vector achieves cell type specific expression. For example, a tissue-specific promoter can be constructed to restrict expression of the transgene (Cas 9 and gRNA) in only the target cell. The specificity of the vector can also be mediated by microRNA- dependent control of transgene expression. In an embodiment, the viral vector has increased efficiency of fusion of the viral vector and a target cell membrane. For example, a fusion protein such as fusion-competent hemagglutin (HA) can be incorporated to increase viral uptake into cells. In an embodiment, the viral vector has the ability of nuclear localization. For example, aviruse that requires the breakdown of the nuclear envelope (during cell division) and therefore will not infect a non-diving cell can be altered to incorporate a nuclear localization peptide in the matrix protein of the virus thereby enabling the transduction of non-proliferating cells.

In some embodiments, the Cas9- and/or gRNA-encoding DNA is delivered by a non- vector based method (e.g., using naked DNA or DNA complexes). For example, the DNA can be delivered, e.g., by organically modified silica or silicate (Ormosil), electroporation, transient cell compression or squeezing (e.g., as described in Lee, et al., Nano Lett 12: 6322-27), gene gun, sonoporation, magnetofection, lipid-mediated transfection, dendrimers, inorganic nanoparticles, calcium phosphates, or a combination thereof.

In an embodiment, delivery via electroporation comprises mixing the cells with the Cas9- and/or gRNA-encoding DNA in a cartridge, chamber or cuvette and applying one or more electrical impulses of defined duration and amplitude. In an embodiment, delivery via electroporation is performed using a system in which cells are mixed with the Cas9-and/or gRNA-encoding DNA in a vessel connected to a device (eg, a pump) which feeds the mixture into a cartridge, chamber or cuvette wherein one or more electrical impulses of defined duration and amplitude are applied, after which the cells are delivered to a second vessel.

In an embodiment, the Cas9- and/or gRNA-encoding DNA is delivered by a combination of a vector and a non- vector based method. In an embodiment, the donor template nucleic acid is delivered by a combination of a vector and a non- vector based method. For example, a virosome comprises a liposome combined with an inactivated virus (e.g., HIV or influenza virus), which can result in more efficient gene transfer, e.g., in a respiratory epithelial cell than either a viral or a liposomal method alone. In an embodiment, the delivery vehicle is a non- viral vector. In an embodiment, the non- viral vector is an inorganic nanoparticle. Exemplary inorganic nanoparticles include, e.g., magnetic nanoparticles (e.g., Fe₃Mn0₂) or silica. The outer surface of the nanoparticle can be conjugated with a positively charged polymer (e.g., polyethylenimine, polylysine, polyserine) which allows for attachment (e.g., conjugation or entrapment) of payload. In an embodiment, the non-viral vector is an organic nanoparticle (e.g., entrapment of the payload inside the nanoparticle). Exemplary organic nanoparticles include, e.g., SNALP liposomes that contain cationic lipids together with neutral helper lipids which are coated with polyethylene glycol (PEG) and protamine and nucleic acid complex coated with lipid coating.

Exemplary lipids for gene transfer are shown below in Table 36.

Table 36. Lipids Used for Gene Transfer

l,2-Distearyloxy-N,N-dimethyl-3-aminopropane DSDMA Cationic

1 ,2-Dimyristoyl-trimethylammonium propane DMTAP Cationic

0,0' -Dimyristyl-N-lysyl aspartate DMKE Cationic l,2-Distearoyl-sn-glycero-3-ethylphosphocholine DSEPC Cationic

N-Palmitoyl D-erythro-sphingosyl carbamoyl- spermine CCS Cationic

N-t-Butyl-N0-tetradecyl-3-tetradecylaminopropionamidine diC14-amidine Cationic

Octadecenolyoxy[ethyl-2-heptadecenyl-3 hydroxyethyl] DOTIM Cationic imidazolinium chloride

Nl-Cholesteryloxycarbonyl-3,7-diazanonane- l,9-diamine CD AN Cationic

2-(3-[Bis(3-amino-propyl)-amino]propylamino)-N- RPR209120 Cationic ditetradecylcarbamoylme-ethyl-acetamide

Exemplary polymers for gene transfer are shown below in Table 37.

Table 37. Polymers Used for Gene Transfer

Polymer Abbreviation

Poly(ethylene)glycol PEG

Polyethylenimine PEI

Dithiobis(succinimidylpropionate) DSP

Dimethyl-3,3'-dithiobispropionimidate DTBP

Poly(ethylene imine) biscarbamate PEIC

Poly(L-lysine) PLL

Histidine modified PLL

Poly(N-vinylpyrrolidone) PVP

Poly(propylenimine) PPI

Poly(amidoamine) PAMAM

Poly(amido ethylenimine) SS-PAEI

Triethylenetetramine TETA

Poly ( β- aminoester)

Poly(4-hydroxy-L-proline ester) PHP

Poly(allylamine)

Poly(a-[4-aminobutyl]-L-glycolic acid) PAGA

Poly(D,L-lactic-co-glycolic acid) PLGA

Poly(N-ethyl-4-vinylpyridinium bromide)

Poly (pho sphazene) s PPZ

Poly (pho sphoester) s PPE

Poly (pho sphoramidate) s PPA

Poly(N-2-hydroxypropylmethacrylamide) pHPMA

Poly (2-(dimethylamino)ethyl methacrylate) pDMAEMA

Poly(2-aminoethyl propylene phosphate) PPE-EA

Chitosan

Galactosylated chitosan

N-Dodacylated chitosan

Histone Collagen

Dextran- spermine D-SPM

In an embodiment, the vehicle has targeting modifications to increase target cell update of nanoparticles and liposomes, e.g., cell specific antigens, monoclonal antibodies, single chain antibodies, aptamers, polymers, sugars, and cell penetrating peptides. In an embodiment, the vehicle uses fusogenic and endosome-destabilizing peptides/polymers. In an embodiment, the vehicle undergoes acid-triggered conformational changes (e.g., to accelerate endosomal escape of the cargo). In an embodiment, a stimuli-cleavable polymer is used, e.g., for release in a cellular compartment. For example, disulfide-based cationic polymers that are cleaved in the reducing cellular environment can be used.

In an embodiment, the delivery vehicle is a biological non-viral delivery vehicle. In an embodiment, the vehicle is an attenuated bacterium (e.g., naturally or artificially engineered to be invasive but attenuated to prevent pathogenesis and expressing the transgene (e.g., Listeria monocytogenes, certain Salmonella strains, Bifidobacterium longum, and modified Escherichia coli), bacteria having nutritional and tissue-specific tropism to target specific tissues, bacteria having modified surface proteins to alter target tissue specificity). In an embodiment, the vehicle is a genetically modified bacteriophage (e.g., engineered phages having large packaging capacity, less immunogenic, containing mammalian plasmid maintenance sequences and having incorporated targeting ligands). In an embodiment, the vehicle is a mammalian virus-like particle. For example, modified viral particles can be generated (e.g., by purification of the "empty" particles followed by ex vivo assembly of the virus with the desired cargo). The vehicle can also be engineered to incorporate targeting ligands to alter target tissue specificity. In an embodiment, the vehicle is a biological liposome. For example, the biological liposome is a phospholipid-based particle derived from human cells (e.g., erythrocyte ghosts, which are red blood cells broken down into spherical structures derived from the subject (e.g., tissue targeting can be achieved by attachment of various tissue or cell-specific ligands), or secretory exosomes - subject (i.e., patient) derived membrane-bound nanovescicle (30 -100 nm) of endocytic origin (e.g., can be produced from various cell types and can therefore be taken up by cells without the need of for targeting ligands).

In an embodiment, one or more nucleic acid molecules (e.g., DNA molecules) other than the components of a Cas system, e.g., the Cas9 molecule component and/or the gRNA molecule component described herein, are delivered. In an embodiment, the nucleic acid molecule is delivered at the same time as one or more of the components of the Cas system are delivered. In an embodiment, the nucleic acid molecule is delivered before or after (e.g., less than about 30 minutes, 1 hour, 2 hours, 3 hours, 6 hours, 9 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, or 4 weeks) one or more of the components of the Cas system are delivered. In an embodiment, the nucleic acid molecule is delivered by a different means than one or more of the components of the Cas system, e.g., the Cas9 molecule component and/or the gRNA molecule component, are delivered. The nucleic acid molecule can be delivered by any of the delivery methods described herein. For example, the nucleic acid molecule can be delivered by a viral vector, e.g., an integration-deficient lentivirus, and the Cas9 molecule component and/or the gRNA molecule component can be delivered by electroporation, e.g., such that the toxicity caused by nucleic acids (e.g., DNAs) can be reduced. In an embodiment, the nucleic acid molecule encodes a therapeutic protein, e.g., a protein described herein. In an embodiment, the nucleic acid molecule encodes an RNA molecule, e.g., an RNA molecule described herein.

Delivery of RNA encoding a Cas9 molecule

RNA encoding Cas9 molecules (e.g., eaCas9 molecules or eiCas9 molecules) and/or gRNA molecules, can be delivered into cells, e.g., target cells described herein, by art-known methods or as described herein. For example, Cas9-encoding and/or gRNA-encoding RNA can be delivered, e.g., by microinjection, electroporation, transient cell compression or squeezing (eg, as described in Lee, et al., 2012, Nano Lett 12: 6322-27), lipid-mediated transfection, peptide-mediated delivery, or a combination thereof. Cas9-encoding and/or gRNA-encoding RNA can be conjugated to molecules) promoting uptake by the target cells (e.g., target cells described herein).

In an embodiment, delivery via electroporation comprises mixing the cells with the RNA encoding Cas9 molecules (e.g., eaCas9 molecules, eiCas9 molecules or eiCas9 fusion protiens) and/or gRNA molecules, with or without donor template nucleic acid molecules, in a cartridge, chamber or cuvette and applying one or more electrical impulses of defined duration and amplitude. In an embodiment, delivery via electroporation is performed using a system in which cells are mixed with the RNA encoding Cas9 molecules (e.g., eaCas9 molecules, eiCas9 molecules or eiCas9 fusion protiens) and/or gRNA molecules, with or without donor template nucleic acid molecules in a vessel connected to a device (eg, a pump) which feeds the mixture into a cartridge, chamber or cuvette wherein one or more electrical impulses of defined duration and amplitude are applied, after which the cells are delivered to a second vessel. Cas9-encoding and/or gRNA-encoding RNA can be conjugated to molecules to promote uptake by the target cells (e.g., target cells described herein).

Delivery Cas9 molecule protein

Cas9 molecules (e.g., eaCas9 molecules or eiCas9 molecules) can be delivered into cells by art-known methods or as described herein. For example, Cas9 protein molecules can be delivered, e.g., by microinjection, electroporation, transient cell compression or squeezing (eg, as described in Lee, et al [2012] Nano Lett 12: 6322-27), lipid-mediated transfection, peptide- mediated delivery, or a combination thereof. Delivery can be accompanied by DNA encoding a gRNA or by a gRNA. Cas9 protein can be conjugated to molecules promoting uptake by the target cells (e.g., target cells described herein).

In an embodiment, delivery via electroporation comprises mixing the cells with the Cas9 molecules (e.g., eaCas9 molecules, eiCas9 molecules or eiCas9 fusion protiens) and/or gRNA molecules, with or without donor nucleic acid, in a cartridge, chamber or cuvette and applying one or more electrical impulses of defined duration and amplitude. In an embodiment, delivery via electroporation is performed using a system in which cells are mixed with the Cas9 molecules (e.g., eaCas9 molecules, eiCas9 molecules or eiCas9 fusion protiens) and/or gRNA molecules, with or without donor nucleic acid in a vessel connected to a device (eg, a pump) which feeds the mixture into a cartridge, chamber or cuvette wherein one or more electrical impulses of defined duration and amplitude are applied, after which the cells are delivered to a second vessel. Cas9-encoding and/or gRNA-encoding RNA can be conjugated to molecules to promote uptake by the target cells (e.g., target cells described herein).

Route of Administration

Systemic modes of administration include oral and parenteral routes. Parenteral routes include, by way of example, intravenous, intrarterial, intraosseous, intramuscular, intradermal, subcutaneous, intranasal and intraperitoneal routes. Components administered systemically may be modified or formulated to target the components to cells of the blood and bone marrow. Local modes of administration include, by way of example, intra-bone marrow, intrathecal, and intra-cerebroventricular routes. In an embodiment, significantly smaller amounts of the components (compared with systemic approaches) may exert an effect when administered locally (for example, intra-bone marrow) compared to when administered systemically (for example, intravenously). Local modes of administration can reduce or eliminate the incidence of potentially toxic side effects that may occur when therapeutically effective amounts of a component are administered systemically.

In an embodiment, components described herein are delivered by intra-bone marrow injection. Injections may be made directly into the bone marrow compartment of one or more than one bone. In an embodiment, nanoparticle or viral, e.g., AAV vector, delivery is via intra- bone marrow injection.

Administration may be provided as a periodic bolus or as continuous infusion from an internal reservoir or from an external reservoir (for example, from an intravenous bag).

Components may be administered locally, for example, by continuous release from a sustained release drug delivery device

In addition, components may be formulated to permit release over a prolonged period of time. A release system can include a matrix of a biodegradable material or a material which releases the incorporated components by diffusion. The components can be homogeneously or heterogeneously distributed within the release system. A variety of release systems may be useful, however, the choice of the appropriate system will depend upon rate of release required by a particular application. Both non-degradable and degradable release systems can be used. Suitable release systems include polymers and polymeric matrices, non-polymeric matrices, or inorganic and organic excipients and diluents such as, but not limited to, calcium carbonate and sugar (for example, trehalose). Release systems may be natural or synthetic. However, synthetic release systems are preferred because generally they are more reliable, more reproducible and produce more defined release profiles. The release system material can be selected so that components having different molecular weights are released by diffusion through or degradation of the material.

Representative synthetic, biodegradable polymers include, for example: polyamides such as poly(amino acids) and poly(peptides); polyesters such as poly(lactic acid), poly(glycolic acid), poly(lactic-co-glycolic acid), and poly(caprolactone); poly(anhydrides); polyorthoesters; polycarbonates; and chemical derivatives thereof (substitutions, additions of chemical groups, for example, alkyl, alkylene, hydroxylations, oxidations, and other modifications routinely made by those skilled in the art), copolymers and mixtures thereof. Representative synthetic, non- degradable polymers include, for example: polyethers such as poly(ethylene oxide),

poly(ethylene glycol), and poly(tetramethylene oxide); vinyl polymers-polyacrylates and polymethacrylates such as methyl, ethyl, other alkyl, hydroxyethyl methacrylate, acrylic and methacrylic acids, and others such as poly(vinyl alcohol), poly(vinyl pyrolidone), and poly(vinyl acetate); poly(urethanes); cellulose and its derivatives such as alkyl, hydroxyalkyl, ethers, esters, nitrocellulose, and various cellulose acetates; polysiloxanes; and any chemical derivatives thereof (substitutions, additions of chemical groups, for example, alkyl, alkylene, hydroxylations, oxidations, and other modifications routinely made by those skilled in the art), copolymers and mixtures thereof.

Poly(lactide-co-glycolide) microsphere can also be used for injection. Typically the microspheres are composed of a polymer of lactic acid and glycolic acid, which are structured to form hollow spheres. The spheres can be approximately 15-30 microns in diameter and can be loaded with components described herein.

Bi-Modal or Differential Delivery of Components

Separate delivery of the components of a Cas system, e.g., the Cas9 molecule component and the gRNA molecule component, and more particularly, delivery of the components by differing modes, can enhance performance, e.g., by improving tissue specificity and safety.

In an embodiment, the Cas9 molecule and the gRNA molecule are delivered by different modes, or as sometimes referred to herein as differential modes. Different or differential modes, as used herein, refer modes of delivery that confer different pharmacodynamic or

pharmacokinetic properties on the subject component molecule, e.g., a Cas9 molecule, gRNA molecule, or template nucleic acid. For example, the modes of delivery can result in different tissue distribution, different half-life, or different temporal distribution, e.g., in a selected compartment, tissue, or organ.

Some modes of delivery, e.g., delivery by a nucleic acid vector that persists in a cell, or in progeny of a cell, e.g., by autonomous replication or insertion into cellular nucleic acid, result in more persistent expression of and presence of a component. Examples include viral, e.g., adeno- associated virus or lentivirus, delivery.

By way of example, the components, e.g., a Cas9 molecule and a gRNA molecule, can be delivered by modes that differ in terms of resulting half-life or persistent of the delivered component the body, or in a particular compartment, tissue or organ. In an embodiment, a gRNA molecule can be delivered by such modes. The Cas9 molecule component can be delivered by a mode which results in less persistence or less exposure to the body or a particular compartment or tissue or organ.

More generally, in an embodiment, a first mode of delivery is used to deliver a first component and a second mode of delivery is used to deliver a second component. The first mode of delivery confers a first pharmacodynamic or pharmacokinetic property. The first pharmacodynamic property can be, e.g., distribution, persistence, or exposure, of the component, or of a nucleic acid that encodes the component, in the body, a compartment, tissue or organ. The second mode of delivery confers a second pharmacodynamic or pharmacokinetic property. The second pharmacodynamic property can be, e.g., distribution, persistence, or exposure, of the component, or of a nucleic acid that encodes the component, in the body, a compartment, tissue or organ.

In an embodiment, the first pharmacodynamic or pharmacokinetic property, e.g., distribution, persistence or exposure, is more limited than the second pharmacodynamic or pharmacokinetic property.

In an embodiment, the first mode of delivery is selected to optimize, e.g., minimize, a pharmacodynamic or pharmacokinetic property, e.g., distribution, persistence or exposure.

In an embodiment, the second mode of delivery is selected to optimize, e.g., maximize, a pharmacodynamic or pharmcokinetic property, e.g., distribution, persistence or exposure.

In an embodiment, the first mode of delivery comprises the use of a relatively persistent element, e.g., a nucleic acid, e.g., a plasmid or viral vector, e.g., an AAV or lentivirus. As such vectors are relatively persistent product transcribed from them would be relatively persistent.

In an embodiment, the second mode of delivery comprises a relatively transient element, e.g., an RNA or protein.

In an embodiment, the first component comprises gRNA, and the delivery mode is relatively persistent, e.g., the gRNA is transcribed from a plasmid or viral vector, e.g., an AAV or lenti virus. Transcription of these genes would be of little physiological consequence because the genes do not encode for a protein product, and the gRNAs are incapable of acting in isolation. The second component, a Cas9 molecule, is delivered in a transient manner, for example as mRNA or as protein, ensuring that the full Cas9 molecule/gRNA molecule complex is only present and active for a short period of time.

Furthermore, the components can be delivered in different molecular form or with different delivery vectors that complement one another to enhance safety and tissue specificity.

Use of differential delivery modes can enhance performance, safety and efficacy. E.g., the likelihood of an eventual off-target modification can be reduced. Delivery of immunogenic components, e.g., Cas9 molecules, by less persistent modes can reduce immunogenicity, as peptides from the bacterially-derived Cas enzyme are displayed on the surface of the cell by MHC molecules. A two-part delivery system can alleviate these drawbacks.

Differential delivery modes can be used to deliver components to different, but overlapping target regions. The formation active complex is minimized outside the overlap of the target regions. Thus, in an embodiment, a first component, e.g., a gRNA molecule is delivered by a first delivery mode that results in a first spatial, e.g., tissue, distribution. A second component, e.g., a Cas9 molecule is delivered by a second delivery mode that results in a second spatial, e.g., tissue, distribution. In an embodiment, the first mode comprises a first element selected from a liposome, nanoparticle, e.g., polymeric nanoparticle, and a nucleic acid, e.g., viral vector. The second mode comprises a second element selected from the group. In an embodiment, the first mode of delivery comprises a first targeting element, e.g., a cell specific receptor or an antibody, and the second mode of delivery does not include that element. In embodiment, the second mode of delivery comprises a second targeting element, e.g., a second cell specific receptor or second antibody.

When the Cas9 molecule is delivered in a virus delivery vector, a liposome, or polymeric nanoparticle, there is the potential for delivery to and therapeutic activity in multiple tissues, when it may be desirable to only target a single tissue. A two-part delivery system can resolve this challenge and enhance tissue specificity. If the gRNA molecule and the Cas9 molecule are packaged in separated delivery vehicles with distinct but overlapping tissue tropism, the fully functional complex is only be formed in the tissue that is targeted by both vectors. Ex vivo delivery

In an embodiment, components described in Table 34 are introduced into cells which are then introduced into the subject, e.g., cells are removed from a subject, manipulated ex vivo and then introduced into the subject. Methods of introducing the components can include, e.g., any of the delivery methods described in Table 35.

VIII. Modified Nucleosides, Nucleotides, and Nucleic Acids

Modified nucleosides and modified nucleotides can be present in nucleic acids, e.g., particularly gRNA, but also other forms of RNA, e.g., mRNA, RNAi, or siRNA. As described herein, "nucleoside" is defined as a compound containing a five-carbon sugar molecule (a pentose or ribose) or derivative thereof, and an organic base, purine or pyrimidine, or a derivative thereof. As described herein, "nucleotide" is defined as a nucleoside further comprising a phosphate group.

Modified nucleosides and nucleotides can include one or more of:

(i) alteration, e.g., replacement, of one or both of the non-linking phosphate oxygens and/or of one or more of the linking phosphate oxygens in the phosphodiester backbone linkage;

(ii) alteration, e.g., replacement, of a constituent of the ribose sugar, e.g., of the 2' hydroxyl on the ribose sugar;

(iii) wholesale replacement of the phosphate moiety with "dephospho" linkers;

(iv) modification or replacement of a naturally occurring nucleobase;

(v) replacement or modification of the ribose-phosphate backbone;

(vi) modification of the 3' end or 5' end of the oligonucleotide, e.g., removal,

modification or replacement of a terminal phosphate group or conjugation of a moiety; and

(vii) modification of the sugar.

The modifications listed above can be combined to provide modified nucleosides and nucleotides that can have two, three, four, or more modifications. For example, a modified nucleoside or nucleotide can have a modified sugar and a modified nucleobase. In an

embodiment, every base of a gRNA is modified, e.g., all bases have a modified phosphate group, e.g., all are phosphorothioate groups. In an embodiment, all, or substantially all, of the phosphate groups of a unimolecular or modular gRNA molecule are replaced with phosphorothioate groups.

In an embodiment, modified nucleotides, e.g., nucleotides having modifications as described herein, can be incorporated into a nucleic acid, e.g., a "modified nucleic acid." In an embodiment, the modified nucleic acids comprise one, two, three or more modified nucleotides. In an embodiment, at least 5% (e.g., at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100%) of the positions in a modified nucleic acid are a modified nucleotides.

Unmodified nucleic acids can be prone to degradation by, e.g., cellular nucleases. For example, nucleases can hydrolyze nucleic acid phosphodiester bonds. Accordingly, in one aspect the modified nucleic acids described herein can contain one or more modified nucleosides or nucleotides, e.g., to introduce stability toward nucleases.

In an embodiment, the modified nucleosides, modified nucleotides, and modified nucleic acids described herein can exhibit a reduced innate immune response when introduced into a population of cells, both in vivo and ex vivo. The term "innate immune response" includes a cellular response to exogenous nucleic acids, including single stranded nucleic acids, generally of viral or bacterial origin, which involves the induction of cytokine expression and release, particularly the interferons, and cell death. In an embodiment, the modified nucleosides, modified nucleotides, and modified nucleic acids described herein can disrupt binding of a major groove interacting partner with the nucleic acid. In an embodiment, the modified nucleosides, modified nucleotides, and modified nucleic acids described herein can exhibit a reduced innate immune response when introduced into a population of cells, both in vivo and ex vivo, and also disrupt binding of a major groove interacting partner with the nucleic acid.

Definitions of Chemical Groups

As used herein, "alkyl" is meant to refer to a saturated hydrocarbon group which is straight-chained or branched. Example alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like. An alkyl group can contain from 1 to about 20, from 2 to about 20, from 1 to about 12, from 1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3 carbon atoms.

As used herein, "aryl" refers to monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example, phenyl, naphthyl, anthracenyl,

phenanthrenyl, indanyl, indenyl, and the like. In an embodiment, aryl groups have from 6 to about 20 carbon atoms.

As used herein, "alkenyl" refers to an aliphatic group containing at least one double bond.

As used herein, "alkynyl" refers to a straight or branched hydrocarbon chain containing 2-12 carbon atoms and characterized in having one or more triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, propargyl, and 3-hexynyl.

As used herein, "arylalkyl" or "aralkyl" refers to an alkyl moiety in which an alkyl hydrogen atom is replaced by an aryl group. Aralkyl includes groups in which more than one hydrogen atom has been replaced by an aryl group. Examples of "arylalkyl" or "aralkyl" include benzyl, 2-phenylethyl, 3-phenylpropyl, 9-fluorenyl, benzhydryl, and trityl groups.

As used herein, "cycloalkyl" refers to a cyclic, bicyclic, tricyclic, or polycyclic non- aromatic hydrocarbon groups having 3 to 12 carbons. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl.

As used herein, "heterocyclyl" refers to a monovalent radical of a heterocyclic ring system. Representative heterocyclyls include, without limitation, tetrahydrofuranyl,

tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, and morpholinyl.

As used herein, "heteroaryl" refers to a monovalent radical of a heteroaromatic ring system. Examples of heteroaryl moieties include, but are not limited to, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrrolyl, furanyl, indolyl, thiophenyl pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolizinyl, purinyl, naphthyridinyl, quinolyl, and pteridinyl.

Phosphate Backbone Modifications

The Phosphate Group

In an embodiment, the phosphate group of a modified nucleotide can be modified by replacing one or more of the oxygens with a different substituent. Further, the modified nucleotide, e.g., modified nucleotide present in a modified nucleic acid, can include the wholesale replacement of an unmodified phosphate moiety with a modified phosphate as described herein. In an embodiment, the modification of the phosphate backbone can include alterations that result in either an uncharged linker or a charged linker with unsymmetrical charge distribution.

Examples of modified phosphate groups include, phosphorothioate, phosphoroselenates, borano phosphates, borano phosphate esters, hydrogen phosphonates, phosphoroamidates, alkyl or aryl phosphonates and phosphotriesters. In an embodiment, one of the non-bridging phosphate oxygen atoms in the phosphate backbone moiety can be replaced by any of the following groups: sulfur (S), selenium (Se), BR₃ (wherein R can be, e.g., hydrogen, alkyl, or aryl), C (e.g., an alkyl group, an aryl group, and the like), H, NR₂ (wherein R can be, e.g., hydrogen, alkyl, or aryl), or OR (wherein R can be, e.g., alkyl or aryl). The phosphorous atom in an unmodified phosphate group is achiral. However, replacement of one of the non-bridging oxygens with one of the above atoms or groups of atoms can render the phosphorous atom chiral; that is to say that a phosphorous atom in a phosphate group modified in this way is a stereogenic center. The stereogenic phosphorous atom can possess either the "R" configuration (herein Rp) or the "S" configuration (herein Sp).

Phosphorodithioates have both non-bridging oxygens replaced by sulfur. The phosphorus center in the phosphorodithioates is achiral which precludes the formation of oligoribonucleotide diastereomers. In an embodiment, modifications to one or both non-bridging oxygens can also include the replacement of the non-bridging oxygens with a group independently selected from S, Se, B, C, H, N, and OR (R can be, e.g., alkyl or aryl).

The phosphate linker can also be modified by replacement of a bridging oxygen, (i.e., the oxygen that links the phosphate to the nucleoside), with nitrogen (bridged phosphoroamidates), sulfur (bridged phosphorothioates) and carbon (bridged methylenephosphonates). The replacement can occur at either linking oxygen or at both of the linking oxygens.

Replacement of the Phosphate Group

The phosphate group can be replaced by non-phosphorus containing connectors. In an embodiment, the charge phosphate group can be replaced by a neutral moiety.

Examples of moieties which can replace the phosphate group can include, without limitation, e.g., methyl phosphonate, hydroxylamino, siloxane, carbonate, carboxymethyl, carbamate, amide, thioether, ethylene oxide linker, sulfonate, sulfonamide, thioformacetal, formacetal, oxime, methyleneimino, methylenemethylimino, methylenehydrazo,

methylenedimethylhydrazo and methyleneoxymethylimino.

Replacement of the Ribophosphate Backbone

Scaffolds that can mimic nucleic acids can also be constructed wherein the phosphate linker and ribose sugar are replaced by nuclease resistant nucleoside or nucleotide surrogates. In an embodiment, the nucleobases can be tethered by a surrogate backbone. Examples can include, without limitation, the morpholino, cyclobutyl, pyrrolidine and peptide nucleic acid (PNA) nucleoside surrogates.

Sugar Modifications

The modified nucleosides and modified nucleotides can include one or more

modifications to the sugar group. For example, the 2' hydroxyl group (OH) can be modified or replaced with a number of different "oxy" or "deoxy" substituents. In an embodiment, modifications to the 2' hydroxyl group can enhance the stability of the nucleic acid since the hydroxyl can no longer be deprotonated to form a 2'-alkoxide ion. The 2'-alkoxide can catalyze degradation by intramolecular nucleophilic attack on the linker phosphorus atom.

Examples of "oxy"-2' hydroxyl group modifications can include alkoxy or aryloxy (OR, wherein "R" can be, e.g., alkyl, cycloalkyl, aryl, aralkyl, heteroaryl or a sugar);

polyethyleneglycols (PEG), 0(CH₂CH₂0)_nCH₂CH₂OR wherein R can be, e.g., H or optionally substituted alkyl, and n can be an integer from 0 to 20 (e.g., from 0 to 4, from 0 to 8, from 0 to 10, from 0 to 16, from 1 to 4, from 1 to 8, from 1 to 10, from 1 to 16, from 1 to 20, from 2 to 4, from 2 to 8, from 2 to 10, from 2 to 16, from 2 to 20, from 4 to 8, from 4 to 10, from 4 to 16, and from 4 to 20). In an embodiment, the "oxy"-2' hydroxyl group modification can include

"locked" nucleic acids (LNA) in which the 2' hydroxyl can be connected, e.g., by a C_1-6 alkylene or Ci-6 heteroalkylene bridge, to the 4' carbon of the same ribose sugar, where exemplary bridges can include methylene, propylene, ether, or amino bridges; O-amino (wherein amino can be, e.g., NH₂; alkylamino, dialkylamino, heterocyclyl, arylamino, diarylamino, heteroarylamino, or diheteroarylamino, ethylenediamine, or polyamino) and aminoalkoxy, 0(CH₂)_n-amino, (wherein amino can be, e.g., NH₂; alkylamino, dialkylamino, heterocyclyl, arylamino, diarylamino, heteroarylamino, or diheteroarylamino, ethylenediamine, or polyamino). In an embodiment, the "oxy"-2' hydroxyl group modification can include the methoxyethyl group (MOE), (OCH₂CH₂OCH3, e.g., a PEG derivative).

"Deoxy" modifications can include hydrogen (i.e. deoxyribose sugars, e.g., at the overhang portions of partially ds RNA); halo (e.g., bromo, chloro, fluoro, or iodo); amino (wherein amino can be, e.g., NH₂; alkylamino, dialkylamino, heterocyclyl, arylamino, diarylamino, heteroarylamino, diheteroarylamino, or amino acid); NH(CH₂CH₂NH)_nCH₂CH₂- amino (wherein amino can be, e.g., as described herein), -NHC(0)R (wherein R can be, e.g., alkyl, cycloalkyl, aryl, aralkyl, heteroaryl or sugar), cyano; mercapto; alkyl-thio-alkyl;

thioalkoxy; and alkyl, cycloalkyl, aryl, alkenyl and alkynyl, which may be optionally substituted with e.g., an amino as described herein.

The sugar group can also contain one or more carbons that possess the opposite stereochemical configuration than that of the corresponding carbon in ribose. Thus, a modified nucleic acid can include nucleotides containing e.g., arabinose, as the sugar. The nucleotide "monomer" can have an alpha linkage at the position on the sugar, e.g., alpha-nucleosides. The modified nucleic acids can also include "abasic" sugars, which lack a nucleobase at C- . These abasic sugars can also be further modified at one or more of the constituent sugar atoms. The modified nucleic acids can also include one or more sugars that are in the L form, e.g. L- nucleosides.

Generally, RNA includes the sugar group ribose, which is a 5-membered ring having an oxygen. Exemplary modified nucleosides and modified nucleotides can include, without limitation, replacement of the oxygen in ribose (e.g., with sulfur (S), selenium (Se), or alkylene, such as, e.g., methylene or ethylene); addition of a double bond (e.g., to replace ribose with cyclopentenyl or cyclohexenyl); ring contraction of ribose (e.g., to form a 4-membered ring of cyclobutane or oxetane); ring expansion of ribose (e.g., to form a 6- or 7-membered ring having an additional carbon or heteroatom, such as for example, anhydrohexitol, altritol, mannitol, cyclohexanyl, cyclohexenyl, and morpholino that also has a phosphoramidate backbone). In an embodiment, the modified nucleotides can include multicyclic forms (e.g., tricyclo; and "unlocked" forms, such as glycol nucleic acid (GNA) (e.g., R-GNA or S-GNA, where ribose is replaced by glycol units attached to phosphodiester bonds), threose nucleic acid (TNA, where ribose is replaced with a-L-threofuranosyl-(3'→2')). Modifications on the Nucleobase

The modified nucleosides and modified nucleotides described herein, which can be incorporated into a modified nucleic acid, can include a modified nucleobase. Examples of nucleobases include, but are not limited to, adenine (A), guanine (G), cytosine (C), and uracil (U). These nucleobases can be modified or wholly replaced to provide modified nucleosides and modified nucleotides that can be incorporated into modified nucleic acids. The nucleobase of the nucleotide can be independently selected from a purine, a pyrimidine, a purine or pyrimidine analog. In an embodiment, the nucleobase can include, for example, naturally-occurring and synthetic derivatives of a base.

Uracil

In an embodiment, the modified nucleobase is a modified uracil. Exemplary nucleobases and nucleosides having a modified uracil include without limitation pseudouridine (ψ), pyridin- 4-one ribonucleoside, 5-aza-uridine, 6-aza-uridine, 2-thio-5-aza-uridine, 2-thio-uridine (s2U), 4- thio-uridine (s4U), 4-thio-pseudouridine, 2-thio-pseudouridine, 5 -hydroxy-uridine (ho⁵U), 5- aminoallyl-uridine, 5-halo-uridine (e.g., 5-iodo-uridine or 5-bromo-uridine), 3-methyl-uridine

3 5 5

(m U), 5-methoxy-uridine (mo U), uridine 5-oxyacetic acid (cmo U), uridine 5-oxyacetic acid methyl ester (mcmo⁵U), 5-carboxymethyl-uridine (cm⁵U), 1-carboxymethyl-pseudouridine, 5- carboxyhydroxymethyl-uridine (chm⁵U), 5-carboxyhydroxymethyl-uridine methyl ester

(mchm⁵U), 5-methoxycarbonylmethyl-uridine (mcm⁵U), 5-methoxycarbonylmethyl-2-thio- uridine (mcm⁵s2U), 5-aminomethyl-2-thio-uridine (nm⁵s2U), 5-methylaminomethyl-uridine (mnm⁵U), 5-methylaminomethyl-2-thio-uridine (mnm⁵s2U), 5-methylaminomethyl-2-seleno-

5 2 5

uridine (mnm se U), 5-carbamoylmethyl-uridine (ncm U), 5-carboxymethylaminomethyl-uridine (cmnm⁵U), 5-carboxymethylaminomethyl-2-thio-uridine (cmnm ⁵s2U), 5-propynyl-uridine, 1- propynyl-pseudouridine, 5-taurinomethyl-uridine (xcm⁵U), 1-taurinomethyl -pseudouridine, 5- taurinomethyl-2-thio-uridine(Tm⁵s2U), 1 -taurinomethyl-4-thio-pseudouridine, 5-methyl-uridine (m⁵U, i.e., having the nucleobase deoxythymine), 1-methyl-pseudouridine (ηι'ψ), 5-methyl-2- thio-uridine (m⁵s2U), l-methyl-4-thio-pseudouridine

4-thio- 1-methyl-pseudouridine, 3- methyl-pseudouridine (m ψ), 2-thio- 1-methyl-pseudouridine, 1 -methyl- 1-deaza-pseudouridine, 2-thio- l -methyl- 1-deaza-pseudouridine, dihydrouridine (D), dihydropseudouridine, 5,6- dihydrouridine, 5-methyl-dihydrouridine (m⁵D), 2-thio-dihydrouridine, 2-thio- dihydropseudouridine, 2-methoxy-uridine, 2-methoxy-4-thio-uridine, 4-methoxy-pseudouridine, 4- methoxy-2-thio-pseudouridine, Nl-methyl-pseudouridine, 3-(3-amino-3- carboxypropyl)uridine (acp 3 U), l-methyl-3-(3-amino-3-carboxypropyl)pseudouridine (acp 3 ψ), 5- (isopentenylaminomethyl)uridine (inm⁵U), 5-(isopentenylaminomethyl)-2-thio-uridine

(inm⁵s2U), a-thio-uridine, 2'-0-methyl-uridine (Um), 5,2'-0-dimethyl-uridine (m⁵Um), 2'-0- methyl-pseudouridine (ψηι), 2-thio-2'-0-methyl-uridine (s2Um), 5-methoxycarbonylmethyl-2'- O-methyl-uridine (mem ⁵Um), 5-carbamoylmethyl-2'-0-methyl-uridine (ncm ⁵Um), 5- carboxymethylaminomethyl-2'-0-methyl-uridine (cmnm 5 Um), 3,2'-0-dimethyl-uridine (m 3 Um),

5- (isopentenylaminomethyl)-2'-0-methyl-uridine (inm⁵Um), 1-thio-uridine, deoxythymidine, 2'- F-ara-uridine, 2'-F-uridine, 2'-OH-ara-uridine, 5-(2-carbomethoxyvinyl) uridine, 5-[3-(l-E- propenylamino)uridine, pyrazolo[3,4-d]pyrimidines, xanthine, and hypoxanthine.

Cytosine

In an embodiment, the modified nucleobase is a modified cytosine. Exemplary nucleobases and nucleosides having a modified cytosine include without limitation 5-aza- cytidine, 6-aza-cytidine, pseudoisocytidine, 3-methyl-cytidine (m C), N4-acetyl-cytidine (act), 5- formyl-cytidine (f⁵C), N4-methyl-cytidine (m⁴C), 5-methyl-cytidine (m⁵C), 5-halo-cytidine (e.g., 5-iodo-cytidine), 5-hydroxymethyl-cytidine (hm⁵C), 1-methyl-pseudoisocytidine, pyrrolo- cytidine, pyrrolo-pseudoisocytidine, 2-thio-cytidine (s2C), 2-thio-5-methyl-cytidine, 4-thio- pseudoisocytidine, 4-thio- 1-methyl-pseudoisocytidine, 4-thio-l -methyl- 1-deaza- pseudoisocytidine, 1 -methyl- 1-deaza-pseudoisocytidine, zebularine, 5-aza-zebularine, 5-methyl- zebularine, 5-aza-2-thio-zebularine, 2-thio-zebularine, 2-methoxy-cytidine, 2-methoxy- 5 -methyl- cytidine, 4-methoxy-pseudoisocytidine, 4-methoxy- 1-methyl-pseudoisocytidine, lysidine (k C), a-thio-cytidine, 2'-0-methyl-cytidine (Cm), 5,2'-0-dimethyl-cytidine (m⁵Cm), N4-acetyl-2'-0- methyl-cytidine (ac⁴Cm), N4,2'-0-dimethyl-cytidine (m⁴Cm), 5-formyl-2'-0-methyl-cytidine (f ⁵Cm), N4,N4,2'-0-trimethyl-cytidine (m⁴ ₂Cm), 1-thio-cytidine, 2'-F-ara-cytidine, 2'-F-cytidine, and 2'-OH-ara-cytidine.

Adenine

In an embodiment, the modified nucleobase is a modified adenine. Exemplary nucleobases and nucleosides having a modified adenine include without limitation 2-amino- purine, 2,6-diaminopurine, 2-amino-6-halo-purine (e.g., 2-amino-6-chloro-purine), 6-halo-purine (e.g., 6-chloro-purine), 2-amino-6-methyl-purine, 8-azido-adenosine, 7-deaza-adenosine, 7- deaza-8-aza-adenosine, 7-deaza-2-amino-purine, 7-deaza-8-aza-2-amino-purine, 7-deaza-2,6- diaminopurine, 7-deaza-8-aza-2,6-diaminopurine, 1 -methyl- adenosine (m A), 2-methyl- adenosine (m²A), N6-methyl-adenosine (m⁶A), 2-methylthio-N6-methyl-adenosine (ms2m⁶A), N6-isopentenyl-adenosine (i⁶A), 2-methylthio-N6-isopentenyl-adenosine (ms²i⁶A), N6-(cis- hydroxyisopentenyl)adenosine (io⁶A), 2-methylthio-N6-(cis-hydroxyisopentenyl)adenosine (ms2io⁶A), N6-glycinylcarbamoyl-adenosine (g⁶A), N6-threonylcarbamoyl-adenosine (t⁶A), N6- methyl-N6-threonylcarbamoyl-adenosine (m⁶t⁶A), 2-methylthio-N6-threonylcarbamoyl- adenosine (ms²g⁶A), N6,N6-dimethyl-adenosine (m⁶ ₂A), N6-hydroxynorvalylcarbamoyl- adenosine (hn⁶A), 2-methylthio-N6-hydroxynorvalylcarbamoyl-adenosine (ms2hn⁶A), N6- acetyl-adenosine (ac⁶A), 7-methyl-adenosine, 2-methylthio-adenosine, 2-methoxy-adenosine, a- thio-adenosine, 2'-0-methyl-adenosine (Am), N⁶,2'-0-dimethyl-adenosine (m⁶Am), N⁶-Methyl- 2'-deoxyadenosine, N6,N6,2'-0-trimethyl-adenosine (m⁶ ₂Am), l,2'-0-dimethyl-adenosine (m'Am), 2'-0-ribosyladenosine (phosphate) (Ar(p)), 2-amino-N6-methyl -purine, 1 -thio- adenosine, 8-azido-adenosine, 2'-F-ara-adenosine, 2'-F-adenosine, 2'-OH-ara-adenosine, and N6- ( 19- amino-pentaoxanonadecyl) - adeno sine .

Guanine

In an embodiment, the modified nucleobase is a modified guanine. Exemplary nucleobases and nucleosides having a modified guanine include without limitation inosine (I), 1- methyl-inosine (iVl), wyosine (imG), methylwyosine (mimG), 4-demethyl-wyosine (imG-14), isowyosine (imG2), wybutosine (yW), peroxywybutosine (o₂yW), hydroxy wybuto sine (OHyW), undermodified hydroxy wybuto sine (OHyW*), 7-deaza-guanosine, queuosine (Q),

epoxyqueuosine (oQ), galactosyl-queuosine (galQ), mannosyl-queuosine (manQ), 7-cyano-7- deaza-guanosine (preQo), 7-aminomethyl-7-deaza-guanosine (preQO, archaeosine (G⁺), 7-deaza- 8-aza-guanosine, 6-thio-guanosine, 6-thio-7-deaza-guanosine, 6-thio-7-deaza-8-aza-guanosine, 7-methyl-guanosine (m G), 6-thio-7-methyl-guanosine, 7-methyl-inosine, 6-methoxy-guanosine, l-methyl-guanosine (m'G), N2-methyl-guanosine (m 2 G), N2,N2-dimethyl-guanosine (m 2 ₂G),

N2,7-dimethyl-guanosine (m 2 ,7G), N2, N2,7-dimethyl-guanosine (m 2 ,2,7G), 8-oxo-guanosine, 7-methyl-8-oxo-guanosine, l-methyl-6- thio-guanosine, N2-methyl-6-thio-guanosine, N2,N2- dimethyl-6-thio-guanosine, a-thio-guanosine, 2'-0-methyl-guanosine (Gm), N2-methyl-2'-0- methyl-guanosine (m 2"Gm), N2,N2-dimethyl-2'-0-methyl- guano sine (m 2 ₂Gm), l-methyl-2'-0- methyl-guanosine (m'Gm), N2,7-dimethyl-2'-0-methyl-guanosine (m",7Gm), 2'-0-methyl- inosine (Im), l,2'-0-dimethyl-inosine (m'lm), 0⁶-phenyl-2'-deoxyinosine, 2'-0-ribosylguanosine (phosphate) (Gr(p)), 1-thio-guanosine, 0⁶-methyl- guanosine, 0⁶-Methyl-2'-deoxy guanosine, z - F-ara-guanosine, and 2'-F-guanosine.

Exemplary Modified gRNAs

In some embodiments, the modified nucleic acids can be modified gRNAs. It is to be understood that any of the gRNAs described herein can be modified in accordance with this section, including any gRNA that comprises a targeting domain from Tables 1A-1D, 2A-2F, 3A- 3C, 4A-4E, 5A-5E, 6A-6B, 7A-7D, 8A-8D, 9, 10A-10D, 11A-11D, 12, 13A-13D, 14A-14C, 15A-15D, 16A-16E, 17A-17B, 18A-18C, 19A-19E, 20A-20C, 21A-21E, 22A-22E, 23A-23C, 24A-24D, 25A-25B, 26, or 31.

As discussed above, transiently expressed or delivered nucleic acids can be prone to degradation by, e.g., cellular nucleases. Accordingly, in one aspect the modified gRNAs described herein can contain one or more modified nucleosides or nucleotides which introduce stability toward nucleases. While not wishing to be bound by theory it is also believed that certain modified gRNAs described herein can exhibit a reduced innate immune response when introduced into a population of cells, particularly the cells of the present invention. As noted above, the term "innate immune response" includes a cellular response to exogenous nucleic acids, including single stranded nucleic acids, generally of viral or bacterial origin, which involves the induction of cytokine expression and release, particularly the interferons, and cell death.

While some of the exemplary modification discussed in this section may be included at any position within the gRNA sequence, in some embodiments, a gRNA comprises a

modification at or near its 5' end (e.g., within 1-10, 1-5, or 1-2 nucleotides of its 5' end). In some embodiments, a gRNA comprises a modification at or near its 3' end (e.g., within 1-10, 1- 5, or 1-2 nucleotides of its 3' end). In some embodiments, a gRNA comprises both a

modification at or near its 5' end and a modification at or near its 3' end.

In an embodiment, the 5' end of a gRNA is modified by the inclusion of a eukaryotic mRNA cap structure or cap analog (e.g., a G(5')ppp(5 ')G cap analog, a m7G(5')ppp(5')G cap analog, or a 3 '-0-Me-m7G(5')ppp(5')G anti reverse cap analog (ARCA)). The cap or cap analog can be included during either chemical synthesis or in vitro transcription of the gRNA. In an embodiment, an in vitro transcribed gRNA is modified by treatment with a phosphatase (e.g., calf intestinal alkaline phosphatase) to remove the 5' triphosphate group.

In an embodiment, the 3' end of a gRNA is modified by the addition of one or more (e.g., 25-200) adenine (A) residues. The polyA tract can be contained in the nucleic acid (e.g., plasmid, PCR product, viral genome) encoding the gRNA, or can be added to the gRNA during chemical synthesis, or following in vitro transcription using a polyadenosine polymerase (e.g., E. coli Poly(A)Polymerase).

In an embodiment, in vitro transcribed gRNA contains both a 5' cap structure or cap analog and a 3' polyA tract. In an embodiment, an in vitro transcribed gRNA is modified by treatment with a phosphatase (e.g., calf intestinal alkaline phosphatase) to remove the 5' triphosphate group and comprises a 3' polyA tract.

In some embodiments, gRNAs can be modified at a 3' terminal U ribose. For example, the two terminal hydroxyl groups of the U ribose can be oxidized to aldehyde groups and a concomitant opening of the ribose ring to afford a modified nucleoside as shown below:

wherein "U" can be an unmodified or modified uridine.

In another embodiment, the 3' terminal U can be modified with a 2' 3' cyclic phosphate as shown below:

wherein "U" can be an unmodified or modified uridine.

In some embodiments, the gRNA molecules may contain 3' nucleotides which can be stabilized against degradation, e.g., by incorporating one or more of the modified nucleotides described herein. In this embodiment, e.g., uridines can be replaced with modified uridines, e.g., 5-(2-amino)propyl uridine, and 5-bromo uridine, or with any of the modified uridines described herein; adenosines and guanosines can be replaced with modified adenosines and guanosines, e.g., with modifications at the 8-position, e.g., 8-bromo guanosine, or with any of the modified adenosines or guanosines described herein.

In some embodiments, sugar-modified ribonucleotides can be incorporated into the gRNA, e.g., wherein the 2' OH-group is replaced by a group selected from H, -OR, -R (wherein R can be, e.g., alkyl, cycloalkyl, aryl, aralkyl, heteroaryl or sugar), halo, -SH, -SR (wherein R can be, e.g., alkyl, cycloalkyl, aryl, aralkyl, heteroaryl or sugar), amino (wherein amino can be, e.g., NH₂; alkylamino, dialkylamino, heterocyclyl, arylamino, diarylamino, heteroarylamino, diheteroarylamino, or amino acid); or cyano (-CN). In some embodiments, the phosphate backbone can be modified as described herein, e.g., with a phosphothioate group. In some embodiments, one or more of the nucleotides of the gRNA can each independently be a modified or unmodified nucleotide including, but not limited to 2' -sugar modified, such as, 2' -O-methyl, 2'-0-methoxyethyl, or 2'-Fluoro modified including, e.g., 2'-F or 2'-0-methyl, adenosine (A), 2'-F or 2' -O-methyl, cytidine (C), 2'-F or 2' -O-methyl, uridine (U), 2'-F or 2' -O-methyl, thymidine (T), 2'-F or 2'-0-methyl, guanosine (G), 2'-0-methoxyethyl-5-methyluridine (Teo), 2'-0-methoxyethyladenosine (Aeo), 2'-0-methoxyethyl-5-methylcytidine (m5Ceo), and any combinations thereof.

In some embodiments, a gRNA can include "locked" nucleic acids (LNA) in which the 2' OH-group can be connected, e.g., by a CI -6 alkylene or CI -6 heteroalkylene bridge, to the 4' carbon of the same ribose sugar, where exemplary bridges can include methylene, propylene, ether, or amino bridges; O-amino (wherein amino can be, e.g., NH₂; alkylamino, dialkylamino, heterocyclyl, arylamino, diarylamino, heteroarylamino, or diheteroarylamino, ethylenediamine, or polyamino) and aminoalkoxy or 0(CH₂)_n-amino (wherein amino can be, e.g., NH₂;

alkylamino, dialkylamino, heterocyclyl, arylamino, diarylamino, heteroarylamino, or

diheteroarylamino, ethylenediamine, or polyamino).

In some embodiments, a gRNA can include a modified nucleotide which is multicyclic (e.g., tricyclo; and "unlocked" forms, such as glycol nucleic acid (GNA) (e.g., R-GNA or S- GNA, where ribose is replaced by glycol units attached to phosphodiester bonds), or threose nucleic acid (TNA, where ribose is replaced with a-L-threofuranosyl-(3'→2')).

Generally, gRNA molecules include the sugar group ribose, which is a 5-membered ring having an oxygen. Exemplary modified gRNAs can include, without limitation, replacement of the oxygen in ribose (e.g., with sulfur (S), selenium (Se), or alkylene, such as, e.g., methylene or ethylene); addition of a double bond (e.g., to replace ribose with cyclopentenyl or cyclohexenyl); ring contraction of ribose (e.g., to form a 4-membered ring of cyclobutane or oxetane); ring expansion of ribose (e.g., to form a 6- or 7-membered ring having an additional carbon or heteroatom, such as for example, anhydrohexitol, altritol, mannitol, cyclohexanyl, cyclohexenyl, and morpholino that also has a phosphoramidate backbone). Although the majority of sugar analog alterations are localized to the 2' position, other sites are amenable to modification, including the 4' position. In an embodiment, a gRNA comprises a 4'-S, 4'-Se or a 4'-C- aminomethyl-2' -O-Me modification.

In some embodiments, deaza nucleotides, e.g., 7-deaza-adenosine, can be incorporated into the gRNA. In some embodiments, O- and N-alkylated nucleotides, e.g., N6-methyl adenosine, can be incorporated into the gRNA. In some embodiments, one or more or all of the nucleotides in a gRNA molecule are deoxynucleotides. miRNA binding sites

microRNAs (or miRNAs) are naturally occurring cellular 19-25 nucleotide long noncoding RNAs. They bind to nucleic acid molecules having an appropriate miRNA binding site, e.g., in the 3' UTR of an mRNA, and down-regulate gene expression. While not wishing to be bound by theory it is believed that the down regulation is either by reducing nucleic acid molecule stability or by inhibiting translation. An RNA species disclosed herein, e.g., an mRNA encoding Cas9 can comprise an miRNA binding site, e.g., in its 3 'UTR. The miRNA binding site can be selected to promote down regulation of expression is a selected cell type. By way of example, the incorporation of a binding site for miR-122, a microRNA abundant in liver, can inhibit the expression of the gene of interest in the liver.

EXAMPLES

The following Examples are merely illustrative and are not intended to limit the scope or content of the invention in any way. Example 1 : Cloning and Initial Screening of gRNAs

The suitability of candidate gRNAs can be evaluated as described in this example.

Although described for a chimeric gRNA, the approach can also be used to evaluate modular gRNAs.

Cloning gRNAs into Vectors

For each gRNA, a pair of overlapping oligonucleotides is designed and obtained.

Oligonucleotides are annealed and ligated into a digested vector backbone containing an upstream U6 promoter and the remaining sequence of a long chimeric gRNA. Plasmid is sequence-verified and prepped to generate sufficient amounts of transfection-quality DNA. Alternate promoters maybe used to drive in vivo transcription (e.g. HI promoter) or for in vitro transcription (e.g., a T7 promoter).

Cloning gRNAs in linear dsDNA molecule (STITCHR)

For each gRNA, a single oligonucleotide is designed and obtained. The U6 promoter and the gRNA scaffold (e.g. including everything except the targeting domain, e.g., including sequences derived from the crRNA and tracrRNA, e.g., including a first complementarity domain; a linking domain; a second complementarity domain; a proximal domain; and a tail domain) are separately PCR amplified and purified as dsDNA molecules. The gRNA- specific oligonucleotide is used in a PCR reaction to stitch together the U6 and the gRNA scaffold, linked by the targeting domain specified in the oligonucleotide. Resulting dsDNA molecule (STITCHR product) is purified for transfection. Alternate promoters may be used to drive in vivo transcription (e.g., HI promoter) or for in vitro transcription (e.g., T7 promoter). Any gRNA scaffold may be used to create gRNAs compatible with Cas9s from any bacterial species.

Initial gRNA Screen

Each gRNA to be tested is transfected, along with a plasmid expressing Cas9 and a small amount of a GFP-expressing plasmid into human cells. In preliminary experiments, these cells can be immortalized human cell lines such as 293T, K562 or U20S. Alternatively, primary human cells may be used. In this case, cells may be relevant to the eventual therapeutic cell target (for example, an erythroid cell). The use of primary cells similar to the potential therapeutic target cell population may provide important information on gene targeting rates in the context of endogenous chromatin and gene expression. Transfection may be performed using lipid transfection (such as Lipofectamine or Fugene) or by electroporation (such as Lonza Nucleofection). Following transfection, GFP expression can be determined either by fluorescence microscopy or by flow cytometry to confirm consistent and high levels of transfection. These preliminary transfections can comprise different gRNAs and different targeting approaches (17-mers, 20-mers, nuclease, dual-nickase, etc.) to determine which gRNAs/combinations of gRNAs give the greatest activity.

Efficiency of cleavage with each gRNA may be assessed by measuring NHEJ-induced indel formation at the target locus by a T7El-type assay or by sequencing. Alternatively, other mismatch- sensitive enzymes, such as Cell/Surveyor nuclease, may also be used.

For the T7E1 assay, PCR amplicons are approximately 500-700bp with the intended cut site placed asymmetrically in the amplicon. Following amplification, purification and size- verification of PCR products, DNA is denatured and re-hybridized by heating to 95 °C and then slowly cooling. Hybridized PCR products are then digested with T7 Endonuclease I (or other mismatch- sensitive enzyme) which recognizes and cleaves non-perfectly matched DNA. If indels are present in the original template DNA, when the amplicons are denatured and re- annealed, this results in the hybridization of DNA strands harboring different indels and therefore lead to double- stranded DNA that is not perfectly matched. Digestion products may be visualized by gel electrophoresis or by capillary electrophoresis. The fraction of DNA that is cleaved (density of cleavage products divided by the density of cleaved and uncleaved) may be used to estimate a percent NHEJ using the following equation: %NHEJ = (1-(1 -fraction cleaved)'⁷²). The T7E1 assay is sensitive down to about 2-5% NHEJ.

Sequencing may be used instead of, or in addition to, the T7E1 assay. For Sanger sequencing, purified PCR amplicons are cloned into a plasmid backbone, transformed, miniprepped and sequenced with a single primer. Sanger sequencing may be used for determining the exact nature of indels after determining the NHEJ rate by T7E1.

Sequencing may also be performed using next generation sequencing techniques. When using next generation sequencing, amplicons may be 300-500bp with the intended cut site placed asymmetrically. Following PCR, next generation sequencing adapters and barcodes (for example Illumina multiplex adapters and indexes) may be added to the ends of the amplicon, e.g., for use in high throughput sequencing (for example on an Illumina MiSeq). This method allows for detection of very low NHEJ rates. Example 2: Assessment of Gene Targeting by NHEJ

The gRNAs that induce the greatest levels of NHEJ in initial tests can be selected for further evaluation of gene targeting efficiency. In this case, cells are derived from disease subjects and, therefore, harbor the relevant mutation.

Following transfection (usually 2-3 days post-transfection,) genomic DNA may be isolated from a bulk population of transfected cells and PCR may be used to amplify the target region. Following PCR, gene targeting efficiency to generate the desired mutations (either knockout of a target gene or removal of a target sequence motif) may be determined by sequencing. For Sanger sequencing, PCR amplicons may be 500-700 bp long. For next generation sequencing, PCR amplicons may be 300-500 bp long. If the goal is to knockout gene function, sequencing may be used to assess what percent of alleles have undergone NHEJ- induced indels that result in a frameshift or large deletion or insertion that would be expected to destroy gene function. If the goal is to remove a specific sequence motif, sequencing may be used to assess what percent of alleles have undergone NHEJ-induced deletions that span this sequence.

Example 3: Assessment of Gene Targeting by HDR

Following transfection (usually 2-3 days post-transfection,) genomic DNA may be isolated from a bulk population of transfected cells and PCR may be used to amplify the target region. Following PCR, gene targeting efficiency can be determined by several methods.

Determination of gene targeting frequency involves measuring the percentage of alleles that have undergone homologous directed repair (HDR) with the exogenously provided donor template or endogenous genomic donor sequence and which therefore have incorporated the desired correction. If the desired HDR event creates or destroys a restriction enzyme site, the frequency of gene targeting may be determined by a RFLP assay. If no restriction site is created or destroyed, sequencing may be used to determine gene targeting frequency. If a RFLP assay is used, sequencing may still be used to verify the desired HDR event and ensure that no other mutations are present. If an exogenously provided donor template is employed, at least one of the primers is placed in the endogenous gene sequence outside of the region included in the homology arms, which prevents amplification of donor template still present in the cells.

Therefore, the length of the homology arms present in the donor template may affect the length of the PCR amplicon. PCR amplicons can either span the entire donor region (both primers placed outside the homology arms) or they can span only part of the donor region and a single junction between donor and endogenous DNA (one internal and one external primer). If the amplicons span less than the entire donor region, two different PCRs should be used to amplify and sequence both the 5' and the 3' junction.

If the PCR amplicon is short (less than 600bp) it is possible to use next generation sequencing. Following PCR, next generation sequencing adapters and barcodes (for example Illumina multiplex adapters and indexes) may be added to the ends of the amplicon, e.g., for use in high throughput sequencing (for example on an Illumina MiSeq). This method allows for detection of very low gene targeting rates.

If the PCR amplicon is too long for next generation sequencing, Sanger sequencing can be performed. For Sanger sequencing, purified PCR amplicons will be cloned into a plasmid backbone (for example, TOPO cloned using the LifeTech Zero Blunt^® TOPO^® cloning kit), transformed, miniprepped and sequenced.

The same or similar assays described above can be used to measure the percentage of alleles that have undergone HDR with endogenous genomic donor sequence and which therefore have incorporated the desired correction.

Example 4: Screening of gRNAs for Targeting BCL11A

In order to identify gRNAs with the highest on target NHEJ efficiency, thirty exemplary S. pyogenes gRNAs were selected for testing (Table 31). The gRNAs tested target three different regions of the BCLA11A locus - 5' of a red blood cell enhancer, 3' of a red blood cell enhancer and downstream of the ATG start codon in exon 2 (specified in Table 31).

Table 31

BCL11A-2984W AUUCACUGGAAACCCUGUUA 20 3' of enhancer 16264

BCL11A-2985W UACUGUACUGCAGGGGAAUU 20 3' of enhancer 16265

BCL11A-2986W AAACUAUUUACAGCCAUAAC 20 3' of enhancer 16266

BCL11A-2987W AAAUACUUACUGUACUGCAG 20 3' of enhancer 16267

BCL11A-2988W CUAUUUACAGCCAUAAC 17 3' of enhancer 16268

BCL11A-2989W CUACUUAUACAAUUCAC 17 3' of enhancer 16269

BCL11A-2990W CACUGGAAACCCUGUUA 17 3' of enhancer 16270

BCL11A-2991W UACUUACUGUACUGCAG 17 3' of enhancer 16271

BCL11A-2992W UGUACUGCAGGGGAAUU 17 3' of enhancer 16272

BCL11A-2993W AAUACUUACUGUACUGC 17 3' of enhancer 16273

BCL11A-2994W AUACUUACUGUACUGCA 17 3' of enhancer 16274

BCL11A-2995W GAAUGUAGAGAGGCAGA 17 5' of enhancer 16275

BCL11A-2996W GGAAUGUAGAGAGGCAG 17 5' of enhancer 16276

BCL11A-2997W GUAAGUAUUUUCUUUCAUUG 20 3' of enhancer 16277

BCL11A-2998W G U A A U U A AG A A AG C AG U G U A 20 5' of enhancer 16278

BCL11A-2999W GUAUUUUCUUUCAUUGG 17 3' of enhancer 16279

BCL11A-32W UGGCAUCCAGGUCACGCCAG 20 Exon 2 16280

BCL11A-40W GAUGCUUUUUUCAUCUCGAU 20 Exon 2 16281

BCL11A-30W GCAUCCAAUCCCGUGGAGGU 20 Exon 2 16282

BCL11A-42W UUUUCAUCUCGAUUGGUGAA 20 Exon 2 16283

BCL11A-24W CCAGAUGAACUUCCCAUUGG 20 Exon 2 16284

BCL11A-53W AGGAGGUCAUGAUCCCCUUC 20 Exon 2 16285

BCL11A-79W CAUCCAGGUCACGCCAG 17 Exon 2 16286

BCL11A-90W GCUUUUUUCAUCUCGAU 17 Exon 2 16287

BCL11A-77W UCCAAUCCCGUGGAGGU 17 Exon 2 16288

BCL11A-92W UCAUCUCGAUUGGUGAA 17 Exon 2 16289

BCL11A-71W GAUGAACUUCCCAUUGG 17 Exon 2 16290

A DNA template comprised of an exemplary gRNA (including the target region and the S. pyogenes TRACR sequence) under the control of a U6 promoter was generated by a PCR StitchR reaction. This DNA template was subsequently transfected into 293 cells using

Lipofectamine 3000 along with a DNA plasmid encoding the S. pyogenes Cas9 downstream of a CMV promoter. Genomic DNA was isolated from the cells 48-72 hours post transfection. To determine the rate of modification at the BCLllA locus, the target region was amplified using a locus PCR with the primers listed in Table 32.

Table 32

TGCCTCATTGACAAATTTGCTC (SEQ I D NO: 16292) BCL11A exon 2 3' primer

AGACCGTCTCTTTGGTGCAG (SEQ ID NO 16293) BCL11A 5' enhancer 5' primer

G C AGTG G CTTT AG G CTGTTT (SEQ ID NO 16294) BCL11A 5' enhancer 3' primer

GTGTGATCTCGGCTCACCAC (SEQ I D NO 16295) BCL11A 3' enhancer 5' primer

CCCTGACTTTGGAGCTCAGC (SEQ I D NO 16296) BCL11A 3' enhancer 3' primer

After PCR amplification, a T7E1 -directed mismatch cleavage assay was performed on the PCR product. Briefly, this assay involves melting the PCR product followed by a re- annealing step. If gene modification has occurred, there will exist double stranded products that are not perfect matches due to some frequency of insertions or deletions. These double stranded products are sensitive to cleavage by a T7 endonuclease 1 enzyme at the site of mismatch.

Therefore, the efficiency of cutting by the Cas9/gRNA complex was determined by analyzing the amount of T7E1 cleavage. The formula that was used to provide a measure of % NHEJ from the T7E1 cutting is the following: 100*(l-(l-(fraction cleaved))^A0.5). The results of this analysis are shown in Fig. 11. The top performing gRNAs in this assay were BCLl 1A-2981, BCLl 1A-2983, BCLl lA-2995, BCLl lA-32, BCLl lA-30, and BCLl 1A-71.

Example 5: Deletion of the Erythroid Enhancer Elements Using Two gRNAs Flanking the Sequence

In order to test whether the erythroid enhancer sequence can be deleted using a two gRNA approach, two pairs of gRNAs were tested in 293 cells. Pair number 1 comprised

BCLl 1A-2983W and BCLl 1A-2981W while Pair number 2 comprised BCLl 1A-2995W and BCLl 1 A-2984W. In this example, a plasmid encoding S. pyogenes Cas9 downstream of a CMV promoter was delivered with either gRNA pair 1 or gRNA pair 2. The gRNAs were delivered as separate STITCHR products with each template comprising the U6 promoter, gRNA target sequence and S. pyogenes TRACR sequence. The DNA templates were delivered to 293 cells using lipid transfection (Lipofectamine 3000, Life Technologies). 72 hours post transfection, the cells were harvested and gDNA was isolated. To detect the deletion of the enhancer region of BCLl 1 A, PCR primers flanking the enhancer sequences were used to amplify the deletion event. The PCR product was TOPO cloned and sequenced by Sanger sequencing. The results of these analyses are presented in Fig. 12A-13B. As shown in Fig. 12A-13B, the deletion for both gRNA pairs that were delivered to the 293 cells were detected. Example 6: Gene Targeting of the HBB Locus by CRISPR/Cas9 to Investigate Repair Pathway Choice in Response to Different Types of DNA Lesions

The CRISPR/Cas9 system was used to target the human HBB gene in the region of the sickle cell anemia-causing mutation.

To examine how the nature of the targeted break affects the frequency of different DNA repair outcomes, blunt double-strand breaks, single-strand nicks, and dual-nicks in which the nicks are placed on opposite strands and leave either 3' or 5' overhangs of varying lengths, were introduced by utilizing the wild type Cas9 nuclease, as well as two different Cas9 nickases. Several different DNA repair outcomes including indel mutations resulting from nonhomologous end-joining, homology-dependent repair (HDR) using the donor as a template, and HDR using the closely related HBD gene as an endogenous template, were characterized using either single-strand oligonucleotide (ssODN) or plasmid DNA donors. The frequency of these various repair outcomes under different conditions offer insight into the mechanisms of DNA repair and how it is impacted by the nature of the DNA break. The data also indicates a therapeutic approach in which correction of the sickle-cell mutation is efficiently mediated through HDR with either a donor template or with the HBD gene.

In this study different gRNA for the HBB region that surrounds the nucleotides encoding the amino acid most commonly mutated in sickle cell disease had been tested in 293T cells with wild type Cas9 molecule. The gRNAs that induced similar high rates of NHEJ and had PAMs facing in opposite orientations were selected to test as pairs with Cas9 D10A and Cas9 N863A nickases.

As shown in Fig. 14, the gRNA pair 8/15 ("8gRNA'7 "15gRNA" pair) was selected as one of the best pairs of gRNA. "8gRNA" has the targeting domain sequence of

GUAACGGCAGACUUCUCCUC (SEQ ID NO: 388) and "15gRNA" has the targeting domain sequence of AAGGUGAACGUGGAUGAAGU (SEQ ID NO: 387). This pair of gRNAs in combination with the mutant Cas9 D10A would generate a 5' overhang of 47 bp, and in combination with the mutant N863A would generate a 3' overhang of 47 bp.

In this Example, U20S cells were electroporated with 200 ng of each gRNA and 750 ng of plasmid that encodes wild type Cas9 or mutant Cas9. Cells were collected 6 days after electroporation and genomic DNA was extracted. PCR amplification of the HBB locus was performed and subcloned into a Topo Blunt Vector. For each condition in each experiment 96 colonies were sequenced with Sanger sequencing. In the experiments assessing HDR efficacy, cells were electroporated with 2.5 ug of single stranded oligo or double stranded oligo in addition to the gRNA and the Cas9-encoding plasmid.

As shown in Fig. 15, the total percentages of all editing events detected by Sanger sequencing of the HBB locus were similar using wild type Cas9 or Cas9 nickases (D10A, N863A).

Figs. 16A-16B show that a majority of the total gene editing events (about 3/4 of the total) were small deletions (<10 bp). This is consistent with the notion that wildtype Cas9 generates a blunt end which are preferentially repaired by canonical NHEJ. In contrast, deletions represented only about a quarter of the total events using either nickase (D10A or N863A).

Moreover, larger deletions of -50 bp that can be mapped to the region between the two nickase sites were observed (Fig. 16A or 16C). The remaining gene-editing events were substantially different between the two nickases.

As shown in Fig. 17A, in the case of Cas9 D10A nickase which leaves a 5' protruding end, the lesion is mostly repaired through a mechanism defined as gene conversion. In gene conversion, the HBD locus will serve as a template to repair the HBB gene. HBD is a highly similar gene (92% identity with HBB) that does not carry the sickle-cell mutation (Fig. 17B). Fig. 18 shows that the majority of the HBD sequence that got incorporated in the HBB locus was in the region between the nickase cuts. In contrast, a low frequency of gene conversion was observed when the N863 nicase was used (Fig. 17A). In the case of Cas9 N863A nickase, a majority of the gene editing events were insertions in which the inserted part was a duplication of the overhangs (Figs. 19A-19B).

To test the effect that different lesions had on the engagement of HDR, a donor template was provided as a single strand oligo or as ds DNA donor. In both cases the length of the donor is approximately 170 bp with 60 bp of homology outside the nicks and with 8 mismatches (Fig. 20A). As shown in Fig. 20B, the Cas9 D10A nickase that resulted in a 5' overhang gave a significantly higher rate of HDR, especially when using the upper stand as a single-strand oligo donor. Fig. 20C shows different forms of donors (dsDNA, upper stand, and lower strand) and there contribution to HDR.

In summary, Cas9 nickases (D10A and N863A) showed comparable levels of efficacy compared to wildtype Cas9. Different DNA ends engage different repair pathways. The use of a wildtype Cas9 generates a blunt end, which are preferentially repaired by canonical NHEJ. Use of a Cas9 nickase with two gRNAs generates either 3' or 5' overhangs, which are not suitable substrates to be repaired by canonical NHEJ but can be repaired by alternative pathways.

The 5' protruding end was mostly repaired through a mechanism called gene conversion in which the HBB gene is repaired by using the HBD locus as a template. Use of nickase is advantageous to promote HDR. In the experiments in which a donor was provided, a significantly higher rate of HDR was observed using a nickase compared to the wildtype Cas9. The nature of the donor template also influences the outcome as HDR was preferentially observed when an SS Oligo was used.

Example 7: Assessment of Gene Targeting in Hematopoietic Stem Cells

Transplantation of autologous CD34⁺ hematopoietic stem cells (HSCs, also known as hematopoietic stem/progenitor cells or HSPCs) genetically modified to correct the Sickle Cell Disease (SCD) mutation in the human β-hemoglobin gene (HBB) would prevent deformability (sickling) after deoxygenation in the erythrocyte progeny of corrected HSCs which could ameliorate symptoms associated with SCD. Genome editing with the CRISPR/Cas9 platform precisely alters endogenous gene targets by creating an indel at the targeted cut site that can lead to knock down of gene expression at the edited locus. In this Example, genome editing in the human K562 bone marrow erythroleukemia cell line, which serve as a proxy for HSCs and which can be predictive of genome editing in HSCs, were electroporated with Cas9 mRNA and gRNA HBB-8 and gRNA HBB-15 to induce gene editing at the human HBB locus.

K562 cells were grown in RPMI media (Life Technologies) containing 10% fetal bovine serum (FBS). For the RNA electroporation, the Maxcyte GT device (http://www.maxcyte.com/) was used. S. pyogenes Cas9 mRNA and gRNA HBB-15 and gRNA HBB-8 were prepared by in vitro transcription using linearized plasmid DNA as templates and the Ambion mMessage mMachine® T7 Ultra Transcription kit (Life Technologies) according to the manufacturer's instructions. In this embodiment, both the Cas9 and gRNA were in vitro transcribed using a T7 polymerase. For example, a 5' ARCA cap was added to both RNA species simultaneous to transcription while a polyA tail was added after transcription to the 3' end of the RNA species by an E. coli polyA polymerase. Capped and tailed gRNA HBB-8 and gRNA HBB-15 were complexed at room temperature with S. pyogenes H-NLS-Cas9 protein at a molar ratio of -25: 1 (gRNA : Cas9 protein) in a total of 30 μg RNP. Briefly, three million K562 cells were suspended in 100 μΐ_^ Maxcyte EP buffer and transferred to the RNP solution (13μί). In addition, K562 cells were electroporated with S. pyogenes Cas9 mRNA and each of the gRNA HBB-8 and gRNA HBB- 15. For the mRNA/gRNA electroporation with the Maxcyte device, 10 μg of gRNA HBB-8 (or 10 μg of HBB gRNA HBB-15) were mixed with 10 μg of Cas9 mRNA. Four million K562 cells were suspended in 100 μΐ_^ Maxcyte EP buffer and then transferred to the mRNA/gRNA solution (13 μί). K562 cells mixed with either RNP or RNA were

electroporated with the Maxcyte GT device. At 48 hours after electroporation, K562 cells were enumerated by trypan blue exclusion and were determined to have >88% viability in the electroporated cell populations. Genomic DNA was extracted from K562 cells 48 hours after electroporation and HBB locus-specific PCR reactions were performed.

In order to detect indels at the HBB Zocus, T7E1 assays were performed on HBB locus- specific PCR products that were amplified from genomic DNA samples from electroporated K562 cells and the percentage of indels detected at the HBB locus was calculated (Fig. 21).

Co-delivery of 10 μg RNP which contains wild-type S. pyogenes Cas9 protein with HBB gRNA 8 or HBB gRNA 15 resulted in 26.8% and 16.1% indels, respectively, at the HBB locus in gDNA from K562 cells (molar ratio protein: gRNA 24: 1). Co-delivery of Cas9 mRNA with gRNA HBB-8 or HBB-15 led to 66.9% and 29.5% indels at the HBB locus in gDNA from K562 cells (10 μg of each RNA/4 million cells). This example shows that delivery of Cas9

mRNA/gRNA and Cas9 RNPs leads to editing of the HBB locus in a relevant bone marrow derived hematopoietic cell line (K562 cells). Clinically, transplantation of autologous HSCs in which the HBB locus has been edited to correct the genetic mutation that causes red blood cell sickling could be used to ameliorate symptoms of SCD.

Incorporation by Reference

All publications, patents, and patent applications mentioned herein are hereby incorporated by reference in their entirety as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

Equivalents

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

Other embodiments are within the following claims. What is claimed is:

1. A gRNA molecule comprising a targeting domain which is complementary with a target domain from the HBB or BCLllA gene.

2. The gRNA molecule of claim 1, wherein said targeting domain is configured to provide a cleavage event selected from a double strand break and a single strand break, within 500, 400, 300, 200, 100, 50, 25, or 10 nucleotides of an SCD target point position or an SCD target knockout position.

3. The gRNA molecule of claim 1 or 2, wherein said targeting domain is configured to

target an early coding region or an enhancer region of the BCLllA gene.

4. The gRNA molecule of claim 1 or 2, wherein said targeting domain is configured to target a mutation in the HBB gene.

5. The gRNA molecule of claim 1, wherein said targeting domain is configured to target an enzymatically inactive Cas9 (eiCas9) or an eiCas9 fusion protein, sufficiently close to an SCD target knockdown position to reduce, decrease or repress expression of the BCLllA gene.

6. The gRNA molecule of claim 1, 2, or 5, wherein said targeting domain is configured to target the promoter region of the BCLllA gene.

7. The gRNA molecule of any of claims 1-6, wherein said targeting domain comprises or consists of a sequence that is the same as, or differs by no more than 3 nucleotides from, a targeting domain sequence from any of Tables 1A-1D, 2A-2F, 3A-3C, 4A-4E, 5A-5E, 6A-6B, 7A-7D, 8A-8D, 9, 10A-10D, 11A-11D, 12, 13A-13D, 14A-14C, 15A-15D, 16A- 16E, 17A-17B, 18A-18C, 19A-19E, 20A-20C, 21A-21E, 22A-22E, 23A-23C, 24A-24D, 25A-25B, 26, or 31.

8. The gRNA molecule of any of claims 1-6, wherein said targeting domain comprises or consists of a sequence that is the same as a targeting domain sequence from any of Tables 1A-1D, 2A-2F, 3A-3C, 4A-4E, 5A-5E, 6A-6B, 7A-7D, 8A-8D, 9, 10A-10D, 11A-11D, 12, 13A-13D, 14A-14C, 15A-15D, 16A-16E, 17A-17B, 18A-18C, 19A-19E, 20A-20C, 21A-21E, 22A-22E, 23A-23C, 24A-24D, 25A-25B, 26, or 31.

9. The gRNA molecule of any of claims 1-3 or 6-8, wherein said targeting domain is selected from those in Tables 2A-2F, 4A-4E, 5A-5E, 6A-6B, 7A-7D, 8A-8D, 9, 15A- 15D, 16A-16E, 17A-17B, 21A-21E, 22A-22E, or 23A-23C.

10. The gRNA molecule of any of claims 1 or 5-8, wherein said targeting domain is selected from those in Tables 3A-3C, 10A-10D, 11A-11D, 12, 18A-18C, 19A-19E, or 20A-20C.

11. The gRNA molecule of any of claims 1, 2, 4, 7, or 8, wherein said targeting domain is selected from those in Tables 1A-1D, 13A-13D, 14A-14C, 24A-24D, 25A-25B, and 26.

12. The gRNA molecule of any of claims 1-11, wherein said gRNA is a modular gRNA molecule.

13. The gRNA molecule of any of claimsl-11, wherein said gRNA is a chimeric gRNA molecule.

14. The gRNA molecule of any of claims 1-13, wherein said targeting domain is 16

nucleotides or more in length.

15. The gRNA molecule of any of claims 1-14, wherein said targeting domain is 17

nucleotides or more in length.

16. The gRNA molecule of any of claims 1-15, wherein said targeting domain is 18

nucleotides or more in length.

17. The gRNA molecule of any of claims 1-16, wherein said targeting domain is 19

nucleotides or more in length.

18. The gRNA molecule of any of claims 1-17, wherein said targeting domain is 20

nucleotides or more in length.

19. The gRNA molecule of any of claims 1-18, wherein said targeting domain is 21

nucleotides or more in length.

20. The gRNA molecule of any of claims 1-19, wherein said targeting domain is 22

nucleotides or more in length.

21. The gRNA molecule of any of claims 1-20, wherein said targeting domain is 23

nucleotides or more in length.

22. The gRNA molecule of any of claims 1-21, wherein said targeting domain is 24

nucleotides or more in length.

23. The gRNA molecule of any of claims 1-22, wherein said targeting domain is 25

nucleotides or more in length.

24. The gRNA molecule of any of claims 1-23, wherein said targeting domain is 26 nucleotides or more in length.

25. The gRNA molecule of any of claims 1-24, comprising from 5' to 3':

a targeting domain;

a first complementarity domain;

a linking domain;

a second complementarity domain;

a proximal domain; and

a tail domain.

26. The gRNA molecule of any of claims 1-25, comprising:

a linking domain of no more than 25 nucleotides in length;

a proximal and tail domain, that taken together, are at least 20 nucleotides in length; and

a targeting domain of 17 or 18 nucleotides in length.

27. The gRNA molecule of any of claims 1-26, comprising:

a linking domain of no more than 25 nucleotides in length;

a proximal and tail domain, that taken together, are at least 25 nucleotides in length; and

a targeting domain of 17 or 18 nucleotides in length.

28. The gRNA molecule of any of claims 1-27, comprising:

a linking domain of no more than 25 nucleotides in length;

a proximal and tail domain, that taken together, are at least 30 nucleotides in length; and

a targeting domain of 17 nucleotides in length.

29. The gRNA molecule of any of claims 1-28, comprising:

a linking domain of no more than 25 nucleotides in length;

a proximal and tail domain, that taken together, are at least 40 nucleotides in length; and

a targeting domain of 17 nucleotides in length.

30. A nucleic acid that comprises: (a) sequence that encodes a gRNA molecule comprising a targeting domain that is complementary with an SCD target domain in the HBB gene or BCL11A gene.

31. The nucleic acid of claim 30, wherein said gRNA molecule is a gRNA molecule of any of claims 1-29.

32. The nucleic acid of claim 30 or 31, wherein said targeting domain is configured to

provide a cleavage event selected from a double strand break and a single strand break, within 500, 400, 300, 200, 100, 50, 25, or 10 nucleotides of the SCD target point position or the SCD target knockout position.

33. The nucleic acid of any of claims 30-32, wherein said targeting domain is configured to target an early coding region or an enhancer region of the BCL11A gene.

34. The nucleic acid of any of claims 30-32, wherein said targeting domain is configured to target a mutation in the HBB gene.

35. The nucleic acid of claim 30 or 31, wherein said targeting domain is configured to target an enzymatically inactive Cas9 (eiCas9) or an eiCas9 fusion protein, sufficiently close to an SCD target knockdown position to reduce, decrease or repress expression of the BCL11A gene.

36. The nucleic acid of claim 30, 31, or 35, wherein said targeting domain is configured to target the promoter region of the BCL11A gene.

37. The nucleic acid of any of claims 30-36, wherein said targeting domain comprises or consists of a sequence that is the same as, or differs by no more than 3 nucleotides from, a targeting domain sequence from any of Tables 1A-1D, 2A-2F, 3A-3C, 4A-4E, 5A-5E, 6A-6B, 7A-7D, 8A-8D, 9, 10A-10D, 11A-11D, 12, 13A-13D, 14A-14C, 15A-15D, 16A- 16E, 17A-17B, 18A-18C, 19A-19E, 20A-20C, 21A-21E, 22A-22E, 23A-23C, 24A-24D, 25A-25B, 26, or 31.

38. The nucleic acid of any of claims 30-36, wherein said targeting domain comprises or consists of a sequence that is the same as a targeting domain sequence from any of Tables 1A-1D, 2A-2F, 3A-3C, 4A-4E, 5A-5E, 6A-6B, 7A-7D, 8A-8D, 9, 10A-10D, 11A-11D, 12, 13A-13D, 14A-14C, 15A-15D, 16A-16E, 17A-17B, 18A-18C, 19A-19E, 20A-20C, 21A-21E, 22A-22E, 23A-23C, 24A-24D, 25A-25B, 26, or 31.

39. The nucleic acid of any of claims 30-38, wherein said gRNA is a modular gRNA molecule.

40. The nucleic acid of any of claims 30-38, wherein said gRNA is a chimeric gRNA

molecule.

41. The nucleic acid of any of claims 30-40, wherein said targeting domain is 16 nucleotides or more in length.

42. The nucleic acid of any of claims 30-41, wherein said targeting domain is 17 nucleotides in length.

43. The nucleic acid of any of claims 30-42, wherein said targeting domain is 18 nucleotides in length.

44. The nucleic acid of any of claims 30-43, wherein said targeting domain is 19 nucleotides in length.

45. The nucleic acid of any of claims 30-44, wherein said targeting domain is 20 nucleotides in length.

46. The nucleic acid of any of claims 30-45, wherein said targeting domain is 21 nucleotides in length.

47. The nucleic acid of any of claims 30-46, wherein said targeting domain is 22 nucleotides in length.

48. The nucleic acid of any of claims 30-47, wherein said targeting domain is 23 nucleotides in length.

49. The nucleic acid of any of claims 30-48, wherein said targeting domain is 24 nucleotides in length.

50. The nucleic acid of any of claims 30-49, wherein said targeting domain is 25 nucleotides in length.

51. The nucleic acid of any of claims 30-50, wherein said targeting domain is 26 nucleotides in length.

52. The nucleic acid of any of claims 30-51, comprising from 5' to 3' :

a targeting domain;

a first complementarity domain;

a linking domain;

a second complementarity domain; a proximal domain; and

a tail domain.

53. The nucleic acid of any of claims 30-52, comprising:

a linking domain of no more than 25 nucleotides in length;

a proximal and tail domain, that taken together, are at least 20 nucleotides in length; and a targeting domain of 17 or 18 nucleotides in length.

54. The nucleic acid of any of claims 30-53, comprising:

a linking domain of no more than 25 nucleotides in length;

a proximal and tail domain, that taken together, are at least 30 nucleotides in length; and a targeting domain of 17 or 18 nucleotides in length.

55. The nucleic acid of any of claims 30-54, comprising:

a linking domain of no more than 25 nucleotides in length;

a proximal and tail domain, that taken together, are at least 30 nucleotides in length; and a targeting domain of 17 nucleotides in length.

56. The nucleic acid of any of claims 30-55, comprising:

a linking domain of no more than 25 nucleotides in length;

a proximal and tail domain, that taken together, are at least 40 nucleotides in length; and a targeting domain of 17 nucleotides in length.

57. The nucleic acid of any of claims 30-56, further comprising: (b) sequence that encodes a Cas9 molecule.

58. The nucleic acid of claim 57, wherein said Cas9 molecule is an eaCas9 molecule.

59. The nucleic acid of claim 58, wherein said eaCas9 molecule comprises a nickase

molecule.

60. The nucleic acid of claim 58, wherein said eaCas9 molecule forms a double strand break in a target nucleic acid.

61. The nucleic acid of any of claims 58-59, wherein said eaCas9 molecule forms a single strand break in a target nucleic acid.

62. The nucleic acid of any of claims 58-59 or 61, wherein said single strand break is formed in the strand of the target nucleic acid to which the targeting domain of said gRNA molecule is complementary.

63. The nucleic acid of any of claims 58-59 or 61, wherein said single strand break is formed in the strand of the target nucleic acid other than the strand to which to which the targeting domain of said gRNA is complementary.

64. The nucleic acid of any of claims 58-59 or 61, wherein said eaCas9 molecule comprises HNH-like domain cleavage activity but has no, or no significant, N-terminal RuvC-like domain cleavage activity.

65. The nucleic acid of any of claims 58-59, 61, or 64, wherein said eaCas9 molecule is an HNH-like domain nickase.

66. The nucleic acid of any of claims 58-59, 61, 64, or 65, wherein said eaCas9 molecule comprises a mutation at D10.

67. The nucleic acid of any of claims 58-59 or 61, wherein said eaCas9 molecule comprises N-terminal RuvC-like domain cleavage activity but has no, or no significant, HNH-like domain cleavage activity.

68. The nucleic acid of any of claims 58-59, 61, or 67, wherein said eaCas9 molecule is an N-terminal RuvC-like domain nickase.

69. The nucleic acid of any of claims 58-59, 61, 67, or 68, wherein said eaCas9 molecule comprises a mutation at H840 or N863.

70. The nucleic acid of claim 57, wherein said Cas9 molecule is an eiCas9 molecule.

71. The nucleic acid of claim 70, wherein said Cas9 molecule is an eiCas9-fusion protein molecule.

72. The nucleic acid of claim 70 or 71, wherein the eiCas9 fusion protein molecule is an eiCas9-transcription repressor domain fusion or eiCas9-chromatin modifying protein fusion.

73. The nucleic acid of any of claims 30-71, further comprising: (c) sequence that encodes a second gRNA molecule described herein having a targeting domain that is

complementary to a second target domain of the HBB gene or BCL11A gene.

74. The nucleic acid of claim 73, wherein said second gRNA molecule is a gRNA molecule of any of claims 1-29.

75. The nucleic acid of claim 73 or 74, wherein said targeting domain of said second gRNA molecule is configured to provide a cleavage event selected from a double strand break and a single strand break, within 500, 400, 300, 200, 100, 50, 25, or 10 nucleotides of the SCD target point position or the SCD target knockout position.

76. The nucleic acid of any of claims 73-75, wherein said targeting domain of said second gRNA molecule is configured to target an early coding region or an enhancer regin of the BCL11A gene.

77. The nucleic acid of any of claims 73-75, wherein said targeting domain of said second gRNA molecule is configured to target a mutation in the HBB gene.

78. The nucleic acid of claim 73 or 74, wherein said targeting domain of said second gRNA molecule is configured to target an enzymatically inactive Cas9 (eiCas9) or an eiCas9 fusion protein, sufficiently close to an SCD target knockdown position to reduce, decrease or repress expression of the BCL11A gene.

79. The nucleic acid of claim 73, 74, or 78, wherein said targeting domain of said second gRNA molecule is configured to target the promoter region of the BCL11A gene.

80. The nucleic acid of any of claims 73-79, wherein said targeting domain of said second gRNA molecule comprises or consists of a sequence that is the same as, or differs by no more than 3 nucleotides from, a targeting domain sequence from any of Tables 1A-1D, 2A-2F, 3A-3C, 4A-4E, 5A-5E, 6A-6B, 7A-7D, 8A-8D, 9, 10A-10D, 11A-11D, 12, 13A- 13D, 14A-14C, 15A-15D, 16A-16E, 17A-17B, 18A-18C, 19A-19E, 20A-20C, 21A-21E, 22A-22E, 23A-23C, 24A-24D, 25A-25B, 26, or 31.

81. The nucleic acid of any of claims 73-79, wherein said targeting domain of said second gRNA molecule comprises or consists of a sequence that is the same as a targeting domain sequence from any of Tables 1A-1D, 2A-2F, 3A-3C, 4A-4E, 5A-5E, 6A-6B, 7A- 7D, 8A-8D, 9, 10A-10D, 11A-11D, 12, 13A-13D, 14A-14C, 15A-15D, 16A-16E, 17A- 17B, 18A-18C, 19A-19E, 20A-20C, 21A-21E, 22A-22E, 23A-23C, 24A-24D, 25A-25B, 26, or 31.

82. The nucleic acid of any of claims 73-81, wherein said second gRNA molecule is a

modular gRNA molecule.

83. The nucleic acid of any of claims 73-81, wherein said second gRNA molecule is a

chimeric gRNA molecule.

84. The nucleic acid of any of claims 73-83, wherein said targeting domain of the second gRNA molecule is 16 nucleotides or more in length.

85. The nucleic acid of any of claims 73-84, wherein said targeting domain of the second gRNA molecule is 17 nucleotides in length.

86. The nucleic acid of any of claims 73-85, wherein said targeting domain of the second gRNA molecule is 18 nucleotides in length.

87. The nucleic acid of any of claims 73-86, wherein said targeting domain of the second gRNA molecule is 19 nucleotides in length.

88. The nucleic acid of any of claims 73-87, wherein said targeting domain of the second gRNA molecule is 20 nucleotides in length.

89. The nucleic acid of any of claims 73-88, wherein said targeting domain of the second gRNA molecule is 21 nucleotides in length.

90. The nucleic acid of any of claims 73-89, wherein said targeting domain of the second gRNA molecule is 22 nucleotides in length.

91. The nucleic acid of any of claims 73-90, wherein said targeting domain of the second gRNA molecule is 23 nucleotides in length.

92. The nucleic acid of any of claims 73-91, wherein said targeting domain of the second gRNA molecule is 24 nucleotides in length.

93. The nucleic acid of any of claims 73-92, wherein said targeting domain of the second gRNA molecule is 25 nucleotides in length.

94. The nucleic acid of any of claims 73-93, wherein said targeting domain of the second gRNA molecule is 26 nucleotides in length.

95. The nucleic acid of any of claims 73-94, wherein said second gRNA molecule comprises from 5' to 3':

a targeting domain;

a first complementarity domain;

a linking domain;

a second complementarity domain;

a proximal domain; and

a tail domain.

96. The nucleic acid of any of claims 73-95, wherein said second gRNA molecule comprises: a linking domain of no more than 25 nucleotides in length;

97. The nucleic acid of any of claims 73-96, wherein said second molecule gRNA molecule comprises:

a linking domain of no more than 25 nucleotides in length;

a proximal and tail domain, that taken together, are at least 25 nucleotides in length; and a targeting domain of 17 or 18 nucleotides in length.

98. The nucleic acid of any of claims 73-97, wherein said second gRNA molecule comprises: a linking domain of no more than 25 nucleotides in length;

99. The nucleic acid of any of claims 73-98, wherein said second gRNA molecule comprises: a linking domain of no more than 25 nucleotides in length;

100. The nucleic acid of any of claims 73-99, further comprising a third gRNA

molecule.

101. The nucleic acid of claim 100, further comprising a fourth gRNA molecule.

102. The nucleic acid of any of claims 30-72, wherein said nucleic acid does not

comprise (c) a sequence that encodes a second gRNA molecule.

103. The nucleic acid 102, wherein each of (a) and (b) is present on the same nucleic acid molecule.

104. The nucleic acid of claim 103, wherein said nucleic acid molecule is an AAV vector.

105. The nucleic acid of any of claims 57-102, wherein: (a) is present on a first nucleic acid molecule; and (b) is present on a second nucleic acid molecule.

106. The nucleic acid of claim 105, wherein said first and second nucleic acid

molecules are AAV vectors.

107. The nucleic acid of any of claims 73-101 or 103-106, wherein each of (a) and (c) is present on the same nucleic acid molecule.

108. The nucleic acid of claim 107, wherein said nucleic acid molecule is an AAV vector.

109. The nucleic acid of any of claims 73-101 or 103-106, wherein: (a) is present on a first nucleic acid molecule; and (c) is present on a second nucleic acid molecule.

110. The nucleic acid of claim 109, wherein said first and second nucleic acid

molecules are AAV vectors.

111. The nucleic acid of any of claims 72-101, 103, 104, 107, or 108, wherein each of (a), (b), and (c) are present on the same nucleic acid molecule.

112. The nucleic acid of claim 111, wherein said nucleic acid molecule is an AAV vector.

113. The nucleic acid of any of claims 73-101 or 103-110, wherein:

one of (a), (b), and (c) is encoded on a first nucleic acid molecule; and

and a second and third of (a), (b), and (c) is encoded on a second nucleic acid molecule.

114. The nucleic acid of claim 113, wherein said first and second nucleic acid

molecules are AAV vectors.

115. The nucleic acid of any of claims 73-101, 105, 106, 109, 110, 113, or 114,

wherein: (a) is present on a first nucleic acid molecule; and (b) and (c) are present on a second nucleic acid molecule.

116. The nucleic acid of claim 115, wherein said first and second nucleic acid

molecules are AAV vectors.

117. The nucleic acid of any of claims 73-101, 105-108, 113, or 114, wherein: (b) is present on a first nucleic acid molecule; and (a) and (c) are present on a second nucleic acid molecule.

118. The nucleic acid of claim 117, wherein said first and second nucleic acid

molecules are AAV vectors.

119. The nucleic acid of any of claims 73-101, 103, 104, 109, 110, 113, or 114,

wherein: (c) is present on a first nucleic acid molecule; and (b) and (a) are present on a second nucleic acid molecule.

120. The nucleic acid of claim 119, wherein said first and second nucleic acid

molecules are AAV vectors.

121. The nucleic acid of any of claims 105, 109, 113, 115, 117, or 119, wherein said first nucleic acid molecule is other than an AAV vector and said second nucleic acid molecule is an AAV vector.

122. The nucleic acid of any of claims 30-121, wherein said nucleic acid comprises a promoter operably linked to the sequence that encodes said gRNA molecule of (a).

123. The nucleic acid of any of claims 73-101 or 103-122, wherein said nucleic acid comprises a second promoter operably linked to the sequence that encodes the second gRNA molecule of (c).

124. The nucleic acid of claim 123, wherein the promoter and second promoter differ from one another.

125. The nucleic acid of claim 123, wherein the promoter and second promoter are the same.

126. The nucleic acid of any of claims 73-125, wherein said nucleic acid comprises a promoter operably linked to the sequence that encodes the Cas9 molecule of (b).

127. A composition comprising the (a) gRNA molecule of any of claims 1-29.

128. The composition of claim 127, further comprising (b) a Cas9 molecule of any of claims 57-72.

129. The composition of any of claims 127-128, further comprising (c) a second gRNA molecule of any of claims 73-99.

130. The composition of claim 129, further comprising a third gRNA molecule.

131. The composition of claim 130, further comprising a fourth gRNA molecule.

132. A method of altering a cell comprising contacting said cell with:

(a) a gRNA of any of claims 1-29;

(b) a Cas9 molecule of any of claims 57-72;

optionally, (c) a second gRNA molecule of any of claims 73-99; and

optionally, (d) a template nucleic acid.

133. The method of claim 132, wherein the gRNA targets the HBB gene and no

exogenous template nucleic acid is contacted with the cell.

134. The method of claim 132 or 133, further comprising contacting said cell with a third gRNA molecule.

135. The method of claim 134, further comprising contacting said cell with a fourth gRNA molecule.

136. The method of claim 132 or 133, comprising contacting said cell with (a), (b), (c), and optionally (d).

137. The method of any of claims 132-136, wherein said gRNA molecule of (a) is selected from any of claims 1-29.

138. The method of any of claims 132-137, wherein said cell is from a subject

suffering from SCD.

139. The method of any of claims 132-138, wherein said cell is from a subject having a mutation at an SCD target position in the HBB gene or from a subject which would benefit from having a mutation at an SCD target position in the BCLllA gene.

140. The method of any of claims 132- 139, wherein said cell is an erythroid cell.

141. The method of any of claims 132- 139, wherein said cell is a bone marrow cell.

142. The method of any of claims 132- 139, wherein said cell is a stem cell.

143. The method of any of claims 132- 142, wherein said contacting step is performed ex vivo.

144. The method of any of claims 132- 143, wherein said contacted cell is returned to said subject's body.

145. The method of any of claims 132- 142, wherein said contacting is performed in vivo.

146. The method of any of claims 132- 145, wherein said cell is from a subject that has

SCD.

147. The method of any of claims 132- 146, comprising acquiring knowledge of the sequence of the SCD target position in said cell.

148. The method of claim 147, comprising acquiring knowledge of the sequence of the SCD target position in said cell by sequencing a portion of the HBB gene or BCLllA gene.

149. The method of any of claims 132-148, comprising correcting a mutation or

introducing a mutation at the SCD target position.

150. The method of any of claims 132-149, wherein the contacting step comprises contacting said cell with a nucleic acid that encodes at least one of (a), (b), (c) and (d).

151. The method of any of claims 132-150, wherein the contacting step comprises contacting the cell with a nucleic acid of any of claims 30-126.

152. The method of any of claims 132-151, wherein the contacting step comprises delivering to said cell said Cas9 molecule of (b) and a nucleic acid which encodes and (a) and optionally (c) and/or (d).

153. The method of any of claims 132-151, wherein the contacting step comprises delivering to said cell said Cas9 molecule of (b), said gRNA molecule of (a) and optionally said second gRNA molecule of (c).

154. The method of any of claims 132-151, wherein the contacting step comprises delivering to said cell said gRNA molecule of (a), optionally said second gRNA molecule of (c) and a nucleic acid that encodes the Cas9 molecule of (b).

155. A method of treating a subject, comprising contacting a subject or a cell from said subject with:

(a) a gRNA of any of claims 1-29;

(b) a Cas9 molecule of any of claims 57-72;

optionally, (c) a second gRNA of any of claims 73-99; and

optionally, (d) a template nucleic acid.

156. The method of claim 155, wherein the gRNA targets the HBB gene and no

exogenous template nucleic acid is contacted with the subject or a cell from the subject.

157. The method of claim 155, further comprising contacting the subject or a cell from the subject with a third gRNA molecule.

158. The method of claim 157, further comprising contacting the subject or a cell from the subject with a fourth gRNA molecule.

159. The method of any one of claims 155-158, further comprising contacting said subject or a cell from said subject with (a), (b), (c), and optionally (d).

160. The method of claims any one of claims 155-159, wherein said subject is

suffering from SCD.

161. The method of any of claims 155-160, wherein said subject has a mutation at the SCD target position in the HBB gene or would benefit from having a mutation at the SCD target position in the BCL11A gene.

162. The method of any of claims 155-161, comprising acquiring knowledge of the sequence of the SCD target position in said subject.

163. The method of claim 162, comprising acquiring knowledge of the sequence of the SCD target position in said subject by sequencing a portion of the HBB gene or BCLllA gene.

164. The method of claim 155-163, comprising correcting a mutation at the SCD target position in the HBB gene or introducing a mutation at the SCD target position in the BCLllA gene.

165. The method of any of claims 155-164, wherein a cell of said subject is contacted ex vivo with (a), (b), and optionally (c) and/or (d).

166. The method of claim 165, wherein said cell is returned to the subject's body.

167. The method of any of claims 155-164, comprising introducing a cell into said subject's body, wherein said cell is contacted ex vivo with (a), (b), and optionally (c) and/or (d).

168. The method of any of claims 155-164, wherein said contacting step is performed in vivo.

169. The method of any of claims 155-164 or 168, wherein said contacting step

comprises intravenous delivery.

170. The method of any of claims 155-164 or 168, wherein said contacting step

comprises intramuscular injection.

171. The method of any of claims 155-164 or 168, wherein said contacting step

comprises subcutaneous delivery.

172. The method of any of claims 155-164 or 168, wherein said contacting step

comprises intra-bone marrow (IBM) injection.

173. The method of any of claims 155-164 or 168-172, comprising contacting said subject or a cell from said subject with a nucleic acid that encodes at least one of (a), (b), and (c).

174. The method of any of claims 155-164 or 168-173, comprising contacting said subject or a cell from said subject with a nucleic acid of any of any of claims 30-126.

175. The method of any of claims 155-174, wherein the contacting step comprises delivering to said subject or a cell from said subject said Cas9 molecule of (b) and a nucleic acid which encodes and (a) and optionally (c), and optionally (d).

176. The method of any of claims 155-175, wherein the contacting step comprises delivering to said subject or a cell from said subject said Cas9 molecule of (b), said gRNA of (a) and optionally said second gRNA of (c), and optionally said template nucleic acid of (d).

177. The method of any of claims 155-176, wherein the contacting step comprises delivering to said subject or a cell from said subject said gRNA of (a), optionally said second gRNA of (c) and a nucleic acid that encodes the Cas9 molecule of (b).

178. A reaction mixture comprising a gRNA, a nucleic acid, or a composition

described herein, and a cell from a subject having SCD, a subject having a mutation at an SCD target position of the HBB gene, or a subject which would benefit from having a mutation at an SCD target position of the BCL11A gene.

179. A kit comprising, (a) gRNA molecule of any of claims 1-29, or nucleic acid that encodes said gRNA, and one or more of the following:

(b) a Cas9 molecule of any of claims 57-72;

(c) a second gRNA molecule of any of claims 73-99;

(d) a template nucleic acid; and

(e) nucleic acid that encodes one or more of (b) and (c).

180. The kit of claim 179, comprising a nucleic acid that encodes one or more of (a), (b) (c) and (d).

181. The kit of claim 179 or 180, further comprising a third gRNA molecule targeting a SCD target point position or a SCD target knockout position.

182. The kit of claim 181, further comprising a fourth gRNA molecule targeting a SCD target point position or a SCD target knockout position.

183. A gRNA molecule of any of claims 1-29 for use in treating SCD in a subject.

184. The gRNA molecule of claim 183, wherein the gRNA molecule is used in

combination with (b) a Cas9 molecule of any of claims 57-72.

185. The gRNA molecule of claim 183 or 184, wherein the gRNA molecule is used in combination with (c) a second gRNA molecule of any of claims 73-99.

186. Use of a gRNA molecule of any of claims 1-29 in the manufacture of a

medicament for treating SCD in a subject.

187. The use of claim 186, wherein the medicament further comprises (b) a Cas9 molecule of any of claim 57-72.

188. The use of claim 186 or 187, wherein the medicament further comprises (c) a second gRNA molecule of any of claim 73-99.

189. A composition of any of claims 127-131 for use in treating SCD in a subject.