WO2001088124A2 - Method and reagent for the inhibition of erg - Google Patents

Abstract

Nucleic acid molecules, including antisense and enzymatic nucleic acid molecules, such as hammerhead ribozymes, DNAzymes, and GeneBlocs, which modulate the expression of ERG (Ets-related gene).

Description

DESCRIPTION

METHOD AND REAGENT FOR THE INHIBITION OF ERG

Background Of The Invention

The present invention concerns compounds, compositions, and methods for the study, diagnosis, and treatment of conditions and diseases related to the expression of Erg (Ets-related- gene).

The following is a brief description of the current understanding of Erg. The discussion is not meant to be complete and is provided only for understanding the invention that follows. The summary is not an admission that any of the work described below is prior art to the claimed invention.

Erg is a member of the Ets oncogene superfamily of transcription factors which share common DNA binding domains yet differ in their transactivation domains. The Ets family of transcription factors are implicated in the control of the constitutive expression of a wide variety of genes. In hematopoietic cells, the Ets family appears to be important in the early stages of lymphocyte cell-type specification. Erg has been identified during arrayed cDNA library screens for genes encoding transcription factors expressed specifically during T cell lineage commitment. Erg expression is induced during T-cell lineage specification and is subsequently silenced permanently (Anderson et al, 1999, Development, 126(14), 3131-3148). Erg is rearranged in human myeloid leukemia with t(16;21) chromosomal translocation. This rearrangement generates the TLS-Erg oncogene which is associated with poor prognosis human acute myeloid leukemia (AML), secondary AML associated with myelodysplastic syndrom (MDS), and chronic myeloid leukemia (CML) in blast crisis (Kong et al.,1997, Blood, 90, 1192-1199). The altered transcriptional activating and DNA-binding activities of the TLS-Erg gene product are implicated in the genesis or progression of t(16;21))-associated human myeloid leukemias (Prasad et al, 1994, Oncogene, 9, 3717-3729). In addition, retroviral transduction of TLS-Erg has been shown to initiate a leukemogenic program in normal human hematopoietic cells (Pereira et al, 1998, PNAS USA, 95, 8239-8244).

The expression of several members of the Ets family of transcription factors, including Erg, correlates with the occurrence of invasive processes such as angiogenesis, including" endothelial cell proliferation, endothelial cell differentiation, and matrix metalloproteinase transduction, during normal and pathological development (for review see Mattot et al, 1999, J. Soc. Biol, 193(2), 147-153 and Soncin et al, 1999, Pathol Biol, 47(4), 358-363). Ets family transcription factors, including Erg, have been implicated in the upregulation of human heme oxygenase gene expression. Overexpression of human heme oxygenase-1 has been shown to have the potential to promote endothelial cell proliferation and angiogenesis. Ets binding sites in regulatory sequences of heme oxygenase-1 have been identified. As such, Ets family trascriptional regulation of human heme oxygenase may play an important role in coronary collateral circulation, tumor growth, angiogenesis, and hemoglobin induced endothelial cell injury (Deramaudt et al, 1999, J. Cell. Biochem., 72(3), 311-321).

The Ets, Fos, and Jun transciption factors control the expression of stromelysin-1 and collagenase-1 genes that encode two matrix metalloproteinases implicated in normal growth and development, as well as in tumor invasion and metastasis. It has been shown that the Ets transcription factors interact with each other and with the c-Fos/c-Jun complex via distinct protein domains in both a DNA-dependent and independent manner (Basuyaux et al, 1997, J. Biol. Chem., 272(42), 26188-95). Moreover, Erg activates collagenase-1 gene by physically interacting with c-Fos/c-Jun (Buttice et al, 1996, Oncogene, 13(11), 2297-2306). Altered expression of Erg is associated with genetic translocations on chromosome 21 in immortal and cervical carcinoma cell lines (Simpson et al, 1997, Oncogene, 14(18), 2149-2157). An additional translocation fusion product of Erg, EWS-Erg, has been identified in a large proportion of Ewing family tumors as a transcriptional activator (Sorensen et al, 1994, Nat. Genet, 6(2), 146-151). Expression of the EWS-Erg fusion protein has been shown to be essential for maintaining the oncogenic and tumorigenic properties of certain human tumor cells via inhibition of apoptosis (Yi et al, 1997, Oncogene, 14(11), 1259-1268). Hart et al, 1995, Oncogene, 10(7), 1423-30, describe human Erg as a proto-oncogene with mitogenic and transforming activity. Transfection of NTH3T3 cells with an Erg expression construct driven by the sheep metallothionein la promoter (sMTERG) results in cells that become morphologically altered, non-serum and non-anchorage dependant, and result in the formation of solid tumors when injected in nude mice (Hart et al, supra).

The endothelium, which lines the blood vessels and acts as a barrier between blood and tissues, plays an important role in maintaining vascular homeostasis. The endothelium regulates processes such as leukocyte infiltration, coagulation, and maintains the integrity of cell-cell junctions. Proliferation of endothelial cells, which occurs in angiogenesis, is a tightly controlled process that can occur in a physiological state (e.g.; in wound healing and the menstrual cycle) but also occurs in a disease. Endothelial activation is involved in diseases such as cancer and metastasis, rheumatoid arthritis, cataract formation, atherosclerosis, thrombosis and many others. Inflammatory mediators such as the pleiotropic cytokine TNF-alpha alter the resting phenotype of the endothelium such that it becomes pro-inflammatory, pro-thrombotic and often pro- angiogenic. The ensuing changes in gene regulation have been extensively studied and involve the up-regulation of inflammatory cell adhesion molecules ICAM-1, E-selectin and NCAM-1 and pro-thrombotic proteins such as tissue factor, both in vitro and in vivo (McEver, 1991, Thrombosis and Haemostasis, 65, 223; Saadi et al, 1995, J. Exp. Med, 182, 1807). The role of TNF-alpha in modulating angiogenesis has been demonstrated in vivo but the evidence of an effect in vitro is less clear and in some cases conflicting. TNF-alpha is pro-angiogenic in rabbit corneal and chick chorioallantoic membrane in vivo models (Frater-Schroder et al, 1987, PNAS USA, 84, 5277; Leibovich et al, 1987, Nature, 329, 630) and more recently in rheumatoid arthritis patients, anti-TNF-alpha therapy decreased circulating levels of vascular endothelial growth factor (VEGF) (Paleolog, 1997, Molecular Pathology, 50, 225). In vitro, TNF-alpha can induce basic fibroblast growth factor (bFGF), platelet activated factor (PAF) and urokinase-type plasminogen activator (u-TPA), all of which are angiogenic and increase transcription of the VEGF receptor (VEGFR-2). On the contrary, TNF-alpha can also inhibit endothelial cell proliferation in vitro and cause tumor regression (Carswell et al, 1975, PNAS USA, 72, 3666). The mechanisms by which TNF-alpha mediates these effects on cell proliferation/angiogenesis are unclear and may involve regulation of genes which are not involved in the pro-inflammatory mode of action of this cytokine.

Studies on the effects of TNF-alpha on endothelial genes have shown that TNF-alpha down-regulates the transcription factor Erg in human umbilical vein endothelial cells (HUVEC) (McLaughlin et al, 1999, J. of Cell Science, 112, 4695). Erg is a member of the Ets family of transcription factors which play roles in embryonic development, inflammation, and cellular transformation. An 85 amino acid Ets domain is conserved throughout the family and is necessary for binding a GGAA core DNA binding site. Erg is a proto-oncogene as shown by the ability of NLH3T3 cells overexpressing Erg to form solid tumors in nude mice. Although downstream targets of Erg have not been clearly identified, in vitro evidence exists which suggests that an Erg cDNA can transactivate the vWF, ICAM-2, VE-Cadherin and collagenase promoters using reporter gene assays and purified Erg/GST protein or Erg from endothelial cell nuclear extracts can bind to the VE-Cadherin, stromelysin and vWF promoter Ets sites (McLaughlin et al, supra).

Yang and Ohno, 1998, Gifu Daigaku Igakubu Kiyo, 46(1), 20-25, describe the basic study of ribozyme gene therapy targeting the EWS/FLi-1 chimeric gene associated with Ewing's sarcoma.

Yi et al, 1997, Oncogene, 14(11), 1259-1268, describe, in general terms, antisense directed against EWS/FLi-1 and EWS/Erg expression leading to increased susceptibility to apoptosis leading to cell death in certain tumor cells.

Ouchida et al, 1995, Oncogene, 11(6), 1049-54, describe the expression of EWS fusion transcripts through transfection of Ewing's sarcoma cells with antisense EWS/FLi-1 and EWS/Erg expression plasmids. Cells expressing antisense EWS fusion transcipts showed loss of anchorage independent growth and tumorigenicity in nude mice, unlike parental Ewing's sarcoma cells.

Summary Of The Invention

The invention features novel nucleic acid-based techniques [e.g., enzymatic nucleic acid molecules (ribozymes), antisense nucleic acids, 2-5A antisense chimeras, triplex DNA, antisense nucleic acids containing RNA cleaving chemical groups] and methods for their use to modulate the expression of ERG gene.

The description below of the various aspects and embodiments is provided with reference to the exemplary gene ERG. However, the various aspects and embodiments are also directed to other genes which express ERG-like transcription factors. Those additional genes can be analyzed for target sites using the methods described for ERG. Thus, the inhibition and the effects of such inhibition of the other genes can be performed as described herein.

In a preferred embodiment, the invention features the use of one or more of the nucleic acid-based techniques independently or in combination to inhibit the expression of the genes encoding ERG. Specifically, the invention features the use of nucleic acid-based techniques to specifically inhibit the expression of ERG gene (GenBank accession Nos. NM_004449, M21535,

M17390, M98833, X67001, S44250, M93255, NM_002017, S45205).

In preferred embodiments, the invention features the use of one or more of the nucleic acid-based techniques independently or in combination to inhibit the expression of the genes encoding ERG fusion genes, for example EWS/ERG (GenBank accession Nos. S82338, S82335,

S73762, S72865, S72622, S72621, S70593, S70579), FUS/ERG (GenBank accession Nos.

AB028209, Y10001), and TLS/ERG (GenBank accession No. S77574).

In another preferred embodiment, the invention features the use of an enzymatic nucleic acid molecule, preferably in the hammerhead, NCH (Inozyme), G-cleaver, amberzyme, zinzyme and/or DNAzyme motif, to inhibit the expression of ERG gene and ERG fusion gene.

By "inhibit" it is meant that the activity of ERG or level of RNAs or equivalent RNAs encoding one or more protein subunits of ERG is reduced below that observed in the absence of the nucleic acid molecules of the invention. In one embodiment, inhibition with enzymatic nucleic acid molecule preferably is below that level observed in the presence of an enzymatically inactive or attenuated molecule that is able to bind to the same site on the target RNA, but is unable to cleave that RNA. In another embodiment, inhibition with antisense oligonucleotides is preferably below that level observed in the presence of, for example, an oligonucleotide with scrambled sequence or with mismatches. In another embodiment, inhibition of ERG genes with the nucleic acid molecule of the instant invention is greater than in the presence of the nucleic acid molecule than in its absence.

By "enzymatic nucleic acid molecule" it is meant a nucleic acid molecule which has complementarity in a substrate binding region to a specified gene target, and also has an enzymatic activity which is active to specifically cleave target RNA. That is, the enzymatic nucleic acid molecule is able to intermolecularly cleave RNA and thereby inactivate a target RNA molecule. These complementary regions allow sufficient hybridization of the enzymatic nucleic acid molecule to the target RNA and thus permit cleavage. One hundred percent complementarity is preferred, but complementarity as low as 50-75% may also be useful in this invention. The nucleic acids may be modified at the base, sugar, and/or phosphate groups. The term enzymatic nucleic acid is used interchangeably with phrases such as ribozymes, catalytic RNA, enzymatic RNA, catalytic DNA, aptazyme or aptamer-binding ribozyme, regulatable ribozyme, catalytic oligonucleotides, nucleozyme, DNAzyme, RNA enzyme, endoribonuclease, endonuclease, minizyme, leadzyme, oligozyme or DNA enzyme. All of these terminologies describe nucleic acid molecules with enzymatic activity. The specific enzymatic nucleic acid molecules described in the instant application are not meant to be limiting and those skilled in the art will recognize that all that is important in an enzymatic nucleic acid molecule of this invention is that it have a specific substrate binding site which is complementary to one or more of the target nucleic acid regions, and that it have nucleotide sequences within or surrounding that substrate binding site which impart a nucleic acid cleaving activity to the molecule (Cech et al, U.S. Patent No. 4,987,071; Cech et al, 1988, JAMA).

By "nucleic acid molecule" as used herein is meant a molecule having nucleotides. The nucleic acid can be single, double, or multiple stranded and may comprise modified or unmodified nucleotides or non-nucleotides or various mixtures and combinations thereof.

By "enzymatic portion" or "catalytic domain" is meant that portion/region of the enzymatic nucleic acid molecule essential for cleavage of a nucleic acid substrate (for example, see Figures 2-5).

By "substrate binding arm" or "substrate binding domain" is meant that portion/region of a ribozyme which is complementary to (i.e., able to base-pair with) a portion of its substrate. Generally, such complementarity is 100%, but can be less if desired. For example, as few as 10 bases out of 14 may be base-paired. Examples of such arms are shown generally in Figures 2-5. That is, these arms contain sequences within a ribozyme which are intended to bring ribozyme and target RNA together through complementary base-pairing interactions. The ribozyme of the invention may have binding arms that are contiguous or non-contiguous and may be of varying lengths. The length of the binding arm(s) are preferably greater than or equal to four nucleotides and of sufficient length to stably interact with the target RNA; specifically 12-100 nucleotides; more specifically 14-24 nucleotides long. If two binding arms are chosen, the design is such that the length of the binding arms are symmetrical (i.e., each of the binding arms is of the same length; e.g., five and five nucleotides, six and six nucleotides or seven and seven nucleotides long) or asymmetrical (i.e., the binding arms are of different length; e.g., six and three nucleotides; three and six nucleotides long; four and five nucleotides long; four and six nucleotides long; four and seven nucleotides long; and the like).

By "NCH" or "Inozyme" motif is meant, an enzymatic nucleic acid molecule comprising a motif as described in Ludwig et al, USSN No. 09/406,643, filed September 27, 1999, entitled

"COMPOSITIONS HAVING RNA CLEAVING ACTIVITY", and International PCT publication Nos. WO 98/58058 and WO 98/58057, all incorporated by reference herein in their entirety including the drawings.

By "G-cleaver" motif is meant, an enzymatic nucleic acid molecule comprising a motif as described in Eckstein et al, International PCT publication No. WO 99/16871, incorporated by reference herein in its entirety including the drawings.

By "zinzyme" motif is meant, a class II enzymatic nucleic acid molecule comprising a motif as described in Beigelman et al, International PCT publication No. WO 99/55857, incorporated by reference herein in its entirety including the drawings. Zinzymes represent a non-limiting example of an enzymatic nucleic acid molecule that does not require a ribonucleotide (2'-OH) group within its own nucleic acid sequence for activity.

By "amberzyme" motif is meant, a class I enzymatic nucleic acid molecule comprising a motif as described in Beigelman et al, International PCT publication No. WO 99/55857, incorporated by reference herein in its entirety including the drawings. Amberzymes represent a non-limiting example of an enzymatic nucleic acid molecule that does not require a ribonucleotide (2' -OH) group within its own nucleic acid sequence for activity.

By 'DNAzyme' is meant, an enzymatic nucleic acid molecule that does not require the presence of a ribonucleotide (2' -OH) group within the DNAzyme molecule for its activity. In particular embodiments the enzymatic nucleic acid molecule may have an attached linker(s) or other attached or associated groups, moieties, or chains containing one or more nucleotides with 2'-OH groups. DNAzyme can be synthesized chemically or expressed endogenously in vivo, by means of a single stranded DNA vector or equivalent thereof.

By "sufficient length" is meant an oligonucleotide of greater than or equal to 3 nucleotides that is of a length great enough to provide the intended function under the expected condition. For example, for binding arms of enzymatic nucleic acid "sufficient length" means that the binding arm sequence is long enough to provide stable binding to a target site under the expected binding conditions. Preferably, the binding arms are not so long as to prevent useful turnover.

By "stably interact" is meant, interaction of the oligonucleotides with target nucleic acid (e.g., by forming hydrogen bonds with complementary nucleotides in the target under physiological conditions).

By "equivalent" RNA to ERG is meant to include those naturally occurring RNA molecules having homology (partial or complete) to ERG proteins or encoding for proteins with similar function as ERG in various organisms, including human, rodent, primate, rabbit, pig, protozoans, fungi, plants, and other microorganisms and parasites. The equivalent RNA sequence also includes in addition to the coding region, regions such as 5 '-untranslated region, 3 '-untranslated region, introns, intron-exon junction and the like.

By "homology" is meant the nucleotide sequence of two or more nucleic acid molecules is partially or completely identical.

By "antisense nucleic acid", it is meant a non-enzymatic nucleic acid molecule that binds to target RNA by means of RNA-KNA or RNA-DNA or RNA-PNA (protein nucleic acid; Egholm et al, 1993 Nature 365, 566) interactions and alters the activity of the target RNA (for a review, see Stein and Cheng, 1993 Science 261, 1004 and Woolf et al, US patent No. 5,849,902). Typically, antisense molecules will be complementary to a target sequence along a single contiguous sequence of the antisense molecule. However, in certain embodiments, an antisense molecule may bind to substrate such that the substrate molecule forms a loop, and/or an antisense molecule may bind such that the antisense molecule forms a loop. Thus, the antisense molecule may be complementary to two (or even more) non-contiguous substrate sequences or two (or even more) non-contiguous sequence portions of an antisense molecule may be complementary to a target sequence or both. For a review of current antisense strategies, see Schniajuk et al, 1999, J Biol. Chem., 274, 21783-21789, Delihas et al, 1997, Nature, 15, 751- 753, Stein et al, 1997, Antisense N A. Drug Dev., 7, 151, Crooke, 1998, Biotech. Genet. Eng. Rev., 15, 121-157, Crooke, 1997, Ad. Pharmacol, 40, 1-49. I-n addition, antisense DNA can be used to target RNA by means of DNA-RNA interactions, thereby activating RNase H, which digests the target RNA in the duplex. Antisense DNA can be synthesized chemically or expressed via the use of a single stranded DNA expression vector or equivalent thereof.

By "2-5A antisense chimera" it is meant, an antisense oligonucleotide containing a 5'- phosphorylated 2'-5 '-linked adenylate residue. These chimeras bind to target RNA in a sequence-specific manner and activate a cellular 2-5A-dependent ribonuclease which, in turn, cleaves the target RNA (Torrence et al, 1993 Proc. Natl Acad. Sci. USA 90, 1300).

By "triplex DNA" it is meant an oligonucleotide that can bind to a double-stranded DNA in a sequence-specific manner to form a triple-strand helix. Formation of such triple helix structure has been shown to inhibit transcription of the targeted gene (Duval- Valentin et al, 1992 Proc. Natl. Acad. Sci. USA 89, 504).

By "gene" it is meant a nucleic acid that encodes an RNA.

By "complementarity" is meant that a nucleic acid can form hydrogen bond(s) with another RNA sequence by either traditional Watson-Crick or other non-traditional types. In reference to the nucleic molecules of the present invention, the binding free energy for a nucleic acid molecule with its target or complementary sequence is sufficient to allow the relevant function of the nucleic acid to proceed, e.g., ribozyme cleavage, antisense or triple helix inhibition. Determination of binding free energies for nucleic acid molecules is well known in the art (see, e.g., Turner et al., 1987, CSH Symp. Quant. Biol. LII pp.123-133; Frier et al, 1986, Proc. Nat. Acad. Sci. USA 83:9373-9377; Turner et al, 1987, J. Am. Chem. Soc. 109:3783-3785). A percent complementarity indicates the percentage of contiguous residues in a nucleic acid molecule which can form hydrogen bonds (e.g., Watson-Crick base pairing) with a second nucleic acid sequence (e.g., 5, 6, 7, 8, 9, 10 out of 10 being 50%, 60%, 70%, 80%, 90%, and 100% complementary). "Perfectly complementary" means that all the contiguous residues of a nucleic acid sequence will hydrogen bond with the same number of contiguous residues in a second nucleic acid sequence.

At least seven basic varieties of naturally occurring enzymatic nucleic acids are known presently. Each can catalyze the hydrolysis of RNA phosphodiester bonds in trans (and thus can cleave other RNA molecules) under physiological conditions. Table I summarizes some of the characteristics of these ribozymes. In general, enzymatic nucleic acids act by first binding to a target RNA. Such binding occurs through the target binding portion of a enzymatic nucleic acid which is held in close proximity to an enzymatic portion of the molecule that acts to cleave the target RNA. Thus, the enzymatic nucleic acid first recognizes and then binds a target RNA through complementary base-pairing, and once bound to the correct site, acts enzymatically to cut the target RNA. Strategic cleavage of such a target RNA will destroy its ability to direct synthesis of an encoded protein. After an enzymatic nucleic acid has bound and cleaved its RNA target, it is released from that RNA to search for another target and can repeatedly bind and cleave new targets. Thus, a single ribozyme molecule is able to cleave many molecules of target RNA. In addition, the ribozyme is a highly specific inhibitor of gene expression, with the specificity of inhibition depending not only on the base-pairing mechanism of binding to the target RNA, but also on the mechanism of target RNA cleavage. Single mismatches, or base- substitutions, near the site of cleavage can completely eliminate catalytic activity of a ribozyme.

The enzymatic nucleic acid molecule that cleave the specified sites in ERG-specific RNAs represent a novel therapeutic approach to treat a broad spectrum of oncology and neovascularization-related indications, including but not limited to cancers of the lung, colon, breast, prostate, cervix, lymphoma, Ewing's sarcoma and related tumors, melanoma, angiogenic disease states such as tumor angiogenesis, diabetic retinopathy, macular degeneration, neovascular glaucoma, myopic degeneration, arthritis such as rheumatoid arthritis, psoriasis, verruca vulgaris, angiofibroma of tuberous sclerosis, pot-wine stains, Sturge Weber syndrome, Kippel-Trenaunay- Weber syndrome, Osier- Weber-rendu syndrome, leukemias such as acute myeloid leukemia, osteoporosis, wound healing and other indications that may respond to the level of ERG.

"Angiogenesis" refers to formation of new blood vessels which is an essential process in reproduction, development and would repair. "Tumor angiogenesis" refers to the induction of the growth of blood vessels from surrounding tissue into a solid tumor. Tumor growth and tumor metastasis are dependant on angiogenesis "for a review, see Folkman, 1990, J. Natl. cancer Inst, 82, 4; Folkman and Sing, 1992, J. Biol. Chem., 267, 10931). Angiogenesis plays an important role in other diseases such as arthritis wherein new blood vessels have been shown to invade the joints and degrade cartilage (Folkman and Shing, supra).

In one of the preferred embodiments of the inventions described herein, the enzymatic nucleic acid molecule is formed in a hammerhead or hairpin motif, but may also be formed in the motif of a hepatitis delta virus, group I intron, group II intron or RNase P RNA (in association with an RNA guide sequence), Neurospora VS RNA, DNAzymes, NCH cleaving motifs, or G- cleavers. Examples of such hammerhead motifs are described by Dreyfus, supra, Rossi et al, 1992, AIDS Research and Human Retroviruses 8, 183; Examples of hairpin motifs are described by Hampel et al, EP0360257, Hampel and Tritz, 1989 Biochemistry 28, 4929, Feldstein et al, 1989, Gene 82, 53, Haseloff and Gerlach, 1989, Gene, 82, 43, Hampel et al, 1990 Nucleic Acids Res. 18, 299; Chowrira & McSwiggen, US. Patent No. 5,631,359. The hepatitis delta virus motif is described by Perrotta and Been, 1992 Biochemistry 31, 16. The RNase P motif is described by Guerrier-Takada et al, 1983 Cell 35, 849; Forster and Airman, 1990, Science 249, 783; Li and Altman, 1996, Nucleic Acids Res. 24, 835. Neurospora VS RNA ribozyme motif is described by Collins (Saville and Collins, 1990 Cell 61, 685-696; Saville and Collins, 1991 Proc. Natl. Acad. Sci USA 88, 8826-8830; Collins and Olive, 1993 Biochemistry 32, 2795-2799; Guo and Collins, 1995, EMBO. J 14, 363). Group II introns are described by Griffin et al, 1995, Chem. Biol 2, 761; Michels and Pyle, 1995, Biochemistry 34, 2965; Pyle et al, International PCT Publication No. WO 96/22689. The Group I intron is described by Cech et al, U.S. Patent 4,987,071. DNAzymes are described by Usnian et al., International PCT Publication No. WO 95/11304; Chartrand et al, 1995, NAR 23, 4092; Breaker et al, 1995, Chem. Bio. 2, 655; Santoro et al, 1997, PNAS 94, 4262. NCH cleaving motifs are described in Ludwig & Sproat, International PCT Publication No. WO 98/58058; and G-cleavers are described in Kore et al, 1998, Nucleic Acids Research 26, 4116-4120 and Eckstein et al, International PCT Publication No. WO 99/16871. Additional motifs such as the Aptazyme (Breaker et al, WO 98/43993), Amberzyme (Class I motif; Figure 3; Beigelman et al, International PCT publication No. WO 99/55857) and Zinzyme (Beigelman et al, International PCT publication No. WO 99/55857), all these references are incorporated by reference herein in their totalities, including drawings and can also be used in the present invention. These specific motifs are not limiting in the invention, and those skilled in the art will recognize that all that is important in an enzymatic nucleic acid molecule of this invention is that it has a specific substrate binding site which is complementary to one or more of the target gene RNA regions, and that it have nucleotide sequences within or surrounding that substrate binding site which impart an RNA cleaving activity to the molecule (Cech et al, U.S. Patent No. 4,987,071).

In preferred embodiments of the present invention, a nucleic acid molecule, e.g., an antisense molecule, a triplex DNA, or a ribozyme, is 13 to 100 nucleotides in length, e.g., in specific embodiments 35, 36, 37, or 38 nucleotides in length (e.g., for particular ribozymes or antisense). In particular embodiments, the nucleic acid molecule is 15-100, 17-100, 20-100, 21- 100, 23-100, 25-100, 27-100, 30-100, 32-100, 35-100, 40-100, 50-100, 60-100, 70-100, or 80- 100 nucleotides in length. Instead of 100 nucleotides being the upper limit on the length ranges specified above, the upper limit of the length range can be, for example, 30, 40, 50, 60, 70, or 80 nucleotides. Thus, for any of the length ranges, the length range for particular embodiments has lower limit as specified, with an upper limit as specified which is greater than the lower limit. For example, in a particular embodiment, the length range can be 35-50 nucleotides in length. All such ranges are expressly included. Also in particular embodiments, a nucleic acid molecule can have a length which is any of the lengths specified above, for example, 21 nucleotides in length.

In a preferred embodiment, the invention provides a method for producing a class of nucleic acid-based gene inhibiting agents which exhibit a high degree of specificity for the RNA of a desired target. For example, the enzymatic nucleic acid molecule is preferably targeted to a highly conserved sequence region of target RNAs encoding ERG proteins such that specific treatment of a disease or condition can be provided with either one or several nucleic acid molecules of the invention. Such nucleic acid molecules can be delivered exogenously to specific tissue or cellular targets as required. Alternatively, the nucleic acid molecules (e.g., . ribozymes and antisense) can be expressed from DNA and/or RNA vectors that are delivered to specific cells.

In a preferred embodiment, the invention features the use of nucleic acid-based inhibitors of the invention to specifically target genes that share homology with the ERG gene and ERG fusion genes.

As used herein "cell" is used in its usual biological sense, and does not refer to an entire multicellular organism, e.g., specifically does not refer to a human. The cell may be present in a non-human multicellular organism, e.g., birds, plants and mammals such as cows, sheep, apes, monkeys, swine, dogs, and cats.

By "ERG proteins" is meant, a protein or a mutant protein derivative thereof, comprising an Ets family type transciption factor.

By "highly conserved sequence region" is meant, a nucleotide sequence of one or more regions in a target gene does not vary significantly from one generation to the other or from one biological system to the other.

The nucleic acid-based inhibitors of ERG expression are useful for the prevention and/or treatment of diseases and conditions including a broad spectrum of oncology and neovascularization-related indications, including but not limited to cancers of the lung, colon, breast, prostate, cervix, lymphoma, Ewing's sarcoma and related tumors, melanoma, angiogenic disease states such as tumor angiogenesis, diabetic retinopathy, macular degeneration, neovascular glaucoma, myopic degeneration, arthritis such as rheumatoid arthritis, psoriasis, verruca vulgaris, angiofibroma of tuberous sclerosis, pot-wine stains, Sturge Weber syndrome, Kippel-Trenaunay- Weber syndrome, Osier- Weber-rendu syndrome, leukemias such as acute myeloid leukemia, osteoporosis, wound healing and any other diseases or conditions that are related to or will respond to the levels of ERG in a cell or tissue, alone or in combination with other therapies.

By "related" is meant that the reduction of ERG expression (specifically ERG gene and ERG fusion gene) RNA levels and thus reduction in the level of the respective protein will relieve, to some extent, the symptoms of the disease or condition.

The nucleic acid-based inhibitors of the invention are added directly, or can be complexed with cationic lipids, packaged within liposomes, or otherwise delivered to target cells or tissues.

The nucleic acid or nucleic acid complexes can be locally administered to relevant tissues ex vivo, or in vivo through injection, infusion pump or stent, with or without their incorporation in biopolymers. In preferred embodiments, the enzymatic nucleic acid inhibitors comprise sequences, which are complementary to the substrate sequences in Tables III to VIII. Examples of such enzymatic nucleic acid molecules also are shown in Tables III to VIII. Examples of such enzymatic nucleic acid molecules consist essentially of sequences defined in these Tables.

In yet another embodiment, the invention features antisense nucleic acid molecules and 2- 5A chimera including sequences complementary to the substrate sequences shown in Tables III to IX. Such nucleic acid molecules can include sequences as shown for the binding arms of the enzymatic nucleic acid molecules in Tables III to VIII and sequences shown as GeneBloc™ sequences in Table IX. Similarly, triplex molecules can be provided targeted to the corresponding DNA target regions, and containing the DNA equivalent of a target sequence or a sequence complementary to the specified target (substrate) sequence. Typically, antisense molecules will be complementary to a target sequence along a single contiguous sequence of the antisense molecule. However, in certain embodiments, an antisense molecule may bind to substrate such that the substrate molecule forms a loop, and/or an antisense molecule may bind such that the antisense molecule forms a loop. Thus, the antisense molecule may be complementary to two (or even more) non-contiguous substrate sequences or two (or even more) non-contiguous sequence portions of an antisense molecule may be complementary to a target sequence or both.

By "consists essentially of is meant that the active nucleic acid molecule of the invention, for example an enzymatic nucleic acid molecule, contains an enzymatic center or core equivalent to those in the examples, and binding arms able to bind mRNA such that cleavage at the target site occurs. Other sequences may be present which do not interfere with such cleavage. Thus, a core region may, for example, include one or more loop or stem-loop structures, which do not prevent enzymatic activity. "X" in the sequences in Tables III and IV can be such a loop. A core sequence for a hammerhead ribozyme can be CUGAUGAG X CGAA where X=GCCGUUAGGC or other stem II region known in the art.

In another aspect of the invention, ribozymes or antisense molecules that interact with target RNA molecules and inhibit ERG (specifically ERG gene and ERG fusion gene) activity are expressed from transcription units inserted into DNA or RNA vectors. The recombinant vectors are preferably DNA plasmids or viral vectors. Ribozyme or antisense expressing viral vectors could be constructed based on, but not limited to, adeno-associated virus, retrovirus, adenovirus, or alphavirus. Preferably, the recombinant vectors capable of expressing the ribozymes or antisense are delivered as described above, and persist in target cells. Alternatively, viral vectors may be used that provide for transient expression of ribozymes or antisense. Such vectors can be repeatedly administered as necessary. Once expressed, the ribozymes or antisense bind to the target RNA and inhibit its function or expression. Delivery of ribozyme or antisense expressing vectors can be systemic, such as by intravenous or intramuscular administration, by administration to target cells ex-planted from the patient followed by reintroduction into the patient, or by any other means that would allow for introduction into the desired target cell. Antisense DNA can be expressed endogenously via the use of a single stranded DNA intracellular expression vector.

By RNA is meant a molecule comprising at least one ribonucleotide residue. By

"ribonucleotide" is meant a nucleotide with a hydroxyl group at the 2' position of a β-D-ribo- furanose moiety.

By "vectors" is meant any nucleic acid- and/or viral-based technique used to deliver a desired nucleic acid.

By "patient" is meant an organism, which is a donor or recipient of explanted cells or the cells themselves. "Patient" also refers to an organism to which the nucleic acid molecules of the invention can be administered. Preferably, a patient is a mammal or mammalian cells. More preferably, a patient is a human or human cells.

The nucleic acid molecules of the instant invention, individually, or in combination or in conjunction with other drugs, can be used to treat diseases or conditions discussed above. For example, to treat a disease or condition associated with the levels of ERG, the patient may be treated, or other appropriate cells may be treated, as is evident to those skilled in the art, individually or in combination with one or more drugs under conditions suitable for the treatment.

In a further embodiment, the described molecules, such as antisense or ribozymes, can be used in combination with other known treatments to treat conditions or diseases discussed above. For example, the described molecules could be used in combination with one or more known therapeutic agents to treat a broad spectrum of oncology and neovascularization-related indications, including but not limited to cancers of the lung, colon, breast, prostate, cervix, lymphoma, Ewing's sarcoma and related tumors, melanoma, angiogenic disease states such as tumor angiogenesis, diabetic retinopathy, macular degeneration, neovascular glaucoma, myopic degeneration, arthritis, psoriasis, verruca vulgaris, angiofibroma of tuberous sclerosis, pot-wine stains, Sturge Weber syndrome, Kippel-Trenaunay-Weber syndrome, Osler-Weber-rendu syndrome, leukemias such as acute myeloid leukemia, rheumatoid arthritis, osteoporosis, wound healing and other indications that may respond to the level of ERG. and/or other disease states or conditions which respond to the modulation of ERG expression.

In another preferred embodiment, the invention features nucleic acid-based inhibitors (e.g., enzymatic nucleic acid molecules (ribozymes), antisense nucleic acids, 2-5A antisense chimeras, triplex DNA, antisense nucleic acids containing RNA cleaving chemical groups) and methods for their use to down regulate or inhibit the expression of genes (e.g., ERG) capable of progression and/or maintenance of cancer, tumor angiogenesis, leukemia, lymphoma, ocular diseases, rheumatoid arthritis, psoriasis, and/or other disease states or conditions which respond to the modulation of ERG expression.

By "comprising" is meant including, but not limited to, whatever follows the word

"comprising". Thus, use of the term "comprising" indicates that the listed elements are required or mandatory, but that other elements are optional and may or may not be present. By "consisting of is meant including, and limited to, whatever follows the phrase "consisting of. Thus, the phrase "consisting of indicates that the listed elements are required or mandatory, and that no other elements may be present. By "consisting essentially of is meant including any elements listed after the phrase, and limited to other elements that do not interfere with or contribute to the activity or action specified in the disclosure for the listed elements. Thus, the phrase "consisting essentially of indicates that the listed elements are required or mandatory, but that other elements are optional and may or may not be present depending upon whether or not they affect the activity or action of the listed elements.

Other features and advantages of the invention will be apparent from the following description of the preferred embodiments thereof, and from the claims.

Description Of The Preferred Embodiments

First the drawings will be described briefly.

Drawings

Figure 1 shows an alignment of Erg related genes used for GeneBloc design. Ets 1/2, Erg, Fli-1, NERFla/b/2 sequences were aligned and GeneBlocs were designed against suitable regions. The Erg GeneBloc 14566, which was used in subsequent experiments, was designed against a region not conserved in other Ets family members (shown in bold).

Figure 2 shows examples of chemically stabilized ribozyme motifs. HH Rz, represents hammerhead ribozyme motif (Us an et al, 1996, Curr. Op. Struct. Bio., 1, 527); NCH Rz represents the NCH ribozyme motif (Ludwig & Sproat, International PCT Publication No. WO 98/58058); G-Cleaver, represents G-cleaver ribozyme motif (Kore et al, 1998, Nucleic Acids Research 26, 4116-4120). N or n, represent independently a nucleotide which may be same or different and have complementarity to each other; rl, represents ribo-Inosine nucleotide; arrow indicates the site of cleavage within the target. Position 4 of the HH Rz and the NCH Rz is shown as having 2'-C-allyl modification, but those skilled in the art will recognize that this position can be modified with other modifications well known in the art, so long as such modifications do not significantly inhibit the activity of the ribozyme.

Figure 3 shows an example of the Amberzyme ribozyme motif that is chemically stabilized (see, for example, Beigelman et al, International PCT publication No. WO 99/55857, incorporated by reference herein; also referred to as Class I Motif). The Amberzyme motif is a class of enzymatic nucleic molecules that do not require the presence of a ribonucleotide (2'-OH) group for its activity.

Figure 4 shows an example of the Zinzyme A ribozyme motif that is chemically stabilized

(Beigelman et al, International PCT publication No. WO 99/55857, incorporated by reference herein; also referred to as Class A or Class II Motif). The Zinzyme motif is a class of enzymatic nucleic molecules that do not require the presence of a ribonucleotide (2'-OH) group for its activity.

Figure 5 shows an example of a DNAzyme motif described by Santoro et al, 1997, PNAS, 94, 4262.

Figure 6 is a bar graph which shows the decrease in Erg mRNA levels in HUVEC in response to treatment with Erg targeting GeneBlocs. Erg specific GeneBlocs 14573, 14566 and control GeneBloc 11698 were added to HUVEC (1.5 x 10³ per well) and RNA was prepared after 24, 48, and 72 hours. Taqman analysis of Erg mRNA levels normalized to Actin mRNA is shown. The Erg mRNA level in resting HUVEC is set at a ration of 1.

Figure 7 is a bar graph which shows how treatment of HUVEC with the Erg mismatch control GeneBloc 17478 does not reduce Erg mRNA levels at 24 or 48 hours. Erg specific GeneBloc 14566, Erg mismatch GeneBloc 17478, and control GeneBloc 11698 were added to HUVEC (1.5 x 10³ per well) and RNA was prepared after 24, 48 and 72 hours. Taqman analysis of Erg mRNA levels normalized to Actin mRNA is shown. The Erg mRNA level in resting HUVEC is set at a ratio of 1.

Figure 8A is a bar graph which shows Taqman data of reduction of ICAM-2 and Rho-A mRNA levels in HUVEC in response to treatment with GeneBlocs targeting Erg. RNA was prepared from a second batch of HUVEC treated with either Erg specific GeneBloc or mismatch control GeneBloc. Taqman was used to quantitate the levels of ICAM-2 and Rho A mRNA after 24 hours of Erg GeneBloc 14566 (black bars) or mismatch GeneBloc 17478 (white bars) treatment. Values are expressed as a ratio of GAPDH mRNA levels. Figure 8B is a bar graph which shows lightcycler data of the reduction of Thrombospondin (TSP), von Willebrand Factor (vWF) and SPARC mRNA levels in HUVEC in response to treatment with GeneBlocs targeting Erg. Values are represented as a ratio to GAPDH mRNA levels. Figure 9 is a bar graph which shows the number of endothelial tube branches quantitated in a study of cells on matrigel after treatment with Erg targeting GeneBloc reagent and the corresponding mismatch control GeneBloc. HUVEC were treated with Erg targeting GeneBloc reagent or mismatch GeneBloc reagent for 24 hours and then plated on Matrigel. After 16 hours, endothelial tube formation was analyzed by photography and the number of endothelial tube branches quantitated.

Mechanism of action of Nucleic Acid Molecules of the Invention

Antisense: Antisense molecules may be modified or unmodified RNA, DNA, or mixed polymer oligonucleotides which primarily function by specifically binding to matching sequences resulting in inhibition of peptide synthesis (Wu-Pong, Nov 1994, BioPharm, 20-33). The antisense oligonucleotide binds to target RNA by Watson Crick base-pairing and blocks gene expression by preventing ribosomal translation of the bound sequences either by steric blocking or by activating RNase H enzyme. Antisense molecules can also alter protein synthesis by interfering with RNA processing or transport from the nucleus into the cytoplasm (Mu hopadhyay & Roth, 1996, Crit. Rev. in Oncogenesis 7, 151-190).

In addition, binding of single stranded DNA to RNA may result in nuclease degradation of the heteroduplex (Wu-Pong, supra; Crooke, supra). To date, the only backbone modified DNA chemistry which will act as substrates for RNase H are phosphorothioates, phosphorodithioates, and borontrifluoridates. Recently it has been reported that 2'-arabino and 2'-fluoro arabino- containing oligos can also activate RNase H activity.

A number of antisense molecules have been described that utilize novel configurations of chemically modified nucleotides, secondary structure, and/or RNase H substrate domains (Woolf et al, International PCT Publication No. WO 98/13526; Thompson et al, International PCT

Publication No. WO 99/54459; Hartmann et al, USSN 60/101,174 which was filed on September 21, 1998) all of these are incorporated by reference herein in their entirety.

In addition, antisense deoxyoligoribonucleotides can be used to target RNA by means of DNA-RNA interactions, thereby activating RNase H, which digests the target RNA in the duplex. Antisense DNA can be expressed endogenously in vivo via the use of a single stranded DNA intracellular expression vector or equivalents and variations thereof.

Triplex Forming Oligonucleotides (TFO): Single stranded DNA may be designed to bind to genomic DNA in a sequence specific manner. TFOs are comprised of pyrimidine-rich oligonucleotides which bind DNA helices through Hoogsteen Base-pairing (Wu-Pong, supra). The resulting triple helix composed of the DNA sense, DNA antisense, and TFO disrupts RNA synthesis by RNA polymerase. The TFO mechanism may result in gene expression or cell death since binding may be irreversible (Mukhopadhyay & Roth, supra).

2-5A Antisense Chimera: The 2-5A system is an interferon mediated mechanism for RNA degradation found in higher vertebrates (Mitra et al, 1996, Proc Nat Acad Sci USA 93, 6780- 6785). Two types of enzymes, 2-5A synthetase and RNase L, are required for RNA cleavage. The 2-5 A synthetases require double stranded RNA to form 2'-5' oligoadenylates (2-5 A). 2-5 A then acts as an allosteric effector for utilizing RNase L which has the ability to cleave single stranded RNA. The ability to form 2-5A structures with double stranded RNA makes this system particularly useful for inhibition of viral replication.

(2'-5') oligoadenylate structures may be covalently linked to antisense molecules to form chimeric oligonucleotides capable of RNA cleavage (Torrence, supra). These molecules putatively bind and activate a 2-5A dependent RNase, the oligonucleotide/enzyme complex then binds to a target RNA molecule which can then be cleaved by the RNase enzyme.

Enzymatic Nucleic Acid: Seven basic varieties of naturally occurring enzymatic RNAs are presently known. In addition, several in vitro selection (evolution) strategies (Orgel, 1979, Proc.

R. Soc. London, B 205, 435) have been used to evolve new nucleic acid catalysts capable of catalyzing cleavage and ligation of phosphodiester linkages (Joyce, 1989, Gene, 82, 83-87;

Beaudry et al, 1992, Science 257, 635-641; Joyce, 1992, Scientific American 267, 90-97;

Breaker et al, 1994, TIBTECH 12, 268; Bartel et α/.,1993, Science 261:1411-1418; Szostak, 1993, TIBS 17, 89-93; Kumar et al, 1995, FASEB J, 9, 1183; Breaker, 1996, Curr. Op. Biotech.,

7, 442; Santoro et al, 1997, Proc. Natl. Acad. Sci, 94, 4262; Tang et al, 1997, RNA 3, 914;

Nakamaye & Eckstein, 1994, supra; Long & Uhlenbeck, 1994, supra; Ishizaka et al, 1995, supra; Vaish et al, 1997, Biochemistry 36, 6495; all of these are incorporated by reference herein). Each can catalyze a series of reactions including the hydrolysis of phosphodiester bonds in trans (and thus can cleave other RNA molecules) under physiological conditions.

Nucleic acid molecules of this invention will block to some extent ERG protein expression and can be used to treat disease or diagnose disease associated with the levels of ERG.

The enzymatic nature of a ribozyme has significant advantages, such as the concentration of ribozyme necessary to affect a therapeutic treatment is lower. This advantage reflects the ability of the ribozyme to act enzymatically. Thus, a single ribozyme molecule is able to cleave many molecules of target RNA. In addition, the ribozyme is a highly specific inhibitor, with the specificity of inhibition depending not only on the base-pairing mechanism of binding to the target RNA, but also on the mechanism of target RNA cleavage. Single mismatches, or base- substitutions, near the site of cleavage can be chosen to completely eliminate catalytic activity of a ribozyme.

Nucleic acid molecules having an endonuclease enzymatic activity are able to repeatedly cleave other separate RNA molecules in a nucleotide base sequence-specific manner. Such enzymatic nucleic acid molecules can be targeted to virtually any RNA transcript, and achieve efficient cleavage in vitro (Zaug et al, 324, Nature 429 1986 ; Uhlenbeck, 1987 Nature 328, 596; Kim et al, 84 Proc. Natl. Acad. Sci. USA 8788, 1987; Dreyfus, 1988, Einstein Quart. J. Bio. Med., 6, 92; Haseloff and Gerlach, 334 Nature 585, 1988; Cech, 260 JAMA 3030, 1988; and Jefferies et al, 17 Nucleic Acids Research 1371, 1989; Santoro et al, 1997 supra).

Because of their sequence specificity, trans-cleaving ribozymes show promise as therapeutic agents for human disease (Usman & McSwiggen, 1995 Ann. Rep. Med. Chem. 30, 285-294; Christoffersen and Marr, 1995 J. Med. Chem. 38, 2023-2037). Ribozymes can be designed to cleave specific RNA targets within the background of cellular RNA. Such a cleavage event renders the RNA non-functional and abrogates protein expression from that RNA. In this mamier, synthesis of a protein associated with a disease state can be selectively inhibited (Warashina et al, 1999, Chemistry and Biology, 6, 237-250).

The nucleic acid molecules of the instant invention are also referred to as GeneBloc reagents, which are essentially nucleic acid molecules (e.g.; ribozymes, antisense) capable of down-regulating gene expression.

GeneBlocs are modified oligonucleotides including ribozymes and modified antisense oligonucleotides that bind to and target specific mRNA molecules. Because GeneBlocs can be designed to target any specific mRNA, their potential applications are quite broad. Traditional antisense approaches have often relied heavily on the use of phosphorothioate modifications to enhance stability in biological samples, leading to a myriad of specificity problems stemming from non-specific protein binding and general cytotoxicity (Stein, 1995, Nature Medicine, 1, 1119). In contrast, GeneBlocs contain a number of modifications that confer nuclease resistance while making minimal use of phosphorothioate linkages, which reduces toxicity, increases binding affinity and minimizes non-specific effects compared with traditional antisense oligonucleotides. Similar reagents have recently been utilized successfully in various cell culture systems (Vassar, et al, 1999, Science, 286, 735) and in vivo (Jarvis et al., manuscript in preparation). In addition, novel cationic lipids can be utilized to enhance cellular uptake in the presence of serum. Since ribozymes and antisense oligonucleotides regulate gene expression at the RNA level, the ability to maintain a steady-state dose of GeneBloc over several days was important for target protein and phenotypic analysis. The advances in resistance to nuclease degradation and prolonged activity in vitro have supported the use of GeneBlocs in target validation applications.

Target sites

Targets for useful ribozymes and antisense nucleic acids can be determined as disclosed in Draper et al, WO 93/23569; Sullivan et al, WO 93/23057; Thompson et al, WO 94/02595; Draper et al, WO 95/04818; McSwiggen et al, US Patent No. 5,525,468. All of these publications are hereby incorporated by reference herein in their totality. Other examples include the following PCT applications, which concern inactivation of expression of disease-related genes: WO 95/23225, WO 95/13380, WO 94/02595, all of which are incorporated by reference herein. Rather than repeat the guidance provided in those documents here, specific examples of such methods are provided herein, not limiting to those in the art. Ribozymes and antisense to such targets are designed as described in those applications and synthesized to be tested in vitro and in vivo, as also described. The sequences of human ERG RNAs were screened for optimal enzymatic nucleic acid and antisense target sites using a computer-folding algorithm. Antisense, hammerhead, DNAzyme, NCH, amberzyme, zinzyme, or G-Cleaver ribozyme binding/cleavage sites were identified. These sites are shown in Tables III to IX (all sequences are 5' to 3' in the tables; X can be any base-paired sequence, the actual sequence is not relevant here). The nucleotide base position is noted in the Tables as that site to be cleaved by the designated type of enzymatic nucleic acid molecule. While human sequences can be screened and enzymatic nucleic acid molecule and/or antisense thereafter designed, as discussed in Stinchcomb et al, WO 95/23225, mouse targeted ribozymes may be useful to test efficacy of action of the enzymatic nucleic acid molecule and/or antisense prior to testing in humans.

Antisense, hammerhead, DNAzyme, NCH, amberzyme, zinzyme or G-Cleaver ribozyme binding/cleavage sites were identified. The nucleic acid molecules are individually analyzed by computer folding (Jaeger et al, 1989 Proc. Natl Acad. Sci. USA, 86, 7706) to assess whether the sequences fold into the appropriate secondary structure. Those nucleic acid molecules with unfavorable intramolecular interactions such as between the binding arms and the catalytic core are eliminated from consideration. Varying binding arm lengths can be chosen to optimize activity.

Antisense, hammerhead, DNAzyme, NCH, amberzyme, zinzyme or G-Cleaver ribozyme binding/cleavage sites were identified and were designed to anneal to various sites in the RNA target. The binding arms are complementary to the target site sequences described above. The nucleic acid molecules were chemically synthesized. The method of synthesis used follows the procedure for normal DNA/RNA synthesis as described below and in Usman et al, 1987 J. Am. Chem. Soc, 109, 7845; Scaringe et al, 1990 Nucleic Acids Res., 18, 5433; Wincott et al, 1995 Nucleic Acids Res. 23, 2677-2684; and Caruthers et al, 1992, Methods in Enzymology 211,3-19.

Synthesis of Nucleic acid Molecules

Synthesis of nucleic acids greater than 100 nucleotides in length is difficult using automated methods, and the therapeutic cost of such molecules is prohibitive. In this invention, small nucleic acid motifs ("small refers to nucleic acid motifs no more than 100 nucleotides in length, preferably no more than 80 nucleotides in length, and most preferably no more than 50 nucleotides in length; e.g., antisense oligonucleotides, hammerhead or the NCH ribozymes) are preferably used for exogenous delivery. The simple structure of these molecules increases the ability of the nucleic acid to invade targeted regions of RNA structure. Exemplary molecules of the instant invention are chemically synthesized, and others can similarly be synthesized.

Oligonucleotides (e.g.; antisense GeneBlocs) are synthesized using protocols known in the art as described in Caruthers et al, 1992, Methods in Enzymology 211, 3-19, Thompson et al, International PCT Publication No. WO 99/54459, Wincott et al, 1995, Nucleic Acids Res. 23, 2677-2684, Wincott et al, 1997, Methods Mol Bio., 74, 59, Brennan et al, 1998, Biotechnol Bioeng., 61, 33-45, and Brennan, US patent No. 6,001,311. All of these references are incorporated herein by reference. The synthesis of oligonucleotides makes use of common nucleic acid protecting and coupling groups, such as dimethoxytrityl at the 5'-end, and phosphoramidites at the 3'-end. In a non-limiting example, small scale syntheses are conducted on a 394 Applied Biosystems, Inc. synthesizer using a 0.2 μmol scale protocol with a 2.5 min coupling step for 2'-O-methylated nucleotides and a 45 sec coupling step for 2'-deoxy nucleotides. Table II outlines the amounts and the contact times of the reagents used in the synthesis cycle. Alternatively, syntheses at the 0.2 μmol scale can be performed on a 96-well plate synthesizer, such as the instrument produced by Protogene (Palo Alto, CA) with minimal modification to the cycle. A 33-fold excess (60 μL of 0.11 M = 6.6 μmol) of 2'-O-methyl phosphoramidite and a 105-fold excess of S-ethyl tetrazole (60 μL of 0.25 M = 15 μmol) can be used in each coupling cycle of 2'-O-methyl residues relative to polymer-bound 5'-hydroxyl. A 22-fold excess (40 μL of 0.11 M = 4.4 μmol) of deoxy phosphoramidite and a 70-fold excess of S-ethyl tetrazole (40 μL of 0.25 M = 10 μmol) can be used in each coupling cycle of deoxy residues relative to polymer-bound 5'-hydroxyl. Average coupling yields on the 394 Applied Biosystems, Inc. synthesizer, determined by colorimetric quantitation of the trityl fractions, are typically 97.5-99%. Other oligonucleotide synthesis reagents for the 394 Applied Biosystems, Inc. synthesizer include; detritylatioii solution is 3% TCA in methylene chloride (ABI); capping is performed with 16% N-methyl imidazole in THF (ABI) and 10% acetic anhydride/10%) 2,6- lutidine in THF (ABI); and oxidation solution is 16.9 mM Tχ, 49 mM pyridine, 9% water in THF

(PERSEPTΓVE™). Burdick & Jackson Synthesis Grade acetonitrile is used directly from the reagent bottle. S-Ethyltetrazole solution (0.25 M in acetonitrile) is made up from the solid obtained from American International Chemical, Inc. Alternately, for the introduction of phosphorothioate linkages, Beaucage reagent (3H-l,2-Benzodithiol-3-one 1,1-dioxide, 0.05 M in acetonitrile) is used.

Deprotection of the antisense oligonucleotides is performed as follows: the polymer-bound trityl-on oligoribonucleoti.de is transferred to a 4 rnL glass screw top vial and suspended in a solution of 40% aq. methylamine (1 mL) at 65 °C for 10 min. After cooling to -20 °C, the supernatant is removed from the polymer support. The support is washed three times with 1.0 mL of EtOH:MeCN:H2O/3:l:l, vortexed and the supernatant is then added to the first supernatant. The combined supematants, containing the oligoribonucleotide, are dried to a white powder.

The method of synthesis used for normal RNA including certain enzymatic nucleic acid molecules follows the procedure as described in Usman et al, 1987, J Am. Chem. Soc, 109, 7845; Scaringe et al, 1990, Nucleic Acids Res., 18, 5433; Wincott et al, 1995, Nucleic Acids Res. 23, 2677-2684 and Wincott et al, 1997, Methods Mol. Bio., 74, 59, and makes use of common nucleic acid protecting and coupling groups, such as dimethoxytrityl at the 5'-end, and phosphoramidites at the 3'-end. In a non-limiting example, small scale syntheses are conducted on a 394 Applied Biosystems, Inc. synthesizer using a 0.2 μmol scale protocol with a 7.5 min coupling step for alkylsilyl protected nucleotides and a 2.5 min coupling step for 2'-O- methylated nucleotides. Table II outlines the amounts and the contact times of the reagents used in the synthesis cycle. Alternatively, syntheses at the 0.2 μmol scale can be done on a 96-well plate synthesizer, such as the instrument produced by Protogene (Palo Alto, CA) with minimal modification to the cycle. A 33-fold excess (60 μL of 0.11 M = 6.6 μmol) of 2'-O-methyl phosphoramidite and a 75-fold excess of S-ethyl tetrazole (60 μL of 0.25 M = 15 μmol) can be used in each coupling cycle of 2'-O-methyl residues relative to polymer-bound 5'-hydroxyl. A 66-fold excess (120 μL of 0.11 M = 13.2 μmol) of alkylsilyl (ribo) protected phosphoramidite and a 150-fold excess of S-ethyl tetrazole (120 μL of 0.25 M = 30 μmol) can be used in each coupling cycle of ribo residues relative to polymer-bound 5'-hydroxyl. Average coupling yields on the 394 Applied Biosystems, Inc. synthesizer, determined by colorimetric quantitation of the trityl fractions, are typically 97.5-99%. Other oligonucleotide synthesis reagents for the 394 Applied Biosystems, Inc. synthesizer include; detritylation solution is 3% TCA in methylene chloride (ABI); capping is performed with 16% N-methyl i idazole in THF (ABI) and 10% acetic anhydride/10% 2,6-lutidine in THF (ABI); oxidation solution is 16.9 mM Tχ, 49 mM pyridine, 9% water in THF (PERSEPTIVE™). Burdick & Jackson Synthesis Grade acetonitrile is used directly from the reagent bottle. S-Ethyltetrazole solution (0.25 M in acetonitrile) is made up from the solid obtained from American International Chemical, Inc. Alternately, for the introduction of phosphorothioate linkages, Beaucage reagent (3H-l,2-Benzodithiol-3-one 1,1- dioxideθ.05 M in acetonitrile) is used.

Deprotection of the RNA is performed using either a two-pot or one-pot protocol. For the two-pot protocol, the polymer-bound trityl-on oligoribonucleotide is transferred to a 4 mL glass screw top vial and suspended in a solution of 40% aq. methylamine (1 mL) at 65 °C for 10 min.

After cooling to -20 °C, the supernatant is removed from the polymer support. The support is washed three times with 1.0 mL of EtOH:MeCN:H2O/3:l:l, vortexed and the supernatant is then added to the first supernatant. The combined supematants, containing the oligoribonucleotide, are dried to a white powder. The base deprotected oligoribonucleotide is resuspended in anhydrous TEA/HF/NMP solution (300 μL of a solution of 1.5 mL N-methylpyrrolidinone, 750 μL TEA and 1 mL TEA-3HF to provide a 1.4 M HF concentration) and heated to 65 °C. After 1.5 h, the oligomer is quenched with 1.5 M NH4HCO3.

Alternatively, for the one-pot protocol, the polymer-bound trityl-on oligoribonucleotide is transferred to a 4 mL glass screw top vial and suspended in a solution of 33% ethanolic methylamine/DMSO: 1/1 (0.8 mL) at 65 °C for 15 min. The vial is brought to r.t. TEA»3HF

(0.1 mL) is added and the vial is heated at 65 °C for 15 min. The sample is cooled at -20 °C and then quenched with 1.5 M NH4HCO3.

For purification of the trityl-on oligomers, the quenched NH4HCO3 solution is loaded onto a C-18 containing cartridge that had been prewashed with acetonitrile followed by 50 mM TEAA. After washing the loaded cartridge with water, the RNA is detritylated with 0.5%> TFA for 13 min. The cartridge is then washed again with water, salt exchanged with 1 M NaCl and washed with water again. The oligonucleotide is then eluted with 30% acetonitrile.

Inactive hammerhead ribozymes or binding attenuated control (BAG) oligonucleotides) are synthesized by substituting a U for G5 and a U for A14 (numbering from Hertel, K. J., et al, 1992, Nucleic Acids Res_., 20, 3252). Similarly, one or more nucleotide substitutions can be introduced in other enzymatic nucleic acid molecules to inactivate the molecule and such molecules can serve as a negative control.

The average stepwise coupling yields are typically >98% (Wincott et al, 1995 Nucleic Acids Res. 23, 2677-2684). Those of ordinary skill in the art will recognize that the scale of synthesis can be adapted to be larger or smaller than the examples described above including but not limited to 96-well format, all that is important is the ratio of chemicals used in the reaction.

Alternatively, the nucleic acid molecules of the present invention can be synthesized separately and joined together post-synthetically, for example by ligation (Moore et al, 1992, Science 256, 9923; Draper et al, International PCT publication No. WO 93/23569; Shabarova et al, 1991, Nucleic Acids Research 19, 4247; Bellon et al, 1997, Nucleosides & Nucleotides, 16, 951; Bellon et al, 1997, Bioconjugate Chem. 8, 204).

The nucleic acid molecules of the present invention are modified extensively to enhance stability by modification with nuclease resistant groups, for example, 2'-amino, 2'-C-allyl, 2'- flouro, 2'-O-methyl, 2'-H (for a review see Usman and Cedergren, 1992, TIBS 17, 34; Usman et al, 1994, Nucleic Acids Symp. Ser. 31, 163). Ribozymes are purified by gel electrophoresis using general methods or are purified by high pressure liquid chromatography (HPLC; See Wincott et al, supra, the totality of which is hereby incorporated herein by reference) and are re-suspended in water. The sequences of the ribozymes and antisense constructs that are chemically synthesized, useful in this study, are shown in Tables III to IX. Those in the art will recognize that these sequences are representative only of many more such sequences where the enzymatic portion of the ribozyme (all but the binding arms) is altered to affect activity. The ribozyme and antisense construct sequences listed in Tables III to IX may be formed of ribonucleotides or other nucleotides or non-nucleotides. Such ribozymes with enzymatic activity are equivalent to the ribozymes described specifically in the Tables.

Optimizing Activity of the nucleic acid molecule of the invention.

Chemically synthesizing nucleic acid molecules with modifications (base, sugar and/or phosphate) that prevent their degradation by serum ribonucleases may increase their potency (see e.g., Eckstein et al, International Publication No. WO 92/07065; Perrault et al, 1990 Nature 344, 565; Pieken et al., 1991, Science 253, 314; Usman and Cedergren, 1992, Trends in Biochem. Sci. 17, 334; Usman et al, International Publication No. WO 93/15187; Rossi et al, International Publication No. WO 91/03162; Sproat, US Patent No. 5,334,711; and Burgin et al, supra; all of these describe various chemical modifications that can be made to the base, phosphate and/or sugar moieties of the nucleic acid molecules described herein. All these references are incorporated by reference herein. Modifications which enhance their efficacy in cells, and removal of bases from nucleic acid molecules to shorten oligonucleotide synthesis times and reduce chemical requirements are desired.

There are several examples in the art describing sugar, base and phosphate modifications that can be introduced into nucleic acid molecules with significant enhancement in their nuclease stability and efficacy. For example, oligonucleotides are modified to enhance stability and/or enhance biological activity by modification with nuclease resistant groups, for example, 2'- arnino, 2'-C-allyl, 2'-flouro, 2'-O-methyl, 2'-H, nucleotide base modifications (for a review see Usman and Cedergren, 1992, TIBS. 17, 34; Usman et al, 1994, Nucleic Acids Symp. Ser. 31, 163; Burgin et al, 1996, Biochemistry , 35, 14090). Sugar modifications of nucleic acid molecules have been extensively described in the art (see Eckstein et al, International Publication PCT No. WO 92/07065; Perrault et al Nature, 1990, 344, 565-568; Pieken et al. Science, 1991, 253, 314-317; Usman and Cedergren, Trends in Biochem. Sci. , 1992, 17, 334- 339; Usman et al. International Publication PCT No. WO 93/15187; Sproat, US Patent No. 5,334,711 and Beigelman et al, 1995, J. Biol. Chem., 270, 25702; Beigelman et al, International PCT publication No. WO 97/26270; Beigelman et al, US Patent No. 5,716,824; Usman et al, US patent No. 5,627,053; Woolf et al, International PCT Publication No. WO 98/13526; Thompson et al., USSN 60/082,404 which was filed on April 20, 1998; Karpeisky et al, 1998, Tetrahedron Lett., 39, 1131; Eamshaw and Gait, 1998, Biopolymers (Nucleic acid Sciences), 48, 39-55; Verma and Eckstein, 1998, Annu. Rev. Biochem., 67, 99-134; and Burlina et al, 1997, Bioorg. Med. Chem., 5, 1999-2010; all of the references are hereby incorporated by reference herein in their totalities). Such publications describe general methods and strategies to determine the location of incorporation of sugar, base and/or phosphate modifications and the like into ribozymes without inhibiting catalysis. In view of such teachings, similar modifications can be used as described herein to modify the nucleic acid molecules of the instant invention.

While chemical modification of oligonucleotide intemucleotide linkages with phosphorothioate, phosphorothioate, and/or 5'-methylρhosphonate linkages improves stability, too many of these modifications may cause some toxicity. Therefore when designing nucleic acid molecules the amount of these intemucleotide linkages should be minimized. The reduction in the concentration of these linkages should lower toxicity resulting in increased efficacy and higher specificity of these molecules.

Nucleic acid molecules having chemical modifications which maintain or enhance activity are provided. Such nucleic acid is also generally more resistant to nucleases than unmodified nucleic acid. Thus, in a cell and/or in vivo the activity may not be significantly lowered. Therapeutic nucleic acid molecules delivered exogenously must optimally be stable within cells until translation of the target RNA has been inhibited long enough to reduce the levels of the undesirable protein. This period of time varies between hours to days depending upon the disease state. Clearly, nucleic acid molecules must be resistant to nucleases in order to function as effective intracellular therapeutic agents. Improvements in the chemical synthesis of RNA and DNA (Wincott et al, 1995 Nucleic Acids Res. 23, 2677; Caruthers et al, 1992, Methods in Enzymology 211,3-19 (incorporated by reference herein) have expanded the ability to modify nucleic acid molecules by introducing nucleotide modifications to enhance their nuclease stability as described above.

Use of these the nucleic acid-based molecules of the invention will lead to better treatment of the disease progression by affording the possibility of combination therapies (e.g., multiple antisense or enzymatic nucleic acid molecules targeted to different genes, nucleic acid molecules coupled with known small molecule inhibitors, or intermittent treatment with combinations of molecules (including different motifs) and/or other chemical or biological molecules). The treatment of patients with nucleic acid molecules may also include combinations of different types of nucleic acid molecules.

Therapeutic nucleic acid molecules (e.g., enzymatic nucleic acid molecules and antisense nucleic acid molecules) delivered exogenously must optimally be stable within cells until translation of the target RNA has been inhibited long enough to reduce the levels of the undesirable protein. This period of time varies between hours to days depending upon the disease state. Clearly, these nucleic acid molecules must be resistant to nucleases in order to function as effective intracellular therapeutic agents. Improvements in the chemical synthesis of nucleic acid molecules described in the instant invention and in the art have expanded the ability to modify nucleic acid molecules by introducing nucleotide modifications to enhance their nuclease stability as described above.

By "enhanced enzymatic activity" is meant to include activity measured in cells and/or in vivo where the activity is a reflection of both catalytic activity and ribozyme stability. In this invention, the product of these properties is increased or not significantly (less than 10-fold) decreased in vivo compared to an all RNA ribozyme or all DNA enzyme.

In yet another preferred embodiment, nucleic acid catalysts having chemical modifications which maintain or enhance enzymatic activity are provided. Such nucleic acid is also generally more resistant to nucleases than unmodified nucleic acid. Thus, in a cell and/or in vivo the activity may not be significantly lowered. As exemplified herein such ribozymes are useful in a cell and/or in vivo even if activity over all is reduced 10 fold (Burgin et al, 1996, Biochemistry, 35, 14090). Such ribozymes herein are said to "maintain" the enzymatic activity of an all RNA ribozyme.

In another aspect the nucleic acid molecules comprise a 5' and/or a 3'- cap structure.

By "cap structure" is meant chemical modifications, which have been incorporated at either terminus of the oligonucleotide (see, for example, Wincott et al, WO 97/26270, incorporated by reference herein). These terminal modifications protect the nucleic acid molecule from exonuclease degradation, and may help in delivery and/or localization within a cell. The cap may be present at the 5 '-terminus (5 '-cap) or at the 3 '-terminus (3 '-cap) or may be present on both termini. In non-limiting examples the 5 '-cap is selected from the group comprising inverted abasic residue (moiety), 4',5'-methylene nucleotide; l-(beta-D-e_rythrofuranosyl) nucleotide, 4'- thio nucleotide, carbocyclic nucleotide; 1,5-anhydrohexitol nucleotide; L-nucleotides; alpha- nucleotides; modified base nucleotide; phosphorodithioate linkage; tbreo-pentofuranosyl nucleotide; acyclic 3',4'-seco nucleotide; acyclic 3,4-dihydroxybutyl nucleotide; acyclic 3,5- dihydroxypentyl nucleotide, 3 '-3 '-inverted nucleotide moiety; 3 '-3 '-inverted abasic moiety; 3'-2'~ inverted nucleotide moiety; 3'-2'-inverted abasic moiety; 1,4-butanediol phosphate; 3'- phosphoramidate; hexylphosphate; aminohexyl phosphate; 3'-phosphate; 3'-phosphorothioate; phosphorodithioate; or bridging or non-bridging methylphosphonate moiety (for more details see Wincott et al, International PCT publication No. WO 97/26270, incorporated by reference herein).

In yet another preferred embodiment, the 3 '-cap is selected from a group comprising, 4',5'- methylene nucleotide; l-(beta-D-eιytbxofuranosyl) nucleotide; 4'-thio nucleotide, carbocyclic nucleotide; 5'-amino-alkyl phosphate; l,3-diamino-2-propyl phosphate, 3-aminoproρyl phosphate; 6-aminohexyl phosphate; 1,2-aminododecyl phosphate; hydroxypropyl phosphate; 1,5-anhydrohexitol nucleotide; L-nucleotide; alpha-nucleotide; modified base nucleotide; phosphorodithioate; t/zreo-pentofuranosyl nucleotide; acyclic 3',4'-seco nucleotide; 3,4- dihydroxybutyl nucleotide; 3,5-dihydroxypentyl nucleotide, 5'-5'-inverted nucleotide moiety; 5'- 5'-inverted abasic moiety; 5'-phosphoramidate; 5'-phosphorothioate; 1,4-butanediol phosphate; 5 '-amino; bridging and/or non-bridging 5'-phosphoramidate, phosphorothioate and/or phosphorodithioate, bridging or non bridging methylphosphonate and 5'-mercapto moieties (for more details, see Beaucage and Iyer, 1993, Tetrahedron 49, 1925; incorporated by reference herein).

By the term "non-nucleotide" is meant any group or compound which can be incorporated into a nucleic acid chain in the place of one or more nucleotide units, including either sugar and/or phosphate substitutions, and allows the remaining bases to exhibit their enzymatic activity. The group or compound is abasic in that it does not contain a commonly recognized nucleotide base, such as adenosine, guanine, cytosine, uracil or thymine.

An "alkyl" group refers to a saturated aliphatic hydrocarbon, including straight-chain, branched-chain, and cyclic alkyl groups. Preferably, the alkyl group has 1 to 12 carbons. More preferably it is a lower alkyl of from 1 to 7 carbons, more preferably 1 to 4 carbons. The alkyl group may be substituted or unsubstituted. When substituted the substituted group(s) is preferably, hydroxyl, cyano, alkoxy, =O, =S, NO2 or N(CH3)2, amino, or SH. The term also includes alkenyl groups which are unsaturated hydrocarbon groups containing at least one carbon-carbon double bond, including straight-chain, branched-chain, and cyclic groups. Preferably, the alkenyl group has 1 to 12 carbons. More preferably it is a lower alkenyl of from 1 to 7 carbons, more preferably 1 to 4 carbons. The alkenyl group may be substituted or unsubstituted. When substituted the substituted group(s) is preferably, hydroxyl, cyano, alkoxy, =O, =S, NO2, halogen, N(CH3)2, amino, or SH. The term "alkyl" also includes alkynyl groups which have an unsaturated hydrocarbon group containing at least one carbon-carbon triple bond, including straight-chain, branched-chain, and cyclic groups. Preferably, the alkynyl group has 1 to 12 carbons. More preferably it is a lower alkynyl of from 1 to 7 carbons, more preferably 1 to 4 carbons. The alkynyl group may be substituted or unsubstituted. When substituted the substituted group(s) is preferably, hydroxyl, cyano, alkoxy, =O, =S, NO2 or N(CH3)2, amino or SH.

Such alkyl groups may also include aryl, alkylaryl, carbocyclic aryl, heterocyclic aryl, amide and ester groups. An "aryl" group refers to an aromatic group which has at least one ring having a conjugated π electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which may be optionally substituted. The preferred substituent(s) of aryl groups are halogen, trihalomethyl, hydroxyl, SH, OH, cyano, alkoxy, alkyl, alkenyl, alkynyl, and amino groups. An "alkylaryl" group refers to an alkyl group (as described above) covalently joined to an aryl group (as described above). Carbocyclic aryl groups are groups wherein the ring atoms on the aromatic ring are all carbon atoms. The carbon atoms are optionally substituted. Heterocyclic aryl groups are groups having from 1 to 3 heteroatoms as ring atoms in the aromatic ring and the remainder of the ring atoms are carbon atoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen, and include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolo, pyrimidyl, pyrazinyl, imidazolyl and the like, all optionally substituted. An "amide" refers to an -C(O)-NH-R, where R is either alkyl, aryl, alkylaryl or hydrogen. An "ester" refers to an -C(O)- OR', where R is either alkyl, aryl, alkylaryl or hydrogen.

By "nucleotide" as used herein is as recognized in the art to include natural bases (standard), and modified bases well known in the art. Such bases are generally located at the 1' position of a nucleotide sugar moiety. Nucleotides generally comprise a base, sugar and a phosphate group. The nucleotides can be unmodified or modified at the sugar, phosphate and/or base moiety, (also referred to interchangeably as nucleotide analogs, modified nucleotides, non- natural nucleotides, non-standard nucleotides and other; see for example, Usman and McSwiggen, supra; Eckstein et al, hitemational PCT Publication No. WO 92/07065; Usman et al, International PCT Publication No. WO 93/15187; Uhlman & Peyman, supra all are hereby incorporated by reference herein). There are several examples of modified nucleic acid bases known in the art as summarized by Limbach et al, 1994, Nucleic Acids Res. 22, 2183. Some of the non-limiting examples of base modifications that can be introduced into nucleic acid molecules include, inosine, purine, pyridin-4-one, pyridin-2-one, phenyl, pseudouracil, 2, 4, 6- trimethoxy benzene, 3-methyl uracil, dihydrouridine, naphthyl, aminophenyl, 5-alkylcytidines (e.g., 5-methylcytidine), 5-alkyluridines (e.g., ribothymidine), 5-halouridine (e.g., 5-bromouridine) or 6-azapyrimidines or 6-alkylpyrimidines (e.g. 6-methyluridine), propyne, and others (Burgin et al, 1996, Biochemistry, 35, 14090; Uhlman & Peyman, supra). By "modified bases" in this aspect is meant nucleotide bases other than adenine, guanine, cytosine and uracil at 1' position or their equivalents; such bases may be used at any position, for example, within the catalytic core of an enzymatic nucleic acid molecule and/or in the substrate-binding regions of the nucleic acid molecule.

In a preferred embodiment, the invention features modified ribozymes with phosphate backbone modifications comprising one or more phosphorothioate, phosphorodithioate, methylphosphonate, morpholino, amidate carbamate, carboxyniethyl, acetamidate, polyamide, sulfonate, sulfonamide, sulfamate, formacetal, thioformacetal, and/or alkylsilyl, substitutions.

For a review of oligonucleotide backbone modifications see Hunziker and Leumann, 1995,

Nucleic Acid Analogues: Synthesis and Properties, in Modern Synthetic Methods, VCH, 331-

^• 417, and Mesmaeker et al, 1994, Novel Backbone Replacements for Oligonucleotides, in Carbohydrate Modifications in Antisense Research, ACS, 24-39. These references are hereby incorporated by reference herein.

By "abasic" is meant sugar moieties lacking a base or having other chemical groups in place of a base at the 1' position, (for more details, see Wincott et al, International PCT publication No. WO 97/26270).

By "unmodified nucleoside" is meant one of the bases adenine, cytosine, guanine, thymine, uracil joined to the 1' carbon of β-D-ribo-furanose.

By "modified nucleoside" is meant any nucleotide base which contains a modification in the chemical structure of an unmodified nucleotide base, sugar and/or phosphate.

In connection with 2 '-modified nucleotides as described for the present invention, by "amino" is meant 2'-NH₂ or 2'-O- NH₂, which may be modified or unmodified. Such modified groups are described, for example, in Eckstein et al, U.S. Patent 5,672,695 and Matulic-Adamic et al, WΟ 98/28317, respectively, which are both incorporated by reference herein in their entireties.

Various modifications to nucleic acid (e.g., antisense and ribozyme) structure can be made to enhance the utility of these molecules. Such modifications will enhance shelf-life, half-life in vitro, stability, and ease of introduction of such oligonucleotides to the target site, e.g., to enhance penetration of cellular membranes, and confer the ability to recognize and bind to targeted cells.

Use of these molecules will lead to better treatment of the disease progression by affording the possibility of combination therapies (e.g., multiple ribozymes targeted to different genes, ribozymes coupled with known small molecule inhibitors, or intermittent treatment with combinations of ribozymes (including different ribozyme motifs) and/or other chemical or biological molecules). The treatment of patients with nucleic acid molecules may also include combinations of different types of nucleic acid molecules. Therapies may be devised which include a mixture of ribozymes (including different ribozyme motifs), antisense and/or 2-5A chimera molecules to one or more targets to alleviate symptoms of a disease.

Administration of Nucleic Acid Molecules

Methods for the delivery of nucleic acid molecules are described in Akhtar et al, 1992,

Trends Cell Bio., 2, 139; and .Debvery Strategies for Antisense Oligonucleotide Therapeutics, ed. Akhtar, 1995 which are both incorporated herein by reference. Sullivan et al, PCT WO 94/02595, further describes the general methods for delivery of enzymatic RNA molecules. These protocols may be utilized for the delivery of virtually any nucleic acid molecule. Nucleic acid molecules may be administered to cells by a variety of methods known to those familiar to the art, including, but not restricted to, encapsulation in liposomes, by iontophoresis, or by incorporation into other vehicles, such as hydrogels, cyclodextrins, biodegradable nanocapsules, and bioadhesive microspheres. For some indications, nucleic acid molecules may be directly delivered ex vivo to cells or tissues with or without the aforementioned vehicles. Alternatively, the nucleic acid/vehicle combination is locally delivered by direct injection or by use of a catheter, infusion pump or stent. Other routes of delivery include, but are not limited to, intravascular, intramuscular, subcutaneous or joint injection, aerosol inhalation, oral (tablet or pill form), topical, systemic, ocular, intraperitoneal and/or intrathecal delivery. More detailed descriptions of nucleic acid delivery and administration are provided in Sullivan et al, supra, Draper et al, PCT WO93/23569, Beigelman et al, PCT WO99/05094, and Klimuk et al, PCT WO99/04819 all of which have been incorporated by reference herein.

The molecules of the instant invention can be used as pharmaceutical agents. Pharmaceutical agents prevent, inhibit the occurrence, or treat (alleviate a symptom to some extent, preferably all of the symptoms) of a disease state in a patient.

The negatively charged polynucleotides of the invention can be administered (e.g., RNA,

DNA or protein) and introduced into a patient by any standard means, with or without stabilizers, buffers, and the like, to form a pharmaceutical composition. When it is desired to use a liposome delivery mechanism, standard protocols for formation of liposomes can be followed. The compositions of the present invention may also be formulated and used as tablets, capsules or elixirs for oral administration; suppositories for rectal administration; sterile solutions; suspensions for injectable administration; and other compositions known in the art.

The present invention also includes pharmaceutically acceptable formulations of the compounds described. These formulations include salts of the above compounds, e.g., acid addition salts, including salts of hydrochloric, hydrobromic, acetic acid, and benzene sulfonic acid.

A pharmacological composition or formulation refers to a composition or formulation in a form suitable for administration, e.g., systemic administration, into a cell or patient, preferably a human. Suitable forms, in part, depend upon the use or the route of entry, for example oral, transdermal, or by injection. Such forms should not prevent the composition or formulation from reaching a target cell (i.e., a cell to which the negatively charged polymer is desired to be delivered to). For example, pharmacological compositions injected into the blood stream should be soluble. Other factors are known in the art, and include considerations such as toxicity and forms which prevent the composition or formulation from exerting its effect.

By "systemic administration" is meant in vivo systemic absorption or accumulation of drugs in the blood stream followed by distribution throughout the entire body. Administration routes that lead to systemic absorption include, without limitations: intravenous, subcutaneous, intraperitoneal, inhalation, oral, intrapulmonary and intramuscular. Each of these administration routes exposes the desired negatively charged polymers, e.g., nucleic acids, to an accessible diseased tissue. The rate of entry of a drug into the circulation has been shown to be a function of molecular weight or size. The use of a liposome or other drug carrier comprising the compounds of the instant invention can potentially localize the drug, for example, in certain tissue types, such as the tissues of the reticular endothelial system (RES). A liposome formulation that can facilitate the association of drug with the surface of cells, such as, lymphocytes and macrophages is also useful. This approach may provide enhanced delivery of the drug to target cells by taking advantage of the specificity of macrophage and lymphocyte immune recognition of abnormal cells, such as cancer cells.

By pharmaceutically acceptable formulation is meant, a composition or formulation that allows for the effective distribution of the nucleic acid molecules of the instant invention in the physical location most suitable for their desired activity. Non-limiting examples of agents suitable for formulation with the nucleic acid molecules of the instant invention include: P- glycoprotein inhibitors (such as Pluronic P85) which can enhance entry of drugs into the CNS

(Jolliet-Riant and Tillement, 1999, Fundαm. Clin. Pharmacol, 13, 16-26); biodegradable polymers, such as poly (DL-lactide-coglycolide) microspheres for sustained release delivery after intracerebral implantation (Emerich, DF et al, 1999, Cell Transplant, 8, 47-58) Alkermes, Inc.

Cambridge, MA; and loaded nanoparticles, such as those made of polybutylcyanoacrylate, which can deliver drugs across the blood brain barrier and can alter neuronal uptake mechanisms (Prog

Neuropsychopharmacol Biol Psychiatry, 23, 941-949, 1999). Other non-limiting examples of delivery strategies for the nucleic acid molecules of the instant invention include material described in Boado et al, 1998, J. Pharm. Sci, 87, 1308-1315; Tyler et al, 1999, FEBS Lett., 421, 280-284; Pardridge et al, 1995, PNAS USA., 92, 5592-5596; Boado, 1995, Adv. Drug Delivery Rev., 15, 73-107; Aldrian-Herrada et al, 1998, Nucleic Acids Res., 26, 4910-4916; and Tyler et al, 1999, PNAS USA., 96, 7053-7058.

The invention also features the use of the composition comprising surface-modified liposomes containing poly (ethylene glycol) lipids (PEG-modified, or long-circulating liposomes or stealth liposomes). These formulations offer a method for increasing the accumulation of drugs in target tissues. This class of drug carriers resists opsonization and elimination by the mononuclear phagocytic system (MPS or RES), thereby enabling longer blood circulation times and enhanced tissue exposure for the encapsulated drug (Lasic et al. Chem. Rev. 1995, 95, 2601- 2627; Ishiwata et al, Chem. Pharm. Bull 1995, 43, 1005-1011). All incorporated by reference herein. Such liposomes have been shown to accumulate selectively in tumors, presumably by extravasation and capture in the neovascularized target tissues (Lasic et al, Science 1995, 267, 1275-1276; Oku et α/., 1995, Biochim. Biophys. Ada, 1238, 86-90). All incorporated by reference herein. The long-circulating liposomes enhance the pharmacokinetics and pharmacodynamics of DNA and RNA, particularly compared to conventional cationic liposomes which are known to accumulate in tissues of the MPS (Liu et al, J. Biol. Chem. 1995, 42, 24864- 24870; Choi et al, International PCT Publication No. WO 96/10391; Ansell et al, International PCT Publication No. WO 96/10390; Holland et al, International PCT Publication No. WO 96/10392; all of which are incorporated by reference herein). Long-circulating liposomes are also likely to protect drugs from nuclease degradation to a greater extent compared to cationic liposomes, based on their ability to avoid accumulation in metabolically aggressive MPS tissues such as the liver and spleen.

In addition, the invention features the use of methods to deliver the nucleic acid molecules of the instant invention to hematopoietic cells, including monocytes and lymphocytes. These methods are described in detail by Hartmann et al, 1998, J Phamacol Exp. Ther., 285(2), 920- 928; Kronenwett et al, 1998, Blood, 91(3), 852-862; Filion and Phillips, 1997, Biochim. Biophys. Ada., 1329(2), 345-356; Ma and Wei, 1996, Leuk. Res., 20(11/12), 925-930; and Bongartz et al, 1994, Nucleic Acids Research, 22(22), 4681-8. Such methods, as described above, include the use of free oligonucleitide, cationic lipid formulations, liposome formulations including pH sensitive liposomes and immunoliposom.es, and bioconjugates including oligonucleotides conjugated to fusogenic peptides, for the transfection of hematopoietic cells with oligonucleotides.

The present invention also includes compositions prepared for storage or administration which include a pharmaceutically effective amount of the desired compounds in a pharmaceutically acceptable carrier or diluent. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A.R. Gennaro edit. 1985) hereby incorporated by reference herein. For example, preservatives, stabilizers, dyes and flavoring agents may be provided. These include sodium benzoate, sorbic acid and esters of -hydroxybenzoic acid. In addition, antioxidants and suspending agents may be used.

A pharmaceutically effective dose is that dose required to prevent, inhibit the occurrence, or treat (alleviate a symptom to some extent, preferably all of the symptoms) of a disease state. The pharmaceutically effective dose depends on the type of disease, the composition used, the route of administration, the type of mammal being treated, the physical characteristics of the specific mammal under consideration, concurrent medication, and other factors which those skilled in the medical arts will recognize. Generally, an amount between 0.1 mg/kg and 100 mg/kg body weight/day of active ingredients is administered dependent upon potency of the negatively charged polymer.

The nucleic acid molecules of the present invention may also be administered to a patient in combination with other therapeutic compounds to increase the overall therapeutic effect. The use of multiple compounds to treat an indication may increase the beneficial effects while reducing the presence of side effects. Radiation treatments and chemotherapeutic agents such as paclitaxel (Taxol), docetaxel, cisplatin (carboplatin), methofrexate, cyclophosphamide, doxorubin (doxorubicin), 5-fluorouracil (5-FU), leucovorin, vinorelbine, vinblastine, cyclophosphamide, ifosfamide, etoposide, methotrexate, gemcitabine, irinotecan, interferons, herceptin, thalidomide, matrix metalloproteinase inhibitors, tyrosine kinase inhibitors, and antibodies are non-limiting examples of compounds and/or methods that can be combined with or used in conjunction with the nucleic acid molecules (e.g. ribozymes and antisense molecules) of the instant invention. Those skilled in the art will recognize that other drug compounds and therapies can be similarly and readily combined with the nucleic acid molecules of the instant invention (e.g. ribozymes and antisense molecules) and are, therefore, within the scope of the instant invention.

Alternatively, certain of the nucleic acid molecules of the instant invention can be expressed within cells from eukaryotic promoters (e.g., Izant and Weintraub, 1985, Science, 229, 345; McGarry and Lindquist, 1986, Proc Natl Acad. Sci, USA 83, 399; Scanlon et al, 1991, Proc. Natl. Acad. Sci. USA, 88, 10591-5; Kashani-Sabet et al, 1992, Antisense Res. Dev., 2, 3- 15; Dropulic et al, 1992, J. Virol, 66, 1432-41; Weerasinghe et al, 1991, J. Virol, 65, 5531-4; Ojwang et al, 1992, Proc Natl Acad. Sci. USA, 89, 10802-6; Chen et al, 1992, Nucleic Acids Res., 20, 4581-9; Sarver et al, 1990 Science, 247, 1222-1225; Thompson et al, 1995, Nucleic Acids Res., 23, 2259; Good et al, 1997, Gene Therapy, 4, 45; all of the references are hereby incorporated in their totality by reference herein). Those skilled in the art realize that any nucleic acid can be expressed in eukaryotic cells from the appropriate DNA/RNA vector. The activity of such nucleic acids can be augmented by their release from the primary transcript by a ribozyme (Draper et al, PCT WO 93/23569, and Sullivan et al, PCT WO 94/02595; Ohkawa et al, 1992, Nucleic Acids Symp. Ser., 27, 15-6; Taira et /., 1991, Nucleic Acids Res., 19, 5125-30; Ventura et al, 1993, Nucleic Acids Res., 21, 3249-55; Chowrira et al, 1994, J. Biol Chem., 269, 25856; all of these references are hereby incorporated in their totalities by reference herein).

In another aspect of the invention, RNA molecules of the present invention are preferably expressed from transcription units (see, for example, Couture et al, 1996, TIG, 12, 510) inserted into DNA or RNA vectors. The recombinant vectors are preferably DNA plasmids or viral vectors. Ribozyme expressing viral vectors could be constructed based on, but not limited to, adeno-associated virus, retrovirus, adenovirus, or alphavirus. Preferably, the recombinant vectors capable of expressing the nucleic acid molecules are delivered as described above, and persist in target cells. Alternatively, viral vectors may be used that provide for transient expression of nucleic acid molecules. Such vectors might be repeatedly administered as necessary. Once expressed, the nucleic acid molecule binds to the target mRNA. Delivery of nucleic acid molecule expressing vectors could be systemic, such as by intravenous or infra-muscular administration, by administration to target cells ex-planted from the patient followed by reintroduction into the patient, or by any other means that would allow for introduction into the desired target cell (for a review, see Couture et al, 1996, TIG, 12, 510).

In one aspect, the invention features an expression vector comprising a nucleic acid sequence encoding at least one of the nucleic acid molecules disclosed in the instant invention. The nucleic acid sequence encoding the nucleic acid molecule of the instant invention is operably linked in a manner which allows expression of that nucleic acid molecule.

hi another aspect, the invention features an expression vector comprising: a) a transcription initiation region (e.g., eukaryotic pol I, II or III initiation region); b) a transcription termination region (e.g., eukaryotic pol I, II or III termination region); c) a nucleic acid sequence encoding at least one of the nucleic acid catalyst of the instant invention; and wherein said sequence is operably linked to said initiation region and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule. The vector may optionally include an open reading frame (ORF) for a protein operably linked on the 5' side or the 3 '-side of the sequence encoding the nucleic acid catalyst of the invention; and/or an intron (intervening sequences).

Transcription of the nucleic acid molecule sequences are driven from a promoter for eukaryotic RNA polymerase I (pol I), RNA polymerase II (pol II), or RNA polymerase III (pol III). Transcripts from pol II or pol III promoters will be expressed at high levels in all cells; the levels of a given pol II promoter in a given cell type will depend on the nature of the gene regulatory sequences (enhancers, silencers, etc.) present nearby. Prokaryotic RNA polymerase promoters are also used, providing that the prokaryotic RNA polymerase enzyme is expressed in the appropriate cells (Elroy-Stein and Moss, 1990, Proc. Natl. Acad. Sci. U S A, 87, 6743-7; Gao and Huang 1993, Nucleic Acids Res.., 21, 2867-72; Lieber et al, 1993, Methods Enzymol, 217, 47-66; Zhou et al, 1990, Mol Cell Biol, 10, 4529-37). All of these references are incorporated by reference herein.

Several investigators have demonstrated that nucleic acid molecules, such as ribozymes expressed from such promoters can function in mammalian cells (e.g. Kashani-Sabet et al, 1992, Antisense Res. Dev., 2, 3-15; Ojwang et al, 1992, Proc Natl Acad. Sci USA, 89, 10802-6; Chen et al, 1992, Nucleic Acids Res., 20, 4581-9; Yu et al, 1993, Proc. Natl Acad. Sci. USA, 90, 6340-4; L'Huillier et al, 1992, EMBO , 11, 4411-8; Lisziewicz et al, 1993, Proc. Natl Acad. Sci. U S. A, 90, 8000-4; Thompson et al, 1995, Nucleic Acids Res., 23, 2259; and Sullenger & Cech, 1993, Science, 262, 1566). More specifically, transcription units such as the ones derived from genes encoding U6 small nuclear (snRNA), transfer RNA (tRNA) and adenovirus VA RNA are useful in generating high concentrations of desired RNA molecules such as ribozymes in cells (Thompson et al, supra; Couture and Stinchcomb, 1996, supra; Noonberg et al, 1994, Nucleic Acid Res., 22, 2830; Noonberg et al, US Patent No. 5,624,803; Good et al, 1997, Gene Ther., 4, 45; and Beigelman et al, International PCT Publication No. WO 96/18736; all of these publications are incorporated by reference herein. The above ribozyme transcription units can be incorporated into a variety of vectors for introduction into mammalian cells, including but not restricted to, plasmid DNA vectors, viral DNA vectors (such as adenovirus or adeno-associated virus vectors), or viral RNA vectors (such as refroviral or alphavirus vectors) (for a review, see Couture and Stinchcomb, 1996, supra).

In yet another aspect, the invention features an expression vector comprising a nucleic acid sequence encoding at least one of the nucleic acid molecules of the invention, in a manner which allows expression of that nucleic acid molecule. The expression vector comprises in one embodiment; a) a transcription initiation region; b) a transcription termination region; c) a nucleic acid sequence encoding at least one said nucleic acid molecule; and wherein said sequence is operably linked to said initiation region and said tennination region, in a manner which allows expression and/or delivery of said nucleic acid molecule.

In another preferred embodiment, the expression vector comprises: a) a transcription initiation region; b) a transcription termination region; c) an open reading frame; d) a nucleic acid sequence encoding at least one said nucleic acid molecule, wherein said sequence is operably linked to the 3'-end of said open reading frame; and wherein said sequence is operably linked to said initiation region, said open reading frame and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule.

In yet another embodiment the expression vector comprises: a) a transcription initiation region; b) a transcription termination region; c) an intron; d) a nucleic acid sequence encoding at least one said nucleic acid molecule; and wherein said sequence is operably linked to said initiation region, said intron and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule.

In another embodiment, the expression vector comprises: a) a transcription initiation region; b) a transcription termination region; c) an intron; d) an open reading frame; e) a nucleic acid sequence encoding at least one said nucleic acid molecule, wherein said sequence is operably linked to the 3'-end of said open reading frame; and wherein said sequence is operably linked to said initiation region, said intron, said open reading frame and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule.

Examples.

The following are non-limiting examples showing the selection, isolation, synthesis and activity of nucleic acids of the instant invention.

The following examples demonstrate the selection and design of Antisense, hammerhead, DNAzyme, NCH, Amberzyme, Zinzyme, or G-Cleaver ribozyme molecules and binding/cleavage sites within ERG RNA. Nucleic acid inhibition of ERG target RNA

Applicant has studied the effects of TNF-alpha on endothelial genes and has shown that TNF-alpha down-regulates the transcription factor Erg in human umbilical vein endothelial cells (HUVEC) (McLaughlin et al, 1999, J of Cell Science, 112, 4695). Erg is a member of the Ets family of transcription factors which are involved in embryonic development, inflammation, and cellular transformation. An 85 amino acid Ets domain is conserved throughout the family and is necessary for binding a GGAA core DNA binding site. Erg is a proto-oncogene as shown by the ability of NIH3T3 cells overexpressing Erg to form solid tumors in nude mice. Although downstream targets of Erg have not been clearly identified, in vitro evidence exists which suggests that an Erg cDNA can transactivate the vWF, ICAM-2, VE-Cadherin and collagenase promoters using reporter gene assays and purified Erg/GST protein or Erg from endothelial cell nuclear extracts can bind to the VE-Cadherin, stromelysin and vWF promoter Ets sites. Applicant has used an antisense approach to decrease levels of Erg mRNA and protein in HUVEC and identify Erg target genes using differential gene expression (DGE) technology. Applicant shows that Erg regulates several genes involved in vascular cell remodeling and shape change, angiogenesis, proliferation and cell adhesion. Applicant has confirmed that ICAM-2 and vWF are downstream targets of Erg and have identified SPARC, Thrombospondin (TSP-1) and RhoA as new Erg target genes.

The endothelium is now recognised as a structure which provides many functions ranging from a physical barrier between circulating blood and the surrounding tissues, to regulation of vasodynamics, coagulation, fibrinolysis and leukocyte infiltration and angiogenesis. As such dysregulation of the endothelium is implicated in several diseases such as atherosclerosis, thrombosis, diabetes mellitus and vasculitis and tumor growth/metastasis. Several factors, such as the pro-inflammatory cytokine TNF-alpha modulate these functions of the endothelium by changing expression of cell adhesion molecules, extracellular matrix components, growth factors and coagulation factors and signalling molecules. Applicant has been studying the effect of TNF-alpha on down regulation of gene expression in human umbilical vein endothelial cells. TNF-alpha down regulates several endothelial genes such as CD34, protein C, protein S, eNOS and thrombomodulin. Applicant has previously shown that the IgG superfamily member ICAM- 2, which is expressed at high levels on resting endothelium, is down regulated by TNF-alpha after 24 hours (McLaughlin et al, 1998, Cell Adhesion and Communication, 6, 381). This regulation is transcriptional and is mediated by ETS binding sites in the ICAM-2 promoter. Erg is the only ETS member in endothelial cells identified to date which is down regulated by cytokines TNF-alpha or IL-1 beta and applicant has shown that Erg can transactivate the ICAM- 2 promoter in HUVEC. Unlike the closely related adhesion molecule ICAM-1, there is little evidence to implicate ICAM-2 in inflammation, rather in vitro evidence suggests an involvement in trans-endothelial migration of eosinophils , neutrophils , lymphocytes and monocytes.

In order to identify other genes which are regulated by Erg in endothelial cells applicant used an antisense oligonucleotide (GeneBloc) approach to decrease expression of Erg in HUVEC. This approach has been successful in inhibiting expression of the founding member of the ETS family Ets-1 in vitro (Iwasaka et al, 1996, J of Cellular Physiology, 169, 522) and in vivo (Wemert et al, 1999, Agnew Chem Int Ed., 38, 3228) and in demonstrating a role for Ets-1 in angiogenesis.

Applicant has demonstrated that a specific Erg targeting GeneBloc decreased levels of Erg mRNA (by 80-90%) and protein (by 60-80%) in HUVEC during a period of 24-72 hours. RNA from HUVEC treated with either Erg specific GeneBlocs or a control GeneBloc was used in a differential gene expression experiment to compare expression of genes in the presence or near absence of Erg at three timepoints. The grids used in these DGE experiments had the advantage of containing known sequence verified cDNAs which represented genes involved in many cell processes including cell adhesion and migration, angiogenesis, vascular cell signalling, proliferation and haemostasis. The most reproducible hits from this study which were down regulated following Erg GeneBloc treatment ie SPARC, TSP-1, vWF, Rho A, ICAM-2; had a strikingly similar functional theme in being involved in regulation of angiogenesis and cell adhesion. The extracellular matrice protein SPARC was initially shown to alter endothelial cell shape (Sage, 1991, Biochemistry and Cell Biology, 70, 56) and barrier properties (Goldblum et al, 1994, PNAS USA, 91, 3448). Evidence for a role of SPARC in promoting angiogenesis comes from several studies including the down regulation of SPARC expression by antisense which significantly decreased the tumorigenicity of human melanoma cells (Ledda et al, 1997, Nature Med., 3, 171) and the overexpression of SPARC which has been associated with the neoplastic progression of breast and colorectal cancer (Porter et al, 1995, J. of Histochemistry and Cytochemistry, 43, 791; Bellahcene and Casfronovo, 1995, Am. J. Path., 146, 95). Thrombospondin —1 (TSP-1) is also a mafricellular protein which is generally regarded as being anti-adhesive and anti-angiogenic. TSP-1 binds to several molecules including alpha- v-beta-3, CD36, TGF-beta and heparin sulphate proteoglygans (HSPGs) through which it modulates cell adhesion, chemotaxis, angiogenesis and proliferation. vWF is a glycoprotein which mediates cell adhesion and aggregation of platelets and also stabilizes and acts as a carrier protein for the coagulation factor VIII. Interestingly, vWF is down regulated by the pro inflammatory cytokine IL-1-beta and is transcriptionally regulated by Erg in HUVEC (Schwachtgen et al, 1997, Oncogene, 15, 3091). Angiogenic growth factors FGF-2 and VEGF have recently been shown to increase vWF expression on human endothelial cells in vitro (Zanetta et al, 2000, International J. Cancer, 85, 281). Rho A is a ras superfamily member which, when microinjected into fibroblasts causes reorganisation of the actin cytoskeleton and bundling of actin filaments into stress fibres (Nobles and Hall, 1995, Cell, 81, 53). hi endothelial cells, Rho is thought not to be involved in contractility but in cell flattening and maintenance of barrier function. Applicant has demonstrated that SPARC, TSP-1 and vWF secreted proteins are down regulated in HUVEC following 24 hours of TNF-alpha treatment. Of the Erg regulated genes presently identified, only the ICAM-2 and vWF promoters have been directly shown to be transactivated by Erg.

Applicant investigated further the role of Erg in vascular cell remodelling and adhesion using and in vitro model of angiogenesis. Endothelial cells plated on Matrigel undergo a morphological rearrangement which requires new mRNA and protein expression and after a period up to 16 hours, tubule formation is complete. HUVEC treated with Erg targeting GeneBlocs for 24 hours were plated on Matrigel and allowed to form tubules overnight. Cells in which Erg expression was decreased due to GeneBloc treatment had a reduced capacity to form tubules than cells treated with a specific control GeneBloc. This assay clearly demonstrates a role for Erg as a direct modulator of the morphological changes of endothelial cells which are a prerequisite for the in vivo process of angiogenesis. Further support for this cellular function of Erg comes from recent work in Xenopus embyros. A Xenopus homologue of Erg, Xl-erg, was microinjected into embryos and several developmental defects were observed including eye malfromations and ectopic endotheial differentiation (Baltzinger et al, 1999, Developmental Dynamics, 216, 420). The authors postulate that Xenopus Erg may be involved in cell motility and regulation of cell adhesion and angiogenesis. Here applicant has identified Erg directly as being a regulator of both cell adhesion molecules and matricellular proteins which can either promote and/or stimulate angiogenesis. One issue which remains unclear is the relationship between the pro-inflammatory cytokine TNF-alphaD which down regulates Erg, and the angiogenic process which is perturbed when Erg protein levels are significantly reduced. Several studies provide evidence of a link between TNF-alpha and angiogenesis in vivo and TNF-alpha regulates expression of angiogenic molecules Vascular Endothelial Growth Factor Receptor-2 and Neurophilin-1 (Giraudo et al, 1998, J. Biol Chem., 273, 22128). Whether TNF-alpha is pro or anti-angiogenic may depend on the system used to study and the particular microenvironment. In tumor endothelium, the upregulation of pro-inflammatory adhesion molecules in response to TNF-alpha is reduced in comparison to normal endothelium and this is mediated by angiogenic factors such as FGF (Griffioen et al, 1996, Blood, 88, 667). In vitro, TNF-alpha has many anti- angiogenic/anti-proliferative properties, for example it blocks basal Fibroblast Growth Factor stimulated growth of endothelial cells (Frater-Schroder et al, 1987, PNAS USA, 84, 5277). Applicant describes experiments where Erg targeting GeneBlocs inhibited the formation of endothelial tube formation in vitro, however TNF-a treatment of HUVEC on Matrigel has never been reported to have this effect. However, the extent of inhibition of Erg expression by GeneBlocs, which is more profound than the inhibition of Erg expression by TNF-alpha, explains these differences in phenotypic effects on endothelial cell tube formation. In conclusion, applicant has demonstrated that the transcription factor Erg regulates expression of cell adhesion and matricellular proteins ICAM-2, SPARC, TSP-1, Rho A and vWF and is a modulator of in vitro angiogenesis. Strategies aimed at regulation of Erg may be of use in the therapy of diseases such as cancer, rheumatoid arthritis, osteoporosis and wound healing.

Example 1 : Identification of Potential Target Sites in Human ERG RNA

The sequence of human ERG is screened for accessible sites using a computer-folding algorithm. Regions of the RNA are identified that do not form secondary folding structures. These regions contain potential ribozyme and/or antisense binding/cleavage sites. The sequences of these binding/cleavage sites are shown in Tables III-IX. Example 2: Selection of Enzymatic Nucleic Acid Cleavage Sites in Human ERG RNA

Ribozyme target sites are chosen by analyzing sequences of Human ERG (GenBank accession numbers: M21535 and NM_004449) and prioritizing the sites on the basis of folding. Ribozymes are designed that could bind each target and are individually analyzed by computer folding (Christoffersen et al, 1994 J. Mol. Struc. Theochem, 311, 273; Jaeger et al, 1989, Proc. Natl. Acad. Sci. USA, 86, 7706) to assess whether the ribozyme sequences fold into the appropriate secondary structure. Those ribozymes with unfavorable intramolecular interactions between the binding arms and the catalytic core are eliminated from consideration. As noted below, varying binding arm lengths can be chosen to optimize activity. Generally, at least 5 bases on each arm are able to bind to, or otherwise interact with, the target RNA.

Example 3: Chemical Synthesis and Purification of Ribozymes and Antisense for Efficient Cleavage and/or blocking of ERG RNA

Ribozymes and antisense constructs are designed to anneal to various sites in the RNA message. The binding arms of the ribozymes are complementary to the target site sequences described above, while the antisense constructs are fully complimentary to the target site sequences described above. The ribozymes and antisense constructs were chemically synthesized. The method of synthesis used followed the procedure for normal RNA synthesis as described above and in Usman et al, (1987 J. Am. Chem. Soc, 109, 7845), Scaringe et al, (1990 Nucleic Acids Res., 18, 5433) and Wincott et al, supra, and made use of common nucleic acid protecting and coupling groups, such as dimethoxytrityl at the 5'-end, and phosphoramidites at the 3'-end. The average stepwise coupling yields were typically >98%.

Ribozymes and antisense constructs are also synthesized from DNA templates using bacteriophage T7 RNA polymerase (Milligan and Uhlenbeck, 1989, Methods Enzymol. 180, 51). Ribozymes and antisense constructs are purified by gel electrophoresis using general methods or are purified by high pressure liquid chromatography (HPLC; see Wincott et al, supra; the totality of which is hereby incorporated herein by reference) and are resuspended in water. The sequences of the chemically synthesized ribozymes and antisense constructs used in this study are shown below in Table III-IX.

Example 4: Ribozyme Cleavage of ERG RNA Target in vitro

Ribozymes targeted to the human ERG RNA are designed and synthesized as described above. These ribozymes can be tested for cleavage activity in vitro, for example, using the following procedure. The target sequences and the nucleotide location within the ERG RNA are given in Tables III-IX. Cleavage Reactions: Full-length or partially full-length, internally-labeled target RNA for ribozyme cleavage assay is prepared by in vitro transcription in the presence of [a-32p] CTP, passed over a G 50 Sephadex® column by spin chromatography and used as substrate RNA without further purification. Alternately, substrates are 5'-32p-end labeled using T4 polynucleotide kinase enzyme. Assays are performed by pre-warming a 2X concentration of purified ribozyme in ribozyme cleavage buffer (50 mM Tris-HCl, pH 7.5 at 37°C, 10 mM MgCl2) and the cleavage reaction was initiated by adding the 2X ribozyme mix to an equal volume of substrate RNA (maximum of 1-5 nM) that was also pre-warmed in cleavage buffer. As an initial screen, assays are carried out for 1 hour at 37 C using a final concentration of either 40 nM or 1 mM ribozyme, i.e., ribozyme excess. The reaction is quenched by the addition of an equal volume of 95% formamide, 20 mM EDTA, 0.05% bromophenol blue and 0.05% xylene o cyanol after which the sample is heated to 95 C for 2 minutes, quick chilled and loaded onto a denaturing polyacrylamide gel. Substrate RNA and the specific RNA cleavage products generated by ribozyme cleavage are visualized on an autoradiograph of the gel. The percentage of cleavage is determined by Phosphor Imager® quantitation of bands representing the intact substrate and the cleavage products.

Example 5: Delivery of GeneBlocs to HUVEC

HUVEC (Biowhittaker, Berkshire UK) were seeded at 1x10(5) cells per well of a six well dish in EGM-2 (BioWhittaker, UK) the day before transfection. GeneBloc (final concentration 50nM) and cationic lipid (from Atugen Inc; final concentration 2μg/ml) were complexed in EGM basal media (Biowhittaker, UK) at 37°C for 30 mins in polystyrene tubes. Following vortexing, the lipid/GeneBloc was added to each well and incubated for the times indicated. For initial optimisation experiments, cells were seeded at lxl 0³ in 96 well plates and lipid GeneBloc added as described. Efficiency of delivery of GeneBloc to HUVEC was determined using a fluorescent GeneBloc, complexed with lipid as described. HUVEC in 6 well dishes were incubated with GeneBloc for 24 hours, rinsed with PBS and fixed in 2% paraformaldehyde for 15 minutes at room temperature. Uptake of GeneBloc was visualised using a fluorescent microscope (Nikon).

Example 6: Taqman and Lightcycler quantification of mRNA

Total RNA was prepared from HUVEC following GeneBloc delivery using Qiagen RNA purification kits for 6 well or Rneasy extraction kit for 96 well assays (Qiagen Ltd, UK). For Taqman analysis, dual-labeled probes were synthesized with the reporter dye, FAM or JOE, covalently linked at the 5' end and the quencher dye TAMRA conjugated to the 3' end. One-step RT-PCR amplifications were performed on the ABI PRISM 7700 Sequence Detector using 50 μl reactions consisting of 10 μl total RNA, 100 nM forward primer, 900 nM reverse primer, 100 nM probe, IX TaqMan PCR reaction buffer (PE-Applied Biosystems), 5.5 mM MgCl₂, 300 μM each dATP, dCTP, dGTP, and dTTP, 10U RNase Inhibitor (Promega), 1.25U AmpliTaq Gold (PE-Applied Biosystems) and 10U M-MLV Reverse Transcriptase (Promega). The thermal cycling conditions consisted of 30 min at 48°C, 10 min at 95°C, followed by 40 cycles of 15 sec at 95°C and 1 min at 60°C. Quantitation of mRNA levels were determined relative to standards generated from serially diluted total HUVEC RNA (300, 100, 33, 11 ng/rxn) and normalizing to ^β-actin or GAPDH mRNA in parallel TaqMan reactions. For each gene of interest an upper and lower primer and a flourescently labelled probe were designed as follows: Erg 5' primer GGAGTGGGCGGTGAAAGA; Erg 3' primer AAGGATGTCGGCGTTGTAGC; Erg probe (FAM)TGGCCTTCCAGACGTCAACATCTTGTTATT; ICAM-2 5' primer

ATCTGTCCTGCTCTGCTTCATCT; ICAM-2 3' primer CGTAGGTGCCCATCCGC; ICAM-2 probe CGGCCAGCACTTGCGCCA; Rho 5' primer TTAACGATGTCCAACCCGTCT; Rho 3' primer GGTGGGAGTGCAGAGGAGG; Rho probe

CAGGGTCCTTTTGACACTGCTCTAACAGCC; Actin 5' primer(GCA TGG GTC AGA AGG ATT CCT AT); Actin 3 ' primer (TGT AGA AGG TGT GGT GCC AGA TT); Actin probe (Joe TCGAGCACGGCATCGTCACCAA); GAPDH primer/ probe (vie) was purchased from Perkin Elmer (cat no 4310884E). For analysis of gene expression using the Lightcycler (Roche Molecular Biochemicals, Germany) the following primers were used: vWF 5' CTTGGTCACATCTTCACATTCACT; vWF 3' GACACAGCTGCCTTCCAACAT; Thrombospondin 5' ATGCTGGTGGTAGACTAGGGTTGTTT; Thrombospondin 3' GAAGGAGGATGTCAGGGTGGTTT; SPARC 5' AATGTTTGGATGGTTTGTTGTTCTGC; SPARC 3' ACGTTCTGGTTGGTGGATTCTGC; GAPDH 5'ACCACAGTCCATGCCATCAC ; GAPDH 3'ACCACAGTCCATGCCATCAC. Real time incorporation of SYBR Green I dye into a specific PCR product was measured in glass capillary tubes using the lightcyler (Roche, Germany). A standard curve was generated for each primer pair using control HUVEC RNA and values are represented as relative expression to GAPDH in each sample.

Example 7: Western blotting

All nuclear extracts were prepared using the micropreparation technique (Andrews and Faller, 1991, Nucleic Acids Research, 19, 2499). Protein extracts from supematants were prepared using TCA precipitation. Briefly, an equal volume of 20% TCA was added to the cell supernatant, incubated on ice for 1 hour and pelleted by centrifugation for 5 minutes. Pellets were washed in acetone, dried and resuspended in water. HUVEC protein extracts were run on a 10% Bis-Tris NuPage (nuclear extracts) or 4-12% Tris-Glycine (supernatant extracts) polyacrylamide gel (Novex, USA) following the manufacturers protocols and transferred onto nitro-cellulose membranes using Novex X Cell-II module at 25mA for 90 minutes. Non-specific binding was blocked by incubation with 5% non-fat milk for 1 hour followed by primary antibody for 16 hour at 4°C. Antibodies for Western blotting were as follows: vWF (Rabbit polyclonal A0082, DAKO) 1:100; SPARC (monoclonal ONl-1, Takara Biomedicals) 1:1000; Thrombospondin (TSP-B7, Sigma) 1:100; Following washes, the secondary antibody was applied (1:10,000 dilution; Sigma, UK) for 1 hour at room temperature and the signal detected with the SuperSignal reagent (Pierce, UK).

Example 8: Differential gene expression

Sequence verified cDNA arrays on nylon filters were prepared. RNA was prepared from HUVEC treated with Erg GeneBloc or a random control GeneBloc 3.3 as described. RNA was precipitated overnight and analysed on a DMSO/Glyoxal/agarose gel to check the quantity and integrity of the RNA. Approximately lOμg total RNA was used to generate duplicate radiolabelled cDNA probes using Superscript II (Sfratagene, USA) and α-³³P dCTP (Amersham, UK). After purification on a G50 column (Amersham, UK), probes were run on a 6% TBE Urea gel (Novex) alongside known size markers and the image data captured using a Storm Scanner (Molecular Dynamics) for quality control of probe length. As all cDNAs on the membrane contain M13 sequence an M13 oligonucleotide probe, end labelled with γ-33P dATP, was hybridised to the membranes to control for differences in loading. For pre-hybridisation, membranes were incubated in DIG Easy Hyb (Boehringer) at 45°C for 30 minutes and were then hybridised overnight in DIG Easy Hyb containing probe at 45°C. Membranes were washed 3x15 minutes in 6xSSC, 0.5%> SDS at 45oC and placed in a phosphoscreen. 48 hours later the image data was captured using a Storm Scanner. The complex probe was spiked with a radiolabelled luciferase probe (for orientation of the grids at a later stage) and quenched by incubation with poly dA₈₀ and Cot-1 DNA (Life Technologies, UK). Filters were pre-hybridised as described and hybridised for 3 days at 45°C. Filters were washed for 3x15 minutes at 68°C and placed in phosphoscreens for at least 2 days. Data was analysed using DGent software (Glaxo Wellcome, UK), nonnalised using M13 hybridisation data and compared in a 4 way analysis using duplicate probes and replica filters. Genes were selected which were consistently down regulated by Erg GeneBloc in each of these analyses.

Example 9: Endothelial tube formation

Aliquots of Matrigel (Becton Dickinson, UK) were thawed on ice and 200μl were plated onto chilled 24 well plates and incubated at 37°C for 30 minutes to form a gel as per the manufacturers instructions. HUVEC in 6 well plates were treated with the Erg GeneBloc or the Mismatch GeneBloc for 24 hours as described, trypsinised, counted, and 4x10⁴ cells in EGM-2 were added to each well containing matrigel. After 16 hours, tubule formation was analysed using a Leica 550 image analyser, capturing dark field low magnification images, processing them to remove background, then skeletonising and counting the total curve length (μM) and the number of branches.

Example 10: Erg GeneBlocs decrease Erg mRNA and protein levels in HUVEC

In order to clearly define Erg regulated genes in endothelial cells, antisense oligonucleotides (GeneBlocs) were designed. GeneBlocs are modified RNA oligonucleotides which less susceptible to degradation, have reduced toxicity and increased target binding affinity than traditional antisense oligonucleotides. GeneBlocs were designed to target a region of human Erg which was not homologous to other closely related Ets family members Ets-1, Ets-2, Fli-1 or Nerf ,which are also expressed in endothelial cells (see Figure 1). In initial studies 8 Erg GeneBlocs were designed and inhibition of Erg mRNA in HUVEC was assayed using Taqman. Two GeneBlocs (14573 and 14566) gave greater than 80% inhibition of Erg mRNA levels after 24 hours, when compared to a random scrambled control GeneBloc (11698). This inhibition lasted for at least 72 hours of continuous GeneBloc delivery, see Figure 6. GeneBloc 14566 was used in all subsequent studies.

In order to investigate whether the observed decrease in Erg mRNA was paralleled in Erg protein, nuclear extracts were prepared from HUVEC seeded in 6 well dishes which were treated with Erg GeneBloc (GB14566) or with the control GeneBloc (11698). Western analysis of these samples demonstrated that Erg protein levels are decreased upon treatment of HUVEC with the Erg specific GeneBloc for 24, 48 and 72 hours. In each case, samples were normalised against expression of the ubiquitous transcription factor Oct-1 which should not be affected by treatment with Erg GeneBloc. Densitometry was performed on the bands representing Erg and Oct-1 proteins and the ratio of Erg:Oct demonstrated that protein levels of Erg were decreased approximately 2.5 fold after 24 and 48 hours of Erg GeneBloc treatment, and by 5 fold after 72 hours of treatment, when compared to the control GeneBloc treatment.

Example 11 : Differential gene expression of HUVEC treated with Erg GeneBloc

Having demonstrated that Erg mRNA and protein were greatly reduced in cells receiving Erg GeneBloc treatment, total RNA from cells treated with Erg GeneBloc (GB14566) or control GB (11698) for 24, 48 and 72 hours was used to prepare radiolabelled cDNA probes for DGE analysis. These probes were hybridised to in-house generated grids which contain 492 sequence verified cDNAs. The hybridisation data was normalised for loading (Ml 3 oligo hybridisation) and then compared using Glaxo Wellcome' s DGent software to look for genes which were down regulated upon Erg GeneBloc treatment. Several hits were identified which were consistently down regulated when comparing duplicate cDNAs on the same grid and comparing across filters hybridised wit replicate radiolabelled probes. Decreases in gene expression of a magnitude less than 1.4 fold were excluded. Many of the genes which were down regulated following Erg GeneBloc treatment had a common functional theme, i.e. were involved in vascular remodelling and cell adhesion. These genes are listed in Table X.

Example 12: Real-time PCR analysis of DGE hits

In order to confirm that the genes listed in Table X were true downstream targets of Erg, applicant attempted to validate the DGE results using a second method of RNA quantification. A new set of RNA was generated from cells treated with the Erg GeneBloc 14566. A different control GeneBloc was used in these experiments which has 4 base mismatches compared to the Erg GeneBloc and is therefore a more specific confrol (GB 17478). This mismatch control GeneBloc was tested using Taqman as before, and did not inhibit Erg mRNA after 24, 48 or 72 hours of treatment (see Figure 7). The Taqman system was used to study expression of ICAM-2 and RhoA in these samples. In order to select an appropriate control gene to be used to normalise the data applicant used the Taqman endogenous control plate, which is designed to assess the variations in expression of a panel of 11 putative housekeeping genes during a particular treatment. As can be seen in Table XI, expression of GAPDH was the least variable between treatments and was therefore used in subsequent experiments to normalise the data. Analysis of ICAM-2 and Rho-A mRNA showed that they are both down regulated in HUVEC after 24 hours of treatment with the Erg GeneBloc compared to the Erg MM (see Figure 8A). Applicant used the Roche Lightcycler to detect levels of SPARC, Thrombospondin (TSP) and von Willebrand Factor (vWF) in same samples as above (see Figure 8B). As can be seen, expression of these genes is decreased to various degrees after 24 hours of Erg GeneBloc treatment. Not all genes applicant analysed by real-time PCR were down regulated, for example fibronectin expression was unchanged after 24 hours of treatment and was upregulated after 48 and 72 hours of Erg GeneBloc treatment. Therefore the 5 genes which applicant has identified as being down regulated in the presence of Erg GeneBloc by DGE were confiπned as being downstream targets of Erg in endothelial cells, using a second set of RNA and real time PCR quantification.

Example 13: TNF-α regulation of DGE hits in endothelial cells

The pro-inflammatory cytokine TNF-alpha down regulates Erg protein in HUVEC after 24 hours (Sage, 1997, Nature Med, 3, 144; Roberts, 1996, FASEB J, 10, 1183; Tolsma et al, 1993, J. Cell Biol, 122, 497). Applicant has also shown that TNF-alpha down regulates ICAM-2 expression with a similar timecourse to the down regulation of Erg. Applicant investigated the effect of TNF-alpha on expression of the secreted proteins vWF, SPARC and TSP-1. HUVEC were treated with TNF-alpha (lOμg/ml) for 24 hours and protein extracts were prepared from the cell supematants. Protein levels of SPARC, TSP and vWF were all markedly decreased in response to 24 hours of TNF-alpha treatment. Therefore SPARC, TSP-1 and vWF, all identified by applicant as being downstream target genes of Erg, are also down regulated by TNF-alpha in endothelial cells.

Example 14: Effect of Erg GeneBloc on endothelial cell tube formation

SPARC and TSP-1 are well characterized to play a role in angiogenesis, cell shape change, motility, differentiation and proliferation. Therefore applicant tested the ability of Erg GeneBlocs to modulate endothelial tube formation in a 3D culture system. An identical number of HUVEC, treated with Erg GeneBloc (14566) or control GeneBloc (17478) for 24 hours, were plated on Matrigel in 24 well dishes and allowed to form tubes over 16 hours. Photographs of cells on matrigel after treatment with Erg GeneBloc or the mismatch control GeneBloc were analyzed. The number of branches formed in each well were quantified and this is shown graphically in Figure 9. There is a clear reduction in tube formation of HUVEC when in the presence of Erg GeneBloc and the number of branches formed is reduced approximately three fold.

Indications

Particular conditions and disease states that can be associated with ERG expression modulation include but are not limited to a broad spectrum of oncology and neovascularization- related indications, including but not limited to cancers of the lung, colon, breast, prostate, and cervix, lymphoma, Ewing's sarcoma and related tumors, melanoma, angiogenic disease states such as tumor angiogenesis, diabetic retinopathy, macular degeneration, neovascular glaucoma, myopic degeneration, arthritis such as rheumatoid arthritis, psoriasis, verruca vulgaris, angiofibroma of tuberous sclerosis, pot- wine stains, Sturge Weber syndrome, Kippel-Trenaunay- Weber syndrome, Osier- Weber-rendu syndrome, leukemias such as acute myeloid leukemia, osteoporosis, wound healing and any other diseases or conditions that are related to or will respond to the levels of ERG in a cell or tissue, alone or in combination with other therapies.

The present body of knowledge in ERG research indicates the need for methods to assay ERG activity and for compounds that can regulate ERG expression for research, diagnostic, and therapeutic use.

The nucleic acid molecules of the present invention may also be administered to a patient in combination with other therapeutic compounds to increase the overall therapeutic effect. The use of multiple compounds to treat an indication may increase the beneficial effects while reducing the presence of side effects. Radiation treatments and chemotherapeutics such as paclitaxel (Taxol), docetaxel, cisplatin (carboplatin), methofrexate, cyclophosphamide, doxorubin (doxorubicin), 5-fluorouracil (5-FU), leucovorin, vinorelbine, vinblastine, cyclophosphamide, ifosfamide, etoposide, methofrexate, gemcitabine, irinotecan, interferons, herceptin, thalidomide, matrix metalloproteinase inhibitors, tyrosine kinase inhibitors, and antibodies are non-limiting examples of compounds and/or methods that can be combined with or used in conjunction with the nucleic acid molecules (e.g. ribozymes and antisense molecules) of the instant invention. Those skilled in the art will recognize that other drug compounds and therapies can be similarly and readily combined with the nucleic acid molecules of the instant invention (e.g. ribozymes and antisense molecules) and are, therefore, within the scope of the instant invention.

Cell Culture

There are several cell-culture models that can be utilized to determine the efficacy of nucleic acid molecules of the instant invention directed against Erg expression. Hart et al, 1995,

Oncogene, 10(7), 1423-30, describe the transfection of NTH3T3 cells with an Erg expression construct consisting of human Erg cDNA diven by the sheep metallothionein la promoter

(sMTERG). Established clonal cell lines overexpressing Erg became morphologically altered, grew in low-serum and serum free media, and gave rise to colonies in soft agar suspension. ^' These colonies resulted in the formation of solid tumors when injected into nude mice. Yi et al,

1997, Oncogene, 14(11), 1259-1268, describe the expression of Erg and aberrant Erg fusion proteins as inhibitory in the induction of apoptosis in NIH3T3 and Ewing's sarcoma cells induced by either serum deprivation or by treatment with calcium ionophore. Inhibition of the expression of the aberrant fusion proteins by antisense RNA techniques resulted in the increased susceptibility of these cells to apoptosis leading to cell death. As such, these cell lines can be used for the evaluation of nucleic acid molecules of the instant invention via Erg RNA knockdown, Erg protein knockdown, and proliferation-based endpoints.

Animal Models

There are several animal models in which the anti-proliferative and anti-angiogenic effect of nucleic acids of the present invention, such as ribozymes, directed against Erg RNA can be tested. The mouse model described by Hart et al, supra, can be used to evaluate nucleic acid molecules of the instant invention in vivo for anti-tumorigenic capacity. Additional models can be used to study the anti-angiogenic capacity of the nucleic acid molecules of the instant invention. Typically a corneal model has been used to study angiogenesis in rat and rabbit since recruitment of vessels can easily be followed in this normally avascular tissue (Pandey et al, 1995 Science 268: 567-569). In these models, a small Teflon or Hydron disk pretreated with an angiogenic compound is inserted into a pocket surgically created in the cornea. Angiogenesis is monitored 3 to 5 days later. Ribozymes directed against ARNT, Tie-2 or integrin subunit RNAs would be delivered in the disk as well, or dropwise to the eye over the time course of the experiment. In another eye model, hypoxia has been shown to cause both increased expression of VEGF and neovascularization in the retina (Pierce et al, 1995 Proc. Natl. Acad. Sci. USA. 92: 905-909; Shweiki et α/., 1992 J. Clin. Invest. 91: 2235-2243).

Another animal model that addresses neovascularization involves Matrigel, an extract of basement membrane that becomes a solid gel when injected subcutaneously (Passaniti et al, 1992 Lab. Invest. 67: 519-528). When the Matrigel is supplemented with angiogenesis factors, vessels grow into the Matrigel over a period of 3 to 5 days and angiogenesis can be assessed. Again, ribozymes directed against ARNT, Tie-2 or integrin subunit RNAs would be delivered in the Matrigel.

Several animal models exist for screening of anti-angiogenic agents. These include corneal vessel formation following corneal injury (Burger et al, 1985 Cornea 4: 35-41; Lepri, et al, 1994 J. Ocular Pharmacol 10: 273-280; Ormerod et α/., 1990 Am. J Pathol 137: 1243-1252) or infracorneal growth factor implant (Grant et al, 1993 Diabetologia 36: 282-291; Pandey et al 1995 supra; Zieche et al, 1992 Lab. Invest. 67: 711-715), vessel growth into Matrigel matrix containing growth factors (Passaniti et al, 1992 supra), female reproductive organ neovascularization following hormonal manipulation (Shweiki et al, 1993 Clin. Invest. 91: 2235-2243), several models involving inhibition of tumor growth in highly vascularized solid tumors (O'Reilly et al, 1994 Cell 79: 315-328; Senger et al, 1993 Cancer andMetas. Rev. 12: 303-324; Takahasi et al, 1994 Cancer Res. 54: 4233-4237; Kim et al, 1993 supra), and transient hypoxia-induced neovascularization in the mouse retina (Pierce et al, 1995 Proc. Natl. Acad. Sci USA. 92: 905-909).

The cornea model, described in Pandey et al. supra, is the most common and well characterized anti-angiogenic agent efficacy screening model. This model involves an avascular tissue into which vessels are recruited by a stimulating agent (growth factor, thermal or alkalai burn, endotoxin). The comeal model would utilize the infrastromal corneal implantation of a Teflon pellet soaked in a angiogenic compound-Hydron solution to recruit blood vessels toward the pellet which can be quantitated using standard microscopic and image analysis techniques. To evaluate their anti-angiogenic efficacy, ribozymes are applied topically to the eye or bound within Hydron on the Teflon pellet itself. This avascular cornea as well as the Matrigel (see below) provide for low background assays. While the comeal model has been performed extensively in the rabbit, studies in the rat have also been conducted. The mouse model (Passaniti et al., supra) is a non-tissue model which utilizes Matrigel, an extract of basement membrane (Kleinman et al., 1986) or Millipore® filter disk, which can be impregnated with growth factors and anti-angiogenic agents in a liquid form prior to injection.

Upon subcutaneous administration at body temperature, the Matrigel or Millipore® filter disk forms a solid implant. An angiogenic compound would be embedded in the Matrigel or

Millipore® filter disk which would be used to recruit vessels within the matrix of the Matrigel or

Millipore® filter disk that can be processed histologically for endothelial cell specific vWF (factor VIII antigen) immunohistochemistry, Trichrome-Masson stain, or hemoglobin content.

Like the cornea, the Matrigel or Millipore® filter disk are avascular; however, it is not tissue. In the Matrigel or Millipore® filter disk model, ribozymes are administered within the matrix of the

Matrigel or Millipore® filter disk to test their anti-angiogenic efficacy. Thus, delivery issues in this model, as with delivery of ribozymes by Hydron- coated Teflon pellets in the rat cornea model, may be less problematic due to the homogeneous presence of the ribozyme within the respective matrix.

Other model systems to study tumor angiogenesis is reviewed by Folkman, 1985 Adv.

Cancer. Res., 43, 175.

Use of murine models

For a typical systemic study involving 10 mice (20 g each) per dose group, 5 doses (1, 3,

10, 30 and 100 mg/kg daily over 14 days continuous administration), approximately 400 mg of ribozyme, formulated in saline would be used. A similar study in young adult rats (200 g) would require over 4 g. Parallel pharmacokinetic studies may involve the use of similar quantities of ribozymes further justifying the use of murine models.

Ribozymes and Lewis lung carcinoma and B-16 melanoma murine models

Identifying a common animal model for systemic efficacy testing of ribozymes is an efficient way of screening ribozymes for systemic efficacy. The Lewis lung carcinoma and B-16 murine melanoma models are well accepted models of primary and metastatic cancer and are used for initial screening of anti-cancer. These murine models are not dependent upon the use of immunodeficient mice, are relatively inexpensive, and minimize housing concerns. Both the Lewis lung and B-16 melanoma models involve subcutaneous implantation of approximately 10⁶ tumor cells from metastatically aggressive tumor cell lines (Lewis lung lines 3LL or D122, LLc- LN7; B-16-BL6 melanoma) in C57BL/6J mice. Alternatively, the Lewis lung model can be produced by the surgical implantation of tumor spheres (approximately 0.8 mm in diameter). Metastasis also may be modeled by injecting the tumor cells directly i.v.. In the Lewis lung model, microscopic metastases can be observed approximately 14 days following implantation with quantifiable macroscopic metastatic tumors developing within 21-25 days. The B-16 melanoma exhibits a similar time course with tumor neovascularization beginning 4 days following implantation. Since both primary and metastatic tumors exist in these models after 21- 25 days in the same animal, multiple measurements can be taken as indices of efficacy. Primary tumor volume and growth latency as well as the number of micro- and macroscopic metastatic lung foci or number of animals exhibiting metastases can be quantitated. The percent increase in lifespan can also be measured. Thus, these models would provide suitable primary efficacy assays for screening systemically administered ribozymes/ribozyme formulations.

In the Lewis lung and B-16 melanoma models, systemic pharmacotherapy with a wide variety of agents usually begins 1-7 days following tumor implantation/inoculation with either continuous or multiple administration regimens. Concurrent pharmacokinetic studies can be performed to determine whether sufficient tissue levels of ribozymes can be achieved for pharmacodynamic effect to be expected. Furthermore, primary tumors and secondary lung metastases can be removed and subjected to a variety of in vitro studies (i.e. target RNA reduction).

Delivery of ribozymes and ribozyme formulations in the Lewis lung model

Several ribozyme formulations, including cationic lipid complexes which may be useful for inflammatory diseases (e.g. DIMRIE/DOPE, etc.) and RES evading liposomes which may be used to enhance vascular exposure of the ribozymes, are of interest in cancer models due to their presumed biodistribution to the lung. Thus, liposome formulations can be used for delivering ribozymes to sites of pathology linked to an angiogenic response.

Diagnostic uses

The nucleic acid molecules of this invention (e.g., ribozymes) may be used as diagnostic tools to examine genetic drift and mutations within diseased cells or to detect the presence of ERG RNA in a cell. The close relationship between ribozyme activity and the structure of the target RNA allows the detection of mutations in any region of the molecule which alters the base-pairing and three-dimensional structure of the target RNA. By using multiple ribozymes described in this invention, one may map nucleotide changes which are important to RNA structure and function in vitro, as well as in cells and tissues. Cleavage of target RNAs with ribozymes may be used to inhibit gene expression and define the role (essentially) of specified gene products in the progression of disease. In this manner, other genetic targets may be defined as important mediators of the disease. These experiments will lead to better treatment of the disease progression by affording the possibility of combinational therapies (e.g., multiple ribozymes targeted to different genes, ribozymes coupled with known small molecule inhibitors, or intermittent treatment with combinations of ribozymes and/or other chemical or biological molecules). Other in vitro uses of ribozymes of this invention are well known in the art, and include detection of the presence of mRNAs associated with ERG-related condition. Such RNA is detected by determining the presence of a cleavage product after treatment with a ribozyme using standard methodology.

In a specific example, ribozymes which can cleave only wild-type or mutant forms of the target RNA are used for the assay. The first ribozyme is used to identify wild-type RNA present in the sample and the second ribozyme will be used to identify mutant RNA in the sample. As reaction controls, synthetic substrates of both wild-type and mutant RNA will be cleaved by both ribozymes to demonstrate the relative ribozyme efficiencies in the reactions and the absence of cleavage of the "non-targeted" RNA species. The cleavage products from the synthetic substrates will also serve to generate size markers for the analysis of wild-type and mutant RNAs in the sample population. Thus, each analysis can require two ribozymes, two substrates and one unknown sample, which will be combined into six reactions. The presence of cleavage products will be determined using an RNAse protection assay so that full-length and cleavage fragments of each RNA can be analyzed in one lane of a polyacrylamide gel. It is not absolutely required to quantify the results to gain insight into the expression of mutant RNAs and putative risk of the desired phenotypic changes in target cells. The expression of mRNA whose protein product is implicated in the development of the phenotype (i.e., ERG) is adequate to establish risk. If probes of comparable specific activity are used for both transcripts, then a qualitative comparison of RNA levels will be adequate and will decrease the cost of the initial diagnosis. Higher mutant form to wild-type ratios will be correlated with higher risk whether RNA levels are compared qualitatively or quantitatively.

Additional Uses

Potential usefulness of sequence-specific enzymatic nucleic acid molecules of the instant invention might have many of the same applications for the study of RNA that DNA restriction endonucleases have for the study of DNA (Nathans et al, 1975 Ann. Rev. Biochem. 44:273). For example, the pattern of restriction fragments could be used to establish sequence relationships between two related RNAs, and large RNAs could be specifically cleaved to fragments of a size more useful for study. The ability to engineer sequence specificity of the enzymatic nucleic acid molecule is ideal for cleavage of RNAs of unknown sequence. Applicant describes the use of nucleic acid molecules to down-regulate gene expression of target genes in bacterial, microbial, fungal, viral, and eukaryotic systems including plant, or mammalian cells.

All patents and publications mentioned in the specification are indicative of the levels of skill of those skilled in the art to which the invention pertains. All references cited in this disclosure are incorporated by reference to the same extent as if each reference had been incorporated by reference in its entirety individually.

One skilled in the art would readily appreciate that the present invention is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those inherent therein. The methods and compositions described herein as presently representative of preferred embodiments are exemplary and are not intended as limitations on the scope of the invention. Changes therein and other uses will occur to those skilled in the art, which are encompassed within the spirit of the invention, are defined by the scope of the claims.

It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. Thus, such additional embodiments are within the scope of the present invention and the following claims.

The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. Thus, for example, in each instance herein any of the terms "comprising", "consisting essentially of and "consisting of may be replaced with either of the other two terms. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments, optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the description and the appended claims.

In addition, where features or aspects of the invention are described in terms of Markush groups or other grouping of alternatives, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group or other group.

Other embodiments are within the following claims.

Table I

TABLE I

Characteristics of naturally occurring ribozymes Group I Introns

^• Size: ~150 to >1000 nucleotides.

^• Requires a U in the target sequence immediately 5' of the cleavage site.

• Binds 4-6 nucleotides at the 5 -side of the cleavage site.

• Reaction mechanism: attack by the 3'-OH of guanosine to generate cleavage products with 3'-OH and 5' -guanosine.

^• Additional protein cof actors required in some cases to help folding and maintainance of the active structure.

^• Over 300 known members of this class. Found as an intervening sequence in Tetrahymena thermophila rRNA, fungal mitochondria, chloroplasts, phage T4, blue- green algae, and others.

• Major structural features largely established through phylogenetic comparisons, mutagenesis, and biochemical studies [V¹].

^• Complete kinetic framework established for one ribozyme [ ,^iv,^v,^vi]-

• Studies of ribozyme folding and substrate docking underway [^vii,^viii,^ix].

• Chemical modification investigation of important residues well established [^x,^xi] .

• The small (4-6 nt) binding site may make this ribozyme too non-specific for targeted RNA cleavage, however, the Tetrahymena group I intron has been used to repair a "defective" D-galactosidase message by the ligation of new D- galactosidase sequences onto the defective message [^xii].

RNAse P RNA (Ml RNA)

• Size: -290 to 400 nucleotides.

• RNA portion of a ubiquitous ribonucleoprotein enzyme.

• Cleaves tRNA precursors to form mature tRNA [^xm].

• Reaction mechanism: possible attack by M -OH to generate cleavage products with 3'-OH and 5'-phosphate.

• RNAse P is found throughout the prokaryotes and eukaryotes. The RNA subunit has been sequenced from bacteria, yeast, rodents, and primates.

• Recruitment of endogenous RNAse P for therapeutic applications is possible through hybridization of an External Guide Sequence (EGS) to the target RNA xiv xvl

• Important phosphate and 2' OH contacts recently identified [^xvi,^wii]

Group II Introns

• Size: >1000 nucleotides.

• Trans cleavage of target RNAs recently demonstrated [^{x in x}-^x].

• Sequence requirements not fully determined.

• Reaction mechanism: 2' -OH of an internal adenosine generates cleavage products with 3'-OH and a "lariat" RNA containing a 3'-5' and a 2'-5' branch point. Table I

• Only natural ribozyme with demonstrated participation in DNA cleavage [^χχ,^χχi] in addition to RNA cleavage and ligation.

^• Major structural features largely established through phylogenetic comparisons

[xxii].

^• Important 21 OH contacts beginning to be identified [^xx ]

• Kinetic framework under development [^xxiv]

Neurospora VS RNA

^• Size: ~144 nucleotides.

• Trans cleavage of hairpin target RNAs recently demonstrated [^xxv].

• Sequence requirements not fully determined.

^• Reaction mechanism: attack by 2'-OH 5' to the scissile bond to generate cleavage products with 2' ,3' -cyclic phosphate and 5'-OH ends.

• Binding sites and structural requirements not fully determined.

• Only 1 known member of this class. Found in Neurospora VS RNA.

Hammerhead Ribozyme

(see text for references)

Size: ~13 to 40 nucleotides.

Requires the target sequence UH immediately 5' of the cleavage site.

Binds a variable number ryucleotides on both sides of the cleavage site.

Reaction mechanism: attack by 2'-OH 5' to the scissile bond to generate cleavage products with 2',3'-cyclic phosphate and 5' -OH ends.

14 known members of this class. Found in a number of plant pathogens

(virusoids) that use RNA as the infectious agent.

Essential structural features largely defined, including 2 crystal structures [x ^xxvii]

Minimal ligation activity demonstrated (for engineering through in vitro selection) rxxvϋil

Complete kinetic framework established for two or more ribozymes [^xxix]. Chemical modification investigation of important residues well established [^xxx].

Hairpin Ribozyme

• Size: ~50 nucleotides.

• Requires the target sequence GUC immediately 3' of the cleavage site.

• Binds 4-6 nucleotides at the 5 '-side of the cleavage site and a variable number to the 3 -side of the cleavage site.

• Reaction mechanism: attack by 2' -OH 5' to the scissile bond to generate cleavage products with 2',3'-cyclic phosphate and 5' -OH ends.

• 3 known members of this class. Found in three plant pathogen (satellite RNAs of the tobacco ringspot virus, arabis mosaic virus and chicory yellow mottle virus) which uses RNA as the infectious agent.

• Essential structural features largely defined [ ^{χχi χii}, ^{χi x iv}]

• Ligation activity (in addition to cleavage activity) makes ribozyme amenable to engineering through in vitro selection [^xxxv]

• Complete kinetic framework established for one ribozyme [*^χχvi].

• Chemical modification investigation of important residues begun [^{χ χ}vii_/X >c __ϋ] _

Hepatitis Delta Virus (HDV) Ribozyme Table I

Size: ~60 nucleotides.

Trans cleavage of target RNAs demonstrated [^χχχi^χ].

Binding sites and structural requirements not fully determined, although no sequences 5' of cleavage site are required. Folded ribozyme contains a pseudoknot structure [^x1].

Reaction mechanism: attack by 2' -OH 5' to the scissile bond to generate cleavage products with 2',3'-cyclic phosphate and 5' -OH ends.

Only 2 known members of this class. Found in human HDV.

Circular form of HDV is active and shows increased nuclease stability [^xli]

¹ . Michel, Francois; Westhof, Eric. Slippery substrates. Nat. Struct. Biol. (1994), 1(1), 5-7.

" . Lisacek, Frederique; Diaz, Yolande; Michel, Francois. Automatic identification of group I intron cores in genomic DNA sequences. J. Mol. Biol. (1994), 235(4), 1206-17. i^;i . Herschlag, Daniel; Cech, Thomas R.. Catalysis of RNA cleavage by the Tetrahymena fhermophila ribozyme. 1. Kinetic description of fhe reaction of an RNA substrate complementary to the active site. Biochemistry (1990), 29(44), 10159-71. i^v . Herschlag, Daniel; Cech, Thomas R.. Catalysis of RNA cleavage by the Tetrahymena thermophila ribozyme. 2. Kinetic description of fhe reaction of an RNA substrate that forms a mismatch at fhe active site. Biochemistry (1990), 29(44), 10172-80. v . Knitt, Deborah S.; Herschlag, Daniel. pH Dependencies of fhe Tetrahymena Ribozyme Reveal an

Unconventional Origin of an Apparent pKa. Biochemistry (1996), 35(5), 1560-70. vⁱ . Bevilacqua, Philip C; Sugimoto, Naoki; Turner, Douglas H.. A mechanistic framework for the second step of splicing catalyzed by the Tetrahymena ribozyme. Biochemistry (1996), 35(2), 648-58. vⁱⁱ . Li, Yi; Bevilacqua, Philip C; Mafhews, David; Turner, Douglas H.. Thermodynamic and activation parameters for binding of a pyrene-labeled substrate by the Teti'ahymena ribozyme: docking is not diffusion-controlled and is driven by a favorable entropy change. Biochemistry (1995), 34(44), 14394-9. iⁱⁱ . Banerjee, Aloke Raj; Turner, Douglas H.. The time dependence of chemical modification reveals slow steps in the folding of a group I ribozyme. Biochemistry (1995), 34(19), 6504-12. i^x . Zarrinkar, Patrick P.; Williamson, James R.. The P9.1-P9.2 peripheral extension helps guide folding of fhe Tetrahymena ribozyme. Nucleic Acids Res. (1996), 24(5), 854-8. x . Strobel, Scott A.; Cech, Thomas R.. Minor groove recognition of fhe conserved G.cntdot.U pair at fhe Tetrahymena ribozyme reaction site. Science (Washington, D. C.) (1995), 267(5198), 675-9. xⁱ . Strobel, Scott A.; Cech, Thomas R.. Exocyclic Amine of the Conserved G.cntdot.U Pair at the

Cleavage Site of fhe Tetrahymena Ribozyme Contributes to 5'-Splice Site Selection and Transition State Stabilization. Biochemistry (1996), 35(4), 1201-11. x^li. Sullenger, Bruce A.; Cech, Thomas R.. Ribozyme-mediated repair of defective mRNA by targeted trans-splicing. Nature (London) (1994), 371(6498), 619-22. ω. Robertson, H.D.; Altaian, S.; Smith, J.D. J. Biol. Chem., 247, 5243-5251 (1972). x^iv. Forster, Anthony C; Altaian, Sidney. External guide sequences for an RNA enzyme. Science

(Washington, D. C, 1883-) (1990), 249(4970), 783-6. χv. Yuan, Y.; Hwang, E. S.; Altaian, S. Targeted cleavage of mRNA by human RNase P. Proc. Natl.

Acad. Sci. USA (1992) 89, 8006-10. χ i . Harris, Michael E.; Pace, Norman R.. Identification of phosphates involved in catalysis by fhe ribozyme RNase P RNA. RNA (1995), 1(2), 210-18. χv» . Pan, Tao; Loria, Andrew; Zhong, Kun. Probing of tertiary interactions in RNA: 2'-hydroxyl-base contacts between the RNase P RNA and pre-tRNA. Proc. Natl. Acad. Sci. U. S. A. (1995), 92(26), 12510-14. xviϋ . Pyle, Anna Marie; Green, Justin B.. Building a Kinetic Framework for Group II Intron Ribozyme Activity: Quantitation of Interdomain Binding and Reaction Rate. Biochemistry (1994), 33(9), 2716-25. ^χi^χ . Michels, William J. Jr.; Pyle, Anna Marie. Conversion of a Group II Intron into a New Multiple- Turnover Ribozyme that Selectively Cleaves Oligonucleotides: Elucidation of Reaction Mechanism and Structure/Function Relationships. Biochemistry (1995), 34(9), 2965-77. χ . Zimmerly, Steven; Guo, Huatao; Eskes, Robert; Yang, Jian; Perlman, Philip S.; Lambowitz, Alan

M.. A group II intron RNA is a catalytic component of a DNA endonuclease involved in intron mobility. Table I

Cell (Cambridge, Mass.) (1995), 83(4), 529-38. x^xi . Griffin, Edmund A., Jr.; Qin, Zhifeng; Michels, Williams J., Jr.; Pyle, Anna Marie. Group II intron ribozymes that cleave DNA and RNA linkages with similar efficiency, and lack contacts with substrate 2'- hydroxyl groups. Chem. Biol. (1995), 2(11), 761-70. x" . Michel, Francois; Ferat, Jean Luc. Structure and activities of group II introns. Annu. Rev. Biochem. (1995), 64, 435-61. x ⁱⁱⁱ . Abramovitz, Dana L.; Friedman, Richard A.; Pyle, Anna Marie. Catalytic role of 2'-hydroxyl groups within a group II intron active site. Science (Washington, D. C.) (1996), 271(5254), 1410-13. x^xiv . Daniels, Danette L.; Michels, William J., Jr.; Pyle, Anna Marie. Two competing pathways for self- splicing by group II introns: a quantitative analysis of in vitro reaction rates and products. J. Mol. Biol. (1996), 256(1), 31-49. x ^v . Guo, Hans C. T.; Collins, Richard A.. Efficient trans-cleavage of a stem-loop RNA substrate by a ribozyme derived from Neurospora VS RNA. EMBO J. (1995), 14(2), 368-76. x^xvi . Scott, W.G., Finch, J.T., Aaron,K. The crystal structure of an all RNA hammerhead ribozyme:Aproposed mechanism for RNA catalytic cleavage. Cell, (1995), 81, 991-1002. x^xvii . McKay, Structure and function of the hammerhead ribozyme: an unfinished story. RNA, (1996), 2, 395-403. x^xviii . Long, D., Uhlenbeck, O., Hertel, K. Ligation with hammerhead ribozymes. US Patent No. 5,633,133. x^xix . Hertel, K.J., Herschlag, D., Uhlenbeck, O. A kinetic and thermodynamic framework for the hammerhead ribozyme reaction. Biochemistry, (1994) 33, 3374-3385.Beigelman, L., et al, Chemical modifications of hammerhead ribozymes. J. Biol. Chem., (1995) 270, 25702-25708. x^x . Beigelman, L., et al., Chemical modifications of hammerhead ribozymes. J. Biol. Chem., (1995) 270, 25702-25708. x^xxi . Hampel, Arnold; Tritz, Richard; Hicks, Margaret; Cruz, Phillip. 'Hairpin' catalytic RNA model: evidence for helixes and sequence requirement for substrate RNA. Nucleic Acids Res. (1990), 18(2), 299- 304. x ^xii . Chowrira, Bharat M.; Berzal-Herranz, Alfredo; Burke, John M.. Novel guanosine requirement for catalysis by fhe hairpin ribozyme. Nature (London) (1991), 354(6351), 320-2. xx^xiϋ Berzal-Herranz, Alfredo; Joseph, Simpson; Chowrira, Bharat M.; Butcher, Samuel E.; Burke, John M.. Essential nucleotide sequences and secondary structure elements of the hairpin ribozyme. EMBO J. (1993), 12(6), 2567-73. x^xxiv . Joseph, Simpson; Berzal-Herranz, Alfredo; Chowrira, Bharat M.; Butcher, Samuel E.. Substrate selection rules for the hairpin ribozyme determined by in vitro selection, mutation, and analysis of mismatched substrates. Genes Dev. (1993), 7(1), 130-8. x^xxv . Berzal-Herranz, Alfredo; Joseph, Simpson; Burke, John M.. In vitro selection of active hairpin ribozymes by sequential RNA-catalyzed cleavage and ligation reactions. Genes Dev. (1992), 6(1), 129-34. xx ^vi Hegg, Lisa A.; Fedor, Martha J.. Kinetics and Thermodynamics of Intermolecular Catalysis by Hairpin Ribozymes. Biochemistry (1995), 34(48), 15813-28. xxx " . Grasby, Jane A.; Mersmann, Karin; Singh, Mohinder; Gait, Michael J.. Purine Functional Groups in Essential Residues of fhe Hairpin Ribozyme Required for Catalytic Cleavage of RNA. Biochemistry (1995), 34(12), 4068-76. xxx^viϋ _ Schmidt, Sabine; Beigelman, Leonid; Karpeisky, Alexander; Usman, Nassim; Sorensen, Ulrik S.; Gait, Michael J.. Base and sugar requirements for RNA cleavage of essential nucleoside residues in internal loop B of the hairpin ribozyme: implications for ^"secondary structure. Nucleic Acids Res. (1996), 24(4), 573-81. xx ix . Perrotta, Anne T.; Been, Michael D.. Cleavage of oligoribonucleotides by a ribozyme derived from the hepatitis .delta, virus RNA sequence. Biochemistry (1992), 31(1), 16-21. ! . Perrotta, Anne T.; Been, Michael D.. A pseudolααot-like structure required for efficient self- cleavage of hepatitis delta virus RNA. Nature (London) (1991), 350(6317), 434-6. χ^Ii . Puttaraju, M.; Perrotta, Anne T.; Been, Michael D„ A circular trans-acting hepatitis delta virus ribozyme. Nucleic Acids Res. (1993), 21(18), 4253-8. Table II

Table II: A. 2.5 μmol Synthesis Cycle ABI 394 Instrument

Table II

C. 0.2 μmol Synthesis Cycle 96 well Instrument

^: Wait time does not include contact time during delivery.

Table III Table III: Human ERG Hammerhead Ribozyme and Target Sequence

Pos Substrate SeqlD Ribozyme RzSeq ID

13 GCGCGUGU C CGCGCCCG 1 CGGGCGCG CUGAUGAG X CGAA ACACGCGC 2126

43 GCGUGCCU U GGCCGUGC 2 GCACGGCC CUGAUGAG X CGAA AGGCACGC 2127

66 AGCCGGGU C GCACUAAC 3 GUUAGUGC CUGAUGAG X CGAA ACCCGGCU 2128

72 GUCGCACU A ACUCCCUC 4 GAGGGAGU CUGAUGAG X CGAA AGUGCGAC 2129

76 CACUAACU C CCUCGGCG 5 CGCCGAGG CUGAUGAG X CGAA AGUUAGUG 2130

80 AACUCCCU C GGCGCCGA 6 UCGGCGCC CUGAUGAG X CGAA AGGGAGUU 2131

99 GCGGCGCU A ACCUCUCG 7 CGAGAGGU CUGAUGAG X CGAA AGCGCCGC 2132

104 GCUAACCU C UCGGUUAU 8 AUAACCGA CUGAUGAG X CGAA AGGUUAGC 2133

106 UAACCUCU C GGUUAUUC 9 GAAUAACC CUGAUGAG X CGAA AGAGGUUA 2134

110 CUCUCGGU U AUUCCAGG 10 CCUGGAAU CUGAUGAG X CGAA ACCGAGAG 2135

111 UCUCGGUU A UUCCAGGA 11 UCCUGGAA CUGAUGAG X CGAA AACCGAGA 2136

113 UCGGUUAU U CCAGGAUC 12 GAUCCUGG CUGAUGAG X CGAA AUAACCGA 2137

114 CGGUUAUU C CAGGAUCU 13 AGAUCCUG CUGAUGAG X CGAA AAUAACCG 2138

121 UCCAGGAU C UUUGGAGA 14 UCUCCAAA CUGAUGAG X CGAA AUCCUGGA 2139

123 CAGGAUCU U UGGAGACC 15 GGUCUCCA CUGAUGAG X CGAA AGAUCCUG 2140

124 AGGAUCUU U GGAGACCC 16 GGGUCUCC CUGAUGAG X CGAA AAGAUCCU 2141

147 AGCCGUGU U GACCAAAA 17 UUUUGGUC CUGAUGAG X CGAA ACACGGCU 2142

171 AAAUGACU C ACAGAGAA 18 UUCUCUGU CUGAUGAG X CGAA AGUCAUUU 2143

206 GGGCAACU A AAGCCGUC 19 GACGGCUU CUGAUGAG X CGAA AGUUGCCC 2144

214 AAAGCCGU C AGGUUCUG 20 CAGAACCU CUGAUGAG X CGAA ACGGCUUU 2145

219 CGUCAGGU U CUGAACAG 21 CUGUUCAG CUGAUGAG X CGAA ACCUGACG 2146

220 GUCAGGUU C UGAACAGC 22 GCUGUUCA CUGAUGAG X CGAA AACCUGAC 2147

233 CAGCUGGU A GAUGGGCU 23 AGCCCAUC CUGAUGAG X CGAA ACCAGCUG 2148

246 GGCUGGCU U ACUGAAGG 24 CCUUCAGU CUGAUGAG X CGAA AGCCAGCC 2149

247 GCUGGCUU A CUGAAGGA 25 UCCUUCAG CUGAUGAG X CGAA AAGCCAGC 2150

262 GACAUGAU U CAGACUGU 26 ACAGUCUG CUGAUGAG X CGAA AUCAUGUC 2151

263 ACAUGAUU C AGACUGUC 27 GACAGUCU CUGAUGAG X CGAA AAUCAUGU 2152

271 CAGACUGU C CCGGACCC 28 GGGUCCGG CUGAUGAG X CGAA ACAGUCUG 2153

287 CAGCAGCU C AUAUCAAG 29 CUUGAUAU CUGAUGAG X CGAA AGCUGCUG 2154

290 CAGCUCAU A UCAAGGAA 30 UUCCUUGA CUGAUGAG X CGAA AUGAGCUG 2155

292 GCUCAUAU C AAGGAAGC 31 GCUUCCUU CUGAUGAG X CGAA AUAUGAGC 2156

303 GGAAGCCU U AUCAGUUG 32 CAACUGAU CUGAUGAG X CGAA AGGCUUCC 2157

304 GAAGCCUU A UCAGUUGU 33 ACAACUGA CUGAUGAG X CGAA AAGGCUUC 2158

306 AGCCUUAU C AGUUGUGA 34 UCACAACU CUGAUGAG X CGAA AUAAGGCU 2159

310 UUAUCAGU U GUGAGUGA 35 UCACUCAC CUGAUGAG X CGAA ACUGAUAA 2160

327 GGACCAGU C GUUGUUUG 36 CAAACAAC CUGAUGAG X CGAA ACUGGUCC 2161

330 CCAGUCGU U GUUUGAGU 37 ACUCAAAC CUGAUGAG X CGAA ACGACUGG 2162

333 GUCGUUGU U UGAGUGUG 38 CACACUCA CUGAUGAG X CGAA ACAACGAC 2163

334 UCGUUGUU U GAGUGUGC 39 GCACACUC CUGAUGAG X CGAA AACAACGA 2164

345 GUGUGCCU A CGGAACGC 40 GCGUUCCG CUGAUGAG X CGAA AGGCACAC 2165

365 ACCUGGCU A AGACAGAG 41 CUCUGUCU CUGAUGAG X CGAA AGCCAGGU 2166

384 GACCGCGU C CUCCUCCA 42 UGGAGGAG CUGAUGAG X CGAA ACGCGGUC 2167

387 CGCGUCCU C CUCCAGCG 43 CGCUGGAG CUGAUGAG X CGAA AGGACGCG 2168

390 GUCCUCCU C CAGCGACU 44 AGUCGCUG CUGAUGAG X CGAA AGGAGGAC 2169

399 CAGCGACU A UGGACAGA 45 UCUGUCCA CUGAUGAG X CGAA AGUCGCUG 2170

410 GACAGACU U CCAAGAUG 46 CAUCUUGG CUGAUGAG X CGAA AGUCUGUC 2171

411 ACAGACUU C CAAGAUGA 47 UCAUCUUG CUGAUGAG X CGAA AAGUCUGU 2172

430 CCACGCGU C CCUCAGCA 48 UGCUGAGG CUGAUGAG X CGAA ACGCGUGG 2173

434 GCGUCCCU C AGCAGGAU 49 AUCCUGCU CUGAUGAG X CGAA AGGGACGC 2174

443 AGCAGGAU U GGCUGUCU 50 AGACAGCC CUGAUGAG X CGAA AUCCUGCU 2175

450 UUGGCUGU C UCAACCCC 51 GGGGUUGA CUGAUGAG X CGAA ACAGCCAA 2176

452 GGCUGUCU C AACCCCCA 52 UGGGGGUU CUGAUGAG X CGAA AGACAGCC 2177

469 GCCAGGGU C ACCAUCAA 53 UUGAUGGU CUGAUGAG X CGAA ACCCUGGC 2178 Table III

475 GUCACCAU C AAAAUGGA 54 UCCAUUUU CUGAUGAG X CGAA AUGGUGAC 2179

488 UGGAAUGU A ACCCUAGC 55 GCUAGGGU CUGAUGAG X CGAA ACAUUCCA 2180

494 GUAACCCU A GCCAGGUG 56 CACCUGGC CUGAUGAG X CGAA AGGGUUAC 2181

510 GAAUGGCU C AAGGAACU 57 AGUUCCUU CUGAUGAG X CGAA AGCCAUUC 2182

519 AAGGAACU C UCCUGAUG 58 CAUCAGGA CUGAUGAG X CGAA AGUUCCUU 2183

521 GGAACUCU C CUGAUGAA 59 UUCAUCAG CUGAUGAG X CGAA AGAGUUCC 2184

577 GACACCGU U GGGAUGAA 60 UUCAUCCC CUGAUGAG X CGAA ACGGUGUC 2185

588 GAUGAACU A CGGCAGCU 61 AGCUGCCG CUGAUGAG X CGAA AGUUCAUC 2186

597 CGGCAGCU A CAUGGAGG 62 CCUCCAUG CUGAUGAG X CGAA AGCUGCCG 2187

652 CGCAGAGU U AUCGUGCC 63 GGCACGAU CUGAUGAG X CGAA ACUCUGCG 2188

653 GCAGAGUU A UCGUGCCA 64 UGGCACGA CUGAUGAG X CGAA AACUCUGC 2189

655 AGAGUUAU C GUGCCAGC 65 GCUGGCAC CUGAUGAG X CGAA AUAACUCU 2190

668 CAGCAGAU C CUACGCUA 66 UAGCGUAG CUGAUGAG X CGAA AUCUGCUG 2191

671 CAGAUCCU A CGCUAUGG 67 CCAUAGCG CUGAUGAG X CGAA AGGAUCUG 2192

676 CCUACGCU A UGGAGUAC 68 GUACUCCA CUGAUGAG X CGAA AGCGUAGG 2193

683 UAUGGAGU A CAGACCAU 69 AUGGUCUG CUGAUGAG X CGAA ACUCCAUA 2194

726 GAAAGAAU A UGGCCUUC 70 GAAGGCCA CUGAUGAG X CGAA AUUCUUUC 2195

733 UAUGGCCU U CCAGACGU 71 ACGUCUGG CUGAUGAG X CGAA AGGCCAUA 2196

734 AUGGCCUU C CAGACGUC 72 GACGUCUG CUGAUGAG X CGAA AAGGCCAU 2197

742 CCAGACGU C AACAUCUU 73 AAGAUGUU CUGAUGAG X CGAA ACGUCUGG 2198

748 GUCAACAU C UUGUUAUU 74 AAUAACAA CUGAUGAG X CGAA AUGUUGAC 2199

750 CAACAUCU U GUUAUUCC 75 GGAAUAAC CUGAUGAG X CGAA AGAUGUUG 2200

753 CAUCUUGU U AUUCCAGA 76 UCUGGAAU CUGAUGAG X CGAA ACAAGAUG 2201

754 AUCUUGUU A UUCCAGAA 77 UUCUGGAA CUGAUGAG X CGAA AACAAGAU 2202

756 CUUGUUAU U CCAGAACA 78 UGUUCUGG CUGAUGAG X CGAA AUAACAAG 2203

757 UUGUUAUU C CAGAACAU 79 AUGUUCUG CUGAUGAG X CGAA AAUAACAA 2204

766 CAGAACAU C GAUGGGAA 80 UUCCCAUC CUGAUGAG X CGAA AUGUUCUG 2205

804 GGACGACU U CCAGAGGC 81 GCCUCUGG CUGAUGAG X CGAA AGUCGUCC 2206

805 GACGACUU C CAGAGGCU 82 AGCCUCUG CUGAUGAG X CGAA AAGUCGUC 2207

814 CAGAGGCU C ACCCCCAG 83 CUGGGGGU CUGAUGAG X CGAA AGCCUCUG 2208

825 CCCCAGCU A CAACGCCG 84 CGGCGUUG CUGAUGAG X CGAA AGCUGGGG 2209

838 GCCGACAU C CUUCUCUC 85 GAGAGAAG CUGAUGAG X CGAA AUGUCGGC 2210

841 GACAUCCU U CUCUCACA 86 UGUGAGAG CUGAUGAG X CGAA AGGAUGUC 2211

842 ACAUCCUU C UCUCACAU 87 AUGUGAGA CUGAUGAG X CGAA AAGGAUGU 2212

844 AUCCUUCU C UCACAUCU 88 AGAUGUGA CUGAUGAG X CGAA AGAAGGAU 2213

846 CCUUCUCU C ACAUCUCC 89 GGAGAUGU CUGAUGAG X CGAA AGAGAAGG 2214

851 UCUCACAU C UCCACUAC 90 GUAGUGGA CUGAUGAG X CGAA AUGUGAGA 2215

853 UCACAUCU C CACUACCU 91 AGGUAGUG CUGAUGAG X CGAA AGAUGUGA 2216

858 UCUCCACU A CCUCAGAG 92 CUCUGAGG CUGAUGAG X CGAA AGUGGAGA 2217

862 CACUACCU C AGAGAGAC 93 GUCUCUCU CUGAUGAG X CGAA AGGUAGUG 2218

872 GAGAGACU C CUCUUCCA 94 UGGAAGAG CUGAUGAG X CGAA AGUCUCUC 2219

875 AGACUCCU C UUCCACAU 95 AUGUGGAA CUGAUGAG X CGAA AGGAGUCU 2220

877 ACUCCUCU U CCACAUUU 96 AAAUGUGG CUGAUGAG X CGAA AGAGGAGU 2221

878 CUCCUCUU C CACAUUUG 97 CAAAUGUG CUGAUGAG X CGAA AAGAGGAG 2222

884 UUCCACAU U UGACUUCA 98 UGAAGUCA CUGAUGAG X CGAA AUGUGGAA 2223

885 UCCACAUU U GACUUCAG 99 CUGAAGUC CUGAUGAG X CGAA AAUGUGGA 2224

890 AUUUGACU U CAGAUGAU 100 AUCAUCUG CUGAUGAG X CGAA AGUCAAAU 2225

891 UUUGACUU C AGAUGAUG 101 CAUCAUCU CUGAUGAG X CGAA AAGUCAAA 2226

901 GAUGAUGU U GAUAAAGC 102 GCUUUAUC CUGAUGAG X CGAA ACAUCAUC 2227

905 AUGUUGAU A AAGCCUUA 103 UAAGGCUU CUGAUGAG X CGAA AUCAACAU 2228

912 UAAAGCCU U ACAAAACU 104 AGUUUUGU CUGAUGAG X CGAA AGGCUUUA 2229

913 AAAGCCUU A CAAAACUC 105 GAGUUUUG CUGAUGAG X CGAA AAGGCUUU 2230

921 ACAAAACU C UCCACGGU 106 ACCGUGGA CUGAUGAG X CGAA AGUUUUGU 2231

923 AAAACUCU C CACGGUUA 107 UAACCGUG CUGAUGAG X CGAA AGAGUUUU 2232

930 UCCACGGU U AAUGCAUG 108 CAUGCAUU CUGAUGAG X CGAA ACCGUGGA 2233

931 CCACGGUU A AUGCAUGC 109 GCAUGCAU CUGAUGAG X CGAA AACCGUGG 2234

941 UGCAUGCU A GAAACACA 110 UGUGUUUC CUGAUGAG X CGAA AGCAUGCA 2235 Table III

Table III

Table III

1754 AAAGCUUU A CUGGGGCU 225 AGCCCCAG CUGAUGAG X CGAA AAAGCUUU 2350

1787 GAAGAGAU C CAAAGACU 226 AGUCUUUG CUGAUGAG X CGAA AUCUCUUC 2351

1796 CAAAGACU C UUGGGAGG 227 CCUCCCAA CUGAUGAG X CGAA AGUCUUUG 2352

1798 AAGACUCU U GGGAGGGA 228 UCCCUCCC CUGAUGAG X CGAA AGAGUCUU 2353

1809 GAGGGAGU U ACUGAAGU 229 ACUUCAGU CUGAUGAG X CGAA ACUCCCUC 2354

1810 AGGGAGUU A CUGAAGUC 230 GACUUCAG CUGAUGAG X CGAA AACUCCCU 2355

1818 ACUGAAGU C UUACUACA 231 UGUAGUAA CUGAUGAG X CGAA ACUUCAGU 2356

1820 UGAAGUCU U ACUACAGA 232 UCUGUAGU CUGAUGAG X CGAA AGACUUCA 2357

1821 GAAGUCUU A CUACAGAA 233 UUCUGUAG CUGAUGAG X CGAA AAGACUUC 2358

1824 GUCUUACU A CAGAAAUG 234 CAUUUCUG CUGAUGAG X CGAA AGUAAGAC 2359

1844 AGGAUGCU A AAAAUGUC 235 GACAUUUU CUGAUGAG X CGAA AGCAUCCU 2360

1852 AAAAAUGU C ACGAAUAU 236 AUAUUCGU CUGAUGAG X CGAA ACAUUUUU 2361

1859 UCACGAAU A UGGACAUA 237 UAUGUCCA CUGAUGAG X CGAA AUUCGUGA 2362

18S7 AUGGACAU A UCAUCUGU 238 ACAGAUGA CUGAUGAG X CGAA AUGUCCAU 2363

1869 GGACAUAU C AUCUGUGG 239 CCACAGAU CUGAUGAG X CGAA AUAUGUCC 2364

1872 CAUAUCAU C UGUGGACU 240 AGUCCACA CUGAUGAG X CGAA AUGAUAUG 2365

1886 ACUGACCU U GUAAAAGA 241 UCUUUUAC CUGAUGAG X CGAA AGGUCAGU 2366

1889 GACCUUGU A AAAGACAG 242 CUGUCUUU CUGAUGAG X CGAA ACAAGGUC 2367

1901 GACAGUGU A UGUAGAAG 243 CUUCUACA CUGAUGAG X CGAA ACACUGUC 2368

1905 GUGUAUGU A GAAGCAUG 244 CAUGCUUC CUGAUGAG X CGAA ACAUACAC 2369

1918 CAUGAAGU C UUAAGGAC 245 GUCCUUAA CUGAUGAG X CGAA ACUUCAUG 2370

1920 UGAAGUCU U AAGGACAA 246 UUGUCCUU CUGAUGAG X CGAA AGACUUCA 2371

1921 GAAGUCUU A AGGACAAA 247 UUUGUCCU CUGAUGAG X CGAA AAGACUUC 2372

1947 AAAGUGGU C UUAAGAAA 248 UUUCUUAA CUGAUGAG X CGAA ACCACUUU 2373

1949 AGUGGUCU U AAGAAAUG 249 CAUUUCUU CUGAUGAG X CGAA AGACCACU 2374

1950 GUGGUCUU A AGAAAUGU 250 ACAUUUCU CUGAUGAG X CGAA AAGACCAC 2375

1959 AGAAAUGU A UAAACUUU 251 AAAGUUUA CUGAUGAG X CGAA ACAUUUCU 2376

1961 AAAUGUAU A AACUUUAG 252 CUAAAGUU CUGAUGAG X CGAA AUACAUUU 2377

1966 UAUAAACU U UAGAGUAG 253 CUACUCUA CUGAUGAG X CGAA AGUUUAUA 2378

1967 AUAAACUU U AGAGUAGA 254 UCUACUCU CUGAUGAG X CGAA AAGUUUAU 2379

1968 UAAACUUU A GAGUAGAG 255 CUCUACUC CUGAUGAG X CGAA AAAGUUUA 2380

1973 UUUAGAGU A GAGUUUGA 256 UCAAACUC CUGAUGAG X CGAA ACUCUAAA 2381

1978 AGUAGAGU U UGAAUCCC 257 GGGAUUCA CUGAUGAG X CGAA ACUCUACU 2382

1979 GUAGAGUU U GAAUCCCA 258 UGGGAUUC CUGAUGAG X CGAA AACUCUAC 2383

1984 GUUUGAAU C CCACUAAU 259 AUUAGUGG CUGAUGAG X CGAA AUUCAAAC 2384

1990 AUCCCACU A AUGCAAAC 260 GUUUGCAU CUGAUGAG X CGAA AGUGGGAU 2385

2011 AUGAAACU A AAGCAAUA 261 UAUUGCUU CUGAUGAG X CGAA AGUUUCAU 2386

2019 AAAGCAAU A GAAACAAC 262 GUUGUUUC CUGAUGAG X CGAA AUUGCUUU 2387

2033 AACACAGU U UUGACCUA 263 UAGGUCAA CUGAUGAG X CGAA ACUGUGUU 2388

2034 ACACAGUU U UGACCUAA 264 UUAGGUCA CUGAUGAG X CGAA AACUGUGU 2389

2035 CACAGUUU U GACCUAAC 265 GUUAGGUC CUGAUGAG X CGAA AAACUGUG 2390

2041 UUUGACCU A ACAUACCG 266 CGGUAUGU CUGAUGAG X CGAA AGGUCAAA 2391

2046 CCUAACAU A CCGUUUAU 267 AUAAACGG CUGAUGAG X CGAA AUGUUAGG 2392

2051 CAUACCGU U UAUAAUGC 268 GCAUUAUA CUGAUGAG X CGAA ACGGUAUG 2393

2052 AUACCGUU U AUAAUGCC 269 GGCAUUAU CUGAUGAG X CGAA AACGGUAU 2394

2053 UACCGUUU A UAAUGCCA 270 UGGCAUUA CUGAUGAG X CGAA AAACGGUA 2395

2055 CCGUUUAU A AUGCCAUU 271 AAUGGCAU CUGAUGAG X CGAA AUAAACGG 2396

2063 AAUGCCAU U UUAAGGAA 272 UUCCUUAA CUGAUGAG X CGAA AUGGCAUU 2397

2064 AUGCCAUU U UAAGGAAA 273 UUUCCUUA CUGAUGAG X CGAA AAUGGCAU 2398

2065 UGCCAUUU U AAGGAAAA 274 UUUUCCUU CUGAUGAG X CGAA AAAUGGCA 2399

2066 GCCAUUUU A AGGAAAAC 275 GUUUUCCU CUGAUGAG X CGAA AAAAUGGC 2400

2076 GGAAAACU A CCUGUAUU 276 AAUACAGG CUGAUGAG X CGAA AGUUUUCC 2401

2082 CUACCUGU A UUUAAAAA 277 UUUUUAAA CUGAUGAG X CGAA ACAGGUAG 2402

2084 ACCUGUAU U UAAAAAUA 278 UAUUUUUA CUGAUGAG X CGAA AUACAGGU 2403

2085 CCUGUAUU U AAAAAUAG 279 CUAUUUUU CUGAUGAG X CGAA AAUACAGG 2404

2086 CUGUAUUU A AAAAUAGU 280 ACUAUUUU CUGAUGAG X CGAA AAAUACAG 2405

2092 UUAAAAAU A GUUUCAUA 281 UAUGAAAC CUGAUGAG X CGAA AUUUUUAA 2406 Table III

2095 AAAAUAGU U UCAUAUCA 282 UGAUAUGA CUGAUGAG X CGAA ACUAUUUU 2407

2096 AAAUAGUU U CAUAUCAA 283 UUGAUAUG CUGAUGAG X CGAA AACUAUUU 2408

2097 AAUAGUUU C AUAUCAAA 284 UUUGAUAU CUGAUGAG X CGAA AAACUAUU 2409

2100 AGUUUCAU A UCAAAAAC 285 GUUUUUGA CUGAUGAG X CGAA AUGAAACU 2410

2102 UUUCAUAU C AAAAACAA 286 UUGUUUUU CUGAUGAG X CGAA AUAUGAAA 2411

2142 UGGCCCAU C AACAGACG 287 CGUCUGUU CUGAUGAG X CGAA AUGGGCCA 2412

2152 ACAGACGU U GAUAUGCA 288 UGCAUAUC CUGAUGAG X CGAA ACGUCUGU 2413

2156 ACGUUGAU A UGCAACUG 289 CAGUUGCA CUGAUGAG X CGAA AUCAACGU 2414

2180 UGUGCUGU U UUGGUUGA 290 UCAACCAA CUGAUGAG X CGAA ACAGCACA 2415

2181 GUGCUGUU U UGGUUGAA 291 UUCAACCA CUGAUGAG X CGAA AACAGCAC 2416

2182 UGCUGUUU U GGUUGAAA 292 UUUCAACC CUGAUGAG X CGAA AAACAGCA 2417

2186 GUUUUGGU U GAAAUCAA 293 UUGAUUUC CUGAUGAG X CGAA ACCAAAAC 2418

2192 GUUGAAAU C AAAUACAU 294 AUGUAUUU CUGAUGAG X CGAA AUUUCAAC 2419

2197 AAUCAAAU A CAUUCCGU 295 ACGGAAUG CUGAUGAG X CGAA AUUUGAUU 2420

2201 AAAUACAU U CCGUUUGA 296 UCAAACGG CUGAUGAG X CGAA AUGUAUUU 2421

2202 AAUACAUU C CGUUUGAU 297 AUCAAACG CUGAUGAG X CGAA AAUGUAUU 2422

2206 CAUUCCGU U UGAUGGAC 298 GUCCAUCA CUGAUGAG X CGAA ACGGAAUG 2423

2207 AUUCCGUU U GAUGGACA 299 UGUCCAUC CUGAUGAG X CGAA AACGGAAU 2424

2221 ACAGCUGU C AGCUUUCU 300 AGAAAGCU CUGAUGAG X CGAA ACAGCUGU 2425

2226 UGUCAGCU U UCUCAAAC 301 GUUUGAGA CUGAUGAG X CGAA AGCUGACA 2426

2227 GUCAGCUU U CUCAAACU 302 AGUUUGAG CUGAUGAG X CGAA AAGCUGAC 2427

2228 UCAGCUUU C UCAAACUG 303 CAGUUUGA CUGAUGAG X CGAA AAAGCUGA 2428

2230 AGCUUUCU C AAACUGUG 304 CACAGUUU CUGAUGAG X CGAA AGAAAGCU 2429

2254 CCCAAAGU U UCCAACUC 305 GAGUUGGA CUGAUGAG X CGAA ACUUUGGG 2430

2255 CCAAAGUU U CCAACUCC 306 GGAGUUGG CUGAUGAG X CGAA AACUUUGG 2431

2256 CAAAGUUU C CAACUCCU 307 AGGAGUUG CUGAUGAG X CGAA AAACUUUG 2432

2262 UUCCAACU C CUUUACAG 308 CUGUAAAG CUGAUGAG X CGAA AGUUGGAA 2433

2265 CAACUCCU U UACAGUAU 309 AUACUGUA CUGAUGAG X CGAA AGGAGUUG 2434

2266 AACUCCUU U ACAGUAUU 310 AAUACUGU CUGAUGAG X CGAA AAGGAGUU 2435

2267 ACUCCUUU A CAGUAUUA 311 UAAUACUG CUGAUGAG X CGAA AAAGGAGU 2436

2272 UUUACAGU A UUACCGGG 312 CCCGGUAA CUGAUGAG X CGAA ACUGUAAA 2437

2274 UACAGUAU U ACCGGGAC 313 GUCCCGGU CUGAUGAG X CGAA AUACUGUA 2438

2275 ACAGUAUU A CCGGGACU 314 AGUCCCGG CUGAUGAG X CGAA AAUACUGU 2439

2284 CCGGGACU A UGAACUAA 315 UUAGUUCA CUGAUGAG X CGAA AGUCCCGG 2440

2291 UAUGAACU A AAAGGUGG 316 CCACCUUU CUGAUGAG X CGAA AGUUCAUA 2441

2314 GGAUGUGU A UAGAGUGA 317 UCACUCUA CUGAUGAG X CGAA ACACAUCC 2442

2316 AUGUGUAU A GAGUGAGC 318 GCUCACUC CUGAUGAG X CGAA AUACACAU 2443

2332 CGUGUGAU U GUAGACAG 319 CUGUCUAC CUGAUGAG X CGAA AUCACACG 2444

2335 GUGAUUGU A GACAGAGG 320 CCUCUGUC CUGAUGAG X CGAA ACAAUCAC 2445

2401 AAGAAACU U CUCAAGCA 321 UGCUUGAG CUGAUGAG X CGAA AGUUUCUU 2446

2402 AGAAACUU C UCAAGCAA 322 UUGCUUGA CUGAUGAG X CGAA AAGUUUCU 2447

2404 AAACUUCU C AAGCAAUG 323 CAUUGCUU CUGAUGAG X CGAA AGAAGUUU 2448

2424 ACUGGACU C AGGACAUU 324 AAUGUCCU CUGAUGAG X CGAA AGUCCAGU 2449

2432 CAGGACAU U UGGGGACU 325 AGUCCCCA CUGAUGAG X CGAA AUGUCCUG 2450

2433 AGGACAUU U GGGGACUG 326 CAGUCCCC CUGAUGAG X CGAA AAUGUCCU 2451

2445 GACUGUGU A CAAUGAGU 327 ACUCAUUG CUGAUGAG X CGAA ACACAGUC 2452

2454 CAAUGAGU U AUGGAGAC 328 GUCUCCAU CUGAUGAG X CGAA ACUCAUUG 2453

2455 AAUGAGUU A UGGAGACU 329 AGUCUCCA CUGAUGAG X CGAA AACUCAUU 2454

2464 UGGAGACU C GAGGGUUC 330 GAACCCUC CUGAUGAG X CGAA AGUCUCCA 2455

2471 UCGAGGGU U CAUGCAGU 331 ACUGCAUG CUGAUGAG X CGAA ACCCUCGA 2456

2472 CGAGGGUU C AUGCAGUC 332 GACUGCAU CUGAUGAG X CGAA AACCCUCG 2457

2480 CAUGCAGU C AGUGUUAU 333 AUAACACU CUGAUGAG X CGAA ACUGCAUG 2458

2486 GUCAGUGU U AUACCAAA 334 UUUGGUAU CUGAUGAG X CGAA ACACUGAC 2459

2487 UCAGUGUU A UACCAAAC 335 GUUUGGUA CUGAUGAG X CGAA AACACUGA 2460

2489 AGUGUUAU A CCAAACCC 336 GGGUUUGG CUGAUGAG X CGAA AUAACACU 2461

2503 CCCAGUGU U AGGAGAAA 337 UUUCUCCU CUGAUGAG X CGAA ACACUGGG 2462

2504 CCAGUGUU A GGAGAAAG 338 CUUUCUCC CUGAUGAG X CGAA AACACUGG 2463 Table III

2523 CACAGCGU A AUGGAGAA 339 UUCUCCAU CUGAUGAG X CGAA ACGCUGUG 2464

2540 AGGGAAGU A GUAGAAUU 340 AAUUCUAC CUGAUGAG X CGAA ACUUCCCU 2465

2543 GAAGUAGU A GAAUUCAG 341 CUGAAUUC CUGAUGAG X CGAA ACUACUUC 2466

2548 AGUAGAAU U CAGAAACA 342 UGUUUCUG CUGAUGAG X CGAA AUUCUACU 2467

2549 GUAGAAUU C AGAAACAA 343 UUGUUUCU CUGAUGAG X CGAA AAUUCUAC 2468

2568 AUGCGCAU C UCUUUCUU 344 AAGAAAGA CUGAUGAG X CGAA AUGCGCAU 2469

2570 GCGCAUCU C UUUCUUUG 345 CAAAGAAA CUGAUGAG X CGAA AGAUGCGC 2470

2572 GCAUCUCU U UCUUUGUU 346 AACAAAGA CUGAUGAG X CGAA AGAGAUGC 2471

2573 CAUCUCUU U CUUUGUUU 347 AAACAAAG CUGAUGAG X CGAA AAGAGAUG 2472

2574 AUCUCUUU C UUUGUUUG 348 CAAACAAA CUGAUGAG X CGAA AAAGAGAU 2473

2576 CUCUUUCU U UGUUUGUC 349 GACAAACA CUGAUGAG X CGAA AGAAAGAG 2474

2577 UCUUUCUU U GUUUGUCA 350 UGACAAAC CUGAUGAG X CGAA AAGAAAGA 2475

2580 UUCUUUGU U UGUCAAAU 351 AUUUGACA CUGAUGAG X CGAA ACAAAGAA 2476

2581 UCUUUGUU U GUCAAAUG 352 CAUUUGAC CUGAUGAG X CGAA AACAAAGA 2477

2584 UUGUUUGU C AAAUGAAA 353 UUUCAUUU CUGAUGAG X CGAA ACAAACAA 2478

2595 AUGAAAAU U UUAACUGG 354 CCAGUUAA CUGAUGAG X CGAA AUUUUCAU 2479

2596 UGAAAAUU U UAACUGGA 355 UCCAGUUA CUGAUGAG X CGAA AAUUUUCA 2480

2597 GAAAAUUU U AACUGGAA 356 UUCCAGUU CUGAUGAG X CGAA AAAUUUUC 2481

2598 AAAAUUUU A ACUGGAAU 357 AUUCCAGU CUGAUGAG X CGAA AAAAUUUU 2482

2607 ACUGGAAU U GUCUGAUA 358 UAUCAGAC CUGAUGAG X CGAA AUUCCAGU 2483

2610 GGAAUUGU C UGAUAUUU 359 AAAUAUCA CUGAUGAG X CGAA ACAAUUCC 2484

2615 UGUCUGAU A UUUAAGAG 360 CUCUUAAA CUGAUGAG X CGAA AUCAGACA 2485

2617 UCUGAUAU U UAAGAGAA 361 UUCUCUUA CUGAUGAG X CGAA AUAUCAGA 2486

2618 CUGAUAUU U AAGAGAAA 362 UUUCUCUU CUGAUGAG X CGAA AAUAUCAG 2487

2619 UGAUAUUU A AGAGAAAC 363 GUUUCUCU CUGAUGAG X CGAA AAAUAUCA 2488

2630 AGAAACAU U CAGGACCU 364 AGGUCCUG CUGAUGAG X CGAA AUGUUUCU 2489

2631 GAAACAUU C AGGACCUC 365 GAGGUCCU CUGAUGAG X CGAA AAUGUUUC 2490

2639 CAGGACCU C AUCAUUAU 366 AUAAUGAU CUGAUGAG X CGAA AGGUCCUG 2491

2642 GACCUCAU C AUUAUGUG 367 CACAUAAU CUGAUGAG X CGAA AUGAGGUC 2492

2645 CUCAUCAU u AUGUGGGG 368 CCCCACAU CUGAUGAG X CGAA AUGAUGAG 2493

2646 UCAUCAUU A UGUGGGGG 369 CCCCCACA CUGAUGAG X CGAA AAUGAUGA 2494

2657 UGGGGGCU U UGUUCUCC 370 GGAGAACA CUGAUGAG X CGAA AGCCCCCA 2495

2658 GGGGGCUU U GUUCUCCA 371 UGGAGAAC CUGAUGAG X CGAA AAGCCCCC 2496

2661 GGCUUUGU U CUCCACAG 372 CUGUGGAG CUGAUGAG X CGAA ACAAAGCC 2497

2662 GCUUUGUU C UCCACAGG 373 CCUGUGGA CUGAUGAG X CGAA AACAAAGC 2498

2664 UUUGUUCU C CACAGGGU 374 ACCCUGUG CUGAUGAG X CGAA AGAACAAA 2499

2673 CACAGGGU C AGGUAAGA 375 UCUUACCU CUGAUGAG X CGAA ACCCUGUG 2500

2678 GGUCAGGU A AGAGAUGG 376 CCAUCUCU CUGAUGAG X CGAA ACCUGACC 2501

2690 GAUGGCCU U CUUGGCUG 377 CAGCCAAG CUGAUGAG X CGAA AGGCCAUC 2502

2691 AUGGCCUU C UUGGCUGC 378 GCAGCCAA- CUGAUGAG X CGAA AAGGCCAU 2503

2693 GGCCUUCU U GGCUGCCA 379 UGGCAGCC CUGAUGAG X CGAA AGAAGGCC 2504

2706 GCCACAAU c AGAAAUCA 380 UGAUUUCU CUGAUGAG X CGAA AUUGUGGC 2505

2713 UCAGAAAU c ACGCAGGC 381 GCCUGCGU CUGAUGAG X CGAA AUUUCUGA 2506

2724 GCAGGCAU u UUGGGUAG 382 CUACCCAA CUGAUGAG X CGAA AUGCCUGC 2507

2725 CAGGCAUU u UGGGUAGG 383 CCUACCCA CUGAUGAG X CGAA AAUGCCUG 2508

2726 AGGCAUUU u GGGUAGGC 384 GCCUACCC CUGAUGAG X CGAA AAAUGCCU 2509

2731 UUUUGGGU A GGCGGCCU 385 AGGCCGCC CUGAUGAG X CGAA ACCCAAAA 2510

2740 GGCGGCCU C CAGUUUUC 386 GAAAACUG CUGAUGAG X CGAA AGGCCGCC 2511

2745 CCUCCAGU U UUCCUUUG 387 CAAAGGAA CUGAUGAG X CGAA ACUGGAGG 2512

2746 CUCCAGUU u UCCUUUGA 388 UCAAAGGA CUGAUGAG X CGAA AACUGGAG 2513

2747 UCCAGUUU u CCUUUGAG 389 CUCAAAGG CUGAUGAG X CGAA AAACUGGA 2514

2748 CCAGUUUU c CUUUGAGU 390 ACUCAAAG CUGAUGAG X CGAA AAAACUGG 2515

2751 GUUUUCCU u UGAGUCGC 391 GCGACUCA CUGAUGAG X CGAA AGGAAAAC 2516

2752 UUUUCCUU u GAGUCGCG 392 CGCGACUC CUGAUGAG X CGAA AAGGAAAA 2517

2757 CUUUGAGU c GCGAACGC 393 GCGUUCGC CUGAUGAG X CGAA ACUCAAAG 2518

2773 CUGUGCGU u UGUCAGAA 394 UUCUGACA CUGAUGAG X CGAA ACGCACAG 2519

2774 UGUGCGUU u GUCAGAAU 395 AUUCUGAC CUGAUGAG X CGAA AACGCACA 2520 Table III

2777 GCGUUUGU C AGAAUGAA 396 UUCAUUCU CUGAUGAG X CGAA ACAAACGC 2521

2788 AAUGAAGU A UACAAGUC 397 GACUUGUA CUGAUGAG X CGAA ACUUCAUU 2522

2790 UGAAGUAU A CAAGUCAA 398 UUGACUUG CUGAUGAG X CGAA AUACUUCA 2523

2796 AUACAAGU C AAUGUUUU 399 AAAACAUU CUGAUGAG X CGAA ACUUGUAU 2524

2802 GUCAAUGU U UUUCCCCC 400 GGGGGAAA CUGAUGAG X CGAA ACAUUGAC 2525

2803 UCAAUGUU U UUCCCCCU 401 AGGGGGAA CUGAUGAG X CGAA AACAUUGA 2526

2804 CAAUGUUU U UCCCCCUU 402 AAGGGGGA CUGAUGAG X CGAA AAACAUUG 2527

2805 AAUGUUUU U CCCCCUUU 403 AAAGGGGG CUGAUGAG X CGAA AAAACAUU 2528

2806 AUGUUUUU c ccccuuuu 404 AAAAGGGG CUGAUGAG X CGAA AAAAACAU 2529

2812 UUCCCCCU u UUUAUAUA 405 UAUAUAAA CUGAUGAG X CGAA AGGGGGAA 2530

2813 UCCCCCUU u UUAUAUAA 406 UUAUAUAA CUGAUGAG X CGAA AAGGGGGA 2531

2814 CCCCCUUU u UAUAUAAU 407 AUUAUAUA CUGAUGAG X CGAA AAAGGGGG 2532

2815 ccccuuuu u AUAUAAUA 408 UAUUAUAU CUGAUGAG X CGAA AAAAGGGG 2533

2816 cccuuuuu A UAUAAUAA 409 UUAUUAUA CUGAUGAG X CGAA AAAAAGGG 2534

2818 CUUUUUAU A UAAUAAUU 410 AAUUAUUA CUGAUGAG X CGAA AUAAAAAG 2535

2820 UUUUAUAU A AUAAUUAU 411 AUAAUUAU CUGAUGAG X CGAA AUAUAAAA 2536

2823 UAUAUAAU A AUUAUAUA 412 UAUAUAAU CUGAUGAG X CGAA AUUAUAUA 2537

2826 AUAAUAAU U AUAUAACU 413 AGUUAUAU CUGAUGAG X CGAA AUUAUUAU 2538

2827 UAAUAAUU A UAUAACUU 414 AAGUUAUA CUGAUGAG X CGAA AAUUAUUA 2539

2829 AUAAUUAU A UAACUUAU 415 AUAAGUUA CUGAUGAG X CGAA AUAAUUAU 2540

2831 AAUUAUAU A ACUUAUGC 416 GCAUAAGU CUGAUGAG X CGAA AUAUAAUU 2541

2835 AUAUAACU U AUGCAUUU 417 AAAUGCAU CUGAUGAG X CGAA AGUUAUAU 2542

2836 UAUAACUU A UGCAUUUA 418 UAAAUGCA CUGAUGAG X CGAA AAGUUAUA 2543

2842 UUAUGCAU U UAUACACU 419 AGUGUAUA CUGAUGAG X CGAA AUGCAUAA 2544

2843 UAUGCAUU U AUACACUA 420 UAGUGUAU CUGAUGAG X CGAA AAUGCAUA 2545

2844 AUGCAUUU A UACACUAC 421 GUAGUGUA CUGAUGAG X CGAA AAAUGCAU 2546

2846 GCAUUUAU A CACUACGA 422 UCGUAGUG CUGAUGAG X CGAA AUAAAUGC 2547

2851 UAUACACU A CGAGUUGA 423 UCAACUCG CUGAUGAG X CGAA AGUGUAUA 2548

2857 CUACGAGU U GAUCUCGG 424 CCGAGAUC CUGAUGAG X CGAA ACUCGUAG 2549

2861 GAGUUGAU C UCGGCCAG 425 CUGGCCGA CUGAUGAG X CGAA AUCAACUC 2550

2863 GUUGAUCU C GGCCAGCC 426 GGCUGGCC CUGAUGAG X CGAA AGAUCAAC 2551

2897 GAGACAAU C GAUAUAAU 427 AUUAUAUC CUGAUGAG X CGAA AUUGUCUC 2552

2901 CAAUCGAU A UAAUGUGG 428 CCACAUUA CUGAUGAG X CGAA AUCGAUUG 2553

2903 AUCGAUAU A AUGUGGCC 429 GGCCACAU CUGAUGAG X CGAA AUAUCGAU 2554

2913 UGUGGCCU U GAAUUUUA 430 UAAAAUUC CUGAUGAG X CGAA AGGCCACA 2555

2918 CCUUGAAU U UUAACUCU 431 AGAGUUAA CUGAUGAG X CGAA AUUCAAGG 2556

2919 CUUGAAUU U UAACUCUG 432 CAGAGUUA CUGAUGAG X CGAA AAUUCAAG 2557

2920 UUGAAUUU U AACUCUGU 433 ACAGAGUU CUGAUGAG X CGAA AAAUUCAA 2558

2921 UGAAUUUU A ACUCUGUA 434 UACAGAGU CUGAUGAG X CGAA AAAAUUCA 2559

2925 UUUUAACU C UGUAUGCU 435 AGCAUACA CUGAUGAG X CGAA AGUUAAAA 2560

2929 AACUCUGU A UGCUUAAU 436 AUUAAGCA CUGAUGAG X CGAA ACAGAGUU 2561

2934 UGUAUGCU U AAUGUUUA 437 UAAACAUU CUGAUGAG X CGAA AGCAUACA 2562

2935 GUAUGCUU A AUGUUUAC 438 GUAAACAU CUGAUGAG X CGAA AAGCAUAC 2563

2940 CUUAAUGU U UACAAUAU 439 AUAUUGUA CUGAUGAG X CGAA ACAUUAAG 2564

2941 UUAAUGUU U ACAAUAUG 440 CAUAUUGU CUGAUGAG X CGAA AACAUUAA 2565

2942 UAAUGUUU A CAAUAUGA 441 UCAUAUUG CUGAUGAG X CGAA AAACAUUA 2566

2947 UUUACAAU A UGAAGUUA 442 UAACUUCA CUGAUGAG X CGAA AUUGUAAA 2567

2954 UAUGAAGU U AUUAGUUC 443 GAACUAAU CUGAUGAG X CGAA ACUUCAUA 2568

2955 AUGAAGUU A UUAGUUCU 444 AGAACUAA CUGAUGAG X CGAA AACUUCAU 2569

2957 GAAGUUAU U AGUUCUUA 445 UAAGAACU CUGAUGAG X CGAA AUAACUUC 2570

2958 AAGUUAUU A GUUCUUAG 446 CUAAGAAC CUGAUGAG X CGAA AAUAACUU 2571

2961 UUAUUAGU U CUUAGAAU 447 AUUCUAAG CUGAUGAG X CGAA ACUAAUAA 2572

2962 UAUUAGUU C UUAGAAUG 448 CAUUCUAA CUGAUGAG X CGAA AACUAAUA 2573

2964 UUAGUUCU U AGAAUGCA 449 UGCAUUCU CUGAUGAG X CGAA AGAACUAA 2574

2965 UAGUUCUU A GAAUGCAG 450 CUGCAUUC CUGAUGAG X CGAA AAGAACUA 2575

2979 CAGAAUGU A UGUAAUAA 451 UUAUUACA CUGAUGAG X CGAA ACAUUCUG 2576

2983 AUGUAUGU A AUAAAAUA 452 UAUUUUAU CUGAUGAG X CGAA ACAUACAU 2577 Table III

2986 UAUGUAAU A AAAUAAGC 453 GCUUAUUU CUGAUGAG X CGAA AUUACAUA 2578

2991 AAUAAAAU A AGCUUGGC 454 GCCAAGCU CUGAUGAG X CGAA AUUUUAUU 2579

2996 AAUAAGCU U GGCCUAGC 455 GCUAGGCC CUGAUGAG X CGAA AGCUUAUU 2580

3002 CUUGGCCU A GCAUGGCA 456 UGCCAUGC CUGAUGAG X CGAA AGGCCAAG 2581

3014 UGGCAAAU C AGAUUUAU 457 AUAAAUCU CUGAUGAG X CGAA AUUUGCCA 2582

3019 AAUCAGAU U UAUACAGG 458 CCUGUAUA CUGAUGAG X CGAA AUCUGAUU 2583

3020 AUCAGAUU U AUACAGGA 459 UCCUGUAU CUGAUGAG X CGAA AAUCUGAU 2584

3021 UCAGAUUU A UACAGGAG 460 CUCCUGUA CUGAUGAG X CGAA AAAUCUGA 2585

3023 AGAUUUAU A CAGGAGUC 461 GACUCCUG CUGAUGAG X CGAA AUAAAUCU 2586

3031 ACAGGAGU C UGCAUUUG 462 CAAAUGCA CUGAUGAG X CGAA ACUCCUGU 2587

3037 GUCUGCAU U UGCACUUU 463 AAAGUGCA CUGAUGAG X CGAA AUGCAGAC 2588

3038 UCUGCAUU U GCACUUUU 464 AAAAGUGC CUGAUGAG X CGAA AAUGCAGA 2589

3044 UUUGCACU U UUUUUAGU 465 ACUAAAAA CUGAUGAG X CGAA AGUGCAAA 2590

3045 UUGCACUU U UUUUAGUG 466 CACUAAAA CUGAUGAG X CGAA AAGUGCAA 2591

3046 UGCACUUU U UUUAGUGA 467 UCACUAAA CUGAUGAG X CGAA AAAGUGCA 2592

3047 GCACUUUU U UUAGUGAC 468 GUCACUAA CUGAUGAG X CGAA AAAAGUGC 2593

3048 CACUUUUU U UAGUGACU 469 AGUCACUA CUGAUGAG X CGAA AAAAAGUG 2594

3049 ACUUUUUU U AGUGACUA 470 UAGUGACU CUGAUGAG X CGAA AAAAAAGU 2595

3050 CUUUUUUU A GUGACUAA 471 UUAGUCAC CUGAUGAG X CGAA AAAAAAAG 2596

3057 UAGUGACU A AAGUUGCU 472 AGCAACUU CUGAUGAG X CGAA AGUCACUA 2597

3062 ACUAAAGU U GCUUAAUG 473 CAUUAAGC CUGAUGAG X CGAA ACUUUAGU 2598

3066 AAGUUGCU U AAUGAAAA 474 UUUUCAUU CUGAUGAG X CGAA AGCAACUU 2599

3067 AGUUGCUU A AUGAAAAC 475 GUUUUCAU CUGAUGAG X CGAA AAGCAACU 2600

3089 CUGAAUGU U GUGGAUUU 476 AAAUCCAC CUGAUGAG X CGAA ACAUUCAG 2601

3096 UUGUGGAU U UUGUGUUA 477 UAACACAA CUGAUGAG X CGAA AUCCACAA 2602

3097 UGUGGAUU U UGUGUUAU 478 AUAACACA CUGAUGAG X CGAA AAUCCACA 2603

3098 GUGGAUUU U GUGUUAUA 479 UAUAACAC CUGAUGAG X CGAA AAAUCCAC 2604

3103 UUUUGUGU U AUAAUUUA 480 UAAAUUAU CUGAUGAG X CGAA ACACAAAA 2605

3104 UUUGUGUU A UAAUUUAC 481 GUAAAUUA CUGAUGAG X CGAA AACACAAA 2606

3106 UGUGUUAU A AUUUACUU 482 AAGUAAAU CUGAUGAG X CGAA AUAACACA 2607

3109 GUUAUAAU U UACUUUGU 483 ACAAAGUA CUGAUGAG X CGAA AUUAUAAC 2608

3110 UUAUAAUU U ACUUUGUC 484 GACAAAGU CUGAUGAG X CGAA AAUUAUAA 2609

3111 UAUAAUUU A CUUUGUCC 485 GGACAAAG CUGAUGAG X CGAA AAAUUAUA 2610

3114 AAUUUACU U UGUCCAGG 486 CCUGGACA CUGAUGAG X CGAA AGUAAAUU 2611

3115 AUUUACUU U GUCCAGGA 487 UCCUGGAC CUGAUGAG X CGAA AAGUAAAU 2612

3118 UACUUUGU C CAGGAACU 488 AGUUCCUG CUGAUGAG X CGAA ACAAAGUA 2613

3127 CAGGAACU U GUGCAAGG 489 CCUUGCAC CUGAUGAG X CGAA AGUUCCUG 2614

3151 AAGGAAAU A GGAUGUUU 490 AAACAUCC CUGAUGAG X CGAA AUUUCCUU 2615

3158 UAGGAUGU U UGGCACCC 491 GGGUGCCA CUGAUGAG X CGAA ACAUCCUA 2616

Input Sequence = HUMERG2. Cut Site = UH/ .

Stem Length = 8 . Core Sequence = CUGAUGAG X CGAA (X = GCCGUUAGGC or other stem

ID

HUMERG2 (Human erg2 gene encoding erg2 protein, complete eds. ; 3166 bp) Table IV

Table IV: Human ERG Inozyme and Target Sequence

Substrate Seq ID Ribozyme RzSeq ID

CGCGUGUC C GCGCCCGC 492 GCGGGCGC CUGAUGAG X CGAA IACACGCG 2617

GUCCGCGC C CGCGUGUG 493 CACACGCG CUGAUGAG X CGAA ICGCGGAC 2618

UCCGCGCC C GCGUGUGC 494 GCACACGC CUGAUGAG X CGAA IGCGCGGA 2619

GCGUGUGC C AGCGCGCG 495 CGCGCGCU CUGAUGAG X CGAA ICACACGC 2620

CGUGUGCC A GCGCGCGU 496 ACGCGCGC CUGAUGAG X CGAA IGCACACG 2621

GCGCGUGC C UUGGCCGU 497 ACGGCCAA CUGAUGAG X CGAA ICACGCGC 2622

CGCGUGCC U UGGCCGUG 498 CACGGCCA CUGAUGAG X CGAA IGCACGCG 2623

GCCUUGGC C GUGCGCGC 499 GCGCGCAC CUGAUGAG X CGAA ICCAAGGC 2624

GUGCGCGC C GAGCCGGG 500 CCCGGCUC CUGAUGAG X CGAA ICGCGCAC 2625

CGCCGAGC C GGGUCGCA 501 UGCGACCC CUGAUGAG X CGAA ICUCGGCG 2626

CGGGUCGC A CUAACUCC 502 GGAGUUAG CUGAUGAG X CGAA ICGACCCG 2627

GGUCGCAC U AACUCCCU 503 AGGGAGUU CUGAUGAG X CGAA IUGCGACC 2628

GCACUAAC U CCCUCGGC 504 GCCGAGGG CUGAUGAG X CGAA IUUAGUGC 2629

ACUAACUC C CUCGGCGC 505 GCGCCGAG CUGAUGAG X CGAA IAGUUAGU 2630

CUAACUCC C UCGGCGCC 506 GGCGCCGA CUGAUGAG X CGAA IGAGUUAG 2631

UAACUCCC U CGGCGCCG 507 CGGCGCCG CUGAUGAG X CGAA IGGAGUUA 2632

CUCGGCGC C GACGGCGG 508 CCGCCGUC CUGAUGAG X CGAA ICGCCGAG 2633

GGCGGCGC U AACCUCUC 509 GAGAGGUU CUGAUGAG X CGAA ICGCCGCC 2634

GCGCUAAC C UCUCGGUU 510 AACCGAGA CUGAUGAG X CGAA lUUAGCGC 2635

CGCUAACC u CUCGGUUA 511 ^• UAACCGAG CUGAUGAG X CGAA IGUUAGCG 2636

CUAACCUC u CGGUUAUU 512 AAUAACCG CUGAUGAG X CGAA IAGGUUAG 2637

GGUUAUUC c AGGAUCUU 513 AAGAUCCU CUGAUGAG X CGAA IAAUAACC 2638

GUUAUUCC A GGAUCUUU 514 AAAGAUCC CUGAUGAG X CGAA IGAAUAAC 2639

CCAGGAUC u UUGGAGAC 515 GUCUCCAA CUGAUGAG X CGAA IAUCCUGG 2640

UUGGAGAC C CGAGGAAA 516 UUUCCUCG CUGAUGAG X CGAA lUCUCCAA 2641

UGGAGACC C GAGGAAAG 517 CUUUCCUC CUGAUGAG X CGAA IGUCUCCA 2642

AGGAAAGC C GUGUUGAC 518 GUCAACAC CUGAUGAG X CGAA ICUUUCCU 2643

GUGUUGAC C AAAAGCAA 519 UUGCUUUU CUGAUGAG X CGAA IUCAACAC 2644

UGUUGACC A AAAGCAAG 520 CUUGCUUU CUGAUGAG X CGAA IGUCAACA 2645

CCAAAAGC A AGACAAAU 521 AUUUGUCU CUGAUGAG X CGAA ICUUUUGG 2646

AGCAAGAC A AAUGACUC 522 GAGUCAUU CUGAUGAG X CGAA IUCUUGCU 2647

CAAAUGAC U CACAGAGA 523 UCUCUGUG CUGAUGAG X CGAA IUCAUUUG 2648

AAUGACUC A CAGAGAAA 524 UUUCUCUG CUGAUGAG X CGAA IAGUCAUU 2649

UGACUCAC A GAGAAAAA 525 UUUUUCUC CUGAUGAG X CGAA lUGAGUCA 2650

AAGAUGGC A GAACCAAG 526 CUUGGUUC CUGAUGAG X CGAA ICCAUCUU 2651

GGCAGAAC C AAGGGCAA 527 UUGCCCUU CUGAUGAG X CGAA IUUCUGCC 2652

GCAGAACC A AGGGCAAC 528 GUUGCCCU CUGAUGAG X CGAA IGUUCUGC 2653

CCAAGGGC A ACUAAAGC 529 GCUUUAGU CUGAUGAG X CGAA ICCCUUGG 2654

AGGGCAAC U AAAGCCGU 530 ACGGCUUU CUGAUGAG X CGAA IUUGCCCU 2655

ACUAAAGC C GUCAGGUU 531 AACCUGAC CUGAUGAG X CGAA ICUUUAGU 2656

AAGCCGUC A GGUUCUGA 532 UCAGAACC CUGAUGAG X CGAA IACGGCUU 2657

UCAGGUUC U GAACAGCU 533 AGCUGUUC CUGAUGAG X CGAA IAACCUGA 2658

UUCUGAAC A GCUGGUAG 534 CUACCAGC CUGAUGAG X CGAA IUUCAGAA 2659

UGAACAGC U GGUAGAUG 535 CAUCUACC CUGAUGAG X CGAA ICUGUUCA 2660

AGAUGGGC U GGCUUACU 536 AGUAAGCC CUGAUGAG X CGAA ICCCAUCU 2661

GGGCUGGC U UACUGAAG 537 CUUCAGUA CUGAUGAG X CGAA ICCAGCCC 2662

UGGCUUAC U GAAGGACA 538 UGUCCUUC CUGAUGAG X CGAA IUAAGCCA 2663

UGAAGGAC A UGAUUCAG 539 CUGAAUCA CUGAUGAG X CGAA IUCCUUCA 2664

CAUGAUUC A GACUGUCC 540 GGACAGUC CUGAUGAG X CGAA IAAUCAUG 2665

AUUCAGAC U GUCCCGGA 541 UCCGGGAC CUGAUGAG X CGAA IUCUGAAU 2666

AGACUGUC C CGGACCCA 542 UGGGUCCG CUGAUGAG X CGAA IACAGUCU 2667

GACUGUCC C GGACCCAG 543 CUGGGUCC CUGAUGAG X CGAA IGACAGUC 2668 Table IV

278 UCCCGGAC C CAGCAGCU 544 AGCUGCUG CUGAUGAG X CGAA IUCCGGGA 2669

279 CCCGGACC C AGCAGCUC 545 GAGCUGCU CUGAUGAG X CGAA IGUCCGGG 2670

280 CCGGACCC A GCAGCUCA 546 UGAGCUGC CUGAUGAG X CGAA IGGUCCGG 2671

283 GACCCAGC A GCUCAUAU 547 AUAUGAGC CUGAUGAG X CGAA ICUGGGUC 2672

286 CCAGCAGC U CAUAUCAA 548 UUGAUAUG CUGAUGAG X CGAA ICUGCUGG 2673

288 AGCAGCUC A UAUCAAGG 549 CCUUGAUA CUGAUGAG X CGAA IAGCUGCU 2674

293 CUCAUAUC A AGGAAGCC 550 GGCUUCCU CUGAUGAG X CGAA IAUAUGAG 2675

301 AAGGAAGC C UUAUCAGU 551 ACUGAUAA CUGAUGAG X CGAA ICUUCCUU 2676

302 AGGAAGCC U UAUCAGUU 552 AACUGAUA CUGAUGAG X CGAA IGCUUCCU 2677

307 GCCUUAUC A GUUGUGAG 553 CUCACAAC CUGAUGAG X CGAA IAUAAGGC 2678

323 GUGAGGAC C AGUCGUUG 554 CAACGACU CUGAUGAG X CGAA IUCCUCAC 2679

324 UGAGGACC A GUCGUUGU 555 ACAACGAC CUGAUGAG X CGAA IGUCCUCA 2680

343 GAGUGUGC C UACGGAAC 556 GUUCCGUA CUGAUGAG X CGAA ICACACUC 2681

344 AGUGUGCC U ACGGAACG 557 CGUUCCGU CUGAUGAG X CGAA IGCACACU 2682

354 CGGAACGC C ACACCUGG 558 CCAGGUGU CUGAUGAG X CGAA ICGUUCCG 2683

355 GGAACGCC A CACCUGGC 559 GCCAGGUG CUGAUGAG X CGAA IGCGUUCC 2684

357 AACGCCAC A CCUGGCUA 560 UAGCCAGG CUGAUGAG X CGAA IUGGCGUU 2685

359 CGCCACAC C UGGCUAAG 561 CUUAGCCA CUGAUGAG X CGAA IUGUGGCG 2686

360 GCCACACC U GGCUAAGA 562 UCUUAGCC CUGAUGAG X CGAA IGUGUGGC 2687

364 CACCUGGC U AAGACAGA 563 UCUGUCUU CUGAUGAG X CGAA ICCAGGUG 2688

370 GCUAAGAC A GAGAUGAC 564 GUCAUCUC CUGAUGAG X CGAA IUCUUAGC 2689

379 GAGAUGAC C GCGUCCUC 565 GAGGACGC CUGAUGAG X CGAA IUCAUCUC 2690

385 ACCGCGUC C UCCUCCAG 566 CUGGAGGA CUGAUGAG X CGAA IACGCGGU 2691

386 CCGCGUCC U CCUCCAGC 567 GCUGGAGG CUGAUGAG X CGAA IGACGCGG 2692

388 GCGUCCUC C UCCAGCGA 568 UCGCUGGA CUGAUGAG X CGAA IAGGACGC 2693

389 CGUCCUCC U CCAGCGAC 569 GUCGCUGG CUGAUGAG X CGAA IGAGGACG 2694

391 UCCUCCUC C AGCGACUA 570 UAGUCGCU CUGAUGAG X CGAA lAGGAGGA 2695

392 CCUCCUCC A GCGACUAU 571 AUAGUCGC CUGAUGAG X CGAA IGAGGAGG 2696

398 CCAGCGAC U AUGGACAG 572 CUGUCCAU CUGAUGAG X CGAA IUCGCUGG 2697

405 CUAUGGAC A GACUUCCA 573 UGGAAGUC CUGAUGAG X CGAA IUCCAUAG 2698

409 GGACAGAC U UCCAAGAU 574 AUCUUGGA CUGAUGAG X CGAA IUCUGUCC 2699

412 CAGACUUC C AAGAUGAG 575 CUCAUCUU CUGAUGAG X CGAA IAAGUCUG 2700

413 AGACUUCC A AGAUGAGC 576 GCUCAUCU CUGAUGAG X CGAA IGAAGUCU 2701

422 AGAUGAGC C CACGCGUC 577 GACGCGUG CUGAUGAG X CGAA ICUCAUCU 2702

423 GAUGAGCC C ACGCGUCC 578 GGACGCGU CUGAUGAG X CGAA IGCUCAUC 2703

424 AUGAGCCC A CGCGUCCC 579 GGGACGCG CUGAUGAG X CGAA IGGCUCAU 2704

431 CACGCGUC C CUCAGCAG 580 CUGCUGAG CUGAUGAG X CGAA IACGCGUG 2705

432 ACGCGUCC C UCAGCAGG 581 CCUGCUGA CUGAUGAG X CGAA IGACGCGU 2706

433 CGCGUCCC U CAGCAGGA 582 UCCUGCUG CUGAUGAG X CGAA IGGACGCG 2707

435 CGUCCCUC A GCAGGAUU 583 AAUCCUGC CUGAUGAG X CGAA IAGGGACG 2708

438 CCCUCAGC A GGAUUGGC 584 GCCAAUCC CUGAUGAG X CGAA ICUGAGGG 2709

447 GGAUUGGC U GUCUCAAC 585 GUUGAGAC CUGAUGAG X CGAA ICCAAUCC 2710

451 UGGCUGUC U CAACCCCC 586 GGGGGUUG CUGAUGAG X CGAA IACAGCCA 2711

453 GCUGUCUC A ACCCCCAG 587 CUGGGGGU CUGAUGAG X CGAA IAGACAGC 2712

456 GUCUCAAC C CCCAGCCA 588 UGGCUGGG CUGAUGAG X CGAA IUUGAGAC 2713

457 UCUCAACC c CCAGCCAG 589 CUGGCUGG CUGAUGAG X CGAA IGUUGAGA 2714

458 CUCAACCC c CAGCCAGG 590 CCUGGCUG CUGAUGAG X CGAA IGGUUGAG 2715

459 UCAACCCC c AGCCAGGG 591 CCCUGGCU CUGAUGAG X CGAA IGGGUUGA 2716

460 CAACCCCC A GCCAGGGU 592 ACCCUGGC CUGAUGAG X CGAA IGGGGUUG 2717

463 CCCCCAGC C AGGGUCAC 593 GUGACCCU CUGAUGAG X CGAA ICUGGGGG 2718

464 CCCCAGCC A GGGUCACC 594 GGUGACCC CUGAUGAG X CGAA IGCUGGGG 2719

470 CCAGGGUC A CCAUCAAA 595 UUUGAUGG CUGAUGAG X CGAA IACCCUGG 2720

472 AGGGUCAC C AUCAAAAU 596 AUUUUGAU CUGAUGAG X CGAA lUGACCCU 2721

473 GGGUCACC A UCAAAAUG 597 CAUUUUGA CUGAUGAG X CGAA IGUGACCC 2722

476 UCACCAUC A AAAUGGAA 598 UUCCAUUU CUGAUGAG X CGAA IAUGGUGA 2723

491 AAUGUAAC C CUAGCCAG 599 CUGGCUAG CUGAUGAG X CGAA IUUACAUU 2724 Table IV

492 AUGUAACC C UAGCCAGG 600 CCUGGCUA CUGAUGAG X CGAA IGUUACAU 2725

493 UGUAACCC U AGCCAGGU 601 ACCUGGCU CUGAUGAG X CGAA IGGUUACA 2726

497 ACCCUAGC C AGGUGAAU 602 AUUCACCU CUGAUGAG X CGAA ICUAGGGU 2727

498 CCCUAGCC A GGUGAAUG 603 CAUUCACC CUGAUGAG X CGAA IGCUAGGG 2728

509 UGAAUGGC U CAAGGAAC 604 GUUCCUUG CUGAUGAG X CGAA ICCAUUCA 2729

511 AAUGGCUC A AGGAACUC 605 GAGUUCCU CUGAUGAG X CGAA IAGCCAUU 2730

518 CAAGGAAC U CUCCUGAU 606 AUCAGGAG CUGAUGAG X CGAA lUUCCUUG 2731

520 AGGAACUC U CCUGAUGA 607 UCAUCAGG CUGAUGAG X CGAA IAGUUCCU 2732

522 GAACUCUC C UGAUGAAU 608 AUUCAUCA CUGAUGAG X CGAA IAGAGUUC 2733

523 AACUCUCC U GAUGAAUG 609 CAUUCAUC CUGAUGAG X CGAA IGAGAGUU 2734

533 AUGAAUGC A GUGUGGCC 610 GGCCACAC CUGAUGAG X CGAA ICAUUCAU 2735

541 AGUGUGGC C AAAGGCGG 611 CCGCCUUU CUGAUGAG X CGAA ICCACACU 2736

542 GUGUGGCC A AAGGCGGG 612 CCCGCCUU CUGAUGAG X CGAA IGCCACAC 2737

563 UGGUGGGC A GCCCAGAC 613 GUCUGGGC CUGAUGAG X CGAA ICCCACCA 2738

566 UGGGCAGC C CAGACACC 614 GGUGUCUG CUGAUGAG X CGAA ICUGCCCA 2739

567 GGGCAGCC C AGACACCG 615 CGGUGUCU CUGAUGAG X CGAA IGCUGCCC 2740

568 GGCAGCCC A GACACCGU 616 ACGGUGUC CUGAUGAG X CGAA IGGCUGCC 2741

572 GCCCAGAC A CCGUUGGG 617 CCCAACGG CUGAUGAG X CGAA IUCUGGGC 2742

574 CCAGACAC C GUUGGGAU 618 AUCCCAAC CUGAUGAG X CGAA IUGUCUGG 2743

587 GGAUGAAC U ACGGCAGC 619 ^• GCUGCCGU CUGAUGAG X CGAA IUUCAUCC 2744

593 ACUACGGC A GCUACAUG 620 CAUGUAGC CUGAUGAG X CGAA ICCGUAGU 2745

596 ACGGCAGC U ACAUGGAG 621 CUCCAUGU CUGAUGAG X CGAA ICUGCCGU 2746

599 GCAGCUAC A UGGAGGAG 622 CUCCUCCA CUGAUGAG X CGAA IUAGCUGC 2747

612 GGAGAAGC A CAUGCCAC 623 GUGGCAUG CUGAUGAG X CGAA ICUUCUCC 2748

614 AGAAGCAC A UGCCACCC 624 GGGUGGCA CUGAUGAG X CGAA IUGCUUCU 2749

618 GCACAUGC C ACCCCCAA 625 UUGGGGGU CUGAUGAG X CGAA ICAUGUGC 2750

619 CACAUGCC A CCCCCAAA 626 UUUGGGGG CUGAUGAG X CGAA IGCAUGUG 2751

621 CAUGCCAC C CCCAAACA 627 UGUUUGGG CUGAUGAG X CGAA IUGGCAUG 2752

622 AUGCCACC C CCAAACAU 628 AUGUUUGG CUGAUGAG X CGAA IGUGGCAU 2753

623 UGCCACCC C CAAACAUG 629 CAUGUUUG CUGAUGAG X CGAA IGGUGGCA 2754

624 GCCACCCC C AAACAUGA 630 UCAUGUUU CUGAUGAG X CGAA IGGGUGGC 2755

625 CCACCCCC A AACAUGAC 631 GUCAUGUU CUGAUGAG X CGAA IGGGGUGG 2756

629 CCCCAAAC A UGACCACG 632 CGUGGUCA CUGAUGAG X CGAA IUUUGGGG 2757

634 AACAUGAC C ACGAACGA 633 UCGUUCGU CUGAUGAG X CGAA IUCAUGUU 2758

635 ACAUGACC A CGAACGAG 634 CUCGUUCG CUGAUGAG X CGAA IGUCAUGU 2759

647 ACGAGCGC A GAGUUAUC 635 GAUAACUC CUGAUGAG X CGAA ICGCUCGU 2760

660 UAUCGUGC C AGCAGAUC 636 GAUCUGCU CUGAUGAG X CGAA ICACGAUA 2761

661 AUCGUGCC A GCAGAUCC 637 GGAUCUGC CUGAUGAG X CGAA IGCACGAU 2762

664 GUGCCAGC A GAUCCUAC 638 GUAGGAUC CUGAUGAG X CGAA ICUGGCAC 2763

669 AGCAGAUC C UACGCUAU 639 AUAGCGUA CUGAUGAG X CGAA IAUCUGCU 2764

670 GCAGAUCC U ACGCUAUG 640 CAUAGCGU CUGAUGAG X CGAA IGAUCUGC 2765

675 UCCUACGC U AUGGAGUA 641 UACUCCAU CUGAUGAG X CGAA ICGUAGGA 2766

685 UGGAGUAC A GACCAUGU 642 ACAUGGUC CUGAUGAG X CGAA IUACUCCA 2767

689 GUACAGAC C AUGUGCGG 643 CCGCACAU CUGAUGAG X CGAA IUCUGUAC 2768

690 UACAGACC A UGUGCGGC 644 GCCGCACA CUGAUGAG X CGAA IGUCUGUA 2769

699 UGUGCGGC A GUGGCUGG 645 CCAGCCAC CUGAUGAG X CGAA ICCGCACA 2770

705 GCAGUGGC U GGAGUGGG 646 CCCACUCC CUGAUGAG X CGAA ICCACUGC 2771

731 AAUAUGGC C UUCCAGAC 647 GUCUGGAA CUGAUGAG X CGAA ICCAUAUU 2772

732 AUAUGGCC U UCCAGACG 648 CGUCUGGA CUGAUGAG X CGAA IGCCAUAU 2773

735 UGGCCUUC C AGACGUCA 649 UGACGUCU CUGAUGAG X CGAA IAAGGCCA 2774

736 GGCCUUCC A GACGUCAA 650 UUGACGUC CUGAUGAG X CGAA IGAAGGCC 2775

743 CAGACGUC A ACAUCUUG 651 CAAGAUGU CUGAUGAG X CGAA IACGUCUG 2776

746 ACGUCAAC A UCUUGUUA 652 UAACAAGA CUGAUGAG X CGAA lUUGACGU 2777

749 UCAACAUC U UGUUAUUC 653 GAAUAACA CUGAUGAG X CGAA IAUGUUGA 2778

758 UGUUAUUC C AGAACAUC 654 GAUGUUCU CUGAUGAG X CGAA IAAUAACA 2779

759 GUUAUUCC A GAACAUCG 655 CGAUGUUC CUGAUGAG X CGAA IGAAUAAC 2780 Table IV

764 UCCAGAAC A UCGAUGGG 656 CCCAUCGA CUGAUGAG X CGAA IUUCUGGA 2781

780 GAAGGAAC U GUGCAAGA 657 UCUUGCAC CUGAUGAG X CGAA IUUCCUUC 2782

785 AACUGUGC A AGAUGACC 658 GGUCAUCU CUGAUGAG X CGAA ICACAGUU 2783

793 AAGAUGAC C AAGGACGA 659 UCGUCCUU CUGAUGAG X CGAA IUCAUCUU 2784

794 AGAUGACC A AGGACGAC 660 GUCGUCCU CUGAUGAG X CGAA IGUCAUCU 2785

803 AGGACGAC U UCCAGAGG 661 CCUCUGGA CUGAUGAG X CGAA IUCGUCCU 2786

806 ACGACUUC C AGAGGCUC 662 GAGCCUCU CUGAUGAG X CGAA IAAGUCGU 2787

807 CGACUUCC A GAGGCUCA 663 UGAGCCUC CUGAUGAG, X CGAA IGAAGUCG 2788

813 CCAGAGGC U CACCCCCA 664 UGGGGGUG CUGAUGAG X CGAA ICCUCUGG 2789

815 AGAGGCUC A CCCCCAGC 665 GCUGGGGG CUGAUGAG X CGAA IAGCCUCU 2790

817 AGGCUCAC C CCCAGCUA 666 UAGCUGGG CUGAUGAG X CGAA IUGAGCCU 2791

818 GGCUCACC C CCAGCUAC 667 GUAGCUGG CUGAUGAG X CGAA IGUGAGCC 2792

819 GCUCACCC C CAGCUACA 668 UGUAGCUG CUGAUGAG X CGAA IGGUGAGC 2793

820 CUCACCCC C AGCUACAA 669 UUGUAGCU CUGAUGAG X CGAA IGGGUGAG 2794

821 UCACCCCC A GCUACAAC 670 GUUGUAGC CUGAUGAG X CGAA IGGGGUGA 2795

824 CCCCCAGC U ACAACGCC 671 GGCGUUGU CUGAUGAG X CGAA ICUGGGGG 2796

827 CCAGCUAC A ACGCCGAC 672 GUCGGCGU CUGAUGAG X CGAA IUAGCUGG 2797

832 UACAACGC C GACAUCCU 673 AGGAUGUC CUGAUGAG X CGAA ICGUUGUA 2798

836 ACGCCGAC A UCCUUCUC 674 GAGAAGGA CUGAUGAG X CGAA IUCGGCGU 2799

839 CCGACAUC C UUCUCUCA 675 UGAGAGAA CUGAUGAG X CGAA IAUGUCGG 2800

840 CGACAUCC U UCUCUCAC 676 GUGAGAGA CUGAUGAG X CGAA IGAUGUCG 2801

843 CAUCCUUC U CUCACAUC 677 GAUGUGAG CUGAUGAG X CGAA IAAGGAUG 2802

845 UCCUUCUC U CACAUCUC 678 GAGAUGUG CUGAUGAG X CGAA IAGAAGGA 2803

847 CUUCUCUC A CAUCUCCA 679 UGGAGAUG CUGAUGAG X CGAA IAGAGAAG 2804

849 UCUCUCAC A UCUCCACU 680 AGUGGAGA CUGAUGAG X CGAA lUGAGAGA 2805

852 CUCACAUC U CCACUACC 681 GGUAGUGG CUGAUGAG X CGAA IAUGUGAG 2806

854 CACAUCUC C ACUACCUC 682 GAGGUAGU CUGAUGAG X CGAA IAGAUGUG 2807

855 ACAUCUCC A CUACCUCA 683 UGAGGUAG CUGAUGAG X CGAA IGAGAUGU 2808

857 AUCUCCAC U ACCUCAGA 684 UCUGAGGU CUGAUGAG X CGAA IUGGAGAU 2809

860 UCCACUAC C UCAGAGAG 685 CUCUCUGA CUGAUGAG X CGAA IUAGUGGA 2810

861 CCACUACC U CAGAGAGA 686 UCUCUCUG CUGAUGAG X CGAA IGUAGUGG 2811

863 ACUACCUC A GAGAGACU 687 AGUCUCUC CUGAUGAG X CGAA IAGGUAGU 2812

871 AGAGAGAC U CCUCUUCC 688 GGAAGAGG CUGAUGAG X CGAA IUCUCUCU 2813

873 AGAGACUC C UCUUCCAC 689 GUGGAAGA CUGAUGAG X CGAA IAGUCUCU 2814

874 GAGACUCC U CUUCCACA 690 UGUGGAAG CUGAUGAG X CGAA IGAGUCUC 2815

876 GACUCCUC U UCCACAUU 691 AAUGUGGA CUGAUGAG X CGAA IAGGAGUC 2816

879 UCCUCUUC C ACAUUUGA 692 UCAAAUGU CUGAUGAG X CGAA IAAGAGGA 2817

880 CCUCUUCC A CAUUUGAC 693 GUCAAAUG CUGAUGAG X CGAA IGAAGAGG 2818

882 UCUUCCAC A UUUGACUU 694 AAGUCAAA CUGAUGAG X CGAA lUGGAAGA 2819

889 CAUUUGAC U UCAGAUGA 695 UCAUCUGA CUGAUGAG X CGAA IUCAAAUG 2820

892 UUGACUUC A GAUGAUGU 696 ACAUCAUC CUGAUGAG X CGAA IAAGUCAA 2821

910 GAUAAAGC C UUACAAAA 697 UUUUGUAA CUGAUGAG X CGAA ICUUUAUC 2822

911 AUAAAGCC U UACAAAAC 698 GUUUUGUA CUGAUGAG X CGAA IGCUUUAU 2823

915 AGCCUUAC A AAACUCUC 699 GAGAGUUU CUGAUGAG X CGAA IUAAGGCU 2824

920 UACAAAAC U CUCCACGG 700 CCGUGGAG CUGAUGAG X CGAA IUUUUGUA 2825

922 CAAAACUC U CCACGGUU 701 AACCGUGG CUGAUGAG X CGAA IAGUUUUG 2826

924 AAACUCUC C ACGGUUAA 702 UUAACCGU CUGAUGAG X CGAA IAGAGUUU 2827

925 AACUCUCC A CGGUUAAU 703 AUUAACCG CUGAUGAG X CGAA IGAGAGUU 2828

936 GUUAAUGC A UGCUAGAA 704 UUCUAGCA CUGAUGAG X CGAA ICAUUAAC 2829

940 AUGCAUGC U AGAAACAC 705 GUGUUUCU CUGAUGAG X CGAA ICAUGCAU 2830

947 CUAGAAAC A CAGAUUUA 706 UAAAUCUG CUGAUGAG X CGAA IUUUCUAG 2831

949 AGAAACAC A GAUUUACC 707 GGUAAAUC CUGAUGAG X CGAA IUGUUUCU 2832

957 AGAUUUAC C AUAUGAGC 708 GCUCAUAU CUGAUGAG X CGAA IUAAAUCU 2833

958 GAUUUACC A UAUGAGCC 709 GGCUCAUA CUGAUGAG X CGAA IGUAAAUC 2834

966 AUAUGAGC C CCCCAGGA 710 UCCUGGGG CUGAUGAG X CGAA ICUCAUAU 2835

967 UAUGAGCC C CCCAGGAG . 711 CUCCUGGG CUGAUGAG X CGAA IGCUCAUA 2836 Table IV

968 AUGAGCCC C CCAGGAGA 712 UCUCCUGG CUGAUGAG X CGAA IGGCUCAU 2837

969 UGAGCCCC C CAGGAGAU 713 AUCUCCUG CUGAUGAG X CGAA IGGGCUCA 2838

970 GAGCCCCC C AGGAGAUC 714 GAUCUCCU CUGAUGAG X CGAA IGGGGCUC 2839

971 AGCCCCCC A GGAGAUCA 715 UGAUCUCC CUGAUGAG X CGAA IGGGGGCU 2840

979 AGGAGAUC A GCCUGGAC 716 GUCCAGGC CUGAUGAG X CGAA IAUCUCCU 2841

982 AGAUGAGC C UGGACCGG 717 CCGGUCCA CUGAUGAG X CGAA ICUGAUCU 2842

983 GAUCAGCC U GGACCGGU 718 ACCGGUCC CUGAUGAG X CGAA IGCUGAUC 2843

988 GCCUGGAC C GGUCACGG 719 CCGUGACC CUGAUGAG X CGAA IUCCAGGC 2844

993 GACCGGUC A CGGCCACC 720 GGUGGCCG CUGAUGAG X CGAA IACCGGUC 2845

998 GUCACGGC C ACCCCACG 721 CGUGGGGU CUGAUGAG X CGAA ICCGUGAC 2846

999 UCACGGCC A CCCCACGC 722 GCGUGGGG CUGAUGAG X CGAA IGCCGUGA 2847

1001 ACGGCCAC C CCACGCCC 723 GGGCGUGG CUGAUGAG X CGAA IUGGCCGU 2848

1002 CGGCCACC C CACGCCCC 724 GGGGCGUG CUGAUGAG X CGAA IGUGGCCG 2849

1003 GGCCACCC C ACGCCCCA 725 UGGGGCGU CUGAUGAG X CGAA IGGUGGCC 2850

1004 GCCACCCC A CGCCCCAG 726 CUGGGGCG CUGAUGAG X CGAA IGGGUGGC 2851

1008 CCCCACGC C CCAGUCGA 727 UCGACUGG CUGAUGAG X CGAA ICGUGGGG 2852

1009 CCCACGCC C CAGUCGAA 728 UUCGACUG CUGAUGAG X CGAA IGCGUGGG 2853

1010 CCACGCCC C AGUCGAAA 729 UUUCGACU CUGAUGAG X CGAA IGGCGUGG 2854

1011 CACGCCCC A GUCGAAAG 730 CUUUCGAC CUGAUGAG X CGAA IGGGCGUG 2855

1021 UCGAAAGC U GCUCAACC 731 GGUUGAGC CUGAUGAG X CGAA ICUUUCGA 2856

1024 AAAGCUGC U CAACCAUC 732 GAUGGUUG CUGAUGAG X CGAA ICAGCUUU 2857

1026 AGCUGCUC A ACCAUCUC 733 GAGAUGGU CUGAUGAG X CGAA IAGCAGCU 2858

1029 UGCUCAAC C AUCUCCUU 734 AAGGAGAU CUGAUGAG X CGAA lUUGAGCA 2859

1030 GCUCAACC A UCUCCUUC 735 GAAGGAGA CUGAUGAG X CGAA IGUUGAGC 2860

1033 CAACCAUC U CCUUCCAC 736 GUGGAAGG CUGAUGAG X CGAA IAUGGUUG 2861

1035 ACCAUCUC C UUCCACAG 737 CUGUGGAA CUGAUGAG X CGAA IAGAUGGU 2862

1036 CCAUCUCC U UCCACAGU 738 ACUGUGGA CUGAUGAG X CGAA IGAGAUGG 2863

1039 UCUCCUUC C ACAGUGCC 739 GGCACUGU CUGAUGAG X CGAA IAAGGAGA 2864

1040 CUCCUUCC A CAGUGCCC 740 GGGCACUG CUGAUGAG X CGAA IGAAGGAG 2865

1042 CCUUCCAC A GUGCCCAA 741 UUGGGCAC CUGAUGAG X CGAA IUGGAAGG 2866

1047 CACAGUGC C CAAAACUG 742 CAGUUUUG CUGAUGAG X CGAA ICACUGUG 2867

1048 ACAGUGCC C AAAACUGA 743 UCAGUUUU CUGAUGAG X CGAA IGCACUGU 2868

1049 CAGUGCCC A AAACUGAA 744 UUCAGUUU CUGAUGAG X CGAA IGGCACUG 2869

1054 CCCAAAAC U GAAGACCA 745 UGGUCUUC CUGAUGAG X CGAA IUUUUGGG 2870

1061 CUGAAGAC C AGCGUCCU 746 AGGACGCU CUGAUGAG X CGAA IUCUUCAG 2871

1062 UGAAGACC A GCGUCCUC 747 GAGGACGC CUGAUGAG X CGAA IGUCUUCA 2872

1068 CCAGCGUC C UCAGUUAG 748 CUAACUGA CUGAUGAG X CGAA IACGCUGG 2873

1069 CAGCGUCC U CAGUUAGA 749 UCUAACUG CUGAUGAG X CGAA IGACGCUG 2874

1071 GCGUCCUC A GUUAGAUC 750 GAUCUAAC CUGAUGAG X CGAA IAGGACGC 2875

1080 GUUAGAUC C UUAUCAGA 751 UCUGAUAA CUGAUGAG X CGAA IAUCUAAC 2876

1081 UUAGAUCC U UAUCAGAU 752 AUCUGAUA CUGAUGAG X CGAA IGAUCUAA 2877

1086 UCCUUAUC A GAUUCUUG 753 CAAGAAUC CUGAUGAG X CGAA IAUAAGGA 2878

1092 UCAGAUUC U UGGACCAA 754 UUGGUCCA CUGAUGAG X CGAA IAAUCUGA 2879

1098 UCUUGGAC C AACAAGUA 755 UACUUGUU CUGAUGAG X CGAA IUCCAAGA 2880

1099 CUUGGACC A ACAAGUAG 756 CUACUUGU CUGAUGAG X CGAA IGUCCAAG 2881

1102 GGACCAAC A AGUAGCCG 757 CGGCUACU CUGAUGAG X CGAA IUUGGUCC 2882

1109 CAAGUAGC C GCCUUGCA 758 UGCAAGGC CUGAUGAG X CGAA ICUACUUG 2883

1112 GUAGCCGC C UUGCAAAU 759 AUUUGCAA CUGAUGAG X CGAA ICGGCUAC 2884

1113 UAGCCGCC U UGCAAAUC 760 GAUUUGCA CUGAUGAG X CGAA IGCGGCUA 2885

1117 CGCCUUGC A AAUCCAGG 761 CCUGGAUU CUGAUGAG X CGAA ICAAGGCG 2886

1122 UGCAAAUC C AGGCAGUG 762 CACUGCCU CUGAUGAG X CGAA IAUUUGCA 2887

1123 GCAAAUCC A GGCAGUGG 763 CCACUGCC CUGAUGAG X CGAA IGAUUUGC 2888

1127 AUCCAGGC A GUGGCCAG 764 CUGGCCAC CUGAUGAG X CGAA ICCUGGAU 2889

1133 GCAGUGGC C AGAUCCAG 765 CUGGAUCU CUGAUGAG X CGAA ICCACUGC 2890

1134 CAGUGGCC A GAUCCAGC 766 GCUGGAUC CUGAUGAG X CGAA IGCCACUG 2891

1139 GCCAGAUC C AGCUUUGG 767 CCAAAGCU CUGAUGAG X CGAA IAUCUGGC 2892 Table IV

1140 CCAGAUCC A GCUUUGGC 768 GCCAAAGC CUGAUGAG X CGAA IGAUCUGG 2893

1143 GAUCCAGC U UUGGCAGU 769 ACUGCCAA CUGAUGAG X CGAA ICUGGAUC 2894

1149 GCUUUGGC A GUUCCUCC 770 GGAGGAAC CUGAUGAG X CGAA ICCAAAGC 2895

1154 GGCAGUUC C UCCUGGAG 771 CUCCAGGA CUGAUGAG X CGAA IAACUGCC 2896

1155 GCAGUUCC U CCUGGAGC 772 GCUCCAGG CUGAUGAG X CGAA IGAACUGC 2897

1157 AGUUCCUC C UGGAGCUC 773 GAGCUCCA CUGAUGAG X CGAA IAGGAACU 2898

1158 GUUCCUCC U GGAGCUCC 774 GGAGCUCC CUGAUGAG X CGAA IGAGGAAC 2899

1164 CCUGGAGC U CCUGUCGG 775 CCGACAGG CUGAUGAG X CGAA ICUCCAGG 2900

1166 UGGAGCUC C UGUCGGAC 776 GUCCGACA CUGAUGAG X CGAA IAGCUCCA 2901

1167 GGAGCUCC U GUCGGACA 777 UGUCCGAC CUGAUGAG X CGAA IGAGCUCC 2902

1175 UGUCGGAC A GCUCCAAC 778 GUUGGAGC CUGAUGAG X CGAA IUCCGACA 2903

1178 CGGACAGC U CCAACUCC 779 GGAGUUGG CUGAUGAG X CGAA ICUGUCCG 2904

1180 GACAGCUC C AACUCCAG 780 CUGGAGUU CUGAUGAG X CGAA IAGCUGUC 2905

1181 ACAGCUCC A ACUCCAGC 781 GCUGGAGU CUGAUGAG X CGAA IGAGCUGU 2906

1184 GCUCCAAC U CCAGCUGC 782 GCAGCUGG CUGAUGAG X CGAA IUUGGAGC 2907

1186 UCCAACUC C AGCUGCAU 783 AUGCAGCU CUGAUGAG X CGAA lAGUUGGA 2908

1187 CCAACUCC A GCUGCAUC 784 GAUGCAGC CUGAUGAG X CGAA IGAGUUGG 2909

1190 ACUCCAGC U GCAUCACC 785 GGUGAUGC CUGAUGAG X CGAA ICUGGAGU 2910

1193 CCAGCUGC A UCACCUGG 786 CCAGGUGA CUGAUGAG X CGAA ICAGCUGG 2911

1196 GCUGCAUC A CCUGGGAA 787 UUCCCAGG CUGAUGAG X CGAA IAUGCAGC 2912

1198 UGCAUCAC C UGGGAAGG 788 CCUUCCCA CUGAUGAG X CGAA IUGAUGCA 2913

1199 GCAUCACC U GGGAAGGC 789 GCCUUCCC CUGAUGAG X CGAA IGUGAUGC 2914

1208 GGGAAGGC A CCAACGGG 790 CCCGUUGG CUGAUGAG X CGAA ICCUUCCC 2915

1210 GAAGGCAC C AACGGGGA 791 UCCCCGUU CUGAUGAG X CGAA IUGCCUUC 2916

1211 AAGGCACC A ACGGGGAG 792 CUCCCCGU CUGAUGAG X CGAA IGUGCCUU 2917

1223 GGGAGUUC A AGAUGACG 793 CGUCAUCU CUGAUGAG X CGAA IAACUCCC 2918

1236 GACGGAUC C CGACGAGG 794 CCUCGUCG CUGAUGAG X CGAA IAUCCGUC 2919

1237 ACGGAUCC C GACGAGGU 795 ACCUCGUC CUGAUGAG X CGAA IGAUCCGU 2920

1249 GAGGUGGC C CGGCGCUG 796 CAGCGCCG CUGAUGAG X CGAA ICCACCUC 2921

1250 AGGUGGCC C GGCGCUGG 797 CCAGCGCC CUGAUGAG X CGAA IGCCACCU 2922

1256 CCCGGCGC U GGGGAGAG 798 CUCUCCCC CUGAUGAG X CGAA ICGCCGGG 2923

1274 GGAAGAGC A AACCCAAC 799 GUUGGGUU CUGAUGAG X CGAA ICUCUUCC 2924

1278 GAGCAAAC C CAACAUGA 800 UCAUGUUG CUGAUGAG X CGAA IUUUGCUC 2925

1279 AGCAAACC C AACAUGAA 801 UUCAUGUU CUGAUGAG X CGAA IGUUUGCU 2926

1280 GCAAACCC A ACAUGAAC 802 GUUCAUGU CUGAUGAG X CGAA IGGUUUGC 2927

1283 AACCCAAC A UGAACUAC 803 GUAGUUCA CUGAUGAG X CGAA IUUGGGUU 2928

1289 ACAUGAAC U ACGAUAAG 804 CUUAUCGU CUGAUGAG X CGAA IUUCAUGU 2929

1299 CGAUAAGC U CAGCCGCG 805 CGCGGCUG CUGAUGAG X CGAA ICUUAUCG 2930

1301 AUAAGCUC A GCCGCGCC 806 GGCGCGGC CUGAUGAG X CGAA IAGCUUAU 2931

1304 AGCUCAGC C GCGCCCUC 807 GAGGGCGC CUGAUGAG X CGAA ICUGAGCU 2932

1309 AGCCGCGC C CUCCGUUA 808 UAACGGAG CUGAUGAG X CGAA ICGCGGCU 2933

1310 GCCGCGCC C UCCGUUAC 809 GUAACGGA CUGAUGAG X CGAA IGCGCGGC 2934

1311 CCGCGCCC U CCGUUACU 810 AGUAACGG CUGAUGAG X CGAA IGGCGCGG 2935

1313 GCGCCCUC C GUUACUAC 811 GUAGUAAC CUGAUGAG X CGAA IAGGGCGC 2936

1319 UCCGUUAC U ACUAUGAC 812 GUCAUAGU CUGAUGAG X CGAA IUAACGGA 2937

1322 GUUACUAC U AUGACAAG 813 CUUGUCAU CUGAUGAG X CGAA IUAGUAAC 2938

1328 ACUAUGAC A AGAACAUC 814 GAUGUUCU CUGAUGAG X CGAA IUCAUAGU 2939

1334 ACAAGAAC A UCAUGACC 815 GGUCAUGA CUGAUGAG X CGAA IUUCUUGU 2940

1337 AGAACAUC A UGACCAAG 816 CUUGGUCA CUGAUGAG X CGAA IAUGUUCU 2941

1342 AUCAUGAC C AAGGUCCA 817 UGGACCUU CUGAUGAG X CGAA IUCAUGAU 2942

1343 UCAUGACC A AGGUCCAU 818 AUGGACCU CUGAUGAG X CGAA IGUCAUGA 2943

1349 CCAAGGUC C AUGGGAAG 819 CUUCCCAU CUGAUGAG X CGAA IACCUUGG 2944

1350 CAAGGUCC A UGGGAAGC 820 GCUUCCCA CUGAUGAG X CGAA IGACCUUG 2945

1361 GGAAGCGC U ACGCCUAC 821 GUAGGCGU CUGAUGAG X CGAA ICGCUUCC 2946

1366 CGCUACGC C UACAAGUU 822 AACUUGUA CUGAUGAG X CGAA ICGUAGCG 2947

1367 GCUACGCC U ACAAGUUC 823 GAACUUGU CUGAUGAG X CGAA IGCGUAGC 2948 Table TV

1370 ACGCCUAC A AGUUCGAC 824 GUCGAACU CUGAUGAG X CGAA IUAGGCGU 2949

1379 AGUUCGAC U UCCACGGG 825 CCCGUGGA CUGAUGAG X CGAA IUCGAACU 2950

1382 UCGACUUC C ACGGGAUC 826 GAUCCCGU CUGAUGAG X CGAA IAAGUCGA 2951

1383 CGACUUCC A CGGGAUCG 827 CGAUCCCG CUGAUGAG X CGAA IGAAGUCG 2952

1393 GGGAUCGC C CAGGCCCU 828 AGGGCCUG CUGAUGAG X CGAA ICGAUCCC 2953

1394 GGAUCGCC C AGGCCCUC 829 GAGGGCCU CUGAUGAG X CGAA IGCGAUCC 2954

1395 GAUCGCCC A GGCCCUCC 830 GGAGGGCC CUGAUGAG X CGAA IGGCGAUC 2955

1399 GCCCAGGC C CUCCAGCC 831 GGCUGGAG CUGAUGAG X CGAA ICCUGGGC 2956

1400 CCCAGGCC C UCCAGCCC 832 GGGCUGGA CUGAUGAG X CGAA IGCCUGGG 2957

1401 CCAGGCCC U CCAGCCCC 833 GGGGCUGG CUGAUGAG X CGAA IGGCCUGG 2958

1403 AGGCCCUC c AGCCCCAC 834 GUGGGGCU CUGAUGAG X CGAA IAGGGCCU 2959

1404 GGCCCUCC A GCCCCACC 835 GGUGGGGC CUGAUGAG X CGAA IGAGGGCC 2960

1407 CCUCCAGC C CCACCCCC 836 GGGGGUGG CUGAUGAG X CGAA ICUGGAGG 2961

1408 CUCCAGCC C CACCCCCC 837 GGGGGGUG. CUGAUGAG X CGAA IGCUGGAG 2962

1409 UCCAGCCC C ACCCCCCG 838 CGGGGGGU CUGAUGAG X CGAA IGGCUGGA 2963

1410 CCAGCCCC A CCCCCCGG 839 CCGGGGGG CUGAUGAG X CGAA IGGGCUGG 2964

1412 AGCCCCAC C CCCCGGAG 840 CUCCGGGG CUGAUGAG X CGAA IUGGGGCU 2965

1413 GCCCCACC C CCCGGAGU 841 ACUCCGGG CUGAUGAG X CGAA IGUGGGGC 2966

1414 CCCCACGC C CCGGAGUC 842 GACUCCGG CUGAUGAG X CGAA IGGUGGGG 2967

1415 CCCACCCC C CGGAGUCA 843 UGACUCCG CUGAUGAG X CGAA IGGGUGGG 2968

1416 CCACCCCC C GGAGUCAU 844 AUGACUCC CUGAUGAG X CGAA IGGGGUGG 2969

1423 CCGGAGUC A UCUCUGUA 845 UACAGAGA CUGAUGAG X CGAA IACUCCGG 2970

1426 GAGUCAUC U CUGUACAA 846 UUGUACAG CUGAUGAG X CGAA IAUGACUC 2971

1428 GUCAUCUC U GUACAAGU 847 ACUUGUAC CUGAUGAG X CGAA IAGAUGAC 2972

1433 CUCUGUAC A AGUACCCC 848 GGGGUACU CUGAUGAG X CGAA IUACAGAG 2973

1439 ACAAGUAC C CCUCAGAC 849 GUCUGAGG CUGAUGAG X CGAA IUACUUGU 2974

1440 CAAGUACC C CUCAGACC 850 GGUCUGAG CUGAUGAG X CGAA IGUACUUG 2975

1441 AAGUACCC C UCAGACCU 851 AGGUCUGA CUGAUGAG X CGAA IGGUACUU 2976

1442 AGUACCCC U CAGACCUC 852 GAGGUCUG CUGAUGAG X CGAA IGGGUACU 2977

1444 UACCCCUC A GACCUCCC 853 GGGAGGUC CUGAUGAG X CGAA IAGGGGUA 2978

1448 CCUCAGAC C UCCCGUAC 854 GUACGGGA CUGAUGAG X CGAA IUCUGAGG 2979

1449 CUCAGACC U CCCGUACA 855 UGUACGGG CUGAUGAG X CGAA IGUCUGAG 2980

1451 CAGACCUC C CGUACAUG 856 CAUGUACG CUGAUGAG X CGAA IAGGUCUG 2981

1452 AGACCUCC C GUACAUGG 857 CCAUGUAC CUGAUGAG X CGAA IGAGGUCU 2982

1457 UCCCGUAC A UGGGCUCC 858 GGAGCCCA CUGAUGAG X CGAA IUACGGGA 2983

1463 ACAUGGGC U CCUAUCAC 859 GUGAUAGG CUGAUGAG X CGAA ICCCAUGU 2984

1465 AUGGGCUC C UAUCACGC 860 GCGUGAUA CUGAUGAG X CGAA IAGCCCAU 2985

1466 UGGGCUCC U AUCACGCC 861 GGCGUGAU CUGAUGAG X CGAA IGAGCCCA 2986

1470 CUCCUAUC A CGCCCACC 862 GGUGGGCG CUGAUGAG X CGAA IAUAGGAG 2987

1474 UAUCACGC C CACCCACA 863 UGUGGGUG CUGAUGAG X CGAA ICGUGAUA 2988

1475 AUCACGCC C ACCCACAG 864 CUGUGGGU CUGAUGAG X CGAA IGCGUGAU 2989

1476 UCACGCCC A CCCACAGA 865 UCUGUGGG CUGAUGAG X CGAA IGGCGUGA 2990

1478 ACGCCCAC C CACAGAAG 866 CUUCUGUG CUGAUGAG X CGAA IUGGGCGU 2991

1479 CGCCCACC C ACAGAAGA 867 UCUUCUGU CUGAUGAG X CGAA IGUGGGCG 2992

1480 GCCCACCC A CAGAAGAU 868 AUCUUCUG CUGAUGAG X CGAA IGGUGGGC 2993

1482 CCACCCAC A GAAGAUGA 869 UCAUCUUC CUGAUGAG X CGAA IUGGGUGG 2994

1493 AGAUGAAC U UUGUGGCG 870 CGCCACAA CUGAUGAG X CGAA IUUCAUCU 2995

1503 UGUGGCGC C CCACCCUC 871 GAGGGUGG CUGAUGAG X CGAA ICGCCACA 2996

1504 GUGGCGCC C CACCCUCC 872 GGAGGGUG CUGAUGAG X CGAA IGCGCCAC 2997

1505 UGGCGCCC C ACCCUCCA 873 UGGAGGGU CUGAUGAG X CGAA IGGCGCCA 2998

1506 GGCGCCCC A CCCUCCAG 874 CUGGAGGG CUGAUGAG X CGAA IGGGCGCC 2999

1508 CGCCCCAC C CUCCAGCC 875 GGCUGGAG CUGAUGAG X CGAA IUGGGGCG 3000

1509 GCCCCACC C UCCAGCCC 876 GGGCUGGA CUGAUGAG X CGAA IGUGGGGC 3001

1510 CCCCACCC U CCAGCCCU 877 AGGGCUGG CUGAUGAG X CGAA IGGUGGGG 3002

1512 CCACCCUC C AGCCCUCC 878 GGAGGGCU CUGAUGAG X CGAA IAGGGUGG 3003

1513 CACCCUCC A GCCCUCCC 879 GGGAGGGC CUGAUGAG X CGAA IGAGGGUG 3004 Table IV

1516 CCUCCAGC C CUCCCCGU 880 ACGGGGAG CUGAUGAG X CGAA ICUGGAGG 3005

1517 CUCCAGCC C UCCCCGUG 881 CACGGGGA CUGAUGAG X CGAA IGCUGGAG 3006

1518 UCCAGCCC U CCCCGUGA 882 UCACGGGG CUGAUGAG X CGAA IGGCUGGA 3007

1520 CAGCCCUC c CCGUGACA 883 UGUCACGG CUGAUGAG X CGAA IAGGGCUG 3008

1521 AGCCCUCC c CGUGACAU 884 AUGUCACG CUGAUGAG X CGAA IGAGGGCU 3009

1522 GCCCUCCC c GUGACAUC 885 GAUGUCAC CUGAUGAG X CGAA IGGAGGGC 3010

1528 CCCGUGAC A UCUUCCAG 886 CUGGAAGA CUGAUGAG X CGAA IUCACGGG 3011

1531 GUGACAUC U UCCAGUUU 887 AAACUGGA CUGAUGAG X CGAA IAUGUCAC 3012

1534 ACAUCUUC C AGUUUUUU 888 AAAAAACU CUGAUGAG X CGAA lAAGAUGU 3013

1535 CAUCUUCC A GUUUUUUU 889 AAAAAAAC CUGAUGAG X CGAA IGAAGAUG 3014

1546 UUUUUUGC U GCCCCAAA 890 UUUGGGGC CUGAUGAG X CGAA ICAAAAAA 3015

1549 UUUGCUGC C CCAAACCC 891 GGGUUUGG CUGAUGAG X CGAA ICAGCAAA 3016

1550 UUGCUGCC C CAAACCCA 892 UGGGUUUG CUGAUGAG X CGAA IGCAGCAA 3017

1551 UGCUGCCC C AAACCCAU 893 AUGGGUUU CUGAUGAG X CGAA IGGCAGCA 3018

1552 GCUGCCCC A AACCCAUA 894 UAUGGGUU CUGAUGAG X CGAA IGGGCAGC 3019

1556 CCCCAAAC C CAUACUGG 895 CCAGUAUG CUGAUGAG X CGAA IUUUGGGG 3020

1557 CCCAAACC C AUACUGGA 896 UCCAGUAU CUGAUGAG X CGAA IGUUUGGG 3021

1558 CCAAACCC A UACUGGAA 897 UUCCAGUA CUGAUGAG X CGAA IGGUUUGG 3022

1562 ACCCAUAC U GGAAUUCA 898 UGAAUUCC CUGAUGAG X CGAA IUAUGGGU 3023

1570 UGGAAUUC A CCAACUGG 899 CCAGUUGG CUGAUGAG X CGAA IAAUUCCA 3024

1572 GAAUUCAC C AACUGGGG 900 CCCCAGUU CUGAUGAG X CGAA IUGAAUUC 3025

1573 AAUUCACC A ACUGGGGG 901 GCCCCAGU CUGAUGAG X CGAA IGUGAAUU 3026

1576 UCACCAAC U GGGGGUAU 902 AUACCCCC CUGAUGAG X CGAA IUUGGUGA 3027

1589 GUAUAUAC C CCAACACU 903 AGUGUUGG CUGAUGAG X CGAA IUAUAUAC 3028

1590 UAUAUACC C CAACACUA 904 UAGUGUUG CUGAUGAG X CGAA IGUAUAUA 3029

1591 AUAUACCC C AACACUAG 905 CUAGUGUU CUGAUGAG X CGAA IGGUAUAU 3030

1592 UAUACCCC A ACACUAGG 906 CCUAGUGU CUGAUGAG X CGAA IGGGUAUA 3031

1595 ACCCCAAC A CUAGGCUC 907 GAGCCUAG CUGAUGAG X CGAA IUUGGGGU 3032

1597 CCCAACAC U AGGCUCCC 908 GGGAGCCU CUGAUGAG X CGAA IUGUUGGG 3033

1602 CACUAGGC U CCCCACCA 909 UGGUGGGG CUGAUGAG X CGAA ICCUAGUG 3034

1604 CUAGGCUC C CCACCAGC 910 GCUGGUGG CUGAUGAG X CGAA IAGCCUAG 3035

1605 UAGGCUCC C CACCAGCC 911 GGCUGGUG CUGAUGAG X CGAA IGAGCCUA 3036

1606 AGGCUCCC C ACCAGCCA 912 UGGCUGGU CUGAUGAG X CGAA IGGAGCCU 3037

1607 GGCUCCCC A CCAGCCAU 913 AUGGCUGG CUGAUGAG X CGAA IGGGAGCC 3038

1609 CUCCCCAC C AGCCAUAU 914 AUAUGGCU CUGAUGAG X CGAA IUGGGGAG 3039

1610 UCCCCACC A GCCAUAUG 915 CAUAUGGC CUGAUGAG X CGAA IGUGGGGA 3040

1613 CCACCAGC C AUAUGCCU 916 AGGCAUAU CUGAUGAG X CGAA ICUGGUGG 3041

1614 CACCAGCC A UAUGCCUU 917 AAGGCAUA CUGAUGAG X CGAA IGCUGGUG 3042

1620 CCAUAUGC C UUCUCAUC 918 GAUGAGAA CUGAUGAG X CGAA ICAUAUGG 3043

1621 CAUAUGCC U UCUCAUCU 919 AGAUGAGA CUGAUGAG X CGAA IGCAUAUG 3044

1624 AUGCCUUC U CAUCUGGG 920 CCCAGAUG CUGAUGAG X CGAA IAAGGCAU 3045

1626 GCCUUCUC A UCUGGGCA 921 UGCCCAGA CUGAUGAG X CGAA IAGAAGGC 3046

1629 UUCUCAUC U GGGCACUU 922 AAGUGCCC CUGAUGAG X CGAA IAUGAGAA 3047

1634 AUCUGGGC A CUUACUAC 923 GUAGUAAG CUGAUGAG X CGAA ICCCAGAU 3048

1636 CUGGGCAC U UACUACUA 924 UAGUAGUA CUGAUGAG X CGAA IUGCCCAG 3049

1640 GCACUUAC U ACUAAAGA 925 UCUUUAGU CUGAUGAG X CGAA IUAAGUGC 3050

1643 CUUACUAC U AAAGACCU 926 AGGUCUUU CUGAUGAG X CGAA IUAGUAAG 3051

1650 CUAAAGAC C UGGCGGAG 927 CUCCGCCA CUGAUGAG X CGAA IUCUUUAG 3052

1651 UAAAGACC U GGCGGAGG 928 CCUCCGCC CUGAUGAG X CGAA IGUCUUUA 3053

1661 GCGGAGGC U UUUCCCAU 929 AUGGGAAA CUGAUGAG X CGAA ICCUCCGC 3054

1666 GGCUUUUC C CAUCAGCG 930 CGCUGAUG CUGAUGAG X CGAA IAAAAGCC 3055

1667 GCUUUUCC C AUCAGCGU 931 ACGCUGAU CUGAUGAG X CGAA IGAAAAGC 3056

1668 CUUUUCCC A UCAGCGUG 932 CACGCUGA CUGAUGAG X CGAA IGGAAAAG 3057

1671 UUCCCAUC A GCGUGCAU 933 AUGCACGC CUGAUGAG X CGAA IAUGGGAA 3058

1678 CAGCGUGC A UUCACCAG 934 CUGGUGAA CUGAUGAG X CGAA ICACGCUG 3059

1682 GUGCAUUC A CCAGCCCA 935 UGGGCUGG CUGAUGAG X CGAA IAAUGCAC 3060 Table IV

1684 GCAUUCAC C AGCCCAUG 936 GAUGGGCU CUGAUGAG X CGAA IUGAAUGC 3061

1685 CAUUCACC A GCCCAUCG 937 CGAUGGGC CUGAUGAG X CGAA IGUGAAUG 3062

1688 UCACCAGC C CAUCGCCA 938 UGGCGAUG CUGAUGAG X CGAA ICUGGUGA 3063

1689 CACCAGCC C AUCGCCAC 939 GUGGCGAU CUGAUGAG X CGAA IGCUGGUG 3064

1690 ACCAGCCC A UCGCCACA 940 UGUGGCGA CUGAUGAG X CGAA IGGCUGGU 3065

1695 CCCAUCGC C ACAAACUC 941 GAGUUUGU CUGAUGAG X CGAA ICGAUGGG 3066

1696 CCAUCGCC A CAAACUCU 942 AGAGUUUG CUGAUGAG X CGAA IGCGAUGG 3067

1698 AUCGCCAC A AACUCUAU 943 AUAGAGUU CUGAUGAG X CGAA IUGGCGAU 3068

1702 CCACAAAC U CUAUCGGA 944 UCCGAUAG CUGAUGAG X CGAA IUUUGUGG 3069

1704 ACAAACUC U AUCGGAGA 945 UCUCCGAU CUGAUGAG X CGAA IAGUUUGU 3070

1715 CGGAGAAC A UGAAUCAA 946 UUGAUUCA CUGAUGAG X CGAA IUUCUCCG 3071

1722 CAUGAAUC A AAAGUGCC 947 GGCACUUU CUGAUGAG X CGAA IAUUCAUG 3072

1730 AAAAGUGC C UCAAGAGG 948 CCUCUUGA CUGAUGAG X CGAA ICACUUUU 3073

1731 AAAGUGCC U CAAGAGGA 949 UCCUCUUG CUGAUGAG X CGAA IGCACUUU 3074

1733 AGUGCCUC A AGAGGAAU 950 AUUCCUCU CUGAUGAG X CGAA IAGGCACU 3075

1751 AAAAAAGC U UUACUGGG 951 CCCAGUAA CUGAUGAG X CGAA ICUUUUUU 3076

1756 AGCUUUAC U GGGGCUGG 952 CCAGCCCC CUGAUGAG X CGAA IUAAAGCU 3077

1762 ACUGGGGC U GGGGAAGG 953 CCUUCCCC CUGAUGAG X CGAA ICCCCAGU 3078

1775 AAGGAAGC C GGGGAAGA 954 UCUUCCCC CUGAUGAG X CGAA ICUUCCUU 3079

1788 AAGAGAUC C AAAGACUC 955 GAGUCUUU CUGAUGAG X CGAA IAUCUCUU 3080

1789 AGAGAUCC A AAGACUCU 956 AGAGUCUU CUGAUGAG X CGAA IGAUCUCU 3081

1795 CCAAAGAC U CUUGGGAG 957 CUCCCAAG CUGAUGAG X CGAA IUCUUUGG 3082

1797 AAAGACUC U UGGGAGGG 958 CCCUCCCA CUGAUGAG X CGAA IAGUCUUU 3083

1812 GGAGUUAC U GAAGUCUU 959 AAGACUUC CUGAUGAG X CGAA IUAACUCC 3084

1819 CUGAAGUC U UACUACAG 960 CUGUAGUA CUGAUGAG X CGAA IACUUCAG 3085

1823 AGUCUUAC U ACAGAAAU 961 AUUUCUGU CUGAUGAG X CGAA IUAAGACU 3086

1826 CUUACUAC A GAAAUGAG 962 CUCAUUUC CUGAUGAG X CGAA IUAGUAAG 3087

1843 GAGGAUGC U AAAAAUGU 963 ACAUUUUU CUGAUGAG X CGAA ICAUCCUC 3088

1853 AAAAUGUC A CGAAUAUG 964 CAUAUUCG CUGAUGAG X CGAA IACAUUUU 3089

1865 AUAUGGAC A UAUCAUCU 965 AGAUGAUA CUGAUGAG X CGAA IUCCAUAU 3090

1870 GACAUAUC A UCUGUGGA 966 UCCACAGA CUGAUGAG X CGAA IAUAUGUC 3091

1873 AUAUCAUC U GUGGACUG 967 CAGUCCAC CUGAUGAG X CGAA IAUGAUAU 3092

1880 CUGUGGAC U GACCUUGU 968 ACAAGGUC CUGAUGAG X CGAA IUCCACAG 3093

1884 GGACUGAC C UUGUAAAA 969 UUUUACAA CUGAUGAG X CGAA IUCAGUCC 3094

1885 GACUGACC U UGUAAAAG 970 CUUUUACA CUGAUGAG X CGAA IGUCAGUC 3095

1896 UAAAAGAC A GUGUAUGU 971 ACAUACAC CUGAUGAG X CGAA IUCUUUUA 3096

1911 GUAGAAGC A UGAAGUCU 972 AGACUUCA CUGAUGAG X CGAA ICUUCUAC 3097

1919 AUGAAGUC U UAAGGACA 973 UGUCCUUA CUGAUGAG X CGAA IACUUCAU 3098

1927 UUAAGGAC A AAGUGCCA 974 UGGCACUU CUGAUGAG X CGAA lUCCUUAA 3099

1934 CAAAGUGC C AAAGAAAG 975 CUUUCUUU CUGAUGAG X CGAA ICACUUUG 3100

1935 AAAGUGCC A AAGAAAGU 976 ACUUUCUU CUGAUGAG X CGAA IGCACUUU 3101

1948 AAGUGGUC U UAAGAAAU 977 AUUUCUUA CUGAUGAG X CGAA IACCACUU 3102

1965 GUAUAAAC U UUAGAGUA 978 UACUCUAA CUGAUGAG X CGAA IUUUAUAC 3103

1985 UUUGAAUC C CACUAAUG 979 CAUUAGUG CUGAUGAG X CGAA IAUUCAAA 3104

1986 UUGAAUCC C ACUAAUGC 980 GCAUUAGU CUGAUGAG X CGAA IGAUUCAA 3105

1987 UGAAUCCC A CUAAUGCA 981 UGCAUUAG CUGAUGAG X CGAA IGGAUUCA 3106

1989 AAUCCCAC U AAUGCAAA 982 UUUGCAUU CUGAUGAG X CGAA IUGGGAUU 3107

1995 ACUAAUGC A AACUGGGA 983 UCCCAGUU CUGAUGAG X CGAA ICAUUAGU 3108

1999 AUGCAAAC U GGGAUGAA 984 UUCAUCCC CUGAUGAG X CGAA IUUUGCAU 3109

2010 GAUGAAAC U AAAGCAAU 985 AUUGCUUU CUGAUGAG X CGAA 1UUUCAUC 3110

2016 ACUAAAGC A AUAGAAAC 986 GUUUCUAU CUGAUGAG X CGAA ICUUUAGU 3111

2025 AUAGAAAC A ACACAGUU 987 AACUGUGU CUGAUGAG X CGAA lUUUCUAU 3112

2028 GAAACAAC A CAGUUUUG 988 CAAAACUG CUGAUGAG X CGAA IUUGUUUC 3113

2030 AACAACAC A GUUUUGAC 989 GUCAAAAC CUGAUGAG X CGAA IUGUUGUU 3114

2039 GUUUUGAC C UAACAUAC 990 GUAUGUUA CUGAUGAG X CGAA IUCAAAAC 3115

2040 UUUUGACC U AACAUACC 991 GGUAUGUU CUGAUGAG X CGAA IGUCAAAA 3116 Table IV

2044 GACCUAAC A UACCGUUU 992 AAACGGUA CUGAUGAG X CGAA IUUAGGUC 3117

2048 UAACAUAC C GUUUAUAA 993 UUAUAAAC CUGAUGAG X CGAA lUAUGUUA 3118

2060 UAUAAUGC C AUUUUAAG 994 CUUAAAAU CUGAUGAG X CGAA ICAUUAUA 3119

2061 AUAAUGCC A UUUUAAGG 995 CCUUAAAA CUGAUGAG X CGAA IGCAUUAU 3120

2075 AGGAAAAC U ACCUGUAU 996 AUACAGGU CUGAUGAG X CGAA lUUUUCCU 3121

2078 AAAACUAC C UGUAUUUA 997 UAAAUACA CUGAUGAG X CGAA IUAGUUUU 3122

2079 AAACUACC U GUAUUUAA 998 UUAAAUAC CUGAUGAG X CGAA IGUAGUUU 3123

2098 AUAGUUUC A UAUCAAAA 999 UUUUGAUA CUGAUGAG X CGAA IAAACUAU 3124

2103 UUCAUAUC A AAAACAAG 1000 CUUGUUUU CUGAUGAG X CGAA IAUAUGAA 3125

2109 UCAAAAAC A AGAGAAAA 1001 UUUUCUCU CUGAUGAG X CGAA IUUUUUGA 3126

2121 GAAAAGAC A CGAGAGAG 1002 CUCUCUCG CUGAUGAG X CGAA IUCUUUUC 3127

2132 AGAGAGAC U GUGGCCCA 1003 UGGGCCAC CUGAUGAG X CGAA IUCUCUCU 3128

2138 ACUGUGGC C CAUCAACA 1004 UGUUGAUG CUGAUGAG X CGAA ICCACAGU 3129

2139 GUGUGGCC C AUCAACAG 1005 CUGUUGAU CUGAUGAG X CGAA IGCCACAG 3130

2140 UGUGGCCC A UCAACAGA 1006 UCUGUUGA CUGAUGAG X CGAA IGGCCACA 3131

2143 GGCCCAUC A ACAGACGU 1007 ACGUCUGU CUGAUGAG X CGAA IAUGGGCC 3132

2146 CCAUCAAC A GACGUUGA 1008 UCAACGUC CUGAUGAG X CGAA IUUGAUGG 3133

2160 UGAUAUGC A ACUGCAUG 1009 CAUGCAGU CUGAUGAG X CGAA ICAUAUC 3134

2163 UAUGCAAC U GCAUGGCA 1010 UGCCAUGC CUGAUGAG X CGAA IUUGCAUA 3135

2166 GCAACUGC A UGGCAUGU 1011 ACAUGCCA CUGAUGAG X CGAA ICAGUUGC 3136

2171 UGCAUGGC A UGUGCUGU 1012 ACAGCACA CUGAUGAG X CGAA ICCAUGCA 3137

2177 GCAUGUGC U GUUUUGGU 1013 ACCAAAAC CUGAUGAG X CGAA ICACAUGC 3138

2193 UUGAAAUC A AAUACAUU 1014 AAUGUAUU CUGAUGAG X CGAA IAUUUCAA 3139

2199 UCAAAUAC A UUCCGUUU 1015 AAACGGAA CUGAUGAG X CGAA IUAUUUGA 3140

2203 AUACAUUC C GUUUGAUG 1016 CAUCAAAC CUGAUGAG X CGAA IAAUGUAU 3141

2215 UGAUGGAC A GCUGUCAG 1017 CUGACAGC CUGAUGAG X CGAA IUCCAUCA 3142

2218 UGGACAGC U GUCAGCUU 1018 AAGCUGAC CUGAUGAG X CGAA ICUGUCCA 3143

2222 CAGCUGUC A GCUUUCUC 1019 GAGAAAGC CUGAUGAG X CGAA IACAGCUG 3144

2225 CUGUCAGC U UUCUCAAA 1020 UUUGAGAA CUGAUGAG X CGAA ICUGACAG 3145

2229 CAGCUUUC U CAAACUGU 1021 ACAGUUUG CUGAUGAG X CGAA IAAAGCUG 3146

2231 GCUUUCUC A AACUGUGA 1022 UCACAGUU CUGAUGAG X CGAA IAGAAAGC 3147

2235 UCUCAAAC U GUGAAGAU 1023 AUCUUCAC CUGAUGAG X CGAA lUUUGAGA 3148

2247 AAGAUGAC C CAAAGUUU 1024 AAACUUUG CUGAUGAG X CGAA IUCAUCUU 3149

2248 AGAUGACC C AAAGUUUC 1025 GAAACUUU CUGAUGAG X CGAA IGUCAUCU 3150

2249 GAUGACCC A AAGUUUCC 1026 GGAAACUU CUGAUGAG X CGAA IGGUCAUC 3151

2257 AAAGUUUC C AACUCCUU 1027 AAGGAGUU CUGAUGAG X CGAA IAAACUUU 3152

2258 AAGUUUCC A ACUCCUUU 1028 AAAGGAGU CUGAUGAG X CGAA IGAAACUU 3153

2261 UUUCCAAC U CCUUUACA 1029 UGUAAAGG CUGAUGAG X CGAA IUUGGAAA 3154

2263 UCCAACUC C UUUACAGU 1030 ACUGUAAA CUGAUGAG X CGAA lAGUUGGA 3155

2264 CCAACUCC U UUACAGUA 1031 UACUGUAA CUGAUGAG X CGAA IGAGUUGG 3156

2269 UCCUUUAC A GUAUUACC 1032 GGUAAUAC CUGAUGAG X CGAA IUAAAGGA 3157

2277 AGUAUUAC C GGGACUAU 1033 AUAGUCCC CUGAUGAG X CGAA IUAAUACU 3158

2283 ACCGGGAC U AUGAACUA 1034 UAGUUCAU CUGAUGAG X CGAA IUCCCGGU 3159

2290 CUAUGAAC U AAAAGGUG 1035 CACCUUUU CUGAUGAG X CGAA IUUCAUAG 3160

2303 GGUGGGAC U GAGGAUGU 1036 ACAUCCUC CUGAUGAG X CGAA IUCCCACC 3161

2339 UUGUAGAC A GAGGGGUG 1037 CACCCCUC CUGAUGAG X CGAA IUCUACAA 3162

2368 GAAGAGGC A GAGAAGGA 1038 UCCUUCUC CUGAUGAG X CGAA ICCUCUUC 3163

2383 GAGGAGAC C AGGCUGGG 1039 CCCAGCCU CUGAUGAG X CGAA IUCUCCUC 3164

2384 AGGAGACC A GGCUGGGA 1040 UCCCAGCC CUGAUGAG X CGAA IGUCUCCU 3165

2388 GACCAGGC U GGGAAAGA 1041 UCUUUCCC CUGAUGAG X CGAA ICCUGGUC 3166

2400 AAAGAAAC U UCUCAAGC 1042 GCUUGAGA CUGAUGAG X CGAA IUUUCUUU 3167

2403 GAAACUUC U CAAGCAAU 1043 AUUGCUUG CUGAUGAG X CGAA lAAGUUUC 3168

2405 AACUUCUC A AGCAAUGA 1044 UCAUUGCU CUGAUGAG X CGAA IAGAAGUU 3169

2409 UCUCAAGC A AUGAAGAC 1045 GUCUUCAU CUGAUGAG X CGAA ICUUGAGA 3170

2418 AUGAAGAC U GGACUCAG 1046 CUGAGUCC CUGAUGAG X CGAA IUCUUCAU 3171

2423 GACUGGAC U CAGGACAU 1047 AUGUCCUG CUGAUGAG X CGAA IUCCAGUC 3172 Table IV

2425 CUGGACUC A GGACAUUU 1048 AAAUGUCC CUGAUGAG X CGAA IAGUCCAG 3173

2430 CUCAGGAC A UUUGGGGA 1049 UCCCCAAA CUGAUGAG X CGAA IUCCUGAG 3174

2440 UUGGGGAC U GUGUACAA 1050 UUGUACAC CUGAUGAG X CGAA lUCCCCAA 3175

2447 CUGUGUAC A AUGAGUUA 1051 UAACUCAU CUGAUGAG X CGAA IUACACAG 3176

2463 AUGGAGAC U CGAGGGUU 1052 AACCCUCG CUGAUGAG X CGAA IUCUCCAU 3177

2473 GAGGGUUC A UGCAGUCA 1053 UGACUGCA CUGAUGAG X CGAA IAACCCUC 3178

2477 GUUCAUGC A GUCAGUGU 1054 ACACUGAC CUGAUGAG X CGAA ICAUGAAC 3179

2481 AUGCAGUC A GUGUUAUA 1055 UAUAACAC CUGAUGAG X CGAA IACUGCAU 3180

2491 UGUUAUAC C AAACCCAG 1056 CUGGGUUU CUGAUGAG X CGAA IUAUAACA 3181

2492 GUUAUACC A AACCCAGU 1057 ACUGGGUU CUGAUGAG X CGAA IGUAUAAC 3182

2496 UACCAAAC C CAGUGUUA 1058 UAACACUG CUGAUGAG X CGAA IUUUGGUA 3183

2497 ACCAAACC C AGUGUUAG 1059 CUAACACU CUGAUGAG X CGAA IGUUUGGU 3184

2498 CCAAACCC A GUGUUAGG 1060 CCUAACAC CUGAUGAG X CGAA IGGUUUGG 3185

2516 GAAAGGAC A CAGCGUAA 1061 UUACGCUG CUGAUGAG X CGAA IUCCUUUC 3186

2518 AAGGACAC A GCGUAAUG 1062 CAUUACGC CUGAUGAG X CGAA IUGUCCUU 3187

2550 UAGAAUUC A GAAACAAA 1063 UUUGUUUC CUGAUGAG X CGAA IAAUUCUA 3188

2556 UCAGAAAC A AAAAUGCG 1064 CGCAUUUU CUGAUGAG X CGAA IUUUCUGA 3189

2566 AAAUGCGC A UCUCUUUC 1065 GAAAGAGA CUGAUGAG X CGAA ICGCAUUU 3190

2569 UGCGCAUC U CUUUCUUU 1066 AAAGAAAG CUGAUGAG X CGAA IAUGCGCA 3191

2571 CGCAUCUC U UUCUUUGU 1067 ACAAAGAA CUGAUGAG X CGAA IAGAUGCG 3192

2575 UCUCUUUC U UUGUUUGU 1068 ACAAACAA CUGAUGAG X CGAA IAAAGAGA 3193

2585 UGUUUGUC A AAUGAAAA 1069 UUUUCAUU CUGAUGAG X CGAA IACAAACA 3194

2601 AUUUUAAC U GGAAUUGU 1070 ACAAUUCC CUGAUGAG X CGAA IUUAAAAU 3195

2611 GAAUUGUC U GAUAUUUA 1071 UAAAUAUC CUGAUGAG X CGAA IACAAUUC 3196

2628 AGAGAAAC A UUCAGGAC 1072 GUCCUGAA CUGAUGAG X CGAA IUUUCUCU 3197

2632 AAACAUUC A GGACCUCA 1073 UGAGGUCC CUGAUGAG X CGAA IAAUGUUU 3198

2637 UUCAGGAC C UCAUCAUU 1074 AAUGAUGA CUGAUGAG X CGAA lUCCUGAA 3199

2638 UCAGGACC U CAUCAUUA 1075 UAAUGAUG CUGAUGAG X CGAA IGUCCUGA 3200

2640 AGGACCUC A UCAUUAUG 1076 CAUAAUGA CUGAUGAG X CGAA IAGGUCCU 3201

2643 ACCUCAUC A UUAUGUGG 1077 CCACAUAA CUGAUGAG X CGAA IAUGAGGU 3202

2656 GUGGGGGC U UUGUUCUC 1078 GAGAACAA CUGAUGAG X CGAA ICCCCCAC 3203

2663 CUUUGUUC U CCACAGGG 1079 CCCUGUGG CUGAUGAG X CGAA IAACAAAG 3204

2665 UUGUUCUC C ACAGGGUC 1080 GACCCUGU CUGAUGAG X CGAA IAGAACAA 3205

2666 UGUUCUCC A CAGGGUCA 1081 UGACCCUG CUGAUGAG X CGAA IGAGAACA 3206

2668 UUCUCCAC A GGGUCAGG 1082 CCUGACCC CUGAUGAG X CGAA IUGGAGAA 3207

2674 ACAGGGUC A GGUAAGAG 1083 CUCUUACC CUGAUGAG X CGAA IACCCUGU 3208

2688 GAGAUGGC C UUCUUGGC 1084 GCCAAGAA CUGAUGAG X CGAA ICCAUCUC 3209

2689 AGAUGGCC U UCUUGGCU 1085 AGCCAAGA CUGAUGAG X CGAA IGCCAUCU 3210

2692 UGGCCUUC U UGGCUGCC 1086 GGCAGCCA CUGAUGAG X CGAA IAAGGCCA 3211

2697 UUCUUGGC U GCCACAAU 1087 AUUGUGGC CUGAUGAG X CGAA ICCAAGAA 3212

2700 UUGGCUGC C ACAAUCAG 1088 CUGAUUGU CUGAUGAG X CGAA ICAGCCAA 3213

2701 UGGCUGCC A CAAUCAGA 1089 UCUGAUUG CUGAUGAG X CGAA IGCAGCCA 3214

2703 GCUGCCAC A AUCAGAAA 1090 UUUCUGAU CUGAUGAG X CGAA IUGGCAGC 3215

2707 CCACAAUC A GAAAUCAC 1091 GUGAUUUC CUGAUGAG X CGAA IAUUGUGG 3216

2714 CAGAAAUC A CGCAGGCA 1092 UGCCUGCG CUGAUGAG X CGAA IAUUUCUG 3217

2718 AAUCACGC A GGCAUUUU 1093 AAAAUGCC CUGAUGAG X CGAA ICGUGAUU 3218

2722 ACGCAGGC A UUUUGGGU 1094 ACCCAAAA CUGAUGAG X CGAA ICCUGCGU 3219

2738 UAGGCGGC C UCCAGUUU 1095 AAACUGGA CUGAUGAG X CGAA ICCGCCUA 3220

2739 AGGCGGCC U CCAGUUUU 1096 AAAACUGG CUGAUGAG X CGAA IGCCGCCU 3221

2741 GCGGCCUC c AGUUUUCC 1097 GGAAAACU CUGAUGAG X CGAA IAGGCCGC 3222

2742 CGGCCUCC A GUUUUCCU 1098 AGGAAAAC CUGAUGAG X CGAA IGAGGCCG 3223

2749 CAGUUUUC C UUUGAGUC 1099 GACUCAAA CUGAUGAG X CGAA IAAAACUG 3224

2750 AGUUUUCC u UUGAGUCG 1100 CGACUCAA CUGAUGAG X CGAA IGAAAACU 3225

2766 GCGAACGC u GUGCGUUU 1101 AAACGCAC CUGAUGAG X CGAA ICGUUCGC 3226

2778 CGUUUGUC A GAAUGAAG 1102 CUUCAUUC CUGAUGAG X CGAA IACAAACG 3227

2792 AAGUAUAC A AGUCAAUG 1103 CAUUGACU CUGAUGAG X CGAA IUAUACUU 3228 19 Table TV

2797 UACAAGUC A AUGUUUUU 1104 AAAAACAU CUGAUGAG X CGAA IACUUGUA 3229

2807 UGUUUUUC C CCCUUUUU 1105 AAAAAGGG CUGAUGAG X CGAA lAAAAACA 3230

2808 GUUUUUCC C CCUUUUUA 1106 UAAAAAGG CUGAUGAG X CGAA IGAAAAAC 3231

2809 UUUUUCCC C CUUUUUAU 1107 AUAAAAAG CUGAUGAG X CGAA IGGAAAAA 3232

2810 UUUUCCCC C UUUUUAUA 1108 UAUAAAAA CUGAUGAG X CGAA IGGGAAAA 3233

2811 UUUCCCCC U UUUUAUAU 1109 AUAUAAAA CUGAUGAG X CGAA IGGGGAAA 3234

2834 UAUAUAAC U UAUGCAUU 1110 AAUGCAUA CUGAUGAG X CGAA IUUAUAUA 3235

2840 ACUUAUGC A UUUAUACA 1111 UGUAUAAA CUGAUGAG X CGAA ICAUAAGU 3236

2848 AUUUAUAC A CUACGAGU 1112 ACUCGUAG CUGAUGAG X CGAA IUAUAAAU 3237

2850 UUAUACAC U ACGAGUUG 1113 CAACUCGU CUGAUGAG X CGAA IUGUAUAA 3238

2862 AGUUGAUC U CGGCCAGC 1114 GCUGGCCG CUGAUGAG X CGAA IAUCAACU 3239

2867 AUCUCGGC C AGCCAAAG 1115 CUUUGGCU CUGAUGAG X CGAA ICCGAGAU 3240

2868 UCUCGGCC A GCCAAAGA 1116 UCUUUGGC CUGAUGAG X CGAA IGCCGAGA 3241

2871 CGGCCAGC C AAAGACAC 1117 GUGUCUUU CUGAUGAG X CGAA ICUGGCCG 3242

2872 GGCCAGCC A AAGACACA 1118 UGUGUCUU CUGAUGAG X CGAA IGCUGGCC 3243

2878 CCAAAGAC A CACGACAA 1119 UUGUCGUG CUGAUGAG X CGAA IUCUUUGG 3244

2880 AAAGACAC A CGACAAAA 1120 UUUUGUCG CUGAUGAG X CGAA IUGUCUUU 3245

2885 CACACGAC A AAAGAGAC 1121 GUCUCUUU CUGAUGAG X CGAA IUCGUGUG 3246

2894 AAAGAGAC A AUCGAUAU 1122 AUAUCGAU CUGAUGAG X CGAA IUCUCUUU 3247

2911 AAUGUGGC C UUGAAUUU 1123 AAAUUCAA CUGAUGAG X CGAA ICCACAUU 3248

2912 AUGUGGCC U UGAAUUUU 1124 AAAAUUCA CUGAUGAG X CGAA IGCCACAU 3249

2924 AUUUUAAC U CUGUAUGC 1125 GCAUACAG CUGAUGAG X CGAA IUUAAAAU 3250

2926 UUUAACUC U GUAUGCUU 1126 AAGCAUAC CUGAUGAG X CGAA IAGUUAAA 3251

2933 CUGUAUGC U UAAUGUUU 1127 AAACAUUA CUGAUGAG X CGAA ICAUACAG 3252

2944 AUGUUUAC A AUAUGAAG 1128 CUUCAUAU CUGAUGAG X CGAA IUAAACAU 3253

2963 AUUAGUUC U UAGAAUGC 1129 GCAUUCUA CUGAUGAG X CGAA IAACUAAU 3254

2972 UAGAAUGC A GAAUGUAU 1130 AUACAUUC CUGAUGAG X CGAA ICAUUCUA 3255

2995 AAAUAAGC U UGGCCUAG 1131 CUAGGCCA CUGAUGAG X CGAA ICUUAUUU 3256

3000 AGCUUGGC C UAGCAUGG 1132 CCAUGCUA CUGAUGAG X CGAA ICCAAGCU 3257

3001 GCUUGGCC U AGCAUGGC 1133 GCCAUGCU CUGAUGAG X CGAA IGCCAAGC 3258

3005 GGCCUAGC A UGGCAAAU 1134 AUUUGCCA CUGAUGAG X CGAA ICUAGGCC 3259

3010 AGCAUGGC A AAUCAGAU 1135 AUCUGAUU CUGAUGAG X CGAA ICCAUGCU 3260

3015 GGCAAAUC A GAUUUAUA 1136 UAUAAAUC CUGAUGAG X CGAA IAUUUGCC 3261

3025 AUUUAUAC A GGAGUCUG 1137 CAGACUCC CUGAUGAG X CGAA IUAUAAAU 3262

3032 CAGGAGUC U GCAUUUGC 1138 GCAAAUGC CUGAUGAG X CGAA IACUCCUG 3263

3035 GAGUCUGC A UUUGCACU 1139 AGUGCAAA CUGAUGAG X CGAA ICAGACUC 3264

3041 GCAUUUGC A CUUUUUUU 1140 AAAAAAAG CUGAUGAG X CGAA ICAAAUGC 3265

3043 AUUUGCAC U UUUUUUAG 1141 CUAAAAAA CUGAUGAG X CGAA IUGCAAAU 3266

3056 UUAGUGAC u AAAGUUGC 1142 GCAACUUU CUGAUGAG X CGAA IUCACUAA 3267

3065 AAAGUUGC u UAAUGAAA 1143 UUUCAUUA CUGAUGAG X CGAA ICAACUUU 3268

3076 AUGAAAAC A UGUGCUGA 1144 UCAGCACA CUGAUGAG X CGAA IUUUUCAU 3269

3082 ACAUGUGC U GAAUGUUG 1145 CAACAUUC CUGAUGAG X CGAA ICACAUGU 3270

3113 UAAUUUAC U UUGUCCAG 1146 CUGGACAA CUGAUGAG X CGAA IUAAAUUA 3271

3119 ACUUUGUC C AGGAACUU 1147 AAGUUCCU CUGAUGAG X CGAA IACAAAGU 3272

3120 CUUUGUCC A GGAACUUG 1148 CAAGUUCC CUGAUGAG X CGAA IGACAAAG 3273

3126 CCAGGAAC U UGUGCAAG 1149 CUUGCACA CUGAUGAG X CGAA IUUCCUGG 3274

3132 ACUUGUGC A AGGGAGAG 1150 CUCUCCCU CUGAUGAG X CGAA ICACAAGU 3275

3142 GGGAGAGC C AAGGAAAU 1151 AUUUCCUU CUGAUGAG X CGAA ICUCUCCC 3276

3143 GGAGAGCC A AGGAAAUA 1152 UAUUUCCU CUGAUGAG X CGAA IGCUCUCC 3277

Input Sequence = HUMERG2. Cut Site = CH/ .

Stem Length = 8 . Core Sequence = CUGAUGAG X CGAA (X = GCCGUUAGGC or other stem II)

HUMERG2 (Human erg2 gene encoding erg2 protein, complete cds. 3166 bp) Table V

Table V: Human ERG G-cleaver Ribozyme and Target Sequence

Table V

352 UACGGAAC G CCACACCU 1185 AGGUGUGG UGAUG GCAUGCACUAUGC GCG GUUCCGUA 3310

376 ACAGAGAU G ACCGCGUC 1186 GACGCGGU UGAUG GCAUGCACUAUGC GCG AUCUCUGU 3311

380 AGAUGACC G CGUCCUCC 1187 GGAGGACG UGAUG GCAUGCACUAUGC GCG GGUCAUCU 3312

395 CCUCCAGC G ACUAUGGA 1188 UCCAUAGU UGAUG GCAUGCACUAUGC GCG GCUGGAGG 3313

418 UCCAAGAU G AGCCCACG 1189 CGUGGGCU UGAUG GCAUGCACUAUGC GCG AUCUUGGA 3314

426 GAGCCCAC G CGUCCCUC 1190 GAGGGACG UGAUG GCAUGCACUAUGC GCG GUGGGCUC 3315

448 GAUUGGCU G UCUCAACC 1191 GGUUGAGA UGAUG GCAUGCACUAUGC GCG AGCCAAUC 3316

486 AAUGGAAU G UAACCCUA 1192 UAGGGUUA UGAUG GCAUGCACUAUGC GCG AUUCCAUU 3317

502 AGCCAGGU G AAUGGCUC 1193 GAGCCAUU UGAUG GCAUGCACUAUGC GCG ACCUGGCU 3318

524 ACUCUCCU G AUGAAUGC 1194 GCAUUCAU UGAUG GCAUGCACUAUGC GCG AGGAGAGU 3319

527 CUCCUGAU G AAUGCAGU 1195 ACUGCAUU UGAUG GCAUGCACUAUGC GCG AUCAGGAG 3320

531 UGAUGAAU G CAGUGUGG 1196 CCACACUG UGAUG GCAUGCACUAUGC GCG AUUCAUCA 3321

536 AAUGCAGU G UGGCCAAA 1197 UUUGGCCA UGAUG GCAUGCACUAUGC GCG ACUGCAUU 3322

583 GUUGGGAU G AACUACGG 1198 CCGUAGUU UGAUG GCAUGCACUAUGC GCG AUCCCAAC 3323

616 AAGCACAU G CCACCCCC 1199 GGGGGUGG UGAUG GCAUGCACUAUGC GCG AUGUGCUU 3324

631 CCAAACAU G ACCACGAA 1200 UUCGUGGU UGAUG GCAUGCACUAUGC GCG AUGUUUGG 3325

637 AUGACCAC G AACGAGCG 1201 CGCUCGUU UGAUG GCAUGCACUAUGC GCG GUGGUCAU 3326

641 CCACGAAC G AGCGCAGA 1202 UCUGCGCU UGAUG GCAUGCACUAUGC GCG GUUCGUGG 3327

645 GAACGAGC G CAGAGUUA 1203 UAACUCUG UGAUG GCAUGCACUAUGC GCG GCUCGUUC 3328

658 GUUAUCGU G CCAGCAGA 1204 UCUGCUGG UGAUG GCAUGCACUAUGC GCG ACGAUAAC 3329

673 GAUCCUAC G CUAUGGAG 1205 CUCCAUAG UGAUG GCAUGCACUAUGC GCG GUAGGAUC 3330

692 CAGACCAU G UGCGGCAG 1206 CUGCCGCA UGAUG GCAUGCACUAUGC GCG AUGGUCUG 3331

694 GACCAUGU G CGGCAGUG 1207 CACUGCCG UGAUG GCAUGCACUAUGC GCG ACAUGGUC 3332

718 UGGGCGGU G AAAGAAUA 1208 UAUUCUUU UGAUG GCAUGCACUAUGC GCG ACCGCCCA 3333

751 AACAUCUU G UUAUUCCA 1209 UGGAAUAA UGAUG GCAUGCACUAUGC GCG AAGAUGUU 3334

767 AGAACAUC G AUGGGAAG 1210 CUUCCCAU UGAUG GCAUGCACUAUGC GCG GAUGUUCU 3335

781 AAGGAACU G UGCAAGAU 1211 AUCUUGCA UGAUG GCAUGCACUAUGC GCG AGUUCCUU 3336

783 GGAACUGU G CAAGAUGA 1212 UCAUCUUG UGAUG GCAUGCACUAUGC GCG ACAGUUCC 3337

790 UGCAAGAU G ACCAAGGA 1213 UCCUUGGU UGAUG GCAUGCACUAUGC GCG AUCUUGCA 3338

800 CCAAGGAC G ACUUCCAG 1214 CUGGAAGU UGAUG GCAUGCACUAUGC GCG GUCCUUGG 3339

830 GCUACAAC G CCGACAUC 1215 GAUGUCGG UGAUG GCAUGCACUAUGC GCG GUUGUAGC 3340

833 ACAACGCC G ACAUCCUU 1216 AAGGAUGU UGAUG GCAUGCACUAUGC GCG GGCGUUGU 3341

886 CCACAUUU G ACUUCAGA 1217 UCUGAAGU UGAUG GCAUGCACUAUGC GCG AAAUGUGG 3342

896 CUUCAGAU G AUGUUGAU 1218 AUCAACAU UGAUG GCAUGCACUAUGC GCG AUCUGAAG 3343

899 CAGAUGAU G UUGAUAAA 1219 UUUAUCAA UGAUG GCAUGCACUAUGC GCG AUCAUCUG 3344

902 AUGAUGUU G AUAAAGCC 1220 GGCUUUAU UGAUG GCAUGCACUAUGC GCG AACAUCAU 3345

Table V

934 CGGUUAAU G CAUGCUAG 1221 CUAGCAUG UGAUG GCAUGCACUAUGC GCG AUUAACCG 3346

938 UAAUGCAU G CUAGAAAC 1222 GUUUCUAG UGAUG GCAUGCACUAUGC GCG AUGCAUUA 3347

962 UACCAUAU G AGCCCCCC 1223 GGGGGGCU UGAUG GCAUGCACUAUGC GCG AUAUGGUA 3348

1006 CACCCCAC G CCCCAGUC 1224 GACUGGGG UGAUG GCAUGCACUAUGC GCG GUGGGGUG 3349

1015 CCCCAGUC G AAAGCUGC 1225 GCAGCUUU UGAUG GCAUGCACUAUGC GCG GACUGGGG 3350

1022 CGAAAGCU G CUCAACCA 1226 UGGUUGAG UGAUG GCAUGCACUAUGC GCG AGCUUUCG 3351

1045 UCCACAGU G CCCAAAAC 1227 GUUUUGGG UGAUG GCAUGCACUAUGC GCG ACUGUGGA 3352

1055 CCAAAACU G AAGACCAG 1228 CUGGUCUU UGAUG GCAUGCACUAUGC GCG AGUUUUGG 3353

1110 AAGUAGCC G CCUUGCAA 1229 UUGCAAGG UGAUG GCAUGCACUAUGC GCG GGCUACUU 3354

1115 GCCGCCUU G CAAAUCCA 1230 UGGAUUUG UGAUG GCAUGCACUAUGC GCG AAGGCGGC 3355

1168 GAGCUCCU G UCGGACAG 1231 CUGUCCGA UGAUG GCAUGCACUAUGC GCG AGGAGCUC 3356

1191 CUCCAGCU G CAUCACCU 1232 AGGUGAUG UGAUG GCAUGCACUAUGC GCG AGCUGGAG 3357

1228 UUCAAGAU G ACGGAUCC 1233 GGAUCCGU UGAUG GCAUGCACUAUGC GCG AUCUUGAA 3358

1238 CGGAUCCC G ACGAGGUG 1234 CACCUCGU UGAUG GCAUGCACUAUGC GCG GGGAUCCG 3359

1241 AUCCCGAC G AGGUGGCC 1235 GGCCACCU UGAUG GCAUGCACUAUGC GCG GUCGGGAU 3360

1254 GGCCCGGC G CUGGGGAG 1236 CUCCCCAG UGAUG GCAUGCACUAUGC GCG GCCGGGCC 3361

1285 CCCAACAU G AACUACGA 1237 UCGUAGUU UGAUG GCAUGCACUAUGC GCG AUGUUGGG 3362

1292 UGAACUAC G AUAAGCUC 1238 GAGCUUAU UGAUG GCAUGCACUAUGC GCG GUAGUUCA 3363

1305 GCUCAGCC G CGCCCUCC 1239 GGAGGGCG UGAUG GCAUGCACUAUGC GCG GGCUGAGC 3364

1307 UCAGCCGC G CCCUCCGU 1240 ACGGAGGG UGAUG GCAUGCACUAUGC GCG GCGGCUGA 3365

1325 ACUACUAU G ACAAGAAC 1241 GUUCUUGU UGAUG GCAUGCACUAUGC GCG AUAGUAGU 3366

1339 AACAUCAU G ACCAAGGU 1242 ACCUUGGU UGAUG GCAUGCACUAUGC GCG AUGAUGUU 3367

1359 UGGGAAGC G CUACGCCU 1243 AGGCGUAG UGAUG GCAUGCACUAUGC GCG GCUUCCCA 3368

1364 AGCGCUAC G CCUACAAG 1244 CUUGUAGG UGAUG GCAUGCACUAUGC GCG GUAGCGCU 3369 -

1376 ACAAGUUC G ACUUCCAC 1245 GUGGAAGU UGAUG GCAUGCACUAUGC GCG GAACUUGU 3370

1391 ACGGGAUC G CCCAGGCC 1246 GGCCUGGG UGAUG GCAUGCACUAUGC GCG GAUCCCGU 3371

1429 UCAUCUCU G UACAAGUA 1247 UACUUGUA UGAUG GCAUGCACUAUGC GCG AGAGAUGA 3372

1472 CCUAUCAC G CCCACCCA 1248 UGGGUGGG UGAUG GCAUGCACUAUGC GCG GUGAUAGG 3373

1489 CAGAAGAU G AACUUUGU 1249 ACAAAGUU UGAUG GCAUGCACUAUGC GCG AUCUUCUG 3374

1496 UGAACUUU G UGGCGCCC 1250 GGGCGCCA UGAUG GCAUGCACUAUGC GCG AAAGUUCA 3375

1501 UUUGUGGC G CCCCACCC 1251 GGGUGGGG UGAUG GCAUGCACUAUGC GCG GCCACAAA 3376

1525 CUCCCCGU G ACAUCUUC 1252 GAAGAUGU UGAUG GCAUGCACUAUGC GCG ACGGGGAG 3377

1544 GUUUUUUU G CUGCCCCA 1253 UGGGGCAG UGAUG GCAUGCACUAUGC GCG AAAAAAAC 3378

1547 UUUUUGCU G CCCCAAAC 1254 GUUUGGGG UGAUG GCAUGCACUAUGC GCG AGCAAAAA 3379

1618 AGCCAUAU G CCUUCUCA 1255 UGAGAAGG UGAUG GCAUGCACUAUGC GCG AUAUGGCU 3380

1676 AUCAGCGU G CAUUCACC 1256 GGUGAAUG UGAUG GCAUGCACUAUGC GCG ACGCUGAU 3381

Table V

1693 AGCCCAUC G CCACAAAC 1257 GUUUGUGG UGAUG GCAUGCACUAUGC GCG GAUGGGCU 3382

1717 GAGAACAU G AAUCAAAA 1258 UUUUGAUU UGAUG GCAUGCACUAUGC GCG AUGUUCUC 3383

1728 UCAAAAGU G CCUCAAGA 1259 UCUUGAGG UGAUG GCAUGCACUAUGC GCG ACUUUUGA 3384

1742 AGAGGAAU G AAAAAAGC 1260 GCUUUUUU UGAUG GCAUGCACUAUGC GCG AUUCCUCU 3385

1813 GAGUUACU G AAGUCUUA 1261 UAAGACUU UGAUG GCAUGCACUAUGC GCG AGUAACUC 3386

1832 ACAGAAAU G AGGAGGAU 1262 AUCCUCCU UGAUG GCAUGCACUAUGC GCG AUUUCUGU 3387

1841 AGGAGGAU G CUAAAAAU 1263 AUUUUUAG UGAUG GCAUGCACUAUGC GCG AUCCUCCU 3388

1850 CUAAAAAU G UCACGAAU 1264 AUUCGUGA UGAUG GCAUGCACUAUGC GCG AUUUUUAG 3389

1855 AAUGUCAC G AAUAUGGA 1265 UCCAUAUU UGAUG GCAUGCACUAUGC GCG GUGACAUU 3390

1874 UAUCAUCU G UGGACUGA 1266 UCAGUCCA UGAUG GCAUGCACUAUGC GCG AGAUGAUA 3391

1881 UGUGGACU G ACCUUGUA 1267 UACAAGGU UGAUG GCAUGCACUAUGC GCG AGUCCACA 3392

1887 CUGACCUU G UAAAAGAC 1268 GUCUUUUA UGAUG GCAUGCACUAUGC GCG AAGGUCAG 3393

1899 AAGACAGU G UAUGUAGA 1269 UCUACAUA UGAUG GCAUGCACUAUGC GCG ACUGUCUU 3394

1903 CAGUGUAU G UAGAAGCA 1270 UGCUUCUA UGAUG GCAUGCACUAUGC GCG AUACACUG 3395

1913 AGAAGGAU G AAGUCUUA 1271 UAAGACUU UGAUG GCAUGCACUAUGC GCG. AUGCUUCU 3396

1932 GACAAAGU G CCAAAGAA 1272 UUCUUUGG UGAUG GCAUGCACUAUGC GCG ACUUUGUC 3397

1957 UAAGAAAU G UAUAAACU 1273 AGUUUAUA UGAUG GCAUGCACUAUGC GCG AUUUCUUA 3398

1980 UAGAGUUU G AAUCCCAC 1274 GUGGGAUU UGAUG GCAUGCACUAUGC GCG AAACUCUA 3399

1993 CCACUAAU G CAAACUGG 1275 CCAGUUUG UGAUG GCAUGCACUAUGC GCG AUUAGUGG 3400

2005 ACUGGGAU G AAACUAAA 1276 UUUAGUUU UGAUG GCAUGCACUAUGC GCG AUCCCAGU 3401

2036 ACAGUUUU G ACCUAACA 1277 UGUUAGGU UGAUG GCAUGCACUAUGC GCG AAAACUGU 3402

2058 UUUAUAAU G CCAUUUUA 1278 UAAAAUGG UGAUG GCAUGCACUAUGC GCG AUUAUAAA 3403

2080 AACUACCU G UAUUUAAA 1279 UUUAAAUA UGAUG GCAUGCACUAUGC GCG AGGUAGUU 3404

2123 AAAGACAC G AGAGAGAC 1280 GUCUCUCU UGAUG GCAUGCACUAUGC GCG GUGUCUUU 3405

2133 GAGAGACU G UGGCCCAU 1281 AUGGGCCA UGAUG GCAUGCACUAUGC GCG AGUCUCUC 3406

2153 CAGACGUU G AUAUGCAA 1282 UUGCAUAU UGAUG GCAUGCACUAUGC GCG AACGUCUG 3407

2158 GUUGAUAU G CAACUGCA 1283 UGCAGUUG UGAUG GCAUGCACUAUGC GCG AUAUCAAC 3408

2164 AUGCAACU G CAUGGCAU 1284 AUGCCAUG UGAUG GCAUGCACUAUGC GCG AGUUGCAU 3409

2173 CAUGGCAU G UGCUGUUU 1285 AAACAGCA UGAUG GCAUGCACUAUGC GCG AUGCCAUG 3410

2175 UGGCAUGU G CUGUUUUG 1286 CAAAACAG UGAUG GCAUGCACUAUGC GCG ACAUGCCA 3411

2178 CAUGUGCU G UUUUGGUU 1287 AACCAAAA UGAUG GCAUGCACUAUGC GCG AGCACAUG 3412

2187 UUUUGGUU G AAAUCAAA 1288 UUUGAUUU UGAUG GCAUGCACUAUGC GCG AACCAAAA 3413

2208 UUCCGUUU G AUGGACAG 1289 CUGUCCAU UGAUG GCAUGCACUAUGC GCG AAACGGAA 3414

2219 GGACAGCU G UCAGCUUU 1290 AAAGCUGA UGAUG GCAUGCACUAUGC GCG AGCUGUCC 3415

2236 CUCAAACU G UGAAGAUG 1291 CAUCUUCA UGAUG GCAUGCACUAUGC GCG AGUUUGAG 3416

2238 CAAACUGU G AAGAUGAC 1292 GUCAUCUU UGAUG GCAUGCACUAUGC GCG ACAGUUUG 3417

Table V

2244 GUGAAGAU G ACCCAAAG 1293 CUUUGGGU UGAUG GCAUGCACUAUGC GCG AUCUUCAC 3418

2286 GGGACUAU G AACUAAAA 1294 UUUUAGUU UGAUG GCAUGCACUAUGC GCG AUAGUCCC 3419

2304 GUGGGACU G AGGAUGUG 1295 CACAUCCU UGAUG GCAUGCACUAUGC GCG AGUCCCAC 3420

2310 CUGAGGAU G UGUAUAGA 1296 UCUAUACA UGAUG GCAUGCACUAUGC GCG AUCCUCAG 3421

2312 GAGGAUGU G UAUAGAGU 1297 ACUCUAUA UGAUG GCAUGCACUAUGC GCG ACAUCCUC 3422

2321 UAUAGAGU G AGCGUGUG 1298 CACACGCU UGAUG GCAUGCACUAUGC GCG ACUCUAUA 3423

2327 GUGAGCGU G UGAUUGUA 1299 UACAAUCA UGAUG GCAUGCACUAUGC GCG ACGCUCAC 3424

2329 GAGCGUGU G AUUGUAGA 1300 UCUACAAU UGAUG GCAUGCACUAUGC GCG ACACGCUC 3425

2333 GUGUGAUU G UAGACAGA 1301 UCUGUCUA UGAUG GCAUGCACUAUGC GCG AAUCACAC 3426

2347 AGAGGGGU G AAGAAGGA 1302 UCCUUCUU UGAUG GCAUGCACUAUGC GCG ACCCCUCU 3427

2412 CAAGCAAU G AAGACUGG 1303 CCAGUCUU UGAUG GCAUGCACUAUGC GCG AUUGCUUG 3428

2441 UGGGGACU G UGUACAAU 1304 AUUGUACA UGAUG GCAUGCACUAUGC GCG AGUCCCCA 3429

2443 GGGACUGU G UACAAUGA 1305 UCAUUGUA UGAUG GCAUGCACUAUGC GCG ACAGUCCC 3430

2450 UGUACAAU G AGUUAUGG 1306 CCAUAACU UGAUG GCAUGCACUAUGC GCG AUUGUACA 3431

2465 GGAGACUC G AGGGUUCA 1307 UGAACCCU UGAUG GCAUGCACUAUGC GCG GAGUCUCC 3432

2475 GGGUUCAU G CAGUCAGU 1308 ACUGACUG UGAUG GCAUGCACUAUGC GCG AUGAACCC 3433

2484 CAGUCAGU G UUAUACCA 1309 UGGUAUAA UGAUG GCAUGCACUAUGC GCG ACUGACUG 3434

2501 AACCCAGU G UUAGGAGA 1310 UCUCCUAA UGAUG GCAUGCACUAUGC GCG ACUGGGUU 3435

2562 ACAAAAAU G CGCAUCUC 1311 GAGAUGCG UGAUG GCAUGCACUAUGC GCG AUUUUUGU 3436

2564 AAAAAUGC G CAUCUCUU 1312 AAGAGAUG UGAUG GCAUGCACUAUGC GCG GCAUUUUU 3437

2578 CUUUCUUU G UUUGUCAA 1313 UUGACAAA UGAUG GCAUGCACUAUGC GCG AAAGAAAG 3438

2582 CUUUGUUU G UCAAAUGA 1314 UCAUUUGA UGAUG GCAUGCACUAUGC GCG AAACAAAG 3439

2589 UGUCAAAU G AAAAUUUU 1315 AAAAUUUU UGAUG GCAUGCACUAUGC GCG AUUUGACA 3440

2608 CUGGAAUU G UCUGAUAU 1316 AUAUCAGA UGAUG GCAUGCACUAUGC GCG AAUUCCAG 3441

2612 AAUUGUCU G AUAUUUAA 1317 UUAAAUAU UGAUG GCAUGCACUAUGC GCG AGACAAUU 3442

2648 AUCAUUAU G UGGGGGCU 1318 AGCCCCCA UGAUG GCAUGCACUAUGC GCG AUAAUGAU 3443

2659 GGGGCUUU G UUCUCCAC 1319 GUGGAGAA UGAUG GCAUGCACUAUGC GCG AAAGCCCC 3444

2698 UCUUGGCU G CCACAAUC 1320 GAUUGUGG UGAUG GCAUGCACUAUGC GCG AGCCAAGA 3445

2716 GAAAUCAC G CAGGCAUU 1321 AAUGCCUG UGAUG GCAUGCACUAUGC GCG GUGAUUUC 3446

2753 UUUCCUUU G AGUCGCGA 1322 UCGCGACU UGAUG GCAUGCACUAUGC GCG AAAGGAAA 3447

2758 UUUGAGUC G CGAACGCU 1323 AGCGUUCG UGAUG GCAUGCACUAUGC GCG GACUCAAA 3448

2760 UGAGUCGC G AACGCUGU 1324 ACAGCGUU UGAUG GCAUGCACUAUGC GCG GCGACUCA 3449

2764 UCGCGAAC G CUGUGCGU 1325 ACGCACAG UGAUG GCAUGCACUAUGC GCG GUUCGCGA 3450

2767 CGAACGCU G UGCGUUUG 1326 CAAACGCA UGAUG GCAUGCACUAUGC GCG AGCGUUCG 3451

2769 AACGCUGU G CGUUUGUC 1327 GACAAACG UGAUG GCAUGCACUAUGC GCG ACAGCGUU 3452

2775 GUGCGUUU G UCAGAAUG 1328 CAUUCUGA UGAUG GCAUGCACUAUGC GCG AAACGCAC 3453

Table V

2783 GUCAGAAU G AAGUAUAC 1329 GUAUACUU UGAUG GCAUGCACUAUGC GCG AUUCUGAC 3454

2800 AAGUCAAU G UUUUUCCC 1330 GGGAAAAA UGAUG GCAUGCACUAUGC GCG AUUGACUU 3455

2838 UAACUUAU G CAUUUAUA 1331 UAUAAAUG UGAUG GCAUGCACUAUGC GCG AUAAGUUA 3456

2853 UACACUAC G AGUUGAUC 1332 GAUCAACU UGAUG GCAUGCACUAUGC GCG GUAGUGUA 3457

2858 UACGAGUU G AUCUCGGC 1333 GCCGAGAU UGAUG GCAUGCACUAUGC GCG AACUCGUA 3458

2882 AGACACAC G ACAAAAGA 1334 UCUUUUGU UGAUG GCAUGCACUAUGC GCG GUGUGUCU 3459

2898 AGACAAUC G AUAUAAUG 1335 CAUUAUAU UGAUG GCAUGCACUAUGC GCG GAUUGUCU 3460

2906 GAUAUAAU G UGGCCUUG 1336 CAAGGCCA UGAUG GCAUGCACUAUGC GCG AUUAUAUC 3461

2914 GUGGCCUU G AAUUUUAA 1337 UUAAAAUU UGAUG GCAUGCACUAUGC GCG AAGGCCAC 3462

2927 UUAACUCU G UAUGCUUA 1338 UAAGCAUA UGAUG GCAUGCACUAUGC GCG AGAGUUAA 3463

2931 CUCUGUAU G CUUAAUGU 1339 ACAUUAAG UGAUG GCAUGCACUAUGC GCG AUACAGAG 3464

2938 UGCUUAAU G UUUACAAU 1340 AUUGUAAA UGAUG GCAUGCACUAUGC GCG AUUAAGCA 3465

2949 UACAAUAU G AAGUUAUU 1341 AAUAACUU UGAUG GCAUGCACUAUGC GCG AUAUUGUA 3466

2970 CUUAGAAU G CAGAAUGU 1342 ACAUUCUG UGAUG GCAUGCACUAUGC GCG AUUCUAAG 3467

2977 UGCAGAAU G UAUGUAAU 1343 AUUACAUA UGAUG GCAUGCACUAUGC GCG AUUCUGCA 3468

2981 GAAUGUAU G UAAUAAAA 1344 UUUUAUUA UGAUG GCAUGCACUAUGC GCG AUACAUUC 3469

3033 AGGAGUCU G CAUUUGCA 1345 UGCAAAUG UGAUG GCAUGCACUAUGC GCG AGACUCCU 3470

3039 CUGCAUUU G CACUUUUU 1346 AAAAAGUG UGAUG GCAUGCACUAUGC GCG AAAUGCAG 3471

3053 UUUUUAGU G ACUAAAGU 1347 ACUUUAGU UGAUG GCAUGCACUAUGC GCG ACUAAAAA 3472

3063 CUAAAGUU G CUUAAUGA 1348 UCAUUAAG UGAUG GCAUGCACUAUGC GCG AACUUUAG 3473

3070 UGCUUAAU G AAAACAUG 1349 CAUGUUUU UGAUG GCAUGCACUAUGC GCG AUUAAGCA 3474

3078 GAAAACAU G UGCUGAAU 1350 AUUCAGCA UGAUG GCAUGCACUAUGC GCG AUGUUUUC 3475

3080 AAACAUGU G CUGAAUGU 1351 ACAUUCAG UGAUG GCAUGCACUAUGC GCG ACAUGUUU 3476

3083 CAUGUGCU G AAUGUUGU 1352 ACAACAUU UGAUG GCAUGCACUAUGC GCG AGCACAUG 3477

3087 UGCUGAAU G UUGUGGAU 1353 AUCCACAA UGAUG GCAUGCACUAUGC GCG AUUCAGCA 3478

3090 UGAAUGUU G UGGAUUUU 1354 AAAAUCCA UGAUG GCAUGCACUAUGC GCG AACAUUCA 3479

3099 UGGAUUUU G UGUUAUAA 1355 UUAUAACA UGAUG GCAUGCACUAUGC GCG AAAAUCCA 3480

3101 GAUUUUGU G UUAUAAUU 1356 AAUUAUAA UGAUG GCAUGCACUAUGC GCG ACAAAAUC 3481

3116 UUUACUUU G UCCAGGAA 1357 UUCCUGGA UGAUG GCAUGCACUAUGC GCG AAAGUAAA 3482

3128 AGGAACUU G UGCAAGGG 1358 CCCUUGCA UGAUG GCAUGCACUAUGC GCG AAGUUCCU 3483

3130 GAACUUGU G CAAGGGAG 1359 CUCCCUUG UGAUG GCAUGCACUAUGC GCG ACAAGUUC 3484

3156 AAUAGGAU G UUUGGCAC 1360 GUGCCAAA UGAUG GCAUGCACUAUGC GCG AUCCUAUU 3485

Input Sequence = HUMERG2. Cut Site = YG/M or UG/U.

Stem Length = 8. Core Sequence = UGAUG GCAUGCACUAUGC GCG

HUMERG2 (Human erg2 gene encoding erg2 protein, complete eds.; 3166 bp)

Table VI

Table VI: Human ERG Zinzyme and Target Sequence

Table VI

692 CAGACCAU G UGCGGCAG 1206 CUGCCGCA GCCGAAAGGCGAGUCAAGGUCU AUGGUCUG 3518

694 GACCAUGU G CGGCAGUG 1207 CACUGCCG GCCGAAAGGCGAGUCAAGGUCU ACAUGGUC 3519

751 AACAUCUU G UUAUUCCA 1209 UGGAAUAA GCCGAAAGGCGAGUCAAGGUCU AAGAUGUU 3520

781 AAGGAACU G UGCAAGAU 1211 AUCUUGCA GCCGAAAGGCGAGUCAAGGUCU AGUUCCUU 3521

783 GGAACUGU G CAAGAUGA 1212 UCAUCUUG GCCGAAAGGCGAGUCAAGGUCU ACAGUUCC 3522

830 GCUACAAC G CCGACAUC 1215 GAUGUCGG GCCGAAAGGCGAGUCAAGGUCU GUUGUAGC 3523

899 CAGAUGAU G UUGAUAAA 1219 UUUAUCAA GCCGAAAGGCGAGUCAAGGUCU AUCAUCUG 3524

934 CGGUUAAU G CAUGCUAG 1221 CUAGCAUG GCCGAAAGGCGAGUCAAGGUCU AUUAACCG 3525

938 UAAUGCAU G CUAGAAAC 1222 GUUUCUAG GCCGAAAGGCGAGUCAAGGUCU AUGCAUUA 3526

1006 CACCCCAC G CCCCAGUC 1224 GACUGGGG GCCGAAAGGCGAGUCAAGGUCU GUGGGGUG 3527

1022 CGAAAGCU G CUCAACCA 1226 UGGUUGAG GCCGAAAGGCGAGUCAAGGUCU AGCUUUCG 3528

1045 UCCACAGU G CCCAAAAC 1227 GUUUUGGG GCCGAAAGGCGAGUCAAGGUCU ACUGUGGA 3529

1110 AAGUAGCC G CCUUGCAA 1229 UUGCAAGG GCCGAAAGGCGAGUCAAGGUCU GGCUACUU 3530

1115 GCCGCCUU G CAAAUCCA 1230 UGGAUUUG GCCGAAAGGCGAGUCAAGGUCU AAGGCGGC 3531

1168 GAGCUCCU G UCGGACAG 1231 CUGUCCGA GCCGAAAGGCGAGUCAAGGUCU AGGAGCUC 3532

1191 CUCCAGCU G CAUCACCU 1232 AGGUGAUG GCCGAAAGGCGAGUCAAGGUCU AGCUGGAG 3533

1254 GGCCCGGC G CUGGGGAG 1236 CUCCCCAG GCCGAAAGGCGAGUCAAGGUCU GCCGGGCC 3534

1305 GCUCAGCC G GGCCCUCC 1239 GGAGGGCG GCCGAAAGGCGAGUCAAGGUCU GGCUGAGC 3535

1307 UCAGCCGC G CCCUCCGU 1240 ACGGAGGG GCCGAAAGGCGAGUCAAGGUCU GCGGCUGA 3536

1359 UGGGAAGC G CUACGCCU 1243 AGGCGUAG GCCGAAAGGCGAGUCAAGGUCU GCUUCCCA 3537

1364 AGCGCUAC G CCUACAAG 1244 CUUGUAGG GCCGAAAGGCGAGUCAAGGUCU GUAGCGCU 3538

1391 ACGGGAUC G CCCAGGCC 1246 GGCCUGGG GCCGAAAGGCGAGUCAAGGUCU GAUCCCGU 3539

1429 UCAUCUCU G UACAAGUA 1247 UACUUGUA GCCGAAAGGCGAGUCAAGGUCU AGAGAUGA 3540

1472 CCUAUCAC G CCCACCCA 1248 UGGGUGGG GCCGAAAGGCGAGUCAAGGUCU GUGAUAGG 3541

1496 UGAACUUU G UGGCGCCC 1250 GGGCGCCA GCCGAAAGGCGAGUCAAGGUCU AAAGUUCA 3542

1501 UUUGUGGC G CCCCACGC 1251 GGGUGGGG GCCGAAAGGCGAGUCAAGGUCU GCCACAAA 3543

1544 GUUUUUUU G CUGCCCCA 1253 UGGGGCAG GCCGAAAGGCGAGUCAAGGUCU AAAAAAAC 3544

1547 UUUUUGCU G CCCCAAAC 1254 GUUUGGGG GCCGAAAGGCGAGUCAAGGUCU AGCAAAAA 3545

1618 AGCCAUAU G CCUUCUCA 1255 UGAGAAGG GCCGAAAGGCGAGUCAAGGUCU AUAUGGCU 3546

1676 AUCAGCGU G CAUUCACC 1256 GGUGAAUG GCCGAAAGGCGAGUCAAGGUCU ACGCUGAU 3547

1693 AGCCCAUG G CCACAAAC 1257 GUUUGUGG GCCGAAAGGCGAGUCAAGGUCU GAUGGGCU 3548

1728 UCAAAAGU G CCUCAAGA 1259 UCUUGAGG GCCGAAAGGCGAGUCAAGGUCU ACUUUUGA 3549

1841 AGGAGGAU G CUAAAAAU 1263 AUUUUUAG GCCGAAAGGCGAGUCAAGGUCU AUCCUCCU 3550

1850 CUAAAAAU G UCACGAAU 1264 AUUCGUGA GCCGAAAGGCGAGUCAAGGUCU AUUUUUAG 3551

1874 UAUCAUCU G UGGACUGA 1266 UCAGUCCA GCCGAAAGGCGAGUCAAGGUCU AGAUGAUA 3552

1887 CUGACCUU G UAAAAGAC 1268 GUCUUUUA GCCGAAAGGCGAGUCAAGGUCU AAGGUCAG 3553

Table VT

1899 AAGACAGU G UAUGUAGA 1269 UCUACAUA GCCGAAAGGCGAGUCAAGGUCU ACUGUCUU 3554

1903 CAGUGUAU G UAGAAGCA 1270 UGCUUCUA GCCGAAAGGCGAGUCAAGGUCU AUACACUG 3555

1932 GACAAAGU G CCAAAGAA 1272 UUCUUUGG GCCGAAAGGCGAGUCAAGGUCU ACUUUGUC 3556

1957 UAAGAAAU G UAUAAACU 1273 AGUUUAUA GCCGAAAGGCGAGUCAAGGUCU AUUUCUUA 3557

1993 CCACUAAU G CAAACUGG 1275 CCAGUUUG GCCGAAAGGCGAGUCAAGGUCU AUUAGUGG 3558

2058 UUUAUAAU G CCAUUUUA 1278 UAAAAUGG GCCGAAAGGCGAGUCAAGGUCU AUUAUAAA 3559

2080 AACUACCU G UAUUUAAA 1279 UUUAAAUA GCCGAAAGGCGAGUCAAGGUCU AGGUAGUU 3560

2133 GAGAGACU G UGGCCCAU 1281 AUGGGCCA GCCGAAAGGCGAGUCAAGGUCU AGUCUCUC 3561

2158 GUUGAUAU G CAACUGCA 1283 UGCAGUUG GCCGAAAGGCGAGUCAAGGUCU AUAUCAAC 3562

2164 AUGCAACU G CAUGGCAU 1284 AUGCCAUG GCCGAAAGGCGAGUCAAGGUCU AGUUGCAU 3563

2173 CAUGGCAU G UGCUGUUU 1285 AAACAGCA GCCGAAAGGCGAGUCAAGGUCU AUGCCAUG 3564

2175 UGGCAUGU G CUGUUUUG 1286 CAAAACAG GCCGAAAGGCGAGUCAAGGUCU ACAUGCCA 3565

2178 CAUGUGCU G UUUUGGUU 1287 AACCAAAA GCCGAAAGGCGAGUCAAGGUCU AGCACAUG 3566

2219 GGACAGCU G UCAGCUUU 1290 AAAGCUGA GCCGAAAGGCGAGUCAAGGUCU AGCUGUCC 3567

2236 CUCAAACU G UGAAGAUG 1291 CAUCUUCA GCCGAAAGGCGAGUCAAGGUCU AGUUUGAG 3568

2310 CUGAGGAU G UGUAUAGA 1296 UCUAUACA GCCGAAAGGCGAGUCAAGGUCU AUCCUCAG 3569

2312 GAGGAUGU G UAUAGAGU 1297 ACUCUAUA GCCGAAAGGCGAGUCAAGGUCU ACAUCCUC 3570

2327 GUGAGCGU G UGAUUGUA 1299 UACAAUCA GCCGAAAGGCGAGUCAAGGUCU ACGCUCAC 3571

2333 GUGUGAUU G UAGACAGA 1301 UCUGUCUA GCCGAAAGGCGAGUCAAGGUCU AAUCACAC 3572

2441 UGGGGACU G UGUACAAU 1304 AUUGUACA GCCGAAAGGCGAGUCAAGGUCU AGUGCCCA 3573

2443 GGGACUGU G UACAAUGA 1305 UCAUUGUA GCCGAAAGGCGAGUCAAGGUCU ACAGUGCC 3574

2475 GGGUUCAU G CAGUCAGU 1308 ACUGACUG GCCGAAAGGCGAGUCAAGGUCU AUGAACCC 3575

2484 CAGUCAGU G UUAUACCA 1309 UGGUAUAA GCCGAAAGGCGAGUCAAGGUCU ACUGACUG 3576

2501 AACCCAGU G UUAGGAGA 1310 UCUCCUAA GCCGAAAGGCGAGUCAAGGUCU ACUGGGUU 3577

2562 ACAAAAAU G CGCAUCUC 1311 GAGAUGCG GCCGAAAGGCGAGUCAAGGUCU AUUUUUGU 3578

2564 AAAAAUGC G CAUCUCUU 1312 AAGAGAUG GCCGAAAGGCGAGUCAAGGUCU GCAUUUUU 3579

2578 CUUUCUUU G UUUGUCAA 1313 UUGACAAA GCCGAAAGGCGAGUCAAGGUCU AAAGAAAG 3580

2582 CUUUGUUU G UCAAAUGA 1314 UCAUUUGA GCCGAAAGGCGAGUCAAGGUCU AAACAAAG 3581

2608 CUGGAAUU G UCUGAUAU 1316 AUAUCAGA GCCGAAAGGCGAGUCAAGGUCU AAUUCCAG 3582

2648 AUCAUUAU G UGGGGGCU 1318 AGCCCCCA GCCGAAAGGCGAGUCAAGGUCU AUAAUGAU 3583

2659 GGGGCUUU G UUCUCCAC 1319 GUGGAGAA GCCGAAAGGCGAGUCAAGGUCU AAAGCCCC 3584

2698 UCUUGGCU G CCACAAUC 1320 GAUUGUGG GCCGAAAGGCGAGUCAAGGUCU AGCCAAGA 3585

2716 GAAAUCAC G CAGGCAUU 1321 AAUGCCUG GCCGAAAGGCGAGUCAAGGUCU GUGAUUUC 3586

2758 UUUGAGUC G CGAACGCU 1323 AGCGUUCG GCCGAAAGGCGAGUCAAGGUCU GACUCAAA 3587

2764 UCGCGAAC G CUGUGCGU 1325 ACGCACAG GCCGAAAGGCGAGUCAAGGUCU GUUCGCGA 3588

2767 CGAACGCU G UGCGUUUG 1326 CAAACGCA GCCGAAAGGCGAGUCAAGGUCU AGCGUUCG 3589

Table VI

2769 AACGCUGU G CGUUUGUC 1327 GACAAACG GCCGAAAGGCGAGUCAAGGUCU ACAGCGUU 3590

2775 GUGCGUUU G UCAGAAUG 1328 CAUUCUGA GCCGAAAGGCGAGUCAAGGUCU AAACGCAC 3591

2800 AAGUCAAU G UUUUUCCC 1330 GGGAAAAA GCCGAAAGGCGAGUCAAGGUCU AUUGACUU 3592

2838 UAACUUAU G CAUUUAUA 1331 UAUAAAUG GCCGAAAGGCGAGUCAAGGUCU AUAAGUUA 3593

2906 GAUAUAAU G UGGCCUUG 1336 CAAGGCCA GCCGAAAGGCGAGUCAAGGUCU AUUAUAUC 3594

2927 UUAACUCU G UAUGCUUA 1338 UAAGCAUA GCCGAAAGGCGAGUCAAGGUCU AGAGUUAA 3595

2931 CUCUGUAU G CUUAAUGU 1339 ACAUUAAG GCCGAAAGGCGAGUCAAGGUCU AUACAGAG 3596

2938 UGCUUAAU G UUUACAAU 1340 AUUGUAAA GCCGAAAGGCGAGUCAAGGUCU AUUAAGCA 3597

2970 CUUAGAAU G CAGAAUGU 1342 ACAUUCUG GCCGAAAGGCGAGUCAAGGUCU AUUCUAAG 3598

2977 UGCAGAAU G UAUGUAAU 1343 AUUACAUA GCCGAAAGGCGAGUCAAGGUCU AUUCUGCA 3599

2981 GAAUGUAU G UAAUAAAA 1344 UUUUAUUA GCCGAAAGGCGAGUCAAGGUCU AUACAUUC 3600

3033 AGGAGUCU G CAUUUGCA 1345 UGCAAAUG GCCGAAAGGCGAGUCAAGGUCU AGACUCCU 3601

3039 CUGCAUUU G CACUUUUU 1346 AAAAAGUG GCCGAAAGGCGAGUCAAGGUCU AAAUGCAG 3602

3063 CUAAAGUU G CUUAAUGA 1348 UCAUUAAG GCCGAAAGGCGAGUCAAGGUCU AACUUUAG 3603

3078 GAAAACAU G UGCUGAAU 1350 AUUCAGCA GCCGAAAGGCGAGUCAAGGUCU AUGUUUUC 3604

3080 AAACAUGU G CUGAAUGU 1351 ACAUUCAG GCCGAAAGGCGAGUCAAGGUCU ACAUGUUU 3605

3087 UGCUGAAU G UUGUGGAU 1353 AUCCACAA GCCGAAAGGCGAGUCAAGGUCU AUUCAGCA 3606

3090 UGAAUGUU G UGGAUUUU 1354 AAAAUCCA GCCGAAAGGCGAGUCAAGGUCU AACAUUCA 3607

3099 UGGAUUUU G UGUUAUAA 1355 UUAUAACA GCCGAAAGGCGAGUCAAGGUCU AAAAUCCA 3608

3101 GAUUUUGU G UUAUAAUU 1356 AAUUAUAA GCCGAAAGGCGAGUCAAGGUCU ACAAAAUC 3609

3116 UUUACUUU G UCCAGGAA 1357 UUCCUGGA GCCGAAAGGCGAGUCAAGGUCU AAAGUAAA 3610

3128 AGGAACUU G UGCAAGGG 1358 CCCUUGCA GCCGAAAGGCGAGUCAAGGUCU AAGUUGCU 3611

3130 GAACUUGU G CAAGGGAG 1359 CUCCCUUG GCCGAAAGGCGAGUCAAGGUCU ACAAGUUC 3612

3156 AAUAGGAU G UUUGGCAC 1360 GUGCCAAA GCCGAAAGGCGAGUCAAGGUCU AUCCUAUU 3613

9 GUCCGCGC G UGUCCGCG 1361 CGCGGACA GCCGAAAGGCGAGUCAAGGUCU GCGCGGAC 3614

23 GCGCCCGC G UGUGCCAG 1362 CUGGCACA GCCGAAAGGCGAGUCAAGGUCU GCGGGCGC 3615

31 GUGUGCCA G CGCGCGUG 1363 CACGCGCG GCCGAAAGGCGAGUCAAGGUCU UGGCACAC 3616

37 CAGCGCGC G UGCCUUGG 1364 CCAAGGCA GCCGAAAGGCGAGUCAAGGUCU GCGCGCUG 3617

45 GUGCCUUG G CCGUGCGC 1365 GCGCACGG GCCGAAAGGCGAGUCAAGGUCU CAAGGCAC 3618

48 CCUUGGCC G UGCGCGCC 1366 GGCGCGCA GCCGAAAGGCGAGUCAAGGUCU GGCCAAGG 3619

59 CGCGCCGA G CCGGGUCG 1367 CGACCCGG GCCGAAAGGCGAGUCAAGGUCU UCGGCGCG 3620

64 CGAGCCGG G UCGCACUA 1368 UAGUGCGA GCCGAAAGGCGAGUCAAGGUCU CCGGCUCG 3621

82 CUCCCUCG G CGCCGACG 1369 CGUCGGCG GCCGAAAGGCGAGUCAAGGUCU CGAGGGAG 3622

91 CGCCGACG G CGGCGCUA 1370 UAGCGCCG GCCGAAAGGCGAGUCAAGGUCU CGUCGGCG 3623

94 CGACGGCG G CGCUAACC 1371 GGUUAGCG GCCGAAAGGCGAGUCAAGGUCU CGCCGUCG 3624

108 ACCUCUCG G UUAUUCCA 1372 UGGAAUAA GCCGAAAGGCGAGUCAAGGUCU CGAGAGGU 3625

Table VT

140 CGAGGAAA G CCGUGUUG 1373 CAACACGG GCCGAAAGGCGAGUCAAGGUCU UUUCCUCG 3626

143 GGAAAGCC G UGUUGACC 1374 GGUCAACA GCCGAAAGGCGAGUCAAGGUCU GGCUUUCC 3627

156 GACCAAAA G CAAGACAA 1375 UUGUCUUG GCCGAAAGGCGAGUCAAGGUCU UUUUGGUC 3628

188 AAAAGAUG G CAGAACCA 1376 UGGUUCUG GCCGAAAGGCGAGUCAAGGUCU CAUCUUUU 3629

200 AACCAAGG G CAACUAAA 1377 UUUAGUUG GCCGAAAGGCGAGUCAAGGUCU CCUUGGUU 3630

209 CAACUAAA G CCGUCAGG 1378 CCUGACGG GCCGAAAGGCGAGUCAAGGUCU UUUAGUUG 3631

212 CUAAAGCC G UCAGGUUC 1379 GAACCUGA GCCGAAAGGCGAGUCAAGGUCU GGCUUUAG 3632

217 GCCGUCAG G UUCUGAAC 1380 GUUCAGAA GCCGAAAGGCGAGUCAAGGUCU CUGACGGC 3633

227 UCUGAACA G CUGGUAGA 1381 UCUACCAG GCCGAAAGGCGAGUCAAGGUCU UGUUCAGA 3634

231 AACAGCUG G UAGAUGGG 1382 CCCAUCUA GCCGAAAGGCGAGUCAAGGUCU CAGCUGUU 3635

239 GUAGAUGG G CUGGCUUA 1383 UAAGCCAG GCCGAAAGGCGAGUCAAGGUCU CCAUCUAC 3636

243 AUGGGCUG G CUUACUGA 1384 UCAGUAAG GCCGAAAGGCGAGUCAAGGUCU CAGCCCAU 3637

281 CGGACCCA G CAGCUCAU 1385 AUGAGCUG GCCGAAAGGCGAGUCAAGGUCU UGGGUCCG 3638

284 ACCCAGCA G CUCAUAUC 1386 GAUAUGAG GCCGAAAGGCGAGUCAAGGUCU UGCUGGGU 3639

299 UCAAGGAA G CCUUAUCA 1387 UGAUAAGG GCCGAAAGGCGAGUCAAGGUCU UUCCUUGA 3640

308 CCUUAUCA G UUGUGAGU 1388 ACUCACAA GCCGAAAGGCGAGUCAAGGUCU UGAUAAGG 3641

315 AGUUGUGA G UGAGGACC 1389 GGUCCUCA GCCGAAAGGCGAGUCAAGGUCU UCACAACU 3642

325 GAGGACCA G UCGUUGUU 1390 AACAACGA GCCGAAAGGCGAGUCAAGGUCU UGGUCCUC 3643

328 GACCAGUC G UUGUUUGA 1391 UCAAACAA GCCGAAAGGCGAGUCAAGGUCU GACUGGUC 3644

337 UUGUUUGA G UGUGCCUA 1392 UAGGCACA GCCGAAAGGCGAGUCAAGGUCU UCAAACAA 3645

362 CACACCUG G CUAAGACA 1393 UGUCUUAG GCCGAAAGGCGAGUCAAGGUCU CAGGUGUG 3646

382 AUGACCGC G UCCUCCUC 1394 GAGGAGGA GCCGAAAGGCGAGUCAAGGUCU GCGGUCAU 3647

393 CUCCUCCA G CGACUAUG 1395 CAUAGUCG GCCGAAAGGCGAGUCAAGGUCU UGGAGGAG 3648

420 CAAGAUGA G CCCACGCG 1396 CGCGUGGG GCCGAAAGGCGAGUCAAGGUCU UCAUCUUG 3649

428 GCCCACGC G UCCCUCAG 1397 CUGAGGGA GCCGAAAGGCGAGUCAAGGUCU GCGUGGGC 3650

436 GUCCCUCA G CAGGAUUG 1398 CAAUCCUG GCCGAAAGGCGAGUCAAGGUCU UGAGGGAC 3651

445 CAGGAUUG G CUGUCUCA 1399 UGAGACAG GCCGAAAGGCGAGUCAAGGUCU CAAUCCUG 3652

461 AACCCCCA G CCAGGGUC 1400 GACCCUGG GCCGAAAGGCGAGUCAAGGUCU UGGGGGUU 3653

467 CAGCCAGG G UCACCAUC 1401 GAUGGUGA GCCGAAAGGCGAGUCAAGGUCU CCUGGCUG 3654

495 UAACCCUA G CCAGGUGA 1402 UCACCUGG GCCGAAAGGCGAGUCAAGGUCU UAGGGUUA 3655

500 CUAGCCAG G UGAAUGGC 1403 GCCAUUCA GCCGAAAGGCGAGUCAAGGUCU CUGGCUAG 3656

507 GGUGAAUG G CUCAAGGA 1404 UCCUUGAG GCCGAAAGGCGAGUCAAGGUCU CAUUCACC 3657

534 UGAAUGCA G UGUGGCCA 1405 UGGCCACA GCCGAAAGGCGAGUCAAGGUCU UGCAUUCA 3658

539 GCAGUGUG G CCAAAGGC 1406 GCCUUUGG GCCGAAAGGCGAGUCAAGGUCU CACACUGC 3659

546 GGCCAAAG G CGGGAAGA 1407 UCUUCCCG GCCGAAAGGCGAGUCAAGGUCU CUUUGGCC 3660

557 GGAAGAUG G UGGGCAGC 1408 GCUGCCCA GCCGAAAGGCGAGUCAAGGUCU CAUCUUCC 3661

Table VI

561 GAUGGUGG G CAGCCCAG 1409 CUGGGCUG GCCGAAAGGCGAGUCAAGGUCU CCACCAUC 3662

564 GGUGGGCA G CCCAGACA 1410 UGUCUGGG GCCGAAAGGCGAGUCAAGGUCU UGCCCACC 3663

575 CAGACACC G UUGGGAUG 1411 CAUCCCAA GCCGAAAGGCGAGUCAAGGUCU GGUGUCUG 3664

591 GAACUACG G CAGCUACA 1412 UGUAGCUG GCCGAAAGGCGAGUCAAGGUCU CGUAGUUC 3665

594 CUACGGCA G CUACAUGG 1413 CCAUGUAG GCCGAAAGGCGAGUCAAGGUCU UGCCGUAG 3666

610 GAGGAGAA G CACAUGCC 1414 GGCAUGUG GCCGAAAGGCGAGUCAAGGUCU UUCUCCUC 3667

643 ACGAACGA G CGCAGAGU 1415 ACUCUGCG GCCGAAAGGCGAGUCAAGGUCU UCGUUCGU 3668

650 AGCGCAGA G UUAUCGUG 1416 CACGAUAA GCCGAAAGGCGAGUCAAGGUCU UCUGCGCU 3669

656 GAGUUAUC G UGCCAGCA 1417 UGCUGGCA GCCGAAAGGCGAGUCAAGGUCU GAUAACUC 3670

662 UCGUGCCA G CAGAUCCU 1418 AGGAUCUG GCCGAAAGGCGAGUCAAGGUCU UGGCACGA 3671

681 GCUAUGGA G UACAGACC 1419 GGUCUGUA GCCGAAAGGCGAGUCAAGGUCU UCCAUAGC 3672

697 CAUGUGCG G CAGUGGCU 1420 AGCCACUG GCCGAAAGGCGAGUCAAGGUCU CGCACAUG 3673

700 GUGCGGCA G UGGCUGGA 1421 UCCAGCCA GCCGAAAGGCGAGUCAAGGUCU UGCCGCAC 3674

703 CGGCAGUG G CUGGAGUG 1422 CACUCCAG GCCGAAAGGCGAGUCAAGGUCU CACUGCCG 3675

709 UGGCUGGA G UGGGCGGU 1423 ACCGCCCA GCCGAAAGGCGAGUCAAGGUCU UCCAGCCA 3676

713 UGGAGUGG G CGGUGAAA 1424 UUUCACCG GCCGAAAGGCGAGUCAAGGUCU CCACUCCA 3677

716 AGUGGGCG G UGAAAGAA 1425 UUCUUUCA GCCGAAAGGCGAGUCAAGGUCU CGCCCACU 3678

729 AGAAUAUG G CCUUCCAG 1426 CUGGAAGG GCCGAAAGGCGAGUCAAGGUCU CAUAUUCU 3679

740 UUCCAGAC G UCAACAUC 1427 GAUGUUGA GCCGAAAGGCGAGUCAAGGUCU GUCUGGAA 3680

811 UUCCAGAG G CUCACCCC 1428 GGGGUGAG GCCGAAAGGCGAGUCAAGGUCU CUCUGGAA 3681

822 CACCCCCA G CUACAACG 1429 CGUUGUAG GCCGAAAGGCGAGUCAAGGUCU UGGGGGUG 3682

908 UUGAUAAA G CCUUACAA 1430 UUGUAAGG GCCGAAAGGCGAGUCAAGGUCU UUUAUCAA 3683

928 UCUCCACG G UUAAUGCA 1431 UGCAUUAA GCCGAAAGGCGAGUCAAGGUCU CGUGGAGA 3684

964 CCAUAUGA G CCCCCCAG 1432 CUGGGGGG GCCGAAAGGCGAGUCAAGGUCU UCAUAUGG 3685

980 GGAGAUCA G CCUGGAGC 1433 GGUCCAGG GCCGAAAGGCGAGUCAAGGUCU UGAUCUCC 3686

990 CUGGACCG G UCACGGCC 1434 GGCCGUGA GCCGAAAGGCGAGUCAAGGUCU CGGUCCAG 3687

996 CGGUCACG G CCACCCCA 1435 UGGGGUGG GCCGAAAGGCGAGUCAAGGUCU CGUGACCG 3688

1012 ACGCCCCA G UCGAAAGC 1436 GCUUUCGA GCCGAAAGGCGAGUCAAGGUCU UGGGGCGU 3689

1019 AGUCGAAA G CUGCUCAA 1437 UUGAGCAG GCCGAAAGGCGAGUCAAGGUCU UUUCGACU 3690

1043 CUUCCACA G UGCCCAAA 1438 UUUGGGCA GCCGAAAGGCGAGUCAAGGUCU UGUGGAAG 3691

1063 GAAGACCA G CGUCCUCA 1439 UGAGGACG GCCGAAAGGCGAGUCAAGGUCU UGGUCUUC 3692

1065 AGACCAGC G UCCUCAGU 1440 ACUGAGGA GCCGAAAGGCGAGUCAAGGUCU GCUGGUCU 3693

1072 CGUCCUCA G UUAGAUCC 1441 GGAUCUAA GCCGAAAGGCGAGUCAAGGUCU UGAGGACG 3694

1104 ACCAACAA G UAGCCGCC 1442 GGCGGCUA GCCGAAAGGCGAGUCAAGGUCU UUGUUGGU 3695

1107 AACAAGUA G CCGCCUUG 1443 CAAGGCGG GCCGAAAGGCGAGUCAAGGUCU UACUUGUU 3696

1125 AAAUCCAG G CAGUGGCC 1444 GGCCACUG GCCGAAAGGCGAGUCAAGGUCU CUGGAUUU 3697

Table VI

1128 UCCAGGCA G UGGCCAGA 1445 UCUGGCCA GCCGAAAGGCGAGUCAAGGUCU UGCCUGGA 3698

1131 AGGCAGUG G CCAGAUCC 1446 GGAUCUGG GCCGAAAGGCGAGUCAAGGUCU CACUGCCU 3699

1141 CAGAUCCA G CUUUGGCA 1447 UGCCAAAG GCCGAAAGGCGAGUCAAGGUCU UGGAUCUG 3700

1147 CAGCUUUG G CAGUUCCU 1448 AGGAACUG GCCGAAAGGCGAGUCAAGGUCU CAAAGCUG 3701

1150 CUUUGGCA G UUCCUCCU 1449 AGGAGGAA GCCGAAAGGCGAGUCAAGGUCU UGCCAAAG 3702

1162 CUCCUGGA G CUCCUGUC 1450 GACAGGAG GCCGAAAGGCGAGUCAAGGUCU UCCAGGAG 3703

1176 GUCGGACA G CUCCAACU 1451 AGUUGGAG GCCGAAAGGCGAGUCAAGGUCU UGUCCGAC 3704

1188 CAACUCCA G CUGCAUCA 1452 UGAUGCAG GCCGAAAGGCGAGUCAAGGUCU UGGAGUUG 3705

1206 CUGGGAAG G CACCAACG 1453 CGUUGGUG GCCGAAAGGCGAGUCAAGGUCU CUUCCCAG 3706

1219 AACGGGGA G UUCAAGAU 1454 AUCUUGAA GCCGAAAGGCGAGUCAAGGUCU UCCCCGUU 3707

1244 CCGACGAG G UGGCCCGG 1455 CCGGGCCA GCCGAAAGGCGAGUCAAGGUCU CUCGUCGG 3708

1247 ACGAGGUG G CCCGGCGC 1456 GCGCCGGG GCCGAAAGGCGAGUCAAGGUCU CACCUCGU 3709

1252 GUGGCCCG G CGCUGGGG 1457 CCCCAGCG GCCGAAAGGCGAGUCAAGGUCU CGGGCCAC 3710

1264 UGGGGAGA G CGGAAGAG 1458 CUCUUCCG GCCGAAAGGCGAGUCAAGGUCU UCUCCCCA 3711

1272 GCGGAAGA G CAAACCCA 1459 UGGGUUUG GCCGAAAGGCGAGUCAAGGUCU UCUUCCGC 3712

1297 UACGAUAA G CUCAGCCG 1460 CGGCUGAG GCCGAAAGGCGAGUCAAGGUCU UUAUCGUA 3713

1302 UAAGCUCA G CCGCGCCC 1461 GGGCGCGG GCCGAAAGGCGAGUCAAGGUCU UGAGCUUA 3714

1314 CGCCCUCC G UUACUACU 1462 AGUAGUAA GCCGAAAGGCGAGUCAAGGUCU GGAGGGCG 3715

1346 UGACCAAG G UCCAUGGG 1463 CCCAUGGA GCCGAAAGGCGAGUCAAGGUCU CUUGGUCA 3716

1357 GAUGGGAA G CGCUACGC 1464 GCGUAGCG GCCGAAAGGCGAGUCAAGGUCU UUCCCAUG 3717

1372 GCCUACAA G UUCGACUU 1465 AAGUCGAA GCCGAAAGGCGAGUCAAGGUCU UUGUAGGC 3718

1397 UCGCCCAG G CCCUCCAG 1466 CUGGAGGG GCCGAAAGGCGAGUCAAGGUCU CUGGGCGA 3719

1405 GCCCUCCA G CCCCACGC 1467 GGGUGGGG GCCGAAAGGCGAGUCAAGGUCU UGGAGGGC 3720

1420 CCCCCGGA G UCAUCUCU 1468 AGAGAUGA GCCGAAAGGCGAGUCAAGGUCU UCCGGGGG 3721

1435 CUGUACAA G UACCCCUC 1469 GAGGGGUA GCCGAAAGGCGAGUCAAGGUCU UUGUACAG 3722

1453 GACCUCCC G UACAUGGG 1470 CCCAUGUA GCCGAAAGGCGAGUCAAGGUCU GGGAGGUC 3723

1461 GUACAUGG G CUCCUAUC 1471 GAUAGGAG GCCGAAAGGCGAGUCAAGGUCU CCAUGUAC 3724

1499 ACUUUGUG G CGCCCCAC 1472 GUGGGGCG GCCGAAAGGCGAGUCAAGGUCU CACAAAGU 3725

1514 ACCCUCCA G CCCUCCCC 1473 GGGGAGGG GCCGAAAGGCGAGUCAAGGUCU UGGAGGGU 3726

1523 CCCUCCCC G UGACAUCU 1474 AGAUGUCA GCCGAAAGGCGAGUCAAGGUCU GGGGAGGG 3727

1536 AUCUUGCA G UUUUUUUG 1475 CAAAAAAA GCCGAAAGGCGAGUCAAGGUCU UGGAAGAU 3728

1581 AACUGGGG G UAUAUACC 1476 GGUAUAUA GCCGAAAGGCGAGUCAAGGUCU CCCCAGUU 3729

1600 AACACUAG G CUCCCCAC 1477 GUGGGGAG GCCGAAAGGCGAGUCAAGGUCU CUAGUGUU 3730

1611 CCCCACCA G CCAUAUGC 1478 GCAUAUGG GCCGAAAGGCGAGUCAAGGUCU UGGUGGGG 3731

1632 UCAUCUGG G CACUUACU 1479 AGUAAGUG GCCGAAAGGCGAGUCAAGGUCU CCAGAUGA 3732

1653 AAGACCUG G CGGAGGCU 1480 AGCCUCCG GCCGAAAGGCGAGUCAAGGUCU CAGGUCUU 3733

Table VI

1659 UGGCGGAG G CUUUUCCC 1481 GGGAAAAG GCCGAAAGGCGAGUCAAGGUCU CUCCGCCA 3734

1672 UCCCAUCA G CGUGCAUU 1482 AAUGCACG GCCGAAAGGCGAGUCAAGGUCU UGAUGGGA 3735

1674 CCAUCAGC G UGCAUUCA 1483 UGAAUGCA GCCGAAAGGCGAGUCAAGGUCU GCUGAUGG 3736

1686 AUUCACCA G CCCAUCGC 1484 GCGAUGGG GCCGAAAGGCGAGUCAAGGUCU UGGUGAAU 3737

1726 AAUCAAAA G UGCCUCAA 1485 UUGAGGCA GCCGAAAGGCGAGUCAAGGUCU UUUUGAUU 3738

1749 UGAAAAAA G CUUUACUG 1486 CAGUAAAG GCCGAAAGGCGAGUCAAGGUCU UUUUUUCA 3739

1760 UUACUGGG G CUGGGGAA 1487 UUCCCCAG GCCGAAAGGCGAGUCAAGGUCU CCCAGUAA 3740

1773 GGAAGGAA G CCGGGGAA 1488 UUCCCCGG GCCGAAAGGCGAGUCAAGGUCU UUCCUUCC 3741

1807 GGGAGGGA G UUACUGAA 1489 UUCAGUAA GCCGAAAGGCGAGUCAAGGUCU UCCCUCCC 3742

1816 UUACUGAA G UCUUACUA 1490 UAGUAAGA GCCGAAAGGCGAGUCAAGGUCU UUCAGUAA 3743

1897 AAAAGACA G UGUAUGUA 1491 UACAUACA GCCGAAAGGCGAGUCAAGGUCU UGUCUUUU 3744

1909 AUGUAGAA G CAUGAAGU 1492 ACUUCAUG GCCGAAAGGCGAGUCAAGGUCU UUCUACAU 3745

1916 AGCAUGAA G UCUUAAGG 1493 CCUUAAGA GCCGAAAGGCGAGUCAAGGUCU UUCAUGCU 3746

1930 AGGACAAA G UGCCAAAG 1494 CUUUGGCA GCCGAAAGGCGAGUCAAGGUCU UUUGUCCU 3747

1942 CAAAGAAA G UGGUCUUA 1495 UAAGACCA GCCGAAAGGCGAGUCAAGGUCU UUUCUUUG 3748

1945 AGAAAGUG G UCUUAAGA 1496 UCUUAAGA GCCGAAAGGCGAGUCAAGGUCU CACUUUCU 3749

1971 ACUUUAGA G UAGAGUUU 1497 AAACUCUA GCCGAAAGGCGAGUCAAGGUCU UCUAAAGU 3750

1976 AGAGUAGA G UUUGAAUC 1498 GAUUCAAA GCCGAAAGGCGAGUCAAGGUCU UCUACUCU 3751

2014 AAACUAAA G CAAUAGAA 1499 UUCUAUUG GCCGAAAGGCGAGUCAAGGUCU UUUAGUUU 3752

2031 ACAACACA G UUUUGACC 1500 GGUCAAAA GCCGAAAGGCGAGUCAAGGUCU UGUGUUGU 3753

2049 AACAUACC G UUUAUAAU 1501 AUUAUAAA GCCGAAAGGCGAGUCAAGGUCU GGUAUGUU 3754

2093 UAAAAAUA G UUUCAUAU 1502 AUAUGAAA GCCGAAAGGCGAGUCAAGGUCU UAUUUUUA 3755

2136 AGACUGUG G CCCAUCAA 1503 UUGAUGGG GCCGAAAGGCGAGUCAAGGUCU CACAGUCU 3756

2150 CAACAGAC G UUGAUAUG 1504 CAUAUCAA GCCGAAAGGCGAGUCAAGGUCU GUCUGUUG 3757

2169 ACUGCAUG G CAUGUGCU 1505 AGCACAUG GCCGAAAGGCGAGUCAAGGUCU CAUGCAGU 3758

2184 CUGUUUUG G UUGAAAUC 1506 GAUUUCAA GCCGAAAGGCGAGUCAAGGUCU CAAAACAG 3759

2204 UACAUUCC G UUUGAUGG 1507 CCAUCAAA GCCGAAAGGCGAGUCAAGGUCU GGAAUGUA 3760

2216 GAUGGACA G CUGUCAGC 1508 GCUGACAG GCCGAAAGGCGAGUCAAGGUCU UGUCCAUC 3761

2223 AGCUGUCA G CUUUCUCA 1509 UGAGAAAG GCCGAAAGGCGAGUCAAGGUCU UGACAGCU 3762

2252 GACCCAAA G UUUCCAAC 1510 GUUGGAAA GCCGAAAGGCGAGUCAAGGUCU UUUGGGUC 3763

2270 CCUUUACA G UAUUACCG 1511 CGGUAAUA GCCGAAAGGCGAGUCAAGGUCU UGUAAAGG 3764

2296 ACUAAAAG G UGGGACUG 1512 CAGUCCCA GCCGAAAGGCGAGUCAAGGUCU CUUUUAGU 3765

2319 UGUAUAGA G UGAGCGUG 1513 CACGCUCA GCCGAAAGGCGAGUCAAGGUCU UCUAUACA 3766

2323 UAGAGUGA G CGUGUGAU 1514 AUCACACG GCCGAAAGGCGAGUCAAGGUCU UCACUCUA 3767

2325 GAGUGAGC G UGUGAUUG 1515 CAAUCACA GCCGAAAGGCGAGUCAAGGUCU GCUCACUC 3768

2345 ACAGAGGG G UGAAGAAG 1516 CUUCUUCA GCCGAAAGGCGAGUCAAGGUCU CCCUCUGU 3769

Table VI

2366 AGGAAGAG G CAGAGAAG 1517 CUUCUCUG GCCGAAAGGCGAGUCAAGGUCU CUCUUCCU 3770

2386 GAGACCAG G CUGGGAAA 1518 UUUCCCAG GCCGAAAGGCGAGUCAAGGUCU CUGGUCUC 3771

2407 CUUCUCAA G CAAUGAAG 1519 CUUCAUUG GCCGAAAGGCGAGUCAAGGUCU UUGAGAAG 3772

2452 UACAAUGA G UUAUGGAG 1520 CUCCAUAA GCCGAAAGGCGAGUCAAGGUCU UCAUUGUA 3773

2469 ACUCGAGG G UUCAUGCA 1521 UGCAUGAA GCCGAAAGGCGAGUCAAGGUCU CCUCGAGU 3774

2478 UUCAUGCA G UCAGUGUU 1522 AACACUGA GCCGAAAGGCGAGUCAAGGUCU UGCAUGAA 3775

2482 UGCAGUCA G UGUUAUAC 1523 GUAUAACA GCCGAAAGGCGAGUCAAGGUCU UGACUGCA 3776

2499 CAAACCCA G UGUUAGGA 1524 UCCUAACA GCCGAAAGGCGAGUCAAGGUCU UGGGUUUG 3777

2519 AGGACACA G CGUAAUGG 1525 CCAUUACG GCCGAAAGGCGAGUCAAGGUCU UGUGUCCU 3778

2521 GACACAGC G UAAUGGAG 1526 CUCCAUUA GCCGAAAGGCGAGUCAAGGUCU GCUGUGUC 3779

2538 AAAGGGAA G UAGUAGAA 1527 UUCUACUA GCCGAAAGGCGAGUCAAGGUCU UUCCCUUU 3780

2541 GGGAAGUA G UAGAAUUC 1528 GAAUUCUA GCCGAAAGGCGAGUCAAGGUCU UACUUCCC 3781

2654 AUGUGGGG G CUUUGUUC 1529 GAACAAAG GCCGAAAGGCGAGUCAAGGUCU CCCCACAU 3782

2671 UCCACAGG G UCAGGUAA 1530 UUACCUGA GCCGAAAGGCGAGUCAAGGUCU CCUGUGGA 3783

2676 AGGGUCAG G UAAGAGAU 1531 AUCUCUUA GCCGAAAGGCGAGUCAAGGUCU CUGACCCU 3784

2686 AAGAGAUG G CCUUCUUG 1532 CAAGAAGG GCCGAAAGGCGAGUCAAGGUCU CAUCUCUU 3785

2695 CCUUCUUG G CUGCCACA 1533 UGUGGCAG GCCGAAAGGCGAGUCAAGGUCU CAAGAAGG 3786

2720 UCACGCAG G CAUUUUGG 1534 CCAAAAUG GCCGAAAGGCGAGUCAAGGUCU CUGCGUGA 3787

2729 CAUUUUGG G UAGGCGGC 1535 GCCGCCUA GCCGAAAGGCGAGUCAAGGUCU CCAAAAUG 3788

2733 UUGGGUAG G CGGCCUCC 1536 GGAGGCCG GCCGAAAGGCGAGUCAAGGUCU CUACCCAA 3789

2736 GGUAGGCG G CCUCCAGU 1537 ACUGGAGG GCCGAAAGGCGAGUCAAGGUCU CGCCUACC 3790

2743 GGCCUCCA G UUUUCCUU 1538 AAGGAAAA GCCGAAAGGCGAGUCAAGGUCU UGGAGGCC 3791

2755 UCCUUUGA G UCGCGAAC 1539 GUUCGCGA GCCGAAAGGCGAGUCAAGGUCU UCAAAGGA 3792

2771 CGCUGUGC G UUUGUCAG 1540 CUGACAAA GCCGAAAGGCGAGUCAAGGUCU GCACAGCG 3793

2786 AGAAUGAA G UAUACAAG 1541 CUUGUAUA GCCGAAAGGCGAGUCAAGGUCU UUCAUUCU 3794

2794 GUAUACAA G UCAAUGUU 1542 AACAUUGA GCCGAAAGGCGAGUCAAGGUCU UUGUAUAC 3795

2855 CACUACGA G UUGAUCUC 1543 GAGAUCAA GCCGAAAGGCGAGUCAAGGUCU UCGUAGUG 3796

2865 UGAUCUCG G CCAGCCAA 1544 UUGGCUGG GCCGAAAGGCGAGUCAAGGUCU CGAGAUCA 3797

2869 CUCGGCCA G CCAAAGAC 1545 GUCUUUGG GCCGAAAGGCGAGUCAAGGUCU UGGCCGAG 3798

2909 AUAAUGUG G CCUUGAAU 1546 AUUCAAGG GCCGAAAGGCGAGUCAAGGUCU CACAUUAU 3799

2952 AAUAUGAA G UUAUUAGU 1547 ACUAAUAA GCCGAAAGGCGAGUCAAGGUCU UUCAUAUU 3800

2959 AGUUAUUA G UUCUUAGA 1548 UCUAAGAA GCCGAAAGGCGAGUCAAGGUCU UAAUAACU 3801

2993 UAAAAUAA G CUUGGCCU 1549 AGGCCAAG GCCGAAAGGCGAGUCAAGGUCU UUAUUUUA 3802

2998 UAAGCUUG G CCUAGCAU 1550 AUGCUAGG GCCGAAAGGCGAGUCAAGGUCU CAAGCUUA 3803

3003 UUGGCCUA G CAUGGCAA 1551 UUGCCAUG GCCGAAAGGCGAGUCAAGGUCU UAGGCCAA 3804

3008 CUAGCAUG G CAAAUCAG 1552 CUGAUUUG GCCGAAAGGCGAGUCAAGGUCU CAUGCUAG 3805

Table VI

Input Sequence = HUMERG2. Cut Site = G/Y

Stem Length = 8 . Core Sequence = GCcgaaagGCGaGuCaaGGuCu

HUMERG2 (Human erg2 gene encoding erg2 protein, complete eds.; 3166 bp)

Table VII

Table VII: Human ERG DNAzyme and Target Sequence

Pos Substrate Seq ID Ribozyme RzSeq ID

111 UCUCGGUU A UUCCAGGA 11 TCCTGGAA GGCTAGCTACAACGA AACCGAGA 3810

247 GCUGGCUU A CUGAAGGA 25 TCCTTCAG GGCTAGCTACAACGA AAGCCAGC 3811

290 CAGCUCAU A UCAAGGAA 30 TTCCTTGA GGCTAGCTACAACGA ATGAGCTG 3812

304 GAAGCCUU A UCAGUUGU 33 ACAACTGA GGCTAGCTACAACGA AAGGCTTC 3813

345 GUGUGCCU A CGGAACGC 40 GCGTTCCG GGCTAGCTACAACGA AGGCACAC 3814

399 CAGCGACU A UGGACAGA 45 TCTGTCCA GGCTAGCTACAACGA AGTCGCTG 3815

588 GAUGAACU A CGGCAGCU 61 AGCTGCCG GGCTAGCTACAACGA AGTTCATC 3816

597 CGGCAGCU A CAUGGAGG 62 CCTCCATG GGCTAGCTACAACGA AGCTGCCG 3817

653 GCAGAGUU A UCGUGCCA 64 TGGCACGA GGCTAGCTACAACGA AACTCTGC 3818

671 CAGAUCCU A CGCUAUGG 67 CCATAGCG GGCTAGCTACAACGA AGGATCTG 3819

676 CCUACGCU A UGGAGUAC 68 GTACTCCA GGCTAGCTACAACGA AGCGTAGG 3820

683 UAUGGAGU A CAGACCAU 69 ATGGTCTG GGCTAGCTACAACGA ACTCCATA 3821

726 GAAAGAAU A UGGCCUUC 70 GAAGGCCA GGCTAGCTACAACGA ATTCTTTC 3822

754 AUCUUGUU A UUCCAGAA 77 TTCTGGAA GGCTAGCTACAACGA AACAAGAT 3823

825 CCCCAGCU A CAACGCCG 84 CGGCGTTG GGCTAGCTACAACGA AGCTGGGG 3824

858 UCUCCACU A CCUCAGAG 92 CTCTGAGG GGCTAGCTACAACGA AGTGGAGA 3825

913 AAAGCCUU A CAAAACUC 105 GAGTTTTG GGCTAGCTACAACGA AAGGCTTT 3826

955 ACAGAUUU A CCAUAUGA 113 TCATATGG GGCTAGCTACAACGA AAATCTGT 3827

960 UUUACCAU A UGAGCCCC 114 GGGGCTCA GGCTAGCTACAACGA ATGGTAAA 3828

1083 AGAUCCUU A UCAGAUUC 129 GAATCTGA GGCTAGCTACAACGA AAGGATCT 3829

1290 CAUGAACU A CGAUAAGC 151 GCTTATCG GGCTAGCTACAACGA AGTTCATG 3830

1317 CCUCCGUU A CUACUAUG 156 CATAGTAG GGCTAGCTACAACGA AACGGAGG 3831

1320 CCGUUACU A CUAUGACA 157 TGTCATAG GGCTAGCTACAACGA AGTAACGG 3832

1323 UUACUACU A UGACAAGA 158 TCTTGTCA GGCTAGCTACAACGA AGTAGTAA 3833

1362 GAAGCGCU A CGCCUACA 161 TGTAGGCG GGCTAGCTACAACGA AGCGCTTC 3834

1368 CUACGCCU A CAAGUUCG 162 CGAACTTG GGCTAGCTACAACGA AGGCGTAG 3835

1431 AUCUCUGU A CAAGUACC 172 GGTACTTG GGCTAGCTACAACGA ACAGAGAT 3836

1437 GUACAAGU A CCCCUCAG 173 CTGAGGGG GGCTAGCTACAACGA ACTTGTAC 3837

1455 CCUCCCGU A CAUGGGCU 176 AGCCCATG GGCTAGCTACAACGA ACGGGAGG 3838

1467 GGGCUCCU A UCACGCCC 178 GGGCGTGA GGCTAGCTACAACGA AGGAGCCC 3839

1560 AAACCCAU A CUGGAAUU 193 AATTCCAG GGCTAGCTACAACGA ATGGGTTT 3840

1583 CUGGGGGU A UAUACCCC 196 GGGGTATA GGCTAGCTACAACGA ACCCCCAG 3841

1585 GGGGGUAU A UACCCCAA 197 TTGGGGTA GGCTAGCTACAACGA ATACCCCC 3842

1587 GGGUAUAU A CCCCAACA 198 TGTTGGGG GGCTAGCTACAACGA ATATACCC 3843

1616 CCAGCCAU A UGCCUUCU 201 AGAAGGCA GGCTAGCTACAACGA ATGGCTGG 3844

1638 GGGCACUU A CUACUAAA 207 TTTAGTAG GGCTAGCTACAACGA AAGTGCCC 3845

1641 CACUUACU A CUAAAGAC 208 GTCTTTAG GGCTAGCTACAACGA AGTAAGTG 3846

1705 CAAACUCU A UCGGAGAA 219 TTCTCCGA GGCTAGCTACAACGA AGAGTTTG 3847

1754 AAAGCUUU A CUGGGGGU 225 AGCCCCAG GGCTAGCTACAACGA AAAGCTTT 3848

1810 AGGGAGUU A CUGAAGUC 230 GACTTCAG GGCTAGCTACAACGA AACTCCCT 3849

1821 GAAGUCUU A CUACAGAA 233 TTCTGTAG GGCTAGCTACAACGA AAGACTTC 3850

1824 GUCUUACU A CAGAAAUG 234 CATTTCTG GGCTAGCTACAACGA AGTAAGAC 3851

1859 UCACGAAU A UGGACAUA 237 TATGTCCA GGCTAGCTACAACGA ATTCGTGA 3852

1867 AUGGACAU A UCAUCUGU 238 ACAGATGA GGCTAGCTACAACGA ATGTCCAT 3853

1901 GACAGUGU A UGUAGAAG 243 CTTCTACA GGCTAGCTACAACGA ACACTGTC 3854

1959 AGAAAUGU A UAAACUUU 251 AAAGTTTA GGCTAGCTACAACGA ACATTTCT 3855

2046 CCUAACAU A CCGUUUAU 267 ATAAACGG GGCTAGCTACAACGA ATGTTAGG 3856

2053 UACCGUUU A UAAUGCCA 270 TGGCATTA GGCTAGCTACAACGA AAACGGTA 3857

2076 GGAAAACU A CCUGUAUU 276 AATACAGG GGCTAGCTACAACGA AGTTTTCC 3858

2082 CUACCUGU A UUUAAAAA 277 TTTTTAAA GGCTAGCTACAACGA ACAGGTAG 3859

2100 AGUUUCAU A UCAAAAAC 285 GTTTTTGA GGCTAGCTACAACGA ATGAAACT 3860

2156 ACGUUGAU A UGCAACUG 289 CAGTTGCA GGCTAGCTACAACGA ATCAACGT 3861 Table VII

2197 AAUCAAAU A CAUUCCGU 295 ACGGAATG GGCTAGCTACAACGA ATTTGATT 3862

2267 ACUCCUUU A CAGUAUUA 311 TAATACTG GGCTAGCTACAACGA AAAGGAGT 3863

2272 UUUACAGU A UUACCGGG 312 CCCGGTAA GGCTAGCTACAACGA ACTGTAAA 3864

2275 ACAGUAUU A CCGGGACU 314 AGTCCCGG GGCTAGCTACAACGA AATACTGT 3865

2284 CCGGGACU A UGAACUAA 315 TTAGTTCA GGCTAGCTACAACGA AGTCCCGG 3866

2314 GGAUGUGU A UAGAGUGA 317 TCACTCTA GGCTAGCTACAACGA ACACATCC 3867

2445 GACUGUGU A CAAUGAGU 327 ACTCATTG GGCTAGCTACAACGA ACACAGTC 3868

2455 AAUGAGUU A UGGAGACU 329 AGTCTCCA GGCTAGCTACAACGA AACTCATT 3869

2487 UCAGUGUU A UACCAAAC 335 GTTTGGTA GGCTAGCTACAACGA AACACTGA 3870

2489 AGUGUUAU A CCAAACCC 336 GGGTTTGG GGCTAGCTACAACGA ATAACACT 3871

2615 UGUCUGAU A UUUAAGAG 360 CTCTTAAA GGCTAGCTACAACGA ATCAGACA 3872

2646 UCAUCAUU A UGUGGGGG 369 CCCCCACA GGCTAGCTACAACGA AATGATGA 3873

2788 AAUGAAGU A UACAAGUC 397 GACTTGTA GGCTAGCTACAACGA ACTTCATT 3874

2790 UGAAGUAU A CAAGUCAA 398 TTGACTTG GGCTAGCTACAACGA ATACTTCA 3875

2816 CCCUUUUU A UAUAAUAA 409 TTATTATA GGCTAGCTACAACGA AAAAAGGG 3876

2818 CUUUUUAU A UAAUAAUU 410 AATTATTA GGCTAGCTACAACGA ATAAAAAG 3877

2827 UAAUAAUU A UAUAACUU 414 AAGTTATA GGCTAGCTACAACGA AATTATTA 3878

2829 AUAAUUAU A UAACUUAU 415 ATAAGTTA GGCTAGCTACAACGA ATAATTAT 3879

2836 UAUAACUU A UGCAUUUA 418 TAAATGCA GGCTAGCTACAACGA AAGTTATA 3880

2844 AUGCAUUU A UACACUAC 421 GTAGTGTA GGCTAGCTACAACGA AAATGCAT 3881

2846 GCAUUUAU A CACUACGA 422 TCGTAGTG GGCTAGCTACAACGA ATAAATGC 3882

2851 UAUACACU A CGAGUUGA 423 TCAACTCG GGCTAGCTACAACGA AGTGTATA 3883

2901 CAAUCGAU A UAAUGUGG 428 CCACATTA GGCTAGCTACAACGA ATCGATTG 3884

2929 AACUCUGU A UGCUUAAU 436 ATTAAGCA GGCTAGCTACAACGA ACAGAGTT 3885

2942 UAAUGUUU A CAAUAUGA 441 TCATATTG GGCTAGCTACAACGA AAACATTA 3886

2947 UUUACAAU A UGAAGUUA 442 TAACTTCA GGCTAGCTACAACGA ATTGTAAA 3887

2955 AUGAAGUU A UUAGUUCU 444 AGAACTAA GGCTAGCTACAACGA AACTTCAT 3888

2979 CAGAAUGU A UGUAAUAA 451 TTATTACA GGCTAGCTACAACGA ACATTCTG 3889

3021 UCAGAUUU A UACAGGAG 460 CTCCTGTA GGCTAGCTACAACGA AAATCTGA 3890

3023 AGAUUUAU A CAGGAGUC 461 GACTCCTG GGCTAGCTACAACGA ATAAATCT 3891

3104 UUUGUGUU A UAAUUUAC 481 GTAAATTA GGCTAGCTACAACGA AACACAAA 3892

3111 UAUAAUUU A CUUUGUCC 485 GGACAAAG GGCTAGCTACAACGA AAATTATA 3893

69 CGGGUCGC A CUAACUCC 502 GGAGTTAG GGCTAGCTACAACGA GCGACCCG 3894

172 AAUGACUC A CAGAGAAA 524 TTTCTCTG GGCTAGCTACAACGA GAGTCATT 3895

257 UGAAGGAC A UGAUUCAG 539 CTGAATCA GGCTAGCTACAACGA GTCCTTCA 3896

288 AGCAGCUC A UAUCAAGG 549 CCTTGATA GGCTAGCTACAACGA GAGCTGCT 3897

355 GGAACGCC A CACCUGGC 559 GCCAGGTG GGCTAGCTACAACGA GGCGTTCC 3898

357 AACGCCAC A CCUGGCUA 560 TAGCCAGG GGCTAGCTACAACGA GTGGCGTT 3899

424 AUGAGCCC A CGCGUCCC 579 GGGACGCG GGCTAGCTACAACGA GGGCTCAT 3900

470 CCAGGGUC A CCAUCAAA 595 TTTGATGG GGCTAGCTACAACGA GACCCTGG 3901

473 GGGUCACC A UCAAAAUG 597 CATTTTGA GGCTAGCTACAACGA GGTGACCC 3902

572 GCCCAGAC A CCGUUGGG 617 CCCAACGG GGCTAGCTACAACGA GTCTGGGC 3903

599 GCAGCUAC A UGGAGGAG 622 CTCCTCCA GGCTAGCTACAACGA GTAGCTGC 3904

612 GGAGAAGC A CAUGCCAC 623 GTGGCATG GGCTAGCTACAACGA GCTTCTCC 3905

614 AGAAGCAC A UGCCACCC 624 GGGTGGCA GGCTAGCTACAACGA GTGCTTCT 3906

619 CACAUGCC A CCCCCAAA 626 TTTGGGGG GGCTAGCTACAACGA GGCATGTG 3907

629 CCCCAAAC A UGACCACG 632 CGTGGTCA GGCTAGCTACAACGA GTTTGGGG 3908

635 AGAUGACC A CGAACGAG 634 CTCGTTCG GGCTAGCTACAACGA GGTCATGT 3909

690 UACAGACC A UGUGCGGC 644 GCCGCACA GGCTAGCTACAACGA GGTCTGTA 3910

746 ACGUCAAC A UCUUGUUA 652 TAACAAGA GGCTAGCTACAACGA GTTGACGT 3911

764 UCCAGAAC A UCGAUGGG 656 CCCATCGA GGCTAGCTACAACGA GTTCTGGA 3912

815 AGAGGCUC A CCCCCAGC 665 GCTGGGGG GGCTAGCTACAACGA GAGCCTCT 3913

836 ACGCCGAC A UCCUUCUC 674 GAGAAGGA GGCTAGCTACAACGA GTCGGCGT 3914

847 CUUCUCUC A CAUCUCCA 679 TGGAGATG GGCTAGCTACAACGA GAGAGAAG 3915

849 UCUCUCAC A UCUCCACU 680 AGTGGAGA GGCTAGCTACAACGA GTGAGAGA 3916

855 ACAUCUCC A CUACCUCA 683 TGAGGTAG GGCTAGCTACAACGA GGAGATGT 3917 Table VII

Table VII

2516 GAAAGGAC A CAGCGUAA 1061 TTACGCTG GGCTAGCTACAACGA GTCCTTTC 3974

2566 AAAUGCGC A UCUCUUUC 1065 GAAAGAGA GGCTAGCTACAACGA GCGCATTT 3975

2628 AGAGAAAC A UUCAGGAC 1072 GTCCTGAA GGCTAGCTACAACGA GTTTCTCT 3976

2640 AGGACCUC A UCAUUAUG 1076 CATAATGA GGCTAGCTACAACGA GAGGTCCT 3977

2643 ACCUCAUC A UUAUGUGG 1077 CCACATAA GGCTAGCTACAACGA GATGAGGT 3978

2666 UGUUCUCC A CAGGGUCA 1081 TGACCCTG GGCTAGCTACAACGA GGAGAACA 3979

2701 UGGCUGCC A CAAUCAGA 1089 TCTGATTG GGCTAGCTACAACGA GGCAGCCA 3980

2714 CAGAAAUC A CGCAGGCA 1092 TGCCTGCG GGCTAGCTACAACGA GATTTCTG 3981

2722 ACGCAGGC A UUUUGGGU 1094 ACCCAAAA GGCTAGCTACAACGA GCCTGCGT 3982

2840 ACUUAUGC A UUUAUACA 1111 TGTATAAA GGCTAGCTACAACGA GCATAAGT 3983

2848 AUUUAUAC A CUACGAGU 1112 ACTCGTAG GGCTAGCTACAACGA GTATAAAT 3984

2878 CCAAAGAC A CACGACAA 1119 TTGTCGTG GGCTAGCTACAACGA GTCTTTGG 3985

2880 AAAGACAC A CGACAAAA 1120 TTTTGTCG GGCTAGCTACAACGA GTGTCTTT 3986

3005 GGCCUAGC A UGGCAAAU 1134 ATTTGCCA GGCTAGCTACAACGA GCTAGGCC 3987

3035 GAGUCUGC A UUUGCACU 1139 AGTGCAAA GGCTAGCTACAACGA GCAGACTC 3988

3041 GCAUUUGC A CUUUUUUU 1140 AAAAAAAG GGCTAGCTACAACGA GCAAATGC 3989

3076 AUGAAAAC A UGUGCUGA 1144 TCAGCACA GGCTAGCTACAACGA GTTTTCAT 3990

11 CCGCGCGU G UCCGCGCC 1153 GGCGCGGA GGCTAGCTACAACGA ACGCGCGG 3991

15 GCGUGUGC G CGCCCGCG 1154 CGCGGGCG GGCTAGCTACAACGA GGACACGC 3992

17 GUGUCCGC G CCCGCGUG 1155 CACGCGGG GGCTAGCTACAACGA GCGGACAC 3993

21 CCGCGCCC G CGUGUGCC 1156 GGCACACG GGCTAGCTACAACGA GGGCGCGG 3994

25 GCCCGCGU G UGCCAGCG 1157 CGCTGGCA GGCTAGCTACAACGA ACGCGGGC 3995

27 CCGCGUGU G CCAGCGCG 1158 CGCGCTGG GGCTAGCTACAACGA ACACGCGG 3996

33 GUGCCAGC G CGCGUGCC 1159 GGCACGCG GGCTAGCTACAACGA GCTGGCAC 3997

35 GCCAGCGC G CGUGCCUU 1160 AAGGCACG GGCTAGCTACAACGA GCGCTGGC 3998

39 GCGCGCGU G CCUUGGCC 1161 GGCCAAGG GGCTAGCTACAACGA ACGCGCGC 3999

50 UUGGCCGU G CGCGCCGA 1162 TCGGCGCG GGCTAGCTACAACGA ACGGCCAA 4000

52 GGCCGUGC G CGCCGAGC 1163 GCTCGGCG GGCTAGCTACAACGA GCACGGCC 4001

54 CCGUGCGC G CCGAGCCG 1164 CGGCTCGG GGCTAGCTACAACGA GCGCACGG 4002

67 GCCGGGUC G CACUAACU 1166 AGTTAGTG GGCTAGCTACAACGA GACCCGGC 4003

84 CCCUCGGC G CCGACGGC 1167 GCCGTCGG GGCTAGCTACAACGA GCCGAGGG 4004

96 ACGGCGGC G CUAACCUC 1169 GAGGTTAG GGCTAGCTACAACGA GCCGCCGT 4005

145 AAAGCCGU G UUGACCAA 1171 TTGGTCAA GGCTAGCTACAACGA ACGGCTTT 4006

269 UUCAGACU G UCCCGGAC 1177 GTCCGGGA GGCTAGCTACAACGA AGTCTGAA 4007

311 UAUCAGUU G UGAGUGAG 1178 CTCACTCA GGCTAGCTACAACGA AACTGATA 4008

331 CAGUCGUU G UUUGAGUG 1181 CACTCAAA GGCTAGCTACAACGA AACGACTG 4009

339 GUUUGAGU G UGCCUACG 1183 CGTAGGCA GGCTAGCTACAACGA ACTCAAAC 4010

341 UUGAGUGU G CCUACGGA 1184 TCCGTAGG GGCTAGCTACAACGA ACACTCAA 4011

352 UACGGAAC G CCACACCU 1185 AGGTGTGG GGCTAGCTACAACGA GTTCCGTA 4012

380 AGAUGACC G CGUCCUCC 1187 GGAGGACG GGCTAGCTACAACGA GGTCATCT 4013

426 GAGCCCAC G CGUCCCUC 1190 GAGGGACG GGCTAGCTACAACGA GTGGGCTC 4014

448 GAUUGGCU G UCUCAACC 1191 GGTTGAGA GGCTAGCTACAACGA AGCCAATC 4015

486 AAUGGAAU G UAACCCUA 1192 TAGGGTTA GGCTAGCTACAACGA ATTCCATT 4016

531 UGAUGAAU G CAGUGUGG 1196 CCACACTG GGCTAGCTACAACGA ATTCATCA 4017

536 AAUGCAGU G UGGCCAAA 1197 . TTTGGCCA GGCTAGCTACAACGA ACTGCATT 4018

616 AAGCACAU G CCACCCCC 1199 GGGGGTGG GGCTAGCTACAACGA ATGTGCTT 4019

645 GAACGAGC G CAGAGUUA 1203 TAACTCTG GGCTAGCTACAACGA GCTCGTTC 4020

658 GUUAUCGU G CCAGCAGA 1204 TCTGCTGG GGCTAGCTACAACGA ACGATAAC 4021

673 GAUCCUAC G CUAUGGAG 1205 CTCCATAG GGCTAGCTACAACGA GTAGGATC 4022

692 CAGACCAU G UGCGGCAG 1206 CTGCCGCA GGCTAGCTACAACGA ATGGTCTG 4023

694 GACCAUGU G CGGCAGUG 1207 CACTGCCG GGCTAGCTACAACGA ACATGGTC 4024

751 AACAUCUU G UUAUUCCA 1209 TGGAATAA GGCTAGCTACAACGA AAGATGTT 4025

781 AAGGAACU G UGCAAGAU 1211 ATCTTGCA GGCTAGCTACAACGA AGTTCCTT 4026

783 GGAACUGU G CAAGAUGA 1212 TCATCTTG GGCTAGCTACAACGA ACAGTTCC 4027

830 GCUACAAC G CCGACAUC 1215 GATGTCGG GGCTAGCTACAACGA GTTGTAGC 4028

899 CAGAUGAU G UUGAUAAA 1219 TTTATCAA GGCTAGCTACAACGA ATCATCTG 4029 Table VII

934 CGGUUAAU G CAUGCUAG 1221 CTAGCATG GGCTAGCTACAACGA ATTAACCG 4030

938 UAAUGCAU G CUAGAAAC 1222 GTTTCTAG GGCTAGCTACAACGA ATGCATTA 4031

1006 CACCCCAC G CCCCAGUC 1224 GACTGGGG GGCTAGCTACAACGA GTGGGGTG 4032

1022 CGAAAGCU G CUCAACCA 1226 TGGTTGAG GGCTAGCTACAACGA AGCTTTCG 4033

1045 UCCACAGU G CCCAAAAC 1227 GTTTTGGG GGCTAGCTACAACGA ACTGTGGA 4034

1110 AAGUAGCC G CCUUGCAA 1229 TTGCAAGG GGCTAGCTACAACGA GGCTACTT 4035

1115 GCCGCCUU G CAAAUCCA 1230 TGGATTTG GGCTAGCTACAACGA AAGGCGGC 4036

1168 GAGCUCCU G UCGGACAG 1231 CTGTCCGA GGCTAGCTACAACGA AGGAGCTC 4037

1191 CUCCAGCU G CAUCACCU 1232 AGGTGATG GGCTAGCTACAACGA AGCTGGAG 4038

1254 GGCCCGGC G CUGGGGAG 1236 CTCCCCAG GGCTAGCTACAACGA GCCGGGCC 4039

1305 GCUCAGCC G CGCCCUCC 1239 GGAGGGCG GGCTAGCTACAACGA GGCTGAGC 4040

1307 UCAGCCGC G CCCUCCGU 1240 ACGGAGGG GGCTAGCTACAACGA GCGGCTGA 4041

1359 UGGGAAGC G CUACGCCU 1243 AGGCGTAG GGCTAGCTACAACGA GCTTCCCA 4042

1364 AGCGCUAC G CCUACAAG 1244 CTTGTAGG GGCTAGCTACAACGA GTAGCGCT 4043

1391 ACGGGAUC G CCCAGGCC 1246 GGCCTGGG GGCTAGCTACAACGA GATCCCGT 4044

1429 UCAUCUCU G UACAAGUA 1247 TACTTGTA GGCTAGCTACAACGA AGAGATGA 4045

1472 CCUAUCAC G CCCACCCA 1248 TGGGTGGG GGCTAGCTACAACGA GTGATAGG 4046

1496 UGAACUUU G UGGCGCCC 1250 GGGCGCCA GGCTAGCTACAACGA AAAGTTCA 4047

1501 UUUGUGGC G CCCCACCC 1251 GGGTGGGG GGCTAGCTACAACGA GCCACAAA 4048

1544 GUϋUUUUU G CUGCCCCA 1253 TGGGGCAG GGCTAGCTACAACGA AAAAAAAC 4049

1547 UUUUUGCU G CCCCAAAC 1254 GTTTGGGG GGCTAGCTACAACGA AGCAAAAA 4050

1618 AGCCAUAU G CCUUCUCA 1255 TGAGAAGG GGCTAGCTACAACGA ATATGGCT 4051

1676 AUCAGCGU G CAUUCACC 1256 GGTGAATG GGCTAGCTACAACGA ACGCTGAT 4052

1693 AGCCCAUC G CCACAAAC 1257 GTTTGTGG GGCTAGCTACAACGA GATGGGCT 4053

1728 UCAAAAGU G CCUCAAGA 1259 TCTTGAGG GGCTAGCTACAACGA ACTTTTGA 4054

1841 AGGAGGAU G CUAAAAAU 1263 ATTTTTAG GGCTAGCTACAACGA ATCCTCCT 4055

1850 CUAAAAAU G UCACGAAU 1264 ATTCGTGA GGCTAGCTACAACGA ATTTTTAG 4056

1874 UAUCAUCU G UGGACUGA 1266 TCAGTCCA GGCTAGCTACAACGA AGATGATA 4057

1887 CUGACCUU G UAAAAGAC 1268 GTCTTTTA GGCTAGCTACAACGA AAGGTCAG 4058

1899 AAGACAGU G UAUGUAGA 1269 TCTACATA GGCTAGCTACAACGA ACTGTCTT 4059

1903 CAGUGUAU G UAGAAGCA 1270 TGCTTCTA GGCTAGCTACAACGA ATACACTG 4060

1932 GACAAAGU G CCAAAGAA 1272 TTCTTTGG GGCTAGCTACAACGA ACTTTGTC 4061

1957 UAAGAAAU G UAUAAACU 1273 AGTTTATA GGCTAGCTACAACGA ATTTCTTA 4062

1993 CCACUAAU G CAAACUGG 1275 CCAGTTTG GGCTAGCTACAACGA ATTAGTGG 4063

2058 UUUAUAAU G CCAUUUUA 1278 TAAAATGG GGCTAGCTACAACGA ATTATAAA 4064

2080 AACUACCU G UAUUUAAA 1279 TTTAAATA GGCTAGCTACAACGA AGGTAGTT 4065

2133 GAGAGACU G UGGCCCAU 1281 ATGGGCCA GGCTAGCTACAACGA AGTCTCTC 4066

2158 GUUGAUAU G CAACUGCA 1283 TGCAGTTG GGCTAGCTACAACGA ATATCAAC 4067

2164 AUGCAACU G CAUGGCAU 1284 ATGCCATG GGCTAGCTACAACGA AGTTGCAT 4068

2173 CAUGGCAU G UGCUGUUU 1285 AAACAGCA GGCTAGCTACAACGA ATGCCATG 4069

2175 UGGCAUGU G CUGUUUUG 1286 CAAAACAG GGCTAGCTACAACGA ACATGCCA 4070

2178 CAUGUGCU G UUUUGGUU 1287 AACCAAAA GGCTAGCTACAACGA AGCACATG 4071

2219 GGACAGCU G UCAGCUUU 1290 AAAGCTGA GGCTAGCTACAACGA AGCTGTCC 4072

2236 CUCAAACU G UGAAGAUG 1291 CATCTTCA GGCTAGCTACAACGA AGTTTGAG 4073

2310 CUGAGGAU G UGUAUAGA 1296 TCTATACA GGCTAGCTACAACGA ATCCTCAG 4074

2312 GAGGAUGU G UAUAGAGU 1297 ACTCTATA GGCTAGCTACAACGA ACATCCTC 4075

2327 GUGAGCGU G UGAUUGUA 1299 TACAATCA GGCTAGCTACAACGA ACGCTCAC 4076

2333 GUGUGAUU G UAGACAGA 1301 TCTGTCTA GGCTAGCTACAACGA AATCACAC 4077

2441 UGGGGACU G UGUACAAU 1304 ATTGTACA GGCTAGCTACAACGA AGTCCCCA 4078

2443 GGGACUGU G UACAAUGA 1305 TCATTGTA GGCTAGCTACAACGA ACAGTCCC 4079

2475 GGGUUCAU G CAGUCAGU 1308 ACTGACTG GGCTAGCTACAACGA ATGAACCC 4080

2484 CAGUCAGU G UUAUACCA 1309 TGGTATAA GGCTAGCTACAACGA ACTGACTG 4081

2501 AACCCAGU G UUAGGAGA 1310 TCTCCTAA GGCTAGCTACAACGA ACTGGGTT 4082

2562 ACAAAAAU G CGCAUCUC 1311 GAGATGCG GGCTAGCTACAACGA ATTTTTGT 4083

2564 AAAAAUGC G CAUCUCUU 1312 AAGAGATG GGCTAGCTACAACGA GCATTTTT 4084 2578 CUUUCUUU G UUUGUCAA 1313 TTGACAAA GGCTAGCTACAACGA AAAGAAAG 4085 Table VII

2582 CUUUGUUU G UCAAAUGA 1314 TCATTTGA GGCTAGCTACAACGA AAACAAAG 4086

2608 CUGGAAUU G UCUGAUAU 1316 ATATCAGA GGCTAGCTACAACGA AATTCCAG 4087

2648 AUCAUUAU G UGGGGGCU 1318 AGCCCCCA GGCTAGCTACAACGA ATAATGAT 4088

2659 GGGGCUUU G UUCUCCAC 1319 GTGGAGAA GGCTAGCTACAACGA AAAGCCCC 4089

2698 UCUUGGCU G CCACAAUC 1320 GATTGTGG GGCTAGCTACAACGA AGCCAAGA 4090

2716 GAAAUCAC G CAGGCAUU 1321 AATGCCTG GGCTAGCTACAACGA GTGATTTC 4091

2758 UUUGAGUC G CGAACGCU 1323 AGCGTTCG GGCTAGCTACAACGA GACTCAAA 4092

2764 UCGCGAAC G CUGUGCGU 1325 ACGCACAG GGCTAGCTACAACGA GTTCGCGA 4093

2767 CGAACGCU G UGCGUUUG 1326 CAAACGCA GGCTAGCTACAACGA AGCGTTCG 4094

2769 AACGCUGU G CGUUUGUC 1327 GACAAACG GGCTAGCTACAACGA ACAGCGTT 4095

2775 GUGCGUUU G UCAGAAUG 1328 CATTCTGA GGCTAGCTACAACGA AAACGCAC 4096

2800 AAGUCAAU G UUUUUCCC 1330 GGGAAAAA GGCTAGCTACAACGA ATTGACTT 4097

2838 UAACUUAU G CAUUUAUA 1331 TATAAATG GGCTAGCTACAACGA ATAAGTTA 4098

2906 GAUAUAAU G UGGCCUUG 1336 CAAGGCCA GGCTAGCTACAACGA ATTATATC 4099

2927 UUAACUCU G UAUGCUUA 1338 TAAGCATA GGCTAGCTACAACGA AGAGTTAA 4100

2931 CUCUGUAU G CUUAAUGU 1339 ACATTAAG GGCTAGCTACAACGA ATACAGAG 4101

2938 UGCUUAAU G UUUACAAU 1340 ATTGTAAA GGCTAGCTACAACGA ATTAAGCA 4102

2970 CUUAGAAU G CAGAAUGU 1342 ACATTCTG GGCTAGCTACAACGA ATTCTAAG 4103

2977 UGCAGAAU G UAUGUAAU 1343 ATTACATA GGCTAGCTACAACGA ATTCTGCA 4104

2981 GAAUGUAU G UAAUAAAA 1344 TTTTATTA GGCTAGCTACAACGA ATACATTC 4105

3033 AGGAGUCU G CAUUUGCA 1345 TGCAAATG GGCTAGCTACAACGA AGACTCCT 4106

3039 CUGCAUUU G CACUUUUU 1346 AAAAAGTG GGCTAGCTACAACGA AAATGCAG 4107

3063 CUAAAGUU G CUUAAUGA 1348 TCATTAAG GGCTAGCTACAACGA AACTTTAG 4108

3078 GAAAACAU G UGCUGAAU 1350 ATTCAGCA GGCTAGCTACAACGA ATGTTTTC 4109

3080 AAACAUGU G CUGAAUGU 1351 ACATTCAG GGCTAGCTACAACGA ACATGTTT 4110

3087 UGCUGAAU G UUGUGGAU 1353 ATCCACAA GGCTAGCTACAACGA ATTCAGCA 4111

3090 UGAAUGUU G UGGAUUUU 1354 AAAATCCA GGCTAGCTACAACGA AACATTCA 4112

3099 UGGAUUUU G UGUUAUAA 1355 TTATAACA GGCTAGCTACAACGA AAAATCCA 4113

3101 GAUUUUGU G UUAUAAUU 1356 AATTATAA GGCTAGCTACAACGA ACAAAATC 4114

3116 UUUACUUU G UCCAGGAA 1357 TTCCTGGA GGCTAGCTACAACGA AAAGTAAA 4115

3128 AGGAACUU G UGCAAGGG 1358 CCCTTGCA GGCTAGCTACAACGA AAGTTCCT 4116

3130 GAACUUGU G CAAGGGAG 1359 CTCCCTTG GGCTAGCTACAACGA ACAAGTTC 4117

3156 AAUAGGAU G UUUGGCAC 1360 GTGCCAAA GGCTAGCTACAACGA ATCCTATT 4118

9 GUCCGCGC G UGUCCGCG 1361 CGCGGACA GGCTAGCTACAACGA GCGCGGAC 4119

23 GCGCCCGC G UGUGCCAG 1362 CTGGCACA GGCTAGCTACAACGA GCGGGCGC 4120

31 GUGUGCCA G CGCGCGUG 1363 CACGCGCG GGCTAGCTACAACGA TGGCACAC 4121

37 CAGCGCGC G UGCCUUGG 1364 CCAAGGCA GGCTAGCTACAACGA GCGCGCTG 4122

45 GUGCCUUG G CCGUGCGC 1365 GCGCACGG GGCTAGCTACAACGA CAAGGCAC 4123

48 CCUUGGCC G UGCGCGCC 1366 GGCGCGCA GGCTAGCTACAACGA GGCCAAGG 4124

59 CGCGCCGA G CCGGGUCG 1367 CGACCCGG GGCTAGCTACAACGA TCGGCGCG 4125

64 CGAGCCGG G UCGCACUA 1368 TAGTGCGA GGCTAGCTACAACGA CCGGCTCG 4126

82 CUCCCUCG G CGCCGACG 1369 CGTCGGCG GGCTAGCTACAACGA CGAGGGAG 4127

91 CGCCGACG G CGGCGCUA 1370 TAGCGCCG GGCTAGCTACAACGA CGTCGGCG 4128

94 CGACGGCG G CGCUAACC 1371 GGTTAGCG GGCTAGCTACAACGA CGCCGTCG 4129

108 ACCUCUCG G UUAUUCCA 1372 TGGAATAA GGCTAGCTACAACGA CGAGAGGT 4130

140 CGAGGAAA G CCGUGUUG 1373 CAACACGG GGCTAGCTACAACGA TTTCCTCG 4131

143 GGAAAGCC G UGUUGACC 1374 GGTCAACA GGCTAGCTACAACGA GGCTTTCC 4132

156 GACCAAAA G CAAGACAA 1375 TTGTCTTG GGCTAGCTACAACGA TTTTGGTC 4133

188 AAAAGAUG G CAGAACCA 1376 TGGTTCTG GGCTAGCTACAACGA CATCTTTT 4134

200 AACCAAGG G CAACUAAA 1377 TTTAGTTG GGCTAGCTACAACGA CCTTGGTT 4135

209 CAACUAAA G CCGUCAGG 1378 CCTGACGG GGCTAGCTACAACGA TTTAGTTG 4136

212 CUAAAGCC G UCAGGUUC 1379 GAACCTGA GGCTAGCTACAACGA GGCTTTAG 4137

217 GCCGUCAG G UUCUGAAC 1380 GTTCAGAA GGCTAGCTACAACGA CTGACGGC 4138

227 UCUGAACA G CUGGUAGA 1381 TCTACCAG GGCTAGCTACAACGA TGTTCAGA 4139

231 AACAGCUG G UAGAUGGG 1382 CCCATCTA GGCTAGCTACAACGA CAGCTGTT 4140

239 GUAGAUGG G CUGGCUUA 1383 TAAGCCAG GGCTAGCTACAACGA CCATCTAC 4141 Table VII

243 AUGGGCUG G CUUACUGA 1384 TCAGTAAG GGCTAGCTACAACGA CAGCCCAT 4142

281 CGGACCCA G CAGCUCAU 1385 ATGAGCTG GGCTAGCTACAACGA TGGGTCCG 4143

284 ACCCAGCA G CUCAUAUC 1386 GATATGAG GGCTAGCTACAACGA TGCTGGGT 4144

299 UCAAGGAA G CCUUAUCA 1387 TGATAAGG GGCTAGCTACAACGA TTCCTTGA 4145

308 CCUUAUCA G UUGUGAGU 1388 ACTCACAA GGCTAGCTACAACGA TGATAAGG 4146

315 AGUUGUGA G UGAGGACC 1389 GGTCCTCA GGCTAGCTACAACGA TCACAACT 4147

325 GAGGACCA G UCGUUGUU 1390 AACAACGA GGCTAGCTACAACGA TGGTCCTC 4148

328 GACCAGUC G UUGUUUGA 1391 TCAAACAA GGCTAGCTACAACGA GACTGGTC 4149

337 UUGUUUGA G UGUGCCUA 1392 TAGGCACA GGCTAGCTACAACGA TCAAACAA 4150

362 CACACCUG G CUAAGACA 1393 TGTCTTAG GGCTAGCTACAACGA CAGGTGTG 4151

382 AUGACCGC G UCCUCCUC 1394 GAGGAGGA GGCTAGCTACAACGA GCGGTCAT 4152

393 CUCCUCCA G CGACUAUG 1395 CATAGTCG GGCTAGCTACAACGA TGGAGGAG 4153

420 CAAGAUGA G CCCACGCG 1396 CGCGTGGG GGCTAGCTACAACGA TCATCTTG 4154

428 GCCCACGC G UCCCUCAG 1397 CTGAGGGA GGCTAGCTACAACGA GCGTGGGC 4155

436 GUCCCUCA G CAGGAUUG 1398 CAATCCTG GGCTAGCTACAACGA TGAGGGAC 4156

445 CAGGAUUG G CUGUCUCA 1399 TGAGACAG GGCTAGCTACAACGA CAATCCTG 4157

461 AACCCCCA G CCAGGGUC 1400 GACCCTGG GGCTAGCTACAACGA TGGGGGTT 4158

467 CAGCCAGG G UCACCAUC 1401 GATGGTGA GGCTAGCTACAACGA CCTGGCTG 4159

495 UAACCCUA G CCAGGUGA 1402 TCACCTGG GGCTAGCTACAACGA TAGGGTTA 4160

500 CUAGCCAG G UGAAUGGC 1403 GCCATTCA GGCTAGCTACAACGA CTGGCTAG 4161

507 GGUGAAUG G CUCAAGGA 1404 TCCTTGAG GGCTAGCTACAACGA CATTCACC 4162

534 UGAAUGCA G UGUGGCCA 1405 TGGCCACA GGCTAGCTACAACGA TGCATTCA 4163

539 GCAGUGUG G CCAAAGGC 1406 GCCTTTGG GGCTAGCTACAACGA CACACTGC 4164

546 GGCCAAAG G CGGGAAGA 1407 TCTTCCCG GGCTAGCTACAACGA CTTTGGCC 4165

557 GGAAGAUG G UGGGCAGC 1408 GCTGCCCA GGCTAGCTACAACGA CATCTTCC 4166

561 GAUGGUGG G CAGCCCAG 1409 CTGGGCTG GGCTAGCTACAACGA CCACCATC 4167

564 GGUGGGCA G CCCAGACA 1410 TGTCTGGG GGCTAGCTACAACGA TGCCCACC 4168

575 CAGACACC G UUGGGAUG 1411 CATCCCAA GGCTAGCTACAACGA GGTGTCTG 4169

591 GAACUACG G CAGCUACA 1412 TGTAGCTG GGCTAGCTACAACGA CGTAGTTC 4170

594 CUACGGCA G CUACAUGG 1413 CCATGTAG GGCTAGCTACAACGA TGCCGTAG 4171

610 GAGGAGAA G CACAUGCC 1414 GGCATGTG GGCTAGCTACAACGA TTCTCCTC 4172

643 ACGAACGA G CGCAGAGU 1415 ACTCTGCG GGCTAGCTACAACGA TCGTTCGT 4173

650 AGCGCAGA G UUAUCGUG 1416 CACGATAA GGCTAGCTACAACGA TCTGCGCT 4174

656 GAGUUAUC G UGCCAGCA 1417 TGCTGGCA GGCTAGCTACAACGA GATAACTC 4175

662 UCGUGCCA G CAGAUCCU 1418 AGGATCTG GGCTAGCTACAACGA TGGCACGA 4176

681 GCUAUGGA G UACAGACC 1419 GGTCTGTA GGCTAGCTACAACGA TCCATAGC 4177

697 CAUGUGCG G CAGUGGCU 1420 AGCCACTG GGCTAGCTACAACGA CGCACATG 4178

700 GUGCGGCA G UGGCUGGA 1421 TCCAGCCA GGCTAGCTACAACGA TGCCGCAC 4179

703 CGGCAGUG G CUGGAGUG 1422 CACTCCAG GGCTAGCTACAACGA CACTGCCG 4180

709 UGGCUGGA G UGGGCGGU 1423 ACCGCCCA GGCTAGCTACAACGA TCCAGCCA 4181

713 UGGAGUGG G CGGUGAAA 1424 TTTCACCG GGCTAGCTACAACGA CCACTCCA 4182

716 AGUGGGCG G UGAAAGAA 1425 TTCTTTCA GGCTAGCTACAACGA CGCCCACT 4183

729 AGAAUAUG G CCUUCCAG 1426 CTGGAAGG GGCTAGCTACAACGA CATATTCT 4184

740 UUCCAGAC G UCAACAUC 1427 GATGTTGA GGCTAGCTACAACGA GTCTGGAA 4185

811 UUCCAGAG G CUCACCCC 1428 GGGGTGAG GGCTAGCTACAACGA CTCTGGAA 4186

822 CACCCCCA G CUACAACG 1429 CGTTGTAG GGCTAGCTACAACGA TGGGGGTG 4187

908 UUGAUAAA G CCUUACAA 1430 TTGTAAGG GGCTAGCTACAACGA TTTATCAA 4188

928 UCUCCACG G UUAAUGCA 1431 TGCATTAA GGCTAGCTACAACGA CGTGGAGA 4189

964 CCAUAUGA G CCCCCCAG 1432 CTGGGGGG GGCTAGCTACAACGA TCATATGG 4190

980 GGAGAUCA G CCUGGACC 1433 GGTCCAGG GGCTAGCTACAACGA TGATCTCC 4191

990 CUGGACCG G UCACGGCC 1434 GGCCGTGA GGCTAGCTACAACGA CGGTCCAG 4192

996 CGGUCACG G CCACCCCA 1435 TGGGGTGG GGCTAGCTACAACGA CGTGACCG 4193

1012 ACGCCCCA G UCGAAAGC 1436 GCTTTCGA GGCTAGCTACAACGA TGGGGCGT 4194

1019 AGUCGAAA G CUGCUCAA 1437 TTGAGCAG GGCTAGCTACAACGA TTTCGACT 4195

1043 CUUCCACA G UGCCCAAA 1438 TTTGGGCA GGCTAGCTACAACGA TGTGGAAG 4196

1063 GAAGACCA G CGUCCUCA 1439 TGAGGACG GGCTAGCTACAACGA TGGTCTTC 4197 Table VII

1065 AGACCAGC G UCCUCAGU 1440 ACTGAGGA GGCTAGCTACAACGA GCTGGTCT 4198

1072 CGUCCUCA G UUAGAUCC 1441 GGATCTAA GGCTAGCTACAACGA TGAGGACG 4199

1104 ACCAACAA G UAGCCGCC 1442 GGCGGCTA GGCTAGCTACAACGA TTGTTGGT 4200

1107 AACAAGUA G CCGCCUUG 1443 CAAGGCGG GGCTAGCTACAACGA TACTTGTT 4201

1125 AAAUCCAG G CAGUGGCC 1444 GGCCACTG GGCTAGCTACAACGA CTGGATTT 4202

1128 UCCAGGCA G UGGCCAGA 1445 TCTGGCCA GGCTAGCTACAACGA TGCCTGGA 4203

1131 AGGCAGUG G CCAGAUCC 1446 GGATCTGG GGCTAGCTACAACGA CACTGCCT 4204

1141 CAGAUCCA G CUUUGGCA 1447 TGCCAAAG GGCTAGCTACAACGA TGGATCTG 4205

1147 CAGCUUUG G CAGUUCCU 1448 AGGAACTG GGCTAGCTACAACGA CAAAGCTG 4206

1150 CUUUGGCA G UUCCUCCU 1449 AGGAGGAA GGCTAGCTACAACGA TGCCAAAG 4207

1162 CUCCUGGA G CUCCUGUC 1450 GACAGGAG GGCTAGCTACAACGA TCCAGGAG 4208

1176 GUCGGACA G CUCCAACU 1451 AGTTGGAG GGCTAGCTACAACGA TGTCCGAC 4209

1188 CAACUCCA G CUGCAUCA 1452 TGATGCAG GGCTAGCTACAACGA TGGAGTTG 4210

1206 CUGGGAAG G CACCAACG 1453 CGTTGGTG GGCTAGCTACAACGA CTTCCCAG 4211

1219 AACGGGGA G UUCAAGAU 1454 ATCTTGAA GGCTAGCTACAACGA TCCCCGTT 4212

1244 CCGACGAG G UGGCCCGG 1455 CCGGGCCA GGCTAGCTACAACGA CTCGTCGG 4213

1247 ACGAGGUG G CCCGGCGC 1456 GCGCCGGG GGCTAGCTACAACGA CACCTCGT 4214

1252 GUGGCCCG G CGCUGGGG 1457 CCCCAGCG GGCTAGCTACAACGA CGGGCCAC 4215

1264 UGGGGAGA G CGGAAGAG 1458 CTCTTCCG GGCTAGCTACAACGA TCTCCCCA 4216

1272 GCGGAAGA G CAAACCCA 1459 TGGGTTTG GGCTAGCTACAACGA TCTTCCGC 4217

1297 UACGAUAA G CUCAGCCG 1460 CGGCTGAG GGCTAGCTACAACGA TTATCGTA 4218

1302 UAAGCUCA G CCGCGCCC 1461 GGGCGCGG GGCTAGCTACAACGA TGAGCTTA 4219

1314 CGCCCUCC G UUACUACU 1462 AGTAGTAA GGCTAGCTACAACGA GGAGGGCG 4220

1346 UGACCAAG G UCCAUGGG 1463 CCCATGGA GGCTAGCTACAACGA CTTGGTCA 4221

1357 GAUGGGAA G CGCUACGC 1464 GCGTAGCG GGCTAGCTACAACGA TTCCCATG 4222

1372 GCCUACAA G UUCGACUU 1465 AAGTCGAA GGCTAGCTACAACGA TTGTAGGC 4223

1397 UCGCCCAG G CCCUCCAG 1466 CTGGAGGG GGCTAGCTACAACGA CTGGGCGA 4224

1405 GCCCUCCA G CCCCACCC 1467 GGGTGGGG GGCTAGCTACAACGA TGGAGGGC 4225

1420 CCCCCGGA G UCAUCUCU 1468 AGAGATGA GGCTAGCTACAACGA TCCGGGGG 4226

1435 CUGUACAA G UACCCCUC 1469 GAGGGGTA GGCTAGCTACAACGA TTGTACAG 4227

1453 GACCUCCC G UACAUGGG 1470 CCCATGTA GGCTAGCTACAACGA GGGAGGTC 4228

1461 GUACAUGG G CUCCUAUC 1471 GATAGGAG GGCTAGCTACAACGA CCATGTAC 4229

1499 ACUUUGUG G CGCCCCAC 1472 GTGGGGCG GGCTAGCTACAACGA CACAAAGT 4230

1514 ACCCUCCA G CCCUCCCC 1473 GGGGAGGG GGCTAGCTACAACGA TGGAGGGT 4231

1523 CCCUCCCC G UGACAUCU 1474 AGATGTCA GGCTAGCTACAACGA GGGGAGGG 4232

1536 AUCUUCCA G UUUUUUUG 1475 CAAAAAAA GGCTAGCTACAACGA TGGAAGAT 4233

1581 AACUGGGG G UAUAUACC 1476 GGTATATA GGCTAGCTACAACGA CCCCAGTT 4234

1600 AACACUAG G CUCCCCAC 1477 GTGGGGAG GGCTAGCTACAACGA CTAGTGTT 4235

1611 CCCCACCA G CCAUAUGC 1478 GCATATGG GGCTAGCTACAACGA TGGTGGGG 4236

1632 UCAUCUGG G CACUUACU 1479 AGTAAGTG GGCTAGCTACAACGA CCAGATGA 4237

1653 AAGACCUG G CGGAGGCU 1480 AGCCTCCG GGCTAGCTACAACGA CAGGTCTT 4238

1659 UGGCGGAG G CUUUUCCC 1481 GGGAAAAG GGCTAGCTACAACGA CTCCGCCA 4239

1672 UCCCAUCA G CGUGCAUU 1482 AATGCACG GGCTAGCTACAACGA TGATGGGA 4240

1674 CCAUCAGC G UGCAUUCA 1483 TGAATGCA GGCTAGCTACAACGA GCTGATGG 4241

1686 AUUCAGCA G CCCAUCGC 1484 GCGATGGG GGCTAGCTACAACGA TGGTGAAT 4242

1726 AAUCAAAA G UGCCUCAA 1485 TTGAGGCA GGCTAGCTACAACGA TTTTGATT 4243

1749 UGAAAAAA G CUUUACUG 1486 CAGTAAAG GGCTAGCTACAACGA TTTTTTCA 4244

1760 UUACUGGG G CUGGGGAA 1487 TTCCCCAG GGCTAGCTACAACGA CCCAGTAA 4245

1773 GGAAGGAA G CCGGGGAA 1488 TTCCCCGG GGCTAGCTACAACGA TTCCTTCC 4246

1807 GGGAGGGA G UUACUGAA 1489 TTCAGTAA GGCTAGCTACAACGA TCCCTCCC 4247

1816 UUACUGAA G UCUUACUA 1490 TAGTAAGA GGCTAGCTACAACGA TTCAGTAA 4248

1897 AAAAGACA G UGUAUGUA 1491 TACATACA GGCTAGCTACAACGA TGTCTTTT 4249

1909 AUGUAGAA G CAUGAAGU 1492 ACTTCATG GGCTAGCTACAACGA TTCTACAT 4250

1916 AGCAUGAA G UCUUAAGG 1493 CCTTAAGA GGCTAGCTACAACGA TTCATGCT 4251

1930 AGGACAAA G UGCCAAAG 1494 CTTTGGCA GGCTAGCTACAACGA TTTGTCCT 4252

1942 CAAAGAAA G UGGUCUUA 1495 TAAGACCA GGCTAGCTACAACGA TTTCTTTG 4253 Table VII

1945 AGAAAGUG G UCUUAAGA 1496 TCTTAAGA GGCTAGCTACAACGA CACTTTCT 4254

1971 ACUUUAGA G UAGAGUUU 1497 AAACTCTA GGCTAGCTACAACGA TCTAAAGT 4255

1976 AGAGUAGA G UUUGAAUC 1498 GATTCAAA GGCTAGCTACAACGA TCTACTCT 4256

2014 AAACUAAA G CAAUAGAA 1499 TTCTATTG GGCTAGCTACAACGA TTTAGTTT 4257

2031 ACAACACA G UUUUGACC 1500 GGTCAAAA GGCTAGCTACAACGA TGTGTTGT 4258

2049 AACAUACC G UUUAUAAU 1501 ATTATAAA GGCTAGCTACAACGA GGTATGTT 4259

2093 UAAAAAUA G UUUCAUAU 1502 ATATGAAA GGCTAGCTACAACGA TATTTTTA 4260

2136 AGACUGUG G CCCAUCAA 1503 TTGATGGG GGCTAGCTACAACGA CACAGTCT 4261

2150 CAACAGAC G UUGAUAUG 1504 CATATCAA GGCTAGCTACAACGA GTCTGTTG 4262

2169 ACUGCAUG G CAUGUGCU 1505 AGCACATG GGCTAGCTACAACGA CATGCAGT 4263

2184 CUGUUUUG G UUGAAAUC 1506 GATTTCAA GGCTAGCTACAACGA CAAAACAG 4264

2204 UACAUUCC G UUUGAUGG 1507 CCATCAAA GGCTAGCTACAACGA GGAATGTA 4265

2216 GAUGGACA G CUGUCAGC 1508 GCTGACAG GGCTAGCTACAACGA TGTCCATC 4266

2223 AGCUGUCA G CUUUCUCA 1509 TGAGAAAG GGCTAGCTACAACGA TGACAGCT 4267

2252 GACCCAAA G UUUCCAAC 1510 GTTGGAAA GGCTAGCTACAACGA TTTGGGTC 4268

2270 CCUUUACA G UAUUACCG 1511 CGGTAATA GGCTAGCTACAACGA TGTAAAGG 4269

2296 ACUAAAAG G UGGGACUG 1512 CAGTCCCA GGCTAGCTACAACGA CTTTTAGT 4270

2319 UGUAUAGA G UGAGCGUG 1513 CACGCTCA GGCTAGCTACAACGA TCTATACA 4271

2323 UAGAGUGA G CGUGUGAU 1514 ATCACACG GGCTAGCTACAACGA TCACTCTA 4272

2325 GAGUGAGC G UGUGAUUG 1515 CAATCACA GGCTAGCTACAACGA GCTCACTC 4273

2345 ACAGAGGG G UGAAGAAG 1516 CTTCTTCA GGCTAGCTACAACGA CCCTCTGT 4274

2366 AGGAAGAG G CAGAGAAG 1517 CTTCTCTG GGCTAGCTACAACGA CTCTTCCT 4275

2386 GAGACCAG G CUGGGAAA 1518 TTTCCCAG GGCTAGCTACAACGA CTGGTCTC 4276

2407 CUUCUCAA G CAAUGAAG 1519 CTTCATTG GGCTAGCTACAACGA TTGAGAAG 4277

2452 UACAAUGA G UUAUGGAG 1520 CTCCATAA GGCTAGCTACAACGA TCATTGTA 4278

2469 ACUCGAGG G UUCAUGCA 1521 TGCATGAA GGCTAGCTACAACGA CCTCGAGT 4279

2478 UUCAUGCA G UCAGUGUU 1522 AACACTGA GGCTAGCTACAACGA TGCATGAA 4280

2482 UGCAGUCA G UGUUAUAC 1523 GTATAACA GGCTAGCTACAACGA TGACTGCA 4281

2499 CAAACCCA G UGUUAGGA 1524 TCCTAACA GGCTAGCTACAACGA TGGGTTTG 4282

2519 AGGACACA G CGUAAUGG 1525 CCATTACG GGCTAGCTACAACGA TGTGTCCT 4283

2521 GACACAGC G UAAUGGAG 1526 CTCCATTA GGCTAGCTACAACGA GCTGTGTC 4284

2538 AAAGGGAA G UAGUAGAA 1527 TTCTACTA GGCTAGCTACAACGA TTCCCTTT 4285

2541 GGGAAGUA G UAGAAUUC 1528 GAATTCTA GGCTAGCTACAACGA TACTTCCC 4286

2654 AUGUGGGG G CUUUGUUC 1529 GAACAAAG GGCTAGCTACAACGA CCCCACAT 4287

2671 UCCACAGG G UCAGGUAA 1530 TTACCTGA GGCTAGCTACAACGA CCTGTGGA 4288

2676 AGGGUCAG G UAAGAGAU 1531 ATCTCTTA GGCTAGCTACAACGA CTGACCCT 4289

2686 AAGAGAUG G CCUUCUUG 1532 CAAGAAGG GGCTAGCTACAACGA CATCTCTT 4290

2695 CCUUCUUG G CUGCCACA 1533 TGTGGCAG GGCTAGCTACAACGA CAAGAAGG 4291

2720 UCACGCAG G CAUUUUGG 1534 CCAAAATG GGCTAGCTACAACGA CTGCGTGA 4292

2729 CAUUUUGG G UAGGCGGC 1535 GCCGCCTA GGCTAGCTACAACGA CCAAAATG 4293

2733 UUGGGUAG G CGGCCUCC 1536 GGAGGCCG GGCTAGCTACAACGA CTACCCAA 4294

2736 GGUAGGCG G CCUCCAGU 1537 ACTGGAGG GGCTAGCTACAACGA CGCCTACC 4295

2743 GGCCUCCA G UUUUCCUU 1538 AAGGAAAA GGCTAGCTACAACGA TGGAGGCC 4296

2755 UCCUUUGA G UCGCGAAC 1539 GTTCGCGA GGCTAGCTACAACGA TCAAAGGA 4297

2771 CGCUGUGC G UUUGUCAG 1540 CTGACAAA GGCTAGCTACAACGA GCACAGCG 4298

2786 AGAAUGAA G UAUACAAG 1541 CTTGTATA GGCTAGCTACAACGA TTCATTCT 4299

2794 GUAUACAA G UCAAUGUU 1542 AACATTGA GGCTAGCTACAACGA TTGTATAC 4300

2855 CACUACGA G UUGAUCUC 1543 GAGATCAA GGCTAGCTACAACGA TCGTAGTG 4301

2865 UGAUCUCG G CCAGCCAA 1544 TTGGCTGG GGCTAGCTACAACGA CGAGATCA 4302

2869 CUCGGCCA G CCAAAGAC 1545 GTCTTTGG GGCTAGCTACAACGA TGGCCGAG 4303

2909 AUAAUGUG G CCUUGAAU 1546 ATTCAAGG GGCTAGCTACAACGA CACATTAT 4304

2952 AAUAUGAA G UUAUUAGU 1547 ACTAATAA GGCTAGCTACAACGA TTCATATT 4305

2959 AGUUAUUA G UUCUUAGA 1548 TCTAAGAA GGCTAGCTACAACGA TAATAACT 4306

2993 UAAAAUAA G CUUGGCCU 1549 AGGCCAAG GGCTAGCTACAACGA TTATTTTA 4307

2998 UAAGCUUG G CCUAGCAU 1550 ATGCTAGG GGCTAGCTACAACGA CAAGCTTA 4308

3003 UUGGCCUA G CAUGGCAA 1551 TTGCCATG GGCTAGCTACAACGA TAGGCCAA 4309 Table Vπ

3008 CUAGCAUG G CAAAUCAG 1552 CTGATTTG GGCTAGCTACAACGA CATGCTAG 4310

3029 AUACAGGA G UCUGCAUU 1553 AATGCAGA GGCTAGCTACAACGA TCCTGTAT 4311

3051 UUUUUUUA G UGACUAAA 1554 TTTAGTCA GGCTAGCTACAACGA TAAAAAAA 4312

3060 UGACUAAA G UUGCUUAA 1555 TTAAGCAA GGCTAGCTACAACGA TTTAGTCA 4313

3140 AAGGGAGA G CCAAGGAA 1556 TTCCTTGG GGCTAGCTACAACGA TCTCCCTT 4314

73 UCGCACUA A CUCCCUCG 1557 CGAGGGAG GGCTAGCTACAACGA TAGTGCGA 4315

88 CGGCGCCG A CGGCGGCG 1558 CGCCGCCG GGCTAGCTACAACGA CGGCGCCG 4316

100 CGGCGCUA A CCUCUCGG 1559 CCGAGAGG GGCTAGCTACAACGA TAGCGCCG 4317

119 AUUCCAGG A UCUUUGGA 1560 TCCAAAGA GGCTAGCTACAACGA CCTGGAAT 4318

129 CUUUGGAG A CCCGAGGA 1561 TCCTCGGG GGCTAGCTACAACGA CTCCAAAG 4319

149 CCGUGUUG A CCAAAAGC 1562 GCTTTTGG GGCTAGCTACAACGA CAACACGG 4320

161 AAAGCAAG A CAAAUGAC 1563 GTCATTTG GGCTAGCTACAACGA CTTGCTTT 4321

165 CAAGACAA A UGACUCAC 1564 GTGAGTCA GGCTAGCTACAACGA TTGTCTTG 4322

168 GACAAAUG A CUCACAGA 1565 TCTGTGAG GGCTAGCTACAACGA CATTTGTC 4323

185 GAAAAAAG A UGGCAGAA 1566 TTCTGCCA GGCTAGCTACAACGA CTTTTTTC 4324

193 AUGGCAGA A CCAAGGGC 1567 GCCCTTGG GGCTAGCTACAACGA TCTGCCAT 4325

203 CAAGGGCA A CUAAAGCC 1568 GGCTTTAG GGCTAGCTACAACGA TGCCCTTG 4326

224 GGUUCUGA A CAGCUGGU 1569 ACCAGCTG GGCTAGCTACAACGA TCAGAACC 4327

235 GCUGGUAG A UGGGCUGG 1570 CCAGCCCA GGCTAGCTACAACGA CTACCAGC 4328

255 ACUGAAGG A CAUGAUUC 1571 GAATCATG GGCTAGCTACAACGA CCTTCAGT 4329

260 AGGACAUG A UUCAGACU 1572 AGTCTGAA GGCTAGCTACAACGA CATGTCCT 4330

266 UGAUUCAG A CUGUCCCG 1573 CGGGACAG GGCTAGCTACAACGA CTGAATCA 4331

276 UGUCCCGG A CCCAGCAG 1574 CTGCTGGG GGCTAGCTACAACGA CCGGGACA 4332

321 GAGUGAGG A CCAGUCGU 1575 ACGACTGG GGCTAGCTACAACGA CCTCACTC 4333

350 CCUACGGA A CGCCACAC 1576 GTGTGGCG GGCTAGCTACAACGA TCCGTAGG 4334

368 UGGCUAAG A CAGAGAUG 1577 CATCTCTG GGCTAGCTACAACGA CTTAGCCA 4335

374 AGACAGAG A UGACCGCG 1578 CGCGGTCA GGCTAGCTACAACGA CTCTGTCT 4336

377 CAGAGAUG A CCGCGUCC 1579 GGACGCGG GGCTAGCTACAACGA CATCTCTG 4337

396 CUCCAGCG A CUAUGGAC 1580 GTCCATAG GGCTAGCTACAACGA CGCTGGAG 4338

403 GACUAUGG A CAGACUUC 1581 GAAGTCTG GGCTAGCTACAACGA CCATAGTC 4339

407 AUGGACAG A CUUCCAAG 1582 CTTGGAAG GGCTAGCTACAACGA CTGTCCAT 4340

416 CUUCCAAG A UGAGCCCA 1583 TGGGCTCA GGCTAGCTACAACGA CTTGGAAG 4341

441 UCAGCAGG A UUGGCUGU 1584 ACAGCCAA GGCTAGCTACAACGA CCTGCTGA 4342

454 CUGUCUCA A CCCCCAGC 1585 GCTGGGGG GGCTAGCTACAACGA TGAGACAG 4343

479 CCAUCAAA A UGGAAUGU 1586 ACATTCCA GGCTAGCTACAACGA TTTGATGG 4344

484 AAAAUGGA A UGUAACCC 1587 GGGTTACA GGCTAGCTACAACGA TCCATTTT 4345

489 GGAAUGUA A CCCUAGCC 1588 GGCTAGGG GGCTAGCTACAACGA TACATTCC 4346

504 CCAGGUGA A UGGCUCAA 1589 TTGAGCCA GGCTAGCTACAACGA TCACCTGG 4347

516 CUCAAGGA A CUCUCCUG 1590 CAGGAGAG GGCTAGCTACAACGA TCCTTGAG 4348

525 CUCUCCUG A UGAAUGCA 1591 TGCATTCA GGCTAGCTACAACGA CAGGAGAG 4349

529 CCUGAUGA A UGCAGUGU 1592 ACACTGCA GGCTAGCTACAACGA TCATCAGG 4350

554 GCGGGAAG A UGGUGGGC 1593 GCCCACCA GGCTAGCTACAACGA CTTCCCGC 4351

570 CAGCCCAG A CACCGUUG 1594 CAACGGTG GGCTAGCTACAACGA CTGGGCTG 4352

581 CCGUUGGG A UGAACUAC 1595 GTAGTTCA GGCTAGCTACAACGA CCCAACGG 4353

585 UGGGAUGA A CUACGGCA 1596 TGCCGTAG GGCTAGCTACAACGA TCATCCCA 4354

627 ACCCCCAA A CAUGACCA 1597 TGGTCATG GGCTAGCTACAACGA TTGGGGGT 4355

632 CAAACAUG A CCACGAAC 1598 GTTCGTGG GGCTAGCTACAACGA CATGTTTG 4356

639 GACCACGA A CGAGCGCA 1599 TGCGCTCG GGCTAGCTACAACGA TCGTGGTC 4357

666 GCCAGCAG A UCCUACGC 1600 GCGTAGGA GGCTAGCTACAACGA CTGCTGGC 4358

687 GAGUACAG A CCAUGUGC 1601 GCACATGG GGCTAGCTACAACGA CTGTACTC 4359

724 GUGAAAGA A UAUGGCCU 1602 AGGCCATA GGCTAGCTACAACGA TCTTTCAC 4360

738 CCUUCCAG A CGUCAACA 1603 TGTTGACG GGCTAGCTACAACGA CTGGAAGG 4361

744 AGACGUCA A CAUCUUGU 1604 ACAAGATG GGCTAGCTACAACGA TGACGTCT 4362

762 AUUCCAGA A CAUCGAUG 1605 CATCGATG GGCTAGCTACAACGA TCTGGAAT 4363

768 GAACAUCG A UGGGAAGG 1606 CCTTCCCA GGCTAGCTACAACGA CGATGTTC 4364

778 GGGAAGGA A CUGUGCAA 1607 TTGCACAG GGCTAGCTACAACGA TCCTTCCC 4365 Table VII

788 UGUGCAAG A UGACCAAG 1608 CTTGGTCA GGCTAGCTACAACGA CTTGCACA 4366

791 GCAAGAUG A CCAAGGAC 1609 GTCCTTGG GGCTAGCTACAACGA CATCTTGC 4367

798 GACCAAGG A CGACUUCC 1610 GGAAGTCG GGCTAGCTACAACGA CCTTGGTC 4368

801 CAAGGACG A CUUCCAGA 1611 TCTGGAAG GGCTAGCTACAACGA CGTCCTTG 4369

828 CAGCUACA A CGCCGACA 1612 TGTCGGCG GGCTAGCTACAACGA TGTAGCTG 4370

834 CAACGCCG A CAUCCUUC 1613 GAAGGATG GGCTAGCTACAACGA CGGCGTTG 4371

869 UCAGAGAG A CUCCUCUU 1614 AAGAGGAG GGCTAGCTACAACGA CTCTCTGA 4372

887 CACAUUUG A CUUCAGAU 1615 ATCTGAAG GGCTAGCTACAACGA CAAATGTG 4373

894 GACUUCAG A UGAUGUUG 1616 CAACATCA GGCTAGCTACAACGA CTGAAGTC 4374

897 UUCAGAUG A UGUUGAUA 1617 TATCAACA GGCTAGCTACAACGA CATCTGAA 4375

903 UGAUGUUG A UAAAGCCU 1618 AGGCTTTA GGCTAGCTACAACGA CAACATCA 4376

918 CUUACAAA A CUCUCCAC 1619 GTGGAGAG GGCTAGCTACAACGA TTTGTAAG 4377

932 CACGGUUA A UGCAUGCU 1620 AGCATGCA GGCTAGCTACAACGA TAACCGTG 4378

945 UGCUAGAA A CACAGAUU 1621 AATCTGTG GGCTAGCTACAACGA TTCTAGCA 4379

951 AAACACAG A UUUACCAU 1622 ATGGTAAA GGCTAGCTACAACGA CTGTGTTT 4380

976 CCCAGGAG A UCAGCCUG 1623 CAGGCTGA GGCTAGCTACAACGA CTCCTGGG 4381

986 CAGCCUGG A CCGGUCAC 1624 GTGACCGG GGCTAGCTACAACGA CCAGGCTG 4382

1027 GCUGCUCA A CCAUCUCC 1625 GGAGATGG GGCTAGCTACAACGA TGAGCAGC 4383

1052 UGCCCAAA A CUGAAGAC 1626 GTCTTCAG GGCTAGCTACAACGA TTTGGGCA 4384

1059 AACUGAAG A CCAGCGUC 1627 GACGCTGG GGCTAGCTACAACGA CTTCAGTT 4385

1077 UCAGUUAG A UCCUUAUC 1628 GATAAGGA GGCTAGCTACAACGA CTAACTGA 4386

1088 CUUAUCAG A UUCUUGGA 1629 TCCAAGAA GGCTAGCTACAACGA CTGATAAG 4387

1096 AUUCUUGG A CCAACAAG 1630 CTTGTTGG GGCTAGCTACAACGA CCAAGAAT 4388

1100 UUGGACCA A CAAGUAGC 1631 GCTACTTG GGCTAGCTACAACGA TGGTCCAA 4389

1119 CCUUGCAA A UCCAGGCA 1632 TGCCTGGA GGCTAGCTACAACGA TTGCAAGG 4390

1136 GUGGCCAG A UCCAGCUU 1633 AAGCTGGA GGCTAGCTACAACGA CTGGCCAC 4391

1173 CCUGUCGG A CAGCUCCA 1634 TGGAGCTG GGCTAGCTACAACGA CCGACAGG 4392

1182 CAGCUCCA A CUCCAGCU 1635 AGCTGGAG GGCTAGCTACAACGA TGGAGCTG 4393

1212 AGGCACCA A CGGGGAGU 1636 ACTCCCCG GGCTAGCTACAACGA TGGTGCCT 4394

1226 AGUUCAAG A UGACGGAU 1637 ATCCGTCA GGCTAGCTACAACGA CTTGAACT 4395

1229 UCAAGAUG A CGGAUCCC 1638 GGGATCCG GGCTAGCTACAACGA CATCTTGA 4396

1233 GAUGACGG A UCCCGACG 1639 CGTCGGGA GGCTAGCTACAACGA CCGTCATC 4397

1239 GGAUCCCG A CGAGGUGG 1640 CCACCTCG GGCTAGCTACAACGA CGGGATCC 4398

1276 AAGAGCAA A CCCAACAU 1641 ATGTTGGG GGCTAGCTACAACGA TTGCTCTT 4399

1281 CAAACCCA A GAUGAACU 1642 AGTTCATG GGCTAGCTACAACGA TGGGTTTG 4400

1287 CAACAUGA A CUACGAUA 1643 TATCGTAG GGCTAGCTACAACGA TCATGTTG 4401

1293 GAACUACG A UAAGCUCA 1644 TGAGCTTA GGCTAGCTACAACGA CGTAGTTC 4402

1326 CUACUAUG A CAAGAACA 1645 TGTTCTTG GGCTAGCTACAACGA CATAGTAG 4403

1332 UGACAAGA A CAUCAUGA 1646 TCATGATG GGCTAGCTACAACGA TCTTGTCA 4404

1340 ACAUCAUG A CCAAGGUC 1647 GACCTTGG GGCTAGCTACAACGA CATGATGT 4405

1377 CAAGUUCG A CUUCCACG 1648 CGTGGAAG GGCTAGCTACAACGA CGAACTTG 4406

1388 UCCACGGG A UCGCCCAG 1649 CTGGGCGA GGCTAGCTACAACGA CCCGTGGA 4407

1446 CCCCUCAG A CCUCCCGU 1650 ACGGGAGG GGCTAGCTACAACGA CTGAGGGG 4408

1487 CACAGAAG A UGAACUUU 1651 AAAGTTCA GGCTAGCTACAACGA CTTCTGTG 4409

1491 GAAGAUGA A CUUUGUGG 1652 CCACAAAG GGCTAGCTACAACGA TCATCTTC 4410

1526 UCCCCGUG A CAUCUUCC 1653 GGAAGATG GGCTAGCTACAACGA CACGGGGA 4411

1554 UGCCCCAA A CCCAUACU 1654 AGTATGGG GGCTAGCTACAACGA TTGGGGCA 4412

1566 AUACUGGA A UUCACCAA 1655 TTGGTGAA GGCTAGCTACAACGA TCCAGTAT 4413

1574 AUUCAGCA A CUGGGGGU 1656 ACCCCCAG GGCTAGCTACAACGA TGGTGAAT 4414

1593 AUACCCCA A CACUAGGC 1657 GCCTAGTG GGCTAGCTACAACGA TGGGGTAT 4415

1648 UACUAAAG A CCUGGCGG 1658 CCGCCAGG GGCTAGCTACAACGA CTTTAGTA 4416

1700 CGCCACAA A CUCUAUCG 1659 CGATAGAG GGCTAGCTACAACGA TTGTGGCG 4417

1713 AUCGGAGA A CAUGAAUC 1660 GATTCATG GGCTAGCTACAACGA TCTCCGAT 4418

1719 GAACAUGA A UCAAAAGU 1661 ACTTTTGA GGCTAGCTACAACGA TCATGTTC 4419

1740 CAAGAGGA A UGAAAAAA 1662 TTTTTTCA GGCTAGCTACAACGA TCCTCTTG 4420

1785 GGGAAGAG A UCCAAAGA 1663 TCTTTGGA GGCTAGCTACAACGA CTCTTCCC 4421 Table VII

1793 AUCCAAAG A CUCUUGGG 1664 CCCAAGAG GGCTAGCTACAACGA CTTTGGAT 4422

1830 CUACAGAA A UGAGGAGG 1665 CCTCCTCA GGCTAGCTACAACGA TTCTGTAG 4423

1839 UGAGGAGG A UGCUAAAA 1666 TTTTAGCA GGCTAGCTACAACGA CCTCCTCA 4424

1848 UGCUAAAA A UGUCACGA 1667 TCGTGACA GGCTAGCTACAACGA TTTTAGCA 4425

1857 UGUCACGA A UAUGGACA 1668 TGTCCATA GGCTAGCTACAACGA TCGTGACA 4426

1863 GAAUAUGG A CAUAUCAU 1669 ATGATATG GGCTAGCTACAACGA CCATATTC 4427

1878 AUCUGUGG A CUGACCUU 1670 AAGGTCAG GGCTAGCTACAACGA CCACAGAT 4428

1882 GUGGACUG A CCUUGUAA 1671 TTACAAGG GGCTAGCTACAACGA CAGTCCAC 4429

1894 UGUAAAAG A CAGUGUAU 1672 ATACACTG GGCTAGCTACAACGA CTTTTACA 4430

1925 UCUUAAGG A CAAAGUGC 1673 GCACTTTG GGCTAGCTACAACGA CCTTAAGA 4431

1955 CUUAAGAA A UGUAUAAA 1674 TTTATACA GGCTAGCTACAACGA TTCTTAAG 4432

1963 AUGUAUAA A CUUUAGAG 1675 CTCTAAAG GGCTAGCTACAACGA TTATACAT 4433

1982 GAGUUUGA A UCCCACUA 1676 TAGTGGGA GGCTAGCTACAACGA TCAAACTC 4434

1991 UCCCACUA A UGCAAACU 1677 AGTTTGCA GGCTAGCTACAACGA TAGTGGGA 4435

1997 UAAUGCAA A CUGGGAUG 1678 CATCCCAG GGCTAGCTACAACGA TTGCATTA 4436

2003 AAACUGGG A UGAAACUA 1679 TAGTTTCA GGCTAGCTACAACGA CCCAGTTT 4437

2008 GGGAUGAA A CUAAAGCA 1680 TGCTTTAG GGCTAGCTACAACGA TTCATCCC 4438

2017 CUAAAGCA A UAGAAACA 1681 TGTTTCTA GGCTAGCTACAACGA TGCTTTAG 4439

2023 CAAUAGAA A CAACACAG 1682 CTGTGTTG GGCTAGCTACAACGA TTCTATTG 4440

2026 UAGAAACA A CACAGUUU 1683 AAACTGTG GGCTAGCTACAACGA TGTTTCTA 4441

2037 CAGUUUUG A CCUAACAU 1684 ATGTTAGG GGCTAGCTACAACGA CAAAACTG 4442

2042 UUGACCUA A CAUACCGU 1685 ACGGTATG GGCTAGCTACAACGA TAGGTCAA 4443

2056 CGUUUAUA A UGCCAUUU 1686 AAATGGCA GGCTAGCTACAACGA TATAAACG 4444

2073 UAAGGAAA A CUACCUGU ' 1687 ACAGGTAG GGCTAGCTACAACGA TTTCCTTA 4445

2090 AUUUAAAA A UAGUUUCA 1688 TGAAACTA GGCTAGCTACAACGA TTTTAAAT 4446

2107 UAUCAAAA A CAAGAGAA 1689 TTCTCTTG GGCTAGCTACAACGA TTTTGATA 4447

2119 GAGAAAAG A CACGAGAG 1690 CTCTCGTG GGCTAGCTACAACGA CTTTTCTC 4448

2130 CGAGAGAG A CUGUGGCC 1691 GGCCACAG GGCTAGCTACAACGA CTCTCTCG 4449

2144 GCCCAUCA A CAGACGUU 1692 AACGTCTG GGCTAGCTACAACGA TGATGGGC 4450

2148 AUCAACAG A CGUUGAUA 1693 TATCAACG GGCTAGCTACAACGA CTGTTGAT 4451

2154 AGACGUUG A UAUGCAAC 1694 GTTGCATA GGCTAGCTACAACGA CAACGTCT 4452

2161 GAUAUGCA A CUGCAUGG 1695 CCATGCAG GGCTAGCTACAACGA TGCATATC 4453

2190 UGGUUGAA A UCAAAUAC 1696 GTATTTGA GGCTAGCTACAACGA TTCAACCA 4454

2195 GAAAUCAA A UACAUUCC 1697 GGAATGTA GGCTAGCTACAACGA TTGATTTC 4455

2209 UCCGUUUG A UGGACAGC 1698^' GCTGTCCA GGCTAGCTACAACGA CAAACGGA 4456

2213 UUUGAUGG A CAGCUGUC 1699 GACAGCTG GGCTAGCTACAACGA CCATCAAA 4457

2233 UUUCUCAA A CUGUGAAG 1700 CTTCACAG GGCTAGCTACAACGA TTGAGAAA 4458

2242 CUGUGAAG A UGACCCAA 1701 TTGGGTCA GGCTAGCTACAACGA CTTCACAG 4459

2245 UGAAGAUG A CCCAAAGU 1702 ACTTTGGG GGCTAGCTACAACGA CATCTTCA 4460

2259 AGUUUCCA A CUCCUUUA 1703 TAAAGGAG GGCTAGCTACAACGA TGGAAACT 4461

2281 UUACCGGG A CUAUGAAC 1704 GTTCATAG GGCTAGCTACAACGA CCCGGTAA 4462

2288 GACUAUGA A CUAAAAGG 1705 CCTTTTAG GGCTAGCTACAACGA TCATAGTC 4463

2301 AAGGUGGG A CUGAGGAU 1706 ATCCTCAG GGCTAGCTACAACGA CCCACCTT 4464

2308 GACUGAGG A UGUGUAUA 1707 TATACACA GGCTAGCTACAACGA CCTCAGTC 4465

2330 AGCGUGUG A UUGUAGAC 1708 GTCTACAA GGCTAGCTACAACGA CACACGCT 4466

2337 GAUUGUAG A CAGAGGGG 1709 CCCCTCTG GGCTAGCTACAACGA CTACAATC 4467

2381 AGGAGGAG A CCAGGCUG 1710 CAGCCTGG GGCTAGCTACAACGA CTCCTCCT 4468

2398 GGAAAGAA A CUUCUCAA 1711 TTGAGAAG GGCTAGCTACAACGA TTCTTTCC 4469

2410 CUCAAGCA A UGAAGACU 1712 AGTCTTCA GGCTAGCTACAACGA TGCTTGAG 4470

2416 CAAUGAAG A CUGGACUC 1713 GAGTCCAG GGCTAGCTACAACGA CTTCATTG 4471

2421 AAGACUGG A CUCAGGAC 1714 GTCCTGAG GGCTAGCTACAACGA CCAGTCTT 4472

2428 GACUCAGG A CAUUUGGG 1715 CCCAAATG GGCTAGCTACAACGA CCTGAGTC 4473

2438 AUUUGGGG A CUGUGUAC 1716 GTACACAG GGCTAGCTACAACGA CCCCAAAT 4474

2448 UGUGUACA A UGAGUUAU 1717 ATAACTCA GGCTAGCTACAACGA TGTACACA 4475

2461 UUAUGGAG A CUCGAGGG 1718 CCCTCGAG GGCTAGCTACAACGA CTCCATAA 4476

2494 UAUACCAA A CCCAGUGU 1719 ACACTGGG GGCTAGCTACAACGA TTGGTATA 4477 Table VII

2514 GAGAAAGG A CACAGCGU 1720 ACGCTGTG GGCTAGCTACAACGA CCTTTCTC 4478

2524 ACAGCGUA A UGGAGAAA 1721 TTTCTCCA GGCTAGCTACAACGA TACGCTGT 4479

2546 GUAGUAGA A UUCAGAAA 1722 TTTCTGAA GGCTAGCTACAACGA TCTACTAC 4480

2554 AUUCAGAA A CAAAAAUG 1723 CATTTTTG GGCTAGCTACAACGA TTCTGAAT 4481

2560 AAACAAAA A UGCGCAUC 1724 GATGCGCA GGCTAGCTACAACGA TTTTGTTT 4482

2587 UUUGUCAA A UGAAAAUU 1725 AATTTTCA GGCTAGCTACAACGA TTGACAAA 4483

2593 AAAUGAAA A UUUUAACU 1726 AGTTAAAA GGCTAGCTACAACGA TTTCATTT 4484

2599 AAAUUUUA A CUGGAAUU 1727 AATTCCAG GGCTAGCTACAACGA TAAAATTT 4485

2605 UAACUGGA A UUGUCUGA 1728 TCAGACAA GGCTAGCTACAACGA TCCAGTTA 4486

2613 AUUGUCUG A UAUUUAAG 1729 CTTAAATA GGCTAGCTACAACGA CAGACAAT 4487

2626 UAAGAGAA A CAUUCAGG 1730 CCTGAATG GGCTAGCTACAACGA TTCTCTTA 4488

2635 CAUUCAGG A CCUCAUCA 1731 TGATGAGG GGCTAGCTACAACGA CCTGAATG 4489

2683 GGUAAGAG A UGGCCUUC 1732 GAAGGCCA GGCTAGCTACAACGA CTCTTACC 4490

2704 CUGCCACA A UCAGAAAU 1733 ATTTCTGA GGCTAGCTACAACGA TGTGGCAG 4491

2711 AAUCAGAA A UCACGCAG 1734 CTGCGTGA GGCTAGCTACAACGA TTCTGATT 4492

2762 AGUCGCGA A CGCUGUGC 1735 GCACAGCG GGCTAGCTACAACGA TCGCGACT 4493

2781 UUGUCAGA A UGAAGUAU 1736 ATACTTCA GGCTAGCTACAACGA TCTGACAA 4494

2798 ACAAGUCA A UGUUUUUC 1737 GAAAAACA GGCTAGCTACAACGA TGACTTGT 4495

2821 UUUAUAUA A UAAUUAUA 1738 TATAATTA GGCTAGCTACAACGA TATATAAA 4496

2824 AUAUAAUA A UUAUAUAA 1739 TTATATAA GGCTAGCTACAACGA TATTATAT 4497

2832 AUUAUAUA A CUUAUGCA 1740 TGCATAAG GGCTAGCTACAACGA TATATAAT 4498

2859 AGGAGUUG A UCUCGGCC 1741 GGCCGAGA GGCTAGCTACAACGA CAACTCGT 4499

2876 AGCCAAAG A CACACGAC 1742 GTCGTGTG GGCTAGCTACAACGA CTTTGGCT 4500

2883 GACACACG A CAAAAGAG 1743 CTCTTTTG GGCTAGCTACAACGA CGTGTGTC 4501

2892 CAAAAGAG A CAAUCGAU 1744 ATCGATTG GGCTAGCTACAACGA CTCTTTTG 4502

2895 AAGAGACA A UCGAUAUA 1745 TATATCGA GGCTAGCTACAACGA TGTCTCTT 4503

2899 GACAAUCG A UAUAAUGU 1746 ACATTATA GGCTAGCTACAACGA CGATTGTC 4504

2904 UCGAUAUA A UGUGGCCU 1747 AGGCCACA GGCTAGCTACAACGA TATATCGA 4505

2916 GGCCUUGA A UUUUAACU 1748 AGTTAAAA GGCTAGCTACAACGA TCAAGGCC 4506

2922 GAAUUUUA A CUCUGUAU 1749 ATACAGAG GGCTAGCTACAACGA TAAAATTC 4507

2936 UAUGCUUA A UGUUUACA 1750 TGTAAACA GGCTAGCTACAACGA TAAGCATA 4508

2945 UGUUUACA A UAUGAAGU 1751 ACTTCATA GGCTAGCTACAACGA TGTAAACA 4509

2968 UUCUUAGA A UGCAGAAU 1752 ATTCTGCA GGCTAGCTACAACGA TCTAAGAA 4510

2975 AAUGCAGA A UGUAUGUA 1753 TACATACA GGCTAGCTACAACGA TCTGCATT 4511

2984 UGUAUGUA A UAAAAUAA 1754 TTATTTTA GGCTAGCTACAACGA TACATACA 4512

2989 GUAAUAAA A UAAGCUUG 1755 CAAGCTTA GGCTAGCTACAACGA TTTATTAC 4513

3012 CAUGGCAA A UCAGAUUU 1756 AAATCTGA GGCTAGCTACAACGA TTGCCATG 4514

3017 CAAAUCAG A UUUAUACA 1757 TGTATAAA GGCTAGCTACAACGA CTGATTTG 4515

3054 UUUUAGUG A CUAAAGUU 1758 AACTTTAG GGCTAGCTACAACGA CACTAAAA 4516

3068 GUUGCUUA A UGAAAACA 1759 TGTTTTCA GGCTAGCTACAACGA TAAGCAAC 4517

3074 UAAUGAAA A CAUGUGCU 1760 AGCACATG GGCTAGCTACAACGA TTTCATTA 4518

3085 UGUGCUGA A UGUUGUGG 1761 CCACAACA GGCTAGCTACAACGA TCAGCACA 4519

3094 UGUUGUGG A UUUUGUGU 1762 ACACAAAA GGCTAGCTACAACGA CCACAACA 4520

3107 GUGUUAUA A UUUACUUU 1763 AAAGTAAA GGCTAGCTACAACGA TATAACAC 4521

3124 GUCCAGGA A CUUGUGCA 1764 TGCACAAG GGCTAGCTACAACGA TCCTGGAC 4522

3149 CCAAGGAA A UAGGAUGU 1765 ACATCCTA GGCTAGCTACAACGA TTCCTTGG 4523

3154 GAAAUAGG A UGUUUGGC 1766 GCCAAACA GGCTAGCTACAACGA CCTATTTC 4524

Input Sequence = HUMERG2. Cut Site = R/Y Stem Length = 8 . Core Sequence = GGCTAGCTACAACGA HUMERG2 (Human erg2 gene encoding erg2 protein, complete eds. ; 3166 bp) Table VTfl

Table VIII: Human ERG Amberzyme and Target Sequence

_ Substrate Seq ID Ribozyme RzSeq ID

CCGCGCGU G UCCGCGCC 1153 GGCGCGGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACGCGCGG 4525

GCGUGUCC G CGCCCGCG 1154 CGCGGGCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGACACGC 4526

GUGUCCGC G CCCGCGUG 1155 CACGCGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCGGACAC 4527

CCGCGCCC G CGUGUGCC 1156 GGCACACG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGCGCGG 4528

GCCCGCGU G UGCCAGCG 1157 CGCUGGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACGCGGGC 4529

CCGCGUGU G CCAGCGCG 1158 CGCGCUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACACGCGG 4530

GUGCCAGC G CGCGUGCC 1159 GGCACGCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCUGGCAC 4531

GCCAGCGC G CGUGCCUU 1160 AAGGCACG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCGCUGGC 4532

GCGCGCGU G CCUUGGCC 1161 GGCCAAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACGCGCGC 4533

UUGGCCGU G CGCGCCGA 1162 UCGGCGCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACGGCCAA 4534

GGCCGUGC G CGCCGAGC 1163 GCUCGGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCACGGCC 4535

CCGUGCGC G CCGAGCCG 1164 CGGCUCGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCGCACGG 4536

UGCGCGCC G AGCCGGGU 1165 ACCCGGCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGCGCGCA 4537

GCCGGGUC G CACUAACU 1166 AGUUAGUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GACCCGGC 4538

CCCUCGGC G CCGACGGC 1167 GCCGUCGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCCGAGGG 4539

UCGGCGCC G ACGGCGGC 1168 GCCGCCGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGCGCCGA 4540

ACGGCGGC G CUAACCUC 1169 GAGGUUAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCCGCCGU 4541

GGAGACCC G AGGAAAGC 1170 GCUUUCCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGGUCUCC 4542

AAAGCCGU G UUGACCAA 1171 UUGGUCAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACGGCUUU 4543

GCCGUGUU G ACCAAAAG 1172 CUUUUGGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AACACGGC 4544

AGACAAAU G ACUCACAG 1173 CUGUGAGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUUUGUCU 4545

CAGGUUCU G AACAGCUG 1174 CAGCUGUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGAACCUG 4546

GGCUUACU G AAGGACAU 1175 AUGUCCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGUAAGCC 4547

AAGGAGAU G AUUCAGAC 1176 GUCUGAAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUGUCCUU 4548

UUCAGACU G UCCCGGAC 1177 GUCCGGGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGUCUGAA 4549

UAUCAGUU G UGAGUGAG 1178 CUCACUCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AACUGAUA 4550

UCAGUUGU G AGUGAGGA 1179 UCCUCACU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACAACUGA 4551

UUGUGAGU G AGGACCAG 1180 CUGGUCCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACUCACAA 4552

CAGUCGUU G UUUGAGUG 1181 CACUCAAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AACGACUG 4553

CGUUGUUU G AGUGUGCC 1182 GGCACACU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAACAACG 4554

GUUUGAGU G UGCCUACG 1183 CGUAGGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACUCAAAG 4555

UUGAGUGU G CCUACGGA 1184 UCCGUAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACACUCAA 4556

Table VTfl

352 UACGGAAC G CCACACCU 1185 AGGUGUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUUCCGUA 4557

376 ACAGAGAU G ACCGCGUC 1186 GACGCGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCUCUGU 4558

380 AGAUGACC G CGUCCUCC 1187 GGAGGACG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGUCAUCU 4559

395 CCUCCAGC G ACUAUGGA 1188 UCCAUAGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCUGGAGG 4560

418 UCCAAGAU G AGCCCACG 1189 CGUGGGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCUUGGA 4561

426 GAGCCCAC G CGUCCCUC 1190 GAGGGACG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUGGGCUC 4562

448 GAUUGGCU G UCUCAACC 1191 GGUUGAGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCCAAUC 4563

486 AAUGGAAU G UAACCCUA 1192 UAGGGUUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUUCCAUU 4564

502 AGCCAGGU G AAUGGCUC 1193 GAGCCAUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCUGGCU 4565

524 ACUCUCCU G AUGAAUGC 1194 GCAUUCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGAGAGU 4566

527 CUCCUGAU G AAUGCAGU 1195 ACUGCAUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCAGGAG 4567

531 UGAUGAAU G CAGUGUGG 1196 CCACACUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUUCAUCA 4568

536 AAUGCAGU G UGGCCAAA 1197 UUUGGCCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACUGCAUU 4569

583 GUUGGGAU G AACUACGG 1198 CCGUAGUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUCCCAAC 4570

616 AAGCACAU G CCACCCCC 1199 GGGGGUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUGUGCUU 4571

631 CCAAACAU G ACCACGAA 1200 UUCGUGGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUGUUUGG 4572

637 AUGACCAC G AACGAGCG 1201 CGCUCGUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUGGUCAU 4573

641 CCACGAAC G AGCGCAGA 1202 UCUGCGCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUUCGUGG 4574

645 GAACGAGC G CAGAGUUA 1203 UAACUCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCUCGUUC 4575

658 GUUAUCGU G CCAGCAGA 1204 UCUGCUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACGAUAAC 4576

673 GAUCCUAC G CUAUGGAG 1205 CUCCAUAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUAGGAUC 4577

692 CAGACCAU G UGCGGCAG 1206 CUGCCGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUGGUCUG 4578

694 GACCAUGU G CGGCAGUG 1207 CACUGCCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACAUGGUC 4579

718 UGGGCGGU G AAAGAAUA 1208 UAUUCUUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACCGCCCA 4580

751 AACAUCUU G UUAUUCCA 1209 UGGAAUAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAGAUGUU 4581

767 AGAACAUC G AUGGGAAG 1210 CUUCCCAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GAUGUUCU 4582

781 AAGGAACU G UGCAAGAU 1211 AUCUUGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGUUCCUU 4583

783 GGAACUGU G CAAGAUGA 1212 UCAUCUUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACAGUUCC 4584

790 UGCAAGAU G ACCAAGGA 1213 UCCUUGGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUCUUGCA 4585

800 CCAAGGAC G ACUUCCAG 1214 CUGGAAGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUCCUUGG 4586

830 GCUACAAC G CCGACAUC 1215 GAUGUCGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUUGUAGC 4587

833 ACAACGCC G ACAUCCUU 1216 AAGGAUGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGCGUUGU 4588

886 CCACAUUU G ACUUCAGA 1217 UCUGAAGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAAUGUGG 4589

896 CUUCAGAU G AUGUUGAU 1218 AUCAACAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUCUGAAG 4590

899 CAGAUGAU G UUGAUAAA 1219 UUUAUCAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUCAUCUG 4591

902 AUGAUGUU G AUAAAGCC 1220 GGCUUUAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AACAUCAU 4592

Table VIII

934 CGGUUAAU G CAUGCUAG 1221 CUAGCAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUUAACCG 4593

938 UAAUGCAU G CUAGAAAC 1222 GUUUCUAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGCAUUA 4594

962 UACCAUAU G AGCCCCCC 1223 GGGGGGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUAUGGUA 4595

1006 CACCCCAC G CCCCAGUC 1224 GACUGGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUGGGGUG 4596

1015 CCCCAGUC G AAAGCUGC 1225 GCAGCUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GACUGGGG 4597

1022 CGAAAGCU G CUCAACCA 1226 UGGUUGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCUUUCG 4598

1045 UCCACAGU G CCCAAAAC 1227 GUUUUGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUGUGGA 4599

1055 CCAAAACU G AAGACCAG 1228 CUGGUCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUUUUGG 4600

1110 AAGUAGCC G CCUUGCAA 1229 UUGCAAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGCUACUU 4601

1115 GCCGCCUU G CAAAUCCA 1230 UGGAUUUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAGGCGGC 4602

1168 GAGCUCCU G UCGGACAG 1231 CUGUCCGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGAGCUC 4603

1191 CUCCAGCU G CAUCACCU 1232 AGGUGAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCUGGAG 4604

1228 UUCAAGAU G ACGGAUCC 1233 GGAUCCGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUCUUGAA 4605

1238 CGGAUCCC G ACGAGGUG 1234 CACCUCGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGGAUCCG 4606

1241 AUCCCGAC G AGGUGGCC 1235 GGCCACCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUCGGGAU 4607

1254 GGCCCGGC G CUGGGGAG 1236 CUCCCCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCCGGGCC 4608

1285 CCCAACAU G AACUACGA 1237 UCGUAGUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUGUUGGG 4609

1292 UGAACUAC G AUAAGCUC 1238 GAGCUUAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUAGUUCA 4610

1305 GCUCAGCC G GGCCCUCC 1239 GGAGGGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGCUGAGC 4611

1307 UCAGCCGC G CCCUCCGU 1240 ACGGAGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCGGCUGA 4612

1325 ACUACUAU G ACAAGAAC 1241 GUUCUUGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUAGUAGU 4613

1339 AACAUCAU G ACCAAGGU 1242 ACCUUGGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUGAUGUU 4614

1359 UGGGAAGC G CUACGCCU 1243 AGGCGUAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCUUCCCA 4615

1364 AGCGCUAC G CCUACAAG 1244 CUUGUAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUAGCGCU 4616

1376 ACAAGUUC G ACUUCCAC 1245 GUGGAAGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GAACUUGU 4617

1391 ACGGGAUC G CCCAGGCC 1246 GGCCUGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GAUCCCGU 4618

1429 UCAUCUCU G UACAAGUA 1247 UACUUGUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGAGAUGA 4619

1472 CCUAUCAC G CCCACCCA 1248 UGGGUGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUGAUAGG 4620

1489 CAGAAGAU G AACUUUGU 1249 ACAAAGUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUCUUCUG 4621

1496 UGAACUUU G UGGCGCCC 1250 GGGCGCCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAAGUUCA 4622

1501 UUUGUGGC G CCCCACCC 1251 GGGUGGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCCACAAA 4623

1525 CUCCCCGU G ACAUCUUC 1252 GAAGAUGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACGGGGAG 4624

1544 GUUUUUUU G CUGCCCCA 1253 UGGGGCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAAAAAAC 4625

1547 UUUUUGCU G CCCCAAAC 1254 GUUUGGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCAAAAA 4626

1618 AGCCAUAU G CCUUCUCA 1255 UGAGAAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUAUGGCU 4627

1676 AUCAGCGU G CAUUCACC 1256 GGUGAAUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACGCUGAU 4628

Table vm

1693 AGCCCAUC G CCACAAAC 1257 GUUUGUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAUGGGCU 4629

1717 GAGAACAU G AAUCAAAA 1258 UUUUGAUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGUUCUC 4630

1728 UCAAAAGU G CCUCAAGA 1259 UCUUGAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUUUUGA 4631

1742 AGAGGAAU G AAAAAAGC 1260 GCUUUUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUUCCUCU 4632

1813 GAGUUACU G AAGUCUUA 1261 UAAGACUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUAACUC 4633

1832 ACAGAAAU G AGGAGGAU 1262 AUCCUCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUUUCUGU 4634

1841 AGGAGGAU G CUAAAAAU 1263 AUUUUUAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCCUCCU 4635

1850 CUAAAAAU G UCACGAAU 1264 AUUCGUGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUUUUUAG 4636

1855 AAUGUCAC G AAUAUGGA 1265 UCCAUAUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUGACAUU 4637

1874 UAUCAUCU G UGGACUGA 1266 UCAGUCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAUGAUA 4638

1881 UGUGGACU G ACCUUGUA 1267 UACAAGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUCCACA 4639

1887 CUGACCUU G UAAAAGAC 1268 GUCUUUUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAGGUCAG 4640

1899 AAGACAGU G UAUGUAGA 1269 UCUACAUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUGUCUU 4641

1903 CAGUGUAU G UAGAAGCA 1270 UGCUUCUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUACACUG 4642

1913 AGAAGGAU G AAGUCUUA 1271 UAAGACUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUGCUUCU 4643

1932 GACAAAGU G CCAAAGAA 1272 UUCUUUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACUUUGUC 4644

1957 UAAGAAAU G UAUAAACU 1273 AGUUUAUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUUUCUUA 4645

1980 UAGAGUUU G AAUCCCAC 1274 GUGGGAUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAACUCUA 4646

1993 CCACUAAU G CAAACUGG 1275 CCAGUUUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUUAGUGG 4647

2005 ACUGGGAU G AAACUAAA 1276 UUUAGUUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUCCCAGU 4648

2036 ACAGUUUU G ACCUAACA 1277 UGUUAGGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAAACUGU 4649

2058 UUUAUAAU G CCAUUUUA 1278 UAAAAUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUUAUAAA 4650

2080 AACUACCU G UAUUUAAA 1279 UUUAAAUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGUAGUU 4651

2123 AAAGACAC G AGAGAGAC 1280 GUCUCUCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUGUCUUU 4652

2133 GAGAGACU G UGGCCCAU 1281 AUGGGCCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGUCUCUC 4653

2153 CAGACGUU G AUAUGCAA 1282 UUGCAUAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AACGUCUG 4654

2158 GUUGAUAU G CAACUGCA 1283 UGCAGUUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUAUCAAC 4655

2164 AUGCAACU G CAUGGCAU 1284 AUGCCAUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGUUGCAU 4656

2173 CAUGGCAU G UGCUGUUU 1285 AAACAGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUGCCAUG 4657

2175 UGGCAUGU G CUGUUUUG 1286 CAAAACAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACAUGCCA 4658

2178 CAUGUGCU G UUUUGGUU 1287 AACCAAAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCACAUG 4659

2187 UUUUGGUU G AAAUCAAA 1288 UUUGAUUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AACCAAAA 4660

2208 UUCCGUUU G AUGGACAG 1289 CUGUCCAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAACGGAA 4661

2219 GGACAGCU G UCAGCUUU 1290 AAAGCUGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCUGUCC 4662

2236 CUCAAACU G UGAAGAUG 1291 CAUCUUCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGUUUGAG 4663

2238 CAAACUGU G AAGAUGAC 1292 GUCAUCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACAGUUUG 4664

Table VHI

2244 GUGAAGAU G ACCCAAAG 1293 CUUUGGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCUUCAC 4665

2286 GGGACUAU G AACUAAAA 1294 UUUUAGUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUAGUCCC 4666

2304 GUGGGACU G AGGAUGUG 1295 CACAUCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUCCCAC 4667

2310 CUGAGGAU G UGUAUAGA 1296 UCUAUACA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCCUCAG 4668

2312 GAGGAUGU G UAUAGAGU 1297 ACUCUAUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAUCCUC 4669

2321 UAUAGAGU G AGCGUGUG 1298 CACACGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACUCUAUA 4670

2327 GUGAGCGU G UGAUUGUA 1299 UACAAUCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACGCUCAC 4671

2329 GAGCGUGU G AUUGUAGA 1300 UCUACAAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACACGCUC 4672

2333 GUGUGAUU G UAGACAGA 1301 UCUGUCUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAUCACAC 4673

2347 AGAGGGGU G AAGAAGGA 1302 UCCUUCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACCCCUCU 4674

2412 CAAGCAAU G AAGACUGG 1303 CCAGUCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUUGCUUG 4675

2441 UGGGGACU G UGUACAAU 1304 AUUGUACA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGUCCCCA 4676

2443 GGGACUGU G UACAAUGA 1305 UCAUUGUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACAGUGCC 4677

2450 UGUACAAU G AGUUAUGG 1306 CCAUAACU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUUGUACA 4678

2465 GGAGACUC G AGGGUUCA 1307 UGAACCCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GAGUCUCC 4679

2475 GGGUUCAU G CAGUCAGU 1308 ACUGACUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUGAACCC 4680

2484 CAGUCAGU G .UUAUACCA 1309 UGGUAUAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACUGACUG 4681

2501 AACCCAGU G UUAGGAGA 1310 UCUCCUAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACUGGGUU 4682

2562 ACAAAAAU G CGCAUCUC 1311 GAGAUGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUUUUUGU 4683

2564 AAAAAUGC G CAUCUCUU 1312 AAGAGAUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCAUUUUU 4684

2578 CUUUCUUU G UUUGUCAA 1313 UUGACAAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAAGAAAG 4685

2582 CUUUGUUU G UCAAAUGA 1314 UCAUUUGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAACAAAG 4686

2589 UGUCAAAU G AAAAUUUU 1315 AAAAUUUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUUUGACA 4687

2608 CUGGAAUU G UCUGAUAU 1316 AUAUCAGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAUUCCAG 4688

2612 AAUUGUCU G AUAUUUAA 1317 UUAAAUAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGACAAUU 4689

2648 AUCAUUAU G UGGGGGCU 1318 AGCCCCCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUAAUGAU 4690

2659 GGGGCUUU G UUCUCCAC 1319 GUGGAGAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAAGCCCC 4691

2698 UCUUGGCU G CCACAAUC 1320 GAUUGUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCCAAGA 4692

2716 GAAAUCAC G CAGGCAUU 1321 AAUGCCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUGAUUUC 4693

2753 UUUCCUUU G AGUCGCGA 1322 UCGCGACU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAAGGAAA 4694

2758 UUUGAGUC G CGAACGCU 1323 AGCGUUCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GACUCAAA 4695

2760 UGAGUCGC G AACGCUGU 1324 ACAGCGUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCGACUCA 4696

2764 UCGCGAAC G CUGUGCGU 1325 ACGCACAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUUCGCGA 4697

2767 CGAACGCU G UGCGUUUG 1326 CAAACGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCGUUCG 4698

2769 AACGCUGU G CGUUUGUC 1327 GACAAACG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACAGCGUU 4699

2775 GUGCGUUU G UCAGAAUG 1328 CAUUCUGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAACGCAC 4700

Table VIII

2783 GUCAGAAU G AAGUAUAC 1329 GUAUACUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUUCUGAC 4701

2800 AAGUCAAU G UUUUUCCC 1330 GGGAAAAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUUGACUU 4702

2838 UAACUUAU G CAUUUAUA 1331 UAUAAAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUAAGUUA 4703

2853 UACACUAC G AGUUGAUC 1332 GAUCAACU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUAGUGUA 4704

2858 UACGAGUU G AUCUCGGC 1333 GCCGAGAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AACUCGUA 4705

2882 AGACACAC G ACAAAAGA 1334 UCUUUUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUGUGUCU 4706

2898 AGACAAUC G AUAUAAUG 1335 CAUUAUAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GAUUGUCU 4707

2906 GAUAUAAU G UGGCCUUG 1336 CAAGGCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUUAUAUC 4708

2914 GUGGCCUU G AAUUUUAA 1337 UUAAAAUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAGGCCAC 4709

2927 UUAACUCU G UAUGCUUA 1338 UAAGCAUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAGUUAA 4710

2931 CUCUGUAU G CUUAAUGU 1339 ACAUUAAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUACAGAG 4711

2938 UGCUUAAU G UUUACAAU 1340 AUUGUAAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUUAAGCA 4712

2949 UACAAUAU G AAGUUAUU 1341 AAUAACUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUAUUGUA 4713

2970 CUUAGAAU G CAGAAUGU 1342 ACAUUCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUUCUAAG 4714

2977 UGCAGAAU G UAUGUAAU 1343 AUUACAUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUUCUGCA 4715

2981 GAAUGUAU G UAAUAAAA 1344 UUUUAUUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUACAUUC 4716

3033 AGGAGUCU G CAUUUGCA 1345 UGCAAAUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGACUCCU 4717

3039 CUGCAUUU G CACUUUUU 1346 AAAAAGUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAAUGCAG 4718

3053 UUUUUAGU G ACUAAAGU 1347 ACUUUAGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACUAAAAA 4719

3063 CUAAAGUU G CUUAAUGA 1348 UCAUUAAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AACUUUAG 4720

3070 UGCUUAAU G AAAACAUG 1349 CAUGUUUϋ GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUUAAGCA 4721

3078 GAAAACAU G UGCUGAAU 1350 AUUCAGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUGUUUUC 4722

3080 AAACAUGU G CUGAAUGU 1351 ACAUUCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACAUGUUU 4723

3083 CAUGUGCU G AAUGUUGU 1352 ACAACAUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCACAUG 4724

3087 UGCUGAAU G UUGUGGAU 1353 AUCCACAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUUCAGCA 4725

3090 UGAAUGUU G UGGAUUUU 1354 AAAAUCCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AACAUUCA 4726

3099 UGGAUUUU G UGUUAUAA 1355 UUAUAACA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAAAUCCA 4727

3101 GAUUUUGU G UUAUAAUU 1356 AAUUAUAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACAAAAUC 4728

3116 UUUACUUU G UCCAGGAA 1357 UUCCUGGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAAGUAAA 4729

3128 AGGAACUU G UGCAAGGG 1358 CCCUUGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAGUUGCU 4730

3130 GAACUUGU G CAAGGGAG 1359 CUCCCUUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACAAGUUC 4731

3156 AAUAGGAU G UUUGGCAC 1360 GUGCCAAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUCCUAUU 4732

9 GUCCGCGC G UGUCCGCG 1361 CGCGGACA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCGCGGAC 4733

23 GCGCCCGC G UGUGCCAG 1362 CUGGCACA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCGGGCGC 4734

31 GUGUGCCA G CGCGCGUG 1363 CACGCGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGCACAC 4735

37 CAGCGCGC G UGCCUUGG 1364 CCAAGGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCGCGCUG 4736

Table VIII

GUGCCUUG G CCGUGCGC 1365 GCGCACGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAGGCAC 4737

CCUUGGCC G UGCGCGCC 1366 GGCGCGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGCCAAGG 4738

CGCGCCGA G CCGGGUCG 1367 CGACCCGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCGGCGCG 4739

CGAGCCGG G UCGCACUA 1368 UAGUGCGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGGCUCG 4740

CUCCCUCG G CGCCGACG 1369 CGUCGGCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGAGGGAG 4741

CGCCGACG G CGGCGCUA 1370 UAGCGCCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGUCGGCG 4742

CGACGGCG G CGCUAACC 1371 GGUUAGCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCCGUCG 4743

ACCUCUCG G UUAUUCCA 1372 UGGAAUAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGAGAGGU 4744

CGAGGAAA G CCGUGUUG 1373 CAACACGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUCCUCG 4745

GGAAAGCC G UGUUGACC 1374 GGUCAACA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGCUUUCC 4746

GACCAAAA G CAAGACAA 1375 UUGUCUUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUUGGUC 4747

AAAAGAUG G CAGAACCA 1376 UGGUUCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUCUUUU 4748

AACCAAGG G CAACUAAA 1377 UUUAGUUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUUGGUU 4749

CAACUAAA G CCGUCAGG 1378 CCUGACGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUUAGUUG 4750

CUAAAGCC G UCAGGUUC 1379 GAACCUGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGCUUUAG 4751

GCCGUCAG G UUCUGAAC 1380 GUUCAGAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGACGGC 4752

UCUGAACA G CUGGUAGA 1381 UCUACCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGUUCAGA 4753

AACAGCUG G UAGAUGGG 1382 CCCAUCUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGCUGUU 4754

GUAGAUGG G CUGGCUUA 1383 UAAGCCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCAUCUAC 4755

AUGGGCUG G CUUACUGA 1384 UCAGUAAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGCCCAU 4756

CGGACCCA G CAGCUCAU 1385 AUGAGCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGGUCCG 4757

ACCCAGCA G CUCAUAUC 1386 GAUAUGAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCUGGGU 4758

UCAAGGAA G CCUUAUCA 1387 UGAUAAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCCUUGA 4759

CCUUAUCA G UUGUGAGU 1388 ACUCACAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGAUAAGG 4760

AGUUGUGA G UGAGGACC 1389 GGUCCUCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCACAACU 4761

GAGGACCA G UCGUUGUU 1390 AACAACGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGUCCUC 4762

GACCAGUC G UUGUUUGA 1391 UCAAACAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GACUGGUC 4763

UUGUUUGA G UGUGCCUA 1392 UAGGCACA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCAAACAA 4764

CACACCUG G CUAAGACA 1393 UGUCUUAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGGUGUG 4765

AUGACCGC G UCCUCCUC 1394 GAGGAGGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCGGUCAU 4766

CUCCUCCA G CGACUAUG 1395 CAUAGUCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGAGGAG 4767

CAAGAUGA G CCCACGCG 1396 CGCGUGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCAUCUUG 4768

GCCCACGC G UCCCUCAG 1397 CUGAGGGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCGUGGGC 4769

GUCCCUCA G CAGGAUUG 1398 CAAUCCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGAGGGAC 4770

CAGGAUUG G CUGUCUCA 1399 UGAGACAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAAUCCUG 4771

AACCCCCA G CCAGGGUC 1400 GACCCUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGGGGUU 4772

Table VIII

467 CAGCCAGG G UCACCAUC 1401 GAUGGUGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUGGCUG 4773

495 UAACCCUA G CCAGGUGA 1402 UCACCUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAGGGUUA 4774

500 CUAGCCAG G UGAAUGGC 1403 GCCAUUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGGCUAG 4775

507 GGUGAAUG G CUCAAGGA 1404 UCCUUGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUUCACC 4776

534 UGAAUGCA G UGUGGCCA 1405 UGGCCACA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCAUUCA 4777

539 GCAGUGUG G CCAAAGGC 1406 GCCUUUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACACUGC 4778

546 GGCCAAAG G CGGGAAGA 1407 UCUUCCCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUUGGCC 4779

557 GGAAGAUG G UGGGCAGC 1408 GCUGCCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUCUUCC 4780

561 GAUGGUGG G CAGCCCAG 1409 CUGGGCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCACCAUC 4781

564 GGUGGGCA G CCCAGACA 1410 UGUCUGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCCCACC 4782

575 CAGACACC G UUGGGAUG 1411 CAUCCCAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGUGUCUG 4783

591 GAACUACG G CAGCUACA 1412 UGUAGCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGUAGUUC 4784

594 CUACGGCA G CUACAUGG 1413 CCAUGUAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCCGUAG 4785

610 GAGGAGAA G CACAUGCC 1414 GGCAUGUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCUCCUC 4786

643 ACGAACGA G CGCAGAGU 1415 ACUCUGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCGUUCGU 4787

650 AGCGCAGA G UUAUCGUG 1416 CACGAUAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCUGCGCU 4788

656 GAGUUAUC G UGCCAGCA 1417 UGCUGGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GAUAACUC 4789

662 UCGUGCCA G CAGAUCCU 1418 AGGAUCUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGCACGA 4790

681 GCUAUGGA G UACAGACC 1419 GGUCUGUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCAUAGC 4791

697 CAUGUGCG G CAGUGGCU 1420 AGCCACUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGCACAUG 4792

700 GUGCGGCA G UGGCUGGA 1421 UCCAGCCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCCGCAC 4793

703 CGGCAGUG G CUGGAGUG 1422 CACUCCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CACUGCCG 4794

709 UGGCUGGA G UGGGCGGU 1423 ACCGCCCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCAGCCA 4795

713 UGGAGUGG G CGGUGAAA 1424 UUUCACCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCACUCCA 4796

716 AGUGGGCG G UGAAAGAA 1425 UUCUUUCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGCCCACU 4797

729 AGAAUAUG G CCUUCCAG 1426 CUGGAAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAUAUUCU 4798

740 UUCCAGAC G UCAACAUC 1427 GAUGUUGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUCUGGAA 4799

811 UUCCAGAG G CUCACCCC 1428 GGGGUGAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCUGGAA 4800

822 CACCCCCA G CUACAACG 1429 CGUUGUAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGGGGUG 4801

908 UUGAUAAA G CCUUACAA 1430 UUGUAAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUUAUCAA 4802

928 UCUCCACG G UUAAUGCA 1431 UGCAUUAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGUGGAGA 4803

964 CCAUAUGA G CCCCCCAG 1432 CUGGGGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCAUAUGG 4804

980 GGAGAUCA G CCUGGAGC 1433 GGUCCAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGAUCUCC 4805

990 CUGGACCG G UCACGGCC 1434 GGCCGUGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGGUCCAG 4806

996 CGGUCACG G CCACCCCA 1435 UGGGGUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGUGACCG 4807

1012 ACGCCCCA G UCGAAAGC 1436 GCUUUCGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGGGCGU 4808

Table Vm

1019 AGUCGAAA G CUGCUCAA 1437 UUGAGCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUCGACU 4809

1043 CUUCCACA G UGCCCAAA 1438 UUUGGGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUGGAAG 4810

1063 GAAGACCA G CGUCCUCA 1439 UGAGGACG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGUCUUC 4811

1065 AGACCAGC G UCCUCAGU 1440 ACUGAGGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCUGGUCU 4812

1072 CGUCCUCA G UUAGAUCC 1441 GGAUCUAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAGGACG 4813

1104 ACCAACAA G UAGCCGCC 1442 GGCGGCUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGUUGGU 4814

1107 AACAAGUA G CCGCCUUG 1443 CAAGGCGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UACUUGUU 4815

1125 AAAUCCAG G CAGUGGCC 1444 GGCCACUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUGGAUUU 4816

1128 UCCAGGCA G UGGCCAGA 1445 UCUGGCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCCUGGA 4817

1131 AGGCAGUG G CCAGAUCC 1446 GGAUCUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACUGCCU 4818

1141 CAGAUCCA G CUUUGGCA 1447 UGCCAAAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGAUCUG 4819

1147 CAGCUUUG G CAGUUCCU 1448 AGGAACUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAAGCUG 4820

1150 CUUUGGCA G UUCCUCCU 1449 AGGAGGAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGCCAAAG 4821

1162 CUCCUGGA G CUCCUGUC 1450 GACAGGAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCAGGAG 4822

1176 GUCGGACA G CUCCAACU 1451 AGUUGGAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGUCGGAC 4823

1188 CAACUCCA G CUGCAUCA 1452 UGAUGCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGAGUUG 4824

1206 CUGGGAAG G CACCAACG 1453 CGUUGGUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUUCCCAG 4825

1219 AACGGGGA G UUCAAGAU 1454 AUCUUGAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCCCGUU 4826

1244 CCGACGAG G UGGCCCGG 1455 CCGGGCCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCGUCGG 4827

1247 ACGAGGUG G CCCGGCGC 1456 GCGCCGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CACCUCGU 4828

1252 GϋGGCCCG G CGCUGGGG 1457 CCCCAGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGGGCCAC 4829

1264 UGGGGAGA G CGGAAGAG 1458 CUCUUCCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCUCCCCA 4830

1272 GCGGAAGA G CAAACCCA 1459 UGGGUUUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCUUCCGC 4831

1297 UACGAUAA G CUCAGCCG 1460 CGGCUGAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUAUCGUA 4832

1302 UAAGCUCA G CCGCGCCC 1461 GGGCGCGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGAGCUUA 4833

1314 CGCCCUCC G UUACUACU 1462 AGUAGUAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGAGGGCG 4834

1346 UGACCAAG G UCCAUGGG 1463 CCCAUGGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUUGGUCA 4835

1357 GAUGGGAA G CGCUACGC 1464 GCGUAGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCCCAUG 4836

1372 GCCUACAA G UUCGACUU 1465 AAGUCGAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUGUAGGC 4837

1397 UCGCCCAG G CCCUCCAG 1466 CUGGAGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGGGCGA 4838

1405 GCCCUCCA G CCCCACGC 1467 GGGUGGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGAGGGC 4839

1420 CCCCCGGA G UCAUCUCU 1468 AGAGAUGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCGGGGG 4840

1435 CUGUACAA G UACCCCUC 1469 GAGGGGUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUGUACAG 4841

1453 GACCUCCC G UACAUGGG 1470 CCCAUGUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGGAGGUC 4842

1461 GUACAUGG G CUCCUAUC 1471 GAUAGGAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCAUGUAC 4843

1499 ACUUUGUG G CGCCCCAC 1472 GUGGGGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CACAAAGU 4844

Table VIII

1514 ACCCUCCA G CCCUCCCC 1473 GGGGAGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGAGGGU 4845

1523 CCCUCCCC G UGACAUCU 1474 AGAUGUGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGGAGGG 4846

1536 AUCUUCCA G UUUUUUUG 1475 CAAAAAAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGAAGAU 4847

1581 AACUGGGG G UAUAUACC 1476 GGUAUAUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCCAGUU 4848

1600 AACACUAG G CUCCCCAC 1477 GUGGGGAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUAGUGUU 4849

1611 CCCCACCA G CCAUAUGC 1478 GCAUAUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGUGGGG 4850

1632 UCAUCUGG G CACUUACU 1479 AGUAAGUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAGAUGA 4851

1653 AAGACCUG G CGGAGGCU 1480 AGCCUCCG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGGUCUU 4852

1659 UGGCGGAG G CUUUUCCC 1481 GGGAAAAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCCGCCA 4853

1672 UCCCAUCA G CGUGCAUU 1482 AAUGCACG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAUGGGA 4854

1674 CCAUCAGC G UGCAUUCA 1483 UGAAUGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCUGAUGG 4855

1686 AUUCACCA G CCCAUCGC 1484 GCGAUGGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGUGAAU 4856

1726 AAUCAAAA G UGCCUCAA 1485 UUGAGGCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUUGAUU 4857

1749 UGAAAAAA G CUUUACUG 1486 CAGUAAAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUUUUCA 4858

1760 UUACUGGG G CUGGGGAA 1487 UUCCCCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCCAGUAA 4859

1773 GGAAGGAA G CCGGGGAA 1488 UUCCCCGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCCUUCC 4860

1807 GGGAGGGA G UUACUGAA 1489 UUCAGUAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCCUCCC 4861

1816 UUACUGAA G UCUUACUA 1490 UAGUAAGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCAGUAA 4862

1897 AAAAGACA G UGUAUGUA 1491 UACAUACA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGUCUUUU 4863

1909 AUGUAGAA G CAUGAAGU 1492 ACUUCAUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCUACAU 4864

1916 AGCAUGAA G UCUUAAGG 1493 CCUUAAGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCAUGCU 4865

1930 AGGACAAA G UGCCAAAG 1494 CUUUGGCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUUGUCCU 4866

1942 CAAAGAAA G UGGUCUUA 1495 UAAGACCA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUUCUUUG 4867

1945 AGAAAGUG G UCUUAAGA 1496 UCUUAAGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CACUUUCU 4868

1971 ACUUUAGA G UAGAGUUU 1497 AAACUCUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCUAAAGU 4869

1976 AGAGUAGA G UUUGAAUC 1498 GAUUCAAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCUACUCU 4870

2014 AAACUAAA G CAAUAGAA 1499 UUCUAUUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUUAGUUU 4871

2031 ACAACACA G UUUUGACC 1500 GGUCAAAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGUGUUGU 4872

2049 AACAUACC G UUUAUAAU 1501 AUUAUAAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGUAUGUU 4873

2093 UAAAAAUA G UUUCAUAU 1502 AUAUGAAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UAUUUUUA 4874

2136 AGACUGUG G CCCAUCAA 1503 UUGAUGGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CACAGUCU 4875

2150 CAACAGAC G UUGAUAUG 1504 CAUAUCAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUCUGUUG 4876

2169 ACUGCAUG G CAUGUGCU 1505 AGCACAUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAUGCAGU 4877

2184 CUGUUUUG G UUGAAAUC 1506 GAUUUCAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAAAACAG 4878

2204 UACAUUCC G UUUGAUGG 1507 CCAUCAAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGAAUGUA 4879

2216 GAUGGACA G CUGUCAGC 1508 GCUGACAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGUCCAUC 4880

Table VIII

2223 AGCUGUCA G CUUUCUCA 1509 UGAGAAAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGACAGCU 4881

2252 GACCCAAA G UUUCCAAC 1510 GUUGGAAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUGGGUC 4882

2270 CCUUUACA G UAUUACCG 1511 CGGUAAUA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUAAAGG 4883

2296 ACUAAAAG G UGGGACUG 1512 CAGUCCCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUUUAGU 4884

2319 UGUAUAGA G UGAGCGUG 1513 CACGCUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUAUACA 4885

2323 UAGAGUGA G CGUGUGAU 1514 AUCACACG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCACUCUA 4886

2325 GAGUGAGC G UGUGAUUG 1515 CAAUCACA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCUCACUC 4887

2345 ACAGAGGG G UGAAGAAG 1516 CUUCUUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCUCUGU 4888

2366 AGGAAGAG G CAGAGAAG 1517 CUUCUCUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCUUCCU 4889

2386 GAGACCAG G CUGGGAAA 1518 UUUCCCAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGGUCUC 4890

2407 CUUCUCAA G CAAUGAAG 1519 CUUCAUUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGAGAAG 4891

2452 UACAAUGA G UUAUGGAG 1520 CUCCAUAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCAUUGUA 4892

2469 ACUCGAGG G UUCAUGCA 1521 UGCAUGAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUCGAGU 4893

2478 UUCAUGCA G UCAGUGUU 1522 AACACUGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCAUGAA 4894

2482 UGCAGUCA G UGUUAUAC 1523 GUAUAACA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGACUGCA 4895

2499 CAAACCCA G UGUUAGGA 1524 UCCUAACA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGGUUUG 4896

2519 AGGACACA G CGUAAUGG 1525 CCAUUACG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGUGUCCU 4897

2521 GACACAGC G UAAUGGAG 1526 CUCCAUUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCUGUGUC 4898

2538 AAAGGGAA G UAGUAGAA 1527 UUCUACUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCCCUUU 4899

2541 GGGAAGUA G UAGAAUUC 1528 GAAUUCUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UACUUCCC 4900

2654 AUGUGGGG G CUUUGUUC 1529 GAACAAAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCCCACAU 4901

2671 UCCACAGG G UCAGGUAA 1530 UUACCUGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCUGUGGA 4902

2676 AGGGUCAG G UAAGAGAU 1531 AUCUCUUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGACCCU 4903

2686 AAGAGAUG G CCUUCUUG 1532 CAAGAAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAUCUCUU 4904

2695 CCUUCUUG G CUGCCACA 1533 UGUGGCAG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAAGAAGG 4905

2720 UCACGCAG G CAUUUUGG 1534 CCAAAAUG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGCGUGA 4906

2729 CAUUUUGG G UAGGCGGC 1535 GCCGCCUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCAAAAUG 4907

2733 UUGGGUAG G CGGCCUCC 1536 GGAGGGCG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUACCCAA 4908

2736 GGUAGGCG G CCUCCAGU 1537 ACUGGAGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGCCUACC 4909

2743 GGCCUCCA G UUUUCCUU 1538 AAGGAAAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGAGGCC 4910

2755 UCCUUUGA G UCGCGAAC 1539 GUUCGCGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCAAAGGA 4911

2771 CGCUGUGC G UUUGUCAG 1540 CUGACAAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCACAGCG 4912

2786 AGAAUGAA G UAUACAAG 1541 CUUGUAUA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCAUUCU 4913

2794 GUAUACAA G UCAAUGUU 1542 AACAUUGA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUGUAUAC 4914

2855 CACUACGA G UUGAUCUC 1543 GAGAUCAA GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCGUAGUG 4915

2865 UGAUCUCG G CCAGCCAA 1544 UUGGCUGG GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGAGAUCA 4916

Table VIII

2869 CUCGGCCA G CCAAAGAC 1545 GUCUUUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGCCGAG 4917

2909 AUAAUGUG G CCUUGAAU 1546 AUUCAAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACAUUAU 4918

2952 AAUAUGAA G UUAUUAGU 1547 ACUAAUAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCAUAUU 4919

2959 AGUUAUUA G UUCUUAGA 1548 UCUAAGAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAAUAACU 4920

2993 UAAAAUAA G CUUGGCCU 1549 AGGCCAAG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUAUUUUA 4921

2998 UAAGCUUG G CCUAGCAU 1550 AUGCUAGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAGCUUA 4922

3003 UUGGCCUA G CAUGGCAA 1551 UUGCCAUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAGGCCAA 4923

3008 CUAGCAUG G CAAAUCAG 1552 CUGAUUUG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUGCUAG 4924

3029 AUACAGGA G UCUGCAUU 1553 AAUGCAGA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUGUAU 4925

3051 UUUUUUUA G UGACUAAA 1554 UUUAGUCA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAAAAAAA 4926

3060 UGACUAAA G UUGCUUAA 1555 UUAAGCAA GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUAGUCA 4927

3140 AAGGGAGA G CCAAGGAA 1556 UUCCUUGG GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUCCCUU 4928

44 CGUGCCUU G GCCGUGCG 1767 CGCACGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAGGCACG 4929

62 GCCGAGCC G GGUCGCAC 1768 GUGCGACC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGCUCGGC 4930

63 CCGAGCCG G GUCGCACU 1769 AGUGCGAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGGCUCGG 4931

81 ACUCCCUC G GCGCCGAC 1770 GUCGGCGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GAGGGAGU 4932

90 GCGCCGAC G GCGGCGCU 1771 AGCGCCGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUCGGCGC 4933

93 CCGACGGC G GCGCUAAC 1772 GUUAGCGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCCGUCGG 4934

107 AACCUCUC G GUUAUUCC 1773 GGAAUAAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GAGAGGUU 4935

117 UUAUUCCA G GAUCUUUG 1774 CAAAGAUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGAAUAA 4936

118 UAUUCCAG G AUGUUUGG 1775 CCAAAGAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGGAAUA 4937

125 GGAUCUUU G GAGACCCG 1776 CGGGUCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAAGAUCC 4938

126 GAUCUUUG G AGACCCGA 1777 UCGGGUCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAAAGAUC 4939

128 UCUUUGGA G ACCCGAGG 1778 CCUCGGGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCAAAGA 4940

135 AGACCCGA G GAAAGCCG 1779 CGGCUUUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCGGGUCU 4941

136 GACCCGAG G AAAGCCGU 1780 ACGGCUUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCGGGUC 4942

160 AAAAGCAA G ACAAAUGA 1781 UCAUUUGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUGCUUUU 4943

175 GACUCACA G AGAAAAAA 1782 UUUUUUCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGUGAGUC 4944

177 CUCACAGA G AAAAAAGA 1783 UCUUUUUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCUGUGAG 4945

184 AGAAAAAA G AUGGCAGA 1784 UCUGCCAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUUUUUCU 4946

187 AAAAAGAU G GCAGAACC 1785 GGUUCUGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUCUUUUU 4947

191 AGAUGGCA G AACCAAGG 1786 CCUUGGUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCCAUCU 4948

198 AGAACCAA G GGCAACUA 1787 UAGUUGCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUGGUUCU 4949

199 GAACCAAG G GCAACUAA 1788 UUAGUUGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUUGGUUC 4950

216 AGCCGUCA G GUUCUGAA 1789 UUCAGAAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGACGGCU 4951

230 GAACAGCU G GUAGAUGG 1790 CCAUCUAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCUGUUC 4952

Table VHI

234 AGCUGGUA G AUGGGCUG 1791 CAGCCCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UACCAGCU 4953

237 UGGUAGAU G GGCUGGCU 1792 AGCCAGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCUACCA 4954

238 GGUAGAUG G GCUGGCUU 1793 AAGCCAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUCUACC 4955

242 GAUGGGCU G GCUUACUG 1794 CAGUAAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCCCAUC 4956

253 UUACUGAA G GACAUGAU 1795 AUCAUGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCAGUAA 4957

254 UACUGAAG G ACAUGAUU 1796 AAUCAUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUCAGUA 4958

265 AUGAUUCA G ACUGUCCC 1797 GGGACAGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAAUCAU 4959

274 ACUGUCCC G GACCCAGC 1798 GCUGGGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGACAGU 4960

275 CUGUCCCG G ACCCAGCA 1799 UGCUGGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGGACAG 4961

295 CAUAUCAA G GAAGCCUU 1800 AAGGCUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGAUAUG 4962

296 AUAUCAAG G AAGCCUUA 1801 UAAGGCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUGAUAU 4963

319 GUGAGUGA G GACCAGUC 1802 GACUGGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCACUCAC 4964

320 UGAGUGAG G ACCAGUCG 1803 CGACUGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCACUCA 4965

347 GUGCCUAC G GAACGCCA 1804 UGGCGUUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUAGGCAC 4966

348 UGCCUACG G AACGCCAC 1805 GUGGCGUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGUAGGCA 4967

361 CCACACCU G GCUAAGAC 1806 GUCUUAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGUGUGG 4968

367 CUGGCUAA G ACAGAGAU 1807 AUCUCUGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUAGCCAG 4969

371 CUAAGACA G AGAUGACC 1808 GGUCAUCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGUCUUAG 4970

373 AAGACAGA G AUGACCGC 1809 GCGGUCAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCUGUCUU 4971

401 GCGACUAU G GACAGACU 1810 AGUCUGUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUAGUCGC 4972

402 CGACUAUG G ACAGACUU 1811 AAGUCUGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAUAGUCG 4973

406 UAUGGACA G ACUUCCAA 1812 UUGGAAGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGUCCAUA 4974

415 ACUUCCAA G AUGAGCCC 1813 GGGCUCAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUGGAAGU 4975

439 CCUCAGCA G GAUUGGCU 1814 AGCCAAUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCUGAGG 4976

440 CUCAGCAG G AUUGGCUG 1815 CAGCCAAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGCUGAG 4977

444 GCAGGAUU G GCUGUCUC 1816 GAGACAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAUCCUGC 4978

465 CCCAGCCA G GGUCACCA 1817 UGGUGACC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGCUGGG 4979

466 CCAGCCAG G GUCACCAU 1818 AUGGUGAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGGCUGG 4980

481 AUCAAAAU G GAAUGUAA 1819 UUACAUUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUUUUGAU 4981

482 UCAAAAUG G AAUGUAAC 1820 GUUACAUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAUUUUGA 4982

499 CCUAGCCA G GUGAAUGG 1821 CCAUUCAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGCUAGG 4983

506 AGGUGAAU G GCUCAAGG 1822 CCUUGAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUUCACCU 4984

513 UGGCUCAA G GAACUCUC 1823 GAGAGUUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUGAGCCA 4985

514 GGCUCAAG G AACUCUCC 1824 GGAGAGUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUUGAGCC 4986

538 UGCAGUGU G GCCAAAGG 1825 CCUUUGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACACUGCA 4987

545 UGGCCAAA G GCGGGAAG 1826 CUUCCCGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUUGGCCA 4988

Table Vffl

548 CCAAAGGC G GGAAGAUG 1827 CAUCUUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCCUUUGG 4989

549 CAAAGGCG G GAAGAUGG 1828 CCAUCUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGCCUUUG 4990

550 AAAGGCGG G AAGAUGGU 1829 ACCAUCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGCCUUU 4991

553 GGCGGGAA G AUGGUGGG 1830 CCCACCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCCCGCC 4992

556 GGGAAGAU G GUGGGCAG 1831 CUGCCCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCUUCCC 4993

559 AAGAUGGU G GGCAGCCC 1832 GGGCUGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCAUCUU 4994

560 AGAUGGUG G GCAGCCCA 1833 UGGGCUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACCAUCU 4995

569 GCAGCCCA G ACACCGUU 1834 AACGGUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGGCUGC 4996

578 ACACCGUU G GGAUGAAC 1835 GUUCAUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AACGGUGU 4997

579 CACCGUUG G GAUGAACU 1836 AGUUCAUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAACGGUG 4998

580 ACCGUUGG G AUGAACUA 1837 UAGUUCAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCAACGGU 4999

590 UGAACUAC G GCAGCUAC 1838 GUAGCUGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUAGUUCA 5000

601 AGCUACAU G GAGGAGAA 1839 UUCUCCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUGUAGCU 5001

602 GCUACAUG G AGGAGAAG 1840 CUUCUCCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAUGUAGC 5002

604 UACAUGGA G GAGAAGCA 1841 UGCUUCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCAUGUA 5003

605 ACAUGGAG G AGAAGCAC 1842 GUGCUUCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCCAUGU 5004

607 AUGGAGGA G AAGCACAU 1843 AUGUGCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCUCCAU 5005

648 CGAGCGCA G AGUUAUCG 1844 CGAUAACU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCGCUCG 5006

665 UGCCAGCA G AUCCUACG 1845 CGUAGGAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCUGGCA 5007

678 UACGCUAU G GAGUACAG 1846 CUGUACUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUAGCGUA 5008

679 ACGCUAUG G AGUACAGA 1847 UCUGUACU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAUAGCGU 5009

686 GGAGUACA G ACCAUGUG 1848 CACAUGGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGUACUCC 5010

696 CCAUGUGC G GCAGUGGC 1849 GCCACUGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCACAUGG 5011

702 GCGGCAGU G GCUGGAGU 1850 ACUCCAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACUGCCGC 5012

706 CAGUGGCU G GAGUGGGC 1851 GCCCACUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCCACUG 5013

707 AGUGGCUG G AGUGGGCG 1852 CGCCCACU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGCCACU 5014

711 GCUGGAGU G GGCGGUGA 1853 UCACCGCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACUCCAGC 5015

712 CUGGAGUG G GCGGUGAA 1854 UUCACCGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CACUCCAG 5016

715 GAGUGGGC G GUGAAAGA 1855 UCUUUCAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCCCACUC 5017

722 CGGUGAAA G AAUAUGGC 1856 GCCAUAUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUUCACCG 5018

728 AAGAAUAU G GCCUUCCA 1857 UGGAAGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUAUUCUU 5019

737 GCCUUCCA G ACGUCAAC 1858 GUUGACGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGAAGGC 5020

760 UUAUUCCA G AACAUCGA 1859 UCGAUGUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGAAUAA 5021

770 ACAUCGAU G GGAAGGAA 1860 UUCCUUCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUCGAUGU 5022

771 CAUCGAUG G GAAGGAAC 1861 GUUCCUUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAUCGAUG 5023

772 AUCGAUGG G AAGGAACU 1862 AGUUCCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCAUCGAU 5024

Table VIII

775 GAUGGGAA G GAACUGUG 1863 CACAGUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCCCAUC 5025

776 AUGGGAAG G AACUGUGC 1864 GCACAGUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUCCCAU 5026

787 CUGUGCAA G AUGACCAA 1865 UUGGUCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGCACAG 5027

796 AUGACCAA G GACGACUU 1866 AAGUCGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGGUCAU 5028

797 UGACCAAG G ACGACUUC 1867 GAAGUCGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUGGUCA 5029

808 GACUUCCA G AGGCUCAC 1868 GUGAGCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGAAGUC 5030

810 CUUCCAGA G GCUCACCC 1869 GGGUGAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUGGAAG 5031

864 CUACCUCA G AGAGACUC 1870 GAGUCUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAGGUAG 5032

866 ACCUCAGA G AGACUCCU 1871 AGGAGUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUGAGGU 5033

868 CUCAGAGA G ACUCCUCU 1872 AGAGGAGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUCUGAG 5034

893 UGACUUCA G AUGAUGUU 1873 AACAUCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAAGUCA 5035

927 CUCUCCAC G GUUAAUGC 1874 GCAUUAAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUGGAGAG 5036

942 GCAUGCUA G AAACACAG 1875 CUGUGUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAGCAUGC 5037

950 GAAACACA G AUUUACCA 1876 UGGUAAAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGUGUUUC 5038

972 GCCCCCCA G GAGAUCAG 1877 CUGAUCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGGGGGC 5039

973 CCCCCCAG G AGAUGAGC 1878 GCUGAUCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGGGGGG 5040

975 CCCCAGGA G AUCAGCCU 1879 AGGCUGAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCUGGGG 5041

984 AUCAGCCU G GACCGGUC 1880 GACCGGUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGCUGAU 5042

985 UCAGCCUG G ACCGGUCA 1881 UGACCGGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGGCUGA 5043

989 CCUGGACC G GUCACGGC 1882 GCCGUGAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGUCCAGG 5044

995 CCGGUCAC G GCCACCCC 1883 GGGGUGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUGACCGG 5045

1058 AAACUGAA G ACCAGCGU 1884 ACGCUGGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCAGUUU 5046

1076 CUCAGUUA G AUCCUUAU 1885 AUAAGGAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UAACUGAG 5047

1087 CCUUAUCA G AUUCUUGG 1886 CCAAGAAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGAUAAGG 5048

1094 AGAUUCUU G GACCAACA 1887 UGUUGGUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAGAAUCU 5049

1095 GAUUCUUG G ACCAACAA 1888 UUGUUGGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAAGAAUC 5050

1124 CAAAUCCA G GCAGUGGC 1889 GCCACUGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGAUUUG 5051

1130 CAGGCAGU G GCCAGAUC 1890 GAUCUGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACUGCCUG 5052

1135 AGUGGCCA G AUCCAGCU 1891 AGCUGGAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGCCACU 5053

1146 CCAGCUUU G GCAGUUCC 1892 GGAACUGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAAGCUGG 5054

1159 UUCCUCCU G GAGCUCCU 1893 AGGAGCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGAGGAA 5055

1160 UCCUCCUG G AGGUCCUG 1894 CAGGAGCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGGAGGA 5056

1171 CUCCUGUC G GACAGCUC 1895 GAGCUGUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GACAGGAG 5057

1172 UCCUGUCG G ACAGCUCC 1896 GGAGCUGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGACAGGA 5058

1200 CAUCACCU G GGAAGGCA 1897 UGCCUUCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGGUGAUG 5059

1201 AUCACCUG G GAAGGCAC 1898 GUGCCUUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGGUGAU 5060

Table VIII

1202 UCACCUGG G AAGGCACC 1899 GGUGCCUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAGGUGA 5061

1205 CCUGGGAA G GCACCAAC 1900 GUUGGUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCCCAGG 5062

1214 GCACCAAC G GGGAGUUC 1901 GAACUCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUUGGUGC 5063

1215 CACCAACG G GGAGUUCA 1902 UGAACUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGUUGGUG 5064

1216 ACCAACGG G GAGUUCAA 1903 UUGAACUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGUUGGU 5065

1217 CCAACGGG G AGUUCAAG 1904 CUUGAACU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCGUUGG 5066

1225 GAGUUCAA G AUGACGGA 1905 UCCGUCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGAACUC 5067

1231 AAGAUGAC G GAUCCCGA 1906 UCGGGAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GUCAUCUU 5068

1232 AGAUGACG G AUCCCGAC 1907 GUCGGGAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGUCAUCU 5069

1243 CCCGACGA G GUGGCCCG 1908 CGGGCCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCGUCGGG 5070

1246 GACGAGGU G GCCCGGCG 1909 CGCCGGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCUCGUC 5071

1251 GGUGGCCC G GCGCUGGG 1910 CCCAGCGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGGCCACC 5072

1257 CCGGCGCU G GGGAGAGC 1911 GCUCUCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCGCCGG 5073

1258 CGGCGCUG G GGAGAGCG 1912 CGCUCUCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGCGCCG 5074

1259 GGCGCUGG G GAGAGCGG 1913 CCGCUCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCAGCGCC 5075

1260 GCGCUGGG G AGAGCGGA 1914 UCCGCUCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCCAGCGC 5076

1262 GCUGGGGA G AGCGGAAG 1915 CUUCCGCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCCCAGC 5077

1266 GGGAGAGC G GAAGAGCA 1916 UGCUCUUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCUCUCCC 5078

1267 GGAGAGCG G AAGAGCAA 1917 UUGCUCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGCUCUCC 5079

1270 GAGCGGAA G AGCAAACC 1918 GGUUUGCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCCGCUC 5080

1330 UAUGACAA G AACAUCAU 1919 AUGAUGUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUGUCAUA 5081

1345 AUGACCAA G GUCCAUGG 1920 CCAUGGAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUGGUCAU 5082

1352 AGGUCCAU G GGAAGCGC 1921 GCGCUUCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUGGACCU 5083

1353 GGUCCAUG G GAAGCGCU 1922 AGCGCUUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAUGGACC 5084

1354 GUCCAUGG G AAGCGCUA 1923 UAGCGCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCAUGGAC 5085

1385 ACUUCCAC G GGAUCGCC 1924 GGCGAUCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GUGGAAGU 5086

1386 CUUCCACG G GAUCGCCC 1925 GGGCGAUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGUGGAAG 5087

1387 UUCCACGG G AUCGCCCA 1926 UGGGCGAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCGUGGAA 5088

1396 AUCGCCCA G GCCCUCCA 1927 UGGAGGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGGGCGAU 5089

1417 CACCCCCC G GAGUCAUC 1928 GAUGACUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGGGGGUG 5090

1418 ACCCCCCG G AGUCAUCU 1929 AGAUGACU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGGGGGGU 5091

1445 ACCCCUCA G ACCUCCCG 1930 CGGGAGGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGAGGGGU 5092

1459 CCGUACAU G GGCUCCUA 1931 UAGGAGCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUGUACGG 5093

1460 CGUACAUG G GCUCCUAU 1932 AUAGGAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAUGUACG 5094

1483 CACCCACA G AAGAUGAA 1933 UUCAUCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGUGGGUG 5095

1486 CCACAGAA G AUGAACUU 1934 AAGUUCAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCUGUGG 5096

Table VIII

1498 AACUUUGU G GCGCCCCA 1935 UGGGGCGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAAAGUU 5097

1563 CCCAUACU G GAAUUCAC 1936 GUGAAUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUAUGGG 5098

1564 CCAUACUG G AAUUCACC 1937 GGUGAAUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGUAUGG 5099

1577 CACCAACU G GGGGUAUA 1938 UAUACCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUUGGUG 5100

1578 ACCAACUG G GGGUAUAU 1939 AUAUACCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGUUGGU 5101

1579 CCAACUGG G GGUAUAUA 1940 UAUAUACC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAGUUGG 5102

1580 CAACUGGG G GUAUAUAC 1941 GUAUAUAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCAGUUG 5103

1599 CAACACUA G GCUCCCCA 1942 UGGGGAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAGUGUUG 5104

1630 UCUCAUCU G GGCACUUA 1943 UAAGUGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGAUGAGA 5105

1631 CUCAUCUG G GCACUUAC 1944 GUAAGUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGAUGAG 5106

1647 CUACUAAA G ACCUGGCG 1945 CGCCAGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUAGUAG 5107

1652 AAAGACCU G GCGGAGGC 1946 GCCUCCGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGGUCUUU 5108

1655 GACCUGGC G GAGGCUUU 1947 AAAGCCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GCCAGGUC 5109

1656 ACCUGGCG G AGGCUUUU 1948 AAAAGCCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGCCAGGU 5110

1658 CUGGCGGA G GCUUUUCC 1949 GGAAAAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCGCCAG 5111

1708 ACUCUAUC G GAGAACAU 1950 AUGUUCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GAUAGAGU 5112

1709 CUCUAUCG G AGAACAUG 1951 CAUGUUCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGAUAGAG 5113

1711 CUAUCGGA G AACAUGAA 1952 UUCAUGUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCGAUAG 5114

1735 UGCCUCAA G AGGAAUGA 1953 UCAUUCCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUGAGGCA 5115

1737 CCUCAAGA G GAAUGAAA 1954 UUUCAUUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCUUGAGG 5116

1738 CUCAAGAG G AAUGAAAA 1955 UUUUCAUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCUUGAG 5117

1757 GCUUUACU G GGGCUGGG 1956 CCCAGCCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGUAAAGC 5118

1758 CUUUACUG G GGCUGGGG 1957 CCCCAGCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGUAAAG 5119

1759 UUUACUGG G GCUGGGGA 1958 UCCCCAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCAGUAAA 5120

1763 CUGGGGGU G GGGAAGGA 1959 UCCUUCCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGCCCCAG 5121

1764 UGGGGCUG G GGAAGGAA 1960 UUCCUUCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGCCCCA 5122

1765 GGGGCUGG G GAAGGAAG 1961 cuuccuuc GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCAGCCCC 5123

1766 GGGCUGGG G AAGGAAGC 1962 GCUUCCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCCAGCCC 5124

1769 CUGGGGAA G GAAGCCGG 1963 CCGGCUUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCCCCAG 5125

1770 UGGGGAAG G AAGCCGGG 1964 CCCGGCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUUCCCCA 5126

1776 AGGAAGCC G GGGAAGAG 1965 CUCUUCCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GGCUUCCU 5127

1777 GGAAGCCG G GGAAGAGA 1966 ucucuucc GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CGGCUUCC 5128

1778 GAAGCCGG G GAAGAGAU 1967 AUCUCUUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCGGCUUC 5129

1779 AAGCCGGG G AAGAGAUC 1968 GAUCUCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCCGGCUU 5130

1782 CCGGGGAA G AGAUCCAA 1969 UUGGAUCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCCCCGG 5131

1784 GGGGAAGA G AUCCAAAG 1970 CUUUGGAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCUUCCCC 5132

Table VIII

1792 GAUCCAAA G ACUCUUGG 1971 CCAAGAGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUGGAUC 5133

1799 AGACUCUU G GGAGGGAG 1972 CUCCCUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAGAGUCU 5134

1800 GACUCUUG G GAGGGAGU 1973 ACUCCCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAAGAGUC 5135

1801 ACUCUUGG G AGGGAGUU 1974 AACUCCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAAGAGU 5136

1803 UCUUGGGA G GGAGUUAC 1975 GUAACUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCCAAGA 5137

1804 CUUGGGAG G GAGUUACU 1976 AGUAACUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCCCAAG 5138

1805 UUGGGAGG G AGUUACUG 1977 CAGUAACU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUCCCAA 5139

1827 UUACUACA G AAAUGAGG 1978 CCUCAUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUAGUAA 5140

1834 AGAAAUGA G GAGGAUGC 1979 GCAUCCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCAUUUCU 5141

1835 GAAAUGAG G AGGAUGCU 1980 AGCAUCCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCAUUUC 5142

1837 AAUGAGGA G GAUGCUAA 1981 UUAGCAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUCAUU 5143

1838 AUGAGGAG G AUGCUAAA 1982 UUUAGCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCCUCAU 5144

1861 ACGAAUAU G GACAUAUC 1983 GAUAUGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUAUUCGU 5145

1862 CGAAUAUG G ACAUAUCA 1984 UGAUAUGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAUAUUCG 5146

1876 UCAUCUGU G GACUGACC 1985 GGUCAGUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACAGAUGA 5147

1877 CAUCUGUG G ACUGACCU 1986 AGGUCAGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CACAGAUG 5148

1893 UUGUAAAA G ACAGUGUA 1987 UACACUGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUUUACAA 5149

1906 UGUAUGUA G AAGCAUGA 1988 UCAUGCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UACAUACA 5150

1923 AGUCUUAA G GACAAAGU 1989 ACUUUGUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUAAGACU 5151

1924 GUCUUAAG G ACAAAGUG 1990 CACUUUGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUUAAGAC 5152

1938 GUGCCAAA G AAAGUGGU 1991 ACCACUUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUUGGCAC 5153

1944 AAGAAAGU G GUCUUAAG 1992 CUUAAGAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACUUUCUU 5154

1952 GGUCUUAA G AAAUGUAU 1993 AUACAUUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUAAGACC 5155

1969 AAAGUUUA G AGUAGAGU 1994 ACUCUACU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UAAAGUUU 5156

1974 UUAGAGUA G AGUUUGAA 1995 UUCAAACU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UACUCUAA 5157

2000 UGCAAACU G GGAUGAAA 1996 UUUCAUCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGUUUGCA 5158

2001 GCAAACUG G GAUGAAAC 1997 GUUUCAUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAGUUUGC 5159

2002 CAAACUGG G AUGAAACU 1998 AGUUUCAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCAGUUUG 5160

2020 AAGCAAUA G AAACAACA 1999 UGUUGUUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UAUUGCUU 5161

2068 CAUUUUAA G GAAAACUA 2000 UAGUUUUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUAAAAUG 5162

2069 AUUUUAAG G AAAACUAC 2001 GUAGUUUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUUAAAAU 5163

2111 AAAAACAA G AGAAAAGA 2002 UCUUUUCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUGUUUUU 5164

2113 AAACAAGA G AAAAGACA 2003 UGUCUUUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCUUGUUU 5165

2118 AGAGAAAA G ACACGAGA 2004 UCUCGUGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUUUCUCU 5166

2125 AGACACGA G AGAGACUG 2005 CAGUCUCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCGUGUCU 5167

2127 ACACGAGA G AGACUGUG 2006 CACAGUCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCUCGUGU 5168

Table VIII

2129 ACGAGAGA G ACUGUGGC 2007 GCCACAGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUCUCGU 5169

2135 GAGACUGU G GCCCAUCA 2008 UGAUGGGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAGUCUG 5170

2147 CAUCAACA G ACGUUGAU 2009 AUCAACGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUUGAUG 5171

2168 AACUGCAU G GCAUGUGC 2010 GCACAUGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUGCAGUU 5172

2183 GCUGUUUU G GUUGAAAU 2011 AUUUCAAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AAAACAGC 5173

2211 CGUUUGAU G GACAGCUG 2012 CAGCUGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AUCAAACG 5174

2212 GUUUGAUG G ACAGCUGU 2013 ACAGCUGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAUCAAAC 5175

2241 ACUGUGAA G AUGACCCA 2014 UGGGUCAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCACAGU 5176

2278 GUAUUACC G GGACUAUG 2015 CAUAGUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG GGUAAUAC 5177

2279 UAUUACCG G GACUAUGA 2016 UCAUAGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CGGUAAUA 5178

2280 AUUACCGG G ACUAUGAA 2017 UUCAUAGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCGGUAAU 5179

2295 AACUAAAA G GUGGGACU 2018 AGUCCCAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUUAGUU 5180

2298 UAAAAGGU G GGACUGAG 2019 CUCAGUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACCUUUUA 5181

2299 AAAAGGUG G GACUGAGG 2020 CCUCAGUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CACCUUUU 5182

2300 AAAGGUGG G ACUGAGGA 2021 UCCUCAGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCACCUUU 5183

2306 GGGACUGA G GAUGUGUA 2022 UACACAUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCAGUCCC 5184

2307 GGACUGAG G AUGUGUAU 2023 AUACACAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCAGUCC 5185

2317 UGUGUAUA G AGUGAGCG 2024 CGCUCACU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UAUACACA 5186

2336 UGAUUGUA G ACAGAGGG 2025 CCCUCUGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UACAAUCA 5187

2340 UGUAGACA G AGGGGUGA 2026 UCACCCCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGUCUACA 5188

2342 UAGACAGA G GGGUGAAG 2027 CUUCACCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCUGUCUA 5189

2343 AGACAGAG G GGUGAAGA 2028 UCUUCACC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCUGUCU 5190

2344 GACAGAGG G GUGAAGAA 2029 UUCUUCAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCUCUGUC 5191

2350 GGGGUGAA G AAGGAGGA 2030 UCCUCCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCACCCC 5192

2353 GUGAAGAA G GAGGAGGA 2031 UCCUCCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCUUCAC 5193

2354 UGAAGAAG G AGGAGGAA 2032 uuccuccu GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUUCUUCA 5194

2356 AAGAAGGA G GAGGAAGA 2033 ucuuccuc GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG uccuucuu 5195

2357 AGAAGGAG G AGGAAGAG 2034 cucuuccu GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG cuccuucu 5196

2359 AAGGAGGA G GAAGAGGC 2035 GCCUCUUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCUCCUU 5197

2360 AGGAGGAG G AAGAGGCA 2036 UGCCUCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG cuccuccu 5198

2363 AGGAGGAA G AGGCAGAG 2037 CUCUGCCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG uuccuccu 5199

2365 GAGGAAGA G GCAGAGAA 2038 UUCUCUGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ucuuccuc 5200

2369 AAGAGGCA G AGAAGGAG 2039 cuccuucu GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCCUCUU 5201

2371 GAGGCAGA G AAGGAGGA 2040 UCCUCCUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCUGCCUC 5202

2374 GCAGAGAA G GAGGAGAC 2041 GUCUCCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUCUCUGC 5203

2375 CAGAGAAG G AGGAGACC 2042 GGUCUCCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUUCUCUG 5204

Table VIII

2377 GAGAAGGA G GAGACCAG 2043 CUGGUCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUUCUC 5205

2378 AGAAGGAG G AGACCAGG 2044 CCUGGUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUCCUUCU 5206

2380 AAGGAGGA G ACCAGGCU 2045 AGCCUGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCUCCUU 5207

2385 GGAGACCA G GCUGGGAA 2046 UUCCCAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGUCUCC 5208

2389 ACCAGGCU G GGAAAGAA 2047 UUCUUUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGCCUGGU 5209

2390 CCAGGCUG G GAAAGAAA 2048 UUUCUUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGCCUGG 5210

2391 CAGGCUGG G AAAGAAAC 2049 GUUUCUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCAGCCUG 5211

2395 CUGGGAAA G AAACUUCU 2050 AGAAGUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUUCCCAG 5212

2415 GCAAUGAA G ACUGGACU 2051 AGUCCAGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUCAUUGC 5213

2419 UGAAGACU G GACUCAGG 2052 CCUGAGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG AGUCUUCA 5214

2420 GAAGACUG G ACUCAGGA 2053 UCCUGAGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGUCUUC 5215

2426 UGGACUCA G GACAUUUG 2054 CAAAUGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAGUCCA 5216

2427 GGACUGAG G ACAUUUGG 2055 CCAAAUGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGAGUCC 5217

2434 GGACAUUU G GGGACUGU 2056 ACAGUCCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAAUGUCC 5218

2435 GACAUUUG G GGACUGUG 2057 CACAGUCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAAAUGUC 5219

2436 ACAUUUGG G GACUGUGU 2058 ACACAGUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCAAAUGU 5220

2437 CAUUUGGG G ACUGUGUA 2059 UACACAGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCCAAAUG 5221

2457 UGAGUUAU G GAGACUCG 2060 CGAGUCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUAACUCA 5222

2458 GAGUUAUG G AGACUCGA 2061 UCGAGUCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAUAACUC 5223

2460 GUUAUGGA G ACUCGAGG 2062 CCUCGAGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCAUAAC 5224

2467 AGACUCGA G GGUUCAUG 2063 CAUGAACC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCGAGUCU 5225

2468 GACUCGAG G GUUCAUGC 2064 GCAUGAAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUCGAGUC 5226

2505 CAGUGUUA G GAGAAAGG 2065 CCUUUCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UAACACUG 5227

2506 AGUGUUAG G AGAAAGGA 2066 UCCUUUCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUAACACU 5228

2508 UGUUAGGA G AAAGGACA 2067 UGUCCUUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCUAACA 5229

2512 AGGAGAAA G GACACAGC 2068 GCUGUGUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUUCUCCU 5230

2513 GGAGAAAG G ACACAGCG 2069 CGCUGUGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUUUCUCC 5231

2526 AGCGUAAU G GAGAAAGG 2070 CCUUUCUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUUACGCU 5232

2527 GCGUAAUG G AGAAAGGG 2071 CCCUUUCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAUUACGC 5233

2529 GUAAUGGA G AAAGGGAA 2072 uucccuuu GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCCAUUAC 5234

2533 UGGAGAAA G GGAAGUAG 2073 CUACUUCC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUUCUCCA 5235

2534 GGAGAAAG G GAAGUAGU 2074 ACUACUUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUUUCUCC 5236

2535 GAGAAAGG G AAGUAGUA 2075 UACUACUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CCUUUCUC 5237

2544 AAGUAGUA G AAUUCAGA 2076 UCUGAAUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UACUACUU 5238

2551 AGAAUUCA G AAACAAAA 2077 UUUUGUUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGAAUUCU 5239

2602 UUUUAACU G GAAUUGUC 2078 GACAAUUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AGUUAAAA 5240

Table VHI

2603 UUUAACUG G AAUUGUCU 2079 AGACAAUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CAGUUAAA 5241

2621 AUAUUUAA G AGAAACAU 2080 AUGUUUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUAAAUAU 5242

2623 AUUUAAGA G AAACAUUC 2081 GAAUGUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCUUAAAU 5243

2633 AACAUUCA G GACCUCAU 2082 AUGAGGUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGAAUGUU 5244

2634 ACAUUCAG G ACCUCAUC 2083 GAUGAGGU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGAAUGU 5245

2650 CAUUAUGU G GGGGCUUU 2084 AAAGCCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG ACAUAAUG 5246

2651 AUUAUGUG G GGGCUUUG 2085 CAAAGCCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACAUAAU 5247

2652 UUAUGUGG G GGCUUUGU 2086 ACAAAGCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCACAUAA 5248

2653 UAUGUGGG G GCUUUGUU 2087 AACAAAGC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCCACAUA 5249

2669 UCUCCACA G GGUCAGGU 2088 ACCUGACC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGUGGAGA 5250

2670 CUCCACAG G GUCAGGUA 2089 UACCUGAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGUGGAG 5251

2675 CAGGGUCA G GUAAGAGA 2090 UCUCUUAC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGACCCUG 5252

2680 UCAGGUAA G AGAUGGCC 2091 GGCCAUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUACCUGA 5253

2682 AGGUAAGA G AUGGCCUU 2092 AAGGCCAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCUUACCU 5254

2685 UAAGAGAU G GCCUUCUU 2093 AAGAAGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUCUCUUA 5255

2694 GCCUUCUU G GCUGCCAC 2094 GUGGCAGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAGAAGGC 5256

2708 CACAAUCA G AAAUCACG 2095 CGUGAUUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGAUUGUG 5257

2719 AUCACGCA G GCAUUUUG 2096 CAAAAUGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCGUGAU 5258

2727 GGCAUUUU G GGUAGGCG 2097 CGCCUACC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAAAUGCC 5259

2728 GCAUUUUG G GUAGGCGG 2098 CCGCCUAC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CAAAAUGC 5260

2732 UUUGGGUA G GCGGCCUC 2099 GAGGCCGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UACCCAAA 5261

2735 GGGUAGGC G GCCUCCAG 2100 CUGGAGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GCCUACCC 5262

2779 GUUUGUCA G AAUGAAGU 2101 ACUUCAUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGACAAAC 5263

2864 UUGAUCUC G GCCAGCCA 2102 UGGCUGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG GAGAUCAA 5264

2875 CAGCCAAA G ACACACGA 2103 UCGUGUGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUUGGCUG 5265

2889 CGACAAAA G AGACAAUC 2104 GAUUGUCU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UUUUGUCG 5266

2891 ACAAAAGA G ACAAUCGA 2105 UCGAUUGU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UCUUUUGU 5267

2908 UAUAAUGU G GCCUUGAA 2106 UUCAAGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACAUUAUA 5268

2966 AGUUCUUA G AAUGCAGA 2107 UCUGCAUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UAAGAACU 5269

2973 AGAAUGCA G AAUGUAUG 2108 CAUACAUU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGCAUUCU 5270

2997 AUAAGCUU G GCCUAGCA 2109 UGCUAGGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AAGCUUAU 5271

3007 CCUAGCAU G GCAAAUCA 2110 UGAUUUGC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG AUGCUAGG 5272

3016 GCAAAUCA G AUUUAUAC 2111 GUAUAAAU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGAUUUGC 5273

3026 UUUAUACA G GAGUCUGC 2112 GCAGACUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG UGUAUAAA 5274

3027 UUAUACAG G AGUCUGCA 2113 UGCAGACU GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG CUGUAUAA 5275

3092 AAUGUUGU G GAUUUUGU 2114 ACAAAAUC GGAGGAAACUCC cu UCAAGGACAUCGUCCGGG ACAACAUU 5276

Table VHI

3093 AUGUUGUG G AUUUUGUG 2115 CACAAAAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CACAACAU 5277

3121 UUUGUCCA G GAACUUGU 2116 ACAAGUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UGGACAAA 5278

3122 UUGUCCAG G AACUUGUG 2117 CACAAGUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUGGACAA 5279

3134 UUGUGCAA G GGAGAGCC 2118 GGCUCUCC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGCACAA 5280

3135 UGUGCAAG G GAGAGCCA 2119 UGGCUCUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUGCACA 5281

3136 GUGCAAGG G AGAGCCAA 2120 UUGGCUCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CCUUGCAC 5282

3138 GCAAGGGA G AGCCAAGG 2121 CCUUGGCU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UCCCUUGC 5283

3145 AGAGCCAA G GAAAUAGG 2122 CCUAUUUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UUGGCUCU 5284

3146 GAGCCAAG G AAAUAGGA 2123 UCCUAUUU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUUGGCUC 5285

3152 AGGAAAUA G GAUGUUUG 2124 CAAACAUC GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG UAUUUCCU 5286

3153 GGAAAUAG G AUGUUUGG 2125 CCAAACAU GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG CUAUUUCC 5287

Input Sequence = HUMERG2. Cut Site = G/ .

Stem Length = 8. Core Sequence = GGAGGAAACUCC CU UCAAGGACAUCGUCCGGG

HUMERG2 (Human erg2 gene encoding erg2 protein, complete eds.; 3166 bp)

Table IX: Human ERG GeneBloc and Target Sequence

Input Sequence = HUMERG2

GB Length = 23

HUMERG2 (Human erg2 gene encoding erg2 protein, complete eds. 3166 bp)

UPPER CASE =DNA lower case =2'-0-methyl

B = 3 '-3 '-inverted deoxyabasic ribonucleoside s = phosphorothioate residue n = a, g, c, u 2'-0-methyl

Table X

Table X: Genes down-regulated by Erg Geneblocs

Table XI

Table XI: Taqman endogenous controls

RNA from HUVEC treated with Erg GB or confrol GB was assayed for expression of the above controls. Data shown represent differences in c numbers (when a significant amount of product is detected) between the two samples. The value closest to zero was chosen as the confrol for subsequent experiments.

Claims

CLAIMS What is claimed is:

1. A nucleic acid molecule which down regulates expression of an ERG gene.

2. The nucleic acid of claim 1, wherein said nucleic acid molecule is used to treat conditions selected from the group consisting of cancer, lymphoma, Ewing's sarcoma, melanoma, tumor angiogenesis, diabetic retinopathy, macular degeneration, neovascular glaucoma, myopic degeneration, arthritis, psoriasis, verruca vulgaris, angiofibroma of tuberous sclerosis, pot-wine stains, Sturge Weber syndrome, Kippel-Trenaunay- Weber syndrome, Osier- Weber-rendu syndrome, leukemia, osteoporosis, wound healing and others.

3. The nucleic acid molecule of claim 1, wherein said nucleic acid molecule is an enzymatic nucleic acid molecule.

4. The nucleic acid of claim 3, wherein a binding arm of said enzymatic nucleic acid molecule comprise sequences complementary to any of sequences defined as Sequence ID Nos. 1-2125 and 5288-5307.

5. The nucleic acid molecule of claim 3, wherein said enzymatic nucleic acid molecule comprises any of sequences defined as sequence ID Nos. 2126-5287.

6. The nucleic acid molecule of claim 1, wherein said nucleic acid molecule is an antisense nucleic acid molecule.

7. The nucleic acid molecule of claim 6, wherein said antisense nucleic acid molecule comprises sequence complementary to any of sequence defined as Sequence ID Nos. 1- 2125 and 5288-5307.

8. The nucleic acid molecule of claim 6, wherein said antisense nucleic acid molecule comprise any of sequences defined as sequence ID Nos. 5308-5327.

9. The nucleic acid molecule of claim 3, wherein said enzymatic nucleic acid molecule is in a hammerhead (HH) motif.

10. The nucleic acid molecule of claim 3, wherein said enzymatic nucleic acid molecule is in a hairpin, hepatitis Delta virus, group I intron, VS nucleic acid, amberzyme, zinzyme or RNAse P nucleic acid motif.

11. The nucleic acid molecule of claim 3, wherein said enzymatic nucleic acid molecule is in an Inozyme motif.

12. The nucleic acid molecule of claim 3, wherein said enzymatic nucleic acid molecule is in a G-cleaver motif.

13. The nucleic acid molecule of claim 3, wherein said enzymatic nucleic acid molecule is a DNAzyme.

14. The nucleic acid molecule of any of claims 3 or 6, wherein said nucleic acid molecule comprises between 12 and 100 bases complementary to the RNA of ERG gene.

15. The nucleic acid of any of claims 3 or 6, wherein said enzymatic nucleic acid molecule comprises between 14 and 24 bases complementary to the RNA of ERG gene.

16. The nucleic acid molecule of claim 1, wherein said nucleic acid is chemically synthesized.

17. The nucleic acid molecule of claim 1, wherein said nucleic acid comprises at least one 2 '-sugar modification.

18. The nucleic acid molecule of claim 1, wherein said nucleic acid comprises at least one nucleic acid base modification.

19. The nucleic acid molecule of claim 1, wherein said nucleic acid comprises at least one phosphate backbone modification.

20. A mammalian cell including the nucleic acid molecule of claim 1.

21. The mammalian cell of claim 20, wherein said mammalian cell is a human cell.

22. A method of reducing ERG activity in a cell, comprising the step of contacting said cell with the nucleic acid molecule of claim 1, under conditions suitable for said reduction of ERG activity.

23. A method of treatment of a patient having a condition associated with the level of ERG, comprising contacting cells of said patient with the nucleic acid molecule of claim 1, under conditions suitable for said treatment.

24. The method of claim 23 further comprising the use of one or more therapies under conditions suitable for said freatment.

25. A method of cleaving RNA of ERG gene, comprising, contacting the nucleic acid molecule of claim 3, with said RNA under conditions suitable for the cleavage of said

RNA.

26. The method of claim 25, wherein said cleavage is carried out in the presence of a divalent cation.

27. The method of claim 26, wherein said divalent cation is Mg2+.

28. The nucleic acid molecule of claim 1, wherein said nucleic acid comprises a cap structure, wherein the cap structure is at the 5 '-end or 3 '-end or both the 5 '-end and the 3 '-end.

29. The enzymatic nucleic acid molecule of claim 9, wherein said hammerhead motif comprises sequences complementary to any of sequences shown as Seq ID Nos 1-491.

30. The enzymatic nucleic acid molecule of claim 11, wherein said Inozyme motif comprises sequences complementary to any of sequences shown as Seq ID Nos 492-1152.

31. The enzymatic nucleic acid molecule of claim 12, wherein said G-cleaver motif comprises sequences complementary to any of sequences shown as Seq ID Nos 1153-

1360.

32. The enzymatic nucleic acid molecule of claim 13, wherein said DNAzyme comprises sequences complementary to any sequence shown as substrate sequences in Table VII.

33. The enzymatic nucleic acid molecule of claim 10, wherein said zinzyme comprises sequences complementary to any sequence shown as substrate sequences in Table VI.

34. The enzymatic nucleic acid molecule of claim 10, wherein said amberzyme comprises sequences complementary to any sequence shown as substrate sequences in Table VIII.

35. An expression vector comprising nucleic acid sequence encoding at least one nucleic acid molecule of claim 1, in a manner which allows expression of that nucleic acid molecule.

36. A mammalian cell including an expression vector of claim 35.

37. The mammalian cell of claim 36, wherein said mammalian cell is a human cell.

38. The expression vector of claim 35, wherein said nucleic acid molecule is an enzymatic nucleic acid molecule.

39. The expression vector of claim 35, wherein said expression vector further comprises a sequence for an antisense nucleic acid molecule complementary to the RNA of ERG gene.

40. The expression vector of claim 35, wherein said expression vector comprises sequence encoding at least two said nucleic acid molecules, which may be same or different.

41. The expression vector of claim 40, wherein one said expression vector further comprises sequence encoding antisense nucleic acid molecule complementary to the RNA of ERG gene.

42. The expression vector of claim 40, wherein one said expression vector further comprises sequence encoding enzymatic nucleic acid molecule complementary to the RNA of ERG gene.

43. A method for freatment of tumor angiogenesis comprising the step of administering to a patient the nucleic acid molecule of claim 1 under conditions suitable for said freatment.

44. A method for treatment of leukemia comprising the step of administering to a patient the nucleic acid molecule of claim 1 under conditions suitable for said freatment.

45. An enzymatic nucleic acid molecule which cleaves RNA derived from ERG gene.

46. The enzymatic nucleic acid molecule of claim 45, wherein said enzymatic nucleic acid molecule is selected from the group consisting of Hammerhead, Hairpin, Inozyme, G- cleaver, DNAzyme, Amberzyme and Zinzyme.

47. The method of any of claims 43 or 44, wherein said method further comprises administering to said patient the nucleic acid molecule of claim 1 in conjunction with one or more of other therapies.

48. The method of claim 47, wherem said other therapies are therapies selected from the group consisting of radiation and chemotherapy treatment.

49. The nucleic acid molecule of claim 7, wherein said nucleic acid molecule comprises at least five ribose residues; at least ten 2'-O-methyl modifications, and a 3'- end modification.

50. The nucleic acid molecule of claim 49, wherein said nucleic acid molecule further comprises a phosphorothioate core with both 3' and 5' -end modifications.

51. The nucleic acid molecule of any of claims 49 and 50, wherein said 3' and/or 5'- end modification is 3 '-3' inverted abasic moiety.

52. The nucleic acid molecule of claim 3, wherem said nucleic acid molecule comprises at least five ribose residues; at least ten 2'-O-methyl modifications, and a 3'- end modification.

53. The nucleic acid molecule of claim 52, wherein said nucleic acid molecule further comprises phosphorothioate linkages on at least three of the 5' terminal nucleotides.

54. The nucleic acid molecule of claim 52, wherein said 3'- end modification is 3'-3' inverted abasic moiety.

55. The enzymatic nucleic acid molecule of claim 13, wherein said DNAzyme comprises at least ten 2'-O-methyl modifications.

56. The enzymatic nucleic acid molecule of claim 55, wherein said DNAzyme further comprises phosphorothioate linkages on at least three of the 5' terminal nucleotides.

57. The enzymatic nucleic acid molecule of claim 55, wherein said DNAzyme further comprises a 3 '-end modification.

58. The enzymatic nucleic acid molecule of claim 57, wherein said 3'- end modification is 3 '-3 ' inverted abasic moiety.