KR20120097483A - Method for genome editing - Google Patents

Abstract

The invention includes a method of creating an animal or cell with at least one chromosome editing. In particular, the present invention relates to the use of targeted zinc finger nucleases to edit chromosomal sequences. The invention further includes animals or cells created by the methods of the invention.

Description

METHOD FOR GENOME EDITING

Reference to Sequence Listing

Computer readable forms of the Sequence Listing that are identical to written copies of the Sequence Listing are attached below and incorporated in their entirety. Information recorded in computer readable form 37 C.F.R. It is identical to the written sequence listing in accordance with 1.821 (f).

Field of invention

The invention includes a method of making an animal or cell in which at least one chromosome has been edited. In particular, the present invention relates to the use of targeted zinc finger nucleases to edit chromosomal sequences.

Rational genomic engineering has numerous potentials for basic research, drug development, and cell-based drugs. Existing methods for targeted gene knock-out or site-specific gene insertion rely on homologous recombination. However, low rates of spontaneous recombination within certain cell types have been a major obstacle to universal genome editing. The amount of screening attempts and the time required to isolate the targeted process are enormous. Thus, in order to significantly reduce the overall engineering effort, a powerful technique for rapid genome editing with high speed and high efficiency in most cell types is needed.

Summary of the Invention

One aspect of the invention includes a method for editing a chromosomal sequence. The method comprises, in part, (a) at least one nucleic acid encoding a zinc finger nuclease capable of recognizing a target sequence in a chromosomal sequence into a cell comprising a chromosomal sequence and cleaving a cleavage site in the chromosomal sequence, and Optionally, (i) at least one donor polynucleotide comprising an integrated donor sequence, an upstream sequence, and a downstream sequence, wherein the donor sequence is on the side of the upstream and downstream sequences, and the upstream and downstream sequences The sequences share substantially sequence identity to either of the cleavage sites), or (ii) an exchange sequence substantially identical to a portion of the chromosomal sequence at the cleavage site, and at least one further comprising at least one nucleotide change Introducing a polynucleotide of; And (b) culturing the cells to express zinc finger nucleases such that the zinc finger nucleases introduce a double-strand break into the chromosomal sequence at the cleavage site, and wherein the double-strand break Is recovered by (i) a non-homologous end-binding repair process so that mutations are introduced into the chromosomal sequence, or optionally (ii) by a homologous-directed repair process, such that the donor sequence is chromosome. Either integrated into the sequence or the exchange sequence is replaced with part of a chromosomal sequence.

Another aspect of the invention includes non-human animals. Non-human animals can be made in part by: (a) a zinc finger nuclease capable of recognizing a target sequence in a chromosome sequence into a cell comprising a chromosome sequence and cleaving a cleavage site in the chromosome sequence At least one nucleic acid to encode, and optionally at least one donor polynucleotide comprising (i) an incorporating donor sequence, an upstream sequence, and a downstream sequence, wherein the donor sequence is flanked by an upstream sequence and a downstream sequence And the upstream and downstream sequences share substantially sequence identity to either of the cleavage sites), or (ii) an exchange sequence that is substantially identical to a portion of the chromosomal sequence at the cleavage site, and at least one nucleotide change. Introducing at least one polynucleotide; And (b) culturing the cells to express zinc finger nucleases such that the zinc finger nucleases introduce a double-stranded gap into the chromosomal sequence at the cleavage site, where the double-stranded gap is (i) Repaired by a non-homologous end-binding repair process such that a mutation is introduced into the chromosomal sequence, or optionally (ii) a homologous-directed repair process, such that the donor sequence is integrated into the chromosomal sequence or the exchange The sequence is replaced with part of the chromosomal sequence.

Another aspect of the invention includes a cell. This cell can be made in part by: (a) encoding a zinc finger nuclease capable of recognizing the target sequence in the chromosome sequence into the cell comprising the chromosome sequence and cleaving a cleavage site in the chromosome sequence At least one nucleic acid, and optionally at least one donor polynucleotide comprising (i) an integrated donor sequence, an upstream sequence, and a downstream sequence, wherein the donor sequence is flanked by the upstream and downstream sequences, and The upstream and downstream sequences share substantially sequence identity to either side of the cleavage site), or (ii) an exchange sequence that is substantially identical to a portion of the chromosomal sequence at the cleavage site, and at least one nucleotide change further Introducing one polynucleotide; And (b) culturing the cells to express zinc finger nucleases such that the zinc finger nucleases introduce a double-stranded gap into the chromosomal sequence at the cleavage site, where the double-stranded gap is (i) Repaired by a non-homologous end-binding repair process such that a mutation is introduced into the chromosomal sequence, or optionally (ii) a homologous-directed repair process, such that the donor sequence is integrated into the chromosomal sequence or the exchange The sequence is replaced with part of the chromosomal sequence.

A further aspect of the present invention includes an embryo. In general, embryos recognize at least one nucleic acid encoding a zinc finger nuclease capable of recognizing a target sequence in a chromosome sequence and cleaving a cleavage site in the chromosome sequence, and optionally (i) a donor sequence for integration, upstream At least one donor polynucleotide comprising a sequence, and a downstream sequence, wherein the donor sequence is on the side of the upstream and downstream sequences, and the upstream and downstream sequences share substantially sequence identity to either side of the cleavage site and Or, (ii) at least one polynucleotide further comprising an exchange sequence and at least one nucleotide change substantially identical to a portion of the chromosomal sequence at the cleavage site.

Other aspects and repeated descriptions of the invention are described more fully below.

This application includes at least one photo taken in color. Color photographs and copies of this application publication will be provided to the Secretariat upon request and with payment of the associated costs.
1 is a diagram showing the recovery results after the targeted ZFN-induced double strands split. Shaded bars represent donor fragments and white bars represent target sites for ZFN double stranded gaps.
2 is a schematic showing the structure of an RFLP donor plasmid. Plasmids and PCR-amplified left and right fragments homologous to integration target positions are shown. Restriction enzymes used for cloning are indicated. The left fragment used KpnI and NotI or PmeI. The right fragment used NotI or PmeI and SacII.
3 is a schematic showing the structure of a donor plasmid expressing GFP. GFP cassettes were PCR amplified from existing plasmids and cloned into NotI RFLP donors using NotI sites.
FIG. 4 is a schematic diagram showing (A) a method for detecting RFLP integration and restriction digestion and (B) a method for integrating a GFP expression cassette using PCR amplification.
5 is a photographic image of fluorescently colored PCR fragments dissociated on agarose gel. The leftmost line contains the DNA ladder. Lines 1 to 6 contain PCR fragments amplified using mouse Mdr1a-specific primers from all or fractions of mouse blastocysts. Lines 1 and 2 were amplified from 5/6 and 1/6 of blastocysts, respectively. Line 3 is one full blastocyst. Lines 4 to 6 are ½, mm, and 1/6 of the same blastocyst, respectively. Line 7 contains positive reference PCR fragments amplified using the same primers in DNA extracted from mouse toes.
6 is a photographic image of fluorescently colored DNA fragments dissociated on an agarose gel. The left end line contains the DNA ladder. (A) Lines 1 to 39 were mMdr1a from 37 mouse embryos cultured in vitro after microinjection of RFF donors with ZFN RNA and NotI sites against mouse Mdr1a, with one positive and negative criterion for PCR amplification. PCR fragments amplified using specific primers. (B) Lines 1 to 39 contain the PCR fragments of (A) after performing a mutation detection assay of the investigator.
7 is a photographic image of fluorescently colored DNA fragments dissociated on an agarose gel. The left end line and the right end line contain the DNA ladder. (A) Lines contain PCR fragments amplified using mMdr1a-specific primers from the mouse embryo of FIG. 6 and cleaved with Not I without purification of the PCR product. FIG. 7B shows the same gel of FIG. 7A shifted longer. Uncleaved PCR products were around 1.8 kb and cleaved products were in two bands around 900 bp.
8 is a photographic image of fluorescently colored DNA fragments dissociated on an agarose gel. The left end line contains the DNA ladder. Lines 1 to 6 contain some of the PCR fragments of FIG. 7 which were digested with NotI after column purification of the PCR products to allow NotI to work in its optimal buffer. Lines 7 and 8 are two of the samples cut with NotI as shown in FIG. This gel shows the perfect NotI digestion in the PCR reaction.
9 is a photographic image of fluorescently colored PCR fragments dissociated on agarose gel. The left end line contains the DNA ladder. Lines 1 to 5 contain PCR fragments amplified using PXR-specific primers from 1, 1/2, 1/6, 1/10, 1/30 of murine blastocysts. Line 6 is a positive criterion amplified using the same primers from Sprague Dawley purified genomic DNA.
10 is a photographic image of fluorescently colored DNA fragments dissociated on an agarose gel. The left end line and the right end line contain the DNA ladder. (A) Lines include PCR fragments amplified with PXR-specific primers from mouse embryos cultured after small injections of PXR ZFN mRNA and NotI RFLP donor and cleaved with NotI. Lines (B) contain the same PCR fragments as shown in FIG. 10A after performing the mutation detection assay of the investigator.
11 is a photographic image of fluorescently colored DNA fragments dissociated on an agarose gel. The first four lines were PCR amplified from four well-developed fetuses at 12.5 days after implantation of embryos injected with mMdr1a ZFN mRNA and NotI RFLP donor. PCR was cleaved with NotI. Line 4 is positive. Lines 5-8 are four decidua, aborted implantations. All four were negative.
12 is a photographic image of fluorescently colored DNA fragments dissociated on an agarose gel. (A) A is a schematic showing the position of the primers used. Panels (B) and (C) show the results of primers PF and GR. Panels (D) and (E) show the results of primers PR + GF. The expected fragment size is 2.4 kb. Two of the 40 fetuses were positive for GFP.
13 is a photographic image of fluorescently colored DNA fragments dissociated on an agarose gel. Line 8 represents 13 dpc fetus positive at the NotI position.
FIG. 14 illustrates ZFN-mediated cleavage of SMAD4 in human and cat and cells as detected by Cel-1 surveyor nuclease assay. G = GFP (no ZFN basis). Z = SMAD4 ZFN (191160/19159). Arrows indicate cleavage products.
Figure 15 shows Cel-1 assay confirming SMAD4 ZFN activity in cat embryos.
16 shows the cleavage of Fel d1 in AKD cells. Cel-1 screening of Fel d1 ZFN pair 17, 18 cleavage of chain 1-exon 1 is shown.
Figure 17 illustrates cleavage of Fel d1 chain 1-exon 2 by Fel d1 ZFN pair 7, 9 in AKD cells.
18 shows Cel-1 analysis of Fel d1 ZFN pair 12/13 cleavage of chain 1-exon 2 in AKD cells.
FIG. 19 illustrates cleavage of the Fel d1 locus by ZFN pairs 17, 18 and 12, 13. FIG. Lines 1, 2, 7, and 8 contain samples of individual blastocysts derived from embryos injected with 40 ng / μl ZFNs. Line 3 shows a sample of individual blastocysts derived from embryos injected with 20 ng / μl ZFNs. Lines 4, 9, and 10 contain samples of individual morula derived from embryos injected with 40 ng / μl ZFNs. Line 3 shows a sample of lost embryos derived from embryos injected with 20 ng / μl ZFNs. Line 6 represents a sample of reference blastocysts.
FIG. 20 shows the DN sequence of an edited Fel d1 locus comprising a 4541 bp deletion (SEQ ID NO: 51) between the coding portion of chain 2 and chain 1. FIG.
FIG. 21 aligns the sequence of the wild type Fel d1 locus (SEQ ID NO: 52) and the edited Fel d1 locus (marked as “sample 5”, indicated by red dotted lines), including the 4541 bp deletion. In the edited sample, the binding position for ZFN 13 was truncated (and the binding position for ZFN 12 was lost), but the binding position for ZFN pair 17, 18 is intact.
FIG. 22 shows cleavage of the cowsin locus by cauxin ZFN pair 1/2 (line 2), ZFN pair 9/10 (line 4), and ZFN pair 17/18 (line 5) in AKD cells. Indicates. Lines 1 and 3 contain samples of reference (GFP) cells.
FIG. 23 shows cleavage of the cowsin locus by cowsin ZFN pair 29/30 (line 2). Line 2 contains a sample of reference (GFP) cells.
24 illustrates the integration at the TUBA1B left. (A) shows the chromosomal sequence showing the ZFN binding site (yellow sequence), ZFN cutting position (yellow arrow), and integration position (green arrow) on the chromosomal target site in the target portion for integration of heterologous coding sequences ( Is a schematic showing SEQ ID NO: 85). (B) shows the schematic of the TUBA1B locus, the site of integration, the design of the SH2 biosensor, and the proteins expressed after successful integration. (C) shows Western blot images of cells integrated with wild type.
25 is a map of a donor plasmid comprising the SH2 biosensor sequence flanking the TUBA1 sequences in the target moiety.
FIG. 26 shows differential interference contrast (DIC) and fluorescence microscopy images of individual isolated cell clones expressing the GFP-2xSH2-Grb1-2A protein. The fluorescence image shows the time course of the biosensor translocation after exposure to 100 ng / μL of EGF.
FIG. 27 shows a donor plasmid map comprising Sh2 biosensor sequences flanking ACTB sequences in the target moiety.
28 shows fluorescence microscopy images of individual isolated cell clones expressing GFP-2 × SH2-Grb1-2A (top panel) and RFP-β-actin (bottom panel). Time course after exposure to 100 ng / μL EGF
29 shows the DN sequences of two edited LRRK2 loci. The upper sequence (SEQ ID NO: 92) has a 10bp deletion in the target sequence of exon 30, and the lower sequence (SEQ ID NO: 93) has an 8bp deletion in the target sequence of exon 30. This exon is shown in green; Target locations are shown in yellow and deletions in dark blue.
30 shows the DN sequences of two edited ApoE loci. The upper sequence (SEQ ID NO: 114) has a 16 bp deletion in the target sequence of exon 2 and the lower sequence (SEQ ID NO: 115) has a 1 bp deletion in the target sequence of exon 2. This exon sequence is shown in green; Target locations are shown in yellow and deletions in dark blue.
Figure 31 shows the DN sequences of the edited leptin locus. The portion of the leptin locus (SEQ ID NO: 116) missing 151 bp from exon 1 and intron 1 is shown. This exon is shown in green; Target locations are shown in yellow and deletions in dark blue.
32 shows DN sequences of an APP locus edited in two animals. (A) Shows the part of the APP locus (SEQ ID NO: 127) of mice lacking 292 bp from exon 9. (B) shows the portion of the APP locus (SEQ ID NO: 128) of mice lacking 309 bp from exon 9 (B). This exon is shown in green; Target locations are shown in yellow and deletions in dark blue.
33 shows the DN sequences of the Rag1 locus edited in two animals. The upper sequence (SEQ ID NO: 131) has a 808bp deletion in exon 2 and the lower sequence (SEQ ID NO: 132) has a 29bp deletion in exon 2. This exon sequence is shown in green; Target locations are shown in yellow and deletions in dark blue.
34 shows DN sequences of the Rag2 locus edited in two animals. The upper sequence (SEQ ID NO: 133) has a 13bp deletion in exon 3 and the lower sequence (SEQ ID NO: 134) has a 2bp deletion in exon 3. This exon sequence is shown in green; Target locations are shown in yellow and deletions in dark blue.
35 shows the DN sequences of the Mdr1a locus edited in two animals. The upper sequence (SEQ ID NO: 157) has a 20 bp deletion in exon 7 and the lower sequence (SEQ ID NO: 158) has a 15 bp deletion and 3 bp insertion (GCT) in exon 7. This exon sequence is shown in green; Target locations are shown in yellow and deletions in dark blue.
36 illustrates knockout of the Mdr1a gene in mice. Western blots are shown with varying amounts of colon lysate and reference cell lysate of Mdr1a knockout mice. On the left side of the image a comparison position of Mdr1a protein and actin protein is indicated.
37 shows the DN sequences of the Mrp1 locus edited in two animals. The upper sequence (SEQ ID NO: 159) has a 43 bp deletion in exon 11 and the lower sequence (SEQ ID NO: 160) has a 14 bp deletion in exon 11. This exon sequence is shown in green; The target position is shown in yellow and the defect is shown in dark blue; And the overlap between the target sequence and exon is shown in gray.
Fig. 38 shows the DN sequence of the edited Mrp2 locus. This sequence (SEQ ID NO: 161) has a 726 bp deletion in exon 7. Exons are shown in green; Target locations are shown in yellow and deletions in dark blue.
39 shows the DN sequences of BCRP loci edited in two animals. (A) shows the portion of the murine BCRP locus (SEQ ID NO: 162) that contains a 588 bp deletion in exon 7. (B) shows the portion of the murine BCRP locus (SEQ ID NO: 163) that contains the 696 bp deletion in exon 7. Exon sequences are shown in green; Target locations are shown in yellow and deletions in dark blue.
40 shows ZFN validation with target sites of Mdr1a and two additional genes, Jag1, and Notch3. (A) shows ZFN target sequences. ZFN binding sites are underlined. (B) shows the mutation detection assay results in NIH 3T3 cells to demonstrate ZFN mRNA activity. Each ZFN mRNA pair was co-transfected into NIH 3T3 cells. Transfected cells were harvested after 24 hours. Genomic DNA was analyzed by mutation detection assay to detect NHEJ products displaying ZFN activity. M, PCR marker; G (lines 1, 3, and 5): GFP transfected criteria; Z (lines 2, 4, and 6), ZFN transfected samples. Uncut and truncated bands indicate the size of each base pair.
41 shows identification of genetically engineered Mdr1a based founders using mutation detection assays. Uncut bands and cut bands indicate the size of each in base pairs. Truncated bands indicate a mutation at the target position. M, PCR marker. 1-44, 44 pups born from injected eggs. Base numbers are underlined.
42 shows amplification of large deletions in the Mdr1a base. PCR products were amplified using primers located 800bp upstream and downstream of the ZFN target site. Significantly smaller bands than the 1.6 kb wild type band show large deletions in the target locus. Four bases not identified in FIG. 7 are underlined.
Figure 43 shows the mutation detection analysis of the Mdr1b position in 44 pups injected with Mdr1a ZFN. M, PCR marker; Toe DNA of FVB / N mice not injected with WT, Mdr1a ZFNs; NIH 3T3 cells transfected with 3T3, Mdr1a ZFNs by reference.
44 shows Mdr1a expression detection using RT-PCR in Mdr1a − / − mice. (A) schematically illustrates the mRNA structure around the Mdr1a genome and target locations. Exons are represented by an open rectangle with each number. The size of each exon on the base is indicated directly below. Intron sequences are shown as broken bars with base pair sizes just below. The ZFN target position in exon 7 is marked with a. The 396 bp deletion position of base # 23 is shown above intron 6 and exon 7. RT-F and RT-R are located at exons 5 and 9, respectively, and are primers used for RT-PCR. In the RT reaction, 40 ng of total RNA is used as template. Normalization of input RNA is confirmed by GAPDH amplification, with or without RT.
45 shows the results of band separation after separation and purification of wild-type species from Mdr1a − / − samples, and as a template for nested PCR.
46 shows DN sequences of BDNF loci edited in two animals. The upper sequence (SEQ ID NO: 211) has a 14 bp deletion in exon 2 and the lower sequence (SEQ ID NO: 212) has a 7 bp deletion in exon 2. Exons are shown in green; Target locations are shown in yellow and deletions in dark blue.
Fig. 47 shows the DN sequence of the edited DISC1 left. The DISC1 portion (SEQ ID NO: 225) of mice with 20bp deletion in the target sequence of exon 5 is shown. Exons are shown in green; Target locations are shown in yellow and deletions in dark blue.
48 illustrates the editing of the p53 locus in rats. A Cel-1 analysis is presented wherein the presence of cleavage products indicates that the p53 gene has been edited.
49 illustrates knockout of the p53 gene in mice. Western blots of cytoplasmic and nuclear lysates of kidney (K) and liver (L) samples from wild type (WT 731RP) and p53 knockout (KO 733RP) animals. The relative positions of the p53 protein and actin protein are shown on the right side of each image.

The present disclosure provides a method of making a genetically modified animal or animal cell comprising at least one edited chromosomal sequence. The edited chromosomal sequence may be (1) inactivated, (2) modified, or (3) integrated sequence. The inactivated chromosomal sequence does not make a functional protein or is altered so that the reference sequence does not function the same as the wild-type reference sequence. Thus, genetically modified animals comprising inactivated chromosomal sequences are termed "knock-out" or "conditional knock-out". Similarly, genetically modified animals comprising integrated sequences can be termed "knock-in" or "conditional knock-in". As described in detail below, the green-in animal can be a humanized animal. Moreover, genetically modified animals comprising modified chromosomal sequences may include other modifications such that targeted point mutation (s) or altered protein products are made. Chromosome sequences are generally edited using zinc finger nuclease-mediated procedures. Briefly, this procedure involves introducing at least one nucleic acid encoding a targeted zinc finger nuclease and optionally at least one accessory polynucleotide into the cell. The method further comprises incubating the cells for expression of the zinc finger nuclease, wherein the double-stranded gap introduced into the chromosomal sequence targeted by the zinc finger nuclease is associated with an error-prone ratio. Repair by homologous end-binding DNA repair or homology-directed DNA repair. In an exemplary embodiment, the cell is an embryo. As described herein, methods for editing chromosomal sequences using targeted zinc finger nuclease technology are fast, accurate, and very efficient.

In addition, the present invention includes animals or cells comprising at least one edited chromosomal sequence. The method of the invention, the animal of the invention, the cells of the invention and their use are described in more detail below.

I. Methods for Editing Chromosomes

One aspect of the invention includes a method for chromosomal editing. As used herein, “chromosomal editing” refers to editing a chromosomal sequence such that the sequence comprises (1) inactivated, (2) modified, or (3) integrated sequences. Generally speaking, methods for editing chromosomal sequences include:

(a) at least one nucleic acid encoding a zinc finger nuclease capable of recognizing a target sequence in a chromosome sequence into a cell and cleaving a site in the chromosome sequence, and optionally (i) one side of the cleavage site At least one donor polynucleotide comprising a sequence flanking the upstream and downstream sequences that share substantial sequence identity, or (ii) is substantially identical to a portion of the chromosomal sequence at the cleavage site, and at least one nucleotide change Introducing at least one exchange polynucleotide further comprising; And (b) culturing the cells to express the zinc finger nuclease such that the zinc finger nuclease introduces a double-stranded gap in the chromosome sequence, wherein the gap of the double-stranded is (i) a non-homologous end. Repair by a binding repair process to introduce a mutation into the chromosomal sequence, or (ii) repair by a homologous-directed repair process so that the sequence in the donor nucleotide is incorporated into a chromosomal sequence or the exchange polynucleotide Is replaced with a portion of the chromosomal sequence.

The components of the zinc finger nuclease-mediated method of editing chromosomal sequences are described in more detail below.

(a) zinc Finger  Nucleic Acids Encoding Nucleases

The method includes some incorporating at least one nucleic acid encoding a zinc finger nuclease into the cell. Typically, zinc finger nucleases include DNA binding domains (eg, zinc fingers) and cleavage domains (eg, nucleases). DNA binding and cleavage domains are described below. Nucleic acids encoding zinc finger nucleases include DNA or RNA. For example, nucleic acids encoding zinc finger nucleases include mRNA. If the nucleic acid encoding a zinc finger nuclease comprises an mRNA, the mRNA molecule may have a 5 'cap. Similarly, if the nucleic acid encoding a zinc finger nuclease comprises an mRNA, the mRNA molecule may be polyadenylation. Typical nucleic acids according to this method are polyadenylated mRNA molecules that are capped and encode zinc finger nucleases. Methods for capping and polyadenylating mRNA are known in the art.

Generally speaking, once the zinc finger nuclease of the invention is introduced into a cell, it creates a double-stranded gap in the chromosome sequence. In certain embodiments, the double-strand gap can be repaired by a non-homologous end-binding repair process of the cell, and mutations are introduced into the chromosomal sequence. As described below, in other embodiments, the homology-directed repair process is used to edit chromosomal sequences.

(i) zinc Finger  Binding domain

The zinc finger binding domain can be engineered to recognize and bind any nucleic acid sequence selected. For example, Beerli meat al . (2002) Nat . Biotechnol . 20: 135-141; Pabo meat al . (2001) Ann . Rev. Biochem. 70: 313-340; Isalan meat al . (2001) Nat . Biotechnol . 19: 656-660; Segal meat al . (2001) Curr. Opin . Biotechnol . 12: 632-637; Choo meat al . (2000) Curr . Opin . Struct . Biol . 10: 411-416; Zhang et al . (2000) J. Biol . Chem . 275 (43): 33850-33860; Doyon meat al . (2008) Nat . Biotechnol . 26: 702-708; And Santiago meat al . (2008) Proc . Natl . Acad . Sci . See USA 105: 5809-5814 . Engineered zinc finger binding domains may have novel binding specificities compared to naturally occurring zinc finger proteins. Manipulation methods include, but are not limited to, rational planning and various types of screening. Rational design includes, for example, using a database comprising doublet, triplet, and / or quadruplet nucleotide sequences and individual zinc finger amino acid sequences, wherein each Double, triple, or quadruple nucleotide sequences are associated with one or more zinc finger nuclease sequences of a zinc finger that bind to a particular triple or quadruple sequence. See, for example, US Pat. Nos. 6,453,242 and 6,534,261, which are incorporated by reference in their entirety. For example, the algorithm described in US Pat. No. 6,453,242 can be used to design zinc finger binding domains to target preselected sequences. Alternative methods, such as rational planning with nondegenerate recognition code tables, may be used to design zinc finger binding domains that target specific sequences ( Sera meat al . (2002) Biochemistry 41: 7074-7081 ). Publicly available web-based tools for the identification of potential target sites in the DN sequences and for the planning of zinc finger binding domains are in turn www.zincfingertools.org and bindr.gdcb.iastate.edu/ZiFiT/ ( Mandell meat al . (2006) Nuc . Acids Res . 34: W516 - W523 ; Sander meat al . (2007) Nuc . Acids Res . 35: W599 - W605 ).

Zinc finger DNA binding domains can be designed to recognize DN sequences ranging from about 3 nucleotides to about 21 nucleotides in length, or from about 8 to about 19 nucleotides in length. In general, the zinc finger binding domains of the zinc finger nucleases described herein comprise at least three zinc finger recognition moieties (eg, zinc fingers). In one embodiment, the zinc finger binding domain may comprise four zinc finger recognition moieties. In another embodiment, the zinc finger binding domain may comprise five zinc finger recognition moieties. In another embodiment, the zinc finger binding domain may comprise six zinc finger recognition moieties. Zinc finger binding domains can be designed to bind to any suitable target DN sequence. See, for example, US Pat. No. 6,607,882; 6,534,261 and 6,453,242, the contents of which are incorporated by reference in their entirety.

Typical methods of selecting a zinc finger recognition portion may include phage display and hybrid systems, and are described in US Pat. Nos. 5,789,538; 5,925,523; 5,925,523; 6,007,988; 6,007,988; 6,013,453; No. 6,410,248; No. 6,140,466; No. 6,200,759; And 6,242,568; WO 98/37186; WO 98/53057; WO 00/27878; WO 01/88197 and GB 2,338,237, each of which is incorporated by reference in its entirety. In addition, binding specificity enhancement for zinc finger binding domains is described, for example, in WO 02/077227.

Zinc finger binding domains and methods for the design and construction of fusion proteins (and polynucleotides encoding them) are known to those skilled in the art and are described in detail in US Patent Application Publication Nos. 20050064474 and 20060188987 The full text is incorporated in the reference. Zinc finger recognition portions and / or multi-fingered zinc finger proteins may be combined together using a suitable linker sequence, eg, a linker comprising a linker of five or more zinc finger nucleases in length. Can be connected. Non-limiting examples of linker sequences of six or more zinc finger nucleases are described in US Pat. No. 6,479,626; No. 6,903,185; And 7,153,949, the contents of which are incorporated by reference in their entirety. The zinc finger binding domains described herein may comprise a combination of linkers suitable between individual zinc fingers of a protein.

In certain embodiments, the zinc finger nuclease may further comprise a nuclear localization signal signal or sequence (NLS). NLS is a zinc finger nuclease sequence that performs targeting of a zinc finger nuclease protein to the nucleus to introduce a double stranded gap into an intrachromosomal target sequence. Nuclear localization signals are known in the art. For example, Makkerh meat al . (1996) Current See Biology 6: 1025- 1027 .

( ii Cutting domain

Zinc finger nucleases also include cleavage domains. The cleavage domain of the zinc finger nucleases described herein can be obtained from any endonuclease or exonuclease. Non-limiting examples of endonucleases from which a cleavage domain is derived include, but are not limited to, restriction endonucleases and homing endonucleases. For example, 2002-2003 Catalog , New England Biolabs , Beverly, Mass .; and Belfort meat al . (1997) Nucleic Acids Res . 25: 3379-3388 or www.neb.com . Additional enzymes that cleave DNA are known (eg S1 nucleases; mung bean nucleases; pancreatic DNase I; micrococcal nucleases; yeast HO endonucleases). Linn et al. ( eds .) Nucleases , Cold Springharbor Laboratory See also Press , 1993 . One or more of these enzymes (or functional fragments thereof) can be used as a source of cleavage domains.

As described above, cleavage domains may also be derived from enzymes or portions thereof that require dimerization for cleavage activity. Two zinc finger nucleases may be required for cleavage because each nuclease contains monomers of an active enzyme dimer. Alternatively, a single zinc finger nuclease may comprise both monomers to make an active enzyme dimer. As used herein, “active enzyme dimer” is an enzyme dimer that can cleave nucleic acid molecules. Two cleavage monomers may be derived from the same endonuclease (or functional fragments thereof), or each monomer may be derived from a different endonuclease (or functional fragments thereof).

When active enzyme dimers are made using two cleavage monomers, the recognition sites for the two zinc finger nucleases are such that the two zinc finger nucleases bind to each of these recognition sites so that the cleavage monomers are, for example, by dimerization. Preferably, the cleavage monomers are located in a spatial direction relative to each other that allow to form the active enzyme dimer. As a result, the proximal edge of the recognition site can be separated by about 5 to about 18 nucleotides. For example, the proximal edges are at about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 nucleotides. Can be separated by. However, it will be appreciated that any integer of nucleotides or nucleotide pairs may be sandwiched between two recognition sites (eg, about 2 to about 50 or more nucleotide pairs). For example, the proximal edges of the recognition site of zinc finger nucleases such as those described herein can be separated by six nucleotides. In general, the cleavage site is between the recognition sites.

Restriction endonucleases (limiting enzymes) are present in many species, capable of sequence-specific binding to DNA (at the recognition site), and cleaving DNA at or near the binding site. Certain restriction enzymes (eg, type IIS) cleave DNA at positions removed from the recognition site and have separable binding and cleavage domains. For example, the type IIS enzyme Fok I catalyzes double-strand cleavage of DNA at 9 nucleotides from its recognition site on one strand and 13 nucleotides from its recognition site on the other strand. See, for example, US Pat. No. 5,356,802; 5,436,150 and 5,487,994; Li et al. (1992) Proc . Natl . Acad . Sci . USA 89: 4275-4279; Li meat al . (1993) Proc . Natl . Acad . Sci . USA 90: 2764-2768; Kim meat al . (1994a) Proc . Natl . Acad . Sci . USA 91: 883-887; Kim meat al . (1994b) J. Biol . Chem . See 269: 31, 978-31, 982 . Thus, zinc finger nucleases may comprise a cleavage domain of at least one type IIS restriction enzyme and one or more zinc finger binding domains, which may or may not be engineered. Typical type IIS restriction enzymes are described, for example, in International Publication WO 07 / 014,275, the contents of which are incorporated by reference in their entirety. Additional restriction enzymes also include separable binding and cleavage domains, and these are also contemplated by this disclosure. For example, Roberts meat al . (2003) Nucleic Acids Res . See 31: 418-420 .

A typical type IIS restriction enzyme with a cleavage domain separable from the binding domain is Fok I. This particular enzyme is active as a dimer ( Bitinaite meat al . (1998) Proc . Natl . Acad . Sci . USA 95: 10, 570-10, 575 ). Thus, for the purposes of this disclosure, a portion of the Fok I enzyme used in zinc finger nucleases is considered cleavage monomer. Thus, for targeted double-strand cleavage using the Fok I cleavage domain, two zinc finger nucleases each containing a FokI cleavage monomer can be used to reconstitute the active enzyme dimer. Alternatively, a single polypeptide molecule comprising a zinc finger binding domain and two Fok I cleavage monomers can also be used.

In certain embodiments, the cleavage domain may comprise one or more engineered cleavage monomers that minimize or prevent homodimerization, as described, for example, in US Patent Publications 20050064474, 20060188987, and 20080131962. Each of which is incorporated by reference in its entirety. Non-limiting examples include amino acid residues at positions 446, 447, 479, 483, 484, 486, 487, 490, 491, 496, 498, 499, 500, 531, 534, 537, and 538 of Fok I. Fok I cleavage is any target that induces dimerization of half-domains. Exemplary engineered cleavage monomers of Fok I which form an absolute heterodimer include a first cleavage monomer comprising mutations at amino acid residue positions 490 and 538 and a mutation at amino acid residue positions 486 and 499 of Fok I A second pair of cleavage monomers.

Thus, in one embodiment, the mutation at amino acid position 490 replaces Glu (E) with Lys (K); The mutation at amino acid residue 538 replaces Iso (I) with Lys (K); The mutation at amino acid residue 486 replaces Gln (Q) with Glu (E); And at position 499 the mutation replaces Iso (I) with Lys (K). In particular, E at position 490 can be mutated to K, I at position 538 to K to make the engineered cleavage monomer “E490K: I538K”, and to mutate Q at position 486 to E in another cleavage monomer. And I at position 499 can be mutated to L to make the engineered cleavage monomer “Q486E: I499L”. The engineered cleavage monomers described above are absolute heterodimers that minimize or eliminate abnormal cleavage. Engineered cleavage monomers can be made using suitable methods such as site-directed mutagenesis of the wild type cleavage monomer (Fok I), as described in US Patent Publication 20050064474 (see Example 5).

The zinc finger nucleases described above can be engineered to introduce a double stranded gap at the target site for integration. These double stranded gaps are at the target location of integration, or at most 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, There may be 40, 45, 50, 100, or 1000 nucleotides away. In certain embodiments, such double stranded gaps may be at 1, 2, 3, 4, 5, 10, 15 or 20 nucleotides from the integration site. In other embodiments, such double stranded gaps may be at 10, 15, 20, 25, 30, 35, 40, 45, or 50 nucleotides from the integration site. In other embodiments, such double stranded gaps may be at 50, 100, or 1000 nucleotides from the integration site.

( iii A) typical zinc Finger  Nuclease

Non-limiting examples of zinc finger nucleases that recognize and bind target sequences found in various animal chromosomal sequences are provided. For example, the zinc finger nucleases of the present invention may comprise SEQ ID NOs: 53, 54, 57-62, 69-76, 104-113, 123-126, 147-156, 201-210, 219-222, 223-224 And at least 80% identical amino acid sequence to a sequence selected from zinc finger nucleases having a sequence number selected from 230-233, 240-243. In other embodiments, sequence identity is about 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94 %, 95%, 96%, 97%, 98%, 99%, or 100%.

Furthermore, the sequence selected from SEQ ID NOs: 53, 54, 57-62, 69-76, 104-113, 123-126, 147-156, 201-210, 219-222, 223-224, 230-233, 240-243 Zinc finger nucleases encoded by number are shown in chromosome sequence numbers 55, 56, 63-68, 77-84, 86-91, 94-103, 117-122, 129, 130, 135, 136, 137, 138 At least about 80%, 81%, 82%, 83%, 84%, 85%, 86 for 139-146, 164-173, 213-218, 226-229, 234, 235, 236, 237, 238, 239 Chromosome sequence with%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity Can be recognized and combined.

( iv ) Targeted  Additional Methods for Cutting

Any nuclease having an intrachromosomal target site can be used in the methods described herein. For example, homing endonucleases and meganucleases have very long recognition sequences, some of which are, once statistically based, present in the human-sized genome. Any such nuclease with a unique target location in the genome can be used in place of the zinc finger nuclease for targeted cleavage of the chromosome or as an additional zinc finger nuclease.

Non-limiting examples of homing endonucleases include I-SceI, I-CeuI, PI-PspI, PI-Sce, I-SceIV, I-CsmI, I-PanI, IS Cells, I-PpoI, I-SceIII , I-CreI, I-TevI, I-TevIl and I-TevIII. Recognition sequences of these enzymes are known in the art. US Patent No. 5,420,032; US Patent No. 6,833,252; Belfort meat al . (1997) Nucleic Acids Res . 25: 3379-3388; Dujon meat al . (1989) Gene 82: 115-118; Perler meat al . (1994) Nucleic Acids Res . 22, 1125-1127; Jasin (1996) Trends Genet . 12: 224-228; Gimble meat al . (1996) J. Mol . Biol . 263: 163-180; Argast meat al . (1998) J. Mol . Biol. 280: 345-353 and the New England Biolabs See catalog .

Although the cleavage specificity of most homing endonucleases is not absolute for these recognition sites, these sites express the expression of homing endonucleases in cells where a single cleavage process per mammalian-sized genome has a single copy of the recognition site. It is of sufficient length to be obtainable by. It has been reported that the specificity of homing endonucleases and meganucleases can be engineered to bind to non-natural target sites. For example, Chevalier meat al . (2002) Molec . Cell 10: 895-905; Epinat meat al . (2003) Nucleic Acids Res . 31: 2952-2962; Ashworth meat al . (2006) Nature 441: 656-659; Paques meat al . (2007) Current Gene Therapy 7: 49-66 .

(b) Selective Exchange Polynucleotides

Editing The method of editing chromosomal sequences may further comprise introducing into the cell at least one exchange polynucleotide further comprising a sequence substantially identical to the chromosomal sequence at the cleavage site and at least one specific nucleotide change.

Typically, the exchange polynucleotide will be DNA. Exchange polynucleotides are DNA plasmids, artificial bacterial chromosomes (BAC), artificial yeast chromosomes (YAC), viral vectors, linear fragments of DNA, PCR fragments, naked nucleic acids, or carrier vehicles such as liposomes or poloxamers. It may be a nucleic acid conjugated to. Typical exchange polynucleotides may be DNA plasmids.

The sequence in the exchange polynucleotide is substantially identical to a portion of the chromosomal sequence at the cleavage site. In general, the sequence of the exchange polynucleotide will share sufficient sequence identity within the chromosomal sequence so that the two sequences can be exchanged by homologous recombination. For example, the sequence within the exchange polynucleotide may be at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% will be the same.

Importantly, the sequence in the exchange polynucleotide comprises at least one specific nucleotide change relative to the sequence of the corresponding chromosomal sequence. For example, one nucleotide in a specific codon will be changed to another nucleotide such that the codon encodes a different amino acid. In one embodiment, the sequence in the exchange polynucleotide may comprise one specific nucleotide change such that the encoded protein comprises one amino acid change. In other embodiments, the sequence in the exchange polynucleotide may comprise two, three, four or more specific nucleotide changes such that the encoded protein comprises one, two, three, four, or more amino acid changes. It may include. In other embodiments, the sequence in the exchange polynucleotide can comprise three nucleotide deletions or insertions such that the frame of the coding read is not altered (and the functional protein can be made). However, the expressed protein will comprise a single amino acid deletion or insertion.

The length of the sequence that is substantially identical to a portion of the chromosomal sequence at the cleavage site in the exchange polynucleotide may vary. In general, the sequences in the exchange polynucleotides may range from about 25 bp to about 10,000 bp in length. In various embodiments, the sequence in the exchange polynucleotide is about 50bp, 100bp, 200bp, 400bp, 600bp, 800bp, 1000bp, 1200bp, 1400bp, 1600bp, 1800bp, 2000bp, 2200bp, 2400bp, 2600bp, 2800bp, 3000bp, 3200bp , 3400bp, 3600bp, 3800bp, 4000bp, 4200bp, 4400bp, 4600bp, 4800bp, or 5000 bp. In other embodiments, the sequence in the exchange polynucleotide is about 5500bp, 6000bp, 6500bp, 6000bp, 6500bp, 7000bp, 7500bp, 8000bp, 8500bp, 9000bp, 9500bp, or 10,000 bp in length.

As described herein, those skilled in the art can employ standard well-known recombinant techniques (eg, Sambrook et. al ., 2001 and Ausubel meat al ., 1996 ) exchange polynucleotides may be constructed.

In the method described above for modifying the chromosomal sequence, the double-strand gap introduced into the chromosomal sequence by zinc finger nuclease is repaired through homologous recombination with the exchange polynucleotide, such that the sequence in the exchange polynucleotide is a part of the chromosome sequence. Will be exchanged. The presence of the double stranded gap facilitates homologous recombination and repair of the gap. The exchange polynucleotide may be physically integrated, or alternatively, the exchange polynucleotide is used as a repair template for the gap, so that sequence information in the exchange polynucleotide is exchanged with some sequence information of the chromosomal sequence. Thus, some of the endogenous chromosomal sequences can be converted to sequences of exchange polynucleotides. The altered nucleotide (s) may be at or near the cleavage site. Alternatively, the changed nucleotide (s) can be anywhere in the exchanged sequences. However, as a result of the exchange, the chromosomal sequence is modified.

(c) optional donor  Polynucleotide

The method of editing chromosomal sequences may alternatively comprise introducing at least one donor polynucleotide comprising the integration sequence into the cell. The donor polynucleotide comprises at least three components: an integrated sequence adjacent to the upstream and downstream sequences, wherein the upstream and downstream sequences share sequence similarity with one side of the site of integration within the chromosome.

Typically, the donor polynucleotide will be DNA. Donor polynucleotides are conjugated to DNA plasmids, artificial bacterial chromosomes (BAC), artificial yeast chromosomes (YAC), viral vectors, linear fragments of DNA, PCR fragments, naked nucleic acids, or carrier vehicles such as liposomes or poloxamers. Nucleic acids. Typical donor polynucleotides may be DNA plasmids.

Donor polynucleotides include sequences for integration. The integration sequence can be an endogenous sequence or an exogenous sequence in an animal or cell. The integration sequence can encode a protein or non-coding RNA (eg, microRNA). Thus, the integration sequence can be linked to be operable to the appropriate reference sequence or sequences. Alternatively, the integrating sequence can provide regulatory function. Thus, the size of the integration sequence will vary. In general, the integrating sequence may range from about 1 nucleotide to several million nucleotides.

Donor polynucleotides also include upstream and downstream sequences flanking the sequence to be integrated. The upstream and downstream sequences in the donor polynucleotides are selected to facilitate recombination between the chromosomal sequence of interest and the donor polynucleotide. As used herein, an upstream sequence refers to a nucleic acid sequence that shares sequence similarity with the chromosomal sequence upstream of the targeted site of integration. Similarly, a downstream sequence refers to a nucleic acid sequence that shares sequence similarity with the chromosomal sequence downstream of the targeted site of integration. The upstream and downstream sequences in the donor polynucleotide will share about 75%, 80%, 85%, 90%, 95%, or 100% sequence identity with the targeted chromosomal sequence. In other embodiments, the upstream and downstream sequences in the donor polynucleotide will share about 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the targeted chromosomal sequence. In an exemplary embodiment, the upstream and downstream sequences in the donor polynucleotide will share about 99% or 100% sequence identity with the targeted chromosomal sequence.

The upstream or downstream sequence may comprise about 20 bp to about 2500 bp. In various embodiments, the upstream or downstream sequence is about 50bp, 100bp, 200bp, 300bp, 400bp, 500bp, 600bp, 700bp, 800bp, 900bp, 1000bp, 1100bp, 1200bp, 1300bp, 1400bp, 1500bp, 1600bp, 1700bp, 1800bp, 1900bp, 2000bp, 2100bp, 2200bp, 2300bp, 2400bp, or 2500 bp. Typical upstream or downstream sequences may comprise about 200 bp to about 2000 bp, about 600 bp to about 1000 bp, or more particularly about 700 bp to about 1000 bp.

In certain embodiments, the donor polynucleotide may further comprise a marker. Such markers may facilitate the screening of targeted integration. Non-limiting examples of suitable labels include restriction sites, fluorescent proteins, or selectable labels.

Those skilled in the art will appreciate, for example, Sambrook using the well known standard recombination techniques described herein. meat al ., 2001 and Ausubel meat al ., 1996 ) donor polynucleotides may be constructed.

In the method described above for editing the chromosomal sequence by incorporation of the sequence, the double-strand gap introduced into the chromosomal sequence by zinc finger nuclease is repaired through homologous recombination with the donor polynucleotide so that the sequence is chromosomal sequence. Is incorporated in. The presence of double stranded gaps facilitates the integration of the sequences. The donor polynucleotide may be physically integrated or, alternatively, the donor polynucleotide may be used as a repair template for gaps so that not only the introduction of the sequence but also all or part of the upstream and downstream sequences of the donor polynucleotide into the chromosome are introduced. . Thus, endogenous chromosomal sequences can be converted into sequences of donor polynucleotides.

(d) nucleic acid Into the cell  Introduction

To mediate zinc finger nuclease genome editing, at least one nucleic acid molecule encoding zinc finger nuclease and optionally at least one exchange polynucleotide or at least one donor polynucleotide is introduced into the cell. As used herein, “cell” includes any animal cell that contains a chromosomal sequence. In certain embodiments, “cell” can refer to an embryo. In certain typical embodiments, the embryo is one cell stage embryo that has been fertilized. In other exemplary embodiments, the embryo may be any stage of embryo.

Suitable methods for introducing nucleic acids into embryos or cells include microinjection, electroporation, sonoporation, biolistics, calcium phosphate-mediated transfection, cationic transfection, Liposome transfection, dendrimer transfection, heat shock transfection, nucleofection transfection, magnetofection, lipofection, impalefection, optical transfection , Incorporation of proprietary agent-enhanced nucleic acids, and delivery via liposomes, immunoliposomes, virosomes, or artificial virions. In one embodiment, the nucleic acid may be introduced into the embryo via microinjection. Nucleic acids can also be microscopically injected into the nucleus or cytoplasm of the embryo. In another embodiment, the nucleic acid can be introduced into the cell by nuclear infection.

In embodiments in which both the nucleic acid encoding a zinc finger nuclease and an exchange (or donor) polynucleotide are introduced into the embryo or cell, the ratio of the exchange (or donor) polynucleotide to the zinc finger nuclease is about 1: 1. 10 to about 10: 1. In various embodiments, the ratio of exchange (or donor) polynucleotide to zinc finger nuclease is about 1:10, 1: 9, 1: 8, 1: 7, 1: 6, 1: 5, 1: 4 , 1: 3, 1: 2, 1: 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, 9: 1, or 10: 1 days Can be. In one embodiment, this ratio will be about 1: 1.

In embodiments in which both the nucleic acid encoding one or more zinc finger nucleases and one or more exchange (or donor) polynucleotides are introduced into the embryo or cell, the nucleic acids may be introduced simultaneously or sequentially. For example, nucleic acids encoding zinc finger nucleases, each specific for a specific recognition sequence, and a selective exchange (or donor) polynucleotide may be introduced simultaneously. Alternatively, nucleic acids encoding each zinc finger nuclease and selective exchange (or donor) polynucleotides may be introduced sequentially.

In one embodiment, at least one nucleic acid molecule encoding a zinc finger nuclease is introduced into the cell. In another embodiment, at least two, three, four, five, or five or more nucleic acid molecules encoding zinc finger nucleases are introduced into the cell. In each of the above embodiments, the one or more corresponding donor or exchange polynucleotides is in a ratio of a donor or exchange polynucleotide to a zinc finger nuclease nucleic acid in a ratio of about 1:10 to about 10: 1, as described above. It can also be introduced into cells.

(e) culture of cells

The method of editing a chromosomal sequence using the zinc finger nuclease-mediated procedure described herein involves culturing cells comprising the introduced nucleic acid (s) to allow expression of at least one zinc finger nuclease. It includes more.

Cells containing the introduced nucleic acid can be cultured using standard procedures to allow expression of zinc finger nucleases. Standard cell culture techniques are described, for example, in Santiago meat al . (2008) PNAS 105: 5809-5814; Moehle meat al . (2007) PNAS 104: 3055-3060; Urnov meat al . (2005) Nature 435: 646-651; and Lombardo et al (2007) Nat . Biotechniques 25: 1298-1306 . Those skilled in the art will appreciate that methods for culturing cells are known in the art and may vary depending on the cell type or cell species. In all cases, routine optimization can be used to determine the best technique for a particular cell type.

In one embodiment where the cells are embryos, the embryos can be cultured in vitro (eg, cell culture). Typically, embryos are cultured for a short period of time in the appropriate medium and at the appropriate temperature with the required O ₂ / CO ₂ ratio to allow for expression of zinc finger nucleases. Those skilled in the art will appreciate that the culture conditions may vary depending on the type of embryo. In all cases, conventional optimization can be used to determine the best culture conditions for a particular embryo type. In some cases, the cell line may be derived from in vitro cultured embryos (eg, embryonic stem cell line).

Preferably, the embryo may be cultured in vivo by moving the embryo into the uterus of a female host. Generally speaking, the female host is the same or similar species as the embryo. Preferably, the female host is pseudo-pregnant. Methods of false pregnancy of female hosts are known in the art. In addition, methods for transferring embryos to female hosts are also known. When embryos are cultured in vivo, the embryos develop and the birth of animals from the embryos can occur. Such animals will generally comprise chromosomal sequence (s) destroyed in all cells of the animal body.

When at least one zinc finger nuclease is expressed in a cell, the chromosomal sequence of the cell can be edited. If the cell comprises an expressed zinc finger nuclease but no exchange (or donor) polynucleotide, the zinc finger nuclease recognizes, binds, and cleaves the target sequence within the chromosomal sequence of interest.

Double-strand breaks introduced into zinc finger nucleases are repaired by an error-prone non-homologous end-binding DNA repair process. As a result, deletions or insertions that result in missense or nonsense mutations can be introduced into the chromosomal sequence so that the sequence can be inactivated.

When embryos or cells contain expressed zinc finger nucleases as well as exchange (or donor) polynucleotides, zinc finger nucleases recognize, bind to, and cleave target sequences within the chromosome. Double-strand gaps introduced by zinc finger nucleases are repaired through homologous recombination with exchange (or donor) polynucleotides, and some of the chromosomal sequences are converted to sequences in the exchange polynucleotides or in donor polynucleotides. Is integrated into the chromosomal sequence. As a result, the chromosomal sequence is edited.

The genetically modified animals described herein can be crossed to create animals comprising one or more edited chromosomal sequences or to create animals that are homologous to one or more edited chromosomal sequences. Those skilled in the art will appreciate that many combinations are possible. Moreover, the genetically modified animals described herein can be crossed with other animals to combine other genetic backgrounds with the edited chromosomal sequence. Non-limiting examples of suitable genetic cultures include wild type, natural mutations that cause known phenotypes, targeted chromosomal integration, non-targeted integration, and the like.

(f) Types of chromosomal editing

As indicated above, the methods of the present invention can be used to (1) inactivate chromosomal sequences, (2) modify chromosomal sequences, or (3) integrate sequences into chromosomes. Each of these is discussed in detail below.

i. Deactivate sequence

In one embodiment, the edited chromosomal sequence is inactivated such that the sequence is not transcribed, the encoded protein is not made, or the sequence does not function as the wild type sequence does. For example, the protein coding sequence is inactivated so that no protein is made. Alternatively, the microRNA coding sequence is inactivated so that no microRNA is made. Moreover, the reference sequence is inactivated and no longer functions as the reference sequence. As used herein, “reference sequence” refers to any nucleic acid sequence that affects the transcription, translation, or accessibility of a nucleic acid sequence. Non-limiting examples include promoters, transcription terminators, and enhancers. An inactivated chromosomal sequence can be used to replace a deletion mutation (eg, deletion of one or more nucleotides), insertion mutation (eg, insertion of one or more nucleotides), or nonsense mutation (eg, replacing a single nucleotide with another nucleotide so that a termination codon is introduced). Include. In certain embodiments, the chromosomal sequence to be inactivated may be termed “knock-out”. In the present invention, “knock-out” animals created by the methods of the present invention do not comprise any exogenous sequence.

ii . Edit of Sequence.

In another embodiment, the edited chromosomal sequence is modified such that it encodes an altered gene product or alters the function of the sequence. The chromosomal sequence encoding the protein is modified to include at least one altered nucleotide so that the codon contains the altered nucleotide code for different amino acids. Thus, the resulting protein contains at least one amino acid change. Moreover, protein coding sequences can be modified by insertions or deletions, so that modified proteins can be made without altering the reading of the sequences. In such embodiments, the modified sequence can cause a phenotypic change.

Alternatively, chromosomal sequences that function as reference sequences are modified. For example, a promoter may be modified to be always active or regulated by exogenous signals.

In another embodiment, at least one chromosomal sequence encoding the protein of interest can be edited such that the expression pattern of the protein is altered. For example, regulatory moieties that regulate expression of a protein, such as a promoter or transcription factor binding site, may be altered, resulting in overproduction of guamsim protein, altered tissue-specific or transient expression of the protein, or a combination thereof. Can be.

iii . Integration of sequences

In another embodiment, the edited chromosomal sequence may comprise an integrated sequence. Such sequences can encode endogenous proteins, exogenous or heterologous proteins, wild type proteins, modified proteins, fusion proteins, microRNAs, or the like. The integrated protein coding sequence may be linked to the reporter sequence (the reporter sequence may be linked 5 'or 3' to the protein coding sequence). Integrated protein coding sequences may also be controlled to endogenous promoters, operably linked to exogenous promoters, or may be fused in-frame with endogenous protein coding sequences. In addition, the integrated sequence can serve as a reference element. Thus, the integrated sequence may be endogenous or exogenous to the cell. Animals or cells comprising such integrated sequences may be referred to as “knock-in.” In one iteration of the above embodiments, it should be understood that no selectable marker is present.

In certain embodiments, the sequence can be integrated to alter the expression pattern of the protein of interest. For example, a conditional knock-out system can be made.

A. Conditional Mutations

In certain embodiments, the sequence can be integrated to alter the expression pattern of the protein of interest. For example, a conditional knock-out system can be made.

As used herein, a “conditional knock-out” system is a model in which the expression of nucleic acid molecules is disrupted within a particular organ, tissue, or cell type in a controlled manner in contrast to the entire animal and / or in a temporary controlled manner. Conditional knock-out allows for the study of gene function even if the total destruction of this gene is fatal.

Non-limiting examples of conditional knock-out systems include the Cre-lox recombination system. Cre-lox recombination systems include Cre recombinase, a location-specific DNA recombinase that can catalyze the recombination of nucleic acid sequences between specific lox sites in nucleic acid molecules. Methods of using such a system to make transient and tissue specific expression are known in the art. Generally, genetically modified cells are made to have lox sites flanking the chromosome sequence of interest. Genetically modified animals, including cells with lox flanking the chromosome sequence of interest, can then be crossed with another genetically modified animal expressing Cre recombinase in one or more cells. Progeny animals are made that contain one or more cells comprising the side-lox of the chromosomal sequence and one or more cells comprising the Cre recombinase. In cells that contain both the flanking lox and the Cre recombinase, the chromosome sequence flanking-lox that encodes the protein of interest is recombined to induce a deletion or inversion of the chromosome sequence that encodes the protein of interest. . The expression of Cre recombinase can be transiently and conditionally regulated, affecting the transient and conditionally controlled recombination of chromosomal sequences encoding the protein of interest.

A. Endogenous  Integration to destroy left integrations )

In another embodiment, the methods of the invention can be used to incorporate mutations that disrupt endogenous loci. For example, chromosomal sequences can be disrupted by replacing endogenous sequences with exogenous sequences, which are under the control of endogenous promoters. In these embodiments, the disrupted endogenous sequence will not be expressed, but the integrated exogenous sequence will be expressed. The exogenous sequence may be a homologue of the endogenous sequence. For example, if the endogenous sequence is non-human, the exogenous sequence may be a human sequence. In certain embodiments, the exogenous sequence may not be related to the endogenous sequence being replaced. For example, an endogenous sequence can replace an exogenous marker such that when the endogenous promoter is active, the marker is detectable. In certain embodiments, the marker can be an enzymatic marker capable of amplifying the detectable signal of the marker.

Alternatively, in some embodiments the methods of the invention may be used to replace an endogenous promoter or other regulatory sequence with an exogenous promoter or modulator sequence. In these embodiments, the expression pattern of the locus will be dictated by the exogenous promoter or regulatory sequence, as opposed to the endogenous promoter or regulatory sequence. Such exogenous promoter or regulatory sequences will be homologous to the endogenous promoter or regulatory sequence. For example, when the endogenous sequence is non-human, the exogenous sequence may be a human sequence. In certain embodiments, the exogenous sequence may be independent of the endogenous sequence being replaced.

C. Exogenous  Integration of Nucleic Acid Sequences

Alternatively, instead of disrupting the locus, exogenous sequences can be integrated into the chromosomal sequence without disrupting expression of the endogenous locus, with or without the promoter, using the methods of the invention. In certain embodiments, this integration may be in a “safe harbor” left, either a Rosa26 locus (or another equivalent animal) in a rat or an HPRT locus (or another equivalent animal) in the X chromosome of a rat.

In one embodiment, a cassette comprising an exogenous promoter operably linked to an exogenous nucleic acid sequence may be integrated into a safe haven locus. In certain embodiments, the exogenous promoter can be conditional. For example, a conditional promoter may be a tissue-specific promoter, an organ specific promoter, or a cell-type specific promoter (such as a stem cell promoter, a B-cell promoter, a hair cell promoter, or the like) or an inducible promoter. Can be. As used herein, an inducible promoter is a promoter that is active only in the presence of certain substances such as antibiotics, drugs, or other exogenous compounds. In certain embodiments, integration of a cassette comprising a conditional promoter can be used to track the cell lineage.

In another embodiment, exogenous nucleic acid sequences can be integrated to serve as detectable markers for specific nucleic acid sequences.

D. Humanized ( humanized )

In further embodiments, the genetically modified animal may be a “humanized” animal comprising at least one chromosomal integrated sequence that encodes a functional human protein. This functional human protein will not have an ortholog inherited from its corresponding ancestor in a genetically modified animal. Alternatively, the nocturnal animal from which the genetically modified animal is derived may comprise an ortholog derived from an ancestor corresponding to a functional human protein. In this case, the genetic sequence inherited from the ancestors of the "humanized" animal is inactivated to prevent the production of endogenous functional proteins, and the "humanized" animal contains sequences integrated into at least one chromosome that encodes a human protein. do. Those skilled in the art will appreciate that "humanized" animals can be made by crossing a knock-out animal with a knock-in animal comprising a sequence integrated on a chromosome.

(g) Multiple Chromosome Editing

Said further embodiment of the invention involves implementing a series of methods of the invention to develop cells with one or more chromosomal edits. For example, embryos with a first edit can be cultured to produce an animal comprising the first genome edit. Embryos derived from such animals can then be used in the present invention to make a second genome edit. The same procedure can be repeated to make three, four, five, six, seven, eight, nine, ten or more genome edits.

Alternatively, cells with multiple genome editing can be generated by simultaneously introducing one or more zinc finger nucleases, each specific for a unique editing site. A corresponding number of donor and / or exchange polynucleotides may also be optionally introduced. The number of zinc finger nucleases and optional corresponding donor or exchange polynucleotides introduced into the cell may be 2, 3, 4, 5 or more.

II . Use derived from the method of the invention

The methods of the invention can be used to create an animal or cell comprising an edited chromosomal sequence. Such animals or cells can be used for several different uses, including, for example, research use, animal use, pet use, or biomolecule production use. Non-limiting examples of such uses are described in detail in paragraphs (a)-(d) below.

(a) research purposes

In certain embodiments, the methods of the invention can be used to create animals or cells that can be used for research use. Such uses may include disease models, pharmacology models, developmental models, cell function models, and humanized models, each of which is described below.

i. Disease model

The methods of the invention can be used to create animals or cells that can be used as disease models. As used herein, “disease” refers to a disease, disorder, or symptom of an individual. For example, in one embodiment, the methods of the invention can be used to create an animal or cell comprising chromosomal editing of one or more nucleic acid sequences associated with a disease. Such nucleic acid sequences may encode disease related protein sequences or may be disease related reference sequences.

In one embodiment, animals or cells created by the methods of the invention can be used to study the effects of mutations and the occurrence and / or progression of the disease in the animal or cell using measurements commonly used in disease research. . Alternatively, such animals or cells can be used to study the pharmaceutical effects of the active compounds in a disease.

In another embodiment, animals or cells created by the methods of the invention can be used to assess the effectiveness of possible gene therapy strategies. That is, the chromosomal sequence encoding a protein associated with a disease can be modified to inhibit or reduce the disease development and / or progression. In particular, the method involves editing a chromosomal sequence that encodes a protein associated with the disease, resulting in an altered protein, resulting in an altered response of the animal or cell. Thus, in some embodiments, genetically modified animals can assess the effectiveness of the gene therapy process as compared to animals vulnerable to the development of the disease.

In certain embodiments, the methods of the present invention can be used to create an animal or cell that may possibly be used as a disease model for the diseases listed in Table A. Such animals or cells may comprise chromosomal editing of the genes listed in Table A. In another embodiment, the methods of the present invention may create an animal or cell that may possibly be used as a disease model for the diseases listed in Table B. Such animals or cells may comprise chromosomal editing of the genes listed in Table B. In Table B, the six-digit number following the description of the disease / disorder / symptom column is the OMIM number (Online Mendelian Inheritance in Man, OMIM (TM)) McKusick - Nathans available on the World Wide Web. Institute of Genetic Medicine , Johns Hopkins University ( Baltimore , MD ) and National Center for Biotechnology Information , National Library of Medicine ( Bethesda , MD ) . The number in parentheses after each disorder name indicates the location of the mutation by mapping the wild type gene (1), mapping the disease phenotype itself (2), or both methods (3). For example, "(3)" includes mapping of wild type genes in combination with examples of mutations in genes associated with the disorder. "

Additional non-limiting examples created by the methods of the method of the invention include Parkinson disease model, addiction model, inflammation model, cardiovascular disease model, Alzheimer disease model, autism spectrum disorder model, macular degeneration model, schizophrenia model, tumor suppression model , Trinucleotide repeat disorder model, neurotransmission disorder model, secretory enzyme-related disorder model, ALS model, prion disease model, ABC carrier protein-related disorder model, and immunodeficiency model. Each model is discussed in more detail below.

A. Parkinson's Disease

In one embodiment, the methods of the invention can be used to create an animal or cell in which at least one chromosomal sequence associated with Parkinson's disease (PD) has been edited. Suitable chromosomal editing includes, but is not limited to, the type of editing detailed in paragraph I (f) above.

In certain embodiments, one or more chromosomal sequences that encode a PD related protein or regulatory sequence can be edited. PD-related protein or regulatory sequences can be selected based on experimental association of the PD-related protein or reference sequence to PD. For non-limiting examples, the production rate or circulating concentration of PD-related proteins may be elevated or inhibited in the population with PD as compared to the population without PD. Differences in protein levels can be assessed by proteomatic or genomic analysis techniques known in the art. Non-limiting examples of proteins associated with Parkinson's disease include α-synuclein, DJ-1, LRRK2, PINK1, Parkin, UCHL1, Synphilin-1, and NURR1.

In certain embodiments, animals created by the methods of the present invention can be used to study the effects of mutations and PD development and / or progression in animals according to measurements commonly used in PD studies. Methods of measuring and studying the progress of PD in animals are known in the art. Measurements commonly used in PD studies include, but are not limited to, amyloidogenesis or protein aggregation, dopamine response, neurodegeneration, development of mitochondrial related dysfunction phenotypes, as well as functional, pathological or biochemical analysis. Other related signs related to the development or progression of PD include coordination, balance, walking gait, impairment of motion, fineness and twitches, stiffness, abnormal reduction of hypokinesia, and cognitive impairment. One is not limited thereto. This analysis can be made in comparison to wild-type littermates.

B. addiction

As used herein, addiction is defined as a chronic disease of brain reward, stimulation, memory and related neurological chronic circuitry included in various brain structures. Specific examples of brain structures that may experience dysfunctions associated with addiction disorders include nuclear accumbens, ventral pallidum, dorsal thalamus, prefrontal cortex, striatum, Brainstem black material (substantia nigra), pontine reticular formation, amygdala, and ventral tegmental area. The dysfunction of these neural circuits will lead to various biological, psychological, social and behavioral symptoms of addiction.

Biological signs of intoxication include overproduction or underproduction of one or more addiction-related proteins; Redistribution of one or more addiction-related proteins in the brain; Development of resistance, adverse resistance or other changes sensitive to the effects of addictive or neurotransmitters in the brain; High blood pressure; And withdrawal signs such as insomnia, anxiety, anorexia, depression, cardiac, excitement, anger, pain, and cravings.

Psychological manifestations of addiction will vary depending on the particular addictive substance and duration of intoxication. Non-limiting examples of psychological signs of addiction include mood swings, paranoia, insomnia, psychosis, schizophrenia, cardiac arrest panic attacks, impaired cognition, and aggressive, forced, criminal and / or distractive maneuvers. Includes a sharp change in toughness.

Social signs of addiction include low self-esteem, verbal hostility, interpersonal ignorance, focus anxiety, such as crowd fears, inflexible interpersonal behavior, grossly unusual behavior, rebellion, and the recognition of individual behavior and interpersonal and serious problems Includes reduction.

Non-limiting examples of behavioral signs of addiction include: impairment in behavioral control, inability to continually abstain from the use of addictive substances, cycles of relapse and mitigation, risk-taking behaviors, pleasure-seeking behaviors, new behaviors, pain Includes behaviors that seek mitigation and those that pursue rewards.

Addiction may be a substance addiction typically associated with ingestion of an addictive substance. Addictive materials can include neuroactive materials that can temporarily alter the chemical environment of the brain, across the blood-brain barrier. Non-limiting examples of addictive substances include alcohols; Opiate compounds such as opiates and heroin; Sedative, hypnotic, or anxiolytic compounds such as benzodiazepines and barbiturates compounds; Cocaine and related compounds; Cannabis and related compounds; Amphetamines and amphetamine-like compounds; Hallucinogenic compounds; Inhalants such as glue or aerosol propellants; Penciclidine or penciclidine-like compounds; And nicotine. In addition, addiction can be a behavioral addiction such as a hard to suppress desire, for example, gaming and computer addiction, which is unrelated to the substance.

In one embodiment, the methods of the invention can be used to create an animal or cell in which at least one addiction-related chromosomal sequence has been edited. Suitable editing includes, but is not limited to, the type of editing described in detail in paragraph (I) f above.

Addiction-related nucleic acid sequences are a diverse series of sequences that are sensitive to the development of addiction, related to the presence of addiction, the severity of addiction, or any combination thereof. Addiction-related nucleic acid sequences may typically be selected based on experimental association of addiction-related nucleic acid sequences to addiction disorders. The addiction-associated nucleic acid sequence may encode an addiction-related protein or may be an addiction-related regulatory sequence. For non-limiting examples, the rate of production or circulating concentration of the addiction-related protein may be elevated or suppressed in the population with addiction disorders as compared to the population lacking addiction disorders. Differences in protein levels can be assessed using proteomic or genomic analysis techniques known in the art.

Non-limiting examples of addiction-related proteins include ABAT (4-aminobutyrate aminotransferase); ACN9 (ACN9 homologue ( S. cerevisae )); ADCYAP1 (adenylate cyclase activating polypeptide 1); ADH1B (alcohol dehydrogenase IB (class I), beta polypeptides); ADH1C (alcohol dehydrogenase 1C (Class I), gamma polypeptide); ADH4 (alcohol dehydrogenase 4); ADH7 (alcohol dehydrogenase 7 (class IV), mu or sigma polypeptide); ADORA1 (adenosine A1 receptor); ADRA1A (adrenergic, alpha-1A-, receptor); ALDH2 (aldehyde dehydrogenase 2 family); ANKK1 (Ankyrin repeat, TaqI A1 allele); ARC (activity-regulated cytoskeleton-related protein); ATF2 (Corticotrophin-releasing factor); AVPR1A (arginine vasopressin receptor 1A); BDNF (brain-induced neurotrophic factor); BMAL1 (aryl hydrocarbon receptor nuclear translocator-like); CDK5 (cyclin-dependent kinase 5); CHRM2 (cholinergic receptor, muscarinic 2); CHRNA3 (cholinergic receptor, nicotinic, alpha 3); CHRNA4 (cholinergic receptor, nicotinic, alpha 4); CHRNA5 (cholinergic receptor, nicotinic, alpha 5); CHRNA7 (cholinergic receptor, nicotinic, alpha 7); CHRNB2 (cholinergic receptor, nicotinic, beta 2); CLOCK (Clock homologue (mouse)); CNR1 (cannabinoid receptor 1); CNR2 (cannabinoid receptor type 2); COMT (catechol-O-methyltransferase); CREB1 (cAMP response element binding protein 1); CREB2 (activating transcription factor 2); CRHR1 (Adrenal Cortical Stimulating Hormone Releasing Hormone Receptor 1); CRY1 (Crimtochrome 1); CSNK1E (casein kinase 1, epsilon); CSPG5 (chondroitin sulfate proteoglycan 5); CTNNB1 (catenin (cadherin-associated protein), beta 1, 88 kDa); DBI (diazepam binding inhibitor); DDN (dendrin); DRD1 (dopamine receptor D1); DRD2 (dopamine receptor D2); DRD3 (dopamine receptor D3); DRD4 (dopamine receptor D4); EGR1 (initial growth response 1); ELTD1 (containing 1 EGF, latropyline and seven transmembrane domains); FAAH (fatty acid amide hydrolase); FOSB (FBJ murine osteosarcoma viral oncogene homolog); FOSB (FBJ murine osteosarcoma viral oncogene homolog B); GABBR2 (gamma-aminobutyl acid (GABA) B receptor, 2); GABRA2 (gamma-aminobutyl acid (GABA) A receptor, alpha 2); GABRA4 (gamma-aminobutyl acid (GABA) A receptor, alpha 4); GABRA6 (gamma-aminobutyl acid (GABA) A receptor, alpha 6); GABRB3 (gamma-aminobutyl acid (GABA) A receptor, alpha 3); GABRE (gamma-aminobutyl acid (GABA) A receptor, epsilon); GABRG1 (gamma-aminobutyl acid (GABA) A receptor, gamma 1); GAD1 (glutamate decarboxylase 1); GAD2 (glutamate decarboxylase 2); GAL (galanine prepropeptide); GDNF (glial derived neurotrophic factor); GRIA1 (glutamate receptor, ionotropic, AMPA 1); GRIA2 (glutamate receptor, ionic, AMPA 2); GRIN1 (glutamate receptor, ionic, N-methyl D-aspartate 1); GRIN2A (glutamate receptor, ionic, N-methyl D-aspartate 2A); GRM2 (glutamate receptor, metabotropic 2, mGluR2); GRM5 (metabotropic glutamate receptor 5); GRM6 (glutamate receptor, metabotropic 6); GRM8 (glutamate receptor, metabotropic 8); HTR1B (5-hydroxytryptamine (serotonin) receptor 1B); HTR3A (5-hydroxytryptamine (serotonin) receptor 3A); IL1 (interleukin 1); IL15 (interleukin 15); IL1A (interleukin 1 alpha); IL1B (interleukin 1 beta); KCNMA1 (potassium large conductive calcium-activated channel, subfamily M, alpha member 1); LGALS1 (lectingalactosid-binding soluble 1); MAOA (monoamine oxidase A); MAOB (monoamine oxidase B); MAPK1 (mitogen-activated protein kinase 1); MAPK3 (mitogen-activated protein kinase 3); MBP (myelin basic protein); MC2R (melanocortin receptor type 2); MGLL (monoglyceride lipase); MOBP (myelin-associated oligodendrocyte basic protein); NPY (neural peptide Y); NR4A1 (nuclear receptor subfamily 4, group A, member 1); NR4A2 (nuclear receptor subfamily 4, group A, member 2); NRXN1 (neulexin 1); NRXN3 (neulexin 3); NTRK2 (neotrophic tyrosine kinase, receptor, type 2); NTRK2 (tyrosine kinase B neurotropin receptor); OPRD1 (delta-opium receptor); OPRK1 (kappa-opium receptor); OPRM1 (mu-opium receptor); PDYN (Dinolpin); PENK (enkephalin); PER2 (Period Homolog 2 (Drosophila)); PKNOX2 (PBX / knotted 1 homeobox 2); PLP1 (protein lipid protein 1); POMC (propiomelanocortin); PRKCE (protein kinase C, epsilon); PROKR2 (prokineticin receptor 2); RGS9 (modulator of G-protein signaling 9); RIMS2 (synaptic membrane exocytosis 2 regulation); SCN9A (sodium channel translocation-gated type IX alpha subunit); SLC17A6 (solute carrier family 17 (sodium-dependent inorganic phosphate cocarrier), member 6); SLC17A7 (solute carrier family 17 (sodium-dependent inorganic phosphate cocarrier), member 7); SLC1A2 (Solute Carrier Family 1 (Glue High Affinity Glutamate Carrier), Member 2); SLC1A3 (Solute Carrier Family 1 (Glue High Affinity Glutamate Carrier), Member 3); SLC29A1 (solute carrier family 29 (nucleoside carrier), member 1); SLC4A7 (Solute Carrier Family 4, Sodium Bicarbonate Salt Cocarrier, Member 7); SLC6A3 (solute carrier family 6 (neurotransmitter transport, dopamine), member 3); SLC6A4 (solute carrier family 6 (neurotransmitter transport, serotonin), member 4); SNCA (synuclein, alpha (non-A4-component of the amyloid precursor)); TFAP2B (transcription factor AP-2 beta); And TRPV1 (transient receptor potential cation channel, subfamily V, member 1).

Preferred addiction-related proteins include ABAT (4-aminobutyrate aminotransferase), DRD2 (dopamine receptor D2), DRD3 (dopamine receptor D3), DRD4 (dopamine receptor D4), GRIA1 (glutamate receptor, ionic, AMPA 1), GRIA2 (glutamate receptor, ionic, AMPA 2), GRIN1 (glutamate receptor, ionic, N-methyl D-aspartate 1), GRIN2A (glutamate receptor, ionic, N-methyl D-aspartate 2A), GRM5 (Metabotropic Glutamate Receptor 5), HTR1B (5-hydroxytrytamine (Serotonin) Receptor 1B), PDYN (Dinolpin), PRKCE (Protein Kinase C, Epsilon), LGALS1 (Lectingalactosid-Binding Soluble 1 ), TRPV1 (temporary receptor capable cation channel subfamily V member 1), SCN9A (sodium channel translocation-gated type IX alpha subunit), OPRD1 (opium receptor delta 1), OPRK1 (opium receptor kappa 1), OPRM1 (opium receptor Mu 1), and any combination thereof It may include.

In certain embodiments, an animal created by the method of the present invention is obtained from a genetically modified animal comprising at least one edited chromosome sequence that encodes an addiction-related protein for analytical measurements using wild-type animals. By comparing the assay measurements, it can be used as a model for signs of addiction disorder. Non-limiting examples of assays used to assess signs of addictive disorders include behavioral analysis, physiological analysis, whole animal analysis, tissue analysis, cell analysis, biomarker analysis, and combinations thereof. Signs of addiction disorder may occur spontaneously or may be promoted by exposure to exogenous substances such as addictive substances or addiction-related proteins. Alternatively, signs of addiction disorder can be induced by the recovery of other compounds, such as addiction-related proteins, administered from the outside.

Additional aspects of the present disclosure include methods for assessing the effectiveness of a treatment that reduces the signs of withdrawal and / or inhibition of addictive behavior in genetically modified animals comprising at least one edited chromosomal sequence associated with addiction. Addiction treatments evaluated include the administration of one or more new candidate therapeutic compounds, the administration of a new combination of settled therapeutic compounds, the novel methods of treatment, and any combination thereof. The novel treatment methods may include various drug delivery mechanisms, nanotechnology application to drug treatment, surgery, and combinations thereof.

Behavioral assessments of genetically modified animals and / or wild-type animals comprising at least one edited addiction-related protein may be used to assess the side effects of a therapeutic compound or combination of therapeutic agents. Genetically modified animals and optionally wild type animals may be treated with a therapeutic compound or combination of therapeutic agents and subject to behavioral assessment. Behavioral assessments may assess behaviors including, but not limited to, learning, memory, anxiety, depression, addiction, and sensory-motor functions.

A further aspect is the effect of selected variables on results obtained from wild-type animals contacting a substance with a genetically modified animal comprising at least one chromosomal sequence encoding an addiction-related protein, and without contact with the same substance. A method of assessing the therapeutic potential of a substance in an animal comprising comparing the same is provided. The variables selected were a) voluntary actions; b) performance during behavioral assessments; c) physiological anomalies; d) abnormalities in tissues or cells; e) biochemical function; And f) molecular structures.

C. Inflammation

In one embodiment, the methods of the invention can be used to create an animal or cell in which at least one chromosomal sequence associated with inflammation has been edited. Suitable chromosomal editing includes, but is not limited to, the type of editing described in paragraph I (f) above.

In the above embodiments, one or more chromosomal sequences associated with inflammation can be edited. Inflammation-related chromosomal sequences may typically be selected based on experimental association of inflammation-related sequences for inflammatory disorders. The inflammation-related sequence may encode an inflammation-related protein or may be an inflammation-related regulatory sequence.

For example, the production rate or circulating concentration of inflammation-related proteins may be elevated or inhibited in populations with inflammatory disorders compared to populations lacking inflammatory disorders. Differences in protein levels can be assessed using proteomic or genomic analysis techniques known in the art.

Non-limiting examples of inflammation-related proteins from which chromosomal sequences can be edited are Ccr2 Mononuclear chemoattractant protein-1 ( MCP1 ) encoded by the gene, CC chemokine receptor type 5 (CCR5) encoded by the Ccr5 gene, IgG receptor IIB encoded by the Fcgr2b gene (also known as FCGR2b, CD32) hereinafter), the encoded Fc epsilon R1g (FCER1g) protein, box encoded fork head (forkhead) by FOXN1 gene N1 transcription factor (FOXN1), it encodes the interferon by IFNg gene by Fcer1g gene-gamma (IFN -γ), Interleukin 4 (IL-4) encoded by the IL-4 gene, Perforin -1 encoded by the PRF- 1 gene, cyclooxygenase 1 protein encoded by the COX1 gene (COX1 ), the encoded protein cyclooxygenase 2 (COX2), the encoded T- box transcription factor (TBX21) protein, the encoded signal generated by a mediation material 1 protein SH2B1 gene by gene TBX21 by the COX2 gene ( SH2-B PH domain containing SH2BPSM1) (also known as SH2BPSM1), FG Encoded fibroblasts by FR2 gene growth factor receptor 2 (FGFR2) protein, (also referred to as SLC22A1) encoding the solute carrier family 22, member 1 (SLC22A1) protein by the OCT1 gene, the encoded peroxy by PPARA gene Some proliferator-activated receptor alpha proteins (PPAR-alpha, also known as nuclear receptor subfamily 1, group C, member 1; NR1C1), phosphatase and tensine homologue proteins (PTEN), IL - encoded by the PTEN gene Interleukin 1 alpha (IL-1α) encoded by the 1A gene, interleukin 1 beta (IL-1β) encoded by the IL- 1B gene, interleukin 6 (IL-6) encoded by the IL- 6 gene , IL-encoded IL-10 by gene -10 (IL-10), IL -12A encoded by the gene IL-12 alpha (IL-12α), the encoded IL-12 beta (IL by IL -12B gene the encoded IL-13 by -12β), IL-13 gene (IL-13), IL -17A The encoding by the electronic Interleukin 17A (IL-17A, CTLA8 also called), IL-encoded IL-17B -17B by the gene (IL-17B), the encoded IL-17C (IL-17C IL -17C by Gene ), IL an IL-17D (IL-17D -17D encoded by the gene), IL an IL-17F (IL-17F) encoded by the gene -17F, IL-encoded IL-23 by gene -23 (IL- 23) chemokine (C-X3-C motif) receptor 1 protein (CX3CR1) encoded by the CX3CR1 gene, Encode a chemokine (C-X3-C motif) ligand by CX3CL1 gene 1 protein (CX3CL1), the encoded recombinant active gene 1 protein (RAG1), the encoded recombinant active gene by RAG2 gene by the RAG1 gene 2 protein (RAG2), protein kinase encoded by PRKDC (DNAPK) gene, DNA-activated, catalytic polypeptide 1 (PRKDC), protein tyrosine phosphatase non-receptor type 22 protein (PTPN22) encoded by PTPN22 gene Tumor necrosis factor alpha (TNFα) encoded by the TNFA gene, nucleotide-binding oligomerization domain containing 2 protein (NOD2) encoded by the NOD2 gene (also known as CARD15), or cells encoded by the CTLA4 gene. Toxic T-lymphocyte antigen 4 protein (also known as CTLA4, CD152).

In certain embodiments, measurements commonly used in the study of inflammation in animals created by the methods of the present invention can be used to study the effects of mutations and the development and / or progression of inflammation in animals. Alternatively, the animals created by the methods of the present invention can be used to study the effects of mutations in these disease states or disorders using measurements commonly used in the study of disease states or disorders associated with inflammation-related proteins. have. Non-limiting examples of measures that can be used include spontaneous behaviors of genetically modified animals, performance during behavioral assessments, physiological anomalies, differential responses to compounds, abnormalities in tissues or cells, and genetic modifications Biochemical or molecular differences between animals and wild-type animals.

D. Cardiovascular Disease

Cardiovascular diseases generally include high blood pressure, heart attack, heart failure, and seizures and TIA. In one embodiment, the methods of the present invention can be used to create an animal or cell that has been edited with at least one chromosomal sequence associated with cardiovascular disease. . Suitable chromosomal editing includes, but is not limited to, the type of editing described in paragraph I (f) above.

Proteins encoded by any chromosomal sequence related to cardiovascular disease or any chromosomal sequence related to cardiovascular disease may be used in the methods of the present invention.

Cardiovascular-related chromosomal sequences may typically be selected based on experimental association of cardiovascular-related sequences for the development of cardiovascular disease. The cardiovascular-related sequence may encode an inflammation-related protein or may be an inflammation-related regulatory sequence.

For example, the production rate or circulating concentration of cardiovascular-related proteins can be elevated or inhibited in the population with cardiovascular disorders as compared to the population lacking cardiovascular disorders. Differences in protein levels can be assessed using proteomic or genomic analysis techniques known in the art.

For example, the chromosomal sequence may be IL1B (interleukin 1, beta), XDH (xanthine dehydrogenase), TP53 (tumor protein p53), PTGIS (prostaglandin I2 (prostacyclin) synthase), MB (myoglobin), IL4 ( Interleukin 4), ANGPT1 (angiopoetine 1), ABCG8 (ATP-binding cassette, sub-family G (WHITE), member 8), CTSK (cathepsin K), PTGIR (prostaglandin I2 (prostacyclin) receptor ( IP)), KCNJ11 (potassium inward-rectifying channel, subfamily J, member 11), INS (insulin), CRP (C-reactive protein, pentracin-associated), PDGFRB (platelet-induced growth factor receptor, Beta polypeptide), CCNA2 (cyclin A2), PDGFB (platelet-derived growth factor beta polypeptide (monkey sarcoma viral (v-sis) oncogene homolog)), KCNJ5 (potassium inward-rectifying channel, subfamily J) , Member 5), KCNN3 (potassium medium / small conducting calcium-activated channel, subfamily N, member 3 ), CAPN10 (calpine 10), PTGES (prostaglandin E synthetase), ADRA2B (adrenergic, alpha-2B-, receptor), ABCG5 (ATP-binding cassette, sub-family G (WHITE), member 5), PRDX2 (Peroxyredoxin 2), CAPN5 (calpine 5), PARP14 (poly (ADP-ribose) polymerase family, member 14), MEX3C (mex-3 homologue C (C. Elegans)), ACE angiotensin I converting enzyme (peptidyl-dipeptidase A) 1), TNF (tumor necrosis factor (TNF superfamily, member 2)), IL6 (interleukin 6 (interferon, beta 2)), STN (Statin), SERPINE1 (serpin peptidase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1), member 1), ALB (albumin), ADIPOQ (adiponectin, C1Q and collagen domains) ), APOB (apolipoprotein B (including Ag (x) antigen)), APOE (apolipoprotein E), LEP (leptin), MTHFR (5,10-methylenetetrahydrofolate reductase (NADPH)), APOA1 (apopolipoprotein AI), EDN1 (endoterin 1), NPPB (natriuretic peptide precursor B), NOS3 (nitric oxide synthase 3 (endothelial cell)), PPARG (peroxysome proliferator-activation Receptor gamma), PLAT (plasminogen activator, tissue), PTGS2 (prostaglandin-andopeoxide synthase 2 (prostaglandin G / H synthase and cyclo) Sigenase)), CETP (cholesteryl ester transfer protein, plasma), AGTR1 (angiotensin II receptor, type 1), HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase), IGF1 (Insulin-like growth factor 1 (somatomedin C)), SELE (serectin E), REN (renin), PPARA (peroxysome proliferator-activated receptor alpha), PON1 (rapapoxonase 1), KNG1 (Kinnogen 1), CCL2 (chemokine (CC motif) ligand 2), LPL (lipoprotein lipase), VWF (von Willebrand factor), F2 (coagulation factor II (thrombin)), ICAM1 (intercellular adhesion molecule 1), TGFB1 (transformation growth factor, beta 1), NPPA (sodium release peptide precursor A), IL10 (interleukin 10), EPO (erythropoietin), SOD1 (superoxide dismutase 1, soluble), VCAM1 (vascular) Cell adhesion molecule 1), IFNG (interferon, gamma), LPA (lipoprotein, Lp (a)), MPO (myeloperoxidase), ESR1 (estrogen receptor 1), MAPK1 (mitogen-activated protein kina 1), HP (haptoglobin), F3 (coagulation factor III (thromboplastin, tissue factor)), CST3 (cistatin C), COG2 (component of oligomer Golgi 2), MMP9 (matrix metalmetalpeptide) Ninth (gelatinase B, 92kDa gelatinase, 92kDa type IV collagenase), SERPINC1 (serpin peptidase inhibitor, clade C (antithrombin), member 1), F8 (coagulation factor VIII, ex Coagulation component), HMOX1 (ham oxygenase (decycling) 1), APOC3 (apolipoprotein C-III), IL8 (interleukin 8), PROK1 (prokineticin 1), CBS (cistathionine-beta- Synthase), NOS2 (nitric oxide synthase 2, inducible), TLR4 (toll-like receptor 4), SELP (selectin P (granular membrane protein 140kDa, antigen CD62)), ABCA1 (ATP-binding cassette, sub-family A (ABC1), member 1), AGT (angiotensinogen (serpin peptidase inhibitor, clade A, member 8)), LDLR (low density lipoprotein receptor), GPT (glutamine-pyruvate transaminase (al Nin aminotransferase)), VEGFA (vascular endothelial factor A), NR3C2 (nuclear receptor subfamily 3, group C, member 2), IL18 (interleukin 18 (interferon-gamma-inducing factor)), NOS1 (nitrogen oxide synthesis) Enzyme 1 (neurons)), NR3C1 (nuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptor)), FGB (fibrinogen beta chain), HGF (hepatocyte growth factor (hepapoetin A); Dispersing factor)), IL1A (interleukin 1, alpha), RETN (resistin), AKT1 (v-akt murine thymoma viral oncogene homolog 1), LIPC (lipase, hepatic), HSPD1 (heat shock 60 kDa protein 1 ( Chaperonin)), MAPK14 (mitogen-activated protein kinase 14), SPP1 (secreted phosphoprotein 1), ITGB3 (integrin, beta 3 (platelet glycoprotein IIIa, antigen CD61)), CAT (catalase), UTS2 (Eurotensin 2), THBD (thrombomodulin), F10 (coagulation factor X), CP (ceruloplasmin (ferrooxidase)), TNFRSF11B (tumor necrosis factor receptor superfamily, member 11b), EDNRA (endo Terin receptor type A), EGFR (epithelial growth factor receptor (erythroblastic leukemia viral (v-erb-b) oncogene homologue, algae)), MMP2 (matrix metalpeptidase 2 (gelatinase A, 72 kDa gela) Tinase, 72kDa type IV collagenase)), PLG (plasminogen), NPY (neuropeptide Y), RHOD (ras homologous gene family, member D), MAPK8 ( Mitogen-activated protein kinase 8), MYC (v-myc myelomyosis myelogenous homologue (bird)), FN1 (fibronectin 1), CMA1 (chymase 1, mast cells), PLAU ( Plasminogen activator, urokinase), GNB3 (guanine nucleotide binding protein (G protein), beta polypeptide 3), ADRB2 (adrenergic, beta-2-, receptor, surface), APOA5 (apolipoprotein AV), SOD2 ( Superoxide dismutase 2, mitochondria), F5 (coagulation factor V (proacerine, unstable factor)), VDR (vitamin D (1,25-dihydroxyvitamin D3) receptor), ALOX5 (arachidonate 5-lipoxygenase), HLA-DRB1 (major histocompatibility complex, class II, DR beta 1), PARP1 (poly (ADP-ribose) polymerase 1), CD40LG (CD40 ligand), PON2 (rapapoxonase 2) , AGER (developed glycosylation end-specific receptor), IRS1 (insulin receptor substrate 1), PTGS1 (prostaglandin-endo) Oxid Synthase 1 (prostaglandin G / H synthetase and cyclooxygenase)), ECE1 (endotherin converting enzyme 1), F7 (coagulation factor VII (serum prothrombin converting accelerator)), IL1RN (interleukin 1 receptor antagonist) , EPHX2 (epoxide hydrolase 2, cytoplasm), IGFBP1 (insulin-like growth factor binding protein 1), MAPK10 (mitogen-activated protein kinase 10), FAS (Fas (TNF receptor superfamily, member 6)) , ABCB1 (ATP-binding cassette, sub-family B (MDR / TAP), member 1), JUN (jun oncogene), IGFBP3 (insulin-like growth factor binding protein 3), CD14 (CD14 molecule), PDE5A (force Podiesterase 5A, cGMP-specific), AGTR2 (angiotensin II receptor, type 2), CD40 (CD40 molecule, TNF receptor superfamily member 5), LCAT (lecithin-cholesterol acyltransferase), CCR5 (ke Mokin (CC motif) receptor 5), MMP1 (matrix metalpeptidase 1 (intercellular collagenase)), TIMP1 (TIMP Soppeptidase inhibitor 1), ADM (adrenomedulin), DYT10 (tension 10), STAT3 (activator of signal transducer and transcription 3 (acute-phase response factor)), MMP3 (matrix metalpeptidase 3 ( Stromelysin 1, progelatinase)), ELN (elastin), USF1 (upstream transcription factor 1), CFH (complement factor H), HSPA4 (heat shock 70kDa protein 4), MMP12 (matrix metalpeptidase 12 ( Macrophage elastase)), MME (membrane metal-endopeptidase), F2R (coagulation factor II (thrombin) receptor), SELL (selectin L), CTSB (cathepsin B), ANXA5 (annexin A5), ADRB1 (adrenergic, beta-1-, receptor), CYBA (cytochrome b-245, alpha polypeptide), FGA (fibrinogen alpha chain), GGT1 (gamma-glutamyltransferase 1), LIPG (lipase, endothelial), HIF1A (hypotropin-inducing factor 1, alpha subunit (basic helix-loop-helix transcription factor)), CXCR4 (chemokine (CXC motif) receptor 4), PROC (protein C (coagulation factor) Inactivators of Va and VIIIa)), SCARB1 (scavenger receptor class B, member 1), CD79A (CD79a molecule, immunoglobulin-associated alpha), PLTP (phospholipid transport protein), ADD1 (educine 1 (alpha)) ), FGG (fibrinogen gamma chain), SAA1 (serum amyloid A1), KCNH2 (potassium potential-gated channel, subfamily H (eag-related), member 2), DPP4 (dipeptides-peptidase 4), G6PD (Glucose-6-phosphate dehydrogenase), NPR1 (sodium release peptide receptor A / guanylate cyclase A (atrial sodium release peptide receptor A)), VTN (Vitronectin), KIAA0101 (KIAA0101), FOS (FBJ murine Osteosarcoma viral oncogene homologues), TLR2 (toll-like receptor 2), PPIG (peptidylprolyl isomerase G (cyclophyllin G)), IL1R1 (interleukin 1 receptor, type I), AR (androgen receptor), CYP1A1 (cytochrome P450, family 1, subfamily A, polypeptide 1), SERPINA1 (serpin peptidase inhibitor, cle De A (alpha-1 antiproteinase, antitrypsin), member 1), MTR (5-methyltetrahydrofolate-homocysteine methyltransferase), RBP4 (retinol binding protein 4, plasma), APOA4 (apopolipoprotein) A-IV), CDKN2A (cyclin-dependent kinase inhibitor 2A (inhibits melanoma, p16, CDK4)), FGF2 (fibroblast growth factor 2 (basic)), EDNRB (endotherin receptor type B), ITGA2 (integrin , Alpha 2 (CD49B, alpha 2 subunit of the VLA-2 receptor), CABIN1 (calcineurin binding protein 1), SHBG (sex hormone-binding globulin), HMGB1 (high mobility group box 1), HSP90B2P (heat shock protein 90 kDa beta (Grp94), member 2 (false genes), CYP3A4 (cytochrome P450, family 3, subfamily A, polypeptide 4), GJA1 (gap binding protein, alpha 1, 43kDa), CAV1 (caberoline 1, cabe Ole protein, 22kDa), ESR2 (estrogen receptor 2 (ER beta)), LTA (lymphotoxin alpha (TNF superfamily, member 1)) , GDF15 (growth differentiation factor 15), BDNF (brain-derived neurotrophic factor), CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6), NGF (nerve growth factor (beta polypeptide)), SP1 ( Sp1 transcription factor), TGIF1 (TGFB-induced factor homeobox 1), SRC (v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (bird)), EGF (epithelial growth factor (beta) -Neugestrone)), PIK3CG (phosphoinositide-3-kinase, catalyst, gamma polypeptide), HLA-A (major histocompatibility complex, class I, A), KCNQ1 (potassium potential-gated channel, KQT-like Subfamily, member 1), CNR1 (cannabinoid receptor 1 (brain)), FBN1 (fibrilin 1), CHKA (choline kinase alpha), BEST1 (vestropin 1), APP (amyloid beta (A4) precursor protein ), CTNNB1 (catenin (cadherin-associated protein), beta 1, 88kDa), IL2 (interleukin 2), CD36 (CD36 molecule (thrombospondin receptor)), PRKAB1 (protein kina Agent, AMP-activated, beta 1 non-catalytic subunit), TPO (thyroid peroxidase), ALDH7A1 (aldehyde dehydrogenase 7 family, member A1), CX3CR1 (chemokine (C-X3-C motif) receptor 1) , TH (tyrosine hydroxylase), F9 (coagulation factor IX), GH1 (growth hormone 1), TF (transferrin), HFE (hemochromatosis), IL17A (interleukin 17A), PTEN (phosphatase and tensine homologs) , GSTM1 (glutathione S-transferase mu 1), DMD (dispropine), GATA4 (GATA binding protein 4), F13A1 (coagulation factor XIII, A1 polypeptide), TTR (transtyretin), FABP4 (fatty acid binding protein 4 , Adipocytes), PON3 (rapapoxonase 3), APOC1 (apopolipoprotein CI), INSR (insulin receptor), TNFRSF1B (tumor necrosis factor receptor superfamily, member 1B), HTR2A (5-hydroxytryptamine (serotonin) ) Receptor 2A), CSF3 (colony stimulating factor 3 (granulocytes)), CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9), TXN ( Oredoxin), CYP11B2 (cytochrome P450, family 11, subfamily B, polypeptide 2), PTH (parathyroid hormone), CSF2 (colonial stimulating factor 2 (granulocyte-macrophage)), KDR (kinase insertion domain receptor (type III) Receptor tyrosine kinase)), PLA2G2A (phospholipase A2, group IIA (platelet, synovial fluid)), B2M (beta-2-microglobulin), THBS1 (thrombospondin 1), GCG (glucagon), RHOA (ras phase Homologous gene family, member A), ALDH2 (aldehyde dehydrogenase 2 family (mitochondria)), TCF7L2 (transcription factor 7-like 2 (T-cell specific, HMG-box)), BDKRB2 (bradykinin receptor B2), NFE2L2 (Nuclear factor (erythrocyte-derived 2) -like 2), NOTCH1 (Notch homologue 1, translocation-related (Drosophila)), UGT1A1 (UDP glucuronosyltransferase 1 family, polypeptide A1), IFNA1 (interferon , Alpha 1), PPARD (peroxysome proliferator-activated receptor delta), SIRT1 (siltuine (silent mating type) Information regulation 2 homologue) 1 ((S. Serbian (S. cerevisiae )))), GNRH1 (gonadotropin-releasing hormone 1 (luteinated-releasing hormone)), PAPPA (pregnancy-associated plasma protein A, paparicin 1), ARR3 (arrestin 3, retina (X-arrestin)) , NPPC (sodium release peptide precursor C), AHSP (alpha hemoglobin stabilizing protein), PTK2 (PTK2 protein tyrosine kinase 2), IL13 (interleukin 13), MTOR (mechanical target of rapamycin (serine / threonine kinase)), ITGB2 (integrin, beta 2 (complement component 3 receptor 3 and 4 subunit)), GSTT1 (glutathione S-transferase theta 1), IL6ST (interleukin 6 signal transducer (gp130, oncostatin M receptor)), CPB2 (carboxypeptide Tidase B2 (plasma)), CYP1A2 (cytochrome P450, family 1, subfamily A, polypeptide 2), HNF4A (hepatocyte nuclear factor 4, alpha), SLC6A4 (solute carrier family 6 (neurotransmitter transport, serotonin), Member 4), PLA2G6 (phospholipase A2, group VI (cytosol, calcium-independent)), TNFSF11 (tumor necrosis Child (ligand) superfamily, member 11), SLC8A1 (solute carrier family 8 (sodium / calcium exchanger), member 1), F2RL1 (coagulation factor II (thrombin) receptor-like 1), AKR1A1 (aldo-keto reductase family 1, member A1 (aldehyde reductase)), ALDH9A1 (aldehyde dehydrogenase 9 family, member A1), BGLAP (bone gamma-carboxyglutamate (gla) protein), MTTP (microsometriglyceride transfer protein), MTRR (5-methyl Tetrahydrofolate-homocysteine methyltransferase reductase), SULT1A3 (sulfotransferase family, cytosol, 1A, phenol-preferred, member 3), RAGE (renal tumor antigen), C4B (complement component 4B (Chido blood group) ), P2RY12 (purinergic receptor P2Y, G-protein linked, 12), RNLS (linalase, FAD-dependent amine oxidase), CREB1 (cAMP response element binding protein 1), POMC (propiomelanocortin) , RAC1 (ras-associated C3 botulinum toxin substrate 1 (rho family, GT small) P binding protein Rac1)), LMNA (Lamine A / C), CD59 (CD59 molecule, complement regulatory protein), SCN5A (sodium channel, translocation-gated, type V, alpha subunit), CYP1B1 (cytochrome P450, family 1 , Subfamily B, polypeptide 1), MIF (macrophage transfer inhibitory factor (glycosylation-inhibiting factor)), MMP13 (matrix metalpeptidase 13 (collagenase 3)), TIMP2 (TIMP metalpeptidase inhibitor 2 ), CYP19A1 (cytochrome P450, family 19, subfamily A, polypeptide 1), CYP21A2 (cytochrome P450, family 21, subfamily A, polypeptide 2), PTPN22 (protein tyrosine phosphatase, non-receptor type 22 (limpoid) )), MYH14 (myosin, heavy chain 14, non-muscle), MBL2 (mannose-linked lectin (protein C) 2, soluble (opsonine deficiency)), SELPLG (selectin P ligand), AOC3 (amine oxidase, copper Containing 3 (vascular adhesion protein 1)), CTSL1 (cathepsin L1), PCNA (proliferating cell nuclear antigen), IGF2 (insulin-like growth factor) 2 (somatomedin A)), ITGB1 (integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12)), CAST (calpastatin), CXCL12 (chemokine (CXC motif) ligand 12 (Mesenchymal-induced factor 1)), IGHE (immunoglobulin heavy chain epsilon), KCNE1 (potassium potential-gated channel, Isk-associated family, member 1), TFRC (transferrin receptor (p90, CD71) )), COL1A1 (collagen, type I, alpha 1), COL1A2 (collagen, type I, alpha 2), IL2RB (interleukin 2 receptor, beta), PLA2G10 (phospholipase A2, group X), ANGPT2 (anggiopo) Ethyne 2), PROCR (protein C receptor, endothelial (EPCR)), NOX4 (NADPH oxidase 4), HAMP (hepcidine antimicrobial peptide), PTPN11 (protein tyrosine phosphatase, non-receptor type 11), SLC2A1 (solute carrier Family 2 (easy glucose transport), member 1), IL2RA (interleukin 2 receptor, alpha), CCL5 (chemokine (CC motif) ligand 5), IRF1 (interferon modulator 1), CFLAR (CASP8 and FADD-like apoptosis modulators), CALCA (calcitonin-associated polypeptide alpha), EIF4E (eukaryotic translation initiation factor 4E), GSTP1 (glutathione S-transition Enzyme pi 1), JAK2 (Janus kinase 2), CYP3A5 (cytochrome P450, family 3, subfamily A, polypeptide 5), HSPG2 (heparan sulfate proteoglycan 2), CCL3 (chemokine (CC motif) ligand 3), MYD88 (myeloid differentiation primary response gene (88)), VIP (vascular intestinal peptide), SOAT1 (sterol O-acyltransferase 1), ADRBK1 (adrenergic, beta, receptor kinase 1), NR4A2 (nuclear receptor subfamily 4) , Group A, member 2), MMP8 (matrix metalpeptidase 8 (neutrophil collagenase)), NPR2 (sodium release peptide receptor B / guanylate cyclase B (ventricular sodium release peptide receptor B)), GCH1 (GTP cyclohydrolase 1), EPRS (glutamyl-proyl-tRNA synthetase), PPARGC1A (peroxysome proliferator-activated receptor gamma, coactivator 1 alpha), F12 (coagulation factor XII (Hageman factor)), PECAM1 (platelet / endothelial adhesion molecule), CCL4 (chemokine (CC motif) ligand 4), SERPINA3 (serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 3), CASR (calcium-receptor receptor), GJA5 (gap binding protein, alpha 5, 40 kDa) ), FABP2 (fatty acid binding protein 2, gut), TTF2 (transcription termination factor, RNA polymerase II), PROS1 (protein S (alpha)), CTF1 (cardiotropin 1), SGCB (sarcoglycan, beta ( 43kDa dispropine-associated glycoprotein)), YME1L1 (YME1-like 1 (S. Cervicier)), CAMP (Catelycidine Antimicrobial Peptide), ZC3H12A (Zinc Finger CCCH-Type Containing 12A), AKR1B1 (Aldo-Keto Reductase Family 1, Member B1 (Aldose Reductase)), DES (Des Min), MMP7 (Matrix Metalpeptidase 7 (Matrilysine, Uterine)), AHR (Aryl Hydrocarbon Receptor), CSF1 (Colony Stimulating Factor 1 (Macrophage)), HDAC9 (Histon Deacetylase 9), CTGF (Connective tissue growth factor), KCNMA1 (potassium large conductive calcium-activated channel, subfamily M, alpha member 1), UGT1A (UDP glucuronosyltransferase 1 family, polypeptide A complex locus), PRKCA (protein kinase C, alpha), COMT (catechol-O-methyltransferase), S100B (S100 calcium binding protein B), EGR1 (initial growth response 1), PRL (prolactin), IL15 (interleukin 15), DRD4 (dopamine receptor D4 ), CAMK2G (calcium / calmodulin-dependent protein kinase II gamma), SLC22A2 (solute carrier family 22 (organic cation transport), member 2 ), CCL11 (chemokine (CC motif) ligand 11), PGF (B321 placental growth factor), THPO (thrombopoietin), GP6 (glycoprotein VI (platelet)), TACR1 (tachikinin receptor 1), NTS ( Neurotensin), HNF1A (HNF1 homeobox A), SST (somatostatin), KCND1 (potassium potential-gated channel, Shal-associated subfamily, member 1), LOC646627 (phospholipase inhibitor), TBXAS1 (thromoxane A synthesis Enzyme 1 (platelet)), CYP2J2 (cytochrome P450, family 2, subfamily J, polypeptide 2), TBXA2R (thromboxane A2 receptor), ADH1C (alcohol dehydrogenase 1C (class I), gamma polypeptide), ALOX12 (araki Donate 12-lipoxygenase), AHSG (alpha-2-HS-glycoprotein), BHMT (betaine-homocysteine methyltransferase), GJA4 (gap binding protein, alpha 4, 37kDa), SLC25A4 (solute carrier family 25 (Mitochondrial carriers; Adenine nucleotide potentials), member 4), ACLY (ATP citrate lyase), ALOX5AP (arachidonate 5-lipoxygenase-activating protein), NUMA1 (nuclear mitogenic tissue protein 1), CYP27B1 (cytochrome P450, family 27 , Subfamily B, polypeptide 1), CYSLTR2 (cysteinyl leukotriene receptor 2), SOD3 (superoxide dismutase 3, extracellular), LTC4S (rucotrien C4 synthase), UCN (urocor Tin), GHRL (ghrelin / oveststatin prepropeptide), APOC2 (apopolipoprotein C-II), CLEC4A (C-type lectin domain family 4, member A), KBTBD10 (kelch repeat and BTB (POZ) Domain containing 10), TNC (tenacin C), TYMS (thymidylate synthetase), SHC1 (SHC (containing Src homology 2 domain) transformed protein 1), LRP1 (low density lipoprotein receptor-associated protein 1), SOCS3 (Inhibitor of cytokine signaling 3), ADH1B (alcohol dehydrogenase 1B (Class I), beta polypeptide), KLK3 (Kallikrein-Related Peptidase 3), HSD11B1 (Hydroxysteroid (11-beta) Dehydrogenase 1), VKORC1 (Vitamin K Epoxide Reductase Complex, Subunit 1), SERPINB2 (Serpin Peptidase Inhibitor) , Clade B (ofalbumin), member 2), TNS1 (tensin 1), RNF19A (ring finger protein 19A), EPOR (erythropoietin receptor), ITGAM (integrin, alpha M (complement component 3 receptor 3 subunit) ), PITX2 (paired-like homeodomain 2), MAPK7 (mitogen-activated protein kinase 7), FCGR3A (Fc fragment of IgG, low affinity IIIa, receptor (CD16a)), LEPR (leptin receptor), ENG (endoglin), GPX1 (glutathione peroxidase 1), GOT2 (glutamine-oxaloacettransamiminase 2, mitochondria (aspartateaminotransferase 2)), HRH1 (histamine receptor H1), NR1I2 (nuclear receptor sub Family 1, Group I, Member 2), CRH (Adrenal Cortical Hormone Release Hormone), HTR1A (5-High Droxytrytamine (Serotonin) Receptor 1A), VDAC1 (potential-dependent anion channel 1), HPSE (heparanase), SFTPD (surfactant protein D), TAP2 (carrier 2, ATP-binding cassette, sub-family B (MDR / TAP)), RNF123 (ring finger protein 123), PTK2B (PTK2B protein tyrosine kinase 2 beta), NTRK2 (neotrophic tyrosine kinase, receptor, type 2), IL6R (interleukin 6 receptor), ACHE (acetylcholinese) Therapase (Yt blood group)), GLP1R (glucagon-like peptide 1 receptor), GHR (growth hormone receptor), GSR (glutathione reductase), NQO1 (NAD (P) H dehydrogenase, quinone 1), NR5A1 (nucleus) Receptor subfamily 5, group A, member 1), GJB2 (gap binding protein, beta 2, 26 kDa), SLC9A1 (solute carrier family 9 (sodium / hydrogen exchanger), member 1), MAOA (monoamine oxidase A), PCSK9 (pro protein convertase subtilisin / kesin type 9), FCGR2A (Fc fragment of IgG, low affinity IIa, receptor (CD32)), SE RPINF1 (serpin peptidase inhibitor, clade F (alpha-2 antiplasmin, pigment epithelial induced factor), member 1), EDN3 (endoterin 3), DHFR (dihydrofolate reductase), GAS6 ( Growth disruption-specific 6), SMPD1 (sphingomyelin phosphodiesterase 1, acid lysosomal), UCP2 (unlinked protein 2 (mitochondria, proton carrier)), TFAP2A (transcription factor AP-2 alpha (activating phosphorus) Henser binding protein 2 alpha)), C4BPA (complementary component 4 binding protein, alpha), SERPINF2 (serpin peptidase inhibitor, clade F (alpha-2 antiplasmin, pigment epithelial induced factor), member 2), TYMP (thymidine phosphorylase), ALPP (alkali phosphatase, placenta (Regan isozyme)), CXCR2 (chemokine (CXC motif) receptor 2), SLC39A3 (solute carrier family 39 (zinc transport), member 3), ABCG2 (ATP-binding cassette, sub-family G (WHITE), member 2), ADA (adenosine deaminase), JAK3 (Janus kinase 3), HSPA1A (Heat shock 70kDa protein 1A), FASN (fatty acid synthase), FGF1 (fibroblast growth factor 1 (acidic)), F11 (coagulation factor XI), ATP7A (ATPase, Cu ++ transport, alpha polypeptide), CR1 (complement component ( 3b / 4b) Receptor 1 (Knops blood group)), GFAP (glucose fibrous acid protein), ROCK1 (Rho-associated, coiled-coil containing protein kinase 1), MECP2 (methyl CpG binding protein 2 (Rett syndrome)) , MYLK (myosin light chain kinase), BCHE (butyrylcholinesterase), LIPE (lipase, hormone-sensitive), PRDX5 (peroxyredoxin 5), ADORA1 (adenosine A1 receptor), WRN (Werner syndrome, RecQ heli Case-like), CXCR3 (chemokine (CXC motif) receptor 3), CD81 (CD81 molecule), SMAD7 (SMAD family member 7), LAMC2 (laminine, gamma 2), MAP3K5 (mitogen-activated protein kinase kinase kinase 5), CHGA (Chromogranin A (parathyroid secretion protein 1)), IAPP (Islet amyloid polypeptide), RHO (Rhodopsin), ENPP1 ( Tonucleotide pyrophosphatase / phosphodiesterase 1), PTHLH (parathyroid hormone-like hormone), NRG1 (neuregulin 1), VEGFC (vascular endothelial growth factor C), ENPEP (glutamyl aminopeptidase (aminopeptidada) A)), CEBPB (CCAAT / enhancer binding protein (C / EBP), beta), NAGLU (N-acetylglucosaminidase, alpha-), F2RL3 (coagulation factor II (thrombin) receptor-like 3), CX3CL1 (chemokine (C-X3-C motif) ligand 1), BDKRB1 (bradykinin receptor B1), ADAMTS13 (ADAM metalpeptidase and thrombospondin type 1 motif, 13), ELINE (elastase, neutrophil expression ), ENPP2 (ectonucleotide pyrophosphatase / phosphodiesterase 2), CISH (cytokine-induced SH2-containing protein), GAST (gastrin), MYOC (myocillin, fine network-induced glucocorticoid reaction), ATP1A2 (ATPase, Na + / K + transport, alpha 2 polypeptide), NF1 (Nurofibromine 1), GJB1 (gap binding protein Vagina, beta 1, 32kDa), MEF2A (muscle cell enhancer factor 2A), VCL (vinculin), BMPR2 (bone forming protein receptor, type II (serine / threonine kinase)), TUBB (tubulin, beta), CDC42 (Cell division cycle 42 (GTP binding protein, 25kDa)), KRT18 (keratin 18), HSF1 (heat shock transcription factor 1), MYB (v-myb myeloma blastoma viral oncogene homolog (bird)), PRKAA2 (protein Kinases, AMP-activated, alpha 2 catalytic subunits), ROCK2 (Rho-associated, coiled-coil containing protein kinase 2), TFPI (tissue factor pathway inhibitors (lipoprotein-associated coagulation inhibitors)), PRKG1 (protein kinases, cGMP-dependent, type I), BMP2 (bone-forming protein 2), CTNND1 (catenin (cadherin-associated protein), delta 1), CTH (cytathionese (cistathionine gamma-lyase)), CTSS (cathepsin S), VAV2 (vav 2 guanine nucleotide exchange factor), NPY2R (neuropeptide Y receptor Y2), IGFBP2 (insulin-like growth factor) Synthesis protein 2, 36 kDa), CD28 (CD28 molecule), GSTA1 (glutathione S-transferase alpha 1), PPIA (peptidylprolyl isomerase A (cyclophyllin A)), APOH (apolipoprotein H (beta-2) Glycoprotein I)), S100A8 (S100 calcium binding protein A8), IL11 (interleukin 11), ALOX15 (arachidonate 15-lipoxygenase), FBLN1 (pibulin 1), NR1H3 (nuclear receptor subfamily 1, group H, member 3), SCD (stearoyl-CoA desaturase (delta-9-desaturase)), GIP (suppressive polypeptide above), CHGB (chromogranin B (secretographin 1)) , PRKCB (protein kinase C, beta), SRD5A1 (steroid-5-alpha-reductase, alpha polypeptide 1 (3-oxo-5 alpha-steroid delta 4-dehydrogenase alpha 1)), HSD11B2 (hydroxysteroid (11 -Beta) dehydrogenase 2), CALCRL (calcitonin receptor-like), GALNT2 (UDP-N-acetyl-alpha-D-galactosamine: polypeptide N-acetylgalactosminyltransferase 2 (GalNAc-T2)), A NGPTL4 (angiopoetine-like 4), KCNN4 (potassium medium / small conducting calcium-activated channel, subfamily N, member 4), PIK3C2A (phosphoinositide-3-kinase, class 2, alpha polypeptide), HBEGF (heparin-binding EGF-like growth factor), CYP7A1 (cytochrome P450, family 7, subfamily A, polypeptide 1), HLA-DRB5 (major histocompatibility complex, class II, DR beta 5), BNIP3 (BCL2 / Adenovirus E1B 19kDa interacting protein 3), GCKR (glucokinase (hexokinase 4) modulator), S100A12 (S100 calcium binding protein A12), PADI4 (peptidyl arginine deaminase, type IV), HSPA14 (heat shock 70kDa Protein 14), CXCR1 (chemokine (CXC motif) receptor 1), H19 (H19, imprinted maternally expressed transcript (non-protein coding)), KRTAP19-3 (keratin related protein 19-3), IDDM2 (insulin -Dependent diabetes mellitus 2), RAC2 (ras-associated C3 botulinum toxin substrate 2 (rho family, small GTP binding protein) Vaginal Rac2)), RYR1 (ryanodine receptor 1 (skeleton)), Clark (clock homologue (mouse)), NGFR (nerve growth factor receptor (TNFR superfamily, member 16)), DBH (dopamine beta- Hydroxylase (dopamine beta-monooxygenase)), CHRNA4 (cholinergic receptor, nicotinic, alpha 4), CACNA1C (calcium channel, potential-dependent, L type, alpha 1C subunit), PRKAG2 (protein Kinases, AMP-activated, gamma 2 non-catalytic subunits), CHAT (choline acetyltransferase), PTGDS (prostaglandin D2 synthase 21kDa (brain)), NR1H2 (nuclear receptor subfamily 1, group H, member 2) , TEK (TEK tyrosine kinase, endothelial), VEGFB (vascular endothelial growth factor B), MEF2C (muscle cell enhancer factor 2C), MAPKAPK2 (mitogen-activated protein kinase-activated protein kinase 2), TNFRSF11A (tumor necrosis Factor receptor superfamily, member 11a, NFKB activator), HSPA9 (heat shock 70kDa protein 9 (mortalin)), CYSLTR1 (C Tenanylucotriene receptor 1), MAT1A (methionine adenosyltransferase I, alpha), OPRL1 (opium receptor receptor-like 1), IMPA1 (inositol (myo) -1 (or 4) -monophosphatase 1), CLCN2 (Chloride channel 2), DLD (dihydroziamide dehydrogenase), PSMA6 (proteasome (prosome, macropine) subunit, alpha type, 6), PSMB8 (proteasome (prosome, macropine) sub Unit, beta type, 8 (multifunctional large peptidase 7), CHI3L1 (chitinase 3-like 1 (cartilage glycoprotein-39)), ALDH1B1 (aldehyde dehydrogenase 1 family, member B1), PARP2 (poly ( ADP-ribose) polymerase 2), STAR (steroidal acute regulatory protein), LBP (lipopolysaccharide binding protein), ABCC6 (ATP-binding cassette, sub-family C (CFTR / MRP), member 6), RGS2 (Modulator of G-protein signaling 2, 24kDa), EFNB2 (epirin-B2), GJB6 (gap binding protein, beta 6, 30kDa), APOA2 (apolipoprotein A-II), AMPD1 (adenosine parent Senate deaminase 1), DYSF (disferin, limb girdle atrophy 2B (autosome recessive)), FDFT1 (farnesyl-diphosphate farnesyltransferase 1), EDN2 (endoterin 2), CCR6 (chemokine (CC motif) receptor 6), GJB3 (gap binding protein, beta 3, 31kDa), IL1RL1 (interleukin 1 receptor-like 1), ENTPD1 (ectonucleoside triphosphate diphosphohydrolase 1), BBS4 (Bardet- Biedl syndrome 4), CELSR2 (cadherin, EGF LAG 7-passed G-type receptor 2 (Flamingo homologue, Drosophila)), F11R (F11 receptor), RAPGEF3 (Rap guanine nucleotide exchange factor (GEF) 3), HYAL1 ( Hyaluroglucosaminidase 1), ZNF259 (zinc finger protein 259), ATOX1 (ATX1 antioxidant protein 1 homologue (yeast)), ATF6 (activating transcription factor 6), KHK (ketohexokinase (fractokinase)), SAT1 (spermidine / spermine N1-acetyltransferase 1), GGH (gamma-glutamyl hydrolase (conjugase, foylpolygammaglu) Tamil hydrolase)), TIMP4 (TIMP metalpeptidase inhibitor 4), SLC4A4 (solute carrier family 4, sodium bicarbonate cocarrier, member 4), PDE2A (phosphodiesterase 2A, cGMP-stimulated), PDE3B (phosphodiesterase 3B, cGMP-inhibited), FADS1 (fatty acid desaturase 1), FADS2 (fatty acid desaturase 2), TMSB4X (thymosin beta 4, X-linked), TXNIP (thioredoxin interaction Agonist protein), LIMS1 (LIM and aging cell antigen-like domain 1), RHOB (ras homologue gene family, member B), LY96 (lymphocyte antigen 96), FOXO1 (forkhead box O1), PNPLA2 (patatin- Similar phospholipase domain 2), TRH (patric acid stimulating hormone-releasing hormone), GJC1 (gap binding protein, gamma 1, 45 kDa), SLC17A5 (solute carrier family 17 (anion / sugar transport), member 5), FTO (Related to fat mass and obesity), GJD2 (gap binding protein, delta 2, 36kDa), PSRC1 (proline / serine-rich coiled-coil 1), CASP12 ( Sparse 12 (gene / false gene)), GPBAR1 (G protein-linked bile acid receptor 1), PXK (PX domain containing serine / threonine kinase), IL33 (interleukin 33), TRIB1 (tribbles homolog 1 ( Drosophila)), PBX4 (pre-B-cell leukemia homeobox 4), NUPR1 (nuclear protein, transcriptional regulator, 1), 15-Sep (15 kDa serenoprotein), CILP2 (cartilage interlayer protein 2), TERC (telomerase RNA component), GGT2 (gamma-glutamyltransferase 2), MT-CO1 (mitochondrial encoded cytochrome c oxidase I), and UOX (urate oxidase, false gene) It is not limited to this.

In a further embodiment, the chromosomal sequence is Pon1 (Rappaoxonase 1), LDLR (LDL Receptor), ApoE (Apolipoprotein E), Apo B-100 (Apolipoprotein B-100), ApoA (Apolipoprotein (a )), ApoA1 (apolipoprotein A1), CBS (cistathione B-synthase), glycoprotein IIb / IIb, MTHRF (5,10-methylenetetrahydrofolate reductase (NADPH), and combinations thereof In one repeat, the cardiovascular related chromosomal sequences and proteins encoded by these chromosomal sequences may be selected from Cacna1C, Sod1, Pten, Ppar (alpha), Apo E, leptin, and combinations thereof. Can be.

In certain embodiments, the measurements commonly used in the study of cardiovascular disease using an animal created by the methods of the present invention can be used to study the effects of mutations and the development and / or progression of cardiovascular disease in the animal. . For example, suitable disease measurements include behavioral, electrophysiological, neurochemical, biochemical, or cellular dysfunction that can be assessed using a number of known diagnostic tests or assays.

E. Alzheimer  disease

In one embodiment, the methods of the invention can be used to create an animal or cell in which at least one chromosomal sequence has been edited associated with Alzheimer's disease. Suitable chromosomal editing includes, but is not limited to, the type of editing described in paragraph I (f) above.

In certain embodiments, one or more chromosomal sequences associated with AD can be edited. AD-related chromosomal sequences can typically be selected based on experimental association of AD-related sequences to AD disorders. The AD-related sequence may encode an AD-related protein or may be an AD-related regulatory sequence. For example, the production rate or circulating concentration of AD-related proteins can be elevated or inhibited in a population with AD disorder compared to a population lacking AD disorder. Differences in protein levels can be assessed using proteomic or genomic analysis techniques known in the art.

Ratio of the AD-related protein-limiting example encode a very-low-density lipoprotein receptor protein (VLDLR), the ubiquitin encoded by the UBA1 gene by VLDLR gene-in by a similar modified material activating enzyme 1 (UBA1), UBA3 gene Encoded NEDD8-activating enzyme E1 catalytic subunit protein (UBE1C), aquaporin 1 protein encoded by the AQP1 gene (AQP1), ubiquitin carboxyl-terminal esterase L1 protein encoded by the UCHL1 gene (UCHL1) , encoding the ubiquitin carboxyl by UCHL3 gene-terminal hydrolase isozyme L3 protein (UCHL3), encoding the ubiquitin by the UBB gene B protein (UBB), the encoded microtubules by MAPT gene-related protein tau ( MAPT ), PTPRA Encode a protein tyrosine phosphatase receptor type by gene A protein (PTPRA), Encoded phosphatidylinositol bond Cloud aminopterin set protein (PICALM), Encoded cluster Ste lean protein (apo-lipoprotein by CLU gene by PICALM gene J also known), the encoded frames enyl Lin 1 protein, encoded by PSEN2 gene presence enyl Lin 2 protein, sorbic the encoded by SORL1 gene motilin by the PSEN1 gene-related receptors, L (DLR classification) a repeat Protein containing (SORL1) protein, amyloid precursor protein (APP) encoded by APP gene, apolipoprotein E precursor (APOE) encoded by APOE gene, or brain encoded by BDNF gene- Including but not limited to induced neurotrophic factor (BDNF), or combinations thereof.

In certain embodiments, measurements commonly used in AD studies in animals created by the methods of the present invention can be used to study the effects of mutations and the development and / or progression of AD in animals. Measurements commonly used in AD studies include, but are not limited to, learning and memory, anxiety, depression, addiction, and sensory-motor function, as well as functional, pathological, metabolic or biochemical analysis. Those skilled in the art are familiar with the signs or other suitable measurements of AD. In general, these measurements can be compared to wild type litters.

Other measures of behavior may include assessment of voluntary behavior. Voluntary behavior can be assessed using any one or more methods for spontaneous behavior observation known in the art. In general, any spontaneous behavior in the animal's known behavior repertoire is observed, including movement, posture, social interaction, parenting, sleep, flickering, eating, drinking, urine, bowel movements, mating and attack. Extensive observational tools for quantifying the spontaneous behavior of mice and mice are known in the art and include our observations such as body position, abnormal movement behaviors such as breathing, tension unconscious movements, walking or shaking, and catatonic behaviors. , But not limited to, vocalization, eyelid closure, frequency of shot, running wheel behavior, we build, and aggressive interaction frequency.

In another embodiment, animals of the invention can be used to study the effects of mutations on disease states or intestinal progression other than AD, using measurements commonly used in these diseases or disorders, They are also associated with AD-related proteins. Non-limiting examples of disease states or disorders other than AD that may be associated with AD-related proteins include mental retardation such as dementia, congenital cerebellar ataxia, learning and memory deficits, gliding encephalopathy, tauopathy or Fibrilization, amyloidosis, neurodegeneration, Parkinson's disease, advanced nuclear palsy, Pick disease, male infertility, prostate and breast cancer, squamous cell carcinoma, lymphoma, leukemia, and atherosclerosis.

Other aspects include methods for assessing the effectiveness of potential gene therapy strategies. That is, compared to untreated animals, chromosomal sequences encoding AD related proteins can be modified such that genetically modified animals have altered responses to AD development and / or progression. In other words, mutated genes that animals are susceptible to AD can be "corrected" through gene therapy.

F. Autism Spectrum Disorder

In one embodiment, the methods of the invention can be used to create an animal or cell in which at least one chromosomal sequence associated with autism spectrum disorder (ASD) has been edited. Suitable chromosomal editing includes, but is not limited to, the type of editing described in paragraph I (f) above.

In each of the above embodiments, one or more chromosomal sequences associated with ASD can be edited. ASD-related protein or regulatory sequences may typically be selected based on experimental association of the protein or regulatory sequence to ASD development or indication. For example, the production rate or circulating concentration of ASD-related proteins may be elevated or inhibited in a population with ASD compared to a population lacking ASD. Differences in protein levels can be assessed using proteomic or genomic analysis techniques known in the art.

The identity of a protein associated with ASD whose chromosomal sequence has been edited can vary. In preferred embodiments, the chromosomal sequence is a protein related to the edited ASD is encoded by BZRAP1 gene benzo dia japin receptor (peripheral) associated protein 1 (BZRAP1), encode the AF4 / FMR2 family by AFF2 gene members 2 protein (AFF2) (MFR2 also called), FXR1 of fragile code division X mental retardation Auto some homologues by the gene 1 protein (FXR1), which tend to code division X mental retardation Auto some homologs by FXR2 gene 2 protein (FXR2), encode the MAM domain containing glycosyl phosphatidylinositol anchor protein 2 (MDGA2), is encoded by the methyl CpG-binding protein 2 (MECP2), MGLUR5 -1 gene by the MECP2 gene by gene MDGA2 Encoded Metabotropic Glutamate Receptor 5 (MGLUR5) (also known as GRM5), Neulexin 1 protein encoded by the NRXN1 gene, or Semaphorin-5A protein encoded by the SEMA5A gene (SEMA 5A).

Edited or integrated chromosomal sequences can be modified to encode altered proteins associated with ASD. Non-limiting examples of mutations in the protein associated with ASD include leucine in L18Q mutation-position 18 in neurolexin 1 replaced by glutamine, arginine in R451C mutation-position 451 in neuroligin 3 by cysteine, in neuroligin 4 R87W mutation—arginine at position 87 is replaced with tryptophan, and I425V mutation—isolucine at position 425 is replaced with valine in serotonin transport. Many other mutations and chromosomal rearrangements in ASD-associated chromosomal sequences are associated with ASD and are known in the art. For example, Freitag meat al . (2010) Eur . Child . Adolesc . Psychiatry 19: 169-178, and Bucan meat al . (2009) PLoS See Genetics 5: e1000536 , which is incorporated by reference in its entirety.

In certain embodiments, measurements commonly used in ASD studies in animals created by the methods of the invention can be used to study the effects of mutations and the development and / or progression of ASD in animals.

G. Macular Degeneration

In one embodiment, the methods of the invention can be used to create an animal or cell in which at least one chromosomal sequence associated with macular degeneration (MD) has been edited. Suitable chromosomal editing includes, but is not limited to, the type of editing described in paragraph I (f) above.

In each of the above embodiments, one or more chromosomal sequences associated with the MD can be edited. MD-related proteins or regulatory sequences may typically be selected based on the experimental association of proteins associated with MD for MD disorders. For example, the production rate or circulating concentration of MD-related proteins may be elevated or inhibited in a population with MD disorders relative to a population lacking MD disorders. Differences in protein levels can be assessed using proteomic or genomic analysis techniques known in the art.

The identity of a protein associated with an MD whose chromosomal sequence has been edited can vary. In preferred embodiments, the protein associated with the MD whose chromosomal sequence has been edited is an ATP-binding cassette encoded by the ABCR gene, sub-family A (ABC1) member 4 protein (ABCA4), APOE Apo A encoded by gene lipoprotein E protein (APOE), the encoded chemokines by CCL2 gene (CC motif) ligand 2 protein (CCL2), the encoded chemokine by the CCR2 gene (CC motif) receptor 2 protein (CCR2), encode the cathepsin D protein (CTSD), or encode a metal protease inhibitor by the TIMP3 gene by plasmin protein (CP), CTSD gene as a cord sserul in by the CP gene 3 Protein (TIMP3).

In certain embodiments, genetically modified animals created by the methods of the present invention can be used to study the effect of mutations on the progression of MD, using measurements commonly used in MD studies. Alternatively, genetically modified animals of the present invention can be used to study the effects of mutations in the progression of disease states or disorders associated with MD, with measurements commonly used in studying such diseases or disorders. Non-limiting examples of measures that can be used include drusen accumulation, lipofucin accumulation, Bruch's membrane thickening, retinal degeneration, choroidal neovascularization, differential response to compounds, abnormalities in tissues or cells, heredity Biochemical or molecular differences or combinations thereof between scientifically modified animals and wild-type animals.

H. Schizophrenia

In one embodiment, the methods of the invention can be used to create an animal or cell in which at least one chromosomal sequence associated with schizophrenia has been edited. Suitable chromosomal editing includes, but is not limited to, the type of editing described in paragraph I (f) above.

In each of the above embodiments, one or more chromosomal sequences associated with schizophrenia can be edited. Schizophrenia-related proteins or regulatory sequences may typically be selected based on experimental association of proteins associated with schizophrenia for schizophrenia development or progression. For example, the rate of production or circulating concentration of schizophrenia-related proteins may be elevated or inhibited in schizophrenic populations relative to schizophrenic populations. Differences in protein levels can be assessed using proteomic or genomic analysis techniques known in the art. Typical non-limiting examples of chromosomal sequences associated with schizophrenia include NRG1, ErbB4, CPLX1, TPH1, TPH2, NRXN1, GSK3A, BDNF, DISC1, GSK3B, and combinations thereof, each of which is described in detail below.

In certain embodiments, animals created by the methods of the present invention can be used to study the effects of mutations and the development and / or progression of schizophrenia in animals using measurements commonly used in schizophrenia studies.

The occurrence or signs of schizophrenia or related disorders may occur spontaneously in genetically modified animals. Alternatively, the occurrence or signs of schizophrenia or related disorders can be facilitated by exposure to destructive substances. Non-limiting examples of destructive substances include proteins, drugs, toxins, chemicals, activated retroviruses, and environmental stress associated with schizophrenia, such as any of those described herein above. Examples of environmental stresses include, but are not limited to, forced swimming, cold water swimming, platform shaking stimulation, loud noises and immobile stress.

I. Tumor Suppression

Tumor suppressor genes are genes that protect cells at one stage of the pathway through which the protein products of the gene proceed to cancer. Mutations in tumor suppressor genes cause loss or reduction of the protective function of the protein product of the gene, increasing the likelihood of tumor formation and developing cancer with other genetic changes. These proteins encoded by tumor suppressor genes have an inhibitory or interfering effect on the regulation of the cell cycle or promote apoptosis and in some cases both. Tumor suppressor proteins include inhibition of genes essential for sustained cell cycles; Link the cell cycle to DNA damage so that the cell cycle can continue; If such damage cannot be repaired, initiate apoptosis intracellularly; And blocking cell adhesion, loss of contact inhibition, and inhibiting metastasis to prevent tumor spreading.

In one embodiment, the methods of the invention can be used to create an animal or cell in which at least one chromosomal sequence associated with tumor suppression has been edited. Suitable chromosomal editing includes, but is not limited to, the type of editing described in paragraph I (f) above.

In each of the above embodiments, one or more chromosomal sequences related to tumor suppression can be edited. Tumor suppression-related proteins or regulatory sequences can typically be selected based on experimental association of proteins involved in tumor suppression. For example, the rate of production or circulating concentration of tumor suppressor-related proteins may be elevated or inhibited in a population with tumors as compared to a population without tumors. Differences in protein levels can be assessed using proteomic or genomic analysis techniques known in the art.

For example, proteins associated with tumor suppression include, but are not limited to: TNF (tumor necrosis factor (TNF superfamily, member 2)), TP53 (tumor protein p53), ERBB2 (v-erb-b2 erythrocytes) Leukemia viral oncogene homologue 2, neuro / glioblastoma induced oncogene homologue (bird)), FN1 (fibronectin 1), TSC1 (nodular sclerosis 1), PTGS2 (prostaglandin-andopeoxide synthase 2 (prostaglandin) G / H synthase and cyclooxygenase)), PTEN (phosphatase and tensine homologues), PCNA (proliferative cell nuclear antigen), COL18A1 (collagen, type XVIII, alpha 1), TSSC4 (tumor suppression sub-delivery candidate 4 ), JUN (jun oncogene), MAPK8 (mitogen-activated protein kinase 8), TGFB1 (morphological growth factor, beta 1), IL6 (interleukin 6 (interferon, beta 2)), IFNG (interferon, gamma) , BRCA1 (breast cancer 1, early signs), TSPAN32 (tetraspanin 32), BCL2 (B-cells CLL / Lymphoma 2), NF2 (Nurofibromine 2 (Merrine)), GJB1 (Gap Binding Protein, Beta 1, 32kDa), MAPK1 (Mitogen-Activated Protein Kinase 1), CD44 (CD44 Molecule (Indian Blood Group) )), PGR (progesterone receptor), TNS1 (tensin 1), PROK1 (prokineticin 1), SIAH1 (7 in absent homologue 1 (Drosophila)), ENG (endoglin), TP73 (tumor protein p73), APC (polyposis colon polyps), BAX (BCL2-associated X protein), SRC (v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (bird)), VHL (von Hippel-Lindau tumor suppression Substance), FHIT (fragile histidine triad gene), NFKB1 (nuclear factor 1 of the light polypeptide gene enhancer in B-cells), IFNA1 (interferon, alpha 1), TGFBR1 (morphological growth factor) , Beta receptor 1), PRKCD (protein kinase C, delta), TGIF1 (TGFB-induced factor homeobox 1), DLC1 (deleted in liver cancer 1), SLC22A18 (solute carrier family 22, member 18), VEGFA (vascular endothelial factor A), MME (membrane metal-endopeptidase), IL3 (interleukin 3 (colonie-stimulating factor, multiple)), MKI67 (antigen identifiable by monoclonal antibody Ki-67), HSPD1 ( Heat shock 60 kDa protein 1 (chaperonin)), HSPB1 (heat shock 27 kDa protein 1), HSP90B2P (heat shock protein 90 kDa beta (Grp94), member 2 (false gene)), MBL2 (mannose-binding lectin (protein C) ) 2, soluble (opsonine deficiency)), ZFYVE9 (zinc finger, 9 containing FYVE domain), TERT (telomerase reverse transcriptase), PML (promyelocytic leukemia), SKP2 (S-phase kinase-related protein 2 ( p45)), CYCS (cytochrome c, of body), MAPK10 (mitogen-activated protein kinase 10), PAX7 (paired box 7), YAP1 (Yes-related protein 1), PARP1 (poly (ADP- Ribose) polymerase 1), MIR34A (microRNA 34a), PRKCA (protein kinase C, alpha), FAS (Fas (TNF receptor superfamily, member 6)), SYK (splenic tyrosine kinase), GSK3B (glycogen sum) Enzyme kinase 3 beta), PRKCE (protein kinase C, epsilon), CYP19A1 (cytochrome P450, family 19, subfamily A, polypeptide 1), ABCB1 (ATP-binding cassette, sub-family B (MDR / TAP), member 1), NFKBIA (nuclear factor inhibitor of kappa light polypeptide polypeptide enhancer, alpha in B cells), RUNX1 (runt-related transcription factor 1), PRKCG (protein kinase C, gamma), RELA (v-rel retinopathy virus) Sex oncogene homologue A (algae)), PLAU (plasminogen activator, urokinase), BTK (Bruton agammaglobulinemia tyrosine kinase), PRKCB (protein kinase C, beta), CSF1 (colony stimulating factor 1 (large) Phagocytes)), POMC (propiomelanocortin), CEBPB (CCAAT / enhancer binding protein (C / EBP), beta), ROCK1 (Rho-associated, coiled-coil containing protein kinase 1), KDR (kinase insertion Domain receptor (type III receptor tyrosine kinase), NPM1 (nucleophosmin (phosphoprotein B23 of phosphorus) , Numatrin)), ROCK2 (Rho-associated, coiled-coil containing protein kinase 2), PRKAB1 (protein kinase, AMP-activated, beta 1 non-catalyst subunit), BAK1 (BCL2-antagonist / killer 1) , AURKA (Aurora kinase A), NTN1 (Netrin 1), FLT1 (fms-associated tyrosine kinase 1 (vascular endothelial growth factor / vascular permeability factor receptor)), NBN (nibrine), DNM3 (dynamin 3), PRDM10 (PR domain containing 10), PAX5 (paired box 5), EIF4G1 (eukaryotic translation initiation factor 4 gamma, 1), KAT2B (K (lysine) acetyltransferase 2B), TIMP3 (TIMP metalpeptidase inhibitor 3 ), CCL22 (chemokine (CC motif) ligand 22), GRIN2B (glutamate receptor, ionic, N-methyl D-aspartate 2B), CD81 (CD81 molecule), CCL27 (chemokine (CC motif) ligand 27) , MAPK11 (mitogen-activated protein kinase 11), DKK1 (dickkopf homologue 1 ( African toenail )), HYAL1 (hyalunoglucosaminidase 1), CTSL1 (cathepsin L1), PKD1 (C Cystic Kidney Disease 1 (autosome dominant)), BUB1B (budding not inhibited by benzimidazole 1 homologue beta (yeast), MPP1 (membrane protein, palmitoylated 1, 55 kDa), SIAH2 (absence) 7 in homolog 2 (Drosophila), DUSP13 (bispecific phosphatase 13), CCL21 (chemokine (CC motif) ligand 21), RTN4 (Reticulon 4), SMO (smooth homolog (Drosophila)), CCL19 ( Chemokine (CC motif) ligand 19), CSTF2 (cleavage stimulating factor, 3 ′ 'pre-RNA, subunit 2, 64 kDa), RSF1 (rebuilding and spacing factor 1), EZH2 (zeste homologue 2 (Drosophila) Enhancer), AK1 (adenylate kinase 1), CKM (creatine kinase, muscle), HYAL3 (hyalunoglucosaminidase 3), ALOX15B (arachidonate 15-lipoxygenase, type B), PAG1 (gly Cosingolipid Microdomain-associated Phosphoprotein 1), MIR21 (microRNA 21), S100A2 (S100 Calcium Binding Protein A2), HYAL2 (Hyalunoglucosaminidase 2), CSTF1 (Cutters) Polar factor, 3 ′ 'pre-RNA, subunit 1, 50kDa), PCGF2 (polycomb group ringfinger 2), THSD1 (thrombospondin, type I, domain containing 1), HOPX (HOP homeobox), SLC5A8 ( Solute carrier family 5 (iodine transport), member 8), EMB (embigin homolog (mouse)), PAX9 (paired box 9), ARMCX3 (with armadillo repeats, X-linked 3), ARMCX2 (armadillo repeats) Containing, X-linked 2), ARMCX1 (containing armadillo repeat, X-linked 1), RASSF4 (Ras association (RalGDS / AF-6) domain family member 4), MIR34B (microRNA 34b), MIR205 (microRNA 205), RB1 (Retinal blastoma 1), DYT10 (tension 10), CDKN2A (cyclin-dependent kinase inhibitor 2A (inhibits melanoma, p16, CDK4)), CDKN1A (cyclin-dependent kinase inhibitor 1A (p21, Cip1)), CCND1 (Cyclin D1), AKT1 (v-akt murine thymoma viral oncogene homologue 1), MYC (v-myc myelomyosis myeloid neoplasm homolog (bird)), CTNNB1 (catenin ( Cadherin-associated protein), beta 1, 88 kDa), MDM2 (Mdm2 p53 binding protein homologue (mouse)), SERPINB5 (serpin peptidase inhibitor, clade B (ofalbumin), member 5), EGF (epithelial Growth factor (beta-neurogenstron)), FOS (FBJ murine osteosarcoma viral oncogene homologue), NOS2 (nitric oxide synthase 2, inducible), CDK4 (cyclin-dependent kinase 4), SOD2 (superoxide) Dismutase 2, mitochondria), SMAD3 (SMAD family member 3), CDKN1B (cyclin-dependent kinase inhibitor 1B (p27, Kip1)), SOD1 (superoxide dismutase 1, soluble), CCNA2 (cyclin A2), LOX (lysyl oxidase), SMAD4 (SMAD family member 4), HGF (hepatocyte growth factor (hepapoetin A; Dispersing factor)), THBS1 (thrombospondin 1), CDK6 (cyclin-dependent kinase 6), ATM (mutated ataxia capillary dilatation), STAT3 (signaling and activator of transcription 3 (acute-phase response factor)) , Mechanical targets of HIF1A (hypotropin-inducing factor 1, alpha subunit (basic helix-loop-helix transcription factor)), IGF1R (insulin-like growth factor 1 receptor), MTOR (rapamycin (serine / threonine kinase) ), TSC2 (nodular sclerosis 2), CDC42 (cell splitting cycle 42 (GTP binding protein, 25kDa)), ODC1 (ornithine decarboxylase 1), SPARC (secreted protein, acidic, cysteine-rich (osteonectin)) ), HDAC1 (histone deacetylase 1), CDK2 (cyclin-dependent kinase 2), BARD1 (BRCA1 related ring domain 1), CDH1 (cadherin 1, type 1, E-cadherin (epithelial)), EGR1 (initial) Growth response 1), INSR (insulin receptor), IRF1 (interferon modulator 1), PHB (prohibitin), PXN (fassil ), HSPA4 (heat shock 70kDa protein 4), TYR (tyrosinase (systemic albinism IA)), CAV1 (caberoline 1, caveole protein, 22kDa), CDKN2B (cyclin-dependent kinase inhibitor 2B (p15, inhibits CDK4)) ), FOXO3 (forkhead box O3), HDAC9 (histone deacetylase 9), FBXW7 (7 containing F-box and WD repeat domains), FOXO1 (forkhead box O1), E2F1 (E2F transcription factor 1), STK11 ( Serine / threonine kinase 11), BMP2 (bone forming protein 2), HSP90AA1 (heat shock protein 90 kDa alpha (cytosol), class A member 1), HNF4A (hepatocyte nuclear factor 4, alpha), CAMK2G (calcium / calmodulin -Dependent protein kinase II gamma), TP53BP1 (tumor protein p53 binding protein 1), CRYAB (crystallin, alpha B), HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase), PLAUR (plasma Minogen activator, urokinase receptor), MCL1 (myeloid cell leukemia sequence 1 (BCL2-associated)), NOTCH1 (Notch homologue 1, translocation-tube (Drosophila)), RASSF1 (Ras association (RalGDS / AF-6) domain family member 1), GSN (gelzoline), CADM1 (cell adhesion molecule 1), ATF2 (activating transcription factor 2), IFNB1 (interferon, beta 1, fibroblasts), DAPK1 (killing-related protein kinase 1), CHFR (checkpoint with forkhead and ringfinger domains), KITLG (KIT ligand), NDUFA13 (NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 13), DPP4 (dipeptides-peptidase 4), GLB1 (galactosidase, beta 1), IKZF1 (IKAROS family zinc finger 1 (Ikaros)), ST5 (inhibition of carcinogenicity 5), TGFA (morphomorphism) Growth factor, alpha), EIF4EBP1 (eukaryotic translation initiation factor 4E binding protein 1), TGFBR2 (morphotropic growth factor, beta receptor II (70 / 80kDa)), EIF2AK2 (eukaryotic translation initiation factor 2-alpha kinase 2), GJA1 (gap binding protein, alpha 1, 43kDa), MYD88 (myeloid differentiation primary response gene (88)), IFI27 (interferon, alpha-induced protein 27), RBMX (RNA binding motif Protein, X-linked), EPHA1 (EPH receptor A1), TWSG1 (twisted gut homolog 1 (Drosophila)), H2AFX (H2A histone family, member X), LGALS3 (lectin, galactosid-binding, soluble, 3), MUC3A (mucin 3A, cell surface related), ILK (integrin-linked kinase), APAF1 (apoptotic peptidase activating factor 1), MAOA (monoamine oxidase A), ERBB3 (v-erb- b2 erythrocyte leukemia viral oncogene homolog 3 (bird)), EIF2S1 (eukaryotic translation initiation factor 2, subunit 1 alpha, 35 kDa), PER2 (period homolog 2 (Drosophila)), IGFBP7 (insulin-like Growth factor binding protein 7), KDM5B (lysine (K) -specific demethylase 5B), SMARCA4 (SWI / SNF related, matrix related, actin-dependent modulators of chromatin, subfamily a, member 4), NME1 ( Non-metastatic cells 1, protein expressed therein (NM23A)), F2RL1 (coagulation factor II (thrombin) receptor-like 1), ZFP36 (zinc finger protein 36, C3H type, homologue (mouse)), HSPA8 (heat shock 70kDa protein 8), WNT5A (wing-type MMTV integration site family, member 5A), ITGB4 (integrin, beta 4), RARB (retinoic acid receptor, beta) , VEGFC (vascular endothelial factor C), CCL20 (chemokine (CC motif) ligand 20), EPHB2 (EPH receptor B2), CSNK2A1 (casein kinase 2, alpha 1 polypeptide), PSMD9 (proteasome (prosome, macro) Fine) 26S subunit, non-ATPase, 9), SERPINB2 (serpin peptidase inhibitor, clade B (ofalbumin), member 2), RHOB (ras homologue gene family, member B), DUSP6 (bispecific Phosphatase 6), CDKN1C (cycline-dependent kinase inhibitor 1C (p57, Kip2)), SLIT2 (slit homologue 2 (Drosophila)), CEACAM1 (carcinogenic antigen-associated cell adhesion molecule 1 (bile glycoprotein)), UBC ( Ubiquitin C), STS (steroid sulfatase (microsome), isozyme S), FST (polystatin), KRT1 (keratin 1), EIF6 (eukaryotic detoxification) Time factor 6), JUP (binding placoglobin), HDAC4 (histone deacetylase 4), NEDD4 (neural precursor cell expressed, developmentally down-regulated 4), KRT14 (keratin 14), GLI2 (GLI Family zinc finger 2), MYH11 (myosin, heavy chain 11, smooth muscle), MAPKAPK5 (mitogen-activated protein kinase-activated protein kinase 5), MAD1L1 (MAD1 mitotic disruption defect-like 1 (yeast)), TNFAIP3 (Tumor necrosis factor, alpha-induced protein 3), WEE1 (WEE1 homologue ( S. pombe )), BTRC (containing beta-transducin repeat), NKX3-1 (NK3 homeobox 1), GPC3 (glypican 3), CREB3 (cAMP response element binding protein 3), PLCB3 (phospholipase C, beta 3 (phosphatidylinositol-specific)), DMPK (muscular dystonia-protein kinase), BLNK (B-cell linker), PPIA (peptidylprolyl isomerase A (cyclophyllin A)), DAB2 (incapacitated homolog 2, mitogen-reactive phosphoprotein (Drosophila)), KLF4 (Kruppel- Four factor 4 (gut)), RUNX3 (runt-related transcription factor 3), FLG (filagrin), IVL (inovolukrin), CCT5 (chaperonin containing TCP1, subunit 5 (epsilon)), LRPAP1 (low density Lipoprotein receptor-associated protein related protein 1), IGF2R (insulin-like growth factor 2 receptor), PER1 (period homologue 1 (Drosophila)), BIK (BCL2-interacting killer (apoptosis-induced)), PSMC4 (Proteasome (prosome, macropine) 26S subunit, ATPase, 4), USF2 (upstream transcription factor 2, c-fos interaction), GAS1 (growth hinder-specific 1), LAMP2 (lysosomal-related Membrane protein 2), PSMD10 (proteasome (prosome, macropine) 26S subunit, non-ATPase, 10), IL24 (interleukin 24), GADD45G (growth inhibition and DNA-damage-induced, gamma), ARHGAP1 (Rho GTPase activating protein 1), CLDN1 (Claudin 1), ANXA7 (annexin A7), CHN1 (chimaerin 1), TXNIP (thioredoxin interacting protein), PEG3 (3) EIF3A (eukaryotic Translation initiation factor 3, subunit A), CASC5 (cancer sensitivity candidate 5), TCF4 (transcription factor 4), CSNK2A2 (casein kinase 2, alpha prime polypeptide), CSNK2B (casein kinase 2, beta polypeptide), CRY1 (creamto Chromium 1 (photoliase-like)), CRY2 (creamtochrome 2 (photoliase-like)), EIF4G2 (eukaryotic translation initiation factor 4 gamma, 2), LOXL2 (lysyl oxidase-like 2), PSMD13 (pro Theasome (prosome, macropine) 26S subunit, non-ATPase, 13), ANP32A (acidic (leucine-rich) nuclear phosphoprotein 32 family, member A), COL4A3 (collagen, type IV, alpha 3 (Goodpasture) Antigen)), SCGB1A1 (secretoglobin, family 1A, member 1 (uteroglobin)), BNIP3L (BCL2 / adenovirus E1B 19kDa interacting protein 3-like), MCC (mutated in colon cancer), EFNB3 (epirine -B3), RBBP8 (retinoblastoma binding protein 8), PALB2 (partner or localizer of BRCA2), HBP1 (HMG-box transcription factor 1), MRPL28 (mitochondrial Ribosomal protein L28), KDM5A (lysine (K) -specific demethylase 5A), QSOX1 (quiescin Q6 sulfhydryl oxidase 1), ZFR (zinc finger RNA binding protein), MN1 (meningioma ( Destroyed within balanced translocation) 1), SMYD4 (4 containing SET and MYND domains), USP7 (ubiquitin specific peptidase 7 (herpes virus-associated)), STK4 (serine / threonine kinase 4), THY1 (Thy- 1 cell surface antigen), PTPRG (protein tyrosine phosphatase, receptor type, G), E2F6 (E2F transcription factor 6), STX11 (syntaxin 11), CDC42BPA (CDC42 binding protein kinase alpha (DMPK-like)), MYOCD (myocardin), DAP (killing-related protein), LOXL1 (lysyl oxidase-like 1), RNF139 (ringfinger protein 139), HTATIP2 (HIV-1 Tat interacting protein 2, 30kDa), AIM1 (black Absent within species 1), BCCIP (BRCA2 and CDKN1A interacting protein), LOXL4 (lysyl oxidase-like 4), WWC1 (containing WW and C2 domain 1), LOXL3 (lysyl oxidase-like 3), CENPN (centromeric protein N), TNS4 (tensin 4), SIK1 (salt-induced kinase 1), PCGF6 (polycomb group ringfinger 6), PHLDA3 (plextrin homology-like domain, family A, member 3), IL32 (interleukin 32), LATS1 (LATS, large tumor suppressor, homolog 1 (Drosophila)), COMMD7 (containing 7 COMM domain), CDHR2 (cadherin-related family member 2), LELP1 (late keratinocytes) Outer layer-like proline-rich 1), NCRNA00188 (non-protein coding RNA 188), and ENSG00000131023.

Typical non-limiting examples of tumor suppressor proteins are ATM (mutated ataxia capillary dilatation), ATR (related to ataxia capillary dilatation and Rad3), EGFR (epithelial growth factor receptor), ERBB2 (v-erb-b2 erythroblastic leukemia viral tumor) Gene homologues 2), ERBB3 (v-erb-b2 erythroblastic leukemia viral oncogene homologue 3), ERBB4 (v-erb-b2 erythroblastic viral oncogene homologue 4), Notch 1, Notch2, Notch 3, Notch 4, ATK1 (v-akt murine thymoma viral oncogene homolog 1), ATK2 (v-akt murine thymoma viral oncogene homologue 2), ATK3 (v-akt murine thymoma viral oncogene homologue 3), HIF1a (hypothyroidism-inducing factor 1a), HIF3a (hypothyroidism-inducing factor 1a), Met (met pronto-tumor gene), HRG (histidine-rich glycoprotein), Bc12, PPAR (alpha) ) (Peroxysome proliferator-activated receptor alpha), Ppar (gamma) Seem proliferator-activated receptor gamma), WT1 (Wilmus Tumor 1), FGF1R (fibroblast growth factor 1 receptor), FGF2R (fibroblast growth factor 1 receptor), FGF3R (fibroblast growth factor 3 receptor), FGF4R (fiber Blast growth factor 4 receptor), FGF5R (fibroblast growth factor 5 receptor), CDKN2a (cyclin-dependent kinase inhibitor 2A), APC (polyposis colon polyp), Rb1 (retinal blastoma 1), MEN1 (multiple endocrine neoplasia 1 ), VHL (von-Hippel-Lindau tumor suppressor), BRCA1 (breast cancer 1), BRCA2 (breast cancer 2), AR (androgen receptor), TSG101 (tumor sensitive gene 101), Igf1 (insulin-like growth factor 1) ), Igf2 (insulin-like growth factor 2), Igf 1R (insulin-like growth factor 1 receptor), Igf 2R (insulin-like growth factor 2 receptor) Bax (BCL-2 related X protein), CASP 1 (caspase) 1), CASP 2 (Caspase 2), CASP 3 (Caspase 3), CASP 4 (Caspase 4), CASP 6 (Caspase 6), CASP 7 (Caspa 7), CASP 8 (Caspase 8), CASP 9 (Caspase 9), CASP 12 (Caspase 12), Kras (v-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog), PTEN (Phosphate and Tensine) Homologs), BCRP (breast cancer receptor protein), p53, and combinations thereof.

In certain embodiments, measurements commonly used in tumor suppression studies in animals created by the methods of the invention can be used to study the effects of mutations and the development and / or progression of tumor suppression in animals. In one embodiment, genetically modified animals comprising inactivated chromosomal sequences related to tumor suppression can be used to determine sensitivity to tumor development. The method involves exposing genetically modified animals and wild type animals, including inactivated tumor suppressor sequences, to carcinogens, and then monitoring tumor development. Animals comprising inactivated tumor suppressor sequences may be at increased risk for tumor formation. Moreover, homozygous animals for inactivated tumor suppressor sequences may have an increased risk compared to heterozygous animals for the same inactivated sequence, which animals will also have an increased risk compared to wild-type animals. Can be. Similar methods can be used to screen spontaneous tumors, wherein the animals described above are not exposed to carcinogens.

In another embodiment, an animal comprising an inactivated chromosomal sequence associated with tumor suppression can be used to assess the carcinogenic potential of the test substance. The method involves contacting genetically modified animals and wild-type animals containing inactivated tumor suppressor sequences with these test agents, and then monitoring tumor development. If the animal comprising the inactivated tumor suppressor sequence has increased tumor incidence compared to wild-type animals, this test substance may be a carcinogen.

J. Secretory Enzyme ( secretase A) related disorders

Secretory enzymes consist of various sets of proteins that affect a number of disorders, the presence of the disorder, the severity of the disorder, or the sensitivity to any combination thereof. Secretory enzymes are enzymes that cut another membrane and protein into smaller pieces. Secretory enzymes are involved in many disorders, including, for example, Alzheimer's disease. In one embodiment, the methods of the present invention can be used to create an animal or cell in which at least one chromosomal sequence associated with a secretory enzyme associated disorder is edited. Suitable chromosomal editing includes, but is not limited to, the type of editing described in paragraph I (f) above.

In each of the above embodiments, one or more chromosomal sequences associated with secretory enzyme disorders can be edited. Secretory enzyme disorder-associated proteins or regulatory sequences may typically be selected based on experimental association of proteins associated with secretory enzyme disorders. For example, the rate of production or circulating concentration of secretory enzyme disorder-related proteins may be elevated or inhibited in populations with secretory enzyme disorders as compared to the population without secretory enzyme disorders. Differences in protein levels can be assessed using proteomic or genomic analysis techniques known in the art.

Non-limiting examples of proteins associated with secretory enzyme disorders include PSENEN (Presenillin Enhancer 2 Homolog ( C. elegans )), CTSB (Cathepsin B), PSEN1 (Presenillin 1), APP (amyloid beta ( A4) precursor protein), APH1B (former pharyngeal defect 1 homologue B ( C. elegans )), PSEN2 (presenillin 2 (Alzheimer disease 4)), BACE1 (beta-position APP-clease 1), ITM2B (Whole membrane protein 2B), CTSD (cathepsin D), NOTCH1 (Notch homologue 1, translocation-related (Drosophila)), TNF (tumor necrosis factor (TNF superfamily, member 2)), INS (insulin), DYT10 (Tension 10), ADAM17 (ADAM metalpeptidase domain 17), APOE (apopolipoprotein E), ACE (angiotensin I converting enzyme (peptidyl-dipeptidase A) 1), STN (statin), TP53 (tumor protein p53), IL6 (interleukin 6 (interferon, beta 2)), NGFR (nerve growth factor receptor (TNFR superfamily, member 16)), IL1B (interleukin 1, beta), ACHE (acetylcholinesterase (Yt blood Group)), CTNNB1 (catenin (cadherin-associated protein), beta 1, 88 kDa), IGF1 (insulin-like growth factor 1 (somatomedin C)), IFNG (interferon, gamma), NRG1 (neuregulin 1) , CASP3 (caspase 3, apoptosis-related cysteine peptidase), MAPK1 (mitogen-activated protein kinase 1), CDH1 (cadherin 1, type 1, E-cadherin (epithelial)), APBB1 ( Amyloid beta (A4) precursor protein-binding, family B, member 1 (Fe65)), HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase), CREB1 (cAMP response element binding protein 1) , PTGS2 (prostaglandin-andopeoxide synthase 2 (prostaglandin G / H synthetase and cyclooxygenase)), HES1 (split 1, hairy and enhancer of (Drosophila)), CAT (catalase), TGFB1 (morphological growth factor, beta 1), ENO2 (enolase 2 (gamma, neurons)), ERBB4 (v-erb-a erythroblastic viral oncogene homolog 4 (algae)), TR APPC10 (trafficking protein particle complex 10), MAOB (monoamine oxidase B), NGF (nerve growth factor (beta polypeptide)), MMP12 (matrix metalpeptidase 12 (macrophage elastase)), JAG1 (jagged 1 (Alagille syndrome)), CD40LG (CD40 ligand), PPARG (peroxysome proliferator-activated receptor gamma), FGF2 (fibroblast growth factor 2 (basic)), IL3 (interleukin 3 (colonie-stimulating) Factor, multiple)), LRP1 (low density lipoprotein receptor-associated protein 1), NOTCH4 (Notch homologue 4 (Drosophila)), MAPK8 (mitogen-activated protein kinase 8), PREP (proyl endopeptidase), NOTCH3 (Notch homologue 3 (Drosophila)), PRNP (prion protein), CTSG (cathepsin G), EGF (epithelial growth factor (beta-neurogenstron)), REN (renin), CD44 (CD44 molecule (Indian blood) Group)), SELP (selectin P (granular membrane protein 140kDa, antigen CD62)), GHR (growth hormone receptor), ADCYAP1 (adenylate) Lase Activating Polypeptide 1 (pituitary gland)), INSR (insulin receptor), GFAP (glucose acidic protein), MMP3 (matrix metalpeptidase 3 (stromericin 1, progelatinase)), MAPK10 (mitogen- Activated protein kinase 10), SP1 (Sp1 transcription factor), MYC (v-myc myelomyosis myelogenous homologue (bird)), CTSE (cathepsin E), PPARA (peroxysome proliferator-activated) Receptor alpha), JUN (jun oncogene), TIMP1 (TIMP metalpeptidase inhibitor 1), IL5 (interleukin 5 (colony-stimulating factor, neutrophils)), IL1A (interleukin 1, alpha), MMP9 (matrix metalpeptides) Ninth (gelatinase B, 92 kDa gelatinase, 92 kDa type IV collagenase), HTR4 (5-hydroxytrytamine (serotonin) receptor 4), HSPG2 (heparan sulfate proteoglycan 2), KRAS (v- Ki-ras2 Kirsten rat sarcoma viral oncogene homologue), CYCS (cytochrome c, bodily), SMG1 (SMG1 homologue, po Party dill inositol 3-kinase-related kinase (C. elegans)), IL1R1 (Interleukin 1 receptor, type I), PROK1 (Pro key geneticin 1), MAPK3 (mitogen-activated protein kinase 3), NTRK1 ( Neurotrophic tyrosine kinase, receptor, type 1), IL13 (interleukin 13), MME (membrane metal-endopeptidase), TKT (transketolase), CXCR2 (chemokine (CXC motif) receptor 2), IGF1R ( Insulin-like growth factor 1 receptor), RARA (retinoic acid receptor, alpha), CREBBP (CREB binding protein), PTGS1 (prostaglandin-andopeoxide synthase 1 (prostaglandin G / H synthetase and cyclooxygenase)) GALT (galactose-1-phosphate uridil monotransferase), CHRM1 (cholinergic receptor, muscarinic 1), ATXN1 (atacin 1), PAWR (PRKC, apoptosis, WT1, modulator), NOTCH2 (Notch homologue 2 (Drosophila)), M6PR (mannose-6-phosphate receptor (cation dependent)), CYP46A1 (cytochrome P450, family 46, standing Family A, polypeptide 1), CSNK1D (casein kinase 1, delta), MAPK14 (mitogen-activated protein kinase 14), PRG2 (proteoglycan 2, bone marrow (natural killer cell activator, neutrophil granule major basic protein)), PRKCA (protein kinase C, alpha), L1CAM (L1 cell adhesion molecule), CD40 (CD40 molecule, TNF receptor superfamily member 5), NR1I2 (nuclear receptor subfamily 1, group I, member 2), JAG2 (jagged 2) , CTNND1 (catenin (cadherin-associated protein), delta 1), CDH2 (cadherin 2, type 1, N-cadherin (neuron)), CMA1 (kinase 1, mast cells), SORT1 (sortin 1) , DLK1 (delta-like 1 homologue (Drosophila)), THEM4 (thioesterase superfamily member 4), JUP (binding flacoglobin), CD46 (CD46 molecule, complement regulatory protein), CCL11 (chemokine (CC) Motifs) ligands 11), CAV3 (caberoline 3), RNASE3 (ribonuclease, RNase A family, 3 (neutrophil cation protein)), HSPA8 (heat show Ck 70kDa protein 8), CASP9 (caspase 9, apoptosis-related cysteine peptidase), CYP3A4 (cytochrome P450, family 3, subfamily A, polypeptide 4), CCR3 (chemokine (CC motif) receptor 3 ), TFAP2A (transcription factor AP-2 alpha (activated enhancer binding protein 2 alpha)), SCP2 (sterol carrier protein 2), CDK4 (cyclin-dependent kinase 4), HIF1A (thrombocytopenia-inducing factor 1, alpha-a) Units (basic helix-loop-helix transcription factor), TCF7L2 (transcription factor 7-like 2 (T-cell specific, HMG-box)), IL1R2 (interleukin 1 receptor, type II), B3GALTL (beta 1,3 Galactosyltransferase-like), MDM2 (Mdm2 p53 binding protein homologue (mouse)), RELA (v-rel retinopathy viral oncogene homolog A (bird)), CASP7 (caspase 7, ah) Poptosis-associated cysteine peptidase), IDE (insulin-degrading enzyme), FABP4 (fatty acid binding protein 4, adipocytes), CASK (calcium / Calmodulin-dependent serine protein kinase (MAGUK family)), ADCYAP1R1 (adenylate cyclase activating polypeptide 1 (pituitary) receptor type I), ATF4 (activating transcription factor 4 (tax-response enhancer element B67)), PDGFA (platelet-induced growth factor alpha polypeptide), C21orf33 (chromosome 21 reading frame 33), SCG5 (secretographin V (7B2 protein)), RNF123 (ring finger protein 123), NFKB1 (B Nuclear factor 1 of the kappa light polypeptide gene enhancer in cells, ERBB2 (v-erb-b2 erythroblastic viral oncogene homologue 2, neuro / glioblastoma-induced oncogene homologue (algae) ), CAV1 (cabolinol 1, caberole protein, 22kDa), MMP7 (Matrix Metalpeptidase 7 (Matrilysine, Uterine)), TGFA (Transformation Growth Factor, Alpha), RXRA (Retinoid X Receptor, Alpha ), STX1A (Syntacin 1A (brain)), PSMC4 (Proteasome (Prosome, Macropine) 26S Unit, ATPase, 4), P2RY2 (purinergic receptor P2Y, G-protein linked, 2), TNFRSF21 (tumor necrosis factor receptor superfamily, member 21), DLG1 (disc, large homolog 1 (Drosophila)), NUMBL (numb homologues (Drosophila) -like), SPN (sialoporin), PLSCR1 (phospholipid scrambles 1), UBQLN2 (ubiquilin 2), UBQLN1 (ubiquilin 1), PCSK7 (proprotein convertase subtilisin / Kesin type 7), SPON1 (spondin 1, extracellular matrix protein), SILV (silver homologue (mouse)), QPCT (glutaminyl-peptide cyclotransferase), HES5 (split 5 (Drosophila) Parent and enhancer), GCC1 (GRIP and coiled-coil domain containing 1), and any combination thereof.

Preferred proteins associated with secretory enzyme disorders include APH-1A (pre-pharyngeal-deleted 1, alpha), APH-1B (pre-pharyngeal-deleted 1, beta), PSEN-1 (presenillin-1), NCSTN (Nicastrin ), PEN-2 (Presenilin Enhancer 2), and any combination thereof.

In certain embodiments, measurements commonly used to study secretory enzyme disorders in animals created by the methods of the invention can be used to study the effects of mutations and the development and / or progression of secretory enzyme related disorders in animals.

The occurrence or signs of secretory enzyme disorders may occur spontaneously in genetically modified animals. Alternatively, the occurrence or signs of secretory enzyme disorders can be promoted by exposure to destructive substances. Non-limiting examples of destructive substances include any of those described above, drugs, toxins, chemicals, activated retroviruses, and proteins associated with secretory enzyme disorders such as environmental stress. Non-limiting examples of environmental stress include, but are not limited to, forced swimming, cold water swimming, platform shake stimulation, loud noises, and restraint stress.

K. Amyotrophic Color  cirrhosis( amyotrophic lateral sclerosis )

Certain nucleic acid sequences, and proteins encoded by them, are associated with motor neuron disorders. These sequences consist of various sequences that affect the development of motor neuron disorders, the presence of motor neuron disorders, the severity of motor neuron disorders, or any combination thereof. In one embodiment, the methods of the present invention can be used to create an animal or cell in which at least one chromosomal sequence associated with specific motor neuron disorder, atrophic lateral sclerosis (ALS) has been edited. Suitable chromosomal editing includes, but is not limited to, the type of editing described in paragraph I (f) above.

In each of the above embodiments, one or more chromosomal sequences associated with ALS can be edited. ALS-related chromosomal sequences can typically be selected based on experimental association of ALS-related proteins to ALS. The ALS-related nucleic acid sequence may encode an ALS-related protein or may be an ALS-related regulatory sequence. For example, the production rate or circulating concentration of ALS-related proteins may be elevated or inhibited in a population with ALS compared to a population without ALS. Differences in protein levels can be assessed using proteomic or genomic analysis techniques known in the art.

Non-limiting examples of proteins related to ALS include SOD1 (superoxide dismutase 1), ALS2 (amyotrophic lateral sclerosis 2), FUS (fused to sarcoma), TARDBP (TAR DNA binding protein), VAGFA (vessels) Endothelial growth factor A), VAGFB (vascular endothelial growth factor B), and VAGFC (vascular endothelial growth factor C), and any combination thereof.

In certain embodiments, an animal created by the methods of the invention can be used to study the effects of mutations and the development and / or progression of ALS in an animal using measurements commonly used in ALS studies.

L. Prion  Diseases Prion Disease )

Prion disorders appear to be a disease of protein conformation, which results in abnormal protein aggregation. In one embodiment, the methods of the present invention can be used to create an animal or cell in which at least one chromosomal sequence associated with prion disease has been edited. Suitable chromosomal editing includes, but is not limited to, the type of editing described in paragraph I (f) above.

In each of the above embodiments, one or more chromosomal sequences associated with prion disease can be edited. Prion disease-associated nucleic acid sequences may typically be selected based on experimental association of nucleic acid sequences associated with prion disease to prion disease. For example, the prion disease related nucleic acid sequence may encode a prion disease-associated protein or isoform thereof, or may be a prion disease related regulatory sequence. For example, the production rate or circulating concentration of prion disease-associated protein or isoform can be elevated or suppressed in the population with prion disease as compared to the population lacking prion disease. Differences in protein levels can be assessed using proteome techniques known in the art, including Western blots, immunohistochemical staining, enzyme linked immunosorbent assay (ELISA), and mass spectrometry. Alternatively, prion disorder-related proteins may be purified using genomic techniques, including but not limited to DNA microarray analysis, serial analysis of gene expression (SAGE), and quantitative real-time polymerase chain reaction (Q-PCR). The gene expression profile of the gene encoding can be obtained and confirmed.

Non-limiting examples of prion disorder-associated proteins include PrP ^C and isoforms thereof, PrP ^Sc and isoforms thereof, HECTD2 (e3-ubiputin ligase protein), STI1 (stress inducible protein 1), DPL (residual Doppel) Protein, encoded by Prnd , APOA1 (apopolipoprotein A1), BCL-2 (B-cell lymphoma 2), HSP60 (heat shock 60kDa protein), BAX-inhibiting peptide (Bcl-2-associated X protein inhibitor ), NRF2 (nuclear respiratory factor 2), NCAMs (nerve cell-adherent molecules), heparin, laminin and laminin receptors.

Moreover, non-limiting examples of genes that may be associated with neurodegenerative conditions during prion disorders include A2M (alpha-2-macroglobulin), AATF (apoptosis antagonistic transcription factor), ACPP (acid phosphatase prostate), ACTA2 ( Actin alpha 2 smooth muscle aorta), ADAM22 (ADAM metalpeptidase domain), ADORA3 (adenosine A3 receptor), ADRA1D (alpha-1D adrenergic receptor for alpha-1D adrenoceptor), AHSG (alpha-2-HS -Glycoprotein), AIF1 (allograft inflammatory factor 1), ALAS2 (delta-aminolevulinate synthase 2), AMBP (alpha-1-microglobulin / bikunin precursor), ANK3 (Ankryn 3), ANXA3 ( Annexin A3), APCS (amyloid P component serum), APOA1 (Apolipoprotein A1), APOA12 (Apolipoprotein A2), APOB (Apolipoprotein B), APOC1 (Apolipoprotein C1), APOE (Apolipoprotein C1) E), APOH (apolipoprotein H), APP (amyloid precursor protein), ARC (activity-modulating Cytoskeleton-associated protein), ARF6 (ADP-ribosylation factor 6), ARHGAP5 (Rho GTPase activating protein 5), ASCL1 (Achaete-scute homologue 1), B2M (beta-2 microglobulin), B4GALNT1 (beta-1) , 4-N-acetyl-galactosaminyl transferase 1), BAX (Bcl-2-related X protein), BCAT (branched chain amino-acid transaminase 1 cytosol), BCKDHA (branched chain Keto acid dehydrogenase E1 alpha), BCKDK (branched chain alpha-ketosan dehydrogenase kinase), BCL2 (B-cell lymphoma 2), BCL2L1 (BCL2-like 1), BDNF (brain-derived neurotrophic factor) , BHLHE40 (category E basic helix-loop-helix protein 40), BHLHE41 (category E basic helix-loop-helix protein 41), BMP2 (bone forming protein 2A), BMP3 (bone forming protein 3), BMP5 (bone forming protein 5), BRD1 (containing bromodomain 1), BTC (betacellulin), BTNL8 (butyrophylline-like protein 8), CALB1 (calvindine 1), CALM1 (calmodulin 1), CAMK1 (calcium / cal Modlin- Red protein kinase type I), CAMK4 (calcium / calmodulin-dependent protein kinase type IV), CAMKIIB (calcium / calmodulin-dependent protein kinase type IIB), CAMKIIG (calcium / calmodulin-dependent protein kinase type IIG ), CASP11 (Caspase-10), CASP8 (Caspase 8 Apoptosis-Related Cysteine Peptidase), CBLN1 (Cerceline 1 Precursor), CCL2 (Chemokine (CC Motif) Ligand 2), CCL22 (KE) Morphine (CC motif) ligand 22), CCL3 (chemokine (CC motif) ligand 3), CCL8 (chemokine (CC motif) ligand 8), CCNG1 (cyclin-G1), CCNT2 (cyclin T2), CCR4 (CC gene Mokin receptor type 4 (CD194)), CD58 (CD58), CD59 (protectin), CD5L (CD5 antigen-like), CD93 (CD93), CDKN2AIP (CDKN2A interacting protein), CDKN2B (cyclin-dependent kinase inhibitor 2B) , CDX1 (homeobox protein CDX-1), CEA (carcinogenic antigen), CEBPA (CCAAT / enhancer-binding protein alpha), CEBPB (CCAAT / enhancer binding protein C / EBP beta), CEBPB (CCAAT / enhancer-binding protein beta), CEBPD (CCAAT / enhancer-binding protein delta), CEBPG (CCAAT / enhancer-binding protein gamma), CENPB (centromeric protein B), CGA ( Glycoprotein Hormone Alpha Chain), CGGBP1 (CGG Triple Repeat-Binding Protein 1), CHGA (Chromogenin A), CHGB (Secretinulin), CHN2 (Beta-chimerine), CHRD (Cordin), CHRM1 ( Cholinergic receptor muscarinic 1), CITED2 (Cbp / p300-interactive transactivator 2), CLEC4E (C-type lectindomain family 4 member E), CMTM2 (CKLF-like MARVEL transmembrane domain-containing protein 2 ), CNTN1 (contactin 1), CNTNAP1 (contactin-related protein-like 1), CR1 (erythrocyte complement receptor 1), CREM (cAMP-responsive element modulator), CRH (adrenal cortical stimulating hormone-releasing hormone), CRHR1 (Adrenal Cortical Stimulating Hormone Releasing Hormone Receptor 1), CRKRS (Cell Division Cycle 2-Related Protein Kinase 7), CSDA (DNA-binding Protein A), CSF3 (Granulocyte Colony) Factor 3), CSF3R (granulocyte colony-stimulating factor 3 receptor), CSP (chemical sensory protein), CSPG4 (chondroitin sulfate proteoglycan 4), CTCF (CCCTC-binding factor zinc finger protein), CTGF (connective tissue growth factor), CXCL12 (Chemokine CXC motif ligand 12), DAD1 (defender 1 against cell death), DAXX (death related protein 6), DBN1 (brebrin 1), DBP (D site of albumin promoter-albumin D-box binding protein), DDR1 (discoidin domain receptor family member 1), DDX14 (DEAD / DEAH box helicase), DEFA3 (defensin alpha 3 neutrophil-specific), DVL3 (scattered dsh homolog 3), EDN1 (endoterin 1), EDNRA (Endotherin receptor type A), EGF (epithelial growth factor), EGFR (epithelial growth factor receptor), EGR1 (initial growth response protein 1), EGR2 (initial growth response protein 2), EGR3 (initial growth response protein 3), EIF2AK2 (eukaryotic translation initiation factor 2-alpha kinase 2), ELINE (Elas Neutrophils expressed), ELK1 (ELK1 member of the ETS oncogene family), ELK3 (ELK3 ETS-domain protein (SRF accessory protein 2)), EML2 (epidermal microtubule related protein-like 2), EPHA4 (EPH receptor A4) , ERBB2 (V-erb-b2 erythroblastic leukemia viral oncogene homologue 2), ERBB3 (receptor tyrosine-protein kinase erbB-3), ESR2 (estrogen receptor 2), ESR2 (estrogen receptor 2), ETS1 (V- ets erythropoietic virus E26 oncogene homolog 1), ETV6 (Ets variant 6), FASLG (Fas ligand TNF superfamily member 6), FCAR (Fc fragment of IgA receptor), FCER1G (IgE high affinity I receptor for gamma polypeptide Fc fragment), FCGR2A (Fc fragment of the IgG low affinity IIa receptor-CD32), FCGR3B (Fc fragment of the IgG low affinity IIIb receptor-CD16b), FCGRT (Fc fragment of the IgG receptor carrying alpha), FGA (basic fibrinogen), FGF1 (acidic fibroblast growth factor 1), FGF14 (fibroblastic Factor 14), FGF16 (fibroblast growth factor 16), FGF18 (fibroblast growth factor 18), FGF2 (basic fibroblast growth factor 2), FIBP (acidic fibroblast growth factor intracellular binding protein), FIGF (C-fos Induced growth factor), FMR1 (fragile X mental retardation 1), FOSB (FBJ murine osteosarcoma viral oncogene homologue B), FOXO1 (forkhead box O1), FSHB (follicle stimulating hormone beta polypeptide), FTH1 ( In ferritin polypeptide 1), FTL (ferritin light polypeptide), G1P3 (interferon alpha-inducible protein 6), G6S (N-acetylglucosamine-6-sulfatase), GABRA2 (gamma-aminobutyl Acid A receptor alpha 2), GABRA3 (gamma-aminobutyl acid A receptor alpha 3), GABRA4 (gamma-aminobutyl acid A receptor alpha 4), GABRB1 (gamma-aminobutyl acid A receptor beta 1), GABRG1 (gamma- Aminobutyl acid A receptor gamma 1), GADD45A (growth obstruction and DNA-damage-induced alpha), GCLC ( Glutamate-cysteine ligand subunits), GDF15 (growth differentiation factor 15), GDF9 (growth differentiation factor 9), GFRA1 (GDNF family receptor alpha 1), GIT1 (G protein-linked receptor kinase interactor 1), GNA13 ( Guanine nucleotide-binding protein / G protein alpha 13), GNAQ (guanine nucleotide binding protein / G protein q polypeptide), GPR12 (G protein-linked receptor 12), GPR18 (G protein-linked receptor 18), GPR22 (G protein- Linked receptor 22), GPR26 (G protein-linked receptor 26), GPR27 (G protein-linked receptor 27), GPR77 (G protein-linked receptor 77), GPR85 (G protein-linked receptor 85), GRB2 (growth factor receptor -Bound protein 2), GRLF1 (glucocorticoid receptor DNA binding factor 1), GST (glutathione S-transferase), GTF2B (universal transcription factor IIB), GZMB (Granzyme B), HAND1 (expressed heart and nerves) Crest inducer 1), HAVCR1 (A Hepatitis virus cell receptor 1), HES1 (parent and enhancer of split 1), HES5 (parent and enhancer of split 5), HLA-DQA1 (major histocompatibility complex classification II DQ alpha), HOXA2 (homeobox A2) , HOXA4 (homeobox A4), HP (haptoglobin), HPGDS (prostaglandin-D synthase), HSPA8 (heat shock 70kDa protein 8), HTR1A (5-hydroxytrytamine receptor 1A), HTR2A (5- Hydroxytryptamine receptor 2A), HTR3A (5-hydroxytrytamine receptor 3A), ICAM1 (intercellular adhesion molecule 1 (CD54)), IFIT2 (interferon-derived protein 2 with tetratricopeptid repeat), IFNAR2 ( Interferon alpha / beta / omega receptor 2), IGF1 (insulin-like growth factor 1), IGF2 (insulin-like growth factor 2), IGFBP2 (insulin-like growth factor binding protein 2, 36 kDa), IGFBP7 (insulin-like growth Factor binding protein 7), IL10 (interleukin 10), IL10RA (interleukin 10 receptor alpha), IL11 (interleukin 11), IL11RA (Interleukin 11 receptor alpha), IL11RB (interleukin 11 receptor beta), IL13 (interleukin 13), IL15 (interleukin 15), IL17A (interleukin 17A), IL17RB (interleukin 17 receptor B), IL18 (interleukin 18), IL18RAP (interleukin) 18 receptor accessory protein), IL1R2 (interleukin 1 receptor type II), IL1RN (interleukin 1 receptor antagonist), IL2RA (interleukin 2 receptor alpha), IL4R (interleukin 4 receptor), IL6 (interleukin 6), IL6R (interleukin 6 receptor) , IL7 (interleukin 7), IL8 (interleukin 8), IL8RA (interleukin 8 receptor alpha), IL8RB (interleukin 8 receptor beta), ILK (integrin-linked kinase), INPP4A (inositol polyphosphate-4-phosphatase type I, 107kDa ), INPP4B (Inositol polyphosphate-4-phosphatase type I beta), INS (insulin), IRF2 (interferon modulator 2), IRF3 (interferon modulator 3), IRF9 (interferon modulator 9), IRS1 (insulin receptor substrate 1), ITGA4 (Integrin Alpha 4), ITGA6 (Integrin Alpha-6), ITGAE (Integrin Alpha E), ITGAV (Integrin Alpha-V), JAG1 (Jagged 1), JAK1 (Janus Kinase 1), JDP2 (Jun Dimerization Protein 2), JUN (Jun Tumor Gene) , JUNB (Jun B proto-tumor gene), KCNJ15 (potassium inward-rectifying channel subfamily J member 15), KIF5B (kinesin family member 5B), KLRC4 (killer cell lectin-like receptor subfamily C member 4), KRT8 (keratin 8), LAMP2 (lysosomal-associated membrane protein 2), LEP (leptin), LHB (luteinizing hormone beta polypeptide), LRRN3 (leucine-rich repeat neuron 3), MAL (Mal T-cell differentiation protein) , MAN1A1 (mannosidasealpha class 1A member 1), MAOB (monoamine oxidase B), MAP3K1 (mitogen-activated protein kinase kinase 1), MAPK1 (mitogen-activated protein kinase 1), MAPK3 ( Mitogen-activated protein kinase 3), MAPRE2 (microtubule-associated protein RP / EB family member 2), MARCKS (myristoylation Alanine-rich protein kinase C substrate), MAS1 (MAS1 oncogene), MASL1 (MAS1 oncogene-like), MBP (myelin basic protein), MCL1 (myeloid cell leukemia sequence 1), MDMX (MDM2-like p53-binding protein ), MECP2 (methyl CpG binding protein 2), MFGE8 (milk fat sphere-EGF factor 8 protein), MIF (macrophage transfer inhibitory factor), MMP2 (matrix metalpeptidase 2), MOBP (myelin-associated oligodendrocytes) Cell basic protein), MUC16 (cancer antigen 125), MX2 (myxovirus (influenza virus) resistant 2), MYBBP1A (MYB binding protein 1a), NBN (nibrin), NCAM1 (nerve cell adhesion molecule 1), NCF4 (neutrophils Cytosol factor 4 40kDa), NCOA1 (nuclear receptor co-activator 1), NCOA2 (nuclear receptor co-activator 2), NEDD9 (neural precursor cell-expressed embryologically down-regulated 9), NEUR (neuramid) NFATC1 (nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 1), N FE2L2 (nuclear factor erythrocyte-induced 2-like 2), NFIC (nuclear factor I / C), NFKBIA (nuclear factor inhibitor alpha of the kappa light polypeptide gene enhancer in B-cells), NGFR (nerve growth Factor receptor), NIACR2 (niacin receptor 2), NLGN3 (neuroligin 3), NPFFR2 (neuropeptide FF receptor 2), NPY (neural peptide Y), NR3C2 (nuclear receptor subfamily 3 group C member 2), NRAS ( Neuroblastoma RAS viral (v-ras) oncogene homologues), NRCAM (neuronal cell adhesion molecule), NRG1 (neuregulin 1), NRTN (neuturulin), NRXN1 (neulexin 1), NSMAF (neutral sphingomyelin) Nase activation related factors), NTF3 (neutropin 3), NTF5 (neutropin 4/5), ODC1 (ornithine decarboxylase 1), OR10A1 (olfactory receptor 10A1), OR1A1 (olfactory receptor family 1 subfamily A Member 1), OR1N1 (olfactory receptor family 1 subfamily N member 1), OR3A2 (olfactory receptor family 3 subfamily A member 2), OR7A17 (olfactory Solution family 7 subfamily A member 17), ORM1 (orthomucoid 1), OXTR (oxytocin receptor), P2RY13 (purinergic receptor P2Y G-protein linked 13), P2Y12 (purinergic receptor P2Y G-protein linked 12), P70S6K (P70S6 kinase), PAK1 (P21 / Cdc42 / Rac1-activated kinase 1), PAR1 (Prader-Willi / Angelman Part-1), PBEF1 (Pre-B-Cell Colony Enhancing Factor 1), PCAF ( P300 / CBP-related factor), PDE4A (cAMP-specific 3 ′, 5′-cycle phosphodiesterase 4A), PDE4B (phosphodiesterase 4B cAMP-specific), PDE4B (phosphodiesterase 4B cAMP-specific), PDE4D (phosphodiesterase 4D cAMP-specific), PDGFA (platelet-derived growth factor alpha polypeptide), PDGFB (platelet-derived growth factor beta polypeptide), PDGFC (platelet induced Growth factor C), PDGFRB (beta-type platelet-derived growth factor receptor), PDPN (grapeplanin), PENK (enkephalin), PER1 (period homolog 1), PLA 2 (phospholipase A2), PLAU (plasminogen activator urokinase), PLXNC1 (flexin C1), PMVK (phosphomevalonate kinase), PNOC (prepronociceptin), POLH (polymerase (DNA oriented)) Eta), POMC (propiomelanocortin (adrenovusine cortical stimulating hormone / beta-lipotropin / alpha-melanin cell stimulating hormone / beta-melanocyte stimulating hormone / beta-endorphin)), POU2AF1 (POU domain classification 2 Association factor 1), PRKAA1 (5′-AMP-activated protein kinase-catalyzed subunit alpha-1), PRL (prolactin), PSCDBP (cytohesine 1 interacting protein), PSPN (percepin), PTAFR (platelet-activation) Factor receptor), PTGS2 (prostaglandin-andopeoxide synthase 2), PTN (fleoprovins), PTPN11 (protein tyrosine phosphatase non-receptor type 11), PYY (peptide YY), RAB11B (RAB11B member RAS oncogene Family), RAB6A (RAB6A member RAS oncogene family), RAD17 (RAD17 Homologue), RAF1 (RAF proto-oncogene serine / threonine-protein kinase), RANBP2 (RAN binding protein 2), RAP1A (RAS oncogene family RAP1A member), RB1 (retinoblastoma 1), RBL2 (retinoblastoma-like 2) (p130)), RCVRN (recovery), REM2 (RAS / RAD / GEM-like GTP binding 2), RFRP (RFamide-related peptide), RPS6KA3 (ribosome protein S6 kinase 90kDa polypeptide 3), RTN4 (Reticuron 4 ), RUNX1 (Runt-related Transcription Factor 1), S100A4 (S100 Calcium Binding Protein A4), S1PR1 (Shippingosine-1-Phosphate Receptor 1), SCG2 (Secretogenin II), SCYE1 (Small Inducible Cytokine Subfamily) E member 1), SELENBP1 (selenium binding protein 1), SGK (serum / glucocorticoid regulated kinase), SKD1 (inhibitor of K + transport growth deficiency 1), SLC14A1 (solute carrier family 14 (urea transport) member 1 (Kidd) Blood group)), SLC25A37 (solute carrier family 25 member 37), SMAD2 (SMAD family member 2), SMAD5 (SMAD family Ver. 5), SNAP23 (synaptosome-associated protein 23kDa), SNCB (synuclein beta), SNF1LK (SNF1-like kinase), SORT1 (Sortilin 1), SSB (Sjogren Syndrome Antigen B), STAT1 (transcriptional signal translator) And Activator 1, 91kDa), STAT5A (Signal Transducer and Activator 5A), STAT5B (Signal Transducer and Activator 5B), STX16 (Syntacin 16), TAC1 (Tachikinin Precursor 1), TBX1 (T-box 1), TEF (thyroid stimulating embryonic factor), TF (transferrin), TGFA (transforming growth factor alpha), TGFB1 (transforming growth factor beta 1), TGFB2 (transforming growth factor beta 2), TGFB3 (transformation growth factor beta 3), TGFBR1 (transformation growth factor beta receptor I), TGM2 (transglutaminase 2), THPO (thrombopoietin), TIMP1 (TIMP metalpeptidase inhibitor 1), TIMP3 (TIMP metalpeptidase inhibitor 3), TMEM129 (transmembrane protein 129), TNFRC6 (TNFR / NGFR cysteine-rich portion), TNFRSF10A (tumor necrosis factor number) Solution superfamily member 10a), TNFRSF10C (tumor necrosis factor receptor superfamily member 10c decoy without intracellular domain), TNFRSF1A (tumor necrosis factor receptor superfamily member 1A), TOB2 (transducer 2 of ERBB2), TOP1 (topo Isomemerase (DNA) I), TOPOII (topoisomemerase 2), TRAK2 (trafficking protein kinesin binding 2), TRH (patric acid stimulating hormone-releasing hormone), TSH (thyroid-stimulating hormone alpha) , TUBA1A (Tublin Alpha 1a), TXK (TXK Tyrosine Kinase), TYK2 (Tyrosine Kinase 2), UCP1 (Unlinked Protein 1), UCP2 (Unlinked Protein 2), ULIP (Unc-33-Like Protein), UTRN (eutropin), VEGF (vascular endothelial growth factor), VGF (VGF nerve growth factor inducible), VIP (vascular intestinal peptide), VNN1 (vanine 1), VTN (bitronectin), WNT2 (wingless- Type MMTV unified location family member 2), XRCC6 (X-ray recovery cross-supplement 6), ZEB2 (zinc finger E-box combined homeobox 2), And ZNF461 (zinc finger protein 461).

Typical prion disorder-related proteins include PrP ^C and isoforms thereof, PrP ^Sc and isoforms thereof, HECTD2 (e3-ubiputin ligase protein), STI1 (stress inducible protein 1), DPL (residual Doppel protein, Prnd) . Encoded by APOA1 (apopolipoprotein A1), BCL-2 (B-cell lymphoma 2), HSP60 (heat shock 60 kDa protein), BAX-inhibiting peptide (Bcl-2-associated X protein inhibitor), NRF2 ( Nuclear respiratory factor 2), NCAMs (nerve cell-adherent molecules), heparin, laminin and laminin receptors and any combination thereof.

In certain embodiments, measurements commonly used to study prion disorders in animals created by the methods of the invention can be used to study the effects of mutations and the development and / or progression of prion disorders in animals.

M. Immunodeficiency

In one embodiment, the methods of the invention can be used to create an animal or cell in which at least one chromosomal sequence associated with an immunodeficiency has been edited. Suitable chromosomal editing includes, but is not limited to, the type of editing described in paragraph I (f) above.

In each of the above embodiments, one or more chromosomal sequences associated with immunodeficiency may be edited. An immunodeficiency protein or regulatory sequence is a protein or regulatory sequence for an activity change associated with an immunodeficiency and may be the primary or secondary symptom of a disease or condition in an animal, preferably a mammal, such as a human. Immunodeficiency sequences can typically be selected based on experimental association of immunodeficiency sequences against an immunodeficiency disease or condition, particularly a disease or condition in a mammal, such as a human. For example, expression of an immunodeficiency protein in certain tissues may be elevated or inhibited in a population with an immunodeficiency disease or condition compared to a population lacking this disease or condition. Differences in protein levels can be assessed using proteomic or genomic analysis techniques known in the art.

Non-limiting examples of human immunodeficiency genes include A2M [alpha-2-macroglobulin]; AANAT [arylalkylamine N-acetyltransferase]; ABCA1 [ATP-binding cassette, sub-family A (ABC1), member 1]; ABCA2 [ATP-binding cassette, sub-family A (ABC1), member 2]; ABCA3 [ATP-binding cassette, sub-family A (ABC1), member 3]; ABCA4 [ATP-binding cassette, sub-family A (ABC1), member 4]; ABCB1 [ATP-binding cassette, sub-family B (MDR / TAP), member 1]; ABCC1 [ATP-binding cassette, sub-family C (CFTR / MRP), member 1]; ABCC2 [ATP-binding cassette, sub-family C (CFTR / MRP), member 2]; ABCC3 [ATP-binding cassette, sub-family C (CFTR / MRP), member 3]; ABCC4 [ATP-binding cassette, sub-family C (CFTR / MRP), member 4]; ABCC8 [ATP-binding cassette, sub-family C (CFTR / MRP), member 8]; ABCD2 [ATP-binding cassette, sub-family D (ALD), member 2]; ABCD3 [ATP-binding cassette, sub-family D (ALD), member 3]; ABCG1 [ATP-binding cassette, sub-family G (WHITE), member 1]; ABCG2 [ATP-binding cassette, sub-family G (WHITE), member 2]; ABCG5 [ATP-binding cassette, sub-family G (WHITE), member 5]; ABCG8 [ATP-binding cassette, sub-family G (WHITE), member 8]; ABHD2 [ab containing hydrolase domain 2]; ABL1 [c-abl oncogene 1, receptor tyrosine kinase]; ABO [ABO blood group (transferase A, alpha 1-3-N-acetylgalactosaminyltransferase; transferase B, alpha 1-3-galactosyltransferase)]; ABP1 [amylolide binding protein 1 (amine oxidase (copper-containing))); ACAA1 [acetyl-coenzyme A acyltransferase 1]; ACACA [acetyl-coenzyme A carboxylase alpha]; ACAN [Agracan]; ACAT1 [acetyl-coenzyme A acetyltransferase 1]; ACAT2 [acetyl-coenzyme A acetyltransferase 2]; ACCN5 [amylolide-sensitive cation channel 5, gut]; ACE [anggiotensin I converting enzyme (peptidyl-dipeptidase A) 1]; ACE2 [anggiotensin I converting enzyme (peptidyl-dipeptidase A) 2]; ACHE [acetylcholinesterase (Yt blood group)]; ACLY [ATP Citrate Lyase]; ACOT9 [acyl-CoA thioesterase 9]; ACOX1 [acyl-coenzyme A oxidase 1, palmitoyl]; ACP1 [acid phosphatase 1, soluble]; ACP2 [acid phosphatase 2, lysosomal]; ACP5 [acid phosphatase 5, tartaric acid resistance]; ACPP [acid phosphatase, prostate]; ACSL3 [acyl-CoA synthase long-chain family member 3]; ACSM3 [acyl-CoA synthase heavy-chain family member 3]; ACTA1 [actin, alpha 1, skeletal muscle]; ACTA2 [actin, alpha 2, smooth muscle, aorta]; ACTB [actin, beta]; ACTC1 [actin, alpha, cardiac muscle 1]; ACTG1 [actin, gamma 1]; ACTN1 [actinin, alpha 1]; ACTN2 [actinin, alpha 2]; ACTN4 [actinin, alpha 4]; ACTR2 [ARP2 Actin-Related Protein 2 Homolog (Yeast)]; ACVR1 [Activin A Receptor, Type I]; ACVR1B [Activin A Receptor, Type IB]; ACVRL1 [Activin A Receptor Type II-Like 1]; ACY1 [aminoacylase 1]; ADA [adenosine deaminase]; ADAM10 [ADAM metalpeptidase domain 10]; ADAM12 [ADAM metalpeptidase domain 12]; ADAM17 [ADAM metalpeptidase domain 17]; ADAM23 [ADAM metalpeptidase domain 23]; ADAM33 [ADAM metalpeptidase domain 33]; ADAM8 [ADAM metalpeptidase domain 8]; ADAM9 [ADAM metalpeptidase domain 9 (meltrin gamma)]; ADAMTS1 [ADAM metalpeptidase with thrombospondin type 1 motif, 1]; ADAMTS12 [ADAM metalpeptidase with thrombospondin type 1 motif, 12]; ADAM metalpeptidase with thrombospondin type 1 motif with ADAMTS13 [13]; ADAM metalpeptidase with ADAMTS15 [ADAM metalpeptidase with thrombospondin type 1 motif, 15]; ADAMTSL1 [ADAMTS-Like 1]; ADAMTSL4 [ADAMTS-Like 4]; ADAR [adenosine deaminase, RNA-specific]; ADCY1 [adenylate cyclase 1 (brain)]; ADCY10 [adenylate cyclase 10 (soluble)]; ADCY3 [adenylate cyclase 3]; ADCY9 [adenylate cyclase 9]; ADCYAP1 [adenylate cyclase activating polypeptide 1 (pituitary)]; ADCYAP1R1 [adenylate cyclase activating polypeptide 1 (pituitary) receptor type I]; ADD1 [Educine 1 (alpha)]; ADH5 [alcohol dehydrogenase 5 (Class III), chi polypeptide]; ADIPOQ [containing adiponectin, C1Q and collagen domains]; ADIPOR1 [adiponectin receptor 1]; ADK [adenosine kinase]; ADM [adrenomedulin]; ADORA1 [adenosine A1 receptor]; ADORA2A [adenosine A2a receptor]; ADORA2B [Adenosine A2b Receptor]; ADORA3 [adenosine A3 receptor]; ADRA1B [adrenergic, alpha-1B-, receptor]; ADRA2A [adrenergic, alpha-2A-, receptor]; ADRA2B [adrenergic, alpha-2B-, receptor]; ADRB1 [adrenergic, beta-1-, receptor]; ADRB2 [adrenergic, beta-2-, receptor, surface]; ADSL [adenysuccinate lyase]; ADSS [adenysuccinate synthetase]; AEBP1 [AE Binding Protein 1]; AFP [alpha-fetoprotein]; AGER [developed glycosylation end product-specific receptor]; AGMAT [Agmatine Ureohydrolase (Agmatinase)]; AGPS [alkylglycerone phosphate synthase]; AGRN [Agrin]; AGRP [Auguti related protein homologues (mouse)]; AGT [angiotensinogen (serpin peptidase inhibitor, clade A, member 8)]; AGTR1 [Angiotensin II Receptor, Type 1]; AGTR2 [angiotensin II receptor, type 2]; AHCY [adenosyl homocysteinase]; AHI1 [Abelson Helper Integration Position 1]; AHR [aryl hydrocarbon acceptor]; AHSP [alpha hemoglobin stabilizing protein]; AICDA [activation-induced cytidine deaminase]; AIDA [associated with Acine Interactors, abdominal formation]; AIMP1 [aminoacyl tRNA synthetase complex-interacting multifunction protein 1]; AIRE [autoimmune modulator]; AK1 [adenylate kinase 1]; AK2 [adenylate kinase 2]; AKR1A1 [Aldo-keto reductase family 1, member A1 (aldehyde reductase)]; AKR1B1 [Aldo-keto reductase family 1, member B1 (Aldose Reductase)]; AKR1C3 [Aldo-keto reductase family 1, member C3 (3-alpha hydroxysteroid dehydrogenase, type II)]; AKT1 [v-akt murine thymoma viral oncogene homologue 1]; AKT2 [v-akt murine thymoma viral oncogene homologue 2]; AKT3 [v-akt murine thymoma viral oncogene homolog 3 (protein kinase B, gamma)]; ALB [albumin]; ALCAM [activated leukocyte cell adhesion molecule]; ALDH1A1 [aldehyde dehydrogenase 1 family, member A1]; ALDH2 [aldehyde dehydrogenase 2 family (mitochondria)]; ALDH3A1 [aldehyde dehydrogenase 3 family, member A1]; ALDH7A1 [aldehyde dehydrogenase 7 family, member A1]; ALDH9A1 [aldehyde dehydrogenase 9 family, member A1]; ALG1 [asparagine-linked glycosylation 1, beta-1,4-mannosyltransferase homologue (S. Serbisier)]; ALG12 [asparagine-linked glycosylation 12, alpha-1,6-mannosyltransferase homologue (S. Serbisier)]; ALK [malignant lymphoma receptor tyrosine kinase]; ALOX12 [arachidonate 12-lipoxygenase]; ALOX15 [arachidonate 15-lipoxygenase]; ALOX15B [arachidonate 15-lipoxygenase, type B]; ALOX5 [arachidonate 5-lipoxygenase]; ALOX5AP [arachidonate 5-lipoxygenase-activated protein]; ALPI [alkali phosphatase, gut]; ALPL [alkali phosphatase, liver / bone / kidney]; ALPP [alkali phosphatase, placenta (Regan isozyme)]; AMACR [alpha-methylacyl-CoA rasemating agent]; AMBP [alpha-1-microglobulin / bikunin precursor]; AMPD3 [Adenosine Monophosphate Deaminase 3]; ANG [angiogenin, ribonuclease, RNase A family, 5]; ANGPT1 [Angiopoietin 1]; ANGPT2 [Angiopoietin 2]; ANK1 [ankyrin 1, erythropoiesis]; ANKH [joint stiffness, progressive homologue (mouse)]; ANKRD1 [ankyrin repeat domain 1 (heart muscle)]; ANPEP [alanyl (membrane) aminopeptidase]; ANTXR2 [anthrax toxin receptor 2]; ANXA1 [annexin A1]; ANXA2 [annexin A2]; ANXA5 [annexin A5]; ANXA6 [annexin A6]; AOAH [acyloxyacyl hydrolase (neutrophil)]; AOC2 [amine oxidase, copper containing 2 (retinal-specific)]; AP2B1 [adapter-associated protein complex 2, beta 1 subunit]; AP3B1 [adapter-associated protein complex 3, beta 1 subunit]; APC [polyposis colon polyps]; APCS [amyloid P component, serum]; APEX1 [APEX nuclease (multifunctional DNA repair enzyme) 1]; APLNR [apelin receptor]; APOA1 [Apolipoprotein A-I]; APOA2 [Apolipoprotein A-II]; APOA4 [Apolipoprotein A-IV]; APOB [apolipoprotein B (including Ag (x) antigen)]; APOBEC1 [apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1]; APOBEC3G [apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3G]; APOC3 [Apolipoprotein C-III]; APOD [Apolipoprotein D]; APOE [Apolipoprotein E]; APOH [Apolipoprotein H (beta-2-glycoprotein I)]; APP [amyloid beta (A4) precursor protein]; APRT [Adenine Phosphoribosyltransferase]; APTX [Aprataxin]; AQP1 [aquaporin 1 (Colton blood group)]; AQP2 [aquaporin 2 (collection duct)]; AQP3 [aquaporin 3 (Gill blood group)]; AQP4 [aquaporin 4]; AQP5 [aquaporin 5]; AQP7 [aquaporin 7]; AQP8 [aquaporin 8]; AR [androgen receptor]; AREG [Amphiregulin]; ARF6 [ADP-ribosylation factor 6]; ARG1 [arginase, liver]; ARG2 [Arginase, Type II]; ARHGAP6 [Rho GTPase Activating Protein 6]; ARHGEF2 [Rho / Rac Guanine Nucleotide Exchange Factor (GEF) 2]; ARHGEF6 [Rac / Cdc42 Guanine Nucleotide Exchange Factor (GEF) 6]; ARL13B [ADP-ribosylation factor-like 13B]; ARNT [aryl hydrocarbon receptor nuclear potentials]; ARNTL [aryl hydrocarbon receptor nuclear potential-like]; ARRB1 [Arrestin, Beta 1]; ARRB2 [Arrestin, Beta 2]; ARSA [arylsulfatase A]; ARSB [arylsulfatase B]; ARSH [Arylsulfatase Family, Member H]; ART1 [ADP-ribosyltransferase 1]; ASAH1 [N-Acipingosine Amidohydrolase (Acid Ceramidase) 1]; ASAP1 [ArfGAP 1 with SH3 domain, ankyrin repeat and PH domain]; ASGR2 [Asialoglycoprotein Receptor 2]; ASL [Argininosuccinate Lyase]; ASNS [asparagine synthetase]; ASPA [aspartoacylase (Canavan disease)]; ASPG [Asparaginase Homolog (S. Servichy)]; ASPH [aspartate beta-hydroxylase]; ASRGL1 [asparaginase like 1]; ASS1 [Argininosuccinate synthase 1]; ATF1 [activation transcription factor 1]; ATF2 [activation transcription factor 2]; ATF3 [activation transcription factor 3]; ATF4 [activation transcription factor 4 (tax-response enhancer element B67)]; ATG16L1 (ATG16 autophagy related 16-like 1 (S. Serbisier)]; ATM [mutated ataxia capillary dilatation]; ATMIN [ATM Interactor]; ATN1 [Atropine 1]; ATOH1 [Azo homolog 1 (Drosophila)]; ATP2A2 [ATPase, Ca ++ transport, cardiac muscle, sluggish spasms 2]; ATP2A3 [ATPase, Ca ++ transporter, ubiquitous]; ATP2C1 [ATPase, Ca ++ transporter, type 2C, member 1]; ATP5E [ATP synthase, H + transport, mitochondrial F1 complex, epsilon subunit]; ATP7B [ATPase, Cu ++ transporter, beta polypeptide]; ATP8B1 [ATPase, Class I, Type 8B, Member 1]; ATPAF2 [ATP synthase mitochondrial F1 complex aggregation factor 2]; ATR [related to ataxia capillary dilatation and Rad3]; ATRIP [ATR interacting protein]; ATRN [attractin]; AURKA [Aurora Kinase A]; AURKB [Aurora Kinase B]; AURKC [Aurora Kinase C]; AVP [arginine vasopressin]; AVPR2 [arginine vasopressin receptor 2]; AXL [AXL Receptor Tyrosine Kinase]; AZGP1 [alpha-2-glycoprotein 1, zinc-bonded]; B2M [beta-2-microglobulin]; B3GALTL [beta 1,3-galactosyltransferase-like]; B3GAT1 [beta-1,3-glucuronyltransferase 1 (glucuronosyltransferase P)]; B4GALNT1 [beta-1,4-N-acetyl-galactosaminyl transferase 1]; B4GALT1 [UDP-Gal: betaGlcNAc beta 1,4-galactosyltransferase, polypeptide 1]; BACE1 [beta-position APP-cleaving enzyme 1]; BACE2 [beta-position APP-cleaving enzyme 2]; BACH1 [BTB and CNC homology 1, basic leucine zipper transcription factor 1]; BAD [BCL2-associated agonists of cell death]; BAIAP2 [BAI1-associated protein 2]; BAK1 [BCL2-antagonist / killer 1]; BARX2 [BARX Homeobox 2]; BAT1 [HLA-B related transcript 1]; BAT2 [HLA-B related transcript 2]; BAX [BCL2-associated X protein]; BBC3 [BCL2 binding component 3]; BCAR1 [breast cancer anti-estrogen resistance 1]; BCAT1 [branched chain aminotransferase 1, cytosol]; BCAT2 [branched chain aminotransferase 2, mitochondria]; BCHE [butyrylcholinesterase]; BCL10 [B-cell CLL / lymphoma 10]; BCL11B [B-cell CLL / lymphoma 11B (zinc finger protein)]; BCL2 [B-cell CLL / lymphoma 2]; BCL2A1 [BCL2-associated protein A1]; BCL2L1 [BCL2-like 1]; BCL2L11 [BCL2-like 11 (apoptosis promoter)]; BCL3 [B-cell CLL / lymphoma 3]; BCL6 [B-cell CLL / lymphoma 6]; BCR [endpoint cluster portion]; BDKRB1 [bradykinin receptor B1]; BDKRB2 [bradykinin receptor B2]; BDNF [brain-induced neurotrophic factor]; BECN1 [Beclin 1, related to self-consumption]; BEST1 [bestospin 1]; BFAR [bifunctional apoptosis modulator]; BGLAP [bone gamma-carboxyglutamate (gla) protein]; BHMT [betaine-homocysteine methyltransferase]; BID [BH3 interacting domain killing agent]; BIK [BCL2-interacting killer (apoptosis-induced)]; BIRC2 [baculoviral IAP repeat-containing 2]; BIRC3 [baculoviral IAP repeat-containing 3]; BIRC5 [baculoviral IAP repeat-containing 5]; BLK [B Lymphoid Tyrosine Kinase]; BLM [Bloom syndrome, RecQ helicase-like]; BLNK [B-Cell Linker]; BLVRB [bililidine reductase B (flavin reductase (NADPH))]; BMI1 [BMI1 Polycom Ringfinger Oncogene]; BMP1 [bone forming protein 1]; BMP2 [bone forming protein 2]; BMP4 [bone forming protein 4]; BMP6 [bone forming protein 6]; BMP7 [bone forming protein 7]; BMPR1A [bone-forming protein receptor, type IA]; BMPR1B [bone-forming protein receptor, type IB]; BMPR2 [bone forming protein receptor, type II (serine / threonine kinase)]; BPI [sterilization / permeability-increasing protein]; BRCA1 [breast cancer 1, early signs]; BRCA2 [breast cancer 2, early signs]; BRCC3 [BRCA1 / BRCA2-containing complex, subunit 3]; BRD8 [bromodomain containing 8]; BRIP1 [BRCA1 interacting protein C-terminal helicase 1]; BSG (basigin (Ok blood group)); BSN [Bashun (Presynaptic Cell Matrix Protein)]; BSX [brain-specific homeobox]; BTD [biotinidases]; BTK [Bruton agammaglobulinemia tyrosine kinase]; BTLA [related to B and T lymphocytes]; BTNL2 [butyrophylline-like 2 (MHC class II related)]; BTRC [containing beta-transducin repeats]; C10orf67 [chromosome 10 open reading frame 67]; C11orf30 [chromosome 11 open reading frame 30]; C11orf58 [chromosome 11 open reading frame 58]; C13orf23 [chromosome 13 open reading frame 23]; C13orf31 [chromosome 13 open reading frame 31]; C15orf2 [chromosome 15 open reading frame 2]; C16orf75 [chromosome 16 open reading frame 75]; C19orf10 [chromosome 19 open reading frame 10]; C1QA [complement component 1, q subcomponent, A chain]; C1QB [complement component 1, q subcomponent, B chain]; C1QC [complement component 1, q subcomponent, C chain]; C1QTNF5 [C1q and Tumor Necrosis Factor Related Protein 5]; C1R [Complement component 1, r subcomponent]; C1S [complement component 1, s subcomponent]; C2 [complement component 2]; C20orf29 [chromosome 20 open reading frame 29]; C21orf33 [chromosome 21 open reading frame 33]; C3 [complement component 3]; C3AR1 [complement component 3a receptor 1]; C3orf27 [chromosome 3 open reading frame 27]; C4A [complement component 4A (Rodgers blood group)]; C4B [complement component 4B (Chido blood group)]; C4BPA [Complement Component 4 Binding Protein, Alpha]; C4BPB [Complement Component 4 Binding Protein, Beta]; C5 [Complement Component 5]; C5AR1 [complement component 5a receptor 1]; C5orf56 [chromosome 5 open reading frame 56]; C5orf62 [chromosome 5 open reading frame 62]; C6 [complement component 6]; C6orf142 [chromosome 6 open reading frame 142]; C6orf25 [chromosome 6 open reading frame 25]; C7 [complement component 7]; C7orf72 [chromosome 7 open reading frame 72]; C8A [complement component 8, alpha polypeptide]; C8B [complement component 8, beta polypeptide]; C8G [complement component 8, gamma polypeptide]; C8orf38 [chromosome 8 open reading frame 38]; C9 [complement component 9]; CA2 [carbonic anhydrase II]; CA6 [carbonic anhydrase VI]; CA8 [carbonic anhydrase VIII]; CA9 [carbonate dehydratase IX]; CABIN1 [calcineurin binding protein 1]; CACNA1C [calcium channel, potential-dependent, L type, alpha 1C subunit]; CACNA1S [calcium channel, potential-dependent, L type, alpha 1S subunit]; CAD [carbamoyl-phosphate synthase 2, aspartate transcarbamoylase, and dehydrourotase]; CALB1 [Calvindine 1, 28 kDa]; CALB2 [Calvindine 2]; CALCA [calcitonin-associated polypeptide alpha]; CALCRL [calcitonin receptor-like]; CALD1 [Caldesmon 1]; CALM1 [calmodulin 1 (phosphorylase kinase, delta)]; CALM2 [calmodulin 2 (phosphorylase kinase, delta)]; CALM3 [calmodulin 3 (phosphorylase kinase, delta)]; CALR [caleticulin]; CAMK2G [calcium / calmodulin-dependent protein kinase II gamma]; CAMP [Catelycidine Antimicrobial Peptides]; CANT1 [calcium activated nucleotidase 1]; CANX [calnexin]; CAPN1 [calpine 1, (mu / I) large subunit]; CARD10 [Caspase Recruitment Domain Family, Member 10]; CARD16 [Caspase Recruitment Domain Family, Member 16]; CARD8 [caspase recruitment domain family, member 8]; CARD9 [caspase recruitment domain family, member 9]; CASP1 [caspase 1, apoptosis-related cysteine peptidase (interleukin 1, beta, convertase)]; CASP10 [caspase 10, apoptosis-related cysteine peptidase]; CASP2 [caspase 2, apoptosis-related cysteine peptidase]; CASP3 [caspase 3, apoptosis-related cysteine peptidase]; CASP5 [caspase 5, apoptosis-related cysteine peptidase]; CASP6 [caspase 6, apoptosis-related cysteine peptidase]; CASP7 [caspase 7, apoptosis-related cysteine peptidase]; CASP8 [caspase 8, apoptosis-related cysteine peptidase]; CASP8AP2 [caspase 8 related protein 2]; CASP9 [caspase 9, apoptosis-related cysteine peptidase]; CASR [calcium-perceptive receptor]; CAST [calpastatin]; CAT [catalase]; CAV1 [caberoline 1, caveole protein, 22 kDa]; CAV2 [caberoline 2]; CBL [Cas-Br-M (murine) ecotropic retroviral transformed sequence]; CBS [cistathionine-beta-synthase]; CBX5 [Chromobox homologue 5 (HP1 alpha homologue, Drosophila)]; CC2D2A [coil-coil and C2 domain containing 2A]; CCBP2 [chemokine binding protein 2]; CCDC144A [coil-coil domain containing 144A]; CCDC144B [coil-coil domain containing 144B]; CCDC68 [coil-coil domain containing 68]; CCK [Cholekistokinin]; CCL1 [chemokine (C-C motif) ligand 1]; CCL11 [chemokine (C-C motif) ligand 11]; CCL13 [chemokine (C-C motif) ligand 13]; CCL14 [chemokine (C-C motif) ligand 14]; CCL17 [chemokine (C-C motif) ligand 17]; CCL18 [chemokine (C-C motif) ligand 18 (lung and activation-regulated)]; CCL19 [chemokine (C-C motif) ligand 19]; CCL2 [chemokine (C-C motif) ligand 2]; CCL20 [chemokine (C-C motif) ligand 20]; CCL21 [chemokine (C-C motif) ligand 21]; CCL22 [chemokine (C-C motif) ligand 22]; CCL24 [chemokine (C-C motif) ligand 24]; CCL25 [chemokine (C-C motif) ligand 25]; CCL26 [chemokine (C-C motif) ligand 26]; CCL27 [chemokine (C-C motif) ligand 27]; CCL28 [chemokine (C-C motif) ligand 28]; CCL3 [chemokine (C-C motif) ligand 3]; CCL4 [chemokine (C-C motif) ligand 4]; CCL4L1 [chemokine (C-C motif) ligand 4-like 1]; CCL5 [chemokine (C-C motif) ligand 5]; CCL7 [chemokine (C-C motif) ligand 7]; CCL8 [chemokine (C-C motif) ligand 8]; CCNA1 [Cyclin A1]; CCNA2 [cyclin A2]; CCNB1 [Cyclin B1]; CCNB2 [Cyclin B2]; CCNC [Cyclin C]; CCND1 [cyclin D1]; CCND2 [Cyclin D2]; CCND3 [Cyclin D3]; CCNE1 [Cyclin E1]; CCNG1 [Cyclin G1]; CCNH [Cyclin H]; CCNT1 [cyclin T1]; CCNT2 [Cyclin T2]; CCNY [Cyclin Y]; CCR1 [chemokine (C-C motif) receptor 1]; CCR2 [chemokine (C-C motif) receptor 2]; CCR3 [chemokine (C-C motif) receptor 3]; CCR4 [chemokine (C-C motif) receptor 4]; CCR5 [chemokine (C-C motif) receptor 5]; CCR6 [chemokine (C-C motif) receptor 6]; CCR7 [chemokine (C-C motif) receptor 7]; CCR8 [chemokine (C-C motif) receptor 8]; CCR9 [chemokine (C-C motif) receptor 9]; CCRL1 [chemokine (C-C motif) receptor-like 1]; CD14 [CD14 molecule]; CD151 [CD151 molecule (Raph blood group)]; CD160 [CD160 molecule]; CD163 [CD163 molecule]; CD180 [CD180 molecule]; CD19 [CD19 molecule]; CD1A [CD1a molecule]; CD1B [CD1b molecule]; CD1C [CD1c molecule]; CD1D [CD1d molecule]; CD2 [CD2 molecule]; CD200 [CD200 molecule]; CD207 [CD207 molecule, langerin]; CD209 [CD209 molecule]; CD22 [CD22 molecule]; CD226 [CD226 molecule]; CD24 [CD24 molecule]; CD244 [CD244 molecule, natural killer cell receptor 2B4]; CD247 [CD247 molecule]; CD27 [CD27 molecule]; CD274 [CD274 molecule]; CD28 [CD28 molecule]; CD2AP [CD2-associated protein]; CD300LF [CD300 Molecular-like Family Member f]; CD34 [CD34 molecule]; CD36 [CD36 molecule (thrombospondine receptor)]; CD37 [CD37 molecule]; CD38 [CD38 molecule]; CD3E [CD3e molecule, epsilon (CD3-TCR complex)]; CD4 [CD4 molecule]; CD40 [CD40 molecule, TNF receptor superfamily member 5]; CD40LG [CD40 Ligand]; CD44 [CD44 molecule (Indian blood group)]; CD46 [CD46 molecule, complement regulatory protein]; CD47 [CD47 molecule]; CD48 [CD48 molecule]; CD5 [CD5 molecule]; CD52 [CD52 molecule]; CD53 [CD53 molecule]; CD55 [CD55 molecule, Decay Accelerating Factor for Complement (Cromer Blood Group)]; CD58 [CD58 molecule]; CD59 [CD59 molecule, complement regulatory protein]; CD63 [CD63 molecule]; CD68 [CD68 molecule]; CD69 [CD69 molecule]; CD7 [CD7 molecule]; CD70 [CD70 molecule]; CD72 [CD72 molecule]; CD74 [CD74 molecule, major histocompatibility complex, class II constant chain]; CD79A [CD79a molecule, immunoglobulin-associated alpha]; CD79B [CD79b molecule, immunoglobulin-related beta]; CD80 [CD80 molecule]; CD81 [CD81 molecule]; CD82 [CD82 molecule]; CD83 [CD83 molecule]; CD86 [CD86 molecule]; CD8A [CD8a molecule]; CD9 [CD9 molecule]; CD93 [CD93 molecule]; CD97 [CD97 molecule]; CDC20 [cell division cycle 20 homologue (S. serbisier)]; CDC25A [Cell Division Cycle 25 Homolog A (S. Pombe)S. pombe)]; CDC25B [Cell Division Cycle 25 Homolog B (S. Pombe)]; CDC25C [cell division cycle 25 homolog C (S. Pombe)]; CDC42 [cell splitting cycle 42 (GTP binding protein, 25 kDa)]; CDC45 [CDC45 cell division cycle 45 homologue (S. Serbisier)]; CDC5L [CDC5 cell division cycle 5-like (S. Pombe)]; CDC6 [cell division cycle 6 homologue (S. serbisier)]; CDC7 [cell division cycle 7 homologue (S. Serbisier)]; CDH1 [Cadherin 1, Type 1, E-Cadherin (Epithelial)]; CDH2 [Cadherin 2, Type 1, N-Cadherin (neurons)]; CDH26 [Cadherin 26]; CDH3 [cadherin 3, type 1, P-cadherin (placental)]; CDH5 [Cadherin 5, Type 2 (vascular endothelial)]; CDIPT [CDP-Diacylglycerol-Inositol 3-Phosphatidyltransferase (Phosphatidyl Inositol Synthetase)]; CDK1 [cyclin-dependent kinase 1]; CDK2 [cyclin-dependent kinase 2]; CDK4 [cyclin-dependent kinase 4]; CDK5 [cyclin-dependent kinase 5]; CDK5R1 [cyclin-dependent kinase 5, regulatory subunit 1 (p35)]; CDK7 [cyclin-dependent kinase 7]; CDK9 [cyclin-dependent kinase 9]; CDKAL1 [CDK5 regulatory subunit related protein 1-like 1]; CDKN1A [cyclin-dependent kinase inhibitor 1A (p21, Cip1)]; CDKN1B [cyclin-dependent kinase inhibitor 1B (p27, Kip1)]; CDKN1C [cyclin-dependent kinase inhibitor 1C (p57, Kip2)]; CDKN2A [cyclin-dependent kinase inhibitor 2A (inhibits melanoma, p16, CDK4)]; CDKN2B [cycline-dependent kinase inhibitor 2B (p15, inhibits CDK4)]; CDKN3 [cyclin-dependent kinase inhibitor 3]; CDR2 [cerebellar degeneration-related protein 2, 62 kDa]; CDT1 [chromatin licensing and DNA replication factor 1]; CDX2 [tailed type homeobox 2]; CEACAM1 [carcinogenic antigen-associated cell adhesion molecule 1 (bile glycoproteins)]; CEACAM3 [carcinogenic antigen-associated cell adhesion molecule 3]; CEACAM5 [carcinogenic antigen-associated cell adhesion molecule 5]; CEACAM6 [carcinogenic antigen-associated cell adhesion molecule 6 (non-specific cross reactive antigen)]; CEACAM7 [carcinogenic antigen-associated cell adhesion molecule 7]; CEBPB [CCAAT / Enhancer Binding Protein (C / EBP), Beta]; CEL [carboxy ester lipase (bile salt-stimulated lipase)]; CENPJ [centromeric protein J]; CENPV [centromeric protein V]; CEP290 [Centrosome Protein 290 kDa]; CERK [ceramide kinase]; CETP [cholesteryl ester transfer protein, plasma]; CFB [complement factor B]; CFD [complement factor D (adipsin)]; CFDP1 [Craniofacial Development Protein 1]; CFH [complement factor H]; CFHR1 [complement factor H-related 1]; CFHR3 [complement factor H-related 3]; CFI [complement factor I]; CFL1 [Kophyrin 1 (non-muscle)]; CFL2 [Kophyrin 2 (Muscle)]; CFLAR [CASP8 and FADD-Like Apoptosis Modulators]; CFP [complement factor properdin]; CFTR [cystic fibrosis transmembrane and conductivity modulator (ATP-binding cassette sub-family C, member 7)]; CGA [glycoprotein hormone, alpha polypeptide]; CGB [villi gonadotropin, beta polypeptide]; CGB5 [villi gonadotropin, beta polypeptide 5]; CHAD [chondroedherin]; CHAF1A [Chromatin Aggregation Factor 1, Subunit A (p150)]; CHAF1B [Chromatin Aggregation Factor 1, Subunit B (p60)]; CHAT [choline acetyltransferase]; CHD2 [Chromodomain helicase DNA binding protein 2]; CHD7 [Chromodomain helicase DNA binding protein 7]; CHEK1 [CHK1 Checkpoint Homolog (S. Pombe)]; CHEK2 [CHK2 checkpoint homologue (S. Pombe)]; CHGA [Chromogranin A (parathyroid secretion protein 1)]; CHGB [Chromogranin B (Checretogenin 1)]; CHI3L1 [chitinase 3-like 1 (cartilage glycoprotein-39)]; CHIA [chitinase, acidic]; CHIT1 [chitinase 1 (chitotrioxidase)]; CHKA [choline kinase alpha]; CHML (choroidal defect-like (Rab escort protein 2)); CHRD [cordin]; CHRDL1 [cordin-like 1]; CHRM1 [cholinergic receptor, muscarinic 1]; CHRM2 [cholinergic receptor, muscarinic 2]; CHRM3 [cholinergic receptor, muscarinic 3]; CHRNA3 [cholinergic receptor, nicotinic, alpha 3]; CHRNA4 [cholinergic receptor, nicotinic, alpha 4]; CHRNA7 [cholinergic receptor, nicotinic, alpha 7]; CHUK [conserved helix-loop-helix ubiquitous kinase]; CIB1 [calcium and integrin binding 1 (calcirin)]; CIITA [Class II, Major Histocompatibility Complex, Transactivator]; CILP [cartilage middle layer protein, nucleotide pyrophosphohydrolase]; CISH [cytokine inducible SH2-containing protein]; CKB [creatine kinase, brain]; CKLF [chemokine-like factor]; CKM [creatine kinase, muscle]; CLC [Charcot-Leyden Determinant Protein]; CLCA1 [chloride channel aid 1]; CLCN1 [chloride channel 1, skeletal muscle]; CLCN3 [chloride channel 3]; CLDN1 [Claudin 1]; CLDN11 [Claudine 11]; CLDN14 [Claudine 14]; CLDN16 [Claudine 16]; CLDN19 [Claudin 19]; CLDN2 [Claudine 2]; CLDN3 [Claudin 3]; CLDN4 [Claudin 4]; CLDN5 [Claudin 5]; CLDN7 [Claudin 7]; CLDN8 [Claudine 8]; CLEC12A [C-type lectin domain family 12, member A]; CLEC16A [C-type lectin domain family 16, member A]; CLEC4A [C-type lectin domain family 4, member A]; CLEC4D [C-type lectin domain family 4, member D]; CLEC4M [C-type lectin domain family 4, member M]; CLEC7A [C-type lectin domain family 7, member A]; CLIP2 [CAP-GLY domain containing linker protein 2]; CLK2 [CDC-like kinase 2]; CLSPN [Klaspin homologues (African claws) (Xenopus laevis); CLSTN2 [calcithenin 2]; CLTCL1 [Clearin, heavy chain-like 1]; CLU [Clusterine]; CMA1 [kinase 1, mast cells]; CMKLR1 [chemokine-like receptor 1]; CNBP [CCHC-type zinc finger, nucleic acid binding protein]; CNDP2 [CNDP Dipeptidase 2 (Metal Peptidase M20 Family)]; CNN1 [calponin 1, basic, smooth muscle]; CNP [2 ', 3'-cycle nucleotide 3' phosphodiesterase]; CNR1 [cannabinoid receptor 1 (brain)]; CNR2 [cannabinoid receptor 2 (macrophages)]; CNTF [ciliary neurotrophic factor]; CNTN2 [contactin 2 (axon)]; COG1 [Component 1 of Oligomeric Golgi]; COG2 [Component 2 of Oligomeric Golgi]; COIL [Coiline]; COL11A1 [collagen, type XI, alpha 1]; COL11A2 [collagen, type XI, alpha 2]; COL17A1 [collagen, type XVII, alpha 1]; COL18A1 [collagen, type XVIII, alpha 1]; COL1A1 [collagen, type I, alpha 1]; COL1A2 [collagen, type I, alpha 2]; COL2A1 [collagen, type II, alpha 1]; COL3A1 [collagen, type III, alpha 1]; COL4A1 [collagen, type IV, alpha 1]; COL4A3 [collagen, type IV, alpha 3 (Goodpasture antigen)]; COL4A4 [collagen, type IV, alpha 4]; COL4A5 [collagen, type IV, alpha 5]; COL4A6 [collagen, type IV, alpha 6]; COL5A1 [collagen, type V, alpha 1]; COL5A2 [collagen, type V, alpha 2]; COL6A1 [collagen, type VI, alpha 1]; COL6A2 [collagen, type VI, alpha 2]; COL6A3 [collagen, type VI, alpha 3]; COL7A1 [collagen, type VII, alpha 1]; COL8A2 [collagen, type VIII, alpha 2]; COL9A1 [collagen, type IX, alpha 1]; COMT [Catechol-O-methyltransferase]; COQ3 [coenzyme Q3 homologues, methyltransferases (S. servichy)]; COQ7 [coenzyme Q7 homologue, ubiquinone (yeast)]; CORO1A [coronine, actin binding protein, 1A]; COX10 [COX10 homologue, cytochrome c oxidase assembly protein, reduced hematin A: farnesyltransferase (yeast)]; COX15 [COX15 homologue, cytochrome c oxidase assembly protein (yeast)]; COX5A [cytochrome c oxidase subunit Va]; COX8A [cytochrome c oxidase subunit VIIIA (local)); CP [ceruloplasmin (peroxidase)]; CPA1 [carboxypeptidase A1 (pancreas)]; CPB2 [carboxypeptidase B2 (plasma)]; CPN1 [carboxypeptidase N, polypeptide 1]; CPOX [copropofynogen oxidase]; CPS1 [carbamoyl-phosphate synthase 1, mitochondria]; CPT2 [carnitine palmitoyltransferase 2]; CR1 [complement component (3b / 4b) receptor 1 (Knops blood group)]; CR2 [complement component (3d / ypstein bar virus) receptor 2]; C rat [carnitine O-acetyltransferase]; CRB1 [crumbs homologue 1 (Drosophila)]; CREB1 [cAMP Response Element Binding Protein 1]; CREBBP [CREB Binding Protein]; CREM [cAMP response element modulator]; CRH [adrenal cortical stimulating hormone releasing hormone]; CRHR1 [adrenal cortical stimulating hormone releasing hormone receptor 1]; CRHR2 [Adrenal Cortical Stimulating Hormone Releasing Hormone Receptor 2]; CRK [v-crk sarcoma virus CT10 oncogene homologue (bird)]; CRKL [v-crk sarcoma virus CT10 oncogene homolog (bird) -like]; CRLF2 [cytokine receptor-like factor 2]; CRLF3 [cytokine receptor-like factor 3]; CROT [carnitine O-octanoyl transferase]; CRP [C-reactive protein, pentracin-associated]; CRX [cone-rod homeobox]; CRY2 [Crimtochrome 2 (photoliase-like)]; CRYAA [crystallin, alpha A]; CRYAB [crystallin, alpha B]; CS [citrate synthase]; CSF1 [colony stimulating factor 1 (macrophages)]; CSF1R [colony stimulating factor 1 receptor]; CSF2 [colony stimulating factor 2 (granulocyte-macrophage)]; CSF2RB [colony stimulating factor 2 receptor, beta, low affinity (granulocyte-macrophages)]; CSF3 [colony stimulating factor 3 (granulocytes)]; CSF3R [colony stimulating factor 3 receptor (granulocytes)]; CSK [c-src tyrosine kinase]; CSMD3 [CUB and Sushi Multi-Domain 3]; CSN1S1 [casein alpha s1]; CSN2 [casein beta]; CSNK1A1 [casein kinase 1, alpha 1]; CSNK2A1 [casein kinase 2, alpha 1 polypeptide]; CSNK2B [casein kinase 2, beta polypeptide]; CSPG4 [chondroitin sulfate proteoglycan 4]; CST3 [cistatin C]; CST8 [cistatin 8 (cystatin-associated testicular specific)]; CSTA [cisstatin A (steppin A)]; CSTB [Cystatin B (Stepin B)]; CTAGE1 [cutaneous T-cell lymphoma-associated antigen 1]; CTF1 [cardiotropin 1]; CTGF [Connective Tissue Growth Factor]; CTH [cistathionease (cistathionine gamma-lyase)]; CTLA4 [cytotoxic T-lymphocyte-related protein 4]; CTNNA1 [catenin (cadherin-associated protein), alpha 1, 102 kDa]; CTNNA3 [catenin (cadherin-associated protein), alpha 3]; CTNNAL1 [catenin (cadherin-associated protein), alpha-like 1]; CTNNB1 [catenin (cadherin-associated protein), beta 1, 88 kDa]; CTNND1 [catenin (cadherin-associated protein), delta 1]; CTNS [cystinoma, nephropathy]; CTRL [chymotrypsin-like]; CTSB [Cathepsin B]; CTSC [Cathepsin C]; CTSD [Cathepsin D]; CTSE [Cathepsin E]; CTSG [Cathepsin G]; CTSH [Cathepsin H]; CTSK [Cathepsin K]; CTSL1 [Cathepsin L1]; CTTN [Cortactin]; CUL1 [Cullin 1]; CUL2 [Cullin 2]; CUL4A [Culin 4A]; CUL5 [Culin 5]; CX3CL1 [chemokine (C-X3-C motif) ligand 1]; CX3CR1 [chemokine (C-X3-C motif) receptor 1]; CXADR [coxsackie virus and adenovirus receptor]; CXCL1 [chemokine (C-X-C motif) ligand 1 (melanoma growth stimulating activity, alpha)]; CXCL10 [chemokine (C-X-C motif) ligand 10]; CXCL11 [chemokine (C-X-C motif) ligand 11]; CXCL12 [chemokine (C-X-C motif) ligand 12 (mesenchymal-derived factor 1)]; CXCL13 [chemokine (C-X-C motif) ligand 13]; CXCL2 [chemokine (C-X-C motif) ligand 2]; CXCL5 [chemokine (C-X-C motif) ligand 5]; CXCL6 [chemokine (C-X-C motif) ligand 6 (granulocyte chemotactic protein 2)]; CXCL9 [chemokine (C-X-C motif) ligand 9]; CXCR1 [chemokine (C-X-C motif) receptor 1]; CXCR2 [chemokine (C-X-C motif) receptor 2]; CXCR3 [chemokine (C-X-C motif) receptor 3]; CXCR4 [chemokine (C-X-C motif) receptor 4]; CXCR5 [chemokine (C-X-C motif) receptor 5]; CXCR6 [chemokine (C-X-C motif) receptor 6]; CXCR7 [chemokine (C-X-C motif) receptor 7]; CXorf40A [chromosome X open reading frame 40A]; CYB5A [cytochrome b5 type A (microsomes)]; CYB5R3 [cytochrome b5 reductase 3]; CYBA [cytochrome b-245, alpha polypeptide]; CYBB [cytochrome b-245, beta polypeptide]; CYC1 [cytochrome c-1]; CYCS [cytochrome c, of the body]; CYFIP2 [cytoplasmic FMR1 interacting protein 2]; CYP11A1 [cytochrome P450, family 11, subfamily A, polypeptide 1]; CYP11B1 [cytochrome P450, family 11, subfamily B, polypeptide 1]; CYP11B2 [cytochrome P450, family 11, subfamily B, polypeptide 2]; CYP17A1 [cytochrome P450, family 17, subfamily A, polypeptide 1]; CYP19A1 [cytochrome P450, family 19, subfamily A, polypeptide 1]; CYP1A1 [cytochrome P450, family 1, subfamily A, polypeptide 1]; CYP1A2 [cytochrome P450, family 1, subfamily A, polypeptide 2]; CYP1B1 [cytochrome P450, family 1, subfamily B, polypeptide 1]; CYP21A2 [cytochrome P450, family 21, subfamily A, polypeptide 2]; CYP24A1 [cytochrome P450, family 24, subfamily A, polypeptide 1]; CYP27A1 [cytochrome P450, family 27, subfamily A, polypeptide 1]; CYP27B1 [cytochrome P450, family 27, subfamily B, polypeptide 1]; CYP2A6 [cytochrome P450, family 2, subfamily A, polypeptide 6]; CYP2B6 [cytochrome P450, family 2, subfamily B, polypeptide 6]; CYP2C19 [cytochrome P450, family 2, subfamily C, polypeptide 19]; CYP2C8 [cytochrome P450, family 2, subfamily C, polypeptide 8]; CYP2C9 [cytochrome P450, family 2, subfamily C, polypeptide 9]; CYP2D6 [cytochrome P450, family 2, subfamily D, polypeptide 6]; CYP2E1 [cytochrome P450, family 2, subfamily E, polypeptide 1]; CYP2J2 [cytochrome P450, family 2, subfamily J, polypeptide 2]; CYP2R1 [cytochrome P450, family 2, subfamily R, polypeptide 1]; CYP3A4 [cytochrome P450, family 3, subfamily A, polypeptide 4]; CYP3A5 [cytochrome P450, family 3, subfamily A, polypeptide 5]; CYP4F3 [cytochrome P450, family 4, subfamily F, polypeptide 3]; CYP51A1 [cytochrome P450, family 51, subfamily A, polypeptide 1]; CYP7A1 [cytochrome P450, family 7, subfamily A, polypeptide 1]; CYR61 [cysteine-rich, angiogenesis inducer, 61]; CYSLTR1 [cysteinyllucotriene receptor 1]; CYSLTR2 [cysteinyllucotriene receptor 2]; DAO [D-amino-acid oxidase]; DAOA [D-Amino Acid Oxidase Active Material]; DAP3 [killing related protein 3]; DAPK1 [kill-associated protein kinase 1]; DARC [Duffy Blood Group, Chemokine Receptor]; DAZ1 [1 missing in aspermatosis]; DBH [dopamine beta-hydroxylase (dopamine beta-monooxygenase)]; DCK [deoxycytidine kinase]; DCLRE1C (DNA cross-link repair 1C (PSO2 homologue, S. Serbisier)]; DCN [Decorin]; DCT [Dopachrome tautomerase (Dopachrome delta-isomerase, tyrosine-related protein 2)]; DCTN2 [Dinactin 2 (p50)]; DDB1 [damage-specific DNA binding protein 1, 127 kDa]; DDB2 [damage-specific DNA binding protein 2, 48 kDa]; DDC [dopa decarboxylase (aromatic L-amino acid decarboxylase)]; DDIT3 [DNA-damaged-inducible transcript 3]; DDR1 [discoidin domain receptor tyrosine kinase 1]; DDX1 [DEAD (Asp-Glu-Ala-Asp) box polypeptide 1]; DDX41 [DEAD (Asp-Glu-Ala-Asp) box polypeptide 41]; DDX42 [DEAD (Asp-Glu-Ala-Asp) box polypeptide 42]; DDX58 [DEAD (Asp-Glu-Ala-Asp) box polypeptide 58]; DEFA1 [defensin, alpha 1]; DEFA5 [defensin, alpha 5, Paneth cell-specific]; DEFA6 [defensin, alpha 6, Paneth cell-specific]; DEFB1 [defensin, beta 1]; DEFB103B [defensin, beta 103B]; DEFB104A [defensin, beta 104A]; DEFB4A [defensin, beta 4A]; DEK [DEK oncogene]; DENND1B [1B containing DENN / MADD domain]; DES [desmin]; DGAT1 [Diacylglycerol O-acyltransferase homolog 1 (mouse)]; DGCR14 [DiGeorge Syndrome Deterministic Partial Gene 14]; DGCR2 [DiGeorge Syndrome Deterministic Partial Gene 2]; DGCR6 [DiGeorge Syndrome Deterministic Partial Gene 6]; DGCR6L [DiGeorge syndrome deterministic partial gene 6-like]; DGCR8 [DiGeorge Syndrome Deterministic Partial Gene 8]; DGUOK [deoxyguanosine kinase]; DHFR [dihydrofolate reductase]; DHODH [dihydroorotate dehydrogenase]; DHPS [Deoxyhippusin Synthetase]; DHRS7B [dehydrogenase / reductase (SDR family) member 7B]; DHRS9 [dehydrogenase / reductase (SDR family) member 9]; DIAPH1 (diaphanous homolog 1 (Drosophila)]; DICER1 [Dicer1, Ribonuclease Type III]; DIO2 [deiodinase, iodine tyrosine, type II]; DKC1 [congenital dikeratosis 1, deskerin]; DKK1 [dickkopf homolog 1 (African claw frog)]; DLAT [dihydroziamide S-acetyltransferase]; DLG2 [disc, large homolog 2 (Drosophila)]; DLG5 [disc, large homolog 5 (Drosophila)]; DMBT1 [removed from malignant brain tumor 1]; DMC1 [DMC1 dosing inhibitor of mck1 homologues, meiosis-specific homologous recombination (yeast)]; DMD [dispropine]; DMP1 [Dentin Matrix Acid Phosphorus Protein 1]; DMPK [muscle dystonia-protein kinase]; DMRT1 [doublesex and mab-3 related transcription factor 1]; DMXL2 [Dmx-like 2]; DNA2 [DNA replication helicase 2 homologue (yeast)]; DNAH1 [dynein, ammonia, heavy chain 1]; DNAH12 [dyne, ammonia, heavy chain 12]; DNAI1 [dyne, ammonia, intermediate chain 1]; DNAI2 [dyne, ammonia, middle chain 2]; DNASE1 [deoxyribonuclease I]; DNM2 [dynamin 2]; DNM3 [dynamin 3]; DNMT1 [DNA (cytosine-5-)-methyltransferase 1]; DNMT3B [DNA (cytosine-5-)-methyltransferase 3 beta]; DNTT [deoxynucleotidyltransferase, terminal]; DOCK1 [Committed to Cell Division 1]; DOCK3 [Committed to Cell Division 3]; DOCK8 [committed substance of cytoplasmic division 8]; DOK1 [docking protein 1, 62 kDa (downstream 1 of tyrosine kinase)]; DOLK [Dorcol Kinase]; DPAGT1 [Doricyl-phosphate (UDP-N-acetylglucosamine) N-acetylglucosamine transcriptase 1 (GlcNAc-1-P transferase)]; DPEP1 [dipeptidase 1 (kidney)]; DPH1 [DPH1 homologue (S. Serbisier)]; DPM1 [Doricyl-phosphate Mannosyltransferase Polypeptide 1, catalytic subunit]; DPP10 [dipeptides-peptidase 10]; DPP4 [dipeptides-peptidase 4]; DPYD [dihydropyrimidine dehydrogenase]; DRD2 [Dopamine Receptor D2]; DRD3 [Dopamine Receptor D3]; DRD4 [Dopamine Receptor D4]; DSC2 [Desmocholine 2]; DSG1 [Desmogloin 1]; DSG2 [Desmogloin 2]; DSG3 [Desmoglyne 3 (Terebral Bullous Antigen)]; DSP [Desmoplakin]; DTNA [Distrobrebin, Alpha]; DTYMK [deoxythymidylate kinase (thymidylate kinase)]; DUOX1 [Dual Oxidase 1]; DUOX2 [Dual Oxidase 2]; DUSP1 [bispecific phosphatase 1]; DUSP14 [bispecific phosphatase 14]; DUSP2 [bispecific phosphatase 2]; DUSP5 [bispecific phosphatase 5]; DUT [deoxyuridine triphosphatase]; DVL1 [scattered, dsh homolog 1 (Drosophila)]; DYNC2H1 [dyne, cytoplasm 2, heavy chain 1]; DYNLL1 [dyne, light chain, LC8-type 1]; DYRK1A [dual-specific tyrosine- (Y) -phosphorylated modulated kinase 1A]; DYSF [disperin, limb girdle muscular dystrophy 2B (autosome recessive)]; E2F1 [E2F transcription factor 1]; EBF2 [initial B-cell factor 2]; EBI3 [Epstein-Barr virus induced 3]; ECE1 [endoterin converting enzyme 1]; ECM1 [extracellular matrix protein 1]; EDA [Ectodisplacin A]; EDAR [Ectodisplacin A Receptor]; EDN1 [Endoterin 1]; EDNRA [endotherin receptor type A]; EDNRB [endotherin receptor type B]; EEF1A1 [eukaryotic detoxification factor 1 alpha 1]; EEF1A2 [eukaryotic detoxification factor 1 alpha 2]; EFEMP2 [EGF-containing fibulin-like extracellular matrix protein 2]; EFNA1 [Epirine-A1]; EFNB2 [Epirine-B2]; EFS [embryonic Fyn-associated substrate]; EGF [epithelial growth factor (beta-neurogenstron)]; EGFR [epithelial growth factor receptor (erythrocyte leukemia viral (v-erb-b) oncogene homolog, algae)]; EGR1 [Initial Growth Reaction 1]; EGR2 [Initial Growth Reaction 2]; EHF [ets homology factor]; EHMT2 [large euchromatic histone-lysine N-methyltransferase 2]; EIF2AK2 [eukaryotic translation initiation factor 2-alpha kinase 2]; EIF2S1 [eukaryotic translation initiation factor 2, subunit 1 alpha, 35 kDa]; EIF2S2 [eukaryotic translation initiation factor 2, subunit 2 beta, 38 kDa]; EIF3A [eukaryotic translation initiation factor 3, subunit A]; EIF4B [eukaryotic translation initiation factor 4B]; EIF4E [eukaryotic translation initiation factor 4E]; EIF4EBP1 [eukaryotic translation initiation factor 4E binding protein 1]; EIF4G1 [eukaryotic translation initiation factor 4 gamma, 1]; EIF6 [eukaryotic translation initiation factor 6]; ELAC2 [elaC homolog 2 (E. coli)E. coli)]; ELINE [elastase, neutrophil expressed]; ELAVL1 [ELAV (embryofatal, abnormal vision, Drosophila) -like 1 (Hu antigen R)]; ELF3 [E74-like factor 3 (ets domain transcription factor, epithelial-specific)]; ELF5 [E74-like factor 5 (ets domain transcription factor)]; ELN [Elastin]; ELOVL4 [extension of very long chain fatty acids (FEN1 / Elo2, SUR4 / Elo3, yeast) -like 4]; EMD [Emerrin]; EMILIN1 [Elastin Microfiber Interface 1]; EMR2 [containing egf-like modules, mucin-like, hormone receptor-like 2]; EN2 [engrailed homeobox 2]; ENG [endoglin]; ENO1 [enolase 1, (alpha)]; ENO2 [enolase 2 (gamma, neuron)]; ENO3 [enolase 3 (beta, muscle)]; ENPP2 [ectonucleotide pyrophosphatase / phosphodiesterase 2]; ENPP3 [Ectonucleotide pyrophosphatase / phosphodiesterase 3]; ENTPD1 [ectonucleoside triphosphate diphosphohydrolase 1]; EP300 [E1A binding protein p300]; EPAS1 [Endothelial PAS Domain Protein 1]; EPB42 [red blood cell membrane protein band 4.2]; EPCAM [epithelial cell adhesion molecule]; EPHA1 [EPH Receptor A1]; EPHA2 [EPH Receptor A2]; EPHB2 [EPH Receptor B2]; EPHB4 [EPH Receptor B4]; EPHB6 [EPH Receptor B6]; EPHX1 [epoxide hydrolase 1, microsome (xenobiotic)]; EPHX2 [Epoxide Hydrolase 2, Cytoplasm]; EPO [erythropoietin]; EPOR [erythropoietin receptor]; EPRS [glutamyl-prolyl-tRNA synthetase]; EPX [neutrophil peroxidase]; ERBB2 [v-erb-b2 erythroblastic leukemia viral oncogene homologue 2, neuro / glioblastoma induced oncogene homologue (algae)]; ERBB2IP [erbb2 interacting protein]; ERBB3 [v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (algae)]; ERBB4 [v-erb-a erythrocyte leukemia viral oncogene homologue 4 (algae)]; ERCC1 [delete repair cross-complementary rodent repair defect, complement group 1 (including nested antisense sequences)]; ERCC2 [Delete Recovery Cross-Complement Rodent Recovery Defect, Complement Group 2]; ERCC3 [Delete Recovery Cross-Complement Rodent Recovery Defect, Complement Group 3 (Complementary Pigmentary Dermatosis Group B)]; ERCC4 [Delete Recovery Cross-Complement Rodent Recovery Defect, Complement Group 4]; ERCC5 [Delete Recovery Cross-Complement Rodent Recovery Defect, Complement Group 5]; ERCC6 [Delete Recovery Cross-Complement Rodent Recovery Defect, Complement Group 6]; ERCC6L [Delete Recovery Cross-Complement Rodent Recovery Defect, Complement Group 6-like]; ERCC8 [Delete Recovery Cross-Complement Rodent Recovery Defect, Complement Group 8]; ERO1LB [ERO1-like beta (S. Serbisier)]; ERVK6 [endogenous retroviral sequence K, 6]; ERVWE1 [endogenous retroviral family W, env (C7), member 1]; ESD [Esterase D / Formylglutathione Hydrolase]; ESR1 [estrogen receptor 1]; ESR2 [estrogen receptor 2 (ER beta)]; ESRRA [estrogen-associated receptor alpha]; ESRRB [estrogen-related receptor beta]; ETS1 [v-ets erythrophilia virus E26 oncogene homolog 1 (algae)]; ETS2 [v-ets erythrophilia virus E26 oncogene homologue 2 (algae)]; EWSR1 [Ewing's Sarcoma Breakpoint Part 1]; EXO1 [exonuclease 1]; EYA1 [Homologue 1 without fruit (Drosophila)]; EZH2 [enhancer of zeste homolog 2 (Drosophila)]; EZR [Izrin]; F10 [coagulation factor X]; F11 [coagulation factor XI]; F12 [coagulation factor XII (Hageman factor)]; F13A1 [coagulation factor XIII, A1 polypeptide]; F13B [coagulation factor XIII, B polypeptide]; F2 [coagulation factor II (thrombin)]; F2R [coagulation factor II (thrombin) receptor]; F2RL1 [coagulation factor II (thrombin) receptor-like 1]; F2RL3 [coagulation factor II (thrombin) receptor-like 3]; F3 [coagulation factor III (thromboplastin, tissue factor)]; F5 [coagulation factor V (proacerine, unstable factor)]; F7 [coagulation factor VII (serum prothrombin conversion accelerator)]; F8 [coagulation factor VIII, precoagulant component]; F9 [coagulation factor IX]; FABP1 [fatty acid binding protein 1, liver]; FABP2 [fatty acid binding protein 2, gut]; FABP4 [fatty acid binding protein 4, adipocytes]; FADD [associated Fas (TNFRSF6) via killing domain); FADS1 [fatty acid desaturase 1]; FADS2 [fatty acid desaturase 2]; FAF1 [Fas (TNFRSF6) related factor 1]; FAH [fumaryl acetoacetate hydrolase (fumaryl acetoacetase)]; FAM189B [SEQ ID NO 189, FAMILY WITH MEMBER B]; FAM92B [SEQ ID NO 92, FAMILY WITH MEMBER B]; FANCA [Fanconi anemia, complement group A]; FANCB [Fancony Anemia, Complement Group B]; FANCC [Fancony Anemia, Complement Group C]; FANCD2 [Fancony Anemia, Complement Group D2]; FANCE [Fancony Anemia, Complement Group E]; FANCF [Fancony Anemia, Complement Group F]; FANCG [Fancony Anemia, Complement Group G]; FANCI [Fancony Anemia, Complement Group I]; FANCL [Fancony Anemia, Complement Group L]; FANCM [Fancony Anemia, Complement Group M]; FANK1 [fibronectin type III and ankyrin repeat domain 1]; FAS [Fas (TNF Receptor Superfamily, Member 6)]; FASLG [Fas Ligand (TNF Superfamily, Member 6)]; FASN [fatty acid synthase]; FASTK [Fas-activated serine / threonine kinase]; FBLN5 [Piboline 5]; FBN1 [fibrillin 1]; FBP1 [fructose-1,6-bisphosphatase 1]; FBXO32 [F-box protein 32]; FBXW7 [7 containing F-box and WD repeat domains]; FCAR [Fc fragment of IgA, receptor]; FCER1A [Fc fragment of IgE, high affinity I, receptor; Alpha polypeptide]; FCER1G [Fc fragment of IgE, high affinity I, receptor; Gamma polypeptide]; FCER2 [Fc fragment of IgE, low affinity II, receptor for (CD23)]; FCGR1A [Fc fragment of IgG, high affinity Ia, receptor (CD64)]; FCGR2A [Fc fragment of IgG, low affinity IIa, receptor (CD32)]; FCGR2B [Fc fragment of IgG, low affinity IIb, receptor (CD32)]; FCGR3A [Fc fragment of IgG, low affinity IIIa, receptor (CD16a)]; FCGR3B [Fc fragment of IgG, low affinity IIIb, receptor (CD16b)]; FCN2 [picorin (collagen / fibrinogen domain containing lectin) 2 (humorin)]; FCN3 [picorin (containing collagen / fibrinogen domain) 3 (Hakata antigen)]; FCRL3 [Fc Receptor-Like 3]; FCRL6 [Fc Receptor-Like 6]; FDFT1 [Farnesyl-Diphosphate Farnesyl Transferase 1]; FDPS [Farnesyl Diphosphate Synthetase (Farnesyl Pyrophosphate Synthetase, Dimethylallyl Transtransferase, Geranyl Transtransferase)]; FDX1 [Perredoxin 1]; FEN1 [flap structure-specific endonuclease 1]; FERMT1 [fermitin family homologue 1 (Drosophila)]; FERMT3 [fermitin family homologue 3 (Drosophila)]; FES [cat and sarcoma oncogene]; FFAR2 [free fatty acid receptor 2]; FGA [fibrinogen alpha chain]; FGB [fibrinogen beta chain]; FGF1 [fibroblast growth factor 1 (acidic)]; FGF2 [fibroblast growth factor 2 (basic)]; FGF5 [fibroblast growth factor 5]; FGF7 [fibroblast growth factor 7 (keratinocyte growth factor)]; FGF8 [fibroblast growth factor 8 (androgen-induced)]; FGFBP2 [fibroblast growth factor binding protein 2]; FGFR1 [fibroblast growth factor receptor 1]; FGFR1OP [FGFR1 Oncogene Partner]; FGFR2 [fibroblast growth factor receptor 2]; FGFR3 [fibroblast growth factor receptor 3]; FGFR4 [fibroblast growth factor receptor 4]; FGG [fibrinogen gamma chain]; FGR [Gardner-Rasheed Cataract Sarcoma Viral (v-fgr) Oncogene Homologs]; FHIT [Fragile histidine triad gene]; FHL1 [4 and 1/2 LIM Domain 1]; FHL2 [4 and 1/2 LIM Domain 2]; FIBP [fibroblast growth factor (acidic) intracellular binding protein]; FIGF [c-fos induced growth factor (vascular endothelial growth factor D)]; FKBP1A [FK506 Binding Protein 1A, 12kDa]; FKBP4 [FK506 Binding Protein 4, 59 kDa]; FKBP5 [FK506 Binding Protein 5]; FLCN [Polycurin]; FLG [filagrin]; FLG2 [filagreen family member 2]; FLNA [Pilamin A, Alpha]; FLNB [Pilamin B, Beta]; FLT1 [fms-associated tyrosine kinase 1 (vascular endothelial growth factor / vascular permeability factor receptor)]; FLT3 [fms-associated tyrosine kinase 3]; FLT3LG [fms-associated tyrosine kinase 3 ligand]; FLT4 [fms-associated tyrosine kinase 4]; FMN1 [formin 1]; FMOD [fibromodulin]; FMR1 [Fragile X Mental Retardation 1]; FN1 [fibronectin 1]; FOLH1 [folate hydrolase (prostate-specific membrane antigen) 1]; FOLR1 [folate receptor 1 (adult)]; FOS [FBJ murine osteosarcoma viral oncogene homologue]; FOXL2 [Forkhead Box L2]; FOXN1 [Forkhead Box N1]; FOXN2 [Forkhead Box N2]; FOXO3 [Forkhead Box O3]; FOXP3 [Forkhead Box P3]; FPGS [Folylpolyglutamate synthetase]; FPR1 [formyl peptide receptor 1]; FPR2 [formyl peptide receptor 2]; FRAS1 [Fraser Syndrome 1]; FREM2 [FRAS1 related extracellular matrix protein 2]; FSCN1 [fascin homolog 1, actin-bundling proteinStrongylocentrotus purpuratus))]; FSHB [follicle stimulating hormone, beta polypeptide]; FSHR [follicle stimulating hormone receptor]; FST [polystatin]; FTCD [formiminotransferase cyclodeaminase]; FTH1 [ferritin, heavy polypeptide 1]; FTL [ferritin, light polypeptide]; Purines [purines (paired basic amino acid cleavage enzymes)]; FUT1 [fucosyltransferase 1 (galactoside 2-alpha-L-fucosyltransferase, H blood group)]; FUT2 [fucosyltransferase 2 (embedded gland state)]; FUT3 [fucosyltransferase 3 (galactosid 3 (4) -L-fucosyltransferase, Lewis blood group)]; FUT4 [fucosyltransferase 4 (alpha (1,3) fucosyltransferase, myeloid-specific)]; FUT7 [fucosyltransferase 7 (alpha (1,3) fucosyltransferase)]; FUT8 [fucosyltransferase 8 (alpha (1,6) fucosyltransferase)]; FXN [pratacin]; FYN [FYN oncogene related to SRC, FGR, YES]; FZD4 [frizzled homolog 4 (Drosophila)]; G6PC3 [glucose 6 phosphatase, catalyst, 3]; G6PD [glucose-6-phosphate dehydrogenase]; GAA [glucosidase, alpha; mountain]; GAB2 [GRB2-associated binding protein 2]; GABBR1 [gamma-aminobutyl acid (GABA) B receptor, 1]; GABRB3 [gamma-aminobutyl acid (GABA) A receptor, beta 3]; GABRE [gamma-aminobutyl acid (GABA) A receptor, epsilon]; GAD1 [glutamate decarboxylase 1 (brain, 67 kDa)]; GAD2 [glutamate decarboxylase 2 (pancreatic islet and brain, 65 kDa)]; GADD45A [growth obstruction and DNA-damage-induced, alpha]; GAL [Galanine Prepropeptide]; GALC [galactosyl ceramidase]; GALK1 [galactokinase 1]; GALR1 [Galan Receptor 1]; GAP43 [growth related protein 43]; GAPDH [glyceraldehyde-3-phosphate dehydrogenase]; GART [phosphoribosilglycineamide formyltransferase, phosphoribosylglycineamide synthetase, phosphoribosylaminoimidazole synthetase]; GAST [Gastrin]; GATA1 [GATA binding protein 1 (globin transcription factor 1)]; GATA2 [GATA Binding Protein 2]; GATA3 [GATA Binding Protein 3]; GATA4 [GATA Binding Protein 4]; GATA6 [GATA Binding Protein 6]; GBA [glucosidase, beta, acid]; GBA3 [glucosidase, beta, acid 3 (cytosol)]; GBE1 [glucan (1 [4-alpha-), branching enzyme 1]; GC [group-specific component (vitamin D binding protein)]; GCG [Glucagon]; GCH1 [GTP cyclohydrolase 1]; GCKR [glucokinase (hexokinase 4) modulator]; GCLC [glutamate-cysteine ligase, catalytic subunit]; GCLM [glutamate-cysteine ligase, modifier subunit]; GCNT2 [glucosaminyl (N-acetyl) transferase 2, I-branching enzyme (I blood group)]; GDAP1 [ganglioside-induced differentiation-related protein 1]; GDF15 [growth differentiation factor 15]; GDNF [glial induced neurotrophic factor]; GFAP [glucose acidic protein]; GGH [gamma-glutamyl hydrolase (conjugase, foylpolygammaglutamyl hydrolase)]; GGT1 [gamma-glutamyltransferase 1]; GGT2 [gamma-glutamyltransferase 2]; GH1 [growth hormone 1]; GHR [growth hormone receptor]; GHRH [growth hormone releasing hormone]; GHRL [Ghrelin / Oveststatin Prepropeptide]; GHSR [growth hormone secretagogue receptor]; GIF [intrinsic factor above (vitamin B synthesis)]; GIP [inhibitory polypeptide above]; GJA1 [gap binding protein, alpha 1, 43kDa]; GJA4 [gap binding protein, alpha 4, 37kDa]; GJB2 [Gap Binding Protein, Beta 2, 26 kDa]; GLA [galactosidase, alpha]; GLB1 [galactosidase, beta 1]; GLI2 [GLI Family Zinc Finger 2]; GLMN [Glomoline, FKBP Related Protein]; GLRX [glutaredoxin (thiol transferase)]; GLS [glutaminase]; GLT25D1 [glycosyltransferase 25 domain containing 1]; GLUL [glutamate-ammonia ligase (glutamine synthase)]; GLYAT [glycine-N-acyltransferase]; GM2A [GM2 ganglioside active material]; GMDS [GDP-Mannose 4 [6-dehydratase]; GNA12 [guanine nucleotide binding protein (G protein) alpha 12]; GNA13 [guanine nucleotide binding protein (G protein), alpha 13]; GNAI1 [guanine nucleotide binding protein (G protein), alpha inhibitory active polypeptide 1]; GNAO1 [guanine nucleotide binding protein (G protein), alpha activating active polypeptide O]; GNAQ [guanine nucleotide binding protein (G protein), q polypeptide]; GNAS [GNAS Complex loci]; GNAZ [guanine nucleotide binding protein (G protein), alpha z polypeptide]; GNB1 [guanine nucleotide binding protein (G protein), beta polypeptide 1]; GNB1L [guanine nucleotide binding protein (G protein), beta polypeptide 1-like]; GNB2L1 [guanine nucleotide binding protein (G protein), beta polypeptide 2-like 1]; GNB3 [guanine nucleotide binding protein (G protein), beta polypeptide 3]; GNE [glucosamine (UDP-N-acetyl) -2-epimerase / N-acetylmannosamine kinase]; GNG2 [guanine nucleotide binding protein (G protein), gamma 2]; GNLY [Granulincin]; GNPAT [glycerone phosphate O-acyltransferase]; GNPDA2 [glucosamine-6-phosphate deaminase 2]; GNRH1 [gonadotropin-releasing hormone 1 (luteinated-releasing hormone)]; GNRHR [gonadotropin-releasing hormone receptor]; GOLGA8B [long A8 family, member B]; GOLGB1 [gol B1]; GOT1 [glutamine-oxaloacet transaminase 1, soluble (aspartate aminotransferase 1)]; GOT2 [glutamine-oxaloacet transaminase 2, mitochondria (aspartate aminotransferase 2)]; GP1BA [glycoprotein Ib (platelet), alpha polypeptide]; GP2 [glycoprotein 2 (zymogen granule membrane)]; GP6 [glycoprotein VI (platelet)]; GPBAR1 [G protein-linked bile acid receptor 1]; GPC5 [glypican 5]; GPI [glucose phosphate isomerase]; GPLD1 [glycosylphosphatidylinositol specific phospholipase D1]; GPN1 [GPN-loop GTPase 1]; GPR1 [G protein-linked receptor 1]; GPR12 [G protein-linked receptor 12]; GPR123 [G protein-linked receptor 123]; GPR143 [G protein-linked receptor 143]; GPR15 [G protein-linked receptor 15]; GPR182 [G protein-linked receptor 182]; GPR44 [G protein-linked receptor 44]; GPR77 [G protein-linked receptor 77]; GPRASP1 [G protein-linked receptor related sorting protein 1]; GPRC6A [G protein-linked receptor, family C, group 6, member A]; GPT [glutamine-pyruvate transaminase (alanine aminotransferase)]; GPX1 [glutathione peroxidase 1]; GPX2 [glutathione peroxidase 2 (gastrointestinal)]; GPX3 [glutathione peroxidase 3 (plasma)]; GRAP2 [GRB2-associated adapter protein 2]; GRB2 [growth factor receptor-bound protein 2]; GRIA2 [glutamate receptor, ionic, AMPA 2]; GRIN1 [glutamate receptor, ionic, N-methyl D-aspartate 1]; GRIN2A [glutamate receptor, ionic, N-methyl D-aspartate 2A]; GRIN2B [glutamate receptor, ionic, N-methyl D-aspartate 2B]; GRIN2C [glutamate receptor, ionic, N-methyl D-aspartate 2C]; GRIN2D [glutamate receptor, ionic, N-methyl D-aspartate 2D]; GRIN3A [glutamate receptor, ionic, N-methyl-D-aspartate 3A]; GRIN3B [glutamate receptor, ionic, N-methyl-D-aspartate 3B]; GRK5 [G protein-linked receptor kinase 5]; GRLF1 [glucocorticoid receptor DNA binding factor 1]; GRM1 [glutamate receptor, metabotropic 1]; GRP [gastrin-releasing peptide]; GRPR [gastrin-releasing peptide receptor]; GSC [goosecoid homeobox]; GSC2 [Gusecoid Homeobox 2]; GSDMB [gasdermin B]; GSK3B [glycogen synthase kinase 3 beta]; GSN [gelzoline]; GSR [glutathione reductase]; GSS [glutathione synthetase]; GSTA1 [glutathione S-transferase alpha 1]; GSTA2 [glutathione S-transferase alpha 2]; GSTM1 [glutathione S-transferase mu 1]; GSTM3 [glutathione S-transferase mu 3 (brain)]; GSTO2 [glutathione S-transferase omega 2]; GSTP1 [glutathione S-transferase pi 1]; GSTT1 [glutathione S-transferase theta 1]; GTF2A1 [universal transcription factor IIA, 1, 19 / 37kDa]; GTF2F1 [universal transcription factor IIF, polypeptide 1, 74 kDa]; GTF2H2 [universal transcription factor IIH, polypeptide 2, 44 kDa]; GTF2H4 [universal transcription factor IIH, polypeptide 4, 52 kDa]; GTF2H5 [universal transcription factor IIH, polypeptide 5]; GTF2I [Universal Transcription Factor IIi]; GTF3A [Universal Transcription Factor IIIA]; GUCA2A [guanylate cyclase activator 2A (guanylin)]; GUCA2B [guanylate cyclase activator 2B (uroguaniline)]; GUCY2C [guanylate cyclase 2C (heat stable endotoxin receptor)]; GUK1 [guanylate kinase 1]; GULP1 [GULP, Engulfment Adapter PTB Domain Containing 1]; GUSB [glucoronidase, beta]; GYPA [glycoporin A (MNS blood group)]; GYPB [glycoporin B (MNS blood group)]; GYPC [Glycoporin C (Gerbich Blood Group)]; GYPE [Glycoporin E (MNS Blood Group)]; GYS1 [glycogen synthase 1 (muscle)]; GZMA [Granzyme A (Granzyme 1, cytotoxic T-lymphocyte-associated serine esterase 3)]; GZMB [Granzyme B (Granzyme 2, cytotoxic T-lymphocyte-associated serine esterase 1)]; GZMK [Granzyme K (Granzyme 3; Tryptase II)]; H1F0 [H1 histone family, member 0]; H2AFX [H2A Histone Family, Member X]; HABP2 [hyaluronan binding protein 2]; HACL1 [2-hydroxyacyl-CoA lyase 1]; HADHA [Hydroxyacyl-Coenzyme A Dehydrogenase / 3-Ketoacyl-Coenzyme A Thiolase / Enoyl-Coenzyme A Hydrolase (trifunctional protein), Alpha Subunit]; HAL [histidine ammonia-lyase]; HAMP [hepcidine antimicrobial peptide]; HAPLN1 [hyaluronan and proteoglycan linking protein 1]; HAVCR1 [hepatitis A virus cell receptor 1]; HAVCR2 [hepatitis A virus cell receptor 2]; HAX1 [HCLS1 related protein X-1]; HBA1 [hemoglobin, alpha 1]; HBA2 [hemoglobin, alpha 2]; HBB [hemoglobin, beta]; HBE1 [hemoglobin, epsilon 1]; HBEGF [heparin-binding EGF-like growth factor]; HBG2 [hemoglobin, gamma G]; HCCS [Holocytochrome c Synthetase (cytochrome c reduced hematin-lyase)]; HCK [hematopoietic cell kinase]; HCRT [hypocretin (oresine) neuropeptide precursor]; HCRTR1 [hypocretin (oresine) receptor 1]; HCRTR2 [hypocretin (oresine) receptor 2]; HCST [hematopoietic cell signal transducer]; HDAC1 [histone deacetylase 1]; HDAC2 [histone deacetylase 2]; HDAC6 [histone deacetylase 6]; HDAC9 [histone deacetylase 9]; HDC [histidine decarboxylase]; HERC2 [hect domain and RLD 2]; HES1 [parent and enhancer of split 1, (Drosophila)]; HES6 [parent and enhancer of split 6 (Drosophila)]; HESX1 [HESX Homeobox 1]; HEXA [hexosaminidase A (alpha polypeptide)]; HEXB [hexosaminidase B (beta polypeptide)]; HFE [hemochromatosis]; HGF [hepatocyte growth factor (hepapoetin A; dispersion factor)]; HGS [hepatocyte growth factor-regulated tyrosine kinase substrate]; HGSNAT [heparan-alpha-glucosaminide N-acetyltransferase]; HIF1A [hypotropin-inducing factor 1, alpha subunit (basic helix-loop-helix transcription factor)]; HINFP [histone H4 transcription factor]; HINT1 [histidine triplet nucleotide binding protein 1]; HIPK2 [homeodomain interacting protein kinase 2]; HIRA [HIR histone cell cycle regulatory deletion homolog A (S.  Serbisier)]; HIST1H1B [histone cluster 1, H1b]; HIST1H3E [histone cluster 1, H3e]; HIST2H2AC [histone cluster 2, H2ac]; HIST2H3C [histone cluster 2, H3c]; HIST4H4 [histone cluster 4, H4]; HJURP [Holliday binding cognitive protein]; HK2 [hexokinase 2]; HLA-A [major histocompatibility complex, class I, A]; HLA-B [major histocompatibility complex, class I, B]; HLA-C [major histocompatibility complex, class I, C]; HLA-DMA [major histocompatibility complex, class II, DM alpha]; HLA-DMB [major histocompatibility complex, class II, DM beta]; HLA-DOA [major histocompatibility complex, class II, DO alpha]; HLA-DOB [major histocompatibility complex, class II, DO beta]; HLA-DPA1 [major histocompatibility complex, class II, DP alpha 1]; HLA-DPB1 [major histocompatibility complex, class II, DP beta 1]; HLA-DQA1 [major histocompatibility complex, class II, DQ alpha 1]; HLA-DQA2 [major histocompatibility complex, class II, DQ alpha 2]; HLA-DQB1 [major histocompatibility complex, class II, DQ beta 1]; HLA-DRA [major histocompatibility complex, class II, DR alpha]; HLA-DRB1 [major histocompatibility complex, class II, DR beta 1]; HLA-DRB3 [major histocompatibility complex, class II, DR beta 3]; HLA-DRB4 [major histocompatibility complex, class II, DR beta 4]; HLA-DRB5 [major histocompatibility complex, class II, DR beta 5]; HLA-E [major histocompatibility complex, class I, E]; HLA-F [major histocompatibility complex, class I, F]; HLA-G [major histocompatibility complex, class I, G]; HLCS [Holocarboxylase Synthetase (Biotin- (Proprionyl-Coenzyme A-carboxylase (ATP-hydrolysis)) Ligase))]; HLTF [helicase-like transcription factor]; HLX [H2. 0-like homeobox]; HMBS [hydroxymethylbiyne synthetase]; HMGA1 [high mobility group AT-hook 1]; HMGB1 [high mobility group box 1]; HMGCR [3-hydroxy-3-methylglutaryl-coenzyme A reductase]; HMOX1 [Ham Oxygenase (Decycling) 1]; HMOX2 [ham oxygenase (deccycling) 2]; HNF1A [HNF1 homeobox A]; HNF4A [hepatocyte nuclear factor 4, alpha]; HNMT [histamine N-methyltransferase]; HNRNPA1 [heteronuclear ribonucleoprotein A1]; HNRNPA2B1 [heteronuclear ribonucleoprotein A2 / B1]; HNRNPH2 [heteronuclear ribonucleoprotein H2 (H ′)]; HNRNPUL1 [heteronuclear ribonucleoprotein U-like 1]; HOXA13 [homeobox A13]; HOXA4 [homeobox A4]; HOXA9 [homeobox A9]; HOXB4 [homeobox B4]; HP [haptoglobin]; HPGDS [hematopoietic prostaglandin D synthase]; HPR [haptoglobin-associated protein]; HPRT1 [Hypoxanthine phosphoribosyltransferase 1]; HPS1 [Hermansky-Pudlak Syndrome 1]; HPS3 [Hermansky-Pudlak Syndrome 3]; HPS4 [Hermansky-Pudlak Syndrome 4]; HPSE [Heparanase]; HPX [hemofesin]; HRAS [v-Ha-ras Harvey rat sarcoma viral oncogene homologue]; HRG [histidine-rich glycoprotein]; HRH1 [histamine receptor H1]; HRH2 [histamine receptor H2]; HRH3 [histamine receptor H3]; HRH4 [histamine receptor H4]; HSD11B1 [hydroxysteroid (11-beta) dehydrogenase 1]; HSD11B2 [hydroxysteroid (11-beta) dehydrogenase 2]; HSD17B1 [hydroxysteroid (17-beta) dehydrogenase 1]; HSD17B4 [hydroxysteroid (17-beta) dehydrogenase 4]; HSF1 [heat shock transcription factor 1]; HSP90AA1 [heat shock protein 90kDa alpha (cytosol), class A member 1]; HSP90AB1 [heat shock protein 90kDa alpha (cytosol), class B member 1]; HSP90B1 [heat shock protein 90kDa beta (Grp94), member 1]; HSPA14 [heat shock 70 kDa protein 14]; HSPA1A [heat shock 70kDa protein 1A]; HSPA1B [heat shock 70kDa protein 1B]; HSPA2 [heat shock 70 kDa protein 2]; HSPA4 [heat shock 70 kDa protein 4]; HSPA5 [heat shock 70 kDa protein 5 (glucose-regulated protein, 78 kDa)]; HSPA8 [heat shock 70kDa protein 8]; HSPB1 [heat shock 27kDa protein 1]; HSPB2 [heat shock 27kDa protein 2]; HSPD1 [heat shock 60 kDa protein 1 (chaperonin)]; HSPE1 [heat shock 10kDa protein 1 (chaperonin 10)]; HSPG2 [heparan sulfate proteoglycan 2]; HTN3 [histatin 3]; HTR1A [5-hydroxytryptamine (serotonin) receptor 1A]; HTR2A [5-hydroxytryptamine (serotonin) receptor 2A]; HTR3A [5-hydroxytryptamine (serotonin) receptor 3A]; HTRA1 [HtrA serine peptidase 1]; HTT [Huntingtin]; HUS1 [HUS1 Inspection Center Homolog (S.  Pombe)]; HUWE1 [containing HECT, UBA and WWE domain 1]; HYAL1 [hyaluroglucosaminidase 1]; HYLS1 [hydrolethalus syndrome 1]; IAPP [islet amyloid polypeptide]; IBSP [integrin-binding sialoprotein]; ICAM1 [intercellular adhesion molecule 1]; ICAM2 [intercellular adhesion molecule 2]; ICAM3 [intercellular adhesion molecule 3]; ICAM4 [intercellular adhesion molecule 4 (Landsteiner-Wiener blood group)]; ICOS [inducible T-cell co-stimulator]; ICOSLG [inducible T-cell co-stimulator ligand]; ID1 [inhibitor of DNA binding 1, dominant negative helix-loop-helix protein]; ID2 [inhibitor of DNA binding 2, dominant negative helix-loop-helix protein]; IDO1 [indoleamine 2 [3-dioxygenase 1]; IDS [iduronate 2-sulfatase]; IDUA [Iduronidase, Alpha-L-]; IFI27 [interferon, alpha-induced protein 27]; IFI30 [interferon, gamma-induced protein 30]; IFITM1 [interferon induced transmembrane protein 1 (9-27)]; IFNA1 [interferon, alpha 1]; IFNA2 [interferon, alpha 2]; IFNAR1 [interferon (alpha, beta and omega) receptor 1]; IFNAR2 [interferon (alpha, beta and omega) receptor 2]; IFNB1 [interferon, beta 1, fibroblasts]; IFNG [interferon, gamma]; IFNGR1 [interferon gamma receptor 1]; IFNGR2 [interferon gamma receptor 2 (interferon gamma converter 1)]; IGF1 [insulin-like growth factor 1 (somatomedin C)]; IGF1R [insulin-like growth factor 1 receptor]; IGF2 [insulin-like growth factor 2 (somatomedin A)]; IGF2R [insulin-like growth factor 2 receptor]; IGFBP1 [insulin-like growth factor binding protein 1]; IGFBP2 [insulin-like growth factor binding protein 2, 36 kDa]; IGFBP3 [insulin-like growth factor binding protein 3]; IGFBP4 [insulin-like growth factor binding protein 4]; IGFBP5 [insulin-like growth factor binding protein 5]; IGHA1 [constant alpha 1 in immunoglobulins]; IGHE [constant epsilon in immunoglobulins]; IGHG1 [constant gamma 1 in immunoglobulin (G1m marker)]; IGHG3 [constant gamma 3 in immunoglobulins (G3m marker)]; IGHG4 [constant gamma 4 in immunoglobulins (G4m marker)]; IGHM [constant mu in immunoglobulins]; IGHMBP2 [immunoglobulin mu binding protein 2]; IGKC [immunoglobulin kappa constant]; IGKV2D-29 [immunoglobulin kappa variable 2D-29]; IGLL1 [immunoglobulin lambda-like polypeptide 1]; IGSF1 [Immune Globulin Superfamily, Member 1]; IKBKAP [Inhibitor of Kappa light polypeptide gene enhancer in B-cells, kinase complex-associated protein]; IKBKB [inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta]; IKBKE [inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase epsilon]; IKBKG [inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma]; IKZF1 [IKAROS Family Zinc Finger 1 (Ikaros)]; IKZF2 [IKAROS Family Zinc Finger 2 (Helios)]; IL10 [interleukin 10]; IL10RA [interleukin 10 receptor, alpha]; IL10RB [interleukin 10 receptor, beta]; IL11 [interleukin 11]; IL12A [interleukin 12A (natural killer cell stimulating factor 1, cytotoxic lymphocyte maturation factor 1, p35)]; IL12B [interleukin 12B (natural killer cell stimulating factor 2, cytotoxic lymphocyte maturation factor 2, p40)]; IL12RB1 [interleukin 12 receptor, beta 1]; IL12RB2 [interleukin 12 receptor, beta 2]; IL13 [interleukin 13]; IL13RA1 [interleukin 13 receptor, alpha 1]; IL13RA2 [interleukin 13 receptor, alpha 2]; IL15 [Interleukin 15]; IL15RA [interleukin 15 receptor, alpha]; IL16 [Interleukin 16 (lymphocyte chemoattractant factor)]; IL17A [interleukin 17A]; IL17F [interleukin 17F]; IL17RA [interleukin 17 receptor A]; IL17RB [interleukin 17 receptor B]; IL17RC [interleukin 17 receptor C]; IL18 [interleukin 18 (interferon-gamma-inducing factor)]; IL18BP [interleukin 18 binding protein]; IL18R1 [interleukin 18 receptor 1]; IL18RAP [interleukin 18 receptor accessory protein]; IL19 [Interleukin 19]; IL1A [Interleukin 1, Alpha]; IL1B [Interleukin 1, Beta]; IL1F9 [Interleukin 1 Family, Member 9]; IL1R1 [interleukin 1 receptor, type I]; IL1RAP [interleukin 1 receptor accessory protein]; IL1RL1 [interleukin 1 receptor-like 1]; IL1RN [interleukin 1 receptor antagonist]; IL2 [interleukin 2]; IL20 [Interleukin 20]; IL21 [interleukin 21]; IL21R [interleukin 21 receptor]; IL22 [interleukin 22]; IL23A [interleukin 23, alpha subunit p19]; IL23R [interleukin 23 receptor]; IL24 [interleukin 24]; IL25 [Interleukin 25]; IL26 [Interleukin 26]; IL27 [Interleukin 27]; IL27RA [interleukin 27 receptor, alpha]; IL29 [interleukin 29 (interferon, lambda 1)]; IL2RA [interleukin 2 receptor, alpha]; IL2RB [interleukin 2 receptor, beta]; IL2RG [interleukin 2 receptor, gamma (heavy combined immunodeficiency)]; IL3 [interleukin 3 (colony-stimulating factor, multiple)]; IL31 [interleukin 31]; IL32 [Interleukin 32]; IL33 [interleukin 33]; IL3RA [interleukin 3 receptor, alpha (low affinity)]; IL4 [interleukin 4]; IL4R [interleukin 4 receptor]; IL5 [interleukin 5 (colony-stimulating factor, neutrophils)]; IL5RA [interleukin 5 receptor, alpha]; IL6 [interleukin 6 (interferon, beta 2)]; IL6R [interleukin 6 receptor]; IL6ST [interleukin 6 signal translator (gp130, oncostatin M receptor)]; IL7 [Interleukin 7]; IL7R [interleukin 7 receptor]; IL8 [interleukin 8]; IL9 [interleukin 9]; IL9R [interleukin 9 receptor]; ILK [integrin-linked kinase]; IMP5 [endomembrane protease 5]; INCENP [Internal Centromeric Protein Antigen 135/155 kDa]; ING1 [inhibitor of growth family, member 1]; INHA [inhibin, alpha]; INHBA [Inhibin, Beta A]; INPP4A [inositol polyphosphate-4-phosphatase, type I, 107 kDa]; INPP5D [inositol polyphosphate-5-phosphatase, 145kDa]; INPP5E [Inositol polyphosphate-5-phosphatase, 72 kDa]; INPPL1 [inositol polyphosphate phosphatase-like 1]; INS [insulin]; INSL3 [insulin-like 3 (Leydig cells)]; INSR [insulin receptor]; IPO13 [Impoldin 13]; IPO7 [Impoldin 7]; IQ gap1 [ITP motif containing GTPase activating protein 1]; IRAK1 [interleukin-1 receptor-associated kinase 1]; IRAK3 [interleukin-1 receptor-associated kinase 3]; IRAK4 [interleukin-1 receptor-associated kinase 4]; IRF1 [interferon modulator 1]; IRF2 [interferon modulator 2]; IRF3 [interferon modulator 3]; IRF4 [interferon modulator 4]; IRF5 [interferon modulator 5]; IRF7 [interferon modulator 7]; IRF8 [interferon modulator 8]; IRGM [immune-related GTPase family, M]; IRS1 [insulin receptor substrate 1]; IRS2 [insulin receptor substrate 2]; IRS4 [insulin receptor substrate 4]; ISG15 [ISG15 Ubiquitin-like Modifier]; ITCH [itchy E3 ubiquitin protein ligase homologue (mouse)]; ITFG1 [integrin alpha FG-gap repeat containing 1]; ITGA1 [integrin, alpha 1]; ITGA2 [integrin, alpha 2 (CD49B, alpha 2 subunit of VLA-2 receptor)]; ITGA2B [integrin, alpha 2b (platelet glycoprotein IIb of IIb / IIIa complex, antigen CD41)]; ITGA3 [integrin, alpha 3 (antigen CD49C, alpha 3 subunit of VLA-3 receptor)]; ITGA4 [integrin, alpha 4 (antigen CD49D, alpha 4 subunit of VLA-4 receptor)]; ITGA5 [integrin, alpha 5 (fibronectin receptor, alpha polypeptide)]; ITGA6 [Integrin, Alpha 6]; ITGA8 [Integrin, Alpha 8]; ITGAE [integrin, alpha E (antigen CD103, human mucosal lymphocyte antigen 1; alpha polypeptide)]; ITGAL [integrin, alpha L (antigen CD11A (p180), lymphocyte function-associated antigen 1; alpha polypeptide)]; ITGAM [integrin, alpha M (complement component 3 receptor 3 subunit)]; ITGAV [integrin, alpha V (vitronectin receptor, alpha polypeptide, antigen CD51)]; ITGAX [integrin, alpha X (complement component 3 receptor 4 subunit)]; ITGB1 [integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12)]; ITGB2 [integrin, beta 2 (complement component 3 receptor 3 and 4 subunits)]; ITGB3 [integrin, beta 3 (platelet glycoprotein IIIa, antigen CD61)]; ITGB3BP [integrin beta 3 binding protein (beta3-endodonxin)]; ITGB4 [Integrin, Beta 4]; ITGB6 [Integrin, Beta 6]; ITGB7 [Integrin, Beta 7]; ITIH4 [inter-alpha (globulin) inhibitor H4 (plasma kallikrein-sensitive glycoprotein)]; ITK [IL2-induced T-cell kinase]; ITLN1 [Inlectectin 1 (galactofuranose bond)]; ITLN2 [Intellectin 2]; ITPA [inosine triphosphatase (nucleoside triphosphate pyrophosphatase)]; ITPR1 [Inositol 1,4,5-triphosphate receptor, type 1]; ITPR3 [Inositol 1,4,5-triphosphate receptor, type 3]; IVD [Osovaleryl Coenzyme A Dehydrogenase]; IVL [inovolukrin]; IVNS1ABP [Influenza Virus NS1A Binding Protein]; JAG1 [jagged 1 (Alagille syndrome)]; JAK1 [Janus Kinase 1]; JAK2 [Janus Kinase 2]; JAK3 [Janus Kinase 3]; JAKMIP1 [janus kinase and microtubule interacting protein 1]; JMJD6 [containing jumonji domain 6]; JPH4 [junctophilin 4]; JRKL [jerky homologue-like (mouse)]; JUN [jun oncogene]; JUND [jun D Proto-tumor Gene]; JUP [binding flacoglobin]; KARS [lysyl-tRNA synthetase]; KAT5 [K (lysine) acetyltransferase 5]; KCNA2 (potassium potential-gated channel, shaker-related subfamily, member 2); KCNA5 [potassium potential-gated channel, shaker-associated subfamily, member 5]; KCND1 [potassium potential-gated channel, Shal-associated subfamily, member 1]; KCNH2 [potassium potential-gated channel, subfamily H (eag-related), member 2]; KCNIP4 [Kv channel interacting protein 4]; KCNMA1 [potassium large conductive calcium-activated channel, subfamily M, alpha member 1]; KCNMB1 [potassium large conductivity calcium-activated channel, subfamily M, beta member 1]; KCNN3 [potassium medium / small conducting calcium-activated channel, subfamily N, member 3]; KCNS3 [potassium potential-gating channel, delayed-rectifier, subfamily S, member 3]; KDR [kinase injector domain receptor (type III receptor tyrosine kinase)]; KHDRBS1 [KH domain containing, RNA binding, signal transduction related 1]; KHDRBS3 [KH domain containing, RNA binding, signal transduction related 3]; KIAA0101 [KIAA0101]; KIF16B [Kinesin Family Member 16B]; KIF20B [Kinesin Family Member 20B]; KIF21B [Kinesin Family Member 21B]; KIF22 [Kinesin Family Member 22]; KIF2B [Kinesin Family Member 2B]; KIF2C [Kinesin Family Member 2C]; KIR2DL1 [killer cell immunoglobulin-like receptor, two domains, long cytoplasmic tail, 1]; KIR2DL2 [killer cell immunoglobulin-like receptor, two domains, long cytoplasmic tail, 2]; KIR2DL3 [killer cell immunoglobulin-like receptor, two domains, long cytoplasmic tail, 3]; KIR2DL5A [killer cell immunoglobulin-like receptor, two domains, long cytoplasmic tail, 5A]; KIR2DS1 [killer cell immunoglobulin-like receptor, two domains, short cytoplasmic tail, 1]; KIR2DS2 [killer cell immunoglobulin-like receptor, two domains, short cytoplasmic tail, 2]; KIR2DS5 [killer cell immunoglobulin-like receptor, two domains, short cytoplasmic tail, 5]; KIR3DL1 [killer cell immunoglobulin-like receptor, three domains, long cytoplasmic tail, 1]; KIR3DS1 [killer cell immunoglobulin-like receptor, three domains, short cytoplasmic tail, 1]; KISS1 [KiSS-1 Transition Inhibitor]; KISS1R [KISS1 Receptor]; KIT [v-kit Hardy-Zuckerman 4 Cat and Sarcoma Viral Oncogene Homologs]; KITLG [KIT Ligand]; KLF2 [Kruppel-like factor 2 (lung)]; KLF4 [Kruppel-like factor 4 (intestinal)]; KLK1 [Kallikrein 1]; KLK11 [Kallikrein-Related Peptidase 11]; KLK3 [Kallikrein-Related Peptidase 3]; KLKB1 [Kallikrein B, Plasma (Fletcher Factor) 1]; KLRB1 [killer cell lectin-like receptor subfamily B, member 1]; KLRC1 [killer cell lectin-like receptor subfamily C, member 1]; KLRD1 [killer cell lectin-like receptor subfamily D, member 1]; KLRK1 [killer cell lectin-like receptor subfamily K, member 1]; KNG1 [kinnogen 1]; KPNA1 [karyopherin alpha 1 (impultin alpha 5)]; KPNA2 [carioferin alpha 2 (RAG cohort 1, impartin alpha 1)]; KPNB1 [carioferin (impultin) beta 1]; KRAS [v-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue]; KRT1 [Keratin 1]; KRT10 [Keratin 10]; KRT13 [Keratin 13]; KRT14 [Keratin 14]; KRT16 [Keratin 16]; KRT18 [Keratin 18]; KRT19 [Keratin 19]; KRT20 [Keratin 20]; KRT5 [Keratin 5]; KRT7 [Keratin 7]; KRT8 [Keratin 8]; KRT9 [Keratin 9]; KRTAP19-3 [Keratin Related Protein 19-3]; KRTAP2-1, keratin related protein 2-1]; L1CAM [L1 cell adhesion molecule]; LACTB [lactamase, beta]; LAG3 [lymphocyte-activating gene 3]; LALBA [lactalbumin, alpha-]; LAMA1 [laminin, alpha 1]; LAMA2 [laminin, alpha 2]; LAMA3 [laminin, alpha 3]; LAMA4 [laminin, alpha 4]; LAMB1 [laminin, beta 1]; LAMB2 [laminin, beta 2 (laminin S)]; LAMB3 [laminin, beta 3]; LAMC1 [laminin, gamma 1 (formerly LAMB2)]; LAMC2 [laminin, gamma 2]; LAMP1 [lysosomal-associated membrane protein 1]; LAMP2 [lysosomal-associated membrane protein 2]; LAMP3 [lysosomal-associated membrane protein 3]; LAP3 [Leucine Aminopeptidase 3]; LAPTM4A [lysosomal protein transmembrane 4 alpha]; LAT [linker for activation of T cells]; LBP [lipopolysaccharide binding protein]; LBR [lamin B receptor]; LBXCOR1 [Lbxcor1 homologues (mouse)]; LCAT [lecithin-cholesterol acyltransferase]; LCK [lymphocyte-specific protein tyrosine kinase]; LCN1 [lipocalin 1 (tear prealbumin)]; LCN2 [lipocalin 2]; LCP1 [lymphocyte cytosolic protein 1 (L-Plastin)]; LCT [lactase]; LDLR [low density lipoprotein receptor]; LDLRAP1 [low density lipoprotein receptor adapter protein 1]; LECT2 [leukocyte cell-induced chemotaxin 2]; LELP1 [late keratinocyte outer layer-like proline-rich 1]; LEMD3 [LEM domain containing 3]; LEP [leptin]; LEPR [leptin receptor]; LGALS1 [lectin, galactosid-binding, soluble, 1]; LGALS3 [lectin, galactosid-binding, soluble, 3]; LGALS3BP [lectin, galactosid-binding, soluble, three binding protein]; LGALS4 [lectin, galactosid-binding, soluble, 4]; LGALS9 [lectin, galactosid-binding, soluble, 9]; LGALS9B [Lectin, galactosid-binding, soluble, 9B]; LGR4 [Leucine-rich repeat-containing G protein-linked receptor 4]; LHCGR [luteinizing hormone / gonadal gonadotropin receptor]; LIF [leukemia inhibitory factor (cholinergic differentiation factor)]; LIFR [leukemia inhibitory factor receptor alpha]; LIG1 [ligase I, DNA, ATP-dependent]; LIG3 [ligase III, DNA, ATP-dependent]; LIG4 [Legase IV, DNA, ATP-dependent]; LILRA3 [leukocyte immunoglobulin-like receptor, subfamily A (without TM domain), member 3]; LILRB4 [leukocyte immunoglobulin-like receptor, subfamily B (with TM and ITIM domains), member 4]; LIMS1 [LIM and aging cell antigen-like domain 1]; LIPA [lipase A, lysosomal acid, cholesterol esterase]; LIPC [lipase, liver]; LIPE [lipase, hormone-sensitive]; LIPG [lipase, endothelial]; LMAN1 [lectin, mannose-binding, 1]; LMLN (leishmanolysin-like (metal peptidase M8 family)); LMNA [Lamine A / C]; LMNB1 [Lamine B1]; LMNB2 [Lamine B2]; LOC646627 [phospholipase inhibitor]; LOX [lysyl oxidase]; LOXHD1 [lipoxygenase homology domain 1]; LOXL1 [lysyl oxidase-like 1]; LPA [Lipoprotein, Lp (a)]; LPAR3 [lysophosphatidic acid receptor 3]; LPCAT2 [lysophosphatidylcholine acyltransferase 2]; LPL [Lipoprotein Lipase]; LPO [lactoperoxidase]; LPP [preferred potential partner containing LIM domain in lipoma]; LRBA (containing LPS-responsive vesicle trafficking, beach and anchor); LRP1 [low density lipoprotein receptor-associated protein 1]; LRP6 [low density lipoprotein receptor-associated protein 6]; LRPAP1 [low density lipoprotein receptor-related protein related protein 1]; LRRC32 [32 containing leucine rich repeat]; LRRC37B [37B containing leucine rich repeat]; LRRC8A [leucine rich repeat containing 8 family, member A]; LRRK2 [Leucine-rich repeat kinase 2]; LRTOMT [containing leucine rich transmembrane and 0-methyltransferase domain]; LSM1 [LSM1 homolog, U6 small nuclear RNA involved (S.  Serbisier)]; LSM2 [LSM2 homolog, U6 small nuclear RNA involved (S.  Serbisier)]; LSP1 [lymphocyte-specific protein 1]; LTA [Limpotoxin Alpha (TNF Superfamily, Member 1)]; LTA4H [Lucotrienne A4 Hydrolase]; LTB [Limpotoxin Beta (TNF Superfamily, Member 3)]; LTB4R [leukotriene B4 receptor]; LTB4R2 [Lucotriene B4 Receptor 2]; LTBR [lymphotoxin beta receptor (TNFR superfamily, member 3)]; LTC4S [Lukotriene C4 Synthetase]; LTF [lactotransferrin]; LY86 [lymphocyte antigen 86]; LY9 [lymphocyte antigen 9]; LYN [v-yes-1 Yamaguchi Sarcoma Viral Related Oncogene Homolog]; LYRM4 [4 containing LYR motif]; LYST [lysosomal trafficking modulator]; LYZ [lysozyme (kidney amyloidosis)]; LYZL6 [Lysozyme-like 6]; LZTR1 [Leucine-zipper-like transcription modulator 1]; M6PR [mannose-6-phosphate receptor (cationic dependent)]; MADCAM1 [mucosal vascular addressin cell adhesion molecule 1]; MAF [v-maf myofascial fibrosarcoma oncogene homologue (bird)]; MAG [myelin related glycoproteins]; MAN2A1 [mannosidase, alpha, class 2A, member 1]; MAN2B1 [mannosidase, alpha, class 2B, member 1]; MANBA [mannosidase, beta A, lysosomal]; MANF [medium brain astrocyte-induced neurotrophic factor]; MAOB [Monoamine Oxidase B]; MAP2 [microtubule-associated protein 2]; MAP2K1 [mitogen-activated protein kinase kinase 1]; MAP2K2 [mitogen-activated protein kinase kinase 2]; MAP2K3 [mitogen-activated protein kinase kinase 3]; MAP2K4 [mitogen-activated protein kinase kinase 4]; MAP3K1 [mitogen-activated protein kinase kinase kinase 1]; MAP3K11 [mitogen-activated protein kinase kinase kinase 11]; MAP3K14 [mitogen-activated protein kinase kinase kinase 14]; MAP3K5 [mitogen-activated protein kinase kinase kinase 5]; MAP3K7 [mitogen-activated protein kinase kinase kinase 7]; MAP3K9 [mitogen-activated protein kinase kinase kinase 9]; MAPK1 [mitogen-activated protein kinase 1]; MAPK10 [mitogen-activated protein kinase 10]; MAPK11 [mitogen-activated protein kinase 11]; MAPK12 [mitogen-activated protein kinase 12]; MAPK13 [mitogen-activated protein kinase 13]; MAPK14 [mitogen-activated protein kinase 14]; MAPK3 [mitogen-activated protein kinase 3]; MAPK8 [mitogen-activated protein kinase 8]; MAPK9 [mitogen-activated protein kinase 9]; MAPKAP1 [mitogen-activated protein kinase related protein 1]; MAPKAPK2 [mitogen-activated protein kinase-activated protein kinase 2]; MAPKAPK5 [mitogen-activated protein kinase-activated protein kinase 5]; MAPT [microtubule-associated protein tau]; MARCKS [myristoylated alanine-rich protein kinase C substrate]; MASP2 [met-binding lectin serine peptidase 2]; MATN1 [Matrilin 1, Cartilage Matrix Protein]; MAVS [mitochondrial antiviral signaling protein]; MB [myoglobin]; MBD2 [methyl-CpG binding domain protein 2]; MBL2 [mannose-binding lectin (protein C) 2, soluble (opsonine deficiency)]; MBP [Myelin Basic Protein]; MBTPS2 [membrane-bound transcription factor peptidase, position 2]; MC2R [melanocortin 2 receptor (adrenocorticotropic hormone)]; MC3R [melanocortin 3 receptor]; MC4R [melanocortin 4 receptor]; MCCC2 [methylcrotonyl-coenzyme A carboxylase 2 (beta)]; MCHR1 [melanin-concentrating hormone receptor 1]; MCL1 [myeloid cell leukemia sequence 1 (BCL2-related)]; MCM2 [minichromosome maintenance complex component 2]; MCM4 [minichromosome maintenance complex component 4]; MCOLN1 [mucurinpin 1]; MCPH1 [Microcephalin 1]; MDC1 [mediator 1 of the DNA-damage check station]; MDH2 [maleate dehydrogenase 2, NAD (mitochondria)]; MDM2 [Mdm2 p53 binding protein homologue (mouse)]; ME2 [malic acid enzyme 2, NAD (+)-dependent, mitochondria]; MECOM [MDS1 and EVI1 Complex Loci]; MED1 [mediator complex subunit 1]; MED12 [mediator complex subunit 12]; MED15 [mediator complex subunit 15]; MED28 [mediator complex subunit 28]; MEFV [Mediterranean Fever]; MEN1 [multiple endocrine neoplasia I]; MEPE [Matrix Extracellular Glycoprotein]; MERTK [c-mer proto-oncogene tyrosine kinase]; MESP2 [mesoderm posterior 2 homologue (mouse)]; MET [met proto-tumor gene (hepatocyte growth factor receptor)]; MGAM [maltase-glucoamylase (alpha-glucosidase)]; MGAT1 [mannosyl (alpha-1,3-)-glycoprotein beta-1,2-N-acetylglucosaminyltransferase]; MGAT2 [mannosyl (alpha-1,6-)-glycoprotein beta-1,2-N-acetylglucosaminyltransferase]; MGLL [monoglyceride lipase]; MGMT [O-6-Methylguanine-DNA Methyltransferase]; MGST2 [Microsomeglutathione S-Transferase 2]; MICA [MHC Class I Polypeptide-Related Sequence A]; MICB [MHC Class I Polypeptide-Related Sequence B]; MIF [macrophage migration inhibitory factor (glycosylation-inhibiting factor)]; MKI67 [antigen identified by monoclonal antibody Ki-67]; MKS1 [Meckel syndrome, type 1]; MLH1 [mutL homolog 1, colon cancer, non-tumor type 2 (E. coli)]; MLL (myeloid / lymphoid or mixed-line leukemia (trithorax homologue, Drosophila)]; MLLT4 [myeloid / lymphoid or mixed-line leukemia (Tritrax homologue, Drosophila); Displaced to 4]; MLN [motilin]; MLXIPL [MLX interacting protein-like]; MMAA [methylmalonic acidemia (cobalamine defect) cblA type]; MMAB [methylmalonic acidemia (cobalamine defect) cblB type]; MMACHC [methylmalonic acidemia (cobalamine deficiency) cblC type, with homocysteineuria]; MME [membrane metal-endopeptidase]; MMP1 [matrix metalpeptidase 1 (intercellular collagenase)]; MMP10 [matrix metalpeptidase 10 (stromericin 2)]; MMP12 [matrix metalpeptidase 12 (macrophage elastase)]; MMP13 [matrix metalpeptidase 13 (collagenase 3)]; MMP14 [matrix metalpeptidase 14 (membrane-inserted)]; MMP15 [matrix metalpeptidase 15 (membrane-inserted)]; MMP17 [matrix metalpeptidase 17 (membrane-inserted)]; MMP2 [matrix metalpeptidase 2 (gelatinase A, 72 kDa gelatinase, 72 kDa type IV collagenase)]; MMP20 [matrix metalpeptidase 20]; MMP21 [matrix metalpeptidase 21]; MMP28 [matrix metalpeptidase 28]; MMP3 [matrix metalpeptidase 3 (stromericin 1, progelatinase)]; MMP7 [Matrix Metalpeptidase 7 (Matrilysine, Uterine)]; MMP8 [matrix metalpeptidase 8 (neutrophil collagenase)]; MMP9 [matrix metalpeptidase 9 (gelatinase B, 92 kDa gelatinase, 92 kDa type IV collagenase)]; MMRN1 [multimerin 1]; MNAT1 (menage a trois homologue 1, cyclin H aggregation factor (African claw frog)]; MOG [myelin oligodendrocyte glycoprotein]; MOGS [mannosyl-oligosaccharide glucosidase]; MPG [N-methylpurine-DNA glycosylase]; MPL [myeloproliferative leukemia virus oncogene]; MPO [myeloperoxidase]; MPZ [myelin protein zero]; MR1 [major histocompatibility complex, class I-related]; MRC1 [mannose receptor, C type 1]; MRC2 [mannose receptor, C type 2]; MRE11A [MRE11 mitogenic recombination 11 homologue A (S.  Serbisier)]; MRGPRX1 [MAS-associated GPR, member X1]; MRPL28 [mitochondrial ribosomal protein L28]; MRPL40 [mitochondrial ribosomal protein L40]; MRPS16 [mitochondrial ribosomal protein S16]; MRPS22 [mitochondrial ribosomal protein S22]; MS4A1 [membrane-spanning 4-domain, subfamily A, member 1]; MS4A2 [membrane-range 4-domain, subfamily A, member 2 (Fc fragment of IgE, high affinity I, receptor; beta polypeptide)]; MS4A3 [membrane-range 4-domain, subfamily A, member 3 (hematopoietic cell-specific)]; MSH2 [mutS homolog 2, colon cancer, non-tumor type 1 (E. coli)]; MSH5 [mutS homologue 5 (E. coli)]; MSH6 [mutS homologue 6 (E. coli)]; MSLN [Mesothelin]; MSN [Moesin]; MSR1 [Macrophage Elimination Receptor 1]; MST1 [macrophage stimulation 1 (hepatocyte growth factor-like)]; MST1R [macrophage stimulation 1 receptor (c-met-associated tyrosine kinase)]; MSTN [myostatin]; MSX2 [msh homeobox 2]; MT2A [metallothionene 2A]; MTCH2 [Mitochondrial Carrier Homolog 2 (C. Elegans)]; MT-CO2 [mitochondrial encoded cytochrome c oxidase II]; MTCP1 [mature T-cell proliferation 1]; MT-CYB [mitochondrially encoded cytochrome b]; MTHFD1 [methylenetetrahydrofolate dehydrogenase (NADP + dependent) 1, methenyltetrahydrofolate cyclohydrolase, formyltetrahydrofolate synthetase]; MTHFR [5 [10-methylenetetrahydrofolate reductase (NADPH)]; MTMR14 [myotubulin related protein 14]; MTMR2 [myotubulin related protein 2]; MT-ND1 [mitochondrial encoded NADH dehydrogenase 1]; MT-ND2 [mitochondrial encoded NADH dehydrogenase 2]; MTOR [mechanical target of rapamycin (serine / threonine kinase)]; MTR [5-methyltetrahydrofolate-homocysteine methyltransferase]; MTRR [5-methyltetrahydrofolate-homocysteine methyltransferase reductase]; MTTP [microsome triglyceride delivery protein]; MTX1 [Metacin 1]; MUC1 [mucin 1, cell surface related]; MUC12 [mucin 12, cell surface related]; MUC16 [mucin 16, cell surface related]; MUC19 [mucin 19, oligomer]; MUC2 [mucin 2, oligomeric mucus / gel-forming]; MUC3A [mucin 3A, cell surface related]; MUC3B [mucin 3B, cell surface related]; MUC4 [mucin 4, cell surface related]; MUC5AC [mucin 5AC, oligomeric mucus / gel-forming]; MUC5B [mucin 5B, oligomeric mucus / gel-forming]; MUC6 [mucin 6, oligomeric mucus / gel-forming]; MUC7 [mucin 7, secreted]; MUS81 [MUS81 endonuclease homologue (S.  Serbisier)]; MUSK [muscle, skeletal, receptor tyrosine kinase]; MUT [Methylmalonyl Coenzyme A Mutase]; MVK [Mevalonate Kinase]; MVP [main vault protein]; MX1 [myxovirus (influenza virus) resistant 1, interferon-inducing protein p78 (mouse)]; MYB [v-myb myeloblastoma viral oncogene homologue (bird)]; MYBPH [myosin binding protein H]; MYC [v-myc myeloma myeloid viral oncogene homologue (bird)]; MYCN [v-myc myeloma myeloma viral related oncogene, neuroblastoma induced (bird)]; MYD88 [myeloid differentiation primary response gene (88)]; MYH1 [myosin, heavy chain 1, skeletal muscle, adult]; MYH10 [myosin, heavy chain 10, non-muscle]; MYH11 [myosin, heavy chain 11, smooth muscle]; MYH14 [myosin, heavy chain 14, non-muscle]; MYH2 [myosin, heavy chain 2, skeletal muscle, adult]; MYH3 [myosin, heavy chain 3, skeletal muscle, embryo]; MYH6 [myosin, heavy chain 6, cardiac muscle, alpha]; MYH7 [myosin, heavy chain 7, heart muscle, beta]; MYH8 [myosin, heavy chain 8, skeletal muscle, perinatal]; MYH9 [myosin, heavy chain 9, non-muscle]; MYL2 [myosin, light chain 2, regulatory, heart, slow]; MYL3 [myosin, light chain 3, alkali; Ventricle, skeletal, slow]; MYL7 [myosin, light chain 7, regulatory]; MYL9 [myosin, light chain 9, modulated]; MYLK [myosin light chain kinase]; MYO15A [myosin XVA]; MYO1A [myosin IA]; MYO1F [myosin IF]; MYO3A [myosin IIIA]; MYO5A [myosin VA (heavy chain 12, myosin)]; MYO6 [myosin VI]; MYO7A [myosin VIIA]; MYO9B [myosin IXB]; MYOC [myocillin, fine network-induced glucocorticoid reaction]; MYOD1 [fungal differentiation 1]; MYOM2 [myomecin (M-protein) 2, 165 kDa]; MYST1 [MYST histone acetyltransferase 1]; MYST2 [MYST histone acetyltransferase 2]; MYST3 [MYST histone acetyltransferase (monocytic leukemia) 3]; MYST4 [MYST histone acetyltransferase (monocytic leukemia) 4]; NAGA [N-acetylgalactosaminidase, alpha-]; NAGLU [N-acetylglucosaminidases, alpha-]; NAMPT [nicotinamide phosphoribosyltransferase]; NANOG [Nanog homeobox]; NANO1 [nanos homologue 1 (Drosophila)]; NAPA [N-ethylmaleimide-sensitive factor adhesion protein, alpha]; NAT1 [N-acetyltransferase 1 (arylamine N-acetyltransferase)]; NAT2 [N-acetyltransferase 2 (arylamine N-acetyltransferase)]; NAT9 [N-acetyltransferase 9 (GCN5-related, putative)]; NBEA [Nurovichin]; NBN [nibrine]; NCAM1 [nerve cell adhesion molecule 1]; NCF1 [neutrophil cytosol factor 1]; NCF2 [neutrophil cytosolic factor 2]; NCF4 [neutrophil cytosolic factor 4, 40 kDa]; NCK1 [NCK Adapter Protein 1]; NCL [nucreoline]; NCOA1 [nuclear receptor coactivator 1]; NCOA2 [nuclear receptor coactivator 2]; NCOR1 [nuclear receptor co-inhibitor 1]; NCR3 [natural cytotoxic trigger receptor 3]; NDUFA13 [NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 13]; NDUFAB1 [NADH dehydrogenase (ubiquinone) 1, alpha / beta subcomplex, 1, 8 kDa]; NDUFAF2 [NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, aggregation factor 2]; NEDD4 [neural precursor cell expressed, developmentally down-regulated 4]; NEFL [nerve, light polypeptide]; NEFM [neurons, medium polypeptide]; NEGR1 [neuron growth regulator 1]; NEK6 [NIMA (not in mitosis gene a) -associated kinase 6]; NELF [nose embryo LHRH factor]; NELL1 [NEL-like 1 (chicken)]; NES [Nestin]; NEU1 [sialidase 1 (lysosomal sialidase)]; NEUROD1 [neurogenic differentiation 1]; NF1 [Nurofibromine 1]; NF2 [Nurofibromine 2 (merlin)]; NFAT5 [nuclear factor, tension-response of activated T-cells 5]; NFATC1 [nuclear factor, cytoplasm, calcineurin-dependent 1 of activated T-cells]; NFATC2 [nuclear factor, cytoplasm, calcineurin-dependent 2 of activated T-cells]; NFATC4 [nuclear factor, cytoplasm, calcineurin-dependent 4 of activated T-cells]; NFE2L2 [nuclear factor (erythrocyte-derived 2) -like 2]; NFKB1 [nuclear factor 1 of light polypeptide gene enhancer kappa in B-cells]; NFKB2 [nuclear factor 2 of light polypeptide gene enhancer kappa in B-cells (p49 / p100)]; NFKBIA [nuclear factor inhibitor of alpha kappa light polypeptide gene enhancer in B-cells, alpha]; NFKBIB [nuclear factor inhibitor of beta light polypeptide gene enhancer in B-cells, beta]; NFKBIL1 [nuclear factor inhibitor-like 1 of kappa light polypeptide gene enhancer in B-cells]; NFU1 [NFU1 iron-sulfur cluster scaffold homolog (S.  Serbisier)]; NGF [nerve growth factor (beta polypeptide)]; NGFR [nerve growth factor receptor (TNFR superfamily, member 16)]; NHEJ1 [non-homologous end-binding factor 1]; NID1 [Nidogen 1]; NKAP [NFkB activating protein]; NKX2-1, NK2 homeobox 1]; NKX2-3 [associated NK2 transcription factor, left 3 (Drosophila)]; NLRP3 [NLR family, pyrine domain containing 3]; NMB [neuromedin B]; NME1 [non-metastatic cells 1, expressed protein (NM23A)]; NME2 [non-metastatic cells 2, expressed protein (NM23B)]; NMU [neuromedin U]; NNAT [neuronatin]; NOD1 [nucleotide-binding oligomerization domain containing 1]; NOD2 [nucleotide-binding oligomerization domain containing 2]; NONO [containing non-POU domain, octamer-linked]; NOS1 [nitric oxide synthase 1 (neuron)]; NOS2 [nitric oxide synthase 2, inducible]; NOS3 [nitric oxide synthase 3 (endothelial cell)]; NOTCH1 [Notch homologue 1, translocation-related (Drosophila)]; NOTCH2 [Notch homologue 2 (Drosophila)]; NOTCH3 [Notch homologue 3 (Drosophila)]; NOTCH4 [Notch homologue 4 (Drosophila)]; NOX1 [NADPH oxidase 1]; NOX3 [NADPH oxidase 3]; NOX4 [NADPH oxidase 4]; NOX5 [NADPH oxidase, EF-hand calcium binding domain 5]; NPAT [nuclear protein, ataxia-capillary dilatation]; NPC1 [Niemann-Pick Disease, Type C1]; NPC1L1 [NPC1 (Niemann-Pick Disease, Type C1, Gene) -Like 1]; NPC2 [Niemann-Pick Disease, Type C2]; NPHP1 [Cyclenephritis 1 (Adolescent)]; NPHS1 [nephropathy 1, congenital, Finnish type (nephiline)]; NPHS2 [nephropathy 2, idiopathic, steroid-resistant (grapevine)]; NPLOC4 [nuclear protein localization 4 homologue (S.  Serbisier)]; NPM1 [nucleophosmin (phosphorus protein B23, numatrine of phosphorus)]; NPPA [sodium release peptide precursor A]; NPPB [Sodium Release Peptide Precursor B]; NPPC [Sodium Release Peptide Precursor C]; NPR1 (sodium release peptide receptor A / guanylate cyclase A (atrionatriuretic peptide receptor A)); NPR3 [sodium release peptide receptor C / guanylate cyclase C (atrial fibrillation sodium release peptide receptor C)]; NPS [neuropeptide S]; NPSR1 [neuropeptide S receptor 1]; NPY [neural peptide Y]; NPY2R [neuropeptide Y receptor Y2]; NQO1 [NAD (P) H Dehydrogenase, Quinone 1]; NR0B1 [nuclear receptor subfamily 0, group B, member 1]; NR1H2 [nuclear receptor subfamily 1, group H, member 2]; NR1H3 [nuclear receptor subfamily 1, group H, member 3]; NR1H4 [nuclear receptor subfamily 1, group H, member 4]; NR1I2 [nuclear receptor subfamily 1, group I, member 2]; NR1I3 [nuclear receptor subfamily 1, group I, member 3]; NR2F2 [nuclear receptor subfamily 2, group F, member 2]; NR3C1 [nuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptor)]; NR3C2 [nuclear receptor subfamily 3, group C, member 2]; NR4A1 [nuclear receptor subfamily 4, group A, member 1]; NR4A3 [nuclear receptor subfamily 4, group A, member 3]; NR5A1 [nuclear receptor subfamily 5, group A, member 1]; NRF1 [nuclear respiratory factor 1]; NRG1 [neuregulin 1]; NRIP1 [nuclear receptor interacting protein 1]; NRIP2 [nuclear receptor interacting protein 2]; NRP1 [Nurophyllin 1]; NSD1 [nuclear receptor binding SET domain protein 1]; NSDHL [NAD (P) dependent steroid dehydrogenase-like]; NSF [N-ethylmaleimide-sensitive factor]; NT5E [5'-nucleotidase, ecto (CD73)]; NTAN1 [N-terminal asparagine amidase]; NTF3 [neutropin 3]; NTF4 [Nurotropin 4]; NTN1 [Netrin 1]; NTRK1 [neotrophic tyrosine kinase, receptor, type 1]; NTRK2 [neotrophic tyrosine kinase, receptor, type 2]; NTRK3 [neotrophic tyrosine kinase, receptor, type 3]; NTS [Nurotensin]; NUCB2 [nucleobindine 2]; NUDT1 (nudix (nucleoside diphosphate linked moiety X) -type motif 1]; NUDT2 [nudics (nucleoside diphosphate linked moiety X) -type motif 2]; NUDT6 [nudics (nucleoside diphosphate linked moiety X) -type motif 6]; NUFIP2 [nuclear fragile X mental retardation protein interacting protein 2]; NUP98 [nucleoporin 98kDa]; NXF1 [nuclear RNA export factor 1]; OCA2 [systemic albinism II]; OCLN [Occludine]; ODC1 [ornithine decarboxylase 1]; OFD1 [Oral-Facial-Amputation Syndrome 1]; OGDH [oxoglutarate (alpha-ketoglutarate) dehydrogenase (ziamide)]; OGG1 [8-oxoguanine DNA glycosase]; OGT [O-linked N-acetylglucosamine (GlcNAc) transferase (UDP-N-acetylglucosamine: polypeptide-N-acetylglucosaminyl transferase)]; OLR1 [oxidized low density lipoprotein (lectin-like) receptor 1]; OMP [olfactory marker protein]; ONECUT2 [One Cut Homeobox 2]; OPN3 [opsin 3]; OPRK1 [opium receptor, kappa 1]; OPRM1 [opium receptor, mu 1]; OPTN [optinulin]; OR2B11 [olfactory receptors, family 2, subfamily B, member 11]; ORMDL3 [ORM1-like 3 (S.  Serbisier)]; OSBP [oxysterol binding protein]; OSGIN2 [oxidative stress induced growth inhibitory family member 2]; OSM [oncostatin M]; OTC [ornithine carbamoyltransferase]; OTOP2 [autopetrin 2]; OTOP3 [autopetrin 3]; OTUD1 [containing OTU domain 1]; OXA1L [oxidase (cytochrome c) set 1-like]; OXER1 [oxoecosanoid (OXE) receptor 1]; OXT [oxytocin, prepropeptide]; OXTR [oxytocin receptor]; P2RX7 [purinergic receptor P2X, ligand-gated ion channel, 7]; P2RY1 [purinergic receptor P2Y, G-protein linked, 1]; P2RY12 [purinergic receptor P2Y, G-protein linked, 12]; P2RY14 [purinergic receptor P2Y, G-protein linked, 14]; P2RY2 [purinergic receptor P2Y, G-protein linked, 2]; P4HA2 [Prolyl 4-hydroxylase, Alpha Polypeptide II]; P4HB [prolyl 4-hydroxylase, beta polypeptide]; P4HTM [prolyl 4-hydroxylase, transmembrane (cytoplasmic network)]; PABPC1 [poly (A) binding protein, cytoplasm 1]; PACSIN3 [nerve protein kinase C and casein kinase substrate 3]; PAEP [progestagen-associated endometrial protein]; PAFAH1B1 [platelet-activating factor acetyl hydrolase 1b, regulatory subunit 1 (45 kDa)]; PAH [phenylalanine hydroxylase]; PAK1 [p21 protein (Cdc42 / Rac) -activated kinase 1]; PAK2 [p21 protein (Cdc42 / Rac) -activated kinase 2]; PAK3 [p21 protein (Cdc42 / Rac) -activated kinase 3]; PAM [peptidylglycine alpha-amidating monooxygenase]; PAPPA [pregnancy-associated plasma protein A, paparicin 1]; PARG [poly (ADP-ribose) glycosylase]; PARK2 [Parkinson's disease (autosome recessive, adolescent) 2, parkin]; PARP1 [poly (ADP-ribose) polymerase 1]; PAWR [PRKC, Apoptosis, WT1, Modulators]; PAX2 [Paired Box 2]; PAX3 [Paired Box 3]; PAX5 [Paired Box 5]; PAX6 [Paired Box 6]; PAXIP1 [PAX interacting (including transcription-activation domain) protein 1]; PC [pyruvate carboxylase]; PCCA [propionyl coenzyme A carboxylase, alpha polypeptide]; PCCB [propionyl coenzyme A carboxylase, beta polypeptide]; PCDH1 [protocadherin 1]; PCK1 [phosphoenolpyruvate carboxykinase 1 (soluble)]; PCM1 (pericentriolar material 1); PCNA [proliferating cell nuclear antigen]; PCNT [Percentrin]; PCSK1 [proprotein convertase subtilisin / kesin type 1]; PCSK6 [proprotein convertase subtilisin / kesin type 6]; PCSK7 [proprotein convertase subtilisin / kesin type 7]; PCYT1A [Phosphate Citidyltransferase 1, Choline, Alpha]; PCYT2 [Phosphate Cytylyltransferase 2, Ethanolamine]; PDCD1 [Scheduled Cell Death 1]; PDCD1LG2 [Scheduled Cell Death 1 Ligand 2]; PDCD6 [Scheduled Cell Death 6]; PDE3B [phosphodiesterase 3B, cGMP-inhibited]; PDE4A (phosphodiesterase 4A, cAMP-specific (phosphodiesterase E2 dunce homologue, Drosophila)]; PDE4B [phosphodiesterase 4B, cAMP-specific (phosphodiesterase E4 Higgs homologue, Drosophila)]; PDE4D [phosphodiesterase 4D, cAMP-specific (phosphodiesterase E3 Higgs homolog, Drosophila)]; PDE7A [phosphodiesterase 7A]; PDGFA [platelet-derived growth factor alpha polypeptide]; PDGFB [platelet-induced growth factor beta polypeptides (monkey sarcoma viral (v-sis) oncogene homologues)]; PDGFRA [platelet-induced growth factor receptor, alpha polypeptide]; PDGFRB [platelet-induced growth factor receptor, beta polypeptide]; PDIA2 [protein disulfide isomerase family A, member 2]; PDIA3 [protein disulfide isomerase family A, member 3]; PDK1 [pyruvate dehydrogenase kinase, isozyme 1]; PDLIM1 [PDZ and LIM Domain 1]; PDLIM5 [PDZ and LIM Domain 5]; PDLIM7 [PDZ and LIM Domain 7 (enigma)]; PDP1 [pyruvate dehydrogenase phosphatase catalyst subunit 1]; PDX1 [pancreatic and duodenal homeobox 1]; PDXK [pyridoxal (pyridoxine, vitamin B6) kinase]; PDYN [prodinol pin]; PECAM1 [platelet / endothelial adhesion molecule]; PEMT [phosphatidylethanolamine N-methyltransferase]; PENK [proenkephalin]; PEPD [peptidase D]; PER1 [Period Homolog 1 (Drosophila)]; PEX1 [peroxysome bioproducing factor 1]; PEX10 [peroxysome bioproducing factor 10]; PEX12 [peroxysome biogenic factor 12]; PEX13 [peroxysome biogenic factor 13]; PEX14 [peroxysome biogenic factor 14]; PEX16 [peroxysome bioproducing factor 16]; PEX19 [peroxysome biogenic factor 19]; PEX2 [Peroxysome Biogenesis Factor 2]; PEX26 [peroxysome biogenic factor 26]; PEX3 [peroxysome biogenic factor 3]; PEX5 [peroxysome bioproducing factor 5]; PEX6 [peroxysome bioproducing factor 6]; PEX7 [peroxysome biogenic factor 7]; PF4 [platelet factor 4]; PFAS [phosphoribosylformylglycineamidine synthase]; PFDN4 [Prepoldine subunit 4]; PFN1 [propylin 1]; PGC [Progestinine (Pepsinogen C)]; PGD [phosphogluconate dehydrogenase]; PGF [placental growth factor]; PGK1 [phosphoglycerate kinase 1]; PGM1 [inglucomutase 1]; PGR [progesterone receptor]; PHB [prohibitin]; PHEX [phosphate modulating endopeptidase homologues, X-linked]; PHF11 [PHD finger protein 11]; PHOX2B [paired-like homeobox 2b]; PHTF1 [estimated homeodomain transcription factor 1]; PHYH [Pythonyl-CoA 2-hydroxylase]; PHYHIP [Pythonyl-CoA 2-hydroxylase Interacting Protein]; PI3 [peptidase inhibitor 3, skin-derived]; PIGA [phosphatidylinositol glycan anchor biosynthesis, class A]; PIGR [polymer immunoglobulin receptor]; PIK3C2A [phosphoinositide-3-kinase, class 2, alpha polypeptide]; PIK3C2B [phosphoinositide-3-kinase, class 2, beta polypeptide]; PIK3C2G [phosphoinositide-3-kinase, class 2, gamma polypeptide]; PIK3C3 [phosphoinositide-3-kinase, class 3]; PIK3CA [phosphoinositide-3-kinase, catalyst, alpha polypeptide]; PIK3CB [phosphoinositide-3-kinase, catalyst, beta polypeptide]; PIK3CD [phosphoinositide-3-kinase, catalyst, delta polypeptide]; PIK3CG [phosphoinositide-3-kinase, catalyst, gamma polypeptide]; PIK3R1 [phosphoinositide-3-kinase, regulatory subunit 1 (alpha)]; PIK3R2 [phosphoinositide-3-kinase, regulatory subunit 2 (beta)]; PIK3R3 [phosphoinositide-3-kinase, regulatory subunit 3 (gamma)]; PIKFYVE [phosphoinositated kinase with FYVE finger]; PIN1 [peptidylprolyl cis / trans isomerase, NIMA-interaction 1]; PINK1 [PTEN derived putative kinase 1]; PIP [prolactin-derived protein]; PIP5KL1 [phosphatidylinositol-4-phosphate 5-kinase-like 1]; PITPNM1 [phosphatidylinositol delivery protein, membrane-related 1]; PITRM1 [Pytrilysine metalpeptidase 1]; PITX2 [paired-like homeodomain 2]; PKD2 [polycystic kidney disease 2 (autosome dominant)]; PKLR [pyruvate kinase, liver and RBC]; PKM2 [pyruvate kinase, muscle]; PKN1 [protein kinase N1]; PL-5283 [PL-5283 Protein]; PLA2G1B [phospholipase A2, group IB (pancreas)]; PLA2G2A [phospholipase A2, group IIA (platelet, synovial fluid)]; PLA2G2D [phospholipase A2, group IID]; PLA2G4A [phospholipase A2, group IVA (cytosol, calcium-dependent)]; PLA2G6 [phospholipase A2, group VI (cytosol, calcium-independent)]; PLA2G7 [phospholipase A2, group VII (platelet-activating factor acetyl hydrolases, plasma)]; PLA2R1 [phospholipase A2 receptor 1, 180 kDa]; PLAT [plasminogen activator, tissue]; PLAU [plasminogen activator, urokinase]; PLAUR [plasminogen activator, urokinase receptor]; PLCB1 [phospholipase C, beta 1 (phosphoinositide-specific)]; PLCB2 [phospholipase C, beta 2]; PLCB4 [phospholipase C, beta 4]; PLCD1 [phospholipase C, delta 1]; PLCG1 [phospholipase C, gamma 1]; PLCG2 [phospholipase C, gamma 2 (phosphatidylinositol-specific)]; PLD1 [phospholipase D1, phosphatidylcholine-specific]; PLEC [plexin]; PLEK [Flextrin]; PLG [plasminogen]; PLIN1 [Perilipin 1]; PLK1 [Polo-Like Kinase 1 (Drosophila)]; PLK2 [Polo-Like Kinase 2 (Drosophila)]; PLK3 [Polo-Like Kinase 3 (Drosophila)]; PLP1 [Protein Protein 1]; PLTP [phospholipid delivery protein]; PMAIP1 [phorball-12-myristate-13-acetate-derived protein 1]; PMCH [pro-melanin-concentrating hormone]; PML [promyelocytic leukemia]; PMP22 [peripheral myelin protein 22]; PMS2 [separation increased after PMS2 meiosis 2 (S.  Serbisier)]; PNLIP [pancreatic lipase]; PNMA3 [Adrenal Antigen Antigen MA3]; PNMT [phenylethanolamine N-methyltransferase]; PNP [purine nucleoside phosphorylase]; POLB [polymerase (DNA oriented), beta]; POLD3 [polymerase (DNA-oriented), delta 3, auxiliary subunit]; POLD4 [polymerase (DNA-directed), delta 4]; POLH [polymerase (DNA oriented), eta); POLL [polymerase (DNA oriented), lambda]; POLR2A [polymerase (RNA) II (DNA directed) polypeptide A, 220 kDa]; POLR2B [polymerase (RNA) II (DNA oriented) polypeptide B, 140 kDa]; POLR2C [polymerase (RNA) II (DNA oriented) polypeptide C, 33 kDa]; POLR2D [polymerase (RNA) II (DNA oriented) polypeptide D]; POLR2E [polymerase (RNA) II (DNA directed) polypeptide E, 25kDa]; POLR2F [polymerase (RNA) II (DNA oriented) polypeptide F]; POLR2G [polymerase (RNA) II (DNA oriented) polypeptide G]; POLR2H [polymerase (RNA) II (DNA oriented) polypeptide H]; POLR2I [polymerase (RNA) II (DNA oriented) polypeptide I, 14. 5 kDa]; POLR2J [polymerase (RNA) II (DNA oriented) polypeptide J, 13. 3 kDa]; POLR2K [polymerase (RNA) II (DNA oriented) polypeptide K, 7. 0 kDa]; POLR2L [Polymerase (RNA) II (DNA oriented) polypeptide L, 7. 6 kDa]; POMC [propiomelanocortin]; POMT1 [Protein-O-Mannosyltransferase 1]; PON1 [rapapoxonase 1]; PON2 [rapapoxonase 2]; PON3 [rapapoxonase 3]; POSTN [periostin, osteoblast specific factor]; POT1 [POT1 protection of telomeres 1 homologues (S.  Pombe)]; POU2AF1 [POU Class 2 Union Factor 1]; POU2F1 [POU Class 2 Homeobox 1]; POU2F2 [POU Class 2 Homeobox 2]; POU5F1 [POU Class 5 Homeobox 1]; PPA1 [Pyrophosphatase (Inorganic) 1]; PPARA [Peroxysome Proliferator-Activated Receptor Alpha]; PPARD [peroxysome proliferator-activated receptor delta]; PPARG [peroxysome proliferator-activated receptor gamma]; PPARGC1A [peroxysome proliferator-activated receptor gamma, coactivator 1 alpha]; PPAT [phosphoribosil pyrophosphoacid amidotransferase]; PPBP [pro-platelet basic protein (chemokine (C-X-C motif) ligand 7)]; PPFIA1 [protein tyrosine phosphatase, receptor type, f polypeptide (PTPRF), interacting protein (liprin), alpha 1]; PPIA [Peptidylprolyl Isomerase A (Cyclophylline A)]; PPIB [Peptidylprolyl Isomerase B (Cyclophylline B)]; PPIG [peptidylprolyl isomerase G (cyclophylline G)]; PPOX [Protoporpyrinogen Oxidase]; PPP1CB [protein phosphatase 1, catalytic subunit, beta isozyme]; PPP1R12A [protein phosphatase 1, modulated (inhibitor) subunit 12A]; PPP1R2 [protein phosphatase 1, modulator (inhibitor) subunit 2]; PPP2R1B [protein phosphatase 2, regulatory subunit A, beta]; PPP2R2B [protein phosphatase 2, regulatory subunit B, beta]; PPP2R4 [protein phosphatase 2A active, regulatory subunit 4]; PPP6C [protein phosphatase 6, catalytic subunit]; PPT1 [palmitoyl-protein thioesterase 1]; PPY [pancreatic polypeptide]; PRDM1 [with PR domain containing 1, ZNF domain]; PRDM2 [with PR domain containing 2, ZNF domain]; PRDX2 [peroxyredoxin 2]; PRDX3 [peroxyredoxin 3]; PRDX5 [peroxyredoxin 5]; PRF1 [Perforin 1 (pore forming protein)]; PRG2 [proteoglycan 2, bone marrow (natural killer cell activator, neutrophil granule major basic protein)]; PRG4 [proteoglycan 4]; PRIM1 [Primase, DNA, Polypeptide 1 (49kDa)]; PRKAA1 [protein kinase, AMP-activated, alpha 1 catalytic subunit]; PRKAA2 [protein kinase, AMP-activated, alpha 2 catalytic subunit]; PRKAB1 [protein kinase, AMP-activated, beta 1 non-catalyst subunit]; PRKACA [protein kinase, cAMP-dependent, catalytic, alpha]; PRKACB [protein kinase, cAMP-dependent, catalyst, beta]; PRKACG [protein kinase, cAMP-dependent, catalyst, gamma]; PRKAR1A (protein kinase, cAMP-dependent, regulatory, type I, alpha (tissue specific extinguisher 1)]; PRKAR2A [protein kinase, cAMP-dependent, regulatory, type II, alpha]; PRKAR2B [protein kinase, cAMP-dependent, regulatory, type II, beta]; PRKCA [Protein Kinase C, Alpha]; PRKCB [protein kinase C, beta]; PRKCD [Protein Kinase C, Delta]; PRKCE [Protein Kinase C, Epsilon]; PRKCG [protein kinase C, gamma]; PRKCH [protein kinase C, actors]; PRKCI [Protein Kinase C, iota]; PRKCQ [protein kinase C, theta]; PRKCZ [Protein Kinase C, Zeta]; PRKD1 [protein kinase D1]; PRKD3 [protein kinase D3]; PRKDC [protein kinase, DNA-activated, catalytic polypeptide; Also known as DNAPK]; PRKG1 [protein kinase, cGMP-dependent, type I]; PRKRIR [inhibitors of protein-kinase, interferon-induced double stranded RNA dependent inhibitor, (P58 inhibitor)]; PRL [Prolactin]; PRLR [prolactin receptor]; PRNP [prion protein]; PROC [protein C (inactive substance of coagulation factors Va and VIIIa)]; PRODH [proline dehydrogenase (oxidase) 1]; PROK1 [Prokineticin 1]; PROK2 [Prokineticin 2]; PROM1 [Prominin 1]; PROS1 [Protein S (alpha)]; PRPH [peripherin]; PRSS1 [protease, serine, 1 (trypsin 1)]; PRSS2 [protease, serine, 2 (trypsin 2)]; PRSS21 [protease, serine, 21 (testisin)]; PRSS3 [protease, serine, 3]; PRTN3 [Protease 3]; PSAP [Prosaposin]; PSEN1 [Presenelin 1]; PSEN2 [Presenilin 2 (Alzheimer's Disease 4)]; PSMA1 [proteasome (prosome, macropine) subunit, alpha type, 1]; PSMA2 [proteasome (prosome, macropine) subunit, alpha type, 2]; PSMA3 [proteasome (prosome, macropine) subunit, alpha type, 3]; PSMA5 [proteasome (prosome, macropine) subunit, alpha type, 5]; PSMA6 [proteasome (prosome, macropine) subunit, alpha type, 6]; PSMA7 [proteasome (prosome, macropine) subunit, alpha type, 7]; PSMB10 [proteasome (prosome, macropine) subunit, beta type, 10]; PSMB2 [proteasome (prosome, macropine) subunit, beta type, 2]; PSMB4 [proteasome (prosome, macropine) subunit, beta type, 4]; PSMB5 [proteasome (prosome, macropine) subunit, beta type, 5]; PSMB6 [proteasome (prosome, macropine) subunit, beta type, 6]; PSMB8 [proteasome (prosome, macropine) subunit, beta type, 8 (large multifunctional peptidase 7)]; PSMB9 [proteasome (prosome, macropine) subunit, beta type, 9 (large multifunctional peptidase 2)]; PSMC3 [proteasome (prosome, macrofine) 26S subunit, ATPase, 3]; PSMC4 [proteasome (prosome, macrofine) 26S subunit, ATPase, 4]; PSMC6 [proteasome (prosome, macrofine) 26S subunit, ATPase, 6]; PSMD4 [proteasome (prosome, macrofine) 26S subunit, non-ATPase, 4]; PSMD9 [proteasome (prosome, macropine) 26S subunit, non-ATPase, 9]; PSME1 [proteasome (prosome, macropine) active subunit 1 (PA28 alpha)]; PSME3 [proteasome (prosome, macropine) activator subunit 3 (PA28 gamma; Ki)]; PSMG2 [proteasome (prosome, macropine) assembly chaperone 2]; PSORS1C1 [Psoriasis Sensitive 1 Candidate 1]; PSTPIP1 [proline-serine-threonine phosphatase interacting protein 1]; PTAFR [platelet-activating factor receptor]; PTBP1 [polypyrimidine tract binding protein 1]; PTCH1 (patched homolog 1 (Drosophila)]; PTEN [Phosphatase and Tensine Homologs]; PTGDR [prostaglandin D2 receptor (DP)]; PTGDS [prostaglandin D2 synthase 21 kDa (brain)]; PTGER1 [prostaglandin E receptor 1 (subtype EP1), 42 kDa]; PTGER2 [prostaglandin E receptor 2 (subtype EP2), 53 kDa]; PTGER3 [prostaglandin E receptor 3 (subtype EP3)]; PTGER4 [prostaglandin E receptor 4 (subtype EP4)]; PTGES [Prostaglandin E Synthetase]; PTGFR [prostaglandin F receptor (FP)]; PTGIR [prostaglandin 12 (prostacyclin) receptor (IP)]; PTGS1 [prostaglandin-andopeoxide synthase 1 (prostaglandin G / H synthase and cyclooxygenase)]; PTGS2 [prostaglandin-andopeoxide synthase 2 (prostaglandin G / H synthase and cyclooxygenase)]; PTH [parathyroid hormone]; PTHLH [parathyroid hormone-like hormone]; PTK2 [PTK2 protein tyrosine kinase 2]; PTK2B [PTK2B protein tyrosine kinase 2 beta]; PTK7 [PTK7 protein tyrosine kinase 7]; PTMS [paratimosin]; PTN [fleoprovins]; PTPN1 [protein tyrosine phosphatase, non-receptor type 1]; PTPN11 [protein tyrosine phosphatase, non-receptor type 11]; PTPN12 [protein tyrosine phosphatase, non-receptor type 12]; PTPN2 [protein tyrosine phosphatase, non-receptor type 2]; PTPN22 [protein tyrosine phosphatase, non-receptor type 22 (lymphoid)]; PTPN6 [protein tyrosine phosphatase, non-receptor type 6]; PTPRC [protein tyrosine phosphatase, receptor type, C]; PTPRD [protein tyrosine phosphatase, receptor type, D]; PTPRE [protein tyrosine phosphatase, receptor type, E]; PTPRJ [protein tyrosine phosphatase, receptor type, J]; PTPRN [protein tyrosine phosphatase, receptor type, N]; PTPRT [protein tyrosine phosphatase, receptor type, T]; PTPRU [protein tyrosine phosphatase, receptor type, U]; PTRF [polymerase I and transcript release factor]; PTS [6-pyruboyltetrahydropterin synthetase]; PTTG1 [pituitary tumor-morphotype 1]; PTX3 [pentrasin 3, long]; PUS10 [Pseudouridelate Synthetase 10]; PXK [PX domain containing serine / threonine kinase]; PXN [Pacillin]; PYCR1 [pyrroline-5-carboxylate reductase 1]; PYCR2 [pyrroline-5-carboxylate reductase family, member 2]; PYGB [phosphorylase, glycogen; brain]; PYGM [phosphorylase, glycogen, muscle]; PYY [peptide YY]; PZP [pregnancy-zone protein]; QDPR [quinoid dihydrophteridine reductase]; RAB11A [RAB11A, member RAS oncogene family]; RAB11FIP1 [RAB11 family interacting protein 1 (Class I)]; RAB27A [RAB27A, member RAS oncogene family]; RAB37 [RAB37, member RAS oncogene family]; RAB39 [RAB39, member RAS oncogene family]; RAB7A [RAB7A, member RAS oncogene family]; RAB9A [RAB9A, member RAS oncogene family]; RAC1 [ras-associated C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1)]; RAC2 [ras-associated C3 botulinum toxin substrate 2 (rho family, small GTP binding protein Rac2)]; RAD17 [RAD17 homologue (S.  Pombe)]; RAD50 [RAD50 homologue (S.  Serbisier)]; RAD51 [RAD51 homologue (RecA homologue, Escherichia coli) (S.  Serbisier)]; RAD51C [RAD51 homologue C (S.  Serbisier)]; RAD51L1 [RAD51-Like 1 (S.  Serbisier)]; RAD51L3 [RAD51-Like 3 (S.  Serbisier)]; RAD54L [RAD54-like (S.  Serbisier)]; RAD9A [RAD9 homolog A (S.  Pombe)]; RAF1 [v-raf-1 murine leukemia viral oncogene homolog 1]; RAG1 [recombinant activation gene 1]; RAG2 [recombinant activation gene 2]; RAN [RAN, member RAS oncogene family]; RANBP1 [RAN binding protein 1]; RAP1A [RAP1A, member of the RAS oncogene family]; RAPGEF4 [Rap Guanine Nucleotide Exchange Factor (GEF) 4]; RARA [retinoic acid receptor, alpha]; RARB [retinoic acid receptor, beta]; RARG [retinoic acid receptor, gamma]; RARRES2 [retinoic acid receptor responder (tazarotene induced) 2]; RARS [arginyl-tRNA synthetase]; RASA1 [RAS p21 protein activator (GTPase activating protein) 1]; RASGRP1 [RAS guanyl release protein 1 (calcium and DAG-regulated)]; RASGRP2 [RAS guanyl releasing protein 2 (calcium and DAG-regulated)]; RASGRP4 [RAS guanyl release protein 4]; RASSF1 [Ras Union (RalGDS / AF-6) Domain Family Member 1]; RB1 [Retinoblastoma 1]; RBBP4 [Retinoblastoma Binding Protein 4]; RBBP8 [Retinoblastoma Binding Protein 8]; RBL1 [Retinoblastoma-like 1 (p107)]; RBL2 [Retinoblastoma-like 2 (p130)]; RBP4 [Retinol Binding Protein 4, Plasma]; RBX1 [Ring-Box 1]; RCBTB1 [modulators of chromosome condensation (RCC1) and BTB (POZ) domain containing protein 1]; RCN1 [reticulocarbine 1, EF-hand calcium binding domain]; RCN2 [Reticulocarbine 2, EF-Hand Calcium Binding Domain]; RDX [radicin]; RECK [reversion-induced-cysteine-rich protein with kazal motif]; RECQL [RecQ protein-like (DNA helicase Q1-like)]; RECQL4 [RecQ Protein-Like 4]; RECQL5 [RecQ Protein-Like 5]; REG1A (islet-derived 1 alpha generation); REG3A [islet-derived 3 alpha generation]; REG4 [island-derived family, member 4 generation]; REL [v-rel retinopathy viral oncogene homolog (bird)]; RELA [v-rel retinopathy viral oncogene homologue A (bird)]; RELB [v-rel retinopathy viral oncogene homolog B]; REN [lenin]; RET [ret proto-tumor gene]; RETN [resistin]; RETNLB [resistin-like beta]; RFC1 [replicate factor C (Active 1) 1,145 kDa]; RFC2 [replicate factor C (Active 1) 2, 40 kDa]; RFC3 [replicate factor C (Active 1) 3, 38 kDa]; RFX1 [regulatory factor X, 1 (influences HLA class II expression)]; RFX5 [regulatory factor X, 5 (affects HLA class II expression)]; RFXANK [regulatory factor X-associated ankyrin-containing protein]; RFXAP [regulatory factor X-associated protein]; RGS18 [modulator 18 of G-protein signaling]; RHAG [Rh-associated glycoprotein]; RHD [Rh blood group, D antigen]; RHO [Rhodopsin]; RHOA [ras homologue gene family, member A]; RHOD [ras homologue gene family, member D]; RIF1 [RAP1 interacting factor homologue (yeast)]; RIPK1 [receptor (TNFRSF) -interacting serine-threonine kinase 1]; RIPK2 [receptor-interacting serine-threonine kinase 2]; RLBP1 [retinaldehyde binding protein 1]; RLN1 [lerasine 1]; RLN2 [lerasin 2]; RMI1 [RMI1, RecQ mediated genomic instability 1, homologues (S.  Serbisier)]; RNASE1 [ribonuclease, RNase A family, 1 (pancreas)]; RNASE2 [ribonuclease, RNase A family, 2 (liver, neutrophil-induced neurotoxin)]; RNASE3 [ribonuclease, RNase A family, 3 (neutrophil cation protein)]; RNASEH1 [ribonuclease H1]; RNASEH2A [ribonuclease H2, subunit A]; RNASEL [ribonuclease L (2 '[5'-oligoisoadenylate synthase-dependent)]; RNASEN [ribonuclease type III, nuclear]; RNF123 [Ring Finger Protein 123]; RNF13 [Ring Finger Protein 13]; RNF135 [Ring Finger Protein 135]; RNF138 [Ring Finger Protein 138]; RNF4 [Ring Finger Protein 4]; RNH1 [ribonuclease / angiogenin inhibitor 1]; RNPC3 [RNA-binding portion (RNP1, RRM) containing 3]; RNPEP [arginyl aminopeptidase (aminopeptidase B)]; ROCK1 [Rho-related, coiled-coil containing protein kinase 1]; ROM1 [outer retinal fragment membrane protein 1]; ROR2 [receptor tyrosine kinase-like orphan receptor 2]; RORA [RAR-associated olphan receptor A]; RPA1 [replicate protein A1, 70 kDa]; RPA2 [replicate protein A2, 32 kDa]; RPGRIP1L [RPGRIP1-like]; RPLP1 [ribosome protein, large, P1]; RPS19 [ribosome protein S19]; RPS6KA3 [ribosome protein S6 kinase, 90 kDa, polypeptide 3]; RPS6KB1 [ribosome protein S6 kinase, 70 kDa, polypeptide 1]; RPSA [ribosome protein SA]; RRBP1 [ribosome binding protein 1 homologue 180 kDa (dog)]; RRM1 [ribonucleotide reductase M1]; RRM2B [ribonucleotide reductase M2 B (TP53 inducible)]; RUNX1 [runt-related transcription factor 1]; RUNX3 [runt-related transcription factor 3]; RXRA [Retinoid X Receptor, Alpha]; RXRB [Retinoid X Receptor, Beta]; RYR1 [lynodine receptor 1 (skeleton)]; RYR3 [lynodine receptor 3]; S100A1 [S100 Calcium Binding Protein A1]; S100A12 [S100 Calcium Binding Protein A12]; S100A4 [S100 Calcium Binding Protein A4]; S100A7 [S100 Calcium Binding Protein A7]; S100A8 [S100 Calcium Binding Protein A8]; S100A9 [S100 Calcium Binding Protein A9]; S100B [S100 Calcium Binding Protein B]; S100G [S100 Calcium Binding Protein G]; S1PR1 [Shippingosine-1-phosphate Receptor 1]; SAA1 [serum amyloid A1]; SAA4 [serum amyloid A4, structure]; SAFB [scaffold adhesion factor B]; SAG [S-antigen; Retina and pineal gland (arrestin)]; SAGE1 [sarcoma antigen 1]; SARDH [sarcosine dehydrogenase]; SART3 [Squamous Cell Carcinoma Antigen 3 Recognized by T Cells]; SBDS [Shwachman-Bodian-Diamond Syndrome]; SBNO2 [strawberry notch homolog 2 (Drosophila)]; SCAMP3 [secretory carrier membrane protein 3]; SCAP [SREBF Chaplong]; SCARB1 [erasing receptor class B, member 1]; SCD [Stearoyl-CoA Desaturase (Delta-9-Desaturase)]; SCG2 [secretographin II]; SCG3 [cycleteronin III]; SCG5 [secretogrinin V (7B2 protein)]; SCGB1A1 [secretoglobin, family 1A, member 1 (uteroglobin)]; SCGB3A2 [secretoglobin, family 3A, member 2]; SCN4A [sodium channel, translocation-gated, type IV, alpha subunit]; SCNN1A [sodium channel, non-potential-gated 1 alpha]; SCNN1G [sodium channel, non-potential-opening 1, gamma]; SCO1 [SCO cytochrome oxidase defect homolog 1 (yeast)]; SCO2 [SCO cytochrome oxidase defect homolog 2 (yeast)]; SCP2 [Sterol Carrier Protein 2]; SCT [secretin]; SDC1 [syndecane 1]; SDC2 [Sindecane 2]; SDC4 [Sindecane 4]; SDHB [succinate dehydrogenase complex, subunit B, iron-sulfur (Ip)]; SDHD [succinate dehydrogenase complex, subunit D, whole membrane protein]; SEC14L2 [SEC14-Like 2 (S.  Serbisier)]; SEC16A [SEC16 homolog A (S.  Serbisier)]; SEC23B [Sec23 homolog B (S.  Serbisier)]; SELE [selectin E]; SELL [Selectin L]; SELP [selectin P (granular membrane protein 140kDa, antigen CD62)]; SELPLG [selectin P ligand]; SEPT5 [Septin 5]; SEPP1 [Serenoprotein P, Plasma, 1]; SEPSECS [Sep (O-Inserine) tRNA: Sec (Serenocysteine) tRNA Synthetase]; SERBP1 [serpin E1 mRNA binding protein 1]; SERPINA1 [serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 1]; SERPINA2 [serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 2]; SERPINA3 [serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 3]; SERPINA5 [serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 5]; SERPINA6 [serpin peptidase inhibitor, Clade A (alpha-1 antiproteinase, antitrypsin), member 6]; SERPINA7 [serpin peptidase inhibitor, Clade A (alpha-1 antiproteinase, antitrypsin), member 7]; SERPINB1 [serpin peptidase inhibitor, clade B (ofalbumin), member 1]; SERPINB2 [serpin peptidase inhibitor, clade B (ofalbumin), member 2]; SERPINB3 [serpin peptidase inhibitor, clade B (ofalbumin), member 3]; SERPINB4 [serpin peptidase inhibitor, clade B (ofalbumin), member 4]; SERPINB5 [serpin peptidase inhibitor, clade B (ofalbumin), member 5]; SERPINB6 [serpin peptidase inhibitor, clade B (ofalbumin), member 6]; SERPINB9 [serpin peptidase inhibitor, clade B (ofalbumin), member 9]; SERPINC1 [serpin peptidase inhibitor, clade C (antithrombin), member 1]; SERPIND1 [serpin peptidase inhibitor, clade D (heparin recognizer), member 1]; SERPINE1 [serpin peptidase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1), member 1]; SERPINE2 [serpin peptidase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1), member 2]; SERPINF2 [serpin peptidase inhibitor, Clade F (alpha-2 antiplasmin, pigment epithelial induced factor), member 2]; SERPING1 [serpin peptidase inhibitor, clade G (C1 inhibitor), member 1]; SERPINH1 [serpin peptidase inhibitor, clade H (heat shock protein 47), member 1, (collagen binding protein 1)]; SET [SET nuclear tumor electron]; SETDB2 [SET domain, split in two]; SETX [cenaatacin]; SFPQ [conjugation (conjugation) factor proline / glutamine-rich (related to polypyrimidine local binding protein)]; SFRP1 [secreted frizz-related protein 1]; SFRP2 [secreted frizz-related protein 2]; SFRP5 [secreted frizz-related protein 5]; SFTPA1 [surfactant protein A1]; SFTPB [Surfactant Protein B]; SFTPC [Surfactant Protein C]; SFTPD [surfactant protein D]; SGCA [sarcoglycan, alpha (50 kDa dispropine-associated glycoprotein)]; SGCB [sarcoglycan, beta (43kDa dispropine-associated glycoprotein)]; SGK1 [serum / glucocorticoid regulated kinase 1]; SGSH [N-sulfoglucosamine sulfohydrolase]; SGTA [small glutamine-rich tetratricopeptiide repeat (TPR) -containing, alpha]; SH2B1 [SH2B Adapter Protein 1]; SH2B3 [SH2B Adapter Protein 3]; SH2D1A [SHA domain containing 1A]; SH2D4B [SH2 domain containing 4B]; SH3KBP1 [SH3-domain kinase binding protein 1]; SHBG [sex hormone-binding globulin]; SHC1 [SHC (containing Src homology 2 domains) transformed protein 1]; SHH [sonic hedgehog homologue (Drosophila)]; SHMT2 [serine hydroxymethyltransferase 2 (mitochondria)]; SI [sucrase-isomaltase (alpha-glucosidase)]; SIGIRR [single immunoglobulin and toll-interleukin 1 receptor (TIR) domains]; SIP1 [survival of motor neuron interacting protein 1]; SIPA1 [signal-induced proliferation-related 1]; SIRPA [signal-regulating protein alpha]; SIRPB2 [signal-regulating protein beta 2]; SIRT1 [Sirtuin (silent mating type information regulation 2 homologue) 1 (S.  Serbisier)]; SKIV2L [superkiller virlicidic activity 2-like (S.  Serbisier)]; SKP2 [S-Phase Kinase-Related Protein 2 (p45)]; SLAMF1 [signaling lymphocyte activating molecule family member 1]; SLAMF6 [SLAM Family Member 6]; SLC11A1 [solute carrier family 11 (quantum-linked divalent metal ion transport), member 1]; SLC11A2 [solute carrier family 11 (quantum-linked divalent metal ion transport), member 2]; SLC12A1 [solute carrier family 12 (sodium / potassium / chloride transport), member 1]; SLC12A2 [solute carrier family 12 (sodium / potassium / chloride transport), member 2]; SLC14A1 [Solute Carrier Family 14 (Urea Transport), Member 1 (Kidd Blood Group)]; SLC15A1 [solute carrier family 15 (oligopeptide transport), member 1]; SLC16A1 [Solute Carrier Family 16, Member 1 (Monocarboxylic Acid Carrier 1)]; SLC17A5 [Solute Carrier Family 17 (anion / sugar transport), member 5]; SLC17A6 [Solute Carrier Family 17 (Sodium-dependent inorganic phosphate cocarrier), member 6]; SLC17A7 [solute carrier family 17 (sodium-dependent inorganic phosphate cocarrier), member 7]; SLC19A1 [solute carrier family 19 (folate transport), member 1]; SLC1A1 [Solute Carrier Family 1 (neuron / epithelial high affinity glutamate transport, System Xag), member 1]; SLC1A2 [Solute Carrier Family 1 (glue high affinity glutamate transport), member 2]; SLC1A4 [solute carrier family 1 (glutamate / neutral amino acid transport), member 4]; SLC22A12 [Solute Carrier Family 22 (Organic Anion / Uricate Transport), Member 12]; SLC22A2 [solute carrier family 22 (organic cation transport), member 2]; SLC22A23 [Solute Carrier Family 22, Member 23]; SLC22A3 [solute carrier family 22 (extraneuronal monoamine transport), member 3]; SLC22A4 [solute carrier family 22 (organic cation / ergothionene transport), member 4]; SLC22A5 [solute carrier family 22 (organic cation / carnitine transport), member 5]; SLC22A6 [Solute Carrier Family 22 (Organic Anion Transport), Member 6]; SLC24A2 [solute carrier family 24 (sodium / potassium / calcium exchanger), member 2]; SLC25A1 [solute carrier family 25 (mitochondrial carrier; citrate transport), member 1]; SLC25A20 [solute carrier family 25 (carnitine / acylcarnitine translocation enzyme (potase)), member 20]; SLC25A3 [solute carrier family 25 (mitochondrial carrier; phosphate carrier), member 3]; SLC25A32 [Solute Carrier Family 25, Member 32]; SLC25A33 [Solute Carrier Family 25, Member 33]; SLC25A4 [solute carrier family 25 (mitochondrial carrier; adenine nucleotide translocation), member 4]; SLC26A4 [Solute Carrier Family 26, Member 4]; SLC27A4 [Solute Carrier Family 27 (fatty acid transport), member 4]; SLC28A1 [solute carrier family 28 (sodium-linked nucleoside transport), member 1]; SLC2A1 [Solute Carrier Family 2 (Easy Glucose Transport), Member 1]; SLC2A13 [Solute Carrier Family 2 (Easy Glucose Transport), Member 13]; SLC2A3 [Solute Carrier Family 2 (Easy Glucose Transport), Member 3]; SLC2A4 [Solute Carrier Family 2 (Easy Glucose Transport), Member 4]; SLC30A1 [solute carrier family 30 (zinc transport), member 1]; SLC30A8 [solute carrier family 30 (zinc transport), member 8]; SLC31A1 [solute carrier family 31 (copper transport), member 1]; SLC35A1 [solute carrier family 35 (CMP-sialic acid transport), member A1]; SLC35A2 [solute carrier family 35 (UDP-galactose delivery), member A2]; SLC35C1 [Solute Carrier Family 35, Member C1]; SLC35F2 [Solute Carrier Family 35, Member F2]; SLC39A3 [solute carrier family 39 (zinc transport), member 3]; SLC3A2 [Solute Carrier Family 3 (Active of Dibasic and Neutral Amino Acid Transport), Member 2]; SLC46A1 [solute carrier family 46 (folate transport), member 1]; SLC5A5 (solute carrier family 5 (sodium iodide symporter), member 5]; SLC6A11 [solute carrier family 6 (neurotransmitter transport, GABA), member 11]; SLC6A14 [solute carrier family 6 (amino acid carrier), member 14]; SLC6A19 [solute carrier family 6 (neutral amino acid transport), member 19]; SLC6A3 [solute carrier family 6 (neurotransmitter transport, dopamine), member 3]; SLC6A4 [solute carrier family 6 (neurotransmitter transport, serotonin), member 4]; SLC6A8 [solute carrier family 6 (neurotransmitter transport, creatine), member 8]; SLC7A1 [solute carrier family 7 (cationic amino acid transport, y + system), member 1]; SLC7A2 [solute carrier family 7 (cationic amino acid transport, y + system), member 2]; SLC7A4 [solute carrier family 7 (cationic amino acid transport, y + system), member 4]; SLC7A5 [solute carrier family 7 (cationic amino acid transport, y + system), member 5]; SLC8A1 [Solute Carrier Family 8 (Sodium / Calcium Exchanger), Member 1]; SLC9A1 [Solute Carrier Family 9 (Sodium / Hydrogen Exchanger), member 1]; SLC9A3R1 [Solute Carrier Family 9 (Sodium / Hydrogen Exchanger), Member 3 Modulator 1]; SLCO1A2 [Solute Carrier Organic Anion Transport Family, Member 1A2]; SLCO1B1 [Solute Carrier Organic Anion Transport Family, Member 1B1]; SLCO1B3 [Solute Carrier Organic Anion Transport Family, Member 1B3]; SLPI [secretory leukocyte peptidase inhibitor]; SMAD1 [SMAD Family Member 1]; SMAD2 [SMAD Family Member 2]; SMAD3 [SMAD Family Member 3]; SMAD4 [SMAD Family Member 4]; SMAD7 [SMAD Family Member 7]; SMARCA4 [SWI / SNF related, matrix related, actin dependent modulators of chromatin, subfamily a, member 4]; SMARCAL1 [SWI / SNF related, matrix related, chromatin actin dependent modulators, subfamily a-like 1]; SMARCB1 [SWI / SNF related, matrix related, chromatin actin dependent modulators, subfamily b, member 1]; SMC1A [structural maintenance of chromosomes 1A]; SMC3 [structural maintenance of chromosomes 3]; SMG1 [SMG1 homologue, phosphatidylinositol 3-kinase-associated kinase (C. Elegans)]; SMN1 [survival of motor neuron 1, terminal granules (terminal granules)]; SMPD1 [sphingomyelin phosphodiesterase 1, acid lysosomal]; SMPD2 [sphingomyelin phosphodiesterase 2, neutral membrane (neutral sphingomyelinase)]; SMTN (smoothelin); SNAI2 [Snail homologue 2 (Drosophila)]; SNAP25 [synaptosome-associated protein, 25 kDa]; SNCA [synuclein, alpha (non-A4 component of amyloid precursor)]; SNCG [synuclein, gamma (breast cancer-specific protein 1)]; SNURF [SNRPN Upstream Reading Framework]; SNW1 [SNW domain containing 1]; SNX9 [sorted nexin 9]; SOAT1 [Sterol O-acyltransferase 1]; SOCS1 [inhibitor 1 of cytokine signaling]; SOCS2 [inhibitor 2 of cytokine signaling]; SOCS3 [inhibitor 3 of cytokine signaling]; SOD1 [Superoxide Dismutase 1, Soluble]; SOD2 [Superoxide Dismutase 2, Mitochondria]; SORBS3 [containing sorbine and SH3 domain 3]; SORD [sorbitol dehydrogenase]; SOX2 [SRY (sex determination part Y) -box 2]; SP1 [Sp1 transcription factor]; SP110 [SP110 nuclear body protein]; SP3 [Sp3 transcription factor]; SPA17 [Cum Autoantigen Protein 17]; SPARC [secreted protein, acidic, cysteine-rich (osteonectin)]; SPHK1 [Shippingosine Kinase 1]; SPI1 [Splenic Focusing Virus (SFFV) Proviral Integrating Oncogene spi1]; SPINK1 [serine peptidase inhibitor, Kazal type 1]; SPINK13 [serine peptidase inhibitor, Kazal type 13 (estimated)]; SPINK5 [serine peptidase inhibitor, Kazal type 5]; SPN [sialoporin]; SPON1 [spondin 1, extracellular matrix protein]; SPP1 [secreted phosphoprotein 1]; SPRED1 (sprouty-related, EVH1 domain containing 1); SPRR2A [small proline-rich protein 2A]; SPRR2B [small proline-rich protein 2B]; SPTB [spectrin, beta, erythropoiesis]; SRC [v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (algae)]; SRD5A1 [steroid-5-alpha-reductase, alpha polypeptide 1 (3-oxo-5 alpha-steroid delta 4-dehydrogenase alpha 1)]; SREBF1 [sterol regulatory element binding transcription factor 1]; SREBF2 [sterol regulatory element binding transcription factor 2]; SRF [serum response factor (c-fos serum response element-binding transcription factor)]; SRGN [Serglycine]; SRP9 [signal recognition particle 9kDa]; SRPX [sushi-repeat-containing protein, X-linked]; SRR [serine lasizing agent]; SRY [sex determination part Y]; SSB [Sjogren Syndrome Antigen B (Autoantigen La)]; SST [somatostatin]; SSTR2 [somatostatin receptor 2]; SSTR4 [somatostatin receptor 4]; ST8SIA4 [ST8 alpha-N-acetyl-neuramid alpha--2,8-sialyltransferase 4]; STAR [steroid productivity acute regulatory protein]; STAT1 [transcriptional signal transducer and active substance 1, 91 kDa]; STAT2 [Signal Transducer and Activator 2, 113 kDa]; STAT3 [signal transducer and activator 3 (acute-phase response factor)]; STAT4 [signal transducer and activator 4 of transcription]; STAT5A [signal transducer and activator 5A of transcription]; STAT5B [transcriptional signal transducer and active substance 5B]; STAT6 [transcriptional signal transducer and activator 6, interleukin-4 derived]; STELLAR [germ and embryonic stem cell rich protein STELLA]; STIM1 [substrate interaction molecule 1]; STIP1 [stress-derived-phosphoprotein 1]; STK11 [serine / threonine kinase 11]; STMN2 (stathmin-like 2); STRAP [serine / threonine kinase receptor related protein]; STRC (stereocilin); STS [steroid steroids (microsomes), isozyme S]; STX6 [Syntacin 6]; STX8 [Syntacin 8]; SULT1A1 [sulfotransferase family, cytosol, 1A, phenol-preferred, member 1]; SULT1A3 [sulfotransferase family, cytosol, 1A, phenol-preferred, member 3]; SUMF1 [sulfatase modification factor 1]; SUMO1 [SMT3 Inhibitor 1 of mif 2 homologues (S. Servichy)]; SUMO3 [SMT3 inhibitor of mif 2 3 homologue 3 (S. Serbisier)]; SUOX [sulfite oxidase]; SUV39H1 (inhibitor of variant 3-9 homolog 1 (Drosophila)]; SWAP70 (SWAP switching B-cell complex 70 kDa subunit); SYCP3 [synaptonemal complex protein 3]; SYK [splenic tyrosine kinase]; SYNM (synemin, intermediate filament protein); SYNPO [synaptopodin]; SYNPO2 [synaptopodin 2]; SYP [synaptophycin]; SYT3 [synaptotamine III]; SYTL1 [synaptotamine-like 1]; T [T, brachyury homologue (mouse)]; TAC1 [tachikinin, precursor 1]; TAC4 [tachikinin 4 (hemokinin)]; TACR1 [tachikinin receptor 1]; TACR2 [tachikinin receptor 2]; TACR3 [tachikinin receptor 3]; TAGLN [transgellin]; TAL1 [T-cell acute lymphocytic leukemia 1]; TAOK3 [TAO Kinase 3]; TAP1 [Transport 1, ATP-binding cassette, sub-family B (MDR / TAP)]; TAP2 [Transport 2, ATP-binding cassette, sub-family B (MDR / TAP)]; TARDBP [TAR DNA Binding Protein]; TARP [TCR Gamma Shift Reading Frame Protein]; TAT [tyrosine aminotransferase]; TBK1 [TANK-binding kinase 1]; TBP [TATA Box Binding Protein]; TBX1 [T-Box 1]; TBX2 [T-box 2]; TBX21 [T-box 21]; TBX3 [T-box 3]; TBX5 [T-Box 5]; TBXA2R [Tromboxane A2 Receptor]; TBXAS1 [Tromboxane A Synthetase 1 (platelet)]; TCEA1 [transcription extension factor A (SII), 1]; TCEAL1 [transcription extension factor A (SII) -like 1]; TCF4 [transcription factor 4]; TCF7L2 [transcription factor 7-like 2 (T-cell specific, HMG-box)]; TCL1A [T-cell leukemia / lymphoma 1A]; TCL1B [T-cell leukemia / lymphoma 1B]; TCN1 [transcobalamin I (vitamin B12 binding protein, R binder family)]; TCN2 [transcobalamin II; Macrocytic anemia]; TDP1 [tyrosyl-DNA phosphodiesterase 1]; TEC [tec protein tyrosine kinase]; TECTA [tectorin alpha]; TEK [TEK tyrosine kinase, endothelial]; TERF1 [terminal repeat binding factor (NIMA-interaction) 1]; TERF2 [terminal repeat repeat factor 2]; TERT [telomerase reverse transcriptase]; TES [testicular induced transcript (3 LIM domain)]; TF [transferrin]; TFAM [transcription factor A, mitochondria]; TFAP2A [transcription factor AP-2 alpha (activating enhancer binding protein 2 alpha)]; TFF2 (trefoil factor 2); TFF3 [Trefoil Factor 3 (Intestines)]; TFPI [tissue factor pathway inhibitors (lipoprotein-associated coagulation inhibitors)]; TFPT [TCF3 (E2A) Fusion Partner (Child Leukemia)]; TFR2 [transferrin receptor 2]; TFRC [transferrin receptor (p90, CD71)]; TG [Tyroglobulin]; TGFA [morphotropic growth factor, alpha]; TGFB1 [morphotropic growth factor, beta 1]; TGFB2 [morphotropic growth factor, beta 2]; TGFB3 [morphotropic growth factor, beta 3]; TGFBR1 [morphotropic growth factor, beta receptor 1]; TGFBR2 [morphotropic growth factor, beta receptor II (70/80 kDa)]; TGIF1 [TGFB-derived factor homeobox 1]; TGM1 [transglutaminase 1 (K polypeptide epithelial type I, protein-glutamine-gamma-glutamyltransferase)]; TGM2 [transglutaminase 2 (C polypeptide, protein-glutamine-gamma-glutamyltransferase)]; TGM3 [transglutaminase 3 (E polypeptide, protein-glutamine-gamma-glutamyltransferase)]; TH [tyrosine hydroxylase]; THAP1 [containing THAP domain, apoptosis related protein 1]; THBD [thrombomodulin]; THBS1 [thrombospondin 1]; THBS3 [thrombospondin 3]; THPO [thrombopoietin]; THY1 [Thy-1 cell surface antigen]; TIA1 [TIA1 cytotoxic granule-associated RNA binding protein]; TIE1 [tyrosine kinases with immunoglobulin-like and EGF-like domain 1]; TIMD4 [containing T-cell immunoglobulin and mucin domain 4]; TIMELESS [timeless homologue (Drosophila)]; TIMP1 [TIMP Metalpeptidase Inhibitor 1]; TIMP2 [TIMP Metalpeptidase Inhibitor 2]; TIMP3 [TIMP Metalpeptidase Inhibitor 3]; TIRAP [toll-interleukin 1 receptor (TIR) domain containing adapter protein]; TJP1 (tight binding protein 1 (Zona Occidentes 1)]; TK1 [thymidine kinase 1, soluble]; TK2 [Thymidine Kinase 2, Mitochondria]; TKT [transketolase]; TLE4 [split 4 (transducin-like enhancer of E (sp1) homologue, Drosophila)]; TLR1 [toll-like receptor 1]; TLR10 [toll-like receptor 10]; TLR2 [toll-like receptor 2]; TLR3 [toll-like receptor 3]; TLR4 [toll-like receptor 4]; TLR5 [toll-like receptor 5]; TLR6 [toll-like receptor 6]; TLR7 [toll-like receptor 7]; TLR8 [toll-like receptor 8]; TLR9 [toll-like receptor 9]; TLX1 [T-cell leukemia homeobox 1]; TM7SF4 [membrane and 7 superfamily member 4]; TMED3 [containing transmembrane and emp24 protein transport domain 3]; TMEFF2 [membrane transmembrane protein with EGF-like and two follistatin-like domain 2]; TMEM132E [membrane and protein 132E]; TMEM18 [membrane and protein 18]; TMEM19 [membrane and protein 19]; TMEM216 [membrane and protein 216]; TMEM27 [membrane and protein 27]; TMEM67 [membranous protein 67]; TMPO [Timophoetine]; TMPRSS15 [membrane and protease, serine 15]; TMSB4X [Thymosin beta 4, X-linked]; TNC [Tenacin C]; TNF [Tumor Necrosis Factor (TNF Superfamily, Member 2)]; TNFAIP1 [tumor necrosis factor, alpha-derived protein 1 (endothelium)]; TNFAIP3 [tumor necrosis factor, alpha-derived protein 3]; TNFAIP6 [tumor necrosis factor, alpha-derived protein 6]; TNFRSF10A [Tumor Necrosis Factor Receptor Superfamily, Member 10a]; TNFRSF10B [Tumor Necrosis Factor Receptor Superfamily, Member 10b]; TNFRSF10C [tumor necrosis factor receptor superfamily, member 10c, decoy without intracellular domain]; TNFRSF10D [tumor necrosis factor receptor superfamily, member 10d, decoy with truncated death domain]; TNFRSF11A [Tumor Necrosis Factor Receptor Superfamily, Member 11a, NFKB Activator]; TNFRSF11B [Tumor Necrosis Factor Receptor Superfamily, Member 11b]; TNFRSF13B [Tumor Necrosis Factor Receptor Superfamily, Member 13B]; TNFRSF13C [Tumor Necrosis Factor Receptor Superfamily, Member 13C]; TNFRSF14 [Tumor Necrosis Factor Receptor Superfamily, Member 14 (Herpes Virus Entry Mediator)]; TNFRSF17 [Tumor Necrosis Factor Receptor Superfamily, Member 17]; TNFRSF18 [Tumor Necrosis Factor Receptor Superfamily, Member 18]; TNFRSF1A [Tumor Necrosis Factor Receptor Superfamily, Member 1A]; TNFRSF1B [Tumor Necrosis Factor Receptor Superfamily, Member 1B]; TNFRSF21 [Tumor Necrosis Factor Receptor Superfamily, Member 21]; TNFRSF25 [Tumor Necrosis Factor Receptor Superfamily, Member 25]; TNFRSF4 [Tumor Necrosis Factor Receptor Superfamily, Member 4]; TNFRSF6B [Tumor Necrosis Factor Receptor Superfamily, Member 6b, Decoy]; TNFRSF8 [Tumor Necrosis Factor Receptor Superfamily, Member 8]; TNFRSF9 [Tumor Necrosis Factor Receptor Superfamily, Member 9]; TNFSF10 [tumor necrosis factor (ligand) superfamily, member 10]; TNFSF11 [tumor necrosis factor (ligand) superfamily, member 11]; TNFSF12 [tumor necrosis factor (ligand) superfamily, member 12]; TNFSF13 [tumor necrosis factor (ligand) superfamily, member 13]; TNFSF13B [tumor necrosis factor (ligand) superfamily, member 13b]; TNFSF14 [tumor necrosis factor (ligand) superfamily, member 14]; TNFSF15 [tumor necrosis factor (ligand) superfamily, member 15]; TNFSF18 [tumor necrosis factor (ligand) superfamily, member 18]; TNFSF4 [tumor necrosis factor (ligand) superfamily, member 4]; TNFSF8 [tumor necrosis factor (ligand) superfamily, member 8]; TNFSF9 [tumor necrosis factor (ligand) superfamily, member 9]; TNKS [tanchiase, TRF1-interacting ankyrin-associated ADP-ribose polymerase]; TNNC1 [Troponin C type 1 (slow)]; TNNI2 [Troponin I Type 2 (skeleton, fast)]; TNNI3 [Troponin I Type 3 (Heart)]; TNNT3 [Troponin T Type 3 (skeleton, fast)]; TNPO1 [transportin 1]; TNS1 [Tensin 1]; TNXB [Tenacin XB]; TOM1L2 [target 2 like chicken 2 (chicken)]; TOP1 [Topoisomerase (DNA) I]; TOP1MT [Topoisomerase (DNA) I, Mitochondria]; TOP2A [Topoisomerase (DNA) II alpha 170kDa]; TOP2B [Topoisomerase (DNA) II Beta 180 kDa]; TOP3A [Topoisomerase (DNA) III alpha]; TOPBP1 [Topoisomerase (DNA) II Binding Protein 1]; TP53 [tumor protein p53]; TP53BP1 [tumor protein p53 binding protein 1]; TP53RK [TP53 Regulatory Kinase]; TP63 [tumor protein p63]; TP73 [tumor protein p73]; TPD52 [Tumor Protein D52]; TPH1 [Tryptophan hydroxylase 1]; TPI1 [triose phosphate isomerase 1]; TPM1 [Troformiocin 1 (alpha)]; TPM2 [Troformiocin 2 (beta)]; TPMT [thiopurine S-methyltransferase]; TPO [thyroid peroxidase]; TPP1 [tripeptidyl peptidase I]; TPP2 [Tripeptidyl Peptidase II]; TPPP [Tublin Polymerization Promoting Protein]; TPPP3 [tubulin polymerization-promoting protein family member 3]; TPSAB1 [Tryptase alpha / beta 1]; TPSB2 [Tryptase beta 2 (gene / false gene)]; TPSD1 [Tryptase delta 1]; TPSG1 [Tryptase gamma 1]; TPT1 [tumor protein, detoxically regulated 1]; TRADD [associated TNFRSF1A via killing domain]; TRAF1 [TNF receptor-related factor 1]; TRAF2 [TNF receptor-related factor 2]; TRAF3IP2 [TRAF3 interacting protein 2]; TRAF6 [TNF receptor-related factor 6]; TRAIP [TRAF interacting protein]; TRAPPC10 [trafficking protein particle complex 10]; TRDN [triadine]; TREX1 [3 prime repair exonuclease 1]; TRH [patric acid stimulating hormone-releasing hormone]; TRIB1 [Tribbles Homolog 1 (Drosophila)]; TRIM21 [motif-containing motif 21]; TRIM22 [three-partite motif-containing 22]; TRIM26 [three-separated motif-containing 26]; TRIM28 [motif-containing motif 28]; TRIM29 [three-branched motif-containing 29]; TRIM68 [third-part motif-containing 68]; TRPA1 [transitory receptor capable cation channel, subfamily A, member 1]; TRPC1 [transitory acceptor cation channel, subfamily C, member 1]; TRPC3 [transitory acceptor cation channel, subfamily C, member 3]; TRPC6 [transitory receptor capable cation channel, subfamily C, member 6]; TRPM1 [transitory acceptor cation channel, subfamily M, member 1]; TRPM8 [transitory receptor capable cation channel, subfamily M, member 8]; TRPS1 [trichorhinophalangeal syndrome I]; TRPV1 [transitory acceptable cation channel, subfamily V, member 1]; TRPV4 [transitory acceptor cation channel, subfamily V, member 4]; TRPV5 [transitory acceptor cation channel, subfamily V, member 5]; TRPV6 [transitory acceptor cation channel, subfamily V, member 6]; TRRAP [transformation / transcription domain-related protein]; TSC1 [Nodular Sclerosis 1]; TSC2 [Nodular Sclerosis 2]; TSC22D3 [TSC22 domain family, member 3]; TSG101 [Tumor Sensitive Gene 101]; TSHR [thyroid stimulating hormone receptor]; TSLP [Thymus Stromal Lymphotein]; TSPAN7 [Tetraspanin 7]; TSPO [potentiator protein (18kDa)]; TSSK2 [testis-specific serine kinase 2]; TSTA3 [tissue specific graft antigen P35B]; TTF2 [transcription termination factor, RNA polymerase II]; TTN [titin]; TTPA [tocopherol (alpha) delivery protein]; TTR [transtyretin]; TUBA1B [Tublin, Alpha 1b]; TUBA4A [Tublin, Alpha 4a]; TUBB [tubulin, beta]; TUBB1 [tubulin, beta 1]; TUBG1 [tubulin, gamma 1]; TWIST1 [twist homolog 1 (Drosophila)]; TWSG1 [Twisted Enteroderm Homolog 1 (Drosophila)]; TXK [TXK tyrosine kinase]; TXN [thioredoxin]; TXN2 [thioredoxin 2]; TXNDC5 [thioredoxin domain containing 5 (cytoplasmic network)]; TXNDC9 [containing thioredoxin domain 9]; TXNIP [thioredoxin interacting protein]; TXNRD1 [thioredoxin reductase 1]; TXNRD2 [Thioredoxin Reductase 2]; TYK2 [tyrosine kinase 2]; TYMP [Thymidine phosphorylase]; TYMS [thymidylate synthetase]; TYR [tyrosinase (systemic whiteness IA)]; TYRO3 [TYRO3 Protein Tyrosine Kinase]; TYROBP [TYRO protein tyrosine kinase binding protein]; TYRP1 [tyrosinase-related protein 1]; UBB [ubiquitin B]; UBC [ubiquitin C]; UBE2C [ubiquitin-conjugating enzyme E2C]; UBE2N [ubiquitin-conjugating enzyme E2N (UBC13 homologue, yeast)]; UBE2U [ubiquitin-conjugating enzyme E2U (estimated)]; UBE3A [ubiquitin protein ligase E3A]; UBE4A [ubiquitination factor E4A (UFD2 homologue, yeast)]; UCHL1 [ubiquitin carboxyl-terminated esterase L1 (ubiquitin thiol esterase)]; UCN [urocortin]; UCN2 [urocortin 2]; UCP1 [unlinked protein 1 (mitochondria, proton carrier)]; UCP2 [unlinked protein 2 (mitochondria, proton carrier)]; UCP3 [unlinked protein 3 (mitochondria, proton carrier)]; UFD1L [ubiquitin fusion degradation 1 like (yeast)]; UGCG [UDP-glucose ceramide glucosyltransferase]; UGP2 [UDP-glucose pyrophosphorylase 2]; UGT1A1 [UDP glucuronosyltransferase 1 family, polypeptide A1]; UGT1A6 [UDP glucuronosyltransferase 1 family, polypeptide A6]; UGT1A7 [UDP glucuronosyltransferase 1 family, polypeptide A7]; UGT8 [UDP glycosyltransferase 8]; UIMC1 [1 containing ubiquitin interaction motif]; ULBP1 [UL16 Binding Protein 1]; ULK2 [unc-51-like kinase 2 (C. Elegans)]; UMOD [uromodulin]; UMPS [uridine monophosphate synthase]; UNC13D [unc-13 homologue D (C. Elegans)]; UNC93B1 [unc-93 homologue B1 (C. Elegans)]; UNG [uracil-DNA glycosylase]; UQCRFS1 [ubiquinol-cytochrome c reductase, Rieske iron-sulfur polypeptide 1]; UROD [uroporpyrinogen decarboxylase]; USF1 [upstream transcription factor 1]; USF2 [upstream transcription factor 2, c-fos interaction]; USP18 [ubiquitin specific peptidase 18]; USP34 [ubiquitin specific peptidase 34]; UTRN [eutropin]; UTS2 [urorotin 2]; VAMP8 [vesicle-associated membrane protein 8 (endobrevin)]; VAPA [VAMP (vesicle-associated membrane protein) -associated protein A, 33 kDa]; VASP [vascular dinerve-stimulated phosphoprotein]; VAV1 [vav 1 guanine nucleotide exchange factor]; VAV3 [vav 3 guanine nucleotide exchange factor]; VCAM1 [vascular cell adhesion molecule 1]; VCAN [versican]; VCL [vinculin]; VDAC1 [potential-dependent anion channel 1]; VDR [vitamin D (1 [25-dihydroxyvitamin D3) receptor]; VEGFA [vascular endothelial growth factor A]; VEGFC [vascular endothelial growth factor C]; VHL [von Hippel-Lindau Tumor Suppressor]; VIL1 [villin 1]; VIM [vimentin]; VIP [vascular intestinal peptide]; VIPR1 [vascular intestinal peptide receptor 1]; VIPR2 [vascular intestinal peptide receptor 2]; VLDLR [ultra low density lipoprotein receptor]; VMAC [non-mentin-type intermediate filament related coiled-coil protein]; VPREB1 [pre-B lymphocyte 1]; VPS39 [horror protein sorting 39 homologue (S. Serbisier)]; VTN [Vitronectin]; VWF [von Willebrand factor]; WARS [Tryptophanyl-tRNA Synthetase]; WAS [Wiskott-Aldrich Syndrome (Eczema- Thrombocytopenia)]; WASF1 [WAS Protein Family, Member 1]; WASF2 [WAS Protein Family, Member 2]; WASL [Wiskott-Aldrich Syndrome-like]; WDFY3 [WD repeat and FYVE domain containing 3]; WDR36 [WD Repeat Domain 36]; WEE1 [WEE1 homologue (S. Pombe)]; WIF1 [WNT inhibitory factor 1]; WIPF1 [WAS / WASL interacting protein family, member 1]; WNK1 [WNK Lysine Defect Protein Kinase 1]; WNT5A [wingless-type MMTV unified location family, member 5A]; WRN [Werner syndrome, RecQ helicase-like]; WT1 [Wilms Tumor 1]; XBP1 [X-box binding protein 1]; XCL1 [chemokine (C motif) ligand 1]; XDH [Xanthine Dehydrogenase]; XIAP [X-linked inhibitor of apoptosis]; XPA [pigmentary dry skin, complementary group A]; XPC [pigmentary dry skin, complementary group C]; XPO5 [export in 5]; XRCC1 [Chinese Hemster Intracellular X-ray Repair Complementary Defect Repair 1]; XRCC2 [Chinese Hemster Intracellular X-ray Recovery Complementary Defect Recovery 2]; XRCC3 [Chinese Hemster Intracellular X-ray Recovery Complementary Defect Recovery 3]; XRCC4 [Chinese hamster intracellular X-ray repair complementary deletion repair 4]; XRCC5 [Chinese Hemster Intracellular X-ray Recovery Complementary Defect Recovery 5 (Double-Strand-Gap Recombination)]; XRCC6 [Chinese Hemster Intracellular X-ray Repair Complementary Defect Repair 6]; YAP1 [Yes-related protein 1]; YARS [tyrosyl-tRNA synthetase]; YBX1 [Y box binding protein 1]; YES1 [v-yes-1 Yamaguchi Sarcoma Viral Oncogene Homolog 1]; YPEL1 [yippee-like 1 (Drosophila)]; YPEL2 [yippee-like 2 (Drosophila)]; YWHAB [tyrosine 3-monooxygenase / tryptophan 5-monooxygenase activating protein, beta polypeptide]; YWHAQ [tyrosine 3-monooxygenase / tryptophan 5-monooxygenase activating protein, theta polypeptide]; YWHAZ [Tyrosine 3-monooxygenase / tryptophan 5-monooxygenase activating protein, zeta polypeptide]; YY1 [YY1 transcription factor]; ZAP70 [zeta-chain (TCR) related protein kinase 70 kDa]; ZBED1 [Zinc finger, BED-type containing 1]; ZC3H12A [Zinc finger CCCH-type containing 12A]; ZC3H12D [Zinc finger CCCH-type containing 12D]; ZFR [Zinc Finger RNA Binding Protein]; ZNF148 [Zinc Finger Protein 148]; ZNF267 [Zinc Finger Protein 267]; ZNF287 [Zinc Finger Protein 287]; ZNF300 [Zinc Finger Protein 300]; ZNF365 [Zinc Finger Protein 365]; ZNF521 [Zinc Finger Protein 521]; ZNF74 [Zinc Finger Protein 74]; And ZPBP2 (zona pellucida binding protein 2).

In certain embodiments, measurements commonly used in immunodeficiency studies in animals created by the methods of the invention can be used to study the effects of mutations and the development and / or progression of immunodeficiency in animals.

Genetically modified animals, such as knock-out and transgenic animals, created by the methods of the invention may be altered by a single or combination of genes including alterations to any one or more of Rag1, Rag2, FoxN1, and DNAPK. It should be recognized that they can include them. Thus, for example, animals that include single, double or triple gene knock-out are considered. Any of these may be used in various ways in which alteration of one or more immunodeficiency genes may be useful. For example, the genetically modified animals described herein include studies of hematopoietic cells, such as the identification of progenitor cells, including lymphoid progenitor and pluripotent stem cells; Identification of new cytokines that play a role in the growth and differentiation of hematopoietic cells; Analysis of the effects of known cytokines; And drug effect analysis on hematopoietic cells. These animals include influenza, West Nile virus, herpes virus, picornavirus, neurotrophic coronavirus, chickenpox-zoster (chicken smallpox), respiratory syncytial virus, vaccinia, hepatitis B, rabies, and Dengue virus. And lymphoma viruses, including human immunodeficiency virus (HIV), human T lymphoma virus (HTLV-1), and Ipstein Barr virus (EBV), and especially mice that produce effects of human-specific viruses in the host. It may also be useful for studying the pathogenesis in diseases caused by infection with infectious viruses, such as but not limited to influenza viruses suitable for mice (eg, H. Lebrec). and GR Burleson (1994) Toxicology . Jul 1 ; 91 (2): 179-88 ).

In other embodiments, animals created by genetically modified methods of the invention are also useful for the study of defense mechanisms against microorganisms causing disease in immunocompromised patients, where the microorganisms are cytomegalovirus, Pneumocystic carinii) or Candida (Candida) can be all day. Genetically modified animals, such as knock-out mice, may be subject for pre-clinical evaluation of specific “gene therapy”. For example, genes are introduced into hematopoietic progenitor cells, such as omnipotent stem cells with self-renewal ability from patients with inherited gene defects, or omnipotent stem cells with self-renewal ability from mouse models with inherited gene defects. Cells can be introduced back into the genetically modified mouse for the purpose of determining the therapeutic utility of the modified cells. Genetically modified animals will also be useful for studying immunodeficient diseases and biological mechanisms hiding by or in conditions linked to immunodeficient genes such as Rag1, Rag2, FoxN1, or DNAPK.

Moreover, genetically modified animals created by the methods of the present invention can also be used to develop diagnostic assays for immunodeficiency disorders, including but not limited to leukemia, which have not been treated or have been previously treated with therapeutic agents. Animals that had been assessed are assessed for the presence of one or more biomarkers compared to the unaffected reference animal. Such genetically modified animals can be used in methods for screening candidate therapeutic or therapeutic compounds for treating immunodeficiency disorders such as leukemia using genetically modified animals, wherein Rag1, Rag2, FoxN1, or One or more immunodeficiency genes, including but not limited to DNAPK, are knocked out and animals that have not been treated or have been previously treated with a therapeutic agent that may be drugs, microorganisms, transplanted cells or other agents may be treated as candidate treatments. Or a biological sample obtained from the animal, treated with the candidate therapeutic material, the obtained biological sample being a sample of a wild-type reference sample unaffected, or a genetically modified animal not affected by the candidate therapeutic or therapeutic material. Evaluate by comparison.

In further embodiments, the method of mimicking an autoimmune disease may comprise selective delivery of B cells in response to an antigen of the autoimmune disease, or selective delivery of activated T cells to an autoimmune disease. Suitable mammals that are not humans with antigenic targets of autoimmune diseases can be immunized as follows.

Prepare immune cells from immunized animals, and then genetically modified animals described herein, such as Rag1, Rag2, FoxN1, or DNAPK knock-out mice, or mice with any combination of these knocked out genes. Can be transplanted to The development of autoimmune phenotypes in recipient knock-out animals was compared with non-transplanted knock-out animals, or with knock-out animals transplanted with non-pathogenic immune cells without auto-responsiveness, or transplanting the immune cells described herein. Evaluation can be made by comparison with wild-type animals received.

In certain embodiments, a method of creating a complex immunodeficiency syndrome model provides an animal, such as a genetically modified mouse, in which Rag1, Rag2, FoxN1, or DNAPK is knocked out as described herein, and such rust The out-of-animal can further impart defects on natural killer (NK) cells by any of several possible methods. Non-limiting examples of how to further impart NK binding to knock-out animals include: i) disruption of the Lyst gene; Or ii) NSAIDs (non-steroidal anti-inflammatory drugs), statins, allosteric LFA-1 inhibitors, vinblastine, paclitaxel, docetaxel, cladribine, chlorambutyl, bortezomib, or MG Treating the FoxN1 mutant animal with a compound that inhibits NK cell activity, including but not limited to -132.

N. Trinucleotide  Repetitive disorder

Trinucleotide repeat expansion disorders fall into two categories, determined by the type of repeat. The most common repetition is triple CAG, which, when present in the coding portion of the gene, encodes the amino acid glutamine (Q). Thus, such disorders are called polyglutamine (polyQ) disorders and include Huntington's disease (HD); Spinal bulb muscular dystrophy (SBMA); Spinal cerebellar ataxia (SCA types 1, 2, 3, 6, 7, and 17); And Dentatorubro-Pallidoluysian atrophy (DRPLA). Other trinucleotide repeat expansion disorders are not related to CAG triples, or CAG triples are not in the coding portion of the gene and are called non-polyglutamine disorders. Non-polyglutamine disorders include brittle X syndrome (FRAXA); Fragile XE mental retardation (FRAXE); Friedreich ataxia (FRDA); Muscular dystrophy (DM); And spinal cerebellar ataxia (SCA types 8, and 12).

In one embodiment, the methods of the invention can be used to create an animal or cell in which at least one chromosomal sequence associated with a trinucleotide repeat disorder has been edited. Suitable chromosomal editing includes, but is not limited to, the type of editing described in paragraph I (f) above.

In each of the above embodiments, one or more chromosomal sequences associated with trinucleotide repeat disorders can be edited. Trinucleotide repeat disorder-associated protein or regulatory sequences can typically be selected based on experimental association of proteins or sequences associated with trinucleotide repeat expansion disorder. Trinucleotide repeat expansion proteins can include related proteins that are sensitive to the development of a trinucleotide repeat expansion disorder, the presence of a trinucleotide repeat expansion disorder, the severity of the trinucleotide repeat expansion disorder, or any combination thereof. For example, the production rate or circulating concentration of a trinucleotide repeat expansion disorder-related protein can be raised or suppressed in a population with a trinucleotide repeat expansion disorder compared to a population without a trinucleotide repeat expansion disorder. Differences in protein levels can be assessed using proteomic or genomic analysis techniques known in the art.

Non-limiting examples of proteins associated with trinucleotide repeat expansion disorders include AR (androgen receptor), FMR1 (fragile X mental retardation 1), HTT (huntingtin), DMPK (muscular dystrophy-protein kinase), FXN ( Pratacin), ATXN2 (atacin 2), ATN1 (atropine 1), FEN1 (flap structure-specific endonuclease 1), TNRC6A (3A containing trinucleotide repeat 6A), PABPN1 (poly (A) binding protein, nucleus 1), JPH3 (jeongtophylline 3), MED15 (mediator complex subunit 15), ATXN1 (atacin 1), ATXN3 (atacin 3), TBP (TATA box binding protein), CACNA1A (calcium channel, potential-dependent) , P / Q type, alpha 1A subunit), ATXN8OS (ATXN8 opposite strand (non-protein coding)), PPP2R2B (protein phosphatase 2, regulatory subunit B, beta), ATXN7 (atacin 7), TNRC6B (trinucleotide repeat containing 6B), TNRC6C (tri-nucleotide repeats contain 6C), CELF3 (CUGBP, Elav- similar family member 3), MAB21L1 (mab-21- Similar 1 (C. L. 3 homolog elegans)), MSH2 (mutS homolog 2, colon cancer, cost trailing type 1 (E. coli)), TMEM185A (transmembrane protein 185A), SIX5 (SIX homeobox 5), CNPY3 (canopy (canopy) ( Zebrafish)), FRAXE (fragile position, folic acid type, rare, fra (X) (q28) E), GNB2 (guanine nucleotide binding protein (G protein), beta polypeptide 2), RPL14 (ribosome protein L14) , ATXN8 (atacin 8), INSR (insulin receptor), TTR (transtyretin), EP400 (E1A binding protein p400), GIGYF2 (GRB10 interacting GYF protein 2), OGG1 (8-oxoguanine DNA glycosylase) , STC1 (stanniocalcin 1), CNDP1 (carnosine dipeptidase 1 (metalpeptidase M20 family)), C10orf2 (chromosome 10 open reading frame 2), MAML3 mastermind-like 3 ( Drosophila), DKC1 (congenital dyskeratosis 1, diskerin), PAXIP1 (PAX interaction (with transcription-activation domain) protein 1), CASK (calcium / calmodulin-dependent) Lean protein kinase (MAGUK family)), MAPT (microtubule-associated protein tau), SP1 (Sp1 transcription factor), POLG (polymerase (DNA oriented), gamma), AFF2 (AF4 / FMR2 family, member 2), THBS1 (Trombospondin 1), TP53 (Tumor Protein p53), ESR1 (Estrogen Receptor 1), CGGBP1 (CGG Triple Repeat Binding Protein 1), ABT1 (Activator 1 of Basic Transcription), KLK3 (Kallikrein-Related Peptidase) 3), PRNP (prion protein), JUN (jun oncogene), KCNN3 (medium potassium / small conducting calcium-activated channel, subfamily N, member 3), BAX (BCL2-associated X protein), FRAXA (cracker) Easy location, folic acid type, rare, fra (X) (q27.3) A (macrorchidism, mental retardation), KBTBD10 (contains Kelch repeat and BTB (POZ) domains 10), MBNL1 (muscle) Blind (muscleblind-like (Drosophila)), RAD51 (RAD51 homologue (RecA homologue, E. coli) (S. CERVISI)), NCOA3 (nuclear receptor coactivator 3), ERDA1 (extended repeat domain, CAG / CTG 1), TSC1 (nodular sclerosis 1), COMP (cartilage oligomer matrix protein), GCLC (glutamate-cysteine lige) Izu, catalytic subunit), RRAD (Ras-associated with diabetes), MSH3 (mutS homologue 3 (E. coli)), DRD2 (dopamine receptor D2), CD44 (CD44 molecule (Indian blood group)), CTCF (CCCTC -Binding factor (zinc finger protein)), CCND1 (cyclin D1), CLSPN (claspin homologue (Africa claw)), MEF2A (muscle cell enhancer factor 2A), PTPRU (protein tyrosine phosphatase, receptor type, U) , GAPDH (glyceraldehyde-3-phosphate dehydrogenase), TRIM22 (triplet motif-containing 22), WT1 (Wilms tumor 1), AHR (aryl hydrocarbon receptor), GPX1 (glutathione peroxidase 1), TPMT (thiopurine S-methyltransferase), NDP (Norrie disease (pseudoglioma)), ARX (aristaless) Related homeobox), MUS81 (MUS81 endonuclease homologue (S. cervici)), TYR (tyrosinase (systemic whiteness IA)), EGR1 (initial growth reaction 1), UNG (uracil-DNA glycosylase) ), NUMBL (numb homologue (Drosophila) -like), FABP2 (fatty acid binding protein 2, gut), EN2 (engrailed homeobox 2), CRYGC (crystallin, gamma C), SRP14 (signal Cognitive particles 14kDa (homologous Alu RNA binding protein)), CRYGB (crystallin, gamma B), PDCD1 (scheduled cell death 1), HOXA1 (homeobox A1), ATXN2L (atacin 2-like), PMS2 (PMS2 Increased segregation after meiosis 2 (S. cervici)), GLA (galactosidase, alpha), CBL (Cas-Br-M (murine) Icotropic retroviral transformed sequence), FTH1 (ferritin, Heavy polypeptide 1), IL12RB2 (interleukin 12 receptor, beta 2), OTX2 (orthodenticle homeobox 2), HOXA5 (homeobox A5), POLG2 (polymerase (DNA directed), gamma 2, Crude subunit), DLX2 (distal-less homeobox 2), SIRPA (signal-regulating protein alpha), OTX1 (orthodental homeobox 1), AHRR (aryl-hydrocarbon receptor inhibitor) , MANF (medium brain astrocyte-derived neurotrophic factor), TMEM158 (membrane transit protein 158 (gene / false gene)), and ENSG00000078687.

Typical proteins associated with trinucleotide repeat expansion disorders are HTT (huntingtin), AR (androgen receptor), FXN (pratacin), Atxn3 (atacin), Atxn1 (atacin), Atxn2 (atacin), Atxn7 (atacin) ), Atxn10 (atacin), DMPK (muscular dystrophy-protein kinase), Atn1 (atropine 1), CBP (creb binding protein), VLDLR (ultra low density lipoprotein receptor), and any combination thereof.

In certain embodiments, measurements commonly used in studies of trinucleotide repeat disorders in animals created by the methods of the invention can be used to study the effects of mutations and the development and / or progression of trinucleotide repeat disorders in animals. .

O. Neurotransmission Disorder

Non-limiting examples of neurotransmission disorders include amyotrophic lateral sclerosis (ALS), spinal cerebellar ataxia (SCA) including SCA2, Alzheimer; Autism, mental retardation, Rett syndrome, brittle X syndrome, depression, schizophrenia, bipolar disorder, learning, memory or behavioral disorders, anxiety, brain damage, seizure disorders, Huntington disease (chorea), manic, neuroleptic malignant Syndrome, pain, Parkinson's disease, Parkinson's disease, delayed dyskinesia, myasthenia gravis, intermittent ataxia, hyperkalemia, paralytic hypokalemia, Lambert-Eaton syndrome, congenital dystonia, Rasmussen encephalitis, surprise Reflexes, stiff baby syndrome), and addiction outcomes such as Bottlinus poisoning, mushroom poisoning, organophosphates, and snake venom of Bungarus multicinctus (Taiwanese banded umbrella snake).

In one embodiment, the methods of the invention can be used to create an animal or cell in which at least one chromosomal sequence has been edited associated with a neurotransmission disorder. Suitable chromosomal editing includes, but is not limited to, the type of editing described in paragraph I (f) above.

In each of the above embodiments, one or more chromosomal sequences associated with neurotransmission disorders can be edited. Neurotransmission Disorders Related proteins or regulatory sequences may typically be selected based on experimental association of proteins involved in neurotransmission disorders. Neurotransmission disorder-related proteins may include related proteins that are sensitive to the development of neurotransmission disorders, the presence of neurotransmission disorders, the severity of neurotransmission disorders, or any combination thereof. For example, the rate of production or circulating concentration of neurotransmission disorder-related proteins may be elevated or inhibited in a population with neurotransmission disorders as compared to a population without neurotransmission disorders. Differences in protein levels can be assessed using proteomic or genomic analysis techniques known in the art.

Non-limiting examples of neurotransmitter disorder-related proteins include SST (somatostatin), NOS1 (nitric oxide synthase 1 (neuron)), ADRA2A (adrenergic, alpha-2A-, receptor), ADRA2C (adrenergic, alpha- 2C-, receptor), TACR1 (tachikinin receptor 1), HTR2C (5-hydroxytryptamine (serotonin) receptor 2C), SLC1A2 (solute carrier family 1 (glue high affinity glutamate transporter), member 2), GRM5 ( Glutamate receptor, metabotropic 5), GRM2 (glutamate receptor, metabotropic 2), GABRG3 (gamma-aminobutyl acid (GABA) A receptor, gamma 3), CACNA1B (calcium channel, potential-dependent, N type, alpha 1B subunit), NOS2 (nitric oxide synthase 2, inducible), SLC6A5 (solute carrier family 6 (neurotransmitter transport, glycine), member 5), GABRG1 (gamma-aminobutyl acid (GABA) A receptor, gamma 1), NOS3 (nitric oxide synthase 3 (endothelial)), GRM3 (glutamate receptor, meta Tropic 3), HTR6 (5-hydroxytrypamine (serotonin) receptor 6), SLC1A3 (solute carrier family 1 (glue high affinity glutamate transport), member 3), GRM7 (glutamate receptor, metabotropic 7), HRH1 ( Histamine receptor H1), SLC1A1 (solute carrier family 1 (neuron / epithelial high affinity glutamate transport, system Xag), member 1), GRM4 (glutamate receptor, metabotropic 4), GLUD2 (glutamate dehydrogenase 2), ADRA2B (adrenaline Sex, alpha-2B-, receptor), SLC1A6 (solute carrier family 1 (high affinity aspartate / glutamate transport), member 6), GRM6 (glutamate receptor, metabotropic 6), SLC1A7 (solute carrier family 1 (glutamate) Transport), member 7), SLC6A11 (solute carrier family 6 (neurotransporter transport, GABA), member 11), CACNA1A (calcium channel, potential-dependent, P / Q type, alpha 1A subunit), CACNA1G (calcium channel , Potential-dependent, T type, alpha 1G subunit), GRM1 (glutamate receptor, metabotropic 1), CACNA1H (calcium channel, translocation-dependent, type T, alpha 1H subunit), GRM8 (glutamate receptor, metabotropic 8), CHRNA3 (Cholinergic receptor, nicotinic, alpha 3), P2RY2 (purinergic receptor P2Y, G-protein linked, 2), TRPV6 (transient receptor capable cation channel, subfamily V, member 6), CACNA1E (calcium channel, Potential-dependent, R type, alpha 1E subunit), ACCN1 (amylolide-sensitive cation channel 1, neurons), CACNA1I (calcium channel, potential-dependent, type T, alpha 1I subunit), GABARAP (GABA (A ) Receptor-associated protein), P2RY1 (purinergic receptor P2Y, G-protein linked, 1), P2RY6 (pyrimidine functional receptor P2Y, G-protein linked, 6), RPH3A (rabphilin 3A homolog (Mouse)), HDC (histidine decarboxylase), P2RY14 (purinergic receptor P2Y, G-protein linked, 14), P2R Y4 (pyrimidine functional receptor P2Y, G-protein linked, 4), P2RY10 (purinergic receptor P2Y, G-protein linked, 10), SLC28A3 (solute carrier family 28 (sodium-linked nucleoside transport), member 3), NOSTRIN (nitric oxide synthase trafficker), P2RY13 (purine agonist P2Y, G-protein linked, 13), P2RY8 (purin agonist P2Y, G-protein linked, 8), P2RY11 ( Purinergic receptor P2Y, G-protein linked, 11), SLC6A3 (solute carrier family 6 (neurotransmitter transport, dopamine), member 3), HTR3A (5-hydroxytrytamine (serotonin) receptor 3A), DRD2 ( Dopamine receptor D2), HTR2A (5-hydroxytrytamine (serotonin) receptor 2A), TH (tyrosine hydroxylase), CNR1 (cannabinoid receptor 1 (brain)), VIP (vascular intestinal peptide), NPY (nerve) Peptide Y), GAL (galanine prepropeptide), TAC1 (tachikinin, precursor 1), SYP (synaptophycin), SLC6A4 ( Solute Carrier Family 6 (neurotransmitter transport, serotonin), member 4), DBH (dopamine beta-hydroxylase (dopamine beta-monooxygenase)), DRD3 (dopamine receptor D3), NR3C1 (nuclear receptor subfamily) 3, group C, member 1 (glucocorticoid receptor)), HTR1B (5-hydroxytryptamine (serotonin) receptor 1B), GABBR1 (gamma-aminobutyl acid (GABA) B receptor, 1), CALCA (calcitonin-associated Polypeptide alpha), CRH (adrenal cortical stimulating hormone), HTR1A (5-hydroxytrytamine (serotonin) receptor 1A), TACR2 (tachikinin receptor 2), COMT (catechol-O-methyltransferase), GRIN2B (glutamate receptor, ionic, N-methyl D-aspartate 2B), GRIN2A (glutamate receptor, ionic, N-methyl D-aspartate 2A), PRL (prolactin), ACHE (acetylcholinesterase (Yt blood group)), ADRB2 (adrenergic, beta-2-, receptor, surface), ACE (angiothene) I converting enzyme (peptidyl-dipeptidase A) 1), SNAP25 (synaptosome-associated protein, 25 kDa), GABRA5 (gamma-aminobutyl acid (GABA) A receptor, alpha 5), MECP2 (methyl CpG binding protein 2 (Rett syndrome)), BCHE (butyrylcholinesterase), ADRB1 (adrenergic, beta-1-, receptor), GABRA1 (gamma-aminobutyl acid (GABA) A receptor, alpha 1), GCH1 (GTP cyclo Hydrolase 1), DDC (dopa decarboxylase (aromatic L-amino acid decarboxylase)), MAOB (monoamine oxidase B), DRD5 (dopamine receptor D5), GABRE (gamma-aminobutyl acid (GABA) A Receptor, epsilon), SLC6A2 (solute carrier family 6 (neurotransmitter transport, noradrenaline), member 2), GABRR2 (gamma-aminobutyl acid (GABA) receptor, rho 2), SV2A (synaptic vesicle glycoprotein 2A), GABRR1 (gamma-aminobutyl acid (GABA) receptor, rho 1), GHRH (growth hormone releasing hormone), CCK (cholecystokinin), PDYN (prodinolpin), SLC6 A9 (solute carrier family 6 (neurotransmitter transport, glycine), member 9), KCND1 (potassium potential-gated channel, Shal-associated subfamily, member 1), SRR (serine lastemating agent), DYT10 (tension 10) , MAPT (microtubule-associated protein tau), APP (amyloid beta (A4) precursor protein), CTSB (cathepsin B), ADA (adenosine deaminase), AKT1 (v-akt murine thymoma viral oncogene phase Fuselage 1), GRIN1 (glutamate receptor, ionic, N-methyl D-aspartate 1), BDNF (brain-derived neurotrophic factor), HMOX1 (ham oxygenase (decycling) 1), OPRM1 (opium Receptor, mu 1), GRIN2C (glutamate receptor, ionic, N-methyl D-aspartate2C), GRIA1 (glutamate receptor, ionic, AMPA 1), GABRA6 (gamma-aminobutyl acid (GABA) A receptor, Alpha 6), FOS (FBJ murine osteosarcoma viral oncogene homologue), GABRG2 (gamma-aminobutyl acid (GABA) A receptor, gamma 2), GABRB3 (gamma-aminobutyl acid (GABA) A receptor, beta 3), OPRK1 (opium receptor, kappa 1), GABRB2 (gamma-aminobutyl acid (GABA) A receptor, beta 2), GABRD (gamma-aminobutyl acid (GABA) A receptor, delta), ALDH5A1 (aldehyde dehydrogenase 5 family, member A1), GAD1 (glutamate decarboxylase 1 (brain, 67kDa)), NSF (N-ethylmaleimide-sensitive factor), GRIN2D (glutamate Receptor, ionic, N-methyl D-aspartate2D), ADORA1 (adenosine A1 receptor), GABRA2 (gamma-aminobutyl acid (GABA) A receptor, alpha 2), GLRA1 (glycine receptor, alpha 1), CHRM3 (Cholinergic receptor, muscarinic 3), CHAT (choline acetyltransferase), KNG1 (kinnogen 1), HMOX2 (ham oxygenase (decycling) 2), DRD4 (dopamine receptor D4), MAOA (mono Amine oxidase A), CHRM2 (cholinergic receptor, muscarinic 2), ADORA2A (adenosine A2a receptor), STXBP1 (synthacin binding protein 1), GABRA3 (gamma) -Aminobutyl acid (GABA) A receptor, alpha 3), TPH1 (tryptophan hydroxylase 1), HCRTR1 (hypocretin (oresine) receptor 1), HCRTR2 (hypocretin (oresine) receptor 2), CHRM1 ( Cholinergic receptors, muscarinic 1), FOLH1 (folate hydrolase (prostate-specific membrane antigen) 1), AANAT (arylalkylamine N-acetyltransferase), INS (insulin), NR3C2 (nuclear receptor) Subfamily 3, group C, member 2), FAAH (fatty acid amide hydrolase), GALR2 (galanine receptor 2), ADCYAP1 (adenylate cyclase activating polypeptide 1 (pituitary)), PPP1R1B (protein phosphatase 1, Regulatory (inhibitor) subunit 1B), HOMER1 (homer homolog 1 (Drosophila)), ADCY10 (adenylate cyclase 10 (soluble)), PSEN2 (presenillin 2 (Alzheimer disease 4)), UBE3A (ubiquitin protein ligase E3A), SOD1 (superoxide dismutase 1, soluble), LYN (v-yes-1 Yamaguchi sarcoma virus Sex-related oncogene homologues), TSC2 (nodular sclerosis 2), PRKCA (protein kinase C, alpha), PPARG (peroxysome proliferator-activated receptor gamma), ESR1 (estrogen receptor 1), NTRK1 (neotrophic tyrosine) Kinase, receptor, type 1), EGFR (epithelial growth factor receptor (erythroblastic leukemia viral (v-erb-b) oncogene homologue, algae)), S100B (S100 calcium binding protein B), NTRK3 (neotrophic tyrosine) Kinase, receptor, type 3), PLCG2 (phospholipase C, gamma 2 (phosphatidylinositol-specific)), NTRK2 (neotrophic tyrosine kinase, receptor, type 2), DNMT1 (DNA (cytosine-5-)-methyl Transferase 1), EGF (epithelial growth factor (beta-neugestrone)), GRIA3 (glutamate receptor, ionotrophic, AMPA 3), NCAM1 (nerve cell adhesion molecule 1), CDKN1A (cyclin-dependent kinase inhibitor 1A (p21, Cip1)), BCL2L1 (BCL2-like 1), TP53 (tumor protein p53), CASP9 (Caspase 9, Apoptosis-Related Cysteine Peptidase), CCKBR (Cholekistokinin B Receptor), PARK2 (Parkinson Disease (Autosome Recession, Adolescence) 2, Parkin), ADRA1B (Adrenergic, Alpha- 1B-, receptor), CASP3 (caspase 3, apoptosis-related cysteine peptidase), PRNP (prion protein), CRHR1 (adrenal cortical stimulating hormone receptor 1), L1CAM (L1 cell adhesion molecule), NGFR (Nerve growth factor receptor (TNFR superfamily, member 16)), CREB1 (cAMP response element binding protein 1), PLCG1 (phospholipase C, gamma 1), CAV1 (caberoline 1, caveol protein, 22kDa), ABCC8 (ATP-binding cassette, sub-family C (CFTR / MRP), member 8), ACTN2 (actinine, alpha 2), GRIA2 (glutamate receptor, ionic, AMPA 2), HPRT1 (hypoxanthine phosphoribosyltransferase 1), SYN1 (synapsin I), CSNK2A1 (casein kinase 2, alpha 1 polypeptide), GRIK1 (glutamate receptor, ion , Catenate 1), ABCB1 (ATP-binding cassette, sub-family B (MDR / TAP), member 1), AVPR2 (arginine vasopressin receptor 2), HTR4 (5-hydroxytrytamine (serotonin) receptor 4), C3 (complement component 3), AGT (anggiotensinogen (serpin peptidase inhibitor, Clade A, member 8)), AGTR1 (anggiotensin II receptor, type 1), CDK5 (cyclin-dependent kinase 5) , LRP1 (low density lipoprotein receptor-associated protein 1), ARRB2 (arrestin, beta 2), PLD2 (phospholipase D2), OPRD1 (opium receptor, delta 1), GNB3 (guanine nucleotide binding protein (G protein), beta Polypeptide 3), PIK3CG (phosphoinositide-3-kinase, catalyst, gamma polypeptide), APAF1 (apoptotic peptidase activating factor 1), SSTR2 (somatostatin receptor 2), IL2 (interleukin 2), ADORA3 ( Adenosine A3 receptor), ADRA1A (adrenergic, alpha-1A-, receptor), HTR7 (5-hydroxytrytamine (three Tonin) receptor 7 (adenylate cyclase-linked)), ADRBK2 (adrenergic, beta, receptor kinase 2), ALOX5 (arachidonate 5-lipoxygenase), NPR1 (sodium release peptide receptor A / guanyl Late cyclase A (atrial fibrillation sodium release peptide receptor A), AVPR1A (arginine vasopressin receptor 1A), CHRNB1 (cholinergic receptor, nicotinic, beta 1 (muscle)), SET (SET nuclear oncogene), PAH (Phenylalanine hydroxylase), POMC (propiomelanocortin), LEPR (leptin receptor), SDC2 (syndecan 2), VIPR1 (vascular intestinal peptide receptor 1), DBI (diazepam binding inhibitor (GABA receptor modulator) , Acyl-coenzyme A binding protein)), NPY1R (neuropeptide Y receptor Y1), NPR2 (sodium release peptide receptor B / guanylate cyclase B (atrial sodium release peptide receptor B)), CNR2 (cannabinoid receptor 2 ( Macrophages)), LEP (leptin), CCKAR (Cholecystokinin A receptor), GLRB (glycine receptor, beta), KCNQ2 (potassium translocation-gated channel, KQT-like subfamily, member 2), CHRNA2 (cholinergic receptor, nicotinic, alpha 2 (neuron) ), BDKRB2 (bradykinin receptor B2), CHRNA1 (cholinergic receptor, nicotinic, alpha 1 (muscle)), CHRND (cholinergic receptor, nicotinic, delta), CHRNA7 (cholinergic receptor, nicotinic, Alpha 7), PLD1 (phospholipase D1, phosphatidylcholine-specific), NRXN1 (neulexin 1), NRP1 (neuphylline 1), DLG3 (disc, large homolog 3 (Drosophila)), GNAQ (guanine nucleotide binding protein (G protein), q polypeptide), DRD1 (dopamine receptor D1), PRKG1 (protein kinase, cGMP-dependent, type I), CNTNAP2 (contactin related protein-like 2), EDN3 (endoterin 3), ABAT (4 -Aminobutyrate aminotransferase), TDO2 (tryptophan 2,3-dioxygenase), NEUROD1 (neurotrophic differentiation 1), CHRNE (cholinergic) Receptor, nicotinic, epsilon), CHRNB2 (cholinergic receptor, nicotinic, beta 2 (neuron)), CHRNB3 (cholinergic receptor, nicotinic, beta 3), HTR1D (5-hydroxytryptamine (serotonin) Receptor 1D), ADRA1D (adrenergic, alpha-1D-, receptor), HTR2B (5-hydroxytrytamine (serotonin) receptor 2B), GRIK3 (glutamate receptor, ionic, kinate 3), NPY2R (neural peptide Y Receptor Y2), GRIK5 (glutamate receptor, ionic, kinate 5), GRIA4 (glutamate receptor, ionic, AMPA 4), EDN1 (endoterin 1), PRLR (prolactin receptor), GABRB1 (gamma-aminobutyl acid ( GABA) A Receptor, Beta 1), GARS (Glysyl-tRNA Synthetase), GRIK2 (Glutamate Receptor, Ionic, Cinate 2), ALOX12 (Arachidonate 12-lipoxygenase), GAD2 (Glutamate Decarboxylase) 2 (pancreatic islet and brain, 65kDa)), LHCGR (Progesterone / Villi Gonadotropin) Receptor), SHMT1 (serine hydroxymethyltransferase 1 (soluble)), PDXK (pyridoxal (pyridoxine, vitamin B6) kinase), LIF (leukemia inhibitory factor (cholinergic differentiation factor)), PLCD1 (phospholipase C , Delta 1), NTF3 (neutropin 3), NFE2L2 (nuclear factor (erythrocyte-derived 2) -like 2), PLCB4 (phospholipase C, beta 4), GNRHR (gonadotropin-releasing hormone receptor ), NLGN1 (Nurorigin 1), PPP2R4 (protein phosphatase 2A activator, regulatory subunit 4), SSTR3 (somatostatin receptor 3), CRHR2 (adrenal cortical stimulating hormone releasing hormone receptor 2), NGF (nerve growth factor (beta) Polypeptides)), NRCAM (neuron cell adhesion molecule), NRXN3 (neulexin 3), GNRH1 (gonadotropin-releasing hormone 1 (luteinated-releasing hormone)), TRHR (palpogenic stimulating hormone-releasing hormone receptor), ARRB1 (Arrestin, Beta 1), INPP1 (Inositol Polyphosphate-1-phosphatase), PTN (Fleotropin), PSMD10 (Prote Asome (Prosome, Macropine) 26S Subunit, Non-ATPase, 10), DLG1 (Disc, Large Homolog 1 (Drosophila)), PSMB8 (Proteasome (Prosome, Macropine) Subunit, Beta Type, 8 (large multifunctional peptidase 7)), CYCS (cytochrome c, bodily), ADORA2B (adenosine A2b receptor), ADRB3 (adrenergic, beta-3-, receptor), CHGA (chromographin A (parathyroid) Secretory protein 1)), ADM (adrenomedulin), GABRP (gamma-aminobutyl acid (GABA) A receptor, pi), GLRA2 (glycine receptor, alpha 2), PRKG2 (protein kinase, cGMP-dependent, type II ), GLS (glutaminase), TACR3 (tachikinin receptor 3), ALDH7A1 (aldehyde dehydrogenase 7 family, member A1), GABBR2 (gamma-aminobutyl acid (GABA) B receptor, 2), GDNF (glia cells) Induced neurotrophic factor), CNTFR (ciliary neurotrophic factor receptor), CNTN2 (contactin 2 (axon)), TOR1A (torsin (torcin) family 1, member A (torsin A)), CNTN1 (contactin One) , CAMK1 (calcium / calmodulin-dependent protein kinase I), NPPB (sodium release peptide precursor B), OXTR (oxytocin receptor), OSM (on costatin M), VIPR2 (vascular intestinal peptide receptor 2), CHRNB4 ( Cholinergic receptor, nicotinic, beta 4), CHRNA5 (cholinergic receptor, nicotinic, alpha 5), AVP (arginine vasopressin), RELN (reelin), GRLF1 (glucocorticoid receptor DNA binding factor 1) , NPR3 (sodium release peptide receptor C / guanylate cyclase C (atrial sodium release peptide receptor C)), GRIK4 (glutamate receptor, ionic, kinate 4), KISS1 (KiSS-1 transition-inhibitor), HTR5A (5-hydroxytrytamine (serotonin) receptor 5A), ADCYAP1R1 (adenylate cyclase activating polypeptide 1 (pituitary) receptor type I), GABRA4 (gamma-aminobutyl acid (GABA) A receptor, alpha 4) , GLRA3 (glycine receptor, alpha 3), INHBA (inhibin, Other A), DLG2 (disc, large homolog 2 (Drosophila)), PPYR1 (pancreatic polypeptide receptor 1), SSTR4 (somatostatin receptor 4), NPPA (sodium release peptide precursor A), SNAP23 (synaptosome-associated protein, 23 kDa), AKAP9 (A kinase (PRKA) anchor protein (yotiao) 9), NRXN2 (neulexin 2), FHL2 (4 and 1/2 LIM domain 2), TJP1 (solid binding protein 1 (Jona Occluden 1) ), NRG1 (neuregulin 1), CAMK4 (calcium / calmodulin-dependent protein kinase IV), CAV3 (caberoline 3), VAMP2 (vesicle-associated membrane protein 2 (synaptobrevin 2)), GALR1 (galanine Receptor 1), GHRHR (growth hormone releasing hormone receptor), HTR1E (5-hydroxytrytamine (serotonin) receptor 1E), PENK (proenkephalin), HTT (huntingtin), HOXA1 (homeobox A1), NPY5R ( Neuropeptide Y receptor Y5), UNC119 (unc-119 homologue ( C. elegans )), TAT (tyrosine aminotransferase), CNTF (ciliary neurotrophic factor), SHMT2 (serine hydroxy) Methyltransferase 2 (mitochondria)), ENTPD1 (ectonucleoside triphosphate diphosphohydrolase 1), GRIP1 (glutamate receptor interacting protein 1), GRP (gastrin-releasing peptide), NCAM2 (nerve cell adhesion molecule 2 ), SSTR1 (somatostatin receptor 1), CLTB (Claterin, Light Chain (Lcb)), DAO (D-Amino-Acid Oxidase), QDPR (quinoid dihydrophteridine reductase), PYY (Peptide YY), PNMT (phenylethanolamine N-methyltransferase), NTSR1 (neurotensin receptor 1 (high affinity)), NTS (neurotensin), HCRT (hypocretin (oresine) neuropeptide precursors), SNAP29 (synaptosome-associated Protein, 29kDa), SNAP91 (synaptosome-related protein, 91kDa homologue (mouse)), MADD (MAP-kinase activating death domain), IDO1 (indolamine 2,3-dioxygenase 1), TPH2 (tryptophan hydroxide Silase 2), TAC3 (tachikinin 3), GRIN3A (glutamate receptor, ionic, N-methyl-D-aspa Lutetate 3A), REN (renin), GALR3 (galanine receptor 3), MAGI2 (membrane related guanylate kinase, WW and PDZ domain containing 2), KCNJ9 (potassium inward-rectifying channel, subfamily J, member 9), BDKRB1 (bradykinin receptor B1), CHRNA6 (cholinergic receptor, nicotinic, alpha 6), CHRM5 (cholinergic receptor, muscarinic 5), CHRNG (cholinergic receptor, nicotinic, gamma) , SLC6A1 (Solute Carrier Family 6 (Nerve Transporter, GABA), Member 1), ENTPD2 (ectonucleoside triphosphate diphosphohydrolase 2), CALCB (calcitonin-associated polypeptide beta), SHBG (sex hormone- Binding globulin), SERPINA6 (serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 6), NRG2 (neuregulin 2), PNOC (prepronociceptin), NAPA ( N-ethylmaleimide-sensitive factor adhesion protein, alpha), PICK1 (protein interaction with PRKCA 1), PLCD4 (force Porifase C, Delta 4), GCDH (glutaryl-Coenzyme A dehydrogenase), NLGN2 (Nurorigin 2), NBEA (Nurovichin), ATP10A (ATPase, Class V, Type 10A), RAPGEF4 (Rap guanine nucleotide Exchange factor (GEF) 4), UCN (urocortin), PCSK6 (proprotein convertase subtilisin / kesin type 6), HTR1F (5-hydroxytrytamine (serotonin) receptor 1F), SGCB (sarcoglycans) , Beta (43kDa dispropine-associated glycoprotein), GABRQ (gamma-aminobutyl acid (GABA) receptor, theta), GHRL (ghrelin / oveststatin prepropeptide), NCALD (neucalcin delta), NEUROD2 ( Neurogenic differentiation 2), DPEP1 (dipeptidase 1 (kidney)), SLC1A4 (solute carrier family 1 (glutamate / neutral amino acid transport), member 4), DNM3 (dynamin 3), SLC6A12 (solute carrier family 6 (nerve) Transporter Transport, Betaine / GABA), Member 12), SLC6A6 (Solute Carrier Family 6 (Nerve Transporter, Taurine), Member 6), YME1L1 (YME1 -Like 1 (S. Servicier)), VSNL1 (biscinin-like 1), SLC17A7 (solute carrier family 17 (sodium-dependent inorganic phosphate cocarrier), member 7), HOMER2 (Homer homolog 2 (Drosophila)), SYT7 (synapse) Totamine VII), TFIP11 (tuftelin interacting protein 11), GMFB (neuroglial maturation factor, beta), PREB (prolactin regulatory element binding), NTSR2 (neurotensin receptor 2), NTF4 (neutropin 4) , PPP1R9B (protein phosphatase 1, modulated (inhibitor) subunit 9B), DISC1 (destructed in schizophrenia 1), NRG3 (neuregulin 3), OXT (oxytocin, prepropeptide), TRH (pyrogenic hormone-releasing hormone ), NISCH (nischarin), CRHBP (Adrenal Cortical Hormone-releasing Hormone Binding Protein), SLC6A13 (Solute Carrier Family 6 (Nuclear Transporter Transport, GABA), Member 13), NPPC (Sodium Release Peptide Precursor C) ), CNTN3 (contactin 3 (associated with cytoplasmic)), KAT5 (K (lysine) acetyltransferase 5), CNTN6 (contact 6), KIAA0101 (KIAA0101), PANX1 (Panexin 1), CTSL1 (Catepsin L1), EARS2 (glutamyl-tRNA synthetase 2, Mitochondria (estimated)), CRIPT (Cysteine-rich PDZ-binding protein), CORT (Cortistatin), DLgap4 (disc, large (Drosophila) homolog-associated protein 4), ASTN2 (Astrotaxin 2), HTR3B (5-hydroxytrytamine (serotonin) receptor 3B), PMCH (pro-melanin) -Enrichment hormone), TSPO (potentiator protein (18kDa)), GDF2 (growth differentiation factor 2), CNTNAP1 (contactin related protein 1), GNRH2 (gonadotropin-releasing hormone 2), AUTS2 (autism sensitive candidate 2 ), SV2C (synaptic vesicle glycoprotein 2C), CARTPT (CART prepropeptide), NSUN4 (NOP2 / Sun domain family, member 4), CNTN5 (contactin 5), NEUROD4 (neurogenic differentiation 4), NEUROG1 (neurogene) 1), SLTM (SAFB-like, transcriptional regulator), GNRHR2 (gonadotropin-releasing hormone (type 2) receptor 2), ASTN1 (astrotrotin 1), SLC22A18 (solute carrier family) 22, member 18), SLC17A6 (solute carrier family 17 (sodium-dependent inorganic phosphate cocarrier), member 6), GABRR3 (gamma-aminobutyl acid (GABA) receptor, rho 3), DAOA (D-amino acid oxidase Active substance), ENSG00000123384, nd NOS2P1 (nitric oxide synthase 2 false gene 1).

Typical neurotransmitter-related proteins include 5-HTT (5-hydroxytryptamine transport), SLC6A4 (solute carrier family 6, member 4), COMT (catechol-O-methyltransferase), DRD1A (dopamine receptor D1A), SLC6A3 (Solute Carrier Family 6, Member 3), DAO1 (D-amino-acid oxidase), DTNBP1 (Distrobrebin binding protein 1), and any combination thereof.

In certain embodiments, measurements commonly used to study neurotransmission disorders in animals created by the methods of the invention can be used to study the effects of mutations and the development and / or progression of neurotransmission disorders in animals.

ii . Pharmacology model

The methods of the invention can be used to create animals or cells that can be used as pharmacological models. Such a pharmacological model may be a model of pharmacokinetics or pharmacodynamics. For example, in one embodiment, the methods of the invention can be used to create an animal or cell comprising chromosomal editing of one or more nucleic acid sequences that are pharmaceutically involved in the metabolism of the active compound. Such animals or cells can be used to study the effect of nucleic acid sequences on pharmaceutical compounds.

Alternatively, the methods of the present invention can be used to create animals or cells comprising chromosomal editing in disease related sequences. Such animals or cells can be used to assess the effect (s) of the therapeutic substance in the development or progression of the disease. For example, the effect (s) of a therapeutic substance is measured in an “humanized” animal, and the information obtained therefrom can be used to predict the effect of the substance in humans. In general, the method comprises contacting a therapeutic agent with a genetically modified animal comprising at least one edited chromosomal sequence encoding a protein associated with a disease, and selecting for results obtained in wild-type animals contacted with the same substance. It involves comparing variables. Non-limiting examples of suitable diseases include those mentioned in paragraph II (a) i.

To assess the effect (s) of a substance in an isolated cell comprising at least one edited chromosomal sequence encoding a protein associated with the disease, as well as to evaluate the effect (s) of the substance Methods of using lysates (or cells derived from genetically modified animals described herein) are provided. For example, the role of proteins associated with disease in the metabolism of certain substances can be determined using these methods. Similarly, these methods can be used to directly measure substrate specificity and pharmacokinetic variables. Those skilled in the art are familiar with suitable tests and / or procedures.

In one embodiment, the methods of the present invention can be used to create an animal or cell in which at least one chromosomal sequence has been edited in toxicology. Suitable chromosomal editing includes, but is not limited to, the type of editing described in paragraph I (f) above. Any chromosomal sequence or protein related to uptake, distribution, metabolism, and excretion (ADME) and toxicology can be used for the purposes of the present invention. ADME and toxicology-related proteins are typically selected based on experimental association of proteins for ADME and toxicology-related disorders. For example, the production rate or circulating concentration of proteins associated with ADME and toxicology-related disorders may be elevated or inhibited in the population with ADME and toxicological disorders as compared to the population without ADME and toxicological disorders. Differences in protein levels can be assessed using proteomic or genomic analysis techniques known in the art.

Typical non-limiting examples of chromosomal sequences or proteins involved in ADME and toxicology include Oct 1, Oct 2, Hfe2, Ppar (alpha) MDR1a (ABC carrying ABCB1a), MDR1b (ABCB1b), BCRP (ABCC1), MRP1 (ABCG2) , MRP2 (ABCC2, cMOAT), and combinations thereof.

A further aspect of the invention includes a method of assessing the effect (s) of a substance. Suitable materials include, but are not limited to, pharmaceutically active ingredients, drugs, food additives, pesticides, herbicides, toxins, industrial chemicals, household chemicals, and other environmental chemicals. For example, the effect (s) of a substance can be measured in genetically modified “humanized” animals and the information obtained from it can be used to predict the effect of the substance in humans. Generally, the method is genetically modified comprising at least one inactivated chromosomal sequence related to ADME and toxicology and a sequence incorporated into at least one chromosome encoding a human protein inherited from an ancestor related to ADME and toxicology. Contacting the material with the animal and comparing the result of the selected variable to results from wild-type animals in contact with the same material. The selected variables include (a) the removal rate of the substance or its metabolite (s); (b) the level of circulation of the substance or metabolite (s) thereof; (c) bioavailability of the substance or metabolite (s) thereof; (d) metabolic rate of the substance or metabolite (s) thereof; (e) the removal rate of the substance or its metabolite (s); (f) toxicity of the substance or its metabolite (s); (g) the effect of the substance or its metabolite (s); (h) the nature of the substance or its metabolite (s); And (i) extrahepatic contributions to the metabolic rate and clearance of the substance or its metabolite (s).

In addition, methods of assessing the effect (s) of a substance in isolated cells comprising at least one edited chromosomal sequence related to ADME and toxicology, as well as those cells (or to assess the effect (s) of the substance) Lysates of cells derived from genetically modified animals described herein are provided. For example, the role of specific proteins involved in ADME and toxicology in the metabolism of certain substances can be determined using these methods. Similarly, these methods can be used to directly measure substrate specificity and pharmacokinetic variables. Those skilled in the art are familiar with suitable tests and / or procedures.

One protein of interest related to drug ADME and toxicology is the ABC carrier, also known as efflux carrier proteins. Thus, for example, genetically modified animals containing edited chromosomal sequences encoding the ABC carriers described herein can screen for biologically active substances, including drugs, and their distribution, effects, Useful for investigating metabolism and / or toxicity. These screening methods are particularly useful for evaluating the behavior of drugs with improved prediction in genetically modified mice as models for the genetically modified animals described herein, such as humans. Thus, the present disclosure also features methods for assessing the ADME profile of a drug in genetically modified animals as part of the drug screening or evaluation process. Candidate therapeutic agents, such as candidate drugs, can be administered to genetically modified animals bearing targeted gene knock-outs and / or expressed transgenes, which can be obtained through the use of ZFNs. Knock-out or knock-in genes are associated with at least one aspect of drug ADME profile or toxicology, and / or metabolism, and can be derived from the mouse, rat, or human genome.

For example, screening methods for targets of test compounds may include transmembrane transport mediated by knocked out proteins by knocking out any one or more of ABC carriers such as Mdr1a, Mdr1b, PXR, BCRP, MRP1, or MRP2. Genetically modified animals that are suppressed or eliminated can be used. Such animals may be exposed to test compounds suspected of inhibitory transport activity of these knock-out protein (s). Inhibition of transport by these compounds in genetically modified animals can be determined using a number of routine laboratory tests and techniques, and inhibition of transport can be compared to that observed in wild-type animals treated with the same test compound. Differences in the effects of test compounds in the two animals may indicate a target of the test compound. Moreover, inhibition of one or more ABC transport proteins such as Mdr1a, Mdr1b, PXR, BCRP, MRP1, or MRP2 may improve certain ADME characteristics of the candidate therapeutic agent. For example, the uptake or effect of a candidate therapeutic compound can be improved by knockout of expression of one or more ABC carrier proteins such as Mdr1a, Mdr1b, PXR, BCRP, MRP1, or MRP2 in a particular tissue. Genetically modified animals and cells, including genetic modifications of one or more ABC transport proteins described herein, can be used to identify targets of test compounds or to improve the ADME characteristics and toxicology of candidate compounds. To confirm, it will be appreciated that it can be beneficially used in many ways to assess the ADME and toxicological characteristics of candidate therapeutic compounds.

You will recognize the absolute need to accurately predict how drugs and environmental chemicals affect a large population. The genetically modified animals, embryos, cells and cell lineages described herein can be used to analyze how various compounds interact with biological systems. Genetically modified cells and cell lineages regulate many known complexities in biological systems to improve the predictable ability of cell-based assay systems such as those used to assess new molecular entities and possible drug-drug interactions. Can be used to In particular, biological systems are typically recognized to include multiple components that respond to exposure to new, potentially harmful compounds.

The "ADMET system" is described as containing five components. The first component includes a biological system that signals the drug metabolism system to activate when destroyed and may include stress response and DNA repair pathways. Once the drug metabolism system is activated, "xenosensors" monitor exogenous molecules to be removed. Detection of exogenous molecules by heterosensors then activates gene induction processes that up-regulate enzymes that metabolize exogenous molecules for faster removal. Enzymes of the third ADMET component include Phase I enzymes containing at least three classes of oxidase, the best known of which is the cytochrome P450 class. Cytochrome 450 enzymes typically add reactive hydroxyl moieties that inactivate potential toxins and confer more polarity (solubility) to these toxins. The fourth component of the ADMET system contains at least seven classes of enzymes that further alter phase I enzymatic modification. Typically, these enzymes are conjugating enzymes that now oxidize oxidized xenobiotics to become more water soluble ADMET and add hydrophilic moieties to be easily collected and released through urine or bile. The final component is a transport system involving transport proteins, such as ABC transporters, that function as a molecular pump that facilitates the transfer of biological foreign material from one tissue to another. Carrier proteins move the drug into, out of, or through the cell.

Each component of the ADMET system has its own substrate structural specificity and this feature must be considered by any analysis. To make even larger attacks predictable, for each determinant member of the five-component class, there is a constellation of genetic polymorphisms in the population, which have a significant impact on activity towards specific biological foreign chemical structures. Can give The growing field of pharmacogenomics focuses on the challenges created by these genetic variations. In addition, gender differences in how different components of the biological foreign body system are known to play various roles in drug metabolism.

Thus, the genetically modified animals, cells and specific cell lineages described herein may be useful as the basis for cell-based assays with improved predictive power on the clinical outcome of drugs or on toxicological problems of chemicals. will be. Panels of cell lines are clearly contemplated for this purpose. For example, cell-based assays can be created with representatives of target tissues where the metabolism or toxicity of drug compounds occurs similarly. Currently, standard assays are derived from target tissues and are usually conducted in transformed cell lineages with some combined functional properties. To make a better cell-based assay to represent a better natural state, genetically modified and differentiated pluripotent cells can be used in place of immortalized cell components. In other words, genetically modified cell lines can be used for highly predictable cell-based assays suitable for high-throughput, high-content compound screening.

Accordingly, the subject matter of the present invention contemplates ZFN-mediated genetic modification of genes for each part of a foreign foreign metabolism mechanism. Such modifications include knock-out, knock-in, induction of certain mutations known to affect the activity of reporter tags, or a combination thereof. For example, genetically modified cells and cell lineages can include tissue-specific, sex-specific, and / or population-reflective delivery panels; Panel of tissue-specific and functionally reflected cell-based heterosensor assay panels; And induction assays that measure the genetic activation of different drug metabolic components and apparent toxin responses such as genotoxicity, cardiotoxicity, and apoptosis.

In accordance with the teachings of the present invention, tissue-specific lines modified to isolate specific transport activity and predict the population's response to individual chemical entities can be made. For example, ZFNs can be used to introduce an important, common polymorphism into the intestinal epithelial cell line, and the intestinal epithelial cell line, and liver, blood-brain-barrier (brain microvascular endothelial cells), kidneys. Carrier gene knockouts can be created in a representative cell lineage and any related tissue-specific cell lineages. Panels of the cell line show individual carrier proteins (eg MDR-1, MRP1, 2, 3, 4) to separate the effects of the individual carriers (eg BCRP and MRP2, MDR-1 and MRP2, MRP-3 and MRP1). , 6, BCRP) knock-out, knock-out combination, and intestinal epithelial cells (Caco2 or BBe1) with carrier null lineages (eg, all seven carriers knocked out). The panel of intestinal epithelial cells may comprise knock-outs of OATP-2B1, PEPT-1, and OCT-N2. Panels of intestinal epithelial cells can influence drug delivery and can include polymorphisms predominant in key carrier genes that are important to drug researchers.

Three heterogeneous sensors in humans (PXR, AhR and CAR) are known to have overlap specificity in response to biological foreign bodies. Knowing which heterosensors are activated by any particular chemical, and to what extent, is also an important consideration in understanding drug reactions and drug-drug interactions. The creation of a panel of cells induced by a heterogeneous sensor can explain specificity. Further modification of cells to target functionally important polymorphisms in heterogeneous sensors will enable population prediction. ZFNs can be used to create knock-out cell lines similar to the carrier knockout cell line as described above, and to create reporter cell lines that express different fluorescent proteins upon induction of different heterosensors. For example, it is possible to create a cell line expressing green FP if PXR is induced, red FP if CAR activity is induced, and blue FP if AhR is induced. All lineages can be constructed within related tissue-type cell lineages such as, for example, visceral, liver, kidney, brain, and heart. Cell panels can be created to represent tissues most involved in drug toxicity and metabolism, with each heterosensor (CAR, PXR, AhR) knocked out. Cell lines can also be made to produce fluorescent proteins when each of the three heterogeneous sensors is activated.

Induction analysis of ADME biotransformation and toxin response genes is also considered. Although the activity of many Phase I and Phase II enzymes may be possible in simple biochemical assays, no assay is available that can measure induction of any particular enzyme by exogenously added bioforeign in a high throughput manner. ZFN can be used to create the genetically modified cell lineages described herein to provide a basis for assays to measure up / down regulation of key phase I and phase II enzymes, along with genes involved in toxin responses. have. For example, ZFN can be used to construct a lineage with a reporter gene (eg, encoding a fluorescent protein or luciferase) inserted adjacent to the promoter of the gene to be measured. Such genetic targets may be any of the critical phase I, phase II, carrier, genotox, or apoptotic / necrotic pathway components. Tissue-specific panels of cells can be created to report phase I or phase II enzymes, activation of genes encoding a transporter, or activation of toxic response pathways (eg, genotoxicity or apoptosis).

iii . Developmental model

The methods of the invention can be used to create animals or cells that can be used as a developmental model. Such models can be used to study embryonic development, organ development, organ system development, or the like. For example, in one embodiment, the methods of the invention can be used to create an animal or cell comprising chromosomal editing in one or more nucleic acid sequences associated with the development of an organ or organ system. Non-limiting examples of organs include brain, eyes, nose, ears, throat, mouth (including teeth, tongue, lips, gums), spine, bones, heart, blood vessels, lungs, liver, pancreas, gallbladder, spleen, esophagus, Stomach, small intestine, colon, appendix, rectum, bladder, reproductive organs, immune system organs (including thyroid, lymph nodes, lymphatic vessels), and endocrine system organs. Non-limiting examples of organ systems include nervous system, circulatory system, digestive system, respiratory system, skeletal system, lymphatic system, reproductive system, muscular system, cortical system, embryonic system, and endocrine system.

In one embodiment, the methods of the invention can be used to create an animal or cell in which at least one chromosomal sequence associated with neurodevelopment has been edited. Suitable chromosomal editing includes, but is not limited to, the type of editing described in paragraph I (f) above. Chromosomal sequences associated with neurodevelopment can be protein coding sequences or reference sequences. In certain embodiments, the neurodevelopment sequence may be associated with a disorder such as neurodevelopmental disorder, biochemical pathways associated with neurodevelopmental disorders, or phenylketonuria closely associated with neurodevelopmental disorders.

Non-limiting examples of neurodevelopment-related sequences include A2BP1 [atacin 2-binding protein 1], AADAT [aminoadipate aminotransferase], AANAT [arylalkylamine N-acetyltransferase], ABAT [4-amino Butyrateaminotransferase], ABCA1 [ATP-binding cassette, sub-family A (ABC1), member 1], ABCA13 [ATP-binding cassette, sub-family A (ABC1), member 13], ABCA2 [ATP-binding cassette , Sub-family A (ABC1), member 2], ABCB1 [ATP-binding cassette, sub-family B (MDR / TAP), member 1], ABCB11 [ATP-binding cassette, sub-family B (MDR / TAP) , Member 11], ABCB4 [ATP-binding cassette, sub-family B (MDR / TAP), member 4], ABCB6 [ATP-binding cassette, sub-family B (MDR / TAP), member 6], ABCB7 [ATP -Binding cassette, sub-family B (MDR / TAP), member 7], ABCC1 [ATP-binding cassette, sub-family C (CFTR / MRP), member 1], ABCC2 [ATP-binding cassette, sub-family C (CFTR / MRP), member 2], ABCC3 [ATP-binding cassette, sub -Family C (CFTR / MRP), member 3], ABCC4 [ATP-binding cassette, sub-family C (CFTR / MRP), member 4], ABCD1 [ATP-binding cassette, sub-family D (ALD), member 1], ABCD3 [ATP-binding cassette, sub-family D (ALD), member 3], ABCG1 [ATP-binding cassette, sub-family G (WHITE), member 1], ABCG2 [ATP-binding cassette, sub- Family G (WHITE), member 2], ABCG4 [ATP-binding cassette, sub-family G (WHITE), member 4], ABHD11 [ab hydrolase domain containing 11], ABI1 [abl-interacter 1], ABL1 [c-abl oncogene 1, receptor tyrosine kinase], ABL2 [v-abl Abelson murine leukemia viral oncogene homologue 2 (arg, Abelson-associated gene)], ABLIM1 [actin binding LIM protein 1], ABLIM2 [actin Binding LIM protein family, member 2], ABLIM3 [actin binding LIM protein family, member 3], ABO [ABO blood group (transferase A, alpha 1-3-N-acetylgalactosaminyltransferase; Transferase B, alpha 1-3-galactosyltransferase)], ACAA1 [acetyl-Coenzyme A acyltransferase 1], ACACA [acetyl-Coenzyme A carboxylase alpha], ACACB [acetyl-Coenzyme A carboxylase Beta], ACADL [acyl-coenzyme A dehydrogenase, long chain], ACADM [acyl-coenzyme A dehydrogenase, C-4 to C-12 straight chain], ACADS [acyl-coenzyme A dehydrogenase, C-2 to C- 3 short chain], ACADSB [acyl-coenzyme A dehydrogenase, short / branched chain], ACAN [agracan], ACAT2 [acetyl-coenzyme A acetyltransferase 2], ACCN1 [amylolide-sensitive cation channel] 1, neurons], ACE [angiotensin I converting enzyme (peptidyl-dipeptidase A) 1], ACE2 [angiotensin I converting enzyme (peptidyl-dipeptidase A) 2], ACHE [acetylcholinese Therapase (Yt Blood Group)], ACLY [ATP Citrate Lyase], ACO1 [Aconitase 1, Soluble], ACTA1 [Actin, Alpha 1, Skeletal Muscle], ACTB [Actin, Beta], ACTC1 [Actin, Alpha, cardiac muscle 1], ACTG1 [actin, gamma 1], ACTL6A [actin-like 6A], ACTL6B [actin-like 6B], ACTN1 [actinin, alpha 1], ACTR1A [ARP1 actin-associated protein 1 homologue A, Centlactin Alpha (Yeast)], ACTR2 [ARP2 Actin-Related Protein 2 Homolog (Yeast)], ACTR3 [ARP3 Actin-Related Protein 3 Homolog (Yeast)], ACTR3B [ARP3 Actin-Related Protein 3 Homolog B (Yeast)], ACVR1 [Activin A Receptor, Type I], ACVR2A [Activin A Receptor, Type IIA], ADA [Adenosine Deaminase], ADAM10 [ADAM Metalpeptidase Domain 10], ADAM11 [ADAM Metalpeptidase domain 11], ADAM12 [ADAM metalpeptidase domain 12], ADAM15 [ADAM metalpeptidase domain 15], ADAM17 [ADAM metalpeptidase domain 17], ADAM18 [ADAM metalpeptidase domain 18 ], ADAM19 [ADAM metalpeptidase domain 19 (meltrine beta)], ADAM2 [ADAM metalpeptidase domain 2], ADAM20 [ADAM metalpeptidase domain 20], ADAM21 [ADAM metalpeptide Domain 21], ADAM22 [ADAM metalpeptidase domain 22], ADAM23 [ADAM metalpeptidase domain 23], ADAM28 [ADAM metalpeptidase domain 28], ADAM29 [ADAM metalpeptidase domain 29], ADAM30 [ ADAM metalpeptidase domain 30], ADAM8 [ADAM metalpeptidase domain 8], ADAM9 [ADAM metalpeptidase domain 9 (meltrin gamma)], ADAMTS1 [ADAM metalpeptide with thrombospondine type 1 motif 1, 1], ADAMTS13 [ADAM metalpeptidase with thrombospondine type 1 motif, 13], ADAMTS4 [ADAM metalpeptidase with thrombospondine type 1 motif, 4], ADAMTS5 [thrombospondin type 1 Motifs ADAM metalpeptidase, 5], ADAP2 [ArfGAP 2 with dual PH domains], ADAR [adenosine deaminase, RNA-specific], ADARB1 [adenosine deaminase, RNA-specific, B1 ( RED1 homologue mice)], ADCY1 [adenylate cyclase 1 (brain)], ADCY10 [adenylate cyclase 10 (soluble)], A DCYAP1 [adenylate cyclase activating polypeptide 1 (pituitary)], ADD1 [educin 1 (alpha)], ADD2 [educin 2 (beta)], ADH1A [alcohol dehydrogenase 1A (class I), alpha polypeptide] , ADIPOQ [containing adiponectin, C1Q and collagen domain], ADK [adenosine kinase], ADM [adrenomethulin], ADNP [activity-dependent neuroprotector homeobox], ADORA1 [adenosine A1 receptor], ADORA2A [adenosine A2a Receptor], ADORA2B [adenosine A2b receptor], ADORA3 [adenosine A3 receptor], ADRA1B [adrenergic, alpha-1B-, receptor], ADRA2A [adrenergic, alpha-2A-, receptor], ADRA2B [adrenergic, alpha- 2B-, receptor], ADRA2C [adrenergic, alpha-2C-, receptor], ADRB1 [adrenergic, beta-1-, receptor], ADRB2 [adrenergic, beta-2-, receptor, surface], ADRB3 [adrenergic Sex, beta-3-, receptor], ADRBK2 [adrenergic, beta, receptor kinase 2], ADSL [adenylsuccine Triase], AFF2 [AF4 / FMR2 family, member 2], AFM [afamin], AFP [alpha-fetoprotein], AGAP1 [ArfGAP 1 with GTPase domain, ankyrin repeat and PH domain], AGER [Advanced glycosylation end product-specific receptor], AGFG1 [ArfGAP 1 with FG repeat], AGPS [alkylglycerone phosphate synthetase], AGRN [Agrin], AGRP [Aguti-associated protein homologue (mouse)] , AGT [angiotensinogen (serpin peptidase inhibitor, Clade A, member 8)], AGTR1 [angiotensin II receptor, type 1], AGTR2 [angiotensin II receptor, type 2], AHCY [ Adenosyl homocysteinase], AHI1 [Abelson helper integration position 1], AHR [aryl hydrocarbon receptor], AHSG [alpha-2-HS-glycoprotein], AICDA [activation-induced cytidine deaminase], AIFM1 [Apoptosis-inducing factor, mitochondion-related, 1], AIRE [autoimmune modulator], AKAP12 [A kinase (PRKA) anchor protein 12], AKAP9 [A kinase (PRKA) Anchor protein (yotiao 9), AKR1A1 [Aldo-keto reductase family 1, member A1 (aldehyde reductase)], AKR1B1 [Aldo-keto reductase family 1, member B1 (Aldose reductase)], AKR1C3 [Aldo -Keto reductase family 1, member C3 (3-alpha hydroxysteroid dehydrogenase, type II)], AKT1 [v-akt murine thymoma viral oncogene homolog 1], AKT2 [v-akt murine thymoma viral tumor Gene homolog 2], AKT3 [v-akt murine thymoma viral oncogene homolog 3 (protein kinase B, gamma)], ALAD [aminolevulinate, delta-, dehydratase], ALB [albumin], ALB [ Albumin], ALCAM [activated leukocyte cell adhesion molecule], ALDH1A1 [aldehyde dehydrogenase 1 family, member A1], ALDH3A1 [aldehyde dehydrogenase 3 family, member A1], ALDH5A1 [aldehyde dehydrogenase 5 family, member A1], ALDH7A1 [aldehyde dehydrogenase 7 family, member A1], ALDH9A1 [Aldehyde dehydrogenase 9 family, member A1], ALDOA [aldolase A, fructose-bisphosphate], ALDOB [aldolase B, fructose-bisphosphate], ALDOC [aldolase C, fructose-bis Phosphate], ALK [malignant lymphoma receptor tyrosine kinase], ALOX12 [arachidonate 12-lipoxygenase], ALOX5 [arachidonate 5-lipoxygenase], ALOX5AP [arachidonate 5-lipoxygenase-activating protein] , ALPI [alkali phosphatase, gut], ALPL [alkali phosphatase, liver / bones / kidney], ALPP [alkali phosphatase, placenta (Regan isozyme)], ALS2 [amyotrophic lateral sclerosis 2 (adolescent)], AMACR [alpha- Methylacyl-CoA racemizing agent], AMBP [alpha-1-microglobulin / bikunin precursor], AMPH [ampificin], ANG [angiogenin, ribonuclease, RNase A family, 5], ANGPT1 [ Angiopoietin 1], ANGPT2 [Angiopoietin 2], ANGPTL3 [Angiopoietin-Like 3], ANK1 [Ankyrin 1, Erythropoiesis], ANK3 [Ankyrin 3, Ranvier's nod (ankyrin G)], ANKRD1 [Ankyrin repeat domain 1 (heart muscle)], ANP32E [acidic (leucine-rich) nuclear phosphoprotein 32 family , Member E], ANPEP [alanyl (membrane) aminopeptidase], ANXA1 [annexin A1], ANXA2 [annexin A2], ANXA5 [annexin A5], AP1S1 [adapter-associated protein complex 1, sigma 1 Subunit], AP1S2 [adapter-associated protein complex 1, sigma 2 subunit], AP2A1 [adapter-associated protein complex 2, alpha 1 subunit], AP2B1 [adapter-associated protein complex 2, beta 1 subunit], APAF1 [Apoptotic peptidase activating factor 1], APBA1 [amyloid beta (A4) precursor protein-binding, family A, member 1], APBA2 [amyloid beta (A4) precursor protein-binding, family A, member 2], APBB1 [amyloid beta (A4) precursor protein-binding, family B, member 1 (Fe65)], APBB2 [amyloid beta (A4) precursor protein -Binding, family B, member 2], APC [polyposis colon polyps], APCS [amyloid P component, serum], APEX1 [APEX nuclease (multifunctional DNA repair enzyme) 1], APH1B [former pharyngeal defect 1 homologue B (C. Elegans)], APLP1 [amyloid beta (A4) precursor-like protein 1], APOA1 [apolipoprotein AI], APOA5 [apolipoprotein AV], APOB [apolipoprotein B (including Ag (x) antigen)]] , APOC2 [Apolipoprotein C-II], APOD [Apolipoprotein D], APOE [Apolipoprotein E], APOM [Apolipoprotein M], APP [Amyloid Beta (A4) Precursor Protein], APPL1 [Adapter] Protein, intyrosine interaction, PH domain and leucine zipper 1], APRT [adenine phosphoribosyltransferase], APTX [aprataxin], AQP1 [aquaporin 1 (Colton blood group)], AQP2 [aqua] Porin 2 (collection duct)], AQP3 [aquaporin 3 (Gill blood group)], AQP4 [aquaporin 4], AR [androgen receptor], ARC [activity-regulated cytoskeleton-associated protein], AREG [ampiree] Gurin], ARFGEF2 [ADP-ribosylation factor guanine nucleotide-exchange factor 2 (brefeldin A-inhibited)], ARG1 [arginase, liver], ARHGAP1 [Rho GTPase bow Protein 1], ARHGAP32 [Rho GTPase Activating Protein 32], ARHGAP4 [Rho GTPase Activating Protein 4], ARHGAP5 [Rho GTPase Activating Protein 5], ARHGDIA [Rho GDP Dissociation Inhibitor (GDI) Alpha], ARHGEF1 [Rho Guanine Nucleotide Exchange Factor (GEF) 1], ARHGEF10 [Rho guanine nucleotide exchange factor (GEF) 10], ARHGEF11 [Rho guanine nucleotide exchange factor (GEF) 11], ARHGEF12 [Rho guanine nucleotide exchange factor (GEF) 12], ARHGEF15 [Rho guanine Nucleotide exchange factor (GEF) 15], ARHGEF16 [Rho guanine nucleotide exchange factor (GEF) 16], ARHGEF2 [Rho / Rac guanine nucleotide exchange factor (GEF) 2], ARHGEF3 [Rho guanine nucleotide exchange factor (GEF) 3], ARHGEF4 [Rho guanine nucleotide exchange factor (GEF) 4], ARHGEF5 [Rho guanine nucleotide exchange factor (GEF) 5], ARHGEF6 [Rac / Cdc42 guanine nucleotide exchange factor (GEF) 6], ARHGEF7 [Rho guanine nucleotide exchange Purple (GEF) 7], ARHGEF9 [Cdc42 guanine nucleotide exchange factor (GEF) 9], ARID1A [AT rich interacting domain 1A (SWI-like)], ARID1B [AT rich interacting domain 1B (SWI1-like)], ARL13B [ADP-ribosylation factor-like 13B], ARPC1A [actin related protein 2/3 complex, subunit 1A, 41kDa], ARPC1B [actin related protein 2/3 complex, subunit 1B, 41kDa], ARPC2 [actin related Protein 2/3 complex, subunit 2, 34kDa], ARPC3 [actin related protein 2/3 complex, subunit 3, 21kDa], ARPC4 [actin related protein 2/3 complex, subunit 4, 20kDa], ARPC5 [actin Related protein 2/3 complex, subunit 5, 16 kDa], ARPC5L [actin related protein 2/3 complex, subunit 5-like], ARPP19 [cAMP-regulated phosphoprotein, 19 kDa], ARR3 [Arrest 3, retina (X-Arrestin)], ARRB2 [Arrestin, Beta 2], ARSA [Arylsulfatase A], ARTN [Artetin], ARX [Aristoles-related Homeobox], ASCL1 [achaete-scuteCopolymers homologue 1 (Drosophila)], ASMT [O- Acetyl serotonin methyl transferase], ASPA [aspartate Toa sila claim (Canavan disease)], ASPG [asparaginase homolog (S.  Servicier)], ASPH [aspartatebeta-hydroxylase], ASPM [asp (abnormal spindle) homologue, microcephaly related (Drosophila)], ASRGL1 [asparaginase-like 1], ASS1 [argininosuccinate] Cinnate synthase 1], ASTN1 [Astrotaxin 1], ATAD5 [ATPase family, containing AAA domain 5], ATF2 [activation transcription factor 2], ATF4 [activation transcription factor 4 (tax-response enhancer element B67)], ATF6 [activating transcription factor 6], ATM [mutated ataxia capillary dilatation], ATOH1 [amorphous homologue 1 (Drosophila)], ATOX1 [ATX1 antioxidant protein 1 homologue (yeast)], ATP10A [ATPase, class V, Type 10A], ATP2A2 [ATPase, Ca ++ transport, cardiac muscle, sluggish spasms 2], ATP2B2 [ATPase, Ca ++ transport, plasma membrane 2], ATP2B4 [ATPase, Ca ++ transport, plasma membrane 4], ATP5O [ATP synthase, H + Transport, mitochondrial F1 complex, O subunit], ATP6AP1 [ATPase, H + transport, lysosomal accessory protein 1], ATP6V0C [ATPase, H + transport, lysosomal 16k Da, V0 subunit c], ATP7A [ATPase, Cu ++ transport, alpha polypeptide], ATP8A1 [ATPase, aminophospholipid transport (APLT), class I, type 8A, member 1], ATR [related to ataxia capillary dilatation and Rad3] , ATRN [attractin], ATRX [alpha thalassemia / mental retardation syndrome X-linked (RAD54 homologue, S.  CERVISI)], ATXN1 [Athacin 1], ATXN2 [Atacin 2], ATXN3 [Atacin 3], AURKA [Aurora Kinase A], AUTS2 [Autism Sensitive Candidate 2], AVP [Arginine Vasopressin], AVPR1A [ Arginine Vasopressin Receptor 1A], Acine2 [Asin 2], AXL [AXL Receptor Tyrosine Kinase], AZU1 [azurocidin 1], B2M [beta-2-microglobulin], B3GNT2 [UDP-GlcNAc: beta Gal beta-1 [3-N-acetylglucosaminyltransferase 2], B9D1 [B9 protein domain 1], BACE1 [beta-position APP-clease 1], BACE2 [beta-position APP-clease 2], BACH1 [BTB and CNC Homology 1, Basic Leucine Zipper Transcription Factor 1], BAD [BCL2-associated Antigen of Cell Death], BAGE2 [B Melanoma Antigen Family, Member 2], BAIAP2 [BAI1-associated Protein 2], BAIAP2L1 [BAI1-associated protein 2-like 1], BAK1 [BCL2-antagonist / killer 1], BARD1 [BRCA1 related ring domain 1], BARHL1 [BarH-like homeobox 1], BARHL2 [BarH-like homeobox 2], BASP1 [ Brain rich, membrane attached signal protein 1], BAX [BCL2-associated X protein], BAZ1A [bromodomain adjacent to zinc finger domain, 1A], BAZ1B [bromodomain adjacent to zinc finger domain, 1B], BBS9 [ Bardet-Biedl syndrome 9], BCAR1 [breast cancer anti-estrogen resistance 1], BCHE [butyrylcholinesterase], BCL10 [B-cell CLL / lymphoma 10], BCL2 [B-cell CLL / lymphoma 2], BCL2A1 [BCL2-associated protein A1], BCL2L1 [BCL2-like 1], BCL2L11 [BCL2-like 11 (apoptosis promoter)], BCL3 [B-cell CLL / lymphoma 3], BCL6 [B-cell CLL / Lymphoma 6], BCL7A [B-cell CLL / lymphoma 7A], BCL7B [B-cell CLL / lymphoma 7B], BCL7C [B-cell CLL / lymphoma 7C], BCR [endpoint cluster portion], BDKRB1 [bradykinin receptor B1], BDNF [brain-induced neurotrophic factor], BECN1 [veclin 1, self-consumed], BEST1 [vespinin 1], BEX1 [brain expressed, X-linked 1], BEX2 [brain expressed X-linked 2], BGLAP [bone gamma-carboxyl Rutamate [gla protein], BGN [biglycan], BID [BH3 interacting domain killing agent], BIN1 [bridging integrator 1], BIRC2 [baculovirus IAP repeat-containing 2], BIRC3 [baculoviral IAP repeat-containing 3], BIRC5 [baculoviral IAP repeat-containing 5], BIRC7 [baculovirus IAP repeat-containing 7], BLK [B lymphoid tyrosine kinase], BLVRB [ Biliberdine reductase B (flavin reductase (NADPH))], BMI1 [BMI1 polycombindinger oncogene], BMP1 [bone forming protein 1], BMP10 [bone forming protein 10], BMP15 [bone forming protein 15] , BMP2 [bone forming protein 2], BMP3 [bone forming protein 3], BMP4 [bone forming protein 4], BMP5 [bone forming protein 5], BMP6 [bone forming protein 6], BMP7 [bone forming protein 7], BMP8A [Bone Forming Protein 8a], BMP8B [Bone Forming Protein 8b], BMPR1A [Bone Forming Protein Receptor, Type IA], BMPR1B [Bone Forming Protein Receptor, Type IB], BMPR2 [Bone-forming protein receptor, type II (serine / threonine kinase)], BOC [Boc homologue (mouse)], BOK [BCL2-associated ovarian killer], BPI [sterile / permeable-increasing protein], BRAF [v-raf Murine sarcoma viral oncogene homologue B1], BRCA1 [breast cancer 1, early signs], BRCA2 [breast cancer 2, early signs], BRWD1 [containing bromodomains and WD repeat domain 1], BSND [Bartter syndrome, infants , Hearing loss (Barttin)], BST2 [bone bone marrow mesenchymal antigen 2], BTBD10 [containing BTB (POZ) domain 10], BTC [betacellulline], BTD [biotinidase], BTG3 [BTG family, Member 3], BTK [Bruton agammaglobulinemia tyrosine kinase], BTN1A1 [butyrophylline, subfamily 1, member A1], BUB1B [budding unrepressed by benzimidazole 1 homologue beta (yeast)] , C15orf2 [chromosome 15 open reading frame 2], C16orf75 [chromosome 16 open reading frame 75], C17orf42 [chromosome 17 open reading frame 42], C1orf187 [chromosome 1 opening] Reading frame 187], C1R [complement component 1, r subcomponent], C1S [complement component 1, s subcomponent], C21orf2 [chromosome 21 open reading frame 2], C21orf33 [chromosome 21 open reading frame 33], C21orf45 [chromosome 21 open reading frame 45, C21orf62 [chromosome 21 open reading frame 62], C21orf74 [chromosome 21 open reading frame 74], C3 [complement component 3], C3orf58 [chromosome 3 open reading frame 58], C4A [complement component 4A ( Rodgers blood group)], C4B [complement component 4B (Chido blood group)], C5AR1 [complement component 5a receptor 1], C6orf106 [chromosome 6 open reading frame 106], C6orf25 [chromosome 6 open reading frame 25], CA1 [carbonic acid Dehydratase I], CA2 [carbonic anhydrase II], CA3 [carbonic anhydrase III, muscle specific], CA6 [carbonic anhydrase VI], CA9 [carbonic anhydrase IX], CABIN1 [calcineurin binding protein 1], CABLES1 [Cdk5 and Abl enzyme substrate 1], CACNA1B [calcium channel, potential-dependent, N type, alpha 1B subunit], CACNA1C [calcium channel, potential-dependent, L type, alpha 1C sub Unit], CACNA1G [calcium channel, potential-dependent, type T, alpha 1G subunit], CACNA1H [calcium channel, potential-dependent, type T, alpha 1H subunit], CACNA2D1 [calcium channel, potential-dependent, alpha 2] / Delta subunit 1], CADM1 [cell adhesion molecule 1], CADPS2 [Ca ++-dependent secretory activator 2], CALB2 [calvindine 2], CALCA [calcitonin-associated polypeptide alpha], CALCR [calcitonin receptor], CALM3 [ Calmodulin 3 (phosphorylase kinase, delta)], CALR [caleticulin], CAMK1 [calcium / calmodulin-dependent protein kinase I], CAMK2A [calcium / calmodulin-dependent protein kinase II alpha] , CAMK2B [calcium / calmodulin-dependent protein kinase II beta], CAMK2G [calcium / calmodulin-dependent protein kinase II gamma], CAMK4 [calcium / calmodulin-dependent protein kinase IV], CAMKK2 [calcium / cal Modulin-dependent protein kinase kinase 2, beta], CAMP [Catelycidine antimicrobial peptide], CANT1 [calcium activated nuclei Ortidase 1], CANX [cal nexin], CAPN1 [calpine 1, (mu / I) large subunit], CAPN2 [calpine 2, (m / II) large subunit], CAPN5 [calpine 5], CAPZA1 [capping protein (actin filament) muscle Z-line, alpha 1], CARD16 [caspase recruitment domain family, member 16], CARM1 [co-activator-associated arginine methyltransferase 1], CARTPT [CART PRE Propeptide], CASK [calcium / calmodulin-dependent serine protein kinase (MAGUK family)], CASP1 [caspase 1, apoptosis-related cysteine peptidase (interleukin 1, beta, convertase)], CASP10 [ Caspase 10, apoptosis-related cysteine peptidase], CASP2 [caspase 2, apoptosis-related cysteine peptidase], CASP3 [caspase 3, apoptosis-related cysteine peptidase], CASP6 [Caspase 6, Apoptosis-Related Cysteine Peptidase], CASP7 [Caspase 7, Apoptosis-Related Cysteine Peptidase], CASP8 [Caspa 8, apoptosis-related cysteine peptidase], CASP8AP2 [caspase 8 related protein 2], CASP9 [caspase 9, apoptosis-related cysteine peptidase], CASR [calcium-receptor], CAST [ Calpastatin], CAT [Catalase], CAV1 [Caveoline 1, Caberole Protein, 22kDa], CAV2 [Caveolin 2], CAV3 [Caveolin 3], CBL [Cas-Br-M (murine) Icotropic Retrovirus Sex Transformation Sequence], CBLB [Cas-Br-M (murine) Icotropic Retroviral Transformation Sequence b], CBR1 [carbonyl reductase 1], CBR3 [carbonyl reductase 3], CBS [cistathionine -Beta-synthase], CBX1 [chromobox homologue 1 (HP1 beta homolog Drosophila)], CBX5 [chromobox homologue 5 (HP1 alpha homologue, Drosophila)], CC2D2A [coil-coil and C2 Domain containing 2A], CCBE1 [collagen and calcium binding EGF domain 1], CCBL1 [cysteine conjugate-betaase, cytoplasm], CCDC50 [coil-coil dome Containing 50], CCK [Colekistokinin], CCKAR [Colekistokinin A Receptor], CCL1 [Chemokine (CC Motif) Ligand 1], CCL11 [Chemokine (CC Motif) Ligand 11], CCL13 [Chemokine (CC motif) ligand 13], CCL17 [chemokine (CC motif) ligand 17], CCL19 [chemokine (CC motif) ligand 19], CCL2 [chemokine (CC motif) ligand 2], CCL20 [chemokine (CC Motif) ligand 20], CCL21 [chemokine (CC motif) ligand 21], CCL22 [chemokine (CC motif) ligand 22], CCL26 [chemokine (CC motif) ligand 26], CCL27 [chemokine (CC motif) Ligand 27], CCL3 [chemokine (CC motif) ligand 3], CCL4 [chemokine (CC motif) ligand 4], CCL5 [chemokine (CC motif) ligand 5], CCL7 [chemokine (CC motif) ligand 7 ], CCL8 [chemokine (CC motif) ligand 8], CCNA1 [cyclin A1], CCNA2 [cyclin A2], CCNB1 [cyclin B1], CCND1 [cyclin D1], CCND2 [cyclin D2], CCND3 [cyclin D3], CCNG1 [company Eclin G1], CCNH [Cyclin H], CCNT1 [Cyclin T1], CCR1 [chemokine (CC motif) receptor 1], CCR3 [chemokine (CC motif) receptor 3], CCR4 [chemokine (CC motif) receptor 4], CCR5 [chemokine (CC motif) receptor 5], CCR6 [chemokine (CC motif) receptor 6], CCR7 [chemokine (CC motif) receptor 7], CCT5 [chaperonin containing TCP1, subunit 5] (Epsilon)], CD14 [CD14 molecule], CD19 [CD19 molecule], CD1A [CD1a molecule], CD1B [CD1b molecule], CD1D [CD1d molecule], CD2 [CD2 molecule], CD209 [CD209 molecule], CD22 [CD22] Molecule], CD244 [CD244 molecule, natural killer cell receptor 2B4], CD247 [CD247 molecule], CD27 [CD27 molecule], CD274 [CD274 molecule], CD28 [CD28 molecule], CD2AP [CD2-associated protein], CD33 [CD33 Molecule], CD34 [CD34 molecule], CD36 [CD36 molecule (thrombospondin receptor)], CD3E [CD3e molecule, epsilon (CD3-TCR complex)], CD3G [CD3g molecule, gamma (CD3-TCR complex)], CD4 [CD4 molecule], CD40 [CD40 molecule, TNF receptor superfamily member 5 ], CD40LG [CD40 ligand], CD44 [CD44 molecule (Indian blood group)], CD46 [CD46 molecule, complement regulatory protein], CD47 [CD47 molecule], CD5 [CD5 molecule], CD55 [CD55 molecule, degeneration to complement] (decay) Accelerating factor (Cromer blood group)], CD58 [CD58 molecule], CD59 [CD59 molecule, complement regulatory protein], CD63 [CD63 molecule], CD69 [CD69 molecule], CD7 [CD7 molecule], CD72 [CD72 molecule ], CD74 [CD74 molecule, major histocompatibility complex, class II constant chain], CD79A [CD79a molecule, immunoglobulin-associated alpha], CD79B [CD79b molecule, immunoglobulin-associated beta], CD80 [CD80 molecule], CD81 [ CD81 molecule], CD86 [CD86 molecule], CD8A [CD8a molecule], CD9 [CD9 molecule], CD99 [CD99 molecule], CDA [cytidine deaminase], CDC25A [cell division cycle 25 Homolog A (S.  Pombe)], CDC25C [cell division cycle 25 homolog C (S.  Pombe)], CDC37 [cell division cycle 37 homologue (S.  Serbisier]], CDC42 [cell division cycle 42 (GTP binding protein, 25 kDa)], CDC5L [CDC5 cell division cycle 5-like (S.  Pombe)], CDH1 [cadherin 1, type 1, E-cadherin (epithelial)], CDH10 [cadherin 10, type 2 (T2-cadherin)], CDH12 [cadherin 12, type 2 (N-cad Herrin 2)], CDH15 [cadherin 15, type 1, M-cadherin (myotubule)], CDH2 [cadherin 2, type 1, N-cadherin (neuron)], CDH4 [cadherin 4 , Type 1, R-cadherin (retina)], CDH5 [cadherin 5, type 2 (vascular endothelial)], CDH9 [cadherin 9, type 2 (T1-cadherin)], CDIPT [CDP-diacylglycerol Inositol 3-phosphatidyltransferase (phosphatidylinositol synthetase), CDK1 [cyclin-dependent kinase 1], CDK14 [cyclin-dependent kinase 14], CDK2 [cyclin-dependent kinase 2], CDK4 [cyclin-dependent kinase 4 ], CDK5 [cyclin-dependent kinase 5], CDK5R1 [cyclin-dependent kinase 5, regulatory subunit 1 (p35)], CDK5RAP2 [CDK5 regulatory subunit related protein 2], CDK6 [cyclin-dependent kinase 6], CDK7 [ Cyclin-dependent Kinase 7], CDK9 [cyclin-dependent kinase 9], CDKL5 [cyclin-dependent kinase-like 5], CDKN1A [cyclin-dependent kinase inhibitor 1A (p21, Cip1)], CDKN1B [cyclin-dependent kinase inhibitor 1B (p27, Kip1)], CDKN1C [cyclin-dependent kinase inhibitor 1C (p57, Kip2)], CDKN2A [cyclin-dependent kinase inhibitor 2A (inhibits melanoma, p16, CDK4)], CDKN2B [cyclin-dependent kinase inhibitor 2B (p15) , Inhibits CDK4)], CDKN2C [cyclin-dependent kinase inhibitor 2C (p18, inhibits CDK4)], CDKN2D [cyclin-dependent kinase inhibitor 2D (p19, inhibits CDK4)], CDNF [cerebral dopamine neurotrophic Factor], CDO1 [cysteine deoxygenase, type I], CDR2 [cerebellar degeneration-associated protein 2, 62 kDa], CDT1 [chromatin tolerance and DNA replication factor 1], CDX1 [tailed type homeobox 1] , CDX2 [tailed type homeobox 2], CEACAM1 [carcinogenic antigen-related Follicle adhesion molecule 1 (bile glycoprotein)], CEACAM3 [carcinogenic antigen-associated cell adhesion molecule 3], CEACAM5 [carcinogenic antigen-related cell adhesion molecule 5], CEACAM7 [carcinogenic antigen-associated cell adhesion molecule 7], CEBPB [CCAAT / Enhancer Binding Protein (C / EBP), Beta], CEBPD [CCAAT / Enhancer Binding Protein (C / EBP), Delta], CECR2 [Cat Eye Syndrome Chromosome Part, Candidate 2], CEL [carboxyl Ester lipase (bile salt-stimulated lipase)], CENPC1 [Centromer Protein C 1], CENPJ [Centromer Protein J], CEP290 [Centrosome Protein 290kDa], CER1 [Cerberus 1, Cysteine Knot ) Superfamily, homologues (African claws)], CETP [cholesteryl ester transfer protein, plasma], CFC1 [cripto, FRL-1, cryptic family 1], CFH [complement factor H] CFHR1 [complement factor H-related 1], CFHR3 [complement factor H-related 3], CFHR4 [complement factor H-related 4], CFI [complement factor I], CFL1 [Kophyrin 1 (non-muscle)], CFL2 [Kophyrin 2 (muscle)], CFLAR [CASP8 and FADD-like apoptosis modulator], CFTR [cystic fibrosis transmembrane and conductivity modulator (ATP-binding) Cassette sub-family C, member 7)], CGA [glycoprotein hormone, alpha polypeptide], CGB [choriole gonadotropin, beta polypeptide], CGB5 [choriole gonadotropin, beta polypeptide 5], CGGBP1 [CGG triple Repeat binding protein 1], CHAF1A [chromatin assembly factor 1, subunit A (p150)], CHAF1B [chromatin assembly factor 1, subunit B (p60)], CHAT [choline acetyltransferase], CHEK1 [CHK1 checkpoint Homolog (S.  Pombe)], CHEK2 [CHK2 checkpoint homolog (S.  Pombe)], CHGA [Chromogranin A (parathyroid secretion protein 1)], CHKA [choline kinase alpha], CHL1 [cell adhesion molecule homologous to L1CAM (homolog homologous to L1)], CHN1 [chimaerin 1), CHP [calcium binding protein P22], CHP2 [calcineurin B homologous protein 2], CHRD [cordin], CHRM1 [cholinergic receptor, muscarinic 1], CHRM2 [cholinergic receptor, mousse Carinogenic 2], CHRM3 [cholinergic receptor, muscarinic 3], CHRM5 [cholinergic receptor, muscarinic 5], CHRNA3 [cholinergic receptor, nicotinic, alpha 3], CHRNA4 [cholinergic Receptor, nicotinic, alpha 4], CHRNA7 [cholinergic receptor, nicotinic, alpha 7], CHRNB2 [cholinergic receptor, nicotinic, beta 2 (neuron)], CHST1 [carbohydrate (keratan sulfate Gal-6 ) Sulfotransferase 1], CHST10 [carbohydrate sulfotransferase 10], CHST3 [carbohydrate (chondroitin 6) sulfotransferase 3], CHUK [conserved helix-loop-helix fragment Kinases], CHURC1 [containing churchill domain 1], CIB1 [calcium and integrin binding 1 (calcirin)], CIITA [class II, major histocompatibility complex, transactivator], CIRBP [cold-induced RNA] Binding protein], CISD1 [CDGSH iron sulfur domain 1], CISH [cytokine inducible SH2-containing protein], CIT [citron (rho-interaction, serine / threonine kinase 21)], CLASP2 [cytoplasmic linker related protein 2] , CLCF1 [cardiotropin-like cytokine factor 1], CLCN2 [chloride channel 2], CLDN1 [claudein 1], CLDN14 [claudein 14], CLDN16 [claudein 16], CLDN3 [claudein 3], CLDN4 [claudein 4] , CLDN5 [Claudin 5], CLDN8 [Claudin 8], CLEC12A [C-type lectin domain family 12, member A], CLEC16A [C-type lectin domain family 16, member A], CLEC5A [C-type lectin domain family 5 , Member A], CLEC7A [C-type lectin domain family 7, member A], CLIP2 [CAP-GLY domain containing linker protein 2], CLSTN1 [calci Nin 1], CLTC [Claterin, Heavy Chain (Hc)], CLU [Clusterin], CMIP [c-Maf-Induced Protein], CNBP [CCHC-type Zinc Finger, Nucleic Acid Binding Protein], CNGA3 [Cycle Nucleotide Opening] Channel alpha 3], CNGB3 [cycle nucleotide-gated channel beta 3], CNN1 [calponin 1, basic, smooth muscle], CNN2 [calponin 2], CNN3 [calponin 3, acidic], CNOT8 [CCR4-NOT transcription complex , Subunit 8], CNP [2 '[3'-cycle nucleotide 3' phosphodiesterase], CNR1 [cannabinoid receptor 1 (brain)], CNR2 [cannabinoid receptor 2 (macrophage)], CNTF [ciliary nerves Trophic factor], CNTFR [ciliary neurotrophic factor receptor], CNTFR [ciliary neurotrophic factor receptor], CNTFR [ciliary neurotrophic factor receptor], CNTLN [centlein, centrosome protein], CNTN1 [contactin 1] , CNTN2 [contactin 2 (axon)], CNTN4 [contactin 4], CNTNAP1 [contactin related protein 1], CNTNAP2 [contactin related protein-like 2], C OBL [cordon-bleu homologue (mouse)], COG2 [component 2 of oligomer Golgi], COL18A1 [collagen, type XVIII, alpha 1], COL1A1 [collagen, type I, alpha 1], COL1A2 [Collagen, type I, alpha 2], COL2A1 [collagen, type II, alpha 1], COL3A1 [collagen, type III, alpha 1], COL4A3 [collagen, type IV, alpha 3 (Goodpasture antigen)], COL4A3BP [collagen , Type IV, alpha 3 (Goodpasture antigen) binding protein], COL5A1 [collagen, type V, alpha 1], COL5A2 [collagen, type V, alpha 2], COL6A1 [collagen, type VI, alpha 1], COL6A2 [collagen , Type VI, alpha 2], COL6A3 [collagen, type VI, alpha 3], COMT [catechol-O-methyltransferase], COPG2 [coatomer protein complex, subunit gamma 2], COPS4 [COP9 Constitutive photogenic homologue subunit 4 (Arabidopsis)], CORO1A [coronine, actin binding protein, 1A], COX5A [cytochrome c oxidase subunit Va], COX7B [cytochrome c oxidase enzyme] Unit VI Ib], CP [ceruloplasmin (peroxidase)], CPA1 [carboxypeptidase A1 (pancreas)], CPA2 [carboxypeptidase A2 (pancreas)], CPA5 [carboxypeptidase A5], CPB2 [Carboxypeptidase B2 (plasma)], CPOX [coproporpynogen oxidase], CPS1 [carbamoyl-phosphate synthase 1, mitochondria], CPT1A [carnitine palmitoyltransferase 1A (liver)], CR1 [complement component (3b / 4b) receptor 1 (Knops blood group)], CR2 [complement component (3d / ypstein bar virus) receptor 2], CRABP1 [cell retinoic acid binding protein 1], CRABP2 [cell retinoic acid Binding protein 2], C rat [carnitine O-acetyltransferase], CRB1 [crumbs homologue 1 (Drosophila)], CREB1 [cAMP response element binding protein 1], CREBBP [CREB binding protein], CRELD1 [ Cysteine-rich 1] with EGF-like domains, CRH [Adrenal cortical stimulating hormone releasing hormone], CRIP1 [Cysteine-rich protein 1 (intestinal)], CRK [v-crk sarcoma virus CT10 Genetic homologues (algae)], CRKL [v-crk sarcoma virus CT10 oncogene homologues (algae) -like], CRLF1 [cytokine receptor-like factor 1], CRLF2 [cytokine receptor-like factor 2], CRLF3 [ Cytokine receptor-like factor 3], CRMP1 [collapsin reaction mediator protein 1], CRP [C-reactive protein, pentracin-associated], CRTC1 [CREB regulated transcriptional coactivator 1], CRX [cone Cone-rod homeobox], CRYAA [crystallin, alpha A], CRYAB [crystallin, alpha B], CS [citrate synthetase], CSAD [cysteine sulfinic acid decarboxylase], CSF1 [colony stimulating factor 1 (macrophage)], CSF1R [colony stimulating factor 1 receptor], CSF2 [colony stimulating factor 2 (granulocyte-macrophage)], CSF2RA [colony stimulating factor 2 receptor, alpha, low affinity (granulocyte- Macrophages)], CSF3 [colony stimulating factor 3 (granulocytes)], CSF3R [colony stimulating factor 3 receptor (granulocytes)], CSH2 [ Membrane somatomatropin hormone 2], CSK [c-src tyrosine kinase], CSMD1 [CUB and Sushi multidomain 1], CSMD3 [CUB and Sushi multidomain 3], CSNK1D [casein kinase 1, delta], CSNK1E [ Casein kinase 1, epsilon], CSNK2A1 [casein kinase 2, alpha 1 polypeptide], CSPG4 [chondroitin sulfate proteoglycan 4], CSPG5 [chondroitin sulfate proteoglycan 5 (neuglycan C)], CST3 [cistine [Csita C], C Tin F (Lucocystatin)], CSTB [Cystatin B (Stepin B)], CTAG1B [Cancer / Testis Antigen 1B], CTBP1 [C-terminal Binding Protein 1], CTCF [CCCTC-binding factor (Zinc Finger Protein) )], CTDSP1 [CTD (carboxy-terminal domain, RNA polymerase II, polypeptide A) small phosphatase 1], CTF1 [cardiotropin 1], CTGF [connected tissue growth factor], CTLA4 [cytotoxic T-lymphocyte- Related protein 4], CTNNA1 [catenin (cadherin-associated protein), alpha 1, 102kDa], CTNNAL1 [catenin (Cadherin-associated protein), alpha-like 1], CTNNB1 [catenin (cadherin-associated protein), beta 1, 88 kDa], CTNND1 [catenin (cadherin-associated protein), delta 1], CTNND2 [catenin ( Cadherin-associated protein), Delta 2 (neuroflacophylline-related arm-repeated protein)], CTNS [cystinoma, nephropathy], CTRL [chymotrypsin-like], CTSB [Cathepsin B], CTSC [Cathepsin C], CTSD [Cathepsin D], CTSG [Cathepsin G], CTSH [Cathepsin H], CTSL1 [Cathepsin L1], CTSS [Cathepsin S], CTTN [Cortactin], CTTNBP2 [ Cortactin binding protein 2], CUL4B [Cullin 4B], CUL5 [Cullin 5], CUX2 [cut-like homeobox 2], CX3CL1 [chemokine (C-X3-C motif) ligand 1], CX3CR1 [chemokine (C-X3-C motif) receptor 1], CXADR [coxaki virus and adenovirus receptor], CXCL1 [chemokine (CXC motif) ligand 1 (melanoma growth stimulating activity, alpha)], CXCL10 [chemokine (CXC Motif) ligand 10], CXCL12 [chemokine (CXC Tip) ligand 12 (mesenchymal-induced factor 1)], CXCL16 [chemokine (CXC motif) ligand 16], CXCL2 [chemokine (CXC motif) ligand 2], CXCL5 [chemokine (CXC motif) ligand 5] , CXCR1 [chemokine (CXC motif) receptor 1], CXCR2 [chemokine (CXC motif) receptor 2], CXCR3 [chemokine (CXC motif) receptor 3], CXCR4 [chemokine (CXC motif) receptor 4], CXCR5 [Chemokine (CXC motif) receptor 5], CYB5A [cytochrome b5 type A (microsome)], CYBA [cytochrome b-245, alpha polypeptide], CYBB [cytochrome b-245, beta polypeptide], CYCS [ Cytochrome c, of the body], CYFIP1 [cytoplasmic FMR1 interacting protein 1], CYLD [spontaneous (Turban tumor syndrome)], CYP11A1 [cytochrome P450, family 11, subfamily A, polypeptide 1], CYP11B1 [cytochrome P450, family 11, subfamily B, polypeptide 1], CYP11B2 [cytochrome P450, family 11, subfamily B, polypeptide 2], CY P17A1 [cytochrome P450, family 17, subfamily A, polypeptide 1], CYP19A1 [cytochrome P450, family 19, subfamily A, polypeptide 1], CYP1A1 [cytochrome P450, family 1, subfamily A, polypeptide 1] , CYP1A2 [Cytochrome P450, Family 1, Subfamily A, Polypeptide 2], CYP1B1 [Cytochrome P450, Family 1, Subfamily B, Polypeptide 1], CYP21A2 [Cytochrome P450, Family 21, Subfamily A, Polypeptide 2 ], CYP2A6 [cytochrome P450, family 2, subfamily A, polypeptide 6], CYP2B6 [cytochrome P450, family 2, subfamily B, polypeptide 6], CYP2C9 [cytochrome P450, family 2, subfamily C, polypeptide 9], CYP2D6 [cytochrome P450, family 2, subfamily D, polypeptide 6], CYP2E1 [cytochrome P450, family 2, subfamily E, polypeptide 1], CYP3A4 [cytochrome P450, family 3, subfamily A, Polypeptide 4], CYP7A1 Troprom P450, family 7, subfamily A, polypeptide 1], CYR61 [cysteine-rich, angiogenesis inducer, 61], CYSLTR1 [cysteinyllucotriene receptor 1], CYSLTR2 [cysteinyllucotriene receptor 2], DAB1 [disabled homologue 1 (Drosophila)], DAGLA [Diacylglycerol Lipase, Alpha], DAGLB [Diacylglycerol Lipase, Beta], DAO [D-Amino-Acid Oxidase], DAOA [D- Amino acid oxidase activator], DAPK1 [kill-related protein kinase 1], DAPK3 [kill-related protein kinase 3], DAXX [kill-domain related protein], DBH [dopamine beta-hydroxylase (dopamine beta-mono) Oxygenase)], DBI [diazepam binding inhibitor (GABA receptor modulator, acyl-coenzyme A binding protein)], DBN1 [brebrin 1], DCAF6 [DDB1 and CUL4 related factor 6], DCC [deleted in colon carcinoma ], DCDC2 [double cortin domain containing 2], DCK [deoxycytidine kinase], DCLK1 [double co Tin-like kinase 1], DCN [decorin], DCTN1 [dynactin 1 (p150, glue homologue, Drosophila)], DCTN2 [dynatin 2 (p50)], DCTN4 [dynatin 4 (p62) )], DCUN1D1 [DCN1, deficiency 1, domain containing 1 (C.  Servicier)], DCX [double cortin], DDB1 [damage-specific DNA binding protein 1, 127 kDa], DDC [dopa decarboxylase (aromatic L-amino acid decarboxylase)], DDIT3 [DNA-damage- Inducible transcript 3], DDIT4 [DNA-damaged-inducible transcript 4], DDIT4L [DNA-damaged-induced transcript 4-like], DDR1 [discoidin domain receptor tyrosine kinase 1], DDX10 [DEAD ( Asp-Glu-Ala-Asp) box polypeptide 10], DDX17 [DEAD (Asp-Glu-Ala-Asp) box polypeptide 17], DEFB4A [defensin, beta 4A], DEK [DEK oncogene], DES [desmin ], DEXI [Dexi homologue (mouse)], DFFA [DNA fragmentation factor, 45kDa, alpha polypeptide], DFNB31 [deaf, autosomal recessive 31], DGCR6 [DiGeorge syndrome determinant partial gene 6], DGUOK [deoxyguanosine Kinase], DHCR7 [7-dehydrocholesterol reductase], DHFR [dihydrofolate reductase], DIAPH1 [nearly transparent homologue 1 (Drosophila)], DICER1 [Dicer 1, ribonu] Rease Type III], DIO1 [iodiolytic enzyme, iodithironin, type I], DIO2 [iodiolytic enzyme, iodideronin, type II], DIP2A [DIP2 disco-interacting protein 2 homologue A (Drosophila)], DIRAS3 [DIRAS family, GTP-linked RAS-like 3], DISC1 [destroyed in schizophrenia 1], DISC2 [destroyed in schizophrenia 2 (non-protein coding)], DKC1 [congenital dyskerosis 1 , Descalin], DLG1 [disc, large homology 1 (Drosophila)], DLG2 [disc, large homology 2 (Drosophila)], DLG3 [disc, large homology 3 (Drosophila)], DLG4 [disc, large image Fuselage 4 (Drosophila)], DLGAP1 [disc, large (Drosophila) homologue-associated protein 1], DLGAP2 [Disc, large (Drosophila) homologue-related protein 2], DLK1 [Delta-like 1 phase Fuselage (Drosophila)], DLL1 [Delta-Like 1 (Drosophila)], DLX1 [Terminal-less Homeobox 1], DLX2 [Terminal-less Homeobox 2], DLX3 [Terminal-free Arc Meobox 3], DLX4 [end- Is homeobox 4], DLX5 [terminal-free homeobox 5], DLX6 [terminal-free homeobox 6], DMBT1 [deleted in malignant brain tumor 1], DMC1 [DMC1 dosing inhibitor of mck1 homologue , Meiosis-specific homologous recombination (yeast)], DMD [dispropine], DMPK [muscular dystonia-protein kinase], DNAI2 [dyne, ammonia, intermediate chain 2], DNAJC28 [DnaJ ( Hsp40) homologue, subfamily C, member 28], DNAJC30 [DnaJ (Hsp40) homologue, subfamily C, member 30], DNASE1 [deoxyribonuclease I], DNER [delta / notch-like EGF repeat Containing], DNLZ [DNL-type zinc finger], DNM1 [dynamin 1], DNM3 [dynamin 3], DNMT1 [DNA (cytosine-5-)-methyltransferase 1], DNMT3A [DNA (cytosine-5- ) -Methyltransferase 3 alpha], DNMT3B [DNA (cytosine-5-)-methyltransferase 3 beta], DNTT [deoxynucleotidyltransferase, terminal], DOC2A [double C2-like domain, alpha], DOCK1 [Committed to Cell Division 1], DOCK3 [Cytoplasm Devotion of Heat 3], DOCK4 [Devotion of Cell Division 4], DOCK7 [Dedication of Cell Division 7], DOK7 [Docking Protein 7], DONSON [SON's Downstream Neighbors], DOPEY1 [dopey family member 1], DOPEY2 [Dope family member 2], DPF1 [D4, zinc and double PHD finger family 1], DPF3 [D4, zinc and double PHD finger, family 3], DPH1 [DPH1 homologue (S.  Serbisier)], DPP10 [dipeptides-peptidase 10], DPP4 [dipeptides-peptidase 4], DPRXP4 [branching-paired related homeobox false gene 4], DPT [der Matopontin], DPYD [dihydropyrimidine dehydrogenase], DPYSL2 [dihydropyrimidinase-like 2], DPYSL3 [dihydropyrimidinase-like 3], DPYSL4 [dihydropyrimidinase-like 4], DPYSL5 [Dehydropyrimidinase-like 5], DRD1 [Dopamine Receptor D1], DRD2 [Dopamine Receptor D2], DRD3 [Dopamine Receptor D3], DRD4 [Dopamine Receptor D4], DRD5 [Dopamine Receptor D5], DRG1 [Genetic] Regulated GTP binding protein 1], DRGX [hind root ganglion homeobox], DSC2 [desmocholine 2], DSCAM [Down syndrome cell adhesion molecule], DSCAML1 [Down syndrome cell adhesion molecule mimic 1], DSCR3 [Down Syndrome deterministic partial gene 3], DSCR4 [Down syndrome deterministic partial gene 4], DSCR6 [Down syndrome deterministic partial genetic 6], DSERG1 [Down Syndrome Encephalopathy Related Protein 1], DSG1 [Desmoglein 1], DSG2 [Desmogloin 2], DSP [Desmoplakin], DST [dystonin], DSTN [Destrin (Actin depolymerization factor)], DTNBP1 [Dystrobrevin binding protein 1], DULLARD [dullard homologue (African claw)], DUSP1 [bispecific phosphatase 1], DUSP13 [bispecific phosphatase 13] , DUSP6 [bispecific phosphatase 6], DUT [deoxyuridine triphosphatase], DVL1 [scattered, dsh homologue 1 (Drosophila)], DYRK1A [bi-specific tyrosine- (Y) -phosphorylated modulated kinase 1A ], DYRK3 [bi-specific tyrosine- (Y) -phosphorylated modulated kinase 3], DYSF [disferin, limb girdle muscular dystrophy 2B (autosome recessive)], DYX1C1 [dyslexia sensitive 1 candidate 1], E2F1 [E2F Transcription factor 1], EARS2 [glutamyl-tRNA synthetase 2, mitochondria (estimated)], EBF4 [initial B-cell factor 4], ECE1 [endoterin conversion Enzyme 1], ECHS1 [Enoyl Coenzyme A Hydase, Short Chain, 1, Mitochondria], EDN1 [Endoterin 1], EDN2 [Endoterin 2], EDN3 [Endoterin 3], EDNRA [Endoterin Receptor Type A] , EDNRB [endotherin receptor type B], EEF1A1 [eukaryotic detoxification factor 1 alpha 1], EEF2 [eukaryotic detoxification factor 2], EEF2K [eukaryotic prolongation factor-2 kinase], EFHA1 [EF-hand ) Domain family, member A1], EFNA1 [Epirine-A1], EFNA2 [Epirine-A2], EFNA3 [Epirine-A3], EFNA4 [Epirine-A4], EFNA5 [Epirine-A5], EFNB2 [ Epilin-B2], EFNB3 [epirin-B3], EFS [embryonic Fyn-associated substrate], EGF [epithelial growth factor (beta-neurogenstron)], EGFR [epithelial growth factor receptor (erythroblastic leukemia viral ( v-erb-b) oncogene homologues, algae)], EGLN1 [egl 9 homologues 1 (C. Elegans)], EGR1 [Initial Growth Reaction 1], EGR2 [Initial Growth Reaction 2], EGR3 [Initial Growth Reaction 3], EHHADH [Enoyl-Coenzyme A, Hydrolase / 3-hydroxyacyl Coenzyme A Dehydrogenase], EHMT2 [Big euchromosomal histone-lysine N-methyltransferase 2], EID1 [EP300 interaction inhibitor 1 of differentiation], EIF1AY [eukaryotic translation initiation factor 1A, Y-linked], EIF2AK2 [eukaryotic translation initiation factor 2- Alpha kinase 2], EIF2AK3 [eukaryotic translation initiation factor 2-alpha kinase 3], EIF2B2 [eukaryotic translation initiation factor 2B, subunit 2 beta, 39kDa], EIF2B5 [eukaryotic translation initiation factor 2B, subunit 5 epsilon, 82 kDa], EIF2S1 [eukaryotic translation initiation factor 2, subunit 1 alpha, 35 kDa], EIF2S2 [eukaryotic translation initiation factor 2, subunit 2 beta, 38 kDa], EIF3M [eukaryotic translation initiation factor 3, subunit M] , EIF4E [eukaryotic translation initiation factor 4E], EIF4EBP1 [eukaryotic translation initiation factor 4E binding protein 1], EIF4G1 [eukaryotic translation initiation factor 4 gamma, 1 ], EIF4H [eukaryotic translation initiation factor 4H], ELINE [elastase, neutrophil expressed], ELAVL1 [ELAV (embryofatal, abnormal vision, Drosophila) -like 1 (Hu antigen R)], ELAVL3 [ELAV (embryonic) Lethal, abnormal vision, Drosophila) -like 3 (Hu antigen C)], ELAVL4 [ELAV (embryofatal, abnormal vision, Drosophila) -like 4 (Hu antigen D)], ELF5 [E74-like factor 5 (ets domain transcription) Factor)], ELK1 [ELK1, a member of the ETS oncogene family], ELMO1 [engulfment and cell mobility 1], ELN [elastin], ELP4 [extension protein 4 homologues (S. Serbisier)], EMP2 [Epithelial membrane protein 2], EMP3 [epithelial membrane protein 3], EMX1 [empty pores homeobox 1], EMX2 [empty pores homeobox 2], EN1 [serrated homeobox 1], EN2 [Sawtooth Homeobox 2], ENAH [enabled homolog (Drosophila)], ENDOG [Endonuclease G], ENG [Endoglin], ENO1 [Enolase 1, (alpha)] , ENO2 [enolase 2 (gamma, Neurons)], ENPEP [glutamyl aminopeptidase (aminopeptidase A)], ENPP1 [Ectonucleotide pyrophosphatase / phosphodiesterase 1], ENPP2 [Ectonucleotide pyrophosphatase / phosphodiesterase 2] , ENSA [endosulphin alpha], ENSG00000174496 [], ENSG00000183653 [], ENSG00000215557 [], ENTPD1 [ectonucleoside triphosphate diphosphatase 1], EP300 [E1A binding protein p300], EPCAM [epithelial cell adhesion molecule ], EPHA1 [EPH Receptor A1], EPHA10 [EPH Receptor A10], EPHA2 [EPH Receptor A2], EPHA3 [EPH Receptor A3], EPHA4 [EPH Receptor A4], EPHA5 [EPH Receptor A5], EPHA6 [EPH Receptor A6] , EPHA7 [EPH receptor A7], EPHA8 [EPH receptor A8], EPHB1 [EPH receptor B1], EPHB2 [EPH receptor B2], EPHB3 [EPH receptor B3], EPHB4 [EPH receptor B4], EPHB6 [EPH receptor B6], EPHX2 [epoxide hydrolase 2, cytoplasm], EPM2A [epilepsy, progressive myoclonus type 2A, Lafora disease (lafor in))], EPO [erythropoietin], EPOR [erythropoietin receptor], EPRS [glutamyl-proyl-tRNA synthetase], EPS15 [epithelial growth factor receptor pathway substrate 15], ERBB2 [v-erb- b2 erythrocyte leukemia viral oncogene homologue 2, neuro / glioblast-derived oncogene homologue (algae)], ERBB3 [v-erb-b2 erythrocyte leukemia viral oncogene homologue 3 (algae)], ERBB4 [v-erb-a erythrocyte leukemia viral oncogene homologue 4 (algae)], ERC2 [ELKS / RAB6-interaction / CAST family member 2], ERCC2 [delete repair cross-complementary rodent repair defect, complement group 2 ], ERCC3 [Delete Recovery Cross-Complemented Rodent Recovery Defect, Complement Group 3 (Complementary Pigmentation Skin B Group)], ERCC5 [Delete Recovery Cross-Complement Rodent Recovery Defect, Complement Group 5], ERCC6 [Delete Recovery Cross-Complement Rodent Recovery Defects, Complementary Group 6], ERCC8 [Delete Recovery Cross-Complemented Rodent Recovery Defects, Complementary He 8], EREG [Epiregulin], ERG [v-ets erythropoietic virus E26 oncogene homolog (bird)], ERVWE1 [endogenous retroviral family W, env (C7), member 1], ESD [S Therapase D / formylglutathione hydrolase], ESR1 [estrogen receptor 1], ESR2 [estrogen receptor 2 (ER beta)], ESRRA [estrogen-associated receptor alpha], ESRRB [estrogen-associated receptor beta], ETS1 [ v-ets erythropoietic virus E26 oncogene homolog 1 (algae)], ETS2 [v-ets erythropoietic virus E26 oncogene homologue 2 (algae)], ETV1 [ets variant 1], ETV4 [ets variant 4], ETV5 [ets variant 5], ETV6 [ets variant 6], EVL [Enah / Vasp-like], EXOC4 [exocyst complex component 4], EXOC8 [exocyst complex component 8], EXT1 [bone prolapse (multiple) 1 ], EXT2 [bone prolapse (multiple) 2], EZH2 [enhancer 2 of the zeste homologue (Drosophila)], EZR [Izrin], F12 [coagulation factor XII (Hageman factor)], F2 [ High factor II (thrombin)], F2R [coagulation factor II (thrombin) receptor], F2RL1 [coagulation factor II (thrombin) receptor-like 1], F3 [coagulation factor III (thromboplastin, tissue factor)], F7 [Coagulation factor VII (serum prothrombin conversion accelerator)], F8 [coagulation factor VIII, precoagulant component], F9 [coagulation factor IX], FAAH [fatty acid amide hydrolase], FABP3 [fatty acid binding protein 3, muscle and heart (Breast-induced growth inhibitors)], FABP4 [fatty acid binding protein 4, adipocytes], FABP5 [fatty acid binding protein 5 (psoriasis-related)], FABP7 [fatty acid binding protein 7, brain], FADD [via a death domain Fas (TNFRSF6) -related], FADS2 [fatty acid desaturase 2], FAM120C [family 120C with sequence similarity], FAM165B [family with sequence similarity 165, member B], FAM3C [family 3, member with sequence similarity C], FAM53A [family 53 with sequence similarity, member A], FARP2 [FERM, RhoGEF and flextrin dome Phosphorus protein 2], FARSA [phenylalanyl-tRNA synthetase, alpha subunit], FAS [Fas (TNF receptor superfamily, member 6)], FASLG [Fas ligand (TNF superfamily, member 6)], FASN [ Fatty acid synthetase], FASTK [Fas-activated serine / threonine kinase], FBLN1 [fibrin 1], FBN1 [fibrillin 1], FBP1 [fructose-1 [6-bisphosphatase 1], FBXO45 [F- Box protein 45], FBXW5 [containing F-box and WD repeat domain 5], FBXW7 [containing F-box and WD repeat domain 7], FCER2 [Fc fragment of IgE, low affinity II, receptor (CD23)], FCGR1A [ Fc fragment of IgG, high affinity Ia, receptor (CD64)], FCGR2A [Fc fragment of IgG, low affinity IIa, receptor (CD32)], FCGR2B [Fc fragment of IgG, low affinity IIb, receptor (CD32)], FCGR3A [Fc fragment of IgG, low affinity IIIa, receptor (CD16a)], FCRL3 [Fc receptor-like 3], FDFT1 [farnesyl-diphosphate farnesyltransferase 1], FDX1 [perredoxin 1], FDXR [perrex Toxin reductase], FECH [ferrocella Taze (porphyrinosis)], FEM1A [fem-1 homologue a (C. Elegans)], FER [fer (fps / fes related) tyrosine kinases], FES [cats and sarcoma oncogenes], FEZ1 [fasciculation and extension protein zeta 1 (zygin I)], FEZ2 [ Multiplexing and Extending Protein Zeta 2 (Zagin II)], FEZF1 [FEZ Family Zinc Finger 1], FEZF2 [FEZ Family Zinc Finger 2], FGF1 [Fibroblast Growth Factor 1 (Acid)], FGF19 [Fibroblast Growth Factor 19], FGF2 [fibroblast growth factor 2 (basic)], FGF20 [fibroblast growth factor 20], FGF3 [fibroblast growth factor 3 (murine breast tumor virus integration site (v-int-2) oncogene homolog) ], FGF4 [fibroblast growth factor 4], FGF5 [fibroblast growth factor 5], FGF7 [fibroblast growth factor 7 (keratinocyte growth factor)], FGF8 [fibroblast growth factor 8 (androgen-derived)] , FGF9 [fibroblast growth factor 9 (neuroglial-activating factor)], FGFBP1 [fibroblast growth factor binding protein 1], FGFR1 [fiber Cell growth factor receptor 1], FGFR2 [fibroblast growth factor receptor 2], FGFR3 [fibroblast growth factor receptor 3], FGFR4 [fibroblast growth factor receptor 4], FHIT [fragile histidine trigene], FHL1 [ 4 and 1/2 LIM domain 1], FHL2 [4 and 1/2 LIM domain 2], FIBP [fibroblast growth factor (acidic) intracellular binding protein], FIGF [c-fos induced growth factor (vascular endothelial growth) Factor D)], FIGNL1 [fidgetin-like 1], FKBP15 [FK506 binding protein 15,133 kDa], FKBP1B [FK506 binding protein 1B, 12. 6 kDa], FKBP5 [FK506 binding protein 5], FKBP6 [FK506 binding protein 6, 36kDa], FKBP8 [FK506 binding protein 8, 38kDa], FKTN [fukutin], FLCN [polycurin], FLG [pillar Green], FLI1 [Friend Leukemia Virus Integration 1], FLNA [Pilamin A, Alpha], FLNB [Pilamin B, Beta], FLNC [Pilamin C, Gamma], FLT1 [fms-associated Tyrosine Kinase 1 (vascular endothelial) Growth factor / vascular permeability factor receptor)], FLT3 [fms-associated tyrosine kinase 3], FMN1 [formin 1], FMNL2 [formin-like 2], FMR1 [fragile X mental retardation 1], FN1 [fibronectin 1], FOLH1 [folate hydrolase (prostate-specific membrane antigen) 1], FOLR1 [folate receptor 1 (adult)], FOS [FBJ murine osteosarcoma viral oncogene homologue], FOSB [ FBJ murine osteosarcoma viral oncogene homologue B], FOXC2 [forkhead box C2 (MFH-1, mesenchyme forkhead 1)], FOXG1 [forkhead box G1], FOXL2 [forkhead gourd] L2], FOXM1 [forkhead box M1], FOXO1 [forkhead box O1], FOXO3 [forkhead box O3], FOXP2 [forkhead box P2], FOXP3 [forkhead box P3], FPR1 [formyl peptide receptor 1 ], FPR2 [formyl peptide receptor 2], FRMD7 [FERM domain containing 7], FRS2 [fibroblast growth factor receptor substrate 2], FRS3 [fibroblast growth factor receptor substrate 3], FRYL [FRY-like], FSCN1 [ Fahsin homolog 1, actin-bundling protein (voluntarily), FSHB [follicle stimulating hormone, beta polypeptide], FSHR [follicle stimulating hormone receptor], FST [polystatin], FSTL1 [polystatin-like 1], FSTL3 [ Follistatin-like 3 (secreted glycoprotein)], FTCD [formiminotransferase cyclodeaminase], FTH1 [ferritin, heavy polypeptide 1], FTL [ferritin, light polypeptide], FTMT [ferritin mitochondria ], FTSJ1 [FtsJ homologue 1 (E. coli)], FUCA1 [fucosidase, alpha-L-1, tissue], purine [purine (paired salt) Sex amino acid cleavage enzyme)], FUT1 [fucosyltransferase 1 (galactoside 2-alpha-L-fucosyltransferase, H blood group)], FUT4 [fucosyltransferase 4 (alpha (1 [3) fuco Transfectase, myeloid-specific)], FXN [pratacin], FXR1 [Fragile X Mental Retardation, Autosome Homolog 1], FXR2 [Fragile X Mental Retardation, Autosome Homolog 2], FXYD1 [FXYD domain containing ion transport modulator 1], FYB [FYN binding protein (FYB-120 / 130)], FYN [SRC-associated FYN oncogene, FGR, YES], FZD1 [curly homolog 1 (Drosophila) ], FZD10 [Curly Homolog 10 (Drosophila)], FZD2 [Curly Homolog 2 (Drosophila)], FZD3 [Curly Homolog 3 (Drosophila)], FZD4 [Curly Homolog 4 ( Drosophila)], FZD5 [curly homolog 5 (Drosophila)], FZD6 [curly homolog 6 (Drosophila)], FZD7 [curly homolog 7 (Drosophila)], FZD8 [curly homologue] 8 (Drosophila)], FZD9 [Curly Homolog 9 (Drosophila)], FZR1 [fizzy / cell division cycle 20 related 1 (Drosophila)], G6PD [glucose-6-phosphate dehydrogenase], GAA [glucosidase, alpha; Acid], GAB1 [GRB2-associated binding protein 1], GABARAP [GABA (A) receptor-associated protein], GABBR1 [gamma-aminobutyl acid (GABA) B receptor, 1], GABBR2 [gamma-aminobutyl acid (GABA) A) B receptor, 2], GABPA [GA binding protein transcription factor, alpha subunit 60 kDa], GABRA1 [gamma-aminobutyl acid (GABA) A receptor, alpha 1], GABRA2 [gamma-aminobutyl acid (GABA) A receptor , Alpha 2], GABRA3 [gamma-aminobutyl acid (GABA) A receptor, alpha 3], GABRA4 [gamma-aminobutyl acid (GABA) A receptor, alpha 4], GABRA5 [gamma-aminobutyl acid (GABA) A Receptor, alpha 5], GABRA6 [gamma-aminobutyl acid (GABA) A receptor, alpha 6], GABRB1 [gamma-aminobutyl acid (GABA) A receptor, beta 1], GABRB2 [gamma-aminobutyl acid (GABA) A receptor, beta 2], GABRB3 [gamma-aminobutyl acid (GABA) A receptor, beta 3], GABRD [gamma-aminobutyl acid (GABA) A receptor, delta], GABRE [gamma-aminobutyl acid (GABA) A receptor, epsilon], GABRG1 [ Gamma-aminobutyl acid (GABA) A receptor, gamma 1], GABRG2 [gamma-aminobutyl acid (GABA) A receptor, gamma 2], GABRG3 [gamma-aminobutyl acid (GABA) A receptor, gamma 3], GABRP [Gamma-aminobutyl acid (GABA) A receptor, pi], GAD1 [glutamate decarboxylase 1 (brain, 67 kDa)], GAD2 [glutamate decarboxylase 2 (pancreatic islet and brain, 65 kDa)], GAL [galanine Prepropeptide], GALE [UDP-galactose-4-epimerase], GALK1 [galactokinase 1], GALT [galactose-1-phosphate urilyltransferase], GAP43 [growth-related protein 43], GAPDH [glyceraldehyde-3-phosphate dehydrogenase], GARS [glycil-tRNA synthetase], GART [phosphoribosil glycineamide formyltransferase, phosphoribosyl glycineamide synthetase, phosphoribosylaminoimidazole synthetase ], GAS1 [growth hindered-specific 1], GAS6 [growth hindered-specific 6], GAST [gastrin], GATA1 [GATA binding protein 1 (globin trans) Factor 1)], GATA2 [GATA binding protein 2], GATA3 [GATA binding protein 3], GATA4 [GATA binding protein 4], GATA6 [GATA binding protein 6], GBA [glucosidase, beta, acid], GBE1 [ Glucan (1 [4-alpha-), Branching Enzyme 1], GBX2 [Gastrointestinal Brain Homeobox 2], GC [Group-Specific Component (Vitamin D Binding Protein)], GCG [Glucagon], GCH1 [GTP Cyclohydrolase 1], GCNT1 [glucosaminyl (N-acetyl) transferase 1, core 2], GDAP1 [ganglioside-induced differentiation-related protein 1], GDF1 [growth differentiation factor 1], GDF11 [ Growth differentiation factor 11], GDF15 [growth differentiation factor 15], GDF7 [growth differentiation factor 7], GDI1 [GDP dissociation inhibitor 1], GDI2 [GDP dissociation inhibitor 2], GDNF [glioblast-derived neurotrophic factor], GDPD5 [Containing glycerophosphodiester phosphodiesterase domain 5], GEM [GTP-binding protein overexpressed in skeletal muscle], GFAP [gyolipidic acid protein], GFER [growth factor, Enhancers of liver regeneration], GFI1B [growth-independent 1B transcription inhibitor], GFRA1 [GDNF family receptor alpha 1], GFRA2 [GDNF family receptor alpha 2], GFRA3 [GDNF family receptor alpha 3], GFRA4 [GDNF family receptor Alpha 4], GGCX [gamma-glutamyl carboxylase], GGNBP2 [gammetogenetin binding protein 2], GGT1 [gamma-glutamyltransferase 1], GGT2 [gamma-glutamyl transferase 2], GH1 [ Growth hormone 1], GHR [growth hormone receptor], GHRH [growth hormone releasing hormone], GHRHR [growth hormone releasing hormone receptor], GHRL [ghrelin / obestatin prepropeptide], GHSR [growth hormone secretagogue receptor], GIPR [Stomach Inhibiting Polypeptide Receptors], GIT1 [G Protein-linked Receptor Kinase Interaction ArfGAP 1], GJA1 [Gap Binding Protein, Alpha 1, 43kDa], GJA4 [Gap Binding Protein, Alpha 4, 37kDa], GJA5 [Gap Binding Protein, alpha 5, 40kDa], GJB1 [gap binding protein, beta 1, 32kDa], GJB2 [gap binding protein, beta 2, 26kDa], GJB6 [gap binding protein, beta 6, 30kDa], GLA [galactosidase, alpha], GLB1 [galactosidase, beta 1], GLDC [glycine dehydrogenase (Decarboxylation)], GLI1 [GLI family zinc finger 1], GLI2 [GLI family zinc finger 2], GLI3 [GLI family zinc finger 3], GLIS1 [GLIS family zinc finger 1], GLIS2 [GLIS family zinc finger 2], GLO1 [glyoxalase I], GLRA2 [glycine receptor, alpha 2], GLRB [glycine receptor, beta], GLS [glutaminase], GLUD1 [glutamate dehydrogenase 1], GLUD2 [glutamate dehydrogenase 2 ], GLUL [glutamate-ammonia ligase (glutamine synthase)], GLYAT [glycine-N-acyltransferase], GMFB [nerve glial maturation factor, beta], GMNN [geminin, DNA replication inhibitor], GMPS [guanine] Phosphate Synthetase], GNA11 [Guanine Nucleotide Binding Protein (G Protein), Alpha 11 (Gq Classification)], GNA12 [Guanine Nucleic] Ored Binding Protein (G Protein) Alpha 12], GNA13 [Guanine Nucleotide Binding Protein (G Protein), Alpha 13], GNA14 [Guanine Nucleotide Binding Protein (G Protein), Alpha 14], GNA15 [Guanine Nucleotide Binding Protein (G) Protein), alpha 15 (Gq classification)], GNAI1 [guanine nucleotide binding protein (G protein), alpha inhibitory active polypeptide 1], GNAI2 [guanine nucleotide binding protein (G protein), alpha inhibitory active polypeptide 2], GNAI3 [guanine Nucleotide binding protein (G protein), alpha inhibitory active polypeptide 3], GNAL [guanine nucleotide binding protein (G protein), alpha activating active polypeptide, olfactory type], GNAO1 [guanine nucleotide binding protein (G protein), alpha activating polypeptide O], GNAQ [guanine nucleotide binding protein (G protein), q polypeptide], GNAS [GNAS complex locus], GNAT1 [guanine Nucleotide binding protein (G protein), alpha transforming active polypeptide 1], GNAT2 [guanine nucleotide binding protein (G protein), alpha transforming active polypeptide 2], GNAZ [guanine nucleotide binding protein (G protein), alpha z polypeptide] , GNB1 [guanine nucleotide binding protein (G protein), beta polypeptide 1], GNB1L [guanine nucleotide binding protein (G protein), beta polypeptide 1-like], GNB2 [guanine nucleotide binding protein (G protein), beta polypeptide 2] , GNB2L1 [guanine nucleotide binding protein (G protein), beta polypeptide 2-like 1], GNB3 [guanine nucleotide binding protein (G protein), beta polypeptide 3], GNB4 [guanine nucleotide binding protein (G protein), beta polypeptide 4 ], GNB5 [guanine nucleotide binding protein (G protein), beta 5], GNG10 [guanine nucleotide binding Synthesis protein (G protein), gamma 10], GNG11 [guanine nucleotide binding protein (G protein), gamma 11], GNG12 [guanine nucleotide binding protein (G protein), gamma 12], GNG13 [guanine nucleotide binding protein (G protein) ), Gamma 13], GNG2 [guanine nucleotide binding protein (G protein), gamma 2], GNG3 [guanine nucleotide binding protein (G protein), gamma 3], GNG4 [guanine nucleotide binding protein (G protein), gamma 4] , GNG5 [Guanine Nucleotide Binding Protein (G Protein), Gamma 5], GNG7 [Guanine Nucleotide Binding Protein (G Protein), Gamma 7], GNLY [Granulincin], GNRH1 [Gonadotropin-Release Hormone 1 (Plated) -Releasing hormone)], GNRHR [gonadotropin-releasing hormone receptor], GOLGA2 [golgin A2], GOLGA4 [golgin A4], GOT2 [glutamine-oxaloacet transaminase 2, mitochondria (aspartate) Aminotransferase 2)], GP1BA [glycoprotein Ib (platelet), alpha polypeptide], GP5 [glycoprotein V (platelet)], GP6 [glycoprotein VI (platelet)], GP9 [glycoprotein IX (platelet)], GPC1 [gly Pecan 1], GPC3 [glypican 3], GPD1 [glycerol-3-phosphate dehydrogenase 1 (soluble)], GPHN [gephyrin], GPI [glucose phosphate isomerase], GPM6A [glycoprotein M6A] , GPM6B [glycoprotein M6B], GPR161 [G protein-linked receptor 161], GPR182 [G protein-linked receptor 182], GPR56 [G protein-linked receptor 56], GPRC6A [G protein-linked receptor, family C, group 6, member A], GPRIN1 [G protein regulated inducer 1 derived from neurites], GPT [glutamine-pyruvate transaminase (alanine aminotransferase)], GPT2 [glutamine pyruvate transaminase (alanine aminotransfer) Enzyme) 2], GPX1 [glutathione peroxidase 1], GPX3 [glutathione peroxidase 3 (plasma)], GPX4 [glutathione peroxidase 4 (phospholipid hydroperoxidase)], GRAP [GRB2-associated adapter protein], GRB10 [growth factor receptor-bound protein 10], GRB2 [growth factor receptor-bound protein 2], GRB7 [growth factor receptor-bound Protein 7], GREM1 [gremlin 1, cysteine knot superfamily, homologue (African claw)], GRIA1 [glutamate receptor, ionic, AMPA 1], GRIA2 [glutamate receptor, ionic, AMPA 2], GRIA3 [glutamate receptor, ionic, AMPA 3], GRID2 [glutamate receptor, ionic, delta 2], GRID2IP [glutamate receptor, ionic, delta 2 (Grid2) interacting protein], GRIK1 [glutamate receptor, Ionic, kinate 1], GRIK2 [glutamate receptor, ionic, kinate 2], GRIN1 [glutamate receptor, ionic, N-methyl D-aspartate 1], GRIN2A [glutamate receptor, ionic, N- Methyl D-aspartate 2A], GRIP 1 [glutamate receptor interacting protein 1], GRLF1 [glucocorticoid receptor DNA binding factor 1], GRM1 [glutamate receptor, metabotropic 1], GRM2 [glutamate receptor, metabotropic 2], GRM5 [glutamate receptor, metabolic Tropic 5], GRM7 [glutamate receptor, metabotropic 7], GRM8 [glutamate receptor, metabotropic 8], GRN [granulin], GRP [gastrin-releasing peptide], GRPR [gastrin-releasing peptide receptor ], GSK3B [glycogen synthase kinase 3 beta], GSN [gelzoline], GSR [glutathione reductase], GSS [glutathione synthase], GSTA1 [glutathione S-transferase alpha 1], GSTM1 [glutathione S-transferase Mu 1], GSTP1 [glutathione S-transferase pi 1], GSTT1 [glutathione S-transferase theta 1], GSTZ1 [glutathione transferase zeta 1], GTF2B [universal transcription factor IIB], GTF2E2 [universal transcription factor IIE, Paul Peptide 2, beta 34kDa], GTF2H1 [universal transcription factor IIH, polypeptide 1, 62kDa], GTF2H2 [universal transcription factor IIH, polypeptide 2, 44kDa], GTF2H3 [universal transcription factor IIH, polypeptide 3, 34kDa], GTF2H4 [Universal transcription factor IIH, polypeptide 4, 52 kDa], GTF2I [universal transcription factor IIi], GTF2IRD1 [containing GTF2I repeat domain 1], GTF2IRD2 [containing GTF2I repeat domain 2], GUCA2A [guanylate cyclase activator 2A (guaniline)], GUCY1A3 [guanylate cyclase 1, soluble, alpha 3], GUSB [glucoronidase, beta], GYPA [glycoporin A (MNS blood group)], GYPC [glycoporin C (Gerbich blood group)], GZF1 [GDNF-induced zinc finger protein 1], GZMA [Granzyme A (Granzyme 1, cytotoxic T-lymphocyte-associated serine esterase 3)], GZMB [Granzyme B ( Granzyme 2, cytotoxic T-lymphocyte-associated serine esterase 1)], H19 [H19, imprinted maternally expressed transcription (Non-protein coding)], H1F0 [H1 histone family, member 0], H2AFX [H2A histone family, member X], H2AFY [H2A histone family, member Y], H6PD [hexose-6-phosphate dehydrogenase (glucose) 1-dehydrogenase)], HADHA [hydroxyacyl-coenzyme A dehydrogenase / 3-ketoacyl-coenzyme A thiolase / enoyl-coenzyme A hydrolase (trifunctional protein), alpha subunit], HAMP [hepcy Dean antimicrobial peptide], HAND1 [heart and neural toxin expressed 1], HAND2 [heart and neural toxin expressed 2], HAP1 [hunting-related protein 1], HAPLN1 [hyaluronan and proteoglycan linkage (link) protein 1], HARS [histidyl-tRNA synthetase], HAS1 [hyaluronan synthase 1], HAS2 [hyaluronan synthase 2], HAS3 [hyaluronan synthetase 3], HAX1 [HCLS1 Related proteins X-1], HBA2 [hemoglobin, alpha 2], HBB [hemoglobin, beta], HBEGF [heparin-binding EGF-like growth factor], HBG1 [he Globin, gamma A], HBG2 [hemoglobin, gamma G], HCCS [holocytochrome c synthase (cytochrome c reduced hematin-lyase)], HCK [hematopoietic cell kinase], HCLS1 [hematopoietic cell-specific Lyn substrate] 1], HCN4 [hyperpolarization activated cycle nucleotide-gated potassium channel 4], HCRT [hypocretin (oresine) neuropeptide precursor], HCRTR1 [hypocretin (oresine) receptor 1], HCRTR2 [ Hypocretin (oresine) receptor 2], HDAC1 [histone deacetylase 1], HDAC2 [histone deacetylase 2], HDAC4 [histone deacetylase 4], HDAC9 [histone deacetylase 9], HDC [histidine dekar Carboxylase], HDLBP [high density lipoprotein binding protein], HEPACAM [hepatocyte cell adhesion molecule], HES1 [split's parent and enhancer 1, (Drosophila)], HES3 [split's parent and enhancer 3 (Drosophila)], HES5 [split's mo and enhancer 5 (Drosophila)], HES6 [split's mo and enhancer 6 (Drosophila)], HE XA [hexosaminidase A (alpha polypeptide)], HFE [hemochromatosis], HFE2 [hemochromatosis type 2 (adolescence)], HGF [hepatocyte growth factor (hepapoietin A; Dispersing factor)], HGS [hepatocyte growth factor-regulated tyrosine kinase substrate], HHEX [hematopoietically expressed homeobox], HHIP [hedgehog interacting protein], HIF1A [hypotropin-inducing factor 1, alpha subunit (Basic helix-loop-helix transcription factor)], HINT1 [histidine triplet nucleotide binding protein 1], HIPK2 [homeodomain interacting protein kinase 2], HIRA [HIR histone cell cycle regulatory deficiency homologue A (S.  CERVISI)], HIRIP3 [HIRA interacting protein 3], HIST1H2AB [histone cluster 1, H2ab], HIST1H2AC [histone cluster 1, H2ac], HIST1H2AD [histone cluster 1, H2ad], HIST1H2AE [histone cluster 1, H2ae] , HIST1H2AG [histone cluster 1, H2ag], HIST1H2AI [histone cluster 1, H2ai], HIST1H2AJ [histone cluster 1, H2aj], HIST1H2AK [histone cluster 1, H2ak], HIST1H2AL [histone cluster 1, H2al], HIST1H2AM [histone cluster 1, H2am], HIST1H3E [histone cluster 1, H3e], HIST2H2AA3 [histone cluster 2, H2aa3], HIST2H2AA4 [histone cluster 2, H2aa4], HIST2H2AC [histone cluster 2, H2ac], HKR1 [GLI-Kruppel family member HKR1] , HLA-A [major histocompatibility complex, class I, A], HLA-B [major histocompatibility complex, class I, B], HLA-C [major histocompatibility complex, class I, C], HLA-DMA [ Major histocompatibility complex, classification II, DM alpha], HLA-DOB [major histocompatibility complex, classification II, DO beta], HLA-DQA1 [major histocompatibility complex, classification II, DQ alpha 1], HLA-DQB1 [major histocompatibility complex, class II, DQ beta 1], HLA-DRA [major histocompatibility complex, classification II, DR alpha], HLA-DRB1 [major histocompatibility complex, classification II, DR beta 1], HLA-DRB4 [major histocompatibility complex, classification II, DR beta 4], HLA-DRB5 [major histocompatibility complex, classification II, DR Beta 5], HLA-E [major histocompatibility complex, class I, E], HLA-F [major histocompatibility complex, class I, F], HLA-G [major histocompatibility complex, class I, G ], HLCS [Holocarboxylase Synthetase (Biotin- (Proprionyl-Coenzyme A-carboxylase) (ATP-Hydrolysis)) Regiase)], HMBS [hydroxymethylbyline synthase], HMGA1 [high Mobility group AT-hook 1], HMGA2 [high mobility group AT-hook 2], HMGB1 [high mobility group box 1], HMGCR [3-hydroxy-3-methylglutaryl-coenzyme A reductase], H MGN1 [high mobility group nucleosome binding domain 1], HMOX1 [ham oxygenase (deccycling) 1], HMOX2 [ham oxygenase (deccycling) 2], HNF1A [HNF1 homeobox A], HNF4A [ Hepatocyte nuclear factor 4, alpha], HNMT [histamine N-methyltransferase], HNRNPA2B1 [heteronuclear ribonucleoprotein A2 / B1], HNRNPK [heteronuclear ribonuclear protein K], HNRNPL [heterologous ribonuclear protein L], HNRNPU [heteronuclear ribonucleoprotein U (scaffold adhesion factor A)], HNRPDL [heteronuclear ribonucleoprotein D-like], HOMER1 [Homer homolog 1 (Drosophila)], HOXA1 [homeobox A1], HOXA10 [ho Meobox A10], HOXA2 [homeobox A2], HOXA5 [homeobox A5], HOXA9 [homeobox A9], HOXB1 [homeobox B1], HOXB4 [homeobox B4], HOXB9 [homeobox B9], HOXD11 [homeobox D11], HOXD12 [homeobox D12], HOXD13 [homeobox D13], HP [haptoglobin], HPD [4-hydroxyphenylpyruvate deoxygenase], HPRT1 [ Hypoxanthine Sporibosyltransferase 1], HPS4 [Hermansky-Pudlak syndrome 4], HPX [hemofesin], HRAS [v-Ha-ras Harvey rat sarcoma viral oncogene homologue], HRG [histidine-rich glycoprotein], HRH1 [histamine receptor H1], HRH2 [histamine receptor H2], HRH3 [histamine receptor H3], HSD11B1 [hydroxysteroid (11-beta) dehydrogenase 1], HSD11B2 [hydroxysteroid (11-beta) dehydrogenase 2] , HSD17B10 [hydroxysteroid (17-beta) dehydrogenase 10], HSD3B2 [hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 2], HSF1 [heat shock transcription factor 1] , HSP90AA1 [heat shock protein 90kDa alpha (cytosol), class A member 1], HSP90B1 [heat shock protein 90kDa beta (Grp94), member 1], HSPA1A [heat shock 70kDa protein 1A], HSPA4 [heat shock 70kDa protein 4 ], HSPA5 [heat shock 70kDa protein 5 (glucose-regulated protein, 78kDa)], HSPA8 [heat shock 70 kDa protein 8], HSPA9 [heat shock 70 kDa protein 9 (mortalin)], HSPB1 [heat shock 27 kDa protein 1], HSPD1 [heat shock 60 kDa protein 1 (chaperonin)], HSPE1 [heat shock 10 kDa protein 1 (Sha) Feronine 10)], HSPG2 [heparan sulfate proteoglycan 2], HTN1 [histatin 1], HTR1A [5-hydroxytrytamine (serotonin) receptor 1A], HTR1B [5-hydroxytrytamine (serotonin) receptor 1B ], HTR1D [5-hydroxytrytamine (serotonin) receptor 1D], HTR1E [5-hydroxytrytamine (serotonin) receptor 1E], HTR1F [5-hydroxytrytamine (serotonin) receptor 1F], HTR2A [5 -Hydroxytryptamine (Serotonin) receptor 2A], HTR2B [5-Hydroxytryptamine (Serotonin) receptor 2B], HTR2C [5-Hydroxytrytamine (Serotonin) receptor 2C], HTR3A [5-hydroxytrytamine (Serotonin) receptor 3A], HTR3B [5-hydroxytrytamine (Serotonin) receptor 3B], HTR5A [5-hydroxytrypta Min (Serotonin) Receptor 5A], HTR6 [5-Hydroxytryptamine (Serotonin) Receptor 6], HTR7 [5-Hydroxytrytamine (Serotonin) Receptor 7 (Adenylate Cylase-linked)], HTT [ Huntingtin], HYAL1 [hyaluroglucosaminidase 1], HYOU1 [hypotropy up-regulated 1], IAPP [small islet amyloid polypeptide], IBSP [integrin-binding sialoprotein], ICAM1 [intercellular adhesions] Molecule 1], ICAM2 [intercellular adhesion molecule 2], ICAM3 [intercellular adhesion molecule 3], ICAM5 [intercellular adhesion molecule 5, teleencephalin], ICOS [inducible T-cell co-stimulator] , ID1 [inhibitor 1 of DNA binding, dominant negative helix-loop-helix protein], inhibitor of ID2 [inhibitor 2 of DNA binding, dominant negative helix-loop-helix protein], ID3 [inhibitor 3 of DNA binding, dominant negative helix -Loop-helix protein], ID4 [inhibitor 4 of DNA binding, dominant negative helix-loop-helix protein], IDE [insulin-digestive enzyme] , IDI1 [isopentenyl-diphosphate delta isomerase 1], IDO1 [indolamine 2 [3-dioxygenase 1], IDS [iduronate 2-sulfatase], IDUA [iduroronidase, alpha -L-], IER3 [immediate initial response 3], IFI27 [interferon, alpha-inducible protein 27], IFNA1 [interferon, alpha 1], IFNA2 [interferon, alpha 2], IFNAR1 [interferon (alpha, beta and omega) ) Receptor 1], IFNAR2 [interferon (alpha, beta and omega) receptor 2], IFNB1 [interferon, beta 1, fibroblast], IFNG [interferon, gamma], IFNGR1 [interferon gamma receptor 1], IFNGR2 [interferon gamma receptor 2 (interferon gamma converter 1)], IGF1 [insulin-like growth factor 1 (somatomedin C)], IGF1R [insulin-like growth factor 1 receptor], IGF2 [insulin-like growth factor 2 (somatomedin A) ], IGF2R [insulin-like growth factor 2 receptor], IGFBP1 [insulin-like growth factor binding protein 1], IGFBP2 [insulin-like growth factor binding Protein 2, 36 kDa], IGFBP3 [insulin-like growth factor binding protein 3], IGFBP4 [insulin-like growth factor binding protein 4], IGFBP5 [insulin-like growth factor binding protein 5], IGFBP6 [insulin-like growth factor binding Protein 6], IGFBP7 [insulin-like growth factor binding protein 7], IGHA1 [constant alpha 1 in immunoglobulin], IGHE [constant epsilon in immunoglobulin], IGHG1 [constant gamma 1 in immunoglobulin (G1m marker)], IGHJ1 [Immunoglobulin heavy binding 1], IGHM [immunoglobulin mu constant], IGHMBP2 [immunoglobulin mu binding protein 2], IGKC [immunoglobulin kappa constant], IKBKAP [B intracellular kappa light polypeptide gene Inhibitors of Enhancers, Kinase Complex-Related Proteins], IKBKB [Inhibitors of B Intracellular Kappa Light Polypeptide Gene Enhancers, Kinase Beta], IKZF1 [IKAROS Family Zinc Finger 1 (Ikaros)], IL10 [Interleukin 10] , IL10RA [Interleukin 10 Solution, alpha], IL10RB [interleukin 10 receptor, beta], IL11 [interleukin 11], IL11RA [interleukin 11 receptor, alpha], IL12A [interleukin 12A (natural killer cell stimulating factor 1, cytotoxic lymphocyte maturation factor 1, p35) ], IL12B [interleukin 12B (natural killer cell stimulating factor 2, cytotoxic lymphocyte maturation factor 2, p40)], IL12RB1 [interleukin 12 receptor, beta 1], IL13 [interleukin 13], IL15 [interleukin 15], IL15RA [interleukin] 15 receptor, alpha], IL16 [interleukin 16 (lymphocyte chemoattractant factor)], IL17A [interleukin 17A], IL18 [interleukin 18 (interferon-gamma-inducing factor)], IL18BP [interleukin 18 binding protein], IL1A [interleukin 1, alpha], IL1B [interleukin 1, beta], IL1F7 [interleukin 1 family, member 7 (zeta)], IL1R1 [interleukin 1 receptor, type I], IL1R2 [interleukin 1 receptor, type II], IL1RAPL1 [interleukin 1 Receptor Assist Protein-Like 1], IL1RL1 [Interleukin 1 Receptor-Like 1], IL1RN [Interleukin 1 receptor antagonist], IL2 [interleukin 2], IL21 [interleukin 21], IL22 [interleukin 22], IL23A [interleukin 23, alpha subunit p19], IL23R [interleukin 23 receptor], IL29 [interleukin 29 (interferon, Lambda 1)], IL2RA [interleukin 2 receptor, alpha], IL2RB [interleukin 2 receptor, beta], IL3 [interleukin 3 (colony-stimulating factor, multiple)], IL3RA [interleukin 3 receptor, alpha (low affinity)], IL4 [interleukin 4], IL4R [interleukin 4 receptor], IL5 [interleukin 5 (colony-stimulating factor, neutrophils)], IL6 [interleukin 6 (interferon, beta 2)], IL6R [interleukin 6 receptor], IL6ST [interleukin 6 Signal transducer (gp130, oncostatin M receptor)], IL7 [interleukin 7], IL7R [interleukin 7 receptor], IL8 [interleukin 8], IL9 [interleukin 9], ILK [integrin-linked kinase], IMMP2L [IMP2 internal mitochondria Membrane peptidase-like (S.  CERVISI)], IMMT [Inner Membrane Protein, Mitochondria (mitofilin)], IMPA1 [Inositol-1 (or 4) -Monophosphatase 1], IMPDH2 [IMP (Inosine Monophosphate) Dehydrogenase 2], INADL [InaD-like (Drosophila)], INCENP [internal centromeric protein antigen 135 / 155kDa], ING1 [inhibitor of growth family, member 1], ING3 [inhibitor of growth family, member 3], INHA [ Hibibin, alpha], INHBA [inhibin, beta A], INPP1 [inositol polyphosphate-1-phosphatase], INPP5D [inositol polyphosphate-5-phosphatase, 145 kDa], INPP5E [inositol polyphosphate-5-phosphatase, 72 kDa ], INPP5J [Inositol polyphosphate-5-phosphatase J], INPPL1 [Inositol polyphosphate phosphatase-like 1], INS [insulin], INSIG2 [insulin derived gene 2], INS-IGF2 [INS-IGF2 readthrough] Transcript], INSL3 [insulin-like 3 (Leydig cells)], INSR [insulin receptor], INVS [inversin], IQCB1 [IQ motif Containing B1], IQGAP1 [IQ motif containing GTPase activating protein 1], IRAK1 [interleukin-1 receptor-associated kinase 1], IRAK4 [interleukin-1 receptor-associated kinase 4], IREB2 [iron-responsive element binding protein 2], IRF1 [interferon modulator 1], IRF4 [interferon modulator 4], IRF8 [interferon modulator 8], IRS1 [insulin receptor substrate 1], IRS2 [insulin receptor substrate 2], IRS4 [insulin receptor substrate 4], IRX3 [ Iroquois homeobox 3], ISG15 [ISG15 ubiquitin-like variant], ISL1 [ISL LIM homeobox 1], ISL2 [ISL LIM homeobox 2], ISLR2 [leucine-containing immunoglobulin superfamily] Abundant repeat 2], ITGA2 [integrin, alpha 2 (CD49B, alpha 2 subunit of VLA-2 receptor)], ITGA2B [integrin, alpha 2b (platelet glycoprotein IIb of IIb / IIIa complex, antigen CD41)], ITGA3 [ Integrin, alpha 3 (antigen CD49C, alpha 3 subunit of VLA-3 receptor)], ITGA4 [integrin, alpha 4 (antigen CD49 D, alpha 4 subunit of VLA-4 receptor)], ITGA5 [integrin, alpha 5 (fibronectin receptor, alpha polypeptide)], ITGA6 [integrin, alpha 6], ITGA9 [integrin, alpha 9], ITGAL [integrin, alpha L (antigen CD11A (p180), lymphocyte function-related antigen 1; Alpha polypeptide)], ITGAM [integrin, alpha M (complement component 3 receptor 3 subunit)], ITGAV [integrin, alpha V (bitronectin receptor, alpha polypeptide, antigen CD51)], ITGAX [integrin, alpha X (complement component) 3 receptor 4 subunit)], ITGB1 [integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 include MDF2, MSK12)], ITGB2 [integrin, beta 2 (complement component 3 receptor 3 and 4 subunit) ], ITGB3 [integrin, beta 3 (platelet glycoprotein IIIa, antigen CD61)], ITGB4 [integrin, beta 4], ITGB6 [integrin, beta 6], ITGB7 [integrin, beta 7], ITIH4 [inter-alpha (globulin] ) Inhibitor H4 (plasma kallikrein-sensitive glycoprotein)], ITM2B [total membrane protein 2B], ITPR1 [Inositol 1 [4 [5-triphosphate receptor, type 1], ITPR2 [Inositol 1 [4 [5-triphosphate] Receptor, type 2], ITPR3 [inositol 1 [4 [5-triphosphate receptor, type 3], ITSN1 [intersectin 1] (SH3 domain protein)], ITSN2 [intersectin 2], IVL [inovoluclin], JAG1 [jagged 1 (Alagille syndrome)], JAK1 [Janus kinase 1], JAK2 [Janus kinase 2], JAK3 [Janus kinase 3 ], JAM2 [conjugated adhesion molecule 2], JARID2 [jumonji, AT rich interaction domain 2], JMJD1C [jumonji domain containing 1C], JMY [binding mediation and regulatory protein, p53 recognizer], JRKL [jerky homologue-like (Mouse)], JUN [jun oncogene], JUNB [jun B proto-tumor gene], JUND [jun D proto-tumor gene], JUP [binding flacoglobin], KAL1 [Kallmann syndrome 1 sequence], KALRN Carl Kalirin, RhoGEF kinase], KARS [lysyl-tRNA synthetase], KAT2B [K (lysine) acetyltransferase 2B], KATNA1 [katanin p60 (ATPase-containing) subunit A 1], KATNB1 [Catanine p80 (with WD repeat) subunit B 1], KCNA4 [potassium potential-gated channel, shaker-related subfamily, member 4], KCND1 [potassium potential-gated channel, Shal-related subfamily,Burr 1], KCND2 [potassium potential-gated channel, Shal-related subfamily, member 2], KCNE1 [potassium potential-gated channel, Isk-related family, member 1], KCNE2 [potassium potential-gated channel, Isk-related Family, member 2], KCNH2 [potassium potential-gated channel, subfamily H (eag-related), member 2], KCNH4 [potassium potential-gated channel, subfamily H (eag-related), member 4], KCNJ15 [ Potassium Inward-Rectifying Channel, Subfamily J, Member 15], KCNJ3 [Potassium Inward-Rectifying Channel, Subfamily J, Member 3], KCNJ4 [Potassium Inward-Rectifying Channel, Subfamily J, Member 4 ], KCNJ5 [Potassium Inward-Rectifying Channel, Subfamily J, Member 5], KCNJ6 [Potassium Inward-Rectifying Channel, Subfamily J, Member 6], KCNMA1 [Potassium Large Conducting Calcium-Activated Channel, Sub Family M, alpha member 1], KCNN1 [potassium medium / small conducting calcium-activated channel, subfamily N, member 1], KCNN2 [potassium medium / Silver conductive calcium-activated channel, subfamily N, member 2], KCNN3 [potassium medium / small conductive calcium-activated channel, subfamily N, member 3], KCNQ1 [potassium potential-gated channel, KQT-like subfamily , Member 1], KCNQ2 [potassium translocation-gating channel, KQT-like subfamily, member 2], KDM5C [lysine (K) -specific demethylase 5C], KDR [kinase insertion domain receptor (type III receptor tyrosine kinase )], KIAA0101 [KIAA0101], KIAA0319 [KIAA0319], KIAA1715 [KIAA1715], KIDINS220 [Kinase D-Interacting Substrate, 220kDa], KIF15 [Kinesin Family Member 15], KIF16B [Kinesin Family Member 16B], KIF1A [Kinesin Family Member 1A], KIF2A [Kinesin Heavy Chain Member 2A], KIF2B [Kinesin Family Member 2B], KIF3A [Kinesin Family Member 3A], KIF5C [Kinesin Family Member 5C], KIF7 [Kinesin Family Member 7], KIR2DL1 [Killer Cell Immunoglobulin -Like receptor, two domains, long cytoplasmic tail, 1], KIR2DL3 [killer Cellular immunoglobulin-like receptor, two domains, long cytoplasmic tail, 3], KIR2DS2 [killer cell immunoglobulin-like receptor, two domains, short cytoplasmic tail, 2], KIR3DL1 [killer cell immunoglobulin-like receptor, 3] Dog domain, long cytoplasmic tail, 1], KIR3DL2 [killer cell immunoglobulin-like receptor, three domains, long cytoplasmic tail, 2], KIRREL3 [kin 3 (Drosophila) of IRRE-like], KISS1 [KiSS-1 metastasis- Inhibitors], KISS1R [KISS1 receptor], KIT [v-kit Hardy-Zuckerman 4 cataract sarcoma viral oncogene homologue], KITLG [KIT ligand], KL [klotho], KLF7 [Kruppel-like factor 7 ( Ubiquitous)], KLK1 [Kallikrein 1], KLK10 [Kallikrein-Related Peptidase 10], KLK11 [Kallikrein-Related Peptidase 11], KLK2 [Kallikrein-Related Peptidase 2], KLK3 [ Kallikrein-Related Peptidase 3], KLK5 [Kallikrein-Related Peptidase 5], KLRD1 [Killer Cell Lectin-like Receptor Sieve subfamily D, member 1], KLRK1 [killer cell lectin-like receptor subfamily K, member 1], KMO [kynurenine 3-monooxygenase (cuneurenin 3-hydroxylase)], KNG1 [kinnogen 1], KPNA2 [carioferrin alpha 2 (RAG cohort 1, impartin alpha 1)], KPNB1 [carioferin (impultin) beta 1], KPTN [kaptin (actin binding protein)], KRAS [v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog], KRIT1 [KRIT1, containing ankyrin repeat], KRT1 [keratin 1], KRT10 [keratin 10], KRT14 [keratin 14], KRT18 [keratin 18 ], KRT19 [Keratin 19], KRT3 [Keratin 3], KRT5 [Keratin 5], KRT7 [Keratin 7], KRT8 [Keratin 8], KRTAP19-3 [Keratin Related Protein 19-3], KRTAP2-1 [Keratin Related] Protein 2-1], L1CAM [L1 Cell Adhesion Molecule], LACTB [Lactase, Beta], LALBA [Lactalbumin, Alpha-], LAMA1 [Laminin, Alpha 1], LAMB1 [Laminin, Beta 1], LAMB2 [Laminin , Beta 2 (laminin S)], LAMB4 [ Laminin, beta 4], LAMP1 [lysosomal-associated membrane protein 1], LAMP2 [lysosomal-related membrane protein 2], LAP3 [leucine aminopeptidase 3], LAPTM4A [lysosomal protein transmembrane 4 alpha], Large [Like-glycosyltransferase], LARS [Louisyl-tRNA synthetase], LASP1 [LIM and SH3 protein 1], LAT2 [linker for activation of T cell family, member 2], LBP [lipopolysaccharide Binding protein], LBR [lamin B receptor], LCA10 [lung carcinoma-associated protein 10], LCA5 [Leber congenital cataract 5], LCAT [lecithin-cholesterol acyltransferase], LCK [lymphocyte-specific protein tyrosine kinase], LCN1 [lipocalin 1 (tear prealbumin)], LCN2 [lipocalin 2], LCP1 [lymphocyte cytosolic protein 1 (L-plastin)], LCP2 [lymphocyte cytosolic protein 2 (SH2 domain-containing leukocyte protein of 76 kDa) )], LCT [lactase], LDB1 [LIM domain binding 1], LDB2 [LIM domain binding 2], LDHA [lactic acid dehydrogenase A], LDLR [ Density lipoprotein receptor], LDLRAP1 [low-density lipoprotein receptor adapter protein 1], LEF1 [lymphotoxin Id enhancer-binding factor 1], LEO1 [Leo1, Paf1 / RNA polymerase II complex component, homolog (S.  Serbisier)], LEP [leptin], LEPR [leptin receptor], LGALS13 [lectin, galactosid-binding, soluble, 13], LGALS3 [lectin, galactosid-binding, soluble, 3], LGMN Legumain], LGR4 [leucine-rich repeat-containing G protein-linked receptor 4], LGTN [ligatin], LHCGR [luteinizing hormone / choriogonadotropin receptor], LHFPL3 [lipoma HMGIC fusion Partner-Like 3], LHX1 [LIM Homeobox 1], LHX2 [LIM Homeobox 2], LHX3 [LIM Homeobox 3], LHX4 [LIM Homeobox 4], LHX9 [LIM Homeobox 9] , LIF [leukemia inhibitory factor (cholinergic differentiation factor)], LIFR [leukemia inhibitory factor receptor alpha], LIG1 [ligature I, DNA, ATP-dependent], LIG3 [ligase III, DNA, ATP-dependent], LIG4 [ligase IV, DNA, ATP-dependent], LILRA3 [leukocyte immunoglobulin-like receptor, subfamily A (without TM domain), member 3], LILRB1 [leukocyte cell immunoglobulin-like receptor, Broken family B (with TM and ITIM domains), member 1], LIMK1 [LIM domain kinase 1], LIMK2 [LIM domain kinase 2], LIN7A [lin-7 homolog A (C. Elegans)], LIN7B [lin-7 homolog B (C. Elegans)], LIN7C [lin-7 homolog C (C. Elegans)], LINGO1 [containing leucine rich repeat and Ig domain 1], LIPC [lipase, hepatic], LIPE [lipase, hormone-sensitive], LLGL1 [fatal giant larvae homolog 1 (Drosophila)], LMAN1 [Lectin, mannose-binding, 1], LMNA [lamin A / C], LMO2 [only LIM domain 2 (rhombotin-like 1)], LMX1A [LIM homeobox transcription factor 1, alpha], LMX1B [LIM homeobox transcription factor 1, beta], LNPEP [Louisyl / cystinyl aminopeptidase], LOC400590 [hypothetical LOC400590], LOC646021 [similar to hCG1774990], LOC646030 [similar to hCG1991475], LOC646627 [force Lipase inhibitor], LOR [lolyricin], LOX [lysyl oxidase], LOXL1 [lysyl oxidase-like 1], LPA [lipoprotein, Lp (a)], LPL [lipoprotein lipase], LPO [lactoperoxidase] , LPP [preferred potential partner containing LIM domain in lipoma], LPPR1 [lipid phosphate phosphatase-related protein type 1], LPPR3 [lipid phosphate phosphatase-related Protein type 3], LPPR4 [lipid phosphate phosphatase-related protein type 4], LPXN [leupaxin], LRP1 [low density lipoprotein receptor-related protein 1], LRP6 [low density lipoprotein receptor-related protein 6], LRP8 [ Low density lipoprotein receptor-related protein 8, apolipoprotein e receptor], LRPAP1 [low density lipoprotein receptor-related protein related protein 1], LRPPRC [containing leucine-rich PPR-motif], LRRC37B [containing leucine rich repeat 37B], LRRC4C [Lucine-rich repeat containing 4C], LRRTM1 [Leucine-rich repeat transmembrane neuron 1], LSAMP [limb system-associated membrane protein], LSM2 [LSM2 homologue, U6 small nuclear RNA related (S. Serbian) ], LSS [lanosterol synthetase (2 [3-oxidosqualene-lanosterol cyclase)], LTA [lymphotoxin alpha (TNF superfamily, member 1)], LTA4H [rukotriene A4 hydrolase] ], LTBP1 [latent transformed growth factor beta Binding protein 1], LTBP4 [latent transforming growth factor beta binding protein 4], LTBR [lymphotoxin beta receptor (TNFR superfamily, member 3)], LTC4S [Lucotriene C4 synthetase], LTF [lactotrans Perrin], LY96 [lymphocyte antigen 96], LYN [v-yes-1 Yamaguchi sarcoma viral related oncogene homolog], LYVE1 [lymphatic endothelial hyaluronan receptor 1], M6PR [mannose-6-phosphate receptor (cation) Dependent)], MAB21L1 [mab-21-like 1 (C. Elegans)], MAB21L2 [mab-21-like 2 (C. Elegans)], MAF [v-maf myofascial fibrosarcoma oncogene homolog (algae)], MAG [myelin-associated glycoprotein], MAGEA1 [melanoma antigen family A, 1 (direct expression of antigen MZ2-E)], MAGEL2 [MAGE-like 2], MAL [mal, T-cell differentiation protein], MAML2 [mastermind-like 2 (Drosophila)], MAN2A1 [mannosidase, alpha, class 2A, member 1], MANBA [ Mannosidase, beta A, lysosomal], MANF [medium brain glial-induced neurotrophic factor], MAOA [monoamine oxidase A], MAOB [monoamine oxidase B], MAP1B [microtubule-associated protein 1B] ], MAP2 [microtubule-associated protein 2], MAP2K1 [mitogen-activated protein kinase kinase 1], MAP2K2 [mitogen-activated protein kinase kinase 2], MAP2K3 [mitogen-activated protein kinase kinase 3] , MAP2K4 [mitogen-activated protein kinase kinase 4], MAP3K1 [mitogen-activated protein kinase kinase kinase 1], MAP3K12 [mitogen-activated Protein kinase kinase kinase 12], MAP3K13 [mitogen-activated protein kinase kinase 13], MAP3K14 [mitogen-activated protein kinase kinase 14], MAP3K4 [mitogen-activated protein kinase kinase 4], MAP3K7 [Mitogen-activated protein kinase kinase kinase 7], MAPK1 [mitogen-activated protein kinase 1], MAPK10 [mitogen-activated protein kinase 10], MAPK14 [mitogen-activated protein kinase 14], MAPK3 [Mitogen-activated protein kinase 3], MAPK8 [mitogen-activated protein kinase 8], MAPK8IP2 [mitogen-activated protein kinase 8 interacting protein 2], MAPK8IP3 [mitogen-activated protein kinase 8 interaction Agonist protein 3], MAPK9 [mitogen-activated protein kinase 9], MAPKAPK2 [mitogen-activated protein kinase-activated protein kinase 2], MAPKSP1 [MAPK scaffold protein 1], MAPRE3 [microtubule-associated group] Vagina, RP / EB family, member 3], MAPT [microtubule-associated protein tau], MARCKS [myristoylated alanine-rich protein kinase C substrate], MARK1 [MAP / microtubule affinity-regulating kinase 1], MARK2 [MAP / microtubule affinity-regulating kinase 2], MAT2A [methionine adenosyltransferase II, alpha], MATR3 [matrin 3], MAX [MYC related factor X], MAZ [MYC-associated zinc finger protein (Purine-binding transcription factor)], MB [myoglobin], MBD1 [methyl-CpG binding domain protein 1], MBD2 [methyl-CpG binding domain protein 2], MBD3 [methyl-CpG binding domain protein 3], MBD4 [methyl -CpG binding domain protein 4], MBL2 [mannose-binding lectin (protein C) 2, soluble (opsonine deficiency)], MBP [myelin basic protein], MBTPS1 [membrane-bound transcription factor peptidase, position 1 ], MC1R [melanocortin 1 receptor (alpha melanocyte stimulating hormone receptor)], MC3R [melanocortin 3 receptor], MC4R [melanocortin 4 number Solution], MCCC2 [methylcrotonyl-coenzyme A carboxylase 2 (beta)], MCF2L [MCF.2 cell line induced transformed sequence-like], MCHR1 [melanin-concentrated hormone receptor 1], MCL1 [myeloid cell leukemia SEQ ID NO: 1 (BCL2-related)], MCM7 [minichromosome maintenance complex component 7], MCPH1 [microcephalin 1], MDC1 [mediator of DNA-damage checkpoint 1], MDFIC [containing the MyoD family inhibitor domain], MDGA1 [ MAM domain containing glycosylphosphatidylinositol anchor 1], MDK [midkine (neurite growth-promoting factor 2)], MDM2 [Mdm2 p53 binding protein homologue (mouse)], ME2 [malic acid enzyme 2, NAD ( +)-Dependent, mitochondria], MECP2 [methyl CpG binding protein 2 (Rett syndrome)], MED1 [mediator complex subunit 1], MED12 [mediator complex subunit 12], MED24 [mediator complex subunit 24] , MEF2A [Muscle Cell Enhancer Factor 2A], MEF2C [Muscle Cell Enhancer Factor 2C], MEIS1 [Meis Homeobox 1], MEN1 [multiple endocrine neoplasia I], MERTK [c-mer proto-tumor gene tyrosine kinase], MESP2 [mesodermal posterior 2 homologue (mouse)], MEST [mesoderm specific transcript homologue (mouse)], MET [met proto-tumor gene (hepatocyte growth factor receptor)], METAP2 [methionyl aminopeptidase 2], METRN [methorine, glial differentiation regulator], MFSD6 [main promoter superfamily domain containing 6], MGAT2 [Mannosyl (alpha-1 [6-)-glycoprotein beta-1 [2-N-acetylglucosaminyltransferase], MGMT [O-6-methylguanine-DNA methyltransferase], MGP [matrix Gla protein] ], MGST1 [microsomeglutathione S-transferase 1], MICA [MHC class I polypeptide-related sequence A], MICAL1 [containing microtubule-associated monooxygenase, calponin and LIM domain 1], MICB [MHC class I Polypeptide-associated sequence B], MIF [macrophage transfer inhibitory factor (glycosylation-inhibiting factor)], MITF [small eye syndrome] -Related transcription factors], MKI67 [antigens identified by monoclonal antibody Ki-67], MKKS [McKusick-Kaufman syndrome], MKNK1 [MAP kinase interacting serine / threonine kinase 1], MKRN3 [makorin ringfinger] Protein 3], MKS1 [Meckel syndrome, type 1], MLH1 [mutL homologue 1, colon cancer, non-cancerous type 2 (E. coli)], MLL [myeloid / lymphoid or mixed-line leukemia (Tritrax homologue, Drosophila) )], MLLT4 [myeloid / lymphoid or mixed-line leukemia (Tritrax homologue, Drosophila); Transposed to, 4], MLPH [melanophylline], MLX [MAX-like protein X], MLXIPL [MLX interacting protein-like], MME [membrane metal-endopeptidase], MMP1 [matrix metalpeptide 1 (intercellular collagenase)], MMP10 [matrix metalpeptidase 10 (stromericin 2)], MMP12 [matrix metalpeptidase 12 (macrophage elastase)], MMP13 [matrix metalpeptide Tidase 13 (collagenase 3)], MMP14 [matrix metalpeptidase 14 (membrane-inserted)], MMP2 [matrix metalpeptidase 2 (gelatinase A, 72 kDa gelatinase, 72 kDa type IV cola) Genease)], MMP24 [matrix metalpeptidase 24 (membrane-inserted)], MMP26 [matrix metalpeptidase 26], MMP3 [matrix metalpeptidase 3 (stromericin 1, progelatinase) ], MMP7 [matrix metalpeptidase 7 (matrilysin, uterine)], MMP8 [matrix metalpeptidase 8 (neutrophil collagenase)], MMP9 [matrix metalpeptidase 9 (gel Tinaase B, 92kDa gelatinase, 92kDa type IV collagenase)], MN1 [meningioma (broken at balanced dislocations) 1], MNAT1 [triangular homologue 1, cyclin H aggregation factor (African claw frog)], MNX1 [motor neuron and pancreatic homeobox 1], MOG [myelin oligodendrocyte glycoprotein], MPL [myeloproliferative leukemia virus oncogene], MPO [myeloperoxidase], MPP1 [membrane protein, palmitoylation] 1, 55 kDa], MPZL1 [myelin protein zero-like 1], MR1 [major histocompatibility complex, class I-related], MRAP [melanocortin 2 receptor co-protein], MRAS [muscle RAS oncogene homologue], MRC1 [mannose receptor, C type 1], MRGPRX1 [MAS-associated GPR, member X1], MS4A1 [membrane-range 4-domain, subfamily A, member 1], MSH2 [mutS homolog 2, colon cancer, non-tumor Type 1 (E. coli)], MSH3 [mutS homologue 3 (E. coli)], MSI1 [musashi homologue 1 (Drosophila)], MSN [Moesin], MSR 1 [Macrophage Scavenging Receptor 1], MSTN [Myostatin], MSX1 [msh Homeobox 1], MSX2 [msh Homeobox 2], MT2A [Metalthione 2A], MT3 [Metalthione 3], MT -ATP6 [mitochondrially encoded ATP synthase 6], MT-CO1 [mitochondrially encoded cytochrome c oxidase I], MT-CO2 [mitochondrially encoded cytochrome c oxidase II] , MT-CO3 [mitochondrially encoded cytochrome c oxidase III], MTF1 [metal-regulated transcription factor 1], MTHFD1 [methylenetetrahydrofolate dehydrogenase (NADP + dependent) 1, methenyltetrahydrofolate Cyclohydrolase, formyltetrahydrofolate synthetase], MTHFD1L [methylenetetrahydrofolate dehydrogenase (NADP + dependent) 1-like], MTHFR [5 [10-methylenetetrahydrofolate reductase (NADPH)] , MTL5 [metalthionene-like 5, testis-specific (tesmine)], M TMR14 [myotubulin-related protein 14], MT-ND6 [mitochondrially encoded NADH dehydrogenase 6], MTNR1A [melatonin receptor 1A], MTNR1B [melatonin receptor 1B], MTOR [rapamycin (serine / threonine kinase) Mechanical targets), MTR [5-methyltetrahydrofolate-homocysteine methyltransferase], MTRR [5-methyltetrahydrofolate-homocysteine methyltransferase reductase], MTTP [microsometriglyceride transfer protein], MUC1 [Mucin 1, cell surface related], MUC16 [mucin 16, cell surface related], MUC19 [mucin 19, oligomer], MUC2 [mucin 2, oligomeric mucus / gel-forming], MUC3A [mucin 3A, cell surface related], MUC5AC [mucin 5AC, oligomeric mucus / gel-forming], MUSK [muscle, skeletal, receptor tyrosine kinase], MUT [methylmalonyl coenzyme A mutase], MVK [mevalonate kinase], MVP [main bolt protein], MX1 [Mixovirus (Influenza Bars) RUS) resistance 1, interferon-inducing protein p78 (mouse)], MXD1 [MAX dimerization protein 1], MXI1 [MAX interactor 1], MYB [v-myb myeloma cell mycoblastic oncogene homolog (bird)] , MYC [v-myc myelomyosis myelogenous homologue (bird)], MYCBP2 [MYC binding protein 2], MYCN [v-myc myeloma myeloma viral related oncogene, neuroblastoma induced (bird)] , MYD88 [myeloid differentiation primary response gene (88)], MYF5 [fungal factor 5], MYH10 [myosin, heavy chain 10, non-muscle], MYH14 [myosin, heavy chain 14, non-muscle], MYH7 [myosin, heavy chain 7, cardiac muscle, beta], MYL1 [myosin, light chain 1, alkali; Skeletal, rapid], MYL10 [myosin, light chain 10, modulated], MYL12A [myosin, light chain 12A, modulated, non-sarcomeric], MYL12B [myosin, light chain 12B, modulated], MYL2 [myosin, light chain 2, Control, heart, slow], MYL3 [myosin, light chain 3, alkali; Ventricle, skeletal, slow], MYL4 [myosin, light chain 4, alkali; Atrial, embryo], MYL5 [myosin, light chain 5, modulated], MYL6 [myosin, light chain 6, alkaline, smooth and non-muscle], MYL6B [myosin, light chain 6B, alkali, smooth and non-muscle], MYL7 [myosin, light chain 7, modulating], MYL9 [myosin, light chain 9, modulating], MYLK [myosin light chain kinase], MYLPF [myosin light chain, phosphorylable, fast skeletal muscle], MYO1D [myosin ID], MYO5A [ Myosin VA (heavy chain 12, myosin)], MYOC [myocillin, fine network-induced glucocorticoid reaction], MYOD1 [fungal differentiation 1], MYOG [myogenin (source factor 4)], MYOM2 [myomecin (M-protein) 2,165 kDa], MYST3 [MYST histone acetyltransferase (monocytic leukemia) 3], NACA [nascent polypeptide-associated complex alpha subunit], NAGLU [N-acetylglucosaminase, Alpha-], NAIP [NLR family, apoptosis inhibitory protein], NAMPT [nicotinamide phosphoribosyltransferase], NANOG [Nanog homeobox] , NANS [N-acetylneuraminic acid synthase], NAP1L2 [nucleosome assembly protein 1-like 2], NAPA [N-ethylmaleimide-sensitive factor adhesion protein, alpha], NAPG [N-ethylmaleimide- Sensitivity factor adhesion protein, gamma], NAT2 [N-acetyltransferase 2 (arylamine N-acetyltransferase)], NAV1 [neuron navigator 1], NAV3 [neuron navigator 3], NBEA [neurovicin], NCALD [neucalincin delta], NCAM1 [nerve cell adhesion molecule 1], NCAM2 [nerve cell adhesion molecule 2], NCF1 [neutrophil cytosolic factor 1], NCF2 [neutrophil cytosolic factor 2], NCK1 [NCK adapter protein 1 ], NCK2 [NCK adapter protein 2], NCKAP1 [NCK-associated protein 1], NCL [nucleolin], NCOA2 [nuclear receptor coactivator 2], NCOA3 [nuclear receptor coactivator 3], NCOR1 [nuclear receptor] Co-inhibitor 1], NCOR2 [nuclear receptor co-inhibitor 2], NDE1 [nudE nuclear distribution gene E homolog 1 (A. Nidulans)], NDEL1 [nudE nuclear distribution gene E homologue (A. nidulans) -like 1], NDN [necdin homologue (mouse)], NDNL2 [nexin-like 2], NDP [Norrie disease (Causative neuroglioma)], NDUFA1 [NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 1, 7.5 kDa], NDUFAB1 [NADH dehydrogenase (ubiquinone) 1, alpha / beta subcomplex, 1, 8 kDa], NDUFS3 [NADH dehydrogenase (ubiquinone) Fe-S protein 3, 30 kDa (NADH-coenzyme Q reductase)], NDUFV3 [NADH dehydrogenase (ubiquinone) flavoprotein 3, 10 kDa], NEDD4 [neural precursor cell expressed , Developmentally down-regulated 4], NEDD4L [neuronal precursor cell expressed, developmentally down-regulated 4-like], NEFH [neurons, heavy polypeptide], NEFL [nerve, light] Polypeptides], NEFM [Nerve-fiber, Medium Polypeptides], NENF [Nuroninduced Neurotrophic Factors], NEO1 [Neogenin Homolog 1 (chicken)], NES [Nestine], NET1 [Neural epithelial cells] Transformation 1], NEU1 [sialidase 1 (lysosomal sialidase)], NEU3 [sialidase 3 (membrane sialidase)], NEUROD1 [neurogenic differentiation 1], NEUROD4 [neurogenic differentiation 4], NEUROG1 [Nurogenin 1], NEUROG2 [Nurogenin 2], NF1 [Nurofibromine 1], NF2 [Nurofibromine 2 (Merrine)], NFASC [Nurofacin Homolog (chicken)], NFAT5 [Activated Nuclear factor 5 of T-cells, strain-response], NFATC1 [nuclear factor of activated T-cells, cytoplasm, calcineurin-dependent 1], NFATC2 [nuclear factor of activated T-cells, cytoplasm, calcineurin-dependent] 2], NFATC3 [nuclear factor of activated T-cells, cytoplasm, calcineurin-dependent 3], NFATC4 [nuclear factor of activated T-cells, cytoplasm, calcineurin-dependent 4], NFE2L2 [nuclear factor (red blood cell- Induced 2) -like 2], NFIC [nuclear factor I / C (CCAAT-binding transcription factor)], NFIL3 [nuclear factor, interleukin 3 regulated], NFKB1 [kappa light polypeptide gene in B-cells Nuclear Factor of Enhancer 1] , NFKB2 [nuclear factor 2 of light kappa polypeptide gene enhancer in B-cells (p49 / p100)], NFKBIA [nuclear factor inhibitor of light kappa polypeptide gene enhancer in B-cells, alpha ], NFKBIB [nuclear factor inhibitor of light kappa polypeptide gene enhancer in B-cells, beta], NFKBIL1 [nuclear factor inhibitor of kappa light polypeptide gene enhancer in B-cells-like 1] NFYA [nuclear transcription factor Y, alpha], NFYB [nuclear transcription factor Y, beta], NGEF [neuron guanine nucleotide exchange factor], NGF [nerve growth factor (beta polypeptide)], NGFR [nerve growth factor receptor (TNFR super) Family, member 16)], NGFRAP1 [nerve growth factor receptor (TNFRSF16) related protein 1], NHLRC1 [NHL repeat containing 1], NINJ1 [ninjurin 1], NINJ2 [ninjurin 2], NIP7 [nuclear import] 7 homolog (S. Serbisier)], NIPA1 [non-imprinted in Prader-Willi / Angelman syndrome 1], NIPA2 [non-imprinted in Prader-Willi / Angelman syndrome 2], NIPAL1 [containing NIPA-like domain 1], NIPAL4 [ NIPA-like domain containing 4], NIPSNAP1 [nipsnap homolog 1 (C. Elegans)], NISCH [Nisharin], NIT2 [Nitrilease Family, Member 2], NKX2-1 [NK2 Homeobox 1], NKX2-2 [NK2 Homeobox 2], NLGN1 [Nuroligin 1], NLGN2 [Nurorigin 2], NLGN3 [Nurorigin 3], NLGN4X [Nurorigin 4, X-linked], NLGN4Y [Nurorigin 4, Y-linked], NLRP3 [NLR family, pyrin domain Containing 3], NMB [neuromedin B], NME1 [non-metastatic cells 1, expressed protein (NM23A)], NME2 [non-metastatic cells 2, expressed protein (NM23B)], NME4 [non-metastatic Cells 4, expressed protein], NNAT [neuronin], NOD1 [nucleotide-binding oligomerization domain containing 1], NOD2 [nucleotide-binding oligomerization domain containing 2], NOG [noggin], NOL6 Protein family 6 (RNA-associated)], NOS1 [nitric oxide synthase 1 (neurons)], NOS2 [nitric oxide synthase 2, inducible], NOS3 [nitric oxide synthase 3 (endothelial)], NOSTRIN [oxidation] Nitrogen synthase trafficker], NOTCH1 [Notch homology 1, translocation-related (Drosophila)], NOTCH2 [Notch homologue 2 (Drosophila)], NOTCH3 [Notch homolog 3 (Drosophila)], NOV [neocytoma overexpressed gene], NOVA1 [neuro-tumor abdominal antigen 1] , NOVA2 [neuro-tumor abdominal antigen 2], NOX4 [NADPH oxidase 4], NPAS4 [neuron PAS domain protein 4], NPFF [neuropeptide FF-amide peptide precursor], NPHP1 [nephropathy 1 (adolescent)] , NPHP4 [Cellulose Pneumonia 4], NPHS1 [nephropathy 1, congenital, Finnish type (nephiline)], NPM1 [nucleophosphamine (phosphorus protein B23, numatrine)], NPPA [sodium release peptide precursor A] , NPPB [sodium release peptide precursor B], NPPC [sodium release peptide precursor C], NPR1 [sodium release peptide receptor A / guanylate cyclase A (atrial fibrillation sodium release peptide receptor A)], NPR3 [sodium Release peptide receptor C / guanylate cyclase C (atrial fibrillation sodium release peptide receptor C)], NPRL2 Nitrogen Permease Modulator-Like 2 (S. Serbisier)], NPTX1 [neuron pentracin I], NPTX2 [neuron pentracin II], NPY [nerve peptide Y], NPY1R [nerve peptide Y receptor Y1], NPY2R [nerve peptide Y receptor Y2], NPY5R [nerve Peptide Y Receptor Y5], NQO1 [NAD (P) H Dehydrogenase, Quinone 1], NQO2 [NAD (P) H Dehydrogenase, Quinone 2], NR0B1 [Nuclear Receptor Subfamily 0, Group B, Member 1], NR0B2 [Nuclear receptor subfamily 0, group B, member 2], NR1H3 [nuclear receptor subfamily 1, group H, member 3], NR1H4 [nuclear receptor subfamily 1, group H, member 4], NR1I2 [nuclear receptor subfamily 1, group I, member 2], NR1I3 [nuclear receptor subfamily 1, group I, member 3], NR2C1 [nuclear receptor subfamily 2, group C, member 1], NR2C2 [nuclear receptor subfamily 2, group C, Member 2], NR2E1 [nuclear receptor subfamily 2, group E, member 1], NR2F1 [nuclear receptor subfamily 2, group F, member 1], NR2F2 [nuclear receptor subfamily 2, group F, member 2], NR3C1 [Nuclear acceptance Subfamily 3, group C, member 1 (glucocorticoid receptor)], NR3C2 [nuclear receptor subfamily 3, group C, member 2], NR4A2 [nuclear receptor subfamily 4, group A, member 2], NR4A3 [nuclear receptor Subfamily 4, group A, member 3], NR5A1 [nuclear receptor subfamily 5, group A, member 1], NR6A1 [nuclear receptor subfamily 6, group A, member 1], NRAS [neuroblastoma RAS viral (v -ras) oncogene homologues], NRCAM [neuronal cell adhesion molecule], NRD1 [nardilysin (N-arginine dibasic convertase)], NRF1 [nuclear respiratory factor 1], NRG1 [neuregulin 1], NRIP1 [nuclear receptor interacting protein 1], NRN1 [neuritin 1], NRP1 [neurophylline 1], NRP2 [neuphylline 2], NRSN1 [neurensin 1], NRTN [neuroturin], NRXN1 [neulexin 1], NRXN3 [neulexin 3], NSD1 [nuclear receptor binding SET domain protein 1], NSF [N-ethylmaleimide-sensitive factor], NSUN5 [NOP2 / Sun domain family, MEM 5], NT5E [5'-nucleotidase, ecto (CD73)], NTF3 [neutropin 3], NTF4 [neutropin 4], NTHL1 [nth endonuclease III-like 1 (E. coli)] , NTN1 [Netrin 1], NTN3 [Netrin 3], NTN4 [Netrin 4], NTNG1 [Netrin G1], NTRK1 [New Management positive tyrosine kinase, receptor, type 1], NTRK2 [New Management positive tyrosine kinase, receptor , Type 2], NTRK3 [neotrophic tyrosine kinase, receptor, type 3], NTS [neutensene], NTSR1 [neurotensin receptor 1 (high affinity)], NUCB2 [nucleobindine 2], NUDC [nuclear distribution gene C] Homolog (A. Nidulans)], NUDT6 [nudics (nucleoside diphosphate linked moiety X) -type motif 6], NUDT7 [nudic (nucleoside diphosphate linked moiety X) -type motif 7], NUMB [numb Homologues (Drosophila)], NUP98 [nucleoporin 98kDa], NUPR1 [nuclear protein, transcriptional regulator, 1], NXF1 [nuclear RNA export factor 1], NXNL1 [nucleoredoxin-like 1], OAT [orni Chitin aminotransferase], OCA2 [systemic albinism II], OCLN [occlusin], OCM [oncomodulin], ODC1 [ornithine decarboxylase 1], OFD1 [oral-facial-damp syndrome 1] , OGDH [oxoglutarate (alpha-ketoglutarate) dehydrogenase (ziamide)], OLA1 [Obg-like ATPase 1], OLIG1 [oligodendrocyte transcription factor 1], OLIG2 [oligodendrocyte lineage] Transcription factor 2], OLR1 [oxidized low density lipoprotein (lectin-like) receptor 1], OMG [oligodendrocyte myelin glycoprotein], OPHN1 [oligoprenin 1], OPN1S W [opsin 1 (cone pigment), short-wave-sensitive], OPRD1 [opium receptor, delta 1], OPRK1 [opium receptor, kappa 1], OPRL1 [opium receptor-like 1], OPRM1 [opium Receptor, mu 1], OPTN [optinurin], OSBP [oxysterol binding protein], OSBPL10 [oxysterol binding protein-like 10], OSBPL6 [oxysterol binding protein-like 6], OSM [oncortin M], OTC Ornithine carbamoyltransferase, OTX2 [orthodentic homeobox 2], OXA1L [oxidase (cytochrome c) set 1-like], OXT [oxytocin, prepropeptide], OXTR [oxytocin receptor] , P2RX7 [purinergic receptor P2X, ligand-gated ion channel, 7], P2RY1 [purinergic receptor P2Y, G-protein linked, 1], P2RY12 [purinergic receptor P2Y, G-protein linked, 12], P2RY2 [purinergic receptor P2Y, G-protein linked, 2], P4HB [prolyl 4-hydroxylase, beta polypeptide], PABPC1 [poly (A) binding protein, three Vaginal 1], PADI4 [peptidyl arginine deaminase, type IV], PAEP [progestagen-associated endometrial protein], PAFAH1B1 [platelet-activating factor acetylhydrolase 1b, regulatory subunit 1 (45kDa)] , PAFAH1B2 [platelet-activating factor acetylhydrolase 1b, catalytic subunit 2 (30kDa)], PAG1 [phosphoprotein 1 associated with glycosphingolipid microdomains], PAH [phenylalanine hydroxylase], PAK1 [p21 Protein (Cdc42 / Rac) -activated kinase 1], PAK2 [p21 protein (Cdc42 / Rac) -activated kinase 2], PAK3 [p21 protein (Cdc42 / Rac) -activated kinase 3], PAK4 [p21 protein ( Cdc42 / Rac) -activated kinase 4], PAK6 [p21 protein (Cdc42 / Rac) -activated kinase 6], PAK7 [p21 protein (Cdc42 / Rac) -activated kinase 7], PAPPA [pregnancy-associated plasma protein A, Paparin 1], PAPPA2 [Paparin 2], PARD6A [par-6 split deletion 6 homologue alpha (C. Elegans)], PARG [poly (ADP-ribose) glycohydrolase], PARK2 [Parkinson disease (autosome recessive, adolescence) 2, parkin], PARK7 [Parkinson disease (autosome recessive, early signs) 7], PARN [Poly (A) -specific ribonuclease (deadenylation nuclease)], PARP1 [poly (ADP-ribose) polymerase 1], PAWR [PRKC, apoptosis, WT1, modulator], PAX2 [Paired Box 2], PAX3 [Paired Box 3], PAX5 [Paired Box 5], PAX6 [Paired Box 6], PAX7 [Paired Box 7], PBX1 [pre-B- Cell leukemia homeobox 1], PC [pyruvate carboxylase], PCDH10 [protocadherin 10], PCDH19 [protocadherin 19], PCDHA12 [protocadherin alpha 12], PCK2 [phosphoenolpyruvate Carboxykinase 2 (Mitochondria)], PCLO [Piccolo (Presynaptic Cell Matrix Protein)], PCM1 [Central Outer substance 1], PCMT1 [Protein-L-Isoaspartate (D-aspartate) O-Met Transferase], PCNA [proliferating cell nuclear antigen], PCNT [percentrin], PCP4 [Purkinje cell protein 4], PCSK7 [proprotein convertase subtilisin / kesin type 7], PDCD1 [scheduled cell death 1], PDE11A [phosphodiesterase 11A], PDE3B [phosphodiesterase 3B, cGMP-inhibited], PDE4A [phosphodiesterase 4A, cAMP-specific (phosphodiesterase E2 dunce homologue) , Drosophila)], PDE4B [phosphodiesterase 4B, cAMP-specific (phosphodiesterase E4 Higgs homologue, Drosophila)], PDE4D [phosphodiesterase 4D, cAMP-specific (phosphodiester) Terase E3 Higgs homologue, Drosophila)], PDE5A [phosphodiesterase 5A, cGMP-specific], PDE8A [phosphodiesterase 8A], PDGFA [platelet-derived growth factor alpha polypeptide], PDGFB [ Platelet-induced growth factor beta polypeptides (monkey sarcoma viral (v-sis) oncogene homologues)], PDGFC [platelet-induced growth] C], PDGFD [platelet-derived growth factor D], PDGFRA [platelet-derived growth factor receptor, alpha polypeptide], PDGFRB [platelet-derived growth factor receptor, beta polypeptide], PDHA1 [pyruvate dehydrogenase (Gia) Meade) alpha 1], PDIA2 [protein disulfide isomerase family A, member 2], PDIA3 [protein disulfide isomerase family A, member 3], PDLIM1 [PDZ and LIM domain 1], PDLIM7 [PDZ and LIM Domain 7 (enigma)], PDP1 [pyruvate dehydrogenase phosphatase-catalyzed subunit 1], PDPN [podoplanin], PDXK [pyridoxal (pyridoxine, vitamin B6) kinase], PDXP [pyridoxal (pyridoxine, vitamin B6) phosphatase], PDYN [prodinolpin], PDZK1 [PDZ domain containing 1], PEBP1 [phosphatidylethanolamine binding protein 1], PECAM1 [platelet / endothelial adhesion molecule], PENK [proenkephalin], PER1 [period Homolog 1 (Drosophila)], PER2 [Period Homolog 2 (sec) L)], PEX13 [Peroxysome Biogeneity Factor 13], PEX2 [Peroxysome Biogeneity Factor 2], PEX5 [Peroxysome Biogeneity Factor 5], PEX7 [Peroxysome Biogeneity Factor 7], PF4 [ Platelet factor 4], PFAS [phosphoribosylformylglycineamidine synthase], PFKL [infractokinase, liver], PFKM [infractokinase, muscle], PFN1 [propylin 1], PFN2 [propylin 2] , PFN3 [propyline 3], PFN4 [propyl family, member 4], PGAM2 [phosphoglycerate mutase 2 (muscle)], PGD [phosphogluconate dehydrogenase], PGF [placental growth factor], PGK1 [Phosphoglycerate kinase 1], PGM1 [inglucomutase 1], PGR [progesterone receptor], PHB [prohibitin], PHEX [phosphate-regulated endopeptidase homologue, X-linked], PHF10 [PHD Finger protein 10], PHF8 [PHD finger protein 8], PHGDH [phosphoglycerate dehydrogenase], PHKA2 [phosphorylase kinase, alpha 2 (liver)], PHLDA2 [Flextrin phase Homology-like domain, family A, member 2], PHOX2B [paired-like homeobox 2b], PHYH [pythonyl-CoA 2-hydroxylase], PHYHIP [pythonyl-CoA 2-hydroxyla Interacting protein], PIAS1 [protein inhibitor of activated STAT, 1], PICALM [phosphatidylinositol-binding clathrin assembly protein], PIGF [phosphatidyl inositol glycan anchor biosynthesis, class F], PIGP [phosphatidyl inositol glycan anchor biosynthesis , Classification P], PIK3C2A [phosphoinositide-3-kinase, class 2, alpha polypeptide], PIK3C2B [phosphoinositide-3-kinase, class 2, beta polypeptide], PIK3C2G [phosphoinositide-3- Kinase, class 2, gamma polypeptide], PIK3C3 [phosphoinositide-3-kinase, class 3], PIK3CA [phosphoinositiated-3-kinase, catalyst, alpha polypeptide], PIK3CB [phosphoinositide-3- Kinases, catalysts, beta polypeptides], PIK3CD [phosphoinositide-3-kina , Catalyst, delta polypeptide], PIK3CG [phosphoinositide-3-kinase, catalyst, gamma polypeptide], PIK3R1 [phosphoinositide-3-kinase, regulatory subunit 1 (alpha)], PIK3R2 [phosphoinositide -3-kinase, regulatory subunit 2 (beta)], PIK3R3 [phosphoinositiated-3-kinase, regulatory subunit 3 (gamma)], PIK3R4 [phosphoinositiated-3-kinase, regulatory subunit 4] , PIK3R5 [phosphoinositide-3-kinase, regulatory subunit 5], PINK1 [PTEN-derived putative kinase 1], PITX1 [paired-like homeodomain 1], PITX2 [paired-like homeo Domain 2], PITX3 [paired-like homeodomain 3], PKD1 [polycystic kidney disease 1 (autosome dominant)], PKD2 [polycystic kidney disease 2 (autosome dominant)], PKHD1 [polycystic kidney and hepatic Disease 1 (autosome recessive)], PKLR [pyruvate kinase, liver and RBC], PKN2 [protein kinase N2], PKNOX1 [PBX / entangled 1 homeobox 1], PL-5283 [PL-5283 protein], PLA2 G10 [phospholipase A2, group X], PLA2G2A [phospholipase A2, group IIA (platelet, synovial fluid)], PLA2G4A [phospholipase A2, group IVA (cytosol, calcium-dependent)], PLA2G6 [force Lipase A2, group VI (cytosol, calcium-independent)], PLA2G7 [phospholipase A2, group VII (platelet-activating factor acetylhydrolase, plasma)], PLAC4 [placental-specific 4], PLAG1 [ Polymorphic adenomas 1], PLAGL1 [polymorphic adenomas-like 1], PLAT [plasminogen activator, tissue], PLAU [plasminogen activator, urokinase], PLAUR [plasminogen activator, urokinase receptor], PLCB1 [phospholipase C, beta 1 (phosphoinositide-specific)], PLCB2 [phospholipase C, beta 2], PLCB3 [phospholipase C, beta 3 (phosphatidylinositol-specific)], PLCB4 [Phospholipase C, beta 4], PLCG1 [phospholipase C, gamma 1], PLCG2 [phospholipase C, gamma 2 (Phosphatidylinositol-specific)], PLCL1 [phospholipase C-like 1], PLD1 [phospholipase D1, phosphatidylcholine-specific], PLD2 [phospholipase D2], PLEK [plextrin], PLEKHH1 [flex Containing the Trine homology domain, family H (with MyTH4 domain) member 1], PLG [plasminogen], PLIN1 [ferilipine 1], PLK1 [polo-like kinase 1 (Drosophila)], PLOD1 [procollagen-lysine 1, 2-oxoglutarate 5-dioxygenase 1], PLP1 [protein lipid protein 1], PLTP [phospholipid transport protein], PLXNA1 [flexin A1], PLXNA2 [flexin A2], PLXNA3 [flexin A3 ], PLXNA4 [flexin A4], PLXNB1 [flexin B1], PLXNB2 [flexin B2], PLXNB3 [flexin B3], PLXNC1 [flexin C1], PLXND1 [flexin D1], PML [promyelocytic leukemia] , PMP2 [peripheral myelin protein 2], PMP22 [peripheral myelin protein 22], PMS2 [increased isolation 2 after PMS2 meiosis (S.  Serbisier)], PMVK [phosphomevalonate kinase], PNOC [prepronoceceptin], PNP [purine nucleoside phosphorylase], PNPLA6 [patatin-like phospholipase domain containing 6], PNPO [Pyridoxamine 5'-phosphate oxidase], POFUT2 [protein O-fucosyltransferase 2], POLB [polymerase (DNA directed), beta], POLR1C [polymerase (RNA) I polypeptide C, 30 kDa], POLR2A [polymerase (RNA) II (DNA oriented) polypeptide A, 220 kDa], POLR3K [polymerase (RNA) III (DNA oriented) polypeptide K, 12. 3 kDa], POM121C [POM121 membrane glycoprotein C], POMC [propiomelanocortin], POMGNT1 [protein O-linked mannose beta1 [2-N-acetylglucosaminyltransferase], POMT1 [protein-O -Mannosyltransferase 1], PON1 [rapapoxonase 1], PON2 [rapapoxonase 2], POR [P450 (cytochrome) oxidoreductase], POSTN [periostin, osteoblast specific factor], POU1F1 [ POU Category 1 Homeobox 1], POU2F1 [POU Category 2 Homeobox 1], POU3F4 [POU Category 3 Homeobox 4], POU4F1 [POU Category 4 Homeobox 1], POU4F2 [POU Category 4 Homeobox 2], POU4F3 [POU Class 4 Homeobox 3], POU5F1 [POU Class 5 Homeobox 1], PPA1 [Pyrophosphatase (Inorganic) 1], PPARA [Peroxysome Proliferator-Activated Receptor Alpha], PPARD [Peroxysome Proliferator-Activated Receptor Delta], PPARG [Peroxysome Proliferator-Activated Receptor Gamma], PPARGC1A [Peroxysome Proliferator-Activated Receptor Gamma, Co-Activator 1 Alpha], PPAT [phosphoribosyl pyrophosphophosphate amidotransferase], PPBP [pro-platelet basic protein (chemokine (CXC motif) ligand 7)], PPFIA1 [protein tyrosine phosphatase, receptor type, f polypeptide (PTPRF ), Interacting protein (lipin), alpha 1], PPFIA2 [protein tyrosine phosphatase, receptor type, f polypeptide (PTPRF), interacting protein (lipin), alpha 2], PPFIA3 [protein tyrosine phosphatase, receptor type, f polypeptide (PTPRF), interacting protein (lipin), alpha 3], PPFIBP1 [PTPRF interacting protein, binding protein 1 (lipin beta 1)], PPIC [peptidylprolyl isomerase C (cyclophylline C) ], PPIG [peptidylprolyl isomerase G (cyclophyllin G)], PPP1R15A [protein phosphatase 1, modulator (inhibitor) subunit 15A], PPP1R1B [protein phosphatase 1, regulator (inhibitor) subunit 1B], PPP1R9A [ Protein phosphatase 1, regulatory (inhibitor) adan 9A], PPP1R9B [protein phosphatase 1, modulating (inhibitor) subunit 9B], PPP2CA [protein phosphatase 2, catalytic subunit, alpha isozyme], PPP2R4 [protein phosphatase 2A active, regulatory subunit 4], PPP3CA [protein Phosphatase 3, catalytic subunit, alpha isozyme], PPP3CB [protein phosphatase 3, catalytic subunit, beta isozyme], PPP3CC [protein phosphatase 3, catalytic subunit, gamma isozyme], PPP3R1 [protein phosphatase 3, regulatory sub Unit B, alpha], PPP3R2 [protein phosphatase 3, regulatory subunit B, beta], PPP4C [protein phosphatase 4, catalytic subunit], PPY [pancreatic polypeptide], PQBP1 [polyglutamine binding protein 1], PRAM1 [PML- RARA regulated adapter molecule 1], PRAME [antigens expressed preferentially in melanoma], PRDM1 [containing PR domain 1, with ZNF domain], PRDM15 [PR domain containing 15], PRDM2 [PR domain containing 2, With ZNF domain], PRDX1 [peroxyredox 1], PRDX2 [Peroxyredoxin 2], PRDX3 [Peroxyredoxin 3], PRDX4 [Peroxyredoxin 4], PRDX6 [Peroxyredoxin 6], PRF1 [Perforin 1 (Pore Formation Protein)] , PRKAA1 [protein kinase, AMP-activated, alpha 1 catalytic subunit], PRKAA2 [protein kinase, AMP-activated, alpha 2 catalyst subunit], PRKAB1 [protein kinase, AMP-activated, beta 1 non-catalyst Subunit], PRKACA [protein kinase, cAMP-dependent, catalyst, alpha], PRKACB [protein kinase, cAMP-dependent, catalyst, beta], PRKACG [protein kinase, cAMP-dependent, catalyst, gamma], PRKAG1 [protein kinase , AMP-activated, gamma 1 non-catalytic subunit], PRKAG2 [protein kinase, AMP-activated, gamma 2 non-catalytic subunit], PRKAR1A [protein kinase, cAMP-dependent, regulatory, type I, alpha ( Tissue specific luminescent 1)], PRKAR1B [protein kinase, cAMP-dependent, regulatory, type I, beta], PRKAR2A [protein kinase, cAMP-dependent, regulatory, type II, alpha], PRKAR2B [protein kinase, cAMP-dependent, regulatory, type II, beta], PRKCA [protein kinase C, alpha], PRKCB [protein kinase C, beta], PRKCD [protein kinase C, delta], PRKCE [protein kinase C, Epsilon], PRKCG [protein kinase C, gamma], PRKCH [protein kinase C, eta], PRKCI [protein kinase C, iota], PRKCQ [protein kinase C, theta], PRKCZ [protein kinase C, zeta], PRKD1 [protein kinase D1], PRKDC [protein kinase, DNA-activated, catalytic polypeptide], PRKG1 [protein kinase, cGMP-dependent, type I], PRL [prolactin], PRLR [prolactin Receptor], PRMT1 [protein arginine methyltransferase 1], PRNP [prion protein], PROC [protein C (inactive substance of coagulation factors Va and VIIIa)], PROCR [protein C receptor, endothelial (EPCR)], PRODH [proline Dehydrogenase (oxidase) 1], PROK1 [Prokineticin 1], PROK2 [Prokineticin 2], PROM1 [Prominin 1], PROS1 [ White matter S (alpha)], PRPF40A [PRP40 pre-mRNA processing factor 40 homolog A (S.  CERVISI)], PRPF40B [PRP40 pre-mRNA processing factor 40 homolog B (S.  CERVISI)], PRPH [ferriferrin], PRPH2 [ferriferin 2 (retinal degeneration, slow)], PRPS1 [phosphoribosil pyrophosphate synthase 1], PRRG4 [proline rich Gla (G-carboxyglutamic acid ) 4 (membrane)], PRSS8 [protease, serine, 8], PRTN3 [proteinase 3], PRX [periaxin], PSAP [prosaposin], PSEN1 [presenillin 1], PSEN2 [Presenilin 2 (Alzheimer disease 4)], PSG1 [pregnancy specific beta-1-glycoprotein 1], PSIP1 [PC4 and SFRS1 interacting protein 1], PSMA5 [proteasome (prosome, macropine) sub Unit, alpha type, 5], PSMA6 [proteasome (prosome, macropine) subunit, alpha type, 6], PSMB8 [proteasome (prosome, macropine) subunit, beta type, 8 (large Multifunctional peptidase 7)], PSMB9 [proteasome (prosome, macropine) subunit, beta type, 9 (large multifunctional peptidase 2)], PSMC1 [proteasome (prosome, macropine) 26S Subunit, ATPase, 1], PSMC4 [Proteasome (Prosome, Macropine) 26S Subunit, ATPase, 4], PSMD9 [Proteasome (Prosome, Macropine) 26S Subunit, Non-ATPase, 9], PSME1 [Proteasome (Pro) Some, macrofine) active subunit 1 (PA28 alpha)], PSME2 [proteasome (prosome, macropine) active substance subunit 2 (PA28 beta)], PSMG1 [proteasome (prosome, macropine) ) Set chaperone 1], PSPH [insulin phosphatase], PSPN [percepin], PSTPIP1 [proline-serine-threonine phosphatase interacting protein 1], PTAFR [platelet-activating factor receptor], PTCH1 [patched phase Fuselage 1 (Drosophila)], PTCH2 [patched homolog 2 (Drosophila)], PTEN [phosphatase and tensine homologues], PTF1A [pancreatic specific transcription factor, 1a], PTGER1 [prostaglandin E receptor 1 (subtype EP1) , 42kDa], PTGER2 [prostaglandin E receptor 2 (subtype EP2), 53kDa], PTGER3 [prostaglandin E receptor 3 (subtype EP3)], PTGER4 [ Prostaglandin E Receptor 4 (subtype EP4)], PTGES [Prostaglandin E Synthetase], PTGES2 [Prostaglandin E Synthetase 2], PTGIR [Prostaglandin I2 (Prostacyclin) Receptor (IP)], PTGS1 [Prostaglandin-Andofeok Seed synthase 1 (prostaglandin G / H synthetase and cyclooxygenase)], PTGS2 [prostaglandin-andopeoxide synthase 2 (prostaglandin G / H synthetase and cyclooxygenase)], PTH [parathyroid hormone] , PTH1R [parathyroid hormone 1 receptor], PTHLH [parathyroid hormone-like hormone], PTK2 [PTK2 protein tyrosine kinase 2], PTK2B [PTK2B protein tyrosine kinase 2 beta], PTK7 [PTK7 protein tyrosine kinase 7], PTN [platelet] Ropin], PTPN1 [protein tyrosine phosphatase, non-receptor type 1], PTPN11 [protein tyrosine phosphatase, non-receptor type 11], PTPN13 [protein tyrosine phosphatase, non-receptor type 13 (APO-1 / CD95 (Fas) -associated phosphatase)], PTPN18 [protein tyrosine phosphatase, non-receptor type 18 (brain-derived)], PTPN2 [protein tyrosine phosphatase, non-receptor type 2], PTPN22 [protein Tyrosine phosphatase, non-receptor type 22 (lymphoid)], PTPN6 [protein tyrosine phosphatase, non-receptor type 6], PTPN7 [protein tyrosine phosphatase, non-receptor type 7], PTPRA [protein tyrosine phosphatase, receptor type, A ], PTPRB [protein tyrosine phosphatase, receptor type, B], PTPRC [protein tyrosine phosphatase, receptor type, C], PTPRD [protein tyrosine phosphatase, receptor type, D], PTPRE [protein tyrosine phosphatase, receptor type, E], PTPRF [protein tyrosine phosphatase, receptor type, F], PTPRJ [protein tyrosine phosphatase, receptor type, J], PTPRK [protein tyrosine phosphatase, receptor type, K], PTPRM [protein tyrosine phosphatase, Solution type, M], PTPRO [protein tyrosine phosphatase, receptor type, O], PTPRS [protein tyrosine phosphatase, receptor type, S], PTPRT [protein tyrosine phosphatase, receptor type, T], PTPRU [protein tyrosine phosphatase, receptor type , U], PTPRZ1 [protein tyrosine phosphatase, receptor-type, Z polypeptide 1], PTS [6-pyruboyltetrahydropterin synthetase], PTTG1 [pituitary tumor-morphomorphism 1], PVR [poliovirus receptor] , PVRL1 [Poliovirus Receptor-Related 1 (Herpes Virus Entry Intermediate C)], PWP2 [PWP2 Intermittent Tryptophan Protein Homolog (Yeast)], PXN [Pacillin], PYCARD [Contains PYD and CARD Domain], PYGB [ Phosphorylase, glycogen; Brain], PYGM [phosphorylase, glycogen, muscle], PYY [peptide YY], QDPR [quinoid dihydrophteridine reductase], QKI [quaking homologues, KH domain RNA binding (mouse )], RAB11A [RAB11A, member RAS oncogene family], RAB11FIP5 [RAB11 family interacting protein 5 (class I)], RAB39B [RAB39B, member RAS oncogene family], RAB3A [RAB3A, member RAS oncogene family], RAB4A [RAB4A, member RAS oncogene family], RAB5A [RAB5A, member RAS oncogene family], RAB8A [RAB8A, member RAS oncogene family], RAB9A [RAB9A, member RAS oncogene family], RABEP1 [rabaptin (rabaptin) ), RAB GTPase binding effector protein 1], RABGEF1 [RAB guanine nucleotide exchange factor (GEF) 1], RAC1 [ras-associated C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1)], RAC2 [ras- Related C3 Botulinum Toxin Substrate 2 (rho Family, Small GTP Binding Protein Rac2)], RAC3 [ras-related C3 botulinum toxin substrate 3 (rho family, small GTP binding protein Rac3)], RAD51 [RAD51 homologue (RecA homologue, E. coli) (S.  Servicie)], RAF1 [v-raf-1 murine leukemia viral oncogene homolog 1], RAG1 [recombinant activation gene 1], RAG2 [recombinant activation gene 2], RAGE [renal tumor antigen], RALA [v -ral monkey leukemia viral oncogene homologue A (ras related)], RALBP1 [ralA binding protein 1], RALGAPA2 [Ral GTPase activating protein, alpha subunit 2 (catalyst)], RALGAPB [Ral GTPase activating protein, beta-a Unit (non-catalyst)], RALGDS [ral guanine nucleotide dissociation stimulant], RAN [RAN, member RAS oncogene family], RAP1A [RAP1A, member of RAS oncogene family], RAP1B [RAP1B, of RAS oncogene family] Member], RAP1GAP [RAP1 GTPase activating protein], RAPGEF3 [Rap guanine nucleotide exchange factor (GEF) 3], RAPGEF4 [Rap guanine nucleotide exchange factor (GEF) 4], RAPH1 [Ras association (RalGDS / AF-6) and flex Trine homology domain 1], RAPSN [receptor-tubule of synapse Protein], RARA [retinoic acid receptor, alpha], RARB [retinoic acid receptor, beta], RARG [retinoic acid receptor, gamma], RARS [arginyl-tRNA synthetase], RASA1 [RAS p21 protein activator (GTPase) Activating protein) 1], RASA2 [RAS p21 protein activator 2], RASGRF1 [Ras protein-specific guanine nucleotide-releasing factor 1], RASGRP1 [RAS guanyl releasing protein 1 (calcium and DAG-regulated)], RASSF1 [Ras Union (RalGDS / AF-6) Domain Family Member 1], RASSF5 [Ras Union (RalGDS / AF-6) Domain Family Member 5], RB1 [Retinoblastoma 1], RBBP4 [Retinoblastoma Binding Protein 4], RBM11 [RNA binding motif protein 11], RBM4 [RNA binding motif protein 4], RBM45 [RNA binding motif protein 45], RBP4 [retinol binding protein 4, plasma], RBPJ [recombinant signal binding protein for immunoglobulin kappa J moiety] , RCAN1 [modulator 1 of calcineurin], RCAN2 [modulator 2 of calcineurin], RCAN3 [RCAN family member 3], R COR1 [REST co-inhibitor 1], RDX [radicin], REEP3 [receptor accessory protein 3], REG1A [regeneration of islet-induced 1 alpha], RELA [v-rel retinopathy viral oncogene homologue A (Algae)], RELN [reelin], REN [renin], REPIN1 [replicate initiator 1], REST [RE1-silent transcription factor], RET [ret proto-oncogene], RETN [resistin], RFC1 [Replication Factor C (Active 1) 1, 145 kDa], RFC2 [Replication Factor C (Active 1) 2, 40 kDa], RFX1 [Regulatory Factor X, 1 (influences HLA class II expression)], RGMA [RGM domain Family, member A], RGMB [RGM domain family, member B], RGS3 [modulator 3 of G-protein signaling], RHD [Rh blood group, D antigen], RHEB [Ras homologues in brain], RHO [Rhodopsin], RHOA [ras homologous gene family, member A], RHOB [ras homologous gene family, member B], RHOC [ras homologous gene family, member C], RHOD [ras homologous gene family, member D ], RHOG [ras homolog gene Family, member G (rho G)], RHOH [ras homologous gene family, member H], RICTOR [RPTOR independent companion of MTOR, complex 2], RIMS3 [regulatory synaptic membrane exocytosis 3], RIPK1 [receptor (TNFRSF ) -Interacting serine-threonine kinase 1], RIPK2 [receptor-interacting serine-threonine kinase 2], RNASE1 [ribonuclease, RNase A family, 1 (pancreas)], RNASE3 [ribonuclease, RNase A Family, 3 (neutrophil cation protein)], RNASEL [ribonuclease L (2 '[5'-oligoisoadenylate synthase-dependent)], RND1 [Rho family GTPase 1], RND2 [Rho family GTPase 2 ], RND3 [Rho family GTPase 3], RNF123 [ring finger protein 123], RNF128 [ring finger protein 128], RNF13 [ring finger protein 13], RNF135 [ring finger protein 135], RNF2 [ring finger protein 2], RNF6 [ringfinger protein (C3H2C3 type) 6], RNH1 [ribonuclease / angiogenin inhibitor 1], RNPC3 [containing RNA-binding moiety (RNP1, RRM) 3], ROBO1 [bypass (roundabout), axon guidance receptor, homologue 1 (Drosophila)], ROBO2 [bypassing, axon-inducing receptor, homologue 2 (Drosophila)], ROBO3 [bypassing, axon-inducing receptor, Homolog 3 (Drosophila)] , ROBO4 [bypassive homologue 4, magical bypass (Drosophila)], ROCK1 [Rho-related, coiled-coil containing protein kinase 1], ROCK2 [Rho-associated, coiled-coil containing protein kinase 2], RPGR [ Retinal pigmentosa GTPase modulator], RPGRIP1 [retinal pigmentosa GTPase modulator interaction protein 1], RPGRIP1L [RPGRIP1-like], RPL10 [ribosome protein L10], RPL24 [ribosome protein L24], RPL5 [ribosome protein L5], RPL7A [ribosome protein L7a], RPLP0 [ribosome protein, large, P0], RPS17 [ribosome protein S17], RPS17P3 [ribosome protein S17 false gene 3], RPS19 [ribosome protein S19], RPS27A [ribosome protein S27a], RPS6 [ Ribosomal protein S6], RPS6KA1 [ribosome protein S6 kinase, 90 kDa, polypeptide 1], RPS6 KA3 [ribosome protein S6 kinase, 90 kDa, polypeptide 3], RPS6KA6 [ribosome protein S6 kinase, 90 kDa, polypeptide 6], RPS6KB1 [ribosome protein S6 kinase, 70 kDa, polypeptide 1], RRAS [associated RAS viral (r-ras) Oncogene homologues], RRAS2 [associated RAS viral (r-ras) oncogene homologue 2], RRBP1 [ribosome binding protein 1 homologue 180 kDa (dog)], RRM1 [ribonucleotide reductase M1], RRM2 [ribo Nucleotide reductase M2], RRM2B [ribonucleotide reductase M2 B (TP53 inducible)], RTN4 [Reticulon 4], RTN4R [Reticulon 4 Receptor], RUFY3 [RUN and FYVE domain containing 3], RUNX1 [runt- Related transcription factor 1], RUNX1T1 [runt-related transcription factor 1; Transposed to, 1 (cyclin D-related)], RUNX2 [runt-related transcription factor 2], RUNX3 [runt-related transcription factor 3], RUVBL2 [RuvB-like 2 (E. coli)], RXRA [retinoid X receptor , Alpha], RYK [RYK receptor-like tyrosine kinase], RYR2 [rhinodine receptor 2 (heart)], RYR3 [rhinodine receptor 3], S100A1 [S100 calcium binding protein A1], S100A10 [S100 calcium binding protein A10] S100A12 [S100 calcium binding protein A12], S100A2 [S100 calcium binding protein A2], S100A4 [S100 calcium binding protein A4], S100A6 [S100 calcium binding protein A6], S100A7 [S100 calcium binding protein A7], S100A8 [S100 calcium Binding protein A8], S100A9 [S100 calcium binding protein A9], S100B [S100 calcium binding protein B], SAA4 [serum amyloid A4, constitutive], SACS [Charlevoix-Saguenay's spastic ataxia (sacsin)], SAFB [scaffold adhesion factor B], SAG [S-antigen; Retina and Pineal Gland (Arrestin)], SAMHD1 [SAM Domain and HD Domain 1], SATB2 [SATB Homeobox 2], SBDS [Shwachman-Bodian-Diamond Syndrome], SCARB1 [Clear Receptor Classification B, Member 1], SCD [Stearoyl-CoA Desaturase (Delta-9-Desaturase)], SCD5 [Stearoyl-CoA Desaturase 5], SCG2 [Secretogenin II], SCG5 [Secretogenin V ( 7B2 protein)], SCGB1A1 [secretoglobin, family 1A, member 1 (uteroglobin)], SCN11A [sodium channel, translocation-opening, type XI, alpha subunit], SCN1A [sodium channel, translocation-opening, type I, alpha subunit], SCN2A [sodium channel, potential-gated, type II, alpha subunit], SCN3A [sodium channel, potential-gated, type III, alpha subunit], SCN5A [sodium channel, potential-opened, Type V, alpha subunit], SCN7A [sodium channel, translocation-opening, type VII, alpha], SCNN1B [sodium channel, non-potential-opening 1, beta], SCNN1G [sodium channel, non-potential-opening 1, Gamma], SCP2 [Sterol Carrier Protein 2], SCT [Secretin], SCTR [Secretin Receptor], SCUBE1 [Signal Peptide, CUB Domain, EGF-Like 1], SDC2 [Sindecan 2], SDC3 [Sindecan 3], SDCBP [Shin Decane binding protein (syntenin)], SDHB [succinate dehydrogenase complex, subunit B, iron sulfur (Ip)], SDHD [succinate dehydrogenase complex, subunit D, whole membrane protein], SDS [ Serine dehydratase], SEC14L2 [SEC14-like 2 (S.  Servicie)], SELE [selectin E], SELL [selectin L], SELP [selectin P (granular membrane protein 140kDa, antigen CD62)], SELPLG [selectin P ligand], SEMA3A [sema domain, immunoglobulin Domain (Ig), short basic domain, secreted, (semaphorin) 3A], SEMA3B [sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3B], SEMA3C [sema domain, Immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3C], SEMA3D [sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3D], SEMA3E [sema Domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3E], SEMA3F [sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3F], SEMA3G [Sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3G], SEMA4A [sema domain, immunoglobulin domain (Ig), transmembrane domain (TM) and short cytoplasmic domain, (semaphorin) 4A], SEMA4B [sema domain, immunoglobulin domain (Ig), transmembrane domain (TM) and short Cytoplasmic domain, (semaphorin) 4B], SEMA4C [sema domain, immunoglobulin domain (Ig), transmembrane domain (TM) and short cytoplasmic domain, (semaphorin) 4C], SEMA4D [sema domain, immunoglobulin domain (Ig) ), Transmembrane domain (TM) and short cytoplasmic domain, (semaphorin) 4D], SEMA4F [sema domain, immunoglobulin domain (Ig), transmembrane domain (TM) and short cytoplasmic domain, (semaphorin) 4F], SEMA4G [sema domain, immunoglobulin domain (Ig), transmembrane domain (TM) and short cytoplasmic domain, (semaphorin) 4G], SEMA5A [sema domain, 7 thrombospondin repeats (type 1 and type 1-like) Transmembrane domain (TM) and short cytoplasmic domain, (semaphorin) 5A], SEMA5B [Sema domain, 7 thrombospondin repeats (type 1 and type 1-like), transmembrane domain (TM) and short cytoplasmic domain, (semaphorin) 5B], SEMA6A [sema domain, transmembrane domain (TM), And cytoplasmic domain, (semaphorin) 6A], SEMA6B [sema domain, transmembrane domain (TM), and cytoplasmic domain, (semaphorin) 6B], SEMA6C [sema domain, transmembrane domain (TM), and cytoplasmic domain, (Semaphorin) 6C], SEMA6D [sema domain, transmembrane domain (TM), and cytoplasmic domain, (semaphorin) 6D], SEMA7A [semaphorin 7A, GPI membrane anchor (John Milton Hagen blood group)], SEPP1 [ Serenoprotein P, plasma, 1], SEPT2 [ceptin 2], SEPT4 [ceptin 4], SEPT5 [ceptin 5], SEPT6 [ceptin 6], SEPT7 [ceptin 7], SEPT9 [ceptin 9], SERPINA1 [serpin Peptidase inhibitors, clade A (alpha-1 antiproteinase, antitrypsin), member 1], SERPINA3 [serpin peptidase inhibitors, clade A (alpha-1 antiproteinase, antitrypsin) Shin), member 3], SERPINA7 [serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 7], SERPINB1 [serpin peptidase inhibitor, clade B (of) Albumin), member 1], SERPINB2 [serpin peptidase inhibitor, clade B (ofalbumin), member 2], SERPINB6 [serpin peptidase inhibitor, clade B (ofalbumin), member 6], SERPINC1 [Serpin Peptidase Inhibitor, Clade C (Anthrombin), Member 1], SERPINE1 [Serpin Peptidase Inhibitor, Clade E (Nexin, Plasminogen Activator Inhibitor Type 1), Member 1], SERPINE2 [Serpin Peptidase Inhibitor, Clade E (Nexin, Plasminogen Activator Inhibitor Type 1), Member 2], SERPINF1 [Serpin Peptidase Inhibitor, Clade F (Alpha-2 Antiplasmin, Pigment Epithelium) Induced factor), member 1], SERPINH1 [serpin peptidase inhibitor, clade H (heat shock protein 47), member 1, (collagen Binding protein 1)], SERPINI1 [serpin peptidase inhibitor, clade I (neuserpinin), member 1], SET [SET nuclear oncogene], SETX [senatacin], SEZ6L2 [Section-related 6 homologues ( Mouse) -like 2], SFPQ [splicing factor proline / glutamine-rich (associated with polypyrimidine tract binding protein)], SFRP1 [secreted curly-related protein 1], SFRP4 [secreted Curly-related protein 4], SFRS15 [conjugation factor, arginine / serine-rich 15], SFTPA1 [surfactant protein A1], SFTPB [surfactant protein B], SFTPC [surfactant protein C], SGCB [sarcogly Can, beta (43kDa dispropine-associated glycoprotein)], SGCE [sarcoglycan, epsilon], SGK1 [serum / glucocorticoid regulated kinase 1], SH2B1 [SH2B adapter protein 1], SH2B3 [SH2B adapter protein 3 ], SH2D1A [SH2 domain containing 1A], SH3BGR [SH3 domain binding glutamic acid-rich protein], SH3BGRL [SH3 Domain-binding glutamic acid-rich protein like], SH3BP1 [SH3-domain binding protein 1], SH3GL1P2 [SH3-domain GRB2-like 1 false gene 2], SH3GL3 [SH3-domain GRB2-like 3], SH3KBP1 [SH3-domain Kinase binding protein 1], SH3PXD2A [SH3 and PX domain 2A], SHANK1 [SH3 and multiple ankyrin repeat domain 1], SHANK2 [SH3 and multiple ankyrin repeat domain 2], SHANK3 [SH3 and multiple ankyrin repeat domain 3] , SHBG [sex hormone-binding globulin], SHC1 [SHC (containing Src homology 2 domain) transformed protein 1], SHC3 [SHC (containing Src homology 2 domain) transformed protein 3], SHH [sonic hedgehog homolog (Drosophila)], SHOC2 [Soc-2 Inhibitors of Clear Homologs (C. Elegans)], SI [Schkrase-Isomaltase (alpha-glucosidase)], SIAH1 [7 in the absence homology 1 (Drosophila)], SIAH2 [7 in the absence homology 2 (Drosophila)], SIGMAR1 [Sigma Non-opium intracellular receptor 1], SILV [silver homologue (mouse)], SIM1 [single-minded homologue 1 (Drosophila)], SIM2 [single-minded homologue 2 (Drosophila)] , SIP1 [survival of motor neuron protein interacting protein 1], SIRPA [signal-regulatory protein alpha], SIRT1 [siltuin (silent mating type information regulating 2 homologue) 1 (S. Serbisier)], SIRT4 [ Sirtuin (silent copulation type information control 2 homologue) 4 (S. servicier)], SIRT6 [Sirtuin (silent copulation type information control 2 homologue) 6 (S. servicier)], SIX5 [ SIX homeobox 5], SKI [v-ski sarcoma viral oncogene homolog (algae)], SKP2 [S-phase kinase-related protein 2 (p45)], SLAMF6 [SLAM family member 6], SLC10A1 [solute Carrier Family 10 (Sodium / Bile Acid Cocarrier family), member 1], SLC11A2 [solute carrier family 11 (proton-linked divalent metal ion transport), member 2], SLC12A1 [solute carrier family 12 (sodium / potassium / chloride transport), member 1], SLC12A2 [Solute Carrier Family 12 (Sodium / Potassium / chloride Transport), Member 2], SLC12A3 [Solute Carrier Family 12 (Sodium / chloride Transport), Member 3], SLC12A5 [Solute Carrier Family 12 (Potassium / chloride Transport), Member 5], SLC12A6 [solute carrier family 12 (potassium / chloride transport), member 6], SLC13A1 [solute carrier family 13 (sodium / sulfate symposers), member 1], SLC15A1 [solute carrier family 15 (oligopeptide transport) , Member 1], SLC16A2 [Solute Carrier Family 16, Member 2 (Monocarboxylic Acid Carrier 8)], SLC17A5 [Solute Carrier Family 17 (anion / sugar transport), Member 5], SLC17A7 [Solute Carrier Family 17 (Sodium- Dependent inorganic phosphate co-carriers), member 7], SLC18A2 [Solute transport Half Family 18 (follicular monoamine), member 2], SLC18A3 [Solute Carrier Family 18 (follicular acetylcholine), member 3], SLC19A1 [Solute Carrier Family 19 (folate carrier), Member 1], SLC19A2 [ Solute Carrier Family 19 (Thiaamine Carrier), Member 2], SLC1A1 [Solute Carrier Family 1 (Nurnal / Epithelial High Affinity Glutamate Carrier, System Xag), Member 1], SLC1A2 [Solute Carrier Family 1 (Glue High Affinity Glutamate Transporter) Substance), member 2], SLC1A3 [solute carrier family 1 (glue high affinity glutamate carrier), member 3], SLC22A2 [solute carrier family 22 (organic cation transport), member 2], SLC25A12 [solute carrier family 25 (mitochondria Carrier, Aralar), member 12], SLC25A13 [solute carrier family 25, member 13 (citrin)], SLC25A20 [solute carrier family 25 (carnitine / acylcarnitine translocation enzyme), member 20], SLC25A3 [Solute luck Half-family 25 (mitochondrial carriers; Phosphate carrier), member 3], SLC26A3 [solute carrier family 26, member 3], SLC27A1 [solute carrier family 27 (fatty acid carrier), member 1], SLC29A1 [solute carrier family 29 (nucleoside carrier), member 1], SLC2A1 [Solute Carrier Family 2 (Promoted Glucose Transporter), Member 1], SLC2A13 [Solute Carrier Family 2 (Promoted Glucose Transporter), Member 13], SLC2A2 [Solute Carrier Family 2 (Promoted Glucose Transporter) Substance), member 2], SLC2A3 [solute carrier family 2 (promoted glucose carrier), member 3], SLC2A4 [solute carrier family 2 (promoted glucose carrier), member 4], SLC30A3 [solute carrier family 30 ( Zinc carrier), member 3], SLC30A4 [solute carrier family 30 (zinc carrier), member 4], SLC30A8 [solute carrier family 30 (zinc carrier), member 8], SLC31A1 [solute carrier family 31 (copper carrier Substance), member 1], SLC32A1 [solute carrier family 32 (G ABA vesicular carrier), member 1], SLC34A1 [solute carrier family 34 (sodium phosphate), member 1], SLC38A3 [solute carrier family 38, member 3], SLC39A2 [solute carrier family 39 (zinc transport), member 2 ], SLC39A3 [Solute Carrier Family 39 (Zinc Carrier), Member 3], SLC40A1 [Solute Carrier Family 40 (Iron-Controlled Carrier), Member 1], SLC4A11 [Solute Carrier Family 4, Sodium Borate Carrier, Member 11], SLC5A3 [Solute Carrier Family 5 (Sodium / myo-Inositol Co-carrier), Member 3], SLC5A8 [Solute Carrier Family 5 (Iodide Transport), Member 8], SLC6A1 [Solute Carrier Family 6 (Nerve Transporter) Carrier, GABA), Member 1], SLC6A14 [Solute Carrier Family 6 (Amino Acid Carrier), Member 14], SLC6A2 [Solute Carrier Family 6 (Neur Transporter, Noradrenaline), Member 2], SLC6A3 [Solute Carrier Family 6 (neurotransporter, dopamine), member 3], S LC6A4 [Solute Carrier Family 6 (Nerve Transporter, Serotonin), Member 4], SLC6A8 [Solute Carrier Family 6 (Nerve Transporter, Creatine), Member 8], SLC7A14 [Solute Carrier Family 7 (Cationic Amino Acid Transport, y + system), member 14], SLC7A5 [solute carrier family 7 (cationic amino acid transport, y + system), member 5], SLC9A2 [solute carrier family 9 (sodium / hydrogen exchanger), member 2], SLC9A3 [solute carrier family 9 (Sodium / hydrogen exchanger), member 3], SLC9A3R1 [solute carrier family 9 (sodium / hydrogen exchanger), member 3 modulator 1], SLC9A3R2 [solute carrier family 9 (sodium / hydrogen exchanger), member 3 modulator 2] , SLC9A6 [Solute Carrier Family 9 (Sodium / Hydrogen Exchanger), Member 6], SLIT1 [slit homologue 1 (Drosophila)], SLIT2 [slit homologue 2 (Drosophila)], SLIT3 [slit homologue 3 (Drosophila)] , SLITRK1 [SLIT and NTRK-like family, member 1], SLN [sarcolipin], SLPI [secretory leukocyte peptidase inhibitor], SMAD1 [SMAD family member 1], SMAD2 [SMAD family member 2], SMAD3 [SMAD family member 3], SMAD4 [SMAD family member 4], SMAD6 [SMAD family member 6] , SMAD7 [SMAD family member 7], SMARCA1 [SWI / SNF related, matrix related, chromatin actin dependent modulator, subfamily a, member 1], SMARCA2 [SWI / SNF related, matrix related, chromatin actin dependent Modulator, subfamily a, member 2], SMARCA4 [SWI / SNF related, matrix related, chromatin actin dependent modulator, subfamily a, member 4], SMARCA5 [SWI / SNF related, matrix related, chromatin Actin-dependent modulators, subfamily a, member 5], SMARCB1 [SWI / SNF related, matrix related, chromatin actin-dependent modulators, subfamily b, member 1], SMARCC1 [SWI / SNF related, matrix related, chroma Martin's Actin-dependent regulator, standing Bfamily c, member 1], SMARCC2 [SWI / SNF related, matrix related, chromatin actin dependent modulator, subfamily c, member 2], SMARCD1 [SWI / SNF related, matrix related, actin dependent modulate chromatin Substance, subfamily d, member 1], SMARCD3 [SWI / SNF related, matrix related, chromatin actin dependent modulator, subfamily d, member 3], SMARCE1 [SWI / SNF related, matrix related, chromatin actin Dependent modulator, subfamily e, member 1], SMG1 [SMG1 homologue, phosphatidylinositol 3-kinase-associated kinase (C. Elegans)], SMN1 [survival of motor neuron 1, telomere], SMO [smooth homolog (Drosophila)], SMPD1 [sphingomyelin phosphodiesterase 1, acid lysosomal], SMS [spermine synthase ], SNAI2 [snail homologue 2 (Drosophila)], SNAP25 [synaptosome-related protein, 25kDa], SNCA [synuclein, alpha (non-A4 component of amyloid precursor)], SNCAIP [synuclein, alpha interacting protein] ], SNCB [synuclein, beta], SNCG [synuclein, gamma (breast cancer-specific protein 1)], SNRPA [small nuclear ribonucleoprotein polypeptide A], SNRPN [small nuclear ribonucleoprotein polypeptide N], SNTG2 [Syntrophin, gamma 2], SNURF [SNRPN upstream reading frame], SOAT1 [sterol O-acyltransferase 1], SOCS1 [inhibitor 1 of cytokine signaling], SOCS3 [inhibitor of cytokine signaling 3], SOD1 [superoxide dismutase 1, soluble], SOD2 [superoxide dismutase 2, mitochondria], SORBS3 [bovine Levin and SH3 domain containing 3], SORL1 [sortholin-associated receptor, L (DLR classification) A repeat-containing], SORT1 [sortholin 1], SOS1 [son 1 of sevenless homologues] , SOS2 [son 2 of the sevenless homologue (Drosophila)], SOSTDC1 [containing sclerostin domain 1], SOX1 [SRY (sex determination part Y) -box 1], SOX10 [SRY ( Sex determination part Y) -box 10], SOX18 [SRY (sex determination part Y) -box 18], SOX2 [SRY (sex determination part Y) -box 2], SOX3 [SRY determination part Y) -box 3 ], SOX9 [SRY (sex determination part Y) -box 9], SP1 [Sp1 transcription factor], SP3 [Sp3 transcription factor], SPANXB1 [SPANX family, member B1], SPANXC [SPANX family, member C], SPARC [ Secreted protein, acidic, cysteine-rich (osteonectin)], SPARCL1 [SPARC-like 1 (hevin)], SPAST [spastin], SPHK1 [shippingosine kinase 1], SPINK1 [serine Peptidase inhibitors, Kazal type 1], SPINT2 [serine peptidase inhibitors, Kunitz type , 2], SPN [sialoporin], SPNS2 [spinster homolog 2 (Drosophila)], SPON2 [spondin 2, extracellular matrix protein], SPP1 [secreted phosphoprotein 1], SPRED2 [soup Roti-related, EVH1 domain containing 2], SPRY2 [Sproti homologue 2 (Drosophila)], SPTA1 [spectrin, alpha, erythropoietic 1 (tower erythrocytosis 2)], SPTAN1 [spectrin, alpha, non-erythrocytes Sex 1 (alpha-fodrin)], SPTB [spectrin, beta, erythropoietic], SPTBN1 [spectrin, beta, non-erythropoietic 1], SRC [v-src sarcoma (Schmidt-Ruppin A- 2) viral oncogene homologues (algae)], SRCRB4D [containing erasing receptor cysteine rich domain, group B (4 domains)], SRD5A1 [steroid-5-alpha-reductase, alpha polypeptide 1 (3-oxo-5) Alpha-steroid delta 4-dehydrogenase alpha 1)], SREBF1 [sterol regulatory element binding transcription factor 1], SREBF2 [sterol regulatory element binding transcription factor 2], SRF [serum response factor (c-fos serum) Response element-binding transcription factor)], SRGAP1 [SLIT-ROBO Rho GTPase activating protein 1], SRGAP2 [SLIT-ROBO Rho GTPase activating protein 2], SRGAP3 [SLIT-ROBO Rho GTPase activating protein 3], SRPX [sushi-repeat -Containing protein, X-linked], SRY [sex determining portion Y], SSB [Sjogren Syndrome Antigen B (autoantigen La)], SSH1 [slingshot homologue 1 (Drosophila)], SSRP1 [structure specific cognitive protein 1] , SST [somatostatin], SSTR1 [somatostatin receptor 1], SSTR2 [somatostatin receptor 2], SSTR3 [somatostatin receptor 3], SSTR4 [somatostatin receptor 4], STSTR5 [somatostatin receptor 5], ST13 [carcinogenic inhibition 13 (colon carcinoma) ) (Hsp70 interacting protein)], ST14 [carcinogenicity inhibition 14 (colon carcinoma)], ST6GAL1 [ST6 beta-galactosamide alpha-2 [6-sialeyltransferase 1], ST7 [inhibition of carcinogenicity 7] , STAG2 [substrate antigen 2], STAG3 [substrate antigen 3], STAR [steroid-producing acute regulatory protein], STAT1 [signal of transcription] Ventilation and Activator 1, 91kDa], STAT2 [Signal Transducer and Activator 2, 113kDa], STAT3 [Signal Transducer and Activator 3 (Acute-Phase Reaction Factor)], STAT4 [Signal Transducer and Activity Substance 4], STAT5A [transcriptional signal transducer and active substance 5A], STAT5B [transcriptional signal transducer and active substance 5B], STAT6 [transcriptional signal transducer and active substance 6, interleukin-4 derived], STATH [staterin (statherin)], STC1 [Staniocalcin 1], STIL [SCL / TAL1 Interfering Left], STIM1 [Substrate Interaction Molecule 1], STK11 [serine / threonine kinase 11], STK24 [serine / threonine kinase 24 (STE20 Homologues, yeast)], STK36 [serine / threonine kinase 36, fused homologs (Drosophila)], STK38 [serine / threonine kinase 38], STK38L [similar to serine / threonine kinase 38], STK39 [serine threonine kinase 39 ( STE20 / SPS1 homologue, yeast)], STMN1 [Stamin 1], STMN2 [Stamin-Like 2], STMN3 [Stamin-Like 3], STMN 4 [Stamin-Like 4], STOML1 [Stomin (EPB72) -Like 1], STS [Steroid Sulfatase (Microsome), Isozyme S], STUB1 [STIP1 Homologous and U-box containing Protein 1] , STX1A [synthacin 1A (brain)], STX3 [synthacin 3], STYX [serine / threonine / tyrosine interacting protein], SUFU [inhibitor of fused homologue (Drosophila)], SULT2A1 [sulfotransferase Family, cytosol, 2A, dehydroepiandrosterone (DHEA) -preferred, member 1], SUMO1 [mif two 3 homologues SMT3 inhibitor 1 (S. CERVISI)], SUMO3 [SMT3 Inhibitor 3 of mif 2 homolog 3 (S. Serbisier)], SUN1 [containing Sad1 and UNC84 domain 1], SUN2 [containing Sad1 and UNC84 domain 2], SUPT16H [ Ty 16 homolog inhibitors (S. cervici)], SUZ12P [zeste 12 homolog inhibitors], SV2A [synaptic vesicle glycoprotein 2A], SYK [spleen tyrosine kinase], SYN1 [synapsin I ], SYN2 [synapsin II], SYN3 [synapsin III], SYNGAP1 [synaptic Ras GTPase activating protein 1 homologue (rat)], SYNJ1 [synaptojanin 1], SYNPO2 [synaptopodin 2] , SYP [synaptophycin], SYT1 [synaptotamine I], TAC1 [tachikinin, precursor 1], TAC3 [tachikinin 3], TACR1 [tachikinin receptor 1], TAF1 [TAF1 RNA polymerase II, TATA box binding protein (TBP) -related factor, 250 kDa], TAF6 [TAF6 RNA polymerase II, TATA box binding protein (TBP) -related factor, 80 kDa], TAGAP [T-cell activating RhoGTPase activating protein], TAGLN [Transgelelin], TAGLN3 [transgelline 3], TAOK2 [TAO kinase 2], TAP1 [carrier 1, ATP-binding cassette, sub-family B (MDR / TAP)], TAP2 [carrier 2, ATP-binding cassette, sub-family B ( MDR / TAP)], TAPBP [TAP Binding Protein (tapasin)], TARDBP [TAR DNA Binding Protein], TARP [TCR Gamma Shift Reading Frame Protein], TAS2R1 [Taste Receptor, Type 2, Member 1], TAT [Tyrosine Aminotransferase], TBC1D4 [TBC1 Domain Family, Member 4], TBCB [Tublin Folding Qualifier B], TBCD [Tublin Folding Qualifier D], TBCE [Tublin Folding Qualifier E], TBL1Y [ Transducin (beta) -like 1, Y-linked], TBL2 [transducin (beta) -like 2], TBP [TATA box binding protein], TBPL2 [TATA box binding protein like 2], TBR1 [T-box, Brain, 1], TBX1 [T-box 1], TBX21 [T-box 21], TBXA2R [Tromboxane A2 Receptor], TBXAS1 [Tromboxane A Synthetase 1 (platelet)], TCEB3 [transcription prolongation factor B (SIII) ), Polypeptide 3 (110 kDa, eginin A)], TCF12 [transcription factor 1 2], TCF19 [transcription factor 19], TCF4 [transcription factor 4], TCF7 [transcription factor 7 (T-cell specific, HMG-box)], TCF7L2 [transcription factor 7-like 2 (T-cell specific, HMG-box)], TCHH [tricohalin], TCN1 [transcobalamine I (vitamin B12 binding protein, R binder family)], TCN2 [transcobalamine II; Macrocytic anemia], TCP1 [t-complex 1], TDO2 [tryptophan 2 [3-dioxygenase], TDRD3 [tudor domain containing 3], TEAD2 [TEA domain family member 2], TEAD4 [TEA domain Family member 4], TEK [TEK tyrosine kinase, endothelial], TERF1 [terminal small repeat repeat factor (NIMA-interacting) 1], TERF2 [terminal small repeat repeat factor 2], TERT [telomerase reverse transcriptase], TET2 [tet oncogene family member 2], TF [transferrin], TFAM [transcription factor A, mitochondria], TFAP2A [transcription factor AP-2 alpha (activating enhancer binding protein 2 alpha)], TFCP2 [transcription factor CP2] , TFF1 [Trefoil Factor 1], TFF2 [Trefoil Factor 2], TFF3 [Trefoil Factor 3 (Intestine)], TFPI [Tissue Factor Pathway Inhibitor (Lipoprotein-Related Coagulation Inhibitor)], TFPI2 [Tissue Factor Pathway Inhibitor 2 ], TFRC [transferrin receptor (p90, CD71)], TG [tyroglobulin], TGFA [transformation growth factor, alpha], TGFB1 [transformation growth Now, beta 1], TGFB1I1 [transforming growth factor beta 1 induced transcript 1], TGFB2 [transforming growth factor, beta 2], TGFB3 [transforming growth factor, beta 3], TGFBR1 [transforming growth factor, Beta receptor 1], TGFBR2 [transforming growth factor, beta receptor II (70/80 kDa)], TGFBR3 [transforming growth factor, beta receptor III], TGIF1 [TGFB-derived factor homeobox 1], TGM2 [trans Glutaminase 2 (C polypeptide, protein-glutamine-gamma-glutamyltransferase)], TH [tyrosine hydroxylase], THAP1 [containing THAP domain, apoptosis related protein 1], THBD [thrombomodule Lean], THBS1 [thrombospondin 1], THBS2 [thrombospondin 2], THBS4 [thrombospondin 4], THEM4 [thioesterase superfamily member 4], THPO [thrombopoetine], THRA [thyroid hormone Receptor, alpha (erythroblastic leukemia viral (v-erb-a) oncogene homologue, algae)], THY1 [Thy-1 cell surface antigen], TIAM1 [T-cell lymphoma invasion and metastasis 1], TIAM2 [T-cell lymphoma invasion and metastasis 2], TIMP1 [TIMP metalpeptidase inhibitor 1], TIMP2 [TIMP metalpeptidase inhibitor 2], TIMP3 [TIMP metal Peptidase Inhibitor 3], TINF2 [TERF1 (TRF1) -Interacting Nuclear Factor 2], TJP1 [Hard Binding Protein 1 (Jona Occidente 1)], TJP2 [Hard Binding Protein 2 (Zona Occidente 2)], TK1 [Thymidine Kinase 1, Soluble], TKT [Transketolase], TLE1 [split 1 (transducin-like enhancer of E (sp1) homologue, Drosophila)], TLR1 [toll-like receptor 1], TLR2 [toll-like receptor 2], TLR3 [toll-like receptor 3], TLR4 [toll-like receptor 4], TLR5 [toll-like receptor 5], TLR7 [toll-like receptor 7], TLR8 [toll-like receptor] 8], TLR9 [toll-like receptor 9], TLX3 [T-cell leukemia homeobox 3], TMEFF1 [EGF-like and transmembrane protein 1 with two follistatin-like domains], TMEM100 [membrane transmembrane protein] 100], TMEM216 [Membrane protein 216], TMEM50B [membrane protein 50B], TMEM67 [membrane protein 67], TMEM70 [membrane protein 70], TMEM87A [membrane protein 87A], TMOD2 [Trofomodulin 2 (neuron)], TMOD4 [Trofomodulin 4 (Muscle)], TMPRSS11A [membrane protease, serine 11A], TMPRSS15 [membrane protease, serine 15], TMPRSS2 [membrane protease, serine 2], TNC [tennasin C], TNF [ Tumor necrosis factor (TNF superfamily, member 2)], TNFAIP3 [tumor necrosis factor, alpha-induced protein 3], TNFRSF10A [tumor necrosis factor receptor superfamily, member 10a], TNFRSF10B [tumor necrosis factor receptor superfamily, member 10b], TNFRSF10C [tumor necrosis factor receptor superfamily, member 10c, decoy without intracellular domain], TNFRSF10D [tumor necrosis factor receptor superfamily, member 10d, decoy with truncated death domain], TNFRSF11B [tumor necrosis factor receptor Superfamily, Member 11b], TNFRSF18 [Tumor Masses Factor Receptor Superfamily, Member 18], TNFRSF19 [Tumor Necrosis Factor Receptor Superfamily, Member 19], TNFRSF1A [Tumor Necrosis Factor Receptor Superfamily, Member 1A], TNFRSF1B [Tumor Necrosis Factor Receptor Superfamily, Member 1B], TNFRSF25 [ Tumor necrosis factor receptor superfamily, member 25], TNFRSF8 [tumor necrosis factor receptor superfamily, member 8], TNFSF10 [tumor necrosis factor (ligand) superfamily, member 10], TNFSF11 [tumor necrosis factor (ligand) superfamily, Member 11], TNFSF13 [tumor necrosis factor (ligand) superfamily, member 13], TNFSF13B [tumor necrosis factor (ligand) superfamily, member 13b], TNFSF4 [tumor necrosis factor (ligand) superfamily, member 4], TNK2 [Tyrosine Kinase, Non-Receptor, 2], TNNI3 [Troponin I Type 3 (heart)], TNNT1 [Troponin T Type 1 (skeleton, slow)], TNNT2 [Troponin T Type 2 (heart)], TNR [Tenacin R (listritin, janusin)], TNS1 [Tensin 1], TNS3 [Tensin 3], TNXB [Tenacin XB], TOLLIP [toll interacting protein], TOP1 [Topoisomerase (DNA) I], TOP2A [Topoisomerase (DNA) II alpha 170kDa], TOP2B [Topoisomerase (DNA) II beta 180kDa], TOR1A [torsin family 1, member A (torsin A)], TP53 [tumor protein p53], TP53BP1 [tumor protein p53 binding protein 1], TP63 [tumor protein p63], TP73 [tumor protein p73], TPH1 [tryptophan hydroxylase 1], TPH2 [tryptophan hydroxylase 2], TPI1 [triozphosphate isomerase 1], TPO [thyroid peroxidase ], TPT1 [tumor protein, detoxically regulated 1], TPTE [membrane phosphatase with tensin homology], TRADD [TNFRSF1A involved through the killing domain], TRAF2 [TNF receptor-associated factor 2], TRAF3 [TNF Receptor-related factor 3], TRAF6 [TNF receptor-related factor 6], TRAP1 [TNF receptor-related protein 1], TREM1 [triggers expressed in myeloid cells ing) receptor 1], TRH [patric acid stimulating hormone-releasing hormone], TRIM21 [three-branched motif-containing 21], TRIM22 [three-branched motif-containing 22], TRIM26 [three-branched motif-containing 26], TRIM27 [three-partite motif-containing 27], TRIM50 [three-partite motif-containing 50], TRIO [triple functional domain (PTPRF interaction)], TRPA1 [transient receptor capable cation channel, subfamily A, member 1] , TRPC1 [Temporary Acceptable Cation Channel, Subfamily C, Member 1], TRPC5 [Temporary Acceptable Cation Channel, Subfamily C, Member 5], TRPC6 [Temporary Acceptable Cation Channel, Subfamily C, Member 6], TRPM1 [Temporary Acceptable Cation Channel, Subfamily M, Member 1], TRPV1 [Temporary Acceptable Cation Channel, Subfamily V, Member 1], TRPV2 [Temporary Acceptable Cation Channel, Subfamily V, Member 2], TRRAP Transform / transcription domain Related proteins], TSC1 [nodular sclerosis 1], TSC2 [nodular sclerosis 2], TSC22D3 [TSC22 domain family, member 3], TSG101 [tumor sensitive gene 101], TSHR [thyroid stimulating hormone receptor], TSN [transrin ( translin)], TSPAN12 [tetraspanin 12], TSPAN7 [tetraspanin 7], TSPO [potentiator protein (18kDa)], TTC3 [tetratricopeptide repeat domain 3], TTF1 [transcription termination factor, RNA polymerase I ], TTF2 [transcription termination factor, RNA polymerase II], TTN [titin], TTPA [tocopherol (alpha) transfer protein], TTR [transtyretin], TUB [tubby homologue (mouse)], TUBA1A [Tublin, Alpha 1a], TUBA1B [Tublin, Alpha 1b], TUBA1C [Tublin, Alpha 1c], TUBA3C [Tublin, Alpha 3c], TUBA3D [Tublin, Alpha 3d], TUBA4A [Tublin, Alpha 4a], TUBA8 [Tublin, Alpha 8], TUBB [Tublin, Beta], TUBB1 [Tublin, Beta 1], TUBB2A [Tublin, Beta 2A], TUBB2B [Tublin, Beta 2B], TUBB2C [Tubin Blin, Beta 2C], TUBB3 [ Tubulin, beta 3], TUBB4 [tubulin, beta 4], TUBB4Q [tubulin, beta polypeptide 4, member Q], TUBB6 [tubulin, beta 6], TUBGCP5 [tubulin, gamma complex related protein 5], TUFM [Tu Detoxification Factor, Mitochondria], TUSC3 [Tumor Inhibitor Candidate 3], TWIST1 [Twisted Homolog 1 (Drosophila)], TXN [Thioredoxin], TXNIP [Thioredoxin Interacting Protein], TXNRD1 [Tee Oredoxin reductase 1], TXNRD2 [thioredoxin reductase 2], TYK2 [tyrosine kinase 2], TYMP [thymidine phosphorylase], TYMS [thymidylate synthetase], TYR [tyrosinase (systemic albinism IA) )], TYRO3 [TYRO3 protein tyrosine kinase], TYROBP [TYRO protein tyrosine kinase binding protein], TYRP1 [tyrosinase-related protein 1], U2AF1 [U2 small nuclear RNA cofactor 1], UBA1 [ubiquitin-like variant activating enzyme 1], UBA52 [ubiquitin A-52 residue ribosomal protein fusion product 1], UBB [ubiquitin B], UBC [ Biquitin C], UBE2A [ubiquitin-conjugating enzyme E2A (RAD6 homologue)], UBE2C [ubiquitin-conjugating enzyme E2C], UBE2D2 [ubiquitin-conjugating enzyme E2D 2 (UBC4 / 5 homologue, yeast)], UBE2H [ubiquitin-conjugating enzyme E2H (UBC8 homologue, yeast)], UBE2I [ubiquitin-conjugating enzyme E2I (UBC9 homolog, yeast)], UBE3A [ubiquitin protein ligase E3A], UBL5 [ubiquitin-like 5 , UCHL1 [ubiquitin carboxyl-terminated esterase L1 (ubiquitin thiol esterase)], UCN [urocortin], UCP1 [unlinked protein 1 (mitochondria, proton carrier)], UCP2 [unlinked protein 2 (mitochondria) , Proton carrier)], UCP3 [unlinked protein 3 (mitochondria, proton carrier)], UGT1A1 [UDP glucuronosyltransferase 1 family, polypeptide A1], UGT1A3 [UDP glucuronosyltransferase 1 family, Polypeptide A3], ULK1 [unc-51-like kinase 1 (C. Elegans)], UNC5A [unc-5 homologue A (C. Elegans)], UNC5B [unc-5 homologue B (C. Elegans)], UNC5C [unc-5 homologue C (C. Elegans)], UNC5D [unc-5 homologue D (C. Elegans)], UNG [uracil-DNA glycosylase], UPF3B [UPF3 modulator of nonsense transcripts homologue B (yeast)], UPK3B [uroplakin 3B], UPP2 [uridine phosphorylase 2], UQCRC1 [ubiquinol-cytochrome c reductase core protein I], USF1 [upstream transcription factor 1], USF2 [upstream transcription factor 2, c-fos interaction], USH2A [Usher syndrome 2A (autosome recessive, Mild)], USP1 [ubiquitin specific peptidase 1], USP15 [ubiquitin specific peptidase 15], USP25 [ubiquitin specific peptidase 25], USP29 [ubiquitin specific peptidase 29] , USP33 [Ubiquitin Specific Peptidase 33], USP4 [Ubiquitin Specific Peptidase 4 (Proto-Tumogen)], USP5 [Ubiquitin Specific Peptidase 5 (isopeptidase T)], USP9X [Ubiquitin Specific peptidase 9, X-linked], USP9Y [ubiquitin specific peptidase 9, Y-linked], UTRN [eutropin], UXT [localized-expressed transcript], VAMP7 [vesicle-associated membrane Protein 7], VASP [vascular-stimulated phosphoprotein], VAV1 [vav 1 guanine nucleotide exchange factor], VAV2 [vav 2 guanine nucleotide exchange factor], VAX1 [abdominal anterior homeobox 1], VCAM1 [vascular cell Adhesion molecule 1], VCL [vinculin], VDAC1 [potential-dependent anion channel 1], VDAC2 [potential-dependent anion channel 2], VDR [vitamin D (1 [25-dihydroxyvitamin D3) receptor], VEGFA [Vascular endothelial growth factor A], VEGFB [vascular endothelial growth factor B], VEGFC [vascular endothelial growth factor C], VGF [VGF nerve growth factor inducible], VHL [von Hippel-Lindau tumor suppressor], VIM [non Mentin], VIP [vascular intestinal peptide], VIPR1 [vascular intestinal peptide receptor 1], VIPR2 [vascular intestinal peptide receptor 2], VKORC1 [vitamin K epoxide reductase complex, subunit 1], VLDLR [super low density Lipoprotein receptor], VPS29 [horror protein sorting 29 homologues (S. Servicier)], VSIG4 [containing V-set and immunoglobulin domain 4], VSX1 [visual system homeobox 1], VTN [Vitronectin], VWC2 [von Willebrand factor C domain containing 2], VWF [von Willebrand Factor], WAS [Wiskott-Aldrich syndrome (Eczema-thrombocytopenia)], WASF1 [WAS protein family, member 1], WASF2 [WAS protein family, member 2], WASL [Wiskott-Aldrich syndrome-like], WBSCR16 [Williams -Beuren syndrome chromosome part 16], WBSCR17 [Williams-Beuren syndrome chromosome part 17], WBSCR22 [Williams Beuren syndrome chromosome part 22], WBSCR27 [Williams Beuren syndrome chromosome part 27], WBSCR28 [Williams-Beuren syndrome chromosome part 28], WDR4 [WD repeat domain 4], WEE1 [WEE1 homologue (S. Pombe)], WHAMM [actin, Golgi and microtubule related WAS protein homologues], WIPF1 [WAS / WASL interacting protein family, member 1], WIPF3 [WAS / WASL Interacting Protein Family, Member 3], WNK3 [WNK Lysine Deficient Protein Kinase 3], WNT1 [Wingless-Type MMTV Integration Location Family, Member 1], WNT10A [Wingless-Type MMTV Integration Location Family, Member 10A], WNT10B [Wingless-Type MMTV Integration Location Family, Member 10B], WNT11 [Wingless-Type MMTV Unified Location Family, Member 11], WNT16 [Wingless-Type MMTV Integrated Location Family, Member 16], WNT2 [Wingless-Type MMTV Integrated Location Family Member 2], WNT2B [Wingless-Type MMTV Unified Location Family, Member 2B], WNT3 [Wingless-Type MMTV Unified Location Family, Member 3], WNT3A [Wingless-Type MMTV Unified Location Family, Member 3A], WNT4 [Wingless-Type MMTV Unified Location Family, Member 4], WNT5A [Wingless-Type MMTV Integration Location Family, Member 5A], WNT5B [Wingless-Type MMTV Integration Location Family, Member 5B], WNT6 [Wingless-Type MMTV Integration Location Family, Member 6], WNT7A [ Wingless-Type MMTV Integrated Position Family, Member 7A], WNT7B [Wingless-Type MMTV Sum Position Family, Member 7B], WNT8A [Wingless-Type MMTV Integration Location Family, Member 8A], WNT8B [Wingless-Type MMTV Integration Location Family, Member 8B], WNT9A [Wingless-Type MMTV Integration Location Family, Member 9A], WNT9B [Wingless-Type MMTV Integration Location Family, Member 9B], WRB [Tryptophan Rich Basic Protein], WRN [Werner Syndrome, RecQ Helicase-like], WT1 [Wilms Tumor 1], XBP1 [X-Box Binding protein 1], XCL1 [chemokine (C motif) ligand 1], XDH [xanthine dehydrogenase], XIAP [X-linked inhibitor of apoptosis], XIRP2 [xin actin-binding repeat containing 2], XPC [ Pigmentary Dermatosis, Complement Group C], XRCC1 [X-ray repair complement deficiency repair in Chinese hamster cells], XRCC5 [X-ray repair complement deficiency repair in Chinese hamster cells 5 (double-strand-gap recombination) )], XRCC6 [X-ray repair complementary deletion repair in Chinese hamster cells 6], XRN1 [5'-3 'exoribonuclease 1], YBX1 [Y Box Binding Protein 1], YWHAB [Tyrosine 3-Monooxygenase / Tryptophan 5-Monooxygenase Activating Protein, Beta Polypeptide], YWHAE [Tyrosine 3-Monooxygenase / Tryptophan 5- Monooxygenase activating protein, epsilon polypeptide], YWHAG [tyrosine 3-monooxygenase / tryptophan 5-monooxygenase activating protein, gamma polypeptide], YWHAQ [tyrosine 3-monooxygenase / tryptophan 5-monoocta Cagenase activating protein, theta polypeptide], YWHAZ [tyrosine 3-monooxygenase / tryptophan 5-monooxygenase activating protein, zeta polypeptide], ZAP70 [zeta-chain (TCR) related protein kinase 70kDa], ZBTB16 [zinc finger and BTB domain containing 16], ZBTB33 [zinc finger and BTB domain containing 33], ZC3H12A [zinc finger CCCH-type containing 12A], ZEB1 [zinc finger E-box binding homeobox 1], ZEB2 [zinc Finger E-box combination Homeobox 2], Z FP161 [Zinc finger protein 161 homologue (mouse)], ZFP36 [Zinc finger protein 36, C3H type, homologue (mouse)], ZFP42 [Zinc finger protein 42 homologue (mouse)], ZFP57 [Zinc finger protein 57 phase Fuselage (mouse)], ZFPM1 [zinc finger protein, multitype 1], ZFPM2 [zinc finger protein, multitype 2], ZFY [zinc finger protein, Y-linked], ZFYVE9 [zinc finger, 9 containing FYVE domain], ZIC1 [Zic Family Member 1 (odd-paired homologue, Drosophila)], ZIC2 [Zic Family Member 2 (odd-paired homologue, Drosophila)], ZIC3 [Zic Family Member 3 (odd-paired) Homologues, Drosophila)], ZMPSTE24 [zinc metalpeptidase (STE24 homologue, S. cervici)], ZNF148 [zinc finger protein 148], ZNF184 [zinc finger protein 184], ZNF225 [zinc finger protein 225] ZNF256 [Zinc Finger Protein 256], ZNF333 [Zinc Finger Protein 333], ZNF385B [Zinc Finger Protein 385B], ZNF44 [Zinc Finger Protein 44], ZN F521 [Zinc Finger Protein 521], ZNF673 [Zinc Finger Family Member 673], ZNF79 [Zinc Finger Protein 79], ZNF84 [Zinc Finger Protein 84], ZW10 [ZW10, Kinetochore Related, Homolog (Drosophila)], And ZYX [zyxin].

Preferred neurodevelopment genes are BMP4 (bone morphogenetic protein 4); CHRD (Cordin); NOG (noggin); WNT2 (wingless-type MMTV unified location family member 2); WNT2B (wingless-type MMTV unified location family, member 2B); WNT3A (wingless-type MMTV unified location family, member 3A); WNT4 (wingless-type MMTV unified location family, member 4); WNT5A (wingless-type MMTV unified location family, member 5A); WNT6 (wingless-type MMTV unified location family, member 6); WNT7B (wingless-type MMTV unified location family, member 7B); WNT8B (wingless-type MMTV unified location family, member 8B); WNT9A (wingless-type MMTV unified location family, member 9A); WNT9B (wingless-type MMTV unified location family, member 9B); WNT10A (wingless-type MMTV unified location family, member 10A); WNT10B (wingless-type MMTV unified location family, member 10B); WNT16 (wingless-type MMTV unified location family, member 16); OTX2 (orthodental homeobox 2); GBX2 (intestinal embryonic brain homeobox 2); FGF8 (fibroblast growth factor 8 (androgen-induced)); RELN (lyline); DAB1 (incapacitated homolog 1 (Drosophila)); POU4F1 (POU Class 4 Homeobox 1); And NUMB (numb homologues (Drosophila).

In certain embodiments, measurements commonly used for neurodevelopmental studies in animals created by the methods of the present invention can be used to study the effects of mutations and neural development and / or progression in animals.

iv . Cell function model

The methods of the invention can be used to create animals or cells that can be used as cell function models. This model can be used to study the effects of edited chromosomal sequences on cell function of interest. For example, cell function models can be used to study the effects of edited chromosomal sequences on intracellular or extracellular signaling. Alternatively, cell functional models can be used to study the effects of edited chromosomal sequences on sensory perception.

In one embodiment, the methods of the present invention can be used to create an animal or cell comprising chromosomal editing in one or more chromosomal sequences associated with signaling biochemical pathways. Non-limiting examples of nucleic acid sequences associated with suitable pathways are listed in Table C.

Alternatively, the methods of the invention can be used to create an animal or cell comprising chromosomal editing in one or more nucleic acid sequences related to cellular function. By way of non-limiting example, chromosomal editing can be made in sequences related to cognition, nociception, taste, and AB carriers, each described below.

A. Awareness

In one embodiment, the methods of the invention can be used to create an animal or cell in which at least one chromosomal sequence related to cognition has been edited. Suitable chromosomal editing includes, but is not limited to, the type of editing described in paragraph I (f) above.

In the foregoing embodiments, the chromosomal sequence associated with cognition may encode a cognitive-related protein or may be a reference sequence. Cognitive-related proteins are a diverse series of proteins that are sensitive to the development of cognitive impairment, the presence of cognitive impairment, the severity of cognitive impairment, or any combination thereof.

 Non-limiting examples of cognitive impairment include Alzheimer's; Mental retardation; Rett syndrome; Brittle X syndrome; Mood disorders such as major depressive disorder, unipolar disorder, manic, dysphoria, bipolar disorder, dysthymia, and circulatory mood disorder; Psychiatric disorders such as schizophrenia, schizoaffective disorders, schizophrenic disorders, delusional disorders, simple psychotic disorders, substance-induced psychotic disorders, and shared psychotic disorders; Personality disorders such as borderline personality disorder and dissociative identity disorder; Anxiety disorders such as generalized anxiety disorder and obsessive compulsive disorder; Childhood disorders; Dementia, such as HIV-related dementia (HAD) and multiple infarction dementia; Autistic disorder; Adaptive disorders; Delirium; Tourette disorders; Attention deficit disorder; And post-traumatic stress disorder.

Cognitive-related proteins or regulatory sequences may typically be selected based on experimental association of cognitive-related sequences for cognitive impairment. The production rate or circulating concentration of cognitive-related proteins may be elevated or suppressed in populations with cognitive impairment as compared to the population without cognitive impairment. Differences in protein levels can be assessed using proteomic or genomic analysis techniques known in the art.

Non-limiting examples of cognitive-related proteins include A2M (alpha-2-macroglobulin), AATF (apoptosis antagonistic transcription factor), ACPP (acid phosphatase prostate), ACTA2 (actin alpha 2 smooth muscle aorta), ADAM22 ( ADAM metalpeptidase domain), ADORA3 (adenosine A3 receptor), ADRA1D (alpha-1D adrenergic receptor for alpha-1D adrenoceptor), AHSG (alpha-2-HS-glycoprotein), AIF1 (allograft inflammation Factor 1), ALAS2 (delta-aminolevulinate synthetase 2), AMBP (alpha-1-microglobulin / bikunin precursor), ANK3 (Ankryn 3), ANXA3 (annexin A3), APCS (amyloid P component Serum), APOA1 (apopolipoprotein A1), APOA12 (apopolipoprotein A2), APOB (apopolipoprotein B), APOC1 (apopolipoprotein C1), APOE (apopolipoprotein E), APOH (apopolipoprotein H) , APP (amyloid precursor protein), ARC (activity-regulated cytoskeleton-associated protein), ARF6 (ADP-ribosyl Factor 6), ARHGAP5 (Rho GTPase activating protein 5), ASCL1 (Achaete-scute homologue 1), B2M (beta-2 microglobulin), B4GALNT1 (beta-1,4-N-acetyl-galactosaminyl transferase 1), BAX (Bcl-2-associated X protein), BCAT (branched chain amino-acid transaminase 1 cytosol), BCKDHA (branched chain keto acid dehydrogenase E1 alpha), BCKDK (branched Chain alpha-ketosan dehydrogenase kinase), BCL2 (B-cell lymphoma 2), BCL2L1 (BCL2-like 1), BDNF (brain-derived neurotrophic factor), BHLHE40 (class E basic helix-loop-helix protein 40 ), BHLHE41 (Class E basic helix-loop-helix protein 41), BMP2 (bone forming protein 2A), BMP3 (bone forming protein 3), BMP5 (bone forming protein 5), BRD1 (bromodomain containing 1), BTC (Betacellulline), BTNL8 (butyrophylline-like protein 8), CALB1 (calvindine 1), CALM1 (calmodulin 1), CAMK1 (calcium / calmodulin-dependent protein kinase type I), CAMK4 (calcium Calmo Lean-dependent protein kinase type IV), CAMKIIB (calcium / calmodulin-dependent protein kinase type IIB), CAMKIIG (calcium / calmodulin-dependent protein kinase type IIG), CASP11 (caspase-10), CASP8 (caspa Eighth apoptosis-related cysteine peptidase), CBLN1 (cecetrin 1 precursor), CCL2 (chemokine (CC motif) ligand 2), CCL22 (chemokine (CC motif) ligand 22), CCL3 (chemokine (CC motif) ligand 3), CCL8 (chemokine (CC motif) ligand 8), CCNG1 (cyclin-G1), CCNT2 (cyclin T2), CCR4 (CC chemokine receptor type 4 (CD194)), CD58 (CD58) , CD59 (protectin), CD5L (CD5 antigen-like), CD93 (CD93), CDKN2AIP (CDKN2A interacting protein), CDKN2B (cyclin-dependent kinase inhibitor 2B), CDX1 (homeobox protein CDX-1), CEA (Carcinogenic antigen), CEBPA (CCAAT / enhancer-binding protein alpha), CEBPB (CCAAT / enhancer-binding protein C / EBP beta), CEBPB (CCAAT / enhancer-binding protein beta ), CEBPD (CCAAT / enhancer-binding protein delta), CEBPG (CCAAT / enhancer-binding protein gamma), CENPB (centromeric protein B), CGA (glycoprotein hormone alpha chain), CGGBP1 (CGG triple repeat-binding) Protein 1), CHGA (Chromogranin A), CHGB (Secretinulin), CHN2 (Beta-chimaerin), CHRD (Cordin), CHRM1 (cholinergic receptor muscarinic 1), CITED2 (Cbp / p300-interacting transactivator 2), CLEC4E (C-type lectin domain family 4 member E), CMTM2 (CKLF-like MARVEL transmembrane domain-containing protein 2), CNTN1 (contactin 1), CNTNAP1 ( Contactin-related protein-like 1), CR1 (erythrocyte complement receptor 1), CREM (cAMP-responsive element modulator), CRH (adrenal cortical stimulating hormone-releasing hormone), CRHR1 (adrenal cortical stimulating hormone releasing hormone receptor 1) , CRKRS (cell division cycle 2-related protein kinase 7), CSDA (DNA-binding protein A), CSF3 (granulocyte colony stimulating factor 3), CSF3R (granulocyte colony-stimulation 3 receptor), CSP (chemosensory protein), CSPG4 (chondroitin sulfate proteoglycan 4), CTCF (CCCTC-binding factor zinc finger protein), CTGF (connective tissue growth factor), CXCL12 (chemokine CXC motif ligand 12), DAD1 (Defender 1 against cell death), DAXX (killing related protein 6), DBN1 (brebrin 1), DBP (D site of albumin promoter-albumin D-box binding protein), DDR1 (discoidin domain receptor family member 1 ), DDX14 (DEAD / DEAH box helicase), DEFA3 (defensin alpha 3 neutrophil-specific), DVL3 (scattered dsh homolog 3), EDN1 (endoterin 1), EDNRA (endoterin receptor type A), EGF (Epithelial growth factor), EGFR (epithelial growth factor receptor), EGR1 (initial growth response protein 1), EGR2 (initial growth response protein 2), EGR3 (initial growth response protein 3), EIF2AK2 (eukaryotic translation initiation factor 2- Alpha kinase 2), ELINE (elastase neutrophil expressed), ELK1 (ETS tumor ELK1 member of the former family), ELK3 (ELK3 ETS-domain protein (SRF accessory protein 2)), EML2 (epidermal microtubule related protein-like 2), EPHA4 (EPH receptor A4), ERBB2 (V-erb-b2 erythrocytes) Leukemia viral oncogene homolog 2), ERBB3 (receptor tyrosine-protein kinase erbB-3), ESR2 (estrogen receptor 2), ESR2 (estrogen receptor 2), ETS1 (V-ets erythropoietic virus E26 oncogene homologue 1 ), ETV6 (Ets variant 6), FASLG (Fas ligand TNF superfamily member 6), FCAR (Fc fragment of IgA receptor), FCER1G (Fc fragment of IgE high affinity I receptor for gamma polypeptide), FCGR2A (IgG low affinity) Fc fragment of IIa receptor-CD32), FCGR3B (Fc fragment for IgG low affinity IIIb receptor-CD16b), FCGRT (Fc fragment of IgG receptor carrying alpha), FGA (basic fibrinogen), FGF1 (acidic fibroblast growth factor 1) , FGF14 (fibroblast growth factor 14), FGF16 (fibroblast Intestinal factor 16), FGF18 (fibroblast growth factor 18), FGF2 (basic fibroblast growth factor 2), FIBP (acidic fibroblast growth factor intracellular binding protein), FIGF (C-fos induced growth factor), FMR1 ( Fragile X mental retardation 1), FOSB (FBJ murine osteosarcoma viral oncogene homologue B), FOXO1 (forkhead box O1), FSHB (follicle stimulating hormone beta polypeptide), FTH1 (polypeptide in ferritin), FTL ( Ferritin light polypeptide), G1P3 (interferon alpha-induced protein 6), G6S (N-acetylglucosamine-6-sulfatase), GABRA2 (gamma-aminobutyl acid A receptor alpha 2), GABRA3 (gamma- Aminobutyl acid A receptor alpha 3), GABRA4 (gamma-aminobutyl acid A receptor alpha 4), GABRB1 (gamma-aminobutyl acid A receptor beta 1), GABRG1 (gamma-aminobutyl acid A receptor gamma 1), GADD45A ( Growth inhibition and DNA-damaging-inducing alpha), GCLC (glutamate-cysteine ligase) Catalytic subunits), GDF15 (growth differentiation factor 15), GDF9 (growth differentiation factor 9), GFRA1 (GDNF family receptor alpha 1), GIT1 (G protein-linked receptor kinase interactor 1), GNA13 (guanine nucleotide-binding protein / G protein alpha 13), GNAQ (guanine nucleotide binding protein / G protein q polypeptide), GPR12 (G protein-linked receptor 12), GPR18 (G protein-linked receptor 18), GPR22 (G protein-linked receptor 22), GPR26 (G protein-linked receptor 26), GPR27 (G protein-linked receptor 27), GPR77 (G protein-linked receptor 77), GPR85 (G protein-linked receptor 85), GRB2 (growth factor receptor-linked protein 2 ), GRLF1 (glucocorticoid receptor DNA binding factor 1), GST (glutathione S-transferase), GTF2B (universal transcription factor IIB), GZMB (Granzyme B), HAND1 (heart and neural toxin inducer 1) , HAVCR1 (Hepatitis A Virus Cell Receptor 1), HES1 (spl parent and enhancer 1) of it, HES5 (parent and enhancer of split 5), HLA-DQA1 (major histocompatibility complex classification II DQ alpha), HOXA2 (homeobox A2), HOXA4 (homeobox A4), HP (haptoglobin), HPGDS (prostaglandin-D synthetase), HSPA8 (heat shock 70 kDa protein 8), HTR1A (5-hydroxytrytamine receptor 1A), HTR2A (5-hydroxytrytamine receptor 2A), HTR3A (5-hydroxytrytamine receptor 3A), ICAM1 (intercellular adhesion molecule 1 (CD54)), IFIT2 (interferon-derived protein with tetratricopeptide repeat 2), IFNAR2 (interferon alpha / beta / omega receptor 2) , IGF1 (insulin-like growth factor 1), IGF2 (insulin-like growth factor 2), IGFBP2 (insulin-like growth factor binding protein 2, 36kDa), IGFBP7 (insulin-like growth factor binding protein 7), IL10 (interleukin) 10), IL10RA (interleukin 10 receptor alpha), IL11 (interleukin 11), IL11RA (interleukin 11 receptor alpha), IL11RB (interleukin) 11 receptor beta), IL13 (interleukin 13), IL15 (interleukin 15), IL17A (interleukin 17A), IL17RB (interleukin 17 receptor B), IL18 (interleukin 18), IL18RAP (interleukin 18 receptor accessory protein), IL1R2 (interleukin 1 Receptor type II), IL1RN (interleukin 1 receptor antagonist), IL2RA (interleukin 2 receptor alpha), IL4R (interleukin 4 receptor), IL6 (interleukin 6), IL6R (interleukin 6 receptor), IL7 (interleukin 7), IL8 (interleukin) 8), IL8RA (interleukin 8 receptor alpha), IL8RB (interleukin 8 receptor beta), ILK (integrin-linked kinase), INPP4A (inositol polyphosphate-4-phosphatase type I, 107 kDa), INPP4B (inositol polyphosphate-4-) Phosphatase type I beta), INS (insulin), IRF2 (interferon modulator 2), IRF3 (interferon modulator 3), IRF9 (interferon modulator 9), IRS1 (insulin receptor substrate 1), ITGA4 (integrin alpha 4), ITGA6 (Integrin Alpha-6), ITGAE (Integrin Alpha E) , ITGAV (integrin alpha-V), JAG1 (Jagged 1), JAK1 (Janus kinase 1), JDP2 (Jun dimerization protein 2), JUN (Jun oncogene), JUNB (Jun B proto-oncogene), KCNJ15 ( Potassium inward-rectifying channel subfamily J member 15), KIF5B (kinesin family member 5B), KLRC4 (killer cell lectin-like receptor subfamily C member 4), KRT8 (keratin 8), LAMP2 (lysosomal-associated membrane Protein 2), LEP (leptin), LHB (luteinizing hormone beta polypeptide), LRRN3 (leucine rich repeat neuron 3), MAL (Mal T-cell differentiation protein), MAN1A1 (mannosidase alpha class 1A member 1), MAOB (monoamine oxidase B), MAP3K1 (mitogen-activated protein kinase kinase 1), MAPK1 (mitogen-activated protein kinase 1), MAPK3 (mitogen-activated protein kinase 3), MAPRE2 (microparticles) Vascular-associated protein RP / EB family member 2), MARCKS (myristoylated alanine-rich protein kinase C substrate), MAS1 (MAS1 oncogene), MASL1 (MAS1 oncogene-like), MBP (myelin basic protein), MCL1 (myeloid cell leukemia sequence 1), MDMX (MDM2-like p53-binding protein), MECP2 (methyl CpG binding protein 2) , MFGE8 (milk fat sphere-EGF factor 8 protein), MIF (macrophage transfer inhibitory factor), MMP2 (matrix metalpeptidase 2), MOBP (myelin-associated oligodendrocyte basic protein), MUC16 (cancer antigen 125 ), MX2 (myxovirus (influenza virus) resistant 2), MYBBP1A (MYB binding protein 1a), NBN (nibrine), NCAM1 (nerve cell adhesion molecule 1), NCF4 (neutrophil cytosol factor 4 40kDa), NCOA1 (nucleus Receptor co-activator 1), NCOA2 (nuclear receptor co-activator 2), NEDD9 (neural precursor cell-expressed embryologically down-regulated 9), NEUR (neuraminidase), NFATC1 (activated T-cells Nuclear factor calcineurin-dependent1), NFE2L2 (red blood cell-derived two-like nuclear factor 2), NFI C (nuclear factor I / C), NFKBIA (nuclear factor inhibitor alpha of the kappa light polypeptide gene enhancer in B-cells), NGFR (nerve growth factor receptor), NIACR2 (niacin receptor 2), NLGN3 (new Lorigin 3), NPFFR2 (neuropeptide FF receptor 2), NPY (neuropeptide Y), NR3C2 (nuclear receptor subfamily 3 group C member 2), NRAS (neoblastoma RAS viral (v-ras) oncogene homologues ), NRCAM (neuronal cell adhesion molecule), NRG1 (neuregulin 1), NRTN (neuturulin), NRXN1 (neulexin 1), NSMAF (neutral sphingomyelin activation factor), NTF3 (neutropin 3), NTF5 (neutropin 4/5), ODC1 (ornithine decarboxylase 1), OR10A1 (olfactory receptor 10A1), OR1A1 (olfactory receptor family 1 subfamily A member 1), OR1N1 (olfactory receptor family 1 subfamily N member 1), OR3A2 (olfactory receptor family 3 subfamily A member 2), OR7A17 (olfactory receptor family 7 subfamily A member 1 7), ORM1 (orthomucoid 1), OXTR (oxytocin receptor), P2RY13 (purinactin receptor P2Y G-protein linked 13), P2Y12 (purinactin receptor P2Y G-protein linked 12), P70S6K (P70S6 kinase ), PAK1 (P21 / Cdc42 / Rac1-activated kinase 1), PAR1 (Prader-Willi / Angelman part-1), PBEF1 (Pre-B-cell colony enhancing factor 1), PCAF (P300 / CBP-related factor) , PDE4A (cAMP-specific 3 ′, 5′-cycle phosphodiesterase 4A), PDE4B (phosphodiesterase 4B cAMP-specific), PDE4B (phosphodiesterase 4B cAMP-specific), PDE4D (phosphodiesterase 4D cAMP-specific), PDGFA (platelet-derived growth factor alpha polypeptide), PDGFB (platelet-derived growth factor beta polypeptide), PDGFC (platelet induced growth factor C), PDGFRB ( Beta-type platelet-induced growth factor receptor), PDPN (grapeplanin), PENK (enkephalin), PER1 (period homolog 1), PLA2 (phospholipase A2), PLAU (plasma Nogen activator urokinase), PLXNC1 (flexin C1), PMVK (phosphomevalonate kinase), PNOC (prepronociceptin), POLH (polymerase (DNA oriented) eta), POMC (propiomelanocorre) Tin (adrenovusine cortical stimulating hormone / beta-lipotropin / alpha-melanocyte stimulating hormone / beta-melanocyte stimulating hormone / beta-endorphin)), POU2AF1 (POU domain class 2 association factor 1), PRKAA1 (5 ' -AMP-activated protein kinase-catalyzed subunit alpha-1), PRL (prolactin), PSCDBP (cytohesine 1 interacting protein), PSPN (percepin), PTAFR (platelet-activating factor receptor), PTGS2 (prostaglandin-an Dopeoxide synthase 2), PTN (pleotropin), PTPN11 (protein tyrosine phosphatase non-receptor type 11), PYY (peptide YY), RAB11B (RAB11B member RAS oncogene family), RAB6A (RAB6A member RAS tumor Gene family), RAD17 (RAD17 homologue), RAF1 (RAF proto-tumor gene Serine / threonine-protein kinase), RANBP2 (RAN binding protein 2), RAP1A (RAP1A member of the RAS oncogene family), RB1 (retinoblastoma 1), RBL2 (retinoblastoma-like 2 (p130)), RCVRN (recoverin) ), REM2 (RAS / RAD / GEM-like GTP binding 2), RFRP (RFamide-related peptide), RPS6KA3 (ribosome protein S6 kinase 90kDa polypeptide 3), RTN4 (Reticulon 4), RUNX1 (Runt-related transcription factor) 1), S100A4 (S100 Calcium Binding Protein A4), S1PR1 (Shippingosine-1-phosphate Receptor 1), SCG2 (Secretogenin II), SCYE1 (Small Inducible Cytokine Subfamily E Member 1), SELENBP1 (Selenium Binding Protein 1), SGK (serum / glucocorticoid regulated kinase), SKD1 (inhibitor of K + carrier growth deficiency 1), SLC14A1 (solute carrier family 14 (urea transport) member 1 (Kidd blood group)), SLC25A37 (solute carrier Family 25 member 37), SMAD2 (SMAD family member 2), SMAD5 (SMAD family member 5), SNAP23 (synaptosome-related White matter 23kDa), SNCB (synuclein beta), SNF1LK (SNF1-like kinase), SORT1 (Sortiline 1), SSB (Sjogren Syndrome Antigen B), STAT1 (Signal Transducer and Activator of Transcription 1, 91kDa), STAT5A ( Signal transducer and activator 5A of transcription, STAT5B (signal transducer and activator 5B of transcription), STX16 (synthacin 16), TAC1 (tachikinin precursor 1), TBX1 (T-box 1), TEF (thyroid gland) Stimulating embryonic factor), TF (transferrin), TGFA (transforming growth factor alpha), TGFB1 (transforming growth factor beta 1), TGFB2 (transforming growth factor beta 2), TGFB3 (transforming growth factor beta 3), TGFBR1 (transforming growth factor beta receptor I), TGM2 (transglutaminase 2), THPO (thrombopoetine), TIMP1 (TIMP metalpeptidase inhibitor 1), TIMP3 (TIMP metalpeptidase inhibitor 3), TMEM129 (membrane protein 129), TNFRC6 (TNFR / NGFR cysteine-rich portion), TNFRSF10A (tumor necrosis factor receptor superfamily member 10a), TNFRSF1 0C (tumor necrosis factor receptor superfamily member 10c decoy without intracellular domain), TNFRSF1A (tumor necrosis factor receptor superfamily member 1A), TOB2 (transducer 2 of ERBB2), TOP1 (topoisomemerase (DNA) I), TOPOII (Topoisomerase 2), TRAK2 (trafficking protein kinesin binding 2), TRH (patric acid stimulating hormone-releasing hormone), TSH (thyroid-stimulating hormone alpha), TUBA1A (tubulin alpha 1a), TXK (TXK tyrosine kinase), TYK2 (tyrosine kinase 2), UCP1 (unlinked protein 1), UCP2 (unlinked protein 2), ULIP (Unc-33-like phosphoprotein), UTRN (eutropin), VEGF (vascular) Endothelial growth factor), VGF (VGF nerve growth factor inducible), VIP (vascular intestinal peptide), VNN1 (vanin 1), VTN (Vitronectin), WNT2 (wingless-type MMTV integration site family member 2), XRCC6 (X-ray repair cross-complement 6), ZEB2 (zinc finger E-box binding homeobox 2), and ZNF461 (zinc finger protein 461) The.

Typical cognitive-related proteins include ANK3 (Ankryn 3), APP (amyloid precursor protein), B2M (beta-2 microglobulin), BRD1 (bromodomain containing 1), FMR1 (fragile X mental retardation) 1), MECP2 (methyl CpG binding protein 2), NGFR (nerve growth factor receptor), NLGN3 (neuroligin 3), NRXN1 (neulexin 1), and any combination thereof.

In certain embodiments, animals created by the methods of the present invention can be used to study mutagenic effects in animals and mutant effects in cognition.

B. Pain Perception and Taste

Sensory-related chromosomal sequences include but are not limited to nociceptive-related genes, pain-related genes, and taste-related genes. In one embodiment, the methods of the present invention can create an animal or cell in which at least one chromosomal sequence is associated with a sensory process. Suitable chromosomal editing includes, but is not limited to, the type of editing described in paragraph I (f) above.

Sensory-related chromosomal sequences may be involved in the process of receiving and responding to nocioception or detrimental stimuli. Non-limiting examples of nociceptive-related chromosomal sequences include CALCA (calcitonin-associated polypeptide alpha); FOS (FBJ murine osteosarcoma viral oncogene homolog); NPY (neural peptide Y); TACR1 (tachikinin receptor 1); OPRM1 (opium receptor mu 1); OPRD1 (opium receptor delta 1); OPRK1 (opium receptor kappa 1); TH (tyrosine hydroxylase); DRD2 (dopamine receptor D2); PTGS2 (prostaglandin-andopeoxide synthase 2 (prostaglandin G / H synthase and cyclooxygenase)); TNF (tumor necrosis factor (TNF superfamily member 2)); PDYN (prodinolpin); KNG1 (kinnogen 1); CCK (cholecystokinin); NOS1 (nitric oxide synthase 1 (neurons)); IL1B (interleukin 1 beta); SST (somatostatin); HTR3A (5-hydroxytryptamine (serotonin) receptor 3A); MAPK1 (mitogen-activated protein kinase 1); GAL (galanine prepropeptide); DYT10 (10 strains); TRPV1 (temporary receptor capable cation channel subfamily V member 1); IL6 (interleukin 6 (interferon beta 2)); HTR2A (5-hydroxytryptamine (serotonin) receptor 2A); CNR1 (cannabinoid receptor 1 (brain)); NOS2 (nitric oxide synthase 2 inducible); PNOC (prepronociceptin); NTS (neurotensin); PTGS1 (prostaglandin-andopeoxide synthase 1 (prostaglandin G / H synthase and cyclooxygenase)); ACHE (acetylcholinesterase (Yt blood group)); NGF (nerve growth factor (beta polypeptide)); CCKBR (cholekistokinin B receptor); HTR1A (5-hydroxytryptamine (serotonin) receptor 1A); NPFF (neuropeptide FF-amide peptide precursor); CCL2 (chemokine (C-C motif) ligand 2); CAT (catalase); BDNF (brain-induced neurotrophic factor); ADORA1 (adenosine A1 receptor); NPR1 (sodium release peptide receptor A / guanylate cyclase A (atrial sodium release peptide receptor A)); GRP (gastrin-releasing peptide); MME (membrane metal-endopeptidase); ABCB1 (ATP-binding cassette sub-family B (MDR / TAP) member 1); PENK (proenkephalin); TAC1 (tachikinin precursor 1); INS (insulin); NTRK1 (neopositive tyrosine kinase receptor type 1); SCN9A (sodium channel translocation-gated type IX alpha subunit); BCHE (butyrylcholinesterase); GALR2 (galanine receptor 2); ADCYAP1 (adenylate cyclase activating polypeptide 1 (pituitary)); HRH2 (histamine receptor H2); OXT (oxytocin prepropeptide); POMC (propiomelanocortin); ADORA2A (adenosine A2a receptor); CPOX (copropofyrronogen oxidase); NTSR2 (neurotensin receptor 2); SLC1A2 (solute carrier family 1 (glue high affinity glutamate transport) member 2); OPRL1 (Opiate Receptor-Like 1); GALR1 (galanine receptor 1); DDC (dopa decarboxylase (aromatic L-amino acid decarboxylase)); P2RX2 (purinergic receptor P2X ligand-gated ion channel 2); HMOX1 (ham oxygenase (decycling) 1); CNR2 (cannabinoid receptor 2 (macrophages)); HTR1B (5-hydroxytryptamine (serotonin) receptor 1B); HRH1 (histamine receptor H1); ADRA2A (adrenergic alpha-2A-receptor); GALR3 (galanine receptor 3); KCND1 (potassium potential-gated channel Shal-related subfamily member 1); PRL (prolactin); IFNG (interferon gamma); GABBR1 (gamma-aminobutyl acid (GABA) B receptor 1); IL10 (interleukin 10); VWF (factor von Willebrand); GPT (glutamine-pyruvate transaminase (alanine aminotransferase)); CSF3 (colony stimulating factor 3 (granulocytes)); IL2 (interleukin 2); IFNA1 (interferon alpha 1); PROK1 (Prokineticin 1); HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase); JUN (jun oncogene); NPPA (sodium release peptide precursor A); ADCY10 (adenylate cyclase 10 (soluble)); IL4 (interleukin 4); MAPK14 (mitogen-activated protein kinase 14); ADA (adenosine deaminase); TGFB1 (morphological growth factor beta 1); MAPK8 (mitogen-activated protein kinase 8); EDNRB (endotherin receptor type B); AKR1B1 (Aldo-keto reductase family 1 member B1 (Aldose Reductase)); NOS3 (nitric oxide synthase 3 (endothelial cells)); GABRE (gamma-aminobutyl acid (GABA) A receptor epsilon); KCNJ5 (potassium inward-rectifying channel subfamily J member 5); EPHX2 (epoxide hydrolase 2 cytoplasm); EDNRA (endoterin receptor type A); NTSR1 (neurotensin receptor 1 (high affinity)); IL13 (interleukin 13); EDN3 (endoterin 3); CRH (Adrenal Cortical Stimulating Hormone-releasing Hormone); PPARA (peroxysome proliferator-activated receptor alpha); CCKAR (cholekistokinin A receptor); FAAH (fatty acid amide hydrolase); EDN1 (endoterin 1); CABIN1 (calcineurin binding protein 1); NTRK3 (neopositive tyrosine kinase receptor type 3); NTF3 (neutropin 3); PL-5283 (PL-5283 protein); APC (polyp colonic polyps); DBH (dopamine beta-hydroxylase (dopamine beta-monooxygenase)); SYP (synaptophycin); SLC8A1 (solute carrier family 8 (sodium / calcium exchanger) member 1); CHRNA4 (cholinergic receptor nicotinic alpha 4); TRPA1 (transitory receptor capable cation channel subfamily A member 1); CYBB (cytochrome b-245 beta polypeptide); RAC1 (ras-associated C3 botulinum toxin substrate 1 (rho family small GTP binding protein Rac1)); IDS (iduronate 2-sulfatase); LTF (lactotransferrin); TRPM8 (transitory receptor capable cation channel subfamily M member 8); MRGPRX3 (MAS-related GPR member X3); CCR5 (chemokine (C-C motif) receptor 5); CCL5 (chemokine (C-C motif) ligand 5); MBL2 (mannose-binding lectin (protein C) 2 soluble (opsonine deficiency)); P2RX3 (purinergic receptor P2X ligand-gated ion channel 3); MRGPRX2 (MAS-related GPR member X2); FAM134B (family B with sequence similarity 134 member); IL8 (interleukin 8); NTRK2 (neopositive tyrosine kinase receptor type 2); GJA1 (gap binding protein alpha 1 43kDa); CACNA1H (calcium channel potential-dependent T type alpha 1H subunit); HDC (histidine decarboxylase); IFT88 (intraflagellar transport 88 homologue (Chlamydomonas)); POU4F3 (POU Class 4 Homeobox 3); ATOH1 (Azo homolog 1 (Drosophila)); GRM3 (glutamate receptor metabotropic 3); ADK (adenosine kinase); RIPK2 (receptor-interacting serine-threonine kinase 2); ANPEP (alanyl (membrane) aminopeptidase); DRD1 (dopamine receptor D1); NFE2L2 (nuclear factor (erythrocyte-derived 2) -like 2); RET (ret proto-tumor gene); AHSP (alpha hemoglobin stabilizing protein); ESR2 (estrogen receptor 2 (ER beta)); HLA-A (major histocompatibility complex class I A); CHRM2 (cholinergic receptor muscarinic 2); ALAD (aminolevulinate delta-dehydratase); CXCL2 (chemokine (C-X-C motif) ligand 2); HSPG2 (heparan sulfate proteoglycan 2); F2R (coagulation factor II (thrombin) receptor); KCNIP3 (Kv channel interacting protein 3 calsenilin); GRIN1 (glutamate receptor ionic N-methyl D-aspartate 1); GRIK1 (glutamate receptor ionic kinate 1); P2RX7 (purinergic receptor P2X ligand-gated ion channel 7); CACNA1B (calcium channel potential-dependent N type alpha 1B subunit); TACR2 (tachikinin receptor 2); NPFFR2 (neuropeptide FF receptor 2); MRGPRX1 (MAS-related GPR member X1); MRGPRX4 (MAS-related GPR member X4); PTH2 (parathyroid hormone 2); DRGX (back root ganglion homeobox); CCR3 (chemokine (C-C motif) receptor 3); CYBA (cytochrome b-245 alpha polypeptide); CCL7 (chemokine (C-C motif) ligand 7); S100A6 (S100 calcium binding protein A6); CHGA (chromogranin A (parathyroid secretion protein 1)); CCL4 (chemokine (C-C motif) ligand 4); HTR5A (5-hydroxytryptamine (serotonin) receptor 5A); KCNC3 (potassium potential-gated channel Shaw-associated subfamily member 3); PNMT (phenylethanolamine N-methyltransferase); CCL8 (chemokine (C-C motif) ligand 8); LTB4R (leukotriene B4 receptor); NOXA1 (NADPH oxidase activator 1); PHOX2B (paired-like homeobox 2b); NOX1 (NADPH oxidase 1); NOX4 (NADPH oxidase 4); TAS1R3 (taste receptor type 1 member 3); NEUROG1 (neurogene 1); NOXO1 (NADPH oxidase tissue 1); TRIM26 (three-branched motif-containing 26); OMP (olfactory marker protein); ZC3H12A (zinc finger CCCH-type containing 12A); CXCR4 (chemokine (C-X-C motif) receptor 4); PLA2G2A (phospholipase A2 group IIA (platelet synovial fluid)); PLA2G1B (phospholipase A2 group IB (pancreas)); GNRH1 (gonadotropin-releasing hormone 1 (luteinated-releasing hormone)); TJP1 (Solid Binding Protein 1 (Zona Occlusion) 1); NRG1 (neuregulin 1); GRIN2B (glutamate receptor ionic N-methyl D-aspartate 2B); COL18A1 (collagen type XVIII alpha 1); HTR6 (5-hydroxytryptamine (serotonin) receptor 6); HTR7 (5-hydroxytryptamine (serotonin) receptor 7 (adenylate cyclase-linked)); SLC1A3 (solute carrier family 1 (glue high affinity glutamate transport) member 3); CACNA1D (calcium channel potential-dependent L type alpha 1D subunit); GRM2 (glutamate receptor metabotropic 2); HNMT (histamine N-methyltransferase); ADORA2B (adenosine A2b receptor); SLC1A1 (solute carrier family 1 (neuron / epithelial high affinity glutamate delivery system Xag) member 1); GABBR2 (gamma-aminobutyl acid (GABA) B receptor 2); PCSK2 (proprotein convertase subtilisin / kesin type 2); CD160 (CD160 molecule); TSPO (potentiator protein (18kDa)); NPSR1 (neuropeptide S receptor 1); PROL1 (lacrimal 1); NPVF (neuropeptide VF precursor); NPS (neuropeptide S); PRNP (prion protein); GRIA2 (glutamate receptor ionic AMPA 2); GRIA1 (glutamate receptor ionic AMPA 1); PRKCE (protein kinase C epsilon); ITPR1 (Inositol 1 (4 (5-triphosphate receptor type 1); CBR1 (carbonyl reductase 1); ADORA3 (adenosine A3 receptor); FMR1 (fragile X mental retardation 1); ALOX5 (arachidonate 5- Lipoxygenase); GRM7 (glutamate receptor metabotropic 7); PRKG1 (protein kinase cGMP-dependent type I); IL7 (interleukin 7); GRIK5 (glutamate receptor ionic kinate 5); HCRTR1 (hypocretin (orresin) ) Receptor 1); CCL21 (chemokine (CC motif) ligand 21); IL1RN (interleukin 1 receptor antagonist); CX3CR1 (chemokine (C-X3-C motif) receptor 1); P2RX4 (purinfunctional receptor P2X ligand- Gated ion channel 4); AVP (arginine vasopressin); PRPH (ferricin); MTOR (mechanical target of rapamycin (serine / threonine kinase)); NFATC4 (nuclear factor calcineurin-dependent 4 of activated T-cells cytoplasm F2RL1 (coagulation factor II (thrombin) receptor-like 1); EDN2 (endoterin 2); ACCN2 (Amylideide-sensitive cation channel 2 neurons); P2RX1 (purinergic receptor P2X ligand-gated ion channel 1); ENPEP (glutamyl aminopeptidase (aminopeptidase A)); CLDN5 (claudin 5); GFRA3 (GDNF Family Receptor Alpha 3); PTGER1 (Prostaglandin E Receptor 1 (Subtype EP1) 42kDa); OCLN (Occludine); P2RX5 (Purinergic Receptor P2X Ligand-Opening Ion Channel 5); CALB1 (Calvindine 1 28kDa CXCL1 (chemokine (CXC motif) ligand 1 (melanoma growth stimulating activity alpha)); BDKRB1 (bradykinin receptor B1); TRPV4 (temporary receptor capable cation channel subfamily V member 4); PRLHR (prolactin releasing hormone receptor) P2RX6 (purinergic receptor P2X ligand-gated ion channel 6); LALBA (lactalbumin alpha-); IL17A (interleukin 17A); NPFFR1 (neuropeptide FF receptor 1); ARTN (artemin); PTH2R (parathyroid hormone 2 receptor); PROK2 (Prokineticin 2); PROKR2 (prokineticin receptor 2); MAS1L (MAS1 Oncogene-like); PROKR1 (prokineticin receptor 1); MRGPRD (MAS-associated GPR Member D); MRGPRE (MAS-related GPR member E); MRGPRF (MAS-related GPR member F); And PRLH (prolactin releasing hormone).

In addition, sensory-related chromosomal sequences may be associated with pain perception.   Non-limiting examples of pain-related chromosomal sequences include PTGS2 (prostaglandin-andopeoxide synthase 2 (prostaglandin G / H synthase and cyclooxygenase)); SCN9A (sodium channel translocation-gated type IX alpha subunit); TRPV1 (temporary receptor capable cation channel subfamily V member 1); KNG1 (kinnogen 1); IL1B (interleukin 1 beta); NTRK1 (neopositive tyrosine kinase receptor type 1); BDKRB1 (bradykinin receptor B1); BDKRB2 (bradykinin receptor B2); P2RX3 (purinergic receptor P2X ligand-gated ion channel 3); POMC (propiomelanocortin); GAL (galanine prepropeptide); SCN10A (sodium channel translocation-gated type X alpha subunit); PRKCG (protein kinase C gamma); PTGS1 (prostaglandin-andopeoxide synthase 1 (prostaglandin G / H synthase and cyclooxygenase)); GRIN1 (glutamate receptor ionic N-methyl D-aspartate 1); NGF (nerve growth factor (beta polypeptide)); CALCA (calcitonin-associated polypeptide alpha); TNF (tumor necrosis factor (TNF superfamily member 2)); IL6 (interleukin 6 (interferon beta 2)); CRP (C-reactive protein pentracin-associated); INS (insulin); OPRM1 (opium receptor mu 1); COMT (catechol-O-methyltransferase); CNR1 (cannabinoid receptor 1 (brain)); IL10 (interleukin 10); CCK (cholecystokinin); TACR1 (tachikinin receptor 1); OPRD1 (opium receptor delta 1); NPFFR2 (neuropeptide FF receptor 2); TGFB1 (morphological growth factor beta 1); NOS1 (nitric oxide synthase 1 (neurons)); CRH (Adrenal Cortical Stimulating Hormone-releasing Hormone); GALR3 (galanine receptor 3); MSD (cephalopathy with painful bilateral palsy (pain syndrome)); IL8 (interleukin 8); MB (myoglobin); DYT10 (10 strains); PRL (prolactin); MAPK1 (mitogen-activated protein kinase 1); TAC1 (tachikinin precursor 1); PDYN (prodinolpin); GCH1 (GTP cyclohydrolase 1); SOD1 (superoxide dismutase 1 soluble); SLC6A4 (solute carrier family 6 (neurotransporter carrying serotonin) member 4); GRIN2B (glutamate receptor ionic N-methyl D-aspartate 2B); NPY (neural peptide Y); OPRK1 (opium receptor kappa 1); PENK (proenkephalin); TRPA1 (transitory receptor capable cation channel subfamily A member 1); IL2 (interleukin 2); CABIN1 (calcineurin binding protein 1); NOS2 (nitric oxide synthase 2 inducible); PNOC (prepronociceptin); GRIN2A (glutamate receptor ionic N-methyl D-aspartate 2A); CHKA (choline kinase alpha); FOS (FBJ murine osteosarcoma viral oncogene homolog); GRIN2D (glutamate receptor ionic N-methyl D-aspartate 2D); CCL2 (chemokine (C-C motif) ligand 2); HTR2A (5-hydroxytryptamine (serotonin) receptor 2A); CYP19A1 (cytochrome P450 family 19 subfamily A polypeptide 1); GRIN2C (glutamate receptor ionic N-methyl D-aspartate 2C); PTGES (prostaglandin E synthetase); HTR3A (5-hydroxytryptamine (serotonin) receptor 3A); FAAH (fatty acid amide hydrolase); NTRK2 (neopositive tyrosine kinase receptor type 2); ACE (angiotensin I converting enzyme (peptidyl-dipeptidase A) 1); GRM1 (glutamate receptor metabotropic 1); GDNF (glial derived neurotrophic factor); TLR4 (toll-like receptor 4); DRD2 (dopamine receptor D2); GRM5 (glutamate receptor metabotropic 5); VIP (vascular intestinal peptide); PROK1 (Prokineticin 1); GALR2 (galanine receptor 2); ESR1 (estrogen receptor 1); NR3C1 (nuclear receptor subfamily 3 group C member 1 (glucocorticoid receptor)); MME (membrane metal-endopeptidase); EDN1 (endoterin 1); NPY1R (neuropeptide Y receptor Y1); ADK (adenosine kinase); NPY2R (neuropeptide Y receptor Y2); GALR1 (galanine receptor 1); TRPC1 (transitory receptor capable cation channel subfamily C member 1); TRPC5 (temporary receptor capable cation channel subfamily C member 5); TRPC6 (transitory receptor capable cation channel subfamily C member 6); HBS1L (HBS1-like (S.  Serbisci)); GRIN3A (glutamate receptor ionic N-methyl-D-aspartate 3A); GRIN3B (glutamate receptor ionic N-methyl-D-aspartate 3B); GPR55 (G protein-linked receptor 55); MRGPRX3 (MAS-related GPR member X3); HSN2 (genetic neuropathy type II); AKR1B1 (Aldo-keto reductase family 1 member B1 (Aldose Reductase)); NGFR (nerve growth factor receptor (TNFR superfamily member 16)); PRKCE (protein kinase C epsilon); TRPM8 (transitory receptor capable cation channel subfamily M member 8); SST (somatostatin); IL1RN (interleukin 1 receptor antagonist); CD40LG (CD40 Ligand); BCHE (butyrylcholinesterase); ACPP (acid phosphatase prostate); NPPC (sodium release peptide precursor C); SCN11A (sodium channel translocation-gated type XI alpha subunit); KLK3 (cali Crane-related peptidase 3); PTGIR (prostaglandin I2 (prostacyclin) receptor (IP)); PPYR1 (pancreatic polypeptide receptor 1); NPY5R (neuropeptide Y receptor Y5); NPFFR1 (neuropeptide FF receptor 1); ACCN4 (amylolide-sensitive cation channel 4 pituitary); MMEL1 (membrane metal-endopeptidase-like 1); UCN (urocortin); IFNG (interferon gamma); CYP2D6 (cytochrome P450 family 2 subfamily D polypeptide 6); CACNA1B (calcium channel potential-dependent N type alpha 1B subunit); ACCN3 (amylolide-sensitive cation channel 3); BDNF (brain-induced neurotrophic factor); MAPK14 (mitogen-activated protein kinase 14); CNR2 (cannabinoid receptor 2 (macrophages)); MMP9 (matrix metalpeptidase 9 (gelatinase B 92kDa gelatinase 92kDa type IV collagenase)); IL4 (interleukin 4); ADRB2 (adrenergic beta-2-receptor surface); GFAP (glucose acidic protein); KCNIP3 (Kv channel interacting protein 3 calsenilin); IL1R1 (interleukin 1 receptor type I); ABCB1 (ATP-binding cassette sub-family B (MDR / TAP) member 1); MAPK8 (mitogen-activated protein kinase 8); MC1R (melanocortin 1 receptor (alpha melanocyte stimulating hormone receptor)); ALB (albumin); CAMK2G (calcium / calmodulin-dependent protein kinase II gamma); PLAT (plasminogen activator tissue); P2RX4 (purinergic receptor P2X ligand-gated ion channel 4); MAPK3 (mitogen-activated protein kinase 3); TNFRSF1A (Tumor Necrosis Factor Receptor Superfamily Member 1A); TTF2 (transcription termination factor RNA polymerase II); ITIH4 (inter-alpha (globulin) inhibitor H4 (plasma kallikrein-sensitive glycoprotein)); CXCR4 (chemokine (C-X-C motif) receptor 4); SOD2 (superoxide dismutase 2 mitochondria); SRC (v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (algae)); PPARA (peroxysome proliferator-activated receptor alpha); CREB1 (cAMP response element binding protein 1); F2 (coagulation factor II (thrombin)); GAD1 (glutamate decarboxylase 1 (brain 67kDa)); P2RX7 (purinergic receptor P2X ligand-gated ion channel 7); F3 (coagulation factor III (thromboplastin tissue factor)); MIF (macrophage migration inhibitory factor (glycosylation-inhibiting factor)); LEP (leptin); GNRH1 (gonadotropin-releasing hormone 1 (luteinated-releasing hormone)); OPRL1 (Opiate Receptor-Like 1); CCL3 (chemokine (C-C motif) ligand 3); UCP1 (unlinked protein 1 (mitochondrial proton carrier)); NTS (neurotensin); SLC12A5 (solute carrier family 12 (potassium / chloride transport) member 5); CD160 (CD160 molecule); NPFF (neuropeptide FF-amide peptide precursor); ANPEP (alanyl (membrane) aminopeptidase); VDR (vitamin D (1 (25-dihydroxyvitamin D3) receptor); JUN (jun oncogene); ADIPOQ (containing adiponectin C1Q and collagen domain); ELK1 (ELK1 member of ETS oncogene family); FGF2 (fibroblast Growth factor 2 (basic)); GABBR1 (gamma-aminobutyl acid (GABA) B receptor 1); COMP (cartilage oligomer matrix protein); SERPINE1 (serpin peptidase inhibitor clade E (nexin plasminogen activator inhibitor Type 1) member 1); GRM2 (glutamate receptor metabotropic 2); GAD2 (glutamate decarboxylase 2 (pancreatic islet and brain 65kDa)); EPO (erythropoietin); NTF3 (neutropin 3); IL1R2 ( Interleukin 1 receptor type II); ADCY1 (adenylate cyclase 1 (brain)); PEPD (peptidase D); HBEGF (heparin-binding EGF-like growth factor); GAST (gastrin); KCND1 (potassium potential -Opening channel Shal-associated subfamily member 1) OXT (oxytocin prepropeptide); SLC17A5 (Solute Carrier Family 17 (anion / sugar transport) member 5); PL-5283 (PL-5283 protein); STN (statin); EGF (epithelial growth factor (beta-neugestrone)); CACNA1A (calcium channel potential -Dependent P / Q type alpha 1A subunit); VWF (von Willebrand factor); ANXA5 (annexin A5); MMP2 (matrix metalpeptidase 2 (gelatinase A 72kDa gelatinase 72kDa type IV collagenase) HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase); SPP1 (secreted phosphoprotein 1); SCN5A (sodium channel translocation-gated type V alpha subunit); GLA (galactosida First alpha); CHRNA4 (cholinergic receptor nicotinic alpha 4); PITX2 (paired-like homeodomain 2); DLG4 (disc large homolog 4 (Drosophila)); GNB3 (guanine nucleotide binding protein (G protein) ) Beta polypeptide 3); ADORA1 (adenosine A1 receptor); MYH7 (myosin heavy chain 7 heart muscle beta); TXN (thioredoxine); CP (ceruloplasmin (peroxidase)); CSF3 (colony stimulating factor 3 (granulocytes)); SLC1A1 (solute carrier family 1 (neuron / epithelial high affinity glutamate delivery system Xag) member 1); IAPP (Pseudoamyloid Polypeptide); GUK1 (guanylate kinase 1); NPPA (sodium release peptide precursor A); ADCYAP1 (adenylate cyclase activating polypeptide 1 (pituitary)); XDH (xanthine dehydrogenase); SRD5A1 (steroid-5-alpha-reductase alpha polypeptide 1 (3-oxo-5 alpha-steroid delta 4-dehydrogenase alpha 1)); IDO1 (indolamine 2 (3-dioxygenase 1); REN (renin); CX3CL1 (chemokine (C-X3-C motif) ligand 1); NEK3 (absolutely absent in NIMA (mitosis gene a) -associated kinase) 3); KIAA0101 (KIAA0101); ARTN (artemin); SLC17A6 (Solute Carrier Family 17 (Sodium-dependent Inorganic Phosphate Cocarrier) Member 6); GPR172B (G Protein-Linked Receptor 172B); BCL2 (B-Cell CLL Lymphoma 2); CREBBP (CREB binding protein); NCAM1 (nerve cell adhesion molecule 1); EPOR (erythropoietin receptor); ATP2A2 (ATPase Ca ++ transports cardiac muscle slugd spasm 2); HTR7 (5-hydroxytryptamine ( Serotonin) receptor 7 (adenylate cyclase-linked)); MYH11 (myosin heavy chain 11 smooth muscle); AGTR2 (angiotensin II receptor type 2); ENO2 (enolase 2 (gamma neurons)); VIM ( Non-mentin); MAP2K3 (mitogen-activated protein kinase kinase 3); ADAM17 (ADAM metalpeptidase domain 17); IL6ST (interleukin 6 signal transducer (gp130 on costin M receptor)); PSMA2 (proteasome (prosome macropine) subunit alpha type 2); MAP2K6 (mitogen-activated protein kinase kinase 6); S100A9 (S100 calcium binding protein A9); S100A8 (S100 calcium binding protein A8); CCL21 (chemokine (CC motif) ligand 21); EPHA4 (EPH receptor A4); ADCYAP1R1 (adenylate cyclase activating polypeptide 1 (pituitary) receptor type I); CGB (chorionic chona Dotropin beta polypeptide); IBSP (integrin-binding sialoprotein); SORT1 (Sortilin 1); CNTF (ciliary neurotrophic factor); DAO (D-amino-acid oxidase); NRTN (neuterurin); HCRT (Hypocretin (oresine) neuropeptide precursor); MAP1B (microtubule-associated protein 1B); ADAMTS13 (ADAM metalpeptidase 13 with thrombospondin type 1 motif); ABP1 (amylolide binding protein 1 (amine oxidase (copper-containing))); SLC17A7 (solute carrier family 17 (sodium-dependent inorganic phosphate cocarrier) member 7); CADM1 (cell adhesion molecule 1); AIF1 (allograft inflammatory factor 1); ADCY10 (adenylate cyclase 10 (soluble)); TRIM26 (three-branched motif-containing 26); GGT2 (gamma-glutamyltransferase 2); IL1A (interleukin 1 alpha); C1S (complement component 1 s subcomponent); MPO (myeloperoxidase); NPPB (sodium release peptide precursor B); F2RL1 (coagulation factor II (thrombin) receptor-like 1); TNNI3 (Troponin I Type 3 (Heart)); SELP (selectin P (granular membrane protein 140kDa antigen CD62)); TNFRSF11B (Tumor Necrosis Factor Receptor Superfamily Member 11b); FABP3 (fatty acid binding protein 3 muscle and heart (breast-induced growth inhibitor)); ADRA2A (adrenergic alpha-2A-receptor); HTR1A (5-hydroxytryptamine (serotonin) receptor 1A); CASP3 (caspase 3 apoptosis-related cysteine peptidase); CPOX (copropofyrronogen oxidase); SCN7A (sodium channel translocation-gated type VII alpha); PPARG (peroxysome proliferator-activated receptor gamma); MYL3 (myosin light chain 3 alkali; ventricular skeletal slow); CRHR1 (Adrenal Cortical Stimulating Hormone Releasing Hormone Receptor 1); ICAM1 (intercellular adhesion molecule 1); MAPK10 (mitogen-activated protein kinase 10); CAMK2A (calcium / calmodulin-dependent protein kinase II alpha); EDNRB (endotherin receptor type B); CSF2 (colony stimulating factor 2 (granulocyte-macrophage)); SCN4A (sodium channel translocation-gated type IV alpha subunit); EPRS (glutamyl-prolyl-tRNA synthetase); HBB (hemoglobin beta); IL5 (interleukin 5 (colony-stimulating factor neutrophils)); EDNRA (endoterin receptor type A); MEFV (Mediterranean Fever); PAPPA (pregnancy-associated plasma protein A paparicin 1); PTGER4 (prostaglandin E receptor 4 (subtype EP4)); PIK3C2A (phosphoinositide-3-kinase class 2 alpha polypeptide); BGLAP (bone gamma-carboxyglutamate (gla) protein); POR (P450 (cytochrome) oxidoreductase); NOS3 (nitric oxide synthase 3 (endothelial cells)); PRKACA (protein kinase cAMP-dependent catalytic alpha); TP53 (tumor protein p53); RPS6KB1 (ribosome protein S6 kinase 70kDa polypeptide 1); PRKAR1A (protein kinase cAMP-dependent regulatory type I alpha (tissue specific luminant 1)); IGF1 (insulin-like growth factor 1 (somatomedin C)); GRIA2 (glutamate receptor ionic AMPA 2); GRIA1 (glutamate receptor ionic AMPA 1); IL13 (interleukin 13); HSP90AA1 (Thermal Shock Protein 90kDa Alpha (Cytosol) Class A Member 1); PIK3CG (phosphoinositide-3-kinase catalyzed gamma polypeptide); IL12B (interleukin 12B (natural killer cell stimulating factor 2 cytotoxic lymphocyte maturation factor 2 p40)); CYP3A4 (cytochrome P450 family 3 subfamily A polypeptide 4); PRKACB (protein kinase cAMP-dependent catalyst beta); PRKAR2A (protein kinase cAMP-dependent regulatory type II alpha); GRM8 (glutamate receptor metabotropic 8); CAMK2D (calcium / calmodulin-dependent protein kinase II delta); GRM7 (glutamate receptor metabotropic 7); GH1 (growth hormone 1); TNNT2 (troponin T type 2 (heart)); MAOA (monoamine oxidase A); CAMK2B (calcium / calmodulin-dependent protein kinase II beta); SERPINC1 (serpin peptidase inhibitor clade C (antithrombin) member 1); SLC12A2 (solute carrier family 12 (sodium / potassium / chloride transport) member 2); COL2A1 (collagen type II alpha 1); PRKAR1B (protein kinase cAMP-dependent regulatory type I beta); CX3CR1 (chemokine (C-X3-C motif) receptor 1); PRKACG (protein kinase cAMP-dependent catalytic gamma); SLC6A2 (solute carrier family 6 (neurotransporter carrying noradrenaline) member 2); MTOR (mechanical target of rapamycin (serine / threonine kinase)); DLG2 (disc large homolog 2 (Drosophila)); MGLL (monoglyceride lipase); ATF3 (activating transcription factor 3); ALPP (alkali phosphatase placenta (Regan isozyme)); COL9A2 (collagen type IX alpha 2); HBG2 (hemoglobin gamma G); MRGPRX1 (MAS-related GPR member X1); FGFR1 (fibroblast growth factor receptor 1); NFKB1 (nuclear factor 1 of the kappa light polypeptide gene enhancer in B cells); EIF4E (eukaryotic translation initiation factor 4E); PRKCA (protein kinase C alpha); EGFR (epithelial growth factor receptor (erythrocyte leukemia viral (v-erb-b) oncogene homolog algae)); PIK3R1 (phosphoinositide-3-kinase modulating subunit 1 (alpha)); PTPN6 (protein tyrosine phosphatase non-receptor type 6); PLCG2 (phospholipase C gamma 2 (phosphatidylinositol-specific)); PRKCQ (protein kinase C theta); PLG (plasminogen); GRIA3 (glutamate receptor ionic AMPA 3); IL6R (interleukin 6 receptor); HIF1A (hypothyroidism-inducing factor 1 alpha subunit (basic helix-loop-helix transcription factor)); ALPL (alkali phosphatase liver / bone / kidney); ADCY6 (adenylate cyclase 6); PRKCZ (protein kinase C zeta); GRM3 (glutamate receptor metabotropic 3); IL2RA (interleukin 2 receptor alpha); PIK3CD (phosphoinositide-3-kinase catalyzed delta polypeptide); SNCA (synuclein alpha (non-A4 component of amyloid precursor)); CYP1A1 (cytochrome P450 family 1 subfamily A polypeptide 1); PLCG1 (phospholipase C gamma 1); DBH (dopamine beta-hydroxylase (dopamine beta-monooxygenase)); GRIK1 (glutamate receptor ionic kinate 1); PRKCH (protein kinase C eta); PRKCD (protein kinase C delta); CAT (catalase); ITPR1 (Inositol 1 (4 (5-triphosphate receptor type 1); PLCB3 (phospholipase C beta 3 (phosphatidylinositol-specific)); PLCB2 (phospholipase C beta 2); PIK3CB (phosphoinositide- 3-kinase catalyzed beta polypeptide); PLA2G2A (phospholipase A2 group IIA (platelet synovial fluid)); PIK3CA (phosphoinositide-3-kinase catalyzed alpha polypeptide); DRD3 (dopamine receptor D3); DMD (dispropine MAPK7 (mitogen-activated protein kinase 7); PIK3C3 (phosphoinositide-3-kinase class 3); LPL (lipoprotein lipase); ADCY8 (adenylate cyclase 8 (brain)); HSPG2 ( Heparan sulfate proteoglycan 2); CCL5 (chemokine (CC motif) ligand 5); ALOX5 (arachidonate 5-lipoxygenase); PRKCI (protein kinase C iota); PRKAR2B (protein kinase cAMP-dependent regulation Type II beta); GLRA1 (glycine receptor alpha 1); MMP12 (matrix metalpeptide Tidase 12 (macrophage elastase)); CHAT (choline acetyltransferase); LRP5 (low density lipoprotein receptor-associated protein 5); TIMP1 (TIMP metalpeptidase inhibitor 1); PLCB1 (phospholipase C beta 1 (Phosphoinositide-specific)); F2R (coagulation factor II (thrombin) receptor); EIF2S1 (eukaryotic translation initiation factor 2 subunit 1 alpha 35kDa); SELL (selectin L); THBS2 (thrombospondin 2) ; ADRA2C (adrenergic alpha-2C-receptor); HTR2B (5-hydroxytrytamine (serotonin) receptor 2B); TF (transferrin); CST3 (cistatin C); PIK3C2B (phosphoinositide-3-kinase Class 2 beta polypeptide); PLCD1 (phospholipase C delta 1); PLCB4 (phospholipase C beta 4); NR1I2 (nuclear receptor subfamily 1 group I member 2); PIK3R2 (phosphoinositide-3-kinase regulation Subunit 2 (beta)); PYGM (phosphorylase glycogen muscle); KCNQ3 (potassium potential-gated channel KQT-like subfamily member 3); PECAM1 (platelet / endothelial adhesion molecule); CCL4 (chemokine (C-C motif) ligand 4); TACR3 (tachikinin receptor 3); GRM4 (glutamate receptor metabotropic 4); 9-Sep (Septin 9); LBP (lipopolysaccharide binding protein); CAMK1 (calcium / calmodulin-dependent protein kinase I); SCN1A (sodium channel translocation-gated type I alpha subunit); OSM (on costintin M); SQSTM1 (sequestosome 1); AVP (arginine vasopressin); PRPH (periferin); GLRA3 (glycine receptor alpha 3); PIK3R3 (phosphoinositide-3-kinase modulating subunit 3 (gamma)); PTGER3 (prostaglandin E receptor 3 (subtype EP3)); SPTLC1 (serine palmitoyltransferase long chain base subunit 1); PIK3C2G (phosphoinositide-3-kinase class 2 gamma polypeptide); PTH (parathyroid hormone); TJP1 (Solid Binding Protein 1 (Zona Occlusion) 1); SCN2B (sodium channel translocation-gated type II beta); EIF2AK2 (eukaryotic translation initiation factor 2-alpha kinase 2); CACNA2D2 (calcium channel potential-dependent alpha 2 / delta subunit 2); ADCY5 (adenylate cyclase 5); PRKCB (protein kinase C beta); TAT (tyrosine aminotransferase); CLDN5 (Claudin 5); HYAL1 (hyalunoglucosaminidase 1); PLCD3 (phospholipase C delta 3); PTGER1 (prostaglandin E receptor 1 (subtype EP1) 42 kDa); KRT7 (Keratin 7); PPIG (peptidylprolyl isomerase G (cyclophylline G)); OCLN (Occludine); CACNA2D1 (calcium channel potential-dependent alpha 2 / delta subunit 1); CXCL1 (chemokine (C-X-C motif) ligand 1 (melanoma growth stimulating activity alpha)); SLC6A1 (solute carrier family 6 (neurotransporter carrying GABA) member 1); SERPINA6 (serpin peptidase inhibitor clade A (alpha-1 antiproteinase antitrypsin) member 6); TRPV4 (temporary receptor capable cation channel subfamily V member 4); NNT (nicotinamide nucleotides); GRM6 (glutamate receptor metabotropic 6); DPP3 (dipeptides-peptidase 3); SLC18A3 (solute carrier family 18 (vesicular acetylcholine) member 3); GPT (glutamine-pyruvate transaminase (alanine aminotransferase)); TFIP11 (tuftelin interaction protein 11); KCNK2 (potassium channel subfamily K member 2); CYB5A (cytochrome b5 type A (microsomes)); PLCZ1 (phospholipase C zeta 1); ANK3 (ankyrin 3 node of Ranvier (Ankyrin G)); BLVRB (bililidine reductase B (flavin reductase (NADPH))); FGF23 (fibroblast growth factor 23); CAMK1G (calcium / calmodulin-dependent protein kinase IG); TRPV2 (temporary receptor capable cation channel subfamily V member 2); PIK3R5 (phosphoinositide-3-kinase modulating subunit 5); GRINA (glutamate receptor ionic N-methyl D-aspartate-related protein 1 (glutamate binding)); PROK2 (Prokineticin 2); ENAM (enamelin); NPBWR1 (neuropeptide B / W receptor 1); LXN (latexin); MRGPRX2 (MAS-related GPR member X2); AMBN (ameloblastine (enamel matrix protein)); UCN2 (urocortin 2); TUFT1 (tuftelin 1); FAM134B (family B with sequence similarity 134 member); TAC4 (tachikinin 4 (hemokin)); NPB (neural peptide B); PDGFRB (platelet-derived growth factor receptor beta polypeptides); ITGB2 (integrin beta 2 (complement component 3 receptor 3 and 4 subunits)); FGFR2 (fibroblast growth factor receptor 2); TSC1 (nodular sclerosis 1); RUNX1 (runt-related transcription factor 1); PTPRC (protein tyrosine phosphatase receptor type C); FYN (FYN oncogene related to SRC FGR YES); APP (amyloid beta (A4) precursor protein); PGR (progesterone receptor); ERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene homologue 2 neuro / glioblastoma induced oncogene homologue (bird)); ERBB3 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (algae)); CSTB (cistatin B (steppin B)); CASP8 (caspase 8 apoptosis-related cysteine peptidase); ADA (adenosine deaminase); WT1 (Wilms Tumor 1); CD44 (CD44 molecule (Indian blood group)); NFKBIA (nuclear factor inhibitor alpha of the kappa light polypeptide gene enhancer in B-cells); RB1 (Retinoblastoma 1); S100B (S100 calcium binding protein B); MYL2 (myosin light chain 2 regulates cardiac slowing); PSEN1 (Presenilin 1); EGR1 (initial growth response 1); GJA1 (gap binding protein alpha 1 43kDa); SLC6A3 (solute carrier family 6 (neurotransporter carrying dopamine) member 3); JAK2 (Janus Kinase 2); RYR1 (rhinodine receptor 1 (skeleton)); CCKBR (cholekistokinin B receptor); RELA (v-rel retinopathy viral oncogene homologue A (bird)); RET (ret proto-tumor gene); ANXA2 (annexin A2); CCR5 (chemokine (C-C motif) receptor 5); TGFBR1 (morphological growth factor beta receptor 1); PARK2 (Parkinson's disease (autosome recessive adolescence) 2 Parkin); ITGA6 (Integrin Alpha 6); DPYD (dihydropyrimidine dehydrogenase); TH (tyrosine hydroxylase); GNAS (GNAS Complex Locus); TNFRSF1B (Tumor Necrosis Factor Receptor Superfamily Member 1B); COL1A1 (collagen type I alpha 1); HMOX1 (ham oxygenase (decycling) 1); LDHA (Late Dehydrogenase A); MBP (myelin basic protein); SERPINA1 (serpin peptidase inhibitor clade A (alpha-1 antiproteinase antitrypsin) member 1); SCNN1A (sodium channel non-potential-opening 1 alpha); ACTN2 (actinin alpha 2); ACHE (acetylcholinesterase (Yt blood group)); TTN (Titin); CCNH (cycline H); SLC1A2 (solute carrier family 1 (glue high affinity glutamate transport) member 2); ESR2 (estrogen receptor 2 (ER beta)); HTR4 (5-hydroxytryptamine (serotonin) receptor 4); KCNH2 (potassium potential-gated channel subfamily H (eag-related) member 2); ADRBK1 (adrenergic beta receptor kinase 1); IRS1 (insulin receptor substrate 1); C3 (complement component 3); LTA4H (leukotriene A4 hydrolase); GSR (glutathione reductase); NF2 (Nurofibromine 2 (merlin)); ATF2 (activating transcription factor 2); IGFBP3 (insulin-like growth factor binding protein 3); BMP4 (bone forming protein 4); CDK5 (cyclin-dependent kinase 5); CDC25C (cell division cycle 25 homolog C)  Pombe)); CD36 (CD36 molecule (thrombospondine receptor)); TPM1 (tropomiosin 1 (alpha)); CD40 (CD40 molecule TNF receptor superfamily member 5); CYP1A2 (cytochrome P450 family 1 subfamily A polypeptide 2); FN1 (fibronectin 1); PKM2 (pyruvate kinase muscle); G6PD (glucose-6-phosphate dehydrogenase); CGA (glycoprotein hormone alpha polypeptide); HSF1 (heat shock transcription factor 1); CD3E (CD3e molecule epsilon (CD3-TCR complex)); CYP3A5 (cytochrome P450 family 3 subfamily A polypeptide 5); CYP2C9 (cytochrome P450 family 2 subfamily C polypeptide 9); ADRA1A (adrenergic alpha-1A-receptor); CD14 (CD14 molecule); IL4R (interleukin 4 receptor); ITPR3 (Inositol 1 (4 (5-triphosphate receptor type 3); IL15 (interleukin 15); MECP2 (methyl CpG binding protein 2 (Rett syndrome)); ANXA1 (annexin A1); PRKAG1 (protein kinase AMP-activated Gamma 1 non-catalytic subunit); DCN (decorin); MYB (v-myb myeloblastoma viral oncogene homologue (bird)); AVPR1A (arginine vasopressin receptor 1A); HLA-DQB1 (major histocompatibility complex classification II DQ beta 1); NEFL (neuropathic light polypeptide); SCNN1B (sodium channel non-potential-opening 1 beta); CACNA1H (calcium channel potential-dependent T type alpha 1H subunit); IFNAR1 (interferon (alpha Beta and omega) receptors 1); PDE4D (phosphodiesterase 4D cAMP-specific (phosphodiesterase E3 Higgs homolog Drosophila)); HDAC9 (histone deacetylase 9); ABCC1 (ATP-binding cassette sub Family C (CFTR / MRP) member 1); PRDX5 (peroxyredoxin 5); EPHX2 (epoxide hydrolase 2 cells ); VCAM1 (vascular cell adhesion molecule 1); PRKAG2 (protein kinase AMP-activated gamma 2 non-catalytic subunit); ADCY2 (adenylate cyclase 2 (brain)); HTR1B (5-hydroxytryptamine (Serotonin) receptor 1B); ADCY9 (adenylate cyclase 9); HLA-A (major histocompatibility complex classification IA); SLC1A3 (solute carrier family 1 (glue high affinity glutamate transport) member 3); HLA-B (Major histocompatibility complex classification IB); ITGA2 (integrin alpha 2 (CD49B alpha 2 subunit of VLA-2 receptor)); GABRA2 (gamma-aminobutyl acid (GABA) A receptor alpha 2); IL2RB (interleukin 2 receptor beta GLRB (glycine receptor beta); SOCS3 (inhibitor of cytokine signaling 3); CSNK2B (casein kinase 2 beta polypeptide); KCNK3 (potassium channel subfamily K member 3); KCNQ2 (potassium potential-gated channel KQT-like subfamily member 2); DPYSL2 (dihydropyrimidinase-like 2); CYP2J2 (cytochrome P450 family 2 subfamily J polypeptide 2); DRD4 (dopamine receptor D4); PRKG1 (protein kinase cGMP-dependent type I); TNFSF11 (tumor necrosis factor (ligand) superfamily member 11); IFNAR2 (interferon (alpha beta and omega) receptor 2); EIF4EBP1 (eukaryotic translation initiation factor 4E binding protein 1); EIF4G1 (eukaryotic translation initiation factor 4 gamma 1); EIF4G3 (eukaryotic translation initiation factor 4 gamma 3); SCNN1G (sodium channel non-potential-opening 1 gamma); SERPIN G1 (serpin peptidase inhibitor clade G (C1 inhibitor) member 1); PABPN1 (poly (A) binding protein nucleus 1); CAST (calpastatin); CTSC (cathepsin C); CTGF (Connective Tissue Growth Factor); CHRNB2 (cholinergic receptor nicotinic beta 2 (neurons)); ADCY3 (adenylate cyclase 3); ADCY7 (adenylate cyclase 7); ADRA1D (adrenergic alpha-1D-receptor); CHRM2 (cholinergic receptor muscarinic 2); DHFR (dihydrofolate reductase); MC2R (melanocortin 2 receptor (adrenocorticotropic hormone)); THBD (thrombomodulin); IL7 (interleukin 7); IL18 (interleukin 18 (interferon-gamma-inducing factor)); SIRT1 (Sirtuin (silent mating type information regulation 2 homologue) 1 (S.  Serbisci)); GRIA4 (glutamate receptor ionic AMPA4); CSNK1E (casein kinase 1 epsilon); CPE (carboxypeptidase E); PRSS1 (protease serine 1 (trypsin 1)); GOT2 (glutamine-oxaloacet transaminase 2 mitochondria (aspartate aminotransferase 2)); GABRB1 (gamma-aminobutyl acid (GABA) A receptor beta 1); ALOX12 (arachidonate 12-lipoxygenase); CCL11 (chemokine (C-C motif) ligand 11); HLA-DRB1 (major histocompatibility complex classification II DR beta 1); RBL2 (Retinoblastoma-like 2 (p130)); AGER (developed glycosylation end product-specific receptor); LAMP1 (lysosomal-associated membrane protein 1); MAPKAPK2 (mitogen-activated protein kinase-activated protein kinase 2); LTA (Limpotoxin Alpha (TNF Superfamily Member 1)); CYP4A11 (cytochrome P450 family 4 subfamily A polypeptide 11); MAOB (monoamine oxidase B); TPH1 (tryptophan hydroxylase 1); SPARC (secreted protein acid cysteine-rich (osteonectin)); PIK3R4 (phosphoinositide-3-kinase modulating subunit 4); CYP17A1 (cytochrome P450 family 17 subfamily A polypeptide 1); CD63 (CD63 molecule); CLCN1 (chloride channel 1 skeletal muscle); NFE2L2 (nuclear factor (erythrocyte-derived 2) -like 2); TNFRSF11A (Tumor Necrosis Factor Receptor Superfamily Member 11a NFKB Activator); CRHR2 (Adrenal Cortical Stimulating Hormone Releasing Hormone Receptor 2); COPE (coatomer protein complex subunit epsilon); CYP4F2 (cytochrome P450 family 4 subfamily F polypeptide 2); APOB (apolipoprotein B (including Ag (x) antigen)); GFRA1 (GDNF Family Receptor Alpha 1); HMBS (hydroxymethylbyline synthetase); F5 (coagulation factor V (proaceerine labile factor)); TPO (thyroid peroxidase); AMPH (ampypicin); PTGER2 (prostaglandin E receptor 2 (subtype EP2) 53 kDa); PKLR (pyruvate kinase liver and RBC); SMPD1 (sphingomyelin phosphodiesterase 1 acid lysosomal); PLA2G4A (phospholipase A2 group IVA (cytosol calcium-dependent)); JUNB (jun B proto-tumor gene); GSN (gelzoline); PLCE1 (phospholipase C epsilon 1); PSMB8 (proteasome (prosome macropine) subunit beta type 8 (large multifunctional peptidase 7)); CYCS (cytochrome c of body); KCNK1 (potassium channel subfamily K member 1); PGF (placental growth factor); IL10RA (interleukin 10 receptor alpha); CHRM1 (cholinergic receptor muscarinic 1); IL12RB1 (interleukin 12 receptor beta 1); CHGA (chromogranin A (parathyroid secretion protein 1)); GABRE (gamma-aminobutyl acid (GABA) A receptor epsilon); GJA4 (gap binding protein alpha 4 37kDa); ALAD (aminolevulinate delta-dehydratase); GLRA2 (glycine receptor alpha 2); ITPR2 (Inositol 1 (4 (5-triphosphate receptor type 2); MPZ (zero myelin protein); AQP1 (aquaporin 1 (Colton blood group)); MYBPC3 (myosin binding protein C heart); CPT2 (carnitine palmitoyl) Dienzyme 2); STAR (steroidal acute regulatory protein); GLB1 (galactosidase beta 1); SCN8A (sodium channel translocation gated type VIII alpha subunit); LGALS1 (lectingalactosid-binding solubility 1); PCSK1 (Proprotein Convertase Subtilisin / Kesin Type 1); IKBKAP (Inhibitor of Kappa Light Polypeptide Gene Enhancer in B-Cell Kinase Complex-Related Proteins); REST (RE1-Silent Transcription Factor); OXTR (Oxytocin Receptor); UGT2B7 (UDP glucuronosyltransferase 2 family polypeptide B7); LTF (lactotransferrin); TYRP1 (tyrosinase-related protein 1); RBL1 (retinoblastoma-like 1 (p107)); TCAP (titin -cap (telethonin); KCNJ1 (potassium inward-rectifying channel standing Bfamily J member 1); KCNN3 (medium potassium / small conducting calcium-activated channel subfamily N member 3); PSMC1 (proteasome (prosome macropine) 26S subunit ATPase 1); RELN (reelin) ); MYH14 (myosin heavy chain 14 non-muscle); ADCY4 (adenylate cyclase 4); MMP10 (matrix metalpeptidase 10 (stromericin 2)); FXN (pratacin); ATF4 (activating transcription factor 4 (tax-responsive enhancer element B67)); NOG (noggin); PPOX (protoporpynogen oxidase); TNNC1 (troponin C type 1 (slow)); HRH2 (histamine receptor H2); PLA2G4C (Phospholipase A2 group IVC (cytosol calcium-independent)); NR3C2 (nuclear receptor subfamily 3 group C member 2); AMPD1 (adenosine monophosphate deaminase 1); FKBP4 (FK506 binding protein 4 59kDa); MBD2 (methyl-CpG binding domain protein 2); NRG1 (neuregulin 1); MBL2 (mannose-binding lectin (protein C) 2 soluble (opsonine deficiency)); AGA (aspartylglucosaminidase); SP1 (Sp1 transcription factor); SCN3A (sodium channel translocation-gated type III alpha subunit); FABP2 (fatty acid binding protein 2 gut); PABPC1 (poly (A) binding protein cytoplasm 1); ACCN2 (amylolide-sensitive cation channel 2 neurons); ACTC1 (Actin Alpha Heart Muscle 1); ACP5 (acid phosphatase 5 tartaric acid resistance); EIF4B (eukaryotic translation initiation factor 4B); EIF4EBP2 (eukaryotic translation initiation factor 4E binding protein 2); EIF4A1 (eukaryotic translation initiation factor 4A1); CAMK4 (calcium / calmodulin-dependent protein kinase IV); CACNB3 (calcium channel potential-dependent beta 3 subunit); CAV3 (caberoline 3); CA6 (carbonate dehydratase VI); ALOX12B (arachidonate 12-lipoxygenase 12R type); CCL17 (chemokine (C-C motif) ligand 17); CCL22 (chemokine (C-C motif) ligand 22); MMP20 (matrix metalpeptidase 20); GAP43 (growth related protein 43); ALOX5AP (arachidonate 5-lipoxygenase-activating protein); ANTXR2 (anthrax toxin receptor 2); HGD (hemogenthiate 1 (2-dioxygenase); SELE (selectin E); MYLK2 (myosin light chain kinase 2); VEGFA (vascular endothelial growth factor A); PRX (ferriacin); IL10RB (interleukin 10 receptor beta) HAS1 (hyaluronan synthetase 1); GTF2IRD1 (containing GTF2I repeat domain 1); IL16 (interleukin 16 (lymphocyte chemoattractant factor)); GRIP1 (glutamate receptor interacting protein 1); PHKA1 (phosphorylase kinase Alpha 1 (muscle)); FOXP3 (forkhead box P3); SFTPC (surfactant protein C); PDIA3 (protein disulfide isomerase family A member 3); SRM (spermidine synthetase); MARCKS (myristo) Illustrated alanine-rich protein kinase C substrate); RAPGEF3 (Rap guanine nucleotide exchange factor (GEF) 3); RAGE (renal tumor antigen); MRC1 (mannose receptor C type 1); SPINK1 (serine peptidase inhibitor Kazal type 1); CYP4F3 (cytochrome P450 family 4 subfamily F polypeptide 3); LPIN 1 (lipin 1); TREX1 (3 prime repair exonuclease 1); CYSLTR2 (cysteinyllucotriene receptor 2); PTX3 (pentrasin 3 long); PTGES2 (prostaglandin E synthase 2); ASAH1 ( N-Acipingosine Amidohydrolase (acid ceramidase) 1); H2AFZ (H2A histone family member Z); HFE (hemochromatosis); PYGB (phosphorylase glycogen; brain); NR2F6 (nuclear receptor) Subfamily 2 group F member 6); CYP3A7 (cytochrome P450 family 3 subfamily A polypeptide 7); RAB6A (RAB6A member RAS oncogene family); F2RL3 (coagulation factor II (thrombin) receptor-like 3); RGS4 (G Modulators of protein signaling 4); SCNN1D (sodium channel non-potential-gated 1 delta); SCN1B (sodium channel potential-gated type I beta); SCN2A (sodium channel potential-gated type II alpha subunit); CALCRL (calcitonin receptor-like); CALB1 (Calvindine 1 28kDa); CACNG2 (calcium channel potential-dependent gamma subunit 2); TACR2 (tachikinin receptor 2); GPC3 (glypican 3); GALNT3 (UDP-N-acetyl-alpha-D-galactosamine: polypeptide N-acetylgalactosminyltransferase 3 (GalNAc-T3)); CXCL10 (chemokine (C-X-C motif) ligand 10); ANKH (joint anabolic progressive homologue (mouse)); PRKD1 (protein kinase D1); KCNN4 (potassium medium / small conductive calcium-activated channel subfamily N member 4); TGM1 (transglutaminase 1 (K polypeptide epithelial type I protein-glutamine-gamma-glutamyltransferase)); SLC26A2 (solute carrier family 26 (sulfate transport) member 2); MTNR1A (melatonin receptor 1A); MIPEP (mitochondrial intermediate peptidase); SI (sucrase-isomaltase (alpha-glucosidase)); RHAG (Rh-associated glycoprotein); SLC12A3 (solute carrier family 12 (sodium / chloride transport) member 3); RNASE1 (ribonuclease RNase A family 1 (pancreas)); ELINE (elastase neutrophil expressed); GPC6 (glypican 6); ENPP2 (ectonucleotide pyrophosphatase / phosphodiesterase 2); SCN3B (sodium channel translocation-gated type III beta); CALB2 (Calvindine 2); CTSA (cathepsin A); EIF2AK1 (eukaryotic translation initiation factor 2-alpha kinase 1); TMSB4X (thymosin beta 4 X-linked); LPO (lactoperoxidase); NDN (nexin homologues (mouse)); PICK1 (protein interaction 1 with PRKCA); PLCD4 (phospholipase C delta 4); CLDN3 (claudin 3); HCN1 (hyperpolarization activated cycle nucleotide-gated potassium channel 1); MATN3 (matrylin 3); COL9A3 (collagen type IX alpha 3); BTG1 (B-cell translocation gene 1 anti-proliferative); LCN1 (lipocalin 1 (tear prealbumin)); FDX1 (Perredoxin 1); UTRN (eutropin); FMOD (fibromodulin); PDE4A (phosphodiesterase 4A cAMP-specific (phosphodiesterase E2 Higgs homolog Drosophila)); RRBP1 (ribosome binding protein 1 homologue 180 kDa (dog)); MLYCD (malonyl-CoA decarboxylase); ANXA3 (annexin A3); PRKD3 (protein kinase D3); GHRL (Ghrelin / Oveststatin Prepropeptide); GDF15 (growth differentiation factor 15); BCL11A (B-cell CLL / lymphoma 11A (zinc finger protein)); CSRP3 (cysteine and glycine-rich protein 3 (heart LIM protein)); CXCL2 (chemokine (C-X-C motif) ligand 2); TOMM40 (transferase of yeast mitochondrial membrane 40 homologue (yeast)); KCNK6 (potassium channel subfamily K member 6); KCNN2 (medium potassium / small conducting calcium-activated channel subfamily N member 2); SLC6A12 (solute carrier family 6 (neurotransporter transporting betaine / GABA) member 12); ALOXE3 (arachidonate lipoxygenase 3); SOST (sclerosis); PRLHR (prolactin-releasing hormone receptor); TIMM44 (transferase of yeast mitochondrial membrane 44 homologue (yeast)); KCNN1 (potassium medium / small conductive calcium-activated channel subfamily N member 1); CHRNA9 (cholinergic receptor nicotinic alpha 9); GPC5 (glypican 5); GPR37 (G protein-linked receptor 37 (endoterin receptor type B-like)); NKX2-1 (NK2 homeobox 1); HMMR (hyaluronan-mediated motility receptor (RHAMM)); PKHD1 (polycystic kidney and liver disease 1 (autosome recessive)); AOC2 (amine oxidase copper containing 2 (retinal-specific)); KRT20 (Keratin 20); CORIN (Corine Serine Peptidase); AZU1 (azurosidine 1); MAPK6 (mitogen-activated protein kinase 6); PAEP (progestagen-associated endometrial protein); CACNA2D4 (calcium channel potential-dependent alpha 2 / delta subunit 4); EIF3A (eukaryotic translation initiation factor 3 subunit A); BTG2 (BTG Family Member 2); P2RY14 (purinergic receptor P2Y G-protein linked 14); PDLIM7 (PDZ and LIM Domain 7 (enigma)); CACNA2D3 (calcium channel potential-dependent alpha 2 / delta subunit 3); LAMP3 (lysosomal-associated membrane protein 3); PLCL2 (phospholipase C-like 2); NOSIP (nitric oxide synthase interacting protein); CRHBP (Adrenal Cortical Stimulating Hormone-releasing Hormone Binding Protein); KLK5 (cali Crane-related peptidase 5); ADAM2 (ADAM metalpeptidase domain 2); SIRPA (signal-regulating protein alpha); PMPCB (peptidase (mitochondrial processing) beta); GPC4 (glypican 4); MYH6 (myosin heavy chain 6 heart muscle alpha); CXCL9 (chemokine (C-X-C motif) ligand 9); KCNK5 (potassium channel subfamily K member 5); KCNK10 (potassium channel subfamily K member 10); NMU (neuromedin U); SCN4B (sodium channel translocation-gated type IV beta); CAMK1D (calcium / calmodulin-dependent protein kinase ID); COL8A2 (collagen type VIII alpha 2); RAB11FIP1 (RAB11 family interacting protein 1 (Class I)); NDOR1 (NADPH dependent diflavin oxidoreductase 1); ZNF318 (Zinc Finger Protein 318); P2RX2 (purinergic receptor P2X ligand-gated ion channel 2); UGT1A6 (UDP glucuronosyltransferase 1 family polypeptide A6); LEMD3 (containing the LEM domain 3); UGT1A1 (UDP glucuronosyltransferase 1 family polypeptide A1); PDLIM3 (PDZ and LIM Domain 3); KCTD12 (containing potassium channel tetramerization domain 12); KCNK9 (potassium channel subfamily K member 9); DSE (dermatan sulfate epimerase); DSPP (dentin sialoin protein); KCNT2 (potassium channel subfamily T member 2); NMUR2 (neuromedin U receptor 2); CHST6 (carbohydrate (N-acetylglucosamine 6-O) sulfotransferase 6); CCL28 (chemokine (C-C motif) ligand 28); SLPI (secretory leukocyte peptidase inhibitor); CCL1 (chemokine (C-C motif) ligand 1); KCNK15 (potassium channel subfamily K member 15); KCTD15 (containing potassium channel tetramerization domain 15); ANKRD1 (ankyrin repeat domain 1 (heart muscle)); SIGMAR1 (Sigma non-opium intracellular receptor 1); SLCO2A1 (solute carrier organic anion transport family member 2A1); MUC16 (associated with mucin 16 cell surface); CNTNAP1 (contactin related protein 1); LGR6 (leucine-rich repeat-containing G protein-linked receptor 6); ASPN (asporin); PLCH2 (phospholipase C ecta 2); PLCL1 (phospholipase C-like 1); AGFG1 (ArfGAP 1 with FG repeats); HOXB8 (homeobox B8); KCNK12 (potassium channel subfamily K member 12); KCNK4 (potassium channel subfamily K member 4); KCNRG (potassium channel modulator); KCTD13 (containing potassium channel tetramerization domain 13); KCNT1 (potassium channel subfamily T member 1); RNF19A (Linkinger Protein 19A); CIAPIN1 (cytokine induced apoptosis inhibitor 1); TNS3 (tensin 3); AMELX (amelogenin X-linked); CRBN (cereblon); MLN (motiline); CXCR1 (chemokine (C-X-C motif) receptor 1); NPBWR2 (neuropeptides B / W receptor 2); KCMF1 (potassium channel modulatory factor 1); KCNK7 (potassium channel subfamily K member 7); KCNV1 (potassium channel subfamily V member 1); KCTD5 (containing potassium channel tetramerization domain 5); KCNV2 (potassium channel subfamily V member 2); KCNK13 (potassium channel subfamily K member 13); ERAP2 (cytoplasmic network aminopeptidase 2); KCTD2 (containing potassium channel tetramerization domain 2); KCTD3 (containing potassium channel tetramerization domain 3); KCNK17 (potassium channel subfamily K member 17); KCTD10 (containing potassium channel tetramerization domain 10); KCTD7 (containing potassium channel tetramerization domain 7); SCT (secretin); NGDN (Nuroguidine EIF4E Binding Protein); MLNR (Motilin Receptor); MPZL2 (myelin protein zero-like 2); PROL1 (lacrimal 1); KCNK16 (potassium channel subfamily K member 16); KCTD9 (containing potassium channel tetramerization domain 9); KCTD11 (11 containing potassium channel tetramerization domain); KCTD8 (containing potassium channel tetramerization domain 8); KCTD4 (containing potassium channel tetramerization domain 4); KCTD6 (containing potassium channel tetramerization domain 6); KCTD1 (potassium channel tetramerization domain containing 1); NPVF (neuropeptide VF precursor); MAGIX (MAGI family member X-linked); MRGPRX4 (MAS-related GPR member X4); MRGPRD (MAS-associated GPR Member D); TET2 (tet oncogene family member 2); KCTD14 (containing potassium channel tetramerization domain 14); GLYATL1 (glycine-N-acyltransferase-like 1); ZNF493 (Zinc Finger Protein 493); ZNF429 (zinc finger protein 429); MRGPRE (MAS-related GPR member E); SUN2 (2 containing Sad1 and UNC84 domains); AMTN (amelotin); MRGPRF (MAS-related GPR member F); CDK20 (cycline-dependent kinase 20); KCNU1 (potassium channel subfamily U member 1); GATS (strand opposite the GATS substrate antigen 3); GLRA4 (glycine receptor alpha 4); IGHE (immunoglobulin, heavy constant epsilon); DRGX (back root ganglion homeobox); MRGPRG (MAS-associated GPR Member G); LOC729977 (hypothetical LOC729977); MT-TK (tRNA lysine encoded on mitochondria); LOC400680 (hypothetical gene supported by AK097381; BC040866); COP (Clatiner-ordered Protein); IGES (immunoglobulin E enriched serum); MGS (Mungen syndrome); TRNAS-AGA (delivery RNA serine (anticodon AGA)); And LOC100132258 (2 similar to secretion carrier membrane proteins).

Non-limiting examples of taste-related genes include TAS2R38 (taste receptor, type 2, member 38); TAS1R1 (taste receptor, type 1, member 1); TAS2R3 (taste receptor, type 2, member 3); TAS2R5 (taste receptor, type 2, member 5); TAS2R1 (taste receptor, type 2, member 1); TAS2R16 (taste receptor, type 2, member 16); TAS2R4 (taste receptor, type 2, member 4); TAS2R14 (taste receptor, type 2, member 14); TAS2R10 (taste receptor, type 2, member 10); TAS2R7 (taste receptor, type 2, member 7); TAS2R13 (taste receptor, type 2, member 13); TAS2R9 (taste receptor, type 2, member 9); TAS2R8 (taste receptor, type 2, member 8); TAS1R3 (taste receptor, type 1, member 3); TAS2R31 (taste receptor, type 2, member 31); TAS1R2 (taste receptor, type 1, member 2); TAS2R43 (taste receptor, type 2, member 43); TAS2R50 (taste receptor, type 2, member 50); TAS2R46 (taste receptor, type 2, member 46); TAS2R30 (taste receptor, type 2, member 30); TAS2R42 (taste receptor, type 2, member 42); PLCB2 (phospholipase C, beta 2); TAS2R20 (taste receptor, type 2, member 20); TAS2R19 (taste receptor, type 2, member 19); GNG13 ((guanine nucleotide binding protein (G protein)), gamma 13); TAS2R12 (taste receptor, type 2, member 12 false gene); GNAT1 (guanine nucleotide binding protein (G protein), alpha transducing active polypeptide 1); TAS2R41 (taste receptor, type 2, member 41); TAS2R60 (taste receptor, type 2, member 60); TAS2R40 (taste receptor, type 2, member 40); TAS2R39 (taste receptor, type 2, member 39); GCG (glucagon); TAS2R18 (taste receptor, type 2, member 18 false gene); GRM4 (glutamate receptor, metabotropic 4); LCN1 (lipocalin 1 (tear prealbumin)); TRPV1 (transitory acceptor cation channel, subfamily V, member 1); ACCN1 (amylolide-sensitive cation channel 1, neurons); TAS2R45 (taste receptor, type 2, member 45); TAS2R15 (taste receptor, type 2, member 15 false gene); FOS (murine osteosarcoma viral oncogene homolog); SLC9A1 (solute carrier family 9 (sodium / hydrogen exchanger), member 1); INS (insulin); ACCN5 (amylolide-sensitive cation channel 5, intestines); TAS2R2 (taste receptor, type 2, member 2 false gene); GRM7 (glutamate receptor, metabotropic 7); NPY (neural peptide Y); LEP (leptin); CASR (calcium-sensitive receptor); GNAZ (guanine nucleotide binding protein (G protein), alpha z polypeptide); CIB1 (calcium and integrin binding 1 (calcirin)); ADCY10 (adenylate cyclase 10 (soluble)); LEPR (leptin receptor); DRD1 (dopamine receptor D1); LGR6 (leucine-rich repeat-containing G protein-linked receptor 6); GRM8 (glutamate receptor, metabotropic 8); GRM6 (glutamate receptor, metabotropic 6); GLP1R (glucagon-like peptide 1 receptor); AGER (developed glycosylation end product-specific receptor); SLC2A2 (Solute Carrier Family 2 (Easy Glucose Transport), Member 2); GIP (inhibitory polypeptide of the stomach); REN (renin); PDYN (prodinolpin); RRBP1 (ribosome binding protein 1 homologue 180 kDa (dog)); SLC15A1 (solute carrier family 15 (oligopeptide transport), member 1); OXT (oxytocin, prepropeptide); IL4I1 (interleukin 4 induced 1); VN1R17P (moisturizing 1 receptor 17 false gene); TAS2R62P (taste receptor, type 2, member 62, false gene); TAS2R64P (taste receptor, type 2, member 64 false gene); TAS2R63P (taste receptor, type 2, member 63 false gene); PS5 (bitter taste receptor false gene PS5); PS3 (bitter taste receptor PS3); PS7 (bitter taste receptor Ps7 false gene); C6orf15 (chromosome 6 open reading frame 15); TAS2R6 (taste receptor, type 2, member 6); TAS2R22 (taste receptor, type 2, member 22); TAS2R33 (taste receptor, type 2, member 33); TAS2R37 (taste receptor, type 2, member 37); TAS2R36 (taste receptor, type 2, member 36); GNAT3 (guanine nucleotide binding protein, alpha transformed 3); TRPM5 (transitory receptor capable cation channel, subfamily M, member 5); TRPM7 (temporary receptor capable cation channel, subfamily M, member 7); GNB1 (guanine nucleotide binding protein (G protein), beta polypeptide 1); ITPR3 (Inositol 1,4,5-triphosphate receptor, type 3); ACE (angiotensin I converting enzyme (peptidyl-dipeptidase A) 1); ENO2 (enolase 2 (gamma, neuron)); CALCA (calcitonin-associated polypeptide alpha); CCK (cholecystokinin); RTP3 (receptor (chemosensory) transporter protein 3); PL-5283 (PL-5283 protein); PRKCG (protein kinase C, gamma); KCNQ1 (potassium potential-gated channel, KQT-like subfamily, member 1); BDNF (brain-induced neurotrophic factor); SCNN1A (sodium channel, non-potential-gated 1 alpha); GNB3 (guanine nucleotide binding protein (G protein), beta polypeptide 3); SCNN1B (sodium channel, non-potential-opening 1, beta); SCNN1G (sodium channel, non-potential-opening 1, gamma); GNB4 (guanine nucleotide binding protein (G protein), beta polypeptide 4); PDE1A (phosphodiesterase 1A, calmodulin-dependent); DMBT1 (1 deleted in malignant brain tumors); PDE3B (phosphodiesterase 3B, cGMP-inhibited); PDE1C (phosphodiesterase 1C, calmodulin-dependent 70 kDa); PRKCA (protein kinase C, alpha); NTRK3 (neotrophic tyrosine kinase, receptor, type 3); NTRK2 (neotrophic tyrosine kinase, receptor, type 2); PRKCQ (protein kinase C, theta); PRKACA (protein kinase, cAMP-dependent, catalytic, alpha); CCKBR (cholekistokinin B receptor); PRKCZ (protein kinase C, zeta); TH (tyrosine hydroxylase); NGFR (nerve growth factor receptor (TNFR superfamily, member 16)); DRD2 (dopamine receptor D2); NOS1 (nitric oxide synthase 1 (neurons)); PRKCE (protein kinase C, epsilon); PRKCH (protein kinase C, eta); PRKCD (protein kinase C, delta); ABCB1 (ATP-binding cassette, sub-family B (MDR / TAP), member 1); MAPK1 (mitogen-activated protein kinase 1); PLCB3 (phospholipase C, beta 3 (phosphatidylinositol-specific)); ADCY8 (adenylate cyclase 8 (brain)); ADRBK2 (adrenergic, beta, receptor kinase 2); PRKACB (protein kinase, cAMP-dependent, catalytic, beta); PRKCI (Protein Kinase C, Iota); CCKAR (cholekistokinin A receptor); KCNK3 (potassium channel, subfamily K, member 3); PLCB1 (phospholipase C, beta 1 (phosphoinositide-specific)); ADCY3 (adenylate cyclase 3); NTF3 (neutropin 3); PLCB4 (phospholipase C, beta 4); GNB5 (guanine nucleotide binding protein (G protein), beta 5); GNAL (guanine nucleotide binding protein (G protein), alpha activated active polypeptide, olfactory type); GNB2 (guanine nucleotide binding protein (G protein), beta polypeptide 2); KCNK1 (potassium channel, subfamily K, member 1); HTR1A (5-hydroxytryptamine (serotonin) receptor 1A); CNGA3 (cycle nucleotide gated channel alpha 3); PRKACG (protein kinase, cAMP-dependent, catalyst, gamma); PRKCB (protein kinase C, beta); RBP4 (Retinol Binding Protein 4, Plasma); GRP (gastrin-releasing peptide); PDE3A (phosphodiesterase 3A, cGMP-inhibited); KRT14 (Keratin 14); SCNN1D (sodium channel, non-potential-opening 1, delta); PRKD1 (protein kinase D1); PDE1B (phosphodiesterase 1B, calmodulin-dependent); PDE2A (phosphodiesterase 2A, cGMP-stimulated); PRKD3 (protein kinase D3); SST (somatostatin); KCNK6 (potassium channel, subfamily K, member 6); KCNK2 (potassium channel, subfamily K, member 2); NTF4 (neutropin 4); GNG3 (guanine nucleotide binding protein (G protein), gamma 3); RNH1 (ribonuclease / angiogenin inhibitor 1); KCNK5 (potassium channel, subfamily K, member 5); KCNK10 (potassium channel, subfamily K, member 10); P2RX2 (purinergic receptor P2X, ligand-gated ion channel, 2); KCTD12 (containing potassium channel tetramerization domain 12); KCNK9 (potassium channel, subfamily K, member 9); KCNT2 (potassium channel, subfamily T, member 2); KCNK15 (potassium channel, subfamily K, member 15); KCTD15 (containing potassium channel tetramerization domain 15); KCNK12 (potassium channel, subfamily K, member 12); KCNK4 (potassium channel, subfamily K, member 4); KCNRG (potassium channel modulator); KCTD13 (containing potassium channel tetramerization domain 13); KCNT1 (potassium channel, subfamily T, member 1); KCMF1 (Potassium Channel Regulator 1); KCNK7 (potassium channel, subfamily K, member 7); KCNV1 (potassium channel, subfamily V, member 1); KCTD5 (containing potassium channel tetramerization domain 5); KCNV2 (potassium channel, subfamily V, member 2); KCNK13 (Potassium Channel, Subfamily K, Member 13); KCTD2 (containing potassium channel tetramerization domain 2); KCTD3 (containing potassium channel tetramerization domain 3); KCNK17 (potassium channel, subfamily K, member 17); KCTD10 (containing potassium channel tetramerization domain 10); KCTD7 (containing potassium channel tetramerization domain 7); KCNK16 (potassium channel, subfamily K, member 16); KCTD9 (containing potassium channel tetramerization domain 9); KCTD11 (11 containing potassium channel tetramerization domain); KCTD8 (containing potassium channel tetramerization domain 8); KCTD4 (containing potassium channel tetramerization domain 4); KCTD6 (containing potassium channel tetramerization domain 6); KCTD1 (potassium channel tetramerization domain containing 1); KCTD14 (containing potassium channel tetramerization domain 14); RTP4 (receptor (chemosensory) transport protein 4); KCNU1 (potassium channel, subfamily U, member 1); LOC730036 (hypothetical LOC730036); RPS6KA3 (ribosome protein S6 kinase, 90 kDa, polypeptide 3); MAPT (microtubule-associated protein tau); CHEK2 (CHK2 checkpoint homologue (S. Pombe)); FYN (FYN oncogene related to SRC, FGR, YES); APP (amyloid beta (A4) precursor protein); PTEN (phosphatase and tensine homologues); SOD1 (superoxide dismutase 1, soluble); CSTB (cistatin B (steppin B)); SHH (sonic hedgehog homologue (Drosophila)); AKR1B1 (Aldo-keto reductase family 1, member B1 (Aldose Reductase)); COMT (catechol-O-methyltransferase); S100B (S100 calcium binding protein B); PTK2B (PTK2B protein tyrosine kinase 2 beta); PLCG2 (phospholipase C, gamma 2 (phosphatidylinositol-specific)); PSEN1 (Presenilin 1); SLC6A3 (solute carrier family 6 (neurotransmitter transport, dopamine), member 3); PAX6 (paired box 6); MMP1 (matrix metalpeptidase 1 (intercellular collagenase)); CACNA1A (calcium channel, potential-dependent, P / Q type, alpha 1A subunit); CASP9 (caspase 9, apoptosis-related cysteine peptidase); PRKAR1A (protein kinase, cAMP-dependent, regulatory, type I, alpha (tissue specific luminant 1)); MMP3 (matrix metalpeptidase 3 (stromericin 1, progelatinase)); ADCY6 (adenylate cyclase 6); CASP3 (caspase 3, apoptosis-related cysteine peptidase); GNAS (GNAS Complex Locus); MMP9 (matrix metalpeptidase 9 (gelatinase B, 92 kDa gelatinase, 92 kDa type IV collagenase)); NOTCH2 (Notch homologue 2 (Drosophila)); CREB1 (cAMP response element binding protein 1); SNCA (synuclein, alpha (non-A4 component of amyloid precursor)); OPRM1 (opium receptor, mu 1); CALM1 (calmodulin 1 (phosphorylase kinase, delta)); PLCG1 (phospholipase C, gamma 1); BRCA1 (breast cancer 1, early signs); APOE (Apolipoprotein E); DBH (dopamine beta-hydroxylase (dopamine beta-monooxygenase)); PTGS2 (prostaglandin-andopeoxide synthase 2 (prostaglandin G / H synthase and cyclooxygenase)); ADRBK1 (adrenergic, beta, receptor kinase 1); ITGB4 (integrin, beta 4); NLGN3 (Nurorigin 3); CD36 (CD36 molecule (thrombospondine receptor)); EEF2 (eukaryotic detoxification factor 2); OPRD1 (opium receptor, delta 1); HSPG2 (heparan sulfate proteoglycan 2); GAD1 (glutamate decarboxylase 1 (brain, 67 kDa)); ANXA1 (annexin A1); PRKAR2A (protein kinase, cAMP-dependent, regulatory, type II, alpha); HHEX (hematopoietically expressed homeobox); GRM1 (glutamate receptor, metabotropic 1); NPR1 (sodium release peptide receptor A / guanylate cyclase A (atrial fibrillation sodium release), peptide receptor A); SYP (synaptophycin); CALM3 (calmodulin 3 (phosphorylase kinase, delta)); PRKAR2B (protein kinase, cAMP-dependent, regulatory, type II, beta); ADCY2 (adenylate cyclase 2 (brain)); SLC1A3 (solute carrier family 1 (glue high affinity glutamate transport), member 3); GABBR1 (gamma-aminobutyl acid (GABA) B receptor, 1); PTPRS (protein tyrosine phosphatase, receptor type, S); KNG1 (kinnogen 1); DDC (dopa decarboxylase (aromatic L-amino acid decarboxylase)); GNAQ (guanine nucleotide binding protein (G protein), q polypeptide); E2F4 (E2F transcription factor 4, p107 / p130-binding); DRD4 (dopamine receptor D4); MAOA (monoamine oxidase A); CALM2 (calmodulin 2 (phosphorylase kinase, delta)); CHRNB2 (cholinergic receptor, nicotinic, beta 2 (neurons)); GRK5 (G protein-linked receptor kinase 5); PRLR (prolactin receptor); ID2 (inhibitor of DNA binding 2, dominant negative helix-loop-helix protein); TPH1 (tryptophan hydroxylase 1); PLCD1 (phospholipase C, delta 1); GNA11 (guanine nucleotide binding protein (G protein), alpha 11 (Gq classification)); GNA12 (guanine nucleotide binding protein (G protein) alpha 12); CRH (Adrenal Cortical Stimulating Hormone-releasing Hormone); GNRH1 (gonadotropin-releasing hormone 1 (luteinated-releasing hormone)); S100A8 (S100 calcium binding protein A8); CYCS (cytochrome c, of the body); KCNB1 (potassium potential-gated channel, Shab-associated subfamily, member 1); DST (distonin); ADCY1 (adenylate cyclase 1 (brain)); CHGA (chromogranin A (parathyroid secretion protein 1)); HTR3A (5-hydroxytryptamine (serotonin) receptor 3A); GAL (galanine prepropeptide); TACR3 (tachikinin receptor 3); ALDH7A1 (aldehyde dehydrogenase 7 family, member A1); PRKAR1B (protein kinase, cAMP-dependent, regulatory, type I, beta); AQP5 (aquaporin 5); AQP2 (aquaporin 2 (collection duct)); AQP1 (aquaporin 1 (Colton blood group)); GLI3 (GLI Family Zinc Finger 3); POU2F1 (POU Class 2 Homeobox 1); OTX2 (orthodental homeobox 2); TTR (transtyretin); CACNA1B (calcium channel, potential-dependent, N type, alpha 1B subunit); IKBKAP (inhibitor of kappa light polypeptide gene enhancer, kinase complex-associated protein in B-cells); RHO (rhodosin); UGT2B7 (UDP glucuronosyltransferase 2 family, polypeptide B7); LCT (lactas); TCOF1 (Treacher Collins-Franceschetti Syndrome 1); KCNJ1 (potassium inward-rectifying channel, subfamily J, member 1); VIP (vascular intestinal peptide); AQP3 (aquaporin 3 (Gill blood group)); TAC1 (tachikinin, precursor 1); ADCY4 (adenylate cyclase 4); HP (haptoglobin); ALDH4A1 (aldehyde dehydrogenase 4 family, member A1); GDI1 (GDP dissociation inhibitor 1); SOX2 (SRY (sex determination portion Y) -box 2); NOG (nogin); FST (polystatin); NDST1 (N-deacetylase / N-sulfotransferase (heparan glucosaminyl) 1); ABLIM1 (actin binding LIM protein 1); NOS2 (nitric oxide synthase 2, inducible); EIF2B1 (eukaryotic translation initiation factor 2B, subunit 1 alpha, 26 kDa); CA6 (carbonate dehydratase VI); DKK1 (dickkopf homolog 1 (African claw frog)); SIX3 (SIX Homeobox 3); SIX1 (SIX Homeobox 1); HTT (hunting tin); AGRP (Auguti Related Protein Homolog (Mouse)); NCAM2 (nerve cell adhesion molecule 2); BBS4 (Bardet-Biedl Syndrome 4); GNA15 (guanine nucleotide binding protein (G protein), alpha 15 (Gq classification)); GNA13 (guanine nucleotide binding protein (G protein), alpha 13); ASCL1 (achaete-scute complex homolog 1 (Drosophila)); MGLL (monoglyceride lipase); PLCD3 (phospholipase C, delta 3); CEBPB (CCAAT / Enhancer Binding Protein (C / EBP), Beta); BBS1 (Bardet-Biedl Syndrome 1); HES1 (split's parent and enhancer 1, (Drosophila)); GNG2 (guanine nucleotide binding protein (G protein), gamma 2); TPH2 (tryptophan hydroxylase 2); P2RX3 (purinergic receptor P2X, ligand-gated ion channel, 3); AQP7 (aquaporin 7); CNGB1 (cycle nucleotide gated channel beta 1); GABRR1 (gamma-aminobutyl acid (GABA) receptor, rho 1); GBX2 (intestinal embryonic brain homeobox 2); SLC6A1 (solute carrier family 6 (neurotransmitter transport, GABA), member 1); PEBP1 (phosphatidylethanolamine binding protein 1); KRT13 (Keratin 13); NAV2 (neuron navigator 2); BBS2 (Bardet-Biedl Syndrome 2); PLCD4 (phospholipase C, delta 4); CLDN8 (Claudine 8); CLDN7 (Claudin 7); CISH (cytokine inducible SH2-containing protein); GNGT2 (guanine nucleotide binding protein (G protein), gamma transducing active polypeptide 2); GNG4 (guanine nucleotide binding protein (G protein), gamma 4); GNA14 (guanine nucleotide binding protein (G protein), alpha 14); UCN (urocortin); PDE4A (phosphodiesterase 4A, cAMP-specific (phosphodiesterase E2 Higgs homologue, Drosophila)); MKKS (McKusick-Kaufman Syndrome); GAST (gastrin); PRKX (protein kinase, X-linked); CHRD (Cordin); PRSS2 (protease, serine, 2 (trypsin 2)); KRT20 (Keratin 20); CLDN6 (Claudin 6); CLCN4 (chloride channel 4); DLX5 (terminal-free homeobox 5); TRPA1 (transitory receptor capable cation channel, subfamily A, member 1); TRPM8 (transitory receptor capable cation channel, subfamily M, member 8); PLCZ1 (phospholipase C, zeta 1); SLC5A2 (solute carrier family 5 (sodium / glucose cocarrier), member 2); GDF11 (growth differentiation factor 11); BLVRB (bililidine reductase B (flavin reductase (NADPH))); SCN7A (sodium channel, translocation-gated, type VII, alpha); PANX1 (Panexin 1); IFI35 (interferon-derived protein 35); NRAP (nebulin-associated anchoring protein); HES5 (split's parent and enhancer 5 (Drosophila)); GSC (goosecoid homeobox); REEP1 (receptor accessory protein 1); CCL28 (chemokine (C-C motif) ligand 28); GJB4 (gap binding protein, beta 4, 30.3 kDa); B3GNT2 (UDP-GlcNAc: betaGal Beta-1,3-N-acetylglucosaminyltransferase 2); CNGA2 (cycle nucleotide gated channel alpha 2); ZNF423 (Zinc Finger Protein 423); HESX1 (HESX Homeobox 1); CNGA4 (cycle nucleotide gated channel alpha 4); GPR158 (G protein-linked receptor 158); MAGEL2 (MAGE-like 2); UBR3 (ubiquitin protein ligase E3 component n-recognin 3 (estimated)); NPTXR (neuron pentracin receptor); SLC24A6 (solute carrier family 24 (sodium / potassium / calcium exchanger), member 6); GPRC6A (G protein-linked receptor, family C, group 6, member A); SLC24A3 (solute carrier family 24 (sodium / potassium / calcium exchanger), member 3); BEST2 (bestospin 2); OR8D2 (olfactory receptors, family 8, subfamily D, member 2); OR5P2 (olfactory receptors, family 5, subfamily P, member 2); FOXG1 (Forkhead Box G1); OR8B8 (olfactory receptors, family 8, subfamily B, member 8); OR8D1 (olfactory receptors, family 8, subfamily D, member 1); OR10A5 (olfactory receptors, family 10, subfamily A, member 5); OMP (olfactory marker protein); TFAP2E (transcription factor AP-2 epsilon (activated enhancer binding protein 2, epsilon); OR5P3 (olfactory receptor, family 5, subfamily P, member 3); OR10A4 (olfactory receptor, family 10, subfamily A, member 4) DMRTA1 (DMRT-like family A1); TMEM147 (membrane transmembrane 147); OR8A1 (olfactory receptors, family 8, subfamily A, member 1); EBF2 (initial B-cell factor 2); PKD1L3 (polycystic kidney disease 1 -Like 3); GPR179 (G protein-linked receptor 179); RTP1 (receptor (chemical sensory) carrier protein 1); KLHL35 (Kelch-like 35 (Drosophila)); RGS21 (modulator 21 of G-protein signaling) RTP2 (receptor (chemosensory) transporter protein 2); ACSM4 (acyl-CoA synthase medium-chain family member 4); GUCY2E (guanylate cyclase 2E); CYP2G1P (cytochrome P450, family 2 , Subfamily G, polypeptide 1 false gene); OR7E35P (olfactory receptor, family 7, subfamily E, member 35 false gene); and NUDT1 6P1 (nudics (nucleoside diphosphate linked moiety X-type motif 16, false gene 1).

Typical sensory-related chromosomal sequences include TRPM7 (temporary receptor capable cation channel, subfamily M, member 7); TRPM5 (transitory receptor capable cation channel, subfamily M, member 5); TRPC5 (temporary receptor capable cation channel subfamily C member 5); TRPC6 (transitory receptor capable cation channel subfamily C member 6); TRPC1 (transitory receptor capable cation channel subfamily C member 1); CNR1 (cannabinoid receptor 1 (brain)); CNR2 (cannabinoid receptor 2 (macrophages)); ADRBK1 (adrenergic beta receptor kinase 1); TRPA1 (transitory receptor capable cation channel subfamily A member 1); POMC (propiomelanocortin); CALCA (CGRP, calcitonin-associated polypeptide alpha); CRF (CRH, corticotropin releasing factor); PRKACA (protein kinase cAMP-dependent catalytic alpha), PRKACB (protein kinase cAMP-dependent catalyst beta), PRKAR1A (protein kinase cAMP-dependent regulatory type I alpha (tissue specific luminescent 1)), and PRKAR2A (protein kinase cAMP- PKA such as dependent regulatory type II alpha); ERAL1 (Era G-protein-like 1 (E. coli)); NR2B (GRIN2B, glutamate receptor ionic N-methyl D-aspartate 2B); LGALS1 (lectingalactosid-binding soluble 1); TRPV1 (temporary receptor capable cation channel subfamily V member 1); SCN9A (sodium channel translocation-gated type IX alpha subunit); OPRD1 (opium receptor delta 1); OPRK1 (opium receptor kappa 1); And OPRM1 (opium receptor mu 1).

In certain embodiments, animals created by the methods of the invention can be used to study the effects of mutations in animals and sensory disorders.

Additional aspects of the disclosure include methods of assessing sensory impairment signs in an animal model, where the animal model comprises a genetically modified animal comprising at least one edited chromosome sequence that encodes a sensory-related protein. do. The method involves comparing selected variables obtained from wild-type animals with selected variables obtained from animal models. Non-limiting examples of selected variables used to assess at least one symptom of sensory disorders include a) spontaneous behaviors; b) performance during behavioral assessments; c) physiological anomalies; d) abnormal in tissue or cells; e) biochemical function; f) molecular structures; And combinations thereof.

Sensory disorders assessed by this method may include any one or more of the perceptual and taste disorders associated with the genes described above. Non-limiting examples of nociceptive disorders such as allodynia; neuralgia; Congenital sensorineural infinite increase, ulceration - cutting neuropathy, Thevenard syndrome, familial neurosis nutrition, family perforation bottles (mal perforant du pied ), familial myelopathy, and HSAN-1 such as Charcot-Marie-Tooth type 2B syndrome; HSAN-2, such as congenital sensory neuropathy or Morvan disease; HSAN-3, such as familial autonomic neuropathy (FD) or Riley-Day syndrome; HSAN-4, such as congenital analgesia (CIPA); And HSAN-5, such as congenital analgesia and infinity. Non-limiting examples of taste disorders include taste disorders, taste decline, and tastelessness.

Signs of sensory disorders may occur spontaneously in animal models or may be promoted by exposure to exogenous substances, including but not limited to nociceptive stimuli, taste stimuli, sensory-related proteins, sensory-related agonists, and sensory-related antagonists. have.

C. ABC  Transport material

ABC carrier proteins are a superfamily of large and important membrane carrier proteins that are ubiquitous in the animal kingdom. These transmembrane proteins include energy for hydrolyzing ATP, including the translocation of molecules across intracellular and extracellular membranes, and sometimes using energy to exert a variety of functions against concentration gradients (see Higgins, CF, ABC). transporters from microorganisms to man , Annu . Rev. Cell Biol . 8 67-113 (1992); and M. Dean , Human ABC Transporter Superfamily , Bethesda ( MD ): National Center for Bitechnology Information ( US ); November 18, 2002, available online at www. ncbi.nlm.nih.gov/bookshelf/br.fcgi? book = mono _001 ).

In one embodiment, the methods of the invention can be used to create an animal or cell in which at least one chromosomal sequence associated with an ABS carrier is edited. Suitable chromosomal editing includes, but is not limited to, the type of editing described in paragraph I (f) above.

The ABC carrier chromosomal sequence may encode an ABC carrier protein or may be an ABC carrier regulatory sequence. ABC carrier sequences are typically selected based on experimental association of ABC carrier sequences for animal diseases or conditions, particularly for mammalian (eg, human) diseases or conditions. For example, the expression of ABC carrier proteins in certain tissues may be elevated or inhibited in populations with ABC carrier related diseases or conditions relative to the population lacking such diseases or conditions. Differences in protein levels can be assessed using proteomic or genomic analysis techniques known in the art.

Non-limiting examples of human ABC carrier genes include: ABCA1 (ABC1), ABCA2 (ABC2), ABCA3 (ABC3), ABCC, ABCA4 (ABCR), ABCA5, ABCA6, ABCA7, ABCA8, ABCA9, ABCA10 , ABCA12, ABCA13, ABCB1 (PGY1, MDR), ABCB2 (TAP1), ABCB3 (TAP2), ABCB4 (PGY3), ABCB5, ABCB6 (MTABC), ABCB7 (ABC7), ABCB8 (MABC1), ABCB9, ABCB10 (MTABC2) , ABCB11 (SPGP), ABCC1 (MRP1), ABCC2 (MRP2), ABCC3 (MRP3), ABCC4 (MRP4), ABCC5 (MRP5), ABCC6 (MRP6), CFTR (ABCC7), ABCC8 (SUR), ABCC9 (SUR2) , ABCC10 (MRP7), ABCC11 (ABCC12), ABCD1 (ALD), ABCD2 (ALDL1, ALDR), ABCD3 (PXMP1, PMP70), ABCD4 (PMP69, P70R), ABCE1 (OABP, RNS4I), ABCF1 (ABC50), ABCF2 (ABCF3), ABCG1 (ABC8, White), ABCG2 (ABCP, MXR, BCRP), ABCG4 (White2), ABCG5 (White3), and ABCG8.

Non-limiting examples of mouse ABC transporter genes include: Abca1, Abca2, Abca3, Abca4, Abca5, Abca6, Abca7, Abca8a, Abca8b, Abca9, Abca12, Abca13, Abcb1a, Abcb1b, Abcb2 (Tap1), Abcb3 (Tap2), Abcb4, Abcb5, Abcb6, Abcb7, Abcb8, Abcb9, Abcb10, Abcb11, Abcc1, Abcc2, Abcc3, Abcc4, Abcc5, Abcc6, Abcc7 (Cftr), Abcc8, Abcc9, Abcc10, Abcc11, Abcd1, Abcd2, Abcd3, Abcd3 , Abcd4, Abce1, Abcf1, Abcf2, Abcf3, Abcg1, Abcg2, Abcg3, Abcg4, Abcg5 and Abcg8.

The Drosophila genome contains 56 ABC carrier genes with at least one representative of each of the known mammalian subfamily. Non-limiting examples of Drosophila ABC transporter genes include: G3156 (AAF45509, AE003417); CG2759 (w; AAF45826; AE003425); CG1703 (AAF48069; AE003486); CG1824 (AAF48177; AE003489); CG9281 (AAF48493; AE003500); CG8473 (AAF48511; AE003500); CG12703 (AE003513; AE003513); CG1819 (AAF50847; AE003569); CG1718 (AAF50837; AE003568); CG1801 (AAF50836; AE003568); CG1494 (AAF50838; AE003568); CG3164 (AAF51548; AE003590); CG4822 (AAF51551; AE003590); CG17646 (AAF51341; AE003585); CG9892 (AAF51223; AE003582); CG9664 (AAF51131; AE003580); CG9663 (AAF51130; AE00358); CG3327 (AAF51122; AE003580); CG2969 (Atet; AAF51027; AE003576); CG11147 (AAF52284; AE003611); CG7806 (AAF52639; AE003620); CG7627 (AAF52648; AE003620); CG5853 (AAF52835; AE003626); CG5772 (Sur; AAF52866; AE003627); CG6214 (AAF53223; AE003637); CG7491 (AAF53328; AE003641); CG17338 (AAF53736; AE003661); CG10441 (AAF53737; AE003661); CG9270 (AAF53950; AE003668); CG8799 (AAF58947; AE003833); CG3879 (Mdr49 AAF58437; AE003820); CG8523 (Mdr50; AAF58271; AE003815); CG8908 (AAF57490; AE003792); CG10505 (AAF46706; AE003453); CG17632 (bw; AAF47020; AE003461); CG7955 (AAF47526; AE003472); CG10226 (AAF50670; AE003563); Mdr65 (AAF50669; AE003563); CG5651 (AAF50342; AE003553); CG7346 (AAF50035; AE003544); CCG4314 (st; AAF49455; AE003527); CG5944 (AAF49305; AE003522); CG6052 (AAF49312; AE003523); CG9330 (AAF49142; AE003516); CG14709 (AAF54656; AE003692); CG4225 (AAF55241; AE003710); CG4562 AAF55707; AE003728); CG4794 (AAF55726; AE003728); CG5789 (AAF56312; AE003748); CG18633 (AAF56360; AE003749); CG11069 (AAF56361; AE003749); CG6162 (AAF56584; AE003756); CG9990 (AAF56807; AE003766); CG11898 (AAF56870; AE003768); CG11897 (AAF56869; AE003768); And CG2316 (AAF59367; AE003844).

Typical ABC carrier proteins include MDR1, BCRP (ABCG2), MRP1 (ABCC2) and MRP2 (ABCC2), and their mouse homologues Mdr1a (Abcb1a), Mdr1b (Abcb1b), Bcrp (Abcg2), Mrp1 (Abcc1), and Mrp2 (Abcc2), and any combination thereof. As used herein, genetic names refer to those of the human and mouse genome, but include, but are not limited to, invertebrates such as C. elegans and D. melanogasster , and mice, hamsters, cats, and dogs. It is to be understood that it includes any of their proximity homologs identified in mammals. Proximity homologues can be identified by sequence analysis, phylogenetic analysis, function analysis, or any combination thereof.

In certain embodiments, animals created by the methods of the present invention can be used to study the effects of mutations in an animal or ABC vehicle.

v. Humanized model

Animals created by the methods of the present invention can be used as humanized models. Humanized models express human nucleic acid sequences in non-human animals as described above. In one embodiment, the field of study or model described in paragraph II (a) can be a humanized model. In another embodiment, livestock or companion animals can also be humanized as described below.

(b) livestock use;

In an embodiment, the methods of the present invention can be used to create livestock with one or more chromosomal edits resulting in one or more desirable properties. As used herein, “livestock” refers to animals that can be raised for profit. Non-limiting examples of livestock are listed in this paragraph and described in detail below.

Non-limiting examples of desirable features include specific skin color or texture, disease resistance, increased fertility, increased meat production, increased muscle to fat ratio, increased milk production, reduced fecal contamination, and the like. In another embodiment, the methods of the invention can be used to create chromosomal edited livestock among the genes listed in Table D.

In addition, in typical embodiments, the livestock may be sheep, horses, cattle, or pigs, as described below.

i. amount( ovine Apply to)

In one embodiment, the methods of the present invention can be used to create an amount or amount of cells in which at least one chromosomal sequence has been edited. Non-limiting examples of the amount of chromosomal sequence to be edited may include encoding proteins associated with skin color, pattern, hair fiber structure, and disease resistance. Non-limiting examples of coat color, pattern, hair fiber structure include MSH receptor proteins, agouti protein, tyrosinase related proteins and keratin-related proteins. Non-limiting examples of suitable envelope color proteins include tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1), aguti signaling protein (ASIP), and melanophylline (MLPH). One of ordinary skill in the art has other proteins associated with skin color, pattern, and hair fiber structure, but the genetic loci encoding these other proteins have not yet been identified. Non-limiting examples of sequences related to disease resistance are associated with disseminated spongiform encephalopathy (TSE) with PRPN.

In one embodiment, the methods of the invention can be used to create a genetically modified amount comprising at least one edited chromosomal sequence that exhibits a desired phenotype in humans. For example, inactivation of chromosomal sequences encoding Aguti can result in sheep with striped colors. In other embodiments, the amount comprising at least one edited chromosomal sequence can be used as a model to study the genetics of skin color, skin pattern, and / or hair growth. In addition, an amount comprising at least one chromosomal sequence that is destroyed can be used as a disease model to study a disease or condition that affects humans or other animals. Non-limiting examples of suitable diseases or conditions include cutaneous albinism, hair disorders, and hairless conditions. In addition, both published cells and lysates of these cells can be used for similar research purposes.

ii . Applied to horse

In one embodiment, the methods of the present invention can be used to create horses or horse cells in which at least one chromosomal sequence has been edited. Non-limiting examples of horse chromosomal sequences that are edited may include encoding proteins associated with envelope color, pattern, and disease resistance.

Non-limiting examples of suitable envelope color genes encoding proteins for envelope color and pattern include Extension (Black / Red Factor), Aguti, MC1R, Gray Modifier, Champagne Dilution, Tobiano, Silver Dilution, MATP (Cream Dilution) , Pearl Dilution, and Sabino1. Those skilled in the art will appreciate that there are other genes and proteins associated with envelope color and envelope pattern, but the genetic loci encoding these other proteins have not yet been identified.

In a further embodiment, the methods of the present invention can be used to create genetically modified horses comprising an edited chromosomal sequence encoding HERDA, wherein the chromosomal sequence is inactivated such that a particular allele of the HERDA protein is not produced. do. Moreover, genetically modified words with inactivated HERDA variants of the chromosomal sequence described herein may represent a reduced development and delivery carrier of HERDA. In a non-limiting embodiment, the genetically modified word may comprise an edited chromosomal sequence that encodes HERDA. In alternative non-limiting embodiments, the genetically modified horse may comprise an edited chromosomal sequence that inactivates HERDA only in a variant form known as a carrier.

In another embodiment, the methods of the present invention can be used to create genetically modified horses comprising an edited chromosomal sequence encoding HYPP, wherein the chromosome sequence is inactivated by the HYPP dominant allele, and the HYPP protein Is disabled so that it is not created. Moreover, genetically modified horses with inactivated HYPP dominant alleles and chromosomal sequences described herein may exhibit a reduction in the transmission and perpetuation of HYPP in horses. By way of non-limiting example, a genetically modified word may comprise an edited chromosomal sequence that encodes HYPP.

In another embodiment, the methods of the invention can be used to create genetically modified horses comprising an edited chromosomal sequence that encodes an Overo protein, wherein the chromosome sequence is produced by a particular allele of the Overo protein. And / or not fatal, but are disabled to still create overo frame phenotypes. By way of non-limiting example, such genetically modified words comprise an edited chromosomal sequence encoding Overo, wherein the dominant allele is inactivated. Alternative non-limiting examples may include an edited chromosomal sequence that inactivates Overo only in variant forms known to express lethal or detrimental phenotypes. In another embodiment, the modification alters a two nucleotide TC-> AG mutation to revert the mutation from an EDNRB protein to isoleucine.

In a further embodiment, the methods of the present invention can be used to create genetically modified horses comprising an edited chromosomal sequence encoding GBE, wherein the chromosomal sequence is inactivated and the corresponding protein is It is disabled so that it is not created. Moreover, genetically modified horses with inactivated GBE variants may indicate a reduced occurrence and carrier of GBE. By way of non-limiting example, such genetically modified words may comprise an edited chromosomal sequence encoding GBE. In alternative non-limiting embodiments, such genetically modified horses may comprise an edited chromosomal sequence that inactivates GBE only in variant forms known to express fatal or detrimental phenotypes.

In alternative embodiments, the methods of the present invention can be used to create genetically modified horses comprising an edited chromosomal sequence encoding JEB, wherein the chromosomal sequence is inactivated by the JEB recessive allele and produced by the JEB protein. It is deactivated so as not to lose. Moreover, genetically modified horses with inactivated JEB variants may indicate reduced occurrence and transmission of JEB. By way of non-limiting example, such genetically modified words may comprise an edited chromosomal sequence encoding JEB. In alternative non-limiting embodiments, such genetically modified horses may comprise an edited chromosomal sequence that inactivates JEB only in variant forms known to express lethal or detrimental phenotypes.

In an alternative embodiment, the methods of the invention can be used to create genetically modified horses comprising an edited chromosomal sequence encoding PSSM, wherein the chromosomal sequence is inactivated and the protein is not made. Is deactivated. Moreover, genetically modified horses with inactivated PSSM dominant alleles and chromosomal sequences described herein may exhibit a decrease in the transmission and perpetuation of PSSM in horses. By way of non-limiting example, genetically modified words can include an edited chromosomal sequence that encodes a PSSM.

In other alternative embodiments, the methods of the present invention comprise an edited chromosomal sequence comprising C / C, C / T or T / T variants of myostatin for speed and sport performance, depending on the nature of the desired phenotypic feature. It can be used to create genetically modified words.

The methods of the invention can also be used to create genetically modified horses comprising any combination of the chromosomal alterations described above. For example, genetically modified horses can include inactivated aguti and / or edited PSSM chromosomal sequences, modified MATP chromosomal sequences, and / or modified or inactivated JEB chromosomal sequences.

The horse or horse cells described herein will have several uses. In one embodiment, a genetically modified horse comprising at least one edited chromosomal sequence may exhibit a desired phenotype by humans. For example, inactivation of the chromosomal sequence encoding Aguti can result in a horse with a striped outer sheath. In other embodiments, a horse comprising at least one edited chromosomal sequence can be used as a model to study the genetics of skin color, skin pattern, and / or hair growth. In addition, a horse comprising at least one disrupted chromosomal sequence can be used as a model for studying a disease or condition affecting humans or other animals (see paragraph II (a) above). Non-limiting examples of suitable diseases or conditions include skin diseases such as Hyperderlastosis Cutis, or muscle diseases such as high calcium cycle paralysis, fatal White Overo syndrome, glycogen branching enzyme defect disorders, and polysaka Ride storage myopathy, recurrent motility rhabdomyolysis (RER), severely complex immunodeficiency disorders (SCID), in addition to skin rash, hair disorders, and peeling. In addition, the described equine cells and lysates of these cells can be used for similar research purposes.

iii . Apply to pig

In one embodiment, the methods of the present invention can be used to create porcine or swine cells in which at least one chromosomal sequence has been edited. Non-limiting examples of porcine chromosomal sequences that are edited and / or inserted include sequences that reduce phosphate contamination such as skin color, pattern, disease resistance, meat quality, litter size increase, meat / fat ratio, and phytase. May contain things that code.

In certain embodiments, the methods of the invention can be used to create a pig comprising a chromosomal sequence in a nucleic acid sequence associated with an envelope color or pattern. Non-limiting examples of porcine chromosomal sequences that affect envelope color or pattern include MC1R. Melanocortin Receptor 1 (MC1R) plays a central role in the regulation of eumelanin (black / brown) and pheo melanin (red / yellow) synthesis in mammalian melanocytes, by traditional Extension (E) envelope color loci. It is encoded.

In other non-limiting embodiments, the methods of the present invention can be used to create pigs that include in-nucleic acid chromosomal editing associated with disease resistance. Such genetically modified pigs may comprise an edited chromosomal sequence such as CD163 or sialoadhension.

In another embodiment, the methods of the present invention can be used to create pigs comprising chromosomal editing in nucleic acids related to meat quality, quantity of meat and / or ratio of meat to fat. For example, non-limiting examples of porcine chromosomal sequences that are deleted or edited in pigs to increase muscle growth include encoding proteins such as myostatin / GDF8. Non-limiting examples of chromosomal sequences related to meat quality include HAL, RN, or PSS. In another embodiment, such genetically modified pigs are edited to encode sequences related to meat / fat ratios such as IGF2, GHRH, H-FABP, GH, IGF1, PIT1, GHRHR, GHR or combinations thereof. Chromosomal sequences may be included.

In another embodiment, the methods of the present invention can be used to create a pig comprising chromosomal editing in nucleic acids associated with litter production. For example, genetically modified pigs may include edited or modified chromosomal sequences that encode ESR for increased litter production.

In a further embodiment, the methods of the present invention can be used to create pigs comprising in-nucleic acid chromosomal editing associated with reduced phosphate contamination. For example, genetically modified pigs may include an edited chromosomal sequence that encodes phytase to reduce phosphate contamination.

Pork animals and cells described herein may have several uses. In one embodiment, a genetically modified pig comprising at least one edited chromosomal sequence may exhibit a desired phenotype by humans. For example, modification of the chromosomal sequence encoding one of the MC1R alleles can result in a pig with the desired coat color or pattern of hair. In other embodiments, a pig comprising at least one edited chromosomal sequence can be used as a model to study the genetics of skin color, skin pattern, and / or hair growth. In addition, pigs comprising at least one disrupted chromosomal sequence can be used as a model to study diseases or conditions that affect humans or other animals (see paragraph II (a) above). Non-limiting examples of suitable diseases or conditions include dermatitis, hair disorders, and exfoliation. In addition, the disclosed porcine cells and lysates of these cells can be used for similar research purposes as described in paragraph II (a) above.

iv . Applied to cattle

In one embodiment, the methods of the invention can be used to create a bovine or bovine cell in which at least one chromosomal sequence has been edited. Non-limiting examples of the chromosomal sequence of the bovine to be edited and / or inserted include those that encode proteins related to milk production, milk quality and processing, meat production and meat, skin color and quality, environmental impact, and breeding. do.

In certain embodiments, the methods of the present invention can be used to create cattle with intrasequential chromosomal editing related to milk production, quality and processing. By way of example, the chromosomal sequence to be edited may include casein, lactase and lactase-related proteins (eg galactosidase, lactase, galactose, beta lactoglobulin, alpha lactalbumin, lactoferrin), osteopontin, acetyl coA carboxes. Regeneration inducing peptide (RIPTAC) and other growth hormones, proline-rich polypeptide (PRP), alpha-lactalbumin (LA), lactoperoxidase, and lysozyme of carboxylase, tyrosinase and related proteins, tissues and cells have.

In another embodiment, the methods of the present invention can be used to create cattle having chromosomal editing of sequences related to meat production and meat, such as FGFR3, EVC2, MC1R, and myostatin (mh).

In other embodiments, the methods of the present invention are bovine with BSE-resistance (such as PRPN), skin color and quality (such as MC1R, TYRP1, MGF or KITLG), environmental effects, and intrasequence chromosomal editing associated with reproduction. You can create In certain embodiments, loci need not be determined, but methods known in the art can be used.

The bovine animals and cells described herein may have several uses. In one embodiment, a genetically modified cow comprising at least one edited chromosomal sequence may exhibit the desired phenotype by humans. For example, inactivation of chromosomal sequences encoding Aguti can result in cows with striped colored hulls. In other embodiments, a cow comprising at least one edited chromosomal sequence can be used as a model for studying the genetics of skin color, skin pattern, and / or hair growth. In addition, cattle comprising at least one disrupted chromosomal sequence can be used as a model to study diseases or conditions (see paragraph II (a) above) that affect humans or other animals. Non-limiting examples of suitable diseases or conditions include dermatitis, hair disorders, and exfoliation. In addition, published bovine cells and lysates of these cells may be used for similar research purposes.

(c) applies to companion animals

In another embodiment, the methods of the present invention can be used to create companion animals with one or more chromosomal edits that make one or more desirable properties. As used herein, “companion” refers to an animal that is generally raised for non-profit purposes. In some cases, however, pets may also be raised for commercial purposes. Non-limiting examples of pets are described herein and described in paragraph III below. Non-limiting examples of suitable properties suitable in companion animals include, for example, hypoallergenic, specific skin color or texture, disease resistance, reduced urine or stool odor, and the like.

In certain embodiments, the methods of the present invention can be used to create companion animals having gene editing in the genes listed in Table D above.

In typical embodiments, the methods of the present invention can be used to create a companion animal such as a cat, canine, or rabbit that includes one or more chromosomal edits. Each is discussed in detail below.

i. Cat

In one embodiment, the methods of the present invention can be used to create a cat or feline animal cell in which at least one chromosomal sequence has been edited. Non-limiting examples of cat and animal chromosomal sequences to be edited include allergen proteins, proteins involved in urine odor generation, and those encoding proteins related to coat color, coat pattern, and / or hair length.

In certain embodiments, the methods of the invention can be used to create cats and animals with chromosomal editing in nucleic acid sequences associated with underallergen production. Preferred allergen proteins are Felis domestikus domesticus ) 1 (Fel d1), which is the primary allergen present in cats, and is a heterodimer of chain 1 and chain 2 peptides encoded by cats and separate genes in the genome.

In another embodiment, the methods of the invention can be used to create cats and animals with chromosomal editing in nucleic acid sequences associated with urine odor development. For example, chromosomal editing may be in proteins associated with urine odor development, such as cauxin, which produces the major urine pheromone felinine.

In another embodiment, the methods of the present invention can be used to create cats and animals having chromosomal sequences in nucleic acid sequences that relate to envelope color, length, or pattern. Non-limiting examples of suitable envelope color proteins include tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1), auguti signaling protein (ASIP), and melanophylline (MLPH). A non-limiting example of a protein associated with hair length is fibroblast growth factor 5 (FGF5). One of ordinary skill in the art would recognize that many other proteins are related to skin color, skin pattern, and hair length, but their genetic loci have not been determined.

The animals and cells described herein may have several uses. In one embodiment, a genetically modified cat and animal comprising at least one edited chromosomal sequence may exhibit the desired phenotype by humans. For example, inactivation of a chromosome sequence encoding Fel d1 can result in a hypoallergenic or non-allergic cat. In other embodiments, a cat and animal comprising at least one edited chromosomal sequence can be used as a model for studying the genetics of skin color, skin pattern, and / or hair growth. Additionally, cats and animals containing at least one disrupted chromosomal sequence can be used as a model to study diseases or conditions (see paragraph II (a) above) that affect humans or other animals. Non-limiting examples of suitable diseases or conditions include skin rash, deafness, skin disorders, hair disorders, and hair peeling. In addition, published bovine cells and lysates of these cells may be used for similar research purposes.

ii . rabbit

In one embodiment, the methods of the invention can be used to create rabbit or rabbit cells in which at least one chromosomal sequence has been edited. Non-limiting examples of rabbit chromosomal sequences to be edited and / or inserted may include those associated with cardiovascular disease, immunodeficiency, and envelope color, pattern, and / or length.

In one embodiment, the methods of the invention can be used to create a rabbit comprising one or more chromosomal edits in a sequence associated with cardiovascular disease. Non-limiting examples of rabbit chromosomal sequences associated with cardiovascular disease include apo A, apoA-I, apoB, apoE2, apoE3 and lecithin-cholesterol acyltransferase (LCAT), as well as rabbit apolipoprotein B, mRNA-editing enzyme catalysis Poly-peptide 1 (APOBEC-1). Moreover, non-limiting examples of rabbit chromosomal sequences to be edited encode proteins associated with autosomal dominant disease-family hypertrophic cardiomyopathy (FHC). FHC can be caused by multiple mutations in the gene encoding various contractile, structural, channel and kinase proteins.

In another embodiment, the methods of the invention can be used to create rabbits comprising chromosomal editing in nucleic acid sequences associated with immunodeficiency. Non-limiting examples of rabbit chromosomal sequences that are edited include fumarylacetoacetate hydrolase (FAH), recombinant-activated gene-1 (Rag1), recombinant-activated gene-1 (Rag2), forkhead box O1 (FOXO1), DNAPK (dsDNA-dependent protein kinase), IL2 gamma receptor.

The method of the invention can also be used to create genetically modified rabbits comprising any combination of the chromosomal modifications described above. For example, genetically modified rabbits may be modified or inactivated FAH, and / or modified or inactivated RAG1 chromosomal sequences, and / or modified RAG2 chromosomal sequences, and / or modified or inactivated FOXO1, DNAPK. And / or IL2 gamma receptors. All chromosomal alterations and any combination described above can be used for hepatocyte expansion in humans or other sources and can be used for drug metabolism studies, toxicology studies, safety assessment studies, infectious disease studies, chronic liver disease, acute liver disease, hepatocytes. Carcinoma, hepatitis, and any other liver infection or disease.

In another embodiment, the methods of the present invention can be used to create a genetically modified rabbit comprising an edited chromosomal sequence that encodes a hairless homolog protein ( hr ). Rabbits with mutations at the hr locus seem to develop normal hair follicles (HF), seemingly to develop, but will be completely stripped of rabbit hair shortly after birth. Genetically modified rabbits containing the edited hr chromosomal sequence are organisms for wound treatment assays, skin irritation assays, viral infections, treatment of bacterial infections, mating to other rabbit models, and any use that requires shaving normal rabbits. Can be used as a model.

In addition, the methods of the present invention can be used to create genetically modified rabbits comprising any combination of the chromosomal alterations described above. For example, genetically modified rabbits may be inactivated ApoE, and / or FAH, and / or RAG1 chromosomal sequences, and / or modified RAG2 chromosomal sequences, and / or modified or inactivated FOXO1, DNAPK, and / or Or IL2 gamma receptors, and / or hairless homologous protein chromosomal sequences.

The animals and cells described herein may have several uses. In one embodiment, a genetically modified rabbit comprising at least one edited chromosomal sequence may exhibit a desired phenotype by humans. For example, inactivation of chromosomal sequences encoding hairless homologous genes can result in hairless rabbits immediately after birth, and these rabbits do not need the hair shaving that is sometimes necessary for various experimental applications. In other embodiments, the rabbit comprising at least one edited chromosomal sequence can be used as a model for genetic studies of skin color, skin pattern, and / or hair growth, body size, bone development, and muscle development and structure. have. In addition, rabbits comprising at least one disrupted chromosomal sequence can be used as a model to study diseases or conditions (see paragraph II (a) above) that affect humans or other animals. Non-limiting examples of suitable diseases or conditions include cardiovascular diseases, eye diseases, thyroid disease, autoimmune diseases, and immunodeficiency. In addition, the published rabbit cells and lysates of these cells can be used for similar research purposes.

iii . Canine  animal( canine )

In one embodiment, the methods of the invention can be used to create canine animals or canine animal cells in which at least one chromosomal sequence has been edited. Non-limiting examples of canine animal chromosomal sequences to be edited and / or inserted include allergenic proteins, limb length, body size, sheath color, patterns, and / or vagina, and those encoding diseases.

In certain embodiments, the methods of the invention can be used to create canine animals having one or more chromosomal edits in nucleic acid sequences associated with underallergen production. Non-limiting examples of such canine animal chromosomal sequences include Can f 1. Dogs with Can f 1 "knock-out" or strain may be underallergen or non-allergenic, and / or not barking excessively.

In other embodiments, the methods of the present invention can be used to create canine animals with one or more chromosomal edits in nucleic acid sequences related to limb length or body size. By way of example, suitable nucleic acid sequences include fibroblast growth factor-4 (FGF4) and insulin-like growth factor-1 (IGF-1).

In another embodiment, the methods of the present invention can be used to create canine animals having one or more chromosomal edits in nucleic acid sequences related to envelope color, pattern, length, and / or quality. For example, suitable nucleic acid sequences include soft and stiff textures (T-spondin-2, PSPO2 for stiff wool), long and short hairs (fibroblast growth factor-5, FGF5), curly hair and straight hair (keratin71). , KRT71), Hairless (Fork Head Box Transcription Factor Family, FOX13), Envelope Color (Melanocortin 1 Receptor, Mclr; Aguti; and β-defensin, CBD103), and Complete or Partial Partial Pigmentation (Small Eyes) Syndrome-associated transcription factor (MITF). One skilled in the art recognizes that other proteins are related to skin color, skin pattern, and hair length, but these loci have not been determined.

In further embodiments, the methods of the present invention can be used to create canine animals having one or more chromosomal edits in nucleic acid sequences associated with human disease. Non-limiting examples of such diseases include vision disorders, kidney cancer, narcolepsy, rheumatoid arthritis, SCIDs, keratin-related diseases, cystinuria, bleeding disorders, ceroid lipofucinosis and copper poisoning. In one embodiment, the genetically modified canine animal may comprise an edited chromosomal sequence that encodes the hypocretin-2-receptor gene HCRTR2. In another embodiment, chromosomal editing may be at the RCND locus. In another embodiment, the genetically modified canine animal may comprise an edited chromosomal sequence that encodes the protein polycurin. In another embodiment, the genetically modified canine animal may comprise chromosomal editing in the RPE65 gene.

The method of the present invention can be used to create genetically modified canines including any combination of chromosomal alterations described above. For example, genetically modified canines may comprise an inactivated Can f 1 and / or aguti chromosome sequence, a modified FGF4 chromosome sequence, and / or a modified or inactivated HCRTR2, RCND, and / or RPE65 chromosome sequence. It may include.

Canine animals and cells created by the methods of the invention may have several uses. In one embodiment, a genetically modified canine animal comprising at least one edited chromosomal sequence may exhibit a desired phenotype by a human. For example, inactivation of the chromosomal sequence encoding Can f 1 may result in dogs that are underallergen or non-allergenic, and / or do not overbark.

In other embodiments, a canine animal comprising at least one edited chromosomal sequence is a model for studying skin color, skin pattern, and / or hair growth, body size, leg length versus width, and skull-like genetics. Can be used as Additionally, canine animals containing at least one disrupted chromosomal sequence can be used as a model to study diseases or conditions (see paragraph II (a) above) that affect humans or other animals. Non-limiting examples of suitable diseases or conditions include cancer, deafness, heart disease, cataracts, hip dysplasia, thyroid disease, fixation, autoimmune diseases, progressive retinal atrophy and epilepsy. In addition, published canine cells and lysates of these cells can be used for similar research purposes.

(d) applied to biomolecule production

In certain embodiments, the methods of the present invention can be used to create animals or cells that produce biomolecules. For example, in one embodiment, the methods of the present invention can be used to create an animal or cell comprising one or more chromosomal edits such that the animal or cell produces a biomolecule that typically does not produce an animal or cell without chromosomal editing. have. For example, the methods of the present invention can be used to create cells that produce antibiotics. Alternatively, the method of the present invention can be used to create cattle that produce the desired biomolecules in their milk, as described in paragraph II (b) above.

A further aspect of the invention includes a method of producing purified biological components using genetically modified cells or animals comprising an edited chromosomal sequence encoding a protein. Non-limiting examples of such biological components include antibodies, cytokines, signal proteins, enzymes, receptor agonists and receptor antagonists.

In another embodiment, the methods of the present invention can be used to create an animal or cell comprising one or more chromosomal edits such that the animal or cell produces a modified biomolecule, compared to the biomolecule typically produced by the animal or cell. Can be. By way of example, the method of the present invention can be used to create silkworms comprising chromosomal editing such that silkworms produce more desirable silk. Non-limiting examples of silkworm chromosomal sequences to be edited are those that encode proteins specifically expressed in the silk gland. The silk gland is the site where silk proteins are synthesized and can be divided into three distinct compartments morphologically and functionally: ASG, MSG and PSG. In one embodiment, genetically modified silkworms comprising modified silk fibroin proteins in PSG, including fibroin heavy chain (FibH), fibroin light chain (FibL), and fibrohexamerin P25, color, texture, softness, length, It can have different phenotypic silk fibers in strength, weight or ability to absorb dyes. In other embodiments, genetically modified silkworms comprise a modified gene that is involved in adolescent hormone signal transduction within the PSG and encodes an adolescent hormone binding protein that mediates the growth and development of silk glands. In another embodiment, the genetically modified silkworm comprises a modified ser1 gene in MSG that makes a sticky glial protein sericin covering the outside of the silk strand over the fibroin protein core. Sericin contains about 10-25% of silk and must be removed during silk processing. Genetically modified silkworms containing a modified ser1 gene can produce silk fibers without excessive sericin removal. As a result, genetically modified silk fibers do not require the "weighting" process of adding metal to the silk fibers in fabric manufacture.

Non-limiting examples of protein groups involved in silk production include, for example, carriers involved in transporting substances involved in silk formation, such as components of the solute carrier family (family 35 member B3, member E1, and family 39 member 9). And transmembrane and trafficking protein isoform 2. One skilled in the art recognizes that silk color, texture, softness, homogeneity, length, strength, weight and ability to absorb dyes are not determined and loci have not been determined.

Protease inhibitors in A / MSG can play an important role in protecting fibroin proteins in the silk gland lumen against digestion by proteases such as antennal esterases and serine proteases, and in A / MSG Expressed. In another embodiment, the genetically modified silkworm may comprise an edited chromosomal sequence that encodes a protease inhibitor in A / MSG. Modified protease inhibitor coding moieties can produce silk proteins with different physical properties. In one embodiment, a genetically modified silkworm comprising a modified protease inhibitor chromosome moiety can have a phenotype that produces silk without a high proportion of sericin but retaining its intrinsic shape and other physical properties.

In another embodiment, the genetically modified silkworm may comprise an edited chromosomal sequence that encodes a fibroin, sericin, solute carrier, protease inhibitor, or combinations thereof. The edited chromosome sequence contains at least one alteration and produces altered forms of fibroin, sericin or other silk fiber formation related proteins. The chromosomal sequence may comprise at least one amino acid change, as described above, in a protein that has been modified to include at least one nucleotide change. Alternatively, the edited chromosomal sequence may include mutations, such that the sequence is inactivated and no protein or missing protein may be made. As described above, mutations may include deletions, insertions, or point mutations. Genetically modified silkworms comprising edited FibH, ser1 and / or protease inhibitor chromosomal sequences may have a different fiber color, quality, and weight than silkworms that are not edited.

Silk is naturally hypoallergenic. However, for a variety of reasons some people experience silk allergies. Occasionally, this allergy remains in the feeding of silkworms, such as mulberry or oak leaves, affecting the protein chain found in silk strands produced by silkworms. Silk allergies can be the cause of asthma or allergic rhinitis. In one embodiment, genetically modified silkworms are involved in glucose hydrolysis and transport in the digestion of alpha and beta glucosidase, glycoside hydrolase, and mulberry leaves, the only food source of silkworms. It may comprise an edited chromosomal sequence that encodes a carrier. These proteins are expressed in the midgut of silkworms and are involved in functions such as nutrient digestion, transport, and uptake. In another embodiment, the genetically modified silkworm may comprise an edited chromosomal sequence that encodes a lipase protein family, tactile esterase, carboxyesterase, and scavenging receptor SR-B1, which is triglyceride It is mainly involved in metabolic lipid metabolism such as hydrolysis of, decomposing deodorant acetate compounds, and binding of modified low density lipoproteins. Genetically modified silkworms comprising an edited chromosomal sequence as described above will generally not contain allergens causing silk allergic reactions in silk fabrication workers and consumers,

The middle intestine also represents the first line of silkworm resistance and immune response. In one embodiment, genetically modified silkworms can include an edited chromosomal sequence that encodes an aminopeptidase that binds to various classed Cry toxins. For example, BtR175, a Cadherin-like protein expressed in silkworms, functions as a Cry toxin receptor in signal transduction. In another embodiment, the genetically modified silkworm may comprise an edited chromosomal sequence of 17 members of the cytochrome P450 gene family in the midgut, including CYP4, CYP6 and CYP9. The intestinal cytochrome P450 gene family is involved in the metabolism of plant toxins and pesticides.

Another mid-specific gene encodes a peptidoglycan recognition protein, which can bind strongly to the cell wall peptidoglycan of Gram-positive bacteria, triggering an immune response. Moreover, two lymphocyte receptor genes, particularly expressed in the midgut, encode binding proteins that function in the recognition of pathogens. In other groups of embodiments, the genetically modified silkworm may comprise an edited chromosomal sequence in a peptidoglycan recognition protein or a lymphocyte binding protein, wherein the chromosomal sequence is up-regulated so that the silkworm is resistant to disease Is bigger. With suitable mutations discussed above, genetically modified silkworms will generally have a better immune system, are free of disease and pathogens, and are less susceptible to plant toxins and pesticides in their food sources.

Similar to silkworm fibers, cobwebs are another naturally occurring fiber that is three times stronger than Kevlar®, the material currently used in military bulletproof vests. The prolonged superior ability of the cobwebs allows more energy to be absorbed to effectively slow down destruction and launch. However, it is impossible to harvest powerful, flexible strings made by spiders. It cloned a gene that makes cobwebs from spider N. clavipes , and there are synthetic genes that mimic spider-induced lines. In one embodiment, the genetically modified silkworm may comprise an edited chromosomal sequence comprising an integrated sequence, such as a flagelliform gene encoding a web. Genetically modified silkworms will enable the production of large amounts of cobwebs that are organized for the needs of new materials with unique properties.

The subject matter also includes genetically modified silkworms comprising any combination of the chromosomal alterations described above. For example, genetically modified silkworms may have modified FibH and / or FibL chromosomal sequences, modified ser1 chromosomal sequences, and / or modified BtR175 , and / or CYP4 chromosomal sequences, and / or integration from other species or organisms. May comprise a sequence.

The silkworms and cells disclosed herein may have several uses. In one embodiment, a genetically modified silkworm comprising at least one edited chromosomal sequence may exhibit a desired phenotype by humans. For example, modification of the chromosomal sequence encoding fibroin can produce silk fibers with a unique color, texture, weight or strength. In other embodiments, silkworms comprising at least one edited chromosomal sequence can be used as a model for genetic studies of silk composition, production, and / or transport. In addition, silkworms comprising at least one disrupted chromosomal sequence can be used as a model to study diseases or conditions affecting humans or other animals. Non-limiting examples of suitable diseases or conditions include mulberry allergy. In addition, published silkworm cells and lysates of cells can be used for similar research purposes.

III. Animals Including Chromosome Editing

One aspect of the present disclosure provides genetically modified animals in which at least one chromosomal sequence has been edited. Suitable chromosomal editing includes, but is not limited to, a partial dip of the type described in paragraph I (f) above.

As used herein, “animal” refers to non-human animals. Animals can be embryos, young animals, or adults. Suitable animals may include vertebrates such as mammals, birds, reptiles, amphibians and fish. Examples of suitable mammals include, but are not limited to, rodents, pets, livestock and primates. Non-limiting examples of rodents include mice, rats, hamsters, gerbils and guinea pigs. Suitable pets include, but are not limited to, cats, dogs, rabbits, hedgehogs, and ferrets. Non-limiting examples of livestock include horses, goats, pigs, cattle, llamas and alpacas. Suitable primates include, but are not limited to, primates such as New World Monkeys, Old World Monkeys and Primates, for example, Tailed Macaques, Chimpanzees, Lemurs, Macaques, Silk Monkeys, Tamarins, Spider Monkeys, Squirrel Monkeys, and Vervet Monkeys. Do not. Non-limiting examples of algae include chickens, turkeys, ducks and geese. Alternatively, the animals can be insects, nematodes and the like. Non-limiting examples of insects include silkworms, fruit flies and mosquitoes.

In one embodiment, the typical animal is a rat. Non-limiting examples of suitable mouse strains include Dahl Salt-Sensitive, Fischer 344, Lewis, Long Evans Hooded, Sprague-Dawley, and Wistar.

In each description of a suitable animal for the present invention, the animal does not comprise exogenously introduced, randomly integrated transposon sequences.

Animals of the invention may comprise intragenic genome editing listed in paragraph II above or listed in Tables A, B, C and D above. In further embodiments, an animal of the present invention may comprise genome editing as described in the Examples.

In an exemplary embodiment, the methods of the invention can be used to generate an animal derived from a embryo, which comprises chromosomal editing on at least one chromosome in all cells of the animal. In certain embodiments, the method can be used to generate an animal comprising chromosomal editing on two intracellular chromosomes. In certain embodiments, chromosomal editing is on at least one autosome. In other embodiments, the chromosomal editing is on at least one sex chromosome.

Two animals of the present invention can be crossed to create animal homozygotes for chromosomal editing. Alternatively, animals can be crossed to combine chromosomal editing with different genetic backgrounds. Non-limiting examples, for example, other genetic cultures include another chromosomal editing, genetic background with non-targeted integration, genetic background with missing mutations, and wild-type genetic background. In one embodiment, for example, animal A may comprise a first chromosome edit and animal B may comprise a second chromosome edit. F1 generation, including both the first and second chromosome editing, can be obtained by crossing animals A and B. This or similar shift is one method for the combination of one or more chromosomal edits in the same animal.

In certain embodiments, an animal comprising chromosomal editing can be used to create a primary cell lineage as described in paragraph IV. The resulting cell line will include chromosomal editing originally introduced into the embryo. Animals of the invention can be used for any of the uses described in paragraph II above.

IV . Genetically modified cells

Another aspect of the invention includes cells created by the methods of the invention, such as cells comprising at least one chromosomal editing. Suitable editing includes, but is not limited to, editing of the types described in paragraph I (f) above.

At least one chromosomal edited cell type can vary. In general, these cells will be eukaryotic cells. In some cases, these cells will be primary cells, cultured cells, or immortalized cell line cells. Suitable cells include fungi or yeasts such as Pichia , Saccharomyces , or Schizosaccharomyces ; SF9 or Drosophila from Spodoptera frugiperda insect cells such as S2 cells of melanogaster ); And animal cells, such as mice, mice, hamsters, non-human primates, or human cells. Typical cells are mammals. Mammalian cells are primary cells. In general, any primary cell that is sensitive to double stranded breaks can be used. These cells may be various types of cells, such as cell types, such as fibroblasts, myoblasts, T or B cells, macrophages, epithelial cells, and the like.

When using a mammalian cell lineage, the cell lineage can be any established cell lineage or primary cell not yet described. The cell lineage may be adsorptive or non-adsorbable, or the cell lineage may be grown under conditions that encourage adsorptive, non-adsorbable or organotypic growth using standard techniques known to those skilled in the art. Non-limiting examples of suitable mammalian cell lineages include: Chinese hamster ovary (CHO) cells, monkey kidney CVI line transformed by SV40 (COS7), human embryonic kidney line 293, baby hamster kidney cells (BHK), mouse Sertoli cells (TM4), monkey kidney cells (CVI-76), African green monkey kidney cells (VERO), human cervical carcinoma cells (HeLa), canine animal kidney cells (MDCK) , Buffalo rat liver cells (BRL 3A), human lung cells (W138), human liver cells (Hep G2), mouse breast tumor cells (MMT), mouse liver tumor cells (HTC), HIH / 3T3 cells Fields, human U2-OS osteosarcoma cell line, human A549 cell line, human K562 cell line, human HEK293 cell line, human HEK293T cell line, and TRI cells. For an extensive list of mammalian cell lines, one skilled in the art can refer to the American Type Collection Collection catalog (ATCC® Mamassas, VA).

In an exemplary embodiment, the cells of the invention are embryonic. The embryo may be one cell embryo or one or more cell embryos. Suitable embryos can be derived from several different vertebrate species, including mammalian, avian, reptile, amphibian and fish species. Generally speaking, suitable embryos are embryos that have been harvested, injected, and cultured to allow expression of zinc finger nucleases. In certain embodiments, suitable boats may include boats of rodents, pets, livestock, and primates. Non-limiting examples of rodents include mice, rats, hamsters, gerbils and guinea pigs. Non-limiting examples of pets include cats, dogs, rabbits, hedgehogs, and ferrets. Non-limiting examples of livestock include horses, goats, pigs, llamas, alpacas and cattle. Non-limiting examples of primates include new world monkeys, old world monkeys and primates such as tail-winding monkeys, chimpanzees, lemurs, macaques, silk monkeys, tamarins, spider monkeys, squirrel monkeys and vervet monkeys. Include. In other embodiments, suitable embryos may include embryos of fish, reptiles, amphibians or algae. Alternatively, a suitable pear may be an insect pear, for example a fruit fly pear, a mosquito pear, or a silkworm pear. Those skilled in the art will appreciate that embryo harvesting, injection and culture are known in the art and can vary depending on the type of embryo. In all cases, conventional optimization can be used to determine the optimal technique for a particular species embryo.

In other embodiments, the cell can be a stem cell. Suitable stem cells include embryonic stem cells, ES-like stem cells, fetal stem cells, adult stem cells, pluripotent stem cells, induced pluripotent stem cells, multipotent stem cells, oligopotent stem Cells, and unipotent stem cells.

In addition, the cells of the invention can be modified to include a tag or reporter gene. Reporter genes encode genes encoding selectable markers such as chloramphenicol acetyltransferase (CAT) and neomycin transferase (neo), and fluorescent proteins such as green fluorescent protein (GFP) and red fluorescent protein. One, or any genetically engineered variant thereof that improves report function. Known non-limiting examples such as SF variants include EGFP, blue fluorescent protein (EBFP, EBFP2, Azurite, mKalama1), cyan fluorescent protein (ECFP, Cerulean, CyPet) and yellow fluorescent protein inducers (YFP, Citrine, Venus, YPet). For example, within a genetic construct comprising a reporter gene, the reporter gene sequence can be directly fused to the targeted gene to create a gene fusion. The reporter sequence may be specifically integrated in the targeted method in the targeted gene, for example the reporter sequences at the 5 'or 3' end of the targeted gene. Both genes are under the control of the same promoter elements and are transcribed into a single messenger RNA molecule. Alternatively, reporter genes can be used to monitor the activity of promoters in the gene construct, eg, the expression of the reporter gene is under the control of the target promoter and the activity of the reporter gene is compared with the activity observed under the strong consensus promoter. The reporter sequence is placed downstream of the target promoter so that it is generally measured directly and quantitatively. It will be appreciated that this may or may not induce the destruction of the targeted gene.

Justice

Unless otherwise stated, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs. The following references provide those skilled in the art with a universal definition of many terms used in the present invention: Singleton meat al ., Dictionary of Microbiology and Molecular Biology (2 nd ed . 1994); The Cambridge Dictionary of Science and Technology ( Walker ed ., 1988); The Glossary of Genetics , 5 th Ed ., R. Rieger meat al . ( eds .), Springer Verlag (1991); and Hale & Marham , The Harper Collins Dictionary of Biology (1991) . As used herein, the following terms have the meanings described herein unless otherwise indicated.

When introducing elements of the present disclosure or introducing preferred embodiment (s) thereof, the articles “a”, “an”, “the” and “said” are meant to include one or more elements. Included ("comprising", "including" and "having") is inclusive and means that there may be additional elements other than the specified elements.

As used herein, a "gene" refers to a DNA portion (including exons and introns) that encodes a gene product, as well as to regulate gene production whether or not regulatory sequences are adjacent to or adjacent to the encoded and / or transcribed sequence. Refers to all DNA portions. Thus, genes may include promoter sequences, terminators, and ribosomal binding sites and internal ribosomal entry sites, enhancers, silencers, insulators, boundary elements, origins of replication, matrix attachment sites, and left reference sites. Translational regulatory sequences such as, but not limited to.

“Nucleic acid” and “polynucleotide” refer to deoxyribonucleotide or ribonucleotide polymers of linear or circular and single- or double-stranded forms. For the purposes of this disclosure, these terms are not considered to be limited by the length of the polymer. These terms may include known analogs of natural nucleotides, as well as modified nucleotides in base, sugar and / or phosphate moieties (eg, phosphorothioate base backbone). In general, analogs of certain nucleotides have the same base pair specificity; For example, the A analog will base pair with T.

"Polypeptides" and "proteins" are used interchangeably with polymers of amino acid residues.

"Recombination" refers to the exchange of genetic information between two polynucleotides. For the purposes of this publication, “homologous recombination” refers to a specialized form of exchange that occurs during repair of, for example, double-strand breaks in a cell. This process requires sequence similarity between the two polynucleotides, uses “donor” or “exchange” molecules to repair the template of the “target” molecule (eg, a molecule that experiences a double-strand break), and “non- Variously known as "crossover gene conversion" or "short tract gene conversion" because they induce the transfer of genetic information from the donor to the target. Such delivery may be involved in mismatch correction of heteroduplex DNA formed between the nicked target and the donor, and / or “synthetic-dependent strand annealing,” where the donor may be part of the target. Existing genetic information is used to resynthesize or related processes. Such specialized homologous recombination often results in sequence alteration of the target molecule such that some or all of the donor or exchange polynucleotide sequences are incorporated into the target polynucleotide.

As used herein, a "target position" or "target sequence" is part of the chromosomal sequence to be edited and, if sufficient conditions exist for binding, the zinc finger nuclease recognizes it and manipulates the nucleic acid sequence engineered to bind thereto. Say.

Techniques for determining nucleic acid and amino acid sequence identity are known in the art. Typically, such techniques include determining the nucleotide sequence of an mRNA for a gene and / or determining an encoded amino acid sequence thereby, and comparing these sequences to a second encoded nucleotide or amino acid sequence. Genomic sequences are also determined in this way and can be compared. In general, identity refers to amino acid-to-amino acid or polypeptide sequences that are significant to the exact nucleotide-to-nucleotide or two polynucleotides. Two or more sequences (polynucleotide or amino acid) can be compared by determining their proportion of identity. The percent identity of two sequences of nucleic acid or amino acid sequences is divided by the length of the shorter sequences and is the exact match between the two arranged sequences multiplied by 100. Suitable arrangement for nucleic acid sequences is Smith and Waterman , Advances in Applied Provided by Mathematics 2: 482-489 (1981) . This algorithm is based on Dayhoff , Atlas of Protein Sequences and Structure , MO Dayhoff ed ., 5 suppl . 3: 353-358, National Biomedical Research Developed by the Foundation , Washington , DC, USA , Gribskov, Nucl . Acids Res . A scoring matrix, standardized by 14 (6): 6745-6763 (1986) , can be used to apply amino acid sequences. A typical implementation of this algorithm to determine the percent identity of sequences is Genetics in the "BestFit" utility application. Computer Provided by the Group ( Madison , Wis .) . Other suitable programs for calculating identity or similarity between sequences are generally known in the art. For example, another array program is BLAST, used with default variables. For example, BLASTN and BLASTP can use the following default variables: Genetic code = standard; filter = none; strand = both; cutoff = 60; expect = 10; matrix = BLOSUM62; Descriptions = 50 sequences; sort by = HIGH SCORE; Databases = non-redundant, GenBank + EMBL + DDBJ + PDB + GenBank CDS translations + Swiss protein + Spupdate + PIR. Detailed description of the program GenBank You can find it on the website . For the sequences described herein, the preferred level range of sequence identity is approximately 80% to 100% and any integer value in between. Typically the percent identity between sequences is at least 70-75%, preferably 80-82%, more preferably 85-90%, even more preferably 92%, even more preferably 95%, and most preferably Is 98% sequence identity.

Alternatively, the level of sequence similarity between polynucleotides can be achieved by hybridization, single-stranded-specific nuclease (s) of the polynucleotide under conditions that allow for the formation of stable duplexes between moieties that share the level of sequence identity. It can be determined by digestion, and by judging the size of the cleaved fragments. As determined using this method above, both sequences are at least 70-75%, preferably 80-82%, more preferably 85-90%, even more preferably 92%, even more preferably 95 When showing%, and most preferably 98% sequence identity, two nucleic acids, or two polypeptide sequences, are substantially similar to each other. As used herein, substantially similar refers to sequences that show complete identity to a specified DNA or polypeptide sequence. Substantially similar DN sequences can be found in Southern hybridization experiments, for example, under stringent conditions, as defined in a particular system. The definition of suitable hybridization conditions is within the skill of the art. For example, Sambrook meat al ., supra ; Nucleic Acid Hybridization : A Practical Approach , editors BD Hames and SJ Higgins , (1985) Oxford ; Washington , DC; IRL Press ).

Selective hybridization of two nucleic acid fragments can be determined as follows. The level of sequence identity of two nucleic acid molecules affects the strength and effectiveness of the hybridization process between these molecules. Partially identical nucleic acid sequences will at least partially inhibit hybridization of sequences that are completely identical to the target sequence. Complete inhibition of hybridization of the same sequence can be assessed using hybridization assays known in the art (eg, Southern (DNA) blots, Northern (RNA) blots, solution hybridization or the like, Sambrook, et. al ., Molecular Cloning : A Laboratory Manual , Second Edition , (1989) Cold Springharbor, NY ). This analysis can be performed using a variety of selectivity, for example using conditions that vary from low stringency to high stringency. Using low stringency conditions, a secondary probe that lacks a partial level of sequence identity (e.g., less than about 30% of the target molecule), so that without the non-specific binding process, the secondary probe does not hybridize to the target. Probes with sequence identity) can be used to assess the absence of non-specific binding.

When using a hybridization-based detection system, nucleic acid probes are selected by selecting complementary conditions that are complementary to the reference nucleic acid sequence and that the probe and the reference sequence selectively hybridize or bind to each other to form a duplex molecule. Nucleic acid molecules that can selectively hybridize to a reference sequence under moderate stringency hybridization conditions permit detection of a target nucleic acid sequence of at least about 10-14 nucleotides in length having at least approximately 70% sequence identity with the selected nucleic acid probe sequence. Hybridized under conditions of Stringent hybridization conditions allow detection of a target nucleic acid sequence of at least about 10-14 nucleotides in length having at least about 90-95% sequence identity with the selected nucleic acid probe sequence. Hybridization conditions useful for probes having a certain level of sequence identity and probe / reference sequence hybridization with reference sequences can be determined as known in the art (eg, Nucleic Acid Hybridization : A Practical Approach , editors BD Hames and SJ Higgins , (1985) Oxford ; Washington , DC; IRL Press ). Hybridization conditions are known in the art.

Hybridization stringency refers to hybridization conditions that are reluctant to form hybrids containing mismatched nucleotides, with higher stringency being less tolerant of mismatched hybrids. Factors affecting hybridization stringency are known in the art and include, but are not limited to, temperature, pH, ionic strength, concentrations of organic solvents such as formamide and dimethyl sulfoxide. As is known in the art, hybridization stringency increases with higher temperatures, lower ionic strengths, and lower solvent concentrations. For stringent conditions for hybridization, the following factors, such as length and nature of the sequences, base composition of the various sequences, salt concentrations and other hybridization solution components, presence of interfering substances in the hybrid solution (eg dextran sulfate) , And polyethylene glycol), hybridization reaction temperature and time variables, as well as by varying washing conditions, it is well known in the art that certain stringency can be established using a number of equivalent conditions. have. A particular set of hybridization conditions can be selected according to standard methods in the art (eg, Sambrook , et al ., Molecular Cloning : A Laboratory Manual , Second Edition , (1989) Cold Spring harbor , NY ).

The following examples are included to illustrate preferred embodiments of the present invention. Those skilled in the art should recognize that the techniques disclosed in the following examples represent techniques discovered by the inventors of the present invention in the practice of the present invention. However, one of ordinary skill in the art appreciates, in light of the disclosure, that many changes can be made in the specific embodiments described herein and that achieve similar or similar results without departing from the spirit and scope of the invention, and therefore All problems presented or those shown in the accompanying drawings are for illustrative purposes and should not be construed as limiting.

Example

The following examples are included to illustrate preferred embodiments of the present invention. Those skilled in the art should recognize that the techniques disclosed in the following examples represent techniques discovered by the inventors of the present invention in the practice of the present invention. However, one of ordinary skill in the art appreciates, in light of the disclosure, that many changes can be made in the specific embodiments described herein and that achieve similar or similar results without departing from the spirit and scope of the invention, and therefore All problems presented or those shown in the accompanying drawings are for illustrative purposes and should not be construed as limiting.

The following examples illustrate various iterations of the invention.

Example  1: of the mouse genome PXR  Polymorphism of restriction fragment length for target integration into the nucleic acid moiety ( RFLP ) donor  Nucleic acid Construction .

There are two possible DNA repair outcomes after targeted, ZFN-induced double-strand breaks (FIG. 1). This gap is repaired by non-homologous end joining (NHEJ), leading to mutations containing base deletions or additions, or in the presence of donor DNA, homologous recombination of donor DNA It can be used as a template for repairing double strand breaks by recombination. If donor DNA encodes specific sequence changes, these deliberate mutations will integrate into the genome of the organism at the target location.

To test targeted integration in the mouse genome using pronuclear injection, constructs for targeted integration into the PXR gene portion in the mouse genome were designed and prepared. The construct was assembled to introduce NotI or PmeI restriction fragment length polymorphism (RFLP) into the PXR gene moiety (FIG. 2). The construct was designed to have base pairs of 200, 800 or 2000 homologous to the PXR gene target site flanking the RFLP site to be introduced. Three sizes of homologous moieties were used to determine the size of homology required for effective targeting and homologous recombination.

Conventional restriction sites for cloning were introduced and clones were assembled using PCR amplification to introduce an RFLP site at the end of the PXR homology portion (FIG. 1). PCR primers used to amplify homologous PXR moieties are shown in Table 5. Accuprime HF DNA polymerase was used to amplify the PCR reaction. A 30 second extension was used for 200 bp fragments, a 1.5 minute extension for 800 bp fragments, and a 4 minute extension for 2 Kbp fragments. PCR fragments were digested with appropriate restriction enzymes and cloned into pBluescript using three mode ligations to produce the six plasmids listed in Table 2.

Example  2: of the mouse genome rRosa26  Polymorphism of restriction fragment length for target integration into the nucleic acid moiety ( RFLP A) of donor nucleic acid Construction .

Plasmids were also constructed to target the integration of NotI and PmeI RFLP sites into the rRosa26 nucleic acid portion of the murine genome. Planning and construction of the plasmid are as described in Example 1 above. PCR primer pairs used to amplify the rRosa26 homology moiety are described in Table 3.

Example  3: of the mouse genome Mdr1a  Polymorphism of restriction fragment length for target integration into the nucleic acid moiety ( RFLP A) of donor nucleic acid Construction .

Plasmids were also constructed to target the integration of NotI and PmeI RFLP sites into the mMdr1a nucleic acid portion of the mouse genome or the rMdr1a nucleic acid portion of the mouse genome. Planning and construction of the plasmid are as described in Example 1 above. PCR primer pairs used to amplify the rMdr1a nucleic acid moiety homology moieties are described in Table 4. “M” represents mice and “r” represents mice.

Example  4: GFP  Of expression integration cassette Construction .

To test the targeted integration of nucleic acid fragments larger than RFLPs, constructs were prepared and prepared for the targeted integration of the GFP expression cassette into the mouse PXR and rRosa26 nucleic acid genomic portions and the mouse mMdr1a nucleic acid genomic portions. Briefly, the GFP expression cassette containing the human PGK promoter, GFP open reading frame, and polyadenylation signal was amplified using PCR to introduce NotI restriction sites at the end using the following primers:

PGKGFP-F NotI (5′-aaagcggccgcttggggttgcgccttttcc) (SEQ ID NO: 49) and

PGKGFP-R NotI (5'-aaaagcggccgccatagagcccaccgcatc) (SEQ ID NO: 50). PCR fragments were then cloned into the NotI-containing plasmid constructed in Examples 1-3.

Example 5: Zinc Fingers for Targeted Integration Preparation of mRNAs .

A pair of zinc finger nucleases was designed and cloned for each targeted integration site as described on the Sigma website. See Science (2009) 325: 433, incorporated by reference for further information. The ZFN expressing mRNAs were then 100 μl reactants containing 10 μl buffer 2 (NEB, # B7002S), 10 μl 10 × BSA (diluted from l00x BSA, NEB, # B9001S), 8 μl XbaI (NEB, # R0145S) 20 μg of each maxiprepped ZFN expressing plasmid DNA was digested first at 37 ° C. for 2 hours in vitro. The reaction was then extracted with 100 μl of phenol / chloroform (Sigma, P2069) and centrifuged at 20,000 × g for 10 minutes. The aqueous supernatant was precipitated with 10 μl 3M NaOAc (Sigma, S7899) and 250 μl 100% ethanol and centrifuged at full speed for 25 minutes at room temperature. The resulting pellet was washed by adding 300 μl 70% ethanol filtered through a 0.02 filter. The pellet was air dried and resuspended in 20 μl 0.02 filtered 0.1 × TE.

Purified cleaved DNA was then used to make ZFN transcripts using in vitro transcription with MessageMax T7 Capped Message Transcription Kit (# MMA60710) (Epicentre Biotechnologies), as described. In summary, the kit components were pre-warmed to room temperature and the reaction components for the 20 μl reaction were combined at room temperature in the following order: 5 μl of 0.02 um filtered RNase-free water, 1 μl prepared template, 2 μl lox transcription. Buffer, 8 μl 2-way Cap / NTP premix, 2 μl 100 mM DTT and 2 μl MessageMax T7 enzyme solution. The reaction was then incubated in a 37 ° C. incubator for 30 minutes.

The caps were then capped and RNA was tailed with PolyA using the A-Plus poly (A) polymerase tailing kit (Epicentre, # PAP5 104H) as described. The reaction components were combined at room temperature in the following order: 55.5 μl 0.02 μm filtered RNase-free water, 10 μl 10 × A-Plus reaction buffer, 10 μl 10 mM ATP, 2.5 μl ScriptGuard RNase inhibitor (40 unit / μl) , 20 μl in vitro transcription capping reaction, 2 μl A-plus poly A polymerase. The reaction was then incubated at 37 ° C. for 30 minutes. And the resulting cap ssuiwojyeo, poly A- with the mRNA tail was purified by precipitation twice with an equal volume of 5M NH ₄ Oac. MRNA pellets were then air dried, resuspended in 30 μl filtered injection buffer (1 mM Tris, pH 7.4, 0.25 mM EDTA), and RNA concentration was measured using a Nanodrop spectrophotometer.

Example  6: by boat Targeted  integrated.

To integrate the nucleic acid into the mouse or mouse genome, zinc finger nuclease mRNA was mixed with maxiprepped target DNA filtered with a 0.02 um filter. The nucleic acid mixture consisted of one part of ZFN mRNAs for one part of donor DNA. The nucleic acid mixture was then microinjected into the pronucleus of a single cell embryo using known methods. The injected embryos were incubated in vitro or transferred to false mothers. Toes / tail clips of the resulting embryos / fetuses or born live animals were harvested for DNA extraction and analysis.

For DNA extraction, tissues were lysed at 50 ° C. for 30 minutes in 100 μl Epicentre's QuickExtract, then incubated at 65 ° C. for 10 minutes, and 98 ° C. for 3 minutes. To determine if targeted integration occurred, PCR was used to amplify the target moiety using appropriate primers. In experiments in which RFLP was integrated into the animal's genome, PCR products were cleaved with the introduced RFLP enzyme to detect integration (FIG. 4A). In addition, we demonstrated whether ZFN mRNA functions in the embryo by detecting NHEJ independent of targeted integration by Cel-I endonuclease analysis using wild-type PCR fragments and PCR fragments. In experiments in which GFP was integrated into the animal's genome, changes in PCR fragment size indicate integration (FIG. 4B). Alternatively, integration of donor nucleic acids was assessed using amplification of integrative bonds in which only one primer was placed in the GFP cassette.

Example  7: in the mouse genome mMdr1a  Of the target site DNA  Extraction and PCR  Evaluation of amplification.

PCR conditions for amplifying target nucleic acids extracted from tissues were tested using embryos with 1-64 cells extracted as described in Example 6. The 900 bp fragment carrying the mouse mMdr1a target moiety was amplified using 36 amplification cycles and a 4 minute extension at 60 ° C. in the reaction containing 5 μl Epicentre's QuickExtract solution in 50 μl reaction (FIG. 5). These results show that QuickExtract can extract DNA from samples extracted from only 1-10 cells without interfering with PCR amplification. To enhance sensitivity, the number of PCR cycles can be increased, or nested PCR reactions can be run.

Example 8: NotI donor Integrating RFLP into the Murine PXR Genomic Portion—Experiment A.

A donor plasmid (800 bp arm) for integrating the NotI RFLP site into the PXR portion of the rat genome was injected into the embryo of rats with ZFN mRNAs as described above. DNA extracted from multiple embryos was used to perform PCR followed by NotI restriction enzyme analysis and Cel-I endonuclease analysis. PCR amplification in many embryos was successful (FIG. 6A), and the Cel-I endonuclease assay showed that most fragments had nucleic acid sequence changes at the desired target (FIG. 6B).

Example 8: NotI donor Incorporation of RFLP into the mouse mMdr1a genomic portion-Experiment B.

As described in Example 8, integration of NotI RFLP into the mouse mMdr1a moiety was repeated. The mMdr1a portion was amplified using the PCR and cleaved NotI. PCR amplification was successful in multiple embryos (FIG. 7), and in digestion with NotI, multiple embryos were shown to contain integrated RFLP sites (eg lines 13, 17, 19, 20 and 23). In total, data were generated on targeted integration in seven of the 32 ships.

This result was confirmed by repeating the NotI digestion reaction after further washing the PCR reaction product (FIG. 8).

Example  10: into the rat genome PXR  Of the target site DNA  Extraction and PCR  Amplification test

PCR amplification of the PXR portion from blastocysts was tested to determine sensitivity levels. PCR reactions included 5 μl template, 5 μl PCR buffer, 5 μl of each primer, 0.5 μl of Taq polymerase enzyme, and 33.5 μl of water for 50 μl of reaction. The template consisted of undiluted DNA extracted from rat blastocysts or DNA diluted in the ratio of 1: 2, 1: 6, 1:10, and 1:30 (FIG. 9).

Example  11: NotI donor RFLP Rat PXR  Integration into genomic parts.

A donor plasmid (800 bp homology arm) for integrating the NotI RFLP site into the PXR portion of the rat genome was injected into the embryo of rats with ZFN mRNAs as described above. A total of 123 embryos were injected and 106 survived. To test for toxicity, the concentration of nucleic acid was reduced and injected. Of 51 embryos injected with 5 ng of nucleic acid, 17 survived and were divided into embryos of two cells on the second day. Of 23 embryos injected with 2 ng of nucleic acid, 14 survived and divided into embryos of two cells on the second day. Of the 29 embryos injected with 10 ng of nucleic acid, 12 survived and were divided into embryos of two cells on the second day. All 10 non-implanted embryos survived and were divided into embryos of two cells on the second day.

DNA extracted from multiple embryos was used to perform PCR amplification of the PXR portion followed by NotI and Cel-I endonuclease assays. PCR amplification was successful in multiple embryos, and 18 of 47 embryos in the NotI and Cel-I endonuclease assays showed nucleic acid sequence changes at the desired targets (FIG. 10).

Example  12: Mouse Genome in the Fetus mMdr1a  As target part RFLP of Targeted  integrated

A donor plasmid (800bp homology arm) for introducing NotI into the mMdr1a portion of the mouse genome was injected into embryos of mice with ZFN mRNAs as described above. One of four well-developed fetuses at 12.5 dpc was positive for the NotI site. All four decidules were negative (FIG. 11).

Example  13: fetal mMdr1a  Left GFP of Targeted  integrated

A donor plasmid (800 bp homology arm) for introducing the GFP cassette into the mMdr1a portion of the mouse genome was injected into embryos of mice with ZFN mRNAs as described above. Two of the 40 fetuses at 12.5 dpc were positive for the GFP cassette. (FIG. 12).

Example 14: Preparation of the donor for the introduction of NotI to PXR portion of the targeted integration rat genome of the RFLP by PXR target portion of the rat genome in the embryo plasmid (800bp homology arm (arm)) is a ZFN mRNAs as described in the Were injected into the embryos of mice. One of eight fetuses at 13 dpc was positive for the NotI site. (FIG. 13).

Example  15: In cat cells SMAD4 Genome editing

Zinc finger nuclease (ZFN) -mediated genome editing in cat cells was tested using ZFN binding to the human SMAD4 chromosome sequence because the DNA binding sites in cats and humans are identical. The amino acid sequence of the SMAD4 ZFN pair (19160/19159) and the corresponding DNA binding sites are provided in Table 5. Known molecular biology techniques were used to create capped and polyadenylation mRNAs encoding SMAD4 ZFNs (19160/19159). mRNA was transfected into human K562, cat and AKD (lung), and cat and CRFK (kidney) cells. Reference cells were injected with mRNA encoding GFP.

Cel-1 nuclease assay was used to determine the ZFN-induced double stranded chromosome gap frequency. This assay detects alleles of the target locus deviating from the wild type as a result of non-homologous end joining (NHEJ) -mediated incomplete repair of ZFN-induced DNA double strand breaks. PCR amplification of the targeted portion from the pool of ZFN-treated cells results in a mixture of WT and mutant amplicons. Melting and reannealing of this mixture results in mismatch formation between the WT and heteroduplexes of the mutant allele. DNA “bubble” formed at the mismatch sites is cleaved by the surveyor nuclease Cel-1, and cleavage products can be dissociated by gel electrophoresis. The relative strength of the cleavage product compared to the parental band is a measure of the Cel-1 cleavage level of the heteroduplex. This reflects the frequency of ZFN-mediated cleavage of endogenous target loci that will undergo incomplete repair by NHEJ. As shown in Figure 14, SMAD4 ZFNs (19160/19159) was cut SMAD4 left in the human and feline cells.

Example  16: cat in the boat SMAD4 Genome editing

Cat embryos were harvested using standard procedures, and capped to encode SMAD4 ZFNs (19160/19159), Geurts with polyadenylation mRNA meat al . Injection was performed using techniques substantially similar to those described in Science (2009) 325: 433, which is incorporated by reference in its entirety. Cat embryos were microinjected at the 2-4 cell stage. Reference embryos were injected with 0.1 mM EDTA. The cutting frequency was measured using Cel-1 analysis as described in Example 15. As described in FIG. 15, the cutting effect was predicted to be about 6-9%.

Table 6 shows the development of the embryo after brown rice injection. About 19% (3/16) of embryos injected with a small amount of SMAD4 ZFN mRNA developed in the blastula stage, and 50% (8/16) of the reference embryos injected with EDTA developed in the blastula stage.

Example  17: In cat cells Fel d1 Genome editing

ZFNs were designed to target different parts of the Fel d1 chromosome sequence in cats ( Geurts meat al . (2009) supra ). ZFNs targeted either chain 1-exon 1, chain 1-exon 2, or chain 2-exon 2 of Fel d1. The amino acid sequence and DNA binding site of each ZFN are shown in Table 7.

Cat and AKD cells were treated with Fel d1 ZFNs (17/18), which target exon 1 of chain 1; Transfection was performed with mRNA encoding Fel d1 ZFNs (7/9) targeting exon 2 of chain 1. The effect of ZFN-mediated cutting was predicted using Cel-1 analysis as described above. The cutting effect of the 17/18 Fel d1 ZFN pair was estimated to be about 17% (see FIG. 16). The 7/9 Fel d1 ZFN pair cleaved chain 1, exon 2 with an effect of about 16% (see FIG. 17). 18 illustrates that chain 2, exon 2 was cleaved by a 12/13 Fel d1 ZFN pair.

Example  18: In the cat boat Fel d1 Genome editing

To facilitate inactivation of the Fel d1 locus, cat embryos were treated with two pairs of Fel d1 ZFNs. One pair (17/18) targeted chain 1-exon 1 and the other pair (12/13) targeted chain 2-exon 2. Due to the genomic organization of the Fel d1 locus, the coding portion for chain 2 (transcribed from the “lower” strand) is located about 4000 bp upstream of the coding portion of chain 1 (transcribed from the “parent” strand). Thus, it was assumed that editing in two separate positions could mediate large deletions from the Fel d1 locus. Cat embryos were capped essentially with a ZFN pair encoding as described in Example 16 and co-injected with polyadenylation mRNAs. Table 8 shows the development of the embryo after brown rice injection. Embryos injected with higher concentrations of Fel d1 ZFNs had higher survival rates than embryos injected with lower concentrations.

On day 8, baseline and experimental embryos were harvested for analysis. The reference blastocyst contained about 150-300 cells, the experimental blastocyst contained about 70-100 cells, and the experimental morula contained about 16-30 cells. Individual embryo DNA was extracted using standard procedures and subjected to Cel-1 analysis (see FIG. 19). Samples of lines 1, 3, and 7 showed the expected Cel-1 digestion products. Sequencing analysis showed that extra bands in other lines (including reference line, 6) were due to nearby SNPs.

For further analysis of the edited Fel d1 locus, the targeted portion was PCR amplified and sequenced using standard methods. Sequencing confirmed that there was a 4541 bp deletion between the coding portion of chain 2 and chain 1 (FIG. 20). In particular, the binding site for ZFN 13 was truncated 2 bp, and binding to ZFN 12 was deleted with an additional downstream sequence. Surprisingly, the binding site for the 17/18 pair was intact, indicating that this is the result of cleavage of the 12/13 ZFN pair (see FIG. 21).

Example  19: In cat cells Of cauxin  Genome editing

ZFN pairs targeting the portion of the cauxin locus were designed and tested in cat cells, as described above. Table 9 shows the amino acid sequence of the zinc finger helix and the DNA binding site of each active ZFN.

FIG. 22 shows the results of Cel-1 analysis confirming cleavage of the cauxin loci by 1/2 pair, 9/10 pair, and 17/18 ZFN pairs. FIG. 23 illustrates cleavage of the cauxin loci by 29/30 ZFN pairs.

Example  20: organism model Intracellularly Aguti  Genome editing

Zinc finger nuclease (ZFN) -mediated genome editing is equivalent to MSH receptor proteins, tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1), aguti signaling protein (ASIP), melanophylline (MLPH) ZFNs that bind to the chromosomal sequence of the hair-color related genes of (ovine) cells can be used to test cells of an organism model such as sheep. The particular envelope color-related gene to be edited may be a gene having the same binding site for the DNA binding site of the corresponding amount of homolog of the gene. Covered with a cap encoding ZFN, polyadenylated mRNA is a known molecule, including but not limited to, techniques substantially similar to those described in Science (2009) 325: 433 , incorporated by reference in its entirety. Can be made using biological techniques. mRNA can be transfected with positive cells. Reference cells can be injected with mRNA encoding GFP.

Cel-1 nuclease assay was used to determine the frequency of ZFN-induced double stranded chromosomal gaps. This assay detects alleles of the target locus deviating from the wild type (WT) as a result of non-homologous end joining (NHEJ) -mediated incomplete repair of ZFN-induced DNA double strand breaks. PCR amplification of the targeted portion from the pool of ZFN-treated cells results in a mixture of WT and mutant amplicons. Dissolution and reannealing of this mixture results in mismatch formation between the WT and the heteroduplex of the mutant allele. DNA “bubbles” formed at the mismatch sites are cleaved by the survey nuclease Cel-1, and cleavage products can be dissociated by gel electrophoresis. The relative strength of the cleavage product in comparison to the paternal band is a measure of the Cel-1 cleavage level of the heteroduplex. This reflects the frequency of ZFN-mediated cleavage of endogenous target loci that will undergo incomplete repair by NHEJ.

The results of this experiment will explain the cleavage of selected hair color-related loci in sheep cells using ZFN.

Example  21: From the organism model ship Aguti  Genome editing

Embryonic models of sheep such as sheep were harvested using standard procedures, and similarly as described in Example 20, capped and encoded with polyadenylation mRNA encoding ZFN. Sheep embryos were microinjected at the 2-4 cell stage. Reference embryos were injected with 0.1 mM EDTA. As described in Example 20, Cel-1 analysis was used to assess the frequency of ZFN-induced double stranded chromosome gaps. The results of the Cel-1 analysis can be used to evaluate the cutting effect.

Embryonic development can be assessed after brown rice injection. Embryos injected with small amounts of ZFN mRNA can determine the effect of ZFN mRNA on viability of embryos up to the blastocyst stage compared to embryos injected with EDTA.

Example  22: organism model Intracellular Fibh Edit

Zinc finger nuclease (ZFN) -mediated genome editing includes fibroin heavy chain (FibH), fibroin light chain (FibL), fibrohexamerin P25, sericin (Ser1), Cry toxin receptor (BtR175), cytochrome P450 (CYP4, ZFNs that bind to the chromosomal sequence of silkworm fiber related genes in silkworm cells such as CYP6, CYP9) can be tested in cells of an organism model such as silkworm ( Bombyx mori ). The particular silk fiber-related gene to be edited can be a gene with the same binding site for the DNA binding site of the corresponding insect, such as the gene homologue of a spider. Covered with a cap encoding ZFN, polyadenylated mRNA is a known molecule, including but not limited to, techniques substantially similar to those described in Science (2009) 325: 433 , incorporated by reference in its entirety. Can be made using biological techniques. mRNA can be transfected with cells of the silkworm ( Bombyx mori ). Reference cells can be injected with mRNA encoding GFP.

Cel-1 nuclease assay was used to determine the ZFN-induced double stranded chromosome gap frequency. This assay detects alleles of the target locus deviating from the wild type (WT) as a result of non-homologous end joining (NHEJ) -mediated incomplete repair of ZFN-induced DNA double strand breaks. PCR amplification of the targeted portion from the pool of ZFN-treated cells results in a mixture of WT and mutant amplicons. Dissolution and reannealing of this mixture results in mismatch formation between the WT and the heteroduplex of the mutant allele. DNA “bubbles” formed at the mismatch sites are cleaved by the survey nuclease Cel-1, and cleavage products can be dissociated by gel electrophoresis. The relative strength of the cleavage product compared to the paternal band is a measure of the Cel-1 cleavage level of the heteroduplex. This reflects the frequency of ZFN-mediated cleavage of endogenous target loci that will undergo incomplete repair by NHEJ.

The results of this experiment were obtained using ZFN for silkworms ( Bombyx). The cleavage of the selected silkworm fiber-associated locus in cells of mori ) will be described.

Example  23: From an organism model ship Fibh Genome editing

Silkworm, Bombyx mori , egg embryos were harvested using standard procedures, and similarly as described in Example 22, capped and encoded with polyadenylation mRNA encoding ZFN. Silkworms, Bombyx mori and egg embryos were injected with rice at the 2-4 cell stage. Reference embryos were injected with 0.1 mM EDTA. As described in Example 22, Cel-1 analysis was used to assess the frequency of ZFN-induced double stranded chromosome gaps. The results of the Cel-1 analysis can be used to evaluate the cutting effect.

Embryonic development can be assessed after brown rice injection. Embryos injected with a small amount of ZFN mRNA can determine the effect of ZFN mRNA on survival in later stages of the embryo as compared to embryos injected with EDTA.

Example  24: TUBA1B  Promoter

The following examples illustrate the use of tubulin promoters to modulate the expression of heterologous protein (s). TUBA1B was selected which encodes tubulin alpha-1B as the target chromosome sequence. A pair of zinc finger nucleases (ZFNs) have been designed to target a position in the TUBA1B coding portion. For further information, see Science (2009) 325: 433, which is incorporated by reference in its entirety. One ZFN was designed to bind SEQ ID NO: 5'CTTCGCCTCCTAATC3 '(SEQ ID NO: 86), and the other ZFN was designed to bind SEQ ID NO: 5'CACTATGGTGAGTAA 3' (SEQ ID NO: 87) (Figure 24A). Upon binding, the ZFN pair introduces a double-stranded gap in sequence 5'CCTAGC 3 'that is between two ZFN recognition sequences. The caps encoding the ZFN pairs were capped and polyadenylated mRNAs were made using known molecular biology techniques.

The gene of interest (eg, the SH2 biosensor) contained a sequence encoding GFP linked to two SH2 domains and a 2A peptide domain (see FIG. 24B). Plasmids (FIG. 25) were constructed to act as donor polynucleotides for targeted integration of SH2 biosensor sequences into the TUBA1B locus of the human cell line. This plasmid contained the coding sequence for the SH2 biosensor side of the upstream and downstream sequences TUBA1B left 700bp and 1Kb of the cutting site introduced by ZFN pairs. This plasmid was designed to integrate in-frame with the endogenous sequence immediately downstream of the tubulin start codon. As shown in Figure 24B, when activated at the TUBA1B locus two separate proteins are made.

Pairs of RNAs encoding donor plasmids and ZFNs were transfected into U2OS, A549, K562, HEK293, or HEK293T cells. The nucleic acid mixture contained one part donor DNA for one part ZZN RNAs. The transfected cells were then cultured at standard conditions. Analysis of individual cell clones showed GFP fluorescence, indicating the expression of heterologous biosensors. Western analysis confirmed that expression of α-tubulin was not affected by targeted integration (FIG. 24C).

Another donor plasmid was constructed to allow insertion for Grb2-containing biosensors (eg, GFP-2xSH2-Grb2-2A). Grb2-containing biosensors are activated by EGF and undergo nuclear translocation. A549 cells were transfected with this nucleic acid and cultured to allow integration and expression of the TUBA1B locus. Cells were exposed to 100 ng / μL of EGF and imaged. 26 shows the potential over time of the SH2 biosensor.

Example  25: ACTB  Promoter

The following example is designed to test the use of stronger promoters. Known potent promoters are in the ACTB locus encoding β-actin. ACTB A pair of ZFNs were designed to target the locus. One ZFN was designed to bind to SEQ ID NO: 5'GTCGTCGACAACGGCTCC 3 '(SEQ ID NO: 88), and another ZFN was designed to bind to SEQ ID NO: 5'TGCAAGGCCGGCTTCGCGG 3' (SEQ ID NO: 89). Upon binding, the ZFN pair introduces a double-stranded gap in sequence 5'GGCATG 3 'that is between two ZFN recognition sequences.

Donor plasmids were designed to tag SH2 biosensor sequences as well as endogenously produced β-actin (eg, GFP-2x-SH2-2A-RFP) (FIG. 27). This nucleic acid was introduced into the cells and two fluorescent proteins were made (eg GFP biosensor and RFP-tagged actin). Fluorescence of each protein was monitored using a fluorescence microscope.

In order to better monitor the different fluorescent proteins, another donor plasmid containing a Grb2-containing biosensor was constructed. Thus, the donor plasmid contained GFP-2xSH2-Grb2-2A-RFP. A549 cells were transfected with this nucleic acid and cultured to allow integration and expression of the ACTB locus. Cells were exposed to 100 ng / μL of EGF and imaged. 28 shows the potential of the GFP-Grb2 biosensor and the position of RFP-actin over time. The amount of biosensor produced is high, so the level of unbound or “free” biosensors is high, and therefore the amount of background fluorescence has increased dramatically.

Example  26: LMNB1  Promoter

To target the LMNB1 locus encoding the Lamin B1 protein, another pair of ZFNs was made. One ZFN was designed to bind to SEQ ID NO: 5'CCTCGCCGCCCCGCT 3 '(SEQ ID NO: 90), and another ZFN was designed to bind to SEQ ID NO: 5'GCCGCCCGCCATGGCG 3' (SEQ ID NO: 91). Upon binding, the ZFN pair introduced a double-strand gap in sequence 5'GTCTCC 3 'in two recognition sequences.

The donor plasmid can be constructed to contain sequences encoding biosensor proteins flanking the LMNB1 sequences upstream and downstream of the ZFN cleavage site. Nucleic acids encoding ZFNs and donor plasmids can be introduced into the cells, and the cells can be monitored as described above.

Example  27: LRRK2  Edited left ZGN Confirmation of

The mouse LRRK2 gene was selected for zinc finger nuclease (ZFN) mediated genome editing. ZFNs were designed, assembled, and demonstrated using the strategies and processes already described (see Geurts et al . Science (2009) 325: 433 ). ZFN planning was made using records of already-proven 1- and 2-finger modules. The LRRK2 gene portion (XM_235581) allows the existing module to be fused to putative zinc finger binding sites, one strand to bind to a 12-18 bp sequence, the other to bind to a 12-18 bp sequence, and about 5 between two binding sites. We looked at what could be paired with 4-, 5-, or 6-finger proteins at -6bp.

The caps encoding each ZFN pair were capped and polyadenylated mRNA was made using known molecular biology techniques. mRNA was transfected into mouse cells. Reference cells were injected with mRNA encoding GFP. Active ZFN pairs were identified by detecting ZFN-induced double stranded chromosomal gaps using Cel-1 nuclease assay. This assay detects alleles of the target locus deviating from the wild type (WT) as a result of non-homologous end joining (NHEJ) -mediated incomplete repair of ZFN-induced DNA double strand breaks. PCR amplification of the targeted portion from the pool of ZFN-treated cells results in a mixture of WT and mutant amplicons. Dissolution and reannealing of this mixture results in mismatch formation between the WT and the heteroduplex of the mutant allele. DNA “bubbles” formed at the mismatch sites are cleaved by the survey nuclease Cel-1, and cleavage products can be dissociated by gel electrophoresis. In this analysis, ZFN pairs targeted to bind 5'-tgGGTCATGAAGTGGGGGTGagtgctgt-3 '(SEQ ID NO: 94; uppercase letters are contact sites) and 5'-gaGCCCTGTACCTGGCTGTCtacgacct'3' (SEQ ID NO: 95) are truncated LRRK2 loci. Turned out.

Example  28: In the mouse's belly LRRK2  Editing

The caps encoding the active ZFN pairs were capped and polyadenylated mRNA was injected into the embryos of fertilized rats using standard procedures (eg, Geurts). meat al . (2009) supra Reference). The injected embryos were transferred to false pregnant female mice that could be incubated or delivered in vitro. Toes / tail clips of embryos / fetuses generated or born live animals were harvested for DNA extraction and analysis. DNA was isolated using standard procedures. Targeted portions of the LRRK2 locus were PCR amplified using appropriate primers. Amplified DNA was subcloned and sequenced into a suitable vector using standard methods. 29 illustrates an LRRK2 loci edited in two animal based animals. One animal had a 10bp deletion in the target sequence of exon 30, and the second animal had an 8bp deletion in the target sequence of exon 30. This deficiency destroys the reading framework of the LRRK2 coding portion.

Example  29: SNCA  Edited left ZFN Confirmation of

ZFNs capable of editing SNCA (α-synuclein) loci were designed by screening a murine SNCA locus (NM_019169) for putative zinc finger binding sites. ZFNs were basically assembled and tested as described in Example 27. This analysis revealed that ZFN pairs targeted to bind 5'-agTCAGCACAGGCATGTccatgttgagt-3 '(SEQ ID NO: 96) and 5'-ccTCTGGGGTAGTGAACAGGtctcccac-3' (SEQ ID NO: 97) were truncated inside the rat SNCA locus.

Example  30: DJ -1 left edited ZFN Confirmation of

As described above, ZFNs with activity at the DJ −1 locus were identified. In other words, the rat DJ- 1 gene (NM_019169) was orthogonal to putative zinc finger binding sites and ZFNs were basically assembled and tested as described in Example 27. It was found that ZFN pairs targeted to bind 5'-aaGCCGACTAGAGAGAGaacccaaacgc-3 '(SEQ ID NO: 98) and 5'-gtGAAGGAGATcCTCAAGgagcaggaga-3' (SEQ ID NO: 99) were edited to DJ- 1 loci.

Example  31: Parkin  Edited left ZFN Confirmation of

To identify the ZFNs that target Parkin loci and cleave it, the rat Parkin gene (NM_020093) was defined for putative zinc finger binding sites. ZFNs were basically assembled and tested as described in Example 27. This analysis revealed that ZFN pairs targeted to bind 5'-gaACTCGGaGTTTCCCAGgctggacctt-3 '(SEQ ID NO: 100) and 5'-gtGCGGCACCTGCAGACaagcaaccctc-3' (SEQ ID NO: 101) were cleaved inside the Parkin gene.

Example  32: PINK1  Edited left ZFN Confirmation of

ZFNs active at the PINK1 locus were basically identified as described above. Murine PINK1 gene (NM_020093) was determined for putative zinc finger binding sites. ZFNs were basically assembled and tested as described in Example 27. This analysis revealed that ZFN pairs targeted to bind 5'-ggGTAGTAGTGTGGGGGtagcatgtcag-3 '(SEQ ID NO: 102) and 5'-aaGGCCTGgGCCACGGCCGCAcactctt-3' (SEQ ID NO: 103) have edited the PINK1 gene.

The table below shows the helix amino acid sequences of active ZFNs.

Example  33: ApoE  Genomic Editing of the Left

A zinc finger nuclease (ZFN), which was cut to the left of the ApoE rabbits targeted using the already described strategy and the planning process was ZFNs, were assembly, and was demonstrated (Geurts meat al . Science (2009) 325: 433 ). ZFN planning was made using records of already-proven 1- and 2-finger modules. The rabbit ApoE gene portion is an existing module fused to the putative zinc finger binding site, one strand may bind to the 12-18 bp sequence, the other strand binds to the 12-18 bp sequence, and about 5-6 bp between the two binding sites. Investigate the possibility of pairing 4-, 5-, or 6-finger proteins.

The caps encoding each ZFN pair were capped and polyadenylated mRNA was made using known molecular biology techniques. mRNA was transfected with rabbit cells. Reference cells were injected with mRNA encoding GFP. Active ZFN pairs were identified by detecting ZFN-induced double stranded chromosomal gaps using Cel-1 nuclease assay. This assay detects alleles of the target locus deviating from the wild type (WT) as a result of non-homologous end joining (NHEJ) -mediated incomplete repair of ZFN-induced DNA double strand breaks. PCR amplification of the targeted portion from the pool of ZFN-treated cells results in a mixture of WT and mutant amplicons. Dissolution and reannealing of this mixture results in mismatch formation between the WT and the heteroduplex of the mutant allele. DNA “bubbles” formed at the mismatch sites are cleaved by the survey nuclease Cel-1, and cleavage products can be dissociated by gel electrophoresis. This analysis can identify active ZFN pairs that have edited ApoE loci.

To mediate the editing of the ApoE locus in animals, mRNA encoding an active ZFN pair is standardized (eg, Geurts). meat al . (2009) supra Can be injected into the fertilized rabbit's belly. Injected embryos can be transferred to false pregnant female rabbits that can be incubated or delivered in vitro. Embryos / fetuses generated for DNA extraction and analysis, or toes / tail clips of born live animals can be collected. DNA can be isolated using standard procedures. Suitable primers can be used to PCR amplify the targeted portion of the ApoE locus. Amplified DNA can be subcloned and sequenced into a suitable vector using standard methods.

Example  34: organism Within the model FAH Genome editing

Rabbit or human disease-associated chromosomes, such as chromosomal sequences encoding fumarylacetoacetate hydrolase (FAH) in genetically modified model animals and cells derived from these animals using ZFN-mediated genome editing The effect of “knock-out” mutations in the sequence can be studied. Such model animals may be rabbits. In general, ZFNs that bind to rabbit chromosomal sequences encoding fumarylacetoacetate hydrolase associated with rabbit immunodeficiency can be used to introduce a deletion or insertion such that the coding portion of the FAH gene is destroyed so that no FAH functional protein is produced. have.

Modified suitable embryos are basically capped to encode ZFN as in Example 33 and can be micro-injected with polyadenylation mRNA. As described above, Cel-1 nuclease assays can be used to determine the frequency of ZFN-induced double stranded chromosomal gaps. As described above, the edited chromosomal sequence can be analyzed. The development of immunodeficiency signs and disorders due to the fumaryl acetoacetate hydrolase “knock out” can be assessed in genetically modified rabbits or their descendants. Moreover, molecular analysis of immunodeficiency-related pathways can be performed in cells derived from genetically modified animals, including FAH “knock outs”.

Example  35: human cTnl Of humanized rabbits expressing a mutant type of

Familial thickening cardiomyopathy (FHC) represents an autosomal dominant mode of heredity and various genetic etiologies. FHC or phenocopy can occur by multiple mutations in genes encoding various contractile, structural, channel and kinase proteins. Usually, arrhythmias associated with FHC, especially ventricular tachycardia and ventricular fibrillation, can lead to sudden death. Single base changes in the cTnl locus lead to alterations of the disease-associated protein, cardiac troponin. Using ZFN-mediated genome editing, a rabbit's cTnl locus can be made of a humanized rabbit replaced with a mutant of a human cTnl locus comprising one or more mutations. Such humanized rabbits can be used to study the development of diseases associated with human FHC. Humanized rabbits can also be used to assess the effects of targeted therapeutic agents on the pathway leading to FHC comprising cTnl.

Genetically modified rabbits can be made using the methods described in the examples above. However, to make humanized rabbits, ZFN mRNA can be co-injected into rabbit embryos with human chromosomal sequences encoding mutated cardiac troponin protein. The rabbit chromosomal sequence can then be replaced with a mutated human sequence by homologous recombination and a humanized rabbit can be made that expresses a mutated form of cardiac troponin protein.

Example  36: in organism model cells PRPN Genome editing

Zinc finger nuclease (ZFN) -mediated genome editing can be tested in cells of an organism model such as cattle using ZFN binding to the chromosomal sequence of prion protein genes of bovine cells such as PRPN. The particular gene to be edited may be a gene having the same DNA binding site for the DNA binding site of the corresponding bovine homologue of this gene. Covered with a cap encoding ZFN, polyadenylated mRNA is a known molecule, including but not limited to, techniques substantially similar to those described in Science (2009) 325: 433 , incorporated by reference in its entirety. Can be made using biological techniques. mRNA can be transfected into bovine cells. Reference cells can be injected with mRNA encoding GFP.

Cel-1 nuclease assays can be used to determine the frequency of ZFN-induced double stranded chromosome gaps. This assay detects alleles of the target locus deviating from the wild type (WT) as a result of non-homologous end joining (NHEJ) -mediated incomplete repair of ZFN-induced DNA double strand breaks. PCR amplification of the targeted portion from the pool of ZFN-treated cells results in a mixture of WT and mutant amplicons. Dissolution and reannealing of this mixture results in mismatch formation between the WT and the heteroduplex of the mutant allele. DNA “bubbles” formed at the mismatch sites are cleaved by the survey nuclease Cel-1, and cleavage products can be dissociated by gel electrophoresis. The relative strength of the cleavage product compared to the paternal band is a measure of the Cel-1 cleavage level of the heteroduplex. This reflects the frequency of ZFN-mediated cleavage of endogenous target loci that will undergo incomplete repair by NHEJ.

The results of this experiment can explain the cleavage of selected PRPN loci in bovine cells using ZFN.

Example  37: From an organism model ship PRPN Genome editing

Embryos of an organism model such as cattle were harvested using standard procedures, and similarly described in Example 36, capped and encoded with polyadenylation mRNA encoding ZFN. Bovine embryos were microinjected at one cell level. Reference embryos were injected with 0.1 mM EDTA. As described in Example 36, Cel-1 analysis can be used to assess the frequency of ZFN-induced double stranded chromosomal gaps. The results of the Cel-1 analysis can be used to evaluate the cutting effect.

Embryonic development can be assessed after brown rice injection. Embryos injected with small amounts of ZFN mRNA can determine the effect of ZFN mRNA on viability of embryos up to the blastocyst stage compared to embryos injected with EDTA.

Example  38: ApoE  Edited left ZFN Confirmation of

ApoE gene was selected for zinc finger nuclease (ZFN) -mediated genome editing. Using the already described strategy and planning process was the ZFNs, was the assembly, and was demonstrated (Geurts meat al . Science (2009) 325: 433 ). ZFN planning was made using records of already-proven 1- and 2-finger modules. The murine ApoE gene portion (NM_138828) has an existing module fused to the putative zinc finger binding site, where one strand can bind to a 12-18 bp sequence, the other strand binds to a 12-18 bp sequence, and between about two binding sites Investigations were made on the possibility of pairing 4-, 5-, or 6-finger proteins with 5-6 bp.

The caps encoding each ZFN pair were capped and polyadenylated mRNA was made using known molecular biology techniques. mRNA was transfected with mouse cells. Reference cells were injected with mRNA encoding GFP.

Active ZFN pairs were identified by detecting ZFN-induced double stranded chromosomal gaps using Cel-1 nuclease assay. This assay detects alleles of the target locus deviating from the wild type (WT) as a result of non-homologous end joining (NHEJ) -mediated incomplete repair of ZFN-induced DNA double strand breaks. PCR amplification of the targeted portion from the pool of ZFN-treated cells results in a mixture of WT and mutant amplicons. Dissolution and reannealing of this mixture results in mismatch formation between the WT and the heteroduplex of the mutant allele. DNA “bubbles” formed at the mismatch sites are cleaved by the survey nuclease Cel-1, and cleavage products can be dissociated by gel electrophoresis. This analysis revealed that ZFN pairs targeted to bind 5 'aaGCGGTTCAGGGCCTGctcccagggtt-3' (SEQ ID NO: 117; capitalized contact site) and 5 'ggGATTACCTGcGCTGGGtgcagacgct-3' (SEQ ID NO: 118) cleaved inside the ApoE locus. lost.

Example  39: In the mouse's belly ApoE  Editing

The caps encode the active ZFN pairs and the polyadenylation of mRNA is standardized (eg, Geurts). et al. (2009) supra And injected into the embryo of fertilized mice. The injected embryos were transferred to false pregnant female mice that could be incubated or delivered in vitro. Toes / tail clips of embryos / fetuses generated or born live animals were harvested for DNA extraction and analysis. DNA was isolated using standard procedures. Targeted portions of the ApoE locus were PCR amplified using appropriate primers. Amplified DNA was subcloned and sequenced into a suitable vector using standard methods. 30 illustrates ApoE locus edited in two animals. One animal had a 16bp deletion in the target sequence of exon 2, and the second animal had a 1bp deletion in the target sequence of exon 2. This deficiency destroys the reading framework of the ApoE coding portion.

Example  40: Leptin  Edited left ZFN Confirmation of

Targeting leptin (leptin) gene in mice, as described above and was confirmed ZFN cutting them. Murine leptin gene (NM_013076) was determined for putative zinc finger binding sites. As described in Example 38, ZFNs were designed, assembled, and tested. In this assay, ZFN pairs targeted to bind 5'-gtGGATAGGCACAGcttgaacataggac -3 '(SEQ ID NO: 119; capitalized contact site) and 5' aaGTCCAGGATGACACCaaaaccctcat-3 '(SEQ ID NO: 120) were cleaved inside the leptin locus. It turned out.

Example  41: in the rat belly Leptin ( leptin ) Edit of left

As described in Example 39, mRNAs basically encoding the active leptin pair ZFN were injected into mice embryos. The injected embryos were incubated and DNA extracted from the resulting animals. Targeted portions of the leptin locus were PCR amplified using appropriate primers. Amplified DNA was subcloned and sequenced into a suitable vector using standard methods. FIG. 31 shows an edited leptin locus lacking a 151 bp portion from the 3 'end of exon 1 and the 5' end of intron 1. FIG.

Example  42: in the rat belly Pten  Editing

ZFNs were designed and tested to target and cleave Pten loci in mice as described in Example 38. Active ZFN pairs were identified. DNA binding sites were 5'-CCCCAGTTTGTGGTCtgcca-3'SEQ ID NO: 121) and 5'-gcTAAAGGTGAAGATCTA-3 '(SEQ ID NO: 122). Caps encoding the active pairs are capped, and polyadenylated mRNA can be injected microscopically into rat embryos, and the resulting embryos can be analyzed as described in Example 39. Thus, the Pten locus can be edited to include deletions or insertions such that the coding moiety is disrupted so that a functional gene product is not made.

Example  43: organism model Intracellularly Canca1c Genome editing

Zinc finger nuclease (ZFN) -mediated genome editing can be performed by an organism model such as ZFN that binds to the chromosomal sequence of cardiovascular-related genes in mouse cells such as Canca1C, Sod1, Pten, Ppar (alpha), and combinations thereof. Can be tested in the cell. The particular chromosomal sequence related to the cardiovascular disease to be edited may be a gene having the same DNA binding site for the DNA binding site of the corresponding human homologue of this gene. Covered with a cap encoding ZFN, polyadenylated mRNA is a known molecule, including but not limited to, techniques substantially similar to those described in Science (2009) 325: 433 , incorporated by reference in its entirety. Can be made using biological techniques. mRNA can be transfected with human K562 cells, assuming that not only mouse cells, but also human K562 cells have the same DNA binding site. Reference cells can be injected with mRNA encoding GFP.

Cel-1 nuclease assays can be used to determine the frequency of ZFN-induced double stranded chromosome gaps. This assay detects alleles of the target locus deviating from the wild type (WT) as a result of non-homologous end joining (NHEJ) -mediated incomplete repair of ZFN-induced DNA double strand breaks. PCR amplification of the targeted portion from the pool of ZFN-treated cells results in a mixture of WT and mutant amplicons. Dissolution and reannealing of this mixture results in mismatch formation between the WT and the heteroduplex of the mutant allele. DNA “bubbles” formed at the mismatch sites are cleaved by the survey nuclease Cel-1, and cleavage products can be dissociated by gel electrophoresis. The relative strength of the cleavage product compared to the paternal band is a measure of the Cel-1 cleavage level of the heteroduplex. This reflects the frequency of ZFN-mediated cleavage of endogenous target loci that will undergo incomplete repair by NHEJ.

The results of this experiment can explain the cleavage of selected cardiovascular-related loci in human and rat cells using ZFN.

Example  44: From an organism model ship Canca1c Genome editing

Embryos of an organism model, such as a mouse, are harvested using standard procedures, and similarly described in Example 43, can be capped and injected with polyadenylation mRNA encoding ZFN. Rat embryos can be microinjected at one cell level. Reference embryos can be injected with 0.1 mM EDTA.

As described in Example 43, Cel-1 analysis can be used to predict ZFN-induced double strand chromosome gap frequency. The results of the Cel-1 analysis can be used to predict the cutting effect.

Embryonic development can be assessed after brown rice injection. Embryos injected with small amounts of ZFN mRNA can determine the effect of ZFN mRNA on viability of embryos up to the blastocyst stage compared to embryos injected with EDTA.

The following table shows the helix amino acid sequence of active ZFNs.

Example  45: in organism model cells Myostatin Of GDF8 , CD163  or Sialoadhesin  Genome editing

Zinc finger nuclease (ZFN) -mediated genome editing involves MC1R, MSH receptor proteins, tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1), aguti signaling protein (ASIP), melanophylline (MLPH) and ZFNs, which bind to the chromosomal sequence of hair color-related genes of the same pig cell, can be used to test intracellularly in an organism model such as pig. The particular envelope color-related gene to be edited may be a gene having the same DNA binding site for the DNA binding site of the corresponding porcine homologue of this gene. Covered with a cap encoding ZFN, polyadenylated mRNA is a known molecule, including but not limited to, techniques substantially similar to those described in Science (2009) 325: 433 , incorporated by reference in its entirety. Can be made using biological techniques. mRNA can be transfected into pig cells. Reference cells can be injected with mRNA encoding GFP.

Cel-1 nuclease assays can be used to determine the frequency of ZFN-induced double stranded chromosome gaps. This assay detects alleles of the target locus deviating from the wild type (WT) as a result of non-homologous end joining (NHEJ) -mediated incomplete repair of ZFN-induced DNA double strand breaks. PCR amplification of the targeted portion from the pool of ZFN-treated cells results in a mixture of WT and mutant amplicons. Dissolution and reannealing of this mixture results in mismatch formation between the WT and the heteroduplex of the mutant allele. DNA “bubbles” formed at the mismatch sites are cleaved by the survey nuclease Cel-1, and cleavage products can be dissociated by gel electrophoresis. The relative strength of the cleavage product compared to the paternal band is a measure of the Cel-1 cleavage level of the heteroduplex. This reflects the frequency of ZFN-mediated cleavage of endogenous target loci that will undergo incomplete repair by NHEJ.

The results of this experiment can explain the cleavage of selected myostatin / GDF8, CD163 or sialoadhesin-associated loci selected from pig cells using ZFN.

Example  46: From an organism model ship HAL , RN , ESR , IGF2 , GHRH , H- FABP , GH , IGF1 , PIT1 , GHRHR  Or GHR Genome editing

Embryos of an organism model such as swine are harvested using standard procedures, and similarly described in Example 45, are capped and encoded with polyadenylated mRNA encoding ZFN. Porcine embryos can be microinjected at 2-4 cell stages. Reference embryos can be injected with 0.1 mM EDTA. Cel-1 analysis can be used to predict ZFN-induced double strand chromosome gap frequency as described in Example 45. The results of the Cel-1 analysis can be used to predict the cutting effect.

Embryonic development can be assessed after brown rice injection. Embryos injected with small amounts of ZFN mRNA can determine the effect of ZFN mRNA on viability of embryos up to the blastocyst stage compared to embryos injected with EDTA.

Example  47: Can  f 1  Genomic Editing of the Left

With canine target the Can f 1 and left the animal, zinc finger nucleases (ZFNs) for cutting it, using the already described strategy and the planning process, the ZFNs, and assembly, and is able to demonstrate (Geurts et al. Science (2009) 325: 433 ). ZFN planning was made using records of already-proven 1- and 2-finger modules. The Can f 1 gene portion of a canine animal is a conventional module fused to a putative zinc finger binding site, capable of binding to a 12-18 bp sequence on one strand, and a 12-18 bp sequence on the other strand, between the two binding sites. Was examined for the possibility of pairing 4-, 5-, or 6-finger proteins, with about 5-6 bp.

The caps encoding the ZFN pairs were capped and the polyadenylated mRNA was made using known molecular biology techniques. mRNA was transfected with canine cells. Reference cells were injected with mRNA encoding GFP. Cel-1 nuclease assays can be used to identify active ZFN pairs by detecting ZFN-induced double stranded chromosomal gaps. This assay detects alleles of the target locus deviating from the wild type (WT) as a result of non-homologous end joining (NHEJ) -mediated incomplete repair of ZFN-induced DNA double strand breaks. PCR amplification of the targeted portion from the pool of ZFN-treated cells results in a mixture of WT and mutant amplicons. Dissolution and reannealing of this mixture results in mismatch formation between the WT and the heteroduplex of the mutant allele. DNA “bubbles” formed at the mismatch sites are cleaved by the survey nuclease Cel-1, and cleavage products can be dissociated by gel electrophoresis. This analysis identifies the active ZFN pairs that edited the Can f 1 locus.

In order to mediate the editing of the Can f 1 locus in animals, mRNA encoding the active ZFN pair is standardized (eg, Geurts). meat al . (2009) supra Brown rice can be injected into fertilized canine and animal belly. Injected embryos can be transferred to false pregnant female dogs that can be incubated or delivered in vitro. Embryos / fetuses generated for DNA extraction and analysis, or toes / tail clips of born live animals can be collected. DNA can be isolated using standard procedures. Suitable primers can be used to PCR amplify the targeted portion of the Can f 1 locus. Amplified DNA can be subcloned and sequenced into a suitable vector using standard methods.

Example  48: In organism models HCRTR2 Genome editing

“Green” in canine or human disease-associated chromosomal sequences, such as chromosomal sequences encoding hypocretin receptor proteins in genetically modified model animals and cells derived from these animals using ZFN-mediated genome editing. -Out "mutations can be studied. Such model animals may be canine. In general, ZFNs that bind to canine animal chromosomal sequences encoding hypocreatinic receptors associated with canine narcolepsy are defective to break the coding portion of the HCRTR2 gene in order to prevent the production of a functioning hypocreatin receptor protein. It can be used to introduce an insert.

Modified suitable embryos are essentially capped with ZFN encoding as in Example 47 and can be micro-injected with polyadenylation mRNA. As described above, Cel-1 nuclease assays can be used to determine the frequency of ZFN-induced double stranded chromosomal gaps. As described above, the edited chromosomal sequence can be analyzed. The development of narcolepsy signs and disorders due to hypocretin receptor “knock-out” can be assessed in genetically modified canines or offspring. Moreover, molecular analysis of the narcolepsy-related pathway can be performed in cells derived from genetically modified animals, including HCRTR2 “knock-out”.

Example  49: human BHD of Mutated  Humanized to express phenotype Canine  Generation of animals

BHD is a multisystem disorder in humans with a very similarity to RCND, a naturally occurring hereditary canine and animal cancer syndrome. RCND in Genome Comparison The left overlaps with the human BHD left. A single base change at the RCND locus leads to alteration of the disease-associated protein folliculin.

ZFN-mediated genome editing can be used to create humanized canine animals in which canine animal RCND is replaced with a mutant of a human BHD locus containing one or more mutations. Such humanized canines can be used to study the development of diseases associated with mutated human BHD. Humanized canine animals can also be used to assess the effect of potential therapeutic agents targeted on pathways leading to renal cancer, including BHD.

Genetically modified canines can be made using the methods described in the examples above. However, to make humanized canine animals, ZFN mRNA can be co-injected into canine embryos with human chromosomal sequences encoding mutated BHD proteins. The canine chromosome sequence can then be replaced with a mutated human sequence by homologous recombination, and a humanized canine animal expressing a mutated form of the BHD protein can be made.

Example  50: Genome Editing of Addiction-associated Proteins in Organism Model Cells

Zinc finger nuclease (ZFN) -mediated genome editing includes ABAT (4-aminobutyrate aminotransferase), DRD2 (dopamine receptor D2), DRD3 (dopamine receptor D3), DRD4 (dopamine receptor D4), GRIA1 (glutamate receptor , Ionic, AMPA 1), GRIA2 (glutamate receptor, ionic, AMPA 2), GRIN1 (glutamate receptor, ionic, N-methyl D-aspartate 1), GRIN2A (glutamate receptor, ionic, N-methyl Such as D-aspartate 2A), GRM5 (metabotropic glutamate receptor 5), HTR1B (5-hydroxytrytamine (serotonin) receptor 1B), PDYN (dinolpin), or PRKCE (protein kinase C, epsilon) ZFNs that bind to the chromosomal sequences of the addiction-associated genes of the mouse cells can be used to test in cells of an organism model, such as a mouse. The particular chromosomal sequence associated with the addiction to be edited may be a gene having the same DNA binding site for the DNA binding site of the corresponding human homologue of this gene. Covered with a cap encoding ZFN, polyadenylated mRNA is a known molecule, including but not limited to, techniques substantially similar to those described in Science (2009) 325: 433 , incorporated by reference in its entirety. Can be made using biological techniques. mRNA can be transfected with human K562 cells, assuming that not only mouse cells, but also human K562 cells have the same DNA binding site. Reference cells can be injected with mRNA encoding GFP.

Cel-1 nuclease assays can be used to determine the frequency of ZFN-induced double stranded chromosome gaps. This assay detects alleles of the target locus deviating from the wild type (WT) as a result of non-homologous end joining (NHEJ) -mediated incomplete repair of ZFN-induced DNA double strand breaks. PCR amplification of the targeted portion from the pool of ZFN-treated cells results in a mixture of WT and mutant amplicons. Dissolution and reannealing of this mixture results in mismatch formation between the WT and the heteroduplex of the mutant allele. DNA “bubbles” formed at the mismatch sites are cleaved by the survey nuclease Cel-1, and cleavage products can be dissociated by gel electrophoresis. The relative strength of the cleavage product compared to the paternal band is a measure of the Cel-1 cleavage level of the heteroduplex. This reflects the frequency of ZFN-mediated cleavage of endogenous target loci that will undergo incomplete repair by NHEJ.

The results of this experiment can explain the cleavage of selected addiction-related loci in human and rat cells using ZFN.

Example  51: Genome Editing of Addiction-associated Proteins in the Tummy of an Organism Model

Embryos of an organism model, such as a rat, are harvested using standard procedures, and similarly as described in Example 50, can be capped and injected with polyadenylation mRNA encoding ZFN. Rat embryos can be microinjected at the single cell stage. Reference embryos can be injected with 0.1 mM EDTA. Cel-1 analysis as described in Example 50 can be used to predict ZFN-induced double stranded chromosome gap frequency. The results of the Cel-1 analysis can be used to predict the cutting effect.

Embryonic development can be assessed after brown rice injection. Embryos injected with small amounts of ZFN mRNA can determine the effect of ZFN mRNA on viability of embryos up to the blastocyst stage compared to embryos injected with EDTA.

Example  52: APP  Genomic Editing of the Left

The left of APP mice with target, zinc finger nucleases (ZFNs) for cutting it, using the already described strategy and the planning process, the ZFNs, and assembly, and is able to demonstrate (Geurts meat al . Science (2009) 325: 433 ). ZFN planning was made using records of already-proven 1- and 2-finger modules. In the rat APP gene portion, the existing module is fused to the putative zinc finger binding site, one strand may bind to a 12-18 bp sequence, the other strand binds to a 12-18 bp sequence, and between about two 5-binding sites. Investigations were made about the ability to make pairs of 4-, 5-, or 6-finger proteins at 6 bp.

The caps encoding the ZFN pairs were capped and the polyadenylated mRNA was made using known molecular biology techniques. mRNA was transfected with mouse cells. Reference cells were injected with mRNA encoding GFP. Cel-1 nuclease assays can be used to identify active ZFN pairs by detecting ZFN-induced double stranded chromosomal gaps. This assay detects alleles of the target locus deviating from the wild type (WT) as a result of non-homologous end joining (NHEJ) -mediated incomplete repair of ZFN-induced DNA double strand breaks. PCR amplification of the targeted portion from the pool of ZFN-treated cells results in a mixture of WT and mutant amplicons. Dissolution and reannealing of this mixture results in mismatch formation between the WT and the heteroduplex of the mutant allele. DNA “bubbles” formed at the mismatch sites are cleaved by the survey nuclease Cel-1, and cleavage products can be dissociated by gel electrophoresis. This analysis identifies the active ZFN pairs that have edited the APP locus. Zinc finger binding sites were 5'-GCCAGCACCCCTGACgcag'3- (SEQ ID NO: 129) and 5'-tcGACAAGTACCTGGAG'3 '(SEQ ID NO: 130).

APP from animals To mediate loci editing, mRNA encoding the active ZFN pair is standardized (eg, Geurts). meat al . (2009) supra And injected into the embryo of fertilized mice. The injected embryos were transferred to false pregnant female mice that could be incubated or delivered in vitro. Toes / tail clips of embryos / fetuses generated or born live animals were harvested for DNA extraction and analysis. DNA was isolated using standard procedures. Targeted portions of the APP locus were PCR amplified using appropriate primers. Amplified DNA was subcloned and sequenced into a suitable vector using standard methods. 32 shows an APP loci edited in two base animals; One had a 292 bp deletion in exon 9 (FIG. 32A) and the other had a 309 bp deletion in exon 9 (FIG. 32B).

Example  53: Genome Editing of Cognitive-Related Genes in Organismal Model Cells

ZFN-mediated genome editing includes ANK3 (Ankryn 3), APP (amyloid precursor protein), B2M (beta-2 microglobulin), BRD1 (bromodomain containing 1), FMR1 (fragile X spirit) ZFNs that bind to the chromosomal sequence of cognitive-related genes such as retardation 1), MECP2 (methyl CpG binding protein 2), NGFR (nerve growth factor receptor), NLGN3 (neurogin 3), or NRXN1 (neulexin 1) Can be tested in cells of an organism model, such as a mouse. As described in Example 52, ZFNs can be basically designed and tested. ZFNs targeted to specific cognitive-related genes can be used to introduce a deletion or insertion such that the coding portion of the gene of interest is inactivated.

Example  54: Editing Cognitive-Related Genes in an Organism Model

Embryos of an organism model, such as a mouse, can be harvested using standard procedures, capped to encode ZFNs targeting cognitive-related genes, and described as polyadenylation mRNA, as described in Example 52. You can inject brown rice. Donor or exchange polynucleotides comprising sequences for integration or exchange may be co-infused with ZFNs. The chromosomal portion edited in the resulting animals can be analyzed as described above. Deformed animals can be phenotyped for changes in behavior, learning, etc. Moreover, genetically modified animals can be used to assess the effect of potential therapeutic agents on cognitive-related disorders.

Example  55: In an organism model CCR2 Genome editing

Effect of “knock-out” mutations on inflammation-associated chromosomal sequences such as chromosomal sequences encoding CCR2 protein in genetically modified model animals and cells derived from these animals using ZFN-mediated genome editing Can study. Such model animals can be rats. In general, ZFNs that bind to the chromosomal sequence of mice encoding protein CCR2 associated with inflammation can be used to introduce non-sense mutations into the coding portion of the CCR2 gene such that no CCR2 active protein is produced.

Covered with a cap encoding ZFN, polyadenylated mRNA is a known molecule, including but not limited to, techniques substantially similar to those described in Science (2009) 325: 433 , incorporated by reference in its entirety. Can be made using biological techniques. mRNA can be transfected into mouse embryos. When injected microscopically, the rat embryo may be at the single cell stage. Reference vessels may be injected with 0.1 mM EDTA. Cel-1 nuclease assays can be used to determine the frequency of ZFN-induced double stranded chromosome gaps. This assay detects alleles of the target locus deviating from the wild type (WT) as a result of non-homologous end joining (NHEJ) -mediated incomplete repair of ZFN-induced DNA double strand breaks. PCR amplification of the targeted portion from the pool of ZFN-treated cells results in a mixture of WT and mutant amplicons. Dissolution and reannealing of this mixture results in mismatch formation between the WT and the heteroduplex of the mutant allele. DNA “bubbles” formed at the mismatch sites are cleaved by the survey nuclease Cel-1, and cleavage products can be dissociated by gel electrophoresis. The relative strength of the cleavage product compared to the paternal band is a measure of the Cel-1 cleavage level of the heteroduplex. This reflects the frequency of ZFN-mediated cleavage of endogenous target loci that will undergo incomplete repair by NHEJ.

Development of embryos after microinjection and the development of inflammation-related signs and disorders by CCR2 “knock-out” can be assessed in genetically modified mice. In the case of CCR2, inflammation-related signs and disorders may include the development of rheumatoid arthritis and the development of an altered inflammatory response against the tumor. This result can be compared with reference mice injected with 0.1 mM EDTA and with no alteration of the chromosomal portion encoding the CCR2 protein. In addition, molecular analysis of inflammation-related pathways can be performed in cells derived from genetically modified animals, including CCR2 “knock outs”.

Example  56: human Perforin -1's Mutated  Production of humanized mice expressing the phenotype

Missense mutations in Perforin-1, the definitive effector of lymphocyte cytotoxicity, lead to disease range from hemophagocytic lymphohistiocytosis to increased risk of tumor development. One such mutation is the V50M missense mutation, wherein the valine amino acid at position 50 of Perforin-1 is replaced with methionine. ZFN- using the intermediary genome editing, PRF1 may rat gene to create a humanized rat replaced with a mutant type human PRF1 gene containing the mutation V50M. Such humanized mice can be used to study the development of diseases associated with mutated human Perforin-1 protein. Humanized mice can also be used to assess the effect of potential therapeutic agents targeting inflammatory pathways including Perforin-1.

Genetically modified mice can be made using the same method as described in Example 55 above. However, to make humanized rats, human chromosomal sequences encoding mutated Perforin-1 protein and ZFN mRNA can be co-injected into rat embryos. The murine chromosomal sequence can then be replaced with a mutated human sequence by homologous recombination, resulting in humanized mice expressing a mutated form of the Perforin-1 protein.

Example  57: Pten  Editing

Targeting the Pten locus in mice was designed ZFN cleavage and tested for activity basically as described in Example 55. ZFN active pairs were identified. DNA binding sites were 5'-CCCCAGTTTGTGGTCtgcca-3 '(SEQ ID NO: 135) and 5'-gcTAAAGGTGAAGATCTA-3' (SEQ ID NO: 136). The caps encoding the active pairs are capped, the polyadenylated mRNA can be microinjected into rat embryos, and the resulting embryos can be analyzed as described in Example 55. Thus, the Pten locus can be edited to include deletions or insertions such that the coding moiety is disrupted so that a functional gene product is not made.

Example  58: Rag1  Edited left ZFN Confirmation of

Rag1 gene was selected for zinc finger nuclease (ZFN) -mediated genome editing. ZFNs were designed, assembled, and demonstrated using the strategies and procedures described in the examples above. ZFN planning was made using records of already-proven 1- and 2-finger modules. Rat Rag1 The gene portion (XM_001079242) is an existing module fused to the putative zinc finger binding site, capable of binding to a 12-18 bp sequence on one strand, binding to a 12-18 bp sequence on the other strand, and about 5-between the two binding sites. Investigations were made about the ability to make pairs of 4-, 5-, or 6-finger proteins at 6 bp. The caps encoding each ZFN pair were covered, polyadenylated mRNA was made, and transfected with mouse cells. Reference cells were injected with mRNA encoding GFP. Active ZFN pairs were identified by detecting ZFN-induced double stranded chromosomal gaps using Cel-1 nuclease assay. In this assay, ZFN pairs targeted to bind 5'-ttCCTTGGGCAGTAGACctgactgtgag-3 '(SEQ ID NO: 137; macromolecules are contact sites) and 5'-gtGACCGTGGAGTGGCAcccccacac-3' (SEQ ID NO: 138) were cleaved inside the Rag1 gene. It turned out.

Example  59: Rag1  Editing

As described in the above examples, capped, polyadenylated mRNA encoding the active ZFN pairs was microinjected into embryos of fertilized mice. The injected embryos were transferred to false pregnant canine animals that could be incubated or delivered in vitro. Toes / tail clips of embryos / fetuses generated or born live animals were harvested for DNA extraction and analysis. DNA was isolated using standard procedures. Targeted portions of the Rag1 locus were PCR amplified using appropriate primers. Amplified DNA was subcloned into a suitable vector using standard methods and sequenced. 33 shows the DNA sequence of the Rag1 locus edited in two animals (SEQ ID NOs: 131 and 132). One animal had a 808 bp deletion in exon 2 and the second animal had a 29 bp deletion in the target sequence of exon 2. These deficiencies destroy the reading frame of the Rag1 coding portion.

Example  60: Rag2  Edited left ZFN Confirmation of

Rag2 ZFNs targeting genes and cleaving them were basically identified as described above. Murine Rag2 gene (XM_001079235) was determined for putative zinc finger binding sites. ZFNs were assembled and tested as described in Example 55. In this assay, a ZFN pair targeted to bind 5'-acGTGGTATATaGCCGAGgaaaaagtgt -3 '(SEQ ID NO: 139; capitalized contact site) and 5'-atACCACGTCAATGGAAtggccatatct -'3' (SEQ ID NO: 140) cleaved the Rag2 locus. Turned out.

Example  61: Rag2  Editing

As described in Example 56, mRNA encoding Rag2 ZFN active pairs was injected into the embryos of fertilized mice. The injected embryos were incubated in vitro and DNA extracted from the resulting animals. Rag2 using appropriate primers The targeted portion of the locus was PCR amplified. Amplified DNA was subcloned into a suitable vector using standard methods and sequenced. 34 shows Rag2 edited in two animals The DNA sequence of the locus is shown. One animal had a 13 bp deletion in the target sequence of exon 3 and the second animal had a 2 bp deletion in the target sequence of exon 3. These deficiencies destroy the reading frame of the Rag2 coding portion.

Example  62: FoxN1  Edited left ZFN Confirmation of

ZFNs targeting and cleaving the FoxN1 gene were basically identified as described in Example 55. The mouse FoxN1 gene (XM_220632) was determined for putative zinc finger binding sites. ZFNs were assembled and tested as described in Example 55. This analysis revealed that two pairs of active ZFNs cleaved the FoxN1 locus: the first pair was 5'-ttAAGGGCCATGAAGATgaggatgctac-3 '(SEQ ID NO: 141; capitalized contact site) and 5'-caGCAAGACCGGAAGCCttccagtcagt-3 Targeted to bind '(SEQ ID NO: 142); The second pair was targeted to bind 5'-ttGTCGATTTTGGAAGGattgagggccc-3 '(SEQ ID NO: 143) and 5'-atGCAGGAAGAGCTGCAgaagtggaaga-3' (SEQ ID NO: 144).

Example  63: DNAPK  Edited left ZFN Confirmation of

ZFNs targeting DNAPK genes and cleaving them were basically identified as described in Example 55. Murine DNAPK gene (NM_001108327) was determined for putative zinc finger binding sites. ZFNs were assembled and tested as described in Example 55. In this analysis, ZFN pairs targeted to bind 5'- taCACAAGTCCtTCTCCAggagctagaa-3 '(SEQ ID NO: 145; capitalized contact site) and 5'- acAAAGCTTATGAAGGTcttagtgaaaa-3' (SEQ ID NO: 146) were cleaved inside the DNAPK locus. It turned out.

The table below shows the helix amino acid sequences of active ZFNs.

Example  64: In the organism model Oct  One Genome editing

Effect of “knock-out” mutations on AD-associated chromosomal sequences such as chromosomal sequences encoding CCR2 protein in genetically modified model animals and cells derived from these animals using ZFN-mediated genome editing Can study. Such model animals can be rats. In general, ZFNs that bind to the chromosomal sequence of murine encoding the Oct1 protein associated with AD can be used to introduce deletions or insertions such that the coding portion of the Oct 1 gene is destroyed such that a functional Oct 1 protein is not produced.

Modified suitable embryos, which may be at the single-cell stage, are capped with ZFN encoding and can be microinjected with polyadenylation mRNA. As described above, Cel-1 nuclease assays can be used to determine the frequency of ZFN-induced double stranded chromosomal gaps. As described above, the edited chromosomal sequence can be analyzed. The development of AD signs and disorders due to Oct- 1 “knock-out” can be assessed in genetically modified mice or their descendants. Moreover, molecular analysis of the AD-related pathways can be performed in cells derived from genetically modified animals, including Oct1 “knock-out”.

Example  65: ADME  And In toxicology  Of related human genes Mutated  Generation of Humanized Rats Expressing a Phenotype

Mutations in any chromosomal sequences related to ADME and toxicology can be used to make humanized mice expressing mutated forms of genes. This gene may be Oct 1, Oct 2, Hfe2, Ppar (alpha), and combinations thereof. ZFN-mediated genome editing can be used to create humanized mice in which mouse genes are replaced with mutated forms of human genes including mutations. Such humanized mice can be used to study the occurrence of diseases associated with mutated human proteins encoded by the gene of interest. Humanized mice can also be used to assess the effect of potential therapeutic agents targeting the pathway leading to AD containing the gene of interest.

Genetically modified mice can be made using the same method as described in the above examples. However, in order to make humanized mice, human chromosomal sequences encoding mutated proteins and ZFN mRNA can be co-injected into rat embryos. The murine chromosomal sequence can then be replaced with mutated human sequences by homologous recombination, resulting in humanized mice expressing the mutated form of protein.

Example  66: Mdr1a  Edited left ZFN Confirmation of

The Mdr1a gene was selected for zinc finger nuclease (ZFN) -mediated genome editing. Using the strategies and processes already described ( Geurts meat al ., Science (2009) 325: 433 ) ZFNs were designed, assembled, and demonstrated. ZFN planning was made using records of already-proven 1- and 2-finger modules. The murine Mdr1a gene portion (NM_133401) allows the existing module to be fused to putative zinc finger binding sites, binding to a 12-18 bp sequence on one strand, binding to a 12-18 bp sequence on the other strand, and between approximately two binding sites. Investigations were made on the possibility of pairing 4-, 5-, or 6-finger proteins with 5-6 bp.

The caps encoding the ZFN pairs were capped and the polyadenylated mRNA was made using known molecular biology techniques. mRNA was transfected with mouse cells. Reference cells were injected with mRNA encoding GFP. Active ZFN pairs were identified by detecting ZFN-induced double stranded chromosomal gaps using Cel-1 nuclease assay. This assay detects alleles of the target locus deviating from the wild type (WT) as a result of non-homologous end joining (NHEJ) -mediated incomplete repair of ZFN-induced DNA double strand breaks. PCR amplification of the targeted portion from the pool of ZFN-treated cells results in a mixture of WT and mutant amplicons. Dissolution and reannealing of this mixture results in mismatch formation between the WT and the heteroduplex of the mutant allele. DNA “bubbles” formed at the mismatch sites are cleaved by the survey nuclease Cel-1, and cleavage products can be dissociated by gel electrophoresis. This analysis 5'-acAGGGCTGATGGCcaaaatcacaagag -3 '(SEQ ID NO: 164; capital letters affected area) and 5'-ttGGACTGTCAGCTGGTatttgggcaaa-'3' (SEQ ID NO: 165), the targeted ZFN pair to couple to the inner cutting was left Mdr1a It turned out.

Example  67: Mdr1a  Editing

Standard course ( Geurts meat al ., Science (2009) 325: 433 ), mRNAs encoding ZFN active pairs were injected microscopically into embryos of fertilized mice. The injected embryos were transferred to false pregnant canine animals that could be incubated or delivered in vitro. Toes / tail clips of embryos / fetuses generated or born live animals were harvested for DNA extraction and analysis. DNA was isolated using standard procedures. Targeted portions of the Mdrla locus were PCR amplified using appropriate primers. Amplified DNA was subcloned into a suitable vector using standard methods and sequenced. 35 shows the DNA sequence of the Mdr1a loci edited in two animals. One animal had a 20 bp deletion in the target sequence of exon 7 and the second animal had a 15 bp deletion and a 3 bp insertion in the target sequence of exon 7. The edited locus has frameshift mutations and multiple translation stop codons.

Run a Western assay to prevent Mdr1a protein from being produced It was checked whether the left hand was deactivated. Cell Lysate Mdr1a Prepared from the basal colon of knock-out mice. Reference cell lysates were prepared from human neuroblastoma cell lines. As shown in FIG. 36, no Mdr1a protein was detected in Mdr1a (− / −) animals, indicating that the Mdr1a locus was inactivated.

Example  68: Mdr1b  Edited left ZFN Confirmation of

ZFNs targeting the Mdr1b gene and cleaving it were basically identified as described above. The murine Mdr1b gene (NM_012623) was determined for putative zinc finger binding sites. ZFNs were assembled and tested as described in Example 64. In this assay, ZFN pairs targeted to bind 5'- agGAGGGGAAGCAGGGTtccgtggatga-3 '(SEQ ID NO: 166; capitalized contact site) and 5'-atGCTGGTGTTCGGatacatgacagata-3' (SEQ ID NO: 167) were cleaved inside the Mdr1b locus. It turned out.

Example  69: Mrp1  Edited left ZFN Confirmation of

ZFNs targeting the Mrp1 gene and cleaving it were basically identified as described in Example 64 above. The mouse Mrp1 gene (NM_022281) was determined for putative zinc finger binding sites. ZFNs were assembled and tested as described in Example 64. In this assay ZFN pair 5'- gaAGGGCCCAGGTTCTAagaaaaagcca-3 '(SEQ ID NO: 168; capital letters affected area) and 5'- tgCTGGCTGGGGTGGCTgttatgatcct-'3': targeted to bind to (SEQ ID NO: 169) ZFN pairs are left inside Mrp1 It was found that was cleaved.

Example  70: Mrp1  Editing

As described in Example 65, mRNA encoding ZFN active pairs was injected into mice embryos. The injected embryos were incubated in vitro and DNA extracted from the resulting animals. Targeted portions of the Mrp1 locus were PCR amplified using appropriate primers. Amplified DNA was subcloned into a suitable vector using standard methods and sequenced. 37 shows the DNA sequence of the Mrp1 locus edited in two animals. One animal had a 43 bp deletion in the target sequence of exon 11 and the second animal had a 14 bp deletion in exon 11. This deficiency destroys the reading framework of the Mrp1 coding portion.

Example  71: Mrp2  Edited left Of ZFN  Confirm

ZFNs targeting and cleaving the Mrp2 gene were basically identified as described in Example 64 above. The mouse Mrp2 gene (NM_012833) was determined for putative zinc finger binding sites. ZFNs were assembled and tested as described in Example 64. In this assay, ZFN pairs targeted to bind 5'-ttGCTGGTGACtGACCTTgttttaaacc-3 '(SEQ ID NO: 170; uppercase is the contact site) and 5'-ttGAGGCGGCCATGACAAAGgacctgca-'3' (SEQ ID NO: 171) were cleaved inside the Mrp2 locus. It turned out.

Example  72: Mrp2  Editing

As described in Example 65, Mrp2 MRNAs encoding ZFN active pairs were injected into mice embryos. The injected embryos were incubated in vitro and DNA extracted from the resulting animals. Targeted portions of the Mrp2 locus were PCR amplified using appropriate primers. Amplified DNA was subcloned into a suitable vector using standard methods and sequenced. Figure 38 is a deficiency from the 726bp exon 7, which due to the reading frame of the coding region Mrp2 destruction Mrp2 The edited DNA sequence of the locus is shown.

Example  73: BCRP  Edited left ZFN Confirmation of

ZFNs targeting and cleaving the BCRP gene were basically identified as described in Example 64 above. Murine BCRP gene (NM_181381) was determined for putative zinc finger binding sites. ZFNs were assembled and tested as described in Example 64. In this analysis, ZFN pairs targeted to bind 5'-atGACGTCAAGGAAGAAgtctgcagggt-3 '(SEQ ID NO: 172; capitalized contact site) and 5'-acGGAGATTCTTCGGCTgtaatgttaaa-3' (SEQ ID NO: 173) were cleaved inside the BCRP locus. It turned out.

Example  74: BCRP  Editing

As described in Example 65, BCRP MRNAs encoding ZFN active pairs were injected into mice embryos. The injected embryos were incubated in vitro and DNA extracted from the resulting animals. Targeted portions of the BCRP locus were PCR amplified using appropriate primers. Amplified DNA was subcloned into a suitable vector using standard methods and sequenced. 39 shows an edited DNA sequence of the BCRP locus in two animals. One animal had a 588 bp deletion in exon 7 and the second animal had a 696 bp deletion in exon 7. This deficiency destroys the reading framework of the BCRP coding portion.

Example  75: Mdr1a Destruction of

ZFN In vitro preparation of mRNAs : ZFN expression plasmids were obtained from Sigma's CompoZr production line. Each plasmid was linearized at the XbaI site located at the 3 'end of FokI ORF. MRNAs with 5 'caps and 3' polyA tails can be used with MessageMax T7 Capped detox kits and poly (A) polymerase tailing kits (Epicentre Biotechnology, Madison, WI) or mMessage Machine T7 kits and poly (A) tailings. Prepared using the kit (Ambion, Austin, TX). The Poly A tailing reaction was precipitated twice with the same amount of 5 M NH 4 OAc and then dissolved in injection buffer (1 mM Tris-HCl, pH 7.4, 0.25 mM EDTA). mRNA concentrations were predicted using a NanoDrop 2000 Spectrometer (Thermo Scientific, Wilmington, DE).

ZFN demonstration in cultured cells : In brief, when ZFNs make a double-stranded gap at a target site that is repaired by a non-homologous end-binding pathway, a deletion or insertion is introduced. Wild-type and mutated alleles are amplified in the same PCR reaction. When the mixture is denatured and reannealing is allowed, the wild type and mutated alleles form a double strand with the unpaired moiety near the cleavage site, which is recognized and cleaved by a single strand specific endonuclease. In addition, the paternal PCR product is added to produce two smaller molecules. The presence of the cleaved PCR bands indicates ZFN activity in the transfected cells.

NIH 3T3 cells were grown in DMEM with 5% CO ₂ , 10% FBS and antibiotics at 37 ° C. ZFN mRNAs were paired at a 1: 1 ratio and transfected with NIH 3T3 cells to confirm ZFN activity using Nucleofector (Lonza, Basel, Switzerland) according to the manufacturer's 96-well shuttle protocol for 3T3 cells. . Culture medium was removed 24 hours after transfection, and cells were incubated with 15 μl trypsin per well at 37 ° C. for 5 minutes. The cell suspension was transferred to 100 μl QuickExtract (Epicentre), incubated at 68 ° C. for 10 minutes, and incubated at 98 ° C. for 3 minutes. The extracted DNA was used as a template in the PCR reaction and amplified around the target site with the following primer pairs:

Mdr1a Cel-I F: ctgtttcttgacaaaacaacactaggctc (SEQ ID NO: 174)

Mdr1a Cel-I R: gggtcatgggaaagagtttaaaatc (SEQ ID NO: 175)

Each 50 μl PCR reaction contained 1 μl of template, 5 μl of buffer II, 5 μl of 10 uM each primer, 0.5 μl of AccuPrime High Fidelity (Invitrogen, Carsbad, Calif.) And 38.5 μl of water. The following PCR program was used: 95 ° C, 5 minutes, 95 ° C, 30 seconds, 60 ° C, 30 seconds, and 68 ° C, 45 seconds, and then 68 ° C, 5 minutes 35 times, 4 Keep at ° C. 3 μl of the PCR reaction was mixed with 7 μl of 1 × Buffer II and incubated under the following program: 95 ° C., 10 min, −2 ° C./s, 95 ° C. to 85 ° C., 85 ° C. -0.1 ° C./s at 25 ° C., maintained at 4 ° C. The reaction was cleaved for 20 minutes by adding 1 μl each of Nuclease S and Enhancer (Transgenomic, Omaha, NE) at 42 ° C. The mixture was dissociated on a 10% polyacrylamide TBE gel (Bio-Rad, Hercules, CA).

Mouse scanning microscopy and animal husbandry (husbandry): FVB / NTac and C57BL / 6NTac mouse and put them in a secure us, and placed under 14h / 10h light / dark cycle to free access to food and water. Females 3 to 4 weeks of age were injected with PMS (5 IU / mouse) and 48 h after hCG (5 IU / mouse). One cell fertilized eggs were harvested 10-12 hours after hCG injection by microinjection. ZFN mRNA was injected at 2 ng / μl. The injected eggs were delivered at 0.5 dpc to false pregnant females (Swiss Webster (SW) females from Taconic Labs, mating with SWJ males).

Founder based mutation detection assay Animal ) Identification : Toe clips were incubated in 100-200 μl of QuickExtract (Epicentre Biotechnology) at 50 ° C for 30 minutes, at 65 ° C for 10 minutes and at 98 ° C for 3 minutes. PCR and mutation detection assays were performed under the same conditions as ZFN demonstration in cells cultured with the same primer set.

TA Cloning and Sequencing : To confirm the modification in the base animal, the extracted DNA was amplified with Sigma's JumpStart Taq ReadyMix PCR kit. Each PCR reaction contained 25 μl 2 × ReadyMix, 5 μl primer, 1 μl template, and 19 μl of water. The same PCR program was used as in ZFN demonstration in cultured cells. Each PCR reaction was cloned using the TOPO TA Cloning Kit (Invitrogen) according to the manufacturer's instructions. At least eight colonies were selected from each transformation, PCR amplified with T3 and T7 primers, and sequenced with T3 or T7 primers. And sequenced in Elim Biopharmaceuticals (Hayward, CA).

He was used, and another primer set for each target to detect a larger defect: a large defect PCR to detect:

Mdr1a 800F: catgctgtgaagcagatacc (SEQ ID NO: 176)

Mdr1a 800R: ctgaaaactgaatgagacatttgc (SEQ ID NO: 177)

Each 50 μl PCR included: 1 μl template, 5 μl 10 × buffer II, 5 μl 10 uM 800F / R primer, 0.5 μl AccuPrime Taq Polymerase High Fidelity (Invitrogen), and 38.5 μl water. The following program was used: 35 cycles of 95 ° C, 5 minutes, 95 ° C, 30 seconds, 62 ° C, 30 seconds, and 68 ° C, 45 seconds, and then 68 ° C, 5 minutes, 4 ° C, long time. Samples were dissociated on 1% agarose gel. Distinct bands of lower molecular weight than the molecular weight were sequenced.

RNA Preparation from Tissue and RT - PCR : Mdr1a-/-or Mdr1a + / + litters were sacrificed for tissue collection at 5-9 weeks of age. Colon, kidney and liver tissues were excised and stored immediately for use or for later processing, and tissue biopsies were placed in RNAlater solution (Ambion) and stored at -20 ° C. Total RNA was prepared using the Genlute Mammalian Total RNA Miniprep Kit (Sigma) according to the manufacturer's instructions. To eliminate any DNA contamination, RNA was treated with DNAseI (New England Biolabs, Ipswich, Mass.) Before loading into the purification column. The RT-PCR reaction was performed with 1 μl total RNA, primers RT-F (5'-GCCGATAAAAGAGCCATGTTTG) (SEQ ID NO: 178) and RT-R (5'-GATAAGGAGAAAAGCTGCACC) (SEQ ID NO: 179), SuperScript ™ III One- Step RT-PCR system and Platinum® Taq High Fidelity Kit (Invitrogen) were used. Reverse transcription and subsequent PCR were performed once every 30 minutes at 55 ° C. and 2 minutes at 94 ° C. for cDNA synthesis; For amplification, 40 cycles of 15 seconds at 94 ° C, 30 seconds at 56 ° C, and 1 minute at 68 ° C were performed. PCR products were loaded onto 1.2% agarose gel and visually confirmed with ethidium bromide.

Interestingly, three small deletions were found in two animal bases respectively: 19 bp deletions were found in base animals 7 and 36, 21 bp deletions were found in base animals 17 and 27, and 6 bp deletions in base animals 34 and 44. Was found (FIG. 43).

High rates of germline transmission were observed from Mdr1a based animals. Nine base animals were selected for backcross with wild-type FVB / N mice to the F1 generation, all of which delivered at least one mutated allele to their descendants. Seven based animals delivered multiple mutated alleles. Interestingly, in some cases, novel alleles not identified in the base animal were also transferred to the germ line such as base animal 6, 8, 13, 21, and 44. (Table 11).

To demonstrate whether a defect inside the Mdr1a gene prevents the expression of Mdr1a, we present exons 5 and 9 in the tRNAs of liver, kidney and colon of Mdr1a-/-mice with 396 bp deletions identified from base animal 23, respectively. RT-PCR was performed using the positioned forward and reverse primers (FIG. 44A). Mdr1a protein is expressed differently in tissues. The liver and colon predominantly express Mdr1a and the kidney express both Mdr1a and Mdr1b. Mdr1a-/-Samples from all tissues produce smaller products with lower yields than the corresponding wild-type samples, and the sequence is associated with exon 7 skipping, which is immature stop at exon 8 in mutated animals. Introduce a large number of codons.

In the RT-PCR results, the Mdr1a-/-sample demonstrates that 172bp exon 7 produces transcripts deficient at levels below the wild-type level, presumably due to immature stop codons introduced by exon skipping (FIG. 44B). This leads to non-sense mediated decay. In the Mdr1a-/-sample, there are faint bands above and above the size of the wild-type transcript, mostly PCR artifacts, since most of the exon skipped products are produced in the amplification of these bands cut from the gel. Wild round sized bands in the round 2 PCR were mixtures that did not produce readable sequences (not shown). The mouse Mdr1a gene has 28 exons, and the encoded protein comprises an ATP binding site with a linker moiety between two units of six transmembrane domains (TMs 1-6 and TMs 7-12). Twelve TM domains as well as two ATP-binding motifs are both essential for Mdr1a function. Mdr1a ZFNs target exon 7 encoding TMs 3 and 4. Partial proteins resulting from exon skip and immature detoxification termination will not function. Thus, Mdr1a − / − mice derived from animal bases exhibit functionally knockout.

To demonstrate the off-target site of Mdr1a ZFN, we identified 20 sites that are most similar to the Mdr1a target site in the mouse genome, all with 5bp mismatch with the multi-ZFN binding sequence. One site is in the Mdr1b gene, which is 88% identical to the Mdr1a gene. To demonstrate the specificity of Mdr1a ZFNs, we tested the Mdr1b site in all 44 Mdr1a F0 pups using mutation detection assays. None of the 44 pups had NHEJ results at the Mdr1b site (FIG. 45). The discovery that no modification was detected at the Mdr1b site in any 44 normal births indicates the specificity of Mdr1a ZFNs. In addition, undesired modifications at the locus unlinked to the target site will be lost during subsequent breeding.

Table 12 lists some of the 20 sites checked for off-target activity of Mdr1a ZFNs, which are very similar to Mdr1a target sites (with five mismatches). List the numbers on the chromosomes they are on and the name of the gene if known. All mismatched bases are shown in lowercase. Spacer sequences between binding sites are shown in bold.

Table 13 below shows the helix amino acid sequences of active ZFNs.

Example  76: APP  Genomic Editing of the Left

The left of APP mice with target, zinc finger nucleases (ZFNs) for cutting it, using the already described strategy and the planning process was ZFNs, were assembly, and was demonstrated (Geurts meat al . Science (2009) 325: 433 ). ZFN planning was made using records of already-proven 1- and 2-finger modules. In the rat APP gene portion, the existing module is fused to the putative zinc finger binding site, one strand may bind to a 12-18 bp sequence, the other strand binds to a 12-18 bp sequence, and between about two 5-binding sites. Investigations were made about the ability to make pairs of 4-, 5-, or 6-finger proteins at 6 bp.

The caps encoding the ZFN pairs were capped and the polyadenylated mRNA was made using known molecular biology techniques. mRNA was transfected with mouse cells. Reference cells were injected with mRNA encoding GFP. Cel-1 nuclease assays can be used to identify active ZFN pairs by detecting ZFN-induced double stranded chromosomal gaps. This assay detects alleles of the target locus deviating from the wild type (WT) as a result of non-homologous end joining (NHEJ) -mediated incomplete repair of ZFN-induced DNA double strand breaks. PCR amplification of the targeted portion from the pool of ZFN-treated cells results in a mixture of WT and mutant amplicons. Dissolution and reannealing of this mixture results in mismatch formation between the WT and the heteroduplex of the mutant allele. DNA “bubbles” formed at the mismatch sites are cleaved by the survey nuclease Cel-1, and cleavage products can be dissociated by gel electrophoresis. This analysis identifies the active ZFN pairs that have edited the APP locus. Zinc finger binding sites were 5'-GCCAGCACCCCTGACgcag-3 '(SEQ ID NO: 213) and 5'-tcGACAAGTACCTGGAG-3' (SEQ ID NO: 214).

APP from animals To mediate loci editing, mRNA encoding the active ZFN pair is standardized (eg, Geurts). meat al . (2009) supra And injected into the embryo of fertilized mice. The injected embryos were transferred to false pregnant female mice that could be incubated or delivered in vitro. Toes / tail clips of embryos / fetuses generated or born live animals were harvested for DNA extraction and analysis. DNA was isolated using standard procedures. Targeted portions of the APP locus were PCR amplified using appropriate primers. Amplified DNA was subcloned and sequenced into a suitable vector using standard methods. 32 shows the APP locus edited in two base animals; One had a 292 bp deletion in exon 9 (FIG. 32A) and the other had a 309 bp deletion in exon 9 (FIG. 32B).

Example  77: ApoE  Genomic Editing of the Left

ZFNs with activity at the ApoE locus were identified as described above. That is, the mouse ApoE gene (NM_138828) was orthogonal to putative zinc finger binding sites, and the ZFNs pairs were basically assembled and tested as described in Example 76. It was found that the ZFN pairs targeted to bind the 5'-aaGCGGTTCAGGGCCTGctcccagggtt-3 '(SEQ ID NO: 215; uppercase letters are contact sites) and 5'-ggGATTACCTGcGCTGGGtgcagacgct-3' (SEQ ID NO: 216) cleaved ApoE loci.

One fertilized cell embryo was injected with mRNA encoding an active ZFN pair as described in Example 76. The resulting animals were analyzed as described in Example 76. 30 shows two edited ApoE loci. One animal had a 16 bp deletion in the target sequence of exon 2 and the second animal had a 1 bp deletion in the target sequence of exon 2. These deficiencies destroy the reading framework of the ApoE coding portion.

Example  78: BDNF  Genomic Editing of the Left

In order to confirm the ZFN to cut the left and BDNF as a target, and ortho to the rat BDNF gene (NM_012513) to estimate the zinc finger binding region. ZFNs pairs were basically assembled and tested, as described in Example 76. This analysis revealed that ZFN pairs targeted to bind 5'-cgGGGTCGGAGtGGCGCCgaaccctcat-3 '(SEQ ID NO: 217) and 5'-cgGGGTCGGAGtGGCGCCgaaccctcat-3' (SEQ ID NO: 218) edited the BDNF locus.

The fertilized rat embryos were microinjected with mRNA encoding the active ZNF pair as described in Example 76 above and analyzed basically. 46 shows edited BDNF loci in two animal based; One had a 14 bp deletion in the target sequence of exon 2 and the other had a 7 bp deletion in the target sequence of exon 2.

Genetically modified mice were observed for phenotypic changes. Homologous animals died within two weeks of birth. Heterozygous and homozygous animals were smaller in size than the corresponding reference animals (eg, animals derived from embryos injected with GFP mRNA).

Example  79: In the organism model PSEN1 Genome editing

ZFN-mediated genome editing studies the effects of “knock-out” mutations in AD-associated chromosomal sequences such as chromosomal sequences encoding PSEN1 protein in genetically modified model animals and cells derived from these animals. It is available. This model animal derived can be a rat. In general, ZFNs that bind to murine chromosomal sequences encoding the PSEN1 protein associated with AD can be used to introduce deletions or insertions such that the coding portion of the PSEN1 gene is disrupted so that a functional PSEN1 protein is not produced.

Suitable modified embryos can be capped and micro-injected with polyadenylation mRNA, as described essentially in Example 76. The frequency of ZFN-induced double stranded chromosomal gaps can be determined using Cel-1 nuclease analysis, as described above. The sequence of the edited chromosomal sequence can be analyzed as described above. The development of AD signs and disorders due to PSEN1 “knock out” can be assessed in genetically modified mice or their descendants. Moreover, molecular analysis of the AD-related pathways is known as PSEN1. It can be performed in cells derived from genetically modified animals, including “knock-outs”.

Example  80: human PSEN2 of Mutated  Generation of Humanized Rats Expressing a Phenotype

Missense mutations in PSEN2, part of an enzyme complex that cleaves amyloid beta peptides from APP, result in type 4 family type AD. One such mutation is the M239V missense mutation in which a methionine residue at position 239 of PSEN2 is replaced with a valine residue. ZFN-mediated genome editing can be used to make humanized mice in which the murine PSEN2 gene has been replaced with a mutant type of the human PSEN2 gene, including the M239V mutation. Such humanized mice can be used to study the development of diseases associated with mutated human PSEN2 proteins. Humanized mice can also be used to assess the effects of potential therapeutic agents targeting the pathway leading to AD including PSEN2.

Genetically modified mice can be made using the methods described in the examples above. However, to make humanized mice, ZFN mRNA can be co-injected into mice embryos with human chromosomal sequences encoding mutated PSEN2 proteins. The murine chromosomal sequence can then be replaced by mutated human sequences by homologous recombination, and humanized mice can be made expressing the mutated form of the PSEN2 protein.

The table below shows the amino acid sequences of the helices of active ZFNs.

Example  81: model In the organism BZRAP1 Genome editing

ZFN-mediated genome editing studies the effects of “knock-out” mutations in ASD-associated chromosomal sequences, such as chromosomal sequences encoding BZRAP1 protein, in genetically modified model animals and cells derived from these animals. It is available. This model animal derived can be a rat. In general, ZFNs that bind to murine chromosomal sequences encoding BZRAP1 protein associated with ASD can be used to introduce non-sense mutations into the coding portion of the BZRAP1 gene such that no active BZRAP1 protein can be produced.

Covered with a cap encoding ZFN, polyadenylated mRNA is a known molecule, including but not limited to, techniques substantially similar to those described in Science (2009) 325: 433 , incorporated by reference in its entirety. Can be made using biological techniques. mRNA can be transfected into mouse embryos. When injected microscopically, the rat embryo may be at the single cell stage. Reference vessels may be injected with 0.1 mM EDTA. Cel-1 nuclease assays can be used to determine the frequency of ZFN-induced double stranded chromosome gaps. This assay detects alleles of the target locus deviating from the wild type (WT) as a result of non-homologous end joining (NHEJ) -mediated incomplete repair of ZFN-induced DNA double strand breaks. PCR amplification of the targeted portion from the pool of ZFN-treated cells results in a mixture of WT and mutant amplicons. Dissolution and reannealing of this mixture results in mismatch formation between the WT and the heteroduplex of the mutant allele. DNA “bubbles” formed at the mismatch sites are cleaved by the survey nuclease Cel-1, and cleavage products can be dissociated by gel electrophoresis. The relative strength of the cleavage product compared to the paternal band is a measure of the Cel-1 cleavage level of the heteroduplex. This reflects the frequency of ZFN-mediated cleavage of endogenous target loci that will undergo incomplete repair by NHEJ.

The development of embryos after microinjection and the development of ASD-related signs and disorders by BZRAP-1 “knock-out” can be assessed in genetically modified mice. In the case of BZRAP-1, ASD-related signs and disorders may include the development of rheumatoid arthritis and the development of an altered inflammatory response against the tumor. This result can be compared with reference mice injected with 0.1 mM EDTA and unaltered with the chromosomal portion encoding the BZRAP-1 protein. In addition, molecular analysis of the ASD-related pathway can be performed in cells derived from genetically modified animals, including BZRAP-1 “knock out”.

Example  82: human Nelexin -1's Mutated  Generation of Humanized Rats Expressing a Phenotype

The missense mutations in neuroxin-1, a presynaptic protein that helps neurons stick together at synapses, are associated with autism. One such mutation is an L18Q missense mutation in which leucine amino acid is replaced by glutamine at position 18 of nelexin-1. ZFN-mediated genome editing can be used to make humanized mice in which the mouse NRXN1 gene has been replaced with a mutant type of the human NRXN1 gene, including the L18Q mutation. Such humanized mice can be used to study the development of mutated autism. In addition, humanized mice can be used to assess the effect of potential therapeutic agents targeting nelexin-1.

Genetically modified mice can be made using the methods described in Example 81 above. However, to make humanized mice, ZFN mRNA can be co-injected into the mouse embryo with human chromosomal sequences encoding the mutated nelexin-1 protein. The murine chromosomal sequence can then be replaced by a mutated human sequence by homologous recombination, and a humanized rat can be made expressing a mutated form of the nelexin-1 protein.

Example  83: NOG  Genomic Editing of the Left

Zinc finger nucleases (ZFNs) targeting and cleaving NOG loci in rats can be used to design and assemble ZFNs using the strategies and procedures already described (see Geurts et al . Science (2009) 325: 433) . And can be demonstrated. ZFN planning can be made using records of already-proven 1- and 2-finger modules. The mouse's NOG gene portion is where existing modules are fused to putative zinc finger binding sites, one strand to bind the 12-18 bp sequence, the other to the 12-18 bp sequence, and about 5-between the two binding sites. Investigations were made about the ability to make pairs of 4-, 5-, or 6-finger proteins at 6 bp.

The caps encoding the ZFN pairs are capped and polyadenylated mRNA can be made using known molecular biology techniques. mRNA can be transfected into mouse cells. Reference cells can be injected with mRNA encoding GFP. Cel-1 nuclease assays can be used to identify active ZFN pairs by detecting ZFN-induced double stranded chromosomal gaps. This assay detects alleles of the target locus deviating from the wild type (WT) as a result of non-homologous end joining (NHEJ) -mediated incomplete repair of ZFN-induced DNA double strand breaks. PCR amplification of the targeted portion from the pool of ZFN-treated cells results in a mixture of WT and mutant amplicons. Dissolution and reannealing of this mixture results in mismatch formation between the WT and the heteroduplex of the mutant allele. DNA “bubbles” formed at the mismatch sites are cleaved by the survey nuclease Cel-1, and cleavage products can be dissociated by gel electrophoresis. This analysis identifies active ZFN pairs that have edited NOG loci.

NOG from animals To mediate loci editing, mRNA encoding the active ZFN pair is standardized (eg, Geurts). meat al . (2009) supra Can be injected into fertilized rat embryos. Injected embryos can be transferred to false pregnant female rats that can be incubated or delivered in vitro. Embryos / fetuses generated for DNA extraction and analysis, or toes / tail clips of born live animals can be collected. DNA can be isolated using standard procedures. Suitable primers may be used to PCR amplify the targeted portion of the NOG locus. Amplified DNA can be subcloned and sequenced into a suitable vector using standard methods.

Example  84: In the organism model BMP4 Genome editing

ZFN-mediated genome editing can be used to study the effects of “knock-out” mutations in neurodevelopment chromosomal sequences such as chromosomal sequences encoding BMP4 protein in genetically modified model animals and cells derived from these animals. Can be. This model animal derived can be a rat. In general, ZFNs that bind to murine chromosomal sequences that encode BMP4 proteins associated with neurodevelopmental pathways can be used to introduce deletions or insertions such that the coding portion of the BMP4 gene is destroyed so that functional BMP4 proteins are not produced. Can be.

Suitable modified embryos can be capped and micro-injected with polyadenylated mRNA, as described essentially in Example 83. The frequency of ZFN-induced double stranded chromosomal gaps can be determined using Cel-1 nuclease analysis, as described above. The edited sequence of the chromosomal sequence can be analyzed as described above. The development of neurodevelopmental signs and disorders due to BMP4 “knock-out” can be assessed in genetically modified mice or their descendants. Moreover, molecular analysis of neurodevelopmental pathways can be performed on cells derived from genetically modified animals, including BMP4 “knock-outs”.

Example  85: human BMP4 of Mutated  Generation of Humanized Rats Expressing a Phenotype

Four missense mutations within BMP4 were detected in a population of spina bifida aperta patients. ZFN-mediated genome editing can be used to make humanized mice in which the murine BMP4 gene has been replaced with a mutated type of human BMP4 gene associated with spondylosis or any combination of four mutations. Such humanized mice can be used to study the development of spina bifida associated with mutated human BMP4 protein. Humanized mice can also be used to assess the effect of a potential therapeutic agent that targets pathways leading to spina bifida, including BMP4.

Genetically modified mice can be made using the methods described in Example 83 above. However, to make humanized mice, ZFN mRNA can be co-injected into the mouse embryo with human chromosomal sequences encoding the mutated BMP4 protein. The murine chromosomal sequence can then be replaced with mutated human sequences by homologous recombination, and humanized mice can be made expressing the mutated form of the BMP4 protein.

Example  86: human Perforin -1's Mutated  Generation of Humanized Rats Expressing a Phenotype

Missense mutations in perforin-1, the definitive effector of lymphocyte cytotoxicity, lead to a range of diseases, from familial hematopoietic lymphocytosis to increased risk of tumorigenesis. One such mutation is a V50M missense mutation in which a valine amino acid is replaced with methionine at position 50 of Perforin-1. ZFN-mediated genome editing can be used to make humanized mice in which the mouse PRF1 gene has been replaced with a mutated form of the human PRF1 gene, including the V50M mutation. Such humanized mice can be used to study the development of diseases associated with mutated human Perforin-1 protein. Humanized mice can also be used to assess the effect of potential therapeutic agents targeting inflammatory pathways, including Perforin-1.

Genetically modified mice can be made using the methods described in Example 83 above. However, to make humanized mice, ZFN mRNA can be co-injected into the mouse embryo with human chromosomal sequences encoding the mutated Perforin-1 protein. The murine chromosomal sequence can then be replaced by mutated human sequences by homologous recombination, and humanized mice can be made expressing the mutated form of the Perforin-1 protein.

The table below shows the amino acid sequences of the helices of active ZFNs.

Example  87: TRPM5  Genomic Editing of the Left

Zinc finger nucleases (ZFNs) that target the rat TRPM5 locus and cleave it have already been described ( Geurts meat al . Science (2009) 325: 433 ) Strategies and processes can be used to plan, assemble, and demonstrate ZFNs. ZFN planning can be made using records of already-proven 1- and 2-finger modules. The TRPM5 gene portion of the rat is a pre-existing module fused to the putative zinc finger binding site, where one strand can bind to a 12-18 bp sequence, the other strand binds to a 12-18 bp sequence, and between about two binding sites Investigations were made about the ability to make pairs of 4-, 5-, or 6-finger proteins at 6 bp.

The caps encoding the ZFN pairs are capped and polyadenylated mRNA can be made using known molecular biology techniques. mRNA can be transfected into mouse cells. Reference cells can be injected with mRNA encoding GFP. Cel-1 nuclease assays can be used to identify active ZFN pairs by detecting ZFN-induced double stranded chromosomal gaps. This assay detects alleles of the target locus deviating from the wild type (WT) as a result of non-homologous end joining (NHEJ) -mediated incomplete repair of ZFN-induced DNA double strand breaks. PCR amplification of the targeted portion from the pool of ZFN-treated cells results in a mixture of WT and mutant amplicons. Dissolution and reannealing of this mixture results in mismatch formation between the WT and the heteroduplex of the mutant allele. DNA “bubbles” formed at the mismatch sites are cleaved by the survey nuclease Cel-1, and cleavage products can be dissociated by gel electrophoresis. This analysis identifies active ZFN pairs that have edited the TRPM5 locus.

In order to mediate the editing of the TRPM5 locus in animals, mRNA encoding the active ZFN pair is standardized (eg, Geurts). meat al . (2009) supra Can be injected into fertilized rat embryos. Injected embryos can be transferred to false pregnant female rats that can be incubated or delivered in vitro. Embryos / fetuses generated for DNA extraction and analysis, or toes / tail clips of born live animals can be collected. DNA can be isolated using standard procedures. Suitable primers can be used to PCR amplify the targeted portion of the TRPM5 locus. Amplified DNA can be subcloned and sequenced into a suitable vector using standard methods.

Example  88: in organism models ERAL1 Genome editing

ZFN-mediated genome editing studies the effects of “knock-out” mutations in nociceptive-related chromosomal sequences, such as chromosomal sequences encoding ERAL1 protein in genetically modified model animals and cells derived from these animals. Can be used to This model animal derived can be a rat. In general, ZFNs that bind to murine chromosomal sequences that encode ERAL1 proteins associated with nociceptive pathways may be used to introduce deletions or insertions such that the coding portion of the ERAL1 gene is disrupted so that a functional ERAL1 protein may not be produced. Can be.

Suitable modified embryos can be capped and micro-injected with polyadenylated mRNA as described essentially in Example 87. The frequency of ZFN-induced double stranded chromosomal gaps can be determined using Cel-1 nuclease analysis, as described above. The sequence of the edited chromosomal sequence can be analyzed as described above. The development of nociceptive-related signs and disorders due to ERAL1 “knock-out” can be assessed in genetically modified mice or their descendants. Moreover, molecular analysis of nociceptive function-related pathways can be performed in cells derived from genetically modified animals, including ERAL1 “knock-outs”.

Example  89: human SCN9A of Mutated  Generation of Humanized Rats Expressing a Phenotype

Missense mutations in SCN9A, a high-level sodium theory channel expressed in the analgesic root ganglion (DRG) neurons, are inherited impaired red limb pain characterized by systemic burning pain in the feet, lower legs and hands. (erythromelagia). Three mutations were characterized in SCN9A: W897X, located in the P-loop of domain 2; I767X, located in the S2 segment of domain 2; And S459X, located in the linker moiety between domains 1 and 2, resulting in a non-functional protein truncated by any one of them. ZFN-mediated genome editing can be used to make humanized mice in which the murine SCN9A gene has been replaced with a mutated type of the human SCN9A gene comprising a W897X mutation, an I767X mutation, an S459X mutation, or any combination of three mutations. Such humanized mice can be used to study the development of measles limb pain associated with mutated human SCN9A protein. In addition, humanized mice can be used to assess the effect of potential therapeutic agents targeting the pathway leading to erythropalgia, including SCN9A.

Genetically modified mice can be made using the methods described in Example 87 above. However, to make humanized mice, ZFN mRNA can be co-injected into mice embryos with human chromosomal sequences encoding mutated SCN9A proteins. The murine chromosomal sequence can then be replaced by mutated human sequences by homologous recombination, and humanized mice can be made expressing the mutated form of the SCN9A protein.

Example  90: DISC1  Edited left ZFN Confirmation of

DISC1 gene was selected for zinc finger nuclease (ZFN) -mediated genome editing. Using the strategies and processes already described ( Geurts meat al ., Science (2009) 325: 433 ) ZFNs were designed, assembled, and demonstrated. ZFN planning was made using records of already-proven 1- and 2-finger modules. The DISC1 gene portion (NM_175596) is an existing module fused to a putative zinc finger binding site, capable of binding to a 12-18 bp sequence on one strand, binding to a 12-18 bp sequence on the other strand, and about 5 between the two binding sites. Investigations were made on the possibility of pairing 4-, 5-, or 6-finger proteins at -6 bp.

The caps encoding the ZFN pairs were capped and the polyadenylated mRNA was made using known molecular biology techniques. mRNA was transfected with mouse cells. Reference cells were injected with mRNA encoding GFP. Active ZFN pairs were identified by detecting ZFN-induced double stranded chromosomal gaps using Cel-1 nuclease assay. This assay detects alleles of the target locus deviating from the wild type (WT) as a result of non-homologous end joining (NHEJ) -mediated incomplete repair of ZFN-induced DNA double strand breaks. PCR amplification of the targeted portion from the pool of ZFN-treated cells results in a mixture of WT and mutant amplicons. Dissolution and reannealing of this mixture results in mismatch formation between the WT and the heteroduplex of the mutant allele. DNA “bubbles” formed at the mismatch sites are cleaved by the survey nuclease Cel-1, and cleavage products can be dissociated by gel electrophoresis. This analysis indicated that ZFN pairs targeted to bind 5'-taGTCCCGGCAGGCTATcctgggcggtg-3 '(SEQ ID NO: 226; capital letters are contact sites) and 5'-ccGTCACCAGGCGGGACtggctgatgcg-3' (SEQ ID NO: 227) were cleaved inside the DISC1 locus. It turned out.

Example  91: in rat belly DISC1  Editing

The caps encode the active ZFN pairs and the polyadenylation of mRNA is standardized (eg, Geurts). et al. (2009) supra And injected into the embryo of fertilized mice. The injected embryos were transferred to false pregnant female mice that could be incubated or delivered in vitro. Toes / tail clips of embryos / fetuses generated or born live animals were harvested for DNA extraction and analysis. DNA was isolated using standard procedures. Targeted portions of the DISC1 locus were PCR amplified using appropriate primers. Amplified DNA was subcloned and sequenced into a suitable vector using standard methods. 47 shows an edited DISC1 lacking 20 bp from the target sequence of exon 5 Indicates left. This deficiency destroys the reading frame of the DISC1 coding portion.

Example  92: BDNF  Edited left ZFN Confirmation of

BDNF To target the locus and identify the ZFNs that cut it, the murine BDNF gene (NM_012513) was defined for putative zinc finger binding sites. ZFNs were basically assembled and tested as described in Example 90. This analysis showed that ZFN pairs targeted to bind 5'-cgGGGTCGGAGtGGCGCCgaaccctcat-3 '(SEQ ID NO: 228) and 5'-ccGCCGTGGGGaGCTGAGcgtgtgtgac-3' (SEQ ID NO: 229) cleaved the BDNF locus.

The fertilized rat embryos were infused with mRNA encoding an active ZNF pair and analyzed basically as described in Example 91. 46 shows edited BDNF loci in two animal based; One had a 14 bp deletion in the target sequence of exon 2 and the other had a 7 bp deletion in the target sequence of exon 2.

Genetically modified mice were observed for phenotypic changes. Homologous animals died within two weeks of birth. Heterozygous and homozygous animals were smaller in size than the corresponding reference animals (eg, animals derived from embryos injected with GFP mRNA).

Example  93: organism In model ErbB4 Genome editing

ZFN-mediated genome editing studies the effects of “knock-out” mutations in schizophrenia-associated chromosomal sequences such as chromosomal sequences encoding ErbB4 protein in genetically modified model animals and cells derived from these animals. Can be used to This model animal derived can be a rat. ErbB4 , commonly associated with schizophrenia ZFNs, which bind to murine chromosomal sequences that encode proteins, are ErbB4 ErbB4 functions by breaking the coding part of the gene Proteins can be used to introduce deletions or insertions so that they can not be produced.

Suitable fertilized embryos are capped with ZFN encoding and can be micro-injected with polyadenylation mRNA. The frequency of ZFN-induced double stranded chromosomal gaps can be determined using Cel-1 nuclease analysis, as described above. The sequence of the edited chromosomal sequence can be analyzed as described above. The development of schizophrenic signs and disorders due to ErbB4 “knock-out” can be assessed in genetically modified mice or their descendants. Moreover, molecular analysis of schizophrenia-related pathways can be performed in cells derived from genetically modified animals, including ErbB4 “knock-outs”.

Example  94: human TPH1 of Mutated  Generation of Humanized Rats Expressing a Phenotype

To develop a “humanized” animal model for evaluating schizophrenia signs and treatments, mice can be created that contain a genome containing a human TPH1 mutated type. The human mutated type may be A218C found in intron 7 of TPH1; A218C is considered to be significantly related to schizophrenia. ZFN-mediated genome editing can be used to make humanized mice in which the mouse gene has been replaced with the A218C mutated type of human TPH1. Such humanized mice can be used to study the development of schizophrenia associated with mutated human proteins encoded by mutated TPH1. In addition, humanized mice can be used to assess the effects of potential therapeutic agents that target pathways associated with TPH1.

Genetically modified mice can be made using the methods described in Example 91 above. However, to make humanized mice, ZFN mRNA can be co-injected into the mouse embryo with human chromosomal sequences encoding the mutated TPH1 protein. The murine chromosomal sequence can then be replaced by mutated human sequences by homologous recombination, and humanized mice can be made expressing the mutated form of this protein.

The table below shows the amino acid sequence of the helix of active ZFNs.

Example  95: p53  Edited left ZFN Confirmation of

P53 gene was selected for zinc finger nuclease (ZFN) -mediated genome editing. Using the strategies and processes already described ( Geurts meat al ., Science (2009) 325: 433 ) ZFNs were designed, assembled, and demonstrated. ZFN planning was made using records of already-proven 1- and 2-finger modules. The murine p53 gene portion (NM_030989) is an existing module fused to a putative zinc finger binding site, capable of binding to a 12-18 bp sequence on one strand, binding to a 12-18 bp sequence on the other strand, and between about two binding sites. Investigations were made on the possibility of pairing 4-, 5-, or 6-finger proteins with 5-6 bp.

The caps encoding the ZFN pairs were capped and the polyadenylated mRNA was made using known molecular biology techniques. mRNA was transfected with mouse cells. Reference cells were injected with mRNA encoding GFP. Active ZFN pairs were identified by detecting ZFN-induced double stranded chromosomal gaps using Cel-1 nuclease assay. This assay detects alleles of the target locus deviating from the wild type (WT) as a result of non-homologous end joining (NHEJ) -mediated incomplete repair of ZFN-induced DNA double strand breaks. PCR amplification of the targeted portion from the pool of ZFN-treated cells results in a mixture of WT and mutant amplicons. Dissolution and reannealing of this mixture results in mismatch formation between the WT and the heteroduplex of the mutant allele. DNA “bubbles” formed at the mismatch sites are cleaved by the survey nuclease Cel-1, and cleavage products can be dissociated by gel electrophoresis. This analysis indicated that the ZFN pair targeted to bind 5'-atCTGGAGGAAGACtGGAGAAcaagagc-3 '(SEQ ID NO: 234; uppercase is the contact site) and 5'-atATTCTGGTAAGGAGCCGGgcaagagg-3' (SEQ ID NO: 235) edited the p53 gene. Turned out.

Example  96: in the rat belly p53  Editing

The caps encode the active ZFN pairs and the polyadenylation of mRNA is standardized (eg, Geurts). et al. (2009) supra And injected into the embryo of fertilized mice. Reference embryos were microinjected with mRNA encoding salt or GFP. The injected embryos were transferred to false pregnant female mice capable of delivering. Toe / tail clips of each living animal born using Cel-1 analysis were harvested for DNA extraction and analysis. As shown in FIG. 48, about 25% of the experimental animals had an edited p53 coding locus.

Example  97: In the rat p53 Deactivation

To determine if the edited p53 locus was inactivated, Western analysis was performed to confirm that no p53 protein was made. Cell lysates were prepared from kidneys and livers of wild-type and p53 knock-out animals. As can be seen in FIG. 49, both the cytoplasm and nuclear lysates of p53 knock-out animals were free of p53 protein. However, the levels of actin protein were constant in wild type and mutated samples. Thus, p53 edited mice are p53 knock-out mice.

Example  98: In the rat BCRP To edit ZFNs Confirmation of

As described in Example 95, ZFNs that target the BCRP gene and cleave it were basically identified. Rat BCRP Against Putative Zinc Finger Binding Sites The gene (NM_1811381) was determined. As described in Example 95, ZFNs were assembled and tested basically. It was found that ZFN pairs targeted to bind 5'-atGACGTCAAGGAAGAAgtctgcagggt-3 '(SEQ ID NO: 236) and 5'-acGGAGATTCTTCGGCTgtaatgttaaa-3' (SEQ ID NO: 237) were edited BCRP genes.

Example  99: BCRP  Editing

As described in Examples 95 and 96, basically, mRNA encoding the active pairs of BCRP ZFNs was injected into rat embryos. The injected embryos were incubated and DNA extracted from the resulting animals. The targeted portion of the BCRP gene was PCR amplified using appropriate primers. Amplified DNA was subcloned and sequenced in a suitable vector using standard methods. 39 shows a BCRP loci edited in two horse based animals. One animal had a 588 bp deletion in exon 7 and the second had a 696 bp deletion in exon 7. These deficits are BCRP Destroy the reading frame of the coding part.

Example  100: Pten  Editing

Pten in rat The ZFNs that target the locus and cut them were designed and tested basically as described in Example 95. Active ZFN pairs were identified. DNA binding sites were 5'-CCCCAGTTTGTGGTCtgcca-3 '(SEQ ID NO: 238) and 5'-gcTAAAGGTGAAGATCTA-3' (SEQ ID NO: 239). The caps encoding the active pairs are capped and the polyadenylated mRNA can be microinjected into rat embryos and the resulting embryos can be analyzed as described in Examples 95 and 96. Thus, the Pten locus can be edited to include deletions or insertions so that the coding moiety is broken so that no functioning protein is made.

The table below shows the amino acid sequence of the helix of active ZFNs.

Example  101: In an organism model HTT Genome editing

ZFN-mediated genome editing is a HTT in genetically modified model animals and cells derived from these animals. It can be used to study the effects of “knock-out” mutations in trinucleotide repeat expansion-related chromosomal sequences, such as chromosomal sequences encoding proteins. This model animal derived can be a rat. In general, HTT associated with trinucleotide repeat expansion ZFNs that bind to murine chromosomal sequences that encode proteins are HTT HTT functions by breaking coding part of gene Proteins can be used to introduce deletions or insertions so that they can not be produced.

Suitable modified embryos are capped to encode ZFN using known molecular biology techniques and can be micro-injected with polyadenylated mRNA. The frequency of ZFN-induced double stranded chromosome breaks can be determined using Cel-1 nuclease assay. This assay detects alleles of the target locus deviating from the wild type (WT) as a result of non-homologous end joining (NHEJ) -mediated incomplete repair of ZFN-induced DNA double strand breaks. PCR amplification of the targeted portion from the pool of ZFN-treated cells results in a mixture of WT and mutant amplicons. Dissolution and reannealing of this mixture results in mismatch formation between the WT and the heteroduplex of the mutant allele. DNA “bubbles” formed at the mismatch sites are cleaved by the survey nuclease Cel-1, and cleavage products can be dissociated by gel electrophoresis. The sequence of the edited chromosomal sequence can be analyzed as described above. HTT The development of trinucleotide repeat expansion disorders due to “knock-out” can be assessed in genetically modified mice or their descendants. Moreover, molecular analysis of trinucleotide repeat expansion-related pathways is possible by HTT It can be performed in cells derived from genetically modified animals, including “knock-outs”.

Example  102: Trinucleotide  Of human genes associated with repetitive expansion disorder Mutated  Generation of Humanized Rats Expressing a Phenotype

Mutations in any chromosomal sequence associated with a trinucleotide repeat expansion disorder can be used to produce humanized mice expressing a mutated form of this gene. This gene is htt , ar , fxn , atxn1, atxn2 , atxn3 , atxn7 , atxn10 , dmpk , atn1 , cbp , vldlr , and combinations thereof. ZFN-mediated genome editing can be used to make humanized mice in which these genes in mice have been replaced with mutated forms of human genes containing these mutations. Such humanized mice can be used for developmental studies of diseases associated with mutated human proteins encoded by the gene of interest. Humanized mice can also be used to assess the effect of potential therapeutic agents targeting pathways leading to trinucleotide repeat expansion disorders involving genes of interest.

Genetically modified mice can be made using the methods described in the examples above. However, to make humanized mice, ZFN mRNA can be co-injected into the mouse embryo with human chromosomal sequences encoding mutated proteins. The murine chromosomal sequence can then be replaced by mutated human sequences by homologous recombination, and humanized mice can be made expressing the mutated form of this protein.

Example  103: In the organism model 5- HTT Genome editing

ZFN-mediated genome editing has the effect of “knock-out” mutations in neurotransmitter-associated chromosomal sequences such as chromosomal sequences encoding 5-HTT protein in genetically modified model animals and cells derived from these animals. Can be used to study This model animal derived can be a rat. Generally, 5- HTT associated with neurotransmission ZFNs binding to murine chromosomal sequences encoding proteins can be used to introduce deletions or insertions such that the coding portion of the 5- HTT gene is disrupted so that a functional 5- HTT protein cannot be produced.

Suitable fertilized embryos are capped with ZFN encoding and can be micro-injected with polyadenylation mRNA. The frequency of ZFN-induced double stranded chromosomal gaps can be determined using Cel-1 nuclease analysis, as described above. The sequence of the edited chromosomal sequence can be analyzed as described above. The development of neurotransmission signs and disorders due to 5- HTT “knock-out” can be assessed in genetically modified mice or their descendants. Moreover, molecular analysis of neurotransmission-related pathways can be performed in cells derived from genetically modified animals, including HTT “knock outs”.

Example  104: neurotransmission of human genes Mutated  Generation of Humanized Rats Expressing a Phenotype

Mutations in any chromosomal sequence associated with neurotransmission disorders can be used to produce humanized mice expressing a mutated form of this gene. This gene 5- HTT, COMT, DRD, SLC6A3 , DAO, DTNBP1, GABAa, NMDA, NMDAR, NR1, NR2a, NR2b, mGLUR1, mGLUR2, mGLUR3, mGLUR5, GLUR1, GLUR2, GAD67, GAT1, TCF4, NPAS3, GR1K4 , COMT , MAO , DBH , TyrH , CB1 , CB2 , FAAH , MAGL And combinations thereof. ZFN-mediated genome editing can be used to make humanized mice in which these genes in mice have been replaced with mutated forms of human genes containing these mutations. Such humanized mice can be used for developmental studies of diseases associated with mutated human proteins encoded by the gene of interest. Humanized mice can also be used to assess the effects of potential therapeutic agents that target pathways leading to neurotransmission disorders involving genes of interest.

Genetically modified mice can be made using the methods described in the examples above. However, to make humanized mice, ZFN mRNA can be co-injected into the mouse embryo with human chromosomal sequences encoding mutated proteins. The murine chromosomal sequence can then be replaced by mutated human sequences by homologous recombination, and humanized mice can be made expressing the mutated form of this protein.

Example  105: APH -One  Genomic Editing of the Left

APH- 1 in rats Zinc finger nucleases (ZFNs) that target loci and cleave them have already been described ( Geurts meat al . Science (2009) 325: 433 ) Strategies and processes can be used to plan, assemble, and demonstrate ZFNs. ZFN planning can be made using records of already-proven 1- and 2-finger modules. The mouse APH- 1 gene portion of the mouse has a conventional module fused to the putative zinc finger binding site, whereby one strand can bind to a 12-18 bp sequence, the other strand binds to a 12-18 bp sequence, and between the two binding sites Investigations were made on the possibility of pairing 4-, 5-, or 6-finger proteins with 5-6 bp.

The caps encoding the ZFN pairs are capped and polyadenylated mRNA can be made using known molecular biology techniques. mRNA can be transfected into mouse cells. Reference cells can be injected with mRNA encoding GFP. Cel-1 nuclease assays can be used to identify active ZFN pairs by detecting ZFN-induced double stranded chromosomal gaps. This assay detects alleles of the target locus deviating from the wild type (WT) as a result of non-homologous end joining (NHEJ) -mediated incomplete repair of ZFN-induced DNA double strand breaks. PCR amplification of the targeted portion from the pool of ZFN-treated cells results in a mixture of WT and mutant amplicons. Dissolution and reannealing of this mixture results in mismatch formation between the WT and the heteroduplex of the mutant allele. DNA “bubbles” formed at the mismatch sites are cleaved by the survey nuclease Cel-1, and cleavage products can be dissociated by gel electrophoresis. This analysis identifies active ZFN pairs that have edited the APH- 1 locus.

To mediate the editing of the APH- 1 locus in animals, mRNA encoding the active ZFN pair is standardized (eg, Geurts). meat al . (2009) supra Can be injected into fertilized rat embryos. Injected embryos can be transferred to false pregnant female rats that can be incubated or delivered in vitro. Embryos / fetuses generated for DNA extraction and analysis, or toes / tail clips of born live animals can be collected. DNA can be isolated using standard procedures. Suitable primers may be used to PCR amplify the targeted portion of the APH-1 locus. Amplified DNA can be subcloned and sequenced into a suitable vector using standard methods.

Example  106: Genome Editing of Secretion Enzyme-Related Genes in an Organismal Cell Model

ZFN-mediated genome editing is a mouse-like organism model using ZFNs that bind to chromosomal sequences of secretory-associated genes such as the secretory-associated genes APH-1A, APH-1B, PSEN1, NCSTN, or PEN-2. Can be tested in cells, or ZFNs can be basically designed and tested as described in Example 105. ZFNs targeted to specific cognitive-related genes can be used to introduce a deletion or insertion such that the coding portion of the gene of interest is inactivated.

Example  107: Genome editing of secretory-associated genes in organism models

Embryos of an organism model such as rats were harvested according to standard procedures, capped to encode ZFNs targeting secretory-associated genes, as described in Example 105, and polyadenylated mRNA was loaded onto the embryos. Can be injected. Donor or exchange polynucleotides comprising sequences for integration or exchange may be co-injected with ZFNs. The chromosomal portion edited in the resulting animals can be analyzed as described above. Animals that have been transformed for changes in behavior, learning, etc. can be phenotyped. Moreover, genetically modified animals can be used to assess the effects of potential therapeutic agents for the treatment of secretory enzyme disorders.

Example  108: SOD1  Genomic Editing of the Left

SOD1 of the rat Zinc finger nucleases (ZFNs) that target loci and cleave them are designed, assembled, and assembled using ZFNs using the strategies and processes already described (see Geurts et al . Science (2009) 325: 433) . I can prove it. ZFN planning can be made using records of already-proven 1- and 2-finger modules. The mouse SOD1 gene portion of the mouse has a conventional module fused to the putative zinc finger binding site, one strand may bind to the 12-18 bp sequence, the other strand binds to the 12-18 bp sequence, and between about five binding sites Investigations were made about the ability to make pairs of 4-, 5-, or 6-finger proteins at 6 bp.

The caps encoding the ZFN pairs are capped and polyadenylated mRNA can be made using known molecular biology techniques. mRNA can be transfected into mouse cells. Reference cells can be injected with mRNA encoding GFP. Cel-1 nuclease assays can be used to identify active ZFN pairs by detecting ZFN-induced double stranded chromosomal gaps. This assay detects alleles of the target locus deviating from the wild type (WT) as a result of non-homologous end joining (NHEJ) -mediated incomplete repair of ZFN-induced DNA double strand breaks. PCR amplification of the targeted portion from the pool of ZFN-treated cells results in a mixture of WT and mutant amplicons. Dissolution and reannealing of this mixture results in mismatch formation between the WT and the heteroduplex of the mutant allele. DNA “bubbles” formed at the mismatch sites are cleaved by the survey nuclease Cel-1, and cleavage products can be dissociated by gel electrophoresis. SOD1 with this analysis You can see the active ZFN pair by editing the left.

To mediate the editing of the SOD1 locus in animals, mRNA encoding the active ZFN pair is standardized (eg, Geurts). meat al . (2009) supra Can be injected into fertilized rat embryos. Injected embryos can be transferred to false pregnant female rats that can be incubated or delivered in vitro. Embryos / fetuses generated for DNA extraction and analysis, or toes / tail clips of born live animals can be collected. DNA can be isolated using standard procedures. Suitable primers can be used to PCR amplify the targeted portion of the SOD1 locus. Amplified DNA can be subcloned and sequenced into a suitable vector using standard methods.

Example  109: in organism cell models ALS Genome editing of related genes

ZFN-mediated genome editing can be performed by ALS -related genes SOD1 , ALS2 , FUS , TARDBP , or VEGF (A, B, or C) ZFNs can be tested in cells of an organism model, such as a mouse, using ZFNs that bind to chromosomal sequences of secretory enzyme-related genes, such as ZFNs, or ZFNs are as described in Example 108. Basically, you can plan and test. ZFNs targeted to specific ALS-related genes can be used to introduce a deletion or insertion such that the coding portion of the gene of interest is inactivated.

Example  110: In the organism model ALS Genome editing of related genes

Embryos of an organism model, such as a rat, were harvested according to standard procedures, capped to encode ZFNs targeting ALS-related genes and injected with polyadenylated mRNA as described in Example 108. can do. Donor or exchange polynucleotides comprising sequences for integration or exchange may be co-injected with ZFNs. The chromosomal portion edited in the resulting animals can be analyzed as described above. Animals that have been transformed for changes in behavior, learning, etc. can be phenotyped. Moreover, genetically modified animals can be used to assess the effectiveness of potential therapeutic agents for treating ALS.

Example  111: prdn  Genomic Editing of the Left

Prdn of rat Zinc finger nucleases (ZFNs) that target loci and cleave them are designed, assembled, and assembled using ZFNs using the strategies and processes already described (see Geurts et al . Science (2009) 325: 433) . I can prove it. ZFN planning can be made using records of already-proven 1- and 2-finger modules. In the mouse prdn gene portion, the existing module is fused to the putative zinc finger binding site, where one strand can bind to a 12-18 bp sequence, the other strand binds to a 12-18 bp sequence, and between about 5 Investigations were made about the ability to make pairs of 4-, 5-, or 6-finger proteins at 6 bp.

The caps encoding the ZFN pairs are capped and polyadenylated mRNA can be made using known molecular biology techniques. mRNA can be transfected into mouse cells. Reference cells can be injected with mRNA encoding GFP. Cel-1 nuclease assays can be used to identify active ZFN pairs by detecting ZFN-induced double stranded chromosomal gaps. This assay detects alleles of the target locus deviating from the wild type (WT) as a result of non-homologous end joining (NHEJ) -mediated incomplete repair of ZFN-induced DNA double strand breaks. PCR amplification of the targeted portion from the pool of ZFN-treated cells results in a mixture of WT and mutant amplicons. Dissolution and reannealing of this mixture results in mismatch formation between the WT and the heteroduplex of the mutant allele. DNA “bubbles” formed at the mismatch sites are cleaved by the survey nuclease Cel-1, and cleavage products can be dissociated by gel electrophoresis. Prdn with this analysis You can see the active ZFN pair by editing the left.

To mediate the editing of the prdn locus in animals, mRNA encoding the active ZFN pair is standardized (eg, Geurts). meat al . (2009) supra Can be injected into fertilized rat embryos. Injected embryos can be transferred to false pregnant female rats that can be incubated or delivered in vitro. Embryos / fetuses generated for DNA extraction and analysis, or toes / tail clips of born live animals can be collected. DNA can be isolated using standard procedures. Suitable primers can be used to PCR amplify the targeted portion of the prdn locus. Amplified DNA can be subcloned and sequenced into a suitable vector using standard methods.

Example  112: In an organism cell model Dpl  Genome editing of genes

ZFN- mediated genome editing in Dpl derived from a genetically modified animal models and animal cells It can be used to study the effects of "knock-out" mutations in AD-related chromosomal sequences, such as chromosomal sequences encoding proteins. This model animal derived can be a rat. In general, ZFNs that bind to murine chromosomal sequences that encode AD-related Dpl proteins are used to introduce deletions or insertions such that the coding portion of the Dpl gene ( Prnd ) is destroyed so that a functional Dpl protein may not be produced. Can be.

Suitable fertilized embryos, as described in Example 111 above, are capped to encode ZFN and can be micro-injected with polyadenylation mRNA. The frequency of ZFN-induced double stranded chromosomal gaps can be determined using Cel-1 nuclease analysis, as described above. The sequence of the edited chromosomal sequence can be analyzed as described above. The development of AD signs and disorders due to Dpl “knock-out” can be assessed in genetically modified mice or their descendants. Moreover, molecular analysis of AD-related pathways can be performed in cells derived from genetically modified animals, including Dpl “knock outs”.

Example  113: In the organism model Prp  Genome editing of genes

Coding polymorphism in PrP codon 129 is strongly associated with disease sensitive and phenotypic modification effects, especially when the amino acid of codon 129 is methionine or valine. ZFN- mediated genome editing can be used to rat Prp gene produce a humanized rat replaced with a mutant type human Prpn gene comprising a sequence having a 129M or 129V. Such humanized mice can be used for the development of diseases associated with mutated human Prp-related proteins. Humanized mice can also be used to assess the effects of potential therapeutic agents targeting pathways leading to prion disorders including neurotoxic PrP isoforms.

Example  114: In organism cell models Aguti ( Agouti )of  Genome editing

Zinc finger nuclease (ZFN) -mediated genome editing allows ZFNs to bind to the chromosomal sequence of hair color-related genes in horse cells such as MSH receptor proteins, aguti signaling protein (ASIP) and melanophylline (MLPH). Can be tested in cells of an organism model such as horse. The particular envelope color-related gene to be edited may be a gene having the same DNA binding site for the DNA binding site of the corresponding equine homolog of this gene. Covered with a cap encoding ZFN, polyadenylated mRNA is a known molecular biology including, but not limited to, techniques substantially similar to those described in Science (2009) 325: 433 (supplied by reference). Can be made using technology. mRNA can be transfected into horse cells. Reference cells can be injected with mRNA encoding GFP.

Cel-1 nuclease assays can be used to determine the frequency of ZFN-induced double stranded chromosome gaps. This assay detects alleles of the target locus deviating from the wild type (WT) as a result of non-homologous end joining (NHEJ) -mediated incomplete repair of ZFN-induced DNA double strand breaks. PCR amplification of the targeted portion from the pool of ZFN-treated cells results in a mixture of WT and mutant amplicons. Dissolution and reannealing of this mixture results in mismatch formation between the WT and the heteroduplex of the mutant allele. DNA “bubbles” formed at the mismatch sites are cleaved by the survey nuclease Cel-1, and cleavage products can be dissociated by gel electrophoresis. The relative strength of the cleavage product compared to the paternal band is a measure of the Cel-1 cleavage level of the heteroduplex. This reflects the frequency of ZFN-mediated cleavage of endogenous target loci that will undergo incomplete repair by NHEJ.

The results of this experiment can explain the cleavage of selected hair color-related loci in horse cells using ZFN.

Example  115: From an organism pear model Aguti ( agouti )of  Genome editing

Embryonic models of horses, such as horses, are harvested using standard procedures, and similarly as described in Example 114, are capped and encoded with polyadenylated mRNA encoding ZFN. Equine embryos can be microinjected at the single cell stage. Reference embryos can be injected with 0.1 mM EDTA. As described in Example 114, Cel-1 analysis can be used to predict ZFN-induced double stranded chromosomal gap frequency. The results of the Cel-1 analysis can be used to predict the cutting effect.

Embryonic development can be assessed after brown rice injection. Embryos injected with small amounts of ZFN mRNA can determine the effect of ZFN mRNA on viability of embryos up to the blastocyst stage compared to embryos injected with EDTA.

Example  116: human SCID of Mutated  Generation of Humanized Horses Expressing Phenotypes

A first human mutation was identified in a gene encoding DNA-PKcs (DNA-dependent protein kinase catalyzed subunit) in radiosensitive T-B-SCID patients. Mutations in the DNA-PKcs gene have long been predicted, but spontaneous mutations have been identified only in mouse, horse and dog models. Single base changes in DNA-PKcs can lead to changes in disease-associated kinase subunit proteins. ZFN-mediated genome editing can be used to produce humanized horses in which horse DNA-PKcs has been replaced with mutated forms of human DNA-PKcs containing one or more mutations. Such humanized horses can be used to study the development of diseases associated with mutated human DNA-PKcs proteins. Humanized horses can also be used to assess the effect of potential therapeutic agents targeting pathways leading to immunodeficiency, including DNA-PKcs.

Genetically modified horses can be made using the methods described in the above examples. However, to make a humanized horse, ZFN mRNA can be co-injected into the embryo of horses with the human chromosomal sequence encoding the mutated DNA-PKcs protein. The horse chromosomal sequence can then be replaced with a mutated human sequence by homologous recombination, and a humanized horse can be made expressing the mutated form of this protein.

                         SEQUENCE LISTING <110> SIGMA-ALDRICH CO.        WEINSTEIN, Edward        CUI, Xiaoxia        SIMMONS, Phil   <120> GENOME EDITING IN ANIMALS <130> 047497-416310 <150> 61 / 228,419 <151> 2009-07-24 <150> 12 / 842,217 <151> 2010-07-23 <150> 12 / 842,219 <151> 2010-07-23 <150> 12 / 842,269 <151> 2010-07-23 <150> 12 / 842,208 <151> 2010-07-23 <150> 12 / 842,204 <151> 2010-07-23 <150> 12 / 842,198 <151> 2010-07-23 <150> 12 / 842,188 <151> 2010-07-23 <150> 12 / 842,719 <151> 2010-07-23 <150> 12 / 842,713 <151> 2010-07-23 <150> 61 / 232,620 <151> 2009-08-10 <150> 61 / 245,877 <151> 2009-09-25 <150> 61 / 308,089 <151> 2010-02-25 <150> 61 / 309,729 <151> 2010-03-02 <150> 61 / 263,696 <151> 2009-11-23 <150> 61 / 263,904 <151> 2009-11-24 <150> 61 / 323,719 <151> 2010-04-13 <150> 61 / 323,702 <151> 2010-04-13 <150> 61 / 323,698 <151> 2010-04-13 <150> 61 / 336,000 <151> 2010-01-14 <150> 61 / 343,287 <151> 2010-04-26 <150> 12 / 842,708 <151> 2010-07-23 <150> 12 / 842,694 <151> 2010-07-23 <150> 12 / 842,678 <151> 2010-07-23 <150> 12 / 842,666 <151> 2010-07-23 <150> 12 / 842,620 <151> 2010-07-23 <150> 12 / 842,578 <151> 2010-07-23 <150> 12 / 842,897 <151> 2010-07-23 <150> 12 / 842,893 <151> 2010-07-23 <150> 12 / 842,886 <151> 2010-07-23 <150> 12 / 842,839 <151> 2010-07-23 <150> 12 / 842,980 <151> 2010-07-23 <150> 12 / 842,978 <151> 2010-07-23 <150> 12 / 842,976 <151> 2010-07-23 <150> 12 / 842,982 <151> 2010-07-23 <150> 12 / 842,991 <151> 2010-07-23 <150> 12 / 842,994 <151> 2010-07-23 <150> 12 / 842,993 <151> 2010-07-23 <150> 12 / 842,999 <151> 2010-07-23 <150> 12 / 843,000 <151> 2010-07-23 <160> 243 <170> PatentIn version 3.5 <210> 1 <211> 35 <212> DNA <213> Rattus rattus <400> 1 aaaaggtacc tctgtgtttt tccgttctag tccag 35 <210> 2 <211> 35 <212> DNA <213> Rattus rattus <400> 2 aaaaccgcgg ctgaagtata cgtggctctc ttgga 35 <210> 3 <211> 34 <212> DNA <213> Rattus rattus <400> 3 gtgtagcggc cgcgacaagg ccaatggcta tcac 34 <210> 4 <211> 34 <212> DNA <213> Rattus rattus <400> 4 gtgtagttta aacgacaagg ccaatggcta tcac 34 <210> 5 <211> 36 <212> DNA <213> Rattus rattus <400> 5 ttgtcgcggc cgctacacgg cagatttgaa gacctc 36 <210> 6 <211> 36 <212> DNA <213> Rattus rattus <400> 6 ttgtcgttta aactacacgg cagatttgaa gacctc 36 <210> 7 <211> 39 <212> DNA <213> Rattus rattus <400> 7 aaaaggtacc tcagactggt ccagatttta gamaagggg 39 <210> 8 <211> 36 <212> DNA <213> Rattus rattus <400> 8 aaaaccgcgg ataaatctac tggttcgcca agctag 36 <210> 9 <211> 32 <212> DNA <213> Rattus rattus <400> 9 aaaaggtacc gaggtagtag gaaatgcact tc 32 <210> 10 <211> 33 <212> DNA <213> Rattus rattus <400> 10 aaaaccgcgg gaagagaatt attgctgaca gtc 33 <210> 11 <211> 22 <212> DNA <213> Rattus rattus <400> 11 gagcctatca acgtagatga gg 22 <210> 12 <211> 24 <212> DNA <213> Rattus rattus <400> 12 cttacatcct tcacaggtca tgac 24 <210> 13 <211> 30 <212> DNA <213> Rattus rattus <400> 13 aaaaggtacc gggagtggat gaaggagttg 30 <210> 14 <211> 28 <212> DNA <213> Rattus rattus <400> 14 aaaaccgcgg cggatcacaa gcaataat 28 <210> 15 <211> 33 <212> DNA <213> Rattus rattus <400> 15 cttcgcggcc gcgatctgca actggagtct ttc 33 <210> 16 <211> 33 <212> DNA <213> Rattus rattus <400> 16 cttcgtttaa acgatctgca actggagtct ttc 33 <210> 17 <211> 32 <212> DNA <213> Rattus rattus <400> 17 gatcgcggcc gcgaagaagg gggaagggaa tc 32 <210> 18 <211> 32 <212> DNA <213> Rattus rattus <400> 18 gatcgtttaa acgaagaagg gggaagggaa tc 32 <210> 19 <211> 30 <212> DNA <213> Rattus rattus <400> 19 aaaaggtacc gcgtgtgaaa acacaaatgg 30 <210> 20 <211> 30 <212> DNA <213> Rattus rattus <400> 20 aaaaccgcgg aaggaaagag gcattcatgg 30 <210> 21 <211> 30 <212> DNA <213> Rattus rattus <400> 21 aaaaggtacc attatggagg ggaggactgg 30 <210> 22 <211> 29 <212> DNA <213> Rattus rattus <400> 22 aaaaccgcgg acatgtggca aacaggaga 29 <210> 23 <211> 19 <212> DNA <213> Rattus rattus <400> 23 tgtcttctga ggaccgccc 19 <210> 24 <211> 19 <212> DNA <213> Rattus rattus <400> 24 ctgcccagaa gactcccgc 19 <210> 25 <211> 30 <212> DNA <213> Mus musculus <400> 25 aaaaggracc aacaacacta ggctcaggag 30 <210> 26 <211> 31 <212> DNA <213> Mus musculus <400> 26 aaaaccgcgg cacatggcta agcacagcat g 31 <210> 27 <211> 31 <212> DNA <213> Mus musculus <400> 27 cctgcggccg cggactgtca gctggtattt g 31 <210> 28 <211> 31 <212> DNA <213> Mus musculus <400> 28 cctgtttaaa cggactgtca gctggtattt g 31 <210> 29 <211> 31 <212> DNA <213> Mus musculus <400> 29 gtccgcggcc gcagggctga tggccaaaat c 31 <210> 30 <211> 31 <212> DNA <213> Mus musculus <400> 30 gtccgtttaa acagggctga tggccaaaat c 31 <210> 31 <211> 29 <212> DNA <213> Mus musculus <400> 31 aaaaggtacc atgctgtgaa gcagatacc 29 <210> 32 <211> 34 <212> DNA <213> Mus musculus <400> 32 aaaaccgcgg ctgaaaactg aatgagacat ttgc 34 <210> 33 <211> 33 <212> DNA <213> Mus musculus <400> 33 aaaaggtacc gtaatgttcc aattgcatct tcc 33 <210> 34 <211> 30 <212> DNA <213> Mus musculus <400> 34 aaaaccgcgg ctctcagttc tctgctgttg 30 <210> 35 <211> 20 <212> DNA <213> Mus musculus <400> 35 gatttacccg tggctggaag 20 <210> 36 <211> 20 <212> DNA <213> Mus musculus <400> 36 ctggactcat ggacttcacc 20 <210> 37 <211> 31 <212> DNA <213> Rattus rattus <400> 37 aaaaggtacc tggctcagga gaaaaattgt g 31 <210> 38 <211> 30 <212> DNA <213> Rattus rattus <400> 38 aaaaccgcgg cacggctaaa gacagcatga 30 <210> 39 <211> 32 <212> DNA <213> Rattus rattus <400> 39 ccctgcggcc gcggactgtc agctggtatt tg 32 <210> 40 <211> 32 <212> DNA <213> Rattus rattus <400> 40 ccctgtttaa acggactgtc agctggtatt tg 32 <210> 41 <211> 31 <212> DNA <213> Rattus rattus <400> 41 gtccgcggcc gcagggctga tggccaaaat c 31 <210> 42 <211> 31 <212> DNA <213> Rattus rattus <400> 42 gtccgtttaa acagggctga tggccaaaat c 31 <210> 43 <211> 30 <212> DNA <213> Rattus rattus <400> 43 aaaaggtacc ggagataggc tggtttgacg 30 <210> 44 <211> 29 <212> DNA <213> Rattus rattus <400> 44 aaaaccgcgg atggtggtag ttcggatgg 29 <210> 45 <211> 31 <212> DNA <213> Rattus rattus <400> 45 aaaaggtacc aggttgttct tggagatgtg c 31 <210> 46 <211> 30 <212> DNA <213> Rattus rattus <400> 46 aaaaccgcgg tcctcttggc tggtgagttt 30 <210> 47 <211> 20 <212> DNA <213> Rattus rattus <400> 47 gatttactcg cggctggaag 20 <210> 48 <211> 19 <212> DNA <213> Rattus rattus <400> 48 ctggactcac gggcttcac 19 <210> 49 <211> 30 <212> DNA <213> Homo sapiens <400> 49 aaagcggccg cttggggttg cgccttttcc 30 <210> 50 <211> 30 <212> DNA <213> Homo sapiens <400> 50 aaaagcggcc gccatagagc ccaccgcatc 30 <210> 51 <211> 192 <212> DNA <213> Felis catus <220> <221> misc_feature <222> (150) .. (150) <223> n is a, c, g, or t <220> <221> misc_feature <222> (179) .. (179) <223> n is a, c, g, or t <220> <221> misc_feature 222 (185) .. (185) <223> n is a, c, g, or t <400> 51 catgactagt ccatccaaga cccacataca tctcctccct ccacagccca tgactagtcc 60 atccaagacc cacatacatc tcctccctcc acagcccatg actagtccat ccaagaccca 120 catacatctc ctccctccac agcccatgan tagtccatcc aagacccaca tacatctcnt 180 ccctncacag cc 192 <210> 52 <211> 372 <212> DNA <213> Felis catus <400> 52 gcacgcgcaa cgtgaaggtt ggggaggcgg ggaaggaaag gaaattacca tgactagtcc 60 atccaagacc ctggataaga gtccgttctc cacgggaagg ggagccaagg tagcgtcatc 120 tgttgactcg gggacttagg atcctgccca cacatacatc tcctccctcc acagccccca 180 ggcagtaagc agcccagaga ggcctggcgg tgcctcctgg aaaaggatgt tagacgcagc 240 cctcccaccc tgccctactg ttgcagccac agcaggtatg ttccaggctg gggagggagc 300 acctgccact gcatcatgaa gggggctcgt gttctcgtgc ttctctgggc tgccttgctc 360 ttgatctggg gt 372 <210> 53 <211> 149 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 53 Val Pro Ala Ala Met Ala Glu Arg Pro Phe Gln Cys Arg Ile Cys Met 1 5 10 15 Arg Asn Phe Ser Arg Ser Asp Asn Leu Ala Arg His Ile Arg Thr His             20 25 30 Thr Gly Glu Lys Pro Phe Ala Cys Asp Ile Cys Gly Arg Lys Phe Ala         35 40 45 Gln Ser Ser Asp Leu Arg Arg His Thr Lys Ile His Thr Gly Gly Gln     50 55 60 Arg Pro Phe Gln Cys Arg Ile Cys Met Arg Asn Phe Ser Arg Ser Asp 65 70 75 80 Thr Leu Ser Gln His Ile Arg Thr His Thr Gly Glu Lys Pro Phe Ala                 85 90 95 Cys Asp Ile Cys Gly Arg Lys Phe Ala Asp Arg Ser Ala Arg Thr Arg             100 105 110 His Thr Lys Ile His Thr Gly Glu Lys Pro Phe Gln Cys Arg Ile Cys         115 120 125 Met Arg Lys Phe Ala Gln Ser Ser Asp Leu Arg Arg His Thr Lys Ile     130 135 140 His Leu Arg Gly Ser 145 <210> 54 <211> 181 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 54 Val Pro Ala Ala Met Ala Glu Arg Pro Phe Gln Cys Arg Ile Cys Met 1 5 10 15 Arg Asn Phe Ser Glu Arg Gly Thr Leu Ala Arg His Ile Arg Thr His             20 25 30 Thr Gly Glu Lys Pro Phe Ala Cys Asp Ile Cys Gly Arg Lys Phe Ala         35 40 45 Gln Ser Ala Asp Arg Thr Lys His Thr Lys Ile His Thr Gly Gly Gln     50 55 60 Arg Pro Phe Gln Cys Arg Ile Cys Met Arg Asn Phe Ser Arg Ser Asp 65 70 75 80 His Leu Ser Thr His Ile Arg Thr His Thr Gly Glu Lys Pro Phe Ala                 85 90 95 Cys Asp Ile Cys Gly Arg Lys Phe Ala Asp Asn Ala Asn Arg Thr Lys             100 105 110 His Thr Lys Ile His Thr Gly Gly Gly Gly Ser Gln Lys Pro Phe Gln         115 120 125 Cys Arg Ile Cys Met Arg Asn Phe Ser Gln Ser Ser Asn Leu Ala Arg     130 135 140 His Ile Arg Thr His Thr Gly Glu Lys Pro Phe Ala Cys Asp Ile Cys 145 150 155 160 Gly Arg Lys Phe Ala Arg Ser Asp Ala Leu Thr Gln His Thr Lys Ile                 165 170 175 His Leu Arg Gly Ser             180 <210> 55 <211> 28 <212> DNA <213> Felis catus <400> 55 ctgctgtcct ggctgaggcc ctgatgct 28 <210> 56 <211> 28 <212> DNA <213> Felis catus <400> 56 gaatggattt actggtcagc cagctact 28 <210> 57 <211> 149 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 57 Val Pro Ala Ala Met Ala Glu Arg Pro Phe Gln Cys Arg Ile Cys Met 1 5 10 15 Arg Asn Phe Ser Arg Ser Asp His Leu Ser Thr His Ile Arg Thr His             20 25 30 Thr Gly Glu Lys Pro Phe Ala Cys Asp Ile Cys Gly Arg Lys Phe Ala         35 40 45 Arg Ser Ala His Leu Ser Arg His Thr Lys Ile His Thr Gly Ser Gln     50 55 60 Lys Pro Phe Gln Cys Arg Ile Cys Met Arg Asn Phe Ser Gln Ser Gly 65 70 75 80 Ser Leu Thr Arg His Ile Arg Thr His Thr Gly Glu Lys Pro Phe Ala                 85 90 95 Cys Asp Ile Cys Gly Arg Lys Phe Ala Arg Ser Asp His Leu Thr Gln             100 105 110 His Thr Lys Ile His Thr Gly Glu Lys Pro Phe Gln Cys Arg Ile Cys         115 120 125 Met Arg Lys Phe Ala Leu Lys Gln His Leu Asn Glu His Thr Lys Ile     130 135 140 His Leu Arg Gly Ser 145 <210> 58 <211> 178 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 58 Val Pro Ala Ala Met Ala Glu Arg Pro Phe Gln Cys Arg Ile Cys Met 1 5 10 15 Arg Asn Phe Ser Arg Ser Asp Asn Leu Ser Ala His Ile Arg Thr His             20 25 30 Thr Gly Glu Lys Pro Phe Ala Cys Asp Ile Cys Gly Arg Lys Phe Ala         35 40 45 Gln Ser Ala Asn Arg Ile Lys His Thr Lys Ile His Thr Gly Ser Gln     50 55 60 Lys Pro Phe Gln Cys Arg Ile Cys Met Arg Asn Phe Ser Gln Ser Gly 65 70 75 80 Ala Leu Ala Arg His Ile Arg Thr His Thr Gly Glu Lys Pro Phe Ala                 85 90 95 Cys Asp Ile Cys Gly Arg Lys Phe Ala Arg Ser Asp Asn Leu Arg Glu             100 105 110 His Thr Lys Ile His Thr Gly Ser Gln Lys Pro Phe Gln Cys Arg Ile         115 120 125 Cys Met Arg Asn Phe Ser Arg Ser Asp His Leu Ser Glu His Ile Arg     130 135 140 Thr His Thr Gly Glu Lys Pro Phe Ala Cys Asp Ile Cys Gly Arg Lys 145 150 155 160 Phe Ala Gln Ser Ala Thr Arg Lys Lys His Thr Lys Ile His Leu Arg                 165 170 175 Gly Ser          <210> 59 <211> 186 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 59 Val Pro Ala Ala Met Ala Glu Arg Pro Phe Gln Cys Arg Ile Cys Met 1 5 10 15 Arg Asn Phe Ser Gln Ser Gly His Leu Ala Arg His Ile Arg Thr His             20 25 30 Thr Gly Glu Lys Pro Phe Ala Cys Asp Ile Cys Gly Arg Lys Phe Ala         35 40 45 Gln Ser Ala Asp Arg Thr Lys His Thr Lys Ile His Thr Gly Ser Gln     50 55 60 Lys Pro Phe Gln Cys Arg Ile Cys Met Arg Asn Phe Ser Arg Ser Asp 65 70 75 80 Thr Leu Ser Glu His Ile Arg Thr His Thr Gly Glu Lys Pro Phe Ala                 85 90 95 Cys Asp Ile Cys Gly Arg Lys Phe Ala Asn Arg Arg Gly Arg Trp Ser             100 105 110 His Thr Lys Ile His Thr Pro Asn Pro His Arg Arg Thr Asp Pro Ser         115 120 125 His Lys Pro Phe Gln Cys Arg Ile Cys Met Arg Asn Phe Ser Arg Ser     130 135 140 Asp His Leu Ser Arg His Ile Arg Thr His Thr Gly Glu Lys Pro Phe 145 150 155 160 Ala Cys Asp Ile Cys Gly Arg Lys Phe Ala Asp Pro Ser Tyr Leu Pro                 165 170 175 Arg His Thr Lys Ile His Leu Arg Gly Ser             180 185 <210> 60 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 60 Val Pro Ala Ala Met Ala Glu Arg Pro Phe Gln Cys Arg Ile Cys Met 1 5 10 15 Arg Asn Phe Ser Arg Ser Asp Ser Leu Ser Val His Ile Arg Thr His             20 25 30 Thr Gly Glu Lys Pro Phe Ala Cys Asp Ile Cys Gly Arg Lys Phe Ala         35 40 45 Gln Asn Ala Asn Arg Lys Thr His Thr Lys Ile His Thr Gly Ser Gln     50 55 60 Lys Pro Phe Gln Cys Arg Ile Cys Met Arg Asn Phe Ser Arg Ser Ala 65 70 75 80 Asn Leu Ala Arg His Ile Arg Thr His Thr Gly Glu Lys Pro Phe Ala                 85 90 95 Cys Asp Ile Cys Gly Arg Lys Phe Ala Thr Ser Gly Ser Leu Thr Arg             100 105 110 His Thr Lys Ile His Leu Arg Gly Ser         115 120 <210> 61 <211> 153 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 61 Val Pro Ala Ala Met Ala Glu Arg Pro Phe Gln Cys Arg Ile Cys Met 1 5 10 15 Arg Asn Phe Ser Arg Ser Asp Thr Leu Ser Ala His Ile Arg Thr His             20 25 30 Thr Gly Glu Lys Pro Phe Ala Cys Asp Ile Cys Gly Arg Lys Phe Ala         35 40 45 Asp Lys Arg Thr Arg Thr Thr His Thr Lys Ile His Thr His Pro Arg     50 55 60 Ala Pro Ile Pro Lys Pro Phe Gln Cys Arg Ile Cys Met Arg Asn Phe 65 70 75 80 Ser Thr Ser Gly Ser Leu Ser Arg His Ile Arg Thr His Thr Gly Glu                 85 90 95 Lys Pro Phe Ala Cys Asp Ile Cys Gly Arg Lys Phe Ala Asp Ser Ser             100 105 110 Asp Arg Lys Lys His Thr Lys Ile His Thr Gly Glu Lys Pro Phe Gln         115 120 125 Cys Arg Ile Cys Met Arg Lys Phe Ala Arg Ser Asp Asn Leu Thr Arg     130 135 140 His Thr Lys Ile His Leu Arg Gly Ser 145 150 <210> 62 <211> 153 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 62 Val Pro Ala Ala Met Ala Glu Arg Pro Phe Gln Cys Arg Ile Cys Met 1 5 10 15 Arg Asn Phe Ser Arg Ser Asp Thr Leu Ser Ala His Ile Arg Thr His             20 25 30 Thr Gly Glu Lys Pro Phe Ala Cys Asp Ile Cys Gly Arg Lys Phe Ala         35 40 45 Asp Lys Arg Thr Arg Thr Thr His Thr Lys Ile His Thr His Pro Arg     50 55 60 Ala Pro Ile Pro Lys Pro Phe Gln Cys Arg Ile Cys Met Arg Asn Phe 65 70 75 80 Ser Thr Ser Gly Ser Leu Ser Arg His Ile Arg Thr His Thr Gly Glu                 85 90 95 Lys Pro Phe Ala Cys Asp Ile Cys Gly Arg Lys Phe Ala Asp Ser Ser             100 105 110 Asp Arg Lys Lys His Thr Lys Ile His Thr Gly Glu Lys Pro Phe Gln         115 120 125 Cys Arg Ile Cys Met Arg Lys Phe Ala Arg Ser Asp Asn Leu Thr Arg     130 135 140 His Thr Lys Ile His Leu Arg Gly Ser 145 150 <210> 63 <211> 28 <212> DNA <213> Felis catus <400> 63 acagtagggc agggtgggag ggctgcgt 28 <210> 64 <211> 28 <212> DNA <213> Felis catus <400> 64 ggccacagca ggtataaaag ggttccag 28 <210> 65 <211> 28 <212> DNA <213> Felis catus <400> 65 tcgtcggggg ttcccgtcag gaataggt 28 <210> 66 <211> 28 <212> DNA <213> Felis catus <400> 66 atgttgagca agtggcacaa tacaatgc 28 <210> 67 <211> 28 <212> DNA <213> Felis catus <400> 67 aagagtccgt tctccacgta gcaatcct 28 <210> 68 <211> 28 <212> DNA <213> Felis catus <400> 68 ccagggtctt ggatggacta gtcatggt 28 <210> 69 <211> 42 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 69 Gln Ser Gly Asn Leu Ala Arg Leu Ala Tyr Asp Arg Arg Lys Arg Ser 1 5 10 15 Asp Thr Leu Ser Glu Gln Ser Ser His Leu Ala Arg Gln Ser Ser Asp             20 25 30 Leu Ser Arg Arg Arg Asp Thr Leu Leu Asp         35 40 <210> 70 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 70 Gln Ser Gly Asp Leu Thr Arg Asn Lys His His Arg Asn Arg Arg Ser 1 5 10 15 Asp Ala Leu Ala Arg Thr Ser Gly Asn Leu Thr Arg Arg Arg Tyr Tyr             20 25 30 Leu Arg Leu         35 <210> 71 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 71 Arg Ser Asp Asn Leu Ala Arg Trp Arg Gly Asp Arg Val Lys Asp Arg 1 5 10 15 Ser His Leu Ala Arg Gln Ser Ser Asp Leu Ser Arg Gln Ser Gly Asp             20 25 30 Leu Thr Arg         35 <210> 72 <211> 42 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 72 Arg Ser Asp Asn Leu Ser Glu Ser Ser Arg Asn Leu Ala Ser Arg Ser 1 5 10 15 Ala Asn Leu Ala Arg Arg Ser Asp Asn Leu Thr Arg Arg Ser Asp Asn             20 25 30 Leu Ser Glu Ser Ser Arg Asn Leu Ala Ser         35 40 <210> 73 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 73 Asp Ser Ser Asp Arg Lys Lys Gln Ser Ser Asp Leu Ser Arg Tyr His 1 5 10 15 Trp Tyr Leu Lys Lys Arg Ser Asp His Leu Ser Gln Thr Ser Ala Asn             20 25 30 Arg Thr Thr         35 <210> 74 <211> 42 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 74 Gln Ser Gly Asn Leu Ala Arg Trp Leu Ser Ser Leu Gly Ile Asp Arg 1 5 10 15 Ser Asp Leu Ser Arg Leu Arg Phe Asn Leu Arg Asn Gln Ser Gly Asp             20 25 30 Leu Thr Arg Gln Ser Gly Asn Leu Ala Arg         35 40 <210> 75 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 75 Asp Arg Ser Asn Leu Ser Arg Asp Ala Phe Thr Arg Thr Arg Arg Ser 1 5 10 15 Asp Asn Leu Ser Val Glu Arg Gly Thr Leu Ala Arg Gln Ser Gly Asp             20 25 30 Leu Thr Arg         35 <210> 76 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 76 Thr Asn His Gly Leu Asn Glu Thr Ser Ser Asn Leu Ser Arg Gln Ser 1 5 10 15 Ser Asp Leu Ser Arg His Lys Tyr His Leu Arg Ser Gln Ser Gly His             20 25 30 Leu Ser Arg         35 <210> 77 <211> 28 <212> DNA <213> Felis catus <400> 77 atccggctgg accgtctgaa ctcctagc 28 <210> 78 <211> 28 <212> DNA <213> Felis catus <400> 78 agtgggatgt gggtgcaccc aggccgga 28 <210> 79 <211> 28 <212> DNA <213> Felis catus <400> 79 cagcagctgg ccctgagggg acacacag 28 <210> 80 <211> 28 <212> DNA <213> Felis catus <400> 80 tgcaccagtg aggagcacca ggctggga 28 <210> 81 <211> 28 <212> DNA <213> Felis catus <400> 81 tacagtggtt tgcttccccc ggacccat 28 <210> 82 <211> 28 <212> DNA <213> Felis catus <400> 82 gggaagcacc atgcctgtga acatgttc 28 <210> 83 <211> 28 <212> DNA <213> Felis catus <400> 83 aggcagccaa ggcggaccca tcgaagga 28 <210> 84 <211> 28 <212> DNA <213> Felis catus <400> 84 gaggacgtgc tgatcgtgac tacccagt 28 <210> 85 <211> 46 <212> DNA <213> Homo sapiens <400> 85 tgtcgccttc gcctcctaat ccctagccac tatggtgagt aagccg 46 <210> 86 <211> 15 <212> DNA <213> Homo sapiens <400> 86 cttcgcctcc taatc 15 <210> 87 <211> 15 <212> DNA <213> Homo sapiens <400> 87 cactatggtg agtaa 15 <210> 88 <211> 18 <212> DNA <213> Homo sapiens <400> 88 gtcgtcgaca acggctcc 18 <210> 89 <211> 19 <212> DNA <213> Homo sapiens <400> 89 tgcaaggccg gcttcgcgg 19 <210> 90 <211> 15 <212> DNA <213> Homo sapiens <400> 90 cctcgccgcc ccgct 15 <210> 91 <211> 16 <212> DNA <213> Homo sapiens <400> 91 gccgcccgcc atggcg 16 <210> 92 <211> 300 <212> DNA <213> Rattus rattus <400> 92 gggagactga aacctctgat atcttctttc aggccgtgag gaattctaca gcactcaccc 60 ccacttcatg acccagagag ccctgtacct ggctgtctac gacctcagca aggggcaggc 120 ggaggtggat gccatgaagc cctggctctt caacatcaag gtgatctctt ctggtgccat 180 ggaaacagag tgggaccgtt gctcactgtt gtatgctatg cttctggttt tgttttgttt 240 tgctttgttt gagtccgaat cttactatgt atccctggct gccctggaac tttctgtgaa 300 <210> 93 <211> 200 <212> DNA <213> Rattus rattus <400> 93 tcttctttca ggccgtgagg aattctacag cactcacccc cacttcatga cccagagagc 60 cctgtacctg gctgtctacg acctcagcaa ggggcaggcg gaggtggatg ccatgaagcc 120 ctggctcttc aacatcaagg tgatctcttc tggtgccatg gaaacagagt gggaccgttg 180 ctcactgttg tatgctatgc 200 <210> 94 <211> 28 <212> DNA <213> Rattus rattus <400> 94 tgggtcatga agtgggggtg agtgctgt 28 <210> 95 <211> 28 <212> DNA <213> Rattus rattus <400> 95 gagccctgta cctggctgtc tacgacct 28 <210> 96 <211> 28 <212> DNA <213> Rattus rattus <400> 96 agtcagcaca ggcatgtcca tgttgagt 28 <210> 97 <211> 28 <212> DNA <213> Rattus rattus <400> 97 cctctggggt agtgaacagg tctcccac 28 <210> 98 <211> 28 <212> DNA <213> Rattus rattus <400> 98 aagccgacta gagagagaac ccaaacgc 28 <210> 99 <211> 28 <212> DNA <213> Rattus rattus <400> 99 gtgaaggaga tcctcaagga gcaggaga 28 <210> 100 <211> 28 <212> DNA <213> Rattus rattus <400> 100 gaactcggag tttcccaggc tggacctt 28 <210> 101 <211> 28 <212> DNA <213> Rattus rattus <400> 101 gtgcggcacc tgcagacaag caaccctc 28 <210> 102 <211> 28 <212> DNA <213> Rattus rattus <400> 102 gggtagtagt gtgggggtag catgtcag 28 <210> 103 <211> 28 <212> DNA <213> Rattus rattus <400> 103 aaggcctggg ccacggccgc acactctt 28 <210> 104 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 104 Trp Arg Ser Cys Arg Ser Ala Gln Ser Gly Ser Leu Thr Arg Arg Ser 1 5 10 15 Asp Asn Leu Arg Glu Gln Ser Gly Ser Leu Thr Arg Gln Ser Ala Asp             20 25 30 Arg Thr Lys         35 <210> 105 <211> 42 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 105 Arg Ser Asp His Leu Ser Ala Asp Arg Ser Asn Arg Lys Thr Arg Ser 1 5 10 15 Ala Ala Leu Ser Arg Gln Ser Gly Ser Leu Thr Arg Arg Ser Asp His             20 25 30 Leu Ser Glu Arg Lys His Asp Arg Thr Lys         35 40 <210> 106 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 106 Arg Ser Asp Ala Leu Ser Val Gln Ser Gln His Arg Thr Thr Arg Ser 1 5 10 15 Asp Asn Leu Ser Val Asp Arg Ser Asn Leu Thr Arg Asp Arg Ser Asp             20 25 30 Leu Ser Arg         35 <210> 107 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 107 Arg Ser Asp Asn Leu Ser Thr Asp Asn Ser Ser Arg Ile Thr Thr Ser 1 5 10 15 Ser Asn Leu Ser Arg Gln Ser Gly His Leu Gln Arg Gln Ser Gly Asn             20 25 30 Leu Ala Arg         35 <210> 108 <211> 42 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 108 Ala Ser Thr Gly Leu Ile Arg Arg Ser Asp His Leu Ser Arg Arg Ser 1 5 10 15 Asp Ala Leu Ser Arg Gln Ser Gly Asn Leu Ala Arg Asn Asn Thr Gln             20 25 30 Leu Ile Glu Thr Ser Ser Ile Leu Ser Arg         35 40 <210> 109 <211> 42 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 109 Asp Arg Ser Ala Leu Ser Arg Gln Ser Ser Asp Leu Arg Arg Arg Ser 1 5 10 15 Asp Val Leu Ser Ala Asp Arg Ser Asn Arg Ile Lys Arg Ser Asp Ser             20 25 30 Leu Ser Ala Asp Arg Ser Ser Arg Thr Lys         35 40 <210> 110 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 110 Arg Ser Asp Asn Leu Ser Gln Ala Ser Asn Asp Arg Lys Lys His Arg 1 5 10 15 Ser Ser Leu Arg Arg Arg Ser Asp His Leu Ser Glu Ala Arg Ser Thr             20 25 30 Arg Thr Asn         35 <210> 111 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 111 Asp Arg Ser Asn Leu Ser Arg Gln Ser Gly Asp Leu Thr Arg His Lys 1 5 10 15 Thr Ser Leu Lys Asp Gln Ser Gly Asp Leu Thr Arg Arg Ser Asp Asp             20 25 30 Leu Thr Arg         35 <210> 112 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 112 Arg Ser Ser His Leu Ser Arg Arg Ser Asp His Leu Ser Thr Ala Ser 1 5 10 15 Ser Ala Arg Lys Thr Gln Ser Gly Ala Leu Ala Arg Gln Ser Gly Ser             20 25 30 Leu Thr Arg         35 <210> 113 <211> 42 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 113 Gln Ser Gly Asp Leu Thr Arg Asp Arg Ser Asp Leu Ser Arg Arg Ser 1 5 10 15 Asp Thr Leu Ser Val Asp Asn Ser Thr Arg Ile Lys Arg Ser Asp Ala             20 25 30 Leu Ser Val Asp Ser Ser His Arg Thr Arg         35 40 <210> 114 <211> 300 <212> DNA <213> Rattus rattus <400> 114 caagagcact gtaggtcctg acccagcctt aaacttacta ctctacacag gatgcctggc 60 cgagggagag ctggaggtga cagatcagct cccagggcaa agcgaccaac cctgggagca 120 ggccctgaac cgcttctggg attacctgcg ctgggtgcag acgctttctg accaggtcca 180 ggaagagctg cagagctccc aagtcacaca ggaactgacg tgagtgctca gcgcttcacc 240 ctccgcacct gctgagtatc cagatccagg ggttcctcct atctgggcac ctacctactt 300 <210> 115 <211> 400 <212> DNA <213> Rattus rattus <400> 115 caagagcact gtaggtcctg acccagcctt aaacttacta ctctacacag gatgcctggc 60 cgagggagag ctggaggtga cagatcagct cccagggcaa agcgaccaac cctgggagca 120 ggccctgaac cgcttctgcg attacctgcg ctgggtgcag acgctttctg accaggtcca 180 ggaagagctg cagagctccc aagtcacaca ggaactgacg tgagtgctca gcgcttcacc 240 ctccgcacct gctgagtatc cagatccagg ggttcctcct atctgggcac ctacctactt 300 gtttcctttc tccatgagtg tgtgggccag gttggccttg aactctcaat acttctgctt 360 tctttagcct tctggatact gggatgaaca ggcattcatt 400 <210> 116 <211> 300 <212> DNA <213> Rattus rattus <400> 116 aagaagaaga agaccccagc gaggaaaatg tgctggagac ccctgtgccg gttcctgtgg 60 ctttggtcct atctgtccta tgttcaagct gtgcctatcc acaaagtcca ggatgacacc 120 aaaaccctca tcaagaccat tgtcaccagg atcaatgaca tttcacacac ggtagggagt 180 ctcttgtggg gaagcaaagg agaagtaggg ctagaaccag agtctgagaa tcacagtgag 240 cgccttctga gtgtcatgca ccccctagaa cctgagaatt tgtaagccta gggtgtccat 300 <210> 117 <211> 28 <212> DNA <213> Rattus rattus <400> 117 aagcggttca gggcctgctc ccagggtt 28 <210> 118 <211> 28 <212> DNA <213> Rattus rattus <400> 118 gggattacct gcgctgggtg cagacgct 28 <210> 119 <211> 28 <212> DNA <213> Rattus rattus <400> 119 gtggataggc acagcttgaa cataggac 28 <210> 120 <211> 28 <212> DNA <213> Rattus rattus <400> 120 aagtccagga tgacaccaaa accctcat 28 <210> 121 <211> 20 <212> DNA <213> Rattus rattus <400> 121 ccccagtttg tggtctgcca 20 <210> 122 <211> 18 <212> DNA <213> Rattus rattus <400> 122 gctaaaggtg aagatcta 18 <210> 123 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 123 Arg Ser Asp Ala Leu Ser Val Asp Ser Ser His Arg Thr Arg Arg Ser 1 5 10 15 Asp Asn Leu Ser Glu Thr Ser Gly Ser Leu Thr Arg Arg Ser Asp Asp             20 25 30 Leu Thr Arg         35 <210> 124 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 124 Arg Ser Asp His Leu Ser Arg Gln Ser Ser Asp Leu Arg Arg Arg Ser 1 5 10 15 Asp Val Leu Ser Ala Asp Arg Ser Asn Arg Ile Lys Thr Ser Ser Asn             20 25 30 Leu Ser Arg         35 <210> 125 <211> 28 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 125 Arg Ser Asp Ala Leu Ser Glu Gln Asn Ala Thr Arg Thr Lys Arg Ser 1 5 10 15 Asp Tyr Leu Ser Thr Gln Asn Ala His Arg Lys Thr             20 25 <210> 126 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 126 Asp Gln Ser Thr Leu Arg Asn Asp Arg Ser Asn Leu Ser Arg Thr Ser 1 5 10 15 Ala Asn Leu Ser Arg Arg Ser Asp Asn Leu Ser Glu Asp Arg Ser Ala             20 25 30 Leu Ala Arg         35 <210> 127 <211> 700 <212> DNA <213> Rattus rattus <400> 127 agtcattgct ggaagaatgc ctatctgggc aggacatttt taatgctaca gtttttaaat 60 gtgctcttta gctacatact ccatactaca tgctacatgc tacatgctac attagtgaaa 120 catgctccag ccatggtaaa atgtctctgg gtgcttcttt agttggcact ggcatctgct 180 gtgtcctgct cctttacacg attctctgtc ctggggaatg attggctctc ttacaaaatg 240 gagcattctt ctcaacttgc cttccggtct cctttccagt tcccacgacg gcagccagca 300 cccctgacgc agtcgacaag tacctggaga cccccggaga tgagaacgag cacgcccatt 360 tccagaaagc caaagagagg ttggaagcca agcaccgaga gagaatgtcc caggtacgga 420 gaaggcttcc aacttctgct gttctgttgt ctagggagat gcacgctcgc ctctgcctca 480 gacgggtaga tacaaagttt aatttaaatg ttttccacga ggacacagat tgtagggttc 540 ccctacatct atccagtgtg cgatcacatc aaggaaaggc aagtacaaga ggattttgaa 600 gcacataatc aattgtgcct ctccgctaaa gaaaaggtac tctgcgagat ggtgaggcaa 660 gggctgttaa ctgatacatt gtagtaaact ttgtgtgtgt 700 <210> 128 <211> 700 <212> DNA <213> Rattus rattus <400> 128 agtcattgct ggaagaatgc ctatctgggc aggacatttt taatgctaca gtttttaaat 60 gtgctcttta gctacatact ccatactaca tgctacatgc tacatgctac attagtgaaa 120 catgctccag ccatggtaaa atgtctctgg gtgcttcttt agttggcact ggcatctgct 180 gtgtcctgct cctttacacg attctctgtc ctggggaatg attggctctc ttacaaaatg 240 gagcattctt ctcaacttgc cttccggtct cctttccagt tcccacgacg gcagccagca 300 cccctgacgc agtcgacaag tacctggaga cccccggaga tgagaacgag cacgcccatt 360 tccagaaagc caaagagagg ttggaagcca agcaccgaga gagaatgtcc caggtacgga 420 gaaggcttcc aacttctgct gttctgttgt ctagggagat gcacgctcgc ctctgcctca 480 gacgggtaga tacaaagttt aatttaaatg ttttccacga ggacacagat tgtagggttc 540 ccctacatct atccagtgtg cgatcacatc aaggaaaggc aagtacaaga ggattttgaa 600 gcacataatc aattgtgcct ctccgctaaa gaaaaggtac tctgcgagat ggtgaggcaa 660 gggctgttaa ctgatacatt gtagtaaact ttgtgtgtgt 700 <210> 129 <211> 19 <212> DNA <213> Rattus rattus <400> 129 gccagcaccc ctgacgcag 19 <210> 130 <211> 17 <212> DNA <213> Rattus rattus <400> 130 tcgacaagta cctggag 17 <210> 131 <211> 1000 <212> DNA <213> Rattus rattus <400> 131 gtccccaaat attatcagga aaaggattga tcatttatgg ctgtacgatc ggcacctaac 60 agagcttagt aaaatagatt taatagctat ctttggaaag aattaaatga atgaaaattt 120 gtgtgcattg atctcagtta tttccagaat actgcaatat gatatgtata cttttccttt 180 ttgttttttg tttgtttgac acttttctta acttgacttt tccctccctc cattttcccc 240 aggtagcttc gccaaaatgg ctgtcccctt gccatctacc ctgagactca gttctgcacc 300 tgatgaaatt cagcacccgc acatcaaatt ttccgagtgg aaatttaagc tgtttagggt 360 gagatccttt gaaaaggcac ccgaagaagc acaaaaagag aaggattcct cagaagggaa 420 accttgtctc gagcagtctc cagtagttct agataaccct gggggtcaga attcagttct 480 gactcaacga gcattgaaac tccatcctaa attttcaaag aaattccatg ttgatgggaa 540 gtcaagcgac aaagcaattc accaagccag gcttagacac ttctgccgca tctgtggcaa 600 tcacttcaag agtgacgggc acaaccggag atacccagtc cacgggcccg tggacgctaa 660 aactcaaagc cttttccgaa agaaggaaaa aagagtcacg tcctggccag atctcattgc 720 cagagttttc cggattgatg tgaagtcaga tgttgactcc atccacccca ctgaattctg 780 ccataactgt tggagcatta tgcacaggaa gttcggcagt gctcacagtc aggtctactg 840 cccaaggaat gtgaccgtgg agtggcaccc ccacacaccg tcctgtgaca tctgctttac 900 tgcccatcgg ggactgaaga ggaagagaca tcagcccaac gtgcagctca gcaagaaact 960 aaaaactgtg ctcaaccatg ctagacggga ccgtcgcaag 1000 <210> 132 <211> 200 <212> DNA <213> Rattus rattus <400> 132 tgcacaggaa gttcggcagt gctcacagtc aggtctactg cccaaggaat gtgaccgtgg 60 agtggcaccc ccacacaccg tcctgtgaca tctgctttac tgcccatcgg ggactgaaga 120 ggaagagaca tcagcccaac gtgcagctca gcaagaaact aaaaactgtg ctcaaccatg 180 ctagacggga ccgtcgcaag 200 <210> 133 <211> 300 <212> DNA <213> Rattus rattus <400> 133 tatcatccac ggagggaaaa cgccaaacaa tgagctttcc gataagattt atatcatgtc 60 tgtcgcttgc aagaataaca aaaaagttac tttccgttgt acagagaaag acttagtagg 120 agatgtccct gaagccagat atggccattc cattgacgtg gtatatagcc gaggaaaaag 180 tgttggtgtt ctctttggag gacggtcata catgccttct acccaaagaa ccacagaaaa 240 atggaatagt gtagctgatt gcctacccca tgttttcttg gtagattttg aatttgggtg 300 <210> 134 <211> 300 <212> DNA <213> Rattus rattus <400> 134 tatcatccac ggagggaaaa cgccaaacaa tgagctttcc gataagattt atatcatgtc 60 tgtcgcttgc aagaataaca aaaaagttac tttccgttgt acagagaaag acttagtagg 120 agatgtccct gaagccagat atggccattc cattgacgtg gtatatagcc gaggaaaaag 180 tgttggtgtt ctctttggag gacggtcata catgccttct acccaaagaa ccacagaaaa 240 atggaatagt gtagctgatt gcctacccca tgttttcttg gtagattttg aatttgggtg 300 <210> 135 <211> 20 <212> DNA <213> Rattus rattus <400> 135 ccccagtttg tggtctgcca 20 <210> 136 <211> 18 <212> DNA <213> Rattus rattus <400> 136 gctaaaggtg aagatcta 18 <210> 137 <211> 28 <212> DNA <213> Rattus rattus <400> 137 ttccttgggc agtagacctg actgtgag 28 <210> 138 <211> 28 <212> DNA <213> Rattus rattus <400> 138 gtgaccgtgg agtggcaccc ccacacac 28 <210> 139 <211> 28 <212> DNA <213> Rattus rattus <400> 139 acgtggtata tagccgagga aaaagtgt 28 <210> 140 <211> 28 <212> DNA <213> Rattus rattus <400> 140 ataccacgtc aatggaatgg ccatatct 28 <210> 141 <211> 28 <212> DNA <213> Rattus rattus <400> 141 ttaagggcca tgaagatgag gatgctac 28 <210> 142 <211> 28 <212> DNA <213> Rattus rattus <400> 142 cagcaagacc ggaagccttc cagtcagt 28 <210> 143 <211> 28 <212> DNA <213> Rattus rattus <400> 143 ttgtcgattt tggaaggatt gagggccc 28 <210> 144 <211> 28 <212> DNA <213> Rattus rattus <400> 144 atgcaggaag agctgcagaa gtggaaga 28 <210> 145 <211> 28 <212> DNA <213> Rattus rattus <400> 145 tacacaagtc cttctccagg agctagaa 28 <210> 146 <211> 28 <212> DNA <213> Rattus rattus <400> 146 acaaagctta tgaaggtctt agtgaaaa 28 <210> 147 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 147 Asp Arg Ser Asn Leu Ser Arg Gln Ser Gly Ser Leu Thr Arg Glu Arg 1 5 10 15 Gly Thr Leu Ala Arg Arg Ser Asp His Leu Thr Thr His Lys Thr Ser             20 25 30 Leu Lys Asp         35 <210> 148 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 148 Gln Asn Ala Thr Arg Ile Lys Arg Ser Asp Ala Leu Ser Arg Gln Ser 1 5 10 15 Gly His Leu Ser Arg Arg Ser Ala Asp Leu Thr Glu Asp Arg Ala Asn             20 25 30 Leu Ser Arg         35 <210> 149 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 149 Arg Ser Asp Asn Leu Ser Arg Asp Ser Ser Thr Arg Lys Lys Asn Ser 1 5 10 15 Gly Asn Leu Asp Lys Gln Ser Gly Ala Leu Ala Arg Arg Ser Asp Ala             20 25 30 Leu Ala Arg         35 <210> 150 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 150 Gln Ser Gly Asn Leu Ala Arg Arg Ser Asp Ser Leu Ser Val Gln Ser 1 5 10 15 Ala Asp Arg Thr Lys Arg Ser Asp Thr Leu Ser Thr Asp Arg Lys Thr             20 25 30 Arg Ile Asn         35 <210> 151 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 151 Thr Ser Gly Asn Leu Thr Arg Gln Ser Gly Asn Leu Ala Arg Leu Lys 1 5 10 15 Gln Asn Leu Asp Ala Asp Arg Ser His Leu Thr Arg Arg Leu Asp Asn             20 25 30 Arg Thr Ala         35 <210> 152 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 152 Asp Arg Ser Asp Leu Ser Arg Gln Ser Gly Asn Leu Ala Arg Arg Ser 1 5 10 15 Asp Thr Leu Ser Glu Gln Arg Gln His Arg Thr Thr Gln Asn Ala Thr             20 25 30 Arg Ile Lys         35 <210> 153 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 153 Arg Ser Asp His Leu Ser Ala Gln Ser Gly His Leu Ser Arg Asp Ser 1 5 10 15 Glu Ser Leu Asn Ala Thr Ser Ser Asn Leu Ser Arg Asp Arg Ser Ser             20 25 30 Arg Lys Arg         35 <210> 154 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 154 Gln Ser Gly Ser Leu Thr Arg Gln Ser Ser Asp Leu Arg Arg Gln Arg 1 5 10 15 Thr His Leu Thr Gln Gln Ser Gly His Leu Gln Arg Gln Ser Gly Asp             20 25 30 Leu Thr Arg         35 <210> 155 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 155 Gln Ser Gly Asp Leu Thr Arg Ser Ser Ser Asp Arg Lys Lys Asp Ser 1 5 10 15 Ser Asp Arg Lys Lys Arg Ser Asp Asn Leu Ser Thr Asp Asn Ser Asn             20 25 30 Arg Ile Asn         35 <210> 156 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 156 Thr Ser Gly His Leu Ser Arg Gln Ser Gly Asn Leu Ala Arg His Leu 1 5 10 15 Gly Asn Leu Lys Thr Gln Ser Ser Asp Leu Ser Arg Gln Ser Gly Asn             20 25 30 Arg Thr Thr         35 <210> 157 <211> 300 <212> DNA <213> Rattus rattus <400> 157 attaatgtac tcactcttgg caaaacaaaa ctggctcagg agaaaaattg tgtatttgca 60 attccgacat tatgtgtaac acaatctctt tcttctttta gtgacgtctc caaaattaat 120 gaaggaattg gtgacaaaat tggaatgttc tttcaggcaa tggcaacatt ttttggtggt 180 tttataatag gatttactcg cggctggaag ctaactcttg tgattttggc catcagccct 240 gttcttggac tgtcagctgg tatttgggca aaggtaggtg aagcccgtga gtccagattt 300 <210> 158 <211> 200 <212> DNA <213> Rattus rattus <400> 158 gtgacgtctc caaaattaat gaaggaattg gtgacaaaat tggaatgttc tttcaggcaa 60 tggcaacatt ttttggtggt tttataatag gatttactcg cggctggaag ctaactcttg 120 tgattttggc catcagccct gttcttggac tgtcagctgg tatttgggca aaggtaggtg 180 aagcccgtga gtccagattt 200 <210> 159 <211> 400 <212> DNA <213> Rattus rattus <400> 159 ggtaaaagga acaattgatt gacagcacgc ttgcttggta gagtctgcct gaagtataca 60 gttcacacta gattatgtgc gtggcagggc tcttctgttt gctgagtgac ttgtcactgg 120 ctttttctta gaacctgggc ccttctgtgc tggctggggt ggctgttatg atcctcatgg 180 tgcccttcaa tgctgtgatg gccatgaaga ccaagactta ccaggtagga tgtccaactc 240 catgagactt cattctgagc cctggcctgg gtctttccag gtgagggtcg cccagtttcc 300 tgatgcttgg gcctaggata gacagcctaa tctattatag gtgtcataat acagggatac 360 tgcttccctc agtggccttc aaatgtctgc aagtttgcca 400 <210> 160 <211> 200 <212> DNA <213> Rattus rattus <400> 160 gctgagtgac ttgtcactgg ctttttctta gaacctgggc ccttctgtgc tggctggggt 60 ggctgttatg atcctcatgg tgcccttcaa tgctgtgatg gccatgaaga ccaagactta 120 ccaggtagga tgtccaactc catgagactt cattctgagc cctggcctgg gtctttccag 180 gtgagggtcg cccagtttcc 200 <210> 161 <211> 900 <212> DNA <213> Rattus rattus <400> 161 atgcacatac tttaaaaatc aactcattaa atttaaatat ctaacaacaa ggatatccta 60 actatctatc tgataagaat cataatttga aagcagcaat tactgtgagt tagctatgga 120 aacatctacg gtttctcctg gtaacaaaga caccatgtta tgctcatatt aggagaaaag 180 gctggatctc agttatggat tgttacaaat aaaggtgaag ctagttttcc atccacattc 240 tccagccctg aattggatag gcccgatcta gacatagact gtgaagacag tggtgaggtc 300 actccatttc ctaagggcat catggagctc cctcgaggac ctgtcagagt gtagagaggt 360 ggccggtacc tgatggagaa ggagccatag gaggactttt gattcaatag agcctctctc 420 cgtctcttct ccatcctgtc ttctagcata ttctcttgtc tctgtgctct ccccccacgc 480 ttctgtcaaa taaaggacca ggagatgtag acagtggaac agtagagaag tccaatgctt 540 catcctctgc ctcagatctg gaggataggt tctgacagaa gcagactgac gtagcccaga 600 gagactcagc ctgtggactg ttctcattcc aggactgttc tgaaaggtta caagcatcca 660 ctgacactag aagatgtctg ggatatcgat gaagggttta aaacaaggtc agtcaccagc 720 aagtttgagg cggccatgac aaaggacctg cagaaagcca ggcaggcttt tcagaggcgg 780 ctgcagaagt cccagcggaa acctgaggcc acactacacg gactgaacaa gaagcagagt 840 cagagccaag acgttctcgt cctggtaact ttaactcaag tgtccgtgtg aatgcactgt 900 <210> 162 <211> 900 <212> DNA <213> Rattus rattus <400> 162 ccaggcccac gtgtggcaca caggcatatg tgcaggcaaa atacccatat acatcaaaaa 60 aaatttttaa gaaaaaatag aataattgag cctaaataag tggggagtta gtagctatga 120 atttgaaata ggcgttaggc cagtttgaga gaactgtaaa gttgagacca gagctaaagt 180 gtgctgtcct gtctatgttc tcttgagaat gacagaagag aattagaatc tctccactta 240 gtaactgaag agacaatgat gacgtgcaga tcttgaagtc agagagcaca agaacagtta 300 atgttttccc ttccttcctt ccttccttcc ttccttcctt ccttccttcc ttccttcttt 360 ctttctttct ggacttggat ttagatctca gacagaagac tagtgagcac cagagcatat 420 cagtagtcct ccgtggctca taatttatga tatacaccaa tgcatgagtt tctcaagtgt 480 ccaaaactcc tctggaatta ttggagtatt tgttaagcat atgagaaaag gatgtgttag 540 tgaagggaga gtgagaatgg ggagaacttg gcgcgttctg tcttcccaag ccttccctgc 600 ctcatctgaa tacaccttct ctattccaag accatcaggg tcgtgtgtcc ttgtgttgcc 660 ttctcttgca ggttaccact gtgagcccta caacaaccct gcagacttct tccttgacgt 720 catcaacgga gattcttcgg ctgtaatgtt aaacagaggg gaacaagacc atgaaggtat 780 atgagtcttg tagattcata cgttggtgtc caattgtttg attgaagccc agtagtgtgt 840 cttattaaag catgcttttg taggccagcc aggactatgt agtgagatcc taccttaaaa 900 <210> 163 <211> 800 <212> DNA <213> Rattus rattus <400> 163 tcttgagaat gacagaagag aattagaatc tctccactta gtaactgaag agacaatgat 60 gacgtgcaga tcttgaagtc agagagcaca agaacagtta atgttttccc ttccttcctt 120 ccttccttcc ttccttcctt ccttccttcc ttccttcttt ctttctttct ggacttggat 180 ttagatctca gacagaagac tagtgagcac cagagcatat cagtagtcct ccgtggctca 240 taatttatga tatacaccaa tgcatgagtt tctcaagtgt ccaaaactcc tctggaatta 300 ttggagtatt tgttaagcat atgagaaaag gatgtgttag tgaagggaga gtgagaatgg 360 ggagaacttg gcgcgttctg tcttcccaag ccttccctgc ctcatctgaa tacaccttct 420 ctattccaag accatcaggg tcgtgtgtcc ttgtgttgcc ttctcttgca ggttaccact 480 gtgagcccta caacaaccct gcagacttct tccttgacgt catcaacgga gattcttcgg 540 ctgtaatgtt aaacagaggg gaacaagacc atgaaggtat atgagtcttg tagattcata 600 cgttggtgtc caattgtttg attgaagccc agtagtgtgt cttattaaag catgcttttg 660 taggccagcc aggactatgt agtgagatcc taccttaaaa caaaaatcgt gggttgggga 720 ttttgctcag tggtagagcg cttgcctaga aagcgcaagg ccctgggttc agtccccagc 780 tccgaaaaaa aagaaccaaa 800 <210> 164 <211> 28 <212> DNA <213> Rattus rattus <400> 164 acagggctga tggccaaaat cacaagag 28 <210> 165 <211> 28 <212> DNA <213> Rattus rattus <400> 165 ttggactgtc agctggtatt tgggcaaa 28 <210> 166 <211> 28 <212> DNA <213> Rattus rattus <400> 166 aggaggggaa gcagggttcc gtggatga 28 <210> 167 <211> 28 <212> DNA <213> Rattus rattus <400> 167 atgctggtgt tcggatacat gacagata 28 <210> 168 <211> 28 <212> DNA <213> Rattus rattus <400> 168 gaagggccca ggttctaaga aaaagcca 28 <210> 169 <211> 28 <212> DNA <213> Rattus rattus <400> 169 tgctggctgg ggtggctgtt atgatcct 28 <210> 170 <211> 28 <212> DNA <213> Rattus rattus <400> 170 ttgctggtga ctgaccttgt tttaaacc 28 <210> 171 <211> 28 <212> DNA <213> Rattus rattus <400> 171 ttgaggcggc catgacaaag gacctgca 28 <210> 172 <211> 28 <212> DNA <213> Rattus rattus <400> 172 atgacgtcaa ggaagaagtc tgcagggt 28 <210> 173 <211> 28 <212> DNA <213> Rattus rattus <400> 173 acggagattc ttcggctgta atgttaaa 28 <210> 174 <211> 29 <212> DNA <213> Rattus rattus <400> 174 ctgtttcttg acaaaacaac actaggctc 29 <175> 175 <211> 25 <212> DNA <213> Rattus rattus <400> 175 gggtcatggg aaagagttta aaatc 25 <210> 176 <211> 20 <212> DNA <213> Rattus rattus <400> 176 catgctgtga agcagatacc 20 <210> 177 <211> 24 <212> DNA <213> Rattus rattus <400> 177 ctgaaaactg aatgagacat ttgc 24 <210> 178 <211> 22 <212> DNA <213> Rattus rattus <400> 178 gccgataaaa gagccatgtt tg 22 <210> 179 <211> 21 <212> DNA <213> Rattus rattus <400> 179 gataaggaga aaagctgcac c 21 <210> 180 <211> 33 <212> DNA <213> Rattus rattus <400> 180 gccatcagcc ctgttcttgg actgtcagct ggt 33 <210> 181 <211> 33 <212> DNA <213> Rattus rattus <400> 181 gccatcagct ctcaaagagg actgtaagaa gct 33 <210> 182 <211> 32 <212> DNA <213> Rattus rattus <400> 182 gccaacagct ctattttgga ctctccgctg ct 32 <210> 183 <211> 33 <212> DNA <213> Rattus rattus <400> 183 gccatcagct ctataacatg actgtctact gat 33 <210> 184 <211> 33 <212> DNA <213> Rattus rattus <400> 184 gtcaccaacc ctctccatgg aaagtcagct ggt 33 <210> 185 <211> 33 <212> DNA <213> Rattus rattus <400> 185 gacttcagcc ctgactgctg actggcaact ggt 33 <210> 186 <211> 33 <212> DNA <213> Rattus rattus <400> 186 gccagcagcc ctttccttga agggtcagct agt 33 <210> 187 <211> 33 <212> DNA <213> Rattus rattus <400> 187 gccatcagcc cgctcatgag cctgtttgct ggt 33 <210> 188 <211> 32 <212> DNA <213> Rattus rattus <400> 188 gccagcagcc ctgcctgggc ctggcagtta gt 32 <210> 189 <211> 33 <212> DNA <213> Rattus rattus <400> 189 gctgtcagcc ctcttattgg attgtcatct gct 33 <210> 190 <211> 33 <212> DNA <213> Rattus rattus <400> 190 gccctcagcc ctcgagatgc tctgtcatca ggt 33 <210> 191 <211> 32 <212> DNA <213> Rattus rattus <400> 191 gccatcagcc cactgtggga ctttgagtgg gt 32 <210> 192 <211> 32 <212> DNA <213> Rattus rattus <400> 192 cacctgagcc cgcaactgga ctgtcagctg gt 32 <210> 193 <211> 33 <212> DNA <213> Rattus rattus <400> 193 cccatcaaca ctaacacagg actggcatct ggt 33 <210> 194 <211> 32 <212> DNA <213> Rattus rattus <400> 194 tccagcagct ctgtctggga ctgttagatg gt 32 <210> 195 <211> 32 <212> DNA <213> Rattus rattus <400> 195 cccaacagcc ctattaggga caggcacctg gt 32 <210> 196 <211> 32 <212> DNA <213> Rattus rattus <400> 196 gccatcaggc atggagagga cattcagctg ga 32 <210> 197 <211> 32 <212> DNA <213> Rattus rattus <400> 197 gccatcgccc ctggcctgga tggtctgctg gt 32 <210> 198 <211> 33 <212> DNA <213> Rattus rattus <400> 198 cccatcagca ctgtggacgg tcggtcatct ggt 33 <210> 199 <211> 33 <212> DNA <213> Rattus rattus <400> 199 gccaggagcc tttcaagtgg actgtcagtt gct 33 <210> 200 <211> 33 <212> DNA <213> Rattus rattus <400> 200 gccagcagct gtgactgtgg gctatcagct ggt 33 <210> 201 <211> 28 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 201 Asp Arg Ser His Leu Ser Arg Thr Ser Gly Asn Leu Thr Arg Gln Ser 1 5 10 15 Ser Asp Leu Ser Arg Arg Ser Asp His Leu Thr Gln             20 25 <210> 202 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 202 Thr Ser Gly His Leu Ser Arg Gln Ser Ser Asp Leu Ser Arg Gln Ser 1 5 10 15 Ala Asp Arg Thr Lys Arg Ser Asp Val Leu Ser Glu Gln Ser Gly His             20 25 30 Leu Ser Arg         35 <210> 203 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 203 Thr Ser Gly His Leu Ser Arg Arg Ser Asp Asn Leu Ser Glu Arg Asn 1 5 10 15 Ala Asn Arg Ile Thr Arg Ser Asp His Leu Ser Glu Arg Asn Asp Asn             20 25 30 Arg Lys Arg         35 <210> 204 <211> 28 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 204 Arg Ser Asp His Leu Ser Glu Asn Asn Ser Ser Arg Thr Arg Thr Ser 1 5 10 15 Gly His Leu Ser Arg Gln Ser Ser Asp Leu Arg Arg             20 25 <210> 205 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 205 Thr Asn Gly Gln Leu Lys Glu Thr Ser Ser Ser Leu Ser Arg Arg Ser 1 5 10 15 Asp Asn Leu Ser Glu Ala Ser Lys Thr Arg Lys Asn Arg Ser Asp His             20 25 30 Leu Thr Gln         35 <210> 206 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 206 Asp Arg Ser Ala Leu Ser Arg Arg Ser Asp Ala Leu Ala Arg Arg Ser 1 5 10 15 Asp His Leu Ser Arg Gln Ser Ser Asp Leu Arg Arg Arg Ser Asp Val             20 25 30 Leu ser glu         35 <210> 207 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 207 Thr Ser Asp His Leu Thr Glu Asp Arg Ser Asn Leu Ser Arg Asp Arg 1 5 10 15 Ser Asn Leu Thr Arg Thr Ser Gly His Leu Ser Arg Gln Ser Ser Asp             20 25 30 Leu Arg Arg         35 <210> 208 <211> 42 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 208 Arg Ser Asp Asn Leu Ser Val Gln Asn Ala Thr Arg Ile Asn Arg Ser 1 5 10 15 Asp Ala Leu Ser Thr Asp Arg Ser Thr Arg Thr Lys Arg Ser Asp Asp             20 25 30 Leu Ser Arg Arg Asn Asp Asn Arg Thr Lys         35 40 <210> 209 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 209 Gln Ser Gly Asn Leu Ala Arg Gln Ser Gly Asn Leu Ala Arg Arg Ser 1 5 10 15 Asp Ser Leu Ser Thr Asp Asn Ala Ser Arg Ile Arg Asp Arg Ser Asn             20 25 30 Leu Thr Arg         35 <210> 210 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 210 Gln Ser Ser Asp Leu Ser Arg Arg Asn Asp Asp Arg Lys Lys Arg Arg 1 5 10 15 Glu Asp Leu Ile Thr Thr Ser Ser Asn Leu Ser Arg Gln Ser Gly His             20 25 30 Leu Ser Arg         35 <210> 211 <211> 400 <212> DNA <213> Rattus rattus <400> 211 tcgaagagct gctggatgag gaccagaagg ttcggcccaa cgaagaaaac cataaggacg 60 cggacttgta cacttcccgg gtgatgctca gcagtcaagt gcctttggag cctcctctgc 120 tctttctgct ggaggaatac aaaaattacc tggatgccgc aaacatgtct atgagggttc 180 ggcgccactc cgaccccgcc cgccgtgggg agctgagcgt gtgtgacagt attagcgagt 240 gggtcacagc ggcagataaa aagactgcag tggacatgtc cggtgggacg gtcacagtcc 300 tggagaaagt cccggtatca aaaggccaac tgaagcaata tttctacgag accaagtgta 360 atcccatggg ttacacgaag gaaggctgca ggggcataga 400 <210> 212 <211> 300 <212> DNA <213> Rattus rattus <400> 212 gcctttggag cctcctctgc tctttctgct ggaggaatac aaaaattacc tggatgccgc 60 aaacatgtct atgagggttc ggcgccactc cgaccccgcc cgccgtgggg agctgagcgt 120 gtgtgacagt attagcgagt gggtcacagc ggcagataaa aagactgcag tggacatgtc 180 cggtgggacg gtcacagtcc tggagaaagt cccggtatca aaaggccaac tgaagcaata 240 tttctacgag accaagtgta atcccatggg ttacacgaag gaaggctgca ggggcataga 300 <210> 213 <211> 19 <212> DNA <213> Rattus rattus <400> 213 gccagcaccc ctgacgcag 19 <210> 214 <211> 17 <212> DNA <213> Rattus rattus <400> 214 tcgacaagta cctggag 17 <210> 215 <211> 28 <212> DNA <213> Rattus rattus <400> 215 aagcggttca gggcctgctc ccagggtt 28 <210> 216 <211> 28 <212> DNA <213> Rattus rattus <400> 216 gggattacct gcgctgggtg cagacgct 28 <210> 217 <211> 28 <212> DNA <213> Rattus rattus <400> 217 cggggtcgga gtggcgccga accctcat 28 <210> 218 <211> 28 <212> DNA <213> Rattus rattus <400> 218 cggggtcgga gtggcgccga accctcat 28 <210> 219 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 219 Arg Ser Asp Ala Leu Ser Val Asp Ser Ser His Arg Thr Arg Arg Ser 1 5 10 15 Asp Asn Leu Ser Glu Thr Ser Gly Ser Leu Thr Arg Arg Ser Asp Asp             20 25 30 Leu Thr Arg         35 <210> 220 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 220 Arg Ser Asp His Leu Ser Arg Gln Ser Ser Asp Leu Arg Arg Arg Ser 1 5 10 15 Asp Val Leu Ser Ala Asp Arg Ser Asn Arg Ile Lys Thr Ser Ser Asn             20 25 30 Leu Ser Arg         35 <210> 221 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 221 Asp Arg Ser Asp Leu Ser Arg Asp Arg Ser His Leu Ala Arg Arg Ser 1 5 10 15 His Asn Leu Ala Arg Arg Ser Asp Asp Leu Ser Lys Arg Ser Ala His             20 25 30 Leu Ser Arg         35 <210> 222 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 222 Arg Ser Asp Asn Leu Ala Arg Gln Ser Ser Asp Leu Arg Arg Arg Ser 1 5 10 15 Ser His Leu Ser Arg Arg Ser Asp Ala Leu Ser Arg Asp Arg Ser Asp             20 25 30 Leu Ser Arg         35 <210> 223 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 223 Arg Ser Asp Ala Leu Ser Val Asp Ser Ser His Arg Thr Arg Arg Ser 1 5 10 15 Asp Asn Leu Ser Glu Thr Ser Gly Ser Leu Thr Arg Arg Ser Asp Asp             20 25 30 Leu Thr Arg         35 <210> 224 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 224 Arg Ser Asp His Leu Ser Arg Gln Ser Ser Asp Leu Arg Arg Arg Ser 1 5 10 15 Asp Val Leu Ser Ala Asp Arg Ser Asn Arg Ile Lys Thr Ser Ser Asn             20 25 30 Leu Ser Arg         35 <210> 225 <211> 200 <212> DNA <213> Rattus rattus <400> 225 tacttcaagg gctggcagcg atgacccaga agccccactt gagggacagc ggaggaccac 60 cgcccaggat agcctgccgg gactagccgt caccaggcgg gactggctga tgcgagagaa 120 agagcaattg caggtgagcg gtatagagtc ttccagagag ggagcggccc tctcttatcc 180 gtgtgagtca gagcagagaa 200 <210> 226 <211> 28 <212> DNA <213> Rattus rattus <400> 226 tagtcccggc aggctatcct gggcggtg 28 <210> 227 <211> 28 <212> DNA <213> Rattus rattus <400> 227 ccgtcaccag gcgggactgg ctgatgcg 28 <210> 228 <211> 28 <212> DNA <213> Rattus rattus <400> 228 cggggtcgga gtggcgccga accctcat 28 <210> 229 <211> 28 <212> DNA <213> Rattus rattus <400> 229 ccgccgtggg gagctgagcg tgtgtgac 28 <210> 230 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 230 Asn Ser Gly Asn Leu Asp Lys Asp Arg Ser His Leu Ser Arg Gln Ser 1 5 10 15 Gly Asp Leu Thr Arg Arg Ser Asp Thr Leu Ser Gln Asp Arg Ser Ala             20 25 30 Arg Thr Arg         35 <210> 231 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 231 Asp Arg Ser Asn Leu Ser Arg Arg Ser Asp Asn Leu Arg Glu Arg Ser 1 5 10 15 Asp His Leu Ser Ala Asp Ser Ser Thr Arg Lys Thr Asp Arg Ser Ser             20 25 30 Arg Lys Arg         35 <210> 232 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 232 Asp Arg Ser Asp Leu Ser Arg Asp Arg Ser His Leu Ala Arg Arg Ser 1 5 10 15 His Asn Leu Ala Arg Arg Ser Asp Asp Leu Ser Lys Arg Ser Ala His             20 25 30 Leu Ser Arg         35 <210> 233 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 233 Arg Ser Asp Asn Leu Ala Arg Gln Ser Ser Asp Leu Arg Arg Arg Ser 1 5 10 15 Ser His Leu Ser Arg Arg Ser Asp Ala Leu Ser Arg Asp Arg Ser Asp             20 25 30 Leu Ser Arg         35 <210> 234 <211> 28 <212> DNA <213> Rattus rattus <400> 234 atctggagga agactggaga acaagagc 28 <210> 235 <211> 28 <212> DNA <213> Rattus rattus <400> 235 atattctggt aaggagccgg gcaagagg 28 <210> 236 <211> 28 <212> DNA <213> Rattus rattus <400> 236 atgacgtcaa ggaagaagtc tgcagggt 28 <210> 237 <211> 28 <212> DNA <213> Rattus rattus <400> 237 acggagattc ttcggctgta atgttaaa 28 <210> 238 <211> 20 <212> DNA <213> Rattus rattus <400> 238 ccccagtttg tggtctgcca 20 <210> 239 <211> 18 <212> DNA <213> Rattus rattus <400> 239 gctaaaggtg aagatcta 18 <210> 240 <211> 42 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 240 Gln Ser Gly Asn Leu Ala Arg Gln Ser Gly His Leu Ser Arg Asp Arg 1 5 10 15 Ser Ala Leu Ser Arg Gln Ser Gly Asn Leu Ala Arg Arg Ser Asp Ala             20 25 30 Leu Ser Arg Arg Ser Asp Ala Leu Thr Gln         35 40 <210> 241 <211> 42 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 241 Arg Ser Asp His Leu Ser Glu Thr Ser Ser Asp Arg Thr Lys Arg Ser 1 5 10 15 Asp His Leu Ser Ala Gln Ser Gly Ser Leu Thr Arg Arg Ser Asp Val             20 25 30 Leu Ser Glu His Ser Asn Ala Arg Lys Thr         35 40 <210> 242 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 242 Gln Ser Gly Asn Leu Ala Arg Gln Ser Gly Asn Leu Ala Arg Arg Ser 1 5 10 15 Asp Ser Leu Ser Thr Asp Asn Ala Ser Arg Ile Arg Asp Arg Ser Asn             20 25 30 Leu Thr Arg         35 <210> 243 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 243 Gln Ser Ser Asp Leu Ser Arg Arg Asn Asp Asp Arg Lys Lys Arg Arg 1 5 10 15 Glu Asp Leu Ile Thr Thr Ser Ser Asn Leu Ser Arg Gln Ser Gly His             20 25 30 Leu Ser Arg         35

Claims (20)

How to edit chromosomal sequences, including:
(a) a nucleic acid encoding at least one zinc finger nuclease capable of recognizing a target sequence in a chromosomal sequence and cleaving a cleavage site in the chromosome sequence and either (i) or (ii) Selectively into the containing cell,
(i) at least one donor polynucleotide comprising an integrating donor sequence, an upstream sequence, and a downstream sequence, wherein the donor sequence is on the upstream and downstream sequence, wherein the upstream and downstream sequence is on one side of the cleavage site Share substantial sequence identity with, or
(ii) at least one exchange polynucleotide comprising an exchange sequence substantially identical to a portion of the chromosomal sequence at the cleavage site, further comprising at least one nucleotide change;
(b) incubating the cells to allow for expression of the zinc finger nuclease so that the zinc finger nuclease introduces a double-stranded break into the chromosome sequence at the cleavage site, where the double-stranded break is
(i) recovered by a non-homologous end-binding repair process such that a mutation is introduced into the chromosomal sequence or, optionally,
(ii) a method for editing a chromosome sequence, characterized by a homology-directed repair process, wherein the donor sequence is integrated into the chromosomal sequence or the exchange sequence is exchanged with a portion of the chromosome sequence. The method of claim 1, wherein the cell is an embryo. The method of claim 2, wherein the embryo is one cell embryo. The method of claim 1, wherein the nucleic acid encoding one or more zinc finger nucleases is introduced into a cell. The method of claim 1, wherein the nucleic acid encoding the zinc finger nuclease is RNA. The method of claim 5, wherein the RNA is capped. The method of claim 5, wherein the RNA is polyadenylated. The method of claim 1, wherein at least one polynucleotide selected from a donor polynucleotide, an exchange polynucleotide, or any combination thereof is introduced into a cell. The method of claim 1, wherein the cells are cultured cells, primary cells, or stem cells. The method of claim 1, wherein the cell is a human cell, mammalian cell, vertebrate cell, invertebrate cell, or fungal cell. Non-human animals created by the method according to claim 1. The non-human animal of claim 11, wherein the animal is a rodent. The non-human animal of claim 11, wherein the animal is a livestock. The non-human animal of claim 11, wherein the animal is a companion animal. Cells created using the method according to claim 1. The cell of claim 15, wherein the cell is an embryo. The cell of claim 16, wherein the embryo is one cell embryo. The cell of claim 15, wherein the cell is a cultured cell, primary cell, or stem cell. A embryo comprising a nucleic acid encoding at least one zinc finger nuclease capable of recognizing a target sequence in a chromosomal sequence and cleaving a cleavage site in the chromosome sequence and optionally one of the following (i) or (ii): emrbyo);
(i) at least one donor polynucleotide comprising an integrating donor sequence, an upstream sequence, and a downstream sequence, wherein the donor sequence is on the upstream and downstream sequence, wherein the upstream and downstream sequence is on one side of the cleavage site Share substantial sequence identity with, or
(ii) at least one exchange polynucleotide comprising an exchange sequence substantially identical to a portion of the chromosomal sequence at the cleavage site, further comprising at least one nucleotide change. The embryo of claim 19, wherein the embryo is one cell embryo.

Images