KR20230069157A - Recombinant adeno-associated virus (rAAV) encoding GJB2 and uses thereof - Google Patents

Abstract

The present disclosure provides, at least in part, non-syndromic hearing by delivering gap junction beta 2 (GJB2) protein to inner ear cells that normally express GJB2 (eg, fibrocytes and supporting cells of the organ of Corti and nearby areas). Compositions (eg, isolated nucleic acids and rAAV) and methods for treating hearing loss and deafness (DFNB1). Isolated nucleic acids of the present disclosure may comprise a gap junction beta 2 (GJB2) gene regulatory element (GRE) (e.g., a GJB2 enhancer, a GJB2 promoter, a GJB2 5' UTR, and/or a GJB2 3' UTR), and a GJB2 protein. An expression cassette comprising a nucleotide sequence that encodes.

Description

Recombinant adeno-associated virus (rAAV) encoding GJB2 and uses thereof

related application

This application claims under 35 U.S.C. § 119(e), the U.S. provisional application filed on March 16, 2021, U.S.S.N. 63/161,619, and the U.S. provisional application filed on September 14, 2020, U.S.S.N. 63/078,233, each of which is incorporated herein by reference.

federally funded research

This invention was made with government support under DA048787 awarded by the National Institutes of Health. The government has certain rights in this invention.

background art

Loss of gap junction beta 2 (GJB2) expression in the inner ear underlies a disorder termed non-syndromic hearing loss and deafness (DFNB1), characterized by recessive, mild to severe sensorineural hearing impairment. Many of these patients are born with severe hearing loss, which is probably irreversible even at birth. Two-thirds have some residual hearing at birth, and most of these lose hearing over the next few years. Thus, these patients are potential candidates for treatment of DFNB1. Previous gene replacement therapy of GJB2 did not rescue hearing, although genetic addition of the GJB2 gene rescued cell survival and gap junction networks. No effective GJB2 gene replacement therapy for hearing rescue has been developed.

summary

The present disclosure relates, at least in part, to an isolated nucleic acid comprising a gap junction beta 2 (GJB2) gene regulatory element (GRE) and an expression cassette comprising a nucleotide sequence encoding a GJB2 protein. In some embodiments, the expression cassette further comprises a promoter (eg, GJB2 promoter). In some embodiments, the expression cassette is flanked by two adeno-associated virus (AAV) inverted terminal repeats (ITRs). The presence of a native GJB2 regulatory element (GRE) in the isolated nucleic acid prevents coexistent GJB2 gene expression in the auris interna that is toxic and impairs hearing. Thus, in some embodiments, the isolated nucleic acids described herein are capable of expressing the GJB2 protein in inner ear cells that normally express the GJB2 gene (e.g., connective tissue cells of the cochlea and supporting cells of the organ of Corti and nearby regions); , but not in cells that do not normally express GJB2 (eg, hair cells and spiral ganglion neurons).

In some aspects, the disclosure provides an isolated nucleic acid comprising an expression cassette, wherein the expression cassette comprises a gap junction beta 2 (GJB2) gene regulatory element (GRE), and a nucleotide sequence encoding a GJB2 protein.

In some embodiments, the GJB2 protein is a human GJB2 protein. In some embodiments, the GJB2 protein comprises an amino acid sequence that is at least 80% identical to SEQ ID NO:1. In some embodiments, the nucleotide sequence encoding human GJB2 protein comprises a nucleotide sequence that is at least 80% identical to SEQ ID NO:2.

In some embodiments, the expression cassette further comprises a promoter operably linked to the nucleotide sequence encoding the GJB2 protein. In some embodiments, the promoter is the human GJB2 promoter. In some embodiments, the promoter comprises 500 nucleotides of a human GJB2 promoter. In some embodiments, the promoter comprises a nucleic acid sequence that is at least 80% identical to SEQ ID NO:5. In some embodiments, the promoter comprises a nucleic acid sequence that is at least 80% identical to SEQ ID NO:102. In some embodiments, the promoter comprises a nucleic acid sequence that is 100% identical to SEQ ID NO:102.

In some embodiments, the promoter is a human GJB2 basal promoter. In some embodiments, the human GJB2 basal promoter comprises a nucleic acid sequence that is at least 80% identical to SEQ ID NO:47.

In some embodiments, an expression cassette comprises a nucleotide sequence encoding a 5' UTR. In some embodiments, a 5' UTR is located between the promoter and the nucleotide sequence encoding the GJB2 protein. In some embodiments, the 5' UTR comprises about 300 nucleotides of the human GJB2 gene 5' UTR. In some embodiments, the promoter and 5' UTR comprise a nucleotide sequence that is at least 80% identical to SEQ ID NO:30.

In some embodiments, a GJB2 gene regulatory element comprises an enhancer. In some embodiments, an enhancer is located 5' to a promoter. In some embodiments, the enhancer is normally within approximately 200 kb upstream or downstream of the GJB2 gene. In some embodiments, the enhancer is typically within approximately 95 kb of the GJB2 gene. In some embodiments, the GJB2 GRE includes one or more enhancers. In some embodiments, one or more enhancers are the same enhancer or different enhancers. In some embodiments, the enhancer comprises a nucleotide sequence that is at least 80% identical to the nucleotide sequence set forth in any one of SEQ ID NOs: 6-29 or a fragment thereof. In some embodiments, the enhancer comprises a nucleotide sequence that is at least 80% identical to the GJB2 enhancer set forth in any of SEQ ID NOs: 37-46 and 55-60. In some embodiments, the enhancer comprises a nucleotide sequence that is at least 80% identical to SEQ ID NO:42.

In some aspects, the disclosure also provides an isolated nucleic acid comprising an expression cassette comprising a gap junction beta 2 (GJB2) promoter and a nucleotide sequence encoding a GJB2 protein.

In some embodiments, the GJB2 promoter comprises a nucleic acid sequence that is at least 80% identical to SEQ ID NO:102. In some embodiments, the GJB2 promoter comprises a nucleic acid sequence that is 100% identical to SEQ ID NO:102.

In some embodiments, the expression cassette further comprises a 5' UTR. In some embodiments, a 5' UTR comprises a first nucleic acid sequence that is at least 80% identical to SEQ ID NO: 103; and/or a second nucleic acid sequence that is at least 80% identical to SEQ ID NO:104. In some embodiments, the expression cassette further comprises a 5' UTR. In some embodiments, a 5' UTR is a first nucleic acid sequence that is 100% identical to SEQ ID NO: 103; and/or a second nucleic acid sequence that is 100% identical to SEQ ID NO:104.

In some embodiments, the isolated nucleic acid comprises a nucleic acid sequence that is at least 80% identical to SEQ ID NO:105. In some embodiments, the isolated nucleic acid comprises a nucleic acid sequence that is 100% identical to SEQ ID NO:105.

In some embodiments, the isolated nucleic acid is capable of expressing GJB2 in cells that normally express the GJB2 gene. In some embodiments, the isolated nucleic acid is capable of expressing GJB2 in cochlear connective tissue cells and supporting cells of the organ of Corti. In some embodiments, the supporting cells of the organ of Corti are pillar cells, diter cells, Hensen cells, Claudius cells, internal phalanx cells, and border cells. In some embodiments, the cochlear connective tissue cells are strial intermediate cells, fibrocytes of the lateral wall and suprastrial zone, basal cells of stria vascularis, fibrocytes in spiral ligaments, Fibrous cells at the edge of the spiral plate, mesenchymal cells lining the bony otic capsule facing the scala vestibuli, and supralimbal dark cells.

In some embodiments, the expression cassette is flanked by two adeno-associated virus inverted terminal repeats (ITRs). In some embodiments, the AAV ITR is from a serotype selected from the group consisting of AAV1 ITR, AAV2 ITR, AAV3 ITR, AAV4 ITR, AAV5 ITR, and AAV6 ITR. In some embodiments, the AAV ITR is an AAV2 ITR.

In some embodiments, an expression cassette comprises a 5' ITR having a nucleotide sequence that is at least 80% identical to SEQ ID NO: 106; and/or a 3' ITR having a nucleotide sequence that is at least 80% identical to SEQ ID NO: 107. In some embodiments, an expression cassette comprises a 5' ITR having a nucleotide sequence that is 100% identical to SEQ ID NO: 106; and/or a 3' ITR with 100% identical nucleotide sequence to SEQ ID NO: 107.

In some embodiments, the expression cassette further comprises a Woodchuck Hepatitis Virus (WHP) post-transcriptional regulatory element (WPRE) 3' to the nucleotide sequence encoding the GJB2 protein.

In some embodiments, the WPRE comprises a nucleotide sequence that is at least 80% identical to SEQ ID NO:108. In some embodiments, the WPRE comprises a nucleotide sequence that is 100% identical to SEQ ID NO:108.

In some embodiments, the expression cassette further comprises a nucleotide sequence encoding a 3' UTR located 5' of the WPRE. In some embodiments, the 3' UTR is the GJB2 exon 2 3' UTR. In some embodiments, the GJB2 exon 2 3' UTR comprises a nucleotide sequence that is at least 80% identical to SEQ ID NO:32.

In some embodiments, the expression cassette further comprises one or more miRNA binding sites located in the 3' UTR. In some embodiments, the miRNA binding site is a neuron-associated miRNA binding site. In some embodiments, the neuron-associated miRNA is miR-124, miR-127, miR-129, miR-129*, miR-136, miR-136*, miR-137, miR-154, miR-300-3p, miR-323, miR-329, miR-341, miR-369-5p, miR-376a, miR-376b-3p, miR-376c, miR-379, miR-382, miR-382*, miR-410, miR -411, miR-433, miR-434, miR-495, miR-541, miR-543*, miR-551b, miR-143, miR-449a, miR-219-2-3p, miR-126, miR- 126*, miR-141, miR-142-3p, miR-142-5p, miR-146a, miR-150, miR-200c and miR-223. In some embodiments, the neuron-associated miRNA is miR-124. In some embodiments, the miRNA binding site is a cochlear hair cell-associated miRNA binding site. In some embodiments, the cochlear hair cell-associated miRNA binding site is selected from miR-124, miR-96, miR-182, and miR-183.

In some embodiments, the expression cassette further comprises a poly A signal. In some embodiments the poly A signal is a bovine growth hormone poly A signal.

In some embodiments, the poly A signal comprises a nucleotide sequence that is at least 80% identical to SEQ ID NO:109. In some embodiments, the poly A signal comprises a nucleotide sequence that is 100% identical to SEQ ID NO:109.

In some aspects, the disclosure also provides an isolated nucleic acid comprising a nucleotide sequence that is 100% identical to SEQ ID NO: 110 or 111. In some aspects, the disclosure also provides an isolated nucleic acid comprising a nucleotide sequence that is at least 80% identical to SEQ ID NO: 110 or 111.

In some aspects, the disclosure also provides vectors comprising an isolated nucleic acid as described herein. In some embodiments, the vector is a plasmid or viral vector. In some embodiments, the viral vector is an AAV vector.

In some aspects, the disclosure also provides a 5' to 3': (a) AAV 5' ITR; (b) a GJB2 promoter, or an underlying GJB2 promoter sequence thereof; (c) GJB2 5'UTR (eg, GJB2 exon 1 5'UTR); (d) a nucleotide sequence encoding the GJB2 protein; (e) GJB2 3' UTR (eg, GJB2 exon 2 3' UTR) (optionally the GJB2 3' UTR comprises one or more miR-124 binding sites); (f) bovine growth hormone poly A signal; and (g) an AAV 3' ITR.

In some aspects, the disclosure also provides a 5' to 3': (a) AAV 5' ITR; (b) a GJB2 enhancer; (c) a GJB2 promoter, or an underlying GJB2 promoter sequence thereof; (d) GJB2 5'UTR (eg, GJB2 exon 1 5'UTR); (e) a nucleotide sequence encoding the GJB2 protein; (f) a GJB2 3' UTR (eg, a GJB2 exon 2 3' UTR) (optionally the GJB2 3' UTR comprises one or more miR-124 binding sites); (g) bovine growth hormone poly A signal; and (h) an AAV 3' ITR.

In some embodiments, the vector comprises a nucleotide sequence that is at least 80% identical to any one of SEQ ID NOs: 36, 48-62, and 61-83. In some embodiments, the vector is an AAV vector. In some embodiments, the vector is capable of expressing the GJB2 gene in cells that normally express GJB2.

In some aspects, the disclosure also relates to (i) a capsid protein; and (ii) a recombinant adeno-associated virus (rAAV) comprising an isolated nucleic acid described herein.

In some aspects, the disclosure also relates to (i) a capsid protein; and (ii) (a) AAV 5' ITR (eg, GJB2 exon 1 5' UTR); (b) a GJB2 promoter, or an underlying GJB2 promoter sequence thereof; (c) a GJB2 5' UTR (eg, a GJB2 exon 2 3' UTR) (optionally, the GJB2 exon 2 3' UTR comprises one or more miR-124 binding sites); (d) a nucleotide sequence encoding the GJB2 protein; (e) GJB2 3'UTR; (f) bovine growth hormone poly A signal; and (g) an isolated nucleic acid comprising an AAV 3' ITR.

In some aspects, the disclosure also relates to (i) a capsid protein; and (ii) (a) AAV 5' ITR; (b) a GJB2 enhancer; (c) a GJB2 promoter, or an underlying GJB2 promoter sequence thereof; (d) GJB2 5'UTR (eg, GJB2 exon 1 5'UTR); (e) a nucleotide sequence encoding the GJB2 protein; (f) a GJB2 3' UTR (eg, a GJB2 exon 2 3' UTR) (optionally the GJB2 exon 2 3' UTR comprises one or more miR-124 binding sites); (g) bovine growth hormone poly A signal; and (h) an isolated nucleic acid comprising an AAV 3' ITR.

In some embodiments, the rAAV has tropism for a subset of cochlear cells that normally express the GJB2 gene. In some embodiments, the rAAV is tropic for cells of the inner ear.

In some embodiments, the capsid protein is an AAV1 capsid protein, an AAV2 capsid protein, an AAV5 capsid protein, an AAV7 capsid protein, an AAV8 capsid protein, an AAV9 capsid protein, an AAV-S capsid protein, or a variant thereof. In some embodiments, the AAV capsid is AAV9.PHP.B, AAV9.PHP.eB, or AAV-S. In some embodiments, the AAV capsid protein is AAV-S.

In some aspects, the disclosure provides a host cell comprising an isolated nucleic acid, vector or rAAV as described herein.

In some aspects, the disclosure provides a pharmaceutical composition comprising an isolated nucleic acid, vector, rAAV or host cell as described herein. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

In some aspects, the disclosure provides specificity for GJB2 in cells that normally express the GJB2 gene in a subject, comprising administering to the subject an effective amount of an isolated nucleic acid, vector, rAAV, host cell, or pharmaceutical composition as described herein. It provides a way to express it as an enemy.

In some aspects, the disclosure provides treatment for non-syndromic deafness and deafness (DFNB1) in a subject, comprising administering to the subject an effective amount of an isolated nucleic acid, vector, rAAV, host cell, or pharmaceutical composition as described herein. provides a way to treat

A method of treating a GJB2-associated disease in a subject in need thereof comprising administering to the subject an effective amount of an isolated nucleic acid, vector, rAAV, host cell or pharmaceutical composition as described herein. .

In some embodiments, the subject is a mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal is a non-human mammal. In some embodiments, the non-human mammal is a mouse, rat, or non-human primate.

In some embodiments, hearing loss is associated with a mutation in the GJB2 gene. In some embodiments, the mutation in the GJB2 gene is a point mutation, missense mutation, nonsense mutation, splice-altering mutation, synonymous mutation, deletion, insertion, or combination thereof. In some embodiments, the subject is a human; The mutation is a mutation or combination thereof listed in Table 2 (below). In some embodiments, the mutation is NM_004004.6 c.101T>C (GRCh37/hg19 Chr13:20763620A>G) or c.35delG (GRCh37/hg19 chr13:20763685AC>A).

In some embodiments, the administration results in expression of the GJB2 protein in cochlear connective tissue cells and supporting cells of the organ of Corti and proximal region. In some embodiments, the supporting cells of the organ of Corti are pillar cells, diter cells, Hensen cells, Claudius cells, internal phalanx cells, and border cells. In some embodiments, the connective tissue cells are vascular interstitial cells, fibrocytes in the region of the lateral wall and supravascular striatum, basal cells in the vascular progenitors, fibrocytes in the spiral ligament, fibrocytes in the margins of the spiral plate, and those facing the vestibular system. mesenchymal cells lining the labyrinth bone cyst, and supermarginal dark cells.

In some embodiments, administration is via injection. In some embodiments, the injection is via the round window membrane of the cochlea, into the scala media of the cochlea, into the scala tympani of the cochlea, into the vestibular system of the cochlea, into the semicircular canals of the inner ear, or into the saccule of the inner ear. ) or in the utricle.

The details of one or more embodiments of the invention are set forth in the description below. Other features or advantages of the present invention will be apparent from the following drawings and detailed description of specific embodiments and also from the appended claims.

The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate certain embodiments and together with the written description serve to provide non-limiting examples of certain aspects of the compositions and methods disclosed herein.
1A-1C show the structure and expression distribution of GJB2 and how loss of GJB2 expression affects patients. Figure 1a shows the structure of the GJB2 hemichannel. The six subunits of the GJB2 protein, each with four transmembrane helices, assemble at the face of the membrane to form a large central pore. GJB2 hemichannels from adjacent cells bind to create channels from the cytoplasm of one cell to the cytoplasm of another cell. Gap junctions are formed by hundreds or thousands of channels packed in synaptic plaques. 1b-1c shows networks of fibroblasts and epithelial cells expressing GJB2 ( FIG. 1b ), and inner and outer hair cells without GJB2 expression ( FIG. 1c ). 1D shows that many patients carrying GJB2 mutation(s) with some residual hearing at birth develop additional hearing loss over the next 3-6 years. The window for treatment exists for 1-5 years after birth, and ~10,000 affected children aged 0-5 years in the United States can be treated.
2A-2B show the delivery of viral vectors to the cochlea by direct injection through the round window membrane (RWM), and the deleterious effects of mixed expression of Gjb2 on the hearing of the injected mice. 2A is a cartoon illustrating round window membrane (RWM) injection. 2B shows that mixed expression of Gjb2 in the inner ear impaired hearing in wild-type mice.
3A-3N show the identification of cis-regulatory elements (eg, enhancers) critical for GJB2 expression in a subset of cochlear cells that naturally express the GJB2 gene. 3A-3B show that certain patients with GJB2-associated hearing loss have GJB2 coding sequence mutations and upstream deletions that occur in trans, suggesting that some patients carry mutation(s) in cis-regulatory elements. and the region flanking the CRYL1 gene is particularly important for the identification of these cis-regulatory elements. 3C (top) shows the identification of gene regulatory elements (GREs) in the UCSC Genome Browser View of ATAC-Seqs from mouse cochleas at developmental stages P2, P5 and P8, spanning ~300 kb in the mouse Gjb2 gene region. Shaded regions indicate regions containing putative GREs. The X-axis is the genomic region on chr14 in the mouse genome. The Y-axis is the number of reads from ATAC-Seq that align to specific regions in the genome. Light shading indicates regions of open chromatin that are characteristic of regions of transcriptional activity enriched in read pile-up, suggesting higher activity in these regions. Regions A and B represent transcriptionally active sequences within mouse Gjb2 itself. The region CM is a transcriptionally active region around Gjb2 that may be part of a cis-regulatory network. 3C (bottom) shows transcriptional active regions within and around light shaded regions detected as specific GREs (dark highlights). Note that GRE was first identified in mice. The human GJB2 GRE was confirmed in silico by modeling the mouse GRE. Human GJB2 GRE was tested in subsequent experiments. Figures 3D-3E show various vector designs with and without incorporation of the GJB2 promoter and/or enhancer. These vectors were tested in the mouse inner ear. The C15 vector, a GJB2 enhancer vector, contains a 500 bp human GJB2 promoter, a human GJB2 5' UTR followed by a coding sequence for GFP and a human GJB2 3' UTR, and three human GJB2 identical to the mouse sequence identified by ATAC-seq. splicing enhancers Vector c20-23 was constructed to test the toxicity of mixed expression of Gjb2 in mice. Vector c20 was lethal at doses exceeding 2×10 ⁹ genome copies. Figure 3f shows the segment of the mouse cochlea from the lateral wall (top) to the interdental cells (bottom). Cells transduced with the AAV9-PHP.B-C15 vector and expressing the GFP marker gene under the Gjb2 enhancer are shown in the left panel. Cells normally expressing GJB2 are shown in the middle panel. In the right panel, IHC and OHC (indicated) are also identified by labeling actin with fluorescent phalloidin. The expression pattern of GFP induced by the c15 construct is consistent with native Gjb2 expression reported by Kikuchi et al., 1995 using the same antibody against GJB2. In particular, c15 does not induce GFP expression in hair cells. 3G shows the expression of Gjb2 in inner hair cells induced by construct c20. A 3D reconstruction of the organ of Corti (including outer and inner hair cells) in an uninjected mouse cochlea is shown in the top panel. GJB2-containing gap junctions in feeder cells were labeled with an antibody against the GJB2 protein. Hair cells do not form gap junctions. Vector c20 with a hybrid promoter drives GJB2 expression in inner hair cells and other cell types (see lower panel). 3H shows that mixed Gjb2 expression impairs hearing in wild-type mice, but targeted expression rescues hearing in Gjb2 knockout mice. However, based on preliminary results from ATAC-Seq, the C70 construct containing the GJB2 promoter/enhancer was able to rescue hearing by 15-20 dB and did not impair hearing in wild type. 3I-3L show maps of c70 vector plasmids encoding mouse GJB2 or human GJB2 with or without an HA tag. 3M shows a schematic of vector c.70 encoding mouse GJB2 or human GJB2 with or without an HA tag. Figure 3n shows additional vectors generated and tested.
4 shows that AAV-S encoding eGFP with a CBA promoter efficiently transduces hair cells, feeder cells, and cells of the lateral wall in both neonatal mice and young NHP cochleas.
5A-5V show vector maps of AAV vectors comprising identified GJB2 GREs 1, 2, 3, 4, 5, 7, 8 and 9, respectively. The vector contains a 5' ITR from 5' to 3', a human GJB2 GRE, a GJB2 basal promoter, a GJB2 exon 1 5' UTR, a nucleotide sequence encoding eGFR, and a GJB2 exon 2 3' UTR. Figure 5a shows vector c.81.1 containing human GJB2 GRE1 and encoding human GJB2; Figure 5b shows vector c.81.1 containing human GJB2 GRE1 and encoding mouse GJB2; Figure 5c shows vector c.81.2 containing human GJB2 GRE2 and encoding eGFP; Figure 5d shows vector c.81.2 containing human GJB2 GRE2 and encoding human GJB2; Figure 5e shows vector c.81.2 containing human GJB2 GRE2 and encoding mouse GJB2; 5F shows vector c.81.3 containing human GJB2 GRE3 and encoding eGFP; Figure 5g shows vector c.81.3 containing human GJB2 GRE3 and encoding human GJB2; Figure 5h shows vector c.81.3 containing human GJB2 GRE3 and encoding mouse GJB2; Figure 5i shows vector c.81.4 containing human GJB2 GRE4 and encoding human GJB2; Figure 5j shows vector c.81.4 containing human GJB2 GRE4 and encoding mouse GJB2; Figure 5K shows vector c.81.5 containing human GJB2 GRE5 and encoding eGFP; 5L shows vector c.81.5 containing human GJB2 GRE5 and encoding human GJB2; 5M shows vector c.81.5 containing human GJB2 GRE5 and encoding mouse GJB2; Figure 5n shows vector c.81.7 containing human GJB2 GRE7 and encoding eGFP; Figure 5O shows vector c.81.7 containing human GJB2 GRE7 and encoding human GJB2; Figure 5P shows vector c.81.7 containing human GJB2 GRE7 and encoding mouse GJB2; Figure 5q shows vector c.81.8 containing human GJB2 GRE8 and encoding human GJB2; 5R shows vector c.81.8 containing human GJB2 GRE8 and encoding mouse GJB2; Figure 5s shows vector c.81.9 containing human GJB2 GRE9 and encoding eGFP; Figure 5t shows vector c.81.9 containing human GJB2 GRE9 and encoding human GJB2; 5U shows vector c.81.9 containing human GJB2 GRE9 and encoding mouse GJB2. 5V shows schematics of c81.2, c81.3, c81.5, c81.7 and c81.9 encoding eGFP, mouse GJB2 and human GJB2 as described above.
6A-6D show GFP expression by the vector c81.5 in cells of the organ of Corti. 6A shows fluorescence images of GFP expressing cells, including various supporting cells within and medial to the organ of Corti. 6B shows antibody labeling of endogenous GJB2 in the region of the organ of Corti. Gjb2 expression largely overlapped with that of exogenous GFP. 6C is an overlay of FIGS. 6A and 6B including a third staining of actin showing stereocilia of hair cells. GFP was not expressed in hair cells. 6D shows frozen section immunofluorescence images of GFP and MYO7A, a protein marker for hair cells. GFP was expressed on various supporting cells in the organ of Corti, but did not overlap with MYO7A expression expressed on hair cells.
7A-7E show the pattern of GFP expression by vector 81.5 in the lateral wall of the cochlea. Figure 7a shows GFP expression in cells containing fibroblasts of the lateral wall. Figure 7b shows antibody labeling of endogenous Gjb2 in the region of the lateral wall. GJB2 expression largely overlaps with exogenous GFP. 7c is an overlay image of FIGS. 7a and 7b. Note that GFP was expressed in cells expressing Gjb2. 7D-7E show frozen section immunofluorescence of GFP (FIG. 7D) and GJB2 (FIG. 7E) in the supporting cells of the organ of Corti and the fibrocytes of the lateral wall.
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate certain embodiments and together with the written description serve to provide non-limiting examples of certain aspects of the compositions and methods disclosed herein.

details

The present disclosure relates, at least in part, to an isolated nucleic acid comprising a gap junction beta 2 (GJB2) gene regulatory element (GRE) and an expression cassette comprising a nucleotide sequence encoding a GJB2 protein. In some embodiments, the expression cassette further comprises a promoter (eg, GJB2 promoter). In some embodiments, the expression cassette is flanked by two adeno-associated virus (AAV) inverted terminal repeats (ITRs). The presence of a native GJB2 regulatory element (GRE) in the isolated nucleic acid prevents coexistent GJB2 gene expression in the auris interna that is toxic and impairs hearing. Thus, in some embodiments, the isolated nucleic acids described herein are capable of expressing the GJB2 protein in inner ear cells that normally express the GJB2 gene (e.g., connective tissue cells of the cochlea and supporting cells of the organ of Corti and nearby regions); , but not in cells that do not normally express the GJB2 gene (eg, hair cells and spiral ganglion neurons).

I. Isolated Nucleic Acids

In some aspects, the present disclosure relates to compositions and methods for treating certain autosomal recessive inherited disorders, such as non-syndromic hearing loss (DFNB1). DFNB1 is caused by a mutation in the GJB2 gene. The GJB2 gene encodes the GJB2 protein, also known as connexin 26. Connexin 26 is a member of the connexin protein family. The GJB2 protein forms channels in clusters called gap junctions, which allow communication between neighboring cells, including cells within the inner ear. Mutations in the GJB2 gene eliminate or change the structure of the gap junction and affect the function or survival of cells required for hearing. Gene replacement therapy (eg, gene therapy with recombinant adeno-associated virus (rAAV)) is attractive due to the small size (less than 700 bp) of the GJB2 gene coding sequence. However, restoration of GJB2 expression in the inner ear using currently available gene therapies does not lead to restoration of hearing.

Thus, the present disclosure provides, in part, that successful GJB2 gene therapy requires GJB2 expression in cells that normally express the GJB2 protein (e.g., connective tissue cells of the cochlea and supporting cells of the organ of Corti and nearby regions) and other It is based on the surprising finding that this is not the case in cells (eg, hair cells and spiral ganglion neurons). Except for sensory cells, most cells within the cochlea are connected via gap junctions, and these gap junctions appear to play a crucial role in cochlear function. The GJB2 protein occurs at gap junctions that connect most cell classes in the cochlea. There are two independent cellular systems, which are bounded by interconnecting gap junctions. The first system, the epithelial gap junction system, consists primarily of the supporting cells of all organs of Corti (e.g. epithelial cells of the inner and outer sulcus, and interdental cells), but also interdental cells at the margins of the spiral plate and Root cells in the spiral ligament. In the inner ear, the sensory area of the cochlea, termed the organ of Corti, contains one row of inner hair cells (IHC) and three to four rows of outer hair cells (OHC) surrounded by various supporting cells. Supporting cells play a critical role in the development, function and maintenance of the inner ear sensory epithelium. Unlike hair cells, which only contact the luminal surface of the epithelium, supporting cells span the entire depth of the epithelium from the basal lamina to the lumen. Supporting cells are connected to each other and to hair cells by tight and adherent synapses; They communicate directly with other supporting cells by gap junctions (see, e.g., Wan et al., Inner ear supporting cells: Rethinking the silent majority, Semin Cell Dev Biol. 2013 May; 24(5): 448-459 ]). Non-limiting examples of supporting cells for the organ of Corti include pillar cells, diter cells, Hensen cells, Claudius cells, inner phalanx cells and border cells. The second system, the connective tissue gap junction system, is composed of vascular interstitial cells, fibrocytes in the lateral wall and supravascular acinar regions, basal cells in the vascular progenitors, fibrocytes in the spiral ligament, fibrocytes at the margin of the spiral plate, and vestibular system. mesenchymal cells lining the labyrinth bone capsule facing the , and dark cells at the marginal upper part. In some embodiments, in the cochlea, GJB2 is expressed in supporting cells (e.g., pillar cells, diter cells, Hensen cells, claudius cells, internal phalanx cells; and border cells), and vascular interstitial cells of the organ of Corti and nearby regions. , fibrocytes in the lateral wall and supravascular region, basal cells in the vascular progenitors, fibrocytes in the spiral ligament, fibrocytes at the margin of the spiral plate, mesenchymal cells lining the labyrinth bone capsule facing the vestibular system, and supermarginal dark color It is normally expressed in connective tissue systems including cells (see, eg, Kikuchi et al. (1995) Gap junctions in the rat cochlea: immunohistochemical and ultrastructural analysis. Anat Embryol (Berl) 191:101-118; and Kikuchi et al., Gap junction systems in the mammalian cochlea, Brain Res Brain Res Rev. 2000 Apr;32(1):163-6. doi: 10.1016/s0165-0173(99)00076-4).

GJB2 expression is important for cochlear function. For example, K ⁺ entering hair cells via transduction channels and released via basal K ⁺ channels is shuttled from the Organ of Corti by the epithelial system and transported by the cytoplasmic system to the vasculature, where it is returned to the endolymph. pumped up In addition, GJB2 is such that even though hair cells do not express Gjb2, mice lacking GJB2 protein in the inner ear have reduced cochlear potential and profound apoptotic loss of hair and supporting cells by postnatal day 30 (P30). Because of this, it plays a role in the development of the cochlea (Cohen-Salmon et al., 2002; Wang et al., 2009; Sun et al., 2009; Crispino et al., 2011; Johnson et al., 2017) . When Gjb2 is deleted after P6, the phenotype is much milder (Chang et al., 2015). However, a long-term requirement for the GJB2 protein remains: hair cell loss occurs after several months as late as P14 despite deletion (Ma et al., 2020). Without wishing to be bound by any particular theory, GJB2's function in the shuttling of K ⁺ may be related to its role in the development of the cochlea: where K ⁺ is not transported away from the hair cell by the gap junction network. , K ⁺ accumulation can depolarize hair cells, causing Ca ²⁺ influx and eventual cell death. Gap junction networks may also be required to transport glucose and nutrients from blood vessels to the sensory epithelium, the absence of which may lead to cell death.

In some embodiments, the present disclosure provides an isolated nucleic acid comprising two adeno-associated virus (AAV) inverted terminal repeats (ITRs) flanked by an expression cassette, wherein the expression cassette comprises a GJB2 gene regulatory element. (GRE) (eg, human GJB2 promoter), and a nucleotide sequence encoding gap junction beta 2 (GJB2) protein. Incorporation of native GJB2 gene regulatory elements and/or tissue/cell-specific promoters within the isolated nucleic acid can be used in cells that normally express it (e.g., connective tissue cells of the cochlea (including fibrocytes) and support of the organ of Corti and nearby regions). cells) to facilitate the expression of the GJB2 gene. Expression cassette, as used herein, refers to a component of a vector DNA that contains a protein coding sequence to be expressed by a cell having the vector and its regulatory sequences. Once delivered to the target cell, the expression cassette directs the cell's machinery to produce RNA and/or protein(s) (eg, the GJB2 protein).

A “nucleic acid” sequence refers to a DNA or RNA sequence. In some embodiments, proteins and nucleic acids of the present disclosure are isolated. As used herein, the term "isolated" means artificially produced. As used herein, the term “isolated” in reference to a nucleic acid means (i) amplified in vitro, for example by polymerase chain reaction (PCR); (ii) produced recombinantly by cloning; (iii) purified, for example by cleavage and gel separation; or (iv) synthesized, for example by chemical synthesis. Isolated nucleic acids are readily manipulable by recombinant DNA techniques well known in the art. Thus, nucleotide sequences contained in vectors for which 5' and 3' restriction sites are known or for which polymerase chain reaction (PCR) primer sequences are disclosed are considered isolated, but nucleic acid sequences that exist in their native state in their natural host. is not Isolated nucleic acids may, but need not be substantially purified. For example, a nucleic acid isolated within a cloning or expression vector is not pure in that it may contain only a small percentage of this material within the cells in which it resides. However, such nucleic acids are readily manipulable by standard techniques known to those skilled in the art, and as such the term is isolated as used herein. As used herein, the term "isolated" in reference to a protein or peptide refers to the protein or peptide being isolated from its natural environment or produced artificially (eg, by chemical synthesis, recombinant DNA techniques, etc.).

In some embodiments, the GJB2 protein is a human GJB2 protein. In some embodiments, the human GJB2 protein is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94% relative to SEQ ID NO:1 %, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical amino acid sequences.

An exemplary human GJB2 protein sequence is set forth in SEQ ID NO:1.

In some embodiments, the expression cassette of the isolated nucleic acid encodes a human GJB2 protein having the amino acid sequence set forth in SEQ ID NO:1. In some embodiments, the nucleotide sequence encoding the human GJB2 protein is at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least relative to SEQ ID NO:2 at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical nucleotide sequences.

An exemplary nucleotide sequence encoding human GJB2 protein is set forth in SEQ ID NO:2.

In some embodiments, the GJB2 protein is a mouse GJB2 protein. In some embodiments, the mouse GJB2 protein is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94% relative to SEQ ID NO:3 %, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical amino acid sequences.

An exemplary mouse GJB2 protein sequence is set forth in SEQ ID NO:3.

In some embodiments, the isolated nucleic acid comprises a nucleotide sequence encoding a mouse GJB2 protein having the amino acid sequence set forth in SEQ ID NO:3. In some embodiments, the nucleotide sequence encoding the mouse GJB2 protein is at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least relative to SEQ ID NO:4 at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical nucleotide sequences.

An exemplary nucleotide sequence encoding the mouse GJB2 protein is set forth in SEQ ID NO:4.

In some embodiments, the nucleotide sequence encoding the GJB2 protein is codon optimized for expression in a host (eg, human). "Codon optimization" as described herein refers to a design process in which codons are altered to codons known to increase the efficiency of maximal protein expression in a desired cell. In some alternatives, codon optimization is described, where codon optimization can be performed using algorithms known to those skilled in the art to generate synthetic gene transcripts optimized for high protein yield. Programs containing algorithms for codon optimization are known to those skilled in the art. Programs may include, for example, OptimumGene™, GeneGPS® algorithms, and the like. Additionally, synthetic codon optimized sequences can be obtained commercially from, for example, Integrated DNA Technologies and other commercially available DNA sequencing services.

As used herein, the term "sequence identity" refers to the amino acids (or nucleic acids) of a reference sequence, e.g., the GJB2 protein and its coding sequence disclosed herein, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent identity. Refers to the percentage of amino acid (or nucleic acid) residues of a candidate sequence that are identical to residues (e.g., gaps may be introduced in one or both of the candidate and reference sequences for optimal alignment, and non-homologous sequences are used for comparison purposes may be overridden for Alterations in the amino acid sequence or nucleic acid coding sequence may be obtained by deletion, addition or substitution of residues in the reference sequence. Alignment for the purpose of determining percent identity can be performed in a variety of ways that are within the skill of the art, for example by using publicly available computer software such as BLAST, BLAST-2, BLAST-P, BLAST-N, BLAST-X, WU - can be achieved using BLAST-2, ALIGN, ALIGN-2, CLUSTAL, or Megaline (DNASTAR) software. One skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms necessary to achieve maximal alignment over the full length of the sequences being compared. For example, a given candidate sequence to, with or against a given reference sequence (alternatively, with a certain percent amino acid (or nucleic acid) sequence identity to, with or against a given reference sequence). The percent amino acid (or nucleic acid) sequence identity of a given candidate sequence that contains or contains the same is calculated as:

100 x (fraction of A/B)

where A is the number of amino acid (or nucleic acid) residues scored identical in the alignment of the candidate sequence and the reference sequence, and B is the total number of amino acid (or nucleic acid) residues in the reference sequence. In particular, a reference sequence aligned for comparison with a candidate sequence indicates that the candidate sequence exhibits, for example, 50% to 100% identity over the full length of the candidate sequence or over a selected portion of contiguous amino acid (or nucleic acid) residues of the candidate sequence. can show The length of a candidate sequence aligned for comparison purposes is at least 30%, such as at least 40%, such as at least 50%, 60%, 70%, 80%, 90%, 95%, 98% of the length of the reference sequence. %, 99%, or 100%. an amino acid (or nucleic acid) whose position in the candidate sequence is identical to the corresponding position in a reference sequence (e.g., a GJB2 amino acid sequence, a coding sequence, a nucleotide sequence for a GJB2 gene regulatory element (GRE), or any other sequence described herein) ) residue, the molecules are identical at that position.

An expression cassette of an isolated nucleic acid sequence described herein (eg, an expression cassette of an isolated nucleic acid comprising a nucleotide sequence encoding a GJB2 protein) is operably linked to a coding sequence (eg, a GJB2 protein coding sequence). A promoter may additionally be included. "Promoter" refers to a DNA sequence recognized by a cell's synthetic machinery or introduced synthetic machinery, which is necessary to initiate transcription of a gene. The phrase “operably linked,” “under control,” or “under transcriptional control” means that the promoter is in the correct position and orientation with respect to the nucleic acid to control RNA polymerase initiation and expression of the gene. means A promoter can be a constitutive promoter, an inducible promoter, or a tissue-specific promoter.

In some embodiments, the promoter is a tissue/cell-specific promoter. A tissue/cell specific promoter as used herein refers to a promoter that is active only in certain cell types. In some embodiments, the promoter used in the isolated nucleic acids described herein is active in cochlear cells that normally express the GJB2 gene. The use of tissue/cell-specific promoters in the isolated nucleic acids described herein can facilitate constitutive transgene expression as well as restrict unwanted transgene (eg, GJB2 gene) expression. In some embodiments, an expression cassette of an isolated nucleic acid includes a tissue/cell specific promoter. In some embodiments, the expression cassette of the isolated nucleic acid includes a GJB2 promoter (eg, a GJB2 promoter for any species in which cell specific GJB2 expression is desired). In some embodiments, the expression cassette of the isolated nucleic acid comprises a human GJB2 promoter. In some embodiments, an expression cassette of an isolated nucleic acid comprises at least 300 bp (e.g., 300 bp, 400 bp, 500 bp, 600 bp, 700 bp, or more) of any contiguous nucleotides of a human GJB2 promoter. include In some embodiments, the expression cassette of the isolated nucleic acid comprises a promoter having 500 bp contiguous nucleotides of a human GJB2 promoter. In some embodiments, an expression cassette of an isolated nucleic acid is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93% relative to SEQ ID NO:5 , a promoter that has a nucleotide sequence that is at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical. An exemplary nucleotide sequence of 500 bp of the human GJB2 promoter is set forth in SEQ ID NO:5.

In some embodiments, the expression cassette of the isolated nucleic acid comprises a GJB2 basal promoter (eg, a human GJB2 basal promoter). The GJB2 basal promoter is the promoter region of the GJB2 gene that is highly conserved across different species (eg, human and mouse). The GJB2 basal promoter is described, for example, in Tu, Z. J., and Kiang, D. T. (1998). Mapping and characterization of the basal promoter of the human connexin26 gene. Biochim. Biophys. Acta 1443, 169-181; Kiang, D. T., Jin, N., Tu, Z. J., and Lin, H. H. (1997). Upstream genomic sequence of the human connexin26 gene. Gene 199, 165-171; and Castillo et al., DFNB1 Non-syndromic Hearing Impairment: Diversity of Mutations and Associated Phenotypes, Front. Mol. Neurosci., 22 December 2017, each of which is incorporated herein by reference. In some embodiments, an expression cassette of an isolated nucleic acid is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93% relative to SEQ ID NO:47 , a GJB2 base promoter that has a nucleotide sequence that is at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical. An exemplary nucleotide sequence of the human GJB2 basal promoter is set forth in SEQ ID NO:47.

Examples of constitutive promoters include, but are not limited to, the retroviral Rous Sarcoma Virus (RSV) long terminal repeat (LTR) promoter (optionally with an RSV enhancer), the cytomegalovirus (CMV) promoter (optionally with a CMV enhancer) ( See, eg, Boshart et al., Cell, 41:521-530 (1985)), monkey vacuolization virus 40 (SV40) promoter, dihydrofolate reductase promoter, β-actin promoter, phospho glycerol kinase (PGK) promoter, and elongation factor 1-alpha 1 (EF1α) promoter. In some embodiments, the promoter is the chicken beta-actin (CBA) promoter. In some embodiments, the promoter is the enhanced chicken β-actin promoter. In some embodiments, the promoter is a U6 promoter. Because the CBA promoter is constitutively active in all cell types, use of the CBA promoter in the isolated nucleic acids described herein can be used in all cell types, including cells that do not normally express the GJB2 protein (eg, hair cells of the cochlea). induces heterogeneous expression of the GJB2 protein. Thus, in some embodiments, a CBA promoter is not used in the isolated nucleic acids described herein.

Inducible promoters allow for the regulation of gene expression, by the presence of exogenously supplied compounds, environmental factors such as temperature, or specific physiological states such as acute phase, specific differentiation states of cells, or only replicating cells can be adjusted only in Inducible promoters and inducible systems are available from a variety of commercial sources including, but not limited to, Invitrogen, Clontech and Ariad. A number of other promoters have been described and can be readily selected by those skilled in the art. Examples of inducible promoters regulated by exogenously supplied promoters include the zinc-inducible sheep metallothioneine (MT) promoter, the dexamethasone (Dex)-inducible mouse mammary tumor virus (MMTV) promoter, the T7 polymerase promoter system (WO 98/10088); Ecdysone insect promoter (No et al., Proc. Natl. Acad. Sci. USA, 93:3346-3351 (1996)), tetracycline-repressor system (Gossen et al., Proc. Natl. Acad. Sci. USA, 89:5547-5551 (1992)), tetracycline-derived systems (Gossen et al., Science, 268:1766-1769 (1995), see also Harvey et al., Curr. Opin. Chem. Biol., 2:512-518 (1998)), the RU486-inducible system (Wang et al., Nat. Biotech., 15:239-243 (1997) and Wang et al., Gene Ther., 4:432-441 (1997)) and rapamycin-inducible systems (Magari et al., J. Clin. Invest., 100:2865-2872 (1997)).

In some embodiments, an isolated nucleic acid comprises a genetic regulatory element (GRE) (eg, GJB2 GRE). Gene regulatory elements as used herein refer to various DNA sequences involved in the regulation of gene expression. For example, GREs can regulate gene expression depending on interactions involving DNA, cellular proteins (eg, histones), and transcription factors.

In some embodiments, the isolated nucleic acid comprises a gene regulatory element that is a cis-regulatory element (eg, a cis-regulatory element for the GJB2 gene). Cis-regulatory elements are regions of non-coding DNA that regulate the transcription of neighboring genes. Cis-regulatory elements are found in the vicinity of the genes they regulate. Cis-regulatory elements typically regulate gene transcription by binding to transcription factors. In some embodiments, a genetic regulatory element confers cell-specific gene expression capability (eg, cell-specific GJB2 gene expression). In some embodiments, the genetic regulatory element is a cis-regulatory element associated with the GJB2 gene.

In some embodiments, the cis-regulatory element of the GJB2 gene is an enhancer. Enhancer, as used herein, refers to a DNA sequence located more distal to the transcription initiation site than a promoter, capable of interacting with site-specific transcription factors to regulate gene expression in a cell-type specific manner. Enhancers confer cell-specific gene expression regulation by binding to a set of transcription factors in cells, which can be achieved through a variety of mechanisms, including the recruitment of epigenetic enzymes that catalyze post-translational histone modifications, and cofactors that promote DNA looping. leading to transcriptional activation or repression through the recruitment of Enhancers can be identified in the vicinity of the genes they regulate, or at a distance of several hundred kilobases from their target genes. Multiple enhancers can act additively and redundantly to regulate gene expression (see, e.g., Doane et al., Regulatory elements in molecular networks, Wiley Interdiscip Rev Syst Biol Med. 2017 May; 9( 3)]). In some embodiments, an enhancer described herein is an enhancer capable of modulating genomic GJB2 gene expression. In some embodiments, a GJB2 enhancer is identified in the transcriptionally active sequence of the GJB2 gene. Transcriptionally active sequence, as used herein, refers to a region of DNA within a chromosome where the DNA exists in an open chromatin conformation such that the sequence is exposed to allow binding of transcription factors and transcription to occur. In some embodiments, the GJB2 enhancer is within approximately 1000 kb of the genomic GJB2 gene (e.g., within 1000 kb, within 900 kb, within 800 kb, within 700 kb, within 600 kb, within 500 kb, 450 kb of the GJB2 gene) within, within 400 kb, within 350 kb, within 300 kb, within 250 kb, within 200 kb, within 150 kb, within 100 kb, within 95 kb, within 90 kb, within 85 kb, within 85 kb, within 80 kb, Within 75 kb, within 70 kb, within 65 kb, within 60 kb, within 55 kb, within 50 kb, within 45 kb, within 40 kb, within 35 kb, within 30 kb, within 25 kb, within 20 kb, within 15 kb within, upstream or downstream within 10 kb, or less). In some embodiments, a GJB2 enhancer is identified within approximately 200 kb of the GJB2 gene. In some embodiments, a GJB2 enhancer is identified within approximately 95 kb of the GJB2 gene (eg, region C-M listed in FIG. 3C). In some embodiments, the GJB2 enhancer is within a region of DNA sequence proximal to the GJB2 gene listed in Table 1 (FIG. 3C).

Table 1. Human and mouse DNA regions containing GJB2 enhancers.

In some embodiments, a GJB2 GRE (eg, GJB2 enhancer) sequence can be identified from the region sequences listed in Table 2. In some embodiments, the GJB2 GRE (eg, GJB2 enhancer) is at least 200, at least 250, at least 300 in any region sequence set forth in Table 2 (eg, human GJB2 region A-M or mouse Gjb2 region A-M). at least 350, at least 400, at least 450, at least 500, at least 550, at least 600, at least 650, at least 700, at least 750, at least 800, at least 850, at least 900; At least 1000, at least 1100, at least 1200, at least 1300, at least 1400, at least 1500, at least 1600, at least 1700, at least 1800, at least 1900, at least 2000, at least 2100, at least 2200 at least 2300, at least 2400, at least 2500, at least 2600, at least 2700, at least 2800, at least 2800, at least 2900, at least 3000, at least 3100, at least 3200, at least 3300; At least 3400, at least 3500, at least 3600, at least 3700, at least 3800, at least 3900, at least 4000, at least 4100, at least 4200, at least 4200, at least 4400, at least 4500, at least 4600 , at least 4700, at least 4800, at least 4900, at least 5000, or more contiguous nucleotides. In some embodiments, a GJB2 GRE (eg, a GJB2 enhancer) is identified in a transcriptionally active region (eg, region A and/or B) of the GJB2 gene. In some embodiments, the GJB2 GRE (eg, GJB2 enhancer) is at least 200, at least 250, at least 300, at least 350, at least 400, at least 450, at least 500 in region A and/or B , at least 550, at least 600, at least 650, at least 700, at least 750, at least 800, at least 850, at least 900, at least 1000, at least 1100, at least 1200, at least 1300, at least 1400, at least 1500, at least 1600, at least 1700, at least 1800, at least 1900, at least 2000, at least 2100, at least 2200, at least 2300, at least 2400, at least 2500, at least 2600 , at least 2700, at least 2800, at least 2800, at least 2900, at least 3000, at least 3100, at least 3200, at least 3300, at least 3400, at least 3500, at least 3600, at least 3700, at least 3800, at least 3900, at least 4000, at least 4100, at least 4200, at least 4200, at least 4400, at least 4500, at least 4600, at least 4700, at least 4800, at least 4900, at least 5000 , or more contiguous nucleotides. In some embodiments, the GJB2 GRE (eg, GJB2 enhancer) is at least 200, at least 250, at least 300, at least 350, at least 400, at least 450, at least 500, at least 550 within regions C-M. , at least 600, at least 650, at least 700, at least 750, at least 800, at least 850, at least 900, at least 1000, at least 1100, at least 1200, at least 1300, at least 1400, at least 1500, at least 1600, at least 1700, at least 1800, at least 1900, at least 2000, at least 2100, at least 2200, at least 2300, at least 2400, at least 2500, at least 2600, at least 2700 , at least 2800, at least 2800, at least 2900, at least 3000, at least 3100, at least 3200, at least 3300, at least 3400, at least 3500, at least 3600, at least 3700, at least 3800, at least 3900, at least 4000, at least 4100, at least 4200, at least 4200, at least 4400, at least 4500, at least 4600, at least 4700, at least 4800, at least 4900, at least 5000, or more contains consecutive nucleotides of In some embodiments, a GJB2 GRE (eg, a GJB2 enhancer) comprises a nucleotide sequence in a region listed in Table 3.

In some embodiments, a GJB2 GRE (eg, a GJB2 enhancer) is located on the sense strand of a GJB2 coding sequence in a genome. In some embodiments, a GJB2 GRE (eg, a GJB2 enhancer) is located on the reverse complement strand of a GJB2 coding sequence in a genome. It is within the skill of the art to select an appropriate sequence (eg, a GRE sequence on the sense strand, or a GRE sequence on the reverse complement strand) when designing a vector using an enhancer sequence as described herein.

In some embodiments, a GJB2 GRE (e.g., a GJB2 enhancer) is at least 200, at least 250, at least 300, at least 350, at least 400, at least 450, at least 500, at least 550, at least 600 at least 650, at least 700, at least 750, at least 800, at least 850, at least 900, at least 1000, at least 1100, at least 1200, at least 1300, at least 1400, at least 1500, At least 1600, at least 1700, at least 1800, at least 1900, at least 2000, at least 2100, at least 2200, at least 2300, at least 2400, at least 2500, at least 2600, at least 2700, at least 2800 at least 2800, at least 2900, at least 3000, at least 3100, at least 3200, at least 3300, at least 3400, at least 3500, at least 3600, at least 3700, at least 3800, at least 3900; at least 4000, at least 4100, at least 4200, at least 4200, at least 4400, at least 4500, at least 4600, at least 4700, at least 4800, at least 4900, at least 5000, or more nucleotides include In some embodiments, a GJB2 GRE (e.g., a GJB2 enhancer) is 200-500 nucleotides or any number of nucleotides in between, 300-600 nucleotides or any number of nucleotides in between, 400-700 nucleotides in between. nucleotides or any number of nucleotides in between, 500-800 nucleotides or any number of nucleotides in between, 600-900 nucleotides or any number of nucleotides in between, 700-1000 nucleotides or any number in between Any number of nucleotides, 1000-1500 nucleotides or any number of nucleotides in between, 1500-2000 nucleotides or any number in between. In some embodiments, a GJB2 GRE (eg, a GJB2 enhancer) comprises 700 nucleotides.

In some embodiments, the GJB2 GRE is a human GJB2 enhancer. In some embodiments, a GJB2 GRE (e.g., a human GJB2 enhancer) is at least 60%, at least 70%, at least 75%, at least 80%, at least 85% relative to any one of the GRE sequences as listed in Table 3. , at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical nucleotide sequences .

Table 3: Human GJB2 enhancer sequences

In some embodiments, the GJB2 GRE is a non-human primate (eg, Cynomolgus macaque) GJB2 enhancer. In some embodiments, a GJB2 GRE (e.g., a Cynomolgus macaque GJB2 enhancer) is at least 60%, at least 70%, at least 75%, at least 80% relative to any one of the GRE sequences as listed in Table 4. , at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical nucleotides contains sequence.

Table 4: Cynomolgus macaque GJB2 (mfGJB2) enhancer sequences

In some embodiments, the human GJB2 GRE shares homology with the mfGJB2 GRE. In some embodiments, the human GJB2 GRE corresponds to the mfGJB2 GRE as shown in Table 5:

Table 5: Homology between human GJB2 GRE and mfGJB2 GRE

In some embodiments, an isolated nucleic acid comprises one or more (eg, 1, 2, 3, 4, 5, 6, 7, 9 or more) enhancers (eg, the GJB2 enhancer). . In some embodiments, an isolated nucleic acid comprises more than one enhancer, and the more than one enhancer is the same enhancer or a different enhancer. In some embodiments, the GJB2 GRE is located 5' to the promoter. In another embodiment, the GJB2 GRE is located 3' of the promoter. In some embodiments, the presence of the GJB2 enhancer(s) in the isolated nucleic acid promotes cell-type specific expression of the GJB2 protein encoded by the isolated nucleic acid. In some embodiments, cells that normally express the GJB2 gene (eg, fibrocytes and support cells of the organ of Corti and nearby regions) have a transcriptional network that activates GJB2 expression regulated by the GJB2 enhancer, but normally express GJB2. This is not the case in cells that do not (e.g., hair cells and spiral ganglion neurons).

In some embodiments, the expression cassette of the isolated nucleic acid further comprises a 5' UTR. In some embodiments, the 5' UTR is the native 5' UTR of the genomic GJB2 gene. The 5' untranslated region (5' UTR) (also known as leader sequence or leader RNA) is the region of mRNA immediately upstream of the initiation codon. The 5' UTR plays an important role in both transcriptional and translational regulation of downstream genes (eg, the GJB2 gene). In some embodiments, an isolated nucleic acid comprising a nucleotide sequence encoding a GJB2 5' UTR may also express GJB2 in a cell-specific manner (eg, express GJB2 in a cell that normally expresses it) . In some embodiments, the nucleotide sequence encoding the GJB2 5' UTR comprises a portion of the nucleotide sequence encoding the full-length human GJB2 gene 5' UTR. In some embodiments, the 5' UTR is the human GJB2 gene exon 1 5' UTR. In some embodiments, a nucleotide sequence encoding a 5' UTR is at least 100 contiguous nucleotides, at least 200 contiguous nucleotides, at least 300 contiguous nucleotides of a native full-length 5' UTR (eg, human GJB2 gene exon 1 5' UTR) nucleotides, at least 400 contiguous nucleotides, at least 500 contiguous nucleotides, at least 600 contiguous nucleotides, at least 700 contiguous nucleotides, at least 800 contiguous nucleotides, at least 900 contiguous nucleotides, at least 1000 contiguous nucleotides, or more . In some embodiments, the expression cassette comprises at least 60%, at least 70%, at least 80%, at least 85%, A 5' UTR having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity It includes a nucleotide sequence that encodes. In some embodiments, the expression cassette is at least 60% relative to a nucleotide sequence encoding a contiguous 300 bp of the human GJB2 gene 5' UTR set forth in SEQ ID NO: 53 (eg, human GJB2 gene exon 1 5' UTR). , at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least A nucleotide sequence encoding a 5' UTR with 99%, or 100% sequence identity. In some embodiments, an exemplary nucleotide sequence encoding 300 bp of the human GJB2 gene exon 1 5' UTR has the nucleotide sequence set forth in SEQ ID NO:53.

In some embodiments, cell specific GJB2 expression is achieved by incorporation of a nucleotide sequence encoding a basal promoter and a GJB2 5'UTR or portion thereof (basal promoter/5'UTR). In some embodiments, an expression cassette (eg, a GJB2 expression cassette) comprises a nucleotide sequence encoding a 5' UTR. In some embodiments, an isolated nucleic acid may further comprise additional nucleotide sequences encoding one or more GJB2 GREs (eg, GJB2 enhancers). The nucleotide sequence encoding the GJB2 GRE and the nucleotide sequence encoding the basal promoter/5'UTR can be placed in any order. In some embodiments, the nucleotide sequence encoding the GJB2 GRE is located 5' to the nucleotide sequence encoding the basal promoter/5' UTR. In some embodiments, an isolated nucleic acid comprising a nucleotide sequence encoding a GJB2 basal promoter/5'UTR also expresses GJB2 in a cell-specific manner (eg, expresses GJB2 in a cell that normally expresses it) can do. In some embodiments, the nucleotide sequence encoding the basal promoter/5' UTR comprises a portion of the nucleotide sequence encoding the full-length human GJB2 gene 5' UTR. In some embodiments, a 5' UTR is at least 100 contiguous nucleotides, at least 200 contiguous nucleotides, at least 300 contiguous nucleotides, at least 400 contiguous nucleotides, at least 500 contiguous nucleotides, at least 600 contiguous nucleotides, at least 700 contiguous nucleotides, at least 800 contiguous nucleotides, at least 900 contiguous nucleotides, at least 1000 contiguous nucleotides, or more. In some embodiments, the 5' UTR is the human GJB2 gene exon 1 5' UTR. In some embodiments, the expression cassette comprises at least a nucleotide sequence encoding a basal promoter and about 300 bp of the human GJB2 gene 5' UTR (eg, human GJB2 gene exon 1 5' UTR) (SEQ ID NO: 30). 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% , a nucleotide sequence encoding a basal promoter/5'UTR having at least 99%, or 100% sequence identity. In some embodiments, an exemplary nucleotide sequence encoding 300 bp of the human GJB2 gene base promoter /exon 1 5' UTR has the nucleotide sequence set forth in SEQ ID NO:30.

In some embodiments, the nucleotide sequence encoding the basal promoter/5'UTR (eg, human GJB2 basal promoter/exon 1 5'UTR) in an expression cassette (eg, a GJB2 expression cassette) is an intron or portion thereof. include additional In some embodiments, the expression cassette of the isolated nucleic acid (eg, a GJB2 expression cassette) further comprises a conserved sequence of intron 1 of the GJB2 gene. In some embodiments, the nucleotide sequence encoding an intron (eg, human GJB2 intron 1) is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least relative to SEQ ID NO: 54 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity. An exemplary nucleotide sequence encoding the conserved sequence of GJB2 intron 1 is set forth in SEQ ID NO:54.

In some embodiments, the nucleotide sequence encoding the basal promoter/5'UTR/intron is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 93%, relative to SEQ ID NO: 31 have at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity. An exemplary nucleotide sequence encoding the conserved sequence of human GJB2 basal promoter / 5'UTR /intron 1 is set forth in SEQ ID NO:31.

In some embodiments, an expression cassette (eg, a GJB2 expression cassette) comprises a nucleotide sequence encoding a proximal promoter of a human GJB2 gene. In some embodiments, the proximal promoter of the human GJB2 gene is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92% relative to the nucleotide sequence set forth in SEQ ID NO: 102 , at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity. In some embodiments, an exemplary nucleotide sequence encoding a promoter proximal to the human GJB2 gene has the nucleotide sequence set forth in SEQ ID NO:102. In some embodiments, an expression cassette (eg, a GJB2 expression cassette) comprises SEQ ID NO:102.

In some embodiments, an expression cassette (eg, a GJB2 expression cassette) comprises a nucleotide sequence encoding the 5' UTR of a human GJB2 gene. In some embodiments, the 5' UTR of the human GJB2 gene is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, relative to the nucleotide sequence set forth in SEQ ID NO: 103 or CC; at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity. In some embodiments, an exemplary nucleotide sequence encoding the human GJB2 gene 5' UTR has the nucleotide sequence set forth in SEQ ID NO: 103 or CC. In some embodiments, an exemplary nucleotide sequence encoding a human GJB2 gene 5' UTR has a nucleotide sequence comprising SEQ ID NO: 103 and SEQ ID NO: 104. In some embodiments, an expression cassette (eg, a GJB2 expression cassette) comprises SEQ ID NO:103.

In some embodiments, an expression cassette (eg, a GJB2 expression cassette) comprises SEQ ID NO:104.

In some embodiments, an expression cassette (eg, a GJB2 expression cassette) comprises a nucleotide sequence encoding a proximal promoter and a 5' UTR of a human GJB2 gene. In some embodiments, the proximal promoter and 5' UTR of the human GJB2 gene are at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91% relative to the nucleotide sequence set forth in SEQ ID NO: 105 , at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity. In some embodiments, an exemplary nucleotide sequence encoding a human GJB2 gene proximal promoter and 5' UTR has the nucleotide sequence set forth in SEQ ID NO: 105. In some embodiments, an expression cassette (eg, a GJB2 expression cassette) comprises SEQ ID NO:105.

The isolated nucleic acids described herein may also contain artificial introns, preferably located between the promoter/enhancer sequence and the protein coding sequence (eg, the nucleotide sequence encoding the GJB2 protein). In some embodiments, an intron is a synthetic or artificial (eg, heterologous) intron. Examples of synthetic introns include an intron sequence derived from SV-40 (referred to as the SV-40 T intron sequence) and an intron sequence derived from the chicken beta-actin gene. In some embodiments, a transgene described by this disclosure comprises one or more (1, 2, 3, 4, 5, or more) artificial introns. In some embodiments, one or more artificial introns are located between the promoter and the nucleotide sequence encoding the GJB2 protein.

In some embodiments, the expression cassette (eg, GJB2) further comprises a nucleotide sequence encoding a 3' UTR located 3' to the nucleotide sequence encoding the GJB2 protein. In some embodiments, the 3' UTR is the GJB2 gene 3' UTR. In some embodiments, the 3'UTR is the GJB2 gene exon 2 3' UTR. In some embodiments, the nucleotide sequence encoding the 3' UTR is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least relative to SEQ ID NO:32 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity. An exemplary nucleotide sequence encoding the GJB2 gene exon 2 3' UTR is set forth in SEQ ID NO:32.

In some embodiments, the expression cassette of the isolated nucleic acid comprises a detargeting agent that limits or reduces transgene expression (eg, GJB2 expression) in a cell type (eg, hair cell or spiral ganglion neuron). In some embodiments, incorporation of one or more miRNA binding sites into expression allows off-targeting of transgene expression in a cell-type specific manner (eg, in hair cells or spiral ganglion neurons). In some embodiments, the one or more miRNA binding sites are located in the 3' UTR (eg, the GJB2 exon 2 3' UTR of an expression cassette of an isolated nucleic acid).

In some embodiments, the expression cassette comprises one or more (e.g., 1, 2, 3, 4 , 5 or more) miRNA binding sites. In some embodiments, the expression cassette of the isolated nucleic acid has one or more miR binding sites for detargeting neuronal cells (eg, spiral ganglion neurons), such as those described in Jovicic et al., Comprehensive Expression Analyzes of Neural Cell-Type-Specific miRNAs Identify New Determinants of the Specification and Maintenance of Neuronal Phenotypes, J Neurosci. 2013 Mar 20; 33(12): 5127-5137, which is incorporated herein by reference. Non-limiting examples of miRs enriched in neurons include miR-124, miR-127, miR-129, miR-129*, miR-136, miR-136*, miR-137, miR-154, miR-300-3p, miR -323, miR-329, miR-341, miR-369-5p, miR-376a, miR-376b-3p, miR-376c, miR-379, miR-382, miR-382*, miR-410, miR- 411, miR-433, miR-434, miR-495, miR-541, miR-543*, miR-551b, miR-143, miR-449a, miR-219-2-3p, miR-126, miR-126 *, miR-141, miR-142-3p, miR-142-5p, miR-146a, miR-150, miR-200c, or miR-223. In some embodiments, an expression cassette of an isolated nucleic acid comprises one or more miR binding sites for detargeting hair cells (eg, inner or outer hair cells), such as those described in Li et al., MicroRNAs in hair cell development and deafness, Curr Opin Otolaryngol Head Neck Surg. 2010 Oct; 18(5): 459-465 (incorporated herein by reference). Non-limiting examples of miRs enriched in neurons include miR-96, miR-182, miR-183, miR-18a, or miR-99a. In some embodiments, the GJB2 exon 2 3' UTR of the expression cassette comprises one or more miR binding sites for detargeting to neuronal cells and hair cells. In some embodiments, the GJB2 exon 2 3' UTR of the expression cassette comprises one or more miR binding sites for miR-124.

Aspects of the present disclosure relate to gene therapy vectors comprising an isolated nucleic acid as described herein. Gene therapy vectors include viral vectors (eg, lentiviral vectors, adeno-associated viral vectors, adenovirus (Ad) vectors, etc.), plasmids, closed-end DNA (eg, ceDNA), lipid/DNA nanoparticles etc. In some embodiments, the gene therapy is a viral vector. In some embodiments, an expression cassette encoding a protein (eg, a GJB2 protein) contains one or more viral replication sequences, such as lentiviral long terminal repeats (LTRs) or adeno-associated virus (AAV) inverted ends. The repeats (ITR) are flanked.

An isolated nucleic acid of the present disclosure may be a recombinant adeno-associated virus (AAV) vector (rAAV vector). In some embodiments, an isolated nucleic acid as described by this disclosure comprises two adeno-associated virus (AAV) inverted terminal repeat (ITR) sequences, or variants thereof. Isolated nucleic acids (eg, recombinant AAV vectors) can be packaged into capsid proteins, administered to a subject, and/or delivered to selected target cells. A "recombinant AAV (rAAV) vector" typically consists of a minimal expression cassette (eg, an expression cassette for GJB2), and 5' and 3' AAV inverted terminal repeats (ITRs). An isolated nucleic acid may also include, for example, regions encoding 5' and 3' untranslated regions (UTRs), and/or expression control sequences (eg, poly-A tails).

Generally, ITR sequences are about 145 bp in length. Preferably, substantially the entire sequence encoding the ITR is used in the isolated nucleic acid, although some minor variations of these sequences are permitted. The ability to modify these ITR sequences is within the skill of the art (eg, Sambrook et al., Molecular Cloning. A Laboratory Manual, 2d ed., Cold Spring Harbor Laboratory, New York (1989); and K. Fisher et al., J Virol., 70:520 532 (1996)). An example of such a molecule used in the present invention is an expression cassette encoding the GJB2 protein, flanked by 5' and 3' AAV ITR sequences, to an expression cassette comprising the nucleotide sequence GJB2 protein and a GJB2 gene regulatory element (GRE). It is an isolated nucleic acid comprising AAV ITR sequences can be obtained from any known AAV, including currently identified mammalian AAV types. In some embodiments, the isolated nucleic acid (e.g., rAAV vector) is at least one having a serotype selected from AAV1, AAV2, AAV5, AAV6, AAV6.2, AAV7, AAV8, AAV9, AAV10, AAV11 and variants thereof. Include ITRs. In some embodiments, an isolated nucleic acid comprises a region (eg, a first region) encoding an AAV2 ITR.

In some embodiments, the isolated nucleic acid further comprises a region comprising a second AAV ITR (eg, a second region, a third region, a fourth region, etc.). In some embodiments, the second AAV ITR has a serotype selected from AAV1, AAV2, AAV5, AAV6, AAV6.2, AAV7, AAV8, AAV9, AAV10, AAV11, and variants thereof. In some embodiments, the second AAV ITR is an AAV2 ITR. In some embodiments, the second ITR is a mutant ITR lacking a functional terminal cleavage site (TRS). The term "lacking a terminal cleavage site" means that an AAV ITR includes mutations (e.g., sense mutations, such as non-synonymous mutations, or missense mutations) that eliminate the function of the terminal cleavage site (TRS) of the ITR. , or a truncated AAV ITR lacking a nucleic acid sequence encoding a functional TRS (eg, ΔTRS ITR, or ΔITR). Without wishing to be bound by any particular theory, rAAV vectors comprising an ITR lacking a functional TRS are self-complementary as described, for example, in McCarthy (2008) Molecular Therapy 16(10):1648-1656. Produce an enemy rAAV vector. In some embodiments, an isolated nucleic acid comprises a 5' AAV2 ITR and a 3' AAV2 ITR.

An exemplary 5' AAV2 ITR nucleotide sequence is set forth in SEQ ID NO:34.

An exemplary 5' ITR nucleotide sequence is set forth in SEQ ID NO: 106.

An exemplary 3' AAV2 ITR nucleotide sequence is set forth in SEQ ID NO:35.

An exemplary 3' ITR nucleotide sequence is set forth in SEQ ID NO: 107.

In some embodiments, an isolated nucleic acid described herein (eg, a rAAV vector) is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least relative to SEQ ID NO: 34 or 106 at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity; .

In some embodiments, an isolated nucleic acid (eg, a rAAV vector) described herein is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least relative to SEQ ID NO: 35 or 107 at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity; .

In some embodiments, an isolated nucleic acid described herein (eg, a rAAV vector) comprises a post-transcriptional response element. As used herein, the term “post-transcriptional response element” refers to a nucleic acid sequence that, when transcribed, adopts a tertiary structure that enhances the expression of a gene. Examples of post-transcriptional regulatory elements include Woodchuck Hepatitis Virus post-transcriptional regulatory element (WPRE), mouse RNA transport element (RTE), constitutive transport element (CTE) of monkey retrovirus type 1 (SRV-1), Mason-Pfizer monkey CTE from virus (MPMV), and the 5' untranslated region of human heat shock protein 70 (Hsp70 5' UTR). In some embodiments, an isolated nucleic acid (eg, a rAAV vector) comprises a Woodchuck hepatitis virus post-transcriptional regulatory element (WPRE).

In some embodiments, an isolated nucleic acid described herein (eg, a rAAV vector) is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91% relative to SEQ ID NO: 108 , at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity. An exemplary post-transcriptional response element is set forth in SEQ ID NO: 108.

In some embodiments, the vector is a conventional control operably linked element of the GJB2 coding sequence in a manner permitting its transcription, translation and/or expression in cells transfected with the vector or infected with the virus produced by the present disclosure. contains additional elements. Expression control sequences include appropriate transcriptional initiation, termination; efficient RNA processing signals such as splicing and polyadenylation (polyA) signals; sequences that stabilize cytoplasmic mRNA; sequences that enhance translational efficiency (eg, Kozak consensus sequence); Contains sequences that enhance protein stability. The polyadenylation sequence is usually inserted after the coding sequence and optionally before the 3' AAV ITR sequence. rAAV constructs useful in the present disclosure may also contain introns, preferably located between the promoter/enhancer sequence and the transgene.

In some embodiments, an isolated nucleic acid described herein (eg, a rAAV vector) is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91% relative to SEQ ID NO: 109 , a polyadenylation signal sequence having at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity. An exemplary polyadenylation signal sequence is set forth in SEQ ID NO: 109.

In some embodiments, an AAV vector described herein encodes a GJB2 proximal promoter (eg, SEQ ID NO: 102), a GJB2 5' UTR (eg, SEQ ID NO: 103 and CC), a GJB2 gene product. nucleotide sequence (eg, SEQ ID NO: 2), GJB2 3' UTR (eg, SEQ ID NO: 32), WPRE (eg, SEQ ID NO: 108), and bovine growth hormone poly A signal (eg SEQ ID NO: 109). In some embodiments, an AAV vector described herein is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 93%, relative to SEQ ID NO: 110; nucleotide sequences having at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity. An exemplary AAV vector sequence is set forth in SEQ ID NO: 110.

In some embodiments, an AAV vector described herein comprises a 5' ITR (eg, SEQ ID NO: 106), a GJB2 proximal promoter (eg, SEQ ID NO: 102), a GJB2 5' UTR (eg, SEQ ID NO: 106). SEQ ID NO: 103 and CC), nucleotide sequence encoding the GJB2 gene product (eg SEQ ID NO: 2), GJB2 3 'UTR (eg SEQ ID NO: 32), WPRE (eg SEQ ID NO: 32) , SEQ ID NO: 108), bovine growth hormone poly A signal (eg SEQ ID NO: 109), and 3' ITR (eg SEQ ID NO: 107). In some embodiments, an AAV vector described herein is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 93%, nucleotide sequences having at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity. An exemplary AAV vector sequence is set forth in SEQ ID NO: 111.

In some embodiments, an AAV vector described herein contains a 5' ITR, a GJB2 basal promoter, a 5' UTR (eg, GJB2 exon 1 5' UTR), a Kozak sequence, a gene product (eg, GJB2 or GFP). nucleotide sequence encoding, optional HA tag, 3' UTR (e.g., GJB2 exon 2 3' UTR), WPRE, bovine growth hormone poly A signal, and 3' ITR (e.g., vector c70) . In some embodiments, an AVV vector described herein is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 93%, a nucleotide sequence having at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity. An exemplary nucleotide sequence for vector c70 encoding mouse GJB2 protein with an HA tag is set forth in SEQ ID NO: 36 (mouse GJB2 coding sequence shown in bold; HA tag underlined).

In some embodiments, an AVV vector described herein is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 93%, a nucleotide sequence having at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity. An exemplary nucleotide sequence for vector c70 encoding human GJB2 protein with an HA tag is set forth in SEQ ID NO: 61 (human GJB2 coding sequence in bold; HA tag underlined).

In some embodiments, an AVV vector described herein is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 93%, a nucleotide sequence having at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity. An exemplary nucleotide sequence for vector c70 encoding mouse GJB2 protein with an HA tag is set forth in SEQ ID NO: 62 (mouse GJB2 coding sequence in bold; no HA tag).

In some embodiments, an AVV vector described herein is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 93%, relative to SEQ ID NO: 63; a nucleotide sequence having at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity. An exemplary nucleotide sequence for vector c70 encoding mouse GJB2 protein with an HA tag is set forth in SEQ ID NO: 63 (human GJB2 coding sequence in bold; no HA tag).

In some embodiments, an AAV vector described herein comprises an AAV 5' ITR, a GJB2 GRE enhancer (hGJB2 GRE1), a GJB2 basal promoter, a GJB2 exon 1 5' UTR, a Kozak sequence, a gene product (eg, GJB2 or GFP). The nucleotide sequence encoding, GJB2 exon 2 3'UTR, WPRE, bovine growth hormone poly A signal, and AAV 3'ITR (eg vector c81.1).

In some embodiments, an AVV vector described herein is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 93%, a nucleotide sequence having at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity. An exemplary nucleotide sequence for vector c81.1 encoding eGFP is shown in SEQ ID NO: 64 (hGJB2 GRE1 underlined; eGFP coding sequence in bold).

In some embodiments, an AVV vector described herein is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 93%, a nucleotide sequence having at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity. An exemplary nucleotide sequence for vector c81.1 encoding human GJB2 is shown in SEQ ID NO: 65 (hGJB2 GRE1 underlined; human GJB2 coding sequence in bold).

In some embodiments, an AVV vector described herein is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 93%, a nucleotide sequence having at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity. An exemplary nucleotide sequence for vector c81.1 encoding mouse GJB2 is shown in SEQ ID NO: 66 (hGJB2 GRE1 underlined; mouse GJB2 coding sequence in bold).

In some embodiments, an AAV vector described herein comprises an AAV 5' ITR, a GJB2 GRE enhancer (hGJB2 GRE2), a GJB2 basal promoter, a GJB2 exon 1 5' UTR, a Kozak sequence, a gene product (eg, GJB2 or GFP). The nucleotide sequence encoding, GJB2 exon 2 3'UTR, WPRE, bovine growth hormone poly A signal, and AAV 3'ITR (eg, vector c81.2).

In some embodiments, an AVV vector described herein is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 93%, a nucleotide sequence having at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity. An exemplary nucleotide sequence for vector c81.2 encoding eGFP is shown in SEQ ID NO: 48 (hGJB2 GRE2 underlined; eGFP coding sequence in bold).

In some embodiments, an AVV vector described herein is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 93%, a nucleotide sequence having at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity. An exemplary nucleotide sequence for vector c81.2 encoding human GJB2 is shown in SEQ ID NO: 67 (hGJB2 GRE2 underlined; human GJB2 coding sequence in bold).

In some embodiments, an AVV vector described herein is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 93%, a nucleotide sequence having at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity. An exemplary nucleotide sequence for vector c81.2 encoding mouse GJB2 is shown in SEQ ID NO: 68 (hGJB2 GRE2 underlined; mouse GJB2 coding sequence in bold).

In some embodiments, an AAV vector described herein comprises an AAV 5' ITR, a GJB2 GRE enhancer (hGJB2 GRE3), a GJB2 basal promoter, a GJB2 exon 1 5' UTR, a Kozak sequence, a gene product (eg, GJB2 or GFP). The nucleotide sequence encoding, GJB2 exon 2 3'UTR, WPRE, bovine growth hormone poly A signal, and AAV 3'ITR (eg, vector c.81.3).

In some embodiments, an AVV vector described herein is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 93%, a nucleotide sequence having at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity. An exemplary nucleotide sequence for vector c.81.3 is shown in SEQ ID NO: 49 (hGJB2 GRE3 underlined; eGFP coding sequence in bold).

In some embodiments, an AVV vector described herein is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 93%, a nucleotide sequence having at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity. An exemplary nucleotide sequence for vector c.81.3 is shown in SEQ ID NO: 70 (hGJB2 GRE3 underlined; human GJB2 coding sequence in bold).

In some embodiments, an AVV vector described herein is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 93%, a nucleotide sequence having at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity. An exemplary nucleotide sequence for vector c.81.3 is shown in SEQ ID NO: 71 (hGJB2 GRE3 underlined; mouse GJB2 coding sequence in bold).

In some embodiments, an AAV vector described herein comprises an AAV 5' ITR, a GJB2 GRE enhancer (hGJB2 GRE4), a GJB2 basal promoter, a GJB2 exon 1 5' UTR, a Kozak sequence, a gene product (eg, GJB2 or GFP). The nucleotide sequence encoding, GJB2 exon 2 3'UTR, WPRE, bovine growth hormone poly A signal, and AAV 3'ITR (eg, vector c.81.4).

In some embodiments, an AVV vector described herein is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 93%, a nucleotide sequence having at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity. An exemplary nucleotide sequence for vector c.81.4 is shown in SEQ ID NO: 72 (hGJB2 GRE4 underlined; eGFP coding sequence in bold).

In some embodiments, an AVV vector described herein is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 93%, a nucleotide sequence having at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity. An exemplary nucleotide sequence for vector c.81.4 is shown in SEQ ID NO: 73 (hGJB2 GRE4 underlined; human GJB2 coding sequence in bold).

In some embodiments, an AVV vector described herein is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 93%, a nucleotide sequence having at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity. An exemplary nucleotide sequence for vector c.81.4 is shown in SEQ ID NO: 74 (hGJB2 GRE4 underlined; mouse GJB2 coding sequence in bold).

In some embodiments, an AAV vector described herein comprises an AAV 5' ITR, a GJB2 GRE enhancer (hGJB2 GRE5), a GJB2 basal promoter, a GJB2 exon 1 5' UTR, a Kozak sequence, a gene product (eg, GJB2 or GFP). The nucleotide sequence encoding, GJB2 exon 2 3'UTR, WPRE, bovine growth hormone poly A signal, and AAV 3'ITR (eg, vector c.81.5).

In some embodiments, an AVV vector described herein is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 93%, a nucleotide sequence having at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity. An exemplary nucleotide sequence for vector c.81.5 is shown in SEQ ID NO: 50 (hGJB2 GRE5 underlined; eGFP coding sequence in bold).

In some embodiments, an AVV vector described herein is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 93%, a nucleotide sequence having at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity. An exemplary nucleotide sequence for vector c.81.5 is shown in SEQ ID NO: 75 (hGJB2 GRE5 underlined; human GJB2 coding sequence in bold).

In some embodiments, an AVV vector described herein is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 93%, a nucleotide sequence having at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity. An exemplary nucleotide sequence for vector c.81.5 is shown in SEQ ID NO: 76 (hGJB2 GRE5 underlined; mouse GJB2 coding sequence in bold).

In some embodiments, an AAV vector described herein comprises an AAV 5' ITR, a GJB2 GRE enhancer (hGJB2 GRE7), a GJB2 basal promoter, a GJB2 exon 1 5' UTR, a Kozak sequence, a gene product (eg, GJB2 or GFP). The nucleotide sequence encoding, GJB2 exon 2 3'UTR, WPRE, bovine growth hormone poly A signal, and AAV 3'ITR (eg, vector c.81.7).

In some embodiments, an AVV vector described herein is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 93%, a nucleotide sequence having at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity. An exemplary nucleotide sequence for vector c.81.7 is shown in SEQ ID NO: 51 (hGJB2 GRE7 underlined; eGFP coding sequence in bold).

In some embodiments, an AVV vector described herein is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 93%, a nucleotide sequence having at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity. An exemplary nucleotide sequence for vector c.81.7 is shown in SEQ ID NO: 77 (hGJB2 GRE7 underlined; human GJB2 coding sequence in bold).

In some embodiments, an AVV vector described herein is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 93%, a nucleotide sequence having at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity. An exemplary nucleotide sequence for vector c.81.7 is shown in SEQ ID NO: 78 (hGJB2 GRE7 underlined; mouse GJB2 coding sequence in bold).

In some embodiments, an AAV vector described herein comprises an AAV 5' ITR, a GJB2 GRE enhancer (hGJB2 GRE8), a GJB2 basal promoter, a GJB2 exon 1 5' UTR, a Kozak sequence, a gene product (eg, GJB2 or GFP). The nucleotide sequence encoding, GJB2 exon 2 3'UTR, WPRE, bovine growth hormone poly A signal, and AAV 3'ITR (eg vector c.81.8).

In some embodiments, an AVV vector described herein is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 93%, a nucleotide sequence having at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity. An exemplary nucleotide sequence for vector c.81.8 is shown in SEQ ID NO: 79 (hGJB2 GRE8 underlined; eGFP coding sequence in bold).

In some embodiments, an AVV vector described herein is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 93%, a nucleotide sequence having at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity. An exemplary nucleotide sequence for vector c.81.8 is shown in SEQ ID NO: 80 (hGJB2 GRE8 underlined; human GJB2 coding sequence in bold).

In some embodiments, an AVV vector described herein is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 93%, a nucleotide sequence having at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity. An exemplary nucleotide sequence for vector c.81.8 is shown in SEQ ID NO: 81 (hGJB2 GRE8 underlined; mouse GJB2 coding sequence in bold).

In some embodiments, an AAV vector described herein comprises an AAV 5' ITR, a GJB2 GRE enhancer (hGJB2 GRE9), a GJB2 basal promoter, a GJB2 exon 1 5' UTR, a Kozak sequence, a gene product (eg, GJB2 or GFP). The nucleotide sequence encoding, GJB2 exon 2 3'UTR, WPRE, bovine growth hormone poly A signal, and AAV 3'ITR (eg, vector c.81.9).

In some embodiments, an AVV vector described herein is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 93%, a nucleotide sequence having at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity. An exemplary nucleotide sequence for vector c.81.9 is shown in SEQ ID NO: 52 (hGJB2 GRE9 underlined; eGFP coding sequence in bold).

In some embodiments, an AVV vector described herein is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 93%, relative to SEQ ID NO: 82; a nucleotide sequence having at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity. An exemplary nucleotide sequence for vector c.81.9 is shown in SEQ ID NO: 82 (hGJB2 GRE9 underlined; human GJB2 coding sequence in bold).

In some embodiments, an AVV vector described herein is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 93%, a nucleotide sequence having at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity. An exemplary nucleotide sequence for vector c.81.9 is shown in SEQ ID NO: 83 (hGJB2 GRE9 underlined; mouse GJB2 coding sequence in bold).

II. Recombinant adeno-associated virus (rAAV)

In some aspects, the present disclosure provides isolated AAV. The term “isolated,” as used herein with reference to AAV, refers to AAV produced, engineered, or obtained artificially. Isolated AAV can be produced using recombinant methods. Such AAVs are referred to herein as “recombinant AAVs”. Recombinant AAV (rAAV) preferably has tissue-specific targeting capabilities, such that the transgene of the rAAV will be specifically delivered to one or more pre-determined tissue(s). AAV capsids are an important factor in determining these tissue-specific targeting abilities. Thus, rAAVs with capsids appropriate for the tissue being targeted can be selected.

Methods of obtaining recombinant AAV having the desired capsid protein are known in the art (see, eg, US 2003/0138772, incorporated herein by reference). Typically, the method comprises a nucleic acid sequence encoding an AAV capsid protein; functional rep gene; a recombinant AAV vector consisting of an AAV inverted terminal repeat (ITR) and an expression cassette (eg, the GJB2 expression cassette); and culturing a host cell containing a helper plasmid expressing the E2b and E4 transcripts from adenovirus such that the recombinant AAV vector is packaged into an AAV capsid. In some embodiments, the capsid protein is a structural protein encoded by the cap gene of AAV. AAV contains three capsid proteins, virion proteins 1 to 3 (named VP1, VP2 and VP3), all of which are transcribed from a single cap gene through alternative splicing. In some embodiments, the molecular weight of VP1, VP2 and VP3 is about 87 kDa, about 72 kDa, and about 62 kDa, respectively. In some embodiments, upon translation, the capsid protein forms a spherical 60-mer protein shell around the viral genome. In some embodiments, the function of the capsid protein is to protect the viral genome, transfer the genome, and/or interact with the host. In some aspects, capsid proteins deliver the viral genome to the host (eg, to cells within the inner ear) in a tissue-specific manner.

The present disclosure is based in part on the discovery that certain AAV serotype capsids can deliver transgenes (eg, the GJB2 gene) to the ear (eg, cells within the inner ear). In some embodiments, the AAV capsid protein is AAV9.PHP.B, AAV9.PHP.eB, exoAAV, Anc80, AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAVrh8, AAV9, AAV10, AAVrh10, and of an AAV serotype selected from the group consisting of AAV-S. AAV2.7m8 can deliver transgenes targeting cochlear hair cells and supporting cells and the retina. AAV2.7m8 exhibits excellent transduction into the inner ear (Isgrig et al., "AAV2.7m8 is a powerful viral vector for inner ear gene therapy," Nature Communications volume 10, Article number: 427 (2019)). In some embodiments, the capsid protein is of AAV serotype 9 (AAV9). In some embodiments, the AAV capsid protein is of a serotype derived from AAV9 (eg, an AAV9 capsid variant), eg, AAV9.PHP.B. In some embodiments, the AAV9 capsid variant is AAV9.PHP.B. In some embodiments, the AAV9 capsid variant is AAV-S. AAV-S is an AAV9 capsid protein variant originally developed to target the central nervous system (CNS) (Hanlon et al., Selection of an Efficient AAV Vector for Robust CNS Transgene Expression, Molecular Therapy Method & Clinical Development, vol. 15, pp. 320-332, December 13, 2019], and PCT/US2020/025720, which are incorporated herein by reference). Surprisingly, AAV-S is an outer hair cell (OHC), inner hair cell (IHC), supporting cell (e.g., border cell, inner phalanx cell, inner column cell, outer column cell, diter cell, Hensen cell, or Claudius cells), spiral ganglion neurons, spiral plate edge cells (e.g., glial cells or interdental cells), outer sulcus cells, lateral wall, vascular progenitors (e.g., basal and intermediate cells), inner sulcus, spiral ligament ( eg, fibrocytes), or cells of the vestibular system, including but not limited to cells of the inner ear (see, eg, Hanlon et al., incorporated herein by reference). AAV-S: A novel AAV vector selected in brain transduces the inner ear with high efficiency, see Molecular Therapy Vol 18 No 4S1, April 28, 2020, Abstract 151). In some embodiments, the AAV capsid is AAV-S. An exemplary amino acid sequence for AAV-S is set forth in SEQ ID NO:33. In some embodiments, the AAV capsid is exoAAV. ExoAAV refers to exosome-associated AAV. The exoAAV capsid protein may be selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAVrh8, AAV9, AAV10, AAVrh10, and AAV.PHP.B. In some instances, the exoAAV is exoAAV1 or exoAAV9.

An exemplary amino acid sequence for AAV-S is set forth in SEQ ID NO:33.

One skilled in the art will also appreciate that conservative amino acid substitutions may be made to provide functionally equivalent variants or homologues of capsid proteins. In some aspects, the disclosure includes sequence alterations that create conservative amino acid substitutions. Conservative amino acid substitutions, as used herein, refer to amino acid substitutions that do not alter the relative charge or size characteristics of the protein in which the amino acid substitution is made. Variants can be prepared according to methods for altering polypeptide sequences known to those skilled in the art, such as references that compile such methods, such as Molecular Cloning: A Laboratory Manual, J. Sambrook. , et al., eds., Second Edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1989, or Current Protocols in Molecular Biology, F.M. Ausubel, et al., eds., John Wiley & Sons, Inc., New York]. Conservative substitutions of amino acids include substitutions made among amino acids within the following groups: (a) M, I, L, V; (b) F, Y, W; (c) K, R, H; (d) A, G; (e) S, T; (f) Q, N; and (g) E, D. Thus, conservative amino acid substitutions may be made to the amino acid sequences of the proteins and polypeptides described herein (eg, the GJB2 protein sequence).

In some embodiments, rAAV is single-stranded AAV (ssAAV). As used herein, ssAAV refers to rAAV that has the coding sequence of the transgene expression cassette and complementary sequences on separate strands and is packaged in separate viral capsids. In some embodiments, the rAAV is self-complementary AAV (scAAV). scAAV, as used herein, refers to rAAV that has both the coding and complementary sequences of a transgene expression cassette present on a single strand of the AAV genome. The coding region of scAAV is designed to form an intramolecular double-stranded DNA template. Upon infection, rather than waiting for cell-mediated synthesis of the second strand, the two complementary halves of scAAV will associate to form one double-stranded DNA (dsDNA) unit that is ready for immediate replication and transcription.

In some embodiments, a rAAV as provided herein is capable of delivering a transgene (eg, GJB2) to a mammal. In some instances, the mammal is a human or non-human mammal, such as a mouse, rat or non-human primate (eg, cynomolgus monkey), cat, dog, pig, horse, donkey, camel, sheep or goat. can be In certain embodiments, the mammal is a human.

In some embodiments, a rAAV as provided herein is capable of delivering a transgene (eg, GJB2) to the ear. In some cases, rAAVs as provided herein are capable of delivering a transgene (eg, GJB2) to cells within the inner ear (eg, cochlea, sac, ovoid, and semicircular canals). Non-limiting examples of target cells include outer hair cells (OHC), inner hair cells (IHC), spiral ganglion neurons, cells of the vascular progenitors, cells of the inner sulcus, cells of the spiral ligament, cells of the vestibular system, organ of Corti supporting cells ( eg, epithelial cells of the inner and outer grooves, and interdental cells), interdental cells at the edge of the spiral plate, root cells in the spiral ligament, column cells, diter cells, Hensen cells, Claudius cells, internal phalanx cells; And border cells, vascular intermediate cells, fibrous cells in the lateral wall and supravascular vascular region, basal cells in vascular progenitors, fibrous cells in spiral ligaments, fibrous cells at the edge of the spiral plate, lining the labyrinth bone sac facing the vestibular system. mesenchymal cells, and supermarginal dark cells. In some embodiments, an AAV capsid (e.g., AAV-S or AAV-PHP.B) that has tropism for the inner ear and an isolated nucleic acid described herein (e.g., that expresses GJB2 under the control of a GJB2 gene regulatory element Inducing GJB2 gene replacement therapy to limit GJB2 expression to cells that normally express it, and to limit the toxicities associated with confluent GJB2 expression (e.g., expression in hair cells and/or central nervous system (CNS)). It is excellent in that it reduces GJB2-associated toxicity).

Components to be cultured in a host cell to package the rAAV vector into an AAV capsid may be provided to the host cell in trans. Alternatively, any one or more required components (e.g., recombinant AAV vectors, rep sequences, cap sequences, and/or helper functions) may be combined with one or more required components using methods known to those skilled in the art. It can be provided by stable host cells engineered to contain the components. Most suitably, such stable host cells will contain the necessary component(s) under the control of an inducible promoter. However, the necessary component(s) may be under the control of a constitutive promoter. Examples of suitable inducible and constitutive promoters are provided herein in the discussion of regulatory elements suitable for use with transgenes. In another alternative, the selected stable host cell may contain the selected component(s) under the control of a constitutive promoter and other selected component(s) under the control of one or more inducible promoters. For example, stable host cells can be generated that are derived from 293 cells (which contain E1 helper functions under the control of a constitutive promoter) but contain the rep and/or cap proteins under the control of an inducible promoter. Other stable host cells can be generated by those skilled in the art.

In some embodiments, the present disclosure relates to a host cell containing a nucleic acid comprising a coding sequence encoding a protein (eg, a GJB2 protein). In some embodiments, the host cell is a mammalian cell (eg, a human cell), a yeast cell, a bacterial cell, an insect cell, a plant cell, or a fungal cell.

Recombinant AAV vectors, rep sequences, cap sequences, and helper functions necessary to produce the rAAV of the present disclosure can be delivered to packaging host cells using any suitable genetic elements (eg, vectors). The selected genetic element may be delivered by any suitable method, including those described herein and known in the art. Methods used to construct any embodiment of the present disclosure are known to those skilled in the art of nucleic acid engineering, and include genetic engineering, recombinant engineering, and synthetic techniques. See, eg, Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, Cold Spring Harbor, N.Y. Similarly, methods for generating rAAV virions are known in the art, and selection of a suitable method is not a limitation of the present disclosure. See, for example, K. Fisher et al., J. Virol., 70:520-532 (1993)] and US Patent No. 5,478,745, each of which is incorporated herein by reference.

In some embodiments, recombinant AAV may be produced using a triple transfection method (described in detail in US Pat. No. 6,001,650, incorporated herein by reference). Typically, recombinant AAV is produced by transfecting a host cell with a recombinant AAV vector (including transgene) to be packaged into AAV particles, an AAV helper function vector, and an accessory function vector. AAV helper function vectors encode "AAV helper function" sequences (eg, rep and cap) that function in trans for productive AAV replication and encapsidation. Preferably, AAV helper functional vectors support efficient AAV vector production without producing any detectable wild-type AAV virions (eg, AAV virions containing functional rep and cap genes). Non-limiting examples of vectors suitable for use in the present disclosure include the pHLP19 described in U.S. Patent No. 6,001,650 and the pRep6cap6 vector described in U.S. Patent No. 6,156,303, both of which are incorporated herein by reference. An accessory function vector encodes nucleotide sequences for non-AAV derived viral and/or cellular functions (ie, “auxiliary functions”) on which AAV depends for replication. Auxiliary functions are required for AAV replication, including but not limited to, activation of AAV gene transcription, step-specific AAV mRNA splicing, AAV DNA replication, synthesis of cap expression products, and moieties involved in AAV capsid assembly includes the function to be Virus-based auxiliary functions may be derived from any known helper virus, such as adenovirus, herpesvirus (other than herpes simplex virus type-1), and vaccinia virus.

In some aspects, the present disclosure provides transfected host cells. The term "transfection" is used to refer to uptake of foreign DNA by a cell, and a cell is "transfected" when the exogenous DNA is introduced inside the cell membrane. A number of transfection techniques are generally known in the art. See, eg, Graham et al. (1973) Virology, 52:456, Sambrook et al. (1989) Molecular Cloning, a Laboratory Manual, Cold Spring Harbor Laboratories, New York, Davis et al. (1986) Basic Methods in Molecular Biology, Elsevier, and Chu et al. (1981) Gene 13:197. These techniques can be used to introduce one or more exogenous nucleic acids into a suitable host cell.

"Host cell" refers to any cell that carries or is capable of carrying a substance of interest. Often the host cell is a mammalian cell. The host cell can be used as a recipient of AAV helper constructs, AAV plasmids, helper function vectors, or other transfer DNA involved in the production of recombinant AAV. The term includes the progeny of the original transfected cell. Thus, a “host cell” as used herein may refer to a cell that has been transfected with an exogenous DNA sequence. It is understood that the progeny of a single parental cell may not necessarily be completely identical in morphology or in genome or total DNA complement to the original parent, due to natural, accidental, or deliberate mutation or manipulation.

As used herein, the term “cell line” refers to a population of cells capable of continuous or prolonged growth and division in vitro. Often, a cell line is a clonal population derived from a single progenitor cell. It is further known in the art that spontaneous or induced changes in karyotype can occur during storage or transfer of such clonal populations. Thus, cells derived from a referenced cell line may not be exactly identical to the progenitor cell or culture, and the referenced cell line includes such variants.

As used herein, the term "recombinant cell" refers to a cell into which an exogenous DNA segment has been introduced, such as a DNA segment that directs the transcription of a biologically active polypeptide (eg, GJB2 protein).

As used herein, the term “vector” refers to any genetic element, such as a plasmid, phage, transposon, cosmid, chromosome, artificial chromosome, capable of replicating and transferring genetic sequences between cells when associated with appropriate control elements. , viruses, virions, etc. Thus, the term includes cloning and expression vehicles as well as viral vectors. In some embodiments, useful vectors are considered to be those in which the nucleic acid segments to be transcribed are placed under the transcriptional control of a promoter. The term “expression vector or construct” refers to any type of genetic construct containing a nucleic acid from which part or all of a nucleic acid coding sequence can be transcribed.

The above method of packaging a recombinant vector into a desired AAV capsid to produce the rAAV of the present disclosure is not intended to be limiting, and other suitable methods will be apparent to those skilled in the art.

The present disclosure provides a rAAV comprising a vector (eg, an AAV vector) for expressing a transgene (eg, GJB2), such a vector comprising an AAV LTR (eg, an AAV2 LTR) and a promoter ( eg, an expression cassette comprising a promoter operably linked to the human GJB2 promoter or a fragment thereof). In addition, the vector may further include specific regulatory elements (eg, GJB2 enhancer, 5' and 3' UTRs of the GJB2 gene, WPRE, and polyadenylation sites). In addition, rAAV can include capsid proteins (eg, AAV9.PHP.B capsid or AAV-S capsid). Such rAAVs can deliver a transgene (eg, GJB2) to a target tissue (eg, cells that normally express GJB2 in the inner ear). In some embodiments, such rAAVs are capable of delivering a transgene (eg, GJB2) into specific cells within a target tissue, such as connective tissue cells of the cochlea and supporting cells of the organ of Corti and nearby regions.

III. pharmaceutical composition

rAAV can be delivered to a subject in a composition according to any suitable method known in the art. The rAAV, preferably suspended in a physiologically compatible carrier (i.e., in a composition), can be administered to a subject, eg, a host animal, patient, laboratory animal. In some embodiments, the subject is a mammal. In some instances, the mammal is a human. In other embodiments, the mammal is a non-human mammal, such as a human, mouse, rat, cat, dog, sheep, rabbit, horse, cow, goat, pig, guinea pig, hamster, chicken, turkey, or non-human primates (eg, cynomolgus monkeys). A subject can be of any developmental stage and of any gender.

rAAV can be delivered to any organ or tissue of interest. In some embodiments, rAAV is delivered to the inner ear. Delivery of rAAV to a mammalian subject can be, for example, by injection into the ear. In some embodiments, the injection is through the round window membrane of the inner ear into the ear, into the middle system of the cochlea, into the vestibular system of the cochlea, into the semicircular canals of the inner ear, or into the sac or ovoid sac of the inner ear. In some embodiments, rAAV is delivered to the ear by topical administration (eg, ear drops). In some embodiments, injection is not topical administration. A combination of methods of administration (eg, topical administration and injection through the round window membrane of the inner ear) may also be used.

A composition of the present disclosure may comprise a rAAV described herein alone or in combination with one or more other viruses (eg, a second rAAV encoding one or more different transgenes). In some embodiments, the composition comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more different rAAVs, each having at least one different transgene.

In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. Suitable carriers can be readily selected by those skilled in the art in view of the indication for which rAAV is indicated. "Acceptable" means that the carrier must be compatible with the rAAV or isolated nucleic acid of the composition (preferably capable of stabilizing the active ingredient) and must not be detrimental to the subject being treated. In some embodiments, the pharmaceutically acceptable carrier/excipient is compatible with the mode of administration. Pharmaceutically acceptable excipients (carriers), including buffers, are well known in the art. See, eg, Remington: The Science and Practice of Pharmacy 20th Ed. (2000) Lippincott Williams and Wilkins, Ed. K. E. Hoover]. For example, one acceptable carrier includes saline, which may be formulated with various buffering solutions (eg, phosphate buffered saline). Other exemplary carriers include sterile saline, lactose, sucrose, calcium phosphate, gelatin, dextran, agar, pectin, peanut oil, sesame oil and water. The choice of carrier is not a limitation of the present disclosure.

The rAAV-containing pharmaceutical compositions disclosed herein may further include suitable buffering agents. A buffer is a weak acid or base used to maintain the pH of a solution close to a selected value after the addition of another acid or base. In some examples, a buffer disclosed herein may be a buffer capable of maintaining physiological pH despite changes in carbon dioxide concentration (eg, produced by cellular respiration). Exemplary buffers include, but are not limited to, HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) buffer, Dulbecco's phosphate-buffered saline (DPBS) buffer, or phosphate-buffered saline (PBS) buffer. does not Such buffering agents may include disodium hydrogen phosphate and sodium chloride, or potassium dihydrogen phosphate and potassium chloride.

Optionally, the compositions of the present disclosure may contain other pharmaceutical ingredients, such as preservatives or chemical stabilizers, in addition to the rAAV and carrier(s). Suitable exemplary preservatives include chlorobutanol, potassium sorbate, sorbic acid, sulfur dioxide, propyl gallate, parabens, ethyl vanillin, glycerin, phenol, and parachlorophenol. Suitable chemical stabilizers include gelatin and albumin.

The rAAV-containing pharmaceutical compositions described herein include one or more suitable surface-active agents, such as surfactants. A surfactant is a compound that lowers the surface tension (or interfacial tension) between two liquids, between a gas and a liquid, or between a liquid and a solid. Surfactants can act as detergents, wetting agents, emulsifying agents, foaming agents and dispersing agents. Suitable surfactants are in particular non-ionic agents such as polyoxyethylenesorbitan (eg Tween™ 20, 40, 60, 80 or 85) and other sorbitans (eg Span ™ 20, 40, 60, 80 or 85). A composition with a surface-active agent will conveniently contain from 0.05 to 5% of the surface-active agent, and may be from 0.1 to 2.5%. It will be appreciated that other ingredients may be added, for example mannitol or other pharmaceutically acceptable vehicles, if desired.

rAAV is administered in an amount sufficient to transfect cells of the tissue of interest (e.g., connective tissue cells of the cochlea and support cells of the organ of Corti and nearby regions) and provide sufficient levels of gene transfer and expression without undue deleterious effects. do. Examples of pharmaceutically acceptable routes of administration include, but are not limited to, direct delivery to a selected organ (eg, ear) or tissue, intravenous, intramuscular, subcutaneous, intradermal, intratumoral, and other parenteral routes of administration. does not Routes of administration can be combined if desired.

The dose of rAAV virion required to achieve a particular "therapeutic effect", e.g., the dose of viral genome copies per kilogram of body weight (GC/kg or VG/kg), determines the route of rAAV virion administration, the therapeutic effect. It will vary based on several factors including, but not limited to, the level of gene or RNA expression required to achieve, the particular disease or disorder being treated, and the stability of the gene or rAAV product. One skilled in the art would treat a patient with a particular disease or disorder (e.g., non-syndromic deafness and hearing loss, or any GJB2-associated disorder) based on the factors mentioned above, as well as other factors. rAAV virion dose ranges for

An effective amount of rAAV can infect an animal (e.g., mouse, rat, non-human primate, or human) or target tissue or cells (e.g., connective tissue cells of the cochlea and supporting cells of the organ of Corti and nearby regions). ) in an amount sufficient to target. The effective amount will depend primarily on factors such as the species, age, weight, health, and tissue to be targeted of the subject, and may therefore vary between animals and tissues. For example, an effective amount of rAAV generally ranges from about 1 ml to about 100 ml of a solution containing about 10 ⁹ to 10 ¹⁶ genome copies. In some cases, a dosage of about 10 ¹¹ to 10 ¹³ rAAV genome copies is appropriate. In certain embodiments, 10 ⁹ rAAV genome copies are effective in targeting inner ear tissues (eg, connective tissue cells of the cochlea and supporting cells of the organ of Corti and nearby regions). In some embodiments, doses more concentrated than 10 ⁹ rAAV genome copies are toxic when administered to the ear of a subject. In some embodiments, the effective amount is produced by multiple doses of rAAV.

In some embodiments, the dose of rAAV is administered to the subject no more than once per day (eg, over a 24-hour period). In some embodiments, the dose of rAAV is administered to the subject no more than once every 2, 3, 4, 5, 6, or 7 days. In some embodiments, the dose of rAAV is administered to the subject no more than once per week (eg, 7 calendar days). In some embodiments, the dose of rAAV is administered to the subject every other week or less (eg, once in a 2-week period). In some embodiments, the dose of rAAV is administered to the subject no more than once per month (eg, once every 30 calendar days). In some embodiments, the dose of rAAV is administered to the subject no more than once every 6 months. In some embodiments, the dose of rAAV is administered to the subject no more than once per year (eg, 365 days or 366 days in a leap year). In some embodiments, the dose of rAAV is administered to the subject once per lifetime.

In some embodiments, the rAAV composition is formulated to reduce aggregation of AAV particles in the composition, particularly when high rAAV concentrations are present (eg, -10 ¹³ GC/ml or greater). Appropriate methods for reducing aggregation may be used, including, for example, addition of surfactants, adjustment of pH, adjustment of salt concentration, etc. (see, for example, Wright et al. , Molecular Therapy (2005) 12, 171-178).

The formulation of pharmaceutically acceptable excipient and carrier solutions is well known to those skilled in the art, as is the development of suitable administration and treatment regimens for use of the particular compositions described herein in a variety of treatment regimens. Factors such as solubility, bioavailability, biological half-life, route of administration, product shelf life, as well as other pharmacological considerations will be taken into account by those skilled in the art of preparing such pharmaceutical formulations, and thus various dosages and A treatment regimen may be desirable.

In some embodiments, the rAAV in a suitably formulated pharmaceutical composition disclosed herein is delivered directly to a target tissue, e.g., to inner ear tissue (e.g., connective tissue cells of the cochlea and supporting cells of the organ of Corti and nearby regions) do. However, in certain circumstances, it is desirable to individually or additionally deliver the rAAV-based therapeutic construct via another route, for example subcutaneously, parenterally, intravenously, intramuscularly, intrathecally, orally or intraperitoneally. can do. In some embodiments, U.S. Patent Nos. 5,543,158; 5,641,515 and 5,399,363, each specifically incorporated herein by reference in its entirety, may be used to deliver rAAV.

Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof, and in oils. Under normal conditions of storage and use, these formulations contain preservatives to prevent the growth of microorganisms. In many cases, the form is sterile. It must be stable under the conditions of manufacture and storage and must be preserved to prevent contamination by microorganisms such as bacteria, fungi and other viruses. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (eg, glycerol, propylene glycol, liquid polyethylene glycol, and the like), suitable mixtures thereof, and/or vegetable oils. Adequate fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of contamination by microorganisms can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases it will be desirable to include a tonicity agent such as a sugar or salt (eg sodium chloride). Prolonged absorption of the injectable compositions can be brought about by using in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin.

For administration of an aqueous injectable solution, for example, the solution may be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are particularly suitable for intravenous administration, intramuscular administration, subcutaneous administration, intraperitoneal administration, and injection through the round window membrane of the inner ear. In this regard, any suitable sterile aqueous medium may be used. For example, a single dose can be dissolved in 1 ml of isotonic NaCl solution and added to 1000 ml of subcutaneous infusion or injected at the proposed site of infusion (see, e.g., Remington's Pharmaceutical Sciences 15th Edition, pages 1035-1038 and 1570-1580). Some variation in dosage will inevitably occur depending on the condition of the host. The person responsible for administration will determine the appropriate dose for the individual subject/host in any case.

Sterile injectable solutions are prepared by incorporating the active rAAV in the required amount in an appropriate solvent with various other ingredients described herein as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of a sterile powder for the preparation of a sterile injectable solution, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which produce a powder of the active ingredient plus any additional desired ingredient from its previously sterile-filtered solution. am.

The rAAV compositions disclosed herein may also be formulated in neutral or salt form. Pharmaceutically acceptable salts include, but are not limited to, hydrochloric or phosphoric acids, or organic acids such as acetic acid, oxalic acid, tartaric acid, mandelic acid, and the like. Salts formed with free carboxyl groups are also derived from inorganic bases such as, for example, sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide or ferric hydroxide, and organic bases such as isopropylamine, trimethylamine, histidine, procaine, and the like. It can be. When formulated, the solution will be administered in a manner compatible with the dosage formulation and in a therapeutically effective amount. The formulation is readily administered in a variety of dosage forms, such as injectable solutions, drug-releasing capsules, and the like.

As used herein, "carrier" includes any and all solvents, dispersion media, vehicles, solvents, coatings, diluents, antibacterial and antifungal agents, isotonic and absorption delaying agents, buffers, carrier solutions, suspensions, colloids, and the like. . The use of such media and agents for pharmaceutical active substances is well known in the art. Supplementary active ingredients may also be incorporated into the compositions. The phrase “pharmaceutically acceptable” refers to molecular substances and compositions that do not cause allergic or similar adverse reactions when administered to a host.

Delivery vehicles such as liposomes, nanocapsules, microparticles, microspheres, lipid particles, vesicles, and the like can be used to introduce compositions of the present disclosure into suitable host cells. In particular, rAAV vector-delivered transgenes can be formulated for delivery encapsulated in lipid particles, liposomes, vesicles, nanospheres, nanoparticles, and the like.

Such formulations may be desirable for incorporation of pharmaceutically acceptable formulations of the nucleic acids or rAAV constructs disclosed herein. The formation and use of liposomes is generally known to those skilled in the art. Recently, liposomes with improved serum stability and circulating half-life have been developed (U.S. Patent No. 5,741,516, incorporated herein by reference). Additionally, various methods of liposomes and liposome-like formulations as potential drug carriers have been described (US Pat. Nos. 5,567,434; 5,552,157; 5,565,213; 5,738,868 and 5,795,587, each of which is incorporated herein by reference).

Alternatively, nanocapsule formulations of rAAV may be used. Nanocapsules can generally entrap substances in a stable and reproducible manner. To avoid side effects due to intracellular polymer overload, these ultrafine particles (approximately 0.1 μm in size) should be designed using polymers that can be degraded in vivo. Biodegradable polyalkyl-cyanoacrylate nanoparticles that meet these requirements are contemplated for use.

IV. therapeutic use

The present disclosure also relates to cells that normally express a transgene (eg, GJB2) in the ear of a subject (eg, connective tissue cells of the cochlea and supporting cells of the organ of Corti and nearby areas) to treat hearing loss. Methods of delivering a transgene (eg, GJB2) (eg, by an isolated nucleic acid, vector, rAAV, host cell, or pharmaceutical composition described herein) are provided. In some aspects, the present disclosure provides cells that normally express a transgene (eg, GJB2) in the ear of a subject (eg, connective tissue cells of the cochlea and supporting cells of the organ of Corti and nearby areas) transgene ( GJB2 associated disease (eg, non-syndromic hearing loss and A method for treating hearing loss (DFNB1)) is provided. In some aspects, the present disclosure provides cells that normally express a transgene (eg, GJB2) in the ear of a subject (eg, connective tissue cells of the cochlea and supporting cells of the organ of Corti and nearby areas) transgene ( eg, GJB2) (eg, by an isolated nucleic acid, vector, rAAV, host cell, or pharmaceutical composition described herein), thereby targeting GJB2 expression in inner ear supporting cells and/or neurons and/or or detargeting GJB2 in cochlear hair cells. In some embodiments, targeted GJB2 expression in inner ear supporting cells and/or detargeting of GJB2 in neurons and/or cochlear hair cells is designed to treat a GJB2-associated disease described herein. In some embodiments, the subject is a mammal. In some examples, the subject is a human. In other embodiments, the subject is a non-human mammal, such as a mouse, rat, cow, goat, pig, camel, or non-human primate (eg, a cynomolgus monkey).

In some embodiments, the subject has or is suspected of having a hearing loss. In certain embodiments, the subject is diagnosed as having non-syndromic deafness and hearing loss (DFNB1). In certain embodiments, hearing loss is associated with mutations in the GJB2 gene. In some embodiments, the mutation of the GJB2 gene is a point mutation, missense mutation, nonsense mutation, deletion, insertion, or combination thereof. Non-limiting examples of mutations in the GJB2 gene are shown in Table 2. Mutation, as used herein, refers to the substitution of a residue in a sequence, eg, a nucleic acid or amino acid sequence, with another residue, or the deletion or insertion of one or more residues in a sequence. Mutations are typically described herein by identifying the original residue, then identifying the location of that residue in the sequence and the identity of the newly substituted residue.

Table 2: Exemplary mutations in the GJB2 gene (nucleotide numbers start at ATG of NM_004004.6).

Aspects of the present disclosure include the use of gene therapy (eg, a rAAV encoding a GJB2 protein) to generate a functional gene product (eg, a GJB2 protein) in the presence of a related gene (eg, a gene product that results in the absence or malfunction of the gene product). For example, by delivering to a target cell (eg, cells that normally express GJB2, such as fibrocytes and support cells of the organ of Corti and nearby regions) comprising one or more mutations in at least one allele in GJB2) A method of treating hearing loss (eg, DFNB1).

Aspects of the invention relate to certain protein-encoding transgenes (eg, GJB2) effective for treating hearing loss (eg, DFNB1) when delivered to a subject. In some embodiments, the subject has or is suspected of having a hearing loss. In some embodiments, hearing loss is associated with a mutation in the GJB2 gene. In some embodiments, the hearing loss is associated with mutations in the GJB2 gene listed in Table 2 (above). In some embodiments, the subject is diagnosed with DFNB1.

Thus, the methods and compositions described by this disclosure are useful, in some embodiments, for the treatment of DFNB1 associated with one or more mutations or deletions in the GJB2 gene.

Methods of delivering a transgene (eg, GJB2) to a subject are provided by the present disclosure. The methods typically involve administering to the subject an effective amount of an isolated nucleic acid encoding a GJB2 protein, or a rAAV comprising a nucleic acid for expressing GJB2.

In some embodiments, GJB2 mutations include, but are not limited to, point mutations, missense mutations, nonsense mutations, insertions and deletions. In some embodiments, GJB2 gene mutations associated with DFNB1 include, but are not limited to, those in Table 2. In some embodiments, the mutation in the GJB2 gene is c.101T>C. In some embodiments, the mutation in the GJB2 gene is 35DelG. A GJB2 mutation in a subject (eg, a subject suspected of having or having DFNB1 associated with a deletion or mutation of the GJB2 gene) can be determined in a sample obtained from the subject by any method known in the art (eg, DNA samples, RNA samples, blood samples, or other biological samples). For example, in some embodiments, nucleic acids (eg, DNA, RNA, or combinations thereof) are extracted from a biological sample obtained from a subject, and nucleic acid sequencing is performed to identify mutations in the GJB2 gene. In some embodiments, mutations in the GJB2 gene are determined, for example, by quantifying GJB2 protein expression (eg, by Western blot) or function (eg, by analysis of structure, function, etc.), or DNA is detected indirectly by direct sequencing and comparing the resulting sequence to a control DNA sequence (eg, wild-type GJB2 DNA sequence).

In some aspects, the present disclosure provides treatment of DFNB1 comprising administering to a subject having or suspected of having DFNB1 a therapeutically effective amount of an isolated nucleic acid, or rAAV encoding a transgene (eg, GJB2). A method of treating DFNB1 in a subject in need thereof is provided. In some embodiments, an rAAV encoding a transgene (eg, GJB2) is injected via injection into the round window membrane of the inner ear, as described by the present disclosure. In some aspects, the present disclosure provides an isolated nucleic acid or rAAV encoding a transgene (eg, GJB2), or a pharmaceutical composition thereof, for use in the manufacture of a medicament in therapy. In some aspects, the present disclosure provides an isolated nucleic acid or rAAV encoding a transgene (e.g., GJB2) for use in the manufacture of a medicament for treating hearing loss and/or deafness associated with the GJB2 gene, or a pharmaceutical thereof. composition is provided. In some aspects, the present disclosure provides an isolated nucleic acid or rAAV encoding a transgene (eg, GJB2) for use in the manufacture of a medicament for treating non-syndromic deafness and/or hearing loss (DFNB1). , or a pharmaceutical composition thereof.

An “effective amount” of a substance is an amount sufficient to produce the desired effect. In some embodiments, an effective amount of an isolated nucleic acid (eg, an isolated nucleic acid comprising a transgene encoding a GJB2 protein) is sufficient to transfect (or rAAV mediated delivery) a sufficient number of target cells of a target tissue of a subject. in an amount sufficient to infect). In some embodiments, the target tissue is the cochlea (eg, connective tissue cells of the cochlea and supporting cells of the organ of Corti and nearby regions, as described herein). In some embodiments, an effective amount of an isolated nucleic acid (eg, one that can be delivered via rAAV) increases or supplements expression of, eg, a gene or protein of interest (eg, a GJB2 protein), or a subject in an amount sufficient to have therapeutic benefit, such as ameliorating one or more symptoms of a disease (eg, symptoms or signs of DFNB1). The effective amount will depend on various factors, such as, for example, the species, age, weight, health, and tissue to be targeted of the subject, and may therefore vary between subjects and tissues as described elsewhere in this disclosure. In some embodiments, an effective amount of rAAV may be an amount sufficient to produce a stable somatic transgenic animal model.

An effective amount may also vary depending on the rAAV used. The present invention relates in part to the fact that rAAVs comprising capsid proteins having a particular serotype (e.g., AAV9.PHP.B or AAV-S) are superior to rAAVs comprising capsid proteins having different serotypes (e.g., AAV9.PHP.B or AAV-S). , inner hair cells, outer hair cells) mediate more efficient transduction of tissues.

In certain embodiments, an effective amount of rAAV is 10 ¹⁰ , 10 ¹¹ , 10 ¹² , 10 ¹³ , or 10 ¹⁴ genome copies per kg. In certain embodiments, an effective amount of rAAV is 10 ¹⁰ , 10 ¹¹ , 10 ¹² , 10 ¹³ , 10 ¹⁴ , or 10 ¹⁵ genome copies per subject.

An effective amount may also depend on the mode of administration. For example, targeting tissue of the cochlea (e.g., connective tissue cells of the cochlea and supporting cells of the organ of Corti and nearby regions) by injection through the round window membrane of the inner ear is, in some cases, another method (e.g., , systemic administration, local administration) requires different (eg, higher or lower) doses to target tissues of the cochlea (eg, connective tissue cells of the cochlea and supporting cells of the organ of Corti and nearby areas) can be done with Thus, in some embodiments, the injection is through the round window membrane of the inner ear. In some embodiments, the administration is topical administration (eg, topical administration to the ear). In some embodiments, the injection is a posterior semicircular canal injection. In some cases, multiple doses of rAAV are administered.

Without wishing to be bound by any particular theory, efficient transduction of cochlear cells (e.g., connective tissue cells of the cochlea as described herein and supporting cells of the organ of Corti and nearby regions) by the rAAVs described herein may It can be useful in the treatment of a subject with a loss (eg, DFNB1). In some embodiments, the compositions and methods described herein may be useful for treating other GJB2-associated diseases. A GJB2-associated disease, as used herein, refers to conditions and/or disorders caused by GJB2 mutations (eg, loss-of-function mutations). Non-limiting GJB2-associated disorders include deafness, autosomal recessive 1A, deafness, autosomal dominant 3A, DFNB1, keratitis-ichthyosis-deafness (KID), ichthyosis, histrix-like-deafness (HID), palmar plantar keratoderma. -includes deafness (PPK), porkeratosis eccrine pits and dermal ductal nevi, Vohwinkel's, Bart-Pumpuri, and atypical mucocutaneous-deafness (see, e.g., Srinivas et al., Human diseases associated with connexin mutations, Biochimica et Biophysica Acta (BBA) - Biomembranes, Volume 1860, Issue 1, January 2018, Pages 192-201; Lossa et al., GJB2 Gene Mutations in Syndromic Skin Diseases with Sensorineural Hearing Loss, Curr Genomics. 2011 Nov;12(7): 475-785).

Accordingly, methods and compositions for treating hereditary hearing loss are also provided herein. In some aspects, the present disclosure provides treatment of a subject having, or suspected of having, a genetic hearing loss (eg, DFNB1) or any other GJB2- described herein, comprising administering an effective amount of rAAV. A method of treating an associated disease is provided, wherein the rAAV comprises (i) a capsid protein having a serotype of AAV9.PHP.B, or AAV-S, and (ii) two adeno-associated viruses flanking an expression cassette. (AAV) an inverted terminal repeat (ITR), wherein the expression cassette comprises a nucleotide sequence encoding a GJB2 gene regulatory element (GRE), and a gap junction beta 2 (GJB2) protein encoding A promoter operably linked to the nucleotide sequence.

In some embodiments, an rAAV (eg, an rAAV encoding GJB2) is 1 day old, 10 days old, 1 month old, 3 months old, 6 months old, 1 year old, 2 years old, 3 years old, 5 years old, 6 years old, 7 years old , 8 years of age, 9 years of age, 10 years of age, 11 years of age, 12 years of age, 13 years of age, 14 years of age, 15 years of age, 16 years of age, 17 years of age, 18 years of age or older (eg, patients with DFNB1) can In some embodiments, the patient is an infant, child, or adult. In some embodiments, the treatment window for a GJB2-associated disease (eg, DFNB1) normally ranges from birth to preschool age (eg, from birth to 1 year, 1 to 2 years, 2-3 years, 3 years -4 years old, 4-5 years old, or 5-6 years old). In some embodiments, an rAAV (eg, an rAAV encoding GJB2) is administered to a patient (eg, a patient with DFNB1) once, every 10 years, every 5 years, every 2 years, every year, 6 years Monthly, every 3 months, monthly, every 2 weeks, or weekly administration. In other embodiments, administration of a rAAV (eg, an rAAV encoding GJB2) is administered to a patient (eg, having DFNB1) in combination with other known methods of treatment for a GJB2-associated disease (eg, DFNB1). administered to the patient).

V. Kits and Related Compositions

Agents described herein, in some embodiments, can be assembled into pharmaceutical or research kits to facilitate their use in therapeutic or research applications. A kit may include one or more containers containing components of the present disclosure (eg, nucleic acids, rAAV) and instructions for use. Specifically, such kits may include one or more agents described herein, along with instructions describing the intended and appropriate uses of these agents. In certain embodiments, the agent in the kit may be a pharmaceutical formulation and dosage suitable for the particular application and method of administration of the agent. Kits for research purposes may contain components in appropriate concentrations or amounts to perform various experiments.

In some embodiments, the disclosure relates to kits for administering rAAV as described herein. In some embodiments, a kit includes a container that contains rAAV, and a device (eg, a syringe) for extracting rAAV from the reservoir. In some embodiments, the device for extracting rAAV from the reservoir is also used for administration (eg, injection).

In some embodiments, the disclosure relates to a kit for producing rAAV comprising a container containing an isolated nucleic acid comprising a transgene encoding a protein (eg, GJB2). In some embodiments, the kit further comprises a container containing an isolated nucleic acid encoding an AAV capsid protein, eg, an AAV.PHP.B capsid protein or an AAV-S capsid protein. In some embodiments, the kit further comprises a vector encoding the rep/cap genes, and a host for producing the rAAV.

In some embodiments, the disclosure relates to kits for treating hearing loss (eg, DFNB1). In some embodiments, the kit uses gene therapy (e.g., a rAAV described herein) to target cells (e.g., connective tissue cells of the cochlea and support cells of the organ of Corti and nearby regions as described herein) ) (eg, DFNB1).

Kits can be designed to facilitate use by researchers of the methods described herein, and can take many different forms. Each composition of the kit may be provided in liquid form (eg, a solution) or solid form (eg, a dry powder), where applicable. In certain instances, some compositions may or may not be provided (e.g., in active form) by addition of a suitable solvent or other medium (e.g., water or cell culture medium), which may or may not be provided in a kit. ) may be configurable or otherwise machinable. As used herein, “instructions” may include elements of instructions and/or publicity, and typically include written instructions on or associated with packaging. Instructions may also include any oral or electronic instructional material, eg audiovisual material (eg videotape, DVD, CD-ROM, downloadable website links to possible files, etc.), Internet and/or web-based communications, and the like. Written instructions may be in the form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceutical or biological products, and these instructions may also reflect approval by the agency of manufacture, use, or sale for veterinary administration. .

A kit may contain any one or more components described herein in one or more containers. By way of example, in one embodiment, a kit may include instructions for mixing one or more components of the kit and/or isolating and mixing a sample and applying to a subject. A kit may include a container containing a rAAV described herein. rAAV can be in the form of a liquid, gel or solid (powder). rAAV can be prepared sterile, packaged in syringes, and shipped refrigerated. Alternatively, rAAV may be housed in vials or other containers for storage. The second container may have the other agent prepared sterilely. Alternatively, the kit may include rAAV premixed and shipped in a syringe, vial, tube, or other container.

VI. general skills

The practice of the present invention will, unless otherwise indicated, employ conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry and immunology, which are within the skill of the relevant art. Molecular Cloning: A Laboratory Manual, second edition (Sambrook, et al., 1989) Cold Spring Harbor Press; Oligonucleotide Synthesis (M. J. Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (J. E. Cellis, ed., 1998) Academic Press; Animal Cell Culture (R. I. Freshney, ed., 1987); Introduction to Cell and Tissue Culture (J. P. Mather and P. E. Roberts, 1998) Plenum Press; Cell and Tissue Culture: Laboratory Procedures (A. Doyle, J. B. Griffiths, and D. G. Newell, eds., 1993-8) J. Wiley and Sons; Methods in Enzymology (Academic Press, Inc.); Handbook of Experimental Immunology (D. M. Weir and C. C. Blackwell, eds.); Gene Transfer Vectors for Mammalian Cells (J. M. Miller and M. P. Calos, eds., 1987); Current Protocols in Molecular Biology (F. M. Ausubel, et al., eds., 1987); PCR: The Polymerase Chain Reaction, (Mullis, et al., eds., 1994); Current Protocols in Immunology (J. E. Coligan et al., eds., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (C. A. Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: a practical approach (D. Catty., ed., IRL Press, 1988-1989); Monoclonal antibodies: a practical approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000); Using antibodies: a laboratory manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999)); The Antibodies (M. Zanetti and J. D. Capra, eds., Harwood Academic Publishers, 1995)].

Without further elaboration, it is believed that a person skilled in the relevant art can utilize the present invention to its fullest extent based on this disclosure. Accordingly, the specific embodiments that follow are to be construed as illustrative only and not limiting the remainder of the disclosure in any way. All publications cited herein are incorporated by reference for the purpose or subject matter mentioned herein.

Exemplary embodiments of the present invention will be described in more detail by means of the following examples. These embodiments are illustrative of the present invention, and those skilled in the art will recognize that they are not limited to the illustrative embodiments.

Example

Hearing impairment of genetic origin occurs in about 1 in 1,000 births; Most are autosomal recessive and non-syndromic. Although more than 70 different hearing loss genes have been identified, nearly half of all cases of severe to severe autosomal recessive non-syndromic hearing loss involve the gap-junction protein connexin 26, which contains six subunits that form a hemichannel. It arises from a mutation in only one gene, GJB2, which encodes. Each subunit has four transmembrane helices, which assemble at the face of the membrane to form a large central pore (FIG. 1A). GJB2 hemichannels from adjacent cells bind to create channels from the cytoplasm of one cell to the cytoplasm of another cell. Gap junctions are formed by hundreds or thousands of channels packed in synaptic plaques.

In the cochlea, GJB2 is expressed in two cell populations: the epithelial system, which includes supporting cells of the organ of Corti, epithelial cells of the inner and outer sulci, and interdental cells; and the cytoplasmic system including fibrocytes of the lateral wall and supravascular regions, basal cells of the vascular progenitors, and supramarginal dark cells (see, e.g., Kikuchi et al., (1995) Gap junctions in the rat cochlea: immunohistochemical and ultrastructural analysis (see Anat Embryol (Berl) 191:101-118). It is not expressed in hair cells. In the cochlea, the epithelial system is predominantly post-mitotic. In contrast, fibroblasts in the cytoplasmic system convert slowly, but some cell division is observed with BrdU labeling (Lang et al., 2002; Li et al., 2017). The structure of the cochlea and fibrocyte/Corti support cell network is shown in FIGS. 1A-1B.

GJB2 expression is important for cochlear function. For example, K ⁺ entering hair cells via transduction channels and released via basal K ⁺ channels is shuttled from the Organ of Corti by the epithelial system and transported by the cytoplasmic system to the vasculature, where it is returned to the endolymph. pumped up In addition, GJB2 plays a role in the development of cochlea, as mice lacking GJB2 in the inner ear have reduced intra-cochlear potential and severe apoptotic loss of hair cells and supporting cells by P30, even though hair cells do not express Gjb2. (Cohen-Salmon et al., 2002; Wang et al., 2009; Sun et al., 2009; Crispino et al., 2011; Johnson et al., 2017). When Gjb2 is deleted after P6, the phenotype is much milder (Chang et al., 2015). However, a long-term requirement for GJB2 remains: hair cell loss occurs after several months as late as P14 despite deletion (Ma et al., 2020). Without wishing to be bound by the theory described herein, GJB2's function in the shuttling of K ⁺ may be related to its role in the development of the cochlea: K ⁺ is not transported away from hair cells by the gap junction network. In some cases, K ⁺ accumulation can depolarize hair cells, causing Ca ²⁺ influx and eventual cell death. The gap junction network may also be required to transport glucose and nutrients from blood vessels to the sensory epithelium, and its absence can lead to cell death (Chang et al., 2008; Mammano, 2019).

Loss of GJB2 expression underlies a disorder called non-syndromic deafness and hearing loss (DFNB1), characterized by recessive, mild to severe sensorineural hearing impairment (Kelsell et al., 1997; Kenna et al., 2010). ). More than 100 mutations have since been described in patients, but nearly 60% of patients have a single base deletion (35delG) leading to frameshifts and arrests (Kenna et al., 2010). In the United States alone, approximately 3,500 children with two mutations in the causative gene, GJB2, are born each year (Kelsell et al., 1997; Zelante et al., 1997; Azaiez et al., 2018). Many are born with severe hearing loss, which is probably irreversible even at birth. Two-thirds have some residual hearing at birth, and most of these lose hearing over the next few years, suggesting that a window for therapeutic intervention exists (Kenna et al., 2010). Thus, there are 5-10,000 preschool-aged children who are potential candidates for treatment of DFNB1 ( FIG. 1D ).

Because the cochlea is a surgically accessible and relatively immunoprotective environment, gene therapy using viral vectors is an attractive approach. The GJB2 coding sequence is small (~680 bp) and will fit easily into an AAV vector. Although AAV does not integrate into the genome and is diluted in dividing cells, most cochlear cells do not divide, and AAV can induce expression for decades or more. Injections of rAAV carrying the coding sequence of GJB2 are normally injected through the round window membrane (RWM) (Fig. 2a). However, previous trials of gene therapy did not rescue hearing, although the genetic addition of GJB2 rescued cell survival and gap junction networks.

Surprisingly, it was found that indiscriminate expression of GJB2 in the cochlea impairs the function of hair cells and neurons, although it rescues function in fibrocytes and supporting cells. Additionally, mixed expression of GJB2 in the inner ear impaired hearing in wild-type mice (Fig. 2b).

Gap junctions create low-resistance pathways between adjacent cells. However, hair cells and neurons of the cochlea rely on highly-resistive membranes to generate depolarization with small transduction or synaptic currents. If either is electrically coupled to an adjacent cell, the depolarization will be shorted and the signal to the brain is lost. The surprising phenomenon of hearing loss induced by confluent GJB2 expression can be explained by indiscriminate gap-junction coupling of hair cells that do not normally express GJB2. Thus, effective gene therapy treatment should induce cell-specific expression of exogenous GJB2 in cells that normally express the gene (eg, fibrocytes and supporting cells) to rescue hearing in subjects with GJB2 mutations.

To achieve cell specific GJB2 expression, cis-regulatory elements of the GJB2 gene were evaluated. Large genomic deletions from 130 to >300 kb upstream of GJB2 have been shown to cause congenital extreme hearing loss. Duplicate analysis of these deletions revealed a ∼95 kb shared region suspected to house the important enhancer(s) for GJB2 expression in the inner ear (FIG. 3A).

A combination of patient genomic data, ATAC-Seq and in vitro assays was used to identify cis-regulatory enhancers of GJB2 in human patients. Patients with suspected GJB2-related hearing loss were screened by targeted genome enrichment or genome sequencing coupled with massively parallel sequencing to search for non-coding disease-causing variants within the -95.4 kb window (FIG. 3B). The genotype and phenotype of patients screened with the OtoSCOPE panel were reviewed. The initial selection round included all patients who were heterozygous for a known or predicted pathogenic variant in the GJB2 coding sequence and had a negative genetic diagnosis for their hearing loss. Next, the cohort of patients was refined based on phenotype. Patients carrying loss-of-function mutations in trans with mutations in cis-regulatory elements will have congenital severe to extreme hearing loss. Families with recessive hearing loss that exhibit linkage/allelic segregation for the GJB2 locus and lack coding variants within GJB2 were also studied.

After sequencing, data were analyzed by a custom bioinformatics pipeline according to the GATK best practices of The Broad Institute. Briefly, the raw sequence was mapped to the genome using a Burrows-Wheeler Aligner, followed by removal of duplicates with a Picard, and a genome analysis tool kit (for variant calling) GATK), and ensemble variant effect predictors and dbNSFP were mapped to annotate for variant annotation. After annotation, variants were filtered based on quality, minor allele frequency and location (within a ~95 kb window). Variants were prioritized based on variants falling within regulatory elements as defined by the Encyclopedia of DNA Elements (ENCODE) and genotype-tissue expression. More than 100 patients were sequenced and more than 200 candidate variants were identified. Approximately 5-10% of DFNB1 patients have a second disease-causing allele in the non-coding region.

Identification of enhancers for genes active in the cochlea using ATAC-Seq (assay for transposase-accessible chromatin using sequencing; Buenrostro et al., 2013) in mice and non-human primates did ATAC-Seq uses a hyperactive mutant Tn5 transposase that inserts sequencing adapters into open regions of the genome. Genomic DNA was then sequenced from the adapters to confirm open chromatin.

Cochleas were dissected from neonatal mice at P2, P5 and P8 stages, when the cochleas had acquired normal function. One cochlea was dissected from an adult macaque monkey. This data set makes an important contribution to the study of gene regulation in the cochlea. It can be used, for example, to induce gene expression in certain cell types that are frequently damaged in both hereditary and acquired hearing loss, such as hair cells, adjacent stem cells, and spiral ganglion neurons.

Eighteen candidate enhancers associated with the mouse Gjb2 gene were identified. Figure 3c shows ~200 kb of mouse genomic sequence in the region of the mouse Gjb2 gene; Regions with multiple ATAC-Seq reads are highlighted. Subsequent studies have focused on enhancers located near the mouse Gjb2 gene that are conserved among mammalian species. Figure 3c (top) shows the identification of the mouse Gjb2 gene regulatory element (GRE) in the UCSC Genome Browser View of ATAC-Seq from mouse cochleas at developmental stages P2, P5 and P8, spanning ~300 kb in the mouse Gjb2 gene region. indicate Shaded regions indicate regions containing putative GREs (human and mouse region sequences containing GREs are listed in Table 1). The X-axis is the genomic region on chr14 in the mouse genome. The Y-axis is the number of reads from ATAC-Seq that align to specific regions in the genome. Light blue highlights indicate regions of open chromatin that are characteristic of regions of transcriptional activity enriched in read pile-up, suggesting higher activity in these regions. Regions A and B represent transcriptionally active sequences within mouse Gjb2 itself. Regions C-M are transcriptionally active regions around Gjb2 that may be part of a cis-regulatory network. The GJB2 GRE sequence was confirmed with the region sequences listed in Table 1. Figure 3c (bottom) shows the transcriptionally active regions within and around light blue shaded regions identified as specific mouse Gjb2 GREs (GREs 2, 3, 5, 7, and 9). The human GJB2 GRE sequence was confirmed in silico by modeling the mouse Gjb2 GRE. The nucleotide sequences of human GREs 1, 2, 3, 4, 5, 7 and 9 are shown in Table 3 and tested in subsequent experiments.

Additionally, the promoter, 5' UTR and/or 3' UTR of the GJB2 gene also contains native regulatory sequences. Constructs containing promoters, 5' UTRs and/or 3' UTRs were designed and tested for their ability in cell specific GJB2 expression. The construct was packaged into rAAV and injected into the inner ear of mice. Cell types expressing the marker gene were compared to cell types expressing GJB2. For example, a C15 vector was constructed to contain a 500 bp human GJB2 promoter, and a 300 bp 5' UTR, followed by the coding sequences for GFP and human GJB2 3' UTR (vector C15 in FIG. 3D). The C15 vector was packaged into rAAV using the AAV9-PHP.B capsid, which was previously shown to be effective in transducing multiple cochlear cell types (Gyorgy et al., 2018). AAV9-PHP.B-C15 virus was injected into the inner ear of PO mouse pups. GJB2 expression was detected by immunofluorescence using an antibody targeting GJB2 (Fig. 3f, middle panel). Cells transduced with the AAV9-PHP.B-c15 vector and expressing the GFP marker gene under the GJB2 enhancer are shown in the left panel. The expression pattern of GJB2 in the inner ear was consistent with that reported by Kikuchi. In the right panel, IHC and OHC (indicated) are also identified by labeling actin with fluorescent phalloidin. In the right panel, IHC and OHC (indicated) are also identified by labeling actin with fluorescent phalloidin. In particular, AAV9-PHP.B-C15 could be efficiently transduced into hair cells, but no GFP expression was observed in hair cells. This may be because the Gjb2 enhancer is not active in hair cells. Figure 3f shows the segment of the mouse cochlea from the lateral wall (top) to the interdental cells (bottom). Cells transduced with the AAV9-PHP.B-C15 vector and expressing the GFP marker gene under the Gjb2 enhancer are shown in the left panel. Cells normally expressing Gjb2 are shown in the middle panel. In the right panel, IHC and OHC (indicated) are also identified by labeling actin with fluorescent phalloidin. The expression pattern of GFP induced by the c15 construct is consistent with native Gjb2 expression reported by Kikuchi et al., 1995 using the same antibody against GJB2. In particular, c15 does not induce GFP expression in hair cells.

Additionally, other constructs (C20-C23) were designed to test exogenous GJB2 expression under the mixed chicken beta actin (CBA) promoter. In the C20 vector, the human GJB2 coding sequence was driven by the CBA promoter (Fig. 3e, vector C20). The C20 vector was packaged into rAAV and injected into the P0 cochlea in mice. GJB2 expression was confirmed in hair cells by immunofluorescence using the GJB2 antibody (FIG. 3g). Expression of GJB2 by hair cells will create electrical coupling to adjacent supporting cells and short-circuit normal sensory receptor potentials. To test this theory, several different vectors were designed. The C21 vector contains a CBA promoter operably linked to the human GJB2 coding sequence carrying the 35delG mutation. Active GJB2 protein cannot be produced by the C21 vector. The C22 vector contains the CBA promoter without the GJB2 coding sequence. The C23 vector contains a CBA promoter that drives expression of human Clarin 1, a protein normally expressed by hair cells. Vectors were packaged into rAAV using AAV1 or AAV9-PHP.B capsids. rAAV was injected into the inner ear of mice through the round window membrane at P1, and the auditory brainstem response (ABR) was measured at P30 (thresholds at 8, 11 and 16 kHz averaged). As shown in Fig. 3h, uninfected wild-type mice had ABR thresholds near 30 dB, and saline mock injection did not change ABR thresholds in wild-type mice. Expression of GJB2 using the CBA promoter in AAV1 or AAV9-PHP.B capsids raised the threshold by 30-40 dB. For comparison, conditional knockout Cre+, Gjb2 ^fl/fl mice did not respond at the highest level tested (90 dB). Additionally, it was observed that mice injected with AAV9-PHP.B-C20 frequently exhibited neurological symptoms including seizures and often death. Vector AAV9-PHP.B-C21 (expressing GJB2 with an inactivating mutation), AAV9-PHP.B-C22 (no GJB2 coding sequence), or AAV9-PHP.B-C23 (clarin 1, a normal hair-cell protein) expression), no lethality was observed. In addition, no toxicity or lethality was observed with either vector when the rAAV was diluted 10-fold or 100-fold prior to injection. It is possible that small amounts of rAAV encoding GJB2 reached the brain due to the brain tropism of AAV9-PHP.B, where the electrical coupling of neurons impairs neural control of the homeostatic system. This unexpectedly but dramatically revealed the need to restrict GJB2 expression to appropriate cells to reduce toxicity.

Sox10-Cre+,Gjb2 ^fl/fl knockout mice were unresponsive at the highest level tested (90 dB) (Fig. 3h). In knockout, AAV1-CBA-GJB2 or AAV9-PHP.B-CBA-GJB2 rAAVs did not cause rescue. A C70 construct was produced to test the enhancer in rescuing hearing. The C70 construct contains an AAV 5' ITR, a GJB2 basal promoter, a GJB2 exon 1 5' UTR, a Kozak sequence, a mouse or human GJB2 coding sequence, an optional HA tag, a GJB2 exon 2 3' UTR, a WPRE, a bovine growth hormone poly A signal, and AAV 3' ITRs. The C70 construct was packaged into rAAV using the AAV9-PHP.B capsid protein and injected into the inner ear of both wild-type mice and Sox10-Cre+,Gjb2 ^fl/fl knockout mice. Gjb2 expression rescued hearing by 15-20 dB in Sox10-Cre+,Gjb2 ^fl/fl knockout mice. The same vector did not impair hearing in wild-type mice (Fig. 3h). 3I-3L show maps of c70 vector plasmids encoding mouse GJB2 or human GJB2 with or without an HA tag. 3M shows a schematic of vector c.70 encoding mouse GJB2 or human GJB2 with or without an HA tag. Figure 3n shows additional vectors generated and tested.

In addition, other AAV capsid proteins with tropism for inner ear cells were tested for their ability to deliver a transgene (eg, GJB2 or GFP) to appropriate inner ear cells and rescue hearing in both mice and primates. The AAV-S capsid protein originally developed for brain orientation showed superior transduction of GJB2-expressing cells in both the mouse and primate cochlea ( FIG. 4 ). An rAAV containing the AAV-S capsid protein and a c70 vector driving expression of GJB2 under the GJB2 basal promoter and 5' UTR was packaged. AAV-S-C70 rAAV is injected into Gjb2 conditional knockout mice. The hearing of these mice was tested. AAV-S-C70 rAAV can rescue hearing similarly, or even better, than AAV9-PHP.B-C70 rAAV.

AAV-S-C70 rAAV is injected into wild type mice. The C70 vector contains an HA tag that allows easy detection of GJB2 expression in the inner ear using an anti-HA antibody. GJB2 expression is expected to be detected only in the feeder cells of the organ of Corti and fibrocytes that normally express GJB2. Hearing of injected wild-type mice is also tested to assess GJB2-associated toxicity.

Additionally, the ability of AAV-S to transduce inner ear cells of non-human primates (NHP) was tested. An rAAV containing a vector encoding AAV-S capsid protein and GFP was injected into both ears of non-human primates. Animals were euthanized after 3 weeks, and cochleas were prepared for histology. GFP expression is assessed in the cochlea of these animals. Similar experiments were performed in parallel in mice.

An AAV-S vector encoding GFP was injected into the inner ear of adult mice using the tracheal route (which robustly delivers the vector across the inner ear in mice). Animals were euthanized 20 days after injection and cochleas were harvested.

To test whether the GJB2 GREs listed in Table 3 enable GJB2 expression in cells that normally express them and prevent GJB2 expression in cells that do not normally express GJB2, the GREs were isolated from the basal GJB2 promoter and GJB2 exon 1, respectively. It was incorporated into AAV vectors driving GFP, human GJB2 or mouse Gjb2 expression under the control of the 5' UTR. Vector maps are presented in Figures 5a-5u. The vector contains, 5' to 3', an AAV 5' ITR, a human GJB2 GRE, a GJB2 basal promoter, a human GJB2 exon 1 5' UTR, an eGFR, a nucleotide sequence encoding human GJB2 or mouse Gjb2, and a GJB2 exon 2 3' UTR includes Vector c.81.1 contains human GJB2 GRE1; vector c.81.2 contains human GJB2 GRE2; vector c.81.3 contains human GJB2 GRE3; vector c.81.4 contains human GJB2 GRE4; vector c.81.5 contains human GJB2 GRE5; vector c.81.7 contains human GJB2 GRE7; vector c.81.8 contains human GJB2 GRE8; Vector c.81.9 contains human GJB2 GRE9 (Figs. 5a-5u). 5V shows schematics of c81.2, c81.3, c81.5, c81.7 and c81.9 encoding eGFP, mouse GJB2 and human GJB2 as described above.

The c.81.2, c81.3, c81.5, c81.7, and c81.9 vectors encoding GFP were each packaged into rAAV using the AAV9.PHP.B capsid protein and postnatal day 1 in wild-type mice. was injected through the round window membrane. Cochleas were fixed for histology at P6 and GFP expression was evaluated in cochlear tissue.

GJB2 gene regulatory element 5 (GJB2 GRE5, in vector c81.5 encoding eGFP as reporter) was found to help target expression of eGFP to GJB2-expressing cells. 6A shows fluorescence images of eGFP expressing cells, including various supporting cells within and medial to the organ of Corti. 6B shows antibody labeling of endogenous GJB2 in the region of the organ of Corti. GJB2 expression largely overlapped with that of exogenous eGFP. 6C is an overlay of FIGS. 6A and 6B including a third staining of actin showing stereocilia of hair cells. eGFP was not expressed in hair cells. 6D shows frozen section immunofluorescence images of eGFP and MYO7A, a protein marker for hair cells. eGFP was expressed on various supporting cells in the organ of Corti, but did not overlap with MYO7A expression expressed on hair cells. Vectors encoding human GJB2 or mouse GJB2 will be tested for GJB2 expression in the intended cells.

7A-7D show the eGFP expression pattern by vector c.81.5 in the lateral wall of the cochlea. Figure 7a shows eGFP expression in cells containing fibroblasts of the lateral wall. Figure 7b shows antibody labeling of endogenous GJB2 in the region of the lateral wall. GJB2 expression largely overlaps with exogenous GFP. 7c is an overlay image of FIGS. 7a and 7b. Note that eGFP was expressed in cells expressing Gjb2. 7D-7E show frozen section immunofluorescence of GFP (FIG. 7D) and GJB2 (FIG. 7E) in the supporting cells of the organ of Corti and the fibrocytes of the lateral wall.

A human GJB2 enhancer identified on the basis of a human deletion can rescue hearing and similarly does not induce GJB2-associated toxicity.

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another embodiment

All features disclosed herein may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is merely an example of a general series of equivalent or similar features.

From the above description, those skilled in the art can readily ascertain the essential features of the present invention, and without departing from its spirit and scope, make various changes and modifications of the present invention to adapt it to various uses and conditions. can make it Accordingly, other embodiments are also within the scope of the claims.

equivalent

Although several embodiments of the present invention have been described and illustrated herein, those skilled in the art will recognize various other means and/or methods for performing the functions described herein and/or obtaining results and/or one or more advantages. Structures will be readily envisioned, and each such alteration and/or variation is considered to be within the scope of the embodiments of the invention described herein. More generally, those skilled in the relevant art will understand that all parameters, dimensions, materials and configurations described herein are intended to be illustrative, and that actual parameters, dimensions, materials and/or configurations are used for specific applications in which the teachings of the present invention are used. Or it will be readily appreciated that it will depend on the applications. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific inventive embodiments described herein. It is therefore to be understood that the foregoing embodiments are presented by way of example only, and that within the scope of the appended claims and equivalents thereto, embodiments of the present invention may be practiced otherwise than as specifically described and claimed. Inventive embodiments of the present disclosure relate to each individual feature, system, article, material, kit, and/or method described herein. In addition, any combination of two or more of these features, systems, articles, materials, kits, and/or methods may be incorporated into the present disclosure, provided that such features, systems, articles, materials, kits, and/or methods do not contradict each other. are included within the scope of the present invention.

All definitions defined and used herein are to be construed as taking precedence over dictionary definitions, definitions in documents incorporated by reference, and/or ordinary meanings of the defined terms.

All references, patents and patent applications disclosed herein are each incorporated by reference with respect to the subject matter cited and may, in some cases, encompass the entirety of the document.

As used herein in the specification and claims, the singular forms "a" and "an" are to be understood to mean "at least one" unless the context clearly dictates otherwise.

As used herein in the specification and claims, the phrase “and/or” refers to “either or both” of the elements so combined, i.e., present in conjunction in some cases and separate in other cases. should be understood as Multiple elements listed with "and/or" should be construed in the same manner, i.e., as "one or more" of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the "and/or" clause, whether related or unrelated to the elements specifically identified. Thus, as a non-limiting example, a reference to “A and/or B,” when used in conjunction with open-ended language such as “comprising,” can, in one embodiment, refer to A alone (optionally including elements other than B). ); In another embodiment, B alone (optionally with elements other than A); in another embodiment, to both A and B (optionally including other elements), and the like.

As used herein in the specification and claims, "or" should be understood to have the same meaning as "and/or" as defined above. For example, when separating items in a list, “or” or “and/or” is inclusive, i.e. includes at least one of a number of elements or lists of elements as well as more than one, optionally with additional It should be construed as including items not listed. To the contrary, only explicitly stated terms such as "only one of" or "exactly one of" or, when used in the claims, "consisting of" refer to the inclusion of exactly one element of a plurality of elements or a list of elements. something to do. In general, as used herein, the term "or" refers to an exclusive alternative (i.e., "one or one but not both"). “Consisting essentially of” when used in the claims shall have its ordinary meaning as used in the field of patent law.

The phrase “at least one” as used herein in the specification and claims with reference to a list of one or more elements means at least one element selected from any one or more of the elements in the list of elements, but specifically recited within the list of elements. It should be understood that it does not necessarily include at least one of each and every element listed, and does not exclude any combination of elements from the list of elements. This definition also permits that there may optionally be elements other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to the elements specifically identified. Thus, as a non-limiting example, "at least one of A and B" (or equivalently, "at least one of A or B", or equivalently "at least one of A and/or B") means, in one embodiment, at least one A, optionally including more than one, in which no B is present (and optionally including elements other than B); in another embodiment, at least one B, optionally including more than one, in which A is absent (and optionally includes elements other than A); in another embodiment, at least one A, optionally including more than one, and at least one B, optionally including more than one (and optionally including other elements), and the like.

Also, unless expressly indicated otherwise, in any method claimed herein that includes more than one step or action, the order of the steps or actions of the method is not necessarily limited to the order in which the steps or actions of the method are recited. should be understood as

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Ser Ile Phe Phe Arg Val Ile 130 135 140 Phe Glu Ala Ala Phe Met Tyr Val Phe Tyr Val Met Tyr Asp Gly Phe 145 150 155 160 Ser Met Gln Arg Leu Val Lys Cys Asn Ala Trp Pro Cys Pro Asn Thr 165 170 175 Val Asp Cys Phe Val Ser Arg Pro Thr Glu Lys Thr Val Phe Thr Val 180 185 190 Phe Met Ile Ala Val Ser Gly Ile Cys Ile Leu Leu Asn Val Thr Glu 195 200 205 Leu Cys Tyr Leu Leu Ile Arg Tyr Cys Ser Gly Lys Ser Lys Lys Pro 210 215 220 Val 225 <210> 2 <211> 678 <212> DNA <213> Homo sapiens <400> 2 atggattggg gcacgctgca gacgatcctg gggggtgtga acaaacactc caccagcatt 60 ggaaagatct ggctcaccgt cctcttcatt tttcgcatta tgatcctcgt tgtggctgca 120 aaggaggtgt ggggagatga gcaggccgac tttgtctgca acaccctgca gccaggctgc 180 aagaacgtgt gctacgatca ctacttcccc atctcccaca tccggctatg ggccctgcag 240 ctgatcttcg tgtccacgcc agcgctccta gtggccatgc acgtggccta ccggagacat 300 gagaagaaga ggaagttcat caagggggag ataaagagg aatttaagga catcgaggag 360 atcaaaaccc agaaggtccg catcgaaggc tccctgtggt ggacctacac aagcagcatc 420 ttcttccggg tcatcttcga agccgccttc atgtacgtct tctatgtcat gtacgacggc 480 ttctccatgc agcggctggt gaagtgcaac gcctggcctt gtcccaacac tgtggactgc 540 tttgtgtccc ggcccacgga gaagactgtc ttcacagtgt tcatgattgc agtgtctgga 600 atttgcatcc tgctgaatgt cactgaattg tgttatttgc taattagata ttgttctggg 660 aagtcaaaaa agccagtt 678 <210> 3 <211> 226 <212> PRT 213 <213> <400> 3 Met Asp Trp Gly Thr Leu Gln Ser Ile Leu Gly Gly Val Asn Lys His 1 5 10 15 Ser Thr Ser Ile Gly Lys Ile Trp Leu Thr Val Leu Phe Ile Phe Arg 20 25 30 Ile Met Ile Leu Val Val Ala Ala Lys Glu Val Trp Gly Asp Glu Gln 35 40 45 Ala Asp Phe Val Cys Asn Thr Leu Gln Pro Gly Cys Lys Asn Val Cys 50 55 60 Tyr Asp His His Phe Pro Ile Ser His Ile Arg Leu Trp Ala Leu Gln 65 70 75 80 Leu Ile Met Val Ser Thr Pro Ala Leu Leu Val Ala Met His Val Ala 85 90 95 Tyr Arg Arg His Glu Lys Lys Arg Lys Phe Met Lys Gly Glu Ile Lys 100 105 110 Asn Glu Phe Lys Asp Ile Glu Glu Ile Lys Thr Gln Lys Val Arg Ile 115 120 125 Glu Gly Ser Leu Trp Trp Thr Tyr Thr Thr Ser Ile Phe Phe Arg Val 130 135 140 Ile Phe Glu Ala Val Phe Met Tyr Val Phe Tyr Ile Met Tyr Asn Gly 145 150 155 160 Phe Phe Met Gln Arg Leu Val Lys Cys Asn Ala Trp Pro Cys Pro Asn 165 170 175 Thr Val Asp Cys Phe Ile Ser Arg Pro Thr Glu Lys Thr Val Phe Thr 180 185 190 Val Phe Met Ile Ser Val Ser Gly Ile Cys Ile Leu Leu Asn Ile Thr 195 200 205 Glu Leu Cys Tyr Leu Phe Val Arg Tyr Cys Ser Gly Lys Ser Lys Arg 210 215 220 Pro Val 225 <210> 4 <211> 678 <212> DNA 213 <213> <400> 4 atggattggg gcacactcca gagcatcctc gggggtgtca acaaacactc caccagcatt 60 ggaaagatct ggctcacggt cctcttcatc ttccgcatca tgatcctcgt ggtggctgca 120 aaggaggtgt ggggagatga gcaagccgat tttgtctgca acacgctcca gcctggctgc 180 aagaatgtat gctacgacca ccacttcccc atctctcaca tccggctctg ggctctgcag 240 ctgatcatgg tgtccacgcc agccctcctg gtagctatgc atgtggccta ccggagacat 300 gaaaagaaac ggaagttcat gaagggagag ataaagaacg agtttaagga catcgaagag 360 atcaaaaccc agaaggtccg tatcgaaggg tccctgtggt ggacctacac caccagcatc 420 ttcttccggg tcatctttga agccgtcttc atgtacgtct tttacatcat gtacaatggc 480 ttcttcatgc aacgtctggt gaaatgcaac gcttggccct gccccaatac agtggactgc 540 ttcatttcca ggcccacaga aaagactgtc ttcaccgtgt ttatgatttc tgtgtctgga 600 atttgcattc tgctaaatat cacagagctg tgctatttgt tcgttaggta ttgctcagga 660 aagtccaaaa gaccagtc 678 <210> 5 <211> 500 <212> DNA <213> Homo sapiens <400> 5 acctgtctcc cgccgtggcg ccttttaacc gcaccccaca ccccgcctct tccctcggag 60 actgggaaag ttacggaggg ggcggcgccg cgggcggagc gcgcccggcc tctgggtcct 120 cagagcttcc cgggtccgcg aacccccgac cgcccccgaa agccccgaac cccccaagtc 180 cccttcgagg tcccgatctc ctagttcctt tgagccccca tgagttcccc aagtgccccc 240 agcgccctga gtctcccccg gttaccccga gcgccgcctc ccccagcccc ttggcggccc 300 gggtgaagcg ggggcggctg agagtcggga ccccccagga agcggcgccc cagaccccgg 360 ctccggcgct gtgccgtggg cggggttcag ggatggctgt ggtcgttgtc ctctgtactc 420 cgcatagtgc gagaggactt ggcatttatg agcgcttctt taatttttta ttgttagaga 480 aacaggcatt cctccaagga 500 <210> 6 <211> 4843 <212> DNA <213> Homo sapiens <400> 6 ctttgtggat ggcttggtgg cctcactgtc aggctggcac tgatggctca gttagcatat 60 ctgttttgat aagtgctgca acagtgcatt ataattgtgg gctgtggttt taatttcaaa 120 gtgtttctta aaagacacat tattttaaaa tgacagaaaa ttcaactccc tcggttactg 180 gcccagctaa gcgacgtcac tgcattgcag ttcagcgctg aagcttggga gagtcccaca 240 ctccttactg caagcggatg tggagaggcc agtggataat ctcctgtgag cccatggcct 300 tcttttcatc ccaggatgg aattgtcttc actgattcat agttacaccc tgcctgccac 360 aaccaacgct ctcctaaaca agattccacc ctctccacaa tccggatgaa tcatctcttt 420 tccacccttc agagctggta gtgaatcctc cttcttcttt ttcttaaaag catcctcctc 480 tcctcatttt aggcaagttg catcccgttt tctgatggac tccagaagca ggctcgtagt 540 gaatgtcttt catgacccac agtcgctgcc acggggcacc aaggtcaggc agaaaccatc 600 cagtgccacc ttggtcagag gctaacagga gagaggtggc cacgaaagtt acatcagatt 660 gacataggcc tgtgaaacat ttagcttcac tgagcttggg aaagacaaca tcattggaaa 720 aaacaatatt ttagcccagg ttcagcactg acccattgat aatccagact gggaggccct 780 taggtgagct ggttgtcctg ctacagcacc cacagctcag gccagtcccg tcccaacagc 840 agaaccaccg aggacagcaa cattccgatt ttaacaaaag catcttatgg aattagacat 900 tcttcattgg ccctcactga gtggaaaaca ggatactccc cgaagtaaac tctctcctgg 960 tttacaacaa tacacctggc caagaatatg gggctgcagg aggaggggtt tatcctttgc 1020 cctcttccac ctgccaaacc caggtcatac acccttctac agacctgtcc agttaccatc 1080 agctgagaaa aatacagttc cgagaaaccc tatattgtta ttttataaag cttgagttga 1140 agctacctgt tttaaagatc ctttttcagg aagaggagta aattaagatt tactccccaa 1200 tgggctaggg ggtcatgggt taagaggggc tcagaagcag gacgaagttg ttttcaatat 1260 tcaagtcaga ggaggagctg ccctcctggc ctcccgaccc tgggcggtta catgcagctt 1320 cctaccgggc ccacgccatc ctgcaccgcc tggagggctg ccagaggcca gcggaggagt 1380 tggttcagtt ccttagggaa gacactaggt gaatcaccag gatccagaaa aggcaaaagg 1440 gactcttcac cccttaaatt tctccaccct taggtgatgg gtggtcgacc ttgcctggct 1500 gtccccagag ggttcctcca cccttctcac cagtgtctga aattgtgacc gactgtgcac 1560 agcagtttcg aaagggactc taaggtcaca tggggacacg gccgtaccac gcttctcaag 1620 gcagtcccag gtgcatggcc acggaaccca gctctcagca gctgttagtt aggtgagcgc 1680 tgttcgggct gccttcctcc tccagtgggg caggatcgag gcactgatgg aaccgtcctg 1740 aggacgcggg tctcagccgc acaccacctc ttcgcgaaca agggtcctaa aaattttcct 1800 tctaggcggg gagcacagcc cggaaacaga ccctcgtgaa gtgtttagga aaaagggaag 1860 ccactgaaat cttggccccg gggtaggccg ggatcggctg gctccgcgtt agttctaggc 1920 aaactccgcc caaatctctg cccggggatt tttctgcaga agccgctcca agaggtaaag 1980 gtcagttcct gcagcgaagg cttcctgctt caccggcgaa acggagcttt gcttcgaagc 2040 taagctttcg gtgaatttaa aacgtttggt ggcagtgggt caagtagcca ggcggctgcg 2100 ctagagtacc ccgaagggac atcggcgaca ccacaaacct cgcgctggcg gctcgcccgc 2160 gcctttttcc cctcccgcgc gcgcccggcc ccactcgcac cccgggcggt gccatcgcgt 2220 ccacttcccc ggccgcccca ttccagctcc ggagctcggc cgcagaaacg cccgctccag 2280 aaggcggccc ccgccccccg gcccaaggac gtgtgttggt ccagcccccc ggttccccga 2340 gacccacgcg gccgggcaac cgctctgggt ctcgcggtcc ctccccgcgc caggttcctg 2400 gccgggcagt ccggggccgg cgggctcacc tgcgtcggga ggaagcgcgg cggggccggg 2460 gcgggggtct cggcgttggg gtctctgcgc tggggctcct gcgctcctag gcgggtcctg 2520 ggccgggcgc cgccgagggg ctccgagtcg gggagaggag cgcgcgggcg ctgcggggcc 2580 gcaacacctg tctcccgccg tggcgccttt taaccgcacc ccacaccccg cctcttccct 2640 cggagactgg gaaagttacg gagggggcgg cgccgcgggc ggagcgcgcc cggcctctgg 2700 gtcctcagag cttcccgggt ccgcgaaccc ccgaccgccc ccgaaagccc cgaacccccc 2760 aagtcccctt cgaggtcccg atctcctagt tcctttgagc ccccatgagt tccccaagtg 2820 cccccagcgc cctgagtctc ccccggttac cccgagcgcc gcctccccca gccccttggc 2880 ggcccgggtg aagcgggggc ggctgagagt cgggaccccc caggaagcgg cgccccagac 2940 cccggctccg gcgctgtgcc gtgggcgggg ttcagggatg gctgtggtcg ttgtcctctg 3000 tactccgcat agtgcgagag gacttggcat ttatgagcgc ttctttaatt ttttattgtt 3060 agagaaacag gcattcctcc aaggactgaa gatctgttcg agtcgcggag gctgcgcggg 3120 cccgcgaggc tctcgcaggg ggacctaggc tgggtggcgg ggcagtgccc tctggaatgg 3180 gggttaacgg tggccgagga gggggcgccg ctggtgccgg cgaagtcccc gcttctttct 3240 cccctcaaaa tctcaccaat ccgaacgaac gccttctcga atttccgatt ttattcaatt 3300 actttcaaca atgtgccaag gactaaggtt gggggcggtg ggagagacaa gcctcgtttt 3360 tgccatggcc ggcagggggg tcccgccatc tgcggagggt gccccccgcg gcccccggcc 3420 cagccaactt cctcctcttt tcgcaactgg ggaactgcaa ggaggtgact cctttcgggg 3480 tgaggaggcc cagacttttc agaaaggaaa gagggcaggt aaaacctgcc aagccccttc 3540 ctgctcgatg cacacagcac gaaaggggga aactgatagg attctgcgga agaccgctgg 3600 ggggctggct ctgcactgca cacctgctgg gggctttctg gataccgtga aactttgtct 3660 cagattatga ggtctcagta tttgcatttg gttggggatt ttgatgtctt gcgatacaaa 3720 tgacagaaga cagatttgca cagcgcaagc ggatgaggga ctaagatgtg cagagcaggc 3780 tgggtgggga ctcccgggga ggtctccccc aacccccgcc ccacctcggg cacccacttc 3840 gcgatttttg cagaggggag ccaggtcaga ggtgcagcct ggtcccctcg cgctcacgtt 3900 tttacccagg tcagttcgaa gttaagtgga aatgatgatt aatcctgaca agtcagatct 3960 ggcctcagaa tggatttccc gtgattgcca ccatattag cattgacttt tccttgaaaa 4020 attggcgccc cgtggccatg ggccgaccta ggcagtttct gcagggacga gcgtgagttt 4080 tgtaccgcgg ttaccaccta ctttccagct ccaggtctta gtctaagagg gagtgtctgc 4140 tcatgaagag gcaaagcccc aggagctgcg aaaagccttg catggcccat ctgagagatg 4200 tgctgagtcg gcttgttaaa aatgacaggc aaagcctgtg gggtggggca gctttcttgg 4260 cctgagcgca tcttggttga gccagaggtg acttggggtg gggagtgggg cgccggttgg 4320 tgggttctcc ctttaatttc tcaaaggctg tggtgtttat gagtctgttg gaatcctggt 4380 tgggttggaa tgaaggaagg ttctagaacc attgtgggaa gctcgctagt aaagatggtt 4440 tggagatcgg aagttgactg actttccccc attgaaaaat gtcacctgag attttagtgc 4500 ctgtatcacg attataggct caactttctt ttccttgttt tctttgattt agttctcctt 4560 atgtgcaaaa ttactgtgtg atgttggcta gtcgtattat cacagccact ccgtgttttc 4620 aggatttgta gctggaagtc ctatagcact taagtcttca cttacagatc agcgcttgct 4680 tttatctgt tttgtgtgat ttctgctgtt ttcctgtgag ttggtgtttt cttcccaagt 4740 aggctcagga ctcctctagg gcaggacatt atatgcatgt acatagtgtc ctccagtgta 4800 ggggaggaga aggagggagag gtgaggtggg aaaagggtga ggg 4843 <210> 7 <211> 5178 <212> DNA 213 <213> <400> 7 ccaaaaaggg acaaaaacag acaaacaaac aacaccaaca caaacaacaa cagcactaaa 60 acgagtctct gcacctaggt cttcgcacgc aggctggtag tcccaccctc aggtagggcc 120 tgtttggtta acgatccgtg tctgttttga tatgtgttgc aagtgagtgt tgcactgtgg 180 actatggttt taaccttgaa gtgattctaa aataaatata tgatgaaaaa tgacggaaaa 240 ttagctcagc ggttcaccag ttgctggtcc aaggagccac ctgatggggg ttttgccttg 300 ggtggcatca cagtgtatcc tgtctgagtg acacagtgtc tatatatggc ctgtgcccta 360 gatgagcctc cataagccaa tgaccttcta tttcatccca gggcaggaac cttccatggc 420 tacacctggt ctgtcacaat caacccctct tttgattaat cccatcttcc cggctgtcct 480 gactcacttg cttccaccccc ttccttccaa gctgtaaaga atcctctgac tctttcttaa 540 aagcacccta ccctcctgct tagcaagtta catcctgttt cgcagtggac tcacagcagg 600 cgcagagaga agtccctcct tgtccctagt ggcggtggca gagcaccagg gaacccactt 660 gctggaaccc actcagctct gccttggaca gaggagatag ggccaggggc atgggaatta 720 aggaatactg acatacaccg gtaaaacatc aagtcctatc caacttggaa agcagaaaca 780 gacaggctcg gcaggttcag ccctgaccca tttataccta gactgtcaga ggccctttgg 840 gaagctggtt gtcctctgaa cagtctctca gctccatgtg gtctgccccc aacagcagaa 900 ggattgaaaa gcaacagtgt tccaagttta acaaaacaat ctgattggaa ttagaccttc 960 tgttcttcct tccccttctc ccgagtggag atcaggacat tgaaataaac atctacacac 1020 ctgacccaaa atacagagct ggaggatccc tttgcctgcc tatagcatcc acagactagc 1080 ccaattatta tcaacacaga aaaaaaaaaa aaccctcaat ttctgcgtaa actgtgcact 1140 tgtttataaa agtacttaag tgtttgttga atttgagttt accgtgttac ccaggatggc 1200 ttctaaatcc atgcagttgg agttagcaca acatgggggt gggggtaggg ggttaataca 1260 tctataatag cagaactctg gaggctgagg taggaggagt gtgctaactt gaggaaaact 1320 tttctgcaga gcaagaccct ggctcaagaa aacaaacacc aaaagagaca agaaaagaaa 1380 agaacagaac caaaacaaaa acaaacaaac aaacaaacaa aaaaccaaaa aatgggaagg 1440 ccggattgaa caaacaaggt caagaagaga gagagagaga gagagagaga gagagagaga 1500 gagagagaga gaaaactcca aaagaaaacc aaatagctgg gacatagctg tgggtcccgg 1560 catatctgat tgcagctgct tgtcttaaat ggcctttcta agtggaagga gaggttaaaa 1620 tttgacctca caaaggggtt aggagtacta agccagcagg tgaaatcgtc aatattcaac 1680 tgtggtgtag gaggtgattt ccaggctggc cttaggacta ggtcacacgc aggtccctac 1740 ctggcatggg acacctggag attgccttga accggtgaat cattcgctcc tgagtagaag 1800 ggagcttctc catgtttata gtatatactg catatgaccc ttaatttgcct taaaggatac 1860 ttcggggagc tggtggactg cctctagatg ctgaccccac cgcaccctcc acccttctca 1920 taattcactg gctttgccca tagttcccaa aggactccgg ggtaagtgta gccatgactg 1980 agccaggctt ctcaggacaa tcccgtggac ctgagcaatg ggtcccattt aggcctacgc 2040 tcccttccct tccattgagg cagcaccaag gggctgatgc aattgtccta aggggacaagt 2100 ttctcagcag cacgccatct gtgaacctgt gccttccctt ccagctgtaa cgtcccgcct 2160 ggacgcaaat ccttaaaaag catttaagga aagaaaaaaa aaaaaagcaa tcaaaatctc 2220 cacccgagtg caggttgggg ttccccagct cgcgggagcg gctacggccg cgcgttttgg 2280 gcggtcgccc acgtcacccc agtgctttag gtggtaaagg tcagtgtctt cccacggagg 2340 cttcctgctt aacaaatgaa actgagtttt cctgctcagc tttcggttag ctaaaaactt 2400 ttcaatggcg gcagacaacg cagccaggag gcctcgggaa aattctagcg aaggaatact 2460 ggcgacacgt cgcagtcgtg cgcggaacag cctggccccc gcgtccctcc ccaccccgcg 2520 ctgtgcggga cctcccggct caggctgtgc gcggcggtga gagcagccgg ctccaacccc 2580 gagccgggcc agacgcctgc agccgaagaa acgcgttcac agctcgggtc cctatgcacg 2640 ggtggcggtg gcccgtaggg accgcgcagc gcgttccggc ctcggtttcc caggaccgtg 2700 gcggcccgca cccctcctcg cacctcacgc gtccctactg gctgagtctc gcgccccagc 2760 caccgtgggg cgttgcggtc gggggcgggt tacaccagtg tgactcggtg gcgcggattg 2820 gcggtcgcac ctgtgtccgg aggagcgtgc agcgttgggt ggcgggaagc ggcgaggcgc 2880 tgtccccggt aaggagcagg tctgaagcgg gtcccggggc cgctcctggg ttggtccgaa 2940 atgggtcgcc ggctgatcct gtgctggtcg ccgcgggtcc cggtggaggc tgcgctcagt 3000 ggactggagc gccgccgact ggctgcgagt tgggaggcg gagcgcgccg cgcgctgcga 3060 tcctggacac ctgttggccg cggcgccttt taaccaaagc cctcaccccg cctctctcac 3120 cctggagcga ttgagaaagt tgcggaggag gcggctccca gtagcccgcc acccccagcg 3180 ccacgggcgg ggctctccgg gcacccagag ccgtcagggc ccgccgagtc gcgagctctc 3240 ctggagccta ggtcactccc caccccactc cgccccaccc cacccccagc tctctttgag 3300 ctcaaggctc ttccagtgtc ctgtcccgag cgcagcctga acagagctgg tagacctgtg 3360 tcttcaccca ggacgcaggt cgcaaagctc caagtcccag ctactcgctt ttgggggatt 3420 gggtgatgtt gaaagagagt tgatgttgct cttactactc tcactagtgg aaagtgtgct 3480 gttatattcg aagcttcgct gtagtaatat tatatatact tgtgtgtgtg tgtgtgtgtg 3540 tgtgtgtgg tgtgtgtgcg tgttagataa acggacggta cagttttgtg ttggcctgca 3600 gcttccagta gcgcacagga gactcctctc ccgtagtgca gtgagctgag gcatctagaa 3660 ttcgggttca aggcagacta acagagggcg ccgccagggc tggccaaatt ctggcttcta 3720 tttctttgaa ttcccgattt aattcgatca ctttgaacag ggtgccagtg gctaggacag 3780 aagaagatgt agaggtgcgt ctccagggct ggcctggaag tggacttgtc acagtctctg 3840 gagggttctc tgcctgtgcc cccgctctct gtgtcctctt ttccacaact gaaagcattg 3900 caaggaaggg gcacccagat tctgccggtg caggggatgc ggaagggggg ggggagcaga 3960 agaggttagg caagcccatc cctcttggag tccaggatgc tgggaagacc tgggcagcct 4020 gcatctacct ctctccgcca agctgttcgt gggttttgag ggctcggtgt tccacattgc 4080 ttggctgtct ggatagtttt gagaggagtt acggtggaca ttcacaagag ctagctacgc 4140 tttgggatac ctaggccagc tagcttcacc ttactacttg caacccgagt cctacagctg 4200 ccaggtttgg aatgaaaacg gcacatcccc acaaagttcc ttcagattag ctttacacgc 4260 agtgaagaga ctgattcatt ctgacaaggc ccgtctggtc gaaggattgg ctttcaatga 4320 aaggaccatg gctgaaggta catgctttcc ctgtaaagct ggcacattgc cgcgggcaga 4380 cctgactgct cttgcttggg cagaggaagg ttgcacgctc gcttgctact acccccacct 4440 cctttctaac tgtaagtctt agtctaagag ggaggtgtctc taaggaagag agcctcggat 4500 ctgtgtccag cccttcagag agagagagat gtgctgaatc agcttgtgtg gaataactgg 4560 ccaagcaaga tggggtggta caactccctt ggcctgagca catctaaaga tgaatcaaag 4620 aggagatgag gtagtggcag caggcagggg tggaaggatg ttggcacctt tagcttctca 4680 tgggtcgtac agtttccagt caattggagc ccctgttcag tgaggatgac agaagcttct 4740 agaatcattg taggaagctg gccagtaaaa gataggttgg agatcagaac tgcttcactt 4800 tctccattga acaatttctc ctgagggtta gtgcccacgt tatgattaca gcttcagcgt 4860 ctagctccct aacttgcttc tacagattcg cctaatggct gtgtgttggc tgatggtcac 4920 aggtgctggg aatattagga tgtatcgcta gctcatctcc tcctctgttc cagccatccc 4980 tccttgtttc ttgttttctc accaactaga ccagaggctc ctctagggta agaaatgcta 5040 aatttatttg tgtatgtgta ttctccagag ggggagaggg gagagggaag gagaagggag 5100 gggaagagag gcaaggagaa gggagaaggg aggagaaggg aggacagggg gacagaggaa 5160 gctagaaaag agctagga 5178 <210> 8 <211> 4964 <212> DNA <213> Homo sapiens <400> 8 taatccagat gttaacactg aaacttccaa gcaggggagt gaaatgagac tttcactttt 60 gacttcgtat actcctgtat tatttaagtg aaaatgtatt tatatattct ataattacaa 120 aaatcacatt ggttgccttt tcattttgaa atgagcaaaa gtgacagggc tgttaaaaag 180 ctaagtcact tgagcaataa cgtgatgtcc agaacagtgg ttccatggct cagccatgtc 240 gggggctgca ctgaggacag ggggccatct gccttctagg aggacactgt ggactggaat 300 attgttcctg ccttgaggag gagtctccca gcacagttac tgctgcttga ctgtcagagc 360 atgcgttttc ttagggaagt tgaaggcagc ctgtatctag taaggtggta tgcagtagtt 420 gcttaatgct gaatgtgtga aggaatgtgg ggctgtggag caggaggata aagtctgaac 480 ttggacctgt tgttctcagc tattcgaagc tttctcaagt ggaaaataga ctgactttgg 540 gtccatcaga gggcagaaca aatgctggag agcagatgct agaattccgt cttaaaacca 600 tgaatcctta cagcggcctg cgtggcctgc gccatctgtc ccagccacgc cctccttggc 660 cccatctccc cctttctcgc cctgactctt tggcatcctg gcctttccgt ctcactggga 720 tgcttcccta agagactcgt gtggtttgct gccctgtatc ctccggatct cctgaccacc 780 ctatgttagt tacattgcaa tttcccgttt ccctcatgac gtcttatttt cctccattta 840 aattacctgc agcaggtacc acctacaggg atctgttgag agtcggcctc cttcaatgtg 900 aagcctgatg ttttgttctg ttcacagcta tgcccccagc ccctaacagt tggtggcagt 960 cagtaaatat tgcctgggaa aacgaatcat tagccatgtg cagaaatgga acagcgtctc 1020 accaagttgg ggttgcccct ggaccctgg aacactgggg cagctggggt gttcctactg 1080 tgcttgttac cggcttcagg aatcaaatgc actagagaat tgtagaagtg cggtccacat 1140 cctctgtgtg gtaggaccag ctgctgttgg cctctgagca ggatctctta cctctctgag 1200 cagtgccttc ctgttgccct cagcaagaat aacactaaca gcctaggact tcagagcact 1260 gctgcgaggt gcaaatgagg tgatatggga aaagcatttg gtgagatgta tggaaagtgt 1320 agagaccctg accagatgag tcaatggcct tcttcgttac tctgttgacc tttctttaat 1380 tacagagtcg catagctgtc accaccttat ccttttttgc tgctatattt gcccccagcc 1440 attcctctcc cggcttatgt ggctagactc acctgcctgt gctgcagtta ctccaggctt 1500 tgtgtaaatg tgcatttttt tccagccccc agtttatcaa gctttgcttg agtcacttgt 1560 atctgaaata ccatctgtca ctcttccagg ttgggatctg tctagtggaa aacagatgac 1620 agtcatatgt tacttagtgc tttactatgt ggagaacgtt tacataaatt atcttatttc 1680 attgccacta agccggggaa agattcagga aacccatttt aagatgagga cactgaggtc 1740 agggtaagtg agtgagcttt tacccacctc tcagctgctc tctagttgtc aaagaccaac 1800 ccgtgggggt ggctcaggcc cgacccctgc agcatattcc ttggggcctc ccaagtgggc 1860 ccgatctgct caccccagct gtgactgtct tttgacagga ggagggagca gcgaggctgc 1920 acccactgct cataaaaagc agagcttgtc cacgccgagg gctcggctgg gtgggaggcc 1980 gcttccacaa ggctttttct tgctccatac aaagtgcaga ctgatgcttt gagatatagt 2040 caggattatc attttcagag ctcaagctct aatttccagg catgtgacca gacctctcta 2100 tccattccta caagtggtcg agagtagccc ataattattt tggcttggtc ttttaatagc 2160 2220 ttgagagtaa taatctacat agcttgtaga agtgaatgta cttattttaa ttttttgatg ttgttgttgt ttgggacagg atcttgctgt cgcctaggct ggagtgcagt 2280 ggcacaatct cagctcactg cagcatggac ctcccaggtt caagcaatct tcccacctca 2340 gcctcctgag tagctgagac tacaggcaca tgttaccacg cctgcctggc taacattttt 2400 attttttata gaaacaatgt ctccctatat tgcccaggct ggttttgaac tcctgggctc 2460 aagtgatcct ctcgtctcag cctcccaaag tgttgggatt ataggtataa gcctctgcac 2520 ccagcttaaa aaatcctatt ttcacagtct atgtgcagag cattttggaa gtcaggtaga 2580 aaccatttcc cattttctat tacctgggtg atagttgact ggtttttgtt ctttgaaatc 2640 cattttaaaa gtgtatggtc ctctatgaaa atacttctaa ttattgatgt gtgaaatgct 2700 ttgaaatcct tggatgggaaa tcttgtacca tgaaagaaca gaactgttgg tggtgtctct 2760 gggagaggct cacgagggcc gggcaagcct gtgggggtag caggcagtca ctcccatggg 2820 gacaggctga cctggcaggc ttatttccca tggaagtggg cactgaggaa taaaaagcag 2880 tttcaggcca ggtgcggtgg cccatgcctg taatccttgc actttaggag actgaggcag 2940 ggggatccct tcagcccagg agttcgagac cagactgggc aatatagtgg gacctcgttt 3000 ctacaaaaaa tgaaaaaatt agtggagtgt ggtggcacac tccagtggtc ccagctactt 3060 gggacgctga ggtggggagga tcgcttgagc ctgggaggca gaggttgcag tgagccaagg 3120 tcatgctatg agtaacattt tgaaggtcca cttctgggat tcatccagga gctaaacggg 3180 tcatgtccag ccaactcagc attcaccaag gtacgtttcc agaccaaaca ccacattgtc 3240 catagactga tatgcctcaa aaacctggta gaggtgggca cggggttagg tagaaatcat 3300 cttcctccct tccttcccca ccaaactttc tggtgacaga agcttttctg taactggggc 3360 agaatggggt cagacactct ggcaacttac ccattggtgt tatgaaatat aaaacattaa 3420 tgtatttata taaaaagtga tagatgaaat taaaatttgc tgttctatta aaaccatatt 3480 agattttaaa ttattataga gattatattt taatgtttta aatgtatttg atacattaca 3540 aaattatttt agttacaagc atatcattaa agctattctt tattattaca aaatgctttt 3600 acaatgctat tcttgacaac aggaaaatac ttaccctcac tgaaatatgt ggagtaccat 3660 tttttggaaa ccatgtcaag cataatggca atattcaggt tcaatcttcc tatagatctg 3720 ctcaatattt atctaaacct tagcttctat tcttttcaca tgttattagc tatattttca 3780 cttaaaaaat tggaggctga aggggtaagc aaacaaactt ttgaagtaga caaagctcat 3840 ctttaatcaa cagactttag agtccagtct ttccaaatct gtttttaacg acagaaactt 3900 ctccctcccc tgccccattt tgtcctcccc attaaatggt actgtgtcaa taaaattccc 3960 aagcgacctc tttaaatcag cgttctttcc gatgctggct accacagtca tggaaaaggg 4020 agatgtgttg gacaggcctg tcattacagg tagtagttgg tggtacatcc agtctgtatt 4080 tcttacacaa aattacatct aaatatttga catgaggcca tttgctatca taagccatca 4140 ctaggaactt ctagtctgtc tcactcgatt gaggctacaa tgttgttagg tgctatgacc 4200 acaatgaata caacagacag cctctcagct gtgctgcaaa gtattcataa ccaaaagacc 4260 atatttcaaa ttaaatcata gtagcgaatg acataccatt tacatattac aatctgagcc 4320 tctgaaacag ggggaacata taatggtatc cagaacatct ttacatcaaa ataacctatc 4380 atactacaaa gttttcactt ccaaaaagtg taacagagtt taaggcactg gtaactttgt 4440 ccactgttag agattaaaac ttccaaagca aatgaaagaa ccaatgttca cctttaacgt 4500 ggggaaagtt ggcaaaaaga accccaggag gacacccaaa ccttctctgt gtcctctgtg 4560 gaacctggct tttttctctt gtcctcagag aaagaaacaa atgccgatat cctctgttta 4620 aaatatgaaa gtaccttaca ccaataaccc ctaacagcct ggggtctcag tggaactaac 4680 ttaagtgaaa gaaaattaag acaggcatag aattaggcct ttgttttgag gctttagggg 4740 agcagagctc cattgtggca tctggagttt cacctgaggc ctacaggggt ttcaaatggt 4800 tgcatttaag gtcagaatct ttgtgttggg aaatgctagc gactgagcct tgacagctga 4860 gcacgggttg cctcatccct ctcatgctgt ctatttctta atctaacaac tgggcaatgc 4920 gttaaactgg cttttttgac ttcccagaac aatatctaat tagc 4964 <210> 9 <211> 5166 <212> DNA 213 <213> <400> 9 catggagaga gatggataac tgagatttct gggcaagaga tgaaatgggc tgaatcccac 60 tcctgactgc acacacctct cagtgattta attagaaata aaaacaagtc tctacattaa 120 catttacata agtaaca gccgtctttt ccattcaaag tgactgaagg agatggtgtt 180 gttaaaagat tgaaattaga cagcagcaac acgtctagaa gagcatccct ggggcagggt 240 tctgcctcaa caccacacag cactacacag caccacactt agcacaaggc tcctcgtggc 300 tcctcatgtc ccttcagcaa gtcaccagtg caccaggagg cgttggggag ggaactcctg 360 accacaatca cagcctgagg gttggagttg tgtttcagtc atcctggggg gcaggggggag 420 cttaaactcg ttggcattta ctagggcagt acacagcagc cgctccacgt tgaacgagtg 480 gatgatcagc ctgagaatca aggctgggct gagcttggct ctatcctcaa ttatctgcag 540 agcgccctgg tagagaacag atctgccttt gagtttccaa gtgagagcgg agcaaggctg 600 ggcacagagc agggtggcaa ggtggctgct gtgggcacag cacagaagat actcaggggc 660 atagatcttc ctggtggctg cttggtctca tgttggtcag gtcacctcca tttttggcct 720 catcatcttc tgacatgcac ctgcttcatg cgtctgcttc ctggaaccca ttcctggctt 780 tttgtcttaa ttctctgagg caggtggctc cattgcttgt ctcctttagg tttcatctaa 840 gagggaccgt cacacacagc ctgtgtggggc atcatgctgg tgcctgacag tcctctctct 900 ctctctctct ctctctctct ctctctctct ctcccccccc cctctgctgt ggctttggcc 960 tctgcagaaa caatctatgg gatttgttga tatgctgcct ccttcaacac aaaggcttaa 1020 gttgtattta tcagctccag tcccagggaa taatcatgtc tggtgcttag ctggtgctca 1080 gtagatagca gctgatgaaa aaaaatcagg agggatacgt aggaactgac cacaaaatct 1140 tgtgggggtg cagttacacc acggactcca gcagtgttgc aacagatgta ggttgtgggc 1200 ctgtggagtt agtcttcatt gtgggagggg caactccaca aggcctatca acataacctc 1260 cgaggggttg gactactctt gctggccttc gatcttgaca attaccagtg ccttcttcac 1320 aacccctccc ccacccctgc acaggtgatg acttgatggt tcttaagttg caataagaat 1380 gacaggaagc aagcaggaag caagagatgt gatatacaca ttaggtcgta tggagaccct 1440 gacagagcaa acctgtaaca ttcattctta ctgttatagc ccctttctta gtcacttatt 1500 aatattcatt tagtcattta gtttttgctg tttgcttgat gcagagtctc atgaagttca 1560 ggctggcttt gaactaagta tgcagctgag gatagccttg aacttcaaat tctcctacct 1620 tcatttctga gccattggga atgcaggcat ccaccttgga gcgccatttc tatttattta 1680 ctttctctaa ggctggggat ggagcctatg gctgtgtgtg gtaggcacag gctggggatg 1740 gagcctatgg ctgtgtgtgg taggtagcat tttggcattg actcacttac tctccagccc 1800 ttgattcttt tgagttacag agtgatacca ttgcctgtca ctcatcttta ctgtgctttt 1860 gtgtatgcac ccagcccccc ttcctctgtt gacctggctg gtctctgagg tcactgtgtt 1920 atgttattt cagtgtcaac ctgcacactc tcaagcttcc ggttaattga gctttgcagg 1980 agacattcct acttactctg tcattcacca tgtcactcag ggtctactga gtggggagaga 2040 gatgacatat taatgctaat atcattctac tgccctaggt ggaggagagg gtctgtgtga 2100 atcaccccat tgcttttcct aggggtgggg agtatttagg aagccccactg taaggtggag 2160 agcctaggcc agggtaagca cggagctccc ttccacccgt ggccacccat tcagcatttg 2220 caagctgctc cctggtgcat cacctagtta gaacagtggc acctgagaca gcttaggcct 2280 ggggaaacca atagaacact ctgttgttcc acttggacta gcagtggcct gtctctccac 2340 agggagcacc acccatgttg gggagcatca cctgtaacct ccagagttca ctcacaccaa 2400 ggcttcttct cttcacaaac tgccatctgc tagtatcagg atgatcatat tccagaggcc 2460 aagcttatgg ccagccctct ccgtcagtcc tatgaagtgg ttgttggcag tttgtaatta 2520 ttttggccct gttctttaat accttaagag taataatctt cataatgtgt aggagtgggaa 2580 ctagccattt aaaaagctgt gcattctttt aacagggtac gtccaggaca ccctggcagg 2640 tgggagac tattcacttt ttctactgtc caagtggacg tgggctaagt tgtatccctt 2700 tcgagctagg ttgtatggtc ctccataaaa acatagtatc actgatgttt aaaatgcctt 2760 gacagcctca gtgtgaagct tataatttaa aggatgatag tgtaggtacc acccaggaga 2820 gagacgtata gcctgtccct tacctgggac acgcttgcct ggcaaggtct gtcccgtggg 2880 aatagacatg gaggaaacaa agaacatggg ccacatgctt ctacacacac acacacacac 2940 3000 agagagagag agtcttgcaa agttctgcag aggacggttc tcaaagtgta gtcttcacag 3060 tggaagatgt tttaattttt aaatataaag aggtttgttg ttgttgtttt ctgtgatact 3120 ggtgttccaa tatgggggcc cacacacgga gacaggtgtt ttagcgctga ttacacactg 3180 agcctaagga ccatgtaaac tgtgagttcc tctgcttctt ctagaaacgg aacggaactg 3240 atcccgtcac caggacttag catcctcctg ctgcactctg actctcagac cttgcagccc 3300 ttaggttggg gctcacggaa cctcttagag tgcgtggatt tgggcagcag tggtctgtct 3360 gttccctctc tctttatcaa gttttctagc cacagggtat tttttgtaac tggagcagaa 3420 tcccagaaca tgttgtaaca tgtgagcata cttctgggat gctttaagat ataaactatg 3480 aaatatatgt atatacaaat tagtatagct gggcatggtg gtgtgcacgt ttaatctcag 3540 tccttgggag gcagagacag gcagatttat gagagttcta ggccagtctg gtgacagagt 3600 gaggccctgt ttcaaagaca aaaacaaatc aaagccagaa aaacttacca ttggtcacgt 3660 tagagtttgg tattctatta aaaaccttat ttaattttaa agtatacaaa ataatcatat 3720 tttaataaag ggcatttagg ggtttacaaa attatatcag tgacaagcat gaaaccacaa 3780 ctcttattta ttgttacaaa atggctttcc aatgacattc ttggcaggaa gaagtgtccc 3840 ctgttggatt tgttgactgt catcttgtag gatacacata aggcatagtg gtaatggttc 3900 aacttgccct agaaaggtta catactgacc taaactagtt tcttctattt cttccaaata 3960 tccacatttc tgtttccagt taagaaggca atgctgaaga gggaggcaaa cacactttca 4020 aaagtagaaa aacttagttt taatcaacag gattgggagt ctagaagttt cattggttct 4080 ctgaaaacca ccccatttgg tttctgcacc attgaattgt cccatggcag tgaaattccc 4140 aagcaaaccc atgaagtccc tatcttctga tgctgactgc aacatcccac agctacagag 4200 tagacaaact ggtggggggt gggggtgggg tggggctgag ttaggctcat ggcaggtggc 4260 agttgtcggc atatcctatc tgtctcttac acaaaattac agttgactat tttaattgag 4320 gcctcttctt gtcagaagcc agcacgagac gcttccagtt tgtctcactt atgacaggca 4380 gtagggttat agccctgagc ccagcacgcc agtgatgaat acaataggtg ggccctcagc 4440 cacactgcag gtttcccata acccaaaggc caacatctta aagaccctgt gagatctggt 4500 tacacaccat gctcacttca cacactgaac ctctggacta ggaggaatgt ataatacttt 4560 ccagatcatt ttaggaaaaa aaagagccta tcttatttta aggttttcat taaaaaaaaa 4620 aagtacacag cacttgaagt attaatagct ttttgtccat tgttgcacac gtaaactatc 4680 aaagcaaata acagtatggc atttctttac ctttagctag gggtaacttg ggggggggga 4740 ctttctcagt ggcaccttcc tcaggaccgg gttcctctct cctgtcctca gaggaagaga 4800 aacaatgtga gatccctttg tttaaactgt gaatgtatcc tccaagcttg gtcgctacca 4860 gcacggggtc tcagtggaac taactttaga acccattaat acaggcatag aattgggcct 4920 ttgtttggga gctttggggg aagggaggcc cacggaggct tctggagttt cataggaggc 4980 ctccagggac ttcaaatggt ggcattttag atgggaatgt ttgtcttggg aactgctggt 5040 ggctgagctc tgccgactaa gcgactaagc atgggttgcc tcatcctctc cctccatctt 5100 tgctctagca gccaggcaat gcattagact ggtcttttgg actttcctga gcaataccta 5160 ACGAAC 5166 <210> 10 <211> 2504 <212> DNA <213> Homo sapiens <400> 10 aaggggacag gacatctctt tccaaaactt aggtttggtg actcctggat ttcacactct 60 ctgactgctt gggtgagggt ggaatggagg gctgtccccc accctcgcac ctgcacggtg 120 gcatgctttc ctcctactcc agggaattcc tcgtggcctc atggcctggg ctgtttctgg 180 cttcaagctc cacgtggcct ggccccagcg gtctggtcca ccttgtactc ggtgcccccg 240 ctgccccctg gcctcagctg gagtgacgca cctcatccat gcgggcctgg cgtctggaag 300 gtggctgggt ctctcgggct tgagcaccat catcttagct ccaacatgtc attattcctt 360 cctcactgag gacttttctg cttcctaatt ggttgttgaa gatgaggccc ccatgctctt 420 ttaagaaaac ctgttgtgcc ccaggcttgg ctgtgatggg cactgactca tacagaagta 480 gaaaggcctg ctgagtcatc aacactcgtg cgacgccctc gcattttcat taatgatggc 540 ctccctgcca cacgtgaatc actccagccc gagatctgaa accaggacac accccagggg 600 cgaggtgacg ctgagtgagc ccagctgtgt ccctttcatg agaactcaga gcacagggct 660 ctgtgtgcat ggccgtcccc tccagagagg aggaagtaaa tgccgggatt agtggaagat 720 catttccttc tatttgcctt ggcttacgtc tttcagaatt caaacacgtg cactgttgac 780 cctgcaatgg tggagttttt ggattttcct tcagtccgat tgctaaaata cttccctctc 840 atgtgagctg ttgtgaaagt catcagccag ataccattct aaaaacaaag aatgtgcttc 900 tcgtatgttg catgctggtt actgaaatat tagggaatta cataaaggtt ttctggggca 960 catattcaag ctgaatgata aaattgaagg tcacacaaag ctaaggtctt tcaaatcctg 1020 acccaattag ctctctgtta gctctctgac tttggacaag ctgtctggtc ctctgaagca 1080 tactttgttc gccctgggta ggggccctct gttttaacag cgtttggcag atgaaaacat 1140 ttgcaaagcc aaaggacaat gaaatctacg gaagcctacc atatgccaat gactccacca 1200 aatgttttct cttcttggga tcttctaaaa ttcatctgaa tacttataag ttatgcaaat 1260 tttggttat aatctaggtt gtattacctt gggggaagtc agttaatctc tttgaactca 1320 gtttctttat ctgtgaacct gaaagaacac cttcaaactc caagggtggc tgtcagaatt 1380 aactatagag gtgcaggtat cagatgaaag ctataaaaca gtttacagat cttagatatt 1440 atgatggatg gctatgatac gtttctcgaa tcactgcttg ccaatgagct gtacaatctt 1500 cctgaagggg tctgcctttc caatctgggc agcaacagtt aatgacggtg tgccaggata 1560 tctgtgtctc cttttatctg ctccagactt taaacacacc ctctgattac atcacactat 1620 caatttgaaa aagggctcag agccaaaatc accactgtta gcgagttctc cagggctgcc 1680 tcctatcctc tggaggtggg gctctcgtct gcagaaatag gcataagggt tttctatggt 1740 ttttgtttgt tttaaagacg aaacatgttt tgggatcttt taagaatcct aatcgttgtg 1800 aaagaaactg aagtaagtta ctgttcaagt gactctcatt ctgctgtgaa tagtttctcc 1860 cacgtgaagt cagctcaaga gactgtgaat tgcttcagcc tacctgagac ctggtacaca 1920 gggaggcttc ctagccacgg aagaggagag cgtttgcagg aggagaagga ggagagaggg 1980 cccacgcagg tgacattctg gaaagggaat gctggtgcga aactgcctca cctactttgc 2040 tccttggatg ttcaggaaaa gccagcccca tccgccccag tccgagggcc tcactcatgg 2100 aacaaatgaa gctgagaaga ggagcttcct gttttccagc tgctggggtc atcattatct 2160 tcaggaagga ccccgaaaag catcgtgtgt tgttgcaaag gcctgcctta tcctggcccc 2220 caggtccctc tccgctggcc ctgtctactg gataagctga ggttgcacga agtaggtcca 2280 ggcctaatgt gacagtgaat aatatggtgt ttggccacac agagatgtgt gtaggtacaa 2340 aaaccaccat gcttttggcg gcaaagtaaa aaatgaagat gtcgtcaaac gatctgaact 2400 ctgatggaga ctgagcgaga gaccctggcc caaaacaatc actccatggc ggatgcgctc 2460 tggggtagac agctactgct ctcagagcag ctgttttcag gcca 2504 <210> 11 <211> 3870 <212> DNA 213 <213> <400> 11 gtaagagcca attaggaagt tccagggtta gtaaaggcca atcagtaagc accagggtaa 60 gagccaatca gtaagctcca aggttagtaa gagccaatca gtaagctcca ggttagtaag 120 aaccaatcgg taagcaccag ggttagtaaa ggccaatcag taaactccag ggttagcaaa 180 gaccaatcag gaagttccag ggttagtaat ggccaatcag taagctcctg ggttagtaag 240 agcttctggt tttggtcctt caatcactgg cctgagcact catgtgattg gctaggctgg 300 ctaatcaacc agctgtggga atactatcca gtgatgggct tgcagacaga tgccacagca 360 tgtggcacct ttaatgtggg tgctgaggat acaaagtcag gtctctccac gcttgcatag 420 gaaacacttt accaaatgag ccatttttct cagtttcgat tttatttat tttttgagac 480 agggtcccac tgtatagctc aggttggaca cagacttgtg atactcctat cttggcctcc 540 ttgactactg gaattgcaag tgtgtggcac catgccagct ggaaaggtaa ctttctaagg 600 tacctctttc taaaatagat gttgaccttt tgtaaggaca gactaaacgc cccctgggct 660 tgaggctggc gccatccaga acagggtaga gcgtattgag cctggcaggt tgaatccatc 720 780 ggagacaaga cagagagtgt tactcagtcc aggtactctc ttgaactaag agcacacagg 840 gaagaagggc ctcatctgag gccaaggtgt cattgtatcc ggtataaggg gacaggatca 900 cctcctttca tgttggagct cgtggatctt acattctcta atgcttgact agatgtgagt 960 ggagctagaa cacgtatctt ctcctggtca ccgcccaggg ttcgtgcgct tttcttactc 1020 ggtacatcat cctcatcgca gtgggctggt ctctggctgc ctcatccagt ttgtcgtctc 1080 agttcatacg gacaccccct ggcttgtcag tgctggccca gtaccctcgg gcctgagcac 1140 ctgtgatgcc cctgcctcca gctcttcctc cccagagtct gcaatgctat cattccttcc 1200 cggcccagag acttacgctt cctcattaga tgtggggagat gaggttctca agctccaaca 1260 aaccagtcct gacctcgttt tggcaggaac tcaaagagaa gtcagaagct tgctgaatca 1320 cccacaccgg ccggccggcc gagcatcctg gcaaggcctg taattagagc ctctctttca 1380 caccttgaat cttgagggcc ccacgtctga aatgaggggt gtcccagtgc ctgctgcaag 1440 tttatgagca gcacacagac tcctttcctt tggaactcag gggtgctgcc tgcgtctggc 1500 ttctgtggag gaggaagtaa tgtgtgtgga ttagtaaaag atcattttcc tgctgtttgt 1560 cttggcctcc gtgcttcaga attcaagcac ttgtactctt gaccctgcag tggtggctgg 1620 ttttgagtcc acttcctgtc tgatcgctaa actgctcctt ctctgaggac cttcagctga 1680 agccacttac ctgctaacac ttaattaatt aataattaat attgtaatta attttttgtt 1740 gcaggattgg cagtgaaacc caaaacgtca cacatgctaa gcaggcacgg ggccatcaaa 1800 tcattttctt aattttttac tttttttt tttgtgtgtg acagggtctc aagtaaccca 1860 ggttgacctt aaacttcctg tgtggccaga atggctttga atctctggcc cttcttctcc 1920 ctcccatggt actgagatta caggtatgta ccaccatgcc tgacaccctg atgctgtggt 1980 ggactcaagg aatgcacata cctaagcttg aatgctcgct gttgaaatac tagagacatt 2040 taaaataatt tgccagttag gaaaagcttt ctatggcaca cagtccaatt gaatcttaac 2100 acacacacac acacacacac acacacacac acacacacac acacaagact taggtctttc 2160 aaattccagc ttggtggctt gttccatgtc ttctttggac aagccctcca gctctcctct 2220 cctctgctct cctccttggt aactaagggg aggccacgcc tactttatg gcatcctaga 2280 gatgccaaca ttggcaaaga gaagggacaa ttaaattcat tgaggcctgt gtggtgtgtc 2340 agcaactctg ccaaccactt tcttatcttg gtatcattta aattagtttg aacacttaaa 2400 aggttgtgta aatgtggctg tctagtatta gaagctgttt tgtattattg ttagttgtgt 2460 tccctcaggg gaagtgagct gccctgagct cagttcttta tctggaaact gggcctaata 2520 cctccagact caaatgactg tcacaggact tagctatgaa ggaaagggtt gaggcagaag 2580 tcagagcact ttacaaatat taggcgcact tactaatgct catgataaat tcttcaaatt 2640 gttgtgcgat aaagatcttg tcagggtttc tcaggcggct atctttccca tcagagctgt 2700 ctgtccaagt taaagacagc ttactggaat atttctgtat ccttttgtcc aatacaggat 2760 ttaaatatac cctgcgatta gattgtaatg ccaataaaaa gaaaagaggg gatgtcagag 2820 cataagccca gggtgacaac cctgggactg gcattctaga ttctggggag gagactcttt 2880 ctgggaagag aggctcatgg cgttttgcag tttttgtttt ctgttttaag acaggagttg 2940 ctttggggag ctttatctta agaatccgaa cggttgtgta ggcaagcaag caagcaaggc 3000 agctactgtt cggttgacct cgttctgctg tgaagaattt gcactgtgtg aagtgtgttc 3060 aggaaaccct gaatagcctt ggcacacctc cgacgtgctg cttcgtggta aagtttcctg 3120 tcctcaaaag agaagacatt taaaggaaga ggagggacca aagaacgggt cacctagaca 3180 acagggatct gggcacctgg taggaaggaa accttagctt atttactcct tgaatgttgg 3240 gagagaacag ccaggaccct gccctagagc ctcactcatg aaagctgaat ctggggacagt 3300 gagtcctccc ctctaactgc tcccagttcc actgtctcca gggtggatcc caagtggatg 3360 ctgtgtacat ggccttcatt ctggtgccta agctccactc tgtggaccct gtcaccaagt 3420 tggtgtgagg aaatgtaaca tttaatatta tgggtctggg ccacaccaat aaactacgag 3480 gcattgtagt caaagctgct gccgcctttc agtcacctga cctcggtggc cattgaataa 3540 gtgaccttgg tctaaaacaa ttgctccaat gttctgttct gatgctctgg gtggatcgct 3600 gcttgtgtca gagcagatgt ttccaggctg ttgctggggc caatgtcacc attcctgtta 3660 gtttcagatt gtctattagt tctagatagg gtctcattat atgagacacc ccaccctcct 3720 gcatggctca aaagtttact gatttttat ctttgtgtgt aagtgtcttg tgtgcacgca 3780 catatatggg caccatatgc attcctggtg gtaggaagct agaagagggg ctcagattct 3840 ctggaactgg agttacagat agtcgtgagt 3870 <210> 12 <211> 1768 <212> DNA <213> Homo sapiens <400> 12 atcacgcagc ccataccctg cggttctccg gggacttatg catcggccca agttgagggt 60 ttgtctgaac tgaaacccgc atcctagacc tggctttctt ctccccaaat ccaaggggac 120 accccggtga cccacaaaag cttagaaaat ccaacacgca gcaaatgaaa cgggggaaag 180 gggcaccggc cctcactctg gcctcttaga cacacgatat gaaaccttca taaaacctgt 240 tgtacaagtc aaaggggacc acgctggggt aaaagtcaaa ccagtccatc ctcgttcctc 300 tgcgtacaga gagagggtcc agcgcgggcg gcgcccactg ccatcgggcc ggggccgggg 360 cgcgtggaca ggaggggtgcg gatagaggca gatcgggggc ccggtcgccc cacgtgcggc 420 cagacaccca tcccggccgc gctctgccgg ctctgatccg gtgccagaca ggagcgacag 480 gggcgaggtg gggaccagcc gccgacctca cctgttttgt tttcttggag gaaattcctc 540 cgctgggggg ccgaggtggc accgcccgct cgccccccgc aagacccagc cggtccgcgc 600 ccgcttacct gctctgcggc cggcggccct ggcgcgggct ctgcgcgggg cggcgccctt 660 cgctccggct gggcaggcag gtcgggctcg ggcgccgccg gctgtcgggc tctcgtcggg 720 tttcgggtga aggccccggc tcccacctgc tgcgcctttt aaccgcgccc caccccgcct 780 ctgccctgac gcggctcggg cgggctgcgg gaggcgagcg ctgtcactcg acgagccccc 840 cgcccccacc tacccggggc gcactagccg ctgggcgcgg accgtccccc tgaggagcaa 900 ggagtgcagg accggggctg tccctccggg gccggatgcg cagagcgggg acctttttcc 960 cgtggcgggg gcgcagggtg ggggacccct aagaagtgca cagtgcgcgg ggccctcttt 1020 ccggcccttg gagggaacgg ggtaccgggg atgcaggggg tagggctctc cctcgggagc 1080 gcagagggcg ggcccagccc cctctgcacg ggtgcaggtg tggggcgcct gctcaggccc 1140 tcgagggaac tcttcctccc tagtgcaccc gtggggagca gtgtgagggg caggctgtgt 1200 ttttgccagg acacatcctc agtctttctg ggtgatccag ccttctcata gcccgcgggg 1260 tgcacagacc tctcctatag gagcctggag gttctttatt aattaatgac cacttagagg 1320 aggtacaggg gttgttttta ttaattacct ccatcctttg aagactcctc cggggaagcg 1380 gagcaggcct tcctcgggac agtgcaccag gagagaccac attgcctccc cgcttttcag 1440 tcaagactag aaagctcagg gccagtacag ggagtggtgc aagggctggt ggggtgggaaa 1500 cgttggaagc tatttaggca cctggcttta caggttcaaa cctgtcacgc atcggacaaa 1560 agatgtgtga cttgcttatt ctacaaaact gttcggtaat taaacgtccc cacctaaacc 1620 atatgccact tgttgggtca tattctccca cgaaacaatt aagatgtctg ttaaaggtca 1680 tggaatttga gccaagactt cataaaaatc cgctttccaa aatattttat ttgaggagaa 1740 caaggttctt aaagaatttg cccaagtc 1768 <210> 13 <211> 1751 <212> DNA 213 <213> <400> 13 aatcatgcag cctgaatggg catttctctc caagtcgcag ggtttgactg accataaaca 60 tcattccttg ctgtgctttt ctgcccgctc cccaaatcga tgacagcccc aaaccagcaa 120 aggaaatgag aaaagggact taatccggac tctagtcact ttaaacagcc tggtgtgttt 180 ataaaacctg tcgtgcaagt cagaggggca tggtgcatgc agaagtcaaa ctagtccatc 240 ccagttccta ctgcagggca cgagggaggg ggcggcgcgg gtgacaacca ccctgccgcg 300 gttccagttc ccggtgggct cgcaaaggcg ggatgccgat gggaggcaga taaggatgct 360 ggcaaacccc cgcctccccc ccccccaccc cccgcatggt caagactgtc tgtaaccgcc 420 gggccgcctg gagatacttg ccaccccctc gtcccacaaa tctggcgaga aagggaacag 480 accacttcct ttacctgccc gggtttctcg gaggaaatgc tcccactcgc gcttacctgc 540 tcggtgggag ccggctccag gctcgcagcg gcactcagag ctcctaccct gagcgtaggt 600 tggatcaggc gccggcggtt cacagcggga atggaatcgg ggacagtgcg ggtggagccc 660 cggtttccac ctgtggcttc ttttaaccgc gcccccaccc cgcctctgcc tgacgccgca 720 cgggagggct gcgggagagg agcgcgggca ctcgacgcgc cttctgtggt gcgcaccgcc 780 ctctctccgg gacagaggag cggggcgggt ccccttctgt ggagcaaggg gcaggggacc 840 ttccctgtta gggccaggtc ttagtggtac tatattaggg cactcgttgg gatccttctt 900 ctgaagccag ggaccactgc gagtgtcccc taggagagac tccaggtgta ggctggtctt 960 cccttgggtt ggggacagaa ggcttgtccc ttcttgtgga tgtgggtgga gcgtggaccg 1020 cgatgggcaa gctcagccag atcccatcaa ggacagggaa aagttgcccg ctggggcctt 1080 gctggggctg gacactggag ggcccttaat gaagtgaggg ctatccagag tacggggaac 1140 aggcttgtgg acccagctag tagtgagtct ctcctgttgg tcatcctggt aggaagacaa 1200 ctggtttgtt ttcatccttt ctagaccctt tgggcaccct ctcctctaga gcagcctgga 1260 ggttctttat tccttaatga ccacttagga gtctcaaagg tttgttttta ttagtcatct 1320 gaatcccttc ctgcattgtc cagggaaggg gagtggactt ccatcttgag agatccccact 1380 gtgtctgctg tcacatcaag ggcagggtaa ggtcaaggca agcatagagg gtggtacagg 1440 gggtcctggg ctggaaatgt tggaagccat gtaaggacct agttttacag ggcctgccct 1500 gtgctacttc agacaagact tgtaacatgt gtaacttggt tattttacaa aattggctgg 1560 caggtatgtt ctacctgtt gggtcatatt ctcactttag ctacattcta cctgttggtt 1620 cacgttctct cacaaaacga gagtaatagt gcttcctaaa atgtctctcc caggtcatgg 1680 aggttgagtc aacgctttat aaaaacccac cttaataaaa tacttgaacc agagttctcg 1740 gaattggacc c 1751 <210> 14 <211> 3358 <212> DNA <213> Homo sapiens <400> 14 taaaagtgag caaacagctt gaaccaatct aaacagctta tttattgag gtaataaact 60 tttccttctt cctgagtttt cctaaattct tctctatcat gaaaatagca ttaatagcta 120 aaattttaag tgtttagagg ttttgccttt caaatccagt aagtctccag agtcaacagg 180 tgctacaaga tgctactggc agtaacagtg cttctccagg attgtggtag gtggtgtcta 240 agggtctttt cagcttgaag gttctgtttc ccagttctgt ctcacttaag atcagatctt 300 ggtgagtata ttggcaaacc atttcattat ttaaatttgt aaaatacagg ctttaggccg 360 ggcgcggtgg ctcacacctg taatcccagc actttgggag gcccaggcgg gcagatcacc 420 tgaggttggg agtttgagac cagcctgacc aacatggtga aactacgtct ctactgaaaa 480 tacaaactta gccaggcttg gtggcacatg cctgtaatcc cagctactcg agaggctgag 540 gcaggagaat cgcttgaacc cgagaggcgg aggttgctgt gagctaagat tgtgccattg 600 cactccagct tgggcaacaa gaatgaaact ccatctcaaa aaaaaaaaaa caacaacaac 660 aacaaaaaca ggctttaatt gtatttcata ctctttaact aactagatat taactataaa 720 atattaacaa tttcaaattt ttgttaaagg aatacattta cacagcttaa aaattcaagt 780 ggaactaaaa ggtttacaag gcaatatttc agtcctctgc cccattctct gctcctccca 840 ccctgtatgc tgtcccagag gcaaccaacg cctttcattt tttagagctc ttctgacgtt 900 tacctttatg tttccaaata atgtgcttat tatgccattt actgattgct ggactttaga 960 cctgttgact ttttctgcta tggtagtgga ggctttagct ctgacctgag ccccactgct 1020 cctgctccac ccaccctct tccctcaccc tcatgacatg atcatggctc atactctggt 1080 caaatacata ttgttattta tattattttg actgcgagca taatgacgtc tggaccaagt 1140 tgtattctat gttacatttt cttttggttg caattgcctc ccttccctga gagtgaacca 1200 tgactggggt tttcatttgc ttggctttct atgtgtctat tgttcggctt ttcctactct 1260 tccaacaaat ctgtcatatg cccggaaaca attttttcaa gttcccagac atggttccgc 1320 acagtccatc tattccatct gtttctttcc cttttcccgg gggctgtggt ctgggcaggg 1380 tgctctggcc ctctgcccag tggtcccctg ggctcccctt gcctttcccc tgggccagag 1440 cttgtgcttt ctggagtccg tgtcttcctg tcttggtctc taccttcatt ttgctgaagc 1500 acacaccttc caggaacttc ctcaggaggg gaatgtggaa ctaaacttct atgcacataa 1560 agtcttcata tcaccctcaa acccgatctg tctccccgcc tccaatgtac tttcctttcc 1620 tctcttattt tctctgtttt tatgaactta cacctttttt cttcactatt gtgtaattgg 1680 catttaagat gggagtagag ataaatgcac ctggtgtaggc tcatactaac cacacgcctc 1740 agtgcatggg tgtttatcag acttctctca atcaagagct gcgctgagta cttgtgaagg 1800 ccctgcaggg ctggtgctga gtaagttcag gattgggcac ctctgagggg tgaggaaatg 1860 gaggttcaga gacgagaagg aacttcccca aggccacatg gttaatgatt ggaagatctg 1920 agattctaaa ccaaacctga gtcgatcact tccctttctg tccactgcac tgataactga 1980 agcccaaggg ctgaggccac acctcagcgt gtgaggatca gcagaggaga ccctgctggc 2040 tgcgggatgt ggataggctt tgaggaagag gaaaagcaca ggcaaaatgt caaagataag 2100 tgggaatgag gttccctgga gcatgagtcg caggtgctca ggaaggtgct ggcagctcta 2160 gagaaggcca gagagaagca cccagtggtg ggagccacag ccccaagaca caggctaaag 2220 ccccagccca gggtgggtga gctccaccct gtcacctatg gggttgcatg caagtggttc 2280 ctctaagcat tggcttcatc tgggaggcgg gggtgacatc gcttctttga gccttatttg 2340 gaggactaaa caacacatgc attttgtcat taggctggtg caaaagtaat tgtggttttt 2400 ttctattact tttaatggta aaaaccgcaa ttagttttgc agcaacatac taactttaaa 2460 gttcttaata catatgagat attatttcta tcagcttaga aggatccatt atgattgtag 2520 aagacctggg atgccagtct gaggaactct tcttttctta agcaaaggag aaacaaaata 2580 attctgatgg ggggagtgact gaccccagtc tggctcaccg gcggctgtga agtcctgagt 2640 gtcctctggc agctgccttt gaaagcgcag tggtgtccgg ggctcgccac tgaatagcgt 2700 ttgttctcag aagggagccc ggtggaaaat ttgaagctgc agttaggaac tgtgtgtatg 2760 gccttggaaa ctgaagatgt tcctttaaaa gaaaaatcac agtgttttta aaactcagat 2820 gacagctttg accattatct gctttcctct cctgccagct ctagagtttt cttgggatgt 2880 tatcaaggat gatatcacaa caatgcccac ttctgttttg tttttaacct gaatgacaaa 2940 ttaaccaatca gcagatgtag gccatccagg gaagtttctt ttaaatgctg gacttttgca 3000 aaaatgtaga gccttggtgg caattgtgat tctttttttt ttcttttctt ttccccaatg 3060 aaggtacttt tttttatgtc cagttttgga aggctcctga agattgtttg agaacttgac 3120 tgctgtgtca gggcagtgct gacactctct gttgccaact gttattcatt attccaaaaa 3180 atcagagaag caaaaacgac ccctccaaac aactccaaga caaactccaa gcaaaacaac 3240 aacacacaca caaacccaca attttccttt ggttgcttct gagaaggagt tttaatggta 3300 tagtaaatac agcatttatc ggatgatttt tgctgccatt gatatgtttc tcttcttg 3358 <210> 15 <211> 5018 <212> DNA 213 <213> <400> 15 aggaggtgtg tcttcctgga ggaaatatgt cacaagggtg ggctttgagc atttaaaaat 60 ttaccccctt tccaggtttt tctctctgct tcctgcttat ggttcaagat acaaactctc 120 agcttccagc ttcagcccct ctgctctcag agatgctcat ctctctggaa ccatgggtcc 180 aaataaactc tttgttctat aagttaccat ggtcacggtg ctttaccaca gcaacagcaa 240 agtagctaat ataatctttt caaggccacg aaaaagagaa aggcaaacca agagtttggc 300 tgaccaaatc agctgagaac acaaaccttc ccatcctaaa ttccccaatg ttcttttatt 360 tttcatcatg caaatagcca ctgatattta aattatatta atgtgctcat tatggcagtt 420 tcatatattt atatattgta ctttgaacat attcacacac ctccaaatac cctcttctgt 480 cccccacatt ttaagactgg aagtctcgtt ttttcaaatc cattattagg tccttagggt 540 caatggggtc atatgatggt gtctgtggtt ctaattagtg gccagctgga tacctgcaga 600 atcaatgact agtgggtaaa aagtgagcag tcagggtcag cagctcacaa agcgtcagtg 660 agaggcggac aaagagagct ttcagcaacc cctaactggg tgggcagcat gtgagccaag 720 tgtgagtccc tcctttttgg acctgggaga ccagcagagt gtgcaggccc tccgttggct 780 tggcccaggt gataagctga cctcagcagg aattacctca gtcttagtcc agctcctgat 840 gtaagtctca ctcaaaacaa aacaaacaag cctagacaaa accagcttgt tgtctttttt 900 ctgttgtggg aactgctccc actcaggaat ttctcagtgg ccccctcaag gaagtttgct 960 tcttctctgc ttccttccac acatctgtgt ctttctggtt ggagaccatg gacttgagag 1020 ttcaagttga gcttccacta ccctaagtgc ctgggtcaag cacacctgcg ctgagaaggg 1080 tcctgccagt ctcaaaactg catcactaga tcagcagtat actctctcac ttaagcatgg 1140 agtggggagg tgcctttgta tgtcttagca atagtcatct acgtgatttt gaggtcattt 1200 tacttttaaa gtatataatc ttcaaaccaa attcaaagac taggcaaaat ttttaaatta 1260 gcttttaaaa aatgagctgg tttgcttact tccctgatct taattcctat aggcagtatt 1320 gtgaggtaac ttatttaggt ttagggatga tagagaaata atgtcttagg gttttactcc 1380 tgtgaacaga cactatgacc aaggcaacac ttataaagac aatgtttaat tggggctggc 1440 ttacaggttc agttgttcag tccattatca aggcaggaac atggcagtgt ctaggcaggt 1500 atggtgcagg aggagctgag agttctacag cttcatctga aggaagctac gagaatcctg 1560 gcttctagga agctaggatg aggatcttaa agcccacgct cacagtgaca cacttcttcc 1620 aacaaggcca cacctccaaa tagtgccact ccttgggcca agcatattca aatcactatg 1680 ggtactctta aaagaatgca tgttttagct ttaaacattg ttcatttatc cgtgtaacag 1740 actggtttga gatctctcag caaagggagt tatccttata cagggactct tttcattctt 1800 tttcttagtg catattcatt gtagatagtg ctgagttgta taaaggcttt atctatctat 1860 ctatctatct atctatctac atcccaaatg ttgcccccct ccccgtaccc cctcaaagag 1920 ttctttctcc cacccccatt ctctttgcct ttaagaggca acctcctctt atatctcccc 1980 aacctgatgc atcaaatctc tgcaggatta ggcctcaggc cagcccatgt atgctctttg 2040 gttggtgact cagtctctgg aagctcccag gggtccaggt tagttgacac tgttggtttt 2100 cttgtggggt tgccatctgc ttgagggcct tcaatccttc ccctaactct cccacagggg 2160 ttcccaacct ccagtcagtc cagtgtttat ctatgggtat ctggatatcc ccctctgtct 2220 catcagctgc tgggtacagc ctctcagagg cctgctatgc taggctcctg tctgcaagca 2280 caacatagta tcatcaatgg tgtgagtgat gggtgcctgc ccatgggatg ggtctcaaaa 2340 cgatctgatc actggtcagc cattccttca gtctttgctc catctttgtc cctgcctttc 2400 ttttagacaa gatcaatttg gggtcaaatt ataaaggcat tttcatgtta agtgtataat 2460 gtattttgac catgtttccc catatcctcc taccctccca tttgccctcc ccctttctca 2520 ttagtattct ttgttctaga caaatttact ctacttttat ggcatatgac acatacatga 2580 tttaatgaaa cataaaatgg agaatctaca gacaaaagaa agcatgaaat atttggctga 2640 agctgactca actcatttaa tatgacaacc tccatttccc tacaaataag agaatctcat 2700 tctttattgc agactaaaat tccacaggtg tatataccac atttctttcc ctatccctct 2760 gtctttggac acctaggcag gttccaccgt gtagctattg tgagtaatgc tgtagtcaac 2820 attgacatgc aagtgtctct gtgacatgtt gacacagagt tctctggata aacacatagg 2880 agtgtcgtag ctgaatggca gtcgattgag aaaacaaata ataaaagggt tggtgagcag 2940 gtgggaaaag gaaactttga acgcattgct ggtgagaagg aaagtcagtc tagctgctat 3000 ggaaatcagg gcgagggttc ctcaggccct aaaaccagaa ctgccttatg acccaggcag 3060 tcttgacagc tgttgttgtc tgtgcttaag ttcttgactc tgtcagacat agagaaacca 3120 gatctcaggc tagaagttcc ttctttctcc atgttccctt aaccaccctc ttctctcctg 3180 cctcagcctt gtagaagtgt gccttccatt aggcacctaa gaagaggaac ttgacagtca 3240 gctgccacct tctagtgact ggaagaacca aatattctgg atctgaataa aagattttac 3300 attctgcttt gtggctcaca ggagactcag tgacaggccc acctaagcac acacagaaca 3360 gtagagcgac aggttgaaac agcttccagg aggagtgggg ggaggacggg ctgaggaagt 3420 gggatgtgta attccagtag agaaagtcat tggaggtacg gaaggtgctg gcaaccctga 3480 gaaacagcag ctgatccacc agctgcaggg ccaggcctct ggatgcaaca gccaagtcag 3540 agcccagctg ggcctggctg tgttccacct gctccctggg tggccccagg caagtgactc 3600 ccctgagaac tggcttcagt agtgagaaga ggggtggggt gacaatagcc tctttacagg 3660 gttacctaga ggactaaata atgcacatac gcatacacac acacagacat gcacacatag 3720 acgcacacat agacacatag acacagacac acacacagaa acagacactg acacacacat 3780 acacatacac aaagacacac agaaacagac acatacatat atgtatacac acagagatat 3840 acaaatatac atacacacat ggacacaaac acacacatac agaaacagac acacagacac 3900 acacaccaac atataataca cacccatata acacacacat ataacacaca cacacaggca 3960 aacacatggg tttatgggct ctgcagtaca ataaggcttt attttcatca gcttagtcag 4020 cagtagccta caaatattag tgttcaaaag tattttctag gcaagggaga gacagaaagt 4080 ggttgtggtg gggagtgagg ctggtgactg tgagtgggca gtgtctagtg tctggggaca 4140 gctgagattg gcagccccact ggccactgac tagagttgct tcccacaagt gagtccagtg 4200 gaaattttta gtttgctctt agaaactgtg ccttcagcct tggaaactga agatgtttct 4260 ttaaaagaaa aatcgtgctt tttgaaactc aaatgagagc attgcctgcg gtctgctttt 4320 ctctctctct ctctcaccag ttttcctggg atgttatcag ggccaatcat cagaacaatg 4380 ctcacttcta tcttgtgtct aacctggatg acaaatggcc agtcagccga tgtaggtcac 4440 gcaaggaagt ctgtctttcg ggttggactg aggtagccgc agtgcgatgg ctgctttgtt 4500 gtttctttcc cttttcttgt cccaactaaa agcgcttctg gtctgggagt aggggcgact 4560 gaaggctgtt tgagaacttg actgctgggc ccctctaaca ttttctgttg ccaacagctt 4620 actccttttg ctaaaaaaaa aaaaaaaaaa aaaaaaagca aacaagccca aactacttct 4680 tcaaacaatt ctaagacacc acacaaacag aacagactga agccccagta acccagcttt 4740 cccagggatg tttgtgagaa ccagggtagt ttttgatcac tactaaattc tacttaaaca 4800 tttttaaagg atttcttttt cttctcgttt ttaaatttgt tcttcgaata caatgtattt 4860 ttgatcatat gtgcacccct cccccaaccc ctccttctat caagccaacc tggtgttccc 4920 tcccctcccc tctccctcct cctctccctc ccctccctct ctccttccct ttccctcatc 4980 tccccctccc cttcccctca tttccccctc cccttccc 5018 <210> 16 <211> 5079 <212> DNA <213> Homo sapiens <400> 16 gttttaatgg tatagtaaat acagcattta tcggatgatt tttgctgcca ttgatatgtt 60 tctcttcttg aaagaggaat tcaaatgaca atgaacattt ttggggtcct cttttatgga 120 gtttgatttt caggggattg tcaggcatgt cgtctccggg ttcccatgct gcacagtccc 180 agcactctct gtggctcagc cttcccgtcc cttgccctct gaataccttg ccgttgactg 240 aatggtcatc gttagcacag gtcatcacaa tacatgactc ctgggcagga ggaacagagg 300 agcggaggtt gtgccatgca tttaaaaccc agttagcatc ccagtgggtc ttccaaggcc 360 gaagatggca aaacgttttt attttacttt gttgaaatca tctgtttccc tccaaatggt 420 gggctgtttg ggcacaaggt catgttgtct tcaatttcat agccccggta cccagcaagg 480 atggctgccc ataggctcta ttaagatgcc gagtgcatcc gtggcacggc caggaggagt 540 gtgctgtggt cagccttcca gaaggaatca atctcctggg agaagtggag aagttggcct 600 gcagcagggg cctcgagaat ggcgggtctc atccaccacc agcaggctcg tctgttgccc 660 agcagtgtga tcctagctga ggttattct ctttccctca ttagactgca gtctcctgaa 720 aggcagggtg tgcacctgac ttgtcttttt gtcccttcat cctgcgccct gcacggtttg 780 atcagtaaat ggtggctgag agacaaggga gtgggaagga aggaggtcag gaggggagag 840 aggtctgagt gcttgaaaga gtccctcctc tgcttcaggg gcttgttctg gggttttctg 900 gatcttcagt acttgcgggt aggatctgag ctctcccggc ccctggtggt tgttggccag 960 gcctggccag cttccagcag cacaggtcat cataatatat gactcctgga caggaggaac 1020 agaggagcgg aggtcgtgcc atgcatttaa aacccagtta gcatcccact gggtcttcca 1080 aggcggaaga tggcaaaacg ttttatttt actttgttga aatgcaggtt gttccttttt 1140 ttttaaccaa cttttatgtt ccaaggctaa aacatagcat aaaacaattt gaaaaagtcg 1200 gtttcaatgt ttcccattgt tcactgagag agggtcacac agggtgcaag gcaacagagg 1260 acaccattgc ttacgtagta cctcgtgagc tgcactgcga gaggcctttc aaaggaaggt 1320 tttatttagg aagcaaggaa tgattaaaaa ctgatggctc taatcaaatg agatttaaaa 1380 ttttccatta aaccttcata gttaggctgc atgcagtggc tcatgcttgt aactccagca 1440 ctttgggagg ctgagatggg aggatcactt gaggccagga ggttgaggct gcagtgagct 1500 gtgactgggg cactgcactt cagtctgagt gacagaggga gactgtatct caaaaaataa 1560 aaaaaattaa aaattaaaag aaataaacct ttaacattgg gtgtaatttt actttccatc 1620 tactccttct tcctcacctg caacgttcaa gagcaggagg gaagatgtga acacacattt 1680 gtgtgtgtgt gtaaacatgc tcatgtgttt ctaaattatc aagtcaggat aagaacttct 1740 actgtgaaat acagatatac aacaatatgt cccaagctat gtttaatgca cttttattat 1800 cctgctagtt cttctaaata tgatcattat acaatagttc tttttttttt tttttttgag 1860 atggagtctt gctctgtcac ctaggctgga gtgcagtagc gcaatctcgg ctcactgcaa 1920 cctccgcccc ccagattcaa gcaattatcc tgactcagcc tcccgagtag ctgggactac 1980 aggcgcgtgc caccacaccc agctaatttt tgtattttta gtagagacgg gggtcttgcc 2040 2100 aaagtgctag gattacaggt gtgagccact gtgcccggcc cattatacaa tagttctaca 2160 aagaaaattt aagagcaagc tctggcttag tctttgaaaa acaagtttgg aatttcctat 2220 acgagtggat aaaatgtcag ctcttggtat tgtccttaag acacagtaca tggtatttac 2280 tctcttttta tagggtaaag atagataaat ccccaaaggc cttggcattt aggaaacaat 2340 catgctttat ctattaactt actctttaag ctctgtcatt ttttgcgtct gagtgagaca 2400 ctctatttac tgagccacag accacctgct agataagcag agactcttcc agggcacaca 2460 gcctggagaa aaaacgcctg aatgcacaac tagaagtatt agcaagtctg gtttaactgt 2520 ccccaaatgt ctaactaaga atattagtgg gccaggcgca gtggctcacg cctgtaatcc 2580 cagcactttg ggaggccgag gcgggcggat catgaggtca ggagatcgag accatcctgg 2640 ctaacacagt gaaaccccat ctctactgaa aatacaaaaa aattagctgg acatggtggc 2700 agccacctgc tctagtccca gctactcggg aggctgaggc aggagaatgg catgaacccg 2760 ggaggcggag cttgcagtga gccgagcccg cgccactgca ctccagcctg ggcgatagag 2820 cgagactctg cctcaaaaaa aaaaaaagaa tattagtgaa tgattagtat atgggaaaca 2880 cctccggacc accctacatt attattagtc ttcactttgt ggtgggtaaa gataaaataa 2940 aagtagctac cgtttattga atgtttacca tgtgtggatg aaaaccatgt taatcattgt 3000 cttctttaat cctcacagca acctaatgaa gtaggtacta taattttgca gatagccaca 3060 ttgagggtga gtgaggttaa acaacttgct catatgactc aaaagtttgg aagccatttt 3120 caaatcagat gtggacaaag tgtgcctttt taaccattgt attattcagt cttcctatga 3180 agacacgcct ctatttgggg catttacttc ctatataact tgatgaaaaa aaacccagca 3240 ttttcattgc ttgcctataa aaactctaaa ggtgtttctg tgggagggtg tgttattcca 3300 ctcagctatt gataaatata gtcctgtctt aatgtttaat gtggatcttt tttctgtttc 3360 atgcttttct gaatttttga gtgaccatgt cactcagaaa agctttgaat cagcaacatt 3420 tccagtggac tgtaggggaaa gcctgttgtt ttggtggaaa gtagagagtc acagatcccc 3480 aaccttcatc tgagccgtgg ttctgcatca gtacagacag gaaaccaact attaggagcc 3540 actacatgaa atagtatttc ctcaggtgag caaaaaattc ttttgctttt gtagattggc 3600 cctgtctata cgtggtagcc actagtcaca tgtggctttt gacgtttgca ttttaattaa 3660 ttaaagtgaa acacaattta aagttcagtc acccctgcca cactataagt gcccagtatt 3720 caatacaact gcccagtggc tgccatgctg ggcggcgcaa acgtagagca cttctgtcct 3780 ggctgaaaat tctactagac agagccatcc aggaatttgg actagcaagc accaagttca 3840 cagttagaga acacagttgc aggccaggcg cggtggctca cgcctgtaat cccagcactt 3900 tgggaggcca aggcggatgg atcacgaaat caggagtttg agaccagcct ggccagcacg 3960 gtgaaacccc atctctacta aaaatacaaa aaattagcca ggcatggtgg tgctcacctg 4020 taatcccagc tactcggggg gctgaggcag aagaatcact tgaacccagg aggcggaggt 4080 tgcagtgagc tgagattgcg tcactgcact ccagcctggg caatagagca agactctgtc 4140 tcaaaaaaaa aaaaaaaaaa aaaaaaaagg aaagaaaaag aaaaaagaga agacagctgc 4200 tttacaaagc aagagggctt caagaatctg gaaaccaaag gagcaatgtc ctttgagttt 4260 ctacaaattt gggccacact gattgggcct ttccacagcc aattccattt gccttcatta 4320 tggaaagtaa acagtttaac ttcctactga catgctctgc agtgcagaca gtaaacagta 4380 gctcaccgct gcttctgcca gctgctctcg ggtgttctac ttgggtgggg aacagcagca 4440 ctggcactgg cactggcccc ggtggcccca cagagcatgg ctccatcagg ctgggtgcta 4500 cagagggatg ccaagaacat ttgggcattg aatgcctctc tctctctctc tctctgaaat 4560 gaaaaccctc atcaattcaa caatagtttc tctaatagaa catatagtga tttgtttcat 4620 ctcaactgtt cccatacaat aatagaaagg agggagtctg tgcctgagag tgcctgcaaa 4680 ccccagggca caccagcccc gtggagccat aacagttgct cacagagaca gcccctcaca 4740 gcagccccg gcacagtgac tcgtgtaatg aaagctggaa aattgcccag gaaaacctga 4800 agatgcattc ctgaagctcc cacactccaa cgcacgcaca cacagacttc tctcctggct 4860 ttaggaacat gaatttacct tgaatcttta aacttaattg aaaatcttgc aaaataacga 4920 gctttccttt gaatcttcat ggcactttgt aataaaatgt ctaaaagggg gccattccat 4980 gaaatcattt aattggcatt aatagtacac tattacttca tataaaatca taatcatata 5040 aatgtactta tataactcca tgtaaattaa tttatataa 5079 <210> 17 <211> 4077 <212> DNA 213 <213> <400> 17 gggtagtttt tgatcactac taaattctac ttaaacattt ttaaaggatt tcttttctt 60 ctcgttttta aatttgttct tcgaatacaa tgtatttttg atcatatgtg cacccctccc 120 ccaacccctc cttctatcaa gccaacctgg tgttccctcc cctcccctct ccctcctcct 180 ctccctcccc tccctctctc cttccctttc cctcatctcc ccctcccctt cccctcattt 240 ccccctcccc ttcccctccc tcctccttcc cctccctttc tctcccctcc tttacctccc 300 ctctcttccc cttccccctc cctccctccc ttcctccttc ttctggaggt tatggtagca 360 ctaggagtca aatccagagc ctgacactca actgctgatt gaacccctga cccttcttat 420 tttttctgtc catgtttatt ttcttgaagg aggaattaca taaaaaatga gcctttcgga 480 ggtcttcctt ccttgagtct gctgttaggg atgagtcccg tttgaatttc tgtccatggc 540 agggtctagc gccgatttct ctctgatccc cagaacctca ccctgatgag gtttgtgcga 600 tgggtgacac taaacagtgt tttctactaa acagtgggct ttgtggggac agggtgacac 660 tgtcttccac ttgctctgag ttccccgcag gcatcacccc cttcctcccc actggtgccc 720 cactctctct atctgggtag gttgcaggcc ccctcacagt tctacctgga acgtgctggg 780 gtcagcgcag gcaggagctg gctggccttt gtaagactgg ccaactagag cgatgcaaag 840 ccggcctggc accaacccgg gctgctctgc agaaagctag ctgatttcca gcctgagcag 900 gtgcctgtga ctccaggggc agggtctctg tcagacgcac ctctatccat ccttcatctt 960 atccctatgt tctgactgtt aaatggcaac tgagtgagga ggggaaggaa ggcagaggag 1020 gggtctgaga gggatttgag tgttcccagg cccttgcaga ggctgtcccg ggtctggagg 1080 gcttcagcca gggtgtccta tgtaacacag gatcctcaga tagcaggtac tgttaaagag 1140 gaggccatca cacctgtgca tttgagacca tgccaaagca aaaggtgtca acacccgcat 1200 tttactgcat ggaaatgtag ttcgttcctt ttcaaccttt tgtatcgtgg ggctgaagag 1260 atgatgtgaa aggactttaa aaactccact aggcttctct gctttgttca ctgtagaagg 1320 tcacagggag ttcaagaaaa caggctaggg ataggaggat gctcatgtgc ttctcttggg 1380 agcggtggca gggccagctc cgtctcaaag caggctttat ctagaaactg gtgaggtggc 1440 aggagcttag gaggagggag aaattgattt aaatattttc attaaacact ccctcactga 1500 tggtaatttc acttgctctc tccctcttag ccccccacac ttcagaacag gagagagagg 1560 atactcgcat acacacacat ttaagtgcag gcacacacat agatatgtat ttctaaacca 1620 tttttcctgt gaatacaatg atgtgctccg atatatactt aagccagtct tactattaaa 1680 ccatctcttc taaaaaatat gatcaaaaca cagttgttct aaaagcaaac tctaaaagac 1740 tgacctagtc tctgacaatg agtttgaaaa agtgcagctc ttggtgttgt ctgcaaaccc 1800 aacactattt gttgacttga caggcaagac agacaaaccc tcaaagttaa tggtttctct 1860 attcgtttac tctgtaagtg ctctctgcat tcaagcgaga tactgcattg gctgacacat 1920 taaatatgct gagactcttc cagaacgcag caggcagaca acccacggtc aacagtgggg 1980 gaatggtatt tgtctggctt agttatctcc aaatgtctag agagagaata atagtatata 2040 atggtgcatg gaaaacaccc atgagccttg gtgtgttatt agtagtagtt actttatagt 2100 gggtaatgac aaaataaagg tagcttccag tttctgaagg tttactatgt gtggatgtaa 2160 cccttgctaa tcaccacctt agttaatcca aacaacagtc ccatgaagta tgactattat 2220 tatccccatt ttacagacaa acaaaatgag gactacagag gttaataact tgccccaagt 2280 catggtacca aagggtttgg gagccattat ttcagtcaaa ttctaaccaa gtgtgcttag 2340 ccatcgtgcc agaggttcca aggaaggagt ttgcttgttt gttttattta tatcacttga 2400 tgaaataaaa ctaccattcc cattacatat aaaacctcct atagatgcct ccttagcatg 2460 ctgtgtgatt ccactaagct gttgatagac acagtcctcg gggctggggg tgtgggtcat 2520 ttgttagcat gcatgaggtc ttgggtttga tccccagcac tgataaagct ggcatggtga 2580 tgtatgcctg tcaccccagg acttcagaga tggaggaagc cattcagtgc catcaccagc 2640 tacataatga gtaagaaaga gaccagcctg gaacacatgg cattttatct taaaaaaaaa 2700 aaaagacatt cgttttgaca tgtatatttt ttgcttttgt aaattttcaa gggaatgttt 2760 cacccagaag ctttgcactg ctgatggtac acgtctgaaa tgtcagcaat ccagaggctg 2820 aggcaggagg attattgagt tccaggtcag ctgggtctaa acacaggagg aaagtagagc 2880 tttgagtgga caccatgttc agatgctcaa tgatcttcag agttatgctt ttggcagaca 2940 ccacaccaac agaaaaacaa gaacaacaat tgccttcaaa gggagggcag ccttgtgaag 3000 ctctgattca aaggagaatt gtcctttgga gtctgaatga atttggaccg ctctttctga 3060 gcctttccaa ttctactggc atccacaact gaaaacaaac agcggtgccc tgattgccac 3120 agacactctc tgctgggcag acagcacacc gcagttccca ggctgttctg ccagcatctc 3180 tcaggtgttc agcctgggtg gggaattgca acatgtgtag caagccaggt ggccctgcag 3240 agcctgtctc caacttcgat gctgctgggg acacaaagaa cattagggca tggagtggct 3300 ctgtcagtct ctgtgaggga agcccttgct caccacataa catcattccc taggtgtgtt 3360 cctgcacata tcctaatttg ttttaactct gtatttatag tgagaattgt taagagaatc 3420 ttaggactga gcaggactga accagacaga gacagcagtt ccatgttgcc agacagatct 3480 tacacaggct tagcctggtc gcagccacca gaccaggtcc ctgttcagtg agaggtggaa 3540 agaaatacac atggattttt tttttcattt tttgctttgt aaatcatggg ggagatgggaa 3600 aagtttacac atagattttt tttttctttt cgttatttgt tttataagtc attactcact 3660 agcctaggct agcttggagc actctctgta gctcaggctg gccttgaact cttagcatct 3720 cagcttcagc ctcctgagaa ctgggattac atagctatga tactatacct ggcgcccaga 3780 tgtgtttaaa agcctcaact tcccaataga cctagacgct cctttctcag tctgaaggac 3840 acaaatgtac ctcaatctac aaacttaatc acaaatctct caagggtgtt tctgaaactt 3900 cagagcactt tggaacaaac tttcctagtg gggaggtttg tttcttcact catttaactg 3960 gcaaagtcac aactatacaa cttcatttat ttatataatt ctatctaact aatggaaata 4020 agaggtgagg ttagagaaga ggaataactt ttaatattct gtagtaaagt agtgaag 4077 <210> 18 <211> 1501 <212> DNA 213 <213> <400> 18 gacttgcagt cttcaagaac ggatgatgcc ccaggcaaaa ggggtatcct accctgccac 60 ttagtgggcc ccaaaggaga ggcttctgct ctagggcaaa gcttcatttc cctcttcctt 120 tgagctcact tatttggaat gagtatgtct gccccttgcc tgccctatca tggtcttttg 180 ggaacacaca acaaacctgg ttttgccggt tcacagccag aggacggatt cccttctaca 240 tgggtctgcc tataccagat gatgtgatac tgtgttgact tgggacttgg agtggtttgg 300 gcatgggtta agactttggg ccagttggga tggggtaagt gcgtttagca tgtgaggatg 360 ctaaatatga acttggggga catagagaat atggagttat agacccagtg gtatccttcc 420 agatttgtaa ttaaatctgt acagttcaat acctcaaaat gtgactatat ttggagacag 480 ggcttccatg gggagatgac attgaaatgg ggccgtcagg atggactcta acctgaatga 540 tgtctttgta agagaatcat tagctacaaa gagagcccag gggcacacac ttagaaagga 600 tcccacaagg acacaggaag ggaggtggaca tgtgcaaggc aggcagaggc ctcctgagaa 660 atcggttctg tctgcacctt gatcttggat atccagcctc tagaattatg aatgcattgc 720 cttctttgac aaatctgtat ctaaaagaaa ggaggggtgtt atttgtttta gctcaagttc 780 tagtacaagg tcacttggcc ccttgtgctt gggtggagca tcataacatt tggcagaaga 840 cagccattcg tgtcatagga gataggatgc agaggacaag tggaagggga ggggactgga 900 cacataggca caacacccgt ggtgacctgc ttaccccagc tgggccgata cctcctgaga 960 ttccagcacc atccaaaaca gcaccatgag caggagaaca gatttgagag ccattatgca 1020 tgcaagccat aacagtgagg gaatacattt ctgctaagtc ataagtaata ctgacttcaa 1080 tcttaaaatc ccagggaagc tgatgaagct cagcggtaag gcacttgctg gcgtgctaga 1140 ggctctgggt tcccatccct cccagacaat ttaccagagt cttcccttgg tgttagcagt 1200 tttgggtcct cttgtcttca cattaaaact gacattcaca tggaatgatt tttgctaatg 1260 gtgagaaagg gttcatttta ttctcattaa gagggtcaac taagtaccac acacacacac 1320 acacacacac acacacacac accccacaga ttaatttgcag cccctcggtc ttaagtgatg 1380 caattgctgt gcactcctgt cttgcaggct gtgctctgtt ctattggtgg ttcaccagcc 1440 tgtgccaaca ctgactggaa gaacaagctc tctctggttc atcttcacag tcttggttat 1500 t-1501 <210> 19 <211> 1909 <212> DNA <213> Homo sapiens <400> 19 gaatgtttac atgtacattt caaacccagt tttctaattg tgcagtctta atttcctagt 60 taatttcact ttacagataa gaagctctgg agacatggcc tttccggtta aagacacaga 120 gcccaggcac tgcccacggc ttcctccaca ctcatgctgc tttcccttag gtaagacaaa 180 cctcaccaaa gctgagactg gctcaagaaa cggggaagcc taatgcttgt aaacattccc 240 ttaattgggaa gcattaggca ccaaaattct tcctaaaaaa tatgtaagcc ccaagaatga 300 aagggccatg gttagcacaa accgcacctc ctgagcccag caaaacccaa caggcacagt 360 gcagcacagc ctgggcggtc tctcaggtga gtctctgcct cgctcttgcc ctgtctgtca 420 cctcatctct gccaagtctg aaaatcctga gctccaggga ctgtgggaac ttcactagac 480 atgtgtgaac aactctacat tctgatccgt agcgtctccc taatgatgca catctaggaa 540 ggagaggggag ggagaggggag cgtgtgcatt ccttggagca acgaggacag cctagtgatt 600 tgcaaactct ttgcggcctc ctggtgggct tcagaatcaa tttgtgagtc ccaaccagaa 660 ttttctacat aattagaata aaacagagtt aagatatgag tgcatcgtat gttgcaagat 720 actgttttgt aaacgttgtt tcagatattt gtgagtgcac atgtgtgtgt gcagtaatgg 780 gtcacaaaat atatttactc tgggtcatgt tttaagaggg ctagaaggca acactaacat 840 aggatggttg gaagatggtc aggctcagaa catcagattt tgcctccttc cagggtacca 900 cttttatcaa gtcacacatt ccttcccgct ctgcttttgt gtttctcaat cgctatccaa 960 atttgcgcag aagtcaggaa tcacgtgggt aaagatttaa gctgtacttc tggtttaatt 1020 aagcacgttg aagaagaggt gctctggggg aacgtggaga aggtgggtag cgagggctcc 1080 aggggctcag aaggtggcct cgaggggctc tcatctgcca tccttgtgag ggagaaagtc 1140 ctaaaccagt cgtaacattg ccagaacaag gggtcccaat ccagacctcc aaagagggtg 1200 cttggatctc tcatgggaag gaattcaagg tgagtcacaa agtgctgtga gaagagagag 1260 ttttttggaa gttacgcaga tacagagtag ggtgtcctca gaaagcaaga ggaggaactg 1320 cctcgtcttt aagtttttct tacataggag tcctctctat gtaaagacag agctaagctg 1380 tgtctctatg tgggtgggct gacagcgtga caaaatttat tattctgttg atttaaagaa 1440 aactatactc aatattttaa tgtgtaagta catcaagtca taattataat tatcttgaaa 1500 gcatatattg ttatgggtat tgggacctct ggacttttcg ttgtcatatg attgtatcct 1560 tgcaggtatc tttaggctgt ttcttcaact gtaaatatct tatgactgtg ggtcgtgacc 1620 ggcaaggaat ggagttggtt tttaaaatgg tgtcaccctg gctcttctat gctcctgttt 1680 ccctaacagt aatagcccag ccattctctc ccatgttctc ctctgccctc aacttcagaa 1740 tgaagtcaat tttatttca gccaaaatag gaggattcta ttctgtctgt tgaggtctgc 1800 tgtggtctaa tgatgttaat aaccagtggc tgggcatgat tacacgacga ggattctaaa 1860 tcctgtttca tgtttccctc tgggccccact ggctatatga ccccttaaa 1909 <210> 20 <211> 1201 <212> DNA 213 <213> <400> 20 gagtatatat gtttctaagc caggttccta actatgtagt attaatttcc taatgaaaca 60 ccctttacag gtagtgaggc ctttggagac cagggcttta aaggccaagt agctgaagcc 120 cagggtcttt ccatggcttc ttcctatgac tgtttatcta atagatgaga caaacctttt 180 caaaactgat tatcagttaa gttccaagaa agcaccactg taaatgttaa tgttcctttg 240 aaatggaagt atttagcgct ctgtgtgtgt gtgtgagtgt gtgtgtgttg tgcagttggg 300 tacatatatg cagatatgca caattgtttg tgtttgtggg tctttgtgg tgtgtgcagg 360 tctaaagttt ttcttttcat tagttatggt ctaaagtggt tttaaaaaaa gaaaaagaag 420 agcagagaag gctatgatag catgaggttc ctttgggatt gtctggctta gaacgctagg 480 ttttcccatg ttttaacagc ttcccatgtc cttcccactc tgcctttgtc tttctcattg 540 tgatccagat ttgccccaga gggggagaac ccagtaggta agagttcacg ctgtacttcc 600 atgttaatta agtgatgtgg aagtcttgga aaggctgggc agtttttcct gtcttcccag 660 gagctggggg aggttcatcc ttaatggaac cagttccatg ccatccccag gaggcaagaa 720 gtctggaaac atcaataatt attcagtcac aacaacccac tttcctctct ccccctaatc 780 ctcaactgct gacttcagga caaagtccat ctgatttcaa tcagatagga agactagtta 840 gaggcctgcc ccagtttact ggctgcagca acaggaagca caggttacaa taccaagtga 900 ttccacgctg aaagcttcac tctgatcatc ctaccaggct gctacatgag cccttgaaag 960 cgaattatcc ccggagactt actttctata taacacatat atacttacat atacatgtcg 1020 actttgtttt ttcttgtatg ctgtaaagat gcctaggata catttaagga tgcaacataa 1080 aagtcacttt cttcatggag taattattat aatagtactt gtttctgggg gagcaaattg 1140 aaatgtttcc cagtgtgaac tgccaagtta aaacaacaaa aagctagttg gagctccccc 1200 t-1201 <210> 21 <211> 3995 <212> DNA <213> Homo sapiens <400> 21 ctaacatagg gtcgttagtg tcagaactga attaaattgt agggacatgca ggtggtgact 60 gcagagaatt ggagcattgc ttggagtgaa aaccaagccc acatatttgg tgtcaaaagt 120 gttatacaag tagaaaaaca ggttctcttt aatggaatat tattcagccg tattaaggaa 180 tgaggttcag acccatacta cagcacatat gaatctccaa aatattgtgt ttagtgaaat 240 aatatagaca caaaggacaa atactgtata attgcactta catgaggtgc ctggaatagg 300 caaatccata gagacaggca gtagaatcat ggttgccagg ggctgggcgg gagggagaat 360 ggagagttag tgcttaatgg gtacagagtt tctgtttaga ggtgatgaaa acagtttgga 420 aatagtggtg atgattgtac tatattgtga atgtatgtaa tgccactcac cgaacactct 480 aaagtgtttg aaatagcaaa tttctattat acgtatttta ccatagtttt taagttaatt 540 accatagttt ttaaaagtta ataggataat attccctgaa ccactataca ctttagattg 600 gtacactgtg tggcatgtgc attatatctc aatgaagttg ttaaaaacaa gatttaaaag 660 cagagattgg gtaaagtaaa ggtttgctct gtgctgagct gtgtggcatg tggacctgtt 720 ttcccaggag ggagcactcc tggggttttg gccgcagctg cacatcagcc ccctgtgcag 780 aggaggtatg gtgtgtgatc tggagattag ctgtttctag tgcagtattt acatttaaag 840 acattgctga gttaggcaga attttctata tccatttgta ttttgcttgg cattcacttt 900 cttacaaaaa tggacaatca agacaaagaa aacaaaaggt ccaattacta ctcttcattt 960 caccccaaag caaaacaata ttagttttca attttttttt cccatagaaa gcaataacag 1020 tcccatacta cctcctcttc catgaaagta gtgcttgaga tgccccaagg aaaaaccatt 1080 ctttccaaag atgaaagact ttgtacctgt caggtgaaga gatggaataa atgccactcc 1140 tagtgggtgt gggacttgtg cagcccctgg tccccagtta tctgcttatc agaatgtggt 1200 ttgcatatca cctttagcgg aattccttgg gatgcttgta attctggggg agatgtctgg 1260 agtctgcatt tttagccagt actcctatga cttaggcaca gtaggggaacc actggtgcca 1320 ttccttcctt cctttcttcc ttccttcctt ccttccttct ttccttcctt ccttccttcc 1380 tccctccctc cgtccttccc tccctccttc tttctctctt tctttctttc ttcggagtct 1440 cactctgtca cccaagctgg attgcaatgg tgtgatcttg gctcactgca acctctgtct 1500 tctgggttca agtgattctc ctgcctcagc ctgctcagta gctggtatta taggtgtgca 1560 ccaccacacc cagctaattt ttttggattt tagtggaggg gtttcaccac gttgagcagg 1620 ctgatcttga actcctggct tcaaatgatc cacccgcctc agcctcccaa agtacttgga 1680 ttacaggcgt gaaccactgc gccctgctgc aatgcttttg ctttccgtat acaaggaggg 1740 gttgcaggct tgactctaaa atgattgact ttatggagga ccgtctcatg tctggatggt 1800 aagtgatagg ggagggggca accctaaatg ggatcccaat gacttgatga aagactggaa 1860 gatgagacac tttcaggtgt gcataatgga agacttacgt aggactagga ccaagcctct 1920 caattatact aagttgtcca tgattgacca gggatttgat gaaaatccca ctgccttcct 1980 agaaaggtta agagaggcct tggtaaagca cacctctcta tctcctgatt cagtcaaggg 2040 acagctaatc ctaaaggatg aatttggctg ggcatggtgg ctcatgcgtg taatcccagc 2100 actttgggag gctgaggtgg gaggatcacc tgaggtcaag agtttgagac cagccttgtc 2160 aacgtggtga aaccctgtct ctactaaaaa tacaaaaaaa attagctggg tgtggtggca 2220 ggtgcctgta atctcagcta ctcgggaggt ggaggcagga gaattgtttg aatctggggag 2280 gcagaggttt gcagggaacc tagatcgcac cattgcactc caacctgggt gacaagcaaa 2340 actccatctc aaaaaaataa aagggataaa tttattactc aagctgcccg atatcaggag 2400 gaagttgcag aaaggggccc tgggtccaga aagtacatta gaggacctcc tgaaaatggc 2460 caccttggtc ttttatgatt gagacaggga ggcctgggaa agagagagga gatacaggta 2520 ttccagggtg cacctgttaa cttctaaaga tatggcaaga acagttctct ctcttctaaa 2580 gtttatctgc ccccgtacaa ggtttaattt ctttcaccag ggtgaaacag cttggagtac 2640 aatgttgttg ttagtatatt tcacttatct ctgttggcac taaattcttt ccttgtataa 2700 tacacatgtt taacttatgc atacttgacc ttataaaact tgtttttttc tctcatgcct 2760 agaagccatc aaactccaaa tggtcaggca actggagcct cagatgatag ctcccctttg 2820 ctaggaaccc ttaaatagac ctctgggagg actctgactg ccattttctc caaaacaaca 2880 ccccttgtca gcaggaagca gcaagactgg tcatcaacca tattctaacg gcagtattcc 2940 tatgatttag ccagtgggcc gtgaccggca aggaatgtgc cttgttagtt tcaagatgga 3000 gttgattttt aaaatcatgt caccctggct cttctatgct cctgttcccc taacagtaat 3060 agcccagcca ttctctgcca tgttttcctc tgcccccagc ttccgaatga agtcaatttt 3120 tatttcttca acgtacctct tcagagggga aattatacag gaggggggca gggaagtgct 3180 gggtagagaa aggtggatcc ccagctaggg ttccaccccc acagacctag gtgaggaaag 3240 gcacttctgg cttcacaccc aaatgttgca ttttcgaaga ccaacctggc ctgccatgcc 3300 cccattctgg gcctataaaa acccaccacc ctagcggaca gacacacagg tggccagacg 3360 tcaagaacag cacatcagca gttgaagaca caaaagggtg gacgacaaga aggcatcaca 3420 agagaacgtc aagggagcac gccgatggaa gaacctgctg gcaggctatc cactgttggc 3480 atgaggggga gtttggctgg ggcagtcaga gaagagcccg gctgcatagc ggcccaattc 3540 caggggaaaa ccatctctct tttggctccc ccggcagaga gctacttctg ctcaataaaa 3600 cttggctttt attcaccaag cccaggtgtg atccgattct tccggtacac caaagcaaga 3660 atccctctgt ccttgtgaca aggtagaggg tctaattgag ctggttaata caagccacct 3720 atagagagca aactaagaaa gcaccctgta acacaggccc actggggctt caggagctgt 3780 aaacattcac ccctagacac tgccgtgggg tcggagcccc ccagcctgcc tatctgtatg 3840 ctcccctaga ggtttgtgca gtgaggcact gaggaagtga gccatactcc catccacgcc 3900 ctacaaaggg gataagggaa tctttcctgt ttcataagta gcaatctctg tggtaacagc 3960 ccctgtggtg atgccgtctc tctcggttct gccct 3995 <210> 22 <211> 1651 <212> DNA 213 <213> <400> 22 tccttggcta ctttctctag ctcctccatt gggagcccta tgatccatcc attagctgac 60 tgatgacact gcattcttta atatatgggg tttgcactaa cttggggtag ttatgtcat 120 gtttgaacta aattatagga cctccagttg ctggagaatt gctctgtgtg gactgtccac 180 acatatttgg tttctaaaat gtcatataag cagacactgc agtttctcca cagtggaatc 240 ttacccgggc ataataaggg aagacattcg gcacaagctt caacacaggt gaaccttaga 300 360 gacacctggc agaggccagc ttaaagagac aggcagaaga tgtgagtccc aaggactgcg 420 gaggggaaat gacagccagt gttttgtggg tgctgagggc aacagtttgg agtagacaat 480 ggtgatgcag ggctgtgaac gggctcagtg ccgctcactg aaccaaacag cctaagtgtt 540 tataataaca aaagtaatac tgacatacac cttccgttgt ttgaaagagt taataaggta 600 acattcccca aatcacttta aacaggcaaa ctatgtgaaa tataaatctg tttctgtgaa 660 gctgcttttt taaatgcttc tcctatcaga ggtcagaaga aagaaggctt gctggggagtg 720 gagttggctg tgtatctcag acctgttttt gcaggaggag tgtgcgctcc gggatttggc 780 agcggctcga gtcatccctg tgagaggcag gcatggtgcg tgatcctggg gcttttctgt 840 ttctagtgtt ctatttattt taaagacatt gctgagttca gcagaaatgt ttcacatcca 900 tttgtatttt ccttggtact catttcctta caaaaatgac gatcaaagca aagaaaacag 960 agaatcttca ttttacccca aagcaaagtg agtgcacttc taataccata acagaaaaaa 1020 cgcttcgggc ccttaggaag tgctgaagaa gctgggcaag gtggtgggtg cctttagacc 1080 caaaggaaag tgattttctc caaatgtgag aggcctgcga tgatggggtg agtggccccc 1140 agaggatgtg gggactgact agcgctgtct ccgtctgtat gcccagtgaa gctgtgggtg 1200 ggacacaatt aacagcacaa gtctgagtgg tgagaccctc tgctgtgacg aaccctgcac 1260 tgatgttact gttgaaggta tctctcaagt gctcatgctg gaaactaagc ccccagtttc 1320 tagttgatgt tgtttggagg tgggatctta tgggaggggga ttaggattag atgatgtcat 1380 aggggtgggg cctccacaat ggcattaatt gctttagagg aagcagacaa gaccaaacta 1440 gcacatttac gctgtcttac cgtgagagta atctgccatc ttctgaggca ggtgagttga 1500 tatcaccaga tgcccacacc atgcatttgg gctccacagt ctccagaatc ataggttttg 1560 aacctttat ctttataagt tttctagact ggggcattct gttacagcag caagaactag 1620 actaatatac atccctcctt ccatctgccc a 1651 <210> 23 <211> 751 <212> DNA 213 <213> <400> 23 tgtgtgcacc agctttgact gctgctggag gctgcccatt tcctgtgatc tcaaccagct 60 tttctgatag gccagtttat ctctggactc tggcctatgc ctgatacaga tgtaatcagg 120 catccaggaa gctatctata tggaggcaaa ggtcctttta ttcaggccac tggaagcctc 180 ttccataaag ttcagtagta cgagtacagt gtcctttcct gtgtacagcc cctcgctttc 240 tcttctggac tcccagctga gccagtgttt gagccaccca tcactctgaa aacagcatct 300 tcatctcctt aggctcagct tctcaagtca cacaggctac attgctgccc tcagggtgag 360 cctcccttca ttcatctcgg tgataattct aaacaatggc ctgtgtgtta tagaaaggcc 420 ctgcaagcat acatgttatc aacttactag ctgtgcccaa ggttgcatag ctagtaagtg 480 gtaagactga aatttgagcc taggggacca taactctaaa caatgttcta tccactaggc 540 ggtactgtgt agaccatggg ctcacacaca cacacacaca cacacacaca aaatgtattg 600 aataaaataa ttgtgggttt tgcatatttt cctgttttat gtcagcttga cacaagctag 660 aatcatttgt gaagagggac tctcaattga gaaaatgctt ccactttttg ttgttttgtt 720 tgttgttttt gcctgtcgga aagtctgcac t 751 <210> 24 <211> 490 <212> DNA <213> Homo sapiens <400> 24 ctgtggagtg cctatagcac tgtgtgtagg cagaatgcaa aggggacagt gtgggtgggg 60 acagtgttgg tgtagaaatg gcggggaggt tagattgcag gcacagaggg cctcagccat 120 ctcgagagcc cagacttcct ccctgaggtg atggcacttg gggaagtcag tcatggaagg 180 attttaagaa agatgtgaaa ggggcaggtt tctattttca gaaaaccatt ctgggccagt 240 ggaagatgga gtacacagga ccacaccttg gtgaagggag attgtaggag cctgggcttg 300 gtggcggggg acagtggaga gaacagcctg ggatgtatga acatggcaag tctcccttcc 360 tggacagtgg ggtttgccta tggtggacag aaggtgagat catcctttga aaaatgccac 420 ttcatagtgt ttccccagct gtgggccttc actcattgga gggtcaaata atcaatgtat 480 taggttgcaa 490 <210> 25 <211> 1505 <212> DNA 213 <213> <400> 25 tcccagagaa cctaagcctg attcccagca cccaaaggac tgcttacaac caactgaaac 60 tccagttcag ggatccaaca ccctcttctg gcctctgtag gcaccaggct tgcatgtggt 120 acccagacat tcgtgcaagc aaaacactca tacatataaa aatagataaa taaatgccta 180 tttaaaaccc ttgcctcatc tgaaattatc tgaatgttga tttctttgga ttccctttcc 240 ttttgccctt gggaaaaata ggtcacccct gtgtcagtta ctgtatgttt tggtcactgt 300 tcatagtttt agagaggatg tctaggaggg cagggtcacc tgtggtgtgg caattggggag 360 ctccatgtgc agaaggaatg cagacacagc agcagagagt gcaggaggcc cggaaggttc 420 caccatcccc acagccccac ttcctccctc tgccgaaggg gttgggggtc aggcagaggc 480 tttaagaggg gcgtggacag ggtagatttc tgttttggga aaaccatcta tcagagggca 540 gaggacaggg tggaacccaa cacagctgag agcttgcaag gggctgggct gggcagcagt 600 gaagaggaac ctcacaggga ggagcccctg gggtgcaggg gctctgaaac tgccctgtga 660 aaaacactgc ctcattgtct tggcagtttg ggccctgacc cagtagcagc aggtcagaca 720 attgttatat aaagttccga aaattcaaac ctcccccttc ctccttcatc cttcttagct 780 acacgtgtgt ccatgagtgg cagagcaggc actcacatag aggtgtgccc actgcagcgg 840 ctacagcact aaagaaaatc cctctctccc cttcctctcc ccctttcttt tacttcaaag 900 cagagtctta ctatagggcc cggcccctgt gggctgctca cttttaatcc tctgccttgg 960 cctatctagc actgagatca cacacctgcc tgtgtcacta tgcctggctt ccagcacttc 1020 tttgagtgct gacagacacc tcaagtggaa aattcttgtc cttgcttcat ttgacagatc 1080 acagtgaaaa tgggagccca ctaaaaatac tttataggat taccctcggg ctgtgtctga 1140 ggcgggtagg taacataagg aatttcaggg ttagacttta gtcctgtcac caagacatct 1200 atctctttat acatataaaa gtattccaca gtctgaaaaa agctctgaaa tagagaatgc 1260 ttcttgtcca tagcatcata gatagagacc cttcagactt gtatataaaa cagaattgaa 1320 aagtcaattc aggtgtgcac acacacatgc atgcacgcac cagcacgcct gacatctctc 1380 agggctgccg ggcatcactc aggtgactgc ttgacgtgtt gatgtttgtg tctttggctt 1440 cttctttgag tcttttgttt ttcttctttt attttattta tgagacaggg ttgagttcat 1500 tgcat 1505 <210> 26 <211> 1840 <212> DNA <213> Homo sapiens <400> 26 cacaccattg catgcttcag ccgttgcccg tgctatttcc tcccttggaa agccctctac 60 tgtgaggccc tcacctctca accctctccc tggcccccat gttgtctatg tgatttcttg 120 ccatttaaaa atctacccag gtgtcagcgc ttgggcagtt tcctcacacc tctcacccag 180 ttcatcctcc cttgcttggt gctatttctg cccttgtcca tatcccccacc acagcatgca 240 ctttggattc caggcacgct ccttgagtgt gaccccgagg ccctctgtgg gctcttggag 300 cagggcaaag ctgggtgtgc tggggcgcag cacgggcctg atgccctgag gttgtttgtt 360 gtgctgggct ggaggcgttc gaagaaacgt ccaaggaggc tgctagactc agttctttct 420 ttctgttttc cctccacctc ctctgctagt ggaagctcca tgtctcccag gctcgtgagc 480 tggcaaacac cccgcttgca tggttcagtg ttgtcgttgg cggcaggcgt acgtggaagg 540 ccagttacag agggtctcta gggctaatgc atttcacaac acaccgccct ctgacactcc 600 acgctctgct tttcctccag aaccactccc tttgcaaaac tctgtttcaa acaaaaagag 660 cacaaagagg ctgaccgtgc cttcctccaa ccaagctccc ctctccacag gtgcacagca 720 agagcccttt gtctgtgatg ggacaggcct gggctccagt gagcaagaca ggcactgtgg 780 gcccatccaa atattaactg tggacacttt cctactttga aaacatgaga ctttgtactc 840 agagccctgc cctccagaga acacaattac ttctgttttt cttttcctag tggaaggagg 900 cttgacactg gtgatggcct tgcctttaca atgctcaggg tttgggaaag tcagggccta 960 gggctgctga tctccaggca ctgtctgctt tccatctatc ctctctgctt ggtccctgaa 1020 aagcaggagg gagacaggag gaatggggagc atgaatgccc tcagggtcca cgggggatcc 1080 cggaaggcct agaacaccag gggtctgggc tccacccatg atggatcatg cctttggggg 1140 aagattggcc tacactcatg tcaagtaata agttttactt cctgcacctg gtgttaggtt 1200 ggttctaaga tgcagctgta acctgtgact aagatcaata tttttcatgt cactatctga 1260 tcatacaatg gtcaatttat cgatttagaa aattgttgca caacgaggca acaccgagtc 1320 atgacttaaa aaaaaaaaaa gtggatctaa ccgaagctag attgtggctt atcacctttg 1380 attgtcagtt tcttgggtca aatcttaatg ccacattgac cactgtgtca agagaggcca 1440 ggttccaact cagctccgtg tatagtgttc atggaatctc aatgctcatc aggcgctgct 1500 ggggctgggc ctcggggagg ggcaggctcc tgtcagcaca agtcaccagc acaggtttta 1560 accagccagt ctgggctact tttaccactg aagcagtggg gcgagaaact ctattttaca 1620 gtgtttctaa aacctctgtg agctaaaagt agaagcaact caaatgcccc tcacctgatg 1680 aataaacaaa cacagtgtgg catcctcgta caatggagta ttattcagcc atagaaaggg 1740 aggaaatagt tgtgctcgat acagtatgga tgaggcttgg agacatgatg ataagtgaaa 1800 agaagccaat cacaaaagga caaataatgt atgattccat 1840 <210> 27 <211> 1451 <212> DNA 213 <213> <400> 27 taagccatca catgcttcaa ccatgggcta cttccacctg ctcccccccc ccccacacac 60 acacactgct acccctcacc cccagcttgg tgcctcactt ctcaggctat aatgctgctt 120 tcatggacat tccttgttct ttggaaacaa gggcccttcc ctctgcagag ttctcctgcc 180 tgaggctgtg tgttcttggt ttgtgggcct ttgcccagct ggtgcccagt gcaaggtgcc 240 ctgctaactg aacaaatgac cttgctcatc gtcatcttct tggtctccat ctttgtggtg 300 gagccttctg gaccaccggc aggtaccctt tgcaggacag cctatcctgc cctgtctccc 360 tacagagcca ctccctgaag ctgcagaaaa caagagagca tagaggtgac cctctccaca 420 ggtgtgtggc cagagccact catccacagt ggccaggccc atccaaatat taatgatggg 480 tgttttctgc tttgaagttg agaatgtcgg tcctcaagag tccaccctga agagaacaca 540 accacatctg tttccttcca gggaacaggg gctgcactgc ccttcttctc tgtccgtgcc 600 cagagcatgt atctgagcat gcccagagcc aaacacagca tctatttcct actgatcttc 660 acagctggac aggctcccac acagccagat gctccctggg gagcctcaaa agcaaggttc 720 accaggtgga gctctgggga aattgctttc aactctgtct tggcagggct tgccttctgc 780 acctggcttt aggagggctc caagatgcag cataacatgg gacggatatc aacgcttctg 840 tctgatctta taacaaaggt caatttgtaa agttgatacc accaagtcct ttcttccttc 900 ctttcttcca caccccgtcc tctctgagaa aatggatcca atagaagcta gagtgtgact 960 tgtaggttct gactgtcact tctttggggt gaattttaat gccaaatcag ccaggggcga 1020 agctgaggag agccaagttc acacacagtt cagcacgaag ttttaattca gtcccatccg 1080 tccgaatctg cactgctgtg ggtgggttaa agggagagca ggctcctgac agcatgtgct 1140 ccagcacagg tgagtctgtc acactttttc ctacagctgc caggcaagac gtcaagtcta 1200 cttaaggttt cttatgcctg gaatcgccta aaacgtaaag caatcaaaat gtctatcacc 1260 caaagagtag ccagacaaaa cacagcaggt ccttttatga agagtcctgt gtcacaagac 1320 acaggaatat caattctcag ccattaaaag gcacgctgta atgacactgg ccacgatatg 1380 ccacatctta gaaatattac aataagtcaa agaagccagc agcaaaaggc taactaatgt 1440 attatttcca t 1451 <210> 28 <211> 6212 <212> DNA <213> Homo sapiens <400> 28 ctctaggtgg tgaaaatgac cagatttggt tgtggggtca tagtggacac taaagatcag 60 caaggggaaaa aagatgtgac tataaacttt ccattctcac agttgttttg agacccgagt 120 gtacgtttaa tgttttcaac agaagaggct gcatgaagaa gagtaagtta accgcgggga 180 ggctgtgaga atttttctgc gcggacaatg gagctcagtg tctgtttcag tgtttgtgct 240 ctctatagat acctggatga ttcttgggcc tcagtgtgtt ctcgctccct ccctgccgag 300 actcaaaggg atgatgcacg ctgcccagcc aaaaccagga cagaacgtct ttttccccgt 360 gggaatgcgc tcccggcgcc aattccaagg cctgcctggg tcctattcag gcagtgctgg 420 ggtgagcagc aggctcgggc ccagctgaca cggccagaga tccccagtga ctactttcct 480 gacatggcag agatggcaga tggagaatcc ataagcccca gttacacccg ggagctcaca 540 ctgtggcttc agtctccaag gagagtgggg agagccctgg ccctccgtga aggattgctt 600 ccgcccaagg ggggccagtg aacccgaatc actctgctgg atggtgctgg ggggctgatg 660 caatctgcat tccttcccct cgcacccctt acccctcgct acctccccct tctcatcctc 720 cccactcgca cctctccttc tcccacacct ggctgacacc cactcttgag tcactgtcag 780 ctccaagaca gaaccggcat cctgggtgct tggcaggagc caaaggagca tgttacagga 840 tctctggctt cacagatggg gagagagcag ttcagagaat tgcgggttcc acatttgctt 900 gaagtcactc atcagccttt atgttacatt acaacaaagc agcccagggg acatggactc 960 atagggtacc tggtgtttcc ccaactgtag gggggattcc gggacaaata aagtttgcca 1020 ctgggaccct cccccgaact gtgccctgtc ccactcctgt gacacactct ctgccccacaa 1080 gagagtggcc aacagtggag gctgagagtg accacctgcc tgccctcagt tattaaaggc 1140 tactggagaa caagccttga gtgcgtgctg agaacacatg cccctagctg ccatcaaaga 1200 gaatcacttc atatgatttt gaccataagc aaactcttcc accttcattt tttaaaataa 1260 cggctttatt gagatatgca tcacttacca tgaaactcac tcttttaaag tgtacaaccc 1320 agggttttca gtgtattcac ggaattgtgc aaccatcacc catcacccct aatttcagga 1380 catttttatc actccaaaaa gaaactttgc acacatcatt cttctctccc cacagcctct 1440 gacaactgct gatctatttt gtctctatgg atttagcagt catggacatt tcatatacat 1500 ggaatcatac actatatgtc ctttcatgac tgacatctgt cacttagcat gattttatga 1560 gattcatcat gttggagcat gcacccatgc ttccatcctt tctttttttt ttttcacagt 1620 cttgctctgt cgtgcaggct gaagtgcaat ggcacgattt tggctcactg caacctctgc 1680 ctcccaggtt caagccattc tcctgcctca gcctcccagg tagctgggac tacaggtatg 1740 tgccactatg cctggctaat ttttttgtat ttttagtaga gatggagttt caccatgctg 1800 gccaggctgg tctcaaactc ctgacctcaa gtgatctgcc cgcttcggcc tcccaaagtg 1860 ctgggattac agacgtgagc caccacatcc tttctaaggc tgaatagtat tgcactgtat 1920 ggatagacca catttagttt atctgcctgc tggcttatgg acaatgagtc actccacttt 1980 ttggctacta tgaatcatgc tgttgtgagc acttgtgtac atgtctttat atggatgtct 2040 gttttccctt ccattgggtt tgcttggggg tggaattgct gggccacctt ctttctccat 2100 gagtggagca tgcctatgcg cccatccccg catctcccat gtgtggaggc actgcccaag 2160 ctcgtctgta ctctgagtca cagggctgg caccattacc gatcaccatc tatgggtcag 2220 ggacttatca atgagcaaga catagcccct gccatcacta actcacattc tgcatcgtcc 2280 tgtgccatcc ccaccacccc accttggtca ggcccagtgt ccaggtgtct tcaactgctc 2340 accttccccc tattttgttg ccctgaagtt catccagaca tcagggtgcc ctattgaaaa 2400 tgctagttaa tatgacctct ctgctctaac cccaatgttg gagtcttgtc atcagtggga 2460 tagagctggt gtgactgcac cagaccagtc aggttcaact tttatgaaag gaagttgtga 2520 gttgctttca gttgccatgg accccaagtc gtaggtcatg taagctgagc atgcccaaac 2580 ggaccaagca tgcaaccatg ggcagaacct gagtgctcag actgaggagc aggggctgaa 2640 ttaagaagca gagcatacat ggcaggatcc aggatccagg agccaatcag actgagtttg 2700 gcatcactcc atggcaggat ccaatcagat cacacctccc tgcagcacct cattgcaaga 2760 tccaatcaga ccacacctca ttaccctagg cttataaaat ccaggccagc cgctagcttg 2820 gggaggcaga tttgagtgtt tttttttttc tgtctccttg ccagactacc agcaaaaaag 2880 gttttctttt ctcaaaagcc ggtgtcatgg tattggcctc tgtgcacatt gggcagtgag 2940 cccactgatt gctcagtaac atgggcacac tctggggccc acacaagcca ggaatgatgt 3000 ggcctttacc tgctgctcca gctgcatctg agcccagtat cccctgaaca caaaccccca 3060 cctgcatgga gctgcatgcg gttctcgggt acctcctggc tatgttcagc tcctgtagat 3120 tccttcagat ccactccttc ccatttcctc atccaactgc ccagcagagt gcctactatg 3180 cgccacacac tgggattcag cagtaaacga cacaaacatg atccccaccc ttatccttct 3240 cccaggactc ttattaatct aaggctcacc tcccttcttg taacttccat gaactcatat 3300 gctccctctc agctcaggga cgttgctgga ggaagcaaga gagcagcaga tgaaccctta 3360 tgttcaggag gcagatggag ctcattcaaa gcccaccttg gcctcttctt aacccgaaga 3420 ttttagcaag tcatataacc tttgaactgc aactccctgg attgtggaat gcccaaagtg 3480 tgctgagcgt gaagtaaata atgcaagtgt aaagtgtgcg gcatggtcct ggttcatctc 3540 aggaggccgt taggaaacta gcacttattt ttgccagggc ttgagcatag aacatatactaa 3600 tttccccaat ggcattatca cattgtatta ctttttattt acatgttctt tctcccctac 3660 caatctcaga gaatctcaag ggcagcaatg attaattatt aattttggaa tccttggttc 3720 ctggcacatt ccttgaaaat aaatcattgg cttactttcc actgattctc ttaattaccc 3780 ctgagaggca gagattggaa ttatactatg ctgagcagct caatgttttc ccagtaacag 3840 caggaaaatc ccaatgcaca gagaaggaac ctgaatgact taggtgggac acaccaggac 3900 agacaccccgt ggtgatgaca ttctgtgccc ttcatcccac agagtggtct gtcttcacag 3960 tggtctcccc tcaccacact gagccctcaa acttcctctt tccgctgacc aaagtgcacc 4020 caggcctgct tgtccattca gacagatgcc agggccctct gcactccatc tgacctctgc 4080 aatatgccgg ttcctaataa gggagcagga tccaggtcca gttgttcaca cttctaattt 4140 cataccggca gcctcagtaa agttctgcca tcaggctaag gccccactga tcgtcgacct 4200 tttctgcata aagattcacc tccagggctc ttagaaaata ctgctgcctg gctaccaccc 4260 catccttagt gtgacatagg gttttttttt cttcttcttc tgttttttgt tttttttaga 4320 ataattaggc agctctgttg cccaggctgg agtgcagtgg catgatctca gctcactgca 4380 acctctgcct cctggttcaa gcaattctcc tacctcagcc tcttgagtac ctaggactat 4440 aggcacacgc caccatgccc ggctaatttt ttgtattttt agtagagacg gggtttcacc 4500 aggttagcca ggatggtctc aatctcctga ccttgtgatc cgcccacctc agcctcccaa 4560 agtgctggga ttacagacgt gaggcaccac acctggcctg ccccgggttg tttttttttt 4620 taaagctccc cagggatttg taagtgcata ccaaagactg ggaacccctg gcttagctca 4680 cagagcaaag agccttttga gggttcccct cgacagttgc tccctcacct ccagctgtgg 4740 ggccacacag agcgctgggc cattgtggtg ttagagacca gagttaaagg gactccatct 4800 gtaatatcca ggacaaatgg gctggcaggt gctgctcaaa cccttacaca cagatagtat 4860 ttggggaggt gaggtcaatt cccccattat ggaacgctgc ggttttaaaa gcaagcaaac 4920 aaacaaaaac aggaaaaaag tgagcttttt aaaactaagg taaaatttgt cctcaacttc 4980 ctggccttga ttgggctctg ctactagagc ggcagaagca actcacttcc ctgcttccac 5040 ggacctgttt catgtaatgc attttgcaga gatttgaaga cagggtcctt gacttgggca 5100 gctaacagcc tgaggctaga ggcagccacc cctgaacagt gaacaattct gcaaggcgcc 5160 tggcaatagt actatgcggg gagggggtag gaacaaggtg ctgcagggcg gggtggagga 5220 ggaaatgaat tctgcctggg agaagcggga gtgcgtattt gagtggggtc tggagcaggt 5280 gcatgcaaag aagcacctca aaggcacggg caggtgtggg caggcgtggg caggcgtggg 5340 caggcgtggg aaggcgtggg caggcgtggg caggtgtggg caggcgtggg caggcgtggg 5400 caggcgtggg caggtgtggg caggtgtggg caggcatgtg ggcacggcac agggcttgtc 5460 caggccagat gccattaagc acaggtatct gtggtgggca ggggacacag tggaagcaga 5520 tagagaaggt ttgctggggt cccatggagg ggcgccttgt aggccatggt cactctaggc 5580 tgatgcaagg tgctcaaggt tgaaggcaga ggtgactgac ctgtgcttga gagagggtag 5640 ggaagagaag ctgccggact tgaggggctg aaattgtcct gtaatagtcc aggtcaggag 5700 tgttaatgat gccccagctc gggcagtgac tacggcaagg agagtttaac atgtggttca 5760 gttcagcaga catggggaac tcactatgtg tgaagcagga cacatcacgg aggcagccct 5820 caaatgcttg aagacagtaa tcctgcccct gtgctgtggc gggttcttta aggggtgtga 5880 cttcctcatc agacccattg ctctcacacc taatgatgct gccatgtggc agggctgtgg 5940 gcagagccat gccctagcag gggaagtgga ggacagcggc ggggagggag tgggggcagg 6000 gctttcctgc cctctgggtc ctctcctctc tttcgtggca gggccttgag gtccattcgc 6060 tgggctgcac agaaggagga ctccagagcc ccccttgggt tcaggatttt atacacgcag 6120 cattccagac agatggaccc gtgtattgac aatgaaagca tgggagaact gtatttcttt 6180 ggtgattaaa gtaaatgcaa aagttatgat gc 6212 <210> 29 <211> 2501 <212> DNA 213 <213> <400> 29 cctcagctgg aattaaccct acacagttcc tcagagccta gggcttagta aaaaggccaa 60 gcctgaccta tgacctctct gacatctgtc cttagcacgt gttcttttct ttccaagtac 120 attgtaccac catgatggcc tgtgccctcc tcccccatcac ctccatacaa cgaatgagct 180 ctcatgagag cagagtggag gctggtgctg tggcctccac tcaggaattg tgaaccactc 240 caaccttctt ttgttaaaca ttacctagcc tcaaatatct tgtgatagca acagaagaga 300 ctaagatact taaaaatatc tatggatgaa gaaaatgacc aatgtgagga cgtcgtggat 360 attggccatc agcaaagaag agagcataaa gttcccattc tcacagatat tctgaaacct 420 gtgtatttca tttttgatgg aaaagagctg cacacagaat agtaagttag ctggaggggaa 480 cttatgagcc tttttttttc cccctcacat aaacaacaat ggagcttagt gtccatttca 540 ttctctttgt gcttgactgg gacccagatg gctcactgtc cctcagtatg tccctgctcc 600 ctccctgctg agatctcatt ggctgtgacg cactgccctg ctccagccag gacactactg 660 tctttcttcc ccgtgggaat gtgttctcaa agccaactcc aacaacgctg acctgggcat 720 cacttgggtg gtgctggagt gagctgtagg ctctggtcct gctgttgtag cctggggtcc 780 tagttgtcat tcccctgaca cagcagagag agcaaacaac agaaccaatg gctgtagcca 840 catggtgaac agctagacct ccagaacaat aggagtaaat gcttctgcca cgaagtgtat 900 ggagaaccta aaccaatctt caggcagaac tggggccagg taccacacac agccctgccc 960 ctttctcagc tggctgttgc ccatgccaga gtcatgatca cccataggat tctcagaccc 1020 agggcattgt gtagctggag ctcaatgagt cttacgggcc ggaagcagcc aattcaggga 1080 actctgggtt ctgcgtttgc tttgcatcta tttggtgaga gacagtgtga gttcttccat 1140 tacaaaattc caatgtttaa agagcaaaca gtcaagaaac aagaaaaaaa aacccaaggg 1200 tgtgtctgtg tgtgtgtgtg tgtgcatgtg tttatgtatg tgcaggtaca tgttggggac 1260 atgtgcatgt gcatgtttac atgtgcatag agaggtcaga agacaacacc agctgttgtt 1320 ccccaagtac aatccatagt tcaaccccct gtgtgtgtgt gtgtgtgtgt ttatgtgtgc 1380 atatgctatg gaagtcaaag attgagtctg gtgtcttcaa ctgccctcta ccctattttc 1440 tgaaacagag tctctcacta aatctagacc tcactggttg ggcatccttg ttagccaatg 1500 agctcaacta tctgcccgtt tgttctctct ctctctctct ctctctctct ctctctctct 1560 ctctctctct ctctctctct ctctccataa atgaatgaat gtgtgttttt aaaaagagag 1620 tttaaaaaaa actaaggtgg catgtatccc agcttctctc cacaatccaa ctggaacggc 1680 tcaggccagc ctcatttcac gcagctcact ctatcaacac atctgctgca cagagcatgc 1740 tttgtgagtg actcaaagat cagaaccctg acttccaatg gcttatagcc taagggtaga 1800 gaagttacct gtattctggc aagataccag ggattgtagg aggggtagca acctggggag 1860 gagggaatgc actctgtgta ggagatgcag aaaggattgg aagagctggt gagtatttga 1920 gttggatgtt ggactgataa atgcagggag catctcacag gttgggatca ggcacaccgg 1980 taggatgttt catccatccg agtcaaatgg agggcaggtg tagggatttc aggttagagg 2040 gcagggaaag aaagtagaga ggagagcctg gggttgtgct ggaggtgtgca cagagcactc 2100 agctggcact ttgaagaaca aagtggactg tccctggacg tgagactgag caggtaaggt 2160 gggttaagag acggtaagat cactactgca ataatccaaa ataagaacct ttatgatctc 2220 taggtgggat aacaaccagg gggagggact tttaacacac aattcagttc aacaggaact 2280 cgcacatcct ggaggcaaca cgtgaactgc gcaggctcag cagtcattgt ctgttctgcg 2340 tggtgctctt ccaagtggca cagtgtcttc atcagacctg gtgctcacat gactgatcta 2400 gtcacagaac aggccatgta tcaagttttg ggaaacagga agcaatggga gaaatgtatt 2460 ttaattggtga ttaagtgaag tgcaaaagat aggacgtgct a 2501 <210> 30 <211> 347 <212> DNA <213> Homo sapiens <400> 30 gggttcgggg ctttcggggg cggtcggggg ttcgcggacc cgggaagctc tgaggaccca 60 gaggccgggc gcgctccgcc cgcggcgccg ccccctccgt aactttccca gtctccgagg 120 gaagaggcgg ggtgtggggt gcggttaaaa ggcgccacgg cgggagacag gtgttgcggc 180 cccgcagcgc ccgcgcgctc ctctccccga ctcggagccc ctcggcggcg cccggcccag 240 gacccgccta ggagcgcagg agccccagcg cagagacccc aacgccgaga cccccgcccc 300 ggccccgccg cgcttcctcc cgacgcagag caaaccgccc agagtag 347 <210> 31 <211> 1131 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 31 gggttcgggg ctttcggggg cggtcggggg ttcgcggacc cgggaagctc tgaggaccca 60 gaggccgggc gcgctccgcc cgcggcgccg ccccctccgt aactttccca gtctccgagg 120 gaagaggcgg ggtgtggggt gcggttaaaa ggcgccacgg cgggagacag gtgttgcggc 180 cccgcagcgc ccgcgcgctc ctctccccga ctcggagccc ctcggcggcg cccggcccag 240 gacccgccta ggagcgcagg agccccagcg cagagacccc aacgccgaga cccccgcccc 300 ggccccgccg cgcttcctcc cgacgcagag caaaccgccc agagtagaag caggtgagtt 360 tgtggtgtcg ccgatgtccc ttcggggtac tctagcgcag ccgcctggct acttgaccca 420 ctgccaccaa acgttttaaa ttcaccgaaa gcttagcttc gaagcaaagc tccgtttcgc 480 cggtgaagca ggaagccttc gctgcaggaa ctgaccttta cctcttggag cggcttctgc 540 agaaaaatcc ccgggcagag atttgggcgg agtttgccta gaactaacgc ggagccagcc 600 gatcccggcc taccccgggg ccaagatttt aaggggtgaa gagtcccttt tgccttttct 660 ggatcctggt gattcaccta gtgtcttccc taaggaactg aaccaactcc tccgctggcc 720 tctggcagcc ctccaggcgg tgcaggatgg cgtgggcccg gtaggaagct gcatgtaacc 780 gcccagggtc gggaggccag gagggcagct cctcctctga cttgaatatt gaaaacaaga 840 ggatgctttt aagaaaaaga agaaggagga ttcactacca gctctgaagg gtggaaaaga 900 gatgattcat ccggattgg gagagggtgg aatcttgttt aggagagcgt tggttgtggc 960 aggcagggtg taactatgaa tcagtgaaga caattcacat cctgggatga aaagaaggcc 1020 atgggctcac aggagattat ccactggcct ctccacatcc gcttgcagta aggagtgtgg 1080 gactctccca agcttcagcg ctgaactgca atgcagtgac gtcgcttaag a 1131 <210> 32 <211> 1431 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 32 cgcattgccc agttgttaga ttaagaaata gacagcatga gagggatgag gcaacccgtg 60 ctcagctgtc aaggctcagt cgctagcatt tcccaacaca aagattctga ccttaaatgc 120 aaccatttga aacccctgta ggcctcaggt gaaactccag atgccacaat ggagctctgc 180 tcccctaaag cctcaaaaca aaggcctaat tctatgcctg tcttaatttt ctttcactta 240 agttagttcc actgagaccc caggctgtta ggggttattg gtgtaaggta ctttcatatt 300 ttaaacagag gatatcggca tttgtttctt tctctgagga caagagaaaa aagccaggtt 360 ccacagagga cacagagaag gtttgggtgt cctcctgggg ttctttttgc caactttccc 420 cacgttaaag gtgaacattg gttctttcat ttgctttgga agttttaatc tctaacagtg 480 gacaaagtta ccagtgcctt aaactctgtt acactttttg gaagtgaaaa ctttgtagta 540 tgataggtta ttttgatgta aagatgttct ggataccatt atatgttccc cctgtttcag 600 aggctcagat tgtaatatgt aaatggtatg tcattcgcta ctatgattta atttgaaata 660 tggtcttttg gttatgaata ctttgcagca cagctgagag gctgtctgtt gtattcattg 720 tggtcatagc acctaacaac attgtagcct caatcgagtg agacagacta gaagttccta 780 gtgatggctt atgatagcaa atggcctcat gtcaaatatt tagatgtaat tttgtgtaag 840 aaatacagac tggatgtacc accaactact acctgtaatg acaggcctgt ccaacacatc 900 tcccttttcc atgactgtgg tagccagcat cggaaagaac gctgatttaa agaggtcgct 960 tgggaatttt attgacacag taccatttaa tggggaggac aaaatggggc agggggaggga 1020 gaagtttctg tcgttaaaaa cagatttgga aagactggac tctaaagtct gttgattaaa 1080 gatgagcttt gtctacttca aaagtttgtt tgcttacccc ttcagcctcc aattttttaa 1140 gtgaaaatat agctaataac atgtgaaaag aatagaagct aaggtttaga taaatattga 1200 gcagatctat aggaagattg aacctgaata ttgccattat gcttgacatg gtttccaaaa 1260 aatggtactc cacatatttc agtgagggta agtattttcc tgttgtcaag aatagcattg 1320 taaaagcatt ttgtaataat aaagaatagc tttaatgata tgcttgtaac taaaataatt 1380 ttgtaatgta tcaaatacat ttaaaacatt aaaatataat ctctataata a 1431 <210> 33 <211> 743 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 33 Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser 1 5 10 15 Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro 20 25 30 Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro 35 40 45 Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro 50 55 60 Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp 65 70 75 80 Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala 85 90 95 Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly 100 105 110 Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro 115 120 125 Leu Gly Leu Val Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg 130 135 140 Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly 145 150 155 160 Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr 165 170 175 Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro 180 185 190 Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly 195 200 205 Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser 210 215 220 Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile 225 230 235 240 Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu 245 250 255 Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn 260 265 270 Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg 275 280 285 Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn 290 295 300 Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile 305 310 315 320 Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn 325 330 335 Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu 340 345 350 Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro 355 360 365 Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp 370 375 380 Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe 385 390 395 400 Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu 405 410 415 Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu 420 425 430 Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser 435 440 445 Lys Thr Ile Asn Gly Ser Gly Gln Asn Gln Gln Thr Leu Lys Phe Ser 450 455 460 Val Ala Gly Pro Ser Asn Met Ala Val Gln Gly Arg Asn Tyr Ile Pro 465 470 475 480 Gly Pro Ser Tyr Arg Gln Gln Arg Val Ser Thr Thr Val Thr Gln Asn 485 490 495 Asn Asn Ser Glu Phe Ala Trp Pro Gly Ala Ser Ser Trp Ala Leu Asn 500 505 510 Gly Arg Asn Ser Leu Met Asn Pro Gly Pro Ala Met Ala Ser His Lys 515 520 525 Glu Gly Glu Asp Arg Phe Phe Pro Leu Ser Gly Ser Leu Ile Phe Gly 530 535 540 Lys Gln Gly Thr Gly Arg Asp Asn Val Asp Ala Asp Lys Val Met Ile 545 550 555 560 Thr Asn Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Ser 565 570 575 Tyr Gly Gln Val Ala Thr Asn His Gln Ser Ala Gln Ser Thr Thr Leu 580 585 590 Tyr Ser Pro Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile 595 600 605 Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro 610 615 620 Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro 625 630 635 640 Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile 645 650 655 Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp 660 665 670 Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val 675 680 685 Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro 690 695 700 Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe 705 710 715 720 Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr 725 730 735 Arg Tyr Leu Thr Arg Asn Leu 740 <210> 34 <211> 149 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 34 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgggcgacc aaaggtcgcc 60 cgacgcccgg gctttgcccg ggcggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactaggggg ttcctagat 149 <210> 35 <211> 139 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 35 cccctagtga tggagttggc cactccctct ctgcgcgctc gctcgctcac tgaggccgcc 60 cgggcaaagc ccgggcgtcg ggcgaccttt ggtcgcccgg cctcagtgag cgagcgagcg 120 cgcagagagg gagtggcca 139 <210> 36 <211> 6374 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 36 ttgctggcct tttgctcaca tgtcctgcag gcagctgcgc gctcgctcgc tcactgaggc 60 cgcccgggca aagcccgggc gtcgggcgac ctttggtcgc ccggcctcag tgagcgagcg 120 agcgcgcaga gagggagtgg ccaactccat cactaggggt tcctgcggcc gcacgcgttt 180 aattaagacc tcgaagggga cttggggggt tcggggcttt cgggggcggt cgggggttcg 240 cggacccggg aagctctgag gacccagagg ccgggcgcgc tccgcccgcg gcgccgcccc 300 ctccgtaact ttcccagtct ccgagggaag aggcggggtg tggggtgcgg ttaaaaggcg 360 ccacggcggg agacaggtgt tgcggccccg cagcgcccgc gcgctcctct ccccgactcg 420 gagcccctcg gcggcgcccg gcccaggacc cgcctaggag cgcaggagcc ccagcgcaga 480 gaccccaacg ccgagacccc cgccccggcc ccgccgcgct tcctcccgac gcagagcaaa 540 ccgcccagag tagaagcgga tccgccacca tggattgggg cacactccag agcatcctcg 600 ggggtgtcaa caaacactcc accagcattg gaaagatctg gctcacggtc ctcttcatct 660 tccgcatcat gatcctcgtg gtggctgcaa aggaggtgtg gggagatgag caagccgatt 720 ttgtctgcaa cacgctccag cctggctgca agaatgtatg ctacgaccac cacttcccca 780 tctctcacat ccggctctgg gctctgcagc tgatcatggt gtccacgcca gccctcctgg 840 tagctatgca tgtggcctac cggagacatg aaaagaaacg gaagttcatg aagggagaga 900 taaagaacga gtttaaggac atcgaagaga tcaaaccca gaaggtccgt atcgaagggt 960 ccctgtggtg gacctacacc accagcatct tcttccgggt catctttgaa gccgtcttca 1020 tgtacgtctt ttacatcatg tacaatggct tcttcatgca acgtctggtg aaatgcaacg 1080 cttggccctg ccccaataca gtggactgct tcatttccag gcccacagaa aagactgtct 1140 tcaccgtgtt tatgatttct gtgtctggaa tttgcattct gctaaatatc acagagctgt 1200 gctatttgtt cgttaggtat tgctcaggaa agtccaaaag accagtctac ccatacgatg 1260 ttccagatta cgcttaaggc gcgccacccc tgcagggaat tccgcattgc ccagttgtta 1320 gattaagaaa tagacagcat gagagggatg aggcaacccg tgctcagctg tcaaggctca 1380 gtcgctagca tttcccaaca caaagattct gaccttaaat gcaaccattt gaaacccctg 1440 taggcctcag gtgaaactcc agatgccaca atggagctct gctcccctaa agcctcaaaa 1500 caaaggccta attctatgcc tgtcttaatt ttctttcact taagttagtt ccactgagac 1560 cccaggctgt taggggttat tggtgtaagg tactttcata ttttaaacag aggatatcgg 1620 catttgtttc tttctctgag gacaagagaa aaaagccagg ttccacagag gacacagaga 1680 aggtttgggt gtcctcctgg ggttcttttt gccaactttc cccacgttaa aggtgaacat 1740 tggttctttc atttgctttg gaagttttaa tctctaacag tggacaaagt taccagtgcc 1800 ttaaactctg ttacactttt tggaagtgaa aactttgtag tatgataggt tattttgatg 1860 taaagatgtt ctggatacca ttatatgttc cccctgtttc agaggctcag attgtaatat 1920 gtaaatggta tgtcattcgc tactatgatt taatttgaaa tatggtcttt tggttatgaa 1980 tactttgcag cacagctgag aggctgtctg ttgtattcat tgtggtcata gcacctaaca 2040 acattgtagc ctcaatcgag tgagacagac tagaagttcc tagtgatggc ttatgatagc 2100 aaatggcctc atgtcaaata tttagatgta attttgtgta agaaatacag actggatgta 2160 ccaccaacta ctacctgtaa tgacaggcct gtccaacaca tctccctttt ccatgactgt 2220 ggtagccagc atcggaaaga acgctgattt aaagaggtcg cttgggaatt ttattgacac 2280 agtaccattt aatggggagg acaaaatggg gcaggggagg gagaagtttc tgtcgttaaa 2340 aacagatttg gaaagactgg actctaaagt ctgttgatta aagatgagct ttgtctactt 2400 caaaagtttg tttgcttacc ccttcagcct ccaatttttt aagtgaaaat atagctaata 2460 acatgtgaaa agaatagaag ctaaggttta gataaatatt gagcagatct ataggaagat 2520 tgaacctgaa tattgccatt atgcttgaca tggtttccaa aaaatggtac tccacatatt 2580 tcagtgaggg taagtatttt cctgttgtca agaatagcat tgtaaaagca ttttgtaata 2640 ataaagaata gctttaatga tatgcttgta actaaaataa ttttgtaatg tatcaaatac 2700 atttaaaaca ttaaaatata atctctataa taatttaaaa tctaatatgg ttttaataga 2760 acagcgatat caagcttatc gataatcaac ctctggatta caaaatttgt gaaagattga 2820 ctggtattct taactatgtt gctcctttta cgctatgtgg atacgctgct ttaatgcctt 2880 tgtatcatgc tattgcttcc cgtatggctt tcattttctc ctccttgtat aaatcctggt 2940 tgctgtctct ttatgaggag ttgtggcccg ttgtcaggca acgtggcgtg gtgtgcactg 3000 tgtttgctga cgcaaccccc actggttggg gcattgccac cacctgtcag ctcctttccg 3060 ggactttcgc tttccccctc cctattgcca cggcggaact catcgccgcc tgccttgccc 3120 gctgctggac aggggctcgg ctgttgggca ctgacaattc cgtggtgttg tcggggaaat 3180 catcgtcctt tccttggctg ctcgcctatg ttgccacctg gattctgcgc gggacgtcct 3240 tctgctacgt cccttcggcc ctcaatccag cggaccttcc ttcccgcggc ctgctgccgg 3300 ctctgcggcc tcttccgcgt cttcgccttc gccctcagac gagtcggatc tccctttggg 3360 ccgcctcccc gcgaattcat cgataccgag cgctgctcga gagatctgtg atagcggcca 3420 tcaagctggc tgtgccttct agttgccagc catctgttgt ttgcccctcc cccgtgcctt 3480 ccttgaccct ggaaggtgcc actcccactg tcctttccta ataaaatgag gaaattgcat 3540 cgcattgtct gagtaggtgt cattctattc tggggggtgg ggtggggcag gacagcaagg 3600 gggaggattg ggaagacaat agcaggcatg ctggggacac gtgcggaccg agcggccgca 3660 ggaaccccta gtgatggagt tggccactcc ctctctgcgc gctcgctcgc tcactgaggc 3720 cgggcgacca aaggtcgccc gacgcccggg ctttgcccgg gcggcctcag tgagcgagcg 3780 agcgcgcagc tgcctgcagg ggcgcctgat gcggtatttt ctccttacgc atctgtgcgg 3840 tatttcacac cgcatacgtc aaagcaacca tagtacgcgc cctgtagcgg cgcattaagc 3900 gcggcgggtg tggtggttac gcgcagcgtg accgctacac ttgccagcgc cctagcgccc 3960 gctcctttcg ctttcttccc ttcctttctc gccacgttcg ccggctttcc ccgtcaagct 4020 ctaaatcggg ggctcccttt agggttccga tttagtgctt tacggcacct cgaccccaaa 4080 aaacttgatt tgggtgatgg ttcacgtagt gggccatcgc cctgatagac ggtttttcgc 4140 cctttgacgt tggagtccac gttctttaat agtggactct tgttccaaac tggaacaaca 4200 ctcaacccta tctcgggcta ttcttttgat ttataaggga ttttgccgat ttcggcctat 4260 tggttaaaaa atgagctgat ttaacaaaaa tttaacgcga attttaacaa aatattaacg 4320 tttacaattt tatggtgcac tctcagtaca atctgctctg atgccgcata gttaagccag 4380 ccccgacacc cgccaacacc cgctgacgcg ccctgacggg cttgtctgct cccggcatcc 4440 gcttacagac aagctgtgac cgtctccggg agctgcatgt gtcagaggtt ttcaccgtca 4500 tcaccgaaac gcgcgagacg aaagggcctc gtgatacgcc tatttttata ggttaatgtc 4560 atgataataa tggtttctta gacgtcaggt ggcacttttc ggggaaatgt gcgcggaacc 4620 cctatttgtt tatttttcta aatacattca aatatgtatc cgctcatgag acaataaccc 4680 tgataaatgc ttcaataata ttgaaaaagg aagagtatga gtattcaaca tttccgtgtc 4740 gcccttattc ccttttttgc ggcattttgc cttcctgttt ttgctcaccc agaaacgctg 4800 gtgaaagtaa aagatgctga agatcagttg ggtgcacgag tgggttacat cgaactggat 4860 ctcaacagcg gtaagatcct tgagagtttt cgccccgaag aacgttttcc aatgatgagc 4920 acttttaaag ttctgctatg tggcgcggta ttatcccgta ttgacgccgg gcaagagcaa 4980 ctcggtcgcc gcatacacta ttctcagaat gacttggttg agtactcacc agtcacagaa 5040 aagcatctta cggatggcat gacagtaaga gaattatgca gtgctgccat aaccatgagt 5100 gataacactg cggccaactt acttctgaca acgatcggag gaccgaagga gctaaccgct 5160 tttttgcaca acatggggga tcatgtaact cgccttgatc gttgggaacc ggagctgaat 5220 gaagccatac caaacgacga gcgtgacacc acgatgcctg tagcaatggc aacaacgttg 5280 cgcaaactat taactggcga actacttact ctagcttccc ggcaacaatt aatagactgg 5340 atggaggcgg ataaagttgc aggaccactt ctgcgctcgg cccttccggc tggctggttt 5400 attgctgata aatctggagc cggtgagcgt gggtctcgcg gtatcattgc agcactgggg 5460 ccagatggta agccctcccg tatcgtagtt atctacacga cggggagtca ggcaactatg 5520 gatgaacgaa atagacagat cgctgagata ggtgcctcac tgattaagca ttggtaactg 5580 tcagaccaag tttactcata tatactttag attgatttaa aacttcattt ttaatttaaa 5640 aggatctagg tgaagatcct ttttgataat ctcatgacca aaatccctta acgtgagttt 5700 tcgttccact gagcgtcaga ccccgtagaa aagatcaaag gatcttcttg agatcctttt 5760 tttctgcgcg taatctgctg cttgcaaaca aaaaaaccac cgctaccagc ggtggtttgt 5820 ttgccggatc aagagctacc aactcttttt ccgaaggtaa ctggcttcag cagagcgcag 5880 ataccaaata ctgtccttct agtgtagccg tagttaggcc accacttcaa gaactctgta 5940 gcaccgccta catacctcgc tctgctaatc ctgttaccag tggctgctgc cagtggcgat 6000 aagtcgtgtc ttaccgggtt ggactcaaga cgatagttac cggataaggc gcagcggtcg 6060 ggctgaacgg ggggttcgtg cacacagccc agcttggagc gaacgaccta caccgaactg 6120 agatacctac agcgtgagct atgagaaagc gccacgcttc ccgaagggag aaaggcggac 6180 aggtatccgg taagcggcag ggtcggaaca ggagagcgca cgagggagct tccaggggga 6240 aacgcctggt atctttatag tcctgtcggg tttcgccacc tctgacttga gcgtcgattt 6300 ttgtgatgct cgtcaggggg gcggagccta tggaaaaacg ccagcaacgc ggccttttta 6360 cggttcctgg cctt 6374 <210> 37 <211> 700 <212> DNA <213> Homo sapiens <400> 37 ccatgatatg ttaagaaaag caaagtgtgg aatagtaggt aaaatattct atcttatgtg 60 caaaagggga aataaaagtc atcaatattc atgtagattc aattcacata tagattcata 120 tcacattcct atatatatag aaattctgga aagacacaaa ataaattaat aaaagttgtt 180 acttcattgt agtttttaaa gttttttgag tcttaagact tactttccac ttctgtagaa 240 aggaattaca aatcctttct ttatagagct atgtgatgaa ataaacataa agcatttggc 300 acacttcagg atagcaactt gtggattaat gattaacaca gtcacctttg caccagatta 360 cacccagaga ttccttcatt tatatttatg tggttttgtg tgtcagttat gcagtctaac 420 tcagtcattc aactatgtta cagctgcaac actctatttt tttctttggt acaggagtcg 480 ccctcttatc cactgtttca tttttgtggt tccagttacc tgtagtcaac cacagttgga 540 aaatatgata gcattttgag agagagactg catccaaaaa ctttatattac aatatattgt 600 tatacattgt tataagtgtt gttttattat tctttattgt taatctctta ccattaagcc 660 ttatggtagg tttgtatgta taggaaaaaa cagattatat 700 <210> 38 <211> 700 <212> DNA <213> Homo sapiens <400> 38 atataatctg ttttttccta tacatacaaa cctaccataa ggcttaatgg taagagatta 60 acaataaaga ataataaaac aacacttata acaatgtata acaatatatt gtaatataag 120 tttttggatg cagtctctct ctcaaaatgc tatcatattt tccaactgtg gttgactaca 180 ggtaactgga accacaaaaa tgaaacagtg gataagaggg cgactcctgt accaaagaaa 240 aaaatagagt gttgcagctg taacatagtt gaatgactga gttagactgc ataactgaca 300 cacaaaacca cataaatata aatgaaggaa tctctgggtg taatctggtg caaaggtgac 360 tgtgttaatc attaatccac aagttgctat cctgaagtgt gccaaatgct ttatgtttat 420 ttcatcacat agctctataa agaaaggatt tgtaattcct ttctacagaa gtggaaagta 480 agtcttaaga ctcaaaaaac tttaaaaact acaatgaagt aacaactttt attaatttat 540 tttgtgtctt tccagaattt ctatatatat aggaatgtga tatgaatcta tatgtgaatt 600 gaatctacat gaatattgat gacttttat tccccttttg cacataagat agaatatttt 660 acctactatt ccacactttg cttttcttaa catatcatgg 700 <210> 39 <211> 700 <212> DNA <213> Homo sapiens <400> 39 gcagagacct acagacagaa gtacatttta cactggatcc aggacacaca tcagtctgaa 60 aacacacaca tgaaccaaac gtttcctaaa gcattactta tccttgctaa tagcaacaca 120 ttctcatatt cttttatact tcatttaatt tcatataaaa aagaaaagga aaggaaagaa 180 atctatttct cagcccatta ataaggtcag gagcagcaac accagactag aagaaaagct 240 tacctataga tttttctgcc acctcttgag tgcgtccagc tttccgacaa gtctcagtgc 300 catctactgt gcgctctggg tattgcaatt gctttttttt tttttttttt ttttttttta 360 gaatgagact aagtcagaga acacaaagaa cttctttccc cacagtggag atggctctga 420 aagcgtttaa ggaatagctt agatgagtgg ctaacacat ctcccggttc tgaattctaa 480 gaccacagac tccatgtcca gtccccaaag agaggctttg caagctacag aatacccctc 540 tgactgggac ctcaggagct aaactgacca cgtaattggt tctagaaagt gaaacgtttt 600 aatttgaaac atccaaatga gcattttgg aaaagctact gccgtccatc aaatacaaca 660 cagccaggga gtcatcgctc tattgccctt gtcaatccta 700 <210> 40 <211> 700 <212> DNA <213> Homo sapiens <400> 40 taggattgac aagggcaata gagcgatgac tccctggctg tgttgtattt gatggacggc 60 agtagctttt cacaaaatgc tcatttggat gtttcaaatt aaaacgtttc actttctaga 120 accaattacg tggtcagttt agctcctgag gtcccagtca gaggggtatt ctgtagcttg 180 caaagcctct ctttggggac tggacatgga gtctgtggtc ttagaattca gaaccggggag 240 aatgtgttag ccactcatct aagctattcc ttaaacgctt tcagagccat ctccactgtg 300 gggaaagaag ttctttgtgt tctctgactt agtctcattc taaaaaaaaa aaaaaaaaaa 360 aaaaaaaagc aattgcaata cccagagcgc acagtagatg gcactgagac ttgtcggaaa 420 gctggacgca ctcaagaggt ggcagaaaaa tctataggta agcttttctt ctagtctggt 480 gttgctgctc ctgaccttat taatgggctg agaaatagat ttctttcctt tccttttctt 540 ttttatatga aattaaatga agtataaaag aatatgagaa tgtgttgcta ttagcaagga 600 taagtaatgc tttaggaaac gtttggttca tgtgtgtgtt ttcagactga tgtgtgtcct 660 ggatccagtg taaaatgtac ttctgtctgt aggtctctgc 700 <210> 41 <211> 700 <212> DNA <213> Homo sapiens <400> 41 atccattatt tgattagcca tttcaaaaac acatttacgg agatcttcat ctgggcagag 60 cattattcca ggcctctgaa gaaccaaaga tgattttgaa aggaggtcac agtgcagaca 120 gcaggtgtgt atataaggtg gctactttac aaaacaggat atggcaagct ggacatgaca 180 ggcacagcaa agtctctgaa cagagttcgg ggcatgaaat tgtttctttt gggggtcttc 240 aggaacaatt tcatgaaagc taaatcatga aagatagcag gcttttgcca ggaaaaaaaa 300 aaacaagact agtgattagt ttggcgtttt cggtttcttt gagaagcgaa ataacttatc 360 aaggactctt tttgccactt gatgttataa ttggttgata ggtctctcag aagccctttg 420 tgcaaactag aacctgcagg gatgtgcaaa gcctctctct gctgccatct gctgtcttac 480 aagaggtaac tgcaagaggt tgaatcctcc aatgccctgg ggattcccat tgcagggcag 540 gggcagcagc ctgtgttaat aaccacccga acagccacat gtacccctcc acaaaagtgt 600 cactgtctcc attgctctgg agtttgtatt cccaatttgt aatctttgtt agggcactca 660 taaaaaatta aaaacaaaaa ttcacacaaa catacactac 700 <210> 42 <211> 700 <212> DNA <213> Homo sapiens <400> 42 gtagtgtatg tttgtgtgaa tttttgtttt taatttttta tgagtgccct aacaaagatt 60 acaaattggg aatacaaact ccagagcaat ggagacagtg acacttttgt ggaggggtac 120 atgtggctgt tcgggtggtt attaacacag gctgctgccc ctgccctgca atgggaatcc 180 ccagggcatt ggaggattca acctcttgca gttacctctt gtaagacagc agatggcagc 240 agagagaggc tttgcacatc cctgcaggtt ctagtttgca caaagggctt ctgagagacc 300 tatcaaccaa ttataacatc aagtggcaaa aagagtcctt gataagttat ttcgcttctc 360 aaagaaaccg aaaacgccaa actaatcact agtcttgttt ttttttttcc tggcaaaagc 420 ctgctatctt tcatgattta gctttcatga aattgttcct gaagaccccc aaaagaaaca 480 atttcatgcc ccgaactctg ttcagagact ttgctgtgcc tgtcatgtcc agcttgccat 540 atcctgtttt gtaaagtagc caccttatat acacacctgc tgtctgcact gtgacctcct 600 ttcaaaatca tctttggttc ttcagaggcc tggaataatg ctctgcccag atgaagatct 660 ccgtaaatgt gtttttgaaa tggctaatca aataatggat 700 <210> 43 <211> 700 <212> DNA <213> Homo sapiens <400> 43 gctaattggg tcaggatttg aaagacctta gctttgtgg accttcaatt ttatcattca 60 gcttgaatat gtgccccaga aaacctttat gtaattccct aatatttcag taaccagcat 120 gcaacatacg agaagcacat tctttgtttt tagaatggta tctggctgat gactttcaca 180 acagctcaca tgagagggaa gtattttagc aatcggactg aaggaaaatc caaaaactcc 240 accattgcag ggtcaacagt gcacgtgttt gaattctgaa agacgtaagc caaggcaaat 300 agaaggaaat gatcttccac taatcccggc atttacttcc tcctctctgg aggggacggc 360 catgcacaca gagccctgtg ctctgagttc tcatgaaagg gacacagctg ggctcactca 420 gcgtcacctc gcccctgggg tgtgtcctgg tttcagatct cgggctggag tgattcacgt 480 gtggcaggga ggccatcatt aatgaaaatg cgagggcgtc gcacgagtgt tgatgactca 540 gcaggccttt ctacttctgt atgagtcagt gcccatcaca gccaagcctg gggcacaaca 600 ggttttctta aaagagcatg ggggcctcat cttcaacaac caattaggaa gcagaaaagt 660 cctcagtgag gaaggaataa tgacatgttg gagctaagat 700 <210> 44 <211> 700 <212> DNA <213> Homo sapiens <400> 44 atcttagctc caacatgtca ttattccttc ctcactgagg acttttctgc ttcctaattg 60 gttgttgaag atgaggcccc catgctcttt taagaaaacc tgttgtgccc caggcttggc 120 tgtgatgggc actgactcat acagaagtag aaaggcctgc tgagtcatca acactcgtgc 180 gacgccctcg cattttcatt aatgatggcc tccctgccac acgtgaatca ctccagcccg 240 agatctgaaa ccaggacaca ccccaggggc gaggtgacgc tgagtgagcc cagctgtgtc 300 cctttcatga gaactcagag cacagggctc tgtgtgcatg gccgtcccct ccagagagga 360 ggaagtaaat gccgggatta gtggaagatc atttccttct atttgccttg gcttacgtct 420 ttcagaattc aaacacgtgc actgttgacc ctgcaatggt ggagtttttg gattttcctt 480 cagtccgatt gctaaaatac ttccctctca tgtgagctgt tgtgaaagtc atcagccaga 540 taccattcta aaaacaaaga atgtgcttct cgtatgttgc atgctggtta ctgaaatatt 600 agggaattac ataaaggttt tctggggcac atattcaagc tgaatgataa aattgaaggt 660 cacacaaagc taaggtcttt caaatcctga cccaattagc 700 <210> 45 <211> 658 <212> DNA <213> Homo sapiens <400> 45 cgcctcggcc tcccaaagtg ctgggattac aggcgtgagc caccaccgtg cctggcttat 60 acaagtaatt gtaaacgaaa aggaaaaaat ggagatacag ttttctcgtg catcttaaac 120 tttggtgctt aaaagcacca ttaaattctg ctttcacatg aacacacaca agattaccac 180 gtttgctctg ggctgctgcg tattggaagg acatacacat tcaacaaata tttgttgaac 240 ttccattctg tacacaaagc acaaagaaag attcgttcac agtccgtgtg ggtactggaa 300 agcagttcca gccctgcctg ccagggggca ccccaggcaa gcacatctca gtggctgcta 360 gaaagtgaat tgaggctgag tctctccaca cccaagtgtt aggcgttcta ggctcagaaa 420 gagacaatga caatgcgggc aattctctct tcactgtgtc ctcttctttg ctagaaatgt 480 tattagaata tggaaatgtg acattcagca ctaatcagtt tgacatatga atatatctat 540 acacatattt ctccctgaaa ttggcctaaa tactctttct tggaaccaaa tgagaagcaa 600 acaaccttta caactaaaca ttaaaccata agatgaacat cttagttgtc tacctaga 658 <210> 46 <211> 682 <212> DNA <213> Homo sapiens <400> 46 ttctaggtag acaactaaga tgttcatctt atggtttaat gtttagttgt aaaggttgtt 60 tgcttctcat ttggttccaa gaaagagtat ttaggccaat ttcagggaga aatatgtgta 120 tagatatatt catatgtcaa actgattagt gctgaatgtc acatttccat attctaataa 180 catttctagc aaagaagagg acacagtgaa gagagaattg cccgcattgt cattgtctct 240 ttctgagcct agaacgccta acacttgggt gtggagagac tcagcctcaa ttcactttct 300 agcagccact gagatgtgct tgcctggggt gccccctggc aggcagggct ggaactgctt 360 tccagtaccc acacggactg tgaacgaatc tttctttgtg ctttgtgtac agaatggaag 420 ttcaacaaat atttgttgaa tgtgtatgtc cttccaatac gcagcagccc agagcaaacg 480 tggtaatctt gtgtgtgttc atgtgaaagc agaatttaat ggtgctttta agcaccaaag 540 tttaagatgc acgagaaaac tgtatctcca ttttttcctt ttcgtttaca attacttgta 600 taagccaggc acggtggtgg ctcacgcctg taatcccagc actttggggg gccgaggcgg 660 gcggatcaca tgaggtcggg ag 682 <210> 47 <211> 135 <212> DNA <213> Homo sapiens <400> 47 gggttcgggg ctttcggggg cggtcggggg ttcgcggacc cgggaagctc tgaggaccca 60 gaggccgggc gcgctccgcc cgcggcgccg ccccctccgt aactttccca gtctccgagg 120 gaagaggcgg ggtgt 135 <210> 48 <211> 7163 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 48 cgatgcctgt agcaatggca acaacgttgc gcaaactatt aactggcgaa ctacttactc 60 tagcttcccg gcaacaatta atagactgga tggaggcgga taaagttgca ggaccacttc 120 tgcgctcggc ccttccggct ggctggttta ttgctgataa atctggagcc ggtgagcgtg 180 ggtctcgcgg tatcattgca gcactggggc cagatggtaa gccctcccgt atcgtagtta 240 tctacacgac ggggagtcag gcaactatgg atgaacgaaa tagacagatc gctgagatag 300 gtgcctcact gattaagcat tggtaactgt cagaccaagt ttactcatat atactttaga 360 ttgatttaaa acttcatttt taatttaaaa ggatctaggt gaagatcctt tttgataatc 420 tcatgaccaa aatcccttaa cgtgagtttt cgttccactg agcgtcagac cccgtagaaa 480 agatcaaagg atcttcttga gatccttttt ttctgcgcgt aatctgctgc ttgcaaacaa 540 aaaaaccacc gctaccagcg gtggtttgtt tgccggatca agagctacca actctttttc 600 cgaaggtaac tggcttcagc agagcgcaga taccaaatac tgtccttcta gtgtagccgt 660 agttaggcca ccacttcaag aactctgtag caccgcctac atacctcgct ctgctaatcc 720 tgttaccagt ggctgctgcc agtggcgata agtcgtgtct taccgggttg gactcaagac 780 gatagttacc ggataaggcg cagcggtcgg gctgaacggg gggttcgtgc acacagccca 840 gcttggagcg aacgacctac accgaactga gatacctaca gcgtgagcta tgagaaagcg 900 ccacgcttcc cgaagggaga aaggcggaca ggtatccggt aagcggcagg gtcggaacag 960 gagagcgcac gagggagctt ccagggggaa acgcctggta tctttatagt cctgtcgggt 1020 ttcgccacct ctgacttgag cgtcgatttt tgtgatgctc gtcagggggg cggagcctat 1080 ggaaaaacgc cagcaacgcg gcctttttac ggttcctggc cttttgctgg ccttttgctc 1140 acatgtcctg caggcagctg cgcgctcgct cgctcactga ggccgcccgg gcaaagcccg 1200 ggcgtcgggc gacctttggt cgcccggcct cagtgagcga gcgagcgcgc agagaggag 1260 tggccaactc catcactagg ggttcctgcg gccgcacgcg tcagtgatgc ctgaaacctc 1320 agatggtact gaaccctcta tataatctgt tttttcctat acatacaaac ctaccataag 1380 gcttaatggt aagagattaa caataaagaa taataaaaca acacttataa caatgtataa 1440 caatatattg taatataagt ttttggatgc agtctctctc tcaaaatgct atcatatttt 1500 ccaactgtgg ttgactacag gtaactggaa ccacaaaaat gaaacagtgg ataagagggc 1560 gactcctgta ccaaagaaaa aaatagagtg ttgcagctgt aacatagttg aatgactgag 1620 ttagactgca taactgacac acaaaaccac ataaatataa atgaaggaat ctctgggtgt 1680 aatctggtgc aaaggtgact gtgttaatca ttaatccaca agttgctatc ctgaagtgtg 1740 ccaaatgctt tatgtttatt tcatcacata gctctataaa gaaaggattt gtaattcctt 1800 tctacagaag tggaaagtaa gtcttaagac tcaaaaaact ttaaaaacta caatgaagta 1860 acaactttta ttaatttatt ttgtgtcttt ccagaatttc tatatatata ggaatgtgat 1920 atgaatctat atgtgaattg aatctacatg aatattgatg acttttatt ccccttttgc 1980 acataagata gaatatttta cctactattc cacactttgc ttttcttaac atatcatggg 2040 atctttttat ataagtgaac aaagagtttc ttcattcttt cacacagttt aattaagacc 2100 tcgaagggga cttggggggt tcggggcttt cgggggcggt cgggggttcg cggacccggg 2160 aagctctgag gacccagagg ccgggcgcgc tccgcccgcg gcgccgcccc ctccgtaact 2220 ttcccagtct ccgagggaag aggcggggtg tggggtgcgg ttaaaaggcg ccacggcggg 2280 agacaggtgt tgcggccccg cagcgcccgc gcgctcctct ccccgactcg gagcccctcg 2340 gcggcgcccg gcccaggacc cgcctaggag cgcaggagcc ccagcgcaga gaccccaacg 2400 ccgagacccc cgccccggcc ccgccgcgct tcctcccgac gcagagcaaa ccgcccagag 2460 tagaagccat ggtgagcaag ggcgaggagc tgttcaccgg ggtggtgccc atcctggtcg 2520 agctggacgg cgacgtaaac ggccacaagt tcagcgtgtc cggcgagggc gagggcgatg 2580 ccacctacgg caagctgacc ctgaagttca tctgcaccac cggcaagctg cccgtgccct 2640 ggcccaccct cgtgaccacc ctgacctacg gcgtgcagtg cttcagccgc taccccgacc 2700 acatgaagca gcacgacttc ttcaagtccg ccatgcccga aggctacgtc caggagcgca 2760 ccatcttctt caaggacgac ggcaactaca agacccgcgc cgaggtgaag ttcgagggcg 2820 acaccctggt gaaccgcatc gagctgaagg gcatcgactt caaggaggac ggcaacatcc 2880 tggggcacaa gctggagtac aactacaaca gccacaacgt ctatatcatg gccgacaagc 2940 agaagaacgg catcaaggtg aacttcaaga tccgccacaa catcgaggac ggcagcgtgc 3000 agctcgccga ccactaccag cagaacaccc ccatcggcga cggccccgtg ctgctgcccg 3060 acaaccacta cctgagcacc cagtccgccc tgagcaaaga ccccaacgag aagcgcgatc 3120 acatggtcct gctggagttc gtgaccgccg ccgggatcac tctcggcatg gacgagctgt 3180 acaagtaaag gcgcgccacc cctgcaggga attccgcatt gcccagttgt tagattaaga 3240 aatagacagc atgagaggga tgaggcaacc cgtgctcagc tgtcaaggct cagtcgctag 3300 catttcccaa cacaaagatt ctgaccttaa atgcaaccat ttgaaacccc tgtaggcctc 3360 aggtgaaact ccagatgcca caatggagct ctgctcccct aaagcctcaa aacaaaggcc 3420 taattctatg cctgtcttaa ttttctttca cttaagttag ttccactgag accccaggct 3480 gttaggggtt attggtgtaa ggtactttca tattttaaac agaggatatc ggcatttgtt 3540 tctttctctg aggacaagag aaaaaagcca ggttccacag aggacacaga gaaggtttgg 3600 gtgtcctcct ggggttcttt ttgccaactt tccccacgtt aaaggtgaac attggttctt 3660 tcatttgctt tggaagtttt aatctctaac agtggacaaa gttaccagtg ccttaaactc 3720 tgttacactt tttggaagtg aaaactttgt agtatgatag gttattttga tgtaaagatg 3780 ttctggatac cattatatgt tccccctgtt tcagaggctc agattgtaat atgtaaatgg 3840 tatgtcattc gctactatga tttaatttga aatatggtct tttggttatg aatactttgc 3900 agcacagctg agaggctgtc tgttgtattc attgtggtca tagcacctaa caacattgta 3960 gcctcaatcg agtgagacag actagaagtt cctagtgatg gcttatgata gcaaatggcc 4020 tcatgtcaaa tatttagatg taattttgtg taagaaatac agactggatg taccaccaac 4080 tactacctgt aatgacaggc ctgtccaaca catctccctt ttccatgact gtggtagcca 4140 gcatcggaaa gaacgctgat ttaaagaggt cgcttgggaa ttttattgac acagtaccat 4200 ttaatgggga ggacaaaatg gggcagggga gggagaagtt tctgtcgtta aaaacagatt 4260 tggaaagact ggactctaaa gtctgttgat taaagatgag ctttgtctac ttcaaaagtt 4320 tgtttgctta ccccttcagc ctccaatttt ttaagtgaaa atatagctaa taacatgtga 4380 aaagaataga agctaaggtt tagataaata ttgagcagat ctataggaag attgaacctg 4440 aatattgcca ttatgcttga catggtttcc aaaaaatggt actccacata tttcagtgag 4500 ggtaagtatt ttcctgttgt caagaatagc attgtaaaag cattttgtaa taataaagaa 4560 tagctttaat gatatgcttg taactaaaat aattttgtaa tgtatcaaat acatttaaaa 4620 cattaaaata taatctctat aataatttaa aatctaatat ggttttaata gaacagcgat 4680 atcaagctta tcgataatca acctctggat tacaaaattt gtgaaagatt gactggtatt 4740 cttaactatg ttgctccttt tacgctatgt ggatacgctg ctttaatgcc tttgtatcat 4800 gctattgctt cccgtatggc tttcattttc tcctccttgt ataaatcctg gttgctgtct 4860 ctttatgagg agttgtggcc cgttgtcagg caacgtggcg tggtgtgcac tgtgtttgct 4920 gacgcaaccc ccactggttg gggcattgcc accacctgtc agctcctttc cgggactttc 4980 gctttccccc tccctattgc cacggcggaa ctcatcgccg cctgccttgc ccgctgctgg 5040 acaggggctc ggctgttggg cactgacaat tccgtggtgt tgtcgggggaa atcatcgtcc 5100 tttccttggc tgctcgccta tgttgccacc tggattctgc gcgggacgtc cttctgctac 5160 gtcccttcgg ccctcaatcc agcggacctt ccttcccgcg gcctgctgcc ggctctgcgg 5220 cctcttccgc gtcttcgcct tcgccctcag acgagtcgga tctccctttg ggccgcctcc 5280 ccgcgaattc atcgataccg agcgctgctc gagagatctg tgatagcggc catcaagctg 5340 gctgtgcctt ctagttgcca gccatctgtt gtttgcccct cccccgtgcc ttccttgacc 5400 ctggaaggtg ccactcccac tgtcctttcc taataaaatg aggaaattgc atcgcattgt 5460 ctgagtaggt gtcattctat tctggggggt ggggtggggc aggacagcaa gggggaggat 5520 tgggaagaca atagcaggca tgctggggac acgtgcggac cgagcggccg caggaacccc 5580 tagtgatgga gttggccact ccctctctgc gcgctcgctc gctcactgag gccgggcgac 5640 caaaggtcgc ccgacgcccg ggctttgccc gggcggcctc agtgagcgag cgagcgcgca 5700 gctgcctgca ggggcgcctg atgcggtatt ttctccttac gcatctgtgc ggtatttcac 5760 accgcatacg tcaaagcaac catagtacgc gccctgtagc ggcgcattaa gcgcggcggg 5820 tgtggtggtt acgcgcagcg tgaccgctac acttgccagc gccctagcgc ccgctccttt 5880 cgctttcttc ccttcctttc tcgccacgtt cgccggcttt ccccgtcaag ctctaaatcg 5940 ggggctccct ttagggttcc gatttagtgc tttacggcac ctcgacccca aaaaacttga 6000 tttgggtgat ggttcacgta gtgggccatc gccctgatag acggtttttc gccctttgac 6060 gttggagtcc acgttcttta atagtggact cttgttccaa actggaacaa cactcaaccc 6120 tatctcgggc tattcttttg atttataagg gattttgccg atttcggcct attggttaaa 6180 aaatgagctg atttaacaaa aatttaacgc gaattttaac aaaatattaa cgtttacaat 6240 tttatggtgc actctcagta caatctgctc tgatgccgca tagttaagcc agccccgaca 6300 cccgccaaca cccgctgacg cgccctgacg ggcttgtctg ctcccggcat ccgcttacag 6360 acaagctgg accgtctccg ggagctgcat gtgtcagagg ttttcaccgt catcaccgaa 6420 acgcgcgaga cgaaagggcc tcgtgatacg cctattttta taggttaatg tcatgataat 6480 aatggtttct tagacgtcag gtggcacttt tcggggaaat gtgcgcggaa cccctatttg 6540 tttattttc taaatacatt caaatatgta tccgctcatg agacaataac cctgataaat 6600 gcttcaataa tattgaaaaa ggaagagtat gagtattcaa catttccgtg tcgcccttat 6660 tccctttttt gcggcatttt gccttcctgt ttttgctcac ccagaaacgc tggtgaaagt 6720 aaaagatgct gaagatcagt tgggtgcacg agtgggttac atcgaactgg atctcaacag 6780 cggtaagatc cttgagagtt ttcgccccga agaacgtttt ccaatgatga gcacttttaa 6840 agttctgcta tgtggcgcgg tattatcccg tattgacgcc gggcaagagc aactcggtcg 6900 ccgcatacac tattctcaga atgacttggt tgagtactca ccagtcacag aaaagcatct 6960 tacggatggc atgacagtaa gagaattatg cagtgctgcc ataaccatga gtgataacac 7020 tgcggccaac ttacttctga caacgatcgg aggaccgaag gagctaaccg cttttttgca 7080 caacatgggg gatcatgtaa ctcgccttga tcgttgggaa ccggagctga atgaagccat 7140 accaaacgac gagcgtgaca cca 7163 <210> 49 <211> 7247 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 49 cgatgcctgt agcaatggca acaacgttgc gcaaactatt aactggcgaa ctacttactc 60 tagcttcccg gcaacaatta atagactgga tggaggcgga taaagttgca ggaccacttc 120 tgcgctcggc ccttccggct ggctggttta ttgctgataa atctggagcc ggtgagcgtg 180 ggtctcgcgg tatcattgca gcactggggc cagatggtaa gccctcccgt atcgtagtta 240 tctacacgac ggggagtcag gcaactatgg atgaacgaaa tagacagatc gctgagatag 300 gtgcctcact gattaagcat tggtaactgt cagaccaagt ttactcatat atactttaga 360 ttgatttaaa acttcatttt taatttaaaa ggatctaggt gaagatcctt tttgataatc 420 tcatgaccaa aatcccttaa cgtgagtttt cgttccactg agcgtcagac cccgtagaaa 480 agatcaaagg atcttcttga gatccttttt ttctgcgcgt aatctgctgc ttgcaaacaa 540 aaaaaccacc gctaccagcg gtggtttgtt tgccggatca agagctacca actctttttc 600 cgaaggtaac tggcttcagc agagcgcaga taccaaatac tgtccttcta gtgtagccgt 660 agttaggcca ccacttcaag aactctgtag caccgcctac atacctcgct ctgctaatcc 720 tgttaccagt ggctgctgcc agtggcgata agtcgtgtct taccgggttg gactcaagac 780 gatagttacc ggataaggcg cagcggtcgg gctgaacggg gggttcgtgc acacagccca 840 gcttggagcg aacgacctac accgaactga gatacctaca gcgtgagcta tgagaaagcg 900 ccacgcttcc cgaagggaga aaggcggaca ggtatccggt aagcggcagg gtcggaacag 960 gagagcgcac gagggagctt ccagggggaa acgcctggta tctttatagt cctgtcgggt 1020 ttcgccacct ctgacttgag cgtcgatttt tgtgatgctc gtcagggggg cggagcctat 1080 ggaaaaacgc cagcaacgcg gcctttttac ggttcctggc cttttgctgg ccttttgctc 1140 acatgtcctg caggcagctg cgcgctcgct cgctcactga ggccgcccgg gcaaagcccg 1200 ggcgtcgggc gacctttggt cgcccggcct cagtgagcga gcgagcgcgc agagaggag 1260 tggccaactc catcactagg ggttcctgcg gccgcacgcg tgctatctat catcttgaag 1320 ggcttctgga acaagttaga atagagtcaa cactcatgaa ctgctgtagc aaaaaaaact 1380 atagatgtag gattgacaag ggcaatagag cgatgactcc ctggctgtgt tgtatttgat 1440 ggacggcagt agcttttcac aaaatgctca tttggatgtt tcaaattaaa acgtttcact 1500 ttctagaacc aattacgtgg tcagtttagc tcctgaggtc ccagtcagag gggtattctg 1560 tagcttgcaa agcctctctt tggggactgg acatggagtc tgtggtctta gaattcagaa 1620 ccgggagaat gtgttagcca ctcatctaag ctattcctta aacgctttca gagccatctc 1680 cactgtgggg aaagaagttc tttgtgttct ctgacttagt ctcattctaa aaaaaaaaaa 1740 aaaaaaaaaa aaaaagcaat tgcaataccc agagcgcaca gtagatggca ctgagacttg 1800 tcggaaagct ggacgcactc aagaggtggc agaaaaatct ataggtaagc ttttcttcta 1860 gtctggtgtt gctgctcctg accttattaa tgggctgaga aatagatttc tttcctttcc 1920 ttttcttttt tatatgaaat taaatgaagt ataaaagaat atgagaatgt gttgctatta 1980 gcaaggataa gtaatgcttt aggaaacgtt tggttcatgt gtgtgttttc agactgatgt 2040 gtgtcctgga tccagtgtaa aatgtacttc tgtctgtagg tctctgccac agaaaagttg 2100 gaaagccatt gttgtattcc atttccaggg caacaaaaga taccactgtc acttcatgtg 2160 aaatggtgtt gtttaattaa gacctcgaag gggacttggg gggttcgggg ctttcggggg 2220 cggtcggggg ttcgcggacc cgggaagctc tgaggaccca gaggccgggc gcgctccgcc 2280 cgcggcgccg ccccctccgt aactttccca gtctccgagg gaagaggcgg ggtgtggggt 2340 gcggttaaaa ggcgccacgg cgggagacag gtgttgcggc cccgcagcgc ccgcgcgctc 2400 ctctccccga ctcggagccc ctcggcggcg cccggcccag gacccgccta ggagcgcagg 2460 agccccagcg cagagacccc aacgccgaga cccccgcccc ggccccgccg cgcttcctcc 2520 cgacgcagag caaaccgccc agagtagaag ccatggtgag caagggcgag gagctgttca 2580 ccggggtggt gcccatcctg gtcgagctgg acggcgacgt aaacggccac aagttcagcg 2640 tgtccggcga gggcgagggc gatgccacct acggcaagct gaccctgaag ttcatctgca 2700 ccaccggcaa gctgcccgtg ccctggccca ccctcgtgac caccctgacc tacggcgtgc 2760 agtgcttcag ccgctacccc gaccacatga agcagcacga cttcttcaag tccgccatgc 2820 ccgaaggcta cgtccaggag cgcaccatct tcttcaagga cgacggcaac tacaagaccc 2880 gcgccgaggt gaagttcgag ggcgacaccc tggtgaaccg catcgagctg aagggcatcg 2940 acttcaagga ggacggcaac atcctggggc acaagctgga gtacaactac aacagccaca 3000 acgtctatat catggccgac aagcagaaga acggcatcaa ggtgaacttc aagatccgcc 3060 acaacatcga ggacggcagc gtgcagctcg ccgaccacta ccagcagaac acccccatcg 3120 gcgacggccc cgtgctgctg cccgacaacc actacctgag cacccagtcc gccctgagca 3180 aagaccccaa cgagaagcgc gatcacatgg tcctgctgga gttcgtgacc gccgccggga 3240 tcactctcgg catggacgag ctgtacaagt aaaggcgcgc cacccctgca gggaattccg 3300 cattgcccag ttgttagatt aagaaataga cagcatgaga gggatgaggc aacccgtgct 3360 cagctgtcaa ggctcagtcg ctagcatttc ccaacacaaa gattctgacc ttaaatgcaa 3420 ccatttgaaa cccctgtagg cctcaggtga aactccagat gccacaatgg agctctgctc 3480 ccctaaagcc tcaaaacaaa ggcctaattc tatgcctgtc ttaattttct ttcacttaag 3540 ttagttccac tgagacccca ggctgttagg ggttattggt gtaaggtact ttcatatttt 3600 aaacagagga tatcggcatt tgtttctttc tctgaggaca agagaaaaaa gccaggttcc 3660 acagaggaca cagagaaggt ttgggtgtcc tcctggggtt ctttttgcca actttcccca 3720 cgttaaaggt gaacattggt tctttcattt gctttggaag ttttaatctc taacagtgga 3780 caaagttacc agtgccttaa actctgttac actttttgga agtgaaaact ttgtagtatg 3840 ataggttatt ttgatgtaaa gatgttctgg ataccattat atgttccccc tgtttcagag 3900 gctcagattg taatatgtaa atggtatgtc attcgctact atgatttaat ttgaaatatg 3960 gtcttttggt tatgaatact ttgcagcaca gctgagaggc tgtctgttgt attcattgtg 4020 gtcatagcac ctaacaacat tgtagcctca atcgagtgag acagactaga agttcctagt 4080 gatggcttat gatagcaaat ggcctcatgt caaatattta gatgtaattt tgtgtaagaa 4140 atacagactg gatgtaccac caactactac ctgtaatgac aggcctgtcc aacacatctc 4200 ccttttccat gactgtggta gccagcatcg gaaagaacgc tgatttaaag aggtcgcttg 4260 ggaattttat tgacacagta ccatttaatg gggaggacaa aatggggcag gggagggaga 4320 agtttctgtc gttaaaaaca gatttggaaa gactggactc taaagtctgt tgattaaaga 4380 tgagctttgt ctacttcaaa agtttgtttg cttacccctt cagcctccaa ttttttaagt 4440 gaaaatatag ctaataacat gtgaaaagaa tagaagctaa ggtttagata aatattgagc 4500 agatctatag gaagattgaa cctgaatatt gccattatgc ttgacatggt ttccaaaaaa 4560 tggtactcca catatttcag tgagggtaag tattttcctg ttgtcaagaa tagcattgta 4620 aaagcatttt gtaataataa agaatagctt taatgatatg cttgtaacta aaataatttt 4680 gtaatgtatc aaatacattt aaaacattaa aatataatct ctataataat ttaaaatcta 4740 atatggtttt aatagaacag cgatatcaag cttatcgata atcaacctct ggattacaaa 4800 atttgtgaaa gattgactgg tattcttaac tatgttgctc cttttacgct atgtggatac 4860 gctgctttaa tgcctttgta tcatgctatt gcttcccgta tggctttcat tttctcctcc 4920 ttgtataaat cctggttgct gtctctttat gaggagttgt ggcccgttgt caggcaacgt 4980 ggcgtggtgt gcactgtgtt tgctgacgca acccccactg gttggggcat tgccaccacc 5040 tgtcagctcc tttccgggac tttcgctttc cccctcccta ttgccacggc ggaactcatc 5100 gccgcctgcc ttgcccgctg ctggacaggg gctcggctgt tgggcactga caattccgtg 5160 gtgttgtcgg ggaaatcatc gtcctttcct tggctgctcg cctatgttgc cacctggatt 5220 ctgcgcggga cgtccttctg ctacgtccct tcggccctca atccagcgga ccttccttcc 5280 cgcggcctgc tgccggctct gcggcctctt ccgcgtcttc gccttcgccc tcagacgagt 5340 cggatctccc tttgggccgc ctccccgcga attcatcgat accgagcgct gctcgagaga 5400 tctgtgatag cggccatcaa gctggctgtg ccttctagtt gccagccatc tgttgtttgc 5460 ccctcccctg tgccttcctt gaccctggaa ggtgccactc ccactgtcct ttcctaataa 5520 aatgaggaaa ttgcatcgca ttgtctgagt aggtgtcatt ctattctggg gggtggggtg 5580 gggcaggaca gcaaggggga ggattgggaa gacaatagca ggcatgctgg ggacacgtgc 5640 ggaccgagcg gccgcaggaa cccctagtga tggagttggc cactccctct ctgcgcgctc 5700 gctcgctcac tgaggccggg cgaccaaagg tcgcccgacg cccgggcttt gcccgggcgg 5760 cctcagtgag cgagcgagcg cgcagctgcc tgcaggggcg cctgatgcgg tattttctcc 5820 ttacgcatct gtgcggtatt tcacaccgca tacgtcaaag caaccatagt acgcgccctg 5880 tagcggcgca ttaagcgcgg cgggtgtggt ggttacgcgc agcgtgaccg ctacacttgc 5940 cagcgcccta gcgcccgctc ctttcgcttt cttcccttcc tttctcgcca cgttcgccgg 6000 ctttccccgt caagctctaa atcgggggct ccctttaggg ttccgattta gtgctttacg 6060 gcacctcgac cccaaaaaac ttgatttggg tgatggttca cgtagtgggc catcgccctg 6120 atagacggtt tttcgccctt tgacgttgga gtccacgttc tttaatagtg gactcttgtt 6180 ccaaactgga acaacactca accctatctc gggctattct tttgatttat aagggatttt 6240 gccgatttcg gcctattggt taaaaaatga gctgatttaa caaaaattta acgcgaattt 6300 taacaaaata ttaacgttta caattttatg gtgcactctc agtacaatct gctctgatgc 6360 cgcatagtta agccagcccc gacacccgcc aacacccgct gacgcgccct gacgggcttg 6420 tctgctcccg gcatccgctt acagacaagc tgtgaccgtc tccgggagct gcatgtgtca 6480 gaggttttca ccgtcatcac cgaaacgcgc gagacgaaag ggcctcgtga tacgcctatt 6540 tttataggtt aatgtcatga taataatggt ttcttagacg tcaggtggca cttttcgggg 6600 aaatgtgcgc ggaaccccta tttgtttatt tttctaaata cattcaaata tgtatccgct 6660 catgagacaa taaccctgat aaatgcttca ataatattga aaaaggaaga gtatgagtat 6720 tcaacatttc cgtgtcgccc ttattccctt ttttgcggca ttttgccttc ctgtttttgc 6780 tcacccagaa acgctggtga aagtaaaaga tgctgaagat cagttgggtg cacgagtggg 6840 ttacatcgaa ctggatctca acagcggtaa gatccttgag agttttcgcc ccgaagaacg 6900 ttttccaatg atgagcactt ttaaagttct gctatgtggc gcggtattat cccgtattga 6960 cgccgggcaa gagcaactcg gtcgccgcat acactattct cagaatgact tggttgagta 7020 ctcaccagtc acagaaaagc atcttacgga tggcatgaca gtaagagaat tatgcagtgc 7080 tgccataacc atgagtgata acactgcggc caacttactt ctgacaacga tcggaggacc 7140 gaaggagcta accgcttttt tgcacaacat gggggatcat gtaactcgcc ttgatcgttg 7200 ggaaccggag ctgaatgaag ccataccaaa cgacgagcgt gacacca 7247 <210> 50 <211> 7243 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 50 cgatgcctgt agcaatggca acaacgttgc gcaaactatt aactggcgaa ctacttactc 60 tagcttcccg gcaacaatta atagactgga tggaggcgga taaagttgca ggaccacttc 120 tgcgctcggc ccttccggct ggctggttta ttgctgataa atctggagcc ggtgagcgtg 180 ggtctcgcgg tatcattgca gcactggggc cagatggtaa gccctcccgt atcgtagtta 240 tctacacgac ggggagtcag gcaactatgg atgaacgaaa tagacagatc gctgagatag 300 gtgcctcact gattaagcat tggtaactgt cagaccaagt ttactcatat atactttaga 360 ttgatttaaa acttcatttt taatttaaaa ggatctaggt gaagatcctt tttgataatc 420 tcatgaccaa aatcccttaa cgtgagtttt cgttccactg agcgtcagac cccgtagaaa 480 agatcaaagg atcttcttga gatccttttt ttctgcgcgt aatctgctgc ttgcaaacaa 540 aaaaaccacc gctaccagcg gtggtttgtt tgccggatca agagctacca actctttttc 600 cgaaggtaac tggcttcagc agagcgcaga taccaaatac tgtccttcta gtgtagccgt 660 agttaggcca ccacttcaag aactctgtag caccgcctac atacctcgct ctgctaatcc 720 tgttaccagt ggctgctgcc agtggcgata agtcgtgtct taccgggttg gactcaagac 780 gatagttacc ggataaggcg cagcggtcgg gctgaacggg gggttcgtgc acacagccca 840 gcttggagcg aacgacctac accgaactga gatacctaca gcgtgagcta tgagaaagcg 900 ccacgcttcc cgaagggaga aaggcggaca ggtatccggt aagcggcagg gtcggaacag 960 gagagcgcac gagggagctt ccagggggaa acgcctggta tctttatagt cctgtcgggt 1020 ttcgccacct ctgacttgag cgtcgatttt tgtgatgctc gtcagggggg cggagcctat 1080 ggaaaaacgc cagcaacgcg gcctttttac ggttcctggc cttttgctgg ccttttgctc 1140 acatgtcctg caggcagctg cgcgctcgct cgctcactga ggccgcccgg gcaaagcccg 1200 ggcgtcgggc gacctttggt cgcccggcct cagtgagcga gcgagcgcgc agagaggag 1260 tggccaactc catcactagg ggttcctgcg gccgcacgcg taagctacta actacaacca 1320 cgagattata gatgtttgct gatattgttc tcagtttggt tattgtgttg tttatgaatg 1380 aaagtagtgt atgtttgtgt gaatttttgt ttttaatttt ttatgagtgc cctaacaaag 1440 attacaaatt gggaatacaa actccagagc aatggagaca gtgacacttt tgtggagggg 1500 tacatgtggc tgttcggggg gttattaaca caggctgctg cccctgccct gcaatgggaa 1560 tccccagggc attggaggat tcaacctctt gcagttacct cttgtaagac agcagatggc 1620 agcagagaga ggctttgcac atccctgcag gttctagttt gcacaaaggg cttctgagag 1680 acctatcaac caattataac atcaagtggc aaaaagagtc cttgataagt tatttcgctt 1740 ctcaaagaaa ccgaaaacgc caaactaatc actagtcttg tttttttttt tcctggcaaa 1800 agcctgctat ctttcatgat ttagctttca tgaaattgtt cctgaagacc cccaaaagaa 1860 acaatttcat gccccgaact ctgttcagag actttgctgt gcctgtcatg tccagcttgc 1920 catatcctgt tttgtaaagt agccacctta tatacacacc tgctgtctgc actgtgacct 1980 cctttcaaaa tcatctttgg ttcttcagag gcctggaata atgctctgcc cagatgaaga 2040 tctccgtaaa tgtgtttttg aaatggctaa tcaaataatg gataccctta ggtatttttg 2100 cagaaacact tggcagcctt ccataatatc cctactatga aatggaaact tgtgaatgag 2160 atgtggcttt aattaagacc tcgaagggga cttggggggt tcggggcttt cgggggcggt 2220 cgggggttcg cggacccggg aagctctgag gacccagagg ccgggcgcgc tccgcccgcg 2280 gcgccgcccc ctccgtaact ttcccagtct ccgagggaag aggcggggtg tggggtgcgg 2340 ttaaaaggcg ccacggcggg agacaggtgt tgcggccccg cagcgcccgc gcgctcctct 2400 ccccgactcg gagcccctcg gcggcgcccg gcccaggacc cgcctaggag cgcaggagcc 2460 ccagcgcaga gaccccaacg ccgagacccc cgccccggcc ccgccgcgct tcctcccgac 2520 gcagagcaaa ccgcccagag tagaagccat ggtgagcaag ggcgaggagc tgttcaccgg 2580 ggtggtgccc atcctggtcg agctggacgg cgacgtaaac ggccacaagt tcagcgtgtc 2640 cggcgagggc gagggcgatg ccacctacgg caagctgacc ctgaagttca tctgcaccac 2700 cggcaagctg cccgtgccct ggcccaccct cgtgaccacc ctgacctacg gcgtgcagtg 2760 cttcagccgc taccccgacc acatgaagca gcacgacttc ttcaagtccg ccatgcccga 2820 aggctacgtc caggagcgca ccatcttctt caaggacgac ggcaactaca agacccgcgc 2880 cgaggtgaag ttcgagggcg acaccctggt gaaccgcatc gagctgaagg gcatcgactt 2940 caaggaggac ggcaacatcc tggggcacaa gctggagtac aactacaaca gccacaacgt 3000 ctatatcatg gccgacaagc agaagaacgg catcaaggtg aacttcaaga tccgccacaa 3060 catcgaggac ggcagcgtgc agctcgccga ccactaccag cagaacaccc ccatcggcga 3120 cggccccgtg ctgctgcccg acaaccacta cctgagcacc cagtccgccc tgagcaaaga 3180 ccccaacgag aagcgcgatc acatggtcct gctggagttc gtgaccgccg ccgggatcac 3240 tctcggcatg gacgagctgt acaagtaaag gcgcgccacc cctgcaggga attccgcatt 3300 gcccagttgt tagattaaga aatagacagc atgagaggga tgaggcaacc cgtgctcagc 3360 tgtcaaggct cagtcgctag catttcccaa cacaaagatt ctgaccttaa atgcaaccat 3420 ttgaaacccc tgtaggcctc aggtgaaact ccagatgcca caatggagct ctgctcccct 3480 aaagcctcaa aacaaaggcc taattctatg cctgtcttaa ttttctttca cttaagttag 3540 ttccactgag accccaggct gttaggggtt attggtgtaa ggtactttca tattttaaac 3600 agaggatatc ggcatttgtt tctttctctg aggacaagag aaaaaagcca ggttccacag 3660 aggacacaga gaaggtttgg gtgtcctcct ggggttcttt ttgccaactt tccccacgtt 3720 aaaggtgaac attggttctt tcatttgctt tggaagtttt aatctctaac agtggacaaa 3780 gttaccagtg ccttaaactc tgttacactt tttggaagtg aaaactttgt agtatgatag 3840 gttattttga tgtaaagatg ttctggatac cattatatgt tccccctgtt tcagaggctc 3900 agattgtaat atgtaaatgg tatgtcattc gctactatga tttaatttga aatatggtct 3960 tttggttatg aatactttgc agcacagctg agaggctgtc tgttgtattc attgtggtca 4020 tagcacctaa caacattgta gcctcaatcg agtgagacag actagaagtt cctagtgatg 4080 gcttatgata gcaaatggcc tcatgtcaaa tatttagatg taattttgtg taagaaatac 4140 agactggatg taccaccaac tactacctgt aatgacaggc ctgtccaaca catctccctt 4200 ttccatgact gtggtagcca gcatcggaaa gaacgctgat ttaaagaggt cgcttgggaa 4260 ttttattgac acagtaccat ttaatgggga ggacaaaatg gggcagggga gggagaagtt 4320 tctgtcgtta aaaacagatt tggaaagact ggactctaaa gtctgttgat taaagatgag 4380 ctttgtctac ttcaaaagtt tgtttgctta ccccttcagc ctccaatttt ttaagtgaaa 4440 atatagctaa taacatgtga aaagaataga agctaaggtt tagataaata ttgagcagat 4500 ctataggaag attgaacctg aatattgcca ttatgcttga catggtttcc aaaaaatggt 4560 actccacata tttcagtgag ggtaagtatt ttcctgttgt caagaatagc attgtaaaag 4620 cattttgtaa taataaagaa tagctttaat gatatgcttg taactaaaat aattttgtaa 4680 tgtatcaaat acatttaaaa cattaaaata taatctctat aataatttaa aatctaatat 4740 ggttttaata gaacagcgat atcaagctta tcgataatca acctctggat tacaaaattt 4800 gtgaaagatt gactggtatt cttaactatg ttgctccttt tacgctatgt ggatacgctg 4860 ctttaatgcc tttgtatcat gctattgctt cccgtatggc tttcattttc tcctccttgt 4920 ataaatcctg gttgctgtct ctttatgagg agttgtggcc cgttgtcagg caacgtggcg 4980 tggtgtgcac tgtgtttgct gacgcaaccc ccactggttg gggcattgcc accacctgtc 5040 agctcctttc cgggactttc gctttccccc tccctattgc cacggcggaa ctcatcgccg 5100 cctgccttgc ccgctgctgg acaggggctc ggctgttggg cactgacaat tccgtggtgt 5160 tgtcggggaa atcatcgtcc tttccttggc tgctcgccta tgttgccacc tggattctgc 5220 gcgggacgtc cttctgctac gtcccttcgg ccctcaatcc agcggacctt ccttcccgcg 5280 gcctgctgcc ggctctgcgg cctcttccgc gtcttcgcct tcgccctcag acgagtcgga 5340 tctccctttg ggccgcctcc ccgcgaattc atcgataccg agcgctgctc gagagatctg 5400 tgatagcggc catcaagctg gctgtgcctt ctagttgcca gccatctgtt gtttgcccct 5460 cccccgtgcc ttccttgacc ctggaaggtg ccactcccac tgtcctttcc taataaaatg 5520 aggaaattgc atcgcattgt ctgagtaggt gtcattctat tctggggggt ggggtggggc 5580 aggacagcaa gggggaggat tgggaagaca atagcaggca tgctggggac acgtgcggac 5640 cgagcggccg caggaacccc tagtgatgga gttggccact ccctctctgc gcgctcgctc 5700 gctcactgag gccgggcgac caaaggtcgc ccgacgcccg ggctttgccc gggcggcctc 5760 agtgagcgag cgagcgcgca gctgcctgca ggggcgcctg atgcggtatt ttctcctac 5820 gcatctgtgc ggtatttcac accgcatacg tcaaagcaac catagtacgc gccctgtagc 5880 ggcgcattaa gcgcggcggg tgtggtggtt acgcgcagcg tgaccgctac acttgccagc 5940 gccctagcgc ccgctccttt cgctttcttc ccttcctttc tcgccacgtt cgccggcttt 6000 ccccgtcaag ctctaaatcg ggggctccct ttagggttcc gatttagtgc tttacggcac 6060 ctcgacccca aaaaacttga tttgggtgat ggttcacgta gtgggccatc gccctgatag 6120 acggtttttc gccctttgac gttggagtcc acgttcttta atagtggact cttgttccaa 6180 actggaacaa cactcaaccc tatctcgggc tattcttttg atttataagg gattttgccg 6240 atttcggcct attggttaaa aaatgagctg atttaacaaa aatttaacgc gaattttaac 6300 aaaatattaa cgtttacaat tttatggtgc actctcagta caatctgctc tgatgccgca 6360 tagttaagcc agccccgaca cccgccaaca cccgctgacg cgccctgacg ggcttgtctg 6420 ctcccggcat ccgcttacag acaagctgtg accgtctccg ggagctgcat gtgtcagagg 6480 ttttcaccgt catcaccgaa acgcgcgaga cgaaagggcc tcgtgatacg cctattttta 6540 taggttaatg tcatgataat aatggtttct tagacgtcag gtggcacttt tcggggaaat 6600 gtgcgcggaa cccctatttg tttattttc taaatacatt caaatatgta tccgctcatg 6660 agacaataac cctgataaat gcttcaataa tattgaaaaa ggaagagtat gagtattcaa 6720 catttccgtg tcgcccttat tccctttttt gcggcatttt gccttcctgt ttttgctcac 6780 ccagaaacgc tggtgaaagt aaaagatgct gaagatcagt tgggtgcacg agtgggttac 6840 atcgaactgg atctcaacag cggtaagatc cttgagagtt ttcgccccga agaacgtttt 6900 ccaatgatga gcacttttaa agttctgcta tgtggcgcgg tatttcccg tattgacgcc 6960 gggcaagagc aactcggtcg ccgcatacac tattctcaga atgacttggt tgagtactca 7020 ccagtcacag aaaagcatct tacggatggc atgacagtaa gagaattatg cagtgctgcc 7080 ataaccatga gtgataacac tgcggccaac ttacttctga caacgatcgg aggacccgaag 7140 gagctaaccg cttttttgca caacatgggg gatcatgtaa ctcgccttga tcgttgggaa 7200 ccggagctga atgaagccat accaaacgac gagcgtgaca cca 7243 <210> 51 <211> 7253 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 51 cgatgcctgt agcaatggca acaacgttgc gcaaactatt aactggcgaa ctacttactc 60 tagcttcccg gcaacaatta atagactgga tggaggcgga taaagttgca ggaccacttc 120 tgcgctcggc ccttccggct ggctggttta ttgctgataa atctggagcc ggtgagcgtg 180 ggtctcgcgg tatcattgca gcactggggc cagatggtaa gccctcccgt atcgtagtta 240 tctacacgac ggggagtcag gcaactatgg atgaacgaaa tagacagatc gctgagatag 300 gtgcctcact gattaagcat tggtaactgt cagaccaagt ttactcatat atactttaga 360 ttgatttaaa acttcatttt taatttaaaa ggatctaggt gaagatcctt tttgataatc 420 tcatgaccaa aatcccttaa cgtgagtttt cgttccactg agcgtcagac cccgtagaaa 480 agatcaaagg atcttcttga gatccttttt ttctgcgcgt aatctgctgc ttgcaaacaa 540 aaaaaccacc gctaccagcg gtggtttgtt tgccggatca agagctacca actctttttc 600 cgaaggtaac tggcttcagc agagcgcaga taccaaatac tgtccttcta gtgtagccgt 660 agttaggcca ccacttcaag aactctgtag caccgcctac atacctcgct ctgctaatcc 720 tgttaccagt ggctgctgcc agtggcgata agtcgtgtct taccgggttg gactcaagac 780 gatagttacc ggataaggcg cagcggtcgg gctgaacggg gggttcgtgc acacagccca 840 gcttggagcg aacgacctac accgaactga gatacctaca gcgtgagcta tgagaaagcg 900 ccacgcttcc cgaagggaga aaggcggaca ggtatccggt aagcggcagg gtcggaacag 960 gagagcgcac gagggagctt ccagggggaa acgcctggta tctttatagt cctgtcgggt 1020 ttcgccacct ctgacttgag cgtcgatttt tgtgatgctc gtcagggggg cggagcctat 1080 ggaaaaacgc cagcaacgcg gcctttttac ggttcctggc cttttgctgg ccttttgctc 1140 acatgtcctg caggcagctg cgcgctcgct cgctcactga ggccgcccgg gcaaagcccg 1200 ggcgtcgggc gacctttggt cgcccggcct cagtgagcga gcgagcgcgc agagaggag 1260 tggccaactc catcactagg ggttcctgcg gccgcacgcg tctcagctgg agtgacgcac 1320 ctcatccatg cgggcctggc gtctggaagg tggctgggtc tctcgggctt gagcaccatc 1380 atcttagctc caacatgtca ttattccttc ctcactgagg acttttctgc ttcctaattg 1440 gttgttgaag atgaggcccc catgctcttt taagaaaacc tgttgtgccc caggcttggc 1500 tgtgatgggc actgactcat acagaagtag aaaggcctgc tgagtcatca acactcgtgc 1560 gacgccctcg cattttcatt aatgatggcc tccctgccac acgtgaatca ctccagcccg 1620 agatctgaaa ccaggacaca ccccaggggc gaggtgacgc tgagtgagcc cagctgtgtc 1680 cctttcatga gaactcagag cacagggctc tgtgtgcatg gccgtcccct ccagagagga 1740 ggaagtaaat gccgggatta gtggaagatc atttccttct atttgccttg gcttacgtct 1800 ttcagaattc aaacacgtgc actgttgacc ctgcaatggt ggagtttttg gattttcctt 1860 cagtccgatt gctaaaatac ttccctctca tgtgagctgt tgtgaaagtc atcagccaga 1920 taccattcta aaaacaaaga atgtgcttct cgtatgttgc atgctggtta ctgaaatatt 1980 agggaattac ataaaggttt tctggggcac atattcaagc tgaatgataa aattgaaggt 2040 cacacaaagc taaggtcttt caaatcctga cccaattagc tctctgttag ctctctgact 2100 ttggacaagc tgtctggtcc tctgaagcat actttgttcg ccctgggtag gggccctctg 2160 ttttaacagc gtttggcatt aattaagacc tcgaagggga cttggggggt tcggggcttt 2220 cgggggcggt cgggggttcg cggacccggg aagctctgag gacccagagg ccgggcgcgc 2280 tccgcccgcg gcgccgcccc ctccgtaact ttcccagtct ccgagggaag aggcggggtg 2340 tggggtgcgg ttaaaaggcg ccacggcggg agacaggtgt tgcggccccg cagcgcccgc 2400 gcgctcctct ccccgactcg gagcccctcg gcggcgcccg gcccaggacc cgcctaggag 2460 cgcaggagcc ccagcgcaga gaccccaacg ccgagacccc cgccccggcc ccgccgcgct 2520 tcctcccgac gcagagcaaa ccgcccagag tagaagccat ggtgagcaag ggcgaggagc 2580 tgttcaccgg ggtggtgccc atcctggtcg agctggacgg cgacgtaaac ggccacaagt 2640 tcagcgtgtc cggcgagggc gagggcgatg ccacctacgg caagctgacc ctgaagttca 2700 tctgcaccac cggcaagctg cccgtgccct ggcccaccct cgtgaccacc ctgacctacg 2760 gcgtgcagtg cttcagccgc taccccgacc acatgaagca gcacgacttc ttcaagtccg 2820 ccatgcccga aggctacgtc caggagcgca ccatcttctt caaggacgac ggcaactaca 2880 agacccgcgc cgaggtgaag ttcgagggcg acaccctggt gaaccgcatc gagctgaagg 2940 gcatcgactt caaggaggac ggcaacatcc tggggcacaa gctggagtac aactacaaca 3000 gccacaacgt ctatatcatg gccgacaagc agaagaacgg catcaaggtg aacttcaaga 3060 tccgccacaa catcgaggac ggcagcgtgc agctcgccga ccactaccag cagaacaccc 3120 ccatcggcga cggccccgtg ctgctgcccg acaaccacta cctgagcacc cagtccgccc 3180 tgagcaaaga ccccaacgag aagcgcgatc acatggtcct gctggagttc gtgaccgccg 3240 ccgggatcac tctcggcatg gacgagctgt acaagtaaag gcgcgccacc cctgcaggga 3300 attccgcatt gcccagttgt tagattaaga aatagacagc atgagaggga tgaggcaacc 3360 cgtgctcagc tgtcaaggct cagtcgctag catttcccaa cacaaagatt ctgaccttaa 3420 atgcaaccat ttgaaacccc tgtaggcctc aggtgaaact ccagatgcca caatggagct 3480 ctgctcccct aaagcctcaa aacaaaggcc taattctatg cctgtcttaa ttttctttca 3540 cttaagttag ttccactgag accccaggct gttaggggtt attggtgtaa ggtactttca 3600 tattttaaac agaggatatc ggcatttgtt tctttctctg aggacaagag aaaaaagcca 3660 ggttccacag aggacacaga gaaggtttgg gtgtcctcct ggggttcttt ttgccaactt 3720 tccccacgtt aaaggtgaac attggttctt tcatttgctt tggaagtttt aatctctaac 3780 agtggacaaa gttaccagtg ccttaaactc tgttacactt tttggaagtg aaaactttgt 3840 agtatgatag gttattttga tgtaaagatg ttctggatac cattatatgt tccccctgtt 3900 tcagaggctc agattgtaat atgtaaatgg tatgtcattc gctactatga tttaatttga 3960 aatatggtct tttggttatg aatactttgc agcacagctg agaggctgtc tgttgtattc 4020 attgtggtca tagcacctaa caacattgta gcctcaatcg agtgagacag actagaagtt 4080 cctagtgatg gcttatgata gcaaatggcc tcatgtcaaa tatttagatg taattttggg 4140 taagaaatac agactggatg taccaccaac tactacctgt aatgacaggc ctgtccaaca 4200 catctccctt ttccatgact gtggtagcca gcatcggaaa gaacgctgat ttaaagaggt 4260 cgcttgggaa tttattgac acagtaccat ttaatgggga ggacaaaatg gggcagggga 4320 gggagaagtt tctgtcgtta aaaacagatt tggaaagact ggactctaaa gtctgttgat 4380 taaagatgag ctttgtctac ttcaaaagtt tgtttgctta ccccttcagc ctccaatttt 4440 ttaagtgaaa atatagctaa taacatgtga aaagaataga agctaaggtt tagataaata 4500 ttgagcagat ctataggaag attgaacctg aatattgcca ttatgcttga catggtttcc 4560 aaaaaatggt actccacata tttcagtgag ggtaagtatt ttcctgttgt caagaatagc 4620 attgtaaaag cattttgtaa taataaagaa tagctttaat gatatgcttg taactaaaat 4680 aattttgtaa tgtatcaaat acatttaaaa cattaaaata taatctctat aataatttaa 4740 aatctaatat ggttttaata gaacagcgat atcaagctta tcgataatca acctctggat 4800 tacaaaattt gtgaaagatt gactggtatt cttaactatg ttgctccttt tacgctatgt 4860 ggatacgctg ctttaatgcc tttgtatcat gctattgctt cccgtatggc tttcattttc 4920 tcctccttgt ataaatcctg gttgctgtct ctttatgagg agttgtggcc cgttgtcagg 4980 caacgtggcg tggtgtgcac tgtgtttgct gacgcaaccc ccactggttg gggcattgcc 5040 accacctgtc agctcctttc cgggactttc gctttccccc tccctattgc cacggcggaa 5100 ctcatcgccg cctgccttgc ccgctgctgg acaggggctc ggctgttggg cactgacaat 5160 tccgtggtgt tgtcgggggaa atcatcgtcc tttccttggc tgctcgccta tgttgccacc 5220 tggattctgc gcgggacgtc cttctgctac gtcccttcgg ccctcaatcc agcggacctt 5280 ccttcccgcg gcctgctgcc ggctctgcgg cctcttccgc gtcttcgcct tcgccctcag 5340 acgagtcgga tctccctttg ggccgcctcc ccgcgaattc atcgataccg agcgctgctc 5400 gagagatctg tgatagcggc catcaagctg gctgtgcctt ctagttgcca gccatctgtt 5460 gtttgcccct cccccgtgcc ttccttgacc ctggaaggtg ccactcccac tgtcctttcc 5520 taataaaatg aggaaattgc atcgcattgt ctgagtaggt gtcattctat tctggggggt 5580 ggggtggggc aggacagcaa gggggaggat tgggaagaca atagcaggca tgctggggac 5640 acgtgcggac cgagcggccg caggaacccc tagtgatgga gttggccact ccctctctgc 5700 gcgctcgctc gctcactgag gccgggcgac caaaggtcgc ccgacgcccg ggctttgccc 5760 gggcggcctc agtgagcgag cgagcgcgca gctgcctgca ggggcgcctg atgcggtatt 5820 ttctccttac gcatctgtgc ggtatttcac accgcatacg tcaaagcaac catagtacgc 5880 gccctgtagc ggcgcattaa gcgcggcggg tgtggtggtt acgcgcagcg tgaccgctac 5940 acttgccagc gccctagcgc ccgctccttt cgctttcttc ccttcctttc tcgccacgtt 6000 cgccggcttt ccccgtcaag ctctaaatcg ggggctccct ttagggttcc gatttagtgc 6060 tttacggcac ctcgacccca aaaaacttga tttgggtgat ggttcacgta gtgggccatc 6120 gccctgatag acggtttttc gccctttgac gttggagtcc acgttcttta atagtggact 6180 cttgttccaa actggaacaa cactcaaccc tatctcgggc tattcttttg atttataagg 6240 gattttgccg atttcggcct attggttaaa aaatgagctg atttaacaaa aatttaacgc 6300 gaattttaac aaaatattaa cgtttacaat tttatggtgc actctcagta caatctgctc 6360 tgatgccgca tagttaagcc agccccgaca cccgccaaca cccgctgacg cgccctgacg 6420 ggcttgtctg ctcccggcat ccgcttacag acaagctgtg accgtctccg ggagctgcat 6480 gtgtcagagg ttttcaccgt catcaccgaa acgcgcgaga cgaaagggcc tcgtgatacg 6540 cctattttta taggttaatg tcatgataat aatggtttct tagacgtcag gtggcacttt 6600 tcggggaaat gtgcgcggaa cccctatttg tttattttc taaatacatt caaatatgta 6660 tccgctcatg agacaataac cctgataaat gcttcaataa tattgaaaaa ggaagagtat 6720 gagtattcaa catttccgtg tcgcccttat tccctttttt gcggcatttt gccttcctgt 6780 ttttgctcac ccagaaacgc tggtgaaagt aaaagatgct gaagatcagt tgggtgcacg 6840 agtgggttac atcgaactgg atctcaacag cggtaagatc cttgagagtt ttcgccccga 6900 agaacgtttt ccaatgatga gcacttttaa agttctgcta tgtggcgcgg tattatcccg 6960 tattgacgcc gggcaagagc aactcggtcg ccgcatacac tattctcaga atgacttggt 7020 tgagtactca ccagtcacag aaaagcatct tacggatggc atgacagtaa gagaattatg 7080 cagtgctgcc ataaccatga gtgataacac tgcggccaac ttacttctga caacgatcgg 7140 aggaccgaag gagctaaccg cttttttgca caacatgggg gatcatgtaa ctcgccttga 7200 tcgttgggaa ccggagctga atgaagccat accaaacgac gagcgtgaca cca 7253 <210> 52 <211> 7057 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 52 cgatgcctgt agcaatggca acaacgttgc gcaaactatt aactggcgaa ctacttactc 60 tagcttcccg gcaacaatta atagactgga tggaggcgga taaagttgca ggaccacttc 120 tgcgctcggc ccttccggct ggctggttta ttgctgataa atctggagcc ggtgagcgtg 180 ggtctcgcgg tatcattgca gcactggggc cagatggtaa gccctcccgt atcgtagtta 240 tctacacgac ggggagtcag gcaactatgg atgaacgaaa tagacagatc gctgagatag 300 gtgcctcact gattaagcat tggtaactgt cagaccaagt ttactcatat atactttaga 360 ttgatttaaa acttcatttt taatttaaaa ggatctaggt gaagatcctt tttgataatc 420 tcatgaccaa aatcccttaa cgtgagtttt cgttccactg agcgtcagac cccgtagaaa 480 agatcaaagg atcttcttga gatccttttt ttctgcgcgt aatctgctgc ttgcaaacaa 540 aaaaaccacc gctaccagcg gtggtttgtt tgccggatca agagctacca actctttttc 600 cgaaggtaac tggcttcagc agagcgcaga taccaaatac tgtccttcta gtgtagccgt 660 agttaggcca ccacttcaag aactctgtag caccgcctac atacctcgct ctgctaatcc 720 tgttaccagt ggctgctgcc agtggcgata agtcgtgtct taccgggttg gactcaagac 780 gatagttacc ggataaggcg cagcggtcgg gctgaacggg gggttcgtgc acacagccca 840 gcttggagcg aacgacctac accgaactga gatacctaca gcgtgagcta tgagaaagcg 900 ccacgcttcc cgaagggaga aaggcggaca ggtatccggt aagcggcagg gtcggaacag 960 gagagcgcac gagggagctt ccagggggaa acgcctggta tctttatagt cctgtcgggt 1020 ttcgccacct ctgacttgag cgtcgatttt tgtgatgctc gtcagggggg cggagcctat 1080 ggaaaaacgc cagcaacgcg gcctttttac ggttcctggc cttttgctgg ccttttgctc 1140 acatgtcctg caggcagctg cgcgctcgct cgctcactga ggccgcccgg gcaaagcccg 1200 ggcgtcgggc gacctttggt cgcccggcct cagtgagcga gcgagcgcgc agagaggag 1260 tggccaactc catcactagg ggttcctgcg gccgcacgcg ttctaggtag acaactaaga 1320 tgttcatctt atggtttaat gtttagttgt aaaggttgtt tgcttctcat ttggttccaa 1380 gaaagagtat ttaggccaat ttcagggaga aatatgtgta tagatatatt catatgtcaa 1440 actgattagt gctgaatgtc acatttccat attctaataa catttctagc aaagaagagg 1500 acacagtgaa gagagaattg cccgcattgt cattgtctct ttctgagcct agaacgccta 1560 acacttgggt gtggagagac tcagcctcaa ttcactttct agcagccact gagatgtgct 1620 tgcctggggt gccccctggc aggcagggct ggaactgctt tccagtaccc acacggactg 1680 tgaacgaatc tttctttgtg ctttgtgtac agaatggaag ttcaacaaat atttgttgaa 1740 tgtgtatgtc cttccaatac gcagcagccc agagcaaacg tggtaatctt gtgtgtgttc 1800 atgtgaaagc agaatttaat ggtgctttta agcaccaaag tttaagatgc acgagaaaac 1860 tgtatctcca ttttttcctt ttcgtttaca attacttgta taagccaggc acggtggtgg 1920 ctcacgcctg taatcccagc actttgggag gccgaggcgg gcggatcaca tgaggtcggg 1980 agttaattaa gacctcgaag gggacttggg gggttcgggg ctttcggggg cggtcggggg 2040 ttcgcggacc cgggaagctc tgaggaccca gaggccgggc gcgctccgcc cgcggcgccg 2100 ccccctccgt aactttccca gtctccgagg gaagaggcgg ggtgtggggt gcggttaaaa 2160 ggcgccacgg cgggagacag gtgttgcggc cccgcagcgc ccgcgcgctc ctctccccga 2220 ctcggagccc ctcggcggcg cccggcccag gacccgccta ggagcgcagg agccccagcg 2280 cagagacccc aacgccgaga cccccgcccc ggccccgccg cgcttcctcc cgacgcagag 2340 caaaccgccc agagtagaag ccatggtgag caagggcgag gagctgttca ccggggtggt 2400 gcccatcctg gtcgagctgg acggcgacgt aaacggccac aagttcagcg tgtccggcga 2460 gggcgagggc gatgccacct acggcaagct gaccctgaag ttcatctgca ccaccggcaa 2520 gctgcccgtg ccctggccca ccctcgtgac caccctgacc tacggcgtgc agtgcttcag 2580 ccgctacccc gaccacatga agcagcacga cttcttcaag tccgccatgc ccgaaggcta 2640 cgtccaggag cgcaccatct tcttcaagga cgacggcaac tacaagaccc gcgccgaggt 2700 gaagttcgag ggcgacaccc tggtgaaccg catcgagctg aagggcatcg acttcaagga 2760 ggacggcaac atcctggggc acaagctgga gtacaactac aacagccaca acgtctatat 2820 catggccgac aagcagaaga acggcatcaa ggtgaacttc aagatccgcc acaacatcga 2880 ggacggcagc gtgcagctcg ccgaccacta ccagcagaac acccccatcg gcgacggccc 2940 cgtgctgctg cccgacaacc actacctgag cacccagtcc gccctgagca aagaccccaa 3000 cgagaagcgc gatcacatgg tcctgctgga gttcgtgacc gccgccggga tcactctcgg 3060 catggacgag ctgtacaagt aaaggcgcgc cacccctgca gggaattccg cattgcccag 3120 ttgttagatt aagaaataga cagcatgaga gggatgaggc aacccgtgct cagctgtcaa 3180 ggctcagtcg ctagcatttc ccaacacaaa gattctgacc ttaaatgcaa ccatttgaaa 3240 cccctgtagg cctcaggtga aactccagat gccacaatgg agctctgctc ccctaaagcc 3300 tcaaaacaaa ggcctaattc tatgcctgtc ttaattttct ttcacttaag ttagttccac 3360 tgagaccccca ggctgttagg ggttattggt gtaaggtact ttcatatttt aaacagagga 3420 tatcggcatt tgtttctttc tctgaggaca agagaaaaaa gccaggttcc acagaggaca 3480 cagagaaggt ttgggtgtcc tcctggggtt ctttttgcca actttcccca cgttaaaggt 3540 gaacattggt tctttcattt gctttggaag ttttaatctc taacagtgga caaagttacc 3600 agtgccttaa actctgttac actttttgga agtgaaaact ttgtagtatg ataggttatt 3660 ttgatgtaaa gatgttctgg ataccattat atgttccccc tgtttcagag gctcagattg 3720 taatatgtaa atggtatgtc attcgctact atgatttaat ttgaaatatg gtcttttggt 3780 tatgaatact ttgcagcaca gctgagaggc tgtctgttgt attcattgtg gtcatagcac 3840 ctaacaacat tgtagcctca atcgagtgag acagactaga agttcctagt gatggcttat 3900 gatagcaaat ggcctcatgt caaatattta gatgtaattt tgtgtaagaa atacagactg 3960 gatgtaccac caactactac ctgtaatgac aggcctgtcc aacacatctc ccttttccat 4020 gactgtggta gccagcatcg gaaagaacgc tgatttaaag aggtcgcttg ggaattttat 4080 tgacacagta ccatttaatg gggaggacaa aatggggcag gggagggaga agtttctgtc 4140 gttaaaaaca gatttggaaa gactggactc taaagtctgt tgattaaaga tgagctttgt 4200 ctacttcaaa agtttgtttg cttacccctt cagcctccaa ttttttaagt gaaaatatag 4260 ctaataacat gtgaaaagaa tagaagctaa ggtttagata aatattgagc agatctatag 4320 gaagattgaa cctgaatatt gccattatgc ttgacatggt ttccaaaaaa tggtactcca 4380 catatttcag tgagggtaag tattttcctg ttgtcaagaa tagcattgta aaagcatttt 4440 gtaataataa agaatagctt taatgatatg cttgtaacta aaataatttt gtaatgtatc 4500 aaatacattt aaaacattaa aatataatct ctataataat ttaaaatcta atatggtttt 4560 aatagaacag cgatatcaag cttatcgata atcaacctct ggattacaaa atttgtgaaa 4620 gattgactgg tattcttaac tatgttgctc cttttacgct atgtggatac gctgctttaa 4680 tgcctttgta tcatgctatt gcttcccgta tggctttcat tttctcctcc ttgtataaat 4740 cctggttgct gtctctttat gaggagttgt ggcccgttgt caggcaacgt ggcgtggtgt 4800 gcactgtgtt tgctgacgca acccccactg gttggggcat tgccaccacc tgtcagctcc 4860 tttccgggac tttcgctttc cccctcccta ttgccacggc ggaactcatc gccgcctgcc 4920 ttgcccgctg ctggacaggg gctcggctgt tgggcactga caattccgtg gtgttgtcgg 4980 ggaaatcatc gtcctttcct tggctgctcg cctatgttgc cacctggatt ctgcgcggga 5040 cgtccttctg ctacgtccct tcggccctca atccagcgga ccttccttcc cgcggcctgc 5100 tgccggctct gcggcctctt ccgcgtcttc gccttcgccc tcagacgagt cggatctccc 5160 tttgggccgc ctccccgcga attcatcgat accgagcgct gctcgagaga tctgtgatag 5220 cggccatcaa gctggctgtg ccttctagtt gccagccatc tgttgtttgc ccctcccccg 5280 tgccttcctt gaccctggaa ggtgccactc ccactgtcct ttcctaataa aatgaggaaa 5340 ttgcatcgca ttgtctgagt aggtgtcatt ctattctggg gggtggggtg gggcaggaca 5400 gcaaggggga ggattgggaa gacaatagca ggcatgctgg ggacacgtgc ggaccgagcg 5460 gccgcaggaa cccctagtga tggagttggc cactccctct ctgcgcgctc gctcgctcac 5520 tgaggccggg cgaccaaagg tcgcccgacg cccgggcttt gcccgggcgg cctcagtgag 5580 cgagcgagcg cgcagctgcc tgcaggggcg cctgatgcgg tattttctcc ttacgcatct 5640 gtgcggtatt tcacaccgca tacgtcaaag caaccatagt acgcgccctg tagcggcgca 5700 ttaagcgcgg cgggtgtggt ggttacgcgc agcgtgaccg ctacacttgc cagcgcccta 5760 gcgcccgctc ctttcgcttt cttcccttcc tttctcgcca cgttcgccgg ctttccccgt 5820 caagctctaa atcgggggct ccctttaggg ttccgattta gtgctttacg gcacctcgac 5880 cccaaaaaac ttgatttggg tgatggttca cgtagtgggc catcgccctg atagacggtt 5940 tttcgccctt tgacgttgga gtccacgttc tttaataggg gactcttgtt ccaaactgga 6000 acaacactca accctatctc gggctattct tttgatttat aagggatttt gccgatttcg 6060 gcctattggt taaaaaatga gctgatttaa caaaaattta acgcgaattt taacaaaata 6120 ttaacgttta caattttatg gtgcactctc agtacaatct gctctgatgc cgcatagtta 6180 agccagcccc gacacccgcc aacacccgct gacgcgccct gacgggcttg tctgctcccg 6240 gcatccgctt acagacaagc tgtgaccgtc tccgggagct gcatgtgtca gaggttttca 6300 ccgtcatcac cgaaacgcgc gagacgaaag ggcctcgtga tacgcctatt tttataggtt 6360 aatgtcatga taataatggt ttcttagacg tcaggtggca cttttcgggg aaatgtgcgc 6420 ggaaccccta tttgtttatt tttctaaata cattcaaata tgtatccgct catgagacaa 6480 taaccctgat aaatgcttca ataatattga aaaaggaaga gtatgagtat tcaacatttc 6540 cgtgtcgccc ttattccctt ttttgcggca ttttgccttc ctgtttttgc tcacccagaa 6600 acgctggtga aagtaaaaga tgctgaagat cagttgggtg cacgagtggg ttacatcgaa 6660 ctggatctca acagcggtaa gatccttgag agttttcgcc ccgaagaacg ttttccaatg 6720 atgagcactt ttaaagttct gctatgtggc gcggtattat cccgtattga cgccgggcaa 6780 gagcaactcg gtcgccgcat acactattct cagaatgact tggttgagta ctcaccagtc 6840 acagaaaagc atcttacgga tggcatgaca gtaagagaat tatgcagtgc tgccataacc 6900 atgagtgata acactgcggc caacttactt ctgacaacga tcggaggacc gaaggagcta 6960 accgcttttt tgcacaacat gggggatcat gtaactcgcc ttgatcgttg ggaaccggag 7020 ctgaatgaag ccataccaaa cgacgagcgt gacacca 7057 <210> 53 <211> 212 <212> DNA <213> Homo sapiens <400> 53 ggggtgcggt taaaaggcgc cacggcggga gacaggtgtt gcggccccgc agcgcccgcg 60 cgctcctctc cccgactcgg agcccctcgg cggcgcccgg cccaggaccc gcctaggagc 120 gcaggagccc cagcgcagag accccaacgc cgagacccccc gccccggccc cgccgcgctt 180 cctcccgacg cagagcaaac cgcccagagt ag 212 <210> 54 <211> 784 <212> DNA <213> Homo sapiens <400> 54 aagcaggtga gtttgtggtg tcgccgatgt cccttcgggg tactctagcg cagccgcctg 60 gctacttgac ccactgccac caaacgtttt aaattcaccg aaagcttagc ttcgaagcaa 120 agctccgttt cgccggtgaa gcaggaagcc ttcgctgcag gaactgacct ttacctcttg 180 gagcggcttc tgcagaaaaa tccccgggca gagatttggg cggagtttgc ctagaactaa 240 cgcggagcca gccgatcccg gcctaccccg gggccaagat tttaaggggt gaagagtccc 300 ttttgccttt tctggatcct ggtgattcac ctagtgtctt ccctaaggaa ctgaaccaac 360 tcctccgctg gcctctggca gccctccagg cggtgcagga tggcgtgggc ccggtaggaa 420 gctgcatgta accgcccagg gtcgggaggc caggagggca gctcctcctc tgacttgaat 480 attgaaaaca agaggatgct tttaagaaaa agaagaagga ggattcacta ccagctctga 540 agggtgggaaa agagatgatt catccggatt gtggagaggg tggaatcttg tttaggagag 600 cgttggttgt ggcaggcagg gtgtaactat gaatcagtga agacaattca catcctggga 660 tgaaaagaag gccatgggct cacaggagat tatccactgg cctctccaca tccgcttgca 720 gtaaggagtg tgggactctc ccaagcttca gcgctgaact gcaatgcagt gacgtcgctt 780 aaga 784 <210> 55 <211> 771 <212> DNA <213> Homo sapiens <400> 55 tcatccatgt ccctacaaag gacatgaact catcattttt tatggctgca taagtcgttc 60 tttcaaacac cctgcagtca gcttctcctc acgagaaacc acatgaaagc cctcggggaa 120 atgcctctcg ggatctactt ttctttgtgt gtatcctact tagcctatcg gtttctgctt 180 cctgtggggc tacagccgtc tcgtcttttt ctgctggctc ctttgctctg ttctccagtg 240 gctatcttct ttctcctttc tttcaaatgt tctccccttat cttctctgat acagacagaa 300 ggtcaggagc cacgcccatt acactgacag aacccgatgt cctgatgcgc tctgtgcctc 360 ccagatttgg atgtggatgc gaggcgagct ggccagagag caatcatttc agcgagggtc 420 gttatccca tcttctctct taggacggag gtagggggac ttctggcccc aaatgttcct 480 tcttccagct gtggctgcct ccatcccgca gagtgagcct ttaatttgga gatcctaatg 540 ccccagtgct gtgccaggca cagtacacgt tctgcatgga ggacggttta cgctcccctt 600 acagaagagg aaggacactc agaaggctga actgttctgc ctaaggtcac cgagttgcta 660 aggcaagaag cagcctccaa ttcctgcctt actgatttct gggatgtgaa accaaaaggg 720 tgaggcggca agccccggct gccctcgggg gctcttccca agtgctctct t 771 <210> 56 <211> 771 <212> DNA <213> Homo sapiens <400> 56 aagagagcac ttgggaagag cccccgaggg cagccggggc ttgccgcctc acccttttgg 60 tttcacatcc cagaaatcag taaggcagga attggaggct gcttcttgcc ttagcaactc 120 ggtgacctta ggcagaacag ttcagccttc tgagtgtcct tcctcttctg taaggggagc 180 gtaaaccgtc ctccatgcag aacgtgtact gtgcctggca cagcactggg gcattaggat 240 ctccaaatta aaggctcact ctgcgggatg gaggcagcca cagctggaag aaggaacatt 300 tggggccaga agtcccccta cctccgtcct aagagagaag atgggaataa cgaccctcgc 360 tgaaatgatt gctctctggc cagctcgcct cgcatccaca tccaaatctg ggaggcacag 420 agcgcatcag gacatcgggt tctgtcagtg taatgggcgt ggctcctgac cttctgtctg 480 tatcagagaa gataagggag aacatttgaa agaaaggaga aagaagatag ccactggaga 540 acagagcaaa ggagccagca gaaaaagacg agacggctgt agccccacag gaagcagaaa 600 ccgataggct aagtaggata cacacaaaga aaagtagatc ccgagaggca tttccccgag 660 ggctttcatg tggtttctcg tgaggagaag ctgactgcag ggtgtttgaa agaacgactt 720 atgcagccat aaaaaatgat gagttcatgt cctttgtagg gacatggatg a 771 <210> 57 <211> 699 <212> DNA <213> Homo sapiens <400> 57 cttgcttacc cagactcaga gaagtctccc tgttctgtcc tagctagtga ttcctgtgtt 60 gtgtgcattc gtcttttcca gagcaaaccg cccagagtag aagatggatt ggggcacgct 120 gcagacgatc ctggggggtg tgaacaaaca ctccaccagc attggaaaga tctggctcac 180 cgtcctcttc atttttcgca ttatgatcct cgttgtggct gcaaaggagg tgtggggaga 240 tgagcaggcc gactttgtct gcaacaccct gcagccaggc tgcaagaacg tgtgctacga 300 tcactacttc cccatctccc acatccggct atgggccctg cagctgatct tcgtgtccac 360 gccagcgctc ctagtggcca tgcacgtggc ctaccggaga catgagaaga agaggaagtt 420 catcaagggg gagataaaga gtgaatttaa ggacatcgag gagatcaaaa cccagaaggt 480 ccgcatcgaa ggctccctgt ggtggaccta cacaagcagc atcttcttcc gggtcatctt 540 cgaagccgcc ttcatgtacg tcttctatgt catgtacgac ggcttctcca tgcagcggct 600 ggtgaagtgc aacgcctggc cttgtcccaa cactgtggac tgctttgtgt cccggcccac 660 ggagaagact gtcttcacag tgttcatgat tgcagtgtc 699 <210> 58 <211> 699 <212> DNA <213> Homo sapiens <400> 58 gacactgcaa tcatgaacac tgtgaagaca gtcttctccg tgggccggga cacaaagcag 60 tccacagtgt tgggacaagg ccaggcgttg cacttcacca gccgctgcat ggagaagccg 120 tcgtacatga catagaagac gtacatgaag gcggcttcga agatgacccg gaagaagatg 180 ctgcttgtgt aggtccacca cagggagcct tcgatgcgga ccttctgggt tttgatctcc 240 tcgatgtcct taaattcact ctttatctcc cccttgatga acttcctctt cttctcatgt 300 ctccggtagg ccacgtgcat ggccactagg agcgctggcg tggacacgaa gatcagctgc 360 agggcccata gccggatgtg ggagatgggg aagtagtgat cgtagcacac gttcttgcag 420 cctggctgca gggtgttgca gacaaagtcg gcctgctcat ctccccacac ctcctttgca 480 gccacaacga ggatcataat gcgaaaaatg aagaggacgg tgagccagat ctttccaatg 540 ctggtggagt gtttgttcac accccccagg atcgtctgca gcgtgcccca atccatcttc 600 tactctgggc ggtttgctct ggaaaagacg aatgcacaca acacaggaat cactagctag 660 gacagaacag ggagacttct ctgagtctgg gtaagcaag 699 <210> 59 <211> 700 <212> DNA <213> Homo sapiens <400> 59 gcctgacaca gtctgagcct cctcaggcgg cctcaggggt tgggatagag tggagaattc 60 aggcaagaat gccaacccta gctccaggcc tgggacccac aggcctgggg aaaagagtgg 120 ttgccccgtc ttgagacagc cgaaaactgt gtccccagga ttgttggttt cataaaagca 180 agtagctagg gaggccacat ttacagggga tcacagaaca cttgggtagg ggcttgctgt 240 aggtgtcatc agggaagtgg gggacggcag gagggatgtg gcccagtacg cagatgaaga 300 caggtgatca tccgctgggc cacacgtggc agggatatgg gcagagtgag cttggctggc 360 cccaggctcc aaagctgccc agcccccgct gaaggtgagg cctcagctgg tgggaatgtc 420 accttccagg tgactggctg gctccaaagg cctttgcatg atctccagga gtttggaggg 480 gagaggccac attccaaatc cagcttgaaa agtgctctgt atcaccctca gcactgaggg 540 ggccagagtc taggaggaag gaggcacagg gttggggggc agccctgacc tggtggccgc 600 acctgccagg tcccgagaga caacccatct cacacacatt caaaaacaca caccagggag 660 cacatggcta aacaaatcgc actaaacgcc aggaaggcag 700 <210> 60 <211> 700 <212> DNA <213> Homo sapiens <400> 60 ctgccttcct ggcgtttagt gcgatttgtt tagccatgtg ctccctggtg tgtgtttttg 60 aatgtgtgtg agatgggttg tctctcggga cctggcaggt gcggccacca ggtcagggct 120 gccccccaac cctgtgcctc cttcctccta gactctggcc ccctcagtgc tgagggtgat 180 acagagcact tttcaagctg gatttggaat gtggcctctc ccctccaaac tcctggagat 240 catgcaaagg cctttggagc cagccagtca cctggaaggt gacattccca ccagctgagg 300 cctcaccttc agcgggggct gggcagcttt ggagcctggg gccagccaag ctcactctgc 360 ccatatccct gccacgtgg gcccagcgga tgatcacctg tcttcatctg cgtactgggc 420 cacatccctc ctgccgtccc ccacttccct gatgacacct acagcaagcc cctacccaag 480 tgttctgtga tcccctgtaa atgtggcctc cctagctact tgcttttatg aaaccaacaa 540 tcctggggac acagttttcg gctgtctcaa gacggggcaa ccactctttt ccccaggcct 600 gtgggtccca ggcctggagc tagggttggc attcttgcct gaattctcca ctctatccca 660 acccctgagg ccgcctgagg aggctcagac tgtgtcaggc 700 <210> 61 <211> 6374 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 61 ttgctggcct tttgctcaca tgtcctgcag gcagctgcgc gctcgctcgc tcactgaggc 60 cgcccgggca aagcccgggc gtcgggcgac ctttggtcgc ccggcctcag tgagcgagcg 120 agcgcgcaga gagggagtgg ccaactccat cactaggggt tcctgcggcc gcacgcgttt 180 aattaagacc tcgaagggga cttggggggt tcggggcttt cgggggcggt cgggggttcg 240 cggacccggg aagctctgag gacccagagg ccgggcgcgc tccgcccgcg gcgccgcccc 300 ctccgtaact ttcccagtct ccgagggaag aggcggggtg tggggtgcgg ttaaaaggcg 360 ccacggcggg agacaggtgt tgcggccccg cagcgcccgc gcgctcctct ccccgactcg 420 gagcccctcg gcggcgcccg gcccaggacc cgcctaggag cgcaggagcc ccagcgcaga 480 gaccccaacg ccgagacccc cgccccggcc ccgccgcgct tcctcccgac gcagagcaaa 540 ccgcccagag tagaagcgga tccgccacca tggattgggg cacgctgcag acgatcctgg 600 ggggtgtgaa caaacactcc accagcattg gaaagatctg gctcaccgtc ctcttcattt 660 ttcgcattat gatcctcgtt gtggctgcaa aggaggtgtg gggagatgag caggccgact 720 ttgtctgcaa caccctgcag ccaggctgca agaacgtgtg ctacgatcac tacttcccca 780 tctcccacat ccggctatgg gccctgcagc tgatcttcgt gtccacgcca gcgctcctag 840 tggccatgca cgtggcctac cggagacatg agaagaagag gaagttcatc aagggggaga 900 taaagagtga atttaaggac atcgaggaga tcaaaaccca gaaggtccgc atcgaaggct 960 ccctgtggtg gacctacaca agcagcatct tcttccgggt catcttcgaa gccgccttca 1020 tgtacgtctt ctatgtcatg tacgacggct tctccatgca gcggctggtg aagtgcaacg 1080 cctggccttg tcccaacact gtggactgct ttgtgtcccg gcccacggag aagactgtct 1140 tcacagtgtt catgattgca gtgtctggaa tttgcatcct gctgaatgtc actgaattgt 1200 gttattgct aattagatat tgttctggga agtcaaaaaa gccagtttac ccatacgatg 1260 ttccagatta cgcttaaggc gcgccacccc tgcagggaat tccgcattgc ccagttgtta 1320 gattaagaaa tagacagcat gagagggatg aggcaacccg tgctcagctg tcaaggctca 1380 gtcgctagca tttcccaaca caaagattct gaccttaaat gcaaccattt gaaacccctg 1440 taggcctcag gtgaaactcc agatgccaca atggagctct gctcccctaa agcctcaaaa 1500 caaaggccta attctatgcc tgtcttaatt ttctttcact taagttagtt ccactgagac 1560 cccaggctgt taggggttat tggtgtaagg tactttcata ttttaaacag aggatatcgg 1620 catttgtttc tttctctgag gacaagagaa aaaagccagg ttccacagag gacacagaga 1680 aggtttgggt gtcctcctgg ggttcttttt gccaactttc cccacgttaa aggtgaacat 1740 tggttctttc atttgctttg gaagttttaa tctctaacag tggacaaagt taccagtgcc 1800 ttaaactctg ttacactttt tggaagtgaa aactttgtag tatgataggt tattttgatg 1860 taaagatgtt ctggatacca ttatatgttc cccctgtttc agaggctcag attgtaatat 1920 gtaaatggta tgtcattcgc tactatgatt taatttgaaa tatggtcttt tggttatgaa 1980 tactttgcag cacagctgag aggctgtctg ttgtattcat tgtggtcata gcacctaaca 2040 acattgtagc ctcaatcgag tgagacagac tagaagttcc tagtgatggc ttatgatagc 2100 aaatggcctc atgtcaaata tttagatgta attttgtgta agaaatacag actggatgta 2160 ccaccaacta ctacctgtaa tgacaggcct gtccaacaca tctccctttt ccatgactgt 2220 ggtagccagc atcggaaaga acgctgattt aaagaggtcg cttgggaatt ttattgacac 2280 agtaccattt aatggggagg acaaaatggg gcaggggagg gagaagtttc tgtcgttaaa 2340 aacagatttg gaaagactgg actctaaagt ctgttgatta aagatgagct ttgtctactt 2400 caaaagtttg tttgcttacc ccttcagcct ccaatttttt aagtgaaaat atagctaata 2460 acatgtgaaa agaatagaag ctaaggttta gataaatatt gagcagatct ataggaagat 2520 tgaacctgaa tattgccatt atgcttgaca tggtttccaa aaaatggtac tccacatatt 2580 tcagtgaggg taagtatttt cctgttgtca agaatagcat tgtaaaagca ttttgtaata 2640 ataaagaata gctttaatga tatgcttgta actaaaataa ttttgtaatg tatcaaatac 2700 atttaaaaca ttaaaatata atctctataa taatttaaaa tctaatatgg ttttaataga 2760 acagcgatat caagcttatc gataatcaac ctctggatta caaaatttgt gaaagattga 2820 ctggtattct taactatgtt gctcctttta cgctatgtgg atacgctgct ttaatgcctt 2880 tgtatcatgc tattgcttcc cgtatggctt tcattttctc ctccttgtat aaatcctggt 2940 tgctgtctct ttatgaggag ttgtggcccg ttgtcaggca acgtggcgtg gtgtgcactg 3000 tgtttgctga cgcaaccccc actggttggg gcattgccac cacctgtcag ctcctttccg 3060 ggactttcgc tttccccctc cctattgcca cggcggaact catcgccgcc tgccttgccc 3120 gctgctggac aggggctcgg ctgttgggca ctgacaattc cgtggtgttg tcggggaaat 3180 catcgtcctt tccttggctg ctcgcctatg ttgccacctg gattctgcgc gggacgtcct 3240 tctgctacgt cccttcggcc ctcaatccag cggaccttcc ttcccgcggc ctgctgccgg 3300 ctctgcggcc tcttccgcgt cttcgccttc gccctcagac gagtcggatc tccctttggg 3360 ccgcctcccc gcgaattcat cgataccgag cgctgctcga gagatctgtg atagcggcca 3420 tcaagctggc tgtgccttct agttgccagc catctgttgt ttgcccctcc cccgtgcctt 3480 ccttgaccct ggaaggtgcc actcccactg tcctttccta ataaaatgag gaaattgcat 3540 cgcattgtct gagtaggtgt cattctattc tggggggtgg ggtggggcag gacagcaagg 3600 gggaggattg ggaagacaat agcaggcatg ctggggacac gtgcggaccg agcggccgca 3660 ggaaccccta gtgatggagt tggccactcc ctctctgcgc gctcgctcgc tcactgaggc 3720 cgggcgacca aaggtcgccc gacgcccggg ctttgcccgg gcggcctcag tgagcgagcg 3780 agcgcgcagc tgcctgcagg ggcgcctgat gcggtatttt ctccttacgc atctgtgcgg 3840 tatttcacac cgcatacgtc aaagcaacca tagtacgcgc cctgtagcgg cgcattaagc 3900 gcggcgggtg tggtggttac gcgcagcgtg accgctacac ttgccagcgc cctagcgccc 3960 gctcctttcg ctttcttccc ttcctttctc gccacgttcg ccggctttcc ccgtcaagct 4020 ctaaatcggg ggctcccttt agggttccga tttagtgctt tacggcacct cgaccccaaa 4080 aaacttgatt tgggtgatgg ttcacgtagt gggccatcgc cctgatagac ggtttttcgc 4140 cctttgacgt tggagtccac gttctttaat agtggactct tgttccaaac tggaacaaca 4200 ctcaacccta tctcgggcta ttcttttgat ttataaggga ttttgccgat ttcggcctat 4260 tggttaaaaa atgagctgat ttaacaaaaa tttaacgcga attttaacaa aatattaacg 4320 tttacaattt tatggtgcac tctcagtaca atctgctctg atgccgcata gttaagccag 4380 ccccgacacc cgccaacacc cgctgacgcg ccctgacggg cttgtctgct cccggcatcc 4440 gcttacagac aagctgtgac cgtctccggg agctgcatgt gtcagaggtt ttcaccgtca 4500 tcaccgaaac gcgcgagacg aaagggcctc gtgatacgcc tatttttata ggttaatgtc 4560 atgataataa tggtttctta gacgtcaggt ggcacttttc ggggaaatgt gcgcggaacc 4620 cctatttgtt tatttttcta aatacattca aatatgtatc cgctcatgag acaataaccc 4680 tgataaatgc ttcaataata ttgaaaaagg aagagtatga gtattcaaca tttccgtgtc 4740 gcccttattc ccttttttgc ggcattttgc cttcctgttt ttgctcaccc agaaacgctg 4800 gtgaaagtaa aagatgctga agatcagttg ggtgcacgag tgggttacat cgaactggat 4860 ctcaacagcg gtaagatcct tgagagtttt cgccccgaag aacgttttcc aatgatgagc 4920 acttttaaag ttctgctatg tggcgcggta ttatcccgta ttgacgccgg gcaagagcaa 4980 ctcggtcgcc gcatacacta ttctcagaat gacttggttg agtactcacc agtcacagaa 5040 aagcatctta cggatggcat gacagtaaga gaattatgca gtgctgccat aaccatgagt 5100 gataacactg cggccaactt acttctgaca acgatcggag gaccgaagga gctaaccgct 5160 tttttgcaca acatggggga tcatgtaact cgccttgatc gttgggaacc ggagctgaat 5220 gaagccatac caaacgacga gcgtgacacc acgatgcctg tagcaatggc aacaacgttg 5280 cgcaaactat taactggcga actacttact ctagcttccc ggcaacaatt aatagactgg 5340 atggaggcgg ataaagttgc aggaccactt ctgcgctcgg cccttccggc tggctggttt 5400 attgctgata aatctggagc cggtgagcgt gggtctcgcg gtatcattgc agcactgggg 5460 ccagatggta agccctcccg tatcgtagtt atctacacga cggggagtca ggcaactatg 5520 gatgaacgaa atagacagat cgctgagata ggtgcctcac tgattaagca ttggtaactg 5580 tcagaccaag tttactcata tatactttag attgatttaa aacttcattt ttaatttaaa 5640 aggatctagg tgaagatcct ttttgataat ctcatgacca aaatccctta acgtgagttt 5700 tcgttccact gagcgtcaga ccccgtagaa aagatcaaag gatcttcttg agatcctttt 5760 tttctgcgcg taatctgctg cttgcaaaca aaaaaaccac cgctaccagc ggtggtttgt 5820 ttgccggatc aagagctacc aactcttttt ccgaaggtaa ctggcttcag cagagcgcag 5880 ataccaaata ctgtccttct agtgtagccg tagttaggcc accacttcaa gaactctgta 5940 gcaccgccta catacctcgc tctgctaatc ctgttaccag tggctgctgc cagtggcgat 6000 aagtcgtgtc ttaccgggtt ggactcaaga cgatagttac cggataaggc gcagcggtcg 6060 ggctgaacgg ggggttcgtg cacacagccc agcttggagc gaacgaccta caccgaactg 6120 agatacctac agcgtgagct atgagaaagc gccacgcttc ccgaagggag aaaggcggac 6180 aggtatccgg taagcggcag ggtcggaaca ggagagcgca cgagggagct tccaggggga 6240 aacgcctggt atctttatag tcctgtcggg tttcgccacc tctgacttga gcgtcgattt 6300 ttgtgatgct cgtcaggggg gcggagccta tggaaaaacg ccagcaacgc ggccttttta 6360 cggttcctgg cctt 6374 <210> 62 <211> 6347 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 62 cagcactggg gccagatggt aagccctccc gtatcgtagt tatctacacg acggggagtc 60 aggcaactat ggatgaacga aatagacaga tcgctgagat aggtgcctca ctgattaagc 120 attggtaact gtcagaccaa gtttactcat atatacttta gattgattta aaacttcatt 180 tttaatttaa aaggatctag gtgaagatcc tttttgataa tctcatgacc aaaatccctt 240 aacgtgagtt ttcgttccac tgagcgtcag accccgtaga aaagatcaaa ggatcttctt 300 gagatccttt ttttctgcgc gtaatctgct gcttgcaaac aaaaaaacca ccgctaccag 360 cggtggtttg tttgccggat caagagctac caactctttt tccgaaggta actggcttca 420 gcagagcgca gataccaaat actgtccttc tagtgtagcc gtagttaggc caccacttca 480 agaactctgt agcaccgcct acatacctcg ctctgctaat cctgttacca gtggctgctg 540 ccagtggcga taagtcgtgt cttaccgggt tggactcaag acgatagtta ccggataagg 600 cgcagcggtc gggctgaacg gggggttcgt gcacacagcc cagcttggag cgaacgacct 660 acaccgaact gagataccta cagcgtgagc tatgagaaag cgccacgctt cccgaaggga 720 gaaaggcgga caggtatccg gtaagcggca gggtcggaac aggagagcgc acgagggagc 780 ttccaggggg aaacgcctgg tatctttata gtcctgtcgg gtttcgccac ctctgacttg 840 agcgtcgatt tttgtgatgc tcgtcagggg ggcggagcct atggaaaaac gccagcaacg 900 cggccttttt acggttcctg gccttttgct ggccttttgc tcacatgtcc tgcaggcagc 960 tgcgcgctcg ctcgctcact gaggccgccc gggcaaagcc cgggcgtcgg gcgacctttg 1020 gtcgcccggc ctcagtgagc gagcgagcgc gcagagaggg agtggccaac tccatcacta 1080 ggggttcctg cggccgcacg cgtttaatta agacctcgaa ggggacttgg ggggttcggg 1140 gctttcgggg gcggtcgggg gttcgcggac ccgggaagct ctgaggaccc agaggccggg 1200 cgcgctccgc ccgcggcgcc gccccctccg taactttccc agtctccgag ggaagaggcg 1260 gggtgtgggg tgcggttaaa aggcgccacg gcgggagaca ggtgttgcgg ccccgcagcg 1320 cccgcgcgct cctctccccg actcggagcc cctcggcggc gcccggccca ggacccgcct 1380 aggagcgcag gagccccagc gcagagaccc caacgccgag acccccgccc cggccccgcc 1440 gcgcttcctc ccgacgcaga gcaaaccgcc cagagtagaa gcggatccgc caccatggat 1500 tggggcacac tccagagcat cctcgggggt gtcaacaaac actccaccag cattggaaag 1560 atctggctca cggtcctctt catcttccgc atcatgatcc tcgtggtggc tgcaaaggag 1620 gtgtggggag atgagcaagc cgattttgtc tgcaacacgc tccagcctgg ctgcaagaat 1680 gtatgctacg accaccactt ccccatctct cacatccggc tctgggctct gcagctgatc 1740 atggtgtcca cgccagccct cctggtagct atgcatgtgg cctaccggag acatgaaaag 1800 aaacggaagt tcatgaaggg agagataaag aacgagttta aggacatcga agagatcaaa 1860 acccagaagg tccgtatcga agggtccctg tggtggacct acaccaccag catcttcttc 1920 cgggtcatct ttgaagccgt cttcatgtac gtcttttaca tcatgtacaa tggcttcttc 1980 atgcaacgtc tggtgaaatg caacgcttgg ccctgcccca atacagtgga ctgcttcatt 2040 tccaggccca cagaaaagac tgtcttcacc gtgtttatga tttctgtgtc tggaatttgc 2100 attctgctaa atatcacaga gctgtgctat ttgttcgtta ggtattgctc aggaaagtcc 2160 aaaagaccag tctaaggcgc gccacccctg cagggaattc cgcattgccc agttgttaga 2220 ttaagaaata gacagcatga gagggatgag gcaacccgtg ctcagctgtc aaggctcagt 2280 cgctagcatt tcccaacaca aagattctga ccttaaatgc aaccatttga aacccctgta 2340 ggcctcaggt gaaactccag atgccacaat ggagctctgc tcccctaaag cctcaaaaca 2400 aaggcctaat tctatgcctg tcttaatttt ctttcactta agttagttcc actgagaccc 2460 caggctgtta ggggttattg gtgtaaggta ctttcatatt ttaaacagag gatatcggca 2520 tttgtttctt tctctgagga caagagaaaa aagccaggtt ccacagagga cacagagaag 2580 gtttgggtgt cctcctgggg ttctttttgc caactttccc cacgttaaag gtgaacattg 2640 gttctttcat ttgctttgga agttttaatc tctaacagtg gacaaagtta ccagtgcctt 2700 aaactctgtt acactttttg gaagtgaaaa ctttgtagta tgataggtta ttttgatgta 2760 aagatgttct ggataccatt atatgttccc cctgtttcag aggctcagat tgtaatatgt 2820 aaatggtatg tcattcgcta ctatgattta atttgaaata tggtcttttg gttatgaata 2880 ctttgcagca cagctgagag gctgtctgtt gtattcattg tggtcatagc acctaacaac 2940 attgtagcct caatcgagtg agacagacta gaagttccta gtgatggctt atgatagcaa 3000 atggcctcat gtcaaatatt tagatgtaat tttgtgtaag aaatacagac tggatgtacc 3060 accaactact acctgtaatg acaggcctgt ccaacacatc tcccttttcc atgactgtgg 3120 tagccagcat cggaaagaac gctgatttaa agaggtcgct tgggaatttt attgacacag 3180 taccatttaa tggggaggac aaaatggggc aggggaggga gaagtttctg tcgttaaaaa 3240 cagatttgga aagactggac tctaaagtct gttgattaaa gatgagcttt gtctacttca 3300 aaagtttgtt tgcttacccc ttcagcctcc aattttttaa gtgaaaatat agctaataac 3360 atgtgaaaag aatagaagct aaggtttaga taaatattga gcagatctat aggaagattg 3420 aacctgaata ttgccattat gcttgacatg gtttccaaaa aatggtactc cacatatttc 3480 agtgagggta agtattttcc tgttgtcaag aatagcattg taaaagcatt ttgtaataat 3540 aaagaatagc tttaatgata tgcttgtaac taaaataatt ttgtaatgta tcaaatacat 3600 ttaaaacatt aaaatataat ctctataata atttaaaatc taatatggtt ttaatagaac 3660 agcgatatca agcttatcga taatcaacct ctggattaca aaatttgtga aagattgact 3720 ggtattctta actatgttgc tccttttacg ctatgtggat acgctgcttt aatgcctttg 3780 tatcatgcta ttgcttcccg tatggctttc attttctcct ccttgtataa atcctggttg 3840 ctgtctcttt atgaggagtt gtggcccgtt gtcaggcaac gtggcgtggt gtgcactgtg 3900 tttgctgacg caacccccac tggttggggc attgccacca cctgtcagct cctttccggg 3960 actttcgctt tccccctccc tattgccacg gcggaactca tcgccgcctg ccttgcccgc 4020 tgctggacag gggctcggct gttgggcact gacaattccg tggtgttgtc ggggaaatca 4080 tcgtcctttc cttggctgct cgcctatgtt gccacctgga ttctgcgcgg gacgtccttc 4140 tgctacgtcc cttcggccct caatccagcg gaccttcctt cccgcggcct gctgccggct 4200 ctgcggcctc ttccgcgtct tcgccttcgc cctcagacga gtcggatctc cctttgggcc 4260 gcctccccgc gaattcatcg ataccgagcg ctgctcgaga gatctgtgat agcggccatc 4320 aagctggctg tgccttctag ttgccagcca tctgttgttt gcccctcccc cgtgccttcc 4380 ttgaccctgg aaggtgccac tcccactgtc ctttcctaat aaaatgagga aattgcatcg 4440 cattgtctga gtaggtgtca ttctattctg gggggtgggg tggggcagga cagcaagggg 4500 gaggattggg aagacaatag caggcatgct ggggacacgt gcggaccgag cggccgcagg 4560 aacccctagt gatggagttg gccactccct ctctgcgcgc tcgctcgctc actgaggccg 4620 ggcgaccaaa ggtcgcccga cgcccgggct ttgcccgggc ggcctcagtg agcgagcgag 4680 cgcgcagctg cctgcagggg cgcctgatgc ggtattttct ccttacgcat ctgtgcggta 4740 tttcacaccg catacgtcaa agcaaccata gtacgcgccc tgtagcggcg cattaagcgc 4800 ggcgggtgtg gtggttacgc gcagcgtgac cgctacactt gccagcgccc tagcgcccgc 4860 tcctttcgct ttcttccctt cctttctcgc cacgttcgcc ggctttcccc gtcaagctct 4920 aaatcggggg ctccctttag ggttccgatt tagtgcttta cggcacctcg accccaaaaa 4980 acttgatttg ggtgatggtt cacgtagtgg gccatcgccc tgatagacgg tttttcgccc 5040 tttgacgttg gagtccacgt tctttaatag tggactcttg ttccaaactg gaacaacact 5100 caaccctatc tcgggctatt cttttgattt ataagggatt ttgccgattt cggcctattg 5160 gttaaaaaat gagctgattt aacaaaaatt taacgcgaat tttaacaaaa tattaacgtt 5220 tacaatttta tggtgcactc tcagtacaat ctgctctgat gccgcatagt taagccagcc 5280 ccgaccccg ccaacacccg ctgacgcgcc ctgacgggct tgtctgctcc cggcatccgc 5340 ttacagacaa gctgtgaccg tctccgggag ctgcatgtgt cagaggtttt caccgtcatc 5400 accgaaacgc gcgagacgaa agggcctcgt gatacgccta tttttatagg ttaatgtcat 5460 gataataatg gtttcttaga cgtcaggtgg cacttttcgg ggaaatgtgc gcggaacccc 5520 tatttgttta tttttctaaa tacattcaaa tatgtatccg ctcatgagac aataaccctg 5580 ataaatgctt caataatatt gaaaaaggaa gagtatgagt attcaacatt tccgtgtcgc 5640 ccttattccc ttttttgcgg cattttgcct tcctgttttt gctcacccag aaacgctggt 5700 gaaagtaaaa gatgctgaag atcagttggg tgcacgagtg ggttacatcg aactggatct 5760 caacagcggt aagatccttg agagttttcg ccccgaagaa cgttttccaa tgatgagcac 5820 ttttaaagtt ctgctatgtg gcgcggtatt atcccgtatt gacgccgggc aagagcaact 5880 cggtcgccgc atacactatt ctcagaatga cttggttgag tactcaccag tcacagaaaa 5940 gcatcttacg gatggcatga cagtaagaga attatgcagt gctgccataa ccatgagtga 6000 taacactgcg gccaacttac ttctgacaac gatcggagga ccgaaggagc taaccgcttt 6060 tttgcacaac atgggggatc atgtaactcg ccttgatcgt tgggaaccgg agctgaatga 6120 agccatacca aacgacgagc gtgacaccac gatgcctgta gcaatggcaa caacgttgcg 6180 caaactatta actggcgaac tacttactct agcttcccgg caacaattaa tagactggat 6240 ggaggcggat aaagttgcag gaccacttct gcgctcggcc cttccggctg gctggtttat 6300 tgctgataaa tctggagccg gtgagcgtgg gtctcgcggt atcattg 6347 <210> 63 <211> 6347 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 63 cagcactggg gccagatggt aagccctccc gtatcgtagt tatctacacg acggggagtc 60 aggcaactat ggatgaacga aatagacaga tcgctgagat aggtgcctca ctgattaagc 120 attggtaact gtcagaccaa gtttactcat atatacttta gattgattta aaacttcatt 180 tttaatttaa aaggatctag gtgaagatcc tttttgataa tctcatgacc aaaatccctt 240 aacgtgagtt ttcgttccac tgagcgtcag accccgtaga aaagatcaaa ggatcttctt 300 gagatccttt ttttctgcgc gtaatctgct gcttgcaaac aaaaaaacca ccgctaccag 360 cggtggtttg tttgccggat caagagctac caactctttt tccgaaggta actggcttca 420 gcagagcgca gataccaaat actgtccttc tagtgtagcc gtagttaggc caccacttca 480 agaactctgt agcaccgcct acatacctcg ctctgctaat cctgttacca gtggctgctg 540 ccagtggcga taagtcgtgt cttaccgggt tggactcaag acgatagtta ccggataagg 600 cgcagcggtc gggctgaacg gggggttcgt gcacacagcc cagcttggag cgaacgacct 660 acaccgaact gagataccta cagcgtgagc tatgagaaag cgccacgctt cccgaaggga 720 gaaaggcgga caggtatccg gtaagcggca gggtcggaac aggagagcgc acgagggagc 780 ttccaggggg aaacgcctgg tatctttata gtcctgtcgg gtttcgccac ctctgacttg 840 agcgtcgatt tttgtgatgc tcgtcagggg ggcggagcct atggaaaaac gccagcaacg 900 cggccttttt acggttcctg gccttttgct ggccttttgc tcacatgtcc tgcaggcagc 960 tgcgcgctcg ctcgctcact gaggccgccc gggcaaagcc cgggcgtcgg gcgacctttg 1020 gtcgcccggc ctcagtgagc gagcgagcgc gcagagaggg agtggccaac tccatcacta 1080 ggggttcctg cggccgcacg cgtttaatta agacctcgaa ggggacttgg ggggttcggg 1140 gctttcgggg gcggtcgggg gttcgcggac ccgggaagct ctgaggaccc agaggccggg 1200 cgcgctccgc ccgcggcgcc gccccctccg taactttccc agtctccgag ggaagaggcg 1260 gggtgtgggg tgcggttaaa aggcgccacg gcgggagaca ggtgttgcgg ccccgcagcg 1320 cccgcgcgct cctctccccg actcggagcc cctcggcggc gcccggccca ggacccgcct 1380 aggagcgcag gagccccagc gcagagaccc caacgccgag acccccgccc cggccccgcc 1440 gcgcttcctc ccgacgcaga gcaaaccgcc cagagtagaa gcggatccgc caccatggat 1500 tggggcacgc tgcagacgat cctggggggt gtgaacaaac actccaccag cattggaaag 1560 atctggctca ccgtcctctt catttttcgc attatgatcc tcgttgtggc tgcaaaggag 1620 gtgtggggag atgagcaggc cgactttgtc tgcaacaccc tgcagccagg ctgcaagaac 1680 gtgtgctacg atcactactt ccccatctcc cacatccggc tatgggccct gcagctgatc 1740 ttcgtgtcca cgccagcgct cctagtggcc atgcacgtgg cctaccggag acatgagaag 1800 aagaggaagt tcatcaaggg ggagataaag agtgaattta aggacatcga ggagatcaaa 1860 acccagaagg tccgcatcga aggctccctg tggtggacct acacaagcag catcttcttc 1920 cgggtcatct tcgaagccgc cttcatgtac gtcttctatg tcatgtacga cggcttctcc 1980 atgcagcggc tggtgaagtg caacgcctgg ccttgtccca acactgtgga ctgctttgtg 2040 tcccggccca cggagaagac tgtcttcaca gtgttcatga ttgcagtgtc tggaatttgc 2100 atcctgctga atgtcactga attgtgttat ttgctaatta gatattgttc tgggaagtca 2160 aaaaagccag tttaaggcgc gccacccctg cagggaattc cgcattgccc agttgttaga 2220 ttaagaaata gacagcatga gagggatgag gcaacccgtg ctcagctgtc aaggctcagt 2280 cgctagcatt tcccaacaca aagattctga ccttaaatgc aaccatttga aacccctgta 2340 ggcctcaggt gaaactccag atgccacaat ggagctctgc tcccctaaag cctcaaaaca 2400 aaggcctaat tctatgcctg tcttaatttt ctttcactta agttagttcc actgagaccc 2460 caggctgtta ggggttattg gtgtaaggta ctttcatatt ttaaacagag gatatcggca 2520 tttgtttctt tctctgagga caagagaaaa aagccaggtt ccacagagga cacagagaag 2580 gtttgggtgt cctcctgggg ttctttttgc caactttccc cacgttaaag gtgaacattg 2640 gttctttcat ttgctttgga agttttaatc tctaacagtg gacaaagtta ccagtgcctt 2700 aaactctgtt acactttttg gaagtgaaaa ctttgtagta tgataggtta ttttgatgta 2760 aagatgttct ggataccatt atatgttccc cctgtttcag aggctcagat tgtaatatgt 2820 aaatggtatg tcattcgcta ctatgattta atttgaaata tggtcttttg gttatgaata 2880 ctttgcagca cagctgagag gctgtctgtt gtattcattg tggtcatagc acctaacaac 2940 attgtagcct caatcgagtg agacagacta gaagttccta gtgatggctt atgatagcaa 3000 atggcctcat gtcaaatatt tagatgtaat tttgtgtaag aaatacagac tggatgtacc 3060 accaactact acctgtaatg acaggcctgt ccaacacatc tcccttttcc atgactgtgg 3120 tagccagcat cggaaagaac gctgatttaa agaggtcgct tgggaatttt attgacacag 3180 taccatttaa tggggaggac aaaatggggc aggggaggga gaagtttctg tcgttaaaaa 3240 cagatttgga aagactggac tctaaagtct gttgattaaa gatgagcttt gtctacttca 3300 aaagtttgtt tgcttacccc ttcagcctcc aattttttaa gtgaaaatat agctaataac 3360 atgtgaaaag aatagaagct aaggtttaga taaatattga gcagatctat aggaagattg 3420 aacctgaata ttgccattat gcttgacatg gtttccaaaa aatggtactc cacatatttc 3480 agtgagggta agtattttcc tgttgtcaag aatagcattg taaaagcatt ttgtaataat 3540 aaagaatagc tttaatgata tgcttgtaac taaaataatt ttgtaatgta tcaaatacat 3600 ttaaaacatt aaaatataat ctctataata atttaaaatc taatatggtt ttaatagaac 3660 agcgatatca agcttatcga taatcaacct ctggattaca aaatttgtga aagattgact 3720 ggtattctta actatgttgc tccttttacg ctatgtggat acgctgcttt aatgcctttg 3780 tatcatgcta ttgcttcccg tatggctttc attttctcct ccttgtataa atcctggttg 3840 ctgtctcttt atgaggagtt gtggcccgtt gtcaggcaac gtggcgtggt gtgcactgtg 3900 tttgctgacg caacccccac tggttggggc attgccacca cctgtcagct cctttccggg 3960 actttcgctt tccccctccc tattgccacg gcggaactca tcgccgcctg ccttgcccgc 4020 tgctggacag gggctcggct gttgggcact gacaattccg tggtgttgtc ggggaaatca 4080 tcgtcctttc cttggctgct cgcctatgtt gccacctgga ttctgcgcgg gacgtccttc 4140 tgctacgtcc cttcggccct caatccagcg gaccttcctt cccgcggcct gctgccggct 4200 ctgcggcctc ttccgcgtct tcgccttcgc cctcagacga gtcggatctc cctttgggcc 4260 gcctccccgc gaattcatcg ataccgagcg ctgctcgaga gatctgtgat agcggccatc 4320 aagctggctg tgccttctag ttgccagcca tctgttgttt gcccctcccc cgtgccttcc 4380 ttgaccctgg aaggtgccac tcccactgtc ctttcctaat aaaatgagga aattgcatcg 4440 cattgtctga gtaggtgtca ttctattctg gggggtgggg tggggcagga cagcaagggg 4500 gaggattggg aagacaatag caggcatgct ggggacacgt gcggaccgag cggccgcagg 4560 aacccctagt gatggagttg gccactccct ctctgcgcgc tcgctcgctc actgaggccg 4620 ggcgaccaaa ggtcgcccga cgcccgggct ttgcccgggc ggcctcagtg agcgagcgag 4680 cgcgcagctg cctgcagggg cgcctgatgc ggtattttct ccttacgcat ctgtgcggta 4740 tttcacaccg catacgtcaa agcaaccata gtacgcgccc tgtagcggcg cattaagcgc 4800 ggcgggtgtg gtggttacgc gcagcgtgac cgctacactt gccagcgccc tagcgcccgc 4860 tcctttcgct ttcttccctt cctttctcgc cacgttcgcc ggctttcccc gtcaagctct 4920 aaatcggggg ctccctttag ggttccgatt tagtgcttta cggcacctcg accccaaaaa 4980 acttgatttg ggtgatggtt cacgtagtgg gccatcgccc tgatagacgg tttttcgccc 5040 tttgacgttg gagtccacgt tctttaatag tggactcttg ttccaaactg gaacaacact 5100 caaccctatc tcgggctatt cttttgattt ataagggatt ttgccgattt cggcctattg 5160 gttaaaaaat gagctgattt aacaaaaatt taacgcgaat tttaacaaaa tattaacgtt 5220 tacaatttta tggtgcactc tcagtacaat ctgctctgat gccgcatagt taagccagcc 5280 ccgaccccg ccaacacccg ctgacgcgcc ctgacgggct tgtctgctcc cggcatccgc 5340 ttacagacaa gctgtgaccg tctccgggag ctgcatgtgt cagaggtttt caccgtcatc 5400 accgaaacgc gcgagacgaa agggcctcgt gatacgccta tttttatagg ttaatgtcat 5460 gataataatg gtttcttaga cgtcaggtgg cacttttcgg ggaaatgtgc gcggaacccc 5520 tatttgttta tttttctaaa tacattcaaa tatgtatccg ctcatgagac aataaccctg 5580 ataaatgctt caataatatt gaaaaaggaa gagtatgagt attcaacatt tccgtgtcgc 5640 ccttattccc ttttttgcgg cattttgcct tcctgttttt gctcacccag aaacgctggt 5700 gaaagtaaaa gatgctgaag atcagttggg tgcacgagtg ggttacatcg aactggatct 5760 caacagcggt aagatccttg agagttttcg ccccgaagaa cgttttccaa tgatgagcac 5820 ttttaaagtt ctgctatgtg gcgcggtatt atcccgtatt gacgccgggc aagagcaact 5880 cggtcgccgc atacactatt ctcagaatga cttggttgag tactcaccag tcacagaaaa 5940 gcatcttacg gatggcatga cagtaagaga attatgcagt gctgccataa ccatgagtga 6000 taacactgcg gccaacttac ttctgacaac gatcggagga ccgaaggagc taaccgcttt 6060 tttgcacaac atgggggatc atgtaactcg ccttgatcgt tgggaaccgg agctgaatga 6120 agccatacca aacgacgagc gtgacaccac gatgcctgta gcaatggcaa caacgttgcg 6180 caaactatta actggcgaac tacttactct agcttcccgg caacaattaa tagactggat 6240 ggaggcggat aaagttgcag gaccacttct gcgctcggcc cttccggctg gctggtttat 6300 tgctgataaa tctggagccg gtgagcgtgg gtctcgcggt atcattg 6347 <210> 64 <211> 7150 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 64 cgatgcctgt agcaatggca acaacgttgc gcaaactatt aactggcgaa ctacttactc 60 tagcttcccg gcaacaatta atagactgga tggaggcgga taaagttgca ggaccacttc 120 tgcgctcggc ccttccggct ggctggttta ttgctgataa atctggagcc ggtgagcgtg 180 ggtctcgcgg tatcattgca gcactggggc cagatggtaa gccctcccgt atcgtagtta 240 tctacacgac ggggagtcag gcaactatgg atgaacgaaa tagacagatc gctgagatag 300 gtgcctcact gattaagcat tggtaactgt cagaccaagt ttactcatat atactttaga 360 ttgatttaaa acttcatttt taatttaaaa ggatctaggt gaagatcctt tttgataatc 420 tcatgaccaa aatcccttaa cgtgagtttt cgttccactg agcgtcagac cccgtagaaa 480 agatcaaagg atcttcttga gatccttttt ttctgcgcgt aatctgctgc ttgcaaacaa 540 aaaaaccacc gctaccagcg gtggtttgtt tgccggatca agagctacca actctttttc 600 cgaaggtaac tggcttcagc agagcgcaga taccaaatac tgtccttcta gtgtagccgt 660 agttaggcca ccacttcaag aactctgtag caccgcctac atacctcgct ctgctaatcc 720 tgttaccagt ggctgctgcc agtggcgata agtcgtgtct taccgggttg gactcaagac 780 gatagttacc ggataaggcg cagcggtcgg gctgaacggg gggttcgtgc acacagccca 840 gcttggagcg aacgacctac accgaactga gatacctaca gcgtgagcta tgagaaagcg 900 ccacgcttcc cgaagggaga aaggcggaca ggtatccggt aagcggcagg gtcggaacag 960 gagagcgcac gagggagctt ccagggggaa acgcctggta tctttatagt cctgtcgggt 1020 ttcgccacct ctgacttgag cgtcgatttt tgtgatgctc gtcagggggg cggagcctat 1080 ggaaaaacgc cagcaacgcg gcctttttac ggttcctggc cttttgctgg ccttttgctc 1140 acatgtcctg caggcagctg cgcgctcgct cgctcactga ggccgcccgg gcaaagcccg 1200 ggcgtcgggc gacctttggt cgcccggcct cagtgagcga gcgagcgcgc agagaggag 1260 tggccaactc catcactagg ggttcctgcg gccgcacgcg taagagagca cttgggaaga 1320 gccccccgagg gcagccgggg cttgccgcct cacccttttg gtttcacatc ccagaaatca 1380 gtaaggcagg aattggaggc tgcttcttgc cttagcaact cggtgacctt aggcagaaca 1440 gttcagcctt ctgagtgtcc ttcctcttct gtaaggggag cgtaaaccgt cctccatgca 1500 gaacgtgtac tgtgcctggc acagcactgg ggcattagga tctccaaatt aaaggctcac 1560 tctgcgggat ggaggcagcc acagctggaa gaaggaacat ttggggccag aagtccccct 1620 acctccgtcc taagagagaa gatgggaata acgaccctcg ctgaaatgat tgctctctgg 1680 ccagctcgcc tcgcatccac atccaaatct gggaggcaca gagcgcatca ggacatcggg 1740 ttctgtcagt gtaatgggcg tggctcctga ccttctgtct gtatcagaga agataaggga 1800 gaacatttga aagaaaggag aaagaagata gccactggag aacagagcaa aggagccagc 1860 agaaaaagac gagacggctg tagccccaca ggaagcagaa accgataggc taagtaggat 1920 acacacaaag aaaagtagat cccgagaggc atttccccga gggctttcat gtggtttctc 1980 gtgaggagaa gctgactgca gggtgtttga aagaacgact tatgcagcca taaaaaatga 2040 tgagttcatg tcctttgtag ggacatggat gattaattaa gacctcgaag gggacttggg 2100 gggttcgggg ctttcggggg cggtcggggg ttcgcggacc cgggaagctc tgaggaccca 2160 gaggccgggc gcgctccgcc cgcggcgccg ccccctccgt aactttccca gtctccgagg 2220 gaagaggcgg ggtgtggggt gcggttaaaa ggcgccacgg cgggagacag gtgttgcggc 2280 cccgcagcgc ccgcgcgctc ctctccccga ctcggagccc ctcggcggcg cccggcccag 2340 gacccgccta ggagcgcagg agccccagcg cagagacccc aacgccgaga cccccgcccc 2400 ggccccgccg cgcttcctcc cgacgcagag caaaccgccc agagtagaag ccatggtgag 2460 caagggcgag gagctgttca ccggggtggt gcccatcctg gtcgagctgg acggcgacgt 2520 aaacggccac aagttcagcg tgtccggcga gggcgagggc gatgccacct acggcaagct 2580 gaccctgaag ttcatctgca ccaccggcaa gctgccccgtg ccctggccca ccctcgtgac 2640 caccctgacc tacggcgtgc agtgcttcag ccgctacccc gaccacatga agcagcacga 2700 cttcttcaag tccgccatgc ccgaaggcta cgtccaggag cgcaccatct tcttcaagga 2760 cgacggcaac tacaagaccc gcgccgaggt gaagttcgag ggcgacaccc tggtgaaccg 2820 catcgagctg aagggcatcg acttcaagga ggacggcaac atcctggggc acaagctgga 2880 gtacaactac aacagccaca acgtctatat catggccgac aagcagaaga acggcatcaa 2940 ggtgaacttc aagatccgcc acaacatcga ggacggcagc gtgcagctcg ccgaccacta 3000 ccagcagaac acccccatcg gcgacggccc cgtgctgctg cccgacaacc actacctgag 3060 cacccagtcc gccctgagca aagaccccaa cgagaagcgc gatcacatgg tcctgctgga 3120 gttcgtgacc gccgccggga tcactctcgg catggacgag ctgtacaagt aataaaggcg 3180 cgccacccct gcagggaatt ccgcattgcc cagttgttag attaagaaat agacagcatg 3240 agagggatga ggcaacccgt gctcagctgt caaggctcag tcgctagcat ttcccaacac 3300 aaagattctg accttaaatg caaccatttg aaacccctgt aggcctcagg tgaaactcca 3360 gatgccacaa tggagctctg ctcccctaaa gcctcaaaac aaaggcctaa ttctatgcct 3420 gtcttaattt tctttcactt aagttagttc cactgagacc ccaggctgtt aggggttatt 3480 ggtgtaaggt actttcatat tttaaacaga ggatatcggc atttgtttct ttctctgagg 3540 acaagagaaa aaagccaggt tccacagagg acacagagaa ggtttgggtg tcctcctggg 3600 gttctttttg ccaactttcc ccacgttaaa ggtgaacatt ggttctttca tttgctttgg 3660 aagttttaat ctctaacagt ggacaaagtt accagtgcct taaactctgt taacacttttt 3720 ggaagtgaaa actttgtagt atgataggtt attttgatgt aaagatgttc tggataccat 3780 tatatgttcc ccctgtttca gaggctcaga ttgtaatatg taaatggtat gtcattcgct 3840 actatgattt aatttgaaat atggtctttt ggttatgaat actttgcagc acagctgaga 3900 ggctgtctgt tgtattcatt gtggtcatag cacctaacaa cattgtagcc tcaatcgagt 3960 gagacagact agaagttcct agtgatggct tatgatagca aatggcctca tgtcaaatat 4020 ttagatgtaa ttttgtgtaa gaaatacaga ctggatgtac caccaactac tacctgtaat 4080 gacaggcctg tccaacacat ctcccttttc catgactgtg gtagccagca tcggaaagaa 4140 cgctgattta aagaggtcgc ttgggaattt tattgacaca gtaccattta atggggagga 4200 caaaatgggg caggggaggg agaagtttct gtcgttaaaa acagatttgg aaagactgga 4260 ctctaaagtc tgttgattaa agatgagctt tgtctacttc aaaagtttgt ttgcttaccc 4320 cttcagcctc caatttttta agtgaaaata tagctaataa catgtgaaaa gaatagaagc 4380 taaggtttag ataaatattg agcagatcta taggaagatt gaacctgaat attgccatta 4440 tgcttgacat ggtttccaaa aaatggtact ccacatattt cagtgagggt aagtattttc 4500 ctgttgtcaa gaatagcatt gtaaaagcat tttgtaataa taaagaatag ctttaatgat 4560 atgcttgtaa ctaaaataat tttgtaatgt atcaaataca tttaaaacat taaaatataa 4620 tctctataat aatttaaaat ctaatatggt tttaatagaa cagcgatatc aagcttatcg 4680 ataatcaacc tctggattac aaaatttgtg aaagattgac tggtattctt aactatgttg 4740 ctccttttac gctatgtgga tacgctgctt taatgccttt gtatcatgct attgcttccc 4800 gtatggcttt cattttctcc tccttgtata aatcctggtt gctgtctctt tatgaggagt 4860 tgtggcccgt tgtcaggcaa cgtggcgtgg tgtgcactgt gtttgctgac gcaaccccca 4920 ctggttgggg cattgccacc acctgtcagc tcctttccgg gactttcgct ttccccctcc 4980 ctattgccac ggcggaactc atcgccgcct gccttgcccg ctgctggaca ggggctcggc 5040 tgttgggcac tgacaattcc gtggtgttgt cggggaaatc atcgtccttt ccttggctgc 5100 tcgcctatgt tgccacctgg attctgcgcg ggacgtcctt ctgctacgtc ccttcggccc 5160 tcaatccagc ggaccttcct tcccgcggcc tgctgccggc tctgcggcct cttccgcgtc 5220 ttcgccttcg ccctcagacg agtcggatct ccctttgggc cgcctccccg cgaattcatc 5280 gataccgagc gctgctcgag agatctgtga tagcggccat caagctggct gtgccttcta 5340 gttgccagcc atctgttgtt tgcccctccc ccgtgccttc cttgaccctg gaaggtgcca 5400 ctcccactgt cctttcctaa taaaatgagg aaattgcatc gcattgtctg agtaggtgtc 5460 attctattct ggggggtggg gtggggcagg acagcaaggg ggaggattgg gaagacaata 5520 gcaggcatgc tggggacacg tgcggaccga gcggccgcag gaacccctag tgatggagtt 5580 ggccactccc tctctgcgcg ctcgctcgct cactgaggcc gggcgaccaa aggtcgcccg 5640 acgcccgggc tttgcccggg cggcctcagt gagcgagcga gcgcgcagct gcctgcaggg 5700 gcgcctgatg cggtattttc tccttacgca tctgtgcggt atttcacacc gcatacgtca 5760 aagcaaccat agtacgcgcc ctgtagcggc gcattaagcg cggcgggtgt ggtggttacg 5820 cgcagcgtga ccgctacact tgccagcgcc ctagcgcccg ctcctttcgc tttcttccct 5880 tcctttctcg ccacgttcgc cggctttccc cgtcaagctc taaatcgggg gctcccttta 5940 gggttccgat ttagtgcttt acggcacctc gaccccaaaa aacttgattt gggtgatggt 6000 tcacgtagtg ggccatcgcc ctgatagacg gtttttcgcc ctttgacgtt ggagtccacg 6060 ttctttaata gtggactctt gttccaaact ggaacaacac tcaaccctat ctcgggctat 6120 tcttttgatt tataagggat tttgccgatt tcggcctatt ggttaaaaaa tgagctgatt 6180 taacaaaaat ttaacgcgaa ttttaacaaa atattaacgt ttacaatttt atggtgcact 6240 ctcagtacaa tctgctctga tgccgcatag ttaagccagc cccgacaccc gccaacaccc 6300 gctgacgcgc cctgacgggc ttgtctgctc ccggcatccg cttacagaca agctgtgacc 6360 gtctccggga gctgcatgtg tcagaggttt tcaccgtcat caccgaaacg cgcgagacga 6420 aagggcctcg tgatacgcct atttttatag gttaatgtca tgataataat ggtttcttag 6480 acgtcaggtg gcacttttcg gggaaatgtg cgcggaaccc ctatttgttt atttttctaa 6540 atacattcaa atatgtatcc gctcatgaga caataaccct gataaatgct tcaataatat 6600 tgaaaaagga agagtatgag tattcaacat ttccgtgtcg cccttattcc cttttttgcg 6660 gcattttgcc ttcctgtttt tgctcaccca gaaacgctgg tgaaagtaaa agatgctgaa 6720 gatcagttgg gtgcacgagt gggttacatc gaactggatc tcaacagcgg taagatcctt 6780 gagagttttc gccccgaaga acgttttcca atgatgagca cttttaaagt tctgctatgt 6840 ggcgcggtat tatcccgtat tgacgccggg caagagcaac tcggtcgccg catacactat 6900 tctcagaatg acttggttga gtactcacca gtcacagaaa agcatcttac ggatggcatg 6960 acagtaagag aattatgcag tgctgccata accatgagtg ataacactgc ggccaactta 7020 cttctgacaa cgatcggagg accgaaggag ctaaccgctt ttttgcacaa catgggggat 7080 catgtaactc gccttgatcg ttgggaaccg gagctgaatg aagccatacc aaacgacgag 7140 cgtgacacca 7150 <210> 65 <211> 7108 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 65 cgatgcctgt agcaatggca acaacgttgc gcaaactatt aactggcgaa ctacttactc 60 tagcttcccg gcaacaatta atagactgga tggaggcgga taaagttgca ggaccacttc 120 tgcgctcggc ccttccggct ggctggttta ttgctgataa atctggagcc ggtgagcgtg 180 ggtctcgcgg tatcattgca gcactggggc cagatggtaa gccctcccgt atcgtagtta 240 tctacacgac ggggagtcag gcaactatgg atgaacgaaa tagacagatc gctgagatag 300 gtgcctcact gattaagcat tggtaactgt cagaccaagt ttactcatat atactttaga 360 ttgatttaaa acttcatttt taatttaaaa ggatctaggt gaagatcctt tttgataatc 420 tcatgaccaa aatcccttaa cgtgagtttt cgttccactg agcgtcagac cccgtagaaa 480 agatcaaagg atcttcttga gatccttttt ttctgcgcgt aatctgctgc ttgcaaacaa 540 aaaaaccacc gctaccagcg gtggtttgtt tgccggatca agagctacca actctttttc 600 cgaaggtaac tggcttcagc agagcgcaga taccaaatac tgtccttcta gtgtagccgt 660 agttaggcca ccacttcaag aactctgtag caccgcctac atacctcgct ctgctaatcc 720 tgttaccagt ggctgctgcc agtggcgata agtcgtgtct taccgggttg gactcaagac 780 gatagttacc ggataaggcg cagcggtcgg gctgaacggg gggttcgtgc acacagccca 840 gcttggagcg aacgacctac accgaactga gatacctaca gcgtgagcta tgagaaagcg 900 ccacgcttcc cgaagggaga aaggcggaca ggtatccggt aagcggcagg gtcggaacag 960 gagagcgcac gagggagctt ccagggggaa acgcctggta tctttatagt cctgtcgggt 1020 ttcgccacct ctgacttgag cgtcgatttt tgtgatgctc gtcagggggg cggagcctat 1080 ggaaaaacgc cagcaacgcg gcctttttac ggttcctggc cttttgctgg ccttttgctc 1140 acatgtcctg caggcagctg cgcgctcgct cgctcactga ggccgcccgg gcaaagcccg 1200 ggcgtcgggc gacctttggt cgcccggcct cagtgagcga gcgagcgcgc agagaggag 1260 tggccaactc catcactagg ggttcctgcg gccgcacgcg taagagagca cttgggaaga 1320 gccccccgagg gcagccgggg cttgccgcct cacccttttg gtttcacatc ccagaaatca 1380 gtaaggcagg aattggaggc tgcttcttgc cttagcaact cggtgacctt aggcagaaca 1440 gttcagcctt ctgagtgtcc ttcctcttct gtaaggggag cgtaaaccgt cctccatgca 1500 gaacgtgtac tgtgcctggc acagcactgg ggcattagga tctccaaatt aaaggctcac 1560 tctgcgggat ggaggcagcc acagctggaa gaaggaacat ttggggccag aagtccccct 1620 acctccgtcc taagagagaa gatgggaata acgaccctcg ctgaaatgat tgctctctgg 1680 ccagctcgcc tcgcatccac atccaaatct gggaggcaca gagcgcatca ggacatcggg 1740 ttctgtcagt gtaatgggcg tggctcctga ccttctgtct gtatcagaga agataaggga 1800 gaacatttga aagaaaggag aaagaagata gccactggag aacagagcaa aggagccagc 1860 agaaaaagac gagacggctg tagccccaca ggaagcagaa accgataggc taagtaggat 1920 acacacaaag aaaagtagat cccgagaggc atttccccga gggctttcat gtggtttctc 1980 gtgaggagaa gctgactgca gggtgtttga aagaacgact tatgcagcca taaaaaatga 2040 tgagttcatg tcctttgtag ggacatggat gattaattaa gacctcgaag gggacttggg 2100 gggttcgggg ctttcggggg cggtcggggg ttcgcggacc cgggaagctc tgaggaccca 2160 gaggccgggc gcgctccgcc cgcggcgccg ccccctccgt aactttccca gtctccgagg 2220 gaagaggcgg ggtgtggggt gcggttaaaa ggcgccacgg cgggagacag gtgttgcggc 2280 cccgcagcgc ccgcgcgctc ctctccccga ctcggagccc ctcggcggcg cccggcccag 2340 gacccgccta ggagcgcagg agccccagcg cagagacccc aacgccgaga cccccgcccc 2400 ggccccgccg cgcttcctcc cgacgcagag caaaccgccc agagtagaag ccatggattg 2460 gggcacgctg cagacgatcc tggggggtgt gaacaaacac tccaccagca ttggaaagat 2520 ctggctcacc gtcctcttca tttttcgcat tatgatcctc gttgtggctg caaaggaggt 2580 gtggggagat gagcaggccg actttgtctg caacaccctg cagccaggct gcaagaacgt 2640 gtgctacgat cactacttcc ccatctccca catccggcta tgggccctgc agctgatctt 2700 cgtgtccacg ccagcgctcc tagtggccat gcacgtggcc taccggagac atgagaagaa 2760 gaggaagttc atcaaggggg agataaagag tgaatttaag gacatcgagg agatcaaaac 2820 ccagaaggtc cgcatcgaag gctccctgg gtggacctac acaagcagca tcttcttccg 2880 ggtcatcttc gaagccgcct tcatgtacgt cttctatgtc atgtacgacg gcttctccat 2940 gcagcggctg gtgaagtgca acgcctggcc ttgtcccaac actgtggact gctttgtgtc 3000 ccggcccacg gagaagactg tcttcacagt gttcatgatt gcagtgtctg gaatttgcat 3060 cctgctgaat gtcactgaat tgtgttattt gctaattaga tattgttctg ggaagtcaaa 3120 aaagccagtt taaaggcgcg ccacccctgc agggaattcc gcattgccca gttgttagat 3180 taagaaatag acagcatgag agggatgagg caacccgtgc tcagctgtca aggctcagtc 3240 gctagcattt cccaacacaa agattctgac cttaaatgca accatttgaa acccctgtag 3300 gcctcaggtg aaactccaga tgccacaatg gagctctgct cccctaaagc ctcaaaacaa 3360 aggcctaatt ctatgcctgt cttaattttc tttcacttaa gttagttcca ctgagacccc 3420 aggctgttag gggtattgg tgtaaggtac tttcatattt taaacagagg atatcggcat 3480 ttgtttcttt ctctgaggac aagagaaaaa agccaggttc cacagaggac acagagaagg 3540 tttgggtgtc ctcctggggt tctttttgcc aactttcccc acgttaaagg tgaacattgg 3600 ttctttcatt tgctttggaa gttttaatct ctaacagtgg acaaagttac cagtgcctta 3660 aactctgtta cactttttgg aagtgaaaac tttgtagtat gataggttat tttgatgtaa 3720 agatgttctg gataccatta tatgttcccc ctgtttcaga ggctcagatt gtaatatgta 3780 aatggtatgt cattcgctac tatgatttaa tttgaaatat ggtcttttgg ttatgaatac 3840 tttgcagcac agctgagagg ctgtctgttg tattcattgt ggtcatagca cctaacaaca 3900 ttgtagcctc aatcgagtga gacagactag aagttcctag tgatggctta tgatagcaaa 3960 tggcctcatg tcaaatattt agatgtaatt ttgtgtaaga aatacagact ggatgtacca 4020 ccaactacta cctgtaatga caggcctgtc caacacatct cccttttcca tgactgtggt 4080 agccagcatc ggaaagaacg ctgatttaaa gaggtcgctt gggaatttta ttgacacagt 4140 accatttaat ggggaggaca aaatggggca ggggagggag aagtttctgt cgttaaaaac 4200 agatttggaa agactggact ctaaagtctg ttgattaaag atgagctttg tctacttcaa 4260 aagtttgttt gcttacccct tcagcctcca attttttaag tgaaaatata gctaataaca 4320 tgtgaaaaga atagaagcta aggtttagat aaatattgag cagatctata ggaagattga 4380 acctgaatat tgccattatg cttgacatgg tttccaaaaa atggtactcc acatatttca 4440 gtgagggtaa gtattttcct gttgtcaaga atagcattgt aaaagcattt tgtaataata 4500 aagaatagct ttaatgatat gcttgtaact aaaataattt tgtaatgtat caaatacatt 4560 taaaacatta aaatataatc tctataataa tttaaaatct aatatggttt taatagaaca 4620 gcgatatcaa gcttatcgat aatcaacctc tggattacaa aatttgtgaa agattgactg 4680 gtattcttaa ctatgttgct ccttttacgc tatgtggata cgctgcttta atgcctttgt 4740 atcatgctat tgcttcccgt atggctttca ttttctcctc cttgtataaa tcctggttgc 4800 tgtctcttta tgaggagttg tggcccgttg tcaggcaacg tggcgtggtg tgcactgtgt 4860 ttgctgacgc aacccccact ggttggggca ttgccaccac ctgtcagctc ctttccggga 4920 ctttcgcttt ccccctccct attgccacgg cggaactcat cgccgcctgc cttgcccgct 4980 gctggacagg ggctcggctg ttgggcactg acaattccgt ggtgttgtcg gggaaatcat 5040 cgtcctttcc ttggctgctc gcctatgttg ccacctggat tctgcgcggg acgtccttct 5100 gctacgtccc ttcggccctc aatccagcgg accttccttc ccgcggcctg ctgccggctc 5160 tgcggcctct tccgcgtctt cgccttcgcc ctcagacgag tcggatctcc ctttgggccg 5220 cctccccgcg aattcatcga taccgagcgc tgctcgagag atctgtgata gcggccatca 5280 agctggctgt gccttctagt tgccagccat ctgttgtttg cccctccccc gtgccttcct 5340 tgaccctgga aggtgccact cccactgtcc tttcctaata aaatgaggaa attgcatcgc 5400 attgtctgag taggtgtcat tctattctgg ggggtggggt ggggcaggac agcaaggggg 5460 aggattggga agacaatagc aggcatgctg gggacacgtg cggaccgagc ggccgcagga 5520 acccctagtg atggagttgg ccactccctc tctgcgcgct cgctcgctca ctgaggccgg 5580 gcgaccaaag gtcgcccgac gcccgggctt tgcccgggcg gcctcagtga gcgagcgagc 5640 gcgcagctgc ctgcaggggc gcctgatgcg gtattttctc cttacgcatc tgtgcggtat 5700 ttcacaccgc atacgtcaaa gcaaccatag tacgcgccct gtagcggcgc attaagcgcg 5760 gcgggtgtgg tggttacgcg cagcgtgacc gctacacttg ccagcgccct agcgcccgct 5820 cctttcgctt tcttcccttc ctttctcgcc acgttcgccg gctttccccg tcaagctcta 5880 aatcgggggc tccctttagg gttccgattt agtgctttac ggcacctcga ccccaaaaaa 5940 cttgatttgg gtgatggttc acgtagtggg ccatcgccct gatagacggt ttttcgccct 6000 ttgacgttgg agtccacgtt ctttaatagt ggactcttgt tccaaactgg aacaacactc 6060 aaccctatct cgggctattc ttttgattta taagggattt tgccgatttc ggcctattgg 6120 ttaaaaaatg agctgattta acaaaaattt aacgcgaatt ttaacaaaat attaacgttt 6180 acaattttat ggtgcactct cagtacaatc tgctctgatg ccgcatagtt aagccagccc 6240 cgacacccgc caacacccgc tgacgcgccc tgacgggctt gtctgctccc ggcatccgct 6300 tacagacaag ctgtgaccgt ctccgggagc tgcatgtgtc agaggttttc accgtcatca 6360 ccgaaacgcg cgagacgaaa gggcctcgtg atacgcctat ttttataggt taatgtcatg 6420 ataataatgg tttcttagac gtcaggtggc acttttcggg gaaatgtgcg cggaacccct 6480 atttgtttat ttttctaaat acattcaaat atgtatccgc tcatgagaca ataaccctga 6540 taaatgcttc aataatattg aaaaaggaag agtatgagta ttcaacattt ccgtgtcgcc 6600 cttattccct tttttgcggc attttgcctt cctgtttttg ctcacccaga aacgctggtg 6660 aaagtaaaag atgctgaaga tcagttgggt gcacgagtgg gttacatcga actggatctc 6720 aacagcggta agatccttga gagttttcgc cccgaagaac gttttccaat gatgagcact 6780 tttaaagttc tgctatgtgg cgcggtatta tcccgtattg acgccgggca agagcaactc 6840 ggtcgccgca tacactattc tcagaatgac ttggttgagt actcaccagt cacagaaaag 6900 catcttacgg atggcatgac agtaagagaa ttatgcagtg ctgccataac catgagtgat 6960 aacactgcgg ccaacttact tctgacaacg atcggaggac cgaaggagct aaccgctttt 7020 ttgcacaaca tgggggatca tgtaactcgc cttgatcgtt gggaaccgga gctgaatgaa 7080 gccataccaa acgacgagcg tgacacca 7108 <210> 66 <211> 7135 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 66 cgatgcctgt agcaatggca acaacgttgc gcaaactatt aactggcgaa ctacttactc 60 tagcttcccg gcaacaatta atagactgga tggaggcgga taaagttgca ggaccacttc 120 tgcgctcggc ccttccggct ggctggttta ttgctgataa atctggagcc ggtgagcgtg 180 ggtctcgcgg tatcattgca gcactggggc cagatggtaa gccctcccgt atcgtagtta 240 tctacacgac ggggagtcag gcaactatgg atgaacgaaa tagacagatc gctgagatag 300 gtgcctcact gattaagcat tggtaactgt cagaccaagt ttactcatat atactttaga 360 ttgatttaaa acttcatttt taatttaaaa ggatctaggt gaagatcctt tttgataatc 420 tcatgaccaa aatcccttaa cgtgagtttt cgttccactg agcgtcagac cccgtagaaa 480 agatcaaagg atcttcttga gatccttttt ttctgcgcgt aatctgctgc ttgcaaacaa 540 aaaaaccacc gctaccagcg gtggtttgtt tgccggatca agagctacca actctttttc 600 cgaaggtaac tggcttcagc agagcgcaga taccaaatac tgtccttcta gtgtagccgt 660 agttaggcca ccacttcaag aactctgtag caccgcctac atacctcgct ctgctaatcc 720 tgttaccagt ggctgctgcc agtggcgata agtcgtgtct taccgggttg gactcaagac 780 gatagttacc ggataaggcg cagcggtcgg gctgaacggg gggttcgtgc acacagccca 840 gcttggagcg aacgacctac accgaactga gatacctaca gcgtgagcta tgagaaagcg 900 ccacgcttcc cgaagggaga aaggcggaca ggtatccggt aagcggcagg gtcggaacag 960 gagagcgcac gagggagctt ccagggggaa acgcctggta tctttatagt cctgtcgggt 1020 ttcgccacct ctgacttgag cgtcgatttt tgtgatgctc gtcagggggg cggagcctat 1080 ggaaaaacgc cagcaacgcg gcctttttac ggttcctggc cttttgctgg ccttttgctc 1140 acatgtcctg caggcagctg cgcgctcgct cgctcactga ggccgcccgg gcaaagcccg 1200 ggcgtcgggc gacctttggt cgcccggcct cagtgagcga gcgagcgcgc agagaggag 1260 tggccaactc catcactagg ggttcctgcg gccgcacgcg taagagagca cttgggaaga 1320 gccccccgagg gcagccgggg cttgccgcct cacccttttg gtttcacatc ccagaaatca 1380 gtaaggcagg aattggaggc tgcttcttgc cttagcaact cggtgacctt aggcagaaca 1440 gttcagcctt ctgagtgtcc ttcctcttct gtaaggggag cgtaaaccgt cctccatgca 1500 gaacgtgtac tgtgcctggc acagcactgg ggcattagga tctccaaatt aaaggctcac 1560 tctgcgggat ggaggcagcc acagctggaa gaaggaacat ttggggccag aagtccccct 1620 acctccgtcc taagagagaa gatgggaata acgaccctcg ctgaaatgat tgctctctgg 1680 ccagctcgcc tcgcatccac atccaaatct gggaggcaca gagcgcatca ggacatcggg 1740 ttctgtcagt gtaatgggcg tggctcctga ccttctgtct gtatcagaga agataaggga 1800 gaacatttga aagaaaggag aaagaagata gccactggag aacagagcaa aggagccagc 1860 agaaaaagac gagacggctg tagccccaca ggaagcagaa accgataggc taagtaggat 1920 acacacaaag aaaagtagat cccgagaggc atttccccga gggctttcat gtggtttctc 1980 gtgaggagaa gctgactgca gggtgtttga aagaacgact tatgcagcca taaaaaatga 2040 tgagttcatg tcctttgtag ggacatggat gattaattaa gacctcgaag gggacttggg 2100 gggttcgggg ctttcggggg cggtcggggg ttcgcggacc cgggaagctc tgaggaccca 2160 gaggccgggc gcgctccgcc cgcggcgccg ccccctccgt aactttccca gtctccgagg 2220 gaagaggcgg ggtgtggggt gcggttaaaa ggcgccacgg cgggagacag gtgttgcggc 2280 cccgcagcgc ccgcgcgctc ctctccccga ctcggagccc ctcggcggcg cccggcccag 2340 gacccgccta ggagcgcagg agccccagcg cagagacccc aacgccgaga cccccgcccc 2400 ggccccgccg cgcttcctcc cgacgcagag caaaccgccc agagtagaag ccatggattg 2460 gggcacactc cagagcatcc tcgggggtgt caacaaacac tccaccagca ttggaaagat 2520 ctggctcacg gtcctcttca tcttccgcat catgatcctc gtggtggctg caaaggaggt 2580 gtggggagat gagcaagccg attttgtctg caacacgctc cagcctggct gcaagaatgt 2640 atgctacgac caccacttcc ccatctctca catccggctc tgggctctgc agctgatcat 2700 ggtgtccacg ccagccctcc tggtagctat gcatgtggcc taccggagac atgaaaagaa 2760 acggaagttc atgaagggag agataaagaa cgagtttaag gacatcgaag agatcaaaac 2820 ccagaaggtc cgtatcgaag ggtccctgg gtggacctac accaccagca tcttcttccg 2880 ggtcatcttt gaagccgtct tcatgtacgt cttttacatc atgtacaatg gcttcttcat 2940 gcaacgtctg gtgaaatgca acgcttggcc ctgccccaat acagtggact gcttcatttc 3000 caggcccaca gaaaagactg tcttcaccgt gtttatgatt tctgtgtctg gaatttgcat 3060 tctgctaaat atcacagagc tgtgctattt gttcgttagg tattgctcag gaaagtccaa 3120 aagaccagtc tacccatacg atgttccaga ttacgcttaa aggcgcgcca cccctgcagg 3180 gaattccgca ttgcccagtt gttagattaa gaaatagaca gcatgagagg gatgaggcaa 3240 cccgtgctca gctgtcaagg ctcagtcgct agcatttccc aacacaaaga ttctgacctt 3300 aaatgcaacc atttgaaacc cctgtaggcc tcaggtgaaa ctccagatgc cacaatggag 3360 ctctgctccc ctaaagcctc aaaacaaagg cctaattcta tgcctgtctt aattttcttt 3420 cacttaagtt agttccactg agaccccagg ctgttagggg ttattggtgt aaggtacttt 3480 catattttaa acagaggata tcggcatttg tttctttctc tgaggacaag agaaaaaagc 3540 caggttccac agaggacaca gagaaggttt gggtgtcctc ctggggttct ttttgccaac 3600 tttccccacg ttaaaggtga acattggttc tttcatttgc tttggaagtt ttaatctcta 3660 acagtggaca aagttaccag tgccttaaac tctgttacac tttttggaag tgaaaacttt 3720 gtagtatgat aggttatttt gatgtaaaga tgttctggat accattatat gttccccctg 3780 tttcagaggc tcagattgta atatgtaaat ggtatgtcat tcgctactat gatttaattt 3840 gaaatatggt cttttggtta tgaatacttt gcagcacagc tgagaggctg tctgttgtat 3900 tcattgtggt catagcacct aacaacattg tagcctcaat cgagtgagac agactagaag 3960 ttcctagtga tggcttatga tagcaaatgg cctcatgtca aatatttaga tgtaattttg 4020 tgtaagaaat acagactgga tgtaccacca actactacct gtaatgacag gcctgtccaa 4080 cacatctccc ttttccatga ctgtggtagc cagcatcgga aagaacgctg atttaaagag 4140 gtcgcttggg aatttattg acacagtacc atttaatggg gaggacaaaa tggggcaggg 4200 gagggagaag tttctgtcgt taaaaacaga tttggaaaga ctggactcta aagtctgttg 4260 attaaagatg agctttgtct acttcaaaag tttgtttgct taccccttca gcctccaatt 4320 ttttaagtga aaatatagct aataacatgt gaaaagaata gaagctaagg tttagataaa 4380 tattgagcag atctatagga agattgaacc tgaatattgc cattatgctt gacatggttt 4440 ccaaaaaatg gtactccaca tatttcagtg agggtaagta ttttcctgtt gtcaagaata 4500 gcattgtaaa agcattttgt aataataaag aatagcttta atgatatgct tgtaactaaa 4560 ataattttgt aatgtatcaa atacatttaa aacattaaaa tataatctct ataataattt 4620 aaaatctaat atggttttaa tagaacagcg atatcaagct tatcgataat caacctctgg 4680 attacaaaat ttgtgaaaga ttgactggta ttcttaacta tgttgctcct tttacgctat 4740 gtggatacgc tgctttaatg cctttgtatc atgctattgc ttcccgtatg gctttcattt 4800 tctcctcctt gtataaatcc tggttgctgt ctctttatga ggagttgtgg cccgttgtca 4860 ggcaacgtgg cgtggtgtgc actgtgtttg ctgacgcaac ccccactggt tggggcattg 4920 ccaccacctg tcagctcctt tccgggactt tcgctttccc cctccctatt gccacggcgg 4980 aactcatcgc cgcctgcctt gcccgctgct ggacaggggc tcggctgttg ggcactgaca 5040 attccgtggt gttgtcgggg aaatcatcgt cctttccttg gctgctcgcc tatgttgcca 5100 cctggattct gcgcgggacg tccttctgct acgtcccttc ggccctcaat ccagcggacc 5160 ttccttcccg cggcctgctg ccggctctgc ggcctcttcc gcgtcttcgc cttcgccctc 5220 agacgagtcg gatctccctt tgggccgcct ccccgcgaat tcatcgatac cgagcgctgc 5280 tcgagagatc tgtgatagcg gccatcaagc tggctgtgcc ttctagttgc cagccatctg 5340 ttgtttgccc ctccccccgtg ccttccttga ccctggaagg tgccactccc actgtccttt 5400 cctaataaaa tgaggaaatt gcatcgcatt gtctgagtag gtgtcattct attctggggg 5460 gtggggtggg gcaggacagc aagggggagg attgggaaga caatagcagg catgctgggg 5520 acacgtgcgg accgagcggc cgcaggaacc cctagtgatg gagttggcca ctccctctct 5580 gcgcgctcgc tcgctcactg aggccgggcg accaaaggtc gcccgacgcc cgggctttgc 5640 ccgggcggcc tcagtgagcg agcgagcgcg cagctgcctg caggggcgcc tgatgcggta 5700 ttttctcctt acgcatctgt gcggtatttc acaccgcata cgtcaaagca accatagtac 5760 gcgccctgta gcggcgcatt aagcgcggcg ggtgtggtgg ttacgcgcag cgtgaccgct 5820 acacttgcca gcgccctagc gcccgctcct ttcgctttct tcccttcctt tctcgccacg 5880 ttcgccggct ttccccgtca agctctaaat cgggggctcc ctttagggtt ccgatttagt 5940 gctttacggc acctcgaccc caaaaaactt gatttgggtg atggttcacg tagtggccca 6000 tcgccctgat agacggtttt tcgccctttg acgttggagt ccacgttctt taatagtgga 6060 ctcttgttcc aaactggaac aacactcaac cctatctcgg gctattcttt tgatttataa 6120 gggattttgc cgatttcggc ctattggtta aaaaatgagc tgatttaaca aaaatttaac 6180 gcgaatttta acaaaatatt aacgtttaca attttatggt gcactctcag tacaatctgc 6240 tctgatgccg catagttaag ccagccccga cacccgccaa cacccgctga cgcgccctga 6300 cgggcttgtc tgctcccggc atccgcttac agacaagctg tgaccgtctc cgggagctgc 6360 atgtgtcaga ggttttcacc gtcatcaccg aaacgcgcga gacgaaaggg cctcgtgata 6420 cgcctatttt tataggttaa tgtcatgata ataatggttt cttagacgtc aggtggcact 6480 tttcggggaa atgtgcgcgg aacccctatt tgtttatttt tctaaataca ttcaaatatg 6540 tatccgctca tgagacaata accctgataa atgcttcaat aatattgaaa aaggaagagt 6600 atgagtattc aacatttccg tgtcgccctt attccctttt ttgcggcatt ttgccttcct 6660 gtttttgctc acccagaaac gctggtgaaa gtaaaagatg ctgaagatca gttgggtgca 6720 cgagtgggtt acatcgaact ggatctcaac agcggtaaga tccttgagag ttttcgcccc 6780 gaagaacgtt ttccaatgat gagcactttt aaagttctgc tatgtggcgc ggtattatcc 6840 cgtattgacg ccgggcaaga gcaactcggt cgccgcatac actattctca gaatgacttg 6900 gttgagtact caccagtcac agaaaagcat cttacggatg gcatgacagt aagagaatta 6960 tgcagtgctg ccataaccat gagtgataac actgcggcca acttacttct gacaacgatc 7020 ggaggaccga aggagctaac cgcttttttg cacaacatgg gggatcatgt aactcgcctt 7080 gatcgttggg aaccggagct gaatgaagcc ataccaaacg acgagcgtga cacca 7135 <210> 67 <211> 7124 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 67 cgatgcctgt agcaatggca acaacgttgc gcaaactatt aactggcgaa ctacttactc 60 tagcttcccg gcaacaatta atagactgga tggaggcgga taaagttgca ggaccacttc 120 tgcgctcggc ccttccggct ggctggttta ttgctgataa atctggagcc ggtgagcgtg 180 ggtctcgcgg tatcattgca gcactggggc cagatggtaa gccctcccgt atcgtagtta 240 tctacacgac ggggagtcag gcaactatgg atgaacgaaa tagacagatc gctgagatag 300 gtgcctcact gattaagcat tggtaactgt cagaccaagt ttactcatat atactttaga 360 ttgatttaaa acttcatttt taatttaaaa ggatctaggt gaagatcctt tttgataatc 420 tcatgaccaa aatcccttaa cgtgagtttt cgttccactg agcgtcagac cccgtagaaa 480 agatcaaagg atcttcttga gatccttttt ttctgcgcgt aatctgctgc ttgcaaacaa 540 aaaaaccacc gctaccagcg gtggtttgtt tgccggatca agagctacca actctttttc 600 cgaaggtaac tggcttcagc agagcgcaga taccaaatac tgtccttcta gtgtagccgt 660 agttaggcca ccacttcaag aactctgtag caccgcctac atacctcgct ctgctaatcc 720 tgttaccagt ggctgctgcc agtggcgata agtcgtgtct taccgggttg gactcaagac 780 gatagttacc ggataaggcg cagcggtcgg gctgaacggg gggttcgtgc acacagccca 840 gcttggagcg aacgacctac accgaactga gatacctaca gcgtgagcta tgagaaagcg 900 ccacgcttcc cgaagggaga aaggcggaca ggtatccggt aagcggcagg gtcggaacag 960 gagagcgcac gagggagctt ccagggggaa acgcctggta tctttatagt cctgtcgggt 1020 ttcgccacct ctgacttgag cgtcgatttt tgtgatgctc gtcagggggg cggagcctat 1080 ggaaaaacgc cagcaacgcg gcctttttac ggttcctggc cttttgctgg ccttttgctc 1140 acatgtcctg caggcagctg cgcgctcgct cgctcactga ggccgcccgg gcaaagcccg 1200 ggcgtcgggc gacctttggt cgcccggcct cagtgagcga gcgagcgcgc agagaggag 1260 tggccaactc catcactagg ggttcctgcg gccgcacgcg tcagtgatgc ctgaaacctc 1320 agatggtact gaaccctcta tataatctgt tttttcctat acatacaaac ctaccataag 1380 gcttaatggt aagagattaa caataaagaa taataaaaca acacttataa caatgtataa 1440 caatatattg taatataagt ttttggatgc agtctctctc tcaaaatgct atcatatttt 1500 ccaactgtgg ttgactacag gtaactggaa ccacaaaaat gaaacagtgg ataagagggc 1560 gactcctgta ccaaagaaaa aaatagagtg ttgcagctgt aacatagttg aatgactgag 1620 ttagactgca taactgacac acaaaaccac ataaatataa atgaaggaat ctctgggtgt 1680 aatctggtgc aaaggtgact gtgttaatca ttaatccaca agttgctatc ctgaagtgtg 1740 ccaaatgctt tatgtttatt tcatcacata gctctataaa gaaaggattt gtaattcctt 1800 tctacagaag tggaaagtaa gtcttaagac tcaaaaaact ttaaaaacta caatgaagta 1860 acaactttta ttaatttatt ttgtgtcttt ccagaatttc tatatatata ggaatgtgat 1920 atgaatctat atgtgaattg aatctacatg aatattgatg acttttatt ccccttttgc 1980 acataagata gaatatttta cctactattc cacactttgc ttttcttaac atatcatggg 2040 atctttttat ataagtgaac aaagagtttc ttcattcttt cacacagttt aattaagacc 2100 tcgaagggga cttggggggt tcggggcttt cgggggcggt cgggggttcg cggacccggg 2160 aagctctgag gacccagagg ccgggcgcgc tccgcccgcg gcgccgcccc ctccgtaact 2220 ttcccagtct ccgagggaag aggcggggtg tggggtgcgg ttaaaaggcg ccacggcggg 2280 agacaggtgt tgcggccccg cagcgcccgc gcgctcctct ccccgactcg gagcccctcg 2340 gcggcgcccg gcccaggacc cgcctaggag cgcaggagcc ccagcgcaga gaccccaacg 2400 ccgagacccc cgccccggcc ccgccgcgct tcctcccgac gcagagcaaa ccgcccagag 2460 tagaagccat ggattggggc acgctgcaga cgatcctggg gggtgtgaac aaacactcca 2520 ccagcattgg aaagatctgg ctcaccgtcc tcttcatttt tcgcattatg atcctcgttg 2580 tggctgcaaa ggaggtgtgg ggagatgagc aggccgactt tgtctgcaac accctgcagc 2640 caggctgcaa gaacgtgtgc tacgatcact acttccccat ctcccacatc cggctatggg 2700 ccctgcagct gatcttcgtg tccacgccag cgctcctagt ggccatgcac gtggcctacc 2760 ggagacatga gaagaagagg aagttcatca aggggggagat aaagagtgaa tttaaggaca 2820 tcgaggagat caaaacccag aaggtccgca tcgaaggctc cctgtggtgg acctacacaa 2880 gcagcatctt cttccgggtc atcttcgaag ccgccttcat gtacgtcttc tatgtcatgt 2940 acgacggctt ctccatgcag cggctggtga agtgcaacgc ctggccttgt cccaacactg 3000 tggactgctt tgtgtcccgg cccacggaga agactgtctt cacagtgttc atgattgcag 3060 tgtctggaat ttgcatcctg ctgaatgtca ctgaattgtg ttatttgcta attagatatt 3120 gttctgggaa gtcaaaaaag ccagtttaaa ggcgcgccac ccctgcaggg aattccgcat 3180 tgcccagttg ttagattaag aaatagacag catgagaggg atgaggcaac ccgtgctcag 3240 ctgtcaaggc tcagtcgcta gcatttccca acacaaagat tctgacctta aatgcaacca 3300 tttgaaaccc ctgtaggcct caggtgaaac tccagatgcc acaatggagc tctgctcccc 3360 taaagcctca aaacaaaggc ctaattctat gcctgtctta attttctttc acttaagtta 3420 gttccactga gaccccaggc tgttaggggt tattggtgta aggtactttc atattttaaa 3480 cagaggatat cggcatttgt ttctttctct gaggacaaga gaaaaaagcc aggttccaca 3540 gaggacacag agaaggtttg ggtgtcctcc tggggttctt tttgccaact ttccccacgt 3600 taaaggtgaa cattggttct ttcatttgct ttggaagttt taatctctaa cagtggacaa 3660 agttaccagt gccttaaact ctgttacact ttttggaagt gaaaactttg tagtatgata 3720 ggttatttg atgtaaagat gttctggata ccattatatg ttccccctgt ttcagaggct 3780 cagattgtaa tatgtaaatg gtatgtcatt cgctactatg atttaatttg aaatatggtc 3840 ttttggttat gaatactttg cagcacagct gagaggctgt ctgttgtatt cattgtggtc 3900 atagcaccta acaacattgt agcctcaatc gagtgagaca gactagaagt tcctagtgat 3960 ggcttatgat agcaaatggc ctcatgtcaa atatttagat gtaattttgt gtaagaaata 4020 cagactggat gtaccaccaa ctactacctg taatgacagg cctgtccaac acatctccct 4080 tttccatgac tgtggtagcc agcatcggaa agaacgctga tttaaagagg tcgcttggga 4140 attttatga cacagtacca tttaatgggg aggacaaaat ggggcagggg agggagaagt 4200 ttctgtcgtt aaaaacagat ttggaaagac tggactctaa agtctgttga ttaaagatga 4260 gctttgtcta cttcaaaagt ttgtttgctt accccttcag cctccaattt tttaagtgaa 4320 aatatagcta ataacatgtg aaaagaatag aagctaaggt ttagataaat attgagcaga 4380 tctataggaa gattgaacct gaatattgcc attatgcttg acatggtttc caaaaaatgg 4440 tactccacat atttcagtga gggtaagtat tttcctgttg tcaagaatag cattgtaaaa 4500 gcattttgta ataataaaga atagctttaa tgatatgctt gtaactaaaa taattttgta 4560 atgtatcaaa tacatttaaa acattaaaat ataatctcta taataattta aaatctaata 4620 tggttttaat agaacagcga tatcaagctt atcgataatc aacctctgga ttacaaaatt 4680 tgtgaaagat tgactggtat tcttaactat gttgctcctt ttacgctatg tggatacgct 4740 gctttaatgc ctttgtatca tgctattgct tcccgtatgg ctttcatttt ctcctccttg 4800 tataaatcct ggttgctgtc tctttatgag gagttgtggc ccgttgtcag gcaacgtggc 4860 gtggtgtgca ctgtgtttgc tgacgcaacc cccactggtt ggggcattgc caccacctgt 4920 cagctccttt ccgggacttt cgctttcccc ctccctattg ccacggcgga actcatcgcc 4980 gcctgccttg cccgctgctg gacaggggct cggctgttgg gcactgacaa ttccgtggtg 5040 ttgtcgggga aatcatcgtc ctttccttgg ctgctcgcct atgttgccac ctggattctg 5100 cgcgggacgt ccttctgcta cgtcccttcg gccctcaatc cagcggacct tccttcccgc 5160 ggcctgctgc cggctctgcg gcctcttccg cgtcttcgcc ttcgccctca gacgagtcgg 5220 atctcccttt gggccgcctc cccgcgaatt catcgatacc gagcgctgct cgagagatct 5280 gtgatagcgg ccatcaagct ggctgtgcct tctagttgcc agccatctgt tgtttgcccc 5340 tcccccgtgc cttccttgac cctggaaggt gccactccca ctgtcctttc ctaataaaat 5400 gaggaaattg catcgcattg tctgagtagg tgtcattcta ttctgggggg tggggtgggg 5460 caggacagca agggggagga ttgggaagac aatagcaggc atgctgggga cacgtgcgga 5520 ccgagcggcc gcaggaaccc ctagtgatgg agttggccac tccctctctg cgcgctcgct 5580 cgctcactga ggccgggcga ccaaaggtcg cccgacgccc gggctttgcc cgggcggcct 5640 cagtgagcga gcgagcgcgc agctgcctgc aggggcgcct gatgcggtat tttctcctta 5700 cgcatctgtg cggtatttca caccgcatac gtcaaagcaa ccatagtacg cgccctgtag 5760 cggcgcatta agcgcggcgg gtgtggtggt tacgcgcagc gtgaccgcta cacttgccag 5820 cgccctagcg cccgctcctt tcgctttctt cccttccttt ctcgccacgt tcgccggctt 5880 tccccgtcaa gctctaaatc gggggctccc tttagggttc cgatttagtg ctttacggca 5940 cctcgacccc aaaaaacttg atttgggtga tggttcacgt agtgggccat cgccctgata 6000 gacggttttt cgccctttga cgttggagtc cacgttcttt aatagtggac tcttgttcca 6060 aactggaaca acactcaacc ctatctcggg ctattctttt gatttataag ggattttgcc 6120 gatttcggcc tattggttaa aaaatgagct gatttaacaa aaatttaacg cgaattttaa 6180 caaaatatta acgtttacaa ttttatggtg cactctcagt acaatctgct ctgatgccgc 6240 atagttaagc cagccccgac acccgccaac acccgctgac gcgccctgac gggcttgtct 6300 gctcccggca tccgcttaca gacaagctgt gaccgtctcc gggagctgca tgtgtcagag 6360 gttttcaccg tcatcaccga aacgcgcgag acgaaagggc ctcgtgatac gcctattttt 6420 ataggttaat gtcatgataa taatggtttc ttagacgtca ggtggcactt ttcggggaaa 6480 tgtgcgcgga acccctattt gtttatttt ctaaatacat tcaaatatgt atccgctcat 6540 gagacaataa ccctgataaa tgcttcaata atattgaaaa aggaagagta tgagtattca 6600 acatttccgt gtcgccctta ttcccttttt tgcggcattt tgccttcctg tttttgctca 6660 cccagaaacg ctggtgaaag taaaagatgc tgaagatcag ttgggtgcac gagtgggtta 6720 catcgaactg gatctcaaca gcggtaagat ccttgagagt tttcgccccg aagaacgttt 6780 tccaatgatg agcactttta aagttctgct atgtggcgcg gtattatccc gtattgacgc 6840 cgggcaagag caactcggtc gccgcataca ctattctcag aatgacttgg ttgagtactc 6900 accagtcaca gaaaagcatc ttacggatgg catgacagta agagaattat gcagtgctgc 6960 cataaccatg agtgataaca ctgcggccaa cttacttctg acaacgatcg gaggaccgaa 7020 ggagctaacc gcttttttgc acaacatggg ggatcatgta actcgccttg atcgttggga 7080 accggagctg aatgaagcca taccaaacga cgagcgtgac acca 7124 <210> 68 <211> 7151 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 68 cgatgcctgt agcaatggca acaacgttgc gcaaactatt aactggcgaa ctacttactc 60 tagcttcccg gcaacaatta atagactgga tggaggcgga taaagttgca ggaccacttc 120 tgcgctcggc ccttccggct ggctggttta ttgctgataa atctggagcc ggtgagcgtg 180 ggtctcgcgg tatcattgca gcactggggc cagatggtaa gccctcccgt atcgtagtta 240 tctacacgac ggggagtcag gcaactatgg atgaacgaaa tagacagatc gctgagatag 300 gtgcctcact gattaagcat tggtaactgt cagaccaagt ttactcatat atactttaga 360 ttgatttaaa acttcatttt taatttaaaa ggatctaggt gaagatcctt tttgataatc 420 tcatgaccaa aatcccttaa cgtgagtttt cgttccactg agcgtcagac cccgtagaaa 480 agatcaaagg atcttcttga gatccttttt ttctgcgcgt aatctgctgc ttgcaaacaa 540 aaaaaccacc gctaccagcg gtggtttgtt tgccggatca agagctacca actctttttc 600 cgaaggtaac tggcttcagc agagcgcaga taccaaatac tgtccttcta gtgtagccgt 660 agttaggcca ccacttcaag aactctgtag caccgcctac atacctcgct ctgctaatcc 720 tgttaccagt ggctgctgcc agtggcgata agtcgtgtct taccgggttg gactcaagac 780 gatagttacc ggataaggcg cagcggtcgg gctgaacggg gggttcgtgc acacagccca 840 gcttggagcg aacgacctac accgaactga gatacctaca gcgtgagcta tgagaaagcg 900 ccacgcttcc cgaagggaga aaggcggaca ggtatccggt aagcggcagg gtcggaacag 960 gagagcgcac gagggagctt ccagggggaa acgcctggta tctttatagt cctgtcgggt 1020 ttcgccacct ctgacttgag cgtcgatttt tgtgatgctc gtcagggggg cggagcctat 1080 ggaaaaacgc cagcaacgcg gcctttttac ggttcctggc cttttgctgg ccttttgctc 1140 acatgtcctg caggcagctg cgcgctcgct cgctcactga ggccgcccgg gcaaagcccg 1200 ggcgtcgggc gacctttggt cgcccggcct cagtgagcga gcgagcgcgc agagaggag 1260 tggccaactc catcactagg ggttcctgcg gccgcacgcg tcagtgatgc ctgaaacctc 1320 agatggtact gaaccctcta tataatctgt tttttcctat acatacaaac ctaccataag 1380 gcttaatggt aagagattaa caataaagaa taataaaaca acacttataa caatgtataa 1440 caatatattg taatataagt ttttggatgc agtctctctc tcaaaatgct atcatatttt 1500 ccaactgtgg ttgactacag gtaactggaa ccacaaaaat gaaacagtgg ataagagggc 1560 gactcctgta ccaaagaaaa aaatagagtg ttgcagctgt aacatagttg aatgactgag 1620 ttagactgca taactgacac acaaaaccac ataaatataa atgaaggaat ctctgggtgt 1680 aatctggtgc aaaggtgact gtgttaatca ttaatccaca agttgctatc ctgaagtgtg 1740 ccaaatgctt tatgtttatt tcatcacata gctctataaa gaaaggattt gtaattcctt 1800 tctacagaag tggaaagtaa gtcttaagac tcaaaaaact ttaaaaacta caatgaagta 1860 acaactttta ttaatttatt ttgtgtcttt ccagaatttc tatatatata ggaatgtgat 1920 atgaatctat atgtgaattg aatctacatg aatattgatg acttttatt ccccttttgc 1980 acataagata gaatatttta cctactattc cacactttgc ttttcttaac atatcatggg 2040 atctttttat ataagtgaac aaagagtttc ttcattcttt cacacagttt aattaagacc 2100 tcgaagggga cttggggggt tcggggcttt cgggggcggt cgggggttcg cggacccggg 2160 aagctctgag gacccagagg ccgggcgcgc tccgcccgcg gcgccgcccc ctccgtaact 2220 ttcccagtct ccgagggaag aggcggggtg tggggtgcgg ttaaaaggcg ccacggcggg 2280 agacaggtgt tgcggccccg cagcgcccgc gcgctcctct ccccgactcg gagcccctcg 2340 gcggcgcccg gcccaggacc cgcctaggag cgcaggagcc ccagcgcaga gaccccaacg 2400 ccgagacccc cgccccggcc ccgccgcgct tcctcccgac gcagagcaaa ccgcccagag 2460 tagaagccat ggattggggc acactccaga gcatcctcgg gggtgtcaac aaacactcca 2520 ccagcattgg aaagatctgg ctcacggtcc tcttcatctt ccgcatcatg atcctcgtgg 2580 tggctgcaaa ggaggtgtgg ggagatgagc aagccgattt tgtctgcaac acgctccagc 2640 ctggctgcaa gaatgtatgc tacgaccacc acttccccat ctctcacatc cggctctggg 2700 ctctgcagct gatcatggtg tccacgccag ccctcctggt agctatgcat gtggcctacc 2760 2820 tcgaagagat caaaacccag aaggtccgta tcgaagggtc cctgtggtgg acctacacca 2880 ccagcatctt cttccgggtc atctttgaag ccgtcttcat gtacgtcttt tacatcatgt 2940 acaatggctt cttcatgcaa cgtctggtga aatgcaacgc ttggccctgc cccaatacag 3000 tggactgctt catttccagg cccacagaaa agactgtctt caccgtgttt atgatttctg 3060 tgtctggaat ttgcattctg ctaaatatca cagagctgtg ctatttgttc gttaggtatt 3120 gctcaggaaa gtccaaaaga ccagtctacc catacgatgt tccagattac gcttaaaggc 3180 gcgccacccc tgcagggaat tccgcattgc ccagttgtta gattaagaaa tagacagcat 3240 gagagggatg aggcaacccg tgctcagctg tcaaggctca gtcgctagca tttcccaaca 3300 caaagattct gaccttaaat gcaaccattt gaaacccctg taggcctcag gtgaaactcc 3360 agatgccaca atggagctct gctcccctaa agcctcaaaa caaaggccta attctatgcc 3420 tgtcttaatt ttctttcact taagttagtt ccactgagac cccaggctgt taggggttat 3480 tggtgtaagg tactttcata ttttaaacag aggatatcgg catttgtttc tttctctgag 3540 gacaagagaa aaaagccagg ttccacagag gacacagaga aggtttgggt gtcctcctgg 3600 ggttcttttt gccaactttc cccacgttaa aggtgaacat tggttctttc atttgctttg 3660 gaagttttaa tctctaacag tggacaaagt taccagtgcc ttaaactctg ttacactttt 3720 tggaagtgaa aactttgtag tatgataggt tattttgatg taaagatgtt ctggatacca 3780 ttatatgttc cccctgtttc agaggctcag attgtaatat gtaaatggta tgtcattcgc 3840 tactatgatt taatttgaaa tatggtcttt tggttatgaa tactttgcag cacagctgag 3900 aggctgtctg ttgtattcat tgtggtcata gcacctaaca acattgtagc ctcaatcgag 3960 tgagacagac tagaagttcc tagtgatggc ttatgatagc aaatggcctc atgtcaaata 4020 tttagatgta attttgtgta agaaatacag actggatgta ccaccaacta ctacctgtaa 4080 tgacaggcct gtccaacaca tctccctttt ccatgactgt ggtagccagc atcggaaaga 4140 acgctgattt aaagaggtcg cttgggaatt ttattgacac agtaccattt aatggggagg 4200 acaaaatggg gcaggggagg gagaagtttc tgtcgttaaa aacagatttg gaaagactgg 4260 actctaaagt ctgttgatta aagatgagct ttgtctactt caaaagtttg tttgcttacc 4320 ccttcagcct ccaatttttt aagtgaaaat atagctaata acatgtgaaa agaatagaag 4380 ctaaggttta gataaatatt gagcagatct ataggaagat tgaacctgaa tattgccatt 4440 atgcttgaca tggtttccaa aaaatggtac tccacatatt tcagtgaggg taagtatttt 4500 cctgttgtca agaatagcat tgtaaaagca ttttgtaata ataaagaata gctttaatga 4560 tatgcttgta actaaaataa ttttgtaatg tatcaaatac atttaaaaca ttaaaatata 4620 atctctataa taatttaaaa tctaatatgg ttttaataga acagcgatat caagcttatc 4680 gataatcaac ctctggatta caaaatttgt gaaagattga ctggtattct taactatgtt 4740 gctcctttta cgctatgtgg atacgctgct ttaatgcctt tgtatcatgc tattgcttcc 4800 cgtatggctt tcattttctc ctccttgtat aaatcctggt tgctgtctct ttatgaggag 4860 ttgtggcccg ttgtcaggca acgtggcgtg gtgtgcactg tgtttgctga cgcaaccccc 4920 actggttggg gcattgccac cacctgtcag ctcctttccg ggactttcgc tttccccctc 4980 cctattgcca cggcggaact catcgccgcc tgccttgccc gctgctggac aggggctcgg 5040 ctgttgggca ctgacaattc cgtggtgttg tcggggaaat catcgtcctt tccttggctg 5100 ctcgcctatg ttgccacctg gattctgcgc gggacgtcct tctgctacgt cccttcggcc 5160 ctcaatccag cggaccttcc ttcccgcggc ctgctgccgg ctctgcggcc tcttccgcgt 5220 cttcgccttc gccctcagac gagtcggatc tccctttggg ccgcctcccc gcgaattcat 5280 cgataccgag cgctgctcga gagatctgtg atagcggcca tcaagctggc tgtgccttct 5340 agttgccagc catctgttgt ttgcccctcc cccgtgcctt ccttgaccct ggaaggtgcc 5400 actcccactg tcctttccta ataaaatgag gaaattgcat cgcattgtct gagtaggtgt 5460 cattctattc tggggggtgg ggtggggcag gacagcaagg gggaggattg ggaagacaat 5520 agcaggcatg ctggggacac gtgcggaccg agcggccgca ggaaccccta gtgatggagt 5580 tggccactcc ctctctgcgc gctcgctcgc tcactgaggc cgggcgacca aaggtcgccc 5640 gacgcccggg ctttgcccgg gcggcctcag tgagcgagcg agcgcgcagc tgcctgcagg 5700 ggcgcctgat gcggtatttt ctccttacgc atctgtgcgg tatttcacac cgcatacgtc 5760 aaagcaacca tagtacgcgc cctgtagcgg cgcattaagc gcggcgggtg tggtggttac 5820 gcgcagcgtg accgctacac ttgccagcgc cctagcgccc gctcctttcg ctttcttccc 5880 ttcctttctc gccacgttcg ccggctttcc ccgtcaagct ctaaatcggg ggctcccttt 5940 agggttccga tttagtgctt tacggcacct cgaccccaaa aaacttgatt tgggtgatgg 6000 ttcacgtagt gggccatcgc cctgatagac ggtttttcgc cctttgacgt tggagtccac 6060 gttctttaat agtggactct tgttccaaac tggaacaaca ctcaacccta tctcgggcta 6120 ttcttttgat ttataaggga ttttgccgat ttcggcctat tggttaaaaa atgagctgat 6180 ttaacaaaaa tttaacgcga attttaacaa aatattaacg tttacaattt tatggtgcac 6240 tctcagtaca atctgctctg atgccgcata gttaagccag ccccgacacc cgccaacacc 6300 cgctgacgcg ccctgacggg cttgtctgct cccggcatcc gcttacagac aagctgtgac 6360 cgtctccggg agctgcatgt gtcagaggtt ttcaccgtca tcaccgaaac gcgcgagacg 6420 aaagggcctc gtgatacgcc tatttttata ggttaatgtc atgataataa tggtttctta 6480 gacgtcaggt ggcacttttc ggggaaatgt gcgcggaacc cctatttgtt tatttttcta 6540 aatacattca aatatgtatc cgctcatgag acaataaccc tgataaatgc ttcaataata 6600 ttgaaaaagg aagagtatga gtattcaaca tttccgtgtc gcccttattc ccttttttgc 6660 ggcattttgc cttcctgttt ttgctcaccc agaaacgctg gtgaaagtaa aagatgctga 6720 agatcagttg ggtgcacgag tgggttacat cgaactggat ctcaacagcg gtaagatcct 6780 tgagagtttt cgccccgaag aacgttttcc aatgatgagc acttttaaag ttctgctatg 6840 tggcgcggta ttatcccgta ttgacgccgg gcaagagcaa ctcggtcgcc gcatacacta 6900 ttctcagaat gacttggttg agtactcacc agtcacagaa aagcatctta cggatggcat 6960 gacagtaaga gaattatgca gtgctgccat aaccatgagt gataacactg cggccaactt 7020 acttctgaca acgatcggag gaccgaagga gctaaccgct tttttgcaca acatggggga 7080 tcatgtaact cgccttgatc gttgggaacc ggagctgaat gaagccatac caaacgacga 7140 gcgtgacacc a 7151 <210> 69 <400> 69 000 <210> 70 <211> 7208 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 70 cgatgcctgt agcaatggca acaacgttgc gcaaactatt aactggcgaa ctacttactc 60 tagcttcccg gcaacaatta atagactgga tggaggcgga taaagttgca ggaccacttc 120 tgcgctcggc ccttccggct ggctggttta ttgctgataa atctggagcc ggtgagcgtg 180 ggtctcgcgg tatcattgca gcactggggc cagatggtaa gccctcccgt atcgtagtta 240 tctacacgac ggggagtcag gcaactatgg atgaacgaaa tagacagatc gctgagatag 300 gtgcctcact gattaagcat tggtaactgt cagaccaagt ttactcatat atactttaga 360 ttgatttaaa acttcatttt taatttaaaa ggatctaggt gaagatcctt tttgataatc 420 tcatgaccaa aatcccttaa cgtgagtttt cgttccactg agcgtcagac cccgtagaaa 480 agatcaaagg atcttcttga gatccttttt ttctgcgcgt aatctgctgc ttgcaaacaa 540 aaaaaccacc gctaccagcg gtggtttgtt tgccggatca agagctacca actctttttc 600 cgaaggtaac tggcttcagc agagcgcaga taccaaatac tgtccttcta gtgtagccgt 660 agttaggcca ccacttcaag aactctgtag caccgcctac atacctcgct ctgctaatcc 720 tgttaccagt ggctgctgcc agtggcgata agtcgtgtct taccgggttg gactcaagac 780 gatagttacc ggataaggcg cagcggtcgg gctgaacggg gggttcgtgc acacagccca 840 gcttggagcg aacgacctac accgaactga gatacctaca gcgtgagcta tgagaaagcg 900 ccacgcttcc cgaagggaga aaggcggaca ggtatccggt aagcggcagg gtcggaacag 960 gagagcgcac gagggagctt ccagggggaa acgcctggta tctttatagt cctgtcgggt 1020 ttcgccacct ctgacttgag cgtcgatttt tgtgatgctc gtcagggggg cggagcctat 1080 ggaaaaacgc cagcaacgcg gcctttttac ggttcctggc cttttgctgg ccttttgctc 1140 acatgtcctg caggcagctg cgcgctcgct cgctcactga ggccgcccgg gcaaagcccg 1200 ggcgtcgggc gacctttggt cgcccggcct cagtgagcga gcgagcgcgc agagaggag 1260 tggccaactc catcactagg ggttcctgcg gccgcacgcg tgctatctat catcttgaag 1320 ggcttctgga acaagttaga atagagtcaa cactcatgaa ctgctgtagc aaaaaaaact 1380 atagatgtag gattgacaag ggcaatagag cgatgactcc ctggctgtgt tgtatttgat 1440 ggacggcagt agcttttcac aaaatgctca tttggatgtt tcaaattaaa acgtttcact 1500 ttctagaacc aattacgtgg tcagtttagc tcctgaggtc ccagtcagag gggtattctg 1560 tagcttgcaa agcctctctt tggggactgg acatggagtc tgtggtctta gaattcagaa 1620 ccgggagaat gtgttagcca ctcatctaag ctattcctta aacgctttca gagccatctc 1680 cactgtgggg aaagaagttc tttgtgttct ctgacttagt ctcattctaa aaaaaaaaaa 1740 aaaaaaaaaa aaaaagcaat tgcaataccc agagcgcaca gtagatggca ctgagacttg 1800 tcggaaagct ggacgcactc aagaggtggc agaaaaatct ataggtaagc ttttcttcta 1860 gtctggtgtt gctgctcctg accttattaa tgggctgaga aatagatttc tttcctttcc 1920 ttttcttttt tatatgaaat taaatgaagt ataaaagaat atgagaatgt gttgctatta 1980 gcaaggataa gtaatgcttt aggaaacgtt tggttcatgt gtgtgttttc agactgatgt 2040 gtgtcctgga tccagtgtaa aatgtacttc tgtctgtagg tctctgccac agaaaagttg 2100 gaaagccatt gttgtattcc atttccaggg caacaaaaga taccactgtc acttcatgtg 2160 aaatggtgtt gtttaattaa gacctcgaag gggacttggg gggttcgggg ctttcggggg 2220 cggtcggggg ttcgcggacc cgggaagctc tgaggaccca gaggccgggc gcgctccgcc 2280 cgcggcgccg ccccctccgt aactttccca gtctccgagg gaagaggcgg ggtgtggggt 2340 gcggttaaaa ggcgccacgg cgggagacag gtgttgcggc cccgcagcgc ccgcgcgctc 2400 ctctccccga ctcggagccc ctcggcggcg cccggcccag gacccgccta ggagcgcagg 2460 agccccagcg cagagacccc aacgccgaga cccccgcccc ggccccgccg cgcttcctcc 2520 cgacgcagag caaaccgccc agagtagaag ccatggattg gggcacgctg cagacgatcc 2580 tggggggtgt gaacaaacac tccaccagca ttggaaagat ctggctcacc gtcctcttca 2640 tttttcgcat tatgatcctc gttgtggctg caaaggaggt gtggggagat gagcaggccg 2700 actttgtctg caacaccctg cagccaggct gcaagaacgt gtgctacgat cactacttcc 2760 ccatctccca catccggcta tgggccctgc agctgatctt cgtgtccacg ccagcgctcc 2820 tagtggccat gcacgtggcc taccggagac atgagaagaa gaggaagttc atcaaggggg 2880 agataaagag tgaatttaag gacatcgagg agatcaaaac ccagaaggtc cgcatcgaag 2940 gctccctgg gtggacctac acaagcagca tcttcttccg ggtcatcttc gaagccgcct 3000 tcatgtacgt cttctatgtc atgtacgacg gcttctccat gcagcggctg gtgaagtgca 3060 acgcctggcc ttgtcccaac actgtggact gctttgtgtc ccggcccacg gagaagactg 3120 tcttcacagt gttcatgatt gcagtgtctg gaatttgcat cctgctgaat gtcactgaat 3180 tgtgtattt gctaattaga tattgttctg ggaagtcaaa aaagccagtt taaaggcgcg 3240 ccacccctgc agggaattcc gcattgccca gttgttagat taagaaatag acagcatgag 3300 agggatgagg caacccgtgc tcagctgtca aggctcagtc gctagcattt cccaacacaa 3360 agattctgac cttaaatgca accatttgaa acccctgtag gcctcaggtg aaactccaga 3420 tgccacaatg gagctctgct cccctaaagc ctcaaaacaa aggcctaatt ctatgcctgt 3480 cttaattttc tttcacttaa gttagttcca ctgagacccc aggctgttag gggttattgg 3540 tgtaaggtac tttcatattt taaacagagg atatcggcat ttgtttcttt ctctgaggac 3600 aagagaaaaa agccaggttc cacagaggac acagagaagg tttgggtgtc ctcctggggt 3660 tctttttgcc aactttcccc acgttaaagg tgaacattgg ttctttcatt tgctttggaa 3720 gttttaatct ctaacagtgg acaaagttac cagtgcctta aactctgtta cactttttgg 3780 aagtgaaaac tttgtagtat gataggttat tttgatgtaa agatgttctg gataccatta 3840 tatgttcccc ctgtttcaga ggctcagatt gtaatatgta aatggtatgt cattcgctac 3900 tatgatttaa tttgaaatat ggtcttttgg ttatgaatac tttgcagcac agctgagagg 3960 ctgtctgttg tattcattgt ggtcatagca cctaacaaca ttgtagcctc aatcgagtga 4020 gacagactag aagttcctag tgatggctta tgatagcaaa tggcctcatg tcaaatattt 4080 agatgtaatt ttgtgtaaga aatacagact ggatgtacca ccaactacta cctgtaatga 4140 caggcctgtc caacacatct cccttttcca tgactgtggt agccagcatc ggaaagaacg 4200 ctgatttaaa gaggtcgctt gggaatttta ttgacacagt accatttaat ggggaggaca 4260 aaatggggca ggggagggag aagtttctgt cgttaaaaac agatttggaa agactggact 4320 ctaaagtctg ttgattaaag atgagctttg tctacttcaa aagtttgttt gcttacccct 4380 tcagcctcca attttttaag tgaaaatata gctaataaca tgtgaaaaga atagaagcta 4440 aggtttagat aaatattgag cagatctata ggaagattga acctgaatat tgccattatg 4500 cttgacatgg tttccaaaaa atggtactcc acatatttca gtgagggtaa gtattttcct 4560 gttgtcaaga atagcattgt aaaagcattt tgtaataata aagaatagct ttaatgatat 4620 gcttgtaact aaaataattt tgtaatgtat caaatacatt taaaacatta aaatataatc 4680 tctataataa tttaaaatct aatatggttt taatagaaca gcgatatcaa gcttatcgat 4740 aatcaacctc tggattacaa aatttgtgaa agattgactg gtattcttaa ctatgttgct 4800 ccttttacgc tatgtggata cgctgcttta atgcctttgt atcatgctat tgcttcccgt 4860 atggctttca ttttctcctc cttgtataaa tcctggttgc tgtctcttta tgaggagttg 4920 tggcccgttg tcaggcaacg tggcgtggtg tgcactgtgt ttgctgacgc aacccccact 4980 ggttggggca ttgccacac ctgtcagctc ctttccggga ctttcgcttt ccccctccct 5040 attgccacgg cggaactcat cgccgcctgc cttgcccgct gctggacagg ggctcggctg 5100 ttgggcactg acaattccgt ggtgttgtcg gggaaatcat cgtcctttcc ttggctgctc 5160 gcctatgttg ccacctggat tctgcgcggg acgtccttct gctacgtccc ttcggccctc 5220 aatccagcgg accttccttc ccgcggcctg ctgccggctc tgcggcctct tccgcgtctt 5280 cgccttcgcc ctcagacgag tcggatctcc ctttgggccg cctccccgcg aattcatcga 5340 taccgagcgc tgctcgagag atctgtgata gcggccatca agctggctgt gccttctagt 5400 tgccagccat ctgttgtttg cccctccccc gtgccttcct tgaccctgga aggtgccact 5460 cccactgtcc tttcctaata aaatgaggaa attgcatcgc attgtctgag taggtgtcat 5520 tctattctgg ggggtggggt ggggcaggac agcaaggggg aggattggga agacaatagc 5580 aggcatgctg gggacacgtg cggaccgagc ggccgcagga acccctagtg atggagttgg 5640 ccactccctc tctgcgcgct cgctcgctca ctgaggccgg gcgaccaaag gtcgcccgac 5700 gcccgggctt tgcccgggcg gcctcagtga gcgagcgagc gcgcagctgc ctgcaggggc 5760 gcctgatgcg gtattttctc cttacgcatc tgtgcggtat ttcacaccgc atacgtcaaa 5820 gcaaccatag tacgcgccct gtagcggcgc attaagcgcg gcgggtgtgg tggttacgcg 5880 cagcgtgacc gctacacttg ccagcgccct agcgcccgct cctttcgctt tcttcccttc 5940 ctttctcgcc acgttcgccg gctttccccg tcaagctcta aatcgggggc tccctttagg 6000 gttccgattt agtgctttac ggcacctcga ccccaaaaaa cttgatttgg gtgatggttc 6060 acgtagtggg ccatcgccct gatagacggt ttttcgccct ttgacgttgg agtccacgtt 6120 ctttaatagt ggactcttgt tccaaactgg aacaacactc aaccctatct cgggctattc 6180 ttttgattta taagggattt tgccgatttc ggcctattgg ttaaaaaatg agctgattta 6240 acaaaaattt aacgcgaatt ttaacaaaat attaacgttt acaattttat ggtgcactct 6300 cagtacaatc tgctctgatg ccgcatagtt aagccagccc cgacacccgc caacacccgc 6360 tgacgcgccc tgacgggctt gtctgctccc ggcatccgct tacagacaag ctgtgaccgt 6420 ctccgggagc tgcatgtgtc agaggttttc accgtcatca ccgaaacgcg cgagacgaaa 6480 gggcctcgtg atacgcctat ttttataggt taatgtcatg ataataatgg tttcttagac 6540 gtcaggtggc acttttcggg gaaatgtgcg cggaacccct atttgtttat ttttctaaat 6600 acattcaaat atgtatccgc tcatgagaca ataaccctga taaatgcttc aataatattg 6660 aaaaaggaag agtatgagta ttcaacattt ccgtgtcgcc cttattccct tttttgcggc 6720 attttgcctt cctgtttttg ctcacccaga aacgctggtg aaagtaaaag atgctgaaga 6780 tcagttgggt gcacgagtgg gttacatcga actggatctc aacagcggta agatccttga 6840 gagttttcgc cccgaagaac gttttccaat gatgagcact tttaaagttc tgctatgtgg 6900 cgcggtatta tcccgtattg acgccgggca agagcaactc ggtcgccgca tacactattc 6960 tcagaatgac ttggttgagt actcaccagt cacagaaaag catcttacgg atggcatgac 7020 agtaagagaa ttatgcagtg ctgccataac catgagtgat aacactgcgg ccaacttact 7080 tctgacaacg atcggaggac cgaaggagct aaccgctttt ttgcacaaca tgggggatca 7140 tgtaactcgc cttgatcgtt gggaaccgga gctgaatgaa gccataccaa acgacgagcg 7200 tgacacca 7208 <210> 71 <211> 7235 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 71 cgatgcctgt agcaatggca acaacgttgc gcaaactatt aactggcgaa ctacttactc 60 tagcttcccg gcaacaatta atagactgga tggaggcgga taaagttgca ggaccacttc 120 tgcgctcggc ccttccggct ggctggttta ttgctgataa atctggagcc ggtgagcgtg 180 ggtctcgcgg tatcattgca gcactggggc cagatggtaa gccctcccgt atcgtagtta 240 tctacacgac ggggagtcag gcaactatgg atgaacgaaa tagacagatc gctgagatag 300 gtgcctcact gattaagcat tggtaactgt cagaccaagt ttactcatat atactttaga 360 ttgatttaaa acttcatttt taatttaaaa ggatctaggt gaagatcctt tttgataatc 420 tcatgaccaa aatcccttaa cgtgagtttt cgttccactg agcgtcagac cccgtagaaa 480 agatcaaagg atcttcttga gatccttttt ttctgcgcgt aatctgctgc ttgcaaacaa 540 aaaaaccacc gctaccagcg gtggtttgtt tgccggatca agagctacca actctttttc 600 cgaaggtaac tggcttcagc agagcgcaga taccaaatac tgtccttcta gtgtagccgt 660 agttaggcca ccacttcaag aactctgtag caccgcctac atacctcgct ctgctaatcc 720 tgttaccagt ggctgctgcc agtggcgata agtcgtgtct taccgggttg gactcaagac 780 gatagttacc ggataaggcg cagcggtcgg gctgaacggg gggttcgtgc acacagccca 840 gcttggagcg aacgacctac accgaactga gatacctaca gcgtgagcta tgagaaagcg 900 ccacgcttcc cgaagggaga aaggcggaca ggtatccggt aagcggcagg gtcggaacag 960 gagagcgcac gagggagctt ccagggggaa acgcctggta tctttatagt cctgtcgggt 1020 ttcgccacct ctgacttgag cgtcgatttt tgtgatgctc gtcagggggg cggagcctat 1080 ggaaaaacgc cagcaacgcg gcctttttac ggttcctggc cttttgctgg ccttttgctc 1140 acatgtcctg caggcagctg cgcgctcgct cgctcactga ggccgcccgg gcaaagcccg 1200 ggcgtcgggc gacctttggt cgcccggcct cagtgagcga gcgagcgcgc agagaggag 1260 tggccaactc catcactagg ggttcctgcg gccgcacgcg tgctatctat catcttgaag 1320 ggcttctgga acaagttaga atagagtcaa cactcatgaa ctgctgtagc aaaaaaaact 1380 atagatgtag gattgacaag ggcaatagag cgatgactcc ctggctgtgt tgtatttgat 1440 ggacggcagt agcttttcac aaaatgctca tttggatgtt tcaaattaaa acgtttcact 1500 ttctagaacc aattacgtgg tcagtttagc tcctgaggtc ccagtcagag gggtattctg 1560 tagcttgcaa agcctctctt tggggactgg acatggagtc tgtggtctta gaattcagaa 1620 ccgggagaat gtgttagcca ctcatctaag ctattcctta aacgctttca gagccatctc 1680 cactgtgggg aaagaagttc tttgtgttct ctgacttagt ctcattctaa aaaaaaaaaa 1740 aaaaaaaaaa aaaaagcaat tgcaataccc agagcgcaca gtagatggca ctgagacttg 1800 tcggaaagct ggacgcactc aagaggtggc agaaaaatct ataggtaagc ttttcttcta 1860 gtctggtgtt gctgctcctg accttattaa tgggctgaga aatagatttc tttcctttcc 1920 ttttcttttt tatatgaaat taaatgaagt ataaaagaat atgagaatgt gttgctatta 1980 gcaaggataa gtaatgcttt aggaaacgtt tggttcatgt gtgtgttttc agactgatgt 2040 gtgtcctgga tccagtgtaa aatgtacttc tgtctgtagg tctctgccac agaaaagttg 2100 gaaagccatt gttgtattcc atttccaggg caacaaaaga taccactgtc acttcatgtg 2160 aaatggtgtt gtttaattaa gacctcgaag gggacttggg gggttcgggg ctttcggggg 2220 cggtcggggg ttcgcggacc cgggaagctc tgaggaccca gaggccgggc gcgctccgcc 2280 cgcggcgccg ccccctccgt aactttccca gtctccgagg gaagaggcgg ggtgtggggt 2340 gcggttaaaa ggcgccacgg cgggagacag gtgttgcggc cccgcagcgc ccgcgcgctc 2400 ctctccccga ctcggagccc ctcggcggcg cccggcccag gacccgccta ggagcgcagg 2460 agccccagcg cagagacccc aacgccgaga cccccgcccc ggccccgccg cgcttcctcc 2520 cgacgcagag caaaccgccc agagtagaag ccatggattg gggcacactc cagagcatcc 2580 tcgggggtgt caacaaacac tccaccagca ttggaaagat ctggctcacg gtcctcttca 2640 tcttccgcat catgatcctc gtggtggctg caaaggaggt gtggggagat gagcaagccg 2700 attttgtctg caacacgctc cagcctggct gcaagaatgt atgctacgac caccacttcc 2760 ccatctctca catccggctc tgggctctgc agctgatcat ggtgtccacg ccagccctcc 2820 tggtagctat gcatgtggcc taccggagac atgaaaagaa acggaagttc atgaagggag 2880 agataaagaa cgagtttaag gacatcgaag agatcaaaac ccagaaggtc cgtatcgaag 2940 ggtccctgtg gtggacctac accaccagca tcttcttccg ggtcatcttt gaagccgtct 3000 tcatgtacgt cttttacatc atgtacaatg gcttcttcat gcaacgtctg gtgaaatgca 3060 acgcttggcc ctgccccaat acagtggact gcttcatttc caggcccaca gaaaagactg 3120 tcttcaccgt gtttatgatt tctgtgtctg gaatttgcat tctgctaaat atcacagagc 3180 tgtgctattt gttcgttagg tattgctcag gaaagtccaa aagaccagtc tacccatacg 3240 atgttccaga ttacgcttaa aggcgcgcca cccctgcagg gaattccgca ttgcccagtt 3300 gttagattaa gaaatagaca gcatgagagg gatgaggcaa cccgtgctca gctgtcaagg 3360 ctcagtcgct agcatttccc aacacaaaga ttctgacctt aaatgcaacc atttgaaacc 3420 cctgtaggcc tcaggtgaaa ctccagatgc cacaatggag ctctgctccc ctaaagcctc 3480 aaaacaaagg cctaattcta tgcctgtctt aattttcttt cacttaagtt agttccactg 3540 agaccccagg ctgttagggg ttattggtgt aaggtacttt catattttaa acagaggata 3600 tcggcatttg tttctttctc tgaggacaag agaaaaaagc caggttccac agaggacaca 3660 gagaaggttt gggtgtcctc ctggggttct ttttgccaac tttccccacg ttaaaggtga 3720 acattggttc tttcatttgc tttggaagtt ttaatctcta acagtggaca aagttaccag 3780 tgccttaaac tctgttacac tttttggaag tgaaaacttt gtagtatgat aggttatttt 3840 gatgtaaaga tgttctggat accattatat gttccccctg tttcagaggc tcagattgta 3900 atatgtaaat ggtatgtcat tcgctactat gatttaattt gaaatatggt cttttggtta 3960 tgaatacttt gcagcacagc tgagaggctg tctgttgtat tcattgtggt catagcacct 4020 aacaacattg tagcctcaat cgagtgagac agactagaag ttcctagtga tggcttatga 4080 tagcaaatgg cctcatgtca aatatttaga tgtaattttg tgtaagaaat acagactgga 4140 tgtaccacca actactacct gtaatgacag gcctgtccaa cacatctccc ttttccatga 4200 ctgtggtagc cagcatcgga aagaacgctg atttaaagag gtcgcttggg aattttattg 4260 acacagtacc atttaatggg gaggacaaaa tggggcaggg gagggagaag tttctgtcgt 4320 taaaaacaga tttggaaaga ctggactcta aagtctgttg attaaagatg agctttgtct 4380 acttcaaaag tttgtttgct taccccttca gcctccaatt ttttaagtga aaatatagct 4440 aataacatgt gaaaagaata gaagctaagg tttagataaa tattgagcag atctatagga 4500 agattgaacc tgaatattgc cattatgctt gacatggttt ccaaaaaatg gtactccaca 4560 tatttcagtg agggtaagta ttttcctgtt gtcaagaata gcattgtaaa agcattttgt 4620 aataataaag aatagcttta atgatatgct tgtaactaaa ataattttgt aatgtatcaa 4680 atacatttaa aacattaaaa tataatctct ataataattt aaaatctaat atggttttaa 4740 tagaacagcg atatcaagct tatcgataat caacctctgg attacaaaat ttgtgaaaga 4800 ttgactggta ttcttaacta tgttgctcct tttacgctat gtggatacgc tgctttaatg 4860 cctttgtatc atgctattgc ttcccgtatg gctttcattt tctcctcctt gtataaatcc 4920 tggttgctgt ctctttatga ggagttgtgg cccgttgtca ggcaacgtgg cgtggtgtgc 4980 actgtgtttg ctgacgcaac ccccactggt tggggcattg ccaccacctg tcagctcctt 5040 tccgggactt tcgctttccc cctccctatt gccacggcgg aactcatcgc cgcctgcctt 5100 gcccgctgct ggacaggggc tcggctgttg ggcactgaca attccgtggt gttgtcgggg 5160 aaatcatcgt cctttccttg gctgctcgcc tatgttgcca cctggattct gcgcgggacg 5220 tccttctgct acgtcccttc ggccctcaat ccagcggacc ttccttcccg cggcctgctg 5280 ccggctctgc ggcctcttcc gcgtcttcgc cttcgccctc agacgagtcg gatctccctt 5340 tgggccgcct ccccgcgaat tcatcgatac cgagcgctgc tcgagagatc tgtgatagcg 5400 gccatcaagc tggctgtgcc ttctagttgc cagccatctg ttgtttgccc ctcccccgtg 5460 ccttccttga ccctggaagg tgccactccc actgtccttt cctaataaaa tgaggaaatt 5520 gcatcgcatt gtctgagtag gtgtcattct attctggggg gtggggtggg gcaggacagc 5580 aagggggagg attgggaaga caatagcagg catgctgggg acacgtgcgg accgagcggc 5640 cgcaggaacc cctagtgatg gagttggcca ctccctctct gcgcgctcgc tcgctcactg 5700 aggccgggcg accaaaggtc gcccgacgcc cgggctttgc ccgggcggcc tcagtgagcg 5760 agcgagcgcg cagctgcctg caggggcgcc tgatgcggta ttttctcctt acgcatctgt 5820 gcggtatttc acaccgcata cgtcaaagca accatagtac gcgccctgta gcggcgcatt 5880 aagcgcggcg ggtgtggtgg ttacgcgcag cgtgaccgct acacttgcca gcgccctagc 5940 gcccgctcct ttcgctttct tcccttcctt tctcgccacg ttcgccggct ttccccgtca 6000 agctctaaat cgggggctcc ctttagggtt ccgatttagt gctttacggc acctcgaccc 6060 caaaaaactt gatttgggtg atggttcacg tagtgggcca tcgccctgat agacggtttt 6120 tcgccctttg acgttggagt ccacgttctt taatagtgga ctcttgttcc aaactggaac 6180 aacactcaac cctatctcgg gctattcttt tgatttataa gggattttgc cgatttcggc 6240 ctattggtta aaaaatgagc tgatttaaca aaaatttaac gcgaatttta acaaaatatt 6300 aacgtttaca attttatggt gcactctcag tacaatctgc tctgatgccg catagttaag 6360 ccagccccga cacccgccaa cacccgctga cgcgccctga cgggcttgtc tgctcccggc 6420 atccgcttac agacaagctg tgaccgtctc cgggagctgc atgtgtcaga ggttttcacc 6480 gtcatcaccg aaacgcgcga gacgaaaggg cctcgtgata cgcctatttt tataggttaa 6540 tgtcatgata ataatggttt cttagacgtc aggtggcact tttcgggggaa atgtgcgcgg 6600 aacccctatt tgtttatttt tctaaataca ttcaaatatg tatccgctca tgagacaata 6660 accctgataa atgcttcaat aatattgaaa aaggaagagt atgagtattc aacatttccg 6720 tgtcgccctt attccctttt ttgcggcatt ttgccttcct gtttttgctc acccagaaac 6780 gctggtgaaa gtaaaagatg ctgaagatca gttgggtgca cgagtgggtt acatcgaact 6840 ggatctcaac agcggtaaga tccttgagag ttttcgcccc gaagaacgtt ttccaatgat 6900 gagcactttt aaagttctgc tatgtggcgc ggtattatcc cgtattgacg ccgggcaaga 6960 gcaactcggt cgccgcatac actattctca gaatgacttg gttgagtact caccagtcac 7020 agaaaagcat cttacggatg gcatgacagt aagagaatta tgcagtgctg ccataaccat 7080 gagtgataac actgcggcca acttacttct gacaacgatc ggaggaccga aggagctaac 7140 cgcttttttg cacaacatgg gggatcatgt aactcgcctt gatcgttggg aaccggagct 7200 gaatgaagcc ataccaaacg acgagcgtga cacca 7235 <210> 72 <211> 7262 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 72 cgatgcctgt agcaatggca acaacgttgc gcaaactatt aactggcgaa ctacttactc 60 tagcttcccg gcaacaatta atagactgga tggaggcgga taaagttgca ggaccacttc 120 tgcgctcggc ccttccggct ggctggttta ttgctgataa atctggagcc ggtgagcgtg 180 ggtctcgcgg tatcattgca gcactggggc cagatggtaa gccctcccgt atcgtagtta 240 tctacacgac ggggagtcag gcaactatgg atgaacgaaa tagacagatc gctgagatag 300 gtgcctcact gattaagcat tggtaactgt cagaccaagt ttactcatat atactttaga 360 ttgatttaaa acttcatttt taatttaaaa ggatctaggt gaagatcctt tttgataatc 420 tcatgaccaa aatcccttaa cgtgagtttt cgttccactg agcgtcagac cccgtagaaa 480 agatcaaagg atcttcttga gatccttttt ttctgcgcgt aatctgctgc ttgcaaacaa 540 aaaaaccacc gctaccagcg gtggtttgtt tgccggatca agagctacca actctttttc 600 cgaaggtaac tggcttcagc agagcgcaga taccaaatac tgtccttcta gtgtagccgt 660 agttaggcca ccacttcaag aactctgtag caccgcctac atacctcgct ctgctaatcc 720 tgttaccagt ggctgctgcc agtggcgata agtcgtgtct taccgggttg gactcaagac 780 gatagttacc ggataaggcg cagcggtcgg gctgaacggg gggttcgtgc acacagccca 840 gcttggagcg aacgacctac accgaactga gatacctaca gcgtgagcta tgagaaagcg 900 ccacgcttcc cgaagggaga aaggcggaca ggtatccggt aagcggcagg gtcggaacag 960 gagagcgcac gagggagctt ccagggggaa acgcctggta tctttatagt cctgtcgggt 1020 ttcgccacct ctgacttgag cgtcgatttt tgtgatgctc gtcagggggg cggagcctat 1080 ggaaaaacgc cagcaacgcg gcctttttac ggttcctggc cttttgctgg ccttttgctc 1140 acatgtcctg caggcagctg cgcgctcgct cgctcactga ggccgcccgg gcaaagcccg 1200 ggcgtcgggc gacctttggt cgcccggcct cagtgagcga gcgagcgcgc agagaggag 1260 tggccaactc catcactagg ggttcctgcg gccgcacgcg taactgggca atgcgttaaa 1320 ctggcttttt tgacttccca gaacaatatc taattagcaa ataacacaat tcagtgacat 1380 tcagcaggat gcaaattcca gacactgcaa tcatgaacac tgtgaagaca gtcttctccg 1440 tgggccggga cacaaagcag tccacagtgt tgggacaagg ccaggcgttg cacttcacca 1500 gccgctgcat ggagaagccg tcgtacatga catagaagac gtacatgaag gcggcttcga 1560 agatgacccg gaagaagatg ctgcttgtgt aggtccacca cagggagcct tcgatgcgga 1620 ccttctgggt tttgatctcc tcgatgtcct taaattcact ctttatctcc cccttgatga 1680 acttcctctt cttctcatgt ctccggtagg ccacgtgcat ggccactagg agcgctggcg 1740 tggacacgaa gatcagctgc agggcccata gccggatgtg ggagatgggg aagtagtgat 1800 cgtagcacac gttcttgcag cctggctgca gggtgttgca gacaaagtcg gcctgctcat 1860 ctccccacac ctcctttgca gccacaacga ggatcataat gcgaaaaatg aagaggacgg 1920 tgagccagat ctttccaatg ctggtggagt gtttgttcac accccccagg atcgtctgca 1980 gcgtgcccca atccatcttc tactctgggc ggtttgctct ggaaaagacg aatgcacaca 2040 acacaggaat cactagctag gacagaacag ggagacttct ctgagtctgg gtaagcaagc 2100 atgcttaaat ctcttcctga gcaaacacca actcttacac aacctcacca aaacaggtga 2160 agacagaacc aacttagttt gtcattaatt aagacctcga aggggacttg gggggttcgg 2220 ggctttcggg ggcggtcggg ggttcgcgga cccgggaagc tctgaggacc cagaggccgg 2280 gcgcgctccg cccgcggcgc cgccccctcc gtaactttcc cagtctccga gggaagaggc 2340 ggggtgtggg gtgcggttaa aaggcgccac ggcgggagac aggtgttgcg gccccgcagc 2400 gcccgcgcgc tcctctcccc gactcggagc ccctcggcgg cgcccggccc aggacccgcc 2460 taggagcgca ggagccccag cgcagagacc ccaacgccga gacccccgcc ccggccccgc 2520 cgcgcttcct cccgacgcag agcaaaccgc ccagagtaga agccatggtg agcaagggcg 2580 aggagctgtt caccggggtg gtgcccatcc tggtcgagct ggacggcgac gtaaacggcc 2640 acaagttcag cgtgtccggc gagggcgagg gcgatgccac ctacggcaag ctgaccctga 2700 agttcatctg caccaccggc aagctgcccg tgccctggcc caccctcgtg accaccctga 2760 cctacggcgt gcagtgcttc agccgctacc ccgaccacat gaagcagcac gacttcttca 2820 agtccgccat gcccgaaggc tacgtccagg agcgcaccat cttcttcaag gacgacggca 2880 actacaagac ccgcgccgag gtgaagttcg agggcgacac cctggtgaac cgcatcgagc 2940 tgaagggcat cgacttcaag gaggacggca acatcctggg gcacaagctg gagtacaact 3000 acaacagcca caacgtctat atcatggccg acaagcagaa gaacggcatc aaggtgaact 3060 tcaagatccg ccacaacatc gaggacggca gcgtgcagct cgccgaccac taccagcaga 3120 acacccccat cggcgacggc cccgtgctgc tgcccgacaa ccactacctg agcacccagt 3180 ccgccctgag caaagacccc aacgagaagc gcgatcacat ggtcctgctg gagttcgtga 3240 ccgccgccgg gatcactctc ggcatggacg agctgtacaa gtaataaagg cgcgccaccc 3300 ctgcagggaa ttccgcattg cccagttgtt agattaagaa atagacagca tgagagggat 3360 gaggcaaccc gtgctcagct gtcaaggctc agtcgctagc atttcccaac acaaagattc 3420 tgaccttaaa tgcaaccatt tgaaacccct gtaggcctca ggtgaaactc cagatgccac 3480 aatggagctc tgctccccta aagcctcaaa acaaaggcct aattctatgc ctgtcttaat 3540 tttctttcac ttaagttagt tccactgaga ccccaggctg ttaggggtta ttggtgtaag 3600 gtactttcat attttaaaca gaggatatcg gcatttgttt ctttctctga ggacaagaga 3660 aaaaagccag gttccacaga ggacacagag aaggtttggg tgtcctcctg gggttctttt 3720 tgccaacttt ccccacgtta aaggtgaaca ttggttcttt catttgcttt ggaagtttta 3780 atctctaaca gtggacaaag ttaccagtgc cttaaactct gttacacttt ttggaagtga 3840 aaactttgta gtatgatagg ttattttgat gtaaagatgt tctggatacc attatatgtt 3900 ccccctgttt cagaggctca gattgtaata tgtaaatggt atgtcattcg ctactatgat 3960 ttaatttgaa atatggtctt ttggttatga atactttgca gcacagctga gaggctgtct 4020 gttgtattca ttgtggtcat agcacctaac aacattgtag cctcaatcga gtgagacaga 4080 ctagaagttc ctagtgatgg cttatgatag caaatggcct catgtcaaat atttagatgt 4140 aattttgtgt aagaaataca gactggatgt accaccaact actacctgta atgacaggcc 4200 tgtccaacac atctcccttt tccatgactg tggtagccag catcggaaag aacgctgatt 4260 taaagaggtc gcttgggaat tttatgaca cagtaccatt taatggggag gacaaaatgg 4320 ggcaggggag ggagaagttt ctgtcgttaa aaacagattt ggaaagactg gactctaaag 4380 tctgttgatt aaagatgagc tttgtctact tcaaaagttt gtttgcttac cccttcagcc 4440 tccaattttt taagtgaaaa tatagctaat aacatgtgaa aagaatagaa gctaaggttt 4500 agataaatat tgagcagatc tataggaaga ttgaacctga atattgccat tatgcttgac 4560 atggtttcca aaaaatggta ctccacatat ttcagtgagg gtaagtattt tcctgttgtc 4620 aagaatagca ttgtaaaagc attttgtaat aataaagaat agctttaatg atatgcttgt 4680 aactaaaata attttgtaat gtatcaaata catttaaaac attaaaatat aatctctata 4740 ataatttaaa atctaatatg gttttaatag aacagcgata tcaagcttat cgataatcaa 4800 cctctggatt acaaaatttg tgaaagattg actggtattc ttaactatgt tgctcctttt 4860 acgctatgtg gatacgctgc tttaatgcct ttgtatcatg ctattgcttc ccgtatggct 4920 ttcattttct cctccttgta taaatcctgg ttgctgtctc tttatgagga gttgtggccc 4980 gttgtcaggc aacgtggcgt ggtgtgcact gtgtttgctg acgcaacccc cactggttgg 5040 ggcattgcca ccacctgtca gctcctttcc gggactttcg ctttccccct ccctattgcc 5100 acggcggaac tcatcgccgc ctgccttgcc cgctgctgga caggggctcg gctgttgggc 5160 actgacaatt ccgtggtgtt gtcggggaaa tcatcgtcct ttccttggct gctcgcctat 5220 gttgccacct ggattctgcg cgggacgtcc ttctgctacg tcccttcggc cctcaatcca 5280 gcggaccttc cttcccgcgg cctgctgccg gctctgcggc ctcttccgcg tcttcgcctt 5340 cgccctcaga cgagtcggat ctccctttgg gccgcctccc cgcgaattca tcgataccga 5400 gcgctgctcg agagatctgt gatagcggcc atcaagctgg ctgtgccttc tagttgccag 5460 ccatctgttg tttgcccctc ccccgtgcct tccttgaccc tggaaggtgc cactcccact 5520 gtcctttcct aataaaatga ggaaattgca tcgcattgtc tgagtaggtg tcattctatt 5580 ctggggggtg gggtggggca ggacagcaag ggggaggatt gggaagacaa tagcaggcat 5640 gctggggaca cgtgcggacc gagcggccgc aggaacccct agtgatggag ttggccactc 5700 cctctctgcg cgctcgctcg ctcactgagg ccgggcgacc aaaggtcgcc cgacgcccgg 5760 gctttgcccg ggcggcctca gtgagcgagc gagcgcgcag ctgcctgcag gggcgcctga 5820 tgcggtattt tctccttacg catctgtgcg gtatttcaca ccgcatacgt caaagcaacc 5880 atagtacgcg ccctgtagcg gcgcattaag cgcggcgggt gtggtggtta cgcgcagcgt 5940 gaccgctaca cttgccagcg ccctagcgcc cgctcctttc gctttcttcc cttcctttct 6000 cgccacgttc gccggctttc cccgtcaagc tctaaatcgg gggctccctt tagggttccg 6060 atttagtgct ttacggcacc tcgaccccaa aaaacttgat ttgggtgatg gttcacgtag 6120 tgggccatcg ccctgataga cggtttttcg ccctttgacg ttggagtcca cgttctttaa 6180 tagtggactc ttgttccaaa ctggaacaac actcaaccct atctcgggct attcttttga 6240 tttataaggg attttgccga tttcggccta ttggttaaaa aatgagctga tttaacaaaa 6300 atttaacgcg aattttaaca aaatattaac gtttacaatt ttatggtgca ctctcagtac 6360 aatctgctct gatgccgcat agttaagcca gccccgacac ccgccaacac ccgctgacgc 6420 gccctgacgg gcttgtctgc tcccggcatc cgcttacaga caagctgtga ccgtctccgg 6480 gagctgcatg tgtcagaggt tttcaccgtc atcaccgaaa cgcgcgagac gaaagggcct 6540 cgtgatacgc ctatttttat aggttaatgt catgataata atggtttctt agacgtcagg 6600 tggcactttt cggggaaatg tgcgcggaac ccctatttgt ttatttttct aaatacattc 6660 aaatatgtat ccgctcatga gacaataacc ctgataaatg cttcaataat attgaaaaag 6720 gaagagtatg agtattcaac atttccgtgt cgcccttatt cccttttttg cggcattttg 6780 ccttcctgtt tttgctcacc cagaaacgct ggtgaaagta aaagatgctg aagatcagtt 6840 gggtgcacga gtggggttaca tcgaactgga tctcaacagc ggtaagatcc ttgagagttt 6900 tcgccccgaa gaacgttttc caatgatgag cacttttaaa gttctgctat gtggcgcggt 6960 attatcccgt attgacgccg ggcaagagca actcggtcgc cgcatacact attctcagaa 7020 tgacttggtt gagtactcac cagtcacaga aaagcatctt acggatggca tgacagtaag 7080 agaattatgc agtgctgcca taaccatgag tgataacact gcggccaact tacttctgac 7140 aacgatcgga ggaccgaagg agctaaccgc ttttttgcac aacatggggg atcatgtaac 7200 tcgccttgat cgttgggaac cggagctgaa tgaagccata ccaaacgacg agcgtgacac 7260 ca 7262 <210> 73 <211> 7220 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 73 cgatgcctgt agcaatggca acaacgttgc gcaaactatt aactggcgaa ctacttactc 60 tagcttcccg gcaacaatta atagactgga tggaggcgga taaagttgca ggaccacttc 120 tgcgctcggc ccttccggct ggctggttta ttgctgataa atctggagcc ggtgagcgtg 180 ggtctcgcgg tatcattgca gcactggggc cagatggtaa gccctcccgt atcgtagtta 240 tctacacgac ggggagtcag gcaactatgg atgaacgaaa tagacagatc gctgagatag 300 gtgcctcact gattaagcat tggtaactgt cagaccaagt ttactcatat atactttaga 360 ttgatttaaa acttcatttt taatttaaaa ggatctaggt gaagatcctt tttgataatc 420 tcatgaccaa aatcccttaa cgtgagtttt cgttccactg agcgtcagac cccgtagaaa 480 agatcaaagg atcttcttga gatccttttt ttctgcgcgt aatctgctgc ttgcaaacaa 540 aaaaaccacc gctaccagcg gtggtttgtt tgccggatca agagctacca actctttttc 600 cgaaggtaac tggcttcagc agagcgcaga taccaaatac tgtccttcta gtgtagccgt 660 agttaggcca ccacttcaag aactctgtag caccgcctac atacctcgct ctgctaatcc 720 tgttaccagt ggctgctgcc agtggcgata agtcgtgtct taccgggttg gactcaagac 780 gatagttacc ggataaggcg cagcggtcgg gctgaacggg gggttcgtgc acacagccca 840 gcttggagcg aacgacctac accgaactga gatacctaca gcgtgagcta tgagaaagcg 900 ccacgcttcc cgaagggaga aaggcggaca ggtatccggt aagcggcagg gtcggaacag 960 gagagcgcac gagggagctt ccagggggaa acgcctggta tctttatagt cctgtcgggt 1020 ttcgccacct ctgacttgag cgtcgatttt tgtgatgctc gtcagggggg cggagcctat 1080 ggaaaaacgc cagcaacgcg gcctttttac ggttcctggc cttttgctgg ccttttgctc 1140 acatgtcctg caggcagctg cgcgctcgct cgctcactga ggccgcccgg gcaaagcccg 1200 ggcgtcgggc gacctttggt cgcccggcct cagtgagcga gcgagcgcgc agagaggag 1260 tggccaactc catcactagg ggttcctgcg gccgcacgcg taactgggca atgcgttaaa 1320 ctggcttttt tgacttccca gaacaatatc taattagcaa ataacacaat tcagtgacat 1380 tcagcaggat gcaaattcca gacactgcaa tcatgaacac tgtgaagaca gtcttctccg 1440 tgggccggga cacaaagcag tccacagtgt tgggacaagg ccaggcgttg cacttcacca 1500 gccgctgcat ggagaagccg tcgtacatga catagaagac gtacatgaag gcggcttcga 1560 agatgacccg gaagaagatg ctgcttgtgt aggtccacca cagggagcct tcgatgcgga 1620 ccttctgggt tttgatctcc tcgatgtcct taaattcact ctttatctcc cccttgatga 1680 acttcctctt cttctcatgt ctccggtagg ccacgtgcat ggccactagg agcgctggcg 1740 tggacacgaa gatcagctgc agggcccata gccggatgtg ggagatgggg aagtagtgat 1800 cgtagcacac gttcttgcag cctggctgca gggtgttgca gacaaagtcg gcctgctcat 1860 ctccccacac ctcctttgca gccacaacga ggatcataat gcgaaaaatg aagaggacgg 1920 tgagccagat ctttccaatg ctggtggagt gtttgttcac accccccagg atcgtctgca 1980 gcgtgcccca atccatcttc tactctgggc ggtttgctct ggaaaagacg aatgcacaca 2040 acacaggaat cactagctag gacagaacag ggagacttct ctgagtctgg gtaagcaagc 2100 atgcttaaat ctcttcctga gcaaacacca actcttacac aacctcacca aaacaggtga 2160 agacagaacc aacttagttt gtcattaatt aagacctcga aggggacttg gggggttcgg 2220 ggctttcggg ggcggtcggg ggttcgcgga cccgggaagc tctgaggacc cagaggccgg 2280 gcgcgctccg cccgcggcgc cgccccctcc gtaactttcc cagtctccga gggaagaggc 2340 ggggtgtggg gtgcggttaa aaggcgccac ggcgggagac aggtgttgcg gccccgcagc 2400 gcccgcgcgc tcctctcccc gactcggagc ccctcggcgg cgcccggccc aggacccgcc 2460 taggagcgca ggagccccag cgcagagacc ccaacgccga gacccccgcc ccggccccgc 2520 cgcgcttcct cccgacgcag agcaaaccgc ccagagtaga agccatggat tggggcacgc 2580 tgcagacgat cctggggggt gtgaacaaac actccaccag cattggaaag atctggctca 2640 ccgtcctctt catttttcgc attatgatcc tcgttgtggc tgcaaaggag gtgtggggag 2700 atgagcaggc cgactttgtc tgcaacaccc tgcagccagg ctgcaagaac gtggtgctacg 2760 atcactactt ccccatctcc cacatccggc tatgggccct gcagctgatc ttcgtgtcca 2820 cgccagcgct cctagtggcc atgcacgtgg cctaccggag acatgagaag aagaggaagt 2880 tcatcaaggg ggagataaag agtgaattta aggagacatcga ggagatcaaa acccagaagg 2940 tccgcatcga aggctccctg tggtggacct acacaagcag catcttcttc cgggtcatct 3000 tcgaagccgc cttcatgtac gtcttctatg tcatgtacga cggcttctcc atgcagcggc 3060 tggtgaagtg caacgcctgg ccttgtccca acactgtgga ctgctttgtg tcccggccca 3120 cggagaagac tgtcttcaca gtgttcatga ttgcagtgtc tggaatttgc atcctgctga 3180 atgtcactga attgtgttat ttgctaatta gatattgttc tgggaagtca aaaaagccag 3240 tttaaaggcg cgccacccct gcagggaatt ccgcattgcc cagttgttag attaagaaat 3300 agacagcatg agagggatga ggcaacccgt gctcagctgt caaggctcag tcgctagcat 3360 ttcccaacac aaagattctg accttaaatg caaccatttg aaacccctgt aggcctcagg 3420 tgaaactcca gatgccacaa tggagctctg ctcccctaaa gcctcaaaac aaaggcctaa 3480 ttctatgcct gtcttaattt tctttcactt aagttagttc cactgagacc ccaggctgtt 3540 aggggttat ggtgtaaggt actttcatat tttaaacaga ggatatcggc atttgtttct 3600 ttctctgagg acaagagaaa aaagccaggt tccacagagg acacagagaa ggtttgggtg 3660 tcctcctggg gttctttttg ccaactttcc ccacgttaaa ggtgaacatt ggttctttca 3720 tttgctttgg aagttttaat ctctaacagt ggacaaagtt accagtgcct taaactctgt 3780 tacacttttt ggaagtgaaa actttgtagt atgataggtt attttgatgt aaagatgttc 3840 tggataccat tatatgttcc ccctgtttca gaggctcaga ttgtaatatg taaatggtat 3900 gtcattcgct actatgattt aatttgaaat atggtctttt ggttatgaat actttgcagc 3960 acagctgaga ggctgtctgt tgtattcatt gtggtcatag cacctaacaa cattgtagcc 4020 tcaatcgagt gagacagact agaagttcct agtgatggct tatgatagca aatggcctca 4080 tgtcaaatat ttagatgtaa ttttgtgtaa gaaatacaga ctggatgtac caccaactac 4140 tacctgtaat gacaggcctg tccaacacat ctcccttttc catgactgtg gtagccagca 4200 tcggaaagaa cgctgattta aagaggtcgc ttgggaattt tattgacaca gtaccattta 4260 atggggagga caaaatgggg caggggaggg agaagtttct gtcgttaaaa acagatttgg 4320 aaagactgga ctctaaagtc tgttgattaa agatgagctt tgtctacttc aaaagtttgt 4380 ttgcttaccc cttcagcctc caatttttta agtgaaaata tagctaataa catgtgaaaa 4440 gaatagaagc taaggtttag ataaatattg agcagatcta taggaagatt gaacctgaat 4500 attgccatta tgcttgacat ggtttccaaa aaatggtact ccacatattt cagtgagggt 4560 aagtattttc ctgttgtcaa gaatagcatt gtaaaagcat tttgtaataa taaagaatag 4620 ctttaatgat atgcttgtaa ctaaaataat tttgtaatgt atcaaataca tttaaaacat 4680 taaaatataa tctctataat aatttaaaat ctaatatggt tttaatagaa cagcgatatc 4740 aagctttcg ataatcaacc tctggattac aaaatttgtg aaagattgac tggtattctt 4800 aactatgttg ctccttttac gctatgtgga tacgctgctt taatgccttt gtatcatgct 4860 attgcttccc gtatggcttt cattttctcc tccttgtata aatcctggtt gctgtctctt 4920 tatgaggagt tgtggcccgt tgtcaggcaa cgtggcgtgg tgtgcactgt gtttgctgac 4980 gcaaccccca ctggttgggg cattgccacc acctgtcagc tcctttccgg gactttcgct 5040 ttccccctcc ctattgccac ggcggaactc atcgccgcct gccttgcccg ctgctggaca 5100 ggggctcggc tgttgggcac tgacaattcc gtggtgttgt cggggaaatc atcgtccttt 5160 ccttggctgc tcgcctatgt tgccacctgg attctgcgcg ggacgtcctt ctgctacgtc 5220 ccttcggccc tcaatccagc ggaccttcct tcccgcggcc tgctgccggc tctgcggcct 5280 cttccgcgtc ttcgccttcg ccctcagacg agtcggatct ccctttgggc cgcctccccg 5340 cgaattcatc gataccgagc gctgctcgag agatctgtga tagcggccat caagctggct 5400 gtgccttcta gttgccagcc atctgttgtt tgcccctccc ccgtgccttc cttgaccctg 5460 gaaggtgcca ctcccactgt cctttcctaa taaaatgagg aaattgcatc gcattgtctg 5520 agtaggtgtc attctattct ggggggtggg gtggggcagg acagcaaggg ggaggattgg 5580 gaagacaata gcaggcatgc tggggacacg tgcggaccga gcggccgcag gaacccctag 5640 tgatggagtt ggccactccc tctctgcgcg ctcgctcgct cactgaggcc gggcgaccaa 5700 aggtcgcccg acgcccgggc tttgcccggg cggcctcagt gagcgagcga gcgcgcagct 5760 gcctgcaggg gcgcctgatg cggtattttc tccttacgca tctgtgcggt atttcacacc 5820 gcatacgtca aagcaaccat agtacgcgcc ctgtagcggc gcattaagcg cggcgggtgt 5880 ggtggttacg cgcagcgtga ccgctacact tgccagcgcc ctagcgcccg ctcctttcgc 5940 tttcttccct tcctttctcg ccacgttcgc cggctttccc cgtcaagctc taaatcgggg 6000 gctcccttta gggttccgat ttagtgcttt acggcacctc gaccccaaaa aacttgattt 6060 gggtgatggt tcacgtagtg ggccatcgcc ctgatagacg gtttttcgcc ctttgacgtt 6120 ggagtccacg ttctttaata gtggactctt gttccaaact ggaacaacac tcaaccctat 6180 ctcgggctat tcttttgatt tataagggat tttgccgatt tcggcctatt ggttaaaaaa 6240 tgagctgatt taacaaaaat ttaacgcgaa ttttaacaaa atattaacgt ttacaatttt 6300 atggtgcact ctcagtacaa tctgctctga tgccgcatag ttaagccagc cccgacaccc 6360 gccaacccc gctgacgcgc cctgacgggc ttgtctgctc ccggcatccg cttacagaca 6420 agctgtgacc gtctccggga gctgcatgtg tcagaggttt tcaccgtcat caccgaaacg 6480 cgcgagacga aagggcctcg tgatacgcct atttttatag gttaatgtca tgataataat 6540 ggtttcttag acgtcaggtg gcacttttcg gggaaatgtg cgcggaaccc ctatttgttt 6600 atttttctaa atacattcaa atatgtatcc gctcatgaga caataaccct gataaatgct 6660 tcaataatat tgaaaaagga agagtatgag tattcaacat ttccgtgtcg cccttattcc 6720 cttttttgcg gcattttgcc ttcctgtttt tgctcaccca gaaacgctgg tgaaagtaaa 6780 agatgctgaa gatcagttgg gtgcacgagt gggttacatc gaactggatc tcaacagcgg 6840 taagatcctt gagagttttc gccccgaaga acgttttcca atgatgagca cttttaaagt 6900 tctgctatgt ggcgcggtat tatcccgtat tgacgccggg caagagcaac tcggtcgccg 6960 catacactat tctcagaatg acttggttga gtactcacca gtcacagaaa agcatcttac 7020 ggatggcatg acagtaagag aattatgcag tgctgccata accatgagtg ataacactgc 7080 ggccaactta cttctgacaa cgatcggagg accgaaggag ctaaccgctt ttttgcacaa 7140 catgggggat catgtaactc gccttgatcg ttgggaaccg gagctgaatg aagccatacc 7200 aaacgacgag cgtgacacca 7220 <210> 74 <211> 7247 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 74 cgatgcctgt agcaatggca acaacgttgc gcaaactatt aactggcgaa ctacttactc 60 tagcttcccg gcaacaatta atagactgga tggaggcgga taaagttgca ggaccacttc 120 tgcgctcggc ccttccggct ggctggttta ttgctgataa atctggagcc ggtgagcgtg 180 ggtctcgcgg tatcattgca gcactggggc cagatggtaa gccctcccgt atcgtagtta 240 tctacacgac ggggagtcag gcaactatgg atgaacgaaa tagacagatc gctgagatag 300 gtgcctcact gattaagcat tggtaactgt cagaccaagt ttactcatat atactttaga 360 ttgatttaaa acttcatttt taatttaaaa ggatctaggt gaagatcctt tttgataatc 420 tcatgaccaa aatcccttaa cgtgagtttt cgttccactg agcgtcagac cccgtagaaa 480 agatcaaagg atcttcttga gatccttttt ttctgcgcgt aatctgctgc ttgcaaacaa 540 aaaaaccacc gctaccagcg gtggtttgtt tgccggatca agagctacca actctttttc 600 cgaaggtaac tggcttcagc agagcgcaga taccaaatac tgtccttcta gtgtagccgt 660 agttaggcca ccacttcaag aactctgtag caccgcctac atacctcgct ctgctaatcc 720 tgttaccagt ggctgctgcc agtggcgata agtcgtgtct taccgggttg gactcaagac 780 gatagttacc ggataaggcg cagcggtcgg gctgaacggg gggttcgtgc acacagccca 840 gcttggagcg aacgacctac accgaactga gatacctaca gcgtgagcta tgagaaagcg 900 ccacgcttcc cgaagggaga aaggcggaca ggtatccggt aagcggcagg gtcggaacag 960 gagagcgcac gagggagctt ccagggggaa acgcctggta tctttatagt cctgtcgggt 1020 ttcgccacct ctgacttgag cgtcgatttt tgtgatgctc gtcagggggg cggagcctat 1080 ggaaaaacgc cagcaacgcg gcctttttac ggttcctggc cttttgctgg ccttttgctc 1140 acatgtcctg caggcagctg cgcgctcgct cgctcactga ggccgcccgg gcaaagcccg 1200 ggcgtcgggc gacctttggt cgcccggcct cagtgagcga gcgagcgcgc agagaggag 1260 tggccaactc catcactagg ggttcctgcg gccgcacgcg taactgggca atgcgttaaa 1320 ctggcttttt tgacttccca gaacaatatc taattagcaa ataacacaat tcagtgacat 1380 tcagcaggat gcaaattcca gacactgcaa tcatgaacac tgtgaagaca gtcttctccg 1440 tgggccggga cacaaagcag tccacagtgt tgggacaagg ccaggcgttg cacttcacca 1500 gccgctgcat ggagaagccg tcgtacatga catagaagac gtacatgaag gcggcttcga 1560 agatgacccg gaagaagatg ctgcttgtgt aggtccacca cagggagcct tcgatgcgga 1620 ccttctgggt tttgatctcc tcgatgtcct taaattcact ctttatctcc cccttgatga 1680 acttcctctt cttctcatgt ctccggtagg ccacgtgcat ggccactagg agcgctggcg 1740 tggacacgaa gatcagctgc agggcccata gccggatgtg ggagatgggg aagtagtgat 1800 cgtagcacac gttcttgcag cctggctgca gggtgttgca gacaaagtcg gcctgctcat 1860 ctccccacac ctcctttgca gccacaacga ggatcataat gcgaaaaatg aagaggacgg 1920 tgagccagat ctttccaatg ctggtggagt gtttgttcac accccccagg atcgtctgca 1980 gcgtgcccca atccatcttc tactctgggc ggtttgctct ggaaaagacg aatgcacaca 2040 acacaggaat cactagctag gacagaacag ggagacttct ctgagtctgg gtaagcaagc 2100 atgcttaaat ctcttcctga gcaaacacca actcttacac aacctcacca aaacaggtga 2160 agacagaacc aacttagttt gtcattaatt aagacctcga aggggacttg gggggttcgg 2220 ggctttcggg ggcggtcggg ggttcgcgga cccgggaagc tctgaggacc cagaggccgg 2280 gcgcgctccg cccgcggcgc cgccccctcc gtaactttcc cagtctccga gggaagaggc 2340 ggggtgtggg gtgcggttaa aaggcgccac ggcgggagac aggtgttgcg gccccgcagc 2400 gcccgcgcgc tcctctcccc gactcggagc ccctcggcgg cgcccggccc aggacccgcc 2460 taggagcgca ggagccccag cgcagagacc ccaacgccga gacccccgcc ccggccccgc 2520 cgcgcttcct cccgacgcag agcaaaccgc ccagagtaga agccatggat tggggcacac 2580 tccagagcat cctcgggggt gtcaacaaac actccaccag cattggaaag atctggctca 2640 cggtcctctt catcttccgc atcatgatcc tcgtggtggc tgcaaaggag gtgtggggag 2700 atgagcaagc cgattttgtc tgcaacacgc tccagcctgg ctgcaagaat gtatgctacg 2760 accaccactt ccccatctct cacatccggc tctgggctct gcagctgatc atggtgtcca 2820 cgccagccct cctggtagct atgcatgtgg cctaccggag acatgaaaag aaacggaagt 2880 tcatgaaggg agagataaag aacgagttta aggacatcga agagatcaaa acccagaagg 2940 tccgtatcga agggtccctg tggtggacct acaccaccag catcttcttc cgggtcatct 3000 ttgaagccgt cttcatgtac gtcttttaca tcatgtacaa tggcttcttc atgcaacgtc 3060 tggtgaaatg caacgcttgg ccctgcccca atacagtgga ctgcttcatt tccaggccca 3120 cagaaaagac tgtcttcacc gtgtttatga tttctgtgtc tggaatttgc attctgctaa 3180 atatcacaga gctgtgctat ttgttcgtta ggtattgctc aggaaagtcc aaaagaccag 3240 tctacccata cgatgttcca gattacgctt aaaggcgcgc cacccctgca gggaattccg 3300 cattgcccag ttgttagatt aagaaataga cagcatgaga gggatgaggc aacccgtgct 3360 cagctgtcaa ggctcagtcg ctagcatttc ccaacacaaa gattctgacc ttaaatgcaa 3420 ccatttgaaa cccctgtagg cctcaggtga aactccagat gccacaatgg agctctgctc 3480 ccctaaagcc tcaaaacaaa ggcctaattc tatgcctgtc ttaattttct ttcacttaag 3540 ttagttccac tgagacccca ggctgttagg ggttattggt gtaaggtact ttcatatttt 3600 aaacagagga tatcggcatt tgtttctttc tctgaggaca agagaaaaaa gccaggttcc 3660 acagaggaca cagagaaggt ttgggtgtcc tcctggggtt ctttttgcca actttcccca 3720 cgttaaaggt gaacattggt tctttcattt gctttggaag ttttaatctc taacagtgga 3780 caaagttacc agtgccttaa actctgttac actttttgga agtgaaaact ttgtagtatg 3840 ataggttatt ttgatgtaaa gatgttctgg ataccattat atgttccccc tgtttcagag 3900 gctcagattg taatatgtaa atggtatgtc attcgctact atgatttaat ttgaaatatg 3960 gtcttttggt tatgaatact ttgcagcaca gctgagaggc tgtctgttgt attcattgtg 4020 gtcatagcac ctaacaacat tgtagcctca atcgagtgag acagactaga agttcctagt 4080 gatggcttat gatagcaaat ggcctcatgt caaatattta gatgtaattt tgtgtaagaa 4140 atacagactg gatgtaccac caactactac ctgtaatgac aggcctgtcc aacacatctc 4200 ccttttccat gactgtggta gccagcatcg gaaagaacgc tgatttaaag aggtcgcttg 4260 ggaattttat tgacacagta ccatttaatg gggaggacaa aatggggcag gggagggaga 4320 agtttctgtc gttaaaaaca gatttggaaa gactggactc taaagtctgt tgattaaaga 4380 tgagctttgt ctacttcaaa agtttgtttg cttacccctt cagcctccaa ttttttaagt 4440 gaaaatatag ctaataacat gtgaaaagaa tagaagctaa ggtttagata aatattgagc 4500 agatctatag gaagattgaa cctgaatatt gccattatgc ttgacatggt ttccaaaaaa 4560 tggtactcca catatttcag tgagggtaag tattttcctg ttgtcaagaa tagcattgta 4620 aaagcatttt gtaataataa agaatagctt taatgatatg cttgtaacta aaataatttt 4680 gtaatgtatc aaatacattt aaaacattaa aatataatct ctataataat ttaaaatcta 4740 atatggtttt aatagaacag cgatatcaag cttatcgata atcaacctct ggattacaaa 4800 atttgtgaaa gattgactgg tattcttaac tatgttgctc cttttacgct atgtggatac 4860 gctgctttaa tgcctttgta tcatgctatt gcttcccgta tggctttcat tttctcctcc 4920 ttgtataaat cctggttgct gtctctttat gaggagttgt ggcccgttgt caggcaacgt 4980 ggcgtggtgt gcactgtgtt tgctgacgca acccccactg gttggggcat tgccaccacc 5040 tgtcagctcc tttccgggac tttcgctttc cccctcccta ttgccacggc ggaactcatc 5100 gccgcctgcc ttgcccgctg ctggacaggg gctcggctgt tgggcactga caattccgtg 5160 gtgttgtcgg ggaaatcatc gtcctttcct tggctgctcg cctatgttgc cacctggatt 5220 ctgcgcggga cgtccttctg ctacgtccct tcggccctca atccagcgga ccttccttcc 5280 cgcggcctgc tgccggctct gcggcctctt ccgcgtcttc gccttcgccc tcagacgagt 5340 cggatctccc tttgggccgc ctccccgcga attcatcgat accgagcgct gctcgagaga 5400 tctgtgatag cggccatcaa gctggctgtg ccttctagtt gccagccatc tgttgtttgc 5460 ccctcccctg tgccttcctt gaccctggaa ggtgccactc ccactgtcct ttcctaataa 5520 aatgaggaaa ttgcatcgca ttgtctgagt aggtgtcatt ctattctggg gggtggggtg 5580 gggcaggaca gcaaggggga ggattgggaa gacaatagca ggcatgctgg ggacacgtgc 5640 ggaccgagcg gccgcaggaa cccctagtga tggagttggc cactccctct ctgcgcgctc 5700 gctcgctcac tgaggccggg cgaccaaagg tcgcccgacg cccgggcttt gcccgggcgg 5760 cctcagtgag cgagcgagcg cgcagctgcc tgcaggggcg cctgatgcgg tattttctcc 5820 ttacgcatct gtgcggtatt tcacaccgca tacgtcaaag caaccatagt acgcgccctg 5880 tagcggcgca ttaagcgcgg cgggtgtggt ggttacgcgc agcgtgaccg ctacacttgc 5940 cagcgcccta gcgcccgctc ctttcgcttt cttcccttcc tttctcgcca cgttcgccgg 6000 ctttccccgt caagctctaa atcgggggct ccctttaggg ttccgattta gtgctttacg 6060 gcacctcgac cccaaaaaac ttgatttggg tgatggttca cgtagtgggc catcgccctg 6120 atagacggtt tttcgccctt tgacgttgga gtccacgttc tttaatagtg gactcttgtt 6180 ccaaactgga acaacactca accctatctc gggctattct tttgatttat aagggatttt 6240 gccgatttcg gcctattggt taaaaaatga gctgatttaa caaaaattta acgcgaattt 6300 taacaaaata ttaacgttta caattttatg gtgcactctc agtacaatct gctctgatgc 6360 cgcatagtta agccagcccc gacacccgcc aacacccgct gacgcgccct gacgggcttg 6420 tctgctcccg gcatccgctt acagacaagc tgtgaccgtc tccgggagct gcatgtgtca 6480 gaggttttca ccgtcatcac cgaaacgcgc gagacgaaag ggcctcgtga tacgcctatt 6540 tttataggtt aatgtcatga taataatggt ttcttagacg tcaggtggca cttttcgggg 6600 aaatgtgcgc ggaaccccta tttgtttatt tttctaaata cattcaaata tgtatccgct 6660 catgagacaa taaccctgat aaatgcttca ataatattga aaaaggaaga gtatgagtat 6720 tcaacatttc cgtgtcgccc ttattccctt ttttgcggca ttttgccttc ctgtttttgc 6780 tcacccagaa acgctggtga aagtaaaaga tgctgaagat cagttgggtg cacgagtggg 6840 ttacatcgaa ctggatctca acagcggtaa gatccttgag agttttcgcc ccgaagaacg 6900 ttttccaatg atgagcactt ttaaagttct gctatgtggc gcggtattat cccgtattga 6960 cgccgggcaa gagcaactcg gtcgccgcat acactattct cagaatgact tggttgagta 7020 ctcaccagtc acagaaaagc atcttacgga tggcatgaca gtaagagaat tatgcagtgc 7080 tgccataacc atgagtgata acactgcggc caacttactt ctgacaacga tcggaggacc 7140 gaaggagcta accgcttttt tgcacaacat gggggatcat gtaactcgcc ttgatcgttg 7200 ggaaccggag ctgaatgaag ccataccaaa cgacgagcgt gacacca 7247 <210> 75 <211> 7204 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 75 cgatgcctgt agcaatggca acaacgttgc gcaaactatt aactggcgaa ctacttactc 60 tagcttcccg gcaacaatta atagactgga tggaggcgga taaagttgca ggaccacttc 120 tgcgctcggc ccttccggct ggctggttta ttgctgataa atctggagcc ggtgagcgtg 180 ggtctcgcgg tatcattgca gcactggggc cagatggtaa gccctcccgt atcgtagtta 240 tctacacgac ggggagtcag gcaactatgg atgaacgaaa tagacagatc gctgagatag 300 gtgcctcact gattaagcat tggtaactgt cagaccaagt ttactcatat atactttaga 360 ttgatttaaa acttcatttt taatttaaaa ggatctaggt gaagatcctt tttgataatc 420 tcatgaccaa aatcccttaa cgtgagtttt cgttccactg agcgtcagac cccgtagaaa 480 agatcaaagg atcttcttga gatccttttt ttctgcgcgt aatctgctgc ttgcaaacaa 540 aaaaaccacc gctaccagcg gtggtttgtt tgccggatca agagctacca actctttttc 600 cgaaggtaac tggcttcagc agagcgcaga taccaaatac tgtccttcta gtgtagccgt 660 agttaggcca ccacttcaag aactctgtag caccgcctac atacctcgct ctgctaatcc 720 tgttaccagt ggctgctgcc agtggcgata agtcgtgtct taccgggttg gactcaagac 780 gatagttacc ggataaggcg cagcggtcgg gctgaacggg gggttcgtgc acacagccca 840 gcttggagcg aacgacctac accgaactga gatacctaca gcgtgagcta tgagaaagcg 900 ccacgcttcc cgaagggaga aaggcggaca ggtatccggt aagcggcagg gtcggaacag 960 gagagcgcac gagggagctt ccagggggaa acgcctggta tctttatagt cctgtcgggt 1020 ttcgccacct ctgacttgag cgtcgatttt tgtgatgctc gtcagggggg cggagcctat 1080 ggaaaaacgc cagcaacgcg gcctttttac ggttcctggc cttttgctgg ccttttgctc 1140 acatgtcctg caggcagctg cgcgctcgct cgctcactga ggccgcccgg gcaaagcccg 1200 ggcgtcgggc gacctttggt cgcccggcct cagtgagcga gcgagcgcgc agagaggag 1260 tggccaactc catcactagg ggttcctgcg gccgcacgcg taagctacta actacaacca 1320 cgagattata gatgtttgct gatattgttc tcagtttggt tattgtgttg tttatgaatg 1380 aaagtagtgt atgtttgtgt gaatttttgt ttttaatttt ttatgagtgc cctaacaaag 1440 attacaaatt gggaatacaa actccagagc aatggagaca gtgacacttt tgtggagggg 1500 tacatgtggc tgttcggggg gttattaaca caggctgctg cccctgccct gcaatgggaa 1560 tccccagggc attggaggat tcaacctctt gcagttacct cttgtaagac agcagatggc 1620 agcagagaga ggctttgcac atccctgcag gttctagttt gcacaaaggg cttctgagag 1680 acctatcaac caattataac atcaagtggc aaaaagagtc cttgataagt tatttcgctt 1740 ctcaaagaaa ccgaaaacgc caaactaatc actagtcttg tttttttttt tcctggcaaa 1800 agcctgctat ctttcatgat ttagctttca tgaaattgtt cctgaagacc cccaaaagaa 1860 acaatttcat gccccgaact ctgttcagag actttgctgt gcctgtcatg tccagcttgc 1920 catatcctgt tttgtaaagt agccacctta tatacacacc tgctgtctgc actgtgacct 1980 cctttcaaaa tcatctttgg ttcttcagag gcctggaata atgctctgcc cagatgaaga 2040 tctccgtaaa tgtgtttttg aaatggctaa tcaaataatg gataccctta ggtatttttg 2100 cagaaacact tggcagcctt ccataatatc cctactatga aatggaaact tgtgaatgag 2160 atgtggcttt aattaagacc tcgaagggga cttggggggt tcggggcttt cgggggcggt 2220 cgggggttcg cggacccggg aagctctgag gacccagagg ccgggcgcgc tccgcccgcg 2280 gcgccgcccc ctccgtaact ttcccagtct ccgagggaag aggcggggtg tggggtgcgg 2340 ttaaaaggcg ccacggcggg agacaggtgt tgcggccccg cagcgcccgc gcgctcctct 2400 ccccgactcg gagcccctcg gcggcgcccg gcccaggacc cgcctaggag cgcaggagcc 2460 ccagcgcaga gaccccaacg ccgagacccc cgccccggcc ccgccgcgct tcctcccgac 2520 gcagagcaaa ccgcccagag tagaagccat ggattggggc acgctgcaga cgatcctggg 2580 gggtgtgaac aaacactcca ccagcattgg aaagatctgg ctcaccgtcc tcttcatttt 2640 tcgcattatg atcctcgttg tggctgcaaa ggaggtgtgg ggagatgagc aggccgactt 2700 tgtctgcaac accctgcagc caggctgcaa gaacgtgtgc tacgatcact acttccccat 2760 ctcccacatc cggctatggg ccctgcagct gatcttcgtg tccacgccag cgctcctagt 2820 ggccatgcac gtggcctacc ggagacatga gaagaagagg aagttcatca aggggggagat 2880 aaagagtgaa tttaaggaca tcgaggagat caaaacccag aaggtccgca tcgaaggctc 2940 cctgtggtgg acctacacaa gcagcatctt cttccgggtc atcttcgaag ccgccttcat 3000 gtacgtcttc tatgtcatgt acgacggctt ctccatgcag cggctggtga agtgcaacgc 3060 ctggccttgt cccaacactg tggactgctt tgtgtcccgg cccacggaga agactgtctt 3120 cacagtgttc atgattgcag tgtctggaat ttgcatcctg ctgaatgtca ctgaattgtg 3180 ttatttgcta attagatatt gttctgggaa gtcaaaaaag ccagtttaaa ggcgcgccac 3240 ccctgcaggg aattccgcat tgcccagttg ttagattaag aaatagacag catgagaggg 3300 atgaggcaac ccgtgctcag ctgtcaaggc tcagtcgcta gcatttccca acacaaagat 3360 tctgacctta aatgcaacca tttgaaaccc ctgtaggcct caggtgaaac tccagatgcc 3420 acaatggagc tctgctcccc taaagcctca aaacaaaggc ctaattctat gcctgtctta 3480 attttctttc acttaagtta gttccactga gaccccaggc tgttaggggt tattggtgta 3540 aggtactttc atattttaaa cagaggatat cggcatttgt ttctttctct gaggacaaga 3600 gaaaaaagcc aggttccaca gaggacacag agaaggtttg ggtgtcctcc tggggttctt 3660 tttgccaact ttccccacgt taaaggtgaa cattggttct ttcatttgct ttggaagttt 3720 taatctctaa cagtggacaa agttaccagt gccttaaact ctgttacact ttttggaagt 3780 gaaaactttg tagtatgata ggttatttg atgtaaagat gttctggata ccattatatg 3840 ttccccctgt ttcagaggct cagattgtaa tatgtaaatg gtatgtcatt cgctactatg 3900 atttaatttg aaatatggtc ttttggttat gaatactttg cagcacagct gagaggctgt 3960 ctgttgtatt cattgtggtc atagcaccta acaacattgt agcctcaatc gagtgagaca 4020 gactagaagt tcctagtgat ggcttatgat agcaaatggc ctcatgtcaa atatttagat 4080 gtaattttgt gtaagaaata cagactggat gtaccaccaa ctactacctg taatgacagg 4140 cctgtccaac acatctccct tttccatgac tgtggtagcc agcatcggaa agaacgctga 4200 tttaaagagg tcgcttggga attttatga cacagtacca tttaatgggg aggacaaaat 4260 ggggcagggg agggaagaagt ttctgtcgtt aaaaacagat ttggaaagac tggactctaa 4320 agtctgttga ttaaagatga gctttgtcta cttcaaaagt ttgtttgctt accccttcag 4380 cctccaattt tttaagtgaa aatatagcta ataacatgtg aaaagaatag aagctaaggt 4440 ttagataaat attgagcaga tctataggaa gattgaacct gaatattgcc attatgcttg 4500 acatggtttc caaaaaatgg tactccacat atttcagtga gggtaagtat tttcctgttg 4560 tcaagaatag cattgtaaaa gcattttgta ataataaaga atagctttaa tgatatgctt 4620 gtaactaaaa taattttgta atgtatcaaa tacatttaaa acattaaaat ataatctcta 4680 taataattta aaatctaata tggttttaat agaacagcga tatcaagctt atcgataatc 4740 aacctctgga ttacaaaatt tgtgaaagat tgactggtat tcttaactat gttgctcctt 4800 ttacgctatg tggatacgct gctttaatgc ctttgtatca tgctattgct tcccgtatgg 4860 ctttcatttt ctcctccttg tataaatcct ggttgctgtc tctttatgag gagttgtggc 4920 ccgttgtcag gcaacgtggc gtggtgtgca ctgtgtttgc tgacgcaacc cccactggtt 4980 ggggcattgc caccacctgt cagctccttt ccgggacttt cgctttcccc ctccctattg 5040 ccacggcgga actcatcgcc gcctgccttg cccgctgctg gacaggggct cggctgttgg 5100 gcactgacaa ttccgtggtg ttgtcgggga aatcatcgtc ctttccttgg ctgctcgcct 5160 atgttgccac ctggattctg cgcgggacgt ccttctgcta cgtcccttcg gccctcaatc 5220 cagcggacct tccttcccgc ggcctgctgc cggctctgcg gcctcttccg cgtcttcgcc 5280 ttcgccctca gacgagtcgg atctcccttt gggccgcctc cccgcgaatt catcgatacc 5340 gagcgctgct cgagagatct gtgatagcgg ccatcaagct ggctgtgcct tctagttgcc 5400 agccatctgt tgtttgcccc tcccccgtgc cttccttgac cctggaaggt gccactccca 5460 ctgtcctttc ctaataaaat gaggaaattg catcgcattg tctgagtagg tgtcattcta 5520 ttctgggggg tggggtgggg caggacagca agggggagga ttgggaagac aatagcaggc 5580 atgctgggga cacgtgcgga ccgagcggcc gcaggaaccc ctagtgatgg agttggccac 5640 tccctctctg cgcgctcgct cgctcactga ggccgggcga ccaaaggtcg cccgacgccc 5700 gggctttgcc cgggcggcct cagtgagcga gcgagcgcgc agctgcctgc aggggcgcct 5760 gatgcggtat tttctcctta cgcatctgtg cggtatttca caccgcatac gtcaaagcaa 5820 ccatagtacg cgccctgtag cggcgcatta agcgcggcgg gtgtggtggt tacgcgcagc 5880 gtgaccgcta cacttgccag cgccctagcg cccgctcctt tcgctttctt cccttccttt 5940 ctcgccacgt tcgccggctt tccccgtcaa gctctaaatc gggggctccc tttagggttc 6000 cgatttagtg ctttacggca cctcgacccc aaaaaacttg atttgggtga tggttcacgt 6060 agtgggccat cgccctgata gacggttttt cgccctttga cgttggagtc cacgttcttt 6120 aatagtggac tcttgttcca aactggaaca acactcaacc ctatctcggg ctattctttt 6180 gatttataag ggattttgcc gatttcggcc tattggttaa aaaatgagct gatttaacaa 6240 aaatttaacg cgaattttaa caaaatatta acgtttacaa ttttatggtg cactctcagt 6300 acaatctgct ctgatgccgc atagttaagc cagccccgac acccgccaac acccgctgac 6360 gcgccctgac gggcttgtct gctcccggca tccgcttaca gacaagctgt gaccgtctcc 6420 gggagctgca tgtgtcagag gttttcaccg tcatcaccga aacgcgcgag acgaaagggc 6480 ctcgtgatac gcctattttt ataggttaat gtcatgataa taatggtttc ttagacgtca 6540 ggtggcactt ttcgggggaaa tgtgcgcgga acccctattt gtttattttt ctaaatacat 6600 tcaaatatgt atccgctcat gagacaataa ccctgataaa tgcttcaata atattgaaaa 6660 aggaagagta tgagtattca acatttccgt gtcgccctta ttcccttttt tgcggcattt 6720 tgccttcctg tttttgctca cccagaaacg ctggtgaaag taaaagatgc tgaagatcag 6780 ttgggtgcac gagtgggtta catcgaactg gatctcaaca gcggtaagat ccttgagagt 6840 tttcgccccg aagaacgttt tccaatgatg agcactttta aagttctgct atgtggcgcg 6900 gtattatccc gtattgacgc cgggcaagag caactcggtc gccgcataca ctattctcag 6960 aatgacttgg ttgagtactc accagtcaca gaaaagcatc ttacggatgg catgacagta 7020 agagaattat gcagtgctgc cataaccatg agtgataaca ctgcggccaa cttacttctg 7080 acaacgatcg gaggaccgaa ggagctaacc gcttttttgc acaacatggg ggatcatgta 7140 actcgccttg atcgttggga accggagctg aatgaagcca taccaaacga cgagcgtgac 7200 acca 7204 <210> 76 <211> 7231 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 76 cgatgcctgt agcaatggca acaacgttgc gcaaactatt aactggcgaa ctacttactc 60 tagcttcccg gcaacaatta atagactgga tggaggcgga taaagttgca ggaccacttc 120 tgcgctcggc ccttccggct ggctggttta ttgctgataa atctggagcc ggtgagcgtg 180 ggtctcgcgg tatcattgca gcactggggc cagatggtaa gccctcccgt atcgtagtta 240 tctacacgac ggggagtcag gcaactatgg atgaacgaaa tagacagatc gctgagatag 300 gtgcctcact gattaagcat tggtaactgt cagaccaagt ttactcatat atactttaga 360 ttgatttaaa acttcatttt taatttaaaa ggatctaggt gaagatcctt tttgataatc 420 tcatgaccaa aatcccttaa cgtgagtttt cgttccactg agcgtcagac cccgtagaaa 480 agatcaaagg atcttcttga gatccttttt ttctgcgcgt aatctgctgc ttgcaaacaa 540 aaaaaccacc gctaccagcg gtggtttgtt tgccggatca agagctacca actctttttc 600 cgaaggtaac tggcttcagc agagcgcaga taccaaatac tgtccttcta gtgtagccgt 660 agttaggcca ccacttcaag aactctgtag caccgcctac atacctcgct ctgctaatcc 720 tgttaccagt ggctgctgcc agtggcgata agtcgtgtct taccgggttg gactcaagac 780 gatagttacc ggataaggcg cagcggtcgg gctgaacggg gggttcgtgc acacagccca 840 gcttggagcg aacgacctac accgaactga gatacctaca gcgtgagcta tgagaaagcg 900 ccacgcttcc cgaagggaga aaggcggaca ggtatccggt aagcggcagg gtcggaacag 960 gagagcgcac gagggagctt ccagggggaa acgcctggta tctttatagt cctgtcgggt 1020 ttcgccacct ctgacttgag cgtcgatttt tgtgatgctc gtcagggggg cggagcctat 1080 ggaaaaacgc cagcaacgcg gcctttttac ggttcctggc cttttgctgg ccttttgctc 1140 acatgtcctg caggcagctg cgcgctcgct cgctcactga ggccgcccgg gcaaagcccg 1200 ggcgtcgggc gacctttggt cgcccggcct cagtgagcga gcgagcgcgc agagaggag 1260 tggccaactc catcactagg ggttcctgcg gccgcacgcg taagctacta actacaacca 1320 cgagattata gatgtttgct gatattgttc tcagtttggt tattgtgttg tttatgaatg 1380 aaagtagtgt atgtttgtgt gaatttttgt ttttaatttt ttatgagtgc cctaacaaag 1440 attacaaatt gggaatacaa actccagagc aatggagaca gtgacacttt tgtggagggg 1500 tacatgtggc tgttcggggg gttattaaca caggctgctg cccctgccct gcaatgggaa 1560 tccccagggc attggaggat tcaacctctt gcagttacct cttgtaagac agcagatggc 1620 agcagagaga ggctttgcac atccctgcag gttctagttt gcacaaaggg cttctgagag 1680 acctatcaac caattataac atcaagtggc aaaaagagtc cttgataagt tatttcgctt 1740 ctcaaagaaa ccgaaaacgc caaactaatc actagtcttg tttttttttt tcctggcaaa 1800 agcctgctat ctttcatgat ttagctttca tgaaattgtt cctgaagacc cccaaaagaa 1860 acaatttcat gccccgaact ctgttcagag actttgctgt gcctgtcatg tccagcttgc 1920 catatcctgt tttgtaaagt agccacctta tatacacacc tgctgtctgc actgtgacct 1980 cctttcaaaa tcatctttgg ttcttcagag gcctggaata atgctctgcc cagatgaaga 2040 tctccgtaaa tgtgtttttg aaatggctaa tcaaataatg gataccctta ggtatttttg 2100 cagaaacact tggcagcctt ccataatatc cctactatga aatggaaact tgtgaatgag 2160 atgtggcttt aattaagacc tcgaagggga cttggggggt tcggggcttt cgggggcggt 2220 cgggggttcg cggacccggg aagctctgag gacccagagg ccgggcgcgc tccgcccgcg 2280 gcgccgcccc ctccgtaact ttcccagtct ccgagggaag aggcggggtg tggggtgcgg 2340 ttaaaaggcg ccacggcggg agacaggtgt tgcggccccg cagcgcccgc gcgctcctct 2400 ccccgactcg gagcccctcg gcggcgcccg gcccaggacc cgcctaggag cgcaggagcc 2460 ccagcgcaga gaccccaacg ccgagacccc cgccccggcc ccgccgcgct tcctcccgac 2520 gcagagcaaa ccgcccagag tagaagccat ggattggggc acactccaga gcatcctcgg 2580 gggtgtcaac aaacactcca ccagcattgg aaagatctgg ctcacggtcc tcttcatctt 2640 ccgcatcatg atcctcgtgg tggctgcaaa ggaggtgtgg ggagatgagc aagccgattt 2700 tgtctgcaac acgctccagc ctggctgcaa gaatgtatgc tacgaccacc acttccccat 2760 ctctcacatc cggctctggg ctctgcagct gatcatggtg tccacgccag ccctcctggt 2820 agctatgcat gtggcctacc ggagacatga aaagaaacgg aagttcatga aggggagagat 2880 aaagaacgag tttaaggaca tcgaagagat caaaacccag aaggtccgta tcgaagggtc 2940 cctgtggtgg acctacacca ccagcatctt cttccgggtc atctttgaag ccgtcttcat 3000 gtacgtcttt tacatcatgt acaatggctt cttcatgcaa cgtctggtga aatgcaacgc 3060 ttggccctgc cccaatacag tggactgctt catttccagg cccacagaaa agactgtctt 3120 caccgtgttt atgatttctg tgtctggaat ttgcattctg ctaaatatca cagagctgtg 3180 ctatttgttc gttaggtatt gctcaggaaa gtccaaaaga ccagtctacc catacgatgt 3240 tccagattac gcttaaaggc gcgccacccc tgcagggaat tccgcattgc ccagttgtta 3300 gattaagaaa tagacagcat gagagggatg aggcaacccg tgctcagctg tcaaggctca 3360 gtcgctagca tttcccaaca caaagattct gaccttaaat gcaaccattt gaaacccctg 3420 taggcctcag gtgaaactcc agatgccaca atggagctct gctcccctaa agcctcaaaa 3480 caaaggccta attctatgcc tgtcttaatt ttctttcact taagttagtt ccactgagac 3540 cccaggctgt taggggttat tggtgtaagg tactttcata ttttaaacag aggatatcgg 3600 catttgtttc tttctctgag gacaagagaa aaaagccagg ttccacagag gacacagaga 3660 aggtttgggt gtcctcctgg ggttcttttt gccaactttc cccacgttaa aggtgaacat 3720 tggttctttc atttgctttg gaagttttaa tctctaacag tggacaaagt taccagtgcc 3780 ttaaactctg ttacactttt tggaagtgaa aactttgtag tatgataggt tattttgatg 3840 taaagatgtt ctggatacca ttatatgttc cccctgtttc agaggctcag attgtaatat 3900 gtaaatggta tgtcattcgc tactatgatt taatttgaaa tatggtcttt tggttatgaa 3960 tactttgcag cacagctgag aggctgtctg ttgtattcat tgtggtcata gcacctaaca 4020 acattgtagc ctcaatcgag tgagacagac tagaagttcc tagtgatggc ttatgatagc 4080 aaatggcctc atgtcaaata tttagatgta attttgtgta agaaatacag actggatgta 4140 ccaccaacta ctacctgtaa tgacaggcct gtccaacaca tctccctttt ccatgactgt 4200 ggtagccagc atcggaaaga acgctgattt aaagaggtcg cttgggaatt ttattgacac 4260 agtaccattt aatggggagg acaaaatggg gcaggggagg gagaagtttc tgtcgttaaa 4320 aacagatttg gaaagactgg actctaaagt ctgttgatta aagatgagct ttgtctactt 4380 caaaagtttg tttgcttacc ccttcagcct ccaatttttt aagtgaaaat atagctaata 4440 acatgtgaaa agaatagaag ctaaggttta gataaatatt gagcagatct ataggaagat 4500 tgaacctgaa tattgccatt atgcttgaca tggtttccaa aaaatggtac tccacatatt 4560 tcagtgaggg taagtatttt cctgttgtca agaatagcat tgtaaaagca ttttgtaata 4620 ataaagaata gctttaatga tatgcttgta actaaaataa ttttgtaatg tatcaaatac 4680 atttaaaaca ttaaaatata atctctataa taatttaaaa tctaatatgg ttttaataga 4740 acagcgatat caagcttatc gataatcaac ctctggatta caaaatttgt gaaagattga 4800 ctggtattct taactatgtt gctcctttta cgctatgtgg atacgctgct ttaatgcctt 4860 tgtatcatgc tattgcttcc cgtatggctt tcattttctc ctccttgtat aaatcctggt 4920 tgctgtctct ttatgaggag ttgtggcccg ttgtcaggca acgtggcgtg gtgtgcactg 4980 tgtttgctga cgcaaccccc actggttggg gcattgccac cacctgtcag ctcctttccg 5040 ggactttcgc tttccccctc cctattgcca cggcggaact catcgccgcc tgccttgccc 5100 gctgctggac aggggctcgg ctgttgggca ctgacaattc cgtggtgttg tcggggaaat 5160 catcgtcctt tccttggctg ctcgcctatg ttgccacctg gattctgcgc gggacgtcct 5220 tctgctacgt cccttcggcc ctcaatccag cggaccttcc ttcccgcggc ctgctgccgg 5280 ctctgcggcc tcttccgcgt cttcgccttc gccctcagac gagtcggatc tccctttggg 5340 ccgcctcccc gcgaattcat cgataccgag cgctgctcga gagatctgtg atagcggcca 5400 tcaagctggc tgtgccttct agttgccagc catctgttgt ttgcccctcc cccgtgcctt 5460 ccttgaccct ggaaggtgcc actcccactg tcctttccta ataaaatgag gaaattgcat 5520 cgcattgtct gagtaggtgt cattctattc tggggggtgg ggtggggcag gacagcaagg 5580 gggaggattg ggaagacaat agcaggcatg ctggggacac gtgcggaccg agcggccgca 5640 ggaaccccta gtgatggagt tggccactcc ctctctgcgc gctcgctcgc tcactgaggc 5700 cgggcgacca aaggtcgccc gacgcccggg ctttgcccgg gcggcctcag tgagcgagcg 5760 agcgcgcagc tgcctgcagg ggcgcctgat gcggtatttt ctccttacgc atctgtgcgg 5820 tatttcacac cgcatacgtc aaagcaacca tagtacgcgc cctgtagcgg cgcattaagc 5880 gcggcgggtg tggtggttac gcgcagcgtg accgctacac ttgccagcgc cctagcgccc 5940 gctcctttcg ctttcttccc ttcctttctc gccacgttcg ccggctttcc ccgtcaagct 6000 ctaaatcggg ggctcccttt agggttccga tttagtgctt tacggcacct cgaccccaaa 6060 aaacttgatt tgggtgatgg ttcacgtagt gggccatcgc cctgatagac ggtttttcgc 6120 cctttgacgt tggagtccac gttctttaat agtggactct tgttccaaac tggaacaaca 6180 ctcaacccta tctcgggcta ttcttttgat ttataaggga ttttgccgat ttcggcctat 6240 tggttaaaaa atgagctgat ttaacaaaaa tttaacgcga attttaacaa aatattaacg 6300 tttacaattt tatggtgcac tctcagtaca atctgctctg atgccgcata gttaagccag 6360 ccccgacacc cgccaacacc cgctgacgcg ccctgacggg cttgtctgct cccggcatcc 6420 gcttacagac aagctgtgac cgtctccggg agctgcatgt gtcagaggtt ttcaccgtca 6480 tcaccgaaac gcgcgagacg aaagggcctc gtgatacgcc tatttttata ggttaatgtc 6540 atgataataa tggtttctta gacgtcaggt ggcacttttc ggggaaatgt gcgcggaacc 6600 cctatttgtt tatttttcta aatacattca aatatgtatc cgctcatgag acaataaccc 6660 tgataaatgc ttcaataata ttgaaaaagg aagagtatga gtattcaaca tttccgtgtc 6720 gcccttattc ccttttttgc ggcattttgc cttcctgttt ttgctcaccc agaaacgctg 6780 gtgaaagtaa aagatgctga agatcagttg ggtgcacgag tgggttacat cgaactggat 6840 ctcaacagcg gtaagatcct tgagagtttt cgccccgaag aacgttttcc aatgatgagc 6900 acttttaaag ttctgctatg tggcgcggta ttatcccgta ttgacgccgg gcaagagcaa 6960 ctcggtcgcc gcatacacta ttctcagaat gacttggttg agtactcacc agtcacagaa 7020 aagcatctta cggatggcat gacagtaaga gaattatgca gtgctgccat aaccatgagt 7080 gataacactg cggccaactt acttctgaca acgatcggag gaccgaagga gctaaccgct 7140 tttttgcaca acatggggga tcatgtaact cgccttgatc gttgggaacc ggagctgaat 7200 gaagccatac caaacgacga gcgtgacacc a 7231 <210> 77 <211> 7214 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 77 cgatgcctgt agcaatggca acaacgttgc gcaaactatt aactggcgaa ctacttactc 60 tagcttcccg gcaacaatta atagactgga tggaggcgga taaagttgca ggaccacttc 120 tgcgctcggc ccttccggct ggctggttta ttgctgataa atctggagcc ggtgagcgtg 180 ggtctcgcgg tatcattgca gcactggggc cagatggtaa gccctcccgt atcgtagtta 240 tctacacgac ggggagtcag gcaactatgg atgaacgaaa tagacagatc gctgagatag 300 gtgcctcact gattaagcat tggtaactgt cagaccaagt ttactcatat atactttaga 360 ttgatttaaa acttcatttt taatttaaaa ggatctaggt gaagatcctt tttgataatc 420 tcatgaccaa aatcccttaa cgtgagtttt cgttccactg agcgtcagac cccgtagaaa 480 agatcaaagg atcttcttga gatccttttt ttctgcgcgt aatctgctgc ttgcaaacaa 540 aaaaaccacc gctaccagcg gtggtttgtt tgccggatca agagctacca actctttttc 600 cgaaggtaac tggcttcagc agagcgcaga taccaaatac tgtccttcta gtgtagccgt 660 agttaggcca ccacttcaag aactctgtag caccgcctac atacctcgct ctgctaatcc 720 tgttaccagt ggctgctgcc agtggcgata agtcgtgtct taccgggttg gactcaagac 780 gatagttacc ggataaggcg cagcggtcgg gctgaacggg gggttcgtgc acacagccca 840 gcttggagcg aacgacctac accgaactga gatacctaca gcgtgagcta tgagaaagcg 900 ccacgcttcc cgaagggaga aaggcggaca ggtatccggt aagcggcagg gtcggaacag 960 gagagcgcac gagggagctt ccagggggaa acgcctggta tctttatagt cctgtcgggt 1020 ttcgccacct ctgacttgag cgtcgatttt tgtgatgctc gtcagggggg cggagcctat 1080 ggaaaaacgc cagcaacgcg gcctttttac ggttcctggc cttttgctgg ccttttgctc 1140 acatgtcctg caggcagctg cgcgctcgct cgctcactga ggccgcccgg gcaaagcccg 1200 ggcgtcgggc gacctttggt cgcccggcct cagtgagcga gcgagcgcgc agagaggag 1260 tggccaactc catcactagg ggttcctgcg gccgcacgcg tctcagctgg agtgacgcac 1320 ctcatccatg cgggcctggc gtctggaagg tggctgggtc tctcgggctt gagcaccatc 1380 atcttagctc caacatgtca ttattccttc ctcactgagg acttttctgc ttcctaattg 1440 gttgttgaag atgaggcccc catgctcttt taagaaaacc tgttgtgccc caggcttggc 1500 tgtgatgggc actgactcat acagaagtag aaaggcctgc tgagtcatca acactcgtgc 1560 gacgccctcg cattttcatt aatgatggcc tccctgccac acgtgaatca ctccagcccg 1620 agatctgaaa ccaggacaca ccccaggggc gaggtgacgc tgagtgagcc cagctgtgtc 1680 cctttcatga gaactcagag cacagggctc tgtgtgcatg gccgtcccct ccagagagga 1740 ggaagtaaat gccgggatta gtggaagatc atttccttct atttgccttg gcttacgtct 1800 ttcagaattc aaacacgtgc actgttgacc ctgcaatggt ggagtttttg gattttcctt 1860 cagtccgatt gctaaaatac ttccctctca tgtgagctgt tgtgaaagtc atcagccaga 1920 taccattcta aaaacaaaga atgtgcttct cgtatgttgc atgctggtta ctgaaatatt 1980 agggaattac ataaaggttt tctggggcac atattcaagc tgaatgataa aattgaaggt 2040 cacacaaagc taaggtcttt caaatcctga cccaattagc tctctgttag ctctctgact 2100 ttggacaagc tgtctggtcc tctgaagcat actttgttcg ccctgggtag gggccctctg 2160 ttttaacagc gtttggcatt aattaagacc tcgaagggga cttggggggt tcggggcttt 2220 cgggggcggt cgggggttcg cggacccggg aagctctgag gacccagagg ccgggcgcgc 2280 tccgcccgcg gcgccgcccc ctccgtaact ttcccagtct ccgagggaag aggcggggtg 2340 tggggtgcgg ttaaaaggcg ccacggcggg agacaggtgt tgcggccccg cagcgcccgc 2400 gcgctcctct ccccgactcg gagcccctcg gcggcgcccg gcccaggacc cgcctaggag 2460 cgcaggagcc ccagcgcaga gaccccaacg ccgagacccc cgccccggcc ccgccgcgct 2520 tcctcccgac gcagagcaaa ccgcccagag tagaagccat ggattggggc acgctgcaga 2580 cgatcctggg gggtgtgaac aaacactcca ccagcattgg aaagatctgg ctcaccgtcc 2640 tcttcatttt tcgcattatg atcctcgttg tggctgcaaa ggaggtgtgg ggagatgagc 2700 aggccgactt tgtctgcaac accctgcagc caggctgcaa gaacgtgtgc tacgatcact 2760 acttccccat ctcccacatc cggctatggg ccctgcagct gatcttcgtg tccacgccag 2820 cgctcctagt ggccatgcac gtggcctacc ggagacatga gaagaagagg aagttcatca 2880 aggggggagat aaagagtgaa tttaaggaca tcgaggagat caaaacccag aaggtccgca 2940 tcgaaggctc cctgtggtgg acctacacaa gcagcatctt cttccgggtc atcttcgaag 3000 ccgccttcat gtacgtcttc tatgtcatgt acgacggctt ctccatgcag cggctggtga 3060 agtgcaacgc ctggccttgt cccaacactg tggactgctt tgtgtcccgg cccacggaga 3120 agactgtctt cacagtgttc atgattgcag tgtctggaat ttgcatcctg ctgaatgtca 3180 ctgaattgtg ttatttgcta attagatatt gttctgggaa gtcaaaaaag ccagtttaaa 3240 ggcgcgccac ccctgcaggg aattccgcat tgcccagttg ttagattaag aaatagacag 3300 catgagaggg atgaggcaac ccgtgctcag ctgtcaaggc tcagtcgcta gcatttccca 3360 acacaaagat tctgacctta aatgcaacca tttgaaaccc ctgtaggcct caggtgaaac 3420 tccagatgcc acaatggagc tctgctcccc taaagcctca aaacaaaggc ctaattctat 3480 gcctgtctta attttctttc acttaagtta gttccactga gaccccaggc tgttaggggt 3540 tattggtgta aggtactttc atattttaaa cagaggatat cggcatttgt ttctttctct 3600 gaggacaaga gaaaaaagcc aggttccaca gaggacacag agaaggtttg ggtgtcctcc 3660 tggggttctt tttgccaact ttccccacgt taaaggtgaa cattggttct ttcatttgct 3720 ttggaagttt taatctctaa cagtggacaa agttaccagt gccttaaact ctgttacact 3780 ttttggaagt gaaaactttg tagtatgata ggttattttg atgtaaagat gttctggata 3840 ccattatatg ttccccctgt ttcagaggct cagattgtaa tatgtaaatg gtatgtcatt 3900 cgctactatg atttaatttg aaatatggtc ttttggttat gaatactttg cagcacagct 3960 gagaggctgt ctgttgtatt cattgtggtc atagcaccta acaacattgt agcctcaatc 4020 gagtgagaca gactagaagt tcctagtgat ggcttatgat agcaaatggc ctcatgtcaa 4080 atatttagat gtaattttgt gtaagaaata cagactggat gtaccaccaa ctactacctg 4140 taatgacagg cctgtccaac acatctccct tttccatgac tgtggtagcc agcatcggaa 4200 agaacgctga tttaaagagg tcgcttggga attttatga cacagtacca tttaatgggg 4260 aggacaaaat ggggcagggg agggaagaagt ttctgtcgtt aaaaacagat ttggaaagac 4320 tggactctaa agtctgttga ttaaagatga gctttgtcta cttcaaaagt ttgtttgctt 4380 accccttcag cctccaattt tttaagtgaa aatatagcta ataacatgtg aaaagaatag 4440 aagctaaggt ttagataaat attgagcaga tctataggaa gattgaacct gaatattgcc 4500 attatgcttg acatggtttc caaaaaatgg tactccacat atttcagtga gggtaagtat 4560 tttcctgttg tcaagaatag cattgtaaaa gcattttgta ataataaaga atagctttaa 4620 tgatatgctt gtaactaaaa taattttgta atgtatcaaa tacatttaaa acattaaaat 4680 ataatctcta taataattta aaatctaata tggttttaat agaacagcga tatcaagctt 4740 atcgataatc aacctctgga ttacaaaatt tgtgaaagat tgactggtat tcttaactat 4800 gttgctcctt ttacgctatg tggatacgct gctttaatgc ctttgtatca tgctattgct 4860 tcccgtatgg ctttcatttt ctcctccttg tataaatcct ggttgctgtc tctttatgag 4920 gagttgtggc ccgttgtcag gcaacgtggc gtggtgtgca ctgtgtttgc tgacgcaacc 4980 cccactggtt ggggcattgc caccacctgt cagctccttt ccgggacttt cgctttcccc 5040 ctccctattg ccacggcgga actcatcgcc gcctgccttg cccgctgctg gacaggggct 5100 cggctgttgg gcactgacaa ttccgtggtg ttgtcgggga aatcatcgtc ctttccttgg 5160 ctgctcgcct atgttgccac ctggattctg cgcgggacgt ccttctgcta cgtcccttcg 5220 gccctcaatc cagcggacct tccttcccgc ggcctgctgc cggctctgcg gcctcttccg 5280 cgtcttcgcc ttcgccctca gacgagtcgg atctcccttt gggccgcctc cccgcgaatt 5340 catcgatacc gagcgctgct cgagagatct gtgatagcgg ccatcaagct ggctgtgcct 5400 tctagttgcc agccatctgt tgtttgcccc tcccccgtgc cttccttgac cctggaaggt 5460 gccactccca ctgtcctttc ctaataaaat gaggaaattg catcgcattg tctgagtagg 5520 tgtcattcta ttctgggggg tggggtgggg caggacagca agggggagga ttgggaagac 5580 aatagcaggc atgctgggga cacgtgcgga ccgagcggcc gcaggaaccc ctagtgatgg 5640 agttggccac tccctctctg cgcgctcgct cgctcactga ggccgggcga ccaaaggtcg 5700 cccgacgccc gggctttgcc cgggcggcct cagtgagcga gcgagcgcgc agctgcctgc 5760 aggggcgcct gatgcggtat tttctcctta cgcatctgtg cggtatttca caccgcatac 5820 gtcaaagcaa ccatagtacg cgccctgtag cggcgcatta agcgcggcgg gtgtggtggt 5880 tacgcgcagc gtgaccgcta cacttgccag cgccctagcg cccgctcctt tcgctttctt 5940 cccttccttt ctcgccacgt tcgccggctt tccccgtcaa gctctaaatc gggggctccc 6000 tttagggttc cgatttagtg ctttacggca cctcgacccc aaaaaacttg atttgggtga 6060 tggttcacgt agtgggccat cgccctgata gacggttttt cgccctttga cgttggagtc 6120 cacgttcttt aatagtggac tcttgttcca aactggaaca acactcaacc ctatctcggg 6180 ctattctttt gatttataag ggattttgcc gatttcggcc tattggttaa aaaatgagct 6240 gatttaacaa aaatttaacg cgaattttaa caaaatatta acgtttacaa ttttatggtg 6300 cactctcagt acaatctgct ctgatgccgc atagttaagc cagccccgac acccgccaac 6360 acccgctgac gcgccctgac gggcttgtct gctcccggca tccgcttaca gacaagctgt 6420 gaccgtctcc gggagctgca tgtgtcagag gttttcaccg tcatcaccga aacgcgcgag 6480 acgaaagggc ctcgtgatac gcctattttt ataggttaat gtcatgataa taatggtttc 6540 ttagacgtca ggtggcactt ttcggggaaa tgtgcgcgga acccctattt gtttatttt 6600 ctaaatacat tcaaatatgt atccgctcat gagacaataa ccctgataaa tgcttcaata 6660 atattgaaaa aggaagagta tgagtattca acatttccgt gtcgccctta ttcccttttt 6720 tgcggcattt tgccttcctg tttttgctca cccagaaacg ctggtgaaag taaaagatgc 6780 tgaagatcag ttgggtgcac gagtggggtta catcgaactg gatctcaaca gcggtaagat 6840 ccttgagagt tttcgccccg aagaacgttt tccaatgatg agcactttta aagttctgct 6900 atgtggcgcg gtattatccc gtattgacgc cgggcaagag caactcggtc gccgcataca 6960 ctattctcag aatgacttgg ttgagtactc accagtcaca gaaaagcatc ttacggatgg 7020 catgacagta agagaattat gcagtgctgc cataaccatg agtgataaca ctgcggccaa 7080 cttacttctg acaacgatcg gaggaccgaa ggagctaacc gcttttttgc acaacatggg 7140 ggatcatgta actcgccttg atcgttggga accggagctg aatgaagcca taccaaacga 7200 cgagcgtgac acca 7214 <210> 78 <211> 7241 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 78 cgatgcctgt agcaatggca acaacgttgc gcaaactatt aactggcgaa ctacttactc 60 tagcttcccg gcaacaatta atagactgga tggaggcgga taaagttgca ggaccacttc 120 tgcgctcggc ccttccggct ggctggttta ttgctgataa atctggagcc ggtgagcgtg 180 ggtctcgcgg tatcattgca gcactggggc cagatggtaa gccctcccgt atcgtagtta 240 tctacacgac ggggagtcag gcaactatgg atgaacgaaa tagacagatc gctgagatag 300 gtgcctcact gattaagcat tggtaactgt cagaccaagt ttactcatat atactttaga 360 ttgatttaaa acttcatttt taatttaaaa ggatctaggt gaagatcctt tttgataatc 420 tcatgaccaa aatcccttaa cgtgagtttt cgttccactg agcgtcagac cccgtagaaa 480 agatcaaagg atcttcttga gatccttttt ttctgcgcgt aatctgctgc ttgcaaacaa 540 aaaaaccacc gctaccagcg gtggtttgtt tgccggatca agagctacca actctttttc 600 cgaaggtaac tggcttcagc agagcgcaga taccaaatac tgtccttcta gtgtagccgt 660 agttaggcca ccacttcaag aactctgtag caccgcctac atacctcgct ctgctaatcc 720 tgttaccagt ggctgctgcc agtggcgata agtcgtgtct taccgggttg gactcaagac 780 gatagttacc ggataaggcg cagcggtcgg gctgaacggg gggttcgtgc acacagccca 840 gcttggagcg aacgacctac accgaactga gatacctaca gcgtgagcta tgagaaagcg 900 ccacgcttcc cgaagggaga aaggcggaca ggtatccggt aagcggcagg gtcggaacag 960 gagagcgcac gagggagctt ccagggggaa acgcctggta tctttatagt cctgtcgggt 1020 ttcgccacct ctgacttgag cgtcgatttt tgtgatgctc gtcagggggg cggagcctat 1080 ggaaaaacgc cagcaacgcg gcctttttac ggttcctggc cttttgctgg ccttttgctc 1140 acatgtcctg caggcagctg cgcgctcgct cgctcactga ggccgcccgg gcaaagcccg 1200 ggcgtcgggc gacctttggt cgcccggcct cagtgagcga gcgagcgcgc agagaggag 1260 tggccaactc catcactagg ggttcctgcg gccgcacgcg tctcagctgg agtgacgcac 1320 ctcatccatg cgggcctggc gtctggaagg tggctgggtc tctcgggctt gagcaccatc 1380 atcttagctc caacatgtca ttattccttc ctcactgagg acttttctgc ttcctaattg 1440 gttgttgaag atgaggcccc catgctcttt taagaaaacc tgttgtgccc caggcttggc 1500 tgtgatgggc actgactcat acagaagtag aaaggcctgc tgagtcatca acactcgtgc 1560 gacgccctcg cattttcatt aatgatggcc tccctgccac acgtgaatca ctccagcccg 1620 agatctgaaa ccaggacaca ccccaggggc gaggtgacgc tgagtgagcc cagctgtgtc 1680 cctttcatga gaactcagag cacagggctc tgtgtgcatg gccgtcccct ccagagagga 1740 ggaagtaaat gccgggatta gtggaagatc atttccttct atttgccttg gcttacgtct 1800 ttcagaattc aaacacgtgc actgttgacc ctgcaatggt ggagtttttg gattttcctt 1860 cagtccgatt gctaaaatac ttccctctca tgtgagctgt tgtgaaagtc atcagccaga 1920 taccattcta aaaacaaaga atgtgcttct cgtatgttgc atgctggtta ctgaaatatt 1980 agggaattac ataaaggttt tctggggcac atattcaagc tgaatgataa aattgaaggt 2040 cacacaaagc taaggtcttt caaatcctga cccaattagc tctctgttag ctctctgact 2100 ttggacaagc tgtctggtcc tctgaagcat actttgttcg ccctgggtag gggccctctg 2160 ttttaacagc gtttggcatt aattaagacc tcgaagggga cttggggggt tcggggcttt 2220 cgggggcggt cgggggttcg cggacccggg aagctctgag gacccagagg ccgggcgcgc 2280 tccgcccgcg gcgccgcccc ctccgtaact ttcccagtct ccgagggaag aggcggggtg 2340 tggggtgcgg ttaaaaggcg ccacggcggg agacaggtgt tgcggccccg cagcgcccgc 2400 gcgctcctct ccccgactcg gagcccctcg gcggcgcccg gcccaggacc cgcctaggag 2460 cgcaggagcc ccagcgcaga gaccccaacg ccgagacccc cgccccggcc ccgccgcgct 2520 tcctcccgac gcagagcaaa ccgcccagag tagaagccat ggattggggc acactccaga 2580 gcatcctcgg gggtgtcaac aaacactcca ccagcattgg aaagatctgg ctcacggtcc 2640 tcttcatctt ccgcatcatg atcctcgtgg tggctgcaaa ggaggtgtgg ggagatgagc 2700 aagccgattt tgtctgcaac acgctccagc ctggctgcaa gaatgtatgc tacgaccacc 2760 acttccccat ctctcacatc cggctctggg ctctgcagct gatcatggtg tccacgccag 2820 ccctcctggt agctatgcat gtggcctacc ggagacatga aaagaaacgg aagttcatga 2880 aggggagat aaagaacgag tttaaggaca tcgaagagat caaaacccag aaggtccgta 2940 tcgaagggtc cctgtggtgg acctacacca ccagcatctt cttccgggtc atctttgaag 3000 ccgtcttcat gtacgtcttt tacatcatgt acaatggctt cttcatgcaa cgtctggtga 3060 aatgcaacgc ttggccctgc cccaatacag tggactgctt catttccagg cccacagaaa 3120 agactgtctt caccgtgttt atgatttctg tgtctggaat ttgcattctg ctaaatatca 3180 cagagctgtg ctatttgttc gttaggtatt gctcaggaaa gtccaaaaga ccagtctacc 3240 catacgatgt tccagattac gcttaaaggc gcgccacccc tgcagggaat tccgcattgc 3300 ccagttgtta gattaagaaa tagacagcat gagagggatg aggcaacccg tgctcagctg 3360 tcaaggctca gtcgctagca tttcccaaca caaagattct gaccttaaat gcaaccattt 3420 gaaacccctg taggcctcag gtgaaactcc agatgccaca atggagctct gctcccctaa 3480 agcctcaaaa caaaggccta attctatgcc tgtcttaatt ttctttcact taagttagtt 3540 ccactgagac cccaggctgt taggggttat tggtgtaagg tactttcata ttttaaacag 3600 aggatatcgg catttgtttc tttctctgag gacaagagaa aaaagccagg ttccacagag 3660 gacacagaga aggtttgggt gtcctcctgg ggttcttttt gccaactttc cccacgttaa 3720 aggtgaacat tggttctttc atttgctttg gaagttttaa tctctaacag tggacaaagt 3780 taccagtgcc ttaaactctg ttaacactttt tggaagtgaa aactttgtag tatgataggt 3840 tattttgatg taaagatgtt ctggatacca ttatatgttc cccctgtttc agaggctcag 3900 attgtaatat gtaaatggta tgtcattcgc tactatgatt taatttgaaa tatggtcttt 3960 tggttatgaa tactttgcag cacagctgag aggctgtctg ttgtattcat tgtggtcata 4020 gcacctaaca acattgtagc ctcaatcgag tgagacagac tagaagttcc tagtgatggc 4080 ttatgatagc aaatggcctc atgtcaaata tttagatgta attttgtgta agaaatacag 4140 actggatgta ccaccaacta ctacctgtaa tgacaggcct gtccaacaca tctccctttt 4200 ccatgactgt ggtagccagc atcggaaaga acgctgattt aaagaggtcg cttgggaatt 4260 ttattgacac agtaccattt aatggggagg acaaaatggg gcaggggagg gagaagtttc 4320 tgtcgttaaa aacagatttg gaaagactgg actctaaagt ctgttgatta aagatgagct 4380 ttgtctactt caaaagtttg tttgcttacc ccttcagcct ccaatttttt aagtgaaaat 4440 atagctaata acatgtgaaa agaatagaag ctaaggttta gataaatatt gagcagatct 4500 ataggaagat tgaacctgaa tattgccatt atgcttgaca tggtttccaa aaaatggtac 4560 tccacatatt tcagtgaggg taagtatttt cctgttgtca agaatagcat tgtaaaagca 4620 ttttgtaata ataaagaata gctttaatga tatgcttgta actaaaataa ttttgtaatg 4680 tatcaaatac atttaaaaca ttaaaatata atctctataa taatttaaaa tctaatatgg 4740 ttttaataga acagcgatat caagcttatc gataatcaac ctctggatta caaaatttgt 4800 gaaagattga ctggtattct taactatgtt gctcctttta cgctatgtgg atacgctgct 4860 ttaatgcctt tgtatcatgc tattgcttcc cgtatggctt tcattttctc ctccttgtat 4920 aaatcctggt tgctgtctct ttatgaggag ttgtggcccg ttgtcaggca acgtggcgtg 4980 gtgtgcactg tgtttgctga cgcaaccccc actggttggg gcattgccac cacctgtcag 5040 ctcctttccg ggactttcgc tttccccctc cctattgcca cggcggaact catcgccgcc 5100 tgccttgccc gctgctggac aggggctcgg ctgttgggca ctgacaattc cgtggtgttg 5160 tcggggaaat catcgtcctt tccttggctg ctcgcctatg ttgccacctg gattctgcgc 5220 gggacgtcct tctgctacgt cccttcggcc ctcaatccag cggaccttcc ttcccgcggc 5280 ctgctgccgg ctctgcggcc tcttccgcgt cttcgccttc gccctcagac gagtcggatc 5340 tccctttggg ccgcctcccc gcgaattcat cgataccgag cgctgctcga gagatctggg 5400 atagcggcca tcaagctggc tgtgccttct agttgccagc catctgttgt ttgcccctcc 5460 cccgtgcctt ccttgaccct ggaaggtgcc actcccactg tcctttccta ataaaatgag 5520 gaaattgcat cgcattgtct gagtaggtgt cattctattc tggggggtgg ggtggggcag 5580 gacagcaagg gggaggattg ggaagacaat agcaggcatg ctggggacac gtgcggaccg 5640 agcggccgca ggaaccccta gtgatggagt tggccactcc ctctctgcgc gctcgctcgc 5700 tcactgaggc cgggcgacca aaggtcgccc gacgcccggg ctttgcccgg gcggcctcag 5760 tgagcgagcg agcgcgcagc tgcctgcagg ggcgcctgat gcggtatttt ctccttacgc 5820 atctgtgcgg tatttcacac cgcatacgtc aaagcaacca tagtacgcgc cctgtagcgg 5880 cgcattaagc gcggcgggtg tggtggttac gcgcagcgtg accgctacac ttgccagcgc 5940 cctagcgccc gctcctttcg ctttcttccc ttcctttctc gccacgttcg ccggctttcc 6000 ccgtcaagct ctaaatcggg ggctcccttt agggttccga tttagtgctt tacggcacct 6060 cgaccccaaa aaacttgatt tgggtgatgg ttcacgtagt gggccatcgc cctgatagac 6120 ggtttttcgc cctttgacgt tggagtccac gttctttaat agtggactct tgttccaaac 6180 tggaacaaca ctcaacccta tctcgggcta ttcttttgat ttataaggga ttttgccgat 6240 ttcggcctat tggttaaaaa atgagctgat ttaacaaaaa tttaacgcga attttaacaa 6300 aatattaacg tttacaattt tatggtgcac tctcagtaca atctgctctg atgccgcata 6360 gttaagccag ccccgacacc cgccaacacc cgctgacgcg ccctgacggg cttgtctgct 6420 cccggcatcc gcttacagac aagctgtgac cgtctccggg agctgcatgt gtcagaggtt 6480 ttcaccgtca tcaccgaaac gcgcgagacg aaagggcctc gtgatacgcc tatttttata 6540 ggttaatgtc atgataataa tggtttctta gacgtcaggt ggcacttttc ggggaaatgt 6600 gcgcggaacc cctatttgtt tatttttcta aatacattca aatatgtatc cgctcatgag 6660 acaataaccc tgataaatgc ttcaataata ttgaaaaagg aagagtatga gtattcaaca 6720 tttccgtgtc gcccttattc ccttttttgc ggcattttgc cttcctgttt ttgctcaccc 6780 agaaacgctg gtgaaagtaa aagatgctga agatcagttg ggtgcacgag tgggttacat 6840 cgaactggat ctcaacagcg gtaagatcct tgagagtttt cgccccgaag aacgttttcc 6900 aatgatgagc acttttaaag ttctgctatg tggcgcggta ttatcccgta ttgacgccgg 6960 gcaagagcaa ctcggtcgcc gcatacacta ttctcagaat gacttggttg agtactcacc 7020 agtcacagaa aagcatctta cggatggcat gacagtaaga gaattatgca gtgctgccat 7080 aaccatgagt gataacactg cggccaactt acttctgaca acgatcggag gaccgaagga 7140 gctaaccgct tttttgcaca acatggggga tcatgtaact cgccttgatc gttgggaacc 7200 ggagctgaat gaagccatac caaacgacga gcgtgacacc a 7241 <210> 79 <211> 7251 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 79 cgatgcctgt agcaatggca acaacgttgc gcaaactatt aactggcgaa ctacttactc 60 tagcttcccg gcaacaatta atagactgga tggaggcgga taaagttgca ggaccacttc 120 tgcgctcggc ccttccggct ggctggttta ttgctgataa atctggagcc ggtgagcgtg 180 ggtctcgcgg tatcattgca gcactggggc cagatggtaa gccctcccgt atcgtagtta 240 tctacacgac ggggagtcag gcaactatgg atgaacgaaa tagacagatc gctgagatag 300 gtgcctcact gattaagcat tggtaactgt cagaccaagt ttactcatat atactttaga 360 ttgatttaaa acttcatttt taatttaaaa ggatctaggt gaagatcctt tttgataatc 420 tcatgaccaa aatcccttaa cgtgagtttt cgttccactg agcgtcagac cccgtagaaa 480 agatcaaagg atcttcttga gatccttttt ttctgcgcgt aatctgctgc ttgcaaacaa 540 aaaaaccacc gctaccagcg gtggtttgtt tgccggatca agagctacca actctttttc 600 cgaaggtaac tggcttcagc agagcgcaga taccaaatac tgtccttcta gtgtagccgt 660 agttaggcca ccacttcaag aactctgtag caccgcctac atacctcgct ctgctaatcc 720 tgttaccagt ggctgctgcc agtggcgata agtcgtgtct taccgggttg gactcaagac 780 gatagttacc ggataaggcg cagcggtcgg gctgaacggg gggttcgtgc acacagccca 840 gcttggagcg aacgacctac accgaactga gatacctaca gcgtgagcta tgagaaagcg 900 ccacgcttcc cgaagggaga aaggcggaca ggtatccggt aagcggcagg gtcggaacag 960 gagagcgcac gagggagctt ccagggggaa acgcctggta tctttatagt cctgtcgggt 1020 ttcgccacct ctgacttgag cgtcgatttt tgtgatgctc gtcagggggg cggagcctat 1080 ggaaaaacgc cagcaacgcg gcctttttac ggttcctggc cttttgctgg ccttttgctc 1140 acatgtcctg caggcagctg cgcgctcgct cgctcactga ggccgcccgg gcaaagcccg 1200 ggcgtcgggc gacctttggt cgcccggcct cagtgagcga gcgagcgcgc agagaggag 1260 tggccaactc catcactagg ggttcctgcg gccgcacgcg tcgacctgaa cgattaaggc 1320 aaaacttcga aatgtgcccc agcagagatt tatttttcag ggggtgtttt gcattccagc 1380 ccctctgcct tcctggcgtt tagtgcgatt tgtttagcca tgtgctccct ggtgtgtgtt 1440 tttgaatgtg tgtgagatgg gttgtctctc gggacctggc aggtgcggcc accaggtcag 1500 ggctgcccccc caaccctgtg cctccttcct cctagactct ggccccctca gtgctgaggg 1560 tgatacagag cacttttcaa gctggatttg gaatgtggcc tctcccctcc aaactcctgg 1620 agatcatgca aaggcctttg gagccagcca gtcacctgga aggtgacatt cccaccagct 1680 gaggcctcac cttcagcggg ggctgggcag ctttggagcc tggggccagc caagctcact 1740 ctgcccatat ccctgccacg tgtggcccag cggatgatca cctgtcttca tctgcgtact 1800 gggccacatc cctcctgccg tcccccactt ccctgatgac acctacagca agcccctacc 1860 caagtgttct gtgatcccct gtaaatgtgg cctccctagc tacttgcttt tatgaaacca 1920 acaatcctgg ggacacagtt ttcggctgtc tcaagacggg gcaaccactc ttttccccag 1980 gcctgtgggt cccaggcctg gagctagggt tggcattctt gcctgaattc tccactctat 2040 cccaacccct gaggccgcct gaggaggctc agactgtgtc aggctaggag gacagtcaaa 2100 ccacaaaaac atgcctttta agaagtataa gcacaaatcc ctctttgatg ttatataaaa 2160 gctcagtgtc actttaatta agacctcgaa ggggacttgg ggggttcggg gctttcgggg 2220 gcggtcgggg gttcgcggac ccgggaagct ctgaggaccc agaggccggg cgcgctccgc 2280 ccgcggcgcc gccccctccg taactttccc agtctccgag ggaagaggcg gggtgtgggg 2340 tgcggttaaa aggcgccacg gcgggagaca ggtgttgcgg ccccgcagcg cccgcgcgct 2400 cctctccccg actcggagcc cctcggcggc gcccggccca ggacccgcct aggagcgcag 2460 gagccccagc gcagagaccc caacgccgag acccccgccc cggccccgcc gcgcttcctc 2520 ccgacgcaga gcaaaccgcc cagagtagaa gccatggtga gcaagggcga ggagctgttc 2580 accggggtgg tgcccatcct ggtcgagctg gacggcgacg taaacggcca caagttcagc 2640 gtgtccggcg agggcgaggg cgatgccacc tacggcaagc tgaccctgaa gttcatctgc 2700 accaccggca agctgcccgt gccctggccc accctcgtga ccaccctgac ctacggcgtg 2760 cagtgcttca gccgctaccc cgaccacatg aagcagcacg acttcttcaa gtccgccatg 2820 cccgaaggct acgtccagga gcgcaccatc ttcttcaagg acgacggcaa ctacaagacc 2880 cgcgccgagg tgaagttcga gggcgacacc ctggtgaacc gcatcgagct gaagggcatc 2940 gacttcaagg aggacggcaa catcctgggg cacaagctgg agtacaacta caacagccac 3000 aacgtctata tcatggccga caagcagaag aacggcatca aggtgaactt caagatccgc 3060 cacaacatcg aggacggcag cgtgcagctc gccgaccact accagcagaa cacccccatc 3120 ggcgacggcc ccgtgctgct gcccgacaac cactacctga gcacccagtc cgccctgagc 3180 aaagacccca acgagaagcg cgatcacatg gtcctgctgg agttcgtgac cgccgccggg 3240 atcactctcg gcatggacga gctgtacaag taataaaggc gcgccacccc tgcagggaat 3300 tccgcattgc ccagttgtta gattaagaaa tagacagcat gagagggatg aggcaacccg 3360 tgctcagctg tcaaggctca gtcgctagca tttcccaaca caaagattct gaccttaaat 3420 gcaaccattt gaaacccctg taggcctcag gtgaaactcc agatgccaca atggagctct 3480 gctcccctaa agcctcaaaa caaaggccta attctatgcc tgtcttaatt ttctttcact 3540 taagttagtt ccactgagac cccaggctgt taggggttat tggtgtaagg tactttcata 3600 ttttaaacag aggatatcgg catttgtttc tttctctgag gacaagagaa aaaagccagg 3660 ttccacagag gacacagaga aggtttgggt gtcctcctgg ggttcttttt gccaactttc 3720 cccacgttaa aggtgaacat tggttctttc atttgctttg gaagttttaa tctctaacag 3780 tggacaaagt taccagtgcc ttaaactctg ttaacactttt tggaagtgaa aactttgtag 3840 tatgataggt tattttgatg taaagatgtt ctggatacca ttatatgttc cccctgtttc 3900 agaggctcag attgtaatat gtaaatggta tgtcattcgc tactatgatt taatttgaaa 3960 tatggtcttt tggttatgaa tactttgcag cacagctgag aggctgtctg ttgtattcat 4020 tgtggtcata gcacctaaca acattgtagc ctcaatcgag tgagacagac tagaagttcc 4080 tagtgatggc ttatgatagc aaatggcctc atgtcaaata tttagatgta attttgtgta 4140 agaaatacag actggatgta ccaccaacta ctacctgtaa tgacaggcct gtccaacaca 4200 tctccctttt ccatgactgt ggtagccagc atcggaaaga acgctgattt aaagaggtcg 4260 cttgggaatt ttattgacac agtaccattt aatggggagg acaaaatggg gcaggggagg 4320 gagaagtttc tgtcgttaaa aacagatttg gaaagactgg actctaaagt ctgttgatta 4380 aagatgagct ttgtctactt caaaagtttg tttgcttacc ccttcagcct ccaatttttt 4440 aagtgaaaat atagctaata acatgtgaaa agaatagaag ctaaggttta gataaatatt 4500 gagcagatct ataggaagat tgaacctgaa tattgccatt atgcttgaca tggtttccaa 4560 aaaatggtac tccacatatt tcagtgaggg taagtatttt cctgttgtca agaatagcat 4620 tgtaaaagca ttttgtaata ataaagaata gctttaatga tatgcttgta actaaaataa 4680 ttttgtaatg tatcaaatac atttaaaaca ttaaaatata atctctataa taatttaaaa 4740 tctaatatgg ttttaataga acagcgatat caagcttatc gataatcaac ctctggatta 4800 caaaatttgt gaaagattga ctggtattct taactatgtt gctcctttta cgctatgtgg 4860 atacgctgct ttaatgcctt tgtatcatgc tattgcttcc cgtatggctt tcattttctc 4920 ctccttgtat aaatcctggt tgctgtctct ttatgaggag ttgtggcccg ttgtcaggca 4980 acgtggcgtg gtgtgcactg tgtttgctga cgcaaccccc actggttggg gcattgccac 5040 cacctgtcag ctcctttccg ggactttcgc tttccccctc cctattgcca cggcggaact 5100 catcgccgcc tgccttgccc gctgctggac aggggctcgg ctgttgggca ctgacaattc 5160 cgtggtgttg tcggggaaat catcgtcctt tccttggctg ctcgcctatg ttgccacctg 5220 gattctgcgc gggacgtcct tctgctacgt cccttcggcc ctcaatccag cggaccttcc 5280 ttcccgcggc ctgctgccgg ctctgcggcc tcttccgcgt cttcgccttc gccctcagac 5340 gagtcggatc tccctttggg ccgcctcccc gcgaattcat cgataccgag cgctgctcga 5400 gagatctgtg atagcggcca tcaagctggc tgtgccttct agttgccagc catctgttgt 5460 ttgcccctcc cccgtgcctt ccttgaccct ggaaggtgcc actcccactg tcctttccta 5520 ataaaatgag gaaattgcat cgcattgtct gagtaggtgt cattctattc tggggggtgg 5580 ggtggggcag gacagcaagg gggaggattg ggaagacaat agcaggcatg ctggggacac 5640 gtgcggaccg agcggccgca ggaaccccta gtgatggagt tggccactcc ctctctgcgc 5700 gctcgctcgc tcactgaggc cgggcgacca aaggtcgccc gacgcccggg ctttgcccgg 5760 gcggcctcag tgagcgagcg agcgcgcagc tgcctgcagg ggcgcctgat gcggtatttt 5820 ctccttacgc atctgtgcgg tatttcacac cgcatacgtc aaagcaacca tagtacgcgc 5880 cctgtagcgg cgcattaagc gcggcgggtg tggtggttac gcgcagcgtg accgctacac 5940 ttgccagcgc cctagcgccc gctcctttcg ctttcttccc ttcctttctc gccacgttcg 6000 ccggctttcc ccgtcaagct ctaaatcggg ggctcccttt agggttccga tttagtgctt 6060 tacggcacct cgaccccaaa aaacttgatt tgggtgatgg ttcacgtagt gggccatcgc 6120 cctgatagac ggtttttcgc cctttgacgt tggagtccac gttctttaat agtggactct 6180 tgttccaaac tggaacaaca ctcaacccta tctcgggcta ttcttttgat ttataaggga 6240 ttttgccgat ttcggcctat tggttaaaaa atgagctgat ttaacaaaaa tttaacgcga 6300 attttaacaa aatattaacg tttacaattt tatggtgcac tctcagtaca atctgctctg 6360 atgccgcata gttaagccag ccccgacacc cgccaacacc cgctgacgcg ccctgacggg 6420 cttgtctgct cccggcatcc gcttacagac aagctgtgac cgtctccggg agctgcatgt 6480 gtcagaggtt ttcaccgtca tcaccgaaac gcgcgagacg aaagggcctc gtgatacgcc 6540 tatttttata ggttaatgtc atgataataa tggtttctta gacgtcaggt ggcacttttc 6600 ggggaaatgt gcgcggaacc cctatttgtt tatttttcta aatacattca aatatgtatc 6660 cgctcatgag acaataaccc tgataaatgc ttcaataata ttgaaaaagg aagagtatga 6720 gtattcaaca tttccgtgtc gcccttattc ccttttttgc ggcattttgc cttcctgttt 6780 ttgctcaccc agaaacgctg gtgaaagtaa aagatgctga agatcagttg ggtgcacgag 6840 tgggttacat cgaactggat ctcaacagcg gtaagatcct tgagagtttt cgccccgaag 6900 aacgttttcc aatgatgagc acttttaaag ttctgctatg tggcgcggta ttatcccgta 6960 ttgacgccgg gcaagagcaa ctcggtcgcc gcatacacta ttctcagaat gacttggttg 7020 agtactcacc agtcacagaa aagcatctta cggatggcat gacagtaaga gaattatgca 7080 gtgctgccat aaccatgagt gataacactg cggccaactt acttctgaca acgatcggag 7140 gaccgaagga gctaaccgct tttttgcaca acatggggga tcatgtaact cgccttgatc 7200 gttgggaacc ggagctgaat gaagccatac caaacgacga gcgtgacacc a 7251 <210> 80 <211> 7209 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 80 cgatgcctgt agcaatggca acaacgttgc gcaaactatt aactggcgaa ctacttactc 60 tagcttcccg gcaacaatta atagactgga tggaggcgga taaagttgca ggaccacttc 120 tgcgctcggc ccttccggct ggctggttta ttgctgataa atctggagcc ggtgagcgtg 180 ggtctcgcgg tatcattgca gcactggggc cagatggtaa gccctcccgt atcgtagtta 240 tctacacgac ggggagtcag gcaactatgg atgaacgaaa tagacagatc gctgagatag 300 gtgcctcact gattaagcat tggtaactgt cagaccaagt ttactcatat atactttaga 360 ttgatttaaa acttcatttt taatttaaaa ggatctaggt gaagatcctt tttgataatc 420 tcatgaccaa aatcccttaa cgtgagtttt cgttccactg agcgtcagac cccgtagaaa 480 agatcaaagg atcttcttga gatccttttt ttctgcgcgt aatctgctgc ttgcaaacaa 540 aaaaaccacc gctaccagcg gtggtttgtt tgccggatca agagctacca actctttttc 600 cgaaggtaac tggcttcagc agagcgcaga taccaaatac tgtccttcta gtgtagccgt 660 agttaggcca ccacttcaag aactctgtag caccgcctac atacctcgct ctgctaatcc 720 tgttaccagt ggctgctgcc agtggcgata agtcgtgtct taccgggttg gactcaagac 780 gatagttacc ggataaggcg cagcggtcgg gctgaacggg gggttcgtgc acacagccca 840 gcttggagcg aacgacctac accgaactga gatacctaca gcgtgagcta tgagaaagcg 900 ccacgcttcc cgaagggaga aaggcggaca ggtatccggt aagcggcagg gtcggaacag 960 gagagcgcac gagggagctt ccagggggaa acgcctggta tctttatagt cctgtcgggt 1020 ttcgccacct ctgacttgag cgtcgatttt tgtgatgctc gtcagggggg cggagcctat 1080 ggaaaaacgc cagcaacgcg gcctttttac ggttcctggc cttttgctgg ccttttgctc 1140 acatgtcctg caggcagctg cgcgctcgct cgctcactga ggccgcccgg gcaaagcccg 1200 ggcgtcgggc gacctttggt cgcccggcct cagtgagcga gcgagcgcgc agagaggag 1260 tggccaactc catcactagg ggttcctgcg gccgcacgcg tcgacctgaa cgattaaggc 1320 aaaacttcga aatgtgcccc agcagagatt tatttttcag ggggtgtttt gcattccagc 1380 ccctctgcct tcctggcgtt tagtgcgatt tgtttagcca tgtgctccct ggtgtgtgtt 1440 tttgaatgtg tgtgagatgg gttgtctctc gggacctggc aggtgcggcc accaggtcag 1500 ggctgcccccc caaccctgtg cctccttcct cctagactct ggccccctca gtgctgaggg 1560 tgatacagag cacttttcaa gctggatttg gaatgtggcc tctcccctcc aaactcctgg 1620 agatcatgca aaggcctttg gagccagcca gtcacctgga aggtgacatt cccaccagct 1680 gaggcctcac cttcagcggg ggctgggcag ctttggagcc tggggccagc caagctcact 1740 ctgcccatat ccctgccacg tgtggcccag cggatgatca cctgtcttca tctgcgtact 1800 gggccacatc cctcctgccg tcccccactt ccctgatgac acctacagca agcccctacc 1860 caagtgttct gtgatcccct gtaaatgtgg cctccctagc tacttgcttt tatgaaacca 1920 acaatcctgg ggacacagtt ttcggctgtc tcaagacggg gcaaccactc ttttccccag 1980 gcctgtgggt cccaggcctg gagctagggt tggcattctt gcctgaattc tccactctat 2040 cccaacccct gaggccgcct gaggaggctc agactgtgtc aggctaggag gacagtcaaa 2100 ccacaaaaac atgcctttta agaagtataa gcacaaatcc ctctttgatg ttatataaaa 2160 gctcagtgtc actttaatta agacctcgaa ggggacttgg ggggttcggg gctttcgggg 2220 gcggtcgggg gttcgcggac ccgggaagct ctgaggaccc agaggccggg cgcgctccgc 2280 ccgcggcgcc gccccctccg taactttccc agtctccgag ggaagaggcg gggtgtgggg 2340 tgcggttaaa aggcgccacg gcgggagaca ggtgttgcgg ccccgcagcg cccgcgcgct 2400 cctctccccg actcggagcc cctcggcggc gcccggccca ggacccgcct aggagcgcag 2460 gagccccagc gcagagaccc caacgccgag acccccgccc cggccccgcc gcgcttcctc 2520 ccgacgcaga gcaaaccgcc cagagtagaa gccatggatt ggggcacgct gcagacgatc 2580 ctggggggtg tgaacaaaca ctccaccagc attggaaaga tctggctcac cgtcctcttc 2640 atttttcgca ttatgatcct cgttgtggct gcaaaggagg tgtggggaga tgagcaggcc 2700 gactttgtct gcaacaccct gcagccaggc tgcaagaacg tgtgctacga tcactacttc 2760 cccatctccc acatccggct atgggccctg cagctgatct tcgtgtccac gccagcgctc 2820 ctagtggcca tgcacgtggc ctaccggaga catgagaaga agaggaagtt catcaagggg 2880 gagataaaga gtgaatttaa ggacatcgag gagatcaaaa cccagaaggt ccgcatcgaa 2940 ggctccctgt ggtggaccta cacaagcagc atcttcttcc gggtcatctt cgaagccgcc 3000 ttcatgtacg tcttctatgt catgtacgac ggcttctcca tgcagcggct ggtgaagtgc 3060 aacgcctggc cttgtcccaa cactgtggac tgctttgtgt cccggcccac ggagaagact 3120 gtcttcacag tgttcatgat tgcagtgtct ggaatttgca tcctgctgaa tgtcactgaa 3180 ttgtgttatt tgctaattag atattgttct gggaagtcaa aaaagccagt ttaaaggcgc 3240 gccacccctg cagggaattc cgcattgccc agttgttaga ttaagaaata gacagcatga 3300 gagggatgag gcaacccgtg ctcagctgtc aaggctcagt cgctagcatt tcccaacaca 3360 aagattctga ccttaaatgc aaccatttga aacccctgta ggcctcaggt gaaactccag 3420 atgccacaat ggagctctgc tcccctaaag cctcaaaaca aaggcctaat tctatgcctg 3480 tcttaatttt ctttcactta agttagttcc actgagaccc caggctgtta ggggttattg 3540 gtgtaaggta ctttcatatt ttaaacagag gatatcggca tttgtttctt tctctgagga 3600 caagagaaaa aagccaggtt ccacagagga cacagagaag gtttgggtgt cctcctgggg 3660 ttctttttgc caactttccc cacgttaaag gtgaacattg gttctttcat ttgctttgga 3720 agttttaatc tctaacagtg gacaaagtta ccagtgcctt aaactctgtt acactttttg 3780 gaagtgaaaa ctttgtagta tgataggtta ttttgatgta aagatgttct ggataccatt 3840 atatgttccc cctgtttcag aggctcagat tgtaatatgt aaatggtatg tcattcgcta 3900 ctatgattta atttgaaata tggtcttttg gttatgaata ctttgcagca cagctgagag 3960 gctgtctgtt gtattcattg tggtcatagc acctaacaac attgtagcct caatcgagtg 4020 agacagacta gaagttccta gtgatggctt atgatagcaa atggcctcat gtcaaatatt 4080 tagatgtaat tttgtgtaag aaatacagac tggatgtacc accaactact acctgtaatg 4140 acaggcctgt ccaacacatc tcccttttcc atgactgtgg tagccagcat cggaaagaac 4200 gctgatttaa agaggtcgct tgggaatttt attgacacag taccatttaa tggggaggac 4260 aaaatggggc aggggaggga gaagtttctg tcgttaaaaa cagatttgga aagactggac 4320 tctaaagtct gttgattaaa gatgagcttt gtctacttca aaagtttgtt tgcttacccc 4380 ttcagcctcc aattttttaa gtgaaaatat agctaataac atgtgaaaag aatagaagct 4440 aaggtttaga taaatattga gcagatctat aggaagatg aacctgaata ttgccattat 4500 gcttgacatg gtttccaaaa aatggtactc cacatatttc agtgagggta agtattttcc 4560 tgttgtcaag aatagcattg taaaagcatt ttgtaataat aaagaatagc tttaatgata 4620 tgcttgtaac taaaataatt ttgtaatgta tcaaatacat ttaaaacatt aaaatataat 4680 ctctataata atttaaaatc taatatggtt ttaatagaac agcgatatca agcttatcga 4740 taatcaacct ctggattaca aaatttgtga aagattgact ggtattctta actatgttgc 4800 tccttttacg ctatgtggat acgctgcttt aatgcctttg tatcatgcta ttgcttcccg 4860 tatggctttc attttctcct ccttgtataa atcctggttg ctgtctcttt atgaggagtt 4920 gtggcccgtt gtcaggcaac gtggcgtggt gtgcactgtg tttgctgacg caacccccac 4980 tggttggggc attgccacca cctgtcagct cctttccggg actttcgctt tccccctccc 5040 tattgccacg gcggaactca tcgccgcctg ccttgcccgc tgctggacag gggctcggct 5100 gttggcact gacaattccg tggtgttgtc ggggaaatca tcgtcctttc cttggctgct 5160 cgcctatgtt gccacctgga ttctgcgcgg gacgtccttc tgctacgtcc cttcggccct 5220 caatccagcg gaccttcctt cccgcggcct gctgccggct ctgcggcctc ttccgcgtct 5280 tcgccttcgc cctcagacga gtcggatctc cctttgggcc gcctccccgc gaattcatcg 5340 ataccgagcg ctgctcgaga gatctgtgat agcggccatc aagctggctg tgccttctag 5400 ttgccagcca tctgttgttt gcccctcccc cgtgccttcc ttgaccctgg aaggtgccac 5460 tcccactgtc ctttcctaat aaaatgagga aattgcatcg cattgtctga gtaggtgtca 5520 ttctattctg gggggtgggg tggggcagga cagcaagggg gaggattggg aagacaatag 5580 caggcatgct ggggacacgt gcggaccgag cggccgcagg aacccctagt gatggagttg 5640 gccactccct ctctgcgcgc tcgctcgctc actgaggccg ggcgaccaaa ggtcgcccga 5700 cgcccgggct ttgcccgggc ggcctcagtg agcgagcgag cgcgcagctg cctgcagggg 5760 cgcctgatgc ggtattttct ccttacgcat ctgtgcggta tttcacaccg catacgtcaa 5820 agcaaccata gtacgcgccc tgtagcggcg cattaagcgc ggcgggtgtg gtggttacgc 5880 gcagcgtgac cgctacactt gccagcgccc tagcgcccgc tcctttcgct ttcttccctt 5940 cctttctcgc cacgttcgcc ggctttcccc gtcaagctct aaatcggggg ctccctttag 6000 ggttccgatt tagtgcttta cggcacctcg accccaaaaa acttgatttg ggtgatggtt 6060 cacgtagtgg gccatcgccc tgatagacgg tttttcgccc tttgacgttg gagtccacgt 6120 tctttaatag tggactcttg ttccaaactg gaacaacact caaccctatc tcgggctatt 6180 cttttgattt ataagggatt ttgccgattt cggcctattg gttaaaaaat gagctgattt 6240 aacaaaaatt taacgcgaat tttaacaaaa tattaacgtt tacaatttta tggtgcactc 6300 tcagtacaat ctgctctgat gccgcatagt taagccagcc ccgacacccg ccaacacccg 6360 ctgacgcgcc ctgacgggct tgtctgctcc cggcatccgc ttacagacaa gctgtgaccg 6420 tctccgggag ctgcatgtgt cagaggtttt caccgtcatc accgaaacgc gcgagacgaa 6480 agggcctcgt gatacgccta tttttatagg ttaatgtcat gataataatg gtttcttaga 6540 cgtcaggtgg cacttttcgg ggaaatgtgc gcggaacccc tatttgttta tttttctaaa 6600 tacattcaaa tatgtatccg ctcatgagac aataaccctg ataaatgctt caataatatt 6660 gaaaaaggaa gagtatgagt attcaacatt tccgtgtcgc ccttattccc ttttttgcgg 6720 cattttgcct tcctgttttt gctcacccag aaacgctggt gaaagtaaaa gatgctgaag 6780 atcagttggg tgcacgagtg ggttacatcg aactggatct caacagcggt aagatccttg 6840 agagttttcg ccccgaagaa cgttttccaa tgatgagcac ttttaaagtt ctgctatgtg 6900 gcgcggtatt atcccgtatt gacgccgggc aagagcaact cggtcgccgc atacactatt 6960 ctcagaatga cttggttgag tactcaccag tcacagaaaa gcatcttacg gatggcatga 7020 cagtaagaga attatgcagt gctgccataa ccatgagtga taacactgcg gccaacttac 7080 ttctgacaac gatcggagga ccgaaggagc taaccgcttt tttgcacaac atgggggatc 7140 atgtaactcg ccttgatcgt tgggaaccgg agctgaatga agccatacca aacgacgagc 7200 gtgacacca 7209 <210> 81 <211> 7236 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 81 cgatgcctgt agcaatggca acaacgttgc gcaaactatt aactggcgaa ctacttactc 60 tagcttcccg gcaacaatta atagactgga tggaggcgga taaagttgca ggaccacttc 120 tgcgctcggc ccttccggct ggctggttta ttgctgataa atctggagcc ggtgagcgtg 180 ggtctcgcgg tatcattgca gcactggggc cagatggtaa gccctcccgt atcgtagtta 240 tctacacgac ggggagtcag gcaactatgg atgaacgaaa tagacagatc gctgagatag 300 gtgcctcact gattaagcat tggtaactgt cagaccaagt ttactcatat atactttaga 360 ttgatttaaa acttcatttt taatttaaaa ggatctaggt gaagatcctt tttgataatc 420 tcatgaccaa aatcccttaa cgtgagtttt cgttccactg agcgtcagac cccgtagaaa 480 agatcaaagg atcttcttga gatccttttt ttctgcgcgt aatctgctgc ttgcaaacaa 540 aaaaaccacc gctaccagcg gtggtttgtt tgccggatca agagctacca actctttttc 600 cgaaggtaac tggcttcagc agagcgcaga taccaaatac tgtccttcta gtgtagccgt 660 agttaggcca ccacttcaag aactctgtag caccgcctac atacctcgct ctgctaatcc 720 tgttaccagt ggctgctgcc agtggcgata agtcgtgtct taccgggttg gactcaagac 780 gatagttacc ggataaggcg cagcggtcgg gctgaacggg gggttcgtgc acacagccca 840 gcttggagcg aacgacctac accgaactga gatacctaca gcgtgagcta tgagaaagcg 900 ccacgcttcc cgaagggaga aaggcggaca ggtatccggt aagcggcagg gtcggaacag 960 gagagcgcac gagggagctt ccagggggaa acgcctggta tctttatagt cctgtcgggt 1020 ttcgccacct ctgacttgag cgtcgatttt tgtgatgctc gtcagggggg cggagcctat 1080 ggaaaaacgc cagcaacgcg gcctttttac ggttcctggc cttttgctgg ccttttgctc 1140 acatgtcctg caggcagctg cgcgctcgct cgctcactga ggccgcccgg gcaaagcccg 1200 ggcgtcgggc gacctttggt cgcccggcct cagtgagcga gcgagcgcgc agagaggag 1260 tggccaactc catcactagg ggttcctgcg gccgcacgcg tcgacctgaa cgattaaggc 1320 aaaacttcga aatgtgcccc agcagagatt tatttttcag ggggtgtttt gcattccagc 1380 ccctctgcct tcctggcgtt tagtgcgatt tgtttagcca tgtgctccct ggtgtgtgtt 1440 tttgaatgtg tgtgagatgg gttgtctctc gggacctggc aggtgcggcc accaggtcag 1500 ggctgcccccc caaccctgtg cctccttcct cctagactct ggccccctca gtgctgaggg 1560 tgatacagag cacttttcaa gctggatttg gaatgtggcc tctcccctcc aaactcctgg 1620 agatcatgca aaggcctttg gagccagcca gtcacctgga aggtgacatt cccaccagct 1680 gaggcctcac cttcagcggg ggctgggcag ctttggagcc tggggccagc caagctcact 1740 ctgcccatat ccctgccacg tgtggcccag cggatgatca cctgtcttca tctgcgtact 1800 gggccacatc cctcctgccg tcccccactt ccctgatgac acctacagca agcccctacc 1860 caagtgttct gtgatcccct gtaaatgtgg cctccctagc tacttgcttt tatgaaacca 1920 acaatcctgg ggacacagtt ttcggctgtc tcaagacggg gcaaccactc ttttccccag 1980 gcctgtgggt cccaggcctg gagctagggt tggcattctt gcctgaattc tccactctat 2040 cccaacccct gaggccgcct gaggaggctc agactgtgtc aggctaggag gacagtcaaa 2100 ccacaaaaac atgcctttta agaagtataa gcacaaatcc ctctttgatg ttatataaaa 2160 gctcagtgtc actttaatta agacctcgaa ggggacttgg ggggttcggg gctttcgggg 2220 gcggtcgggg gttcgcggac ccgggaagct ctgaggaccc agaggccggg cgcgctccgc 2280 ccgcggcgcc gccccctccg taactttccc agtctccgag ggaagaggcg gggtgtgggg 2340 tgcggttaaa aggcgccacg gcgggagaca ggtgttgcgg ccccgcagcg cccgcgcgct 2400 cctctccccg actcggagcc cctcggcggc gcccggccca ggacccgcct aggagcgcag 2460 gagccccagc gcagagaccc caacgccgag acccccgccc cggccccgcc gcgcttcctc 2520 ccgacgcaga gcaaaccgcc cagagtagaa gccatggatt ggggcacact ccagagcatc 2580 ctcgggggtg tcaacaaaca ctccaccagc attggaaaga tctggctcac ggtcctcttc 2640 atcttccgca tcatgatcct cgtggtggct gcaaaggagg tgtggggaga tgagcaagcc 2700 gattttgtct gcaacacgct ccagcctggc tgcaagaatg tatgctacga ccaccacttc 2760 cccatctctc acatccggct ctgggctctg cagctgatca tggtgtccac gccagccctc 2820 ctggtagcta tgcatgtggc ctaccggaga catgaaaaga aacggaagtt catgaaggga 2880 gagataaaga acgagtttaa ggacatcgaa gagatcaaaa cccagaaggt ccgtatcgaa 2940 gggtccctgt ggtggaccta caccaccagc atcttcttcc gggtcatctt tgaagccgtc 3000 ttcatgtacg tcttttacat catgtacaat ggcttcttca tgcaacgtct ggtgaaatgc 3060 aacgcttggc cctgccccaa tacagtggac tgcttcattt ccaggcccac agaaaagact 3120 gtcttcaccg tgtttatgat ttctgtgtct ggaatttgca ttctgctaaa tatcacagag 3180 ctgtgctatt tgttcgttag gtattgctca ggaaagtcca aaagaccagt ctacccatac 3240 gatgttccag attacgctta aaggcgcgcc acccctgcag ggaattccgc attgcccagt 3300 tgttagatta agaaatagac agcatgagag ggatgaggca acccgtgctc agctgtcaag 3360 gctcagtcgc tagcatttcc caacacaaag attctgacct taaatgcaac catttgaaac 3420 ccctgtaggc ctcaggtgaa actccagatg ccacaatgga gctctgctcc cctaaagcct 3480 caaaacaaag gcctaattct atgcctgtct taattttctt tcacttaagt tagttccact 3540 gagaccccag gctgttaggg gttattggtg taaggtactt tcatatttta aacagaggat 3600 atcggcattt gtttctttct ctgaggacaa gagaaaaaag ccaggttcca cagaggacac 3660 agagaaggtt tgggtgtcct cctggggttc tttttgccaa ctttccccac gttaaaggtg 3720 aacattggtt ctttcatttg ctttggaagt tttaatctct aacagtggac aaagttacca 3780 gtgccttaaa ctctgttaca ctttttggaa gtgaaaactt tgtagtatga taggttattt 3840 tgatgtaaag atgttctgga taccattata tgttccccct gtttcagagg ctcagattgt 3900 aatatgtaaa tggtatgtca ttcgctacta tgatttaatt tgaaatatgg tcttttggtt 3960 atgaatactt tgcagcacag ctgagaggct gtctgttgta ttcattgtgg tcatagcacc 4020 taacaacatt gtagcctcaa tcgagtgaga cagactagaa gttcctagtg atggcttatg 4080 atagcaaatg gcctcatgtc aaatatttag atgtaatttt gtgtaagaaa tacagactgg 4140 atgtaccacc aactactacc tgtaatgaca ggcctgtcca acacatctcc cttttccatg 4200 actgtggtag ccagcatcgg aaagaacgct gatttaaaga ggtcgcttgg gaattttatt 4260 gacacagtac catttaatgg ggaggacaaa atggggcagg ggagggagaa gtttctgtcg 4320 ttaaaaacag atttggaaag actggactct aaagtctgtt gattaaagat gagctttgtc 4380 tacttcaaaa gtttgtttgc ttaccccttc agccctccaat tttttaagtg aaaatatagc 4440 taataacatg tgaaaagaat agaagctaag gtttagataa atattgagca gatctatagg 4500 aagattgaac ctgaatattg ccattatgct tgacatggtt tccaaaaaat ggtactccac 4560 atatttcagt gagggtaagt attttcctgt tgtcaagaat agcattgtaa aagcattttg 4620 taataataaa gaatagcttt aatgatatgc ttgtaactaa aataattttg taatgtatca 4680 aatacattta aaacattaaa atataatctc tataataatt taaaatctaa tatggtttta 4740 atagaacagc gatatcaagc ttatcgataa tcaacctctg gattacaaaa tttgtgaaag 4800 attgactggt attcttaact atgttgctcc ttttacgcta tgtggatacg ctgctttaat 4860 gcctttgtat catgctattg cttcccgtat ggctttcatt ttctcctcct tgtataaatc 4920 ctggttgctg tctctttatg aggagttgg gcccgttgtc aggcaacgtg gcgtggtgtg 4980 cactgtgttt gctgacgcaa cccccactgg ttggggcatt gccaccacct gtcagctcct 5040 ttccgggact ttcgctttcc ccctccctat tgccacggcg gaactcatcg ccgcctgcct 5100 tgcccgctgc tggacagggg ctcggctgtt gggcactgac aattccgtgg tgttgtcggg 5160 gaaatcatcg tcctttcctt ggctgctcgc ctatgttgcc acctggattc tgcgcgggac 5220 gtccttctgc tacgtccctt cggccctcaa tccagcggac cttccttccc gcggcctgct 5280 gccggctctg cggcctcttc cgcgtcttcg ccttcgccct cagacgagtc ggatctccct 5340 ttgggccgcc tccccgcgaa ttcatcgata ccgagcgctg ctcgagagat ctgtgatagc 5400 ggccatcaag ctggctgtgc cttctagttg ccagccatct gttgtttgcc cctcccccgt 5460 gccttccttg accctggaag gtgccactcc cactgtcctt tcctaataaa atgaggaaat 5520 tgcatcgcat tgtctgagta ggtgtcattc tattctgggg ggtggggtgg ggcaggacag 5580 caagggggag gattgggaag acaatagcag gcatgctggg gacacgtgcg gaccgagcgg 5640 ccgcaggaac ccctagtgat ggagttggcc actccctctc tgcgcgctcg ctcgctcact 5700 gaggccgggc gaccaaaggt cgcccgacgc ccgggctttg cccgggcggc ctcagtgagc 5760 gagcgagcgc gcagctgcct gcaggggcgc ctgatgcggt attttctcct tacgcatctg 5820 tgcggtattt cacaccgcat acgtcaaagc aaccatagta cgcgccctgt agcggcgcat 5880 taagcgcggc gggtgtggtg gttacgcgca gcgtgaccgc tacacttgcc agcgccctag 5940 cgcccgctcc tttcgctttc ttcccttcct ttctcgccac gttcgccggc tttccccgtc 6000 aagctctaaa tcgggggctc cctttagggt tccgatttag tgctttacgg cacctcgacc 6060 ccaaaaaact tgatttgggt gatggttcac gtagtgggcc atcgccctga tagacggttt 6120 ttcgcccttt gacgttggag tccacgttct ttaatagtgg actcttgttc caaactgggaa 6180 caacactcaa ccctatctcg ggctattctt ttgatttata agggattttg ccgatttcgg 6240 cctattggtt aaaaatgag ctgatttaac aaaaatttaa cgcgaatttt aacaaaatat 6300 taacgtttac aattttatgg tgcactctca gtacaatctg ctctgatgcc gcatagttaa 6360 gccagccccg acacccgcca acacccgctg acgcgccctg acgggcttgt ctgctcccgg 6420 catccgctta cagacaagct gtgaccgtct ccgggagctg catgtgtcag aggttttcac 6480 cgtcatcacc gaaacgcgcg agacgaaagg gcctcgtgat acgcctattt ttataggtta 6540 atgtcatgat aataatggtt tcttagacgt caggtggcac ttttcgggga aatgtgcgcg 6600 gaacccctat ttgtttattt ttctaaatac attcaaatat gtatccgctc atgagacaat 6660 aaccctgata aatgcttcaa taatattgaa aaaggaagag tatgagtatt caacatttcc 6720 gtgtcgccct tattcccttt tttgcggcat tttgccttcc tgtttttgct cacccagaaa 6780 cgctggtgaa agtaaaagat gctgaagatc agttgggtgc acgagtgggt tacatcgaac 6840 tggatctcaa cagcggtaag atccttgaga gttttcgccc cgaagaacgt tttccaatga 6900 tgagcacttt taaagttctg ctatgtggcg cggtattatc ccgtattgac gccgggcaag 6960 agcaactcgg tcgccgcata cactattctc agaatgactt ggttgagtac tcaccagtca 7020 cagaaaagca tcttacggat ggcatgacag taagagaatt atgcagtgct gccataacca 7080 tgagtgataa cactgcggcc aacttacttc tgacaacgat cggaggaccg aaggagctaa 7140 ccgctttttt gcacaacatg ggggatcatg taactcgcct tgatcgttgg gaaccggagc 7200 tgaatgaagc cataccaaac gacgagcgtg acacca 7236 <210> 82 <211> 7018 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 82 cgatgcctgt agcaatggca acaacgttgc gcaaactatt aactggcgaa ctacttactc 60 tagcttcccg gcaacaatta atagactgga tggaggcgga taaagttgca ggaccacttc 120 tgcgctcggc ccttccggct ggctggttta ttgctgataa atctggagcc ggtgagcgtg 180 ggtctcgcgg tatcattgca gcactggggc cagatggtaa gccctcccgt atcgtagtta 240 tctacacgac ggggagtcag gcaactatgg atgaacgaaa tagacagatc gctgagatag 300 gtgcctcact gattaagcat tggtaactgt cagaccaagt ttactcatat atactttaga 360 ttgatttaaa acttcatttt taatttaaaa ggatctaggt gaagatcctt tttgataatc 420 tcatgaccaa aatcccttaa cgtgagtttt cgttccactg agcgtcagac cccgtagaaa 480 agatcaaagg atcttcttga gatccttttt ttctgcgcgt aatctgctgc ttgcaaacaa 540 aaaaaccacc gctaccagcg gtggtttgtt tgccggatca agagctacca actctttttc 600 cgaaggtaac tggcttcagc agagcgcaga taccaaatac tgtccttcta gtgtagccgt 660 agttaggcca ccacttcaag aactctgtag caccgcctac atacctcgct ctgctaatcc 720 tgttaccagt ggctgctgcc agtggcgata agtcgtgtct taccgggttg gactcaagac 780 gatagttacc ggataaggcg cagcggtcgg gctgaacggg gggttcgtgc acacagccca 840 gcttggagcg aacgacctac accgaactga gatacctaca gcgtgagcta tgagaaagcg 900 ccacgcttcc cgaagggaga aaggcggaca ggtatccggt aagcggcagg gtcggaacag 960 gagagcgcac gagggagctt ccagggggaa acgcctggta tctttatagt cctgtcgggt 1020 ttcgccacct ctgacttgag cgtcgatttt tgtgatgctc gtcagggggg cggagcctat 1080 ggaaaaacgc cagcaacgcg gcctttttac ggttcctggc cttttgctgg ccttttgctc 1140 acatgtcctg caggcagctg cgcgctcgct cgctcactga ggccgcccgg gcaaagcccg 1200 ggcgtcgggc gacctttggt cgcccggcct cagtgagcga gcgagcgcgc agagaggag 1260 tggccaactc catcactagg ggttcctgcg gccgcacgcg ttctaggtag acaactaaga 1320 tgttcatctt atggtttaat gtttagttgt aaaggttgtt tgcttctcat ttggttccaa 1380 gaaagagtat ttaggccaat ttcagggaga aatatgtgta tagatatatt catatgtcaa 1440 actgattagt gctgaatgtc acatttccat attctaataa catttctagc aaagaagagg 1500 acacagtgaa gagagaattg cccgcattgt cattgtctct ttctgagcct agaacgccta 1560 acacttgggt gtggagagac tcagcctcaa ttcactttct agcagccact gagatgtgct 1620 tgcctggggt gccccctggc aggcagggct ggaactgctt tccagtaccc acacggactg 1680 tgaacgaatc tttctttgtg ctttgtgtac agaatggaag ttcaacaaat atttgttgaa 1740 tgtgtatgtc cttccaatac gcagcagccc agagcaaacg tggtaatctt gtgtgtgttc 1800 atgtgaaagc agaatttaat ggtgctttta agcaccaaag tttaagatgc acgagaaaac 1860 tgtatctcca ttttttcctt ttcgtttaca attacttgta taagccaggc acggtggtgg 1920 ctcacgcctg taatcccagc actttgggag gccgaggcgg gcggatcaca tgaggtcggg 1980 agttaattaa gacctcgaag gggacttggg gggttcgggg ctttcggggg cggtcggggg 2040 ttcgcggacc cgggaagctc tgaggaccca gaggccgggc gcgctccgcc cgcggcgccg 2100 ccccctccgt aactttccca gtctccgagg gaagaggcgg ggtgtggggt gcggttaaaa 2160 ggcgccacgg cgggagacag gtgttgcggc cccgcagcgc ccgcgcgctc ctctccccga 2220 ctcggagccc ctcggcggcg cccggcccag gacccgccta ggagcgcagg agccccagcg 2280 cagagacccc aacgccgaga cccccgcccc ggccccgccg cgcttcctcc cgacgcagag 2340 caaaccgccc agagtagaag ccatggattg gggcacgctg cagacgatcc tggggggtgt 2400 gaacaaacac tccaccagca ttggaaagat ctggctcacc gtcctcttca tttttcgcat 2460 tatgatcctc gttgtggctg caaaggaggt gtggggagat gagcaggccg actttgtctg 2520 caacaccctg cagccaggct gcaagaacgt gtgctacgat cactacttcc ccatctccca 2580 catccggcta tgggccctgc agctgatctt cgtgtccacg ccagcgctcc tagtggccat 2640 gcacgtggcc taccggagac atgagaagaa gaggaagttc atcaaggggg agataaagag 2700 tgaatttaag gacatcgagg agatcaaaac ccagaaggtc cgcatcgaag gctccctggg 2760 gtggacctac acaagcagca tcttcttccg ggtcatcttc gaagccgcct tcatgtacgt 2820 cttctatgtc atgtacgacg gcttctccat gcagcggctg gtgaagtgca acgcctggcc 2880 ttgtcccaac actgtggact gctttgtgtc ccggcccacg gagaagactg tcttcacagt 2940 gttcatgatt gcagtgtctg gaatttgcat cctgctgaat gtcactgaat tgtgttattt 3000 gctaattaga tattgttctg ggaagtcaaa aaagccagtt taaaggcgcg ccacccctgc 3060 agggaattcc gcattgccca gttgttagat taagaaatag acagcatgag agggatgagg 3120 caacccgtgc tcagctgtca aggctcagtc gctagcattt cccaacacaa agattctgac 3180 cttaaatgca accatttgaa acccctgtag gcctcaggtg aaactccaga tgccacaatg 3240 gagctctgct cccctaaagc ctcaaaacaa aggcctaatt ctatgcctgt cttaattttc 3300 tttcacttaa gttagttcca ctgagacccc aggctgttag gggttattgg tgtaaggtac 3360 tttcatattt taaacagagg atatcggcat ttgtttcttt ctctgaggac aagagaaaaa 3420 agccaggttc cacagaggac acagagaagg tttgggtgtc ctcctggggt tctttttgcc 3480 aactttcccc acgttaaagg tgaacattgg ttctttcatt tgctttggaa gttttaatct 3540 ctaacagtgg acaaagttac cagtgcctta aactctgtta cactttttgg aagtgaaaac 3600 tttgtagtat gataggttat tttgatgtaa agatgttctg gataccatta tatgttcccc 3660 ctgtttcaga ggctcagatt gtaatatgta aatggtatgt cattcgctac tatgatttaa 3720 tttgaaatat ggtcttttgg ttatgaatac tttgcagcac agctgagagg ctgtctgttg 3780 tattcattgt ggtcatagca cctaacaaca ttgtagcctc aatcgagtga gacagactag 3840 aagttcctag tgatggctta tgatagcaaa tggcctcatg tcaaatattt agatgtaatt 3900 ttgtgtaaga aatacagact ggatgtacca ccaactacta cctgtaatga caggcctgtc 3960 caacacatct cccttttcca tgactgtggt agccagcatc ggaaagaacg ctgatttaaa 4020 gaggtcgctt gggaatttta ttgacacagt accatttaat ggggaggaca aaatggggca 4080 ggggagggag aagtttctgt cgttaaaaac agatttggaa agactggact ctaaagtctg 4140 ttgattaaag atgagctttg tctacttcaa aagtttgttt gcttacccct tcagcctcca 4200 attttttaag tgaaaatata gctaataaca tgtgaaaaga atagaagcta aggtttagat 4260 aaatattgag cagatctata ggaagattga acctgaatat tgccattatg cttgacatgg 4320 tttccaaaaa atggtactcc acatatttca gtgagggtaa gtattttcct gttgtcaaga 4380 atagcattgt aaaagcattt tgtaataata aagaatagct ttaatgatat gcttgtaact 4440 aaaataattt tgtaatgtat caaatacatt taaaacatta aaatataatc tctataataa 4500 tttaaaatct aatatggttt taatagaaca gcgatatcaa gcttatcgat aatcaacctc 4560 tggattacaa aatttgtgaa agattgactg gtattcttaa ctatgttgct ccttttacgc 4620 tatgtggata cgctgcttta atgcctttgt atcatgctat tgcttcccgt atggctttca 4680 ttttctcctc cttgtataaa tcctggttgc tgtctcttta tgaggagttg tggcccgttg 4740 tcaggcaacg tggcgtggtg tgcactgtgt ttgctgacgc aacccccact ggttggggca 4800 ttgccacac ctgtcagctc ctttccggga ctttcgcttt ccccctccct attgccacgg 4860 cggaactcat cgccgcctgc cttgcccgct gctggacagg ggctcggctg ttgggcactg 4920 acaattccgt ggtgttgtcg gggaaatcat cgtcctttcc ttggctgctc gcctatgttg 4980 ccacctggat tctgcgcggg acgtccttct gctacgtccc ttcggccctc aatccagcgg 5040 accttccttc ccgcggcctg ctgccggctc tgcggcctct tccgcgtctt cgccttcgcc 5100 ctcagacgag tcggatctcc ctttgggccg cctccccgcg aattcatcga taccgagcgc 5160 tgctcgagag atctgtgata gcggccatca agctggctgt gccttctagt tgccagccat 5220 ctgttgtttg cccctccccc gtgccttcct tgaccctgga aggtgccact cccactgtcc 5280 tttcctaata aaatgaggaa attgcatcgc attgtctgag taggtgtcat tctattctgg 5340 ggggtggggt ggggcaggac agcaaggggg aggattggga agacaatagc aggcatgctg 5400 gggacacgtg cggaccgagc ggccgcagga acccctagtg atggagttgg ccactccctc 5460 tctgcgcgct cgctcgctca ctgaggccgg gcgaccaaag gtcgcccgac gcccgggctt 5520 tgcccgggcg gcctcagtga gcgagcgagc gcgcagctgc ctgcaggggc gcctgatgcg 5580 gtattttctc cttacgcatc tgtgcggtat ttcacaccgc atacgtcaaa gcaaccatag 5640 tacgcgccct gtagcggcgc attaagcgcg gcgggtgtgg tggttacgcg cagcgtgacc 5700 gctacacttg ccagcgccct agcgcccgct cctttcgctt tcttcccttc ctttctcgcc 5760 acgttcgccg gctttccccg tcaagctcta aatcgggggc tccctttagg gttccgattt 5820 agtgctttac ggcacctcga ccccaaaaaa cttgatttgg gtgatggttc acgtagtggg 5880 ccatcgccct gatagacggt ttttcgccct ttgacgttgg agtccacgtt ctttaatagt 5940 ggactcttgt tccaaactgg aacaacactc aaccctatct cgggctattc ttttgattta 6000 taagggattt tgccgatttc ggcctattgg ttaaaaaatg agctgattta acaaaaattt 6060 aacgcgaatt ttaacaaaat attaacgttt acaattttat ggtgcactct cagtacaatc 6120 tgctctgatg ccgcatagtt aagccagccc cgacacccgc caacacccgc tgacgcgccc 6180 tgacgggctt gtctgctccc ggcatccgct tacagacaag ctgtgaccgt ctccgggagc 6240 tgcatgtgtc agaggttttc accgtcatca ccgaaacgcg cgagacgaaa gggcctcgtg 6300 atacgcctat ttttataggt taatgtcatg ataataatgg tttcttagac gtcaggtggc 6360 actttcggg gaaatgtgcg cggaacccct atttgtttat ttttctaaat acattcaaat 6420 atgtatccgc tcatgagaca ataaccctga taaatgcttc aataatattg aaaaaggaag 6480 agtatgagta ttcaacattt ccgtgtcgcc cttattccct tttttgcggc attttgcctt 6540 cctgtttttg ctcacccaga aacgctggtg aaagtaaaag atgctgaaga tcagttgggt 6600 gcacgagtgg gttacatcga actggatctc aacagcggta agatccttga gagttttcgc 6660 cccgaagaac gttttccaat gatgagcact tttaaagttc tgctatgtgg cgcggtatta 6720 tcccgtattg acgccgggca agagcaactc ggtcgccgca tacactattc tcagaatgac 6780 ttggttgagt actcaccagt cacagaaaag catcttacgg atggcatgac agtaagagaa 6840 ttatgcagtg ctgccataac catgagtgat aacactgcgg ccaacttact tctgacaacg 6900 atcggaggac cgaaggagct aaccgctttt ttgcacaaca tgggggatca tgtaactcgc 6960 cttgatcgtt gggaaccgga gctgaatgaa gccataccaa acgacgagcg tgacacca 7018 <210> 83 <211> 7045 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 83 cgatgcctgt agcaatggca acaacgttgc gcaaactatt aactggcgaa ctacttactc 60 tagcttcccg gcaacaatta atagactgga tggaggcgga taaagttgca ggaccacttc 120 tgcgctcggc ccttccggct ggctggttta ttgctgataa atctggagcc ggtgagcgtg 180 ggtctcgcgg tatcattgca gcactggggc cagatggtaa gccctcccgt atcgtagtta 240 tctacacgac ggggagtcag gcaactatgg atgaacgaaa tagacagatc gctgagatag 300 gtgcctcact gattaagcat tggtaactgt cagaccaagt ttactcatat atactttaga 360 ttgatttaaa acttcatttt taatttaaaa ggatctaggt gaagatcctt tttgataatc 420 tcatgaccaa aatcccttaa cgtgagtttt cgttccactg agcgtcagac cccgtagaaa 480 agatcaaagg atcttcttga gatccttttt ttctgcgcgt aatctgctgc ttgcaaacaa 540 aaaaaccacc gctaccagcg gtggtttgtt tgccggatca agagctacca actctttttc 600 cgaaggtaac tggcttcagc agagcgcaga taccaaatac tgtccttcta gtgtagccgt 660 agttaggcca ccacttcaag aactctgtag caccgcctac atacctcgct ctgctaatcc 720 tgttaccagt ggctgctgcc agtggcgata agtcgtgtct taccgggttg gactcaagac 780 gatagttacc ggataaggcg cagcggtcgg gctgaacggg gggttcgtgc acacagccca 840 gcttggagcg aacgacctac accgaactga gatacctaca gcgtgagcta tgagaaagcg 900 ccacgcttcc cgaagggaga aaggcggaca ggtatccggt aagcggcagg gtcggaacag 960 gagagcgcac gagggagctt ccagggggaa acgcctggta tctttatagt cctgtcgggt 1020 ttcgccacct ctgacttgag cgtcgatttt tgtgatgctc gtcagggggg cggagcctat 1080 ggaaaaacgc cagcaacgcg gcctttttac ggttcctggc cttttgctgg ccttttgctc 1140 acatgtcctg caggcagctg cgcgctcgct cgctcactga ggccgcccgg gcaaagcccg 1200 ggcgtcgggc gacctttggt cgcccggcct cagtgagcga gcgagcgcgc agagaggag 1260 tggccaactc catcactagg ggttcctgcg gccgcacgcg ttctaggtag acaactaaga 1320 tgttcatctt atggtttaat gtttagttgt aaaggttgtt tgcttctcat ttggttccaa 1380 gaaagagtat ttaggccaat ttcagggaga aatatgtgta tagatatatt catatgtcaa 1440 actgattagt gctgaatgtc acatttccat attctaataa catttctagc aaagaagagg 1500 acacagtgaa gagagaattg cccgcattgt cattgtctct ttctgagcct agaacgccta 1560 acacttgggt gtggagagac tcagcctcaa ttcactttct agcagccact gagatgtgct 1620 tgcctggggt gccccctggc aggcagggct ggaactgctt tccagtaccc acacggactg 1680 tgaacgaatc tttctttgtg ctttgtgtac agaatggaag ttcaacaaat atttgttgaa 1740 tgtgtatgtc cttccaatac gcagcagccc agagcaaacg tggtaatctt gtgtgtgttc 1800 atgtgaaagc agaatttaat ggtgctttta agcaccaaag tttaagatgc acgagaaaac 1860 tgtatctcca ttttttcctt ttcgtttaca attacttgta taagccaggc acggtggtgg 1920 ctcacgcctg taatcccagc actttgggag gccgaggcgg gcggatcaca tgaggtcggg 1980 agttaattaa gacctcgaag gggacttggg gggttcgggg ctttcggggg cggtcggggg 2040 ttcgcggacc cgggaagctc tgaggaccca gaggccgggc gcgctccgcc cgcggcgccg 2100 ccccctccgt aactttccca gtctccgagg gaagaggcgg ggtgtggggt gcggttaaaa 2160 ggcgccacgg cgggagacag gtgttgcggc cccgcagcgc ccgcgcgctc ctctccccga 2220 ctcggagccc ctcggcggcg cccggcccag gacccgccta ggagcgcagg agccccagcg 2280 cagagacccc aacgccgaga cccccgcccc ggccccgccg cgcttcctcc cgacgcagag 2340 caaaccgccc agagtagaag ccatggattg gggcacactc cagagcatcc tcgggggtgt 2400 caacaaacac tccaccagca ttggaaagat ctggctcacg gtcctcttca tcttccgcat 2460 catgatcctc gtggtggctg caaaggaggt gtggggagat gagcaagccg attttgtctg 2520 caacacgctc cagcctggct gcaagaatgt atgctacgac caccacttcc ccatctctca 2580 catccggctc tgggctctgc agctgatcat ggtgtccacg ccagccctcc tggtagctat 2640 gcatgtggcc taccggagac atgaaaagaa acggaagttc atgaagggag agataaagaa 2700 cgagtttaag gacatcgaag agatcaaaac ccagaaggtc cgtatcgaag ggtccctgtg 2760 gtggacctac accaccagca tcttcttccg ggtcatcttt gaagccgtct tcatgtacgt 2820 cttttacatc atgtacaatg gcttcttcat gcaacgtctg gtgaaatgca acgcttggcc 2880 ctgccccaat acagtggact gcttcatttc caggcccaca gaaaagactg tcttcaccgt 2940 gtttatgatt tctgtgtctg gaatttgcat tctgctaaat atcacagagc tgtgctattt 3000 gttcgttagg tattgctcag gaaagtccaa aagaccagtc tacccatacg atgttccaga 3060 ttacgcttaa aggcgcgcca cccctgcagg gaattccgca ttgcccagtt gttagattaa 3120 gaaatagaca gcatgagagg gatgaggcaa cccgtgctca gctgtcaagg ctcagtcgct 3180 agcatttccc aacacaaaga ttctgacctt aaatgcaacc atttgaaacc cctgtaggcc 3240 tcaggtgaaa ctccagatgc cacaatggag ctctgctccc ctaaagcctc aaaacaaagg 3300 cctaattcta tgcctgtctt aattttcttt cacttaagtt agttccactg agaccccagg 3360 ctgttagggg ttattggtgt aaggtacttt catattttaa acagaggata tcggcatttg 3420 tttctttctc tgaggacaag agaaaaaagc caggttccac agaggacaca gagaaggttt 3480 gggtgtcctc ctggggttct ttttgccaac tttccccacg ttaaaggtga acattggttc 3540 tttcatttgc tttggaagtt ttaatctcta acagtggaca aagttaccag tgccttaaac 3600 tctgttacac tttttggaag tgaaaacttt gtagtatgat aggttatttt gatgtaaaga 3660 tgttctggat accattatat gttccccctg tttcagaggc tcagattgta atatgtaaat 3720 ggtatgtcat tcgctactat gatttaattt gaaatatggt cttttggtta tgaatacttt 3780 gcagcacagc tgagaggctg tctgttgtat tcattgtggt catagcacct aacaacattg 3840 tagcctcaat cgagtgagac agactagaag ttcctagtga tggcttatga tagcaaatgg 3900 cctcatgtca aatatttaga tgtaattttg tgtaagaaat acagactgga tgtaccacca 3960 actactacct gtaatgacag gcctgtccaa cacatctccc ttttccatga ctgtggtagc 4020 cagcatcgga aagaacgctg atttaaagag gtcgcttggg aattttattg acacagtacc 4080 atttaatggg gaggacaaaa tggggcaggg gagggagaag tttctgtcgt taaaaacaga 4140 tttggaaaga ctggactcta aagtctgttg attaaagatg agctttgtct acttcaaaag 4200 tttgtttgct taccccttca gcctccaatt ttttaagtga aaatatagct aataacatgt 4260 gaaaagaata gaagctaagg tttagataaa tattgagcag atctatagga agattgaacc 4320 tgaatattgc cattatgctt gacatggttt ccaaaaaatg gtactccaca tatttcagtg 4380 agggtaagta ttttcctgtt gtcaagaata gcattgtaaa agcattttgt aataataaag 4440 aatagcttta atgatatgct tgtaactaaa ataattttgt aatgtatcaa atacatttaa 4500 aacattaaaa tataatctct ataataattt aaaatctaat atggttttaa tagaacagcg 4560 atatcaagct tatcgataat caacctctgg attacaaaat ttgtgaaaga ttgactggta 4620 ttcttaacta tgttgctcct tttacgctat gtggatacgc tgctttaatg cctttgtatc 4680 atgctattgc ttcccgtatg gctttcattt tctcctcctt gtataaatcc tggttgctgt 4740 ctctttatga ggagttgtgg cccgttgtca ggcaacgtgg cgtggtgtgc actgtgtttg 4800 ctgacgcaac ccccactggt tggggcattg ccaccacctg tcagctcctt tccgggactt 4860 tcgctttccc cctccctatt gccacggcgg aactcatcgc cgcctgcctt gcccgctgct 4920 ggacaggggc tcggctgttg ggcactgaca attccgtggt gttgtcgggg aaatcatcgt 4980 cctttccttg gctgctcgcc tatgttgcca cctggattct gcgcgggacg tccttctgct 5040 acgtcccttc ggccctcaat ccagcggacc ttccttcccg cggcctgctg ccggctctgc 5100 ggcctcttcc gcgtcttcgc cttcgccctc agacgagtcg gatctccctt tgggccgcct 5160 ccccgcgaat tcatcgatac cgagcgctgc tcgagagatc tgtgatagcg gccatcaagc 5220 tggctgtgcc ttctagttgc cagccatctg ttgtttgccc ctcccccgg ccttccttga 5280 ccctggaagg tgccactccc actgtccttt cctaataaaa tgaggaaatt gcatcgcatt 5340 gtctgagtag gtgtcattct attctggggg gtggggtggg gcaggacagc aagggggagg 5400 attgggaaga caatagcagg catgctgggg acacgtgcgg accgagcggc cgcaggaacc 5460 cctagtgatg gagttggcca ctccctctct gcgcgctcgc tcgctcactg aggccgggcg 5520 accaaaggtc gcccgacgcc cgggctttgc ccgggcggcc tcagtgagcg agcgagcgcg 5580 cagctgcctg caggggcgcc tgatgcggta ttttctcctt acgcatctgt gcggtatttc 5640 acaccgcata cgtcaaagca accatagtac gcgccctgta gcggcgcatt aagcgcggcg 5700 ggtgtggtgg ttacgcgcag cgtgaccgct acacttgcca gcgccctagc gcccgctcct 5760 ttcgctttct tcccttcctt tctcgccacg ttcgccggct ttccccgtca agctctaaat 5820 cgggggctcc ctttagggtt ccgatttagt gctttacggc acctcgaccc caaaaaactt 5880 gatttgggtg atggttcacg tagtgggcca tcgccctgat agacggtttt tcgccctttg 5940 acgttggagt ccacgttctt taatagtgga ctcttgttcc aaactggaac aacactcaac 6000 cctatctcgg gctattcttt tgatttataa gggattttgc cgatttcggc ctattggtta 6060 aaaaatgagc tgatttaaca aaaatttaac gcgaatttta acaaaatatt aacgtttaca 6120 attttatggt gcactctcag tacaatctgc tctgatgccg catagttaag ccagccccga 6180 cacccgccaa cacccgctga cgcgccctga cgggcttgtc tgctcccggc atccgcttac 6240 agacaagctg tgaccgtctc cgggagctgc atgtgtcaga ggttttcacc gtcatcaccg 6300 aaacgcgcga gacgaaaggg cctcgtgata cgcctatttt tataggttaa tgtcatgata 6360 ataatggttt cttagacgtc aggtggcact tttcggggaa atgtgcgcgg aacccctatt 6420 tgtttatttt tctaaataca ttcaaatatg tatccgctca tgagacaata accctgataa 6480 atgcttcaat aatattgaaa aaggaagagt atgagtattc aacatttccg tgtcgccctt 6540 attccctttt ttgcggcatt ttgccttcct gtttttgctc acccagaaac gctggtgaaa 6600 gtaaaagatg ctgaagatca gttgggtgca cgagtgggtt acatcgaact ggatctcaac 6660 agcggtaaga tccttgagag ttttcgcccc gaagaacgtt ttccaatgat gagcactttt 6720 aaagttctgc tatgtggcgc ggtattatcc cgtattgacg ccgggcaaga gcaactcggt 6780 cgccgcatac actattctca gaatgacttg gttgagtact caccagtcac agaaaagcat 6840 cttacggatg gcatgacagt aagagaatta tgcagtgctg ccataaccat gagtgataac 6900 actgcggcca acttacttct gacaacgatc ggaggaccga aggagctaac cgcttttttg 6960 cacaacatgg gggatcatgt aactcgcctt gatcgttggg aaccggagct gaatgaagcc 7020 ataccaaacg acgagcgtga cacca 7045 <210> 84 <211> 700 <212> DNA <213> Cynomolgus macaque <400> 84 atggcaccag cttttgaaaa aagaaaacct ttttgctggt agtctggcaa ggagacagaa 60 aaaaaccact cacatctgcc tccccaggct gggggctggg ccggatttta taaggatagg 120 gtaatgaggg gtggtctgtt tggatcttgc aatgaggtgc tgctgggagg tgtgatctga 180 ttggatcctg ccatggagtg atgccaaagc tccatctgat tggatcctgg atcctgccgt 240 gtgtgctctg cttcttaatg caacccctgc tcctcagtct gagcccttag attctgccca 300 cggttgcacg cttggttcac tttggcatgc tcaggttaca tgaccttcag cttggggtcc 360 atggcaactg aaaagcaact cacaacttcc tttcataaaa attgaacctg actggtctgg 420 tgcagtcaca ccagctctat cccattgatg acaggaccgc atcatgggga ttagagcaga 480 gaggtcatag taactagcat tttcaagagg gcaccctgat gtctggatga acttcagggc 540 aacaaaatag cgggcaggtg agcagttgaa gacacccaga cactgggcct gaccaaggtg 600 gggtggtggg gatggcacag gaggacacag gatgggaatt aatgagggca ggggctttgt 660 cttgctcact gataagtcca tggcacatag agggtgatcg 700 <210> 85 <211> 700 <212> DNA <213> Cynomolgus macaque <400> 85 cgatcaccct ctatgtgcca tggacttatc agtgagcaag acaaagcccc tgccctcatt 60 aattcccatc ctgtgtcctc ctgtgccatc cccaccaccc caccttggtc aggcccagtg 120 tctgggtgtc ttcaactgct cacctgcccg ctattttgtt gccctgaagt tcatccagac 180 atcagggtgc cctcttgaaa atgctagtta ctatgacctc tctgctctaa tccccatgat 240 gcggtcctgt catcaatggg atagagctgg tgtgactgca ccagaccagt caggttcaat 300 ttttatgaaa ggaagttggg agttgctttt cagttgccat ggaccccaag ctgaaggtca 360 tgtaacctga gcatgccaaa gtgaaccaag cgtgcaaccg tgggcagaat ctaagggctc 420 agactgagga gcaggggttg cattaagaag cagagcacac acggcaggat ccaggatcca 480 atcagatgga gctttggcat cactccatgg caggatccaa tcagatcaca cctcccagca 540 gcacctcatt gcaagatcca aacagaccac ccctcattac cctatcctta taaaatccgg 600 cccagccccc agcctgggga ggcagatggg agtggttttt ttctgtctcc ttgccagact 660 accagcaaaa aggttttctt ttttcaaaag ctggtgccat 700 <210> 86 <211> 700 <212> DNA <213> Cynomolgus macaque <400> 86 ccgttaggaa aagaaaaaca gaaggaattg tgttctctgg agggcagggc tctgagtact 60 gagtctcatg ttttcaaagt cggaaagtgt ccacagttaa tatttggatg ggcccacagt 120 gcccgtcttg ctcgccggag cccaggcctg tcccatcaca gacaaagggc tcttgctgtg 180 240 gtttgaagca gagttttgca aagggagtgg ctctggaaga aaagcagagc gtggagtgtc 300 agaggccggc gtgttgtgaa atgcataagc cctggagacc ctctgtaact ggccttcaca 360 cacgcccgcc gccaaggaca acactgaacc acggaagcgg ggtgtttgcc agctcacgag 420 acggggagac atgaagcttc taccagcaga ggagctggag gggaaacaga aagaaagaac 480 tgagtctagc agcctccttg gacatttctt ccaacgcctc cagcccagca caacaaacaa 540 cctcagggca tccggcccgt gtcgcgccct ggcacaccca actctgccct gctccaagag 600 cccacagagg gcctcggggt cacactcaag gagcatgctt ggaatccaaa gtgcatgctg 660 tggtggggag atggacaagg acagaaatag cacccagcaa 700 <210> 87 <211> 700 <212> DNA <213> Cynomolgus macaque <400> 87 ttgctgggtg ctatttctgt ccttgtccat ctccccacca cagcatgcac tttggattcc 60 aagcatgctc cttgagtgg accccgaggc cctctgtggg ctcttggagc agggcagagt 120 tgggtgtgcc agggcgcgac acgggccgga tgccctgagg ttgtttgttg tgctgggctg 180 gaggcgttgg aagaaatgtc caaggaggct gctagactca gttctttctt tctgtttccc 240 ctccagctcc tctgctggta gaagcttcat gtctccccgt ctcgtgagct ggcaaacacc 300 ccgcttccgt ggttcagtgt tgtccttggc ggcgggcgtg tgtgaaggcc agttacagag 360 ggtctccagg gcttatgcat ttcacaacac gccggcctct gacactccac gctctgcttt 420 tcttccagag ccactccctt tgcaaaactc tgcttcaaac aaaaagagca caaagaggct 480 gaccctgcct tccccagcca agctcccctc tccacaggtg cacagcaaga gccctttgtc 540 tgtgatggga caggcctggg ctccggcgag caagacgggc actgtgggcc catccaaata 600 ttaactgtgg acactttccg actttgaaaa catgagactc agtactcaga gccctgccct 660 ccagagaaca caattccttc tgtttttctt ttcctaacgg 700 <210> 88 <211> 510 <212> DNA <213> Cynomolgus macaque <400> 88 aaaaaagaat cacaattgcc accaaggctc tatgttttcg caaaagtcca gcatttaaaa 60 gaaacttcct gcatggccta catctgctga ttggtaattt gtcgttcagg ttaaaaacaa 120 aacaagcggg cattgttgtg atatcatcct tgataacatc ccaagaaaac tctagagctg 180 gcaagagagg aaagcagata atggtcaaag ctgtcatctg agttttaaaa acactgtgat 240 ttttctttta aaggaacatc ttcagtttcc aaggccatac acacggctcc taactgcagc 300 ttaaaatttt ccactgggct cccttctgag aacaaacgct attcagtggc gagtgccgga 360 caccactgcg ctttcaaagg tggctgccag aggacactca ggacttcaca gcagccggta 420 agccagactg gggtcagtca ctcccccatc agaattattt tgtttctcct ttgcttagga 480 aaggaaggat tcctcagatt ggcatcccag 510 <210> 89 <211> 510 <212> DNA <213> Cynomolgus macaque <400> 89 ctgggatgcc aatctgagga atccttcctt tcctaagcaa aggagaaaca aaataattct 60 gatggggggag tgactgaccc cagtctggct taccggctgc tgtgaagtcc tgagtgtcct 120 ctggcagcca cctttgaaag cgcagtggtg tccggcactc gccactgaat agcgtttgtt 180 ctcagaaggg agcccagtgg aaaattttaa gctgcagtta ggagccgtgt gtatggcctt 240 ggaaactgaa gatgttcctt taaaagaaaa atcacagtgt ttttaaaact cagatgacag 300 ctttgaccat tatctgcttt cctctcttgc cagctctaga gttttcttgg gatgttatca 360 aggatgatat cacaacaatg cccgcttgtt ttgtttttaa cctgaacgac aaattaccaa 420 tcagcagatg taggccatgc aggaagtttc ttttaaatgc tggacttttg cgaaaacata 480 gagccttggt ggcaattgtg attctttttt 510 <210> 90 <211> 643 <212> DNA <213> Cynomolgus macaque <400> 90 ataatgagca acataaggtt aaaataacat tgcaacccca tggaagcaag agaaatggaa 60 attattaata aatggaccac atgtaaggga atgctgtggt tctattgtag agattacaga 120 gagcaattta ggagagccag gcgctggggg caagagggaa atgaaacgaa aaccgaaggg 180 atttgttcag gaagaaaaat gaaaacagat aaaaggtgtt catttcaaag cttccctctt 240 tcccagcatt tttctgaagt agagtttgaa aggaaagcaa aataactgca aaccaataca 300 gtggcacgag ttcactgacg cagagctagg aacgacgtcc agagatctcc agccccgcct 360 cccgttctgg gtcacctggc tccttgacag ccctgaaaac tgcctgtgca aatctccagg 420 catgttatac ccatgagcgg ggacgtgtgg caccgacaaa gggacctgta cacctttgaa 480 gtatcctggg agaccagact cacattccac acacgctcac gagtcactga gcagccccat 540 tggaaatacg tggcaccgtc tcattccata tttgaccaaa accagtgttt acccagctca 600 gccgatagtt tcattttttt aaccaaacct aatgcagaat ggc 643 <210> 91 <211> 643 <212> DNA <213> Cynomolgus macaque <400> 91 gccattctgc attaggtttg gttaaaaaaa tgaaactatc ggctgagctg ggtaaacact 60 ggttttggtc aaatatggaa tgagacggtg ccacgtattt ccaatggggc tgctcagtga 120 ctcgtgagcg tgtgtggaat gtgagtctgg tctcccagga tacttcaaag gtgtacaggt 180 ccctttgtcg gtgccacacg tccccgctca tgggtataac atgcctggag atttgcacag 240 gcagttttca gggctgtcaa ggagccaggt gacccagaac gggaggcggg gctggagatc 300 tctggacgtc gttcctagct ctgcgtcagt gaactcgtgc cactgtattg gtttgcagtt 360 attttgcttt cctttcaaac tctacttcag aaaaatgctg ggaaagaggg aagctttgaa 420 atgaacacct tttatctgtt ttcatttttc ttcctgaaca aatcccttcg gttttcgttt 480 catttccctc ttgcccccag cgcctggctc tcctaaattg ctctctgtaa tctctacaat 540 agaaccacag cattccctta catgtggtcc atttattaat aatttccatt tctcttgctt 600 ccatggggtt gcaatgttat tttaacctta tgttgctcat tat 643 <210> 92 <211> 542 <212> DNA <213> Cynomolgus macaque <400> 92 cacgtcttgt aattttttta ctgaatgtta gacattgcat ataaaagact atccaggagt 60 gttttgtttt tgttttttct agtgagtgca agtcccttgc tctctgccag ttggctggaa 120 tgagaatctg atcagatttc atcaagagtc aggttgagct gagactgagc ggtagtgttc 180 actaaattga gtgcaccact gatatctaat ggaaacaagg acattttaact ttgctcctca 240 gcctaacctg aatttcctat gccaccactg tataatggct ggtttctttg gttctcctaa 300 tgtgtgagct ggaagcaggt tgagacatag atttcatatc attttggctt cccttgcatc 360 taacatggct ccacaattca agcactatga aattgtttaa ctgttttcca gtcttgcctc 420 cacagccact tttgcagtaa aatcacggat ggggggtgacg ttgagccaaa ctatttttgc 480 atttggtgga cttctaaatt ccaatccagc tccaaatctt ttggcagatt tttcttaaag 540 gt 542 <210> 93 <211> 542 <212> DNA <213> Cynomolgus macaque <400> 93 acctttaaga aaaatctgcc aaaagatttg gagctggatt ggaatttaga agtccaccaa 60 atgcaaaaat agtttggctc aacgtcaccc ccatccgtga ttttactgca aaagtggctg 120 tggaggcaag actggaaaac agttaaacaa tttcatagtg cttgaattgt ggagccatgt 180 tagatgcaag ggaagccaaa atgatatgaa atctatgtct caacctgctt ccagctcaca 240 cattaggaga accaaagaaa ccagccatta tacagtggtg gcataggaaa ttcaggttag 300 gctgaggagc aaagtaaaat gtccttgttt ccattagata tcagtggtgc actcaattta 360 gtgaacacta ccgctcagtc tcagctcaac ctgactcttg atgaaatctg atcagattct 420 cattccagcc aactggcaga gagcaaggga cttgcactca ctagaaaaaa caaaaacaaa 480 acactcctgg atagtctttt atatgcaatg tctaacattc agtaaaaaaa ttacaagacg 540 tg 542 <210> 94 <211> 523 <212> DNA <213> Cynomolgus macaque <400> 94 cggcagagac ctacagacca aagtacattt cacactggat ccaggacaca catcagtctg 60 aaagcacaca catgaaccaa acgtttccta aagcattact tacccttgct aatagcaaca 120 cattctcata ttcttttata cttcatttaa tttcatttaa aaaagaaaaa gataggaaag 180 aaatctattt ctccgcccat taataaggtc agacgcagca acgctagact agaagaaaag 240 tttacctact gatttttctc ccacctcctg agtgcgcaca gctttccgac aagtgtcagt 300 gccatctact gtgcgctctg ggtactgcaa tagccttttt tttttttttt ttttttttta 360 gaatgagact aaatgagaga acacaaagaa cttctttccc cacagtggag atggctctga 420 aagcgtttaa ggaatggctt agatgagtgg ctaacacat atcccagttc tgaattctaa 480 gaccacagac tccatgtccg atccccaaag agaggctttg caa 523 <210> 95 <211> 523 <212> DNA <213> Cynomolgus macaque <400> 95 ttgcaaagcc tctctttggg gatcggacat ggagtctgtg gtcttagaat tcagaactgg 60 gataatgtgt tagccactca tctaagccat tccttaaacg ctttcagagc catctccact 120 gtgggggaaag aagttctttg tgttctctca tttagtctca ttctaaaaaa aaaaaaaaaa 180 aaaaaaaagg ctattgcagt acccagagcg cacagtagat ggcactgaca cttgtcggaa 240 agctgtgcgc actcaggagg tgggagaaaa atcagtaggt aaacttttct tctagtctag 300 cgttgctgcg tctgacctta ttaatgggcg gagaaataga tttctttcct atctttttct 360 tttttaaatg aaattaaatg aagtataaaa gaatatgaga atgtgttgct attagcaagg 420 gtaagtaatg ctttaggaaa cgtttggttc atgtgtgtgc tttcagactg atgtgtgtcc 480 tggatccagt gtgaaatgta ctttggtctg taggtctctg ccg 523 <210> 96 <211> 579 <212> DNA <213> Cynomolgus macaque <400> 96 ggtgtgtata tcaggtggtt actttacaaa acaggatgtg gcaagctgga cctgatagac 60 acatcaaagc ctctgaacag agttcaggggc atgaaatggt ttcttttggg ggtcttcagg 120 aacaatttca tgaaagctaa atcatgaaag atagcagact tttgccagga aaaaaaaaca 180 aaacaaaacg agactagtga ttagtttggc gttttcggtt tctttgagaa gcgaaataac 240 ttatcaagga ctctttgtgc cgcttgatgt tctaatcggt tgatgggtct ctcagaagcc 300 ctttctgcaa actagaacct gcagggatgt gcaaagcctc tctctgctgc catctgctgt 360 cttacaagag gtcactgcga gaggctgaat cccccaatgc cttggggatt cccactgcag 420 ggcaggggcg ccagcctgtg ttacaaccac ctgaacggcc acgtggacct tccacaaaag 480 tgtcactgtt tccattgctc tggtgtttgt attcccaatg tgtagtcttt gttagggcac 540 tcacaaaaag ttaaaaacaa aaattcacac aagcataca 579 <210> 97 <211> 579 <212> DNA <213> Cynomolgus macaque <400> 97 tgtatgcttg tgtgaatttt tgtttttaac tttttgtgag tgccctaaca aagactacac 60 attgggaata caaacaccag agcaatggaa acagtgacac ttttgtggaa ggtccacgtg 120 gccgttcagg tggttgtaac acaggctggc gcccctgccc tgcagtggga atccccaagg 180 cattggggga ttcagcctct cgcagtgacc tcttgtaaga cagcagatgg cagcagagag 240 aggctttgca catccctgca ggttctagtt tgcagaaagg gcttctgaga gacccatcaa 300 ccgattagaa catcaagcgg cacaaagagt ccttgataag ttatttcgct tctcaaagaa 360 accgaaaacg ccaaactaat cactagtctc gttttgtttt gttttttttt cctggcaaaa 420 gtctgctatc tttcatgatt tagctttcat gaaattgttc ctgaagaccc ccaaaagaaa 480 ccatttcatg ccctgaactc tgttcagagg ctttgatgtg tctatcaggt ccagcttgcc 540 acatcctgtt ttgtaaagta accacctgat atacacacc 579 <210> 98 <211> 700 <212> DNA <213> Cynomolgus macaque <400> 98 ggtcaggatt tgaaagacct tagctttgtg tgaccttcag ttttatcatt cagtttgaat 60 atgtgcccca gaaaaccttt atgtaatttc ctaatatttc agtaacatat ttcacaacat 120 acaagcagca cattctcttt ttttagaatg gtgtctcgct gatgactttg acgacagctc 180 acgtgagagg gaagtatttc agcaatcaga ccgaaggaga atccaaaaac cccactattg 240 cggggtcaag agtgcacgtg tttgaattct gaaagatgta agccaaggca aacagaagga 300 aatgatcttc cactaatccc tgcatttact tcctcctctc tggaggggac ggccacacac 360 acagagccct gtgctctgac ttctcctgaa ggggacacag ctgggctcac tcagtgtcac 420 ctcgcccctg gggtgtgccc gggtttcaga tctcaggctg gagtgattca cggtgtagcag 480 ggaggccgtc attaatgaaa atgcaggggc gtcgcgggag tgttgatgat tcagcaggcc 540 tttctacttc tctatgagtc agtacccgtc gcagccaagc ctggggcaga acaggttttc 600 ttaaaagagc atgggggcct cgtcttcaac aaccaattag gaggcagaaa agtcctcagt 660 gaggaaggaa taatgacatg ttggagctaa gatgatggtg 700 <210> 99 <211> 700 <212> DNA <213> Cynomolgus macaque <400> 99 caccatcatc ttagctccaa catgtcatta ttccttcctc actgaggact tttctgcctc 60 ctaattggtt gttgaagacg aggcccccat gctcttttaa gaaaacctgt tctgccccag 120 gcttggctgc gacgggtact gactcataga gaagtagaaa ggcctgctga atcatcaaca 180 ctccccgcgac gcccctgcat tttcattaat gacggcctcc ctgctacacg tgaatcactc 240 cagcctgaga tctgaaaccc gggcacaccc caggggcgag gtgacactga gtgagcccag 300 ctgtgtcccc ttcaggagaa gtcagagcac agggctctgt gtgtgtggcc gtcccctcca 360 gagaggagga agtaaatgca gggattagtg gaagatcatt tccttctgtt tgccttggct 420 tacatctttc agaattcaaa cacgtgcact cttgaccccg caatagtggg gtttttggat 480 tctccttcgg tctgattgct gaaatacttc cctctcacgt gagctgtcgt caaagtcatc 540 agcgagacac cattctaaaa aaagagaatg tgctgcttgt atgttgtgaa atatgttact 600 gaaatattag gaaattacat aaaggttttc tggggcacat attcaaactg aatgataaaa 660 ctgaaggtca cacaaagcta aggtctttca aatcctgacc 700 <210> 100 <211> 532 <212> DNA <213> Cynomolgus macaque <400> 100 gttttttcat gcatcttaaa ctttggtgct taaagaaaag caccattaaa tcctgctctc 60 acacgaacac acacaagatt accacgtttg ctctgggctg ccgcgtatag gaaggacatag 120 tacattcaat aaatatttgt tgaacttcca ttctgtacac aaagcacaaa gaaagattcg 180 ttcacagtcc gcgtgggtac aggaaagcag ttccagccct gcctgccagg gggcacccca 240 ggcaagcaca tctcagtggc tgcaagaaag tcagcgagtt gaggctgagt ctctctctat 300 acccaagtgt taggtgttct aggctcaaag agagacaatg acaatgcggg caattctctc 360 ttcactgtgt ccctttcttt gctagaaatg ttattagaat gtggaaatgt gacccgtcga 420 ttgagaattc agcactaatc agtttgacat atgagtatat ctacatagac acatatttct 480 ccctgaaatt gtcctaaaca ctgtcttcct tgaaaccaaa tgagaaggaa ac 532 <210> 101 <211> 532 <212> DNA <213> Cynomolgus macaque <400> 101 gtttccttct catttggttt caaggaagac agtgtttagg acaatttcag ggagaaatat 60 gtgtctatgt agatatactc atatgtcaaa ctgattagtg ctgaattctc aatcgacggg 120 tcacatttcc acattctaat aacatttcta gcaaagaaag ggacacagtg aagagagaat 180 tgcccgcatt gtcattgtct ctctttgagc ctagaacacc taacacttgg gtatagagag 240 agactcagcc tcaactcgct gactttcttg cagccactga gatgtgcttg cctggggtgc 300 cccctggcag gcagggctgg aactgctttc ctgtacccac gcggactggg aacgaatctt 360 tctttgtgct ttgtgtacag aatggaagtt caacaaatat ttattgaatg tatatgtcct 420 tcctatacgc ggcagcccag agcaaacgtg gtaatcttgt gtgtgttcgt gtgagagcag 480 gatttaatgg tgcttttctt taagcaccaa agtttaagat gcatgaaaaa ac 532 <210> 102 <211> 120 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 102 gacctcgaag gggacttggg gggttcgggg ctttcggggg cggtcggggg ttcgcggacc 60 cgggaagctc tgaggaccca gaggccgggc gcgctccgcc cgcggcgccg ccccctccgt 120 <210> 103 <211> 228 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 103 aactttccca gtctccgagg gaagaggcgg ggtgtggggt gcggttaaaa ggcgccacgg 60 cgggagacag gtgttgcggc cccgcagcgc ccgcgcgctc ctctccccga ctcggagccc 120 ctcggcggcg cccggcccag gacccgccta ggagcgcagg agccccagcg cagagacccc 180 aacgccgaga cccccgcccc ggccccgccg cgcttcctcc cgacgcag 228 <210> 104 <211> 22 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 104 agcaaaccgc ccagagtaga ag 22 <210> 105 <211> 370 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 105 gacctcgaag gggacttggg gggttcgggg ctttcggggg cggtcggggg ttcgcggacc 60 cgggaagctc tgaggaccca gaggccgggc gcgctccgcc cgcggcgccg ccccctccgt 120 aactttccca gtctccgagg gaagaggcgg ggtgtggggt gcggttaaaa ggcgccacgg 180 cgggagacag gtgttgcggc cccgcagcgc ccgcgcgctc ctctccccga ctcggagccc 240 ctcggcggcg cccggcccag gacccgccta ggagcgcagg agccccagcg cagagacccc 300 aacgccgaga cccccgcccc ggccccgccg cgcttcctcc cgacgcagag caaaccgccc 360 agagtagaag 370 <210> 106 <211> 130 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 106 ctgcgcgctc gctcgctcac tgaggccgcc cgggcaaagc ccgggcgtcg ggcgaccttt 60 ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact 120 aggggttcct 130 <210> 107 <211> 130 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 107 aggaacccct agtgatggag ttggccactc cctctctgcg cgctcgctcg ctcactgagg 60 ccgggcgacc aaaggtcgcc cgacgcccgg gctttgcccg ggcggcctca gtgagcgagc 120 gagcgcgcag 130 <210> 108 <211> 602 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 108 gataatcaac ctctggatta caaaatttgt gaaagattga ctggtattct taactatgtt 60 gctcctttta cgctatgtgg atacgctgct ttaatgcctt tgtatcatgc tattgcttcc 120 cgtatggctt tcattttctc ctccttgtat aaatcctggt tgctgtctct ttatgaggag 180 ttgtggcccg ttgtcaggca acgtggcgtg gtgtgcactg tgtttgctga cgcaaccccc 240 actggttggg gcattgccac cacctgtcag ctcctttccg ggactttcgc tttccccctc 300 cctattgcca cggcggaact catcgccgcc tgccttgccc gctgctggac aggggctcgg 360 ctgttgggca ctgacaattc cgtggtgttg tcggggaaat catcgtcctt tccttggctg 420 ctcgcctgtg ttgccacctg gattctgcgc gggacgtcct tctgctacgt cccttcggcc 480 ctcaatccag cggaccttcc ttcccgcggc ctgctgccgg ctctgcggcc tcttccgcgt 540 cttcgccttc gccctcagac gagtcggatc tccctttggg ccgcctcccc gcatcggact 600 ag 602 <210> 109 <211> 237 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 109 gtcgactaga gctcgctgat cagcctcgac tgtgccttct agttgccagc catctgttgt 60 ttgcccctcc cccgtgcctt ccttgaccct ggaaggtgcc actcccactg tcctttccta 120 ataaaatgag gaaattgcat cgcattgtct gagtaggtgt cattctattc tggggggtgg 180 ggtggggcag gacagcaagg gggaggattg ggaagacaat agcaggcatg ctgggga 237 <210> 110 <211> 3493 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 110 gacctcgaag gggacttggg gggttcgggg ctttcggggg cggtcggggg ttcgcggacc 60 cgggaagctc tgaggaccca gaggccgggc gcgctccgcc cgcggcgccg ccccctccgt 120 aactttccca gtctccgagg gaagaggcgg ggtgtggggt gcggttaaaa ggcgccacgg 180 cgggagacag gtgttgcggc cccgcagcgc ccgcgcgctc ctctccccga ctcggagccc 240 ctcggcggcg cccggcccag gacccgccta ggagcgcagg agccccagcg cagagacccc 300 aacgccgaga cccccgcccc ggccccgccg cgcttcctcc cgacgcagag caaaccgccc 360 agagtagaag cggatccgcc accatggatt ggggcacgct gcagacgatc ctggggggtg 420 tgaacaaaca ctccaccagc attggaaaga tctggctcac cgtcctcttc atttttcgca 480 ttatgatcct cgttgtggct gcaaaggagg tgtggggaga tgagcaggcc gactttgtct 540 gcaacaccct gcagccaggc tgcaagaacg tgtgctacga tcactacttc cccatctccc 600 acatccggct atgggccctg cagctgatct tcgtgtccac gccagcgctc ctagtggcca 660 tgcacgtggc ctaccggaga catgagaaga agaggaagtt catcaagggg gagataaaga 720 gtgaatttaa ggacatcgag gagatcaaaa cccagaaggt ccgcatcgaa ggctccctgt 780 ggtggaccta cacaagcagc atcttcttcc gggtcatctt cgaagccgcc ttcatgtacg 840 tcttctatgt catgtacgac ggcttctcca tgcagcggct ggtgaagtgc aacgcctggc 900 cttgtcccaa cactgtggac tgctttgtgt cccggcccac ggagaagact gtcttcacag 960 tgttcatgat tgcagtgtct ggaatttgca tcctgctgaa tgtcactgaa ttgtgttatt 1020 tgctaattag atattgttct gggaagtcaa aaaagccagt ttacccatac gatgttccag 1080 attacgctta aggcgcgcca cccctgcagg gaattccgca ttgcccagtt gttagattaa 1140 gaaatagaca gcatgagagg gatgaggcaa cccgtgctca gctgtcaagg ctcagtcgct 1200 agcatttccc aacacaaaga ttctgacctt aaatgcaacc atttgaaacc cctgtaggcc 1260 tcaggtgaaa ctccagatgc cacaatggag ctctgctccc ctaaagcctc aaaacaaagg 1320 cctaattcta tgcctgtctt aattttcttt cacttaagtt agttccactg agaccccagg 1380 ctgttagggg ttattggtgt aaggtacttt catattttaa acagaggata tcggcatttg 1440 tttctttctc tgaggacaag agaaaaaagc caggttccac agaggacaca gagaaggttt 1500 gggtgtcctc ctggggttct ttttgccaac tttccccacg ttaaaggtga acattggttc 1560 tttcatttgc tttggaagtt ttaatctcta acagtggaca aagttaccag tgccttaaac 1620 tctgttacac tttttggaag tgaaaacttt gtagtatgat aggttattt gatgtaaaga 1680 tgttctggat accattatat gttccccctg tttcagaggc tcagattgta atatgtaaat 1740 ggtatgtcat tcgctactat gatttaattt gaaatatggt cttttggtta tgaatacttt 1800 gcagcacagc tgagaggctg tctgttgtat tcattgtggt catagcacct aacaacattg 1860 tagcctcaat cgagtgagac agactagaag ttcctagtga tggcttatga tagcaaatgg 1920 cctcatgtca aatatttaga tgtaattttg tgtaagaaat acagactgga tgtaccacca 1980 actactacct gtaatgacag gcctgtccaa cacatctccc ttttccatga ctgtggtagc 2040 cagcatcgga aagaacgctg atttaaagag gtcgcttggg aattttattg acacagtacc 2100 atttaatggg gaggacaaaa tggggcaggg gagggagaag tttctgtcgt taaaaacaga 2160 tttggaaaga ctggactcta aagtctgttg attaaagatg agctttgtct acttcaaaag 2220 tttgtttgct taccccttca gcctccaatt ttttaagtga aaatatagct aataacatgt 2280 gaaaagaata gaagctaagg tttagataaa tattgagcag atctatagga agattgaacc 2340 tgaatattgc cattatgctt gacatggttt ccaaaaaatg gtactccaca tatttcagtg 2400 agggtaagta ttttcctgtt gtcaagaata gcattgtaaa agcattttgt aataataaag 2460 aatagcttta atgatatgct tgtaactaaa ataattttgt aatgtatcaa atacatttaa 2520 aacattaaaa tataatctct ataataattt aaaatctaat atggttttaa tagaacagcg 2580 atatcaagct tatcgatgat aatcaacctc tggattacaa aatttgtgaa agattgactg 2640 gtattcttaa ctatgttgct ccttttacgc tatgtggata cgctgcttta atgcctttgt 2700 atcatgctat tgcttcccgt atggctttca ttttctcctc cttgtataaa tcctggttgc 2760 tgtctcttta tgaggagttg tggcccgttg tcaggcaacg tggcgtggtg tgcactgtgt ttgctgacgc aacccccact ggttggggca ttgccaccac ctgtcagctc ctttccggga 2880 ctttcgcttt ccccctccct attgccacgg cggaactcat cgccgcctgc cttgcccgct 2940 gctggacagg ggctcggctg ttgggcactg acaattccgt ggtgttgtcg gggaaatcat 3000 cgtcctttcc ttggctgctc gcctgtgttg ccacctggat tctgcgcggg acgtccttct 3060 gctacgtccc ttcggccctc aatccagcgg accttccttc ccgcggcctg ctgccggctc 3120 tgcggcctct tccgcgtctt cgccttcgcc ctcagacgag tcggatctcc ctttgggccg 3180 cctccccgca tcggactagg aattcatcga taccgagcgc tgctcgagag atctgtgata 3240 gcggccatca agctgggtcg actagagctc gctgatcagc ctcgactgtg ccttctagtt 3300 gccagccatc tgttgtttgc ccctcccccg tgccttcctt gaccctggaa ggtgccactc 3360 ccactgtcct ttcctaataa aatgaggaaa ttgcatcgca ttgtctgagt aggtgtcatt 3420 ctattctggg gggtggggtg gggcaggaca gcaaggggga ggattgggaa gacaatagca 3480 ggcatgctgg gga 3493 <210> 111 <211> 3918 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 111 ctgcgcgctc gctcgctcac tgaggccgcc cgggcaaagc ccgggcgtcg ggcgaccttt 60 ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact 120 aggggttcct tgtagttaat gattaacccg ccatgctact tatctaccag ggtaatgggg 180 atcctctaga acgcgtttaa ttaagacctc gaaggggact tggggggttc ggggctttcg 240 ggggcggtcg ggggttcgcg gacccgggaa gctctgagga cccagaggcc gggcgcgctc 300 cgcccgcggc gccgccccct ccgtaacttt cccagtctcc gagggaagag gcggggtgtg 360 gggtgcggtt aaaaggcgcc acggcgggag acaggtgttg cggccccgca gcgcccgcgc 420 gctcctctcc ccgactcgga gcccctcggc ggcgcccggc ccaggacccg cctaggagcg 480 caggagcccc agcgcagaga ccccaacgcc gagacccccg ccccggcccc gccgcgcttc 540 ctcccgacgc agagcaaacc gcccagagta gaagcggatc cgccaccatg gattggggca 600 cgctgcagac gatcctgggg ggtgtgaaca aacactccac cagcattgga aagatctggc 660 tcaccgtcct cttcattttt cgcattatga tcctcgttgt ggctgcaaag gaggtgtggg 720 gagatgagca ggccgacttt gtctgcaaca ccctgcagcc aggctgcaag aacgtgtgct 780 acgatcacta cttccccatc tcccacatcc ggctatgggc cctgcagctg atcttcgtgt 840 ccacgccagc gctcctagtg gccatgcacg tggcctaccg gagacatgag aagaagagga 900 agttcatcaa gggggagata aagagtgaat ttaaggacat cgaggagatc aaaacccaga 960 aggtccgcat cgaaggctcc ctgtggtgga cctacacaag cagcatcttc ttccgggtca 1020 tcttcgaagc cgccttcatg tacgtcttct atgtcatgta cgacggcttc tccatgcagc 1080 ggctggtgaa gtgcaacgcc tggccttgtc ccaacactgt ggactgcttt gtgtcccggc 1140 ccacggagaa gactgtcttc acagtgttca tgattgcagt gtctggaatt tgcatcctgc 1200 tgaatgtcac tgaattgtgt tatttgctaa ttagatattg ttctgggaag tcaaaaaagc 1260 cagtttaccc atacgatgtt ccagattacg cttaaggcgc gccacccctg cagggaattc 1320 cgcattgccc agttgttaga ttaagaaata gacagcatga gagggatgag gcaacccgtg 1380 ctcagctgtc aaggctcagt cgctagcatt tcccaacaca aagattctga ccttaaatgc 1440 aaccatttga aacccctgta ggcctcaggt gaaactccag atgccacaat ggagctctgc 1500 tcccctaaag cctcaaaaca aaggcctaat tctatgcctg tcttaatttt ctttcactta 1560 agttagttcc actgagaccc caggctgtta ggggttattg gtgtaaggta ctttcatatt 1620 ttaaacagag gatatcggca tttgtttctt tctctgagga caagagaaaa aagccaggtt 1680 ccacagagga cacagagaag gtttgggtgt cctcctgggg ttctttttgc caactttccc 1740 cacgttaaag gtgaacattg gttctttcat ttgctttgga agttttaatc tctaacagtg 1800 gacaaagtta ccagtgcctt aaactctgtt acactttttg gaagtgaaaa ctttgtagta 1860 tgataggtta ttttgatgta aagatgttct ggataccatt atatgttccc cctgtttcag 1920 aggctcagat tgtaatatgt aaatggtatg tcattcgcta ctatgattta atttgaaata 1980 tggtcttttg gttatgaata ctttgcagca cagctgagag gctgtctgtt gtattcattg 2040 tggtcatagc acctaacaac attgtagcct caatcgagtg agacagacta gaagttccta 2100 gtgatggctt atgatagcaa atggcctcat gtcaaatatt tagatgtaat tttgtgtaag 2160 aaatacagac tggatgtacc accaactact acctgtaatg acaggcctgt ccaacacatc 2220 tcccttttcc atgactgtgg tagccagcat cggaaagaac gctgatttaa agaggtcgct 2280 tgggaatttt attgacacag taccatttaa tgggggaggac aaaatggggc aggggaggga 2340 gaagtttctg tcgttaaaaa cagatttgga aagactggac tctaaagtct gttgattaaa 2400 gatgagcttt gtctacttca aaagtttgtt tgcttacccc ttcagcctcc aattttttaa 2460 gtgaaaatat agctaataac atgtgaaaag aatagaagct aaggtttaga taaatattga 2520 gcagatctat aggaagattg aacctgaata ttgccattat gcttgacatg gtttccaaaa 2580 aatggtactc cacatatttc agtgagggta agtattttcc tgttgtcaag aatagcattg 2640 taaaagcatt ttgtaataat aaagaatagc tttaatgata tgcttgtaac taaaataatt 2700 ttgtaatgta tcaaatacat ttaaaacatt aaaatataat ctctataata atttaaaatc 2760 taatatggtt ttaatagaac agcgatatca agcttatcga tgataatcaa cctctggatt 2820 acaaaatttg tgaaagatg actggtattc ttaactatgt tgctcctttt acgctatgtg 2880 gatacgctgc tttaatgcct ttgtatcatg ctattgcttc ccgtatggct ttcattttct 2940 cctccttgta taaatcctgg ttgctgtctc tttatgagga gttgtggccc gttgtcaggc 3000 aacgtggcgt ggtgtgcact gtgtttgctg acgcaacccc cactggttgg ggcattgcca 3060 ccacctgtca gctcctttcc gggactttcg ctttccccct ccctattgcc acggcggaac 3120 tcatcgccgc ctgccttgcc cgctgctgga caggggctcg gctgttgggc actgacaatt 3180 ccgtggtgtt gtcgggggaaa tcatcgtcct ttccttggct gctcgcctgt gttgccacct 3240 ggattctgcg cgggacgtcc ttctgctacg tcccttcggc cctcaatcca gcggaccttc 3300 cttcccgcgg cctgctgccg gctctgcggc ctcttccgcg tcttcgcctt cgccctcaga 3360 cgagtcggat ctccctttgg gccgcctccc cgcatcggac taggaattca tcgataccga 3420 gcgctgctcg agagatctgt gatagcggcc atcaagctgg gtcgactaga gctcgctgat 3480 cagcctcgac tgtgccttct agttgccagc catctgttgt ttgcccctcc cccgtgcctt 3540 ccttgaccct ggaaggtgcc actcccactg tcctttccta ataaaatgag gaaattgcat 3600 cgcattgtct gagtaggtgt cattctattc tggggggtgg ggtggggcag gacagcaagg 3660 gggaggattg ggaagacaat agcaggcatg ctggggacac gtgcggaccg agcggccgcg 3720 gtaccaaacc taggtaatac ccattaccct ggtagataag tagcatggcg ggttaatcat 3780 taactacaag gaacccctag tgatggagtt ggccactccc tctctgcgcg ctcgctcgct 3840 cactgaggcc gggcgaccaa aggtcgcccg acgcccgggc tttgcccggg cggcctcagt 3900 gagcgagcga gcgcgcag 3918

Claims (76)

An isolated nucleic acid comprising an expression cassette comprising a gap junction beta 2 (GJB2) gene regulatory element (GRE), and a nucleotide sequence encoding a GJB2 protein. The isolated nucleic acid of claim 1 , wherein the GJB2 protein is a human GJB2 protein. 3. The isolated nucleic acid of claim 2, wherein the GJB2 protein comprises an amino acid sequence that is at least 80% identical to SEQ ID NO:1. 4. The isolated nucleic acid of any one of claims 1 to 3, wherein the nucleotide sequence encoding the GJB2 protein comprises a nucleotide sequence that is at least 80% identical to SEQ ID NO:2. 5. The isolated nucleic acid of any one of claims 1 to 4, wherein the expression cassette further comprises a promoter operably linked to the nucleotide sequence encoding the GJB2 protein. 6. The isolated nucleic acid of claim 5, wherein the promoter is the human GJB2 promoter. 7. The isolated nucleic acid of claim 6, wherein the promoter comprises 500 nucleotides of the human GJB2 promoter. 8. The isolated nucleic acid of claim 7, wherein the promoter comprises a nucleic acid sequence that is at least 80% identical to SEQ ID NO:5. 7. The isolated nucleic acid of claim 6, wherein the promoter comprises a nucleic acid sequence that is at least 80% identical to SEQ ID NO: 102, optionally 100% identical to SEQ ID NO: 102. 10. The isolated nucleic acid of any one of claims 1-9, wherein the gap junction beta 2 (GJB2) gene regulatory element (GRE) comprises a nucleotide sequence encoding a 5' UTR. 10. The isolated nucleic acid according to claim 9, wherein the 5' UTR is located between the promoter and the nucleotide sequence encoding the GJB2 protein. 12. The isolated nucleic acid of claim 10 or 11, wherein the 5' UTR comprises about 300 nucleotides of the human GJB2 gene 5' UTR. 13. The isolated nucleic acid of claim 12, wherein the promoter and 5' UTR comprise a nucleotide sequence that is at least 80% identical to SEQ ID NO:30. 14. The isolated nucleic acid according to any one of claims 1 to 13, wherein the GJB2 gene regulatory element further comprises an enhancer. 15. The isolated nucleic acid of claim 14, wherein the enhancer is located 5' to the promoter. 16. The isolated nucleic acid of claim 14 or 15, wherein the enhancer normally resides within approximately 200 kb upstream or downstream of the GJB2 gene. 17. The isolated nucleic acid of any one of claims 14-16, wherein the enhancer normally resides within approximately 95 kb of the GJB2 gene. 18. The isolated nucleic acid of any one of claims 14-17, wherein the GJB2 GRE comprises one or more enhancers. 19. The isolated nucleic acid of claim 18, wherein the one or more enhancers are the same enhancer or different enhancers. 20. The isolated nucleic acid of any one of claims 14-19, wherein the enhancer comprises a nucleotide sequence that is at least 80% identical to the nucleotide sequence set forth in any one of SEQ ID NOs: 6-29 or a fragment thereof. 21. The isolated nucleic acid of any one of claims 14-20, wherein the enhancer comprises a nucleotide sequence that is at least 80% identical to the GJB2 enhancer set forth in any one of SEQ ID NOs: 37-46. 22. The isolated nucleic acid of claim 21, wherein the enhancer comprises a nucleotide sequence that is at least 80% identical to SEQ ID NO:42. An isolated nucleic acid comprising an expression cassette comprising a gap junction beta 2 (GJB2) promoter and a nucleotide sequence encoding a GJB2 protein. 24. The isolated nucleic acid of claim 23, wherein the GJB2 promoter comprises a nucleic acid sequence that is at least 80% identical to SEQ ID NO: 102, optionally 100% identical to SEQ ID NO: 102. 25. The isolated nucleic acid of claim 23 or 24, wherein the expression cassette further comprises a 5' UTR. 26. The method of claim 25, wherein the 5 'UTR is
a first nucleic acid sequence that is at least 80% identical to SEQ ID NO: 103, optionally 100% identical to SEQ ID NO: 103; and/or
A second nucleic acid sequence that is at least 80% identical to SEQ ID NO: 104, optionally 100% identical to SEQ ID NO: 104
An isolated nucleic acid comprising a. 28. The isolated nucleic acid of any one of claims 23-27 comprising a nucleic acid sequence that is at least 80% identical to SEQ ID NO: 105, optionally 100% identical to SEQ ID NO: 105. 28. The isolated nucleic acid according to any one of claims 1 to 27, capable of expressing GJB2 in cells that normally express the GJB2 gene. 29. The isolated nucleic acid of claim 28, capable of expressing GJB2 in cochlear connective tissue cells and supporting cells of the organ of Corti. 30. The isolated nucleic acid of claim 29, wherein the supporting cells of the organ of Corti are pillar cells, diter cells, Hensen cells, Claudius cells, internal phalanx cells and border cells. 30. The method of claim 29, wherein the cochlear connective tissue cells are strial intermediate cells, fibrocytes in the lateral wall and supraangiole region, basal cells of the stria vascularis, fibrocytes in spiral ligaments, spiral plate edges Isolated nucleic acids that are fibrocytes in , mesenchymal cells lining the bony otic capsule facing the scala vestibuli, and supralimbal dark cells. 32. The isolated nucleic acid according to any one of claims 1 to 31, wherein the expression cassette is flanked by two adeno-associated virus inverted terminal repeats (ITRs). 33. The isolated nucleic acid of claim 32, wherein the AAV ITR is from a serotype selected from the group consisting of AAV1 ITR, AAV2 ITR, AAV3 ITR, AAV4 ITR, AAV5 ITR and AAV6 ITR. 34. The isolated nucleic acid of claim 32 or 33, wherein the AAV ITR is an AAV2 ITR. 34. The expression cassette of claim 32 or 33
a 5' ITR having a nucleotide sequence that is at least 80% identical to SEQ ID NO: 106, optionally 100% identical to SEQ ID NO: 106; and/or
A 3' ITR having a nucleotide sequence that is at least 80% identical to SEQ ID NO: 107, optionally 100% identical to SEQ ID NO: 107.
An isolated nucleic acid comprising a. 36. The isolation of any one of claims 1-35, wherein the expression cassette further comprises a Woodchuck Hepatitis Virus (WHP) post-transcriptional regulatory element (WPRE) 3' to the nucleotide sequence encoding the GJB2 protein. nucleic acid. 37. The isolated nucleic acid of claim 36, wherein the WPRE comprises a nucleotide sequence that is at least 80% identical to SEQ ID NO: 108, optionally 100% identical to SEQ ID NO: 108. 38. The isolated nucleic acid of any one of claims 1-37, wherein the expression cassette further comprises a nucleotide sequence encoding a 3' UTR located 3' of the WPRE. 39. The isolated nucleic acid of claim 38, wherein the 3' UTR is the GJB2 3' UTR. 40. The isolated nucleic acid of claim 39, wherein the GJB2 3' UTR comprises a nucleotide sequence that is at least 80% identical to SEQ ID NO:32. 41. The isolated nucleic acid of any one of claims 1-40, wherein the expression cassette further comprises a poly A signal. 42. The isolated nucleic acid of claim 41, wherein the poly A signal is a bovine growth hormone poly A signal. 42. The isolated nucleic acid of claim 41, wherein the poly A signal comprises a nucleotide sequence that is at least 80% identical to SEQ ID NO: 109, optionally 100% identical to SEQ ID NO: 109. An isolated nucleic acid comprising a nucleotide sequence that is at least 80% identical to SEQ ID NO: 110 or 111, optionally 100% identical to SEQ ID NO: 110 or 111. A vector comprising the isolated nucleic acid of any one of claims 1-44. 46. The vector according to claim 45, which is a plasmid or viral vector. 47. The vector of claim 46, wherein the viral vector is an AAV vector. Vector containing 5' to 3':
(a) 5'ITR;
(b) a GJB2 promoter, or an underlying GJB2 promoter sequence thereof;
(c) GJB2 5'UTR;
(d) a nucleotide sequence encoding the GJB2 protein;
(e) GJB2 3'UTR;
(f) bovine growth hormone poly A signal; and
(g) 3' ITRs. Vector containing 5' to 3':
(a) 5'ITR;
(b) a GJB2 enhancer;
(c) a GJB2 promoter, or an underlying GJB2 promoter sequence thereof;
(d) GJB2 5'UTR;
(e) a nucleotide sequence encoding the GJB2 protein;
(f) GJB2 3'UTR;
(g) bovine growth hormone poly A signal; and
(h) 3' ITRs. Recombinant adeno-associated virus (rAAV) comprising:
(i) capsid proteins; and
(ii) the isolated nucleic acid of any one of claims 1-44. Recombinant adeno-associated virus (rAAV) comprising:
(i) capsid proteins; and
(ii) (a) 5'ITR;
(b) a GJB2 promoter, or an underlying GJB2 promoter sequence thereof;
(c) GJB2 5'UTR;
(d) a nucleotide sequence encoding the GJB2 protein;
(e) GJB2 3'UTR;
(f) bovine growth hormone poly A signal; and
(g) 3'ITR
An isolated nucleic acid comprising Recombinant adeno-associated virus (rAAV) comprising:
(i) capsid proteins; and
(ii) (a) 5'ITR;
(b) a GJB2 enhancer;
(c) a GJB2 promoter, or an underlying GJB2 promoter sequence thereof;
(d) GJB2 5'UTR;
(e) a nucleotide sequence encoding the GJB2 protein;
(f) GJB2 3'UTR;
(g) bovine growth hormone poly A signal; and
(h) 3'ITR
An isolated nucleic acid comprising 53. The rAAV of any one of claims 50-52, which has tropism for a subset of cochlear cells that normally express the GJB2 gene. 54. The rAAV of any one of claims 50-53, which is tropic for cells of the inner ear. 55. The method of any one of claims 50-54, wherein the capsid protein is an AAV1 capsid protein, an AAV2 capsid protein, an AAV5 capsid protein, an AAV7 capsid protein, an AAV8 capsid protein, an AAV9 capsid protein, an AAV-S capsid protein, or variants thereof. rAAV. 56. The rAAV of any one of claims 50-55, wherein the AAV capsid is AAV9.PHP.B, AAV9.PHP.eB, or AAV-S. 57. The rAAV of claim 56, wherein the AAV capsid protein is AAV-S. A cell comprising the isolated nucleic acid of any one of claims 1 - 44 , the vector of any one of claims 45 - 49 , or the rAAV of any one of claims 50 - 57 . A pharmaceutical comprising the isolated nucleic acid of any one of claims 1 to 44, the vector of any one of claims 45 to 49, the rAAV of any one of claims 50 to 57, or the cell of claim 58. composition. 60. The pharmaceutical composition of claim 59, further comprising a pharmaceutically acceptable carrier. The isolated nucleic acid of any one of claims 1 to 44, the vector of any one of claims 45 to 49, the rAAV of any one of claims 50 to 57, the cell of claim 58, Or a method of specifically expressing GJB2 in cells that normally express the GJB2 gene in a subject comprising administering the pharmaceutical composition of claim 59 or 60 . An effective amount of the isolated nucleic acid of any one of claims 1 to 44, the vector of any one of claims 45 to 49, A method of treating DFNB1 in a subject comprising administering the rAAV of any one of claims 50-57, the cell of claim 58, or the pharmaceutical composition of claims 59 or 60. The isolated nucleic acid of any one of claims 1 to 44, the vector of any one of claims 45 to 49, or any of claims 50 to 57 in an effective amount to a subject in need of treatment for a GJB2-associated disease. A method of treating a GJB2-associated disease in a subject comprising administering the rAAV of any one of claims 58 , the cell of claim 58 , or the pharmaceutical composition of claim 59 or 60 . 64. The method of any one of claims 61-63, wherein the subject is a mammal. 65. The method of claim 64, wherein the mammal is a human. 65. The method of claim 64, wherein the mammal is a non-human mammal. 67. The method of claim 66, wherein the non-human mammal is a mouse, rat or non-human primate. 68. The method of any one of claims 61-67, wherein the hearing loss is associated with a mutation in the GJB2 gene. 69. The method of claim 68, wherein the mutation in the GJB2 gene is a point mutation, missense mutation, nonsense mutation, deletion, insertion, or combination thereof. 70. The method of claim 69, wherein the subject is a human; A method in which the mutation is a mutation listed in Table 2 or a combination thereof. 71. The method of claim 69 or 70, wherein the mutation is c 101.T>C or Del35G. 72. The method of any one of claims 61-71, wherein the administering step causes expression of the GJB2 protein in cochlear connective tissue cells and supporting cells of the organ of Corti. 73. The method of claim 72, wherein the supporting cells of the organ of Corti are pillar cells, diter cells, Hensen cells, Claudius cells, internal phalanx cells and border cells. 73. The method of claim 72, wherein the cochlear connective tissue cells are vascular intermediate cells, fibrocytes in the lateral wall and supravascular acinar regions, basal cells in the vascular progenitors, fibrocytes in the spiral ligament, fibrocytes in the spiral plate margins, in the vestibular system. mesenchymal cells lining the facing labyrinth bone capsule, and supermarginal dark cells. 75. The method of any one of claims 61-74, wherein the administration is via injection. 76. The method of claim 75, wherein the injection is through the round window membrane of the cochlea, into the scala media of the cochlea, into the vestibular system of the cochlea, into the semicircular canals of the inner ear, or into the saccule or utricle of the inner ear. how it would be.

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