Gene therapy for neurodegenerative diseases

Abstract

The present disclosure in some aspects relates to compositions and methods for treating neurodegenerative diseases (e.g., amyotrophic lateral sclerosis (ALS) and / or frontotemporal dementia (FTD), Alzheimer's disease, Gaucher's disease, Parkinson's disease, Lewy body dementia, or lysosomal storage disease). In some embodiments, the present disclosure provides expression constructs comprising a transgene encoding one or more inhibitory nucleic acids (e.g., targeting C9orf72, TMEM106B, ATNX2, RPS25, etc.), a wild-type C9orf72 protein, or a portion thereof, or any combination of the above substances. In some embodiments, the present disclosure provides methods for treating ALS / FTD by administering these expression constructs to subjects in need.

Description

[0001] Related Applications

[0002] This application claims the benefit under 35 U.S.C. 119(e) of U.S. Provisional Application Serial Nos. 62 / 742,723, filed on October 8, 2018, entitled “GENETHERAPIES FOR NEURODEGENERATIVE DISEASE,” and 62 / 575,795, filed on October 23, 2017, entitled “GENE THERAPIES FOR NEURODEGENERATIVE DISEASE,” the entire contents of each of which are incorporated herein by reference. Background Art

[0003] In humans, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases associated with expansions of the hexanucleotide repeat region in the C9orf72 gene. Typically, diseases associated with expansions of the C9orf72 repeat region are caused by reduced expression of the C9orf72 protein and gain of function due to the accumulation of toxic RNA foci. Currently, treatment options for ALS / FTD are limited. Summary of the invention

[0004] Aspects of the present disclosure relate to compositions and methods useful for treating neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and / or frontotemporal dementia (FTD), Alzheimer's disease, Gaucher's disease, Parkinson's disease, Lewy body dementia, or lysosomal storage diseases. In some embodiments, the methods and compositions described herein are used to treat subjects with ALS / FTD characterized by expansion of the dipeptide repeat region of the C9orf72 gene.

[0005] In some aspects, the present disclosure provides an isolated nucleic acid comprising an expression cassette encoding an inhibitory nucleic acid that inhibits the expression or activity of C9orf72 and / or spinocerebellar ataxia protein 2 (ATXN2) and / or ribosomal protein 25 (RPS25). In some embodiments, the inhibitory nucleic acid targeting ATXN comprises or consists of a sequence set forth in any one of SEQ ID NOs: 10-25. In some embodiments, the inhibitory nucleic acid targeting C9orf72 comprises or consists of a sequence set forth in any one of SEQ ID NOs: 37-50.

[0006] In some aspects, the disclosure provides an isolated nucleic acid comprising an expression cassette encoding a codon-optimized C9orf72 protein (or portion thereof). In some embodiments, the codon-optimized C9orf72 protein comprises the amino acid sequence set forth in SEQ ID NO: 4. In some embodiments, the codon-optimized C9orf72 protein is encoded by a nucleic acid having a sequence set forth in SEQ ID NO: 51.

[0007] In some aspects, the disclosure provides an isolated nucleic acid comprising an inhibitory nucleic acid that inhibits the expression or activity of C9orf72 and / or ATXN2 and / or RPS25, and an expression cassette of a wild-type C9orf72 protein (e.g., a C9orf72 protein lacking a pathogenic dipeptide repeat expansion). In some embodiments, the wild-type C9orf72 protein is encoded by SEQ ID NO: 3 or a portion thereof. In some embodiments, the wild-type C9orf72 protein comprises or consists of the sequence set forth in SEQ ID NO: 4 or a portion thereof.

[0008] In some aspects, the present disclosure provides an isolated nucleic acid comprising an expression cassette encoding a first inhibitory nucleic acid that inhibits the expression or activity of C9orf72, and a second inhibitory nucleic acid that inhibits the expression or activity of spinocerebellar ataxia protein 2 (ATXN2). In some aspects, the present disclosure provides an isolated nucleic acid comprising an expression cassette encoding a first inhibitory nucleic acid that inhibits the expression or activity of C9orf72, and a second inhibitory nucleic acid that inhibits the expression or activity of transmembrane protein 106B (TMEM106B). In some aspects, the present disclosure provides an isolated nucleic acid comprising an expression cassette encoding a first inhibitory nucleic acid that inhibits the expression or activity of C9orf72 and a second inhibitory nucleic acid that inhibits the expression or activity of RPS25. In some embodiments, the isolated nucleic acid further comprises a nucleic acid sequence encoding a wild-type C9orf72 protein (e.g., set forth in SEQ ID NO: 3).

[0009] In some aspects, the present disclosure provides an isolated nucleic acid comprising an expression cassette encoding an inhibitory nucleic acid that inhibits the expression or activity of C9orf72 and a β-glucocerebrosidase (GBA) protein. In some embodiments, the GBA protein is a GBA1 protein (e.g., a protein encoded by a GBA1 gene or a portion thereof). In some aspects, the present disclosure provides an isolated nucleic acid comprising an expression cassette encoding an inhibitory nucleic acid that inhibits the expression or activity of ATXN2 and a β-glucocerebrosidase (GBA) protein. In some embodiments, the GBA protein is a GBA1 protein (e.g., a protein encoded by a GBA1 gene or a portion thereof). In some aspects, the present disclosure provides an isolated nucleic acid comprising an expression cassette encoding an inhibitory nucleic acid that inhibits the expression or activity of TMEM106B and a β-glucocerebrosidase (GBA) protein. In some embodiments, the GBA protein is a GBA1 protein (e.g., a protein encoded by a GBA1 gene or a portion thereof).

[0010] In some embodiments, the inhibitory nucleic acid (e.g., a first inhibitory nucleic acid, a second inhibitory nucleic acid, a third inhibitory nucleic acid, etc.) binds to a nucleic acid encoding a dipeptide repeat region of C9orf72 (e.g., a C9orf72 mRNA transcript comprising a dipeptide repeat region). In some embodiments, the dipeptide repeat region comprises one or more GGGGCC repeat sequences, or one or more CCCCGG repeat sequences (e.g., a dipeptide repeat region of C9orf72). In some embodiments, the dipeptide repeat region comprises 23 or more (e.g., any integer between 23 and 10,000, such as 24, 25, 30, 50, 100, 1000, 5000, or 10,000) GGGGCC repeats (e.g., the sense chain dipeptide repeat region of C9orf72) or 23 or more (e.g., any integer between 23 and 10,000, such as 24, 25, 30, 50, 100, 1000, 5000, or 10,000) CCCCGG repeats (e.g., the antisense chain dipeptide repeat region of C9orf72).

[0011] In some embodiments, the inhibitory nucleic acid binds to a region of nucleic acid encoding C9orf72 that is not a dipeptide repeat region (e.g., a portion of the nucleic acid outside of the dipeptide repeat region of C9orf72). In some embodiments, the inhibitory nucleic acid binds to an isolated nucleic acid sequence between 1 nucleotide within the dipeptide repeat region (e.g., adjacent to the dipeptide repeat region) to about 500 nucleotides. In some embodiments, the inhibitory nucleic acid targets an intronic region of a gene encoding a C9orf72 protein.

[0012] In some embodiments, the inhibitory nucleic acid (e.g., a first inhibitory nucleic acid, a second inhibitory nucleic acid, a third inhibitory nucleic acid, etc.) binds to a nucleic acid sequence encoding ATXN2 (e.g., an ATXN2 mRNA transcript), such as set forth in SEQ ID NO: 9. In some embodiments, the inhibitory nucleic acid targeting ATXN2 binds to an untranslated region (e.g., 5'UTR, 3'UTR, etc.) of the nucleic acid sequence encoding ATXN2.

[0013] In some embodiments, the inhibitory nucleic acid (e.g., a first inhibitory nucleic acid, a second inhibitory nucleic acid, a third inhibitory nucleic acid, etc.) binds to a nucleic acid sequence encoding TMEM106B (e.g., a TMEM106B mRNA transcript), such as set forth in SEQ ID NO: 7. In some embodiments, the inhibitory nucleic acid targeting TMEM106B binds to an untranslated region (e.g., 5'UTR, 3'UTR, etc.) of the nucleic acid sequence encoding TMEM106B.

[0014] In some embodiments, the inhibitory nucleic acid (e.g., a first inhibitory nucleic acid, a second inhibitory nucleic acid, a third inhibitory nucleic acid, etc.) binds to a nucleic acid sequence encoding RPS25 (e.g., an RPS25 mRNA transcript), such as set forth in SEQ ID NO: 60. In some embodiments, the inhibitory nucleic acid targeting RPS25 binds to an untranslated region (e.g., 5'UTR, 3'UTR, etc.) of the nucleic acid sequence encoding RPS25.

[0015] In some embodiments, the inhibitory nucleic acid (e.g., the first inhibitory nucleic acid and / or the second inhibitory nucleic acid) is siRNA, shRNA, miRNA, and dsRNA. In some embodiments, the miRNA is an artificial miRNA (amiRNA), which comprises an inhibitory nucleic acid sequence flanked by miRNA scaffold sequences, such as miR-155 scaffold sequences.

[0016] In some embodiments, the inhibitory nucleic acid (eg, the first inhibitory nucleic acid and / or the second inhibitory nucleic acid) is located in an untranslated region of the expression construct. In some embodiments, the untranslated region is an intron, a 5' untranslated region (5'UTR), or a 3' untranslated region (3'UTR).

[0017] In some embodiments, the isolated nucleic acid comprises one or more promoters. In some embodiments, the promoter is an RNA pol III promoter (e.g., U6 or H1), an RNA pol II promoter, a chicken beta actin (CBA) promoter, a CAG promoter, a CD68 promoter, or a JeT promoter.

[0018] In some embodiments, the expression construct is flanked by two adeno-associated virus (AAV) inverted terminal repeat (ITR) sequences. In some embodiments, one of the ITR sequences flanking the expression construct lacks a functional terminal resolution site.

[0019] In some aspects, the present disclosure relates to rAAV vectors comprising ITRs having a modified "D" region (e.g., a modified D sequence relative to the wild-type AAV2 ITR, i.e., SEQ ID NO: 32). In some embodiments, the ITR having a modified D region is the 5' ITR of the rAAV vector. In some embodiments, the modified "D" region comprises an "S" sequence, such as that set forth in SEQ ID NO: 29. In some embodiments, the ITR having a modified "D" region is the 3' ITR of the rAAV vector. In some embodiments, the modified "D" region comprises a 3' ITR, wherein the "D" region is located at the 3' end of the ITR (e.g., on the outside or end of the ITR relative to the transgenic insert of the vector). In some embodiments, the modified "D" region comprises a sequence set forth in SEQ ID NO: 29 or 30.

[0020] In some embodiments, the isolated nucleic acid (eg, rAAV vector) comprises a TRY region. In some embodiments, the TRY region comprises the sequence set forth in SEQ ID NO: 31.

[0021] In some embodiments, the isolated nucleic acid comprises the sequence set forth in any one of SEQ ID NOs: 1-62, or a portion thereof (or encodes the amino acid sequence set forth in any one of SEQ ID NOs: 1-62, or a portion thereof).

[0022] In some aspects, the present disclosure provides a vector comprising an isolated nucleic acid described in the present disclosure. In some embodiments, the vector is a plasmid or a viral vector. In some embodiments, the viral vector is a recombinant adeno-associated viral vector (rAAV) (e.g., a transgene with AAV ITRs on both sides, the transgene comprising an isolated nucleic acid sequence encoding one or more inhibitory nucleic acids and / or an isolated nucleic acid encoding one or more proteins such as wild-type C9orf72 and / or GBA1) or a baculovirus vector. In some embodiments, the rAAV vector is single-stranded (e.g., single-stranded DNA).

[0023] In some aspects, the present disclosure provides a composition comprising an isolated nucleic acid or vector described in the present disclosure. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0024] In some aspects, the present disclosure provides a host cell comprising an isolated nucleic acid or vector described in the present disclosure. In some embodiments, the host cell is a eukaryotic cell (eg, a mammalian cell, an insect cell, etc.) or a prokaryotic cell (eg, a bacterial cell).

[0025] In some aspects, the present disclosure provides a recombinant adeno-associated virus (rAAV) comprising a capsid protein and an isolated nucleic acid or vector described in the present disclosure. In some embodiments, the capsid protein is capable of crossing the blood-brain barrier. In some embodiments, the capsid protein is an AAV9 capsid protein, an AAVrh.10 capsid protein, or an AAV-PHP.B capsid protein. In some embodiments, rAAV transduces neuronal cells and / or non-neuronal cells of the central nervous system (CNS).

[0026] In some aspects, the present disclosure provides a method of treating a subject having or suspected of having a neurodegenerative disorder (e.g., amyotrophic lateral sclerosis (ALS) and / or frontotemporal dementia (FTD), Alzheimer's disease, Gaucher's disease, Parkinson's disease, Lewy body dementia, or a lysosomal storage disease), the method comprising administering to the subject an isolated nucleic acid, vector, composition, or rAAV described in the present disclosure.

[0027] In some embodiments, administration comprises direct injection into the CNS of the subject. In some embodiments, direct injection into the CNS comprises direct injection into the cerebrospinal fluid (CSF) of the subject, such as intracranial injection, intraventricular injection, intralumbar injection, or any combination thereof. In some embodiments, direct injection is intracerebral injection, intraparenchymal injection, intrathecal injection, intracisternal injection, or any combination thereof. In some embodiments, direct injection comprises convection enhanced delivery (CED).

[0028] In some embodiments, the subject is a mammal, such as a human subject. In some embodiments, the subject is characterized by having between about 30 and about 5000 (e.g., any integer between 30 and 5000 (inclusive)) GGGGCC dipeptide repeats and / or between about 30 and 5000 (e.g., any integer between 30 and 5000 (inclusive)) CCCCGG repeats. In some embodiments, the subject is characterized by having more than 5000 GGGGCC dipeptide repeats and / or CCCCGG repeats. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1is a schematic diagram depicting one embodiment of a plasmid comprising a rAAV vector, the rAAV vector comprising an expression construct encoding an inhibitory nucleic acid targeting repeat expansion of C9orf72, an inhibitory nucleic acid targeting transmembrane protein 106B (TMEM106B), and a wild-type C9orf72 coding sequence. The rAAV vector further comprises AAV inverted terminal repeat sequences on both sides of the expression construct.

[0030] Figure 2 is a schematic diagram depicting one embodiment of a plasmid comprising rAAV, the rAAV comprising an expression construct encoding an inhibitory nucleic acid targeting repeat sequence expansion of C9orf72 and a β-glucocerebrosidase (GBA1) coding sequence. The rAAV vector also comprises AAV inverted terminal repeat sequences on both sides of the expression construct.

[0031] Figure 3 is a schematic diagram depicting one embodiment of a plasmid comprising a rAAV vector including an expression construct encoding an inhibitory nucleic acid targeting repeat sequence expansion of C9orf72 and a wild-type C9orf72 coding sequence.

[0032] Figure 4 Schematic diagram of one embodiment of a plasmid comprising an rAAV vector comprising an expression construct encoding an inhibitory nucleic acid targeting ATXN2 (e.g., a gene encoding ATNX2) operably linked to a pol III (H1) promoter. The rAAV vector further comprises AAV inverted terminal repeats on both sides of the expression construct. The "D" sequence of the 3'UTR is located in the "outside" position.

[0033] Figure 5 Schematic diagram depicting one embodiment of a plasmid comprising an rAAV vector comprising an expression construct encoding an inhibitory nucleic acid targeting ATXN2 (e.g., a gene encoding ATNX2) operably linked to a pol II (CBA) promoter. The rAAV vector further comprises AAV inverted terminal repeat sequences on both sides of the expression construct. The "D" sequence of the 3'UTR is located in the "outside" position.

[0034] Figure 6 is a schematic diagram depicting one embodiment of a plasmid comprising an expression construct encoding an inhibitory nucleic acid targeting ATXN2 (eg, a gene encoding ATNX2) operably linked to a polII (CBA) promoter.

[0035] Figure 7is a schematic diagram depicting one embodiment of a plasmid comprising an expression construct encoding two inhibitory nucleic acids each targeting ATXN2 (eg, a gene encoding ATNX2) operably linked to a polII (CBA) promoter.

[0036] Figure 8 is a schematic diagram depicting one embodiment of a plasmid comprising an expression construct encoding an inhibitory nucleic acid targeting ATXN2 (eg, a gene encoding ATNX2) operably linked to a polII (CBA) promoter.

[0037] Fig. 9 is a schematic diagram depicting one embodiment of a plasmid comprising an rAAV vector comprising an expression construct encoding an inhibitory nucleic acid targeting ATXN2 (e.g., a gene encoding ATNX2) operably linked to a pol II (CBA) promoter and a codon-optimized nucleic acid sequence encoding a wild-type C9orf72 protein. The rAAV vector further comprises AAV inverted terminal repeat sequences on both sides of the expression construct. The "D" sequence of the 3'UTR is located in the "outside" position.

[0038] Fig.10 is a schematic diagram depicting one embodiment of a plasmid comprising an expression construct encoding an inhibitory nucleic acid targeting C9orf72 operably linked to a pol II (CBA) promoter and a codon-optimized nucleic acid sequence encoding a wild-type C9orf72 protein.

[0039] Fig.11 is a schematic diagram depicting one embodiment of a plasmid comprising an expression construct encoding an inhibitory nucleic acid targeting C9orf72 operably linked to a pol II (CBA) promoter and a codon-optimized nucleic acid sequence encoding a wild-type C9orf72 protein.

[0040] Fig.12 is a schematic diagram depicting one embodiment of a plasmid comprising an expression construct encoding an inhibitory nucleic acid targeting C9orf72 operably linked to a pol II (CBA) promoter and a codon-optimized nucleic acid sequence encoding a wild-type C9orf72 protein.

[0041] Fig.13 is a schematic diagram depicting one embodiment of a plasmid comprising an expression construct encoding an inhibitory nucleic acid targeting C9orf72 operably linked to a pol III (eg, H1) promoter.

[0042] Fig.14is a schematic diagram depicting one embodiment of a plasmid comprising an expression construct encoding an inhibitory nucleic acid targeting C9orf72 operably linked to a pol II (CBA) promoter.

[0043] Fig.15 is a schematic diagram depicting one embodiment of a plasmid comprising an expression construct encoding two inhibitory nucleic acids targeting C9orf72 operably linked to a pol II (CBA) promoter and a codon-optimized nucleic acid sequence encoding a wild-type C9orf72 protein.

[0044] Fig.16 is a schematic diagram depicting one embodiment of a plasmid comprising an expression construct encoding two inhibitory nucleic acids targeting C9orf72 operably linked to a pol II (CBA) promoter and a codon-optimized nucleic acid sequence encoding a wild-type C9orf72 protein.

[0045] Fig.17 is a schematic diagram depicting one embodiment of a plasmid comprising an expression construct encoding two inhibitory nucleic acids targeting C9orf72 operably linked to a pol II (CBA) promoter and a codon-optimized nucleic acid sequence encoding a wild-type C9orf72 protein.

[0046] Fig.18 Schematic diagram depicting rAAV vectors containing a "D" region located "outside" of the ITR (e.g., proximal to the end of the ITR relative to a transgenic insert or expression construct) (top) and wild-type rAAV vectors having ITRs "inside" the vector (e.g., proximal to the transgenic insert of the vector).

[0047] Figures 19A-19B Representative data of in vitro C9orf72 expression and knockdown assays are shown. Fig.19A Representative data shown indicate statistically significant silencing of endogenous C9orf72 by rAAV vectors. Fig.19B Representative data shown indicate a statistically significant increase in wild-type C9orf72 expression following transfection with rAAV vectors.

[0048] Fig. 20 is a schematic diagram depicting one embodiment of a plasmid comprising an expression construct encoding an inhibitory nucleic acid targeting RPS25 operably linked to a pol II (CBA) promoter and a codon-optimized nucleic acid sequence encoding a wild-type C9orf72 protein.

[0049] Fig.21is a schematic diagram depicting one embodiment of a plasmid comprising an expression construct encoding an inhibitory nucleic acid targeting RPS25 operably linked to a pol II (CBA) promoter and a codon-optimized nucleic acid sequence encoding a wild-type C9orf72 protein. DETAILED DESCRIPTION

[0050] Various aspects of the present disclosure relate to compositions and methods for treating neurodegenerative diseases such as ALS / FTD, Parkinson's disease, Alzheimer's disease, lysosomal storage diseases, and Lewy body dementia. The present disclosure is based in part on expression constructs encoding ALS / FTD-related gene products (e.g., C9orf72, ATXN2, TMEM106B, inhibitory nucleic acids targeting the above genes, etc.) and combinations thereof in a subject. The gene product can be a protein, a fragment (e.g., a portion) of a protein, an interfering nucleic acid that inhibits an ALS / FTD-related gene, and the like. In some embodiments, the gene product is a protein or a protein fragment encoded by an ALS / FTD-related gene. In some embodiments, the gene product is an interfering nucleic acid (e.g., shRNA, siRNA, miRNA, amiRNA, etc.) that inhibits an ALS / FTD-related gene.

[0051] ALS / FTD-associated genes refer to genes encoding gene products that are genetically, biochemically, or functionally associated with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), or ALS and FTD (ALS / FTD). For example, individuals with more than 23 GGGGCC hexanucleotide repeats in the C9orf72 gene have been observed to have an increased risk of developing ALS / FTD compared to individuals without repeat region expansion. In some embodiments, the expression cassettes described herein encode a wild-type or non-mutated form of an ALS / FTD-associated gene (or its coding sequence). In general, a "wild-type" or "non-mutated" form of a gene refers to a nucleic acid encoding a protein associated with normal or non-pathogenic activity (e.g., a protein lacking a mutation or change such as a repeat region expansion that leads to the occurrence or progression of a neurodegenerative disease). For example, in some embodiments, the wild-type C9orf72 protein comprises or consists of the sequence set forth in SEQ ID NO: 4.

[0052] Isolated nucleic acids and vectors

[0053] The isolated nucleic acid can be DNA or RNA. In some aspects, the present disclosure provides isolated nucleic acids (e.g., rAAV vectors) encoding one or more inhibitory nucleic acids targeting one or more ALS / FTD-related genes such as C9orf72 (e.g., the dipeptide repeat region of C9orf72), ATXN2, TMEM106B, RPS25, etc. The inhibitory nucleic acid can target the sense strand of the gene (e.g., mRNA transcribed from the gene), the antisense strand of the gene (e.g., mRNA transcribed from the gene), or both the sense and antisense strands of the gene (e.g., mRNA transcribed from the gene).

[0054] Typically, the isolated nucleic acids described herein can encode 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more inhibitory nucleic acids (e.g., dsRNA, siRNA, shRNA, miRNA, amiRNA, etc.). In some embodiments, the isolated nucleic acids encode more than 10 inhibitory nucleic acids. In some embodiments, each of the one or more inhibitory nucleic acids targets a different gene or gene portion (e.g., a first miRNA targets a first target sequence of a gene, and a second miRNA targets a second target sequence of the gene that is different from the first target sequence). In some embodiments, each of the one or more inhibitory nucleic acids targets the same target sequence of the same gene (e.g., the isolated nucleic acid encodes multiple copies of the same miRNA).

[0055] Aspects of the present disclosure relate to an isolated nucleic acid comprising an expression construct encoding one or more interfering nucleic acids (e.g., dsRNA, siRNA, miRNA, amiRNA, etc.) targeting a C9orf72 protein (e.g., a dipeptide repeat region of a C9orf72 mRNA transcript). In some embodiments, the dipeptide repeat region is encoded by 5 or more polymer units of the hexanucleotide repeat sequence GGGGCC (e.g., a region comprising 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 100, 200, 500, 1000 or more repeats of the GGGGCC repeat sequence).

[0056] Generally, C9orf72 protein refers to a protein found in the cytoplasm and presynaptic terminals of neurons, which is believed to be an exchange factor for small GTPases such as Rab. In humans, the C9orf72 gene is located on chromosome 9. In some embodiments, the C9orf72 gene encodes a peptide represented by the NCBI reference sequence NP_060795.1. In some embodiments, the C9orf72 gene comprises a sequence set forth in SEQ ID NO: 3 or encodes an amino acid sequence set forth in SEQ ID NO: 4.

[0057] Inhibitory nucleic acids targeting C9orf72 can comprise a complementary region between 6 and 50 nucleotides in length (e.g., a region of the inhibitory nucleic acid that hybridizes to a target gene, such as C9orf72, or a portion of a target gene, such as a dipeptide repeat region of C9orf72, or a region outside of a dipeptide repeat region). In some embodiments, the inhibitory nucleic acid comprises a region complementary to C9orf72 between about 6 and 30, about 8 to 20, or about 10 to 19 nucleotides in length. In some embodiments, the inhibitory nucleic acid is complementary to at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 contiguous nucleotides of a C9orf72 sequence. In some embodiments, the C9orf72 sequence targeted (e.g., bound) by the inhibitory nucleic acid is between 1 nucleotide and 500 nucleotides (e.g., any integer number of nucleotides between 1 and 500, inclusive) away from the dipeptide repeat region of the C9orf72 (relative to it at 5' or 3'). In some embodiments, the inhibitory nucleic acid targets an intronic region (e.g., a non-protein coding region) of a gene encoding a C9orf72 protein.

[0058] Aspects of the present disclosure relate to an isolated nucleic acid comprising an expression construct encoding one or more interfering nucleic acids (e.g., dsRNA, siRNA, miRNA, amiRNA, etc.) targeting a TMEM106B protein (e.g., a gene product of a TMEM106B gene). The TMEM106B protein refers to the transmembrane protein 106B, which is a protein involved in the regulation of dendritic morphogenesis and lysosomal trafficking. In humans, the TMEM106B gene is located on chromosome 7. In some embodiments, the TMEM106B gene encodes a peptide represented by the NCBI reference sequence NP_060844.2. In some embodiments, the TMEM106B gene comprises a sequence set forth in SEQ ID NO: 7 or encodes an amino acid sequence set forth in SEQ ID NO: 6.

[0059] The inhibitory nucleic acid targeting TMEM106B can include a complementary region (e.g., a region of the inhibitory nucleic acid hybridized to a target gene, such as TMEM106B) having a length between 6 and 50 nucleotides. In some embodiments, the inhibitory nucleic acid includes a region complementary to TMEM106B having a length between about 6 and 30, about 8 to 20, or about 10 to 19 nucleotides. In some embodiments, the inhibitory nucleic acid is complementary to at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 adjacent nucleotides of the TMEM106B sequence.

[0060] Aspects of the present disclosure relate to an isolated nucleic acid comprising an expression construct encoding one or more interfering nucleic acids (e.g., dsRNA, siRNA, miRNA, amiRNA, etc.) targeting an ATXN2 protein (e.g., a gene product of the ATXN2 gene, also known as the SCA gene). The ATXN2 protein refers to spinocerebellar ataxia protein 2, which is a protein involved in regulating mRNA translation through its interaction with poly(A) binding protein. In humans, the ATXN2 gene is located on chromosome 12. In some embodiments, the ATXN2 gene encodes a peptide represented by the NCBI reference sequence NP_002964.3. In some embodiments, the ATXN2 gene comprises a sequence set forth in SEQ ID NO: 9 or encodes an amino acid sequence set forth in SEQ ID NO: 8.

[0061] Inhibitory nucleic acids targeting ATXN2 can comprise a complementary region (e.g., a region of the inhibitory nucleic acid that hybridizes to a target gene, such as ATXN2) between 6 and 50 nucleotides in length. In some embodiments, the inhibitory nucleic acid comprises a region complementary to ATXN2 between about 6 and 30, about 8 to 20, or about 10 to 19 nucleotides in length. In some embodiments, the inhibitory nucleic acid is complementary to at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 contiguous nucleotides of the ATXN2 sequence.

[0062] Aspects of the present disclosure relate to an isolated nucleic acid comprising an expression construct encoding one or more interfering nucleic acids (e.g., dsRNA, siRNA, miRNA, amiRNA, etc.) targeting ribosomal protein s25 (RPS25) (e.g., a gene product of RPS25). The RPS25 protein refers to a ribosomal protein that is a subunit of the protein complex s40 ribosome involved in protein synthesis. In humans, the RPS25 gene is located on chromosome 11. In some embodiments, the RPS25 gene encodes a peptide represented by the NCBI reference sequence NP_001019.1. In some embodiments, the RPS25 gene comprises the sequence set forth in SEQ ID NO: 60.

[0063] Inhibitory nucleic acids targeting RPS25 can comprise a complementary region (e.g., a region of the inhibitory nucleic acid that hybridizes to a target gene, such as RPS25) between 6 and 50 nucleotides in length. In some embodiments, the inhibitory nucleic acid comprises a region complementary to RPS25 between about 6 and 30, about 8 to 20, or about 10 to 19 nucleotides in length. In some embodiments, the inhibitory nucleic acid is complementary to at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 contiguous nucleotides of the RPS25 sequence.

[0064] Various aspects of the present disclosure relate to expression constructs comprising a first gene product encoding one or more inhibitory nucleic acids (e.g., inhibitory nucleic acids targeting the dipeptide repeat region of C9orf72, inhibitory nucleic acids targeting the non-dipeptide repeat region of C9orf72 and / or inhibitory nucleic acids targeting TMEM106B and / or inhibitory nucleic acids targeting ATXN2 and / or inhibitory nucleic acids targeting RPS25, etc.) and a second gene product encoding a protein, e.g., a wild-type C9orf72 protein or a GBA protein.

[0065] In some embodiments, the isolated nucleic acid comprises an expression cassette encoding a first inhibitory nucleic acid that inhibits the expression or activity of C9orf72 and a second inhibitory nucleic acid that inhibits the expression or activity of TMEM106B.

[0066] In some embodiments, the isolated nucleic acid comprises an expression cassette encoding a first inhibitory nucleic acid that inhibits the expression or activity of C9orf72 and a second inhibitory nucleic acid that inhibits the expression or activity of ATXN2.

[0067] In some embodiments, the isolated nucleic acid comprises an expression cassette encoding a first inhibitory nucleic acid that inhibits the expression or activity of C9orf72 and a second inhibitory nucleic acid that inhibits the expression or activity of RPS25.

[0068] In some embodiments, the isolated nucleic acid comprises an expression cassette encoding an inhibitory nucleic acid that inhibits the expression or activity of C9orf72 and a β-glucocerebrosidase (GBA) protein. In some embodiments, the GBA protein is a GBA1 protein (eg, a protein encoded by a GBA1 gene or a portion thereof).

[0069] In some embodiments, the isolated nucleic acid comprises an expression cassette encoding an inhibitory nucleic acid that inhibits the expression or activity of C9orf72 and a wild-type C9orf72 protein (e.g., a C9orf72 protein that lacks a pathogenic dipeptide repeat expansion). In some embodiments, the nucleic acid sequence encoding the wild-type C9orf72 protein, or a portion thereof, is a codon-optimized nucleic acid sequence. In some embodiments, the wild-type C9orf72 protein is encoded by the nucleic acid sequence set forth in SEQ ID NO: 3, or a portion thereof. In some embodiments, the wild-type C9orf72 protein comprises or consists of the sequence set forth in SEQ ID NO: 4, or a portion thereof. In some embodiments, the isolated nucleic acid encoding a codon-optimized C9orf72 comprises or consists of the sequence set forth in SEQ ID NO: 51.

[0070] The skilled artisan recognizes that the order of expression of the first gene product (e.g., a nucleic acid sequence encoding a C9orf72 protein or a GBA protein) and the second gene product (e.g., an inhibitory RNA targeting C9orf72, ATXN2, TMEM106B, etc.) can generally be reversed (e.g., the inhibitory RNA is the first gene product, and the protein coding sequence is the second gene product). In some embodiments, the gene product is a fragment (e.g., a portion) of a gene (e.g., C9orf72, TMEM106B, ATXN2, GBA1, etc.). The protein fragment may comprise about 50%, about 60%, about 70%, about 80%, about 90%, or about 99% of the protein (e.g., C9orf72 protein, GBA protein, etc.). In some embodiments, the protein fragment comprises between 50% and 99.9% (e.g., any value between 50% and 99.9%) of the C9orf72 protein or the GBA protein. In some embodiments, the gene product (e.g., inhibitory RNA) hybridizes to a portion of a target gene (e.g., is complementary to 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or more contiguous nucleotides of a target gene, e.g., C9orf72, ATXN2, or TMEM106B).

[0071] In some embodiments, the expression construct is monocistronic (e.g., the expression construct encodes a single fusion protein comprising a first gene product and a second gene product). In some embodiments, the expression construct is polycistronic (e.g., the expression construct encodes two different gene products, e.g., two different proteins or protein fragments).

[0072] The polycistronic expression vector may comprise one or more (e.g., 1, 2, 3, 4, 5 or more) promoters. Any suitable promoter may be used, such as a constitutive promoter, an inducible promoter, an endogenous promoter, a tissue-specific promoter (e.g., a CNS-specific promoter), etc. In some embodiments, the promoter is a chicken β-actin promoter (CBA promoter), a CAG promoter (e.g., described by Alexopoulou et al., (2008) BMC Cell Biol. 9:2; doi: 10.1186 / 1471-2121-9-2), a CD68 promoter, or a JeT promoter (e.g., described by et al., (2002) Gene 297(1-2):21-32 or Karumuthil-Melethil et al., (2016) Human Gene Therapy 27(7):509-521). In some embodiments, the promoter is operably linked to a nucleic acid sequence encoding a first gene product, a second gene product, or a first gene product and a second gene product. In some embodiments, the expression cassette comprises one or more additional regulatory sequences, including but not limited to transcription factor binding sequences, intron splicing sites, poly (A) addition sites, enhancer sequences, repressor protein binding sites, or any combination of the above sequences.

[0073] In some embodiments, the nucleic acid sequence encoding the first gene product and the nucleic acid sequence encoding the second gene product are separated by a nucleic acid sequence encoding an internal ribosome entry site (IRES). Examples of IRES sites are described, for example, by Mokrejs et al., (2006) Nucleic Acids Res.34 (Database issue): D125-30. In some embodiments, the nucleic acid sequence encoding the first gene product and the nucleic acid sequence encoding the second gene product are separated by a nucleic acid sequence encoding a self-cleaving peptide. Examples of self-cleaving peptides include, but are not limited to, T2A, P2A, E2A, F2A, BmCPV 2A, and BmIFV 2A, as well as by Liu et al., (2017) Sci Rep.7: 2193. In some embodiments, the self-cleaving peptide is a T2A peptide.

[0074] Pathologically, disorders such as ALS and FTD are associated with the accumulation of protein aggregates composed primarily of non-ATG (RAN) translated proteins associated with repeat sequences derived from the C9orf72 gene. Thus, in some embodiments, the isolated nucleic acids described herein comprise inhibitory nucleic acids that reduce or prevent the expression of C9orf72 proteins (e.g., C9orf72 proteins encoded by genes with pathogenic dipeptide repeat sequence expansions). The sequence encoding the inhibitory nucleic acid can be placed in an untranslated region (e.g., intron, 5'UTR, 3'UTR, etc.) of the expression construct.

[0075] In some embodiments, the inhibitory nucleic acid is placed in an intron of the expression construct, for example, in an intron upstream of the sequence encoding the first gene product. The inhibitory nucleic acid can be a double-stranded RNA (dsRNA), siRNA, micro RNA (miRNA), artificial miRNA (amiRNA) or RNA aptamer. Typically, the inhibitory nucleic acid binds to (e.g., hybridizes with) between about 6 and about 30 (e.g., any integer between 6 and 30 (inclusive)) contiguous nucleotides of the target RNA (e.g., mRNA). In some embodiments, the inhibitory nucleic acid molecule is a miRNA or amiRNA, such as a miRNA targeting C9orf72 (a gene encoding a pathogenic C9orf72 protein). In some embodiments, the miRNA does not contain any mismatches with the region of the C9orf72 mRNA to which it hybridizes (e.g., the miRNA is "perfect"). In some embodiments, the miRNA comprises between 2 and 20 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) mismatches, e.g., "bulges," to the region of the C9orf72 mRNA to which it hybridizes. In some embodiments, the miRNA comprises more than 20 mismatches to the region of the C9orf72 mRNA to which it hybridizes.

[0076] In some embodiments, the inhibitory nucleic acid is a shRNA (e.g., a shRNA targeting C9orf72). In some embodiments, the inhibitory nucleic acid is a miRNA (e.g., a miRNA targeting C9orf72). In some embodiments, expression of one or more inhibitory RNAs of the expression construct is driven by one or more RNA pol III promoters, such as an H1 promoter or a U6 promoter. Each inhibitory RNA can be driven by a different promoter or the same promoter.

[0077] In some embodiments, the inhibitory nucleic acid is an artificial microRNA (amiRNA). MicroRNA (miRNA) generally refers to a small non-coding RNA found in plants and animals and plays a role in transcriptional and post-translational regulation of gene expression. MiRNA is transcribed by RNA polymerase to form a hairpin-loop structure called pri-miRNA, which is then processed by an enzyme (e.g., Drosha, Pasha, spliceosome, etc.) to form a pre-miRNA hairpin structure, which is then processed by Dicer to form a miRNA / miRNA* duplex (where * indicates the follower strand of the miRNA duplex), one of which is subsequently incorporated into the RNA-induced silencing complex (RISC). In some embodiments, the inhibitory RNA described herein is a miRNA targeting C9orf72 (e.g., a dipeptide repeat region of C9orf72 or a non-dipeptide repeat region of C9orf72), ATXN2, or TMEM106B.

[0078] In some embodiments, the inhibitory nucleic acid targeting C9orf72 comprises a miRNA / miRNA* duplex. In some embodiments, the miRNA strand of the miRNA / miRNA* duplex comprises a sequence set forth in any one of SEQ ID NOs: 24 or 25, 37 or 38, 40 or 41, or a portion thereof, or consists of a sequence set forth in any one of SEQ ID NOs: 24 or 25, 37 or 38, 40 or 41, or a portion thereof. In some embodiments, the miRNA* strand of the miRNA / miRNA* duplex comprises a sequence set forth in any one of SEQ ID NOs: 24 or 25, 37 or 38, 40 or 41, or a portion thereof, or consists of a sequence set forth in any one of SEQ ID NOs: 24 or 25, 37 or 38, 40 or 41, or a portion thereof.

[0079] In some embodiments, the inhibitory nucleic acid targeting TMEM106B comprises a miRNA / miRNA* duplex. In some embodiments, the miRNA strand of the miRNA / miRNA* duplex comprises a sequence set forth in SEQ ID NO: 1 or 7, or a portion thereof, or consists of a sequence set forth in SEQ ID NO: 1 or 7, or a portion thereof. In some embodiments, the miRNA* strand of the miRNA / miRNA* duplex comprises a sequence set forth in SEQ ID NO: 1 or 7, or a portion thereof, or consists of a sequence set forth in SEQ ID NO: 1 or 7, or a portion thereof.

[0080] In some embodiments, the inhibitory nucleic acid targeting ATXN2 comprises a miRNA / miRNA* duplex. In some embodiments, the miRNA strand of the miRNA / miRNA* duplex comprises a sequence set forth in any one of SEQ ID NOs: 10-23, or a portion thereof, or consists of a sequence set forth in any one of SEQ ID NOs: 10-23, or a portion thereof. In some embodiments, the miRNA* strand of the miRNA / miRNA* duplex comprises a sequence set forth in any one of SEQ ID NOs: 10-23, or a portion thereof, or consists of a sequence set forth in any one of SEQ ID NOs: 10-23, or a portion thereof.

[0081] Artificial microRNA (amiRNA) is derived by modifying native miRNA (native miRNA) to replace the natural targeting region of pre-mRNA with the targeting region of interest. For example, naturally occurring expressed miRNA can be used as a scaffold or skeleton (e.g., pri-miRNA scaffold), and the stem sequence is replaced with the stem sequence of the miRNA targeting the gene of interest. Artificial precursor microRNA (pre-amiRNA) is usually processed so that a single stable small RNA is preferably produced. In some embodiments, the scAAV vector and scAAV described herein include nucleic acids encoding amiRNA. In some embodiments, the pri-miRNA scaffold of the amiRNA is derived from a pri-miRNA selected from pri-MIR-21, pri-MIR-22, pri-MIR-26a, pri-MIR-30a, pri-MIR-33, pri-MIR-122, pri-MIR-375, pri-MIR-199, pri-MIR-99, pri-MIR-194, pri-MIR-155 and pri-MIR-451. In some embodiments, the amiRNA comprises a nucleic acid sequence targeting C9orf72, ATNX2, or TMEM106B and an eSIBR amiRNA scaffold, such as described in Fowler et al., Nucleic Acids Res. 2016 Mar 18; 44(5):e48.

[0082] In some aspects, the present disclosure relates to expression constructs comprising a combination of inhibitory RNAs for treating neurodegenerative diseases (e.g., ALS / FTD). For example, in some embodiments, the expression constructs described by the present disclosure comprise an inhibitory RNA targeting C9orf72 and an inhibitory RNA targeting transmembrane protein 106B (TMEM106B). The order in which the isolated nucleic acid encodes the sequence of the inhibitory nucleic acid can vary. For example, the isolated nucleic acid can encode an shRNA targeting C9orf72 and TMEM106B, or targeting TMEM106B and C9orf72 from the 5' end to the 3' end.

[0083] The isolated nucleic acid described herein can exist by itself or as part of a vector. Generally, the vector can be a plasmid, a cosmid, a phagemid, a bacterial artificial chromosome (BAC) or a viral vector (e.g., an adenoviral vector, an adeno-associated virus (AAV) vector, a retroviral vector, a baculovirus vector, etc.). In some embodiments, the vector is a plasmid (e.g., a plasmid comprising an isolated nucleic acid described herein). In some embodiments, the vector is a recombinant AAV (rAAV) vector (e.g., an expression construct encoding a transgenic with AAV ITR on both sides). In some embodiments, the rAAV vector is single-stranded (e.g., single-stranded DNA). In some embodiments, the vector is a baculovirus vector (e.g., Autographa californica nuclear polyhedrosis virus (AcNPV) vector).

[0084] Typically, the rAAV vector comprises a transgene with two AAV reverse terminal repeat (ITR) sequences on both sides. In some embodiments, the transgene of the rAAV vector comprises an isolated nucleic acid described in the present disclosure. In some embodiments, each of the two ITR sequences of the rAAV vector is a full-length ITR (e.g., a length of about 145bp, and containing a functional Rep binding site (RBS) and a terminal melting site (trs)). In some embodiments, one of the ITRs of the rAAV vector is truncated (e.g., shortened or non-full-length). In some embodiments, the truncated ITR lacks a functional terminal melting site (trs) and is used to produce a self-complementary AAV vector (scAAV vector). In some embodiments, the truncated ITR is a ΔITR, such as described by McCarty et al., (2003) Gene Ther. 10 (26): 2112-8.

[0085] Various aspects of the present disclosure relate to isolated nucleic acids (e.g., rAAV vectors) comprising ITRs having one or more modifications (e.g., nucleic acid additions, deletions, substitutions, etc.) relative to wild-type AAV ITRs, e.g., relative to wild-type AAV2 ITRs (e.g., SEQ ID NO: 32). The structure of the wild-type AAV2 ITR is shown in Fig.18 Typically, the wild-type ITR contains a 125-nucleotide region that self-anneals to form a palindromic double-stranded T-shaped hairpin structure consisting of two cross arms (formed by sequences called B / B' and C / C', respectively), a longer stem region (formed by the sequence A / A'), and a single-stranded terminal region called the "D" region ( Fig.18 ). Typically, the "D" region of the ITR is located between the stem region formed by the A / A' sequence and the insert containing the transgene of the rAAV vector (e.g., located "inside" of the ITR or proximal to the transgene insert or expression construct of the rAAV vector relative to the end of the ITR). In some embodiments, the "D" region comprises the sequence set forth in SEQ ID NO: 30. It has been observed that the "D" region plays an important role in the encapsidation of the rAAV vector by the capsid protein, such as disclosed by Ling et al., (2015) J Mol Genet Med 9 (3).

[0086] The present disclosure is based in part on the surprising discovery that rAAV vectors comprising a "D" region located on the "outside" of the ITR (e.g., proximal to the end of the ITR relative to a transgenic insert or expression construct) are efficiently encapsidated by AAV capsid proteins compared to rAAV vectors having unmodified (e.g., wild-type) ITRs. In some embodiments, rAAV vectors having modified "D" sequences (e.g., "D" sequences in the "outside" position) have reduced toxicity relative to rAAV vectors having wild-type ITR sequences.

[0087] In some embodiments, the modified "D" sequence comprises at least one nucleotide substitution relative to the wild-type "D" sequence (e.g., SEQ ID NO: 30). The modified "D" sequence may have at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 nucleotide substitutions relative to the wild-type "D" sequence (e.g., SEQ ID NO: 30). In some embodiments, the modified "D" sequence comprises at least 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleic acid substitutions relative to the wild-type "D" sequence (e.g., SEQ ID NO: 30). In some embodiments, the modified "D" sequence has between about 10% and about 99% (e.g., 10%, 15%, 20%, 25%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 99%) identity to the wild-type "D" sequence (e.g., SEQ ID NO: 30). In some embodiments, the modified "D" sequence comprises the sequence set forth in SEQ ID NO: 29, which is also referred to as the "S" sequence, as described in Wang et al., (1995) J Mol Biol 250(5): 573-80.

[0088] The isolated nucleic acid or rAAV vector described in the present disclosure may also comprise a "TRY" sequence, such as set forth in SEQ ID NO: 31, as described by Francois et al., 2005, The Cellular TATA Binding Protein Is Required for Rep-Dependent Replication of a Minimal Adeno-Associated Virus Type 2p5 Element, J Virol. In some embodiments, the TRY sequence is located between the ITR (e.g., 5' ITR) of the isolated nucleic acid or rAAV vector and the expression construct (e.g., an insert encoding a transgene).

[0089] In some aspects, the disclosure relates to a baculovirus vector comprising an isolated nucleic acid or rAAV vector described in the disclosure. In some embodiments, the baculovirus vector is an Autographa californica nuclear polyhedrosis virus (AcNPV) vector, such as described by Urabe et al., (2002) Hum Gene Ther 13(16):1935-43 and Smith et al., (2009) Mol Ther 17(11):1888-1896.

[0090] In some aspects, the present disclosure provides a host cell comprising an isolated nucleic acid or vector described herein. The host cell can be a prokaryotic cell or a eukaryotic cell. For example, the host cell can be a mammalian cell, a bacterial cell, a yeast cell, an insect cell, etc. In some embodiments, the host cell is a mammalian cell such as a HEK293T cell. In some embodiments, the host cell is a bacterial cell such as an Escherichia coli cell.

[0091] rAAV

[0092] In some aspects, the present disclosure relates to recombinant AAV (rAAV) comprising a transgene encoding a nucleic acid described herein (e.g., an rAAV vector described herein). The term "rAAV" generally refers to a viral particle comprising an rAAV vector encapsidated with one or more AAV capsid proteins. The rAAV described in the present disclosure may comprise a capsid protein having a serotype selected from AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, and AAV10. In some embodiments, rAAV comprises a capsid protein from a non-human host, such as an AAV capsid protein of a rhesus monkey, such as AAVrh.10, AAVrh.39, etc. In some embodiments, the rAAV described in the present disclosure comprises a capsid protein that is a variant of a wild-type capsid protein, such as a capsid protein variant that includes at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more than 10 (e.g., 15, 20, 25, 50, 100, etc.) amino acid substitutions (e.g., mutations) relative to the wild-type AAV capsid protein from which it is derived.

[0093] In some embodiments, the rAAV described in the present disclosure is easily propagated through the CNS, particularly when introduced into the CSF space or directly into the brain parenchyma. Therefore, in some embodiments, the rAAV described in the present disclosure comprises a capsid protein capable of crossing the blood-brain barrier (BBB). For example, in some embodiments, the rAAV comprises a capsid protein having an AAV9 or AAVrh.10 serotype. In some embodiments, the rAAV comprises an AAV9 variant such as an AAV-PHP.B serotype that crosses the blood-brain barrier, as described by Deverman et al., (2016) Nature Biotechnology 34: 204-209. In general, the production of rAAV is described by, for example, Samulski et al., (1989) J Virol. 63 (9): 3822-8 and Wright (2009) Hum Gene Ther. 20 (7): 698–706.

[0094] In some embodiments, the rAAV described in the present disclosure (e.g., comprising a recombinant rAAV genome encapsidated by an AAV capsid protein to form rAAV capsid particles) is produced in a baculovirus vector expression system (BEVS). The use of BEVS to produce rAAV is described, for example, by Urabe et al., (2002) Hum Gene Ther 13 (16): 1935-43, Smith et al., (2009) Mol Ther 17 (11): 1888-1896, U.S. Pat. No. 8,945,918, U.S. Pat. No. 9,879,282, and International PCT Publication WO 2017 / 184879. However, rAAV can be produced using any suitable method (e.g., using recombinant rep and cap genes).

[0095] Pharmaceutical composition

[0096] In some aspects, the present disclosure provides a pharmaceutical composition comprising an isolated nucleic acid or rAAV described herein and a pharmaceutically acceptable carrier. As used herein, the term "pharmaceutically acceptable" refers to a material, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively non-toxic, such as a material that can be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any component of the composition comprising it.

[0097] As used herein, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition or carrier such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent or encapsulating material, which participates in carrying or transporting the useful compound of the present invention within a patient, or carrying or transporting it to a patient so that the compound can perform its target function. Other ingredients that may be included in the pharmaceutical composition used in the practice of the present invention are known in the art and are described in, for example, Remington's Pharmaceutical Sciences (Genaro, ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0098] Compositions (e.g., pharmaceutical compositions) provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracisternal, subcutaneous, intraventricular, transdermal, intradermal, rectal, intravaginal, intraperitoneal, topical (e.g., by powders, ointments, creams, and / or drops), mucosal, nasal, buccal, sublingual, by intratracheal instillation, bronchial instillation, and / or inhalation, and / or as oral sprays, nasal sprays, and / or aerosols. Specific envisioned routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration by blood and / or lymphatic supply, and / or direct administration to the affected area. Typically, the most suitable route of administration depends on various factors, including the nature of the medicament (e.g., its stability in the gastrointestinal environment) and / or the condition of the subject (e.g., whether the subject can tolerate oral administration).

[0099] method

[0100] The present disclosure is based in part on compositions expressing one or more ALS-FTD-related gene products (or combinations thereof) in a subject, which act together (e.g., synergistically) to treat neurodegenerative diseases (e.g., ALS / FTD, etc.). As used herein, "treat" or "treating" refers to (a) preventing or delaying the onset of a neurodegenerative disease (e.g., ALS / FTD, Alzheimer's disease, Gaucher's disease, Parkinson's disease, Lewy body dementia, lysosomal storage disease, etc.); (b) reducing the severity of a neurodegenerative disease; (c) reducing or preventing the occurrence of symptoms characteristic of a neurodegenerative disease; (d) and / or preventing the worsening of symptoms characteristic of a neurodegenerative disease. For example, symptoms of ALS / FTD include, for example, motor dysfunction (e.g., paralysis, shaking, stiffness, slow movement, difficulty walking), cognitive dysfunction (e.g., dementia, depression, anxiety), mood and behavioral dysfunction.

[0101] Thus, in some aspects, the disclosure provides a method of treating a subject having or suspected of having a neurodegenerative disease, the method comprising administering to the subject a composition described in the disclosure (e.g., a composition comprising an isolated nucleic acid or vector or rAAV). In some embodiments, the neurodegenerative disease is ALS / FTD, Alzheimer's disease, Gaucher's disease, Parkinson's disease, Lewy body dementia, or a lysosomal storage disease.

[0102] In some embodiments, the composition is administered directly to the CNS of the subject, for example, by direct injection into the brain and / or spinal cord of the subject. Examples of direct CNS administration include, but are not limited to, intracerebral injection, intraventricular injection, intracranial injection, intraparenchymal injection, intrathecal injection, and any combination of the above. In some embodiments, direct injection into the CNS of the subject causes expression of the transgene in the midbrain, striatum, and / or cerebral cortex of the subject (e.g., expression of the first gene product, the second gene product, and, if applicable, the third gene product).

[0103] In some embodiments, the compositions described in the present disclosure are administered directly to the cerebrospinal fluid (CSF) of the subject. In some embodiments, direct injection into the CNS causes expression of the transgene in the spinal cord and / or CSF of the subject (e.g., expression of the first gene product, the second gene product, and, if applicable, the third gene product). Examples of direct injection into the CSF of a subject include, but are not limited to, intracranial injection, intraventricular injection, lumbar injection, or any combination thereof.

[0104] In some embodiments, direct injection into the CNS of a subject comprises convection enhanced delivery (CED). Convection enhanced delivery is a treatment strategy that involves surgically exposing the brain and placing a small diameter catheter directly into a target area of ​​the brain, followed by infusion of a therapeutic agent (e.g., a composition described herein or rAAV) directly into the brain of the subject. CED is described, for example, by Debinski et al., (2009) Expert Rev Neurother. 9(10): 1519-27.

[0105] In some embodiments, the composition is administered to the subject peripherally, such as by peripheral injection. Examples of peripheral injections include subcutaneous injection, intravenous injection, intraarterial injection, intraperitoneal injection, or any combination of the above. In some embodiments, the peripheral injection is intraarterial injection, such as injection into the subject's carotid artery.

[0106] In some embodiments, the compositions described in the present disclosure (e.g., compositions comprising isolated nucleic acids or vectors or rAAVs) are administered to the CNS of the subject in both peripheral and direct ways. For example, in some embodiments, the subject administers the composition by intra-arterial injection (e.g., injection into the carotid artery) and by intraparenchymal injection (e.g., intraparenchymal injection by CED). In some embodiments, the direct injection and peripheral injection to the CNS are simultaneous (e.g., occurring at the same time). In some embodiments, the direct injection occurs before the peripheral injection (e.g., 1 minute to 1 week or more before). In some embodiments, the direct injection occurs after the peripheral injection (e.g., 1 minute to 1 week or more after).

[0107] The amount of a composition described in the present disclosure (e.g., a composition comprising an isolated nucleic acid or vector or rAAV) administered to a subject will vary depending on the method of administration. For example, in some embodiments, the rAAV described herein is administered in an amount of about 10 9 Genome copies (GC) / kg to about 10 14 GC / kg (e.g. about 10 9 GC / kg, about 10 10 GC / kg, about 10 11 GC / kg, about 10 12 GC / kg, about 10 12 GC / kg or about 10 14 GC / kg) is administered to a subject. In some embodiments, a subject is administered a high titer (e.g., >10 GC / kg) by injection into the CSF space or by intraparenchymal injection. 12 genome copies GC / kg of rAAV).

[0108] The compositions described in the present disclosure (e.g., compositions comprising isolated nucleic acids or vectors or rAAVs) can be administered to a subject once or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 20 times or more). In some embodiments, the composition is administered to a subject continuously (e.g., chronically), e.g., by an infusion pump.

[0109] Example

[0110] Example 1: rAAV vector

[0111] AAV vectors are produced using cells such as HEK293 cells for triple plasmid transfection. The ITR sequences flank the expression construct, which contains a promoter / enhancer element, a 3' polyA signal, and a post-translational signal such as a WPRE element for each transgene of interest. Multiple gene products such as C9orf72 protein or GBA1 protein and one or more inhibitory nucleic acids (e.g., inhibitory nucleic acids targeting C9orf72 and / or TMEM106B) can be expressed simultaneously, for example by using a single expression cassette or separate expression cassettes. The presence of a short intron sequence that is efficiently spliced ​​upstream of the expressed gene can increase the expression level. Inhibitory RNA (e.g., miRNA, shRNA, etc.) and other regulatory RNAs can potentially be included in these sequences. Examples of expression constructs described in the present disclosure are shown in Figure 1-17 and 20-21 and Table 1 below.

[0112] Table 1

[0113]

[0114]

[0115] Example 2: Cell-based assay for viral transduction in ALS / FTD cells

[0116] Cells characterized by repeat expansion of C9orf72 are obtained, for example, as fibroblasts, monocytes or hES cells from ALS / FTD patients or patient-derived induced pluripotent stem cells (iPSCs). These cells accumulate RNA foci and RAN-translated proteins.

[0117] Using these cell models, cell diseases are quantified based on the accumulation of protein aggregates, such as aggregates of RAN protein, using anti-RAN protein antibodies and then using fluorescence microscopy imaging. Abnormal accumulation of RAN protein is quantified using Western blot and / or ELISA.

[0118] Therapeutic endpoints (e.g., reduction of ALS / FTD-related disease) are measured in the context of transduced expression of AAV vectors to confirm and quantify activity and function. Reduction in endogenous (e.g., pathogenic repeat expansion-containing) C9orf72 mRNA levels can be quantified, for example, using quantitative RT-PCR (qRT-PCR).

[0119] Example 3: In vitro studies

[0120] This example describes in vitro testing of the C9orf72 rAAV vectors described in this disclosure. The effects of C9orf72 knockdown and overexpression were studied in mammalian cells. Examples of tested constructs are listed in Table 2.

[0121] ID Promoter Knock off Promoter Overexpression I00017 H1 C9_sh CMV opt-C9 I00018 CMV C9_sh,TMEM_mi CMV opt-C9 I00030 CMV_intronic C9_sh(cons) CMV opt-C9 I00031 CMV_intronic C9repeat_sh CMV opt-C9 I00032 CMV_intronic C9_sh(validated) CMV opt-C9 I00037 CMV_intronic C9r_sh,ATXN_sh CMV opt-C9

[0122] Gene knockdown and overexpression were determined by quantitative PCR (qPCR) and ELISA. Fig.19A Representative data shown demonstrate statistically significant silencing of C9orf72 by rAAV vectors. Fig.19B Representative data shown demonstrate statistically significant increase in wild-type C9orf72 expression following transfection with rAAV vectors.

[0123] sequence

[0124] In some embodiments, the expression cassette encoding one or more gene products (e.g., the first, second, and / or third gene product) comprises or consists of (or encodes) a sequence set forth in any one of SEQ ID NOs: 1-62. In some embodiments, the gene product comprises or consists of (or encodes) a portion (e.g., a fragment) of any one of SEQ ID NOs: 1-62. In some embodiments, the "T" nucleotides in the following sequences are replaced by "U" nucleotides, for example, in the case of RNA molecules.

[0125] The skilled person will recognize that "part" of the above sequence can be a sequence of the expression cassette lacking the plasmid backbone (e.g., replication origin sequence, selection marker sequence, etc.) (e.g., sequences encoding ITRs, interfering RNA, coding sequences, regulatory sequences, etc.). Sequence Listing <110> Prevail Therapeutics, Inc. <120> Gene therapy for neurodegenerative diseases <130> P1094.70005WO00 <140> Not yet assigned <141> 2018-10-23 <150> 62 / 742723 <151> 2018-10-08 <150> 62 / 575795 <151> 2017-10-23 <160> 62 <170> PatentIn version 3.5 <210> 1 <211> 10953 <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotides <400> 1 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgggcgacc aaaggtcgcc 60 cgacgcccgg gctttgcccg ggcggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgctag ctctgggtat ttaagcccga gtgagcacgc 180 agggtctcca ttttgaagcg ggaggttacg cgttcgtcga ctactagtgg gtaccagagc 240 tccctaggtt ctagaaccgg tgacgtctcc catggtgaag cttggatctg aattcggtac 300 cctagttatt aatagtaatc aattacgggg tcattagttc atagcccata tatggagttc 360 cgcgttacat aacttacggt aaatggcccg cctggctgac cgcccaacga cccccgccca 420 ttgacgtcaa taatgacgta tgttcccata gtaacgccaa tagggacttt ccattgacgt 480 caatgggtgg actatttacg gtaaactgcc cacttggcag tacatcaagt gtatcatatg 540 ccaagtacgc cccctattga cgtcaatgac ggtaaatggc ccgcctggca ttatgcccag 600 tacatgacct tatgggactt tcctacttgg cagtacatct acgtattagt catcgctatt 660 accatggtcg aggtgagccc cacgttctgc ttcactctcc ccatctcccc cccctcccca 720 cccccaattt tgtatttatt tattttttaa ttattttgtg cagcgatggg ggcggggggg 780 ggggggggc gcgcgccagg cggggcgggg cggggcgagg ggcggggcgg ggcgaggcgg 840 agaggtgcgg cggcagccaa tcagagcggc gcgctccgaa agtttccttt tatggcgagg 900 cggcggcgg ggcggcccta taaaaagcga agcgcgcgg gggcgggagt cgctgcgacg 960 ctgccttcgc cccgtgcccc gctccgccgc cgcctcgcgc cgcccgcccc ggctctgact 1020 gaccgcgtta ctcccacagg tgagcgggcg ggacggccct tctcctccgg gctgtaatta 1080 gcgcttggtt taatgacggc ttgttggagg cttgctgaag gctgtatgct gttgtcgggg 1140 ccggtttcgg ggccttagtg aagccacaga tgtacggccc cgaaaccggc cccaggacac 1200 aaggcctgtt actagcactc acatggaaca aatggccacc gtgggaggat gacaagtgat 1260 atcacaaggt cccagggctg gggtcagaaa ttctctcccg agggaatgaa gccacaggag 1320 ccaagagcag gaggaccaag gccctggcga aggccgtggc ctcgttcaag taaaagatcc 1380 tagtacagtg caggtcccaa tgtgtactag gatcttttac ttgaacgggg acgccggcat 1440 ccgggctcag gacccccctc tctgccagag gcaccaacac cagagttcac aaatcagtct 1500 cctgcccttt gcatgtagca aatttctgtg gctgcgtgaa agccttgagg ggctccggga 1560 gctagagcct ctgctaacca tgttcatgcc ttcttctttt tcctacagct cctgggcaac 1620 gtgctggtta ttgtgctgtc tcatcatttt ggcaaagaat tcctcgaaga tccgaaggga 1680 aagtcttcca cgactgtggg atccgttcga agatatcacc ggttgagcca ccatgagcac 1740 cctgtgcccc ccccccagcc ccgccgtggc caagaccgag atcgccctga gcggcaagag 1800 ccccctgctg gccgccacct tcgcctactg ggacaacatc ctgggccccc gcgtgcgcca 1860 catctgggcc cccaagaccg agcaggtgct gctgagcgac ggcgagatca ccttcctggc 1920 caaccacacc ctgaacggcg agatcctgcg caacgccgag agcggcgcca tcgacgtgaa 1980 gttcttcgtg ctgagcgaga agggcgtgat catcgtgagc ctgatcttcg acggcaactg 2040 gaacggcgac cgcagcacct acggcctgag catcatcctg ccccagaccg agctgagctt 2100 ctacctgccc ctgcaccgcg tgtgcgtgga ccgcctgacc cacatcatcc gcaagggccg 2160 catctggatg cacaaggagc gccaggagaa cgtgcagaag atcatcctgg agggcaccga 2220 gcgcatggag gaccagggcc agagcatcat ccccatgctg accggcgagg tgatccccgt 2280 gatggagctg ctgagcagca tgaagagcca cagcgtgccc gaggagatcg acatcgccga 2340 caccgtgctg aacgacgacg acatcggcga cagctgccac gagggcttcc tgctgaacgc 2400 catcagcagc cacctgcaga cctgcggctg cagcgtggtg gtgggcagca gcgccgagaa 2460 ggtgaacaag atcgtgcgca ccctgtgcct gttcctgacc cccgccgagc gcaagtgcag 2520 ccgcctgtgc gaggccgaga gcagcttcaa gtacgagagc ggcctgttcg tgcagggcct 2580 gctgaaggac agcaccggca gcttcgtgct gcccttccgc caggtgatgt acgcccccta 2640 ccccaccacc cacatcgacg tggacgtgaa caccgtgaag cagatgcccc cctgccacga 2700 gcacatctac aaccagcgcc gctacatgcg cagcgagctg accgccttct ggcgcgccac 2760 cagcgaggag gacatggccc aggacaccat catctacacc gacgagagct tcacccccga 2820 cctgaacatc ttccaggacg tgctgcaccg cgacaccctg gtgaaggcct tcctggacca 2880 ggtgttccag ctgaagcccg gcctgagcct gcgcagcacc ttcctggccc agttcctgct 2940 ggtgctgcac cgcaaggccc tgaccctgat caagtacatc gaggacgaca cccagaaggg 3000 caagaagccc ttcaagagcc tgcgcaacct gaagatcgac ctggacctga ccgccgaggg 3060 cgacctgaac atcatcatgg ccctggccga gaagatcaag cccggcctgc acagcttcat 3120 cttcggccgc cccttctaca ccagcgtgca ggagcgcgac gtgctgatga ccttctaatg 3180 acaattgtta attaagttta aaccctcgag gccgcaagct tatcgataat caacctctgg 3240 attacaaaat ttgtgaaaga ttgactggta ttcttaacta tgttgctcct tttacgctat 3300 gtggatacgc tgctttaatg cctttgtatc atgctattgc ttcccgtatg gctttcattt 3360 tctcctcctt gtataaatcc tggttgctgt ctctttatga ggagttgtgg cccgttgtca 3420 ggcaacgtgg cgtggtgtgc actgtgtttg ctgacgcaac ccccactggt tggggcattg 3480 ccaccacctg tcagctcctt tccgggactt tcgctttccc cctccctatt gccacggcgg 3540 aactcatcgc cgcctgcctt gcccgctgct ggacaggggc tcggctgttg ggcactgaca 3600 attccgtggt gttgtcgggg aaatcatcgt cctttccttg gctgctcgcc tgtgttgcca 3660 cctggattct gcgcgggacg tccttctgct acgtcccttc ggccctcaat ccagcggacc 3720 ttccttcccg cggcctgctg ccggctctgc ggcctcttcc gcgtcttcgc cttcgccctc 3780 agacgagtcg gatctccctt tgggccgcct ccccgcatcg ataccgtcga ctagagctcg 3840 ctgatcagcc tcgactgtgc cttctagttg ccagccatct gttgtttgcc cctcccccgt 3900 gccttccttg accctggaag gtgccactcc cactgtcctt tcctaataa atgaggaaat tgcatcgcat tgtctgagta ggtgtcattc tattctgggg ggtggggtgg ggcaggacag 4020 4080. caagggggag gattgggag acaatagcag gcatgctggg gagagatcca cgataacaaa cagctttttt ggggtgaaca tattgactga attccctgca ggttggccac tccctctctg cgcgctcgct cgctcactga ggccgcccgg gcaaagcccg ggcgtcggggc gaccttttggt 4200. cgcccggcct cagtgagcga gcgagcgcgc agagagggag tggccaactc catcactagg 4260. ggttcctgcg gccgctcgta cggtctcgag gattcctgc aggataactt gccaacctca 4320. ttctaaaatg father cccaaaagac grandfather atattcttgt grandfather gggaaagaat gttccactaa atatcaagat ttagagcaaa gcatgagatg tgtggggata 4440 gacagtgagg ctgataaaat agagtagagc tcagaaacag acccattgat atatgtaagt 4500 gacctatgaa aaaaatatgg cattttacaa tgggaaaatg atggtctttt tcttttttag 4560 aaaaacaggg aaatatattt atatgtaaaa aataaaaggg aacccatatg tcataccata 4620 cacacaaaaa aattccagtg aattataagt ctaaatggag aaggcaaaac tttaaatctt 4680 ttagaaaata atatagaagc atgcagacca gcctggccaa catgaatgaaa ccctctctac 4740 4800 agacttcttt ggccaaaatt aggctcttaaa tgcaaggaga tagtgcatca tgcctggctg 4860 4920 4980 ttaaaaaagc agatttttgc cagcagaact attcattcag aggtaggaaa cttagaatag 5040 atgatgtcac tgattagcat ggcttcccca tctccacagc tgcttcccac ccaggttgcc 5100 cacagttgag tttgtccagt gctcagggct gcccactctc agtaagaagc cccacaccag 5160 cccctctcca aatatgttgg ctgttccttc cattaaagtg accccacttt agagcagcaa 5220 gtggatttct gtttcttaca gttcaggaag gaggagtcag ctgtgagaac ctggagcctg 5280 agatgcttct aagtcccact gctactgggg tcagggaagc cagactccag catcagcagt 5340 caggagcact aagcccttgc caacatcctg tttctcagag aaactgcttc cattataatg 5400 gttgtccttt tttaagctat caagccaaac aaccagtgtc taccattatt ctcatcacct 5460 gaagccaagg gttctagcaa aagtcaagct gtcttgtaat ggttgatgtg cctccagctt 5520 ctgtcttcag tcactccact cttagcctgc tctgaatcaa ctctgaccac agttccctgg 5580 agcccctgcc acctgctgcc cctgccacct tctccatctg cagtgctgtg cagccttctg 5640 cactcttgca gagctaatag gtggagactt gaaggaagag gaggaaagtt tctcataata 5700 gccttgctgc aagctcaaat gggaggtggg cactgtgccc aggagccttg gagcaaaggc 5760 tgtgcccaac ctctgactgc atccaggttt ggtcttgaca gagataagaa gccctggctt 5820 ttggagccaa aatctaggtc agacttaggc aggattctca aagtttatca gcagaacatg 5880 aggcaagaga ccctttctgc tccagcttct tcaggctcaa ccttcatcag aatagataga 5940 aagagaggct gtgagggttc taaaacaga agcaaatctg actcagagaa taaacaacct 6000 cctagtaac tacagcttag agagagcatc tggtggtgag tgtgctcagt gtcctactca 6060 actgtctggt atcagccctc atgaggactt ctcttctttc cctcatagac ctccatctct 6120 gttttcctta gcctgcagaa atctggatgg ctattcacag aatgcctgtg ctttcagagt 6180 tgcattttt ctctggtatt ctggttcaag catttgaagg taggaaaggt tctccaagtg 6240 caagaaagcc agccctgagc ctcaactgcc tggctagtgt ggtcagtagg atgcaaaggc 6300 tgttgaatgc caaaggcca aactttaacc tgtgtaccac aagcctagca gcagaggcag 6360 ctctgctcac tggaactctc tgtcttcttt ctcctgagcc ttttcttttc ctgagttttc 6420 tagctctcct caaccttacc tctgccctac ccaggacaaa cccaagagcc actgtttctg 6480 tgatgtcctc tccagcccta attaggcatc atgacttcag cctgaccttc catgctcaga 6540 agcagtgcta atccacttca gatgagctgc tctatgcaac acaggcagag cctacaacc 6600 ttgcaccag agccctccac atatcagtgt ttgttcatac tcactcac agcaatgtg 6660 actgctgaga ttaagatttt acacagatg gtctgtaatt tcacagttag ttttaccca 6720 ttaggtag aagattagc atattcccc ttaaacatga atgaatctta gattttttta 6780 taaatagttt tggagtaaa gagagaca tcaggagac aaggatagc ctgagagac 6840 aaacagaaca agaagagtc tggaaataca caggatgttc tggcctcct caagcaagt 6900 gcaagcagat agtaccagca gccccaggct atcagagccc agtgaagaga agtaccatga 6960 aagccacagc tctaccacc ctgttccaga gtgacagaca gtccccaga caagccagcc 7020 tgagccagag agagactgc agagaaagt ttctaattta ggttctgtta gattcagaca 7080 agtgcaggtc atcctctctc cacagctact cacctcca gcctaacaa gcctgcagtc 7140 cacactccaa ccctgtgtc tcaccta gcctccca acatcctgct ctctgaccat 7200 cttctgcatc tctcatctca ccatctccca ctgtctacag cctacttg caactaccat 7260 ctcattttct gacatcctgt ctacatcttc tgccatactc tgccatctac cataccacct 7320 cttaccatct accacaccat cttttatctc catccctctc agaagcctcc aagctgaatc 7380 ctgctttatg tgttcatctc agcccctgca tggaaagctg accccagagg cagaactatt 7440 cccagagagc ttggccaaga aaaacaaaac taccagcctg gccaggctca ggagtagtaa 7500 gctgcagtgt ctgttgtgtt ctagcttcaa cagctgcagg agttccactc tcaaatgctc 7560 cacatttctc acatcctcct gattctggtc actacccatc ttcaaagaac agaatatctc 7620 acatcagcat actgtgaagg actagtcatg ggtgcagctg ctcagagctg caaagtcatt 7680 ctggatggtg gagagcttac aaacatttca tgatgctccc cccgctctga tggctggagc 7740 ccaatcccta cacagactcc tgctgtatgt gttttccttt cactctgagc cacagccaga 7800 gggcaggcat tcagtctcct cttcaggctg gggctggggc actgagaact cacccaacac 7860 cttgctctca ctccttctgc aaaacaagaa agagctttgt gctgcagtag ccatgaagaa 7920 tgaaaggaag gctttaacta aaaaatgtca gagattattt tcaacccctt actgtggatc 7980 accagcaagg aggaacaca acacagagac atttttccc ctcaattat caaagaatc 8040 actgcatttg ttaagag caacgaatc aggaagcaga gtttgaca tatcagagt 8100 taggaatctg catcagagac aaatgcagtc atggttgtt gctgcatacc agccctaatc 8160 attagaagcc tcatggactt siacatcat tccctgac agatgctct agcctactc 8220 catgagataa aaaatctg cctttcagag ccaagaga gtccaccagc ttctctcag 8280 tgtgaacaag agctccagtc aggttagtca gtccagtgca gtagaggaga ccagtctgca 8340 tcctctaatt ttcaaggca agagatttg tttaccctgg acaccaggca agagaggt 8400 cacagagctc ttagatatgc agtcctcatg agtgaggaga ctaaagcgca tgccatcaag 8460 acttcagtgt agagaaaacc tccaaaaag cctcctcact acttctggaa tagctcagag 8520 gccgaggcgg cctcggccctc tgcataaata aaaaaatta gtcagccatg gggcggagaa 8580 tgggcggac tgggcggagt tgggcggg tggggcgg tggggcgg tgggtggtt 8640 gctgactaat tgagatgcat gcttgcata cttctgcctg ctggggagcc tggggacttt 8700 ccacacctgg ttgctgacta attgagatgc atgctttgca tacttctgcc tgctggggag 8760 cctggggact ttccacaccc taactgacac acattccaca gctgcattaa tgaatcggcc 8820 aacgcgcggg gagaggcggt ttgcgtattg ggcgctcttc cgcttcctcg ctcactgact 8880 cgctgcgctc ggtcgttcgg ctgcggcgag cggtatcagc tcactcaaag gcggtaatac 8940 ggttatccac agaatcaggg gataacgcag gaaagaacat gtgagcaaaa ggccagcaaa 9000 aggccaggaa ccgtaaaaag gccgcgttgc tggcgttttt ccataggctc cgcccccctg 9060 acgagcatca caaaaatcga cgctcaagtc agaggtggcg aaacccgaca ggactataaa 9120 gataccaggc gtttccccct ggaagctccc tcgtgcgctc tcctgttccg accctgccgc 9180 ttaccggata cctgtccgcc tttctccctt cgggaagcgt ggcgctttct catagctcac 9240 gctgtaggta tctcagttcg gtgtaggtcg ttcgctccaa gctgggctgt gtgcacgaac 9300 cccccgttca gcccgaccgc tgcgccttat ccggtaacta tcgtcttgag tccaacccgg 9360 taagacacga cttatcgcca ctggcagcag ccactggtaa caggattagc agagcgaggt 9420 atgtaggcgg tgctacagag ttcttgaagt ggtggcctaa ctacggctac actagaagaa 9480 fttttgg tatctgcgct ctgctgaagc cagttacctt cggaaaaaga gttggtagct 9540 cttgatccgg caaacaaacc accgctggta gcggtggttt ttttgtttgc aagcagcaga 9600 ttacgcgcag aaaaaaaagga tctcaagaag atcctttgat cttttctacg gggtctgacg 9660 ctcagtggaa cgaaaactca cgttaaggga ttttggtcat gagattatca aaaaggatct 9720 tcacctagat ccttttaaat taaaaatgaa gttttaaatc aatctaaagt atatatgagt 9780 aaacttggtc tgacagttac caatgcttaa tcagtgaggc acctatctca gcgatctgtc 9840 tatttcgttc atccatagtt gcctgactcc tgcaaaccac gttgtgtctc aaaatctctg 9900 atgttacatt gcacaagata aaaatatatc atcatgaaca ataaaactgt ctgcttacat 9960 aaacagtaat acaaggggtg ttatgagcca tattcaacgg gaaacgtctt gctcgaggcc 10020 gcgattaaat tccaacatgg atgctgattt atatgggtat aaatgggctc gcgataatgt 10080 cgggcaatca ggtgcgacaa tctatcgatt gtatgggaag cccgatgcgc cagagttgtt 10140 tctgaaacat ggcaaaggta gcgttgccaa tgatgttaca gatgagatgg tcagactaaa 10200 ctggctgacg gaattatgc ctcttccgac catcaagcat tttatccgta ctcctgatga 10260 tgcatggtta ctcaccactg cgatccccgg gaaaacagca ttccaggtat tagaagaata 10320 tcctgattca ggtgaaaata ttgttgatgc gctggcagtg ttcctgcgcc ggttgcattc 10380 gattcctgtt tgtaattgtc cttttaacag cgatcgcgta tttcgtctcg ctcaggcgca 10440 atcacgaatg aataacggtt tggttgatgc gagtgattttt gatgacgagc gtaatggctg 10500 gcctgttgaa caagtctgga aagaaatgca taagcttttg ccattctcac cggattcagt 10560 cgtcactcat ggtgatttct cacttgataa ccttattttt gacgagggga aattaatagg 10620 ttgtattgat gttggacgag tcggaatcgc agaccgatac caggatcttg ccatcctatg 10680 gaactgcctc ggtgagtttt ctccttcatt acagaaacgg cttttcaaa aatatggtat 10740 tgataatcct gatatgaata aattgcagtt tcatttgatg ctcgatgagt ttttctaagg 10800 gcggcctgcc accataccca cgccgaaaca agcgctcatg agcccgaagt ggcgagcccg 10860 atcttcccca tcggtgatgt cggcgatata ggcgccagca accgcacctg tggcgccggt 10920 gatgagggcg cgccaagtcg acgtccggca gtc 10953 <210> 2 <211> 10848 <212> DNA <213> Artificial Sequence <220> <223> Synthetic polynucleotide <400> 2 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgggcgacc aaaggtcgcc 60 cgacgcccgg gctttgcccg ggcggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgctag ctctgggtat ttaagcccga gtgagcacgc 180 agggtctcca ttttgaagcg ggaggttacg cgttcgtcga ctactagtgg gtaccagagc 240 tccctaggtt ctagaaccgg tgacgtctcc catggtgaag cttggatctg aattcggtac 300 cctagttatt aatagtaatc aattacgggg tcattagttc atagcccata tatggagttc 360 cgcgttacat aacttacggt aaatggcccg cctggctgac cgcccaacga cccccgccca 420 ttgacgtcaa taatgacgta tgttcccata gtaacgccaa tagggacttt ccattgacgt 480 caatgggtgg actatttacg gtaaactgcc cacttggcag tacatcaagt gtatcatatg 540 ccaagtacgc cccctattga cgtcaatgac ggtaaatggc ccgcctggca ttatgcccag 600 tacatgacct tatgggactt tcctacttgg fotcatct acgtattagt catcgctatt 660 accatggtcg aggtgagccc cacgttctgc ttcactctcc ccatctcccc cccctcccca 720 cccccaattt tgtatttatt tattttttaa ttattttgtg cagcgatggg ggcgggggg 780 ggggggggc gcgcgccagg cggggcgggg cggggcgagg ggcggggcgg ggcgaggcgg 840 agaggtgcgg cggcagccaa tcagagcggc gcgctccgaa agtttccttt tatggcgagg 900 cggcggcgg ggcggcccta taaaaagcga agcgcgcgg gggcgggagt cgctgcgacg 960 ctgccttcgc cccgtgcccc gctccgccgc cgcctcgcgc cgcccgcccc ggctctgact 1020 gaccgcgtta ctcccacagg tgagcgggcg ggacggccct tctcctccgg gctgtaatta 1080 gcgcttggtt taatgacggc ttgttggagg cttgctgaag gctgtatgct gttgtcgggg 1140 ccggtttcgg ggccttagtg aagccacaga tgtacggccc cgaaaccggc cccaggacac 1200 aaggcctgtt actagcactc acatggaaca aatggccacc gtgggaggat gacaatttct 1260 gtggctgcgt gaaagccttg aggggctccg ggagctagag cctctgctaa ccatgttcat 1320 gccttcttct ttttcctaca gctcctgggc aacgtgctgg ttattgtgct gtctcatcat 1380 tttggcaaag aattcctcga agatccgaag ggaaagtctt ccacgactgt gggatccgtt 1440 cgaagatatc accggttgag ccaccatgga attcagcagc cccagcagag aggaatgccc 1500 caagcctctg agccgggtgt caatcatggc cggatctctg acaggactgc tgctgcttca 1560 ggccgtgtct tgggcttctg gcgctagacc ttgcatcccc aagagcttcg gctacagcag 1620 cgtcgtgtgc gtgtgcaatg ccacctactg cgacagcttc gaccctccta cctttcctgc 1680 tctgggcacc ttcagcagat acgagagcac cagatccggc agacggatgg aactgagcat 1740 gggacccatc caggccaatc acacaggcac tggcctgctg ctgacactgc agcctgagca 1800 gaaattccag aaagtgaaag gcttcggcgg agccatgaca gatgccgccg ctctgaatat 1860 cctggctctg tctccaccag ctcagaacct gctgctcaag agctacttca gcgaggaagg 1920 catcggctac aacatcatca gagtgcccat ggccagctgc gacttcagca tcaggaccta 1980 cacctacgcc gacacacccg acgatttcca gctgcacaac ttcagcctgc ctgaagagga 2040 caccaagctg aagatccctc tgatccacag agccctgcag ctggcacaaa gacccgtgtc 2100 actgctggcc tctccatgga catctcccac ctggctgaaa acaaatggcg ccgtgaatgg 2160 caagggcagc ctgaaaggcc aacctggcga catctaccac cagacctggg ccagatactt 2220 cgtgaagttc ctggacgcct atgccgagca caagctgcag ttttgggccg tgacagccga 2280 gaacgaacct tctgctggac tgctgagcgg ctaccccttt cagtgcctgg gctttacacc 2340 cgagcaccag cgggacttta tcgcccgtga tctgggaccc acactggcca atagcaccca 2400 ccataatgtg cggctgctga tgctggacga ccagagactg cttctgcccc actgggctaa 2460 agtggtgctg acagatcctg aggccgccaa atacgtgcac ggaatcgccg tgcactggta 2520 tctggacttt ctggcccctg ccaaggccac actgggagag acacacagac tgttccccaa 2580 caccatgctg ttcgccagcg aagcctgtgt gggcagcaag ttttgggaac agagcgtgcg 2640 gctcggcagc tgggatagag gcatgcagta cagccacagc atcatcacca acctgctgta 2700 ccacgtcgtc ggctggaccg actggaatct ggccctgaat cctgaaggcg gccctaactg 2760 ggtccgaaac ttcgtggaca gccccatcat cgtggacatc accaaggaca ccttctacaa 2820 gcagcccatg ttctaccacc tgggacactt cagcaagttc atccccgagg gctctcagcg 2880 cgttggactg gtggcttccc agaagaacga tctggacgcc gtggctctga tgcaccctga 2940 tggatctgct gtggtggtgg tcctgaaccg cagcagcaaa gatgtgcccc tgaccatcaa 3000 ggatcccgcc gtgggattcc tggaaacaat cagccctggc tactccatcc acacctacct 3060 gtggcgtaga cagtgacaat tgttaattaa gtttaaaccc tcgaggccgc aagcttatcg 3120 ataatcaacc tctggattac aaaatttgtg aaagattgac tggtattctt aactatgttg 3180 ctccttttac gctatgtgga tacgctgctt taatgccttt gtatcatgct attgcttccc 3240 gtatggcttt cattttctcc tccttgtata aatcctggtt gctgtctctt tatgaggagt 3300 tgtggcccgt tgtcaggcaa cgtggcgtgg tgtgcactgt gtttgctgac gcaaccccca 3360 ctggttgggg cattgccacc acctgtcagc tcctttccgg gactttcgct ttccccctcc 3420 ctattgccac ggcggaactc atcgccgcct gccttgcccg ctgctggaca ggggctcggc 3480 tgttgggcac tgacaattcc gtggtgttgt cggggaaatc atcgtccttt ccttggctgc 3540 tcgcctgtgt tgccacctgg attctgcgcg ggacgtcctt ctgctacgtc ccttcggccc 3600 tcaatccagc ggaccttcct tcccgcggcc tgctgccggc tctgcggcct cttccgcgtc 3660 ttcgccttcg ccctcagacg agtcggatct ccctttgggc cgcctccccg catcgatacc 3720 gtcgactaga gctcgctgat cagcctcgac tgtgccttct agttgccagc catctgttgt 3780 ttgcccctcc cccgtgcctt ccttgaccct ggaaggtgcc actcccactg tcctttccta 3840 ataaaatgag gaaattgcat cgcattgtct gagtaggtgt cattctattc tggggggtgg 3900 ggtggggcag gacagcaagg gggaggattg ggaagacaat agcaggcatg ctggggagag 3960 atccacgata acaaacagct tttttggggt gaacatattg actgaattcc ctgcaggttg 4020 gccactccct ctctgcgcgc tcgctcgctc actgaggccg cccgggcaaa gcccgggcgt 4080 cggcgacct ttggtcgccc ggcctcagtg agcgagcgag cgcgcagaga gggagtggcc 4140 aactccatca ctaggggttc ctgcggccgc tcgtacggtc tcgaggaatt cctgcaggat 4200 aacttgccaa cctcattcta aaatgtatat agaagcccaa aagacaataa CAaaatatt 4260 cttgtagaac aaatgggaa agaatgttcc actaaatac aagatttaga gcaagcatg 4320 agatgtgtgg ggatagacag tgaggctgat aaatagagt agagctcaga aacagaccca 4380 ttgatatatg taagtgacct atgaaaaaa tatggcattt tacaatggga aaatgatggt 4440 ctttttcttt tttagaaaaa tatttatag taaaaaata aagggaaccc 4500 atatgtcata ccatacacac aaaaaaattc cagtgaatta taagtctaaa tggaaggc 4560 aaaactttaa atctttaga aaatatata gagcatgca gaccagcctg gccacatga 4620 tgaaaccctc tctactaata ataaatcag tagactact caggactact tgagtggga 4680 agtccttttc tatgagact tctttggcca aaattaggct ctaaatgcaa ggagatagtg 4740 catcatgcct ggctgcactt actgataaat catgttatca ccatctttaa ccaatgcac 4800 aggaacaagt tatggtactg atgtgctgga ttgagaagga gctctacttc cttgacagga 4860 cacatttgta tcaacttaaa aaagcagatt tttgccagca gaactattca ttcagaggta 4920 ggaaacttag aatagatgat gtcactgatt agcatggctt ccccatctcc acagctgctt 4980 cccacccagg ttgcccacag ttgagtttgt ccagtgctca gggctgccca ctctcagtaa 5040 gaagccccac accagcccct ctccaaatat gttggctgtt ccttccatta aagtgacccc 5100 actttagagc agcaagtgga tttctgtttc ttacagttca ggaaggagga gtcagctgtg 5160 agaacctgga gcctgagatg cttctaagtc ccactgctac tggggtcagg gaagccagac 5220 tccagcatca gcagtcagga gcactaagcc cttgccaaca tcctgtttct cagagaaact 5280 gcttccatta taatggttgt ccttttttaa gctatcaagc caaacaacca gtgtctacca 5340 ttattctcat cacctgaagc caagggttct agcaaaagtc aagctgtctt gtaatggttg 5400 atgtgcctcc agcttctgtc ttcagtcact ccactcttag cctgctctga atcaactctg 5460 accacagttc cctggagccc ctgccacctg ctgcccctgc caccttctcc atctgcagtg 5520 ctgtgcagcc ttctgcactc ttgcagagct aataggtgga gacttgaagg aagaggagga 5580 aagtttctca tatagcctt gctgcaagct caaatgggag gtgggcactg tgcccaggag 5640 ccttggagca aaggctgtgc ccaacctctg actgcatcca ggtttggtct tgacagagat 5700 aagaagccct ggcttttgga gccaaaatct aggtcagact taggcaggat tctcaaagtt 5760 tatcagcaga acatgaggca gaagaccct tctgctccag cttcttcagg ctcaaccttc 5820 atcagaatag atagaaagag aggctgtgag ggttcttaaa acagaagcaa atctgactca 5880 gagaataaac aacctcctag taaactacag cttagacaga gcatctggtg gtgagtgtgc 5940 tcagtgtcct actcaactgt ctggtatcag ccctcatgag gacttctctt ctttccctca 6000 tagacctcca tctctgtttt ccttagcctg cagaaatctg gatggctatt cacagaatgc 6060 ctgtgctttc agagttgcat ttttctctg gtattctggt tcaagcattt gaaggtagga 6120 aaggttctcc aagtgcaaga aagccagccc tgagcctcaa ctgcctggct agtgtggtca 6180 gtaggatgca aaggctgttg aatgccacaa ggccaaactt taacctgtgt accacaagcc 6240 tagcagcaga ggcagctctg ctcactggaa ctctctgtct tcttctcct gagccttttc 6300 tttcctgag ttttctagct ctcctcaacc ttaccctgc cctacccagg acaaacccaa 6360 gagccactgt ttctgtgatg tcctctccag ccctattag gcatcatgac ttcagcctga 6420 ccttccatgc tcagaagcag tgctaatcca cttcagatga gctgcttat gcaacacagg 6480 cagagcctac aaacctttgc accagagccc tccacatatc agtgttttgtt catactcact 6540 tcacagcaa atgtgactgc tgagattaag attttacaca agatggtctg taatttcaca 6600 gttagtttta tcccattagg tatgaagaa ttagcataat tccccttaaa catgaatgaa 6660 tcttagattt tttaataat agttttggaa gtaagacag agacatcagg agcacaagga 6720 atagcctgag aggacaaca gacagaaa gagtctggaa atacacagga tgttcttggc 6780 ctcctcaaag caagtgcaag cagatagtac cagcagcccc aggctcag agcccagtga 6840 agagaagtac catgaaagcc acagctctaa ccaccctgtt ccagagtgac agacagtccc 6900 cagacaagc cagcctgagc cagagagaga actgcaagg aaagttttcta atttaggttc 6960 tgttagattc agacaagtgc agttcactcct ctctccacag ctactcacct ctccagccta 7020 aaagcctg cagtcacac tcccacctg gtgtctcacc tcctagcctc tcccacac 7080 ctgctctg accatcttct gcatctca tccaccatc tcccactgtc tacagcctac 7140 tcttgcact accatctcat tttctgacat cctgtctaca tcttctgcca tactctgcca 7200 tctaccatac cacctcttac catctaccac accatctttt atctccatcc ctctcagaag 7260 cctccaagct gatcctgct ttatgtgttc atctcagccc ctgcatggaa agctgacccc 7320 agaggcagaa ctattcccag agagcttggc caaaaaac aaactacca gcctggccag 7380 gctcaggagt agtaagctgc agtgtctgtt gtgttcttagc ttcacagct gcaggagttc 7440 cactctcaa tgctcacat tctcacatc cactctcattc tgtcatc cactctcaa 7500 agaacagaat atctcacatc agcatactgt gaaggactag tcatgggtgc agctgctcag 7560 agctgcaaag tcattctgga tggtggag cttacaaca ttcatgatg ctcccccgc 7620 tctgatggct ggagcccaat ccctacacag actcctgctg tatgtgttt ccttcactc 7680 tgagccacag ccagagggca ggcattcagt ctcctcttca ggctggggct ggggcactga 7740 gaactcaccc aacaccttgc tctcactcct tctgcaaaac aagaaagagc tttgtgctgc 7800 agtagccatg aagaatgaaa ggaaggcttt aactaaaaaa tgtcagagat tattttcaac 7860 cccttactgt ggatcaccag caaggaggaa acacaacaca gagacatttt ttcccctcaa 7920 attatcaaaa gaatcactgc atttgttaaa gagagcaact gaatcaggaa gcagagtttt 7980 gaacatatca gaagttagga atctgcatca gagacaaatg cagtcatggt tgtttgctgc 8040 ataccagccc taatcattag aagcctcatg gacttcaaac atcattccct ctgacaagat 8100 gctctagcct aactccatga gataaaataa atctgccttt cagagccaaa gaagagtcca 8160 ccagcttctt ctcagtgtga acaagagctc cagtcaggtt agtcagtcca gtgcagtaga 8220 ggagaccagt ctgcatcctc taattttcaa aggcaagaag atttgtttac cctggacacc 8280 aggcacaagt gaggtcacag agctcttaga tatgcagtcc tcatgagtga ggagactaaa 8340 gcgcatgcca tcaagacttc agtgtagaga aaacctccaa aaaagcctcc tcactacttc 8400 tggaatagct cagaggccga ggcggcctcg gcctctgcat aaataaaaaa aattagtcag 8460 ccatggggcg gagaatgggc ggaactgggc ggagttaggg gcgggatggg cggagttagg 8520 ggcgggacta tggttgctga ctaattgaga tgcatgcttt gcatacttct gcctgctggg 8580 gagcctgggg actttccaca cctggttgct gactaattga gatgcatgct ttgcatactt 8640 ctgcctgctg gggagcctgg ggactttcca caccctaact gacacacatt ccacagctgc 8700 attaatgaat cggccaacgc gcggggagag gcggtttgcg tattgggcgc tcttccgctt 8760 cctcgctcac tgactcgctg cgctcggtcg ttcggctgcg gcgagcggta tcagctcact 8820 caaaggcggt aatacggtta tccacagaat caggggataa cgcaggaaag aacatgtgag 8880 caaaaggcca gcaaaaggcc aggaaccgta aaaaggccgc gttgctggcg tttttccata 8940 ggctccgccc ccctgacgag catcacaaaa atcgacgctc aagtcagagg tggcgaaacc 9000 cgacaggact ataaagatac caggcgtttc cccctggaag ctccctcgtg cgctctcctg 9060 ttccgaccct gccgcttacc ggatacctgt ccgcctttct cccttcggga agcgtggcgc 9120 tttctcatag ctcacgctgt aggtatctca gttcggtgta ggtcgttcgc tccaagctgg 9180 gctgtgtgca cgaacccccc gttcagcccg accgctgcgc cttatccggt aactatcgtc 9240 ttgagtccaa cccggtaaga cacgacttat cgccactggc agcagccact ggtaacagga 9300 ttagcagagc gaggtatgta ggcggtgcta cagagttctt gaagtggtgg cctaactacg 9360 gctacactag aagaacagta tttggtatct gcgctctgct gaagccagtt accttcggaa 9420 aaagagttgg tagctcttga tccggcaaac aaaccaccgc tggtagcggt ggtttttttg 9480 tttgcaagca gcagattacg cgcagaaaaa aaggatctca agaagatcct ttgatctttt 9540 ctacggggtc tgacgctcag tggaacgaaa actcacgtta agggattttg gtcatgagat 9600 tatcaaaaag gatcttcacc tagatccttt taaattaaaa atgaagtttt aaatcaatct 9660 aaagtatata tgagtaaact tggtctgaca gttaccaatg cttaatcagt gaggcaccta 9720 tctcagcgat ctgtctattt cgttcatcca tagttgcctg actcctgcaa accacgttgt 9780 gtctcaaaat ctctgatgtt acattgcaca agataaaaat atatcatcat gaacaataaa 9840 actgtctgct tacataaca gtaatacaag gggtgttatg agccatattc aacgggaac gtcttgctcg aggccgcgat taattccaa catggatgct gatttatatg ggtataaatg ggctcgcgat aatgtcgggc aatcaggtgc gacaatctat cgattgtatg ggaagcccga tgcgccagag ttgtttctga aacatggcaa aggtagcgtt gccaatgatg ttacagatga gatggtcaga ctaaactggc tgacggaatt tatgcctctt ccgaccatca agcattttat ccgtactcct gatgatgcat ggttactcac cactgcgatc cccgggaaaa cagcattcca ggtattagaa gaatatcctg attcaggtga aaatattgtt gatgcgctgg cagtgttcct gcgccggttg cattcgattc ctgtttgtaa ttgtcctttt aacagcgatc gcgtatttcg tctcgctcag gcgcaatcac gatgaata cggtttggtt gatgcgagtg attttgatga cgagcgtaat ggctggcctg ttgaacaagt ctggaaaga atgcataagc ttttgccatt ctcaccggat tcagtcgtca ctcatggtga tttctcactt gataacctta tttttgacga ggggaatta ataggttgta ttgatgttgg acgagtcgga atcgcagacc gataccagga tcttgccatc ctatggaact gcctcggtga gttttctcct tcattacaga aacggctttt 10620 tcaaaaatat ggtattgata atcctgatat gaataaattg cagtttcatt tgatgctcga 10680 tgagtttttc taagggcggc ctgccaccat acccacgccg aaacaagcgc tcatgagccc 10740 gaagtggcga gcccgatctt ccccatcggt gatgtcggcg atataggcgc cagcaaccgc 10800 acctgtggcg ccggtgatga gggcgcgcca agtcgacgtc cggcagtc 10848 <210> 3 <211> 1446 <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotide <400> 3 atgagcaccc tgtgcccccc ccccagcccc gccgtggcca agaccgagat cgccctgagc 60 ggcaagagcc ccctgctggc cgccaccttc gcctactggg acaacatcct gggcccccgc 120 gtgcgccaca tctgggcccc caagaccgag caggtgctgc tgagcgacgg cgagatcacc 180 ttcctggcca accacaccct gaacggcgag atcctgcgca acgccgagag cggcgccatc 240 gacgtgaagt tcttcgtgct gagcgagaag ggcgtgatca tcgtgagcct gatcttcgac 300 ggcaactgga acggcgaccg cagcacctac ggcctgagca tcatcctgcc ccagaccgag 360 ctgagcttct acctgcccct gcaccgcgtg tgcgtggacc gcctgaccca catcatccgc 420 aagggccgca tctggatgca caaggagcgc caggagaacg tgcagaagat catcctggag 480 ggcaccgagc gcatggagga ccagggccag agcatcatcc ccatgctgac cggcgaggtg 540 atccccgtga tggagctgct gagcagcatg aagagccaca gcgtgcccga ggagatcgac 600 atcgccgaca ccgtgctgaa cgacgacgac atcggcgaca gctgccacga gggcttcctg 660 ctgaacgcca tcagcagcca cctgcagacc tgcggctgca gcgtggtggt gggcagcagc 720 gccgagaagg tgaacaagat cgtgcgcacc ctgtgcctgt tcctgacccc cgccgagcgc 780 aagtgcagcc gcctgtgcga ggccgagagc agcttcaagt acgagagcgg cctgttcgtg 840 cagggcctgc tgaaggacag caccggcagc ttcgtgctgc ccttcgcca ggtgatgtac 900 gcccccctacc ccaccaccca catcgacgtg gacgtgaaca ccgtgaagca gatgcccccc 960 tgccacgagc acatctacaa ccagcgccgc tacatgcgca gcgagctgac cgccttctgg 1020 cgcgccacca gcgaggagga catggcccag gacaccatca tctacaccga cgagagcttc 1080 acccccgacc tgaacatctt ccaggacgtg ctgcaccgcg acaccctggt gaaggccttc 1140 ctggaccagg tgttccagct gaagcccggc ctgagcctgc gcagcacctt cctggcccag 1200 ttcctgctgg tgctgcaccg caaggccctg accctgatca agtacatcga ggacgacacc 1260 cagaagggca agaagccctt caagagcctg cgcaacctga agatcgacct ggacctgacc 1320 gccgagggcg acctgaacat catcatggcc ctggccgaga agatcaagcc cggcctgcac 1380 agcttcatct tcggccgccc cttctacacc agcgtgcagg agcgcgacgt gctgatgacc 1440 ttctaa 1446 <210> 4 <211> 481 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <400> 4 Met Ser Thr Leu Cys Pro Pro Pro Ser Pro Ala Val Ala Lys Thr Glu 1 5 10 15 Ile Ala Leu Ser Gly Lys Ser Pro Leu Leu Ala Ala Thr Phe Ala Tyr 20 25 30 Trp Asp Asn Ile Leu Gly Pro Arg Val Arg His Ile Trp Ala Pro Lys 35 40 45 Thr Glu Gln Val Leu Leu Ser Asp Gly Glu Ile Thr Phe Leu Ala Asn 50 55 60 His Thr Leu Asn Gly Glu Ile Leu Arg Asn Ala Glu Ser Gly Ala Ile 65 70 75 80 Asp Val Lys Phe Phe Val Leu Ser Glu Lys Gly Val Ile Ile Val Ser 85 90 95 Leu Ile Phe Asp Gly Asn Trp Asn Gly Asp Arg Ser Thr Tyr Gly Leu 100 105 110 Ser Ile Ile Leu Pro Gln Thr Glu Leu Ser Phe Tyr Leu Pro Leu His 115 120 125 Arg Val Cys Val Asp Arg Leu Thr His Ile Ile Arg Lys Gly Arg Ile 130 135 140 Trp Met His Lys Glu Arg Gln Glu Asn Val Gln Lys Ile Ile Leu Glu 145 150 155 160 Gly Thr Glu Arg Met Glu Asp Gln Gly Gln Ser Ile Ile Pro Met Leu 165 170 175 Thr Gly Glu Val Ile Pro Val Met Glu Leu Leu Ser Ser Met Lys Ser 180 185 190 His Ser Val Pro Glu Glu Ile Asp Ile Ala Asp Thr Val Leu Asn Asp 195 200 205 Asp Asp Ile Gly Asp Ser Cys His Glu Gly Phe Leu Leu Asn Ala Ile 210 215 220 Ser Ser His Leu Gln Thr Cys Gly Cys Ser Val Val Val Gly Ser Ser 225 230 235 240 Ala Glu Lys Val Asn Lys Ile Val Arg Thr Leu Cys Leu Phe Leu Thr 245 250 255 Pro Ala Glu Arg Lys Cys Ser Arg Leu Cys Glu Ala Glu Ser Ser Phe 260 265 270 Lys Tyr Glu Ser Gly Leu Phe Val Gln Gly Leu Leu Lys Asp Ser Thr 275 280 285 Gly Ser Phe Val Leu Pro Phe Arg Gln Val Met Tyr Ala Pro Tyr Pro 290 295 300 Thr Thr His Ile Asp Val Asp Val Asn Thr Val Lys Gln Met Pro Pro 305 310 315 320 Cys His Glu His Ile Tyr Asn Gln Arg Arg Tyr Met Arg Ser Glu Leu 325 330 335 Thr Ala Phe Trp Arg Ala Thr Ser Glu Glu Asp Met Ala Gln Asp Thr 340 345 350 Ile Ile Tyr Thr Asp Glu Ser Phe Thr Pro Asp Leu Asn Ile Phe Gln 355 360 365 Asp Val Leu His Arg Asp Thr Leu Val Lys Ala Phe Leu Asp Gln Val 370 375 380 Phe Gln Leu Lys Pro Gly Leu Ser Leu Arg Ser Thr Phe Leu Ala Gln 385 390 395 400 Phe Leu Leu Val Leu His Arg Lys Ala Leu Thr Leu Ile Lys Tyr Ile 405 410 415 Glu Asp Asp Thr Gln Lys Gly Lys Lys Pro Phe Lys Ser Leu Arg Asn 420 425 430 Leu Lys Ile Asp Leu Asp Leu Thr Ala Glu Gly Asp Leu Asn Ile Ile 435 440 445 Met Ala Leu Ala Glu Lys Ile Lys Pro Gly Leu His Ser Phe Ile Phe 450 455 460 Gly Arg Pro Phe Tyr Thr Ser Val Gln Glu Arg Asp Val Leu Met Thr 465 470 475 480 Phe <210> 5 <211> 10900 <212> DNA <213> Artificial Sequence <220> <223> Synthetic polynucleotide <400> 5 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgggcgacc aaaggtcgcc 60 cgacgcccgg gctttgcccg ggcggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgctag ctctgggtat ttaagcccga gtgagcacgc 180 agggtctcca ttttgaagcg ggaggttacg cgttcgtcga ctactagtgg gtaccagagc 240 tccctaggtt ctagaaccgg tgacgtcttg tcatcctccc acggtggcca tttgttccat 300 gtgagtgcta gtaacaggcc ttgtgtcctg gggccggttt cggggccgta catctgtggc 360 ttcactaagg ccccgaaacc ggccccgaca acagcataca gccttcagca agcctccagt 420 ggtctcatac agaacttata agattcccaa atccaaagac atttcacgtt tatggtgatt 480 tcccagaaca catagcgaca tgcaaatatt gcagggcgcc actcccctgt ccctcacagc 540 catcttcctg ccagggcgca cgcgcgctgg gtgttcccgc ctagtgacac tgggcccgcg 600 attccttgga gcgggttgat gacgtcagcg tttcccatgg tgaagcttgg atctgaattc 660 ggtaccctag ttattaatag taatcaatta cggggtcatt agttcatagc ccatatatgg 720 agttccgcgt tacataactt acggtaaatg gcccgcctgg ctgaccgccc aacgaccccc 780 gcccattgac gtcaataatg acgtatgttc ccatagtac gccaataggg actttccatt 840 gacgtcaatg ggtggactat ttacggtaaa ctgcccactt ggcagtacat caagtgtatc atatgccaag tacgccccct attgacgtca atgacggtaa atggcccgcc tggcattatg cccagtacat gaccttatgg gactttccta cttggcagta catctacgta ttagtcatcg ctattaccat ggtcgaggtg agccccacgt tctgcttcac tctccccatc tcccccccct 1080 ccccaccccc aatttttgtat ttttttttttttttttttgtgcagcg atggggggcgg 1140 gggggggggg ggggcggcgcg ccaggcgggg cggggcgggg cgaggggcgg ggcggggcga ggcggagagg tgcggcggca gccaatcaga gcggcgcgct ccgaaagttt ccttttatgg 1260 cgaggcggcg gcggcggcgg ccctaaaa agcgaagcgc gcggcgggcg ggagtcgctg 1320 cgacgctgcc ttcgccccgt gccccgctcc gccgccgcct cgcgccgccc gccccggctc 1380 tgactgaccg cgttactccc acaggtgagc gggcgggacg gcccttctcc tccgggctgt 1440 aattagcgct tggtttaatg acggcttgtt ttctgtggct gcgtgaaagc cttgaggggc tccggggagct agagcctctg ctaaccatgt tcatgccttc ttctttttcc tacagctcct 1560 gggcaacgtg ctggttattg tgctgtctca tcattttggc aagaattcc tcgaagatcc gaagggaag tcttccacga ctgtgggatc cgttcgaaga tatcaccggt tgagccacca tgagcaccct gtgcccccc cccagccccg ccgtggccaa gaccgagatc gccctgagcg 1740 gcaagagccc cctgctggcc gccaccttcg cctactgggga caacatcctg ggcccccgcg tgcgccacat ctggggcccc aagaccgagc aggtgctgct gagcgacggc gagatcacct 1860. tcctggccaa ccacaccctg aacggcgaga tcctgcgcaa cgccgagagc ggcgccatcg acgtgaagtt cttcgtgctg agcgagaagg gcgtgatcat cgtgagcctg atcttcgacg gcaactggaa cggcgaccgc agcacctacg gcctgagcat catcctgccc cagaccgagc tgagcttcta cctgcccctg caccgcgtgt gcgtggaccg cctgacccac atcatccgca 2100 agggccgcat ctggatgcac aaggagcgcc aggagacgt gcagaagatc atcctggagg gcaccgagcg catggaggac cagggccaga gcatcatccc catgctgacc ggcgaggtga 2220 tccccgtgat ggagctgctg agcagcatga agagccacag cgtgcccgag gagatcgaca 2280 tcgccgacac cgtgctgaac gacgacgaca tcggcgacag ctgccacgag ggcttcctgc 2340 tgaacgccat cagcagccac ctgcagacct gcggctgcag cgtggtggtg ggcagcagcg 2400 ccgagaaggt gaacaagatc gtgcgcaccc tgtgcctgtt cctgaccccc gccgagcgca 2460 agtgcagccg cctgtgcgag gccgagagca gcttcaagta cgagagcggc ctgttcgtgc 2520 agggcctgct gaaggacagc accggcagct tcgtgctgcc cttccgccag gtgatgtacg 2580 ccccctaccc caccacccac atcgacgtgg acgtgaacac cgtgaagcag atgcccccct 2640 gccacgagca catctacaac cagcgccgct acatgcgcag cgagctgacc gccttctggc 2700 gcgccaccag cgaggaggac atggcccagg acaccatcat ctacaccgac gagagcttca 2760 cccccgacct gaacatcttc caggacgtgc tgcaccgcga caccctggtg aaggccttcc 2820 tggaccaggt gttccagctg aagcccggcc tgagcctgcg cagcaccttc ctggcccagt 2880 tcctgctggt gctgcaccgc aaggccctga ccctgatcaa gtacatcgag gacgacaccc 2940 agaagggcaa gaagcccttc aagagcctgc gcaacctgaa gatcgacctg gacctgaccg 3000 ccgagggcga cctgaacatc atcatggccc tggccgagaa gatcaagccc ggcctgcaca 3060 gcttcatctt cggccgcccc ttctacacca gcgtgcagga gcgcgacgtg ctgatgacct 3120 tctaatgaca attgttaatt aagtttaaac cctcgaggcc gcaagcttat cgataatcaa 3180 cctctggatt acaaaatttg tgaaagattg actggtattc ttaactatgt tgctcctttt 3240 acgctatgtg gatacgctgc tttaatgcct ttgtatcatg ctattgcttc ccgtatggct 3300 ttcattttct cctccttgta taaatcctgg ttgctgtctc tttatgagga gttgtggccc 3360 gttgtcaggc aacgtggcgt ggtgtgcact gtgtttgctg acgcaacccc cactggttgg 3420 ggcattgcca ccacctgtca gctcctttcc gggactttcg ctttccccct ccctattgcc 3480 acggcggaac tcatcgccgc ctgccttgcc cgctgctgga caggggctcg gctgttgggc 3540 actgacaatt ccgtggtgtt gtcggggaaa tcatcgtcct ttccttggct gctcgcctgt 3600 gttgccacct ggattctgcg cgggacgtcc ttctgctacg tcccttcggc cctcaatcca 3660 gcggaccttc cttcccgcgg cctgctgccg gctctgcggc ctcttccgcg tcttcgcctt 3720 cgccctcaga cgagtcggat ctccctttgg gccgcctccc cgcatcgata ccgtcgacta 3780 gagctcgctg atcagcctcg actgtgcctt ctagttgcca gccatctgtt gtttgcccct 3840 cccccgtgcc ttccttgacc ctggaaggtg ccactcccac tgtcctttcc taataaaatg 3900 aggaaattgc atcgcattgt ctgagtaggt gtcattctat tctggggggt ggggtggggc 3960 aggacagcaa gggggaggat tgggaagaca atagcaggca tgctggggag agatccacga 4020 taacaaacag cttttttggg gtgaacatat tgactgaatt ccctgcaggt tggccactcc 4080 ctctctgcgc gctcgctcgc tcactgaggc cgcccgggca aagcccgggc gtcgggcgac 4140 ctttggtcgc ccggcctcag tgagcgagcg agcgcgcaga gagggagtgg ccaactccat 4200 cactaggggt tcctgcggcc gctcgtacgg tctcgaggaa ttcctgcagg ataacttgcc 4260 aacctcattc taaaatgtat atagaagccc aaaagacaat aacaaaaata ttcttgtaga 4320 acaaaatggg aaagaatgtt spring tcagattta gagshaagca tgagatgtgt 4380 ggggatagac agtgaggctg aaaataga gtagagctca gaaacagacc cattgatata 4440 tgtaagtgac ctatgaaaaa atatggcat tttacaatgg gaaatgatg gtctttttct 4500 tttttagaaa aacagggaa tatattatta tgtaaaaaat aaagggaac ccatatgtca 4560 taccatacac aaaaaaat tccagtgaat taagtcta atggagag gcaaacttt 4620 aaatctttta gaaaataata tagacatg cagaccagcc tggccacat gatgaaccc 4680 tcttactaa tataaaatc agtagaacta ctcaggacta ctttgagtgg gaagtccttt 4740 tctatgaaga cttctttggc caaattagg ctctaaatgc aaggagatag tgcatcatgc 4800 ctggctgcac ttactgataa atgatgttat caccatcttt aaccaaatgc acaggaacaa 4860 gttatggtac tgatgtgctg gattgagaag gagctctact tccttgacagzgacatttg 4920 tatcaactta aaaaagcaga tttcaactta cagaactatt cattcagagg taggaactt 4980 agaatagatg atgtcactga ttagcatggc ttcccatct ccacagctgc ttcccaccca 5040 ggttgcccac agttgagttt gtccagtgct cagggctgcc cactctcagt aagaagcccc 5100 acaccagccc ctctccaaat atgttggctg ttccttccat taaagtgacc ccactttaga 5160 gcagcaagtg gatttctgtt tcttacagtt caggaaggag gagtcagctg tgagaacctg 5220 gagcctgaga tgcttctaag tcccactgct actggggtca gggaagccag actccagcat 5280 cagcagtcag gagcactaag cccttgccaa catcctgttt ctcagagaaa ctgcttccat 5340 tataatggtt gtcctttttt aagctatcaa gccaaacaac cagtgtctac cattattctc 5400 atcacctgaa gccaagggtt ctagcaaaag tcaagctgtc ttgtaatggt tgatgtgcct 5460 ccagcttctg tcttcagtca ctccactctt agcctgctct gaatcaactc tgaccacagt 5520 tccctggagc ccctgccacc tgctgcccct gccaccttct ccatctgcag tgctgtgcag 5580 ccttctgcac tcttgcagag ctaataggtg gagacttgaa ggaagaggag gaaagtttct 5640 cataatagcc ttgctgcaag ctcaaatggg aggtgggcac tgtgcccagg agccttggag 5700 caaaggctgt gcccaacctc tgactgcatc caggtttggt cttgacagag ataagaagcc 5760 ctggcttttg gagccaaaat ctaggtcaga cttaggcagg attctcaaag tttatcagca 5820 gaacatgagg cagaagaccc tttctgctcc agcttcttca ggctcaacct tcatcagaat 5880 agatagaaag agaggctgtg agggttctta aaacagaagc aaatctgact cagagaataa 5940 acaacctcct agtaaactac agcttagaca gagcatctgg tggtgagtgt gctcagtgtc 6000 ctactcaact gtctggtatc agccctcatg aggacttctc ttctttccct catagacctc 6060 catctctgtt ttccttagcc tgcagaaatc tggatggcta ttcacagaat gcctgtgctt 6120 tcagagttgc attttttctc tggtattctg gttcaagcat ttgaaggtag gaaaggttct 6180 ccaagtgcaa gaaagccagc cctgagcctc aactgcctgg ctagtgtggt cagtaggatg 6240 caaaggctgt tgaatgccac aaggccaaac tttaacctgt gtaccacaag cctagcagca 6300 gaggcagctc tgctcactgg aactctctgt cttctttctc ctgagccttt tcttttcctg 6360 agttttctag ctctcctcaa ccttacctct gccctaccca ggacaaaccc aagagccact 6420 gtttctgtga tgtcctctcc agccctaatt aggcatcatg acttcagcct gaccttccat 6480 gctcagaagc agtgctaatc cacttcagat gagctgctct atgcaacaca ggcagagcct 6540 acaaaccttt gcaccagagc cctccacata tcagtgtttg ttcatactca cttcaacagc 6600 aaatgtgact gctgagatta agattttaca caagatggtc tgtaatttca cagttagttt 6660 tatcccatta ggtatgaaag aattagcata attcccctta aacatgaatg aatcttagat 6720 tttttaataa atagttttgg aagtaaagac agagacatca ggagcacaag gaatagcctg 6780 agaggacaaa cagaacaaga aagagtctgg aaatacacag gatgttcttg gcctcctcaa 6840 agcaagtgca agcagatagt accagcagcc ccaggctatc agagcccagt gaagagaagt 6900 accatgaaag ccacagctct aaccaccctg ttccagagtg acagacagtc cccaagacaa 6960 gccagcctga gccagagaga gaactgcaag agaaagtttc taatttaggt tctgttagat 7020 tcagacaagt gcaggtcatc ctctctccac agctactcac ctctccagcc taacaaagcc 7080 tgcagtccac actccaaccc tggtgtctca cctcctagcc tctcccaaca tcctgctctc 7140 tgaccatctt ctgcatctct catctcacca tctccactg tctacagcct actcttgcaa 7200 ctaccatctc attttctgac atcctgtcta catcttctgc catactctgc catctaccat 7260 accacctctt accatctacc acaccatctt ttatctccat ccctctcaga agcctccaag 7320 ctgaatcctg ctttatgtgt tcatctcagc ccctgcatgg aaagctgacc ccagaggcag 7380 aactattccc agagagcttg gccaagaaaa acaaaactac cagcctggcc aggctcagga 7440 gtagtaagct gcagtgtctg ttgtgttcta gcttcaacag ctgcaggagt tccactctca 7500 aatgctccac atttctcaca tcctcctgat tctggtcact acccatcttc aaagaagaga 7560 atatctcaca tcagcatact gtgaaggact agtcatgggt gcagctgctc agagctgcaa 7620 agtcattctg gatggtggag agcttacaaa catttcatga tgctcccccc gctctgatgg 7680 ctggagccca atccctacac agactcctgc tgtatgtgtt ttcctttcac tctgagccac 7740 agccagaggg caggcattca gtctcctctt caggctgggg ctggggcact gagaactcac 7800 ccaacacctt gctctcactc cttctgcaaa aacaaaaga gctttgtgct gcagtagcca 7860 tgaagaatga areaaggct ttaactaaaa aatgtcagag attattttca acccccttact 7920 gtggatcacc agcaaggagg aaacacaaca cagagacatt ttttcccctc aaattatcaa 7980 aagaatcact gcatttgtta aagagagcaa ctgaatcagg aagcagagtt ttgaacatat 8040 cagaagttag gaatctgcat cagagacaaa tgcagtcatg gttgtttgct gcataccagc 8100 cctaatcatt agaagcctca tggacttcaa acatcattcc ctctgacaag atgctctagc 8160 ctaactccat gagataaaat aaatctgcct ttcagagcca aagaagagtc caccagcttc 8220 ttctcagtgt gaacaagagc tccagtcagg ttagtcagtc cagtgcagta gaggagacca 8280 gtctgcatcc tctaattttc aaaggcaaga agatttgttt accctggaca ccaggcacaa 8340 gtgaggtcac agagctctta gatatgcagt cctcatgagt gaggagacta aagcgcatgc 8400 catcaagact tcagtgtaga gaaaacctcc aaaaaagcct cctcactact tctggaatag 8460 ctcagaggcc gaggcggcct cggcctctgc ataataaaaa aaaattagtc agccatgggg 8520 cggagaatgg gcggaactgg gcggagttag gggcgggatg ggcggagtta ggggcgggac 8580 tatggttgct gactaattga gatgcatgct ttgcatactt ctgcctgctg gggagcctgg 8640 ggactttcca cacctggttg ctgactaatt gagatgcatg ctttgcatac ttctgcctgc 8700 tggggagcct ggggactttc cacaccctaa ctgacacaca ttccacagct gcattaatga 8760 atcggccaac gcgcggggag aggcggtttg cgtattgggc gctcttccgc ttcctcgctc 8820 actgactcgc tgcgctcggt cgttcggctg cggcgagcgg tatcagctca ctcaaaggcg 8880 gtaatacggt tatccacaga atcaggggat aacgcaggaa agaacatgtg agcaaaaggc 8940 cagcaaaagg ccaggaaccg taaaaaggcc gcgttgctgg cgtttttcca taggctccgc 9000 ccccctgacg agcatcacaa aaatcgacgc tcaagtcaga ggtggcgaaa cccgacagga 9060 ctataaagat accaggcgtt tccccctgga agctccctcg tgcgctctcc tgttccgacc 9120 ctgccgctta ccggatacct gtccgccttt ctcccttcgg gaagcgtggc gctttctcat 9180 agctcacgct gtaggtatct cagttcggtg taggtcgttc gctccaagct gggctgtgtg 9240 cacgaacccc ccgttcagcc cgaccgctgc gccttatccg gtaactatcg tcttgagtcc 9300 aacccggtaa gacacgactt atcgccactg gcagcagcca ctggtaacag gattagcaga 9360 gcgaggtatg taggcggtgc tacagagttc ttgaagtggt ggcctaacta cggctacact 9420 agaagaacag tatttggtat ctgcgctctg ctgaagccag ttaccttcgg aaaaagagtt 9480 ggtagctctt gatccggcaa acaaaccacc gctggtagcg gtggtttttt tgtttgcaag 9540 cagcagatta cgcgcagaaa aaaaggatct caagaagatc ctttgatctt ttctacgggg 9600 tctgacgctc agtggaacga aaactcacgt taagggattt tggtcatgag attatcaaaa 9660 aggatcttca cctagatcct tttaaattaa aaatgaagtt ttaaatcaat ctaaagtata 9720 tatgagtaaa cttggtctga cagttaccaa tgcttaatca gtgaggcacc tatctcagcg 9780 atctgtctat ttcgttcatc catagttgcc tgactcctgc aaaccacgtt gtgtctcaaa 9840 atctctgatg ttacattgca caagataaa atatatcatc atgaacaata aaactgtctg 9900 cttacataa cattaataca aggggtgtta tgagccatat tcaacgggaa acgtcttgct 9960 cgaggccgcg attaaattcc aacatggatg ctgatttata tgggtataaa tgggctcgcg 10020 ataatgtcgg gcaatcaggt gcgacaatct atcgattgta tgggaagccc gatgcgccag 10080 agttgtttct gaaacatggc aaaggtagcg ttgccaatga tgttacagat gagatggtca 10140 gactaaactg gctgacggaa tttatgcctc ttccgaccat caagcattt atccgtactc 10200 ctgatgatgc atggtactc accactgcga tccccgggaa aacagcattc caggtattag 10260 aagaatatcc tgattcaggt gaaaatattg ttgatgcgct ggcagtgttc ctgcgccggt 10320 tgcattcgat tcctgtttgt aattgtcctt ttaacagcga tcgcgtattt cgtctcgctc 10380 aggcgcaatc acgaatgaat aacggtttgg ttgatgcgag tgattttgat gacgagcgta 10440 atggctggcc tgttgaacaa gtctggaaag aaatgcataa gcttttgcca ttctcaccgg 10500 attcagtcgt cactcatggt gatttctcac ttgataacct tatttttgac gaggggaaat 10560 taataggttg tattgatgtt ggacgagtcg gaatcgcaga ccgataccag gatcttgcca 10620 tcctatggaa ctgcctcggt gagttttctc cttcattaca gaaacggctt tttcaaaaat 10680 atggtattga taatcctgat atgaataaat tgcagtttca tttgatgctc gatgagtttt 10740 tctaagggcg gcctgccacc atacccacgc cgaaacaagc gctcatgagc ccgaagtggc 10800 gagcccgatc ttccccatcg gtgatgtcgg cgatataggc gccagcaacc gcacctgtgg 10860 cgccggtgat gagggcgcgc caagtcgacg tccggcagtc 10900 <210> 6 <211> 274 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <400> 6 Met Gly Lys Ser Leu Ser His Leu Pro Leu His Ser Ser Lys Glu Asp 1 5 10 15 Ala Tyr Asp Gly Val Thr Ser Glu Asn Met Arg Asn Gly Leu Val Asn 20 25 30 Ser Glu Val His Asn Glu Asp Gly Arg Asn Gly Asp Val Ser Gln Phe 35 40 45 Pro Tyr Val Glu Phe Thr Gly Arg Asp Ser Val Thr Cys Pro Thr Cys 50 55 60 Gln Gly Thr Gly Arg Ile Pro Arg Gly Gln Glu Asn Gln Leu Val Ala 65 70 75 80 Leu Ile Pro Tyr Ser Asp Gln Arg Leu Arg Pro Arg Arg Thr Lys Leu 85 90 95 Tyr Val Met Ala Ser Val Phe Val Cys Leu Leu Leu Ser Gly Leu Ala 100 105 110 Val Phe Phe Leu Phe Pro Arg Ser Ile Asp Val Lys Tyr Ile Gly Val 115 120 125 Lys Ser Ala Tyr Val Ser Tyr Asp Val Gln Lys Arg Thr Ile Tyr Leu 130 135 140 Asn Ile Thr Asn Thr Leu Asn Ile Thr Asn Asn Asn Tyr Tyr Ser Val 145 150 155 160 Glu Val Glu Asn Ile Thr Ala Gln Val Gln Phe Ser Lys Thr Val Ile 165 170 175 Gly Lys Ala Arg Leu Asn Asn Ile Thr Ile Ile Gly Pro Leu Asp Met 180 185 190 Lys Gln Ile Asp Tyr Thr Val Pro Thr Val Ile Ala Glu Glu Met Ser 195 200 205 Tyr Met Tyr Asp Phe Cys Thr Leu Ile Ser Ile Lys Val His Asn Ile 210 215 220 Val Leu Met Met Gln Val Thr Val Thr Thr Thr Tyr Phe Gly His Ser 225 230 235 240 Glu Gln Ile Ser Gln Glu Arg Tyr Gln Tyr Val Asp Cys Gly Arg Asn 245 250 255 Thr Thr Tyr Gln Leu Gly Gln Ser Glu Tyr Leu Asn Val Leu Gln Pro 260 265 270 Gln Gln <210> 7 <211> 6514 <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotide <400> 7 aggcgcggac gcaggttaca gcagcgcttg gcctctgctg atgccgtcgt tatcctaccc 60 ctcccccgtc ccagctctac ggcggccgcg cgctccaggc cggtcgctcc accccccggc 120 tcccgggact gtggactcca cgaccctgtc ctcggccctg tccgcgccga agcagcccgg 180 gactgcgcag cgccccgcgt gccgatcttt tcctaattca gcagcgattt aaccaagagc 240 ctggaatatt ttaaggagta ataagagaca tttacaaact attctctctg aagcctgcta 300 cctggaggca tcatctagat aatcagaacc ttggcttcca catcctcctc ccttgtctta 360 actacaaaca tttctttctg ctgacttcaa ctcctcagac atgggaaagt ctctttctca 420 tttgcctttg cattcaagca aagaagatgc ttatgatgga gtcacatctg aaaacatgag 480 gaatggactg gttaatagtg aagtccataa tgaagatgga agaaatggag atgtctctca 540 gtttccatat gtggaattta caggaagaga tagtgtcacc tgccctactt gtcagggaac 600 aggaagaatt cctagggggc aagaaaacca actggtggca ttgattccat atagtgatca 660 gagattagg ccaagaagaa caaagctgta tgtgatggct tctgtgtttg tctgtctact 720 cctttctgga ttggctgtgt ttttcctttt ccctcgctct atcgacgtga aatacattgg 780 tgtaaaatca gcctatgtca gttatgatgt tcagaagcgt acaatttatt taaatatcac 840 aaacacacta aatataacaa acaataacta ttactctgtc gaagttgaaa acatcactgc 900 ccaagttcaa ttttcaaaaa cagttatgg aaaggcacgc ttaaaaca taaccattat 960 1020 gagttatatg tatgatttct gtactctgat atccatcaaa gtgcataaca tagtactcat 1080 gatgcaagtt actgtgacaa caacatactt tggccactct gaacagatat cccaggagag 1140 gtatcagtat gtcgactgtg gaagaacac aacttatcag ttggggcagt ctgaatattt 1200 1260 attgatattt cctatactct caatgaagag gtatttccta ataggagacc ttaaattgaa 1320 caaacctaaa gtttacactt ctaagagtac agttaaaagt atgtggacct gcagttcttg taactctcca ctctgtgtta atgatatatt tgtactagga tcttttactt gaatctaat ttactggttg atttccttct ccagcctatc ccctacaggg aaaagctgat acttccccta tagtacaata aatattatt taaagtcat agctccagtc actactgaaa acataatttt ggtgataaac ataatttgag aaacttaatt tctgaatgtt tttatagaaa attactgaaa gtctattact catggaagac ttttaaaga taacctttttt tcctgtttta taattccca ttgttatatg gtagtatttc agctacacaa tatttagct tttagctaga catttatagc ttttcatttg ttgaaatggt aatcatctgc atgtttttgt cacttattc aggttagtga ttgcctaaca cttataagcc aaataatct ttgcaaaatt ccatacctaa aaatttgaaa gcccctaatg ttttcacaca tctttctgta ttagttatag ttttgtgaaa tctttgtgtg atcttcaaac attcattt aatgtacaat actgtaaata aactgtgcat ggcttttata cagctttagt aaatgtcaaa taaagtggta cagactcatt acaacaagtt tctcataaaa atacaataaa taggaaaatg aaattcagaa acccatagac tgggaatagg ttccagttac 2100 agcttggatc tggcataaaa taaatttgaa ataaaatatt ttgatgctcc attttttat 2160 gttgctttc atactaaaga atggtgtaga catgttttgc aactgttagg tacccagtta 2220 tcaattttat caatgtttta gaggaggaaa ttattttttt ggtagaaatt gttcaagaaa 2280 tccttaattg aatgtcatta aatgatggtg gccaaaataa aacctattta gaaatttaat 2340 cactttgcac atcacttgga atatgatgcc tctagtagtt actttttat agttttctac 2400 ttttggtttt attaaaatt gttttcaaat atagattatt gacttattca actttgctgt 2460 tttatatttt cagtatcattt ttcattttt tttttttttt gtcttttcac ttaccaagtt 2520 ctagggacat ttaaaatatg tactaagtgt aggagtggtt atgataccaa aaaatgtagc 2580 tgggttgaga ttaatttcgt tctgttttct catgacagaa atcaggtttc cctttcccca 2640 ccctaagtg cctaacttag gtctgaaaca gcctgttat tagtctgact ctctcaacca 2700 taaaacataa gctttattta attctgcctt taaacacact caggttttccc cttaattttc 2760 atattatttt ctgcaagttt tcttgagtat cttcaattcg ttgaatgtgg tttttggtt 2820 ttttttgttt taacactagt cttcccttaa ttcattgcta actcaagcca tccttactat 2880 taaacccaaa tcagtccttt aagttcatta tggcctttct agtatttaaa aaaaaaaaa 2940 tcattttcat ttttcttctg ctacgtttcc tgactactac tgcatacttc tctgatacag 3000 gttctgtttg tattttttat atcattctca tttctcatt tgacatgatc tatgtctata 3060 tatgatatag gtcccctttt gtctcaaaat ttttaattat gtgacttcaa aaatcacctg 3120 tatctgtagt agggcttcca aatctgcttc tccatatgtg accagtcacc tgtctgcttt 3180 cacatttagc tagtgaacta cacatttact aaaatgtgta aattttacac atttagtgac 3240 tgtgtaaaat aaaaaaaag ttattttatc atatcctttc tattatgttc ccatcctgtc 3300 ctcatgtccc atttacttta ttcaccat tcatttcttc aaaattatct tttagatacg 3360 ctcatacaaa aatcaatcct tgttttcttg cttgtgtctt ttaaccttgg aaaattacat 3420 cgtgtaaatt aaacagattt ttctgatgat ctgtgcttct tatatactat tagagtgcat 3480 gatagtatct cctgaaaagg atggaagta gaagcatttg cttttagtca cttaatttg 3540 aatcttttt cttcatcttt tgaatttatt tatctacttt tag 3600 tgagtcaga aaaaaaaaaaaaaaaaaca agtaaaaga tagagaa aaaagatgg 3660 tatgtgacta ctttcagaga gagttaagta actgtcagaa taagcctgga aaaacagg 3720 ctgtaaatta aaaactac aacacacat tcaggtgag cagagtata gccataaaac 3780 atctagaaag agtgaatgag gcttttagct ttcttaggt caatgtccag tgtgcttttt 3840 tccatgggaa taggataggt attatacgc ttttctaac tgctctcaga ccttatccag 3900 aggacatggt aagatatgt tacagaattt ttctgatac ttcctggaat aactttaagt 3960 tacaccctag tagactggtc attctata aatccagtac tatacaac ctctgtatgt 4020 tgatagcaca ttggcccttt ttagagttct ttcctatgtt ttcttacgt gatttcccac 4080 agttccatga gtccacaaa ggagagtgat aggctcctta tctttagaa gaggaaggaa 4140 agcatgaag aagttgagggg actggctgaa gatcacgtac ttactagta gtacaactgg 4200 agcaagatca agtatctctg tctcccatat ctgtgttcta tcatttaaaa tatatattgg 4260 aaatccctgc tgactcagat tggtatgatt aaaatgaga ggaagttca atagttagt 4320 agtgacaaac taatactgct ggactagat ttgtagca ttgttttcta aaatatttta 4380 aatggagaat gaacacttat aaatgcttt ggacataat ctttagctta attttctgtt 4440 aaaatttagt accccttcat cattccaata agatagac tgatccattg tctaggaaa 4500 ttattatta attagaga ttattattat tgagatttga ataagaata gtatgaaat 4560 attagatacc actaaattg tttgaatta ctgaataacc atcttaagta tggaacttt 4620 aaatggctat atttttg tgtacagtttt ttctgtgcct tgttaggcca gtgaagcaat 4680 tattttct aagaaaatga cataaaata taacacactt cagattgtct gatttacagt 4740 ttggaagga caccgcaatg ttcaatagg taggagacca tcaaaaacac aattaaagta 4800 acatattagg agacttgaa cttcagccta ataatcctt catggttctt agccttatta 4860 ttgtgatata attcgata tttcttgga gggcatgtgc cacactctcc cgcaccccat 4920 tttgtttgtc ttttaaagtt cttagaataa acagttcttt atataataat tatattttat 4980 ttaagaaat agttgttag gtacttttta aagatgtaa atttttaat ttacaatac 5040 atatgggtct ttgataagca attaggaattg aattacaagt tactagggtt ataagcaaaa 5100 ggttgcttac cataatgtca ttaggtcacg atttttagct cacatctgga agcagcact 5160 acttggctca agtacatata agagtatta gttttattct ctcttttta taaaatcggg 5220 tttcagatga gatgtttatc ttagactatt ttagggaaaa attcagatg tttgagatgg 5280 tggagtaaaa agactgttaa acatttctt taaaaaatta tttttacatt acacaat 5340 atttatgatg tgttcagatc aaaaatttaa cttctgtgtc ccagatctac ttcaagtg 5400 agattttcac ttgtcagctt aaatttctga ctagaactaa cattgtgta ttttgtgct 5460 tagtcggaat acaaatttca cagtggatttt ttgaagtttg tccttaaatt ggataaaatc 5520 aagtgatta agttaactaaa gagataaaa tggtaatttc cattttaaa agtaatttgg 5580 ttgtgtttat agttattgt acagtattt atcacagact ctaaattgaa aaatgtagta 5640 tgatctat ttgaccctaa aaatgttgga ttaatttaac aaatatggca gatttttcat 5700 aactaagtct taagtcttct aaaaggaagc tgttaccctt ctgtttttaa ttacattaat 5760 tgaaatgtgt tttaagagat acaatttcag catattttat attaaaaa acaaaaaagg 5820 attagtattg agccagtggc caaaaggtaa tattactacc atgtagactg ttatagttca 5880 aattgccca cttcacccag aattttagaa actagaagtc tgggaggtac tatatcagct 5940 gtagttgggt aattccaagt gctgatagta ctattcatct tttttattat tgtgtcagat 6000 gaaacaaatg ccaagttgca aaatatgcag atttttatta tataatggtt ttaggcataa 6060 attattaaca agccatgcct tatgtgtttc atcttatatt tttctttaga actaaactat 6120 aacagattt ggaaaatgat ttgacgtgct tgctcacttg attgacttgg tcagatattt 6180 gaatgatggt attacctaga ttctaatcct tgattctagt tataataataa ataataga 6240 atatgaaaat atgtttgggc atttactgtt tatattatgt agtagcctcc atcatgacac 6300 acttactaca tttatgaatt gagcagttct gtaattgtaa ttattattgc tgttcatgta 6360 acaaaacatg cttataatag caaacaaata gaaatgcccc caaaatgcta tttttttaat 6420 tcagttataa ctgttactct tgtagttgtg tatgacgcaa taaaatttgt aaaaaaattt 6480 cagcatgaaa aataaaattt gtatcactta tgta 6514 <210> 8 <211> 1313 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <400> 8 Met Arg Ser Ala Ala Ala Ala Pro Arg Ser Pro Ala Val Ala Thr Glu 1 5 10 15 Ser Arg Arg Phe Ala Ala Ala Arg Trp Pro Gly Trp Arg Ser Leu Gln 20 25 30 Arg Pro Ala Arg Arg Ser Gly Arg Gly Gly Gly Gly Ala Ala Pro Gly 35 40 45 Pro Tyr Pro Ser Ala Ala Pro Pro Pro Pro Gly Pro Gly Pro Pro Pro 50 55 60 Ser Arg Gln Ser Ser Pro Pro Ser Ala Ser Asp Cys Phe Gly Ser Asn 65 70 75 80 Gly Asn Gly Gly Gly Ala Phe Arg Pro Gly Ser Arg Arg Leu Leu Gly 85 90 95 Leu Gly Gly Pro Pro Arg Pro Phe Val Val Leu Leu Leu Pro Leu Ala 100 105 110 Ser Pro Gly Ala Pro Pro Ala Ala Pro Thr Arg Ala Ser Pro Leu Gly 115 120 125 Ala Arg Ala Ser Pro Pro Arg Ser Gly Val Ser Leu Ala Arg Pro Ala 130 135 140 Pro Gly Cys Pro Arg Pro Ala Cys Glu Pro Val Tyr Gly Pro Leu Thr 145 150 155 160 Met Ser Leu Lys Pro Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln 165 170 175 Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Pro Pro Pro Ala 180 185 190 Ala Ala Asn Val Arg Lys Pro Gly Gly Ser Gly Leu Leu Ala Ser Pro 195 200 205 Ala Ala Ala Pro Ser Pro Ser Ser Ser Ser Val Ser Ser Ser Ser Ala 210 215 220 Thr Ala Pro Ser Ser Val Val Ala Ala Thr Ser Gly Gly Gly Arg Pro 225 230 235 240 Gly Leu Gly Arg Gly Arg Asn Ser Asn Lys Gly Leu Pro Gln Ser Thr 245 250 255 Ile Ser Phe Asp Gly Ile Tyr Ala Asn Met Arg Met Val His Ile Leu 260 265 270 Thr Ser Val Val Gly Ser Lys Cys Glu Val Gln Val Lys Asn Gly Gly 275 280 285 Ile Tyr Glu Gly Val Phe Lys Thr Tyr Ser Pro Lys Cys Asp Leu Val 290 295 300 Leu Asp Ala Ala His Glu Lys Ser Thr Glu Ser Ser Ser Gly Pro Lys 305 310 315 320 Arg Glu Glu Ile Met Glu Ser Ile Leu Phe Lys Cys Ser Asp Phe Val 325 330 335 Val Val Gln Phe Lys Asp Met Asp Ser Ser Tyr Ala Lys Arg Asp Ala 340 345 350 Phe Thr Asp Ser Ala Ile Ser Ala Lys Val Asn Gly Glu His Lys Glu 355 360 365 Lys Asp Leu Glu Pro Trp Asp Ala Gly Glu Leu Thr Ala Asn Glu Glu 370 375 380 Leu Glu Ala Leu Glu Asn Asp Val Ser Asn Gly Trp Asp Pro Asn Asp 385 390 395 400 Met Phe Arg Tyr Asn Glu Glu Asn Tyr Gly Val Val Ser Thr Tyr Asp 405 410 415 Ser Ser Leu Ser Ser Tyr Thr Val Pro Leu Glu Arg Asp Asn Ser Glu 420 425 430 Glu Phe Leu Lys Arg Glu Ala Arg Ala Asn Gln Leu Ala Glu Glu Ile 435 440 445 Glu Ser Ser Ala Gln Tyr Lys Ala Arg Val Ala Leu Glu Asn Asp Asp 450 455 460 Arg Ser Glu Glu Glu Lys Tyr Thr Ala Val Gln Arg Asn Ser Ser Glu 465 470 475 480 Arg Glu Gly His Ser Ile Asn Thr Arg Glu Asn Lys Tyr Ile Pro Pro 485 490 495 Gly Gln Arg Asn Arg Glu Val Ile Ser Trp Gly Ser Gly Arg Gln Asn 500 505 510 Ser Pro Arg Met Gly Gln Pro Gly Ser Gly Ser Met Pro Ser Arg Ser 515 520 525 Thr Ser His Thr Ser Asp Phe Asn Pro Asn Ser Gly Ser Asp Gln Arg 530 535 540 Val Val Asn Gly Gly Val Pro Trp Pro Ser Pro Cys Pro Ser Pro Ser 545 550 555 560 Ser Arg Pro Pro Ser Arg Tyr Gln Ser Gly Pro Asn Ser Leu Pro Pro 565 570 575 Arg Ala Ala Thr Pro Thr Arg Pro Pro Ser Arg Pro Pro Ser Arg Pro 580 585 590 Ser Arg Pro Pro Ser His Pro Ser Ala His Gly Ser Pro Ala Pro Val 595 600 605 Ser Thr Met Pro Lys Arg Met Ser Ser Glu Gly Pro Pro Arg Met Ser 610 615 620 Pro Lys Ala Gln Arg His Pro Arg Asn His Arg Val Ser Ala Gly Arg 625 630 635 640 Gly Ser Ile Ser Ser Gly Leu Glu Phe Val Ser His Asn Pro Pro Ser 645 650 655 Glu Ala Ala Thr Pro Pro Val Ala Arg Thr Ser Pro Ser Gly Gly Thr 660 665 670 Trp Ser Ser Val Val Ser Gly Val Pro Arg Leu Ser Pro Lys Thr His 675 680 685 Arg Pro Arg Ser Pro Arg Gln Asn Ser Ile Gly Asn Thr Pro Ser Gly 690 695 700 Pro Val Leu Ala Ser Pro Gln Ala Gly Ile Ile Pro Thr Glu Ala Val 705 710 715 720 Ala Met Pro Ile Pro Ala Ala Ser Pro Thr Pro Ala Ser Pro Ala Ser 725 730 735 Asn Arg Ala Val Thr Pro Ser Ser Glu Ala Lys Asp Ser Arg Leu Gln 740 745 750 Asp Gln Arg Gln Asn Ser Pro Ala Gly Asn Lys Glu Asn Ile Lys Pro 755 760 765 Asn Glu Thr Ser Pro Ser Phe Ser Lys Ala Glu Asn Lys Gly Ile Ser 770 775 780 Pro Val Val Ser Glu His Arg Lys Gln Ile Asp Asp Leu Lys Lys Phe 785 790 795 800 Lys Asn Asp Phe Arg Leu Gln Pro Ser Ser Thr Ser Glu Ser Met Asp 805 810 815 Gln Leu Leu Asn Lys Asn Arg Glu Gly Glu Lys Ser Arg Asp Leu Ile 820 825 830 Lys Asp Lys Ile Glu Pro Ser Ala Lys Asp Ser Phe Ile Glu Asn Ser 835 840 845 Ser Ser Asn Cys Thr Ser Gly Ser Ser Lys Pro Asn Ser Pro Ser Ile 850 855 860 Ser Pro Ser Ile Leu Ser Asn Thr Glu His Lys Arg Gly Pro Glu Val 865 870 875 880 Thr Ser Gln Gly Val Gln Thr Ser Ser Pro Ala Cys Lys Gln Glu Lys 885 890 895 Asp Asp Lys Glu Glu Lys Lys Asp Ala Ala Glu Gln Val Arg Lys Ser 900 905 910 Thr Leu Asn Pro Asn Ala Lys Glu Phe Asn Pro Arg Ser Phe Ser Gln 915 920 925 Pro Lys Pro Ser Thr Thr Pro Thr Ser Pro Arg Pro Gln Ala Gln Pro 930 935 940 Ser Pro Ser Met Val Gly His Gln Gln Pro Thr Pro Val Tyr Thr Gln 945 950 955 960 Pro Val Cys Phe Ala Pro Asn Met Met Tyr Pro Val Pro Val Ser Pro 965 970 975 Gly Val Gln Pro Leu Tyr Pro Ile Pro Met Thr Pro Met Pro Val Asn 980 985 990 Gln Ala Lys Thr Tyr Arg Ala Val Pro Asn Met Pro Gln Gln Arg Gln 995 1000 1005 Asp Gln His His Gln Ser Ala Met Met His Pro Ala Ser Ala Ala 1010 1015 1020 Gly Pro Pro Ile Ala Ala Thr Pro Pro Ala Tyr Ser Thr Gln Tyr 1025 1030 1035 Val Ala Tyr Ser Pro Gln Gln Phe Pro Asn Gln Pro Leu Val Gln 1040 1045 1050 His Val Pro His Tyr Gln Ser Gln His Pro His Val Tyr Ser Pro 1055 1060 1065 Val Ile Gln Gly Asn Ala Arg Met Met Ala Pro Pro Thr His Ala 1070 1075 1080 Gln Pro Gly Leu Val Ser Ser Ser Ala Thr Gln Tyr Gly Ala His 1085 1090 1095 Glu Gln Thr His Ala Met Tyr Ala Cys Pro Lys Leu Pro Tyr Asn 1100 1105 1110 Lys Glu Thr Ser Pro Ser Phe Tyr Phe Ala Ile Ser Thr Gly Ser 1115 1120 1125 Leu Ala Gln Gln Tyr Ala His Pro Asn Ala Thr Leu His Pro His 1130 1135 1140 Thr Pro His Pro Gln Pro Ser Ala Thr Pro Thr Gly Gln Gln Gln 1145 1150 1155 Ser Gln His Gly Gly Ser His Pro Ala Pro Ser Pro Val Gln His 1160 1165 1170 His Gln His Gln Ala Ala Gln Ala Leu His Leu Ala Ser Pro Gln 1175 1180 1185 Gln Gln Ser Ala Ile Tyr His Ala Gly Leu Ala Pro Thr Pro Pro 1190 1195 1200 Ser Met Thr Pro Ala Ser Asn Thr Gln Ser Pro Gln Asn Ser Phe 1205 1210 1215 Pro Ala Ala Gln Gln Thr Val Phe Thr Ile His Pro Ser His Val 1220 1225 1230 Gln Pro Ala Tyr Thr Asn Pro Pro His Met Ala His Val Pro Gln 1235 1240 1245 Ala His Val Gln Ser Gly Met Val Pro Ser His Pro Thr Ala His 1250 1255 1260 Ala Pro Met Met Leu Met Thr Thr Gln Pro Pro Gly Gly Pro Gln 1265 1270 1275 Ala Ala Leu Ala Gln Ser Ala Leu Gln Pro Ile Pro Val Ser Thr 1280 1285 1290 Thr Ala His Phe Pro Tyr Met Thr His Pro Ser Val Gln Ala His 1295 1300 1305 His Gln Gln Gln Leu 1310 <210> 9 <211> 4712 <212> DNA <213> Artificial Sequence <220> <223> Synthetic polynucleotide <400> 9 acccccgaga aagcaaccca gcgcgccgcc cgctcctcac gtgtccctcc cggccccggg 60 gccacctcac gttctgcttc cgtctgaccc ctccgacttc cggtaaagag tccctatccg 120 cacctccgct cccacccggc gcctcggcgc gcccgccctc cgatgcgctc agcggccgca 180 gctcctcgga gtcccgcggt ggccaccgag tctcgccgct tcgccgcagc caggtggccc 240 gggtggcgct cgctccagcg gccggcgcgg cggagcgggc ggggcggcgg tggcgcggcc 300 ccgggaccgt atccctccgc cgcccctccc ccgcccggcc ccggcccccc tccctcccgg 360 cagagctcgc ctccctccgc ctcagactgt tttggtagca acggcaacgg cggcggcgcg 420 tttcggcccg gctcccggcg gctccttggt ctcggcgggc ctccccgccc cttcgtcgtc 480 ctccttctcc ccctcgccag cccgggcgcc cctccggccg cgccaacccg cgcctccccg 540 ctcggcgccc gcgcgtcccc gccgcgttcc ggcgtctcct tggcgcgccc ggctcccggc 600 tgtccccgcc cggcgtgcga gccggtgtat gggcccctca ccatgtcgct gaagccccag 660 cagcagcagc agcagcagca gcagcagcag cagcagcaac agcagcagca gcagcagcag 720 cagcagccgc cgcccgcggc tgccaatgtc cgcaagcccg gcggcagcgg ccttctagcg 780 tcgcccgccg ccgcgccttc gccgtcctcg tcctcggtct cctcgtcctc ggccacggct 840 ccctcctcgg tggtcgcggc gacctccggc ggcggggaggc ccggcctggg cagaggtcga 900 aacagtaaca aaggactgcc tcagtctacg atttcttttg atggaatcta tgcaaatatg aggatggttc atatacttac atcagttgtt ggctccaaat gtgaagtaca agtgaaaaat ggaggtatat atgaaggagt ttttaaaact tacagtccga agtgtgattt ggtacttgat gccgcacatg agaaaagtac agaatccagt tcggggccga aacgtgaaga aataatggag agtattttgt tcaaatgttc agactttgtt gtggtacagt ttaagatat ggactccagt 1260. tatgcaaaaa gagatgcttt tactgactct gctatcagtg ctaaagtgaa tggcgaacac aaagagaagg acctggagcc ctgggatgca ggtgaactca cagccaatga ggaacttgag gctttggaaa atgacgtatc taatggatgg gatcccaatg atatgtttcg atataatgaa gaaaattatg gtgtagtgtc tacgtatgat agcagtttat cttcgtatac agtgccctta 1440. gaaagagata actcagaaga atttttaaaa cgggaagcaa gggcaaacca gttagcagaa 1500 gaaattgagt caagtgccca gtacaaagct cgagtggccc tggaaaatga tgataggagt 1560 gaggaagaaa aatacacagc agttcagaga aattccagtg aacgtgaggg gcacagcata 1620 aacactaggg aaaataaata tattcctcct ggacaaagaa atagagaagt catatcctgg 1680 ggaagtggga gacagaattc accgcgtatg ggccagcctg gatcgggctc catgccatca 1740 agatccactt ctcacacttc agatttcaac ccgaattctg gttcagacca aagagtagtt 1800 aatggaggtg ttccctggcc atcgccttgc ccatctcctt cctctcgcc acctctcgc 1860 taccagtcag gtcccaactc tcttccacct cgggcagcca ccctacacg gccgccctcc 1920 aggcccccct cgcggccatc cagaccccg tctcacccct ctgctcatgg ttctccagct 1980 cctgtctcta ctatgcctaa acgcatgtct tcagaagggc ctccaaggat gtccccaaag 2040 gcccagcgac atcctcgaaa tcacagagtt tctgctggga ggggttccat atccagtggc 2100 ctagaatttg tatcccacaa cccacccagt gaagcagcta ctcctccagt agcaaggacc 2160 agtccctcgg ggggaacgtg gtcatcagtg gtcagtgggg ttccagatt atcccctaaa 2220 actcatagac ccaggtctcc cagacagac agtattggaa ataccccag tggccagtt 2280 cttgctctc cccaagctgg tattattcca actgaagctg ttgccatgcc tattccagct 2340 gcatctccta cgcctgctag tcctgcatcg aacagagctg ttaccccttc tagtgaggct 2400 aaagattcca gggcttcaaga tcaggcag aactctcctg caggataa agaaaatatt 2460 aaacccaatg aaaaccacc tagctctca aaagctgaaa aaaggtat atcaccagtt 2520 gtttctgaac atagaaaca gattgatgat ttaaagaat ttaagaatga ttttaggtta 2580 cagccaagtt ctacttctga atctatggat ctactta aaaaatag agagggaa 2640 aaatcaagg atttgatcaa agacaaatt gaaccaagtg ctaggattc tttcattgaa 2700 atagcagca gcaactgtac cagtggcagc agcaagccga atagccccag cattcccct 2760 tcaatactta gtaacacgga gcacaagagg ggacctgagg tcactccca aggggttcag 2820 acttccagcc cagcatgtaa acagagaaa gacgatagg agagagaa acagcagct 2880 gagcaagtta ggaaatcaac attgaatccc aatgcaaagg agttcaaccc acgttccttc 2940 tctcagccaa agcctttac taccccaact tcacctcggc ctcaagcaca acctagccca 3000 tctatggtgg gtcatcaaca gccaactcca gtttatactc agcctgtttg ttttgcacca 3060 aatatgatgt atccagtccc agtgagccca ggcgtgcaac ctttataccc aatacctatg 3120 acgcccatgc cagtgaatca agccaagaca tatagagcag taccaaatat gccccaacag 3180 cggcaagacc agcatcatca gagtgccatg atgcacccag cgtcagcagc gggcccaccg 3240 attgcagcca ccccaccagc ttactccacg caatatgttg cctacagtcc tcagcagttc 3300 ccaaatcagc cccttgttca gcatgtgcca cattatcagt ctcagcatcc tcatgtctat 3360 agtcctgtaa tacagggtaa tgctagaatg atggcaccac caacacacgc ccagcctggt 3420 ttagtatctt cttcagcaac tcagtacggg gctcatgagc agacgcatgc gatgtatgca 3480 tgtcccaaat taccatacaa caaggagaca agcccttctt tctactttgc catttccacg 3540 ggctcccttg ctcagcagta tgcgcaccct aacgctaccc tgcacccaca tactccacac 3600 cctcagcctt cagctacccc cactggacag cagcaaagcc aacatggtgg aagtcatcct 3660 gcacccagtc ctgttcagca ccatcagcac caggccgccc aggctctcca tctggccagt 3720 ccacagcagc agtcagccat ttaccacgcg gggcttgcgc caactccacc ctccatgaca 3780 cctgcctcca acacgcagtc gccacagaat agtttcccag cagcacaaca gactgtcttt 3840 acgatccatc cttctcacgt tcagccggcg tataccaacc caccccacat ggcccacgta 3900 cctcaggctc atgtacagtc aggaatggtt ccttctcatc caactgccca tgcgccaatg 3960 atgctaatga cgacacagcc acccggcggt ccccaggccg ccctcgctca aagtgcacta 4020 cagcccattc cagtctcgac aacagcgcat ttcccctata tgacgcaccc ttcagtacaa 4080 gcccaccacc aacagcagtt gtaaggctgc cctggaggaa ccgaaaggcc aaattccctc 4140 ctcccttcta ctgcttctac caactggaag cacagaaaac tagaatttca tttattttgt 4200 ttttaaaata tatatgttga tttcttgtaa catccaatag gaatgctaac agttcacttg 4260 cagtggaaga tacttggacc gagtagaggc atttaggaac ttggggcta ttccataatt 4320 ccatatgctg tttcagagtc ccgcaggtac cccagctctg cttgccgaaa ctggaagtta 4380 tttatttttt aataaccctt gaaagtcatg aacacatcag ctagcaaaag aagtaacaag 4440 agtgattctt gctgctatta ctgctaaaaa aaaaaaaaaa aaaaaatcaa gacttggaac 4500 gcccttttac taaacttgac aaagtttcag taaattctta ccgtcaaact gacggattat 4560 tatttataaa tcaagtttga tgaggtgatc actgtctaca gtggttcaac ttttaagtta 4620 agggaaaaac ttttactttg tagataatat aaaataaaaa cttaaaaaaa atttaaaaaa 4680 taaaaaaagt tttaaaaact gaaaaaaaaa aa 4712 <210> 10 <211> 19 <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotide <400> 10 ttggcctttc ggttcctcc 19 <210> 11 <211> 19 <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotide <400> 11 ggaggaaccg aaaggccaa 19 <210> 12 <211> 148 <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotides <400> 12 tggaggcttg ctgaaggctg tatgctgttg tcttggcctt tcggttcctc cagtgaagcc 60 acagatggga ggaaccgaaa ggccaaagga cacaaggcct gttactagca ctcacatgga 120 acaaatggcc accgtggggaggatgacaa 148 <210> 13 <211> 148 <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotides <400> 13 ttgtcatcct cccacggtgg ccatttgttc catgtgagtg ctagtaacag gccttgtgtc 60 ctttggcctt tcggttcctc ccatctgtgg cttcactgga ggaaccgaaa ggccaagaca 120 acagcataca gccttcagca agcctcca 148 <210> 14 <211> twenty two <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotides <400> 14 atagcagcaa gaatcactct tg 22 <210> 15 <211> twenty two <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotides <400> 15 caagagtgat tcttgctgct at 22 <210> 16 <211> 151 <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotides <400> 16 ctggaggctt gctttgggct gtatgctgat agcagcaaga atcactcttg ttttggcctc 60 tgactgaaca agaggatctt gctgctatca ggacacaagg ccctttatca gcactcacat 120 ggaacaaatg gccaccgtgg gaggatgaca a 151 <210> 17 <211> 151 <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotides <400> 17 ttgtcatcct cccacggtgg ccatttgttc catgtgagtg ctgataaagg gccttgtgtc 60 ctgatagcag caagatcctc ttgttcagtc agaggccaaa acaagagtga ttcttgctgc 120 tatcagcata cagcccaaag caagcctcca g 151 <210> 18 <211> 300 <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotides <400> 18 tggaggcttg ctgaaggctg tatgctgttg tctactgctc tatatgtctt ggcagtgaag 60 ccacagatgg ccaagacata tagagcagta aggacacaag gcctgttact agcactcaca 120 tggaacaaat ggccaccgtg ggaggatgac aatggaggct tgctgaaggc tgtatgctgt 180 tgtcttggcc tttcggttcc tccagtgaag ccacagatgg gaggaaccga aaggccaaag 240 gacacaaggc ctgttactag cactcacatg gaacaaatgg ccaccgtggg aggatgacaa 300 <210> 19 <211> 300 <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotide <400> 19 ttgtcatcct cccacggtgg ccatttgttc catgtgagtg ctagtaacag gccttgtgtc 60 ctttggcctt tcggttcctc ccatctgtgg cttcactgga ggaaccgaaa ggccaagaca 120 acagcataca gccttcagca agcctccatt gtcatcctcc cacggtggcc atttgttcca 180 tgtgagtgct agtaacaggc cttgtgtcct tactgctcta tatgtcttgg ccatctgtgg 240 cttcactgcc aagacatata gagcagtaga caacagcata cagccttcag caagcctcca 300 <210> 20 <211> 23 <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotides <400> 20 ttccagttgg tagaagcagt aga 23 <210> twenty one <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotides <400> twenty one tctactgctt ctaccaactg gaa 23 <210> twenty two <211> 152 <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotides <400> twenty two ctggaggctt gctttgggct gtatgctgtt ccagttggta gaagcagtag attttggcct 60 ctgactgatc tactgttcac caactggaac aggacacaag gccctttatc agcactcaca 120 tggaacaaat ggccaccgtg ggagaggatgac aa 152 <210> twenty three <211> 152 <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotides <400> twenty three ttgtcatcct cccacggtgg ccatttgttc catgtgagtg ctgataaagg gccttgtgtc 60 ctgttccagt tggtgaacag tagatcagtc agaggccaaa atctactgct tctaccaact 120 ggaacagcat acagcccaaa gcaagcctcc ag 152 <210> twenty four <211> 151 <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotides <400> twenty four tggaggcttg ctgaaggctg tatgctgttg tcggggccgg tttcggggcc ttagtgaagc 60 cacagatgta cggccccgaa accggcccca ggacacaagg cctgttacta gcactcacat 120 ggaacaaatg gccaccgtgg gaggatgaca a 151 <210> 25 <211> 151 <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotides <400> 25 ttgtcatcct cccacggtgg ccatttgttc catgtgagtg ctagtaacag gccttgtgtc 60 ctggggccgg tttcggggcc gtacatctgt ggcttcacta aggccccgaa accggccccg 120 acaacagcat acagccttca gcaagcctcc a 151 <210> 26 <211> 4145 <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotides <400> 26 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgggcgacc aaaggtcgcc 60 cgacgcccgg gctttgcccg ggcggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgctag ctctgggtat ttaagcccga gtgagcacgc 180 agggtctcca ttttgaagcg ggaggttacg cgttcgtcga ctactagtgg gtaccagagc 240 tccctaggtt ctagaaccgg tgacgtctcc catggtgaag cttggatctg aattcggtac 300 cctagttatt aatagtaatc aattacgggg tcattagttc atagcccata tatggagttc 360 cgcgttacat aacttacggt aaatggcccg cctggctgac cgcccaacga cccccgccca 420 ttgacgtcaa taatgacgta tgttcccata gtaacgccaa tagggacttt ccattgacgt 480 caatgggtgg actatttacg gtaaactgcc cacttggcag tacatcaagt gtatcatatg 540 ccaagtacgc cccctattga cgtcaatgac ggtaaatggc ccgcctggca ttatgcccag 600 tacatgacct tatgggactt tcctacttgg cagtacatct acgtattagt catcgctatt 660 accatggtcg aggtgagccc cacgttctgc ttcactctcc ccatctcccc cccctcccca 720 cccccaattt tgtatttatt tattttttaa ttattttgtg cagcgatggg ggcgggggg 780 ggggggggc gcgcgccagg cggggcgggg cggggcgagg ggcggggcgg ggcgaggcgg 840 agaggtgcgg cggcagccaa tcagagcggc gcgctccgaa agtttccttt tatggcgagg 900 cggcggcgg ggcggcccta taaaaagcga agcgcgcgg gggcgggagt cgctgcgacg 960 ctgccttcgc cccgtgcccc gctccgccgc cgcctcgcgc cgcccgcccc ggctctgact 1020 gaccgcgtta ctcccacagg tgagcgggcg ggacggccct tctcctcagc gctgtaatta 1080 gcgcttggtt taatgacggc ttgttggagg cttgctgaag gctgtatgct gttgtcgggg 1140 ccggtttcgg ggccttagtg aagccacaga tgtacggccc cgaaaccggc cccaggacac 1200 aaggcctgtt actagcactc acatggaaca aatggccacc gtgggaggat gacaatggag 1260 gcttgctgaa ggctgtatgc tgttgtcttg gcctttcggt tcctccagtg aagccacaga 1320 tgggaggaac cgaaaggcca aggacacaa ggcctgttac tagcactcac atggaacaaa 1380 tggccaccgt gggaggatga caatttctgt ggctgcgtga aagccttgag gggctccggg 1440 agctagagcc tctgctaacc atgttcatgc cttcttcttt ttcctacagc tcctgggcaa 1500 cgtgctggtt attgtgctgt ctcatcattt tggcaaagaa ttcctcgaag atccgaaggg 1560 aaagtcttcc acgactgtgg gatccgttcg aagatatcac cggttgagcc accatgagca 1620 ccctgtgccc cccccccagc cccgccgtgg ccaagaccga gatcgccctg agcggcaaga 1680 gccccctgct ggccgccacc ttcgcctact gggacaacat cctgggcccc cgcgtgcgcc 1740 acatctgggc ccccaagacc gagcaggtgc tgctgagcga cggcgagatc accttcctgg 1800 ccaaccacac cctgaacggc gagatcctgc gcaacgccga gagcggcgcc atcgacgtga 1860 agttcttcgt gctgagcgag aagggcgtga tcatcgtgag cctgatcttc gacggcaact 1920 ggaacggcga ccgcagcacc tacggcctga gcatcatcct gccccagacc gagctgagct 1980 tctacctgcc cctgcaccgc gtgtgcgtgg accgcctgac ccacatcatc cgcaagggcc 2040 gcatctggat gcacaaggag cgccaggaga acgtgcagaa gatcatcctg gagggcaccg 2100 agcgcatgga ggaccagggc cagagcatca tccccatgct gaccggcgag gtgatccccg 2160 tgatggagct gctgagcagc atgaagagcc acagcgtgcc cgaggagatc gacatcgccg acaccgtgct gaacgacgac gacatcggcg acagctgcca cgagggcttc ctgctgaacg ccatcagcag ccacctgcag acctgcggct gcagcgtggt ggtgggcagc agcgccgaga 2340 aggtgaacaa gatcgtgcgc accctgtgcc tgttcctgac ccccgccgag cgcaagtgca gccgcctgtg cgaggccgag agcagcttca agcaggag cggcctgttc gtgcagggcc 2460 tgctgaagga cagcaccggc agcttcgtgc tgcccttccg ccaggtgatg tacgccccct accccaccac ccacatcgac gtggacgtga acaccgtga gcagatgccc ccctgccacg agcacatcta caaccagcgc cgctacatgc gcagcgagct gaccgccttc tggcgcgcca 2640. ccagcgagga ggacatggcc caggacacca tcatctacac cgacgagagc ttcacccccg 2760. acctgaacat cttccaggac gtgctgcacc gcgacaccct ggtgaaggcc ttcctggacc aggtgttcca gctgaagccc ggcctgagcc tgcgcagcac cttcctggcc cagttcctgc 2820 tggtgctgca ccgcaaggcc ctgaccctga tcaagtacat cgaggacgac acccagaagg gcaagaagcc cttcaagagc ctgcgcaacc tgaagatcga cctggacctg accgccgagg 2940 gcgacctgaa catcatcatg gccctggccg agaagatcaa gcccggcctg cacagcttca 3000 tcttcggccg ccccttctac accagcgtgc aggagcgcga cgtgctgatg accttctaac 3060 aattgttaat taagtttaaa ccctcgaggc cgcaagctta tcgataatca acctctggat 3120 tacaaaattt gtgaaagatt gactggtatt cttaactatg ttgctccttt tacgctatgt 3180 ggatacgctg ctttaatgcc tttgtatcat gctattgctt cccgtatggc tttcattttc 3240 tcctccttgt ataaatcctg gttgctgtct ctttatgagg agttgtggcc cgttgtcagg 3300 caacgtggcg tggtgtgcac tgtgtttgct gacgcaaccc ccactggttg gggcattgcc 3360 accacctgtc agctcctttc cgggactttc gctttccccc tccctattgc cacggcggaa 3420 ctcatcgccg cctgccttgc ccgctgctgg acaggggctc ggctgttggg cactgacaat 3480 tccgtggtgt tgtcggggaa atcatcgtcc tttccttggc tgctcgcctg tgttgccacc 3540 tggattctgc gcgggacgtc cttctgctac gtcccttcgg ccctcaatcc agcggacctt 3600 ccttcccgcg gcctgctgcc ggctctgcgg cctcttccgc gtcttcgcct tcgccctcag 3660 acgagtcgga tctccctttg ggccgcctcc ccgcatcgat accgtcgact agagctcgct 3720 gatcagcctc gactgtgcct tctagttgcc agccatctgt tgtttgcccc tcccccgtgc 3780 cttccttgac cctggaaggt gccactccca ctgtcctttc ctaataaaat gaggaaattg 3840 catcgcattg tctgagtagg tgtcattcta ttctgggggg tggggtgggg caggacagca 3900 agggggagga ttgggaagac aatagcaggc atgctgggga gagatccacg ataacaaaca 3960 gcttttttgg ggtgaacata ttgactgaat tccctgcagg ttggccactc cctctctgcg 4020 cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg cgtcgggcga cctttggtcg 4080 cccggcctca gtgagcgagc gagcgcgcag agagggagtg gccaactcca tcactagggg 4140 ttcct 4145 <210> 27 <211> 899 <212> DNA <213> Artificial Sequence <220> <223> Synthetic polynucleotide <400> 27 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgggcgacc aaaggtcgcc 60 cgacgcccgg gctttgcccg ggcggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgctag ctctgggtat ttaagcccga gtgagcacgc 180 agggtctcca ttttgaagcg ggaggttacg cgttcgtcga ctactagtgg gtaccagagc 240 aaaaaaattg tcatcctccc acggtggcca tttgttccat gtgagtgcta gtaacaggcc 300 ttgtgtcctt tggcctttcg gttcctccca tctgtggctt cactggagga accgaaaggc 360 caagacaaca gcatacagcc ttcagcaagc ctccagtggt ctcatacaga acttataaga 420 ttcccaaatc caaagacatt tcacgtttat ggtgatttcc cagaacacat agcgacatgc 480 aaatattgca gggcgccact cccctgtccc tcacagccat cttcctgcca gggcgcacgc 540 gcgctgggtg ttcccgccta gtgacactgg gcccgcgatt ccttggagcg ggttgatgac 600 gtcagcgttt cccatggtga agcttggatc tgatccctag gttctagaac cggtgaccaa 660 ttgttaatta agtttaaacc ctcgaggccg caagcagatc cacgataaca aacagctttt 720 ttggggtgaa catattgact gaattccctg caggttggcc actccctctc tgcgcgctcg 780 ctcgctcact gaggccgccc gggcaaagcc cgggcgtcgg gcgacctttg gtcgcccggc 840 ctcagtgagc gagcgagcgc gcagagaggg agtggccaac tccatcacta ggggttcct 899 <210> 28 <211> 2547 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Polynucleotide <400> 28 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgctag ctctgggtat ttaagcccga gtgagcacgc 180 agggtctcca ttttgaagcg ggaggttacg cgttcgtcga ctactagtgg gtaccagagc 240 tccctaggtt ctagaaccgg tgacgtctcc catggtgaag cttggatctg aattcggtac 300 ctagttatta atagtaatca attacggggt cattagttca tagcccatat atggagttcc 360 gcgttacata acttacggta aatggcccgc ctggctgacc gcccaacgac ccccgcccat 420 tgacgtcaat aatgacgtat gttcccatag taacgccaat agggactttc cattgacgtc 480 aatgggtgga gtatttacgg taaactgccc acttggcagt acatcaagtg tatcatatgc 540 caagtacgcc ccctattgac gtcaatgacg gtaaatggcc cgcctggcat tatgcccagt 600 acatgacctt atgggacttt cctacttggc agtacatcta cgtattagtc atcgctatta 660 ccatggtcga ggtgagcccc acgttctgct tcactctccc catctccccc ccctccccac 720 ccccaatttt gtatttattt attttttaat tattttgtgc agcgatgggg gcgggggggg 780 ggggggggcg cgcgccaggc ggggcggggc ggggcgaggg gcggggcggg gcgaggcgga 840 gaggtgcggc ggcagccaat cagagcggcg cgctccgaaa gtttcctttt atggcgaggc 900 ggcggcggcg gcggccctat aaaaagcgaa gcgcgcggcg ggcgggagtc gctgcgacgc 960 tgccttcgcc ccgtgccccg ctccgccgcc gcctcgcgcc gcccgccccg gctctgactg 1020 accgcgttac tcccacaggt gagcgggcgg gacggccctt ctcctcagcg ctgtaattag 1080 cgcttggttt aatgacggct tgttggaggc ttgctgaagg ctgtatgctg ttgtcttggc 1140 ctttcggttc ctccagtgaa gccacagatg ggaggaaccg aaaggccaaa ggacacaagg 1200 cctgttacta gcactcacat ggaacaaatg gccaccgtgg gaggatgaca atttctgtgg 1260 ctgcgtgaaa gccttgaggg gctccgggag ctagagcctc tgctaaccat gttcatgcct 1320 tcttcttttt cctacagctc ctgggcaacg tgctggttat tgtgctgtct catcattttg 1380 gcaaagaatt cctcgaagat ccgaagggaa agtcttccac gactgtggga tccgttcgaa 1440 gatatcaccg gttgagccac ccaattgtta attaagttta aaccctcgag gccgcaagct 1500 tatcgataat caacctctgg attacaaaat ttgtgaaaga ttgactggta ttcttaacta 1560 tgttgctcct tttacgctat gtggatacgc tgctttaatg cctttgtatc atgctattgc 1620 ttcccgtatg gctttcattt tctcctcctt gtataaatcc tggttgctgt ctctttatga 1680 ggagttgtgg cccgttgtca ggcaacgtgg cgtggtgtgc actgtgtttg ctgacgcaac 1740 ccccactggt tggggcattg ccaccacctg tcagctcctt tccgggactt tcgctttccc 1800 cctccctatt gccacggcgg aactcatcgc cgcctgcctt gcccgctgct ggacaggggc 1860 tcggctgttg ggcactgaca attccgtggt gttgtcgggg aaatcatcgt cctttccttg 1920 gctgctcgcc tgtgttgcca cctggattct gcgcgggacg tccttctgct acgtcccttc 1980 ggccctcaat ccagcggacc ttccttcccg cggcctgctg ccggctctgc ggcctcttcc 2040 gcgtcttcgc cttcgccctc agacgagtcg gatctccctt tgggccgcct ccccgcatcg 2100 ataccgtcga ctagagctcg ctgatcagcc tcgactgtgc cttctagttg ccagccatct 2160 gttgtttgcc cctcccccgt gccttccttg accctggaag gtgccactcc cactgtcctt 2220 tcctaataaa atgaggaaat tgcatcgcat tgtctgagta ggtgtcattc tattctgggg 2280 ggtggggtgg ggcaggacag caagggggag gattgggaag acaatagcag gcatgctggg 2340 gagagatcca cgataacaaa cagctttttt ggggtgaaca tattgactga attccctgca 2400 ggttggccac tccctctctg cgcgctcgct cgctcactga ggccgcccgg gcaaagcccg 2460 ggcgtcgggc gacctttggt cgcccggcct cagtgagcga gcgagcgcgc agagagggag 2520 tggccaactc catcactagg ggttcct 2547 <210> 29 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Polynucleotide <400> 29 tattagatct gatggccgc 19 <210> 30 <211> 20 <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotides <400> 30 ctccatcact aggggttcct 20 <210> 31 <211> 60 <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotides <400> 31 agctctgggt atttaagccc gagtgagcac gcagggtctc cattttgaag cgggaggtta 60 <210> 32 <211> 145 <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotides <400> 32 aggaacccct agtgatggag ttggccactc cctctctgcg cgctcgctcg ctcactgagg 60 ccgggcgacc aaaggtcgcc cgacgcccgg gctttgcccg ggcggcctca gtgagcgagc 120 gagcgcgcag agaggggagtg gccaa 145 <210> 33 <211> twenty four <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotides <400> 33 gtgtactagg atcttttact tgaa 24 <210> 34 <211> twenty four <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotides <400> 34 ttcaagtaaa agatcctagt acac 24 <210> 35 <211> 267 <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotides <400> 35 gtgatatcac aaggtcccag ggctggggtc agaaattctc tcccgaggga atgaagccac 60 aggagccaag agcaggagga ccaaggccct ggcgaaggcc gtggcctcgt tcaagtaaaa 120 gatcctagta cagtgcaggt cccaatgtgt actaggatct tttacttgaa cggggacgcc 180 ggcatccggg ctcaggaccc ccctctctgc cagaggcacc aacaccagag ttcacaaatc 240 agtctcctgc cctttgcatg tagcaaa 267 <210> 36 <211> 267 <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotides <400> 36 tttgctacat gcaaagggca ggagactgat ttgtgaactc tggtgttggt gcctctggca 60 gagagggggg tcctgagccc ggatgccggc gtccccgttc aagtaaaaga tcctagtaca 120 cattgggacc tgcactgtac taggatcttt tacttgaacg aggccacggc cttcgccagg 180 gccttggtcc tcctgctctt ggctcctgtg gcttcattcc ctcgggagag aatttctgac 240 cccagccctg ggaccttgtg atatcac 267 <210> 37 <211> 19 <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotides <400> 37 atgcatccat attcttcct 19 <210> 38 <211> 19 <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotides <400> 38 aggaagaata tggatgcat 19 <210> 39 <211> 148 <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotides <400> 39 tggaggcttg ctgaaggctg tatgctgttg tcatgcatcc atattcttcc tagtgaagcc 60 acagatgagg aagaatatgg atgcatagga cacaaggcct gttactagca ctcacatgga 120 acaaatggcc accgtggggaggatgacaa 148 <210> 40 <211> 19 <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotides <400> 40 ttatttactt tctctgcac 19 <210> 41 <211> 19 <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotides <400> 41 gtgcagagaa agtaaataa 19 <210> 42 <211> 148 <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotides <400> 42 tggaggcttg ctgaaggctg tatgctgttg tcttatttac tttctctgca cagtgaagcc 60 acagatggtg cagagaaagt aaataaagga cacaaggcct gttactagca ctcacatgga 120 acaaatggcc accgtggggaggatgacaa 148 <210> 43 <211> 151 <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotides <400> 43 tggaggcttg ctgaaggctg tatgctgttg tcggggccgg tttcggggcc ttagtgaagc 60 cacagatgta cggccccgaa accggcccca ggacacaagg cctgttacta gcactcacat 120 ggaacaaatg gccaccgtgg gaggatgaca a 151 <210> 44 <211> 151 <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotide <400> 44 tggaggcttg ctgaaggctg tatgctgttg tcggggccgg tttcggggcc ttagtgaagc 60 cacagatgta cggccccgaa accggcccca ggacacaagg cctgttacta gcactcacat 120 ggaacaaatg gccaccgtgg gaggatgaca a 151 <210> 45 <211> 296 <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotide <400> 45 ttgtcatcct cccacggtgg ccatttgttc catgtgagtg ctgataaagg gccttgtgtc 60 ctgtctggtt aatctttatc aggttcagtc agaggccaaa aacctgataa agattaacca 120 gacagcatac agcccaaagc aagcctccag ttgtcatcct cccacggtgg ccatttgttc 180 catgtgagtg ctgataaagg gccttgtgtc ctgcggttgc ggtgcctgcg cctcagtcag 240 aggccaaaag gcgcaggcac cgcaaccgca gcatacagcc caaagcaagc ctccag 296 <210> 46 <211> 296 <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotide <400> 46 ctggaggctt gctttgggct gtatgctgcg gttgcggtgc ctgcgccttt tggcctctga 60 ctgaggcgca ggcaccgcaa ccgcaggaca caaggccctt tatcagcact cacatggaac 120 aaatggccac cgtgggagga tgacaactgg aggcttgctt tgggctgtat gctgtctggt 180 taatctttat caggtttttg gcctctgact gaacctgata aagattaacc agacaggaca 240 caaggccctt tatcagcact cacatggaac aaatggccac cgtgggagga tgacaa 296 <210> 47 <211> 297 <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotide <400> 47 ttgtcatcct cccacggtgg ccatttgttc catgtgagtg ctgataaagg gccttgtgtc 60 ctgggttgtt tccctccttg ttttcagtca gaggccaaaa taaacaagga gggaaacaac 120 ccagcataca gcccaaagca agcctccagt tgtcatcctc ccacggtggc catttgttcc 180 atgtgagtgc tgataaaggg ccttgtgtcc tggctgcggt tgcggtgcct gctcagtcag 240 aggccaaaag caggcaccgc aaccgcagcc agcatacagc ccaaagcaag cctccag 297 <210> 48 <211> 297 <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotide <400> 48 ctggaggctt gctttgggct gtatgctggc tgcggttgcg gtgcctgctt ttggcctctg 60 actgagcagg caccgcaacc gcagccagga cacaaggccc tttatcagca ctcacatgga 120 acaaatggcc accgtgggag gatgacaact ggaggcttgc tttgggctgt atgctgggtt 180 gtttccctcc ttgtttattt tggcctctga ctgaaaacaa ggagggaaac aacccaggac 240 acaaggccct ttatcagcac tcacatggaa caaatggcca ccgtgggagg atgacaa 297 <210> 49 <211> 294 <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotide <400> 49 ttgtcatcct cccacggtgg ccatttgttc catgtgagtg ctgataaagg gccttgtgtc 60 ctgtttcttc tggttaatct ttatcagtca gaggccaaaa taaagattaa ccagaagaaa 120 cagcatacag cccaaagcaa gcctccagtt gtcatcctcc cacggtggcc atttgttcca 180 tgtgagtgct gataaagggc cttgtgtcct gcggtgcctg cgcccgcggc tcagtcagag 240 gccaaaagcc gcgggcgcag gcaccgcagc atacagccca aagcaagcct ccag 294 <210> 50 <211> 294 <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotide <400> 50 ctggaggctt gctttgggct gtatgctgcg gtgcctgcgc ccgcggcttt tggcctctga 60 ctgagccgcg ggcgcaggca ccgcaggaca caaggccctt tatcagcact cacatggaac 120 aaatggccac cgtgggagga tgacaactgg aggcttgctt tgggctgtat gctgtttctt 180 ctggttaatc tttattttgg cctctgactg ataaagatta accagaagaa acaggacaca 240 aggcccttta tcagcactca catggaacaa atggccaccg tgggaggatg acaa 294 <210> 51 <211> 1446 <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotide <400> 51 atgagcaccc tgtgcccccc ccccagcccc gccgtggcca agaccgagat cgccctgagc 60 ggcaagagcc ccctgctggc cgccaccttc gcctactggg acaacatcct gggcccccgc 120 gtgcgccaca tctgggcccc caagaccgag caggtgctgc tgagcgacgg cgagatcacc 180 ttcctggcca accacaccct gaacggcgag atcctgcgca acgccgagag cggcgccatc 240 gacgtgaagt tcttcgtgct gagcgagaag ggcgtgatca tcgtgagcct gatcttcgac 300 ggcaactgga acggcgaccg cagcacctac ggcctgagca tcatcctgcc ccagaccgag 360 ctgagcttct acctgcccct gcaccgcgtg tgcgtggacc gcctgaccca catcatccgc 420 aagggccgca tctggatgca caaggagcgc caggagaacg tgcagaagat catcctggag 480 ggcaccgagc gcatggagga ccagggccag agcatcatcc ccatgctgac cggcgaggtg 540 atccccgtga tggagctgct gagcagcatg aagagccaca gcgtgcccga ggagatcgac 600 atcgccgaca ccgtgctgaa cgacgacgac atcggcgaca gctgccacga gggcttcctg 660 ctgaacgcca tcagcagcca cctgcagacc tgcggctgca gcgtggtggt gggcagcagc 720 gccgagaagg tgaacaagat cgtgcgcacc ctgtgcctgt tcctgacccc cgccgagcgc 780 aagtgcagcc gcctgtgcga ggccgagagc agcttcaagt acgagagcgg cctgttcgtg 840 cagggcctgc tgaaggacag caccggcagc ttcgtgctgc ccttcgcca ggtgatgtac 900 gcccccctacc ccaccaccca catcgacgtg gacgtgaaca ccgtgaagca gatgcccccc 960 tgccacgagc acatctacaa ccagcgccgc tacatgcgca gcgagctgac cgccttctgg 1020 cgcgccacca gcgaggaga catggcccag gacaccatca tctacaccga cgagagcttc 1080 acccccgacc tgaacatctt ccaggacgtg ctgcaccgcg acaccctggt gaaggccttc 1140 ctggaccagg tgttccagct gaagcccggc ctgagcctgc gcagcacctt cctggcccag 1200 1260 cagaagggca agaagccctt caagagcctg cgcaacctga agatcgacct ggacctgacc 1320 gccgagggcg acctgaacat catcatggcc ctggccgaga agatcaagcc cggcctgcac 1380 agcttcatct tcggccgccc cttctacacc agcgtgcagg agcgcgacgt gctgatgacc 1440 ttctaa 1446 <210> 52 <211> 3994 <212> DNA <213> Artificial sequence <220> <223> Synthetic polynucleotide <400> 52 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgggcgacc aaaggtcgcc 60 cgacgcccgg gctttgcccg ggcggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgctag ctctgggtat ttaagcccga gtgagcacgc 180 agggtctcca ttttgaagcg ggaggttacg cgttcgtcga ctactagtgg gtaccagagc 240 tccctaggtt ctagaaccgg tgacgtctcc catggtgaag cttggatctg aattcggtac 300 cctagttatt aatagtaatc aattacgggg tcattagttc atagcccata tatggagttc 360 cgcgttacat aacttacggt aaatggcccg cctggctgac cgcccaacga cccccgccca 420 ttgacgtcaa taatgacgta tgttcccata gtaacgccaa tagggacttt ccattgacgt 480 caatgggtgg actatttacg gtaaactgcc cacttggcag tacatcaagt gtatcatatg 540 ccaagtacgc cccctattga cgtcaatgac ggtaaatggc ccgcctggca ttatgcccag 600 tacatgacct tatgggactt tcctacttgg cagtacatct acgtattagt catcgctatt 660 accatggtcg aggtgagccc cacgttctgc ttcactctcc ccatctcccc cccctcccca 720 cccccaattt tgtatttatt tattttttaa ttattttgtg cagcgatggg ggcggggggg 780 gggggggggc gcgcgccagg cggggcgggg cggggcgagg ggcggggcgg ggcgaggcgg 840 agaggtgcgg cggcagccaa tcagagcggc gcgctccgaa agtttccttt tatggcgagg 900 cggcggcggc ggcggcccta taaaaagcga agcgcgcggc gggcgggagt cgctgcgacg 960 ctgccttcgc cccgtgcccc gctccgccgc cgcctcgcgc cgcccgcccc ggctctgact 1020 gaccgcgtta ctcccacagg tgagcgggcg ggacggccct tctcctcagc gctgtaatta 1080 gcgcttggtt taatgacggc ttgttggagg cttgctgaag gctgtatgct gttgtcatgc 1140 atccatattc ttcctagtga agccacagat gaggaagaat atggatgcat aggacacaag 1200 gcctgttact agcactcaca tggaacaaat ggccaccgtg ggaggatgac aatttctgtg 1260 gctgcgtgaa agccttgagg ggctccggga gctagagcct ctgctaacca tgttcatgcc 1320 ttcttcttt tcctacagct cctgggcaac gtgctggtta ttgtgctgtc tcatcattttt 1380 ggcaaagaat tcctcgaaga tccgaaggga aagtcttcca cgactgtggg atccgttcga 1440 agatatcacc ggttgagcca ccatgagcac cctgtgcccc ccccccagcc ccgccgtggc 1500 caagaccgag atcgccctga gcggcaagag ccccctgctg gccgccacct tcgcctactg 1560 ggacaacatc ctgggccccc gcgtgcgcca catctgggcc cccaagaccg agcaggtgct 1620 gctgagcgac ggcgagatca ccttcctggc caaccacacc ctgaacggcg agatcctgcg 1680 caacgccgag agcggcgcca tcgacgtgaa gttcttcgtg ctgagcgaga agggcgtgat 1740 catcgtgagc ctgatcttcg acggcaactg gaacggcgac cgcagcacct acggcctgag 1800 catcatcctg ccccagaccg agctgagctt ctacctgccc ctgcaccgcg tgtgcgtgga 1860 ccgcctgacc cacatcatcc gcaagggccg catctggatg cacaaggagc gccaggagaa 1920 cgtgcagaag atcatcctgg agggcaccga gcgcatggag gaccagggcc agagcatcat 1980 ccccatgctg accggcgagg tgatccccgt gatggagctg ctgagcagca tgaagagcca 2040 cagcgtgccc gaggagatcg acatcgccga caccgtgctg aacgacgacg acatcggcga 2100 cagctgccac gagggcttcc tgctgaacgc catcagcagc cacctgcaga cctgcggctg 2160 cagcgtggtg gtgggcagca gcgccgagaa ggtgaacaag atcgtgcgca ccctgtgcct 2220 gttcctgacc cccgccgagc gcaagtgcag ccgcctgtgc gaggccgaga gcagcttcaa 2280 gtacgagagc ggcctgttcg tgcagggcct gctgaaggac agcaccggca gcttcgtgct 2340 gcccttccgc caggtgatgt acgcccccta ccccaccacc cacatcgacg tggacgtgaa 2400 caccgtgaag cagatgcccc cctgccacga gcacatctac aaccagcgcc gctacatgcg 2460 cagcgagctg accgccttct ggcgcgccac cagcgaggag gacatggccc aggacaccat 2520 catctacacc gacgagagct tcacccccga cctgaacatc ttccaggacg tgctgcaccg 2580 cgacaccctg gtgaaggcct tcctggacca ggtgttccag ctgaagcccg gcctgagcct 2640 gcgcagcacc ttcctggccc agttcctgct ggtgctgcac cgcaaggccc tgaccctgat 2700 caagtacatc gaggacgaca cccagaaggg caagaagccc ttcaagagcc tgcgcaacct 2760 gaagatcgac ctggacctga ccgccgaggg cgacctgaac atcatcatgg ccctggccga 2820 gaagatcaag cccggcctgc acagcttcat cttcggccgc cccttctaca ccagcgtgca 2880 ggagcgcgac gtgctgatga ccttctaaca attgttaatt aagtttaaac cctcgaggcc 2940 gcaagcttat cgataatcaa cctctggatt acaaaatttg tgaaagattg actggtattc 3000 ttaactatgt tgctcctttt acgctatgtg gatacgctgc tttaatgcct ttgtatcatg 3060 ctattgcttc ccgtatggct ttcattttct cctccttgta taaatcctgg ttgctgtctc 3120 tttatgagga gttgtggccc gttgtcaggc aacgtggcgt ggtgtgcact gtgtttgctg 3180 acgcaacccc cactggttgg ggcattgcca ccacctgtca gctcctttcc gggactttcg 3240 ctttccccct ccctattgcc acggcggaac tcatcgccgc ctgccttgcc cgctgctgga 3300 caggggctcg gctgttgggc actgacaatt ccgtggtgtt gtcggggaaa tcatcgtcct 3360 ttccttggct gctcgcctgt gttgccacct ggattctgcg cgggacgtcc ttctgctacg 3420 tcccttcggc cctcaatcca gcggaccttc cttcccgcgg cctgctgccg gctctgcggc 3480 ctcttccgcg tcttcgcctt cgccctcaga cgagtcggat ctccctttgg gccgcctccc 3540 cgcatcgata ccgtcgacta gagctcgctg atcagcctcg actgtgcctt ctagttgcca 3600 gccatctgtt gtttgcccct cccccgtgcc ttccttgacc ctggaaggtg ccactcccac 3660 tgtcctttcc taataaaatg aggaaattgc atcgcattgt ctgagtaggt gtcattctat 3720 tctggggggt ggggtggggc aggacagcaa gggggaggat tgggaagaca atagcaggca 3780 tgctggggag agatccacga taacaaacag cttttttggg gtgaacatat tgactgaatt 3840 ccctgcaggt tggccactcc ctctctgcgc gctcgctcgc tcactgaggc cgcccgggca 3900 aagcccgggc gtcgggcgac ctttggtcgc ccggcctcag tgagcgagcg agcgcgcaga 3960 gagggagtgg ccaactccat cactaggggt tcct 3994 <210> 53 <211> 3997 <212> DNA <213> Artificial Sequence <220> <223> Synthetic polynucleotide <400> 53 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgggcgacc aaaggtcgcc 60 cgacgcccgg gctttgcccg ggcggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgctag ctctgggtat ttaagcccga gtgagcacgc 180 agggtctcca ttttgaagcg ggaggttacg cgttcgtcga ctactagtgg gtaccagagc 240 tccctaggtt ctagaaccgg tgacgtctcc catggtgaag cttggatctg aattcggtac 300 cctagttatt aatagtaatc aattacgggg tcattagttc atagcccata tatggagttc 360 cgcgttacat aacttacggt aaatggcccg cctggctgac cgcccaacga cccccgccca 420 ttgacgtcaa taatgacgta tgttcccata gtaacgccaa tagggacttt ccattgacgt 480 caatgggtgg actatttacg gtaaactgcc cacttggcag tacatcaagt gtatcatatg 540 ccaagtacgc cccctattga cgtcaatgac ggtaaatggc ccgcctggca ttatgcccag 600 tacatgacct tatgggactt tcctacttgg cagtacatct acgtattagt catcgctatt 660 accatggtcg aggtgagccc cacgttctgc ttcactctcc ccatctcccc cccctcccca 720 cccccaattt tgtatttatt tattttttaa ttattttgtg cagcgatggg ggcgggggg 780 ggggggggc gcgcgccagg cggggcgggg cggggcgagg ggcggggcgg ggcgaggcgg 840 agaggtgcgg cggcagccaa tcagagcggc gcgctccgaa agtttccttt tatggcgagg 900 cggcggcgg ggcggcccta taaaaagcga agcgcgcgg gggcgggagt cgctgcgacg 960 ctgccttcgc cccgtgcccc gctccgccgc cgcctcgcgc cgcccgcccc ggctctgact 1020 gaccgcgtta ctcccacagg tgagcgggcg ggacggccct tctcctcagc gctgtaatta 1080 gcgcttggtt taatgacggc ttgttggagg cttgctgaag gctgtatgct gttgtcgggg 1140 ccggtttcgg ggccttagtg aagccacaga tgtacggccc cgaaaccggc cccaggacac 1200 aaggcctgtt actagcactc acatggaaca aatggccacc gtgggaggat gacaatttct 1260 gtggctgcgt gaaagccttg aggggctccg ggagctagag cctctgctaa ccatgttcat 1320 gccttcttct ttttcctaca gctcctgggc aacgtgctgg ttatgtgct gtctcatcat 1380 tttggcaaag aattcctcga agatccgaag ggaaagtctt ccacgactgt gggatccgtt 1440 cgaagatatc accggttgag ccaccatgag caccctgtgc ccccccccca gccccgccgt 1500 ggccaagacc gagatcgccc tgagcggcaa gagccccctg ctggccgcca ccttcgccta 1560 ctgggacaac atcctgggcc cccgcgtgcg ccacatctgg gcccccaaga ccgagcaggt 1620 gctgctgagc gacggcgaga tcaccttcct ggccaaccac accctgaacg gcgagatcct 1680 gcgcaacgcc gagagcggcg ccatcgacgt gaagttcttc gtgctgagcg agaagggcgt 1740 gatcatcgtg agcctgatct tcgacggcaa ctggaacggc gaccgcagca cctacggcct 1800 gagcatcatc ctgccccaga ccgagctgag cttctacctg cccctgcacc gcgtgtgcgt 1860 ggaccgcctg acccacatca tccgcaaggg ccgcatctgg atgcacaagg agcgccagga 1920 gaacgtgcag aagatcatcc tggagggcac cgagcgcatg gaggaccagg gccagagcat 1980 catccccatg ctgaccggcg aggtgatccc cgtgatggag ctgctgagca gcatgaagag 2040 ccacagcgtg cccgaggaga tcgacatcgc cgacaccgtg ctgaacgacg acgacatcgg 2100 cgacagctgc cacgagggct tcctgctgaa cgccatcagc agccacctgc agacctgcgg 2160 ctgcagcgtg gtggtgggca gcagcgccga gaaggtgaac aagatcgtgc gcaccctgtg 2220 cctgttcctg acccccgccg agcgcaagtg cagccgcctg tgcgaggccg agagcagctt 2280 caagtacgag agcggcctgt tcgtgcaggg cctgctgaag gacagcaccg gcagcttcgt 2340 gctgcccttc cgccaggtga tgtacgcccc ctaccccacc acccacatcg acgtggacgt 2400 gaacaccgtg aagcagatgc ccccctgcca cgagcacatc tacaaccagc gccgctacat 2460 gcgcagcgag ctgaccgcct tctggcgcgc caccagcgag gaggacatgg cccaggacac 2520 catcatctac accgacgaga gcttcacccc cgacctgaac atcttccagg acgtgctgca 2580 ccgcgacacc ctggtgaagg ccttcctgga ccaggtgttc cagctgaagc ccggcctgag 2640 cctgcgcagc accttcctgg cccagttcct gctggtgctg caccgcaagg ccctgaccct 2700 gatcaagtac atcgaggacg acacccagaa gggcaagaag cccttcaaga gcctgcgcaa 2760 cctgaagatc gacctggacc tgaccgccga gggcgacctg aacatcatca tggccctggc 2820 cgagaagatc aagcccggcc tgcacagctt catcttcggc cgccccttct acaccagcgt 2880 gcaggagcgc gacgtgctga tgaccttcta acaattgtta attaagttta aaccctcgag 2940 gccgcaagct tatcgataat caacctctgg attacaaaat ttgtgaaaga ttgactggta 3000 ttcttaacta tgttgctcct tttacgctat gtggatacgc tgctttaatg cctttgtatc 3060 atgctattgc ttcccgtatg gctttcattt tctcctcctt gtataaatcc tggttgctgt 3120 ctctttatga ggagttgtgg cccgttgtca ggcaacgtgg cgtggtgtgc actgtgtttg 3180 ctgacgcaac ccccactggt tggggcattg ccaccacctg tcagctcctt tccgggactt 3240 tcgctttccc cctccctatt gccacggcgg aactcatcgc cgcctgcctt gcccgctgct 3300 ggacaggggc tcggctgttg ggcactgaca attccgtggt gttgtcgggg aaatcatcgt 3360 cctttccttg gctgctcgcc tgtgttgcca cctggattct gcgcgggacg tccttctgct 3420 acgtcccttc ggccctcaat ccagcggacc ttccttcccg cggcctgctg ccggctctgc 3480 ggcctcttcc gcgtcttcgc cttcgccctc agacgagtcg gatctccctt tgggccgcct 3540 ccccgcatcg ataccgtcga ctagagctcg ctgatcagcc tcgactgtgc cttctagttg 3600 ccagccatct gttgtttgcc cctcccccgt gccttccttg accctggaag gtgccactcc 3660 cactgtcctt tcctaataaa atgaggaaat tgcatcgcat tgtctgagta ggtgtcattc 3720 tattctgggg ggtggggtgg ggcaggacag caagggggag gattgggaag acaatagcag 3780 gcatgctggg gagagatcca cgataacaaa cagctttttt ggggtgaaca tattgactga 3840 attccctgca ggttggccac tccctctctg cgcgctcgct cgctcactga ggccgcccgg 3900 gcaaagcccg ggcgtcgggc gacctttggt cgcccggcct cagtgagcga gcgagcgcgc 3960 agagagggag tggccaactc catcactagg ggttcct 3997 <210> 54 <211> 3994 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Polynucleotide <400> 54 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgggcgacc aaaggtcgcc 60 cgacgcccgg gctttgcccg ggcggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgctag ctctgggtat ttaagcccga gtgagcacgc 180 agggtctcca ttttgaagcg ggaggttacg cgttcgtcga ctactagtgg gtaccagagc 240 tccctaggtt ctagaaccgg tgacgtctcc catggtgaag cttggatctg aattcggtac 300 cctagttatt aatagtaatc aattacgggg tcattagttc atagcccata tatggagttc 360 cgcgttacat aacttacggt aaatggcccg cctggctgac cgcccaacga cccccgccca 420 ttgacgtcaa taatgacgta tgttcccata gtaacgccaa tagggacttt ccattgacgt 480 caatgggtgg actatttacg gtaaactgcc cacttggcag tacatcaagt gtatcatatg 540 ccaagtacgc cccctattga cgtcaatgac ggtaaatggc ccgcctggca ttatgcccag 600 tacatgacct tatgggactt tcctacttgg cagtacatct acgtattagt catcgctatt 660 accatggtcg aggtgagccc cacgttctgc ttcactctcc ccatctcccc cccctcccca 720 cccccaattt tgtatttatt tattttttaa ttattttgtg cagcgatggg ggcggggggg 780 gggggggggc gcgcgccagg cggggcgggg cggggcgagg ggcggggcgg ggcgaggcgg 840 agaggtgcgg cggcagccaa tcagagcggc gcgctccgaa agtttccttt tatggcgagg 900 cggcggcggc ggcggcccta taaaaagcga agcgcgcggc gggcgggagt cgctgcgacg 960 ctgccttcgc cccgtgcccc gctccgccgc cgcctcgcgc cgcccgcccc ggctctgact 1020 gaccgcgtta ctcccacagg tgagcgggcg ggacggccct tctcctcagc gctgtaatta 1080 gcgcttggtt taatgacggc ttgttggagg cttgctgaag gctgtatgct gttgtcttat 1140 ttactttctc tgcacagtga agccacagat ggtgcagaga aagtaaata aggacacaag 1200 gcctgttact agcactcaca tggaacaaat ggccaccgtg ggaggatgac aatttctgtg 1260 gctgcgtgaa agccttgagg ggctccggga gctagagcct ctgctaacca tgttcatgcc 1320 ttctttttt tcctacagct cctgggcaac gtgctggtta ttgtgctgtc tcatcatttt 1380 ggcaaagaat tcctcgaaga tccgaaggga aagtcttcca cgactgtggg atccgttcga 1440 agatatcacc ggttgagcca ccatgagcac cctgtgcccc ccccccagcc ccgccgtggc 1500 caagaccgag atcgccctga gcggcaagag ccccctgctg gccgccacct tcgcctactg 1560 ggacaacatc ctgggccccc gcgtgcgcca catctgggcc cccaagaccg agcaggtgct 1620 gctgagcgac ggcgagatca ccttcctggc caaccacacc ctgaacggcg agatcctgcg 1680 caacgccgag agcggcgcca tcgacgtgaa gttcttcgtg ctgagcgaga agggcgtgat 1740 catcgtgagc ctgatcttcg acggcaactg gaacggcgac cgcagcacct acggcctgag 1800 catcatcctg ccccagaccg agctgagctt ctacctgccc ctgcaccgcg tgtgcgtgga 1860 ccgcctgacc cacatcatcc gcaagggccg catctggatg cacaaggagc gccaggagaa 1920 cgtgcagaag atcatcctgg agggcaccga gcgcatggag gaccagggcc agagcatcat 1980 ccccatgctg accggcgagg tgatccccgt gatggagctg ctgagcagca tgaagagcca 2040 cagcgtgccc gaggagatcg acatcgccga caccgtgctg aacgacgacg acatcggcga 2100 cagctgccac gagggcttcc tgctgaacgc catcagcagc cacctgcaga cctgcggctg 2160 cagcgtggtg gtgggcagca gcgccgagaa ggtgaacaag atcgtgcgca ccctgtgcct 2220 gttcctgacc cccgccgagc gcaagtgcag ccgcctgtgc gaggccgaga gcagcttcaa 2280 gtacgagagc ggcctgttcg tgcagggcct gctgaaggac agcaccggca gcttcgtgct 2340 gcccttccgc caggtgatgt acgcccccta ccccaccacc cacatcgacg tggacgtgaa 2400 caccgtgaag cagatgcccc cctgccacga gcacatctac aaccagcgcc gctacatgcg 2460 cagcgagctg accgccttct ggcgcgccac cagcgaggag gacatggccc aggacaccat 2520 catctacacc gacgagagct tcacccccga cctgaacatc ttccaggacg tgctgcaccg 2580 cgacaccctg gtgaaggcct tcctggacca ggtgttccag ctgaagcccg gcctgagcct 2640 gcgcagcacc ttcctggccc agttcctgct ggtgctgcac cgcaaggccc tgaccctgat 2700 caagtacatc gaggacgaca cccagaaggg caagaagccc ttcaagagcc tgcgcaacct 2760 gaagatcgac ctggacctga ccgccgaggg cgacctgaac atcatcatgg ccctggccga 2820 gaagatcaag cccggcctgc acagcttcat cttcggccgc cccttctaca ccagcgtgca 2880 ggagcgcgac gtgctgatga ccttctaaca attgttaatt aagtttaaac cctcgaggcc 2940 gcaagcttat cgataatcaa cctctggatt acaaaatttg tgaaagattg actggtattc 3000 ttaactatgt tgctcctttt acgctatgtg gatacgctgc tttaatgcct ttgtatcatg 3060 ctattgcttc ccgtatggct ttcattttct cctccttgta taaatcctgg ttgctgtctc 3120 tttatgagga gttgtggccc gttgtcaggc aacgtggcgt ggtgtgcact gtgtttgctg 3180 acgcaacccc cactggttgg ggcattgcca ccacctgtca gctcctttcc gggactttcg 3240 ctttccccct ccctattgcc acggcggaac tcatcgccgc ctgccttgcc cgctgctgga 3300 caggggctcg gctgttgggc actgacaatt ccgtggtgtt gtcggggaaa tcatcgtcct 3360 ttccttggct gctcgcctgt gttgccacct ggattctgcg cgggacgtcc ttctgctacg 3420 tcccttcggc cctcaatcca gcggaccttc cttcccgcgg cctgctgccg gctctgcggc 3480 ctcttccgcg tcttcgcctt cgccctcaga cgagtcggat ctccctttgg gccgcctccc 3540 cgcatcgata ccgtcgacta gagctcgctg atcagcctcg actgtgcctt ctagttgcca 3600 gccatctgtt gtttgcccct cccccgtgcc ttccttgacc ctggaaggtg ccactcccac 3660 tgtcctttcc taataaaatg aggaaattgc atcgcattgt ctgagtaggt gtcattctat 3720 tctggggggt ggggtggggc aggacagcaa gggggaggat tgggaagaca atagcaggca 3780 tgctggggag agatccacga taacaaacag cttttttggg gtgaacatat tgactgaatt 3840 ccctgcaggt tggccactcc ctctctgcgc gctcgctcgc tcactgaggc cgcccgggca 3900 aagcccgggc gtcgggcgac ctttggtcgc ccggcctcag tgagcgagcg agcgcgcaga 3960 gagggagtgg ccaactccat cactaggggt tcct 3994 <210> 55 <211> 902 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Polynucleotide <400> 55 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgggcgacc aaaggtcgcc 60 cgacgcccgg gctttgcccg ggcggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgctag ctctgggtat ttaagcccga gtgagcacgc 180 agggtctcca ttttgaagcg ggaggttacg cgttcgtcga ctactagtgg gtaccagagc 240 aaaaaaattg tcatcctccc acggtggcca tttgttccat gtgagtgcta gtaacaggcc 300 ttgtgtcctg gggccggttt cggggccgta catctgtggc ttcactaagg ccccgaaacc 360 ggccccgaca acagcataca gccttcagca agcctccagt ggtctcatac agaacttata 420 agattcccaa atccaaagac atttcacgtt tatggtgatt tcccagaaca catagcgaca 480 tgcaaatatt gcagggcgcc actcccctgt ccctcacagc catcttcctg ccagggcgca 540 cgcgcgctgg gtgttcccgc ctagtgacac tgggcccgcg attccttgga gcgggttgat 600 gacgtcagcg tttcccatgg tgaagcttgg atctgatccc taggttctag aaccggtgac 660 caattgttaa ttaagtttaa accctcgagg ccgcaagcag atccacgata acaaacagct 720 tttttggggt gaacatattg actgaattcc ctgcaggttg gccactccct ctctgcgcgc 780 tcgctcgctc actgaggccg cccgggcaaa gcccgggcgt cgggcgacct ttggtcgccc 840 ggcctcagtg agcgagcgag cgcgcagaga gggagtggcc aactccatca ctaggggttc 900 ct 902 <210> 56 <211> 2550 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Polynucleotide <400> 56 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgcccgggc aaagcccggg 60 cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgctag ctctgggtat ttaagcccga gtgagcacgc 180 agggtctcca ttttgaagcg ggaggttacg cgttcgtcga ctactagtgg gtaccagagc 240 tccctaggtt ctagaaccgg tgacgtctcc catggtgaag cttggatctg aattcggtac 300 ctagttatta atagtaatca attacggggt cattagttca tagcccatat atggagttcc 360 gcgttacata acttacggta aatggcccgc ctggctgacc gcccaacgac ccccgcccat 420 tgacgtcaat aatgacgtat gttcccatag taacgccaat agggactttc cattgacgtc 480 aatgggtgga gtatttacgg taaactgccc acttggcagt acatcaagtg tatcatatgc 540 caagtacgcc ccctattgac gtcaatgacg gtaaatggcc cgcctggcat tatgcccagt 600 acatgacctt atgggacttt cctacttggc agtacatcta cgtattagtc atcgctatta 660 ccatggtcga ggtgagcccc acgttctgct tcactctccc catctccccc ccctccccac 720 ccccaatttt gtatttattt attttttaat tattttgtgc agcgatgggg gcgggggggg 780 ggggggggcg cgcgccaggc ggggcggggc ggggcgaggg gcggggcggg gcgaggcgga 840 gaggtgcggc ggcagccaat cagagcggcg cgctccgaaa gtttcctttt atggcgaggc 900 ggcggcggcg gcggccctat aaaaagcgaa gcgcgcggcg ggcgggagtc gctgcgacgc 960 tgccttcgcc ccgtgccccg ctccgccgcc gcctcgcgcc gcccgccccg gctctgactg 1020 accgcgttac tcccacaggt gagcgggcgg gacggccctt ctcctcagcg ctgtaattag 1080 cgcttggttt aatgacggct tgttggaggc ttgctgaagg ctgtatgctg ttgtcggggc 1140 cggtttcggg gccttagtga agccacagat gtacggcccc gaaaccggcc ccaggacaca 1200 aggcctgtta ctagcactca catggaacaa atggccaccg tgggaggatg acaatttctg 1260 tggctgcgtg aaagccttga ggggctccgg gagctagagc ctctgctaac catgttcatg 1320 ccttcttctt tttcctacag ctcctgggca acgtgctggt tattgtgctg tctcatcatt 1380 ttggcaaaga attcctcgaa gatccgaagg gaaagtcttc cacgactgtg ggatccgttc 1440 gaagatatca ccggttgagc cacccaattg ttaattaagt ttaaaccctc gaggccgcaa 1500 gcttatcgat aatcaacctc tggattacaa aatttgtgaa agattgactg gtattcttaa 1560 ctatgttgct ccttttacgc tatgtggata cgctgcttta atgcctttgt atcatgctat 1620 tgcttcccgt atggctttca ttttctcctc cttgtataaa tcctggttgc tgtctcttta 1680 tgaggagttg tggcccgttg tcaggcaacg tggcgtggtg tgcactgtgt ttgctgacgc 1740 aacccccact ggttggggca ttgccaccac ctgtcagctc ctttccggga ctttcgcttt 1800 ccccctccct attgccacgg cggaactcat cgccgcctgc cttgcccgct gctggacagg 1860 ggctcggctg ttgggcactg acaattccgt ggtgttgtcg gggaaatcat cgtcctttcc 1920 ttggctgctc gcctgtgttg ccacctggat tctgcgcggg acgtccttct gctacgtccc 1980 ttcggccctc aatccagcgg accttccttc ccgcggcctg ctgccggctc tgcggcctct 2040 tccgcgtctt cgccttcgcc ctcagacgag tcggatctcc ctttgggccg cctccccgca 2100 tcgataccgt cgactagagc tcgctgatca gcctcgactg tgccttctag ttgccagcca 2160 tctgttgttt gcccctcccc cgtgccttcc ttgaccctgg aaggtgccac tcccactgtc 2220 ctttcctaat aaaatgagga aattgcatcg cattgtctga gtaggtgtca ttctattctg 2280 gggggtgggg tggggcagga cagcaagggg gaggattggg aagacaatag caggcatgct 2340 ggggagagat ccacgataac aaacagcttt tttggggtga acatattgac tgaattccct 2400 gcaggttggc cactccctct ctgcgcgctc gctcgctcac tgaggccgcc cgggcaaagc 2460 ccgggcgtcg ggcgaccttt ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg 2520 gagtggccaa ctccatcact aggggttcct 2550 <210> 57 <211> 4142 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Polynucleotide <400> 57 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgggcgacc aaaggtcgcc 60 cgacgcccgg gctttgcccg ggcggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgctag ctctgggtat ttaagcccga gtgagcacgc 180 agggtctcca ttttgaagcg ggaggttacg cgttcgtcga ctactagtgg gtaccagagc 240 tccctaggtt ctagaaccgg tgacgtctcc catggtgaag cttggatctg aattcggtac 300 cctagttatt aatagtaatc aattacgggg tcattagttc atagcccata tatggagttc 360 cgcgttacat aacttacggt aaatggcccg cctggctgac cgcccaacga cccccgccca 420 ttgacgtcaa taatgacgta tgttcccata gtaacgccaa tagggacttt ccattgacgt 480 caatgggtgg actatttacg gtaaactgcc cacttggcag tacatcaagt gtatcatatg 540 ccaagtacgc cccctattga cgtcaatgac ggtaaatggc ccgcctggca ttatgcccag 600 tacatgacct tatgggactt tcctacttgg cagtacatct acgtattagt catcgctatt 660 accatggtcg aggtgagccc cacgttctgc ttcactctcc ccatctcccc cccctcccca 720 cccccaattt tgtatttatt tattttttaa ttattttgtg cagcgatggg ggcggggggg 780 gggggggggc gcgcgccagg cggggcgggg cggggcgagg ggcggggcgg ggcgaggcgg 840 agaggtgcgg cggcagccaa tcagagcggc gcgctccgaa agtttccttt tatggcgagg 900 cggcggcggc ggcggcccta taaaaagcga agcgcgcggc gggcgggagt cgctgcgacg 960 ctgccttcgc cccgtgcccc gctccgccgc cgcctcgcgc cgcccgcccc ggctctgact 1020 gaccgcgtta ctcccacagg tgagcgggcg ggacggccct tctcctccgg gctgtaatta 1080 gcgcttggtt taatgacggc ttgtctggag gcttgctttg ggctgtatgc tgcggttgcg 1140 gtgcctgcgc cttttggcct ctgactgagg cgcaggcacc gcaaccgcag gacacaaggc 1200 cctttatcag cactcacatg gaacaaatgg ccaccgtggg aggatgacaa ctggaggctt 1260 gctttgggct gtatgctgtc tggttaatct ttatcaggtt tttggcctct gactgaacct 1320 gataaagatt aaccagacag gacacaaggc cctttatcag cactcacatg gaacaaatgg 1380 ccaccgtggg aggatgacaa tttctgtggc tgcgtgaaag ccttgagggg ctccgggagc 1440 tagagcctct gctaaccatg ttcatgcctt cttctttttc ctacagctcc tgggcaacgt 1500 gctggttatt gtgctgtctc atcattttgg caaagaattc ctcgaagatc cgaagggaaa 1560 gtcttccacg actgtgggat ccgttcgaag atatcaccgg ttgagccacc atgagcaccc 1620 tgtgcccccc ccccagcccc gccgtggcca agaccgagat cgccctgagc ggcaagagcc 1680 ccctgctggc cgccacctt gcctactggg acaacatcct gggcccccgc gtgcgccaca 1740 tctgggcccc caagaccgag caggtgctgc tgagcgacgg cgagatcacc ttcctggcca 1800 accacaccct gaacggcgag atcctgcgca acgccgagag cggcgccatc gacgtgaagt 1860 tcttcgtgct gagcgagaag ggcgtgatca tcgtgagcct gatcttgac ggcaactgga 1920 acggcgaccg cagcacctac ggcctgagca tcatcctgcc ccagaccgag ctgagcttct 1980 acctgcccct gcaccgcgtg tgcgtggacc gcctgaccca catcatccgc aagggccgca 2040 tctggatgca caaggagcgc caggagaacg tgcagaagat catcctggag ggcaccgagc 2100 gcatggagga ccagggccag agcatcatcc ccatgctgac cggcgaggtg atccccgtga 2160 tggagctgct gagcagcatg aagagccaca gcgtgcccga ggagatcgac atcgccgaca 2220 ccgtgctgaa cgacgacgac atcggcgaca gctgccacga gggcttcctg ctgaacgcca 2280 tcagcagcca cctgcagacc tgcggctgca gcgtggtggt gggcagcagc gccgagaagg 2340 tgaacaagat cgtgcgcacc ctgtgcctgt tcctgacccc cgccgagcgc aagtgcagcc 2400 gcctgtgcga ggccgagagc agcttcaagt acgagagcgg cctgttcgtg cagggcctgc 2460 tgaagcag caccggcagc ttcgtgctgc ccttccgcca ggtgatgtac gcccccctacc 2520 ccaccaccca catcgacgtg gacgtgaaca ccgtgaagca gatgcccccc tgccacgagc 2580 acatctacaa ccagcgccgc tacatgcgca gcgagctgac cgccttctgg cgcgccacca 2640 gcgaggagga catggcccag gacaccatca tctacaccga cgagagcttc accccccgacc 2700 tgaacatctt ccaggacgtg ctgcaccgcg acaccctggt gaaggccttc ctggaccagg 2760 tgttccagct gaagcccggc ctgagcctgc gcagcacctt cctggcccag ttcctgctgg 2820 2880 agaagccctt caagagcctg cgcaacctga agatcgacct ggacctgacc gccgagggcg 2940 acctgaacat catcatggcc ctggccgaga agatcaagcc cggcctgcac agcttcatct 3000 tcggccgccc cttctacacc agcgtgcagg agcgcgacgt gctgatgacc ttctaacaat 3060 tgttaattaa gtttaaaccc tcgaggccgc aagcttatcg ataatcaacc tctggattac 3120 aaaatttgtg aaagattgac tggtattctt aactatgttg ctccttttac gctatgtgga 3180 tacgctgctt taatgccttt gtatcatgct attgcttccc gtatggcttt cattttctcc 3240 tccttgtata aatcctggtt gctgtctctt tatgaggagt tgtggcccgt tgtcaggcaa 3300 cgtggcgtgg tgtgcactgt gtttgctgac gcaaccccca ctggttgggg cattgccacc 3360 acctgtcagc tcctttccgg gactttcgct ttccccctcc ctattgccac ggcggaactc 3420 atcgccgcct gccttgcccg ctgctggaca ggggctcggc tgttgggcac tgacaattcc 3480 gtggtgttgt cggggaaatc atcgtccttt ccttggctgc tcgcctgtgt tgccacctgg 3540 attctgcgcg ggacgtcctt ctgctacgtc ccttcggccc tcaatccagc ggaccttcct 3600 tcccgcggcc tgctgccggc tctgcggcct cttccgcgtc ttcgccttcg ccctcagacg 3660 agtcggatct ccctttgggc cgcctccccg catcgatacc gtcgactaga gctcgctgat 3720 cagcctcgac tgtgccttct agttgccagc catctgttgt ttgcccctcc cccgtgcctt 3780 ccttgaccct ggaaggtgcc actcccactg tcctttccta ataaaatgag gaaattgcat 3840 cgcattgtct gagtaggtgt cattctattc tggggggtgg ggtggggcag gacagcaagg 3900 gggaggattg ggaagacaat agcaggcatg ctggggagag atccacgata acaaacagct 3960 tttttggggt gaacatattg actgaattcc ctgcaggttg gccactccct ctctgcgcgc 4020 tcgctcgctc actgaggccg cccgggcaaa gcccgggcgt cgggcgacct ttggtcgccc 4080 ggcctcagtg agcgagcgag cgcgcagaga gggagtggcc aactccatca ctaggggttc 4140 ct 4142 <210> 58 <211> 4143 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Polynucleotide <400> 58 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgggcgacc aaaggtcgcc 60 cgacgcccgg gctttgcccg ggcggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgctag ctctgggtat ttaagcccga gtgagcacgc 180 agggtctcca ttttgaagcg ggaggttacg cgttcgtcga ctactagtgg gtaccagagc 240 tccctaggtt ctagaaccgg tgacgtctcc catggtgaag cttggatctg aattcggtac 300 cctagttatt aatagtaatc aattacgggg tcattagttc atagcccata tatggagttc 360 cgcgttacat aacttacggt aaatggcccg cctggctgac cgcccaacga cccccgccca 420 ttgacgtcaa taatgacgta tgttcccata gtaacgccaa tagggacttt ccattgacgt 480 caatgggtgg actatttacg gtaaactgcc cacttggcag tacatcaagt gtatcatatg 540 ccaagtacgc cccctattga cgtcaatgac ggtaaatggc ccgcctggca ttatgcccag 600 tacatgacct tatgggactt tcctacttgg fotcatct acgtattagt catcgctatt 660 accatggtcg aggtgagccc cacgttctgc ttcactctcc ccatctcccc cccctcccca 720 cccccaattt tgtatttatt tattttttaa ttattttgtg cagcgatggg ggcgggggg 780 ggggggggc gcgcgccagg cggggcgggg cggggcgagg ggcggggcgg ggcgaggcgg 840 agaggtgcgg cggcagccaa tcagagcggc gcgctccgaa agtttccttt tatggcgagg 900 cggcggcgg ggcggcccta taaaaagcga agcgcgcgg gggcgggagt cgctgcgacg 960 ctgccttcgc cccgtgcccc gctccgccgc cgcctcgcgc cgcccgcccc ggctctgact 1020 gaccgcgtta ctcccacagg tgagcgggcg ggacggccct tctcctccgg gctgtaatta 1080 gcgcttggtt taatgacggc ttgtctggag gcttgctttg ggctgtatgc tggctgcggt 1140 tgcggtgcct gcttttggcc tctgactgag caggcaccgc aaccgcagcc aggacacaag 1200 gccctttatc agcactcaca tggaacaaat ggccaccgtg ggaggatgac aactggaggc 1260 ttgctttggg ctgtatgctg ggttgtttcc ctccttgttt attttggcct ctgactgaaa 1320 acaaggaggg aaacaaccca ggacacaagg ccctttatca gcactcacat ggaacaaatg 1380 gccaccgtgg gaggatgaca atttctgtgg ctgcgtgaaa gccttgaggg gctccgggag 1440 ctagagcctc tgctaaccat gttcatgcct tcttcttttt cctacagctc ctgggcaacg 1500 tgctggttat tgtgctgtct catcattttg gcaaagaatt cctcgaagat ccgaagggaa 1560 agtcttccac gactgtggga tccgttcgaa gatatcaccg gttgagccac catgagcacc 1620 ctgtgccccc cccccagccc cgccgtggcc aagaccgaga tcgccctgag cggcaagagc 1680 cccctgctgg ccgccacctt cgcctactgg gacaacatcc tgggcccccg cgtgcgccac 1740 atctgggccc ccaagaccga gcaggtgctg ctgagcgacg gcgagatcac cttcctggcc aaccacaccc tgaacggcga gatcctgcgc aacgccgaga gcggcgccat cgacgtgaag ttcttcgtgc tgagcgagaa gggcgtgatc atcgtgagcc tgatcttcga cggcaactgg aacggcgacc gcagcaccta cggcctgagc atcatcctgc cccagaccga gctgagcttc 1980. tacctgcccc tgcaccgcgt gtgcgtggac cgcctgaccc acatcatccg caagggccgc atctggatgc acaaggagcg ccaggagac gtgcagaga tcatcctgga gggcaccgag cgcatggagg accagggcca gagcatcatc cccatgctga ccggcgaggt gatccccgtg atggagctgc tgagcagcat gaagagccac agcgtgcccg aggagatcga catcgccgac accgtgctga acgacgacga catcggcgac agctgccacg agggcttcct gctgaacgcc 2280 atcagcagcc acctgcagac ctgcggctgc agcgtggtgg tgggcagcag cgccgagaag gtgaacaaga tcgtgcgcac cctgtgcctg ttcctgaccc ccgccgagcg caagtgcagc cgcctgtgcg aggccgagag cagcttcaag tacgagagcg gcctgttcgt gcagggcctg 2460 ctgaaggaca gcaccggcag cttcgtgctg cccttccgcc aggtgatgta cgccccctac 2520 cccaccaccc acatcgacgt ggacgtgaac accgtgaagc agatgccccc ctgccacgag 2580 cacatctaca accagcgccg ctacatgcgc agcgagctga ccgccttctg gcgcgccacc 2640 agcgaggagg acatggccca ggacaccatc atctacaccg acgagagctt caccccgac 2700 ctgaacatct tccaggacgt gctgcaccgc gacaccctgg tgaaggcctt cctggaccag 2760 gtgttccagc tgaagcccgg cctgagcctg cgcagcacct tcctggccca gttcctgctg 2820 gtgctgcacc gcaaggccct gaccctgatc aagtacatcg aggacgacac ccagaagggc 2880 aagaagccct tcaagagcct gcgcaacctg aagatcgacc tggacctgac cgccgagggc 2940 gacctgaaca tcatcatggc cctggccgag aagatcaagc ccggcctgca cagcttcatc 3000 ttcggccgcc ccttctacac cagcgtgcag gagcgcgacg tgctgatgac cttctaacaa 3060 ttgttaatta agtttaaacc ctcgaggccg caagcttatc gataatcaac ctctggatta 3120 caaaatttgt gaaagattga ctggtattct taactatgtt gctcctttta cgctatgtgg 3180 atacgctgct ttaatgcctt tgtatcatgc tattgcttcc cgtatggctt tcattttctc 3240 ctccttgtat aaatcctggt tgctgtctct ttatgaggag ttgtggcccg ttgtcaggca 3300 acgtggcgtg gtgtgcactg tgtttgctga cgcaaccccc actggttggg gcattgccac 3360 cacctgtcag ctcctttccg ggactttcgc tttccccctc cctattgcca cggcggaact 3420 catcgccgcc tgccttgccc gctgctggac aggggctcgg ctgttgggca ctgacaattc 3480 cgtggtgttg tcggggaaat catcgtcctt tccttggctg ctcgcctgtg ttgccacctg 3540 gattctgcgc gggacgtcct tctgctacgt cccttcggcc ctcaatccag cggaccttcc 3600 ttcccgcggc ctgctgccgg ctctgcggcc tcttccgcgt cttcgccttc gccctcagac 3660 gagtcggatc tccctttggg ccgcctcccc gcatcgatac cgtcgactag agctcgctga 3720 tcagcctcga ctgtgccttc tagttgccag ccatctgttg tttgcccctc ccccgtgcct 3780 tccttgaccc tggaaggtgc cactcccact gtcctttcct aataaaatga ggaaattgca 3840 tcgcattgtc tgagtaggtg tcattctatt ctggggggtg gggtggggca ggacagcaag 3900 ggggaggatt gggaagacaa tagcaggcat gctggggaga gatccacgat aacaaacagc 3960 ttttttgggg tgaacatatt gactgaattc cctgcaggtt ggccactccc tctctgcgcg 4020 ctcgctcgct cactgaggcc gcccgggcaa agcccgggcg tcgggcgacc tttggtcgcc 4080 cggcctcagt gagcgagcga gcgcgcagag agggagtggc caactccatc actaggggtt 4140 cct 4143 <210> 59 <211> 4140 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Polynucleotide <400> 59 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgggcgacc aaaggtcgcc 60 cgacgcccgg gctttgcccg ggcggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgctag ctctgggtat ttaagcccga gtgagcacgc 180 agggtctcca ttttgaagcg ggaggttacg cgttcgtcga ctactagtgg gtaccagagc 240 tccctaggtt ctagaaccgg tgacgtctcc catggtgaag cttggatctg aattcggtac 300 cctagttatt aatagtaatc aattacgggg tcattagttc atagcccata tatggagttc 360 cgcgttacat aacttacggt aaatggcccg cctggctgac cgcccaacga cccccgccca 420 ttgacgtcaa taatgacgta tgttcccata gtaacgccaa tagggacttt ccattgacgt 480 caatgggtgg actatttacg gtaaactgcc cacttggcag tacatcaagt gtatcatatg 540 ccaagtacgc cccctattga cgtcaatgac ggtaaatggc ccgcctggca ttatgcccag 600 tacatgacct tatgggactt tcctacttgg fotcatct acgtattagt catcgctatt 660 accatggtcg aggtgagccc cacgttctgc ttcactctcc ccatctcccc cccctcccca 720 cccccaattt tgtatttatt tattttttaa ttattttgtg cagcgatggg ggcgggggg 780 ggggggggc gcgcgccagg cggggcgggg cggggcgagg ggcggggcgg ggcgaggcgg 840 agaggtgcgg cggcagccaa tcagagcggc gcgctccgaa agtttccttt tatggcgagg 900 cggcggcgg ggcggcccta taaaaagcga agcgcgcgg gggcgggagt cgctgcgacg 960 ctgccttcgc cccgtgcccc gctccgccgc cgcctcgcgc cgcccgcccc ggctctgact 1020 gaccgcgtta ctcccacagg tgagcgggcg ggacggccct tctcctccgg gctgtaatta 1080 gcgcttggtt taatgacggc ttgtctggag gcttgctttg ggctgtatgc tgcggtgcct 1140 gcgcccgcgg cttttggcct ctgactgagc cgcgggcgca ggcaccgcag gacacaaggc 1200 cctttatcag cactcacatg gaacaaatgg ccaccgtggg aggatgacaa ctggaggctt 1260 gctttgggct gtatgctgtt tcttctggtt aatctttatt ttggcctctg actgataaag 1320 attaaccaga agaaacagga cacaaggccc tttatcagca ctcacatgga acaaatggcc 1380 accgtgggag gatgacaatt tctgtggctg cgtgaaagcc ttgaggggct ccgggagcta 1440 gagcctctgc taaccatgtt catgccttct tctttttcct acagctcctg ggcaacgtgc 1500 tggttattgt gctgtctcat cattttggca aagaattcct cgaagatccg aagggaaagt 1560 cttccacgac tgtgggatcc gttcgaagat atcaccggtt gagccaccat gagcaccctg 1620 tgcccccccc ccagccccgc cgtggccaag accgagatcg ccctgagcgg caagagcccc 1680 ctgctggccg ccaccttcgc ctactgggac aacatcctgg gcccccgcgt gcgccacatc 1740 tgggccccca agaccgagca ggtgctgctg agcgacggcg agatcacctt cctggccaac 1800 cacaccctga acggcgagat cctgcgcaac gccgagagcg gcgccatcga cgtgaagttc 1860 ttcgtgctga gcgagaaggg cgtgatcatc gtgagcctga tcttcgacgg caactggaac 1920 ggcgaccgca gcacctacgg cctgagcatc atcctgcccc agaccgagct gagcttctac 1980 ctgcccctgc accgcgtgtg cgtggaccgc ctgacccaca tcatccgcaa gggccgcatc 2040 tggatgcaca aggagcgcca ggagaacgtg cagaagatca tcctggaggg caccgagcgc 2100 atggaggacc agggccagag catcatcccc atgctgaccg gcgaggtgat ccccgtgatg 2160 gagctgctga gcagcatgaa gagccacagc gtgcccgagg agatcgacat cgccgacacc 2220 gtgctgaacg acgacgacat cggcgacagc tgccacgagg gcttcctgct gaacgccatc 2280 agcagccacc tgcagacctg cggctgcagc gtggtggtgg gcagcagcgc cgagaaggtg 2340 aacaagatcg tgcgcaccct gtgcctgttc ctgacccccg ccgagcgcaa gtgcagccgc 2400 ctgtgcgagg ccgagagcag cttcaagtac gagagcggcc tgttcgtgca gggcctgctg 2460 aggcagca ccggcagctt cgtgctgccc ttccgccagg tgatgtacgc cccctacccc 2520 accacccaca tcgacgtgga cgtgaacacc gtgaagcaga tgcccccctg ccacgagcac 2580 atctacaacc agcgccgcta catgcgcagc gagctgaccg ccttctggcg cgccaccagc 2640 gaggaggaca tggcccagga caccatcatc tacaccgacg agagcttcac ccccgacctg 2700 aacatcttcc aggacgtgct gcaccgcgac accctggtga aggccttcct ggaccaggtg 2760 ttccagctga agcccggcct gagcctgcgc agcaccttcc tggcccagtt cctgctggtg 2820 ctgcaccgca aggccctgac cctgatcaag tacatcgagg acgacaccca gaagggcaag 2880 aagcccttca agagcctgcg caacctgaag atcgacctgg acctgaccgc cgagggcgac 2940 ctgaacatca tcatggccct ggccgagaag atcaagcccg gcctgcacag cttcatcttc 3000 ggccgcccct tctacaccag cgtgcaggag cgcgacgtgc tgatgacctt ctaacaattg 3060 ttaattaagt ttaaaccctc gaggccgcaa gcttatcgat aatcaacctc tggattacaa 3120 aatttgtgaa agattgactg gtattcttaa ctatgttgct ccttttacgc tatgtggata 3180 cgctgcttta atgcctttgt atcatgctat tgcttcccgt atggctttca ttttctcctc 3240 cttgtataaa tcctggttgc tgtctcttta tgaggagttg tggcccgttg tcaggcaacg 3300 tggcgtggtg tgcactgtgt ttgctgacgc aacccccact ggttggggca ttgccaccac 3360 ctgtcagctc ctttccggga ctttcgcttt ccccctccct attgccacgg cggaactcat 3420 cgccgcctgc cttgcccgct gctggacagg ggctcggctg ttgggcactg acaattccgt 3480 ggtgttgtcg gggaaatcat cgtcctttcc ttggctgctc gcctgtgttg ccacctggat 3540 tctgcgcggg acgtccttct gctacgtccc ttcggccctc aatccagcgg accttccttc 3600 ccgcggcctg ctgccggctc tgcggcctct tccgcgtctt cgccttcgcc ctcagacgag 3660 tcggatctcc ctttgggccg cctccccgca tcgataccgt cgactagagc tcgctgatca 3720 gcctcgactg tgccttctag ttgccagcca tctgttgttt gcccctcccc cgtgccttcc 3780 ttgaccctgg aaggtgccac tcccactgtc ctttcctaat aaaatgagga aattgcatcg 3840 cattgtctga gtaggtgtca ttctattctg gggggtgggg tggggcagga cagcaagggg 3900 gaggattggg aagacaatag caggcatgct ggggagagat ccacgataac aaacagcttt 3960 tttggggtga acatattgac tgaattccct gcaggttggc cactccctct ctgcgcgctc 4020 gctcgctcac tgaggccgcc cgggcaaagc ccgggcgtcg ggcgaccttt ggtcgcccgg 4080 cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact aggggttcct 4140 <210> 60 <211> 3793 <212> DNA <213> Artificial Sequence <220> <223> Synthetic polynucleotide <400> 60 tctcattaga agtgaggcgg ggccggccaa atcgaatgga caccgggtaa ttagcagggt 60 tacccagata ctccagcacc tctttcccgt cggccgtgta cctgccattc acgtccatgc 120 cattgatggc cagcactgca tgacccactg cagaggtgaa gctaacggtc agcgaaggtg 180 cagcccgggg attccgccga ggggacaagg gacccgacac aacccctttt cccccaaccc 240 cgcacctaca accagcccac ttctacagca ctggggccct cccacccccg cacccgccac 300 gggcccgagc ctagcccacc tcggatgccg tcccgctggc cgaaagcaac caacacacgc 360 tcatcgtgta gcttgagcag cagatccagc ggataactga aagttttctc agcctcagcc 420 cgtggcgcgt agctgtccaa ctggtaaatc aagccgccag ctttgttcac cacatacaca 480 ctaaaaatcg ccatcgctgc cttgccgctc ggaaactggt attcagcctc tacccgacgg 540 cccctccccg gaaccgcatc acagcacttg ccgccggccc caccccagcc tcctcctcct 600 cctcctcctc ctcccgcgcc ccccgtgcag ccacctgctg cacttgcgca ctgggagcga 660 cacgctcggg cataagtagt gccgaaaagt tagctgccga gacctggtgg attgcttttc 720 gtttatcagt gcaggaaaac agcgctatag tactgcgtca caactagcgc agactccggc 780 agtatttagg cggtgcggct tgggaactag aatccacttc ctgtcttccg cctcaggcta 840 gagggcgagc gcttcgccgt gggacttctt ctgcctggct ccgcctcttg ccccggaagt 900 actcacagcg gacggtggtt tttgggcccg tttctgagca gcgcttcctt tttgtccgac 960 atcttgacga ggctgcggtg tctgctgcta ttctccgagc ttcgcaatgg taagcttcag 1020 gggtgtgaag tcgccggcgt tcttgggttt gaggactcag tggggagagc cttcggcggg 1080 agcgctcctt ggcctgccgg cctcggttgc agggcgggcg cggttattgc ttggcccatg 1140 tgctctggtg gtggagtttg cgggggctga gggcgcagta ttaggggact ttggcgctat 1200 ttgaggacct ggttgcattc ccgctgccct cctacagccg cctaaggacg acaagaagaa 1260 gaaggacgct ggaaagtcgg ccaagaaaga caaagaccca gtgaacaaat ccgggggcaa 1320 ggccaaaaag aaggtagaaa taagacctct ctgaaagaga ctaggggtaa ctctctcgta 1380 atcctctagt aataggtaac ttgtatagta agtggttttt caggtgtaga tttctagagt 1440 caaaatgtga gagtttatct tcccgtcacc actcgttctt tttcccatta ggatcatgaa 1500 aatgggtctg ttgtgcgaag tgtctgccgc tgtgcctgct gtgttatttt taactgatct 1560 agtggggctc ggcccctgtt tgaaggccaa aaacgtgtcg gtgttttttt tttgtttttg 1620 ttttagtaat gtgtaattta tccttgataa cggtggaaca gatttctctg acgcagatta 1680 ctcgagaggg aaagggtgct tctgccagaa atactaactt gtttctgttt tgttttggtg 1740 agcagaagtg gtccaaaggc aaagttcggg acaagctcaa taacttagtc ttgtttgaca 1800 aagctaccta tgataaactc tgtaaggaag ttcccaacta taaacttata accccagctg 1860 tggtctctga gagactgaag attcgaggct ccctggccag ggcagccctt caggagctcc 1920 ttagtaaagg tgaggggtgt atcctacatg tgtgttttg taggttaaat tgtcttgacc 1980 atgttaagca tcttcagtgg ttttgctgga aaagcagaat taaaaaaaa aagcgtggct 2040 tgaccattgg ctgttagtaa tgtaattctg acgtcttact cctgatcctg agatgaattc 2100 tcagggttct tagccacttt tgtgccgtgg accctgtggc agtttagtga agcccaagga 2160 tcttttatgt ttcgagtaaa tggatgcata gaattacagg gacaaccgtt tttgaaataa 2220 ttagattact attttgaaac aactttgaaa atgtttaaaa cctttatggt aaatattttg 2280 ttgatgtatt aaattttaaa accagaaatt tagtacggtc tactcagtag tatggtctga 2340 ttaccataat tccacaataa taaggctcag ctaactatag tgactgaacg tctataattc 2400 tagcactttg ggaggccaag gcgggtgaat caacggaggt caggagttaa agaccagcct 2460 ggccaatatg gtgaaaacct gctctactga aagttagctg gacgtggggg cacacgtctg 2520 taatcccagc tactcaggat gctgaggcat gaggatccct tgaacccagg agatggaggt 2580 ggcagtgagc cgagatgaca ccactgcact ccagccttag tgacagcaaa agactgtctc 2640 agaaaggggg gggggtgga agataatgga gccctaattt aaaggaaaag taggataga 2700 tgatccgtta aaaacttgga ttctcggtta ccgaacgtca gattaagcaa ttctggagcc 2760 aggtgcagtg gtacccttgt atttctagct acttgggagg ccaaagcagg aggatcattt 2820 gagccaagga gttttaagac cattctgggc acctctgaga gaactctgtc tttttgtttt 2880 ccttttcttt aataagat gcggttttgc catgttgccc aggctggtct cctgggctca 2940 agagatccac ctgtccaaag tgctgggatt acaggcatga gcctctgcac ccggccaaaa 3000 caaaccttac tagagtctca ttctgttgcc caggttggag tgcggagggg cagtcttggc 3060 tcaatgcaac caccaattcc tgggttcagg tggtcctcac ctcagcttcc caagtagctg 3120 gaattacaag catgtgccac catgcccagc taatttttgt atttttggta gagatggggt 3180 ttcaccttgt tggccaggct ggtgtgcaac tccttacctc aagctatctg cccgtctcca 3240 cctcccaaag cagtgggatt ataagcatga gccaccgcgc ccagccaaaa accttactag 3300 tttctattgt agcatctgtt aagcatctca tcgtgctatt ctctccccct aggacttatc 3360 aaactggttt caaagcacag agctcaagta atttacacca gaaataccaa gggtggagat 3420 gctccagctg ctggtgaaga tgcatgaata ggtgagtagg aatgtgtggg ctcatggtgt 3480 aggaggtaga tacaaagctt tatggttctg attcttttaa ttttttttta caggtccaac 3540 cagctgtaca tttggaaaaa taaaacttta ttaaatcaaa tgaatgagta tgtctgtttc 3600 ctaagaaaga caatgataaa gaatttggtg gaaggtataa taggggtttg ttgactttgc 3660 ttttagcctc atggtagttg gtagagagca tgattagctt ttttctgtat gtgactgctt 3720 cttcattgct gcagcttcag ttttgaattg atgtctgaaa ggaaataaag ggttaacacg 3780 atgatgaagg gtg 3793 <210> 61 <211> 3996 <212> DNA <213> Artificial Sequence <220> <223> Synthetic polynucleotide <400> 61 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgggcgacc aaaggtcgcc 60 cgacgcccgg gctttgcccg ggcggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgctag ctctgggtat ttaagcccga gtgagcacgc 180 agggtctcca ttttgaagcg ggaggttacg cgttcgtcga ctactagtgg gtaccagagc 240 tccctaggtt ctagaaccgg tgacgtctcc catggtgaag cttggatctg aattcggtac 300 cctagttatt aatagtaatc aattacgggg tcattagttc atagcccata tatggagttc 360 cgcgttacat aacttacggt aaatggcccg cctggctgac cgcccaacga cccccgccca 420 ttgacgtcaa taatgacgta tgttcccata gtaacgccaa tagggacttt ccattgacgt 480 caatgggtgg actatttacg gtaaactgcc cacttggcag tacatcaagt gtatcatatg 540 ccaagtacgc cccctattga cgtcaatgac ggtaaatggc ccgcctggca ttatgcccag 600 tacatgacct tatgggactt tcctacttgg cagtacatct acgtattagt catcgctatt 660 accatggtcg aggtgagccc cacgttctgc ttcactctcc ccatctcccc cccctcccca 720 cccccaattt tgtatttatt tattttttaa ttattttgtg cagcgatggg ggcggggggg 780 ggggggggc gcgcgccagg cggggcgggg cggggcgagg ggcggggcgg ggcgaggcgg 840 agaggtgcgg cggcagccaa tcagagcggc gcgctccgaa agtttccttt tatggcgagg 900 cggcggcgg ggcggcccta taaaaagcga agcgcgcgg gggcgggagt cgctgcgacg 960 ctgccttcgc cccgtgcccc gctccgccgc cgcctcgcgc cgcccgcccc ggctctgact 1020 gaccgcgtta ctcccacagg tgagcgggcg ggacggccct tctcctccgg gctgtaatta 1080 gcgcttggtt taatgacggc ttgtctggag gcttgctttg ggctgtatgc tgataccttc 1140 caccaaattc tttattttgg cctctgactg ataaagaatt gtggaaggta tcaggacaca 1200 aggcccttta tcagcactca catggaacaa atggccaccg tgggaggatg acaatttctg 1260 tggctgcgtg aaagccttga ggggctccgg gagctagagc ctctgctaac catgttcatg 1320 ccttcttctt tttcctacag ctcctgggca acgtgctggt tattgtgctg tctcatcatt 1380 ttggcaaaga attcctcgaa gatccgaagg gaaagtcttc cacgactgtg ggatccgttc 1440 gaagatatca ccggttgagc caccatgagc accctgtgcc ccccccccag ccccgccgtg 1500 gccaagaccg agatcgccct gagcggcaag agccccctgc tggccgccac cttcgcctac 1560 tgggacaaca tcctgggccc ccgcgtgcgc cacatctggg cccccaagac cgagcaggtg 1620 ctgctgagcg acggcgagat caccttcctg gccaaccaca ccctgaacgg cgagatcctg 1680 cgcaacgccg agagcggcgc catcgacgtg aagttcttcg tgctgagcga gaagggcgtg 1740 atcatcgtga gcctgatctt cgacggcaac tggaacggcg accgcagcac ctacggcctg 1800 agcatcatcc tgccccagac cgagctgagc ttctacctgc ccctgcaccg cgtgtgcgtg 1860 gaccgcctga cccacatcat ccgcaagggc cgcatctgga tgcacaagga gcgccaggag 1920 aacgtgcaga agatcatcct ggagggcacc gagcgcatgg aggaccaggg ccagagcatc 1980 atccccatgc tgaccggcga ggtgatcccc gtgatggagc tgctgagcag catgaagagc 2040 cacagcgtgc ccgaggagat cgacatcgcc gacaccgtgc tgaacgacga cgacatcggc 2100 gacagctgcc acgagggctt cctgctgaac gccatcagca gccacctgca gacctgcggc 2160 tgcagcgtgg tggtgggcag cagcgccgag aaggtgaaca agatcgtgcg caccctgtgc 2220 ctgttcctga cccccgccga gcgcaagtgc agccgcctgt gcgaggccga gagcagcttc 2280 aagtacgaga gcggcctgtt cgtgcagggc ctgctgaagg acagcaccgg cagcttcgtg 2340 ctgcccttcc gccaggtgat gtacgcccccc tacccacca cccacatcga cgtggacgtg 2400 aacaccgtga agcagatgcc cccctgccac gagcacatct acaaccagcg ccgctacatg 2460 cgcagcgagc tgaccgcctt ctggcgcgcc accagcgagg aggacatggc ccaggacacc 2520 atcatctaca ccgacgagag cttcacccc gacctgaaca tcttccagga cgtgctgcac 2580 cgcgacaccc tggtgaaggc cttcctggac caggtgttcc agctgaagcc cggcctgagc 2640 ctgcgcagca ccttcctggc ccagttcctg ctggtgctgc accgcaaggc cctgaccctg 2700 atcaagtaca tcgaggacga caccagaag ggcaagaagc ccttcaagag cctgcgcaac 2760 ctgaagatcg acctggacct gaccgccgag ggcgacctga acatcatcat ggccctggcc 2820 gagaagatca agcccggcct gcacagcttc atcttcggcc gccccttcta caccagcgtg 2880 caggagcgcg acgtgctgat gaccttctaa caattgttaa ttaagtttaa accctcgagg 2940 ccgcaagctt atcgataatc aacctctgga ttacaaaatt tgtgaaagat tgactggtat 3000 tcttaactat gttgctcctt ttacgctatg tggatacgct gctttaatgc ctttgtatca 3060 tgctattgct tcccgtatgg ctttcatttt ctcctccttg tataaatcct ggttgctgtc 3120 tctttatgag gagttgtggc ccgttgtcag gcaacgtggc gtggtgtgca ctgtgtttgc 3180 tgacgcaacc cccactggtt ggggcattgc caccacctgt cagctccttt ccgggacttt 3240 cgctttcccc ctccctattg ccacggcgga actcatcgcc gcctgccttg cccgctgctg 3300 gacaggggct cggctgttgg gcactgacaa ttccgtggtg ttgtcgggga aatcatcgtc 3360 ctttccttgg ctgctcgcct gtgttgccac ctggattctg cgcgggacgt ccttctgcta 3420 cgtcccttcg gccctcaatc cagcggacct tccttcccgc ggcctgctgc cggctctgcg 3480 gcctcttccg cgtcttcgcc ttcgccctca gacgagtcgg atctcccttt gggccgcctc 3540 cccgcatcga taccgtcgac tagagctcgc tgatcagcct cgactgtgcc ttctagttgc 3600 cagccatctg ttgtttgccc ctcccccgtg ccttccttga ccctggaagg tgccactccc 3660 actgtccttt cctaataaaa tgaggaaatt gcatcgcatt gtctgagtag gtgtcattct 3720 attctggggg gtggggtggg gcaggacagc aagggggagg attgggaaga caatagcagg 3780 catgctgggg agagatccac gataacaaac agcttttttg gggtgaacat attgactgaa 3840 ttccctgcag gttggccact ccctctctgc gcgctcgctc gctcactgag gccgcccggg 3900 caaagcccgg gcgtcgggcg acctttggtc gcccggcctc agtgagcgag cgagcgcgca 3960 gagagggagt ggccaactcc atcactaggg gttcct 3996 <210> 62 <211> 3994 <212> DNA <213> Artificial Sequence <220> <223> Synthetic polynucleotide <400> 62 ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgggcgacc aaaggtcgcc 60 cgacgcccgg gctttgcccg ggcggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcctgctag ctctgggtat ttaagcccga gtgagcacgc 180 agggtctcca ttttgaagcg ggaggttacg cgttcgtcga ctactagtgg gtaccagagc 240 tccctaggtt ctagaaccgg tgacgtctcc catggtgaag cttggatctg aattcggtac 300 cctagttatt aatagtaatc aattacgggg tcattagttc atagcccata tatggagttc 360 cgcgttacat aacttacggt aaatggcccg cctggctgac cgcccaacga cccccgccca 420 ttgacgtcaa taatgacgta tgttcccata gtaacgccaa tagggacttt ccattgacgt 480 caatgggtgg actatttacg gtaaactgcc cacttggcag tacatcaagt gtatcatatg 540 ccaagtacgc cccctattga cgtcaatgac ggtaaatggc ccgcctggca ttatgcccag 600 tacatgacct tatgggactt tcctacttgg fotcatct acgtattagt catcgctatt 660 accatggtcg aggtgagccc cacgttctgc ttcactctcc ccatctcccc cccctcccca 720 cccccaattt tgtatttatt tattttttaa ttattttgtg cagcgatggg ggcgggggg 780 ggggggggc gcgcgccagg cggggcgggg cggggcgagg ggcggggcgg ggcgaggcgg 840 agaggtgcgg cggcagccaa tcagagcggc gcgctccgaa agtttccttt tatggcgagg 900 cggcggcgg ggcggcccta taaaaagcga agcgcgcgg gggcgggagt cgctgcgacg 960 ctgccttcgc cccgtgccc gctccgcgc cgcctcgcgc cgcccgccc ggctctgact 1020 gaccgcgtta ctcccacagg tgagcgggcg ggacggccct tctcctccgg gctgtaatta 1080 gcgcttggtt taatgacggc ttgtctggag gcttgctttg ggctgtatgc tgataagtcc 1140 tttactaagg agcttttggc ctctgactga gctccttgta aggacttatc aggacacaag 1200 gcccttatc agcactcaca tggaacaaat ggccaccgtg ggaggatgac aatttctgtg 1260 gctgcgtgaa agccttgagg ggctccggga gctagagcct ctgctaacca tgttcatgcc 1320 ttcttcttt tcctacagct cctgggcaac gtgctggtta ttgtgctgtc tcatcattttt 1380 ggcaaagaat tcctcgaaga tccgaaggga aagtcttcca cgactgtggg atccgttcga 1440 agatatcacc ggttgagcca ccatgagcac cctgtgcccc ccccccagcc ccgccgtggc 1500 caagaccgag atcgccctga gcggcaagag ccccctgctg gccgccacct tcgcctactg 1560 ggacaacatc ctgggccccc gcgtgcgcca catctgggcc cccaagaccg agcaggtgct 1620 gctgagcgac ggcgagatca ccttcctggc caaccacacc ctgaacggcg agatcctgcg 1680 caacgccgag agcggcgcca tcgacgtgaa gttcttcgtg ctgagcgaga agggcgtgat 1740 catcgtgagc ctgatcttcg acggcaactg gaacggcgac cgcagcacct acggcctgag 1800 catcatcctg ccccagaccg agctgagctt ctacctgccc ctgcaccgcg tgtgcgtgga 1860 ccgcctgacc cacatcatcc gcaagggccg catctggatg cacaaggagc gccaggagaa 1920 cgtgcagaag atcatcctgg agggcaccga gcgcatggag gaccagggcc agagcatcat 1980 ccccatgctg accggcgagg tgatccccgt gatggagctg ctgagcagca tgaagagcca 2040 cagcgtgccc gaggagatcg acatcgccga caccgtgctg aacgacgacg acatcggcga 2100 cagctgccac gagggcttcc tgctgaacgc catcagcagc cacctgcaga cctgcggctg 2160 cagcgtggtg gtgggcagca gcgccgagaa ggtgaacaag atcgtgcgca ccctgtgcct 2220 gttcctgacc cccgccgagc gcaagtgcag ccgcctgtgc gaggccgaga gcagcttcaa 2280 gtacgagagc ggcctgttcg tgcagggcct gctgaaggac agcaccggca gcttcgtgct 2340 gcccttccgc caggtgatgt acgcccccta ccccaccacc cacatcgacg tggacgtgaa 2400 caccgtgaag cagatgcccc cctgccacga gcacatctac aaccagcgcc gctacatgcg 2460 cagcgagctg accgccttct ggcgcgccac cagcgaggag gacatggccc aggacaccat 2520 catctacacc gacgagagct tcacccccga cctgaacatc ttccaggacg tgctgcaccg 2580 cgacaccctg gtgaaggcct tcctggacca ggtgttccag ctgaagcccg gcctgagcct 2640 gcgcagcacc ttcctggccc agttcctgct ggtgctgcac cgcaaggccc tgaccctgat 2700 caagtacatc gaggacgaca cccagaaggg caagaagccc ttcaagagcc tgcgcaacct 2760 gaagatcgac ctggacctga ccgccgaggg cgacctgaac atcatcatgg ccctggccga 2820 gaagatcaag cccggcctgc acagcttcat cttcggccgc cccttctaca ccagcgtgca 2880 ggagcgcgac gtgctgatga ccttctaaca attgttaatt aagtttaaac cctcgaggcc 2940 gcaagcttat cgataatcaa cctctggatt acaaaatttg tgaaagattg actggtattc 3000 ttaactatgt tgctcctttt acgctatgtg gatacgctgc tttaatgcct ttgtatcatg 3060 ctattgcttc ccgtatggct ttcattttct cctccttgta taaatcctgg ttgctgtctc 3120 tttatgagga gttgtggccc gttgtcaggc aacgtggcgt ggtgtgcact gtgtttgctg 3180 acgcaacccc cactggttgg ggcattgcca ccacctgtca gctcctttcc gggactttcg 3240 ctttccccct ccctattgcc acggcggaac tcatcgccgc ctgccttgcc cgctgctgga 3300 caggggctcg gctgttgggc actgacaatt ccgtggtgtt gtcggggaaa tcatcgtcct 3360 ttccttggct gctcgcctgt gttgccacct ggattctgcg cgggacgtcc ttctgctacg 3420 tcccttcggc cctcaatcca gcggaccttc cttcccgcgg cctgctgccg gctctgcggc 3480 ctcttccgcg tcttcgcctt cgccctcaga cgagtcggat ctccctttgg gccgcctccc 3540 cgcatcgata ccgtcgacta gagctcgctg atcagcctcg actgtgcctt ctagttgcca 3600 gccatctgtt gtttgcccct cccccgtgcc ttccttgacc ctggaaggtg ccactcccac 3660 tgtcctttcc taataaaatg aggaaattgc atcgcattgt ctgagtaggt gtcattctat 3720 tctggggggt ggggtggggc aggacagcaa gggggaggat tgggaagaca atagcaggca 3780 tgctggggag agatccacga taacaaacag cttttttggg gtgaacatat tgactgaatt 3840 ccctgcaggt tggccactcc ctctctgcgc gctcgctcgc tcactgaggc cgcccgggca 3900 aagcccgggc gtcgggcgac ctttggtcgc ccggcctcag tgagcgagcg agcgcgcaga 3960 gagggagtgg ccaactccat cactaggggt tcct 3994

Claims

1. An isolated nucleic acid comprising (i) an expression construct comprising a transgene encoding (a) and (b): (a) a C9orf72 protein encoded by the sequence set forth in SEQ ID NO:51, and (b) an inhibitory nucleic acid consisting of the sequence set forth in SEQ ID NO:39, and (ii) two adeno-associated virus inverted terminal repeat (ITR) sequences flanking the expression construct.

2. The isolated nucleic acid of claim 1, wherein the transgene is operably linked to a promoter.

3. The isolated nucleic acid of claim 2, wherein the promoter is the chicken beta actin (CBA) promoter.

4. The isolated nucleic acid of claim 2, further comprising a CMV enhancer.

5. The isolated nucleic acid of any one of claims 1-4, further comprising a Woodchuck Hepatitis Virus Post-transcriptional Regulatory Element (WPRE).

6. The isolated nucleic acid of any one of claims 1-4, further comprising a bovine growth hormone polyA signal tail.

7. The isolated nucleic acid of any one of claims 1-4, wherein each ITR sequence is a wild-type AAV2 ITR sequence.

8. A recombinant adeno-associated virus (rAAV) vector comprising an expression construct comprising a transgene encoding (i) and (ii): (i) a C9orf72 protein encoded by the sequence set forth in SEQ ID NO: 51; and (ii) an inhibitory nucleic acid consisting of the sequence set forth in SEQ ID NO: 39; The expression construct is flanked by two adeno-associated virus (AAV) inverted terminal repeat sequences (ITR).

9. The rAAV vector of claim 8, wherein the transgene is operably linked to a promoter.

10. The rAAV vector of claim 9, wherein the promoter is a chicken beta actin (CBA) promoter.

11. The rAAV vector of claim 9, further comprising a CMV enhancer.

12. The rAAV vector according to any one of claims 8-11, further comprising a woodchuck hepatitis virus post-transcriptional regulatory element (WPRE).

13. The rAAV vector according to any one of claims 8-11, further comprising a bovine growth hormone polyA signal tail.

14. The rAAV vector of any one of claims 8-11, wherein each ITR sequence is a wild-type AAV2 ITR sequence.

15. A recombinant adeno-associated virus (rAAV), comprising: (i) AAV capsid protein; and (ii) The rAAV vector according to any one of claims 8 to 14.

16. The rAAV of claim 15, wherein the AAV capsid protein is an AAV9 capsid protein.

17. A recombinant adeno-associated virus (rAAV) vector comprising a nucleic acid comprising, in 5' to 3' order: (a) 5' AAV ITR; (b) CMV enhancer; (c) CBA promoter; (d) a transgene encoding a C9orf72 protein and an inhibitory nucleic acid consisting of the sequence set forth in SEQ ID NO: 39, wherein the C9orf72 protein is encoded by the nucleic acid sequence set forth in SEQ ID NO: 51; (e) WPRE; (f) bovine growth hormone polyA signal tail; and (g) 3'AAVITR.

18. A recombinant adeno-associated virus (rAAV), comprising: (i) AAV capsid protein; and (ii) The rAAV vector according to claim 17.

19. The rAAV of claim 18, wherein the AAV capsid protein is an AAV9 capsid protein.

20. A plasmid comprising the rAAV vector according to any one of claims 8-14 and 17.

21. A baculovirus vector comprising (i) the nucleic acid sequence set forth in SEQ ID NO: 51, and (ii) a nucleic acid sequence consisting of the sequence set forth in SEQ ID NO:

39.

22. A cell comprising: (i) a first vector encoding one or more adeno-associated virus rep proteins and / or one or more adeno-associated virus cap proteins; and (ii) a second vector comprising an expression construct encoding a C9orf72 protein encoded by the sequence set forth in SEQ ID NO:51 and an inhibitory nucleic acid consisting of the sequence set forth in SEQ ID NO:

39.

23. The cell of claim 22, wherein the first vector is a plasmid and the second vector is a plasmid.

24. The cell according to claim 22 or 23, wherein the cell is a mammalian cell.

25. The cell according to claim 24, wherein the mammalian cell is a HEK293 cell.

26. The cell of claim 22, wherein the first vector is a baculoviral vector and the second vector is a baculoviral vector.

27. The cell of claim 26, wherein the cell is an insect cell.

28. The cell according to claim 27, wherein the insect cell is a SF9 cell.

29. A method of producing the rAAV of claim 15, 16, 18 or 19, the method comprising: (i) delivering a first vector encoding one or more adeno-associated virus rep proteins and / or one or more adeno-associated virus cap proteins and a recombinant AAV vector comprising an expression construct encoding a C9orf72 protein encoded by the sequence set forth in SEQ ID NO: 51 and an inhibitory nucleic acid consisting of the sequence set forth in SEQ ID NO: 39 to a cell; (ii) culturing the cells under conditions that allow for packaging of rAAV; as well as (iii) harvesting the cultured host cells or the culture medium to collect the rAAV.

30. Use of the isolated nucleic acid of any one of claims 1-7, the rAAV vector of any one of claims 8-14 and 17, or the rAAV of any one of claims 15, 16, 18 and 19 in the preparation of a medicament for treating a subject having or suspected of having amyotrophic lateral sclerosis (ALS).

31. The use according to claim 30, wherein the medicament is formulated for direct injection into the central nervous system (CNS) of the subject.

32. The use according to claim 31, wherein the direct injection is intracerebral injection, intrathecal injection or any combination thereof.

33. The use according to claim 31, wherein the direct injection is an intraparenchymal injection.

34. The use of claim 30, wherein the medicament is formulated for direct injection into the cerebrospinal fluid (CSF) of the subject.

35. The use according to claim 34, wherein the direct injection is intracisternal injection, intracerebroventricular injection, and / or intralumbar injection.

Images