Gene cluster for fostriecin biosynthesis

Abstract

Domains of fostriecin polyketide synthase and modification enzymes and polynucleotides encoding them are provided. Methods to prepare fostriecin in pharmaceutically useful quantities are described, as are methods to prepare fostriecin analogs and other polyketides using the polynucleotides encoding fostriecin polyketide synthase domains or modifying enzymes.

Description

FIELD OF THE INVENTION

The invention relates to materials and methods for biosynthesis of fostriecin, fostriecin derivatives and analogs, and other useful polyketides. The invention finds application in the fields of molecular biology, chemistry, recombinant DNA technology, human and veterinary medicine, and agriculture.

BACKGROUND OF THE INVENTION

Polyketides are complex natural products that are produced by microorganisms such as fungi and mycelial bacteria. There are about 10,000 known polyketides, from which numerous pharmaceutical products in many therapeutic areas have been derived, including: adriamycin, epothilone, erythromycin, mevacor, rapamycin, tacrolimus, tetracycline, rapamycin, and many others. However, polyketides are made in very small amounts in microorganisms and are difficult to make or modify chemically. For this and other reasons, biosynthetic methods are preferred for production of therapeutically active polyketides. See PCT publication Nos. WO 93/13663; WO 95/08548; WO 96/40968; WO 97/02358; and WO 98/27203; U.S. Pat. Nos. 4,874,748; 5,063,155; 5,098,837; 5,149,639; 5,672,491; 5,712,146 and 6,410,301; Fu et al., 1994, Biochemistry 33: 9321-26; McDaniel et al., 1993, Science 262: 1546-1550; Kao et al., 1994, Science, 265: 509-12, and Rohr, 1995, Angew. Chem. Int. Ed. Engl. 34: 881-88, each of which is incorporated herein by reference.

Biosynthesis of polyketides may be accomplished by heterologous expression of Type I or modular polyketide synthase enzymes (PKSs). Type I PKSs are large multifunctional protein complexes, the protein components of which are encoded by multiple open reading frames (ORF) of PKS gene clusters. Each ORF of a Type I PKS gene cluster can encode one, two, or more modules of ketosynthase activity. Each module activates and incorporates a two-carbon (ketide) unit into the polyketide backbone. Each module also contains multiple ketide-modifying enzymatic activities, or domains. The number and order of modules, and the types of ketide-modifying domains within each module, determine the structure of the resulting product. Polyketide synthesis may also involve the activity of nonribosomal peptide synthetases (NRPSs) to catalyze incorporation of an amino acid-derived building block into the polyketide, as well as post-synthesis modification, or tailoring enzymes. The modification enzymes modify the polyketide by oxidation or reduction, addition of carbohydrate groups or methyl groups, or other modifications.

In PKS polypeptides, the regions that encode enzymatic activities (domains) are separated by linker regions. These regions collectively can be considered to define boundries of the various domains. Generally, this organization permits PKS domains of different or identical substrate specificities to be substituted (usually at the level of encoding DNA) from other PKSs by various available methodologies. Using this method, new polyketide synthases (which produce novel polyketides) can be produced.

It will be recognized from the foregoing that genetic manipulation of PKS genes and heterologous expression of PKSs can be used for the efficient production of known polyketides, and for production of novel polyketides structurally related to, but distinct from, known polyketides (see references above, and Hutchinson, 1998, Curr. Opin. Microbiol. 1: 319-29; Carreras and Santi, 1998, Curr. Opin. Biotech. 9: 403-11; and U.S. Pat. Nos. 5,712,146 and 5,672,491, each of which is incorporated herein by reference).

One valuable class of polyketides includes fosteriecin and its analogs. Fostriecin (CI-920) is a structurally novel phosphate ester produced by Streptomyces pulveraceus having potent antitumor activity. Fostriecin's antitumor activity is believed to result from selective inhibition of protein phosphatase 2A (PP2A) and protein phosphatase 4 (PP4). Both synthetic and naturally produced analogs of fostriecin with similar activities have been described. See, e.g., Lewy et al., 2002, “Fostriecin: Chemistry and Biology” Current Medicinal Chemistry 9: 2005-2032, and references cited therein, for additional information regarding fostriecin and its analogs.

The chemical structure of fostriecin and congeners PD 113,270 and PD 113, 271, as reported by Lewy et al., 2002, is shown below:

• 1. Fostriecin
• 2. PD 113, 270
• 3. PD 113, 271

Phase I clinical trials of fostriecin were halted due to the unpredictable chemical purity and storage instability of the compound. Accordingly, there is a need for methods for producing fostriecin and both known and novel analogs with sufficient purity and, preferably, with superior storage stability. Fostriecin is synthesized by a modular PKS and modification enzymes.

There is a need for recombinant nucleic acids, host cells, and methods of using those host cells to produce polyketides including but not limited to fostriecin and fostriecin analogs.

These and other needs are met by the materials and methods provided by the present invention.

SUMMARY OF THE INVENTION

The present invention provides recombinant nucleic acids encoding polyketide synthases and polyketide modification enzymes. The recombinant nucleic acids of the invention are useful in the production of polyketides, including but not limited to fostriecin and fostriecin analogs and derivatives, in recombinant host cells.

In nature, the biosynthesis of fostriecin is performed by a modular PKS, the fostriecin polyketide synthase, and polyketide modification enzymes. Nucleic acids encoding the PKS, modification enzymes, and other polypeptides, have been cloned and characterized. The present invention provides polypeptide, modules, and domains of the fostriecin polyketide synthase, and corresponding nucleic acid sequences encoding them and/or parts thereof. Such compounds are useful, for example, in the production of hybrid PKS enzymes and the recombinant genes that encode them. The present invention also provides post-synthesis modification enzymes, and other proteins involved in fostriecin biosynthesis, and corresponding nucleic acid sequences encoding them and/or parts thereof.

The present invention provides these nucleic acid sequences in isolated, synthetic or recombinant form, including but not limited to isolated form sequences incorporated into a vector of the chromosomal DNA of a host cell.

The present invention also provides recombinant host cells that contain the nucleic acids of the invention. In one embodiment, the host cell provided by the invention is a Streptomyces host cell that produces a fostriecin modification enzyme and/or a domain, module, or protein of the fostriecin PKS. Methods for the genetic manipulation of Streptomyces are described in Kieser et al, “Practical Streptomyces Genetics,” The John Innes Foundation, Norwich (2000), which is incorporated herein by reference in its entirety.

Accordingly, there is provided a recombinant PKS wherein at least 10, 15, 20, or more consecutive amino acids in one or more domains of one or more modules thereof are derived from one or more domains of one or more modules of fostriecin polyketide synthase. In an embodiment at least an entire domain of a module of fostriecin polyketide synthase is included. Representative fostriecin PKS domains useful in this aspect of the invention include, for example, KR, DH, ER, AT, ACP and KS domains. In one embodiment of the invention, the PKS assembled from polypeptides encoded by DNA molecules that comprise coding sequences for PKS domains, wherein at least one encoded domain corresponds to a domain of fostriecin PKS. In such DNA molecules, the coding sequences are operably linked to control sequences so that expression therefrom in host cells is effective. In this manner, fostriecin PKS coding sequences or modules and/or domains can be made to encode PKS to biosynthesize compounds having antibiotic or other useful bioactivity other than fostriecin.

In one aspect, the invention provides a recombinant DNA molecule comprising a sequence encoding at least one domain, and optionally one or more modules, of fostriecin polyketide synthase polypeptide. In an embodiment, the recombinant DNA molecule includes a sequence encoding an open reading frame encoding a polypeptide encoded by fosA, fosB, fosC, fosD, fosE or fosf or encoding a conservative variant of such a polypeptide. In an embodiment, the recombinant DNA molecule encodes a modified fostriecin polyketide synthase polypeptide in which at least one fostriecin PKS domain is inactivated.

In one aspect, the invention provides a recombinant DNA molecule that encodes a chimeric polyketide synthase (PKS) module composed of at least a portion of fostriecin PKS and at least a portion of a second PKS for a polyketide other than fostriecin.

DNA molecules of the invention may be integrated into a host cell chromosome, or into a recombinant vector such as an expression vector in which the DNA molecule is operably linked to a promoter.

In one aspect, the invention provides a host cell comprising a recombinant DNA molecule as described above.

In one aspect, the invention provides a recombinant Streptomyces pulveraceus cell in which at least one domain-encoding region of an endogenous fostriecin polyketide synthase gene is deleted or otherwise inactivated. In an embodiment, the domain has been replaced by a different PKS domain. Also provided is a recombinant Streptomyces pulveraceus cell in which at least polypeptide-encoding ORF of the fostriecin polyketide synthase gene cluster is deleted or otherwise inactivated.

In one aspect, the invention provides an isolated, synthetic or recombinant DNA molecule having a sequence encoded by the insert of pKOS279-117.1F70; pKOS279-117.3F45; pKOS279-117.2F15; or pKos279-117.5F58. The DNA molecule may contain sequence encoding a complete fostriecin PKS module or domain.

The invention provides a method of producing a polyketide by culturing a cell under conditions under which the cell produces the polyketide, where the cell contains a recombinant polynucleotide synthase that contains at least one domain from the Streptomyces pulveraceus fostriecin polyketide synthase, and where the cell does not make the polyketide in the absence of the recombinant polynucleotide. In one embodiment, the domain is encoded by a subsequence of SEQ ID NO:1 or a sequence that hybridizes under stringent conditions to a subsequence of SEQ ID NO:1. In one embodiment the cell is not Streptomyces pulveraceus. In an embodiment, the polyketide is fostriecin, PD 113,270 or PD 113, 271.

The invention provides a method of producing a polyketide by recombinantly modifying a gene in the fostriecin PKS gene cluster of a cell comprising the gene cluster to produce a recombinant cell, or obtaining a progeny of the recombinant cell and growing the cell, or progeny, under conditions whereby a polyketide other than fostriecin is synthesized by the cell. Non-limiting examples of such modifications include (a)substitution of a fostriecin AT domain with an AT domain having a different specificity; (b) inactivation of a domain of a fostriecin polyketide synthase module, where the domain is selected from the group consisting of a KS domain, an AT domain, an ACP domain, a KR domain, a DH domain, and an ER domain; or, (c) substitution of KS domain, an ACP domain, a KR domain, a DH domain, or an ER domain with a domain having a different specificity.

The aforementioned methods can also include the step of recovering the synthesized polyketide. The recovered polyketide may be chemically modified and/or formulated for administration to a mammal.

These and other aspects of the present invention are described in more detail in the Detailed Description of the Invention, below.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A, 1B and 1C show the organization of the fostriecin PKS biosynthetic gene cluster.

FIG. 2 shows hypothetical roles for the nine modules of the fostriecin polyketide synthase complex (modules 0-8)) by showing hypothetical PKS-bound intermediates, the product released from the PKS (in brackets) and the result of post-PKS modification enzymes (symbolized by three arrows).

FIG. 3 shows the approximate relationship of cosmids from “overlap family 1,” encoding the fostriecin PKS gene cluster as estimated during cloning.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides recombinant materials for the production of polyketides including, but not limited to, fostriecin and its derivatives and analogs. In an aspect, the invention provides recombinant nucleic acids encoding at least one domain of a fostriecin polyketide synthase. In another aspect, the present invention provides recombinant nucleic acids encoding an enzyme involved in fostriecin biosynthesis or post synthesis modification. Methods and host cells for using these nucleic acid sequences to produce or modify a polyketide in recombinant host cells are also provided. Given the valuable properties of fostriecin and its derivatives and analogs, means to produce useful quantities of these molecules in a highly pure form is of great value. The nucleotide sequences of the fostriecin biosynthetic gene cluster encoding domains, modules and polypeptides of fostriecin polyketide synthase, and modifying enzymes, and other polypeptides can be used, for example, to make both known and novel polyketides. Further, the fostriecin modifying enzymes can be used to modify other polyketides and produce derivatives with enhanced solubility and/or bioactivity. The compounds produced using methods of the invention may be used, without limitation, as antitumor agents or for other therapeutic or research uses, as intermediates for further enzymatic or chemical modification, as agents for in vitro inhibition of protein phosphatase and/or for other therapeutic, industrial and agricultural purposes.

The polynucleotides encoding fostriecin PKS domains, modules and polypeptides, and encoding fostriecin modifying proteins of the present invention were isolated from Streptomyces pulveraceus as described in Example 1. Tables 1-4, and FIG. 1 describe the genes or open reading frames of the fostriecin polyketide synthase gene cluster and the encoded polypeptides, modules and domains. These tables and figure also describe the characteristics of non-coding sequences and sequences encoding other genes of the fostriecin gene cluster, including genes encoding regulatory proteins, transport proteins, and others.

It will be understood that each reference herein to a nucleic acid sequence is also intended to refer to and include the complementary sequence, unless otherwise stated or apparent from context. Provided with the nucleic acid sequences disclosed herein, it will be trivial for the reader to immediately determine the sequence of a complementary stand based on base-pairing rules (e.g., A:T, A:U, C:G). Similarly, provided with the nucleic acid sequences disclosed herein one of skill can easily, by reference to the genetic code, identify open reading frames and the amino acid sequences of encoded polypeptides.

Table 1, below, describes the positions of fostriecin polyketide synthase polypeptides, modules and domains with reference to the DNA sequence set forth in Table 3 (SEQ ID NO:1). “Complement” indicates that the polypeptide sequence is encoded by the complement of SEQ ID NO: 1. Abbreviations used in the table, and elsewhere in the specification, include: ketosynthase (“KS”) domain or activity; acyltransferase (“AT”) domain or activity; acyl carrier protein (“ACP”) domain or activity; ketoreductase (“KR”) domain or activity, a dehydratase (“DH”) domain or activity; enoylreductase (“ER”) domain or activity; thioesterase (“TE”).

TABLE 1
Fostriecin polyketide synthase ORFs, Modules and Domains
		Position in SEQ ID NO: 1
ORF	# aa	coding strand (nucleotide pair)
fosC	3542	Modules 3-4	complement(56750 . . . 67378)
		KS3	complement(65783 . . . 67063)
		AT3	complement(64382 . . . 65431)
		DH3	complement(63770 . . . 64357)
		KR3	complement(62039 . . . 62839)
		ACP3	complement(61757 . . . 62014)
		KS4	complement(60401 . . . 61678)
		AT4	complement(59054 . . . 60067)
		KR4	complement(57368 . . . 58105)
		ACP4	complement(57014 . . . 57271)
fosD	1738	Module 5	complement(51497 . . . 56713)
		KS5	complement(55328 . . . 56605)
		AT5	complement(53942 . . . 54994)
		KR5	complement(52241 . . . 52918)
		ACP5	complement(51809 . . . 52066)
fosE	3537	Modules 6-7;	complement(40820 . . . 51433)
		KS6	complement(50024 . . . 51334)
		AT6	complement(48608 . . . 49648)
		DH6	complement(47993 . . . 48574)
		KR6	complement(46151 . . . 47017)
		ACP6	complement(45854 . . . 46114)
		KS7	complement(44474 . . . 45754)
		AT7	complement(43058 . . . 44098)
		KR7	complement(41429 . . . 42229)
		ACP7	complement(41093 . . . 41350)
fosF	1932	Module 8 and TE;	complement(34979 . . . 40774)
		KS8	complement(39428 . . . 40672)
		AT8	complement(38003 . . . 39079)
		KR8	complement(36212 . . . 37009)
		ACP8	complement(35912 . . . 36169)
		TE	complement(34979 . . . 35911)
fosA	3414	Modules 0-1	complement(17358 . . . 27602)
		KS0q	complement(26019 . . . 27278)
		AT0	complement(24722 . . . 25640)
		ACP0a	complement(24414 . . . 24671)
		ACP0b	complement(24039 . . . 24296)
		KS1	complement(22701 . . . 23990)
		AT1	complement(21336 . . . 22394)
		DH1	complement(20715 . . . 21302)
		ER1	complement(18813 . . . 19685)
		KR1	complement(17952 . . . 18797)
		ACP1	complement(17631 . . . 17891)
fosB	1880	Module 2	complement(11623 . . . 17265)
		KS2	complement(15883 . . . 17163)
		AT2	complement(14455 . . . 15576)
		DH2	complement(13855 . . . 14424)
		KR2	complement(12247 . . . 13026)
		ACP2	complement(11920 . . . 12177)

In one aspect of the invention, purified and isolated DNA molecules are provided that comprise coding sequences for one or more domains or modules of a Streptomyces pulveraceus fostriecin polyketide synthase. Examples of such encoded domains include fostriecin polyketide synthase KR, DH, ER, AT, ACP, and KS domains. In one aspect, the invention provides DNA molecules which sequences encoding one or more polypeptides of fostriecin polyketide synthase are operably linked to expression control sequences that are effective in suitable host cells to produce fostriecin, its analogs or derivatives, or novel polyketides. In one aspect, the complete set of synthase-encoding genes is provided.

In one aspect, the invention provides an isolated or recombinant DNA molecule comprising a nucleotide sequence that encodes at least one domain, alternatively at least one module, alternatively at least one polypeptide, involved in the biosynthesis of a fostriecin.

In one aspect, the invention provides an isolated or recombinant DNA molecule encoding a polypeptide or portion thereof, including a PKS module or domain, encoded in the Streptomyces pulveraceus fostriecin polyketide synthase gene cluster sequence.

In one aspect, the invention provides an isolated or recombinant DNA molecule encoding a complete polypeptide, module or domain comprising an amino acid sequence encoded in SEQ ID NOS: 1, 23, 27 or 33, or a conservatively modified variant thereof. In one aspect, the invention provides an isolated or recombinant DNA molecule encoding a subsequence from a polypeptide, module or domain comprising an amino acid sequence encoded in SEQ ID NOS: 1, 23, 27 or 33, or a conservatively modified variant thereof. The subsequence may comprise a sequence encoding a catalytically active fragment (having an activity characteristic of the domain, e.g., AT, KR, KS, DH, ER, ACP, TE activity) of a PKS module or domain. The DNA molecule may comprise a sequence encoding a polypeptide involved in post-synthesis modification of the fostriecin precursor or encoding another polypeptide of the fostriecin gene cluster.

In one aspect, the invention provides the present invention provides an isolated or recombinant DNA molecule comprising a nucleotide sequence that encodes an open reading frame, module or domain having an amino acid sequence identical or substantially similar to an ORF, module or domain encoded by an ORF of the fostriecin polyketide synthase cluster sequence. A polypeptide, module or domain having a sequence substantially similar to a reference sequence may have substantially the same activity as the reference protein, module or domain (e.g., when integrated into an appropriate PKS framework using methods known in the art).

In an embodiment, the invention provides a nucleotide sequence that encodes a polypeptide, such as a conservatively modified variant of a polypeptide, module or domain involved in the biosynthesis of a fostriecin, and comprises at least 10, 20, 25, 30, 35, 40, 45, or 50 contiguous base pairs identical to a sequence of SEQ ID NOS: 1, 23, 27 or 33. In one aspect, the invention provides an isolated or recombinant DNA molecule comprising a nucleotide sequence that encodes at least one polypeptide, module or domain that comprises at least 10, 15, 20, 30, or 40 contiguous residues of a corresponding polypeptide, module or domain comprising a sequence of SEQ ID NOS: 1, 23, 27 or 33.

It will be understood that, due to the degeneracy of the genetic code, a large number of DNA sequences encode the amino acid sequences of the domains, modules, and proteins of the fostriecin PKS, the enzymes involved in fostriecin modification and other polypeptides encoded by the genes of the fostriecin biosynthetic gene cluster. The present invention contemplates all such DNAs. For example, it may be advantageous to optimize sequence to account for the codon preference of a host organism. The invention also contemplates naturally occurring genes encoding the fostriecin PKS and modifying (or “tailoring”) enzymes that are polymorphic or other variants.

As used herein, a conservatively modified variant of a protein or fragment (e.g., domain) has substantial sequence identity to a reference amino acid sequence or is encoded by a DNA substantial sequence identity to a reference nucleic acid sequence.

The terms “substantial identity,” “substantial sequence identity,” or “substantial similarity” in the context of nucleic acids, refers to a measure of sequence similarity between two polynucleotides. Substantial sequence identity can be determined by hybridization under stringent conditions, by direct comparison, or other means. For example, two polynucleotides can be identified as having substantial sequence identity if they are capable of specifically hybridizing to each other under stringent hybridization conditions. Other degrees of sequence identity (e.g., less than “substantial”) can be characterized by hybridization under different conditions of stringency. “Stringent hybridization conditions” refers to conditions in a range from about 5° C. to about 20° C. or 25° C. below the melting temperature (Tm) of the target sequence and a probe with exact or nearly exact complementarity to the target. As used herein, the melting temperature is the temperature at which a population of double-stranded nucleic acid molecules becomes half-dissociated into single strands. Methods for calculating the Tm of nucleic acids are well known in the art (see, e.g., Berger and Kimmel, 1987, Methods In Enzymology, Vol. 152: Guide To Molecular Cloning Techniques, San Diego: Academic Press, Inc. and Sambrook et al., 1989, Molecular Cloning: A Laboratory Manual, 2nd Ed., Vols. 1-3, Cold Spring Harbor Laboratory). Typically, stringent hybridization conditions for probes greater than 50 nucleotides are salt concentrations less than about 1.0 M sodium ion, typically about 0.01 to 1.0 M sodium ion at pH 7.0 to 8.3, and temperatures at least about 50° C., preferably at least about 60° C. As noted, stringent conditions may also be achieved with the addition of destabilizing agents such as formamide, in which case lower temperatures may be employed. Exemplary conditions include hybridization at 7% sodium dodecyl sulfate (SDS), 0.5 M NaPO₄ pH 7.0, 1 mM EDTA at 50° C.; wash with 2×SSC, 1% SDS, at 50° C.

Alternatively, substantial sequence identity can be described as a percentage identity between two nucleotide or amino acid-sequences. Two nucleic acid sequences are considered substantially identical when they are at least about 70% identical, or at least about 80% identical, or at least about 90% identical, or at least about 95% or 98% identical. Two amino acid sequences are considered substantially identical when they are at least about 60%, sequence identical, more often at least about 70%, at least about 80%, or have at least about 90% sequence identity. Percentage sequence (nucleotide or amino acid) identity is typically calculated using art known means to determine the optimal alignment between two sequences and comparing the two sequences. Optimal alignment of sequences may be conducted using the local homology algorithm of Smith and Waterman (1981) Adv. Appl. Math. 2: 482, by the homology alignment algorithm of Needleman and Wunsch (1970) J. Mol. Biol. 48: 443, by the search for similarity method of Pearson and Lipman (1988) Proc. Nail. Acad. Sci. U.S.A. 85: 2444, by the BLAST algorithm of Altschul (1990) J. Mol. Biol. 215: 403-410; and Shpaer (1996) Genomics 38: 179-191, or by the Needleham et al. (1970) J. Mol. Biol. 48: 443-453; and Sankoff et al., 1983, Time Warps, String Edits, and Macromolecules, The Theory and Practice of Sequence Comparison, Chapter One, Addison-Wesley, Reading, Mass.; generally by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.; BLAST from the National Center for Biotechnology Information (http://www.ncbi.nlm.nih.gov/). In each case default parameters are used (for example the BLAST program uses as defaults a wordlength (W) of 11, the BLOSUM62 scoring matrix (see Henikoff(1992) Proc. Natl. Acad.

Sci. USA 89: 10915-10919) alignments (B) of 50, expectation (E) of 10, M=5, N=4, and a comparison of both strands).

As discussed in Example 1, the gene cluster sequences disclosed herein were determined from the inserts of cosmids pKOS279-117.1 F70, pKOS279-117.3F45, pKOS279-117.2F15, and pKos279-117.5F58. Accordingly, the invention provides an isolated or recombinant DNA molecule comprising a sequence from the insert of one or more of these cosmids. In an embodiment, the isolated or recombinant DNA molecule encodes a polypeptide or portion thereof, such as a module or domain. In an embodiment, the isolated or recombinant DNA molecule comprises at least 10, 20, 30, 40, 50 or 100 basepairs having a sequence of the cosmid insert.

The invention methods may be directed to the preparation of an individual polyketide. The polyketide may or may not be novel, but the method of preparation permits a more convenient or alternative method of preparing it. The resulting polyketides may be further modified to convert them to other useful compounds. Examples of chemical structures of that can be made using the materials and methods of the present invention include PD 113,270 and PD 113, 271, other known analogs, such as those described in Lewy et al., 2002, “Fostriecin: Chemistry and Biology” Current Medicinal Chemistry 9: 2005-2032 and the references cited therein, and novel molecules produced by modified or chimeric PKSs comprising a portion of the fosteriecin PKS sequence, molecules produced by the action of polyketide modifying enzymes from the fosteriecin PKS cluster on products of other PKSs, molecules produced by the action on products of the fosteriecin PKS of polyketide modifying enzymes from other PKSs, and the like.

As noted, in one aspect the invention provides recombinant PKS wherein at least 10, 15, 20, 30, or more consecutive amino acids in one or more domains of one or more modules thereof are derived from one or more domains of one or more modules of fostriecin polyketide synthase.

In one aspect, the invention provides a recombinant polyketide synthase derived from a naturally occurring PKS. A PKS “derived from” a naturally occurring PKS contains the scaffolding encoded by all the portion employed of the naturally occurring synthase gene, contains at least two modules that are functional, and contains mutations, deletions, or replacements of one or more of the activities of these functional modules so that the nature of the resulting polyketide is altered. This definition applies both at the protein and genetic levels.

Particular embodiments include those wherein a KS, AT, KR, DH, or ER has been inactivated (e.g., by deletion or other mutation), mutated to change its activity, and/or replaced by a version of the activity from a different PKS or from another location within the same PKS. Embodiments include derivatives where at least one noncondensation cycle enzymatic activity (KR, DH, or ER) has been inactivated (e.g., by deletion or other mutation) wherein any of these activities has been added or mutated so as to change the ultimate polyketide synthesized. There are at least five degrees of freedom for constructing a polyketide synthase in terms of the polyketide that will be produced. See, U.S. Pat. No. 6,509,455 for a discussion.

As can be appreciated by those skilled in the art, polyketide biosynthesis can be manipulated to make a product other than the product of a naturally occurring PKS biosynthetic cluster. For example, AT domains can be altered or replaced to change specificity. The variable domains within a module can be deleted and or inactivated or replaced with other variable domains found in other modules of the same PKS or from another PKS. See e.g., Katz & McDaniel, Med Res Rev 19: 543-558 (1999) and WO 98/49315. Similarly, entire modules can be deleted and/or replaced with other modules from the same PKS or another PKS. See e.g., Gokhale et al., Science 284: 482 (1999) and WO 00/47724 each of which are incorporated herein by reference. Protein subunits of different PKSs also can be mixed and matched to make compounds having the desired backbone and modifications. For example, subunits of 1 and 2 (encoding modules 1-4) of the pikromycin PKS were combined with the DEBS3 subunit to make a hybrid PKS product (see Tang et al., Science, 287: 640 (2001), WO 00/26349 and WO 99/6159).

It will be appreciated that an amino acid sequence of a protein or domain can be changed without eliminating or substantially changing the function or activity of the wild-type protein or domain, for example, by making conservative substitutions of amino acids. The present invention encompasses polypeptides that are conservatively modified variants of a polypeptide encoded in SEQ ID NO:1 and retain the activity of the wild-type polypeptide. Such polypeptides can be identified by routine screening methods. For example, a polypeptide having a substitution or combination of substitutions relative to wild-type can be prepared by mutation of DNA encoding the fostriecin cluster polypeptide or domain, and the effect (if any) of the sequence modification can be assessed by expressing the protein in a suitable host cell under conditions in which fostriecin is produced in the cell when the unmodified protein is expressed.

This assay can be carried out in Streptomyces pulveraceus by modification of endogenous genes or, alternatively, polynucleotides modified in vitro can be expressed in heterologous hosts as described elsewhere herein. Production of fostriecin at a level not less that 60% of the level produced by the wild-type sequence, preferably at least 80%, and most preferably not less than 95% of the level produced by the wild-type sequence is indicative that the modified polypeptide or domain has the same activity as the unmodified-parent. The invention includes such modified polypeptides and the nucleic acid sequences encoding them.

In other embodiments, a domain or other region of a fostriecin polyketide synthase polypeptide can be removed or otherwise inactivated or replaced with a different PKS domain.

Mutations can be introduced into PKS genes such that polypeptides with altered activity are encoded. Polypeptides with “altered activity” include those in which one or more domains are inactivated or deleted, or in which a mutation changes the substrate specificity of a domain, as well as other alterations in activity. Mutations can be made to the native sequences using conventional techniques. The substrates for mutation can be an entire cluster of genes or only one or two of them; the substrate for mutation may also be portions of one or more of these genes. Techniques for mutation include preparing synthetic oligonucleotides including the mutations and inserting the mutated sequence into the gene encoding a PKS subunit using restriction endonuclease digestion. (See, e.g., Kunkel, T. A. Proc Natl Acad Sci USA (1985) 82: 448; Geisselsoder et al. BioTechniques (1987) 5: 786.) Alternatively, the mutations can be effected using a mismatched primer (generally 10-20 nucleotides in length) that hybridizes to the native nucleotide sequence (generally cDNA corresponding to the RNA sequence), at a temperature below the melting temperature of the mismatched duplex. The primer can be made specific by keeping primer length and base composition within relatively narrow limits and by keeping the mutant base centrally located. (See Zoller and Smith, Methods in Enzymology (1983) 100: 468). Primer extension is effected using DNA polymerase. The product of the extension reaction is cloned, and those clones containing the mutated DNA are selected. Selection can be accomplished using the mutant primer as a hybridization probe. The technique is also applicable for generating multiple point mutations. (See, e.g., Dalbie-McFarland et al. Proc Natl Acad Sci USA (1982) 79: 6409). PCR mutagenesis can also be used for effecting the desired mutations.

Random mutagenesis of selected portions of the nucleotide sequences encoding enzymatic activities can be accomplished by several different techniques known in the art, e.g., by inserting an oligonucleotide linker randomly into a plasmid,

In addition to providing mutated forms of regions encoding enzymatic activity, regions encoding corresponding activities from different PKS synthases or from different locations in the same PKS synthase can be recovered, for example, using PCR techniques with appropriate primers. By “corresponding” activity encoding regions is meant those regions encoding the same general type of activity—e.g., a ketoreductase activity in one location of a gene cluster would “correspond” to a ketoreductase-encoding activity in another location in the gene cluster or in a different gene cluster; similarly, a complete reductase cycle could be considered corresponding—e.g., KR/DH/ER could correspond to KR alone.

If replacement of a particular target region in a host polyketide synthase is to be made, this replacement can be conducted in vitro using suitable restriction enzymes or can be effected in vivo using recombinant techniques involving homologous sequences framing the replacement gene. One such system involving plasmids of differing temperature sensitivities is described in PCT application WO 96/40968. Another useful method for modifying a PKS gene (e.g., making domain substitutions or “swaps”) is a RED/ET cloning procedure developed for constructing domain swaps or modifications in an expression plasmid without first introducing restriction sites. The method is related to ET cloning methods (see, Datansko & Wanner, 2000, Proc. Natl. Acad. Sci. U.S.A. 97, 6640-45; Muyrers et al, 2000, Genetic Engineering 22: 77-98). The RED/ET cloning procedure is used to introduce a unique restriction site in the recipient plasmid at the location of the targeted domain. This restriction site is used to subsequently linearize the recipient plasmid in a subsequent ET cloning step to introduce the modification. This linearization step is necessary in the absence of a selectable marker, which cannot be used for domain substitutions. An advantage of using this method for PKS engineering is that restriction sites do not have to be introduced in the recipient plasmid in order to construct the swap, which makes it faster and more powerful because boundary junctions can be altered more easily.

In a further aspect, the invention provides methods for expressing chimeric or hybrid PKSs and products of such PKSs. For example, the invention provides (1) encoding DNA for a chimeric PKS that is substantially patterned on a non-fostriecin producing enzyme, but which includes one or more functional domains, modules or polypeptides of fostriecin PKS; and (2) encoding DNA for a chimeric PKS that is substantially patterned on the fostriecin PKS, but which includes one or more functional domains, modules, or polypeptides of another PKS or NRPS.

With respect to item (1) above, in one embodiment, the invention provides chimeric PKS enzymes in which the genes for a non-fostriecin PKS function as accepting genes, and one or more of the above-identified coding sequences for fostriecin domains or modules are inserted as replacements for one or more domains or modules of comparable function. Construction of chimeric molecules is most effectively achieved by construction of appropriate encoding polynucleotides. In making a chimeric molecule, it is not necessary to replace an entire domain or module accepting of the PKS with an entire domain or module of fostriecin PKS: subsequences of a PKS domain or module that correspond to a peptide subsequence in an accepting domain or module, or which otherwise provide useful function, may be used as replacements. Accordingly, appropriate encoding DNAs for construction of such chimeric PKS include those that encode at least 10, 15, 20, 40 or more amino acids of a selected fostriecin domain or module.

Recombinant methods for manipulating modular PKS genes to make chimeric PKS enzymes are described in U.S. Pat. Nos. 5,672,491; 5,843,718; 5,830,750; and 5,712,146; and in PCT publication Nos. 98/49315 and 97/02358. A number of genetic engineering strategies have been used with DEBS to demonstrate that the structures of polyketides can be manipulated to produce novel natural products, primarily analogs of the erythromycins (see the patent publications referenced supra and Hutchinson, 1998, Curr Opin Microbiol. 1: 319-329, and Baltz, 1998, Trends Microbiol. 6: 76-83). In one embodiment, the components of the chimeric PKS are arranged onto polypeptides having interpolypeptide linkers that direct the assembly of the polypeptides into the functional PKS protein, such that it is not required that the PKS have the same arrangement of modules in the polypeptides as observed in natural PKSs. Suitable interpolypeptide linkers to join polypeptides and intrapolypeptide linkers to join modules within a polypeptide are described in PCT publication WO 00/47724.

A partial list of sources of PKS sequences for use in making chimeric molecules, for illustration and not limitation, includes Avermectin (U.S. Pat. No. 5,252,474; MacNeil et al., 1993, Industrial Microorganisms: Basic and Applied Molecular Genetics, Baltz, Hegeman, & Skatrud, eds. (ASM), pp. 245-256; MacNeil et al., 1992, Gene 115: 119-25); Candicidin (FRO008) (Hu et al., 1994, Mol. Microbiol. 14: 163-72); Epothilone (U.S. Pat. No. 6,303,342); Erythromycin (WO 93/13663; U.S. Pat. No. 5,824,513; Donadio et al., 1991, Science 252: 675-79; Cortes et al., 1990, Nature 348: 176-8); FK-506 (Motamedi et al., 1998, Eur. J. Biochem. 256: 528-34; Motamedi et al., 1997, Eur. J. Biochem. 244: 74-80); FK-520 (U.S. Pat. No. 6,503,737; see also Nielsen et al., 1991, Biochem. 30: 5789-96); Lovastatin (U.S. Pat. No. 5,744,350); Nemadectin (MacNeil et al., 1993, supra); Niddamycin (Kakavas et al., 1997, J. Bacteriol. 179: 7515-22); Oleandomycin (Swan et al., 1994, Mol. Gen. Genet. 242: 358-62; U.S. Pat. No. 6,388,099; Olano et al., 1998, Mol. Gen. Genet. 259: 299-308); Platenolide (EP Pat. App. 791,656); Rapamycin (Schwecke et al., 1995, Proc. Natl. Acad. Sci. USA 92: 7839-43); Aparicio et al., 1996, Gene 169: 9-16); Rifamycin (August et al., 1998, Chemistry & Biology, 5: 69-79); Soraphen (U.S. Pat. No. 5,716,849; Schupp et al., 1995, J. Bacteriology 177: 3673-79); Spiramycin (U.S. Pat. No. 5,098,837); Tylosin (EP 0 791,655; Kuhstoss et al., 1996, Gene 183: 231-36; U.S. Pat. No. 5,876,991). Additional suitable PKS coding sequences remain to be discovered and characterized, but will be available to those of skill (e.g., by reference to GenBank).

The fostriecin PKS-encoding polynucleotides of the invention may also be used in the production of libraries of PKSs (i.e., modified and chimeric PKSs comprising at least a portion of the fostriecin PKS sequence. The invention provides libraries of polyketides by generating modifications in, or using a portion of, the fostriecin PKS so that the protein complexes produced by the cluster have altered activities in one or more respects, and thus produce polyketides other than the natural fostriecin product of the PKS. Novel polyketides may thus be prepared, or polyketides in general prepared more readily, using this method. By providing a large number of different genes or gene clusters derived from a naturally occurring PKS gene cluster, each of which has been modified in a different way from the native PKS cluster, an effectively combinatorial library of polyketides can be produced as a result of the multiple variations in these activities. Expression vectors containing nucleotide sequences encoding a variety of PKS systems for the production of different polyketides can be transformed into the appropriate host cells to construct a polyketide library. In one approach, a mixture of such vectors is transformed into the selected host cells and the resulting cells plated into individual colonies and selected for successful transformants. Each individual colony has the ability to produce a particular PKS synthase and ultimately a particular polyketide. A variety of strategies can be devised to obtain a multiplicity of colonies each containing a PKS gene cluster derived from the naturally occurring host gene cluster so that each colony in the library produces a different PKS and ultimately a different polyketide. The number of different polyketides that are produced by the library is typically at least four, more typically at least ten, and preferably at least 20, more preferably at least 50, reflecting similar numbers of different altered PKS gene clusters and PKS gene products. The number of members in the library is arbitrarily chosen; however, the degrees of freedom outlined above with respect to the variation of starter, extender units, stereochemistry, oxidation state, and chain length is quite large. The polyketide producing colonies can be identified and isolated using known techniques and the produced polyketides further characterized. The polyketides produced by these colonies can be used collectively in a panel to represent a library or may be assessed individually for activity. See, for example,

Colonies in the library are induced to produce the relevant synthases and thus to produce the relevant polyketides to obtain a library of candidate polyketides. The polyketides secreted into the media can be screened for binding to desired targets, such as receptors, signaling proteins, and the like. The supernatants per se can be used for screening, or partial or complete purification of the polyketides can first be effected. Typically, such screening methods involve detecting the binding of each member of the library to receptor or other target ligand. Binding can be detected either directly or through a competition assay. Means to screen such libraries for binding are well known in the art. Alternatively, individual polyketide members of the library can be tested against a desired target. In this event, screens wherein the biological response of the target is measured can be included.

As noted above, the DNA compounds of the invention can be expressed in host cells for production of proteins and of known and novel compounds. Preferred hosts include fungal systems such as yeast and prokaryotic hosts, but single cell cultures of, for example, mammalian cells could also be used. A variety of methods for heterologous expression of PKS genes and host cells suitable for expression of these genes and production of polyketides are described, for example, in U.S. Pat. Nos. 5,843,718 and 5,830,750; WO 01/31035, WO 01/27306, and WO 02/068613; and U.S. patent application Ser. Nos. 10/087,451 (published as U.S. 2002000087451); 60/355,211; and 60/396,513 (corresponding to published application 20020045220).

Appropriate host cells for the expression of the hybrid PKS genes include those organisms capable of producing the needed precursors, such as malonyl-CoA, methylmalonyl-CoA, ethylmalonyl-CoA, and methoxymalonyl-ACP, and having phosphopantotheinylation systems capable of activating the ACP domains of modular PKSs. See, for example, U.S. Pat. No. 6,579,695. However, as disclosed in U.S. Pat. No. 6,033,883, a wide variety of hosts can be used, even though some hosts natively do not contain the appropriate post-translational mechanisms to activate the acyl carrier proteins of the synthases. Also see WO 97/13845 and WO 98/27203. The host cell may natively produce none, some, or all of the required polyketide precursors, and may be genetically engineered so as to produce the required polyketide precursors. Such hosts can be modified with the appropriate recombinant enzymes to effect these modifications. In one embodiment the host cell is a bacterium. In another embodiment the host cell is a fungus, such as a yeast cell. Suitable host cells include Streptomyces, E. coli, yeast, and other prokaryotic hosts which use control sequences compatible with Streptomyces spp. Examples of suitable hosts that either natively produce modular polyketides or have been engineered so as to produce modular polyketides include but are not limited to actinomyctes such as Streptomyces coelicolor, Streptomyces venezuelae, Streptomyces fradiae, Streptomyces ambofaciens, and Saccharopolyspora erythraea, eubacteria such as Escherichia coli, myxobacteria such as Myxococcus xanthus, and yeasts such as Saccharomyces cerevisiae.

In sone embodiments, any native modular PKS genes in the host cell have been deleted to produce a “clean host,” as described in U.S. Pat. No. 5,672,491.

Host cells can be selected, or engineered, for expression of a glycosylatation apparatus (discussed below), amide synthases, (see, for example, U.S. patent publication 20020045220 “Biosynthesis of Polyketide Synthase Substrates”). For example and not limitation, the host cell can contain the desosamine, megosamine, and/or mycarose biosynthetic genes, corresponding glycosyl transferase genes, and hydroxylase genes (e.g., picK, megK, eryK, megF, and/or eryF). Methods for glycosylating polyketides are generally known in the art and can be applied in accordance with the methods of the present invention; the glycosylation may be effected intracellularly by providing the appropriate glycosylation enzymes or may be effected in vitro using chemical synthetic means as described herein and in WO 98/493-15, incorporated herein by reference. Glycosylation with desosamine, mycarose, and/or megosamine is effected in accordance with the methods of the invention in recombinant host cells provided by the invention. Alternatively and as noted, glycosylation may be effected intracellularly using endogenous or recombinantly produced intracellular glycosylases. In addition, synthetic chemical methods may be employed.

Alternatively, the aglycone compounds can be produced in the recombinant host cell, and the desired modification (e.g., glycosylation and hydroxylation) steps carried out in vitro (e.g., using purified enzymes, isolated from native sources or recombinantly produced) or in vivo in a converting cell different from the host cell (e.g., by supplying the converting cell with the aglycone).

Modification or tailoring enzymes for modification of a product of the fostriecin PKS, a non-fostriecin PKS, or a chimeric PKS, can be those normally associated with fostriecin biosynthesis or “heterologous” tailoring enzymes. Tailoring enzymes can be expressed in the organism in which they are naturally produced, or as recombinant proteins in heterologous hosts. In some cases, the structure produced by the heterologous or hybrid PKS may be modified with different efficiencies by post-PKS tailoring enzymes from different sources. In such cases, post-PKS tailoring enzymes can be recruited from other pathways to obtain the desired compound.

In some embodiments, the host cell expresses, or is engineered to express, a polyketide “tailoring” or “modifying” enzyme. Once a PKS product is released, it is subject to post-PKS tailoring reactions. These reactions are important for biological activity and for the diversity seen among polyketides. Tailoring enzymes normally associated with polyketide biosynthesis include oxygenases, glycosyl- and methyltransferases, acyltransferases, halogenases, cyclases, aminotransferases, and hydroxylases.

In the case of fostriecin biosynthesis, tailoring enzymes include P450 hydroxylases for addition of hydroxyl groups. The PKS is expected to initially produce hydroxyls at C3, C5, C9 and C11, with the C9 hydroxyl further modified by phosphorylation, the C5 hydroxyl further reacting to help create the 6-membered lactone ring, and the C3 hydroxyl being removed by dehydration in the creation of a double bond between C2 and C3. In addition hydroxyls at C8 and C18 (and C4 in PD 113, 271) are expected to be introduced by post-PKS-acting accessory proteins. The fostriecin gene cluster encodes three cytochrome-P450-hydroxylase homologs (FosG, FosJ and FosK). Based on apparent homology between FosJ and the PlmT4 P450 hydrolase encoded in the Streptomyces phoslactomycin synthase gene cluster, apparent homology between FosK and the PlmS2 P450 hydrolase encoded in the Streptomyces phoslactomycin synthase gene cluster, evidence that PlmS2 is responsible for cyclohexyl modification at C18 but not C8 of the polyketide phoslactomycin, and the presence of hydroxyls at the tertiary C8 of fostriecin and the tertiary C8 of phoslactomycin, FosJ may produce the C8 hydroxyl of fostriecin. FosG and/or FosK are expected to modify the C4 and C8 positions, with perhaps a specific P450 for each site. The phosphorylation of the hydroxyl group at C9 is predicted to be accomplished by FosH, a distant homolog of homoserine kinases. ORF7 encodes a type II thioesterase.

The P450 hydroxylases and kinase of the fostriecin PKS gene cluster can be expressed heterologously to modify polyketides produced by non-fostriecin polyketide synthases or can be inactivated in the Fostriecin producer.

In addition to biosynthetic accessory activities, secondary metabolite clusters often code for activities such as transport and regulation. FosI appears to be a permease having a transport function. ORF1 and ORF3 are putative transcriptional regulators. ORF1 is a homolog of MarR-family transcriptional regulators, including SC07709, SC07639 and SC00447 from Streptomyces coelicolor. ORF3 is a homolog of LuxR family transcriptional regulators.

ORF2 is a homolog of a conserved family, including SC7708, SC6340 and SC5938 from Streptomyces coelicolor, and SAV1967 and SAV0886 from S. avermitilis. ORF4 is a homolog of a conserved family, including PlmT2 from the phoslactomycin biosynthetic cluster, SAV4898 from Streptomyces avermitilis and SC04633 from S. coelicolor. ORF5 is a homolog of BorL from the borrelidin biosynthetic cluster. ORF6 encodes a homolog of the product of plu4507 from Photorhabdus luminescens subsp. laumondii TTO1, and has some similarity to 3-hydroxy-3-methylglutaryl coenzyme A reductases. ORF8 encodes a homolog of chaperone protein HtpG (heat shock protein HtpG) from Streptomyces coelicolor.

Tables 2 and 4 describe the characteristics of open reading frames of the fostriecin polyketide synthase gene cluster. Table 2 shows the position of each ORF relative to SEQ ID NO: 1, as well as identifying certain homologous proteins.

TABLE 2
ORFs Encoding Additional Polypeptides Encoded in the Fostriecin polyketide synthase Cluster
	amino		Position in SEQ ID NO: 1
ORF	acids	putative function	coding strand(nucleotide pair)	homology	% identity
orf1	165	MarR-family	SEQ ID NO 1(72775 . . . 73272)	SC07709 (142 aa; 43%	43%/137aa
		transcriptional		identity/137 aa),
		regulator		SC07639 and SC00447
				from Streptomyces
				coelicolor
orf2	213		complement(72055 . . . 72696)	SC7708 (216 aa; 48%	48%/216aa
				identity/192 aa),
				SC6340 and SC5938 from
				Streptomyces coelicolor
orf3	967	LuxR-family	complement(68498 . . . 71401)	PikD (Streptomyces	29%/977aa
		transcriptional		venezuelae)
		regulator
orf4	295	unknown	complement(67600 . . . 68487)	PlmT2 from the	41%/212aa
				phoslactomycin
				biosynthetic cluster
fosG	409	P450; possible C8 or	complement(33643 . . . 34872)	ORF4 from the mitomycin	48%/395aa
		C4-hydroxylase		C biosynthetic cluster
				in Streptomyces
				lavendulae
fosH	316	polyketide kinase	complement(32552 . . . 33502)	PlmT5 from the	43%/259aa
				phoslactomycin
				biosynthetic cluster
fosI	444	polyketide export	complement(31111 . . . 32445)	PlmS4 from the	50%/431aa
				phoslactomycin
				biosynthetic cluster
				[COG0477: Permeases of
				the major facilitator
				superfamily]
fosJ	420	P450; possible C4- or	complement(29742 . . . 31004)	PlmT4 from the	54%/397aa
		C8-hydroxylase		phoslactomycin
				biosynthetic cluster
fosK	398	P450; possible C18-	SEQ ID NO 1(28443 . . . 29639)	PlmS2 from the	57%/404aa
		hydroxylase		phoslactomycin
				biosynthetic cluster
orf5	538		complement(7892 . . . 9508)	BorL from the	30%/536aa
				borrelidin biosynthetic
				cluster
orf6	781	homology to 3-hydroxy-	complement(5550 . . . 7895)	plu4507 from	39%/774aa
		3-methylglutaryl		Photorhabdus
		coenzyme A reductases		luminescens subsp.
				laumondii TTO1
orf7	258	thioesterase (TEII	complement(3840 . . . 4616)	AveG (Streptomyces	52%/238aa
		family)		avermitilis)
orf8	633	chaperone protein htpG	complement(1424 . . . 3325)	HtpG (Streptomyces	79%/638aa
		(heat shock protein		coelicolor)
		htpG)
*fosG, H, I, J and K were previously called ORFs 1, 2, 3, 4 and 5

It will be apparent to the reader that a variety of recombinant vectors can be utilized in the practice of aspects of the invention. As used herein, “vector” refers to polynucleotide elements that are used to introduce recombinant nucleic acid into cells for either expression or replication. Selection and use of such vehicles is routine in the art. An “expression vector” includes vectors capable of expressing DNAs that are operatively linked with regulatory sequences, such as promoter regions. Thus, an expression vector refers to a recombinant DNA or RNA construct, such as a plasmid, a phage, recombinant virus or other vector that, upon introduction into an appropriate host cell, results in expression of the cloned DNA. Appropriate expression vectors are well known to those of skill in the art and include those that are replicable in eukaryotic cells and/or prokaryotic cells and those that remain episomal or those which integrate into the host cell genome.

The vectors used to perform the various operations to replace the enzymatic activity in the host PKS genes or to support mutations in these regions of the host PKS genes may be chosen to contain control sequences operably linked to the resulting coding sequences in a manner that expression of the coding sequences may be effected in an appropriate host. Suitable control sequences include those which function in eukaryotic and prokaryotic host cells. If the cloning vectors employed to obtain PKS genes encoding derived PKS lack control sequences for expression operably linked to the encoding nucleotide sequences, the nucleotide sequences are inserted into appropriate expression vectors. This can be done individually, or using a pool of isolated encoding nucleotide sequences, which can be inserted into host vectors, the resulting vectors transformed or transfected into host cells, and the resulting cells plated out into individual colonies.

Suitable control sequences for single cell cultures of various types of organisms are well known in the art. Control systems for expression in yeast are widely available and are routinely used. Control elements include promoters, optionally containing operator sequences, and other elements depending on the nature of the host, such as ribosome binding sites.

Particularly useful promoters for prokaryotic hosts include those from PKS gene clusters which result in the production of polyketides as secondary metabolites, including those from Type I or aromatic (Type II) PKS gene clusters. Examples are act promoters, tcm promoters, spiramycin promoters, and the like. However, other bacterial promoters, such as those derived from sugar metabolizing enzymes, such as galactose, lactose (lac) and maltose, are also useful. Additional examples include promoters derived from biosynthetic enzymes such as for tryptophan (trp), the β-lactamase (bla), bacteriophage lambda PL, and T5. In addition, synthetic promoters, such as the tac promoter (U.S. Pat. No. 4,551,433), can be used.

As noted, particularly useful control sequences are those which themselves, or with suitable regulatory systems, activate expression during transition from growth to stationary phase in the vegetative mycelium. The system contained in the plasmid identified as pCK7, i.e., the actI/actIII promoter pair and the actII-ORF4 (an activator gene), is particularly preferred. Particularly preferred hosts are those which lack their own means for producing polyketides so that a cleaner result is obtained. Illustrative control sequences, vectors, and host cells of these types include the modified S. coelicolor CH999 and vectors described in PCT publication WO 96/40968 and similar strains of S. lividans. See U.S. Pat. Nos. 5,672,491; 5,830,750, 5,843,718; and 6,177,262, each of which is incorporated herein by reference.

Other regulatory sequences may also be desirable which allow for regulation of expression of the PKS sequences relative to the growth of the host cell. Regulatory sequences are known to those of skill in the art, and examples include those which cause the expression of a gene to be turned on or off in response to a chemical or physical stimulus, including the presence of a regulatory compound. Other types of regulatory elements may also be present in the vector, for example, enhancer sequences.

Selectable markers can also be included in the recombinant expression vectors. A variety of markers are known which are useful in selecting for transformed cell lines and generally comprise a gene whose expression confers a selectable phenotype on transformed cells when the cells are grown in an appropriate selective medium. Such markers include, for example, genes which confer antibiotic resistance or sensitivity to the plasmid. Alternatively, several polyketides are naturally colored, and this characteristic provides a built-in marker for screening cells successfully transformed by the present constructs.

The various PKS nucleotide sequences, or a mixture of such sequences, can be cloned into one or more recombinant vectors as individual cassettes, with separate control elements or under the control of a single promoter. The PKS subunits or components can include flanking restriction sites to allow for the easy deletion and insertion of other PKS subunits so that hybrid or chimeric PKSs can be generated. The design of such restriction sites is known to those of skill in the art and can be accomplished using the techniques described above, such as site-directed mutagenesis and PCR. Methods for introducing the recombinant vectors of the present invention into suitable hosts are known to those of skill in the art and typically include the use of CaCl₂ other agents, such as divalent cations, lipofection, DMSO, protoplast transformation, conjugation, and electroporation.

Thus, the present invention provides recombinant DNA molecules and vectors comprising those recombinant DNA molecules that encode all or a portion of the fostriecin PKS and/or fostriecin modification enzymes and that, when transformed into a host cell and the host cell is cultured under conditions that lead to the expression of said fostriecin PKS and/or modification enzymes, results in the production of polyketides including but not limited to fostriecin and/or analogs or derivatives thereof in useful quantities. The present invention also provides recombinant host cells comprising those recombinant vectors.

Suitable culture conditions for production of polyketides using the cells of the invention will vary according to the host cell and the nature of the polyketide being produced, but will be know to those of skill in the art. See, for example, the examples below and WO 98/27203 “Production of Polyketides in Bacteria and Yeast” and WO 01/83803 “Overproduction Hosts for Biosynthesis of Polyketides.”

The polyketide product produced by host cells of the invention can be recovered (i.e., separated from the producing cells and at least partially purified) using routine techniques (e.g., extraction from broth followed by chromatography).

The compositions, cells and methods of the invention may be directed to the preparation of an individual polyketide or a number of polyketides. The polyketide may or may not be novel, but the method of preparation permits a more convenient or alternative method of preparing it. It will be understood that the resulting polyketides may be further modified to convert them to other useful compounds. For example, an ester linkage may be added to produce a “pharmaceutically acceptable ester” (i.e., an ester that hydrolyzes under physiologically relevant conditions to produce a compound or a salt thereof). Illustrative examples of suitable ester groups include but are not limited to formates, acetates, propionates, butyrates, succinates, and ethylsuccinates.

The polyketide product can be modified by addition of a protecting group, for example to produce prodrug forms. A variety of protecting groups are disclosed, for example, in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York (1999). Prodrugs are in general functional derivatives of the compounds that are readily convertible in vivo into the required compound. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs,” H. Bundgaard ed., Elsevier, 1985.

Similarly, improvements in water solubility of a polyketide compound can be achieved by addition of groups containing solubilizing functionalities to the compound or by removal of hydrophobic groups from the compound, so as to decrease the lipophilicity of the compound. Typical groups containing solubilizing functionalities include, but are not limited to: 2-(dimethylaminoethyl)amino, piperidinyl, N-alkylpiperidinyl, hexahydropyranyl, furfuryl, tetrahydrofurfuryl, pyrrolidinyl, N-alkylpyrrolidinyl, piperazinylamino, N-alkylpiperazinyl, morpholinyl, N-alkylaziridinylmethyl, (1-azabicyclo[1.3.0]hex-1-yl)ethyl, 2-(N-methylpyrrolidin-2-yl)ethyl, 2-(4-imidazolyl)ethyl, 2-(1-methyl-4-imidazolyl)ethyl, 2-(1-methyl-5-imidazolyl)ethyl, 2-(4-pyridyl)ethyl, and 3-(4-morpholino)-1-propyl. Solubilizing groups can be added by reaction with amines. Typical amines containing solubilizing functionalities include 2-(dimethylamino)-ethylamine, 4-aminopiperidine, 4-amino-1-methylpiperidine, 4-aminohexahydropyran, furfurylamine, tetrahydrofurfurylamine, 3-(aminomethyl)-tetrahydrofuran, 2-(amino-methyl)pyrrolidine, 2-(aminomethyl)-1-methylpyrrolidine, 1-methylpiperazine, morpholine, 1-methyl-2(aminomethyl)aziridine, 1-(2-aminoethyl)-1-azabicyclo-[1.3.0]hexane, 1-(2-aminoethyl)piperazine, 4-(2-aminoethyl)morpholine, 1-(2-amino-ethyl)pyrrolidine, 2-(2-aminoethyl)pyridine, 2-fluoroethylamine, 2,2-difluoroethylamine, and the like.

In addition to post synthesis chemical or biosynthetic modifications, various polyketide forms or compositions can be produced, including but not limited to mixtures of polyketides, enantiomers, diastereomers, geometrical isomers, polymorphic crystalline forms and solvates, and combinations and mixtures thereof can be produced.

Many other modifications of polyketides produced according to the invention will be apparent to those of skill, and can be accomplished using techniques of pharmaceutical chemistry.

Prior to use the PKS product (whether modified or not) can be formulated for storage, stability or administration. For example, the polyketide products can be formulated as a “pharmaceutically acceptable salt.” Suitable pharmaceutically acceptable salts of compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, benzoic acid, acetic acid, citric acid, tartaric acid, phosphoric acid, carbonic acid, or the like. Where the compounds carry one or more acidic moieties, pharmaceutically acceptable salts may be formed by treatment of a solution of the compound with a solution of a pharmaceutically acceptable base, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, tetraalkylammonium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, ammonia, alkylamines, or the like.

Prior to administration to a mammal the PKS product will be formulated as a pharmaceutical composition according to methods well known in the art, e.g., combination with a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable carrier” refers to a medium that is used to prepare a desired dosage form of a compound. A pharmaceutically acceptable carrier can include one or more solvents, diluents, or other liquid vehicles; dispersion or suspension aids; surface active agents; isotonic agents; thickening or emulsifying agents; preservatives; solid binders; lubricants; and the like. Remington's Pharmaceutical Sciences, Fifteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1975) and Handbook of Pharmaceutical Excipients, Third Edition, A. H. Kibbe ed. (American Pharmaceutical Assoc. 2000), disclose various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof.

The composition may be administered in any suitable form such as solid, semisolid, or liquid form. See Pharmaceutical Dosage Forms and Drug Delivery Systems, 5^th edition, Lippicott Williams & Wilkins (1991). In an embodiment, for illustration and not limitation, the polyketide is combined in admixture with an organic or inorganic carrier or excipient suitable for external, enteral, or parenteral application. The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, pessaries, solutions, emulsions, suspensions, and any other form suitable for use. The carriers that can be used include water, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, and other carriers suitable for use in manufacturing preparations, in solid, semi-solid, or liquified form. In addition, auxiliary stabilizing, thickening, and coloring agents and perfumes may be used.

It will be appreciated by those of skill that recombinant polynucleotides and polypeptides of the invention have a variety of uses, including, but not limited to, those described above and including use as probes and primers (e.g., for gene amplification or targeting) or as enzymes, or components of enzymes, useful for the synthesis or modification of polyketides. Recombinant polypeptides encoded by the fostriecin PKS gene cluster are also useful as antigens for production of antibodies. Such antibodies find use for purification of bacterial (e.g., Streptomyces pulveraceus) proteins, detection and typing of bacteria, and particularly, as tools for strain improvement (e.g., to assay PKS protein levels to identify “up-regulated” strains in which levels of polyketide producing or modifying proteins are elevated) or assessment of efficiency of expression of recombinant proteins. Polyclonal and monoclonal antibodies can be made by well known and routine methods (see, e.g., Harlow and Lane, 1988, ANTIBODIES: A LABORATORY MANUAL, COLD SPRING HARBOR LABORATORY, New York; Koehler and Milstein 1075, Nature 256: 495). In selecting-polypeptide sequences for antibody induction, it is not to retain biological activity; however, the protein fragment must be immunogenic, and preferably antigenic (as can be determined by routine methods). Generally the protein fragment is produced by recombinant expression of a DNA comprising at least about 60, more often at least about 200, or even at least about 500 or more base pairs of protein coding sequence, such as a polypeptide, module or domain derived from a fostriecin polyketide synthase (PKS) gene cluster. Methods for expression of recombinant proteins are well known. (See, e.g., Ausubel et al., 2002, Current Protocols In Molecular Biology, Greene Publishing and Wiley-Interscience, New York.)

EXAMPLES

The following examples are provided to illustrate, but are not intended to limit, the present invention.

Example 1

Cloning and Sequencing of Gene Cluster for Fostriecin Biosynthesis

Growth of Organism and Extraction of Genomic DNA.

For genomic DNA extraction, a spore stock of Streptomyces pulveraceus subsp. fostreus ATCCC 31906 was used to inoculate 35 ml of Tryptitone Soy Broth (TSB) liquid media. After two days growth in 30° C., a 10 ml portion of the cell suspension was centrifuged (10,000×g). The pellet was suspended into 3.5 ml of buffer 1(Tris, 50 mM, pH7.5; 20 mM EDTA, 150 μg/ml RNase (Sigma-Aldrich) and 1 mg/ml of lysozyme (Sigma)). After incubation of the mixture at 37° C. for 30 min, the salt concentration was adjusted by adding 850 μl 5 M NaCl solution, then the mixture was extracted two times with phenol:chloroform:isoamylaclohol (25: 24: 1, vol/vol) with gentle agitation followed by centrifugation for 10 min at 3500×g. After precipitation with 1 vol of isopropanol, the genomic DNA knot was spooled on a glass rod and redissolved in 500 μl of water.

Genomic Library Preparation

Approximately 10 μg of genomic DNA was partially digested with Sau3A1 (1 hr incubation using dilutions of the enzyme) and the digested DNA was run on an agarose gel with DNA standards. One of the conditions used was found to have generated fragments of size 30-45 kb. The DNA from this digestion was ligated with pSuperCos-1 (Stratagene), pre-linearized with BamHI and XbaI and the ligation mixture was packaged using a Gigapack XIII (Stragene) in vitro packaging Kit and the mixture was subsequently used for infection of Escherichia coli DH5α employing protocols supplied by the manufacturer.

Identification of Fostriecin Biosynthetic Gene Cluster

To find the gene cluster for fostriecin biosynthesis, cosmids from 1 IX 95 E. coli transductants resulted from the above ligation mixture were sequenced with using convergent primersT7cos (5′-CATAATACGACTCACTATAGGG) [SEQ ID NO: 21] and T3cos-1 (5′-TTCCCCGAAAAGTGCCAC) [SEQ ID NO: 22]. After BLAST analysis, the sequences revealed 28 cosmids carrying DNA fragment encoded type I or type II PKS (polyketide synthase) genes at either of ends or both ends. Based on sequence and restriction enzyme maps of the 21 cosmids most likely related to modular PKS, most could be assigned to two major groups (“overlap family 1” and “overlap family 3”). Since overlap family 3 carries genes (homologous to gdmI and K) for methoxymalonyl-ACP, which is not needed for the biosynthesis of fostriecin, we focused on overlap family 1 (See FIG. 2). Based on the relation of among these cosmids, we chose to sequence pKOS279-117.3F70, pKOS279-117.3F45, pKOS279-117.2F15, and pKos279-117.5F58 from the overlap family 1. Other cosmids in this family were pKOS279-127.11 F54; pKOS279-127.10F6; pKOS279-127.10F75; pKOS279-127.3F46; pKOS279-127.5F58.

DNA Sequencing

In initial sequencing efforts the sequence of inserts of three cosmids (pKOS279-117.1F70, pKOS279-117.3F45 and pKOS279-117.2F15) was determined. The results of this sequencing effort are provided in the appended sequence listings (which are part of and incorporated into this specification) as SEQ ID NOs: 23, 27 and 33. Small gaps in the sequence indicated as “x” or “n.” Complete or partial open reading frames (ORFs) encoded by these sequences can be determined by reference to the genetic code and are also provided in SEQ ID NOs: 24-26,28-32 and 34-36. Complete sequencing was carried out using (pKOS279-117.1F70, pKOS279-117.3F45, pKOS279-117.2F15, and pKos279-117.5F58).

TABLE 3
FOSTRIECIN SYNTHASE GENE CLUSTER
from Streptomyces pulveraceus subsp. fostreus ATCC31906
source 1 . . . 18774 from pKos279-117.1F70
source 18651 . . . 29679 from pKos279-117.3F45
source 28694 . . . 29679 from pKos279-117.2F15
source 29683 . . . 53913 from pKos279-117.3F45
source 29683 . . . 66484 from pKos279-117.2F15
source 58636 . . . >73984 from pKos279-117.5F58
29680 . . . 29682 is an unsequenced
fragment of putative hairpin terminator″
1     AGGCCGACGG GCAGTGCCCG CGGCGTATCG GTGGCCGCCC ACGCGCGGGC GGGGAACGCA
61    CGGACGGCCC CCGCGGCGAG CGCGGCCACG GGCAGCGCCG ATCCTGCGCC GAGGAAGCCG
121   GGCCGGCTGA AGGCGGGATG GGGGCGGGGG GTGGGCGAGT CGGGGCCGTG AGGGGTGGGC
181   GAGTCGGGGC CGTGGGGGGT GGTCTGACTG GCCAACGGAG TACTCCTTCA CACACGTCGG
241   GCGAAGCAGG ACGGCTCAGC TGTACGGCGG ACAGGGACGG GAGCGACCGG TCCCGAAGCG
301   GGATTGAAAC GTTTCAATAA GGTGGTGCGG TCGTACGGTA CGAGAGTGAC CAAGGGGGGT
361   CAAGGGGTTC GGCACACCGT TTGGGACGGC CCCACGCCCG CCTCGCGCGC ACCTCGGCGC
421   ACTCGCCACG CACACTCGGC CTCGAACACC CGGCGAGGAA GCCCGTGGGA TCGGCAGGAT
481   CCGGCGACAG CGGCTGCGGA GCGCGGTGAC GCACACTGGG AAAGGCACCC CATCGAGGTG
541   CTCCGAGATC GTCGAGGGAA CCGTAGGCGG CCGGGATCCT GCGGCACGGA CCGGGAGGGC
601   CATGACACCA GGTACGACAC CAGGTATACC CGGACGACGG TCGGGCGCAC TGCGTCGGCA
661   TGCCGTGCGC CTCCTGGCGA AGCCGAGAGG CCGCCCCGCA CCGGCCCCTC CCCCGCGCTC
721   CGCCCAGCTG CGGGCGCTCA CCGCCCTGCT GGACGAGGCG GTGGCGGCGC AGGCACCGGC
781   GGACCGGAGG GTGGCGGCCT GCGGCGAACC GGGCCCCCTC GCCGGGCAGA CCGCCCGGGA
841   AGCCGGACGG CAGTACAGGG TCCTGCACGG GCTGCACGCG CGCGTGCGCG ATCTGCCGCT
901   GACGGAGGCC GATCTCGTCC GGGCCCAGGA GTACGCGGGA CGCCTGCTCT CCTACGGCCA
961   GTGGATGATG CGCGAGGCCA TGGACCTCGC CTTCCCCTCG AACCCGCGTC CGAGCGTCGA
1021  GGCGGCCGGG CTCCACCTCA ACGGCCTGGG AAGGCCCGCC GACGACCTGC GCAGGCTCCG
1081  CGACGCCCTC CGCTCCGAGT GCGGCGGCGG ACGGGCGGGT CGAGGGCACT GAGCCGGAGG
1141  GCCGTCGCGG ACGGTGGTCC GCGTCGTACG GGAGCGGGCC GCACCGGTCA AGGGCAGGAC
1201  GCCGCAGAGC TCTGCGATCC GGCCGTCGCG GGCGGTGCGG TGCGGTTCGG CGCGGTCGCA
1261  CGCGTTCGGT GCGGTTCGGT GCCGTGACGC GGTCGGCCGA CCGTCATGGG CGGCGGCGCC
1321  GACGCGTACC CGGGCCCCTT CCGGCCGAGA GCCGGATACG CGTCGAGGCC GCCGGTCCGG
1381  TGGACGCCGC CGTCCGGCTC GGCGGCCGGC GGCGCTGTCC GGCTCAGCGA AGCGTGCGCT
1441  CCAGTCGCTC CGCCACCAGC TTCACGAAAC GCCCCGGGTG CGTCGGCCGC CCGCGCTCCG
1501  CGAGCACCGC GAGTCCGTAC AGCAGGTCGG CGGTCTCGGC GAGCCCGGAG CGGTCCTCAC
1561  CCTCCTGGTA GGCCTGGTTC AGGCCCTGGA CCAGGGGGTG GGCGGGGTTG AGTTCGAGGA
1621  TCCGCCGGGC GGACGGAATC TCCTGGCCCA TGGCCCGGTA CATGCTCTCC AGCGCCGGGG
1681  TGAGGTCATG GGCGTCGGAG ACGACACAGG CCGGGGAGAC GGTCAGCCGG GTCGACAGGC
1741  GGACGTCCTT CATCTCCTCC CCGAGGTGTT CCTTCATCCA GCCCAGCAGA GCGGCGTACG
1801  TCTCGGCCTG CTTCTCCCGC CCGCCGTCGG CCTGTTCGCC GCCCTGGACG TCGAGATCGA
1861  TCTCGGCCTT GGCGACGGAC CTCAGCCGCT TGCCCTCGAA CTCGGCCACG ACGTCGACCC
1921  ACACCTCGTC GACGGGGTCG GTGAGCAGGA GGACCTCAAG ACCCCGGTCC CGGAACGCCT
1981  CCATGTGCGG GGAGTTCTCG ATGGTCTGCC GGGACGCGCC GGTCATGTAG TAGATGTCGT
2041  CGTGGGCTTC CTTCATCCGC TCCAGGTACT GCTGGAGCGT GGTCGGCGTC TCCTCGGCGT
2101  GGGTGCTGGC GAAGGACGGC ACGGCCAGCA GGGCGTCGCG GTCGTCGGTG TCGCCGAGGA
2161  AGCCCTCCTT CAGTACGGCG CCGAACTCCC GCCAGAACGC GGCGTACTTG TCGGCGTCGT
2221  TCGCCTTCAT CTCCTTGACC GAGGACAGGA CCTTCTTGGT CAGCCGGCGC TGGATCATCC
2281  GGATGTGCCG GTCCTGCTGG AGGATGTCCC GGGAGACGTT GAGCGAGAGG TCCTGCGCGT
2341  CGACGACACC CTTGACGAAG CGGAGGTGGG GCGGCAGCAG CGCCTCGCAG TCGTCCATGA
2401  TCAGTACGCG CTTGACGTAC AGCTGCAGAC CGCGGCGGAA GTCCCGGGTG AACAGGTCGT
2461  GGGGCGCGTG AGCGGGAAGG AACAGCAGCG CCTGGTACTC GAAGGTGCCC TCGGCCTGGA
2521  GGCGGATCGT CTCGAGGGGG TGGGGCCAGT CGTGGCTGAC GTGCTTGTAC AGCTCGTGGT
2581  ACTCGTCGTC GGAGACCTCG TCGGGCGAGC GTGCCCACAG CGCGTTCATC GAGTTCAGCG
2641  TCTCGGGTTC GGGCGTTTCC TCGCCGTCGG TCGCCTGCGG GAGGAGCCGG ACCGGCCAGG
2701  TGATGAAGTC GGAGTACCGC TTGACGATCT CCTTGATGTT CCAGGCGGAG GTGTAGTGGT
2761  GCAGTTGGTC GTCGGGGTCG GCCGGCTTGA GGTGGAGCGT GACGGCACTG CCCTGCGGCA
2821  GGTCGTCGAC CGTCTCCAGG GTGTAGGTGG CGTCACCGCG CGACGACCAC CGCGTGCCGC
2881  TGCGCTCCCC GGCACGCCGG GTCACCAGGG TCATCTCGTC GGCCACCATG AAGCCGGAGT
2941  AGAAAGCGAC GGCGAACTGT CCGATGAGGC CGTCGGCCCC GGCCGCGTCC TGCGCCTCCT
3001  TCAGCTCCTG GAGGAAGGCG GCCGTGCCCG AATTGGCGAT GGTGGCGATG AGCTTGGCGA
3061  CCTCGTCGTA CGACATCCCG ATGCCGTTGT CCCGCACGGT GAGCGTACGG GCCTTCTGGT
3121  GGAGCTCGAT CTCGATGTGC GGGTCGGACG TGTCGGCGTC GAGCCCGTCG TCCCGCAACG
3181  CGGCGAGACG CAGCTTGTCG AGCGCGTCGG AGGCGTTGGA GACGAGCTCG CGCAGGAAGA
3241  CGTCCTTGTT CGAGTAGACC GAGTGGATCA TCAGCTGGAG CAGCTGGCGT GGTTCTACCT
3301  GGAACTCGAA CGTTTCGGTC GCCATGCTTC GTATTCCTCA CAGGTTCCTG GGTGGCCGAA
3361  TCGGGCGAGA GCCACTGTAA GACACCAAGT CGGCGCATTG TCACCGCCGT TCGCCGCGCG
3421  GCGTCCGCAT CTGCGTCTGC GTCTGCGTCA GACCTCGCCG TGGGCGCGCC TGCCCCGGCC
3481  GTCCCGCCAG GACGTGGGGC AGGTGCCCCG CGCGGTCGCG GCCCCGGCGT CGGCGAACAC
3541  GGGCGCTCCA GCCGCCTTCG GAAGGCATCC CGGATGCGGA GCGGAGACCT TCGAACACGC
3601  CGGTCCTGAC CCGGTCGCAC GCCCCTGCTC CGGCTCGCTC CCGGGGATCC GGCACAATCG
3661  GACCGCGGAC CGACGGCCGC ATGCGCCTTC CTGGTGTGGT GCCGGACGGA GCCGTGGGAT
3721  CTGCGCTCCT ACGGCCACGT CGTCAAGCTG GAGCAGGAAC GTCTCGCCTA CCGGGCCCGC
3781  CGCACTCCCG CTTCGGCCGC TCCTGTCGCC GCAAGGCCCC GGCGACGCCC ACCGCCCCAT
3841  CACACGTACG GAGGGGCGAC CAGCAAGGTG TTGCGGATCG CCTCGACGAT CTCAGGCTGG
3901  TGCTGCACCA GGTAGAAGTG GCCGCCCGGC AGCAGTGTCA GGTCGAACGA ACCGGCGGTG
3961  TGGTCGGCCC ACAGGTTCAT CTGGCCCTCG TCGACCTTCG GGTCCTGCGC GCCGAGGAAG
4021  CCGCGGATGG GACAGGCCAC AGGCGGGCCG GGCACGTAGC GGTAGGTCTC GATGAGGGGG
4081  TACTCGTTGC GCAGCGGGGG CATGATCATC TCGATGATCT CGGGATCGTC GAACATCCGG
4141  GTGTCCGTGC CCTCCAGGCC GCGCAGTTCG GCCAGCACGT CTTCCTGCGA CATGGCGTGC
4201  ACCCGCTCGG CGCGGTTGAC CGACGGGGCG CCGCGGCCAG ACGCGAAGAG CGCCGTCACC
4261  GGCGTCGTGG AGTCCTCGAG GAGGCGGATG ACCTCGAAGG CCACCGCCGC CCGCATGCTG
4321  TGCCCGAAGA ACGCCGTCGG TACGGGCGGT TCTCCGCACA GCGCCTCGGC GACGTGGGCG
4381  GGGAGGTCTT GCAGCGTGGC GGGGAACGGG TCGGCCCTGC GGTCCTGCGG CCCCGGGTAC
4441  TGGACGGCGA CGATGTCGAT CTCCGGGGCC AGGGCACGCG CGAGCGGCAT GTAGAAGCTG
4501  GCGGAACCGC CCGCGTGCGG CAGGCAGACG AGCCGGTGGC GGGCGTCCGG GGCGTTCGTG
4561  TAACGGCGCA GCCACGCCTG CCGGTCCGTG GACGGTTTCG GGGTCGGGGC GTACATCAAG
4621  GTTTCTCCAG AGTGCGGAAG GCGAAGCGCC GAGGCGGAGG TCGCCCGCGG CGGTGGGTGC
4681  GTCAGTGGGC GACCGCGGCC CCCGGTTCGG TGACCGCGGT GTGCTGCTCC ATGACCCGGC
4741  TCGGACGCGC CGGCCCTGTC ACCGGCGCCC GAGCCTGTGT GTCCAGTCCC AGCAGGCCGG
4801  CCACCTCGTC GGCGACGGAC GTCGCGTCGC GGCCGACGCA GTCGACCCGG TGCACGGTGA
4861  CGCGGCCGGA GAGCGCGTCG AGCACGTCGT CGTAGGCGTG GGCGAGCCCG GTGAGCAGCC
4921  GGGCGTCCTC GTGCAGTTCG GTGCCGTTCC GGCGGCTGCG GGTGCGCCGC AGTGCCTCGT
4981  CGACCGGCAG TCGGAGCCGT ACCACGGCGT CCGGCGGGGC GGTCGAGAAC ATGTCGGCCA
5041  GGCGCTGCGC CAGTTCCTCG CGGGGCGCGG CGGCGAGCCG CAGCAGGTCC AGGCCGAGCG
5101  CCCACGGATC CGTACCGCCC GAGCAGGCCT CCAGCCAATC CCGCACCTCG CGCGCGGTCT
5161  CCGGACCCTG CTCCGCCCAC CAGCGCCGGA CGGCGTCGCC GGGATCGGGA TCGCCCGCGA
5221  TCCGCGCGAA CATCGGCAGA TAGACGAGGG GGTCGACCAG CGGGTGCCTG TCCGCCAGGA
5281  CGATCGCGCC ACGCTGCGTG GCGCGGCGCT CGGCCGGGGC GTACTGGGAC AGTTGCAGAT
5341  AGAGCACCGC GACCTTCAGC GGCGAACTGC CGATCAGGTC CGCGGCGGCG GACGCCCGCG
5401  CCAGGTGCAG GGAGCGCGTC GCCTCGGGGC TGTCCGGGTC CTCGTGCGCG CGGATCGCGT
5461  GGACGACGGA AACGCCGGGC ACGGTGCTCA GCAGCCGCGC CACCGTCGTC TTGCCGGTGG
5521  CGTCGATGCC CACCAGGGCG GCCCGCATCT CACTCACCGT CCCGGGCGGC TTCCAGGTTC
5581  CACAGGTGGA ACGTGGTGTC CAGCACGGCC GGGAGGAACG GCAGTTCCCG GTGGCTGTGC
5641  GCGGCGGTGT ACAGCTGGAG GCGGCTCAGG AGCATCTCAC GCAGCGCGAG CCCGTAGCGG
5701  CGCCGCCACT GTTCCGGCTG CGGCACGGTC GCGTCCGGTC CGGCCGCGGC GGCGACCGCG
5761  GCGCGGTGCA CCTCCAGATG GTGGTCGACC TCGTCGGTGG TGCTGTGCGG GGTGAGGGTG
5821  AAGGCCAGCA GTTCGGCCAG GTCGCGCTGG GGCACTGCGA CGGTGGCCAG CTCCCAGTCG
5881  TAGGCGGTGA CGCGTTCGCT CTGTCGGCTG ATGTTGCGGG GGTTGAAGTC GTTGTGGACG
5941  AGTGTGCGGG GCATCGCGTC CATCTCCTGC ACCCAGAACT GCGCCTCGGC CGCCGCCGCG
6001  AGCGCCGTCC TGGTGCGCTG CGGCGTCATC AGTTCGGGCA GTTCCGCGGC GTTGTGGCGG
6061  ACCAGCGCGT CCCACAGTTC GCGTGCGTTG ACGAGGTGGG CGGTCGTGCC GTCGCGGTAG
6121  AGCCAGCGCT CGGCCAGGAT GTGCTGGTCG CGTCCGAGCC AGTGCCCGTG CACGGGGGCG
6181  ATGGCGCGCA GCGCGCGGTC CAGGTCGGTG CGGCTCCACG GCCCGGTCGT GATGTCGAGG
6241  CGTTCCATGA GGATCACGTA CGCTTGGCGC GCCTCGTCCT GGATGATGCC GTAGCAGACC
6301  GGGAGCAGGC TGGTCAGTAC GCCTTCGGGC CGCCGGAAGA CGGCCAGTTC GCGCCGGTGG
6361  GCGGCAGGGA AGTGGCTGCC GCCGCCCCAG GTCTCGCAGG CCGAGGACAC CTCGGGGCCG
6421  CACAGCGAGG CGATCCGGCC GATGCCGGCG GCGATGTCCT CGCCCCGCGG TTTGGCCTTC
6481  GCCACCAGTT CGGCGGTGGT CTGCGGGCGG TCGTCCTCGG TCCAGCTCAC GGTGATGGGG
6541  ATGACGCCGG TCAGCTTGCG CCGTTCGCCG AGGGCGCGGA GTTCGGTGGA GATGCCGTCG
6601  CCGACCATCG CCGGCGGCCG TACGACGTCG GTGACGCGCA GCCGGGGGCT GTGGAGCCGC
6661  TCGGCCATGG CCGGCTGGAG GAGGCCGGGG CGGAGGTCGT CGGCGCGCAG CCAGTCCACC
6721  CGCCGGGCCC GGCCCAGCCG CCGGTGCGCA TCGGCGAACT GGCCGCTGAC CAGGGCCGAC
6781  GCGGTCGACA CGTCGAGCGC CAGGGCGAAG CCGGCGATGA TCTCGGCCAG CGGGGCCGTG
6841  CCGCCTTCGC CGCGGCATCC GAGGACACCG AGCCAGTCGC GCTGGTCGGG CAGGCCGGTG
6901  CCGCCGCCGA CGGTGCCGAT CACGAGGTTC GGCAGCAGGA GCGTCGCGAT CAGGTCGTCG
6961  CCGTCGGAGT CGAAGGAGAG CACGGACACA GCGGACTCGT GCACGCAGGC GATGTCGTGT
7021  CCGGTGGCCA CGAACAGCGC GGGGATCACG TTGGCGGCGT TGATGCCGTA CCCGGTGATG
7081  CCGGCCTGCT GGGCTCCGAT GACGGGGACC CGGTGTCCGC GGGCGATCGC CGCCGGGGTG
7141  GTCTTCAGGA CCGAGGCGAC CACGTCGCCG GGGATGACGC ACTCGGCGGT GACCCGGGTG
7201  CCGCGGCGGG CGAGCAGCGA GACCGAGCTG ACCTTCTTGT CACTGCTCAG GTTGCCTTCG
7261  AGCAGCGTGT TCCGCGGTCG CAGCCCGGGC TCGTCGGCGA GCACCTGGTT CAGCCAGGTG
7321  CAGATCTGCC AGGTGGCCGC GGTGGTCATG TTCTGTCCGG GCGCGTCCGC GGTCTCGAAG
7381  ACGAACGGCA CGTGCAGGTA GCGGCCGATC TGGTACGGGT CGACCGCGAC GAGCCGGGCG
7441  TGCTGCGAGA CCAGCCGGAC CTGGTCCTCC AGCTGCGGGC GGCGGGTGCC GAGCCACCGG
7501  CTGAAGCGGG CGGCGCCGGC CAGGTCGTCG AACTCGAAGG CGGGCGCGCG GCTCATCCGC
7561  TGGGAGAGCA CCCGGGTGGA CACTCCGCCG GCCAGGCTCA GGGCGCGTGC GCCGCGGGAG
7621  GCGGAGGCTA CGAGCGCGCC CTCGGTGGTG GCCATCGGGG CGACGACGGC TTCCCGGACG
7681  CCCTGGCCGC GGAACTGCAG CGGTCCGGCG AGCCCCACCG GGACCTCGAC CGATCCGGCG
7741  AAGTTCTCCA GGTTCCCGGT CAGCGACGCG GCCTCGATCG CCGTGTGTGC GGCGGAATCG
7801  AGGGTCGCGC CGGTCCGGGC GAGCAGCCAT GCCAGCCGCG CTGCGCGGGC CTGTTCGGTG
7861  TACCGGCCAC GGCCCGGTAT CGCGTCGTCG GTCACGCGTG TGCCCTTTCG TCGGCGGTGA
7921  TCCGCGCCCA GCTGTCGGGC GCGGGCTGGA AGATCCTGTC CTTGACGCGG GTGCGGCGCT
7981  GGCCGGAGCG GATCGCGTGC TCCCACTCGC GCTGGAAGGC GTCCTGGTGC ACCTGGAGCA
8041  CCTCGACGGG GGCCAGGGCT CCGGCGTCGC GCGCCGCGCG GTATCCGTCG GCGGTCTCGC
8101  CCAGGTGCTT GTCCAGCAGC GTCGCGAAAC CGGCGGGCAG CGGTCCCGGC AGTGCGGAGG
8161  CGATCGCCGC GCGGAACCGG TCCGTTCCGG TCTCGACCGT CGCGTTGCGC AGCTCCGCCG
8221  CGGTGTCGGC CAGGGTGCCG GCCAGGGCGC GGACCACCGC GCGTTCCGTC AGGTCCACGC
8281  CGGCGGCCGT GCGCAGCACG TCACGTCCGG TGTAGGCGAT GCGCGGCGTA CGCCCGACGT
8341  GGTCGACGAC GTGCACGACG TCGTTGACGG GGCACCGGTA CAGACCGCCG ATGTGGCTGA
8401  GTACGAGGTG GTAGTCGCGG CCGGGTTCGA GTTCGGCGGC GGTCACGGTC GGGCTGTCCT
8461  CGCGGATCGG GTCGGCGGCG TCGGCGAACT CGAAGTAGCA GCCGGGCAGA TAGAGCGGGG
8521  CGGGGTTGGG ATGGTCGTCG ACGGGGACGG CGACCGGGCC CTCCGAGGAT CCGATCGGCG
8581  CGGCGAACAG GCGTACGCCG GGACCGTAGC GTTCGCGCAC GCGTGGCAGG TAGAGCGAGG
8641  CGAGGGCGCT GTTCCACGCG ACGGCGGCCC GGAGGTTGGG GCACAGGTGG TACGGATCCA
8701  GGACGCCGTA CTCGTCGGCG CGGCGCGCGA TCTGCTCGGC GCGCCGCGGA TCGGGCGTGG
8761  TGTGCGGCAC TCCGCCGACC GTGCCGCGGG CGATCTCCTC GACGATCCGG GGCCACTGGG
8821  CGGCCAGTTG GTGGGGCAGC CGGGCGATCA GGGCCGGGTT GACGCCGATC AGGACCTTGA
8881  TGTGGCGTTC GGCGGCGAGC CGCAGTTGAA GGTATGCCCG CTCCCACGGG TCGGCGTCGG
8941  AGAGCTGCTC GGGGATCGTG GCCCAGGCGG CGCCGTCCTC CGGCCGGGCG CCCTCGCCGA
9001  AGAGGCGGTG GTCGATCTGG CTGGGGCCCA GATGCGGCCG GCCGTCGGCG GTGCGCGCGT
9061  GCGGCGAGGT CGGATCGCGC CACAGGTTCA GCACGCCGCC GGGGTCCGCG GCGAGGTCGG
9121  GGAACGCGCC GAGCAGGACG GCGAAACTGG CGTGGTAGAA GGGCAGGAAG CAGCGTTTCA
9181  TGTAGGTGGG CGTGACCGGG ATGCGCTTCT CCTGGCGGGT GCTGGCGCTG GAGGAGAAAA
9241  ACGCGACCGG CCGCTCGGCG GTCAGGACCC CGTCCTCGCC GGCAATCGCC CGCTCGATCC
9301  AGGGACCGAA CGCGTTCTGC GTGCGGATCG GCAGGGCCTT GCGGAACTCC TCGGCGCCGC
9361  TTCGCTCGTT CAGGCCGTGC TCGCGCAGGT AGCTCGTCGC ACCGTTCGCC GCGAGGAGTT
9421  CCGCGAGGAC CGTCTGCTGG GTCTGGTCGG GGTGGTCGAG CGTGGCGAGG AACCTGTGGT
9481  GTTCGGTCAG AATGGGTTCG GTGTGCAAGC TTTCCCTCCA GCGCGGTCGG AGAAGAGGGC
9541  TCCGTACAGG CGGAGCCGCT CGGGGTCGGC GGTGTCGTGC GTGATCCGGC TGTCGACGGG
9601  GTGGGGACGG GCCGGGTCGA GCGCGGCGCG CAGCCGCGGT GGGTCGAGCG CCGGGCGGTG
9661  CGTCACGTGC ACGGTGTCGC CGGGACGGAC CAGACCGCGC AGGGCGGCCT CGGGGAAGAG
9721  GTGATGGGTG TGGACGAGGT AGTCCAGGAC GGTGACGTCC GCGGTCGCCA TCACGGCCTC
9781  GGCCCGGAAT CCGGTGTCGG GGCCGGGCAG CCGCACGGTG AAGGGCTCCG GCGCGGGGGC
9841  CGGTGCCGGA GCCGTGAAGG CGCGGAACAG CCGTGCCAGG TTCTTCAGTT GCGGCGTCGG
9901  CACCGGGCCG TACCAGCTCA GCGCGTTGTC GGGGGTCGCG TACCCGTCCG GGAACCGGGC
9961  CGCCACCGTG GCGGGCCGGC CCGCCAGGAA GATGGTGCGG GTGAACGTCC GCAGGCATGC
10021 GTCGGCCGGC TGCTCGGGGA GCGAGAGCGC GAAGTCGAGG AGGCCGCGGA CGAAGGACTG
10081 GGGGGTGAGG GrGTCCACCA GGACCGCCAC GGTGTGGAAG TGGTGTCCCG GTTGGTCGTC
10141 GAGGGGGGCC AGGCGGGCCG CCGCGGAGGC TTGCAGCAAC GTGTGGAGCG AACCATGCGG
10201 GTCTTCGACG TCCGGGAGGT CGATGTCCGG GAGCGCGGGG TCGCTCACGC GGGGTGGGGT
10261 CTGTCCGGTC ATACGAGCAC CTCGCGCAAC AGGGCGGGCA GCGGCGCCGG GCGCGGTCCG
10321 AGCAGCGAGC AGGCCAGGCG GTGCGGGTCG ACATAGCCGT GCGGGCTGAG CGGCAGTACC
10381 GGGTCCTCCC GTTCGTCCGA CGGCCCCAGG GCCAGGATCC GGGCCGCGCG CCCGACGCAG
10441 CGGCGCAGCA GGTCGATCCG GAAGGACTGG CTGCACTGCC GGTCGAGCAG ACCGACGAAG
10501 TAGAGGCGCA TGCCGAGCCG GTAGGCGTCG GCGTCCGCGG AGGCGGAGAT GGCCGACAGG
10561 TCCGAGAGCG TCGAGCCGGT CCACCCGCCG TACTTGCTGG AGACGACCTT GCCGCCGATC
10621 GGCACCCGGG TGAGCGGGAG CCGGGTGGTG TGGGCGCCGA ACTCGGCCAG GATCCGGTCA
10681 AGGAGCAGGT AGTCGACGCC GAGCCCTTCG TCGAAGAGCA GGAGGAAGAG CCTGCCGGGC
10741 GCGACGGCGG GCAGCAGCGA GCGCAGGATC GGGAGCAGGT AGTTCGCGTG GCCGTCCGTC
10801 GAGACGATCT GCCGGATCGG CACGCCCCAG CGGGCGCCGT CCAGGTAGAC GGGCCCGCCG
10861 TGCGGCCTGT GGTCGATGAG CAGCCCGCGG TCCGCGAGGG CCGCCAGGGC GCGCTGCTCC
10921 GAGCAGGTCA GCGGGCGGGT GTCGGTCAGG CCGGGGTCGC GCACGTGCAG CAGGTCGAGT
10981 TCGGTGCGCC ACAGCTCCAG CAGGCGGTGG GAGGCCGGAT GGATCCAGCC GTCCCGGTGG
11041 ATCCGGGCGA AGTAGGGGTC GAGTGCGCGG GGGTGGGTCG TCGGACGGCC GCGGTGGAAC
11101 TGGAGGTAGC GCCGGCCGAT CGCGGTCTCG TCCTCGCCGG AGCAGTCCGT GTCCGGTTCC
11161 GTGGGGTCCA GGTGGTTCCA GAACGCCGTG GTCTGGGTCG TGAGCGTGGA CATCCGGGGA
11221 TTCCAGACCA GGGTGGTGGG GCCGAGGGTG GCCGTCGCCT TGAACAGGGC GTCGGCCCAC
11281 AGCAGGCCTT TGACATGGGT GGGGGTCAGC GGGTTGGTGG GGGTGATCGT CACCGGGGCG
11341 ATCACGAACT CCCTCGCGGC GCGGCGGGCG CCGGGATGCG CGCGGTGTGC GCGGCTCGCG
11401 GGTGTGGGCG GGCCGGTCGT CGCGGTTCGT ACGGTGCTCG GGGTGCGCAC GGTGCTCGAG
11461 GTGCGCAGGG TGGTGCTCAT GGATGGCTCC TGTCGATGTC TGCCGCGACC GGGCGGACGA
11521 GGTCGTGCGC GGCGCGCGAC ATGCCGGTCG CGGCGCAGGA CGTGCCGGTT GCGGCGCGCG
11581 CCGCGTGGGC CGTGACGCGC GCCGCGTTCG AATCGACAGC GGTCACGACG TGGTCGGCCG
11641 GGACGGGTCG GACGCCGTCC CGTCGGAGGC CCCGTATTCG GCGTGGAGGA ACTGCATGAG
11701 GTCGGTCGCG CTCGCCGTCT CCAGGTCATC GGTGCCGGAG TTCCTGCCGG CTCCCCCGGC
11761 TCCGGTGGCC GTGCCGGAGA GCCGGTCCAG GAGCGCGGAG AGACGGGTGG CGAGCGCGGC
11821 CCGGGTGTCT GCCGGTGTGA ACGGCGAGAG CACCTTGGCG TCAAGGCGGT CGAAATCCTC
11881 GAGGACCGGA CCGTCGTCGG CGGGGGCTTC CTCGAGGTGC AGTTCCGTGA GCAGCCGCTC
11941 GGCGAGCGAC TCGGGCGTGG GGTGGTCGAA CGCCAGCGTG GCCGGCAGCC GGGCGCCGAC
12001 GAGTTCGCCG AGCCTGTTCC GCAGCTCCAC GGACATCATC GAGTCGAAGC CGAGTTCCCG
12061 CAGCGCCCGG TCCGCCTGCA CCTGTTGCGG GTCGCCCCGC CCGATGAGCT GCGCCACGTG
12121 GGTGCGCACG ACGTGGAGCA GTACGGGCAG CCGCTCGTCG TCGGGCAGCG CGCCCACCCG
12181 GTCCTTCAGC GCGCCCGCGG TGGTGCCCGC GCCGGGGAGG GCGGGGGACG CTGCGTCCCG
12241 GCCGCCGCCC GCCGTGTCCG CGGGCGCGAA TCCGCTGAGC AGCGGGCTGG GGCGAAGGAC
12301 GGTGAACGCG GGGAGGAAGC GCGACCAGGC CACGTCCACC ACGACCGGGT CGGTGTCGCC
12361 CGGCACGGCG CGCTCGAGCG CTTCGACGGG GCTGGGCACG GCGAGCGGGA GCAGCCCGGG
12421 CTTGCGCAGT TCCCGGTCCT CGTACTCGGT GACCATGCCG CCGCCCGACC AGGGCCCCCA
12481 GGCGATGGAG ACGGCGGACG CGCCCCGCTC GCGGCGTCGG CGGGCGAGCG CGTCGAGGCA
12541 GGCGTTGCCC GCGGCGTAGG CGGCCTGGTC CGCGGCGCCC CAGATCCCGG CGATGGAGGA
12601 GAACATGACG AACTCGTCGG CGTCGGGCAG CAGTTCGTCG AGCAACAGCG CGCCGTTCAC
12661 CTTCGCCGCC ATGTCGGTCT CGAAAGCCTC GGGGTCGACG TCCGCGATGC GCGCGTACCG
12721 GATCACGCCG GCGGCGTGGA CGAGGGTACG CACCGGGTCG TCCTCGGCAT CAAGACGGGA
12781 GAGCAGTTGC GTGACGGCGG TGCGGTCGGT GATGTCGATC GCCGCGGCTT CGGCCCGGAC
12841 GCCCGATTCG CCGAGTTCTG CCAGGAGTTC GGCGGCACGG GGTGACTCGG CGCCGCGGCG
12901 GGAGAGCAGG ACCAGGCGGT CGGCCGTGCC GAGAGCGGCG AGGGGGCGGG GGACGTGCGC
12961 GCCCAGGCCG CCGGTTCCGC CGGTGATCAG GACGGTGCGC TTGGGCTGCC AGGTTCCCGC
13021 GTCGGCCGCG GGTGCGGTGC CGAGCCGGCG GGCCCACAGG CGCCCGTGGC GCACCGGGAG
13081 CTGGTCCTCG GGGCCATGGC CGGTGAGCAC GCCGGCGAGC AGACGTGCGG TGGTCCGCCC
13141 GGCGTTGTCG TCAGCCGTCC CGAGGTCGGC CGTCTCCGGA ACGTCGACGA GTCCGGCCCA
13201 GCGCGAAGGG AGTTCGAGGG CGGCGACCCG GCCGAGCCCC CAGGCGCCCG CCGCGGCCAC
13261 GTGCGTCGCG GGGTCGTGGA CACCGACGCC GACCGCGCCG CTGGTCACGC ACCAGACCGG
13321 CGCGTCGAGC CGCTCGGTCT CCCGCAGCGC GGGGAGCAGT TCGGAGGCGT CGGCGGGGCA
13381 GACGAGCACG CCTTCGAGCG GTGTCGAGGC CGATGCATCC CATTCGGTGG ACGTGAGGAC
13441 GTGCTCGAAC AGCTCGGCGA GTCCGGGGCG TGCGGTGCCG AAGAGCAGCC AGGTGCCGGG
13501 CACGCGCTCG GCGATCCGCG CGTGGCTCAG CGGCTCCCAC CGCACGGCGA AGGTCGCGGC
13561 CTGTCCGACG GCCCCTTCGG CCGCCTGGAG CTGTGTGCGC TCCACGGCGC GCAGGATCAG
13621 CGATTGCATG GCGAGGACCG GGGTTCCGGC GGCGTCCGTG ATCCACACCG AGGTCGCGTC
13681 CGGCCGCGGG CGCAGCCGTA GGCGGACGCG CCGCACGTCC GTGGCGAAGA GGGTGACGCC
13741 GCCGAAGGAG AAGGGCAGGC GCACCTCGTC GTCGGTCTCG TAGAAGCTGC GGGTGATGGG
13801 CAGGGCGTGC AACGAGGCGT CCAGCAGAGC GGGGTGGGCG CCGAAGCCGT AGGGCTGGTC
13861 GTGGGGCAGG ACGACCTGCG CGAAGAGATC GTCGCCGCGC CGCCACAGCG CCTTGAGCGA
13921 CCGGAAGGCG GGGCCGTACT CGTAGCCGCG CTCGGCGAGG TCCGGGTAGA ACGTGTCACC
13981 GGGGATCTGT TCCGCGCCCG CGGGCGGCCA CACCGCGCCG GTCCAGTCGG GCGTGAAGCC
14041 GTCGGTGTCC ACGCGGGAGG CGGTCACGAC GCCGGTGGCG TGCAGCGTCC AGTCCTCGCC
14101 CGGCGTACGC GTGCGGATCA GCAGTTCGCG CTCGCGGCCC TGGTCGGGTG CGACCCAGAC
14161 CTGGAGGTCG CGGGCCCGGC CGCCCGGGAA CACCATCGGG GCGCGCAGGA CGAGTTCTTC
14221 GACGCGGCCC GCGCCGACCG CGCGCGCGGC CTCCAGCGCG AGTTCCACGA ATCCGGTGCC
14281 GGGCAGCAGC AGGGTGCCCA TGACGGCGTG GTGGGGCAGC CACGGGTCCG TGCCGGGCGC
14341 GAGGCGGCCG GAGAACAGGA CGCCGCCCCC GCCGGGGAGG TGCGTGCGCT GGGACAGCAT
14401 CGGGTGCGGC AGCGCGTCGG CCCCGGCGCC GGGGCCGGTA CCCGAGGACG GGGCCGTCAG
14461 CCAGTAGTTC TCGTGCTGGA AGGGGTAGGT GGGCAGGTCG AGGTCCGGGA CCGTGGCGCT
14521 GCCGCGCTCG TGTCCGCGGC CGTCGGCGGT ATCGGCGTTG TCGGCGTCCG CCTCGGCATG
14581 GTCGGCGAAC CAGGTGACCG GCGTCCCGGT CACGTGCAGG GTCGCAAGGG CCCTGAGGAA
14641 CGTGTCGGGC TCGGGCTGCC CGGCACGCAG CGTCGGCACG AGCGCCGCGG GAGCGGCGGA
14701 CGCGTCCTCG AGTGTCTCGG CGGCGAGCGG CGGGAGTGTG GGGTGCGCGG TGAGTTCGAG
14761 GTAGCGGGTG GTGCCGAGTC CGTGCAGGGT GGTGACGGCG TCGGGGTGGC GGACGGTGTG
14821 GCGCAGCTGT TCGGTCCAGT GGTCGGCGGT CGTGATCCGG TCCTGCTCGG CGAGCAGTCC
14881 GGTGAGCGTC GAGACGATGG GAATGCGCGG CGCGCGGTAC GTGAGCCCCG CCGCGATGCG
14941 GCGGAACTCG TCCAGGATCT GGTCCTGGTG CGGACTGTGG AAGGCGTGGC TGACGGTCAG
15001 CCGCCTGCTC CTGATCCCCC GCTCCGCCAG CTGTGCGGCG ATGTCCGCGA GGACCTCGGG
15061 ATCACCGGAC AGGACGGTCG ACTCCGGCGC GTTGACCGCC GCGAGCGAGA CGACGTCCTC
15121 ACGCCCCGCC ACGAGACCCC GCGCGGTGGC CTCGCCGGCC TGGAGGGCGA GGATGGTGCC
15181 GGGGGTGGTG ATCTGCTGCA TCAGACGGGC CCGGTGGAAG ACCAGGGTGG CCGCATCAGC
15241 CAAAGAGAGC ATCCCGGCGG CATGCGCCGC GGACAGCTCA CCGATCGAAT GCCCCACCAG
15301 ATGGTCCGGC CGCACACCGA ACGACTCCAG CAGCCGGAAC AACGCGGTGT GCAGAACGAA
15361 CAACGCCGGC TGCGTGAACG CGGTCCGGTT CAGCAGTTCC GCCCCCTCCG ACCCCGGCCC
15421 CGCGAACATG ACCTCACGCA GGGAGCGGCC CAGCAGGGGA TCGAAGACCG CACAGGCCTC
15481 ATCGACGGCA GCGGCGAACA CGGGATACGA CGCATACAAC TCCCGCCCCG CACCCGGGCG
15541 TTGACTGCCC TGACCGGAGA ACAGGAACGC AGTCCTGCCC GTGGTGACCT GCCCGCGGAC
15601 GAGGCTCGGG TGCCCGGAGC CCGACGCGAG CGCCGACAAC GCCTCGGTCA GTCCGGCACG
15661 GTCGGCGCCG ATGAGGGCGG CGCGCTGCTG GAACTGCGAC CGGGTCGTCG CGAGCGCGCG
15721 GGCGAGGTGA CCGGTGCCGG TCTGCGGGCG GGCGGCGAGG AACTCCGTCA GGCGGTCGGC
15781 CTGCGCGCGC AGCGGGTCGG GGCTTTTCGC GGAGACCAGC CATACGGCGG GGTCTGCGGA
15841 GTCGGCTTCG GCCTCGTACG CGGTCCGCTC CTTGAGCGGA GGCTCTTCGA GGATCAGGTG
15901 CGCGTTGGTA CCACTGATCC CGAACGACGA CACGGCGGCA CGACGCGGCC GCTCCCCCGC
15961 CTCCCAGACG ACCGGCCCGG TCAACAACCT GACCTCACCC GCCTCGGAGT CCACATGGGG
16021 CGAAGGCTCG TCGACATGCA AGGTCCTGGG AAGCACCCCG CCCCGCATCG CCATGACCAT
16081 CTTGATCACA CCACCCACAC CCGGCGCGGC CTGCGTGTGC CCGATGTTCG ACTTCAGCGA
16141 ACCGAGCCAC AACGGACGAC CCTCGAACCG GCCCTGTCCA TAGGTGGCCA GCAACGCCTG
16201 CGGGTCGATC GGGTCACCGA GCGTGGTGCC GGTGCCGTGC GCCTCGACGG GGTCGATGTC
16261 GGCGGCCTCG AGCCCGGCGT CGGCCAGGGC CTGACGGATC ACCCGCTGCT GCGAGGGGCC
16321 GTTCGGCGGG GTCAGACCAT TGCTCGCACC GTCCTGATTG ACCGCCGAGC CGCGAATGAC
16381 CGCGAGCACA CGGTGCCCGT TGGGCCGCGC GTCACCGAGA CGTTCGAGCA CCAGCATGCC
16441 CACACGCTCG CCCCACGGCG TACCGTCCGC CGGCGCCGCG AACGACTTGC ACCGTCGGTC
16501 CGGCGCCAGG CCCCGCTGCC GGCTGAACTC CACGAAGGTG CCGGGGTTCG CCATCACCGT
16561 CACGCGGCCG GCCAGCGCCA CGTCGCACTC GCCCGAGCGC AGCGCCTGCG TCGCCAGATG
16621 GATGGCGACC AGCGAGGAGG AGCACGCGGT GTCGAGCGTG ACCGCCGGGC CCTCCAGGCC
16681 CAGCGTGTAG GCGATCCGGC CGGACAGGAC GCTGGTCGTG GTGCCGGTCA GCAGGTGACC
16741 GCTGACTCCC TGCCCCGTCG CCTCGTACAG GCGCGGCGCG TACTCCTGCG GCATCACGCC
16801 GACGAACACG CCGGCCCGGC TCCCGGCGAG GCTCAGCGGA TCGATGCCGG CCCGCTGCAC
16861 CGCCTCCCAC GAGGTCTCCA GCACAAGGCG CTGCTGGGGG TCGATGGGCA AGGCCTCACG
16921 GCGGCTGATG CCGAAGAACG GCGCGTCGAA CTGTCCGGCG TCGTGCAGGA AGCGTCCCTC
16981 CCGGACGTAC ACCTTGCCCT CGGCGTGCGG GTCGGGGTCG TAGAGCCGCT CCAGGTCCCA
17041 GCCACGTCGC GAGGGGAATC CGCTCACCGC GTCGATTCCC CCGGCGGCCA GCTCCCACAA
17101 CTGCTCCGGG TCCGTCACGC CGCCCGGATA ACGGCATGCC ATGCCGAGGA TCGCGATCGG
17161 TTCCCGCTTG CGTGCCTCGA TGTCCCTGAT GCGCAGGCGC GTCTGGTGCA GGTCGGCGGT
17221 GACCCGCTTG AGGTAGTCGC GGAGCTTGTC GTCGTTCGCT GGCATGGAGG AACCTGCGCC
17281 TTGTGCGTGT TCTGCATCGC GCGGCCGGTC CGGTGGGACC GACCGCGCGG CGTGGCGGAG
17341 TCGGACTGGG GGGACCGTCA GGTCAGTCCG AGTTCGTTGT CGATGAAGTC GAAGATCTCG
17401 TCGTCGCTGG CCGACTCGAA TCGGTCGGTG GCCCCGGCGG CGTCCTCGGC GTCCGGCCGG
17461 CCCGCTTCCT GCCGGCCGTG CAGCCACACG AGCAGGTCCT CGAGGCGGGC GGTGAACGGG
17521 GTGAGTGTCG CCTCGTCCGC GTCGGTGGCG ATCGCCGTGT CCACCAGCCG GTCCAGTTCG
17581 GCGAGGACCG CCAGGCTGTC GGACGTGGCA GTCCGCGGGG TCTGCGAGGC CAGTCGCGTG
17641 TAGAGGAAGT CGGCCACGGC CAAGGGCGTC GGGTGGTCGA AGATCAGTGT GCCGGGGAGC
17701 CGCAGACCGC TGACGGCACC GAGCCGGTTG CGCAGCTCCA ACGCGGTGAG CGAGTCGAAG
17761 CTCAGCTCCT TGAATCTCCG CTCCGGGTCC ACCGTCGCCG CGGTCGCGTG TCCCAGGACC
17821 GCCGCGGCGC TGTCCTGAAG CAGCTCCAGC AGCATCCGTC GTCGCGCGGC CTCGGTCGGC
17881 AGTTCGGCCA CGCGCCGGGC CAGGTCCGGT CCCGCGTCCA CCGCGGTCTG GCGCGGTGCG
17941 GGGAGGCGGG CGCCGTCGGC TGTTGCGGCG GCCTGTGGCA GACGCCGTAC GGGCCGGGCC
18001 GGTGCGACGT GCCGGAACAG CAGCGGCACC TCGGCGACGT CCCCCGCTCT CCCGGCACCA
18061 CGGGCGCTTT CGGCCAGGGC CGCGAGGTCG AGCCGTACCG GCACCAGGGC CGGTACCGCC
18121 GCGTCGCGCG TGGCGTCGAA GAGGGCGAGG CCCTCGTCGG TGGACAGGGG CAGTACGCCG
18181 GTGCGTGCCA TCCGGTTCAG ATCGGTCGCG CTCAACGCCT GCGTCATACC GCCGGCGGCG
18241 TGCTCCCAGG GGCCCCACGC CGCGGCGACC GCGGGCAGCC CGCACCGGTG TCGGGGGTAT
18301 GCGGCCAGAC CGTCCAGGAA GGCGTTCGCG GCGGCGTAGT TGCCCTGTCC GGCGTGGCCG
18361 ATCACTCCGG CGACGGACGA GAACAGTACG AAAGCCGACA GGTCGGCGTG GGCGGTGAGT
18421 TCGTGCAGAT TCCACGCCGC GTCCGCCTTG GGCCGCAGCA CGGTGTCGAG CGGCTCGGGC
18481 GTCAGTGCTT CGACCGGGGC GTCGTCGAGC ACGCCCGCGG CGTGCACCAG GGCGGTCAGT
18541 GGATGCGCCT CCGGGACCGC AGCGACGACC CGCGCCAGCG CCGTGCGGTC CGGCGCGTCG
18601 CAGGCCTCGA CGGTCACCTC GACGGCGCCC GCCGCGCGCA GTTCCGCGAC GATCTCGGTC
18661 ACGCCCTCGG CGGCCGGGCC GCGCCGCCCG GTGAGCAGCA GTCGCCTGAC GCCGTGCCGG
18721 GTGACGAGGT GGCGGGCCAC GTTGCCGCCC AGCGCGCCCG TGCCGCCGGT GATCAGGACG
18781 GTCCCCTCCG GGTCCAGCGG CGCCGGGACG GTGAGGACGA CCTTGCCGAC GTGGCGGGGC
18841 CGGCTCAGGT GCCGGAACGC GTCCTGCGCG CGCCGCACGT CCCACGCGGC GACCGGGAGC
18901 GGACGCAGCG CGCCGCGCTC GAACAGCTCC GTCAGCTCGC CCAGCATGGC GCCGACGTGC
18961 GGGGGTTCCA GCTTCGTCAG ATCGAACGAG CGGTGGTCGA CGCCCGGGTG CCGGGCGGCG
19021 ACCGCCTCGG AGTCGGGGGT GTCGGTGCTG CCCGTGTCGA CGAACCGGCC GCCGGACGAC
19081 AGCAGCCGCA GCGAGGCGTC CACGGCGTCT CCGGCCGGGC AGTCGAGTAC CACGTCCACG
19141 GCGGCGCCGC CGGTCGCGGC CCGGAACCGG GCCGCGAACT CCTGGGTGTG CGACGGCGCG
19201 AGGTGCGTGT CGTCGAGCCC ATGTGCACCC AGGTCCGCCC ATTCGCCGGG GCCCGCTGTG
19261 CCGAACACGT CGGCGCCCCG GTGCCGGGCG AGCTGCGCCG CCGCCAGGCC GAGGCCGTCG
19321 GCCACCGAGT GGATCAGCAG CCGCTCGCCC GGTACGACGG CGGCCAGTTC GACGAGTGCG
19381 TGATAGGCCG TCAGGAACGC GACGGGCACC GACGCGGCCT GCGTGAACGT CCAGCCCGCC
19441 GGGATACGAG CGAGGGTGTG CGGCTCCGCC ACGGCCTGGG GGCGGAAGTT GCCGGTGAGC
19501 AGGCCGAACA CCCGGTCGCC GACGGCGAGA TCGGACACGC CGGGGGCGGT CTCGGTGACC
19561 ACACCCGCGC CTTCGAGCCC GAGGATGTCG TGGTCCGGCG GTGTGTGGCG GGCGAGGACC
19621 GGGGCGCGGA GATCGAGTCC GGCGGCGCGC ACCGCGATCC TCACCTGCCC GGTGGCGAGC
19681 GGGGCGCGCT GGGGCGCCCG GACCTGCTCG GCGACGTCGG GCGGTGCGGG CGACGGGACG
19741 TCGGCGTCCT GCGCGGCGCG AGGGAGTCGC GGTACGAGCA CCTCGCCGTC GCGCACCGCG
19801 AGTTGCGGTT CGCCGGTGCG CAGGGCGGCG GGCAGGGCGG CGTATCCGTC GGACGGGTCG
19861 CCGTCGATGT CGACGAGGGT GAAGCAGCCC GGGTTCTCGG TCTGGGCGGT GCGCACCAGG
19921 CCCCAGGCGG TGGCCTGCGG CAGGCCGAGT GCGTCCGGCG CCGTCGCCGG GGCCGTCGCA
19981 TCGTGCGTGA CGAGGAGCAG GCGGCCGACC GTGAGGGCGG GCGGGTCGAG CCAGGACGTG
20041 AGGAGGGCGA GCGTGCGGCG GGCGACGGCG TGCGCGCCGG CCGCACCTCC TTCGTGCTCT
20101 CGCGTCCGCT CTCCTTCGTG GGGCGGAAGT TCGGCTCCGT GCGCAGCGAG ATCGGCGAGC
20161 ACGACGGACG GGTGCGGGTC ACCGTTCTCG ATGCCGTGGA CCAGGGCGTC GAGGTTCGGG
20221 TACGTGCGGA TGTCGACCGC GTCGGCCGCC AGCGTGGAGA GCGGATCGGG CACGGGGCTC
20281 CGACCGATGA GCGCCGACTG CTCCGGCGCG TCCGGAGCCG CGGCGCCGAC CGGTGCCGCT
20341 GCCGGTGTGG CGGACGAGTC GACGTGGTAG AGCGACCGGG GTCCGGCCGG TTGCGTGCCG
20401 GAGCCGTCGC TCAACCGGTC CAACACCACG GGACGCAGGG ACAGTTCCCC TGCGGTCAGT
20461 ATGAGGGGGC CGGACGGATC GCTCGCGACG ACGCGGACGG TGGTCGGCCC GGTCCGGGTG
20521 AACCGGACCC GCAGCGCGGT GGCGCCCAGC GCGTGCAGGG CGACATCGCC CCAGGAGAAG
20581 GGCAGCAGCG TGCCCGAGGC ATCGGTTCCG GACACCCCGT CCGCGAGCAG TCCGCTGCGC
20641 AGCAGGGCGT GCAGCGAGGC GTCGAGCAGC GCCGGGTGCA CCGAGAACCG GTCCACGTCG
20701 TCCGAGGCGG CGGCATCGTC ACCCAGCTCG ACCTGTGCGA ACACGTCATC GTCCGTGCGC
20761 CACGCGGCGG TCAGCAACCG GAAGTCGGGG CCGTACTCGT AGCCGGTCAG GGCCAGAGCG
20821 GGGTAGAGGT CCGTCAGGTC GACCGGCGCC GCGTCGGCGG GCGGCCACTG CGGTGCACGG
20881 TCCGCGGCGT CGGGCGCCTC GGTGGGCCCC AGGGCTCCGC TCGCGTGCCG GGTGCAGGAG
20941 GACGAGCCGG AGGCGTCGTC GCCGGCGGGC GCCGGGCGCG AATGGACGGC GAAGGCGCGC
21001 AGGCCGGACT CGTCCGCCTC CTGGACGGTC ACCGGGATGT CGACGCCGCG CTCGCGGGGC
21061 AGCACGAGCG GTGCCTGAAG CGCGAGTTGC GCGACAGCCG GGTGCTCCCC CGCGCCGTCC
21121 GACGCGGCAT GCAGCACCAG ATCGAGCAGG GCGGTGCCGG GCAGCAGCGT CGTGCCGTGG
21181 ATCGCATGAT CGGCGAGCCA GGGGTGCGTG AGCGTGCCGA TACGCCCGGT GTGGACGAAG
21241 CCGCCGCCCT CGGGCAGTTC GACGGCCGCC GCGAGCAGCG GATGCGGCGT GCGCGTCAGC
21301 CCGGCCTGCG TGACATCGGC GCGCGGCGCG GGCGGCGTGA GCCAGTAACG CTCGCGCTGG
21361 AAGGCGTACG TGGGCAGTTC GGGCAGAGCA GCGGAGCGAG GGCCGGGGAG TGCCGGCCAG
21421 GGGACGTCGG CACCGCTCGT GTGCAGGGTC GCGAGGGCGC GCAGCAGGGC GTCGTGCTCC
21481 GGCCGTCCGT GGCGCAGCAC CGGGACCAGA GCCGCGGGGC TCTCCTCCAG GGTCTCGGCG
21541 ACCAGCGTGG CCAGCGTCGG AGTGGGAGTG AGTTCGAGGT AGCGGGTGGT GCCGAGCCCG
21601 TGCAGGGTGG TGACGGCATC GGCGTGGCGG ACGGTGCGGC GCAGCTGTTC GGTCCAGTAG
21661 TCGGCGGTCG TGATCCGGTC CTGCTCGGCG AGCAGTCGGG TGAGCGTCGA GACGATGGGA
21721 ATGCGCGGGG CCCGGTACGT GAGCCGCGCC GCGATCCGGC GGAACTCGTC CAGGATCTGG
21781 TCCTGGTGCG GACTGTGGAA GGCGTGACTG ACGGTCAGCC GCCTGGTCCT GATCCCCCGC
21841 TCCGCCAGCT GTGCGGCGAT GTCCGCGAGG ACCTCGGGAT CACCGGACAG GACGGTCGAC
21901 TCCGGCGCGT TGACCGCCGC GAGCGAGACC ACGTCCTCAC GCCCCGCCAC GAGACCCCGC
21961 GCGGTGGCCT CGCCGGCCTG GAGGGCGAGC ATGGTGCCGG GCGTGGTGAT CTGCTGCATC
22021 AGACGGGCCC GGTGGAAGAC CAGCGTGGCC GCATCCGCCA AAGAGAGCAT CCCGGCGGCA
22081 TGCGCCGCGG ACAGCTCACG GATCGAATGC CCCACCAGAT GGTCCGGCCG CACACCGAAC
22141 GACTCCAGGA GCCGGAACAA CGCGGTGTGC AGAACGAACA ACACCGGCTG CGTGAACGCG
22201 GTCCGGTTCA GCAGTTCCGC CCCCTCCGAC CCCGGCCCCG CGAACATGAC CTCACGCAGC
22261 GAGCGGCCCA GCAGCGGATC GAAGAGCGCA CACGCCTCAT CGACGGCAGC GGCGAACACG
22321 GGATACGACG CATACAACTC CCGCCCCGCA CCCGGGCGCT GACTGCCCTG ACCGGAGAAC
22381 AGGAACGCAG TCCTGCCCAC CGTGGCCCGA CCACGTACCA CCATGGGATG CCCGGCACCC
22441 GAGGCAAGCG CGGACAGCGC CTCGGCGAGT GCGTCCCGGT CCTGGGCGAC GACCGCCGCC
22501 CGGTGGTCGA AGTGCGTACG GCCGGTGGCC AGGGCCCGAG CGGCCCGGCG GATGCCGACC
22561 TCCGTCCGGG TCCTGGCGAA CTCGGCCAGC CGGCCGGCCT GTTCCCCGAG CGCGTCGGCT
22621 TTCTTCGCGG AGACCAGCCA TACGGCGGGG TCTGCGGAGT CGGCTTCGGC CTCGTACGCG
22681 GTCCGCTCCT TGACCGGAGG CTCTTCGAGG ATCAGGTGCG CGTTGGTACC ACTGATCCCG
22741 AACGACGACA CGGCGGCACG ACGCGGCCGC TCCCCCGCCT CCCAGACGAC CGGCCCGGTC
22801 AACAGCCTGA CCTCACCCGC CTCCCAGTCC ACATGCGGCG AAGGCTCGTC CACATGCAAG
22861 GTCCTGGGAA GCAGCCCGCC CCGCATCGCC ATGACCATCT TGATCACACC ACCCACACCC
22921 GCCGGGGCCT GCGTGTGCCC GATGTTGGAC TTCAGCGAAC CGAGCCACAA CGGACGACCC
22981 TCCGACCGAC CGTGTCCATA GGTGGCCAGC AACGCCCGTG CCTCGATCGG GTCAGCGAGC
23041 GCCGTTCCCG TCGCATGAGC CTGGACGGCG TGGACATCGG GGGCCTCCAG CCCCGCGTCG
23101 GCCAGGGCCT GAGGGATCAC CCGCTGCTGG GACGGGCCGT TCGGCGCGGT CAGACCATTG
23161 CTCGCACCGT CCTGATTGAC CGCCGAGCCG CGAATGACCG CGAGGACACG GTGCCCGTTG
23221 CGCCGCGCGT CACCGAGACG TTCGAGCACC AGCATGGCCA CACGCTCGGC CCATGAGGTG
23281 CCGTGGGCGG CGGCGGAGAA CGACTTGCAC CGTCCGTCGC CCGCGAGGCG GCGCTGCCTC
23341 GCGAATTCGA GGAACATGCC GGGGCTCGCC ATGACGGCGG CGCCGCCTGC GAGCGCCAGT
23401 TCGCATTCGC CGTTACGCAG CGACGGGGGG GCGAGGTGCG CGGCGACGAG CGACGACGAG
23461 CAGGGGGTGT CCACCGTCAT CGCGGGGCCG TCGAACCCGA AGGTGTAGGC GATGCGTCCG
23521 GAGGCCACGG TGACGGTGCT GCCGGTCAGC AGATAGCCGC CGACGCTTCC CGCCGTCTCG
23581 GGGAGCGTCT CGTGCAGCCG GGGGCCGTAT TCCATGGCCG TCGGGCCGAC GAACACGCCG
23641 GTGCGGCTTC CGGCCAGGCC GGTCGGGTCG ATGCCGGCCC GCTCCACGGC CTCCCAGGAG
23701 GTCTCCAGCA GGAGACGCTG CTGCGGGTCG ACGGCCAGGG GCTCGCGGGG CGAGATGCCG
23761 AAGAACTGCG CGTCGAACCG GTCGGCGTCG TAGAGGAAAC CGCCCTCGCG CGCGTAGGTC
23821 CGGCCCGGTG CGTCGGGGTC CGGGTCGTAG AGGCCCTCCA GGTCCCAGCC ACGGTTCTCG
23881 GGGAACACGT GGATCGCGTC GGCGGCCTCG GCGACAAGCT GCCACAGGGC TTCGGGGGAA
23941 TCGGCGGCGC CGGGGTAACG GCAGGCCATG CCGACGATCG CGATCGGCTC GTCGGAGACC
24001 GAGGGCGGCG ACGTGGCGTC GCTCTGCGTG GTACGGGCCA GCTCCGCTCC CAGCACTCGT
24061 GCCAGGGCTC GTGGCGTCGG AGTGTCGTAC AACAGGGTTG CCGGCAGGCT CAGTTGGAGC
24121 ACAGCGGCCA GCCGGTCGCA CAGGTCCTCC GCGGACTGCG ACTCCAGGCC GAGATCGTTG
24181 AAGGAGCGGG CCAGGTCCAC TTCGCGCGGA TCGGAGTGAC CGAGCAGCGC CGCCGCCTCG
24241 TCACGGATGA GGTCCAGCAA CTGCTCGTCA CGCCCGGCAG GAGCGGCCTC GACCAGCCCT
24301 CGCAGCCAGT CGGAGTCCCG CACGGACGCG GGTGCGGAGA CAGCGGACGT CTTCTCCGGG
24361 CGGGCCGTGA CGGCCGATGC GGCCGACGCG GTGGCACGCC GCGCGGCACC CTTCAACTCC
24421 AGACCCAACA CCTGCGCGAG GACCTTCGGC GTCGGGCTCT CGTACAACAG CGTTGCGGGC
24481 AGACGCAGTT GCAGCACGGA ACCCAACCGC TCGACCAACT CCACACCCGA CGCCGACTCC
24541 AGGCCGAGGT CCTTGAACGA GCGGGCGAGA TGCACTTCGC GCGGATCGGA GTGACCGAGC
24601 ACCGCCGCCG CCTCGTCACG GATGAGGTCC AGCAACTGCT CGTCACGCCC GGCAGGAGCG
24661 GGCTCGACCA GCCCTCGCAG CCAGTCGGAG TCCCGCACGG ACGCAGACGC GGACACAGGG
24721 GGCCCGGAGG CGGGCACAGC GGCGCCAGCG GGAGCAGCAG GGTTCGGCGT CGGAACGGCG
24781 GCAGCGCCCT GGCGTGCCAC GGGCGCGGAC GTCGGCGTGG GCTCGGGCCA ATACCGGCGC
24841 CGGTCGAAGG CGTAGCCGGG CAGTTCGACG CGGCGCGCCG CCGGAAGGCC GTAGAGCGCC
24901 GGCCAGTCGA CGGCAGCGCC CCGCACGTGC GCGGCGGCGA GCGAGGACAG CAGCCGCGGC
24961 CGGCCGCCGT CGCCGCGGCC CAGGGCGGGA ATGCCGACCG CGCCCGCGGC GTCGAGGAGT
25021 TCCAGGATCT CGGGCGGCAG CACGGCGTGC GGGCCGACCT CGATGAAGAC GGTGTGCCCG
25081 TCGTCCATCA GTTCCTCGAC GGGCGGATGG AAGGGCGCCG GCTGCCGGAA GTTGCGGTAG
25141 CAGTGGTCCG CGTCCAGGGC GGGGGTGTCC ACCGGACCGC CGAGGGTCGT CGACTGGAAG
25201 CGCGTCCGGC TCGGCGTGGG CTCGATGCCG CTCAGCTCGT CGAGGAGCGC GTCGCGCACC
25261 GCCTCGGCCT GCTCGCCGTG CGCACGGCCG CGTGCGACGA CGAGAGCCGC GGCGTCCTGG
25321 AGGGTGAGCG CGCCGATGCT GTACGCGGCG GCGATTTCGC CCGCGGCGTG GCCGAGCACG
25381 GCATGGGGCT GGACGCCGAG CGTGCGCCAG GTGTGCGCGA GGGCGGTCGT GACGGCGAAC
25441 AGCACGGGCT GGACGTGGTC GGGGGTGTCC GGCAGGGTCT CCGGACCGGT GAGGTGGTCG
25501 AGGAGGGACC AGCCGGTGAG CGGGTCGAGG GCGGCGGCGG CGGCCTCCAC GTGCTCGCGG
25561 AAGACGGGCA GGGTCGCCAT CAGGTCGCGG ACCGTGCCGG CCCACTGCAC GCCCTGGCCG
25621 GGAAACACGA ACACGGTCTT GGGCCCGGTG CCGGGCGTGG TGCCGGTCCC GGGGTCGGGC
25681 GGGGTGCCGC GCAGCAGGCC GTCCGAGGGG CGGCCCTGCG CGAGGGTGCG CAGCTGGGAG
25741 AGCAGGGCGG ACCGGTCGCC GCCGAACGCG GCGGCGGGGT GCTCGTGATG CGTGCGAATG
25801 GTGGCCAGGC CGCGCGCCAC GGTGGCGGCG TCCAGCTCGG GGTGCTGCTC CAGGTGCGCG
25861 GCGAGGGCCG CGGGCTGACC GCGCAGCGCC GCCTCGCTGC GCGCGGAGAT CAGCCACGGC
25921 GACGCGACGT GCTGCGGGAC GGCAACGGGA ACAGGAAGGG TCGCGGGCGG GGCCGCCGAT
25981 GACGTCGCGG GTGACGGCGC CGACGACTCG GCCGGGGCGT CGCAGAGCAC GACGTGGCAG
26041 TTGGTGCCGC CCATGCCGAA CGAGCTGACG CGTGCGACGA TCCGACCGTC CGGGCGCGGC
26101 CACGGTGTCA GCCCGACCTG GACGCGCAGG CTGAGCTCGT CGAAGGCGAT CTTCGGGTTC
26161 GGCGTGACGA AGTTCAGGCT CGGCGGCAGC TTCCGGTGCC GGATGGCCAG AGCCGTCTTG
26221 ACCAGGCCCA CCACGCCCGA AGCACCCTCG AGATGCCCGA TGTTGGTGTT CGCGGAGCCC
26281 ACCAGCAGCG CGTTGTCGGC CACCCGGCCC ACGCGCGCGC CGAAGGCGGT GCCGAGCGCC
26341 GCCGCCTCTA TCGGGTCGCC CACGGCGGTG CCCGTGCCGT GCAGTTCCAC GTACTGCACG
26401 TCGCGGGGGG CCACGTCCGC CTGCCGGCAG GCGGCGCGCA GCAGCTCCGT CTGCGCGGGC
26461 GCGCTGGGCA CCGTCAGTCC GTCGGTGGCG CGGTCGTTGT TGACGGCGCT GCCCCGGATG
26521 ACGCAGTACA CGAAGTCGCC GTCGGCACGG GCCTGTTCCA GCGGCTTGAG TACGACCAGT
26581 GCGCGGCCCT CGCCGCGAAC GTACCCGTTG GCCCGCGCGT CGAAGGTGTG GCAGCGGGCG
26641 TCGGGCGAGA GGGCGCCGAA GCTCATCGAC GCGGCCATGC CGTCCGGCGC GGCGATCAGG
26701 TTCACGCCGC CCGCCAGCGC CACCCGCGAG TCGCCGCGGC GCAGGCTCTC GCAGGCGAGG
26761 TGCACGGCGA CCAGCGACGA GGCCTGCGCG GCGTCCAGGG TCATGCTGGG GCCGCGCAGG
26821 CCCAGCGTGT ACGACACACG GTTCGGGATG AGCCCACGGC CCATGCCGGT CATCGTGTGC
26881 TGGTTGAAGG AGGCGGTTCC GGCCCGGGCG ACGACGCTGC GGTAGTCGTC CCAGATCGCT
26941 CCGACGAACA CTCCGGTGCC GCTGCCGCCG AGCGAGGCGG GGACGATCGC GGCGTCCTCC
27001 AGCGGCTGCC AGCTCAGTTC CAGCATCAGC CGCTGCTGGG GGTCCATCGC CCGTGCCTCG
27061 TGCGGCGAGA TACCGAAGAA CCCGGGGTCG AAGGTGTCGA TCCGGTCCAG GTAGGCGCGG
27121 TACCGGGCCG CACCGGTGGG CGTGGCGGCC GGGTCGGGCC AGCGGTCGGC GGGCGTCTCG
27181 CCCACCGCGT CCACGCCCTC GCTCAGCAGC CGCCAGAAAG TCGCAGGGTC CGGAGCCGGC
27241 GGCAGCCGAC AGGCCATACC GACGACGGCG ATGGGCATGA ACCCTTCAGA GATGAAGCGC
27301 ACCCTCGACG GATATGGAGG AGTCGCCGCG GTGGGCGGCG GGCCGGCCGA GCGTCTCCAA
27361 CGACGGAAGG AAGTCGAGCT CTTCCAGCGG ACGATCGGTG AAGAAGCGCG CGATCGTCTC
27421 GGCCCAGTCG GCGGCAGGCG CGAGGAACAC GAGATGGTCG GCCTCCGGGA TGACGGCGAA
27481 CAGCGCACCC TCGATCTCGG CGGGCAGGGC GCGCGCGCCC TCCATGGTGG CGAAGGTGTC
27541 GTGCTCCCCG ACCAGGCACA GGCTGGGTAC GCCGCTGATG CCGCCGGGCA GGACGGCATC
27601 ATCCTGGAGG AGGAGGTCCG AGACGTTGAG GTAGCCGGGA AGATCGGGCT CCTCGATCGT
27661 GCTGAAGCGA CCGTTGAGGG CCGTGCGGAC GATTTCACGG TTGCGCACCG TGACCGCGGG
27721 GTGCAGGCAC ATGAGCAGGT CCAGCAGACC TTCGGCGAAC TCGGCGAAGC GGCCCGCCGT
27781 GAGGATCGGA TACATCTGCG TCATCCGCTC CCGGTTGCGC GGCGGGCAGT CGGCGGCGCC
27841 GGCCAGGACG AGACGGGAGA CCCGCGACGG GCTCTGCTGG GCGTAGCGGT AGGCCGGCGG
27901 GAATCCGTTG CTGATCCCCA GCAGGTTCAC ACGCGGCAGC CCCAGCTCGT CGATGAGGTG
27961 GGCGAGGGCT TCGGTCTGGA CGTCATAGCG GCCTTCGGCG GGCACGGGGT CCGCCGTGCG
28021 CGAGCCCGGC AGATCCACAC AGACGATGGT GGCCGTGTCC TGCCAGTACT TGTCGAACCG
28081 CCGGTAGCTG AACTTGTCCT GGTACGCACC GGACAGCACA ACAAAAGGCT CGGTGACCGG
28141 TGCTTCGCAT TCGACCATCC GGTAGCTGAA CGCAAGACCT TTGTAATGAA GCTCTTCGAG
28201 CTGCTCGCGC GGATTTCCGG CGCCCACGGA TCAGCTCCTC GAATTTCGGG CGGATGTGCA
28261 CGGACGGACA ACGGATACAC GTCGGTGCAT GAGCCCGATC TTTGTCGCCG GCCAGGGCAC
28321 CGACAACCCC TATTTCCCCC CTTAGCCGAA CCGGCTTGCC GGATCGGAGG TGGTCGGAGC
28381 TGCGAGATGA GTCCCGATAC GAATCCTCTC CAGATTCACC CCCTGGCACA CGACCCATCG
28441 ACATGTATTC TCGGCGTATG CCCATCATCG AACTTGGCGA ATACGGGCCA GACTTTCTCG
28501 CAGATCGTTA CCCGTATTAC GCGAAACTCC GCGAGGAGGG ACGCGTGCAC GAGGTACGGG
28561 CCCCGGACGG CTATCGATTC TGGCTGATCG TCGGATATGC CGAGGGGCGC GCCGCCCTGA
28621 CCGATTCGCG GCTGGTCAAG GCACGCGACA CGATGGCGAC GTCCGAGGCG TCGCCACTGG
28681 GCAAGCATGT GCTGATCGCC GACCCGCCGG ACCACACCCG GCTGCGCAAG CTGATCTCCC
28741 GGGAGTTCAC CGTGCGGCGG GTGGACAACC TGCGCCCGCG CATCCAGGAA CTCACCGACG
28801 ACTTGGTGGA CGTCATGCTG CCGGCGGGGC GGGCCGACCT GGTGGAGGCG CTGGCCCGGC
28861 CGCTGCCGAT GGCCGTGCTG TGCGAACTGC TCGGAGTGCC GAACGCCGAC CGGGACGAGT
28921 TCCACTCCTG GGCCAAGGGC ATCCTCGCGC CGCAGAACGG GAGCGAGACG CACACGGCCG
28981 TCAAGGCCTT GATGAGTTAT CTCGACGACC TGATCGAGGA CAAGCGGCAC GGAGAGCCCA
29041 CCGGTGACCT GCTGTCGGGT GTCATACGCA CCACCATGGA GAAGGGCGAC CGCCTCTCCT
29101 CGGAGGAAGT GCGCTCCACG GCCTTCGTCC TGATGATCGC CGGACACGAG ACGACGGCGA
29161 ACGTCATCTC CAACGGAACG CGGGCGCTGC TCACGCACCG GGACCAACTG GACCTGCTGC
29221 GCTCCGACAT GGACCTCCTC GACGGCGCCG TCGAGGAGAT GCTCCGCTAC GACGGCTCGC
29281 TGGAGAGCAC GACCAAGCGG TTCACCGGTG TGCCGGTCCA GATCGGCGAC ACGGTCATCC
29341 CGCCGGGCGA GACGGTGCTG GTCAGCCTCG CGTCGGCGGA CCGCGACCCG GCGAACTTCG
29401 ACGACCCCGA CCGCTTCGAC ATCCGTCGCG GCACCCCGGC CGGCGTCGGC CACCTCGCGT
29461 TCGGGCACGG GATCCACTAC TGCCTGGGAG CCTCACTCGC CCGCGCAGAG GGCCGGATCG
29521 CGTTCCGCGC GCTGCTGGAG CGCTGCCCCG ACCTCGAACT CGACCCCGAG GCACCGCCGT
29581 TCGAGTGGAT GCCGGGGGTT CTGGTCCGGG GCGTGCAGCG GTTGTCGCTG CGCTGGTAGG
29641 CCGAAGAGAG GCACGTATAC GGATGCAACG GCGAAGCGGN NNCCGCTTCG CGATGAGGGT
29701 GTGACCGCCG ACGGTGTGGC TGTCGGCGGC ATGACCACTC GTCACCAGGT GACGGGCAGG
29761 CTCTTCGCTC CCTGGACGTC AAGTCCCGTG GAGAACGGGA TCTCGTTCGG CGCGACGGCC
29821 AGGCGCAGCT GCGGGATGCG GCTGAACAGC CGTCCGTAGA CCACCTCCAG CTCCATGCGT
29881 GCCACGCTGT GCGCGACGGA CAGGTGGATG GCGGAGGCGA AGGCGAGGTG GTCGGGGGCC
29941 GACCGCTGGA TGTCCAGGTC GTCGGGGCGC TCGTACACCG ATTCGTCCCG GTCGGCTGAG
30001 CTGATCAGGC AGATGATTCC GTCGCCGGGC CGGATGGTCT GCCCGCCGAT CTCGATCTCC
30061 TCCACCGCCA CGCGCTTGGG CGCGAACTCG GCGACGGTGA GGTAGCGCAG CAGTTCCTCG
30121 GTGGCCGCCG CGGCCCGTTC GGGCTCCTTG GGCAGCAGGG CGGCCTGCTC GGGGTGGCCG
30181 AGCAGCGCCA GCACAGCGGT GGTGATGATC TTGACGGTGG TGTCGTATCC GGCGCCGAGC
30241 AGCAGCCCGA TCTGCATGAG CAGGTTCGTC TCCGTGAGCC TGCCTTCGTC GGCGAAGCCG
30301 ACCAGGCGGC TGACGATGTT GCGGTCCGGT TCCGCACGGC GCAGTTCGAC CAGTTCCTTG
30361 AGCTGCTCGA ACAGTTCACG GCGGGCGGCG ACGGCGGTTT CGGCGGAGCC GTCCTCGTCG
30421 AACAGCCGGG CGGTGGTCTC GCCGAACCGG GCCATCGCCT CGGCAGGCAC CGCGAGCAGC
30481 CAGCCGACGA CCGTCGACGG GACAGGAGGG GCCAGCGCCG GCACGAGGTC GGCGGGGGTC
30541 GGGCCCTCCA GCATCCGGTC GATGAGCCCG TCGACGAGCT GCTCGGTCGC CGGACGCAGC
30601 GCCGGCACCC GCTTGATCAG GAAGTGCGGC GCGAGCATCC GCCGGAGTTC GGTGTGGTCG
30661 GGCGGGTCCA TCCGGCCCAG CGGCCGTACG CCGCCCTCCG CGGTGTTCAT GGCCTTCGCG
30721 ACCTCACTCA GCCATGGGAA ACGGGGGTTG AGCGCGTCCA CGCTGGCCCG GGAGTCGGAG
30781 AGGATCTTGC GCACGTCCTC GTGCCGGCTG ATCAGCCAGG CCTCCCGCCC GTTGTAGAGC
30841 CGCGCCTTGG ACACCGGCTG CTCGGCGCGC AACGTGCGGT AGACGGGCGG GGGATCCATC
30901 GGGCAGCCGG GCGCCTTCGG CATCGGATAT GCCGGCGGCG TCTCGGAGGA GCTGTCCGTC
30961 GTCAGGGGCG GTGTACCGGT GGGCACGGCG TCGGTCGAGG TCATCGTGGC GACCCTCCTG
31021 GGAAGACTTC TGGTGGGGTG GTTCTGTCGC GGCGGGCGCG TGTCACGTTT CGACAGGCCT
31081 GGGCGCGCGT CACATCTCGG TGGGTGGGTG TCATGCCCTG GCCGACACAA GCCCGTGGTT
31141 CCGTTCGGCC CGCTTCGAGC CGATGTACGA GAGGACCGTC GCGCACAGCG CGAGGGCGGC
31201 GCCGACCGCG ACCGACGTGG CAGGACCCGA GGCCTCCAGC AGCACGCCGG TCACCGGCAT
31261 GCTGAGCGCG GGGCCGCCGG TGCCGGCGGT GGCCAGCCAG CCGAAGGCTT CCGCCCGGCG
31321 CTGCTGCGGC ACCGCTCCGG ACACCTGCGG GAAGTTGCCG GCCATGCTCG GGGCGATGGC
31381 GGTGCCACCG AGGAAGAGCA CGACCAGCAC GAGCCAGACC GGAGCGGTTT CGGTGACCGG
31441 CGGCAGCAGC AGCGCGAGCA GCGCCATGCC GACTGCCATC GCCGCGAACC GGGCGCTGTG
31501 CGGCACGTCC TTGCGCAGGG CGCCCATGCC GAAGCCGCCG ACCACGGATC CGATCGTCCA
31561 GCATGCGATG AGCACGCCGG ACAGTCCGGA CTCGTGGCTG TCGCGGGCCC AGGCGACCAG
31621 GGAGAGGTTC ACCGAGAAGA GGGCGGCCAT CATCACCAGG GTCACGACGA TGGCGAGGGT
31681 GAACTTCGGC AGGGGGAAGA GGGTACGTCG CTCCTCGGGC TCCGGTGCGG ATGCTCTCGT
31741 GACCGCGGAC GCCGACGTGG CCGTGTCTCC TTCCGTGCCG GCGTGCGCTC CCGTTTCCGC
31801 TGCTGTCCGC GTCTCTGGTT GTGGTTTCGC GGCGGTCCGC TCCGCCCCGC CGCGGATCCC
31861 GGCGCTGCCC AGCGCGGCGG CGAAGGCGAG CGCGCCGAGG AACGCCACGA CGCCGCACGC
31921 GATGACGGCG TATCCGGGGT CGAGGGCGGT CACGAGCAGT GAGGTGAGCA GCGGCCCGGT
31981 GGTCTGCACC ACCTCCGAGC CGGTGGCCTC CAGTGTGAAC AGCGTGCGGG CGAGTTCGCC
32041 GGGCACGATC TTGGGCCACA CCGGGCGGCT GACCTGCGAG ATGGGCACGG TGCTCATTCC
32101 GGTGAGCAGG GCGACCAGCA CCGCGATCGG CCAGCCGCCG CCCGGCACGG TGCGGGTCAT
32161 CGTCACCAGT GCACCGAGGC CGACGAGGTA GCCGATGCCG GTCAGGACCA GCAGCTTGCG
32221 GACCGCGCCC CGGTCCGCGG CGCGGCCCCG GGCGGGTCCG ACGAGCGCCT GCCCCGCGGT
32281 GAGCGCCCCG CCGAGCACGC CGGCGGCGAC GTAGGAATCG CTCGAGCCGA CCAGCACCAG
32341 CGTGAGGCCG ATCGGCAGCA TGGAGACGTT GAGGCGGGGC AGCATGGACC AGAGGAACAG
32401 GCGCGGCAGG TGCGGAATGC CTGCCAATGC CTTGTAGGAC TTCACGGTTC ACACCCTGTT
32461 TCGCAAGTCA TGACGCATAC GCGCCCGCCG TGCGGTTCGG CGCCGGCGGA CGCTGCGTCT
32521 TGATCAGGTC TCTTCGGACG TTCGGGGCCG CTCAGAAAAC CTGGAAACGG GCGGCGATGC
32581 GGTCGGCGTT GTCGGGGTTC TGCCGGGCCC GCTCGATCAG CTTCTCGTTG CTCCAGGTGC
32641 TGGCGGTGGT GGCTGTCTCG TCGCCCGCGT TCTGGCGTGC GGGGTAGATC CAGCCCTCGG
32701 CGGCGCAGCG GAACCGGAGG ATGTCGGCGA GGAAACGGAG TTCGGCCCGG TCGGCGGGCG
32761 CCTCCTCGAA GTAGCCGCGC ACGAGCGGCT CGCCGTCCGT GTCGTCCTCC AAGTAGCTGA
32821 GTGTGGTGGC CAGTTCCAGC ATGCAGGGTG CGTACATGGC CTCCGACCAG TCGAGCAGAG
32881 CCGCGGTGTC GCCGAGGACC CGGAACTCCT TGGCCGCGGC GTCGGAGTTG ATCAGGCCGA
32941 TGGTCAGGTC GTCGGGCGAC AGCGCGCCGC CCGCCTGCTG CAGCGTGCGC CGGATCCAGT
33001 GGTGTGGCTT GAGGAAGTCC TGTTCGAGCA GGAAGAGTTC GAGCACCTCG TTCCAGCGCG
33061 GCACGCCCTC GGGGACGGGG GCGTGCAGCA GGACGGAGTC GATCCGTCCG AGGGTCCGGC
33121 CGACGGCGCG CAGGTGGGCC GGGTGGGTCT CGTCGACACG CTCACCGTCG AGGTAGGTCA
33181 GCAGGCTGTA GCAGAAGTCG CCCTGATAGG CGGTGACTTC TCCGCCGGTG GTCGGCAGCG
33241 GGCCGCCGGC GGCGATGCCG TGCCGCTCCA CCTCCTGGGC CAGCAGGAGT CGTGCGGTGA
33301 GCTTCGGCCC CATGTCCTTG CGGAGGGCCT TGACGACGTG GCGTACGCCG TGGTGCCGGA
33361 GGAGGTAGGT GTGGGAGCTG TACCCCTCGT CTCCGGGCAG CCGCTCCCAC GGCTCGACGG
33421 TCCAGTCCTG CCAGCCCCAG AGGGTCAGCG GCAGGTCGTG CGCTTCGGGT ACCGCGGCTG
33481 CGGCGTCGGT CGATTCCGGC ATTGAAGGGG TTTTCGTTGT CTGGTCGTGA TGTTCCGAGT
33541 TCCATGTCCG ACGGCCGCGC GGTCGCGGGG TCGCGCGGTC GCGCGGTCGC GCGGTCGCGC
33601 GGTGGCGCGG TCGCGGCATC ATGTGGTCAT GTGGTCATGC GGTCACGGGG CAGGGTCATG
33661 GTCCGCGGGC GCGTCCCAGG CGACGGGGAG CGAATTGACG CCGTACACCA CGGAGTTCGC
33721 GCGGAACTCG ATGTCCTCGA AGGGCACGGC GAGGCGGAGC GTGGGGAAGC GGTCGAACAG
33781 GCGCAGGTAG GTCACCTTCA TCTCGACGCT GGCGAGGTGG TGGCCGATGC ACAGGTGGAT
33841 GCGGTGGCCG AACGCCAGGT TGCGCTCCTC CGCCCGGTCG AGGCGCAGCC GGTGCGGGTC
33901 GGTGTAGAGC TCCGGGTCGT GGTTGGCCGC GGCCATCGAA CCGACCACGG TCTCGCGCGC
33961 CTTGATGAGG TGCGCGCCGA TCTCCACGTC CTCGGTCGCC AGGCGGGCGA AGTTGAACTG
34021 CACGATGGAC AGGTAGCGCA GCAGTTCCTC GACGGCGGTG TCGATGAGCG ACGGATCGGA
34081 GGGCAGGAGG GCGAGCTGGT GCGGGTTGCG CAGCGGGGCC AGGGTGGCGA GGCTGAGGAT
34141 GTTCGAGGTC GACTCGTGCC CGGCCATCAG CATCAGGGCG CACATTCGGG CGATCTCGAA
34201 CTCGGATATC CGGTCCTTCT CCTCCGCTGG ATCGAGCAGA TCGCTGATCA GGTCGTCCGA
34261 CGGGTTCTTC TTCTTGTCCT CGATCAGGTC CAGCATGAAC TTGGTGCCTT CGAGGACGGT
34321 GCGCTGCTGC TCCTCGTCGG ACAGTTGGGT GTCGAGGATG CTCAGGGACC AGCGCTGGAA
34381 GTCGTCGCGC GCGTCGTAGG GCACGCCGAG CAGGTCGCAG ATGATGAGCG ACGGGATGGG
34441 CAGGGCGTAG GCGGTGACGA GGTCGACCGG GCCGCCCGCC GTCTCCTCCA TCCGGTCCAG
34501 GTGCTCACGG GTGTACTGCT CGATCTTCGG CTCAAGAGCC TTGATCTTCC GGACCGCGAA
34561 ACGGCTCGCG GCCAGTCGCC GGTAACGGGT GTGGTCCGGC GGGTCCATGG TGAAGAAGGC
34621 GCCGGGCAGC GGCGTGGGGC GGCCCTCGGT ACGACGAGTG CGGGCGGCCT TCTCCCGGAC
34681 CGAGCTGAAG GACGGGTTCG CCAGCATCGC CTTGACGTCC GCATGGCGGG TGAGCAGCCA
34741 GCCCTGGTTG CCGTCCGGGA AGGCGATGGG ACTCACGGGC GCCTCGGCGC GCACGTTCGC
34801 GTAGCCGTCC GGGGGGCTGA AGGGGTCGCT GCGGTGCAGG GGCAGGCCCT GCAGGAGAGA
34861 AAGAGTGTTC ATGGTCGTCC TTCCTCAGAG GGCGTCGGTG TTTCGAGTCG GTGCGTACTG
34921 AGGGGTGCGG AGTGGTACGG GGCGGGCGCG GACGCGCGGC GGCCCCGTAC CTGCTCGATC
34981 AGGGCCGGGT GAGGCCCGGC GTACGGCTCA GCCACTCGTC CACCGCCGCG GCCGTGGTCT
35041 CGGAGAATTC GCCGATCATG GTGCAGTGGT CGCCCGGCAC CTGCGTCTCC TCGTGGTCGA
35101 GGGGCCACGC CGCCTGCGAG TCGGGGCCGG CCATGGGTTC CTCGGGGGAA CCCGGGATGC
35161 AGCTGTCCGG GCGGACGAAG AGAGTCGGCA CGGCGAGTTG CCGGGGCTGC CAGCCGCGGA
35221 ACATACCGCG GTACGTACCG AGGGCGGTGA GGCCGTCGTA GTGCATCGAC GTGAACCGCA
35281 TCCGGCGCTC GACGACCTCG TAGGTCATGG CCTTGCGCAT CTCCAGCGTC ATGCTGTCGG
35341 GCGGGTAGGT GTCCAGCAGG ACGACGCCGA CCGGGCCTGT TCCGCGCTCC TCCAGCCAAG
35401 TGGCGGCGGC CTGGGCGAGC CAGCCGCTGG ACGAGTAGCC GAGCAGCGCG TACGGCCGGC
35461 CGTCCGCCGC ACGCAGCACC GCCTCCGCCA GTGTCTCGAT CAGCAGCTCC AGGGAAGCGG
35521 CGAGAGGCTC GCCGGCCATG AAGCCCGGGA CGGTGACCAC GGAGACCCGG CGGCGGCCAC
35581 GGAAGTGGTT GGCGAGGCGG GCGAACTGGA GCGAGCCGTC CAGGGGCGCG AACGGCGGGA
35641 AGGAGAGGAG CTGCGGCTCC GCCTCGCCGT GGCCGAGGGT GGTGACGTGC GCGCCGCGGC
35701 CCAGGTCCTC GGCGCCGTGG AATCTGGTGC GCAGGGCGGA GGCGCTGCTG AGGAAGGCCT
35761 CGACCTCCTG CATCCGGGCT TGCAACGAGA GCTTGCGGTA GATGCCGACG ACGGAGTCGT
35821 TGGAGTCCTG CGGCGGCGCG GCGGCCAGGG AGGCGGACGG CGCCGCGGAC ACGCCGGGCG
35881 CCGGTGACGC GCCGGCGTGG CCGCCCGGCG CGGCATTGTC CAGCAGATGG GTCACCAGGG
35941 CGCCGAGCGT CGGATGGTCG AACACCAGGG AGCTGGGCAG CGCCAGGCCG GTCAACACGG
36001 TCAGCCGGCC GCGCAGTTCG ACCGCGGCCA GGGAGTCGAA GCCGAGCGCC AGGAACTCCT
36061 GGTCCTCGGT GATCGTGCCG GCGTCCGCGT GCCCGAGGAC GCGCGCGGCG TGGCGACGGA
36121 CGATATCGAG GACGTAAGGG CGCTGATCGG CGAGCGGAAG GTCCGGCAGG CGCTGCCATT
36181 CGCCGGGCTG CGCGGCACCG GTGGGTCCGG CATCGGGGTG TCCGGCACCG GACTCCGTAT
36241 CGTCGAAGTC GGCGAACAGG TGGTTCGGCC GGCCCGCGGT GAAGACGCCG ATGAACCGTG
36301 GCCAGTCCAG GTCCGCGACG ACGATGGCGG TGTCCTCCTG CCTGACCGCC CGGTCGAGGG
36361 CGGTGGTGGC CAAGCGCGGG GTGAGCGGCC GAAGGCCCCG GCGCTGCATC TCCTGCGGGA
36421 ACTGTTCTCC GGCCATGCCG CCGCCGCTCC AGGGCCCCCA GGCCAGCGTG GTGGCGGCGG
36481 CGCGGCGGGG GCGGCGGCGC TCGACCAGCG CGTCCAGGAA GGCGTTCCCG GCCGCGTACG
36541 CACCGCCGCG GGTGGTGGCC GAGGTCCCCG CGATGGACGA GTAGACGACG AACGCGGCGA
36601 GTCGGTCGCC CAGCACCTCG TCCAGGATGA GGGCACCGGT GACCTTCGCG TCGACGACGG
36661 CGGCGAATTC GGTCGCGTCG AGATCAGCCA GCGGATGTTC GGCCGCCACG CCCGCCGTGT
36721 GCACGACCGC ACCGACGGGG GCACCGCGGC CGGCCAGGTC GGGGGCGAGC GCCGGGAGCT
36781 CGTCGCGGCT GGTCACGTCG GAGGACACCA GGTCCACCGT GGCACCGTGG GCGGCCAGTT
36841 CGGCCCGCAG GTCCGCGGCG CCGGGGGCGT CGGGCCCCTG GCGGCTGGCG AGGACGAGGT
36901 GCGGGGCACC CTGCTCGGCG AGCCGACGCG CCGTGTGCGC GCCGAGGGCG CCGGTGCCTC
36961 CCGTGATGAG GACCGAGCCG TGCGACCACC AGGGTTCGCG CGCGGCGGGC GGCTGCGGAT
37021 CACCGGTCCG CCCGGTGGCG TCGGCCCCCT CCGGGGCGAC GAGGGATTCC GGGGCGACGG
37081 GGCGTACGGG CTCGGGTGCG CCGTCCGGGC CTGGGGGCCG CAGGCGGCGC ACCCGTGCTC
37141 CGTCGGCACG CAGCGCGACC TGGTCCTCAC CACTGGATCC GGCCAGCAGC GCCGCCAGGC
37201 CGAAGGAGGC CTCGGCCGTC GCGGCGAGGG CGTGCCCGTC TGCCGCGGAC AGGTCGGGCG
37261 CGGGCAGGTC GACCAGGCCG CCCCACAGGG TGGGGTGTTC GAGGGCCGCG ACCCGTCCGA
37321 GGCCCCAGAC CTGGGCCTGC CACGGGTCGG GAGCGTCGTC GGACGCCGTC GCGCGGACCG
37381 CTCCGCGGGT GAGCGTCCAC AACCGGGTCG CGCTCCAGCC CGTGTCGAGC AGCGCTTGGA
37441 GAAGGCACAC GGAGGCCCAG GCGCCGGAGC CGACGCCGCG CGGCCCGGTG TGCTCGCGGC
37501 CGGACAGGGC GAGCAGCGAG ACCACTCCGG CGGGAGTGTC GTCGAGCCCG TTCAGCAGCT
37561 TGGCGATGGT CTGGCGGTCG ATGTCCTCGG GCGCGAGGGA CAGCGACTTC ACCTCGGCGC
37621 CGGCATCGGT CAGCACCCGA CGCACCTCGC CGTGCAGCCC GTCGTGCAGC CCGTCGTTGT
37681 CGAGCAGGTG GCCCGCGCGC AGGTCGCCTT CGGGTACGAC GATCAGCGAG GTGCCGTGCA
37741 GGGTGGCGGG CCCCTCGGGG GCGTGCTGCG CGGTCGGCCG CTCCCAGGCG ACGCGATAGC
37801 GCCATCCGTC CGTCTCGGAG GCCTCGATGT GCGTCTGGTG CCAGTCGCCG AGCGCGGGCA
37861 GGACGGTGTG CAGCGGAGCG TCGGGGTCCA CGCCGAGGTC GCTCGCCAGC CGCTGGAGGT
37921 CCTGTTCCTG GACGACCTTC CAGAACGCGC CGTCGCTCCC GGCCGTCCGG GATGCCGCCG
37981 ATCCGGGCCG GACGGAGGCG CCCTTGAGCC AGTGGTGTTC GTGCTGGAAG GCGTAGGTGG
38041 GGAGTTCACG GGCGAGGTCG TCGGCCCGGC CGAGAGCGGT CCAATCGACC TGGTGACCAC
38101 GCGCGTGCAC CCGGGCCAGC ATGCCGAGGA ACGCCCGGGT GTCCGTGGAA CGCCGGCTCA
38161 GCGTGGGCAC GAACGCCACG TCCCGCGCCG CCGAGTCCCG CTCGGCGGAC GCGGCGCGCA
38221 CGCGCTCGCC CAGCGCCGTC AGGACGGGGT CGGGCCCGAG TTCGACGACG GTCGCGACGC
38281 CCTGGGCCAG GACCGCGCCG ACTCCGTCCC CGAACCGCAC CGCTTCGCGC ACGTGCCGCA
38341 CCCAGTACTC CGGCGAGCAC AGCTCCTCGG CGTCCGCGAT CGTGCCGGTC ACGTTGGACA
38401 CGACCGGAAT CGACGGGGCA CGGAACTCCA CCTGCGCCAG CACGTCCGCG AACTCGGCGA
38461 GCATCGGCTC CATCAACGGC GAATGGAACG CGTGGCTGAC CGCCAACGCC CGTGTGCGCC
38521 GCCCCCGTCC GGCAAAGATG TCCGCGATCT GGTCCACCGC GGCGTCCTGA CCGGACACGA
38581 CCACAGCCCC TGGAGCGTTC ACGGCTGCCA GCGACACCAT GCCCCCGGCA GCCGCCACAT
38641 CCGCGACGAG CGGCGCGACC TCCTCCTCGG TGGCCTCCAC CGCCACCATC CGCCCACCCG
38701 ACGGCAACGA ACCCATCAAC CGGGCCCGGG CCACCACCAC CCGCACCGCA TCCGCCAACG
38761 ACCACACACC CGCCACATAC GCGGCGGACA ACTCCCCCAG CGAATGCCCG ATCAACACAT
38821 CCGCACGCAC ACCGAAAGAC TCCGCCAGCC GATACAACGC CACCTCGACC GCGAACAACG
38881 CAGGCTGAGC AACCCCCGTA TCCTCCAAAA CCCCCGCATC ATCACCGAAG ACCACCCCAA
38941 GCAGCTCTGC TCCCGTCTGC GCCTCGACCT CCGCACACAC CTCGTCCAAC GCAGCCGCGA
39001 AGACCGGGAA CCGCCCATAC AACTCACGCC CCATCCCCGG ACGCTGCGAG CCCTGACCCG
39061 AGAACGCCAC ACCCACACCA CCAGCGACAC GACGCTCAAA CACCACACCA CCGGCAGCGG
39121 AACCGTCACC CCGCGCAACC CCACCCACAC CGGCCAACAA CTCGTCCAAC GACCCACCAC
39181 TGACCACAGC ACTGTGATCG AACACCGAAC GCGACGACAC CAACGCCAGA CCCACACCCC
39241 CCACATCCAG CGCACCACCC CCGCGTCCCG CCACGAACGC CGCAAGCCGC GCCGCCTGAG
39301 CCCGCACCGC ACCCTCAGTA CGACCCGACA CAACCCACGG CAACTCCCCA GCAACCACCA
39361 GCGCTTGAGT GGACTCCACC GGAACCTGAG CGGACCCCAC CGGAGCTTCA GTGGATTCCA
39421 CGGGCTCGTG CTCCAGGATC ACGTGCGCGT TCGTCCCGCT GATACCGAAC GACGACACAC
39481 CCGCCCGCCG CGCACGACCC GTCTGCGGCC ACTGCCGAGC CCGCGTCAAC AACTCCACCG
39541 CACCCGCAGA CCAATCCACA TGCGGCGACG GCTGCGACAC ATGCAACGTC CGCGGCAACA
39601 CCCCGTGCCG CATCGCCATC ACCATCTTGA TCACGCCACC GACACCGGCA GCCGCCTGCG
39661 TATGACCGAT GTTCGACTTC AACGACCCCA GCCACAACGG ACGGCCCTCC GCCCGGCCCT
39721 GCCCGTACGT CGCGATCAAC GCCTGCGCCT CGATCGGATC ACCCAGCCTC GTCCCCGTCC
39781 CGTGCGCCTC CATCACATCC ACGTCCGACG TCGACAACCC CGCACCCGCC AACGCCCGCA
39841 CGATCACCCG CTGCTGCGAG GGACCGTTCG GCGCCGTCAA CCCGTTCGAC GCACCGTCCT
39901 GGTTCACCGC ACTGCCCCGC ACCACCGCCA ACACCTCGTG CCCGTTGCGC CGCGCGTCCG
39961 ACAAACGCTC CAGCACCACC ACACGCACAG CCTCGGACCA GCCCGTCCCC TCCGCATCCG
40021 CGGAAAAAGA ACGACACCGG CCGTCCGCCG ACAGAGGACC CTGACGACCG AACTCCACGA
40081 AGGCGTACGG CGTCGCCATC ACCGTCACAC CACCCGCGAG CGCCAACGAA CACTCCCCCG
40141 CACGCAACGA CTGCACCGCC AGATGCAACG CCACGAACGA CGACGAACAC GCCGTGTCCA
40201 CCGTCACCGC AGGAGCCTCG AACCCGAACG AATACGAGAC CCGGCCCGAG ATGACGGAGC
40261 TGGCCGATCG CGTTCCGCCG AGGCCTTCGG GCGCGTCGAC GATCTCCGTG CCGACCAGGC
40321 CGTAGCCCTG GACGGCGCCG CGCATGAAGA CGCCAACCGG CTTGCCGCGC AACGAGTCGG
40381 CGCTGATGCC GGACCGCTCC ACCGCCTCCG AGCAGGTGTC CAGGGCGATG CGCTGCTGGG
40441 GGTCCATGGC GGCGGCATCG CGCGGCGAGA TGCCGAAGAA GCCCGCGTCG AACTGCGCGG
40501 CGTCGTGCAG GAACCGGCCG CCCGCGGCAG GCAGTCGTCC GAGGTCCGAG CCGCGGTGGG
40561 CCGGGAACGG CGAGATCGCG TCCCGCCCCT CGGCGACCAG TCGCCACAGG TCCTCGGGCG
40621 AGGCAACCCG GCCCGGATAC TTGCAGGCCA TGCCGACGAG CGCGATCGGC TCGTTCCCGG
40681 CTGCCTCGAG TTCGCGCAGC CGGCCGCGGG TAGGCAGCAG ATCGCCGGTC AGTTCCTTGA
40741 CGTAGTGGGG AAGCTTGTCT TCGTTGGTGG ACACGGTGCG CCAGCTCCTT GTTGGTGCTG
40801 AGGTTTGCGA ACGCCGGCGT CAGGAGATGC GGAATTCCTT CTCGATCAGA TCGAAGAGCT
40861 GATCGTCGGT TGCCGAGTCG AGTTGCTGGG GAGCTGTTTC CGCCGCGCCG GAGGCGGCGG
40921 TGGGCTCGTC GTCGGCGTTC TGGAACCTGG TCAACAGGTT GGAAAGCCGC AGGGTGATAC
40981 GGCCGCGGGC GGCCGGGTCG GACCCGGCGT CGAGCGCGGC GAGGGCCGCT TCGAGCCGGT
41041 CCAGCTCACC GAGGACCGCC GACGCGCCCG ACGCGGCGCC GAGCCGCTCC GCGAGGGCGG
41101 TCGCGACGAC CTGTGCCAGG GCCGCGGGCG TGGGGTGGTC GAAGACGAGC GTGGCGGGCA
41161 GCTTGAGGCC GGTGAGCTTT TCGAGCCGCT GCCGCAGACG GACTGCAGCC AGCGAGTCGA
41221 ACCCGAGTTC CTGGAAAGGG CGTTCCGGCT CGATCGTGCC GCCCGAGGCG TGCCCGAGTT
41281 CCGCGGCGGC CTGCGTGCAG ACGGTCTCCA GCAGCACGCG TCGGGGTTCC CCGCCGGACA
41341 GCGCGGTCCA GCGGGCGAGG AAGGGGGTGG CCCCTGCGGT ACCGGCGTCG CTGTCGCCCG
41401 GGCCGGAGAC GTCGTCCGCA CCGGCCGTGC CGGCCGCCGT CCCGTCCGCG CCGACGCCGC
41461 CGCGTTCCGT TTGCACGGTG CGGAGCGGGT CGAACAGGGG GCTCGGACGG TTGACGGTGA
41521 AGATGTCGGC CAGGCGTGAC CAGTCGATGT CGGCGAGGAC GACGGTGCCG TAGTCCGCCC
41581 TCACGACGCG GCCGAACGCG GCGACGGCCT CCTCCGGGTC GAGCGCGCTG ACGCCGCGGG
41641 CCTGCATCTC CCGTGTGAGG CGTTCGTCGG CCATGCCGCC CCCGCCCCAG GGGCCCCAGG
41701 CGAGGGCGGT GCCGGGACGT CCCTGGGCGC GCGGCGGCTC GATCAGCGCG TCGAGATGCG
41761 CGTTTCCTGC GGCGTAGGCA CCGGCACGAG CGCTGCCCCA GACCCCGGCG ATGGAGGAGT
41821 AGACGACGAA CGCGGCGAGT CCGTCGCCCA AGACCTCATC GAGGACCTGC GCGCCGACGA
41881 CCTTCGCGCG TACGACGGCG GCGTAGCCGT CCTCGTCGAG CTCCGCGAGC GGCAGTTCCG
41941 AGGCGACGCC CGCGGTGTGG ACCACGGTGC TGAGCGGCGT TCCCGCGTCG GCAAGCCTGT
42001 CCCGGAGGGC GGCGAGGGCC ACGGCGTCGG TGACGTCGCA GGACTCGACG ACGACGTCGG
42061 CACCCCGCTC CTCGAGTTCC GTGCGCAGCG CGGCCACCGC GGGTGCGGCA GGGCCCTGAC
42121 GGCTGGTGAG GACGAGGGTC CGCGCGCCGT TCCGGGCGAG CCAGCGCGCC GTCTGCGCGC
42181 CGAGGGCGCC GGTGCCGCCG GTGATCAGGA CGGAGCCGTC GGTCGAGGGC GCCGTGGAGC
42241 CGGTCTCCGG CTCCGGCACG CTCGTGGGTA CCGTGCCGCG GATCAGCCGA CGACCGAGCA
42301 ACAGCTGGCC TCGCAGGGCG ATTTGGTCGT CACCGGTGGT GTTGGCAAGG GCAGCGGCAA
42361 GGCCGGTGAG GTGCGCTGCG GGACTCGTAC CGGAGACGTC GATCAGACCG CCCCAGAGGG
42421 TGGGGTGTTC GAGGGCCGCG ACCCGTCCGA GGCCGCAGAC CTGGGCCTGC CACGGGTCCG
42481 GCGCCGCGTC GTCGGCCTGC GCACACACCG CGTCGCACGT GAGGGCCCAT ACGCGGGTGT
42541 CGACTCCCGC GTCCTGCACG GTGTGCAGGA GATCGAGCAC GGCCAGGGCG CCGGTCGCGA
42601 TGCGGCGCTC CCGGTCGCCG TCGCGCTGGG CGCCGACCGC GGGCAGGCAG AGCACGCCGC
42661 GGGGCGGCAC TGCGGCCAGC CGTGCGCGCA GCTCGGCCGT CTGGCACCGC TCCACGCGCG
42721 CCCCCGGGTC GACGAGCGCG TTTTCGACCG CAATTACGAG GTCCGGTTGG ACGGGCTCGC
42781 CGGGCACCGC GACCAGCCAC GTGCCGTCGA GCGGCACCGC GTCCGTCGGC GACGGAAGCT
42841 CCGTCCAGGA GACGCGGTAG CGCAGGGCGT CGGCCGCTGG GAGCCGGGCC TGTTCCCTGG
42901 ACCAGGTCTG GAGCGCGGGC AGCACCGCGG TGAGCGGCGC GTCCGGCGCG AGGCCGAGGG
42961 TATGGGCGAG GCGGTCGACG TCCTGCTGCG CGACCGCGTT CAGGAGTACG GCCTGCTCCG
43021 GGACGTGCTC GACGACGCCG GGCTCGGGCG CGGGGGCGTC GAGCCAGTAA CGCTGATGCT
43081 GGAAGGGGTA GGTGGGGAGT TCACGGGCGA GGTCGTTCGG CCGGCCGAGA GCGGTCCAGT
43141 CGAGCTGGTG ACGACGCGCG TGCACCCGGG CCAGAGCCGT CAGGAAACCG TTCACATCAC
43201 CCGTCCGCCG CCCCAGGGTG GGCAGGAACA CGGCACCGTT GTCGACGACT CCCGGATGCG
43261 AGGGACCCAT CGCCGTCAAC ACCGGCTCGG GCCCCAGCTC GACAACGGTC GCGACGCCCT
43321 GCGCCAGGAC CGCACGGACC CCGTCCCCGA ACCGCACCGC TTCCCGCACG TGCCGCACCC
43381 AGTACTCCGG CGAGCACAAC TCCGCAGCGG ATGCGACCTC ACCCGTCACG TTCGACACGA
43441 CCGGAATCGA CGGGGCACGG AACTCCACGC GCGCCAGCAC GTGCGGGAAC CCGGGGAGCA
43501 TCGGCTCCAT CAACGGCGAA TGGAACGCGT GCGAGACACG AAGACGAGTC GCACGACGCC
43561 CTCCGCCGCG CGCCCGGTCC ACCACCGCCT GAACGGCACC CTCCAGACCC GAAACAACCA
43621 CCGCCGCCGG CCCGTTGACA GCAGCGATCA GCGCACCGTC CACCAGCCAG CGGGACACCT
43681 CCTCCTCGGT GGCCTCCACC GCCACCATCC GGCCACCCGA CGGCAACGAA CGCATCAACC
43741 GGCCCCGGGC CACCACCACC CGCACCGCAT CCGCCAACGA CCACACAGCC GCCACATACG
43801 CGGCGGACAA CTCCCCCAGC GAATGCCCGA TCAACACATC CGCACGCACA CCGAAAGACT
43861 CCGCCAGCCG ATACAACGCC ACCTCGACCG GGAACAACGC AGGCTGAGCA AGCCCCGTAT
43921 CGTCCAAAAC CCGCGCATCA TCACCGAAGA CCACCGAAAG CAGCTCTGCT CCCGTCTGCG
43981 CCTCGACCTC CGCACAGACC TCGTCCAACG CAGCCGCGAA GACCGGGAAC CGCCCATACA
44041 ACTCACGCCC CATCCGCGGA CGCTGCGAGC CCTGACCCGA GAACGCCACA CCCACACCAC
44101 CCGCGACACG ACGCTCAAGC ACCACACCAC CGGCAGCGGA ACCGTCACCC CGCGCAACCC
44161 CACCCACACC GGCCAACAAC TCGTCCAACG ACCCACCACT GACCACAGCA CTGTGATCGA
44221 ACACCGACCG CGACGACACC AGCGCCAGAC CCACACCCCC CACATCCAGC GCCCCCGCAC
44281 CGCCCCCGCG TCCCGCCACG AACGCCGCAA GCCGCGCCGC CTGAGCCCGC ACCGCACCCT
44341 CAGTACGACC CGACACAACC CACGGCAACT CCCCAGCAAC CAACGGAGCT TCAGTGGACT
44401 CCACCCGAGC CTGCACAGAC CCCACCGGAA CCTGAGCGGA CCCCACCGGA GCTTCAGTGG
44461 ATTCCACGGG CTCGTGCTCC AGGATCACGT GCGCGTTCGT CCCGCTGATA CCGAACGACG
44521 ACACCCCCGC CCGCCGCGCA CGACCCGTCT CCGGCCACTG CCGAGCCCGC GTCAACAACT
44581 CCACCGCACC CGCAGACCAA TCCACATGCG GCGACGGCTG CGACACATGC AACGTCCGCG
44641 GCAACACCCC GTGCCGCATC GCCATCACCA TCTTGATCAC ACCACCCACA CCGGCAGCCG
44701 CCTGCGTATG ACCGATGTTC GACTTCAACG ATCCCAGCCA CAACGGACGG CCCTCCGCCC
44761 GGCCCTGCCC GTACGTCGCG ATCAACGCCT GCGCCTCGAT CGGATCACCC AGCCTCGTCC
44821 CCGTCCCGTG CGCCTCGACC GCGTCCACAT CCGCCACGGA AAGTCCCGCG CCCGCCAGTG
44881 CCTGGCGAAT CACGCGCTGC TGGGACGGGC CGTTCGGCGC CGTGAGCCCG TTCGACGCAC
44941 CGTCCTGGTT CACCGCACTA CCCCGCACCA CCGCCAACAC CTCGTGCCCG TTGCGCCGCG
45001 CGTCCGACAA ACGCTCCAGC ACCACCACAC CCACACCCTC GGACCAACCG GTGCCCGATG
45061 CGTCGGCGGA GAACGAACGG CACCGGCCGT CGACGGCCAG TCCGCCGTGG CGTCCGAACT
45121 CCACGAACGC GTACGGCGTC GCCATCACCG TCACGCCACC GGCGAGCGCC ATCGAGCACT
45181 CCCCCGCACG CAACGACTGT GCCGCCAGAT GCATCGCGAC CAGCGACGAC GAACACGCCG
45241 TGTCCACCGT CACCGCAGGA CCCTCGAACC CGAACGAGTA CGAGACCCGT CCCGACGCGA
45301 TGCTGCCGGA GCTTCCGTTG CTGATGTAGC CCTCGTACCC CTGCGGCGAG CGGTTCAGGT
45361 GGCGGGCGCC GTAGTCGTTG TACATGACGC CCATGAACAC GCCGGTGCGG CTGCCGGTGA
45421 GCGTCTCCGG CCGGGTGCCG GCCGACTCCA GGGCCTCCCA GGAGGTCTCC AGGAGCAGTC
45481 GCTGCTGCGG GTCGGTCGCG GTCGCCTCGC GTGGCGAGAT GCCGAAGAAC TCCGCGTCGA
45541 ACTGGGCCGC GTCGTGCAGG AACCCGCCCT CACGGGTGTA CGTCTTGCCG GGCTGCTGCG
45601 GGTCCGGGTC GTAGATGCCG TCGAGGTCCC AGCCGCGGTC GGCCGGGAAC GGCGAGATGG
45661 CGTCCCGCCC CTCGGCCACC AGCCGCCACA GGTCCTCGGG CGAGGCAACC CCGCCCGGAT
45721 ACTTGCAGGC CATGCCGACG ATGACGATCG GGTCGTCGCC CGCATCCTGC GGATGGCTCG
45781 CCGACGCCCG CGCCGCGGGC TCGGCGACCG CGAGCGCGGT GGACCCGGCC GGCTCCCCGA
45841 CGACTCCGCG AGCGAGTTCG TCGTACAGGA ATTCCGCGAC CGCGAGCGGA GTCGGGTGGT
45901 CGAAGACCAG CGTCGCCGGA AGGCGCACGC CGGTGGCGGC GCCGAGCTGG TTGCGCAGTT
45961 CGACGGCGGT GAGGGAGTCG AGGCCGAGCC GGTTGAACGG CTGGGCGCGG TCGACGGCCT
46021 CGCGGTCGGC GTGTCCGAGC ACGTACGCGA CCTTCTCCGC GACGAGGCCG CCGAGGATCT
46081 GAAGGCGCTC CTCGCGGTCG GCCACGCGAA GCTCGGCGAG CAGCGGCGCG CTCGCGCTGC
46141 CGGCGGTCGC CGCGGTGCCG CCGGCCACAC GGGAAGAGGG TCGGGGCCTG GTGCTGACGA
46201 CCGCTTGGAA GACGGCGGGC AGCGATCCGG CCGCGGCCTG CTCGTCGAGG ACGGGGGCGT
46261 TCAGCCGGGC GGGCACGAGC AGGCCGTCGG CGTGCGTTCC GACGGTCTCC GGGCCGGCCT
46321 CCGAAGCGCC GAAGGCTGCG CCGGCTGCTG CGAGAGCGGC GTCGAACAGC GTGACGCCCT
46381 GTTCGCGGCT GATCTCCAGG AGGCCGGTGC GCTTCAGCCG GGCCACGTTG GCCCGGTCGA
46441 GCTCCGCGGT CATCCCGCCC TCGGTGCTCC ACAGGCCCCA CGCGAGCGAG ACGCCCGGCA
46501 GCCCGAGCGC CCGGCGCCGA CGCGCCAGTG CGTCGAGGAA GGCGTTGGCT GCGGCGTAGT
46561 TGGCCTGTCC GGCCCCGCCG AAGACACCGG CGACCGAGGA GAACAGGACG AACGCGGAGA
46621 GGGGGGCCGG CGACGTCAGG TCGTGGAGGT GCAGCGCGGC GTCGGCCTTC GCGCGCAGCA
46681 GCTTCGTCAG CTGCGCGGGA GTGAGGGATT CGAGGAGCCC GTCGTCGAGT ACGCCCGCGG
46741 TGTGGACCAC GCCGGTGAGC GGATGGTCGC CCGGTACGCC GGCGAGCAGT TCGGCGACGG
46801 CGGAGCGGTC GGACATGTCG CAGGCGGCGA GCGTCACGTC GGGCCCGAGT GGTTCCAGTT
46861 CCGCGATGAG CTCGGCGGCG CCCGGGGCGT CCGGACCACG GGGGCTGGTC AGCAGCAGGT
46921 GCCGCACTCC GTGGACGGTG ACGAGGTGGC GGGCGAAGAG CGAGCCGAGG TCGCCGGTGC
46981 CACCGGTGAT CAGGACCGTT CCCTCGCCGG AGAAGGCGGG GGCGTGGGCG GAGCCATCGG
47041 CGTCGGTCGT CTCGGGGGCC GCGATCGGGC GGAGTCGCGG GACGGAGGGG ACCCCGGCAC
47101 GGAGCGCGAT CTGCGGGTGC GCGACGACGC CGGTGCCCGT GCCGATGTCT GTGCCGTTGC
47161 CGGTGCCGAG CAGCGTCGGC AGGGCGCGCA GCGAGGCCTC CTCCCCGTCG GTGTCGATCA
47221 GGCGGAACCG GCCCGGGTGC TCAAGCTGGG CGGTGCGTAT CAGGCCGCCC ACGGCGGGGG
47281 ACGCCAGGTC GACGGCTGCG GCCTCGGCCG CGTCGACCGC GAGCGCACCG CGGGTGAGCA
47341 GGGTCGCGGT GACGGATGCG AAGCGCGGCT GCTTCAGCCA GTCCTGGAGG AGATGGAGGA
47401 GCGTCTGCGT CCGCTGATGG GTGGCCGCGG CGATGTCGCC GTCCAGTCCG CCCAGGGCGG
47461 GCAGCGCTAT CAGGACGTCA GGAGGCGCCT CGGCCGGATC GGGGTCGATG GCGGCGGCGA
47521 GGGCTGGGAG GTCGGCGTGG CGGCGCGCCG GAACGGATTC GACGGACCAG TCGGCGCCGA
47581 GGTCGAGGAG CGCCAATCCG GTCCCGGAGG CGGACACGGC CGCAGACACA GCGGAACCGG
47641 CGCTTTGCAG CGGCGACGAC GCGATGCCGT ACAGCGATTC GACGGTCGAC ACGCGGGCCG
47701 AGCGAAGCTG CTCCAGCGTC ACGGGACGGA GCGCCAGCGA CCGCACGGTG GCGAGTGCCG
47761 CCCCCGCCTC GTCCAGCAGC TCCACGGAGG TCGCGCCCTC ACCGAGGCGG CGTATGCGGA
47821 CCGGGGCCGA ACTCACGGCG GTGGCGTGCA GGGTGACGCC GCTCCAGGAG AACGGCAGAT
47881 GGCACTCGTC CTGCCCGGAC AGCAGGTGGG GCAGCGCGAG CGAGTGCAGG GCGGTGTGCA
47941 GGAGCGCCGG ATGGATGCTG AAACGCCCGG CGTCGTCCGT CTGCCGGGTG GGCAGACGGA
48001 CTTCGGCGTA GACGGTGTCG CCGTGCCGCC ACGCCGTGTG CAGCCCGCGG AACGCGGGAG
48061 CGTAGTCGAA TCGGAGGCCG ATCAACCGCT CGTAGACGGC ATCGAGGTCG ACCGGTGTGG
48121 CCCCGCGCGG AGGCCATGCC TGCACCTGCG ACGGCTCCGG GGCGAGCACC GGGGCCGGCT
48181 CCGCCGCGTC GGAACGGAGG GTGCCGGTGG CGTGCCGGGT CCAGGGGGCG TCCTCGGCGG
48241 CGTGGACAGG GCGGGAGTGC ACGGTGATCG CACGGCCGCC GCCGGCCGCC TCGGCCTCGC
48301 CGACCAGGAC CTGCACGACG TGGGCCGACC GGCCGTCGAG GATGAGCGGC GCCTCCAGCG
48361 TGAGTTCCTC GACGGCCGCG CAGCCCACGC GGGCCGCGGC GGTGAAGGCG AGTTCGAGGA
48421 ACGCGGTCCC GGGCAGCAGC GTCGAGCCGA GCACGACGTG GTCGCCGAGC CACGGGTGGG
48481 TTCCCGGGGA GATCGTGCCG GTCAGCACTG TGCCACCGGT GCCGGGCAAG GTGACCGCGG
48541 CGCCGAGGAA CGGGTGGTCG ACGGCGCGCA TACCGAGGTG CGCGGCGTCG ACGGAGGCGG
48601 CATTGCCGGC AAGCCAGTGG TGTTCGTGCT GGAAGGCGTA GGTGGGGAGT TCACGGGCGA
48661 GGTCGTTCGC CCGGCCGAGC GCGGTCCAGT CGACCTGGTG ACCACGCGCG TGCACCCGGG
48721 CCAGAGCCGT CAGGAAACCG TTCACATCAC CCGTCCGCGG CCCCAGGGTG GGGAGGAACA
48781 CGGCACCGTT CTGGACGACT CCCGGATGCG AGGCACCCAT CGCCGTCAAC ACCGCCTCGG
48841 GCCCCAGCTC GACAACGGTC GCGACGCCCT GCGCCAGGAC CGCACCGACC CCGTCCCCGA
48901 ACCGCACCGC TTCCCGCACG TGCCGCACCC AGTACTCCGG CGAGCACAAC TCCGCAGCGG
48961 ATGGGACCTC ACCCGTCACG TTCGACACGA CCGGAATCGA CGGGGCACGG AACTCCACCC
49021 GCGCGAGCAC CTGCGCGAAC CCGGGGAGCA TCGGCTCCAT CAACGGCGAA TGGAACGCGT
49081 GGGAGACACG AAGACGAGTC GCACGACGCC GTCCCCCGCG CGCCCGCTCC ACCACCGCCT
49141 CAACGGCACC CTCCACACCC GAAACAACCA CCGCCGCCGG CCCGTTGACA GCAGCGATCA
49201 CCGCACCGTC CAGCAGCCAG CCCGACACCT CCTCCTCGGT GGCCTCCACC GCCACCATGC
49261 GCCCACCGGA CGGCAACGAA CCCATCAACC GGCCCCGGGC CACCACCACC CGCAGCGCAT
49321 CCGCCAACGA CCACACACCC GCCACATACG CGGCGGACAA CTCCCCCAGC GAATGCCCGA
49381 TCAACACATC CGCACGCACA CCGAAAGACT CCGCCAGCCG ATACAACGCC ACCTCGACCG
49441 CGAACAACGC AGGGTGAGCA ACCCCCGTAT CCTCCAAAAC CCCCGCATCA TCACCGAAGA
49501 CCACCGAAAG CAGCTGTGCT CCCGTCTGCG CCTCGACCTC CGCACACACC TCGTCCAACG
49561 CAGCCGCGAA GAGGGGGAAC CGCCCATACA ACTGACGCCC CATGCCCGGA CGCTGCGAGC
49621 CCTGACCCGA GAACGCCACA CCGACACCAC CCGCGACACG AGGCTCAAGC ACCACACCAC
49681 CGGCAGCGGA ACCGTCACCC CGCGCAACCC CACCCACACC GGCCAACAAC TCGTCCAACG
49741 ACCCACCACT GACCACAGGA CTGTGATCGA ACACCGACCG CGACGACACC AGCGCCAGAC
49801 CCACACCCCC CACATCCAGC GCCCCCGCAC CGCCCCCGCG TCCCGCCACG AACGCCGCAA
49861 GCCGCGCCGC CTGAGCCCGC ACCGCACCCT CAGTACGACC CGACACAACC CACGGCAACT
49921 CCCCAGCAAC CAACGGAGCT TCAGTGGACT CCACCCGAGC CTGCACAGAC CCCACCGGAA
49981 CCTGAGCGGA CCCGACCGGA GCTTCAGTGG ATTCCACGGG GTCGTGGTCC AGGATCACGT
50041 GCGCGTTCGT CCCGCTGATA CCGAACGACG ACACACCCGC CCGCCGCGCA CGACCCGTGT
50101 CCGGCCACTG CCGAGCCCGC GTCAACAACT CCACCGCACG CGCAGAGCAA TCCACATGCG
50161 GCGACGGCTG CGACACATGC AACGTCCGCG GGAAGACCCC GTGCCGCATC GCCATCACCA
50221 TCTTGATCAC ACCACCCACA CGGGCAGCCG CCTGCGTATG ACCGATGTTC GACTTCAACG
50281 ACCCCAGCCA CAAGGGAGGG CGCTCCGCCC GGCCCTGGCC ATACGTCGCG ATCAACGCCT
50341 GCGCCTCGAT CGGATCACCC AGCCTCGTCC CCGTCGCGTG CGCCTGCATC ACATCGACGT
50401 CGGACGTCGA CAACGCCGCA CCCGCCAACG CCCGCAGGAT CACGGGCTGC TGCGACGGAC
50461 CGTTCGGCGC CGTCAACCCG TTCGACGCAC CGTCCTGGTT CACCGCACTG CCCCGCACCA
50521 CCGCCAACAC GTCGTGCCCG TTGCGCCGCG CGTCCGAGAA ACGCTCCAGC ACCACCACAC
50581 CCACACCCTC CGACCAGCCC GTCCCCTCCG CATCCGCGGA AAAAGAACGA CACCGGCCGT
50641 CCGCCGACAG ACCACCCTGA CGACCGAACT CCACGAACGC GTACGGCGTC GCCATCACCG
50701 TCACACCACC CGCGAGCGCC AACGAACACT CCCCCGCACG CAACGACTGC ACCGCCAGAT
50761 GCAACGCCAC CAACGACGAC GAACACGCCG TGTCCACCGT CACCGCAGGA CCCTCGAACC
50821 CGAACGAATA CGAAAGGCGT CCGGAGAGCA CGGAGCTGGC GTTGCCGGTG ATGAGGAATC
50881 CGGAGGCCTC GGTCGCACGG GACTCGCGCA GGTGTCCGAG GTAGTCCTGC ATGCCGGCGC
50941 CGATGAACAC GCCGGTGTCG CCGCCGCGCA GCGACTCGGG GACGATGCCG GTGCGCTCGA
51001 TCGCCTCCCA CGAGGTCTCC AGCAGCAGCC GCTGCTGGGG GTCCATGGCG GCGGCCTCGC
51061 GCGGCGAGAT GCCGAAGAAG CCCGCGTCGA ACTCCGCGGC GTCGTGCAGG AACCCACCGC
51121 CCGCGGTGAG CAGCCCGTCG GGAGCGGACG TCGAGCCGTC ACCGGCCACC CCGCCACTGG
51181 CCGGCCCGGC GCCGACGCCG TCGAGGTCCC AGCCGCGGTC GGCCGGGAAC GGCGAGATCG
51241 CGTCCCGCCC CTCGGCCACC AACTCCCACA GGTCCTCGGG CGAGGCCACC CCGCCCCGAT
51301 ACTTGCAGGC CATGCCGACG ACGGCGATGG GTTCCCGGGC CGCGTCTTCG ACGTCCTGGA
51361 GCCCACCACC CGTCTCGTGC AGCTCGGCGC TGACGCGCTT CAGGTAATCC AACAGCTGGT
51421 TCTCGGATGC CATTTCCCGC TCTCCCCATC AATTCCCGGA GGGTTCTCCA CTTGCCGCCG
51481 ACGACTCAGG ACTCGTCTAT CCCGGGCCCT CCAGCGGGGA GATGCCGAGC TGCCGGGTGA
51541 CGAAGTCGAG GACTTCGTCC TCGGTGGCCG ACTCCAGCAG CGCCCCCGTG TCCGGTGTGC
51601 CCCTCTCGGA CGAGGACCCG GAGGGCGAGG AGAACATCAC CGTCTCGGAA GCGGACCGTT
51661 TGCCTTCCCA GCCGTCCGCG AGCGCCCTGA GCCGGGACGC CGCGGCCTTC CGCAGGGCGG
51721 CGTCCAGCCG GAGTTCCTCG AGGCTCTGCG CCACTCGGTA CAGCTCGGCG AGGGCGGATT
51781 CCGCGGTGAC GGCCCGCTCC TCCGGCTGGA TCAGGCCGTG CAGTTGCGCG GCGAGTGCCT
51841 TGGGCGTCGG GTGGTCGAAG ACCATCGTGG CGGCCAGGTC CACGCCCGCG GCCCGCTGCA
51901 GTCTGTTCCG CAGCGCCATC GCGGTCATCG AGTCGATCCC CAGCTCCTTG AAGGGCTGGT
51961 CGACGGCGAG GGCGGCGGGC TCGGCGTAGC CGAGCACCGC CGCCGCGTGA TCACGGACGG
52021 TGTCCAGGAG CAGGCGGTCC GCGTCGGTCC GCGCCATGCC GGGCAGTCGC CGGGCGAGCG
52081 TGGGACCACC CGCGCCGCCC GCGCCGTCGG AACGCCCGGC GTCGGAGCCG TCGTCCGCGG
52141 CTTCCCCGGA TCGTGCGAAT GCGGCGAGCA GCGGGCTGGG CCGGGCCGCG GTGAAGCCGT
52201 CGGCGAACAG CGGCCATTCG ATCTCGGCCA GCACCTGGCT CGCGGGGCCG TCCTGGGCCA
52261 GCGCGAGGTC GAGGGCCCGC ACCCCGAGTT CGGGCTCGAT CGGCGGCAGT CCGTTGCGCC
52321 GCATCCGCTG TTCCGTGGCC GCGTCGACCA GACCGCCGCC GCCCCAGGGC CCCCAGGCGA
52381 TCGAGAGGGC CGGGAGGCCC GCGGCGCGGC GGTGCTCGGC GACGGCGTCG AGCACCGCGT
52441 TGGCCGCGGC GTAGTTGCCC TGGCCGATGC CGCCGACGGT ACCGACGAAG CCGGAGTAGA
52501 GCACGAACGA CGACAGGTTC AGGCCGGCGG TCAGTTCGTG CAGGTGCCAG GCGCCGAGCG
52561 CCTTGGGGCC GAGAACCGCG TCGAGCCGGT CGGCGTCCAG GTTCTCCAGT GCGGCGTCGT
52621 CGAGGACCGC CGCCGCGTGC ACCACGGAGA CGAGCGGCCC GTCGGCCGGT ACCCACTCCA
52681 GCAGGGCGCG TACGGCCTCG CCGTCGGCGA GATCGCAGGC GGCGATCGTC ACGCGCGCGC
52741 CCATGCTCTC GAGGTCGGCG CCAAGTCCGT CCGCGTCCAG CGCCTCAGGA CCGCGGCGGC
52801 TGGTGAGCAG CAGATGTTGC CCGCCCTGCG CCGCCAGCCG GCGGGCCAGG CGGCTGCCGA
52861 GGGCGCCGGT GCCGCCGGTG ATCAGGACCG TGCCCTCGCG CGGCCACACC GCATCCGCGC
52921 CCACGTTCCC GTCCGTGTCC GTGTCCGTGT CCGTGTCCGA CAGGGAAACC TGACCGCCGT
52981 CGCGTCCGCC GGTCGTGGGG TCCGGCAGCC GGAACGGGGT GCGGACGAGG CGTCGGGCGA
53041 GCACGCCCGT CGGGCGCAGC GCGAGTTGGT CCTCGTCGCC CGGGTCGGCC AGCACCGCGC
53101 AGAGCTGAGC GGCGGTGGCG GCGTCCGGCG CGGTCCGTCC GTCCTGCCCG TCGGCCTCAC
53161 GGGGCGCACG GGGCAGGTCG ATCAGACCGC CCCACAGCGT GGGGTGTTCG AGGGCGGCGA
53221 CGCGGCCGAG GCCCCAGACC GCGGCGGCGT GCGGTGCCGC CGGAGGGTCG GTCGGGTCCG
53281 TTCCCACGGC GCCGTGCGTG AGGCACCACA GCCGGCCCGG CAGGTTTGTC TGCGCGAGCG
53341 CCCGCACCAG GAGCGTCCTC CCGGCCAGGC CGCGCCCGAC CGCGGGGCGT CCAGGTAGCG
53401 GGCGGTGGTC GAGCGCGAGC AGGGAGAGGA TCCCGGGCGG CCGGGCATCG GCCGCCGCGG
53461 CGTGCAGCGA CGGGGCCCAT GCGGCCGGGT CGGTGTCCTC GCGCGGGTCG AGTTCCACGA
53521 GCAGCGCCCG GCCGCCCGCG GCCTCGACGG CGTCGAGCAC CGACGCGACG AGCCGGTGGT
53581 CGGGGGCGAA TCGGTGCTCG GCGCCGGGTA TGGCGAGCAG CCAGGTGCCG GCGAGGGGGG
53641 GGACGGCGCC CGGGGCGTGC AGGACCGGCT CCCAGCGGAC GCCGTAGCGC CAACTGCCCA
53701 GCCGTGCGTG CTCCAGGTGG TCGCGCCGCC ATGCCGCGAG GGCGGGCAGC AGGGCGTCCG
53761 CCGACTCGCC GTCCTTCAGC CCGAG6GCGT CCAGGAGCGC GGCGGGGTCG GCCTCCAGCG
53821 CCTCCCACAG ACCCGAGTCG GCCGCCTGCG CGGCATGCGG CGCGGACGCT CCGGCCAGGG
53881 CCGAGGGGCG CCCGCCCCGG CCGGCCTCGG ATCCGGCCCC GGAGCCATTC GTGGTGCGCG
53941 GCGTCGGCGA GAAGCGGCTG CGCTGGAAGG GATAGGTGGG CAGGTGGGTC ACCCGGCCGT
54001 CGCTGTCGCG CAGCAGGGCG GCCCAGTCCA CGTCGAGACC GTGCACCCAG CCCTCGGGAG
54061 CCGAGGTGAG GAAGCGGTCG GCTCCGCCCG GGTCGCGGGG CAGCGTCGGC ACGGTCGCCG
54121 GTCGGACGCC CGCCTCCTCC GCGGTGCGTT CCATCGCCGC GGTGAGCAGC GGGTGCGGGC
54181 TGATTTCGAC GAATACGGCG TCCCCGGACT CGGCGAGGCG GCGGACCGCG GCCTCGAACT
54241 CCACCGGGGC CCGGAGGTTG CGCACCCAGT ACTCCGCGGT CAGTTCGCCG TCGCGGACCG
54301 GCTCGCGGGT GAGGGTGGAC AGCATCTCGA CCTCGGGGCG GCCCGGTGCG ACGTCCGCGA
54361 GCTCCGTCAG GATCCGCGGG CCGATCCGGT GGACGTGCGG CGAGTGCGAC GCGTAGTCGA
54421 CCGCGATCCG CCGGAGGCGC ACGTTGTCGG CCTCGCAGAC GGTGAAGAAC TCGTCCAGCG
54481 CGTCGGCGTC GCGGGACACC ACGGTGGCCT CGGGGCCGTT GGCGGCGGCG AGGAAGACGC
54541 GGCCTTGGAA GGGCGCGAGG CGGGGGGCGG TCTCGGCTCG GCCGAGCGCG ACGGACAGCA
54601 TGCCGCCGGC GCCCGCGATC CCGGTCAGCG TGGGGCTGCG CAAGGCCAGG ATCTTCGCGG
54661 CGTGTTCGAG GCTGAGGGCG CCCGCGACGC AGGCCGCCGC GACCTCGCCC TGGGAGTGGC
54721 CGACCACCGT GTGGGGGCGG ACGCCGACGG AGCGGCACAG CTCGGCCAGG GACACCATCA
54781 TCGCGAACAG CACGGGCTGG AGGAGGTCGA CCCGGTCCAG GGACGGTTCG GCGGGGTCGC
54841 CGTTCAGCAC GTCGAGGAGC GACCAGTCGA CGTGCGGGGC GAGCGCGTCG GCGCAGTCGC
54901 GCACCCGCGC GGCGAACACC GGCGAGCTGT GCAGCAGTTC GCGAGCCATG GCGGCCCACT
54961 GCGCGCCCTG TCCGGGGAAG ACGAACACCA CCCGGCGGCG AGGGGCTGCG GCGCCGTCAC
55021 CGTCCACCCG GTTCGCGCTC GGCACGCCCG GGGCCAGCGA CTCGAGTTCG GCGACGACCG
55081 TCGGACGGTC GCCGCCGAGC ACGACGGCCC GCTGCTCGAA GGCCGTCCTG GTCGTCGCGA
55141 GCGACAGCGC CACATCGGCC AGGGGCGACT CGTCGGCGGT CAGGCGCCTG GCGATCAGCG
55201 GGGCCTGGGC CGACAGGGCG TCGGGGGTGC GTGCGGAGAC CAGGAAGGGC AGAACTCCCG
55261 ATCCCTGAGC CGGAGTTCCG GTGCCCTTGG CCGTCGGCGC GGGTACGTCC GGTTCCGGGT
55321 CGGGGGCCTG TTCGAGGATC ACGTGTGCGT TGGTGGCGCT GATGCCGAAG GACGAGATGC
55381 CGGCGCGGCG GGGCCGGTCG GTCCGCGGCC ACGGCTGTGC CTCGGTGAGC AGGCGGACGG
55441 CGCCCGCCGA CCAGTCGACG TGCGTGGCCG GCCGGTCGAC GTGCAGCGTG CGCGGCAGCA
55501 CGCCGTCGCG CATGGCCATC ACCATCTTGA TGATGCCGCC GACCCCGGCC GCGCCCTGCG
55561 TGTGACCCAG GTTCGACTTC AACGAACCAA GCCAGAGCGG GCGTTCGGCC GGGTGCTCGC
55621 GCCCGTAGGT GGCGAGCAGC GCCCGTGCCT CGATCGGGTC GCCGAGCGTC GTGCCGGTGC
55681 CGTGCGCCTC CACGACGTCG ACGTCTGCGG CCTGGACCTG CGCGTCCTGG AGGGCGCGCC
55741 AGATCACGCG CTCCTGCGCG GGGGCGCTCG GCGCGGCCAG ACCGTTGGAC GCGCCGTCCT
55801 GGTTGACCGC CGAACCGCGC ACGACGGCCA GCACGCGGTG CCCGTTGCGC TGCGCGTCCG
55861 AGAGGCGTTC GAGGACAAGC ATGCCGGCGC CCTCACCCCA GGAGGTGCCG TCGGCGGCGT
55921 CCGCGAAGGA CTTGCTGCGG CCGTCCGCGG CGAGGGCACG CTGCCGGGAG AACTCGGTGA
55981 AGGTGATGGG CGTCGGCATG ACTGTGACGC CGCCTGCGAG CGCCAGCGAG CATTCGCGGC
56041 GGCGCAGCGA CTGGGCGGCC AGATGCAGCG CCACCAGCGA CGACGAGCAG GCGGTGTCGA
56101 TCGTGACCGG GGGCCCGGAC AGCCCGAGGG CGTAGGAGAC ACGGCCCGAG ACGACGGGGC
56161 TGTTGTTGCC CCTCACGAGG TAGGCCTCGT ACTCCTCGGA CGAGGCCTGC AAGGGCACGT
56221 CGTAGAACGA GTAGTAGGCG CCGGTGAACA CGCCGGTCTC GCTCTCGGGC AGCGTGTCCG
56281 GGGCGATGCC GGCGCGCTCC AGGGACTCCC AGGCCACTTC GAGCATGAGG CGCTGCTGCG
56341 GGTCCATGGC GACGGCCTCG CGGGGCGAGA GGGCGAAGAA ACGTGCGTCG AACCAGGCGG
56401 CGCCGTGCAG GAACCCGCCC TCGCGGACGT ACGAGGTGCC CTCGTCGGTG CCGTCGCCGG
56461 CGAAGAGCGC GTGGAGGTCC CAGTCCCGGT CCTTGGGGAA GGCGCCGATC GCGTCGCGGC
56521 CCGTGCGCAC CAGGTCCCAC AGCGCCTCGG GGGAGTCGGA GCCGCCGGGG AAGCGGCAGC
56581 CCATGCCCAC GATCGGGATG GGCTCGGTGG CGCGGCGCTC GGTGTCCTTC AGGCGCCGGC
56641 GGGAGTCCTG GAGGTCGCCG GTGACCTTCC CCAGCGCCTG AAGAAGCTGT TCCTGGCTTA
56701 CGTCGTCAGA CATCCACGCG AGCGTTTTCC ACTGTCGGGC AAAGCACTGT CACTCGAAGC
56761 CCTTCTCGAT CAGCGCCAGC AGGTCGGAGG CGCTGGGGGT CGCGATGGCC GCGCCGCCGT
56821 CCGTGTCGTC GTCCGCGGCT TGTGCGGCCG GTTCGGTGTC GCGGGGTGTC TCGCGCAGCC
56881 GGGCGGCCAG CGCGCCGAGC CGGGTGGCGA GCCGGTCCCG GTCGGCGGCG GAGCCTTCGA
56941 GGTCCGCGAG CGACCGCTCC AGCGAGGCGA GGTCGGCCAG GGCGCGGGCG GCCTGTCCGC
57001 CGCCGTCCGG GACGGCTTGG CGGCAGAGGA ACGCGGCGAC GTCGGTCGGC GTCGGATGCT
57061 CGTAGACGAG CGTGGCGGGC AGGTCGAGAC CGGTGGACTC GCGCAGCCGG GTGCGGAGTT
57121 CGACGGCCAT GAGGGAGTCG AAGCCGAGGT CCTTGAAGGC GTGGTGCGGC GCGACGTCCC
57181 GGGCCGCGGC GTGACCGAGC ACGGCGGCGA TCTGGGCGCG CACTAGGTCG AGCGCGACGC
57241 GCTGCTGTTC GTCGGGACTG TGGCCGGCCA GCACTTTGGC GAAGTCCGGC GTGGTGCCGC
57301 GGGTCTCGTC GGTGCCCGGA CCCGCGCCGG TGAGGCCGGC GAGGTCGGAG GCGGCACCGG
57361 GCACCGGAAC GAGTCGGGCG AGCAGCGGGC TGGGGCGGGC GGCGGTGAAG ACGGCGGTGA
57421 AGCGTCCCCA GTCGACGTCC GCGACGGTGA CCGTGGTGTC GCCGTGCCGC AGCGCCCGGT
57481 CCAGGGCGGT GACGGCGAGT TCCGGCGCCA TCGGGGCGAT GCCGAGTCGG CGCAGGTCGT
57541 CACCGAAGCT CCCGGCAGGC ATGCCGCCGC CGTCCCAGGG GCCCCAGGCG ATGGCCTTGC
57601 CTGCGGCGCC CCGGGCGCGG CGCCGCTCCA TCAGCGCGTC GACATGCGCG TTCGAGGGGG
57661 CGTAGGCGCC GCGGGACGCG TTGCCCCAGA CGGCTGCGAC GGAGGTGAAG GCGACGAACG
57721 CCGACAGGCC GTCGCCGAAG AGCTCGTCGA GGTTGCGGGC GCCGGTCACC TTCGGCGCCA
57781 TGACGGTCGG GAAGGTGTCG GCGTCGAGCG CGGCGACGGG GTTCTGGTCC CCGGTGCCCG
57841 CGGCGTGCAC CACCGCGGCG AGGGGCGTGT CCGCGGCGGC GAACCGGGCG GCCAGTTCCT
57901 CGACGTCGGC CCGGCGGGAG ACGTCGCAGT CCGCGAGGAC GAGTTCGGTG CCGTGCCGCG
57961 CCAGTTCGGC GCGGAGCCGG TGCGCGTCGG CGAAGCCACT GGCGCGGGGG CTGGCGAGCA
58021 CGACGATGGG CGCGCCGGAC TCGGCGAGCC GGCGGGCGGT GTGGACGGCG AGGGCGCCGG
58081 TGCCGGTGAT CAGCACCGGT CCCGAGGACC ACAGGTCCGC GTCCTCGGTG TCCTCGGCGG
58141 GCCGTTCGTG GGGGCTCACG GTCGGCTCGG CGCGGGTCAG GCGCGGGGCG TGGACGCTGT
58201 CGTCCCGCAG CGCGAGCTGG TCGTCGCCGC CGGATCGCCC GGCGAGGACG GCGGCCAGCC
58261 GGGCGAGCCC GCCGCAGCCG AGGGGATCGT CGTCCGTGCT CGCCGCGAGG TCGATCAACG
58321 CGCCCCAGAG TCCCGGGTGT TCGAGTCCGA CGACCCGGCC GAGGCCCCAG ACCTGGGCCT
58381 GCCACGGGTC CGGCGCCGCG TCACTCTCCA GCGCCCGCAC CGGGCCACGG GTCAGGGTCC
58441 ACAGCGGCGG GTCCGTGCGG CCCGTGTCGA GCAGAGCCTG TACGAGCAGC AGGGTGGCGT
58501 CCGCGGCGGC CGACACGCCG TCGCGGCGCG CGGTCTCACC GCTCGGCCAG GGCAGGGCGA
58561 GCACGCCCGC GAACCGCTCG TCCGACGCCG GGGTCCGGTC CAGTTGCCGG GCGAGTTCCT
58621 TCGCCAGGGT CGCGCGATCG GCGGTCGCCA CGTCGACCGT CAGGAGGCGG GTCGTCGCGC
58681 CCGCGTGGGC.CAGTGCGGCC GTGACGGCGT CGGCGAGCGC GGCCGACGCG CGGTCTTCGG
58741 CGGTGTCGGC GTCGGATTCG GGGGCGACGA TGAGCCAGGT GCCGTCAAGT GCCGCCGCCG
58801 GGGGCGCGGC GTCCGGAAGA CGTTCCCAGG TGACGTCGTA GCGCCACCTG TCGGTTCTGG
58861 CGATCATGTC CTGTCCGCGC CGCCAGTTGC CGAGCGCGGG GAGCACGGCG CTCACCGGCG
58921 CGTCGGCGCC GAGGCCGAGC GTGGGGGCCA GGCGGTCGAG GTTCTGCTCC TCGACGACCT
58981 GCCAGAACGC CGTGTCCTCC GCGCTGTGCG TGCCGTCCGG CGCGGCCGGA ACGTCCGCCG
59041 TGTCCGGTGC GGCGTCCAGC CAGTAGCGCC GGTGCCGGAA GGCGTACGTC GGCAGTGCGA
59101 CACGCCGGGC GCGGGGCGTG AGCGCGGTCC AGTCGACCGG CACGCCGTTG ACGTAGGTCC
59161 GGCTCAGCGC GGTCAGCACG GTCGCCGCCT CCGGCCGGCC GCGCCGGGAG GAGGCCGCGA
59221 CGGGCCGAGT CCCCTCGAAC AGCGGCGTCA GGGCGGCGTC CGGGCCGATC TCGATCAGCA
59281 CGTCCGCGTC CGGCAGGCCG CGCACCGCGT CGGCGAAGCG CACCGCGCGC CGCGCGTGCT
59341 CGATCCAGTA CTCGGGGGTG TCGAAGGCGT GCGTGGTGTC CGCGGCCGGG CTGACCTGGA
59401 TCTCGGCCGG GTGGAAGGTG AGGCCGTCGA CCACGGCGGC GAACTGCGCA AGCATCGGTT
59461 CCATCAGCGG GGAGTGGAAC GCATGGCTCA CCGGCAGCCG GGTCGTCCTG CGGCCCTCGC
59521 CGCGCCAGTG CTGCGCGATG CGCGTGACCG CGTCCTCGGC TCCCGAGACG ACGACCGCGG
59581 AAGGCCCGTT CACCGCCGCG ATCTCGGCTT CGGAAGTGTC CAGGAGGTAG GCGAGGCTCG
59641 CGGCGACCTC GTCGTCGGTC GCGTGGATCG CGACCATCGC GCCGCCCTCG GGCAGCGCCT
59701 GCATCAGGCG TCCGCGGGCG ACCACGAGCC GGGCGGCGTC CTCGACGGAC AGCACGCCGG
59761 CGACCACGGC CGCCGCGATC TCCCCGACGG AGTGCCCGGC GAGGGCCGAG AACTCGACGC
59821 CCCACGACAT CCACAGTCGC GCCATGGCGA GTTCGAAGGC GAACAGGGCG GGCTGCGCGA
59881 ACTCGGTTCG CTCCAGCACC TCCGCGGGCT CCTGCCACAG TACGTCGCGC AGCGGACGTC
59941 CGAGCAGGGG GTGGATCACG TCGCAGATGT CGTCCAGGGC GGCGGCGAAC ACCGGGAAGT
60001 GCTCGGCGAG TTGACGCCCC ATCGCGGGCC GCTGTGCTCC CTGGCCGGAA AACAGCGCCG
60061 CGGCCCGTGT GCCGCCCGTG GTGCCGGCCT CGGGACCGGT GACCGCCTCG GCCGGGTGCA
60121 CCGCGTCCGG GGTACCGAGG GCCGCGAGCG CACCGAGCAG GCCGTCGCGG TCCTCCGCGA
60181 CGACCACCGC GCGGTGGTGG AAGTCGCTGG GCGTGGCGGC CAGCGAATAC GCCACGTCCC
60241 GGAGACCGAG TCCGGGGTTG GCGAGCAGGT GGCCGTGCAG GGCTCGGGCC TGTGCGTGCA
60301 GACCGTCCCG CGTACGGGCG TTGACGGGGA TCGCGACGGC GACGGGGGCG TCGTCGTCCG
60361 TAGCGGCCTC GGGGCTCTGC GGCACGTGCC GCGCGTCGCC CTCTTCCAGG ACCACGTGCG
60421 CGTTCGTGCG GCTGATGCCG AACGACGACA CCGCCGCCAG CCGGGGACGC TCCGTGCGCG
60481 GCCAGGGCCG TTCCTCCGTC AGCAGCTCCA GCGCGCCCGC CGACCAGTCC ACGTCGCTGG
60541 AGGGCTTCTC GGCGTGCAGG GTCCTGGGCA GCAGTTCGTG GCGCAGCGCC TGCACCATCT
60601 TGATCACGCC GCCGACACGC GCCGCCGCCT GGGCATGGCC GATGTTCGAC TTGAGGGAGC
60661 CGAGGTACAC CGGGCGGCCT GCCGGAGGCC GCGCGCCGTA CTCGGCGAGC ACGGCCTGCG
60721 CCTCGATCGG GTCGCCGAGC CGGGTGGCGG TGCCGTGCGC CTCGACCGCA TCGACGTCGG
60781 CGGCGGGGAC GCGCGCCTGC TCCAGCGCGG CCTGGATGAC GCGGTGCTGG GCCGGCCGGT
60841 TCGGGGCGGT CAGACCGTTG GACGGGCCGT CCTGGTTCAC CGCGGAGCCG CGCACCACGG
60901 CCAGGACGTC GTGCCCGAGG CGCGGCGCGT GGGAGAGCCG TTCCACCGCG AGCACGCGCA
60961 CGCCCTCGGC CCAGCCGGTG CCGTGCGCGT CGTCGGAGAA CGACTTGCAG CGGCCGTCCG
61021 CGGCCAGGCC GCCCTGGCGG GCGAACTCGA CGAAGAGGTG CGGCGAGGCC ATGACGGTCG
61081 CCCCGCCCGC GAGGGGGAGA TCGCATTCGC CCGCGCGCAG TGCCTGGCAG GCCAGGTGCA
61141 GGGCGACGAG GGAGGACGAG CAGGCGGTGT CCAGGGTGAC CGCGGGGCCT TCGAGACCGA
61201 GCAGATAGGA GACCCGGCCG GAGATCACGC TGTTGCTGTT GGCGATCCGG ATGATGCCTT
61261 CGAGGGTCTC CGGGGTGCCG TTCAGCCTGC TGAAGTAGTC GTTGTACATG ACGCCCGCGA
61321 ACACAGCGGT GCGGCTGCCG CGCAGCGTCT TGGGGTCGAT CCCGGCGTGC TCGACGCTCT
61381 CCCAGGGTGC CTCCAGCAGG AGCCGCTGCT GCGGGTCCAT CGGCAGCGCC TCGCGGGGAG
61441 GGATGCCGAA GAAGGCGGCG TCGAACCCGG CGGGGTCGTC GAGGAATCCG CCGCCACGGG
61501 CGTACGTGGT GCCGGTCGCG GCGGGGTCGG GGCTGTAGAT GGGCGTCAGG TCCCAGCCGC
61561 GGTCGGCGGG GAAGGGCGCG ATGGCGTCAC GGCCCTCGGC CAGCAGCCGC CAGAGGTCGT
61621 CGGGCGGGCT GACGCCGCCG GGGTAGCGGC AGGCCATGGC GACGATCGCG ATGGGCTCGT
61681 CCCGCTCCGT CCTGCCGGTG GTGAAGTCGG GCTTCCTGTC GGGCATTACG GTGTCGCCGG
61741 TCCCCGTGGG CGGTGCGAGC CGTATTTCCA GGTGGCGGGC GAGCGCGGCC GACGTCGGGT
61801 GGTCGAAGAC GAGCGTCGCG GGGAGGTGGA CACCGGTCTC GGCGGAGAGC CGGTTGCGCA
61861 GTTGCACCGA CATGAGCGAG TCGAAGCCCA GCTCGCCGAG CGGGCGATCG GCGTCGATCC
61921 GGCCCGCGTC GGCGTGGCCG ACCGCCGCGG CGATCTCGGC GCGCACAAGG TCGAGGAGAT
61981 CCGTGCCCCG GTAGGCGGAC CGCGCGGGGC GCGCCCCTGC GGCGGCGCGG GGCGCGGCGC
62041 CGGACGATGC CGCGCCGCGC GCCCGTACGA GGTCGGTGAA CAGCGGGGCC GGGCGGACGG
62101 CGGTGAACAG CGGCAGGAAC CGCGACCAGG CGACGTCCGC GAGGAGGCAG TCGGTGCCGA
62161 GCGCGAGCGA GCGGGCCAGC GCGGTCACGG CGTCGGCCGC GGGCAGCGGG ATCAGGCCGC
62221 TGCGACGGAA CCGCTGTTCC CGGGTCGCGT CCAGCATGCC GCCGCCCGCC CACGGTCCGA
62281 AGGCGAGGGA CGTCGCGGCG CGGCCCTGGG CACGGCGGCG CGCGGCGAGC GCGTCCAGTG
62341 CGGCGTTGCC GGCGCCGTAC CGGGCCTGCC CGGGGGCGCC CCAGATTCCG GATACGGAGG
62401 AGAAGAGGAG GAAGGCATCG AGGCCGGCGT CGGCGAGCAC GTCGTCGAGG ACGAGGGCGC
62461 CGCGCGTCTT CGCGTCGAGC ACGGCGCGGA AGTCGTCCGC ATCCGTCTCC AGCAGCGGGG
62521 CCTCGTGCGC GATGCCGGCG GCGTGGAAGA CGGCGCGGAT CGGCGCGCCC GACGCCGCGG
62581 CCTCCTGGAC GACAGCGGCC ATCGCGGCGC GGTCGGCGGT GTCGGCGGCG ACGACGCGCA
62641 CCGGGACGCC GGTGGGGGAC AGCTCCTCCA GCAGCTCCGC GGCGCCGGGC GGTTCGGGGC
62701 CGCGGCGGGA GACCAGCAGC AACGAGCATC CGTCCGCGAC CTGTTGCGTT GCGGACCCGG
62761 CCGCCAGTCC CGCGACCCAG CGGGCGACGT GCCCGCCGAG CGCCCCCGTG CCGCCGGTGA
62821 TCAGCACCGT GCCGGAGGGC TGCCAGTGCG TGAGGTCCTG GTTCGGCGCC GGGTCGTTGT
62881 CCGGTGCGGA CCTGACGACG GGTGGTACCT CGAGCCCGTC GCCCGCCACG CGTACCTGGT
62941 CCTCCCGGGT GTCCCCGGCG AGGAGGGCGG CCAACTGTCC GAGGGGCGGT TCGGCGCCGT
63001 CGGCAGGCAG GTCGATCAAG CCGCCCCAGG TATCGGGCAG TTCGAGGGCG GCGGCGCGGC
63061 CGGCTCCCCA GACCGCCGCG GCGTCCGGGT CGGTGCCGCT GTCCCGGGTC AGGCACCACA
63121 CCTTGGCGGT CACGCGGGCG TCGGTGAGCG CCTGGAGCGC GGTCAGCAGG GTCTCGGGGC
63181 GGTCCGCGAA GCACAGTAGG CCCGCGAAGC CGTCGGCGAT CGCGTCGGCC GGCTGAGCGG
63241 AGAGGGGGCA GAGGGCGGAC GCGAGCGTGG CGCGGTCCGC GGCCTCGTGC GGCGGGACGG
63301 TCACGGTGTG CTCGACGAGT TCGCCCACCC ACGCGGGGAT GTCCGACGCG CCGTCCGCCG
63361 CCGCGGGCGG GACGACCAGC CAGGTGCCCG GCACGGGGAC GGTACGCGGC GCGAGGTCGG
63421 CGGGCTGCCA TGTCAGCTCG TACCGCAGCC GGTCGAGGGC GGCGTCGGCC TGCGCCGACA
63481 ACCGGGCCGG GTCCGCCTCG CGGAGCACCA GCTCGCGGAC GGTGACGACC GGCTCTCCGT
63541 CGCTCGTCAG CGCGTCCAGC CGCGCGCTGT GCCCCGCAGT GCGCAGCCGG AGCCGTATCG
63601 GGGCGCCGTC CGCGGTGGCC GAGCCCCGCG ACGGGCACAG GGTGGCACCG TTGAAGGCGA
63661 ACGGCAGCCG GATCCGCCGG CTCTCGTCCC CGGTCAGGGC GAGCGGGTGC AGCGCGGCGT
63721 CGAGCAGCGC CGGGTGGATG CCGAAGCGCC CGTCGTACCG GCCGTCGGGC AGCGCGACCT
63781 CGGAGAACAG GTCGTCGCCC GCCCGCCATA CGGCACGCAG GCCGCGGAAG GCGGGTGCGT
63841 AGCCGTAGCC GCGGTCGGCC AGATCCGCGT ACAGGTGGTG GACCGGTACG GGTTGCGCCC
63901 CGGCGGGCGG CCACGCGCGC ACGGCCCAGT CGACGTCGCT GTGTTCGGGC TCGTGAGGTT
63961 CATGTCGTTC CGGCAGGGGC TCCGTGAGTG TCCCGGTGAC GTGCACCGTC CACTGGCCTG
64021 GCACGTGGCC CGTCGCCTGC CGCGCGCGAA TCGTCAGGTC AGGAGCGGCC GTCCCTTCCG
64081 ACGGGCCGAC GCAGACCTGA ACGTCCGGGC CGCCGTCGCC CGGCACCAGC GGGGCCTGGA
64141 TGACGAGTTC GGAGATCTCA CGGCAGCCCG CCTGCCGGGG GGGCTGTGCG GCCAGTTCGA
64201 CGAAGCGCGC GCCGGGGAAC AGGACGCTGC CGGGTATCGG GTGGTCCGCG AGCCACGGGT
64261 CGGCGGACGG GGAGATGTGG CCGGTGAGCA CGAGGCCGCC GGGGCCGGGC AGTTCCACCG
64321 CGCCGGACAG CAGCGGGTGC GCGAGCGGGT CGGTCCCGGC ACCGGCGGTC GCCCGGGGCG
64381 GCGCGAGCCA GTAGGTGTGG CGTTGGAACG CGTACGGAGG CAGGTCGACG AGGGGCGCGG
64441 CGGGCAGCAG CGGCGCCCAG TCGACGCGCA GGCCGTGTGC GTAGGCCTGG GCGAGGGTGG
64501 TGAGGACGGT GTGCGTCTCG GACCGGTCGC GCCGGGTGCT GGCGAGGACG GTACGCCCGT
64561 CGTCCCCATG GGCCTGCGCA GCACCCACCA TCGGTGCGAG GAGGGCGTCC GGGCCGATCT
64621 CCACGAGGAC GTCGGCGGCG GCGAGGCCGC GGACCGCGTC GTGGAAACGG ACCGCGTTGC
64681 GGGCGTGGTC GATCCAGTAG TCCGCGCTGT GGAAGGGGTG GTGGCTCGCC GCCGAGGCCG
64741 CGATAGGAGT CTTCGGAATG CTGAAGGTCA GGCCCCTGAC GACCTCGGCG AAGTCGTCGA
64801 GCATGGGCTC CATCAGAGCG GAGTGGAAGG CGTGGCTGAC ACGCAGGCGC GTCGTACGGC
64861 GTGCGGGACC GCGCCAGATC TCGCCCACGC GCTCCACGGC GTCGAGCGCA CCCGAGACGA
64921 GGACGGCATC GGGCCCGTTG ACGGCGGCGA TGTCCACGGC GCGGTCGGCC GCGTGCGGAC
64981 CGTCCGTGAC CGTGGCCAGC GTTTCGGCCG CCTCCGTCTC GCTCGCCGCG ATCGCGAGCA
65041 TCGCCCCGCC CTGGGGCAGC GCCTGCATCA ACCGGCCTCG GGCCACGACG AGTCGGGCGG
65101 CGTCCTGAAG GGTGAGCACC TCGGCGACGA CCGCGGCGGC GATCTCCCCG ACGGAGTGGC
65161 CGGCGAGGGC GGTGAAGGTC ACGCCCCAGG ACTGCCACAG GCGTGCCAGA GCGAATTCGA
65221 AGGCGAACAG GGCGGGTTGC GCGAACTCGG TGCGGGCGAC GGTCTGTGCG TCGGACTCCC
65281 ACATCACCTC TCGCAGGGGG CGCCCGAGGA GCGGGTCGAC GCAGGCGCAC ACCTGGTCGA
65341 GCGGGGCGGC GAAGGCCGGG AAGTGCGCGT CGAGTTCGCG GCCCATGCCG GGCCGCTGCG
65401 CACCCTGGCC GGTGAACAGC GCGGCGACCC GTCCGGCGCC CGCCTCGACC GGGGCGGTGT
65461 CGGCGAGCCC GGCGAGCAGG CCCGCGCGGT CCCCGGCGAG CGCGACGCGG TGGGCGAACA
65521 GCGACCTGTG GTCCACGAGG TTGCGGGCGG CGTCCACGAT CGGCAGCCCG GGGTGGAGCG
65581 CCAAGTGGTC AGGCAGCGCG GTCGCCTGGG CCCGGGCCGC TTCGGGCGTC TTGCCGGAGA
65641 CGACCACCGG GACGGCGACG CGCGGGCAGT CCTGGCCGTT CGCGGCGGAG TCCTGATCCA
65701 CGGACCGCCG GGTGTTCGCG GCGGAACCCT GGCCCGCGAG CCGCTGCGCG TCCGCGGTCG
65761 CACCCGCGTC CTCGGACACG AACTCCTCGA GGATGACGTG CGCGTTGGTG CCGCTCATGC
65821 GGAACGACGA GATGCCCGCC CGGCGCGGGC CGGCCGGGGC GTCCCATTCC CGGGCCTGCG
65881 CGAGCAGCCG CACCGTTGGG GCCGACCAGT CCACCTCGGT CGTGGGGTTC TCCGCGTACA
65941 GGCTGGTGGG CATGACGCCG TGGCGCATCG CCTGCACCAT CTTGATGACG CCCGCGACAC
66001 CGGCCGCCGC CTGTGTGTGC GCGAGGTTCG ACTTGAGCGA GCCGAGGTAG AGCGGGCGGC
66061 CGGCCCGGCG GCTGCGCCCG TAGGTGGCCA TCAGCGCCTG TGCGTCGATG GGGTCGCCGA
66121 GCCGGGTGCC GGTGCCGTGC GCCTCGACGA CGTCGACCTC GTCGGCCGAG AGCCCTGCGC
66181 TGCTCAGGGC CGTCTCGATG AGGCGCTGCT GAGCCGGGCC GCTCGGTGCG GTCAGGCCGT
66241 TGGACGCGCC GTCCTGGTTC ACCGCGGACC CACGCACCAC GGCCAGCACA CGGTGGCCCA
66301 GCCGCCGGGC GTCCGACAGC CGCTCCAGAG CCAGGACGCC CACGCCCTCC GACCATCCGG
66361 TGCGGTCGCC GTCGTCGGCG AAGGAGCGGC AGCGCCCGTC GGTGGAGACG ACCCGCTGGC
66421 GGCTGTACTC GATGAAGAAC AGGGGGCTGG ACATCACCGC GACGCCGCCG GCCAGCGCGA
66481 GATCGCACTC GCCGCTGCGC AGCGCCTGCG CGGCCAGGTG CAGCGAGACC AGCGAGGAGG
66541 AGCAGGCGGT GTCGACCGTG ACCGCGGGGC CTTCGAACCC GTACAGGTAC GAGACCCGGC
66601 CGACTGCCAT GCTGCCCGCG CTGCCCGAGT GGATATAGCC GTCGTATCCG TCGGGCGCGG
66661 CCGTGGCGAA CCGGCCGCCG TAGTCGTGGT GCATGACGCC GGTGAACACG CCCGTCCGGC
66721 TGCCGCGCAG GGTCGCCGGG GGAATGCCCG CGTCCTCCAA GGCCCGCCAG GTCGTCTCCA
66781 GCAGCAGCCG CTGTTGGGGG TCCATGGAGA AGGCCTCGCG GGGGCTGAGC CCGAAGAAGT
66841 CGGCGTCGAA CAGGTCGATG TCGCGGAGGA ATCCGCGCTC GCGCGTATAC GAACGGGCGG
66901 TCGCGTCGGG GTCGGGGTCG TAGAGGGCTG CGACGTCGCA GCCCCGGTCC GTCGGGAAGC
66961 CGGTGATCGC GTCGCGTCCC TCGGCCACCA GGTCCCACAG CTCCTCGGGC GAGGTCACCC
67021 CGCCCGGGTA GCGGCAGCTC ATGCCGACGA TCGCGATCGG CTCGCGGGCC GGGGCCTCCG
67081 CATCGCGCAG CCGGGATCGC GTACGTTGCA GGTCGGGGGT CACCTTCCGC AGGTAGTCGA
67141 CGAGCTGCTG TTGGTCAGTC ATGTTCCTCG CCCATCGGCG TACGGCGGGT TCGCTGGCTT
67201 CGCGAACCCG GCATCGAATG AACTGCACGA GCCCGCCGAC CGGATCGAAT CCGGCGGTCT
67261 TCGTCTCGGC TCTCAATGCG GGGCGGACTG CGGCGGCCGT GCCGAATCGG ATTTCTTCGA
67321 TCCAAGCACG GAAACAGCGG CGCCCCCTAC TCAGGCACCC CCCTAAAACA CCCGGCATGG
67381 GCTTCGGTTG GGGTTGGACC AGGGGTGATG CGGCAGCGCC GGATGGGCGG GCACGGCATG
67441 CAAGAGGCGG GCGGGGGCAG CGGGGATCGC GGCCGGCGCC CGGCGCGGTT CAGTCGTCCC
67501 CAGGGAACCG TGGATCAATG GCTCCACGAA CCACGGATCT ACGGATCTGG AGGGAACTGG
67561 AGGGGATACG GATCCGGAGG GGACACCAGA ATTCAGGATT CAGGAAGCCG GTGAGTCGGC
67621 ACGGTTCTCG GCGGCTCCCT CGGCACGCTC TTCGGCACAC CACCATGGCG GCTGTACGGT
67681 GGGCTGGGGG ACCGAGCCGA GAGCGGCCCG GATGGGCTGG GCGCCCGCCG AGACGGGCAG
67741 CACGCCGCGC ACCGGCTCCG GCGCGAACAG CGCCTCGCAG ATCGTGTCGG CGAGATCCGT
67801 CCTGGAGACC GTGCCCTCGG GCTGCGGGTC GGCGCGGCCG CGTACCGTGA CCAGGCCGGT
67861 GGCCGGGGAG TTGTCGAGCA TCCCGGGACG CAGCACGCAC CAGTCCAGGT CGTGTCCGGC
67921 GAGCTTCCGC TCCACGTCCC GGTTCTCCGC GAGGTACGAC TCCAGCTCGT CACCGAGCCT
67981 GGTGTGCAGC TCGTCGTCGG GCAGATATGC GCTGACCAGG ACGAAGCGCC GGATGCCGAC
68041 CAACTGCGCG ACCCCCATCA ACTCCCCTAC GAGCGAGGTG GACGAGGTGT CCGTGGCGTC
68101 CGGGCCCCAG GCGGTCCCGG TGGCCACGGC GATCCCGCCG CAGTCGCCCA TCGCCCGTAG
68161 CGCCGCGGGG CTGGTCCTGT GCGCCTCGGA CGCGATCACC AGCGGGTCTG TCCCTGCGGC
68221 CCGCAACGAC TCGCTGTGCC CGGCCTCCCC GATGAGCCCC ACCGGGGTCA GGCCGCGGGC
68281 GAGGATCGAC TCGGCGAGCC GCCGGCCCAG GGCGCTCGTG ACGGCGAGGA CGACGACGTT
68341 GTTCTTCCCC GCCATCGGCC CCGCCTGCGC CGTCCGTGCG GCTTCCGCCC TCAGCGCGGC
68401 ATCGGCTGTC CGCGGGGCGT CCGCCGTCTC ATCGGCTTTC GATATCGGGA TGTTCGAGAT
68461 GTCTTCTTTC ATCGGCTCGG TCGCCATATC AGTCCGCTCA CGCCACGTCC TGGATTTCCG
68521 CGGGCGTGTG GTCCGGAGCA CCGCGCGATT CGACGATGGC GCCGATCTCG GCGCGGCGGG
68581 TGATATCAAA TTTTCGGTAA ATACGGGTCA AGTGCTGTTC AATGGTGCTC GCGGTGACGT
68641 AGAGCGACTC CGCGATTTCG CGGTTCGTGT ATCCCTGAGC CGCCATTCTG GCGACATTCC
68701 ACTCGGCGGG GGTGAGGCTG CGCCCGTCGC GTCGTGCCGG GGGCGGCGGG ACCTTGCGCC
68761 TCGCCTGCGA TCCGCCGGAC ATCTCCGCAA GCGCCCACTG CGCCCCGCAG CCGCGCGCCG
68821 TCTTCTCGGC GAGCCGCATC GTCTTACGAC CGCCGGCCAG GTCTCCGGTG TGCTTGTAGA
68881 TCTGCGCGAG CTGGCCGAGC GCGCGGGCGT ATTCGAGTTC GTCGCCGCAG GACTGGAGAA
68941 CGGCGATGGA TTTCCGGCAC GCCAGCGCCC GTTCCCCCGG CGGGACCGTC GCCACCCGCA
69001 GGCGCAGCCC GATGCCGCGC GCCCGGGTGT TCGAGTCCGG CGAGAACGCC AGCTGCTCGT
69061 CGATGAGCTC CGCCGCCTCG GCGTACTCGT CCAGCTTCAG CAGCGCCTCC GCGAGGTCCA
69121 GGCGCCACGG CACCAGGCCC GGCATCTCCA TGCCCCAGGC CGTGAGGATG GCGCCGCAGC
69181 TGCGGAAATC CGCGACGGCG GCGCGCAGGG CGCCGGTCGC CAGCCGGAAA GGCCCGCGGG
69241 CGCGCAGGTA CACCAGGCGG TACGGGCTGG CCAGGTCCGC CTCGGTCATC GGGCGGGCGA
69301 GTTGCGCGGC TGCCTCCTCG AAGCGTCCTT GCTCGGTCAG CATCAGCGGG GACAGGCCGC
69361 GCGGCAGACC GGCGAGCACG CCCCACCGGT CCGCGTCCCA GCGCTCGAAG CCGCGGCGCA
69421 CGGCCGTCTG GGCCGCGACG AGGTCACCCT TCCAGCAGGC AGCGACCGCC TCGGCCACGC
69481 TGAGCATGGA GGCCAGCGGC AGCGGCATAC GTTCGTTGTC GGCGAGGGCG GCGTTGTGGG
69541 CGAGGGCGGC GTACCAGGGG GCGCGCGGGT CGAGTCGTCC CGTCGCCATC AGGCAGAACA
69601 GCGCCACGAG CATCGGCTCC AGGCTCGAAT AGTCGAAGTT GGCGGACTGG AGGATCTCCT
69661 CCGCGCAGGT CACCGCGGCT TCCGCGTCTT TCACGGCCTT CGCGGAACCT GCGGAATCCG
69721 CGGAACCCGT GGGCCGTGGA CCGGAGTTCG GCGCATCGGA GCACTGGACG CCCGGGGCGA
69781 GCAGCCACGA GAGCCGTTGC GCGCTGGACA GCCACGAGAA TCCCTCGGCG ATCAGCTGGG
69841 GGTGCGGCTG GTGGTCGGGC GCGGGCGCGT CCGGGCAGGC GTCGGGGAAC AGATGACGCA
69901 ACCACAGCCC GCTGAGCGTT CTCTGGACCT CGGCACGGAC ATCCGCGGCG CCGAGGGCGT
69961 CGCCGGGACT GACAGGACCG ACAGCGTTGC CGCGTCCAGG CGCGGGTTCG GCCAGGCGCA
70021 GCATGTCGGA CGCCTGGGCC ATCTCGCCGT GTCTGGCCAG ATGCCGGGAG AGACGGGCTA
70081 ACGAACCCGG CTTGAAAGTG CCGTCGGACG CGGCAGCCGC CAGGCGCCGC AGCCGCGGTG
70141 CGGTGAGCGC CGGGTCCATC CACCACACCA TGTCGGTGAT CCGGACGCCG GCCTCCTCCC
70201 GCAGGTCGGG CCCGGAGCCC CAGAACGAGG CGGACTCCAG GAGTTGGACA GCCAGCCGGT
70261 GCCGGCCGAG ACGCGAGGCG TGCTCGGCGG CCTCATAGAG GACCCCACCC GCCCAGGGCT
70321 GCGGCGCGAT CCCGGCCTCG TGCAGATACG GAGCGATCTC CCAGGCGGGC ACGCCCTGTT
70381 CGTGCAGGAC CTGGGCGGCA CGCAGCCGTA AGGACCGCAG TGGCGCGGGG TGCGTGGACC
70441 AGAGGACGGC GTCGCGCAGA TACGGATGGA GGGTCATGTC GGGGCGCACG ATCCCGCTCG
70501 CGATGGCCTG GCCCGCCACG TGGGAGACGT ACTCGGCATC CTTCTCCAGC ACGTTGCACA
70561 GCCGCTGGGG TGTGCACTGC GCGTCGAGGA CCGCGACGGC CTCCACCAGG TTCATCACCT
70621 CACGGGAGGT GTGCTCGCGG AGCCGCCGGG CCAGGCCGGC CGACGGAGGT CCGTCCGGCG
70681 CGTCCGGATC CCGGGCGATC GCGGCCGCGG CCTCGTGCAG CATCGCGAGG GTCAGGGCCG
70741 GGTTGCGGCC GGTGATCGGA TGGATCGCCT CTGCCAGAGG GTCGGCGCGG GGGGCGGGGA
70801 CGCGGGCGCG CGCCAGTTCA GCGACCGCGG CCCGGCCCAG CGGCCGTACG CGAACGCGCT
70861 CCGCCCAACC CGCGGCGAGC TCACGCAGTT CATCGACGAT CGAGGGCACC GTAGCGGCGC
70921 TGACGCCGGT CAGCAGGACC CTGATCCTTC CGGTGTGCGT GAGGCGGACC ACCTCGCGGA
70981 CGAACACCTG GGATTCGGGG GCCAGCAGGT CCGTCTCGTC CACCGCCAGC AGCAGCGAGC
71041 GGGTGGCGGC GGCCACGAGG CGCCGCGCGT GGTCGCCGGG CTCTCGCGCG CCGAACTCGC
71101 CCAGTTCCTC GGCGTATCCG ACGCCGCACA GACTGCCGCG CACGGTCAGG ACGCCGATCC
71161 CCATCCGTCG CGCTTCGGCG CACGCCGCTT CCAGCAAGGC CGTCTTGCCG CACAGGGCAG
71221 GGGCCTCGAT CACGCAGAGC CCGGCGCTGT CGGCCGGACG GCGTCGCAGC CATCGTCCTA
71281 GTTCGGCGAG CTCTCCATCG CGGTCGACGA GAGACACCGC ACAATTCGAC TCGGACCCGG
71341 AACTCGGCTT GGGCCGGCAA CTCGACCTGA ACACCGGGTT ACCACCGCCG GGTCGAGTCA
71401 TGGTTCACAC ATCGACGTCC CCGCGCGGCC GCCGCATATA ACACGCGGTG GACGTCTCGC
71461 GGGCCCTGAC AACGCGACAG GTGGTCAGCC CGCCCGTTCA GGGTGTAAGC GACAGCTTTC
71521 ATGGCTTCGT CTTTCGAAAG AGTGGATCGG CGGGCACGAA GGTGACCGCT GCTTTTGCCG
71581 TGGGCGACAG AGCGAGTGCA CAGCAAAGCG GTCCCCCAGT GCCTGGGCCC ATCGCCGGCG
71641 AATGAAAGGG TGGGCCGGCG CGATGGTCAA GTCATGCCGG CGGGGCGACA GACGGAGTGC
71701 GGGCCGCGCT GAGCAGGTCC GGTCCGGTCC GGTTCATCGT CCCCGTGACG CGACGACGCA
71761 GAGGCGGGCG TCCGGTGGGA CGCTTCGGAG CGAATTGCAT GATGAGACGT TCCCCCGTTG
71821 CGTAGTGCGG CCCACCGACC CCGGTACCGG CTGCCCTTTT CTGAATTCTT GCCCAACAGA
71881 CATGTGCGAT GGGGGATCAG GTTGGTCAAC AATGAGTTAA CCCTATGTGA GGTGAGGACA
71941 GCATGCTGCA AGGGCGTGGT CGAGTTGGCG ACATCCGGAC GCCGACCGGC CTCGGCCGCG
72001 GTGAACGTCA GCATCCCGCG GCCTACCGGC GCAGGGCAGC ACAGCCGACC GGGCTCACAC
72061 GGTGATCGCC TCCCCCTCCG GGACGATGGT CAGAGGCACC TCGGTCAGCG CCGCCGGGCT
72121 GAGGAACCGG GCCATCGACT CCTGACCGGT CCGGCTGAGC ATGATCTCGT GGATCTGGAC
72181 GAGACGGTTG GGGGGGACCT CGCGTACGTA GTCGGCCGCC CGGCCGAGCT GGGTCCACGG
72241 CCCGCTGGTG GGCAGCAGCA GCGTGTCGAG GGGCGCGGGC GGTACGTGGT ACGCGTCGCC
72301 GGGGTGGTGG ACCCGGCCGT CGACGAGGTA GCCGACGTTG GTGACGCGGG GGATGTCGCG
72361 GTGGATCGCG GCATGCAGGT CGCCGGACAC CGCCACGTCA AAACCGGCGA CGTCGAGGCG
72421 GTCGCCGTCC GCGACCGCGA CGACCTGGCC GCGCCGGGCC GCGCAGCGTC CGACCACACG
72481 GACCGGTCCG TAGACCCGCA GGCCGGGGCG GGCGTCCAGG GCCCGGGCGA TCAGGTCCTC
72541 GTCGAAGTGG TCGAAGTGGT CGTGCGTGAT CAGGAGGGCG TCGGCGGCGG CGACCACCTC
72601 GTTCGCGTCA GGGGTGAACG TGCCTGGGTC GATGGCGATC CGCCCACCGT CGTTGACCAG
72661 CGACACACAT GCGTGGGCGT GCTTGATCAG CTGCACTGCC GGCTCCTATC GGTGTGATGT
72721 ACAGGGTGCA CTGTAATACA GTCGCCCCTG TACTCTTTTG CTAGACTGGG GGGTGTGAAC
72781 GACGCGCGTT CGAACGAACC GGCCCCCCTC CCCGACGAGT TGGCGGTCCG CCTCCGGGCG
72841 GTTGTCGGCA CCCTGGTCCG TAGCGCCCGT ACCGTCGATC GGCTCGCATC CGTTCCGGCG
72901 GCGGTGCTCG GCCTCCTCGA CACGCGGGGG CCGATGACCA CGGCCGACCT GGCGGCGACC
72961 CGCGGAGTGC GCCACCAGAC GATGGCCGCG ACCGTCAGGG AACTGACCGA GGCCGGGTTC
73021 CTGGCCTCAC GCACCGATCC GGGCGATGCC CGGAGGAAGG TCCTCGCTCT GACGAAAGCG
73081 GGGAAGAAGG CGCTCGACAC GGACCGCCGT CAGCGCGTCG GCGTGCTTGC CGACGCGCTG
73141 GAGGAAACGC TGGACGATGA GGAGCGGGGC GCCTTGGCGC ACGCCCTTGA CCTCATCGAT
73201 CGGATCAGCG GCAGCATGCG GGGGGGCGAC TCCTTCTCCG GCGAGCGCGA GTTCAACACC
73261 GGAGCATGGT GACGAGGCCG GAGTAGCCTG CTCCGGCTGG TTTAGGCGCG TTTTCCACGC
73321 GCGCGCGAAC GCGTGGGGGT TGTCGAACAT GACGTTGTGG CCGGTGTCCG GGACGATGCG
73381 GAGCTTCACC CCCGCGCTCT CCGCAGCCCG TCCCTGCCGG GCAGTTCGCC GCGCGGGTCG
73441 CCCTGAAGGC GGATGCGTTC CATGCGTGCC CGCTCGGGCA TCACCCCCAT CGCCGGGCCG
73501 GTGCCGCGAT AGAGGTCAAA TGGCTGAGAA GTCCCTGGTG CGAGCGGATC CGTCGCCGCT
73561 ACCCGCGCGA GGGCGGCATG GACCAGCTCC ACCTCGAGCT CCCCGGACGT GCCTCCGCGC
73621 CGGCCAACAC CACCAAGACG ACGTCTCGTT GACCGGCTGC ACCACAAGAA AGGACATAAT
73681 CCCGATCTCG CTGGTTCGTC GGCGGCCCGG GGTGCCCGTT GAACGGTCGT GAACCGGGCT
73741 GAACGAGACG GAAACCGGGA CGGCCCGTAC GGGGCGTTGT CAGTGGCCTT ACCTCGTGCC
73801 GCATCAGACA GCGTTCACCC TGTAGCACCC CGGGAAAAGT CGTCGAAACA GTCTCCCTGC
73861 AGGAACCGAG GATGGCCCGC CTCCGGCCCT TGACGGCTGG CTGGGCGGAC GCGGACTCGG
73921 GGGCTAGAGT GGGTTGCTTG CCGGTGGCCT CCGGGGCTCG CAACGGCCCG TCCCAGCCGT
73981 CGCC

TABLE 4
FOSTRIECIN SYNTHASE GENE CLUSTER
ORF 8
MATETFEFQVEARQLLQLMIHSVYSNKDVFLRELVS SEQ ID NO.: 19
NASDALDKLRLAALRDDGLDADTSDPHIEIELDQKA
RTLTVRDNGIGMSYDEVGKLIGTIANSGTAAFLQEL
KEAQDAAGAEGLIGQFGVGFYSGFMVADEMTLVTRR
AGERSGTRWSSRGEGTYTLETVDDVPQGSAVTLHLK
PADADDQLHDYTSAWKIKEIVKRYSDFITWPVRLLP
QATDGEETPEPETLNSMKALWARSRDEVSDDEYHEL
YKHVSHDWRDPLETIRLQAEGTFEYQALLFLPAHAP
HDLFTRDFRRGLQLYVKRVLIMDDCEALLPPHLRFV
KGVVDAQDLSLNVSREILQQDRHIRMIQRRLTKKVL
SSVKEMKANDADKYAAFWREFGAVLKEGLLGDTDDR
DALLAVASFASTHAEETPTTLQQYVERMKEGQDDIY
YMTGASRQTIENSPHMEAFRDRGLEVLLLTDPVDEV
WVDVVGEFEGKRLRSVAKGEIDLDVQGGEQADGGRE
KQAETYAALLGWMKEHLGEEMKDVRLSTRLTVSPAC
VVSDAHDLTPALESMYRAMGQEIPSARRILELNPAH
PLVQGLNQAYQEGEDRSGLAETADLLYGLAVLAEGG
RPTHPGRFVKLVAERLERTLR*″
ORF7
MYAPTPKPSTDRQAWLRRYTNAPDARHRLVCLPHAG SEQ ID NO.: 18
GSASFYMPLARALAPEIDIVAVQYPGRQDRRADPFP
ATLQDLAAHVAEALCGEPAVPTAFFGHSMGAAVAFE
VIRLLEDSTTPVTALFASGRGAPSVNRGERVHAMSQ
EDVLAELRGLEGTDSRMFDDPEIIEMIMPPLRNDYR
LIETYRYVPGPPVACPIRGFLGAQDPKVDEGEMKLW
ADHTAGSFDLTLLPGGHFYLVQHQPEIVEAIRNTLL
VAPPYV*″
ORF6
MTDDAIPGRGRYTEQARAARLAWLLARTGATLDSAA SEQ ID NO.: 17
HTAIEAASLTGNLENFAGSVEVPVGLAGPLQFRGQG
VREAVVAPMATTEGALVASASRGARALSLAGGVSTR
VLSQRMSRAPAFEFDDLAGAARFSRWLGTRRPQLED
QVRLVSQHARLVAVDPYQIGRYLHVRFVFETADAAG
QNMTTAATWQICTWLNEVLADEPGLRPRNTLLEGNL
SSDKKVSSVSLLAGRGTRVTAECVIPGDVVASVLKT
TPAAIARGHRVAVIGGQQAGMTGYGINAANVIAALF
VATGQDIACVHESAVSVLSFDSDGDDLIATLLLPNL
VIGTVGGGTGLPDQRDWLGVLGCRGEGGTARLAEII
AGFALALDVSTASALVSGQFADAHRRLGRARRVDWL
RADDLGPGLLQPAMAERLDSPRLRVTDVVRAPAMVG
DGISTELGALGERRKLTGVIPMTVSWTEDDGPQTTA
ELVAKAKPRGEEIAAGIGRIASLCGPEVSSAWETWG
GGSDFPAAHRRELAVFRRPEGVLTSLLPVCYGIIED
EAREAYVILMERLDITTGPWSRTDVDRALRAIAPVH
GHWLGRDQQILAEGWLYRDGTTAHLVKARELWEALV
RHNAAELPELMTPQRTRTALAAAAEAEFWVQEMDAM
PRTLVHNDFNPRNISRQSERVTAYDWELATVAVPQR
DLAELLAFTLTPHSTTDEVDHHLEVHRAAVAAAAGP
DATVPQPEQWRRGYGLALREMLLSRLQLYTAAHSHR
ELPFLPAVLDTTFHLWNLEAARDGE*″
ORF5
MHTERILTEHHRFLATLDHPEQTQQTVLAELLAANG SEQ ID NO.: 16
ATSYLREHGLNERSGAEEFRKALPIRTQNAFGPWIE
RAIAGEDGVLTAERPVAFFSSSGSTGQEKRIPVTPT
YMKRCFLPFYHASFAVLLGAFPDLAADPGGVLNLWR
DPTSPHARTADGRPHLGPSQIDHRLFGEGGGPEDGA
AWATIPEQLSDADPWERAYLQLRLAAERDIKVLIGV
NPALIAGLPHQLAAQWPRIVEEIARGTVGGVPHTTP
DPRRAEQIARRADEYGVLDPYHLWPNLRAAVAWNSA
LASLYLPRVRERYGPGVRLFAAPIGSSEGPVAVPVD
DHPNAAPLYLPGCYFEFADAAEPIREDSPTVTAAEL
EPGRDYHLVLSHIGGLYRCAVNDVVHVVDHVGRTPR
IAYTGRDVLRTAGGVDLTERAVVRALAGTLADTGAE
LRNATVETGTDRFRAAIASALPGPLPAGFATLLDKH
LGETADGYRAARDAGALAPVEVLQVHQDAFQREWEH
AIRSGQRRTRVKDRIFQPAPDSWARITADERAHA*″
FosB (module 2)″
MPANDDKLRDYLKRVTADLHQTRLRIRDIEARKREP SEQ ID NO.: 7
IAIVGMACRYPGGVTDPEQLWELAAGGIDAVSGFPS
GRGWDLEGLYDPDPDAEGKVYVREGGFLHDAGQFDA
PFFGISRREALAIDPQQRLVLETSWEAVERAGIDPL
SLAGSRAGVFVGVMPQEYGPRLYEATGQGVSGHLLT
GTTTSVLSGRIAYTLGLEGPAVTLDTACSSSLVAMH
LATQALRSGECEVALAGGVTVMANPGTFVEFSRQRG
LAPDGRCKSFAAAADGTAWGEGVGMLVLERLGDARR
NGHRVLAVIRGSAVNQDGASNGLTAPNGPSQQRVIR
QALADAGLEAADIDAVEAHGTGTTLGDPIEAQALLA
TYGQGRFEGRPLWLGSLKSNIGHTQAAAGVGGVIKM
VMAMRGGVLPRTLHVDEPSPHVDWEAGEVRLLTGPV
VWEAGERPRRAAVSSFGISGTNAHLILEEPPVKERT
AYEAEADSADPAVWLVSAKSPDALRAQADRLTEFLA
ARPQTGTGHLARALATTRSQFEQRAALIGADRAGLT
EALSALASGSGHPSLVRGQVTTGRTAFLFSGQGSQR
PGAGRELYASYPVFAAAVDEACAVFDPLLGRSLREV
MFAGPGSEGAELLNRTAFTQPALFVLHTALFRLLES
FGVRPDHLVGHSIGELSAAHAAGMLSLADAATLVFH
RARLMQQITTPGTMLALQAGEATARGLVAGREDVVS
LAAVNAPESTVLSGDPEVLADIAAQLAERGIRSRRL
TVSHAFHSPHQDQILDEFRRIAAGLTYRAPRIPIVS
TLTGLLAEQDRITTADHWTEQLRHTVRHADAVTTLH
GLGTTRYLELTAHPTLAPLAAETLEDASAAPAALVP
TLRAGQPEPDTFLRALATLHVTGTPVTWFADHAEAD
ADNADTADGRGHERGRATVPHLDLPTYPFQHENYWL
TAPSSGTGPGAGADALPHPMLSQRTDLPGGGGVLFS
GRLAPGTDPWLPDHAVMGTLLLPGTGFVELALEAAR
AVGAGRVEELVLRAPMVFPGGRARDLQVWVAPDQGG
ERELLIRTRTPGEDWTLHATGVVTASRVDTDGFTPD
WTGAVWPPAGAEQIPGDTFYPDLAERGYEYGPAFRS
VKALWRRGDDLFAEVVLPEDQPYGFGAHPALLDASL
HALPITRSFYETDDEVRLPFSFGGVSLFATDVRRVR
VRLRPRPEATSVWITDAAGTPVLAMESLILRAVERT
QLQAAEGAVGQAATFAVRWEPLSEARIAERVPGTWL
LFGTARPGLAELFEHVLTSTEWDASASTPVEGVLVC
PADASELLAALRETERLDAPVWCVTSGAVGVGVDDP
ATDVAAAGAWGLGRVAALELPSRWAGLVDVPETADL
GTADDNAGRTTARLLAGVLTGDGAEDQLAVRDGRLW
ARRLGTAPAADAGTWQPKGTVLITGGTGGLGAHVAR
RLAALGTADRLVLLSRRGAESPGAAELLAELGESGV
RAEAAAIDITDRTAVTQLLSRLDAEDDPVRTVVHAA
GVIRYARIADVDPEAFETDMAAKVNGALLLDELLPD
ADEFVMFSSIAGIWGAADQAAYAAGNACLDALARRR
RERGASAVSIAWGPWSGGGMVTEYEDRELRKRGLLP
LAVPSAVEALERAVPGDTDPVVVDVAWSRFLPAFTV
LRPSPLLSGFAPADTAGGGRDAASAALPGAGTTAGA
LKDRVGALPEDERLPVLLDVVRTHVAQLIGRGDPQQ
VQADRALRELGFDSMMSVELRNRLGELVGARLPATL
AFDHPTPESLAERLLTELDLDEAPADDGPVLEDFDR
LEAKVLSPFTPADTRAALATRLSALLDRLSGTGTGA
GGAGRNSGTDDLETASASDLMQFLDAEYGASDGTAS
DPSRPTTS*″
FosA (modules 0-1)
MMPSCPAASAAYPACAWSGSTTPSPPWRARAPWPPR SEQ ID NO.: 6
SRVRCSPSSRRPTISCSSGVPPSGPRRSRASSPIVR
WKSSTSLRRWRRSAGPPRTAATPPYPSRVRFMSEGF
MPIAVVGMACRLPAAPDPATFWRLLSEGVDAVGETP
ADRWPDAAGTPTGAARYGAYLDRIDTFDPGFFGISP
HEARAMDPQQRLMLELSWEALEDAAIVPASLGGSGT
GVFVGAIWDDYRSVVARAGTASFNQHTMTGMGRGLI
ANRVSYTLGLRGPSMTVDAAQASSLVAVHLACESLR
RGESRVALAGGVNLIAAPEGMAASMSFGALSPDGRC
HTFDARANGYVRGEGGALVVLKPLEQARADGDFVYC
VIRGSAVNNDGATDGLTVPSAPAQTELLRAACRQAD
VAPGDVQYVELHGTGTAVGDPIEAAALGTAFGAGVG
RVADNALLVGSAKTNIGHLEGASGVVGLVKTALAIR
HRKLPPSLNFVTPNPKIAFDELSLRVQVGLTPWPRP
DGPIVAGVSSFGMGGTNCHVVLCDAPAESSAPSPAT
SSAAPPATVPVPVAVPQDVASPWLISARSEAALRGQ
AAALAAHLEQHPELDAATVARGLATIRTHHEHRAAA
FGGDRSALLSELRTLAQGRPSDGLLRGTAPDPGTGT
TPGTGPKTVFVFPGQGVQWAGTVRDLMATLPVFREH
VEAAAAALDPLTGWSLVDHLTGPETLPDTPDHVQPV
LFAVTTALAHTWRTLGVQPHAVLGHAAGEIAAAYSI
GALTLQDAAALVVARGRAHGEQAEAVRDALLDELSG
IEPRPSGTRFQSTTLGGPVDTAALDADHWYRNFRQP
APFHPAVEELMDDGHTVFIEVGPHAVLPPEILELLD
AAGAVGIPALGRGDGGRPRLLSSLAAAHVRGAAVDW
PALYGLPAARRVELPGYAFDRRRYWPEPTPTSAPVA
RQGAAAVPTPNPAAPAGAAVPASGPPVSASASVRDS
DWLRGLVEAAPAGRDEQLLDLIRDEAAAVLGHSDPR
EVDLARSFKDLGLESASGVELVERLGSVLQLRLPAT
LLYESPTPKVLAQVLGLELKGAARRATASAASAVTA
RPEKTSAVSAPASVRDSDWLRGLVEAAPAGRDEQLL
DLIRDEAAAVLGHSDPREVDLARSFNDLGLESQSAE
DLCERLAAVLQLSVPATLLYDSPTPRALARVLGAEL
AGTTQSDATSAASVSDEPIAIVGMACRYPGAADSPE
ALWQLVAEGADAIDVFPENRGWDLEGLYDPDPDAPG
RTYAREGGFLYEADRFDAQFFGISPREALAVDPQQR
LLLETSWEAVERAGIDPTGLAGSRTGVFVGATAMEY
GPRLHETVPETAGSVGGYLLTGSTVSVASGRIAYTF
GFEGPAMTVDTACSSSLVAAHLAARSLRNGECELAL
AGGAAVMASPGMFVEFARQRGLAGDGRCKSFSAAAD
GTSWAEGVGMLVLERLGDARRNGHRVLAVIRGSAVN
QDGASNGLTAPNGPSQQRVIRQALADAGLEAADVDA
VEAHGTGTALGDPIEARALLATYGQGRSEGRPLWLG
SLKSNIGHTQAAAGVGGVIKMVMAMRGGVLPRTLHV
DEPSPHVDWEAGEVRLLTGPVVWEAGERPRRAAVSS
FGISGTNAHLILEEPPVKERTAYEAEADSADPAVWL
VSAKKADALGEQAGRLAEFARTRTEVGIRRAARALA
TGRTHFDHRAAVVAQDRDALAEALSALASGAGHPMV
VRGRATVGRTAFLFSGQGSQRPGAGRELYASYPVFA
AAVDEACAVFDPLLGRSLREVMFAGPGSEGAELLNR
TAFTQPVLFVLHTALFRLLESFGVRPDHLVGHSIGE
LSAAHAAGMLSLADAATLVFHRARLMQQITTPGTML
ALQAGEATARGLVAGREDVVSLAAVNAPESTVLSGD
PEVLADIAAQLAERGIRSRRLTVSHAFHSPHQDQIL
DEFRRIAAGLTYRAPRIPIVSTLTGLLAEQDRITTA
DYWTEQLRRTVRHADAVTTLHGLGTTRYLELTPTPT
LATLVAETLEESPAALVPVLRHGRPEHDALLRALAT
LHTSGADVAWPALPGPRSAALPELPTYAFQRERYWL
TPPAPRADVTQAGLTGTPHPLLAAAVELPEGGGFVH
TGRIGTLTHPWLADHAIHGTTLLPGTALLDLVLHAA
SDGAGEHPAVAELALQAPLVLPGERGVDIRVTVQEA
DESGLRAFAVHSRPAPAGDDASGSSSWTRHASGALG
PTEAPDAADRAPQWPPADAAPVDLTDLYPALALTGY
EYGPDFRLLTAAWRTDDDVFAQVELGDDAAASDDVD
RFSVHPALLDASLHALLRSGLLADGVSGTDASGTLL
PFSWGDVALHALGATALRVRFTRTGPTTVRVVASDP
SGALILTAGELSLRPVVLDRLSDGSGTEAGGPRSLY
HVEWSATPAAAPVGAAAPDAPEQWALIGRSPVPDPV
STLAAEAVDIRTYPNLDALVHGTENGDPHPSVVLAD
LAAHGAELPAHEGERTGEHEGGAAGAHAVARRTLAL
LTSWLDAPALTVGRLVLVTHDATAAATAPDALGLPQ
ATAWGLVRSAQTENPGCFTLVDIDGDPSDGYAALPA
ALRTGEPQLAVRDGEVLVPRLARAAQDADVPWPAPA
DVAEQVGAAQRAPLGTGQVRIAVRAAGVDLRAPVLA
RDTPPDHDILGLEGAGVVTETGPGVSDLAVGDRVFG
LLTGNFGPQAVAERDTLARIPAGWTFTQAASVPVAF
LTAYHALVELAAVVPGERLLIHSVADGVGLAAAQLA
RHRGAEVFGTAGPGEWADLRAHGLDDTHLAPSHTQE
FAARFRAATGGAGVDVVLDCPAGDAVDASLRLLSSG
GRFVETGRTDTPDSEAVAARHPGVDHRSFDLTKLEP
AHVGAMLGELTELFERGALRPLPVAAWDVRRAQDAF
RHLSRPRHVGKVVLTVPAPLDPEGTVLITGGTGALG
GNVARHLVTRHGVRRLVLTGRRGPAAEGVTEIVAEL
PAAGAVEVTVEACDAADRTALARVVAAVPEAHPLTA
VVHAAGVLDDAPVEALTPERLDTVLRPKADAAWNLH
ELTAHADLSAFVLFSSVAGVIGHAGQGNYAAANAFL
DGLAAYRRHRCGLPAVAAAWGPWEHAAGGMTQALSA
TDLNRMARTGVLPLSTDEGLALFDATRDAAVPAVVP
VRLDLAALAESAGGAGRAGDVAEVPLLFRHVAPARP
VRRLPQAAATADGARLPAPRQTAVDAGPDLARRVAE
LPTEAARRGMLLELVQDSAAAVLGHATAATVDPERR
FKELSFDSLTALELRNRLGAVSGLRLPGTLIFDHPT
PLAVADFLYTRLASQTPRTATSDSLAVLAELDRLVD
TAIATDADEATLTRFTARLEDLLVWLHGRQEAGRPD
AEDAAGATDRFESASDDEIFDFIDNELGLT*″
FosK
MYSRRMPIIELAEYGPDFLADPYPYYAKLREEGPVH SEQ ID NO.: 15
EVRAPDGYRFWLIVGYAEGRAALTDSRLVKARDTMA
TSEASPLGKHVLIADPPDHTRLRKLISREFTVRRVD
NLRPRIQELTDDLLDVMLPAGRADLVEALARPLPIA
VLCELLGVPNADRDEFHSWAKGILAPQNPTETHTAV
KALMSYLDDLIEDKRHGEPTGDLLSGLIRTSIENGD
RLSSEEVRSTAFLLMIAGHETTANLISNGTRALLTH
RDQLDLLRSDMDLLDGAVEEMLRYDGSLESTTKRFT
GVPVQIGDTVIPPGETVLVSLASADRDPANFDDPDR
FDIRRGTPAGVGHLAFGHGIHYCLGASLARAEGRIA
FRALLERCPDLELDPEAPPFEWMPGVLVRGVQRLSL
RW*″
Fos J
MTSTDAVPTGTPPLTTDSSSETPPAYPMPKAPGCPM SEQ ID NO.: 14
DPPPVYRTLRAEQPVSKARLYNGREAWLISRHEDVR
KILSDSRASVDALNPGFPWLSEVAKAMNTAEGGVRP
LGRMDPPDHTELRRMLAPHFLIKRVRALRPATEELV
DGLIDRMLEGPSPADLVPALARPVPSTVVGWLLGVP
AEAMAREGETTARLEDEDGSAETAVAARGELEEQLK
ELVELRRAEPDGNIVSRLVGFADEGRLTETNLLMQI
GLLLGAGYDTTVKMITTGVLALLGHPEQAALLAKEP
ERAAGATEELLRYLTVAEFAPKRVAVEEIEIGGQTI
RPGDGIICLISSADRDESVYERPDELDIQRSARDHL
AFGSGIHLCVGHSVARMELEVVYGRLFSRIPQLRLA
VAPNEIPFSRGLDVQGAKSLPVTW*″
FosI
MKSYKALAGIPHLPRLFLWSMLARLNVSMLPIGLTL SEQ ID NO.: 13
VLVGWSDSYVAAGVLGGALTAGQALVGPARGRAADR
GAVRKLLVLTGIGYLVGLGALVTMTRTVPGGGWPIA
VLVALLTGMSTVPISQVSRAVWPKIVPGELGRTLFT
LEATGSEVVQTTGPLLTSLLVTALDPGYAVIACGVV
AFVGALAFAAALGSAGIRGGAERTAAKPQAETGTAA
ETGADAGTEGDTATSASAVTRASAPEPEERRTLFAL
PKFTLAIVVTLVMMAALFSVNLSLVAWARDSHESGL
SGVLIACWTIGSVVGGFGMGALRKDVPHSARFAANA
VGMALLAVLLPPVTETAPVWLVLVVLFLGGTAIAPS
MAGNFAQVSGAVPQERRAEAFGWLATAGTGGAALSM
PVTGVLLEASGPATSVAVGAALALCATVLSYIGSKR
AERNDGLVSARA*″
FosH
MPESTDAAAAVPEAHDLPLTLWGWQDWTVEPWERLP SEQ ID NO.: 12
GDEGYSSHTYLVRHDGVRHVVKAVRKDMGPKLTAGL
LVAQEVERHGIAAGGPLPTTGGEVTAYQGDFCYSLL
TYLDGERVDETDPAHLRAVGRTLGRIDSVLLHAPVP
EGVPRWNEVLELFLLEQDFLKGHDWIRRTLEQAGGA
LSPDDLTIGLINCDAAAKEFRVLGDTAGLLDWSEAM
YAPCMLELATTLSYLEDETDGEPLVRGYFEEGPADR
AELGFLADILRFRCAAEGWIYAARQNAGDETGTTAS
TWSNEKLIERARQNAENADRIAARFQVF*″
FosG″
MNTLSLLQGLPLHRSDPFSPPDGYAKVRAEAPVSPI SEQ ID NO.: 11
AFPDGNQGWLLTRHADVKAMLANPSFSSVREKAART
RRTEGRPTPLPGAFFTMDPPDHTRYRRLAASRFAVR
KIKALEPKIEQYTREHLDRMEETGGGPVDLVTAYAL
PIPSLIICDLLGVPYDARDDFQRWSLSILDTELSEE
EQQRTVLEGTKFMLDLIEDKKKNPSDDLISDLLDPA
EEKDRISEFEIAGMCGLMLMAGHESTSNMLSLGTLA
ALRNPDQLALLRSDPSLIDTAVEELLRYLSIVQFNF
ARLATEDVEIGGQLIKACETVVGSMAAANHDPEVYT
DPHRLRLDRAEERNLAFGHGIHLCIGHQLARVEMKV
TYLRLFERFPTLRLAVPFEDIEFRANSVVYGVNSLP
VAWDAPADHDPAP*″
FosF(module 8 and thioesterase)
MSTNEDKLRHYVKELTGDLLRTRGRLRELEAAGNEP SEQ ID NO.: 5
IALVGMACKYPGGVASPEDLWRLVAEGRDAISPFPA
DRGWDLGRLPAAGGGFLHDAAEFDAGFFGISPRDAA
AMDPQQRIALETCWEAVERSGISADSLRGKPVGVFM
GGAVQGYGLVGTEIVDAPEGVGGTGSASSVISGRVS
YSFGFEGPAVTVDTACSSSLVALHLAVQSLRAGECS
LALAGGVTVMATPYAFVEFGRQGGLSADGRCRSFSA
DAEGTGWSEGVGVVVLERLSDARRNGHEVLAVVRGS
AVNQDGASNGLTAPNGPSQQRVIVRALAGAGLSTSD
VDVMEAHGTGTRLGDPIEAQALIATYGQGRAEGRPL
WLGSLKSNIGHTQAAAGVGGVIKMVMAMRHGVLPRT
LHVSQPSPHVDWSAGAVELLTRARQWPQTGRARRAG
VSSFGISGTNAHVILEHEPVESTEAPVGSAQVPVES
TQALVVAGELPWVVSGRTEGAVRAQAARLAAFVAGR
GGGALDVGGVGLALVSSRSVFDHSAVVSGGSLDELL
AGVGGVARGDGSAAGGVVFERRVAGGVGVAFSGQGS
QRPGMGRELYGRFPVFAAALDEVCAEVEAQTGAELL
GVVFGDDAGVLEDTGVAQPALFAVEVALYRLAESFG
VRADVLIGHSLGELSAAYVAGVWSLADAVRVVVARA
RLMGSLPSGGRMVAVEATEEEVAPLVADVAAAGGMV
SLAAVNAPGAVVVSGQDAAVDQIADIFAGRGRRTRA
LAVSHAFHSPLMEPMLAEFADVLAQVEFRAPSIPVV
SNVTGTIADAEELCSPEYWVRHVREAVRFGDGVGAV
LAQGVATVVELGPDPVLTALGERVRAASAERDSAAR
DVAFVPTLSRRSTDTRAFLGMLARVHARGHQVDWTA
LGRADDLARELPTYAFQHEHHWLKGASVRPGSAASR
TAGSDGAFWKVVQEQDLQRLASDLGVDPDAPLHTVL
PALGDWHQTHIEASETDGWRYRVAWERPTAQHAPEG
PATLHGTWLIVVPEGDLRAGHLLDNDGLHDGLHGEV
RRVLTDAGAEVKSLSLAPEDIDRQTIAKLLNGLDDT
PAGVVSLLALSGREHTGPRGVGSGAWASVCLLQALL
DTGWSATRLWTLTRGAVRATASDDAPDPWQAQVWGL
GRVAALEHPTLWGGLVDLPAPDLSAADGHALAATAE
ASFGLAALLAGSSGEDQVALRADCARVRRLRPAGPD
GAPEPVRPVAPESLVAPEGADATGRTGDPQPPAARE
PWWSHGSVLITGGTGALGAHTARRLAEQGAPHLVLA
SRQGPDAPGAADLRAELAAHGATVDLVSCDVTSRDE
VAALAADLAGRGAPVGAVVHTAGVAAEHPLADLDAT
EFAAVVDAKVTGAVILDEVLGDGLAAFVVYSSIAGT
WGSTRGGAYAAGNAFLDALVERRRARRAAATTLAWG
PWSGGGMAGEEFRQEMQRRGLRPLTPRLATTALDRA
VRQEDTAIVVADLDWPRFIGVFTAGRPNHLFADFDD
TESGAGHPDAGRTGAAQPGEWQRLPDLPLADQRPYV
LDIVRREAARVLGHADAGTITEDQEFLALGFDSLAA
VELRGRLTVLTGLALPSSLVFDHPTLGALVTHLLDN
AAPGGDAGASPAPGVSAAPSASVAAAPPQDSNDSVV
GIYRKLSLQGRMQEVEAFLSSASALRTRFHGAEDLG
RGAHVTTLGHGEAEPQLVCFPPFAPVDGSLQFARLA
NHFRGRRRVSVVTVPGFMAGEPLAASLEVLIETLAE
AVLRAADGRPYALLGYSSSGWLAQAAATWLEERGTG
PVGVVLLDTYPPDSMTLEMRKANTYEVVERRMRFTS
MHYDGLTALGTYRGMFRGWQPRQLAVPTLFVRPDSC
IPGSPEEPMAGPDWQAAWPLDHEETQVPGDHCTMIG
EFSETTAAAVDEWLSRTPGLTRP*″
EasE (modules 6-7)
MASENQLLDYLKRVSAELHETRGRLQDVEDAAREPI SEQ ID NO.: 4
AVVGMACKYPGGVASPEDLWELVAEGRDAISPEPAD
RGWDLDGVGAGPASGGVAGDGSTSAPDGLLTAGGGF
LHDAAEFDAGFFGISPREAAAMDPQQRLLLETSWEA
IERTGIVPESLRGGDTGVFIGAGMQDYLGHLRESRA
TEASGFLITGNASSVLSGRLSYSFGFEGPAVTVDTA
CSSSLVALHLAVQSLRAGECSLALAGGVTVMATPYA
EVEFGRQGGLSADGRCRSFSADAEGTGWSEGVGVVV
LERLSDARRNGHEVLAVVRGSAVNQDGASNGLTAPN
GPSQQRVIVRALAGAGLSTSDVDVMEAHGTGTRLGD
PIEAQALIATYGQGRAEGRPLWLGSLKSNIGHTQAA
AGVGGVIKMVMAMRHGVLPRTLHVSQPSPHVDWSAG
AVELLTRARQWPETGRARRAGVSSEGISGTNAHVIL
EHEPVESTEAPVGSAQVPVGSVQARVESTEAPLVAG
ELPWVVSGRTEGAVRAQAARLAAEVAGRGGGAGALD
VGGVGLALVSSRSVFDHSAVVSGGSLDELLAGVGGV
ARGDGSAAGGVVLERRVAGGVGVAFSGQGSQRPGMG
RELYGRFPVFAAALDEVCAEVEAQTGAELLSVVFGD
DAGVLEDTGVAQPALFAVEVALYRLAESFGVRADVL
IGHSLGELSAAYVAGVWSLADAVRVVVARGRLMGSL
PSGGRMVAVEATEEEVSGWLVDGAVIAAVNGPAAVV
VSGVEGAVEAVVERARGGGRRATRLRVSHAFHSPLM
EPMLAGFAQVLARVEFRAPSIPVVSNVTGEVASAAE
LCSPEYWVRHVREAVRFGDGVGAVLAQGVATVVELG
PEAVLTAMGASHPGVVENGAVFLPTLGRRTGDVNGF
LTALARVHARGHQVDWTALGRANDLARELPTYAFQH
EHHWLAGNAASVDAAHLGMRAVDHPFLGAAVTLPGT
GGTVLTGTISPGTHPWLGDHVVLGSTLLPGTAFLEL
AFTAAARVGCAGVEELTLEAPLILDGGSAHVVQVLV
GEAEAAGGGRAITVHSRPVHAAEDAPWTRHATGTLR
SDAAEPAPVLAPEPSQVQAWPPRGATPVDLDAVYER
LIGLGFDYGPAFRGLHTAWRDGDTVYAEVRLPTRQT
DDAGRFSIHPALLDTALHSLALPDLLSGQDECHLPF
SWSGVTLHATAVSSARVRIRRLGEGATSVELLDEAG
AALATVRSLALRPVTLEQLRSARVSSVESLYGIAWS
PLESAGSAVSAAVSASGTGLALLDLGADWSVESVPA
RRHADLAALAAAIDADPAEAPRDVLIALPALGGVDG
DIAAATHQRTQTVLHLLQDWLKQPRFASVTATLLTR
GALAVDAAEAAAVDLASAAVGGLIRSAQLEHPGRFR
LIDTDGEEASLRALPTLLGTGNGTDIGTGTGVVAEP
QIALRAGVPSVPRLRAIAAPETTDADGSADAPAFSG
EGTVLITGGTGDLGSLFARHLVTVHGVRHLLLTSRR
GPDAPGAAELIAELEALGADVTLAACDMSDRSAVAE
LLAGVPGDHPLTGVVHTAGVLDDGLLESLTPAQLTK
VLRAKADAALHLHELTSRAPLSAFVLFSSVAGVFGG
AGQANYAAANAFLDALARRRRALGLPGVSLAWGLWS
TEGGMTAELDRANVARLKRTGLLEISREQGVTLFDA
ALAAAGAAFGASEAGPETVGTHADGLLVPARLNAPV
LDEQAAAGSLPAVFQAVVSTRPRPSSRVAGGTAATA
GSASAPLLAELRVADREERLQILGGLVAEKVAYVLG
HADREAVDRAQPFNRLGLDSLTAVELRNQLGAATGV
RLPATLVFDHPTPLAVAEELYDELARGVLGEPAGST
ALAVAEPAARASASHPQDAGDDPIVIVGMACKYPGG
VASPEDLWRLVAEGRDAISPEPADRGWDLDGIYDPD
PQQPGKTYTREGGFLHDAAQFDAEFFGISPREATAT
DPQQRLLLETSWEALESAGTRPETLTGSRTGVEMGV
MYNDYGARHLNRSPQGYEGYISNGSSGSIASGRVSY
SFGFEGPAVTVDTACSSSLVANHLAAQSLRAGECSM
ALAGGVTVMATPYAFVEFGRHGGLAVDGRCRSFSAD
ASGTGWSEGVGVVVLERLSDARRNGHEVLAVVRGSA
VNQDGASNGLTAPNGPSQQRVIRQALAGAGLSVADV
DAVEAHGTGTRLGDPIEAQALIATYGQGRAEGRPLW
LGSLKSNIGHTQAAAGVGGVIKMVMAMRHGVLPRTL
HVSQPSPHVDWSAGAVELLTRARQWPETGRARRAGV
SSFGISGTNAHVILEHEPVESTEAPVGSAQVPVGSV
QARVESTEAPLVAGELPWVVSGRTEGAVRAQAARLA
AFVAGRGGGAGALDVGGVGLALVSSRSVFDHSAVVS
GGSLDELLAGVGGVARGDGSAAGGVVLERRVAGGVG
VAFSGQGSQRPGMGRELYGRPPVFAAALDEVCAEVE
AQTGAELLSVVPGDDAGVLEDTGVAQPALFAVEVAL
YRLAESFGVRADVLIGHSLGELSAAYVAGVWSLADA
VRVVVARGRLMGSLPSGGRMVAVEATEEEVSGWLVD
GAVIAAVNGPAAVVVSGVEGAVEAVVERARGGGRRA
TRLRVSHAFHSPLMEPNLAGFAQVLARVEFRAPSIP
VVSNVTGEVASAAELCSPEYWVRHVREAVRFGDGVG
AVLAQGVATVVELGPEAVLTAMGASHPGVVENGAVF
LPTLGRRTGDVNGFLTALARVHARGHQVDWTALGRA
NDLARELPTYAFQHQRYWLDAPAPEPGVVEHVPEQA
VLLNAVAQQDVDGLAHTLGLAPDAPLTAVLPALQTW
SREQARLAAADALRYRVSWTELPSPTDAVPLDGTWL
VAVPGEPVEPDLVIAVEKALVDAGARVERCETAELR
ARLAAVAPRGVLCLPAVGAQRDRDRERGIATGALAV
LDLLHTVQDAGVDTRVWALTCDAVCAQADDAAPDPW
QAQVWGLGRVAALEHPTLWGGLTDVSGTSPAAQLTG
LAAALANTTGDDQIALRGELLLGRRLIRGTVPTSVP
EPETGSTAPWTDGSVLITGGTGALGAQTARWLARNG
ARTLVLTSRQGPAAPAVAALRTELEERGADVVVESC
DVTDAVALAALRDRLADAGTPVSTVVHTAGVASELP
LAELDEDGYAAVVRAKVVGAQVLDEVLGDGLAAFVV
YSSIAGVWGSARAGAYAAGNAHLDALIERRRAQGRP
GTALAWGPWGGGGMADERLTREMQARGVSALDPEEA
VAAFGRVVRADYGTVVLADTDWSRLADIFTVNRPSP
LFDPLRTVETERGGVGADGTAAGTAGADDVSGPGDS
DAGTAGATPFVARWTALSGGERRRVLVETVCTQAAA
ELGHASGGTIEPERPFQELCFDSLAAVGLRQRLEKL
TGLKLPATLVFDHPTPAALAQVVASALAERVGGASG
ASAVLGELDRLEAALAALDAGSDPAARGRITLRLSN
LLTRFQNADDEPTAASGAAETAAEQLDSATDDQLFD
LIEKEFGIS*″
FosD″ (module 5)
MSDDVSQEQLLQALRKVTGDLQDSRRRLKDTERRAT SEQ ID NO.: 3
EPIAIVGMGCRFPGGSDSPEALWDLVRTGRDAIGAF
PKDRDWDLDALFAGDGTEEGTSYVREGGFLHGAAWF
DAGFTGVSPREAVAMDPQQRLMLEVAWESLERAGIA
PDTLRESETGVFTGAYYSFYDVPLQASSEEYEGYLV
TGNNSAVVSGRVSYALGLSGPAVTIDTACSSSLVAL
HLAAQSLRRGECSLALAGGVTVMPTPITFTEFSRQR
GLAADGRSKSFADAADGTSWGEGAGMLVLERLSDAQ
RNGHRVLAVVRGSAVNQDGASNGLAAPSGPAQERVI
WRALQDAQVQAADVDVVEAHGTGTTLGDPIEARALL
ATYGREHPAERPLWLGSLKSNLGHTQGAAGVGGIIK
MVMAMRDGVLPRTLHVDRPATHVDWSAGAVRLLTEA
QPWPRTDRPRRAGISSFGISGTNAHVILEQAPDPEP
DVPAPTAKGTGTPAQGSGVLPFLVSARTPDALSAQA
RLICRRLTADESPLADVALSLATTRTAFEQRAVVLG
GDRATVVAELESLAAGVPSANRVDGDGAAAPRRRVV
EVFPGQGAQWAGMARELLHSSPVFAARVRECADALA
PHVDWSLLDVLNGEPGEPSLDRVDVVQPVLFAMMVS
LAELWRSVGVRPHTVVGHSQGEVAAACVAGALSLED
AAKIVALRSRTLTGIAGAGGMLSVALGRAETAARLA
PFEGRVFLAAANGPEATVVSGDADALDEFFTVCEAD
NVRVRRIAVDYASHSPHVDRTGPRILTELADVAPGR
PEVEMLSTVTGEPVRDGELTAEYWVRNLRAPVEFEA
AVRRLAESGDAVFVEISPHPLLTGAMERTAEEAGVR
PATVPTLRRDAGGADRFLTSAAEGWVHGLDVDWAAL
LRDSDGRVTDLPTYPFQRSRFWPTPRTTNGSGAGSE
ACRGGRPSALAGASAPHAAQAADSGLWEALEADPAA
LLDALGLKDGESADALLPALAAWRRDHLEQARLGSW
RYGVRWEPVLHAPGAVPALAGTWLLAIPGAEHGFGP
DHRLVGWVLDAVEAAGGRALLVELDPREDTDPAAWA
ASLHAAAADARPAGILSLLALDDRPLPGRPAVGRGL
AGTTLLVRALAQTNLPGRLWCLTHGAVGTDPTDPPA
APHAAAVWGLGRVAALEHPTLWGGLIDLPRAPREAD
GQDGRTAPDAATAAQLCAVLADPGDEDQLALRPTGV
LARRLVRTPFRLPDPTTGGRDGGQVSLSDTDTDTDT
DGNVGADAVWPREGTVLITGGTGALGSRLARRLAAQ
GAQHLLLTSRRGPEALDADGLGADLESMGARVTIAA
CDLADREAVRALLESVPADAPLVSVVHAAAVLDDAA
LENLDADRLDAVLGPKALGAWHLHELTAGLNLSSFV
LYSGFVGTVGGIGQGNYAAANAVLDALAEHRRAAGL
PALSIAWGPWGGGGLVDAATEQRMRRNCLPPIEPEL
GVRALDLALAQDGPASQVLAEIEWPLFADGFTAARP
SPLLAAFARSGEAADDGSDAGRSDGAGGAGGPTLAR
RLPGMARTDADRLLLDTVRDHAAAVLCYADPAALAV
DQPFKELGIDSMTAMALRNRLQRAAGVDLPATMVFD
HPTPKALAAQLHGLIQPEERAVTAESALAELYRVAQ
SLEELRLDAALRKAAASRLRALADGWEGKRSASETV
MFSSPSGSSSERGTPDTGALLESATEDEVLDFVTRQ
LGISPLEGPG*″
FosC (modules 3-4)
MPGVLGGCLSRGRRCFRAWIEEIRFGTAAAVRAALR SEQ ID NO.: 2
AETKTAGFDPVGGLVQFIRCRVREASEPAVRRWARN
MTDEQQLVEYLRKVTADLQRTRSRLRDAEAAAREPI
AIVGMSCRYPGGVTSPEELWELVAEGRDAITGFPTD
RGWDVAGLYDPDPDATGRSYTREGGFLGDIDLFDAD
FFGLSPREAFSMDPQQRLLLETTWRALEDAGIPPAT
LRGSRTGVFTGVMHHDYGGRFATAAPDGYEGYIHSG
SAGSMAVGRVSYLYGFEGPAVTVDTACSSSLVSLHL
AAQALRSGECDLALAGGVAVMSSPLFFIEYSRQRVV
STDGRCRSFADDGDGTGWSEGVGVLALERLSDARRL
GHRVLAVVRGSAVNQDGASNGLTAPSGPAQQRLIET
ALSSAGLSADEVDVVEAHGTGTRLGDPIEAQALMAT
YGRSRRAGRPLYLGSLKSNLGHTQAAAGVAGVIKMV
QANRHGVMPSSLYAENPTTEVDWSAGTVRLLAQARE
WDAPAGPRRAGISSFGMSGTNAHVILEEFVSEDAGA
TADAQRLAGQGSAANTRRSVDQDSAANGQDWARVAV
PVVVSGKTPEAARAQATALRDHLAVHPGLPIVDAAR
NLVDHRSLFAHRVAVAGDRAGLLAGLADTAPVEAGA
GRVAALFTGQGAQRPGMGRELDAHFPAFAAALDEVC
ACVDPLLGRGLREVMWESDAQTVARTEFAQPALFAF
EFALARLWQSWGVTFTALAGHSVGEIAAAVVAEVLT
LQDAARLVVARGRLMQALPEGGAMLAIAASETEAAE
TLATVTDGPHAADGAVDIAAVNGPDAVVVSGALDAV
ERVGEIWRGRGRRTTRLRVSHAFHSALMEPMLDDFA
EVVRGLTFSIPKTAIAASAASDHPFHSADYWIDHAR
NAVRFHDAVRGLAAADVLVEIGPDAVLAPMVGAAQA
HGDDGRTVLASTRRDRSETHTVLTTLAQAYAHGVRV
DWAALLPAAPLVDLPPYAFQRQSYWLAPPRATAGAG
TDALAHPLLSGAVELPGPGGLVLTGHISPSADPWLA
DHAIAGSVLFPGAGFVELAAQAARQAGCREISELVI
QAPLVPGDGGADVQVWVGPSEGTAGRELTIRARQAT
GQVPGQWTVHVTGTLTEPLPERHEPHEPERSDVDWA
VGAWPPAGAEPVPVQDLYADLADRGYGYGPAFRGLR
AVWRAGDDLFSEVALPDGRYDGRFGIHPALLDAALH
PLALTGDESRRIRLPFAFNGATVWPSRGSATADGAP
IRVRLRTAGDSARLDAVTSDGEPVVTVRELVLREAD
PARLSAQADAALDRLRYEVTWQPADLAPRTVPVPGT
WLVVPPAAADGASDIPAWVGELVEHTVTVPPHEAAD
RATLASALCALSAQPADAIADGFAGVLCFADRPETL
LTALQALTDARVTAKVWCLTRDSGTDPDAAAVWGAG
RAAALELPDTWGGLIDLPADGAEPPLGQLAALLAGD
TREDQVRVAGDGLEVRRVVRSAPDNDPAPNQDLTHW
QPSGTVLITGGTGALGGHVARWVAGLAAGSATQQVA
DGCSLLLVSRRGPEAPGAAELLEELSATGVPVRVVA
ADTADRAAMAAVVQEAAASGAPIRAVFHAAGIAHEA
PLLETDADDFRAVLDGKTRGALVLDDVLADAGLDAF
VLFSSVSGIWGAAGQAGYGAGNAALDALAARRRAQG
RAATSLAFGPWACGGMVDATREQRFRRSGLIPLPAA
DAVTALARSLALGTDCVLADVAWSRFLPLFTAVRPA
PLFTDLVRARGAASSGAAPRAAAGAGPARSAYRGTD
LLDLVRAEIAAAVCHADAGRIDADRPLGELGFDSLM
SVQLRNRLSAETGVQLPATLVFDHPTSAALARHLEI
RLAPPTGTGDTVMPDRKPDFTTGRTERDEPIAIVGM
ACRYPGGVSAPDDLWRLLAEGRDAIAPFPADRGWDL
TRIYSPDPAATGTTYARGGGELDDPAGFDAAFFGIP
PREALAMDPQQRLLLEAAWESVEHAGIDPKTLRGSR
TGVFAGVMYNDYFSRLNGTPESLEGITGIANSNSVM
SGRVSYLLGLEGPAVTLDTACSSSLVALHLACQALR
AGECDLALAGGATVMASPHLFVEFARQGGLAADGRC
KSFSDDADGTGWAEGVGVLAVERLSDARRLGHDVLA
VVRGSAVNQDGASNGLTAPNGPAQQRVIQAALEQAR
VAAADVDAVEAHGTGTRLGDPIEAQAVLAEYGARRP
AGRPVYLGSLKSNIGHAQAAAGVGGVIKMVQALRHE
LLPRTLHAEKPSSDVDWSAGALELLTEERPWPRTER
PRLAAVSSFGISGTNAHVVLEEGDARHVPQSPEAGT
DDDAPVAVAIPVNARTRDGLHAQARALHGHLVANPG
LGLRDVAYSLAATRSDFDHRAVVVAEDRDGLLGALA
ALGTPDAVHPAEAVTGPEAGTTGGTRAAALFSGQGA
QRPGMGRELAEHFPVFAAALDETCDVIDPLLGRPLR
DVLWQEPAEVLERTEFAQPALFAFELAMARLWMSWG
VEFSALAGHSVGEIAAAVVAGVLSVEDAARLVVARG
RLMQALPEGGAMVAIQATDDEVAASLAYLVDTSEAE
IAAVNGPSAVVVSGAEDAVTRIAEHWRGEGRRTTRL
RVSHAFHSPLMEPMLAQFAAVVDGLTFHPAEIQVSP
AADTTHAFDTPEYWTEHARRAVRFADAVRGLPDADV
LIEIGPDAALTPLFEGTRPVAASSRRGRPEAATVLT
ALSRTYVNGVPVDWTALTPGARRVALPTYAFRHRRY
WLDAAPDTADVPAAPDGTHSAEDTAFWQVVEEQNLD
GLAPTLGLGADAPLSAVLPALGNWRRGQDMTARTDR
WRYHVTWERLPDAAPPAAALDGTWLIVAPESDADTA
EDGASAALADAVTAALADAGATTRLLTVDVATADRA
TLAKELARELDRTPASDERFAGVLALPWPSGETARR
DGVSAAADATLLLVQALLDTGRTDPPLWTLTRGAVR
ALESDAAPDPWQAQVWGLGRVVGLEHPGLWGGLIDL
AASTDDDPLGCGGLARLAAVLACRSGGDDQLALRDD
SVHARRLTRAEPTVSPHERPAEDTEDADLWSSGPVL
ITGTGALAVHTARRLAESGAPIVVLASRRASGFADA
DRLRAELARHGTELVLADCDVSRRADVEELAARFAA
ADTPVGAVVHAAGTGDQNPVAALDADTFATVMAAKV
TGARNLDEVFGDGLSAFVAFTSVAGVWGNASGGAYA
ASNAHVDALMERRRARGAAGKAIAWGPWDGGGMAAG
SFGDDLRRLGIAPMAPELAVTALDRALRHGDTTVTV
ADVDWGRFTAVFTAARPSPLLAGLVPVPGAASDLAG
VTGAGPGTDETGGTTPDFAKVLAGHSPDEQQRVALD
LVRAQIAAVLGHAAARDVAPHHAFKDLGFDSLMAVE
LRTRLRESTGLDLPATLVYEHPTPTDVAAFLCRQAV
PDGGGQAARALADLASLERSLADLEGSAADRDRLAT
RLGALAARLRETPRDTEPAAQAADDDTDGGAAIATA
SASDLLALIEKGFE*″
ORF4
MATEPMKEDISNMPISKADETADAPRTADAALRAEA SEQ ID NO.: 10
ARTAQAGPMAGKKNVVVLGVTSALGRRLAESILARG
LTPVGLIGEAGHSESLRAAGTEPLVIASEADRTSPA
ALRAMGECGGIAVATGTGWGPDATDTSSTSLVGELM
GVAQLVGIRRFVLVSAYLPDDELHTRLGDELESYLA
EKRDVERKLAGHDLDWCVVRPGMLDNSPATGLVTVR
GGADPQPEGTVSRTDLAETICEALFAPEPVRGVLAV
SAGAQPIRAALGSVPQATVQPAWWCAEERAEGAAEK
RADSPAS*″
ORF3
MTRPGGGNPVFRSSCGPKPSSGSESNCAVSLVDRDG SEQ ID NO.: 9
ELAELGRWLRRRPADSAGLCVIEGPALCGKTALLEA
ACAEARRMGIGVLTVRGSVCGVGYAEELGEFGAREP
GEQARRLVAAATRSLLLAVDETDLLAPESQVFVREV
VRLTHTGRIRVLLTGVSAATVPSIVDELRELAAGWA
ERVRVRPLGRAAVAELARARVPGPRADALAEAIHPI
TGGNPGLTLAMLDEAAAAIGRDPDAPDGPPSAGLAR
RLREHTSREVMNLVEAVAVLDAQCTPERLWNVLEKD
AEYVSHVAGQAIASGIVRPDMTLHPYLRDAVLWSTH
PAGLRSLRLRAAQVLHEQGVPAWEIAPYLHEAGIAP
QPWAGGVLYEAAEHASRLGRHRLAVQLLESASFWGS
GPDLREEAGVRITDMVWWMDPALTAPRLRRLAAAAS
DGTFKPGSLARLSRHLARHGEMAQASDMLRLAEPAP
GRGNAVGAVSPGDALGAADVRAEVQRTLSGLWLRHL
FPDACPDAPAPDDQPHPQLIAEGFSWLSSAQRLSWL
LAPGVQCSDAPNSGPRPTGSADSAGSAKAVKDAEAA
VTCAEEILQSANFDYSSLEPMLVALFCLMATGRLDP
RAPWYAALADNAALADNERMPLPLASMLSVAEAVAA
WWKGDLVAAQTAVRRGFERWDADRWGVLAGLPRGLS
ALMLTEQGRFEEAAAQLARPMTEADLASPYGLVYLR
ARGRFRLATGALRAAVADERSCGAILTAWGMEMPGL
VPWRLDLAEALLKLEEYAEAAELIDEQLAFSPDSNT
RARGIGLRLRVATVPPGERALACRKSIAVLQSCGDE
LEYARALGQLAQIYKHTGDLAGGRKTMRLAEKTARG
CGAQWALAEMSGGSQARRKVPPPAARRDGRSLTPAE
WNVARMAAQGYTNREIAESLYVTASTIEQHLTRIYR
KFDIRRRAEIGAIVESRCAPDHTPAEIQDVA*″
ORF2
MQLIKHAHACVSLVKDGGRIAIDPGTFTPDAKEVVA SEQ ID NO.: 8
AADAVLITHDHFDHFDEDLIARALDARPGLRVYGPV
RVVGRWAARRGQVVAVADGDRLDVAGFDVAVSGDLH
AAIHRDIPRVTNVGYLVDGRVHHPGDAYHVPPAPVD
TLLLPTSGPWTQLGRAADYVREVAPNRLVQIHEIML
SRTGQESMARFLSPAALTEVPLTIVPEGEAITV″
ORF1
MNDAPSNEPAPLPDELAVRLRAVVGTLVRSARTVDR SEQ ID NO.: 20
LASVPAAVLGLLDTRGPMTTADLAATRGVRHQTMAA
TVRELTEAGFLASRTDPGDARRKVLALTKAGKKALD
TDRRQRVGVLADALEETLDDEDRRALAHALDLIDRI
SGSIRGGHSFSGEREFNTGAW*″

All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference.

Although the present invention has been described in detail with reference to specific embodiments, those of skill in the art will recognize that modifications and improvements are within the scope and spirit of the invention. Citation of publications and patent documents is not intended as an admission that any such document is pertinent prior art, nor does it constitute any admission as to the contents or date of the same. The invention having now been described by way of written description, those of skill in the art will recognize that the invention can be practiced in a variety of embodiments and that the foregoing description are for purposes of illustration and not limitation of the following claims.

Claims

1. A method of producing a polyketide, comprising culturing a cell under conditions under which the cell produces the polyketide, wherein said cell comprises a recombinant polynucleotide synthase that comprises at least one domain from the Streptomyces pulveraceus fostriecin polyketide synthase, and wherein said cell does not make the polyketide in the absence of said recombinant polynucleotide.

2. The method of claim 1 wherein the domain is encoded by a subsequence of SEQ ID NO:1 or a sequence that hybridizes under stringent conditions to a subsequence of SEQ ID NO:1.

3. The method of claim 1 wherein the cell is not Streptomyces pulveraceus.

4. The method of claim 3 wherein the polyketide is fostriecin, PD 113,270 or PD 113, 271.

5. The method of claim 4 further comprising recovering said polyketide from the cell.

6. A recombinant DNA molecule comprising a sequence encoding at least one domain of fostriecin polyketide synthase polypeptide.

7. The recombinant DNA molecule of claim 6 that encodes one or more modules of fostriecin polyketide synthase.

8. The recombinant DNA molecule of claim 6 that encodes a chimeric polyketide synthase (PKS) module composed of at least a portion of fostriecin PKS and at least a portion of a second PKS for a polyketide other than fostriecin.

9. The recombinant DNA molecule of claim 6 comprising a sequence encoding an open reading frame encoding a polypeptide encoded by fosA, fosB, fosC, fosD, fosE or fosF or encoding a conservative variant of such a polypeptide.

10. The recombinant DNA molecule of claim 6 that encodes a modified fostriecin polyketide synthase polypeptide that differs from the fostriecin polyketide synthase polypeptide encoded in SEQ ID NO:1 by inactivation of at least one fostriecin PKS domain.

11. A recombinant DNA expression vector comprising the DNA molecule of claim 6 operably linked to a promoter.

12. A host cell comprising the DNA molecule of claim 6.

13. A recombinant Streptomyces pulveraceus cell in which at least one domain-encoding region of an endogenous fostriecin polyketide synthase gene is deleted or otherwise inactivated.

14. The cell of claim 13 wherein said domain has been replaced by a different PKS domain.

15. A recombinant Streptomyces pulveraceus cell in which at least polypeptide-encoding ORF of the fostriecin polyketide synthase gene cluster is deleted or otherwise inactivated.

16. A method of producing a polyketide, which method comprises growing the recombinant host cell of claim 12 under conditions whereby a polyketide synthesized by a PKS comprising a protein encoded by said recombinant DNA molecule is produced in the cell and recovering the synthesized polyketide.

17. The method of claim 16 further comprising chemically modifying said recovered polyketide.

18. The method of claim 17 further comprising formulating said polyketide for administration to a mammal.

19. A method of producing a polyketide, which method comprises growing the recombinant host cell of claim 14 under conditions whereby a polyketide is produced in the cell and recovering the synthesized polyketide.

20. A method of producing a polyketide comprising (a) recombinantly modifying a gene in the fostriecin PKS gene cluster of a cell comprising said gene cluster to produce a recombinant cell, or obtaining a progeny of said recombinant cell; (b) growing said recombinant cell comprising a DNA encoding a modified or progeny under conditions whereby a polyketide other than fostriecin is synthesized by the cell and, (c) recovering the synthesized polyketide.

21. The method of claim 20 wherein said modifying comprises: (a) substitution of a fostriecin AT domain with an AT domain having a different specificity; (b) inactivation of a domain of a fostriecin polyketide synthase module, wherein said domain is selected from the group consisting of a KS domain, an AT domain, an ACP domain, a KR domain, a DH domain, and an ER domain; or, (c) substitution of KS domain, an ACP domain, a KR domain, a DH domain, or an ER domain with a domain having a different specificity.