MYCOBACTERIAL SPECIES-SPECIFIC REPORTER MYCOBACTERIOPHAGES

Abstract: This invention relates to mycobacterial species-specific reporter mycobacteriophages (reporter mycobacteriophages), methods of producing such reporter mycobacteriophages and the use of such reporter mycobacteriophages for the rapid diagnosis of mycobacterial infection and the assessment of drug susceptibilities of mycobacterial strains in clinical samples. In particular, this invention is directed to the production and use of luciferase reporter mycobacteriophages to diagnose tuberculosis. The mycobacterial species-specific reporter mycobacteriophages comprise mycobacterial species-specific mycobacteriophages which contain reporter genes and transcriptional promoters therein. When the reporter mycobacteriophages are incubated with clinical samples which may contain the mycobacteria of interest, the gene product of the reporter genes will be expressed if the sample contains the mycobacteria of interest, thereby diagnosing mycobacterial infection.

Description: MYCOBACTERIAL SPECIES-SPECIFIC REPORTER MYCOBACTERIOPHAGES STATEMENT OF GOVERNMENT INTEREST This invention was made with government support under NIH Grant Number AI26170. FIELD OF THE INVENTION This invention relates to mycobacterial species-specific reporter mycobacteriophages (reporter mycobacteriophages), methods of making such reporter ycobacteriophages, and the use of such reporter mycobacteriophages, for example, to rapidly diagnose mycobacterial infection and to assess drug susceptibilities of mycobacterial strains in clinical samples. Specifically, this invention relates to the use of mycobacterial species-specific luciferase reporter mycobacteriophages to diagnose tuberculosis and to assess the drug susceptibilities of the various strains of Mvcobacterium tuberculosis (M. tuberculosis) . To produce the mycobacterial species-specific reporter mycobacteriophages of the invention, transcriptional promoters and reporter genes are introduced into the genomes of mycobacterial species-specific mycobacteriophages. These reporter genes may be the genes for luciferase or the β-galactosidase gene, and provide the DNA which encodes production of a gene product. The reporter mycobacteriophages may be used by incubating same with samples which may contain the specific mycobacteria of interest. If the mycobacteria of interest is present, then the reporter mycobacteriophages introduce the recombinant nucleic acids which encode expression of the gene product into the mycobacteria of interest, and the mycobacteria then express the gene product. The expressed reporter gene product may be detected by a suitable assay, for example, through the detection of photons or the conversion of an easily assayable chemical reaction. The presence of such gene product indicates that the sample contains the mycobacteria of interest, and hence the mycobacterial species-specific reporter mycobacteriophages may be used to detect and thereby diagnose the specific mycobacterial infection. In addition, since signals may not be generated by cells which are not metabolically active in the presence of antibiotics, the mycobacteria species-specific reporter mycobacteriophages of this invention may be used to assess the drug susceptibilities of various strains of mycobacteria. If antibiotic drugs are added to the sample containing the reporter mycobacteriophages and the gene product is detected, the mycobacteria is metabolically active and hence resistant to the antibiotic drug. BACKGROUND OF THE INVENTION In 1990, there was a 10% increase in the incidence of tuberculosis in the United States. In addition, there has been an increase in the appearance of clinical isolates of tuberculosis that are resistant to antibiotics used to treat the disease. This problem is exacerbated by the length of time that is currently needed both to diagnose tuberculosis, and to determine the drug susceptibilities of various strains of M. tuberculosis. As a result, patients with M. tuberculosis may remain infectious for long periods of time without being treated, or may be treated with a drug to which the bacterial strain is resistant. Therefore, a need has arisen in the field for a method of diagnosis of M. tuberculosis (and other mycobacterial infections) which is rapid, sensitive and specific, which method is also capable of assessing the drug susceptibilities of the various strains of M. tuberculosis and other mycobacterial strains. It is critical that a mycobacterial strain be assessed for drug resistance rapidly because a patient infected with a strain of M. tuberculosis or another mycobacteria must be treated immediately with the particular antibiotic drug(s) to which the strain is not resistant, and not with antibiotic drug(s) to which the strain is resistant, or the patient may die. Currently, the most rapid test available for the diagnosis of M. tuberculosis is the staining of sputum samples for acid-fast bacilli, which is a tedious procedure, and which procedure has high sensitivity. Alternative methods for diagnosis require cultivation of the bacilli for approximately two to six weeks followed by classification of the cultured organism. Typical diagnostic tools include biochemical tests, analysis of mycolic acids and serotyping. All of these tests are time-consuming. More recently, the use of oligonucleotide probes and Polymerase Chain Reaction have been suggested for the identification of M. tuberculosis species. Although these methods may be useful approaches, their uses in a clinical setting have not yet been determined. Further, these methods do not distinguish between live and dead organisms, and are therefore of limited use in the determination of drug sensitivities of clinical isolates. In addition, Mvcobacterium avium (M. aviu ) is a mycobacteria which is often found in immunosuppressed patients. This mycobacteria is typically disseminated throughout the bodies of immunosuppressed patients, such as AIDS patients, and causes M. avium infection. Because this mycobacteria often causes death in immunosuppressed patients, it is necessary to be able to diagnose and assess the drug susceptibilities of the various strains of M. avium. It is therefore an object of this invention to construct broad mycobacterial host range and mycobacterial species-specific reporter mycobacteriophages. It is another object of this invention to provide mycobacterial species-specific reporter mycobacteriophages which may be used to rapidly diagnose mycobacterial infections. It is still another object of this invention to provide mycobacterial species-specific reporter mycobacteriophages which may be used to rapidly assess the drug susceptibilities of different strains of mycobacteria in clinical samples. It is yet another object of this invention to provide mycobacterial species-specific reporter mycobacteriophages wherein the reporter genes are luciferase genes, which mycobacterial species-specific reporter mycobacteriophages may be used to rapidly diagnose mycobacterial infections and to rapidly assess the drug susceptibilities of various strains of mycobacteria. It is a further object of this invention to provide mycobacterial species-specific luciferase gene reporter mycobacteriophages which may be used to rapidly diagnose tuberculosis and assess the drug susceptibilities of the various strains of M. tuberculosis. SUMMARY OF THE INVENTION This invention relates to broad host range and mycobacterial species-specific reporter mycobacteriophages, (reporter mycobacteriophages), methods of producing such reporter mycobacteriophages, and the use of such reporter mycobacteriophages to rapidly diagnose mycobacterial infection, such as M. tuberculosis, and to distinguish which strains of the mycobacteria are drug-resistant. To produce these reporter mycobacteriophages, reporter genes and transcriptional promoters are introduced into the genomes of mycobacterial species-specific mycobacteriophages. The promoter and reporter gene-containing mycobacteriophages (reporter mycobacteriophages) are then incubated with a clinical sample which may contain the mycobacteria of interest, such as M. tuberculosis. The reporter mycobacteriophages are specific for the mycobacteria which is sought to be detected. The reporter mycobacteriophages efficiently introduce the recombinant nucleic acids which encode the expression of the reporter gene's gene product into the mycobacteria of interest, and the mycobacteria then express the gene product. A substrate or other means capable of allowing for the detection of the gene product is then added to the sample. If the gene product or the signal generated by the gene product is detected, the presence of the infectious mycobacteria is known, thereby diagnosing the disease. To assess drug susceptibility of mycobacteria, drugs such as antibiotics ma,, be added to a sample containing the reporter mycobacteriophages of this invention. If the mycobacteria are susceptible to a drug after exposure to the drug, the mycobacteria will be killed. However, drug-resistant mycobacteria will continue to be metabolically active in the presence of the drug, and will continue to express the detectable gene product of the reporter genes. The preferred reporter genes of the present invention are the Firefly luciferase lux gene (FFlux) . the luciferase lux genes of Vibrio fischeri, the luciferase lux genes of Xenorhabdus luminescens and the E. coli β-galactosidase gene (lacZ) . The preferred promoters of the present invention are hsp60 and L5 gene 62 promoter, and the preferred mycobacteriophages are L5, TM4 and D56A. These reporter mycobacteriophages are preferably used for the rapid diagnosis of tuberculosis and M. avium infection, and the accurate assessment of drug susceptibilities of the various strains of M. tuberculosis and M. avium. BRIEF DESCRIPTION OF THE DRAWINGS The above brief description, as well as further objects and features of the present invention, will be more fully understood by reference to the following detailed description of the presently preferred, albeit illustrative, embodiment of the present invention when taken in conjunction with the accompanying drawings wherein: FIGURE 1 represents the genome organization of mycobacteriophage L5; FIGURE 2 represents a luciferase shuttle plasmid pYUBlδO wherein reporter gene FFlux is fused to the BCG hsp60 promoter; FIGURE 3 represents the amount of luciferase activity of M. smeqmatis which contains the pYUBlδO shuttle plasmid and the FFlux gene; FIGURE 4 represents the effect of various antibiotic drugs on the metabolic activity of control mycobacteria and drug resistant mycobacteria in the presence of reporter mycobacteriophages which contain luciferase reporter genes; FIGURE 5 represents shuttle plasmid phAE39 wherein the reported gene is FFlux, the promoter is hspβO, the phage is TM4 and the cosmid is pYUB216. FIGURE 6 represents luciferase activity of M. smeqmatis cells infected with shuttle phasmids phAE39; and FIGURE 7 represents a flow chart for cloning different promoters into TM : :lux shuttle phasmid phAE39. DETAILED DESCRIPTION OF THE INVENTION This invention is directed to mycobacterial species-specific reporter mycobacteriophages, (reporter mycobacteriophages), methods of producing such reporter mycobacteriophages and the use of such reporter mycobacteriophages for the rapid diagnosis of mycobacterial infections and the accurate assessment of mycobacterial drug susceptibilities. In order to produce such reporter mycobacteriophages, mycobacterial species-specific mycobacteriophage genomes are modified by introducing therein transcriptional promoters and reporter genes whose gene product can be sensitively detected. The reporter mycobacteriophages may then be incubated with clinical samples suspected of containing the mycobacteria of interest, either directly of after culture, and the samples tested for the presence of the reporter gene product, thereby diagnosing mycobacterial infection. The method of this invention allows for rapid diagnosis because only the amount of time necessary for the reporter mycobacteriophages to infect their host cells and the amount of time necessary for the host cells to synthesize the reporter gene product are required to allow for diagnosis. Typically, the amount of time required for the reporter mycobacteriophages to infect their host cells and for the host cells to synthesize the reporter gene product is between ten minutes and sixteen hours. The assessment of drug susceptibilities with the reporter mycobacteriophages of this invention is accurate because the reporter mycobacteriophages only allow for the detection of metabolically active mycobacterial organisms, the presence of which metabolic activity indicates that a drug has not killed the mycobacteria and that the mycobacteria is resistant to the drug. To enhance diagnosis specificity, a series of similar reporter mycobacteriophages, each of which having well-defined but different specificities for mycobacterial species, is selected. Mycobacteriophage L5, a temperate virus with a broad host-range among mycobacteria, is the most thoroughly characterized of the mycobacteriophages. L5 particles are morphologically similar to the family of phages that includes phage g and contain a linear dsDNA genome with cohesive ends. The inventors have determined the DNA sequence of the entire gene as well as several gene functions. The DNA sequence of the L5 mycobacteriophage is as follows: S E Q U E N C E 1 GGTCGGTTAT GCGGCCGAGC CATCCTGTAC GGGTTTCCAA GTCGATCAGA GGTAGGGGCC 61 GGCACAGAAA CCACTCACAT CAGGGCTGTG CGCCTCCAGG GCGCGTGAAC TCCCACACCC 121 CGGTGTAGTT ACATCCCGGA ATTGTCTCAG CGCCTCTCAG GGCGCTTCTC ATAAACAGTG 181 ATCTACGCCA CTCCTGACGG GTGGCTGTCA AGGATACTCA CCTTCCCTAC TAATGAGGGG 241 CTAAGAGCCC CTCTCTATAG AGCGCCGCAC AGGCGGCGCG ATAAGAGCGC CACCAGGCGC 301 TCATCTAAAG ACCGGCCTTG AAGGGCCGGT CATAGAGATC TATTCGATCC GGCAACCGCC 361 GGATCTCAAG GCCGCGCCAG TGCGCGGCCC TATAGAGGGG TGACTCAACT GTGCATGGCA 421 CTCGCTCGAG TGCCCACTGG AGCACTCAAC CGGGGAAGTT CGACGTTCTC AACCTGCGAA 481 TGACGTTTGA ATCGTCATCC GCGTACGAAA TCCCCGATCT GCGGCCGACC GACTTCGTGC 541 CGGCCTATCT CGCGGCCTGG AATATGCCGC GTCACCGCGA TTACGCCGCC AAGAACGGCG 601 GCGCGCTGCA CTTCTTCCTT GACGATTACC GGTTTGAGAC CGCGTGGTCG TCCCCCGAGC 661 GCCTTCTCGA CCGCGTAAAG CAGGTCGGCG CTGCACTCAC GCCGGATTTC AGCCTCTGGA 721 CGAACATGCC GAAGGCGGCG CAGCTATGGA ACGTCTACCG CTCCCGCTGG TGTGGCGCGT 781 ATTGGCAGTC GGAAGGAATC GAGGTGATTC CGACGGCGTG TTGGGCGACT CCCGACACGT 841 TCGATTTCTG TTTCGACGGG ATCCCGATGG OATCGACCGT CGCAATTTCT TCGATGGGCA 901 TTCGCTCTTC AAAAGTCGAC CAGGAGCTTT TCCGGTACGG ACTACGCGAA CTCATCGATC 961 GCACTCAACC GCAACTGCTT TTGGCATATG GCCAGCTTCG GCATTGCGAC GACATGGATT 1021 TACCAGAGGT CCGCGAATAC CCGACCTACT GGGACAGACG ACGAAAGTGG GTAACTGCCG 1081 ATGGGAGGCC GGGGAAGTAA AGGCGGCCCC GGTCCCGGAA CCGGAGCACG CAACCGCAGA 1141 GGCGCTGGAG CCCCCGGATC GGGCGGCGTA GGCGGCGTCG GAGGCGGGGG TGGAGCTGCA 1201 GGGAGCAGCG GAGGCGGCAA GGGAACGGCA GCGCCGGTAC CGGAGGCGTC ACCGGTGGCG 1261 GCGGAAGTGG AGCCGGCGGC GGTGGCAGCA GCCCCAACAC CCCGGTGCCC CCCACCGAGC 1321 TGGAGAAGAA GCGCGGCGAA TACAACCAGA TCGCCATCGA CGCCCAGAAA CAGCACGCGC 1381 CCACCGATGA GAAGCGCGAG GCCAAGCGCA AGCAACTGAT GGATCGAGTC GGAGGAGACT 1441 GGCAGGCTTT GGACCCGGAT CACCACGACG CCATCAAGGT GGCGATGGAT GACGCCATGC 1501 GGAAGATCCT CTCCGAGGAG GAGATCGTCC ACCGCACCAA GCACTTCGGC GACCTACTCG 1561 ACTCCGGTCG ACTCAAGTCG CTGTTCGAGG TCGGCTTCTC AGCCGGTGGC GACACCCCGA 1621 CCGAACGCGC CCTCCTCGAG GACGCCTGGT TCGGCGCAGG CAAGGTTCCC CCGATCTACT 1681 CGGCAATCGA GTTCAACGGC GCTCCGACAG CCGGCCTCGG CATGTACGGC GGCACCAAGC 1741 TCTACATGAA GGACTCGGTC AAGGACCGCG TCACCGTGAC CATCGGCGAC TCGCTGATGT 1801 CGAGCTGGGA CGTATTCCCC GGCCGTCCTG GCGACGGCGT GGGGCTGTGG GCCAGCCTGT 1861 CGAAGATCGA GGGGCTGGTC GATCCGAGCA AGACCCGCGA AGAGAACATG CAGGCGGTGT 1921 ACGACTCGTT CAAGAAGTAC GGCACCCTGG ACGGCTTCAT CGAGGCGCAG ATCCAcσσcG 1981 GCGTCCTGGT CGAGGACATC AAGAAGGTCG TGTTCACGCA GCCGCCGAGC CCGATCTTCA 2041 CCGATAAACT GGACGAACTT GGAATCCCGT GGGAGGTGCA GTAATGGCGC AGATGCAGGC 2101 GACACACACA ATCGAGGGGT TCCTGOCTGT CGAGGTGGCC CCTCGGGCGT TCGTCGCAGA 2161 GAACGGCCAC GTACTGACCC GGCTGTCGGC CACGAAGTGG GGCGGTGGCG AGGGTCTCGA 2221 GATCCTCAAC TACGAGGGTC CAGGGACCGT CGAGGTCTCC GACGAGAAGC TCGCCGAAGC 2281 CCAGCGGGCC AGCGAGGTCG AGGCTGAACT TCGCCGCGAG GTCGGCAAGG AGTGAGCTGG 2341 GCCGGCTCAG GCCGGCGACA GGAACTACCA GAGGACTGGG AGCTGAATTA CCGGCTCCCG 2401 GTCCTTTCTG CTGCCAACTG GCTTTGCCAG ATCAACGGTC CCGGATGCGT AAGGGCCGCA 2461 ACCGATGTCG ACCACATCAA GCGCGGGAAC GACCACAGCC GGTCCAATCT GCAGGCAGCC 2521 TGCCATGTCT GTCACGGCAA GAAATCAGCC GCCGAGGGCG TAGCCCGACG GCGGGAACTT 2581 AGAGCCCGGA GGAAGCGACC ACCCGAACGC CATCCTGGGC GTCGATAAGC GGGCCAGGTG 2641 CCCGCTCCAC CCAGGAGGTG AACAGTGGGC ACGCGAGGCC CAATCGGAAA ACGAGATGAA 2701 GAGCGGGTTC GTCGGAACAC CCCGGACAGT CCAACCGACA CGATCCAGAT GCCCGGTCTG 2761 GTGACGATCC CCGAGATGGG CGATCTAAGC CACGACCGCC GCACGCACCA GCTCGTCAAG 2821 GACATGTACG AGTCGATCAA σcAGTcσσcA GCCGTGAAGT ACTACGAGCC GACCGACTGG 2881 CAGATGGCCC GACTCGCCCT CTACACACTT AACCAGGAAC TCATCGCAGC CGAGAACAAC 2941 GGCAAGCCCG TGGGCGCGAT GAAGCTCACT GCCATCAACC AGATGCTCTC CGCGCTGCTG 3001 CTGACCGAAG GTGACCGACG CCGCGTCCGA CTCGAAGTCG AACGAGCACC CGCTGACCCG 3061 ACAGGCGGGA AGGTCGTTGA CGTGACCGAC GTGCTCAAGC AGCGCCTCGC CAAGGCGAGC 3121 GGCGGGAGCT GATGGTCCCC CGAGGGGTTT CTAGAGCCGC TGCCGCTACC AGCCGCTCCC 3181 CCTCGGGGTA GACATCGAAA GGAACCACAT GGCCGACCTC GGCAACCCAC TCGACCTCGA SUBSTSTUTE SHEET 3241 GATGCTCTGC CTGGTCACAG GCCGGGACTT CCGCTGGACC ATCGATTACC CGTGGGGTCC 3301 GGGAGAGCTG TTCCTCGAAC TCGAGACCGG CGGCGAACAC AACGCGCTGC ATCAGGTCTA 3361 TGTCACCGGG GCGACCGGAG GCACGTACAC GCTGAACGTC AACGGCACCA ACACCCCGGC 3421 CATCGACTAC AACGACGTGT CGGAGAATCC GCAGGGGCTG GCAGGCGACA TCCAAGACGC 3481 TCTGGACGCA GCCGTCGGAG CCGGAAACGC TGTCGTGCAT CCGGTCTCGC TGTTCCCTGC 3541 GTGGACACTG AACTTCAACC TCAACGCCAG CAAGCCGCTC ACCGAGCAGT TGGTCAACAC 3601 GATCAACAAG GCCGCGAACG ACTTCTTCGA CACGTTCGAC CAACTACTTG GGGTCGACGT 3661 GGAGATGACG GTCACCGACA CCCTGAACTT CAAGCTCAAG GTGACCTCGC GGCGCTCGTT 3721 CGATGAGGTC GGTGTCGTCA CGTTCGCGGT CGACGTGACC AGCCAGGCAG TCATCAACTT 3781 CTTCAACTCC GTCGCCGAAC TCACCGGAGC GGTGAACACC GTCAACGTCG ACTTCTACTG 3841 GAACCGGACG TATGACATCG AGTTCACCGG ATCCCTTGGG CTGCAGCCGA TTCCGGCTAC 3901 TACAGCCGAC ATCACCAACC TGGCGGGTAC CAGCAAGGCC GTCTCAGTCA CGGTGGTCGA 3961 GCCAGGAAAG AAGAGGCTGA CCATCTGGCC GTTCACGGTC AACGGTGAAA CCGCAACCAT 4021 CAAGGTCGAG TCCGAAGAGG CCGACAAGAT CCCCAACCGC TGCCGCTGGC AGTTGGTTCA 4661 CATGCCGACC GGCGAGGCAG CCGGCGGCGA TGCAAAGCAG CTCGGCCGCG TTTACCGACA 4141 GCCGAGGTAA CACCGCACCC ATCAGAGATG GTGGGCCAGA cσσccTTCGG GCCGTCCCCT 4201 GACGTGTAGC TCAATGGCAG AGCGCCCGAC TGTTAATCGG GTGGTTGAAG GTTCGAGTCC 4261 TTCCATGTCA GCGAGGGCTG AACCGGACCC GTGTCCGGTG TAGGCACTTT CCGCAGGCGG 4321 TTCCCCAGAG CGTGGGGAGC CCCTGCCCTG TACACGTAGC TCAATTGGTA GAGCAGCGGT 4381 CTCCAAAGCC GCCGGTTCCA GGTTCGACTC CTGGCGTGTA TGCACACACC CCTGACTCCT 4441 GCTAGCGGAG TGTTCGCCTT TCGGGCCTGG GGTCTTTTTC CCCGTTCGTC TAATCGGTAA 4501 GACACCCGGC TCTGGACCGG GCAATTGAGG TTCGAGTCCT TGGCGGGGAG CCAACTTGAC 4561 ATCCACCCGA AAGGAACAAC ATGACCTTCA CAGTCACCCG CGAGAGAGCG CAGTGGGTCC 4621 ACGACATGGC CCGCGCTCGC GACGGTCTCC CCTACGCGTA CGGCGGGGCG TTCACCAACA 4481 ACCCGAGGGT GTCGACTGAC TGCTCTGGCC TGGTGCTGCA GACCGGGGCT TGGTATGGAG 47 1 GTCGCACCGA CTGGGTCGGA AACCGTTACG GCTCAACCGA ATCGTTCCGG CTCGACCACA 4801 AGATCGTCTA CGACCTAGGG TTCAAGCGGA TGCCCCGAGG CGGGCCAGCG GCCTTGCCGA 4861 TCAAGCCGGT GATGCTCGTC GGGCTCCAGC ACGGAGGCGG CGGGGTCTAC TCGCACACCG 4921 CTTGCACGTT GATGACGATG GACCACCCCG GTGGCCCGGT CAAGATGTCC GACCGAGGCG 4981 TCGACTGGGA GTCCCACGGC AACCGCAACG GCGTAGGCGT CGAACTTTAC GAGGGCGCAC 5041 GGGCATGGAA CGACCCTCTG TTCCATGACT TTTGGTACCT GGACGCAGTC CTCGAAGACG 5101 AAGGAGACGA TGACGAATTG GCTGACCCAG TTCTAGGGAA GATGATCCGC GAGATCCACG 5221 CGTGCCTGTT CAATCAGACC GCGTCGACCA GCGATCTGGC GACCCCTGGT GAAGGCGCTA 5281 TCTGGCAGCT ACACCAGAAG ATCCACTCGA TTGACGGCAT GCTCCACCCG ATCCACGCTG 5341 AGCGGCGCGC TCGCGCAGGC GATCTCGGTG AGCTGCACCG AATCGTGTTG GCCGCGAAGG 5401 GCTTGGGCGT GAAGCGCGAC GAGGTGACCA AGCGGGTCTA CCAGAGCATC CTCGCCGACA 5461 TCGAGCGGGA CAACCCCGAA GTACTTCAGC GATACATCGC AGAAAGAGGT GGCCTATGAG 5521 CCCCAAGATC CGACAGACCA TCTAccτσcT CGGCACCGCC GCCCCGGCAC TGCTGGGCAT 5581 CGTCCTGATC TGGGGCGGGC TCGACGCTGA GTCGGcσσcT GACCTCGGTG ACATCATTGC 5641 GGGCGTCGTG TCGATACTAG TCTCCGGTGC GCCGGCCGTA GCGGCAGGCA CCGTACGCAG 5701 CCAGCGCAAG GACGGCACGT TGTCCACCAG CCCGGTGGAT CAGGTCACCA AGGGCGTCGA 5761 GCAGGTGCTC GCGGCCAGGC AGAGTGCCGA GGCTGAAGTC GCGAAGGTCA AGCAGGCGCT 5821 GGAGACCGCC GTCAGCGGTT CTCTCCCCCA GCTCGGCCCG CTGGCCACGC AGATCCTCAA 5881 CGTGGCTGAC GACACCGTCT σσcGTccATG AGCAAGCCCT GGCTGTTCAC CGTCCACGGC 5941 ACAGGCCAGC CCGACCCGCT CGGGCCTGGT CTGCCTGCCG ATACcσcAcσ 6001 GGACGTACTT GACATCTACC GGTGGCAGCC CATCGGCAAC TACCCGGCAG CGGCGTTCCC 6061 GATGTGGCCG TCGGTCGAAA AGGGTGTCGC 6121 TGAGCTGATC CTGCAGATCG AGCTGAAGCT GGACGCAGAT ccGTACGcσσ ACTTcσcσcT 6181 GGCCGGCTAC TCGCAGGGAG CCATCGTGGT GGGCCAGGTG CTCAAGCACC ACATCATCAA 6241 CCCGAGAGGT CGACTGCACC GGTTCCTGCA CCGGCTCAGG AAGGTCATCT TCTGGGGTAA 6301 CCGATGCGG CAGAAGGGCT TTGCCCACAC CGACGAGTGG ATTCACCAGG TCGCTGCCTC 6361 GGACACGATG GGCATCCTCG AGGACCGACT GGAGAACCTC GAGCAGTACG GCTTTGAGGT 6421 CCGCGACTAC GCGCACGACG GCGACATGTA CGCCTCCATC AAGGAGGACG ACATGCACGA 6481 GTACGAGGTG GCCATTGGCC GAATCGTGAT GAGCGCTAGG CGATTCATCG GAGGTAAGGA 6541 CTCCGTCATC GCCCAGCTCA TCGAGCTTGG ACAGCGTCCG ATCTGGGAGG GAATCGCGAT 6601 GGCCAGAGCC ATCATCGACG CCCTCACGTT CTTCGCCAAG TCGACCCAAG GCCCGAGCTG 6661 GCCGCATTTG TACAACCGCT TCCCGGCGGT CGAGTTCCTA CGACGAATCT GAGAAAGGAG 6721 GCGGGGTGAG CCTCAACAAC CACCACCCGG AGCTTGCCCC GTCTCCCCCT CACATCATCG GCCCGTCCTG GCAGAAGACG GTCGATGGTG AGTGGTATCT 6781 GCCTGAGAAG ACCCTCGGCT GGGGAGTCCT GAAGTGGCTC TCCGAGTACG TGAATACCCC TGGCGGGCAT GACGATCCGA ACCGTCTGGC GACGTTGATC GCGCTCTCCG AGGCAGGTCT • 6841 TCTCGACAAC GAGAACATGT TCATCCCCAC CGACGAGCAG GTACGCCTGG TCCTCTGGTG 6901 GTACGCAGTA GATGACCAGG GCCAGTACAT CTACCGCGAG GGCGTGATCC GCCGGCTCAA 6961 GGGCTGGGGC AAGGATCCGT TCACCGCCGC GCTCTGCTTG GCGGAACTCT GTGGCCCCGT 7021 AGCCTTTTCA CACTTCGACG CCGACGGTAA CCCGGTCGGC AAGCCGCGTT CAGCCGCGTG 7081 GATCACCGTC GCGGCCGTCA GCCAGGACCA GACGAAGAAC ACGTTCTCGC TGTTCCCGGT 7141 GATGATCAGC AAGAAGCTGA AGGCCGAGTA CGGCCTGGAC GTGAACCGCT TCATCATCTA 7201 CTCCGCAGCC GGTGGCCGTA TTGAGGCAGC GACCTCGAGC CCCGCGTCGA TGGAGGGTAA 7261 CCGCCCGACG TTCGTCGTCC AGAACGAGAC GCAGTGGTGG GGCCAAGGCC CCGACGGCAA 7321 GGTCAATGAA GGCCACGCGA TGGCAGAGGT CATCGAAGGC AACATGACCA AGGTCGAGGG 7381 CTCCCGCACC CTGTCGATCT GCAACGCCCA CATCCCCGGC ACCGAGACGG TCGCCGAGAA 7441 GGCATGGGAC GAGTACCAGA AGGTCCAGGC AGGCGACTCT GTCGACACCG GGATGATGTA 7501 CGACGCGCTG GAAGCGCCGG CCGACACCCC GGTCTCCGAG ATCCCCCCGC 7561 AGAAGGAGGA TCCCGAGGGA TTCGAGAAGG GCATCGAGAA GCTCCGCGAG GGCCTGCTCA 7621 TCGCCCGAGG CGACTCCACC TGGCTGCCGA TAGACGACAT CATCAAGTCG ATTCTGTCGA 7681 CCAAGAACCC GATCACCGAG TCGcσσcGCA AGTTCCTGAA TCAGGTAAAC 7741 GCCGCTGAGG ACTCGTGGCT CTCACCGCAG GAATGGAACC GGTGCCAGGT CGACCTGGCC AAGTACCTGG 7801 ATAAGCACGG CAGGGAGTTC GCTCCGCTGC AGCGCGGTGA CCGGATCACC CTCGGGTTCG 7861 ACGGGTCGAA GTCCAACGAC TGGACCGCGC TCGTCGGCTG CCGTGTCAGC GACGGCCTGC TGTTCGTCAT 7921 CGACATCTGG GATCCCCAGA AGTACGGCGG GGAGGTTCCC CGCGAAGACG 7981 TTGACGCCAA GGTCCATTCG GCGTTCGCCC ACTACGACGT GGTGGCGTTC 8041 CGCGCCGACG TGAAGGAGTT CGAGGCGTAC GTCGACCAGT GGGGCCGGAC CTACAAGAAG AAGCTCAAGG TCAACGCCAG 8101 CCCGAACAAC CCGGTGGCGT TCGACATGCG CGGACAGCAG AAGAGGTTCG CGTTCGACTG 8161 CGAGCGACTC GAGGACGCGG TCCTTGAGGG CGAGGTCTGO CACGACGGCA ATCCCGTTCT 8221 GCGCCAACAC GTTCTGAACG CCAAACGACA CCCAACGAAC TACGACGCCA. TCGCGATTCG 8281 CAAGGTCACG AAGGACTCCA GCAAGAAAAT CGACGCTGCA GTCTGCGCTG TCCTCGCGTT 8341 CGGGGCGAGA CAGGACTACC 8401 TCATGAGCAA GAAGGCCCGT AGCGGCCGGG TGGTGATGGT TCGATGACAG CACcσcTccc CGGTATGGAG GAGATCGAAG ACCCCGCAGT CGTACGAGAA X8461 GAGATGATCT CGGCCTTCGA GGATGCTTCC AAGGATCTCG CCAGCAACAC CAGCTACTAC 8521 GACGCTGAGC GCCGGCCAGA GGCCATCGGC GTCACCGTCC CGAGAGAGAT GCAGCAACTG 8581 CTGGCTCACG TCGGATACCC CAGGCTCTAC GTCGACTCAG TCGCCGAGCG CCAGGCCGTC 8641 GAGGGTTTCC GCCTCGGCGA TGCCGACGAG GCTGACGAAG AGCTGTGGCA GTGGTGGCAG 8701 GCCAACAACC TCGACATCGA GGCACCACTG GGCTACACCG ACGCTTACGT TCACGGCCGG 8761 TCGTTCATCA CGATCAGCAA GCCAGACCCG CAGCTCGACC TGGGTTGGGA TCAGAACGTC ■ 8821 CCGATCATCC GCGTCGAGCC GCCCACCCGA ATGCACGCCG AGATCGACCC CCGGATCAAC 8881 CGGGTGTCCA AGGCCATCCG AGTCGCATAT GACAAGGAGG GCAACGAGAT TCAGGCTGCC 8941 ACGCTGTACA CGCCGATGGA GAccATcσσc TGGTTccσcσ CTGACGGTGA GTGGGCTGAG 9001 -fGGTTCAACG TCCCGCACGG TCTGGGCGTC GTTCCCGTTG TGCCGCTTCC GAACCGGACC 9061 C GCTCTCGG ACCTGTACGG CACCAGTGAG ATCACGCCCG AGCTTCGGTC GATGACCGAC 9121 GCGGCGGCGC GCATCCTCAT GTTGATGCAG GCGACCGCCG AGCTGATGGG TGTCCCCCAG 9181 CGCCTGATCT TcσσcATCAA GCCCGAAGAG ATCGGCGTCG ACTCCGAGAC CGGCCAGACG 9241 CTGTTCGATG CGTACCTGGC CCGGATCCTG GCGTTCGAGG ACGCTGAGGG CAAGATCCAG 9301 CAGTTCTCTG CAGCCGAGCT σσccAACTTc AccAAcσcσc TCGATCAGAT CGCCAAACAG 9361 GTCGCTGCGT ACACGGGATT GCCTCCCCAG TACCTGAGTA CCGCCGCAGA CAATCCGGCC 9421 TCCGCTGAGG CGATCAGGGC CGCTGAGAGC CGACTCATCA AGAAGGTCGA GCGGAAGAAC 9481 TCG GCGGCGCATG GGAAGAGGCC ATGCGGATCG CCTACCGGAT CATGAAGGGC 9541 CTGATGT GGCGACGTTC CCCCGGACAT GCTCCGCATG GAGACCGTCT GGCGAGACCC GAGCACTCCC 9601 ACCTACGCGG CCAAGGCCGA CGCAGCCACG AAGCTGTACG GCAACGGCCA GGGTGTCATC 9661 CCGCGTGAAC GTGCTCGCAT CGACATGGGC TACTCCGTCA AGGAGCGCGA AGAGATGCGC 9721 CGATGGGACG AGGAAGAGGC CGCAATGGGT CTCGGCCTGT TGGGCACGAT GGTCGACGCC 9781 GACCCGACGG TCCCAGGCTC CCCGAGCCCC ACGGCACCGC CGAAGCCACA GCCGGCCATC 9841 GAGTCGTCTG GTGGTGATGC GTGACCGCAG AGGAGTACGC GGCGGCTCAA GCCGCGATCA 9901 CTGCGGGTCT TGCCACATAC GTCCAGAGGT TCGCTTCGCT CTTCGTCGGT CCAGCTCTCG 9961 TGTAGGTGA GTGGCTGCGA CTGCTGCAGG TGCTGTTCCC CGAAATCCAA CGGCGGTATG 10021 C GCTGC CGCCTTGGGC AGGGACTTCT ACGACTCCCA ACGCGCACTA CACCACCCAG 10081 CAGAT 10141 AGCTGCCCCG GAACGAGAGG TTCCGGGGAG AGCTTCGGTG GGAGTGGTTC GTCCAGAACA 10201 TGGAGCCCGC TCGAAAAGAG ATGTCGCAGG CCGACTCTCC GCCGAGTGCG ACCTCTAAGT 10261 TGGCTCTGGC CGCAGTTCGC GAAGTGGAGA TGGCAGCACG CCGACAGATC ATCGGCGCTG 10321 TCAAGAACGA TCCGGCCCCG CAGATCGTGC AGGGCTGGGC GAGGGTCGCC ACCGGGCGCG AAACATGCGC CTGGTGTCTG ATGCTCATCT CACGGGGTGC CGAGCTGAAT CACAAGGGCA 10381 ACTTCGCCTA CAGCTCAGCG GAAGCCGCAG GGCTCAACCT CGATGACGAG ACCGTGATCG 14 10441 ACCTCTGGAA CGAGTCCGGT CACGACCTTG AGAAGTTCCG CGAGGAGACC AGAGAGGACT 10501 TCGAGAAGTG GCACGCAGGG TGCGACTGTC TGGTGGTCCC GGTCTTCGAT GTGCAGAACT 10561 GGCCCGGAAG AGACGCTGCC CTACGGGCGC AGCAACTTTG GATCGAAGCC AGCGACGAAG 10621 CTGACGACCT CATTGCGTCA GGCAAGGCCC GCTCCAAGAA CAAGAACACG GAGACGCTCA 10681 AcσcGCTccσ ACGCCGCCTA GCACGCGGCG AAATCACCAT GTCCAACTAC GCCCTCGCTG 10741 CGTAGTCCCT CGAACCCCAG GTGGGTTCTC TCAACATGCC CAGGAGGCGA AAACACATGT 10801 CCGACAACCC CACTCCCGAG AGCACCCCAG AGGCCGAGAC CCCGGAGGTC GAGAAGCCGA 10861 TGGAACCGCA GGGCAAGGTC TTCGATGAAG CGTACGTTCA GTCGCTTCGC CAGGAGGCTG 10921 CAGCCGCTCG GGTGGCGAAG AAGGACGCCG TAGAAGCGGC AGAGGCTCGA GTGAAGGCCG 10981 AGTACGAGGC CAAGCTCGCT GAGCGCGACA CCGCTTACAC CGAACTGCAG AACCAGTTGG 11041 GACAGGCGTG GATTGAGCTG GAGAAGGTCT ACCTCTCTCT CGACGCCAAG GTGCCCAACG 11101 ACAAGGTTCG GGCGTTTGTC GAGATCCTCG AAGGCAACGA CAGGGACAGC ATCGCTGAGT 11161 CAGTGAAGTC CCGTCTGGAG CTGGTCGGCG GATTCGGCAA CAAGACCCCG AGTCCTGCGT 11221 TCGACCCGTC TCAGGGTCGC GGCGGTAAGC CGCCGATCCC GCTGAACGGT GACCCGATCC 11281 TCGAGGCCAT CAAGGCCGCT GTCGGGATCA AGAAGTAACC CACCCAACAG ATCTCAAGGA 11341 GAGATAAACA ATGGCAGTCA ACCCTGACCG CACCACGCCG TTCCTCGGCG TGAACGACCC 11401 CAAGGTCGCG CAGACCGGCG ACTCGATGTT CGAGGGCTAC CTCGAGCCCG AGCAGGCCCA 11461 GGACTACTTC GCCGAAGCGG AGAAGATCTC CATCGTCCAG CAGTTCGCCC AGAAGATCCC 11521 GATGGGCACG ACCGGCCAGA AGATCCCGCA cTGGACcσσc GACGTGAGTG CGTCGTGGAT 11581 CGGTGAAGGC GACATGAAGC CCATCACCAA GGGCAACATG ACCTCGCAGA CCATCGCCCC 11641 CCACAAGATC GCGACGATCT TCGTGGCCTC GGCGGAAACC GTCCGTGCGA ACCCGGCCAA 11701 CTACCTGGGC ACCATGCGGA CCAAGGTCGC GACCGCCTTC GCGATGGCGT TCGACAACGC 11761 CGCGATCAAC GGCACCGACA GCCCGTTCCC GACCTTCCTA GCGCAGACCA CCAAGGAGGT 11821 CTCGCTGGTG GACCCGGACG GCACCGGCTC CAACGCCGAC CTCACCGTCT ACGACGCGGT 11881 CGCCGTCAAC GCCCTGTCGC TGTTGGTCAA TGCCGGCAAG AAGTGGACCC ACACTCTGCT 11941 GGACGACATC ACCGAGCCGA TCCTCAACGG CGCGAAGGAC AAGAGCGGTC GCCCGCTGTT 12001 CATCGAGTCG ACCTACACCG AGGAGAACAG CCCGTTCCGC CTCGGTCGGA TTGTGGCCCG 12061 TCCGACCATC CTGAGCGACC ACGTCGCCTC GGGCACGGTC GTCGGCTACC AGGGTGACTT 12121 CCGCCAGCTC GTCTGGGGCC AGGTCGGCGG CCTGTCCTTC GACGTGACGG ATCAGGCGAC 12181 TCTGAACCTG GGCACCCCCC AGGCTCCGAA CTTCGTCTCG CTGTGGCAGC ACAACCTCGT 12241 CGCAGTCCGA GTCGAGGCCG AGTACGCCTT CCACTGCAAC GACAAGGACG CGTTCGTCAA 12301 GCTCACGAAC GTGGACGCCA CCGAAGCCTG ATCCAGGCTT GACATCCACC GGGAGGGGGC 12361 TCCTTCGGGA GCCCTCTCCT GATGTGGAGC AGGAAGGACC ACATGCGAAT CCAGTCCACC 12421 CTCAACGGCG GTTTCGCCGA GGTTTCCGAG GAGTTCGCCA AGCAGTTGAT CGCCACTGGC 12481 GGCTGGAAGG TGCCCCGGAA ACCGCGCAAC ACCAAGACCA AGACCGCTCC TGAGGAGCCC 12541 AAGAACGAGG AGTAACCCGT GGCCTACGCG ACCGCCGAAG ACGTTGTGAC GTTGTGGGCC 12601 AAGGAGCCTG AGCCCGAAGT GATGGCGCTG ATCGAGCGCC GOCTCCAGCA GATCGAGCGC 12661 GCCGGATCCC CGACCTGGAC GTGAAAGCCG CTGCGTCGGC GACGTTCcσσ 12721 ATGATCAAGC GCCGATCTGA TCGACATCGA AGCTGATGCT GTTCTGCGCC TCGTGCGTAA CCCGGAGGGC 12781 TACCTcτcσσ AGACCGACGG TGCGTACACC TATCAGCTCC AGGCCGACCT GTCGCAAGGC 12841 AAGCTCACCA TCCTCGATGA GGAGTGGGAG ATCCTCGGGG TCAACTCCCA GAAGCGCATG 12901 GCGGTCATCG TCCCGAACGT GGTGATGCCG ACGTGAGCGC GAGCGACCGA CACCGCGCCC 12961 CGATTGTCTA TCCGCCTGGC ACTCAGGCGG TTACGCCGGA TCGGGTCAAC GCGTTTGACT 13021 GCGATCACGA AGCTGATCCT CCGGTGTGCC GGTGCGTCCA CGACTGGCGC ATCGAGTGGG 13081 GAAACGTCAA GAAGGCCACC GCCAGATCAC GGTCGGCGGT GCTCTGATGA GCCTCCTCGA 13141 CACCGGTGCC CGGTACCAGA CCTGCATCGT CTACCCCGAA GAGATGGTCA TCGACTCCGA 13201 TGGCAACAAG CGGACCAGGC CGTCGAATAC CGGCATCCCG GCCATCGCAC GGTTCCAGGT 13261 AGCCAACCAG TCTGGTACGT CGGCACGACG TGCTGAGCAG GACAACGAGG GGTTCGAGAC 13321 CGAGAAGGTC TACCGGATGC GGTTTCCCCG CTCGTTCACC AAGGAGCACG GCATCCTCGG 13381 GGCCCAGTCC CAGATCGAGT GGCGAGACCA GCGGTGGGCG CTCTTCGGAG ACGCCACCGT 13441 CTACGACTCA TCCCCTGCGT TGGCGCGGGT CGACTACACG ATCAAGAGGT ACTGATGGCC 13501 GGTCTACG CGAACGCGAA CAAGGTCGCG GCCCGGTACG TCGAGACGAG GGACGCCGTC 13561 AA GAGC GGAACAAGGT CACCCGTCGA GCCAAAGCCA ATCTGGCGCG GCAGAACTCG 13621 CGAGAC A TCACCGAGCA AGACGGCGAT 13681 ACCACCCGCA TCACCGACGA GGGCTACTTC CCGGCCACC 13741 GTCGACTTCC ACACGATCCT CAACGCGCCC AACGCGTTGG CGCTTGAGTT CGGCCACGCG 13801 CCGTCTGGCT TCTTCGCTGG CACCGACACG AAACCACCGG AGGCCACTTA CATCCTCACC CGAGCCGCCA TCGGCGGCAC CGTCTCATAA GGAGGTCACA TGGCGCGAAT GCCTCGCGTC 13861 CAGGCAGTAG CGGCCCCGAT CCTCCGGTCA 13921 GACCCCCGAC TGGAGGGAGT GACGGTCACG ' ACATGGGTTC CAGACGTGGA CTTCCGAGAG TTCCCGATGA TCAACCTCCG CCGCATAGGC 13981 GGCACG GGA ACCCCAACGC ACCGACGCTG CACACGCTGC CGGTGGTCGA AATGACCGCC 14041 TACACCAGAG ACGGTCTCAT CGAGACTGAG GAGCTGTACG AGACCGCGCT AGAGGTTCTC 14101 TACGACGCGG TGGAGAACGG AACACAAACT CCCGCAGGGT ATTTGACCTC CATCTTCGAG 14161 ACGATGGGCG CCACTCAGTT CAGCTCCCTC TACCAGGACT CCTGGCGCAT CCAGGGTCTG 14221 ATCAGGCTCG GCGTCCGCAG ACCGAGAACC ACCCTCTAAC CGAAAGGTAA AGCCACATGG 14281 CTGAAAACGA CGACGCAGTG TTGACTGCGG CGGTCGGCTA CGTGTACGTC GGTGCTGCAG 14341 GCACCGCTGC TCCTACGCCG GCCTTGCTCA AGACCATCGA CCTCAGCAAG CCCGAGACCT 14401 GGACCGGTGC TACCGGTTGG ACGAGCGTCG GCCACACCAG CCGAGGCACG CTCCCTGAGT 14461 TCGGCTTCGA AGGCGGCGAG TCCGAGGTCA AGGGCTCCTG GCAGAAGAAG AAGcτccσcσ 14521 AGATCACCAC CGAGGATCCC ATCGACTACG TCACGGTCCT ACTGCACCAG TTCGATGAGC 14581 AGTCGCTGGG TCTGTACTAC GGCCCCAACG CCTCTGAGAC TCCTGGTGTG TTCGGTGTGA 14641 AGACCGGCCA GACCAACGAG AAGGCCGTGC TGGTCGTGAT CGAAGACGGC GACATGCGCC 14701 TGGGGCATCA CGCCCACAAG GCTGGAGTTC GCCGCGACGA CGCGATTGAG CTGCCCATCG 14761 ATGACCTGGC TGCGCTGCCC GTCCGGTTCA CCTACCTGGA CCACGAAGAC GAGCTGCCGT 14821 TCTCCTGGAT CAACGAAGAC CTCTTCAACG TGCCCGAGGT TCCCGAGGGC TGATCCCAAC 14881 TTGACAGCCA CCCGGCTGTC TACCCCGGAG GGGGAGGTTT CCTTGGCGGG CCTGGCCTCC 14941 CCCTCCTCCC GCCACTCACA GACCCGCCGA CACTGAAAGG TTCGCCATGA CAAACGTATT 15001 CACCATCGAC GCATTCCGCG AAGAGGTCAA GAAGAAGTAC GCTCCGGTCC TCATCGGCCT 15061 GTCCGACGAT GTGACCGTCG AGCTGAAGCC 15121 GCTGCTGAAG CTGGGCCAGA AGGCCCGCGA AGCGGTGGTC GAGGTGTTCA AGGAGTTCGC 15181 GGACATCCCC GACCTCGAAG AGGACGACGA CGACGAGTTG GTCGATGAGT ACTCGCTCCA 15241 GGTCTGCGAC ATCATCGCCA AGGCGTTCCG GCTGATCGCC ACGAAGCCCA AGAAGCTGAT 15301 CGCCGCCTTG GACGAGGAGC CGGATCCCCG TATCCGCGCA GAGCTGTATG 15361 CAGCGGTACT CAACACCTGG AAGCGAGAGA CGCAACTGGG GGAAGCCGCG CCCTCGCCGA 15421 GCTGATCGAC AAGTTCGGCG GGGCGATCCT CGCAGACCTG • CTCCAGTACT 15481 ACCGGGTAGA CCTGCGCGAC CTGTTCCGCG ACGAGGATCC σcTTTCGCcσ AGATTCGTTC 15541 TGTCCCTGGT GCTCTGCCTT CCCAAAGACG GCGCGTTCTA CGCAGAACGT CGTGGTGGGC 15601 AGCAGTACCG GGGCTGGACC GAGGACCGCT ACGCGCTCGC GGACATCTAC GACGCCATCC 15661 AGGCGGGCAA CCACATCCTG CTGCTGGCGA ATCGTGATCC GAAGAAGCCA AAGCCCAAGG 15721 CACCCAAGTC ATACCCGCGT CCCGACGACC TAGAGAAGAC CACACCGAAG CCGGGTTCGT 15781 TCGCCGCAAT GGTCGTGCGA GCGAAGAAGG CGGCTCGAGA GAGAAGGGAA AGGGAGGAGG AGAGTGCCGA ATAGTGCTGG CGTAGAAGΓC GCCCGGATCT CGGTCAAGGT 15841 CAGCCCGAAC ACCAAGGAGT TCCGCCGGGA ACTCAAGACC GAACTCGAGA AGATCGAGCG 15901 GGAGCTTAAG GGCGATGTCG AGATCAACGG CATCTCGAT GCGGCCCAGG CCAAGGCCGA 15961 CTTCAAGCGC ATGATGATGC AGCTCAAGAC CGAAGCTGCC AAGGGCGTTC ACGTCCCGGT 16021 CGACGTAACC GTCGACAAGA AGAGCAAGAA GGGAGGTCTC CTCGGAGGTC TCCTCGGCGG 16081 CAGCCGGGGG CTCGGAGATC TAGGCGATGA CGCCGAGAAG GCGTCGTCTC AAGTACAACA 16141 CCTTGGCAAG TCGTTCCTGG GCCTCACACG AGCCGCCTGG ATAGGCGTAG GCATCGTCGC 16201 CGTAGCAGCT CCGCTGGTCG GCATCGTGGC CGGTCTGCTG GCCGGTCTGC CGTCGCTGCT 16261 GTCTGCGTTC GGAGCCGGCG CTGGCGTAGT CGCGCTCGGC ATGGACGGCA TCAAGGCAGC 16321 CGCCTCGACG CTG-GCCC GA CGCTGGAGAC GGTCAAGGCC GCTGTCTCCT CGACGTTCCA 16381 GCAGGGACTC ACCCCGGTOT TCCAGCAGCT CGGCCCGATG CTGACCGCGA TCACCCCCAA 16441 CCTGCAGAAC GTGGCCTCGG GCCTCGTGAA CATGGCCGGG TCGATCACCG ACGTGATCAC 16501 CCAGGCTCCT GGTCTGCAGC AGATCCAGAA CATCCTCACC AAGACCGGAG AGTTCTTCAC 16561 GGGCCTCGGC CCTGTGCTCG CTACCGGCAC GCAGGCGTTC CTGACGCTGT CCAACGCCGG 16621 cσcGAACTcσ TTCGGCACGC TCCTGGCTCC CCTGCAGGAG TTCACCAACG GCTTCAACGA 16681 CATGGTCAAC CGAGTCACGT ccAAcσσcGT GTTCGAGGGT GCCATGCAAG GGCTTTCGCA 16741 GACGCTGGGC AGCGTCCTCA ACCTGTTCAA CCGGCTCATG GAGTCCGGTC TGCAGGCGAT 16801 GGGACAGCTC GGCGGTCCGC TGTCGACGTT CATCAACGGG TTCGGAGATC TCTTCGTCTC 16861 GCTGATGCCG GCGCTGACTT CGGTCTCTGG TCTGATCGGC AACGTCCTCG GGACGCTGGG 16921 CACACAGCTC GCTCCCATCG TCACGGCGCT CACGCCGGCC TTCCAGACGC TGGCGAGCAC 16981 GCTCGGCACG ATGCTCACCG GAGCCCTCCA AGCTCTGGGT CCGATCCTGA CTCAGGTCGC 17041 TACGTTGATC GGCACGACGC TGAACACGGC GCTGCAGGCT CTCCAGCCGA TGCTGCCGTC 17101 GCTCATGCAG AGCTTCCAGC AGATCTCCGA CGTACTGGTG ACCAGTCTGG CCCCGCACAT 17161 CCCGGCGCTG GCGACGGCCC TCGGCCAGGT CGCAGGCGCG GTGCTGCAGC TCGCTCCGAC 17221 GATCATCTCG ACGTTGGTTC CGGCGTTCGT TCAGTTGGTC CCAAAGGTCG CTGAGCTAGT 17281 TCCGACCATC GTCAACCTGG TCCAGTCGTT CGCCAACCTG ATGCCGGTGG TTCTGCCCCT 17341 GGCGCAGGCT CTGGTCAGCG TTGCTGGCGC GGTGATTCAG GTGGGTGTCT CCATCGGCGG 17401 CGCGCTCATC GGCGCGCTGG CGAACCTCAC GGAGATCATC TCCAACGTCA TCAAGAAGGT 17461 GTCCGAGTGG GTCAGCAGCT TCTCCAGCGG AGCCCAGCAG ATCGCTGCGA AGGCAGCGGA 17521 ACTGCCGGGG ATGATCCAGT CGGCTCTCGC CAACCTGATG GCCATCGGCC TGCAGGCCGG. 17581 TAAGGATCTC GTCCAGGGCC TGATCAACGG CATCGGCGGG ATGGTCAGCt-- irt * jC * -3vjl * _rtΛ 16 17641 CAAGGCCAAG GAGCTGGCGT CCAGCGTGGC TGGTGCAGTG AAGGGCTTCC TGGGCATCGA 17701 GTCCCCGTCG AAGTTGTTCA CCGAGTACGG CCAGTTCACC GCCGAGGGAT TCGGCAACGG 17761 CATGGAGGCA GGGTTCAAGC CCGTCATCGA ACGGGCCAAG GATCTCGCGG CTGAGCTGTC 17821 CAGGGCGATG GAGTCGGGCA CCGACCCCTC CGGGATTCTC GCTGGGCTGG ATCAGAATGA 17881 GCTGAAGCAG ATGCTGGCGG CTCTCGAAGA GGAGCGCAAG CGACTCAAGG TCGAGAAGAA 17941 CGGTATCCCC AAGGGAGACA AGGCAGGCCG AGAGGCGCTG CAGAACCAGC TCGACCAGAT 18001 CCAGGCGCAG AAGGACATCC TGTCCTACCA GCGTGACCGC ATCAAGAACG AGTCTGAGTA 18061 CGGCGACATG GCCGGCGAAG ACCCGTTGGT GAAGGCAGCC TCCGGGCTGA TGAGCGCACC 18121 GGTCGACTTC GCGAAAGCGA CTGGCAAGCA 18181 GTTCCTTTcσ GACATCGGCA TCAGCGGAGA TGGGTTCATC TCGAAGGCCA TCACCGAGGG 18241 CATCCAGTAC ATCTTCCAGA TCGGCTCTGT CGATGAGGCG CTGTCGATCA AGGACCGCGA 18301 GGAGTCGAAG AACGCGCTGT CCGTCGTTGG CCGCTGACTT GACATCCACC AGGAGGTAAG CATTGATCAC CGACACCATC GTTGAACTCG 18361 AGGGTGTCAA TGGTGAGCGT TTCAACTTGA CGACCGGTGA CCAGGGTGTG TACCTGGCCA 18421 CAGACGTGGA GGGTTGTTTC TACGACCCTC CCGTCAAGGT CGTTGTTGAA GAGCCGGGGA 18481 ACTACCCCGG CGCTCGCTAC TTGTCCCACC GAGCCCTGAA GCGAGACATC GTCTTTGGGG 18541 TCGTCATCCT CAACGACGCG AAGCAGGGGC CGCGCTCCTG GCTGTCGCGA GACTCCGAGT 18601 GGCGCAAGGC GTGGGCGTTC AACCGCACCT GCAAGCTCTA CGTCACCACC CCGGACTCCG 18661 GTACCCGCTA CCTGAAGCTG GCGCTGTTCG AGTCCCCCAC CGTCAAGATG GACACCGACC 18721 CAAGAGGTAA ACCCCTTGAG GTCACGGTGA TGTCGTGCAT CGCGTACGAC CCGTTCTGGT 18781 ACGAGGACGA CAAGGTCTTC TCGGCCAAGA CCAAGACCGA CACCCGGTTC GACCCGTCGT 18841 TCTGGACGCC GCCGTGGCCG TGGGAGGAAC TGCCCAAGGA GACGCTGCGG ATCAAGGTCG 18901 GCCGCGAGCA GGGTGGGCTA AACCCCACCG ACCAGTACAT CTTCCCGAAG TGGACCGTTC 18961 CCGGCTCCAC CGAGAAGGTG CCGAACTTCC CCTGGCCGTT CCCCCCGAAC GTCCCGATCC 19021 CGTGGGAGAC AGCACCGTTC ACTCAGTTCG TCATCCCGGA CTACTCGTTC GAGGATGAGG 19081 AGTTCCGCAA CCGCCGGCTC AAGACGCCGG GGTTGATCTA CGGCGAGAAC TGCGTCATCG 19141 ACACCGACCG GCGCGAGGAG CAGATCGCTT CCGAGTCGGG CTCCCCGGTG TGGGCTCGGA 19201 TGAACGGTGT CCGGTTCCGC AACTCGATCC CGCCCTACAC CGAAGAGGCT GAGTTCGTCA 19261 TAGACGCATC GGGATGCGCT CCGGGACAGG TAGTTACCCT CCGGCTCACG AGGCCGTGGT 19321 CGCGCTGCTG GGGGCTAGAG TGAGTGGTCT GACGAGCGTT CGTGAGGCCG AAGATCTCTG 19381 GCAGAAGATC CAATTGCGGC GCTGCAAGCG CGAGCAGGAA CGGCTCAAGC ATCCCGACGT 19441 AGAGCTGCGC GATGGCGACT TCCGCCTGCG CGGCCTGGTC GC GGCGAGC GGGTGCTCGA 19501 GTGGGAGTTC ATCGAGAACG AGACTGGCAC CTGCACCTTG CAGCTCTCAC TGAGCCATTA 19561 CCTGGCGAAG TGGGTGATGG ACCACCGGGG TCGAGCAAAG CGCAACGTCA TCATCAACAT 19621 CGAGAAGCAA GGCGCTCGAT GGACCGGGAT GATGGACCAC TACCGGGTCA TCAAGACCGA 19681 CGCAGGGGAC GCCTACATCG AGATCGTGTT TTTGCACGAC TTCGAGCAGA CCAAGCATAT 19741 19801 CCGGGTATGG TGCAACCCGT TCCTACGCCC CGAGCTGCAG TTCCCCAAGG TGTGGATCAT 19861 CTTCGGGCCG GCCAAGTGG GTTTGCTGGT GACACTGTTC GTCAACCTGC TCAGGCTCGA 19921 GACGAGCTTG TGGACGCTGC CTGATGACCC CACGGACATC AACGAGTGGA TGGGTCCGAG CTTCAACCCA GCAAATTGGC GGAACATCGT CAAGCCGTTC CCGTTCCTGG CCGACAACTC 19981 CGCCA AGAAGATCCT 20041 ACCGGTCACG ATGGTGTTCA GCCGGTTCGG GACGTTCTAC GACAC 20101 CGAAGACCAT CAGCTCACGC TGACGTGTCG TCGGTACATC AAGGACCGCG ACCCGCATCC 20161 GTTCGAAGAT CTCAAGGGGC TCTGGGGAAT TGATCCTGTC GAAGACCTGC TGCAGAAGAT 20221 CCCGCTCCGG GACGGCTGCG TGGTCTGGGA CATCGAGGAC AACTCAGGTT GGGGCACTCA ACTGGCCGG 20281 GACCGCGTTC GGCGGTTCGT GGCTGACCGG GTTCGTCCGA GGGATGGTCC A GGCGAGTA 20341 CGACGGCCAG GTCGAGGGCG TCGATGTGTT CACCGGGGAC TACACGTTCC CA AAGAAGG 20401 CTACTCCCCC TGGTTCATGG GCACCAGCCC GATAGCACCC CACGTCGTGT TCG ACCGCTGACC GGGATCAAGT CGTCGGAGTT CTCGTACTAC GAGGCCACCG ACACCAGCTT 20461 CCTGGCTGGT GGACAGAGCG CACCTGGCAT CAACGAGGGC ATCTCGGCCC TGGTGAACAT 20521 CGGTGGCGAC CTGCTGACCT CGTTCATCAA CAGCCAGCTC GCCGCGCTCG GCGCGGTCGG 20581 TGGAGCGATT GACCTCCCGC CTCTGGGCGG TCTGCTCGAT GCGGTGTTGC AGCCTCTGTA 20641 CTCCGATGTG TTCGGCGCGT TCATGGAAGT TCCGACTCTG CGTGCGATGG GCATCTCGCT 20701 CCCGATCTCC GGGCTCGAGG ACATCGTCAC CGGACTGGGC GACTTCCACT ACTTCGAGAA 20761 CATGGCCGAC GGGGCGATGA AGGCGTTCAC GCTGTCAGCG TTCGCAGCCA TCGCATCGCA 20821 GATCCACAAG ACGAGGGCTC GAACGACCCA CACCCTCAAG GTGTCTGACG CCGCTCCGTA 20881 CATCTTCGCG CCAAAGCCCT ACGGGCACTG CTGGATCGGA GATCGCGTCG GCACGTCGGT 20941 CCTCGGCTAC CCGGTCGAGC ACCAGTTGTT CGTGGAGCGC ATCCGCAAGG TGAAGTACCG 21001 CATCGACAAA GACGGCATGA AGCCGTTGGA GATCGAGATC GGTTACCGCG AACCGAAGAA 21061 CCCAGCACTA CACATCCTCG AAGAGATCAA GCGCGTCAAC GGCGCTCTTG GCACTGCGGG 21121 GATTCTCTAA ACCGAAAGGC ACGCCGCATG ATTCCCTCAC AAGAGTCTCA CAATCCGAAC 21181 GACCCGCGAC AGCACGTCAT GTGGGCGCTA CGCAATCTCC CGATGATTGC TGGCGTCGGG 21241 GCGATCACGC ATCCGGGTTA CCTGGCGGAT TGGTCAGAGC ACTTGTGGAA GTGCGGCTTT 21301 CGGCACGTCG ACTGGCTCCG GGAGCTGGCT GATGAGGACG GCAACATCCA CGTCAGTCAG 21361 CTTCCTGACC AGGAGATCAA GTTTCAGCAG CCCTTCCGGG GCCAGCGAAG CGACTACAAC 21421 AACGCAGCTC GATGGGTCGG CAAAGACGAT CCTGACCCAG AGCCCGTGCG TATTCCAGAC 21481 ATTCGCAAGC TCACAGACC&. GGAGAACAGA GCGATGATCG CGCAGTACGA ACGAGACGGT 21541 TGGATCAAGG ATGGATCCc: CGGCCCAGCG ATAGCCGAGG TCGTGGAGTG ACCCCGTTCA 21601 ACCCAGACTC CATAGGCGAC TACGTGACAC TGCTCGGCGT TGCGTTCCTG ACCTTCTCGG 21661 TTCCCGCATG GTTCACCGGA CGAGCACGCA AGCACAGCAG TGACATCGGC GAAATCAAGG 21721 AACAGGTATG TAACACCCAC GACACGAACC TGCGCGATGA CCTCGACAGC GTCAAGGCAG 21781 ACATCAGCGA CTTGAAAGAG ATTGTGTTGC AAGGGTTCCA CCAGGTGAAC GAGTCGATCA 21841 ACCTCGAGCG CCGTGAGCGG ATCGAAGGAG ACCGCCGAAA GGAGGTTGCG TGACCTACCC 21901 CACCAACCCA CTAGAGGCCA TCGGCGCTGA CGGCGCATTC GAGATCGGTG GGGGCGACTG 21961 GAGCTTCGGC CAGGACTACA CCGAACAGGC CATCCGGGCT CTGTTCACGA TGCCAGCGGT 22021 CACGATGGAG AACGCTCTCG GCCTGCTCGA AGAGCACCTG CTGAAGCTGC CTCTGGAGGC 22081 GCTGCAGGGC TTCAAAGACA TGATCCCGGA CTGGGTCGAA GGAGCATTCG ACACGGTCAC 22141 cσσcGCTGTG CAGGCGATCA TGAACGCGCT CCAAGACGGC CCGCTGTTCC TGAAGTTCGC 22201 CGAGTTCCAG CTCTTCCTGC AGCGTCTGCT GAACAACCCG GCCGAGGTCA TCGGCGAGAT 22261 CCCCCAGACG TTGATCGACG GCCTACAGGA CGCGCTCAAC ACCGTCAACA ACACCATCCA 22321 GACCATCGTG GACATGCTCC TGCAGGCGCT GGGCATCACC CCGGAGGGGG AGCTGATCGA 22381 CCGGATCTTC GACCTGAGCG ATGAGATGGA GTGGCTGCAG ACCGCAGCCT CGAATGCAGC 22441 TACCGGCATC CAGGACACCT GGAACAAGTT CTGGGGAGCC CTCACCGGGC GCGTCCCAGA 22501 CCAGGACCAG ACCGTCGCTG AGCCCGCCGA GCGTATCGGC GAGCTGGCCG GCACCACGTC 22561 TGCTAACTCG TCTGCCATCG CGGAGCTGCA GCGTCGACTG GACAACCAGC AGAACGCTGG 22621 CGGCGTGGCC GGCGGTGACG ACTTCGAGCG ACTGAACATA TCCGGTTGGG ACATCAGGTA 22681 TTCCAACGGA TCCAGCGGCC GAGGGTACTA CCGTGCCGAC GGCCACCAAC TGGTCTGGAT 22741 GGACGAAGGC AACCAGCAGA ACACCGCGAC GTTCGTCCGC ACCAACCCCG CAGACGAGAA 22801 GACAGCCACC GACTACCAGA AGATGACGTT GGTCGTCGGG ACTATCTCCG GTGAGGTACA 22861 GACCGTGTTC CCGCCGCAGG GAGGTTCGCA CACCCGGCTA TGGGTCCGCG TCAACGACAA 22921 CGCTCCGACC GTCGGCATCA CCGACGGCGT GTTCGTAGAG ATCGGCGGCG TATCGAAGGC • 22981 CCAGATCGGC TACCGCCGCA ACGGCAATGA CACGTTCGTC GGATCTATGG TCGACTGCAC 23041 CTGGGGTGCT GGATCGATCT TCGCTCTGAC CGCCGGCACG GCCAACGGTG CTGAGAAGTT 23101 CGAGGTCTCG AAGAACGGCC CCGTGCTGGC CACATGGTCG GACGACGGCG TCGTCTCCGC 23161 GATGGGTGCG AACTACCGCC GCTGGGGCTG GGAAGGCCAG GCTCGTAACC GCAACCTCGG 23221 CCAGGGCACT CCGAACTCGG TCACCCGAGT GACGATCACC GACAACGATC CTACCGGCGC 23281 AGGCGGTGGA GCTGTCAACG TCGGAGGAGA TGTCGTAGGT GTACTCCCCA TAGAGAACGG 23341 AGGCACCGGA GCTTCGACAG CTTCGGCAGC CCGTACCGCT CTCGGAATCG ATGACCTGGT 23401 CGAAGATATG TCCGACGTAG TTCGTGGATC CGTCGAAGGA CTCCCGTTGA TACCGAAGAT 23461 CTGGGTAGGA ACAGAAGCTC AGTACACGGC TCTCGCCACC AAGGATCAGT CCACGCTATA 23521 CTTCAGGACC GCTTAATGAC TGGTATCTCG TTGGGTGTCA ACGACATCCG CAACCTCTCG 23581 ATATTCTTAG GCGTCAGCAA CAAGATATTG AAGGTCAGTC TAGGCACAGA AAAGGTCTGG 23641 CCTGCGTTCA CCCCGGTGCT GACCACGTTC GCCACGGTCG GCACGTACAC CTACAACATC 23701 CCCGACGGGG CCAAGTTCAT CGACGTCATC CTCCTCGGAG GAGGCGGCGG GGGTAAAGGC 23761 ATGGCCCTGG CTGACGGCTG GGGCAGAGGT GGAGACGCCG GAAGCTGGGC TATCGTCACT 23821 CTCGAACGCG GGGTACACAT CCCGTTGTCG ACCAAGACGA TCACCGGGCT CGTCGGAGCT 23881 GGAGGCGCAG CGGGAGCTGG CTCTGTATTC TCAGGCAAGG CCGGAGGCCC TGGAGGAAAC 23941 ACCACGGCGT CCGCTGTCGG ATGGTCAGGT TTGACCGCAA CCGGCGGTCC CGGAGGCTCT 24001 GTGATCGACA TCCTCAGCGT CGCCGGAAAG TCGCCTGGAG ATCGGACCTA CAACGACCAG 24061 CTCTACATAG GCGGCGCACA ACAGAACTCA GCTGGCGGGA ACGGCAATOC TCCTGGCGGC 24121 GGCGGGGCTG GTGCCCAGGT CTCCGCACAG AGCGGCGGTG CTGGCGCTCG CGGCCAGGCG 24181 TGGTTCTTCG CGTACTGACA AGAAACCCCC CTCTTTAGGA CTCAGTGTCC TTGGGAGGGG 24241 GGCTTTTTGC GTTTCAGGAG GTCTTGGCCA GCTTGGACAT CGCCTCAGCG ATAGCCTCGT 24301 CGCGGGCCTC AGACGCCATC TGGTACTTCA TCGCCATCCT AGGAGTCGTG TGACCGAGAC 24361 GGGCCATCAG CTCCTTGGTC GTCGCACCTG CCTGAGCGGC GAACGTAGCG CCGACAGCGC 24421 GGAGGTCGTG GATGCGGAGT TCCGGCCGAC CGATCTTGGC GTAGCCACGC TTCAGCGACT 24481 TGGTGAACGC GGACTTCGAC AGCCGGTTGC CCTGCGTCGT GGTCACCAGG AATGCCTCGG 24541 GGCCCTTGTT CATCTTCGTA CGGTCCTTCA TGTGCGCTCG GATCATCTCC GCGACGTGAG 24601 GCGGAACCGT CACAGGACGC TTCGACCGGA CGGTCTTGGC GTTGCCAACG ACGATCTTGT 24661 TCCCCACGCG GGAAGCGCCA CGGCGCACCC GGAGCTTCAT CGTCATGCCG TCGTCCACGA " 24721 TGTCCTTGCG GCGAAGCTCG ATCAGCTCTC CGAACCGGAG GCTCGTCCAC GCCAGGATC- *1* 24781 ATGCCGCGAT CCGGTAGTGC TCGAAGATCT CAGCGGCGAC GATGTCCAGC TCCTCAGGCG SUBSTITUTE SHEET 24841 TCAGCGCCTC TACGTCGCGC TCATCGGCTG CCTTCTGCTC GATCCGGCAC GGGTTCTCTG 24901 CGATCAGCTT GTCCTCGACC GCTGTGTTCA TCACCGCCCG GAGGACGTTG TAGGCATGCC 24961 GGCGGGCAGT CGGGTGCTTC CTACCCATCC CGGCCCACCA CGCACGCACC AGAGCTGGCG 25021 TCATCTCTGT GACCGCCACT TCACCTAGCA CCGGGTAGAT GCGGCGCTCC GCGTGCCCGC 25081 TGTACAGATC CCTGGTGCCG TCTGCGAGGT CGCGCTCCAC GAGCCACTTC CGGGTGTACT 25141 CCTCCAGCGT GATGGCGCTG GCGGCTGCCT TCTTCGCCCG GTCCTGTGGA GGGGTCCAGG 25201 TTCTCGcccσ CGAGCCAGGC TTCGGCGTCC ATCTTGTTGT 25261 TACCTCACAC CGTCCTGCGG GTTGACGTAT GAGGCTTGGA 25321 TTCAGCGATC CCCATCCGCG ACGTGCCAAC TAGGTCTCCT 25381 CGGGTTGCAA CTCCTGTGCA ACTCTCAGGC TTCAACGCGC 25441 TTCCACTTAG AGGATGCAGC CGAGAGGGGG TAAAAACCTA 25501 GTCGGCAGAC ACCCATTCTT CCAAACTAGC TACGCGGGTT 25561 GCTGGTCAGA GGGTGTTTTC GCCCTCTGGC CATTTTTCTT 25621 GTGCGACTCT TCTGACCTGG GCATACGCGG TTGCAACGCA 25681 GATGCTGACA AACGAATAGA GCCCCCCGCC TGCGCGAACA 25741 GACGAGGGGC ATTCACACCA GATTGGAGCT GGTGCAGTGA AGAGAATAGA CCGGGACAAG 25801 GTTGCACCGG GAGTTGCAGC GGTCGGAACC CTCGCCGTCG GCGGGCTGGC GTTCGCCCTG 25861 TCGTTCACGG CTCTCAGCGA σcTGGCTGcσ GCCAACGGGG TGGCCCAAGC AGAGATGGTG 25921 CCCTTGGTGG TCGACGGCCT GACGCTCGTC GCCACGGTCG CCACAGTGGC CCTCAΛGCAG 25981 AACAGTTGGT ACGCGTGGTC GCTGCTGATC CTGTCCACCG TCGTATCGGT GGCCGGCAAC 26041 GTGGCACACG CCTACCCCCA CGGCATCATC GCGATGGTGA TCGCTGCGAT CCCTCCGCTC 26101 TGGCTACTGG CGTCGACCCA CCTAACCGTG ATGCTGGCGA AGCAGCACTC GGAGCACGCC 26161 GAAGTACCTG TCTCGCGGCC AGAACCCGCG CCTCGGGGCC TGGAGCCCGC TGCCGCTTGA 26221 CTGCGCCCGA CCGGGACAGA AATACATAGA GAACCTATGG ATGTAGGAGG CACAAAAAAA 26281 TACCCCCCGA GCCAGCCCGA AGGCCAGCCC AGGGGGCATG GTTCTGCTTC AGTAGACCTT 26341 GCGAGTCCGA CCCGAGTTGA TCATCGCCAT GATGACCCAG ACGGGCAACC ACATTCCGCA 26401 GGTGATGAGC GAAAGCAACA GGTGCATCGC GTGGTTCGTC CTGACAGGCA TGACAGTGGG 26461 CTGCGGCATC GGAGGAGGCG CGACCGGGTA CGGCGAGCCC GCGTACCACT GAGGTCGATC 26521 TTGTTGGGGC GGATACTGAT TGGTCATCCC GACAGCCTAC TTGCCGATGG GTCGCATCAG 26581 CTCCTCGACC GACTcσcσcT CCACGCGGAT CAGCCGGGGA CCGAGCCGAA cσσccTTGAG 26641 CCGGCCGTCG GCGATGTAGT TGCGGACGGT CTTGGTGCTG ACACCGAGGT AGTCAGCGGT 26701 CTCCTGGATG GATGCTCTCG GGGGCATCAG CGCGGTCCTC CGTGCTTCAT CGGTTGTCTC 26761 CCGAACCCTG GATCACGCCA CGATCCTTGC GGCTCTGGAG CTTGTTGAGG TTCCTCTGGG 26821 TGACGGTGCT CAACCAGACA TCGAGCTGGT TGGCTAGCTG GGCGACGTAC CACATCACGT 26881 CTCCGAGTTC CGCCTGGAGG TCGTCTCGGT TCTCCTGGGT GATGACACCG TCTTTATCCC 26941 GGAGGATTTT CTTGACCTTG TTGGCGATCT CGCCGGCTTC GCCTACGAGA CCCATCGTCA 27001 CGTAGGAGAG ACCCTCGATG CTGTCGCAGT CGCCTGCACC GGGGTAGATC GCTGTGTCGC 27061 TCGCGGCGAT CTGGTAGATG TCGACGTGCA TCAGATCATC ACCGGGAACA ACTGGCCACC 27121 GGGCATCTGG ATGAACACCG GGACGCTGGG GGTGTAGTCC GACGAACCCG TGCCGCCCTC 27181 27241 ACAGGCGGAC AGGCTCAGGG TGGCGGCAAG GCCGATGATG GCTGCTGCGA TGGTCTTCTT 27301 CATCTGTTGC TCCAGTAGCT AAGTTCGGAC TCCAGTTCGC GGATACGCTC CTGTAGCCCT 27361 TGGTTTTCCA GGTACGCCTC GGCGAGGTTG GCCTCGGCGC GGTCACGGGC CTCGTCCTTC 27421 GACGTGGCCT CATCGATTGC CTCGTGTAGC CGGCGGATCA GATCTGGGAT GGCACCGTGC 27481 AGACCGCATA TGAAGTCGGC GTCTGCCTCG GAGAGGTGGG ACGCCACCAG ATCCTTGTCC 27541 TGGGTCTCCT GGTTGACCGC CCAGATGACG TGATCCTCTA GCCCGTGGTC GGTCTCGCAG 27601 ATAGAAGGCG GTTCTACCTC CTCTGGCATC CAGTAAGTCT TCTCAGCCCC GGTGGACTTC 27661 GCCCACTGCT GGTAGAGGAT GTCGAAGAAC TCGTGGTCCT GTTCGTCGGC GGTAATCACA 27721 GATCGTCCTC TTCATCCCAT TCGTCGTAGT AACACGTACA GCCGCAGCAG GTGCAGCAGC 27781 CGCACTCGTA GGTGCCGTAG TCGTAGTCAT CCCAGTCGTC TTCGTCCATC TAGCTGTACT 27841 CCTTCATGAT TCGGTCGAAC GCACGCGTCT GCACGCGCAT CTCCAGGTCG ACCGTTCGCT 27901 TCAACCACGC CCATTCGCCG TCGTGGTTGA TCTCCCACTG GCTCTTGAAT GTCGCTGTCT 27961 CAACGAGGAA CTCGACAGTC AACGTGTGCA GTCCGTTGTT GCTGGGCTGG AATCCGATAC 28021 CGTCCTCAGC GATGTACCAG GGCAACTCCT GGCCGTCGAA GTAGACGGCC TTGTCGGTCA 28081 CCAGTACTTC AGGGAAGGTG TGCTCGGTCA ACGGCGTCCC AGGTATGGGA TGACGCTGGC 28141 CCGGAACTCA AGGAACACCA TGTTGTCCGG GCAGTCCTCG GGGACGTTGT CGGGGCGTTC 28201 GGCGGTGTAG ACGCCGATCT CGTTGCCCTC CAGGGTTCCA AGCTCGTTGA GCTTGTAGAT 28261 CGCCAGACCC ATCAGCTCTT CATCGAGACC GTTCGGTGCT GGCAGTACAA CTTTGGCTTG 28321 TGGCATTAGC CCTCCCTCGG AATTACGTAT GCGCTGAACT CGACGGCCGT AATGCCGTCT GGCAGTTGGA 28381 ATCCGAACCG CTCTTCGAAC TCCTCGTTGG TGATGGGGCC GTACTCGAAG GTTCCGGGCA CTACCTCGCC iU CCCTCG ATCAGGAGGT ACGCAccσσc GGCGTACACC 28441 TCCTCGTCGT TCGGCCATCC GACTACGGTC CCGAGGACCG TGAACTTCCT CGGCTCCATC 28501 AGGGCACGTC CACTTCGTTG ATGAGGAACC GCATCGGAGG TGGAGTGAGC ATTGCCTCGG 28561 CTATGGCGAT GAGGGCGTTC AACTGACCCT TCAGCAGCTT CTCCTCGTCG CCTGCGGGAA 28621 GGTGGCGCAC TCGGCGCTCC ATCTCCTTGG CGCGTTCCAG ATATTCGGTG GCTGTCAAGT 28681 TGTCCTCCTT AGTAATCAGC GCCGTAGAGC GAACCCCACG AACGCTTTCC GACCTCGGGG 28741 TCGGTGCCAA ccAGCACcσσ ACCCATCTGT TCTTGCATCA GGTGGCCAAT GTGTGCAGCG 28801 GCTCTCTCAG CCTCTGAGGC GGGCAGAGAC GCGACGATCT CGTCGTGGAT AGGCAACCGT 28861 AGGTACGGGG TGTATCCGGC CTCGTGGAGG CGAATCAGAG CCCGACAGGT CACGTCCCGC 28921 GACGACGACT GGATCATGTA GTTCAGcσcσ GAGTATGTCC GCGAGCTGTC CAccσσcAGc 28981 cσccσσcccA TCGCGTTGAC GATGTAGCCG TTGCGGCCAG cTTccATcσc 29041 CAGCTTCTTG CTCAGCCGCT CCACACCGGG GTATGTCGCA GAGAACGCCT CATGAACTCG CTTGGCCACA 29101 GGGATCGAGA TCCCCACTGC CTCAGCGAGA GCCTTCGCCC CACCGCCGTA GACCTTCTGA 29161 AAGTTGGCGG TCTTCCCAAC CTTTCGCGGC ACCTGGGCTG CGTCAGCGGT CATCTGGTGG 29221 AGGTCCGCAC CGTTCTCGAA TGCCTCGATC ATGTTGCGGT CGCCCGACAG CGCCGCCAGG 29281 ACGCGAAGCT CCTGCGCCTG GTAGTCGACT GAGGCCATCA CATCGCCTGG CTCAGCGATG 29341 AAGCATCGCC GCACGATCCA GTCCGACGAC GGCAGCGTCT GCGCCGGGAT GCCGGTGATC 29401 GACATGCGCG AGGTCCGCGC CTGCAGTGGG TTGATGAACG TGTGGCAGCG GTCCTCAGAG 29461 TCCCTGGTGT CGATGAACTT CTGGACCCAG GTCTTCCGCC ACTTCCCCAG CTTCTTAGCC 29521 TCCTGAGCGA TGGCGGCAAG CTCGTTGCCA TCTTCGACCA GCTTGTCGAG CAGAGCCGCG 29581 TTGACCTGGC GCTTGCCAGT CTCGGTGCGA CCGGTGATCT TGACGCCCAT CTCCTCAAGC 29641 CCCTCGGCCA GATCCTCGGT CGAGTTGACC TTCTCCACGC CGTACTCGGT GAAAGCGATT 29701 GCCTCCCAGA CCTCCTGATC GGCCAACCAC TTCTCGGCGA GCGACCGCGA GTACTCCACA 29761 TCGAGCAGGA AGCCCTGCCT GTCGATGTAG CTGCAGATCT CACTGATCTT GTGCΓΠΓΓAC 29821 GGCACCAGCG ACCGACTCAC GTCGGGCACC AACGGTGTCA GGCTCTTGCA GACCCTCGCG 29881 GTGAAGATCG TGTCCATCCC GGCGTACAGC AGGTACTCCG GGTGGAACAG GTCGAΓGGTC 29941 GACCAGATCT TGGCCTTGGT CGTCTTGTGC TCGGCGGCTA GCTTGGCCAT GAGCTTCTTG 30001 ACGTTCTcσσ CCTGGTCCTC GGAGATGAAC TTCGCGATCA GCTCTTCGAG CGAGTGCCCG 30061 AACccσccσσ CCTCGAAGGG CCGGGGGTCC ACCAGCTTCG CCAGGATCTG CGTGTCAAGC 30121 ACGCGGGGCC ACAGACCCTC CAΓCTCGATC CCGAAGCACT GGTCGAGCAC CTGGAGGTCG 30181 AAGGAGGCGT TCTGGAGCAC CATGCGCTTG AGAGCGCCGA TGGCGATCCG CACGTCCTCG 30241 ATGAACACGT CTCCCAGCTC CACCGGCACC ACCCAGGCTT CGTCCTGAGT ACCGAACTGG 30301 ACGAGGCGGC ACTCGAAGGT GTCGCTGTAG ATGTCCAGCC CGGTGGTCTC AGTGTCGACG 30361 GCGAGGCAGT TCAGGTGAGC CCGGATGAAG TTGCGGAAGC CTTCCAGATC CTCTGGGGTT 30421 TCAACGACGT TGACGGTGAC GAGGTCTCCC TGAACCTCAT GCCGCAGCTC GATCAAAATG 30481 CTCTCCTACT GGAAGTACTG AGGCGGAATC CAGGTGGCTG AGGCCATCTC CTTGATGGCC 30541 TGCTGCATGG CCGCTTCGAA CGGACAGTCC GGGTCGATGT CCGGCTTGTA ATGGGTGACG 30601 ATGATCCGGC TGTTGCCGCC GAAGTCGTGG CTGACCAAGC CCTTTGGGGG CAGCTTCTTC 30661 AGCGCCTTGA TCAGTTCCTC AACCGTGGTC CCGGTAGGGG CCTTGCCGTC AGGCAATGCC 30721 TCCCCTCCGT ACGGCACGTC CAATGGGATC GTGTACCGCT CAACGTCTTT GATCTTCATC 30781 GAGCCTCTTC CTCTTCGACT ACCTCGTCTA CCCGGCGGAA TAACTCCGCT AGTTCTGCGG 30841 GTAGCAATAC TGGGTACTTC TCTCGGGCTT CCTGCATCGC TACCGCGATC CCAATCAGGG 30901 CAGCGAGCAG TTCATTGACG GAGTACGCCA ACAGCTCTTC GCGGATCTCT TCTCGGGTCA 30961 TTAGTGGTAG ATCCCCCGGA CGGTGCGCGA GATCGTGGCA GGGTTCACGC CGTAGTTCTC 31021 GGCGAGATCC TTCTGCTTCA TACCGCCCAG GTACGCCTGG CGGATGTCCT TGAccTcσcσ 31081 CTCGGTGAGC TTCTTGCGGT TCGGCCGGCT CGGGCCGGTC TCAGGCTTGA CCTGAGCCAG 31141 CGCCTTGCCG AACAGCTCGT TCTGCGTCCG CTGCTTGATC GCGTACCGAC GGTTCGCTGC 31201 AAGCACCTCG TTGAGCCGCT GGGACAACTT GACATTGGCC TCACGCACTA CCTCGACCTC 31261 TCCGAGCAAG TTCGTGATCC GGTAGTCCTT GTCCTGGTTC TCGATGGCCA ACCGGTTGTT 31321 CTCCTCGGAA AGCATCGAGA CCTTGTATTG CGCCTCTCCC AGCGCAGCTT TCAGGTGCTT 31381 CTTCCTCATT CAGCGCCCCT CTCTCGGCGG AACTGTTCGT ACTCGTCTTC GGTCATGTAG 31441 TAGTAGTAGT CAACGACCTT GTCCCAGTTG AAGGTTCGGG ACGTGCCGTC ATCGAACGCG 315.01 ATGATCAGGA CACCCTCTTG GGTGTCTAGG ATCGGCTCGC CAGCCACGAC GTGGAAGCGG 3156 " l TCCTCGAGGG TCACCGCAGT CGCTCTGCGT GCCATGTCAG TTCCTCTCAG TAGCTGTAGG 31621 GGACATCCGG GATGTCCTGG TAGGTGTTGG GTGCGATCTG TCGGAGCTGC CGAAGCAATT 31681 CCCCTGCCAG CTCACGGATC TCGGCATCCG CGGCCTCGTG ccAGcσσσcc TTGATGACGT 31741 ACCGCCACGC CCGATGGTTG CCCGTGACGA CCATCGGTGA GTTCGTCATG TTCGGCAGGA 31801 CAGCTCGCGC TGCCTCGCGG GCCTGCTTGC GCGGCAAGCC CCGGTCAGCC AGCCGGTTGA 31861 CGATGTGTTC GTAGACAGCG TCAATCTCAG AGCTGACGGA CTCCATGATG TGGACGAGGT 31921 CGTCTCGGTC GTCGGGGTGG AGCTTGAACA GAGCCGGGGG CAGATGGATG CCAAGGTCGG, 31981 TCGGATCCAC ATATCGCTGA GACACCACCG AGAAGCTCAA GTGACGGTGA CGCTCCAGCT 32041 CGGTCAGCAC CGACCTGCTG GCCTCGATGT AGAACGTCGC CGAGGCGTGC TCGAACACGC 32101 TCTCGTGGCC CAGATCGATG ATGTGGTTGA GGTAGTCCTC GTTCTcσσcA GTTGCCGGGT 32161 TCGGTCGGTG GAACGACCGG TAGCAGTTCC GGCCCGCGAA CTCGGCCAGC TCGTCGGCAT 32221 CGAAGTCGCC GAAGTAGGGA TCTTCGTCCT TGGATTCTTC GAAGTCATCG ACCTCGAATC 32281 CGATGTCCCG CAACGCACCC GGATCGATCT CGGTGGCAGC GATCAGTTTG GCTTTCATAC 32341 TCTCCGCTCA GAGTTGGTGG AACGAGGTCA GCCAGGGGGC AGCGAAGCCC TTCTACAGCT 32401 CCCCTTGGCT CGTTACCGGC TTCTCGACCT CGGTGGATGT CAAGTAGTCG AGATGACTAC 32461 TTCTTGTCGG GCCATTGCGC GTCACACTGC TGATCGCGAG GTGCGGTGCA GGAGAACAGC 32521 GCGTACGGCT TGCCCGTCTT CTTCGAGACG CCCGACTTGT AGACCATCTC GCCGTGCTGG 32581 CAGTACCGCT τcTcσccAcc AGGCGCTTCC TGAGCTGCCT GCGGGGCGCG AGACTGCTGC 32641 TGGCCACCGC CGCCGCCGTT GGCCGGCGCG GATCCACCGG AGCCTGCGTA GTGGCCTGCG 32701 ATCTGCTGGA CCTTGTCCAT CAGCGCCTTG AACTCGGCGG TGTTGACCTT GGCCAGCACG 32761 TcσσccGGGT CCGCACCCTT CACGACCACC CACGGGTCGC TGTACTGACC GGCGAACTTG 32821 AACGTGGCCG ACACCCCATC GGTGGAGTGC TGGACCGCCA TCGAGTCGCG CACAGCAGCC 32881 GAGGCCGTCG TCACCGTCGC CGACGGCGCG GTCTCAGGCT CAGGAGCCGG GGCCGGCTCG 32941 GGCTGGGCAG GGGCGGTGCT CCACGGATCG TCGTAGGACA ACTGGTTACC TTTCACTTAA 33001 TGGGGCATGC GCCGTTGGCG CACTCTTCAT CGACACCGTC TTCGACGGCT TTGGCCGCAG 33061 CAGATTCGTA CTGCTGCTTG GTGATTCGCT CGTACGGAGC CTGCGGGAAG CTGGACTCCG 33121 GGAAGATCCT GGAGCCCTTG ATGAGCCCCG CGAACCTCTT GAGATCGGCT GCGACATCCT 33181 33241 CGGCCTCGTA GGCGTCTGGA TGGACGTTGG CGGTGAACGA CACCGCGTTG TCAGCCCAGC 33301 ACATCTGGTA GAGCGCCTGG AACGCCAGGA GCTGGTGGAG GGTCAACTCG TCGGCTGACT 33361 CAACGATCTC CTCGTCCCAA CCGAGTTCCT CGACAGCCTG GACCAACGTG TCCTTGGTCG 33421 GGATCGAAAC CACCTCGGTG TTCGGAGCGA AGAGATCCTT CTCGATCTCG TAACCCTCGG CTGCCAACCT CCGCAGCTCG GCCATGTCGC TGTTGAGGTT GAACCσCACA CGCCGGATGA 33481 AGTACCGCGA GAAGATCGGG TGGATCCCCT CGGAGACTCC TGGCATCTTC GCCACCGTGC 33541 CTGTGGGAGC GATGGTTCGC TTCTTCACCG GGACAGGGAT CCTCAGATCA TGGGCGAACC 33601 GTTCGGCCTC TGAGTCGACC TCAGCGGCCA TCTCCCGCAA GAACTGGGTG AACCGCTTAT 33661 CTCCGGGTGC CTCGGAGTAC CTGCTACCTG TGAGGGCCAA ATAGGAGGCA ACTCCGAGAT 33721 GACCCACGCC GATGCGACGG TTTCGGTCCA GAACCTCCCG GCTCTTCGGG TCGGCCACTT 33781 CCGAGAACGT CGCCCGGATC AGGAATCTCG TCATCAGACG ATGCGCCCGG ATCAGGTCGA 33841 GGTAGTCGGT CTTGCCGGCC GGCGTCACGA ACGCCGCCAG GTTGATGTGG CCGAGGTTGC 33901 ACGGCTCCCA CGGTTCGAGA GTGATCTCGC CGCATGGGTT GGTGCAGACC ACCCGGTTGG 33961 GCTCACCGAC GTTGGACAGT GACGAGTCCC ACATCCCCGG CTCTCCGTTG CGTACGGCTC 34021 CCTCGGAGAG TGCCTTGAGC ACTCGGTGGG CTCGCTTCTG CTTGGGCATG TCCTCGCGGG 34081 CGACCGCGAA GCTGCCGTAG CC TCCTTGG CCAGACGCCA GAACTCGTCG TCAACCTCGA 34141 CCGAGATGTT CGTCGTCCAG TGCTCGCCCG TGCTCGCCTT GATGTTGATG AACTTGTCGA 34201 TCTGGTAGTC GTCCCAGTGC ATCATCGACA TCCGCGCCOA CCGGCGCACA CCGCCGGCCA 34261 CAACACACTG AGCGATGGCG TGGTCGACCT CCATCGCGGC GATGCCGTCG AGCGTGATCC 34321 CTGCGTACTC CGAGAAGATG TTGGCGACCT TCTGCAGCAT CACAGCGAAC GGCAGCGGGC 34381 CGCTGGCCAC TCCACCGAAC GTCTTGAGCT TGGCCCCTTG CGGCCGGATG CGGCTCACGT 34441 CGTACACCCG CTGGTAGTGG ACCGTGCCGG GTCGGTAGTG CGTGTCGATC AGATCGACCA 34501 GCGCAGCAGC CCAGCCCTCT CGTGAGTCCT CGATGGCGTA GGCACCGGCC CAGTCGTGGC 34561 TGTAGTGCTC CGACAGAATG CCTACATCCT TCATCGGCTG GTAGTCGACA TGCTCTGGAT 34621 CACAGACGAT CTCGACCCGC AGGGGGTTTA CGACCTCGGG GTAGCCTTCG AGGTAGTGGT 34681 TCGAGTAGTT CGCCCCGACT cccccσcccT CCATCAGGCG CATGAACGTG AACTGGAAGT 34741 GGTCCGAGAT CTTCTCGGGC CAGCCAGCTA CCCAGCAGTT GAAGAGGTGC TGCGCGTTCT 34801 TGACCCCCGA GGCCCACAGA TGCCGACCTG CCGGCAGCAC CTTGAACTTG GTCATCAGAC 34861 GAACGAGATC TTCTCGCTC CCTTCCAACA TATGTCGCCG GTCGACAAGA GCAAGATTGC 34921 CGTCCACGAC CCTCTCGACC GTTTCCGGCC AGGTTTCCTT CGAGCCGTCA GGCTTGGTCC 34981 TGGCGTAGGT TCGGTTGTAA ACGAGTTCAC CGGTTGGTCC CCAAGGGATT TCGTCAGTCA 35041 ACTACTTCCT CTCAGTCAGT TCGTATCGCT TGAAATAGGC GTCGGCAGAG TCGCCGCCAG 35J.01 AGAACGAGAC CCCGTACTCG ACCGGGCCTG CACCACGCAC CTCGCAGGTA ACGACGCCCT 35161 TccTTCcccσ GAACATCGGC CAGGTTCCCT TGGAGGGGTG CTTGGTCTCG TCCCGCTGGA 35221 CGATGACCTT GGTGCCCTTC TTCATGCCGA CTTCCGTTCT CCGTAGCCGG GAGTGAAGCA 35281 ACCCCCGACG TACAGCTCGA GATCTTCTTG CGACCAGTTC TCCAGTCGCA TCGGCGGCTG 35341 GTGCGGGAAC AGCTCCGGGA ACACCTCGGC CCGGTACAGC TCCGAACCGG GCATCCCGTT 35401 GAACGTCGGA TCAAGAATGT TGTGCATGGC ACCTCCCTCC CAAGAACTCG GAGATCGGCG 35461 GCTCGTAGAG GTAGCCATCG CGCAGCTCGG GGTTCTCGAT GAGCATGATC GCGATGTTCG 35521 CTGTGGGGTC AGAGTGCCCA TCCCCCTGCG ACTTTCGGAT GTCTGGGAAG ATAGCGTGCT 35581 TGCTGCCCGG ACCATCCTTG ACGATGACCT TGCCCTTGTC GTCCTTCTCC ACGCCAGCCG SUBSTITUTE SHEET 35641 TGATCGCGAT GATGTTGACG TGCTCGGTCA GCGACTTGTG AGCGCGGAAC AACCGGTTCT 35701 GCCCGCTCTT ATCCTTCGGG GAGATCCCGT CGGTGTAGCG GCTCCTGATC GCCTCTGCAT 35761 AGCCCCCGTT CTGAGCGTCC AGAGCCTTCA TCGCCAGCGG GAGGATGTCG ACCAGGTACC 35821 GATTGGTCGA CTCCCCCTGC AGAGCCTCTT TGACGTTCTC GGACGAGTAG TGGCTGCGCT 35881 CCTGGAACAA GTCGCGGGCC TTGGCCGCTC CCGACAGGAT GTTGCGAACC TGATTGCGTA 35941 CGTAGTGAAC TGCCTCACCA CGGTGCAAGC TCTCCAGCGT CTTCTGGATG TACGGGCTCT 36001 CGAGGTACCA GACCCACAGC TCTTGGATGA TCTCCTCGGC TGTCAGGTTG GTCTCCCAAC 36061 CGATCAGCGC CTTCCGGGTG GCCCTGCTGA ACAGCTTGCT GATGTCGTCG GTCAAGGCAT 36121 CACCTTTCGT AGGTACTCCT CCCGGTCCAA TCGGCGGTCG AGGTGTCGAG TGACCTCCTC 36181 CGCGAAGACC TCGCGGACTT CGCTGGAGGT GATCTGGCGC GAACGTGCGT TCTTGTGCAG 36241 GTACGGCAGC TTGGTGGCTG TCAAGTTCTA GACCTCCCAG ACTCGGCCGT CGACCGAGAA 36301 CCGGCCTCCG ACAATCGGAA CAAGCTCAGG CTTGACGTGC TGGCCGTCGA CCGTCAGCAG 36361 AGCAAAACCA CTCTGCCAGT TGGCTGTTGC ACCCTTGAGG TACTGAGCTA GCTTCATGTT 36421 CATCAGGTTG CCGACCTCCA TCGACCACAG CACCTTCTGG TTGCCGCCGT AGCCCAGCGT 36481 GTGTGGCTTG ATGCCCTGGC GGTGGGTGTG TCCGATGATC ACCGACGTGC CGAACCGCAT 36541 CATCGCGTTG TACGCGGTGT CAGCGGACTT CTGCGTCACC CGGACCCCAC CACGGTGGCC 36601 GTGGGTGGAG ATCCAGCCTG GAGCGATCTT GTAGAACTCA GGCAGCACGT CAACACCGAA 36661 CCCGTCGAAG TCCAGCAGGT TCTGGAACTG GAACGAGCTG ACGTACTCGA CCAGCGCCGG 36721 GGCGAACTGG TGCAGGTAGT CGACTGGCCG GCGGTCGTGG TTGCCCTCGT GGACACCAAC 36781 CGGGCCGTCG TAGACCTGGC GCAGCGGCTC CAGGAACCGC CGCTTGCACT GCTCGGAGTC 36841 GGGCTTGATC CGCTGAGCGA ACTCTTCCTT GGTGCCCTTG GTCCACCGAG ACGGGCTCGG 36901 GTAGTCCATC AGGTCACCGA TGTGGACGAC CTCGTCAGGC TGGGTGTCCC CGATGTAGCC 36961 GATGACCGCC TTCAACTGCT TGCGATCATC GAACGGAATC TGGGTGTCCG AGATGACGAC 37021 GATGCGCTTG CTCACTCAGC GACCTCGGTG AAGGGGCCCC GCATACGTTC CTCGTGGGAG 37081 CTGGCGTTGC CTCCTGACCA GCGTCGCTTG CCCACCTTGG TGTGGTGCAA CCCGTTGGGG 37141 TAGTAGATCC ACTTCACTCC TGTGGCGTTG GTGACGGTCT TCACATCGGC AGGAACGTCC 37201 AGCAAGGTGT CCCACTGGCG AGGCCCCTTG GGATACCGCT CGTCCTCGGG GAGCTGCATC 37261 TTCTCCAGAA CGCCTGCGTA ACCGGCGATG TCGACCACCG TGTCCTGGTG GTAGCCGTTC 37321 TCCATGAACC GGGCGATCTT CAGCAGGATC ATCATGACGG CCACGTCCTC CGGGGTGAAC 37381 TCGACC CGC GCTTGTACGC GCCCCACAGG GTCGCGATGC GTTCGTGGTT CTCCTTGGCG 37441 TCCCCCTAGT CCTGGGCTCG CTGTCCGTTG ATGATCTCTT CGGCGGTGGT CAGAATGCTC 37501 ACAGT CAGT CTCCGATGCG GTGTAGTAGT CGATCAGCTC ATCGAGCTGG TCCGGTTGAT 37561 AGCCGAGGAT CGGCTTGTGG GTGTCAGTGA CGACGACGGG AACCGACATC GCGTTGAGCA 37621 CCTTGGTGAC GTAGTCGTAC GCCTCCGAGT TGGCCGTGAC ATCGACTGCG TCGAAGTCGA 37681 TCCCGGCAGC CGTCAGCTTG TCTTTGACTC GCTCGCATGG CTTGCAGCCG GGACGGGTGT 37741 ACACCGTGAC CGGCGCGAAC AGCGTTCTCA CGTGAGCACC ATCCCAGTCG ATGTATCGGT 37801 CTCCATACAT CAGATCCTTT CCAGCAGAGC AGCTTTGCCC TGCGATGTGA CTAGTGAGTT 37861 GACATCCTCG CCTTCTGGCA TCGGGATGAT TCGGGCGTTC GGCAGCGTCT TCGCCACCGA 37921 CCGGGCGAAC TCCATACCGG CGTCGTCGCC GTCGGCCAGG ATGTTCACGT TGCGGTAGCC 37981 CAGGAACAGC TCTCGGAAGT ACGGCTTCCA CTTCTGGGCT CCGCTGAGCC CCACCGTCGG 38041 CAGCCCACAC AGCTCGGCGG TGATCGTGTC GAGTTCTCCC TCGCAGATCG CCATGTCCTT 38101 GCTGTATTTG GTCAGCGCGT AGGTGTTGTA GAGCCGGTCC TTCTCCCCTG GCATCGACAG 38161 GTACTTCGGT GTGCCACCGT CGATTCGGCG ATACCGGATC GCAGCTACCG TCCAGTGACG 38221 CCAGGGCGAC CACCGCATAT ACGGAATCGC CAGGCAGCCC CGGTACATCT CATGTCCAGG 38281 GAGTGGGTCG TCCACGAATC CCAGACCGAA CCGGCTTAGT TCCGCTCGGC CGGCCAGCCC 38341 GCGACTCGCC ΆI ATACTCGT CGGCTGGGCT TCCGGGCAGG CTTTCTCTGT ACCGGGACGT 38401 TGCCTCCCAC AC- .TAGGTTC TCTGCGATTC GCTTAGCCTC TGCAAATGTC ACCTCCTCTT 38461 CGTGACGAAT GATCGAGATC ACGTCTCCAC GGACCCCGCA GGCCATGCAG TTGTAGCCCT 38521 GTAGGTCGTA ACTGACTGCG GCAGACGGCG TTTCGTCGCC GTGGAAGGGG CACAGGCACT 38581 TGTTCCACTC GTGGTGGTCA GGTGGTGGTT CCCAATCCGG GTGGTAGCGA AGAATCGCCC 38641 TCGCGATGGG CGAGTCGTTC ATTCGTCCTC GTCAAGCTCC TCGGGAGAGA GCCCTTCGAA 38701 GATCCCGTTC AGGACGGCGG CGAAGCCCTC GCCGGTCTCC GCTGCGTCGA GCATCTCTGC 38761 AATCGTCTTT GCCATGTTTC CTCCTGGTGG ATGTCAAGTT CGAGACAGCT TGTCAGCCTC 38821 GACTGGAGCG ATGCGCTCCC CGATGACTTG GACGGCCGGC GGGTTCAGCA GGTACTCGAT 38881 GGCCCGTTTG AAGAACTCGA TGCAGTCCCT CGCCCAGCCC AGCGTGTACT TGTTGCACAT 38941 CGTGCAGAGC AACCCTCGGA CGATGCCTGT CTTGTGATCG TGGTCGACCG ACAGGCGCTT 39001 CTTCTTACCG TTGGCTCGCT GGCAGATGTA GCACCGACCA CCTTGGAACT CGTAGATCTG 39061 CCAATACTCA TCGCCGGTGA TGCCGTAGGT GGCCAGGATC CGGGTCTCCC AGCTCGTAGA 39121 GCTGCGAGCC GTCCTGAACT CTCGGTGATG AGTAGCGCAT CGTGGCCCTG GATACTTGGC 39181 GTCTCGCGTG AGCGGGAGCC CCTGTGCGAC ACAGTCTTTG CAAGGCTTCC GCTTGTGCTT SUBSTITUTE SKEE" 39241 ACGGTTCTGC ACCCGGTACC CCGGAGACCT CTTCGCCGCC CTCGGCACGC GCGTCCTCCT 39301 CCCGGTTCTC CATCACCATG CAGAACCACG ACAGCAGCCC TGCCAGGGAG ATGTAGAAGG 39361 CCACCAGAAC TTGGCCGCTC ACTTCACCAT TCCTCGAACC CACCAGCGAG ACAGCGCCTT 39421 ACGCCCTTTG TCGAGCGGGG TCAGCTCGCG CTCATCGTCC TCACCGAAGT CGAACTCGAT 39481 GCTGGCGATC TCGTAGCCGA GGATCTTGAA CGACACGTTC ATAGGCGGTC TCCGAAGTTG 39541 ATGACGGGAA TGCCGGCCCT TTCGGCCTCT CGCATGCAGT GCCGGGTGCC GACTGAGTTG 3 601 CCGAGGGGGA ACGCCAGACA GATGTCCGCA CCGGCCCTGA CCATCTCGAT GTTGCGGAGG 39661 ATGCCAGCCC GCTTGCCGTA GCGTTCCCAG TCGGCTCGGT GCAGCTCGGG GAGCACGTCC 39721 CATCCCTCCT GCTTCATCCC CCAGGCCCAG CGGTCTGCGA TGTCGTCAGC GCCGCGAGCG 39781 CCGCCGTGGA CGACCGTGAG ACCGGAGAAG GACCGGTGGT ACTCAGTGGC CAACGCTTCC 39841 CAGACCGTGG TGCGGTCCTT CCAGATCCGA GATCCGGTGA TCAGTACTCG CCGCATCAGA 39901 TCGCCTCCCA CTGCAGGCCG TCGTGCGACG TGACCAGCTC CGCTTCGTAG ACGCCGTAGC 39961 GGGTGGCCAG GAACTGGATC ATCTGCGCCT GCTTGTACCC GAAGGGACAT TCGTGGACGC 40021 cσcTGATcσσ GTATCTGACT CCGTATTTCA CTTGATCCAC CGCTTCGCGA TTCGGTCGAC 40081 GTTCTCCTCG GAGACGTTGC GGGCGAGGCC GGTGAACTCC TGGCCGTGGA CCTTGGTCTC 40141 GATCACGCGA GGCTTGCGGG GATCCGGGCT CTCCGGGTCG ATCCGCTTGT GGGTCCAGAC 40201 GGTCGGCTTC GTCTTGATCA GAGCGCCCAG CACCTGCTGG CGCAGTGGGT TGGTCTTGCG 40261 GGGCATAGCG TTTGGAGTGG TCATCTGGAT CCTTTCCTCG GTGGCTGTCA AGTCGGTGTG 40321 CGTAGTGAAG CCCCCCCAGG CATGCGCGCC CCGCCTGGGG AGAGTTGATC AGCGCAGTTC 40381 GATGTCGGGC AGGATCGCCT GCGGCTTGAA GTTGACCTGG TAGAAGTCGG TCGAGACGTT 40441 TGCGCCATCG ACCTGCTCCA TGAAGTAGGA GACGTTGTCC GACAGGCCCA GGAAGTGCTT 40501 CTTGATCCCG TCCTTGGTCT TGCAGGTCAC GTCGAGCTTC TTCGACGCGG TGTCCGCGTT 40561 GATTGAGCAC CGGCCCTGGA TCTCGAGCAG GTACTTGTCC GTGATCCCGT TGAAGAACAC 40621 GATCCGGCGA TTGATCTCGA AGTTGTCAGC GGCCTTGCTG ACGTTCTCCG ATGCGACGTC 40681 GGCGTCGGAG GTACACGCGG AGAGGCCCAG GATCGCCGAT CCGGCGATGA GTGCGGTGGC 40741 GATGATCTTC TTCATGTTCG CTACTTTCTG TTTGGTGGAT GTCAAGTTAG TGACCGAAGT 40801 CGTTGATCTG CATAGTGTCT CCGACGAACT CCAAGGAAGC GAAGTCTTGT CCCGACGGGT 40861 CCGACTTCCC CCCTCGGTTC TTGACCGTGG AGACGTTGAG CATGTCCGGG CCGAACCCGT 40921 CCGATACTCG GTGGAGAGTG AGGATCATCT CAGGAACACG CCCGATCTGA CCTTTGATGC 40981 CCGACAACGG GATCGGCTTG TCGCCGTCGT TGTGCGGGCC GGTGACGTGG TGGAGCCCGA *"?| CGACGCATGA GCCTGTCTCA CGGCCCATCT CGTGTAGGTA GTCCATCAGC GACTCCAGAC * f ° * J * CCGAGAACGG GTCGTCTCCC TCGCTTGAAT CGGTGCGGAC GTTGGTGATG TTGTCCACGA ^, , ι CGATCAACGC TGGGAAGTCC TCGTAC.'.GCG CGTCATACGC GGCCAGAGCG TTCTCGATCT --21 CGTCCAACGA CGGTGATGCC TTGTAGTTGA ACCGGATCGG GATCTCGTCT AGTGAGTCAG 41281 CTACCGCGTC CTCGATGTTC TGCTCGCGAA CAGCCCGCGT AGCTCGTTCG AGCGACCATC 41341 CGCTGAGGAT GGACACCGAA CGGGAGAGCT GGGTGAACGC ATCAGAGTCG GCCGAGAAGT 41,401 ACAACGTCGG CACCTTCGήC TTGAGCGCGT AGGCGAGGAC GAACGCCGAC TTCCCGGTGC 41461 CGGGGCCGGC GCAGACCAGG ACTAGCTGGC CTCGTCGGAG ATGTGTACCT TTCTGGTCAA 41521 GCGCGGCCCA GACCGGGGGT AGCGGATCCC CCGCCGACCC TCGGATGTAG AGCGATTGTC 41581 TAGGTGTGTA CACCTTCCTC CTCGTGGATG TGATTGACCA GGTCATAGAT CTCGTCGCGA 41641 GAGACCAGCC GGCCCCAGGC GTCGATCCCC ACGTGGATCT GTCTCCGGTG GATGTGTCGG 41701 GACAGGATCA TCGGCGAATG CGTGTGCCCG TGGATCAGGA TCTTGCCATC GTCACGGAGC 41761 CTCCACTGGG TGTGTCGGTC CTCGCTGGTG TGGTCCCCGA CGTATGGGAA GTGGCTCAGC 41821 AGAACATCTG TGTGCCCGCC AGCGTCCCCG TACAGCGGCA CCCGGATACG AGCTGCCGTC 41881 GACACATGCT CGAACACCAT CCAGTACGCA CCAACCAGCT TGTGAGCATC GCGGTTCATC 41941 GGGTGGGGCC CATCGTGGTT GCCCAGGATC AGCCGTTTGC GGCCTGGCCG ATCCGAGATC 42001 CACCCGAGGG CATGTATCTG CCCCTTGGTG GAGCCAGAGG AGATGTCACC TAGGATCCAG 42061 ACCGTGTCGT CCTTGCCGAC GACCGAGTCC CACGCCTTCG CCAGGGTGGC GTCGTGCTCT 42121 TCGACATCAT CCGCCAGGTT GCGGATCTCC ATCAGCCGCT TGTGTCCGAT GTGTAGATCG 42 81 GACGTGAACC AGGTGTTGCT CATGGCTTCC TTTCAGAACG GCGGGCCGTA CAGCTCGATC j ACCAGCGCGT GCAGCTCCTC TGCCGCGTCG TCACGCTCGA ATCCGCAGCA GGAATCGTGC 42301 CGGTCGAGGA TTGCGACGAT CTGGTCGTAG AGGCTGGGCC TCACTTCACC TTCTTCGGAT 42361 CGATCAAGGC GTCGTGAATC GGCCGACCGG CGCGAGCCGC GTGCGTCTCG GCGTCCAAGG 42421 CTCGCTGCAT CTGGTTCATC AGCCGGGTGC CGCGCAGCTT GAGGATCTTC ATGGTCGCCC 42481 GACCCTTGTA TCCAGCGCGG TGCATCCGTA GGACGCAGGC TGTCTCGTGC GGGGCTATAG 42541 GTGACCTCAG CGACGGGTGG TTTGGATCCC AGTTCGTCAT GTCTTCCTCT CGGTGGCTGT 42601 CAAGTTGGTC ACAGACCGAA CTCTTCCTGG TACTGCGGGA TGAAGTGGCC GGCCGTTCAT 42661 GTTCGGCTCG ATACCTCTCG CGTCACGAAC TCCTGCCCGT TCCATCTCCG ACCGTCCTCG _\ ll AACTCGATCA CGATCTCTCG TCCGGGATGA CGCACGGCCT CCGCTTGGGC AAACCTGCGT 42781 GCAGCCTCTG GGGTCGGGAA CGGAAACTTC TGCGAGGCGT ACAGCTCCTG GTGCCACTTC 42841 UGCTTGTCAG GAATCGGCCC CATTTCCACG TACGTGTAAC CCGCGTCGGG GTCGAGTTCG 42901 AGCGTTTTCT TGTATTCCTT CGTGCCTGCC TTAGAGGGAA GGTGAGTATC GGTGGCTGTC 42961 AAGGTGACCT CACTTAAAAA CAGGGCAGCT GTAATTCACA TCACAGAAGC CGCATTTGTC 43021 AGGTTCAGGC AGAGGCTCGA AGTCACCAGC CTGGATCCGA GCCTCGACCT CATGGAACCT 43081 CTCGGTGATC CGCTCCCGCG TCCAATCGGT CAGGTCGTAG GGCGCAGTGG GCTTCGCCTT 43141 GATGCCCTTC TTCCCCGCCA TGAAGTAGTC GCCCGTCTTC GGAGCCTCCA CGTCATAGGT 43201 CATCGCGACC GCGAGCGCGT ACACGCCGAG CTGGAAGTCG TCACCCGGCG AGTTGCCGGT 43261 CTTGTAGTCC CGGACTCGAA GCTCACCGTT GACCACGACG ACCGCGTCGA TGAACCCTCG 43321 GACGCGGATG CCGTCCAGCT CGATGTTGAA CGGAAGCTCG ATGGCCGGCT TGGGCTGTTC 43381 ACACTCCTTG CAGTTGGTGT CTTTCCACGC CTCCGTAGAG CAGATCCCTC GCCCAGGGGT 43441 AGTCCAGATC TGCTGGCCCT TGTCCTTCCG CCACGCGATG AACTTCTCTA CCTGCTCCAG 43501 TCCAAGGTGG AACCGGCGCT CGATGTCACG CTCACCGTTG TACGGCCCGG ACCAAAACCA 43561 CCACTCGAAG TTCGGGGTTT CGTCGCACAG TGCTCCGATG TCCTTGGCGT ACTCCTCGCG 43621 GAAGATCTCT TGTGCCCGTT CGAGGCTCAT CTCGCGGCCC TCGGCCAGAG CCTTCTCGTA 43681 GACCTCAGCG ACGGTGTGAA ACGCGGTGCC CTGCGGCAAC CACGCCGCAG GACGAGCCCA 43741 TACCTTGTCG ATGCGAGCCA GC.TTGTACGC CTGCGGGCAA CGTGTGTATT GGTTCAACTG 43801 GCTGACGCTT CGCAGCGGCA GCAATGTCTT GGTGTCTGTC ACGCAGCGGC CATCCTTCCC 43861 TTGCCTATCG TCTCGTTCAG CGCCCCGTCG ACAGCGACAC TGAGCAGTTT TGCGACCTCC 43921 GACATGTCAA TCGGATCCTT GGGGAATTGG TCAGCCTGAG TCATCCTGAG CACCATCCAC 43981 TCGGTGCCCT TGTCGCAGTG GATCATGGTC GGATCAAAGC GAGTTCCCCG TGCTACGTAC 44041 TCGACTTTGT TCGCGGAAAG AATCAAATTC GACACAGGCC GATAAAGTCG TGAGGTGTCT 44101 TTTACACGAG GACTGCGGTA GACGAGCAGA ACTGAGACTG GGTCTTCGTC CAGTTGGCCC 44161 TTCCACCACG CCTCACACCT CTGCGCGAAC AGCCACCCTG GATGATCGGC GATGACTTGC. 44221 GGTGAGGTGT GGACGAGGTT GTCTGCGAAC AGCTTTGCGA GCCGAGTGAG GGGCACGGGG 44281 TTTCCTTTCG TTGCGCGGCC TGGGTTGGCT CACACAACCG GTCGTGACTT TTAGGGCTCC 44341 GAGAGAAGCT CCTCGATGTC GTCTGGCCAC GACCAGAGGA GTTCACCCTC GGCGGTGAGG 44401 TTGGTGTGCT CGTTCACCCG GATCAGGAGA TCGTCATCCT CGATGCCTCG GGGGACGTAC 44461 CTGAACCCGC CGCCGGCCAT ACCTTCGTAG GGCTCGATGG ATGGGTCGAA CTCGAGCACT 44521 AAGTCGTCGT CGCGGAGCAT CTTCCACCAC GACAATAGGC GCTTCTTCTT GTCTTCGGAC 44581 ATCGTGCGGA AGCTACCCAC TCGCATGTAC TCGCCGTGAT CCCGGAGCCT CTGAAAAGCC 44641 TTCGACTTAT CGTGAGGTTT CCGCGTGTCC CACGGCCAGT TCTGCTGGAC GATCTGCCTG 44701 GTGGTCAACC GTCCTCCGTA GGTCTTCTTG TGCCACGACA CCGCTTGTCG AG CACGCCA 44761 TACAGCTCTG CGATTTCGGT CTGATTAAAC CCCTTCCTGC GAAGATCTTC GATCTCGCTG 44821 AGAGTGAGTG GTATTCGGCT AGGGGCCGGA ACCACTGCTT TGTGTTGGAT TTTGCCGCTC 44881 ATGTTTCCCT CCATGAGAAA GGTGCGTGCG TCTCCGCCGA TTACGGAGAC ATGTTGGTGC 44941 CTGTCAAGGA TACCCCTAAT TTAGTTGCGT CTGCGGAACC ATATTCAGTT GTGTTCCCCG 45001 ACGCCGTGGC CGTCTCCCAC TGGGCGTGGG ATCGACTGGC GTTACGCGGT CGTAAATGTA 45061 GCGGCCTGCC CCACTCGGTA GCAAACCTTG TGACAGGTAT CACTTAGGTC GCCTTCTGTT 45121 ACACGTTGAC CTCGGGTTTC ATCGTCACGA CTCTC TTTC TTAGACAGCC TCAAGATCGT 45181 TACACCGGCT TGCGAAGATG TACCTTCGCC TTGAATCCGG CCCTTGCCAG CTCGAACTCG 45241 ACCACCTGGC GGGCGGTCTC CTTCAGGTCG GACTTCGCCG ACAGCGGCCC GACGAACCCG 45301 TAGCTCTTGA TGTACTCCTC GAGGTCGATG TCGACGTACA GCGTGACAGG GACCACCGAC 45361 AAGTCACACC TCCAATTCGT GGGGCTTGAT CTCGTTGGTC ACGTCGTAGT CGTTCAGCAG 45421 CGACTGGAAG TCGGAGTCTG TCAAGTCGTC CAACTCATCC TGCTCGAACG GCGCGGGCTC 45481 GTCATGCCAC GTCTTCCACT GGTCGTGGTC GGCGCGGAAC CACTTCCGCA GATCCTTGAT 45541 GGCCTCGTCC TCGGTGGCGA AGACGTAGGT CTCGAGCACG TCCTCGTACT CGACGGTCAG 45601 CGACCAGACG GTGATCTTCA CTCCCCGTTC ACCTCCGCTT TGTAGTTCAT CTCGGCGGTC 45661 TCCTCCTAGT TGGGTAGCAG TCGGTTGTAC TCGTCGTGGC TGATCTCGCC AACGATGAAC 45721 TGGCGCATCA GATTTGCGAC CGAAGCCGCG TCCATCCCTT CGGGAATGGG CTTGGCGTGG 45781 CCGAACTGCC AGTCTCGTGA GCGCCAGCGG AACCAGAGTT GGACCTTGTC CAGTGAGGTC 45841 AGGTGCAGGC ACTGAAACGT CATGCCTCCG AACGGGAACT CCATCACACC TCCTGTTTGA 45901 CCTTGACGGT GTGGCCTGTC ATTACTTCGT GGATTCGGAT GCTGGTGCCG AACGTCTTTC 45Θ61 GCGTCTCGGC CTTGAACTCG GTGGAGCACC CCGAGCACTT CGCTTTGAAT CGCACTAGCA 46021 GTACCAACGC TTTCTGCAGA ATCGGGACTT GCCGCCGTCC CGGTTGTCGT TGTCCCGGCG 46081 GGCTTCGCCC TTCGGTGATT CGTCACATGΛ CGGAAGCTCG CCATGCTTGA TGTGCCATGC 46141 GTCGTCGGCG ACTTTTCCGC CGTGCTCGGC GATGTGCGCT GCGCTCCGGT ACTCACAGAG 46201 CGGGGAAGCC GATGCCTCGG CGATGATCCC AGGCAGGTTG CCTAGAACCA CCGCCAAGCA 46261 CATCAGCAGA ACGACGTGCC ACGCCTTCAT CAGCCCGCCA GCGCGTGGTT CATCGCCGCG 46321 TTGCGGCCGT CGCGCTGACC GTGGGCATAG CCGCTGAGGT CGTACCGGGT CCGAGGCTTG 46381 ACGTTCTTGG TGCGAGGATG CGCCTGGCGC AGAGCCAGCG CAGCTCGTTC CTTGTCGCCT E S HEET 46441 CGGTAGAGCA CCAACGCTCC CCCGCCGGCC GATTCCACGG CCTTGTTCTC CTCGGCGGTC 46501 AGGCGTTCCT TGACGGCCTG GGCGAAGCCT GCGATCCACG ACCGGCGGTA GCTCTTGAGC 46561 TGGCCAGCGG TGCTCTTCGG CTTGTACTCC CCGGTGTTGT AGTCGTACTT GTACCGAGGC 46621 TCGAAAGCCT GCTCCGGGCG GACATTCTCA ACCAGGCGCA TCATCTGCGG CTGCATGATC 46681 GACCAGAGGA ATTGGAGCCT CTCGATGTGG CGGGGCACGC CGTAGACGTA GATCCGCTGA 46741 CCGCCCGTGA GGCTGGCGTA CACCGTCTTG CAGTGCAGGG CCTGAGCCAT GCCGTGCAGC 46801 AACAACGCTT GTGCGGCAAC GTACTTGCCG GTGACGTAGG TGACCCACTG GATGGCGTCG 46861 GGCAGGTCGG TGGTGTCCAA CCCTTGCTTG CTCGCCTCGA CCTGGGCCAT CTCCAGCCCG 46921 TACTTGGCCA TCAGCTCGAA CGCTTTCGCC TGGAACACAG CCTCTTCCGG CGTACCGGCC 46981 ACGTCTTCGG CCTGGCGCAG CAGCTTGGCG ACCTTGTCCT GCATCTTCTT CGTCTTGCCG 47041 TCGATCATGG TCAGTACTCC TTCTTCCAGT TGTTCCGGTT GCCCTTGCCG GGGCGCTTCA 47101 TCTCTCGCTT GCGGTTACGG TGCGGCTGCG CCGCGTTGGA GAGACGCAAC TCGAGCCGTG 47161 CCTTGAGCTG GTCGCTCATC TTCTTCACCT CTTCTGGTTC AGCGGATCTG GTCGACGTGG 47221 ATGCAGCCGA CGCGGTCTGG CCCGAACTCG GGAGCGAAGC CCAAGACTTC GTCCTCCTCG 47281 CATGGGAACG CTCGCTGGTC GAACGTGATT GGGTCGGCCG AAGCCTCGTA TGGATCGGCC 47341 AAGGCCATCG CTCCGACCGC TGTAGCGAAT GCAACGACGA CGGTGATCAG GTGCTTCTTC 47401 ACTCTTCTTC CCTCCACTTT TGGTCTGCGA GAAGCCTTCT GGCGATCTCG ATAGGTTCGA 47461 TCTCAGGAGT CACTCATCGC CCTCCAAGAT CTTCAGGTTG GCCAGCAGTG CATTGGCCAC 47521 AGCTCCGATG TGGCCACCGC CCTTACCTCC ACGGCGGGAG TACTCGCGGT TCGCGGCCTG 47581 CATGAAGTGG AACCTCGGTG AGCCGTCCTC GTGAACCCAC GAGGCTTTCT CGGCGGGCAG 47641 AGCCCGGTTC ATCTCCACCG ACATCGTGAC GATGATGTGG TCCCTCTGGA GCCGAGCCTC 47701 GGTCTCGGCG TAGTGGGCAG CTTGGATTAC TGCGCCTCGT GTGGTCATGT CTTCTCCTTC 47761 GGTAGATGTC AAGCTGTCGT CACCACTCTT CGACCGGTAT CGGTTTGTCA CAGCCAGCAA 47821 GGATCGCGGC GTTGCTGCGG TGATGCCCGT CCCACAGCGT CTTTCGGTCC CTCGAAACCT 47881 CGAGGGGTTC GAACGGCCAC TCGTTCGATG AGTTGAGGAT GTCCACGACT TCGTGGACCT 47941 TGGCCCAGAA CTTGCCGGTC ACGCCTCCCT GGTAGTTGTA GCGGGGCGTG GTCTGGTAGA 48001 ACTCTTCGAG CACTGGTCCG CTGTCGGCGA CGGTGCAGTC GACACCAGCG CAGGACATGC 48061 AGTCGCTGGC GCGGAGCTGG GCAACTTCAT CGGTGGTCAT GAACGCCGTG GTCACATCGA 48121 GCCTTTCAGG TGTATGTCAA GCGGCGCGGA CGCCGGAATC GGAGAGGTAG ACGCGGTCAG 48181 CTCCCAGGAA CGGAGCCTGT GTGTTGGCGT GGACGAACGT GTCGTTCTCG TAGGGGTTGT 48241 AGGCGATCTT CGATCCCACG AAGTCTTGCG GGAGAAGCGA GATCAGCTCG CCTACGATGC 48301 CAGCGTGGAC CACCTTGCGG CGCTCGCGCC GTACCTTGTC GCGGCCGGCC GGCCGAACCA 48361 CACCCTTGGC GTGGGCCAGC AGGACGTGGC CGCTGCGGTG GATGACTCGA CCCTTGAAGT 48421 CTCCCTCCAA GGCTTGCACC GAGTACCACG GCTTGCCCTC GCGGTGCGTG CGGTGCAGGT 48481 TCTTGTAGAC GAAGACTCGG ATCGGCTTGG GAGTCATGAG ACCTCCAGTG TGCGAACGGC 48541 CTTGTAGGCA CTGATGAGTG ACGCCCCCGA CAGCTCGTTA CCGTGCAGGT GATACCTGTA 48601 TTTCAGATAC ACGGCTTGGT CGACCGGCTT GTACTCGACC GAAGTGACCT CGACAACCAT 48661 CCCGTCGATG ATCGCGAAGT CTCCAGCGCG GAGATGGGTG GGGAATTTGA TCTCGGTGTT 48721 GACTACGGTC ACAGCTTCGA AACCTCCCAG GTACCAACGA ACTTGCCGTT GCGCTTGATG ' TATCCGCTCT CACCGGGCTC GTACCAATCG ACCTCGAACC CGTAGCGGGC GGCGCAAGCC 48841 TCGAGGTGGT CGAGCAGGAC GCGGCGACCG GACGCGGTAG CTTCTCCGGT CAGCCCGCTG 48901 TCGTTCTTGC GGACGATGAG CTTGAACACT TGGTGCCTAC CCTTCTGCGA TGTCTCGGGA 48961 GATCTCGGCG AAGACTTTCT TTGCCCACGC CACGCCGTCC CAGGTGATGT CGAACAGTGC 49021 CTCGTAGAAC TGGTCTCGCA AGGCTTCGTT GCCGTCGGCC AGCGTTGTGA CGAGCCGGTC 49081 GATGCGGTCC TCGTGGAACT TGTAGACCGA GTGGTTGTAC GGCTCAGCCA TATTGGCGTT 49141 GGCTCGTTTC ACGTTCTCAA CCACGATGGC TTCGAATAGG TGGTTAACCA GCTCCTCGGT 49201 CATGTTCTAT CTCTCCTCAG TAGTCGCTGT GCTGGGTCTC GAAGCCTTCG AGGTCACCGA 49261 CCTCGTCGTC GTACGCGCTC GGGTTGCCGC GCCAGTCGTC GCGGAGCCTT TGACCGCTGG 49321 CGTTGTAGCA GGCACCACAG TTCGGGCAGT CCACATCGCT CTGGCCGTAG TAGCGGCAAA 49381 CCTCGCCGCC GCAGCGTTGG CAGTCCCACG CGCTGTAACC AGGGATCAGG AAACCTTGGT 49441 CGTCGGTCTG ATCAGGGATG CGTCGGAAGT TCTTGGCAGG CATAGCTACT CCTCATAGAA 49501 ACTCGTGGTT GATGGCTCGG TGGGCAGCCT CGCGGAAGGT CAGCCCGTCG TCGTACGCGT 49561 CCCGGTACGT CCAGTCCGCG ATGTCTTGGT AACCAAGACC AAAGGTCTCG GTCATGTAGC 49621 CGTCCAGCGC GGCCATCCAG GTCTCGAAGC TCATGTCTTC CCTCACTTCT TTGTGGTCGA 49681 GAACAGCACG TTCCTGCGGC CGTTGACGCA CAGACCGCAA CGGGCACAAG CCGATCCCTT 49741 GTCGTTGATC AGGTCGATGG CTTTGTTGTT CTCCGGGCAG CGCACCGCCG TCGGAAACTC 49801 GGCCTTGCCT TTGGCGAACG TGGTGTCGAC GTAGGCGATG TTGATGCCCT TGTCTTCCAA 49861 GAAGCGCGCC ACGTCGATGT TGTCCGGGTC TGCGCTGAAG TACAGCGCCA GGTTGTCGAG 49921 CCTCTGCGAG TGCAGGTAGA CAGCCGCCGT CTGAACCCTT GTGTAGGCCC AGAACTGGAC 49981 ATCCGGGTTG TCGCGGATGA CTCGACCCCA AOCGGCCACA TAGGTGOGGC TGAAGAAGTC SUBSTITUTESHEET TCCATCCCAG TGGATGCGGA ACAGCTTCGG AGCCTTGCGA CGGTCGCAAT CCTTGACGAA CTCGGCGACC ATCTCGGACA GCAGCGTCAC GGTGTCTGTC AAGTCAGCGT CACGCAACAG TTCCCAGTTG TGCAGCAGGA CCGAGCTGAC AGCCTTGCGA ACTTTCTCCA GCTTGCCGGC GTAGCACACC TTGGCACAGA AGGCCGTCGC GTCCGGGCAG GAGAAGCCTT GACCGGAGGG CAGGCCGATG CTGTTGGCGA TACCTACGGT GGCGTTGCCG CCCTTGGTGA CGTGGACGTA GTTGGTGACC TTGCGGTCGT TCGAACGCTT CAGCTTGGCC ATACCTAGCC TTCCTTCGGT GGCTGTCAAG TTGTTGGATA CAAAGCGCCC CGAGAGGGAG TCGAACCCTC ACACCGCGAA CCGTCGCGGG GCCACCGTGC CTAGTCGATA GAGGTCACTC GACTCTCGTG GACGTAGACC ACGGTGTTGC CTACGTTCAC CGCGTAGTAC AGGCCATCGG CACCTCGTAG CTTGTGCCGA ACCGTGCCCG ACGTGGCCGT CATGTCTTCG CCCCAGTCGG CGTTAGGTGC CCAGGTGACT CGCATGGTGA TCCCTTCAGT AGTCGGTGGC TGTCAAGTCA GCGGATACGG ACGTACCCGT TGCCTCGAGC GACGTAGATC TTGCCGTCGA TGTAAACGCG CTGCTGCTGG TTCATAATCC TATTCCTTTC GGTGGCTGTC AAGTCTCAGG CCCAGCGACG AGTCGTcσσc CGGGGGCGGC GCACCTTGGG CGCGTTGGCT CGCGGTGCCT TACGGATGGC GGTGCCTACC GTGATCTCTT CCAACTGGCG TTCAGCCAGG CCGACAGGCC GGGCGTCACC GGGCAGTTCG ATCTTGTAAT CGAAGTCAGT CCACCCCTTC AGACCCTTCT CCAGCTCGCG ATCCAACAGA CGCGGAGCCG ACAGCTCAGG CGCAACAAAC GGTGTCTTGA CGCTCTCGCG GGCAGTAACC CGAACCTCAC GGTGCTCAGC GAAGACTGGC ATAGTTCACC CCTTTGGTGG ATGTCAAGCC TGAGCACCAA AGCTCAGGCG TAGTGGGTAG TCGGGAATCG AACCCGATAG CTTCATAGCC ACGTTCTACG GCTCAGCCAT AGCTCAGCGA TCATTCCATC GCGCCAAGAG CTACCCTCCC GAATGCCGAA CCAAAGCTCA GCATTCGTAA GTGTGTATTC TCCCCGTGGC TCAGACAGTA TCTATCAGAA CCTAACCACA GGTCTACATT TAGTTATCCG CAGTGCTCGC ACTTTAACGG CATCGAGCTT CCGCCGACCC TCAGTCCTCT GGCAGCGAAC TAAAGGTTTG AGTCGGGCTG CGGCCCTTCT CGGTCTTGCG TGATTCTCAC TCTACCGGAT GTTTCGGTGG CTGTCAAGCG GGCCGTTTTG GTGTTGCAAC GATGCCCTCG TTTAGCGCCG CTGGCGTAAT GCGCTACCCG CCTGATCTCA CCGGTCCAAG TTGGTGATGC TTGCAGCTTA CCCGATAACC GGGTGGCTGT CAAACCGGAG AATCTTGCCG CCGGATTTTC ACCGGCACCG GCACGATCCT CTCGGATCCG CCTACCGCCT TOCTGCTGCG GTCΛCACAAG AATGCACTAC TGGCCGGGTG GCTGTCAAGC CCTAATCGCA AATTGGTGCC CTAGCTGCAG ATATGGCGCG TTCTCGGTGG CTGTAAAGGG CACTACGTGC CGCTATCCGC TGGTCACGCT GGACAGTCCC GGCAGCCCGT GCCGCGCATA GGCTGCTCAC TACGTGCCCG GTATCGGCGT TGTCGTGCCG CTGTCGTGGT CGTCGCCCCG TCGCTGTCGC TGGTCTCGGT GGCATCGCTT GACAGTCGCC ccσcTATCcc CCGTTGCCGC TGGTCAGACG CTAATCCGCT TATTTCGCAT AGGCTGCTCA CTATCGCATC GGTATGCGTA TGCGCTGGTC ACATATGCGT GTGGTGGTGG TGTGGTGTGC GTGTGTTTGC GCTGGTCAGC CGTGTGCGTA CCGTATCCGC ACACTGTGCT TGTGCGTTTG CTGTGTGTCG AGGCCGGCTC TCGCATCGTC GCATGTCAGC GCGGGTATGG GCGTGTATCG CACGCTTTGC TAGCCGCGTG CCGCGGCGCT CTCGCATCGC ATCGAGTGTT TGCTGTGTCT CTCATCGTCG CAGGTCAGAA GGGGTAGGGG GGTTCCCCCT AGGGGTCGGT CCTTGACCGG TCGGTTAT It is known that during the establishment of lysogeny, the L5 genome becomes integrated into the mycobacterial chromosome and the attachment site (attP) . Integration-proficient plasmid vectors have been constructed which efficiently transform both fast-growing and slow-growing mycobacteria through stable integration of the plasmid sequences into the bacterial chromosomal attachment site (attB) . Because the L5 sequence is now known, and because L5 has been previously characterized, the use of transcriptional promoters with this mycobacteriophage may be evaluated efficiently, and host synthesis inhibition may also be evaluated efficiently. Figure 1 represents the genome organization of the entire L5 genome. DNA analysis has indicated that the L5 genome is organized into a right and left arm with the attachment site and integrase at the center of the genome. The integration functions have been successfully employed to construct integration-proficient vectors for mycobacteria. Part of the L5 genome is not essential for mycobacteriophage growth. It has been demonstrated that all or most of the gene 62-61-60 can be deleted without affecting the cycle of the L5 phage. Therefore, there is a suitable region in the L5 mycobacteriophage for the insertion of reporter genes. It is critical that reporter genes be inserted into non-essential regions of the mycobacteirophage. Otherwise, the mycobacteriophage will be unable to survive and replicate. The L5 mycobacteriophage may have introduced therein promoter gene 62 fused to reporter gene lacZ, and this reporter mycobacteriophage will be capable of rapid diagnosis of mycobacterial infection and accurate assessment of mycobacterial strain drug susceptibilities. Another mycobacteriophage which may be successfully used to produce the reporter mycobaceriophages is the mycobacteriophage TM4. TM4 has been used to construct a first generation reporter mycobaceriophage, and has the ability to discriminate between M. tuberculosis and BCG. A shuttle plasmid may be employed with TM4, and may be useful in the construction of recombinant and other mycobacteriophages. Unlike L5, which is a broad host-range mycobacteriophage, TM4 is a species-specific mycobacteriophage. However, TM4 is not as well characterized as the L5 mycobacteriophage, and therefore it is more difficult to analyze its functions. DS6A is a mycobaceriophage that has been found to be specific for the M. tuberculosis complex of mycobacteria. It has been shown to infect both M. tuberculosis and BCG. It has been demonstrated that DS6A can infect over 3,000 different types of M. tuberculosis strains. Current efforts are under way to develop DS6A shuttle phasmids containing Firefly luciferase genes as the reporter molecule. It is possible that a combination of different mycobacteriophages may be needed to increase specificity and then increase the ability to distinguish drug susceptibilities. DS6A grows on BCG and M. tuberculosis, but does not grow on M. smegmatis. In anticipation of the need for a diverse set of mycobacteriophages that can effect a broad or limited range of mycobacterial cells, a total of more than 50 unique mycobacteriophages have been collected and isolated by the inventors. 21 new mycobacteriophages have been isolated from soil samples from India, France, England, Israel, Tunisia, Carville, LA and New York. In addition, another 30 mycobacteriophages from both the Centers for Disease Control in Atlanta and the World Health Organization Phage Reference Laboratory in Amsterdam were collected. The characterization of the nucleic acid content of the phage particles of 30 of these mycobacteriophages have revealed that all of the mycobacteriophages contain double stranded DNA whose genome sizes range from 45 to lOOkb as sized on pulsed field gels. Restriction analysis has shown that all of these mycobacteriophages are different, except that one of the mycobacteriophages from France had a considerable similarity to the L5 mycobacteriophage, which was originally isolated in Japan. The host range of the mycobacteriophages varies greatly, some being able to infect only M. smeqmatis and others being able to infect M. smeαmatis. BCG and M. tuberculosis. but not M. avium. These mycobacteriophages may be developed into reporter mycobacteriophages and cosmid cloning systems, and may provide a source of useful transcriptional translation initiating sequences, transcriptional terminators, or host-range specificity genes. In addition, the choice of reporter gene and its method of expression are critical. It is necessary to choose a reporter gene whose product would not normally be found in clinical samples, but whose product is also easily detectable. Luciferase reporter genes have been used in many diversified biological systems, including E. coli. cyanobacteria, phytopathogenic bacteria and Bacillus. The presence of luciferase reporter genes can be detected by the emission of photons in the presence of a substrate, such as luciferin or decanal. Luciferin and decanal can permeate mycobacteria, and thereby allow for the detection of gene products, such as photons. Since one molecule of the luciferase gene product can yield 0.85 photons of light, it is the most sensitive biological reporter molecule known. The preferred reporter genes of this invention are luciferase reporter genes, such as the Firefly lux gene (FFlux) , the Vibrio fischeri lux genes and the Xenorhabdus luminescens lux genes, as well as the E. coli β-galactosidase (lacZ) genes. Luciferase genes, especially the Firetly lux gene, geneate a high amount of luminescence activity. They generate photons, the detection of which is simple and sensitive, using commercially available luminometers that can detect 100-1000 molecules of luciferase with a linear relationship to enzyme concentration. In addition, it is unlikely that clinical samples will contain significant levels of endogenous luciferase activity. In choosing transcriptional promoters to be introduced into the mycobacteriophages, it is desirable to use strong promoters since this will increase the sensitivity of the system. In addition, it is important that the promoter be active following mycobacteriophage infection. The best promoter candidates currently available are the BCG hsp60 promoter and the L5 gene 62 promoter, which are of comparable strength. The hsp60 promoter gives good levels of luciferase expression from plasmid recombinants, but lower levels of luciferase expression where the mycobacteriophage is TM4. It is possible that the reason for this is that the hsp60 promoter is shut off by the TM4 enzymes following infection, thus producing only a modest level of luciferase. The gene 62 promoter may behave in a similar manner with the TM4 phage since the gene 62 product is a good candidate for the L5 repressor and is expressed at high levels in the absence of other mycobacteriophage functions. Knowing the sequence of the mycobacteriophage used will help in identifying, characterizing and cloning the appropriate promoter to be used in the reporter mycobacteriophages of this invention. There are several methods which can be utilized to introduce the reporter genes and transcriptional promoters into mycobacterial species-specific mycobacteriophages. One method is the utilization of shuttle phasmids. When utilizing shuttle phasmid technology, it is necessary to know the sequence of the mycobacteriophage so that the reporter genes are inserted into non-essential regions of the mycobacteriophage. Insertion of reporter genes into non-essential regions permits the mycobacteriophage to survive and replicate. In order to use the shuttle phasmid methodology, it is necessary to first generate a cosmid library of large double-stranded recombinant DNA fragments of mycobacteriophage. This can be done using cosmid cloning in E. coli. Next, the cosmid library is introduced into the mycobacteria of interest to select for cosmids which have been inserted into non-essential regions of the mycobacteriophage. The shuttle phasmids, which consist of the E. coli cosmid, the reporter genes and mycobacteriophage promoters, may then be characterized. Shuttle phasmids can be propagated in E. coli as plasmids, and propagated in mycobacteria as mycobacteriophages. A second method of introducing the reporter genes and transcriptional promoters into mycobacteriophages is by homologous recombination or PCR. First, non-essential regions of a mycobacteriophage must be determined. Again, in order to do this, it is necessary to know the sequence of the mycobacteriophage. Consequently, L5 is an ideal phage to use with this method as its genome has already been sequenced and characterized by the inventors. Next, plasmids are constructed wherein reporter genes hooked to transcriptional promoters are flanked by mycobacteriophage non-essential region sequences in mycobacterial plasmids. Then, homologous recombination systems or PCR may be utilized in M. smeqmatis or E. coli to perform gene replacement whereby the plasmid constructs containing the reporter genes are put into mycobacteriophages. A third method of introducing reporter genes and transcriptional promoters into mycobacteriophages is by use of transposons. For example, transposon IS1096 may be utilized. In order to use this methodology, reporter genes and transcriptional promoters are put into transposons, and the transposons containing the reporter genes and transcriptional promoters are delivered on plasmids in mycobacteria. Next, it is necessary to grow up the mycobacteriophages on a strain such as M. smeqmatis, which strain contains the transposons. At certain frequencies, the t: nsposons will hop into non-essential regions of the mycobacteriophages, thereby introducing themselves therein. The mycobacteriophages are still viable, and contain the reporter genes and transcriptional promoters. A fourth method of introducing reporter genes and transcriptional promoters into mycobacteriophages is by debilitated phages packaged into phage heads and tails (phage particles). To utilize this methodology, it is necessary to develop helper phage systems which allow for pieces of DNA containing pac sites to be packaged. These helper phages allow for the synthesis of head and tail genes at will in mycobacteria, prevent themselves from being packaged into phage heads and tails, and facilitate packaging of pacmids into phage heads and tails. Helper phage systems may be generated from the L5 mycobacteriophage. The genome of the helper phage is put into the mycobacterial chromosome, at which time the mycobacteria are grown up. Next, pacmids which comprise phages which have pac sites, reporter genes, transcriptional promoters and mycobacterial replicons are transformed onto the mycobacterial strain. The production of head and tail proteins may be induced, for example, through an increase in temperature, and the pacmids are then packaged into phage heads and tails. The L5 genome has cohesive (cos) termini. This suggests the possibility of constructing L5 cosmid vectors, which could be packaged through the cos sites into L5 particles either in vivo or in vitro. Then, a large number of genes could be easily and efficiently delivered to mycobacteria. Packaging into phage heads and tails may also be utilized in a fifth methodology wherein the pacmid is a plasmid. The methodology is similar to the methodology wherein a debilitated phage is used, however, instead of using phage pacmids, the pacmids comprise plasmids which have pac sites, reporter genes, transcriptional promoters, and plasmid replicons. Finally, direct cloning using recombinant DNA techniques in vitro may be used to introduce reporter genes and transcriptional promoters into mycobacteriophages. This methodology consists of ligating a mycobacteriophage, identifying or introducing unique restriction enzyme sites in non-essential regions of the mycobacteriophage, cleaving the mycobacteriophage with the restriction enzyme sites, and cleaving DNA which encodes the promoter and the reporter gene so that it has the unique sites flanking it on either side. Next, ligation is set up in vitro between the cleaved mycobacteriophage with the unique restriction enzyme sites and the reporter gene cassette. The result is a circular DNA molecule which consists of the mycobacteriophage, the reporter genes and the transcriptional promoters. The circular DNA may then be electroporated directly into mycobacteria. EXAMPLES Expression of Reporter Gene lacZ and FFlux in Mycobacteria A promoter probe vector was constructed which incorporated a truncated E. coli β-galactosidase (lacZ) gene as a reporter probe into a shuttle plasmid vector that replicated in either mycobacteria or E. coli. Random DNA fragments from the three mycobacteriophages LI, TM4 and Bxbl were cloned into a unique BamHI site immediately upstream of the lacZ gene and screened for their ability to produce β-galactosidase. This established that lacZ could be used as a reporter gene in the mycobacteria, and identified the DNA sequences which could effectively express foreign genes in both M. smeqmatis and M. tuberculosis. β-galactosidase activity could be detected from lysed cells using OMPG, or from unlysed cells using either X-gal or a fluorescent methylumbelliferyl β-galactosidase derivative. The promoter hsp60 gene highly expressed the lacZ gene in both M. smeqmatis and BCG. The FFlux gene was cloned into pMV261 downstream from the hsp60 promoter in plasmid pYUBlδO (see Figure 2), which plasmid was shown to express the FFlux gene in M. smeqmatis, BCG and M. tuberculosis H37Ra. The expression of the FFlux gene was detected by observing luminescence of mycobacterial clones containing the cloned gene in the dark room, and verified use in photographic film. This demonstrated that the luciferase was expressed in the mycobacteria, and that luciferin, the substrate used, was able to penetrate mycobacterial cell walls and yield photons expressed by the mycobacteria. Detection of Photons In Mycobacterial Cells Expressing FFlux The expression of FFlux from the plasmid pYUBlδO in M. smeqmatis provided a model with which to determine a minimal number of individual cells detectable with the luciferase assay. M. smeqmatis containing pYUBlδO were grown in the presence of kanamycin to ensure that every cell contained the plasmid. The cells were diluted 10-fold serially and the amount of luciferase activity was determined using a luminometer. Figure 3 shows that the amount of 7 luciferase activity from 5 X 10 cells approached Q 10 luciferase units, though at this level of activity the luminometer was unable to yield an accurate measurement. However, the activity decreased in a linear manner down to 1200 units for 500 cells. Hence, 5000 cells expressing the FFlux gene can be clearly discerned above the background measurement, which approaches the number of cells that one would expect to observe in clinical samples. Distinguishing Drug-Resistant Mycobacteria From Drug-Sensitive Mycobacteria Using Luciferase Activity Since Firefly luciferase activity requires ATP, and ATP is produced only by living cells which are metabolically active, luciferase is a powerful indicator of the metabolic abilities of a bacterial cell. Since anti-tuberculosis drugs are likely to significantly decrease the metabolic activity of a cell, the measurement of luciferase activity should provide a sensitive means of distinguishing drug-resistant mycobacteria from drug-sensitive mycobacteria. First, the kinetics of the production of luciferase activity of M. smeqmatis containing pYUBlδO following the addition of streptomycin, isoniazid, ethambutol, rifampicin, ciprofloxacin, novobiocin or cyanide, added at levels that inhibit the growth of M. smeqmatis in plate assays, was measured. As shown in Figure 4, Panel A, the levels of luciferase production were 100 to 1000 times less at eight hours after the addition of the drugs compared to the untreated control. Next, this approach was used to distinguish drug-resistant from drug-sensitive mycobacteria. The pYUBlδO deposit was transformed into streptomycin-resistant or novobiocin-resistant M. smeqmatis mutants. Photon production by the drug-sensitive parent was compared to the streptomycin-resistant or novobiocin-resistant mutants. The drug-resistant mutants continued to produce luciferase activity levels comparable to the untreated patent in the presence of the appropriate antibiotic. In addition, the drug-resistant mutants produced 100 to 1000 times more luciferase activity than the drug-sensitive parent (see Figure 4, Panels B and C) . Hence, a luciferase-based assay may be used to determine mycobacterial drug susceptibility. Construction of TM4 Reporter Mycobacteriophages and Detection of Photons Following TM : : lux Infection The first vectors developed to introduce recombinant DNA into mycobacteria were shuttle phasmid phage vectors. Shuttle phasmids have the ability to replicate in E. coli as cosmids and then replicate in mycobacteria as phages. Shuttle phasmids of TM4 which contained the FFlux and lacZ genes transcribed from hsp60 and LI promoters, respectively, were constructed (see Figure 5) . A deposit of the shuttle phasmid (reporter mycobaceriophage) phAE39 which contains mycobacteriophage TM4, cosmid ρYUB216, reporter gene FFlux and promoter hsp60, was made with the American Type Culture Collection on January 12, 1992 and catalogued as ATCC #75163. When the TM4: :1JX shuttle phasmid phAE39 was mixed with M. smeqmatis cells, luciferase activity could be detected within 15 minutes of incubation, and continued to increase slightly over the next 4 hours (see Figure 6) . These results show that the TM4 : : lux mycobacteriophage is capable of introducing the FFlux gene into mycobacterial cells, and that the FFlux gene can be expressed in mycobacteriophage-infected cells. Figure 7 represents a flow chart for cloning different promoters into the TM4 : : lux shuttle phasmid phAE39. A deposit of the shuttle phasmid (reporter mycobaceriophage) phAE37 which contains mycobacteriophage TM4 , cosmid pYUB216, reporter gene lacZ and promoter LI, was made with the American Type Culture Collection on , 1992 and catalogued as ATCC # . The TM4 : : lacZ mycobacteriophage formed bright blue plaques when plated on media containing X-gal. Construction of the L5 Reporter Mvcobacterophaqe Strategies for construction of the recombinant L5 mycobacteriophage may be investigated. The possibility of using the shuttle phasmid approach starting with L5 deletion derivatives, in which the size of the genome has been reduced, may also be explored. Initially, the largest gene 62 deletion available should be used. However, other deletion derivatives in which more of the gene 62-61-60 segment is lost should also be isolated. Another approach would be to attempt to introduce genes by homologous recombination with plasmids. Still another approach would be to transpose lux genes onto L5 using either the mini-Mu i_n vitro transposition system or a mycobacterial transposon such as IS1096. Recombining reporter genes from recombinant plasmids onto L5 using a double recombination event may also be performed. This involves first constructing a recombinant plasmid that carries a reporter gene ( lacZ may be more suitable) inserted into gene 62 such that both the upstream and downstream parts of gene 62 are present. Advantages of this approach are that lacZ can be easily detected in agar media, that gene 62 is not an essential gene, and that lacZ is efficiently expressed from a promoter immediately upstream of gene 62. An L5 mycobacteriophage lysate may be prepared by growth of the plasmid-containing strain and recombinant mycobacteriophage progeny identified by plating the lysate on wild-type M. smeqmatis for individual plaques on agar containing the indicator X-gal. This recombination approach may be expanded to introduce other gene or DNA segments of the L5 genome. For example, it should be possible to add luciferase genes from FFlux in an identical manner, provided that packaging limits are not exceeded. In addition, inclusion of polylinker containing restriction enzyme sites unique for L5 would open the way for construction of L5 recombinants in vitro. Similar genetic strategies may be used to systematically reduce the size of the L5 genome by deletion of non-essential sequences. Transposition offers an alternative method for the construction of reporter mycobacteriophages. A transposition system which is available is the mini-Mu in vitro transposition system. This is a defined biochemical reaction in which a mini-Mu transposon carrying the desired gene is transposed onto the phage genome using purified MuA and MuB proteins. Similar transposition experiments have been tried with L5, but few L5 mini-Mu derivatives have been isolated. It is possible that this is due to the relatively large size of the transposon used. It is necessary to first construct a small Mu transposon which contains the reporter gene, a promoter and the two Mu in order for these experiments to be successful. Development of L5 in. vivo and in vitro Packaging Systems g cosmids and packaging systems provide the efficiency of mycobacteriophage infection with the ability to inject large segments of non-mycobacteriophage DNA. Analogous mycobacterial systems would overcome packaging constraints encountered with recombinant mycobacteriophage genomes and allow the introduction of multiple copies or types of reporter genes into mycobacteria, potentially enhancing the sensitivity of the assay. In addition, they would help overcome any problems with host synthesis inhibition. The development of L5 cosmids and packaging systems is dependent on the finding that the L5 genome contains cohesive termini. The g paradigm suggests that a relatively small region of DNA (approximately 500bp) around the cos site (in the ligated form) is necessary to promote packaging. The first series of experiments with L5 would therefore be to identify the segment of the genome required for packaging by constructing a series of plasmids containing the L5 cos site and surrounding sequences. Cos activity may be determined by preparation of an L5 lysate on plasmid-containing M. smeqmatis strains, followed by the identification of antibiotic-resistant transductants in the lysate, by transduction of M. smeqmatis. This assay assumes that plasmid multimers of a total size of approximately 50kb are present in the cell and will be packaged. Although the presence of such multimers has not been demonstrated directly, they are likely to be generated by the homologous recombination system of M. smeqmatis. If this assay should fail, cosmid vectors which contain both L5 g cos sites may be constructed. Insertion of 40-45kb of DNA (as in the construction of cosmid libraries) followed by g packaging in vitro and infection with E. coli will generate 50kb sized molecules containing L5 cos site. These should be isolated from E. coli and introduced by electroporation into M. smeqmatis. Assuming that one of these approaches is successful, it would then be possible to define a small segment of L5 DNA required for packaging. The construction of in vivo cosmid packaging systems is a particularly attractive idea since it has proven very useful in E. coli. Thermoinducible lysogens of L5 may be suitable for in vivo packaging of L5 cosmids without further modification, since prophage excision may be a temperature-sensitive event. Efficient packaging of extrachromosomal cosmids present in the lysogen may be achieved by simple induction and growth at 42°C. It is possible that some process other than excision is temperature-sensitive in lysogen induction. If so, it will be necessary to further debilitate the prophage in order to prevent DNA packaging of the prophage. There are a variety of ways to accomplish this. For example, the excise gene itself could be deleted (using a recombination strategy similar to that described above) such as to prevent excision. Another approach is to damage the cohesive termini (by exonucleolytic digestion) of an L5 thermoinducible derivative and construct a defective lysogen. A combination of approaches may be desirable, since even if prophage excision is a temperature-sensitive process, the destruction of cos might effectively reduce the background of spontaneous mycobacteriophage release. Construction of in vitro packaging systems will follow similar lines. Extracts may be prepared from thermoinducible strains with non-packagable prophages and assessed for their ability to package exogenously added L5 cosmid or mycobacteriophage DNA. Optimization of conditions should follow both empirical biochemical approaches and the well-established g systems. For example, it may be necessary to supplement the extracts with purified mycobacteriophage products such as the terminase or the tape-measure analogues (genes A/Nu and H of g respectively) , neither of which have yet been identified. Construction of Novel Shuttle Phasmids From Any Mycobacteriophage Although mycobacteriophages L5 and TM4 can be used in the development of diagnostic luciferase and β-galactosidase shuttle phasmids, there may be other mycobacteriophages, such as the mycobacteriophage DS6A which only infects BCG and M. tuberculosis strains, that might prove to have a more useful host range for clinical isolates. Diagnostic luciferase mycobacteriophages from these other mycobacteriophages may be developed by using the shuttle phasmid methodology described herein that has been proven successful for constructing mycobacteriophage vectors from both TM4 and phage LI. Isolate Mycobacteriophage L5 and TM4 Mutants to Infect the Maximum Number of Clinial Isolates For the diagnostic luciferase mycobacteriophage system to have maximal use in the clinical laboratory, it will be essential that to develop a set of diagnostic mycobacteriophages that can efficiently infect any clinical isolate and possibly distinguish M. tuberculosis from M. avium and BCG. Both mycobacteriophages TM4 and L5 appear to have the ability to infect a large number of M. tuberculosis isolates. TM4 is very closely related to phage 33D, a mycobacteriophage that has been found not to infect every M. tuberculosis isolate used to define the mycobacteriophage typing schemes for M. tuberculosis isolates. However, this mycobacteriophage does not infect BCG. TM4 has been found to be almost identical by DNA hybridization and restriction analysis to 33D, and it shares the host-specificity with 33D in that it infects M. tuberculosis, but fails to infect BCG. mycobacteriophage L5 appears to share the same receptor as mycobacteriophage D29 which receptor has been previously shown to infect a very large number of M. tuberculosis isolates. L5, unlike 33D or TM4, infects all three morphotypes of M. avium including a wide range of serovariants. If L5 or TM4 are found not to infect certain M. tuberculosis isolates, it may be possible to isolate mutants of these mycobacteriophages which plaque on the particular isolate. The inability to plaque on a particular isolate could result from the lack of a mycobacteriophage receptor or be the result of lysogenization of the isolate with a homoimmune phage. Phage mutants with altered host range specificities or mutants which no longer bind a repressor (equivalent to virulent mutant of g) have been isolated in other systems. Variants of TM4 which can efficiently infect BCG have been isolated at 7 frequencies of 10 . Previous work has demonstrated that 33D, similarly to TM4, can not adsorb to BCG cells. Host-range variants of TM4 which not only plaque BCG, but also still plaque M. tuberculosis have been isolated. Similar strategies for M. tuberculosis isolates which are uninfected by L5 or TM4 may be used. Detecting the Presence of M. tuberculosis in Cli eal Samples The combined sensitivities of luciferase and mycobacteriophage infections should permit the detection of previously undetectable levels of M. tuberculosis cells in sputum, blood samples, or cerebral spinal fluid. A number of preliminary studies to optimize the detection of M. tuberculosis cells in a variety of body samples will be performed. Detecting M. tuberculosis Grown In Primary Human Macrophages and Macrophage Cell Lines As a model system for optimizing detection of M. tuberculosis in infected monocytes and macrophages, primary human monocytes which have been purified by ' adherence for 1 hour or primary macrophages which have been cultured for 6 days in microwells will be infected with M. tuberculosis H37Ra at varying multiplicities. The number of cells initially infected will be determined microscopically, and then at various periods of time from 2 hours to 30 days, the cells will by lysed by non-ionic detergent NP40 which has no effect on viability of mycobacteria, concentrated by centrifugation, plated for viable organisms and infected with the luciferase plasmids. Quantitative studies at different oi's and with varying numbers of infected cells will indicate how few bacilli/cell and bacilli/specimen can be detected. The inability of M. tuberculosis cells isolated from macrophages to be infected with diagnostic shuttle phasmids could result from either the absence of the expression of the mycobacteriophage-receptor or the masking of the receptor with a membrane from a phagosome of the macrophage. The level of expression of phage receptors may be regulated by the environment in which the host cell is grown. For example, the g repressor of E. coli is induced by maltose and repressed by glucose. Studies to identify the receptors for mycobacteriophage L5 have been initiated. Similar studies for mycobacteriophage TM4 will also be performed. By identifying the genes encoding the receptor, it is possible to assay gene repression of the mycobacteriophage receptor of M. tuberculosis cells when grown in macrophages by hybridization for the mRNA synthesis. If the receptor is not expressed in macrophages, it may be necessary to use a mycobacteriophage which recognizes a receptor that is constitutively expressed. If the receptor is masked by a membrane of the macrophage, the cells isolated from macrophages may be treated with a variety of different detergents to find a treatment that would allow infection of the M. tuberculosis cells with the mycobacteriophages. Again, it may be necessary to cultivate the detergent-treated macrophages in broth for a few generations to gain expression of the receptors. The assays to determine the infectability of macrophages from mycobacteria include not only the luciferase assay for the TM : :lux mycobacteriophages, but also infectious centers assays in which free mycobacteriophages are removed and mycobacteriophage-producing cells are scored by a mixed plating on a lawn of M. smeqmatis. This assay would be useful since infectability can be scored even if there are insufficient M. tuberculosis cells to form a bacterial lawn. It is important to re-evaluate the host range specificities of all of the mycobacteriophages in this assay. Free mycobacteriophages can simply be removed through the use of specific anti-mycobacteriophage antibodies. Detecting M. tuberculosis in Sputum Samples Sputum from a patient infected with M. tuberculosis contains a mixture of mucoploysaccharide, free M. tuberculosis cells, macrophages containing M. tuberculosis cells and a variety of cellular debris. Sputum samples from patients thought to have pulmonary tuberculosis may be used for a study in which various numbers of M. tuberculosis cells are added to sputum samples found to have no or few organisms by acid-fast staining. A variety of methods can be used to treat sputum samples so as to liquify the mucous and decontaminate the specimen under conditions in which all bacteria other than mycobacteria are killed. Because of the specificity of the phasmids, decontamination may not be as important as preserving the mycobacteriophage receptors. Nonetheless, the sputum samples may be treated initially with 2% w/v NaOH for 30 minutes at 37°C or with 0.5% N-acetyl cysteine + 1% NaOH. Alternatively, the sample may be treated with a variety of hydrolytic enzymes, such as collagenase, to help dissolve the sputum sample. If mycobacteriophage receptors are carbohydrates possibly sensitive to these conditions, other conditions may be utilized or the cells will be cultured 3-16 hours to allow recovery of infectivity before mycobacteriophage infection. Detecting Mycobacteria In Blood Samples Tuberculosis has been known to have a bacteremia. If the sensitivity necessary to detect 100 to 200 M. tuberculosis cells in a ml of sample can be obtained, levels of bacteremia in tuberculosis patients which were not previously observable may be observed. White cells should be purified over Ficoil-hypaque and lysed with 2% NP40, 1% SDS or freeze-thawing in the presence of DNAse to liberate intracellular mycobacteria. The pellet should then be infected with the diagnostic luciferase mycobacteriophage, or if only few organisms are present they can be concentrated by filtration onto filters, and filter areas cut out and infected. Assuring Specificity On a Variety of Clinical Isolates and Species; Assessment of False Positives and Negatives The luciferase assay may be optimized such that positive correlations of M. tuberculosis infections as indicated in the clinical lab may be obtained. The recombinant mycobacteriophages may be tested to ascertain the range of specificity that they have for other mycobacteria, and for the closely related genera Norcardia, Corvnebacterium, and Actinomycetes strains. These strains may be obtained from the ATCC. A number of blinded tests including negative controls, M. tuberculosis-infected patients, samples from patients infected with M. avium, and samples infected with other non-mycobacterial pathogens may be performed to ascertain the range of specificity. The ability to rapidly assess the susceptibilities of M. tuberculosis isolates to isoniazid, etha butol, rifampicin, pyrazinamide and other antibiotics will have a major impact on the treatment of tuberculosis patients. After the isolation of M. tuberculosis cells from a sputum sample, which may take several weeks, the assessment of drug-susceptibilities may take an additional 2 to 9 weeks. Diagnostic reporter mycobacteriophages may allow for evaluations of drug-susceptibilities at the time a sputum sample is collected. Alternatively, this approach would shorten the time necessary to assess drug-susceptibilities of purified M. tuberculosis colonies grown up from clinical samples . Luciferase Assays for M. tuberculosis Cells in the Presence of Drugs The results of the experiments suggest that by using luciferase as an indicator for the metabolic ability of the cell, it may be possible to define conditions which will enable us to distinguish drug-resistant mycobacteria from drug-sensitive mycobacteria. To test this hypothesis, isolated mutants of M. tuberculosis H37Ra which are resistant to isoniazid, rifampicin, ethambutol, or pyrazinamide would be used to generate a set of cogenic mutants. These independent mutants and the parent strains would be transformed with pYUBlδO. Luciferase activity will be assessed in the presence and absence of drugs in order to determine the optimal conditions for distinguishing between drug-resistant and drug-sensitive cells. It is quite possible that the window of time to observe differences for different drugs could vary and require different incubation times for each drug. The choice of the promoter for expressing luciferase may provide a needed parameter to more readily assess drug action. For example, in the case of E. coli, gyrase promoters are greatly stimulated in the presence of gyrase inhibitors. Clinical isolates of M. tuberculosis may be transformed with PYUB160 and tested for luciferase activity in the presence and absence of drugs. The luciferase assays with mycobacteriophage infections with lux mycobacteriophages on in vitro-grown M. tuberculosis cells will first be optimized, and then extended to M. tuberculosis cells grown in macrophages or isolated from sputum samples. Critical Assessment of Drug-Susceptibility Testing As for the detection of M. tuberculosis from clinical samples, the luciferase assay may be optimized so that the drug-susceptibility patterns for any clinical isolate may be obtained. It may be possible to add diagnostic mycobacteriophages to a single clinical specimen, aliquot the mixture into various tubes and add antibiotic drugs. Thus every experiment would have an internal control and each drug-treated sample could be compared to an untreated control. The critical parameter to conclude drug-resistance or sensitivity lies in the comparison. Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of various aspects of the invention. Thus, it is to be understood that numerous modifications may be made in the illustrative embodiments and other arrangements may be devised without departing from the spirit and scope of the invention.

Claims: WHAT IS CLAIMED IS: 1. A method of producing mycobacterial species-specific reporter mycobacteriophages which comprises introducing reporter genes and transcriptional promoters into the genomes of • *-* ■ mycobacterial species-specific mycobacteriophages wherein upon incubation with the mycobacteria for which said reporter mycobacteriophage is specific, the reporter genes of said reporter mycobacteriophage will express a gene product which is detectable. 10 2. The method according to Claim 1 wherein . the reporter genes and transcriptional promoters are introduced into the mycobacteriophages by shuttle phasmid technology. 3. The method according to Claim 1 wherein 15 the reporter genes and transcriptional promoters are introduced into the mycobacteriophages by homologous recominbation or PCR. 4 . The method according to Claim 1 wherein the reporter genes and transcriptional promoters are 0 introduced into the mycobacteriophages by transposon technology. 5. The method according to Claim 1 wherein the reporter genes and transcriptional promoters are introduced into the mycobacteriophages by debilitated phages packaged into page heads and tails. 6. The method according to Claim 1 wherein the reporter genes and transcriptional promoters are introduced into the mycobacteriophages by plasmids packaged into phage heads and tails. 7. The method according to Claim 1 wherein the reporter genes and transcriptional promoters are introduced into the mycobacteriophages by recombinant DNA techniques. δ. The method according to Claim 1 wherein the mycobacteria is M. tuberculosis. 9. The method according to Claim 1 wherein the mycobacterial species-specific mycobacteriophage is L5, TM4 or DS6A. 10. The method according to Claim 1 wherein the reporter genes are luciferase genes or the β-galactosidase gene. 11. The method according to Claim 10 wherein the luciferase genes are selected from the group consisting of Firefly lux gene, Vibrio fischeri lux genes, Xenorhabdus luminescens lux genes and lacZ genes. 12. The method according to Claim 1 wherein the transcriptional promoter is hsp60 or the L5 gene 62 promoter. 13. The method according to Claim 1 wherein the gene product is photons. 14. The method according to Claim 1 wherein the gene product is made detectable by contacting said gene product with a substrate. 15. The method according to Claim 14 wherein the substrate is luciferin or decanal. 16. The mycobacterial species-specific reporter mycobacteriophage produced by the method of Claim 1. 17. A mycobacterial species-specific reporter mycobacteriophage. comprising a mycobacterial species-specific mycobacteriophage which contains in its genome reporter genes and a transcriptional promoter, wherein the reporter genes express a gene product upon incubation with the mycobacteria for which the reporter mycobacteriophage is specific. lδ. The mycobacterial species-specific reporter mycobacteriophage according to Claim 17 wherein the mycobacteria is M. tuberculosis. 19. The mycobacterial species-specific reporter mycobacteriophage according to Claim 17 wherein the mycobacterial species-specific mycobacteriophage is L5, TM4 or DS6A. 20. The mycobacterial species-specific reporter mycobacteriophage according to Claim 17 wherein the reporter genes are luciferase genes or the β-galactosidase gene. 21. The mycobacterial species-specific reporter mycobacteriophage according to Claim 20 wherein the luciferase genes are selected from the group consisting of Firefly lux gene, Vibrio fischeri lux genes, Xenorhabdus luminescens lux genes and lacZ genes. 22. The mycobacterial species-specific reporter mycobacteriophage according to Claim 17 wherein the transcriptional promoter is hsp60 or the L5 gene 62 promoter. 23. The mycobacterial species-specific reporter mycobacteriophage according to Claim 17 wherein the gene product is photons. 24. The mycobacterial species-specific reporter mycobacteriophage according to Claim 17 wherein the gene product is made detectable by contacting said gene product with a substrate. 25. The mycobacterial species-specific reporter mycobacteriophage according to Claim 24 wherein the substrate is luciferin or decanal. 26. A method of diagnosing a mycobacterial disease which comprises incubating a sample which may contain myco- bacteria with mycobacterial species-specific mycobacteriophages which contain reporter genes and transcriptional promoters in their genomes, wherein the reporter genes produce a gene product upon incubation with the mycobacteria for which the mycobacteriophage is specific, and wherein the gene product is detectable. 27. The method according to Claim 26 wherein the mycobacterial disease is tuberculosis. 2δ. The method according to Claim 26 wherein the mycobacteria is M. tuberculosis. 29. The method according to Claim 26 wherein the mycobacterial species-specific mycobacteriophage is L5, TM4 or DS6A. 30. The method according to Claim 26 wherein the reporter genes are luciferase genes or the β-galactosidase gene. 31. The method according to Claim 30 wherein the luciferase genes are selected from the group consisting of Firefly lux gene, Vibrio fischeri lux genes, Xenorhabdus luminescens lux genes and lacZ genes. 32. The method according to Claim 26 wherein the transcriptional promoter is hsp60 or the L5 gene 62 promoter. 33. The method according to Claim 26 wherein the gene product is photons. 34. The method according to Claim 26 wherein the gene product is made detectable by contacting said gene product with a substrate. 35. The method according to Claim 34 wherein the substrate is luciferin or decanal. 36. The method according to Claim 26 wherein the sample is blood or sputum. 37. A method of assessing drug resistance of a mycobacterial strain which comprises: (a) incubating a sample which contains a myco- bacterial strain with mycobacterial species-specific mycobacteriophages which contain in their genomes transcriptional promoters and reporter genes which produce gene products; (b) adding an anti-mycobacterial drug to the incubation; and (c) detecting whether the gene product is present in the sample, such presence indicating drug resistance of the mycobacterial strain. 36. The method according to Claim 37 wherein the mycobacterial strain is a strain of M. tuberculosis. 39. The method according to Claim 37 wherein the mycobacterial species-specific mycobacteriophage is L5, or TM4 or DS6A. 40. The method according to Claim 37 wherein the reporter genes are luciferase genes or the β-galactosidase. 41. The method according to Claim 40 wherein 5 the luciferase genes are selected from the group consisting of Firefly lux, gene. Vibrio fischeri lux genes, Xenorhabdus luminescens lux genes and lacZ genes . 42. The method according to Claim 37 wherein " 10 the gene product is photons. 43. The method according to Claim 37 wherein the transcriptional promoter is hsp60 or the L5 gene 62 promoter. 44. The method according to Claim 37 wherein 15 the anti-mycobacterial drug is selected from the group consisting of streptomycin, isoniazid, ethambutol, rifampicin, ciproflo- xacin, novobiocin and cyanide. 45. The method according to Claim 37 wherein the gene product is made detectable by contacting said 20 gene product with a substrate. 46. The method according to Claim 45 wherein the substrate is luciferin or decanal. 47. The method according to Claim 37 wherein the sample is blood or sputum.

Inventors: BLOOM BARRY R, HATFULL GRAHAM F, JACOBS WILLIAM R JR, BLOOM, BARRY, R., HATFULL, GRAHAM, F., JACOBS, WILLIAM, R., JR.
Applicants: EINSTEIN COLL MED, UNIV PITTSBURGH, ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNI, UNIVERSITY OF PITTSBURGH
Application year: 1993
Main classification: C12P21
IPC codes: C07K14, C12N7, C12N15, C12Q1