US2014162260A1PendingUtilityA1

Primers, snp markers and method for genotyping mycobacterium tuberculosis

Assignee: NAT HEALTH RESEARCH INSTITUTESPriority: Nov 26, 2012Filed: Nov 26, 2013Published: Jun 12, 2014
Est. expiryNov 26, 2032(~6.3 yrs left)· nominal 20-yr term from priority
C12Q 2600/156C12Q 2600/16C12Q 1/689C12Q 2600/172
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Claims

Abstract

The present application provides a primer set for genotyping M. tuberculosis selected from the group consisting of primer sets 1-25 (SEQ ID Nos. 1-50), and also provides an extension primer for genotyping M. tuberculosis selected from one of the group consisting of SEQ ID Nos. 51-75. The present application provides a combination of single-nucleotide polymorphism markers of M. tuberculosis . Further, the present application provides a method and a kit for genotyping M. tuberculosis.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A primer set for genotyping  Mycobacterium tuberculosis  selected from one of the group consisting of: 
       
         
           
                 
                 
               
                     
                   Primer set 1: 
                 
                     
                   (SEQ ID No. 1) 
                 
                     
                   ACGTTGGATGTTCTGGACGACCTGTCCTAC 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   (SEQ ID No. 2) 
                 
                     
                   ACGTTGGATGAGCTGCGCCAAGGTTCGTG, 
                 
                     
                     
                 
                     
                   Primer set 2: 
                 
                     
                   (SEQ ID No. 3) 
                 
                     
                   ACGTTGGATGTTGTAGCTGCCCAAATTGCC 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   (SEQ ID No. 4) 
                 
                     
                   ACGTTGGATGGGCTTCAATCTCGGCTTGG, 
                 
                     
                     
                 
                     
                   Primer set 3: 
                 
                     
                   (SEQ ID No. 5) 
                 
                     
                   ACGTTGGATGTATTCAACACCGGCATCGGG 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   (SEQ ID No. 6) 
                 
                     
                   ACGTTGGATGTCGCCTGGTCGTGGAAGAAC, 
                 
                     
                     
                 
                     
                   Primer set 4: 
                 
                     
                   (SEQ ID No. 7) 
                 
                     
                   ACGTTGGATGATCGGACAGCAGAAGGCAC 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   (SEQ ID No. 8) 
                 
                     
                   ACGTTGGATGACTCCCGCGGAACGTGGTG, 
                 
                     
                     
                 
                     
                   Primer set 5: 
                 
                     
                   (SEQ ID No. 9) 
                 
                     
                   ACGTTGGATGCAACACCGGCAACTTCAAC 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   (SEQ ID No. 10) 
                 
                     
                   ACGTTGGATGAATTAGCGTCTCCTCCGTTG, 
                 
                     
                     
                 
                     
                   Primer set 6: 
                 
                     
                   (SEQ ID No. 11) 
                 
                     
                   ACGTTGGATGTCGAACCCGCCGACAAATG 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   (SEQ ID No. 12) 
                 
                     
                   ACGTTGGATGTCGATTGGTCGCATGCACTG, 
                 
                     
                     
                 
                     
                   Primer set 7: 
                 
                     
                   (SEQ ID No. 13) 
                 
                     
                   ACGTTGGATGAAACCTCGGCATAGGGATCG  
                 
                     
                     
                 
                     
                   (SEQ ID No. 14) 
                 
                     
                   ACGTTGGATGTCGACAGGACTATTGGTAGC, 
                 
                     
                   and  
                 
                     
                     
                 
                     
                   Primer set 8: 
                 
                     
                   (SEQ ID No. 15) 
                 
                     
                   ACGTTGGATGAAGACGACGGGCCGGATATG 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   (SEQ ID No. 16) 
                 
                     
                   ACGTTGGATGCGTCAAGAGCTTCCCAAATC, 
                 
                     
                     
                 
                     
                   Primer set 9: 
                 
                     
                   (SEQ ID No. 17) 
                 
                     
                   ACGTTGGATGCATCCGGGAACACCGTAAAC 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   (SEQ ID No. 18) 
                 
                     
                   ACGTTGGATGATCACCTTCTTATCGGGTGG, 
                 
                     
                     
                 
                     
                   Primer set 10: 
                 
                     
                   (SEQ ID No. 19) 
                 
                     
                   ACGTTGGATGCCTGGATTTCAGATATTGCC 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   (SEQ ID No. 20) 
                 
                     
                   ACGTTGGATGTGGCCAGCCCTAGCAAGTC, 
                 
                     
                     
                 
                     
                   Primer set 11: 
                 
                     
                   (SEQ ID No. 21) 
                 
                     
                   ACGTTGGATGAGAACAAACGCGGGATTCAC 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   (SEQ ID No. 22) 
                 
                     
                   ACGTTGGATGTCTCCCGGAGATCACCATTC, 
                 
                     
                     
                 
                     
                   Primer set 12: 
                 
                     
                   (SEQ ID No. 23) 
                 
                     
                   ACGTTGGATGGTTGTTTTTGGCCGGGCAG 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   (SEQ ID No. 24) 
                 
                     
                   ACGTTGGATGATCGAGCAGACTCAGCGCTT, 
                 
                     
                     
                 
                     
                   Primer set 13: 
                 
                     
                   (SEQ ID No. 25) 
                 
                     
                   ACGTTGGATGTGCTACCGCCAATGTTCAAC 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   (SEQ ID No. 26) 
                 
                     
                   ACGTTGGATGATGGCGTTGACATAACTCGG, 
                 
                     
                     
                 
                     
                   Primer set 14: 
                 
                     
                   (SEQ ID No. 27) 
                 
                     
                   ACGTTGGATGATAGCAAGCACGATTGCGAC 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   (SEQ ID No. 28) 
                 
                     
                   ACGTTGGATGACCCCCCGCTGAGGGCGTA, 
                 
                     
                     
                 
                     
                   Primer set 15: 
                 
                     
                   (SEQ ID No. 29) 
                 
                     
                   ACGTTGGATGGATTCGATTGGGGAAACGGC 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   (SEQ ID No. 30) 
                 
                     
                   ACGTTGGATGTTCCACATTGGTGATCAGCG, 
                 
                     
                     
                 
                     
                   Primer set 16: 
                 
                     
                   (SEQ ID No. 31) 
                 
                     
                   ACGTTGGATGCAAACGGCGTCACTTTGGTC 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   (SEQ ID No. 32) 
                 
                     
                   ACGTTGGATGTGAAATGTGGGCCCAAGACG, 
                 
                     
                     
                 
                     
                   Primer set 17: 
                 
                     
                   (SEQ ID No. 33) 
                 
                     
                   ACGTTGGATGCGATTTCGATCGGGATGTTG 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   (SEQ ID No. 34) 
                 
                     
                   ACGTTGGATGCAATCACGATCCCCTCAATC, 
                 
                     
                     
                 
                     
                   Primer set 18: 
                 
                     
                   (SEQ ID No. 35) 
                 
                     
                   ACGTTGGATGAGGCAAAGGAAAATCGACCG 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   (SEQ ID No. 36) 
                 
                     
                   ACGTTGGATGTTGACAAACTGAAACACCGC, 
                 
                     
                     
                 
                     
                   Primer set 19: 
                 
                     
                   (SEQ ID No. 37) 
                 
                     
                   ACGTTGGATGACAACCGGCCGCAGCGTTT 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   (SEQ ID No. 38) 
                 
                     
                   ACGTTGGATGAAGAACACCGAAAGTGGCTG, 
                 
                     
                     
                 
                     
                   Primer set 20: 
                 
                     
                   (SEQ ID No. 39) 
                 
                     
                   ACGTTGGATGTGCATTGGCCACTAAAGCTC 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   (SEQ ID No. 40) 
                 
                     
                   ACGTTGGATGTCGATGACTATCTGCGGATG, 
                 
                     
                     
                 
                     
                   Primer set 21: 
                 
                     
                   (SEQ ID No. 41) 
                 
                     
                   ACGTTGGATGACCCATTTGCCGAACGTGTC 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   (SEQ ID No. 42) 
                 
                     
                   ACGTTGGATGTGCTTGGCGACTTTGTGCAG, 
                 
                     
                     
                 
                     
                   Primer set 22: 
                 
                     
                   (SEQ ID No. 43) 
                 
                     
                   ACGTTGGATGAGCGTGAAGAAGACGACGA 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   (SEQ ID No. 44) 
                 
                     
                   ACGTTGGATGGTCTGTTGTCATTACGGGAG, 
                 
                     
                     
                 
                     
                   Primer set 23: 
                 
                     
                   (SEQ ID No. 45) 
                 
                     
                   ACGTTGGATGACATCAGGTGATGGTCATGC 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   (SEQ ID No. 46) 
                 
                     
                   ACGTTGGATGCGAAGGGAACAATGGATGTG, 
                 
                     
                     
                 
                     
                   Primer set 24: 
                 
                     
                   (SEQ ID No. 47) 
                 
                     
                   ACGTTGGATGTATGCCAACCGATTTGCCTG 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   (SEQ ID No. 48) 
                 
                     
                   ACGTTGGATGACATATTGTCCACCGCGTAG, 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   Primer set 25: 
                 
                     
                   (SEQ ID No. 49) 
                 
                     
                   ACGTTGGATGTCTTGGCAGCGGCATGGAC 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   (SEQ ID No. 50) 
                 
                     
                   ACGTTGGATGCCGAATTTCCAGTCTCACAG. 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         2 . The primer set of  claim 1 , which is applied in polymerase chain reaction to amplify a DNA fragment containing a single-nucleotide polymorphism (SNP) of  M. tuberculosis.    
     
     
         3 . An extension primer for genotyping  Mycobacterium tuberculosis  selected from one of the group consisting of: 
       
         
           
                 
                 
               
                     
                   (SEQ ID No. 51) 
                 
                     
                   GACCTGTCCTACGAACCGGTGATGG, 
                 
                     
                     
                 
                     
                   (SEQ ID No. 52) 
                 
                     
                   CGTTGCCCACGTTGTTGGCG, 
                 
                     
                     
                 
                     
                   (SEQ ID No. 53) 
                 
                     
                   CACCGGCCAACGTCTCGGGCATG, 
                 
                     
                     
                 
                     
                   (SEQ ID No. 54) 
                 
                     
                   CCCCCGACCGGCCGTTCTTCG, 
                 
                     
                     
                 
                     
                   (SEQ ID No. 55) 
                 
                     
                   TTCAACGGCGGCATCAT, 
                 
                     
                     
                 
                     
                   (SEQ ID No. 56) 
                 
                     
                   GCCGAAACAAGATTTGC, 
                 
                     
                     
                 
                     
                   (SEQ ID No. 57) 
                 
                     
                   CCTTCTGCGTCTCCAAT, 
                 
                     
                     
                 
                     
                   (SEQ ID No. 58) 
                 
                     
                   GATATGGGGCCGCGGAT, 
                 
                     
                     
                 
                     
                   (SEQ ID No. 59) 
                 
                     
                   ACCGTAAACGGGCCTAACCCTCC, 
                 
                     
                     
                 
                     
                   (SEQ ID No. 60) 
                 
                     
                   TTGGGGCTGGGAACTGGG, 
                 
                     
                     
                 
                     
                   (SEQ ID No. 61) 
                 
                     
                   ATTCACGTGAAAACCCTCG,, 
                 
                     
                     
                 
                     
                   (SEQ ID No. 62) 
                 
                     
                   AGCTCAGCGCGCGGCTGGTGT, 
                 
                     
                     
                 
                     
                   (SEQ ID No. 63) 
                 
                     
                   CAAAATACGGCGATCATCATGGG, 
                 
                     
                     
                 
                     
                   (SEQ ID No. 64) 
                 
                     
                   CCACCAGTACTTGCCGC, 
                 
                     
                     
                 
                     
                   (SEQ ID No. 65) 
                 
                     
                   ATCGGGGTGACGATGAG, 
                 
                     
                     
                 
                     
                   (SEQ ID No. 66) 
                 
                     
                   GCCGAGGAGCCCGCGTAACCGT, 
                 
                     
                     
                 
                     
                   (SEQ ID No. 67) 
                 
                     
                   TGTTGATCGGCCCGAGGC, 
                 
                     
                     
                 
                     
                   (SEQ ID No. 68) 
                 
                     
                   GCGGGCGTGGAACGCTGGTC, 
                 
                     
                     
                 
                     
                   (SEQ ID No. 69) 
                 
                     
                   AGCGTTTCCAGGTCACCGCA, 
                 
                     
                     
                 
                     
                   (SEQ ID No. 70) 
                 
                     
                   CCAGAGCGCAACAACAA, 
                 
                     
                     
                 
                     
                   (SEQ ID No. 71) 
                 
                     
                   CACGCTGGCATCAAGTTC,, 
                 
                     
                     
                 
                     
                   (SEQ ID No. 72) 
                 
                     
                   GAAGACGACGAGGACGACTGGG, 
                 
                     
                     
                 
                     
                   (SEQ ID No. 73) 
                 
                     
                   GACGATTCCGGGCATGCG, 
                 
                     
                     
                 
                     
                   (SEQ ID No. 74) 
                 
                     
                   TGCCTGCCTGGTATGAC, 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   (SEQ ID No. 75) 
                 
                     
                   GGCATGGACGGGATCGG. 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         4 . The extension primer of  claim 3 , which is applied in polymerase chain reaction to amplify a DNA fragment having a single-nucleotide polymorphism (SNP) of  M. tuberculosis  as a terminal nucleotide of the DNA fragment. 
     
     
         5 . A combination of single-nucleotide polymorphism markers of  M. tuberculosis  is selected from the group consisting of “T” at position 301 of SEQ ID No.76, “A” at position 301 of SEQ ID No. 77, “A” at position 301 of SEQ ID No. 78, “G” at position 301 of SEQ ID No. 79, “G” at position 301 of SEQ ID No. 80, “G” at position 301 of SEQ ID No. 81, “C” at position 301 of SEQ ID No. 82, “G” at position 301 of SEQ ID No. 83, “C” at position 301 of SEQ ID No. 84, “A” at position 301 of SEQ ID No. 85, “A” at position 301 of SEQ ID No. 86, “A” at position 301 of SEQ ID No. 87, “G” at position 301 of SEQ ID No. 88, “A” at position 301 of SEQ ID No. 89, “G” at position 301 of SEQ ID No. 90, “G” at position 301 of SEQ ID No. 91, “A” at position 301 of SEQ ID No. 92, “C” at position 301 of SEQ ID No. 93, “C” at position 301 of SEQ ID No. 94, “T” at position 301 of SEQ ID No. 95, “T” at position 301 of SEQ ID No. 96, “T” at position 301 of SEQ ID No. 97, “T” at position 301 of SEQ ID No. 98, “T” at position 301 of SEQ ID No. 99, and “C” at position 301 of SEQ ID No.100. 
     
     
         6 . A method for genotyping  Mycobacterium tuberculosis  comprising obtaining a sample, amplifying and obtain at least one of first DNA fragment by using one or more primer sets selected from the group consisting of primer sets 1 to 25 (SEQ ID Nos. 1 to 50), amplifying and obtain at least one of second DNA fragment by using the obtained first DNA fragment as template and using one or more extension primers selected from the group consisting of SEQ ID Nos. 51 to 75, and detecting the second DNA fragment by using mass spectrometry. 
     
     
         7 . The method of  claim 6 , which further comprising analyzing the mass spectrometry data based on the single-nucleotide polymorphism markers selected from the group consisting of combination of single-nucleotide polymorphism markers of  M. tuberculosis  is selected from the group consisting of “T” at position 301 of SEQ ID No.76, “A” at position 301 of SEQ ID No. 77, “A” at position 301 of SEQ ID No. 78, “G” at position 301 of SEQ ID No. 79, “G” at position 301 of SEQ ID No. 80, “G” at position 301 of SEQ ID No. 81, “C” at position 301 of SEQ ID No. 82, “G” at position 301 of SEQ ID No. 83, “C” at position 301 of SEQ ID No. 84, “A” at position 301 of SEQ ID No. 85, “A” at position 301 of SEQ ID No. 86, “A” at position 301 of SEQ ID No. 87, “G” at position 301 of SEQ ID No. 88, “A” at position 301 of SEQ ID No. 89, “G” at position 301 of SEQ ID No. 90, “G” at position 301 of SEQ ID No. 91, “A” at position 301 of SEQ ID No. 92, “C” at position 301 of SEQ ID No. 93, “C” at position 301 of SEQ ID No. 94, “T” at position 301 of SEQ ID No. 95, “T” at position 301 of SEQ ID No. 96, “T” at position 301 of SEQ ID No. 97, “T” at position 301 of SEQ ID No. 98, “T” at position 301 of SEQ ID No. 99, and “C” at position 301 of SEQ ID No.100. 
     
     
         8 . The method of  claim 6 , wherein the mass spectrometry is matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). 
     
     
         9 . The method of  claim 6 , wherein the sample is bacterial culture, nasal mucus, phlegm saliva, blood, section of tissues or organ, and/or biopsy. 
     
     
         10 . A kit for genotyping  Mycobacterium tuberculosis  comprising: at least one primer set selected from the group consisting of primer sets 1 to 25 (SEQ ID Nos. 1 to 50), and at least one extension primer selected from the group consisting of SEQ ID Nos. 51 to 75. 
     
     
         11 . The kit of  claim 10 , which further comprises a database of genotypes of  M. tuberculosis  based on single-nucleotide polymorphism markers. 
     
     
         12 . The kit of  claim 11 , wherein the single-nucleotide polymorphism markers is selected from the group consisting of the combination of single-nucleotide polymorphism (SNP) markers of  M. tuberculosis  can be selected from the group consisting of “T” at position 301 of SEQ ID No.76, “A” at position 301 of SEQ ID No. 77, “A” at position 301 of SEQ ID No. 78, “G” at position 301 of SEQ ID No. 79, “G” at position 301 of SEQ ID No. 80, “G” at position 301 of SEQ ID No. 81, “C” at position 301 of SEQ ID No. 82, “G” at position 301 of SEQ ID No. 83, “C” at position 301 of SEQ ID No. 84, “A” at position 301 of SEQ ID No. 85, “A” at position 301 of SEQ ID No. 86, “A” at position 301 of SEQ ID No. 87, “G” at position 301 of SEQ ID No. 88, “A” at position 301 of SEQ ID No. 89, “G” at position 301 of SEQ ID No. 90, “G” at position 301 of SEQ ID No. 91, “A” at position 301 of SEQ ID No. 92, “C” at position 301 of SEQ ID No. 93, “C” at position 301 of SEQ ID No. 94, “T” at position 301 of SEQ ID No. 95, “T” at position 301 of SEQ ID No. 96, “T” at position 301 of SEQ ID No. 97, “T” at position 301 of SEQ ID No. 98, “T” at position 301 of SEQ ID No. 99, and “C” at position 301 of SEQ ID No.100.

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