Genomic analysis identifies targets of convergent positive selection in drug-resistant Mycobacterium tuberculosis
M. tuberculosis is evolving antibiotic resistance, threatening attempts at tuberculosis epidemic control. Mechanisms of resistance, including genetic changes favored by selection in resistant isolates, are incompletely understood. Using 116 newly sequenced and 7 previously sequenced M. tuberculosis...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Nature Publishing Group
2014
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| Online Access: | http://hdl.handle.net/1721.1/86358 |
| _version_ | 1826197546842718208 |
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| author | Farhat, Maha R. Shapiro, B. Jesse Kieser, Karen J. Sultana, Razvan Jacobson, Karen R. Victor, Thomas C. Warren, Robin M. Streicher, Elizabeth M. Calver, Alistair Sloutsky, Alex Kaur, Devinder Posey, Jamie E. Plikaytis, Bonnie Oggioni, Marco R. Gardy, Jennifer L. Johnston, James C. Rodrigues, Mabel Tang, Patrick K. C. Kato-Maeda, Midori Borowsky, Mark L. Muddukrishna, Bhavana Kreiswirth, Barry N. Kurepina, Natalia Galagan, James E. Gagneux, Sebastien Birren, Bruce W. Rubin, Eric J. Sabeti, Pardis C. Murray, Megan B. Lander, Eric Steven |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Farhat, Maha R. Shapiro, B. Jesse Kieser, Karen J. Sultana, Razvan Jacobson, Karen R. Victor, Thomas C. Warren, Robin M. Streicher, Elizabeth M. Calver, Alistair Sloutsky, Alex Kaur, Devinder Posey, Jamie E. Plikaytis, Bonnie Oggioni, Marco R. Gardy, Jennifer L. Johnston, James C. Rodrigues, Mabel Tang, Patrick K. C. Kato-Maeda, Midori Borowsky, Mark L. Muddukrishna, Bhavana Kreiswirth, Barry N. Kurepina, Natalia Galagan, James E. Gagneux, Sebastien Birren, Bruce W. Rubin, Eric J. Sabeti, Pardis C. Murray, Megan B. Lander, Eric Steven |
| author_sort | Farhat, Maha R. |
| collection | MIT |
| description | M. tuberculosis is evolving antibiotic resistance, threatening attempts at tuberculosis epidemic control. Mechanisms of resistance, including genetic changes favored by selection in resistant isolates, are incompletely understood. Using 116 newly sequenced and 7 previously sequenced M. tuberculosis whole genomes, we identified genome-wide signatures of positive selection specific to the 47 drug-resistant strains. By searching for convergent evolution—the independent fixation of mutations in the same nucleotide position or gene—we recovered 100% of a set of known resistance markers. We also found evidence of positive selection in an additional 39 genomic regions in resistant isolates. These regions encode components in cell wall biosynthesis, transcriptional regulation and DNA repair pathways. Mutations in these regions could directly confer resistance or compensate for fitness costs associated with resistance. Functional genetic analysis of mutations in one gene, ponA1, demonstrated an in vitro growth advantage in the presence of the drug rifampicin. |
| first_indexed | 2024-09-23T10:49:21Z |
| format | Article |
| id | mit-1721.1/86358 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T10:49:21Z |
| publishDate | 2014 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/863582022-09-30T23:16:28Z Genomic analysis identifies targets of convergent positive selection in drug-resistant Mycobacterium tuberculosis Farhat, Maha R. Shapiro, B. Jesse Kieser, Karen J. Sultana, Razvan Jacobson, Karen R. Victor, Thomas C. Warren, Robin M. Streicher, Elizabeth M. Calver, Alistair Sloutsky, Alex Kaur, Devinder Posey, Jamie E. Plikaytis, Bonnie Oggioni, Marco R. Gardy, Jennifer L. Johnston, James C. Rodrigues, Mabel Tang, Patrick K. C. Kato-Maeda, Midori Borowsky, Mark L. Muddukrishna, Bhavana Kreiswirth, Barry N. Kurepina, Natalia Galagan, James E. Gagneux, Sebastien Birren, Bruce W. Rubin, Eric J. Sabeti, Pardis C. Murray, Megan B. Lander, Eric Steven Massachusetts Institute of Technology. Department of Biology Lander, Eric S. M. tuberculosis is evolving antibiotic resistance, threatening attempts at tuberculosis epidemic control. Mechanisms of resistance, including genetic changes favored by selection in resistant isolates, are incompletely understood. Using 116 newly sequenced and 7 previously sequenced M. tuberculosis whole genomes, we identified genome-wide signatures of positive selection specific to the 47 drug-resistant strains. By searching for convergent evolution—the independent fixation of mutations in the same nucleotide position or gene—we recovered 100% of a set of known resistance markers. We also found evidence of positive selection in an additional 39 genomic regions in resistant isolates. These regions encode components in cell wall biosynthesis, transcriptional regulation and DNA repair pathways. Mutations in these regions could directly confer resistance or compensate for fitness costs associated with resistance. Functional genetic analysis of mutations in one gene, ponA1, demonstrated an in vitro growth advantage in the presence of the drug rifampicin. 2014-05-02T14:15:26Z 2014-05-02T14:15:26Z 2013-09 2013-01 Article http://purl.org/eprint/type/JournalArticle 1061-4036 1546-1718 http://hdl.handle.net/1721.1/86358 Farhat, Maha R, B Jesse Shapiro, Karen J Kieser, Razvan Sultana, Karen R Jacobson, Thomas C Victor, Robin M Warren, et al. “Genomic Analysis Identifies Targets of Convergent Positive Selection in Drug-Resistant Mycobacterium Tuberculosis.” Nature Genetics 45, no. 10 (September 1, 2013): 1183–1189. en_US http://dx.doi.org/10.1038/ng.2747 Nature Genetics Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Nature Publishing Group PMC |
| spellingShingle | Farhat, Maha R. Shapiro, B. Jesse Kieser, Karen J. Sultana, Razvan Jacobson, Karen R. Victor, Thomas C. Warren, Robin M. Streicher, Elizabeth M. Calver, Alistair Sloutsky, Alex Kaur, Devinder Posey, Jamie E. Plikaytis, Bonnie Oggioni, Marco R. Gardy, Jennifer L. Johnston, James C. Rodrigues, Mabel Tang, Patrick K. C. Kato-Maeda, Midori Borowsky, Mark L. Muddukrishna, Bhavana Kreiswirth, Barry N. Kurepina, Natalia Galagan, James E. Gagneux, Sebastien Birren, Bruce W. Rubin, Eric J. Sabeti, Pardis C. Murray, Megan B. Lander, Eric Steven Genomic analysis identifies targets of convergent positive selection in drug-resistant Mycobacterium tuberculosis |
| title | Genomic analysis identifies targets of convergent positive selection in drug-resistant Mycobacterium tuberculosis |
| title_full | Genomic analysis identifies targets of convergent positive selection in drug-resistant Mycobacterium tuberculosis |
| title_fullStr | Genomic analysis identifies targets of convergent positive selection in drug-resistant Mycobacterium tuberculosis |
| title_full_unstemmed | Genomic analysis identifies targets of convergent positive selection in drug-resistant Mycobacterium tuberculosis |
| title_short | Genomic analysis identifies targets of convergent positive selection in drug-resistant Mycobacterium tuberculosis |
| title_sort | genomic analysis identifies targets of convergent positive selection in drug resistant mycobacterium tuberculosis |
| url | http://hdl.handle.net/1721.1/86358 |
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