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Genomic analysis identifies targets of convergent positive selection in drug-resistant Mycobacterium tuberculosis

Farhat, Maha R. and Shapiro, B. Jesse and Kieser, Karen J. and Sultana, Razvan and Jacobson, Karen R. and Victor, Thomas C. and Warren, Robin M. and Streicher, Elizabeth M. and Calver, Alistair and Sloutsky, Alex and Kaur, Devinder and Posey, Jamie E. and Plikaytis, Bonnie and Oggioni, Marco R. and Gardy, Jennifer L. and Johnston, James C. and Rodrigues, Mabel and Tang, Patrick K. C. and Kato-Maeda, Midori and Borowsky, Mark L. and Muddukrishna, Bhavana and Kreiswirth, Barry N. and Kurepina, Natalia and Galagan, James and Gagneux, Sebastien and Birren, Bruce and Rubin, Eric J. and Lander, Eric S. and Sabeti, Pardis C. and Murray, Megan. (2013) Genomic analysis identifies targets of convergent positive selection in drug-resistant Mycobacterium tuberculosis. Nature genetics, Vol. 45, H. 10. S. 1183-1189.

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Official URL: http://edoc.unibas.ch/dok/A6183914

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Abstract

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.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Tuberculosis Research (Gagneux)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
UniBasel Contributors:Gagneux, Sebastien
Item Type:Article, refereed
Bibsysno:Link to catalogue
Publisher:Nature Publ
ISSN:1061-4036
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:27 Feb 2014 15:46
Deposited On:27 Feb 2014 15:46

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