Genomic analysis identifies targets of convergent positive selection in drug-resistant Mycobacterium tuberculosis by 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, Gagneux Sebastien, Birren Bruce, Rubin Eric J, Lander Eric S, Sabeti Pardis C, Murray Megan in Nature genetics (2013). PubMed

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.

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