title: Genomic analysis identifies targets of convergent positive selection in drug-resistant Mycobacterium tuberculosis.
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.
authors.affiliation: 1] Pulmonary and Critical Care Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. [2].
authors.forename: Maha R
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authors.lastname: Farhat
authors.forename: B Jesse
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authors.lastname: Shapiro
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authors.lastname: Kieser
authors.forename: Razvan
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authors.lastname: Sultana
authors.forename: Karen R
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authors.lastname: Jacobson
authors.forename: Thomas C
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authors.lastname: Victor
authors.forename: Robin M
authors.initials: RM
authors.lastname: Warren
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Streicher
authors.forename: Alistair
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authors.lastname: Calver
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authors.lastname: Sloutsky
authors.forename: Devinder
authors.initials: D
authors.lastname: Kaur
authors.forename: Jamie E
authors.initials: JE
authors.lastname: Posey
authors.forename: Bonnie
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authors.lastname: Plikaytis
authors.forename: Marco R
authors.initials: MR
authors.lastname: Oggioni
authors.forename: Jennifer L
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authors.lastname: Gardy
authors.forename: James C
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authors.lastname: Johnston
authors.forename: Mabel
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authors.lastname: Rodrigues
authors.forename: Patrick K C
authors.initials: PK
authors.lastname: Tang
authors.forename: Midori
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authors.lastname: Kato-Maeda
authors.forename: Mark L
authors.initials: ML
authors.lastname: Borowsky
authors.forename: Bhavana
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authors.lastname: Muddukrishna
authors.forename: Barry N
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authors.lastname: Kreiswirth
authors.forename: Natalia
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authors.lastname: Kurepina
authors.forename: James
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authors.lastname: Galagan
authors.forename: Sebastien
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authors.lastname: Gagneux
authors.forename: Bruce
authors.initials: B
authors.lastname: Birren
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Rubin
authors.forename: Eric S
authors.initials: ES
authors.lastname: Lander
authors.forename: Pardis C
authors.initials: PC
authors.lastname: Sabeti
authors.forename: Megan
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authors.lastname: Murray
mesh_terms: D004260:DNA Repair; D004352:Drug Resistance, Microbial / Q000235:genetics*; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics; D012641:Selection, Genetic