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Nat Genet. 2013 Oct;45(10):1183-9. doi: 10.1038/ng.2747. Epub 2013 Sep 1.

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

Author information

1
1] Pulmonary and Critical Care Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. [2].

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.

PMID:
23995135
PMCID:
PMC3887553
DOI:
10.1038/ng.2747
[Indexed for MEDLINE]
Free PMC Article

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