University of Massachusetts Medical School Faculty Publications

Title

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

UMMS Affiliation

Commonwealth Medicine, Massachusetts Supranational TB Reference Laboratory

Date

10-1-2013

Document Type

Article

Medical Subject Headings

DNA Repair; Drug Resistance, Microbial; Mutation; Mycobacterium tuberculosis; *Selection, Genetic

Disciplines

Bacteriology | Genetics and Genomics | Genomics | Immunology and Infectious Disease | Microbiology

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.

Rights and Permissions

Citation: Nat Genet. 2013 Oct;45(10):1183-9. doi: 10.1038/ng.2747. Epub 2013 Sep 1. Link to article on publisher's site

Comments

Full author list omitted for brevity. For the full list of authors, see article.

Related Resources

Link to Article in PubMed

PubMed ID

23995135