Genomic analysis identifies targets of convergent positive selection in drug-resistant Mycobacterium tuberculosis
Commonwealth Medicine, Massachusetts Supranational TB Reference Laboratory
DNA Repair; Drug Resistance, Microbial; Mutation; Mycobacterium tuberculosis; *Selection, Genetic
Bacteriology | Genetics and Genomics | Genomics | Immunology and Infectious Disease | Microbiology
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.
DOI of Published Version
Nat Genet. 2013 Oct;45(10):1183-9. doi: 10.1038/ng.2747. Epub 2013 Sep 1. Link to article on publisher's site
Farhat, Maha R.; Shapiro, B. Jesse; Sloutsky, Alex; Kaur, Devinder; and Murray, Megan, "Genomic analysis identifies targets of convergent positive selection in drug-resistant Mycobacterium tuberculosis" (2013). University of Massachusetts Medical School Faculty Publications. 752.