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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.

SUBMITTER: Farhat MR

PROVIDER: S-EPMC3887553 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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

Farhat Maha R MR Shapiro B Jesse BJ Kieser Karen J KJ Sultana Razvan R Jacobson Karen R KR Victor Thomas C TC Warren Robin M RM Streicher Elizabeth M EM Calver Alistair A Sloutsky Alex A Kaur Devinder D Posey Jamie E JE Plikaytis Bonnie B Oggioni Marco R MR Gardy Jennifer L JL Johnston James C JC Rodrigues Mabel M Tang Patrick K C PK Kato-Maeda Midori M Borowsky Mark L ML Muddukrishna Bhavana B Kreiswirth Barry N BN Kurepina Natalia N Galagan James J Gagneux Sebastien S Birren Bruce B Rubin Eric J EJ Lander Eric S ES Sabeti Pardis C PC Murray Megan M

Nature genetics 20130901 10

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 ...[more]

PMID: 23995135

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Project description:Tuberculosis caused by multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis (MTB) strains is a growing problem in many countries. The availability of the complete nucleotide sequences of several MTB genomes allows to use the comparative genomics as a tool to study the relationships of strains and differences in their evolutionary history including acquisition of drug-resistance. In our work, we sequenced three genomes of Russian MTB strains of different phenotypes--drug susceptible, MDR and XDR. Of them, MDR and XDR strains were collected in Tomsk (Siberia, Russia) during the local TB outbreak in 1998-1999 and belonged to rare KQ and KY families in accordance with IS6110 typing, which are considered endemic for Russia. Based on phylogenetic analysis, our isolates belonged to different genetic families, Beijing, Ural and LAM, which made the direct comparison of their genomes impossible. For this reason we performed their comparison in the broader context of all M. tuberculosis genomes available in GenBank. The list of unique individual non-synonymous SNPs for each sequenced isolate was formed by comparison with all SNPs detected within the same phylogenetic group. For further functional analysis, all proteins with unique SNPs were ascribed to 20 different functional classes based on Clusters of Orthologous Groups (COG). We have confirmed drug resistant status of our isolates that harbored almost all known drug-resistance associated mutations. Unique SNPs of an XDR isolate CTRI-4(XDR), belonging to a Beijing family were compared in more detail with SNPs of additional 14 Russian XDR strains of the same family. Only type specific mutations in genes of repair, replication and recombination system (COG category L) were found common within this group. Probably the other unique SNPs discovered in CTRI-4(XDR) may have an important role in adaptation of this microorganism to its surrounding and in escape from antituberculosis drugs treatment.

Dataset Information

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

Publications

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

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