Genomic analysis identifies targets of convergent positive selection in drug-resistant Mycobacterium tuberculosis.pdf (949.54 kB)
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journal contribution
posted on 2018-01-15, 11:40 authored by Maha R. Farhat, B. Jesse Shapiro, Karen J. Kieser, Razvan Sultana, Karen R. Jacobson, Thomas C. Victor, Robin M. Warren, Elizabeth M. Streicher, Alistair Calver, Alex Sloutsky, Devinder Kaur, Jamie E. Posey, Bonnie Plikaytis, Marco R. Oggioni, Jennifer L. Gardy, James C. Johnston, Mabel Rodrigues, Patrick K. C. Tang, Midori Kato-Maeda, Mark L. Borowsky, Bhavana Muddukrishna, Barry N. Kreiswirth, Natalia Kurepina, James Galagan, Sebastien Gagneux, Bruce Birren, Eric J. Rubin, Eric S. Lander, Pardis C. Sabeti, Megan MurrayM. 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.
Funding
We thank the technical staff of the British Columbia Centre for Disease Control Public Health Microbiology and Reference Mycobacteriology Laboratory in Vancouver, M. Bosman from the National Health Laboratory Service in Cape Town and L. Fattorini from the Istituto Superiore di Sanita in Rome. This work was funded by a Senior Ellison Foundation Award (M.M.) and in part by a contact from the National Institute of Allergy and Infectious Diseases (HHSN266200400001C to B.B.), the Department of Pulmonary and Critical Care at Massachusetts General Hospital (M.R.F.), a postdoctoral fellowship from the Harvard MIDAS Center for Communicable Disease Dynamics (B.J.S.) and a Packard Foundation Fellowship (P.C.S.). S.G. was supported by the Swiss National Science Foundation (PP0033_119205).
History
Citation
Nature Genetics, 2013, 45 (10), pp. 1183-1189Author affiliation
/Organisation/COLLEGE OF LIFE SCIENCES/Biological Sciences/Genetics and Genome BiologyVersion
- AM (Accepted Manuscript)
