Genomic Analysis Identifies Targets of Convergent Positive Selection in Drug Resistant Mycobacterium tuberculosis

Details

• Alternative Title:
  Nat Genet
• Personal Author:
  Farhat, Maha R. ; Shapiro, B. Jesse ; Kieser, Karen J. ; Sultana, Razvan ; Jacobson, Karen R. ; Victor, Thomas C. ; Warren, Robin M. ; Streicher, Elizabeth M ; Calver, Alistair ; Sloutsky, Alex ; Kaur, Devinder ; Posey, Jamie E. ; Plikaytis, Bonnie ; Oggioni, Marco R. ; Gardy, Jennifer L. ; Johnston, James C. ; Rodrigues, Mabel ; Tang, Patrick K. C. ; Kato-Maeda, Midori ; Borowsky, Mark L. ; Muddukrishna, Bhavana ; Kreiswirth, Barry N. ; Kurepina, Natalia ; Galagan, James ; Gagneux, Sebastien ; Birren, Bruce ; Rubin, Eric J. ; Lander, Eric S. ; Sabeti, Pardis C. ; Murray, Megan
• Description:
  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.
• Subjects:
  Article DNA Repair Drug Resistance, Microbial Mutation Mycobacterium Tuberculosis Selection, Genetic
• Source:
  Nat Genet. 45(10).
• Document Type:
  Journal Article
• Funding:
  HHSN266200400001C/AO/NIAID NIH HHS/United States ; HHSN266200400001C/PHS HHS/United States ; K01 TW009213/TW/FIC NIH HHS/United States ; U54 GM088558/GM/NIGMS NIH HHS/United States
• Volume:
  45
• Issue:
  10
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:e13119c2a3882d12b5914b702145c98cec90037e9542016c60f4b3af19c726bb
• Download URL:
  https://stacks.cdc.gov/view/cdc/28569/cdc_28569_DS1.pdf
• File Type:
  [PDF - 1.32 MB ]