Mycobacterium tuberculosis mutation rate estimates from different lineages predict substantial differences in the emergence of drug-resistant tuberculosis

Nat Genet. 2013 Jul;45(7):784-90. doi: 10.1038/ng.2656. Epub 2013 Jun 9.


A key question in tuberculosis control is why some strains of M. tuberculosis are preferentially associated with resistance to multiple drugs. We demonstrate that M. tuberculosis strains from lineage 2 (East Asian lineage and Beijing sublineage) acquire drug resistances in vitro more rapidly than M. tuberculosis strains from lineage 4 (Euro-American lineage) and that this higher rate can be attributed to a higher mutation rate. Moreover, the in vitro mutation rate correlates well with the bacterial mutation rate in humans as determined by whole-genome sequencing of clinical isolates. Finally, using a stochastic mathematical model, we demonstrate that the observed differences in mutation rate predict a substantially higher probability that patients infected with a drug-susceptible lineage 2 strain will harbor multidrug-resistant bacteria at the time of diagnosis. These data suggest that interventions to prevent the emergence of drug-resistant tuberculosis should target bacterial as well as treatment-related risk factors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibiotics, Antitubercular / therapeutic use
  • Biomarkers, Pharmacological / analysis
  • Communicable Diseases, Emerging / diagnosis
  • Communicable Diseases, Emerging / drug therapy
  • Communicable Diseases, Emerging / genetics
  • Communicable Diseases, Emerging / microbiology*
  • Computer Simulation
  • Drug Resistance, Multiple, Bacterial / genetics*
  • Genetic Speciation
  • Humans
  • Mutation / physiology
  • Mutation Rate*
  • Mycobacterium tuberculosis / genetics*
  • Prognosis
  • Tuberculosis, Multidrug-Resistant / diagnosis
  • Tuberculosis, Multidrug-Resistant / drug therapy
  • Tuberculosis, Multidrug-Resistant / genetics
  • Tuberculosis, Multidrug-Resistant / microbiology*


  • Antibiotics, Antitubercular
  • Biomarkers, Pharmacological