Silent nucleotide polymorphisms and a phylogeny for Mycobacterium tuberculosis

Emerg Infect Dis. 2004 Sep;10(9):1568-77. doi: 10.3201/eid1009.040046.


Much remains unknown of the phylogeny and evolution of Mycobacterium tuberculosis, an organism that kills 2 million people annually. Using a population-based approach that analyzes multiple loci around the chromosome, we demonstrate that neutral genetic variation in genes associated with antimicrobial drug resistance has sufficient variation to construct a robust phylogenetic tree for M. tuberculosis. The data describe a clonal population with a minimum of four distinct M. tuberculosis lineages, closely related to M. bovis. The lineages are strongly geographically associated. Nucleotide substitutions proven to cause drug resistance are distributed throughout the tree, whereas nonsynonymous base substitutions unrelated to drug resistance have a restricted distribution. The phylogenetic structure is concordant with all the previously described genotypic and phenotypic groupings of M. tuberculosis strains and provides a unifying framework for both epidemiologic and evolutionary analysis of M. tuberculosis populations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidohydrolases / genetics
  • Antitubercular Agents / pharmacology
  • Bacterial Proteins / genetics
  • Base Sequence
  • Catalase / genetics
  • DNA Fingerprinting
  • DNA Gyrase / genetics
  • DNA-Directed RNA Polymerases / genetics
  • Drug Resistance, Multiple, Bacterial / genetics
  • Evolution, Molecular
  • Genetic Variation
  • Molecular Sequence Data
  • Mycobacterium tuberculosis / genetics*
  • Phylogeny
  • Polymorphism, Single Nucleotide
  • Ribosomal Proteins / genetics
  • Sequence Alignment
  • Sequence Analysis, DNA


  • Antitubercular Agents
  • Bacterial Proteins
  • Ribosomal Proteins
  • Catalase
  • katG protein, Mycobacterium tuberculosis
  • DNA-Directed RNA Polymerases
  • RNA polymerase beta subunit
  • Amidohydrolases
  • PncA protein, Mycobacterium tuberculosis
  • DNA Gyrase