title: Dynamic population changes in Mycobacterium tuberculosis during acquisition and fixation of drug resistance in patients.
abstract: BACKGROUND
  Drug-resistant tuberculosis poses a growing challenge to global public health. However, the diversity and dynamics of the bacterial population during acquisition of drug resistance have yet to be carefully examined.
  
  
  METHODS
  Whole-genome sequencing was performed on 7 serial Mycobacterium tuberculosis (M. tuberculosis) populations from 3 patients during different stages in the development of drug resistance. The population diversity was assessed by the number and frequencies of unfixed mutations in each sample.
  
  
  RESULTS
  For each bacterial population, 8-41 unfixed mutations were monitored by the fraction of single-nucleotide polymorphisms at specific loci. Among them, as many as 4 to 5 resistance-conferring mutations were transiently detected in the same single sputum, but ultimately only a single type of mutant was fixed. In addition, we identified 14 potential compensatory mutations that occurred during or after the emergence of resistance-conferring mutations.
  
  
  CONCLUSIONS
  M. tuberculosis population within patients exhibited considerable genetic diversity, which underwent selections for most fit resistant mutant. These findings have important implications and emphasize the need for early diagnosis of tuberculosis to decrease the chance of evolving highly fit drug-resistant strains.
authors.affiliation: Key Laboratory of Medical Molecular Virology, Institutes of Biomedical Sciences and Institute of Medical Microbiology, Fudan University, Shanghai, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Sun
authors.forename: Tao
authors.initials: T
authors.lastname: Luo
authors.forename: Chongguang
authors.initials: C
authors.lastname: Yang
authors.forename: Xinran
authors.initials: X
authors.lastname: Dong
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Zhu
authors.forename: Huajun
authors.initials: H
authors.lastname: Zheng
authors.forename: Weidong
authors.initials: W
authors.lastname: Tian
authors.forename: Shengyue
authors.initials: S
authors.lastname: Wang
authors.forename: Clifton E
authors.initials: CE
authors.lastname: Barry
authors.forename: Jian
authors.initials: J
authors.lastname: Mei
authors.forename: Qian
authors.initials: Q
authors.lastname: Gao
mesh_terms: D000995:Antitubercular Agents / Q000627:therapeutic use*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D005075:Biological Evolution; D024901:Drug Resistance, Multiple, Bacterial; D015964:Gene Expression Regulation, Bacterial / Q000502:physiology; D016680:Genome, Bacterial; D006801:Humans; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D018088:Tuberculosis, Multidrug-Resistant / Q000382:microbiology*; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000382:microbiology*
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins