title: Evolution and diversity of clonal bacteria: the paradigm of Mycobacterium tuberculosis.
abstract: BACKGROUND
  Mycobacterium tuberculosis complex species display relatively static genomes and 99.9% nucleotide sequence identity. Studying the evolutionary history of such monomorphic bacteria is a difficult and challenging task.
  
  
  RESULTS
  We found that single-nucleotide polymorphism (SNP) analysis of DNA repair, recombination and replication (3R) genes in a comprehensive selection of M. tuberculosis complex strains from across the world, yielded surprisingly high levels of polymorphisms as compared to house-keeping genes, making it possible to distinguish between 80% of clinical isolates analyzed in this study. Bioinformatics analysis suggests that a large number of these polymorphisms are potentially deleterious. Site frequency spectrum comparison of synonymous and non-synonymous variants and Ka/Ks ratio analysis suggest a general negative/purifying selection acting on these sets of genes that may lead to suboptimal 3R system activity. In turn, the relaxed fidelity of 3R genes may allow the occurrence of adaptive variants, some of which will survive. Furthermore, 3R-based phylogenetic trees are a new tool for distinguishing between M. tuberculosis complex strains.
  
  
  CONCLUSIONS
  This situation, and the consequent lack of fidelity in genome maintenance, may serve as a starting point for the evolution of antibiotic resistance, fitness for survival and pathogenicity, possibly conferring a selective advantage in certain stressful situations. These findings suggest that 3R genes may play an important role in the evolution of highly clonal bacteria, such as M. tuberculosis. They also facilitate further epidemiological studies of these bacteria, through the development of high-resolution tools. With many more microbial genomes being sequenced, our results open the door to 3R gene-based studies of adaptation and evolution of other, highly clonal bacteria.
authors.affiliation: Unité de Génétique mycobactérienne, Institut Pasteur, Paris, France.
authors.forename: Tiago
authors.initials: T
authors.lastname: Dos Vultos
authors.forename: Olga
authors.initials: O
authors.lastname: Mestre
authors.forename: Jean
authors.initials: J
authors.lastname: Rauzier
authors.forename: Marcin
authors.initials: M
authors.lastname: Golec
authors.forename: Nalin
authors.initials: N
authors.lastname: Rastogi
authors.forename: Voahangy
authors.initials: V
authors.lastname: Rasolofo
authors.forename: Tone
authors.initials: T
authors.lastname: Tonjum
authors.forename: Christophe
authors.initials: C
authors.lastname: Sola
authors.forename: Ivan
authors.initials: I
authors.lastname: Matic
authors.forename: Brigitte
authors.initials: B
authors.lastname: Gicquel
mesh_terms: D019295:Computational Biology / Q000379:methods; D004260:DNA Repair / Q000235:genetics; D004261:DNA Replication / Q000235:genetics; D019143:Evolution, Molecular; D016680:Genome, Bacterial / Q000235:genetics; D009169:Mycobacterium tuberculosis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011995:Recombination, Genetic / Q000235:genetics