title: Modeling bacterial evolution with comparative-genome-based marker systems: application to Mycobacterium tuberculosis evolution and pathogenesis.
abstract: The comparative-genomic sequencing of two Mycobacterium tuberculosis strains enabled us to identify single nucleotide polymorphism (SNP) markers for studies of evolution, pathogenesis, and epidemiology in clinical M. tuberculosis. Phylogenetic analysis using these "comparative-genome markers" (CGMs) produced a highly unusual phylogeny with a complete absence of secondary branches. To investigate CGM-based phylogenies, we devised computer models to simulate sequence evolution and calculate new phylogenies based on an SNP format. We found that CGMs represent a distinct class of phylogenetic markers that depend critically on the genetic distances between compared "reference strains." Properly distanced reference strains generate CGMs that accurately depict evolutionary relationships, distorted only by branch collapse. Improperly distanced reference strains generate CGMs that distort and reroot outgroups. Applying this understanding to the CGM-based phylogeny of M. tuberculosis, we found evidence to suggest that this species is highly clonal without detectable lateral gene exchange. We noted indications of evolutionary bottlenecks, including one at the level of the PHRI "C" strain previously associated with particular virulence characteristics. Our evidence also suggests that loss of IS6110 to fewer than seven elements per genome is uncommon. Finally, we present population-based evidence that KasA, an important component of mycolic acid biosynthesis, develops G312S polymorphisms under selective pressure.
authors.affiliation: Department of Medicine, Center for Emerging Pathogens, New Jersey Medical School, Newark, New Jersey 07103, USA. allandda@umdnj.edu
authors.forename: David
authors.initials: D
authors.lastname: Alland
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Whittam
authors.forename: Megan B
authors.initials: MB
authors.lastname: Murray
authors.forename: M Donald
authors.initials: MD
authors.lastname: Cave
authors.forename: Manzour H
authors.initials: MH
authors.lastname: Hazbon
authors.forename: Kim
authors.initials: K
authors.lastname: Dix
authors.forename: Mark
authors.initials: M
authors.lastname: Kokoris
authors.forename: Andreas
authors.initials: A
authors.lastname: Duesterhoeft
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Eisen
authors.forename: Claire M
authors.initials: CM
authors.lastname: Fraser
authors.forename: Robert D
authors.initials: RD
authors.lastname: Fleischmann
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D019295:Computational Biology; D003198:Computer Simulation; D004251:DNA Transposable Elements; D019143:Evolution, Molecular; D016680:Genome, Bacterial; D006801:Humans; D009169:Mycobacterium tuberculosis / Q000235:genetics* / Q000472:pathogenicity*; D010802:Phylogeny; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide
chemical_list: D001426:Bacterial Proteins; D004251:DNA Transposable Elements