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Journal of Bacteriology, June 2003, p. 3392-3399, Vol. 185, No. 11
0021-9193/03/$08.00+0     DOI: 10.1128/JB.185.11.3392-3399.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Modeling Bacterial Evolution with Comparative-Genome-Based Marker Systems: Application to Mycobacterium tuberculosis Evolution and Pathogenesis

David Alland,1* Thomas S. Whittam,2 Megan B. Murray,3 M. Donald Cave,4 Manzour H. Hazbon,1 Kim Dix,5 Mark Kokoris,5 Andreas Duesterhoeft,5 Jonathan A. Eisen,6 Claire M. Fraser,6 and Robert D. Fleischmann6

Department of Medicine, Center for Emerging Pathogens, New Jersey Medical School, Newark, New Jersey,1 National Food Safety and Toxicology Center, Michigan State University, East Lansing, Michigan,2 Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts,3 Department of Anatomy and Neurobiology, University of Arkansas for Medical Sciences, Little Rock, Arkansas,4 Qiagen Genomics, Inc., Bothell, Washington,5 The Institute for Genomic Research, Rockville, Maryland6

Received 18 December 2002/ Accepted 17 March 2003

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.

* Corresponding author. Mailing address: Center for Emerging Pathogens, New Jersey Medical School, MSB A-920C, P.O. Box 1709, Newark, NJ 07103. Phone: (973) 972-2179. Fax: (973) 972-7790. E-mail: allandda{at}umdnj.edu.

Journal of Bacteriology, June 2003, p. 3392-3399, Vol. 185, No. 11
0021-9193/03/$08.00+0     DOI: 10.1128/JB.185.11.3392-3399.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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