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Antimicrob. Agents Chemother. doi:10.1128/AAC.00309-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Convergent evolutionary analysis identifies significant mutations in drug resistance targets of Mycobacterium tuberculosis

Division of Infectious Disease, Department of Medicine and the Ruy V. Lourenço Center for the Study of Emerging and Re-emerging Pathogens, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey; Department of Preventive Medicine, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, 07103, USA; Microbial Evolution Laboratory, National Food Safety & Toxicology Center, Michigan State University, East Lansing, MI 48824

^* To whom correspondence should be addressed. Email: allandda{at}umdnj.edu.

	Abstract

Mycobacterium tuberculosis adapts to the environment by selecting for advantageous single nucleotide polymorphisms (SNPs). We studied whether advantageous SNPs could be distinguished from neutral mutations occurring within genes associated with drug resistance. A total of 1003 clinical isolates of M. tuberculosis were related phylogenetically and tested for the distribution of SNPs in putative drug-resistance genes. Drug-resistant associated versus not drug-resistant associated SNPs in putative drug-resistance genes were compared for associations with single versus multiple-branch outcomes using chi-square and Fisher exact tests. All 286 (100%) isolates containing isoniazid (INH)-resistant SNPs had multi-branch distributions suggestive of multiple ancestry and convergent-evolution. In contrast, all 327 (100%) isolates containing not drug-resistant SNPs were monophyletic; and thus, without evidence of convergent-evolution (p<0.001). Convergence testing was then applied to SNPs at positions 481 of the iniA (Rv0342) and 306 of the embB genes, both potential drug-resistance targets for INH and/or ethambutol. Mutant embB306 alleles showed multi-branch distributions suggested convergent-evolution; however, all 44 iniAH481Q mutations were monophyletic. In conclusion, this study validates convergence analysis as a tool for identifying mutations that cause INH-resistance and then explores mutations in other genes. Our results suggest that embB306 mutations are likely to confer drug resistance while iniAH481Q mutations are not. This approach may be applied on a genome-wide scale to identify SNPs that impact antibiotic resistance and other types of biological fitness.