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Journal of Bacteriology, October 2005, p. 6726-6732, Vol. 187, No. 19
0021-9193/05/$08.00+0     doi:10.1128/JB.187.19.6726-6732.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Natural Transposon Mutagenesis of Clinical Isolates of Mycobacterium tuberculosis: How Many Genes Does a Pathogen Need?

Hasan Yesilkaya,^1, Jeremy W. Dale,² Norval J. C. Strachan,³ and Ken J. Forbes^1*

Department of Medical Microbiology, University of Aberdeen, Medical School Building, Foresterhill, Aberdeen, United Kingdom AB25 2ZD,¹ Microbial Sciences Group, School of Biomedical and Molecular Sciences, University of Surrey, Guildford, Surrey, United Kingdom GU2 7XH,² School of Biological Sciences, Cruickshank Building, University of Aberdeen, St Machar Drive, Aberdeen, United Kingdom AB24 3UU³

Received 4 October 2004/ Accepted 23 June 2005

Transposable elements can affect an organism's fitness through the insertional inactivation of genes and can therefore be used to identify genes that are nonessential for growth in vitro or in animal models. However, these models may not adequately represent the genetic requirements during chains of human infection. We have therefore conducted a genome-wide survey of transposon mutations in Mycobacterium tuberculosis isolates from cases of human infection, identifying the precise, base-specific insertion sites of the naturally occurring transposable element IS6110. Of 294 distinct insertions mapped to the strain H37Rv genome, 180 were intragenic, affecting 100 open reading frames. The number of genes carrying IS6110 in clinical isolates, and hence apparently not essential for infection and transmission, is very much lower than the estimates of nonessential genes derived from in vitro studies. This suggests that most genes in M. tuberculosis play a significant role in human infection chains. IS6110 insertions were underrepresented in genes associated with virulence, information pathways, lipid metabolism, and membrane proteins but overrepresented in multicopy genes of the PPE family, genes of unknown function, and intergenic sequences. Population genomic analysis of isolates recovered from an organism's natural habitat is an important tool for determining the significance of genes or classes of genes in the natural biology of an organism.

Present address: Department of Infection, Immunity and Inflammation, University of Leicester, University Road, P.O. Box 138, Leicester, United Kingdom.

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