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Journal of Clinical Microbiology, December 2002, p. 4457-4465, Vol. 40, No. 12
0095-1137/02/$04.00+0     DOI: 10.1128/JCM.40.12.4457-4465.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Microevolution of the Direct Repeat Region of Mycobacterium tuberculosis: Implications for Interpretation of Spoligotyping Data

R. M. Warren,1 E. M. Streicher,1 S. L. Sampson,1 G. D. van der Spuy,1 M. Richardson,1 D. Nguyen,2 M. A. Behr,2 T. C. Victor,1 and P. D. van Helden1*

MRC Centre for Molecular and Cellular Biology, Department of Medical Biochemistry, Faculty of Health Sciences, Stellenbosch University, Tygerberg 7505, South Africa,1 Department of Medicine, McGill University Health Centre, Montreal H3G 1A4, Canada2

Received 21 June 2002/ Returned for modification 6 August 2002/ Accepted 14 September 2002

The direct repeat (DR) region has been determined to be an important chromosomal domain for studying the evolution of Mycobacterium tuberculosis. Despite this, very little is known about microevolutionary events associated with clonal expansion and how such events influence the interpretation of both restriction fragment length polymorphism (RFLP) and spoligotype data. This study examined the structure of the DR region in three independently evolving lineages of M. tuberculosis with a combination of DR-RFLP, spoligotyping, and partial DNA sequencing. The results show that the duplication of direct variable repeat (DVR) sequences and single-nucleotide polymorphisms is rare; conversely, the deletion of DVR sequences and IS6110-mediated mutation is observed frequently. Deletion of either single or contiguous DVR sequences was observed. The deletion of adjacent DVR sequences occurred in a dependent manner rather than as an accumulation of independent events. Insertion of IS6110 into either the direct repeat or spacer sequences influenced the spoligotype pattern, resulting in apparent deletion of DVR sequences. Homologous recombination between adjacent IS6110 elements led to extensive deletion in the DR region, again demonstrating a dependent evolutionary mechanism. Different isolates from the same strain family and isolates from different strain families were observed to converge to the same spoligotype pattern. In conclusion, the binary data of the spoligotype are unable to provide sufficient information to accurately establish genotypic relationships between certain clinical isolates of M. tuberculosis. This has important implications for molecular epidemiologic strain tracking and for the application of spoligotype data to phylogenetic analysis of M. tuberculosis isolates.

* Corresponding author. Mailing address: MRC Centre for Molecular and Cellular Biology, Department of Medical Biochemistry, Stellenbosch University, P.O. Box 19063, Tygerberg 7505, South Africa. Phone: 27 21 9389401. Fax: 27 21 9389467. E-mail: pvh{at}sun.ac.za.

Journal of Clinical Microbiology, December 2002, p. 4457-4465, Vol. 40, No. 12
0095-1137/02/$04.00+0     DOI: 10.1128/JCM.40.12.4457-4465.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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