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Journal of Clinical Microbiology, January 2007, p. 39-46, Vol. 45, No. 1
0095-1137/07/$08.00+0     doi:10.1128/JCM.02483-05
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Role of Large Sequence Polymorphisms (LSPs) in Generating Genomic Diversity among Clinical Isolates of Mycobacterium tuberculosis and the Utility of LSPs in Phylogenetic Analysis ^,

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,¹ National Food Safety and Toxicology Center, Michigan State University, East Lansing, Michigan,² The Institute for Genomic Research, Rockville, Maryland³

Received 30 November 2005/ Returned for modification 26 January 2006/ Accepted 10 October 2006

Mycobacterium tuberculosis strains contain different genomic insertions or deletions called large sequence polymorphisms (LSPs). Distinguishing between LSPs that occur one time versus ones that occur repeatedly in a genomic region may provide insights into the biological roles of LSPs and identify useful phylogenetic markers. We analyzed 163 clinical M. tuberculosis isolates for 17 LSPs identified in a genomic comparison of M. tuberculosis strains H37Rv and CDC1551. LSPs were mapped onto a single-nucleotide polymorphism (SNP)-based phylogenetic tree created using nine novel SNP markers that were found to reproduce a 212-SNP-based phylogeny. Four LSPs (group A) mapped to a single SNP tree segment. Two LSPs (group B) and 11 LSPs (group C) were inferred to have arisen independently in the same genomic region either two or more than two times, respectively. None of the group A LSPs but one group B LSP and five group C LSPs were flanked by IS6110 sequences in the references strains. Genes encoding members of the proline-glutamic acid or proline-proline-glutamic acid protein families were present only in group B or C LSPs. SNP- versus LSP-based phylogenies were also compared. We classified each isolate into 58 LSP types by using a separate LSP-based phylogenetic analysis and mapped the LSP types onto the SNP tree. LSPs often assigned isolates to the correct phylogenetic lineage; however, significant mistakes occurred for 6/58 (10%) of the LSP types. In conclusion, most LSPs occur in genomic regions that are prone to repeated insertion/deletion events and were responsible for an unexpectedly high degree of genomic variation in clinical M. tuberculosis. Group B and C LSPs may represent polymorphisms that occur due to selective pressure and affect the phenotype of the organism, while group A LSPs are preferable phylogenetic markers.

Published ahead of print on 1 November 2006.

Supplemental material for this article may be found at http://jcm.asm.org/.

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