Mycobacterium tuberculosis remains a major cause of morbidity and mortality worldwide. Studies have reported human pathogens to have geographically structured population genetics, some of which have been linked to ancient human migrations. However, no study has addressed the potential evolutionary consequences of such longstanding human-pathogen associations. Here, we demonstrate that the global population structure of M. tuberculosis is defined by six phylogeographical lineages, each associated with specific, sympatric human populations. In an urban cosmopolitan environment, mycobacterial lineages were much more likely to spread in sympatric than in allopatric patient populations. Tuberculosis cases that did occur in allopatric hosts disproportionately involved high-risk individuals with impaired host resistance. These observations suggest that mycobacterial lineages are adapted to particular human populations. If confirmed, our findings have important implications for tuberculosis control and vaccine development.coevolution ͉ deletions ͉ lineage ͉ polymorphism ͉ population

Multidrug-resistant tuberculosis (MDR-TB), caused by drug resistant strains of Mycobacterium tuberculosis, is an increasingly serious problem worldwide. In this study, we examined a dataset of 5,310 M. tuberculosis whole genome sequences from five continents. Despite great diversity with respect to geographic point of isolation, genetic background and drug resistance, patterns of drug resistance emergence were conserved globally. We have identified harbinger mutations that often precede MDR. In particular, the katG S315T mutation, conferring resistance to isoniazid, overwhelmingly arose before rifampicin resistance across all lineages, geographic regions, and time periods. Molecular diagnostics that include markers for rifampicin resistance alone will be insufficient to identify pre-MDR strains. Incorporating knowledge of pre-MDR polymorphisms, particularly katG S315, into molecular diagnostics will enable targeted treatment of patients with pre-MDR-TB to prevent further development of MDR-TB.

Mutations in the 81-bp rifampin resistance-determining region (RRDR) of the rpoB gene were analyzed by DNA sequencing of 50 Mycobacterium tuberculosis clinical isolates (44 resistant and 6 sensitive) from various parts of India. Fifty-three mutations of 18 different kinds, 17 point mutations and one deletion, were observed in 43 of 44 resistant isolates. Three novel mutations and three new alleles within the RRDR, along with two novel mutations outside the RRDR, are reported in this study.Tuberculosis (TB), though curable, still remains a major killer disease worldwide. The magnitude of the problem is reflected in estimates of new cases, which are predicted to number around 10 million in the year 2000 and 12 million by 2005 (7). Global prevalence of infection due to Mycobacterium tuberculosis is 32%. Eighty percent of all new TB cases are found in around 22 countries, with more than half the cases occurring in 5 Southeast Asian countries (6). Thirty percent of the world's TB-infected population is in India. The enormity of the problem has increased with the emergence of multidrugresistant (MDR) strains of M. tuberculosis. Dual infection with human immunodeficiency virus and MDR TB is a virtual death sentence in this era.Rifampin (RIF) resistance serves as a surrogate marker for the detection of MDR TB, as 90% of Rif r isolates are also isoniazid resistant (5). RIF interferes with transcription and elongation of RNA by binding to the DNA-dependent RNA polymerase. It was observed that resistance to RIF follows a single-step, high-level resistance pattern in which mutations occur spontaneously at a frequency of 10 Ϫ9 . The genetic basis for RIF resistance in approximately 95% of the cases is due to mutations in an 81-bp RIF resistance-determining region (RRDR) of the rpoB gene, corresponding to codons 507 to 533 (Escherichia coli numbering system), which codes for the beta subunit of the RNA polymerase of M. tuberculosis.Different groups of workers from diverse regions of the world (4, 8-12, 14, 16, 19, 20, 21, 23, 24) have thus far reported around 65 substitutions, 12 deletions, and 4 insertions in the RRDR of the rpoB gene. Only one of these earlier reports is concerned with Indian isolates, and in that study rpoB mutations were observed in three Rif r isolates (8). Determination of the mutation patterns among large numbers of isolates from different parts of India is essential, since this would help not only in the design of a suitable diagnostic method for rapid detection of MDR TB but also in the identification of any hot-spot regions in the country for proper implementation of TB control programs. It would also help in understanding whether mutated alleles arise independently or due to the spread of a particular genotype. Moreover, it is well known that clinical isolates from southern India are very different from isolates from other parts of the world. The former have lower virulence in guinea pigs (2), higher susceptibility to hydrogen peroxide (13, 18) and thiophene-2-carboxylic acid hydrazide (TCH), lowe...

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Molecular epidemiologic findings suggest an ancient focus of TB.