Tuberculosis: evolution in millennia and minutes.

Tuberculosis remains a global public health threat: the causative organism, Mycobacterium tuberculosis, was once thought to show little genetic variation, but research in the last 10 years has demonstrated an ability to change in a series of different time frames. Related species of mycobacteria have undergone evolution by deletion of segments of DNA, allowing Mycobacterium bovis and other species to emerge from the M. tuberculosis complex, disproving the previously accepted theories. Deletions also affect the pathogenic potential of different lineages of M. tuberculosis. Over shorter time periods genetic variation is achieved by the movement of insertion sequences such as IS6110. Some lineages identified by this means are over-represented in patient populations, suggesting a genetic advantage, although the mechanism for this is not yet apparent. M. tuberculosis must also adapt to host and antibiotic selection pressure, and this is achieved by point mutations. Almost all antibiotic resistance emerges in this way, and data from clinical and in vitro studies indicate that M. tuberculosis exists with pre-existent mutants that remain as a small proportion of the population because of fitness deficits. Under certain physiological conditions, these rarer mutants may be favoured and, when antibiotic selection pressure is applied, will rise to dominate the bacterial population. M. tuberculosis is a highly effective pathogen that has caused disease in human populations for millennia. We are now starting to understand some of the genetic mechanisms behind this phenomenon.