Ancient Origin and Gene Mosaicism of the Progenitor of Mycobacterium tuberculosis

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Abstract
The highly successful human pathogen Mycobacterium tuberculosis has an extremely low level of genetic variation, which suggests that the entire population resulted from clonal expansion following an evolutionary bottleneck around 35,000 y ago. Here, we show that this population constitutes just the visible tip of a much broader progenitor species, whose extant representatives are human isolates of tubercle bacilli from East Africa. In these isolates, we detected incongruence among gene phylogenies as well as mosaic gene sequences, whose individual elements are retrieved in classical M. tuberculosis. Therefore, despite its apparent homogeneity, the M. tuberculosis genome appears to be a composite assembly resulting from horizontal gene transfer events predating clonal expansion. The amount of synonymous nucleotide variation in housekeeping genes suggests that tubercle bacilli were contemporaneous with early hominids in East Africa, and have thus been coevolving with their human host much longer than previously thought. These results open novel perspectives for unraveling the molecular bases of M. tuberculosis evolutionary success. Mycobacterium tuberculosis, the agent of tuberculosis, is a highly successful human pathogen and kills nearly 3 million persons each year. This pathogen and its close relatives sum up in a single and compact clonal group dating back only a few tens of thousands of years. Using genetic data, the researchers have discovered that human tubercle bacilli from East Africa represent extant bacteria of a much broader progenitor species from which the M. tuberculosis clonal group evolved. They estimate that this progenitor species is as old as 3 million years. This suggests that our remote hominid ancestors may well have already suffered from tuberculosis. In addition, the researchers show that tubercle bacilli are able to exchange parts of their genome with other strains, a process that is known to play a crucial role in adaptation of pathogens to their hosts. Thus, the M. tuberculosis genome appears to be a composite assembly, resulting from ancient horizontal DNA exchanges before its clonal expansion. These findings open novel perspectives for unraveling the origin and the molecular bases of M. tuberculosis evolutionary success, and lead to reconsideration of the impact of tuberculosis on human natural selection.