Genomic determinants of sympatric speciation of the Mycobacterium tuberculosis complex across evolutionary timescales.

Models on how bacterial lineages differentiate increase our understanding on early bacterial speciation events and about the relevant niche-specific loci involved. In the light of those models we analyse the population genomics events leading to the emergence of the Mycobacterium tuberculosis complex (MTBC) from related mycobacteria species. Emergence is characterised by a combination of recombination events involving multiple core pathogenesis functions and purifying selection on early diverging loci. After the separation from closely related mycobacteria we identify the phoR gene, a transcriptional regulator involved in multiple aspects of MTBC virulence, as a key functional player subject to pervasive positive selection. First, during the early diversification of the MTBC, PhoR played a central role defining the host range of the various MTBC members. Later, following adaption to the human host, PhoR mediates host-pathogen interaction during human-to-human transmission. We thus show that linking pathogen evolution across evolutionary and epidemiological timescales lead to the identification of past and present virulence determinants of interest for biomedical research.