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14 páginas, 6 figuras ; Models on how bacterial lineages differentiate increase our understanding of early bacterial speciation events and the genetic loci involved. Here, we analyze the population genomics events leading to the emergence of the tuberculosis pathogen. The emergence is characterized by a combination of recombination events involving core pathogenesis functions and purifying selection on early diverging loci. We identify the phoR gene, the sensor kinase of a two-component system involved in virulence, as a key functional player subject to pervasive positive selection after the divergence of the Mycobacterium tuberculosis complex from its ancestor. Previous evidence showed that phoR mutations played a central role in the adaptation of the pathogen to different host species. Now, we show that phoR mutations have been under selection during the early spread of human tuberculosis, during later expansions, and in ongoing transmission events. Our results show that linking pathogen evolution across evolutionary and epidemiological time scales points to past and present virulence determinants. ; : This work was funded by projects of the European Research Council (638553-TB-ACCELERATE) and Ministerio de Economía y Competitividad (Spanish government) research grant SAF2016-77346-R (to I.C.); BFU2014-58656-R and BFU2017-89594-R from Ministerio de Economía y Competitividad (Spanish government) and PROMETEO/2016/122 from Generalitat Valenciana (to F.G.-C); and the Swiss National Science Foundation (grants 310030_166687, IZRJZ3_164171, IZLSZ3_170834, and CRSII5_177163), the European Research Council (309540-EVODRTB), and SystemsX.ch (to S.G.). Á.C.-O. is the recipient of an FPU fellowship from Ministerio de Ciencia, Innovación y Universidades FPU13/00913 (Spanish government). L.S.-B. was funded by Wellcome grant number 098051. ; Peer reviewed