Gene evolutionary trajectories in Mycobacterium tuberculosis reveal temporal signs of selection

Genetic differences between different Mycobacterium tuberculosis complex (MTBC) strains determine their ability to transmit within different host populations, their latency times, and their drug resistance profiles. Said differences usually emerge through de novo mutations and are maintained or discarded by the balance of evolutionary forces. Using a dataset of ∼5,000 strains representing global MTBC diversity, we determined the past and present selective forces that have shaped the current variability observed in the pathogen population. We identified regions that have evolved under changing types of selection since the time of the MTBC common ancestor. Our approach highlighted striking differences in the genome regions relevant for host–pathogen interaction and, in particular, suggested an adaptive role for the sensor protein of two-component systems. In addition, we applied our approach to successfully identify potential determinants of resistance to drugs administered as second-line tuberculosis treatments.