Diversity and disease pathogenesis in Mycobacterium tuberculosis

•Mycobacterium tuberculosis was historically associated with limited genotypic diversity.•Recent evidence suggests infecting bacillary populations are more diverse than previously thought.•We consider the consequences of diversity for mycobacterial pathogenesis.•Diversity enables exploration of fitness landscapes while retaining core functions.•Systems biology approaches must be developed to understand TB.

The increasing availability of whole-genome sequence (WGS) data for Mycobacterium tuberculosis, the bacterium that causes tuberculosis (TB), suggests that circulating genotypes have been molded by three dominant evolutionary forces: long-term persistence within the human population, which requires a core programme of infection, disease, and transmission; selective pressure on specific genomic loci, which provides evidence of lineage-specific adaptation to host populations; and drug exposure, which has driven the rapid emergence of resistant isolates following the global implementation of anti-TB chemotherapy. Here, we provide an overview of these factors in considering the implications of genotypic diversity for disease pathogenesis, vaccine efficacy, and drug treatment.