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.