Tuberculosis is an ancient disease caused by the bacterium Mycobacterium tuberculosis (Mtb). Although it is perhaps best known for causing 20% of deaths between the seventeenth and nineteenth centuries, the origin of Mtb is much older. Many thought that tuberculosis-causing Mtb arose 10,000 years ago, during the ‘Neolithic demographic transition’ (NDT), when humans transitioned from a hunter-gatherer lifestyle to one of agriculture and animal domestication. This new lifestyle increased population density and led to a rise in zoonotic transmission of novel pathogens that cause ‘crowd diseases’, which have high transmission rates owing to high virulence and usually an aerosol mode of transmission, as is the case for Mtb. However, Mtb can also exhibit chronic latency and slow disease progression — traits often associated with pre-NDT diseases — making the origins of Mtb less clear. Further complicating the study of Mtb is the subsequent coevolution of Mtb with human populations into different lineages capable of causing tuberculosis, collectively known as the Mycobacterium tuberculosis complex (MTBC).

In a seminal 2013 publication in Nature Genetics, Comas et al. used a population genetics approach to trace the origins of Mtb and subsequent human coevolution. The authors used whole-genome sequencing data from 259 Mtb isolates, mapping to seven MTBC lineages, and applied over 34,000 genetic variants to construct phylogenetic relationships between the strains, which broadly segregated human- and animal-adapted as well as modern and ancient MTBC lineages. The initial analysis also showed that, despite Mtb being an ancient pathogen, it is largely clonal with minimal heterogeneity. Additionally, Mtb strains rarely independently evolved the same genetic variants (which can indicate positive selection or recombination between strains in mixed infections), suggesting that the pathogen successfully coevolved with humans to evade invasion and required minimal mutations to adapt.