Title: Evolutionary dynamics and local adaptation of Mycobacterium tuberculosis encountering different host populations

Author: Qingyun Liu¹

Affiliation: ¹Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA

Abstract: During its global dispersal, Mycobacterium tuberculosis (Mtb) has encountered varied geographic environments and host populations, which could have imposed selective pressure and forced Mtb to evolve. While the mutation rate of Mtb is extremely slow, 6,000 years of evolution have generated numerous mutations that allowed natural selection to act. A key question is how those selective pressures shaped Mtb genomes and further affected the population dynamics of this pathogen. China has the world’s third-highest TB burden, but it was unclear when the epidemic forms of TB first arose, and what course these epidemics may have followed throughout Chinese history. We analyzed a countrywide collection of 4,578 isolates from China and found that 99.4% of the contemporary Mtb population traced back to only four ancestors strains that were introduced to China around 1,000 years ago. Coalescent analyses indicated that those strains expanded in parallel from the twelfth century onwards, and that the whole Mtb population peaked in the late eighteenth century. More recently, sublineage L2.3, which emerged indigenously in China but exhibited enhanced transmissibility and extensive global dissemination, came to dominate the recent population dynamics of Mtb. Strikingly, we found different host populations imposed distinct selective pressures on Mtb as we observed that Mtb strains from the Tibetan high plateau were subjected to local positive selection on genes associated with DNA repair and redox, with the most prominent feature of favoring truncating mutations in the thiol-oxidoreductase encoding gene sseA, while no such selection was observed in the Mtb from the plains regions. Collectively, our findings demonstrated a long-term genetic continuity of the indigenous Mtb population in China, and highlighted the bacterial population dynamics were heavily skewed by the pathogenic evolution of Mtb with genetic evidence indicating that Mtb has adapted to local environments.