Genetic composition and evolution of the prevalent Mycobacterium tuberculosis lineages 2 and 4 in the Chinese and Zhejiang Province populations

The causative agent of tuberculosis (TB) comprises seven human-adapted lineages. Human movements and host genetics are crucial to TB dissemination. We analyzed whole-genome sequencing data for a countrywide collection of 1154 isolates and a provincial collection of 1296 isolates, constructed the best-scoring maximum likelihood phylogenetic tree, conducted Bayesian evolutionary analysis to compute the most recent common ancestors of lineages 2 and 4, and assessed the antigenic diversity in human T cell epitopes by calculating pairwise dN/dS ratios. Of the 1296 Zhejiang isolates, 964 (74.38%) belonged to lineage 2 and 332 (25.62%) belonged to lineage 4. L2.2 is the most ancient sub-lineage in Zhejiang, first appearing approximately 6897 years ago (95% HDI: 6513-7298). L4.4 is the most modern sub-lineage, first appearing approximately 2217 years ago (95% HDI: 1864-2581). The dN/dS ratios revealed that the epitope and non-epitope regions of lineage 2 strains were significantly (P<0.001) more conserved than those of lineage 4. An increase in the frequency of lineage 4 may reflect its successful transmission over the last 20 years. The recent common ancestors and transmission routes of the sub-lineages are related to the entry of humans into China and Zhejiang Province.