Transmission history of major China-prevalent Mycobacterium tuberculosis sub-lineages in East Asia.

Mycobacterium tuberculosis complex (MTBC) is distributed globally and has posed a severe threat to human health throughout history. In this study, we analyzed whole-genome data from the four major MTBC sub-lineages prevalent in China (L2.2, L4.2, L4.4, and L4.5) to reconstruct their transmission and expansion histories across East Asia and parts of Central Asia. We found that L2.2 has established a highly connected transmission network centered in Southern China, whereas L4.2 is characterized by cross-border transmission between Central Asia and Western China, and L4.4 and L4.5 exhibit repeated transmission events between Southeast Asia and Southern China. By reconstructing their population histories, we demonstrated that these sub-lineages have experienced multi-stage expansions since the 15th century, accompanied by a recent rapid proliferation of evolutionary clades. These findings reveal that the MTBC epidemic in East Asia may follow a pattern of long-term historical adaptation superimposed with recent concentrated outbreaks, providing potential genomic evidence to inform precise regional tuberculosis control strategies in China.