Global genetic diversity of Mycobacterium tuberculosis L2.1 based on pe-ppe gene family

There are four major lineages of Mycobacterium tuberculosis (Mtb) whose geographic ranges vary considerably. Mtb lineage 2 (L2) or the East Asia lineage is particularly common in East and Southeast Asia, and also reported worldwide. Most L2 isolates belong to a sublineage L2.2 while L2.1 is more restricted to the Southern part of East Asia. It was reported that the L2.1 isolates in Thailand usually resisted isoniazid, rifampin and fluoroquinolones, i.e. , being pre-XDR strains. It is, therefore, of particular public health concern. Our previous study in a limited number of available complete genomes of L2.1 suggested unique structural variations of some pe-ppe genes. The gene family plays roles in immune evasion and host-pathogen interactions and, hence, is integral to the bacterium's virulence. Here we examine the identified structural variations of the pe-ppe gene family among all 180 L2.1 samples from eight countries, whose WGS data with high-quality are available in GenBank. We identified the deletion of the esxR-esxS gene segment in 26 L2.1 genomes, 19 of which, primarily restricted to Vietnam, Thailand, and China, belonged to a single clade. Additionally, we confirmed the deletions of four pe-ppe genes, wag22, ppe38, ppe50 and ppe66 , in all L2.1 samples. These genetic deletions may contribute to the virulence, pathogenesis, and evolutionary dynamics of the L2.1 strains, with significant implications for understanding the molecular mechanisms underlying the persistence and spread of this lineage. • L2.1 Mtb strains in Thailand exhibit pre-XDR drug resistance and genetic clustering profiles. • Deletions of four pe-ppe genes, wag22, ppe38, ppe50 and ppe66 were common to all L2.1 isolates. • Recombination of ppe46 and ppe47-ppe48 , resulting in the loss of esxR-esxS occurred repeatedly in L2.1 and was common to a basal L2.1 clade, consisting of isolates from Vietnam, Thailand and China.