Analysis of complete genomes of Mycobacterium tuberculosis sublineage 2.1 (Proto-Beijing) revealed the presence of three pe_pgrs3-pe_pgrs4-like genes.

Mycobacterium tuberculosis Complex (MTBC), the etiological agent of tuberculosis (TB), demonstrates considerable genotypic diversity with distinct geographic distributions and variable virulence profiles. The pe-ppe gene family is especially noteworthy for its extensive variability and roles in host immune response modulation and virulence enhancement. We sequenced an Mtb genotype L2.1 isolate from Chiangrai, Northern Thailand, using second and third-generation sequencing technologies. Comparative genomic analysis with two additional L2.1 isolates and two L2.2.AA3 (Asia Ancestral 3 Beijing) isolates revealed significant pe-ppe gene variations. Notably, all L2.1 isolates harbored three copies of pe_pgrs3-pe_pgrs4-like genes (pe_pgrs3*, pe_pgrs4*, and pe_pgrs4), different from L2.2.AA3 and H37Rv strains. Additionally, ppe53 was duplicated in all but H37Rv, and ppe50 was deleted in L2.1 isolates, contrasting with an extended ppe50 in an L2.2 isolate (Mtb 18b), which contains an additional SVP motif. Complete deletion of ppe66 and loss of wag22 were observed in L2.1 isolates. These findings highlight the high structural variability of the pe-ppe gene family, emphasizing its complex roles in Mtb-host immune interactions. This genetic complexity offers potentially critical insights into mycobacterial pathogenesis, with significant implications for vaccine development and diagnostics.