OR04

1:EPHE, PSL University, Paris, France; 2:Institut de Systématique, Evolution, Biodiversité, ISYEB, Muséum national d’Histoire naturelle, CNRS, Sorbonne, Université des Antilles, Paris, France; 3:Molecular and Experimental Mycobacteriology, Research Center Borstel, Germany; 4:Evolution of the Resistome, Research Center Borstel, Germany; 5:German Center for Infection Research, Partner site Hamburg-Lübeck-Borstel-Riems, Germany

The Mycobacterium tuberculosis (M.tb) lineage 2, known as the Beijing genotype, is closely associated with the spread of multidrug-resistant strains and exhibits increased virulence  and transmission efficiency compared with other M.tb lineages, thereby significantly impacting the global burden of tuberculosis. This study aims to elucidate the biological factors driving the epidemic success of this lineage  through genome-wide association (GWAS) and transmission analysis. We implemented an innovative approach combining GWAS and an epidemiological success index, time-scaled haplotypic density (THD), to assess transmission dynamics and underlying mutations. This method was applied to a global whole-genome dataset of 10,646 M.tb  isolates from 15 geographical regions, encompassing the full diversity of the Beijing genotype. The geographical distribution of subclade diversity shows regional patterns, with a notable overrepresentation of modern sublineages. Among them, the L2.2.M4 sublineage stands out, including several subgroups associated with major local outbreaks, such as the Russian clone W148, the Central Asian outbreak (CAO) and a South African subgroup (L2.2.M4.4), each showing increased epidemic success. Our pangenomic association study found  39 significant loci (P < 0.05) in genes related to drug tolerance, virulence, persistence and adaptative mechanisms. A quarter of these loci were either convergent across all modern subclades or specific to highly transmissible groups. Selection analysis using dN/dS ratios indicated that some of these positions were under diversifying selection.Overall, these results highlight the role of specific mutations in the epidemic success of the associated sublineages and contribute to a better understanding of the enhanced adaptive landscape of the Beijing lineage.