OR22

Mycobacterium tuberculosis lineage 2 (L2) presents a significant public health threat, particularly in Eurasia, due to its widespread prevalence and association with multi-drug resistant strains. Despite its dominance in this region, the reasons behind L2's success remain poorly understood. Here, we employed an integrative approach to unveil the factors contributing to this lineage’s advantage. Utilizing whole-genome sequencing data from hundreds to thousands of M.tb isolates, we employed Bayesian phylogenomics and demogenetics to reconstruct the evolutionary history of L2. This analysis revealed novel insights into the strength, spread, and timing of major L2 epidemics, confirming its dominance in terms of both antibiotic resistance and overall epidemiological success. Additionally, we investigated the potential influence of major socio-economic events, such as the collapse of the Soviet Union, on ongoing L2 epidemics. To understand the mechanisms underpinning L2's success, we leveraged a suite of complementary techniques. Predictive simulations and epidemicity indices allowed us to quantify the transmission potential of L2 strains. Furthermore, genome-wide association studies (GWAS) were employed to identify genetic factors associated with L2's advantageous traits. Finally, laboratory fluctuation assays revealed higher mutation rates in L2 compared to other lineages, potentially explaining its dominance by enhancing its adaptive landscape and facilitating the acquisition of resistance or compensatory mutations. Our multi-pronged approach provided a comprehensive understanding of the factors driving L2's success. This knowledge is crucial for the development of effective control strategies to combat this concerning lineage of M.tb.