Unraveling Epistatic Interactions Between Sites Under Drug-Dependent Selection in the Mycobacterium tuberculosis Genome

Molecular Biology and Evolution. 2025. Vol. 42. No. 11. Article msaf264.

Anfisa V. Popova, Bykova D., Fedonin G., Bosov D., Reshetnikov K., Alexey D. Neverov

Many Mycobacterium tuberculosis (MTB) genome sites experience different selective forces depending on whether a patient is treated with antibiotics. Here, we searched for pairs of such sites that evolve interdependently. We reconstructed the phylogeny of more than 11,000 MTB clinical isolates with known phenotypes for at least one of 13 antitubercular drugs. By analyzing the distributions of substitutions and phenotypic state changes on the phylogeny, we identified sites where substitutions were associated with the acquisition of drug resistance or occurred preferentially in resistant or susceptible lineages. Among these sites, we searched for concordantly (CSP) and discordantly evolving site pairs (DSP), carefully accounting for the presence of drug-associated selection and other coordinated selective forces. We identified one CSP and fourteen DSPs between sites that are known to be strongly associated with resistance to anti-TB drugs. The CSP and five out of 14 DSPs were between sites whose substitutions were associated with resistance to different drugs, while the other nine DSPs were between sites located either in the same genes or in different genes involved in alternative adaptive pathways to the same drugs. Overall, our findings emphasize the dual role of epistasis, which can both promote and limit the acquisition of resistance to multiple drugs.

Keywords: Drug resistance, fitness landscape, Mycobacterium tuberculosis, Epistasis