An Epistatic Network Describes and as Relevant Genes for .

is an acid-fast bacterium that causes tuberculosis worldwide. The role of epistatic interactions among different loci of the genome under selective pressure may be crucial for understanding the disease and the molecular basis of antibiotic resistance acquisition. Here, we analyzed polymorphic loci interactions by applying a model-free method for epistasis detection, SpydrPick, on a pan-genome-wide alignment created from a set of 254 complete reference genomes. By means of the analysis of an epistatic network created with the detected epistatic interactions, we found that (-1,4-glucan branching enzyme) and (oligopeptide-binding protein) are putative targets of co-selection in as they were associated in the network with genes related to virulence, pathogenesis, transport system modulators of the immune response, and antibiotic resistance. In addition, our work unveiled potential pharmacological applications for genotypic antibiotic resistance inherent to the mutations of and as they epistatically interact with and , two genes recently included as antibiotic-resistant genes in the catalog of the World Health Organization. Our findings showed that this approach allows the identification of relevant epistatic interactions that may lead to a better understanding of by deciphering the complex interactions of molecules involved in its metabolism, virulence, and pathogenesis and that may be applied to different bacterial populations.