Description
Tuberculosis remains a threat in numerous developing countries around the globe. In esponse to this danger, information on how species of the Mycobacterium tuberculosis complex adapt to hostile environmental conditions or stimuli remains a priority. Despite advancements in treatment success with more effective antibiotics and increased detection of M. tuberculosis resistance-conferring markers, the M. tuberculosis genome evolves in ways that are not completely understood, and many patients are infected with strains that are difficult to treat as a consequence. To examine this, I established an approach with two separate components. The former focuses on identifying new markers for second-line injectable drug resistance with the goal of informing future researchers on potential alternative mechanisms of resistance. To accomplish this, a genome-wide association study was performed across the M. tuberculosis genome for variants that appear across injectable resistant and susceptible isolates. Several genetic variants and whole genes that associate with resistance were identified, in addition to a few potential compensatory mutations that may offset fitness costs of several notable variants. The latter component of this project examines the effects of variable methylation on the evolution of the M. tuberculosis genome. Across genotypes with fully functional and knocked out methyltransferase activity, clinical isolates were examined for the presence of methylation motifs and transposable elements indicative of distinct levels of evolutionary pressure. Analysis of motifs and IS6110 elements revealed no association between methyltransferase activity level and motif alteration rate or IS6110 occurrence. Lastly, methylation motifs within the vicinity of several genes were observed to overlap with binding sites meant for transcription factors and sigma factors. This suggested that some methylation motifs may influence expression of a select few genes. The connection between occurrences of several compensatory mutations and existing resistance conferring mutations, in addition to links between changes in methylation motifs with transcription and sigma factors, helps elucidate several mechanisms that M. tuberculosis can use to promote its survival.
