Investigating the genomic basis of antimicrobial resistance in Mycobacterium tuberculosis (Mtb) using genome-wide methodologies

Characterizing the drug resistance mutations that have evolved in Mycobacterium tuberculosis (Mtb), has important implications for control of tuberculosis (TB) disease, through more accurate and timely use of therapy. Whole genome sequencing of Mtb can assist this characterization by providing insights into loci and specific mutations underlying drug resistance and the transmission success that enables their spread. We hypothesised that genetic variation outside of known resistance-conferring mutations might give additional information concerning drug resistance and fitness. Firstly, we explored the effect of lineage on the identification of drug resistance associations, applying novel lineage level genome-wide association study (GWAS) and convergence-based (PhyC) methods to drug resistance phenotypes of a global dataset of Mtb lineages 2 and 4. We identified known drug resistance variants and novel associations, uniquely identifying associations for lineage-specific GWAS analyses and reporting 17 novel associations between antimicrobial resistance phenotypes and Mtb genomic variants, demonstrating the utility of lineage-specific GWAS. To further examine the genomic basis of extensively drug resistant (XDR)-TB, ... (continues)