Abstract:
Drug resistance (DR) remains a global challenge in tuberculosis (TB) control. In order to
develop molecular-based diagnostic methods to replace the traditional culture-based diagnostics,
there is a need for a thorough understanding of the processes that govern TB drug resistance. The
use of whole-genome sequencing coupled with statistical and computational methods has shown
great potential in unraveling the complexity of the evolution of DR-TB. In this study, we took an
innovative approach that sought to determine nonrandom associations between polymorphic sites in
Mycobacterium tuberculosis (Mtb) genomes. Attributable risk statistics were applied to identify the
epistatic determinants of DR in different clades of Mtb and the possible evolutionary pathways of DR
development. It was found that different lineages of Mtb exploited different evolutionary trajectories
towards multidrug resistance and compensatory evolution to reduce the DR-associated fitness cost.
Epistasis of DR acquisition is a new area of research that will aid in the better understanding of
evolutionary biological processes and allow predicting upcoming multidrug-resistant pathogens
before a new outbreak strikes humanity.
