PT - JOURNAL ARTICLE AU - Tatum D. Mortimer AU - Alexandra M. Weber AU - Caitlin S. Pepperell TI - Signatures of selection at drug resistance loci in <em>Mycobacterium tuberculosis</em> AID - 10.1101/173229 DP - 2017 Jan 01 TA - bioRxiv PG - 173229 4099 - http://biorxiv.org/content/early/2017/08/07/173229.short 4100 - http://biorxiv.org/content/early/2017/08/07/173229.full AB - Tuberculosis (TB) is the leading cause of death by an infectious disease, and global TB control efforts are increasingly threatened by drug resistance in Mycobacterium tuberculosis (M. tb). Unlike most bacteria, where lateral gene transfer is an important mechanism of resistance acquisition, resistant M. tb arises solely by de novo chromosomal mutation. Using whole genome sequencing data from two natural populations of M. tb, we characterized the population genetics of known drug resistance loci using measures of diversity, population differentiation, and convergent evolution. We found resistant sub-populations to be less diverse than susceptible sub-populations, consistent with ongoing transmission of resistant M. tb. A subset of resistance genes (“sloppy targets”) were characterized by high diversity and multiple rare variants; we posit that a large genetic target for resistance and relaxation of purifying selection contribute to high diversity at these loci. For “tight targets” of selection, the path to resistance appeared narrower, evidenced by single favored mutations that arose numerous times on the phylogeny and segregated at markedly different frequencies in resistant and susceptible sub-populations. These results suggest that diverse genetic architectures underlie drug resistance in M. tb, and combined approaches are needed to identify causal mutations. Extrapolating from patterns observed in well-characterized genes, we identified novel candidate variants involved in resistance. The approach outlined here can be extended to identify resistance variants for new drugs, to investigate the genetic architecture of resistance, and, when phenotypic data are available, to find candidate genetic loci underlying other positively selected traits in clonal bacteria.Importance Mycobacterium tuberculosis (M. tb), the causative agent of tuberculosis (TB), is a significant burden on global health. Antibiotic treatment imposes strong selective pressure on M. tb populations. Understanding causative and compensatory mutations for drug resistance in M. tb is important for treatment of TB infections and controlling the increasing prevalence of drug resistance. Whole genome sequencing (WGS) can be used to identify novel loci mediating drug resistance and predict resistance patterns in the clinic faster than traditional methods. We have used WGS from natural populations of drug resistant M. tb to characterize the effect of positive selection on patterns of diversity at known resistance mediating loci. These methods can be used to identify novel mutations under positive selection, including resistance loci, in M. tb and other clonal pathogens.