Mutation rates and adaptive variation among the clinically dominant clusters of Mycobacterium abscessus

Mycobacterium abscessus (Mab) is a multi-drug resistant pathogen increasingly responsible for severe pulmonary infections. Analysis of whole genome sequences (WGS) of Mab demonstrates dense genetic clustering of clinical isolates collected from disparate geographic locations. This has been interpreted as supporting patient-to-patient transmission, but epidemiological studies have contradicted this interpretation. Here we present evidence for a slowing of the Mab molecular clock rate coincident with the emergence of phylogenetic clusters. We find that clustered isolates are enriched in mutations affecting DNA repair machinery and have lower spontaneous mutation rates in in vitro. We propose that Mab adaptation to the host environment through variation in DNA repair genes affects the organism’s mutation rate and that this manifests as phylogenetic clustering. These results inform our understanding of niche switching for facultative pathogens, and challenge the model of transmission as the major mode of dissemination of clinically dominant Mab clusters.