Population genomics of the emerging pathogen Mycobacterium abscessus

Abstract

Mycobacterium abscessus is an emerging pathogen that is increasingly responsible for pulmonary-associated morbidity and mortality, most commonly in patients with underlying lung disease. Previous work has revealed the existence of dense, clinically dominant clusters (DCs) in the M. abscessus phylogeny that are associated with increased virulence and antibiotic resistance. The reasons for increasing incidence of M. abscessus infections and DC emergence are currently unclear due to conflicting lines of genomic and epidemiological evidence. In this thesis we investigate adaptive variation in M. abscessus using a dataset of publicly available whole genome sequencing (WGS) of M. abscessus clinical isolates to better understand the genetic basis of DC emergence and potential host adaptation. In Chapter 1 we use evolutionary phylogenetic approaches to estimate the rate of mutation accumulation, or molecular clock rate. We find evidence that emergence of DCs has coincided with a slowing of the molecular clock rate. We provide further evidence that changes in the mutation rate are genetically encoded and hypothesize that these changes may confer an adaptive advantage in the human host environment. In Chapter 2 we characterize the diversity and phylogeographic distribution of the M. abscessus accessory genome. We find that DCs contribute less diversity to the M. abscessus pangenome but have a larger genome size, suggesting that DC emergence involved acquisition of a finite set of adaptive genes. We describe the functional classes of genes that are associated with DC emergence and their potential role in host adaptation. Finally, we investigate potential sources of gene acquisition through HGT with bacteria outside of the genus Mycobacterium.