Broadly speaking, we are interested in understanding the causes of variation in rates and patterns of molecular evolution. Our bacterial wet-lab work focuses on the evolution of antibiotic resistance, and patho-adaptation more generally. We also use comparative methods to investigate molecular evolution in both prokaryotes and eukaryotes.
Ongoing projects in the lab include:
- Genetic interactions of antibiotic resistance mutations in E. coli: The study of genetic interactions – also known as epistasis – is integral to contemporary systems biology and to evolutionary genetics. Genetic interactions can provide insight into the functions of previously uncharacterized genes, and can indicate whether genes participate in the same or in parallel pathways. Moreover, in the evolutionary genetics literature, theory and experiment have suggested an important role for epistasis in determining the trajectory of evolution, in the evolution of sex, and in determining rates of adaptation. We have devised a novel method for measuring genetic interactions in E. coli, and have applied it to a stereotypical quinolone resistance mutation in DNA gyrase A. Ongoing studies are aimed at discovering new interactions, validating interactions, understanding the mechanisms underlying these interactions, and at leveraging genetic interactions for therapeutic applications.
- Compensatory evolution: Antibiotic resistance is often accompanied by fitness costs, insofar as many resistance mutations confer reduced fitness in the absence of antibiotic. Nonetheless, widespread withdrawal of an antibiotic may have little to no effect on the prevalence of resistance in a patient population. Compensatory mutations – mutations that restore fitness to resistant strains without eliminating resistance – may contribute to the persistence of resistance following antibiotic withdrawal. We use laboratory selection experiments and whole-genome sequencing to understand patterns and mechanisms of compensatory evolution.
- Pathogen comparative genomics: We use comparative genomic methods to understand the population structure of pathogens, and to identify genomic loci contributing to pathogen adaptation. One current study focuses on the evolution of quinolone and beta-lactam resistance in E. coli, and we will soon be starting work on bovine tuberculosis and Brucella.