Strong genotype-by-genotype and genotype-by-environment interactions induced by antibiotic resistance mutations

The often parallel evolution of antibiotic resistance in different species offers a promising basis for predicting evolutionary change. However, the extent to which parallel genetic evolution is reflected at the phenotypic level remains unclear. We investigated how genetic background and temperature influence the fitness effects of homologous rifampicin resistance mutations in absence of antibiotics across two temperatures and three species (Escherichia coli, Acinetobacter baylyi and Lactiplantibacillus plantarum). We measured the effect of resistance mutations on two growth traits (maximum growth rate and maximum optical density) across all conditions and fit linear models to this data using Bayesian inference. Our model fits provide evidence for pervasive genetic interactions in both growth traits, including mutation by species (GxG), mutation by temperature (GxE), and GxGxE interactions. In particular, the effect of resistance mutations was strongly dependent on genomic background, to the extent that mutations often reduced growth in one species but increased it in another (sign epistasis). Similarly, the effect of mutations on growth was strongly influenced by temperature, with some mutations increasing growth at one but decreasing growth at the other temperature. Most notably, three resistance mutations induced strong heat sensitivity in A. baylyi. Our results reinforce previous studies that report strong epistatic and GxE effects of resistance mutations, indicating that in the absence of additional data and more mechanistic models, predicting fitness effects of resistance mutations across species and environments can be very challenging.