Abstract

While the terms “gene-by-gene interaction” (GxG) and “gene-by-environment interaction” (GxE) are commonplace within the fields of quantitative and evolutionary genetics, “environment-by-environment interaction” (ExE) is a term used less often. In this study, we find that environment-by-environment interactions are a meaningful driver of phenotypes, and that they differ across different genotypes (suggestive of ExExG). To reach this conclusion, we analyzed a large dataset of roughly 1,000 mutant yeast strains with varying degrees of resistance to different antifungal drugs. We show that the effectiveness of a drug combination, relative to single drugs, often varies across different drug resistant mutants. Even mutants that differ by only a single nucleotide change can have dramatically different drug x drug (ExE) interactions. We also introduce a new framework that better predicts the direction and magnitude of ExE interactions for some mutants. Studying how ExE interactions change across genotypes (ExExG) is not only important when modeling the evolution of pathogenic microbes, but also for broader efforts to understand the cell biology underlying these interactions and to resolve the source of phenotypic variance across populations. The relevance of ExExG interactions have been largely omitted from canon in evolutionary and population genetics, but these fields and others stand to benefit from perspectives that highlight how interactions between external forces craft the complex behavior of living systems.