Environment by environment interactions (ExE) differ across genetic backgrounds (ExExG).

While the terms "gene-by-gene interaction" (GxG) and "gene-by-environment interaction" (GxE) are commonplace within the field of quantitative and evolutionary genetics, "environment-by-environment interaction" (ExE) is a term used less often. However, in this study, we find that environment-by-environment interactions are common and differ for different genotypes (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. Many researchers endeavor to predict combinations of drugs that are more lethal than either single drug. But we show that the effectiveness of a drug combination, relative to the effectiveness of 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. Studying how ExE interactions change across genotypes (ExExG) is not only important when modeling the evolution of pathogenic microbes. High throughput screens of GxG and GxE have taught us about the basic cell biology and gene regulatory networks underlying genetic interactions. ExExG has been omitted but stands to impart similar lessons about the architecture of living systems. In this study, we call attention to ExExG, measure its prevalence, introduce a new framework that in some instances better predicts its direction and magnitude, and make the case for further study of this type of genetic interaction.