Widespread epistasis among beneficial genetic variants revealed by high-throughput genome editing

Genetic interactions occur when a variant’s phenotypic effect is altered by variation at other genomic loci. Also known as epistasis, these interactions shape the genetic architecture of complex traits and modify phenotypes across genetic backgrounds. However, the factors associated with their occurrence remain poorly understood. To investigate this, we employed high-throughput genome editing to measure the fitness effects of 1,826 naturally polymorphic variants in four genetically diverse strains of Saccharomyces cerevisiae . About 31% of variants affect fitness in a common laboratory environment, of which 24% have strain-specific fitness effects indicative of epistasis. We found that beneficial variants are more likely to exhibit genetic interactions, and that genetic interactions are depleted among variants at higher allele frequencies. In addition, we demonstrate that these epistatic interactions for fitness can be mediated by specific traits such as flocculation ability. This work suggests that adaptive evolution from standing variation will often involve trade-offs where a variant is only beneficial in some genetic backgrounds, potentially explaining why many beneficial variants remain polymorphic. In sum, we provide a framework to understand the factors influencing epistasis in natural genetic variants with single-nucleotide resolution, revealing widespread epistasis among beneficial variants.