Yeast growth responses to environmental perturbations are associated with rewiring of large epistatic networks

The phenotypic effects of genetic polymorphisms often depend on the genetic and environmental context. Here, we explore how polymorphic loci in large interaction networks contribute to complex trait variation and in particular how genetic effects and network topologies are influenced by environmental perturbations. This was done by reanalysing a dataset of >4,000 haploid yeast segregants grown on 20 different media. In total, 130 epistatic loci were associated with growth in at least one environment. The across-environment interaction network defined by these loci explained 69 - 100% of the narrow sense heritability in the individual environments. Environmental changes often resulted in network hubs being connected and disconnected from their interactors, leading to changes in additive effects of individual loci, epistatic effects of multi-locus interactions and the total level of genetic variance in growth. The largest variation in genetic effects across environments was found for epistatic loci that were highly connected network hubs in some environments but not in others. In environments where loci were highly connected, the segregating alleles epistatically suppressed or released genetic effects from their interactors. In environments where they were lowly connected, the same alleles made small or no contributions to growth. Hub-loci thus often serve as modulators, influencing the phenotypic effects of environmentally specific sets of interacting effector genes, rather than being effectors themselves. These findings illustrate the importance of the interplay between large genetic interactions networks and the living environment, both for individual phenotypes and population level metrics of genetic variation.