Environmental robustness of the global yeast genetic interaction network

Abstract

Environmental impacts on gene networks A phenotype can be affected by genes interacting with other genes, the environment, or both other genes and the environment (a differential interaction). To better understand how these interactions function in yeast, Costanzo et al. mapped gene-gene interactions using single- and double-mutant deletions and temperature-sensitive alleles under 14 environmental conditions. Many deleted or temperature-sensitive nonessential genes affected yeast fitness both positively and negatively under at least one of the environmental conditions tested. In these cases, up to 24% of yeast genes were affected. A minority of these differential interactions point to previously unknown genetic connections across functional networks, informing on how genetic architecture responds to environmental variation. Science, this issue p. eabf8424 The global yeast genetic interaction network is robust to environmental perturbation and elucidates the functional architecture of a eukaryote. INTRODUCTION Genetic interactions are identified when variants in different genes combine to generate an unusual phenotype compared with the expected combined effect of the corresponding individual variants. For example, a synthetic lethal genetic interaction occurs when two mutations, neither of which is lethal on their own, combine to generate a lethal double-mutant phenotype. Although there are millions of possible gene-gene combinations for any eukaryotic cell, only a rare subset of gene pairs will display a genetic interaction. Digenic, or gene-by-gene (GxG), interactions appear to underlie key aspects of biology, including the relationship between genotype and phenotype. Environmental conditions can modulate the phenotype associated with genetic variants, giving rise to gene-by-environment (GxE) interactions, when a single variant phenotype is modified, or gene-by-gene-by-environment (GxGxE) interactions when a genetic interaction is changed. RATIONALE A global genetic interaction network has been mapped for the budding yeast Saccharomyces cerevisiae, identifying thousands of connections that often occur between functionally related genes. Because the global genetic network was mapped in a specific reference condition, the potential for different environmental conditions to rewire the network remains unclear. Automated yeast genetics, combined with knowledge of a reference map, enables quantification of the extent to which new environmental conditions either modulate known genetic interactions or generate novel genetic interactions to influence the genetic landscape of a cell. RESULTS We tested ~4000 yeast single mutants for GxE interactions across 14 diverse environments, including an alternative carbon source, osmotic and genotoxic stress, and treatment with 11 bioactive compounds targeting distinct yeast bioprocesses. To quantify GxGxE interactions, we constructed ~30,000 different double mutants, involving genes annotated to all major yeast bioprocesses, and we scored them for genetic interactions. The plasticity of the network is revealed by differential genetic interactions, which occur when a genetic interaction observed in a particular condition deviates from that scored in the control reference network. Although ~10,000 differential interactions were discovered across all 14 conditions, we observed ~60% fewer differential interactions per condition as compared with genetic interactions in the reference condition, indicating that GxGxE interactions are rare relative to GxG interactions. On average, a single environmental perturbation modulated ~14% of the reference genetic interactions and revealed a smaller subset of ~7% novel differential interactions. Whereas GxG genetic interactions tend to connect pairs of genes that share a close functional relationship, novel differential GxGxE interactions mediate weaker connections between gene pairs with diverse roles. CONCLUSION Our general findings reveal how environmental conditions modulate the yeast global genetic interaction network, allowing us to assess the plasticity of genetic networks and the extent to which mapping genetic interactions in different environments can expand a reference network. Although different environments have the potential to reveal novel interactions and uncover previously unidentified but weaker functional connections between genes, the vast majority of genetic interactions remained unchanged in different conditions, suggesting that the global yeast genetic interaction network is largely robust to environmental perturbation. Systematic analysis of environmental impact on the global yeast genetic interaction network. (Top left) Mapping GxE interactions and (bottom left) GxGxE differential interactions reveals (top right) the environmental robustness of the global yeast genetic interaction network, (bottom right) highlighting new and distant functional connections associated with novel differential interactions. Phenotypes associated with genetic variants can be altered by interactions with other genetic variants (GxG), with the environment (GxE), or both (GxGxE). Yeast genetic interactions have been mapped on a global scale, but the environmental influence on the plasticity of genetic networks has not been examined systematically. To assess environmental rewiring of genetic networks, we examined 14 diverse conditions and scored 30,000 functionally representative yeast gene pairs for dynamic, differential interactions. Different conditions revealed novel differential interactions, which often uncovered functional connections between distantly related gene pairs. However, the majority of observed genetic interactions remained unchanged in different conditions, suggesting that the global yeast genetic interaction network is robust to environmental perturbation and captures the fundamental functional architecture of a eukaryotic cell.