Interaction of Genetic Variants Activates Latent Metabolic Pathways in Yeast

Genetic interactions are prevalent across species, from yeast to humans, and play a crucial role in shaping complex traits. However, the molecular mechanisms underlying these interactions remain largely unexplored. Here, we answer the question of whether interactions between genetic variants can activate novel unique pathways and if such pathways can be targeted to modulate phenotypic outcomes. The model organism Saccharomyces cerevisiae was used to investigate the interaction between two key SNPs, MKT189G and TAO34477C, during sporulation, a complex dynamic metabolic process. By integrating temporal gene expression and proteomics data, we show that these SNPs, in combination, activate amino acid metabolism, particularly the arginine biosynthesis pathway, while downregulating ribosome biogenesis, an energy-intensive process in response to nutrient starvation. This metabolic trade-off reveals a key mechanism by which SNP interactions modulate cellular responses to environmental stress, thereby enhancing sporulation. Further, the essential role of the arginine biosynthetic pathway in maintaining mitochondrial activity when these SNPs interact has been validated experimentally with deletion mutants. Our findings illustrate a broader impact beyond yeast, especially on complex human metabolic diseases like cancer, where specific SNP combinations hyperactivate ribosomal pathways while suppressing metabolic pathways that usually control cell growth, leading to uncontrolled proliferation.