Interaction of genetic variants activates latent metabolic pathways in yeast.

Genetic interactions are fundamental to the architecture of complex traits, yet the molecular mechanisms by which variant combinations influence cellular pathways remain poorly understood. Here, we answer the question of whether interactions between genetic variants can activate unique pathways and if such pathways can be targeted to modulate phenotypic outcomes. The model organism Saccharomyces cerevisiae was used to dissect how two causal SNPs, MKT1(89G) and TAO3(4477C), interact to modulate metabolic and phenotypic outcomes during sporulation. By integrating time-resolved transcriptomics, absolute proteomics, and targeted metabolomics in isogenic allele replacement yeast strains, we show that the combined presence of these SNPs uniquely activates the arginine biosynthesis pathway and suppresses ribosome biogenesis, reflecting a metabolic trade-off that enhances sporulation efficiency. Functional validation demonstrates that the arginine pathway is essential for mitochondrial activity and efficient sporulation only in the double-SNP background. Our findings show how genetic variant interactions can rewire core metabolic networks, providing a mechanistic framework for understanding polygenic trait regulation and the emergence of additive effects in complex traits.