Temporal transcriptomic and proteomic profiling of causal variants in combination uncovers molecular drivers of phenotypic additivity

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 , MKT189G and TAO34477C, 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.遗传互作是复杂性状遗传架构的核心基础，但目前学界对遗传变异组合调控细胞通路的分子机制仍不甚明晰。本研究旨在解答两个核心科学问题：遗传变异间的互作是否能够激活独特的细胞通路，以及此类通路是否可被靶向调控以改变表型结果。本研究以模式生物酿酒酵母（Saccharomyces cerevisiae）为实验对象，解析两个因果性单核苷酸多态性位点（Single Nucleotide Polymorphism，下文简称SNP）——MKT189G与TAO34477C——如何在孢子形成过程中互作，进而调控代谢与表型结局。研究团队通过在同基因等位基因替换酵母菌株中整合时间分辨转录组学、绝对定量蛋白质组学与靶向代谢组学数据，证实这两个SNP同时存在时，会特异性激活精氨酸生物合成通路并抑制核糖体生物发生，这一代谢权衡效应可提升孢子形成效率。功能验证实验表明，仅在双SNP遗传背景下，精氨酸通路才对线粒体活性与高效孢子形成至关重要。本研究结果揭示了遗传变异互作如何重塑核心代谢网络，为理解多基因性状调控以及复杂性状中加性效应的产生提供了机制层面的研究框架。