A genome-to-proteome map reveals how natural variants drive proteome diversity and shape fitness

Understanding how genetic variation translates into complex phenotypes remains a fundamental challenge. Here, we address this by mapping genome-to-proteome relationships in 800 progeny of a cross between two yeast strains adapted to distinct environments. Despite the modest genetic distance between the parents, we observed remarkable proteomic diversity and mapped over 6,400 genotype-protein associations, with more than 1,600 linked to individual genetic variants. Proteomic adaptation emerged from a conserved network of cis- and trans-regulatory variants, often originating from proteins not traditionally linked to gene regulation. This atlas allowed us to forecast organismal fitness effects across diverse conditions. By connecting genomic and proteomic landscapes at unprecedented resolution, our study provides a framework for predicting the phenotypic outcomes of natural genetic variation.