Genetic landscape of an in vivo protein interactome.

Protein-protein interaction (PPI) networks accurately map environmental perturbations to their molecular consequences in cells, yet the effects of natural genetic variation on PPIs remain poorly understood. Here we measured 61 reporter PPIs across inbred strains of Saccharomyces cerevisiae harboring ~12,000 single-nucleotide polymorphisms and identified protein-interaction quantitative trait loci (piQTLs) linking genomic variation to in vivo PPI strength. trans-acting piQTLs were significantly enriched and exhibited stronger per-variant effect sizes than cis-acting piQTLs. Consistent with the small-world architecture of PPI networks, trans-piQTLs often mapped to genes encoding proteins in close network proximity to reporter PPIs. We identified and validated piQTLs in poorly annotated regions, including noncoding RNAs and 3'UTRs, with effects comparable to coding single-nucleotide polymorphisms. piQTLs also overlapped more with protein abundance QTLs than expression QTLs, highlighting how PPI networks capture post-transcriptional and proteome-level regulation. This study provides a roadmap for dissecting complex traits through PPI network analysis.