Genetic landscape of an in vivo protein interactome

If a PPI network integrates both genetic and environmental effects to phenotype, then probing it could help define biochemical mechanisms underlying complex polygenic traits. Here, using inbred strains of the yeast Saccharomyces cerevisiae with ~12,000 single-nucleotide polymorphisms (SNPs) spread across the genome at a density of ~1 SNP/kb, we identified genomic loci that significantly modulate 61 in vivo PPIs.

In contrast to mRNA expression and protein abundance that are primarily affected by SNPs local to the gene (in “cis”), PPIs are dominantly affected by SNPs far (in “trans”) from the gene locus of the interacting protein pair. Consistent with the small-world characteristic of PPI networks, these trans-acting SNPs, although distant in the genome, are enriched in genes that are neighboring nodes in the PPI network. We likewise discovered several SNPs in cryptic non-coding RNAs and post-transcriptional regulators (3' UTRs) with, counterintuitively, larger PPI-modulating effects than SNPs within protein-coding regions.