Genetic Variation Shapes Protein Networks Mainly through Non-transcriptional Mechanisms

Networks of co-regulated transcripts in genetically diverse populations have been studied extensively, but little is known
about the degree to which these networks cause similar co-variation at the protein level. We quantified 354 proteins in a
genetically diverse population of yeast segregants, which allowed for the first time construction of a coherent protein covariation
matrix. We identified tightly co-regulated groups of 36 and 93 proteins that were made up predominantly of genes
involved in ribosome biogenesis and amino acid metabolism, respectively. Even though the ribosomal genes were tightly
co-regulated at both the protein and transcript levels, genetic regulation of proteins was entirely distinct from that of
transcripts, and almost no genes in this network showed a significant correlation between protein and transcript levels. This
result calls into question the widely held belief that in yeast, as opposed to higher eukaryotes, ribosomal protein levels are
regulated primarily by regulating transcript levels. Furthermore, although genetic regulation of the amino acid network was
more similar for proteins and transcripts, regression analysis demonstrated that even here, proteins vary predominantly as a
result of non-transcriptional variation. We also found that cis regulation, which is common in the transcriptome, is rare at
the level of the proteome. We conclude that most inter-individual variation in levels of these particular high abundance
proteins in this genetically diverse population is not caused by variation of their underlying transcripts.