Defining the consequences of genetic variation on a proteome-wide scale.

1. Nature. 2016 Jun 23;534(7608):500-5. doi: 10.1038/nature18270. Epub 2016 Jun 15. Defining the consequences of genetic variation on a proteome-wide scale. Chick JM(1), Munger SC(2), Simecek P(2), Huttlin EL(1), Choi K(2), Gatti DM(2), Raghupathy N(2), Svenson KL(2), Churchill GA(2), Gygi SP(1). Author information: (1)Harvard Medical School, Boston, Massachusetts 02115, USA. (2)The Jackson Laboratory, Bar Harbor, Maine 04609, USA. Erratum in Nature. 2022 Jun;606(7915):E16. doi: 10.1038/s41586-022-04920-w. Genetic variation modulates protein expression through both transcriptional and post-transcriptional mechanisms. To characterize the consequences of natural genetic diversity on the proteome, here we combine a multiplexed, mass spectrometry-based method for protein quantification with an emerging outbred mouse model containing extensive genetic variation from eight inbred founder strains. By measuring genome-wide transcript and protein expression in livers from 192 Diversity outbred mice, we identify 2,866 protein quantitative trait loci (pQTL) with twice as many local as distant genetic variants. These data support distinct transcriptional and post-transcriptional models underlying the observed pQTL effects. Using a sensitive approach to mediation analysis, we often identified a second protein or transcript as the causal mediator of distant pQTL. Our analysis reveals an extensive network of direct protein-protein interactions. Finally, we show that local genotype can provide accurate predictions of protein abundance in an independent cohort of collaborative cross mice. DOI: 10.1038/nature18270 PMCID: PMC5292866 PMID: 27309819 [Indexed for MEDLINE]