Defining the consequences of genetic variation on a proteome-wide scale.
Document Type
Article
Publication Date
6-23-2016
JAX Source
Nature 2016 Jun 23; 534:500-5
ISSN
1476-4687
PMID
27309819
Grant
P50GM076468, F32HD074299
Abstract
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. Nature 2016 Jun 23; 534:500-5
Recommended Citation
Chick J,
Munger SC,
Simecek P,
Huttlin E,
Choi K,
Gatti DM,
Raghupathy N,
Svenson KL,
Churchill G,
Gygi S.
Defining the consequences of genetic variation on a proteome-wide scale. Nature 2016 Jun 23; 534:500-5