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

Reputable Mentor II
Reputable Mentor II
Joel M. Chick1*, Steven C. Munger2*, Petr Simecek2, Edward L. Huttlin1, Kwangbom Choi2, Daniel M. Gatti2, Narayanan Raghupathy2, Karen L. Svenson2, Gary A. Churchill2§ & Steven P. Gygi1§

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.
1Harvard Medical School, Boston, Massachusetts 02115, USA. 2The Jackson Laboratory, Bar Harbor, Maine 04609, USA. *These authors contributed equally to this work. §These authors jointly supervised this work.
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Last update:
‎10-15-2021 10:56 AM
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