Defining the consequences of genetic variation on a proteome-wide scale.
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.
Harvard Medical School, Boston, Massachusetts 02115, USA.
Joel M
JM
Chick
The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
Steven C
SC
Munger
The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
Petr
P
Simecek
Harvard Medical School, Boston, Massachusetts 02115, USA.
Edward L
EL
Huttlin
The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
Kwangbom
K
Choi
The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
Daniel M
DM
Gatti
The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
Narayanan
N
Raghupathy
The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
Karen L
KL
Svenson
The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
Gary A
GA
Churchill
Harvard Medical School, Boston, Massachusetts 02115, USA.
Steven P
SP
Gygi
D000818:Animals; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D016678:Genome / Q000235:genetics; D005838:Genotype; D008099:Liver / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008957:Models, Genetic; D060066:Protein Interaction Maps; D020543:Proteome / Q000032:analysis* / Q000096:biosynthesis / Q000235:genetics*; D040901:Proteomics; D040641:Quantitative Trait Loci / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D059467:Transcriptome / Q000235:genetics
D020543:Proteome; D012333:RNA, Messenger