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Abstract
We proteotyped blood plasma from 30 mouse knockout strains and corresponding wild-type mice from the International Mouse Phenotyping Consortium. We used targeted proteomics with internal standards to quantify 375 proteins in 218 samples. Our results provide insights into the manifested effects of each gene knockout at the plasma proteome level. We first investigated possible contamination by erythrocytes during sample preparation and labeled, in one case, up to 11 differential proteins as erythrocyte originated. Second, we showed that differences in baseline protein abundance between female and male mice were evident in all mice, emphasizing the necessity to include both sexes in basic research, target discovery, and preclinical effect and safety studies. Next, we identified the protein signature of each gene knockout and performed functional analyses for all knockout strains. Further, to demonstrate how proteome analysis identifies the effect of gene deficiency beyond traditional phenotyping tests, we provide in-depth analysis of two strains, C8a−/− and Npc2+/−. The proteins encoded by these genes are well-characterized providing good validation of our method in homozygous and heterozygous knockout mice. Ig alpha chain C region, a poorly characterized protein, was among the differentiating proteins in C8a−/−. In Npc2+/− mice, where histopathology and traditional tests failed to differentiate heterozygous from wild-type mice, our data showed significant difference in various lysosomal storage disease-related proteins. Our results demonstrate how to combine absolute quantitative proteomics with mouse gene knockout strategies to systematically study the effect of protein absence. The approach used here for blood plasma is applicable to all tissue protein extracts.
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1 University of Victoria—Genome BC Proteomics Centre, Victoria, Canada (GRID:grid.143640.4) (ISNI:0000 0004 1936 9465); Leiden University Medical Center, Center for Proteomics and Metabolomics, Leiden, Netherlands (GRID:grid.10419.3d) (ISNI:0000000089452978)
2 University of Victoria—Genome BC Proteomics Centre, Victoria, Canada (GRID:grid.143640.4) (ISNI:0000 0004 1936 9465)
3 The Center for Phenogenomics, Toronto, Canada (GRID:grid.143640.4); The Hospital for Sick Children, Toronto, Canada (GRID:grid.42327.30) (ISNI:0000 0004 0473 9646)
4 The Center for Phenogenomics, Toronto, Canada (GRID:grid.143640.4); Sinai Health Lunenfeld-Tanenbaum Research Institute, Toronto, Canada (GRID:grid.250674.2) (ISNI:0000 0004 0626 6184)
5 The Center for Phenogenomics, Toronto, Canada (GRID:grid.250674.2); The Hospital for Sick Children, Toronto, Canada (GRID:grid.42327.30) (ISNI:0000 0004 0473 9646)
6 Covance Inc., Chantilly, USA (GRID:grid.417600.4)
7 University of California, Department of Surgery, School of Medicine, and Mouse Biology Program, Davis, USA (GRID:grid.27860.3b) (ISNI:0000 0004 1936 9684)
8 The Hospital for Sick Children, Toronto, Canada (GRID:grid.42327.30) (ISNI:0000 0004 0473 9646)
9 McGill University, Proteomics Centre, Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, Montreal, Canada (GRID:grid.14709.3b) (ISNI:0000 0004 1936 8649); Jewish General Hospital, Gerald Bronfman Department of Oncology, Montreal, Canada (GRID:grid.414980.0) (ISNI:0000 0000 9401 2774); Skolkovo Innovation Center, Department of Data Intensive Science and Engineering, Skolkovo Institute of Science and Technology, Moscow, Russia (GRID:grid.454320.4) (ISNI:0000 0004 0555 3608)