Pervasive mislocalization of pathogenic coding variants underlying human disorders.

Autor:	Lacoste J; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Canada.; Department of Molecular Genetics, University of Toronto, Canada.; These authors contributed equally., Haghighi M; Broad Institute of Harvard and MIT, Cambridge, MA, USA.; These authors contributed equally., Haider S; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Canada.; Department of Molecular Genetics, University of Toronto, Canada., Lin ZY; Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, Canada., Segal D; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Canada.; Department of Molecular Genetics, University of Toronto, Canada., Reno C; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Canada.; Department of Molecular Genetics, University of Toronto, Canada., Qian WW; Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, IL, USA., Xiong X; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Canada.; Department of Molecular Genetics, University of Toronto, Canada., Shafqat-Abbasi H; Broad Institute of Harvard and MIT, Cambridge, MA, USA., Ryder PV; Broad Institute of Harvard and MIT, Cambridge, MA, USA., Senft R; Broad Institute of Harvard and MIT, Cambridge, MA, USA., Cimini BA; Broad Institute of Harvard and MIT, Cambridge, MA, USA., Roth FP; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Canada.; Department of Molecular Genetics, University of Toronto, Canada.; Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, Canada.; Department of Computer Science, University of Toronto, Toronto, Ontario, Canada., Calderwood M; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA., Hill D; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA., Vidal M; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA., Yi SS; Livestrong Cancer Institutes, Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, TX, USA.; Oden Institute for Computational Engineering and Sciences (ICES), The University of Texas at Austin, Austin, TX, USA.; Department of Biomedical Engineering, Cockrell School of Engineering, The University of Texas at Austin, Austin, TX, USA.; Interdisciplinary Life Sciences Graduate Programs (ILSGP), College of Natural Sciences, The University of Texas at Austin, Austin, TX, USA., Sahni N; Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Quantitative and Computational Biosciences Program, Baylor College of Medicine, Houston, TX, USA., Peng J; Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, IL, USA., Gingras AC; Department of Molecular Genetics, University of Toronto, Canada.; Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, Canada., Singh S; Broad Institute of Harvard and MIT, Cambridge, MA, USA., Carpenter AE; Broad Institute of Harvard and MIT, Cambridge, MA, USA., Taipale M; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Canada.; Department of Molecular Genetics, University of Toronto, Canada.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Sep 05. Date of Electronic Publication: 2023 Sep 05.
DOI:	10.1101/2023.09.05.556368
Abstrakt:	Widespread sequencing has yielded thousands of missense variants predicted or confirmed as disease-causing. This creates a new bottleneck: determining the functional impact of each variant - largely a painstaking, customized process undertaken one or a few genes or variants at a time. Here, we established a high-throughput imaging platform to assay the impact of coding variation on protein localization, evaluating 3,547 missense variants of over 1,000 genes and phenotypes. We discovered that mislocalization is a common consequence of coding variation, affecting about one-sixth of all pathogenic missense variants, all cellular compartments, and recessive and dominant disorders alike. Mislocalization is primarily driven by effects on protein stability and membrane insertion rather than disruptions of trafficking signals or specific interactions. Furthermore, mislocalization patterns help explain pleiotropy and disease severity and provide insights on variants of unknown significance. Our publicly available resource will likely accelerate the understanding of coding variation in human diseases. Competing Interests: DECLARATION OF INTERESTS A.E.C. serves as a scientific advisor for Recursion, which uses image-based profiling and Cell Painting for drug discovery and receives honoraria for occasional talks at pharmaceutical and biotechnology companies. The other authors declare no competing interests relevant to this manuscript.
Databáze:	MEDLINE
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