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A framework for exhaustively mapping functional missense variants
Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada.;Univ Toronto, Donnelly Ctr, Toronto, ON, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON, Canada.;Univ Toronto, Dept Comp Sci, Toronto, ON, Canada..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada.;Univ Toronto, Donnelly Ctr, Toronto, ON, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON, Canada.;Univ Toronto, Dept Comp Sci, Toronto, ON, Canada..
Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada.;Univ Toronto, Donnelly Ctr, Toronto, ON, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON, Canada..
Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada.;Univ Toronto, Donnelly Ctr, Toronto, ON, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON, Canada..
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2017 (English)In: Molecular Systems Biology, ISSN 1744-4292, E-ISSN 1744-4292, Vol. 13, no 12, article id 957Article in journal (Refereed) Published
Abstract [en]

Although we now routinely sequence human genomes, we can confidently identify only a fraction of the sequence variants that have a functional impact. Here, we developed a deep mutational scanning framework that produces exhaustive maps for human missense variants by combining random codon mutagenesis and multiplexed functional variation assays with computational imputation and refinement. We applied this framework to four proteins corresponding to six human genes: UBE2I (encoding SUMO E2 conjugase), SUMO1 (small ubiquitin-like modifier), TPK1 (thiamin pyrophosphokinase), and CALM1/2/3 (three genes encoding the protein calmodulin). The resulting maps recapitulate known protein features and confidently identify pathogenic variation. Assays potentially amenable to deep mutational scanning are already available for 57% of human disease genes, suggesting that DMS could ultimately map functional variation for all human disease genes.

Place, publisher, year, edition, pages
WILEY , 2017. Vol. 13, no 12, article id 957
Keywords [en]
complementation, deep mutational scanning, genotype-phenotype, variants of uncertain significance
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-340268DOI: 10.15252/msb.20177908ISI: 000418750100007PubMedID: 29269382OAI: oai:DiVA.org:uu-340268DiVA, id: diva2:1178731
Available from: 2018-01-30 Created: 2018-01-30 Last updated: 2018-01-30Bibliographically approved

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