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Regional missense constraint improves variant deleteriousness prediction

Kaitlin E. Samocha, Jack A. Kosmicki, Konrad J. Karczewski, Anne H. O’Donnell-Luria, Emma Pierce-Hoffman, Daniel G. MacArthur, Benjamin M. Neale, Mark J. Daly
doi: https://doi.org/10.1101/148353
Kaitlin E. Samocha
1Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
3Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
4Program in Genetics and Genomics, Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts, USA.
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Jack A. Kosmicki
1Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
3Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
5Program in Bioinformatics and Integrative Genomics, Harvard University, Cambridge, Massachusetts, USA.
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Konrad J. Karczewski
1Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
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Anne H. O’Donnell-Luria
1Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
6Division of Genetics and Genomics, Boston Children’s Hospital, Boston, Massachusetts, USA.
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Emma Pierce-Hoffman
1Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
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Daniel G. MacArthur
1Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
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Benjamin M. Neale
1Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
3Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
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Mark J. Daly
1Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
3Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
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  • For correspondence: mjdaly@atgu.mgh.harvard.edu
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Abstract

Given increasing numbers of patients who are undergoing exome or genome sequencing, it is critical to establish tools and methods to interpret the impact of genetic variation. While the ability to predict deleteriousness for any given variant is limited, missense variants remain a particularly challenging class of variation to interpret, since they can have drastically different effects depending on both the precise location and specific amino acid substitution of the variant. In order to better evaluate missense variation, we leveraged the exome sequencing data of 60,706 individuals from the Exome Aggregation Consortium (ExAC) dataset to identify sub-genic regions that are depleted of missense variation. We further used this depletion as part of a novel missense deleteriousness metric named MPC. We applied MPC to de novo missense variants and identified a category of de novo missense variants with the same impact on neurodevelopmental disorders as truncating mutations in intolerant genes, supporting the value of incorporating regional missense constraint in variant interpretation.

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Posted June 12, 2017.
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Regional missense constraint improves variant deleteriousness prediction
Kaitlin E. Samocha, Jack A. Kosmicki, Konrad J. Karczewski, Anne H. O’Donnell-Luria, Emma Pierce-Hoffman, Daniel G. MacArthur, Benjamin M. Neale, Mark J. Daly
bioRxiv 148353; doi: https://doi.org/10.1101/148353
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Regional missense constraint improves variant deleteriousness prediction
Kaitlin E. Samocha, Jack A. Kosmicki, Konrad J. Karczewski, Anne H. O’Donnell-Luria, Emma Pierce-Hoffman, Daniel G. MacArthur, Benjamin M. Neale, Mark J. Daly
bioRxiv 148353; doi: https://doi.org/10.1101/148353

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