title: Human genomics. Effect of predicted protein-truncating genetic variants on the human transcriptome.
abstract: Accurate prediction of the functional effect of genetic variation is critical for clinical genome interpretation. We systematically characterized the transcriptome effects of protein-truncating variants, a class of variants expected to have profound effects on gene function, using data from the Genotype-Tissue Expression (GTEx) and Geuvadis projects. We quantitated tissue-specific and positional effects on nonsense-mediated transcript decay and present an improved predictive model for this decay. We directly measured the effect of variants both proximal and distal to splice junctions. Furthermore, we found that robustness to heterozygous gene inactivation is not due to dosage compensation. Our results illustrate the value of transcriptome data in the functional interpretation of genetic variants.
authors.affiliation: Wellcome Trust Centre for Human Genetics, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. rivas@well.ox.ac.uk tlappalainen@nygenome.org macarthur@atgu.mgh.harvard.edu.
authors.forename: Manuel A
authors.initials: MA
authors.lastname: Rivas
authors.affiliation: FInstitute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors.forename: Matti
authors.initials: M
authors.lastname: Pirinen
authors.affiliation: Washington University in St. Louis, St. Louis, MO, USA.
authors.forename: Donald F
authors.initials: DF
authors.lastname: Conrad
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Monkol
authors.initials: M
authors.lastname: Lek
authors.affiliation: Department of Genetics, Stanford University, Stanford, CA, USA. Department of Pathology, Stanford University, Stanford, CA, USA. Biomedical Informatics Program, Stanford University, Stanford, CA, USA.
authors.forename: Emily K
authors.initials: EK
authors.lastname: Tsang
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Konrad J
authors.initials: KJ
authors.lastname: Karczewski
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Julian B
authors.initials: JB
authors.lastname: Maller
authors.affiliation: Department of Genetics, Stanford University, Stanford, CA, USA. Department of Pathology, Stanford University, Stanford, CA, USA.
authors.forename: Kimberly R
authors.initials: KR
authors.lastname: Kukurba
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: DeLuca
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. Department of Psychiatry, Mt. Sinai Hospital, NY, USA.
authors.forename: Menachem
authors.initials: M
authors.lastname: Fromer
authors.affiliation: Department of Genetic Medicine and Development,University of Geneva, Geneva, Switzerland. Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland. Swiss Institute of Bioinformatics, Geneva, Switzerland.
authors.forename: Pedro G
authors.initials: PG
authors.lastname: Ferreira
authors.affiliation: Department of Genetics, Stanford University, Stanford, CA, USA. Department of Pathology, Stanford University, Stanford, CA, USA.
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Smith
authors.affiliation: Department of Genetics, Stanford University, Stanford, CA, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Fengmei
authors.initials: F
authors.lastname: Zhao
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Banks
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Poplin
authors.affiliation: Department of Psychiatry, Mt. Sinai Hospital, NY, USA. Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, NY, USA.
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Ruderfer
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. Department of Psychiatry, Mt. Sinai Hospital, NY, USA. Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, NY, USA.
authors.forename: Shaun M
authors.initials: SM
authors.lastname: Purcell
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Taru
authors.initials: T
authors.lastname: Tukiainen
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Eric V
authors.initials: EV
authors.lastname: Minikel
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, UK.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Stenson
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, UK.
authors.forename: David N
authors.initials: DN
authors.lastname: Cooper
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: Katharine H
authors.initials: KH
authors.lastname: Huang
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Sullivan
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: Jared
authors.initials: J
authors.lastname: Nedzel
authors.affiliation: Department of Genetics, Stanford University, Stanford, CA, USA.
authors.forename: Carlos D
authors.initials: CD
authors.lastname: Bustamante
authors.affiliation: Department of Genetics, Stanford University, Stanford, CA, USA.
authors.forename: Jin Billy
authors.initials: JB
authors.lastname: Li
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.affiliation: Center for Genomic Regulation (CRG), Universitat Pompeu Fabra (UPF), Barcelona, Catalonia, Spain.
authors.forename: Roderic
authors.initials: R
authors.lastname: Guigo
authors.affiliation: Wellcome Trust Centre for Human Genetics, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. Department of Statistics, University of Oxford, Oxford, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Donnelly
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: Kristin
authors.initials: K
authors.lastname: Ardlie
authors.affiliation: Center for Genomic Regulation (CRG), Universitat Pompeu Fabra (UPF), Barcelona, Catalonia, Spain. National Institute for Scientific Computing (LNCC), Petropolis, Rio de Janeiro, Brazil.
authors.forename: Michael
authors.initials: M
authors.lastname: Sammeth
authors.affiliation: Department of Genetic Medicine and Development,University of Geneva, Geneva, Switzerland. Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland. Swiss Institute of Bioinformatics, Geneva, Switzerland.
authors.forename: Emmanouil T
authors.initials: ET
authors.lastname: Dermitzakis
authors.affiliation: Wellcome Trust Centre for Human Genetics, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. Oxford Center for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK.
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.affiliation: Department of Genetics, Stanford University, Stanford, CA, USA. Department of Pathology, Stanford University, Stanford, CA, USA.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Montgomery
authors.affiliation: Department of Genetics, Stanford University, Stanford, CA, USA. Department of Genetic Medicine and Development,University of Geneva, Geneva, Switzerland. Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland. Swiss Institute of Bioinformatics, Geneva, Switzerland. New York Genome Center, New York, NY, USA. Department of Systems Biology, Columbia University, New York, NY, USA. rivas@well.ox.ac.uk tlappalainen@nygenome.org macarthur@atgu.mgh.harvard.edu.
authors.forename: Tuuli
authors.initials: T
authors.lastname: Lappalainen
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. Department of Medicine, Harvard Medical School, Boston, MA, USA. rivas@well.ox.ac.uk tlappalainen@nygenome.org macarthur@atgu.mgh.harvard.edu.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: MacArthur
mesh_terms: D017398:Alternative Splicing; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D020868:Gene Silencing; D014644:Genetic Variation; D015894:Genome, Human / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D059365:Nonsense Mediated mRNA Decay; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D059467:Transcriptome
chemical_list: D011506:Proteins