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Effect of predicted protein-truncating genetic variants on the human transcriptome

Manuel A. Rivas [email protected], Matti Pirinen, Donald F. Conrad, Monkol Lek, Emily K. Tsang, Konrad J. Karczewski, Julian B. Maller, Kimberly R. Kukurba, David S. DeLuca, Menachem Fromer, Pedro G. Ferreira, Kevin S. Smith, Rui Zhang, Fengmei Zhao, Eric Banks, Ryan Poplin, Douglas M. Ruderfer, Shaun M. Purcell, Taru Tukiainen, Eric V. Minikel, Peter D. Stenson, David N. Cooper, Katharine H. Huang, Timothy J. Sullivan, Jared Nedzel, The GTEx Consortium, The Geuvadis Consortium, Carlos D. Bustamante, Jin Billy Li, Mark J. Daly, Roderic Guigo, Peter Donnelly, Kristin Ardlie, Michael Sammeth, Emmanouil T. Dermitzakis, Mark I. McCarthy, Stephen B. Montgomery, Tuuli Lappalainen [email protected], Daniel G. MacArthur [email protected], Ayellet V. Segre, Taylor R. Young, Ellen T. Gelfand, Casandra A. Trowbridge, Lucas D. Ward, Pouya Kheradpour, Benjamin Iriarte, Yan Meng, Cameron D. Palmer, Tonu Esko, Wendy Winckler, Joel Hirschhorn, Manolis Kellis, Gad Getz, Andrey A. Shablin, Gen Li, Yi-Hui Zhou, Andrew B. Nobel, Ivan Rusyn, Fred A. Wright, Alexis Battle, Sara Mostafavi, Marta Mele, Ferran Reverter, Jakob Goldmann, Daphne Koller, Eric R. Gamazon, Hae Kyung Im, Anuar Konkashbaev, Dan L. Nicolae, Nancy J. Cox, Timothe Flutre, Xiaoquan Wen, Matthew Stephens, Jonathan K. Pritchard, Zhidong Tu, Bin Zhang, Tao Huang, Quan Long, Luan Lin, Jialiang Yang, Jun Zhu, Jun Liu, Amanda Brown, Bernadette Mestichelli, Denee Tidwell, Edmund Lo, Mike Salvatore, Saboor Shad, Jeffrey A. Thomas, John T. Lonsdale, Roswell Christopher Choi, Ellen Karasik, Kimberly Ramsey, Michael T. Moser, Barbara A. Foster, Bryan M. Gillard, John Syron, Johnelle Fleming, Harold Magazine, Rick Hasz, Gary D. Walters, Jason P. Bridge, Mark Miklos, Susan Sullivan, Laura K. Barker, Heather Traino, Magboeba Mosavel, Laura A. Siminoff, Dana R. Valley, Daniel C. Rohrer, Scott Jewel, Philip Branton, Leslie H. Sobin, Mary Barcus, Liqun Qi, Pushpa Hariharan, Shenpei Wu, David Tabor, Charles Shive, Anna M. Smith, Stephen A. Buia, Anita H. Undale, Karna L. Robinson, Nancy Roche, Kimberly M. Valentino, Angela Britton, Robin Burges, Debra Bradbury, Kenneth W. Hambright, John Seleski, Greg E. Korzeniewski, Kenyon Erickson, Yvonne Marcus, Jorge Tejada, Mehran Taherian, Chunrong Lu, Barnaby E. Robles, Margaret Basile, Deborah C. Mash, Simona Volpi, Jeffery P. Struewing, Gary F. Temple, Joy Boyer, Deborah Colantuoni, Roger Little, Susan Koester, Latarsha J. Carithers, Helen M. Moore, Ping Guan, Carolyn Compton, Sherilyn J. Sawyer, Joanne P. Demchok, Jimmie B. Vaught, Chana A. Rabiner, Nicole C. Lockhart, Marc R. Friedlander, Peter A. C. ’t Hoen, Jean Monlong, Mar Gonzàlez-Porta, Natalja Kurbatova, Thasso Griebel, Matthias Barann, Thomas Wieland, Liliana Greger, Maarten van Iterson, Jonas Almlof, Paolo Ribeca, Irina Pulyakhina, Daniela Esser, Thomas Giger, Andrew Tikhonov, Marc Sultan, Gabrielle Bertier, Esther Lizano, Henk P. J. Buermans, Ismael Padioleau, Thomas Schwarzmayr, Olof Karlberg, Halit Ongen, Helena Kilpinen, Sergi Beltran, Marta Gut, Katja Kahlem, Vyacheslav Amstislavskiy, Oliver Stegle, Paul Flicek, Tim M. Strom, Hans Lehrach, Stefan Schreiber, Ralf Sudbrak, Angel Carracedo, Stylianos E. Antonarakis, Robert Hasler, Ann-Christine Syvanen, Gert-Jan van Ommen, Alvis Brazma, Thomas Meitinger, Philip Rosenstiel, Ivo G. Gut, and Xavier Estivill
Science8 May 2015Vol 348, Issue 6235pp. 666-669DOI: 10.1126/science.1261877

Expression, genetic variation, and tissues

Human genomes show extensive genetic variation across individuals, but we have only just started documenting the effects of this variation on the regulation of gene expression. Furthermore, only a few tissues have been examined per genetic variant. In order to examine how genetic expression varies among tissues within individuals, the Genotype-Tissue Expression (GTEx) Consortium collected 1641 postmortem samples covering 54 body sites from 175 individuals. They identified quantitative genetic traits that affect gene expression and determined which of these exhibit tissue-specific expression patterns. Melé et al. measured how transcription varies among tissues, and Rivas et al. looked at how truncated protein variants affect expression across tissues.
Science, this issue p. 648, p. 660, p. 666; see also p. 640

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.
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Supplementary Material

Summary

Materials and Methods
Figs. S1 to S42
Tables S1 to S7
Data File S1
References (2856)

Resources

File (1261877_datafiles1.xls)
File (rivas-sm.pdf)

References and Notes

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Science
Volume 348 | Issue 6235
8 May 2015

Submission history

Received: 29 September 2014
Accepted: 2 April 2015
Published in print: 8 May 2015

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Acknowledgments

We thank all the members of the GTEx and Geuvadis consortia and L. Solomon for assistance with the figures. This work was supported by the National Institutes of Health (NIGMS R01GM104371 to D.G.M.; NIMH R01MH101814 to E.T.D, C.D.B., S.B.M., R.G., T.L., and M.I.M.; R01MH090941 to E.T.D. and M.I.M.; U01HG007593 to J.B.L. and S.B.M.; and R01MH101810 to D.F.C.); Academy of Finland (257654 to M.P.); a Hewlett-Packard Stanford Graduate Fellowship and a doctoral fellowship from the Natural Science and Engineering Research Council of Canada to E.K.T.; a National Defense Science and Engineering Graduate Fellowship (NDSEG) from the United States Department of Defense (DoD) to K.R.K.; European Research Council, Swiss National Science Foundation, and Louis-Jeantet Foundation to E.T.D.; Wellcome Trust (095552/Z/11/Z and 090532/Z/09/Z to P.D. and 098381 to M.I.M.); and a Clarendon Scholarship, NDM Studentship, and Green Templeton College Award from University of Oxford to M.A.R. The Genotype-Tissue Expression (GTEx) project was supported by the Common Fund of the Office of the Director of NIH. Additional funds were enrolled at Biospecimen Source sites funded by NCI/SAIC-Frederick, Inc. (SAIC-F) subcontracts to the National Disease Research Interchange (10XS170), Roswell Park Cancer Institute (10XS171), and Science Care, Inc. (X10S172). The Laboratory, Data Analysis, and Coordinating Center (LDACC) was funded through a contract (HHSN268201000029C) to the Broad Institute, Inc. Biorepository operations were funded through an SAIC-F subcontract to Van Andel Institute (10ST1035). Additional data repository and project management were provided by SAIC-F (HHSN261200800001E). The Brain Bank was supported by a supplement to University of Miami grant DA006227. Statistical methods development grants were made to the University of Geneva (MH090941), the University of Chicago (MH090951 and MH090937), the University of North Carolina–Chapel Hill (MH090936), and Harvard University (MH090948). The primary and processed data used to generate the analyses presented here are available in the following locations: All primary sequence and clinical data files, and any other protected data, are deposited in and available from the database of Genotypes and Phenotypes (www.ncbi.nlm.nih.gov/gap) (phs000424.v3.p1, except for whole-exome sequencing data in phs000424.v5.p1 and mmPCR-seq data and processed ASE data in phs000424.v6.p1); derived analysis files are available on the GTEx Portal (www.gtexportal.org). Biospecimens remaining from the study may be requested for research studies. The sample request form, biospecimen access policy, and material transfer agreement are available on the GTEx Portal (www.gtexportal.org/home/samplesPage). The Geuvadis data are available in ArrayExpress accession E-GEUV-1. Further details and links to data and software are available in www.well.ox.ac.uk/~rivas/ptv2015. C.D.B. is a paid member of the Scientific Advisory Boards of Personalis, InVitae, and Ancestry.com; he is founder and chair of the SAB of Identify Genomics, LLC; he also owns stock options in Personalis, Invitae, and Identify Genomics, LLC.

Authors

Affiliations

Manuel A. Rivas*, [email protected]
Wellcome Trust Centre for Human Genetics, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
Matti Pirinen
FInstitute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
Donald F. Conrad
Washington University in St. Louis, St. Louis, MO, USA.
Monkol Lek
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
Emily K. Tsang
Department of Genetics, Stanford University, Stanford, CA, USA.
Department of Pathology, Stanford University, Stanford, CA, USA.
Biomedical Informatics Program, Stanford University, Stanford, CA, USA.
Konrad J. Karczewski
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
Julian B. Maller
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
Kimberly R. Kukurba
Department of Genetics, Stanford University, Stanford, CA, USA.
Department of Pathology, Stanford University, Stanford, CA, USA.
David S. DeLuca
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Menachem Fromer
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.
Pedro G. Ferreira
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.
Kevin S. Smith
Department of Genetics, Stanford University, Stanford, CA, USA.
Department of Pathology, Stanford University, Stanford, CA, USA.
Rui Zhang
Department of Genetics, Stanford University, Stanford, CA, USA.
Fengmei Zhao
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
Eric Banks
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Ryan Poplin
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Douglas M. Ruderfer
Department of Psychiatry, Mt. Sinai Hospital, NY, USA.
Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, NY, USA.
Shaun M. Purcell
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.
Taru Tukiainen
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
Eric V. Minikel
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
Peter D. Stenson
Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, UK.
David N. Cooper
Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, UK.
Katharine H. Huang
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Timothy J. Sullivan
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Jared Nedzel
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
The GTEx Consortium
The Geuvadis Consortium
Carlos D. Bustamante
Department of Genetics, Stanford University, Stanford, CA, USA.
Jin Billy Li
Department of Genetics, Stanford University, Stanford, CA, USA.
Mark J. Daly
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
Roderic Guigo
Center for Genomic Regulation (CRG), Universitat Pompeu Fabra (UPF), Barcelona, Catalonia, Spain.
Peter Donnelly
Wellcome Trust Centre for Human Genetics, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
Department of Statistics, University of Oxford, Oxford, UK.
Kristin Ardlie
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Michael Sammeth
Center for Genomic Regulation (CRG), Universitat Pompeu Fabra (UPF), Barcelona, Catalonia, Spain.
National Institute for Scientific Computing (LNCC), Petropolis, Rio de Janeiro, Brazil.
Emmanouil T. Dermitzakis
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.
Mark I. McCarthy
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.
Stephen B. Montgomery
Department of Genetics, Stanford University, Stanford, CA, USA.
Department of Pathology, Stanford University, Stanford, CA, USA.
Tuuli Lappalainen*, [email protected]
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.
Daniel G. MacArthur*, [email protected]
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.
Casandra A. Trowbridge
Bernadette Mestichelli
Roswell Christopher Choi
Vyacheslav Amstislavskiy
Stylianos E. Antonarakis

Notes

*Corresponding author. E-mail: [email protected] (M.A.R.); [email protected] (T.L.); [email protected] (D.G.M.)
These authors contributed equally to this work.
These authors contributed equally to this work.

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