Effect of predicted protein-truncating genetic variants on the human transcriptome
Manuel A. Rivas(Centre for Human Genetics), Matti Pirinen(Institute for Molecular Medicine Finland), Donald F. Conrad(Washington University in St. Louis), Monkol Lek(Broad Institute), Emily K. Tsang(Stanford University), Konrad J. Karczewski(Broad Institute), Julian Maller(Broad Institute), Kimberly R. Kukurba(Stanford University), David S. DeLuca(Broad Institute), Menachem Fromer(Broad Institute), Pedro G. Ferreira(University of Geneva), Kevin S. Smith(Stanford University), Rui Zhang(Stanford University), Fengmei Zhao(Broad Institute), Eric Banks(Broad Institute), Ryan Poplin(Broad Institute), Douglas M. Ruderfer(Sinai Hospital), Shaun Purcell(Broad Institute), Taru Tukiainen(Broad Institute), Eric Vallabh Minikel(Broad Institute), Peter D. Stenson(Cardiff University), D.N. Cooper(Cardiff University), Katharine H. Huang(Broad Institute), Timothy J. Sullivan(Broad Institute), Jared L. Nedzel(Broad Institute), Carlos D. Bustamante(Stanford University), Jin Billy Li(Stanford University), Mark J. Daly(Broad Institute), Roderic Guigó(Universitat Pompeu Fabra), Peter Donnelly(Centre for Human Genetics), Kristin Ardlie(Broad Institute), Michael Sammeth(Universitat Pompeu Fabra), Emmanouil T. Dermitzakis(University of Geneva), Mark I. McCarthy(Centre for Human Genetics), Stephen B. Montgomery(Stanford University), Tuuli Lappalainen(University of Geneva), Daniel G. MacArthur(Broad Institute), Ayellet V. Segrè, Taylor Young, Ellen Gelfand, Casandra A. Trowbridge, Lucas D. Ward, Pouya Kheradpour, Benjamin Iriarte, Yan Meng(Broad Institute), Cameron D. Palmer, Tõnu Esko, Wendy Winckler, Joel N. Hirschhorn, Manolis Kellis, Gad Getz, Andrey A. Shablin, Gen Li(Stanford University), Yi‐Hui Zhou, Andrew B. Nobel, Ivan Rusyn(Broad Institute), Fred A. Wright, Alexis Battle, Sara Mostafavi, Marta Melé, Ferrán Reverter, Jakob M. Goldmann, Daphne Koller, Eric R. Gamazon, Hae Kyung Im(Centre for Human Genetics), Anuar Konkashbaev, Dan L. Nicolae, Nancy J. Cox, Timothe Flutre, Xiaoquan Wen, Matthew Stephens, Jonathan K. Pritchard, Zhidong Tu(Stanford University), Bin Zhang(Stanford University), Tao Huang(Broad Institute), Quan Long, Luan Lin(Broad Institute), Jialiang Yang, Jun Zhu, Jun S. Liu, Amanda Brown, Bernadette Mestichelli, Denee Tidwell, Edmund Lo(Stanford University), Mike Salvatore, Saboor Shad, Jeffrey A. Thomas, John T. Lonsdale, Roswell Christopher Choi, Ellen Karasik, Kimberly Ramsey(Stanford University), Michael T. Moser, Barbara A. Foster, Bryan M. Gillard, John Syron, Johnelle Fleming, Harold I. Magazine, Rick Hasz, Gary Walters, Jason Bridge, Mark Miklos(Centre for Human Genetics), Susan Sullivan(Broad Institute), Laura K. Barker, Heather M. Traino, Magboeba Mosavel, Laura A. Siminoff, Dana R. Valley, Daniel C. Rohrer, Scott Jewel, Philip A. Branton, Leslie H. Sobin, Mary E. Barcus, Liqun Qi, Pushpa Hariharan, Shenpei Wu, David E. Tabor(Cardiff University), Charles Shive, Anna M. Smith(Stanford University), Stephen A. Buia(Stanford University), Anita H. Undale, Karna 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(Broad Institute), Barnaby E. Robles, Margaret J. Basile, Deborah C. Mash, Simona Volpi, Jeffery P. Struewing, Gary F. Temple, Joy T Boyer, Deborah Colantuoni, Roger Little, Susan E. Koester, Latarsha J. Carithers, Helen M. Moore, Ping Guan, Carolyn C. Compton, Sherilyn J. Sawyer, Joanne P. Demchok, Jimmie B. Vaught, Chana A. Rabiner, Nicole C. Lockhart, Marc R. Friedländer, Peter A.C. ’t Hoen, Jean Monlong, Mar Gonzàlez-Porta(Centre for Human Genetics), Natalja Kurbatova, Thasso Griebel, Matthias Barann, Thomas Wieland, Liliana Greger, Maarten van Iterson, Jonas Carlsson Almlöf, Paolo Ribeca, Irina Pulyakhina, Daniela Esser, Thomas Giger, Andrew Tikhonov, Marc Sultan, Gabrielle Bertier, Esther Lizano, Henk P.J. Buermans, Ismaël Padioleau, Thomas Schwarzmayr, Olof Karlberg, Halit Ongen, Helena Kilpinen, Sergi Beltrán, Marta Gut, Katja Kahlem, Vyacheslav Amstislavskiy, Oliver Stegle, Paul Flicek, Tim M. Strom, Hans Lehrach, Stefan Schreiber, Ralf Sudbrak, Ãngel Carracedo, Stylianos E. Antonarakis, Robert Häsler, Ann‐Christine Syvänen, Gert‐Jan B. van Ommen, Alvis Brāzma, Thomas Meitinger, Philip Rosenstiel, Marta Gut, Xavier Estivill
Cited by 345Open Access
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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