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Science. 2015 May 8;348(6235):666-9. doi: 10.1126/science.1261877.

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

Collaborators (189)

Ardlie KG, Deluca DS, Segre AV, Sullivan TJ, Young TR, Gelfand ET, Trowbridge CA, Maller JB, Tukiainen T, Lek M, Ward LD, Kheradpour P, Iriarte B, Meng Y, Palmer CD, Esko T, Winckler W, Hirschhorn J, Kellis M, MacArthur DG, Getz G, Shablin AA, Li G, Zhou YH, Nobel AB, Rusyn I, Wright FA, Lappalainen T, Ferreira PG, Ongen H, Rivas MA, Battle A, Mostafavi S, Monlong J, Sammeth M, Mele M, Reverter F, Goldmann J, Koller D, Guigo R, McCarthy MI, Dermitzakis ET, Gamazon ER, Kyung H, Konkashbaev A, Nicolae DL, Cox NJ, Flutre T, Wen X, Stephens M, Pritchard JK, Tu Z, Zhang B, Huang T, Long Q, Lin L, Yang J, Zhu J, Liu J, Brown A, Mestichelli B, Tidwell D, Lo E, Salvatore M, Shad S, Thomas JA, Lonsdale JT, Choi C, Karasik E, Ramsey K, Moser MT, Foster BA, Gillard BM, Syron J, Fleming J, Magazine H, Hasz R, Walters GD, Bridge JP, Miklos M, Sullivan S, Barker LK, Traino H, Mosavel M, Siminoff LA, Valley DR, Rohrer DC, Jewel S, Branton P, Sobin LH, Barcus M, Qi L, Hariharan P, Wu S, Tabor D, Shive C, Smith AM, Buia SA, Undale AH, Robinson KL, Roche N, Valentino KM, Britton A, Burges R, Bradbury D, Hambright KW, Seleski J, Korzeniewski GE, Erickson K, Marcus Y, Tejada J, Taherian M, Lu C, Robles BE, Basile M, Mash DC, Volpi S, Struewing JP, Temple GF, Boyer J, Colantuoni D, Little R, Koester S, Carithers LJ, Moore HM, Guan P, Compton C, Sawyer SJ, Demchok JP, Vaught JB, Rabiner CA, Lockhart NC, Lappalainen T, Sammeth M, Friedlander MR, 't Hoen PA, Monlong J, Rivas MA, Gonzlez-Porta M, Kurbatova N, Griebel T, Ferreira PG, Barann M, Wieland T, Greger L, van Iterson M, Almlof J, Ribeca P, Pulyakhina I, Esser D, Giger T, Tikhonov A, Sultan M, Bertier G, MacArthur DG, Lek M, Lizano E, Buermans HP, Padioleau I, Schwarzmayr T, Karlberg O, Ongen H, Kilpinen H, Beltran S, Gut M, Kahlem K, Amstislavskiy V, Stegle O, Pirinen M, Montgomery SB, Donnelly P, McCarthy MI, Flicek P, Strom TM, Lehrach H, Schreiber S, Sudbrak R, Carracedo A, Antonarakis SE, Hasler R, Syvanen AC, van Ommen GJ, Brazma A, Meitinger T, Rosenstiel P, Guigo R, Gut IG, Estivill X, Dermitzakis ET.

Author information

1
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.
2
FInstitute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
3
Washington University in St. Louis, St. Louis, MO, USA.
4
Broad Institute of MIT and Harvard, Cambridge, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
5
Department of Genetics, Stanford University, Stanford, CA, USA. Department of Pathology, Stanford University, Stanford, CA, USA. Biomedical Informatics Program, Stanford University, Stanford, CA, USA.
6
Department of Genetics, Stanford University, Stanford, CA, USA. Department of Pathology, Stanford University, Stanford, CA, USA.
7
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
8
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.
9
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.
10
Department of Genetics, Stanford University, Stanford, CA, USA.
11
Department of Psychiatry, Mt. Sinai Hospital, NY, USA. Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, NY, USA.
12
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.
13
Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, UK.
14
Center for Genomic Regulation (CRG), Universitat Pompeu Fabra (UPF), Barcelona, Catalonia, Spain.
15
Wellcome Trust Centre for Human Genetics, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. Department of Statistics, University of Oxford, Oxford, UK.
16
Center for Genomic Regulation (CRG), Universitat Pompeu Fabra (UPF), Barcelona, Catalonia, Spain. National Institute for Scientific Computing (LNCC), Petropolis, Rio de Janeiro, Brazil.
17
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.
18
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.
19
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.

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.

PMID:
25954003
PMCID:
PMC4537935
DOI:
10.1126/science.1261877
[Indexed for MEDLINE]
Free PMC Article

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