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

Manuel A Rivas, 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, - -, 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, Daniel G MacArthur
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Science : a weekly journal devoted to the advancement of science / American Association for the Advancement of Science
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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.