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

Science
Authors
Keywords
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.

Year of Publication
2015
Journal
Science
Volume
348
Issue
6235
Pages
666-9
Date Published
2015 May 08
ISSN
1095-9203
URL
DOI
10.1126/science.1261877
PubMed ID
25954003
PubMed Central ID
PMC4537935
Links
Grant list
090532/Z/09/Z / Wellcome Trust / United Kingdom
R01GM104371 / GM / NIGMS NIH HHS / United States
095552 / Wellcome Trust / United Kingdom
R01 DA006227 / DA / NIDA NIH HHS / United States
MH090937 / MH / NIMH NIH HHS / United States
R01MH090941 / MH / NIMH NIH HHS / United States
R01 MH101810 / MH / NIMH NIH HHS / United States
DA006227 / DA / NIDA NIH HHS / United States
U01 HG007593 / HG / NHGRI NIH HHS / United States
R01 MH090936 / MH / NIMH NIH HHS / United States
MH090948 / MH / NIMH NIH HHS / United States
MH090936 / MH / NIMH NIH HHS / United States
MH090941 / MH / NIMH NIH HHS / United States
095552/Z/11/Z / Wellcome Trust / United Kingdom
090532 / Wellcome Trust / United Kingdom
HHSN261200800001E / PHS HHS / United States
R01 MH090951 / MH / NIMH NIH HHS / United States
HHSN268201000029C / PHS HHS / United States
R01 MH101820 / MH / NIMH NIH HHS / United States
R01MH101810 / MH / NIMH NIH HHS / United States
R01 MH090948 / MH / NIMH NIH HHS / United States
R01 MH090941 / MH / NIMH NIH HHS / United States
MH090951 / MH / NIMH NIH HHS / United States
T32 GM007790 / GM / NIGMS NIH HHS / United States
098381 / Wellcome Trust / United Kingdom
R01MH101814 / MH / NIMH NIH HHS / United States
HHSN261200800001C / RC / CCR NIH HHS / United States
R01 MH090937 / MH / NIMH NIH HHS / United States
R01 GM104371 / GM / NIGMS NIH HHS / United States
HHSN268201000029C / HL / NHLBI NIH HHS / United States
U01HG007593 / HG / NHGRI NIH HHS / United States
HHSN261200800001E / CA / NCI NIH HHS / United States
R01 MH101814 / MH / NIMH NIH HHS / United States
P30 DK020595 / DK / NIDDK NIH HHS / United States