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

被引：196

作者：

Rivas, Manuel A. ^{[1
]}

Pirinen, Matti ^{[2
]}

Conrad, Donald F. ^{[3
]}

Lek, Monkol ^{[4
,5
]}

Tsang, Emily K. ^{[6
,7
,8
]}

Karczewski, Konrad J. ^{[4
,5
]}

Maller, Julian B. ^{[4
,5
]}

Kukurba, Kimberly R. ^{[6
,7
]}

DeLuca, David S. ^{[4
]}

Fromer, Menachem ^{[4
,5
,9
]}

Ferreira, Pedro G. ^{[10
,11
,12
]}

Smith, Kevin S. ^{[6
,7
]}

Zhang, Rui ^{[6
]}

Zhao, Fengmei ^{[4
,5
]}

Banks, Eric ^{[4
]}

Poplin, Ryan ^{[4
]}

Ruderfer, Douglas M. ^{[9
,13
]}

Purcell, Shaun M. ^{[4
,5
,9
,13
]}

Tukiainen, Taru ^{[4
,5
]}

Minikel, Eric V. ^{[4
,5
]}

Stenson, Peter D. ^{[14
]}

Cooper, David N. ^{[14
]}

Huang, Katharine H. ^{[4
]}

Sullivan, Timothy J. ^{[4
]}

Nedzel, Jared ^{[4
]}

Bustamante, Carlos D. ^{[6
]}

Li, Jin Billy ^{[6
]}

Daly, Mark J. ^{[4
,5
]}

Guigo, Roderic ^{[15
]}

Donnelly, Peter ^{[1
,16
]}

Ardlie, Kristin ^{[4
]}

Sammeth, Michael ^{[15
,17
]}

Dermitzakis, Emmanouil T. ^{[10
,11
,12
]}

McCarthy, Mark I. ^{[1
,18
]}

Montgomery, Stephen B. ^{[6
,7
]}

Lappalainen, Tuuli ^{[6
,10
,11
,12
,19
,20
]}

MacArthur, Daniel G. ^{[4
,5
,21
]}

机构：

[1] Univ Oxford, Nuffield Dept Clin Med, Wellcome Trust Ctr Human Genet, Oxford, England

[2] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland

[3] Washington Univ, St Louis, MO USA

[4] Broad Inst MIT & Harvard, Cambridge, MA USA

[5] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[6] Stanford Univ, Dept Genet, Stanford, CA 94305 USA

[7] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA

[8] Stanford Univ, Biomed Informat Program, Stanford, CA 94305 USA

[9] Mt Sinai Hosp, Dept Psychiat, New York, NY USA

[10] Univ Geneva, Dept Genet Med & Dev, Geneva, Switzerland

[11] Univ Geneva, Inst Genet & Genom Geneva iGE3, Geneva, Switzerland

[12] Swiss Inst Bioinformat, Geneva, Switzerland

[13] Icahn Sch Med Mt Sinai, Dept Psychiat, Div Psychiat Genom, New York, NY 10029 USA

[14] Cardiff Univ, Sch Med, Inst Med Genet, Cardiff CF10 3AX, S Glam, Wales

[15] UPF, CRG, Barcelona, Catalonia, Spain

[16] Univ Oxford, Dept Stat, Oxford OX1 3TG, England

[17] Natl Inst Sci Comp LNCC, Rio De Janeiro, Brazil

[18] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England

[19] New York Genome Ctr, New York, NY USA

[20] Columbia Univ, Dept Syst Biol, New York, NY USA

[21] Harvard Univ, Sch Med, Dept Med, Boston, MA USA

来源：

SCIENCE | 2015年 / 348卷 / 6235期

基金：

英国惠康基金; 美国国家卫生研究院; 芬兰科学院; 欧洲研究理事会; 瑞士国家科学基金会; 英国生物技术与生命科学研究理事会;

关键词：

EXPRESSION; DOSAGE;

D O I：

10.1126/science.1261877

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：666 / 669

页数：4

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