The human splicing code reveals new insights into the genetic determinants of disease

被引：897

作者：

Xiong, Hui Y. ^{[1
,2
,3
,4
]}

Alipanahi, Babak ^{[1
,2
,3
,4
]}

Lee, Leo J. ^{[1
,2
,3
,4
]}

Bretschneider, Hannes ^{[1
,3
,4
,5
]}

Merico, Daniele ^{[6
,7
,8
]}

Yuen, Ryan K. C. ^{[6
,7
,8
]}

Hua, Yimin ^{[9
]}

Gueroussov, Serge ^{[2
,8
]}

Najafabadi, Hamed S. ^{[1
,2
,3
,4
]}

Hughes, Timothy R. ^{[2
,3
,4
,8
]}

Morris, Quaid ^{[1
,2
,3
,4
,8
]}

Barash, Yoseph ^{[1
,2
,10
]}

Krainer, Adrian R. ^{[9
]}

Jojic, Nebojsa ^{[11
]}

Scherer, Stephen W. ^{[3
,4
,6
,7
,8
]}

Blencowe, Benjamin J. ^{[2
,6
,8
]}

Frey, Brendan J. ^{[1
,2
,3
,4
,5
,6
,8
,11
]}

机构：

[1] Univ Toronto, Dept Elect & Comp Engn, Toronto, ON M5S 3G4, Canada

[2] Univ Toronto, Donnelly Ctr Cellular & Biomol Res, Toronto, ON M5S 3E1, Canada

[3] Canadian Inst Adv Res, Program Genet Networks, Toronto, ON M5G 1Z8, Canada

[4] Canadian Inst Adv Res, Program Neural Computat & Adapt Percept, Toronto, ON M5G 1Z8, Canada

[5] Univ Toronto, Dept Comp Sci, Toronto, ON M5S 3G4, Canada

[6] Univ Toronto, McLaughlin Ctr, Toronto, ON M5G 0A4, Canada

[7] Hosp Sick Children, Ctr Appl Genom, Toronto, ON M5G 1X8, Canada

[8] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada

[9] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA

[10] Univ Penn, Sch Med, Philadelphia, PA 19104 USA

[11] Microsoft Res, eSci Grp, Redmond, WA 98052 USA

来源：

SCIENCE | 2015年 / 347卷 / 6218期

基金：

加拿大自然科学与工程研究理事会;

关键词：

AUTISM SPECTRUM DISORDER; COPY NUMBER VARIATION; MESSENGER-RNA; MISSENSE MUTATIONS; FUNCTIONAL IMPACT; MISMATCH REPAIR; EXONIC VARIANTS; HUMAN CANCERS; PREDICTION; GENOME;

D O I：

10.1126/science.1254806

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：

To facilitate precision medicine and whole-genome annotation, we developed a machine-learning technique that scores how strongly genetic variants affect RNA splicing, whose alteration contributes to many diseases. Analysis of more than 650,000 intronic and exonic variants revealed widespread patterns of mutation-driven aberrant splicing. Intronic disease mutations that are more than 30 nucleotides from any splice site alter splicing nine times as often as common variants, and missense exonic disease mutations that have the least impact on protein function are five times as likely as others to alter splicing. We detected tens of thousands of disease-causing mutations, including those involved in cancers and spinal muscular atrophy. Examination of intronic and exonic variants found using whole-genome sequencing of individuals with autism revealed misspliced genes with neurodevelopmental phenotypes. Our approach provides evidence for causal variants and should enable new discoveries in precision medicine.

引用

页数：9

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