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Science. 2015 Jan 9;347(6218):1254806. doi: 10.1126/science.1254806. Epub 2014 Dec 18.

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

Author information

1
Department of Electrical and Computer Engineering, University of Toronto, Toronto, Ontario M5S 3G4, Canada. Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada. Program on Genetic Networks and Program on Neural Computation & Adaptive Perception, Canadian Institute for Advanced Research, Toronto, Ontario M5G 1Z8, Canada.
2
Department of Electrical and Computer Engineering, University of Toronto, Toronto, Ontario M5S 3G4, Canada. Program on Genetic Networks and Program on Neural Computation & Adaptive Perception, Canadian Institute for Advanced Research, Toronto, Ontario M5G 1Z8, Canada. Department of Computer Science, University of Toronto, Toronto, Ontario M5S 3G4, Canada.
3
McLaughlin Centre, University of Toronto, Toronto, Ontario M5G 0A4, Canada. Centre for Applied Genomics, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada. Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
4
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
5
Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada. Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
6
Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada. Program on Genetic Networks and Program on Neural Computation & Adaptive Perception, Canadian Institute for Advanced Research, Toronto, Ontario M5G 1Z8, Canada. Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
7
Department of Electrical and Computer Engineering, University of Toronto, Toronto, Ontario M5S 3G4, Canada. Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada. Program on Genetic Networks and Program on Neural Computation & Adaptive Perception, Canadian Institute for Advanced Research, Toronto, Ontario M5G 1Z8, Canada. Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
8
Department of Electrical and Computer Engineering, University of Toronto, Toronto, Ontario M5S 3G4, Canada. Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada. School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
9
eScience Group, Microsoft Research, Redmond, WA 98052, USA.
10
Program on Genetic Networks and Program on Neural Computation & Adaptive Perception, Canadian Institute for Advanced Research, Toronto, Ontario M5G 1Z8, Canada. McLaughlin Centre, University of Toronto, Toronto, Ontario M5G 0A4, Canada. Centre for Applied Genomics, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada. Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
11
Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada. McLaughlin Centre, University of Toronto, Toronto, Ontario M5G 0A4, Canada. Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
12
Department of Electrical and Computer Engineering, University of Toronto, Toronto, Ontario M5S 3G4, Canada. Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada. Program on Genetic Networks and Program on Neural Computation & Adaptive Perception, Canadian Institute for Advanced Research, Toronto, Ontario M5G 1Z8, Canada. Department of Computer Science, University of Toronto, Toronto, Ontario M5S 3G4, Canada. McLaughlin Centre, University of Toronto, Toronto, Ontario M5G 0A4, Canada. Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada. eScience Group, Microsoft Research, Redmond, WA 98052, USA. frey@psi.toronto.edu.

Abstract

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.

Comment in

PMID:
25525159
PMCID:
PMC4362528
DOI:
10.1126/science.1254806
[Indexed for MEDLINE]
Free PMC Article

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