Publication Date:
2014-12-20
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4362528/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4362528/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xiong, Hui Y -- Alipanahi, Babak -- Lee, Leo J -- Bretschneider, Hannes -- Merico, Daniele -- Yuen, Ryan K C -- Hua, Yimin -- Gueroussov, Serge -- Najafabadi, Hamed S -- Hughes, Timothy R -- Morris, Quaid -- Barash, Yoseph -- Krainer, Adrian R -- Jojic, Nebojsa -- Scherer, Stephen W -- Blencowe, Benjamin J -- Frey, Brendan J -- P30 CA045508/CA/NCI NIH HHS/ -- R37 GM042699/GM/NIGMS NIH HHS/ -- R37-GM42699A/GM/NIGMS NIH HHS/ -- Canadian Institutes of Health Research/Canada -- New York, N.Y. -- Science. 2015 Jan 9;347(6218):1254806. doi: 10.1126/science.1254806. Epub 2014 Dec 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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 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. ; 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. ; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. ; 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. ; 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. ; 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. ; 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. ; eScience Group, Microsoft Research, Redmond, WA 98052, USA. ; 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. ; 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. ; 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.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25525159" target="_blank"〉PubMed〈/a〉
Keywords:
Adaptor Proteins, Signal Transducing/genetics
;
*Artificial Intelligence
;
Child Development Disorders, Pervasive/*genetics
;
Colorectal Neoplasms, Hereditary Nonpolyposis/*genetics
;
Computer Simulation
;
DNA/genetics
;
Exons/genetics
;
Genetic Code
;
Genetic Markers
;
Genetic Variation
;
Genome-Wide Association Study/*methods
;
Humans
;
Introns/genetics
;
Models, Genetic
;
Molecular Sequence Annotation/*methods
;
Muscular Atrophy, Spinal/*genetics
;
Mutation, Missense
;
Nuclear Proteins/genetics
;
Polymorphism, Single Nucleotide
;
Quantitative Trait Loci
;
RNA Splice Sites/genetics
;
RNA Splicing/*genetics
;
RNA-Binding Proteins/genetics
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
Permalink
