title: RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease.
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.
authors.affiliation: 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.
authors.forename: Hui Y
authors.initials: HY
authors.lastname: Xiong
authors.affiliation: 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.
authors.forename: Babak
authors.initials: B
authors.lastname: Alipanahi
authors.affiliation: 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.
authors.forename: Leo J
authors.initials: LJ
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Hannes
authors.initials: H
authors.lastname: Bretschneider
authors.affiliation: 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.
authors.forename: Daniele
authors.initials: D
authors.lastname: Merico
authors.affiliation: 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.
authors.forename: Ryan K C
authors.initials: RK
authors.lastname: Yuen
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Yimin
authors.initials: Y
authors.lastname: Hua
authors.affiliation: 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.
authors.forename: Serge
authors.initials: S
authors.lastname: Gueroussov
authors.affiliation: 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.
authors.forename: Hamed S
authors.initials: HS
authors.lastname: Najafabadi
authors.affiliation: 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.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Hughes
authors.affiliation: 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.
authors.forename: Quaid
authors.initials: Q
authors.lastname: Morris
authors.affiliation: 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.
authors.forename: Yoseph
authors.initials: Y
authors.lastname: Barash
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Adrian R
authors.initials: AR
authors.lastname: Krainer
authors.affiliation: eScience Group, Microsoft Research, Redmond, WA 98052, USA.
authors.forename: Nebojsa
authors.initials: N
authors.lastname: Jojic
authors.affiliation: 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.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
authors.affiliation: 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.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Blencowe
authors.affiliation: 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.
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Frey
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D001185:Artificial Intelligence; D002659:Child Development Disorders, Pervasive / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D003198:Computer Simulation; D004247:DNA / Q000235:genetics; D005091:Exons / Q000235:genetics; D005815:Genetic Code; D005819:Genetic Markers; D014644:Genetic Variation; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D007438:Introns / Q000235:genetics; D008957:Models, Genetic; D058977:Molecular Sequence Annotation / Q000379:methods*; D009134:Muscular Atrophy, Spinal / Q000235:genetics*; D000070957:MutL Protein Homolog 1; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D022821:RNA Splice Sites / Q000235:genetics; D012326:RNA Splicing / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D005819:Genetic Markers; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D022821:RNA Splice Sites; D016601:RNA-Binding Proteins; D004247:DNA; D000070957:MutL Protein Homolog 1