title: Semi-supervised Learning Predicts Approximately One Third of the Alternative Splicing Isoforms as Functional Proteins.
abstract: Alternative splicing acts on transcripts from almost all human multi-exon genes. Notwithstanding its ubiquity, fundamental ramifications of splicing on protein expression remain unresolved. The number and identity of spliced transcripts that form stably folded proteins remain the sources of considerable debate, due largely to low coverage of experimental methods and the resulting absence of negative data. We circumvent this issue by developing a semi-supervised learning algorithm, positive unlabeled learning for splicing elucidation (PULSE; http://www.kimlab.org/software/pulse), which uses 48 features spanning various categories. We validated its accuracy on sets of bona fide protein isoforms and directly on mass spectrometry (MS) spectra for an overall AU-ROC of 0.85. We predict that around 32% of "exon skipping" alternative splicing events produce stable proteins, suggesting that the process engenders a significant number of previously uncharacterized proteins. We also provide insights into the distribution of positive isoforms in various functional classes and into the structural effects of alternative splicing.
authors.affiliation: Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 1AS, Canada; Department of Computer Science, University of Toronto, Toronto, ON M5S 3G4, Canada.
authors.forename: Yanqi
authors.initials: Y
authors.lastname: Hao
authors.affiliation: Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 1AS, Canada; Department of Computer Science, University of Toronto, Toronto, ON M5S 3G4, Canada.
authors.forename: Recep
authors.initials: R
authors.lastname: Colak
authors.affiliation: Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 1AS, Canada.
authors.forename: Joan
authors.initials: J
authors.lastname: Teyra
authors.affiliation: Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 1AS, Canada.
authors.forename: Carles
authors.initials: C
authors.lastname: Corbi-Verge
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
authors.forename: Alexander
authors.initials: A
authors.lastname: Ignatchenko
authors.affiliation: Chair for Proteomics and Bioanalytics, TU Muenchen, Freising 85354, Germany.
authors.forename: Hannes
authors.initials: H
authors.lastname: Hahne
authors.affiliation: Chair for Proteomics and Bioanalytics, TU Muenchen, Freising 85354, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Wilhelm
authors.affiliation: Chair for Proteomics and Bioanalytics, TU Muenchen, Freising 85354, Germany; German Cancer Consortium (DKTK), Munich, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Center for Integrated Protein Science Munich, Munich, Germany; Bavarian Biomolecular Mass Spectrometry Center, Technische Universität München, Freising, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Kuster
authors.affiliation: Lehrstuhl fuer Systembiologie der Pflanzen, TU Muenchen, Munich, Germany.
authors.forename: Pascal
authors.initials: P
authors.lastname: Braun
authors.affiliation: Frontier Research Core for Life Sciences, University of Toyama, Toyama 930-8555, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kaida
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5T 2M9, Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kislinger
authors.affiliation: Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 1AS, Canada; Department of Computer Science, University of Toronto, Toronto, ON M5S 3G4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1AS, Canada. Electronic address: pi@kimlab.org.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Kim
mesh_terms: D017398:Alternative Splicing; D019540:Area Under Curve; D005091:Exons; D006801:Humans; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012372:ROC Curve; D000069553:Supervised Machine Learning
chemical_list: D020033:Protein Isoforms; D011506:Proteins