title: Does conservation account for splicing patterns?
abstract: Alternative mRNA splicing is critical to proteomic diversity and tissue and species differentiation. Exclusion of cassette exons, also called exon skipping, is the most common type of alternative splicing in mammals.
  
  
  
  We present a computational model that predicts absolute (though not tissue-differential) percent-spliced-in of cassette exons more accurately than previous models, despite not using any 'hand-crafted' biological features such as motif counts. We achieve nearly identical performance using only the conservation score (mammalian phastCons) of each splice junction normalized by average conservation over 100 bp of the corresponding flanking intron, demonstrating that conservation is an unexpectedly powerful indicator of alternative splicing patterns. Using this method, we provide evidence that intronic splicing regulation occurs predominantly within 100 bp of the alternative splice sites and that conserved elements in this region are, as expected, functioning as splicing regulators. We show that among conserved cassette exons, increased conservation of flanking introns is associated with reduced inclusion. We also propose a new definition of intronic splicing regulatory elements (ISREs) that is independent of conservation, and show that most ISREs do not match known binding sites or splicing factors despite being predictive of percent-spliced-in.
  
  
  
  These findings suggest that one mechanism for the evolutionary transition from constitutive to alternative splicing is the emergence of cis-acting splicing inhibitors. The association of our ISREs with differences in splicing suggests the existence of novel RNA-binding proteins and/or novel splicing roles for known RNA-binding proteins.
authors.affiliation: Department of Electrical and Computer Engineering, University of Toronto, 10 King's College Road, Toronto, M5S 3G4, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Wainberg
authors.affiliation: Department of Electrical and Computer Engineering, University of Toronto, 10 King's College Road, Toronto, M5S 3G4, Canada.
authors.forename: Babak
authors.initials: B
authors.lastname: Alipanahi
authors.affiliation: Department of Electrical and Computer Engineering, University of Toronto, 10 King's College Road, Toronto, M5S 3G4, Canada. frey@psi.toronto.edu.|Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, M5S 3E1, Canada. frey@psi.toronto.edu.|Program on Genetic Networks and Program on Neural Computation & Adaptive Perception, Canadian Institute for Advanced Research, 180 Dundas Street West, Suite 1400, Toronto, M5G 1Z8, Canada. frey@psi.toronto.edu.
authors.forename: Brendan
authors.initials: B
authors.lastname: Frey
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D019540:Area Under Curve; D001921:Brain / Q000378:metabolism; D019143:Evolution, Molecular; D005091:Exons; D005786:Gene Expression Regulation; D006801:Humans; D007438:Introns; D008954:Models, Biological; D009928:Organ Specificity / Q000235:genetics; D022821:RNA Splice Sites; D012045:Regulatory Sequences, Nucleic Acid
chemical_list: D022821:RNA Splice Sites
keywords: Alternative splicing; Conservation; Splicing regulation