title: Deciphering the splicing code.
abstract: Alternative splicing has a crucial role in the generation of biological complexity, and its misregulation is often involved in human disease. Here we describe the assembly of a 'splicing code', which uses combinations of hundreds of RNA features to predict tissue-dependent changes in alternative splicing for thousands of exons. The code determines new classes of splicing patterns, identifies distinct regulatory programs in different tissues, and identifies mutation-verified regulatory sequences. Widespread regulatory strategies are revealed, including the use of unexpectedly large combinations of features, the establishment of low exon inclusion levels that are overcome by features in specific tissues, the appearance of features deeper into introns than previously appreciated, and the modulation of splice variant levels by transcript structure characteristics. The code detected a class of exons whose inclusion silences expression in adult tissues by activating nonsense-mediated messenger RNA decay, but whose exclusion promotes expression during embryogenesis. The code facilitates the discovery and detailed characterization of regulated alternative splicing events on a genome-wide scale.
authors.affiliation: Biomedical Engineering, Department of Electrical and Computer Engineering, University of Toronto, 10 King's College Road, Toronto M5S 3G4, Canada.
authors.forename: Yoseph
authors.initials: Y
authors.lastname: Barash
authors.forename: John A
authors.initials: JA
authors.lastname: Calarco
authors.forename: Weijun
authors.initials: W
authors.lastname: Gao
authors.forename: Qun
authors.initials: Q
authors.lastname: Pan
authors.forename: Xinchen
authors.initials: X
authors.lastname: Wang
authors.forename: Ofer
authors.initials: O
authors.lastname: Shai
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Blencowe
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Frey
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D005786:Gene Expression Regulation; D020868:Gene Silencing; D005815:Genetic Code / Q000235:genetics*; D006801:Humans; D051379:Mice; D008957:Models, Genetic; D012333:RNA, Messenger / Q000378:metabolism*; D015203:Reproducibility of Results
chemical_list: D012333:RNA, Messenger
references.citation: RNA. 1997 Nov;3(11):1275-88
references.pmid: 9409619
references.citation: Int J Biochem Cell Biol. 2007;39(12):2195-214
references.pmid: 17625949
references.citation: Proc Natl Acad Sci U S A. 2002 Apr 2;99(7):4233-8
references.pmid: 11917126
references.citation: Nature. 2008 Nov 27;456(7221):464-9
references.pmid: 18978773
references.citation: Cell. 2006 Jul 14;126(1):37-47
references.pmid: 16839875
references.citation: J Biol Chem. 2002 Mar 1;277(9):6974-84
references.pmid: 11744705
references.citation: J Cell Biol. 2009 Apr 6;185(1):27-34
references.pmid: 19349578
references.citation: Nucleic Acids Res. 2007;35(14):4845-57
references.pmid: 17626050
references.citation: RNA. 1997 Jul;3(7):764-78
references.pmid: 9214659
references.citation: Nature. 2010 Jan 28;463(7280):457-63
references.pmid: 20110989
references.citation: Nat Biotechnol. 2009 Jul;27(7):667-70
references.pmid: 19561594
references.citation: Bioinformatics. 2006 Mar 1;22(5):606-13
references.pmid: 16403798
references.citation: Genes Dev. 2008 Sep 15;22(18):2550-63
references.pmid: 18794351
references.citation: Nat Genet. 2008 Dec;40(12):1413-5
references.pmid: 18978789
references.citation: Nucleic Acids Res. 2005 Feb 03;33(2):714-24
references.pmid: 15691898
references.citation: PLoS Genet. 2006 Nov 24;2(11):e191
references.pmid: 17121466
references.citation: Annu Rev Biochem. 2003;72:291-336
references.pmid: 12626338
references.citation: Nature. 2006 Nov 30;444(7119):580-6
references.pmid: 17065982
references.citation: Nature. 2008 Nov 27;456(7221):470-6
references.pmid: 18978772
references.citation: Nat Struct Mol Biol. 2005 Aug;12(8):691-8
references.pmid: 16041388
references.citation: Mol Cell Biol. 2005 Feb;25(3):879-87
references.pmid: 15657417
references.citation: EMBO J. 2003 Feb 17;22(4):905-12
references.pmid: 12574126
references.citation: Cell. 2009 Sep 4;138(5):898-910
references.pmid: 19737518
references.citation: Nat Genet. 2008 Dec;40(12):1416-25
references.pmid: 18978788
references.citation: RNA. 2008 Aug;14(8):1463-9
references.pmid: 18579871
references.citation: Genome Res. 2003 Jul;13(7):1631-7
references.pmid: 12840041
references.citation: Mol Cell. 2004 Jan 16;13(1):91-100
references.pmid: 14731397
references.citation: Nat Rev Genet. 2007 Oct;8(10):749-61
references.pmid: 17726481
references.citation: RNA. 2008 May;14(5):802-13
references.pmid: 18369186
references.citation: Mol Cell Biol. 2000 Oct;20(20):7463-79
references.pmid: 11003644
references.citation: Science. 2002 Aug 9;297(5583):1007-13
references.pmid: 12114529
references.citation: Genome Biol. 2006;7(1):R1
references.pmid: 16507133
references.citation: Genes Dev. 2004 Jun 1;18(11):1241-50
references.pmid: 15145827
references.citation: Curr Opin Cell Biol. 2009 Jun;21(3):377-86
references.pmid: 19307111
references.citation: Mol Cell Biol. 1998 Jul;18(7):3900-6
references.pmid: 9632774
references.citation: PLoS Genet. 2007 May 25;3(5):e85
references.pmid: 17530930
references.citation: Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18583-8
references.pmid: 17998536
references.citation: EMBO J. 2000 Aug 15;19(16):4362-71
references.pmid: 10944119
references.citation: Science. 2005 Sep 23;309(5743):2054-7
references.pmid: 16179478
references.citation: RNA. 2005 Dec;11(12):1825-34
references.pmid: 16314456
references.citation: RNA. 1997 Sep;3(9):996-1015
references.pmid: 9292499
references.citation: Mol Cell Biol. 1997 Aug;17(8):4667-76
references.pmid: 9234723
references.citation: Genome Biol. 2007;8(6):R108
references.pmid: 17565696
references.citation: Proc Natl Acad Sci U S A. 2001 Jan 30;98(3):938-43
references.pmid: 11158574
references.citation: Cell. 2008 Nov 28;135(5):852-64
references.pmid: 19012953
references.citation: FEBS J. 2010 Feb;277(4):856-66
references.pmid: 20082635
references.citation: J Biol Chem. 1996 Jul 26;271(30):17613-6
references.pmid: 8663598
references.citation: PLoS Comput Biol. 2006 Jan;2(1):e4
references.pmid: 16424921