title: A new view of transcriptome complexity and regulation through the lens of local splicing variations.
abstract: Alternative splicing (AS) can critically affect gene function and disease, yet mapping splicing variations remains a challenge. Here, we propose a new approach to define and quantify mRNA splicing in units of local splicing variations (LSVs). LSVs capture previously defined types of alternative splicing as well as more complex transcript variations. Building the first genome wide map of LSVs from twelve mouse tissues, we find complex LSVs constitute over 30% of tissue dependent transcript variations and affect specific protein families. We show the prevalence of complex LSVs is conserved in humans and identify hundreds of LSVs that are specific to brain subregions or altered in Alzheimer's patients. Amongst those are novel isoforms in the Camk2 family and a novel poison exon in Ptbp1, a key splice factor in neurogenesis. We anticipate the approach presented here will advance the ability to relate tissue-specific splice variation to genetic variation, phenotype, and disease.
authors.affiliation: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.|Department of Computer and Information Science, University of Pennsylvania, Philadelphia, United States.
authors.forename: Jorge
authors.initials: J
authors.lastname: Vaquero-Garcia
authors.affiliation: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.|Department of Computer and Information Science, University of Pennsylvania, Philadelphia, United States.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Barrera
authors.affiliation: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.|Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Gazzara
authors.affiliation: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.|Department of Computer and Information Science, University of Pennsylvania, Philadelphia, United States.
authors.forename: Juan
authors.initials: J
authors.lastname: González-Vallinas
authors.affiliation: Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Lahens
authors.affiliation: Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
authors.forename: John B
authors.initials: JB
authors.lastname: Hogenesch
authors.affiliation: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.|Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
authors.forename: Kristen W
authors.initials: KW
authors.lastname: Lynch
authors.affiliation: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.|Department of Computer and Information Science, University of Pennsylvania, Philadelphia, United States.
authors.forename: Yoseph
authors.identifier: http://orcid.org/0000-0003-3005-5048
authors.initials: Y
authors.lastname: Barash
mesh_terms: D017398:Alternative Splicing; D000544:Alzheimer Disease / Q000473:pathology; D000818:Animals; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D059467:Transcriptome
keywords: alternative splicing; alzheimer's disease; camk2; chromosomes; computational biology; genes; human; mouse; ptb1; statistical modeling; systems biology; transcriptomics
references.citation: Annu Rev Physiol. 1995;57:417-45
references.pmid: 7778873
references.citation: Mol Neurodegener. 2009 May 06;4:20
references.pmid: 19419557
references.citation: EMBO J. 1990 Nov;9(11):3539-44
references.pmid: 2120043
references.citation: Proc Natl Acad Sci U S A. 2014 Dec 23;111(51):E5593-601
references.pmid: 25480548
references.citation: Mol Cell. 2007 Aug 3;27(3):435-48
references.pmid: 17679093
references.citation: Mol Cell Biol. 2000 Jan;20(1):70-80
references.pmid: 10594010
references.citation: Science. 2002 Oct 25;298(5594):824-7
references.pmid: 12399590
references.citation: Proc Natl Acad Sci U S A. 2015 Mar 17;112(11):3445-50
references.pmid: 25737549
references.citation: Nature. 2010 May 6;465(7294):53-9
references.pmid: 20445623
references.citation: Bioinformatics. 2013 Jan 15;29(2):273-4
references.pmid: 23172860
references.citation: Nat Methods. 2010 Dec;7(12):1009-15
references.pmid: 21057496
references.citation: Nat Neurosci. 2012 Mar;15(3):381-8, S1
references.pmid: 22246437
references.citation: RNA. 2012 May;18(5):1029-40
references.pmid: 22454538
references.citation: Genome Biol. 2013;14(10):R114
references.pmid: 24156756
references.citation: Genes Dev. 2012 Jul 15;26(14):1626-42
references.pmid: 22802532
references.citation: Proc Natl Acad Sci U S A. 2014 Nov 11;111(45):16219-24
references.pmid: 25349387
references.citation: Crit Rev Biochem Mol Biol. 2012 Jul-Aug;47(4):360-78
references.pmid: 22655688
references.citation: Bioinformatics. 2013 Jan 1;29(1):15-21
references.pmid: 23104886
references.citation: Nat Biotechnol. 2013 Jan;31(1):46-53
references.pmid: 23222703
references.citation: Proc Natl Acad Sci U S A. 2015 Jun 9;112(23):E3020-9
references.pmid: 26039991
references.citation: Nat Biotechnol. 2010 May;28(5):511-5
references.pmid: 20436464
references.citation: Nat Struct Mol Biol. 2013 Dec;20(12):1434-42
references.pmid: 24213538
references.citation: PLoS Comput Biol. 2008;4(8):e1000147
references.pmid: 18688268
references.citation: Genome Res. 2005 Aug;15(8):1034-50
references.pmid: 16024819
references.citation: Nucleic Acids Res. 2013 Jan;41(2):e39
references.pmid: 23155066
references.citation: Genome Res. 2014 Nov;24(11):1774-86
references.pmid: 25258385
references.citation: Science. 2012 Dec 21;338(6114):1587-93
references.pmid: 23258890
references.citation: Nature. 2011 Oct 20;478(7369):343-8
references.pmid: 22012392
references.citation: Cell. 2005 Jan 14;120(1):59-72
references.pmid: 15652482
references.citation: Mol Cell. 2003 Nov;12(5):1317-24
references.pmid: 14636588
references.citation: Nat Commun. 2014;5:3603
references.pmid: 24752171
references.citation: Elife. 2014;3:e01201
references.pmid: 24448406
references.citation: J Neurosci. 2004 Sep 29;24(39):8391-3
references.pmid: 15456809
references.citation: Mol Cell. 2004 Jan 16;13(1):91-100
references.pmid: 14731397
references.citation: Proc Natl Acad Sci U S A. 2013 Oct 8;110(41):16562-7
references.pmid: 24023061
references.citation: Science. 2015 Jan 9;347(6218):1254806
references.pmid: 25525159
references.citation: Cell. 2009 Feb 20;136(4):777-93
references.pmid: 19239895
references.citation: Nature. 2008 Nov 27;456(7221):470-6
references.pmid: 18978772
references.citation: Bioinformatics. 2002;18 Suppl 1:S181-8
references.pmid: 12169546
references.citation: Methods Mol Biol. 2014;1126:357-97
references.pmid: 24549677
references.citation: BMC Bioinformatics. 2011;12:480
references.pmid: 22177264
references.citation: Science. 2012 Dec 21;338(6114):1593-9
references.pmid: 23258891
references.citation: Genes Dev. 2007 Jan 1;21(1):71-84
references.pmid: 17210790
references.citation: RNA. 2015 Dec;21(12):2053-66
references.pmid: 26437669
references.citation: Proc Natl Acad Sci U S A. 2014 Feb 18;111(7):2638-43
references.pmid: 24497505
references.citation: Nature. 2011 Sep 15;477(7364):289-94
references.pmid: 21921910
references.citation: Nat Protoc. 2009;4(1):44-57
references.pmid: 19131956
references.citation: Nat Genet. 2008 Dec;40(12):1413-5
references.pmid: 18978789
references.citation: Mol Cell. 2012 Jun 29;46(6):884-92
references.pmid: 22749401
references.citation: Nucleic Acids Res. 2012 Apr;40(8):e61
references.pmid: 22266656
references.citation: Genes Dev. 2007 Mar 15;21(6):708-18
references.pmid: 17369403
references.citation: Mol Cell Biol. 2014 Jan;34(1):71-83
references.pmid: 24164894
references.citation: Bioinformatics. 2011 Nov 1;27(21):3010-6
references.pmid: 21896509
references.citation: Bioinformatics. 2006 May 15;22(10):1211-6
references.pmid: 16500940
references.citation: Cell. 1986 Aug 29;46(5):681-90
references.pmid: 2427200