title: Evolution of alternative splicing in primate brain transcriptomes.
abstract: Alternative splicing is a predominant form of gene regulation in higher eukaryotes. The evolution of alternative splicing provides an important mechanism for the acquisition of novel gene functions. In this work, we carried out a genome-wide phylogenetic survey of lineage-specific splicing patterns in the primate brain, via high-density exon junction array profiling of brain transcriptomes of humans, chimpanzees and rhesus macaques. We identified 509 genes showing splicing differences among these species. RT-PCR analysis of 40 exons confirmed the predicted splicing evolution of 33 exons. Of these 33 exons, outgroup analysis using rhesus macaques confirmed 13 exons with human-specific increase or decrease in transcript inclusion levels after humans diverged from chimpanzees. Some of the human-specific brain splicing patterns disrupt domains critical for protein-protein interactions, and some modulate translational efficiency of their host genes. Strikingly, for exons showing splicing differences across species, we observed a significant increase in the rate of silent substitutions within exons, coupled with accelerated sequence divergence in flanking introns. This indicates that evolution of cis-regulatory signals is a major contributor to the emergence of human-specific splicing patterns. In one gene (MAGOH), using minigene reporter assays, we demonstrated that the combination of two human-specific cis-sequence changes created its human-specific splicing pattern. Together, our data reveal widespread human-specific changes of alternative splicing in the brain and suggest an important role of splicing in the evolution of neuronal gene regulation and functions.
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Lin
authors.forename: Shihao
authors.initials: S
authors.lastname: Shen
authors.forename: Peng
authors.initials: P
authors.lastname: Jiang
authors.forename: Seiko
authors.initials: S
authors.lastname: Sato
authors.forename: Beverly L
authors.initials: BL
authors.lastname: Davidson
authors.forename: Yi
authors.initials: Y
authors.lastname: Xing
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002531:Cerebellum / Q000378:metabolism; D019143:Evolution, Molecular; D005091:Exons / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D014644:Genetic Variation; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D011323:Primates / Q000235:genetics*; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013045:Species Specificity
chemical_list: D012333:RNA, Messenger
references.citation: RNA. 2007 Apr;13(4):563-72
references.pmid: 17307815
references.citation: Genome Res. 2007 Dec;17(12):1797-808
references.pmid: 17984227
references.citation: Nat Rev Genet. 2007 Sep;8(9):711-23
references.pmid: 17680008
references.citation: Cytogenet Genome Res. 2005;111(2):107-9
references.pmid: 16103650
references.citation: Genes Dev. 2007 Nov 15;21(22):2963-75
references.pmid: 17978102
references.citation: Proc Natl Acad Sci U S A. 2006 Jan 3;103(1):135-40
references.pmid: 16371466
references.citation: J Biol Chem. 2008 Feb 1;283(5):2543-53
references.pmid: 18055463
references.citation: Nat Genet. 2008 Dec;40(12):1413-5
references.pmid: 18978789
references.citation: Nat Rev Neurosci. 2007 Nov;8(11):819-31
references.pmid: 17895907
references.citation: Proc Natl Acad Sci U S A. 2006 Sep 5;103(36):13427-32
references.pmid: 16938881
references.citation: Bioinformatics. 2007 Nov 1;23(21):2947-8
references.pmid: 17846036
references.citation: Genome Res. 2002 Dec;12(12):1805-14
references.pmid: 12466284
references.citation: Cell. 2009 May 1;137(3):536-48
references.pmid: 19410547
references.citation: Nucleic Acids Res. 2009 Jul;37(12):e90
references.pmid: 19474342
references.citation: Methods Mol Biol. 2000;132:365-86
references.pmid: 10547847
references.citation: Cell. 2004 Dec 29;119(7):1027-40
references.pmid: 15620360
references.citation: RNA. 2008 Jul;14(7):1290-6
references.pmid: 18515550
references.citation: Genome Res. 2000 Aug;10(8):1065-70
references.pmid: 10958623
references.citation: Mol Biol Evol. 2000 Jan;17(1):32-43
references.pmid: 10666704
references.citation: J Comput Biol. 2004;11(2-3):377-94
references.pmid: 15285897
references.citation: Nature. 2008 Nov 27;456(7221):464-9
references.pmid: 18978773
references.citation: Nat Protoc. 2009;4(1):44-57
references.pmid: 19131956
references.citation: Genome Res. 2005 Nov;15(11):1566-75
references.pmid: 16251466
references.citation: Genome Res. 2007 Aug;17(8):1210-8
references.pmid: 17671095
references.citation: Nat Rev Genet. 2006 Feb;7(2):98-108
references.pmid: 16418745
references.citation: Genome Res. 2002 Dec;12(12):1837-45
references.pmid: 12466287
references.citation: Nat Biotechnol. 2000 Feb;18(2):233-4
references.pmid: 10657137
references.citation: Cell. 2006 Jul 14;126(1):37-47
references.pmid: 16839875
references.citation: Science. 1975 Apr 11;188(4184):107-16
references.pmid: 1090005
references.citation: Genome Res. 2008 Apr;18(4):533-43
references.pmid: 18204002
references.citation: PLoS Genet. 2008 Nov;4(11):e1000271
references.pmid: 19023414
references.citation: Nat Biotechnol. 2004 May;22(5):535-46
references.pmid: 15122293
references.citation: Cell. 2004 Dec 17;119(6):831-45
references.pmid: 15607979
references.citation: Nucleic Acids Res. 2003 May 15;31(10):2544-52
references.pmid: 12736303
references.citation: PLoS One. 2008 Mar 05;3(3):e1712
references.pmid: 18320033
references.citation: Trends Genet. 2000 Jun;16(6):276-7
references.pmid: 10827456
references.citation: Science. 2002 Apr 12;296(5566):340-3
references.pmid: 11951044
references.citation: PLoS One. 2006 Dec 20;1:e88
references.pmid: 17183719
references.citation: Nat Rev Genet. 2006 Sep;7(9):693-702
references.pmid: 16921347
references.citation: RNA. 2007 Oct;13(10):1603-8
references.pmid: 17709368
references.citation: PLoS Comput Biol. 2009 Dec;5(12):e1000608
references.pmid: 20019791
references.citation: PLoS Biol. 2007 Jul;5(7):e171
references.pmid: 17579516
references.citation: Mol Psychiatry. 2008 Feb;13(2):162-72
references.pmid: 17579610
references.citation: PLoS Genet. 2007 Nov;3(11):e203
references.pmid: 18020709
references.citation: Genome Res. 2004 Aug;14(8):1462-73
references.pmid: 15289471
references.citation: Nature. 2007 Oct 18;449(7164):913-8
references.pmid: 17943131
references.citation: Hum Mol Genet. 2003 Jun 1;12(11):1313-20
references.pmid: 12761046
references.citation: Nature. 2005 Oct 20;437(7062):1153-7
references.pmid: 16237444
references.citation: PLoS Biol. 2006 Mar;4(3):e72
references.pmid: 16494531
references.citation: PLoS Biol. 2007 Feb;5(2):e40
references.pmid: 17298178
references.citation: Cytogenet Genome Res. 2003;103(1-2):58-62
references.pmid: 15004465
references.citation: PLoS One. 2007 Mar 14;2(3):e286
references.pmid: 17356696
references.citation: RNA Biol. 2009 Nov-Dec;6(5):546-62
references.pmid: 19829082
references.citation: Cell. 2000 Oct 27;103(3):367-70
references.pmid: 11081623
references.citation: Nature. 2005 Oct 27;437(7063):1299-320
references.pmid: 16255080
references.citation: Genome Biol. 2003;4(5):P3
references.pmid: 12734009
references.citation: Genome Biol. 2007;8(5):R82
references.pmid: 17504534
references.citation: Science. 2006 Jun 16;312(5780):1614-20
references.pmid: 16778047
references.citation: Mol Cell. 2004 Dec 22;16(6):929-41
references.pmid: 15610736
references.citation: Genes Dev. 2009 Jun 15;23(12):1379-86
references.pmid: 19528315
references.citation: Mol Cell. 2009 Mar 13;33(5):591-601
references.pmid: 19285943
references.citation: PLoS Genet. 2008 Oct 17;4(10):e1000225
references.pmid: 18841251
references.citation: FASEB J. 2009 Aug;23(8):2605-15
references.pmid: 19299482
references.citation: Trends Mol Med. 2002 Dec;8(12):555-62
references.pmid: 12470988
references.citation: Nature. 2008 Nov 27;456(7221):470-6
references.pmid: 18978772
references.citation: Hum Genet. 2009 Feb;125(1):81-93
references.pmid: 19052777
references.citation: Trends Genet. 2005 Feb;21(2):73-7
references.pmid: 15661351
references.citation: Genome Res. 2005 May;15(5):674-80
references.pmid: 15867429
references.citation: Nat Rev Genet. 2004 Oct;5(10):773-82
references.pmid: 15510168
references.citation: Am J Physiol Lung Cell Mol Physiol. 2005 Sep;289(3):L497-508
references.pmid: 15894557
references.citation: Bioinformatics. 2010 Jan 15;26(2):268-9
references.pmid: 19933160
references.citation: Cell. 2005 Jan 14;120(1):59-72
references.pmid: 15652482
references.citation: RNA. 1997 May;3(5):453-63
references.pmid: 9149227
references.citation: Annu Rev Genomics Hum Genet. 2008;9:143-60
references.pmid: 18505377
references.citation: PLoS Genet. 2007 Jun;3(6):e90
references.pmid: 17542651
references.citation: Nat Rev Genet. 2009 Jan;10(1):57-63
references.pmid: 19015660
references.citation: Blood. 2009 Apr 2;113(14):3363-70
references.pmid: 19196664
references.citation: Nat Genet. 2002 Jan;30(1):13-9
references.pmid: 11753382
references.citation: Science. 2005 Sep 16;309(5742):1850-4
references.pmid: 16141373
references.citation: Curr Opin Genet Dev. 2006 Dec;16(6):553-8
references.pmid: 17008090
references.citation: Heredity (Edinb). 2009 Oct;103(4):279-80
references.pmid: 19491926
references.citation: Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13526-31
references.pmid: 16157889
references.citation: Genome Res. 2010 Feb;20(2):180-9
references.pmid: 20009012
references.citation: Nat Rev Genet. 2002 Apr;3(4):285-98
references.pmid: 11967553
references.citation: Proc Natl Acad Sci U S A. 2007 May 1;104(18):7489-94
references.pmid: 17449636
references.citation: Nat Rev Genet. 2002 Nov;3(11):838-49
references.pmid: 12415314
references.citation: Science. 2003 Dec 19;302(5653):2141-4
references.pmid: 14684825
references.citation: Nucleic Acids Res. 2001 May 1;29(9):e45
references.pmid: 11328886
references.citation: Neurobiol Aging. 2009 May;30(5):691-6
references.pmid: 17904251
references.citation: Genetics. 1999 Aug;152(4):1711-22
references.pmid: 10430595
references.citation: Comput Appl Biosci. 1997 Oct;13(5):555-6
references.pmid: 9367129
references.citation: Nat Rev Genet. 2007 Oct;8(10):749-61
references.pmid: 17726481
references.citation: Nat Methods. 2008 Jul;5(7):621-8
references.pmid: 18516045
references.citation: Nature. 2007 Oct 18;449(7164):851-61
references.pmid: 17943122
references.citation: RNA. 2008 May;14(5):802-13
references.pmid: 18369186
references.citation: Trends Genet. 2001 Feb;17(2):62-5
references.pmid: 11173101
references.citation: Science. 2002 Aug 9;297(5583):1007-13
references.pmid: 12114529
references.citation: PLoS Comput Biol. 2009 Dec;5(12):e1000598
references.pmid: 20011106
references.citation: Hum Mol Genet. 2009 Jun 15;18(12):2204-14
references.pmid: 19324900
references.citation: Genome Res. 2005 Nov;15(11):1553-65
references.pmid: 16251465
references.citation: Trends Genet. 2006 Nov;22(11):608-13
references.pmid: 16978728
references.citation: Nat Rev Genet. 2006 Jul;7(7):499-509
references.pmid: 16770337
references.citation: Nature. 1998 Jun 18;393(6686):702-5
references.pmid: 9641683
references.citation: BMC Genomics. 2008 Jun 04;9:273
references.pmid: 18533039
references.citation: Genes Dev. 2007 Jul 1;21(13):1636-52
references.pmid: 17606642
references.citation: Endocrinology. 2002 Jul;143(7):2541-7
references.pmid: 12072386
references.citation: Nat Genet. 2003 Jun;34(2):177-80
references.pmid: 12730695
references.citation: Trends Biochem Sci. 2000 Aug;25(8):381-8
references.pmid: 10916158
references.citation: Nucleic Acids Res. 2009 Jan;37(Database issue):D755-61
references.pmid: 18996895
references.citation: Proc Natl Acad Sci U S A. 1999 May 25;96(11):6307-11
references.pmid: 10339583
references.citation: Genome Biol. 2007;8(9):R183
references.pmid: 17784955
references.citation: Science. 2003 May 23;300(5623):1288-91
references.pmid: 12764196
references.citation: Biochemistry. 2006 Dec 26;45(51):15168-78
references.pmid: 17176038
references.citation: Genome Biol. 2007;8(4):R64
references.pmid: 17456239
references.citation: Nucleic Acids Res. 1994 Nov 11;22(22):4673-80
references.pmid: 7984417
references.citation: Bioinformatics. 2008 Dec 15;24(24):2887-93
references.pmid: 18984598
references.citation: Science. 2003 Aug 15;301(5635):967-9
references.pmid: 12920299
references.citation: Nat Genet. 2008 Feb;40(2):225-31
references.pmid: 18193047
references.citation: Nature. 2006 Mar 9;440(7081):242-5
references.pmid: 16525476
references.citation: RNA. 2008 Aug;14(8):1470-9
references.pmid: 18566192
references.citation: Mol Biol Evol. 2007 Aug;24(8):1821-31
references.pmid: 17522087