Evolution of alternative splicing in primate brain transcriptomes.
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.
Lin
Lan
L
Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.
Shen
Shihao
S
Jiang
Peng
P
Sato
Seiko
S
Davidson
Beverly L
BL
Xing
Yi
Y
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
D012333:RNA, Messenger
RNA. 2007 Apr;13(4):563-72
17307815
Genome Res. 2007 Dec;17(12):1797-808
17984227
Nat Rev Genet. 2007 Sep;8(9):711-23
17680008
Cytogenet Genome Res. 2005;111(2):107-9
16103650
Genes Dev. 2007 Nov 15;21(22):2963-75
17978102
Proc Natl Acad Sci U S A. 2006 Jan 3;103(1):135-40
16371466
J Biol Chem. 2008 Feb 1;283(5):2543-53
18055463
Nat Genet. 2008 Dec;40(12):1413-5
18978789
Nat Rev Neurosci. 2007 Nov;8(11):819-31
17895907
Proc Natl Acad Sci U S A. 2006 Sep 5;103(36):13427-32
16938881
Bioinformatics. 2007 Nov 1;23(21):2947-8
17846036
Genome Res. 2002 Dec;12(12):1805-14
12466284
Cell. 2009 May 1;137(3):536-48
19410547
Nucleic Acids Res. 2009 Jul;37(12):e90
19474342
Methods Mol Biol. 2000;132:365-86
10547847
Cell. 2004 Dec 29;119(7):1027-40
15620360
RNA. 2008 Jul;14(7):1290-6
18515550
Genome Res. 2000 Aug;10(8):1065-70
10958623
Mol Biol Evol. 2000 Jan;17(1):32-43
10666704
J Comput Biol. 2004;11(2-3):377-94
15285897
Nature. 2008 Nov 27;456(7221):464-9
18978773
Nat Protoc. 2009;4(1):44-57
19131956
Genome Res. 2005 Nov;15(11):1566-75
16251466
Genome Res. 2007 Aug;17(8):1210-8
17671095
Nat Rev Genet. 2006 Feb;7(2):98-108
16418745
Genome Res. 2002 Dec;12(12):1837-45
12466287
Nat Biotechnol. 2000 Feb;18(2):233-4
10657137
Cell. 2006 Jul 14;126(1):37-47
16839875
Science. 1975 Apr 11;188(4184):107-16
1090005
Genome Res. 2008 Apr;18(4):533-43
18204002
PLoS Genet. 2008 Nov;4(11):e1000271
19023414
Nat Biotechnol. 2004 May;22(5):535-46
15122293
Cell. 2004 Dec 17;119(6):831-45
15607979
Nucleic Acids Res. 2003 May 15;31(10):2544-52
12736303
PLoS One. 2008 Mar 05;3(3):e1712
18320033
Trends Genet. 2000 Jun;16(6):276-7
10827456
Science. 2002 Apr 12;296(5566):340-3
11951044
PLoS One. 2006 Dec 20;1:e88
17183719
Nat Rev Genet. 2006 Sep;7(9):693-702
16921347
RNA. 2007 Oct;13(10):1603-8
17709368
PLoS Comput Biol. 2009 Dec;5(12):e1000608
20019791
PLoS Biol. 2007 Jul;5(7):e171
17579516
Mol Psychiatry. 2008 Feb;13(2):162-72
17579610
PLoS Genet. 2007 Nov;3(11):e203
18020709
Genome Res. 2004 Aug;14(8):1462-73
15289471
Nature. 2007 Oct 18;449(7164):913-8
17943131
Hum Mol Genet. 2003 Jun 1;12(11):1313-20
12761046
Nature. 2005 Oct 20;437(7062):1153-7
16237444
PLoS Biol. 2006 Mar;4(3):e72
16494531
PLoS Biol. 2007 Feb;5(2):e40
17298178
Cytogenet Genome Res. 2003;103(1-2):58-62
15004465
PLoS One. 2007 Mar 14;2(3):e286
17356696
RNA Biol. 2009 Nov-Dec;6(5):546-62
19829082
Cell. 2000 Oct 27;103(3):367-70
11081623
Nature. 2005 Oct 27;437(7063):1299-320
16255080
Genome Biol. 2003;4(5):P3
12734009
Genome Biol. 2007;8(5):R82
17504534
Science. 2006 Jun 16;312(5780):1614-20
16778047
Mol Cell. 2004 Dec 22;16(6):929-41
15610736
Genes Dev. 2009 Jun 15;23(12):1379-86
19528315
Mol Cell. 2009 Mar 13;33(5):591-601
19285943
PLoS Genet. 2008 Oct 17;4(10):e1000225
18841251
FASEB J. 2009 Aug;23(8):2605-15
19299482
Trends Mol Med. 2002 Dec;8(12):555-62
12470988
Nature. 2008 Nov 27;456(7221):470-6
18978772
Hum Genet. 2009 Feb;125(1):81-93
19052777
Trends Genet. 2005 Feb;21(2):73-7
15661351
Genome Res. 2005 May;15(5):674-80
15867429
Nat Rev Genet. 2004 Oct;5(10):773-82
15510168
Am J Physiol Lung Cell Mol Physiol. 2005 Sep;289(3):L497-508
15894557
Bioinformatics. 2010 Jan 15;26(2):268-9
19933160
Cell. 2005 Jan 14;120(1):59-72
15652482
RNA. 1997 May;3(5):453-63
9149227
Annu Rev Genomics Hum Genet. 2008;9:143-60
18505377
PLoS Genet. 2007 Jun;3(6):e90
17542651
Nat Rev Genet. 2009 Jan;10(1):57-63
19015660
Blood. 2009 Apr 2;113(14):3363-70
19196664
Nat Genet. 2002 Jan;30(1):13-9
11753382
Science. 2005 Sep 16;309(5742):1850-4
16141373
Curr Opin Genet Dev. 2006 Dec;16(6):553-8
17008090
Heredity (Edinb). 2009 Oct;103(4):279-80
19491926
Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13526-31
16157889
Genome Res. 2010 Feb;20(2):180-9
20009012
Nat Rev Genet. 2002 Apr;3(4):285-98
11967553
Proc Natl Acad Sci U S A. 2007 May 1;104(18):7489-94
17449636
Nat Rev Genet. 2002 Nov;3(11):838-49
12415314
Science. 2003 Dec 19;302(5653):2141-4
14684825
Nucleic Acids Res. 2001 May 1;29(9):e45
11328886
Neurobiol Aging. 2009 May;30(5):691-6
17904251
Genetics. 1999 Aug;152(4):1711-22
10430595
Comput Appl Biosci. 1997 Oct;13(5):555-6
9367129
Nat Rev Genet. 2007 Oct;8(10):749-61
17726481
Nat Methods. 2008 Jul;5(7):621-8
18516045
Nature. 2007 Oct 18;449(7164):851-61
17943122
RNA. 2008 May;14(5):802-13
18369186
Trends Genet. 2001 Feb;17(2):62-5
11173101
Science. 2002 Aug 9;297(5583):1007-13
12114529
PLoS Comput Biol. 2009 Dec;5(12):e1000598
20011106
Hum Mol Genet. 2009 Jun 15;18(12):2204-14
19324900
Genome Res. 2005 Nov;15(11):1553-65
16251465
Trends Genet. 2006 Nov;22(11):608-13
16978728
Nat Rev Genet. 2006 Jul;7(7):499-509
16770337
Nature. 1998 Jun 18;393(6686):702-5
9641683
BMC Genomics. 2008 Jun 04;9:273
18533039
Genes Dev. 2007 Jul 1;21(13):1636-52
17606642
Endocrinology. 2002 Jul;143(7):2541-7
12072386
Nat Genet. 2003 Jun;34(2):177-80
12730695
Trends Biochem Sci. 2000 Aug;25(8):381-8
10916158
Nucleic Acids Res. 2009 Jan;37(Database issue):D755-61
18996895
Proc Natl Acad Sci U S A. 1999 May 25;96(11):6307-11
10339583
Genome Biol. 2007;8(9):R183
17784955
Science. 2003 May 23;300(5623):1288-91
12764196
Biochemistry. 2006 Dec 26;45(51):15168-78
17176038
Genome Biol. 2007;8(4):R64
17456239
Nucleic Acids Res. 1994 Nov 11;22(22):4673-80
7984417
Bioinformatics. 2008 Dec 15;24(24):2887-93
18984598
Science. 2003 Aug 15;301(5635):967-9
12920299
Nat Genet. 2008 Feb;40(2):225-31
18193047
Nature. 2006 Mar 9;440(7081):242-5
16525476
RNA. 2008 Aug;14(8):1470-9
18566192
Mol Biol Evol. 2007 Aug;24(8):1821-31
17522087