Seattle Children's Hospital Research Institute Sign up for PNAS Online eTocs
Link: Info for AuthorsLink: Editorial BoardLink: AboutLink: SubscribeLink: AdvertiseLink: ContactLink: Sitemap Link: PNAS Home
Proceedings of the National Academy of Sciences
Link: Current Issue "" Link: Archives "" Link: Online Submission ""  Link: Advanced Search

Published online on February 11, 2005, 10.1073/pnas.0409742102 OPEN ACCESS ARTICLE


This Article
Free via Open Access: OA
Right arrow Full Text (PDF)
Right arrow Supporting Information
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Yeo, G. W.
Right arrow Articles by Burge, C. B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yeo, G. W.
Right arrow Articles by Burge, C. B.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg  
What's this?

Genetics
Identification and analysis of alternative splicing events conserved in human and mouse

( exon skipping | regulatory element | cassette exon | transcriptome | comparative genomics )

Gene W. Yeo *{dagger}{ddagger}{sect}, Eric Van Nostrand *, Dirk Holste *, Tomaso Poggio {dagger}{ddagger}, and Christopher B. Burge *¶

Departments of *Biology and {dagger}Brain and Cognitive Sciences and {ddagger}Center for Biological and Computational Learning, Massachusetts Institute of Technology, Cambridge, MA 02319

Communicated by Phillip A. Sharp, Massachusetts Institute of Technology, Cambridge, MA, December 30, 2004 (received for review November 23, 2004)

Alternative pre-mRNA splicing affects a majority of human genes and plays important roles in development and disease. Alternative splicing (AS) events conserved since the divergence of human and mouse are likely of primary biological importance, but relatively few of such events are known. Here we describe sequence features that distinguish exons subject to evolutionarily conserved AS, which we call alternative conserved exons (ACEs), from other orthologous human/mouse exons and integrate these features into an exon classification algorithm, ACESCAN. Genome-wide analysis of annotated orthologous human-mouse exon pairs identified {approx}2,000 predicted ACEs. Alternative splicing was verified in both human and mouse tissues by using an RT-PCR-sequencing protocol for 21 of 30 (70%) predicted ACEs tested, supporting the validity of a majority of ACESCAN predictions. By contrast, AS was observed in mouse tissues for only 2 of 15 (13%) tested exons that had EST or cDNA evidence of AS in human but were not predicted ACEs, and AS was never observed for 11 negative control exons in human or mouse tissues. Predicted ACEs were much more likely to preserve the reading frame and less likely to disrupt protein domains than other AS events and were enriched in genes expressed in the brain and in genes involved in transcriptional regulation, RNA processing, and development. Our results also imply that the vast majority of AS events represented in the human EST database are not conserved in mouse.

Author contributions: G.W.Y., D.H., and C.B.B. designed research; G.W.Y., E.V.N., and D.H. performed research; G.W.Y., D.H., and T.P. contributed new reagents/analytic tools; G.W.Y., E.V.N., D.H., and C.B.B. analyzed data; and G.W.Y., D.H., and C.B.B. wrote the paper.

Freely available online through the PNAS open access option.

{sect}To whom correspondence may be sent at the present address: Crick-Jacobs Center for Computational and Theoretical Biology, The Salk Institute, La Jolla, CA 92037.

To whom correspondence may be addressed.

Gene W. Yeo, E-mail: geneyeo{at}salk.edu
Christopher B. Burge, E-mail: cburge{at}mit.edu

www.pnas.org/cgi/doi/10.1073/pnas.0409742102
Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg    What's this?


This article has been cited by other articles in HighWire Press-hosted journals:


Home page
 RNAHome page
Z. Wang and C. B. Burge
Splicing regulation: From a parts list of regulatory elements to an integrated splicing code
RNA, May 1, 2008; 14(5): 802 - 813.
[Abstract] [Full Text] [PDF]

Home page
 BioinformaticsHome page
Y. Xiao and M. R. Segal
Biological sequence classification utilizing positive and unlabeled data
Bioinformatics, May 1, 2008; 24(9): 1198 - 1205.
[Abstract] [Full Text] [PDF]

Home page
 RNAHome page
M. Hiller, K. Szafranski, R. Sinha, K. Huse, S. Nikolajewa, P. Rosenstiel, S. Schreiber, R. Backofen, and M. Platzer
Assessing the fraction of short-distance tandem splice sites under purifying selection
RNA, April 1, 2008; 14(4): 616 - 629.
[Abstract] [Full Text] [PDF]

Home page
 Genome Res.Home page
S. Ke, X. H.-F. Zhang, and L. A. Chasin
Positive selection acting on splicing motifs reflects compensatory evolution
Genome Res., April 1, 2008; 18(4): 533 - 543.
[Abstract] [Full Text] [PDF]

Home page
 Mol Biol EvolHome page
M. Irimia, J. L. Rukov, D. Penny, J. Garcia-Fernandez, J. Vinther, and S. W. Roy
Widespread Evolutionary Conservation of Alternatively Spliced Exons in Caenorhabditis
Mol. Biol. Evol., February 1, 2008; 25(2): 375 - 382.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
D. Karolchik, R. M. Kuhn, R. Baertsch, G. P. Barber, H. Clawson, M. Diekhans, B. Giardine, R. A. Harte, A. S. Hinrichs, F. Hsu, et al.
The UCSC Genome Browser Database: 2008 update
Nucleic Acids Res., January 11, 2008; 36(suppl_1): D773 - D779.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
G. G. Leparc and R. D. Mitra
A sensitive procedure to detect alternatively spliced mRNA in pooled-tissue samples
Nucleic Acids Res., December 18, 2007; 35(21): e146 - e146.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
C. He, Z. Zuo, H. Chen, L. Zhang, F. Zhou, H. Cheng, and R. Zhou
Genome-wide detection of testis- and testicular cancer-specific alternative splicing
Carcinogenesis, December 1, 2007; 28(12): 2484 - 2490.
[Abstract] [Full Text] [PDF]

Home page
 Genes Dev.Home page
J. A. Calarco, Y. Xing, M. Caceres, J. P. Calarco, X. Xiao, Q. Pan, C. Lee, T. M. Preuss, and B. J. Blencowe
Global analysis of alternative splicing differences between humans and chimpanzees
Genes & Dev., November 15, 2007; 21(22): 2963 - 2975.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
C. Zhang, M. L. Hastings, A. R. Krainer, and M. Q. Zhang
Dual-specificity splice sites function alternatively as 5' and 3' splice sites
PNAS, September 18, 2007; 104(38): 15028 - 15033.
[Abstract] [Full Text] [PDF]

Home page
 Physiol. GenomicsHome page
Y. Radhakrishnan, M. A. Fares, F. S. French, and S. H. Hall
Comparative genomic analysis of a mammalian {beta}-defensin gene cluster
Physiol Genomics, August 20, 2007; 30(3): 213 - 222.
[Abstract] [Full Text] [PDF]

Home page
 Genes Dev.Home page
P. L. Boutz, P. Stoilov, Q. Li, C.-H. Lin, G. Chawla, K. Ostrow, L. Shiue, M. Ares Jr., and D. L. Black
A post-transcriptional regulatory switch in polypyrimidine tract-binding proteins reprograms alternative splicing in developing neurons
Genes & Dev., July 1, 2007; 21(13): 1636 - 1652.
[Abstract] [Full Text] [PDF]

Home page
 Genome Res.Home page
R. B. Voelker and J. A. Berglund
A comprehensive computational characterization of conserved mammalian intronic sequences reveals conserved motifs associated with constitutive and alternative splicing
Genome Res., July 1, 2007; 17(7): 1023 - 1033.
[Abstract] [Full Text] [PDF]

Home page
 Genome Res.Home page
K. Garg and P. Green
Differing patterns of selection in alternative and constitutive splice sites
Genome Res., July 1, 2007; 17(7): 1015 - 1022.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
H. van Praag, M. J. Lucero, G. W. Yeo, K. Stecker, N. Heivand, C. Zhao, E. Yip, M. Afanador, H. Schroeter, J. Hammerstone, et al.
Plant-Derived Flavanol (-)Epicatechin Enhances Angiogenesis and Retention of Spatial Memory in Mice
J. Neurosci., May 30, 2007; 27(22): 5869 - 5878.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
G. G. Leparc and R. D. Mitra
Non-EST-based prediction of novel alternatively spliced cassette exons with cell signaling function in Caenorhabditis elegans and human
Nucleic Acids Res., May 11, 2007; 35(10): 3192 - 3202.
[Abstract] [Full Text] [PDF]

Home page
 Mol Biol EvolHome page
J. L. Rukov, M. Irimia, S. Mork, V. K. Lund, J. Vinther, and P. Arctander
High Qualitative and Quantitative Conservation of Alternative Splicing in Caenorhabditis elegans and Caenorhabditis briggsae
Mol. Biol. Evol., April 1, 2007; 24(4): 909 - 917.
[Abstract] [Full Text] [PDF]

Home page
 Genes Dev.Home page
J. Z. Ni, L. Grate, J. P. Donohue, C. Preston, N. Nobida, G. O'Brien, L. Shiue, T. A. Clark, J. E. Blume, and M. Ares Jr.
Ultraconserved elements are associated with homeostatic control of splicing regulators by alternative splicing and nonsense-mediated decay
Genes & Dev., March 15, 2007; 21(6): 708 - 718.
[Abstract] [Full Text] [PDF]

Home page
 Genome Res.Home page
B. Tian, Z. Pan, and J. Y. Lee
Widespread mRNA polyadenylation events in introns indicate dynamic interplay between polyadenylation and splicing
Genome Res., February 1, 2007; 17(2): 156 - 165.
[Abstract] [Full Text] [PDF]

Home page
 Genome Res.Home page
D. Baek, C. Davis, B. Ewing, D. Gordon, and P. Green
Characterization and predictive discovery of evolutionarily conserved mammalian alternative promoters
Genome Res., February 1, 2007; 17(2): 145 - 155.
[Abstract] [Full Text] [PDF]

Home page
 BioinformaticsHome page
L. Goh, S. K. Murphy, S. Muhkerjee, and T. S. Furey
Genomic sweeping for hypermethylated genes
Bioinformatics, February 1, 2007; 23(3): 281 - 288.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
H. Xia, J. Bi, and Y. Li
Identification of alternative 5'/3' splice sites based on the mechanism of splice site competition
Nucleic Acids Res., December 4, 2006; 34(21): 6305 - 6313.
[Abstract] [Full Text] [PDF]

Home page
 RNAHome page
Y. Dou, K. L. Fox-Walsh, P. F. Baldi, and K. J. Hertel
Genomic splice-site analysis reveals frequent alternative splicing close to the dominant splice site
RNA, December 1, 2006; 12(12): 2047 - 2056.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
J.-i. Takeda, Y. Suzuki, M. Nakao, R. A. Barrero, K. O. Koyanagi, L. Jin, C. Motono, H. Hata, T. Isogai, K. Nagai, et al.
Large-scale identification and characterization of alternative splicing variants of human gene transcripts using 56 419 completely sequenced and manually annotated full-length cDNAs
Nucleic Acids Res., September 1, 2006; 34(14): 3917 - 3928.
[Abstract] [Full Text] [PDF]

Home page
 GeneticsHome page
Y. Xing, Q. Wang, and C. Lee
Evolutionary Divergence of Exon Flanks: A Dissection of Mutability and Selection
Genetics, July 1, 2006; 173(3): 1787 - 1791.
[Abstract] [Full Text] [PDF]

Home page
 RNAHome page
E. A. Newman, S. J. Muh, R. H. Hovhannisyan, C. C. Warzecha, R. B. Jones, W. L. McKeehan, and R. P. Carstens
Identification of RNA-binding proteins that regulate FGFR2 splicing through the use of sensitive and specific dual color fluorescence minigene assays
RNA, June 1, 2006; 12(6): 1129 - 1141.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
J. L. Ponthier, C. Schluepen, W. Chen, R. A. Lersch, S. L. Gee, V. C. Hou, A. J. Lo, S. A. Short, J. A. Chasis, J. C. Winkelmann, et al.
Fox-2 Splicing Factor Binds to a Conserved Intron Motif to Promote Inclusion of Protein 4.1R Alternative Exon 16
J. Biol. Chem., May 5, 2006; 281(18): 12468 - 12474.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
B.-B. Wang and V. Brendel
Genomewide comparative analysis of alternative splicing in plants
PNAS, May 2, 2006; 103(18): 7175 - 7180.
[Abstract] [Full Text] [PDF]

Home page
 Mol Biol EvolHome page
F.-C. Chen, S.-S. Wang, C.-J. Chen, W.-H. Li, and T.-J. Chuang
Alternatively and Constitutively Spliced Exons Are Subject to Different Evolutionary Forces
Mol. Biol. Evol., March 1, 2006; 23(3): 675 - 682.
[Abstract] [Full Text] [PDF]

Home page
 Mol Biol EvolHome page
J. L. Parmley, J. V. Chamary, and L. D. Hurst
Evidence for Purifying Selection Against Synonymous Mutations in Mammalian Exonic Splicing Enhancers
Mol. Biol. Evol., February 1, 2006; 23(2): 301 - 309.
[Abstract] [Full Text] [PDF]

Home page
 Genes Dev.Home page
Q. Pan, A. L. Saltzman, Y. K. Kim, C. Misquitta, O. Shai, L. E. Maquat, B. J. Frey, and B. J. Blencowe
Quantitative microarray profiling provides evidence against widespread coupling of alternative splicing with nonsense-mediated mRNA decay to control gene expression
Genes & Dev., January 15, 2006; 20(2): 153 - 158.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
R. H. Hovhannisyan, C. C. Warzecha, and R. P. Carstens
Characterization of sequences and mechanisms through which ISE/ISS-3 regulates FGFR2 splicing
Nucleic Acids Res., January 12, 2006; 34(1): 373 - 385.
[Abstract] [Full Text] [PDF]

Home page
 Genome Res.Home page
P. Akiva, A. Toporik, S. Edelheit, Y. Peretz, A. Diber, R. Shemesh, A. Novik, and R. Sorek
Transcription-mediated gene fusion in the human genome
Genome Res., January 1, 2006; 16(1): 30 - 36.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
D. Holste, G. Huo, V. Tung, and C. B. Burge
HOLLYWOOD: a comparative relational database of alternative splicing
Nucleic Acids Res., January 1, 2006; 34(suppl_1): D56 - D62.
[Abstract] [Full Text] [PDF]

Home page
 Mol Biol EvolHome page
B. P. Cusack and K. H. Wolfe
Changes in Alternative Splicing of Human and Mouse Genes Are Accompanied by Faster Evolution of Constitutive Exons
Mol. Biol. Evol., November 1, 2005; 22(11): 2198 - 2208.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
M. Hiller, K. Huse, M. Platzer, and R. Backofen
Non-EST based prediction of exon skipping and intron retention events using Pfam information
Nucleic Acids Res., October 4, 2005; 33(17): 5611 - 5621.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
M. Pritsker, T. T. Doniger, L. C. Kramer, S. E. Westcot, and I. R. Lemischka
Diversification of stem cell molecular repertoire by alternative splicing
PNAS, October 4, 2005; 102(40): 14290 - 14295.
[Abstract] [Full Text] [PDF]

Home page
 BioinformaticsHome page
Y. Xing and C. Lee
Assessing the application of Ka/Ks ratio test to alternatively spliced exons
Bioinformatics, October 1, 2005; 21(19): 3701 - 3703.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
Z. Kan, P. W. Garrett-Engele, J. M. Johnson, and J. C. Castle
Evolutionarily conserved and diverged alternative splicing events show different expression and functional profiles
Nucleic Acids Res., September 29, 2005; 33(17): 5659 - 5666.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
D. Baek and P. Green
Sequence conservation, relative isoform frequencies, and nonsense-mediated decay in evolutionarily conserved alternative splicing
PNAS, September 6, 2005; 102(36): 12813 - 12818.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
M. Sironi, G. Menozzi, G. P. Comi, R. Cagliani, N. Bresolin, and U. Pozzoli
Analysis of intronic conserved elements indicates that functional complexity might represent a major source of negative selection on non-coding sequences
Hum. Mol. Genet., September 1, 2005; 14(17): 2533 - 2546.
[Abstract] [Full Text] [PDF]