.gif?ad=16839&adview=true)
![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
RESEARCH PAPER
Department of Biological Sciences, MC2433, Columbia University, New York, New York 10027, USA
We have searched for sequence motifs that contribute to the recognition of human pre-mRNA splice sites by comparing the frequency of 8-mers in internal noncoding exons versus unspliced pseudo exons and 5' untranslated regions (5' untranslated regions [UTRs]) of transcripts of intronless genes. This type of comparison avoids the isolation of sequences that are distinguished by their protein-coding information. We classified sequence families comprising 2069 putative exonic enhancers and 974 putative exonic silencers. Representatives of each class functioned as enhancers or silencers when inserted into a test exon and assayed in transfected mammalian cells. As a class, the enhancer sequencers were more prevalent and the silencer elements less prevalent in all exons compared with introns. A survey of 58 reported exonic splicing mutations showed good agreement between the splicing phenotype and the effect of the mutation on the motifs defined here. The large number of effective sequences implied by these results suggests that sequences that influence splicing may be very abundant in pre-mRNA.
[Keywords: splicing; pre-mRNA; motifs; exon; enhancers; silencers]
Received February 17, 2004; revised version accepted April 9, 2004.
Supplemental material is available at http://www.genesdev.org.
1 Corresponding author.
E-MAIL lac2{at}columbia.edu; FAX (212) 865-8246.
CiteULike 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  I. Aznarez, Y. Barash, O. Shai, D. He, J. Zielenski, L.-C. Tsui, J. Parkinson, B. J. Frey, J. M. Rommens, and B. J. Blencowe A systematic analysis of intronic sequences downstream of 5' splice sites reveals a widespread role for U-rich motifs and TIA1/TIAL1 proteins in alternative splicing regulation Genome Res., August 1, 2008; 18(8): 1247 - 1258. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Cloutier, J. Toutant, L. Shkreta, S. Goekjian, T. Revil, and B. Chabot Antagonistic Effects of the SRp30c Protein and Cryptic 5 ' Splice Sites on the Alternative Splicing of the Apoptotic Regulator Bcl-x J. Biol. Chem., August 1, 2008; 283(31): 21315 - 21324. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Goina, N. Skoko, and F. Pagani Binding of DAZAP1 and hnRNPA1/A2 to an Exonic Splicing Silencer in a Natural BRCA1 Exon 18 Mutant Mol. Cell. Biol., June 1, 2008; 28(11): 3850 - 3860. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 C. Zhang, W.-H. Li, A. R. Krainer, and M. Q. Zhang RNA landscape of evolution for optimal exon and intron discrimination PNAS, April 15, 2008; 105(15): 5797 - 5802. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Gal-Mark, S. Schwartz, and G. Ast Alternative splicing of Alu exons--two arms are better than one Nucleic Acids Res., April 1, 2008; 36(6): 2012 - 2023. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
K. J. Hertel Combinatorial Control of Exon Recognition J. Biol. Chem., January 18, 2008; 283(3): 1211 - 1215. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Davidson, H. Northrup, T. M. King, J. M. Fletcher, I. Townsend, G. H. Tyerman, and Kit Sing Au Genes in Glucose Metabolism and Association With Spina Bifida Reproductive Sciences, January 1, 2008; 15(1): 51 - 58. [Abstract] [PDF]
|
|
|
|
|
|
E. Vela, J. M. Hilari, X. Roca, A. M. Munoz-Marmol, A. Ariza, and M. Isamat Multisite and bidirectional exonic splicing enhancer in CD44 alternative exon v3 RNA, December 1, 2007; 13(12): 2312 - 2323. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Kralovicova and I. Vorechovsky Global control of aberrant splice-site activation by auxiliary splicing sequences: evidence for a gradient in exon and intron definition Nucleic Acids Res., October 8, 2007; 35(19): 6399 - 6413. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Aartsma-Rus and G.-J. B. van Ommen Antisense-mediated exon skipping: A versatile tool with therapeutic and research applications RNA, October 1, 2007; 13(10): 1609 - 1624. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Akker, S. Misra, S. Aslam, E. L. Morgan, P. J. Smith, B. Khoo, and S. L. Chew Pre-Spliceosomal Binding of U1 Small Nuclear Ribonucleoprotein (RNP) and Heterogenous Nuclear RNP E1 Is Associated with Suppression of a Growth Hormone Receptor Pseudoexon Mol. Endocrinol., October 1, 2007; 21(10): 2529 - 2540. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Buratti, M. Chivers, J. Kralovicova, M. Romano, M. Baralle, A. R. Krainer, and I. Vorechovsky Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization Nucleic Acids Res., July 26, 2007; 35(13): 4250 - 4263. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Buratti, A. Dhir, M. A. Lewandowska, and F. E. Baralle RNA structure is a key regulatory element in pathological ATM and CFTR pseudoexon inclusion events Nucleic Acids Res., July 26, 2007; 35(13): 4369 - 4383. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 I. Aznarez, J. Zielenski, J. M Rommens, B. J Blencowe, and L.-C. Tsui Exon skipping through the creation of a putative exonic splicing silencer as a consequence of the cystic fibrosis mutation R553X J. Med. Genet., May 1, 2007; 44(5): 341 - 346. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kashima, N. Rao, and J. L. Manley An intronic element contributes to splicing repression in spinal muscular atrophy PNAS, February 27, 2007; 104(9): 3426 - 3431. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Raponi, F. E. Baralle, and F. Pagani Reduced splicing efficiency induced by synonymous substitutions may generate a substrate for natural selection of new splicing isoforms: the case of CFTR exon 12 Nucleic Acids Res., January 28, 2007; 35(2): 606 - 613. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Szeszel-Fedorowicz, I. Talukdar, B. N. Griffith, C. M. Walsh, and L. M. Salati An Exonic Splicing Silencer Is Involved in the Regulated Splicing of Glucose 6-Phosphate Dehydrogenase mRNA J. Biol. Chem., November 10, 2006; 281(45): 34146 - 34158. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. J. Smith, C. Zhang, J. Wang, S. L. Chew, M. Q. Zhang, and A. R. Krainer An increased specificity score matrix for the prediction of SF2/ASF-specific exonic splicing enhancers Hum. Mol. Genet., August 15, 2006; 15(16): 2490 - 2508. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Buratti, M. Baralle, and F. E. Baralle Defective splicing, disease and therapy: searching for master checkpoints in exon definition Nucleic Acids Res., July 19, 2006; 34(12): 3494 - 3510. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Collins and D. Penny Investigating the Intron Recognition Mechanism in Eukaryotes Mol. Biol. Evol., May 1, 2006; 23(5): 901 - 910. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Schattner and M. Diekhans Regions of extreme synonymous codon selection in mammalian genes Nucleic Acids Res., March 23, 2006; 34(6): 1700 - 1710. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-N. Grellscheid and C. W. J. Smith An Apparent Pseudo-Exon Acts both as an Alternative Exon That Leads to Nonsense-Mediated Decay and as a Zero-Length Exon. Mol. Cell. Biol., March 1, 2006; 26(6): 2237 - 2246. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Florea Bioinformatics of alternative splicing and its regulation Brief Bioinform, March 1, 2006; 7(1): 55 - 69. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. K. Singh, N. N. Singh, E. J. Androphy, and R. N. Singh Splicing of a Critical Exon of Human Survival Motor Neuron Is Regulated by a Unique Silencer Element Located in the Last Intron Mol. Cell. Biol., February 15, 2006; 26(4): 1333 - 1346. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Kralovicova and I. Vorechovsky Position-Dependent Repression and Promotion of DQB1 Intron 3 Splicing by GGGG Motifs J. Immunol., February 15, 2006; 176(4): 2381 - 2388. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D.-Q. Xu and W. Mattox Identification of a splicing enhancer in MLH1 using COMPARE, a new assay for determination of relative RNA splicing efficiencies Hum. Mol. Genet., January 15, 2006; 15(2): 329 - 336. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. L. ZHENG, X.-D. FU, and M. GRIBSKOV Characteristics and regulatory elements defining constitutive splicing and different modes of alternative splicing in human and mouse RNA, December 1, 2005; 11(12): 1777 - 1787. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Wang, P. J. Smith, A. R. Krainer, and M. Q. Zhang Distribution of SR protein exonic splicing enhancer motifs in human protein-coding genes Nucleic Acids Res., September 7, 2005; 33(16): 5053 - 5062. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Kralovicova, M. B. Christensen, and I. Vorechovsky Biased exon/intron distribution of cryptic and de novo 3' splice sites Nucleic Acids Res., September 1, 2005; 33(15): 4882 - 4898. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Lei and I. Vorechovsky Identification of Splicing Silencers and Enhancers in Sense Alus: a Role for Pseudoacceptors in Splice Site Repression Mol. Cell. Biol., August 15, 2005; 25(16): 6912 - 6920. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. H.-F. Zhang, T. Kangsamaksin, M. S. P. Chao, J. K. Banerjee, and L. A. Chasin Exon Inclusion Is Dependent on Predictable Exonic Splicing Enhancers Mol. Cell. Biol., August 15, 2005; 25(16): 7323 - 7332. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Madsen and C. M. Stoltzfus An Exonic Splicing Silencer Downstream of the 3' Splice Site A2 Is Required for Efficient Human Immunodeficiency Virus Type 1 Replication J. Virol., August 15, 2005; 79(16): 10478 - 10486. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Lei, I. N. M. Day, and I. Vorechovsky Exonization of AluYa5 in the human ACE gene requires mutations in both 3' and 5' splice sites and is facilitated by a conserved splicing enhancer Nucleic Acids Res., July 14, 2005; 33(12): 3897 - 3906. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. H-F. Zhang, C. S. Leslie, and L. A. Chasin Dichotomous splicing signals in exon flanks Genome Res., June 1, 2005; 15(6): 768 - 779. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Pagani, M. Raponi, and F. E. Baralle Synonymous mutations in CFTR exon 12 affect splicing and are not neutral in evolution PNAS, May 3, 2005; 102(18): 6368 - 6372. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. J. Wagner, A. P. Baraniak, O. M. Sessions, D. Mauger, E. Moskowitz, and M. A. Garcia-Blanco Characterization of the Intronic Splicing Silencers Flanking FGFR2 Exon IIIb J. Biol. Chem., April 8, 2005; 280(14): 14017 - 14027. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. L. Black A simple answer for a splicing conundrum PNAS, April 5, 2005; 102(14): 4927 - 4928. [Full Text] [PDF]
|
|
|
|
|
|
C. HOLLINS, D. A.R. ZORIO, M. MACMORRIS, and T. BLUMENTHAL U2AF binding selects for the high conservation of the C. elegans 3' splice site RNA, March 1, 2005; 11(3): 248 - 253. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Minovitsky, S. L. Gee, S. Schokrpur, I. Dubchak, and J. G. Conboy The splicing regulatory element, UGCAUG, is phylogenetically and spatially conserved in introns that flank tissue-specific alternative exons Nucleic Acids Res., February 3, 2005; 33(2): 714 - 724. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Webb, C. M. Romfo, W. J. van Heeckeren, and J. A. Wise Exonic splicing enhancers in fission yeast: functional conservation demonstrates an early evolutionary origin Genes & Dev., January 15, 2005; 19(2): 242 - 254. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Kralovicova, S. Houngninou-Molango, A. Kramer, and I. Vorechovsky Branch site haplotypes that control alternative splicing Hum. Mol. Genet., December 15, 2004; 13(24): 3189 - 3202. [Abstract] [Full Text] [PDF]
|
|
