Nucleic Acids Research Advance Access originally published online on September 18, 2007
Nucleic Acids Research 2007 35(19):6399-6413; doi:10.1093/nar/gkm680
Nucleic Acids Research, 2007, Vol. 35, No. 19 6399-6413
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Global control of aberrant splice-site activation by auxiliary splicing sequences: evidence for a gradient in exon and intron definition
ová
echovsk
*University of Southampton, School of Medicine, Division of Human Genetics, MP808, Southampton SO16 6YD, UK
*To whom correspondence should be addressed. Tel: +44 2380 796425; Fax: +44 2380 794264; Email: i.vorechovsky{at}soton.ac.uk
Received June 25, 2007. Revised August 6, 2007. Accepted August 19, 2007.
Auxiliary splicing signals play a major role in the regulation of constitutive and alternative pre-mRNA splicing, but their relative importance in selection of mutation-induced cryptic or de novo splice sites is poorly understood. Here, we show that exonic sequences between authentic and aberrant splice sites that were activated by splice-site mutations in human disease genes have lower frequencies of splicing enhancers and higher frequencies of splicing silencers than average exons. Conversely, sequences between authentic and intronic aberrant splice sites have more enhancers and less silencers than average introns. Exons that were skipped as a result of splice-site mutations were smaller, had lower SF2/ASF motif scores, a decreased availability of decoy splice sites and a higher density of silencers than exons in which splice-site mutation activated cryptic splice sites. These four variables were the strongest predictors of the two aberrant splicing events in a logistic regression model. Elimination or weakening of predicted silencers in two reporters consistently promoted use of intron-proximal splice sites if these elements were maintained at their original positions, with their modular combinations producing expected modification of splicing. Together, these results show the existence of a gradient in exon and intron definition at the level of pre-mRNA splicing and provide a basis for the development of computational tools that predict aberrant splicing outcomes.
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