Global control of aberrant splice-site activation by auxiliary splicing sequences: evidence for a gradient in exon and intron definition


Kralovicova, Jana and Vorechovsky, Igor (2007) Global control of aberrant splice-site activation by auxiliary splicing sequences: evidence for a gradient in exon and intron definition. Nucleic Acids Research, 35, (19), 6399-6413. (doi:10.1093/nar/gkm680).

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Original Publication URL: http://dx.doi.org/10.1093/nar/gkm680

Description/Abstract

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.

Item Type: Article
ISSNs: 0305-1048 (print)
Related URLs:
Keywords: humans, combination, role, regulatory sequences, chemistry, exons, human,ribonucleic acid, genes, rna splice sites, research support, introns, disease, proinsulin, poly g, genetics, research, alternative splicing, rna, comparative study, cell line, mutation,acid
Subjects: R Medicine
R Medicine > RM Therapeutics. Pharmacology
Q Science > QR Microbiology
Divisions: University Structure - Pre August 2011 > School of Medicine > Developmental Origins of Health and Disease
University Structure - Pre August 2011 > School of Medicine
University Structure - Pre August 2011 > School of Medicine > Human Genetics
ePrint ID: 59946
Date Deposited: 08 Sep 2008
Last Modified: 27 Mar 2014 18:42
URI: http://eprints.soton.ac.uk/id/eprint/59946

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