Ab initio prediction of mutation-induced cryptic splice-site activation and exon skipping
Ab initio prediction of mutation-induced cryptic splice-site activation and exon skipping
Mutations that affect splicing of precursor messenger RNAs play a major role in the development of hereditary diseases. Most splicing mutations have been found to eliminate GT or AG dinucleotides that define the 5' and 3' ends of introns, leading to exon skipping or cryptic splice-site activation. Although accurate description of the mis-spliced transcripts is critical for predicting phenotypic consequences of these alterations, their exact nature in affected individuals cannot often be determined experimentally. Using a comprehensive collection of exons that sustained cryptic splice-site activation or were skipped as a result of splice-site mutations, we have developed a multivariate logistic discrimination procedure that distinguishes the two aberrant splicing outcomes from DNA sequences. The new algorithm was validated using an independent sample of exons and implemented as a free online utility termed CRYP-SKIP (http://www.dbass.org.uk/cryp-skip/). The web application takes up one or more mutated alleles, each consisting of one exon and flanking intronic sequences, and provides a list of important predictor variables and their values, the overall probability of activating cryptic splice vs exon skipping, and the location and intrinsic strength of predicted cryptic splice sites in the input sequence. These results will facilitate phenotypic prediction of splicing mutations and provide further insights into splicing enhancer and silencer elements and their relative importance for splice-site selection in vivo
mutation, gene, splicing, cryptic splice site, exon skipping, RNA
759-765
Divina, Petr
12563f84-24b2-4855-9429-890816fcf9dc
Kvitkovicova, Andrea
619afdfe-8034-4c04-aeac-45c5fc739514
Buratti, Emanuele
57e8e002-a8c2-409a-ac29-2fc4a1d1c8b9
Vorechovsky, Igor
7245de2f-8c9b-4034-8935-9a451d9b682e
June 2009
Divina, Petr
12563f84-24b2-4855-9429-890816fcf9dc
Kvitkovicova, Andrea
619afdfe-8034-4c04-aeac-45c5fc739514
Buratti, Emanuele
57e8e002-a8c2-409a-ac29-2fc4a1d1c8b9
Vorechovsky, Igor
7245de2f-8c9b-4034-8935-9a451d9b682e
Divina, Petr, Kvitkovicova, Andrea, Buratti, Emanuele and Vorechovsky, Igor
(2009)
Ab initio prediction of mutation-induced cryptic splice-site activation and exon skipping.
European Journal of Human Genetics, 17 (6), .
(doi:10.1038/ejhg.2008.257).
Abstract
Mutations that affect splicing of precursor messenger RNAs play a major role in the development of hereditary diseases. Most splicing mutations have been found to eliminate GT or AG dinucleotides that define the 5' and 3' ends of introns, leading to exon skipping or cryptic splice-site activation. Although accurate description of the mis-spliced transcripts is critical for predicting phenotypic consequences of these alterations, their exact nature in affected individuals cannot often be determined experimentally. Using a comprehensive collection of exons that sustained cryptic splice-site activation or were skipped as a result of splice-site mutations, we have developed a multivariate logistic discrimination procedure that distinguishes the two aberrant splicing outcomes from DNA sequences. The new algorithm was validated using an independent sample of exons and implemented as a free online utility termed CRYP-SKIP (http://www.dbass.org.uk/cryp-skip/). The web application takes up one or more mutated alleles, each consisting of one exon and flanking intronic sequences, and provides a list of important predictor variables and their values, the overall probability of activating cryptic splice vs exon skipping, and the location and intrinsic strength of predicted cryptic splice sites in the input sequence. These results will facilitate phenotypic prediction of splicing mutations and provide further insights into splicing enhancer and silencer elements and their relative importance for splice-site selection in vivo
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Published date: June 2009
Keywords:
mutation, gene, splicing, cryptic splice site, exon skipping, RNA
Identifiers
Local EPrints ID: 69623
URI: http://eprints.soton.ac.uk/id/eprint/69623
ISSN: 1018-4813
PURE UUID: 4287e36a-ffc6-4a74-b710-7da860e17c35
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Date deposited: 20 Nov 2009
Last modified: 14 Mar 2024 02:48
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Contributors
Author:
Petr Divina
Author:
Andrea Kvitkovicova
Author:
Emanuele Buratti
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