Spliceman--a computational web server that predicts sequence variations in pre-mRNA splicing

Abstract

Summary: It was previously demonstrated that splicing elements are positional dependent. We exploited this relationship between location and function by comparing positional distributions between all possible 4096 hexamers around a database of human splice sites. The distance measure used in this study found point mutations that produced higher distances disrupted splicing, whereas point mutations with smaller distances generally had no effect on splicing. Reasoning the idea that functional splicing elements have signature positional distributions around constitutively spliced exons, we introduce Spliceman-an online tool that predicts how likely distant mutations around annotated splice sites were to disrupt splicing. Spliceman takes a set of DNA sequences with point mutations and returns a ranked list to predict the effects of point mutations on pre-mRNA splicing. The current implementation included the analyses of 11 genomes: human, chimp, rhesus, mouse, rat, dog, cat, chicken, guinea pig, frog and zebrafish.

Availability: Freely available on the web at http://fairbrother.biomed.brown.edu/spliceman/

Contact: fairbrother@brown.edu.

Fig. 1.

L1 distance metric is predictive of distant splicing mutations. ROC curve analysis using HGMD splicing mutations to compare L1 distances in three distinct regions around the annotated human splice sites. True positive samples are derived from a total of 1987 HGMD splicing mutants found outside of the donor and acceptor sites, and false positive samples are constructed from simulated mutations using equal rates of transversions and transitions. The exonic region is shown in green; upstream and downstream introns are shown in blue and red, respectively. AUC, area under curve; C.I., confidence interval.