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Open Access Methodology article

A method of predicting changes in human gene splicing induced by genetic variants in context of cis-acting elements

Alexander Churbanov1*, Igor Vořechovský2 and Chindo Hicks3

Author Affiliations

1 New Mexico State University, Biology Dept., MSC 3AF, PO Box 30001, Las Cruces, NM 88003, USA

2 University of Southampton, Southampton University Hospital, MP808, Tremona Road, Southampton SO16 6YD, UK

3 Loyola University Medical Center, 2160 S. First Ave., Maywood, IL 60153, USA

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BMC Bioinformatics 2010, 11:22  doi:10.1186/1471-2105-11-22

Published: 12 January 2010

Abstract

Background

Polymorphic variants and mutations disrupting canonical splicing isoforms are among the leading causes of human hereditary disorders. While there is a substantial evidence of aberrant splicing causing Mendelian diseases, the implication of such events in multi-genic disorders is yet to be well understood. We have developed a new tool (SpliceScan II) for predicting the effects of genetic variants on splicing and cis-regulatory elements. The novel Bayesian non-canonical 5'GC splice site (SS) sensor used in our tool allows inference on non-canonical exons.

Results

Our tool performed favorably when compared with the existing methods in the context of genes linked to the Autism Spectrum Disorder (ASD). SpliceScan II was able to predict more aberrant splicing isoforms triggered by the mutations, as documented in DBASS5 and DBASS3 aberrant splicing databases, than other existing methods. Detrimental effects behind some of the polymorphic variations previously associated with Alzheimer's and breast cancer could be explained by changes in predicted splicing patterns.

Conclusions

We have developed SpliceScan II, an effective and sensitive tool for predicting the detrimental effects of genomic variants on splicing leading to Mendelian and complex hereditary disorders. The method could potentially be used to screen resequenced patient DNA to identify de novo mutations and polymorphic variants that could contribute to a genetic disorder.