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Open Access Highly Accessed Research article

Speeding disease gene discovery by sequence based candidate prioritization

Euan A Adie*, Richard R Adams, Kathryn L Evans, David J Porteous and Ben S Pickard

Author Affiliations

Medical Genetics Section, Department of Medical Sciences, The University of Edinburgh, Edinburgh, UK

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BMC Bioinformatics 2005, 6:55  doi:10.1186/1471-2105-6-55

Published: 14 March 2005

Abstract

Background

Regions of interest identified through genetic linkage studies regularly exceed 30 centimorgans in size and can contain hundreds of genes. Traditionally this number is reduced by matching functional annotation to knowledge of the disease or phenotype in question. However, here we show that disease genes share patterns of sequence-based features that can provide a good basis for automatic prioritization of candidates by machine learning.

Results

We examined a variety of sequence-based features and found that for many of them there are significant differences between the sets of genes known to be involved in human hereditary disease and those not known to be involved in disease. We have created an automatic classifier called PROSPECTR based on those features using the alternating decision tree algorithm which ranks genes in the order of likelihood of involvement in disease. On average, PROSPECTR enriches lists for disease genes two-fold 77% of the time, five-fold 37% of the time and twenty-fold 11% of the time.

Conclusion

PROSPECTR is a simple and effective way to identify genes involved in Mendelian and oligogenic disorders. It performs markedly better than the single existing sequence-based classifier on novel data. PROSPECTR could save investigators looking at large regions of interest time and effort by prioritizing positional candidate genes for mutation detection and case-control association studies.