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Predicting functional regulatory polymorphisms.

ABSTRACT: MOTIVATION:Limited availability of data has hindered the development of algorithms that can identify functionally meaningful regulatory single nucleotide polymorphisms (rSNPs). Given the large number of common polymorphisms known to reside in the human genome, the identification of functional rSNPs via laboratory assays will be costly and time-consuming. Therefore appropriate bioinformatics strategies for predicting functional rSNPs are necessary. Recent data from the Encyclopedia of DNA Elements (ENCODE) Project has significantly expanded the amount of available functional information relevant to non-coding regions of the genome, and, importantly, led to the conclusion that many functional elements in the human genome are not conserved. RESULTS:In this article we describe how ENCODE data can be leveraged to probabilistically determine the functional and phenotypic significance of non-coding SNPs (ncSNPs). The method achieves excellent sensitivity ( approximately 80%) and speci.city ( approximately 99%) based on a set of known phenotypically relevant and non-functional SNPs. In addition, we show that our method is not overtrained through the use of cross-validation analyses. AVAILABILITY:The software platforms used in our analyses are freely available (http://www.cs.waikato.ac.nz/ml/weka/). In addition, we provide the training dataset (Supplementary Table 3), and our predictions (Supplementary Table 6), in the Supplementary Material. SUPPLEMENTARY INFORMATION:Supplementary data are available at Bioinformatics online.

SUBMITTER: Torkamani A

PROVIDER: S-EPMC2732211 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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Predicting functional regulatory polymorphisms.

Torkamani Ali A Schork Nicholas J NJ

Bioinformatics (Oxford, England) 20080618 16

<h4>Motivation</h4>Limited availability of data has hindered the development of algorithms that can identify functionally meaningful regulatory single nucleotide polymorphisms (rSNPs). Given the large number of common polymorphisms known to reside in the human genome, the identification of functional rSNPs via laboratory assays will be costly and time-consuming. Therefore appropriate bioinformatics strategies for predicting functional rSNPs are necessary. Recent data from the Encyclopedia of DNA ...[more]

PMID: 18562267

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Project description:BackgroundConnectivity networks, which reflect multiple interactions between genes and proteins, possess not only a descriptive but also a predictive value, as new connections can be extrapolated and tested by means of computational analysis. Integration of different types of connectivity data (such as co-expression and genetic interactions) in one network has proven to benefit 'guilt by association' analysis. However predictive values of connectives of different types, that had their specific functional meaning and topological characteristics were not obvious, and have been addressed in this analysis.MethodseQTL data for 3 experimental C.elegans age groups were retrieved from WormQTL. WormNet has been used to obtain pair-wise gene interactions. The Shortest Path Function (SPF) has been adopted for statistical validation of the co-expressed gene clusters and for computational prediction of their potential gene expression regulators from a network context. A new SPF-based algorithm has been applied to genetic interactions sub-networks adjacent to the clusters of co-expressed genes for ranking the most likely gene expression regulators causal to eQTLs.ResultsWe have demonstrated that known co-expression and genetic interactions between C. elegans genes can be complementary in predicting gene expression regulators. Several algorithms were compared in respect to their predictive potential in different network connectivity contexts. We found that genes associated with eQTLs are highly clustered in a C. elegans co-expression sub-network, and their adjacent genetic interactions provide the optimal functional connectivity environment for application of the new SPF-based algorithm. It was successfully tested in the reverse-prediction analysis on groups of genes with known regulators and applied to co-expressed genes and experimentally observed expression quantitative trait loci (eQTLs).ConclusionsThis analysis demonstrates differences in topology and connectivity of co-expression and genetic interactions sub-networks in WormNet. The modularity of less continuous genetic interaction network does not correspond to modularity of the dense network comprised by gene co-expression interactions. However the genetic interaction network can be used much more efficiently with the SPF method in prediction of potential regulators of gene expression. The developed method can be used for validation of functional significance of suggested eQTLs and a discovery of new regulatory modules.

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Predicting functional regulatory polymorphisms.

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Predicting functional regulatory polymorphisms.

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