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A method to predict the impact of regulatory variants from DNA sequence.

ABSTRACT: Most variants implicated in common human disease by genome-wide association studies (GWAS) lie in noncoding sequence intervals. Despite the suggestion that regulatory element disruption represents a common theme, identifying causal risk variants within implicated genomic regions remains a major challenge. Here we present a new sequence-based computational method to predict the effect of regulatory variation, using a classifier (gkm-SVM) that encodes cell type-specific regulatory sequence vocabularies. The induced change in the gkm-SVM score, deltaSVM, quantifies the effect of variants. We show that deltaSVM accurately predicts the impact of SNPs on DNase I sensitivity in their native genomic contexts and accurately predicts the results of dense mutagenesis of several enhancers in reporter assays. Previously validated GWAS SNPs yield large deltaSVM scores, and we predict new risk-conferring SNPs for several autoimmune diseases. Thus, deltaSVM provides a powerful computational approach to systematically identify functional regulatory variants.

SUBMITTER: Lee D

PROVIDER: S-EPMC4520745 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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A method to predict the impact of regulatory variants from DNA sequence.

Lee Dongwon D Gorkin David U DU Baker Maggie M Strober Benjamin J BJ Asoni Alessandro L AL McCallion Andrew S AS Beer Michael A MA

Nature genetics 20150615 8

Most variants implicated in common human disease by genome-wide association studies (GWAS) lie in noncoding sequence intervals. Despite the suggestion that regulatory element disruption represents a common theme, identifying causal risk variants within implicated genomic regions remains a major challenge. Here we present a new sequence-based computational method to predict the effect of regulatory variation, using a classifier (gkm-SVM) that encodes cell type-specific regulatory sequence vocabul ...[more]

PMID: 26075791

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Project description:BackgroundMost disease-associated variants identified by genome-wide association studies (GWAS) exist in noncoding regions. In spite of the common agreement that such variants may disrupt biological functions of their hosting regulatory elements, it remains a great challenge to characterize the risk of a genetic variant within the implicated genome sequence. Therefore, it is essential to develop an effective computational model that is not only capable of predicting the potential risk of a genetic variant but also valid in interpreting how the function of the genome is affected with the occurrence of the variant.ResultsWe developed a method named kmerForest that used a random forest classifier with k-mer counts to predict accessible chromatin regions purely based on DNA sequences. We demonstrated that our method outperforms existing methods in distinguishing known accessible chromatin regions from random genomic sequences. Furthermore, the performance of our method can further be improved with the incorporation of sequence conservation features. Based on this model, we assessed importance of the k-mer features by a series of permutation experiments, and we characterized the risk of a single nucleotide polymorphism (SNP) on the function of the genome using the difference between the importance of the k-mer features affected by the occurrence of the SNP. We conducted a series of experiments and showed that our model can well discriminate between pathogenic and normal SNPs. Particularly, our model correctly prioritized SNPs that are proved to be enriched for the binding sites of FOXA1 in breast cancer cell lines from previous studies.ConclusionsWe presented a novel method to interpret functional genetic variants purely base on DNA sequences. The proposed k-mer based score offers an effective means of measuring the impact of SNPs on the function of the genome, and thus shedding light on the identification of genetic risk factors underlying complex traits and diseases.

Project description:BACKGROUND: Proteases play a central role in cellular homeostasis and are responsible for the spatio-temporal regulation of function. Many putative proteases have been recently identified through genomic approaches, leading to a surge in global profiling attempts to characterize their function. Through such efforts and others it has become evident that many proteases play non-traditional roles. Accordingly, the number and the variety of the substrate repertoire of proteases are expected to be much larger than previously assumed. In line with such global profiling attempts, we present here a method for the prediction of natural substrates of endo proteases (human proteases used as an example) by employing short peptide sequences as specificity determinants. METHODOLOGY/PRINCIPAL FINDINGS: Our method incorporates specificity determinants unique to individual enzymes and physiologically relevant dual filters namely, solvent accessible surface area--a parameter dependent on protein three-dimensional structure and subcellular localization. By incorporating such hitherto unused principles in prediction methods, a novel ligand docking strategy to mimic substrate binding at the active site of the enzyme, and GO functions, we identify and perform subjective validation on putative substrates of matriptase and highlight new functions of the enzyme. Using relative solvent accessibility to rank order we show how new protease regulatory networks and enzyme cascades can be created. CONCLUSION: We believe that our physiologically relevant computational approach would be a very useful complementary method in the current day attempts to profile proteases (endo proteases in particular) and their substrates. In addition, by using functional annotations, we have demonstrated how normal and unknown functions of a protease can be envisaged. We have developed a network which can be integrated to create a proteolytic world. This network can in turn be extended to integrate other regulatory networks to build a system wide knowledge of the proteome.

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A method to predict the impact of regulatory variants from DNA sequence.

Publications

A method to predict the impact of regulatory variants from DNA sequence.

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