Dataset Information

Predicting the change of exon splicing caused by genetic variant using support vector regression.

ABSTRACT: Alternative splicing can be disrupted by genetic variants that are related to diseases like cancers. Discovering the influence of genetic variations on the alternative splicing will improve the understanding of the pathogenesis of variants. Here, we developed a new approach, PredPSI-SVR to predict the impact of variants on exon skipping events by using the support vector regression. From the sequence of a particular exon and its flanking regions, 42 comprehensive features related to splicing events were extracted. By using a greedy feature selection algorithm, we found eight features contributing most to the prediction. The trained model achieved a Pearson correlation coefficient (PCC) of 0.570 in the 10-fold cross-validation based on the training data set provided by the "vex-seq" challenge of the 5th Critical Assessment of Genome Interpretation. In the blind test also held by the challenge, our prediction ranked the 2nd with a PCC of 0.566 that demonstrates the robustness of our method. A further test indicated that the PredPSI-SVR is helpful in prioritizing deleterious synonymous mutations. The method is available on https://github.com/chenkenbio/PredPSI-SVR.

SUBMITTER: Chen K

PROVIDER: S-EPMC6744342 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Predicting the change of exon splicing caused by genetic variant using support vector regression.

Chen Ken K Lu Yutong Y Zhao Huiying H Yang Yuedong Y

Human mutation 20190618 9

Alternative splicing can be disrupted by genetic variants that are related to diseases like cancers. Discovering the influence of genetic variations on the alternative splicing will improve the understanding of the pathogenesis of variants. Here, we developed a new approach, PredPSI-SVR to predict the impact of variants on exon skipping events by using the support vector regression. From the sequence of a particular exon and its flanking regions, 42 comprehensive features related to splicing eve ...[more]

PMID: 31070294

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Project description:BACKGROUND:The residue-wise contact order (RWCO) describes the sequence separations between the residues of interest and its contacting residues in a protein sequence. It is a new kind of one-dimensional protein structure that represents the extent of long-range contacts and is considered as a generalization of contact order. Together with secondary structure, accessible surface area, the B factor, and contact number, RWCO provides comprehensive and indispensable important information to reconstructing the protein three-dimensional structure from a set of one-dimensional structural properties. Accurately predicting RWCO values could have many important applications in protein three-dimensional structure prediction and protein folding rate prediction, and give deep insights into protein sequence-structure relationships. RESULTS:We developed a novel approach to predict residue-wise contact order values in proteins based on support vector regression (SVR), starting from primary amino acid sequences. We explored seven different sequence encoding schemes to examine their effects on the prediction performance, including local sequence in the form of PSI-BLAST profiles, local sequence plus amino acid composition, local sequence plus molecular weight, local sequence plus secondary structure predicted by PSIPRED, local sequence plus molecular weight and amino acid composition, local sequence plus molecular weight and predicted secondary structure, and local sequence plus molecular weight, amino acid composition and predicted secondary structure. When using local sequences with multiple sequence alignments in the form of PSI-BLAST profiles, we could predict the RWCO distribution with a Pearson correlation coefficient (CC) between the predicted and observed RWCO values of 0.55, and root mean square error (RMSE) of 0.82, based on a well-defined dataset with 680 protein sequences. Moreover, by incorporating global features such as molecular weight and amino acid composition we could further improve the prediction performance with the CC to 0.57 and an RMSE of 0.79. In addition, combining the predicted secondary structure by PSIPRED was found to significantly improve the prediction performance and could yield the best prediction accuracy with a CC of 0.60 and RMSE of 0.78, which provided at least comparable performance compared with the other existing methods. CONCLUSION:The SVR method shows a prediction performance competitive with or at least comparable to the previously developed linear regression-based methods for predicting RWCO values. In contrast to support vector classification (SVC), SVR is very good at estimating the raw value profiles of the samples. The successful application of the SVR approach in this study reinforces the fact that support vector regression is a powerful tool in extracting the protein sequence-structure relationship and in estimating the protein structural profiles from amino acid sequences.

Project description:BackgroundFor successful protein structure prediction by comparative modeling, in addition to identifying a good template protein with known structure, obtaining an accurate sequence alignment between a query protein and a template protein is critical. It has been known that the alignment accuracy can vary significantly depending on our choice of various alignment parameters such as gap opening penalty and gap extension penalty. Because the accuracy of sequence alignment is typically measured by comparing it with its corresponding structure alignment, there is no good way of evaluating alignment accuracy without knowing the structure of a query protein, which is obviously not available at the time of structure prediction. Moreover, there is no universal alignment parameter option that would always yield the optimal alignment.ResultsIn this work, we develop a method to predict the quality of the alignment between a query and a template. We train the support vector regression (SVR) models to predict the MaxSub scores as a measure of alignment quality. The alignment between a query protein and a template of length n is transformed into a (n + 1)-dimensional feature vector, then it is used as an input to predict the alignment quality by the trained SVR model. Performance of our work is evaluated by various measures including Pearson correlation coefficient between the observed and predicted MaxSub scores. Result shows high correlation coefficient of 0.945. For a pair of query and template, 48 alignments are generated by changing alignment options. Trained SVR models are then applied to predict the MaxSub scores of those and to select the best alignment option which is chosen specifically to the query-template pair. This adaptive selection procedure results in 7.4% improvement of MaxSub scores, compared to those when the single best parameter option is used for all query-template pairs.ConclusionThe present work demonstrates that the alignment quality can be predicted with reasonable accuracy. Our method is useful not only for selecting the optimal alignment parameters for a chosen template based on predicted alignment quality, but also for filtering out problematic templates that are not suitable for structure prediction due to poor alignment accuracy. This is implemented as a part in FORECAST, the server for fold-recognition and is freely available on the web at http://pbil.kaist.ac.kr/forecast.

Dataset Information

Predicting the change of exon splicing caused by genetic variant using support vector regression.

Publications

Predicting the change of exon splicing caused by genetic variant using support vector regression.

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