regSNPs-splicing: a tool for prioritizing synonymous single-nucleotide substitution

While synonymous single-nucleotide variants (sSNVs) have largely been unstudied, since they do not alter protein sequence, mounting evidence suggests that they may affect RNA conformation, splicing, and the stability of nascent-mRNAs to promote various diseases. Accurately prioritizing deleterious sSNVs from a pool of neutral ones can significantly improve our ability of selecting functional genetic variants identified from various genome-sequencing projects, and, therefore, advance our understanding of disease etiology. In this study, we develop a computational algorithm to prioritize sSNVs based on their impact on mRNA splicing and protein function. In addition to genomic features that potentially affect splicing regulation, our proposed algorithm also includes dozens structural features that characterize the functions of alternatively spliced exons on protein function. Our systematical evaluation on thousands of sSNVs suggests that several structural features, including intrinsic disorder protein scores, solvent accessible surface areas, protein secondary structures, and known and predicted protein family domains, show significant differences between disease-causing and neutral sSNVs. Our result suggests that the protein structure features offer an added dimension of information while distinguishing disease-causing and neutral synonymous variants. The inclusion of structural features increases the predictive accuracy for functional sSNV prioritization

Identification of microRNA precursors based on random forest with network-level representation method of stem-loop structure

<p>Abstract</p> <p>Background</p> <p>MicroRNAs (miRNAs) play a key role in regulating various biological processes such as participating in the post-transcriptional pathway and affecting the stability and/or the translation of mRNA. Current methods have extracted feature information at different levels, among which the characteristic stem-loop structure makes the greatest contribution to the prediction of putative miRNA precursor (pre-miRNA). We find that none of these features alone is capable of identifying new pre-miRNA accurately.</p> <p>Results</p> <p>In the present work, a pre-miRNA stem-loop secondary structure is translated to a network, which provides a novel perspective for its structural analysis. Network parameters are used to construct prediction model, achieving an area under the receiver operating curves (AUC) value of 0.956. Moreover, by repeating the same method on two independent datasets, accuracies of 0.976 and 0.913 are achieved, respectively.</p> <p>Conclusions</p> <p>Network parameters effectively characterize pre-miRNA secondary structure, which improves our prediction model in both prediction ability and computation efficiency. Additionally, as a complement to feature extraction methods in previous studies, these multifaceted features can reflect natural properties of miRNAs and be used for comprehensive and systematic analysis on miRNA.</p

Improving the resolution of interaction maps: A middleground between high-resolution complexes and genome-wide interactomes

Protein-protein interactions are ubiquitous in Biology and therefore central to understand living organisms. In recent years, large-scale studies have been undertaken to describe, at least partially, protein-protein interaction maps or interactomes for a number of relevant organisms including human. Although the analysis of interaction networks is proving useful, current interactomes provide a blurry and granular picture of the molecular machinery, i.e. unless the structure of the protein complex is known the molecular details of the interaction are missing and sometime is even not possible to know if the interaction between the proteins is direct, i.e. physical interaction or part of functional, not necessary, direct association. Unfortunately, the determination of the structure of protein complexes cannot keep pace with the discovery of new protein-protein interactions resulting in a large, and increasing, gap between the number of complexes that are thought to exist and the number for which 3D structures are available. The aim of the thesis was to tackle this problem by implementing computational approaches to derive structural models of protein complexes and thus reduce this existing gap. Over the course of the thesis, a novel modelling algorithm to predict the structure of protein complexes, V-D2OCK, was implemented. This new algorithm combines structure-based prediction of protein binding sites by means of a novel algorithm developed over the course of the thesis: VORFFIP and M-VORFFIP, data-driven docking and energy minimization. This algorithm was used to improve the coverage and structural content of the human interactome compiled from different sources of interactomic data to ensure the most comprehensive interactome. Finally, the human interactome and structural models were compiled in a database, V-D2OCK DB, that offers an easy and user-friendly access to the human interactome including a bespoken graphical molecular viewer to facilitate the analysis of the structural models of protein complexes. Furthermore, new organisms, in addition to human, were included providing a useful resource for the study of all known interactomes

Analysis of Machine Learning Based Methods for Identifying MicroRNA Precursors

MicroRNAs are a type of non-coding RNA that were discovered less than a decade ago but are now known to be incredibly important in regulating gene expression despite their small size. However, due to their small size, and several other limiting factors, experimental procedures have had limited success in discovering new microRNAs. Computational methods are therefore vital to discovering novel microRNAs. Many different approaches have been used to scan genomic sequences for novel microRNAs with varying degrees of success. This work provides an overview of these computational methods, focusing particularly on those methods based on machine learning techniques. The results of experiments performed on several of the machine learning based microRNA detectors are provided along with an analysis of their performance

A data science approach to pattern discovery in complex structures with applications in bioinformatics

Pattern discovery aims to find interesting, non-trivial, implicit, previously unknown and potentially useful patterns in data. This dissertation presents a data science approach for discovering patterns or motifs from complex structures, particularly complex RNA structures. RNA secondary and tertiary structure motifs are very important in biological molecules, which play multiple vital roles in cells. A lot of work has been done on RNA motif annotation. However, pattern discovery in RNA structure is less studied. In the first part of this dissertation, an ab initio algorithm, named DiscoverR, is introduced for pattern discovery in RNA secondary structures. This algorithm works by representing RNA secondary structures as ordered labeled trees and performs tree pattern discovery using a quadratic time dynamic programming algorithm. The algorithm is able to identify and extract the largest common substructures from two RNA molecules of different sizes, without prior knowledge of locations and topologies of these substructures. One application of DiscoverR is to locate the RNA structural elements in genomes. Experimental results show that this tool complements the currently used approaches for mining conserved structural RNAs in the human genome. DiscoverR can also be extended to find repeated regions in an RNA secondary structure. Specifically, this extended method is used to detect structural repeats in the 3\u27-untranslated region of a protein kinase gene