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Computational Methods for Predicting Functions at the mRNA Isoform Level.

ABSTRACT: Multiple mRNA isoforms of the same gene are produced via alternative splicing, a biological mechanism that regulates protein diversity while maintaining genome size. Alternatively spliced mRNA isoforms of the same gene may sometimes have very similar sequence, but they can have significantly diverse effects on cellular function and regulation. The products of alternative splicing have important and diverse functional roles, such as response to environmental stress, regulation of gene expression, human heritable, and plant diseases. The mRNA isoforms of the same gene can have dramatically different functions. Despite the functional importance of mRNA isoforms, very little has been done to annotate their functions. The recent years have however seen the development of several computational methods aimed at predicting mRNA isoform level biological functions. These methods use a wide array of proteo-genomic data to develop machine learning-based mRNA isoform function prediction tools. In this review, we discuss the computational methods developed for predicting the biological function at the individual mRNA isoform level.

SUBMITTER: Mishra SK

PROVIDER: S-EPMC7460821 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Computational Methods for Predicting Functions at the mRNA Isoform Level.

Mishra Sambit K SK Muthye Viraj V Kandoi Gaurav G

International journal of molecular sciences 20200808 16

Multiple mRNA isoforms of the same gene are produced via alternative splicing, a biological mechanism that regulates protein diversity while maintaining genome size. Alternatively spliced mRNA isoforms of the same gene may sometimes have very similar sequence, but they can have significantly diverse effects on cellular function and regulation. The products of alternative splicing have important and diverse functional roles, such as response to environmental stress, regulation of gene expression, ...[more]

PMID: 32784445

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Project description:MOTIVATION:Alternative splicing generates multiple isoforms from a single gene, greatly increasing the functional diversity of a genome. Although gene functions have been well studied, little is known about the specific functions of isoforms, making accurate prediction of isoform functions highly desirable. However, the existing approaches to predicting isoform functions are far from satisfactory due to at least two reasons: (i) unlike genes, isoform-level functional annotations are scarce. (ii) The information of isoform functions is concealed in various types of data including isoform sequences, co-expression relationship among isoforms, etc. RESULTS:In this study, we present a novel approach, DIFFUSE (Deep learning-based prediction of IsoForm FUnctions from Sequences and Expression), to predict isoform functions. To integrate various types of data, our approach adopts a hybrid framework by first using a deep neural network (DNN) to predict the functions of isoforms from their genomic sequences and then refining the prediction using a conditional random field (CRF) based on co-expression relationship. To overcome the lack of isoform-level ground truth labels, we further propose an iterative semi-supervised learning algorithm to train both the DNN and CRF together. Our extensive computational experiments demonstrate that DIFFUSE could effectively predict the functions of isoforms and genes. It achieves an average area under the receiver operating characteristics curve of 0.840 and area under the precision-recall curve of 0.581 over 4184 GO functional categories, which are significantly higher than the state-of-the-art methods. We further validate the prediction results by analyzing the correlation between functional similarity, sequence similarity, expression similarity and structural similarity, as well as the consistency between the predicted functions and some well-studied functional features of isoform sequences. AVAILABILITY AND IMPLEMENTATION:https://github.com/haochenucr/DIFFUSE. SUPPLEMENTARY INFORMATION:Supplementary data are available at Bioinformatics online.

Project description:Understanding and controlling biological function of proteins at the atomic level is of great importance; allosteric mechanisms provide such an interface. Experimental and computational methods have been developed to search for residue mutations that produce changes in function by altering sites of correlated motion. These methods are often observational in that altered motions are achieved by random sampling without revealing the underlying mechanism(s). We present two deterministic methods founded on structure-function relationships that predict dynamic control sites (i.e., locations that experience correlated motions as a result of altered dynamics). The first method ("static") is based on a single structure conformation (e.g., the wild type (WT)) and utilizes a graph description of atomic connectivity. The local atomic interactions are used to compute the propagation of contact paths. This description of structure connectivity reveals flexible locations that are susceptible to altered dynamics. The second method ("dynamic") is a comparative analysis between the normal modes of a WT structure and a mutant structure. A mapping function is defined that quantifies the significance of the motions in one structure projected onto the motions of the other. Each mode is considered up- or down-regulated according to its change in relative significance. This description of altered dynamics is the basis for a motion correlation analysis, from which the dynamic control sites are readily identified. The methods are theoretically derived and applied using the canonical system dihydrofolate reductase (DHFR). Both methods demonstrate a very high predictive value (p<0.005) in identifying known dynamic control sites. The dynamic method also produces a new hypothesis regarding the mechanism by which the DHFR mutant achieves hyperactivity. These tools are suitable for allosteric investigations and may greatly enhance the speed and effectiveness of other computational and experimental methods.

Dataset Information

Computational Methods for Predicting Functions at the mRNA Isoform Level.

Publications

Computational Methods for Predicting Functions at the mRNA Isoform Level.

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