Tissue Specificity Based Isoform Function Prediction

Alternative splicing enables a gene spliced into different isoforms and hence protein variants. Identifying individual functions of these isoforms help deciphering the functional diversity of proteins. Although much efforts have been made for automatic gene function prediction, few efforts have been moved toward computational isoform function prediction, mainly due to the unavailable (or scanty) functional annotations of isoforms. Existing efforts directly combine multiple RNA-seq datasets without account of the important tissue specificity of alternative splicing. To bridge this gap, we introduce a novel approach called TS-Isofun to predict the functions of isoforms by integrating multiple functional association networks with respect to tissue specificity. TS-Isofun first constructs tissue-specific isoform functional association networks using multiple RNA-seq datasets from tissue-wise. Next, TS-Isofun assigns weights to these networks and models the tissue specificity by selectively integrating them with adaptive weights. It then introduces a joint matrix factorization-based data fusion model to leverage the integrated network, gene-level data and functional annotations of genes to infer the functions of isoforms. To achieve coherent weight assignment and isoform function prediction, TS-Isofun jointly optimizes the weights of individual networks and the isoform function prediction in a unified objective function. Experimental results show that TS-Isofun significantly outperforms state-of-the-art methods and the account of tissue specificity contributes to more accurate isoform function prediction.