Computational extraction of a neural molecular network through alternative splicing

Abstract

Background: Generally, the results of high throughput analyses contain information about gene expressions, and about exon expressions. Approximately 90% of primary protein-coding transcripts undergo alternative splicing in mammals. However, changes induced by alternative exons have not been properly analyzed for their impact on important molecular networks or their biological events. Even when alternative exons are identified, they are usually subjected to bioinformatics analysis in the same way as the gene ignoring the possibility of functionality change because of the alteration of domain caused by alternative exon. Here, we reveal an effective computational approach to explore an important molecular network based on potential changes of functionality induced by alternative exons obtained from our comprehensive analysis of neuronal cell differentiation. Results: From our previously identified 262 differentially alternatively spliced exons during neuronal cell differentiations, we extracted 241 sets that changed the amino acid sequences between the alternatively spliced sequences. Conserved domain searches indicated that annotated domain(s) were changed in 128 sets. We obtained 49 genes whose terms overlapped between domain description and gene annotation. Thus, these 49 genes have alternatively differentially spliced in exons that affect their main functions. We performed pathway analysis using these 49 genes and identified the EGFR (epidermal growth factor receptor) and mTOR (mammalian target of rapamycin) signaling pathway as being involved frequently. Recent studies reported that the mTOR pathway is associated with neuronal cell differentiation, vindicating that our approach extracted an important molecular network successfully. Conclusions: Effective informatics approaches for exons should be more complex than those for genes, because changes in alternative exons affect protein functions via alterations of amino acid sequences and functional domains. Our method extracted alterations of functional domains and identified key alternative splicing events. We identified the EGFR and mTOR signaling pathway as the most affected pathway. The mTOR pathway is important for neuronal differentiation, suggesting that this in silico extraction of alternative splicing networks is useful. This preliminary analysis indicated that automated analysis of the effects of alternative splicing would provide a rich source of biologically relevant information.