Systematic detection of protein regions affected by alternative splicing

Shionyu, Masafumi*; Yura, Kei; Hijikata, Atsushi*; Nakahara, Taku*; Shinoda, Kazuki*; Yamaguchi, Akihiro*; Takahashi, Kenichi*; Go, Michiko*

Alternative splicing (AS) is a cellular process where multiple mature mRNAs are produced from a single gene by different usage of exons. From computational and experimental approaches, it is estimated that 30-70% of human genes undergo alternative splicing. There are a number of reports on spliced mRNAs involved in biological processes, yet functional analyses of a large number of proteins produced by AS remain to be performed. Functional analyses of these proteins by experiments are time-consuming, and therefore, a computational approach that can estimate effect of AS on proteins is required. We have developed a pipeline that can systematically detect AS regions, which are defined as protein regions modified by alternatively spliced exon, using genomic sequences and full-length transcripts data. The pipeline further assigned AS regions to protein three-dimensional structures and can estimate effects of AS on protein conformation stability and functional sites. We analyzed human AS regions using our pipeline and found that about half of AS regions fell into a size shorter than 100 amino acid residues. We, then, assessed the relationship between AS regions and protein structural domains and found that about 40% of AS regions were placed within a domain and the ratio of AS regions corresponding to domains was only about 10%. This result suggests that AS regulates protein function through alteration of segments within a domain rather than through switching protein domains. We will discuss how AS regulates protein function through alteration of segments within a domain.