Alternative splicing: Protein impact and genome evolution.

摘要

Alternative splicing has emerged as an increasingly important contributor to genomic complexity and gene function. Unlike prokaryotic genomes, which do not undergo alternative splicing, eukaryotic genomes utilize this mechanism as a tool for increasing the number of unique transcripts encoded by a single gene. In the human genome more than 30,000 alternative splice relationships have been identified from expressed sequence tags (ESTs) and mRNA sequences mapped onto genomic sequence, approximately doubling the number of transcript forms expected from the estimated 32,000 genes. Confronted with so many new splice forms from high-throughput EST sequencing, it is natural to ask whether these splice forms are functional, and if so, how they contribute to the regulation of gene function.; We have constructed a database of Alternatively Spliced Protein isoforms (ASP database) to assess the impact of alternative splicing on the human proteome. We identified 50 protein domain types that were selectively removed by alternative splicing at much higher frequencies than average. Our bioinformatics analysis indicates that a major impact of alternative splicing is removal of protein-protein interaction domains that mediate key linkages in protein interaction networks.; We evaluated the role of alternative splicing in mammalian evolution by measuring the fraction of alternatively spliced single exonskips that preserve protein reading frame in five eukaryotic genomes (human, mouse, rat, zebrafish and Drosophila). We observed an association between conserved, orthologous alternative splicing events and increased selection pressure for protein frame-preservation. This effect became stronger as a function of decreasing exon inclusion level; for alternatively spliced exons that were included in a majority of the gene's transcripts, the frame-preservation bias was no higher than that of constitutive exons, whereas for alternatively spliced exons that were included in only a minority of the gene's transcripts, the frame-preservation bias increased newly 20-fold. These data indicate that a subpopulation of modern alternative splicing events was present in the common ancestors of these genomes, and was under functional selection pressure to preserve the protein reading frame.