As a service to the research community, Genome Biology used to publish non-peer-reviewed articles in a 'preprint' depository to which any research can be submitted and which all individuals can access free of charge.From January 2006 Genome Biology no longer publishes new articles in this section. Any article could be submitted by authors, who have sole responsibility for the article's content. The only screening process is to ensure relevance of the preprint to Genome Biology's scope and to avoid abusive, libellous or indecent articles. Articles in this section of the journal have not been peer-reviewed. Each preprint has a permanent URL, by which it can be cited. Research submitted to the preprint depository may be simultaneously or subsequently submitted to Genome Biology or any other publication for peer review; the only requirement is an explicit citation of, and link to, the preprint in the article that is eventually published. If possible, Genome Biology will provide a reciprocal link from the preprint depository to the published article.

Deposited research article

Evidence of functional selection pressure for alternative splicing events that accelerate evolution of protein subsequences

Yi Xing and Christopher Lee

Molecular Biology Institute, Center for Genomics and Proteomics, Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles,CA 90095-1570, USA

author email corresponding author email

Genome Biology 2005, 6:P8doi:10.1186/gb-2005-6-5-p8

Published:	11 April 2005

This was the first version of this article to be made available publicly.

Subject areas: Genome studies, Bioinformatics, Evolution, Molecular biology

Abstract

Recently, it was proposed that alternative splicing may act as a mechanism for opening accelerated paths of evolution, by reducing negative selection pressure, but there has been little evidence so far whether this could produce adaptive benefit. Here we employ metrics of very different types of selection pressures (e.g. against amino acid mutations (Ka/Ks); against mutations at synonymous sites (Ks); and for protein reading-frame preservation) to address this question via genome-wide analyses of human, chimpanzee, mouse, and rat. These data show that alternative splicing relaxes Ka/Ks selection pressure up to seven-fold, but intriguingly that this effect is accompanied by a strong increase in selection pressure against synonymous mutations, which propagates into the adjacent intron, and correlates strongly with the alternative splicing level observed for each exon. These effects are highly local to the alternatively spliced exon. Comparisons of these four genomes consistently show an increase in the density of amino acid mutations (Ka) in alternatively spliced exons, and a decrease in the density of synonymous mutations (Ks). This selection pressure against synonymous mutations in alternatively spliced exons was accompanied in all four genomes by a striking increase in selection pressure for protein reading-frame preservation, and both increased markedly with increasing evolutionary age. Restricting our analysis to a subset of exons with strong evidence for biologically functional alternative splicing produced identical results. Thus alternative splicing apparently can create evolutionary “hotspots” within a protein sequence, and these events have evidently been selected for during mammalian evolution.