Evidence of functional selection pressure for alternative splicing events that accelerate evolution of protein subsequences
- Molecular Biology Institute, Center for Genomics and Proteomics, Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095
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Edited by Samuel Karlin, Stanford University, Stanford, CA, and approved July 1, 2005 (received for review February 11, 2005)
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 that this mechanism could produce adaptive benefit. Here, we use 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 by genomewide analyses of human, chimpanzee, mouse, and rat. These data show that alternative splicing relaxes Ka/Ks selection pressure up to 7-fold, but intriguingly 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.
Footnotes
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↵ * To whom correspondence should be addressed. E-mail: leec{at}mbi.ucla.edu.
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This paper results from the Arthur M. Sackler Colloquium of the National Academy of Sciences, “Frontiers in Bioinformatics: Unsolved Problems and Challenges,” held October 15-17, 2004, at the Arnold and Mabel Beckman Center of the National Academies of Sciences and Engineering in Irvine, CA. Papers from this Colloquium will be available as a collection on the PNAS web site. See the introduction to this Colloquium on page 13355. The complete program is available on the NAS web site at www.nasonline.org/bioinformatics.
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This paper was submitted directly (Track II) to the PNAS office.
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Abbreviation: My, million years.
- Copyright © 2005, The National Academy of Sciences
