Evidence of functional selection pressure for alternative splicingevents that accelerate evolution of protein subsequences |
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Authors: | Yi?Xing Email author" target="_blank">Christopher?LeeEmail author |
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Institution: | (1) Molecular Biology Institute, Center for Genomics and Proteomics, Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095-1570, USA |
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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. |
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