 |
|
 |
|
Monday Seminar: Oct. 2, Chris Lee of UCLA on "How alternative splicing helped build the genome: exon creation, locally accelerated sequence evolution, and the production of new tissue-specific functions"4pm in Biosciences West (map), Room 301 Host: Joanna Monti-Masel Visit Chris Lee's website |
|
Talk Abstract Recently, it was proposed that alternative splicing may act as a mechanism for opening accelerated paths of evolution, by reducing negative selection pressure. What fraction of new gene features is attributable to such a mechanism, and how can we assess whether they are biologically functional? To answer these questions, we have analyzed metrics of very different types of evolutionary selection pressures (e.g. against amino acid mutations (Ka/Ks); against mutations at synonymous sites (Ks); and for protein reading- frame preservation: exons that are anexact multiple of 3nt in length can be spliced in or out without affecting the downstream protein reading frame) to address this question via genome-wide analyses of human, chimpanzee, mouse, and rat. These data show that alternative splicing relaxes Ka/Ksselection pressure up to seven-fold, but intriguingly that this effect is accompanied by a strong increasein 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. Analysis of microarray data for 3126 alternatively spliced exons across 10 mouse tissues generated by Pan and coworkers reveals that frame-preserving exons are strongly associated with tissue-specific regulation of alternative splicing. Exons that are alternatively spliced at uniformly high transcript inclusion levels or uniformly low levels show no preference for protein frame-preservation. In contrast, alternatively spliced exons with dramatic changes of inclusion levels across mouse tissues (referred to as “tissue-switched” exons) are both strikingly biased to be frame-preserving, and are strongly conserved between human and mouse. |
email the department 
email EEB tech support
email the webmaster EEB Help 
Search EEB
About EEB All contents copyright © 2003-2006 Arizona Board of Regents. All rights reserved. |