RNA Bioinformatics

This is an interesting study by Ken Wolfe group.

Mol Biol Evol. 2005 Jul 27 [Epub ahead of print]
Changes in Alternative Splicing of Human and Mouse Genes are Accompanied by Faster Evolution of Constitutive Exons.

Cusack BP, Wolfe KH.

Department of Genetics, Smurfit Institute, University of Dublin, Trinity College, Dublin 2, Ireland.

Alternative splicing is known to be an important source of protein sequence variation, but its evolutionary impact has not been explored in detail. Studying alternative splicing requires extensive sampling of the transcriptome, but new datasets based on ESTs aligned to chromosomes make it possible to study alternative splicing on a genome-wide scale. Although genes showing alternative splicing by exon skipping are conserved as compared to the genome as a whole, we find that genes where structural differences between human and mouse result in genome-specific alternatively spliced exons in one species show almost 60% greater non-synonymous divergence in constitutive exons than genes where exon skipping is conserved. This effect is also seen for genes showing species-specific patterns of alternative splicing where gene structure is conserved. Our observations are not attributable to an inherent difference in rate of evolution between these two sets of proteins, or to differences with respect to predictors of evolutionary rate such as expression level, tissue specificity or genetic redundancy. Where genome-specific alternatively spliced exons are seen in mammals, the vast majority of skipped exons appear to be recent additions to gene structures. Furthermore, among genes with genome-specific alternatively spliced exons, the degree of non-synonymous divergence in constitutive sequence is a function of the frequency of incorporation of these alternative exons into transcripts. These results suggest that alterations in alternative splicing pattern can have knock-on effects in terms of accelerated sequence evolution in constant regions of the protein.

In my view the main messege of this paper is that accelerated gene structure evolution and accelerate nonsynonymous divergence is correlated.

8/12-9/10: from Los Angeles to China
8/24-8/29: from my hometown to Beijing

8/25: Invited Talk, Institute of Genetics, Chinese Academy of Sciences

Click for more information.

Xing and Lee 2005, Bioinformatics

Summary: Recently, the Ka/Ks ratio test, which assesses the protein-coding potentials of genomic regions based on their nonsynonymous to synonymous divergence rates, has been proposed and successfully used in genome annotations of eukaryotes. In this manuscript we systematically performed the Ka/Ks ratio test on 925 transcript-confirmed alternatively spliced exons in the human genome. We found that 22.3% of evolutionarily conserved alternatively spliced exons cannot pass the Ka/Ks ratio test, compared to 9.8% for constitutive exons. The false negative rate was the highest (85.7%) for exons with low frequencies of transcript inclusion. Analyses of alternatively spliced exons supported by full-length mRNA sequences yielded similar results, and nearly half of exons involved in ancestral alternative splicing events couldn’t pass this test. Our analysis suggests a future direction to incorporate comparative genomics-based alternative splicing predictions with the Ka/Ks ratio test in higher eukaryotes with extensive RNA alternative splicing.

Contact: Christopher Lee (leec@mbi.ucla.edu)

Click here to access the fulltext at Bioinformatics.

By the way, Chris Burge group's UNCOVER paper reported a similar finding on a set of ancestral alternative exons. See their supplemental material.

I am in Shanghai for 5 days. Tomorrow I'll travel to my hometown (Hefei). On August 23rd I'll travel to Beijing for a couple of invited talks. It's good to spend my summer vacation in China :).

I renewed my visa in US Consulate in Shanghai on August 16th after a 30-sec interview :). So I'll return to Los Angeles on September 10, as planned.