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Published online on August 25, 2005, 10.1073/pnas.0506139102 OPEN ACCESS ARTICLE


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Evolution
Sequence conservation, relative isoform frequencies, and nonsense-mediated decay in evolutionarily conserved alternative splicing

Daehyun Baek *{dagger} and Phil Green {dagger}{ddagger}

*Department of Bioengineering and {ddagger}Howard Hughes Medical Institute and Department of Genome Sciences, University of Washington, Box 357730, Seattle, WA 98195

Contributed by Phil Green, July 19, 2005

Studies of expressed sequence tag data sets have revealed large numbers of splicing variants for human genes, but it remains challenging to distinguish functionally important variants from aberrant splicing, clarify the nature of the alternative functions, and understand the signals that regulate splicing choices. To help address these issues, we have constructed and analyzed a large data set of 1,478 exon-skipping alternative splicing (AS) variants evolutionarily conserved in human and mouse. In about one-fifth of cases, one isoform appears subject to nonsense-mediated mRNA decay (NMD), supporting the idea that a major role of AS is to regulate gene expression; one-quarter of these NMD-inducing cases involve a conserved exon whose apparent sole purpose is to mediate destruction of the message when included. We explore sequence conservation likely related to splicing regulation, using in part a measure of the overall amount of conserved information in a sequence, and find that the increased conservation that has been observed within AS exons primarily affects synonymous sites, suggesting that regulatory signals significantly constrain synonymous substitution rates. We show that a lower frequency of the inclusion isoform relative to the exclusion isoform tends to be associated with weaker splice site signals, smaller exon size, and higher intronic sequence conservation, and provide evidence that all of these factors are under selection to control relative isoform frequencies. Some conserved instances of AS appear to represent aberrant splicing events that by chance have occurred in both species, and we develop a nonparametric likelihood approach to identify these.

Author contributions: D.B. and P.G. designed research; D.B. performed research; P.G. contributed new reagents/analytic tools; D.B. analyzed data; and D.B. and P.G. wrote the paper.

Freely available online through the PNAS open access option.

{dagger}To whom correspondence may be addressed.

Daehyun Baek, E-mail: baek{at}u.washington.edu
Phil Green, E-mail: phg{at}u.washington.edu

www.pnas.org/cgi/doi/10.1073/pnas.0506139102
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