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. 2005 Sep 6;102(36):12813-8.
doi: 10.1073/pnas.0506139102. Epub 2005 Aug 25.

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

Daehyun Baek  1 , Phil Green
Affiliations

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

Daehyun Baek et al. Proc Natl Acad Sci U S A. .

Abstract

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.

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Figures

Fig. 1.
Fig. 1.
Sequence conservation in exons and splice site windows (20 bp comprising 5 exonic and 15 intronic bases flanking the site) (A) and effective number of conserved nucleotides in exonic synonymous sites and in 20-bp intronic region adjacent to splice site window (B) as a function of NMD status.
Fig. 2.
Fig. 2.
Synonymous (Ks) and nonsynonymous (Ka) substitution rates as a function of exonic position (A) and exon size (B) in filtered frame-preserving single-exon skipping AS exons and CS exons. In A, the horizontal scale represents fractional exonic position (displacement from 5′ end of exon, divided by exon size).
Fig. 3.
Fig. 3.
Effective number of conserved nucleotides (Nc) as a function of exon size in filtered frame-preserving single-exon skipping AS exons and CS exons.
Fig. 4.
Fig. 4.
Splice site score and exon size as a function of exclusion rate in filtered CS and frame-preserving single-exon skipping AS exons shorter than 200 bp.
Fig. 5.
Fig. 5.
Sequence conservation in splice sites and adjacent intronic 20-bp region, and effective number of intronic conserved nucleotides (Nc) as a function of exclusion rate in filtered CS and frame-preserving single-exon skipping AS exons.
Fig. 6.
Fig. 6.
Splice site score and sequence conservation as a function of exon size in filtered CS exons.
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