Abstract
BackgroundAlternative splicing increases protein diversity by generating multiple transcript isoforms from a single gene through different combinations of exons or through different selections of splice sites. It has been reported that RNA secondary structures are involved in alternative splicing. Here we perform a genomic study of RNA secondary structures around splice sites in humans (Homo sapiens), mice (Mus musculus), fruit flies (Drosophila melanogaster), and nematodes (Caenorhabditis elegans) to further investigate this phenomenon.ResultsWe observe that GC content around splice sites is closely associated with the splice site usage in multiple species. RNA secondary structure is the possible explanation, because the structural stability difference among alternative splice sites, constitutive splice sites, and skipped splice sites can be explained by the GC content difference. Alternative splice sites tend to be GC-enriched and exhibit more stable RNA secondary structures in all of the considered species. In humans and mice, splice sites of first exons and long exons tend to be GC-enriched and hence form more stable structures, indicating the special role of RNA secondary structures in promoter proximal splicing events and the splicing of long exons. In addition, GC-enriched exon-intron junctions tend to be overrepresented in tissue-specific alternative splice sites, indicating the functional consequence of the GC effect. Compared with regions far from splice sites and decoy splice sites, real splice sites are GC-enriched. We also found that the GC-content effect is much stronger than the nucleotide-order effect to form stable secondary structures.ConclusionAll of these results indicate that GC content is related to splice site usage and it may mediate the splicing process through RNA secondary structures.
Highlights
Alternative splicing increases protein diversity by generating multiple transcript isoforms from a single gene through different combinations of exons or through different selections of splice sites
Difference of pre-mRNA secondary structures between alternative, constitutive, and skipped splice sites It has been reported that stable RNA secondary structures are associated with alternative splicing events [16]
Since pre-mRNA sequences favor local structures rather than global ones in vivo [20], 70 nucleotides were added up- and down-stream of each splice site to predict the secondary structure by the free energy minimization program RNAfold [21,22]
Summary
Alternative splicing increases protein diversity by generating multiple transcript isoforms from a single gene through different combinations of exons or through different selections of splice sites. It has been reported that RNA secondary structures are involved in alternative splicing. It has been reported that local RNA secondary structures affect splice site selection through experimental observations from individual genes [8,9,10,11,12]. Patterson et al [13] reported that the splice site prediction can be improved by adding the localized pre-mRNA secondary structure information to the conventional sequence-based approaches. Shepard et al [16] discovered that stable and conserved pre-mRNA secondary structures around splice sites may promote alternative splicing to a large extent. All of these results indicate that the secondary structure of pre-mRNA is part of the mRNA splicing code [6,17,18]
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