Article

Deciphering the splicing code. Nature, 465, 53-59

Biomedical Engineering, Department of Electrical and Computer Engineering, University of Toronto, 10 King's College Road, Toronto M5S 3G4, Canada.
Nature (Impact Factor: 41.46). 05/2010; 465(7294):53-9. DOI: 10.1038/nature09000
Source: PubMed

ABSTRACT

Alternative splicing has a crucial role in the generation of biological complexity, and its misregulation is often involved in human disease. Here we describe the assembly of a 'splicing code', which uses combinations of hundreds of RNA features to predict tissue-dependent changes in alternative splicing for thousands of exons. The code determines new classes of splicing patterns, identifies distinct regulatory programs in different tissues, and identifies mutation-verified regulatory sequences. Widespread regulatory strategies are revealed, including the use of unexpectedly large combinations of features, the establishment of low exon inclusion levels that are overcome by features in specific tissues, the appearance of features deeper into introns than previously appreciated, and the modulation of splice variant levels by transcript structure characteristics. The code detected a class of exons whose inclusion silences expression in adult tissues by activating nonsense-mediated messenger RNA decay, but whose exclusion promotes expression during embryogenesis. The code facilitates the discovery and detailed characterization of regulated alternative splicing events on a genome-wide scale.

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    • "In recent years a number of technologies have been developed to characterize different features related to the gene translation and multiple roles of the coding sequence have been proposed. Recent studies suggested that the order of codons along the mRNA plays an important role in determining translation efficiency[4,91011. It was suggested that there is weak folding of mRNA molecule in the region surrounding the start codons910111213141516, and endogenous genes tend to perform strong mRNA folding in the region after the start codon[10,17,18], which can improve the fidelity of translation initiation [10,17,19,20]. "
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    • "Studies have shown that FIRs of alternative exons are enriched with splicing regulatory sequences and are evolutionarily conserved to a greater degree than FIRs of constitutive exons (Sorek & Ast, 2003; Barash et al, 2010), implying that they may contribute to the regulation of the precision of inclusion levels. To examine this role of FIR conservation, we focused on the cassette type of alternative exons and compiled a dataset of all human cassette exons (Table EV1). "

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    • "However, this question still holds since former studies have limited power. Thus in this study, we analyzed the alternative splicing dataset from Barash, Y. et al. (Barash et al., 2010) with mutual information based feature analysis to further address it. We observed that for different tissues, the preferred features vary to some extent. "

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