Alternative splicing greatly expands the proteome of many organisms (~74% of multi-exon human genes undergo alternative splicing). Splicing is disrupted in ~15% of genetic diseases. Alternative splicing involves a choice among competing splice sites, and is mediated by cis-acting regulatory signals in pre-mRNAs. These signals can lie within exons or introns, and can enhance or silence splicing. The regulation of tissue-specific alternative splicing is understood only in isolated cases, and few motifs are known to function in multiple genes. Based on microarray measurements of splice-junction usage across 49 human tissues, we identified sets of splice junctions with mutually similar tissue-dependent splicing patterns. Using a Gibbs motif sampling approach, we sought motifs enriched in the neighboring RNA sequences. Through analysis of positional preferences and conservation with mouse, we validated new human tissue-dependent splice-regulatory motifs.
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