Evolutionarily conserved and diverged alternative splicing events show different expression and functional profiles

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Abstract
To better decipher the functional impact of alternative splicing, we classified alternative splicing events in 10 818 pairs of human and mouse genes based on conservation at genome and transcript levels. Expression levels of conserved alternative splices in human and mouse expressed sequence tag databases show strong correlation, indicating that alternative splicing is similarly regulated in both species. A total of 43% (8921) of mouse alternative splices could be found in the human genome but not in human transcripts. Five of eleven tested mouse predictions were observed in human tissues, demonstrating that mouse transcripts provide a valuable resource for identifying alternative splicing events in human genes. Combining gene-specific measures of conserved and diverged alternative splicing with both gene classification based on Gene Ontology (GO) and microarray-determined gene expression in 52 diverse human tissues and cell lines, we found conserved alternative splicing most enriched in brain-expressed signaling pathways. Diverged alternative splicing is more prevalent in testis and cancerous cell line up-regulated processes, including protein biosynthesis, responses to stress and responses to endogenous stimuli. Using conservation as a surrogate for functional significance, these results suggest that alternative splicing plays an important role in enhancing the functional capacity of central nervous systems, while non-functional splicing more frequently occurs in testis and cell lines, possibly as a result of cellular stress and rapid proliferation.