Abstract
The role of alternative splicing is one of the great unanswered questions in cellular biology. There is strong evidence for alternative splicing at the transcript level, and transcriptomics experiments show that many splice events are tissue specific. It has been suggested that alternative splicing evolved in order to remodel tissue-specific protein-protein networks. Here we investigated the evidence for tissue-specific splicing among splice isoforms detected in a large-scale proteomics analysis. Although the data supporting alternative splicing is limited at the protein level, clear patterns emerged among the small numbers of alternative splice events that we could detect in the proteomics data. More than a third of these splice events were tissue-specific and most were ancient: over 95% of splice events that were tissue-specific in both proteomics and RNAseq analyses evolved prior to the ancestors of lobe-finned fish, at least 400 million years ago. By way of contrast, three in four alternative exons in the human gene set arose in the primate lineage, so our results cannot be extrapolated to the whole genome. Tissue-specific alternative protein forms in the proteomics analysis were particularly abundant in nervous and muscle tissues and their genes had roles related to the cytoskeleton and either the structure of muscle fibres or cell-cell connections. Our results suggest that this conserved tissue-specific alternative splicing may have played a role in the development of the vertebrate brain and heart.
Highlights
Almost all multi-exon genes are able to undergo alternative splicing [1,2] via a range of mechanisms which include exon skipping, alternative splice site usage and alternative promoter and poly-A usage
We find that there is strong evidence for tissue-specific splicing at the protein level in a minority of genes, and that these tissue-specific protein isoforms are generally found in muscle or nervous tissues
We first used the peptides identified in the proteomics experiment to define the set of alternative splice events that would be used in the analysis
Summary
Almost all multi-exon genes are able to undergo alternative splicing [1,2] via a range of mechanisms which include exon skipping, alternative splice site usage and alternative promoter and poly-A usage This is reflected in the human reference set; at present human coding genes are annotated with an average of four distinct gene products [3]. Almost all of these transcripts are translated into functional alternative splice isoforms, we would expect the overall protein population to increase 10-fold from 20,000 (the number of human coding genes) to 200,000. This increase alone would have profound biological consequences. If we take into account all the possible interactions of these distinct proteins [6], we would be likely to see an exponential increase in the number of cellular functions
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