![]() If this process is not properly defined, transcripts encoding altered amino acid sequences or premature stop codons can be produced. Apart from the splice sites, pre-mRNAs contain exonic and intronic sequences that interact with different splicing factors to regulate how often each exon is included in the final transcript ( Wang and Burge, 2008). These boundaries consist of highly-conserved splice site sequences including intronic and exonic nucleotides. To carry out the splicing reaction, exon-intron boundaries in the pre-mRNA must be correctly identified. Pre-mRNA splicing is a regulated step in eukaryotic gene expression in which introns are removed from primary transcripts and exons are joined together to form mature mRNAs that are subsequently exported to the cytoplasm for translation ( Braunschweig et al., 2013). These results provide a resource for prioritising synonymous and other variants as disease-causing mutations. Therefore, mutations that affect splicing are not evenly distributed across primary transcripts but are focussed in and around alternatively spliced exons with intermediate inclusion levels. This is true for both exonic and intronic mutations as well as for perturbations in trans. Here, by performing deep mutagenesis of highly-included exons and by analysing the association between genome sequence variation and exon inclusion across the transcriptome, we report that mutations only very rarely alter the inclusion of highly-included exons. However, most exons expressed in any cell are highly-included in mature mRNAs. Genetic analyses and systematic mutagenesis have revealed that synonymous, non-synonymous and intronic mutations frequently alter the inclusion levels of alternatively spliced exons, consistent with the concept that altered splicing might be a common mechanism by which mutations cause disease.
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