Genomic features defining exonic variants that modulate splicing

We assessed the features of single-nucleotide genomic variants verified to cause exon skipping and compared them to a large set of coding SNPs common in the human population, which are likely to have no effect on splicing. Our findings implicate a number of features important for their ability to discriminate splice-affecting variants, including the naturally occurring density of exonic splicing enhancers and exonic splicing silencers of the exon and intronic environment, extensive changes in the number of predicted exonic splicing enhancers and exonic splicing silencers, proximity to the splice junctions and evolutionary constraint of the region surrounding the variant. By extending this approach to additional datasets, we also identified relevant features of variants that cause increased exon inclusion and ectopic splice site activation.We identified a number of features that have statistically significant representation among exonic variants that modulate splicing. These analyses highlight putative mechanisms responsible for splicing outcome and emphasize the role of features important for exon definition. We developed a web-tool, Skippy, to score coding variants for these relevant splice-modulating features.The majority of genes in mammalian genomes are made up of multiple exons separated by much longer introns. To create a mature mRNA, exons must be identified accurately from within the transcript and then spliced together by removing the intervening introns. This process is carried out by a large complex of small nuclear RNAs and polypeptides known as the spliceosome. Disruption to the fidelity of splicing, particularly of exons that are constitutively spliced, can effectively inactivate a gene by creating unstable mRNAs and defective protein structure, or cause disease by disrupting the balance of expression of different splice isoforms [1]. The most important features for exon recognition are the splice junctions that define the boundaries of the exons, at w