title: Determinants of the Usage of Splice-Associated cis-Motifs Predict the Distribution of Human Pathogenic SNPs.
abstract: Where in genes do pathogenic mutations tend to occur and does this provide clues as to the possible underlying mechanisms by which single nucleotide polymorphisms (SNPs) cause disease? As splice-disrupting mutations tend to occur predominantly at exon ends, known also to be hot spots of cis-exonic splice control elements, we examine the relationship between the relative density of such exonic cis-motifs and pathogenic SNPs. In particular, we focus on the intragene distribution of exonic splicing enhancers (ESE) and the covariance between them and disease-associated SNPs. In addition to showing that disease-causing genes tend to be genes with a high intron density, consistent with missplicing, five factors established as trends in ESE usage, are considered: relative position in exons, relative position in genes, flanking intron size, splice sites usage, and phase. We find that more than 76% of pathogenic SNPs are within 3-69 bp of exon ends where ESEs generally reside, this being 13% more than expected. Overall from enrichment of pathogenic SNPs at exon ends, we estimate that approximately 20-45% of SNPs affect splicing. Importantly, we find that within genes pathogenic SNPs tend to occur in splicing-relevant regions with low ESE density: they are found to occur preferentially in the terminal half of genes, in exons flanked by short introns and at the ends of phase (0,0) exons with 3' non-"AGgt" splice site. We suggest the concept of the "fragile" exon, one home to pathogenic SNPs owing to its vulnerability to splice disruption owing to low ESE density.
authors.affiliation: Milner Centre for Evolution, Department of Biology and Biochemistry, University of Bath, Bath, Somerset, United Kingdom.
authors.forename: XianMing
authors.initials: X
authors.lastname: Wu
authors.affiliation: Milner Centre for Evolution, Department of Biology and Biochemistry, University of Bath, Bath, Somerset, United Kingdom l.d.hurst@bath.ac.uk.
authors.forename: Laurence D
authors.initials: LD
authors.lastname: Hurst
mesh_terms: D004742:Enhancer Elements, Genetic; D005091:Exons; D020022:Genetic Predisposition to Disease; D006801:Humans; D007438:Introns; D009154:Mutation; D059372:Nucleotide Motifs; D016366:Open Reading Frames; D020641:Polymorphism, Single Nucleotide; D019655:Quantitative Trait, Heritable; D022821:RNA Splice Sites; D012326:RNA Splicing
chemical_list: D022821:RNA Splice Sites
keywords: exonic splicing enhancer; pathogenic SNPs; splice site; splicing cis-motif