Identification of Common Genetic Variation That Modulates Alternative Splicing. Export

@article{hull:2007, abstract = {Alternative splicing of genes is an efficient means of generating variation in protein function. Several disease states have been associated with rare genetic variants that affect splicing patterns. Conversely, splicing efficiency of some genes is known to vary between individuals without apparent ill effects. What is not clear is whether commonly observed phenotypic variation in splicing patterns, and hence potential variation in protein function, is to a significant extent determined by naturally occurring DNA sequence variation and in particular by single nucleotide polymorphisms (SNPs). In this study, we surveyed the splicing patterns of 250 exons in 22 individuals who had been previously genotyped by the International HapMap Project. We identified 70 simple cassette exon alternative splicing events in our experimental system; for six of these, we detected consistent differences in splicing pattern between individuals, with a highly significant association between splice phenotype and neighbouring SNPs. Remarkably, for five out of six of these events, the strongest correlation was found with the SNP closest to the intron-exon boundary, although the distance between these SNPs and the intron-exon boundary ranged from 2 bp to greater than 1,000 bp. Two of these SNPs were further investigated using a minigene splicing system, and in each case the SNPs were found to exert cis-acting effects on exon splicing efficiency in vitro. The functional consequences of these SNPs could not be predicted using bioinformatic algorithms. Our findings suggest that phenotypic variation in splicing patterns is determined by the presence of SNPs within flanking introns or exons. Effects on splicing may represent an important mechanism by which SNPs influence gene function.}, author = {Hull, Jeremy and Campino, Susana and Rowlands, Kate and Chan, Man-Suen S. and Copley, Richard R. R. and Taylor, Martin S. S. and Rockett, Kirk and Elvidge, Gareth and Keating, Brendan and Knight, Julian and Kwiatkowski, Dominic}, citeulike-article-id = {1543418}, citeulike-linkout-0 = {http://dx.doi.org/10.1371/journal.pgen.0030099}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/17571926}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=17571926}, day = {15}, doi = {10.1371/journal.pgen.0030099}, issn = {1553-7404}, journal = {PLoS Genet}, keywords = {alternative, ceph, splicing}, month = {June}, number = {6}, posted-at = {2007-08-08 15:17:08}, priority = {0}, title = {Identification of Common Genetic Variation That Modulates Alternative Splicing.}, url = {http://dx.doi.org/10.1371/journal.pgen.0030099}, volume = {3}, year = {2007} }

TY - JOUR ID - hull:2007 L3 - citeulike-article-id:1543418 N2 - Alternative splicing of genes is an efficient means of generating variation in protein function. Several disease states have been associated with rare genetic variants that affect splicing patterns. Conversely, splicing efficiency of some genes is known to vary between individuals without apparent ill effects. What is not clear is whether commonly observed phenotypic variation in splicing patterns, and hence potential variation in protein function, is to a significant extent determined by naturally occurring DNA sequence variation and in particular by single nucleotide polymorphisms (SNPs). In this study, we surveyed the splicing patterns of 250 exons in 22 individuals who had been previously genotyped by the International HapMap Project. We identified 70 simple cassette exon alternative splicing events in our experimental system; for six of these, we detected consistent differences in splicing pattern between individuals, with a highly significant association between splice phenotype and neighbouring SNPs. Remarkably, for five out of six of these events, the strongest correlation was found with the SNP closest to the intron-exon boundary, although the distance between these SNPs and the intron-exon boundary ranged from 2 bp to greater than 1,000 bp. Two of these SNPs were further investigated using a minigene splicing system, and in each case the SNPs were found to exert cis-acting effects on exon splicing efficiency in vitro. The functional consequences of these SNPs could not be predicted using bioinformatic algorithms. Our findings suggest that phenotypic variation in splicing patterns is determined by the presence of SNPs within flanking introns or exons. Effects on splicing may represent an important mechanism by which SNPs influence gene function. IS - 6 JF - PLoS Genet SN - 1553-7404 TI - Identification of Common Genetic Variation That Modulates Alternative Splicing. VL - 3 KW - alternative KW - ceph KW - splicing AU - Hull, Jeremy AU - Campino, Susana AU - Rowlands, Kate AU - Chan, Man-Suen AU - Copley, Richard AU - Taylor, Martin AU - Rockett, Kirk AU - Elvidge, Gareth AU - Keating, Brendan AU - Knight, Julian AU - Kwiatkowski, Dominic PY - 2007/06/15/ UR - http://dx.doi.org/10.1371/journal.pgen.0030099 ER -