Heritability of alternative splicing in the human genome Export

@article{kwan07, abstract = {Alternative pre-mRNA splicing increases proteomic diversity and provides a potential mechanism underlying both phenotypic diversity and susceptibility to genetic disorders in human populations. To investigate the variation in splicing among humans on a genome-wide scale, we use a comprehensive exon-targeted microarray to examine alternative splicing in lymphoblastoid cell lines (LCLs) derived from the CEPH HapMap population. We show the identification of transcripts containing sequence verified exon skipping, intron retention, and cryptic splice site usage that are specific between individuals. A number of novel alternative splicing events with no previous annotations in either the RefSeq and EST databases were identified, indicating that we are able to discover de novo splicing events. Using family-based linkage analysis, we demonstrate Mendelian inheritance and segregation of specific splice isoforms with regulatory haplotypes for three genes: OAS1, CAST, and CRTAP. Allelic association was further used to identify individual SNPs or regulatory haplotype blocks linked to the alternative splicing event, taking advantage of the high-resolution genotype information from the CEPH HapMap population. In one candidate, we identified a regulatory polymorphism that disrupts a 5' splice site of an exon in the CAST gene, resulting in its exclusion in the mutant allele. This report illustrates that our approach can detect both annotated and novel alternatively spliced variants, and that such variation among individuals is heritable and genetically controlled. 10.1101/gr.6281007}, author = {Kwan, Tony and Benovoy, David and Dias, Christel and Gurd, Scott and Serre, David and Zuzan, Harry and Clark, Tyson A. and Schweitzer, Anthony and Staples, Michelle K. and Wang, Hui and Blume, John E. and Hudson, Thomas J. and Sladek, Rob and Majewski, Jacek}, citeulike-article-id = {1529962}, citeulike-linkout-0 = {http://dx.doi.org/10.1101/gr.6281007}, citeulike-linkout-1 = {http://www.genome.org/cgi/content/abstract/17/8/1210}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/17671095}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=17671095}, day = {1}, doi = {10.1101/gr.6281007}, journal = {Genome Res.}, keywords = {affy, exonarray, splice, transcriptomic}, month = {August}, number = {8}, pages = {1210--1218}, posted-at = {2008-04-24 10:03:27}, priority = {2}, title = {Heritability of alternative splicing in the human genome}, url = {http://dx.doi.org/10.1101/gr.6281007}, volume = {17}, year = {2007} }

TY - JOUR ID - kwan07 L3 - citeulike-article-id:1529962 N2 - Alternative pre-mRNA splicing increases proteomic diversity and provides a potential mechanism underlying both phenotypic diversity and susceptibility to genetic disorders in human populations. To investigate the variation in splicing among humans on a genome-wide scale, we use a comprehensive exon-targeted microarray to examine alternative splicing in lymphoblastoid cell lines (LCLs) derived from the CEPH HapMap population. We show the identification of transcripts containing sequence verified exon skipping, intron retention, and cryptic splice site usage that are specific between individuals. A number of novel alternative splicing events with no previous annotations in either the RefSeq and EST databases were identified, indicating that we are able to discover de novo splicing events. Using family-based linkage analysis, we demonstrate Mendelian inheritance and segregation of specific splice isoforms with regulatory haplotypes for three genes: OAS1, CAST, and CRTAP. Allelic association was further used to identify individual SNPs or regulatory haplotype blocks linked to the alternative splicing event, taking advantage of the high-resolution genotype information from the CEPH HapMap population. In one candidate, we identified a regulatory polymorphism that disrupts a 5' splice site of an exon in the CAST gene, resulting in its exclusion in the mutant allele. This report illustrates that our approach can detect both annotated and novel alternatively spliced variants, and that such variation among individuals is heritable and genetically controlled. 10.1101/gr.6281007 IS - 8 JF - Genome Res. EP - 1218 TI - Heritability of alternative splicing in the human genome VL - 17 SP - 1210 KW - affy KW - exonarray KW - splice KW - transcriptomic AU - Kwan, Tony AU - Benovoy, David AU - Dias, Christel AU - Gurd, Scott AU - Serre, David AU - Zuzan, Harry AU - Clark, Tyson AU - Schweitzer, Anthony AU - Staples, Michelle AU - Wang, Hui AU - Blume, John AU - Hudson, Thomas AU - Sladek, Rob AU - Majewski, Jacek PY - 2007/08/01/ UR - http://dx.doi.org/10.1101/gr.6281007 ER -