Genome-wide survey of allele-specific splicing in humans

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dc.contributor.authorNembaware, Victoriaen_ZA
dc.contributor.authorLupindo, Bukiween_ZA
dc.contributor.authorSchouest, Katherineen_ZA
dc.contributor.authorSpillane, Charlesen_ZA
dc.contributor.authorScheffler, Konraden_ZA
dc.contributor.authorSeoighe, Cathalen_ZA
dc.date.accessioned2015-10-28T07:01:15Z
dc.date.available2015-10-28T07:01:15Z
dc.date.issued2008en_ZA
dc.description.abstractBACKGROUND: Accurate mRNA splicing depends on multiple regulatory signals encoded in the transcribed RNA sequence. Many examples of mutations within human splice regulatory regions that alter splicing qualitatively or quantitatively have been reported and allelic differences in mRNA splicing are likely to be a common and important source of phenotypic diversity at the molecular level, in addition to their contribution to genetic disease susceptibility. However, because the effect of a mutation on the efficiency of mRNA splicing is often difficult to predict, many mutations that cause disease through an effect on splicing are likely to remain undiscovered. RESULTS: We have combined a genome-wide scan for sequence polymorphisms likely to affect mRNA splicing with analysis of publicly available Expressed Sequence Tag (EST) and exon array data. The genome-wide scan uses published tools and identified 30,977 SNPs located within donor and acceptor splice sites, branch points and exonic splicing enhancer elements. For 1,185 candidate splicing polymorphisms the difference in splicing between alternative alleles was corroborated by publicly available exon array data from 166 lymphoblastoid cell lines. We developed a novel probabilistic method to infer allele-specific splicing from EST data. The method uses SNPs and alternative mRNA isoforms mapped to EST sequences and models both regulated alternative splicing as well as allele-specific splicing. We have also estimated heritability of splicing and report that a greater proportion of genes show evidence of splicing heritability than show heritability of overall gene expression level. Our results provide an extensive resource that can be used to assess the possible effect on splicing of human polymorphisms in putative splice-regulatory sites. CONCLUSION: We report a set of genes showing evidence of allele-specific splicing from an integrated analysis of genomic polymorphisms, EST data and exon array data, including several examples for which there is experimental evidence of polymorphisms affecting splicing in the literature. We also present a set of novel allele-specific splicing candidates and discuss the strengths and weaknesses of alternative technologies for inferring the effect of sequence variants on mRNA splicing.en_ZA
dc.identifier.apacitationNembaware, V., Lupindo, B., Schouest, K., Spillane, C., Scheffler, K., & Seoighe, C. (2008). Genome-wide survey of allele-specific splicing in humans. <i>BMC Genomics</i>, http://hdl.handle.net/11427/14453en_ZA
dc.identifier.chicagocitationNembaware, Victoria, Bukiwe Lupindo, Katherine Schouest, Charles Spillane, Konrad Scheffler, and Cathal Seoighe "Genome-wide survey of allele-specific splicing in humans." <i>BMC Genomics</i> (2008) http://hdl.handle.net/11427/14453en_ZA
dc.identifier.citationNembaware, V., Lupindo, B., Schouest, K., Spillane, C., Scheffler, K., & Seoighe, C. (2008). Genome-wide survey of allele-specific splicing in humans. BMC genomics, 9(1), 265.en_ZA
dc.identifier.ris TY - Journal Article AU - Nembaware, Victoria AU - Lupindo, Bukiwe AU - Schouest, Katherine AU - Spillane, Charles AU - Scheffler, Konrad AU - Seoighe, Cathal AB - BACKGROUND: Accurate mRNA splicing depends on multiple regulatory signals encoded in the transcribed RNA sequence. Many examples of mutations within human splice regulatory regions that alter splicing qualitatively or quantitatively have been reported and allelic differences in mRNA splicing are likely to be a common and important source of phenotypic diversity at the molecular level, in addition to their contribution to genetic disease susceptibility. However, because the effect of a mutation on the efficiency of mRNA splicing is often difficult to predict, many mutations that cause disease through an effect on splicing are likely to remain undiscovered. RESULTS: We have combined a genome-wide scan for sequence polymorphisms likely to affect mRNA splicing with analysis of publicly available Expressed Sequence Tag (EST) and exon array data. The genome-wide scan uses published tools and identified 30,977 SNPs located within donor and acceptor splice sites, branch points and exonic splicing enhancer elements. For 1,185 candidate splicing polymorphisms the difference in splicing between alternative alleles was corroborated by publicly available exon array data from 166 lymphoblastoid cell lines. We developed a novel probabilistic method to infer allele-specific splicing from EST data. The method uses SNPs and alternative mRNA isoforms mapped to EST sequences and models both regulated alternative splicing as well as allele-specific splicing. We have also estimated heritability of splicing and report that a greater proportion of genes show evidence of splicing heritability than show heritability of overall gene expression level. Our results provide an extensive resource that can be used to assess the possible effect on splicing of human polymorphisms in putative splice-regulatory sites. CONCLUSION: We report a set of genes showing evidence of allele-specific splicing from an integrated analysis of genomic polymorphisms, EST data and exon array data, including several examples for which there is experimental evidence of polymorphisms affecting splicing in the literature. We also present a set of novel allele-specific splicing candidates and discuss the strengths and weaknesses of alternative technologies for inferring the effect of sequence variants on mRNA splicing. DA - 2008 DB - OpenUCT DO - 10.1186/1471-2164-9-265 DP - University of Cape Town J1 - BMC Genomics LK - https://open.uct.ac.za PB - University of Cape Town PY - 2008 T1 - Genome-wide survey of allele-specific splicing in humans TI - Genome-wide survey of allele-specific splicing in humans UR - http://hdl.handle.net/11427/14453 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/14453
dc.identifier.urihttp://dx.doi.org/10.1186/1471-2164-9-265
dc.identifier.vancouvercitationNembaware V, Lupindo B, Schouest K, Spillane C, Scheffler K, Seoighe C. Genome-wide survey of allele-specific splicing in humans. BMC Genomics. 2008; http://hdl.handle.net/11427/14453.en_ZA
dc.language.isoengen_ZA
dc.publisherBioMed Central Ltden_ZA
dc.publisher.departmentInstitute of Infectious Disease and Molecular Medicineen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.rightsThis is an Open Access article distributed under the terms of the Creative Commons Attribution Licenseen_ZA
dc.rights.holder2008 Nembaware et al; licensee BioMed Central Ltd.en_ZA
dc.rights.urihttp://creativecommons.org/licenses/by/2.0en_ZA
dc.sourceBMC Genomicsen_ZA
dc.source.urihttp://www.biomedcentral.com/bmcgenomics/en_ZA
dc.subject.otherAllelesen_ZA
dc.subject.otherExpressed Sequence Tagsen_ZA
dc.subject.otherenome, Humanen_ZA
dc.subject.otherRNA Splicingen_ZA
dc.subject.otherRNA, Messengeren_ZA
dc.titleGenome-wide survey of allele-specific splicing in humansen_ZA
dc.typeJournal Articleen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceArticleen_ZA
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