Heritability in the efficiency of nonsense-mediated mRNA decay in humans

Handle URI:
http://hdl.handle.net/10754/325285
Title:
Heritability in the efficiency of nonsense-mediated mRNA decay in humans
Authors:
Seoighe, Cathal; Gehring, Christoph A. ( 0000-0003-4355-4591 )
Abstract:
Background: In eukaryotes mRNA transcripts of protein-coding genes in which an intron has been retained in the coding region normally result in premature stop codons and are therefore degraded through the nonsense-mediated mRNA decay (NMD) pathway. There is evidence in the form of selective pressure for in-frame stop codons in introns and a depletion of length three introns that this is an important and conserved quality-control mechanism. Yet recent reports have revealed that the efficiency of NMD varies across tissues and between individuals, with important clinical consequences. Principal Findings: Using previously published Affymetrix exon microarray data from cell lines genotyped as part of the International HapMap project, we investigated whether there are heritable, inter-individual differences in the abundance of intron-containing transcripts, potentially reflecting differences in the efficiency of NMD. We identified intronic probesets using EST data and report evidence of heritability in the extent of intron expression in 56 HapMap trios. We also used a genome-wide association approach to identify genetic markers associated with intron expression. Among the top candidates was a SNP in the DCP1A gene, which forms part of the decapping complex, involved in NMD. Conclusions: While we caution that some of the apparent inter-individual difference in intron expression may be attributable to different handling or treatments of cell lines, we hypothesize that there is significant polymorphism in the process of NMD, resulting in heritable differences in the abundance of intronic mRNA. Part of this phenotype is likely to be due to a polymorphism in a decapping enzyme on human chromosome 3. © 2010 Seoighe, Gehring.
KAUST Department:
Computational Bioscience Research Center (CBRC)
Citation:
Seoighe C, Gehring C (2010) Heritability in the Efficiency of Nonsense-Mediated mRNA Decay in Humans. PLoS ONE 5: e11657. doi:10.1371/journal.pone.0011657.
Publisher:
Public Library of Science (PLoS)
Journal:
PLoS ONE
Issue Date:
21-Jul-2010
DOI:
10.1371/journal.pone.0011657
PubMed ID:
20657766
PubMed Central ID:
PMC2908117
Type:
Article
ISSN:
19326203
Appears in Collections:
Articles; Computational Bioscience Research Center (CBRC)

Full metadata record

DC FieldValue Language
dc.contributor.authorSeoighe, Cathalen
dc.contributor.authorGehring, Christoph A.en
dc.date.accessioned2014-08-27T09:44:54Z-
dc.date.available2014-08-27T09:44:54Z-
dc.date.issued2010-07-21en
dc.identifier.citationSeoighe C, Gehring C (2010) Heritability in the Efficiency of Nonsense-Mediated mRNA Decay in Humans. PLoS ONE 5: e11657. doi:10.1371/journal.pone.0011657.en
dc.identifier.issn19326203en
dc.identifier.pmid20657766en
dc.identifier.doi10.1371/journal.pone.0011657en
dc.identifier.urihttp://hdl.handle.net/10754/325285en
dc.description.abstractBackground: In eukaryotes mRNA transcripts of protein-coding genes in which an intron has been retained in the coding region normally result in premature stop codons and are therefore degraded through the nonsense-mediated mRNA decay (NMD) pathway. There is evidence in the form of selective pressure for in-frame stop codons in introns and a depletion of length three introns that this is an important and conserved quality-control mechanism. Yet recent reports have revealed that the efficiency of NMD varies across tissues and between individuals, with important clinical consequences. Principal Findings: Using previously published Affymetrix exon microarray data from cell lines genotyped as part of the International HapMap project, we investigated whether there are heritable, inter-individual differences in the abundance of intron-containing transcripts, potentially reflecting differences in the efficiency of NMD. We identified intronic probesets using EST data and report evidence of heritability in the extent of intron expression in 56 HapMap trios. We also used a genome-wide association approach to identify genetic markers associated with intron expression. Among the top candidates was a SNP in the DCP1A gene, which forms part of the decapping complex, involved in NMD. Conclusions: While we caution that some of the apparent inter-individual difference in intron expression may be attributable to different handling or treatments of cell lines, we hypothesize that there is significant polymorphism in the process of NMD, resulting in heritable differences in the abundance of intronic mRNA. Part of this phenotype is likely to be due to a polymorphism in a decapping enzyme on human chromosome 3. © 2010 Seoighe, Gehring.en
dc.language.isoenen
dc.publisherPublic Library of Science (PLoS)en
dc.rightsSeoighe, Gehring. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en
dc.rightsArchived with thanks to PLoS ONEen
dc.subjectmessenger RNAen
dc.subjectDCP1A protein, humanen
dc.subjectribonucleaseen
dc.subjecttransactivator proteinen
dc.subjectbioinformaticsen
dc.subjectchromosome 3en
dc.subjectcontrolled studyen
dc.subjectexpressed sequence tagen
dc.subjectgene expressionen
dc.subjectgenetic associationen
dc.subjectgenetic markeren
dc.subjectgenotypeen
dc.subjecthaplotype mapen
dc.subjectheritabilityen
dc.subjectintronen
dc.subjectnonsense mediated mRNA decayen
dc.subjectphenotypeen
dc.subjectsingle nucleotide polymorphismen
dc.subjectDNA microarrayen
dc.subjectgeneticsen
dc.subjectRNA stabilityen
dc.subjectstop codonen
dc.subjectEukaryotaen
dc.subjectCodon, Nonsenseen
dc.subjectEndoribonucleasesen
dc.subjectExpressed Sequence Tagsen
dc.subjectGenome-Wide Association Studyen
dc.subjectGenotypeen
dc.subjectIntronsen
dc.subjectOligonucleotide Array Sequence Analysisen
dc.subjectRNA Stabilityen
dc.subjectTrans-Activatorsen
dc.titleHeritability in the efficiency of nonsense-mediated mRNA decay in humansen
dc.typeArticleen
dc.contributor.departmentComputational Bioscience Research Center (CBRC)en
dc.identifier.journalPLoS ONEen
dc.identifier.pmcidPMC2908117en
dc.eprint.versionPublisher's Version/PDFen
dc.contributor.institutionSchool of Mathematics, Statistics and Applied Mathematics, National University of Ireland Galway, Galway, Irelanden
dc.contributor.institutionInstitute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africaen
dc.contributor.affiliationKing Abdullah University of Science and Technology (KAUST)en
kaust.authorGehring, Christoph A.en

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