heritability in the efficiency of nonsense-mediated mrna decay in humans遗传在人类nonsense-mediated mrna的效率衰减.pdfVIP

Heritability in the Efficiency of Nonsense-Mediated mRNA Decay in Humans Cathal Seoighe1,2*, Chris Gehring3 1 School of Mathematics, Statistics and Applied Mathematics, National University of Ireland Galway, Galway, Ireland, 2 Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa, 3 Computational Bioscience Research Centre, King Abdullah University of Science and Technology, Thuwal, Kingdom of Saudi Arabia 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 int