Abstract
BackgroundParent-of-origin-dependent expression of alleles, imprinting, has been suggested to impact a substantial proportion of mammalian genes. Its discovery requires allele-specific detection of expressed transcripts, but in some cases detected allelic expression bias has been interpreted as imprinting without demonstrating compatible transmission patterns and excluding heritable variation. Therefore, we utilized a genome-wide tool exploiting high density genotyping arrays in parallel measurements of genotypes in RNA and DNA to determine allelic expression across the transcriptome in lymphoblastoid cell lines (LCLs) and skin fibroblasts derived from families.ResultsWe were able to validate 43% of imprinted genes with previous demonstration of compatible transmission patterns in LCLs and fibroblasts. In contrast, we only validated 8% of genes suggested to be imprinted in the literature, but without clear evidence of parent-of-origin-determined expression. We also detected five novel imprinted genes and delineated regions of imprinted expression surrounding annotated imprinted genes. More subtle parent-of-origin-dependent expression, or partial imprinting, could be verified in four genes. Despite higher prevalence of monoallelic expression, immortalized LCLs showed consistent imprinting in fewer loci than primary cells. Random monoallelic expression has previously been observed in LCLs and we show that random monoallelic expression in LCLs can be partly explained by aberrant methylation in the genome.ConclusionsOur results indicate that widespread parent-of-origin-dependent expression observed recently in rodents is unlikely to be captured by assessment of human cells derived from adult tissues where genome-wide assessment of both primary and immortalized cells yields few new imprinted loci.
Highlights
Parent-of-origin-dependent expression of alleles, imprinting, has been suggested to impact a substantial proportion of mammalian genes
Validated imprinting in lymphoblast cell lines and fibroblasts First, we assessed the level of evidence for non-overlapping genes suggested to be imprinted (Catalogue of Parent of Origin Effects [24]), looking for demonstration of monoallelic expression with parent-of-origin-specific transmission in at least one pedigree
We were able to assess 73% of the confirmed imprinted genes (32 of 44) in either lymphoblasts or fibroblasts (Table 1; Table S1 in Additional file 1), as 12 loci were uninformative in our analysis (Table S2 in Additional file 1)
Summary
Parent-of-origin-dependent expression of alleles, imprinting, has been suggested to impact a substantial proportion of mammalian genes. Most mammalian autosomal genes are thought to be expressed co-dominantly from the two parental chromosomes. The allele inherited from one parent is suppressed through epigenetic mechanisms. This monoallelic expression, referred to as imprinting, leads to genetic vulnerability that can contribute to rare monogenic syndromes, such as Angelman and PraderWilli syndromes [1]. Classical imprinting of a there is no global explanation for the role of imprinting in mammalian development and physiology, a parental conflict over the distribution of resources to offspring theory has been hypothesized [4], and reviewed in [5]. Since not all imprinted genes are involved in development or growth and imprinting, they have likely evolved more than once [7]
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