Insights into imprinting from parent-of-origin phased methylomes and transcriptomes


Imprinting is the preferential expression of one parental allele over the other. It is controlled primarily through differential methylation of cytosine at CpG dinucleotides. Here we combine 285 methylomes and 11,617 transcriptomes from peripheral blood samples with parent-of-origin phased haplotypes, to produce a new map of imprinted methylation and gene expression patterns across the human genome. We demonstrate how imprinted methylation is a continuous rather than a binary characteristic. We describe at high resolution the parent-of-origin methylation pattern at the 15q11.2 Prader–Willi/Angelman syndrome locus, with nearly confluent stochastic paternal methylation punctuated by ‘spikes’ of maternal methylation. We find examples of polymorphic imprinted methylation unrelated (at VTRNA2-1 and PARD6G) or related (at CHRNE) to nearby SNP genotypes. We observe RNA isoform-specific imprinted expression patterns suggestive of a methylation-sensitive transcriptional elongation block. Finally, we gain new insights into parent-of-origin-specific effects on phenotypes at the DLK1/MEG3 and GNAS loci.

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Fig. 1: Overview of the study strategy.
Fig. 2: Ideogram showing the genomic locations of PofO-specific methylation (PofO-DMRs) and allele-specific expression (PofO-ASE).
Fig. 3: Mean methylation levels of PofO-DMRs in gametes, blood, and blastocysts.
Fig. 4: VTRNA2-1 PofO-DMR shows polymorphic imprinting whereas ZNF331 does not.
Fig. 5: Selected examples of imprinted loci.
Fig. 6: LINC00664 locus zoomed in (above) (chr19:21475770–21503852) and zoomed out (below) (chr19:20494411–21567958), showing a maternally methylated PofO-DMR at the LINC00664 promoter and preferential expression of the paternal allele.
Fig. 7: PofO-specific phenotypic associations and methylation at the DLK1/MEG3 and GNAS loci.

Data availability

We have made available data files with average methylation levels per CpG site (methylationFraction.tsv), P values for PofO-specific methylation per CpG site (PofO_ASM.tsv), and P values for PofO-specific expression per exonic SNP (PofO_ASE.tsv). Data are available at,


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This study was funded by deCODE genetics/AMGEN Inc.

Author information

F.Z., O.T.M., U.T., B.V.H., S.N.S., and K.S. designed the study and interpreted the results. D.N.M., N.J.W., T.J.M., O.T.M., and A.S. carried out the sequencing and genotyping. J.G., T.R., I.J., H.H., G.I.E., O.S., I.O., U.T., and S.N.S. assessed the participants and collected the data. F.Z., G.H.H., S.A.G., P.M., H.I., S.K., K.F.A., A.H., G.M., D.F.G., B.V.H., and S.N.S. carried out the statistical and bioinformatics analysis. F.Z., S.N.S., and K.S. drafted the manuscript. All authors contributed to the final version of the paper.

Correspondence to Simon N. Stacey or Kari Stefansson.

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All deCODE authors are employees of the biotechnology company deCODE genetics/AMGEN. N.J.W. and T.J.M. are employees of Cambridge Epigenetix Ltd. Cambridge Epigenetix Ltd retains the rights for diagnostic use of the oxBS-seq technology and receives royalties from the sale of oxBS kits under the terms of a partnership agreement with NuGEN Technologies.

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Zink, F., Magnusdottir, D.N., Magnusson, O.T. et al. Insights into imprinting from parent-of-origin phased methylomes and transcriptomes. Nat Genet 50, 1542–1552 (2018) doi:10.1038/s41588-018-0232-7

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