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DNA methylation profiling of uniparental disomy cases provides a map of parental epigenetic bias in the human genome

DNA methylation profiling of uniparental disomy cases provides a map of parental epigenetic bias in the human genome
DNA methylation profiling of uniparental disomy cases provides a map of parental epigenetic bias in the human genome
Genomic imprinting is a mechanism in which gene expression varies depending on parental origin. Imprinting occurs through differential epigenetic marks on the two parental alleles, with most imprinted loci marked by the presence of differentially methylated regions (DMRs). To identify sites of parental epigenetic bias, here we have profiled DNA methylation patterns in a cohort of 57 individuals with uniparental disomy (UPD) for 19 different chromosomes, defining imprinted DMRs as sites where the maternal and paternal methylation levels diverge significantly from the biparental mean. Using this approach we identified 77 DMRs, including nearly all those described in previous studies, in addition to 34 DMRs not previously reported. These include a DMR at TUBGCP5 within the recurrent 15q11.2 microdeletion region, suggesting potential parent-of-origin effects associated with this genomic disorder. We also observed a modest parental bias in DNA methylation levels at every CpG analysed across ~1.9Mb of the 15q11-q13 Prader-Willi/Angelman syndrome region, demonstrating that the influence of imprinting is not limited to individual regulatory elements such as CpG islands, but can extend across entire chromosomal domains. Using RNAseq data we detected signatures consistent with imprinted expression associated with nine novel DMRs. Finally, using a population sample of 4,004 blood methylomes we define patterns of epigenetic variation at DMRs, identifying rare individuals with global gain or loss of methylation across multiple imprinted loci. Our data provide a detailed map of parental epigenetic bias in the human genome, providing insights into potential parent-of-origin effects
0002-9297
555-566
Joshi, R.S.
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Garg, P.
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Zaitlen, N.
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Lappalainen, T.
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Watson, C.
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Azam, N.
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Ho, D.H.
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Li, Xin
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Antonarakis, S.
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Brunner, Han
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Buiting, K.
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Cheung, S.W.
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Coffee, B.
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Eggermann, T.
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Francis, D.
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Geraedts, J.
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Gimelli, G.
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Jacobson, S.
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Le Caignec, C.
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de Leeuw, N.
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Liehr, T.
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Mackay, Deborah
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Montgomery, S.
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Pagnamenta, A.
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Papenhausen, P.
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Robinson, D.
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Ruivenkamp, C.
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Schwartz, C.
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Steiner, B.
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Stevenson, D.
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Surti, U.
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Wassink, T.
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Sharp, A.J.
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Joshi, R.S.
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Garg, P.
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Zaitlen, N.
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Lappalainen, T.
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Watson, C.
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Azam, N.
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Ho, D.H.
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Li, Xin
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Antonarakis, S.
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Brunner, Han
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Buiting, K.
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Cheung, S.W.
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Coffee, B.
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Eggermann, T.
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Francis, D.
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Geraedts, J.
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Gimelli, G.
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Jacobson, S.
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Le Caignec, C.
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de Leeuw, N.
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Liehr, T.
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Mackay, Deborah
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Montgomery, S.
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Pagnamenta, A.
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Papenhausen, P.
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Robinson, D.
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Ruivenkamp, C.
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Schwartz, C.
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Steiner, B.
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Stevenson, D.
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Surti, U.
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Wassink, T.
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Sharp, A.J.
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Joshi, R.S., Garg, P., Zaitlen, N., Lappalainen, T., Watson, C., Azam, N., Ho, D.H., Li, Xin, Antonarakis, S., Brunner, Han, Buiting, K., Cheung, S.W., Coffee, B., Eggermann, T., Francis, D., Geraedts, J., Gimelli, G., Jacobson, S., Le Caignec, C., de Leeuw, N., Liehr, T., Mackay, Deborah, Montgomery, S., Pagnamenta, A., Papenhausen, P., Robinson, D., Ruivenkamp, C., Schwartz, C., Steiner, B., Stevenson, D., Surti, U., Wassink, T. and Sharp, A.J. (2016) DNA methylation profiling of uniparental disomy cases provides a map of parental epigenetic bias in the human genome. The American Journal of Human Genetics, 99 (3), 555-566. (doi:10.1016/j.ajhg.2016.06.032).

Record type: Article

Abstract

Genomic imprinting is a mechanism in which gene expression varies depending on parental origin. Imprinting occurs through differential epigenetic marks on the two parental alleles, with most imprinted loci marked by the presence of differentially methylated regions (DMRs). To identify sites of parental epigenetic bias, here we have profiled DNA methylation patterns in a cohort of 57 individuals with uniparental disomy (UPD) for 19 different chromosomes, defining imprinted DMRs as sites where the maternal and paternal methylation levels diverge significantly from the biparental mean. Using this approach we identified 77 DMRs, including nearly all those described in previous studies, in addition to 34 DMRs not previously reported. These include a DMR at TUBGCP5 within the recurrent 15q11.2 microdeletion region, suggesting potential parent-of-origin effects associated with this genomic disorder. We also observed a modest parental bias in DNA methylation levels at every CpG analysed across ~1.9Mb of the 15q11-q13 Prader-Willi/Angelman syndrome region, demonstrating that the influence of imprinting is not limited to individual regulatory elements such as CpG islands, but can extend across entire chromosomal domains. Using RNAseq data we detected signatures consistent with imprinted expression associated with nine novel DMRs. Finally, using a population sample of 4,004 blood methylomes we define patterns of epigenetic variation at DMRs, identifying rare individuals with global gain or loss of methylation across multiple imprinted loci. Our data provide a detailed map of parental epigenetic bias in the human genome, providing insights into potential parent-of-origin effects

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Accepted/In Press date: 28 June 2016
e-pub ahead of print date: 24 August 2016
Published date: September 2016
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 398596
URI: http://eprints.soton.ac.uk/id/eprint/398596
ISSN: 0002-9297
PURE UUID: 73c59738-0071-419e-b2de-4990dccaf5a5
ORCID for Deborah Mackay: ORCID iD orcid.org/0000-0003-3088-4401

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Date deposited: 28 Jul 2016 12:31
Last modified: 07 Oct 2020 05:13

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Contributors

Author: R.S. Joshi
Author: P. Garg
Author: N. Zaitlen
Author: T. Lappalainen
Author: C. Watson
Author: N. Azam
Author: D.H. Ho
Author: Xin Li
Author: S. Antonarakis
Author: Han Brunner
Author: K. Buiting
Author: S.W. Cheung
Author: B. Coffee
Author: T. Eggermann
Author: D. Francis
Author: J. Geraedts
Author: G. Gimelli
Author: S. Jacobson
Author: C. Le Caignec
Author: N. de Leeuw
Author: T. Liehr
Author: Deborah Mackay ORCID iD
Author: S. Montgomery
Author: A. Pagnamenta
Author: P. Papenhausen
Author: D. Robinson
Author: C. Ruivenkamp
Author: C. Schwartz
Author: B. Steiner
Author: D. Stevenson
Author: U. Surti
Author: T. Wassink
Author: A.J. Sharp

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