Characterization of genome-methylome interactions in 22 nuclear pedigrees.

Genetic polymorphisms can shape the global landscape of DNA methylation, by either changing substrates for DNA methyltransferases or altering the DNA binding affinity of cis-regulatory proteins. The interactions between CpG methylation and genetic polymorphisms have been previously investigated by m...

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Autores principales:	Nongluk Plongthongkum, Kristel R van Eijk, Simone de Jong, Tina Wang, Jae Hoon Sul, Marco P M Boks, René S Kahn, Ho-Lim Fung, Roel A Ophoff, Kun Zhang
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f5d0effff05d4b79a19c8b1fd408af88
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spelling	oai:doaj.org-article:f5d0effff05d4b79a19c8b1fd408af882021-11-25T06:08:36ZCharacterization of genome-methylome interactions in 22 nuclear pedigrees.1932-620310.1371/journal.pone.0099313https://doaj.org/article/f5d0effff05d4b79a19c8b1fd408af882014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25019935/?tool=EBIhttps://doaj.org/toc/1932-6203Genetic polymorphisms can shape the global landscape of DNA methylation, by either changing substrates for DNA methyltransferases or altering the DNA binding affinity of cis-regulatory proteins. The interactions between CpG methylation and genetic polymorphisms have been previously investigated by methylation quantitative trait loci (mQTL) and allele-specific methylation (ASM) analysis. However, it remains unclear whether these approaches can effectively and comprehensively identify all genetic variants that contribute to the inter-individual variation of DNA methylation levels. Here we used three independent approaches to systematically investigate the influence of genetic polymorphisms on variability in DNA methylation by characterizing the methylation state of 96 whole blood samples in 52 parent-child trios from 22 nuclear pedigrees. We performed targeted bisulfite sequencing with padlock probes to quantify the absolute DNA methylation levels at a set of 411,800 CpG sites in the human genome. With mid-parent offspring analysis (MPO), we identified 10,593 CpG sites that exhibited heritable methylation patterns, among which 70.1% were SNPs directly present in methylated CpG dinucleotides. We determined the mQTL analysis identified 49.9% of heritable CpG sites for which regulation occurred in a distal cis-regulatory manner, and that ASM analysis was only able to identify 5%. Finally, we identified hundreds of clusters in the human genome for which the degree of variation of CpG methylation, as opposed to whether or not CpG sites were methylated, was associated with genetic polymorphisms, supporting a recent hypothesis on the genetic influence of phenotypic plasticity. These results show that cis-regulatory SNPs identified by mQTL do not comprise the full extent of heritable CpG methylation, and that ASM appears overall unreliable. Overall, the extent of genome-methylome interactions is well beyond what is detectible with the commonly used mQTL and ASM approaches, and is likely to include effects on plasticity.Nongluk PlongthongkumKristel R van EijkSimone de JongTina WangJae Hoon SulMarco P M BoksRené S KahnHo-Lim FungRoel A OphoffKun ZhangPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 7, p e99313 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Nongluk Plongthongkum Kristel R van Eijk Simone de Jong Tina Wang Jae Hoon Sul Marco P M Boks René S Kahn Ho-Lim Fung Roel A Ophoff Kun Zhang Characterization of genome-methylome interactions in 22 nuclear pedigrees.
description	Genetic polymorphisms can shape the global landscape of DNA methylation, by either changing substrates for DNA methyltransferases or altering the DNA binding affinity of cis-regulatory proteins. The interactions between CpG methylation and genetic polymorphisms have been previously investigated by methylation quantitative trait loci (mQTL) and allele-specific methylation (ASM) analysis. However, it remains unclear whether these approaches can effectively and comprehensively identify all genetic variants that contribute to the inter-individual variation of DNA methylation levels. Here we used three independent approaches to systematically investigate the influence of genetic polymorphisms on variability in DNA methylation by characterizing the methylation state of 96 whole blood samples in 52 parent-child trios from 22 nuclear pedigrees. We performed targeted bisulfite sequencing with padlock probes to quantify the absolute DNA methylation levels at a set of 411,800 CpG sites in the human genome. With mid-parent offspring analysis (MPO), we identified 10,593 CpG sites that exhibited heritable methylation patterns, among which 70.1% were SNPs directly present in methylated CpG dinucleotides. We determined the mQTL analysis identified 49.9% of heritable CpG sites for which regulation occurred in a distal cis-regulatory manner, and that ASM analysis was only able to identify 5%. Finally, we identified hundreds of clusters in the human genome for which the degree of variation of CpG methylation, as opposed to whether or not CpG sites were methylated, was associated with genetic polymorphisms, supporting a recent hypothesis on the genetic influence of phenotypic plasticity. These results show that cis-regulatory SNPs identified by mQTL do not comprise the full extent of heritable CpG methylation, and that ASM appears overall unreliable. Overall, the extent of genome-methylome interactions is well beyond what is detectible with the commonly used mQTL and ASM approaches, and is likely to include effects on plasticity.
format	article
author	Nongluk Plongthongkum Kristel R van Eijk Simone de Jong Tina Wang Jae Hoon Sul Marco P M Boks René S Kahn Ho-Lim Fung Roel A Ophoff Kun Zhang
author_facet	Nongluk Plongthongkum Kristel R van Eijk Simone de Jong Tina Wang Jae Hoon Sul Marco P M Boks René S Kahn Ho-Lim Fung Roel A Ophoff Kun Zhang
author_sort	Nongluk Plongthongkum
title	Characterization of genome-methylome interactions in 22 nuclear pedigrees.
title_short	Characterization of genome-methylome interactions in 22 nuclear pedigrees.
title_full	Characterization of genome-methylome interactions in 22 nuclear pedigrees.
title_fullStr	Characterization of genome-methylome interactions in 22 nuclear pedigrees.
title_full_unstemmed	Characterization of genome-methylome interactions in 22 nuclear pedigrees.
title_sort	characterization of genome-methylome interactions in 22 nuclear pedigrees.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/f5d0effff05d4b79a19c8b1fd408af88
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Characterization of genome-methylome interactions in 22 nuclear pedigrees.

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