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Functional variation in allelic methylomes underscores a strong genetic contribution and reveals novel epigenetic alterations in the human epigenome.

Abstract：

BACKGROUND:The functional impact of genetic variation has been extensively surveyed, revealing that genetic changes correlated to phenotypes lie mostly in non-coding genomic regions. Studies have linked allele-specific genetic changes to gene expression, DNA methylation, and histone marks but these investigations have only been carried out in a limited set of samples. RESULTS:We describe a large-scale coordinated study of allelic and non-allelic effects on DNA methylation, histone mark deposition, and gene expression, detecting the interrelations between epigenetic and functional features at unprecedented resolution. We use information from whole genome and targeted bisulfite sequencing from 910 samples to perform genotype-dependent analyses of allele-specific methylation (ASM) and non-allelic methylation (mQTL). In addition, we introduce a novel genotype-independent test to detect methylation imbalance between chromosomes. Of the ~2.2 million CpGs tested for ASM, mQTL, and genotype-independent effects, we identify ~32% as being genetically regulated (ASM or mQTL) and ~14% as being putatively epigenetically regulated. We also show that epigenetically driven effects are strongly enriched in repressed regions and near transcription start sites, whereas the genetically regulated CpGs are enriched in enhancers. Known imprinted regions are enriched among epigenetically regulated loci, but we also observe several novel genomic regions (e.g., HOX genes) as being epigenetically regulated. Finally, we use our ASM datasets for functional interpretation of disease-associated loci and show the advantage of utilizing naïve T cells for understanding autoimmune diseases. CONCLUSIONS:Our rich catalogue of haploid methylomes across multiple tissues will allow validation of epigenome association studies and exploration of new biological models for allelic exclusion in the human genome.

journal_name

Genome Biol

journal_title

Genome biology

authors

Cheung WA,Shao X,Morin A,Siroux V,Kwan T,Ge B,Aïssi D,Chen L,Vasquez L,Allum F,Guénard F,Bouzigon E,Simon MM,Boulier E,Redensek A,Watt S,Datta A,Clarke L,Flicek P,Mead D,Paul DS,Beck S,Bourque G,Lathrop M,

doi

10.1186/s13059-017-1173-7

subject

Has Abstract

pub_date

2017-03-10 00:00:00

pages

issue

eissn

1474-7596

issn

1474-760X

pii

10.1186/s13059-017-1173-7

journal_volume

pub_type

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Functional variation in allelic methylomes underscores a strong genetic contribution and reveals novel epigenetic alterations in the human epigenome.