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Genome Biol. 2017 Mar 10;18(1):50. doi: 10.1186/s13059-017-1173-7.

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

Author information

1
Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
2
McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
3
Team of Environmental Epidemiology applied to Reproduction and Respiratory Health, Inserm U1209, CNRS, University Grenoble Alpes, Institute for Advanced Biosciences, Grenoble, France.
4
Department of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1HH, UK.
5
Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK.
6
Institute of Nutrition and Functional Foods (INAF), Laval University, Québec, QC, G1V 0A6, Canada.
7
Genetic Variation and Human Diseases Unit, UMR-946, INSERM, Université Paris Diderot, Université Sorbonne Paris Cité, Paris, France.
8
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK.
9
UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6BT, UK.
10
Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, CB1 8RN, UK.
11
Québec Heart and Lung Institute, Laval University, Québec, QC, G1V 4G5, Canada.
12
Pédiatrie, Centre Hospitalier Universitaire (CHU) Grenoble Alpes, Grenoble, France.
13
National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK.
14
Faculty of Science, Department of Molecular Biology, Radboud University, Nijmegen, 6525GA, The Netherlands.
15
British Heart Foundation Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK.
16
The National Institute for Health Research Blood and Transplant Unit (NIHR BTRU) in Donor Health and Genomics, University of Cambridge, Strangeways Research Laboratory, Wort's Causeway, Cambridge, CB1 8RN, UK.
17
Department of Human Genetics, McGill University, Montreal, Quebec, Canada. tomi.pastinen@gmail.com.
18
McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada. tomi.pastinen@gmail.com.
19
Department of Human Genetics, McGill University, Montreal, Quebec, Canada. elin.grundberg@mcgill.ca.
20
McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada. elin.grundberg@mcgill.ca.

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.

PMID:
28283040
PMCID:
PMC5346261
DOI:
10.1186/s13059-017-1173-7
[Indexed for MEDLINE]
Free PMC Article

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