Population whole-genome bisulfite sequencing across two tissues highlights the environment as the principal source of human methylome variation
Year: 2015
Type: article
Study design: Observational Study
Abstract: BACKGROUND: CpG methylation variation is involved in human trait formation and disease susceptibility. Analyses within populations have been biased towards CpG-dense regions through the application of targeted arrays. We generate whole-genome bisulfite sequencing data for approximately 30 adipose and blood samples from monozygotic and dizygotic twins for the characterization of non-genetic and genetic effects at single-site resolution. RESULTS: Purely invariable CpGs display a bimodal distribution with enrichment of unmethylated CpGs and depletion of fully methylated CpGs in promoter and enhancer regions. Population-variable CpGs account for approximately 15-20 % of total CpGs per tissue, are enriched in enhancer-associated regions and depleted in promoters, and single nucleotide polymorphisms at CpGs are a frequent confounder of extreme methylation variation. Differential methylation is primarily non-genetic in origin, with non-shared environment accounting for most of the variance. These non-genetic effects are mainly tissue-specific. Tobacco smoking is associated with differential methylation in blood with no evidence of this exposure impacting cell counts. Opposite to non-genetic effects, genetic effects of CpG methylation are shared across tissues and thus limit inter-tissue epigenetic drift. CpH methylation is rare, and shows similar characteristics of variation patterns as CpGs. CONCLUSIONS: Our study highlights the utility of low pass whole-genome bisulfite sequencing in identifying methylome variation beyond promoter regions, and suggests that targeting the population dynamic methylome of tissues requires assessment of understudied intergenic CpGs distal to gene promoters to reveal the full extent of inter-individual variation.
Source: Genome biology
Authors: The Multiple Tissue Human Expression Resource, Stephan Busche, Xiaojian Shao, Maxime Caron, Tony Kwan, Fiona Allum, Warren A. Cheung, Bing Ge, Susan Westfall, Marie-Michelle Simon, Amy Barrett, Jordana T. Bell, Mark I. McCarthy, Panos Deloukas, Mathieu Blanchette, Guillaume Bourque, Timothy D. Spector, Mark Lathrop, Tomi Pastinen, Elin Grundberg
Institutions: McGill University, McGill University and Génome Québec Innovation Centre, Churchill Hospital, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism, King's College London, Centre for Human Genetics, Queen Mary University of London, William Harvey Research Institute, Wellcome Sanger Institute
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,490
Funders: McGill University, Queen Mary University of London, Wellcome Trust, Génome Québec, NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research, National Institute for Health and Care Research, King's College London, University of Oxford, Université de Genève, National Institutes of Health, Canadian Institutes of Health Research, Fonds de Recherche du Québec - Santé, Seventh Framework Programme, Division of Mathematical Sciences
Awards: G103470996, G119964413, G2473961061, G2973790809, G297885364, Whole-genome transcriptomic profiling: A resource for the discovery of expression QTLs associated with common disease., Whole-genome transcriptomic profiling: A resource for the discovery of expression QTLs associated with common disease., G4690771677, Multidimensional Epigenomics Mapping Centre (EMC) at McGill, NIHR Senior Investigator Award, Full Resolution Metabolic Disease Epigenomics in Human Populations, G6420605804, Understanding the genetic basis of common human diseases: core funding for the Wellcome Trust Centre for Human Genetics., G8528690534
OpenAlex ID: W2211682249