Busche Stephan, Shao Xiaojian, Caron Maxime, Kwan Tony, Allum Fiona, Cheung Warren A, Ge Bing, Westfall Susan, Simon Marie-Michelle, Barrett Amy, Bell Jordana T, McCarthy Mark I, Deloukas Panos, Blanchette Mathieu, Bourque Guillaume, Spector Timothy D, Lathrop Mark, Pastinen Tomi, Grundberg Elin
Department of Human Genetics, McGill University, 740 Dr. Penfield Avenue, H3A 0G1, Montreal, Quebec, Canada.
McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
Genome Biol. 2015 Dec 23;16:290. doi: 10.1186/s13059-015-0856-1.
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.
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.
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.
CpG甲基化变异参与人类性状形成和疾病易感性。通过应用靶向阵列，人群内分析偏向于CpG密集区域。我们对来自单卵双胞胎和双卵双胞胎的约30份脂肪和血液样本进行全基因组亚硫酸氢盐测序，以在单碱基分辨率下表征非遗传和遗传效应。
纯不变的CpG呈现双峰分布，在启动子和增强子区域中未甲基化的CpG富集，完全甲基化的CpG缺失。群体可变的CpG占每个组织中总CpG的约15 - 20%，在增强子相关区域富集，在启动子中缺失，并且CpG处的单核苷酸多态性是极端甲基化变异的常见混杂因素。差异甲基化主要源于非遗传因素，非共享环境占大部分变异。这些非遗传效应主要是组织特异性的。吸烟与血液中的差异甲基化相关，没有证据表明这种暴露会影响细胞计数。与非遗传效应相反，CpG甲基化的遗传效应在不同组织间共享，从而限制了组织间的表观遗传漂移。CpH甲基化很少见，并且显示出与CpG相似的变异模式特征。
我们的研究强调了低通量全基因组亚硫酸氢盐测序在识别启动子区域以外的甲基化组变异方面的作用，并表明针对组织的群体动态甲基化组需要评估基因启动子远端研究较少的基因间CpG，以揭示个体间变异的全部范围。
