Functional variation in allelic methylomes underscores a strong genetic contribution and reveals novel epigenetic alterations in the human epigenome.
Functional variation in allelic methylomes underscores a strong genetic contribution and reveals novel epigenetic alterations in the human epigenome.
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DOI：
10.1186/s13059-017-1173-7
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发表时间：
2017-03-10
期刊：
影响因子：
12.3
通讯作者：
Grundberg E
中科院分区：
文献类型：
--
作者：
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;Tchernof A;Vohl MC;Demenais F;Pin I;Downes K;Stunnenberg HG;Soranzo N;Pastinen T;Grundberg E
遗传变异的功能影响已被广泛调查，揭示了与表型相关的遗传变化主要位于非编码基因组区域。研究已经将等位基因特异性遗传变化与基因表达，DNA甲基化和组蛋白标记联系起来，但这些研究仅在有限的样本中进行。我们描述了一个大规模的协调研究等位基因和非等位基因对DNA甲基化，组蛋白标记沉积和基因表达的影响，检测表观遗传和功能特征之间的相互关系，在前所未有的分辨率。我们使用来自910个样本的全基因组和靶向亚硫酸氢盐测序的信息来进行等位基因特异性甲基化（ASM）和非等位基因甲基化（mQTL）的基因型依赖性分析。此外，我们引入了一种新的基因型无关的测试来检测染色体之间的甲基化不平衡。在针对ASM、mQTL和基因型独立效应测试的约220万个CpG中，我们确定约32%为受遗传调控的（ASM或mQTL），约14%为受表观遗传调控的。我们还表明，表观遗传驱动的影响强烈富集在抑制区域和附近的转录起始位点，而基因调控的CpG富含增强子。已知的印迹区域在表观遗传调控的基因座中富集，但我们也观察到几个新的基因组区域（例如，HOX基因）作为表观遗传调控。最后，我们使用我们的ASM数据集对疾病相关基因座进行功能解释，并展示了利用幼稚T细胞了解自身免疫性疾病的优势。我们在多个组织中的单倍体甲基化组的丰富目录将允许验证表观基因组关联研究和探索人类基因组中等位基因排除的新生物模型。本文的在线版本（doi：10.1186/s13059-017-1173-7）包含补充材料，可供授权用户使用。
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. 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. 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. The online version of this article (doi:10.1186/s13059-017-1173-7) contains supplementary material, which is available to authorized users.