There is growing recognition that epivariations, most often recognized as promoter hypermethylation events that lead to gene silencing, are associated with a number of human diseases. However, little information exists on the prevalence and distribution of rare epigenetic variation in the human population. In order to address this, we performed a survey of methylation profiles from 23,116 individuals using the Illumina 450k array. Using a robust outlier approach, we identified 4,452 unique autosomal epivariations, including potentially inactivating promoter methylation events at 384 genes linked to human disease. For example, we observed promoter hypermethylation of BRCA1 and LDLR at population frequencies of ∼1 in 3,000 and ∼1 in 6,000, respectively, suggesting that epivariations may underlie a fraction of human disease which would be missed by purely sequence-based approaches. Using expression data, we confirmed that many epivariations are associated with outlier gene expression. Analysis of variation data and monozygous twin pairs suggests that approximately two-thirds of epivariations segregate in the population secondary to underlying sequence mutations, while one-third are likely sporadic events that occur post-zygotically. We identified 25 loci where rare hypermethylation coincided with the presence of an unstable CGG tandem repeat, validated the presence of CGG expansions at several loci, and identified the putative molecular defect underlying most of the known folate-sensitive fragile sites in the genome. Our study provides a catalog of rare epigenetic changes in the human genome, gives insight into the underlying origins and consequences of epivariations, and identifies many hypermethylated CGG repeat expansions.

人们越来越认识到，表观变异（最常被认为是导致基因沉默的启动子高甲基化事件）与许多人类疾病有关。然而，关于人类罕见表观遗传变异的流行和分布的信息很少。为了解决这个问题，我们使用 Illumina 450k 阵列对 23,116 名个体的甲基化谱进行了调查。使用稳健的离群值方法，我们鉴定了 4,452 个独特的常染色体表观变异，包括与人类疾病相关的 384 个基因的潜在失活启动子甲基化事件。例如，我们观察到BRCA1和LDLR启动子高甲基化的群体频率分别为 3,000 人中约 1 例和 6,000 人中约 1 例，这表明表观变异可能是人类疾病的一部分，而纯粹基于序列的方法可能会忽略这一点。使用表达数据，我们证实许多表观变异与异常基因表达相关。对变异数据和单卵双胞胎的分析表明，大约三分之二的表观变异在群体中因潜在序列突变而分离，而三分之一可能是合子后发生的散发事件。我们鉴定了 25 个位点，其中罕见的高甲基化与不稳定的 CGG 串联重复的存在相一致，验证了多个位点处 CGG 扩展的存在，并确定了基因组中大多数已知叶酸敏感脆弱位点背后的推定分子缺陷。我们的研究提供了人类基因组中罕见的表观遗传变化的目录，深入了解表观变异的潜在起源和后果，并识别了许多超甲基化的 CGG 重复扩展。