Allelic Skewing of DNA Methylation Is Widespread across the Genome
Allelic Skewing of DNA Methylation Is Widespread across the Genome
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DOI：
10.1016/j.ajhg.2010.01.014
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发表时间：
2010-02-12
影响因子：
9.8
通讯作者：
Mill, Jonathan
中科院分区：
文献类型：
--
作者：
Schalkwyk, Leonard C.;Meaburn, Emma L.;Mill, Jonathan
DNA 甲基化被认为在整个基因组的两个等位基因上是互补的，尽管也有例外，特别是在受基因组印记影响的区域。我们对 DNA 甲基化的等位基因偏斜程度进行了全基因组调查，目的是识别以前未报告的差异甲基化区域 (DMR)，这些区域主要与基因组印记或顺式作用的 DNA 序列变异相关。我们使用 SNP 微阵列定量评估扩增子中的等位基因特异性 DNA 甲基化 (ASM)，这些扩增子在用甲基化敏感限制性酶 (MSRE) 混合物切割后覆盖了人类基因组的 7.6%。使用亚硫酸氢盐图谱和基因表达分析验证了选定的结果，随后在同一个体的第二个组织中进行测试，并在从 30 个亲子三人组获得的 DNA 中进行复制。我们的方法在已知印记位点附近检测到了 ASM 的明显例子，突出了该方法的有效性。总共，我们的 183,605 个信息丰富且经过严格过滤的 SNP 中的 2,704 个 (1.5%) 显示 MSRE 消化后平均相对等位基因评分 (RAS) 变化 >= 0.10。与之前的报道一致，大多数 ASM（大约 90%）本质上似乎是顺式的，并且识别出了一些组织特异性 ASM 的例子。我们的数据表明，ASM 是一种广泛存在的现象，整个基因组中可能存在超过 35,000 个此类位点，并且可能存在一系列 ASM，在个体之间和组织之间具有异质性。这些发现影响了我们对个体表型差异起源的理解，并对复杂疾病的遗传学研究具有影响。
DNA methylation is assumed to be complementary on both alleles across the genome, although there are exceptions, notably in regions subject to genomic imprinting. We present a genome-wide survey of the degree of allelic skewing of DNA methylation with the aim of identifying previously unreported differentially methylated regions (DMRs) associated primarily with genomic imprinting or DNA sequence variation acting in cis. We used SNP microarrays to quantitatively assess allele-specific DNA methylation (ASM) in amplicons covering 7.6% of the human genome following cleavage with a cocktail of methylation-sensitive restriction enzymes (MSREs). Selected findings were verified using bisulfite-mapping and gene-expression analyses, subsequently tested in a second tissue from the same individuals, and replicated in DNA obtained from 30 parent-child trios. Our approach detected clear examples of ASM in the vicinity of known imprinted loci, highlighting the validity of the method. In total, 2,704 (1.5%) of our 183,605 informative and stringently filtered SNPs demonstrate an average relative allele score (RAS) change >= 0.10 following MSRE digestion. In agreement with previous reports, the majority of ASM (similar to 90%) appears to be cis in nature, and several examples of tissue-specific ASM were identified. Our data show that ASM is a widespread phenomenon, with >35,000 such sites potentially occurring across the genome, and that a spectrum of ASM is likely, with heterogeneity between individuals and across tissues. These findings impact Our understanding about the origin of individual phenotypic differences and have implications for genetic studies of complex disease.