Genomic surveys by methylation-sensitive SNP analysis identify sequence-dependent allele-specific DNA methylation
Genomic surveys by methylation-sensitive SNP analysis identify sequence-dependent allele-specific DNA methylation
复制标题
DOI：
10.1038/ng.174
复制
发表时间：
2008-07-01
期刊：
影响因子：
30.8
通讯作者：
Tycko, Benjamin
中科院分区：
文献类型：
--
作者：
Kerkel, Kristi;Spadola, Alexandra;Tycko, Benjamin
等位基因特异性DNA甲基化(ASM)是印迹基因的一个标志，但基因组中较大的非印迹部分的ASM特征较差。利用甲基化敏感的SNP分析(MSNP)，我们在50K和250K分辨率下对人类基因组进行了调查，确定ASM是当基因组DNA用甲基化敏感的限制性内切酶HpaII简化时，从杂合到纯合的反复基因型转换。使用独立的分析方法，我们确认了分布在不同染色体上的16个SNP标记的基因座上的ASM。在这些基因座中有12个(75%)，ASM与相邻的SNP序列有很强的追踪性。进一步的分析表明，在这个基于甲基化的筛查中，有两个基因座的等位基因特异性的mRNA表达--Vanin和CYP2A6-CYP2A7基因簇--都与医学上的重要特征有关。这种重复出现的序列依赖的ASM现象对于定位和解释非编码SNPs和单倍型与人类表型的关联具有实际意义。
Allele-specific DNA methylation (ASM) is a hallmark of imprinted genes, but ASM in the larger nonimprinted fraction of the genome is less well characterized. Using methylation-sensitive SNP analysis (MSNP), we surveyed the human genome at 50K and 250K resolution, identifying ASM as recurrent genotype call conversions from heterozygosity to homozygosity when genomic DNAs were predigested with the methylation-sensitive restriction enzyme HpaII. Using independent assays, we confirmed ASM at 16 SNP-tagged loci distributed across various chromosomes. At 12 of these loci (75%), the ASM tracked strongly with the sequence of adjacent SNPs. Further analysis showed allele-specific mRNA expression at two loci from this methylation-based screen -the vanin and CYP2A6-CYP2A7 gene clusters -both implicated in traits of medical importance. This recurrent phenomenon of sequence-dependent ASM has practical implications for mapping and interpreting associations of noncoding SNPs and haplotypes with human phenotypes.