Kerkel Kristi, Spadola Alexandra, Yuan Eric, Kosek Jolanta, Jiang Le, Hod Eldad, Li Kerry, Murty Vundavalli V, Schupf Nicole, Vilain Eric, Morris Mitzi, Haghighi Fatemeh, Tycko Benjamin
Institute for Cancer Genetics, Columbia University Medical Center, New York, New York 10032, USA.
Nat Genet. 2008 Jul;40(7):904-8. doi: 10.1038/ng.174. Epub 2008 Jun 22.
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.
等位基因特异性DNA甲基化（ASM）是印记基因的一个标志，但基因组中较大的非印记部分的ASM特征尚不明确。我们使用甲基化敏感SNP分析（MSNP），以50K和250K分辨率对人类基因组进行了检测，当基因组DNA用甲基化敏感限制酶HpaII预消化时，将ASM鉴定为从杂合性到纯合性的反复出现的基因型调用转换。我们通过独立检测，在分布于不同染色体上的16个SNP标记位点证实了ASM。在其中12个位点（75%），ASM与相邻SNP的序列密切相关。进一步分析显示，基于甲基化筛选的两个位点——血管生成素和CYP2A6 - CYP2A7基因簇——存在等位基因特异性mRNA表达，这两个基因簇都与具有医学重要性的性状有关。这种序列依赖性ASM的反复出现现象对于绘制和解释非编码SNP及单倍型与人类表型的关联具有实际意义。
