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Genomic surveys by methylation-sensitive SNP analysis identify sequence-dependent allele-specific DNA methylation

2008; Nature Portfolio; Volume: 40; Issue: 7 Linguagem: Inglês

10.1038/ng.174

1546-1718

Kristi Kerkel, Alexandra Spadola, Rui Yuan, Jolanta Kosek, Le Jiang, Eldad A. Hod, Kerry Li, Vundavalli V. Murty, Nicole Schupf, Éric Vilain, Mitzi Morris, Fatemeh Haghighi, Benjamin Tycko,

Cancer-related gene regulation

Ben Tycko and colleagues report the identification of genotype-dependent allele-specific methylation at many loci through the use of genomic methylation-sensitive SNP array analysis. Using independent assays, they confirm allele-specific methylation at 16 SNP-tagged loci on various chromosomes. 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.