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


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.

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Figure 1: Genotype-dependent ASM in LTF intron 13.
Figure 2: Genotype-dependent ASM and ASE in the CYP2 gene cluster.
Figure 3: Genotype-dependent ASM in the VNN1 gene and allele-specific mRNA expression of all three genes in the vanin cluster.

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This work was supported by grants to B.T. from the US National Institutes of Health, the March of Dimes and the Leukemia and Lymphoma Society in collaboration with the Douglas Kroll Research Program.

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Authors and Affiliations



Study design: K.K. and B.T. MSNP, molecular validations and analysis of ASE: K.K., A.S., E.Y., J.K., L.J., E.H., K.L. and V.V.M. Bioinformatic analyses: E.H., M.M. and F.H. Statistical analyses: N.S. and F.H. Provision of biological samples: A.S., V.V.M., N.S., E.V. and B.T. Interpretation and writing the paper: K.K., N.S., E.V. and B.T.

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Correspondence to Benjamin Tycko.

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Kerkel, K., Spadola, A., Yuan, E. et al. Genomic surveys by methylation-sensitive SNP analysis identify sequence-dependent allele-specific DNA methylation. Nat Genet 40, 904–908 (2008).

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