Genomic surveys by methylation-sensitive SNP analysis identify sequence-dependent allele-specific DNA methylation |
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Authors: | 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 |
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Affiliation: | Institute for Cancer Genetics, Columbia University Medical Center, New York, New York 10032, USA. |
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Abstract: | 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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