Allelic skewing of DNA methylation is widespread across the genome

Schalkwyk LC, Meaburn EL, Smith R, Dempster EL, Jeffries AR, Davies MN, Plomin R, Mill J (2010). American Journal of Human Genetics 86(2):196-212

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Tycko B (2010). Mapping Allele-Specific DNA Methylation: A New Tool for Maximizing Information from GWAS American Journal of Human Genetics 86(2):109-112 doi:10.1016/j.ajhg.2010.01.021

Meaburn EL, Schalkwyk LC, Mill J (2010) Allele-specific methylation in the human genome: Implications for genetic studies of complex disease Epigenetics 5(7):578-582

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DNA methylation is assumed to be complementary on both alleles across the genome although there are exceptions, notably in regions subject to genomic imprinting. We present a genome-wide survey of the degree of allelic skewing of DNA methylation with the aim of identifying novel differentially methylated regions (DMRs) associated primarily with genomic imprinting or DNA sequence variation acting in cis. We used SNP microarrays to quantitatively assess allele-specific DNA methylation (ASM) in amplicons covering 7.6% of the human genome following cleavage with a cocktail of methylation-sensitive restriction enzymes (MSREs). Selected findings were verified using bisulfite-mapping and gene expression analyses, subsequently tested in a second tissue from the same individuals, and replicated in DNA obtained from 30 parent-child trios. Our approach detected clear examples of allele-specific DNA methylation (ASM) in the vicinity of known imprinted loci, highlighting the validity of the method. In total 2,7045 (1.5%) of our 183,605 informative and stringently filtered SNPs demonstrate an average relative allele score (RAS) change >0.10 following MSRE digestion. In agreement with previous reports, the majority of ASM (~90%) appears to be cis in nature, and several examples of tissue-specific ASM were identified. Our data show that ASM is a widespread phenomenon with >35,000 such sites potentially occurring across the genome, and that a spectrum of ASM is likely, with heterogeneity between individuals and across tissues. These findings impact upon our understanding about the origin of individual phenotypic differences and have implications for genetic studies of complex disease.