d. Allele-specific DNA methylation
A major research focus of our group is to examine patterns of allele-specific DNA methylation (ASM) across the genome. We are interested in uncovering both cis-mediated ASM (i.e. looking for genetic influences on local epigenetic signatures) and novel regions of the genome characterised by parental-origin-dependent DNA methylation (i.e. genomic imprinting).
Recent Publication: 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
Abstract: 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.author
manuscript doi:10.1016/j.ajhg.2010.01.014.
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Commentary: 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
We recently published a ’Point of View’ article, describing the implications of widespread ASM for genetic studies of complex disease. You can download this article here.