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

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.

Neonatal DNA methylation profile in human twins is specified by a complex interplay between intrauterine environmental and genetic factors, subject to tissue-specific influence

“…Although low power makes comparison difficult, the range of heritability within the top 5% of probes in the Boks and colleagues study (0.62-0.94) is similar to that found for the top 5% of probes for CBMCs in our study (0.48-0.94). Studies of allele-specific methylation (ASM) have also found evidence for a high heritability of DNA methylation at a subset of genomic loci, with proportions varying with the method of analysis and the tissue examined (Kerkel et al 2008;Boks et al 2009;Zhang et al 2009Zhang et al , 2010Meaburn et al 2010;Schalkwyk et al 2010;Shoemaker et al 2010;Gertz et al 2011). Surprisingly, we found little evidence for an effect of common environment on the overall DNA methylation profile at birth using variance component analysis.…”

Genomic landscape of human allele-specific DNA methylation

“…First, they can be confounded by ASM that is associated with genotype, but which may not have any regulatory effect. The amount of ASM typically associated with genotype is not well understood, but recent reports suggest it is significant (20). More importantly, because imprinted methylation is not necessarily associated with genotypic variation, these methods will be inherently blind to some portion of ASM.…”

Principles for the post-GWAS functional characterisation of risk loci

“…Studies of hereditary non-polyposis colorectal cancer (Lynch syndrome) suggest that germline genetic variation may affect epigenetic marks resulting in cancer predisposition 28,29 31 . Further epigenetic mechanisms that modulate gene expression include miRNAs and miRNA binding sites which can be directly affected by SNPs 32 , and tandem repeats that can impact gene expression e.g.…”