Allele-specific methylation in the human genome: implications for genetic studies of complex disease

Epigenetics. 2010 Oct 1;5(7):578-82. doi: 10.4161/epi.5.7.12960. Epub 2010 Oct 1.

Abstract

Across the genome, outside of a small number of known imprinted genes and regions subject to X-inactivation in females, DNA methylation at CpG dinucleotides is often assumed to be complementary across both alleles in a diploid cell. However, recent findings suggest the reality is more complex, with the discovery that allele-specific methylation (ASM) is a common feature across the genome. A key observation is that the majority of ASM is associated with genetic variation in cis, although a noticeable proportion is also non-cis in nature and mediated, for example, by parental origin. ASM appears to be both quantitative, characterized by subtle skewing of DNA methylation between alleles, and heterogeneous, varying across tissues and between individuals. These findings have important implications for complex disease genetics; whilst cis-mediated ASM provides a functional consequence for non-coding genetic variation, heterogeneous and quantitative ASM complicates the identification of disease-associated loci. We propose that non-cis ASM could contribute toward the 'missing heritability' of complex diseases, rendering certain loci hemizygous and masking the direct association between genotype and phenotype. We suggest that the interpretation of results from genomewide association studies can be improved by the incorporation of epi-allelic information, and that in order to fully understand the extent and consequence of ASM in the human genome, a comprehensive sequencing-based analysis of allelic methylation patterns across tissues and individuals is required.

Publication types

  • Review

MeSH terms

  • Alleles
  • DNA Methylation / genetics*
  • Disease / genetics*
  • Environment
  • Female
  • Genetic Complementation Test
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Genome, Human
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Models, Biological
  • X Chromosome Inactivation