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Open Access Highly Accessed Research

Non-imprinted allele-specific DNA methylation on human autosomes

Yingying Zhang1, Christian Rohde1, Richard Reinhardt2, Claudia Voelcker-Rehage3 and Albert Jeltsch1*

Author Affiliations

1 School of Engineering and Science, Jacobs University Bremen, Campus Ring 1, D-28759 Bremen, Germany

2 Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, D-14195 Berlin-Dahlem, Germany

3 Jacobs Center on Lifelong Learning and Institutional Development, Jacobs University Bremen, Campus Ring 1, D-28759 Bremen, Germany

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Genome Biology 2009, 10:R138  doi:10.1186/gb-2009-10-12-r138

Published: 3 December 2009

Abstract

Background

Differential DNA methylation between alleles is well established in imprinted genes and the X chromosomes in females but has rarely been reported at non-imprinted loci on autosomes.

Results

We studied DNA methylation of cytosine-guanine dinucleotide (CpG) islands on chromosome 21 in leukocytes from several healthy individuals and observed novel cases of pronounced differential methylation of alleles. Allele-specific methylation affected complete CpG islands with methylation differences between alleles of up to 85%. The methylation differences between alleles were strongly correlated with the genotypes, excluding a connection to imprinting. We show that allele-specific methylation can lead to allelic repression of the methylated gene copy. Based on our results, allele-specific methylation is likely to affect about 10% of all human genes and to contribute to allele-specific expression and monoallelic gene silencing. Therefore, allele-specific methylation represents an epigenetic pathway of how genetic polymorphisms may lead to phenotypic variability. In most cases, we observed that some, but not all, heterozygous individuals showed allele-specific methylation, suggesting that allele-specific methylation is the outcome of an epigenetic drift, the direction of which is determined by the genetic differences between the alleles. We could show that the tendency to acquire hypermethylation in one allele was inherited.

Conclusions

We observed that larger differences in methylation levels between individuals were often coupled to allele-specific methylation and genetic polymorphisms, suggesting that the inter-individual variability of DNA methylation is strongly influenced by genetic differences. Therefore, genetic differences must be taken into account in future comparative DNA methylation studies.