Non-imprinted allele-specific DNA methylation on human autosomes.
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.
Zhang
Yingying
Y
School of Engineering and Science, Jacobs University Bremen, Campus Ring 1, D-28759 Bremen, Germany. y.zhang@jacobs-university.de
Rohde
Christian
C
Reinhardt
Richard
R
Voelcker-Rehage
Claudia
C
Jeltsch
Albert
A
D000429:Alcohol Oxidoreductases / Q000235:genetics; D000483:Alleles; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D017931:DNA Primers / Q000235:genetics; D020869:Gene Expression Profiling; D023281:Genomics; D006360:Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics
D017931:DNA Primers; D006360:Heat-Shock Proteins; D014157:Transcription Factors; C070389:HSF2 protein, human; D000429:Alcohol Oxidoreductases; C531129:CBR1 protein, human