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Non-imprinted allele-specific DNA methylation on human autosomes.

Zhang Y, Rohde C, Reinhardt R, Voelcker-Rehage C, Jeltsch A - Genome Biol. (2009)

Bottom Line: 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.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.Therefore, genetic differences must be taken into account in future comparative DNA methylation studies.

View Article: PubMed Central - HTML - PubMed

Affiliation: School of Engineering and Science, Jacobs University Bremen, Campus Ring 1, D-28759 Bremen, Germany. y.zhang@jacobs-university.de

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.

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Correlation of DNA methylation with age in amplicon 262. (a) Methylation of amplicon 262 in old and young individuals analyzed without considering genotypes. An age-related highly significant increase in methylation appears to be detected. (b) Distribution of A and G genotypes among old and young individuals in our study. (c) Comparison of DNA methylation in old and young individuals with the same genotypes. This panel shows a re-analysis of the data plotted in (a); error bar represent the standard deviations of the data. This representation of the data clearly indicates that there is no age-related gain of methylation in this amplicon.
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Figure 5: Correlation of DNA methylation with age in amplicon 262. (a) Methylation of amplicon 262 in old and young individuals analyzed without considering genotypes. An age-related highly significant increase in methylation appears to be detected. (b) Distribution of A and G genotypes among old and young individuals in our study. (c) Comparison of DNA methylation in old and young individuals with the same genotypes. This panel shows a re-analysis of the data plotted in (a); error bar represent the standard deviations of the data. This representation of the data clearly indicates that there is no age-related gain of methylation in this amplicon.

Mentions: In most cases, we observed that some but not all heterozygous individuals showed ASM. Therefore, the ASM could be an outcome of an epigenetic drift, the direction of which is determined by the genetic differences between the alleles ('facilitated epigenetic variation' [13]). For one individual with ASM, we were also able to study the methylation and genotypes of the parents. In this case, the tendency to acquire hypermethylation at one allele was inherited from the mother to the son. Our data show that genetic polymorphisms strongly influence epigenetic differences among individuals, which can affect the interpretation of inter-individual variability of DNA methylation level and its potential connection to human health. For example, an initial comparison of the results obtained with amplicon 262 suggested a very significant difference between old and young individuals in the methylation levels of the right part of this amplicon (with a P-value of 0.0026 in two-sided t-test using the entire dataset; Figure 5a). However, amplicon 262 is subject to ASM and the distribution of genotypes was unequal between both groups (Figure 5b). When DNA methylation levels were compared among identical genotypes, there was no difference in the DNA methylation of old and young individuals (Figure 5c). We conclude that genotype-coupled changes in DNA methylation may influence comparative DNA methylation analyses between groups of individuals. It should be considered that (undiscovered) genetic polymorphisms outside of the region analyzed may have such effects as well.


Non-imprinted allele-specific DNA methylation on human autosomes.

Zhang Y, Rohde C, Reinhardt R, Voelcker-Rehage C, Jeltsch A - Genome Biol. (2009)

Correlation of DNA methylation with age in amplicon 262. (a) Methylation of amplicon 262 in old and young individuals analyzed without considering genotypes. An age-related highly significant increase in methylation appears to be detected. (b) Distribution of A and G genotypes among old and young individuals in our study. (c) Comparison of DNA methylation in old and young individuals with the same genotypes. This panel shows a re-analysis of the data plotted in (a); error bar represent the standard deviations of the data. This representation of the data clearly indicates that there is no age-related gain of methylation in this amplicon.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2812945&req=5

Figure 5: Correlation of DNA methylation with age in amplicon 262. (a) Methylation of amplicon 262 in old and young individuals analyzed without considering genotypes. An age-related highly significant increase in methylation appears to be detected. (b) Distribution of A and G genotypes among old and young individuals in our study. (c) Comparison of DNA methylation in old and young individuals with the same genotypes. This panel shows a re-analysis of the data plotted in (a); error bar represent the standard deviations of the data. This representation of the data clearly indicates that there is no age-related gain of methylation in this amplicon.
Mentions: In most cases, we observed that some but not all heterozygous individuals showed ASM. Therefore, the ASM could be an outcome of an epigenetic drift, the direction of which is determined by the genetic differences between the alleles ('facilitated epigenetic variation' [13]). For one individual with ASM, we were also able to study the methylation and genotypes of the parents. In this case, the tendency to acquire hypermethylation at one allele was inherited from the mother to the son. Our data show that genetic polymorphisms strongly influence epigenetic differences among individuals, which can affect the interpretation of inter-individual variability of DNA methylation level and its potential connection to human health. For example, an initial comparison of the results obtained with amplicon 262 suggested a very significant difference between old and young individuals in the methylation levels of the right part of this amplicon (with a P-value of 0.0026 in two-sided t-test using the entire dataset; Figure 5a). However, amplicon 262 is subject to ASM and the distribution of genotypes was unequal between both groups (Figure 5b). When DNA methylation levels were compared among identical genotypes, there was no difference in the DNA methylation of old and young individuals (Figure 5c). We conclude that genotype-coupled changes in DNA methylation may influence comparative DNA methylation analyses between groups of individuals. It should be considered that (undiscovered) genetic polymorphisms outside of the region analyzed may have such effects as well.

Bottom Line: 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.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.Therefore, genetic differences must be taken into account in future comparative DNA methylation studies.

View Article: PubMed Central - HTML - PubMed

Affiliation: School of Engineering and Science, Jacobs University Bremen, Campus Ring 1, D-28759 Bremen, Germany. y.zhang@jacobs-university.de

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.

Show MeSH