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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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Inter-individual variation of DNA methylation. (a) DNA methylation levels of all amplicons studied in blood from ten old (1 to 10) and ten young (11 to 20) individuals. The data were sorted by the average level of DNA methylation among amplicons and individuals. Old individuals are represented by black numbers, young individuals by red numbers. The continuous yellow to blue color code represents the DNA methylation level of the PCR products. (b) Average DNA methylation level of all 16 amplicons among 20 individuals (1 to 20). The error bars indicate the standard deviation among the samples. Amplicon 262 was split into 262_L (left part) and 262_R (right part) because of the different methylation observed in these two parts. Green color labeled amplicons showed a maximal methylation difference between individuals of more than 50%; orange labels indicate amplicons with >30% methylation difference. (c) DNA methylation pattern of amplicon 23_1 in individuals 1 to 20. Each column represents a single CpG site. Each row corresponds to one individual.
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Figure 1: Inter-individual variation of DNA methylation. (a) DNA methylation levels of all amplicons studied in blood from ten old (1 to 10) and ten young (11 to 20) individuals. The data were sorted by the average level of DNA methylation among amplicons and individuals. Old individuals are represented by black numbers, young individuals by red numbers. The continuous yellow to blue color code represents the DNA methylation level of the PCR products. (b) Average DNA methylation level of all 16 amplicons among 20 individuals (1 to 20). The error bars indicate the standard deviation among the samples. Amplicon 262 was split into 262_L (left part) and 262_R (right part) because of the different methylation observed in these two parts. Green color labeled amplicons showed a maximal methylation difference between individuals of more than 50%; orange labels indicate amplicons with >30% methylation difference. (c) DNA methylation pattern of amplicon 23_1 in individuals 1 to 20. Each column represents a single CpG site. Each row corresponds to one individual.

Mentions: A summary of the methylation of all amplicons in different individuals is shown in Figure 1a. The methylation levels of highly methylated or completely unmethylated amplicons were usually similar among individuals, while the intermediately methylated amplicons showed higher variability (Figure 1b). Four amplicons showed a maximal inter-individual difference in their methylation levels of >50% and another five amplicons showed variances of >30%. As an example, the methylation pattern of amplicon 23_1 in 20 individuals is shown in Figure 1c. When comparing the methylation difference among individuals, we did not observe any significant methylation difference between old and young individuals or males and females. This is consistent with former results where no significant correlation of methylation changes with gender or age was detected [14].


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

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

Inter-individual variation of DNA methylation. (a) DNA methylation levels of all amplicons studied in blood from ten old (1 to 10) and ten young (11 to 20) individuals. The data were sorted by the average level of DNA methylation among amplicons and individuals. Old individuals are represented by black numbers, young individuals by red numbers. The continuous yellow to blue color code represents the DNA methylation level of the PCR products. (b) Average DNA methylation level of all 16 amplicons among 20 individuals (1 to 20). The error bars indicate the standard deviation among the samples. Amplicon 262 was split into 262_L (left part) and 262_R (right part) because of the different methylation observed in these two parts. Green color labeled amplicons showed a maximal methylation difference between individuals of more than 50%; orange labels indicate amplicons with >30% methylation difference. (c) DNA methylation pattern of amplicon 23_1 in individuals 1 to 20. Each column represents a single CpG site. Each row corresponds to one individual.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Inter-individual variation of DNA methylation. (a) DNA methylation levels of all amplicons studied in blood from ten old (1 to 10) and ten young (11 to 20) individuals. The data were sorted by the average level of DNA methylation among amplicons and individuals. Old individuals are represented by black numbers, young individuals by red numbers. The continuous yellow to blue color code represents the DNA methylation level of the PCR products. (b) Average DNA methylation level of all 16 amplicons among 20 individuals (1 to 20). The error bars indicate the standard deviation among the samples. Amplicon 262 was split into 262_L (left part) and 262_R (right part) because of the different methylation observed in these two parts. Green color labeled amplicons showed a maximal methylation difference between individuals of more than 50%; orange labels indicate amplicons with >30% methylation difference. (c) DNA methylation pattern of amplicon 23_1 in individuals 1 to 20. Each column represents a single CpG site. Each row corresponds to one individual.
Mentions: A summary of the methylation of all amplicons in different individuals is shown in Figure 1a. The methylation levels of highly methylated or completely unmethylated amplicons were usually similar among individuals, while the intermediately methylated amplicons showed higher variability (Figure 1b). Four amplicons showed a maximal inter-individual difference in their methylation levels of >50% and another five amplicons showed variances of >30%. As an example, the methylation pattern of amplicon 23_1 in 20 individuals is shown in Figure 1c. When comparing the methylation difference among individuals, we did not observe any significant methylation difference between old and young individuals or males and females. This is consistent with former results where no significant correlation of methylation changes with gender or age was detected [14].

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