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Mendelian inheritance of trimodal CpG methylation sites suggests distal cis-acting genetic effects

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ABSTRACT

Background: Environmentally influenced phenotypes, such as obesity and insulin resistance, can be transmitted over multiple generations. Epigenetic modifications, such as methylation of DNA cytosine-guanine (CpG) pairs, may be carriers of inherited information. At the population level, the methylation state of such “heritable” CpG sites is expected to follow a trimodal distribution, and their mode of inheritance should be Mendelian.

Methods: Using the Illumina Infinium 450 K DNA methylation array, we determined DNA CpG-methylation in blood cells from a family cohort 123 individuals of Arab ethnicity, including 18 elementary father-mother-child trios, we asked whether Mendelian inheritance of CpG methylation is observed, and most importantly, whether it is independent of any genetic signals. Using 40× whole genome sequencing, we therefore excluded all CpG sites with possibly confounding genetic variants (SNP) within the binding regions of the Illumina probes.

Results: We identified a total of 955 CpG sites that displayed a trimodal distribution and confirmed trimodality in a study of 1805 unrelated Caucasians. Of 955 CpG sites, 99.9% observed a strict Mendelian pattern of inheritance and had no SNP within +/−110 nucleotides of the CpG site by design. However, in 97% of these cases a distal cis-acting SNP within a +/−1 Mbp window was found that explained the observed CpG distribution, excluding the hypothesis of epigenetic inheritance for these clear-cut trimodal sites. Using power analysis, we showed that in 46% of all cases, the closest CpG-associated SNP was located more than 1000 bp from the CpG site.

Conclusions: Our findings suggest that CpG methylation is maintained over larger genomic distances. Furthermore, nearly half of the SNPs associated with these trimodal sites were also associated with the expression of nearby genes (P = 4.08 × 10−6), implying a regulatory effect of these trimodal CpG sites.

Electronic supplementary material: The online version of this article (doi:10.1186/s13148-016-0295-1) contains supplementary material, which is available to authorized users.

No MeSH data available.


An example of Mendelian inheritance at a trimodal CpG site. The histograms on the left show the distribution of the methylation of CpG probe cg18285337 (β values) for both studies. On the right, examples of pedigrees from four families (constituting 12 father-mother-child trios) for this CpG are given, showing strict Mendelian inheritance of methylation β value
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Fig2: An example of Mendelian inheritance at a trimodal CpG site. The histograms on the left show the distribution of the methylation of CpG probe cg18285337 (β values) for both studies. On the right, examples of pedigrees from four families (constituting 12 father-mother-child trios) for this CpG are given, showing strict Mendelian inheritance of methylation β value

Mentions: Within the 123 subjects from the Qatari cohort, 18 trios were available. The 955 trimodal sites in all 18 trios were tested for Mendelian violations. All but one of the sites showed Mendelian agreement in all trios. Using 1000 randomisations of the subjects, we found that the average number of sites violating Mendelian inheritance under the hypothesis was 23.1% ± 2.5, making the results of study being a chance event highly unlikely (P = 1.19 × 10-6, chi-squared test). An example of a trimodal methylation site that follows Mendelian inheritance in different families having several offspring is shown in Fig. 2.Fig. 2


Mendelian inheritance of trimodal CpG methylation sites suggests distal cis-acting genetic effects
An example of Mendelian inheritance at a trimodal CpG site. The histograms on the left show the distribution of the methylation of CpG probe cg18285337 (β values) for both studies. On the right, examples of pedigrees from four families (constituting 12 father-mother-child trios) for this CpG are given, showing strict Mendelian inheritance of methylation β value
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5120560&req=5

Fig2: An example of Mendelian inheritance at a trimodal CpG site. The histograms on the left show the distribution of the methylation of CpG probe cg18285337 (β values) for both studies. On the right, examples of pedigrees from four families (constituting 12 father-mother-child trios) for this CpG are given, showing strict Mendelian inheritance of methylation β value
Mentions: Within the 123 subjects from the Qatari cohort, 18 trios were available. The 955 trimodal sites in all 18 trios were tested for Mendelian violations. All but one of the sites showed Mendelian agreement in all trios. Using 1000 randomisations of the subjects, we found that the average number of sites violating Mendelian inheritance under the hypothesis was 23.1% ± 2.5, making the results of study being a chance event highly unlikely (P = 1.19 × 10-6, chi-squared test). An example of a trimodal methylation site that follows Mendelian inheritance in different families having several offspring is shown in Fig. 2.Fig. 2

View Article: PubMed Central - PubMed

ABSTRACT

Background: Environmentally influenced phenotypes, such as obesity and insulin resistance, can be transmitted over multiple generations. Epigenetic modifications, such as methylation of DNA cytosine-guanine (CpG) pairs, may be carriers of inherited information. At the population level, the methylation state of such “heritable” CpG sites is expected to follow a trimodal distribution, and their mode of inheritance should be Mendelian.

Methods: Using the Illumina Infinium 450 K DNA methylation array, we determined DNA CpG-methylation in blood cells from a family cohort 123 individuals of Arab ethnicity, including 18 elementary father-mother-child trios, we asked whether Mendelian inheritance of CpG methylation is observed, and most importantly, whether it is independent of any genetic signals. Using 40× whole genome sequencing, we therefore excluded all CpG sites with possibly confounding genetic variants (SNP) within the binding regions of the Illumina probes.

Results: We identified a total of 955 CpG sites that displayed a trimodal distribution and confirmed trimodality in a study of 1805 unrelated Caucasians. Of 955 CpG sites, 99.9% observed a strict Mendelian pattern of inheritance and had no SNP within +/−110 nucleotides of the CpG site by design. However, in 97% of these cases a distal cis-acting SNP within a +/−1 Mbp window was found that explained the observed CpG distribution, excluding the hypothesis of epigenetic inheritance for these clear-cut trimodal sites. Using power analysis, we showed that in 46% of all cases, the closest CpG-associated SNP was located more than 1000 bp from the CpG site.

Conclusions: Our findings suggest that CpG methylation is maintained over larger genomic distances. Furthermore, nearly half of the SNPs associated with these trimodal sites were also associated with the expression of nearby genes (P = 4.08 × 10−6), implying a regulatory effect of these trimodal CpG sites.

Electronic supplementary material: The online version of this article (doi:10.1186/s13148-016-0295-1) contains supplementary material, which is available to authorized users.

No MeSH data available.