Abstract
BackgroundEnvironmentally 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.MethodsUsing 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.ResultsWe 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.ConclusionsOur 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 materialThe online version of this article (doi:10.1186/s13148-016-0295-1) contains supplementary material, which is available to authorized users.
Highlights
Influenced phenotypes, such as obesity and insulin resistance, can be transmitted over multiple generations
Mendelian methylation quantitative trait loci (meQTL) are enriched in eQTLs Using SNiPA [30], we investigated enrichment of the meQTLs associated with trimodal sites for overlap with an expression quantitative trait locus
Trimodal CpG sites have the highest estimates of genetic heritability For each of our triomodal CpG sites, we looked up the genetic heritability estimates of DNA methylation levels provided by McRae et al [35]
Summary
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. Environmental factors can affect phenotype in a heritable manner without altering the DNA sequence [1], as evidenced by studies of environmental stresses such as exposure to chemicals, dietary intake, and temperature changes, among others [2,3,4]. Epigenetic changes, such as cytosine methylation in the context of cytosine-guanine (CpG) dinucleotides are hypothesized to occur in response to environmental challenges that indirectly affect. In another study [16], the hereditary transmission of environmental information in the form of parental traumatic exposure was reported to trace back to epigenetics
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