Evolutionary Origin and Methylation Status of Human Intronic CpG Islands that Are Not Present in Mouse

Abstract

Imprinting of the human RB1 gene is due to the presence of a differentially methylated CpG island (CGI) in intron 2, which is part of a retrocopy derived from the PPP1R26 gene on chromosome 9. The murine Rb1 gene does not have this retrocopy and is not imprinted. We have investigated whether the RB1/Rb1 locus is unique with respect to these differences. For this, we have compared the CGIs from human and mouse by in silico analyses. We have found that the human genome does not only contain more CGIs than the mouse, but the proportion of intronic CGIs is also higher (7.7% vs. 3.5%). At least 2,033 human intronic CGIs are not present in the mouse. Among these CGIs, 104 show sequence similarities elsewhere in the human genome, which suggests that they arose from retrotransposition. We could narrow down the time points when most of these CGIs appeared during evolution. Their methylation status was analyzed in two monocyte methylome data sets from whole-genome bisulfite sequencing and in 18 published methylomes. Four CGIs, which are located in the RB1, ASRGL1, PARP11, and PDXDC1 genes, occur as methylated and unmethylated copies. In contrast to imprinted methylation at the RB1 locus, differential methylation of the ASRGL1 and PDXDC1 CGIs appears to be sequence dependent. Our study supports the notion that the epigenetic fate of the retrotransposed DNA depends on its sequence and selective forces at the integration site.

Stat3 is a candidate epigenetic biomarker of perinatal Bisphenol A exposure associated with murine hepatic tumors with implications for human health

“…37 Rademacher et al reported that the human genome contains at least 2,000 intronic CpG islands that are not present in the mouse genome, a subset of which show sequence similarities elsewhere in the human genome, suggesting that they arose via retrotransposition. 38 Transposable elements, such as the murine A vy metastable epiallele, have been previously implicated as targets for early environmental effects on the epigenome. 39 These data suggest that the human genome may contain a larger number of intronic epigenetic targets for environmental perturbation than rodents, indicating the importance of including intronic targets in studies evaluating the impact of environmental epigenetics on human health.…”

Genome-wide methylation analysis of retrocopy-associated CpG islands and their genomic environment

“…20 By comparing the position of CGIs and retrocopies using the Perl programming language (http://www.perl.org/), all CGIs overlapping a retrocopy were determined. To divide CGIs/retrocopies in intergenic and intragenic once, we compared the positions of all CGIs/retrocopies to the positions of RefSeq genes.…”

“…As described in Rademacher et human/non-murine intronic CGIs reported previously by Rademacher et al 20 In addition to monocytes, we analyzed the newly discovered 17 CGIs/retrocopies in an additional methylome data set (Rademacher et al; EGA accession: EGAS000001000719), 16 already published methylome data sets by Ziller et al and two oocyte methylome data sets published by Okae et al (Table S8). [20][21][22] Out of these 17 CGIs/retrocopies, seven CGIs (2391_1_hg19, 9224_1_hg19, 9261_1_hg19, 9377_1_hg19, 17031_1_hg19, 23548_1_hg19 and 24982_1_hg19) showed an intermediate methylation level in nearly all tissues except for human sperm DNA, where all CGIs are typically unmethylated. No methylation in nearly all tissues was found in three CGIs (13250_1_hg19, 16458_1_hg19, and 20403_1_hg19), six CGIs are fully methylated in at least three tissues, and one CGI (6141_1_hg19) is not methylated in fetal tissues.…”

“…Single reads were not available for these data sets. 20 In addition to CGI_ID, genome coordinates, ancestral gene, mean methylation, mean coverage the number of reads is shown. The reads are divided into three classes, unmethylated (< 20% methylation), methylated ( 80% methylation) and partially methylated ( 20% and < 80% methylation).…”

“…41 The monocyte methylome data (methylome 1: ENA accession PRJEB5800; methylome 2: EGA accession EGAS000001000719) were already published by Rademacher et al 20 In addition, 16 methylomes of different tissues published by Ziller et al were downloaded from the gene expression omnibus (GSE46644) and two oocyte methylomes published by Okae et al were downloaded from the Japanese Genotype-phenotype archive under the Accession number JGA S00000000006.…”