Abstract
BackgroundGenomic imprinting is an evolutionary conserved mechanism of epigenetic gene regulation in placental mammals that results in silencing of one of the parental alleles. In order to decipher interactions between allele-specific DNA methylation of imprinted genes and evolutionary conservation, we performed a genome-wide comparative investigation of genomic sequences and highly conserved elements of imprinted genes in human and mouse.ResultsEvolutionarily conserved elements in imprinted regions differ from those associated with autosomal genes in various ways. Whereas for maternally expressed genes strong divergence of protein-encoding sequences is most prominent, paternally expressed genes exhibit substantial conservation of coding and noncoding sequences. Conserved elements in imprinted regions are marked by enrichment of CpG dinucleotides and low (TpG+CpA)/(2·CpG) ratios indicate reduced CpG deamination. Interestingly, paternally and maternally expressed genes can be distinguished by differences in G+C and CpG contents that might be associated with unusual epigenetic features. Especially noncoding conserved elements of paternally expressed genes are exceptionally G+C and CpG rich. In addition, we confirmed a frequent occurrence of intronic CpG islands and observed a decelerated degeneration of ancient LINE-1 repeats. We also found a moderate enrichment of YY1 and CTCF binding sites in imprinted regions and identified several short sequence motifs in highly conserved elements that might act as additional regulatory elements.ConclusionsWe discovered several novel conserved DNA features that might be related to allele-specific DNA methylation. Our results hint at reduced CpG deamination rates in imprinted regions, which affects mostly noncoding conserved elements of paternally expressed genes. Pronounced differences between maternally and paternally expressed genes imply specific modes of evolution as a result of differences in epigenetic features and a special response to selective pressure. In addition, our data support the potential role of intronic CpG islands as epigenetic key regulatory elements and suggest that evolutionary conserved LINE-1 elements fulfill regulatory functions in imprinted regions.
Highlights
Genomic imprinting is an evolutionary conserved mechanism of epigenetic gene regulation in placental mammals that results in silencing of one of the parental alleles
Imprinted genes are flanked by long intergenic regions In order to get a comprehensive picture of DNA sequence properties in imprinted regions, we compared a set of 58 protein-coding imprinted genes to all 17,916 protein-coding autosomal human genes from the UCSC Genome Browser RefSeq genes track [33]
In order to differentiate between the contribution of protein-coding sequences and adjacent intronic parts to phastCons28wayPlacMammal most conserved sequence (PCS), we separately investigated the subsets of PCSs that are completely located in coding exons
Summary
Genomic imprinting is an evolutionary conserved mechanism of epigenetic gene regulation in placental mammals that results in silencing of one of the parental alleles. In order to decipher interactions between allele-specific DNA methylation of imprinted genes and evolutionary conservation, we performed a genome-wide comparative investigation of genomic sequences and highly conserved elements of imprinted genes in human and mouse. Imprinted genes are monoallelically expressed in a parent-of-origin way, i.e. one of the two alleles is silenced depending on its parental origin. They are often found in clusters around differentially methylated regions (DMRs) that are characterized by hypermethylated DNA on one chromosome but hypomethylated DNA on the other [1,2]. In combination with other sequence features, the distinct distribution of repetitive elements has subsequently been used to predict putative imprinted genes in the mouse and human genomes [9,10]
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