The origin and evolution of genomic imprinting and viviparity in mammals

Abstract

Genomic imprinting is widespread in eutherian mammals. Marsupial mammals also have genomic imprinting, but in fewer loci. It has long been thought that genomic imprinting is somehow related to placentation and/or viviparity in mammals, although neither is restricted to mammals. Most imprinted genes are expressed in the placenta. There is no evidence for genomic imprinting in the egg-laying monotreme mammals, despite their short-lived placenta that transfers nutrients from mother to embryo. Post natal genomic imprinting also occurs, especially in the brain. However, little attention has been paid to the primary source of nutrition in the neonate in all mammals, the mammary gland. Differentially methylated regions (DMRs) play an important role as imprinting control centres in each imprinted region which usually comprises both paternally and maternally expressed genes (PEGs and MEGs). The DMR is established in the male or female germline (the gDMR). Comprehensive comparative genome studies demonstrated that two imprinted regions, PEG10 and IGF2-H19, are conserved in both marsupials and eutherians and that PEG10 and H19 DMRs emerged in the therian ancestor at least 160 Ma, indicating the ancestral origin of genomic imprinting during therian mammal evolution. Importantly, these regions are known to be deeply involved in placental and embryonic growth. It appears that most maternal gDMRs are always associated with imprinting in eutherian mammals, but emerged at differing times during mammalian evolution. Thus, genomic imprinting could evolve from a defence mechanism against transposable elements that depended on DNA methylation established in germ cells.

Figure 1.

The timing of genomic imprinting acquisition and of the divergence of birds and reptiles, monotremes, marsupials and eutherians. The vertical axes represent the time line from 400 Ma to the present. The coloured boxes represent each geological period. The green and red lines represent the evolution of the groups with and without genomic imprinting. The silhouettes represent one example species from each group. LTR, long terminal repeat.

Figure 2.

Regulation of the paternal and maternal expression in the Igf2–H19 imprinted domain by a single gDMR. The open lollipops represent unmethylated CpG islands and the black lollipops represent methylated CpG islands. The boxes represent Igf2 and H19 genes and the arrows from the boxes indicate expression of the genes. The yellow and green circles represent the CTCF insulator protein and a downstream enhancer, respectively.

Figure 3.

(a) Comparison of CpG contents and conservation among the orthologous genomic regions around the Nnat gDMR. The upper blue graphs show the CpG content in the genomic sequences. The lower pink graphs show conserved regions in the genomic sequences between one species and the other species located just below (eg. the pink graph seen in the mouse row is the comparison of mouse (base) and human and the graph in the human row is the comparison of human (base) and cow). The broken lines indicate where some conservation peaks in the upper row correspond in the next lower row. The arrowhead indicates the transcription start site (TSS) with the direction and the grey box shows the exon. Gaps in the sequences are represented by the light grey shadows in graph regions. The CGI forming gDMR in the mouse and the corresponding CGI in other species are highlighted in yellow. (b) Comparison of CpG contents and conservation among the orthologous genomic regions around the Lit1/Kcnq1ot1 gDMR. Explanations for the each component are the same as (a).

Figure 4.

The timing of the novel CpG island emergence in each maternal gDMR locus during mammalian evolution. The black circles represent the acquisition of novel CGI to the locus. The genes associated with novel CGI emergence are shown above the black circles. The silhouettes represent several example species from each group.