The Parental Non-Equivalence of Imprinting Control Regions during Mammalian Development and Evolution

Abstract

In mammals, imprinted gene expression results from the sex-specific methylation of imprinted control regions (ICRs) in the parental germlines. Imprinting is linked to therian reproduction, that is, the placenta and imprinting emerged at roughly the same time and potentially co-evolved. We assessed the transcriptome-wide and ontology effect of maternally versus paternally methylated ICRs at the developmental stage of setting of the chorioallantoic placenta in the mouse (8.5dpc), using two models of imprinting deficiency including completely imprint-free embryos. Paternal and maternal imprints have a similar quantitative impact on the embryonic transcriptome. However, transcriptional effects of maternal ICRs are qualitatively focused on the fetal-maternal interface, while paternal ICRs weakly affect non-convergent biological processes, with little consequence for viability at 8.5dpc. Moreover, genes regulated by maternal ICRs indirectly influence genes regulated by paternal ICRs, while the reverse is not observed. The functional dominance of maternal imprints over early embryonic development is potentially linked to selection pressures favoring methylation-dependent control of maternal over paternal ICRs. We previously hypothesized that the different methylation histories of ICRs in the maternal versus the paternal germlines may have put paternal ICRs under higher mutational pressure to lose CpGs by deamination. Using comparative genomics of 17 extant mammalian species, we show here that, while ICRs in general have been constrained to maintain more CpGs than non-imprinted sequences, the rate of CpG loss at paternal ICRs has indeed been higher than at maternal ICRs during evolution. In fact, maternal ICRs, which have the characteristics of CpG-rich promoters, have gained CpGs compared to non-imprinted CpG-rich promoters. Thus, the numerical and, during early embryonic development, functional dominance of maternal ICRs can be explained as the consequence of two orthogonal evolutionary forces: pressure to tightly regulate genes affecting the fetal-maternal interface and pressure to avoid the mutagenic environment of the paternal germline.

Imprinted gene expression in hybrids: perturbed mechanisms and evolutionary implications

“…At the maternally methylated ICRs, there is even a tendency to strongly maintain CpG density. At paternal ICRs, in contrast, CpG density is lost during evolution, which indicates that these ICR regions evolve more quickly than the maternal ICRs (Schulz et al, 2010).…”

Coadaptation and conflict, misconception and muddle, in the evolution of genomic imprinting

“…How does the maternal genome facilitate expression of paternal alleles? Moreover, the example of Igf2 was ill-chosen because this is one of the few imprinted genes with an ICR that is methylated in paternal rather than maternal germlines (Schulz et al, 2010).…”

DNA Sequence Characteristics and Phylogenetics of Putative Imprinted Genes on Bovine Chromosome 29

“…Genomic imprinting is widely studied due to its involvement in various biological processes such as brain function and behaviour (Garfield et al, 2011), tumorigenesis (Lim & Maher, 2010), control of intra-uterine growth and birth weight (Schulz et al, 2010), reprogramming during embryo and nuclear transfer as well as in somatic cell cloning (Kedia-Mokashi et al, 2011). It provides a mechanism to distinguish between the paternal and maternal genomes and also regulate biological processes.…”