Evolution of imprinting mechanisms: the battle of the sexes begins in the zygote

Imprinted genes in the mammalian genome are those genes for which one of the parental alleles is repressed, whereas the other one is transcribed1, 2. Forty imprinted genes are currently known in the mouse (excluding antisense transcripts), and maternally and paternally repressed genes are represented equally3. Almost all imprinted genes have differentially methylated regions (DMRs); some DMRs are methylated differently in egg and sperm, and these differences can be inherited in the somatic tissues of the offspring1, 2. DNA methylation is normally associated with gene silencing4; however, 7 of 18 imprinted genes have DMRs that are methylated on the active allele3. In mouse embryos that fail to maintain methylation because of a deficiency in DNA methyltransferase I, some imprinted genes (H19, Snrpn) are expressed from both parental alleles, but others (Igf2, Igf2r) are silenced on both parental alleles5, 6. Imprinted genes can be silenced 'epigenetically' by mechanisms such as promoter methylation, or 'genetically' by mechanisms involving, for example, antisense RNA, silencers or chromatin boundaries1 (Fig. 1). Significantly, in this case the allele is silent in the absence of epigenetic modification, and the methylation of such silencing elements is required for the expression of the imprinted gene. Here we show that, for most genes from either category, the methylation imprint is derived from the oocyte, and attempt to provide an explanation for this intriguing asymmetry.