CSIRO PUBLISHING Reproduction, Fertility and Development, 2019, 31, 1219–1227 Review https://doi.org/10.1071/RD18127 Evolution of viviparity in mammals: what genomic imprinting tells us about mammalian placental evolution Tomoko Kaneko-IshinoA,C and Fumitoshi Ishino B,C ASchool of Health Sciences, Tokai University, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan. BDepartment of Epigenetics, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan. CCorresponding authors. Emails: [email protected]; [email protected] Abstract. Genomic imprinting is an epigenetic mechanism of regulating parent-of-origin-specific monoallelic expres- sion of imprinted genes in viviparous therian mammals such as eutherians and marsupials. In this review we discuss several issues concerning the relationship between mammalian viviparity and genomic imprinting, as well as the domestication of essential placental genes: why has the genomic imprinting mechanism been so widely conserved despite the evident developmental disadvantages originating from monoallelic expression? How have genomic imprinted regions been established in the course of mammalian evolution? What drove the evolution of mammalian viviparity and how have genomic imprinting and domesticated genes contributed to this process? In considering the regulatory mechanism of imprinted genes, reciprocal expression of paternally and maternally expressed genes (PEGs and MEGs respectively) and the presence of several essential imprinted genes for placental formation and maintenance, it is likely that complementary, thereby monoallelic, expression of PEGs and MEGs is an evolutionary trade-off for survival. The innovation in novel imprinted regions was associated with the emergence of imprinting control regions, suggesting that genomic imprinting arose as a genome defence mechanism against the insertion of exogenous DNA. Mammalian viviparity emerged in the period when the atmospheric oxygen concentration was the lowest (,12%) during the last 550 million years (the Phanerozoic eon), implying this low oxygen concentration was a key factor in promoting mammalian viviparity as a response to a major evolutionary pressure. Because genomic imprinting and gene domestication from retrotransposons or retroviruses are effective measures of changing genomic function in therian mammals, they are likely to play critical roles in the emergence of viviparity for longer gestation periods. Additional keywords: complementation hypothesis, domesticated genes, evolutionary trade-off, genome defence mechanism, Peg10, Peg11/Rtl1, reciprocal monoallelic expression, retrotransposons. Received 5 April 2018, accepted 1 October 2018, published online 10 January 2019 Why has genomic imprinting been widely conserved in discovery. For example, the prevention of parthenogenetic viviparous mammals? development may be advantageous for mammalian reproduc- This question may be put alternatively as ‘What is the merit of tion because females can avoid childbearing in seasons unfit for genomic imprinting in the therian mammals that overwhelms child rearing (Solter 1988). Another advantage is the prevention its developmental disadvantages originating from monoallelic of the development of trophoblast cells, placental cells with an expression of a series of essential imprinted genes?’ All the invasive nature, to avoid developing malignant ovarian ter- human genomic imprinting diseases, such as Silver–Russell, atocarcinomas that arise during parthenogenesis (Varmuza and Beckwith–Wiedemann, Prader–Willi, Angelman, Albright, Mann 1994). However, it is difficult to test such hypotheses by Kagami–Ogata and Temple syndromes (Kalish et al. 2014), as purely experimental procedures. To address these types of well as their related developmental, growth and behavioural issues, it is reasonable to expect that it will be necessary to at abnormalities observed in mice, are attributable to the mono- least advance our knowledge of the regulatory mechanism allelic expression of imprinted genes. This is because (partial) underlying genomic imprinting, the evolutionary relationship uniparental chromosome duplications induce a lack and/or between genomic imprinting and viviparity, the environmental overexpression of relevant imprinted genes (Cattanach and pressure that drove their evolution and the genetic factors Beechey 1990; Blake et al. 2010). Several advantages conferred that enabled these processes. Knowledge accumulated so far by genomic imprinting have been proposed since its initial warrants further discussion. Journal Compilation Ó CSIRO 2019 Open Access CC BY-NC-ND www.publish.csiro.au/journals/rfd 1220 Reproduction, Fertility and Development T. Kaneko-Ishino and F. Ishino Maternally imprinted region Methylated DMRs In the two versions of ‘the conflict hypothesis’, the weak Non-metylated DMRs version has come to be widely accepted as the concept of MEG ‘parental conflict’ (Moore and Haig 1991). This version states PEG that in viviparous organisms, such as therian mammals, under polygamous conditions in which females are able to accept more than one male, the genes from the paternal alleles tend to PEG promote embryo growth, whereas genes from the maternal MEG alleles tend to inhibit embryo growth as a consequence of the Paternally imprinted region genetic conflict between the paternal and maternal alleles. A Maternally derived Paternally derived substantial number of paternally and maternally expressed genome genome genes (PEGs and MEGs respectively) fit well with this predic- Fig. 1. Reciprocal monoallelic expression of paternally and maternally tion, such as the paternally expressed insulin-like growth factor expressed genes (PEGs and MEGs respectively). In both paternally or 2(IGF2) and maternally expressed insulin-like growth factor 2 maternally imprinted regions, PEGs and MEGs exhibit reciprocal mono- receptor (IGF2R) genes (Killian et al. 2000; Reik and Walter allelic expression. The DNA methylation status of differentially methylated 2001; Wilkins and Haig 2003; Hore et al. 2007; Renfree et al. regions (DMRs) is indicated by the black (methylated) and white (non- 2009). The former encodes the embryonic growth factor IGF2, methylated) circles. whereas IGF2R protein binds IGF2 and degrades it by transport- ing it to the lysosome. Conversely, the so-called strong version Maternally derived chromosome of the conflict hypothesis predicts that under the continuous Insulator-binding pressure exerted by genetic conflict, the genomic imprinting protein (CTCF) mechanism inevitably originates in viviparous organisms during the course of evolution (Wilkins and Haig 2003). Through a process known as evolutionary equilibrium, a locus that was MEGX initially expressed in both alleles gradually comes to be Paternally derived chromosome expressed from a single allele, with the other allele made silent by means of natural selection. This process involves the increased expression of one allele and the decreased expression DMR of the other. For example, a growth factor gene initially showing PEGZ PEGY biallelic expression is gradually changed to paternal allele- Promoters Insulator Enhancer specific expression over a long period, when fitness is deter- mined by the level of the growth factor and natural selection Fig. 2. The differentially methylated region (DMR) acting as an imprint- ing regulator: an insulator model. In this case of a paternally imprinted favours higher production when an allele is paternally derived region, the paternal DMR is fully methylated whereas the maternal DMR is than when it is maternally derived. It is known that genomic not methylated. The DNA methylation status of the DMR regulates recipro- imprinting is also observed in plants, such as angiosperms, cal monoallelic expression of paternally and maternally expressed genes providing strong support for this hypothesis (Haig and Westoby (PEGs and MEGs respectively). Importantly, expression of PEGs requires 1991). However, the emergence of genomic imprinting regions DNA methylation of the DMR. CTCF, CCCTC-Binding Factor. They are in mammals is likely to arise as a genome defence mechanism model examples of one MEG and two PEG genes, numbered X, Y, Z. against the insertion of exogenous DNA, suggesting that target chromosomal regions and/or genes were at first randomly mutated. Some were then selected as imprinted regions and/or Hark et al. 2000) or transcriptional start site of antisense RNA imprinted genes as a result of developmental advantages, which (antisense of IGF2R non-protein coding RNA (AIRN) in the has also been predicted by the weak version of the conflict IGF2R region; Sleutels et al. 2002; Latos et al. 2012; Fig. 2). hypothesis. This is the mechanism by which the methylated DMR sequence In considering the regulatory mechanism of imprinted gene not only represses certain imprinted genes, but also induces expression, we have proposed ‘the complementary hypothesis’ expression of other imprinted genes over a substantially wide (Kaneko-Ishino et al. 2003, 2006; Kaneko-Ishino and Ishino imprinted region, sometimes up to 500 Mb. In the maternally 2015), in which the monoallelic expression mechanism emerged imprinted regions, DMR DNA methylation represses PEGs but as an evolutionary trade-off for survival. Usually, each induces MEGs. Conversely, DMR DNA methylation in pater- imprinted region comprises both PEGs and MEGs and their nally imprinted regions represses MEGs while inducing PEGs reciprocal