Placentas are most diverse organs across mammalian species. Although the mammals obtained several new genes specific to pregnancy recognition and/or maintenance, wthich are often species’ specific, gene expressions for placental development and/or their structural diversity have not been well characterizede diversity of placental structures cannot be explained through the expression and functions of functional genes. It has long been thought that viral/transposon components exist in organism’ genomes. In 2000, Mi et al. found that endogenous retrovirus (ERV, Syncytin-1) exists in the human placenta ^[1]. Since then, syncytin-typlike ERV structures and their functions have been reported in many animal species ^[1][2][3][4], but none of them contain the same nucleotide structures, strongly suggesting that these ERVs are independently captured and integrated into mammalian genomes ^[54].

Mammalian placentas are extraordinarily diverse in terms of cell types, structure and their association with maternal blood, although placentas play the same roles such as physical and immunological protection against the maternal immune system, nutrient and gas exchanges, and endocrinological regulation ^[6]. During the last several decades, scientists in developmental biology and/or virologists have occasionally proposed retrovirus’s role in placental evolution. For example, Haig (2012) proposed that the placenta became a mammalian tissue in which retroviral genes were domesticated to serve an adaptive function in the host ^[7]. Such an interplay may have contributed to evolutionally mechanisms associated with genomic imprinting of numerous genes.

Figure legend: Mammalian placentas as classified by the distribution of chorionic villi. A: Diffuse placentas to which pigs and horses belong. B: Cotyledonary placentas, commonly found in ruminant ungulates. C: Zonary placentas to which dogs and cats belong. D: Discoid placentas, seen in murine and primate species including humans.

Imprinting genes such as those of paternally expressed genes, PEG10 ^[85] and PEG11/RTL1 ^[96], have been extensively studied for their contribution to the evolutional development of mammalian species. Thand through gene ablation studies, these genes are found necessary for the formation of placental structures ^[107][118]. Because PEG10 is acquired more than 146 million years ago, PEG10 gene could explain the initial formation of placentas in mammals. However, struplacturental diversity of placentas cacannot be explained through the integration and function of PEG10 and PEG11/RTL1 g. The renes. The phylogenetic record shows multiple independent instances of syncytin-typearchers have presented re ERV gcenes’ entry into disparate clades over the last 50 million years and related findings that explain how ^[5], stroyngly suggesting that syncytin-type cytin genes as prime candidates for the emergence of structure involved in placental diversification of mammalian placentas. Recently, more and more data have been accumulated, demonstrating thatty. The researchers presented recent observations on ERVs and how syncytin-typhese ERVs control gene expression of both functional genes as well as ERV themselves ^[129][1310]. It iBas often observed that ERV integratied ons into mammalian genomes proceed successively: one ERVthe recent exaptation is followed by successive invasions of new ERVs. Tnformation, the new interloper retroviral genes may subsume the role previouresearchers ERVs played. These ongoing and successive ERV acquisitions fopr the establishment of more advantageous systems are explained by “a baton ented the baton-pass hypothesis” ^[14].

In general, the placentas have lower DNA methylation levels than embryos, allowing freer expression of ERVs and transposons dsuring gestation, thereby facilitating selection of advantageous genes from a wider market. Such extraembryonic circumstances might have allowed for not only domestication of ERVs cessive into establish novel endogenous genes via multiple of selections but also the dissemination ogration of ERVs and^[11] transposons throughout genomes as transcriptional regulators. Similarly, various degrees of maternal-fetal cell interactions in the uterine compartment may have led to change in kinds and degree of gene usage ^[7], possibd new modely resulting in cellular and morphological changes in placentas. It is interesting to speculate that the placentas themselves might have served as an evolutionary laboratory to promote mammalian evolution ^[15] explaining placental diversity.

The Fusouter most cell layer at the fetal side of placentas is called “trophectoderm”. Across genic activity in the mammalian species, the ttrophectodermal cells e exhibits a great deal of fusogenic activitysimilarity across species, notwithstanding the huge diversity in placental structures and type of placentation such as invasive (humans and murine) or non-invasive (pigs and ruminants) to the maternal endometrium. Based on actual experimentation and typical amino acid sequences, ERVs’ their functions are generally limited to fusogenic activity and immunotolerance, which on their own are not sufficient to fully explain the structural diversity of placentas.

Dunn-Fletcher and colleagues (2018) have demonstrated that retroviral THE1B sequence serves as a cis-element for the regulation of corticotropin-releasing hormone (CRH) gene expression ^[16]. Recently, progress has been made on research into ERV sequences serving as transcriptional and translational regulators ^[129][1310]. These sequences could be co-opted for newly integrated retroviral gene regulation.

Nevertheless, solid confirmation of a retrovirus integration into sperm or egg has not been obtained, and the mechanism of integration remains unclear. The rarity of such events owes in no small part to the narrow windows of possibility for infection, but conversion to active ERVs is also contingent on the perfect confluence of criteria as follows:

1. The insertion of ERVs can make functional genes of the host placenta-specific. i.e., Fematirn-1 integration into the intron 18 of pregnancy specific FAT2
2. Its own LTR is sufficient to transcribe its own gene segments, which serves as the cis-acting element(s), resulting in the activation of a host gene. i.e., IFNG, THE1B on CRH.
3. It can make use of transcription factors utilized by the pre-existing gene, as per the baton-pass hypothesis. i.e., A transcription factor GCM1 for syncytin-1 and syncytin-2.
4. The ERV is co-opted along with its promoter/enhancer in the integrated genome; i.e., SPRE (syncytin post-transcriptional regulatory element).
5. There is cooperation with miRNAs and/or lncRNAs, yet not definitely characterized under placental/trophectodermal conditions, either alone or together with ERV

In a) Thge insertion of ERVs cneran make functional genes of the host , the placenta-specific.

 s have  lower    i.e., Fematirn-1 inDNA metegrhylation into the intron 18 of pregnancy specificlevels than embryos, allowing freer expression of FAT2ERVs geane.

 d b) Its own LTR is sufficient to transcribe itransposons during gestation, thereby facilitating selection of advantageous gene segments, which serves as the cis-acting element(s), resulting in the activs from a wider market. Such extraembryonic circumstances might have allowed for not only domestication of ERVs to establish host gene.

 novel endogenous genes      vi.e., IFNG, THE1B on CRH.

  c) It can make use of transcription factors utilized by the pre-existing gene,ultiple of selections but also the dissemination of aERVs perand the baton-pass hypothesis.

 ransposons throughout genomes as    i.e., A transcription factor GCM1 for syncytin-1 and syncytin-2.

  d) Thal regulators. Moreover, ERV is co-opted along with its promoter/enhancer in the integrated genome.

 uld serve as cis- and/or trans-acting factors for functional genes  of  i.e., Syncytin post-transcriptional regulatory element (SPRE).

 the host. Similarly, various degrees of maternal-fetal cell interactions in the uterine compartment may have) There is cooperation with miRNAs and/or lncRNAs led to change in kinds and degree of gene usage ^[12], possiblyet not definitely characterized under resulting in cellular and morphological changes in placental/trophectodermal conditions, either alone or together with s. It is interesting to speculate that the placentas themselves might have served as an evolutionary laboratory to promote mammalian evolution        ERV^[13].

It is now clear that the emergence of mammalian placentas was made possible with the acquisition of therian PEG10 and eutherian PEG11/RTL1 genes, followed by independent, yet successive integrations of syncytin-type ERV genes. for Sstructural variations in mammalian placentas could have been obtained through ERVns’own functions as well as the regulation of functional genes and/or ERVs themselves. A question still arises as to whether the placental structures that we know now are the ultimate forms or are still evolving. If the latter is the case, placental structures may still be diversifying and new variations could be awaiting discovery.