Retroviruses push the envelope for mammalian placentation

Retroviruses have had a tremendous, recurring impact on animal genomes. At least eight percent of the human genome is comprised of retroviruses at various stages of “fossilization” (1). These elements represent retroviruses that have directly infected genomes of germline tissues such that their imprints can now be passed on with the rest of the genome. Most insertions into host genomes are likely to (i) be instantly so deleterious that they are never passed on, or alternatively (ii) have very little consequence to host biology and be expected to abrade away via the accumulation of mutations (2). Although the large fraction of retroviral imprints show expected signatures of mutational degeneration, some retroviral genes have been surprisingly preserved against mutational inactivation. These represent instances in which host genomes have usurped some retroviral genes for their own use. Particularly intriguing are host domestications of retroviral envelope (env) genes. The best-known classes of these genes are the syncytin genes, which have been coopted by the host to mediate nutrient transfer from the mother to the developing embryo in eutherian mammals. In PNAS, Dupressoir and coworkers describe the oldest known domestication of retroviral envelopes represented by the Syncytin-Car1 gene (3), which was domesticated at least 60 Mya, before the radiation of Carnivora. These results extend the range and age of syncytin domestications in mammals, but also raise intriguing questions about the biology underlying their recurrent invention.

Domestication of the syncytin genes represents a dramatic example of convergent evolution via the cooption of a retroviral gene for a key biological function in reproductive biology. In fact, syncytin domestication from a retroviral envelope gene has been previously shown to have independently occurred at least seven times during mammalian evolution (4⇓⇓⇓⇓–9). In the context of retroviral genomes, the env gene encodes a protein precursor that is cleaved into surface (SU) and transmembrane (TM) proteins that allow virions to attach to target cells and penetrate the cell membrane by fusion. SU protein serves to bind the virion to the host cell by interactions with receptors on the cell surface, whereas the TM protein serves to anchor the entire viral glycoprotein complex on the virion surface and to mediate the fusion of the virion with the host-cell membrane during entry. Many envelope proteins also encode a short peptide motif within the TM domain that has potent immunosuppressive activities, suppressing the production of cytokines and cell-mediated immunity (10). Intriguingly, these two activities—the abilities to

Dupressoir and coworkers describe the oldest known domestication of retroviral envelopes represented by the Syncytin-Car1 gene.

mediate cell–cell fusion and evasion of the immune system—are key to the survival of the developing fetus in many mammals. The cell\x{2013}cell fusion properties are essential for embryonic viability in mice (11) and prevention of pregnancy loss in sheep (12) because they allow the development of a placental syncytiotrophoblast layer that mediates transfer of nutrients and gases from the maternal blood. Retroviral envelope-associated immunosuppressive properties might help protect the fetal tissues from immune attack by the maternal immune system, although a requirement for this function has not yet been demonstrated.

Three types of placental forms are found in eutherian mammals. Simian primates, rodents, and lagomorphs, in which syncytin genes have been described previously, all share the hemochorial type of placenta, in which fetal chorion is directly exposed to the mother's blood (13). A second, endotheliochorial form of placenta is also found among mammals including carnivores, wherein the fetal chorion is in contact with the endothelial wall of the mother's blood vessels (13). Despite the precedent of the seven separate syncytin genes (4⇓⇓⇓⇓–9), it was unclear whether mammals with endotheliochorial placentation also bear a syncytin. To address this question, the authors queried the completed genome sequences of cat, dog, and giant panda to identify any env-derived domesticated genes that had been preserved as intact ORFs (3). One gene appeared to have retained intact features of retroviral envelopes and was preserved in orthologous locations among the cat, dog, and giant panda genomes. Furthermore, this gene (Syncytin-Car1) had exclusive expression in the placenta, and in situ hybridization revealed that the expression pattern exactly coincided with the location where placental cells invade surrounding maternal tissues. Finally, pseudotyping experiments revealed that this particular envelope had retained fusogenic properties, i.e., it was able to confer infectious ability to an env-lacking recombinant retrovirus. Thus, a single envelope gene has been preserved in the same proviral context in the same genetic location since the common ancestor of dogs, cats, and bears. Detailed sequencing and analysis of Syncytin-Car1 in 26 species representing all the suborders of Carnivora also revealed that the gene has been preserved largely under purifying selection since its birth (3). All evidence (e.g., maternofetal boundary placental expression, preservation of fusogenic activity) suggests that the Syncytin-Car1 gene likely plays the same key role in placentation among all Carnivores first proposed in primate genomes and later demonstrated via genetic KOs in rodent genomes (3).