EVE-rybody ought to know about the Placenta

The placenta is one of the first organs to form during pregnancy. It sustains the fetus by exchanging nutrients, gases and waste between the fetus and its mother. But the placenta is also the interface between two genetically distinct individuals whose evolutionary interests are not always perfectly aligned. The maternal-fetal conflict hypothesis proposes that the offspring benefits from maximizing its own growth, even at the expense of the mother, whereas the mother benefits from countering these demands and balancing investments among several offspring. Work from the Hoekstra lab at Harvard showed that 20.5% of genes expressed specifically in the mature murine placenta are rapidly evolving and may be reflective of this evolutionary tug-of-war in resource allocation. 

Placental forms also vary remarkably amongst mammals, representing different evolutionary solutions to the challenges of pregnancy. Horses, whose offspring are relatively mature at birth, have placentas in which the maternal and fetal tissues remain separated by several layers of cells. Humans, who are born comparatively helpless and dependent, have placentas where fetal cells directly contact maternal blood. So how is the placenta built? The answer, in part, lies hidden within the mammalian genomes.

Viruses in our genomes

Endogenous retroviral elements or EVEs are remnants of viruses that infected our ancestors and became embedded in the genome. The viruses are often retroviruses which can copy their RNA genomes into DNA using the enzyme reverse transcriptase (yes, the same enzyme used in RT-PCRs!) and insert that DNA into the host genome. A retrovirus that is integrated with the host genome is known as an endogenous retrovirus or ERV. When this integration event happens in an egg or sperm producing cell, the viral sequence can be passed to future generations. Most of these sequences have accumulated mutations, deletions or other changes that prevent them from producing functional viruses. Some, however, still contain genes that can make proteins, others have been repurposed as regulatory sequences that influence when nearby genes are turned on.  

As obligate intracellular parasites, viruses carry proteins and regulatory elements that are exceptionally good at entering cells, redirecting cellular resources and evading immune defenses. Even separated from the rest of the virus, these viral elements are still a treasure trove of evolutionary possibilities that can be adapted for the host’s benefit. Over millions of years of coexistence with their host, ancient viral elements that provided a fitness advantage become retained in our genome through natural selection. In this way, some EVEs have become “domesticated” and given new roles that support cellular survival. 

Building and protecting the placenta

The placenta contains several remarkable examples of this viral domestication. One of the clearest examples of an EVE is Syncytin-1, a viral envelope protein. An important function of these types of protein is to bind to the host cells so that the viral envelope can fuse with the cell membrane and the virus can enter the cell. Syncytin-1 performs a similar function in the placenta. Produced by a special kind of human placental cells called trophoblasts, Syncytin-1 binds to a specific receptor on the surface of other trophoblasts allowing neighboring cells to fuse. Repeated fusion transforms many individual trophoblasts into one continuous layer called the syncytiotrophoblast. This layer forms the surface of the placental villi that is directly exposed to maternal blood. Thus, a protein that once helped a virus enter a host has now been repurposed to build a structure essential for pregnancy. 

Interestingly, the Syncytin-1 receptor may also represent an “Achilles heel” for placental cells. Certain types of retroviruses can use this receptor to sneak into primate placental cells and cause disease. While these retroviruses have not been found to infect humans, viral invasion of the placenta would have posed a serious threat to the developing fetus in early primates. Another ERV-derived envelope protein, Suppressyn or SUPYN can bind to the Syncytin-1 receptor during a retrovirus infection and block viral access to the receptor, making it more difficult for the invading virus to establish an infection. In this way, SUPYN may have therefore been repurposed from a protein that once facilitated viral entry into a protective shield at the maternal-fetal interface. 

Other viral remnants support fetal survival by helping the mother tolerate the fetus. The fetus contains genetic material from both parents and is therefore not identical to the mother. Normally, the immune system is trained to attack foreign material, so pregnancy requires mechanisms that can prevent an immune attack against the developing fetus. Syncytin-2, another viral envelope protein, along with Syncytin-1, have been detected in vesicles released from the placenta into the maternal circulation. Both proteins contain an immunosuppressive domain which has been shown to dampen maternal inflammatory responses, helping to create an immune tolerant environment for the fetus to develop safely. As such, a feature that may have once helped a virus evade the host immune system is now used to protect a developing mammal. 

Viral DNA plays important roles in pregnancy even without producing proteins. Some EVEs contain long repetitive sequences called long terminal repeats, or LTRs. These LTRs can function as switches that regulate nearby genes. In the placenta, these viral derived switches can influence genes involved in hormone production, the timing of birth and even regulate Syncytin-1 for the fusion of placental cells. Thus, ancient viral DNA contributes not only individual proteins but also parts of the regulatory system that coordinates pregnancy. This broader question—how viral regulatory sequences reshape gene expression—is also being explored in other viral systems, including work from the Li lab at Harvard on EBV-associated regulatory elements.

An evolutionary partnership

Our relationship with viruses is not solely one of conflict. Studying influenza, measles, COVID-19 and other viral diseases has deepened our understanding of human biology, history, and society. Viral genomes can help trace patterns of migration, while the spread of viral diseases reflects changes in urbanization and human behavior. Efforts to control viral infection have also driven major advances in vaccination, sanitation, and public health. 

ERVs take this relationship even further. Embedded within our very own genomes, they are traces of ancient threats that evolution has transformed into a resource, helping to shape the organisms we are today. At the recent Harvard Virology Retreat, our keynote speaker, Dr Daniel Blanco-Melo from the Fred Hutchinson Institute reminded us exactly how studying ERVs and other ancient viruses can illuminate our evolutionary past. Harvard researchers, including Michael Segel, are also examining ERVs in other contexts, such as aging and development. Viruses have accompanied us throughout our evolutionary history. To understand them is therefore also to understand where we came from, how we got here, and where we can go next. 

This article was written by JC Lin (G3) with graphics designed by Peter Hoferle (G3).