Now Reading
Why Humans Don’t Lay Eggs: A Viral Story

Why Humans Don’t Lay Eggs: A Viral Story

Representative image of various eggs. Photo: HTO/Wikimedia Commons, CC BY 3.0,

In 2011, a team of scientists led by the paleontologist Zhe-Xi Luo discovered a well-preserved fossil from North-east China that will push back the timeline of the emergence of a very important group of animals by 35 million years to 160 million years ago. Named Juraimaia sinesis i.e., the Jurassic mother from China, the fossil revealed a shrew-like mammal, barely 100 mm in length, that had walked upon the Earth alongside the gigantic dinosaurs of the Jurassic era.

The discovery of Juramaia is considered ‘a giant leap for mammal-kind’ as it represented the earliest known ancestor of Eutherians or placental mammals which roamed the Mesozoic earth. Eventually, this group of mammals were destined to rule the animal kingdom with the impending extinction of the giant reptiles at the end of the Cretaceous era. Placental mammals i.e., mammals that nourish the developing foetus through placenta, from bats to whales to humans, are very different from the two other mammalian groups that emerged before the Eutherians and which still have living representatives amongst us. These are the egg-laying mammals (Prototherians whose surviving examples are duck-billed platypus and echidna) and the pouched mammals (Metatherians represented by the Marsupials like Kangaroos and Opossums).

It has been argued by diverse groups of researchers that in a harsh Jurassic environment strewn with ferocious predators, Juramaia and its offspring would not have had a fair chance to thrive, if not for the placenta. The placenta allows for continuous nutrition supply, efficient exchange of respiratory gases, and a means for waste disposal in the live-bearing mammal. In other words, the placenta acts as the gut, lungs, kidney, and liver of the foetus in addition to secreting major hormones which will control the metabolism of not just the developing foetus but also of the mother. All these actions of the placenta will result in faster brain development, larger mature brains at birth, and a high metabolic rate – future trump cards for becoming the apex predator which descendants of Juramaia are destined for in the ensuing Cenozoic era, also known as the Age of Mammals. 

The obvious question is whether acquiring the placenta is a once-in-a-million-years flash in the evolutionary pan, a genetic prerogative that empowered the ancestral Eutherians to get a head start on ensuring the survival of offspring. The answer surprisingly is no! Let’s take the seminal definition of the placenta by professor H. W. Mossman as “apposition or fusion of the fetal membranes to the uterine mucosa (of the mother) for physiological exchange”. Placentas have evolved within every vertebrate class (fishes, amphibia, and reptiles) other than birds. It makes us wonder what sets apart the primitive placenta of these non-mammalian vertebrates from the more advanced placenta of 5,000 species of Eutherian mammals that are present on today’s earth. Are there greater adaptive driving forces? The quest for this answer leads us to a fascinating history of natural infection and invasion of placental tissues by viruses that occurred million years ago.

Soon after fertilisation, the embryo implants into the uterine wall, wherein all its future physiological demands will be met through the placenta that begins forming at about week four post-conception for humans. As the ball-like embryo attaches to the wall of the uterus, the outermost layer of this ball extends finger-like projections known as placental villi to invade the uterine tissue. A continuous layer of fused cells known as syncytiotrophoblasts line the outermost border of these finger-like villi and stand guard at the junction of the mother’s tissue with the fetal tissue. They act as the placental barrier ensuring nutrient and gas exchange occurs with the mother’s blood but nothing undesirable can get in from the maternal circulation to harm the embryo and the future fetus. Behind this critical ability of syncytiotrophoblasts to act as selective filter is the contribution of a unique gene and its encoded protein known as syncytin-1. In 1999, French researchers stumbled upon the origin of the syncytin-1 gene in human placenta and were amazed to find that the gene sequence showed a 100% match with the envelope protein of a human endogenous retrovirus known as HERV-W2. Further studies on laboratory mice subsequently revealed that if syncytin-1 is removed or inhibited, it will surely lead to the abortion of the foetus or cause embryonic death – thereby underlying the central role in mammalian reproduction.

Human placenta shown in the uterus connected to the fetus with the umbilical cord. Photo: Magnus Manske, Amada44/Wikimedia Commons, Public domain

Human endogenous retroviruses (HERVs) can be considered as fossil remains of ancient retroviruses (a family of viruses of which the most well-known representative is the human immunodeficiency virus type 1, which causes AIDS) which had infected our proto-placental ancestors. After gaining entry inside the host cell, retroviruses typically insert themselves into the host’s DNA, hijack the host’s cellular machinery to make thousands of copies of themselves, and then exit to infect more cells. During such an insertion event, it is likely that some ancient retroviruses lost their ability to multiply, eventually getting trapped inside the cells of the proto-placental ancestor and their genes consequently becoming a part of our DNA. Although the retroviruses of today are known to infect only bodily (somatic) cells, it is believed that in the past, they might have occasionally integrated into the germline DNA (DNA of eggs and sperms), enabling vertical transmission from one generation to the next.

The Human Genome Project, which mapped the entire DNA sequence found in humans, revealed upon its completion that as much as 8% of our DNA is in fact derived from different retroviruses which were endogenised over the course of mammalian evolution. For a long time, it was believed that these HERVs are part of our “junk DNA” i.e., DNA with no known function. But recent findings indicate the contrary, that many of the genes derived from HERVs possess biological activity that directly influences our healthy and diseased states (including multiple cancers and auto-immune disorders).

So, how did our placental ancestors gain syncytin-1? Paleovirologists estimate that retroviruses started infecting vertebrates around 450 million years ago. Somewhere between 150 and 200 million years ago, an ancestor of HERV-W2 may have infected a proto-placental ancestor of Juramaia. During infection, this retrovirus infected cells in the germ line (eggs and sperms) and owing to some random mutation lost its ability to multiply or exit thereby becoming an endogenous retrovirus. Through millions of years of evolution, most of the genes of this retrovirus got silenced but one gene continued to be functional. This is the syncytin-1 gene, originally responsible for encoding envelope glycoproteins to help the virus ‘to fuse’ with the host cell during the initiation of infection. Having lost its ability to contribute to the viral life cycle, the function of syncytin-1 was repurposed for the development of a multi-nucleate tissue layer which separates maternal and fetal blood in placental circulation thereby ensuring the integrity of the developing embryo. 

Is syncytin-1 the only ERV-derived gene that contributes to mammalian development in utero? A recent report in Science in 2022 by John A. Frank and colleagues from Cornell University indicates otherwise. Scanning the human genome for HERV-derived proteins, they found more than 1,500 coding sequences with 50% or more of these sequences suspected to play some role in human physiology. More detailed analysis identified a gene called suppresyn that is now believed to have infected our mammalian ancestors as recently as 30 million years ago and continues to be expressed in the embryo and the placenta. Experimental evidence indicates that suppresyn ironically plays a critical role in safeguarding the placenta from the invasion of other viruses. Another HERV-K-derived protein discovered in 2011 was proposed to play a defining role in suppressing the mother’s immune system, thereby ensuring that the embryo is not rejected during implantation.

Other than contributing to placental selectivity, host immunity, and maternal immune suppression, non-coding gene sequences from multiple HERVs have also contributed to other stages of mammalian pregnancy. In a study published in 2018 in PLoS Biology, Dunn-Fletcher and colleagues presented evidence that sequences residing within ERVs that integrated into our mammalian ancestors 50 million years ago control the timing of birth by regulating the levels of the immensely critical corticotrophin-releasing hormone (CRH).

A growing body of evidence continues to reveal and build on this remarkable evolutionary relationship between retroviruses and the placenta. Retroviral genes once destined to aid the virus in infection, hijacking, and multiplication within a susceptible host suddenly found themselves in a position from where they underwent exaptation by co-opting for roles that would prove critical to the survival and triumph of the placental mammals. It is incredibly tempting to speculate that human pregnancy would perhaps be very different, even non-existent, if not for the waves of successive viral pandemics afflicting our evolutionary ancestors since Juraimaia. As we return to the new normal in the post-COVID world, one may wonder if there will be far-reaching evolutionary consequences of this recently concluded pandemic. We indeed continue to exist in a virosphere, where the estimated number of viruses is greater than the estimated number of stars in the galaxies across the universe. The viruses have got the means and the motive. Are they just waiting for more opportunities to shape our future?

Sayandip Mukherjee has a PhD in molecular virology from Rutgers University, New Brunswick, NJ, US. He presently works as a senior research scientist in the R&D wing of a multinational company based out of Bangalore. The views expressed in this article are his own.

Scroll To Top