The viral footprints: Are we the living fossils...?

Recall what you know about DNA, genes, and genome. We usually know that it is the genetic makeup of an organism that makes the organism unique including us. We are humans because we have the DNA content that makes us look like and think like humans. 

The greatest breakthroughs in science don't come by proving something but asking more proximate questions to the old problems only to come up with a more stunning revelation. Considering the human species on this planet, we have a very brief history to tell on evolutionary time scales since the origins of life. Most of the time our planet has cherished the existence of microbes and later on primitive single-celled eukaryotes. While we call the present year as the year of pandemic worst-hit by a virus, there is an immense battle going on between bacteria and viruses in the environment, for millions of years and still continuing today on an unimaginable large scale. This led to another discovery of bacterial DNA carrying the genes of the viruses. This was long known. But wait is it true for us humans too?

Do we contain the genes from viruses? Now, this question is as philosophical as it seems to be. While the hypothesis in science requires some preemptive data, so does this question. If you take a tour into the human genome, it consists of around 3.2 billion base pairs. Out of this only, ~2% are genes coding for proteins making us who we are while the largest chunk of the DNA was considered to be the part of the maligned "Junk DNA". These larger unexplored regions of our genomes remained mysterious as the dark matter in our universe for many years since the discovery of the Double Helix. But not too long. So, let's take a ride..!

The viral footprints...!

The year 1960, proved to be a catastrophe for the domestic chickens. Strangely a large population of hens was dying of a cancer-causing Avian Leukosis virus. This virus swept out the poultry industry to a large scale. Further studies led to it being classified into a group of viruses called, "Retrovirus". It switched on several genes inside the host which could lead to cancer. 

Upon looking at the blood samples of the healthy chickens, something extraordinary was found. The virus proteins were also found in the healthy chickens that never developed the disease in its lifetime. Robert Weiss, the Beijerinck Virology Laureate for his work in retroviruses wondered if the virus was already a part of the chickens' genome.  

Robert Weiss [1]

The expedition for these viral fossils was on. He and his group found that the genetic copies of these viruses were implanted into all of the cells including the germline cells. This led to the inheritance of these viral elements into their offsprings following the Mendelian Inheritance patterns just as the rest of the genes followed. Upon subjecting the cells of the healthy chickens with mutating chemicals, the virus particles started to pop off from the cells. 

Further evolutionary history suggests that the presence of these viral sequences into the healthy chickens was due to these sequences were robbed of their activity due to attaining large scale mutations upon passing through millions of generations. These viruses then became embedded in their genome staying inactive. Such viruses were then grouped as Endogenous Retrovirus (ERVs). 

Viral Fossils within Us and the way they shaped humanity...!

Looking into the human genome, it was found that nearly 8% of the genome was actually made of Endogenous Retroviral elements (ERVs) [2]. That's right! In the face of 2% of the coding genes, it seems we are more virus than humans. ERV sequences in humans are called HERVs (H stands for Humans). 

HERVs are proviral elements trapped within our genomes, were not simply inactive baggage of DNA as seen in case of chickens. These viral elements were actually coding for proteins or were part of the regulatory sequences. They were behaving like Retrotransposons (called Jumping genes) which could self copy and attach to different regions of the genome. On the other side of evidence, these sequences were quite conserved during the evolutionary course of human history suggesting that they were vital to us. On what scale they were important to us was the next exploration into the wild unknown.

HERV and the Embryonic cells

Several groups of HERV sequences were discovered in human genomes and their roles were studied [3]. A certain group of the viral elements called HERV-H was seen to be highly expressed in embryonic pluripotent cells and was silent throughout the rest of the life. It was found that HERV-H was actually maintaining the pluripotent stage of the embryo up to a definite amount of time required. Removing these elements resulted in the differentiation of the cells and expressing these sequences in adult cells resulted in a transient conversion of Human Embryonic Stem Cells (hESC) showing pluripotency. Not until very recently, the complete role of HERV-H was discovered. In 2014, Lu et al [4] discovered that HERv-H was expressed into a Long Noncoding RNA. Being huge in size it tethers two important proteins taking part in regulating other genes maintaining the pluripotent cell stage in the embryo. 

Joanna Wysocka [5]

Another interesting family of HERV called HERV-K was found in embryonic cells to be quite active especially during the Blastocyst stage. This viral element appeared quite later than other sequences in an evolutionary sense [6]. A team led by Joanna Wysocka at Stanford University took up this challenge to scrap HERV-K at the molecular level to understand: What is it? and Why is it? Again it was a Eureka moment for them. One of the protein HERV-K codes was seen to provide protection against harmful viral infections. It was unbelievable to see for the first time that an ancient viral fossil was actually helping a very immature embryo against environmental viruses and develop the first innate antiviral defense into it. Thanks to these HERVs that saved us from infections even before the immune system was planning to do so.

HERV and the fetus

The story of the debt of these viruses continues later to the fetal stage. As a brief recap fetus gets its nutrition from its mother through the placenta. Placental tissue adheres strongly to the uterine wall helping the fetus for nutrient exchange. A distinct family of HERVs was seen to be tremendously active in specialized placental cells called Syncytiotrophoblasts. Upon diving into its protein products, it was revealed that they were actually coding for Syncytin. 

Syncytin is a sticky protein that helps to form intercellular adhesions and thus helping the placenta to remain tethered to the uterine wall. Upon looking at its function in the virus, it was observed that proteins similar to Syncytin were responsible for the fusion of the virus to its host cells. But this property was lost with mutations and it was harnessed by the jawed vertebrates to form the placenta. This co-evolutionary evidence of syncytin with vertebrates suggests that these HERV guests played a vital role in giving rise to the viviparity itself [7]. 

But humans have two Syncytins: Syncytin 1 and 2. The second one contained an Immunosuppressive domain (ISD) in its structure. Well if it was a virus it is obvious to have played a role in a successful infection. But now since it is fossilized as Syncytin 2 in humans, what it is supposed to be doing? Well, we know that fetus carries 50% of the genetic makeup from its father. This is alien to the mother's immune system and the fetus might get rejected easily. But here comes the role of Syncytin 2. Its ISD helps to attenuate the mother's immune system preventing the rejection of the fetus. 

Apart from this, HERVs are also seen to play a role in neurological disorders like Multiple Sclerosis and ALS. The story continues in the adult stage where HERV codes for your Salivary Amylase which breaks down complex sugars in your mouth to give you the sweet taste and ease the digestion by your intestine. 

Perspectives

These ancient viral fossils helped us not only to survive the crucial stages of the development but have also shaped humanity from placental bearing beings to an adult with organs at the right position at right time with an ability to enjoy the sweetness better. These microbial world though seems unpredictably dangerous to us, it always continues its saga of success of its own as well as other beings on this planet. To end here, this is the quote by one of my favorite authors, Carl Zimmer:

"In our most intimate moment, as new human life emerges from old, viruses are essential to our survival. There is no us and them— just a gradually blending and shifting mix of DNA."

References:

1. Image adapted from https://www.i-sense.org.uk/professor-robin-weiss-talks-us-about-his-career-during-early-years-hiv-research.
2. Hattori M. Tanpakushitsu Kakusan Koso. 2005;50(2):162-168.
3. Nelson PN, Carnegie PR, Martin J, et al. Demystified. Human endogenous retroviruses. Mol Pathol. 2003;56(1):11-18. DOI:10.1136/mp.56.1.11
4. Lu X, Sachs F, Ramsay L, et al. The retrovirus HERVH is a long noncoding RNA required for human embryonic stem cell identity. Nat Struct Mol Biol. 2014;21(4):423-425. DOI:10.1038/nsmb.2799
5. Image adapted from https://wysocka.stanford.edu/
6. Shin W, Lee J, Son SY, Ahn K, Kim HS, Han K. Human-specific HERV-K insertion causes genomic variations in the human genome. PLoS One. 2013;8(4):e60605. Published 2013 Apr 12. DOI:10.1371/journal.pone.0060605
7. Villarreal LP. On viruses, sex, and motherhood [published correction appears in J Virol 1998 Jul;72(7):6277. Villareal LP [corrected to Villarreal LP]]. J Virol. 1997;71(2):859-865.