The story of our rise, the all-too-familiar emergence of Homo sapiens, comes with a plot-twist that many are not familiar with. We owe our survival to viruses, because if not for them, we may not be here at all. Like pulling invisible strings, viruses quietly influenced our existence and shaped our evolution for hundreds of thousands of years.

Where it all started

For the last 500 million years, ever since they evolved, several viruses have tucked away their genes into the DNA of their hosts, humans included. However, this viral integration remained in the dark until a century ago.

It all started one night in 1910, at the Rockefeller Institute in New York. Biologist Peyton Rous, curious about the cause of tumors, transplanted a small piece of tumor from one chicken to another. Soon enough, the other chickens developed highly invasive cancer. This was most surprising to him because he had filtered out all the cancerous cells before the transplantation. So, what could possibly be causing raging cancer in the transplanted chickens if there were no cancer cells? After a relentless pursuit, the cause was found to be Rous sarcoma virus (RSV), a member of the retroviridae family. Soon enough, other retroviruses embedded in the chicken genome were identified. 

This caused a wild intriguing theory among the scientists back then: Could we have parts of the viral genome in us too? With the human genome sequenced in the 1990s, we had our answer. Our genome showed countless genes of viruses embedded in our DNA. In fact, they were so common (occupying ~8% of our genome), and the scientists called these the ‘human endogenous retroviruses’ (HERV). 

How viruses became permanent residents

Viruses are largely infectious agents. They enter the hosts, command the cell machinery to work in their favor, replicate to form new viruses and release to infect other cells. That’s just all how viruses work. 

Since viruses have existed from time immemorial, our ancestors were exposed to a plethora of them. Some of the viruses are just temporary ‘visitors,’ exiting the host after establishing an infection. Others, however, are stealthier and make their way into the genome to integrate their genes into the host DNA without tipping off the immune system. Once they infiltrate, the viral genetic material can hop around, inserting chunks of their genes at random in the host genome. This causes a drastic rewiring of the human genome network and gets passed on from one generation to the next. Just like that, these viruses become one with the host.

Our cells’ fool-proof mechanisms

If the viruses are long integrated with our DNA, what stops them from being infectious again? Thanks to the years of co-evolvement with the viruses, our cells have developed counter-active mechanisms to stop the infection. First, some of our genes have evolved to encode proteins that mainly work to render HERV’s proteins non-functional. Second, our DNA is twisted and tightly packed to accommodate into the nucleus. This means that proteins can be produced only if the region containing the gene to be transcribed is slightly loosened and accessible. The mechanisms tightening and loosening our DNA ensure that the viral genes remain inaccessible. Finally, over the course of evolution, much of the integrated viral genome pick up mutations that happen in human DNA. The mutations, once accumulated, may essentially inactivate the infectious components of the viral genome.

Are HERVs opportunistic pathogens?

Like other cellular mechanisms, these fool-proofs to prevent the expression of the viral genome are compromised when the cell is under stress, such as during infection by another pathogen. There is mounting evidence for the role of these endogenous viruses in many illnesses (mostly neurological) such as schizophrenia, multiple sclerosis, and amyotrophic lateral sclerosis. For example, in multiple sclerosis, a protein produced by HERV, called ENV, activates microglial cells (brain’s immune cells). This leads to an attack on the neurons, causing auto-immune conditions. Several lines of research also hint at the link between HERVs and idiopathic conditions (unknown origin). However, HERVs mostly remain dormant unless there is a unique combination of cellular stress and genetic predisposition.

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Viruses that shaped human evolution

HERVs are not just passive stowaways in our genome. Scientists are now unearthing clues about how they might’ve played a role in branching us off from our primate ancestors. This means our species started off with parts of the viral genome in our DNA. The viruses were believed to have influenced the expression of certain human genes, refashioning them and deciding which gene to activate when. This activated certain gene networks that gave our species the upper hand over the other primates.

Viruses: Friend or foe? 

One such effort to understand HERVs led to a key finding. HERVs decide which immune genes to turn ON or OFF. The first example came from studying MER41, an endogenous virus in our genome. MER41 was regulated by STAT proteins that are important for initiating the immune response. It is located right next to AIM2, a gene that issues the self-destruct code to the cell when pathogens invade. When scientists removed the MER41 sequence to test its importance, they found that the cells could no longer self-destruct in the face of threats. Soon after, many more immunity genes controlled by HERVs were identified. This provided further proof that we owe our survival to these viruses.    

Viruses are protectors of new life

The most recent infiltrations into our DNA by the HERVK virus happened tens of thousands of years ago. They’re still found to be active, particularly in human embryos. Researchers at Stanford University made a startling discovery when analyzing gene expression in an embryo that was three days old. They found gene sequences from HERVK that produced viral proteins in the 8-cell embryo. When studying them further, the researchers were astounded to see that the main role of these viral proteins was to prevent the entry and infection of other viruses. They were safeguarding the embryo, practically acting as an immune system substitute.

Another example that viruses play a role in our existence comes from studying the syncytin-1 protein (encoded by the ERVW1 gene). This protein, originating from HERVs, plays a crucial role in the formation of the placenta. However, humans are not the only species that have this protein. Other primates have them as well, most likely integrated close to 10 million years ago. 

Conclusion

Over tens of thousands of viruses were identified to be integrated into our genomes. Scientists have just started on what appears to be a long journey to discover the roles these viruses might have played in shaping our evolution. Research on identifying the potential effects of viral integration on the genome is currently in its infancy, and we’re not sure what it may reveal. One thing’s for certain: our genome appears to be way more complicated than we’d ever imagined. 

References

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3256973/ 
2. https://www.pnas.org/content/93/11/5177.short
3. https://www.pnas.org/content/116/30/15216.long
4. https://www.nature.com/articles/nature14308
5. https://www.nature.com/articles/35001608?

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