Human endogenous retroviruses: the hidden heroes of the genome

After once hijacking our DNA and inserting themselves into it, HERVs now play a crucial role in our survival

 

According to British biologist Sir Peter Medawar, “A virus is a piece of bad news wrapped in protein.” I believe that this opinion is outdated. While it is unlikely that you would find anyone who would disagree that rabies, HIV and Ebola are anything but bad news, not all viruses that interact with the human body are something to fear. There exist some viruses which, rather than causing us harm, are crucial to our existence.

There are retroviruses (viruses which use RNA as their genetic material and, using reverse transcription, convert their RNA into DNA and insert a copy of it into the host cell) living inside us from the moment we are conceived, embedded into the human genome. The genetic material of these viruses, known as HERVs, or human endogenous retroviruses, form part of our DNA. In fact, they are thought to make up about 8% of the human genome1. Their presence can be traced back to our early ancestors² from millions of years ago and these hidden passengers exist without causing us harm.

It is believed that HERVs are descendants of even older exogenous viruses (infectious viruses that can be transmitted horizontally i.e. from human to human; for example HIV) that were once fatal, and evolved to be less harmful so as to not kill the host². Over millions of years, they have lost the ability to transmit to other hosts and are confined to the cell that they originate from.

HERVs form part of our noncoding DNA, which makes up about 98% of our total DNA and is sometimes referred to by those in the scientific community as ‘the dark matter of the genome3’ because there is so much we still do not know about it. These retroviruses are not just passive genetic hitchhikers that have inserted themselves into our genome to continue their germline – some of them are actually crucial to our survival and have important functions that ensure our health in various ways.

Firstly, some endogenous retroviruses protect us from potentially fatal infections. HERV-K protects human embryos by producing a protein which makes the penetration of the embryo by another virus more difficult4. This is a mutually beneficial arrangement; the embryo is protected from infection by viruses such as influenza, increasing its likelihood of survival, and HERV-K has a place to live.

In addition, it seems we owe our placentas to a virus. Placental formation in most mammals is dependent on the ‘syncytin gene’5, which arose from a virus and produces a protein that allows the placenta to fuse to the uterine wall. Since the initial discovery and naming of syncytin in 2000, further discoveries have shown other forms of syncytin in other mammals. The mammals that belong to the order Carnivora have syncytin-Car1. In 2009, a version named syncytin-Ory1, was found in rabbits6.

The version of the rhesus macaquegene which is present in humans (and primates) was described as “the envelope gene of a recently identified human endogenous defective retrovirus, HERV-W” by the team who discovered it in 20007. The discovery of this curious gene explained why, when examining placental tissue from a rhesus macaque, virus particles were seen budding from the tissue (pictured above). It also may explain the way in which placental cells fuse to the uterine wall is unusual in mammalian cells but characteristic of the influences that viruses can have on cells. Viruses use this mechanism because fused cells make it easier for virus particles to spread from one cell to another, but in the case of the placenta, this mechanism makes it easier for nutrients to pass from the mother to her foetus.

Syncytin does this by producing protein that is expressed in the syncytiotrophoblast (epithelial cells between the mother and the developing foetus; the syncytiotrophoblast fuses to the uterine wall and ruptures maternal capillaries to facilitate the exchange of materials). Another form of syncytin, discovered in 2003 and named syncytin 2, is required to suppress the mother’s immune system to prevent it from attacking the foetus8.

Research conducted by Anne Dupressoir et al.9 demonstrated that mice embryos deprived of syncytin 1 died before reaching maturity, proving that it is an essential feature of placenta formation and therefore foetal development for mammalian life forms which have the gene.

Without the existence of the HERV-W retrovirus that gave rise to syncytinjoey in primates, human pregnancy would certainly be a peculiar affair compared to the pregnancy we are familiar with (if primates managed to even survive without HERV-W). A lack of syncytin could have meant that primates never developed placentas. Perhaps this would’ve lead to a pregnancy like the marsupials such as the kangaroo have, culminating in the birth of a tiny, almost foetus-like baby (see the joey pictured above). Surely this would’ve had a huge impact on the development of humans as a species, and the outcome of 65 million years of primate evolution would be completely different.

As the dark matter of the genome and the viruses that live within it are still a rather enigmatic topic, hopefully future research will further highlight how dependent on viruses we are. In the case of HERV-W, it was a stroke of luck for humans that an early primate was infected with it millions of years ago. Such a stroke of luck, in fact, that one might even go as far as to say that HERV-W was a ‘present wrapped in protein’.

 

 

 

Bibliography

 

1 – Griffiths D J. (June 2001) “Endogenous retroviruses in the human genome sequence” [ONLINE] Genome Biology. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC138943/pdf/gb-2001-2-6-reviews1017.pdf [Accessed: 01 Sep. 15]

2 – Zimmer C. (Feb 2015) “Our Inner Viruses: Forty Million Years In The Making”. National Geographic. Available from: http://phenomena.nationalgeographic.com/2015/02/01/our-inner-viruses-forty-million-years-in-the-making/  [Accessed: 01 Sep. 15]

3 – One example of this: http://science.psu.edu/news-and-events/2013-news/Pugh9-2013 [Accessed: 16 Sep. 15]

4 – Coghlan A. (April 2015) “Ancient virus is embryo protector”. New Scientist. Page 10.

5 – Javan R.R. (June 2015) “The Syncytin Gene: Viruses Responsible for Human Life” Available from: http://www.isciencemag.co.uk/features/the-syncytin-gene-viruses-responsible-for-human-life/ [Accessed: 01 Sep. 15]

6- Heidmann O, Vernochet C, Dupressoir A, Heidmann T. (2009) “Identification of an endogenous retroviral envelope gene with fusogenic activity and placenta-specific expression in the rabbit: a new “syncytin” in a third order of mammals.” Retrovirology. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19943933 

7 – Mi S, Lee X, Li X, Veldman G M, Finnerty H, Racie L, LaVallie E, Tang X, Edouard P, Howes S, Keith J C, McCoy John, McCoy Junior (2000) “Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis” Nature. [ONLINE] Available from:  http://www.nature.com/nature/journal/v403/n6771/abs/403785a0.html [Accessed: 01 Sep. 15]

8 – Blaise S, de Parseval N, Bénit L, Heidmann T (2003) “Genomewide screening for fusogenic human endogenous retrovirus envelopes identifies syncytin 2, a gene conserved on primate evolution”. [ONLINE]  Available from: http://www.pnas.org/content/100/22/13013.abstract [Accessed: 01 Sep. 15]

9 – Dupressoir A, Vernochet C, Bawa O, Harper F, Pierron G, Opolon P and Heidmann T (2009) “Syncytin-A knockout mice demonstrate the critical role in placentation of a fusogenic, endogenous retrovirus-derived, envelope gene” [ONLINE:] Available from: http://www.pnas.org/content/106/29/12127.abstract [Accessed: 01 Sep. 15]

 

Also used:

Zimmer C. (February 2012) “Mammals made by viruses” Discover.  Available from: http://blogs.discovermagazine.com/loom/2012/02/14/mammals-made-by-viruses/#.VcpQHzZRE2y [Accessed: 01 Sep. 15]

 

Lower R, Lower J and Kurth R (1995) “The viruses in all of us: Characteristics and biological significance of human endogenous retrovirus sequences”. [ONLINE] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC39218/ [Accessed: 01 Sep. 15]

 

 

 

 

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1 Comment

  1. Jasmine….I am sorry that I missed your talk today on HERVs. I did hear from several reliable sources that it was both fascinating and well delivered! I would love for you to present this to our class when we discuss the action of retroviruses later in the year. :). :).

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