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August 01, 2012 | By:  Paige Brown
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Once upon a time: The possible story of viruses

Thursday 26th July saw the launch of, a new English language science blog network., the brand-new home for Nature Network bloggers, forms part of the SciLogs international collection of blogs which already exist in German,Spanish and Dutch. To celebrate this addition to the NPG science blogging family, some of the NPG blogs are publishing posts focusing on "Beginnings".

Participating in this cross-network blogging festival is's Soapbox Science blog, Scitable's Student Voices blog and bloggers from,, Scitable and Scientific American's Blog Network. Join us as we explore the diverse interpretations of beginnings - from scientific examples such as stem cells to first time experiences such as publishing your first paper. You can also follow and contribute to the conversations on social media by using the #BeginScights hashtag.

Guest Blog Post by Audrey Richard

One thing that virologists agree on is that they do not agree with each other very much. Everything about viruses seems to be the subject of much controversy, from their taxonomy to the biosafety issues underlying their study to the definition of their very nature even. And their origin, of course, is no exception.

Meet the protagonists

First things first: what is a virus exactly? Again: controversial (see this and this). But there are nonetheless several traits that define viruses adequately. In a few words, viruses are infectious agents with either a DNA or RNA genome that absolutely need to parasite a host - without any restriction as to its nature (Eukarya, Archae or Bacteria) - to replicate. The genetic material (and possibly other viral elements) is carried in a sort of a protein "shell" called the capsid, but depending on the species, viral particles (or virions) may also be surrounded by a lipid envelope. Virions are able to enter at least one type of cell to direct the production of viral building blocks and assembly of new virions. They are parasitic because their genomes do not store all the information necessary to generate their progeny. To do so, they need to complement their incomplete machinery with a host's genetic material.


How viruses could have emerged: three hypotheses

In the absence of a clear‑cut, unshakable answer, virologists have over the years built up three hypotheses (described in greater details right here on Scitable) to explain how viruses could have appeared. The virus‑first hypothesis supposes that viruses are relics of pre‑cellular life forms. The reduction hypothesis, on the other hand, states that viruses resulted from the reduction of unicellular "modern" organisms (Bacteria, Archaea, Eukarya) to parasitic forms while the third one, the escape hypothesis, suggests that genetic material escaped modern cells at some point and became parasitic to persist over time.

A so‑called consensus

The virus-first hypothesis, as pointed out by Dr. Patrick Forterre at Paris‑Sud University, in one of his reviews, has not really been given much credit since it does not appear to take the very nature of viruses into account. Assuming that viruses have always been parasitic, how could they possibly have existed before the cellular host they depend on so tightly to replicate appeared? Likewise, the reduction hypothesis has not gained much acceptance either over the years. The arguments against it are that, first of all, we currently don't know any intermediate that would link cells to viruses to support such a hypothesis, and secondly, no extant parasites known to genuinely descend from either Eukarya, Bacteria or Archaea have actually lost their cellular characters (like ribosomes and whole protein synthesis machinery, or ability to produce ATP), making it unlikely that viruses could result from such a mechanism. So, the escape hypothesis has been retained above the others for the past years although there are actually no overwhelmingly compelling reasons for its acceptance.

Pitfalls in the consensus

And sure enough, the escape hypothesis has not convinced everyone in the field. Dr. Forterre and Dr. Edward C. Holmes at Pennsylvania State University, amongst others, argue that it is not supported by enough data. If anything, they even believe that the available data tends to contradict the escape hypothesis. The hypothesis states that viruses' precursors previously escaped from the cells they are presently able to infect. In other words, bacteriophages, viruses able to infect bacteria, would come from bacterial genetic material and on the other hand, eukaryotic viruses would be figments of eukaryotic genetic material themselves. If viruses' ancestral paths were as clear-cut as this hypothesis maintains, one could reasonably expect that viral proteins share more homologies with proteins from their hosts than with any others, but this is not even close to being always the case. For instance, some T4 bacteriophage proteins are much more closely related to eukaryotic proteins (or proteins from eukaryotic viruses) than to their bacterial counterparts. And so far, the escape theory has failed to convincingly explain such contradictions.

So, is one of those three hypotheses closer to elucidating the truth about the origin of viruses than the others? In fact, finding a real consensus as to how viruses originated probably greatly depends on the prior elucidation of another mystery: when did viruses actually emerge? Hard to tell because this point is - shockingly - controversial.

Viruses vs. modern cells: what came first?

Obviously, modern viruses are able to infect modern cells. But have things always been this way? To put it in a different way, can one believe that viruses' precursors emerged before those cells? Several virologists - but not all of them - seem to think so. Modern cells are all evolutionarily linked, meaning they share an ancient cellular life form known as the Last Universal Cellular Ancestor (LUCA) as a common ancestor (see this open access review for further details on the LUCA). So, is the LUCA - or its descendants - the "patient zero" of the history of viral infection or were viruses actually already around when the three domains of life arose?

Is there an ancient, common ancestor to all viruses?

As Dr. Forterre mentions in his review, the notion of viral antiquity seems easier to accept for RNA viruses as they can be seen quite "intuitively" as relics of the ancestral RNA world. Such a hypothesis is hardly falsifiable but still, there are clues pointing in this direction. First, some extant double‑stranded RNA viruses infecting Bacteria (Cystoviridae to be specific) and some infecting Eukarya (Reoviridae and Totiviridae) have similar structure and life cycle as well as homologous RNA‑dependent RNA polymerases, the enzymes required for replicating the viral genome. Such homologies in such distant hosts appear to suggest that the protein might have appeared in a world where Bacteria and Eukarya did not exist yet, that is in a world predating the LUCA. Similarly, evolutionarily‑linked RNA replicases/transcriptases (also involved in viral replication) from single‑stranded and double‑stranded RNA viruses speak for a unique, very ancient lineage of all RNA viruses.

But what about those viruses that possess DNA genomes and thus probably can't be direct relics of the RNA world? Unexpectedly, some replication proteins from DNA viruses might reflect their antiquity and unique origin very well. For instance, the DNA polymerases expressed by viruses as distant as human adenovirus and a Bacillus subtilis phage both work in the same, very atypical way to replicate viral DNA. This is all the more intriguing since such functioning has never been observed in the modern cellular world. Forterre suggests that these viruses are very unlikely to have acquired such an unusual polymerase independently. To him, it seems more plausible that they were inherited from a common pre‑LUCA viral ancestor that has subsequently evolved as Bacteria and Eukarya arose.

But assuming there really is only one lineage for RNA viruses and one for DNA viruses, is it conceivable that both share a common ancestor? According to the remarkably conserved structural motifs found in viral capsids, it could be. The "jelly‑roll capsid" for example ("a tightly structured protein barrel that represents the major capsid subunits of virions with an icosahedral structure") is so highly conserved that it extends to both RNA and DNA viruses. Again, this can't be considered as direct evidence of the pre‑LUCA emergence of viruses, but such deep structural conservation does make a case for the ancient common ancestry of RNA and DNA viruses for those who embrace this hypothesis. But it certainly does not for others who believe that viruses did not predate modern cellular life because they interpret similar data a very different way.

Opponents of the pre‑LUCA emergence of viruses also have a point. Or several.

In an opinion piece published three years ago by Nature Reviews Microbiology, Drs. Moreira and López‑García, both at Paris‑Sud University, not only said that they don't think that viruses are older than the LUCA but also argued that scientific evidence downright dismisses this very idea. According to them, trying to build a monophylethic (i.e. a unique origin for all viruses) "viral tree" to eventually uncover their antiquity is artificial and irrelevant. Firstly, the extreme diversity of the viral families we currently know of strongly suggests that viruses are polyphylethic. Secondly, since not a single gene has been identified so far as common to all viruses (unlike modern cells), it appears unlikely that viruses descend from the same viral ancestor, either very ancient or not actually. Yet, viruses do share sequence homologies that some virologists see as evidence of evolutionary links. But as we are reminded of by Moreira and López‑García, genes are able to move from one genome to another (possibly distantly related) through horizontal gene transfer (HGT ­- see here for a radical story on HGT, by Ed Yong). So, finding homologies in viral genomes wouldn't be enough evidence to show they are evolutionarily linked, all the more so as HGT is thought to be particularly frequent in viruses ("Distant hosts do not imply antiquity" to quote the authors).

Regardless of genetic homologies, highly conserved structural similarities in viral capsids are also claimed as arguments in favor of viral antiquity. But Moreira and López‑García don't buy those either. Compared to the huge number of extant viruses, the geometrical structures that capsids adopt are actually simple and in limited number, supposedly because those are the structures more likely to keep virions as small as possible. As a consequence, the number of structures and foldings that the proteins building these capsids can adopt are also probably limited. Hence, convergent rather than divergent evolution could very well have driven the independent selection of similar features in unrelated viruses so that they can adjust the best they can to the same kind of "spatial" pressure. In fact, Moreira and López‑García have points to dismiss every single argument proponents of viral antiquity set forth. And according to the series of comments that their opinion piece elicited (in this issue of Nature Reviews Microbiology), it seems that the debate won't stop raging anytime soon...

Pre‑ or post‑LUCA, viruses are old players anyway

What predominantly gets in the way of uncovering the true origins of viruses is probably that there aren't any actual viral fossils to rely on. So how can we uncover their history? As a matter of fact, our own genes are a gold mine for information. Retroviruses (like HIV‑1) require integration into chromosomal DNA to achieve their life cycle. When germ cells are infected, retroviral sequences can become part of the host genome. What are called Endogenous RetroViruses (or ERVs, further described here by Ed Yong) are actually remnants of those ancient retroviral infections. As noted by Abbie Smith in her well‑named blog ERV, those retroviruses that have been endogenized at some point are extinct and "ERVs [...] are nothing like modern [...] viruses". But the most recent studies have unexpectedly revealed that any kind of viral genetic material, even non-retroviral, can be endogenized just as well (original articles in PLoS Genetics in 2010 and in PLoS Biology in 2010 and 2012).

The discovery of these Endogenous Viral Elements or EVEs sheds new light on the evolution of viruses. Using EVEs related to present viruses, the most recent ancestors of certain viral families have been re‑dated. For example, while Circoviridae and Hepadnaviridae were thought to be respectively less than 500 and 30,000 years old, EVEs actually trace their origin back to at least 40 million and 19 million years ago. However, since these extinct "paleoviruses" are found in the genomes of modern cells, EVEs won't ever provide any direct evidence of the possible pre‑LUCA emergence of viruses. But they do show that viruses are undeniably much older than previous data had suggested so far. The burgeoning field of paleovirology - "the study of ancient extinct viruses and the effects that they have had on the evolution of their hosts" - is probably making (or eventually will make) a major difference in the whole field of virology in general and the deciphering of viral evolution in particular.

How the antiquity of viruses could explain (almost) everything: revising the three hypotheses for viral origins

Unequivocally proving (or disproving) that viruses emerged before the LUCA will probably remain an impossible goal. But such an assumption can interestingly help resolve some of the drawbacks of the initial hypotheses on viral origins.

Some proponents of the virus‑first hypothesis proposed that viruses appeared in an acellular world using the primitive soup as host. But according to Dr. Forterre, because viruses are made of proteins (at least as we presently know them), they must have emerged after the ancestral ribosome. He can't possibly imagine that all the sophisticated metabolic reactions required to produce viral building blocks could develop without Darwinian selection. To make that possible, well‑defined entities must have competed, so he assumes that an ancestral cellular life performing such reactions arose before the LUCA in the form of RNA cells. From this reasoning, it follows that RNA cells came before viruses (so that viral components can be produced). Thus, Forterre refutes the "radical" form of the virus‑first hypothesis: it is very unlikely that viruses emerged before any cellular life form. But the hypothesis can be slightly reformulated: viruses came before cellular life as we currently know it, before the LUCA that is. As a matter of fact, Forterre ultimately considers that it isn't a hypothesis for the origin of viruses per se but more of a prerequisite to better defend the other two hypotheses.

In a pre‑LUCA scenario in which viruses can't predate ancient cells, there aren't many possibilities to explain their emergence: either RNA cells regressed until they became parasitic entities, or genetic material of RNA cells escaped them and at some point became parasitic. Those alternatives are nothing more than new versions of the reduction and the escape hypothesis respectively. On one hand, assuming that the ancient RNA cells were way less sophisticated than their modern descendants, their regressive evolution is more likely to have resulted in parasitic entities without any cellular characteristics left: the reduction hypothesis is then more conceivable. Also, in this context, for viral proteins to share more homologies with proteins expressed by the host than with any others wouldn't be particularly expected anymore, which makes the escape theory much more solid. While fixing the pitfalls of other theories does not make a hypothesis any truer it certainly gives it some kind of additional appeal. And actually, embracing that viruses predated the LUCA even opens new possibilities to explain other kinds of fascinating origins like those of the three domains of life or even DNA itself. But I'll tell you about that another time. It is only the beginning after all.

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