The origins of viruses

By Ella Knüpling

Not only the year 2020, but the entire evolutionary course of life has been shaped by viruses. These microscopic, intracellular parasites are the most abundant biological units on earth and are found in almost all cells. As an understanding of the origins of viruses could provide information on the development of cellular organisms, researchers have been trying to elucidate when and how viruses evolved for years. However, even now, these origins of viruses remain unclear. (Krupovic, Dolja & Koonin, 2019)

Unlike that of viruses, the evolutionary root of cells seems to be straightforward. All cells which constitute cellular organisms share the same way of living, using the same informational macromolecules, RNA, DNA and proteins, as well as the same genetic code to transfer information between these molecules during metabolism. This has led scientists to believe that modern cells all originate from a single ancestor, the Last Universal Cellular Ancestor or LUCA. (Forterre & Prangishvili, 2009) 

Viruses are different. They do not have a metabolism of their own and are therefore only alive and able to reproduce inside a host cell; viruses are obligate parasites. Once it has infected a susceptible cell by releasing its genetic material into it, a virus hijacks the replication, transcription and translation machineries of that cell, which therefore immediately start replicating the viral genome and producing so-called capsid proteins encoded in this genome. Afterwards, the replicated viral genes, in the form of RNA or DNA, are packed into coats of newly synthesised capsid proteins to form inanimate viral particles called virions. Finally, the virus lyses the infected cell and the virions are released, going on to infect new host cells. (Ryu, 2017) 

This obligate parasitic behaviour of viruses cannot be described as life, which finds its definition in the concept of cells and its ancestry in the cellular evolutionary tree starting with the LUCA. Rather, it is characterized as a unique way of being and replicating, an individual lifestyle. Viruses thus have their own roots. (The Economist, 2020) 

The roots of viruses, however, cannot be traced back to one common ancestor analogous to the LUCA, as it is commonly accepted that viruses have multiple origins (Forterre & Prangishvili, 2009). This idea has been supported by structural analyses of distinct viral lineages, each characterised by unique coat protein structures and virion architectures, which revealed that viral capsids evolved on multiple, independent occasions (Bamford, Grimes & Stuart, 2005; Krupovic & Koonin, 2017). Moreover, new viruses have often emerged by the swapping of different capsids and viral genomes, which can, for example, easily happen when two viruses simultaneously infect one cell (Forterre & Prangishvili, 2009; Frank, 2001). Although these findings make it difficult to determine the ultimate origin of viruses, three possible scenarios for the first appearances of viruses on earth have been taken into consideration in the past (Krupovic, Dolja & Koonin, 2019; Wessner, 2010). 

The ‘virus early’ theory suggests that viruses existed before cells and directly descended from the first independently replicating entities (replicons) on our planet (Krupovic, Dolja & Koonin, 2019). Following this scenario, the role of viruses as obligate parasites of cells was thus an adaptation which took place later in evolution (Holmes, 2011). By contrast, in the ‘escaped genes’ scenario, viruses evolved through a progressive process, where in different cellular organisms, on multiple occasions, mobile host genes acquired the ability to induce selfish replication and to exit one cell and enter another (Krupovic, Dolja & Koonin, 2019; Wessner, 2010). Finally, the ‘reductive virus origin’ hypothesis sees viruses as regression products of autonomous cells, which lost genetic information and thus complexity as they evolved into obligate intracellular parasites (Krupovic, Dolja & Koonin, 2019; Wessner, 2010). Over the years, these three scenarios have been examined by various researchers and, for each of them, potentially relevant arguments have been proposed (Krupovic, Dolja & Koonin, 2019). 

One important point which needs to be considered in order to decide which one of these three theories best describes the origins of viruses, is whether viruses appeared before or after the LUCA (Holmes, 2011). Most viral replication proteins have no closely related homologues in modern cells. This suggests that the genes encoding these proteins are ancient and evolved before the LUCA. (Forterre & Prangishvili, 2009; Krupovic, Dolja & Koonin, 2019)

Most compatible with these findings is the ‘virus early’ theory and thus the assumption that ancient viral replication genes evolved from the first replicating systems on earth. Indeed, research on the nature of precellular replicons also seems to support this scenario. Biologists assume that the first replicating systems consisted of RNA. This hypothesis is greatly supported by the facts that RNA likely could have arisen under prebiotic conditions (Powner, Gerland & Sutherland, 2009) and that some RNA molecules, ribozymes, have catalytic properties, potentially allowing primitive RNA systems to catalyse their own replication (Wessner, 2010). The intrinsic replication fidelity of RNA, in contrast to that of double-stranded DNA, is low; relatively many mutations arise when RNA is replicated. Therefore, the first simple RNA replicons, which probably did not have any error correction, must have been very small in order to keep the number of mutations introduced per replication low enough to prevent fitness losses. (Holmes, 2011) 

Modern RNA viruses still have very small genomes and high mutation rates. Consequently, it seems likely that their replication genes directly evolved from precellular, low-fidelity RNA replication systems. Later, the first viral DNA replication genes may have evolved but only once double-stranded DNA systems with lower mutation rates had appeared, genomes may have been able to grow in size and complexity to allow the evolution of the first cells. (Holmes, 2011) 

Another argument for the ‘virus early’ theory is based on the genomic diversity found in viruses. Viruses use various nucleic acid forms to store their genetic information, single-stranded or double-stranded RNA or DNA, and many different methodologies for replication and expression, which all use the host cell’s machinery in a unique way. This clearly contrasts with the uniform genomic strategy of cells and supports the possibility that viral origins lie in a precellular world. (Koonin, Senkevich & Dolja, 2006) 

However, the ‘virus early’ scenario is not the only possible explanation for the fact that many viral replication genes seem to predate the LUCA. Some researchers argue that these genes were recruited from cellular lineages now extinct, which could be in line with either the ‘escaped genes’ or the ‘reductive virus origin’ theory (Holmes, 2011). RNA viruses may have evolved from ancient RNA-cells by escape or reduction, becoming parasites on these cells. Later, these RNA viruses could have evolved DNA and given rise to the first DNA viruses to circumvent the host cell’s defence mechanisms. Consequently, viruses could have been directly responsible for one of the most important innovations in the evolution of life; the use of DNA as the carrier of genes. (Forterre, 2006)

The ‘reductive virus origin’ scenario has been additionally boosted by the research on viruses of one particular group, the nucleo-cytoplasmic large DNA viruses (NCLDVs) like mimiviruses (Krupovic, Dolja & Koonin, 2019). The fact that NCLDVs have a much greater size and complexity than most viruses and the discovery that they possess genes encoding several translation system components, which may be remains of a once complete translation machinery, made researchers believe that these viruses are reduction products of more complex organisms (Abrahão et al., 2017).  

In addition to the three historical theories, a new possible scenario explaining the origin of viruses has been published recently, in response to analyses of viral capsid proteins (Krupovic & Koonin, 2017; Krupovic, Dolja & Koonin, 2019). In contrast to viral replication genes, several structural folds in capsid proteins seem to have diverse homologues in bacteria, archaea and eukaryotes. One could therefore hypothesize that capsid proteins evolved from proteins which originally performed cellular tasks but were recruited to form virions. Based hereon, researchers suggested that the origin of viruses could be seen as a mixture of the ‘virus early’ and ‘gene escape’ theories, where ancient viral replication genes directly descended from precellular replicons, but only became true viruses after they had captured, on multiple occasions, escaped cellular proteins which evolved into capsid proteins. In this theory, the translation-related genes present in NCLDVs are seen as descendants from eukaryotic host genes, acquired during the evolution of large viruses from smaller viral ancestors. (Krupovic & Koonin, 2017; Krupovic, Dolja & Koonin, 2019)

Certainly, this is not the only new theory on the origins of viruses which has been proposed in recent years and, despite the extensive research, the evolution of viruses is therefore still debated. However, it may not be necessary to choose only one scenario. Viruses of different lineages could have emerged in different ways and multiple of the proposed and other, yet to be discovered, theories could thus be true (Krupovic, Dolja & Koonin, 2019). But, regardless of what the viral origin exactly looked like, it is clear that viruses have not stopped evolving since. Virus-host coevolution has shaped cellular genomes and induced the constant development of new viral species, SARS-CoV-2 being only one of many examples (The Economist, 2020). Because of this continuing impact of viruses on all aspects of modern life, viral research will be carried on and, undoubtedly, reveal much more about the evolution of these mysterious parasites.

References:

Abrahão, J. S., Araújo, R., Colson, P. & La Scola, B. (2017) The analysis of translation-related gene set boosts debates around origin and evolution of mimiviruses. PLoS Genetics. 13 (2), e1006532. Available from: https://search.datacite.org/works/10.1371/journal.pgen.1006532. Available from: doi: 10.1371/journal.pgen.1006532. 

Bamford, D. H., Grimes, J. M. & Stuart, D. I. (2005) What does structure tell us about virus evolution? Current Opinion in Structural Biology. 15 (6), 655-663. Available from: https://search.datacite.org/works/10.1016/j.sbi.2005.10.012. Available from: doi: 10.1016/j.sbi.2005.10.012. 

Forterre, P. (2006) The origin of viruses and their possible roles in major evolutionary transitions. Virus Research. 117 (1), 5-16. Available from: https://search.datacite.org/works/10.1016/j.virusres.2006.01.010. Available from: doi: 10.1016/j.virusres.2006.01.010. 

Forterre, P. & Prangishvili, D. (2009) The origin of viruses. Research in Microbiology. 160 (7), 466-472. Available from: https://search.datacite.org/works/10.1016/j.resmic.2009.07.008. Available from: doi: 10.1016/j.resmic.2009.07.008. 

Frank, S. A. (2001) Multiplicity of infection and the evolution of hybrid incompatibility in segmented viruses. Heredity. 87 (5), 522-529. Available from: http://dx.doi.org/10.1046/j.1365-2540.2001.00911.x. Available from: doi: 10.1046/j.1365-2540.2001.00911.x. 

Holmes, E. C. (2011) What Does Virus Evolution Tell Us about Virus Origins? Journal of Virology. 85 (11), 5247-5251. Available from: https://search.datacite.org/works/10.1128/jvi.02203-10. Available from: doi: 10.1128/jvi.02203-10. 

Koonin, E. V., Senkevich, T. G. & Dolja, V. V. (2006) The ancient Virus World and evolution of cells. Biology Direct. 1 (1), 29. Available from: https://www.ncbi.nlm.nih.gov/pubmed/16984643. Available from: doi: 10.1186/1745-6150-1-29. 

Krupovic, M., Dolja, V. V. & Koonin, E. V. (2019) Origin of viruses: primordial replicators recruiting capsids from hosts. Nature Reviews. Microbiology. 17 (7), 449-458. Available from: https://search.datacite.org/works/10.1038/s41579-019-0205-6. Available from: doi: 10.1038/s41579-019-0205-6. 

Krupovic, M. & Koonin, E. V. (2017) Multiple origins of viral capsid proteins from cellular ancestors. Proceedings of the National Academy of Sciences – PNAS. 114 (12), E2401-E2410. Available from: https://search.datacite.org/works/10.1073/pnas.1621061114. Available from: doi: 10.1073/pnas.1621061114. 

Powner, M. W., Gerland, B. & Sutherland, J. D. (2009) Synthesis of activated pyrimidine ribonucleotides in prebiotically plausible conditions. Nature (London). 459 (7244), 239-242. Available from: https://search.datacite.org/works/10.1038/nature08013. Available from: doi: 10.1038/nature08013. 

Ryu, W. (2017) Virus Life Cycle. 

The Economist (20 Aug 2020) Viruses have big impacts on ecology and evolution as well as human health. Availabe from: https://www.economist.com/essay/2020/08/20/viruses-have-big-impacts-on-ecology-and-evolution-as-well-as-human-health [Accessed 10 Sep 2020].

Wessner, D. R. (2010) The Origins of Viruses. Nature Education 3(9):37

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