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Institut Pasteur, 25 rue du Dr Roux, 75015, Paris, France.
Univ Paris-Sud, centre d’Orsay, 91405 Orsay-Cedex
CNRS, UMR 8621 forterre@pasteur.fr
Tel: 01 45 68 87 91
FAX: 01 45 68 88 34
Summary (200 words)
For a long time, the viral world has been divided in two apparently unrelated groups: bacteriophages and eukaryotic viruses. Indeed, viruses were though to have originated from genetic material derived from their respective host cells. Several recent findings have concurred to reevaluate this assumption. Comparative analysis of 16S/18S rRNA has first replaced the prokaryote/eukaryote dichotomy by a division of the living world into three cellular domain, archaea, bacteria and eukarya. Then, it has been found that viruses infecting hosts from different domains can share homologous traits (e.g. capsid proteins) otherwise unknown in the cellular world. Comparative genomics has shown that most viral protein have no cellular homologues, also suggesting the existence of an ancient and extremely diverse viral world that always co-existed and possibly predated the world of modern cells. This has prompted new hypotheses on the origin of viruses.
Depending of the authors, viruses could have originated either before cells (using selfreplicating macromolecules as the first hosts) or from ancient RNA or DNA cells (by parasitic reduction or from escaped genomic material). In these scenarios, it has been speculated that viruses have played important roles in the origin of modern cells, either as inventors of DNA, and/or as progenitors of the eukaryotic nucleus.
Keywords (10-15)

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Virus evolution, RNA world, Universal tree of life, LUCA, Archaea, Bacteria, Eukarya,
RNA/DNA transition, DNA origin, viral eucaryogenesis, mimivirus, viral factory
Glossary
Archaea : a domain of prokaryotic micro-organisms whose informational mechanisms (DNA replication, transcription and translation) are closely related to those of eukaryotes.
Homology : two biological structures are homologues if they originated from a common ancestral structure. The homology cannot be quantified (a protein is or is not homologuous to another one). Many biologists without an evolutionary background still confuse homology and similarity (only the latter can be quantified).
LUCA (Last Universal Common Ancestor): the most recent common ancestor shared by all modern cellular organisms. The modern genetic code was already established in LUCA. Other features of LUCA (cellular versus acellular, RNA versus DNA genome) are still highly controversial.
RNA world : the period of life evolution before the invention of DNA. Depending on the authors, the RNA world is viewed as either cellular (a world of RNA cells) or acellular (a world of free living macromolecules).
Universal tree of life : the tree based on 16S/18S rRNA comparison, in which the cellular living world is divided into three domains: archaea, bacteria, and eukarya. The evolutionary relationships between these domains are controversial. u-DNA : DNA containing uracile dNTP : any deoxynucleotide triphosphate rNTP : any ribonucleotide triphosphate dUMP : deoxyuridine monophosphate

dTMP : deoxythymidine monophosphate
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The classical view of virus origin and its consequences
The origin of viruses and their evolutionary relationships with cellular organisms are still enigmatic, but recent advances from comparative genomics and structural biology have produced a new framework to discuss these issues on firmer grounds. Historically, three hypotheses have been proposed to explain the origin of viruses: i) they originated in a precellular world ( the virus first hypothesis ), ii) they originated by reductive evolution from parasitic cells ( the reduction hypothesis ), (iii) they originated from fragments of cellular genetic material that escaped from cell control ( the escape hypothesis ). All these hypotheses had specific drawbacks. The virus first hypothesis was usually rejected first hand, since all known viruses require a cellular host. The reduction hypothesis was difficult to reconcile with the observation that the most reduced cellular parasites in the three domains of life, such as
Mycoplasma in Bacteria, Microsporidia in Eukaryotes or Nanoarchaea in Archaea, do not look like intermediate forms between viruses and cells. Finally, the escape hypothesis failed to explain how such elaborate structures as complex capsids and nucleic acid injection mechanisms evolved from cellular structures, since we don’t know any cellular homologues of these crucial viral components.
Because of these drawbacks, the problem of virus origin was for a long time considered untractable and not worth of serious consideration (similarly, the study of bacterial evolution was considered a hopeless and futile task prior to the pioneering work of Carl Woese).
However, since the problem of the origin is so entrenched in the human mind, it was never completely ignored. Much like the concept of prokaryotes became the paradigm on how to think about bacterial evolution, the escape hypothesis became the paradigm favoured by most virologists to solve the problem of virus origin.
This scenario was chosen mainly because it was apparently supported by the observation that modern viruses can pick up genes from their hosts. In its classical version, the escape theory suggested that bacteriophages originated from bacterial genomes and eukaryotic viruses from eukaryotic genomes (Figure 1a). This led to a damaging division of the virologist community into those studying bacteriophages and those studying eukaryotic viruses, “phages” and viruses being somehow considered to be completely different entities. The artificial division of the viral world between “viruses” and bacteriophages also lead to much confusion on the nature of archaeal viruses. Indeed, although most of them are completely unrelated to bacterial viruses, they are often called

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“bacteriophages”, since archaea (formerly archaebacteria) are still considered by some biologists as “strange bacteria”. For instance, archaeal viruses are grouped with bacteriophages in the drawing that illustrates viral diversity in the last edition of the Virus
Taxonomy Handbook. Hopefully, these outdated visions will finally succumb to the accumulating evidences from molecular analyses.
Viruses are not derived from modern cells
Abundant data are now already available to discredit the escape hypothesis in its classical adaptation of the prokaryote/eukaryote paradigm. This hypothesis indeed predicts that proteins encoded by bacterial viruses (I will avoid the term bacteriophage here) should be evolutionarily related to bacterial proteins, whereas proteins encoded by viruses infecting eukaryotes should be related to eukaryotic proteins. This turned out to be wrong since, with a few exceptions (that can be identified as recent transfers from their hosts), most viral encoded proteins have either no homologues in any cell or only distantly related homologues. In the latter cases, the most closely related cellular homologue is rarely from the host and can even be from cells of a domain different from the host. More and more biologists are thus now fully aware that viruses form a world of their own, and that it is futile to speculate on their origin in the framework of the old prokaryote/eukaryote dichotomy. As all other aspects of microbiology, the problem of the nature and origin of viruses made a great leap forward when this dichotomy was successfully challenged by the trinity concept introduced by Carl Woese, i.e. the division of the living cellular world into three domains, Archaea, Bacteria and
Eukarya.
Here figure 1
The building of a universal tree of life based on rRNA sequence comparisons, and the idea that all living organisms did not diverge from a “primitive bacterium”, as previously assumed in most texbooks, but from a less defined Last Universal Common Ancestor (LUCA) opened the way to think about the origin and evolution of viruses in a new context (Figure 1b).
Indeed, the main problem with the initial formulation of the three major hypotheses for the origin of viruses was that all of them were based on our knowledge of modern cells
(themselves viewed as either prokaryotes or eukaryotes). Hence, modern viruses need modern cells to replicate, modern cells cannot regress to viral forms, and free RNA or DNA does not

- 6 - recruit today’s proteins from modern cells to form capsids and other elaborated viral structures. The major innovation introduced by the work of Carl Woese was to open a window on the possibility of ancient worlds populated by cells most likely very different from modern ones. As early as 1980, Woese and co-workers coined the term urkaryote to name the cellular lineage that gave rise to modern eukaryotic cells (prior to the mitochondrial endosymbiosis and possibly before the origin of the nucleus itself). Later on, Woese discussed in detail the fact that the organisms that populated the basal branches of the universal tree were probably not yet modern cells, and suggested that some proteins with puzzling phylogenetic patterns could have originated in ancestral cell lineages that have now disappeared. These theoretical considerations laid the ground to the interpretation of observations that could not have been understood in the classical linear and dichotomic view of cellular evolution, such as the discovery that viruses infecting either prokaryotic or eukaryotic hosts could share homologous features (see below). In the new framework introduced by Woese’s universal tree of life, these observations led to the idea that viruses might be relics of lost domains, or else that viruses predated LUCA. As a result,viruses now appear in the literature as additional branches in the universal tree or the universal tree itself is immersed in a “viral ocean”.
The metaphor of the viral ocean, proposed by Dennis Bamford, illustrates both the concept of virus antiquity and their predominance in the modern biosphere. Another major breakthrough in recent viral research was indeed the realization that viruses are much more abundant than cells and much more diverse than previously suspected. It is thus currently assumed that viral genokmes represent the major throve of genetic diversity on Earth. All these trends make it irrelevant to ask whether viruses are alive. As recently pointed out by Jean-Michel Claverie, the question of the nature of viruses has been for a long time obscured by the confusion between virus and virus particle, whereas the major components of the virus life cycle correspond to the intracellular viral factory. All this concurs to put again the question of virus origin on the agenda. I will thus rapidly summarize here the main data that presently point to an tancient origin of viruses and discuss how the three major hypotheses explaining the origin of viruses have been rejuvenated in this new framework.
Viruses are ancient

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For a long time, virologists thought that the various virus families were evolutionary unrelated, indicating a polyphyletic origin. In recent years, this view has progressively changed with the identification of more and more relationships (sometimes totally unexpected) between different viral lineages, making it possible to define a limited number of large viral groups whose hosts encompass the three cellular domains. For example, it has been clearly established that some double-stranded RNA viruses infecting bacteria are homologous to those infecting eukarya, suggesting that they predated the divergence between bacteria and eukaryotes. Since the RNA replicases/transcriptases of these double-stranded RNA viruses are homologous to those of single-stranded RNA viruses, all RNA viruses presently know seems to be evolutionary related (at least in term of their replication apparatus). In the case of DNA viruses, structural analyses of their capsid proteins have revealed an unexpected close evolutionary relationship between some bacterial spherical viruses, eukaryotic viruses of the
Nucleo-Cytoplasmic-Large-DNA viruses (NCLDV) superfamily and an archaeal virus isolated at Yellowstone. Structural comparative analyses also indicate that head and tailed bacterial viruses ( Caudavirales ) share homologous features with herpes viruses. These data clearly indicate that some viral specific proteins originated before the divergence between the three domains (hence before LUCA). It is tempting to suggest that a similar ancient origin also explains why most viral proteins either have no cellular homologues (except for plasmid versions or viral remnants in cellular genomes) or are only very distantly related to their cellular homologues. All these considerations thus push back the origin of viruses before the emergence of modern cells. We will now discuss how the three classical hypotheses for the origin of viruses have been revisited in this new context.
The virus-first hypothesis
The virus-first hypothesis was for a long time politically incorrect. It clashes with the cellular theory of life and the traditional assumption that viruses are non living entities. This hypothesis was first revived in the eighties by Wolfram Zillig who suggested that viruses originated in a prebiotic word, using the “primitive soup” as a host. Such hypothesis has gained strength in recent years, in parallel with the suggestion that cellular organisms originated only at a late stage of life evolution. The idea that “life” first evolved in an acellular context can be traced back to the first version of the RNA world theory. More recently, it was boosted by the discovery that archaeal lipids are dramatically different from the bacterial ones (with an opposite stereochemistry of the glycerol backbone linkages and a

- 8 - different type of carbon chains). To explain this dichotomy, several authors have proposed that LUCA was not a cellular entity and that cellular membranes originated independently after the divergence of Archaea and Bacteria. A more elaborate version of this scenario has been proposed by William Martin and Eugene Koonin, who suggested that life originated and evolved in the cell-like mineral compartments of a warm hydrothermal chimney. In that model, viruses emerged from the assemblage of self-replicating elements using these inorganic compartments as the first hosts. The formation of true cells occurred twice independently only at the end of the process (and at the top of the chimney), producing the first archaea and bacteria. The latter escaped from the same chimney system as already fully elaborated modern cells. In the model, viruses first coevolved with acellular machineries producing nucleotide precursors and proteins (Figure 2a). This acellular “life” evolved by competition between different machineries and associated viruses to infect more and more compartments of the hydrothermal system.
Cellular versus acellular evolution of early life
The acellular model of early life evolution (up to LUCA) raises several problems. First, comparative genomics analyses indicate that some membrane proteins (ATP synthetases, signal recognition particles receptors) are homologous and ubiquitous in the three domains of life, hence were probably already present in LUCA. Some authors have further stressed that the emergence of viruses involves at least the existence of complex mechanisms to produce
ATP, RNA and proteins. This means an elaborated metabolism to produce rNTP and aminoacids, RNA polymerases and ribosomes, as well as an ATP-generating system. If such a complex metabolism was present, it appears unlikely that it was unable to produce lipid precursors, hence membranes. If this is correct, then “modern” viruses did not predate cells, but originated in a world populated by primitive cells. The proponents of this scenario consider that it fits better with the contention that Darwinian selection requires competition between well-defined individual entities. It has been often assumed that RNA viruses are relics of the RNA world. In that case, viruses might have originated in a world of primitive cells with RNA genomes. In that context, it is even possible that cellularisation occurred before the emergence of the modern protein synthetizing machinery and that RNA cells existed that contained no proteins (at least no proteins produced by an RNA machinery related to modern ribosomes). Modern viroids may be relics of this stage, whereas true viruses might have only appeared after the establishment of the ribosome-based mechanism for protein

- 9 - synthesis. In such a cellular scenario, one has now to explain how RNA viruses originated from RNA cells. Interestingly, this has led to a revival of the reduction and escape hypothesis, but in a new context.
The reduction hypothesis
The reduction hypothesis revisited in the context of pre-LUCA cells posits that RNA viruses originated by reduction from parasitic RNA cells, by losing progressively their own machinery for protein synthesis and for energy production (Figure 2b). An analogy for the possible mechanism of reduction can be seen in the reductive evolution that led to modern
Chlamydia. Indeed, an interesting parallel can be drawn between the viral particles (the virion) and the infectious form of this bacterium (the elementary body) that is small and metabolically inactive. The main difference between viruses and Chlamydia is that the intracellular form of the latter, called the “reticulate body”, is a fully developed intracellular bacterium that uses its own ribosomes for protein synthesis, whereas the intracellular viral factories (although often physically separated from the host cytoplasm) have somehow a direct access to the host ribosomes. A first step in the evolution of a parasitic RNA cell towards a viral state might thus have been the division of its cell cycle between an inert extracellular stage (the protovirion) and an intracellular stage. The second step would have been the dissolution of the membrane of the intracellular parasitic cell to gain access to the protein machinery of the host. One can argue that the transformation of an intracellular parasitic cell into a viral type factory became impossible with modern cells (such as
Chlamydia) because, as stated by Carl Woese, the latter are too complex and too integrated to be “deconstructed” into free-living sub-entities. In contrast, small parasitic RNA cells reproducing inside larger RNA cells were probably much simpler and could have been easily reduced into a viral factory by loss of their own membrane and translation machinery.
The escape hypothesis
The escape hypothesis is also easier to defend in the context of an ancestral world of RNA cells. It has been often argued that the genomes of ancestral RNA cells may have been fragmented and composed of semi-autonomous chromosomes that were replicated independently and transferred randomly from cell to cell. The coupling between the segregation of the cellular genome and of the cellular machinery for protein synthesis (the

- 10 - genotype and the phenotype) was probably not so efficient in these RNA cells than it is in modern cells. The reproduction of such primitive RNA cells could have produced a mixture of progenies, some of them containing both systems (chromosomes plus ribosomes) but others containing only either RNA chromosomes or ribosomes. The latter two types of progenies would have died, except if a cell containing only chromosomes turned out to be able to infect a complete cell (or a cell containing only ribosomes). The RNA chromosomes carrying genes facilitating specifically their infectious ability and/or protecting their integrity during their resting stages would have been selected in such a situation (Figure 2c).
Relationships between RNA and DNA viruses
If the first viruses were RNA viruses infecting RNA cells, one is left with a major question: did DNA viruses originate independently from RNA viruses or did they evolve from RNA viruses? One possibility is that DNA viruses originated either by escape or reduction from primitive DNA cells, much like RNA viruses could have originated from RNA cells. Such hypothesis supposes the existence of primitive DNA cells (less integrated than modern ones) that live either before LUCA (if the latter was already a cellular organism) or shortly after
LUCA (corresponding to early branches of the universal tree which have disappeared without descendants). The possibility that some large DNA viruses originated by reduction from extinct DNA cells evolutionary related to early eukaryotic cells was recently boosted by the discovery of the giant mimivirus whose genome size (1.2 Mb) is three times larger than the smallest genomes of parasitic archaea or bacteria. This virus encodes a few components of the translation system that could be relics of ancient cellular lineages now extinct. On the other hand, the huge diversity of DNA viruses suggests that different lineages of DNA viruses could have originated at different periods and by different mechanisms. Indeed, there are arguments to suggest that at least some DNA viruses originated from RNA viruses. In particular, the RNA replicases/transcriptases of RNA viruses are homologous to the reversetranscriptase of retroviruses and to DNA polymerases of the A family encoded by many DNA viruses. Similarly, RNA and DNA viruses encode homologous RNA/DNA helicases. The hypothesis of an evolutionary transition from RNA to DNA viruses could explain the existence of intermediate forms such as retroviruses (with an RNA genome and an RNA-
DNA-RNA cycle) and hepadnaviruses (with a DNA genome and a DNA-RNA-DNA cycle).
Interestingly, retroviruses and hepadnaviruses are evolutionary related, suggesting that the transition from RNA to DNA occurred in the virosphere.

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Viruses and the origin of DNA
Considering the possibility that at least some DNA viruses originated from RNA viruses, it has been suggested that DNA itself could have appeared in the course of virus evolution (in the context of competition between viruses and their cellular hosts). Indeed, DNA is a modified form of RNA, and both viruses and cells often chemically modify their genomes to protect themselves from nucleases produced by their competitor. It is usually considered that
DNA replaced RNA in the course of evolution simply because it is more stable (thanks to the removal of the reactive oxygen in position 2’of the ribose) and because cytosine deamination
(producing uracil) can be corrected in DNA (where uracil is recognized as an alien base) but not in RNA. The replacement of RNA by DNA as cellular genetic material would have thus allowed genome size to increase, with a concomitant increase in cellular complexity (and efficiency) leading to the complete elimination of RNA cells by the ancestors of modern DNA cells. This traditional textbook explanation has been recently criticized as incompatible with
Darwinian evolution, since it does not explain what immediate selective advantage allowed the first organism with a DNA genome to predominate over former organisms with RNA genomes. Indeed, the newly emerging DNA cell could not have immediately enlarged its genome and could not have benefited straight away from a DNA repair mechanism to remove uracil from DNA. Instead, if the replacement of RNA by DNA occurred in the framework of the competition between cells and viruses, either in an RNA virus or in an RNA cell, modification of the RNA genome into a DNA genome would have immediately produced a benefit for the virus or the cell. It has been argued that the transformation of RNA genomes into DNA genomes occurred preferentially in viruses because it was simpler to change in one step the chemical composition of the viral genome than that of the cellular genomes (the latter interacting with many more proteins). Furthermore, modern viruses exhibit very different types of genomes (RNA, DNA, single-stranded, double-stranded), including highly modified
DNA whereas all modern cellular organisms have double-stranded DNA genomes. This suggests a higher degree of plasticity for viral genomes compared to cellular ones. The idea that DNA originated first in viruses could also explain why many DNA viruses encode their own enzymes for dNTP production, ribonucleotide reductases (the enzymes that produce deoxyribonucleotides from ribonucleotides) and thymidylate synthases (the enzymes that produce dTMP from dUMPp. Because, in modern cells, dTMP is produced from dUMP, the transition from RNA to DNA occurred likely in two steps, first with the invention of

- 12 - ribonucleotide reductase and production of U-DNA, followed by the invention of thymidylate synthases and formation of T-DNA. The existence of a few bacterial viruses with U-DNA genomes has been taken as evidence that they could be relics of this period of evolution.
If DNA first appeared in the ancestral virosphere, one has also to explain how it was later on transferred to cells. One scenario posits the coexistence for some time of an RNA cellular chromosome and a DNA viral genome (episome) in the same cell, with the progressive transfer of the information originally carried by the RNA chromosome to the DNA “plasmid” via retro-transposition.
New hypotheses about the role of viruses in the origin of modern cells
The idea that viruses « invented » DNA implies that they have been major players in the origin of modern cells. Indeed, several provocative hypotheses have been proposed in recent years that put viruses as central players of various evolutionary scenarios In the context of an ancient DNA virosphere, it has been argued that different lineages of DNA viruses would have « invented » different enzymatic activities to replicate, repair and recombine their DNA, explaining why the proteins dealing with DNA are now so diverse, often belonging to several non homologous protein families. It has thus been proposed that many (possibly all) cellular enzymes involved today in cellular DNA replication, repair and/or recombination first originated in viruses before being transferred to cells. More specifically, several authors suggested that either the bacterial DNA replication mechanism, the eukaryotic/archaeal ones, or both, are of viral origin, in order to explain why the major proteins of the DNA replication machineries in eukaryotes and archaea (DNA polymerase, helicase and primase) are not homologous to their functional analogues in bacteria (suggesting that LUCA had still an RNA genome). In order to explain why the archaeal and eukaryotic DNA replication machineries also exhibit some crucial differences (beside a core of homologous proteins) it was even suggested that the three cellular domains (archaea, bacteria and eukarya) originated from the independent fusions of three RNA cells and three large DNA viruses. In the latter scenario, the replacement of an RNA genome by a DNA genome at the onset of domain formation would have produced a drastic reduction in the rate of protein and rRNA evolution, explaining why proteins evolved apparently much less rapidly after the formation of the three domains than during the period between LUCA and the last common ancestor of each domain. The formation of each domain from three different types of RNA cells could have also selected

- 13 - three groups of RNA and DNA viruses specific for each domain, those that were able to infect these three ancestral RNA cells and their immediate descendants. This could explain a paradox in the modern biosphere, i.e. that each domain is characterized by its own set of viruses (for instance NCLDV, are specific for eukaryotes) despite the fact that these viruses probably originated from a virosphere that predated LUCA. It must be remembered that
NCLDV share homologous capsid proteins with some bacterial and archaeal viruses.
Another area in which evolutionists have now recruited viruses for help is the problem of eukaryote origin. The viral eukaryogenesis hypothesis posits that the eukaryotic nucleus originated from a large DNA virus, possibly related to NCLDV. This hypothesis was inspired by the analogies between the life cycle of the nucleus and those of poxviruses. In particular, both the eukaryotic nucleus and poxviruses build their membrane from the endoplasmic reticulum. Again, the discovery of the mimivirus (a member of the NCLDV family) led credence to such hypothesis. The relationships between the eukaryotic nucleus and giant viruses might have been even more complex. Hence, it was also recently proposed that a bidirectional evolutionary pathway was operating early on, with both large DNA viruses producing nuclei by infecting ancestral proto-eukaryotic cells, but also infectious nuclei producing new large DNA viruses. Finally, it was suggested that several different viruses might have been involved in eukaryogenesis to explain the presence of multiple RNA and
DNA polymerases in eukaryotic cells.
Although most hypotheses previously discussed will probably always lack definitive proof, comparative genomics analyses have recently revealed a clear case of viral intervention in the formation of modern eukaryotic cells, i.e. the viral origin of the DNA transcription and replication apparatus of mitochondria. This was inferred from the discovery that the RNA polymerase, DNA polymerase, and DNA helicase operating in mitochondria are of viral origin These enzymes probably originated from a provirus that was integrated into the genome of the  -proteo-bacterium at the origin of mitochondria, since proviruses encoding homologues of these enzymes have been detected in the genome of several proteobacteria.
Conclusions
The idea that modern viruses are not simple extensions of prokaryotic or eukaryotic cells but derived from an ancient virosphere whose evolution encompassed the RNA world and the

- 14 - period of the RNA to DNA transition has far reaching consequences. One of the most important in terms of practical consequences for all biologists is that modern viruses (and plasmids, which most likely originated from them) would have inherited from this ancient virosphere many molecular mechanisms that have disappeared from modern DNA cells. This would explain why the molecular biology of the viral world for transcription, replication repair and recombination is more diverse than that of the cellular world (despite the fact that we have only explored a tiny fraction of the modern virosphere). If this view is correct, many still unknown molecular mechanisms (and their associated proteins) remain to be discovered in viruses. The exploration of viral diversity will be for sure one of the major challenges of biology in this new century.
Further Reading
Forterre, P., Krish, H (2003) Special issue: viruses: origin, evolution and biodiversity.
Research in Microbiology, 154 , 223-311.
Bamford, D.H., Grimes, J.M., and Stuart, D.I. (2006). What does structure tell us about virus evolution? Current Opinion in Structural Biology . 15 , 655-663.
Bell, P.J.L. (2001). Viral eukaryogenesis: was the ancestor of the nucleus a complex DNA virus? Journal of Molecular Evolution , 53 , 251-256.
Claverie, J.M. (2006) Virus takes center stage in cellular evolution. Genome Biology , 7 , 1-10.
Fauquet, C.M. Mayo, M.A., Maniloff, et al. (2005) Virus Taxonomy . VIII edition, San Diego and London, Elsevier, Academic Press
Filée, J., Forterre, P. (2005) Viral proteins functioning in organelles: a cryptic origin? Trends in Microbiology , 13 , 510-513
Forterre, P. (2005) The two ages of the RNA world, and the transition to the DNA world, a story of viruses and cells. Biochimie , 87 , 793-803.
Forterre, P. (2006) Three RNA cells for ribosomal lineages and three DNA viruses to replicate their genomes: a hypothesis for the origin of cellular domain. Proceeding of
National Academy of Science USA , 103 , 3669-3374.
Hamilton, G. (2006) Virology: the gene weavers. Nature . 441 :683-685.
Koonin, E.V. and Martin, W. (2005) On the origin of genomes and cells within inorganic compartments. Trends in Genetics . 21 :647-654.
Ortmann, A.C., Wiedenheft, B., Douglas, T. et al.. (2006) Hot crenarchaeal viruses reveal deep evolutionary connections. Nature Microbiological Review 4 . 520, 528.

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Prangishvili D, Forterre P, Garrett RA. (2006) Viruses of the Archaea: a unifying view.
Nat Rev Microbiol . 11 :837-848.
Raoult, D., Audic, S., Robert, C., et al. (2004) The 1.2-megabase genome sequence of
Mimivirus. Science , 306 , 1344-1350.
Villarreal, L.P. (2005). Viruses and the Evolution of Life . Washington. ASM Press,
Woese CR, Kandler O, Wheelis ML. (1990) Towards a natural system of organisms: proposal for the domains Archaea, Bacteria, and Eucarya. Proc Natl Acad Sci U S A . 12 : 4576-4579.
Figure legends
Figure 1: Two conflicting views of virus origin and evolution
Figure 2 : The three revisited hypotheses for virus evolution: a) the virus first hypothesis, b) the reduction hypothesis, c) the escape hypothesis.