3. The three hypotheses for virus origin revisited
The hypothesis that viruses were already present before the emergence of modern DNA-cells opens
new perspectives about their origin and suggests we revisit the three classical hypotheses in this new
context.
3.1. The virus-first hypothesis
The virus-first hypothesis has been revived in the last decade by Wolfram Zillig who suggested that
viruses originated in the prebiotic word, using the primitive soup as a host (Prangishvili et al., 2001).
Such hypothesis is in line with the view, advocated by several molecular biologists, that the formation of
cells occurred relatively late in the evolution of life. It was common for some time to imagine the RNA
world as a community of free molecules competing with each others (Gilbert, 1986). Recently, some
authors have even proposed that the Last Universal Common Ancestor (LUCA) was not a cellular entity
(Kandler, 1998; Martin and Russell, 2003; Koga et al., 1998). In particular, they suggested that cellular
membranes originated independently after the divergence of Archaea and Bacteria, in order to explain
why archaeal lipids are so different from eukaryotic/bacterial ones (with opposite stereochemistry and
different carbon chains). If all life evolution from the very beginning up to LUCA occurred in an acellular
context, it is indeed possible to imagine that viruses first emerged as individual entities in a world of
competing proteins and nucleic acids, either bathing in a !primitive soup” or located on a mineral
platform. However, the hypothesis of a LUCA without membrane is contradicted by the existence of
homologous proteins functioning at the membrane level that are encoded by all sequenced genomes
from the three domains of life, strongly suggesting that these proteins (hence a membrane) were
already present in LUCA (Pereto et al., 2004). In fact, the first cells probably arose well before the
emergence of LUCA. For instance, it appears unlikely that a world of free molecules could have
evolved to such an extent to produce a ribozyme capable of synthesizing proteins (the ancestor of
present-day ribosomes). Even in the early RNA world, a primitive metabolism should have produced at
least precursors for RNA and lipid syntheses, as well as the energy required to perform these reactions.
It is difficult to imagine the emergence of such a metabolism without Darwinian selection, and this
requires the competition between well-defined individual entities (at least proto-cells). Since modern
viruses contain proteins, they should have originated after the emergence of the ancestral ribosome,
i.e. well after the apparition of primitive RNA-cells (in the second age of the RNA world, sensu Forterre,
2005). Accordingly, in my opinion, the virus first theory can be rejected for present-day viruses (even
viroids would need a suitable cellular environment providing nucleotides for their emergence). In this
case, one is presently left with only two possibilities: either the first RNA viruses originated from RNA
cells by regressive evolution (a new version of the reduction theory), or from RNA fragments that
escaped from RNA cells (a new version of the escape theory).
3.2. The escape hypothesis
The traditional hypothesis viewing viruses as elements of cell genomes that escaped from their cellular
environment, becoming autonomous and infectious selfish elements, is easier to defend in the context
of a pre-LUCA scenario for virus origin. In this context, one does not expect anymore any specific
relationship between proteins encoded by viruses and those encoded by their hosts, since viruses now
derive from genome fragments escaped from cells predating LUCA. Furthermore, one can reasonably
assume that it was easier for a genome fragment to become autonomous in ancient RNA cells, since
the different molecular mechanisms operating in these proto-cells were probably much simpler and less
integrated than in modern DNA cells (Woese, 2002). In particular, it has been often argued that the
genomes of ancestral RNA cells were fragmented (as in the case of modern double-stranded RNA
viruses). These genomes could have been composed of semi-autonomous chromosomes (possibly
formed by a few RNA genes) that were replicated independently and transferred randomly from cells to
cells (Woese, 1987 ; Poole et al., 1998). Some RNA chromosomes could have encoded a coat protein
that helps the proto-virus to be transferred, finally becoming infectious (Fig. 2). This process would be
reminiscent of the moron theory proposed by Hendrix and co-workers for the origin of virus (Hendrix et
al., 2000). Although this theory was inferred from the observation that modern DNA viruses can easily
acquire more DNA by illegitimate recombination it can be easily extrapolated for the origin of RNA
viruses in the RNA world.
3.3. The reduction hypothesis
The transformation of a cellular organism into a viral one could have been also much easier in a world
of RNA cells, again because these cells were much simpler than modern ones. Just as modern
parasites can loose part of their metabolic channels, an RNA-cell living as a parasitic endosymbiont in
another RNA cell could have lost its own machinery for protein synthesis and for energy production,
using instead those of the host (Fig. 2) (Forterre, 2005). In this model, viral capsids could have
originated from the envelopes of RNA cells composed of identical proteins, resembling the S-layer of
modern prokaryotes. The reduction hypothesis might have been driven by the harsh competition that
most likely occurred between RNA cells all along the evolution of the RNA world. As a consequence of
this competition, early life evolution probably went through several bottlenecks each time a crucial new
molecular mechanism was invented. At each of these bottlenecks, the descendents of the individual
endorsed with such a great selective advantage (the winners) would have eliminated all other lineages
of proto-cells that previously coexisted with them (the losers). The only chance of survival for the losers
was to become parasites of the winners. In this hypothesis, viruses evolved by parasitic reduction from
ancient lineages of RNA cells that were out-competed in the Darwinian selection process, and thus
could only survive by parasiting the winner of this competition (Forterre, 1992).
Fig. 2. Two alternative hypotheses for the origin of viruses in the second age of the RNA world (after invention of protein
synthesis), black circles correspond to translation machinery (e.g. ancestral ribosomes) and lines to linear RNA chromosomes.
Upper panel, the escape hypothesis: unequal cell division produces minicells with single chromosome (a or b) but no
translation apparatus. The chromosome a will be eliminated but chromosome b will survive because it is associated with a
proteins coat that allows its transfer into a new RNA cell, it becomes a virus. Lower panel, the reduction hypothesis: a small
RNA cell became an endosymbiont of a larger RNA cell. It looses its translation apparatus but continue to replicate
autonomously and become infectious (similar to some pathogenic bacteria in eukaryotic cells).
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3. A re-examination of the three virus origin hypotheses
The possibility that viruses existed prior to the emergence of modern DNA-cells is raised.
new perspectives on their origins and proposes revisiting the three classic hypotheses in this new study
context.
The virus-first hypothesis (3.1)
Wolfram Zillig revived the virus-first hypothesis in the last decade, claiming that
Viruses first appeared in the prebiotic world, using primitive soup as a host (Prangishvili et al., 2001).
This hypothesis is consistent with the view held by several molecular biologists that the formation of
Cells appeared relatively late in life’s evolution. For a long time, it was common to imagine the RNA.
The world is viewed as a community of free molecules competing with one another (Gilbert, 1986).
