Viruses and cells intertwined since the dawn of evolution

Nowadays, to give a concise definition of virus nature is troublesome. Researchers
of different standpoints have proposed several interpretations. Viruses by their nature
seem to be entities somewhere in between inert and living worlds 1]. For decades viruses were simply considered as pathogenic biochemical entities composed
of two major elements: nucleic acid (RNA or DNA) constituting their genome and protein
coat (capsid). Many viral particles (virions) are even more complex and contain lipid-protein
envelope or an additional capsid, and specific viral enzymes required for replication
2], 3]. On the other hand, viruses can also be considered as living organisms since upon
infection of cells they turn them into virocells 4]–6]. Moreover, a concept of a greater virus world has recently been formulated covering
bona fide capsid-encoding viruses and other capsidless replicons such as plasmids,
transpozons and viroids. The major feature of this world is not presence of a capsid
but genetic, informational parasitism 7]. These capsidless replicons were also named orphan replicons 8]. Emergence of capsid coding sequences and proteins was a big evolutionary step as
appearance of these vehicles to transfer and protect nucleic acids was one of prerequisites
for evolution. A few years ago, a new division for all living organisms into two distinct
groups has been proposed: ribosome-encoding organisms (REOs) and capsid-encoding organisms
(CEOs) 8]. Similarly to viruses, life itself is also difficult to define and throughout history
of science from Aristotle to K. Ruiz-Mirazo definition of life has been modified many
times and since life is a process and not a substance, it is challenging to confine
“life” in a simple, yet exhaustive formula. A very detailed timeline with changing
definitions of life or living beings is nicely depicted by Moreira and Lopez-Garcia
9]. It is important to know these different explanations for the sake of further discussion
presented herein.

The range of viral genome sizes spans three orders of magnitude and simple size-based
distinction between viruses and cells valid for over a century cannot be used any
longer after the discovery of giant viruses, also known as giruses 10]. One of the smallest double-stranded DNA (dsDNA) viruses is hepatitis B virus (HBV)
containing a 3.2 kb genome with only several genes. Even smaller “subviral” partner
of HBV is human hepatitis delta virus (HDV), quite similar to viroids in many regards.
It contains a 1.7 kb genome encoding one antigen and shows ribozyme activity 11], 12]. On the other hand, the largest dsDNA viruses, Pandoraviruses, have genomes of 2.5 Mb
encompassing some of 2500 coding sequences 13]. According to the Baltimore classification developed by David Baltimore in the early
‘70s, there are seven types of all known viruses depending on the nucleic acid content
and its replication mode: dsDNA, ssDNA, dsRNA, (+)ssRNA and (?)ssRNA, ssRNA-RT and
dsDNA-RT viruses, each with a different replication strategy within infected cells
14]. Cellular forms of life use the canonical DNA-RNA-protein replication-expression
pattern, whereas viruses are totally dependent on cells for multiplication and exploit
all possible DNA and RNA interconversions 15]. Retroviruses and hepadnaviruses can reverse transcribe their RNA to DNA and this
process is rare to occur in cells, although exceptions have been recently reported
such as telomere synthesis and presence of reverse transcriptase-related cellular
genes in eukaryotes 16]–18]. Eukaryotic telomeres essential for the linear chromosome organization most probably
derived from an ancient retroviral activity 19].

Many researchers postulate that viruses are of polyphyletic origin and different RNA
and DNA viruses derived independently as opposed to monophyletic cellular domains
coming from one ancient ancestor LUCA (last universal common ancestor), which is a
logical consequence of the binary mechanism of cell division 6]. There is no physical ‘fossil record’ of viruses; virions persist for short time
periods, and rapidly degrade leaving no direct trace of their existence. However,
many viral genomes have always had the capacity to integrate into cellular genomes
and the study of this genomic ‘fossil record’, called paleovirology, helps to understand
the long-term evolutionary history of virus–host interactions 20]. Viruses have been major players in the evolution by imposing high selection pressure
on their hosts and manipulating the whole environment 21]. According to recent hypotheses, viruses might have played a direct role in the origin
of DNA and DNA replication mechanisms 22], cellular envelopes 23], of pathogenicity 24], alternative genetic codes 25] and formation of the three domains of life: Archaea, Bacteria and Eukarya 23], which were identified by 16/18S rRNA comparison 26]. A previously described link between reverse transcriptase activity and telomeres
indicates a possible early retroviral colonization of large dsDNA viruses, which are
putative ancestors of the eukaryotic nucleus 19], although a different concept on the origin of nucleus was also reported 27].

With the advent of this new knowledge it was a bit unthoughtfully proposed by Carl
Woese that cellular evolution could not be solely explained by the classical Darwinian
mode of thinking 28]. However, it has been recently pointed out that the core of Darwin concept of evolution
relying on variation/selection processes is still sufficient to explain the history
of life. Horizontal, also called lateral gene transfer (HGT or LGT) should be considered
a special case of genetic variation along with mutations, recombination, and different
kinds of ploidies and others 29]–31]. All these processes enrich biodiversity and influence cellular evolution 32], and thus HGT is supplementary to vertical evolutionary mechanisms. If a proto-cell
was simple and highly modular in organization, it implies that HGT could have played
a greater role in evolution 33]. This modularity of ancient RNA cells is somehow reflected by structure of current
viral genomes built of major functional blocks of genes (modules): 1) replicon – ORFs
involved in replication, 2) structural genes encoding coat proteins and 3) elements
manipulating metabolism of infected cells. Phage genomes could be considered as collections
of functional modules that evolved independently in host genomes and were acquired
over time by the phage 34]. However, nowadays an overall similarity of viral and cellular proteins having probably
resulted from horizontal gene transfer is small 35].

If we imagine that 1 ml of seawater contains 1 million bacteria cells and ten or even
a thousand times more viral sequences (up to 10
⁹
virions/ml), it can be determined that 10
³¹
bacteriophages infect 10
²⁴
bacteria cells per second 36], 37]. This abundance and replication rate of viruses have also been one of the sources
of novel functions in cellular lineages via the insertion of genes of viral origin
into cellular genomes. It has been recently suggested that viruses are real nature’s
genomic laboratory and a virocentric perspective on the evolution of life was put
forward 15], 38], 39]. However, the viral insertion should be distinguished from the real HGT consisting
of DNA exchange between cells by transformation, conjugation and transduction; in
the latter viruses play the role of vehicles for cellular gene exchange 29]. These different processes can be exemplified by a prophage providing the acquisition
of more than 100 new genes in a single genome editing event 40] or an insertion sequence named IS607 and carried by Phycodnaviridae (members of nucleo-cytoplasmic large DNA viruses, NCLDVs) as well as by Amoeba and
Algae. It suggests that these viruses could mediate horizontal transfers between different
cellular genomes 41]. The majority of sequences in viromes represent a so-called “dark matter”, they have
no detectable homologues in the current databases 42]. In case of phages, it means that their ability to transduce cellular genes does
not translate into domination of these cellular “hitchhiker” genes in the phage genomic
reservoir 43]. Although the number of sequenced genomes now included in the databases dramatically
increased in the last years, the percentage of unknown sequences within bacteriophages
has not really decreased 39].

Hypotheses of virus origin

Viruses cannot multiply or carry out living processes outside the cells, therefore
the ancestry of both is most probably highly intertwined. Origin of viruses is enigmatic
and controversial in the light of cellular theory of life. Comparison of viral and
cellular sequences shed more light on hypotheses of virus origin. It is important
to know that evolutionarily, three classes of viral genes can be distinguished: 1)
genes with detectable homologues in cellular life forms, 2) virus-specific genes such
as ORFans and 3) viral hallmark genes with only distant homologues in cellular organisms
44]. None of the theories is exhaustive and each has gaps difficult to explain, and for
each theory pros and cons have been discussed in literature (Fig. 1).

Fig. 1. Three major theories of virus origin. Arrows show the direction of evolutionary changes.
a. According to the virus-first hypothesis at the dawn of life there were no cellular
forms but only first RNA molecules possessing enzymatic activities and capable of
self-replication, also called selfish genetic elements. b. According to the escape hypothesis viruses derived from cellular RNA or/and DNA
fragments such as plasmids and transpozons. During asymmetrical cell fission a vesicle
(smaller cell-like entity) could have formed engulfing a self replicating RNA and
a coat encoding RNA segment. c. According to the reduction hypothesis viruses come from small primordial cells (not
necessarily primitive), which lost their cellular elements in the course of evolution.
They maintained, however, their genetic material and certain elements needed for replication.
Proto-cells presented in this picture already contained ribosomes (black small plain
circles) and were able to produce proteins/capsids, whereas cells containing a nucleus
correspond to modern cells, which descended from LUCA. Eukaryotic cells were used
to depict all three hypotheses of virus origin and underline a possible involvement
of viruses in eukaryogenesis

The virus-first (or co-evolution) hypothesis was first proposed by d’Herelle who claimed
that viruses are ancestral to cells 45]. Others suggested that viruses originated in the pre-cellular world using a soup
as a host 15], 46]. Evolution of life started with a virus-like stage and the advent of modern-type
cells was a comparatively late event 15]. At the dawn of life there were no cellular forms but only first RNA molecules possessing
enzymatic activities and capable of self-replication. Some of these subviral forms
still exist in the current world – they are viroids – the smallest (from ~250 to ~400
nucleotides) and simplest replicating RNA molecules known today 47]. Viroids of the family Avsunviroidae possess a hammerhead ribozyme structure and can carry out cleavage of oligomeric
forms of RNA to the monomeric forms, which potentially makes them descendants of the
earliest biomolecules present on Earth 48], 49]. Viroids are good candidates for being survivors of the RNA world as they have a
number of special features such as a small size imposed by error-prone replication,
high G?+?C content, lack of protein-coding ability consistent with a ribosome-free
habitat and several others. On the timeline of evolution, when DNA and proteins molecules
already existed, those protoviroids (ancient viroids) lost some abilities to become
the plant parasites and today they are dependent on cellular enzymes such as RNA polymerase,
RNAaseH and RNA ligase for replication 49]. However, it is more reasonable to claim that these protoviroids would have always
relied on efficient cellular metabolism producing ATP and other ribonucleotides, and
therefore ancient viroids and cells co-evolved.

Even though we have no insight, whether there were the same rules in this ancient
realm, according to our knowledge of the current living world there is a strong inverse
relationship between genome size and mutation rate across all replication systems,
therefore it is possible that pre-LUCA genomes were both small and highly error prone
and hence RNA virus-like 50]. In the era of nucleic acid life in a niche of “supramolecular aggregates” (or SMAs),
the nucleic acids evolved to accommodate available peptides 28], or RNA molecules could have evolved independently of host proto-cells as their “parasites”,
inhabiting a common environment. RNA viruses evolved first from the nucleoprotein
world, followed by retroid elements, and DNA viruses 44]. Ancient RNA viruses, specifically (+)ssRNA, are relics of the RNA world, retroviruses
and hepatitis B viruses relics of an RNA-to-DNA transition in evolutionary history
of life. This seems to be confirmed by the existence of tRNA-like structures (TLSs),
which are involved in virus replication (link between replication and translation)
and by the discovery of reverse transcriptase 51]. Transfer RNA-like structures (TLSs) that are sophisticated functional mimics of
tRNAs are found at the 3?-termini of the genomes of a number of plant positive strand
RNA viruses and three natural aminoacylation identities are represented: valine, histidine,
and tyrosine 52]. Indeed, tRNA-like motifs could be inherited from RNA replication signals accommodated
to assist in the translation process. Plant RNA viruses make use of TLSs to control
translation initiation and viral RNA replication 53].

There is a growing body of evidence that viruses arose even before LUCA, that more
appropriately should be denoted as Last Universal Cellular Ancestral State (LUCAS)
54]. Moreover, while discussing concepts of virus origin, it is crucial to distinguish
viruses evolved before ancient cells and viruses evolved before modern cells, the
descendants of LUCA. The theory of ancient virus origin is supported by the presence
of homologous capsids and homologous packaging ATPases among diverse viruses infecting
the three domains of life. Capsid protein is the most prominent example, and the sole
protein found in most viruses and not in cellular organisms 51], 55], 56]. Several years ago Abrescia and colleagues identified major viral lineages based
on structural comparison of non homologous capsid proteins and non homologhous packaging
ATPases, where genomic similarities are no longer observable. At least two lineages
of DNA viruses predating LUCA, adenovirus/PRD1 containing the double-jelly roll fold
and the Hong Kong fold in the HK97 lineage were described 3]. In the context of these two completely different structures a criticism of the virus-first
theory based on structural convergence of most viral capsids adopting to a small number
of simple geometrical structures can be refuted. Thus, the convergence towards similar
folds for adaptation of certain capsid proteins, as their tertiary conformation is
subject to strong constraints, concerns only a part of the viral world and cannot
be ground for a universal evolutionary concept. Furthermore, the invention of a self-assembling
capsid is very difficult to achieve and its formation by evolutionary mechanisms is
very rare. It suggests that structure based lineages may tend to reflect homology
rather than structural convergence 3]. To conclude it should be noted that there is no a single gene, or a coding sequence
that would be common to all the viruses, hence a common pre-LUCA viral ancestor is
often questioned 9].

The escape or vagrancy (cell-first) hypothesis describes viruses as derived from cellular
RNA or/and DNA fragments such as plasmids and transpozons, which escaped from cells.
When such RNA or DNA fragments acquired protein coat they became independent entities
capable of infecting cells from which they had escaped previously 57]. As already mentioned, ancient RNA genomes were modular (“RNA chromosomes”), and
were randomly distributed from cells to cells 58]. During asymmetrical cell fission a vesicle (smaller cell-like entity) could have
formed engulfing a self replicating RNA and a coat encoding RNA segment. The translation
apparatus was not transferred to the newly formed vesicle and thus an ancient RNA
virus emerged 51]. In a model for early virus evolution, viruses can be regarded less as having derived
from proto-cells and more as being partners in their mutual co-evolution 59]. This model somehow merges the virus-first and the escape hypotheses into one more
complex theory. On the other hand, it would be difficult to demonstrate how nucleic
acids released from cells started to code for coat proteins. It can be easily imagined
that plasmids evolved quite late from dsDNA viruses (not the other way round) and
lost genes encoding coat proteins. Otherwise, it would be hard to prove how viruses
evolved from plasmids and acquired the ability to encode capsids in the absence of
already existing capsid modules 60], 61]. Furthermore, viruses resemble plasmids which do not encode cellular homologues including
proteins involved in DNA replication such as rolling-circle Rep proteins and DNA polymerase
E 62]. This would indicate common evolutionary tract for plasmids and viruses. Moreover,
viruses derived from cells should share a high sequence homology with their hosts,
yet proteins encoded by bacteriophage T4 are more similar to eukaryotic proteins or
eukaryotic viral proteins than to their bacterial homologues 63], and most proteins encoded by viral genomes are deprived of their cellular homologues
64]. However, it is easier to defend the escape theory in the context of a pre-LUCA scenario
for virus origin. Since viruses derived from genome fragments escaped from cells predating
LUCA, any specific relationship between proteins encoded by viruses and those encoded
by their hosts are not expected anymore 51]. A good documented example of new viruses being created through gene escape events
is human hepatitis delta virus (HDV), which has been shown to contain a ribozyme sequence
that is closely related to the CPEB3 ribozyme present in a human intron 65]. HDV is found only in humans and requires human hepatitis B virus to replicate. Thus,
HDV probably derives from the human transcriptome, and not necessarily from a pre-LUCA
world 50].

The reduction or degeneracy (cell-first) hypothesis states that viruses come from
small primordial cells (not necessarily primitive), which lost their cellular elements
in the course of evolution. They maintained, however, their genetic material and certain
elements needed for replication. For a long time it has been believed that there is
no intermediary form between a cell and a virus, because parasites known for the three
domains of life have kept their cellular character; they still have ribosomes and
are able to synthesize ATP. It is also for that reason that the reduction theory can
be easily counter-argued. But then again, it is much easier to imagine this reduction
leading to a virus emergence in a world of RNA cells, because these cells were much
simpler than the modern ones. 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 60]. The presence of virus hallmark genes may be considered as evidence for their possible
origin from virocells or these sequences may have been recruited from ancient cells
now extinct. For instance, it was described that both human adenovirus and Bacillus subtilis bacteriophage ?29, use a similar atypical protein-priming mechanism to replicate
their DNA (unknown in the cellular world) and encode a unique type of DNA polymerase
from the subfamily of polymerases B. It can use such a DNA template to initiate its
own replication and has no representatives in currently living cells 66]. It seems likely, that the DNA polymerase is a viral hallmark gene in disguise 44], and that these two viruses originated from a common ancestor that had existed before
the divergence between Eukarya and Bacteria 51]. However, it must be mentioned here that a small set of virus hallmark genes encoding
essential functions shared by a vast range of viruses is a strong evidence, especially
for positive-strand RNA, that viruses are direct descendants of the primordial RNA-protein
world 15].

In recent years, the reduction hypothesis was revived by the discovery and genomic
characterization of Acanthamoeba polyphaga mimivirus (APMV) 67] with a very complex set of genes (1,2 Mb genome and 911 genes) showing little horizontal
gene transfer. It strongly suggested a process of reductive evolution from an even
more complex ancestor that had been endowed with a protein synthetic capability 57]. Furthermore, sequence and phylogenetic analyses of the components of the packaging
machinery present in APMV show that some large DNA viruses such as mimivirus, vaccinia
virus, and pandoravirus are remarkably more similar to prokaryotes (bacteria and archaea)
than to other viruses in the way they process their newly synthesized genetic material
to make sure that only one copy of the complete genome is generated and meticulously
placed inside a newly synthesized viral particle 68]. The discovery of giruses such as Mimiviruses 10], Megaviruses (Megavirus chilensis) 69], Pandoraviruses 70], and Pithoviruses 71] created a continuum in genome size and functional complexity between the virosphere
and cells. Megavirus retained all of the genomic features unique to Mimivirus, in
particular its genes encoding key-elements of the translation apparatus (seven aminoacyl-tRNA
synthetases), a trademark of cellular organisms. It could suggest that large DNA viruses
derived from an ancestral cellular genome by reductive evolution, which can be supported
further by the presence of a large number of enzymes in genomes of giruses like various
hydrolases, proteases, kinases, phosphatases and many others involved in cellular
metabolic processes. The nature of this cellular ancestor remains hotly debated 70]–72]. It has been pointed out by Claverie and Ogata that despite life being an all or
nothing concept, “living” organisms span a continuum of autonomy and complexity in
which large DNA viruses (giruses) largely overlap the smallest bacteria. It is a well
described evolutionary scenario for Bacteria and Archaea to become parasites by reductive
evolution. Since giruses could have predated the divergence of today’s three cellular
domains, their case may be similar supported by the presence of bacterial-like, archaeal-like
and eukaryan-like genes in their genome 73]. That is why it has recently been proposed that giruses coexisted with the cellular
ancestors and represent a distinct supergroup along with superkingdoms Archaea, Bacteria
and Eukarya 74].

However, this evolutionary theory suffers from several major weaknesses. More than
93 % of Pandoraviruses genes resemble nothing known in all available sequence databases,
therefore their origin cannot be traced back to any known cellular lineage 70], quite similarly to previously described bacteriophages. Furthermore, the term “fourth
domain” is controversial and many arguments were given by opponents against viruses
belonging to the tree of life (actually, the tree of cells), among others, inability
to produce and capture energy or inexistence of integrated fully developed metabolic
pathways 6], 9]. NCLDVs genomes do not display any characteristics of genome decay that have been
observed in intracellular bacteria such as Rickettsia or parasitic protists such as
microsporidia, where presence of pseudogenes, non-coding DNA, shorter genes, massive
gene loss and disappearance of metabolic pathways were noted. This picture is blurred
even more by the fact that Megaviruses are related to small DNA viruses and could
have derived from them using a complex process of genomic accordion. It implies successive
steps of genome expansions (duplication and gene transfers) and genome reduction,
in addition to movement and amplification of diverse genetic elements 75]. Furthermore, giruses can be infected by their own viruses called virophages such
as Sputnik that could be a vehicle mediating lateral gene transfer between them 76]. As Sputnik multiplies in giant factories, it resembles satellite viruses of animals
(adeno-associated virus or hepatitis D virus). However, Sputnik reproduction cycle
seems to impair the production of normal APMV virions significantly, indicating that
it is a genuine parasite, a first virus described to propagate at the expense of its
viral host 76]. According to Krupovic and Koonin Megaviruses evolved from virophages, which in turn
derived from Polintons and Tectiviridae as it is shown by homology of the major capsid protein (MCP) in these groups. The
evolution of giant viruses had been pushed to the extreme, which explains their big
genome size 3], 77], 78]. To conclude, one should avoid supporting the reduction concept of virus origin using
NCLDVs biology.

The origin of cells and nuclei

The co-evolution of viral elements and cellular forms has also been described as incessant
arms race with various forms of cooperation 79]. It started 3 or 4 billion years ago, when LUCA also emerged 80] to give life to all cellular organisms we know nowadays with universal genetic code
from bacterial to human cells, wherein basic processes are similar. To reconstruct
LUCA as it was back in time is extremely difficult because organisms have lost many
genes in the course of evolution, and additionally a horizontal gene transfer (HGT)
interfered. The very nature of LUCA is still under discussion. According to a group
of researchers, although it does not seem very likely in the light of more robust
theories, LUCA could have been an inorganically housed assemblage of expressed and
replicable genetic elements. The evolution of the enzymatic systems for DNA replication,
membrane and cell wall biosynthesis, enabled independent escape of the first archaebacterial
and eubacterial cells from their hydrothermal hatchery, within which the LUCA itself
remained 81], 82]. A concept of LUCA growing on the H
₂
/CO
₂
couple, and being naturally chemiosmotic is among many other hypotheses. This point
goes a long way towards explaining why chemiosmosis, and the proteins that harness
ion gradients, are universal among living cells 83]. LUCA could have used proton gradients to drive carbon and energy metabolism, but
only if the membranes were leaky. This requirement precluded ion pumping and the early
evolution of phospholipid membranes 84]. However, other researchers demonstrated in an evidence-based manner that LUCA was
enclosed by a lipid membrane with secretory and insertion apparatus of protein nature.
Comparative genomic analyses showed that LUCA already encoded several critical membrane-bound
proteins 85], 86] as well as ATP-ase, contained ribosomes and most likely DNA 28], 87]. These sophisticated ribosomes of LUCA were built of 34 proteins that are shared
by all ribosome-encoding organisms 8], 88]. The following issue after deciphering LUCA’s nature in tracing early cellular evolution
is to explain the differences in the membrane composition (cytoplasmic, nuclear and
belonging to reticulum) among the three major domains of life that came after LUCA.
Eukarya and Bacteria are much more similar to each other in this regard than Archaea.
Eukaryan lipids are bacteria-like and have an opposite chirality as compared to Archaea
85]. Two viruses with related DNA replication systems could have infected RNA cells with
different types of lipids, and some cellular lineages ended up using specifically
one of the two types of lipids to produce Archaea and Eukarya 61].

Viruses can be considered as living organisms only when they redirect cellular metabolism
to reproduce virions, hence infection transforms the ribocell (cell encoding ribosomes
and dividing by binary fission) into a virocell (cell producing virions) or ribovirocell
(cell that produces virions but can still divide by binary fission) 4], 5]. This nomenclature is in line with a well documented observation of a variety of
nonrelated viruses inducing a recruitment of organelles, usually to the perinuclear
area, and building a new structure called “virus factory” that functions in viral
replication, assembly, or both. The virus factory is enclosed by a membrane, contains
ribosomes and cytoskeletal elements and it can also recruit mitochondria, from which
it obtains ATP 89]. At this stage of NCLDVs replication cycle the virus factory is very similar to small
unicellular parasites such as bacteria. From this perspective it is much easier to
consider NCLDVs as entities linking inert world and living cells. Another interesting
aspect is that a large poxvirus-like dsDNA virus might be at the origin of the eukaryotic
nucleus, enclosed by an ancestral cell and adapted as an organelle. This virus factory
in ancient times was very similar to a “viral nucleus” that could have evolved into
a modern eukaryotic nucleus according to eukaryogenesis hypothesis 90]. The nucleus could have already appeared in a RNA LUCA and two independent transfers
of DNA from viruses to cells were suggested to explain the existence of two nonhomologous
DNA replication machineries – one in Bacteria, the other in Archaea and Eukarya, which
for that reason are placed on a common branch of the tree of life as opposed to Bacteria
(Fig. 2) 91]–93].

Fig. 2. Tree of life. Schematic presentation of the tree of life. Viruses are depicted as
small hexagons. Viral lineages are traced as “lianas” wrapping around the trunk and
three major branches – domains of life. Horizontal gene transfer (HGT) between cells
and viruses is marked as a source of genetic diversity. Viral origin of eukaryal nucleus
and bacterial origin of mitochondria and chloroplasts are depicted. Only chosen phyla
are presented on the top of the tree. The taxonomy of Archaea is presented according
to Brochier-Armanet et al. 91]. For a more detailed taxonomy of major phyla in Eukarya and Bacteria one may refer
to Zhao et al. 92], and Chun et al. 93], respectively

Later, it was proposed that DNA replication machineries of each domain could have
also originated from three different viruses that helped create three major branches
of life: LACA – last archaeal common ancestor, LBCA – last bacterial common ancestor,
and finally LECA – last eukaryotic common ancestor 61]. This concept of polyphyletic ancestry of viruses is called “Three RNA cells, three
DNA viruses”. It is interesting to denote that RNA viruses might have been at the
origin of DNA biochemistry. RNA-based viruses replicating in RNA-based cells would
have acquired an RNA-to-DNA modification system to resist cellular RNA-degrading enzymes
(Darwinian selection). For this to happen, RNA viruses acquired the ribonucleotide
reductase for conversion of diphosphate-ribonucelotides to diphosphate-deoxyribonucelotides,
and thymidylate synthase to make dTMP from dUMP, cellular RNA was then replaced by
DNA of possible viral origin in the course of evolution 57]. The genetic DNA-RNA takeover may have been driven by a combination of increased
chemical stability, increased genome size and irreversibility as it was demonstrated
experimentally several years ago 94]. This scenario is supported by the fact that many modern viruses encode viral-specific
versions of ribonucleotide reductases and thymidylate synthases. Interestingly, to
further support the above, deoxyuridine is known to replace thymidine in the DNA of
several bacteriophages 95]. Given the complexity of ribosomes and sophisticated nature of aforementioned enzymes
it would be really difficult to imagine that they originated in the world without
proto-cells. The RNA-to-DNA transition must have taken place in a cellular context
60].