The origins of giant
viruses, virophages and their relatives in host genomes
Aris Katzourakis* and Amr Aswad
Author Affiliations
Department of Zoology, University of Oxford, Oxford OX1 3PS,
UK
BMC Biology 2014, 12:51
doi:10.1186/s12915-014-0051-y
Accepted: 24 June
2014
Published: 30
June 2014
© 2014 Katzourakis and Aswad; licensee BioMed Central
This is an Open Access article distributed under the terms
of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is
properly cited. credited. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made
available in this article, unless otherwise stated.
Giant viruses have revealed a number of surprises that
challenge conventions on what constitutes a virus. The Samba virus newly
isolated in Brazil expands the known distribution of giant mimiviruses to a
near-global scale. These viruses, together with the transposon-related
virophages that infect them, pose a number of questions about their
evolutionary origins that need to be considered in the light of the complex
entanglement between host, virus and virophage genomes.
Giant DNA viruses are double-stranded DNA (dsDNA) viruses
that have particle and genome sizes comparable to those of small bacteria, and
a number of features that are uncharacteristic of viruses. These include the
presence of several genes that are similar to cellular genes such as those
involved in DNA repair, translation, protein folding, and polysaccharide
synthesis [[1]]. Acanthamoeba polyphaga mimivirus was the first of the giant
DNA viruses to be discovered, initially isolated in the search for the
causative agent of pneumonia during a hospital outbreak in Bradford, UK [[1]].
Since then, related viruses have been identified in a range of environments,
including the discovery last year of the morphologically and genetically
distinct pandoraviruses, which are even larger than the mimiviruses [[2]]. More
recently, the 30,000-year-old Pithovirus sibericum was unearthed and brought
back to life from Siberian permafrost [[3]].
Determining the evolutionary relationships among viruses is
crucial to investigating the origins of features such as their size, but is
complicated by the absence of universally conserved viral genes. The Baltimore
system classifies viruses according to genome type and replication strategy,
therefore placing giant viruses among others with dsDNA genomes. They are also
considered on the basis of distinguishing biological features to belong within
the nucleocytoplasmic large DNA viruses (NCLDVs) alongside viral families such
as poxviruses and iridoviruses [[5]]. While dsDNA viruses in general do not
appear to have a single evolutionary origin, the NCLDVs all contain five core
genes and tend to share a suite of 50 or so likely ancestral genes [[5]] that
partition them from other large eukaryotic dsDNA viruses such as nudiviruses,
herpesviruses and baculoviruses. NCLDVs do share some genes with these other
large DNA viruses, but are additionally distinguished by an either completely
or largely cytoplasmic replication cycle [[5]].
The genome sizes of the NCLDVs vary greatly, from the 150 kb
genomes of the poxviruses to the 2.5 Mb genomes of pandoraviruses [[2],[5]].
This hints at the possibility that viruses with intermediate genome sizes may
exist. While many lineages may be extinct, it seems likely that at least some
will eventually be found through metagenomic sampling. It would be premature to
conclude that mimivirus and pandoravirus represent the largest DNA viruses that
will be found. Interestingly, the recently uncovered pithoviruses are
phylogenetically closer to the mimivirus/marseillevirus group despite a
morphological resemblance to pandoraviruses that have ovoid rather than
icosahedral morphology [[3]]. Moreover, of the more than 1,000 pandoravirus
genes, 93% are previously unknown to biologists [[2]]. Many viruses contain
some of these so-called orphan genes, but the high percentage of orphans in a
single virus highlights how limited our sampling of the diversity of viral
genes is.
Giant viruses reproduce in ‘viral factories’, which are
cytoplasmic compartments of the host cell that can be as large as the nucleus
(Figure 2). Accompanying the surprise of discovering giant viruses was the
discovery of a group of associated viruses that are not capable of replication
in their absence, and instead exploit the viral factory for replication. Other
viruses are known to require helper viruses for replication, but these
‘virophages’ result in the formation of defective mimiviruses, implying a
parasitic relationship [[6]]; they make the giant viruses ill. For example, the
infection of Samba virus by its virophage results in a reduction of viral titer
of over 80%, as well as partial recovery of the host amoebae [[4]]. This
parasitism is therefore part of a complex relationship between giant viruses,
their hosts and the virophages [[6]]. Virophage genomes are dwarfed by the
mimiviruses that they infect, being approximately 20 kbp in length, and have
been identified in association with several members of Mimiviridae [[6],[7]].
There are now multiple strains of the first virophage, named Sputnik [[6]],
including the Rio Negro isolate from the Samba virus [[4]] and more distantly
related virophages such as Mavirus, identified from the Cafeteria roenbergensis
virus (CroV) [[7]].
Virophages are related to a class of eukaryotic DNA
transposons called Mavericks (or Polintons). These genomic parasites share a
set of four core genes [[7]], as well as widespread conservation of the
characteristically viral jelly-roll capsid [[8]]. Two of these core genes are
present in virophages, indicating a close evolutionary relationship, and the
Mavirus virophage in particular shares a total of seven homologs with Mavericks
[[7],[8]]. This indicates a much closer evolutionary relationship between
Mavirus and Maverick transposons than Mavirus has with other virophages like
Sputnik, with which it only shares four genes in total [[7]]. Mavericks are
thought to derive from a DNA virus that integrated into the host genome, and
the discovery of Mavirus strongly suggests a virophage-like progenitor to Mavericks.
Several features indicate that the Mavirus ancestor was also a virophage rather
than an escaped Maverick-like transposon [[7]], although this has been debated
[[8]]. One such notable feature is the dependence on CroV for replication, as
indicated by the high similarity of Mavirus promoters to those of CroV [[7]].
It is hard to imagine how a DNA transposon’s replication strategy would evolve
to rely on CroV infection, whereas the post-integration loss of this feature in
Mavericks is more readily explained [[7]]. Interestingly, some Maverick
elements are more closely related to some virophages than to other Mavericks
[[8]], suggesting that these integrations are a recurring event. The fact that
Mavericks are widespread in the animal kingdom indicates that a number of
virophages, and therefore NCLDVs, are yet to be discovered in association with
these hosts.
Gene flow has played a central role in the evolutionary
history of virophages. Integrated virophages have been found in a mimivirus
genome, and virophage genes also share similarity to genes in other DNA
transposons, such as a class of linear plasmids called transpovirons that are
also found in mimiviruses [[9]]. Some virophage genes also show similarity to
bacteriophages, cellular genes, and their respective viral hosts [[7]]. This
compound nature of virophage genomes is evidence of extensive horizontal gene
transfer, and although the precise details of this gene flow are not fully
understood, perspectives from paleovirology - the study of viral remnants, or
‘fossils’, found in host genomes - may help to clarify them. Analysis of these
viral remnants, known as endogenous viral elements (EVEs), has revealed that
all viruses can in principle integrate in a heritable fashion into the host
genome, thus preserving information from the distant evolutionary past [[10]].
Mimivirus EVEs have not been found, and one might suspect that their
extraordinarily large genomes mean that they are unlikely to form EVEs.
However, we could consider a virophage EVE to exist in the form of Mavericks;
in some sense, a mimivirus that donates genes to a subsequently endogenized
virophage could be thought of as a ‘vicarious EVE’. This flow of genes, from
mimivirus to virophage to host genome, is therefore evident in the amoeba
genome.
The discovery of giant viruses has crossed some of the
boundaries between viruses and cellular life, although ribosomes remain a
distinguishing feature. The conflict between giant viruses and their hosts,
with the former also infected by virophages, alongside genomic invasions with
related transposons, is reminiscent of Darwin’s tangled bank, recapitulated at
the microscopic scale in a droplet of water. Elucidating the role of gene flow
between these microscopic entities will reveal their evolutionary dynamics and
aspects of the origins of viruses and cellular life.
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