Virus Research 117 (2006) 156–184
Evolutionary genomics of nucleo-cytoplasmic large DNA viruses
Lakshminarayan M. Iyer, S. Balaji, Eugene V. Koonin, L. Aravind∗
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA
Available online 21 February 2006
A previous comparative-genomic study of large nuclear and cytoplasmic DNA viruses (NCLDVs) of eukaryotes revealed the monophyletic
origin of four viral families: poxviruses, asfarviruses, iridoviruses, and phycodnaviruses [Iyer, L.M., Aravind, L., Koonin, E.V., 2001. Common
origin of four diverse families of large eukaryotic DNA viruses. J. Virol. 75 (23), 11720–11734]. Here we update this analysis by including
the recently sequenced giant genome of the mimiviruses and several additional genomes of iridoviruses, phycodnaviruses, and poxviruses. The
parsimonious reconstruction of the gene complement of the ancestral NCLDVshows that it was a complex virus with at least 41 genes that encoded
packaging apparatus, and structural components of an icosahedral capsid and the viral membrane. The phylogeny of the NCLDVs is reconstructed
by cladistic analysis of the viral gene complements, and it is shown that the two principal lineages of NCLDVs are comprised of poxviruses
by several derived shared characters, which seemed to rule out the previously suggested basal position of the mimivirus [Raoult, D., Audic, S.,
Robert, C., Abergel, C., Renesto, P., Ogata, H., La Scola, B., Suzan, M., Claverie, J.M. 2004. The 1.2-megabase genome sequence of Mimivirus.
Science 306 (5700), 1344–1350]. These results indicate that the divergence of the major NCLDV families occurred at an early stage of evolution,
prior to the divergence of the major eukaryotic lineages. It is shown that subsequent evolution of the NCLDV genomes involved lineage-specific
expansion of paralogous gene families and acquisition of numerous genes via horizontal gene transfer from the eukaryotic hosts, other viruses,
and bacteria (primarily, endosymbionts and parasites). Amongst the expansions, there are multiple families of predicted virus-specific signaling
and regulatory domains. Most NCLDVs have also acquired large arrays of genes related to ubiquitin signaling, and the animal viruses in particular
have independently evolved several defenses against apoptosis and immune response, including growth factors and potential inhibitors of cytokine
like peptidases. It is further demonstrated that a significant number of genes found in NCLDVs also have homologs in bacteriophages, although a
vertical relationship between the NCLDVs and a particular bacteriophage group could not be established. On the basis of these observations, two
alternative scenarios for the origin of the NCLDVs and other groups of large DNA viruses of eukaryotes are considered. One of these scenarios
posits an early assembly of an already large DNA virus precursor from which various large DNA viruses diverged through an ongoing process
of displacement of the original genes by xenologous or non-orthologous genes from various sources. The second scenario posits convergent
emergence, on multiple occasions, of large DNA viruses from small plasmid-like precursors through independent accretion of similar sets of genes
due to strong selective pressures imposed by their life cycles and hosts.
Published by Elsevier B.V.
Keywords: DNA viruses; Evolution; Poxvirus; Capping enzyme; Triphosphatase; Iridovirus; Coccolithovirus; Phycodnavirus; Primase; Origin of viruses; DNA
replication; Origin of DNA replication; Papain-like peptidase; Sugar metabolism; Ubiqutin signaling; Growth factors; Cytokine signaling; Apoptosis
The origin(s) of viruses had been a topic of intense specula-
tion and debate ever since their discovery (Gibbs et al., 1995;
Koonin, 1992). With the first biochemical studies on viruses, it
became clear that only two common features were shared by all
∗Corresponding author. Tel.: +1 301 594 2445; fax: +1 301 480 9241.
E-mail address: email@example.com (L. Aravind).
viruses: (1) their obligate intracellular parasitism; and (2) their
virion architecture comprised of a genomic nucleic acid, typi-
cally of a single type (either RNA or DNA), packaged into a
protein capsid, which in some cases is further associated with
general features, viruses show tremendous diversity in every
respect, including genome size and organization, capsid archi-
tecture, mechanisms of propagation, and interactions with host
cells. Viruses infect organisms from all three superkingdoms of
0168-1702/$ – see front matter. Published by Elsevier B.V.
L.M. Iyer et al. / Virus Research 117 (2006) 156–184
viruses suggests that they must have had multiple evolutionary
origins, and the common features observed in all viruses reflect
convergences emerging from adaptations to intracellular para-
sitism. The times and the modes of origins of the various types
of viruses and their relationships to cellular genomes remain
major issues of debate among evolutionary biologists. Broadly,
the early theories of viral origins could be placed in two cate-
phases of life’s evolution and associated them with the primi-
tive precursors of cellular systems (Alstein, 1992; Gibbs et al.,
1995). The second group of theories saw viruses as secondary
derivatives of cellular systems that underwent drastic degener-
ation as a consequence of extreme parasitism, or “break away”
elements from cellular genomes that survived as minimal para-
sitic replicons (Gibbs et al., 1995). The two groups of theories
are not mutually exclusive: conceivably, some classes of viruses
could be primordial whereas others could be later derivatives
of “break away” elements from cellular systems. The advent of
the first complete genome sequences of viruses did not resolve
these debates entirely, but threw considerable light on the actual
diversity in the coding capacity of various viruses, the affinities
between different viral groups and homologies between viral
genes and those of cellular organisms.
The first decade of viral comparative genomics revealed sev-
eral major assemblages of viruses that were unified on the
basis of the evolutionarily conserved proteins of their repli-
cation apparatus. Firstly, it became clear that the retroviruses,
together with their various relatives such as the hepadnaviruses,
plant badnaviruses, and tungroviruses, and the diverse retro-
scriptase (RT) as their principal replication polymerase (Xiong
and Eickbush, 1990). The RNA-dependent RNA polymerases
(RDRP) of diverse positive strand RNA viruses and several
ing a common origin for this entire assembly of viruses (Kamer
and Argos, 1984; Koonin et al., 1989). At a deeper level, the
RTs and RDRPs have been shown to descend from an ancestral
replicase that utilized an RNA template (Delarue et al., 1990;
might have ultimately descended from an ancient replicon with
an RNA genome. This unification also suggested that the diver-
sification of these viruses might be linked to one of the funda-
genomes (Forterre, 2002; Leipe et al., 1999; Wintersberger and
Similarly, certain assemblages sharing common replication
systems also became apparent amongst the DNA viruses. In
particular, many small DNA viruses and related plasmids and
transposons were unified on the basis of a shared rolling circle
replication endonuclease (RCRE), which initiates the epony-
mous form of replication of these elements (Ilyina and Koonin,
1992; Iyer et al., 2005; Kapitonov and Jurka, 2001). However,
genomes with dozens or even hundreds of genes remained far
more difficult to elucidate. Amongst the bacteriophages, several
major monophyletic groups, such as the lambdoid phages, were
identified (Hendrix, 2003). Among the animal large dsDNA
of these families have been partially reconstructed and, in each
case, inferred to have had over 50 genes (Davison et al., 2005;
Hughes and Friedman, 2005; Lauzon et al., 2005; McLysaght et
salient features of replication, gene expression and virion archi-
tecture apparently emerged early in their evolution and were
retained over vast evolutionary time spans. In contrast, higher-
order relationships between various groups of large eukaryotic
DNA viruses, if any, remained uncertain. In our previous work,
we addressed this issue through comprehensive comparative
analysis of the protein sequences encoded by large eukaryotic
DNA viruses, followed by cladistic analysis using a character
matrix based on the conserved features of these proteins (Iyer et
of several families of large eukaryotic DNA viruses, including
the animal poxviruses, iridoviruses, and asfarviruses (with a
single representative, the African Swine Fever Virus, ASFV),
and the phycodnaviruses, which infect phylogenetically diverse
We named this major, monophyletic assemblage of large
eukaryotic DNA viruses the Nucleo-Cytoplasmic Large DNA
Virus (NCLDV) clade as they either replicate exclusively in
the cytoplasm of the host cell or start their life cycle in the
host nucleus but complete it in the cytoplasm. Typically, the
NCLDVs do not exhibit much dependence on the host repli-
cation or transcription systems for completing their replication
because, even in viruses like Paramecium bursaria Chlorella
virus (PBCV), which initiate replication in the nucleus, disrup-
replication (Van Etten et al., 1986). This relative independence
of the NCLDVs from the host cells is consistent with the fact
ing most key life-cycle processes, such as DNA polymerases,
tion resolvases and topoisomerases for genome manipulation,
gation, ATPase pumps for DNA packaging, and chaperones
involved in the capsid assembly (Iyer et al., 2001). In the origi-
shared by all families of NCLDVs and 22 additional proteins
shared by at least three of the four families (Iyer et al., 2001).
This suggested that all extant NCLDV families have descended
from a common ancestor that already had a fairly complex gene
repertoire and was capable of completing its replication cycle in
relative autonomy from the cell.
Subsequent to the original description of the NCLDV group,
several major developments have occurred, the chief among
them being sequencing of the 1.2-megabase genome of the
gigantic Acanthamoeba polyphaga Mimivirus (Raoult et al.,
2004). Analysis of the mimivirus genome showed that it was
a new branch of the NCLDV group. In addition, this largest
known viral genome contains numerous multi-gene families as
L.M. Iyer et al. / Virus Research 117 (2006) 156–184
well as genes that might have been accrued by the viral genome
via extensive horizontal gene transfer (HGT) (Desjardins et
al., 2005; Koonin, 2005; Raoult et al., 2004). Additionally, the
genomes of several new vertebrate iridoviruses have been pub-
lished and shown to contain many genes beyond those found
in the originally sequenced isolate of fish lymphocystis disease
virus (Do et al., 2004; He et al., 2001, 2002; Jancovich et al.,
2003; Song et al., 2004; Tsai et al., 2005). Concomitantly, there
have been several advances in the sequence analysis of the viral
proteins, including the prediction of the replicative primase of
the NCLDVs and its relationship to the herpesvirus primases
(Iyer et al., 2005). The accumulating data on phage genomes
have also provided additional material to compare diverse large
In light of this new information, we herewith revisit the
NCLDVs to address several major issues relevant for the evolu-
tion of this group of viruses: (i) new support for the monophyly
of the NCLDV clade; (ii) reconstruction of key biological fea-
(iii) contributions of lineage-specific expansions of gene fami-
lies and gene accretion, via HGT from hosts and co-occurring
symbionts and parasites, to the genomic growth of large DNA
viruses; (iv) the relationship between NCLDVs and other large
DNA viruses, phages, and plasmids; (v) the implications of the
emerging picture of the evolution of NCLDVs and other large
DNA viruses for the origins of cellular life.
2. Re-examination of the NCLDV phylogeny and
derivation of core gene sets for different NCLDV clades
To re-evaluate the original results concerning the monophyly
and evolutionary radiation of the NCLDVs in light of the
new genome sequences, we performed a systematic analysis
of the proteins encoded by the mimivirus and the following
iridoviruses: the new Chinese isolate of lymphocystis disease
virus, Singapore Grouper virus, Rock Bream iridovirus, Infec-
tigrinum stebbensi virus, and Chilo iridescent virus. The new
LDV isolate has 70–90 additional genes, which were not found
in the originally sequenced LDV isolate, but are often present
in other iridoviruses. Accordingly, we used this strain as it
is a more representative form of this virus. The genome of a
phycodnavirus infecting the prymnesiophyte (haptophyte) alga
Emiliania huxleyi [EHV; (Wilson et al., 2005)] was released
when the present manuscript was being finalized. Therefore,
we could not include the EHV genome in the cladistic analyses;
nevertheless, analysis of the predicted protein sequences of this
virus was performed to identify interesting features relevant
to the overall description of the NCLDVs. The Feldmannia
irregularis virus, another phycodnavirus, was also analyzed but
not used in any further comparisons because it is closely related
to the Ectocarpus siliculosus virus and did not provide any
described here are: Chordopoxviruses (Vaccinia virus, VV;
Molluscum Contagiosum virus, MCV; Fowlpox virus, FPV),
Entomopoxviruses (Amsacta moorei Virus, AMV; Melanoplus
sanguinipes Virus, MSV), Asfarviruses (African Swine Fever
Virus, ASFV), Fish iridoviruses (lymphocystis disease virus
Chinese isolate, LDV; Singapore Grouper virus, SGV; Rock
Bream iridovirus, RBV), Amphibian iridoviruses (Frog virus
3, FV3; Ambystoma tigrinum stebbensi virus, ATSV), Insect
iridoviruses (Chilo iridescent virus, CIV), Phycodnaviruses
(Paramecium bursaria Chlorella Virus, PBCV; Ectocarpus
siliculosus Virus, ESV; and Emiliania huxleyi virus-EHV), and
mimivirus (Acanthamoeba polyphaga mimivirus). All con-
using a combination of clustering with the BLASTCLUST pro-
and sequence profile searches with PSIBLAST (Altschul et al.,
1997). Clustering of the entire set of NCLDV proteins was also
carried out to identify lineage-specific expansions of protein
families. All proteins were further investigated using PSI-
BLAST position-specific scoring matrices to identify potential
conserved domains; identification of such domains often leads
to new insights into the functions of the respective proteins
(Aravind and Koonin, 1999b). These features were used to
develop a standard annotation of the protein complements of
the NCLDVs. The evolutionary affinities of viral proteins with
their homologs from other viruses and cellular organisms were
assessed where feasible by using conventional phylogenetic
trees constructed with neighbor-joining, minimum evolution,
and maximum likelihood methods (Felsenstein, 2004).
The sequenced NCLDV genomes contain from ∼150 (LDV)
to ∼900 (the mimivirus) predicted protein-coding genes. We re-
by removing short open reading frames (ORFs) that did not
have detectable homologs in the current databases, ORFs with
completely biased amino acid composition, and ORFs which
overlapped with well-defined genes but lacked homologs, and
plotting the resulting number of predicted genes against the
genome size. The numbers of genes identified by this conser-
vative approach show a good linear fit (R2=0.94; Fig. 1). Thus,
Fig. 1. Linear correlation between the number of predicted genes and the
genome size (in nucleotides) in NCLDVs. The number of genes in each genome
was corrected by removing short, compositionally biased ORFs, and predicted
ORFs that overlap with well-defined genes but lack homologs.
L.M. Iyer et al. / Virus Research 117 (2006) 156–184
vations suggest that the NCLDVs have a nearly constant gene
density, which is indicative of similar selective forces affecting
proteome size range, and the enormous range of hosts infected
tor behind the observed pattern.
Having obtained, through the comprehensive protein
sequence comparison, the conserved characters for the NCLDV
assemblage, including the new sequences, we rebuilt the phylo-
Fig. 2. A phylogenetic tree of the NCLDVs built on the basis of conserved gene set analysis. The tree topology is based on the consensus cladogram derived by
cladistic analysis. The number of proteins reconstructed as being present in the ancestral core of a clade of viruses is shown next to the blue circles. Shown in
brackets are the numbers of proteins that are unique to a particular clade. Proteins that are predicted to be part of the ancestral NCLDV genome are shown on the
left. Protein names in red and marked with an asterisk represent members of the ancestral genes set that have not been identified in our previous reconstruction (Iyer
et al., 2001). The transcription factor A7L protein was formerly called the ASFV-B385R-like protein (abbreviations: THP, Terminal hairpin; TIR, Terminal inverted
repeats; CPTR, Circularly permuted terminally redundant).
L.M. Iyer et al. / Virus Research 117 (2006) 156–184
parsimonious trees implemented in the PAUP program package
with at least 41 proteins (10 additional proteins beyond the
originally defined set) traceable to their last common ances-
tor (Fig. 2). These proteins belong to a wide range of functional
stantially changed the internal relationships within the NCLDV
are not found in any other NCLDV. Overall, at least 74 proteins
were confidently assigned to the last common ancestor of the
naviruses within this clade was supported by another set of 12
had a number of specific adaptations that allowed it to spread
widely and infect a range of phylogenetically diverse protists.
However, perhaps, unexpectedly, the new analysis did not
recover any support for a clade uniting all animal NCLDV
lineages. Instead, a set of 11 proteins was identified that sup-
ported a higher-order clade consisting of the iridoviruses and
the mimivirus+phycodnavirus clade (Fig. 2). The alternative
grouping of the three animal NCLDV lineages resulted in only
three synapomorphies (unique proteins) supporting their mono-
phyly; furthermore, there was no support for the grouping of
either ASFV or the poxviruses with iridoviruses. As in the pre-
vious analysis (Iyer et al., 2001), the most parsimonious tree
had ASFV and poxviruses as sister groups, but this node was
absence of further evidence. This phylogeny supports an early
radiation of the major NCLDV groups in protists as opposed
to the emergence of all animal NCLDVs from a single, ances-
and iridoviruses can be reconstructed in greater detail thanks to
diverse animals. The common ancestor of all known poxviruses
the known iridoviruses was inferred to contain at least 59 genes.
Within both poxviruses and iridoviruses, there is strong support
for the monophyly of the viruses infecting vertebrates, with the
ancestor of the chordopoxviruses predicted to encode at least
119 proteins and that of the vertebrate iridoviruses at least 59
proteins. Likewise, the monophyly of the entomopoxviruses is
strongly supported with a set of 117 proteins predicted for their
sequenced insect iridovirus, the ascovirus, similarly supports
a monophyletic arthropod iridovirus lineage. Within the verte-
brates, the phylogenies of poxviruses seemed to recapitulate the
phylogeny of the animal hosts (Fig. 2). However, the amphib-
ian iridoviruses are closer to the fish SGV, to the exclusion
of the other fish virus LDV. These observations are best com-
patible with a single invasion of the animals by the ancestors
of poxviruses and iridoviruses each. Whereas the poxviruses
appear to have subsequently followed a vertical co-evolution
with the host, the vertebrate iridoviruses might have spread
across different vertebrate hosts sharing the same aquatic envi-
reconstructed cores of both this progenitor and the ancestors of
individual clades are considerably smaller than the proteomes
of the extant viruses. Thus, evolution of the NCLDVs must have
included either growth in the size of their genomes through-
out their existence, or extensive turnover of some genes of
an already gene-rich ancestor, except those belonging to the
relatively stable core. These two trends are not mutually exclu-
sive, and indeed, below we present evidence for gene accretion,
lineage-specific expansions, as well as loss and displacement of
many genes throughout the history of the NCLDV genomes.
3. Core functional systems of NCLDVs and their
elaboration in different viral lineages
by all or most of the NCLDVs and inferred to have been present
in their common ancestor, we discuss below the reconstructions
3.1. DNA replication
All NCLDVs share a DNA polymerase of the B family,
which, like the principal replicative polymerases of archaea and
eukaryotes, contains the polymerase catalytic domain fused to
an N-terminal 3?→5?exonuclease domain (Leipe et al., 1999).
The NCLDVs, except for the entomopoxviruses, also encode a
tein (vaccinia G8R) is extremely divergent (Iyer et al., 2001),
which might be related to the additional role of this protein in
transcription (Dellis et al., 2004; Iyer et al., 2001). In contrast to
the DNA clamps, the clamp-loader ATPases, related to eukary-
codnaviruses and the mimiviruses. The D5R-like ATPase, typi-
fied by the eponymous vaccinia protein essential for DNA repli-
cation, appears to be the replicative helicase that is conserved
in all NCLDVs. The D5R family belongs to the helicase Super-
family (SF) III within the AAA+ ATPase class, which includes
the primary replicative helicases of many other DNA and RNA
viruses (Gorbalenya et al., 1990; Iyer et al., 2004b). Our recent
analysis showed that the D5R helicases are distinguished from
other SFIII family members by the presence of a unique N-
terminal domain, the D5N domain (Iyer et al., 2005). The strict
association between the D5N and the AAA+ ATPase domain in
the D5R family suggests that D5N mediates recognition of the
substrate and/or primer initiation sites by these proteins.
We recently showed that the N-terminal region of the
related to the archaeo-eukaryote type primases (AEPs). Further
L.M. Iyer et al. / Virus Research 117 (2006) 156–184
like the NCLDVs, or in cells with lipid membranes. Hence, it
might have originally operated in the context of lipid micelles
that coated nucleic acids within protein capsids. The emergence
of the secretory apparatus might have allowed these systems to
break free from the capsid and stabilize or protect their lipid
membrane more effectively. This might have ultimately led to
the earliest cells, which continued to segregate their DNA using
a DNA pump inherited from the ancestral virus-like elements.
Alternatively, it is imaginable that the emerging cells (without
specifying the scenario of cell origin) captured the HerA/FtsK-
based pumping apparatus from the primordial virus-like entities
and adopted it for chromosome segregation during cell division.
tems of the NCLDVs and other DNA viruses might cast light on
some of the early stages of life’s evolution including the origin
of replication systems and even of cells themselves.
The present re-investigation of the NCLDVs in light of the
as a monophyletic group (Iyer et al., 2001) resulted in greater
ary connections to other viruses and cellular systems. We also
hope that this type of analysis may serve as a general model for
future comparative-genomic and phylogenetic studies on vari-
ous classes of large DNA viruses as more sequences become
Appendix A. Supplementary data
in the online version, at doi:10.1016/j.virusres.2006.01.009.
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