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Journal of Invertebrate Pathology 147 (2017) 23–36

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Review article

Reprint of: Diversity of small, single-stranded DNA viruses of invertebrates and their chaotic evolutionary past☆ ⁎

Peter Tijssena, , Judit J. Pénzesa, Qian Yua, Hanh T. Phama, Max Bergoina,b, a b

MARK

⁎

Laboratoire de Virologie (Bldg 18), Institut National de Recherche Scientifique-Institut Armand-Frappier, 531 Boul. des Prairies, Laval, QC, H7V 1B7, Canada Laboratoire de Pathologie Comparée, Faculté des Sciences, Université Montpellier, Place Eugène Bataillon, 34095 Montpellier, France

A R T I C L E I N F O

A B S T R A C T

Keywords: Taxonomy Parvoviruses Densovirus Bidensovirus Circular Rep-encoding ssDNA (CRESS-DNA) viruses Replication Recombination and tropism Viral evolution Viral chimerism Review

A wide spectrum of invertebrates is susceptible to various single-stranded DNA viruses. Their relative simplicity of replication and dependence on actively dividing cells makes them highly pathogenic for many invertebrates (Hexapoda, Decapoda, etc.). We present their taxonomical classification and describe the evolutionary relationships between various groups of invertebrate-infecting viruses, their high degree of recombination, and their relationship to viruses infecting mammals or other vertebrates. They share characteristics of the viruses within the various families, including structure of the virus particle, genome properties, and gene expression strategy.

1. Synopsis of single-stranded DNA virus features The number of single-stranded DNA (ssDNA) virus families of animals is limited since: (i), ssDNA cannot be transcribed/translated, e.g. to yield DNA polymerase; (ii), linear ssDNA cannot, in contrast to linear single-stranded RNA, be replicated without loss of genomic integrity (corresponding to Okazaki fragments) unless complex hairpin structures, or a protein-primed mechanism (Tijssen and Bergoin, 1995) are introduced to create first a double-stranded DNA (iii), the absence of a complementary DNA strand, as a repair template, increases the mutation rate, and therefore limits the maximum length (2–12 kb with very few exceptions, Mochizuki et al., 2012) to that of RNA viruses (Shackelton et al., 2005). Moreover, these viruses have small icosahedral capsids with a diameter of 18–27 nm with a limited packaging capacity. Although many densoviruses are highly pathogenic, some are essential for the life cycle of the host. Ryabov et al. (2009) demonstrated that infection with Dysaphis plantaginea densovirus (DplDV) is essential for the production of the winged morph in asexual clones of the rosy apple aphid and its colony dispersal to neighboring plants. This mutualistic relationship between the rosy apple aphid and this virus results both in a negative impact of DplDV on rosy apple aphid

reproduction, but also contribute to the survival of aphid colonies by inducing wing development and promoting dispersal. Despite the limited number of ssDNA virus families, these viruses are exceptionally widespread, including medically and economically important pathogens (Krupovic, 2013) in all domains of life. Metagenomic studies dramatically boosted our knowledge about ssDNA viruses in the biosphere, from the human gut to hot springs (Rosario et al., 2012). The diversity of ssDNA viruses appears to be determined by two principal factors: extremely high nucleotide substitution rates that approach those of RNA viruses (Shackelton et al., 2005) facilitating adaptation to different environments, extending to the oceans (Labonté and Suttle, 2013), and pervasive recombination, both by DNA and RNA donors (Martin et al., 2011). Known ssDNA viruses of invertebrates belong to the families Parvoviridae, of which the subfamily that infects invertebrates is called Densovirinae, Circoviridae (usually from the genus Cyclovirus) and Bidnaviridae (thus far solely in insects). Although different parvovirus genera exist, they have a common Non Structural (rep) gene set, coding for proteins that are accessory to Rolling Circle Replication (Section 2.1) at the left half of the genome and a structural capsid protein (cap, Section 2.2) gene set at the right hand of the genome. Because host cell DNA

DOI of original article: http://dx.doi.org/10.1016/j.jip.2016.09.005 ☆ This article is a reprint of a previously published article. For citation purposes, please use the original publication details; Journal of Invertebrate Pathology, 140C, pp. 83-96. ⁎ Corresponding authors at: Laboratoire de Virologie (Bldg 18), Institut National de Recherche Scientifique-Institut Armand-Frappier, 531 Boul. des Prairies, Laval, QC, H7V 1B7, Canada (P. Tijssen), Laboratoire de Pathologie Comparée, Faculté des Sciences, Université Montpellier, Place Eugène Bataillon, 34095 Montpellier, France (M. Bergoin). http://dx.doi.org/10.1016/j.jip.2017.06.008 Received 25 July 2016; Received in revised form 14 September 2016; Accepted 19 September 2016 0022-2011/ © 2017 Published by Elsevier Inc.

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of the N-terminal βA strand, allowing βA to hydrogen bond with βB of the neighboring, twofold-related subunit and thereby increasing the number of interactions between subunits (Simpson et al., 1998). In vertebrate parvoviruses, however, βA folds back and hydrogen bonds with the βB strand from its own subunit ((Fig. 1). The same structural difference was observed for small icosahedral RNA viruses from invertebrates vs those of vertebrates, e.g. human rhinovirus versus cricket paralysis virus (Kaufmann et al., 2010, 2011; Meng et al., 2013). The presence in the same genome of genes with different evolutionary histories (rep compared to cap) illustrates the pitfalls of genome-based virus classification.

polymerase can synthesize the double-stranded molecule as a prelude to transcription/translation only during the S-phase of the cell cycle, these ssDNA viruses have a tropism for rapidly dividing cells which translates in common pathogenic features. The family Parvoviridae is a very diverse group of viruses and occurs both in invertebrates and vertebrates, including mammals. The rep and cap genes of the Circoviridae do have a less fixed position with respect to the origin of replication. 2. Imperative genes of single-stranded DNA viruses 2.1. Rep protein: conserved sequence with initiator proteins for rolling-circle replication (RCR)

3. Densoviruses (subfamily Densovirinae of Parvoviridae) An HuHuuu amino acid motif (in which u represents bulky hydrophobic residues) near the N-terminus was identified in the Rep protein (HUH endonuclease superfamily) that is conserved in two vast classes of proteins, one of which is involved in initiation and termination of rollingcircle DNA replication, or RCR (Rep proteins), and the other in mobilization (conjugal transfer) of plasmid DNA (Mob proteins) (Ilyina and Koonin, 1992). An additional conserved motif in this superfamily of proteins is located closer to the N-terminus, and another, downstream of the HuHuu motif, with a conserved Tyr residue. The major role of these HUH endonucleases is processing a range of mobile genetic elements by catalyzing cleavage and rejoining of single-stranded DNA using the active-site Tyr residue in the downstream motif to make a transient 5′phosphotyrosine bond with the DNA substrate, such as in rolling-circle replication, in various types of transposition and in intron homing (Chandler et al., 2013). HUH enzyme activities require a divalent metal ion, coordination of which is provided by the HUH motif, to facilitate cleavage by locating and polarizing the scissile phosphodiester bond. Rep proteins also contain a C-terminal superfamily 3 (SF3) 3–5′ helicase domain. RCR uses this ringlike, hexameric 3–5′ helicase activity acting on the template strand to facilitate DNA unwinding at the replication fork (see Section 3.3). The crystal structure of an SF3 DNA helicase, Rep40, from adeno-associated virus 2 (AAV2) has been reported (James et al., 2003) and delineates the expected Walker A and B motifs, but also reveals an unexpected “arginine finger”. The so-called arginine finger penetrates the active site of a neighboring subunit. Mutation of the Arg finger to alanine resulted in deficiency in helicase activity. The presence of a functional arginine finger directly implicates the requirement for oligomerization in order to create a competent catalytic center for cooperative ATP hydrolysis (James et al., 2003). The peptide linker between the HUH endonuclease and the SF3 helicase domains has a critical role in helicase oligomerization (Maggin et al., 2012). The helicase is also required for packaging of the ssDNA genome in the preformed procapsids (King et al., 2001).

3.1. Pathology and host range The family Parvoviridae is a very diverse group of viruses and occurs both in invertebrates (“densoviruses”) and vertebrates (“parvoviruses”), including mammals. The knowledge of the host range of densoviruses (DVs) infecting invertebrates, mainly insects (orders of Lepidoptera (e.g. L32896), Diptera (e.g. NC_011317), Hymenoptera (e.g. red imported fire ant, KC991097), Blattodea (e.g. AY189948), Hemiptera (e.g. FJ040397.1), Orthoptera (e.g. HQ827781) but also of Crustacea (shrimp (e.g. AF273215) and crayfish (KP410260)) and echinoderms (starfish (KP410260), sea urchins (PRJNA223197)) is still very limited. Invertebrates constitute over 1 million species and some species, e.g. crickets are infected by at least four different ssDNA viruses. A definite classification is therefore not yet possible. Phylogenetic analysis revealed that these densoviruses may be as diverse as their host, this in contrast with their vertebrate/mammalian counterparts (Fig. 2). The hypertrophied nuclei intensely stained by Feulgen reagent is a salient feature shared by all infected tissues. Thin sections of heavily infected cells observed by EM show hypertrophied nuclei filled by a virogenic stroma containing thousands of virions and cytoplasmic paracrystalline virions arrays (Vago et al., 1966; Suto et al., 1979; Barreau et al., 1996). Most of the DVs so far isolated are lethal for their natural hosts, the first symptoms being anorexia and lethargy followed by flaccidity. After a progressive paralysis, a slow melanization and death follow. The cockroach densovirus (PfDV) displays very characteristic hind leg paralysis, uncoordinated movements and a hypertrophied abdomen. The oil palm pests Casphalia extranea and Sibine fusca (in Ivory Coast and Colombia, respectively) when infected with CeDV and SfDV display tumour lesions in the gut (Fédière et al., 1991, 2002; Meynadier et al., 1977). Infections are highly contagious and rapidly spread leading to severe epizootics both in noxious insects such as lepidopteran defoliators, mosquito larvae, aphids or cockroaches but also unfortunately in mass rearing facilities of useful insects such as B. mori in sericultural farms (Watanabe and Shimizu, 1980), cricket farms (Szelei et al. 2011; Weissman et al. 2012) and industrial shrimp farming (Lightner, 1996). A densovirus is the causative agent of the recent extensive outbreak of sea-star wasting disease (SSWD) (Hewson et al., 2014). Due to their high pathogenicity, DVs have been successfully used to control Limacodidae larvae in oil palm plantations (Genty and Mariau, 1975; Fédière, 1996). Most DV’s are polytropic and infect the fat body, hypodermis, central nervous system, silk gland, muscular membrane, tracheal cells, Malpighian tubules, foregut, hindgut, hemocytes, ovaries and molting gland but not the midgut. However, some iteraviruses, such as BmDV (Bombyx mori), and the above mentioned CeDV and SfDV multiply predominantly in the midgut. The host range of the different DV’s varies considerably. Some, like GmDV of Galleria mellonella, and CeDV are restricted to their original hosts, some, like AdDV of Acheta domesticus and PfDV of Periplaneta

2.2. Cap protein: homology to that of small, icosahedral RNA viruses Capsid proteins of small RNA viruses have a so-called β-barrel (or jelly-roll capsid, JRC), consisting of at least 8 β-strands, that are highly conserved. There is strong evidence that these viruses donated the cap gene to the T = 1 ssDNA viruses (Koonin et al., 2015a,b). The JRC is indeed highly conserved while the loops between the β-strands are very different from the loops of viruses in other genera. Also, when the icosahedral symmetry axes of two ssDNA viruses are superimposed, the β barrel may have to be rotated and translated radially in order to superimpose them (Simpson et al., 1998). The barrels are located on the inside of the capsid proteins and the loops mostly on the outside of the capsid (Fig. 1). The JRC consists of 8 β-strands making 2 opposing β-sheets (CHEF and BIDG, naming β-strands from N- to C-terminal βA to βG, respectively). Interestingly, in densoviruses, the βB strand is a linear extension 24

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Fig. 1. Comparison of viral capsids of vertebrate parvoviruses and densoviruses. Left column (A1–3) represents a typical vertebrate parvovirus, porcine parvovirus (PPV), and the right column a typical densovirus (B1–3), GmDV, of the capsid subunit (its bottom with N-termini represents inside of capsid), of viral capsid with a depth-cued subunit with rounded ribbons and flat β-strands, and of zoom-in view to show the degree of intertwining of the subunits. The two β-sheets face each other and form a β-barrel whereas the loops connecting the βstrands mainly form the surface of the virion. The two virions are represented at the same resolution. Striking differences are the size of the capsid proteins with the vertebrate parvoviruses being larger and having a larger degree of intertwining. To compensate for the fewer interactions, densoviruses have in contrast to the vertebrate parvoviruses an extended N-terminus to stabilize the capsid. Another consequence is the smaller size of the loops between the β-strands in the densoviruses and the pronounced spherical structure compared to the vertebrate parvoviruses (see outline of particles). This could be a result of the adaptation of vertebrate parvoviruses to immune escape. Especially around 5-fol axis (left-bottom in zoom-in views) DVs are flat compared to vertebrate parvoviruses. Pentons, triangles and ellipses represent the 5-fold, 3-fold and 2-fold axes of symmetry, respectively.

essentially in the columnar cells of midgut epithelium (Watanabe, 1981; Meynadier et al., 1977; Fédière, 2000). Hepandensoviruses of P. monodon infect hepatopancreatic tubule epithelial cells characterized by basophilic intranuclear inclusions (Flegel, 2006). The penstyldensoviruses are cosmopolitan and infect different species of the Penaeus genus. It should be mentioned that these viruses do not infect vertebrates or cells derived from vertebrates (Jousset et al., 1993; El-Far et al., 2004), nor was any pathogenic effect observed after inoculation of rabbits or mice with these viruses. However, their ability to integrate

fuliginosa to closely-related hosts, while others, e.g. Junonia coenia densovirus (JcDV), Mythimna loreyi densovirus (MlDV) and the mosquito DVs infect many different hosts. Although those infecting the midgut have a restricted host range, the inverse is not true for the polytropic viruses. Mosquito larva infected with mosquito DVs exhibit symptoms of paralysis. Mosquito cells cultured in vitro often contain DVs, despite the lack of cytopathic effects, that are pathogenic for mosquito larvae by per os infection. The Ld652 cell line derived from the gypsy moth (Lymantria dispar) seems also contaminated with a DV despite the lack of a cytopathic effect. Iteradensoviruses replicate 25

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Fig. 2. Phylogenetic calculations based on the conserved tripartite helicase domain of parvoviral NS proteins. The topology presented was obtained by Bayesian inference, however maximum likelihood calculations were also performed. Posterior probability values of the Bayesian inference as well as bootstrap values and aLRT SH-like values of the maximum likelihood analyses are presented as node labels. Alignment was constructed incorporating structural data of the parvo NS pfam domain (pfam 1u0j). Model selection indicated the LG + I + G + F substitution model the most suitable, with alpha = 1.963, pinv = 0.001. Clades of vertebrate parvoviruses are collapsed to genus level. Branches of viruses with no PLA2 domain present in their structural proteins are highlighted by heavier lines. Viruses not assigned to any current genus yet are presented in bold. The small black arrows facing towards each other indicate viruses with ambisense genome. As genus Ambidensovirus does not cluster as a monophyletic group in any of the trees calculated, names of its official members are underlined. Densoviruses associated with echinoderms are marked by grey background as the only non-arthropod members of subfamily Densovirinae.

2013). This allows the structure of other densoviruses from the same genera to be predicted to a high degree of reliability by bioinformatics (SWISS-MODEL). Except for the internal jelly-roll, there is little structural resemblance among the DVs from different genera. The capsid performs a multitude of functions such as allotropic determinants, host cell surface receptor recognition, pathogenicity determination, self-assembly into capsids and viral DNA encapsidation, escape from endosomes during infection and host immune response detection and evasion ((Tijssen, 1999; Zádori et al., 2001; Agbandje and Chapman, 2006). Our discovery of phospholipase A2 activity (PLA2) in the capsid shed light how the densovirus enters the cell (Zádori et al., 2001; Canaan et al., 2004). During clathrin-mediated endocytosis (Vendeville et al., 2009), the PLA2-containing part of the capsid protein is externalized through the channel at the 5-fold axis which then enables the virion to breach the endosomal membrane. Almost all parvoviruses contain a calcium-binding loop (GPGN) and the active site (DxxAxxHDxxY) required for PLA2 activity in the N-terminus of the

into the host chromosome has been exploited for stable expression of foreign proteins in insect cells and somatic transformation of insects (see reviews by Afanasiev and Carlson (2000) and Bergoin and Tijssen (2010)). 3.2. Physicochemical properties of densoviruses The T = 1 icosahedral virions of DVs are small, (25 nm), non-enveloped ssDNA viruses with an outstanding stability. Their genome is small (4–6 kb) with 5′- and 3-terminal palindromic sequences involved in the generation of dsDNA for translation and DNA replication with compact genetic information. The relatively high content of DNA (about 25–35%) results in a buoyant density of about 1.4 g/ml but a relatively low sedimentation coefficient of about 100–120S. We have determined the 3D structure to near-atomic resolution of capsids of 4 different DVs of different genera: GmDV (Simpson et al., 1998; Fig. 1), penstyldensovirus PstDV of Penaeus stylirostris (Kaufmann et al., 2010), BmDV (Kaufmann et al., 2011) and AdDV (Meng et al., 26

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4. Circular Rep-encoding ssDNA (CRESS-DNA) viruses

capsid protein. Brevidensoviruses and hepandensoviruses lack this enzymatic activity and enter probably by direct membrane fusion/penetration reactions at the plasma membrane. Of the two or three nonstructural (Rep) proteins of DVs, only Rep-1 shares significant homology domains with Rep-1 of vertebrate parvoviruses, including two enzymatic activities: a site-specific DNA-binding and a single-strand endonuclease and an AAA+ helicase. The binding site of Rep-1 at a specific GAC repeat sequence in the 3′-terminal palindrome of JcDNV and the Rep-1 nicking activity have been demonstrated (Ding et al., 2002). The functions of Rep-2 and NS3 are still unknown, but Rep-3 was shown to be essential for replication (Abd-Alla et al., 2004).

A distinct group of ssDNA viruses that avoided the necessity of having hairpins or protein primers constitute a highly diverse group with a circular genome (CRESS-DNA viruses; e.g. family Circoviridae). The remarkable diversity of this group of CRESS-DNA viruses will probably rise to more families in this group, such as the Genomoviridae (Krupovic et al., 2016). Like parvoviruses they have a rep gene, a cap gene, an origin of replication and sometimes a few accessory genes. This group of circular ssDNA viruses (2–4 kb) occurs in invertebrates, vertebrates and mammals. Terrestrial and aquatic invertebrates have been among the most studied and have yielded a remarkable broad range of CRESS-DNA virus types. Like the densoviruses in the case of parvoviruses, they are usually defined by the identity of the replication protein to that of already known CRESS-DNA and CRESS-DNA-like viral genomes and the origin of replication, a nonanucleotide sequence incorporated into a stem-loop structure. Many of the invertebrate CRESSDNA genomes were recovered from Crustacea, insectivorous bats and different dragonfly species since these are insect-hunting top predators that accumulate viruses from their insect prey (Li et al., 2010; Delwart and Li, 2012; Rosario et al., 2012). Most were identified with metagenomics approaches. Interestingly, representatives of the Cyclovirus genus dominate in invertebrates. The genomes of cycloviruses are smaller than 2 kb, contain two ambisense major ORFs encoding putative rep and cap genes, the 3′-ends of which are very close together (reminiscent of the ambidensoviruses), and exhibit the circovirus origin of replication (ori) nonanucleotide motif TAGTATTAC in the capsidencoding strand at the apex of a potential stem–loop structure. CRESS-DNA viruses are very small non-enveloped icosahedral viruses with a monomeric single-stranded circular DNA genome which is typically 1800–2000 nucleotides long and has a guanine + cytosine content of 48.4–53.1 %. The capsid is spherical and exhibits icosahedral symmetry (T = 1) with 60 capsomers and a diameter of 17–22 nm. The genome is replicated through double-stranded intermediates. The replication (Rep) protein initiates and terminates rolling-circle replication, the host DNA polymerase being used for DNA replication itself. Until a few years ago, only a relatively few circoviruses had been isolated and characterized. However, in the past few years a prodigious amount and diversity of novel CRESS-DNA viruses has been unearthed from various hosts and environmental sources using different methods. In vitro rolling circle amplification and/or degenerate/consensus PCR combined with NGS/metagenomics approaches have all been extensively used to identify novel circoviruses in invertebrates (Ng et al., 2011; Rosario et al., 2011; Rosario et al., 2015; Pham et al., 2013a,b; Dayaram et al., 2015). Analysis of the Rep encoded by their viral genomes reveals that these CRESS-DNA viruses are highly diverse. In one study (Rosario et al., 2015), 27 CRESS-DNA viruses, were recovered from 21 invertebrate species, mainly crustaceans. Phylogenetic analysis based on the Rep, sharing less than 60% identity with previously reported viruses, revealed a novel clade of CRESS-DNA viruses that included approximately one third of the marine invertebrate associated viruses identified and whose members may represent a novel family (Rosario et al., 2015). Novel circular ssDNA viruses were also discovered in gelatinous zooplankton, such as jellyfish and ctenophores (Breitbart et al., 2015) and the Forbes sea star echinoderm (Fahsbender et al., 2015). The genome architecture of the CRESS-DNA viruses varies significantly, but they all have at least two major open reading frames (encoding Rep and Cap) that have either an ambisense or monosense arrangements (Fig. 5). The large number and diversity of ssDNA viruses identified through metagenomic studies makes it difficult to classify them into the current taxonomic system established by the International Committee on Taxonomy of Viruses and many remain unclassified, prompting the

3.3. Densovirus genome structure and replication As a general rule, capsids of monosense DVs package primarily the “−” DNA strand (complementary to mRNA) and the ambisense DVs both the “+” and the “−” strands in separate particles. There is a great variety in the organization of the genome structures (Table 1), such as size of DV genomes, imperfect palindromic sequences at each extremity able to fold into duplex telomeric structures designated hairpins (Tijssen, 1999; Tijssen et al., 2006). The structural similarities of DV and vertebrate parvovirus genomes suggest common strategies in the replication of their DNA by a singlestrand displacement, probably by DNA polymerase δ, and encapsidation by helicase hexamers into the channel at the 5-fold axis of the preformed capsids. The self-priming hairpin at the 3′end of the genome serves as primers for complementary strand synthesis according to the RHR model to generate concatemeric intermediates chain resolved in monomers by the nicking activity of Rep (Bergoin and Tijssen, 2000; Cotmore and Tattersall, 2006). This site-specific nick generates a second 3′-OH at a specific site (the terminal resolution site, trs) in the hairpin so that the complementary strand can be extended to completion. Both terminal hairpins on the two strands can then be refolded while the hairpins at the two ends are separated by a duplex. These selfpriming hairpins allow for a second round of replication. Based on their viral replication model, the 5′ and 3′ terminal hairpins of all DVs with inverted terminal repeats, including terminal hairpins (ITRs), can exist in either of two orientations termed “flip” and its reverse-complement “flop”orientation. The significant differences in size and structure of palindromic 5′- and 3′- terminal sequences within the different genera of DVs (Table 1) might reflect their dependence on specific cellular factors necessary for the replication of their genome or promote their encapsidation. Ambisense DVs have ITRs whereas monosense can have unique terminal hairpins (e.g. brevidensoviruses) or ITRs (e.g. iteraviruses). The expression strategies among the DVs differ considerably (Tijssen et al., 2006; Figs. 3 and 4). The promoters of the rep and cap cassettes of the ambisense promoters tend, at least partially, to be in the ITRs. In addition to unspliced transcripts, splicing and leaky scanning, and even overlapping promoters/ORFs (brevidensoviruses), are used to produce a large array of proteins from a compact genome. Classification of DVs is so far based on sequence identity of Rep; other genes may be absent or lack any identity. Phylogenetic analysis demonstrated that DVs are much more diverse than the vertebrate parvoviruses. Invertebrates have been around much longer than vertebrates, including mammals, and the diversity of hosts is much larger. It is becoming increasingly difficult to classify DVs since the first attempts in 1975 (Bachmann et al., 1975; Cotmore et al., 2014), due to the extraordinary diversity of genome structures and sequences of new isolates, as shown in Figs. 2–4. Moreover, the lack of sequential homology does not make this issue less complicated (Cotmore et al., 2014). 27

28

4.2 kb

6.3 kb

Genus Brevidensovirus Species Dipteran brevidensovirus

Genus Hepandensovirus Species Decapod hepandensovirus

Hairpin-like structures of 0.2 kb

5′ and 3′ different sequences

ITRs (0.14 kb)

ITRs (0.5 kb)

6 kb

Species Lepidopteran ambidensovirus

5.3 kb

ITRs (incomplete)

5.5 kb

Species Hemipteran ambidensovirus

Species Orthopteran ambidensovirus

ITRs (0.3 kb)

ITRs (0.15 kb)

5.8 kb

5.5 kb

Genus Ambidensovirus Species Blattodean ambidensovirus

Termini

Species Dipteran ambidensovirus

Genome size

Classification

I-like

T-Shaped

I-Shaped

Y-shaped

J-Shaped

J-shaped

Hairpins

Table 1 Organization of densovirus genomes according to classification (Cotmore et al., 2014).

NS1, NS2

NS1, NS2

NS1, NS2, NS3

NS1, NS2, NS3

NS1-NS1′, NS2NS2′

NS1-NS1′, NS2NS2′, NS3

NS1, NS2, NS3

Rep ORFs (rep = NS)

Two promoters P2 for NS2 P22 for NS1

Two overlapping promoters NS1 transcript start upstream NS1 initiation codon NS2 transcript start downstream NS1 initiation codon

One promoter, alternate splicing NS3: unspliced transcript NS1 + NS2 spliced transcript

One promoter, alternate splicing NS3: unspliced transcript NS1 + NS2 spliced transcript

One promoter spliced to put in frame the 4 NS1-NS2 ORFs

Two promoters P7 for NS3 P17 for NS1 + NS2 Splicing to put in frame the 4 NS1-NS2 ORFs

One promoter, alternate splicing NS3: unspliced transcript NS1 + NS2 spliced transcript

Expression strategy

Single ORF one promoter

Single ORF one promoter

Unspliced transcript

Unspliced transcript

VP1 transcript: splicing eliminates VP2 AUG initiation codon VP2 transcript: splicing eliminates VP1 splicing donor site

Unspliced transcript

Single ORF one promoter

Split: VP-A, VP-B one promoter

Unspliced transcript: VP1 spliced transcript: VP2

Unspliced transcript

Single ORF one promoter

Split: VP-A, VP-B one promoter

Unspliced transcript: VP1 spliced transcript: VP2

Expression strategy

Split: VP-A, VP-B one promoter

VP ORFs

Sukhumsirichart et al. (2006)

Afanasiev et al. (1991) and Pham et al. (2013b)

Liu et al. (2011c)

Tijssen et al. (2003); Fédière et al. (2004), Jourdan et al. (1990) and Wang et al. (2013)

van Munster et al. (2003) and Ryabov et al. (2009)

Baquerizo-Audiot et al. (2009)

Mukha et al. (2006) and Kapelinskaya et al. (2011)

References

P. Tijssen et al.

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Fig. 3. Genome organization and transcription strategy types of genus Ambidensovirus. The genome is marked by the thick line in the middle, whereas ITRs are indicated by thin lines. Bars mark proteins, whereas mRNA is shown as thin lines. Polyadenylation signals are presented as vertical bars and the small squiggle lines stand for poly(A) tails. Promoters are displayed as small arrows, facing the direction of transcription. The VP start codons are marked by arrows facing the direction they translate. The phospholipase A2 (PLA2) domain of VPs and the NTPase domain of the NS are presented as boxes.

the two major ORFs are at most few bases (Li et al., 2010). The gemycircularviruses (about 2170 nts) have been recently classified into the family Genomoviridae (Krupovic et al., 2016). A number of genomoviruses have been sequenced from damselflies, dragonflies and mosquitoes (Krupovic et al., 2016) although the real hosts remain unknown.

proposal of new groupings, such as the smacoviruses and cycloviruses (genome 1.7–1.9 kb; proposed genus with dragonfly cyclovirus and Florida woods cockroach-associated cyclovirus (Dayaram et al., 2013)). Compared to circoviruses, the Rep and Cap proteins of cycloviruses are slightly smaller and the 3′-intergenic regions between the stop codons of 29

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Fig. 4. Genome organization and transcription strategy types of the four recognized genera of Densovirinae that possess monosense genomes. The genome is marked by the middle thick line and ITRs are presented as thin lines. The protein-coding ORFs are displayed over the symbolic genome as bars, whereas mRNA transcripts are below. Expressed proteins are also presented as bars and poly(A) tails as small squiggle lines. Promoters are displayed as small arrows, indicating the direction of transcription. The VP start codons are marked by arrows facing the direction they translate. The phospholipase A2 (PLA) domain of VPs and the NTPase domain of the NS are presented as boxes.

Fig. 5. Circular ssDNA viruses have a typical stem loop including a conserved nonanucleotide (CATTATRAT) origin of replication. Sizes may vary as shown here by the cricket volvovirus, AdVVV, and CtaCV-3 from gelatinous zooplankton (such as jellyfish and ctenophores (comb jelly, a predator)). The number, orientation and size of ORFs may also vary. The Cyclovirus genus prominent in dragonflies is characterized by ori on the cap strand and close location of the 3′-ends of cap and rep (see DfCyV-7).

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Fig. 6. (A) Genome organization of Bombyx mori bidensovirus (BmBDV). Terminal inverted repeats (TIR)are shown in grey. Viral genes are shown as arrows indicating the direction of transcription. Possessed ancestral parvovirus genes are vertically striped, genes supposedly derived from polintoviruses (ORF4), reoviruses (ORF3), and perhaps granuloviruses (ORF2) are presented as horizontally striped, checked, and hatched, respectively. The region of the PolB gene encoding the potential terminal protein implicated in the protein-primed DNA replication is shown in grey with dots. The gene for nonstructural protein 2 (NS2), for which provenance remains unclear, is depicted with an open white arrow. ORF 2 shares an evolutionary history with NS3 of MlDV (AY461507) and granulosis viruses (AY293731) and related viruses (based on Tijssen et al. (2006) and Krupovic and Koonin (2014)). (B) Bipartite densovirus isolated from crickets with an NS segment and a VP segment. The left hairpins are identical as are the right hairpins (both > 200 nts). The NS segment has a brevidensovirus evolutionary history and the VP segment has one major ORF with a brevidensovirus history and one major ORF with an ambidensovirus evolutionary history, indicating a horizontal gene transfer. In this transfer, an ambisense densovirus VP with a phospholipase A2 (PLA2) motif is incorporated into an ancestral brevidensovirus. Deletion of either the NS-gene cassette or the VP-gene cassette yields the bipartite densovirus.

complementary strands (6–6.5 kb) in separate capsids (Fig. 6). Therefore 4 different capsids exist, but only two are sufficient to start an infection. Instead of the endonuclease, bindnaviruses encode a proteinprimed type B DNA polymerase (PolB). Krupovic and Koonin (2014) argued that in a turbulent evolutionary history the radiation of bidnaviruses from parvoviruses was probably triggered by integration of the ancestral parvovirus genome into a large virus-derived DNA transposon of the Polinton (polintovirus) family resulting in the acquisition of the polintovirus PolB gene along with terminal inverted repeats (lacking hairpins, see below). The unusual evolutionary history of bidnaviruses emphasizes the key role of horizontal gene transfer, sometimes between viruses with completely different genomes but occupying the same niche, in the emergence of new viral types. The Polinton/Maverick family of self-synthesizing transposons probably played a quintessential role (Krupovic and Koonin, 2015). These transposons/viruses contain a DNA pol and a retrovirus-like integrase, most of the polintons also encode homologs of the major and minor jelly-roll capsid proteins, DNApackaging ATPase and capsid maturation protease (Krupovic and Koonin, 2016). They are widespread in eukaryotes and are predicted to alternate between the transposon and viral lifestyles (Koonin et al., 2015a,b). Another group of predicted self-synthesizing transposons was discovered in prokaryotes. These elements, denoted casposons, encode a DNA pol and a homolog of the CRISPR-associated Cas1 endonuclease that has an integrase activity but no capsid proteins and gave rise to the adaptation module of the CRISPR-Cas systems (Krupovic et al., 2014). Initially, members of this family, infecting the silkworm Bombyx

The, thus far unique, cricket volvovirus with an icosahedral capsid of about 20 nm (Fig. 5), isolated and sequenced both in North America and Japan by conventional methods (no metagenomics), has a genome that is significantly longer at 2.5 kb with the typical 1-TAGTATTAC nonanucleotide origin of replication with 4 ORFs (130–361 aa) and rep in the antisense orientation (Pham et al., 2013a, 2014; Fig. 5). In contrast, the rep of cyclovirus genomes from dragonflies and bats exhibited characteristics typical of cycloviruses and phylogenetically clustered with them with high (60–68%) amino acid similarity with the Rep of mammalian cycloviruses, an evolutionary distance no greater than that seen among mammalian cycloviruses. Cycloviruses isolated from dragonflies, could have been consumed by feeding on small insects, or were from another unknown source. On the other hand, cycloviruses detected in human feces may be from food contaminated with insects. Cyclovirus detection in non-blood feeding insects does indicate that these viruses may infect some invertebrates (Li et al., 2010).

5. Bidnaviridae 5.1. Viral properties and classification A separate group of ssDNA viruses that do not replicate by the rolling-circle-like mechanism and is not initiated by a distinct virusencoded endonuclease are the bidensoviruses (Bidnaviridae) that, so far, occur only in invertebrates. These bi-segmented viruses package both 31

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protein functions as a receptor for BmBDV, and that the site that the virus recognizes as a target is present in the deleted portion of this membrane protein, Nsd-2. Using total RNA isolated from the anterior, middle, and posterior parts of the midgut, Ito et al. (2016) showed that the resistance gene nsd-2 and the susceptibility allele +(nsd-2) were strongly expressed in the posterior part of the midgut but very low in the anterior and middle parts. Quantitative RT-PCR analysis showed that the expression levels of BmBDV-derived transcripts were correlated with the levels of +(nsd-2) expression suggesting that the infectivity of BmBDV depends mainly on the expression of +(nsd-2). However, BmBDV-derived transcripts were clearly detected in all parts of the midgut, even in the middle part where the expression levels of +(nsd2) were exceedingly low or undetectable, indicating that infection may also occur independent of +(nsd-2). Virus rescue has been a bottleneck in the study and application of this virus. Zhang et al. (2016) constructed full-length genomic clones of BmBDV including a green fluorescence protein (GFP) gene, infected BmN cells and showed that its terminal structures were restored. A recombinant BmBDV that expressed green fluorescence protein (GFP) gene was constructed. Furthermore, typical densonucleosis viruses were observed in reinfected silkworm larvae and larval midgut tissues infected by BmBDV, as evidenced by the emission of green fluorescence. This system will be critical for the study of the molecular biology of these viruses. A practical aspect of these observations was to recommend the rearing of silkworm strains homozygous for the non-susceptibility gene, in order to avoid DV epizootics in sericultural farms.

mori, were classified among the Densovirinae and named Bombyx mori densonucleosis virus type 2 (BmDNV-2). Instead of a rolling circle initiation endonuclease (RCRE) this virus encodes a type B DNA polymerase and has 2 large genome segments, VD1 (GenBank # AB033596) and VD2 (GenBank # S78547), of 6.5 and 6 kb that are packaged into separate capsids (Fig. 6). These genomes have long inverted terminal repeats but lack terminal hairpins. Consequently, these viruses have been reclassified in a new family, the Bidnaviridae, and the silkworm virus has been renamed Bombyx mori bidensovirus (BmBDV). So far only a few geographical variants of this virus are known and none from other insects than those of the Bombycidae. Bidnaviruses have adopted genes from many different viruses and can be considered real kleptomaniacs. The superfamily 3 helicase (S3H) motif found in the C-terminus of NS1 proteins of the parvoviruses is also encoded by VD1 ORF2 and is particularly closely related to those from densoviruses (Krupovic and Koonin, 2014). These authors also suggested that the coat protein coded by VD1 ORF3 is a homolog, at least in structure, of parvoviral capsid proteins. The BmBDV capsid protein does not have phospholipase A2 (PLA2) activity that is required to breach the endosomal membrane and is ubiquitous in parvovirus capsids (Zádori et al., 2001). The role of triacylglycerol lipases of B. mori associated to BmDV purified from feces (Lv et al., 2011) is not clear and has not yet been shown to have a similar role as PLA2. As already indicated above, studies by Krupovic and Koonin (2014) suggested that the bidnavirus PolB is of polintovirus origin and hinted that VD1 recombination-deletion events may have occurred in the polintovirus background. VD2 also encodes a structural protein with some identity with an insect reovirus, cytoplasmic polyhedrosis virus, outer capsid shell protein and could have been acquired in the same niche (Krupovic and Koonin, 2014). NS3 of densoviruses is not conserved (Tijssen and Bergoin, 1995) although it is essential for viral DNA replication (AbdAlla et al., 2004). Similarly, its homolog encoded by VD2 ORF2 is rather conserved with densovirus NS3 and a ClGV (granulosisvirus) gene (AY293731; Tijssen et al., 2006). It has been suggested (Krupovic and Koonin, 2014) to represent a novel family of apoptosis inhibitors.

6. Origin and evolution of ssDNA viruses As discussed above, almost all ssDNA viruses lack a DNA polymerase gene and use a pleiotropic Non Structural protein 1 (named NS1 or Rep) for Rolling-Circle Replication (RCR, circoviruses). The exception is Bombyx mori bidnavirus (BmBDV) which acquired a pol gene by horizontal gene transfer (Krupovic and Koonin, 2014) (see Section 5.1). Metagenomics and phylogenetic advances accelerated the discovery of chimeric viruses which have both an RNA and a DNA history and the profound role of horizontal gene transfer (see Section 7). There is strong evidence that recombination between RNA viruses and plasmids might have played a central role in the origin and evolution of parvoviruses and circoviruses (Koonin et al., 2015a,b). The prevalence of non-retroviral RNA virus genomes chromosomally integrated in the host germ cells (endogenized) in diverse eukaryotic lineages (Feschotte and Gilbert, 2012) supports the possibility of RNA-DNA recombination events. Interestingly, all eukaryotic DNA viruses using RCR Rep-like proteins for genome replication have jelly-roll capsid (JRC) proteins, homologous to those in small RNA viruses in the proposed order of Picornavirales. Retroviruses integrate in the host chromosome as a required step in their replication and have been known for a long time to have left many Endogenous Viral Elements (EVEs) in the germ line of their hosts. In the last few years, members of the families Circoviridae and Parvoviridae were also found to be present as EVEs (Belyi et al., 2010). These ssDNAderived EVEs were widely distributed among different species and estimated to be “fossilized” 40–50 million years ago. Endogenous densoviruses exist in the germ lines of diverse animal species, including mammals, fishes, birds, tunicates, arthropods, and flatworms for at least 98 million years (Liu et al., 2011a, 2011b). Some of the endogenized parvoviral genes were expressed in eukaryotic organisms, suggesting that these viral genes are also functional in the host genomes. Rep-related sequences of geminiviruses, nanoviruses and circoviruses have been frequently identified in host chromosomes and transposable elements of plants, fungi, animals and protists (Ilyina and Koonin, 1992;

5.2. Bombyx mori bidensovirus (BmBDV) as a pathogenic agent BmBDV, which causes fatal flacherie disease in the silkworm, replicates in contrast to most parvo-like densoviruses, but like BmDV, only in midgut columnar cells. B. mandarina and B. mori are considered to have a common ancestor (Goldsmith et al., 2005) and both (at least native strains) are susceptible to BmBDV. Many Japanese strains acquired BmBDV-resistance through improved breeding (Furuta, 1994, 1995). These resistant strains became susceptible to the parvovirus-like BmDV (Furuta, 1995). BmBDV is, therefore, likely the native disease of Bombyx, whereas the origin of BmDV is likely to be a pathogen from other insects. The pyralid Glyphodes pyloalis, a pest of mulberry plantations of sericultural farms is also susceptible to BmDV (Watanabe, 1981) and probably the real host of BmDV (Bergoin and Tijssen, 2000). The silkworm strains that became resistant to BmBDV became in this selection process susceptible to BmDV The nonsusceptibility to BmBDV was found to be controlled by a recessive non-susceptibility gene in B. mori, nsd-2 (non-susceptibility to DNV-2 (previous name)) in B. mori (Ogoyi et al., 2003) and three other resistance genes, nid-1, nsd-1, and nsd-Z 1 in B. mori (Watanabe and Maeda, 1981; Eguchi, 2007; Qin and Yi, 1996). Despite several attempts, the nsd-Z-related resistance could not be confirmed (Q. Yao, personal communication). Ito et al. (2008) isolated the nsd-2 gene, a putative amino acid transporter gene, and showed that a deletion corresponding to 9 of 12 predicted transmembrane domains confers resistance to BmBDV. They suggested that the complete membrane 32

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Another hybrid ssDNA virus, named NIH-CQV, has been serendipitously isolated as a contamination of nucleic acid-isolation spin columns, (Xu et al., 2013). This virus encodes a CP related to CPs of parvoviruses and a replication protein distantly related to the replication proteins of circoviruses and nanoviruses. Thus, NIH-CQV appears to be a chimera consisting of genes derived from two families of ssDNA viruses. In addition to the recombination of genes, Krupovic et al. (2015) reported a second layer of chimerism by showing that rep genes themselves are chimeras of functional domains inherited from viruses with different evolutionary histories. For instance, the viral rep gene may have originated through recombination between unrelated viruses, with its N-terminal region being donated by small single-stranded circular DNA viruses with segmented genomes of the Nanoviridae family (infecting plants) and a C-terminal region being related to the RNAbinding 2C helicase protein of positive strand RNA viruses in the proposed order Picornavirales (Gibbs and Weiller, 1999). The fact that a DNA virus has incorporated a gene from an RNA virus, and that none of these DNA and RNA viruses code for a reverse transcriptase suggests that another agent with this capacity was involved. In case of Drosophila melanogaster RNA viruses, however, an important role has been ascribed to cellular reverse transcriptases as well as to such enzymes of RNAi in maintaining persistence by transcribing DNA intermediates (Goic et al., 2013). This phenomenon could provide another possibility of DNA-RNA recombination to take place. These observations underscore the importance of horizontal gene transfer in the evolution of ssDNA viruses and the role of genetic recombination in the emergence of novel virus groups. In our lab (Penzes et al., unpublished results; Fig. 6) we isolated a segmented densovirus, the rep segment having a brevidensoviral evolutionary history and the cap segment carrying 2 capsid genes, one with a brevidensoviral evolutionary history and one with an ambidensoviral evolutionary history (Tijssen et al., 2006). Both segments carry identical terminal hairpins to the left and identical hairpins to the right of > 200 nts. Many RNA viruses have segmented genomes as a result of higher stability of the virions that enclose the shorter RNA (Ojosnegros et al., 2011). This genome segmentation in this particular densovirus may have evolved as a molecular mechanism of a trade-off between genomic size and virion stability so that the amount of genetic information can be optimized while relaxing packaging density. Indeed, the combined size of the genome segments of this segmented densovirus is large (6.7 kb) compared to the size of the capsid proteins and, presumably, the capsid and the risk of deleterious mutations. In addition to ssDNA viruses having invertebrates as a host, plant geminiviruses and nanoviruses are known to be transmitted by hemipteroid insect vectors, often beginning a few hours or days after acquisition and for up to the life of the insect, i.e., in a persistent-circulative or persistent-propagative mode (Hogenhout et al., 2008). Metagenomic approaches yield a plethora of new virus sequences, which, however, should be handled carefully: they may be endogenous ancient remnants in the chromosomes of the hosts. Examples (Tang and Lightner, 2006) are the penstylvirus-related sequences found in samples of Penaeus monodon from Madagascar and Tanzania. These sequences are incomplete, vary considerably (14 and 8%, respectively) from that of IHHNV found in association with viral epidemics and are non-infectious. Another incomplete densovirus sequence, isolated from sea barley (François et al., 2014), resembles iteraviruses, but has not been shown to be infectious. Viral fossil rep sequences that were often millions of years old were also identified integrated in the chromosomes of mammals, frogs, lancelets, crustaceans, mites, gastropods, roundworms, placozoans, hydrozoans, protozoans, land plants, fungi, algae, and phytoplasma bacterias and their plasmids, reflecting their past host

Koonin et al., 2015a,b). Some of these virus-derived genes were conserved and expressed, and may have cellular functions in the host genomes and eukaryotic transposons could have been originated from ssDNA viruses. Thézé et al. (2014) followed a host-centered approach whereby the genomes of a given species of isopods were comprehensively screened for the presence of EVEs using all available complete viral genomes as queries. They found that 54 EVEs corresponding to 10 different viral lineages belonging to 5 viral families (Bunyaviridae, Circoviridae, Parvoviridae, and Totiviridae) and one viral order (Mononegavirales) became endogenized in the genome of the isopod crustacean Armadillidium vulgare and that this viral endogenization occurred recurrently during the evolution of these isopods. 30 A. vulgare EVEs have uninterrupted open reading frames, suggesting they result from recent endogenization of viruses likely to be currently infecting isopod populations. Crustacean Parvoviridae-like EVEs fall into at least two distinct lineages within the Densovirinae (Metegnier et al., 2015). The first one corresponds to Daphnia EVEs and is related to the former Densovirus, Pefudensovirus and Iteravirus genera. The second one includes Armadillidium and Lepeophtheirus salmonis EVEs, as well as exogenous brevidensoviruses from Aedes mosquitoes and PstDNV from shrimp. The existence of this EVEs together with recent crustacean densoviruses suggests that members of the extremely diverse group Crustacea had been infected at least four individual times by densoviruses. Sixteen species of marsupial Macropodiformes, to the exclusion of other Diprotodontian lineages carried an adeno-associated virus (AAV) (Parvoviridae) EVE1 locus, representing a speciation history spanning an estimated 30 million years (Smith et al., 2016). These sequences facilitated compilation of an inferred ancestral sequence that recapitulates the genome of an ancient AAV that circulated during the late Eocene to early Oligocene. In silico gene reconstruction and molecular modelling indicated remarkable conservation of viral structure over a geologic time scale and insight into AAV evolution. Interestingly, the catalytic site HDxxY of the conserved phospholipase A2 motif, required for cell entry (Zádori et al., 2001), was not conserved as EVEs do not need this property. 7. Chimerism in single-stranded DNA viruses Recombination occurs frequently in many groups of eukaryotic ssDNA viruses (Martin et al., 2011; Koonin et al., 2015a,b; Lefeuvre and Moriones, 2015). Many ssDNA viruses with chimeric genomes have recently been discovered through viral metagenomics. They combine genes from viruses with different types of genomic nucleic acids (positive-strand RNA, such as Tombusviridae from plants, and DNA, such as Circoviridae, Nanoviridae, Geminiviridae, and Parvoviridae), but also the genes themselves in some of these hybrid viruses are chimeric, with different functional domains donated by virus genes from different families (Krupovic et al., 2015). Therefore, the exact evolutionary relationships among these viruses often remain obscure. As an example, Diemer and Stedman (2012) revealed by bioinformatic analysis of metagenomic sequences of a virus (RDHV), derived from a hot, acidic lake, a circular, putatively single-stranded DNA virus encoding a major capsid protein similar to those found only in positive single-stranded RNA viruses. The virus genome appears to be the result of a RNA-DNA recombination event between two ostensibly unrelated virus groups. Three similar putative ssDNA virus genomes from marine environments were identified indicating the existence of a widespread but previously undetected group of viruses. Interestingly, ssDNA viruses appear to have access to the gene pool of both DNA and RNA viruses, further expanding opportunities for recombination. Recently, chimeric viruses with even larger genetic diversity and environmental distribution have been reported (Roux et al., 2013; Steel et al., 2016). 33

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range (Liu et al., 2011a,b,c; Delwart and Li, 2012). As a rule of thumb, a new virus could be recognized with infectious particles or complete endogenous sequences. Host assignment of data revealed by metagenomics analyses can be problematic, in particular for predators and easily contaminated samples such as those living in seawater or episomal elements such as plasmids or helitrons that also replicate via an RCR mechanism and have ssDNA intermediates (Koonin and Dolja, 2014). 8. Conclusions In recent years, advances in viral metagenomic approaches have revolutionized the discovery of novel viruses. In particular, the number of described single-stranded DNA (ssDNA) viruses has grown rapidly, but also the evidence of recombination and chimaerism has increased, even between DNA and RNA donors. Such recombination events yielded new types of viruses and led to the integration of ssDNA viruses into host chromosomes, now existing as EVEs. We noted a chimaerism in densoviruses from donors with different evolutionary histories but also the ensuing genome segmentation to promote capsid stability. The turbulent evolutionary activity is particularly evident with the bidnaviruses with chimeric inserts from several RNA and DNA viruses. The high diversity of the hosts is reflected in ssDNA viruses and makes a definite classification extremely difficult. Acknowledgments The authors wish to acknowledge the support received from the Natural Sciences and Engineering Research Council of Canada. References Agbandje, M., Chapman, M.S., 2006. Correlating structure with function in the viral capsid. In: Kerr, J.R. (Ed.), Parvoviruses. Hodder Arnold, London, UK, pp. 125–139. Abd-Alla, A., Jousset, F.X., Li, Y., Fédière, G., Cousserans, F., Bergoin, M., 2004. NS-3 protein of the Junonia coenia densovirus is essential for viral DNA replication in an Ld652 cell line and Spodoptera littoralis larvae. J. Virol. 78, 790–797. Afanasiev, B.N., Galyov, E.E., Buchatsky, L.P., Kozlov, Y.V., 1991. Nucleotide sequence and genomic organization of Aedes densonucleosis virus. Virology 185, 323–336. Afanasiev, B., Carlson, J., 2000. Densovirinae as gene transfer vehicles. Contrib. Microbiol. 4, 33–58. Bachmann, P.A., Hoggan, M.D., Melnick, J.L., Pereira, H.G., Vago, C., 1975. Parvoviridae. Intervirology 5, 83–92. Baquerizo-Audiot, E., Abd-Alla, A., Jousset, F.X., Cousserans, F., Tijssen, P., Bergoin, M., 2009. Structure and expression strategy of the genome of Culex pipiens densovirus, a mosquito densovirus with an ambisense organization. J. Virol. 83, 6863–6873. Barreau, C., Jousset, F.X., Bergoin, M., 1996. Pathogenicity of the Aedes albopictus Parvovirus (AaPV), a denso-like virus for Aedes aegypti mosquitoes. J. Invertebr. Pathol. 68, 299–309. Belyi, V.A., Levine, A.J., Skalka, A.M., 2010. Sequences from ancestral single-stranded DNA viruses in vertebrate genomes: the Parvoviridae and Circoviridae are more than 40–50 million years old. J. Virol. 84, 12458–12462. Bergoin, M., Tijssen, P., 2000. Molecular biology of Densovirinae. Contrib. Microbiol. 4, 12–32. Bergoin, M., Tijssen, P., 2010. Densoviruses: a highly diverse group of arthropod parvoviruses. In: Asgari, S., Johnson, K.N. (Eds.), Insect virology. Horizon Scientific Press, Norwich, United Kingdom, pp. 57–90. Breitbart, M., Benner, B.E., Jernigan, P.E., Rosario, K., Birsa, L.M., Harbeitner, R.C., Fulford, S., Graham, C., Walters, A., Goldsmith, D.B., Berger, S.A., Nejstgaard, J.C., 2015. Discovery, prevalence, and persistence of novel circular single-stranded DNA viruses in the ctenophores Mnemiopsis leidyi and Beroe ovata. Front. Microbiol. 6, 1–10, 1427. Canaan, S., Zádori, Z., Ghomashchi, F., Bollinger, J., Sadilek, M., Moreau, M.E., Tijssen, P., Gelb, M.H., 2004. Interfacial enzymology of parvovirus phospholipases A2. J. Biol. Chem. 279, 14502–14508. Chandler, M., de la Cruz, F., Dyda, F., Hickman, A.B., Moncalian, G., Ton-Hoang, B., 2013. Breaking and joining single-stranded DNA: the HUH endonuclease superfamily. Nat. Rev. Microbiol. 11, 525–538. Cotmore, S.F., Tattersall, P., 2006. Structure and organization of the viral genome. In: Kerr, J.R. (Ed.), Parvoviruses. Hodder Arnold, London, UK, pp. 73–94. Cotmore, S.F., Agbandje-McKenna, M., Chiorini, J.A., Mukha, D.V., Pintel, D.J., Qiu, J., Soderlund-Venermo, M., Tattersall, P., Tijssen, P., Gatherer, D., Davison, A.J., 2014. The family Parvoviridae. Arch. Virol. 159, 1239–1247. Dayaram, A., Potter, K.A., Moline, A.B., Rosenstein, D.D., Marinov, M., Thomas, J.E.,

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