Comparative analysis reveals the long-term co-evolutionary history of parvoviruses and vertebrates [preprint]

Parvoviruses (family Parvoviridae) are small, non-enveloped DNA viruses that infect a broad range of animal species. Comparative studies, supported by experimental evidence, show that many vertebrate species contain sequences derived from ancient parvoviruses embedded in their genomes. These ‘endogenous parvoviral elements’ (EPVs), which arose via recombination-based mechanisms in infected germline cells of ancestral organisms, constitute a form of ‘molecular fossil record’ that can be used to investigate the origin and evolution of the parvovirus family. Here, we use comparative approaches to investigate 198 EPV loci, represented by 470 EPV sequences identified in a comprehensive in silico screen of 752 published vertebrate genomes. We investigated EPV loci by constructing an open resource that contains all of the data items required for comparative sequence analysis of parvoviruses and uses a relational database to represent the complex semantic relationships between them. We used this standardised framework to implement reproducible comparative phylogenetic analysis of combined EPV and virus data. Our analysis reveals that viruses closely related to contemporary parvoviruses have circulated among vertebrates since the Late Cretaceous epoch (100-66 million years ago). We present evidence that the subfamily Parvovirinae, which includes ten vertebrate-specific genera, has evolved in broad congruence with the emergence and diversification of major vertebrate groups. Furthermore, we infer defining aspects of evolution within individual parvovirus genera - mammalian vicariance for protoparvoviruses (genus Protoparvovirus), and inter-class transmission for dependoparvoviruses (genus Dependoparvovirus) - thereby establishing an ecological and evolutionary perspective through which to approach analysis of these virus groups. We also identify evidence of EPV expression at RNA level and show that EPV coding sequences have frequently been maintained during evolution, adding to a growing body of evidence that EPV loci have been co-opted or exapted by vertebrate species, and especially by mammals. Our findings offer fundamental insights into parvovirus evolution. In addition, we establish novel genomic resources that can advance the development of parvovirus-related research - including both therapeutics and disease prevention efforts - by enabling more efficient dissemination and utilisation of relevant, evolution-related domain knowledge

Metastatic Melanomas Express Inhibitory Low Affinity Fc Gamma Receptor and Escape Humoral Immunity

Our research, inspired by the pioneering works of Isaac Witz in the 1980s, established that 40% of human metastatic melanomas express ectopically inhibitory Fc gamma receptors (FcγRIIB), while they are detected on less than 5% of primary cutaneous melanoma and not on melanocytes. We demonstrated that these tumoral FcγRIIB act as decoy receptors that bind the Fc portion of antimelanoma IgG, which may prevent Fc recognition by the effector cells of the immune system and allow the metastatic melanoma to escape the humoral/natural immune response. The FcγRIIB is able to inhibit the ADCC (antibody dependent cell cytotoxicity) in vitro. Interestingly, the percentage of melanoma expressing the FcγRIIB is high (70%) in organs like the liver, which is rich in patrolling NK (natural killer) cells that exercise their antitumoral activity by ADCC. We found that this tumoral FcγRIIB is fully functional and that its inhibitory potential can be triggered depending on the specificity of the anti-tumor antibody with which it interacts. Together these observations elucidate how metastatic melanomas interact with and potentially evade humoral immunity and provide direction for the improvement of anti-melanoma monoclonal antibody therapy

Comparative analysis reveals the long-term coevolutionary history of parvoviruses and vertebrates

Parvoviruses (family Parvoviridae) are small DNA viruses that cause numerous diseases of medical, veterinary, and agricultural significance and have important applications in gene and anticancer therapy. DNA sequences derived from ancient parvoviruses are common in animal genomes and analysis of these endogenous parvoviral elements (EPVs) has demonstrated that the family, which includes twelve vertebrate-specific genera, arose in the distant evolutionary past. So far, however, such “paleovirological” analysis has only provided glimpses into the biology of ancient parvoviruses and their long-term evolutionary interactions with hosts. Here, we comprehensively map EPV diversity in 752 published vertebrate genomes, revealing defining aspects of ecology and evolution within individual parvovirus genera. We identify 364 distinct EPV sequences and show these represent approximately 200 unique germline incorporation events, involving at least five distinct parvovirus genera, which took place at points throughout the Cenozoic Era. We use the spatiotemporal and host range calibrations provided by these sequences to infer defining aspects of long-term evolution within individual parvovirus genera, including mammalian vicariance for genus Protoparvovirus, and interclass transmission for genus Dependoparvovirus. Moreover, our findings support a model of virus evolution in which the long-term cocirculation of multiple parvovirus genera in vertebrates reflects the adaptation of each viral genus to fill a distinct ecological niche. Our findings show that efforts to develop parvoviruses as therapeutic tools can be approached from a rational foundation based on comparative evolutionary analysis. To support this, we published our data in the form of an open, extensible, and cross-platform database designed to facilitate the wider utilisation of evolution-related domain knowledge in parvovirus research

Comparative analysis reveals the long-term coevolutionary history of parvoviruses and vertebrates

Parvoviruses (family Parvoviridae) are small DNA viruses that cause numerous diseases of medical, veterinary, and agricultural significance and have important applications in gene and anticancer therapy. DNA sequences derived from ancient parvoviruses are common in animal genomes and analysis of these endogenous parvoviral elements (EPVs) has demonstrated that the family, which includes twelve vertebrate-specific genera, arose in the distant evolutionary past. So far, however, such “paleovirological” analysis has only provided glimpses into the biology of ancient parvoviruses and their long-term evolutionary interactions with hosts. Here, we comprehensively map EPV diversity in 752 published vertebrate genomes, revealing defining aspects of ecology and evolution within individual parvovirus genera. We identify 364 distinct EPV sequences and show these represent approximately 200 unique germline incorporation events, involving at least five distinct parvovirus genera, which took place at points throughout the Cenozoic Era. We use the spatiotemporal and host range calibrations provided by these sequences to infer defining aspects of long-term evolution within individual parvovirus genera, including mammalian vicariance for genus Protoparvovirus, and interclass transmission for genus Dependoparvovirus. Moreover, our findings support a model of virus evolution in which the long-term cocirculation of multiple parvovirus genera in vertebrates reflects the adaptation of each viral genus to fill a distinct ecological niche. Our findings show that efforts to develop parvoviruses as therapeutic tools can be approached from a rational foundation based on comparative evolutionary analysis. To support this, we published our data in the form of an open, extensible, and cross-platform database designed to facilitate the wider utilisation of evolution-related domain knowledge in parvovirus research. "Fossilized" virus sequences littered throughout animal genomes reveal that vertebrate parvoviruses have evolved unique specializations over tens of millions of years; comparative analysis can reveal the stable genetic basis of parvovirus properties, including those that constitute pre-adaptations to therapeutic use

Incorporation of EPVs into the vertebrate germline.

A time-calibrated evolutionary tree of vertebrate species examined in this study, illustrating the distribution of germline incorporation events over time. Colours indicate parvovirus genera as shown in the key. Diamonds on internal nodes indicate minimum age estimates for EPV loci endogenization (calculated for EPV loci found in >1 host species). Coloured circles adjacent to tree tips indicate the presence of EPVs in host taxa, with the diameter of the circle reflecting the number of EPVs identified (see count key). Brackets show taxonomic groups within vertebrates. The phylogeny shown here was obtained from TimeTree, a database of organism timelines, timetrees, and divergence times [35]. The data underlying this figure can be found in https://github.com/MacCampbell/parvoviridae-coevolution.</p

Vertebrate endogenous parvoviral elements that are not derived from proto- or dependoparvoviruses.

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Vertebrate endogenous parvoviral elements identified derived from protoparvoviruses.

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A constrained alignment tree for the <i>Parvoviridae</i>.

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Phylogenetic relationships of protoparvoviruses and protoparvovirus-like EPVs.

An ML-based phylogeny showing the reconstructed evolutionary relationships between contemporary protoparvovirus species and the ancestral protoparvovirus species represented by EPVs. The phylogeny was constructed from an MSA spanning 712 amino acid residues in the Rep protein (substitution model = LG likelihood) and is midpoint rooted for display purposes. Asterisks indicate nodes with bootstrap support >85% (1,000 replicates). The scale bar shows evolutionary distance in substitutions per site. Coloured brackets to the right indicate the following: (i) robustly supported subclades within the Protoparvovirus genus (outer set of brackets) and (ii) the implied host range of each subclade (inner set of brackets). Terminal nodes are represented by squares (EPVs) and circles (viruses) and are coloured based on the biogeographic distribution of the host species in which they were identified (see key). Coloured diamonds on internal nodes show the biogeographic distribution of host species ancestors (based on fossil evidence) [33]. *Phylogenetic evidence for the presence of “mesoprotoparvoviruses” in Afrotherian species is presented in Fig 4. EPV, endogenous parvoviral element; ML, maximum likelihood; MSA, multiple sequence alignment.</p

Vertebrate endogenous parvoviral elements identified derived from dependoparvoviruses.

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