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Endogenous Amdoparvovirus-Related Elements Reveal Insights Into the Biology and Evolution of Vertebrate Parvoviruses

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Endogenous Amdoparvovirus-Related Elements Reveal Insights Into the Biology and Evolution of Vertebrate Parvoviruses bioRxiv preprint doi: https://doi.org/10.1101/224584; this version posted July 16, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Title: Endogenous amdoparvovirus-related elements reveal insights into the biology and 2 evolution of vertebrate parvoviruses. 3 4 Authors: Judit J Pénzes1*, Soledad Marsile-Medun2,3, Mavis Agbandje-McKenna1, and 5 Robert James Gifford3* 6 7 Affiliations: 8 1. University of Florida McKnight Brain Institute, 1149 Newell Dr, Gainesville, FL 32610, 9 USA 10 2. Agrocampus Ouest, 65 Rue de Saint-Brieuc, 35000 Rennes, France 11 3. MRC-University of Glasgow Centre for Virus Research, 464 Bearsden Road, 12 Glasgow, UK 13 14 *Corresponding author emails: 15 [email protected] 16 [email protected] 17 18 1 bioRxiv preprint doi: https://doi.org/10.1101/224584; this version posted July 16, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 ABSTRACT 2 Amdoparvoviruses (family Parvoviridae: genus Amdoparvovirus) infect 3 carnivores, and are a major cause of morbidity and mortality in farmed animals. In this 4 study, we systematically screened animal genomes to identify PVe disclosing a high 5 degree of similarity to amdoparvoviruses, and investigated their genomic, phylogenetic 6 and protein structural features. We report the first examples of full-length, 7 amdoparvovirus-derived PVe in the genome of the Transcaucasian mole vole (Ellobius 8 lutescens). Furthermore, we identify four further PVe in mammal and reptile genomes 9 that are intermediate between amdoparvoviruses and their sister genus 10 (Protoparvovirus) in terms of their phylogenetic placement and genomic features. In 11 particular, we identify a genome-length PVe in the genome of a pit viper (Protobothrops 12 mucrosquamatus) that is more like a protoparvovirus than an amdoparvovirus in terms of 13 its phylogenetic placement and the structural features of its capsid protein (as revealed 14 by homology modeling), yet exhibits characteristically amdoparvovirus-like genome 15 features including: (i) a putative middle ORF gene; (ii) a capsid gene that lacks a 16 phospholipase A2 (PLA2) domain; (iii) a genome structure consistent with an 17 amdoparvovirus-like mechanism of capsid gene expression. Our findings indicate that 18 amdoparvovirus host range has extended to rodents in the past, and that parvovirus 19 lineages possessing a mixture of proto- and amdoparvovirus-like characteristics have 20 circulated in the past. In addition, we show that PVe in the mole vole and pit viper 21 encode intact, expressible replicase genes that have potentially been co-opted or 22 exapted in these host species. 2 bioRxiv preprint doi: https://doi.org/10.1101/224584; this version posted July 16, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Introduction 2 Parvoviruses (family Parvoviridae) are small, single-stranded DNA viruses that 3 infect vertebrate (subfamily Parvovirinae) and invertebrate (subfamily Densovirinae) 4 hosts. The small (4-6 kb) genome is encompassed by characteristic terminal palindromic 5 repeats, which form hairpin-like secondary structures characteristic for each genus 6 (Cotmore et al. 2014; Tijssen et al. 2011). Despite exhibiting a low level of sequence 7 similarity, parvovirus genomes are highly conserved in overall structure, containing two 8 large gene cassettes responsible for encoding the non-structural (NS) and the structural 9 (VP) proteins. The N-terminal region of the minor capsid protein VP1 includes a highly 10 conserved phospholypase A2 (PLA2) motif that is required for escape from the 11 endosomal compartments after entering the host cell (Zadori et al. 2001). The parvovirus 12 capsid is icosahedral with a T=1 symmetry, displaying a jelly roll fold of conserved β- 13 sheets linked by variable surface loops, designated variable region (VR) I to IX (M.S. 14 Chapman and Agbandje-McKenna 2006). 15 Endogenous parvoviral elements (PVe) are parvovirus sequences that are 16 thought to have been generated when DNA sequences derived from viruses were 17 incorporated into the germline of the ancestral host species (via infection of germline 18 cells), such that they were subsequently inherited as host alleles (Holmes 2011). These 19 sequences provide a useful source of information about the biology and evolution of 20 ancient parvoviruses (Feschotte and Gilbert 2012; Holmes 2011). For example, the 21 identification of orthologous PVe in the genomes of distantly related mammalian species 22 demonstrates an association between parvoviruses and mammals that extends over 23 tens of millions of years (Belyi et al. 2010; Kapoor et al. 2010; Katzourakis and Gifford 24 2010; Smith et al. 2016). 25 Amdoparvovirus is a recently defined genus in the family Parvoviridae (Cotmore 26 et al. 2014). The type species was originally called Aleutian mink disease virus (AMDV) 27 – hence the genus name. However, AMDV is now considered to represent a variant of 28 the renamed species Carnivore amdoparvovirus 1 (Cotmore et al. 2014). AMDV causes 29 an immune complex-associated progressive syndrome in American mink (Neovison 30 vison) called Aleutian disease (AD) or plasmacytosis (Bloom et al. 1994) which is 31 considered to be one of the most important infectious diseases affecting farm-raised 32 mink (Canuti et al. 2015; Canuti et al. 2016). AMDV infection is known to be widespread 33 in wild mink as well as in farmed animals (Canuti et al. 2015), and related 34 amdoparvoviruses have been identified in other carnivore species, including raccoon 3 bioRxiv preprint doi: https://doi.org/10.1101/224584; this version posted July 16, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 dogs, foxes, skunks, and red pandas (Alex et al. 2018; LaDouceur et al. 2015; Li et al. 2 2011; Pennick et al. 2007; Shao et al. 2014). Findings from metagenomic studies 3 suggest that amdoparvoviruses may infect a broader range of mammalian orders 4 (Bexfield and Kellam 2011), but this has yet to be fully demonstrated. 5 Phylogenetic studies support a common evolutionary origin for amdoparvoviruses 6 and protoparvoviruses (genus Protoparvovirus) (Cotmore et al. 2014). Protoparvoviruses 7 infect a wide range of mammalian hosts, encompassing several distinct mammalian 8 orders (Sasaki et al. 2015; Tijssen et al. 2011). For example, rodent protoparvoviruses 9 are known for their oncolytic properties (Marchini et al. 2015), while carnivore and 10 ungulate protoparvoviruses are significant pathogens of domestic pets and livestock 11 (Hueffer and Parrish 2003; Kailasan et al. 2015; Meszaros et al. 2017). Although they 12 are relatively closely related, amdoparvoviruses and protoparvoviruses are distinguished 13 by certain features of their genomes and replication strategies. In particular, 14 amdoparvovirus mRNAs are transcribed from one single upstream promoter and are 15 polyadenylated at two distinct polyadenylation signals. To provide the VP1 encoding 16 transcript, an intron is spliced out, leaving a short, three amino acid-encoding exon 17 leader sequence (transcribed from a short, upstream ORF) positioned in-frame with the 18 VP ORF (Qiu et al. 2006). In contrast, the NS and VP-encoding mRNAs of 19 protoparvoviruses are transcribed from two different promoters, being polyadenylated at 20 a mutual polyadenylation signal close to the 3’ end of the genome. Although splicing has 21 been reported in the protoparvovirus VP-encoding mRNA, this always occurs within the 22 VP ORF itself (Tijssen et al. 2011). Amdoparvoviruses are also unique within the 23 Parvovirinae in lacking a PLA2 domain in their VP unique region (VP1u) (Cotmore et al. 24 2014; Zadori et al. 2001). 25 In this study, we performed a systematic screen of 688 animal genomes to 26 identify PVe disclosing similarity to amdoparvoviruses. We identify and characterise six 27 such PVe, examining their genomic, phylogenetic and protein structural characteristics. 28 29 Methods 30 in silico genome screening 31 We used the database-integrated genome screening (DIGS) tool (Zhu et al. 32 2018) to screen while genome sequence (WGS) assemblies for PVe. The DIGS tool 33 provides a framework for similarity-search based genome screening. It uses the basic 34 local alignment search tool (BLAST) program (Altschul et al. 1997) to systematically 4 bioRxiv preprint doi: https://doi.org/10.1101/224584; this version posted July 16, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 screen WGS files for sequences matching to a nucleotide or peptide ‘probe’. Sequences 2 that disclose above-threshold similarity to the probe are extracted and classified, with 3 results being captured in a MySQL relational database (Axmark and Widenius 2015). To 4 identify PVe, we used parvovirus peptide sequences to screen all 362 vertebrate 5 genome assemblies available in the NCBI whole genome sequence (WGS) database as 6 of the 15th December 2017. Sequences that produced statistically significant matches to 7 these probes were extracted and classified by BLAST-based comparison to a set of 8 reference peptide sequences selected to represent the broad range of diversity in 9 subfamily Parvovirinae.
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