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Filoviruses Are Ancient and Integrated Into Mammalian Genomes

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Filoviruses Are Ancient and Integrated Into Mammalian Genomes

Derek J Taylor et al. BMC Evol Biol.

Abstract

Background: Hemorrhagic diseases from Ebolavirus and Marburgvirus (Filoviridae) infections can be dangerous to humans because of high fatality rates and a lack of effective treatments or vaccine. Although there is evidence that wild mammals are infected by filoviruses, the biology of host-filovirus systems is notoriously poorly understood. Specifically, identifying potential reservoir species with the expected long-term coevolutionary history of filovirus infections has been intractable. Integrated elements of filoviruses could indicate a coevolutionary history with a mammalian reservoir, but integration of nonretroviral RNA viruses is thought to be nonexistent or rare for mammalian viruses (such as filoviruses) that lack reverse transcriptase and replication inside the nucleus. Here, we provide direct evidence of integrated filovirus-like elements in mammalian genomes by sequencing across host-virus gene boundaries and carrying out phylogenetic analyses. Further we test for an association between candidate reservoir status and the integration of filoviral elements and assess the previous age estimate for filoviruses of less than 10,000 years.

Results: Phylogenetic and sequencing evidence from gene boundaries was consistent with integration of filoviruses in mammalian genomes. We detected integrated filovirus-like elements in the genomes of bats, rodents, shrews, tenrecs and marsupials. Moreover, some filovirus-like elements were transcribed and the detected mammalian elements were homologous to a fragment of the filovirus genome whose expression is known to interfere with the assembly of Ebolavirus. The phylogenetic evidence strongly indicated that the direction of transfer was from virus to mammal. Eutherians other than bats, rodents, and insectivores (i.e., the candidate reservoir taxa for filoviruses) were significantly underrepresented in the taxa with detected integrated filovirus-like elements. The existence of orthologous filovirus-like elements shared among mammalian genera whose divergence dates have been estimated suggests that filoviruses are at least tens of millions of years old.

Conclusions: Our findings indicate that filovirus infections have been recorded as paleoviral elements in the genomes of small mammals despite extranuclear replication and a requirement for cooption of reverse transcriptase. Our results show that the mammal-filovirus association is ancient and has resulted in candidates for functional gene products (RNA or protein).

Figures

Figure 1
Figure 1
Genome map of a filovirus showing the gene order and regions of homology with proposed filovirus-like elements in mammals. Dashed lines indicate the boundaries of the non-retroviral integrated RNA virus elements (NIRVs) and depict a bias for the N-terminal region of the NP gene. Mammalian genera that show homology with a gene of filovirus are listed above the genome map. Solid colors within the coding region arrows indicate the size of the product. Red shading indicates proteins associated with the viral RNA in the ribonucleoprotein complex.
Figure 2
Figure 2
Midpoint rooted maximum likelihood phylogram of nucleoprotein (NP) amino acid sequences from filoviruses, morbilliviruses and related mammalian genomic and EST sequences. Branches with more than two sequences and strong support (at least 90 for bootstrap or 95 for Bayesian posterior probability) have values shown above the branch (in the order of approximate likelihood ratio tests, Bayesian Posterior Probabilities, and non-parametric bootstrap values). Parentheses contain GenBank Accession numbers and are followed by the range of the sequence for nucleotide submissions. Red filled branches indicate clades of viruses (Mononegavirales), black filled branches indicate mammalian sequences, and blue filled lines indicate expressed sequence tags. Geographic origins are given in parentheses adjacent to species names. Shaded cartoons indicate outlines of species represented in the analysis.
Figure 3
Figure 3
Midpoint rooted maximum likelihood phylogram of L protein amino acid sequences from filoviruses, Paramyxoviridae, and a South American marsupial genomic sequence. Labeling and shading details are as in Fig. 2 except that the species name and continent for the mammalian sequence are provided in the caption: Monodelphis domestica (South America).
Figure 4
Figure 4
Midpoint rooted maximum likelihood phylogram of nucleoprotein (NP) amino acid sequences from filoviruses and related mammalian genomic and EST sequences showing the paraphyly of mammals. Branches with more than two sequences and strong support (at least 90 for bootstrap or 95 for Bayesian posterior probability) have values shown above the branch (in the order of approximate likelihood ratio tests, Bayesian Posterior Probabilities, and non-parametric bootstrap values). Parentheses contain GenBank Accession numbers and are followed by the range of the sequence for nucleotide submissions. Red filled branches indicate clades of viruses (Mononegavirales), black filled branches indicate mammalian sequences, and blue filled lines indicate expressed sequence tags. Geographic origins are given in parentheses adjacent to species names. Shaded cartoons indicate outlines of species represented in the analysis.
Figure 5
Figure 5
Histograms of Ka/Ks values calculated from alignment sites of the filovirus-like elements in eleven species of mammals. Values are calculated using Bayesian methods and a model that accommodates neutral, positive and negative selection (M8 below), and a model that accommodates largely negative or purifying selection (M7 above). Note the better fit of the purifying selection model. Red dashed lines indicate the expected values under neutral evolution for non-functional pseudogenes, while values <<1 are consistent with purifying selection.
Figure 6
Figure 6
Summary graph showing mammalian genomes assayed for filovirus-like elements and the phylogenetic distribution of the mammals with filovirus-like elements. Red shading indicates that species with detected filovirus-like elements fall into a marsupial and a eutherian group. The platypus genome was also assayed but is not depicted here. The mammalian phylogeny is based on a composite of recent studies [30,44,45].
Figure 7
Figure 7
Chromosome maps showing synteny of regions flanking filovirus-like elements in rat and mouse genomes with a whole chromosome view (A) and a local view (B). White asterisks represent the locations of the phylogenetic sister copies of filovirus-like elements. Five synteny blocks with a reversal distance of 2 were found between CHR 16 of the mouse and CHR 11 of the rat. The filovirus-like elements are located on a reversed synteny block (purple shading). A close up view shows the flanking gene locations and acronyms.

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