Horizontal gene transfer virus

Another virus , called Sputnik , also infects amoebae, but it cannot reproduce unless mimivirus has already infected the same cell. Although 13 of its genes show little similarity to any other known genes , three are closely related to mimivirus and mamavirus genes, perhaps cannibalized by the tiny virus as it packaged up particles sometime in its history.

This suggests that the satellite virus could perform horizontal gene transfer between viruses, paralleling the way that bacteriophages ferry genes between bacteria. Published online Jul Alita R. Burmeister 1, 2, 3. Author information Copyright and License information Disclaimer. Corresponding author. This article has been cited by other articles in PMC.

Open in a separate window. Figure 1. Evolution of MRSA during hospital transmission and intercontinental spread. Science ; — Nature Microbiology , ; DOI: ScienceDaily, 5 January University of British Columbia.

New research shows gene exchange between viruses and hosts drives evolution. Retrieved January 14, from www. Featured Content. Using publicly available metagenome data, researchers assembled genomes for more than giant viruses and A new study reveals that the parasitic plant dodder A new study has discovered a specific host protein that many For clarity, viral taxa were mapped to their nearest family, phylum, or higher-level classification.

Because of this, multiple families from the same phylum are shown, such as the NCLDV lineages which are denoted with an asterisk note that some unclassified viruses include candidate NCLDV lineages. Transfers assigned to the last eukaryotic common ancestor are excluded but are listed in Supplementary Table 1.

The boxes span from the first to the third quartiles, with whiskers extending 1. Higher-level taxa encompassing both uni- and multicellular organisms were omitted. The resulting HGTs revealed trends regarding the nature of viral—eukaryotic gene exchange. Transfers from eukaryotes to viruses were observed approximately twice as frequently as transfers in the reverse direction Fig.

This imbalance is explained by the higher number of viral recipients compared with donors per eukaryotic taxon Fig. Although sampling bias could influence these numbers, taxon representation affects both recipient and donor frequencies, and bootstrap estimates based on random sampling of protein phylogenies corroborated the observed disparity Fig. This bias may reflect the expanded repertoire of eukaryotic genes or differing recombination and fixation rates in eukaryotes and viruses 25 , 26 , all of which could generate greater opportunity for viral gene acquisition during host—pathogen interactions.

Identifying the taxonomy of donors and recipients revealed the propensity of certain lineages to participate in HGT. The vast majority of transfers involved double-stranded DNA viruses Among eukaryotes, gene exchange was more prevalent in unicellular compared with multicellular organisms Fig.

This included numerous HGTs coinciding with the diversification of SAR, and the largest influx of viral genes was detected around the origin of the dinoflagellates Fig. Elevated gene transfer among unicellular eukaryotes may result from more frequent encounters with NCLDV, which are hyper-diverse and abundant in aquatic environments 8 , as well as a lack of germline segregation Weissman barrier , which probably contributes to the reduced frequency of HGTs observed in animals and plants Fig. However, it is important to note that our methodology under-represents retroviral acquisitions, which are commonly observed throughout animal and plant lineages, but whose detection is limited in this analysis by the poor availability of host-free retroviral genome assemblies that are required for phylogenetic interpretation We also noted eukaryotic species harbouring particularly large numbers of viral genes Fig.

These included species previously described to contain substantial viral genomic insertions from phycodnaviruses Ectocarpus siliculosus and Tetrabaena socialis , phycodnaviruses and asfarviruses Hyphochytrium catenoides , or multiple poorly classified viruses Acanthamoeba castellanii , indicating a single or few sources Fig.

Whether these genes retain functional roles, such as in antiviral virophage production 23 , 39 , or reflect remnants of past infections 40 , 41 , is unclear. This suggests that large-scale transfers, potentially resulting from viral integrations, have recurrently affected diverse eukaryotic lineages, but are generally only transiently retained, possibly providing an opportunity for the longer-term retention and co-option of individual viral genes given adaptive importance.

Along with these transfers to eukaryotes, we identified a number of genes seemingly exchanged before the eukaryotic radiation. These transfers are inherently challenging to interpret given their antiquity, potential rooting uncertainty and ambiguity resulting from intra-eukaryotic HGT Nonetheless, we observed multiple HGTs probably representing either ancient transfers from NCLDV viruses to early eukaryotic ancestors or recurrent viral acquisitions of eukaryotic genes during eukaryogenesis.

Furthermore, GDP- l -fucose synthase, which functions in fructose and mannose metabolism, was also involved in an ancient exchange Extended Data Fig.

These data suggest that genetic exchange between ancestral eukaryotes and NCLDV viruses may have been important during eukaryogenesis, corroborating earlier observations and hypotheses 11 , 21 , To further investigate the functional relevance of these HGTs, we examined the transfer direction and functional annotations of exchanged protein families.

By moving across the phylogenies of all families exhibiting virus-to-eukaryote transfers, from viral donors towards the root, we estimated that The remainder had unclear origins These data demonstrate that over evolutionary time, viruses have a capacity to mediate intra-eukaryotic and inter-domain HGT that is, transfers between eukaryotes and prokaryotes through transduction, the relative frequencies of which will be important to assess comprehensively in the future.

This provides further evidence that viruses act as a gene conduit between diverse eukaryotic lineages, as suggested previously 45 , 46 , which is reminiscent of prokaryotes where viral transduction is key in ecological adaptation and genome evolution 47 , Individual points represent protein families and functional annotations for exemplary families are highlighted.

Histograms denoting point density along the x and y axes are displayed above and to the right of the scatterplot. Labelling has been summarized for clarity, but complete terms are available in Supplementary Table 3. Direction of transfer was also associated with distinct functional biases. Relative to eukaryotic protein families as a whole, eukaryote-to-virus transfers were enriched in functions associated with cellular activity and housekeeping, such as metabolic proteins, E3-ligases and tRNA synthetases Fig.

Additionally, signalling and stress response proteins were frequently acquired and probably also contribute to regulating host physiology, gene expression, immune responses and viral assembly 9 , Bidirectionally transferred genes are also enriched in metabolic processes, protein modification and stress response proteins, which represent a subset of functions most often acquired by viruses Fig. These data show that eukaryote-to-virus and virus-to-eukaryote HGTs both involve functional tendencies that are not equivalent, but may reflect the different adaptive contexts of viruses and eukaryotes To understand how these genes are used in viral and eukaryotic systems, we first examined the subcellular targets of eukaryote-derived viral proteins to understand where the proteins may operate in host cells.

However, relative to all eukaryotic protein families, viral acquisitions were enriched in cytoplasmic, endoplasmic reticulum ER , extracellular and peroxisomal proteins, the last of which suggests functions involving lipid catabolism and oxidation Fig. Moreover, predicted localizations were generally equivalent between donor and recipient proteins, with variation probably resulting from prediction inconsistencies, viral sequence divergence or potentially from neofunctionalization Fig.

This indicates that eukaryote-derived gene products tend to function in the same subcellular context as the original host-encoded proteins. The relative frequencies and proportions are indicated by edge thickness and colour, respectively. Labelling has been summarized for clarity but complete terms are available in Supplementary Table 4.

To examine the processes that these genes impact in given cellular compartments, we conducted localization-based functional enrichments revealing the functional breadth and cellular processes associated with eukaryote-derived viral genes. Cytoplasmic proteins were largely involved in translation, metabolism, proteolysis and signalling, whereas nuclear proteins mainly functioned in DNA processing, chromatin organization, cell cycle regulation and protein modification Fig.

Endoplasmic reticulum proteins were predominantly associated with lipid metabolism and membrane remodelling Fig. Proteins such as sphingolipid synthesis enzymes contributed to the localization bias, since many function in the ER, were frequently transferred Supplementary Table 1 , and are known to be used by diverse viruses for cellular regulation 13 , 56 , Additionally, ER remodelling is important for generating membrane-enclosed viral factories and for replication Extracellular proteins acquired by viruses were enriched for functions including carbohydrate metabolism and proteolysis, reflecting proteins such as glycosyl hydrolases, glycosyltransferases and S1 peptidases, and implying a tendency for cell-surface alteration Fig.

This is consistent with repeated observations of viruses manipulating cell membranes and extracellular spaces through polysaccharide and protein modification 13 , 59 , These results therefore highlight the key cellular systems associated with eukaryote-derived viral genes which, given their known roles in host manipulation 1 , 6 , may provide insights into common viral infection strategies.

Indeed, many of these processes are also known to be manipulated by viruses that lack eukaryotic genes for example, many non-NCLDV viruses , which instead often rely on small effectors and host-encoded proteins 61 , 62 , This suggests that cellular manipulation strategies may be ubiquitous across viral lineages, but that the mechanism through which modification is accomplished may depend on viral coding capacity for example, large genome sizes and increased coding capacity in the NCLDV could permit the more flexible use of acquired eukaryotic genes.

Notably, the characterization of host—virus interactomes has been proposed as a promising avenue for host-targeting antiviral drug discovery 64 , Therefore, if host-manipulation mechanisms are similar across viral lineages, we hypothesize that eukaryote-derived viral genes could facilitate the prediction of cellular components pertinent for infection by diverse viral lineages.

Although indirect, this could provide an analytically simplistic for example, homology-based approach for predicting therapeutic targets that could complement data from experimental host—virus model systems Lastly, to gain insights into the role viral genes play in eukaryotic systems, we inspected the distributions and functions of viral-derived glycosyltransferases, which were strongly enriched in the identified virus-to-eukaryote HGTs Fig.

We identified 63 instances of eukaryotes acquiring viral glycosyltransferases, of which 13 mapped to ancestral nodes, implying functional relevance under long-term selection Supplementary Table 5. Plotting transfer events and annotations over a eukaryotic phylogeny revealed the functional diversity and recurrent acquisitions of these enzymes across eukaryotic lineages Fig.

These HGTs were often correlated with morphological and structural synapomorphies, including algal cell wall elaboration for example, lipopolysaccharide LPS and cellulose synthesis enzymes 66 , long-chain polyamine-containing scale formation in haptophytes spermidine synthase 67 , cellular aggregation in opisthokonts and dictyostelid slime moulds hyaluronan synthase and GlcNAc transferase , and mitochondrial structural divergence in the kinetoplastids fucosyltransferase , a group primarily comprised of animal parasites such as trypanosomes Fig.

Experimental data supported a number of these correlations, including the unusual identification of LPS in the cell walls of Chlorella 68 , the importance of hyaluronan in vertebrate tissues 69 , and the role of the dictyostelid N -acetylglucosamine transferase, Gnt2, in calcium-independent cellular aggregation 70 , indicating that virally sourced genes are co-opted during the evolution of novel cellular traits Fig.

We further examined two glycosyltransferase acquisitions in kinetoplastids, hypothesizing that, given the correlation between the HGT acquisitions and the origin of the highly derived kinetoplastid mitochondria containing kinetoplasts , they should function in that compartment.

Phylogenetic analyses revealed that both genes were derived from NCLDV, highlighted the prokaryotic origin of the fucosyltransferase C , and confirmed that both genes are conserved throughout kinetoplastids Fig. Moreover, both proteins localized to the mitochondria and kinetoplast in Trypanosoma brucei identifiable as a non-nuclear DNA-stained foci both when tagged with mNeonGreen Fig. A recent report also suggested an essential role for the fucosyltransferase in mitochondrial function in T.

These data, in combination with the capacity for viruses to modify cell surfaces and induce morphological alterations in their hosts for example, cytopathic effects 72 , suggest that viral-derived genes may have played various roles in the evolution of cellular morphology across the eukaryotic tree of life. Protein families and annotations are denoted with numbers and phenotypic correlations are noted with colours.

Kinetoplastid genera and the gene identifiers for Trypanosoma brucei orthologues are noted. Representative TrypTag fluorescent micrographs, based on observations of at least 20 individual cells, depicting the localization of two glycosyltransferases Tb White arrowheads and asterisks denote kinetoplasts and nuclei, respectively. Proteomic data were assessed using TriTrypDB. Horizontal gene transfer between viruses and eukaryotes has been observed and assumed to impact the evolution of both participants, but until now we lacked the systematic characterization necessary to generalize the mode and functional importance of these transfers in both viral and eukaryotic contexts 2 , 29 , As with all computational surveys, our dataset is limited by specificity and sensitivity, but nonetheless it provides an extensive resource from which phylogenetic patterns can be observed and their genomic and functional importance may be predicted.

From a viral perspective, the preponderance of host-derived genes in the NCLDV reiterates the importance of gene exchange in the evolution of these viruses 27 , and underscores the ubiquity of certain viral host-manipulation strategies.

Indeed, many important emerging human pathogens, such as Zika and coronaviruses, depend on the manipulation of similar eukaryotic systems, such as autophagy, proteolysis, ER modification and sphingolipid metabolism 57 , 73 , Similarly, functional investigations of eukaryote-derived viral genes, particularly using heterologous expression 6 , may also provide insights into how viruses manipulate these cellular pathways while circumventing the need for tractable host—virus model systems.

From a eukaryotic perspective, our analyses provide further evidence that viruses participate in eukaryotic transduction and implicate viral—eukaryotic gene exchange in eukaryogenesis and the evolution of eukaryotic morphology. In particular, horizontally acquired glycosyltransferases have recurrently impacted transitions as fundamental as the evolution of tissues and divergence of mitochondria, reminiscent of how retroviral genes, such as fusogens, have repeatedly driven placental evolution in animals 19 , Our survey also identified protein candidates for which experimental characterizations could help reveal the impact of these genes on cellular systems and their roles in driving the evolution of eukaryotic complexity.

To systematically and conservatively identify instances of viral—eukaryotic gene exchange, groups of homologous eukaryotic, viral and prokaryotic proteins were clustered into protein families and phylogenetic analyses were performed Extended Data Fig.

Additional viral proteins were acquired from nucleocytoplasmic large DNA virus NCLDV metagenomes previously assembled from diverse environments and assessed as having low contamination on the basis of gene content see Contamination scoring below 8. Viral taxonomic annotations were assigned to metagenomes on the basis of previously conducted phylogenomic analyses 8.

Protein families containing both viral and eukaryotic representatives were retained, aligned with MAFFT v. In this case, HMMs were used to improve the detection of distant prokaryotic homologues. Due to the large number of prokaryotic sequences, the resulting hits were reduced by taking the most significant hit based on E -value per genus or per strain, to a maximum of sequences; this allowed for diverse taxon sampling while avoiding an overabundance of prokaryotic proteins Extended Data Fig.

Sequences assigned to viral—eukaryotic protein families were then combined with the prokaryotic proteins and re-clustered as described above Extended Data Fig.

Phylogenetic trees were generated from clustered protein families to infer the evolutionary relationships between viral and eukaryotic homologues. Maximum likelihood phylogenies were conducted in IQ-Tree v1. Phylogenetic rooting was done using minimal ancestral deviation, which is a rooting method that is more robust to heterotachy than midpoint rooting For individual phylogenies of particular interest, such as those shown in Fig. Notably, the topologies of these trees were consistent with their initial iterations and ModelFinder consistently selected the Le and Gascuel LG substitution model similar to that used in the other phylogenies, corroborating the use of the aforementioned methods see Extended Data Figs.

Before phylogenetic inference, the trimmed alignments for protein families inferred to exhibit ancient gene transfers for example, Extended Data Fig. To detect instances of HGT, we developed a conservative algorithmic approach that emphasized specificity over sensitivity, given the potential for contamination in the underlying dataset and the risk of phylogenetic artefacts. We developed an automated pipeline using the python package, ETE 3 91 , to identify HGT-indicative topologies in the phylogenetic trees generated from each protein family.

Specifically, we aimed to identify eukaryotic species nested within viral clades viral-to-eukaryote HGT or viral taxa within eukaryotic clades eukaryote-to-virus HGT Extended Data Fig. To this end, phylogenies were initially processed to account for statistical support and directionality that is, rooting , and to assign taxonomic annotations.

Collapsed phylogenies were then rooted using minimal ancestral deviation rooting 87 and taxa were annotated as eukaryotic, viral or prokaryotic using the National Centre for Biotechnology Information NCBI Taxonomy database Extended Data Fig. Following tree processing and annotation, but before identifying HGT events, the phylogenies were analysed to assess rooting ambiguity Extended Data Fig. In particular, we checked whether viral and eukaryotic sequences could be separated into two monophyletic groups using alternative root placements.

In this case, rooting becomes unclear unless the phylogeny is strongly biased toward viral or eukaryotic species representation for example, it is unlikely that a gene conserved throughout a eukaryotic supergroup was derived from a single virus. To evaluate this, if a phylogeny could be split into two discrete taxonomic clades, the ratio of eukaryotic to viral species was determined. Otherwise, the topology would be classified as an HGT with unknown directionality.

Lastly, single prokaryotic sequences and HGTs between prokaryotes and viruses or eukaryotes identified as described below were removed to reduce topology complexity, but this did not increase the false positive rate among viral—eukaryotic HGTs Extended Data Fig. A eukaryote-to-virus HGT topology was defined as a viral clade with a eukaryotic sister and cousin whereas a virus-to-eukaryote HGT required a eukaryotic clade with a viral sister and cousin Extended Data Fig.

Initially, viral and eukaryotic clades were identified and the taxonomy of their sister and cousin groups were assessed. To classify the taxonomy of these groups, the numbers of viral, eukaryotic and prokaryotic sequences in each group were counted. Sister and cousin groups were then classified as viral, eukaryotic or prokaryotic if the taxonomies were consistent across the members of the group.

In the event of a polytomy, multiple sister and cousin groups could be present. To account for this, the taxonomy of the polytomy-wide group would be summarized by determining the taxonomy of each group within the polytomy as described above. If all candidate sisters or cousins within the polytomy were classified consistently, the group would be identified as viral, eukaryotic or prokaryotic according to the consistent classification. After classifying both sister and cousin groups, if the topology was consistent with one of the aforementioned scenarios, an HGT event would be noted Extended Data Fig.

Each phylogeny was screened for eukaryote-to-virus and virus-to-eukaryote HGTs three times iteratively, given that once a viral or eukaryotic clade had been classified as an HGT, it would be interpreted as eukaryotic or viral, respectively, in subsequent iterations.