The movement of genetic material from one organism to another by horizontal gene transfer (HGT) bypasses vertical inheritance from parent to offspring (Keeling and Palmer, 2008). HGT can shortcut more gradual mutational processes by providing the opportunity for adaptive leaps through single mutational events where genes can be transferred between genomes across kingdoms of life (Keeling and Palmer, 2008). HGT plays a central role in the diversification of many infectious microbes, which contend with complex environments and host immune defenses to persist and replicate. HGT is particularly well-described in bacteria, where it can contribute to the emerging crisis of multi-antibiotic resistant pathogens (Wijayawardena et al., 2013).

Many classes of viruses acquire genes from the hosts they infect by horizontal transfer (Caprari et al., 2015). A conspicuous example is Rous Sarcoma virus, in which recognition of the horizontal transfer of the host c-Src gene into the virus genome led to the discovery of oncogenes (Swanstrom et al., 1983). Other co-opted host genes diverge to aid the virus in inhibiting host defenses (Kawagishi-Kobayashi et al., 1997; Elde and Malik, 2009). It has become increasingly clear that the acquisition of host genes is a common mechanism by which viruses of many classes gain adaptive advantages to propagate (Dolja and Koonin, 2018). Despite the prevalence of HGT in diverse viruses and its importance in virus evolution, the mechanisms by which genes are transferred from host to virus genomes are not well understood.

To investigate mechanisms of transfer we examined poxviruses, which encode a plethora of genes gained by horizontal transfer. Based on phylogenetic analysis, more than 25% of poxvirus genes were acquired by HGT from hosts (Hughes and Friedman, 2005), although similarities not evident in sequence comparisons but revealed by shared protein structures suggest that a higher proportion of genes were acquired by horizontal transfer (Bahar et al., 2011). Many captured genes adapt to act as inhibitors of host immune defenses to favor virus replication (Elde and Malik, 2009). Some act as host range factors because their deletion leads to restriction of infectible cell types or species, implying that new acquisitions may aid in host jumps (Bratke et al., 2013; Haller et al., 2014). While the most notorious poxvirus, variola virus which caused smallpox, has been eradicated, other extant poxviruses are capable of infecting humans and pose the risk of new pandemics, as appears to be the case for monkeypox (Sklenovská and Van Ranst, 2018). Poxviruses also serve as useful model systems for other viruses with large double-stranded (ds) DNA genomes (Deeg et al., 2018).

Because poxvirus-encoded copies of host genes lack introns, it was hypothesized that transfer occurs through a spliced mRNA intermediate (Lefkowitz et al., 2006). For integration, mRNA templates need to be reverse transcribed into virus genomes by either a retrovirus or a retrotransposon. The discovery of a provirus encoded in the genome of fowlpox virus (Hertig et al., 1997) and a Short Interspersed Nuclear Element (SINE) retrotransposon found in the taterapox virus genome (Piskurek and Okada, 2007) indicate that either is capable of catalyzing insertions in poxvirus genomes.

Given differences in biochemical activity, it is possible to detect patterns distinguishing mechanisms of retroviral versus retrotransposon-based transfer of host genes into virus genomes. Long Interspersed Nuclear Element-1 (LINE-1) retrotransposons are known to reverse transcribe and integrate host genes in a sequence independent manner, resulting in collections of processed pseudogenes in diverse host genomes (Esnault et al., 2000). LINE-1 transcripts encode two proteins: an RNA binding protein (ORF1) and an endonuclease (EN)/reverse transcriptase (RT) protein (ORF2). ORF2 preferentially nicks one strand of DNA at a TTTT/AA site in the host genome, and reverse transcription is primed from the exposed 3′hydroxl. LINE-1 elements can also integrate at sites of dsDNA breaks in an endonuclease-independent manner (Morrish et al., 2002). LINE-1 RT shows cis-preference, meaning it is most likely to transcribe the RNA from which it was translated, but SINE elements like the one found in the taterapox genome can hijack LINE-1 machinery to integrate following replication.

Sometimes LINE-1 enzymes promiscuously reverse transcribe host mRNA, which might facilitate transfers of host genes to virus genomes. It is plausible that the poly(A) tail of either the host mRNA or a poly(A) tract in SINE transcripts initializes LINE-1 reverse transcription, in addition to faithful recognition of LINE-1 transcripts. Short target site duplications (TSDs) of sequences ~8–20 bp flank LINE-1 insertions of either LINE-1 or host sequences, likely a product of repairing staggered breaks during integration. The resulting LINE-1-mediated flanking duplications are copies of host sequences as opposed to specific retrovirus sequences. Additional evidence of LINE-1 action comes from comparisons with closely related species lacking the insertion and instead containing what is termed an ‘empty site’. Taken together, these features can help distinguish whether LINE-1 is involved in the transfer of host genes to virus genomes.

However, given that viruses rapidly mutate, unique signatures of retrovirus or LINE-1-mediated horizontal transfer may quickly degrade and obscure mechanisms of transfer. Therefore, we devised an experimental system to screen for the horizontal transfer of a gene from host to virus genomes using an artificial selection scheme. Combined with observations of viruses encoding recently acquired and highly conserved genes, we reveal LINE-1 elements as molecular accomplices in the transfer of host genes to virus genomes.

We hypothesized that examination of genes recently acquired by HGT might provide clues for revealing mechanisms of gene transfer. Virus homologs of the host Golgi Anti-Apoptotic Protein (GAAP; also called transmembrane Bax inhibitor motif protein family 4 or TMBIM4), found in several orthopoxviruses, are ~75% identical to human GAAP (Gubser et al., 2007; Saraiva et al., 2013), suggesting a recent acquisition and/or highly conserved function favoring virus replication. Strikingly, we observed nearly identical 21 base pair sequences flanking the open reading frame of virus GAAP (vGAAP), indicative of a TSD, consistent with gene capture resulting from LINE-1-mediated retrotransposition of host mRNA (Figure 1A and Figure 1—figure supplement 1). The vGAAP gene is situated near one of two identical inverted terminal repeat (ITR) regions of the virus genome, and on opposite ends of the genome in various viruses, suggesting that it was originally transferred into the ITR. A single copy of the putative 21 bp TSD at an analogous position near the other ITR in the cowpox genome suggests a pseudo-empty site (Figure 1A). Taken together, with a published account of a non-autonomous SINE in the genome of taterapox virus (Piskurek and Okada, 2007), these observations suggest that host genes can be retrotransposed into poxvirus genomes by LINE-1 activity in a process akin to the generation of processed pseudogenes.

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Phylogenetic analysis revealed a single origin for the horizontal transfer of GAAP into poxvirus genomes. In addition, at least two other classes of DNA viruses, herpesviruses and iridoviruses, independently acquired GAAP by horizontal transfer (Figure 1B; Bellehumeur et al., 2016; de Groof et al., 2015). Another study of Squirrel Monkey cytomegalovirus revealed that the S1 gene encodes a protein more than 95% identical to squirrel monkey Signaling lymphocytic activation molecule family 6 (SLAMF6), followed by portions of the 3′ untranslated region (UTR) of the host mRNA (Pérez-Carmona et al., 2015). Taken together, these findings suggest that many DNA viruses acquire host genes by retrotransposition. However, the majority of host to virus gene transfers lack signatures of retrotransposition, which can quickly degrade through mutation, motivating our development of an experimental strategy for capturing HGT events in real time.

We developed a selection scheme using vaccinia virus (Copenhagen strain), which encodes nearly 200 genes in a 191,737 bp genome (See Materials and methods). We focused on K3L, a gene that was presumably acquired from a host by an ancient poxvirus based on sequence identity with human eukaryotic initiation factor 2α (eIF2α; 27.6% identical) (Beattie et al., 1991; Elde et al., 2009; Elde and Malik, 2009). K3L diverged from eIF2α to encode a protein that blocks the host defense Protein Kinase R (PKR) pathway. PKR is activated by dsRNA produced by viruses in the cytoplasm during transcription of virus genes and virus replication. Upon activation, PKR phosphorylates eIF2α, leading to a block in protein translation and virus replication. K3L acts as a pseudo-substrate of PKR to competitively inhibit PKR from binding eIF2α (Figure 2—figure supplement 1; Beattie et al., 1991; Kawagishi-Kobayashi et al., 1997), and can be essential for productive infections depending on the host (Langland and Jacobs, 2002; Park et al., 2019; Park et al., 2021).

Using a mutant virus deleted for K3L and another PKR inhibitor, E3L (Brennan et al., 2014), we infected a rabbit kidney cell line (RK13) expressing chromosome-integrated copies of K3L fused to the gene encoding mCherry fluorescent protein (RK13-K3L) (Figure 2A and see Materials and methods for details). The host copy of mCherry-K3L complements the mutant virus lacking K3L, allowing it to replicate. Viruses grown in RK13-K3L cells were transferred to a non-complementing baby hamster kidney (BHK) cell line. Viruses lacking K3L replicate poorly in BHK cells, providing strong selection for viruses that ‘reclaimed’ the mCherry-K3L gene by horizontal transfer and/or somehow adapted in the absence of K3L to block host PKR and regain productive replication.

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Using this scheme, we screened ~500 million viruses over many experiments and recovered ten virus isolates from mCherry-positive infected cell clones. In the restrictive BHK cells, viruses encoding K3L replicate ~100-fold better than the parent virus deleted for K3L (Figure 2B), allowing us to identify viruses with improved replication compared to the larger population of K3L-deficient viruses. After plaque purification of candidate mCherry positive isolates, we infected BHK cells with each recovered virus isolate and observed titers on par with viruses encoding K3L (Figure 2C). By sequencing the genome of each recovered virus isolate, we found that the mCherry-K3L fusion gene was integrated into the virus genome at a unique position in every isolate (Figures 2D and 3A), providing the opportunity to compare each independent integration event.

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All integrations were consistent with a mechanism of LINE-1 retrotransposition-mediated HGT. The sequence of each transferred gene revealed hallmark features of mRNA gene capture, including 5′ and 3′ UTRs, precise intron splicing, and poly(A) tails (Figure 3B). For 7 of 10 isolates, TSDs flanked mCherry-K3L insertions and contained cut site sequences matching the consensus (TTTT/AA) of LINE-1 endonuclease (Figure 3 and Figure 3—figure supplement 1). Although there were no TSDs flanking mCherry-K3L in isolates 5, 9, and 10, these integrations might result from an endonuclease-independent LINE-1 mechanism at DNA breaks (Morrish et al., 2002). Because our experiments lack any exogenous reverse transcriptase, we tested for endogenous activity in the RK13 cells and detected robust LINE-1 activity (Figure 3—figure supplement 2). These results suggest that LINE-1-mediated retrotransposition may be a common mechanism of HGT in poxvirus genomes. While we do not exclude the possibility that genes can also be transposed into the viral genome by retroviruses, this would require co-infection. LINE-1-mediated retrotransposition may be more likely simply because LINE-1 enzymes are nearly ubiquitous in mammals.

In general, poxvirus genomes are arranged with the essential genes, shared by all poxviruses, in the central region of the genome. Clade- or species-specific genes, which more commonly exhibit evidence of HGT, are enriched near the ends of the genome (Lefkowitz et al., 2006; McLysaght et al., 2003). This pattern may reflect that gene transfer into the central genomic region genome is more likely to interrupt genes vital for virus replication (Lefkowitz et al., 2006). Consistent with this, all but 1 of the 10 isolates, we recovered integrated K3L outside a roughly defined central region of the genome containing 90 core chordopoxvirus genes (Lefkowitz et al., 2006; Figure 2D). In the case of isolate 5, the K3L integration involved a duplication of two essential genes, G9R and L1R (Figure 3B). In a contemporaneous study (Rahman et al., 2022), virus genomes that acquired a host gene by horizontal transfer within a duplicated gene also propagated. In both cases, gene functions were preserved by duplication. Spurious gene duplications can appear frequently in poxvirus genomes (Hughes and Friedman, 2005), pointing to a flexible means of poxvirus adaptation involving horizontal transfer even into essential genes.

Previous studies found that duplication of poxvirus genes, followed by rapid gene copy amplification, can boost virus replication (Brennan et al., 2014; Elde et al., 2012). In our analysis, we discovered two isolates where K3L had undergone polymorphic copy number increases (isolates 4 and 5; Figure 4A). Homologous recombination, including unequal crossovers leading to duplications, requires as little as 16 bp of homology in poxviruses (Yao and Evans, 2001), suggesting that LINE-1 induced TSDs might facilitate gene amplification. Genes transferred within the ITR are duplicated on the other end by replication-based mechanisms (McFadden and Dales, 1979), as we observed in isolates 4 and 9 (Figure 2C). Genes integrated near the termini of the genome by HGT, like isolate 4, may be especially prone to duplication due to stretches of short, high copy tandem repeats found in and near the ITR regions (Figure 4A and Figure 5—figure supplement 1A). These observations are consistent with the idea that HGT occurs evenly across poxvirus genomes, but with an enrichment of transferred genes persisting near the ends, where insults to essential genes are less probable and duplication-based adaptation is favored (Figure 5—figure supplement 1). Along these lines, gene families found only in specific lineages of poxviruses, indicating more recent acquisition, are more likely to be present in multiple copies than single-copy host-acquired genes found among diverse poxviruses (Hughes and Friedman, 2005).

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While our experimental system revealed LINE-1-driven mechanisms of HGT, the selection scheme involved viruses regaining K3L, an existing virus gene as opposed to gaining a bona fide host gene. To better model virus adaptation following acquisition of a host gene, we engineered viruses with the human eIF2α gene in place of K3L (Figure 4—figure supplement 1; see Materials and methods). This recombinant virus better approximates the original ancient HGTs of the eIF2α gene that then evolved to become K3L in diverse clades of modern poxviruses (Kawagishi-Kobayashi et al., 2000). Because the viruses we engineered to encode eIF2α in place of K3L also lack E3L, which encodes another inhibitor of the host PKR antiviral pathway, experiments with these viruses focus strong selective pressure on eIF2α to adapt to inhibit PKR.

We performed four serial infections of viruses expressing eIF2α or an eIF2α variant lacking the PKR phosphorylation site (S51A) in RK13 cells. While the recombinant viruses replicate weakly, we observed a nearly tenfold increase in virus replication for both eIF2α-encoding viruses after passaging (Figure 4B). By sequencing the eIF2α region in evolved virus isolates, we found independent gene copy increases of eIF2α in both viruses (Figure 4C). These results support a critical role for gene copy increases following HGT in poxvirus evolution, as also observed for K3L and other genes (Brennan et al., 2014; Elde et al., 2012) and suggest a common pathway facilitating adaptation of host genes captured by poxviruses.

HGT is an important process facilitating virus evolution (Caprari et al., 2015; Deeg et al., 2018; Hughes and Friedman, 2005; Koonin and Yutin, 2019; McLysaght et al., 2003). Our discovery of LINE-1 retrotransposition-mediated HGT from host to poxvirus genomes has several notable implications. In addition to self-propagation in host genomes, retrotransposition to virus genomes could greatly extend the range of LINE-1 or related elements that subsequently mobilize to a newly infected virus host (Piskurek and Okada, 2007). The extensive host range of some poxviruses, for example, between rodent and primate species, suggests the possibility of cross-host lineage transfer of LINE-1s, non-autonomous SINEs, and host transcripts between mammals. A process involving the frequent appearance of DNA transposons in some insect viruses suggests an analogous mechanism for the spread of transposable elements between insect species (Gilbert et al., 2016). In cases of retrotransposition of host transcripts, the resulting processed pseudogene products are enriched for highly expressed genes (Zhang et al., 2004). The overrepresentation of certain transcripts might provide clues for understanding and predicting how viruses might adapt with repurposed genes mimicking host functions (Elde and Malik, 2009). Currently recognized cases of HGT involving oncogenes, regulators of translation, like eIF2α, and antiviral genes that are highly expressed in response to infection. These examples of transcripts exhibit high gene expression and encode cellular functions easily repurposed to promote virus replication.

Repetitive TSDs generated by LINE-1 activity may also enhance poxvirus adaptation by facilitating rapid gene copy number amplification of horizontally transferred genes on arrival. Increases in gene copy number augment the probability of beneficial mutations appearing, allowing for swift diversification of newly acquired genes (Elde et al., 2012). Thus, form follows function as the repetitive termini of poxvirus genomes further enable the emergence and persistence of acquired genes predominately at the ends of the genome (Figure 5). As beneficial virus gene variants endure, they end up closer to the center of the genome as subsequently captured genes appear near the ends.

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Similar mechanisms of virus adaptation by HGT may be shared by other diverse classes of nucleocytoplasmic DNA viruses (NCLDVs), in addition to poxviruses (Deeg et al., 2018; Koonin and Yutin, 2019). Many giant viruses, which can exceed a megabase in genome size and infect diverse host species, encode a variety of genes acquired by HGT, including ribosomal genes. Given a primary role for LINE-1 elements in facilitating gene transfer, we speculate that other classes of transposable elements may spur NCDLV evolution by mobilizing host genes into virus genomes across diverse ecosystems.

Sequencing data have been deposited in the NCBI SRA database under project code PRJNA614958. All data generated or analyses during this study are included in the manuscript and supplementary files.

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Author details

1. Sarah M Fixsen

   Department of Human Genetics, University of Utah, Salt Lake City, United States

   Contribution

   Data curation, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing - original draft

   Competing interests

   No competing interests declared

2. Kelsey R Cone

   Department of Human Genetics, University of Utah, Salt Lake City, United States

   Contribution

   Data curation, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing - original draft

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-4547-7174

3. Stephen A Goldstein

   Department of Human Genetics, University of Utah, Salt Lake City, United States

   Contribution

   Data curation, Formal analysis, Investigation, Writing – review and editing

   Competing interests

   No competing interests declared

4. Thomas A Sasani

   Department of Human Genetics, University of Utah, Salt Lake City, United States

   Contribution

   Data curation, Formal analysis, Validation, Visualization

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-2317-1374

5. Aaron R Quinlan

   Department of Human Genetics, University of Utah, Salt Lake City, United States

   Contribution

   Supervision, Funding acquisition, Validation

   Competing interests

   No competing interests declared

6. Stefan Rothenburg

   Department of Medical Microbiology and Immunology, University of California, Davis, Davis, United States

   Contribution

   Resources, Funding acquisition, Validation

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-2525-8230

7. Nels C Elde

   1. Department of Human Genetics, University of Utah, Salt Lake City, United States
   2. Howard Hughes Medical Institute, Chevy Chase, United States

   Contribution

   Conceptualization, Resources, Supervision, Funding acquisition, Methodology, Project administration, Writing – review and editing

   For correspondence

   nelde@genetics.utah.edu

   Competing interests

   Reviewing editor, eLife

   "This ORCID iD identifies the author of this article:" 0000-0002-0426-1377

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