# A life LINE for large viruses

Eugene Koonin, Mart Krupovic

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Eugene Koonin, Mart Krupovic. A life LINE for large viruses. eLife, 2022, 11, pp.e83488. 10.7554/eLife.83488. pasteur-03834397

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Submitted on 29 Oct 2022

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EVOLUTION

# A life LINE for large viruses

As long suspected, poxviruses capture host genes through a reverse-transcription process now shown to be mediated by retrotransposons.

EUGENE V KOONIN AND MART KRUPOVIC

**Related research article** Rahman MJ, Haller SL, Stoian AMM, Li J, Brennan G, Rothenburg S. 2022. LINE-1 retrotransposons facilitate horizontal gene transfer into poxviruses. *eLife* **11**:e63327. doi: 10.7554/eLife.63327

**Related research article** Fixsen SM, Cone KR, Goldstein SA, Sasani TA, Quinlan AR, Rothenburg S, Elde NC. 2022. Poxviruses capture host genes by LINE-1 retrotransposition. *eLife* **11**:e63332. doi: 10.7554/eLife.63332

Viruses with double-stranded DNA genomes have been stealing genes from their hosts for billions of years. In fact, these acquisitions represent the major force in viral evolution, with some ancient gene gains apparently underlying the emergence of the main groups of viruses we know today (Caprari et al., 2015; Koonin et al., 2022). Captured genes are often involved in the complex interactions between a virus and its specific host, leading to virus families having dramatically different repertoires of stolen genes (Elde and Malik, 2009; Koonin et al., 2022).

Herpesviruses and poxviruses are the two most common groups of double-stranded DNA viruses that infect animals. While herpesviruses reproduce in the nucleus and poxviruses in the cytoplasm, both have captured and then repurposed numerous host genes for counter-defense. In particular, the genome of orthopoxviruses – a group that includes the smallpox, monkeypox and cowpox viruses – contains about 100 captured genes that primarily help the viruses to evade the immune system (Moss and Smith, 2021). These

sequences were acquired in batches over the 500 million years of evolution which separate fish poxviruses from the sub-family which includes orthopoxviruses (Senkevich et al., 2021).

Despite the importance of this phenomenon, exactly how double-stranded DNA viruses capture host genes remains unclear. In principle, two routes appear possible: virus and host could exchange segments of their genomes in the nucleus via a process known as recombination; or a messenger RNA (mRNA) from the host could be reverse-transcribed into DNA that is then integrated into the viral genome. This second mechanism, however, would require external assistance since neither poxviruses nor herpesviruses encode the enzymes responsible for reverse transcription.

This help could come from retrotransposons, the widespread mobile elements that can replicate and insert themselves into new locations in the genome of eukaryotes. In particular, retrotransposons such as LINE-1 (an element common in vertebrate genomes) are transcribed into an mRNA molecule which is then translated in the cytoplasm. The produced proteins import the LINE-1 RNA back into the nucleus and reverse transcribe it into DNA, concomitantly inserting it into new genomic locations (Figure 1A). DNA viruses could co-opt this process to turn host mRNAs into DNA that is incorporated into viral genomes.

Two strong arguments support the reverse-transcription route. First, all viral genes lack introns (with a single exception in the herpesvirus family). These non-coding sequences are present within cellular genes but are removed from mature mRNA molecules – suggesting that host genes are acquired through an mRNA-mediated process rather than through DNA material being

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of the taterapox virus carries signals from SINE retrotransposons, which depend on LINE-1 for their genomic insertion (Gubser et al., 2007; Piskurek and Okada, 2007).

Large cytoplasmic DNA viruses have long been suspected to capture host genes through a reverse-transcription route, yet comparative genomics approaches had been unable to convincingly identifying the mechanism at play. And indeed, the signatures of LINE-1-mediated insertion quickly decay during evolution, making them difficult to identify by genome comparison. Instead, ingeniously designed evolutionary experiments came to the rescue. As these methods get refined, we can expect to uncover similar evolutionary mechanisms in other viruses, and even perhaps alternative strategies for capturing host genes. Beyond the implications for poxvirus evolution, the experiments of Rahman et al. and Fixsen et al. demonstrate that LINE-1 elements can be active not only in the nucleus, but also in the cytoplasm of mammalian cells. The consequences of such activity remain to be investigated.

**Eugene V Koonin** is in the National Center for Biotechnology Information, National Library of Medicine, Bethesda, United States
koonin@ncbi.nlm.nih.gov

http://orcid.org/0000-0003-3943-8299

**Mart Krupovic** is at the Institut Pasteur, Université Paris Cité, CNRS UMR6047, Archaeal Virology Unit, Paris, France

**Competing interests:** The authors declare that no competing interests exist.

**Published** 25 October 2022

**References**

Caprari S, Metzler S, Lengauer T, Kalinina OV. 2015. Sequence and structure analysis of distantly-related

viruses reveals extensive gene transfer between viruses and hosts and among viruses. *Viruses* **7**:5388–5409. DOI: https://doi.org/10.3390/v7102882, PMID: 26492264

Elde NC, Malik HS. 2009. The evolutionary conundrum of pathogen mimicry. *Nature Reviews Microbiology* **7**:787–797. DOI: https://doi.org/10.1038/nrmicro2222, PMID: 19806153

Fixsen SM, Cone KR, Goldstein SA, Sasani TA, Quinlan AR, Rothenburg S, Elde NC. 2022. Poxviruses capture host genes by LINE-1 retrotransposition. *eLife* **11**:e63332. DOI: https://doi.org/10.7554/eLife.63332, PMID: 36069526

Gubser C, Bergamaschi D, Hollinshead M, Lu X, van Kuppeveld FJM, Smith GL. 2007. A new inhibitor of apoptosis from vaccinia virus and eukaryotes. *PLOS Pathogens* **3**:e17. DOI: https://doi.org/10.1371/journal.ppat.0030017, PMID: 17319741

Koonin EV, Dolja VV, Krupovic M. 2022. The logic of virus evolution. *Cell Host & Microbe* **30**:917–929. DOI: https://doi.org/10.1016/j.chom.2022.06.008, PMID: 35834963

Lefkowitz EJ, Wang C, Upton C. 2006. Poxviruses: past, present and future. *Virus Research* **117**:105–118. DOI: https://doi.org/10.1016/j.virusres.2006.01.016, PMID: 16503070

Moss D, Smith GL. 2021. Poxviridae: The viruses and their replication in fields virology. LWW.

Piskurek O, Okada N. 2007. Poxviruses as possible vectors for horizontal transfer of retroposons from reptiles to mammals. *PNAS* **104**:12046–12051. DOI: https://doi.org/10.1073/pnas.0700531104, PMID: 17623783

Rahman MJ, Haller SL, Stoian AMM, Li J, Brennan G, Rothenburg S. 2022. LINE-1 retrotransposons facilitate horizontal gene transfer into poxviruses. *eLife* **11**:e63327. DOI: https://doi.org/10.7554/eLife.63327, PMID: 36069678

Senkevich TG, Yutin N, Wolf YI, Koonin EV, Moss B. 2021. Ancient gene capture and recent gene loss shape the evolution of orthopoxvirus-host interaction genes. *mBio* **12**:e0149521. DOI: https://doi.org/10.1128/mBio.01495-21, PMID: 34253028