1. Evolutionary Biology
  2. Microbiology and Infectious Disease

Poxviruses capture host genes by LINE-1 retrotransposition

  1. Sarah M Fixsen
  2. Kelsey R Cone
  3. Stephen A Goldstein
  4. Thomas A Sasani
  5. Aaron R Quinlan
  6. Stefan Rothenburg
  7. Nels C Elde  Is a corresponding author
  1. University of Utah, United States
  2. University of California, Davis, United States
https://doi.org/10.7554/eLife.63332
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  1. Sarah M Fixsen
  2. Kelsey R Cone
  3. Stephen A Goldstein
  4. Thomas A Sasani
  5. Aaron R Quinlan
  6. Stefan Rothenburg
  7. Nels C Elde
(2022)
Poxviruses capture host genes by LINE-1 retrotransposition
eLife 11:e63332.
https://doi.org/10.7554/eLife.63332
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Abstract

Horizontal gene transfer (HGT) provides a major source of genetic variation. Many viruses, including poxviruses, encode genes with crucial functions directly gained by gene transfer from hosts. The mechanism of transfer to poxvirus genomes is unknown. Using genome analysis and experimental screens of infected cells, we discovered a central role for Long Interspersed Nuclear Element-1 (LINE-1) retrotransposition in HGT to virus genomes. The process recapitulates processed pseudogene generation, but with host messenger RNA directed into virus genomes. Intriguingly, hallmark features of retrotransposition appear to favor virus adaption through rapid duplication of captured host genes on arrival. Our study reveals a previously unrecognized conduit of genetic traffic with fundamental implications for the evolution of many virus classes and their hosts.

Data availability

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 supplemental files.

The following data sets were generated

Article and author information

Author details

  1. Sarah M Fixsen

    Department of Human Genetics, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.

  2. Kelsey R Cone

    Department of Human Genetics, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
    ORCID icon "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
    Competing interests
    No competing interests declared.

  4. Thomas A Sasani

    Department of Human Genetics, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
    ORCID icon "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
    Competing interests
    No competing interests declared.

  6. Stefan Rothenburg

    Department of Medical Microbiology and Immunology, University of California, Davis, Davis, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2525-8230

  7. Nels C Elde

    Department of Human Genetics, University of Utah, Salt Lake City, United States
    For correspondence
    nelde@genetics.utah.edu
    Competing interests
    Nels C Elde, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0426-1377

Funding

National Institutes of Health (R35GM134936)

  • Nels C Elde

National Institutes of Health (T32GM007464)

  • Sarah M Fixsen
  • Thomas A Sasani

National Institutes of Health (T32AI055434)

  • Kelsey R Cone

Burroughs Wellcome Fund (1015462)

  • Nels C Elde

University of Utah (HA and Edna Benning Presidential Endowed Chair)

  • Nels C Elde

National Institutes of Health (R01AI146915)

  • Stefan Rothenburg

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2022, Fixsen et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Sarah M Fixsen
  2. Kelsey R Cone
  3. Stephen A Goldstein
  4. Thomas A Sasani
  5. Aaron R Quinlan
  6. Stefan Rothenburg
  7. Nels C Elde
(2022)
Poxviruses capture host genes by LINE-1 retrotransposition
eLife 11:e63332.
https://doi.org/10.7554/eLife.63332

Share this article

https://doi.org/10.7554/eLife.63332

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Further reading

    1. Microbiology and Infectious Disease

    LINE-1 retrotransposons facilitate horizontal gene transfer into poxviruses

    M Julhasur Rahman, Sherry L Haller ... Stefan Rothenburg
    Research Article Updated

    There is ample phylogenetic evidence that many critical virus functions, like immune evasion, evolved by the acquisition of genes from their hosts through horizontal gene transfer (HGT). However, the lack of an experimental system has prevented a mechanistic understanding of this process. We developed a model to elucidate the mechanisms of HGT into vaccinia virus, the prototypic poxvirus. All identified gene capture events showed signatures of long interspersed nuclear element-1 (LINE-1)-mediated retrotransposition, including spliced-out introns, polyadenylated tails, and target site duplications. In one case, the acquired gene integrated together with a polyadenylated host U2 small nuclear RNA. Integrations occurred across the genome, in some cases knocking out essential viral genes. These essential gene knockouts were rescued through a process of complementation by the parent virus followed by nonhomologous recombination during serial passaging to generate a single, replication-competent virus. This work links multiple evolutionary mechanisms into one adaptive cascade and identifies host retrotransposons as major drivers for virus evolution.

    1. Evolutionary Biology
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    Evolution: A life LINE for large viruses

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

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    The domesticated transposon protein L1TD1 associates with its ancestor L1 ORF1p to promote LINE-1 retrotransposition

    Gülnihal Kavaklioglu, Alexandra Podhornik ... Christian Seiser
    Research Article

    Repression of retrotransposition is crucial for the successful fitness of a mammalian organism. The domesticated transposon protein L1TD1, derived from LINE-1 (L1) ORF1p, is an RNA-binding protein that is expressed only in some cancers and early embryogenesis. In human embryonic stem cells, it is found to be essential for maintaining pluripotency. In cancer, L1TD1 expression is highly correlative with malignancy progression and as such considered a potential prognostic factor for tumors. However, its molecular role in cancer remains largely unknown. Our findings reveal that DNA hypomethylation induces the expression of L1TD1 in HAP1 human tumor cells. L1TD1 depletion significantly modulates both the proteome and transcriptome and thereby reduces cell viability. Notably, L1TD1 associates with L1 transcripts and interacts with L1 ORF1p protein, thereby facilitating L1 retrotransposition. Our data suggest that L1TD1 collaborates with its ancestral L1 ORF1p as an RNA chaperone, ensuring the efficient retrotransposition of L1 retrotransposons, rather than directly impacting the abundance of L1TD1 targets. In this way, L1TD1 might have an important role not only during early development but also in tumorigenesis.