Poxviruses capture host genes by LINE-1 retrotransposition
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.
Article and author information
Author details
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.
Reviewing Editor
- Karla Kirkegaard, Stanford University School of Medicine, United States
Version history
- Received: September 22, 2020
- Preprint posted: October 27, 2020 (view preprint)
- Accepted: September 6, 2022
- Accepted Manuscript published: September 7, 2022 (version 1)
- Version of Record published: October 18, 2022 (version 2)
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.
Metrics
-
- 1,401
- Page views
-
- 369
- Downloads
-
- 7
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Evolutionary Biology
- Microbiology and Infectious Disease
As long suspected, poxviruses capture host genes through a reverse-transcription process now shown to be mediated by retrotransposons.
-
- Evolutionary Biology
- Microbiology and Infectious Disease
Drug resistance remains a major obstacle to malaria control and eradication efforts, necessitating the development of novel therapeutic strategies to treat this disease. Drug combinations based on collateral sensitivity, wherein resistance to one drug causes increased sensitivity to the partner drug, have been proposed as an evolutionary strategy to suppress the emergence of resistance in pathogen populations. In this study, we explore collateral sensitivity between compounds targeting the Plasmodium dihydroorotate dehydrogenase (DHODH). We profiled the cross-resistance and collateral sensitivity phenotypes of several DHODH mutant lines to a diverse panel of DHODH inhibitors. We focus on one compound, TCMDC-125334, which was active against all mutant lines tested, including the DHODH C276Y line, which arose in selections with the clinical candidate DSM265. In six selections with TCMDC-125334, the most common mechanism of resistance to this compound was copy number variation of the dhodh locus, although we did identify one mutation, DHODH I263S, which conferred resistance to TCMDC-125334 but not DSM265. We found that selection of the DHODH C276Y mutant with TCMDC-125334 yielded additional genetic changes in the dhodh locus. These double mutant parasites exhibited decreased sensitivity to TCMDC-125334 and were highly resistant to DSM265. Finally, we tested whether collateral sensitivity could be exploited to suppress the emergence of resistance in the context of combination treatment by exposing wildtype parasites to both DSM265 and TCMDC-125334 simultaneously. This selected for parasites with a DHODH V532A mutation which were cross-resistant to both compounds and were as fit as the wildtype parent in vitro. The emergence of these cross-resistant, evolutionarily fit parasites highlights the mutational flexibility of the DHODH enzyme.