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Fast-forwarding evolution—Accelerated adaptation in a proofreading-deficient hypermutator herpesvirus

Evolution relies on the availability of genetic diversity for fitness-based selection. However, most deoxyribonucleic acid (DNA) viruses employ DNA polymerases (Pol) capable of exonucleolytic proofreading to limit mutation rates during DNA replication. The relative genetic stability produced by high...

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Autores principales: Xing, Na, Höfler, Thomas, Hearn, Cari J, Nascimento, Mariana, Camps Paradell, Georgina, McMahon, Dino P, Kunec, Dusan, Osterrieder, Nikolaus, Cheng, Hans H, Trimpert, Jakob
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9671156/
https://www.ncbi.nlm.nih.gov/pubmed/36405341
http://dx.doi.org/10.1093/ve/veac099
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author Xing, Na
Höfler, Thomas
Hearn, Cari J
Nascimento, Mariana
Camps Paradell, Georgina
McMahon, Dino P
Kunec, Dusan
Osterrieder, Nikolaus
Cheng, Hans H
Trimpert, Jakob
author_facet Xing, Na
Höfler, Thomas
Hearn, Cari J
Nascimento, Mariana
Camps Paradell, Georgina
McMahon, Dino P
Kunec, Dusan
Osterrieder, Nikolaus
Cheng, Hans H
Trimpert, Jakob
author_sort Xing, Na
collection PubMed
description Evolution relies on the availability of genetic diversity for fitness-based selection. However, most deoxyribonucleic acid (DNA) viruses employ DNA polymerases (Pol) capable of exonucleolytic proofreading to limit mutation rates during DNA replication. The relative genetic stability produced by high-fidelity genome replication can make studying DNA virus adaptation and evolution an intensive endeavor, especially in slowly replicating viruses. Here, we present a proofreading-impaired Pol mutant (Y547S) of Marek’s disease virus that exhibits a hypermutator phenotype while maintaining unimpaired growth in vitro and wild-type (WT)-like pathogenicity in vivo. At the same time, mutation frequencies observed in Y547S virus populations are 2–5-fold higher compared to the parental WT virus. We find that Y547S adapts faster to growth in originally non-permissive cells, evades pressure conferred by antiviral inhibitors more efficiently, and is more easily attenuated by serial passage in cultured cells compared to WT. Our results suggest that hypermutator viruses can serve as a tool to accelerate evolutionary processes and help identify key genetic changes required for adaptation to novel host cells and resistance to antiviral therapy. Similarly, the rapid attenuation achieved through adaptation of hypermutators to growth in cell culture enables identification of genetic changes underlying attenuation and virulence, knowledge that could practically exploited, e.g. in the rational design of vaccines.
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spelling pubmed-96711562022-11-18 Fast-forwarding evolution—Accelerated adaptation in a proofreading-deficient hypermutator herpesvirus Xing, Na Höfler, Thomas Hearn, Cari J Nascimento, Mariana Camps Paradell, Georgina McMahon, Dino P Kunec, Dusan Osterrieder, Nikolaus Cheng, Hans H Trimpert, Jakob Virus Evol Research Article Evolution relies on the availability of genetic diversity for fitness-based selection. However, most deoxyribonucleic acid (DNA) viruses employ DNA polymerases (Pol) capable of exonucleolytic proofreading to limit mutation rates during DNA replication. The relative genetic stability produced by high-fidelity genome replication can make studying DNA virus adaptation and evolution an intensive endeavor, especially in slowly replicating viruses. Here, we present a proofreading-impaired Pol mutant (Y547S) of Marek’s disease virus that exhibits a hypermutator phenotype while maintaining unimpaired growth in vitro and wild-type (WT)-like pathogenicity in vivo. At the same time, mutation frequencies observed in Y547S virus populations are 2–5-fold higher compared to the parental WT virus. We find that Y547S adapts faster to growth in originally non-permissive cells, evades pressure conferred by antiviral inhibitors more efficiently, and is more easily attenuated by serial passage in cultured cells compared to WT. Our results suggest that hypermutator viruses can serve as a tool to accelerate evolutionary processes and help identify key genetic changes required for adaptation to novel host cells and resistance to antiviral therapy. Similarly, the rapid attenuation achieved through adaptation of hypermutators to growth in cell culture enables identification of genetic changes underlying attenuation and virulence, knowledge that could practically exploited, e.g. in the rational design of vaccines. Oxford University Press 2022-10-14 /pmc/articles/PMC9671156/ /pubmed/36405341 http://dx.doi.org/10.1093/ve/veac099 Text en © The Author(s) 2022. Published by Oxford University Press. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Research Article
Xing, Na
Höfler, Thomas
Hearn, Cari J
Nascimento, Mariana
Camps Paradell, Georgina
McMahon, Dino P
Kunec, Dusan
Osterrieder, Nikolaus
Cheng, Hans H
Trimpert, Jakob
Fast-forwarding evolution—Accelerated adaptation in a proofreading-deficient hypermutator herpesvirus
title Fast-forwarding evolution—Accelerated adaptation in a proofreading-deficient hypermutator herpesvirus
title_full Fast-forwarding evolution—Accelerated adaptation in a proofreading-deficient hypermutator herpesvirus
title_fullStr Fast-forwarding evolution—Accelerated adaptation in a proofreading-deficient hypermutator herpesvirus
title_full_unstemmed Fast-forwarding evolution—Accelerated adaptation in a proofreading-deficient hypermutator herpesvirus
title_short Fast-forwarding evolution—Accelerated adaptation in a proofreading-deficient hypermutator herpesvirus
title_sort fast-forwarding evolution—accelerated adaptation in a proofreading-deficient hypermutator herpesvirus
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9671156/
https://www.ncbi.nlm.nih.gov/pubmed/36405341
http://dx.doi.org/10.1093/ve/veac099
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