Evolutionary potential of the monkeypox genome arising from interactions with human APOBEC3 enzymes

APOBEC3, an enzyme subfamily that plays a role in virus restriction by generating mutations at particular DNA motifs or mutational ‘hotspots’, can drive viral mutagenesis with host-specific preferential hotspot mutations contributing to pathogen variation. While previous analysis of viral genomes fr...

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Autores principales: Delamonica, Brenda, Davalos, Liliana, Larijani, Mani, Anthony, Simon J, Liu, Jia, MacCarthy, Thomas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10422979/
https://www.ncbi.nlm.nih.gov/pubmed/37577211
http://dx.doi.org/10.1093/ve/vead047
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author Delamonica, Brenda
Davalos, Liliana
Larijani, Mani
Anthony, Simon J
Liu, Jia
MacCarthy, Thomas
author_facet Delamonica, Brenda
Davalos, Liliana
Larijani, Mani
Anthony, Simon J
Liu, Jia
MacCarthy, Thomas
author_sort Delamonica, Brenda
collection PubMed
description APOBEC3, an enzyme subfamily that plays a role in virus restriction by generating mutations at particular DNA motifs or mutational ‘hotspots’, can drive viral mutagenesis with host-specific preferential hotspot mutations contributing to pathogen variation. While previous analysis of viral genomes from the 2022 Mpox (formerly Monkeypox) disease outbreak has shown a high frequency of C>T mutations at TC motifs, suggesting recent mutations are human APOBEC3-mediated, how emerging monkeypox virus (MPXV) strains will evolve as a consequence of APOBEC3-mediated mutations remains unknown. By measuring hotspot under-representation, depletion at synonymous sites, and a combination of the two, we analyzed APOBEC3-driven evolution in human poxvirus genomes, finding varying hotspot under-representation patterns. While the native poxvirus molluscum contagiosum exhibits a signature consistent with extensive coevolution with human APOBEC3, including depletion of TC hotspots, variola virus shows an intermediate effect consistent with ongoing evolution at the time of eradication. MPXV, likely the result of recent zoonosis, showed many genes with more TC hotspots than expected by chance (over-representation) and fewer GC hotspots than expected (under-representation). These results suggest the MPXV genome: (1) may have evolved in a host with a particular APOBEC GC hotspot preference, (2) has inverted terminal repeat (ITR) regions—which may be exposed to APOBEC3 for longer during viral replication—and longer genes likely to evolve faster, and therefore (3) has a heightened potential for future human APOBEC3-meditated evolution as the virus spreads in the human population. Our predictions of MPXV mutational potential can both help guide future vaccine development and identification of putative drug targets and add urgency to the task of containing human Mpox disease transmission and uncovering the ecology of the virus in its reservoir host.
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spelling pubmed-104229792023-08-13 Evolutionary potential of the monkeypox genome arising from interactions with human APOBEC3 enzymes Delamonica, Brenda Davalos, Liliana Larijani, Mani Anthony, Simon J Liu, Jia MacCarthy, Thomas Virus Evol Research Article APOBEC3, an enzyme subfamily that plays a role in virus restriction by generating mutations at particular DNA motifs or mutational ‘hotspots’, can drive viral mutagenesis with host-specific preferential hotspot mutations contributing to pathogen variation. While previous analysis of viral genomes from the 2022 Mpox (formerly Monkeypox) disease outbreak has shown a high frequency of C>T mutations at TC motifs, suggesting recent mutations are human APOBEC3-mediated, how emerging monkeypox virus (MPXV) strains will evolve as a consequence of APOBEC3-mediated mutations remains unknown. By measuring hotspot under-representation, depletion at synonymous sites, and a combination of the two, we analyzed APOBEC3-driven evolution in human poxvirus genomes, finding varying hotspot under-representation patterns. While the native poxvirus molluscum contagiosum exhibits a signature consistent with extensive coevolution with human APOBEC3, including depletion of TC hotspots, variola virus shows an intermediate effect consistent with ongoing evolution at the time of eradication. MPXV, likely the result of recent zoonosis, showed many genes with more TC hotspots than expected by chance (over-representation) and fewer GC hotspots than expected (under-representation). These results suggest the MPXV genome: (1) may have evolved in a host with a particular APOBEC GC hotspot preference, (2) has inverted terminal repeat (ITR) regions—which may be exposed to APOBEC3 for longer during viral replication—and longer genes likely to evolve faster, and therefore (3) has a heightened potential for future human APOBEC3-meditated evolution as the virus spreads in the human population. Our predictions of MPXV mutational potential can both help guide future vaccine development and identification of putative drug targets and add urgency to the task of containing human Mpox disease transmission and uncovering the ecology of the virus in its reservoir host. Oxford University Press 2023-08-02 /pmc/articles/PMC10422979/ /pubmed/37577211 http://dx.doi.org/10.1093/ve/vead047 Text en © The Author(s) 2023. 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
Delamonica, Brenda
Davalos, Liliana
Larijani, Mani
Anthony, Simon J
Liu, Jia
MacCarthy, Thomas
Evolutionary potential of the monkeypox genome arising from interactions with human APOBEC3 enzymes
title Evolutionary potential of the monkeypox genome arising from interactions with human APOBEC3 enzymes
title_full Evolutionary potential of the monkeypox genome arising from interactions with human APOBEC3 enzymes
title_fullStr Evolutionary potential of the monkeypox genome arising from interactions with human APOBEC3 enzymes
title_full_unstemmed Evolutionary potential of the monkeypox genome arising from interactions with human APOBEC3 enzymes
title_short Evolutionary potential of the monkeypox genome arising from interactions with human APOBEC3 enzymes
title_sort evolutionary potential of the monkeypox genome arising from interactions with human apobec3 enzymes
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10422979/
https://www.ncbi.nlm.nih.gov/pubmed/37577211
http://dx.doi.org/10.1093/ve/vead047
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