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ORF-Interrupting Mutations in Monkeypox Virus Genomes from Washington and Ohio, 2022

Monkeypox virus, the causative agent of the 2022 monkeypox outbreak, is a double-stranded DNA virus in the Orthopoxvirus genus of the Poxviridae family. Genes in terminal regions of Orthopoxvirus genomes mostly code for host-pathogen interaction proteins and are prone to selective pressure and modif...

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Autores principales: Sereewit, Jaydee, Lieberman, Nicole A. P., Xie, Hong, Bakhash, Shah A. K. Mohamed, Nunley, B. Ethan, Chung, Benjamin, Mills, Margaret G., Roychoudhury, Pavitra, Greninger, Alexander L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9695478/
https://www.ncbi.nlm.nih.gov/pubmed/36366490
http://dx.doi.org/10.3390/v14112393
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author Sereewit, Jaydee
Lieberman, Nicole A. P.
Xie, Hong
Bakhash, Shah A. K. Mohamed
Nunley, B. Ethan
Chung, Benjamin
Mills, Margaret G.
Roychoudhury, Pavitra
Greninger, Alexander L.
author_facet Sereewit, Jaydee
Lieberman, Nicole A. P.
Xie, Hong
Bakhash, Shah A. K. Mohamed
Nunley, B. Ethan
Chung, Benjamin
Mills, Margaret G.
Roychoudhury, Pavitra
Greninger, Alexander L.
author_sort Sereewit, Jaydee
collection PubMed
description Monkeypox virus, the causative agent of the 2022 monkeypox outbreak, is a double-stranded DNA virus in the Orthopoxvirus genus of the Poxviridae family. Genes in terminal regions of Orthopoxvirus genomes mostly code for host-pathogen interaction proteins and are prone to selective pressure and modification events. Using viral whole genome sequencing, we identified twenty-five total clinical samples with ORF-disrupting mutations, including twenty samples encoding nonsense mutations in MPXVgp001/191 (OPG001), MPXVgp004/188 (OPG015), MPXVgp010 (OPG023), MPXVgp030 (OPG042), MPXVgp159 (OPG0178), or MPXVgp161 (OPG181). Additional mutations include a frameshift leading to an alternative C-terminus in MPXVgp010 (OPG023) and an insertion in an adenine homopolymer at the beginning of the annotated ORF for MPXVgp153 (OPG151), encoding a subunit of the RNA polymerase, suggesting the virus may instead use the start codon that encodes Met9 as annotated. Finally, we detected three samples with large (>900 bp) deletions. These included a 913 bp deletion that truncates the C-terminus of MPXVgp010 (OPG023); a 4205 bp deletion that eliminates MPXVgp012 (OPG025), MPXVgp013 (OPG027), and MPXVgp014 (OPG029) and truncates MPXVgp011 (OPG024; D8L) and MPXVgp015 (OPG030); and a 6881 bp deletion that truncates MPXVgp182 (OPG210) and eliminates putative ORFs MPXVgp184, MPXVgp185 (OPG005), and MPXVgp186, as well as MPXVgp187 (OPG016), and MPXVgp188 (OPG015) from the 3’ ITR only. MPXVgp182 encodes the monkeypox-specific, highly immunogenic surface glycoprotein B21R which has been proposed as a serological target. Overall, we find greater than one-tenth of our sequenced MPXV isolates have at least one gene inactivating mutation and these genes together comprised greater than one-tenth of annotated MPXV genes. Our findings highlight non-essential genes in monkeypox virus that may be evolving as a result of selective pressure in humans, as well as the limitations of targeting them for therapeutics and diagnostic testing.
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spelling pubmed-96954782022-11-26 ORF-Interrupting Mutations in Monkeypox Virus Genomes from Washington and Ohio, 2022 Sereewit, Jaydee Lieberman, Nicole A. P. Xie, Hong Bakhash, Shah A. K. Mohamed Nunley, B. Ethan Chung, Benjamin Mills, Margaret G. Roychoudhury, Pavitra Greninger, Alexander L. Viruses Article Monkeypox virus, the causative agent of the 2022 monkeypox outbreak, is a double-stranded DNA virus in the Orthopoxvirus genus of the Poxviridae family. Genes in terminal regions of Orthopoxvirus genomes mostly code for host-pathogen interaction proteins and are prone to selective pressure and modification events. Using viral whole genome sequencing, we identified twenty-five total clinical samples with ORF-disrupting mutations, including twenty samples encoding nonsense mutations in MPXVgp001/191 (OPG001), MPXVgp004/188 (OPG015), MPXVgp010 (OPG023), MPXVgp030 (OPG042), MPXVgp159 (OPG0178), or MPXVgp161 (OPG181). Additional mutations include a frameshift leading to an alternative C-terminus in MPXVgp010 (OPG023) and an insertion in an adenine homopolymer at the beginning of the annotated ORF for MPXVgp153 (OPG151), encoding a subunit of the RNA polymerase, suggesting the virus may instead use the start codon that encodes Met9 as annotated. Finally, we detected three samples with large (>900 bp) deletions. These included a 913 bp deletion that truncates the C-terminus of MPXVgp010 (OPG023); a 4205 bp deletion that eliminates MPXVgp012 (OPG025), MPXVgp013 (OPG027), and MPXVgp014 (OPG029) and truncates MPXVgp011 (OPG024; D8L) and MPXVgp015 (OPG030); and a 6881 bp deletion that truncates MPXVgp182 (OPG210) and eliminates putative ORFs MPXVgp184, MPXVgp185 (OPG005), and MPXVgp186, as well as MPXVgp187 (OPG016), and MPXVgp188 (OPG015) from the 3’ ITR only. MPXVgp182 encodes the monkeypox-specific, highly immunogenic surface glycoprotein B21R which has been proposed as a serological target. Overall, we find greater than one-tenth of our sequenced MPXV isolates have at least one gene inactivating mutation and these genes together comprised greater than one-tenth of annotated MPXV genes. Our findings highlight non-essential genes in monkeypox virus that may be evolving as a result of selective pressure in humans, as well as the limitations of targeting them for therapeutics and diagnostic testing. MDPI 2022-10-29 /pmc/articles/PMC9695478/ /pubmed/36366490 http://dx.doi.org/10.3390/v14112393 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Sereewit, Jaydee
Lieberman, Nicole A. P.
Xie, Hong
Bakhash, Shah A. K. Mohamed
Nunley, B. Ethan
Chung, Benjamin
Mills, Margaret G.
Roychoudhury, Pavitra
Greninger, Alexander L.
ORF-Interrupting Mutations in Monkeypox Virus Genomes from Washington and Ohio, 2022
title ORF-Interrupting Mutations in Monkeypox Virus Genomes from Washington and Ohio, 2022
title_full ORF-Interrupting Mutations in Monkeypox Virus Genomes from Washington and Ohio, 2022
title_fullStr ORF-Interrupting Mutations in Monkeypox Virus Genomes from Washington and Ohio, 2022
title_full_unstemmed ORF-Interrupting Mutations in Monkeypox Virus Genomes from Washington and Ohio, 2022
title_short ORF-Interrupting Mutations in Monkeypox Virus Genomes from Washington and Ohio, 2022
title_sort orf-interrupting mutations in monkeypox virus genomes from washington and ohio, 2022
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9695478/
https://www.ncbi.nlm.nih.gov/pubmed/36366490
http://dx.doi.org/10.3390/v14112393
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