Mutation rate variability in viral populations: Implications for lethal mutagenesis.
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| Title: | Mutation rate variability in viral populations: Implications for lethal mutagenesis. |
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| Authors: | Arcos, Sarah1 sarcos@med.umich.edu, Lauring, Adam S.1,2 alauring@med.umich.edu |
| Source: | Proceedings of the National Academy of Sciences of the United States of America. 1/13/2026, Vol. 123 Issue 2, p1-7. 10p. |
| Subjects: | Mutagenesis, RNA viruses, Biological extinction, Poisson distribution, Viral ecology, Drug resistance, Viral mutation, Antiviral agents |
| Abstract: | Lethal mutagenesis is a strategy to achieve viral extinction by drugging viral mutation rates beyond an extinction threshold. Accurate estimation of the extinction threshold is critical, as elevating viral mutation rates near, but not past this threshold increases the likelihood of mutations that could result in drug resistance, vaccine escape, or increased pathogenesis. Traditional models of lethal mutagenesis rely on the Poisson distribution, which assumes a uniform mutation rate across individuals. Yet, RNA viruses like influenza A virus (IAV) can have varied mutation rates due to mutations in the polymerase complex. This variability suggests that lethal mutagenesis models incorporating mutation rate diversity, such as ones using the gamma-Poisson distribution, may be more accurate for RNA viruses. Poisson models assume count data have equal mean and variance, while gamma-Poisson counts are overdispersed (variance greater than mean). Here, we provide experimental data showing that IAV mutations are overdispersed, indicating that the gamma-Poisson distribution is more appropriate for modeling IAV mutations. Modeling of lethal mutagenesis using the gamma-Poisson distribution reveals that the degree of overdispersion is critical in determining survival or extinction. Increased overdispersion shifts the extinction threshold higher, indicating that Poisson-based models have underestimated the mutation rate required to achieve viral extinction and avoid viral escape or accelerated evolution. Furthermore, time to extinction in simulated populations is significantly longer with gamma-Poisson-based models than Poisson-based. This investigation of how mutation rate variability affects lethal mutagenesis will directly impact antiviral drug design and strategy, thus advancing efforts to combat virus outbreaks and future pandemics. [ABSTRACT FROM AUTHOR] |
| Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) | |
| Database: | Engineering Source |
| FullText | Text: Availability: 0 |
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| Header | DbId: egs DbLabel: Engineering Source An: 190848383 AccessLevel: 6 PubType: Academic Journal PubTypeId: academicJournal PreciseRelevancyScore: 0 |
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| Items | – Name: Title Label: Title Group: Ti Data: Mutation rate variability in viral populations: Implications for lethal mutagenesis. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Arcos%2C+Sarah%22">Arcos, Sarah</searchLink><relatesTo>1</relatesTo><i> sarcos@med.umich.edu</i><br /><searchLink fieldCode="AR" term="%22Lauring%2C+Adam+S%2E%22">Lauring, Adam S.</searchLink><relatesTo>1,2</relatesTo><i> alauring@med.umich.edu</i> – Name: TitleSource Label: Source Group: Src Data: <searchLink fieldCode="JN" term="%22Proceedings+of+the+National+Academy+of+Sciences+of+the+United+States+of+America%22">Proceedings of the National Academy of Sciences of the United States of America</searchLink>. 1/13/2026, Vol. 123 Issue 2, p1-7. 10p. – Name: Subject Label: Subjects Group: Su Data: <searchLink fieldCode="DE" term="%22Mutagenesis%22">Mutagenesis</searchLink><br /><searchLink fieldCode="DE" term="%22RNA+viruses%22">RNA viruses</searchLink><br /><searchLink fieldCode="DE" term="%22Biological+extinction%22">Biological extinction</searchLink><br /><searchLink fieldCode="DE" term="%22Poisson+distribution%22">Poisson distribution</searchLink><br /><searchLink fieldCode="DE" term="%22Viral+ecology%22">Viral ecology</searchLink><br /><searchLink fieldCode="DE" term="%22Drug+resistance%22">Drug resistance</searchLink><br /><searchLink fieldCode="DE" term="%22Viral+mutation%22">Viral mutation</searchLink><br /><searchLink fieldCode="DE" term="%22Antiviral+agents%22">Antiviral agents</searchLink> – Name: Abstract Label: Abstract Group: Ab Data: Lethal mutagenesis is a strategy to achieve viral extinction by drugging viral mutation rates beyond an extinction threshold. Accurate estimation of the extinction threshold is critical, as elevating viral mutation rates near, but not past this threshold increases the likelihood of mutations that could result in drug resistance, vaccine escape, or increased pathogenesis. Traditional models of lethal mutagenesis rely on the Poisson distribution, which assumes a uniform mutation rate across individuals. Yet, RNA viruses like influenza A virus (IAV) can have varied mutation rates due to mutations in the polymerase complex. This variability suggests that lethal mutagenesis models incorporating mutation rate diversity, such as ones using the gamma-Poisson distribution, may be more accurate for RNA viruses. Poisson models assume count data have equal mean and variance, while gamma-Poisson counts are overdispersed (variance greater than mean). Here, we provide experimental data showing that IAV mutations are overdispersed, indicating that the gamma-Poisson distribution is more appropriate for modeling IAV mutations. Modeling of lethal mutagenesis using the gamma-Poisson distribution reveals that the degree of overdispersion is critical in determining survival or extinction. Increased overdispersion shifts the extinction threshold higher, indicating that Poisson-based models have underestimated the mutation rate required to achieve viral extinction and avoid viral escape or accelerated evolution. Furthermore, time to extinction in simulated populations is significantly longer with gamma-Poisson-based models than Poisson-based. This investigation of how mutation rate variability affects lethal mutagenesis will directly impact antiviral drug design and strategy, thus advancing efforts to combat virus outbreaks and future pandemics. [ABSTRACT FROM AUTHOR] – Name: AbstractSuppliedCopyright Label: Group: Ab Data: <i>Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.) |
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| RecordInfo | BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.1073/pnas.2523734123 Languages: – Code: eng Text: English PhysicalDescription: Pagination: PageCount: 10 StartPage: 1 Subjects: – SubjectFull: Mutagenesis Type: general – SubjectFull: RNA viruses Type: general – SubjectFull: Biological extinction Type: general – SubjectFull: Poisson distribution Type: general – SubjectFull: Viral ecology Type: general – SubjectFull: Drug resistance Type: general – SubjectFull: Viral mutation Type: general – SubjectFull: Antiviral agents Type: general Titles: – TitleFull: Mutation rate variability in viral populations: Implications for lethal mutagenesis. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Arcos, Sarah – PersonEntity: Name: NameFull: Lauring, Adam S. IsPartOfRelationships: – BibEntity: Dates: – D: 13 M: 01 Text: 1/13/2026 Type: published Y: 2026 Identifiers: – Type: issn-print Value: 00278424 Numbering: – Type: volume Value: 123 – Type: issue Value: 2 Titles: – TitleFull: Proceedings of the National Academy of Sciences of the United States of America Type: main |
| ResultId | 1 |
