Rare haplotype load as marker for lethal mutagenesis.
RNA viruses replicate with a template-copying fidelity, which lies close to an extinction threshold. Increases of mutation rate by nucleotide analogues can drive viruses towards extinction. This transition is the basis of an antiviral strategy termed lethal mutagenesis. We have introduced a new dive...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2018-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC6169937?pdf=render |
| _version_ | 1818107644773138432 |
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| author | Josep Gregori María Eugenia Soria Isabel Gallego Mercedes Guerrero-Murillo Juan Ignacio Esteban Josep Quer Celia Perales Esteban Domingo |
| author_facet | Josep Gregori María Eugenia Soria Isabel Gallego Mercedes Guerrero-Murillo Juan Ignacio Esteban Josep Quer Celia Perales Esteban Domingo |
| author_sort | Josep Gregori |
| collection | DOAJ |
| description | RNA viruses replicate with a template-copying fidelity, which lies close to an extinction threshold. Increases of mutation rate by nucleotide analogues can drive viruses towards extinction. This transition is the basis of an antiviral strategy termed lethal mutagenesis. We have introduced a new diversity index, the rare haplotype load (RHL), to describe NS5B (polymerase) mutant spectra of hepatitis C virus (HCV) populations passaged in absence or presence of the mutagenic agents favipiravir or ribavirin. The increase in RHL is more prominent in mutant spectra whose expansions were due to nucleotide analogues than to multiple passages in absence of mutagens. Statistical tests for paired mutagenized versus non-mutagenized samples with 14 diversity indices show that RHL provides consistently the highest standardized effect of mutagenic treatment difference for ribavirin and favipiravir. The results indicate that the enrichment of viral quasispecies in very low frequency minority genomes can serve as a robust marker for lethal mutagenesis. The diagnostic value of RHL from deep sequencing data is relevant to experimental studies on enhanced mutagenesis of viruses, and to pharmacological evaluations of inhibitors suspected to have a mutagenic activity. |
| first_indexed | 2024-12-11T02:02:45Z |
| format | Article |
| id | doaj.art-3dc563c663c840a38a05813182a0b0b7 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-11T02:02:45Z |
| publishDate | 2018-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-3dc563c663c840a38a05813182a0b0b72022-12-22T01:24:27ZengPublic Library of Science (PLoS)PLoS ONE1932-62032018-01-011310e020487710.1371/journal.pone.0204877Rare haplotype load as marker for lethal mutagenesis.Josep GregoriMaría Eugenia SoriaIsabel GallegoMercedes Guerrero-MurilloJuan Ignacio EstebanJosep QuerCelia PeralesEsteban DomingoRNA viruses replicate with a template-copying fidelity, which lies close to an extinction threshold. Increases of mutation rate by nucleotide analogues can drive viruses towards extinction. This transition is the basis of an antiviral strategy termed lethal mutagenesis. We have introduced a new diversity index, the rare haplotype load (RHL), to describe NS5B (polymerase) mutant spectra of hepatitis C virus (HCV) populations passaged in absence or presence of the mutagenic agents favipiravir or ribavirin. The increase in RHL is more prominent in mutant spectra whose expansions were due to nucleotide analogues than to multiple passages in absence of mutagens. Statistical tests for paired mutagenized versus non-mutagenized samples with 14 diversity indices show that RHL provides consistently the highest standardized effect of mutagenic treatment difference for ribavirin and favipiravir. The results indicate that the enrichment of viral quasispecies in very low frequency minority genomes can serve as a robust marker for lethal mutagenesis. The diagnostic value of RHL from deep sequencing data is relevant to experimental studies on enhanced mutagenesis of viruses, and to pharmacological evaluations of inhibitors suspected to have a mutagenic activity.http://europepmc.org/articles/PMC6169937?pdf=render |
| spellingShingle | Josep Gregori María Eugenia Soria Isabel Gallego Mercedes Guerrero-Murillo Juan Ignacio Esteban Josep Quer Celia Perales Esteban Domingo Rare haplotype load as marker for lethal mutagenesis. PLoS ONE |
| title | Rare haplotype load as marker for lethal mutagenesis. |
| title_full | Rare haplotype load as marker for lethal mutagenesis. |
| title_fullStr | Rare haplotype load as marker for lethal mutagenesis. |
| title_full_unstemmed | Rare haplotype load as marker for lethal mutagenesis. |
| title_short | Rare haplotype load as marker for lethal mutagenesis. |
| title_sort | rare haplotype load as marker for lethal mutagenesis |
| url | http://europepmc.org/articles/PMC6169937?pdf=render |
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