Theory of lethal mutagenesis for viruses
Open accessAbstract
Mutation is the basis of adaptation. Yet, most mutations are detrimental, and elevating mutation rates will impair a population's fitness in the short term. The latter realization has led to the concept of lethal mutagenesis for curing viral infections, and work with drugs such as ribavirin has supported this perspective. As yet, there is no formal theory of lethal mutagenesis, although reference is commonly made to Eigen's error catastrophe theory. Here, we propose a theory of lethal mutagenesis. With an obvious parallel to the epidemiological threshold for eradication of a disease, a sufficient condition for lethal mutagenesis is that each viral genotype produces, on average, less than one progeny virus that goes on to infect a new cell. The extinction threshold involves an evolutionary component based on the mutation rate, but it also includes an ecological component, so the threshold cannot be calculated from the mutation rate alone. The genetic evolution of a large population undergoing mutagenesis is independent of whether the population is declining or stable, so there is no runaway accumulation of mutations or genetic signature for lethal mutagenesis that distinguishes it from a level of mutagenesis under which the population is maintained. To detect lethal mutagenesis, accurate measurements of the genome-wide mutation rate and the number of progeny per infected cell that go on to infect new cells are needed. We discuss three methods for estimating the former. Estimating the latter is more challenging, but broad limits to this estimate may be feasible.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The origin of their conclusion is the existence of nonzero degradation rate, initiated by the first equation in Eq. (60).
“The origin of their conclusion is the existence of nonzero degradation rate , initiated by the first equation in Eq.(60).”
From Lethal mutants and truncated selection together solve a paradox of the origin of life (2011) · cites this paper as [36]
Increasing the mutation rate to precipitate an error catastrophe appears to be a practical anti-retroviral strategy.
“Indeed, increasing the mutation rate to precipitate an error catastrophe appears to be a practical anti-retroviral strategy (14–16).”
From The prebiotic evolutionary advantage of transferring genetic information from RNA to DNA (2011) · cites this paper as [14]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Infectious Diseases of Humans: Dynamics and Control
(1992) · Annals of Internal Medicine · doi:10.7326/0003-4819-117-2-174_4 · Cited by 7,818 · see citing works
Mutations of bacteria from virus sensitivity to virus resistance
Luria, S. E., & Delbrück, M. (1943) · Genetics · doi:10.1093/genetics/28.6.491 · Cited by 3,894 · see citing works
Selforganization of matter and the evolution of biological macromolecules
Eigen, M. (1971) · Die Naturwissenschaften · doi:10.1007/bf00623322 · Cited by 3,788 · see citing works
The relation of recombination to mutational advance
Muller, H. J. (1964) · Mutation Research · doi:10.1016/0027-5107(64)90047-8 · Cited by 2,512 · see citing works
Genetics and Demography in Biological Conservation
Lande, R. (1988) · Science · doi:10.1126/science.3420403 · Cited by 2,460 · see citing works
The Theory of Branching Processes
Ney, P. E., & Harris, T. E. (1965) · Technometrics · doi:10.2307/1266137 · Cited by 2,460 · see citing works
The Masterpiece of Nature: The Evolution and Genetics of Sexuality
Bell, G. (1981) · Cited by 1,704 · see citing works
Mutation rates among RNA viruses
Drake, J. W., & Holland, J. J. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.24.13910 · Cited by 1,143 · see citing works
Evolution of high mutation rates in experimental populations of E. coli
Sniegowski, P. D., Gerrish, P. J., & Lenski, R. E. (1997) · Nature · doi:10.1038/42701 · Cited by 879 · see citing works
RNA virus error catastrophe: Direct molecular test by using ribavirin
Crotty, S., Cameron, C. E., & Andino, R. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.111085598 · Cited by 853 · see citing works
Rates of spontaneous mutation among RNA viruses.
Drake, J. W. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.9.4171 · Cited by 715 · see citing works
Eigen, M., McCaskill, J., & Schuster, P. (1988) · The Journal of Physical Chemistry · doi:10.1021/j100335a010 · Cited by 670 · see citing works
The Mathematical Theory of Selection, Recombination, and Mutation
Buerger, R. (2000) · IIASA PURE (International Institute of Applied Systems Analysis) · Cited by 638 · see citing works
Evolution of digital organisms at high mutation rates leads to survival of the flattest
Wilke, C. O., Wang, J. L., Ofria, C., Lenski, R. E., & Adami, C. (2001) · Nature · doi:10.1038/35085569 · Cited by 636 · see citing works
Self-citationThe Mutational Meltdown in Asexual Populations
Lynch, M., Bürger, R., Butcher, D. L., & Gabriel, W. (1993) · Journal of Heredity · doi:10.1093/oxfordjournals.jhered.a111354 · Cited by 633 · see citing works
The distribution of fitness effects caused by single-nucleotide substitutions in an RNA virus.
Sanjuán, R., Moya, A., & Elena, S. F. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0400146101 · Cited by 582 · see citing works
Mechanisms of action of ribavirin against distinct viruses
Graci, J. D., & Cameron, C. E. (2005) · Reviews in Medical Virology · doi:10.1002/rmv.483 · Cited by 552 · see citing works
THE MUTATIONAL LOAD WITH EPISTATIC GENE INTERACTIONS IN FITNESS
Kimura, M., & Maruyama, T. (1966) · Genetics · doi:10.1093/genetics/54.6.1337 · Cited by 531 · see citing works
The accumulation of deleterious genes in a population—Muller's Ratchet
Haigh, J. (1978) · Theoretical Population Biology · doi:10.1016/0040-5809(78)90027-8 · Cited by 489 · see citing works
Fitness of RNA virus decreased by Muller’s ratchet
Chao, L. (1990) · Nature · doi:10.1038/348454a0 · Cited by 488 · see citing works
Mukai, T. (1964) · Genetics · doi:10.1093/genetics/50.1.1 · Cited by 482 · see citing works
Pfeiffer, J. K., & Kirkegaard, K. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1232294100 · Cited by 405 · see citing works
Whitlock, M. C. (2000) · Evolution · doi:10.1111/j.0014-3820.2000.tb01232.x · Cited by 404 · see citing works
Lethal mutagenesis of HIV with mutagenic nucleoside analogs
Loeb, L. A., Essigmann, J. M., Kazazi, F., Zhang, J., Rose, K. D., & Mullins, J. I. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.4.1492 · Cited by 357 · see citing works
Rapid fitness losses in mammalian RNA virus clones due to Muller’s ratchet
Duarte, E., Clarke, D., Moya, A., Domingo, E., & Holland, J. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.13.6015 · Cited by 331 · see citing works
Quasispecies theory in the context of population genetics
Wilke, C. O. (2005) · BMC Evolutionary Biology · doi:10.1186/1471-2148-5-44 · Cited by 276 · see citing works
Self-citationHolland, J. J., Domingo, E., de la Torre, J. C., & Steinhauer, D. A. (1990) · Journal of Virology · doi:10.1128/jvi.64.8.3960-3962.1990 · Cited by 260 · see citing works
The solitary wave of asexual evolution
Rouzine, I. M., Wakeley, J., & Coffin, J. M. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.242719299 · Cited by 260 · see citing works
The distribution of mutation effects on viability in Drosophila melanogaster.
Keightley, P. D. (1994) · Genetics · doi:10.1093/genetics/138.4.1315 · Cited by 260 · see citing works
Redundancy, antiredundancy, and the robustness of genomes
Krakauer, D. C., & Plotkin, J. B. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.032668599 · Cited by 254 · see citing works
Sierra, S., Dávila, M., Lowenstein, P. R., & Domingo, E. (2000) · Journal of Virology · doi:10.1128/jvi.74.18.8316-8323.2000 · Cited by 222 · see citing works
Viral error catastrophe by mutagenic nucleosides
Anderson, J. P., Daifuku, R., & Loeb, L. A. (2004) · Annual Review of Microbiology · doi:10.1146/annurev.micro.58.030603.123649 · Cited by 221 · see citing works
COMPENSATING FOR OUR LOAD OF MUTATIONS: FREEZING THE MELTDOWN OF SMALL POPULATIONS
Poon, A. F. Y., & Otto, S. P. (2000) · Evolution · doi:10.1111/j.0014-3820.2000.tb00693.x · Cited by 202 · see citing works
Stationary mutant distributions and evolutionary optimization
Schuster, P., & Swetina, J. (1988) · Bulletin of Mathematical Biology · doi:10.1016/s0092-8240(88)80059-4 · Cited by 202 · see citing works
Ribavirin Causes Error Catastrophe during Hantaan Virus Replication
Severson, W. E., Schmaljohn, C. S., Javadian, A., & Jonsson, C. B. (2002) · Journal of Virology · doi:10.1128/jvi.77.1.481-488.2003 · Cited by 198 · see citing works
The Mathematical Theory of Selection, Recombination, and Mutation
Bürger, R. (2000) · Cited by 191 · see citing works
Suppression of viral infectivity through lethal defection
Grande-Pérez, A., Lázaro, E., Lowenstein, P. R., Domingo, E., & Manrubia, S. C. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0408871102 · Cited by 184 · see citing works
The Rate and Character of Spontaneous Mutation in an RNA Virus
Malpica, J. M., Fraile, A., Moreno, I., Obies, C. I., Drake, J. W., & García‐Arenal, F. (2002) · Genetics · doi:10.1093/genetics/162.4.1505 · Cited by 184 · see citing works
Bull, J. J., Ancel, L. W., & Lachmann, M. (2005) · PLoS Computational Biology · doi:10.1371/journal.pcbi.0010061 · Cited by 182 · see citing works
Self-citationThe effect of ribavirin and IMPDH inhibitors on hepatitis C virus subgenomic replicon RNA
Zhou, S. S., Liu, R., Baroudy, B. M., et al. (2003) · Virology · doi:10.1016/s0042-6822(03)00152-1 · Cited by 181 · see citing works
Drastic Fitness Loss in Human Immunodeficiency Virus Type 1 upon Serial Bottleneck Events
Yuste, E., Sánchez‐Palomino, S., Casado, C., Domingo, E., & López‐Galíndez, C. (1999) · Journal of Virology · doi:10.1128/jvi.73.4.2745-2751.1999 · Cited by 156 · see citing works
Progress of a half century in the study of the Luria-Delbrück distribution
Zheng, Q. (1999) · Mathematical Biosciences · doi:10.1016/s0025-5564(99)00045-0 · Cited by 144 · see citing works
Grande-Pérez, A., Sierra, S., Castro, M. G., Domingo, E., & Lowenstein, P. R. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.182426999 · Cited by 143 · see citing works
Epistasis and Its Relationship to Canalization in the RNA Virus φ6
Burch, C. L., & Chao, L. (2004) · Genetics · doi:10.1534/genetics.103.021196 · Cited by 141 · see citing works
The Viability of Near-normal Irradiated Chromosomes
BATEMAN, A. J. (1959) · International Journal of Radiation Biology and Related Studies in Physics Chemistry and Medicine · doi:10.1080/09553005914550241 · Cited by 140 · see citing works
Subclonal components of consensus fitness in an RNA virus clone
Duarte, E. A., Novella, I. S., Ledesma, S., Clarke, D. K., Moyá, A., Elena, S. F., Domingo, E., & Holland, J. J. (1994) · Journal of Virology · doi:10.1128/jvi.68.7.4295-4301.1994 · Cited by 137 · see citing works
Evolution of mutational robustness
Wilke, C. O., & Adami, C. (2003) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/s0027-5107(02)00307-x · Cited by 136 · see citing works
Self-citationExtinction in relation to demographic and environmental stochasticity in age-structured models
Engen, S., Lande, R., Sæther, B.-E., et al. (2005) · Mathematical Biosciences · doi:10.1016/j.mbs.2005.02.003 · Cited by 130 · see citing works
Retrovirus mutation rates and their role in genetic variation.
Mansky, L. M. (1998) · Journal of General Virology · doi:10.1099/0022-1317-79-6-1337 · Cited by 118 · see citing works
Dynamic fitness landscapes in molecular evolution
Wilke, C. O. (2001) · Physics Reports · doi:10.1016/s0370-1573(00)00118-6 · Cited by 116 · see citing works
Self-citationMuller's ratchet, epistasis and mutation effects.
Butcher, D. L. (1995) · Genetics · doi:10.1093/genetics/141.1.431 · Cited by 112 · see citing works
Schrag, S. J., Rota, P. A., & Bellini, W. J. (1999) · Journal of Virology · doi:10.1128/jvi.73.1.51-54.1999 · Cited by 112 · see citing works
The cost of replication fidelity in an RNA virus
Furió, V., Moyá, A., & Sanjuán, R. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0501062102 · Cited by 111 · see citing works
The constraints of finite size in asexual populations and the rate of the ratchet
Gessler, D. D. G. (1995) · Genetics Research · doi:10.1017/s0016672300034686 · Cited by 95 · see citing works
Heterogeneity of the mutation rates of influenza A viruses: isolation of mutator mutants
Suarez, P., Valcárcel, J., & Ortı́n, J. (1992) · Journal of Virology · doi:10.1128/jvi.66.4.2491-2494.1992 · Cited by 93 · see citing works
Negative effects of chemical mutagenesis on the adaptive behavior of vesicular stomatitis virus
Lee, C. H., Gilbertson, D. L., Novella, I. S., Huerta, R., Domingo, E., & Holland, J. J. (1997) · Journal of Virology · doi:10.1128/jvi.71.5.3636-3640.1997 · Cited by 84 · see citing works
Chao, L., Rang, C. U., & Wong, L. E. (2002) · Journal of Virology · doi:10.1128/jvi.76.7.3276-3281.2002 · Cited by 82 · see citing works
Risk of population extinction from fixation of deleterious and reverse mutations
Lande, R. (1998) · Genetica · doi:10.1023/a:1017018405648 · Cited by 78 · see citing works
Elena, S. F., & Moyá, A. (1999) · Journal of Evolutionary Biology · doi:10.1046/j.1420-9101.1999.00110.x · Cited by 74 · see citing works
Risk of population extinction from fixation of deleterious and reverse mutations
Lande, R. (1998) · Contemporary issues in genetics and evolution · doi:10.1007/978-94-011-5210-5_2 · Cited by 74 · see citing works
Flanagan, E. B., Ball, L. A., & Wertz, G. W. (2000) · Journal of Virology · doi:10.1128/jvi.74.17.7895-7902.2000 · Cited by 67 · see citing works
Wiehe, T. (1997) · Genetics Research · doi:10.1017/s0016672397002619 · Cited by 66 · see citing works
COMPENSATING FOR OUR LOAD OF MUTATIONS: FREEZING THE MELTDOWN OF SMALL POPULATIONS
Poon, A. F. Y., & Otto, S. P. (2000) · Evolution · doi:10.1554/0014-3820(2000)054[1467:cfolom]2.0.co;2 · Cited by 40 · see citing works
Challenges for the Development of Ribonucleoside Analogues as Inducers of Error Catastrophe
Graci, J. D., & Cameron, C. E. (2004) · Antiviral chemistry & chemotherapy · doi:10.1177/095632020401500101 · Cited by 37 · see citing works
Fredericksen, B. L., & Whitt, M. A. (1998) · Virology · doi:10.1006/viro.1997.8921 · Cited by 31 · see citing works
Minimum Distance Estimation of Mutational Parameters for Quantitative Traits
García‐Dorado, A., & Marin, J. M. (1998) · Biometrics · doi:10.2307/2533860 · Cited by 29 · see citing works
SELECTION PROMOTES ORGAN COMPARTMENTALIZATION IN HIV-1: EVIDENCE FROMGAGANDPOLGENES
Bordería, A. V., Codoñer, F. M., & Sanjuán, R. (2007) · Evolution · doi:10.1111/j.1558-5646.2007.00025.x · Cited by 10 · see citing works
Ceruloplasmin variants in mouse serum
Meier, H. (1971) · Die Naturwissenschaften · doi:10.1007/bf00624624 · Cited by 4 · see citing works
Flagged first, then by citations
Research works printed but not linked: 2
- [5]Bordería, A. V., F. M. Codoñer, and R. Sanjuán. Selection drives organ compartmentalization in HIV-1: evidence from gag and pol genes. Evolution, in press. [DOI] [PubMed]
- [45]Maynard Smith, J. 1978. The evolution of sex. Cambridge University Press, Cambridge, United Kingdom.
Cited by
Sorted by citations
Domingo, E., Sheldon, J., & Perales, C. (2012) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.05023-11 · Cited by 1,009 · see citing works
The prebiotic evolutionary advantage of transferring genetic information from RNA to DNA
Leu, K., Obermayer, B., Rajamani, S., Gerland, U., & Chen, I. A. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkr525 · Cited by 85 · see citing works
Lethal mutagenesis of bacteria.
Bull, J. J., & Wilke, C. O. (2008) · Genetics · doi:10.1534/genetics.108.091413 · Cited by 48 · see citing works
Self-citationPhase diagram for the Eigen quasispecies theory with a truncated fitness landscape
Saakian, D. B., Biebricher, C. K., & Hu, C.-K. (2009) · Physical Review E · doi:10.1103/physreve.79.041905 · Cited by 28 · see citing works
Lethal mutants and truncated selection together solve a paradox of the origin of life
Saakian, D. B., Biebricher, C. K., & Hu, C.-K. (2011) · PLoS ONE · doi:10.1371/journal.pone.0021904 · Cited by 27 · see citing works
Evolution models with lethal mutations on symmetric or random fitness landscapes.
Kirakosyan, Z., Saakian, D. B., & Hu, C.-K. (2010) · Physical Review E · doi:10.1103/physreve.82.011904 · Cited by 15 · see citing works
- Authors
- Bull, J. J., Sanjuán, R., & Wilke, C. O.
- Affiliations
- The University of Texas at Austin (US)
- Section of Integrative Biology, The University of Texas at Austin, Austin, Texas 78712
- Corresponding author
- Wilke, C. O.
- Venue
- Journal of Virology
- Publisher
- American Society for Microbiology
- Published
- 2007-03-15
- Volume
- 81
- Issue
- 6
- Pages
- 2930-2939
- ISSN
- 0022-538X (ISSN-L)
- 1098-5514
- PMC
- PMC1865999
- OpenAlex
- W2042712534
- Cited by
- 281
- References
- 68
- Citations by year
- 2026: 8 · 2025: 6 · 2024: 11 · 2023: 17 · 2022: 19 · 2021: 12 · 2020: 16 · 2019: 15 · 2018: 13 · 2017: 16 · 2016: 9 · 2015: 11 · 2014: 12 · 2013: 18 · 2012: 22
- FWCI
- 9.82
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Virology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Generalitat Valenciana
- National Institutes of Health
- National Institute of General Medical Sciences (GM 57756, R01GM057756)
- National Institute of Allergy and Infectious Diseases (R01AI065960, AI 065960)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Mathematical and Theoretical Epidemiology and Ecology Models
- Physical Sciences › Environmental Science › Ecology › Bacteriophages and microbial interactions
- Keywords
- lethal mutagenesis, ribavirin, error catastrophe, extinction threshold, mutation rate, viral fitness, viral population dynamics, antiviral therapy
- MeSH terms
- Antiviral Agents, Models, Genetic, Mutation, Ribavirin, RNA Viruses, Viruses, Mutagenesis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
