scholarly journals Population persistence under high mutation rate: From evolutionary rescue to lethal mutagenesis

Evolution ◽  
2019 ◽  
Vol 73 (8) ◽  
pp. 1517-1532 ◽  
Author(s):  
Yoann Anciaux ◽  
Amaury Lambert ◽  
Ophélie Ronce ◽  
Lionel Roques ◽  
Guillaume Martin
Keyword(s):  
Mutation Rate ◽  
Population Persistence ◽  
High Mutation Rate ◽  
Lethal Mutagenesis ◽  
Evolutionary Rescue

scholarly journals Effective Lethal Mutagenesis of Influenza Virus by Three Nucleoside Analogs

2015 ◽  
Vol 89 (7) ◽  
pp. 3584-3597 ◽  
Author(s):  
Matthew D. Pauly ◽  
Adam S. Lauring
Keyword(s):  
Influenza Virus ◽  
Mutation Rate ◽  
Broad Spectrum ◽  
Rna Viruses ◽  
Nucleoside Analogs ◽  
High Mutation Rate ◽  
Induced Mutations ◽  
Genetic Barrier ◽  
Defective Interfering Particles ◽  
Lethal Mutagenesis

ABSTRACTLethal mutagenesis is a broad-spectrum antiviral strategy that exploits the high mutation rate and low mutational tolerance of many RNA viruses. This approach uses mutagenic drugs to increase viral mutation rates and burden viral populations with mutations that reduce the number of infectious progeny. We investigated the effectiveness of lethal mutagenesis as a strategy against influenza virus using three nucleoside analogs, ribavirin, 5-azacytidine, and 5-fluorouracil. All three drugs were active against a panel of seasonal H3N2 and laboratory-adapted H1N1 strains. We found that each drug increased the frequency of mutations in influenza virus populations and decreased the virus' specific infectivity, indicating a mutagenic mode of action. We were able to drive viral populations to extinction by passaging influenza virus in the presence of each drug, indicating that complete lethal mutagenesis of influenza virus populations can be achieved when a sufficient mutational burden is applied. Population-wide resistance to these mutagenic agents did not arise after serial passage of influenza virus populations in sublethal concentrations of drug. Sequencing of these drug-passaged viral populations revealed genome-wide accumulation of mutations at low frequency. The replicative capacity of drug-passaged populations was reduced at higher multiplicities of infection, suggesting the presence of defective interfering particles and a possible barrier to the evolution of resistance. Together, our data suggest that lethal mutagenesis may be a particularly effective therapeutic approach with a high genetic barrier to resistance for influenza virus.IMPORTANCEInfluenza virus is an RNA virus that causes significant morbidity and mortality during annual epidemics. Novel therapies for RNA viruses are needed due to the ease with which these viruses evolve resistance to existing therapeutics. Lethal mutagenesis is a broad-spectrum strategy that exploits the high mutation rate and the low mutational tolerance of most RNA viruses. It is thought to possess a higher barrier to resistance than conventional antiviral strategies. We investigated the effectiveness of lethal mutagenesis against influenza virus using three different drugs. We showed that influenza virus was sensitive to lethal mutagenesis by demonstrating that all three drugs induced mutations and led to an increase in the generation of defective viral particles. We also found that it may be difficult for resistance to these drugs to arise at a population-wide level. Our data suggest that lethal mutagenesis may be an attractive anti-influenza strategy that warrants further investigation.

scholarly journals Population persistence under high mutation rate: from evolutionary rescue to lethal mutagenesis

2019 ◽  
Author(s):  
Yoann Anciaux ◽  
Amaury Lambert ◽  
Ophelie Ronce ◽  
Lionel Roques ◽  
Guillaume Martin
Keyword(s):  
Mutation Rate ◽  
Geometric Model ◽  
Resistance Mutation ◽  
Theoretical Work ◽  
Mutation Rates ◽  
Moderate Increase ◽  
Asexual Population ◽  
Lethal Mutagenesis ◽  
Recent Theoretical Work ◽  
Evolutionary Rescue

AbstractPopulations may genetically adapt to severe stress that would otherwise cause their extirpation. Recent theoretical work, combining stochastic demography with Fisher’s geometric model of adaptation, has shown how evolutionary rescue becomes unlikely beyond some critical intensity of stress. Increasing mutation rates may however allow adaptation to more intense stress, raising concerns about the effectiveness of treatments against pathogens. This previous work assumes that populations are rescued by the rise of a single resistance mutation. However, even in asexual organisms, rescue can also stem from the accumulation of multiple mutations in a single genome. Here, we extend previous work to study the rescue process in an asexual population where the mutation rate is sufficiently high so that such events may be common. We predict both the ultimate extinction probability of the population and the distribution of extinction times. We compare the accuracy of different approximations covering a large range of mutation rates. Moderate increase in mutation rates favors evolutionary rescue. However, larger increase leads to extinction by the accumulation of a large mutation load, a process called lethal mutagenesis. We discuss how these results could help design “evolution-proof” anti-pathogen treatments that even highly mutable strains could not overcome.

scholarly journals Generation of Rodent Malaria Parasites with a High Mutation Rate by Destructing Proofreading Activity of DNA Polymerase δ

DNA Research ◽  
2014 ◽  
Vol 21 (4) ◽  
pp. 439-446 ◽  
Author(s):  
Hajime Honma ◽  
Makoto Hirai ◽  
Shota Nakamura ◽  
Hassan Hakimi ◽  
Shin-ichiro Kawazu ◽  
...  
Keyword(s):  
Dna Polymerase ◽  
Mutation Rate ◽  
High Mutation Rate ◽  
Malaria Parasites ◽  
Rodent Malaria ◽  
Dna Polymerase Δ

scholarly journals Rhopalocnemis phalloides has one of the most reduced and mutated plastid genomes known

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e7500 ◽  
Author(s):  
Mikhail I. Schelkunov ◽  
Maxim S. Nuraliev ◽  
Maria D. Logacheva
Keyword(s):  
Plant Species ◽  
Mutation Rate ◽  
Plastid Genome ◽  
Gene Content ◽  
High Mutation Rate ◽  
Base Pairs ◽  
Plastid Genomes ◽  
The Family

Although most plant species are photosynthetic, several hundred species have lost the ability to photosynthesize and instead obtain nutrients via various types of heterotrophic feeding. Their plastid genomes markedly differ from the plastid genomes of photosynthetic plants. In this work, we describe the sequenced plastid genome of the heterotrophic plant Rhopalocnemis phalloides, which belongs to the family Balanophoraceae and feeds by parasitizing other plants. The genome is highly reduced (18,622 base pairs vs. approximately 150 kbp in autotrophic plants) and possesses an extraordinarily high AT content, 86.8%, which is inferior only to AT contents of plastid genomes of Balanophora, a genus from the same family. The gene content of this genome is quite typical of heterotrophic plants, with all of the genes related to photosynthesis having been lost. The remaining genes are notably distorted by a high mutation rate and the aforementioned AT content. The high AT content has led to sequence convergence between some of the remaining genes and their homologs from AT-rich plastid genomes of protists. Overall, the plastid genome of R. phalloides is one of the most unusual plastid genomes known.

1. What are viruses?

2018 ◽  
pp. 2-16
Author(s):  
Dorothy H. Crawford
Keyword(s):  
Electron Microscope ◽  
Mutation Rate ◽  
Molecular Clock ◽  
Antiviral Drugs ◽  
High Mutation Rate ◽  
Virus Identification ◽  
Obligate Parasites ◽  
Protein Coat ◽  
A Cell

‘What are viruses?’ introduces viruses and their structure. Martinus Beijerinck, in 1898, was the first to coin the term ‘virus’, and invention of the electron microscope in the late 1930s greatly enhanced virus identification. Viruses are not cells, but obligate parasites that must infect a cell and use its organelles in order to reproduce. They carry either DNA or RNA, and have a protein coat called a capsid. The whole structure is called a virion. Viruses have a high mutation rate, which helps them to survive and boost their resistance to antiviral drugs. The molecular clock technique to track a virus’s history is also explained.

204. Isolation of CAG repeat containing genes from human placenta and decidua

2005 ◽  
Vol 17 (9) ◽  
pp. 77
Author(s):  
K. A. Freed ◽  
S. P. Brennecke ◽  
E. K. Moses
Keyword(s):  
Mutation Rate ◽  
Dna Sequences ◽  
Human Placenta ◽  
Trinucleotide Repeat ◽  
Normal Population ◽  
Repeat Expansion ◽  
Cag Repeat ◽  
High Mutation Rate ◽  
Strong Negative Selection ◽  
Expansion Mutation

Pre-eclampsia is a serious disorder of pregnancy that manifests clinically in the mother as new-onset hypertension and proteinuria. Although the precise cause remains unknown, the placenta and the decidua play a fundamental role. The worldwide incidence of pre-eclampsia is 2–5% and such a high incidence, in the face of strong negative selection, suggests that the gene(s) involved have a selective advantage and/or a high mutation rate. One class of genetic diseases that involve a high mutation rate are the trinucleotide repeat expansion diseases. In these diseases repeated trinucleotide DNA sequences within specific genes multiply or expand up to 1000-fold. The result of this gene expansion/mutation is altered gene function that confers genetic susceptibility. Thus, the overall objective of this study was to determine whether there is an association between a trinucleotide (CAG) repeat expansion and pre-eclampsia. The specific aim of this study was to isolate CAG repeat containing genes from human placenta and decidua. An adaptation of the mRNA differential display technique and traditional cDNA library screening was used. In total, 72 placental and 51 decidual sequences were analyzed using the BLAST nucleotide comparison program. Five cDNAs were analyzed further. The unique sequences surrounding the CAG repeat regions of these five genes will be used to generate primers to ascertain if any of these repeat DNA sequences vary in number in the normal population. If polymorphic genes are identified, the primers will be used on pre-eclamptic pedigrees to determine if pre-eclampsia is associated with a repeat expansion mutation.

High mutation rate ofNPHP3in 18 Chinese infantile nephronophthisis patients

Nephrology ◽  
2016 ◽  
Vol 21 (3) ◽  
pp. 209-216 ◽  
Author(s):  
Liangzhong Sun ◽  
Huajuan Tong ◽  
Haiyan Wang ◽  
Zhihui Yue ◽  
Ting Liu ◽  
...  
Keyword(s):  
Mutation Rate ◽  
High Mutation Rate
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