The optimal burst of mutation to create a phenotype

Bull, James J.

doi:10.1016/j.jtbi.2008.06.006

Cited by 5 publications

(6 citation statements)

References 46 publications

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“…This is of relevance because not all mutagen-induced DNA lesions—like cross-links produced by nitrous acid ( 70 ) —can be bypassed by polymerases or repaired ( 16 , 70 ). In this regard, the greater part of the lethality seen after mutagen exposure may be due to collateral viral inactivation—consequential to irresolvable DNA lesions and damaged protein components—rather than bona fide genetic mutations ( 17 ). Importantly, this mutagen-associated excess lethality compromises the effective complexities of the diversified populations ( 17 ).…”

Section: Discussionmentioning

confidence: 99%

“…In this regard, the greater part of the lethality seen after mutagen exposure may be due to collateral viral inactivation—consequential to irresolvable DNA lesions and damaged protein components—rather than bona fide genetic mutations ( 17 ). Importantly, this mutagen-associated excess lethality compromises the effective complexities of the diversified populations ( 17 ). While these issues are not so much a problem in single mutational-pulse experiments (because the amount of input virus can be chosen sufficiently high), they thwart schemes involving repeated mutagenic treatments, e.g.…”

Section: Discussionmentioning

confidence: 99%

“…First, the use of mutator viral polymerases avoids the direct virus inactivating effects normally associated with mutagens (i.e. damage to the virus particle and irresolvable DNA lesions) ( 16 , 17 ). Second, and relatedly, our approach is inherently capable of bringing about genetic diversity over repeated viral infection rounds.…”

Section: Introductionmentioning

confidence: 99%

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Directed adenovirus evolution using engineered mutator viral polymerases

Uil

Vellinga

Vrij

et al. 2010

Nucleic Acids Research

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Adenoviruses (Ads) are the most frequently used viruses for oncolytic and gene therapy purposes. Most Ad-based vectors have been generated through rational design. Although this led to significant vector improvements, it is often hampered by an insufficient understanding of Ad’s intricate functions and interactions. Here, to evade this issue, we adopted a novel, mutator Ad polymerase-based, ‘accelerated-evolution’ approach that can serve as general method to generate or optimize adenoviral vectors. First, we site specifically substituted Ad polymerase residues located in either the nucleotide binding pocket or the exonuclease domain. This yielded several polymerase mutants that, while fully supportive of viral replication, increased Ad’s intrinsic mutation rate. Mutator activities of these mutants were revealed by performing deep sequencing on pools of replicated viruses. The strongest identified mutators carried replacements of residues implicated in ssDNA binding at the exonuclease active site. Next, we exploited these mutators to generate the genetic diversity required for directed Ad evolution. Using this new forward genetics approach, we isolated viral mutants with improved cytolytic activity. These mutants revealed a common mutation in a splice acceptor site preceding the gene for the adenovirus death protein (ADP). Accordingly, the isolated viruses showed high and untimely expression of ADP, correlating with a severe deregulation of E3 transcript splicing.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Directed adenovirus evolution using engineered mutator viral polymerases

Uil

Vellinga

Vrij

et al. 2010

Nucleic Acids Research

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“…This formula reflects both an increased appearance of beneficial mutations with longer exposures (β t ) as well as a decreased survival rate from longer exposures (e − wt ). This quantity is maximized over t at wt = 1, hence an exposure that kills 63% of the population, or a survival of 0.37—a low level of killing ( Mundry & Gierer, 1958 ; Gierer & Mundry, 1958 ; Bull, 2008 ). Thus, independently of the beneficial mutation rate, the highest success rate in acquiring a surviving beneficial mutation is with a relatively low kill rate.…”

Section: The Nature Of Survival and Selection In The Empirical Systemmentioning

confidence: 99%

Experimental evolution of UV resistance in a phage

Tom

Molineux

Paff

et al. 2018

PeerJ

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The dsDNA bacteriophage T7 was subjected to 30 cycles of lethal ultraviolet light (UV) exposure to select increased resistance to UV. The exposure effected a 0.9999 kill of the ancestral population, and survival of the ending population was nearly 50-fold improved. At the end point, a 2.1 kb deletion of early genes and three substitutions in structural-genes were the only changes observed at high frequency throughout the 40 kb genome; no changes were observed in genes affecting DNA metabolism. The deletion accounted for only a two-fold improvement in survival. One possible explanation of its benefit is that it represents an error catastrophe, whereby the genome experiences a reduced mutation rate. The mechanism of benefit provided by the three structural-gene mutations remains unknown. The results offer some hope of artificially evolving greater protection against sunlight damage in applications of phage therapy to plants, but the response of T7 is weak compared to that observed in bacteria selected to resist ionizing radiation. Because of the weak response, mathematical analysis of the selection process was performed to determine how the protocol might have been modified to achieve a greater response, but the greatest protection may well come from evolving phages to bind materials that block the UV.

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“…The concept of mutations as a double-edged sword has been explored in many situations. For example, Bull studied the mean number of adaptive mutants produced by a single episode of mutagenesis [20], while Iranzo et al calculated the mean growth rate of a pathogen population exposed to a combination of a drug reducing growth and another drug increasing the mutation rate [21]. There is an extensive literature on adaptation rates (i.e.…”

Section: Introductionmentioning

confidence: 99%

Evolutionary Invasion and Escape in the Presence of Deleterious Mutations

Loverdo

Lloyd‐Smith

2013

PLoS ONE

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Replicators such as parasites invading a new host species, species invading a new ecological niche, or cancer cells invading a new tissue often must mutate to adapt to a new environment. It is often argued that a higher mutation rate will favor evolutionary invasion and escape from extinction. However, most mutations are deleterious, and even lethal. We study the probability that the lineage will survive and invade successfully as a function of the mutation rate when both the initial strain and an adaptive mutant strain are threatened by lethal mutations. We show that mutations are beneficial, i.e. a non-zero mutation rate increases survival compared to the limit of no mutations, if in the no-mutation limit the survival probability of the initial strain is smaller than the average survival probability of the strains which are one mutation away. The mutation rate that maximizes survival depends on the characteristics of both the initial strain and the adaptive mutant, but if one strain is closer to the threshold governing survival then its properties will have greater influence. These conclusions are robust for more realistic or mechanistic depictions of the fitness landscapes such as a more detailed viral life history, or non-lethal deleterious mutations.

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The optimal burst of mutation to create a phenotype

Abstract: Mutagenesis is commonly applied to genes and genomes to create novel variants with desired properties. This paper calculates the level of mutagenesis that maximizes the appearance of favorable mutants, assuming that the mutagenesis is applied in a single episode.

Cited by 5 publications

References 46 publications

Directed adenovirus evolution using engineered mutator viral polymerases

Directed adenovirus evolution using engineered mutator viral polymerases

Experimental evolution of UV resistance in a phage

Evolutionary Invasion and Escape in the Presence of Deleterious Mutations

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