scholarly journals Evading resistance to gene drives

Genetics ◽  
2021 ◽  
Vol 217 (2) ◽  
Author(s):  
Richard Gomulkiewicz ◽  
Micki L Thies ◽  
James J Bull
Keyword(s):  
Computational Models ◽  
Animal Species ◽  
Resistance Evolution ◽  
Evolution Of Resistance ◽  
Favorable Case ◽  
Transmission Distortion ◽  
Partial Suppression ◽  
A Minor ◽  
Gene Drives ◽  
Population Suppression

AbstractGene drives offer the possibility of altering and even suppressing wild populations of countless plant and animal species, and CRISPR technology now provides the technical feasibility of engineering them. However, population-suppression gene drives are prone to select resistance, should it arise. Here, we develop mathematical and computational models to identify conditions under which suppression drives will evade resistance, even if resistance is present initially. Previous models assumed resistance is allelic to the drive. We relax this assumption and show that linkage between the resistance and drive loci is critical to the evolution of resistance and that evolution of resistance requires (negative) linkage disequilibrium between the two loci. When the two loci are unlinked or only partially so, a suppression drive that causes limited inviability can evolve to fixation while causing only a minor increase in resistance frequency. Once fixed, the drive allele no longer selects resistance. Our analyses suggest that among gene drives that cause moderate suppression, toxin-antidote systems are less apt to select for resistance than homing drives. Single drives of moderate effect might cause only moderate population suppression, but multiple drives (perhaps delivered sequentially) would allow arbitrary levels of suppression. The most favorable case for evolution of resistance appears to be with suppression homing drives in which resistance is dominant and fully suppresses transmission distortion; partial suppression by resistance heterozygotes or recessive resistance are less prone to resistance evolution. Given that it is now possible to engineer CRISPR-based gene drives capable of circumventing allelic resistance, this design may allow for the engineering of suppression gene drives that are effectively resistance-proof.

scholarly journals Evading resistance to gene drives

2020 ◽  
Author(s):  
Richard Gomulkiewicz ◽  
Micki L. Thies ◽  
James J. Bull
Keyword(s):  
Computational Models ◽  
Animal Species ◽  
Resistance Evolution ◽  
Evolution Of Resistance ◽  
Favorable Case ◽  
Transmission Distortion ◽  
Partial Suppression ◽  
A Minor ◽  
Gene Drives ◽  
Population Suppression

Gene drives offer the possibility of altering and even suppressing wild populations of countless plant and animal species, and CRISPR technology now provides the technical feasibility of engineering them. However, population-suppression gene drives are prone to select resistance, should it arise. Here we develop mathematical and computational models to identify conditions under which suppression drives will evade resistance, even if resistance is present initially. Previous models assumed resistance is allelic to the drive. We relax this assumption and show that linkage between the resistance and drive loci is critical to the evolution of resistance and that evolution of resistance requires (negative) linkage disequilibrium between the two loci. When the two loci are unlinked or only partially so, a suppression drive that causes limited inviability can evolve to fixation while causing only a minor increase in resistance frequency. Once fixed, the drive allele no longer selects resistance. Our analyses suggest that among gene drives that cause moderate suppression, toxin-antidote systems are less apt to select for resistance than homing drives. Single drives of moderate effect might cause only moderate population suppression, but multiple drives (perhaps delivered sequentially) would allow arbitrary levels of suppression. The most favorable case for evolution of resistance appears to be with suppression homing drives in which resistance is dominant and fully suppresses transmission distortion; partial suppression by resistance heterozygotes or recessive resistance are less prone to resistance evolution. Given that it is now possible to engineer CRISPR-based gene drives capable of circumventing allelic resistance, this design may allow for the engineering of suppression gene drives that are effectively resistance-proof.

scholarly journals Gene drive escape from resistance depends on mechanism and ecology

2021 ◽  
Author(s):  
Forest Cook ◽  
James J Bull ◽  
Richard Gomulkiewicz
Keyword(s):  
Cleavage Site ◽  
Ecological Effects ◽  
Gene Drive ◽  
Resistance Evolution ◽  
Gene Drives ◽  
Population Suppression ◽  
Modest Effect

AbstractGene drives can potentially be used to suppress pest populations, and the advent of CRISPR technology has made it feasible to engineer them in many species, especially insects. What remains largely unknown for implementations is whether anti-drive resistance will evolve to block the population suppression. An especially serious threat to some kinds of drive is mutations in the CRISPR cleavage sequence that block the action of CRISPR, but designs have been proposed to avoid this type of resistance. Various types of resistance at loci away from the cleavage site remain a possibility, which is the focus here. It is known that modest-effect suppression drives can essentially ‘outrun’ unlinked resistance even when that resistance is present from the start. We demonstrate here how the risk of evolving (unlinked) resistance can be further reduced without compromising overall suppression by introducing multiple suppression drives or by designing drives with specific ecological effects. However, we show that even modest-effect suppression drives remain vulnerable to the evolution of extreme levels of inbreeding, which halt the spread of the drive without actually interfering with its mechanism. The landscape of resistance evolution against suppression drives is therefore complex, but avenues exist for enhancing gene drive success.

scholarly journals A cognitive model’s view of animal cognition

2011 ◽  
Vol 57 (4) ◽  
pp. 499-513 ◽  
Author(s):  
Sidney D’mello ◽  
Stan Franklin
Keyword(s):  
Empirical Research ◽  
Cognitive Processes ◽  
Computational Models ◽  
Animal Species ◽  
Animal Cognition ◽  
Cognitive Model ◽  
Field Of Study ◽  
Working Model ◽  
Hypotheses Generation

Abstract Although it is a relatively new field of study, the animal cognition literature is quite extensive and difficult to synthesize. This paper explores the contributions a comprehensive, computational, cognitive model can make toward organizing and assimilating this literature, as well as toward identifying important concepts and their interrelations. Using the LIDA model as an example, a framework is described within which to integrate the diverse research in animal cognition. Such a framework can provide both an ontology of concepts and their relations, and a working model of an animal’s cognitive processes that can compliment active empirical research. In addition to helping to account for a broad range of cognitive processes, such a model can help to comparatively assess the cognitive capabilities of different animal species. After deriving an ontology for animal cognition from the LIDA model, we apply it to develop the beginnings of a database that maps the cognitive facilities of a variety of animal species. We conclude by discussing future avenues of research, particularly the use of computational models of animal cognition as valuable tools for hypotheses generation and testing.

Plasticity in the Mechanical Behaviour of Cardiovascular Stents during Stent Preparation (Crimping) and Placement (Expansion)

2007 ◽  
Vol 340-341 ◽  
pp. 847-852 ◽  
Author(s):  
Matthieu De Beule ◽  
Peter Mortier ◽  
Rudy Van Impe ◽  
Benedict Verhegghe ◽  
Patrick Segers ◽  
...  
Keyword(s):  
Mechanical Behaviour ◽  
Computational Models ◽  
Von Mises Stress ◽  
Stent Deployment ◽  
Low Profile ◽  
Nominal Strain ◽  
Von Mises ◽  
Intravascular Stent ◽  
A Minor ◽  
Expansion Behaviour

In Western countries, cardiovascular disease is the most common cause of death, often related to atherosclerosis which can lead to a narrowing of the arteries. To restore perfusion of downstream tissues, an intravascular stent (i.e. a small tube-like structure) can be deployed in the obstructed vessel. The vast majority of stents are balloon expandable and crimped on a folded balloon to obtain a low profile for deliverability and lesion access. Several studies have exploited the finite element method to gain insight in their mechanical behaviour or to study the vascular reaction to stent deployment. However, to date – to the best of our knowledge – none of them include the balloon itself in its actual folded shape. Furthermore, literature on the effect of the crimping process on the expansion behaviour of the stent is even scarcer. Our numerical results - accounting for the presence of the balloon in its actual folded shape - correspond very well with data provided by the manufacturer and consequently our approach could be the basis for new realistic computational models of angioplasty procedures. The plastic deformation, prior to the stent expansion and induced by the crimping procedure, has a minor influence on the overall expansion behaviour of the stent but nevertheless influences the maximum von Mises stress and nominal strain. The maximum von Mises stress drops from 440 N/mm² to 426 N/mm² and the maximum nominal strain value lowers from 0.23 to 0.22 at the end of the expansion phase when neglecting the presence of the residual stresses. Depending on the context in which to use the developed mathematical models, the crimping phase can be discarded from the simulations in order to speed up the analyses.

scholarly journals Spatial structure undermines parasite suppression by gene drive cargo

2019 ◽  
Author(s):  
James J Bull ◽  
Christopher H Remien ◽  
Richard Gomulkiewicz ◽  
Stephen M Krone
Keyword(s):  
Spatial Structure ◽  
The Other ◽  
Gene Drive ◽  
High Coverage ◽  
Disease Eradication ◽  
Vector Population ◽  
Evolution Of Resistance ◽  
Disease Agent ◽  
Gene Drives ◽  
Simple Models

ABSTRACTGene drives may be used in two ways to curtail vectored diseases. Both involve engineering the drive to spread in the vector population. One approach uses the drive to directly depress vector numbers, possibly to extinction. The other approach leaves intact the vector population but suppresses the disease agent during its interaction with the vector. This second application may use a drive engineered to carry a genetic cargo that blocks the disease agent. An advantage of the second application is that it is far less likely to select vector resistance to block the drive, but the disease agent may instead evolve resistance to the inhibitory cargo. However, some gene drives are expected to spread so fast and attain such high coverage in the vector population that, if the disease agent can evolve resistance only gradually, disease eradication may be feasible. Here we use simple models to show that spatial structure in the vector population can greatly facilitate persistence and evolution of resistance by the disease agent. We suggest simple approaches to avoid some types of spatial structure, but others may be intrinsic to the populations being challenged and difficult to overcome.

scholarly journals Targeting conserved sequences circumvents the evolution of resistance in a viral gene drive against human cytomegalovirus

2021 ◽  
Author(s):  
Marius Walter ◽  
Rosalba Perrone ◽  
Eric Verdin
Keyword(s):  
Cell Culture ◽  
Human Cytomegalovirus ◽  
Viral Population ◽  
Viral Gene ◽  
Gene Drive ◽  
Conserved Sequences ◽  
Evolution Of Resistance ◽  
Gene Drives ◽  
Over Time

Gene drives are genetic systems designed to efficiently spread a modification through a population. They have been designed almost exclusively in eukaryotic species, and especially in insects. We recently developed a CRISPR-based gene drive system in herpesviruses that relies on similar mechanisms and could efficiently spread into a population of wildtype viruses. A common consequence of gene drives in insects is the appearance and selection of drive-resistant sequences that are no longer recognized by CRISPR-Cas9. Here, we analyze in cell culture experiments the evolution of resistance in a viral gene drive against human cytomegalovirus. We report that, after an initial invasion of the wildtype population, a drive-resistant population is positively selected over time and outcompetes gene drive viruses. However, we show that targeting evolutionary conserved sequences ensures that drive-resistant viruses acquire long-lasting mutations and are durably attenuated. As a consequence, and even though engineered viruses do not stably persist in the viral population, remaining viruses have a replication defect, leading to a long-term reduction of viral levels. This marks an important step toward developing effective gene drives in herpesviruses, especially for therapeutic applications. Importance The use of defective viruses that interfere with the replication of their infectious parent after co-infecting the same cells – a therapeutic strategy known as viral interference – has recently generated a lot of interest. The CRISPR-based system that we recently reported in herpesviruses represents a novel interfering strategy that causes the conversion of wildtype viruses into new recombinant viruses and drives the native viral population to extinction. In this report, we analyzed how targeted viruses evolved resistance against the technology. Through numerical simulations and cell culture experiments with human cytomegalovirus, we show that, after the initial propagation, a resistant viral population is positively selected and outcompetes engineered viruses over time. We show however that targeting evolutionary conserved sequences ensures that resistant viruses are mutated and attenuated, which leads to a long-term reduction of viral levels. This marks an important step toward the development of novel therapeutic strategies against herpesviruses.

scholarly journals Immune selection suppresses the emergence of drug resistance in malaria parasites but facilitates its spread

2021 ◽  
Vol 17 (7) ◽  
pp. e1008577
Author(s):  
Alexander O. B. Whitlock ◽  
Jonathan J. Juliano ◽  
Nicole Mideo
Keyword(s):  
Drug Resistance ◽  
Immune Selection ◽  
Global Pattern ◽  
Agent Based ◽  
Low Transmission ◽  
Resistance Evolution ◽  
High Transmission ◽  
Population Immunity ◽  
Evolution Of Resistance ◽  
Selection For

Although drug resistance in Plasmodium falciparum typically evolves in regions of low transmission, resistance spreads readily following introduction to regions with a heavier disease burden. This suggests that the origin and the spread of resistance are governed by different processes, and that high transmission intensity specifically impedes the origin. Factors associated with high transmission, such as highly immune hosts and competition within genetically diverse infections, are associated with suppression of resistant lineages within hosts. However, interactions between these factors have rarely been investigated and the specific relationship between adaptive immunity and selection for resistance has not been explored. Here, we developed a multiscale, agent-based model of Plasmodium parasites, hosts, and vectors to examine how host and parasite dynamics shape the evolution of resistance in populations with different transmission intensities. We found that selection for antigenic novelty (“immune selection”) suppressed the evolution of resistance in high transmission settings. We show that high levels of population immunity increased the strength of immune selection relative to selection for resistance. As a result, immune selection delayed the evolution of resistance in high transmission populations by allowing novel, sensitive lineages to remain in circulation at the expense of the spread of a resistant lineage. In contrast, in low transmission settings, we observed that resistant strains were able to sweep to high population prevalence without interference. Additionally, we found that the relationship between immune selection and resistance changed when resistance was widespread. Once resistance was common enough to be found on many antigenic backgrounds, immune selection stably maintained resistant parasites in the population by allowing them to proliferate, even in untreated hosts, when resistance was linked to a novel epitope. Our results suggest that immune selection plays a role in the global pattern of resistance evolution.

scholarly journals Superinfection and the evolution of resistance to antimalarial drugs

2012 ◽  
Vol 279 (1743) ◽  
pp. 3834-3842 ◽  
Author(s):  
Eili Y. Klein ◽  
David L. Smith ◽  
Ramanan Laxminarayan ◽  
Simon Levin
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
General Theory ◽  
Mathematical Models ◽  
Random Sampling ◽  
Transmission Rate ◽  
Drug Resistant ◽  
Antimalarial Drug Resistance ◽  
Resistance Evolution ◽  
Evolution Of Resistance

A major issue in the control of malaria is the evolution of drug resistance. Ecological theory has demonstrated that pathogen superinfection and the resulting within-host competition influences the evolution of specific traits. Individuals infected with Plasmodium falciparum are consistently infected by multiple parasites; however, while this probably alters the dynamics of resistance evolution, there are few robust mathematical models examining this issue. We developed a general theory for modelling the evolution of resistance with host superinfection and examine: (i) the effect of transmission intensity on the rate of resistance evolution; (ii) the importance of different biological costs of resistance; and (iii) the best measure of the frequency of resistance. We find that within-host competition retards the ability and slows the rate at which drug-resistant parasites invade, particularly as the transmission rate increases. We also find that biological costs of resistance that reduce transmission are less important than reductions in the duration of drug-resistant infections. Lastly, we find that random sampling of the population for resistant parasites is likely to significantly underestimate the frequency of resistance. Considering superinfection in mathematical models of antimalarial drug resistance may thus be important for generating accurate predictions of interventions to contain resistance.

scholarly journals Gene-drive-mediated extinction is thwarted by population structure and evolution of sib mating

2019 ◽  
Vol 2019 (1) ◽  
pp. 66-81 ◽  
Author(s):  
James J Bull ◽  
Christopher H Remien ◽  
Stephen M Krone
Keyword(s):  
Population Structure ◽  
Genome Engineering ◽  
Random Mating ◽  
Structured Populations ◽  
Target Sequence ◽  
Gene Drive ◽  
Resistance Evolution ◽  
Sib Mating ◽  
Mean Fitness ◽  
Gene Drives

AbstractBackground and objectivesGenetic engineering combined with CRISPR technology has developed to the point that gene drives can, in theory, be engineered to cause extinction in countless species. Success of extinction programs now rests on the possibility of resistance evolution, which is largely unknown. Depending on the gene-drive technology, resistance may take many forms, from mutations in the nuclease target sequence (e.g. for CRISPR) to specific types of non-random population structures that limit the drive (that may block potentially any gene-drive technology).MethodologyWe develop mathematical models of various deviations from random mating to consider escapes from extinction-causing gene drives. A main emphasis here is sib mating in the face of recessive-lethal and Y-chromosome drives.ResultsSib mating easily evolves in response to both kinds of gene drives and maintains mean fitness above 0, with equilibrium fitness depending on the level of inbreeding depression. Environmental determination of sib mating (as might stem from population density crashes) can also maintain mean fitness above 0. A version of Maynard Smith’s haystack model shows that pre-existing population structure can enable drive-free subpopulations to be maintained against gene drives.Conclusions and implicationsTranslation of mean fitness into population size depends on ecological details, so understanding mean fitness evolution and dynamics is merely the first step in predicting extinction. Nonetheless, these results point to possible escapes from gene-drive-mediated extinctions that lie beyond the control of genome engineering.Lay summaryRecent gene drive technologies promise to suppress and even eradicate pests and disease vectors. Simple models of gene-drive evolution in structured populations show that extinction-causing gene drives can be thwarted both through the evolution of sib mating as well as from purely demographic processes that cluster drive-free individuals.

scholarly journals Differential Hormetic Response of Fenoxaprop-p-Ethyl Resistant and Susceptible Phalaris minor Populations: a Potential Factor in Resistance Evolution

2019 ◽  
Vol 37 ◽  
Author(s):  
N. FAROOQ ◽  
T. ABBAS ◽  
A. TANVEER ◽  
M.M. JAVAID ◽  
H.H. ALI ◽  
...  
Keyword(s):  
Growth Traits ◽  
Dose Range ◽  
Vital Role ◽  
Phalaris Minor ◽  
Resistance Evolution ◽  
Development Of Resistance ◽  
Wide Range ◽  
Evolution Of Resistance ◽  
Potential Factor ◽  
Susceptible Populations

ABSTRACT: Resistance evolution in weeds against all major herbicide groups demand investigations to identify various factors responsible for resistance development. Herbicide hormesis has not yet been included in the list of factors promoting the evolution of resistance. Studies were conducted to evaluate the degree of hormesis in fenoxaprop-p-ethyl susceptible and resistant Phalaris minor to provide a first indication of whether hormesis is a potential factor in the development of resistance. In the first experiment, a wide range of doses up to 160% of the recommended field rate was used to identify potential hormetic doses for resistant and susceptible P. minor populations. Doses below 40% have been designated as potential hormetic doses. In the second experiment, ten different doses of fenoxaprop below 40% (0, 2, 4, 8, 12, 16, 20, 24, 28 and 32% of the recommended rate) were sprayed at the 4-5 leaf stage of both resistant and susceptible P. minor populations. At fifteen days after spraying, dose range of 2-12% and 2-20% caused a significant increase (up to 22% and 24%) in growth traits of susceptible and resistant populations, respectively. At maturity, dose range of 2-12% for susceptible and 2-24% for resistant populations caused a significant increase (up to 20% and 57%) in growth and seed production potential (13% and 17%), respectively. The upper limit of the hormetic dose range (16 to 24%) for the resistant population was inhibitory for the susceptible populations. These results indicate that fenoxaprop hormesis could play a vital role in the evolution of fenoxaprop resistance in P. minor.

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