scholarly journals Population‐level multiplexing: A promising strategy to manage the evolution of resistance against gene drives targeting a neutral locus

2020 ◽  
Vol 13 (8) ◽  
pp. 1939-1948 ◽  
Author(s):  
Matthew P. Edgington ◽  
Tim Harvey‐Samuel ◽  
Luke Alphey
Keyword(s):  
Population Level ◽  
Promising Strategy ◽  
Neutral Locus ◽  
Evolution Of Resistance ◽  
Gene Drives

scholarly journals An overview of the evolution of overproduced esterases in the mosquito Culex pipiens

1998 ◽  
Vol 353 (1376) ◽  
pp. 1707-1711 ◽  
Author(s):  
M. Raymond ◽  
C. Chevillon ◽  
T. Guillemaud ◽  
T. Lenormand ◽  
N. Pasteur
Keyword(s):  
Resistance Genes ◽  
Culex Pipiens ◽  
Population Level ◽  
Chemical Application ◽  
Gene Level ◽  
Genetic Mechanisms ◽  
Evolution Of Resistance ◽  
Passive Transportation ◽  
Term Monitoring

Insecticide resistance genes have developed in a wide variety of insects in response to heavy chemical application. Few of these examples of adaptation in response to rapid environmental change have been studied both at the population level and at the gene level. One of these is the evolution of the overproduced esterases that are involved in resistance to organophosphate insecticides in the mosquito Culex pipiens . At the gene level, two genetic mechanisms are involved in esterase overproduction, namely gene amplification and gene regulation. At the population level, the co–occurrence of the same amplified allele in distinct geographic areas is best explained by the importance of passive transportation at the worldwide scale. The long–term monitoring of a population of mosquitoes in southern France has enabled a detailed study to be made of the evolution of resistance genes on a local scale, and has shown that a resistance gene with a lower cost has replaced a former resistance allele with a higher cost.

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 Targeting evolutionary 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):  
Human Cytomegalovirus ◽  
Viral Gene ◽  
Gene Drive ◽  
Eukaryotic Species ◽  
Resistant Population ◽  
Evolution Of Resistance ◽  
Gene Drives ◽  
Over Time ◽  
Selection Of

Gene drives are genetic systems designed to efficiently spread a modification through a population. Most engineered gene drives rely on CRISPR-Cas9 and were designed in insects or other eukaryotic species. We recently developed a viral gene drive in herpesviruses that efficiently spread into a population of wildtype viruses. A common consequence of gene drives 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 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 regions ensures that drive-resistant 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 viruses, especially for therapeutic applications.

scholarly journals The effect of mating complexity on gene drive dynamics

2021 ◽  
Author(s):  
Prateek Verma ◽  
R. Guy Reeves ◽  
Samson Simon ◽  
Mathias Otto ◽  
Chaitanya S. Gokhale
Keyword(s):  
Mate Choice ◽  
Mating Systems ◽  
Population Level ◽  
Gene Drive ◽  
Wild Populations ◽  
Transgenic Organisms ◽  
Drive Systems ◽  
The Impact ◽  
Gene Drives ◽  
Drive Dynamics

AbstractGene drive technology is being presented as a means to deliver on some of the global challenges humanity faces today in healthcare, agriculture and conservation. However, there is a limited understanding of the consequences of releasing self-perpetuating transgenic organisms into the wild populations under complex ecological conditions. In this study, we analyze the impact of three factors, mate-choice, mating systems and spatial mating network, on the population dynamics for two distinct classes of modification gene drive systems; distortion and viability-based ones. All three factors had a high impact on the modelling outcome. First, we demonstrate that distortion based gene drives appear to be more robust against the mate-choice than viability-based gene drives. Second, we find that gene drive spread is much faster for higher degrees of polygamy. With fitness cost, speed is the highest for intermediate levels of polygamy. Finally, the spread of gene drive is faster and more effective when the individuals have fewer connections in a spatial mating network. Our results highlight the need to include mating complexities while modelling the population-level spread of gene drives. This will enable a more confident prediction of release thresholds, timescales and consequences of gene drive in populations.

scholarly journals Spatial structure undermines parasite suppression by gene drive cargo

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e7921 ◽  
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

Gene 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 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.

Mentoring: A Promising Strategy for Youth Development

2001 ◽  
Author(s):  
Susan M. Jekielek ◽  
Kristin M. Moore ◽  
Elizabeth C. Hair ◽  
Harriet J. Scarupa
Keyword(s):  
Youth Development ◽  
Promising Strategy
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