scholarly journals Synthetically EngineeredMedeaGene Drive System in the Worldwide Crop Pest,D. suzukii

2017 ◽  
Author(s):  
Anna Buchman ◽  
John M. Marshall ◽  
Dennis Ostrovski ◽  
Ting Yang ◽  
Omar S. Akbari
Keyword(s):  
Wild Population ◽  
Mendelian Inheritance ◽  
Gene Drive ◽  
Fitness Costs ◽  
High Frequencies ◽  
Toxin Resistance ◽  
Crop Pest ◽  
Naturally Occurring ◽  
Drive Systems ◽  
Significant Disease

AbstractSynthetic gene drive systems possess enormous potential to replace, alter, or suppress wild populations of significant disease vectors and crop pests; however, their utility in diverse populations remains to be demonstrated. Here, we report the creation of the first-ever syntheticMedeagene drive element in a major worldwide crop pest,D. suzukii. We demonstrate that this drive element, based on an engineered maternal “toxin” coupled with a linked embryonic “antidote,” is capable of biasing Mendelian inheritance rates with up to 100% efficiency. However, we find that drive resistance, resulting from naturally occurring genetic variation and associated fitness costs, can hinder the spread of such an element. Despite this, our results suggest that this element could maintain itself at high frequencies in a wild population, and spread to fixation, if either its fitness costs or toxin resistance were reduced, providing a clear path forward for developing future such systems.

scholarly journals Synthetically engineered Medea gene drive system in the worldwide crop pest Drosophila suzukii

2018 ◽  
Vol 115 (18) ◽  
pp. 4725-4730 ◽  
Author(s):  
Anna Buchman ◽  
John M. Marshall ◽  
Dennis Ostrovski ◽  
Ting Yang ◽  
Omar S. Akbari
Keyword(s):  
Mendelian Inheritance ◽  
Drive System ◽  
Gene Drive ◽  
Fitness Costs ◽  
Drosophila Suzukii ◽  
Toxin Resistance ◽  
Crop Pest ◽  
Naturally Occurring ◽  
Drive Systems ◽  
Significant Disease

Synthetic gene drive systems possess enormous potential to replace, alter, or suppress wild populations of significant disease vectors and crop pests; however, their utility in diverse populations remains to be demonstrated. Here, we report the creation of a synthetic Medea gene drive system in a major worldwide crop pest, Drosophila suzukii. We demonstrate that this drive system, based on an engineered maternal “toxin” coupled with a linked embryonic “antidote,” is capable of biasing Mendelian inheritance rates with up to 100% efficiency. However, we find that drive resistance, resulting from naturally occurring genetic variation and associated fitness costs, can be selected for and hinder the spread of such a drive. Despite this, our results suggest that this gene drive could maintain itself at high frequencies in a wild population and spread to fixation if either its fitness costs or toxin resistance were reduced, providing a clear path forward for developing future such systems in this pest.

scholarly journals Invasion and migration of spatially self-limiting gene drives: a comparative analysis

2017 ◽  
Author(s):  
Sumit Dhole ◽  
Michael R. Vella ◽  
Alun L. Loyd ◽  
Fred Gould
Keyword(s):  
Target Population ◽  
Gene Drive ◽  
Fitness Costs ◽  
Invasion And Migration ◽  
Migration Rates ◽  
Chain System ◽  
Drive Systems ◽  
And Migration ◽  
The One ◽  
Gene Drives

AbstractRecent advances in research on gene drives have produced genetic constructs that could theoretically spread a desired gene (payload) into all populations of a species, with a single release in one place. This attribute has advantages, but also comes with risks and ethical concerns. There has been a call for research on gene drive systems that are spatially and/or temporally self-limiting. Here we use a population genetics model to compare the expected characteristics of three spatially self-limiting gene drive systems: one-locus underdominance, two-locus underdominance, and daisy-chain drives. We find large differences between these gene drives in the minimum release size required for successfully driving a payload into a population. The daisy-chain system is the most efficient, requiring the smallest release, followed by the two-locus underdominance system, and then the one-locus underdominance system. However, when the target population exchanges migrants with a non-target population, the gene drives requiring smaller releases suffer from higher risks of unintended spread. For payloads that incur relatively low fitness costs (up to 30%), a simple daisy-chain drive is practically incapable of remaining localized, even with migration rates as low as 0.5% per generation. The two-locus underdominance system can achieve localized spread under a broader range of migration rates and of payload fitness costs, while the one-locus underdominance system largely remains localized. We also find differences in the extent of population alteration and in the permanence of the alteration achieved by the three gene drives. The two-locus underdominance system does not always spread the payload to fixation, even after successful drive, while the daisy-chain system can, for a small set of parameter values, achieve a temporally-limited spread of the payload. These differences could affect the suitability of each gene drive for specific applications.Note:This manuscript has been accepted for publication in the journal Evolutionary Applications and is pending publication. We suggest that any reference to or quotation of this article should be made with this recognition.

scholarly journals Experiments confirm a dispersive phenotype associated with a natural gene drive system

2021 ◽  
Vol 8 (5) ◽  
Author(s):  
Jan-Niklas Runge ◽  
Anna K. Lindholm
Keyword(s):  
Sperm Competition ◽  
Local Density ◽  
House Mice ◽  
Gene Drive ◽  
Wild Type ◽  
Fitness Costs ◽  
Oestrus Cycle ◽  
Drive Systems ◽  
Average Body ◽  
Average Body Weight

Meiotic drivers are genetic entities that increase their own probability of being transmitted to offspring, usually to the detriment of the rest of the organism, thus ‘selfishly’ increasing their fitness. In many meiotic drive systems, driver-carrying males are less successful in sperm competition, which occurs when females mate with multiple males in one oestrus cycle (polyandry). How do drivers respond to this selection? An observational study found that house mice carrying the t haplotype, a meiotic driver, are more likely to disperse from dense populations. This could help the t avoid detrimental sperm competition, because density is associated with the frequency of polyandry. However, no controlled experiments have been conducted to test these findings. Here, we confirm that carriers of the t haplotype are more dispersive, but we do not find this to depend on the local density. t -carriers with above-average body weight were particularly more likely to disperse than wild-type mice. t -carrying mice were also more explorative but not more active than wild-type mice. These results add experimental support to the previous observational finding that the t haplotype affects the dispersal phenotype in house mice, which supports the hypothesis that dispersal reduces the fitness costs of the t .

scholarly journals Mathematical modeling of self-contained CRISPR gene drive reversal systems

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Matthew G. Heffel ◽  
Gregory C. Finnigan
Keyword(s):  
Mendelian Inheritance ◽  
Ecological Systems ◽  
Mathematical Work ◽  
Gene Drive ◽  
Key Species ◽  
Type Population ◽  
Reversal Mechanism ◽  
Drive Systems ◽  
External Stimuli ◽  
Gene Drives

AbstractThere is a critical need for further research into methods to control biological populations. Numerous challenges to agriculture, ecological systems, and human health could be mitigated by the targeted reduction and management of key species (e.g. pests, parasites, and vectors for pathogens). The discovery and adaptation of the CRISPR/Cas editing platform co-opted from bacteria has provided a mechanism for a means to alter an entire population. A CRISPR-based gene drive system can allow for the forced propagation of a genetic element that bypasses Mendelian inheritance which can be used to bias sex determination, install exogenous information, or remove endogenous DNA within an entire species. Laboratory studies have demonstrated the potency by which gene drives can operate within insects and other organisms. However, continued research and eventual application face serious opposition regarding issues of policy, biosafety, effectiveness, and reversal. Previous mathematical work has suggested the use of modified gene drive designs that are limited in spread such as daisy chain or underdominance drives. However, no system has yet been proposed that allows for an inducible reversal mechanism without requiring the introduction of additional individuals. Here, we study gene drive effectiveness, fitness, and inducible drive systems that could respond to external stimuli expanding from a previous frequency-based population model. We find that programmed modification during gene drive propagation could serve as a potent safeguard to either slow or completely reverse drive systems and allow for a return to the original wild-type population.

scholarly journals Genetic conversion of a split-drive into a full-drive element

2021 ◽  
Author(s):  
Gerard Terradas ◽  
Jared B. Bennett ◽  
Zhiqian Li ◽  
John M. Marshall ◽  
Ethan Bier
Keyword(s):  
Gene Drive ◽  
Fitness Costs ◽  
Experimental Proof ◽  
Guide Rna ◽  
Split Gene ◽  
Core Components ◽  
Beneficial Traits ◽  
Drive Systems ◽  
Genetic Conversion ◽  
Gene Drives

AbstractGene-drive systems offer an important new avenue for spreading beneficial traits into wild populations. Their core components, Cas9 and guide RNA (gRNA), can either be linked within a single cassette (full gene drive, fGD) or provided in two separate elements (split gene drive, sGD) wherein the gRNA-bearing element drives in the presence of an independent static source of Cas9. We previously designed a system engineered to turn split into full gene drives. Here, we provide experimental proof-of-principle for such a convertible system inserted at the spo11 locus, which is recoded to restore gene function. In multigenerational cage studies, the reconstituted spo11 fGD cassette initially drives with slower kinetics than the unlinked sGD element (using the same Mendelian vasa-Cas9 source), but eventually reaches a similar level of final introgression. Different kinetic behaviors may result from transient fitness costs associated with individuals co-inheriting Cas9 and gRNA transgenes during the drive process.

scholarly journals CRISPR gene-drive systems based on Cas9 nickases promote super-Mendelian inheritance in Drosophila

2021 ◽  
Author(s):  
Víctor López Del Amo ◽  
Sara Sanz Juste ◽  
Valentino M. Gantz
Keyword(s):  
Dna Repair ◽  
Mendelian Inheritance ◽  
Essential Genes ◽  
Gene Products ◽  
Gene Drive ◽  
Repair Pathway ◽  
Wild Populations ◽  
Drive Systems ◽  
Gene Drives ◽  
Wildtype Allele

ABSTRACTCRISPR-based gene drive systems can be used to modify entire wild populations due to their ability to bias their own inheritance towards super-Mendelian rates (>100%). Current gene drives contain a Cas9 and a gRNA gene inserted at the location targeted by the gRNA. These gene products are able to cut the opposing wildtype allele, and lead to its replacement with a copy of the gene drive through the homology-directed DNA repair pathway. When this allelic conversion occurs in the germline it leads to the preferential inheritance of the engineered allele — a property that has been proposed to disseminate engineered traits for managing disease-transmitting mosquito populations. Here, we report a novel gene-drive strategy relying on Cas9 nickases which operates by generating staggered paired-nicks in the DNA to promote propagation of the gene drive allele. We show that only when 5’ overhangs are generated, the system efficiently leads to allelic conversion. Further, the nickase gene-drive arrangement produces large stereotyped deletions, providing potential advantages for targeting essential genes. Indeed, the nickase-gene-drive design should expand the options available for gene drive designs aimed at applications in mosquitoes and beyond.

scholarly journals Optimized CRISPR tools and site-directed transgenesis in Culex quinquefasciatus mosquitoes for gene drive development

2021 ◽  
Author(s):  
Xuechun Feng ◽  
Víctor López Del Amo ◽  
Enzo Mameli ◽  
Megan Lee ◽  
Alena L. Bishop ◽  
...  
Keyword(s):  
Culex Quinquefasciatus ◽  
Technology Development ◽  
Companion Animals ◽  
Fruit Fly ◽  
Valuable Insight ◽  
Gene Drive ◽  
Future Technology ◽  
Drive Systems ◽  
Global Vector ◽  
Human And Animal Diseases

ABSTRACTCulex mosquitoes are a global vector for multiple human and animal diseases, including West Nile virus, lymphatic filariasis, and avian malaria, posing a constant threat to public health, livestock, companion animals, and endangered birds. While rising insecticide resistance has threatened the control of Culex mosquitoes, advances in CRISPR genome-editing tools have fostered the development of alternative genetic strategies such as gene drive systems to fight disease vectors. However, though gene-drive technology has quickly progressed in other mosquitoes, advances have been lacking in Culex. Here, we developed a Culex-specific Cas9/gRNA expression toolkit and used site-directed homology-based transgenesis to generate and validate a Culex quinquefasciatus Cas9-expressing line. We showed that gRNA scaffold variants improve transgenesis efficiency in both Culex and Drosophila and boost gene-drive performance in the fruit fly. These findings support future technology development to control Culex mosquitoes and provide valuable insight for improving these tools in other species.

scholarly journals A Killer–Rescue system for self-limiting gene drive of anti-pathogen constructs

2008 ◽  
Vol 275 (1653) ◽  
pp. 2823-2829 ◽  
Author(s):  
Fred Gould ◽  
Yunxin Huang ◽  
Mathieu Legros ◽  
Alun L Lloyd
Keyword(s):  
Gene Action ◽  
Natural Populations ◽  
Gene Drive ◽  
Fitness Costs ◽  
Molecular Approaches ◽  
Genetic Mechanisms ◽  
Rescue System ◽  
Near Term ◽  
Killer Gene ◽  
Over Time

A number of genetic mechanisms have been suggested for driving anti-pathogen genes into natural populations. Each of these mechanisms requires complex genetic engineering, and most are theoretically expected to permanently spread throughout the target species' geographical range. In the near term, risk issues and technical limits of molecular methods could delay the development and use of these mechanisms. We propose a gene-drive mechanism that can be self-limiting over time and space, and is simpler to build. This mechanism involves one gene that codes for toxicity (killer) and a second that confers immunity to the toxic effects (rescue). We use population-genetic models to explore cases with one or two independent insertions of the killer gene and one insertion of the rescue gene. We vary the dominance and penetrance of gene action, as well as the magnitude of fitness costs. Even with the fitness costs of 10 per cent for each gene, the proportion of mosquitoes expected to transmit the pathogen decreases below 5 per cent for over 40 generations after one 2 : 1 release (engineered : wild) or after four 1 : 2 releases. Both the killer and rescue genes will be lost from the population over time, if the rescue construct has any associated fitness cost. Molecular approaches for constructing strains are discussed.

scholarly journals Gene Therapy: A Promising Therapeutic Strategy for Malaria

2018 ◽  
Vol 8 (2) ◽  
pp. 40-44
Author(s):  
Raafay Shehzad
Keyword(s):  
Gene Therapy ◽  
Therapeutic Strategy ◽  
Homing Endonuclease ◽  
Genetic Material ◽  
Gene Drive ◽  
Treatment And Prevention ◽  
Preventative Measures ◽  
Drive Systems ◽  
Embryonic Arrest ◽  
Diabetes And Obesity

Malaria is a serious illness caused by the Plasmodium parasite, which places approximately 3.5 billion people at risk. Currently, preventative measures are key in combatting this disease. However, gene therapy is an emerging field that shows promising results for the treatment of malaria, by modifying cells through the delivery of genetic material. Most notable was the discovery of CRISPR-Cas9, which not only allows deleterious mutations to be repaired, but does so with specificity, speed, and simplicity. There are numerous ongoing trials focusing on gene therapy in malaria treatment and prevention. They involve different approaches such as the genetic modification of vector mosquitoes to interfere with malaria transmission, use of CRISPR-Cas9, maternal-effect dominant embryonic arrest, homing endonuclease gene drive systems, and the design of specific Morpholino oligomers to interfere with the expression of parasitic characteristics. Overall, this emerging field shows promising results to treat and prevent not just malaria, but other diseases such as cancer, diabetes, and obesity.

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