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 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 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 Small-molecule control of super-Mendelian inheritance in gene drives

2019 ◽  
Author(s):  
Víctor López Del Amo ◽  
Brittany S. Leger ◽  
Kurt J. Cox ◽  
Shubhroz Gill ◽  
Alena L. Bishop ◽  
...  
Keyword(s):  
Small Molecule ◽  
Chemical Control ◽  
Control Strategies ◽  
Mendelian Inheritance ◽  
Drive System ◽  
Gene Drive ◽  
Crop Pests ◽  
Vector Borne Diseases ◽  
Vector Borne ◽  
Gene Drives

ABSTRACTBy surpassing the 50% inheritance limit of Mendel’s law of independent assortment, CRISPR-based gene drives have the potential to fight vector-borne diseases or suppress crop pests. However, contemporary gene drives could spread unchecked, posing safety concerns that limit their use in both laboratory and field settings. Current technologies also lack chemical control strategies, which could be applied in the field for dose, spatial and temporal control of gene drives. We describe in Drosophila the first gene-drive system controlled by an engineered Cas9 and a synthetic, orally-available small molecule.Graphical Abstract

scholarly journals Genomic insertion locus and Cas9 expression in the germline affect CRISPR/Cas9-based gene drive performance in the yellow fever mosquito Aedes aegypti

2021 ◽  
Author(s):  
William R Reid ◽  
Jingyi Lin ◽  
Adeline E Williams ◽  
Rucsanda Juncu ◽  
Ken E Olson ◽  
...  
Keyword(s):  
Aedes Aegypti ◽  
Yellow Fever ◽  
Drive System ◽  
Gene Drive ◽  
Yellow Fever Mosquito ◽  
Genomic Locus ◽  
Population Replacement ◽  
Novel Approach ◽  
Drive Systems ◽  
Insertion Locus

The yellow fever mosquito Aedes aegypti is a major vector of arthropod-borne viruses, including dengue, chikungunya, and Zika. A novel approach to mitigate arboviral infections is to generate mosquitoes refractory to infection by overexpressing antiviral effector molecules. Such an approach requires a mechanism to spread these antiviral effectors through a population, for example, by using CRISPR/Cas9-based gene drive systems. Here we report an autonomous single-component gene drive system in Ae. aegypti that is designed for persistent population replacement. Critical to the design of a single-locus autonomous gene drive is that the selected genomic locus be amenable to both gene drive and the appropriate expression of the antiviral effector. In our study, we took a reverse engineering approach to target two genomic loci ideal for the expression of antiviral effectors and further investigated the use of three promoters for Cas9 expression (nanos, β2-tubulin, or zpg) for the gene drive. We found that both promoter selection and genomic target site strongly influenced the efficiency of the drive, resulting in 100% inheritance in some crosses. We also observed the formation of inheritable gene drive blocking indels (GDBI) in the genomic locus with the highest levels of gene drive. Overall, our drive system forms a platform for the further testing of driving antipathogen effector genes through Ae. aegypti populations.

scholarly journals Development and testing of a novel Killer-Rescue self-limiting gene drive system in Drosophila melanogaster

2019 ◽  
Author(s):  
Sophia H. Webster ◽  
Michael R. Vella ◽  
Maxwell J. Scott
Keyword(s):  
Drosophila Melanogaster ◽  
Core Promoter ◽  
Expression System ◽  
Drive System ◽  
Gene Drive ◽  
Drosophila Suzukii ◽  
Population Replacement ◽  
Gal4 Expression ◽  
Rescue System ◽  
Release Ratio

AbstractWe report the development and laboratory testing of a novel Killer-Rescue (K-R) self-limiting gene drive system in Drosophila melanogaster. This K-R system utilizes the well-characterized Gal4/UAS binary expression system and the Gal4 inhibitor, Gal80. Three killer (K) lines were tested; these used either an autoregulated UAS-Gal4 or UAS-Gal4 plus UAS-hid transgene. One universal rescue (R) line was used, UAS-Gal80, to inhibit Gal4 expression. The K lines are lethal and cause death in the absence of R. We show that Gal4 RNA levels are high in the absence of R. Death is possibly due to transcriptional squelching from high levels of Gal4. When R is present, Gal4 activation of Gal80 would lead to inhibition of Gal4 and prevent overexpression. With a single release ratio of 2:1 engineered K-R to wildtype, we find that K drives R through the population while the percent of wild type individuals decreases each generation. The choice of core promoter for a UAS-Gal4 construct strongly influences the K-R system. With the strong hsp70 core promoter, K was very effective but was quickly lost from the population. With the weaker DSCP core promoter, K persisted for longer allowing the frequency of individuals with at least one copy of R to increase to over 98%. This simple gene drive system could be readily adapted to other species such as mosquito disease vectors for driving anti-viral or anti-parasite genes.SignificanceHere we report the development and testing of a novel self-limiting gene drive system, Killer-Rescue, in Drosophila melanogaster. This system is composed of an auto-regulated Gal4 Killer (K) and a Gal4-activated Gal80 Rescue (R). Overexpression of Gal4 is lethal but in the presence of R, activation of Gal80 leads to much lower levels of Gal4 and rescue of lethality. We demonstrate that with a single 2:1 engineered to wildtype release, more than 98% of the population carry R after eight generations. We discuss how this Killer-Rescue system may be used for population replacement in a human health pest, Aedes aegypti, or for population suppression in an agricultural pest, Drosophila suzukii.

scholarly journals Gene Drives Across Engineered Fitness Valleys: Modeling a Design to Prevent Drive Spillover

2020 ◽  
Author(s):  
Frederik J.H. de Haas ◽  
Sarah P. Otto
Keyword(s):  
Local Population ◽  
Target Population ◽  
Drive System ◽  
High Threshold ◽  
Gene Drive ◽  
Time Model ◽  
Population Replacement ◽  
Low Threshold ◽  
Drive Systems ◽  
Gene Drives

1AbstractEngineered gene drive techniques for population replacement and/or suppression have potential for tackling complex challenges, including reducing the spread of diseases and invasive species. Unfortunately, the self-propelled behavior of drives can lead to the spread of transgenic elements beyond the target population, which is concerning. Gene drive systems with a low threshold frequency for invasion, such as homing-based gene drive systems, require initially few transgenic individuals to spread and are therefore easy to implement. However their ease of spread presents a double-edged sword; their low threshold makes these drives much more susceptible to spread outside of the target population (spillover). We model a proposed drive system that transitions in time from a low threshold drive system (homing-based gene drive) to a high threshold drive system (underdominance) using daisy chain technology. This combination leads to a spatially restricted drive strategy, while maintaining an attainable release threshold. We develop and analyze a discrete-time model as proof of concept and find that this technique effectively generates stable local population suppression, while preventing the spread of transgenic elements beyond the target population under biologically realistic parameters.

scholarly journals Daisy-chain gene drives for the alteration of local populations

2019 ◽  
Vol 116 (17) ◽  
pp. 8275-8282 ◽  
Author(s):  
Charleston Noble ◽  
John Min ◽  
Jason Olejarz ◽  
Joanna Buchthal ◽  
Alejandro Chavez ◽  
...  
Keyword(s):  
Drive System ◽  
Chain Gene ◽  
Gene Drive ◽  
Rna Sequences ◽  
Guide Rna ◽  
Highly Active ◽  
Wide Range ◽  
Fitness Parameters ◽  
Drive Systems ◽  
Gene Drives

If they are able to spread in wild populations, CRISPR-based gene-drive elements would provide new ways to address ecological problems by altering the traits of wild organisms, but the potential for uncontrolled spread tremendously complicates ethical development and use. Here, we detail a self-exhausting form of CRISPR-based drive system comprising genetic elements arranged in a daisy chain such that each drives the next. “Daisy-drive” systems can locally duplicate any effect achievable by using an equivalent self-propagating drive system, but their capacity to spread is limited by the successive loss of nondriving elements from one end of the chain. Releasing daisy-drive organisms constituting a small fraction of the local wild population can drive a useful genetic element nearly to local fixation for a wide range of fitness parameters without self-propagating spread. We additionally report numerous highly active guide RNA sequences sharing minimal homology that may enable evolutionarily stable daisy drive as well as self-propagating CRISPR-based gene drive. Especially when combined with threshold dependence, daisy drives could simplify decision-making and promote ethical use by enabling local communities to decide whether, when, and how to alter local ecosystems.

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.

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