scholarly journals Control of malaria-transmitting mosquitoes using gene drives

2020 ◽  
Vol 376 (1818) ◽  
pp. 20190803 ◽  
Author(s):  
Tony Nolan
Keyword(s):  
Malaria Control ◽  
Control Strategies ◽  
Technical Development ◽  
Gene Drive ◽  
Theme Issue ◽  
Genetic Elements ◽  
Selfish Genetic Elements ◽  
Gene Drives ◽  
Transmit Disease ◽  
Proof Of Principle

Gene drives are selfish genetic elements that can be re-designed to invade a population and they hold tremendous potential for the control of mosquitoes that transmit disease. Much progress has been made recently in demonstrating proof of principle for gene drives able to suppress populations of malarial mosquitoes, or to make them refractory to the Plasmodium parasites they transmit. This has been achieved using CRISPR-based gene drives. In this article, I will discuss the relative merits of this type of gene drive, as well as barriers to its technical development and to its deployment in the field as malaria control. This article is part of the theme issue ‘Novel control strategies for mosquito-borne diseases'.

scholarly journals Making gene drive biodegradable

2020 ◽  
Vol 376 (1818) ◽  
pp. 20190804 ◽  
Author(s):  
Josef Zapletal ◽  
Neda Najmitabrizi ◽  
Madhav Erraguntla ◽  
Mark A. Lawley ◽  
Kevin M. Myles ◽  
...  
Keyword(s):  
Laboratory Experiments ◽  
Control Strategies ◽  
Single Component ◽  
Gene Drive ◽  
Theme Issue ◽  
Component System ◽  
Time Limits ◽  
Single Component System ◽  
Drive Systems ◽  
Gene Drives

Gene drive systems have long been sought to modify mosquito populations and thus combat malaria and dengue. Powerful gene drive systems have been developed in laboratory experiments, but may never be used in practice unless they can be shown to be acceptable through rigorous field-based testing. Such testing is complicated by the anticipated difficulty in removing gene drive transgenes from nature. Here, we consider the inclusion of self-elimination mechanisms into the design of homing-based gene drive transgenes. This approach not only caused the excision of the gene drive transgene, but also generates a transgene-free allele resistant to further action by the gene drive. Strikingly, our models suggest that this mechanism, acting at a modest rate (10%) as part of a single-component system, would be sufficient to cause the rapid reversion of even the most robust homing-based gene drive transgenes, without the need for further remediation. Modelling also suggests that unlike gene drive transgenes themselves, self-eliminating transgene approaches are expected to tolerate substantial rates of failure. Thus, self-elimination technology may permit rigorous field-based testing of gene drives by establishing strict time limits on the existence of gene drive transgenes in nature, rendering them essentially biodegradable. This article is part of the theme issue ‘Novel control strategies for mosquito-borne diseases'.

Towards CRISPR/Cas9-based gene drive in the diamondback moth Plutella xylostella

2021 ◽  
Author(s):  
Xuejiao Xu ◽  
Tim Harvey-Samuel ◽  
Hamid Anees Siddiqui ◽  
Joshua Ang ◽  
Michelle E Anderson ◽  
...  
Keyword(s):  
Genetic Control ◽  
Plutella Xylostella ◽  
Control Strategies ◽  
Diamondback Moth ◽  
Regulatory Elements ◽  
Strategy Development ◽  
Gene Drive ◽  
Global Agriculture ◽  
High Level ◽  
Gene Drives

Promising to provide powerful genetic control tools, gene drives have been constructed in multiple dipterans, yeast and mice, for the purposes of population elimination or modification. However, it remains unclear whether these techniques can be applied to lepidopterans. Here, we used endogenous regulatory elements to drive Cas9 and sgRNA expression in the diamondback moth, (Plutella xylostella), and test the first split-drive system in a lepidopteran. The diamondback moth is an economically important global agriculture pest of cruciferous crops and has developed severe resistance to various insecticides, making it a prime candidate for such novel control strategy development. A very high level of somatic editing was observed in Cas9/sgRNA transheterozygotes, although no significant homing was revealed in the subsequent generation. Although heritable, Cas9-medated germline cleavage, as well as maternal and paternal Cas9 deposition was observed, rates were far lower than for somatic cleavage events, indicating robust somatic but limited germline activity of Cas9/sgRNA under the control of selected regulatory elements. Our results provide valuable experience, paving the way for future construction of gene drive-based genetic control strategies in DBM or other lepidopterans.

scholarly journals Evolutionary dynamics of CRISPR gene drives

2016 ◽  
Author(s):  
Charleston Noble ◽  
Jason Olejarz ◽  
Kevin M. Esvelt ◽  
George M. Church ◽  
Martin A. Nowak
Keyword(s):  
Evolutionary Dynamics ◽  
Evolutionary Stability ◽  
Clear Understanding ◽  
Gene Drive ◽  
Host Organism ◽  
Wild Populations ◽  
Selfish Genetic Elements ◽  
Real World Applications ◽  
Drive Systems ◽  
Gene Drives

AbstractThe alteration of wild populations has been discussed as a solution to a number of humanity’s most pressing ecological and public health concerns. Enabled by the recent revolution in genome editing, CRISPR gene drives, selfish genetic elements which can spread through populations even if they confer no advantage to their host organism, are rapidly emerging as the most promising approach. But before real-world applications are considered, it is imperative to develop a clear understanding of the outcomes of drive release in nature. Toward this aim, we mathematically study the evolutionary dynamics of CRISPR gene drives. We demonstrate that the emergence of drive-resistant alleles presents a major challenge to previously reported constructs, and we show that an alternative design which selects against resistant alleles greatly improves evolutionary stability. We discuss all results in the context of CRISPR technology and provide insights which inform the engineering of practical gene drive systems.

scholarly journals Tethered homing gene drives: a new design for spatially restricted population replacement and suppression

2018 ◽  
Author(s):  
Sumit Dhole ◽  
Alun L. Lloyd ◽  
Fred Gould
Keyword(s):  
Mathematical Model ◽  
Genetic Load ◽  
Target Population ◽  
Gene Drive ◽  
Population Replacement ◽  
Additional Release ◽  
New Gene ◽  
Gene Drives ◽  
Population Suppression ◽  
Proof Of Principle

ABSTRACTOptimism regarding potential epidemiological and conservation applications of modern gene drives is tempered by concern about the potential unintended spread of engineered organisms beyond the target population. In response, several novel gene drive approaches have been proposed that can, under certain conditions, locally alter characteristics of a population. One challenge for these gene drives is the difficulty of achieving high levels of localized population suppression without very large releases in face of gene flow. We present a new gene drive system, Tethered Homing (TH), with improved capacity for localized population alteration, especially for population suppression. The TH drive is based on driving a payload gene using a homing construct that is anchored to a spatially restricted gene drive. We use a proof of principle mathematical model to show the dynamics of a TH drive that uses engineered underdominance as an anchor. This system is composed of a split homing drive and a two-locus engineered underdominance drive linked to one part of the split drive (the Cas endonuclease). In addition to improved localization, the TH system offers the ability to gradually adjust the genetic load in a population after the initial alteration, with minimal additional release effort.

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 Veterinary endectocides for malaria control and elimination: prospects and challenges

2020 ◽  
Vol 376 (1818) ◽  
pp. 20190810 ◽  
Author(s):  
Carlos Chaccour
Keyword(s):  
Malaria Transmission ◽  
Malaria Control ◽  
Malaria Elimination ◽  
Control Strategies ◽  
Intestinal Parasites ◽  
Scale Up ◽  
Malaria Risk ◽  
Theme Issue ◽  
Outdoor Biting ◽  
Domestic Livestock

Residual transmission is the persistence of malaria transmission after scale-up of appropriate vector control tools and is one of the key challenges for malaria elimination today. Although long associated with outdoor biting, other mosquito behaviours such as partly feeding upon animals contribute greatly to sustaining transmission. Peri-domestic livestock can be used as decoy to protect humans from blood-seeking vectors but this approach often leads to an increased malaria risk in a phenomenon known as zoopotentiation. Treating the said livestock with drugs capable of killing intestinal parasites as well as mosquitoes that feed upon them has the potential to tackle malaria through a previously unexplored mechanism. The advantages and challenges associated with this approach are briefly discussed here. Numerous references are purposely provided. This article is part of the theme issue ‘Novel control strategies for mosquito-borne diseases’.

scholarly journals Gene drive and resilience through renewal with next generation Cleave and Rescue selfish genetic elements

2019 ◽  
Author(s):  
Georg Oberhofer ◽  
Tobin Ivy ◽  
Bruce A Hay
Keyword(s):  
Essential Gene ◽  
Functional Genes ◽  
Gene Drive ◽  
Genetic Elements ◽  
Selfish Genetic Elements ◽  
Genetic Modifications ◽  
Genes Encoding ◽  
Long Time ◽  
Beneficial Traits

AbstractGene drive-based strategies for modifying populations face the problem that genes encoding cargo and the drive mechanism are subject to separation, mutational inactivation, and loss of efficacy. Resilience, an ability to respond to these eventualities in ways that restore population modification with functional genes is needed for long-term success. Here we show that resilience can be achieved through cycles of population modification with “Cleave and Rescue” (ClvR) selfish genetic elements. ClvR comprises a DNA sequence-modifying enzyme such as Cas9/gRNAs that disrupts endogenous versions of an essential gene, and a recoded version of the essential gene resistant to cleavage. ClvR spreads by creating conditions in which those lacking ClvR die because they lack functional versions of the essential gene. Cycles of modification can in principal be carried out if two ClvR elements targeting different essential genes are located at the same genomic position, and one of them, ClvRn+1, carries a Rescue transgene from an earlier element, ClvRn. ClvRn+1 should spread within a population of ClvRn, while also bringing about a decrease in its frequency. To test this hypothesis we first show that multiple ClvRs, each targeting a different essential gene, function when located at a common chromosomal position in Drosophila. We then show that when several of these also carry the Rescue from a different ClvR, they spread to transgene fixation in populations fixed for the latter, and at its expense. Therefore, genetic modifications of populations can be overwritten with new content, providing an ongoing point of control.SignificanceGene drive can spread beneficial traits through populations, but will never be a one-shot project in which one genetic element provides all desired modifications, for an indefinitely long time. Here we show that gene drive mediated population modification in Drosophila can be overwritten with new content while eliminating old, using Cleave and Rescue (ClvR) selfish genetic elements. The ability to carry out cycles of modification that create and then leave behind a minimal genetic footprint while entering and exiting a population provides important points of control. It makes possible the replacement of broken elements, upgrades with new elements that better carry out their tasks and/or provide new functions, all while promoting the removal of modifications no longer needed.

scholarly journals Viral gene drive in herpesviruses

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Marius Walter ◽  
Eric Verdin
Keyword(s):  
Cell Culture ◽  
High Efficiency ◽  
Human Herpesvirus ◽  
Viral Gene ◽  
Gene Drive ◽  
Dna Viruses ◽  
Successful Transmission ◽  
Genetic Modifications ◽  
Gene Drives ◽  
Proof Of Principle

Abstract Gene drives are genetic modifications designed to propagate in a population with high efficiency. Current gene drive strategies rely on sexual reproduction and are thought to be restricted to sexual organisms. Here, we report on a gene drive system that allows the spread of an engineered trait in populations of DNA viruses and, in particular, herpesviruses. We describe the successful transmission of a gene drive sequence between distinct strains of human cytomegalovirus (human herpesvirus 5) and show that gene drive viruses can efficiently target and replace wildtype populations in cell culture experiments. Moreover, by targeting sequences necessary for viral replication, our results indicate that a viral gene drive can be used as a strategy to suppress a viral infection. Taken together, this work offers a proof of principle for the design of a gene drive in viruses.

scholarly journals Selfish genetic elements and male fertility

2020 ◽  
Vol 375 (1813) ◽  
pp. 20200067
Author(s):  
Rudi L. Verspoor ◽  
Tom A. R. Price ◽  
Nina Wedell
Keyword(s):  
Sperm Competition ◽  
Male Fertility ◽  
Next Generation ◽  
Theme Issue ◽  
Genetic Elements ◽  
Selfish Genetic Elements ◽  
Genomic Conflict ◽  
Offspring Sex ◽  
Competitive Success ◽  
Males And Females

Selfish genetic elements (SGEs) are diverse and near ubiquitous in Eukaryotes and can be potent drivers of evolution. Here, we discuss SGEs that specifically act on sperm to gain a transmission advantage to the next generation. The diverse SGEs that affect sperm often impose costs on carrier males, including damaging ejaculates, skewing offspring sex ratios and in particular reducing sperm-competitive success of SGE-carrying males. How males and females tolerate and mitigate against these costs is a dynamic and expanding area of research. The intense intra-genomic conflict that these selfish elements generate could also have implications for male fertility and spermatogenesis more widely. This article is part of the theme issue ‘Fifty years of sperm competition’.

scholarly journals Gene drive and resilience through renewal with next generation Cleave and Rescue selfish genetic elements

2020 ◽  
Vol 117 (16) ◽  
pp. 9013-9021 ◽  
Author(s):  
Georg Oberhofer ◽  
Tobin Ivy ◽  
Bruce A. Hay
Keyword(s):  
Dna Sequence ◽  
Gene Function ◽  
Essential Gene ◽  
Functional Genes ◽  
Gene Drive ◽  
Genetic Elements ◽  
Selfish Genetic Elements ◽  
Genetic Modifications ◽  
Genes Encoding

Gene drive-based strategies for modifying populations face the problem that genes encoding cargo and the drive mechanism are subject to separation, mutational inactivation, and loss of efficacy. Resilience, an ability to respond to these eventualities in ways that restore population modification with functional genes, is needed for long-term success. Here, we show that resilience can be achieved through cycles of population modification with “Cleave and Rescue” (ClvR) selfish genetic elements. ClvR comprises a DNA sequence-modifying enzyme such as Cas9/gRNAs that disrupts endogenous versions of an essential gene and a recoded version of the essential gene resistant to cleavage. ClvR spreads by creating conditions in which those lacking ClvR die because they lack functional versions of the essential gene. Cycles of modification can, in principle, be carried out if two ClvR elements targeting different essential genes are located at the same genomic position, and one of them, ClvRn+1, carries a Rescue transgene from an earlier element, ClvRn. ClvRn+1 should spread within a population of ClvRn, while also bringing about a decrease in its frequency. To test this hypothesis, we first show that multiple ClvRs, each targeting a different essential gene, function when located at a common chromosomal position in Drosophila. We then show that when several of these also carry the Rescue from a different ClvR, they spread to transgene fixation in populations fixed for the latter and at its expense. Therefore, genetic modifications of populations can be overwritten with new content, providing an ongoing point of control.

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