Modeling the efficacy of CRISPR gene drive for schistosomiasis control

CRISPR gene drives could revolutionize the control of infectious diseases by accelerating the spread of engineered traits that limit parasite transmission in wild populations. While much effort has been spent developing gene drives in mosquitoes, gene drive technology in molluscs has received little attention despite the role of freshwater snails as obligate, intermediate hosts of parasitic flukes causing schistosomiasis -- a disease of poverty affecting more than 200 million people worldwide. A successful drive in snails must overcome self-fertilization, which prevents a drive's spread. Simultaneous hermaphroditism is a feature of snails -- distinct from gene drive model organisms -- and is not yet incorporated in gene drive models of disease control. Here we developed a novel population genetic model accounting for snails' sexual and asexual reproduction, susceptibility to parasite infection regulated by multiple alleles, fitness differences between genotypes, and a range of drive characteristics. We then integrated this model with an epidemiological model of schistosomiasis transmission and snail population dynamics. Simulations showed that gene drive establishment can be hindered by a variety of biological and ecological factors, including selfing. However, our model suggests that, under a range of conditions, gene drive mediated immunity in snails could maintain rapid disease reduction achieved by annual chemotherapy treatment of the human population, leading to long-term elimination. These results indicate that gene drives, in coordination with existing public health measures, may become a useful tool to reduce schistosomiasis burden in selected transmission settings with effective CRISPR construct design and close evaluation of the genetic and ecological landscape.

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Containment strategies for synthetic gene drive organisms and impacts on gene flow.

10.1079/9781789247480.0010 ◽

2021 ◽

pp. 137-152

Author(s):

Lei Pei ◽

Markus Schmidt

Keyword(s):

Gene Flow ◽

Fungal Infections ◽

Basic Research ◽

Fruit Fly ◽

Mitigation Strategies ◽

Synthetic Gene ◽

Model Organisms ◽

Gene Drive ◽

Comprehensive Overview ◽

Gene Drives

Abstract Gene drives, particularly synthetic gene drives, may help to address some important challenges, by efficiently altering specific sections of DNA in entire populations of wild organisms. Here we review the current development of the synthetic gene drives, especially those RNA-guided synthetic gene drives based on the CRISPR nuclease Cas. Particular focuses are on their possible applications in agriculture (e.g. disease resistance, weed control management), ecosystem conservation (e.g. evasion species control), health (e.g. to combat insect-borne and fungal infections), and for basic research in model organisms (e.g. Saccharomyces, fruit fly, and zebra fish). The physical, chemical, biological, and ecological containment strategies that might help to confine these gene drive-modified organisms are then explored. The gene flow issues, those from gene drive-derived organisms to the environment, are discussed, while possible mitigation strategies for gene drive research are explored. Last but not least, the regulatory context and opinions from key stakeholders (regulators, scientists, and concerned organizations) are reviewed, aiming to provide a more comprehensive overview of the field.

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Rodent gene drives for conservation: opportunities and data needs

Proceedings of The Royal Society B Biological Sciences ◽

10.1098/rspb.2019.1606 ◽

2019 ◽

Vol 286 (1914) ◽

pp. 20191606 ◽

Cited By ~ 6

Author(s):

John Godwin ◽

Megan Serr ◽

S. Kathleen Barnhill-Dilling ◽

Dimitri V. Blondel ◽

Peter R. Brown ◽

...

Keyword(s):

Food Security ◽

Human Health ◽

Genetic Model ◽

Current Control ◽

Invasive Pest ◽

Gene Drive ◽

Knowledge Gaps ◽

Drive Systems ◽

Invasive Rodents ◽

Gene Drives

Invasive rodents impact biodiversity, human health and food security worldwide. The biodiversity impacts are particularly significant on islands, which are the primary sites of vertebrate extinctions and where we are reaching the limits of current control technologies. Gene drives may represent an effective approach to this challenge, but knowledge gaps remain in a number of areas. This paper is focused on what is currently known about natural and developing synthetic gene drive systems in mice, some key areas where key knowledge gaps exist, findings in a variety of disciplines relevant to those gaps and a brief consideration of how engagement at the regulatory, stakeholder and community levels can accompany and contribute to this effort. Our primary species focus is the house mouse, Mus musculus , as a genetic model system that is also an important invasive pest. Our primary application focus is the development of gene drive systems intended to reduce reproduction and potentially eliminate invasive rodents from islands. Gene drive technologies in rodents have the potential to produce significant benefits for biodiversity conservation, human health and food security. A broad-based, multidisciplinary approach is necessary to assess this potential in a transparent, effective and responsible manner.

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Gene Drive Dynamics in Natural Populations: The Importance of Density Dependence, Space, and Sex

Annual Review of Ecology Evolution and Systematics ◽

10.1146/annurev-ecolsys-031120-101013 ◽

2020 ◽

Vol 51 (1) ◽

pp. 505-531 ◽

Cited By ~ 3

Author(s):

Sumit Dhole ◽

Alun L. Lloyd ◽

Fred Gould

Keyword(s):

Density Dependence ◽

Natural Populations ◽

Ecological Factors ◽

Single Individual ◽

Gene Drive ◽

Deterministic Models ◽

Realistic Assessment ◽

Dependence Space ◽

Gene Drives ◽

Drive Dynamics

The spread of synthetic gene drives is often discussed in the context of panmictic populations connected by gene flow and described with simple deterministic models. Under such assumptions, an entire species could be altered by releasing a single individual carrying an invasive gene drive, such as a standard homing drive. While this remains a theoretical possibility, gene drive spread in natural populations is more complex and merits a more realistic assessment. The fate of any gene drive released in a population would be inextricably linked to the population's ecology. Given the uncertainty often involved in ecological assessment of natural populations, understanding the sensitivity of gene drive spread to important ecological factors is critical. Here we review how different forms of density dependence, spatial heterogeneity, and mating behaviors can impact the spread of self-sustaining gene drives. We highlight specific aspects of gene drive dynamics and the target populations that need further research.

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Novel combination of CRISPR-based gene drives eliminates resistance and localises spread

Scientific Reports ◽

10.1038/s41598-021-83239-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Nicky R. Faber ◽

Gus R. McFarlane ◽

R. Chris Gaynor ◽

Ivan Pocrnic ◽

C. Bruce A. Whitelaw ◽

...

Keyword(s):

Driving Forces ◽

Spatial Models ◽

Cost Effective ◽

Biodiversity Loss ◽

Invasive Pest ◽

Economic Losses ◽

Sciurus Carolinensis ◽

Gene Drive ◽

Grey Squirrel ◽

Gene Drives

AbstractInvasive species are among the major driving forces behind biodiversity loss. Gene drive technology may offer a humane, efficient and cost-effective method of control. For safe and effective deployment it is vital that a gene drive is both self-limiting and can overcome evolutionary resistance. We present HD-ClvR in this modelling study, a novel combination of CRISPR-based gene drives that eliminates resistance and localises spread. As a case study, we model HD-ClvR in the grey squirrel (Sciurus carolinensis), which is an invasive pest in the UK and responsible for both biodiversity and economic losses. HD-ClvR combats resistance allele formation by combining a homing gene drive with a cleave-and-rescue gene drive. The inclusion of a self-limiting daisyfield gene drive allows for controllable localisation based on animal supplementation. We use both randomly mating and spatial models to simulate this strategy. Our findings show that HD-ClvR could effectively control a targeted grey squirrel population, with little risk to other populations. HD-ClvR offers an efficient, self-limiting and controllable gene drive for managing invasive pests.

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Insights into mammalian biology from the wild house mouse Mus musculus

eLife ◽

10.7554/elife.05959 ◽

2015 ◽

Vol 4 ◽

Cited By ~ 45

Author(s):

Megan Phifer-Rixey ◽

Michael W Nachman

Keyword(s):

House Mouse ◽

Mus Musculus ◽

Genetic Model ◽

Inbred Strains ◽

Mendelian Inheritance ◽

Model Organisms ◽

House Mice ◽

Small Subset ◽

Wild Mice ◽

Wide Range

The house mouse, Mus musculus, was established in the early 1900s as one of the first genetic model organisms owing to its short generation time, comparatively large litters, ease of husbandry, and visible phenotypic variants. For these reasons and because they are mammals, house mice are well suited to serve as models for human phenotypes and disease. House mice in the wild consist of at least three distinct subspecies and harbor extensive genetic and phenotypic variation both within and between these subspecies. Wild mice have been used to study a wide range of biological processes, including immunity, cancer, male sterility, adaptive evolution, and non-Mendelian inheritance. Despite the extensive variation that exists among wild mice, classical laboratory strains are derived from a limited set of founders and thus contain only a small subset of this variation. Continued efforts to study wild house mice and to create new inbred strains from wild populations have the potential to strengthen house mice as a model system.

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A circadian clock in Saccharomyces cerevisiae

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0907902107 ◽

2010 ◽

Vol 107 (5) ◽

pp. 2043-2047 ◽

Cited By ~ 44

Author(s):

Zheng Eelderink-Chen ◽

Gabriella Mazzotta ◽

Marcel Sturre ◽

Jasper Bosman ◽

Till Roenneberg ◽

...

Keyword(s):

Saccharomyces Cerevisiae ◽

Genetic Model ◽

Circadian Clocks ◽

Model Systems ◽

Model Organisms ◽

Biological Clocks ◽

Experimental Systems ◽

Fundamental Biological Process ◽

Free Running ◽

And Behavior

Circadian timing is a fundamental biological process, underlying cellular physiology in animals, plants, fungi, and cyanobacteria. Circadian clocks organize gene expression, metabolism, and behavior such that they occur at specific times of day. The biological clocks that orchestrate these daily changes confer a survival advantage and dominate daily behavior, for example, waking us in the morning and helping us to sleep at night. The molecular mechanism of circadian clocks has been sketched out in genetic model systems from prokaryotes to humans, revealing a combination of transcriptional and posttranscriptional pathways, but the clock mechanism is far from solved. Although Saccharomyces cerevisiae is among the most powerful genetic experimental systems and, as such, could greatly contribute to our understanding of cellular timing, it still remains absent from the repertoire of circadian model organisms. Here, we use continuous cultures of yeast, establishing conditions that reveal characteristic clock properties similar to those described in other species. Our results show that metabolism in yeast shows systematic circadian entrainment, responding to cycle length and zeitgeber (stimulus) strength, and a (heavily damped) free running rhythm. Furthermore, the clock is obvious in a standard, haploid, auxotrophic strain, opening the door for rapid progress into cellular clock mechanisms.

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

10.1101/2021.10.05.462963 ◽

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.

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Habituation in high-throughput genetic model organisms as a tool to investigate the mechanisms of neurodevelopmental disorders

Neurobiology of Learning and Memory ◽

10.1016/j.nlm.2020.107208 ◽

2020 ◽

Vol 171 ◽

pp. 107208 ◽

Cited By ~ 2

Author(s):

Lexis D. Kepler ◽

Troy A. McDiarmid ◽

Catharine H. Rankin

Keyword(s):

High Throughput ◽

Neurodevelopmental Disorders ◽

Genetic Model ◽

Model Organisms

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A CRISPR homing gene drive targeting a haplolethal gene removes resistance alleles and successfully spreads through a cage population

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2004373117 ◽

2020 ◽

Vol 117 (39) ◽

pp. 24377-24383 ◽

Cited By ~ 7

Author(s):

Jackson Champer ◽

Emily Yang ◽

Esther Lee ◽

Jingxian Liu ◽

Andrew G. Clark ◽

...

Keyword(s):

Gene Drive ◽

End Joining ◽

Large Cage ◽

Vector Borne Diseases ◽

Guide Rnas ◽

Genetic Modifications ◽

New Strategy ◽

Cage Population ◽

Vector Borne ◽

Gene Drives

Engineered gene drives are being explored as a new strategy in the fight against vector-borne diseases due to their potential for rapidly spreading genetic modifications through a population. However, CRISPR-based homing gene drives proposed for this purpose have faced a major obstacle in the formation of resistance alleles that prevent Cas9 cleavage. Here, we present a homing drive in Drosophila melanogaster that reduces the prevalence of resistance alleles below detectable levels by targeting a haplolethal gene with two guide RNAs (gRNAs) while also providing a rescue allele. Resistance alleles that form by end-joining repair typically disrupt the haplolethal target gene and are thus removed from the population because individuals that carry them are nonviable. We demonstrate that our drive is highly efficient, with 91% of the progeny of drive heterozygotes inheriting the drive allele and with no functional resistance alleles observed in the remainder. In a large cage experiment, the drive allele successfully spread to all individuals within a few generations. These results show that a haplolethal homing drive can provide an effective tool for targeted genetic modification of entire populations.

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