Dual effector population modification gene-drive strains of the African malaria mosquitoes, Anopheles gambiae and Anopheles coluzzii

Proceedings of the National Academy of Sciences, Год журнала: 2023, Номер 120(29)

Опубликована: Июль 10, 2023

Proposed genetic approaches for reducing human malaria include population modification, which introduces genes into vector mosquitoes to reduce or prevent parasite transmission. We demonstrate the potential of Cas9/guide RNA (gRNA)–based gene-drive systems linked dual antiparasite effector spread rapidly through mosquito populations. Two strains have an autonomous system coupled anti- Plasmodium falciparum comprising single-chain variable fragment monoclonal antibodies targeting ookinetes and sporozoites in African Anopheles gambiae (AgTP13) coluzzii (AcTP13). The achieved full introduction within 3 6 mo after release small cage trials. Life-table analyses revealed no fitness loads affecting AcTP13 dynamics but AgTP13 males were less competitive than wild types. molecules reduced significantly both prevalence infection intensities. These data supported transmission modeling conceptual field releases island setting that shows meaningful epidemiological impacts at different sporozoite threshold levels (2.5 10 k) by incidence optimal simulations 50 90% as few 1 2 a series releases, ≥90% mo. Modeling outcomes low thresholds are sensitive loads, gametocytemia intensities during challenges, formation potentially drive-resistant genome target sites, extending predicted times achieve incidence. TP13-based could be effective control strategies following validation numbers testing field-derived strains. similar viable candidates future trials malaria-endemic region.

Язык: Английский

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Gene drive and genetic sex conversion in the global agricultural pest Ceratitis capitata

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Янв. 8, 2024

Homing-based gene drives are recently proposed interventions promising the area-wide, species-specific genetic control of harmful insect populations. Here we characterise a first set in tephritid agricultural pest species, Mediterranean fruit fly Ceratitis capitata (medfly). Our results show that medfly is highly amenable to homing-based drive strategies. By targeting transformer gene, also demonstrate how CRISPR-Cas9 can be coupled sex conversion, whereby females transformed into fertile and harmless XX males. Given this unique malleability determination, modelled couple conversion female sterility found such approaches could effective tolerant resistant allele selection target population. open door for developing strains population suppression related pests by co-targeting reproduction shifting reproductive ratio towards They untapped potential tackle an environmentally friendly economical way.

Язык: Английский

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Considerations for first field trials of low-threshold gene drive for malaria vector control

Malaria Journal, Год журнала: 2024, Номер 23(1)

Опубликована: Май 21, 2024

Sustainable reductions in African malaria transmission require innovative tools for mosquito control. One proposal involves the use of low-threshold gene drive Anopheles vector species, where a 'causal pathway' would be initiated by (i) release system target leading to (ii) its subsequent generations, (iii) increase frequency and spread populations, (iv) simultaneous propagation linked genetic trait aimed at reducing vectorial capacity Plasmodium, (v) reduced parasites populations as reaches fixation causing (vi) decreased incidence prevalence. Here scope, objectives, trial design elements, approaches monitoring initial field releases such dive systems are considered, informed successful implementation trials biological control agents, well other tools, including insecticides, Wolbachia, larvicides, attractive-toxic sugar bait systems. Specific research questions addressed identified, adaptive is explored potentially constructive flexible approach facilitate testing causal pathway. A fundamental question decision-makers first will whether there should selective focus on earlier points pathway, efficacy via measurement or wider interrogation entire pathway entomological epidemiological efficacy. How when eventually assessed an essential consideration before decisions any protocols finalized implemented, regardless exclusively efficacy, broader aspects Statistical modelling currently under active development inform design, locations, endpoints. Collectively, considerations here advance realization developer ambitions within next 5 years.

Язык: Английский

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Engineering gene drive docking sites in a haplolethal locus in Anopheles gambiae

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 3, 2025

ABSTRACT Gene drives are selfish genetic elements which promise to be powerful tools in the fight against vector-borne diseases such as malaria. We previously proposed population replacement gene designed better withstand evolution of resistance by homing through haplolethal loci. Because most mutations wild-type allele that would otherwise confer lethal, only successful drive permits cell survive. Here we outline development and characterization two ΦC31-Recombination mediated cassette exchange (RMCE) docking lines with these features Anopheles gambiae , a first step towards construction robust this important malaria vector. adaption technique HACK (Homology Assisted CRISPR knockin) knock-in site sequences into paired haplolethal-haplosufficient (Ribosome-Proteasome) locus, confirm permit insertion drive-relevant transgenes. report anopheline proteasome knockouts, identify ribosome mutants reveal major hurdle designs must overcome develop future. Although do not achieve drive, work provides new tool for constructing future evolution-robust systems reveals critical challenges target loci anophelines and, potentially, other metazoans.

Язык: Английский

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A self-limiting sterile insect technique alternative for Ceratitis capitata

BMC Biology, Год журнала: 2025, Номер 23(1)

Опубликована: Апрель 12, 2025

Genetic biocontrol systems have broad applications in population control of insects implicated both disease spread and food security. Ceratitis capitata (the Mediterranean fruit fly), a major agricultural pest with global distribution, is one the appealing targets for such genetic control. In this study, we establish characterise novel split-CRISPR/Cas9 system term Sex Conversion Induced by CRISPR (SCIC) C. capitata. Using white eye gene toolkit selection achieved up to 100% CRISPR/Cas9 efficiency, displaying feasibility using constitutive promoters. We then induce sex conversion targeting transformer SCIC approach aimed SIT-mediated releases upon radiation-based sterilisation. Knock-out induced partial full female-to-male conversion, remaining individuals all being intersex sterile. modelling shows strong potential outcompete traditional SIT, allowing faster elimination fewer released sterile males. Overall, construct an appropriate use C Our results build foundation further methods species related tephritid pests.

Язык: Английский

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Driving down malaria transmission with engineered gene drives

Frontiers in Genetics, Год журнала: 2022, Номер 13

Опубликована: Окт. 19, 2022

The last century has witnessed the introduction, establishment and expansion of mosquito-borne diseases into diverse new geographic ranges. Malaria is transmitted by female Anopheles mosquitoes. Despite making great strides over past few decades in reducing burden malaria, transmission now on rise again, part owing to emergence mosquito resistance insecticides, antimalarial drug and, more recently, challenges COVID-19 pandemic, which resulted reduced implementation efficiency various control programs. utility genetically engineered gene drive mosquitoes as tools decrease malaria controlling disease-transmitting being evaluated. To date, there been remarkable progress development CRISPR/Cas9-based homing endonuclease designs due successful proof-of-principle multigenerational experiments. In this review, we examine lessons learnt from current drives, providing a framework for systems targeted wild malaria-transmitting populations that overcome such with evolving drive-resistance. We also discuss additional substantial works required scientific discovery further study subsequent field application endemic settings.

Язык: Английский

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Gene drive and genetic sex conversion in the global agricultural pestCeratitis capitata

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Авг. 17, 2023

Abstract Homing-based gene drives are novel interventions promising the area-wide, species-specific genetic control of harmful insect populations. Here we characterise a first set in tephritid agricultural pest species, Mediterranean fruit fly Ceratitis capitata (medfly). Our results show that medfly is highly amenable to homing-based drive strategies. By targeting transformer gene, also demonstrate two different mechanisms by which CRISPR-Cas9 can be coupled sex conversion, whereby females transformed into fertile and harmless XX males. Given this unique malleability determination, modelled couple conversion female sterility found such approaches could effective tolerant resistant allele selection target population. open door for developing strains population suppression related pests co-targeting reproduction shifting reproductive ratio towards They untapped potential tackle an environmentally friendly economical way.

Язык: Английский

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Measuring the Impact of Genetic Heterogeneity and Chromosomal Inversions on the Efficacy of CRISPR-Cas9 Gene Drives in Different Strains of Anopheles gambiae

The CRISPR Journal, Год журнала: 2023, Номер 6(5), С. 419 - 429

Опубликована: Сен. 13, 2023

The human malaria vector Anopheles gambiae is becoming increasingly resistant to insecticides, spurring the development of genetic control strategies. CRISPR-Cas9 gene drives can modify a population by creating double-stranded breaks at highly specific targets, triggering copying drive into cut site ("homing"), ensuring its inheritance. DNA repair mechanism responsible requires homology between donor and recipient chromosomes, presenting challenges for invasion laboratory-developed wild populations target species An. complex, which show high levels genome variation. Two (vas2-5958 zpg-7280) were introduced three strains collected across Africa with 5.3–6.6% variation around sites, effect this on homing was measured. Gene different karyotypes 2La chromosomal inversion also assessed. No decrease in seen despite heterology, demonstrating applicability populations.

Язык: Английский

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Genetic and geographic population structure in the malaria vector, Anopheles farauti, provides a candidate system for pioneering confinable gene-drive releases

Heredity, Год журнала: 2024, Номер 132(5), С. 232 - 246

Опубликована: Март 18, 2024

Abstract Indoor insecticide applications are the primary tool for reducing malaria transmission in Solomon Archipelago, a region where Anopheles farauti is only common vector. Due to evolution of behavioural resistance some An . populations, these have become less effective. New control interventions therefore needed this region, and gene-drives provide promising new technology. In considering developing population-specific (local) gene-drive An. , we detail species’ population genetic structure using microsatellites whole mitogenomes, finding many spatially confined populations both within between landmasses. This strong suggests that would be useful system population-specific, confinable field release, private alleles can used as Cas9 targets. Previous work on gambiae has Cardinal gene development global replacement gene-drive. We also analyse assess whether it may suitable target engineer modification local populations. Despite extensive observed microsatellites, one remote island from Vanuatu contained fixed at locus. Nonetheless, study provides an initial framework further genomic investigations discover high-frequency allele targets localized enable strains modifying localised with minimal chance escape low-risk route trial evaluations.

Язык: Английский

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Advancements and Future Prospects of CRISPR-Cas-Based Population Replacement Strategies in Insect Pest Management

Insects, Год журнала: 2024, Номер 15(9), С. 653 - 653

Опубликована: Авг. 30, 2024

Population replacement refers to the process by which a wild-type population of insect pests is replaced possessing modified traits or abilities. Effective necessitates gene drive system capable spreading desired genes within natural populations, operating under principles akin super-Mendelian inheritance. Consequently, releasing small number genetically edited insects could potentially achieve control objectives. Currently, several approaches are exploration, including newly adapted CRISPR-Cas genome editing system. Multiple studies investigating methods engineer that incapable causing crop damage transmitting vector-borne diseases, with notable successful examples documented. This review summarizes recent advancements in realm and provides insights into research methodologies, testing protocols, implementation strategies for techniques. The also discusses emerging trends prospects establishing genetic tools pest management.

Язык: Английский

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