Gene drives gaining speed

Nature Reviews Genetics, Год журнала: 2021, Номер 23(1), С. 5 - 22

Опубликована: Авг. 6, 2021

Gene drives are selfish genetic elements that transmitted to progeny at super-Mendelian (>50%) frequencies. Recently developed CRISPR–Cas9-based gene-drive systems highly efficient in laboratory settings, offering the potential reduce prevalence of vector-borne diseases, crop pests and non-native invasive species. However, concerns have been raised regarding unintended impacts systems. This Review summarizes phenomenal progress this field, focusing on optimal design features for full-drive (drives with linked Cas9 guide RNA components) either suppress target mosquito populations or modify them prevent pathogen transmission, allelic updating elements, mitigating strategies including trans-complementing split-drives neutralizing adaptation drive technology other organisms. These scientific advances, combined ethical social considerations, will facilitate transparent responsible advancement these technologies towards field implementation. In Review, Ethan Bier discusses how several impactful technical advancements, particularly involving CRISPR-based methods, providing a diverse toolkit control such as insect vectors disease.

Язык: Английский

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Gene-drive suppression of mosquito populations in large cages as a bridge between lab and field

Nature Communications, Год журнала: 2021, Номер 12(1)

Опубликована: Июль 28, 2021

Abstract CRISPR-based gene-drives targeting the gene doublesex in malaria vector Anopheles gambiae effectively suppressed reproductive capability of mosquito populations reared small laboratory cages. To bridge gap between and field, this gene-drive technology must be challenged with ecology. Here we report suppressive activity age-structured An. large indoor cages that permit complex feeding behaviours. The element spreads rapidly through populations, fully supresses population within one year without selecting for resistance to drive. Approximate Bayesian computation allowed retrospective inference life-history parameters from a more accurate prediction behaviour under ecologically-relevant settings. Generating data field studies invasive technologies is challenging. Our study represents paradigm stepwise sound development control tools based on gene-drive.

Язык: Английский

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CRISPR/Cas9-based split homing gene drive targeting doublesex for population suppression of the global fruit pest Drosophila suzukii

Proceedings of the National Academy of Sciences, Год журнала: 2023, Номер 120(25)

Опубликована: Июнь 12, 2023

Genetic-based methods offer environmentally friendly species-specific approaches for control of insect pests. One method, CRISPR homing gene drive that target genes essential development, could provide very efficient and cost-effective control. While significant progress has been made in developing drives mosquito disease vectors, little with agricultural Here, we report the development evaluation split doublesex (dsx) Drosophila suzukii, an invasive pest soft-skinned fruits. The component, consisting dsx single guide RNA DsRed genes, was introduced into female-specific exon dsx, which is function females but not males. However, most strains, hemizygous were sterile produced male transcript. With a modified included optimal splice acceptor site, from each four independent lines fertile. High transmission rates (94 to 99%) observed line expressed Cas9 two nuclear localization sequences D. suzukii nanos promoter. Mutant alleles small in-frame deletions near cut site functional thus would resistance drive. Finally, mathematical modeling showed strains be used suppression lab cage populations repeated releases at relatively low release ratios (1:4). Our results indicate potentially effective means populations.

Язык: Английский

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Suppression gene drive in continuous space can result in unstable persistence of both drive and wild‐type alleles

Molecular Ecology, Год журнала: 2021, Номер 30(4), С. 1086 - 1101

Опубликована: Янв. 8, 2021

Abstract Rapid evolutionary processes can produce drastically different outcomes when studied in panmictic population models vs. spatial models. One such process is gene drive, which describes the spread of “selfish” genetic elements through a population. Engineered drives are being considered for suppression disease vectors or invasive species. While laboratory experiments and modelling populations have shown that rapidly eliminate population, it remains unclear if these results translate to natural environments where individuals inhabit continuous landscape. Using spatially explicit simulations, we show release drive result what term “chasing” dynamics, wild‐type recolonize areas has locally eliminated Despite subsequently reconquering areas, complete often fails occur substantially delayed. This increases likelihood lost resistance evolves. We analyse how chasing dynamics influenced by type its efficiency, fitness costs, ecological factors as maximal growth rate levels dispersal inbreeding. find more common lower efficiency low some mechanisms prone behaviour than others. Our demonstrate determined complex interplay factors, highlighting need realistic predict outcome releases populations.

Язык: Английский

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Symbionts and gene drive: two strategies to combat vector-borne disease

Trends in Genetics, Год журнала: 2022, Номер 38(7), С. 708 - 723

Опубликована: Март 21, 2022

Safe and sustainable approaches for mosquito control are critical due to the global increasing burden of mosquito-transmitted diseases.Novel based on symbionts currently proposed modify or suppress populations Wolbachia-based methods have already achieved some success in field trials.Transgenic mosquitoes carrying gene drives that spread through a promising approach block disease transmission vector species.Transgenic-based potentially offer more power flexibility, but symbiont-based usually socially accepted well-developed. Mosquitoes bring health problems by transmitting parasites viruses such as malaria dengue. Unfortunately, current insecticide-based strategies only moderately effective because high cost resistance. Thus, scalable, sustainable, cost-effective needed mosquito-borne control. Symbiont-based genome engineering-based provide new tools show promise meeting these criteria, enabling modification suppression approaches. Symbiotic bacteria like Wolbachia maternally inherited manipulate host reproduction enhance their vertical transmission. Genome drive methods, which genetically altered alleles throughout wild populations, also proving be powerful laboratory. Here, we review latest developments both drive-based methods. We describe notable similarities, well distinctions obstacles, relating technologies. can found almost anywhere world, tropics subtropics, half world's population is under threat pathogens dengue virus (DENV), Zika (ZIKV), chikungunya (CHIKV), yellow fever, West Nile (WNV), malaria, filarial nematodes [1.World Health Organization Working Overcome Global Impact Neglected Tropical Diseases: First WHO Report Diseases. WHO, 2010Google Scholar,2.Tahir D. et al.Vector-borne nematode diseases pets humans Mediterranean Basin: an update.Vet. World. 2019; 12: 1630-1643Crossref PubMed Scopus (15) Google Scholar]. For example, DENV incidence has grown over 30-fold past 50 years, now reaching about 400 million cases per year [3.Bhatt S. al.The distribution dengue.Nature. 2013; 496: 504-507Crossref (5268) The recent ZIKV outbreak resulted hundreds thousands infections large-scale social economic disruption [4.World Virus Outbreak Response: Interim Report. 2016Google While falling southeast Asia, rising other parts world remain 'unacceptably high' according World [5.Guglielmi G. Malaria worldwide.Nature. (Published online December 4, 2019. https://doi.org/10.1038/d41586-019-03746-3)Crossref Re-emergence expansion many factors, including increased urbanization travel trade, climate change, land use pattern changes, unreliable piped water supply [6.World Vector Control Response 2017-2030. 2017Google Current strategies, long-lasting insecticide-treated bed nets, chemical insecticides, environmental management [7.Schreck C.E. Permethrin dimethyl phthalate tent fabric treatments against Aedes aegypti.J. Am. Mosq. Assoc. 1991; 7: 533-535PubMed Scholar], been unable address genetic behavioral resistance interventions [8.Succo T. al.Autochthonous Nîmes, South France, July September 2015.Euro Surveill. 2016; 21: 21Crossref (0) In addition, unintended effect important nontarget insects, pollinators [9.Ware G.W. Effects pesticides organisms.Residue Rev. 1980; 76: 173-201Crossref (49) new, urgently diseases. response this growing need, number novel technologies expanded years. Many involve release aim achieve (see Glossary) type mosquitoes. Population reduce eliminate populations. Such include sterile insect technique (SIT), incompatible (IIT), transgenic-based technologies, where insects mate with sizes next generation. Gene approaches, increase frequency multiple generations, could after single refractory resistant prevent pathogen symbiont into enable result entire becoming pathogen. review, summarize symbiont-infected transgenic focusing different varieties capabilities. early symbiont-mediated [10.Laven H. Eradication Culex pipiens fatigans cytoplasmic incompatibility.Nature. 1967; 216: 383-384Crossref (275) Scholar] was introduction nonmodified microorganisms competence (Box 1). most extensively studied system natural It may common intracellular endosymbiont arthropods nematodes, 60% all harboring [11.Hilgenboecker K. al.How species infected Wolbachia?--A statistical analysis data.FEMS Microbiol. Lett. 2008; 281: 215-220Crossref transmitted vertically from mother offspring maximize manipulating feminization, parthenogenesis, male killing, and/or incompatibility (CI). CI induced when Wolbachia-infected males uninfected females, results nonviable offspring. inhibit infection DENV, ZIKV, arboviruses, parasite (Figure 1, Key figure ) [12.Bian al.Wolbachia invades Anopheles stephensi induces refractoriness Plasmodium infection.Science. 340: 748-751Crossref (289) Scholar, 13.Dutra H.L. blocks circulating isolates Brazilian aegypti mosquitoes.Cell Host Microbe. 19: 771-774Abstract Full Text PDF 14.Hughes G.L. virulent human falciparum gambiae.PLoS Pathog. 2011; 7e1002043Crossref (214) Transfected native used Scholar,15.Zheng X. al.Incompatible techniques combined mosquitoes.Nature. 572: 56-61Crossref (212) Interestingly, species, aegypti, naturally free [16.Gloria-Soria A. al.Lack evidence (Diptera: Culicidae).J. Med. Entomol. 2018; 55: 1354-1356PubMed Scholar,17.Ross P.A. al.An elusive endosymbiont: does occur aegypti?.Ecol. Evol. 2020; 10: 1581-1591Crossref (27) providing open niche infection. there conjecture if major vectors truly [18.Chrostek E. Gerth M. Is gambiae Wolbachia?.mBio. 10e00784-19Crossref (24) reports indicate Anopheline possess high-density [19.Walker al.Stable moucheti demeilloni mosquitoes.Curr. Biol. 2021; 31: 2310-2320Abstract (12) This offers renewed medically relevant strains adapted environment. Several reviews covered progress exploit bacterium [20.Flores H.A. O'Neill S.L. Controlling vector-borne releasing modified mosquitoes.Nat. 16: 508-518Crossref (145) 21.Wang G.-H. al.Combating using technologies.Nat. Commun. 4388Crossref 22.Caragata E.P. translational science: controlling pathogens.Trends Parasitol. 37: 1050-1067Abstract Scholar].Box 1Using strategiesThe increasingly emerging interactions among hosts, infection, inspiring development [111.Gupta Nair Dynamics insect-microbiome interaction influence microbial symbiont.Front. 11: 1357Crossref (25) Most importantly, shows potential minimize problem cause minimal side effects application includes: (i) delivering directly disrupt physiology display antipathogen effects; (ii) express effector molecules, then engineered so decreased [112.Gao al.Mosquito microbiota implications control.Trends 36: 98-111Abstract (28) vectorial capacity [113.Cansado-Utrilla C. microbiome capacity: rich discovery translation.Microbiome. 9: 111Crossref (9) I).Figure 1Key figure. control.Show full caption(A) Natural bacteria-based (CI) Serratia Y1 Asaia induce immunity slow development. secondary metabolites ureilytica Su_YN1 Chromobacterium responsible antiplasmodial (DENV)-2. (B) fungus-based Wickerhamomyces anomalus secreting toxin protein Beauveria bassiana DENV-2 (ZIKV) activity inducing system. (C) insect-specific (Eilat virus, cell fusing agent Phasi Charoen-like Negevirus) arbovirus development, either alone combination. (D) Engineered AS1 proteins Dirofilaria immitis. (E) Metarhizium pingshaense-infected shorter life spans reproductive output than (F) virus-based Negevirus expressed anti-chikungunya (CHIKV) antibody CHIKV replication.View Large Image Figure ViewerDownload Hi-res image Download (PPT) I). (A) replication. Besides Wolbachia, research made rapid recently 1A,B). field-caught sinensis berghei modulating genes [23.Bai L. al.A gut symbiotic marcescens renders activation immune responses.Front. 1580Crossref interact [24.Cappelli al.Asaia activates eliciting anti-Plasmodium response: control.Front. Genet. 836Crossref (20) Symbionts not interfere pathogens, they directly. secretes antimalarial lipase kills at stages, effectively preventing [25.Gao via secretion lipase.Nat. 6: 806-817Crossref (6) [26.Wu P. commensal promotes permissiveness arboviruses.Cell 25: 101-112Abstract (76) Likewise, inhibits midgut growth displays entomopathogenic larvae adults. Romidepsin might metabolite [27.Saraiva R.G. al.Chromobacterium spp. mediate histone deacetylase inhibitor romidepsin.Sci. Rep. 8: 6176Crossref (23) Scholar]; aminopeptidase interferes attachment degradation Flavivirus E [28.Saraiva al.Aminopeptidase secreted sp. Panama degrading protein.PLoS Negl. Trop. Dis. 12e0006443Crossref fungi yeast killer strong developmental stages [29.Cappelli al.Killer yeasts exert anti-plasmodial activities mice.Parasite Vector. 329Crossref Toll/Jak-Stat pathways reduces [30.Dong Y. fungus activate toll JAK-STAT pathway-controlled anti-dengue aegypti.Insect Biochem. Mol. 2012; 42: 126-132Crossref (80) albopictus [31.Deng S.Q. al.Beauveria virus.J. Pest. Sci. 92: 781-789Crossref (8) Beyond fungi, (ISVs) arboviruses. Cell (CFAV) recognized ISV cells phenotype [32.Stollar V. Thomas V.L. An line (Peleg) causes fusion cells.Virology. 1975; 64: 367-377Crossref (167) Another ISV, Eilat (EILV), titers delay replication vitro. When were EILV, dissemination delayed heterologous interference mechanism [33.Nasar F. al.Eilat homologous interference.Am. J. Hyg. 2015; 93: 226Google Co-infection ISVs CFAV co-infection [34.Schultz M.J. al.Dual specific limits 518: 406-413Crossref (46) another discovered [35.Vasilakis N. al.Negevirus: taxon wide geographic distribution.J. Virol. 87: 2475-2488Crossref (121) cells, Mayaro [36.Patterson E.I. al.Negeviruses alphaviruses during coinfection.J. 95e0043321Crossref (2) All suggest arboviruses superinfection exclusion, needs further testing population. producing immunomodulatory molecules (termed paratransgenesis) 1C,D). 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U. 2007; 104: 9047-9051Crossref (296) Recently, successfully conditionally scorpine, significantly parasites, displaying reduced compared stain constitutively expressing [41.Shane J.L. al.Blood meal-induced inhibition microbiota.Nat. 4127Crossref (31) More recently, within heartworm immitis [42.Epis al.Chimeric stimulate development.Commun. 3: 105Crossref Notably, keep capability laboratory semi-field conditions Intriguingly, appear antagonistic one another. showed lower densities counterparts, removing enabled [43.Rosso al.Reduced diversity two areas invasion.Sci. 16091Crossref Scholar,44.Hughes al.Native impedes mosquitoes.Proc. 2014; 111: 12498-12503Crossref (137) Genetically pingshaense (Mp-hybrid) coluzzii had lifespans Mp-hybrid higher virulence inoculum load trial Faso Finally, modifying Negevirus, anti-CHIKV antibodies inhibited bacteria, fungus, even existing basis identified compelling genes, cifA cifB, involved induction rescue. models mechanism(s) still elucidated, expression bacterial germline recapitulate phenotype. 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Язык: Английский

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A homing suppression gene drive with multiplexed gRNAs maintains high drive conversion efficiency and avoids functional resistance alleles

G3 Genes Genomes Genetics, Год журнала: 2022, Номер 12(6)

Опубликована: Апрель 8, 2022

Abstract Gene drives are engineered alleles that can bias inheritance in their favor, allowing them to spread throughout a population. They could potentially be used modify or suppress pest populations, such as mosquitoes diseases. CRISPR/Cas9 homing drives, which copy themselves by homology-directed repair drive/wild-type heterozygotes, powerful form of gene drive, but they vulnerable resistance preserve the function target gene. Such prevent successful population suppression. Here, we constructed suppression drive Drosophila melanogaster utilized multiplexed gRNAs inhibit formation functional its female fertility The selected gRNA sites were close together, preventing reduction conversion efficiency. construct reached moderate equilibrium frequency cage populations without apparent alleles. However, fitness cost prevented elimination population, showing importance using highly efficient strategy, even if addressed. Nevertheless, our results experimentally demonstrate viability strategy drives.

Язык: Английский

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Dispersal inference from population genetic variation using a convolutional neural network

Genetics, Год журнала: 2023, Номер 224(2)

Опубликована: Апрель 13, 2023

The geographic nature of biological dispersal shapes patterns genetic variation over landscapes, making it possible to infer properties from data. Here, we present an inference tool that uses geographically distributed genotype data in combination with a convolutional neural network estimate critical population parameter: the mean per-generation distance. Using extensive simulation, show our deep learning approach is competitive or outperforms state-of-the-art methods, particularly at small sample sizes. In addition, evaluate varying nuisance parameters during training-including density, demographic history, habitat size, and sampling area-and this strategy effective for estimating distance when other model are unknown. Whereas competing methods depend on information about local density accurate identity-by-descent tracts, method only single-nucleotide-polymorphism spatial scale as input. Strikingly, unlike does not use coordinates genotyped individuals. These features make method, which call "disperseNN," potentially valuable new nonmodel systems whole genome reduced representation We apply disperseNN 12 different species publicly available data, yielding reasonable estimates most species. Importantly, estimated consistently larger distances than mark-recapture calculations same species, may be due limited area covered by some studies. Thus tools like ours complement direct improving understanding dispersal.

Язык: Английский

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Anti-CRISPR Anopheles mosquitoes inhibit gene drive spread under challenging behavioural conditions in large cages

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

Опубликована: Фев. 1, 2024

CRISPR-based gene drives have the potential to spread within populations and are considered as promising vector control tools. A doublesex-targeting drive was able suppress laboratory Anopheles mosquito in small large cages, it is for field application. Challenges related field-use of evolving regulatory framework suggest that systems modulate or revert action drives, could be part post-release risk-mitigation plans. In this study, we challenge an AcrIIA4-based anti-drive inhibit age-structured gambiae population under complex feeding behavioural conditions. stochastic model predicts experimentally-observed genotype dynamics medium-sized cages highlights necessity large-sized cage trials. These experiments experimental-modelling demonstrate effectiveness different scenarios, providing further corroboration its use controlling Anopheles.

Язык: Английский

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Regulatory and policy considerations for the implementation of gene drive-modified mosquitoes to prevent malaria transmission

Transgenic Research, Год журнала: 2023, Номер 32(1-2), С. 17 - 32

Опубликована: Март 15, 2023

Abstract Gene drive-modified mosquitoes (GDMMs) are being developed as possible new tools to prevent transmission of malaria and other mosquito-borne diseases. To date no GDMMs have yet undergone field testing. This early stage is an opportune time for developers, supporters, users begin consider the potential regulatory requirements eventual implementation these technologies in national or regional public health programs, especially some practical implications may take considerable planning, coordination address. Several currently unresolved questions pertinent examined, including: how product will be defined; what registration/approval process placing GDMM products on market; transboundary movement can addressed; role might played by existing multinational bodies agreements authorization decisions. Regulation policies applied registration genetically modified organisms living mosquito assessed relevance use case Africa. Multiple authorities likely involved decision-making, according laws place within each country certain classes. Requirements under Cartagena Protocol Biodiversity considered relevant most countries, frameworks conventional pesticide, medical, biocontrol products. Experience suggests that standard processes, evidence requirements, liability differ from country. Regional mechanisms useful address important challenges.

Язык: Английский

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Adversarial interspecies relationships facilitate population suppression by gene drive in spatially explicit models

Ecology Letters, Год журнала: 2023, Номер 26(7), С. 1174 - 1185

Опубликована: Май 10, 2023

Suppression gene drives bias their inheritance to spread through a population, potentially eliminating it when they reach high frequency. CRISPR homing suppression have already seen success in the laboratory, but several models predict that may be elusive population with realistic spatial structure due extinction-recolonization cycles. Here, we extend our continuous space framework include two competing species or predator-prey pairs. We find both general and mosquito-specific models, predators can facilitate drive-based suppression, albeit at cost of an increased rate drive loss outcomes. These results are robust mosquito seasonal fluctuations. Our study illustrates difficulty predicting outcomes complex ecosystems. However, promising for prospects less powerful successfully eliminate target other pest populations.

Язык: Английский

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