Scholarly Literature

This is a database of scholarly literature that concentrates currently on natural and engineered selfish genetic elements (gene drives).  The latest are shown here.
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A Y chromosome-linked genome editor for efficient population suppression in the malaria vector Anopheles gambiae

34215
Tolosana, I., Willis, K., Gribble, M. et al.,  Nature Communications,  16:206. 2025-01-07 09:21:41.
Genetic control – the deliberate introduction of genetic traits to control a pest or vector population – offers a powerful tool to augment conventional mosquito control tools that have been successful in reducing malaria burden but that are compromised by a range of operational challenges. Self-sustaining genetic control strategies have shown great potential in laboratory settings, but hesitancy due to their invasive and persistent nature may delay their implementation. Here, instead, we describe a self-limiting strategy, designed to have geographically and temporally restricted effect, based on a Y chromosome-linked genome editor (YLE). The YLE comprises a CRISPR-Cas9 construct that is always inherited by males yet generates an autosomal dominant mutation that is transmitted to over 90% of the offspring and results in female-specific sterility. To our knowledge, our system represents a pioneering approach in the engineering of the Y chromosome to generate a genetic control strain for mosquitoes. Mathematical modelling shows that this YLE technology is up to seven times more efficient for population suppression than optimal versions of other self-limiting strategies, such as the widely used Sterile Insect Technique or the Release of Insects carrying a Dominant Lethal gene.

Wolbachia-based mosquito control: Environmental perspectives on population suppression and replacement strategies

34213
Joydeb Bhattacharyya, Daniel L. Roelke,  Acta Tropica,  262. 2025-01-07 09:07:50.
Mosquito-borne diseases pose a significant threat to global health, and traditional mosquito control methods often fall short of effectiveness. A promising alternative is the biological control strategy of transinfecting mosquitoes with Wolbachia, a bacterium capable of outcompeting harmful pathogens and reducing the ability of mosquitoes to transmit diseases. However, Wolbachia infections are sensitive to abiotic environmental factors such as temperature and humidity, which can affect their densities in mosquitoes and, consequently, their ability to block pathogens. This review evaluates the effectiveness of different Wolbachia strains transinfected into mosquitoes in reducing mosquito-borne diseases. It explores how Wolbachia contributes to mosquito population control and pathogen interference, highlighting the importance of mathematical models in understanding Wolbachia transmission dynamics. Additionally, the review addresses the potential impact on arboviral transmission and the challenges posed by environmental fluctuations in mosquito control programs.

Meiotic Drive and Speciation

34057
Jeremy B. Searle and Fernando Pardo-Manuel de Villena,  Annual Review of Genetics,  58:341-363. 2024-12-16 15:22:27.
Meiotic drive is the biased transmission of alleles from heterozygotes, contrary to Mendel's laws, and reflects intragenomic conflict rather than organism-level Darwinian selection. Theory has been developed as to how centromeric properties can promote female meiotic drive and how conflict between the X and Y chromosomes in males can promote male meiotic drive. There are empirical data that fit both the centromere drive and sex chromosome drive models. Sex chromosome drive may have relevance to speciation through the buildup of Dobzhansky-Muller incompatibilities involving drive and suppressor systems, studied particularly in Drosophila. Centromere drive may promote fixation of chromosomal rearrangements involving the centromere, and those fixed rearrangements may contribute to reproductive isolation, studied particularly in the house mouse. Genome-wide tests suggest that meiotic drive promotes allele fixation with regularity, and those studying the genomics of speciation need to be aware of the potential impact of such fixations on reproductive isolation. New species can originate in many different ways (including multiple factors acting together), and a substantial body of work on meiotic drive point to it being one of the processes involved.

Public attitudes to genetic technology for invasive pest control and preferences for engagement and information: A segmentation analysis

34055
Elizabeth Virginia Hobman, Aditi Mankad, Lucy Carter, Kerry Collins,  Frontiers in Bioengineering and Biotechnology,  12. 2024-12-16 14:49:47.
This research focusses on understanding (1) how people perceive genetic technology to control invasive animal pests (feral pigs, cats etc.), and (2) how people would like to be engaged on, and/or informed about, decisions regarding the development of this genetic technology. The results have direct relevance to biotechnology developers as they seek to better understand public likely response to genetic technology. Results revealed the presence of distinct segments where people varied systematically in their attitudes towards the technology, and their engagement beliefs and preferences, and information needs. The results provide practical direction on (1) how to design public engagement activities and science communications that accord with people's preferences, and (2) the issues that biotechnology developers should address as they endeavour to create socially responsible genetic technologies.

Biased social chromosome transmission in males of the fire ant Solenopsis invicta

34049
Daniel R Hettesheimer, Haolin Zeng, Brendan G Hunt, Kenneth G Ross,  G3: Genes|Genomes|Genetics,  2024-12-16 14:21:28.
Selfish genetic elements subvert the normal rules of inheritance to unfairly propagate themselves, often at the expense of other genomic elements and the fitness of individuals carrying them. Social life provides diverse avenues for the propagation of such elements. In the fire ant Solenopsis invicta, polymorphic social organization is controlled by a social chromosome, one variant of which (Sb) enhances its own transmission in polygyne colonies through effects on caste development and queen acceptance by workers. Whether the selfish effects of Sb extend to haploid (reproductive) males in this system is less clear. Here, we demonstrate a strong overrepresentation of the Sb social chromosome haplotype in reproductive males, relative to Mendelian expectations, in both the pupal and adult stages. We tested for the presence of selective execution of adult SB males by workers but did not detect such behavior. Combined with the presence of a strong imbalance in the haplotype frequencies already early in the pupal stage, these results indicate that the Sb supergene may distort male haplotype frequencies during larval or embryonic development. These findings are significant because they demonstrate yet another mode by which the selfish tendencies of the Sb supergene are manifested, illuminate complex interactions between Sb and the fire ant breeding system, inform the development of models of the population dynamics of Sb, and illustrate how a selfish supergene can increase in frequency in a population despite harboring deleterious mutations.

Assessing the Efficacy of Gene-Drive Technology in Reducing Malaria Transmission in Sub-Saharan Africa: Current Progress and Future Prospects

33876
Bizimana Rukundo T.,  IAA Journal of Applied Sciences,  12(1):1-5. 2024-12-10 16:43:06.
Malaria continues to pose a significant public health challenge in Sub-Saharan Africa, necessitating innovative solutions to combat its transmission. This review examined the efficacy of gene-drive technology as a novel approach to reducing malaria transmission through genetic modifications of Anopheles mosquitoes. Utilizing a comprehensive literature review and analysis of experimental studies and pilot projects, we assessed the mechanisms of gene drives, including population suppression and replacement strategies. The findings indicated that gene-drive technology has the potential to significantly alter mosquito populations, thereby diminishing the burden of malaria. However, challenges such as ecological concerns, regulatory complexities, and public acceptance must be addressed for successful implementation. The integration of gene drives with existing malaria control measures, collaborative research efforts, and robust ethical governance is crucial for maximizing effectiveness and ensuring sustainable outcomes. Furthermore, monitoring and evaluation systems are essential for assessing the safety and efficacy of gene-drive initiatives. This review underscored the transformative potential of gene-drive technology in malaria prevention, advocating for continued dialogue among stakeholders to navigate the complexities associated with its application in Sub-Saharan Africa.

A meiotic driver hijacks an epigenetic reader to disrupt mitosis in noncarrier offspring

33620
Yu Hua, Jianxiu Zhang, et al.,  PNAS,  121. 2024-11-12 14:39:25.
Killer meiotic drivers (KMDs) are selfish genetic elements that distort Mendelian inheritance by selectively killing meiotic products lacking the KMD element, thereby promoting their own propagation. Although KMDs have been found in diverse eukaryotes, only a limited number of them have been characterized at the molecular level, and their killing mechanisms remain largely unknown. In this study, we identify that a gene previously deemed essential for cell survival in the fission yeast Schizosaccharomyces pombe is a single-gene KMD. This gene, tdk1, kills nearly all tdk1Δ progeny in a tdk1+ × tdk1Δ cross. By analyzing polymorphisms of tdk1 among natural strains, we identify a resistant haplotype, HT3. This haplotype lacks killing ability yet confers resistance to killing by the wild-type tdk1. Proximity labeling experiments reveal an interaction between Tdk1, the protein product of tdk1, and the epigenetic reader Bdf1. Interestingly, the nonkilling Tdk1-HT3 variant does not interact with Bdf1. Cryoelectron microscopy further elucidated the binding interface between Tdk1 and Bdf1, pinpointing mutations within Tdk1-HT3 that disrupt this interface. During sexual reproduction, Tdk1 forms stable Bdf1-binding nuclear foci in all spores after meiosis. These foci persist in germinated tdk1Δ progeny and impede chromosome segregation during mitosis by generating aberrant chromosomal adhesions. This study identifies a KMD that masquerades as an essential gene and reveals the molecular mechanism by which this KMD hijacks cellular machinery to execute killing. Additionally, we unveil that losing the hijacking ability is an evolutionary path for this single-gene KMD to evolve into a nonkilling resistant haplotype.

Structural duality enables a single protein to act as a toxin–antidote pair for meiotic drive

33617
Yu Hua, Jianxiu Zhang, et al.,  PNAS,  121. 2024-11-12 14:30:22.
In sexual reproduction, selfish genetic elements known as killer meiotic drivers (KMDs) bias inheritance by eliminating gametes that do not carry them. The selective killing behavior of most KMDs can be explained by a toxin–antidote model, where a toxin harms all gametes while an antidote provides resistance to the toxin in carriers. This study investigates whether and how the KMD element tdk1 in the fission yeast Schizosaccharomyces pombe deploys this strategy. Intriguingly, tdk1 relies on a single protein product, Tdk1, for both killing and resistance. We show that Tdk1 exists in a nontoxic tetrameric form during vegetative growth and meiosis but transforms into a distinct toxic form in spores. This toxic form acquires the ability to interact with the histone reader Bdf1 and assembles into supramolecular foci that disrupt mitosis in noncarriers after spore germination. In contrast, Tdk1 synthesized during germination of carrier spores is nontoxic and acts as an antidote, dismantling the preformed toxic Tdk1 assemblies. Replacement of the N-terminal region of Tdk1 with a tetramer-forming peptide reveals its dual roles in imposing an autoinhibited tetrameric conformation and facilitating the assembly of supramolecular foci when autoinhibition is released. Moreover, we successfully reconstituted a functional KMD element by combining a construct that exclusively expresses Tdk1 during meiosis (“toxin-only”) with another construct that expresses Tdk1 specifically during germination (“antidote-only”). This work uncovers a remarkable example of a single protein employing structural duality to form a toxin–antidote pair, expanding our understanding of the mechanisms underlying toxin–antidote systems.

Exploring The Dynamics of Gene Drive Mosquitoes Within Wild Populations Using an Agent-Based Simulation

33614
S. Wickramasooriya, I. Mahmood, et al.,  IEEE Xplore,  2024-11-12 13:33:12.
Gene drive technology is emerging as a potentially powerful tool in combating vector-borne diseases – notably malaria. This study introduces an agent-based model (ABM) focused on the deployment of genetically engineered mosquitoes with gene drive (GEM) in Príncipe Island, Republic of São Tomé and Príncipe, an island nation in the Gulf of Guinea, West Africa. Grounded in empirical data from laboratory and field studies, our model forecasts the dynamics of mosquito populations central to devising efficacious GEM release strategies. The core objective is to evaluate the time required for GEMs to constitute 90% of the mosquito population and to elucidate their dispersal throughout the island. This research is instrumental in understanding GEM potential in controlling malaria vectors.

The Meiotic Drive: Intragenomic Competition and Selection

33610
I. A. Zakharov,  Russian Journal of Genetics,  60:1311-1318. 2024-11-12 12:02:24.
The article considers the distribution and mechanisms of the meiotic drive as a phenomenon manifested in unequal transmission of gene alleles and/or homologous chromosomes into gametes during meiosis. The meiotic drive has been studied in the most detail in Drosophila, mice, corn, and ascomycete fungi of the genera Neurospora and Podospora. The consequence of the meiotic drive is a shift in the frequencies of alleles in the gene pool and the maintenance of nonadaptive traits in the population.

Variable effects of transient Wolbachia infections on alphaviruses in Aedes aegypti

33429
Brittany L. Dodson, Sujit Pujhari, et al.,  PLoS Neglected Tropical Diseases,  2024-11-05 11:32:58.
Wolbachia pipientis (= Wolbachia) has promise as a tool to suppress virus transmission by Aedes aegypti mosquitoes. However, Wolbachia can have variable effects on mosquito-borne viruses. This variation remains poorly characterized, yet the multimodal effects of Wolbachia on diverse pathogens could have important implications for public health. Here, we examine the effects of transient somatic infection with two strains of Wolbachia (wAlbB and wMel) on the alphaviruses Sindbis virus (SINV), O’nyong-nyong virus (ONNV), and Mayaro virus (MAYV) in Ae. aegypti. We found variable effects of Wolbachia including enhancement and suppression of viral infections, with some effects depending on Wolbachia strain. Both wAlbB- and wMel-infected mosquitoes showed enhancement of SINV infection rates one week post-infection, with wAlbB-infected mosquitoes also having higher viral titers than controls. Infection rates with ONNV were low across all treatments and no significant effects of Wolbachia were observed. The effects of Wolbachia on MAYV infections were strikingly strain-specific; wMel strongly blocked MAYV infections and suppressed viral titers, while wAlbB had more modest effects. The variable effects of Wolbachia on vector competence underscore the importance of further research into how this bacterium impacts the virome of wild mosquitoes including the emergent human pathogens they transmit.

Biotechnology-enhanced genetic controls of the global pest Drosophila suzukii

33392
Ying Yan, Hassan M.M. Ahmed, Ernst A. Wimmer, et al.,  Trends in Biotechnology,  2024-11-04 17:35:39.
Genetic control is a biological control method that introduces traits that sterilize, kill, or modify the population via intraspecific mating. Therefore, it is regarded as a species-specific and environmentally friendly management option for pest species. Spotted wing Drosophila (SWD) is an ideal insect model for studying genetic control strategies due to its pest status, laboratory-friendly biology, and close relationship to Drosophila melanogaster, which has abundant genetic resources. Different biotechnology-enhanced genetic control strategies of SWD are featured. The working schematics, control efficacies, some resistance mechanisms, and possible future development of these strategies are described. The designs and experience from these studies aid in the sustainable control of SWD and serve as essential references to other insect pests of economic or public health importance.

Improving the suppressive power of homing gene drive by co-targeting a distant-site female fertility gene

33386
Faber, N.R., Xu, X., Chen, J. et al.,  Nature Communications,  15. 2024-11-04 17:07:21.
Gene drive technology has the potential to address major biological challenges. Well-studied homing suppression drives have been shown to be highly efficient in Anopheles mosquitoes, but for other organisms, lower rates of drive conversion prevent elimination of the target population. To tackle this issue, we propose a gene drive design that has two targets: a drive homing site where drive conversion takes place, and a distant site where cleavage induces population suppression. We model this design and find that the two-target system allows suppression to occur over a much wider range of drive conversion efficiency. Specifically, the cutting efficiency now determines the suppressive power of the drive, rather than the conversion efficiency as in standard suppression drives. We construct a two-target drive in Drosophila melanogaster and show that both components of the gene drive function successfully. However, cleavage in the embryo from maternal deposition as well as fitness costs in female drive heterozygotes both remain significant challenges for both two-target and standard suppression drives. Overall, our improved gene drive design has the potential to ease problems associated with homing suppression gene drives for many species where drive conversion is less efficient.

Navigating biosafety regulatory frameworks for genetic engineering in Africa: a focus on genome editing and gene drive technologies

33383
Tilahun Rabuma, Felix Moronta-Barrios, Wendy Craig,  Frontiers in Bioengineering and Biotechnology,  12. 2024-11-04 16:05:02.
Genome editing and gene drive technologies are increasingly gaining attraction in Africa, with researchers exploring their potential applications in agriculture, health and the environment. Acknowledging that robust regulatory frameworks are crucial in facilitating the development and utilization of these technologies, informed decision-making is, however, being impeded by the fragmented information availability and readiness of regulatory authorities on the continent. This study investigates the regulatory frameworks governing genome editing and gene drive technologies in African countries, identifies common regulatory challenges and proposes actionable solutions. Primary data were collected through questionnaires and complemented by analyzing existing biosafety regulations from online databases and scientific literature. Our findings suggest that while a few African countries have recently updated their regulatory frameworks, many are still under discussion. Challenges to development and implementation include limited resources, expertise, awareness, and public resistance. The findings underscore the urgent need for further development in regulatory capacities. By shedding light on these challenges, our study could provide African regulators with valuable insights to guide the formulation of effective regulatory frameworks. Such frameworks are essential for harnessing the potential of genome editing and gene drive technologies while safeguarding human health and the environment in Africa.

Engineering Resilient Gene Drives Towards Sustainable Malaria Control: Predicting, Testing and Overcoming Target Site Resistance

33379
Ioanna Morianou, Lee Phillimore, Bhavin S. Khatri,,  bioRxiv,  2024-11-04 13:56:24.
CRISPR-based gene drives are selfish genetic elements with the potential to spread through entire insect populations for sustainable vector control. Gene drives designed to disrupt the reproductive capacity of females can suppress laboratory populations of the malaria mosquito. However, any suppressive intervention will inevitably exert an evolutionary pressure for resistance. Here, we present a pipeline for the accelerated discovery, engineering, and testing of both natural and drive-induced variants that could reverse gene drive spread. We applied our method to stress-test a highly effective gene drive that has evaded resistance in all laboratory-contained releases to date, known as Ag(QFS)1. We showed that previously undetected resistant alleles can arise at low frequency, and discovered novel, partially resistant alleles that can perturb drive-invasion dynamics. We then engineered next-generation gene drives that can actively remove resistant alleles by targeting several highly conserved and non-overlapping sites in the female-specific exon of the doublesex gene. Our models predict that such gene drive designs could suppress large, natural populations of the malaria mosquito in the field.

Pest control gets the CRISPR treatment

33376
Seydel, C.,  Nature Biotechnology,  2024-11-04 13:45:02.
In June 2024, the St. Louis–based pest control company Agragene released genetically modified fruit flies on berry farms in California and Oregon, moving the technology out of the laboratory and into contained field testing. The trial marked a milestone for a next-generation biocontrol technology called the precision-guided sterile insect technique, or pgSIT. “The spotted wing drosophila (SWD) is the number 1 problem for any kind of strawberry, blueberry, raspberry, blackberry grower,” said Bryan Witherbee, president and CEO of Agragene. The flies have developed resistance to conventional chemical pesticides, and fruit growers suffer enormous economic losses due to the pest. “Growers are crying out for new tools,” Witherbee said. Hope is on the horizon, not only for farmers battling SWD and other agricultural pests but also for public health agencies struggling to control disease vectors. Several companies, including Agragene, are bringing biological pest control into the CRISPR era with pgSIT and other molecular tools that can specifically target the pest without killing beneficial insects, polluting the water or blanketing communities with toxic airborne chemicals. San Diego–based Synvect is applying pgSIT to disease-causing mosquitoes. Meanwhile, Oxitec, which has already successfully commercialized its “Friendly” genetic modification platform in mosquitoes, is turning its attention to crop pests.

Parental-effect gene-drive elements under partial selfing, or why do Caenorhabditis genomes have hyperdivergent regions?

33170
Matthew V Rockman,  Genetics,  2024-10-31 08:57:53.
Self-fertile Caenorhabditis nematodes carry a surprising number of Medea elements, alleles that act in heterozygous mothers and cause death or developmental delay in offspring that don’t inherit them. At some loci, both alleles in a cross operate as independent Medeas, affecting all the homozygous progeny of a selfing heterozygote. The genomic coincidence of Medea elements and ancient, deeply coalescing haplotypes, which pepper the otherwise homogeneous genomes of these animals, raises questions about how these apparent gene-drive elements persist for long periods of time. Here I investigate how mating system affects the evolution of Medeas, and their paternal-effect counterparts, peels. Despite an intuition that antagonistic alleles should induce balancing selection by killing homozygotes, models show that, under partial selfing, antagonistic elements experience positive frequency dependence: the common allele drives the rare one extinct, even if the rare one is more penetrant. Analytical results for the threshold frequency required for one allele to invade a population show that a very weakly penetrant allele, one whose effects would escape laboratory detection, could nevertheless prevent a much more penetrant allele from invading under high rates of selfing. Ubiquitous weak antagonistic Medeas and peels could then act as localized barriers to gene flow between populations, generating genomic islands of deep coalescence. Analysis of gene expression data, however, suggest that this cannot be the whole story. A complementary explanation is that ordinary ecological balancing selection generates ancient haplotypes on which Medeas can evolve, while high homozygosity in these selfers minimizes the role of gene drive in their evolution.

Exploring The Dynamics of Gene Drive Mosquitoes Within Wild Populations Using an Agent-Based Simulation

34602
S. Wickramasooriya, I. Mahmood, A. Calinescu, M. Wooldridge and G. Lanzaro,  2024 Annual Modeling and Simulation Conference,  Washington, D.C.:1-14. 2024-10-29 10:38:49.
Gene drive technology is emerging as a potentially powerful tool in combating vector-borne diseases – notably malaria. This study introduces an agent-based model (ABM) focused on the deployment of genetically engineered mosquitoes with gene drive (GEM) in Príncipe Island, Republic of São Tomé and Príncipe, an island nation in the Gulf of Guinea, West Africa. Grounded in empirical data from laboratory and field studies, our model forecasts the dynamics of mosquito populations central to devising efficacious GEM release strategies. The core objective is to evaluate the time required for GEMs to constitute 90% of the mosquito population and to elucidate their dispersal throughout the island. This research is instrumental in understanding GEM potential in controlling malaria vectors.

Stalk-eyed flies carrying a driving X chromosome compensate by increasing fight intensity

32712
Kimberly A. Paczolt, Macy E. Pritchard, Gabrielle T. Welsh, et al.,  Frontiers in Ethology,  3. 2024-10-22 17:39:40.
Exaggerated ornaments provide opportunities to understand how selection can operate at different levels to shape the evolution of a trait. While these features aid their bearer in attracting mates or fending off competitors, they can also be costly and influenced by the environment and genetic variation. The eyestalks of the stalk-eyed fly, Teleopsis dalmanni, are of interest because eyestalk length is the target of both intra- and intersexual selection and is also reduced by loci on a highly-divergent sex ratio X chromosome (XSR), a meiotic driver accounting for up to 30% of wild X chromosomes. Male stalk-eyed flies fight to control access to females and over food using a combination of low-intensity displays and high-intensity physical fights. We staged, filmed, and scored contests between pairs of eyespan-matched males to evaluate whether X chromosome type impacts the behavior and outcome of aggressive interactions. While our results broadly match expectations from previous studies, we found that XSR males used more high-intensity behaviors than males carrying a non-driving, standard X chromosome (XST), particularly when their eyestalks were of similar size or smaller than their opponents. Additionally, we found that when XSR males use high-intensity behaviors, they win more bouts than when they use low-intensity behaviors. Taken together, these results suggest that XSR impacts male aggressive behavior to compensate for the shorter eyestalks of XSR males and may help to explain how this selfish chromosome is maintained.

Wolbachia Invasion in Mosquitoes with Incomplete CI, Imperfect Maternal Transmission and Maturation Delay

32710
Ma X, Su Y,  Bulletin of Mathematical Biology,  2024-10-22 17:32:46.
The mechanism of cytoplasmic incompatibility (CI) is important in the study of Wolbachia invasion in wild mosquitoes. Su et al. (Bull Math Biol 84(9):95, 2022) proposed a delay differential equation model by relating the CI effect to maturation delay. In this paper, we investigate the dynamics of this model by allowing the same density-dependent death rate and distinct density-independent death rates. Through analyzing the existence and stability of equilibria, we obtain the parameter conditions for Wolbachia successful invasion if the maternal transmission is perfect. While if the maternal transmission is imperfect, we give the ranges of parameters to ensure failure invasion, successful invasion and partially suppressing, respectively. Meanwhile, numerical simulations indicate that the system may exhibit monostable and bistable dynamics when parameters vary. Particularly, in the bistable situation an unstable separatrix, like a line, exists when choosing constant functions as initial values; and the maturation delay affects this separatrix in an interesting way.

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