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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Gene drive to reduce malaria transmission in sub-Saharan Africa
3963Burt, AC, Mamadou; Crisanti, Andrea; Diabate, Abdoulaye; Kayondo, Jonathan K., Journal of Responsible Innovation, 5:S66-S80. 2018-01-21 00:00:00.
Despite impressive progress, malaria continues to impose a substantial burden of mortality and morbidity, particularly in sub-Saharan Africa, and new tools will be needed to achieve elimination. Gene drive is a natural process by which some genes are inherited at a greater-than-Mendelian rate and can spread through a population even if they cause harm to the organisms carrying them. Many different synthetic gene drive systems have been proposed to suppress the number of mosquitoes and/or reduce vector competence. As with any control measure, due attention should be paid to the possible evolution of resistance. No gene drive construct has yet been reported that is "field-ready" for release, and when such constructs are developed, they should be assessed on a case-by-case basis. Gene drive approaches to vector control promise to have a number of key features that motivate their continued development, and scrutiny, by all concerned.
Safe Driving: CRISPR and the Gene Drive Landscape
4003Nolan, T, CRISPR Journal, 1:16-18. 2018-01-21 00:00:00.
A New Study Highlights Issues About the Capability to Limit Gene Drives in the Field to a Target Population
Using gene drive technologies to control vector-borne infectious diseases
3983James, ST, K. H., Sustainability, 10:4789. 2018-01-21 00:00:00.
After years of success in reducing the global malaria burden, the World Health Organization (WHO) recently reported that progress has stalled. Over 90% of malaria deaths world-wide occurred in the WHO African Region. New tools are needed to regain momentum and further decrease the burden of malaria. Gene drive, an emerging technology that can enhance the inheritance of beneficial genes, offers potentially transformative solutions for overcoming these challenges. Gene drives may decrease disease transmission by interfering with the growth of the malaria parasite in the mosquito vector or reducing mosquito reproductive capacity. Like other emerging technologies, development of gene drive products faces technical and non-technical challenges and uncertainties. In 2018, to begin addressing such challenges, a multidisciplinary group of international experts published comprehensive recommendations for responsible testing and implementation of gene drive-modified mosquitoes to combat malaria in Sub-Saharan Africa. Considering requirements for containment, efficacy and safety testing, monitoring, stakeholder engagement and authorization, as well as policy and regulatory issues, the group concluded that gene drive products for malaria can be tested safely and ethically, but that this will require substantial coordination, planning, and capacity development. The group emphasized the importance of co-development and co-ownership of products by in-country scientists.
Current CRISPR gene drive systems are likely to be highly invasive in wild populations
4002Noble, CA, Ben; Church, George M.; Esvelt, Kevin M.; Nowak, Martin A., eLife, 7:e33423. 2018-01-20 00:00:00.
Recent reports have suggested that self-propagating CRISPR-based gene drive systems are unlikely to efficiently invade wild populations due to drive-resistant alleles that prevent cutting. Here we develop mathematical models based on existing empirical data to explicitly test this assumption for population alteration drives. Our models show that although resistance prevents spread to fixation in large populations, even the least effective drive systems reported to date are likely to be highly invasive. Releasing a small number of organisms will often cause invasion of the local population, followed by invasion of additional populations connected by very low rates of gene flow. Hence, initiating contained field trials as tentatively endorsed by the National Academies report on gene drive could potentially result in unintended spread to additional populations. Our mathematical results suggest that self-propagating gene drive is best suited to applications such as malaria prevention that seek to affect all wild populations of the target species.
Means and ends of effective global risk assessments for genetic pest management
4022Turner, GB, Camilla; Roda, Lucia, BMC Proceedings, 12:13. 2018-01-20 00:00:00.
The development and use of genetic technologies is regulated by countries according to their national laws and governance structures. Legal frameworks require comprehensive technical evidence to be submitted by an applicant on the biology of the organism, its safety to human, animal health and the environment in which it will be released. Some countries also require information on socio-economic and trade impacts. One of the key elements that assists decision-making under those legal frameworks is the use of risk assessments. The risk assessment paradigm of problem formulation based on risk hypothesis, and the assessment of plausible scientific pathways leading to potential environmental and human harms being realised, has been used widely to assess potential risks of genetic technologies to human health and the environment, from crops to mosquitoes. This paper uses the case study of a genetically modified self-limiting olive fly (Bactrocera oleae) for a first deliberate release in Spain to examine the regulatory processes and stakeholders involved in the assessment of risk. It is anticipated that existing risk assessment frameworks are equally applicable to gene drive technologies that may spread and persist in the environment and cross-national borders, but it is the governance structures surrounding the involvement of civil society in regulatory processes that must be administered in a more transparent and defined manner.
Pathway to deployment of gene drive mosquitoes as a potential biocontrol tool for elimination of malaria in sub-Saharan Africa: Recommendations of a scientific working group
3982James, SC, Frank H.; Welkhoff, Philip A.; Emerson, Claudia; Godfray, H. Charles J.; Gottlieb, Michael; Greenwood, Brian; Lindsay, Steve W.; Mbogo, Charles M.; Okumu, Fredros O.; Quemada, Hector; Savadogo, Moussa; Singh, Jerome A.; Tountas, Karen H.; Touré, American Journal of Tropical Medicine and Hygiene, 98:1-49. 2018-01-20 00:00:00.
Gene drive technology offers the promise for a high-impact, cost-effective, and durable method to control malaria transmission that would make a significant contribution to elimination. Gene drive systems, such as those based on clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated protein, have the potential to spread beneficial traits through interbreeding populations of malaria mosquitoes. However, the characteristics of this technology have raised concerns that necessitate careful consideration of the product development pathway. A multidisciplinary working group considered the implications of low-threshold gene drive systems on the development pathway described in the World Health Organization Guidance Framework for testing genetically modified (GM) mosquitoes, focusing on reduction of malaria transmission by Anopheles gambiae s.l. mosquitoes in Africa as a case study. The group developed recommendations for the safe and ethical testing of gene drive mosquitoes, drawing on prior experience with other vector control tools, GM organisms, and biocontrol agents. These recommendations are organized according to a testing plan that seeks to maximize safety by incrementally increasing the degree of human and environmental exposure to the investigational product. As with biocontrol agents, emphasis is placed on safety evaluation at the end of physically confined laboratory testing as a major decision point for whether to enter field testing. Progression through the testing pathway is based on fulfillment of safety and efficacy criteria, and is subject to regulatory and ethical approvals, as well as social acceptance. The working group identified several resources that were considered important to support responsible field testing of gene drive mosquitoes.
Synthetically engineered Medea gene drive system in the worldwide crop pest Drosophila suzukii
3962Buchman, AM, John M.; Ostrovski, Dennis; Yang, Ting; Akbari, Omar S., Proceedings of the National Academy of Sciences of the United States of America, 115:4725-4730. 2018-01-20 00:00:00.
Here we describe a fully functional gene drive system constructed in a major worldwide crop pest, Drosophila suzukii. This system is composed of a synthetic Medea drive with a maternal miRNA “toxin” and a zygotic “antidote,” and we demonstrate that it can bias inheritance with 100% efficiency and can persist in a population given high release frequencies. We discuss how such a system may be used to suppress D. suzukii populations or render them harmless to target crops.Synthetic gene drive systems possess enormous potential to replace, alter, or suppress wild populations of significant disease vectors and crop pests; however, their utility in diverse populations remains to be demonstrated. Here, we report the creation of a synthetic Medea gene drive system in a major worldwide crop pest, Drosophila suzukii. We demonstrate that this drive system, based on an engineered maternal “toxin” coupled with a linked embryonic “antidote,” is capable of biasing Mendelian inheritance rates with up to 100% efficiency. However, we find that drive resistance, resulting from naturally occurring genetic variation and associated fitness costs, can be selected for and hinder the spread of such a drive. Despite this, our results suggest that this gene drive could maintain itself at high frequencies in a wild population and spread to fixation if either its fitness costs or toxin resistance were reduced, providing a clear path forward for developing future such systems in this pest.
Development of community of practice to support quantitative risk assessment for synthetic biology products: contaminant bioremediation and invasive carp control as cases
4021Trump, BF, C.; Rycroft, T.; Wood, M. D.; Bandolin, N.; Cains, M.; Cary, T.; Crocker, F.; Friedenberg, N. A.; Gurian, P.; Hamilton, K.; Hoover, J.J.; Meyer, C.; Pokrzywinski, K.; Ritterson, R.; Schulte, P.; Warner, C. ; Perkins, E.; Linkov, I., Environmental Systems and Decisions, 38:517-527. 2018-01-19 00:00:00.
Synthetic biology has the potential for a broad array of applications. However, realization of this potential is challenged by the paucity of relevant data for conventional risk assessment protocols, a limitation due to to the relative nascence of the field, as well as the poorly characterized and prioritized hazard, exposure, and dose–response considerations associated with the development and use of synthetic biology-derived organisms. Where quantitative risk assessment approaches are necessarily to fulfill regulatory requirements for review of products containing genetically modified organisms, this paper reviews one potential avenue for early-stage quantitative risk assessment for biosafety considerations of synthetic biology organism deployment into the environment. Building from discussion from a March 2018 US Army Engineer Research and Development Center workshop on developing such quantitative risk assessment for synthetic biology, this paper reviews the findings and discussion of workshop participants. This paper concludes that, while synthetic biology risk assessment and governance will continue to refine and develop in the coming years, a quantitative framework that builds from existing practice is one potentially beneficial option for risk assessors that must contend with the technology’s limited hazard characterization or exposure assessment considerations in the near term.
Engineered Reciprocal Chromosome Translocations Drive High Threshold, Reversible Population Replacement in Drosophila
3961Buchman, ABI, Tobin; Marshall, John M.; Akbari, Omar S.; Hay, Bruce A., ACS Synthetic Biology, 7:1359-1370. 2018-01-19 00:00:00.
Replacement of wild insect populations with transgene-bearing individuals unable to transmit disease or survive under specific environmental conditions using gene drive provides a self-perpetuating method of disease prevention. Mechanisms that require the gene drive element and linked cargo to exceed a high threshold frequency in order for spread to occur are attractive because they offer several points of control: they bring about local, but not global population replacement; and transgenes can be eliminated by reintroducing wildtypes into the population so as to drive the frequency of transgenes below the threshold frequency required for drive. Reciprocal chromosome translocations were proposed as a tool for bringing about high threshold population replacement in 1940 and 1968. However, translocations able to achieve this goal have only been reported once, in the spider mite Tetranychus urticae, a haplo-diploid species in which there is strong selection in haploid males for fit homozygotes. We report the creation of engineered translocation-bearing strains of Drosophila melanogaster, generated through targeted chromosomal breakage and homologous recombination. These strains drive high threshold population replacement in laboratory populations. While it remains to be shown that engineered translocations can bring about population replacement in wild populations, these observations suggest that further exploration of engineered translocations as a tool for controlled population replacement is warranted.
Population seasonality and release timing significantly affect the probability of establishment for small releases of gene drive mosquitoes
4001Nikolov, MO, A. L.; Beaghton, A. K.; Beaghton, P. J.; Wenger, E. A.; Burt, A.; Welkhoff, P. A., American Journal of Tropical Medicine and Hygiene, 99:367-367. 2018-01-19 00:00:00.
Highly efficient CRISPR/Cas9 gene-drive systems have recently been developed, targeting reproductive-capacity and malaria-competency loci of malaria transmitting vector species, such as An. gambiae. The resulting drive systems aim to either suppress the local wild-type population or alter its genome, conveying desirable phenotypes such as P. falciparum refractoriness. The potential for sustained spread of gene drive constructs as proposed for malaria and a variety of other applications (pest control, tick borne diseases, dengue) has raised concerns for unintentional or unauthorized organism release outside approved and strictly-regulated trial sites. Previous analyses posit that as few as one or two gene drive organisms carrying efficient gene drive cassettes may establish a permanent (sub)population of genetically-modified (GM) mosquitoes with probability >50%. While these results are broad and cautionary, we show that seasonality is a fundamental environmental characteristic to consider when modeling decision variables. For the first time, we investigate the impact of gene-drive release timing and numbers on the establishment probability of GM vectors in the context of realistic seasonal population variation. We model a male sex bias, driving-Y population suppression gene drive, targeting An. gambiae, since these are among the first field trials candidate constructs. We analyze gene-drive establishment in geographies of different seasonality and spatial vector population features. We show that releasing a small number of gene-drive mosquitoes over the few weeks in the beginning of the wet season facilitates population founder effects and high establishment probability: between 60% - 80% for releases of as few as one or two mosquitoes. However, releasing genedrive mosquitoes outside this time results in much lower establishment probability, typically <20%. Our findings address crucial ethical and environmental concerns, which may guide whether, how, and where to set up gene-drive trials.
The impact of releasing sterile mosquitoes on malaria transmission
3981Hongyan, YC, Yang; Xin'an, Zhang; Jia, Li, Discrete & Continuous Dynamical Systems - B, 23:3837-3853. 2018-01-19 00:00:00.
The sterile mosquitoes technique in which sterile mosquitoes are released to reduce or eradicate the wild mosquito population has been used in preventing the malaria transmission. To study the impact of releasing sterile mosquitoes on the malaria transmission, we first formulate a simple SEIR (susceptible-exposed-infected-recovered) malaria transmission model as our baseline model, derive a formula for the reproductive number of infection, and determine the existence of endemic equilibria. We then include sterile mosquitoes in the baseline model and consider the case of constant releases of sterile mosquitoes. We examine how the releases affect the reproductive numbers and endemic equilibria for the model with interactive mosquitoes and investigate the impact of releasing sterile mosquitoes on the malaria transmission.
Developing standard operating procedures for gene drive research in disease vector mosquitoes
15680Z. N. Adelman, D. Pledger and K. M. Myles, Pathogens and Global Health, 111:436-447. 2018-01-18 14:41:42.
Here we discuss information to be considered by principal investigators, biosafety officers, and institutional biosafety committees as they work together to develop SOPs for experiments involving gene drive in arthropods, and describe various courses of action that can be used to maintain the effectiveness of SOPs through evaluation and revision. The information provided herein will be especially useful to investigators and regulatory personnel who may lack extensive experience working with arthropods under containment conditions.
Engineered integrative and conjugative elements for efficient and inducible DNA transfer to undomesticated bacteria
3960Brophy, JANT, Alexander J.; Adams, Bryn L.; Renberg, Rebecca L.; Stratis-Cullum, Dimitra N.; Grossman, Alan D.; Voigt, Christopher A., Nature Microbiology, 3:1043-1053. 2018-01-18 00:00:00.
Engineering microorganisms to promote human or plant health will require manipulation of robust bacteria that are capable of surviving in harsh, competitive environments. Genetic engineering of undomesticated bacteria can be limited by an inability to transfer DNA into the cell. Here we developed an approach based on the integrative and conjugative element from Bacillus subtilis (ICEBs1) to overcome this problem. A donor strain (XPORT) was built to transfer miniaturized integrative and conjugative elements (mini-ICEBs1) to undomesticated bacteria. The strain was engineered to enable inducible control over conjugation, to integrate delivered DNA into the chromosome of the recipient, to restrict spread of heterologous DNA through separation of the type IV secretion system from the transferred DNA, and to enable simple isolation of engineered bacteria through a d-alanine auxotrophy. Efficient DNA transfer (10–1 to 10–7 conjugation events per donor) is demonstrated using 35 Gram-positive strains isolated from humans (skin and gut) and soil. Mini-ICEBs1 was used to rapidly characterize the performance of an isopropyl-?-d-thiogalactoside (IPTG)-inducible reporter across dozens of strains and to transfer nitrogen fixation to four Bacillus species. Finally, XPORT was introduced to soil to demonstrate DNA transfer under non-ideal conditions.
Evaluating active genetic options for the control of Sea Lampreys (Petromyzon marinus) in the Laurentian Great Lakes
4020Thresher, REJ, Michael; Drake, D. Andrew, Canadian Journal of Fisheries and Aquatic Sciences, 76:1186-1202. 2018-01-18 00:00:00.
For more than two decades the Great Lakes Fishery Commission has sought tactics to complement, and potentially replace, the use of barriers and lampricides to control Sea Lamprey in the Great Lakes, but thus far without success. This paper examines the potential of modern genetic technology to suppress these invasive populations. We identified six recombinant options that appeared to be moderately to highly feasible, most of which were judged by an expert panel as extremely low or low risk, and for which R&D was broadly supported by stakeholders. The two options judged to overall best combine high efficacy and low risks were a Mendelian “sex ratio drive” and genetically modifying a prey species as to kill or sterilize Sea Lamprey that fed on it. Core issues regarding use of genetic biocontrol in the Great Lakes include technical problems associated with maintaining a Sea Lamprey brood line, information gaps for most options, the extent of broader public support, and the extent and nature of national and international consultation required in making decisions about control options.
Gene drive systems: Do they have a place in agricultural weed management?
4000Neve, P, Pest Management Science, 74:2672-2679. 2018-01-18 00:00:00.
There is a pressing need for novel control techniques in agricultural weed management. Direct genetic control of agricultural pests encompasses a range of techniques to introduce and spread novel, fitness-reducing genetic modifications through pest populations. Recently, the development of CRISPR-Cas9 gene editing has brought these approaches into sharper focus. Proof of concept for CRISPR-Cas9 based gene drives has been demonstrated for control of disease-vectoring insects. This article considers whether and how gene drives may be applied in agricultural weed management, focusing on CRISPR-Cas9 based systems. Population suppression drives might be employed to introduce and proliferate deleterious mutations that directly impact fitness and weediness, whereas population sensitizing drives would seek to edit weed genomes so that populations are rendered more sensitive to subsequent management interventions. Technical challenges relating to plant transformation and gene editing in planta are considered, and the implementation of gene drives for timely and sustainable weed management is reviewed in the light of weed population biology. The technical, biological, practical and regulatory challenges remain significant. Modelling-based studies can inform how and if gene drives could be employed in weed populations. These studies are an essential first step towards determining the utility of gene drives for weed management. This article is protected by copyright. All rights reserved.
Identifying and detecting potentially adverse ecological outcomes associated with the release of gene-drive modified organisms
3980Hayes, KRH, G. R.; Dana, G. V.; Foster, S. D.; Ford, J. H.; Thresher, R.; Ickowicz, A.; Peel, D.; Tizard, M.; De Barro, P.; Strive, T.; Dambacher, J. M., Journal of Responsible Innovation, 5:S139-S158. 2018-01-18 00:00:00.
Synthetic gene drives could provide new solutions to a range of old problems such as controlling vector-borne diseases, agricultural pests and invasive species. In this paper, we outline methods to identify hazards and detect potentially adverse ecological outcomes at the individual (genotype, phenotype), population, community and ecosystem level, when progressing Gene Drive Modified Organisms through a phased test and release pathway. We discuss the strengths and weaknesses of checklists and structured hazard analysis techniques, identify methods to help meet some of the challenges of detecting adverse ecological outcomes in experiments and confined field trials, and discuss ways to improve the efficiency and statistical rigour of post-release monitoring strategies.
Evolutionary genetics of cytoplasmic incompatibility genes cifA and cifB in prophage WO of Wolbachia
5929Lindsey, A. R. I., D. W. Rice, S. R. Bordenstein, A. W. Brooks, S. R. Bordenstein and I. L. G. Newton, Genome Biology and Evolution, 10:434-451. 2018-01-17 17:04:14.
The bacterial endosymbiont Wolbachia manipulates arthropod reproduction to facilitate its maternal spread through host populations. The most common manipulation is cytoplasmic incompatibility (CI): Wolbachia-infected males produce modified sperm that cause embryonic mortality, unless rescued by embryos harboring the same Wolbachia. The genes underlying CI, cifA and cifB, were recently identified in the eukaryotic association module of Wolbachia’s prophage WO. Here, we use transcriptomic and genomic approaches to address three important evolutionary facets of the cif genes. First, we assess whether or not cifA and cifB comprise a classic toxin–antitoxin operon in wMel and show that the two genes exhibit striking, transcriptional differences across host development. They can produce a bicistronic message despite a predicted hairpin termination element in their intergenic region. Second, cifA and cifB strongly coevolve across the diversity of phage WO. Third, we provide new domain and functional predictions across homologs within Wolbachia, and show that amino acid sequences vary substantially across the genus. Finally, we investigate conservation of cifA and cifB and find frequent degradation and loss of the genes in strains that no longer induce CI. Taken together, we demonstrate that cifA and cifB exhibit complex transcriptional regulation in wMel, provide functional annotations that broaden the potential mechanisms of CI induction, and report recurrent erosion of cifA and cifB in non-CI strains, thus expanding our understanding of the most widespread form of reproductive parasitism.
Genetic villains: Killer meiotic drivers
3959Bravo Núñez, MAN, Nicole L.; Zanders, Sarah E., Trends in Genetics, 34:424-433. 2018-01-17 00:00:00.
Unbiased allele transmission into progeny is a fundamental genetic concept canonized as Mendel’s Law of Segregation. Not all alleles, however, abide by the law. Killer meiotic drivers are ultra-selfish DNA sequences that are transmitted into more than half (sometimes all) of the meiotic products generated by a heterozygote. As their name implies, these loci gain a transmission advantage in heterozygotes by destroying otherwise viable meiotic products that do not inherit the driver. We review and classify killer meiotic drive genes across a wide spectrum of eukaryotes. We discuss how analyses of these ultra-selfish genes can lead to greater insight into the mechanisms of gametogenesis and the causes of infertility.
Rapid comeback of males: evolution of male-killer suppression in a green lacewing population
3979Hayashi, MN, M.; Kageyama, D., Proceedings of the Royal Society B-Biological Sciences, 285:6. 2018-01-17 00:00:00.
Evolutionary theory predicts that the spread of cytoplasmic sex ratio distorters leads to the evolution of host nuclear suppressors, although there are extremely few empirical observations of this phenomenon. Here, we demonstrate that a nuclear suppressor of a cytoplasmic male killer has spread rapidly in a population of the green lacewing Mallada desjardinsi. An M. desjardinsi population, which was strongly female-biased in 2011 because of a high prevalence of the male-killing Spiroplasma endosymbiont, had a sex ratio near parity in 2016, despite a consistent Spiroplasma prevalence. Most of the offspring derived from individuals collected in 2016 had 1 : 1 sex ratios in subsequent generations. Contrastingly, all-female or female-biased broods appeared frequently from crossings of these female offspring with males derived from a laboratory line founded by individuals collected in 2011. These results suggest near-fixation of a nuclear suppressor against male killing in 2016 and reject the notion that a non-male-killing Spiroplasma variant has spread in the population. Consistently, no significant difference was detected in mitochondrial haplotype variation between 2011 and 2016. These findings, and earlier findings in the butterfly Hypolimnas bolina in Samoa, suggest that these quick events of male recovery occur more commonly than is generally appreciated.
Simulating the effects of clumped egg laying on mosquito population dynamics in relation to gene-drive interventions
3999Morris, ALF, N.; Ghani, A., American Journal of Tropical Medicine and Hygiene, 99:279-280. 2018-01-17 00:00:00.
Gene-drive based vector control methods are a rapidly developing tool in the fight against malaria. They utilise highly targeted insertions of genes to express specific traits, such as biases in offspring sex ratio or inhibited vector competence, which are preferentially inherited by copying themselves between chromosomes. Although theoretically selfsustaining, most gene-drive methods are sensitive to numerous aspects of local mosquito population dynamics. Often however, due to gaps in our knowledge, mathematical modelling of gene drive systems makes highly simplifying assumptions about key aspects of mosquito ecology. There is an urgent need to better understand fine scale population processes to improve predictions of the likely impact of gene-drive releases and refine development of target product profiles. The principal drivers of local mosquitoes dynamics can be traced to the larval stages, where density-dependent mortality in larval habitats is a key regulator of local adult density. In this study, we explored these drivers by simulating non-homogenous egg-laying over time and analysing its relationship with differing functional forms of density dependence. We developed a discrete-time stochastic model of mosquito population dynamics, which incorporated the random, temporal clumping of egg laying. The model was fitted to historical longitudinal mosquito trapping data using advanced particle MCMC methods. From this we were able to better quantify the relationship between clumping of egg laying and densitydependent regulation of larval populations, and thus refine estimates of the mosquito reproduction number, Rm - a key determinant of the predicted impact of gene-drive interventions. We find incorporation of clumping of egg-laying improves model fit, and reduces estimates of Rm, thus making establishment and spread of gene-drive constructs more likely than predicted by models assuming higher Rm value.
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