Scholarly Literature
This is an aggregation of scholarly literature from peer-reviewed journals, bioRxiv , medRxiv and arXiv preprint servers focused on natural and engineered selfish genetic elements and genetic biocontrol. New citations are added as they appear. This content is intended for anyone interested in the scholarly literature on gene drive and genetic biocontrol.
Gene drives and the management of agricultural pests
13810R. F. Medina, Journal of Responsible Innovation, 5:S255-S262. 2018-01-24 16:01:13.
Like all pest control strategies, gene drives are not hazard-free. Ecological risk assessment of gene drives designed to control agricultural pests should be conducted before their deployment. The present commentary provides some thoughts on some of the issues one should consider when contemplating using gene drives in the management of agricultural pests.
Summary
13808Committee on Gene Drive Research in Non-Human Organisms: Recommendations for Responsible, Journal of Responsible Innovation, 5:S243-S254. 2018-01-24 15:58:19.
Scientists have studied gene drives for more than 50 years. The development of a powerful genome editing tool in 2012, CRISPR/Cas9,1 led to recent breakthroughs in gene drive research that built on that half century’s worth of knowledge, and stimulated new discussion of the potential applications and implications of gene drive technologies.
Anomaly handling and the politics of gene drives
13806S. W. Evans and M. J. Palmer, Journal of Responsible Innovation, 5:S223-S242. 2018-01-24 15:56:09.
Decisions about the development and use of gene drives are framing broader debates about the need for fundamental changes to biotechnology regulatory systems. We summarize this debate and describe how gene drives are being constructed as potential anomalies within the regulatory landscape.
Regulating animals with gene drive systems: lessons from the regulatory assessment of a genetically engineered mosquito
13804Z. Meghani and J. Kuzma, Journal of Responsible Innovation, 5:S203-S222. 2018-01-24 15:52:57.
In this paper, we consider the question of whether the United States Food and Drug Administration is prepared to effectively regulate insects and other animals with gene drives. Given the profound impact that gene drives could have on species and ecosystems, their use is a highly contentious issue. The rigorous regulation of insects and other animals with gene drive systems is crucial.
Developing gene drive technologies to eradicate invasive rodents from islands
13798C. M. Leitschuh, D. Kanavy, G. A. Backus, R. X. Valdez, M. Serr, E. A. Pitts, D. Threadgill and J. Godwin, Journal of Responsible Innovation, 5:S121-S138. 2018-01-24 15:45:57.
Gene drive methods of rodent eradication offer an alternative to killing that has the potential to be more species-specific, more humane, and more biologically safe for use around humans. Implementing this technology would involve releasing laboratory-developed engineered mice into wild populations. Some areas for further research include assessing the ecological effects of releasing engineered mice, the potential risks for the accidental or deliberate release of genetically modified organisms into mainland mouse populations, and the social, ethical, and regulatory acceptability of the technology.
Agricultural production: assessment of the potential use of Cas9-mediated gene drive systems for agricultural pest control
13796M. J. Scott, F. Gould, M. Lorenzen, N. Grubbs, O. Edwards and D. O’Brochta, Journal of Responsible Innovation, 5:S98-S120. 2018-01-24 15:43:20.
To highlight how gene drives could be useful for control of agricultural insect pests, we selected species that are pests of animals (New World screwworm), plants (spotted wing Drosophila, diamondback moth, Bemisia tabaci whitefly), or stored grains (red flour beetle). We provide examples of gene drives that target specific genes including female-essential genes. Further, we discuss issues related to containment in the laboratory and eventual field testing of strains harboring a Cas9-mediated gene drive system.
A roadmap for gene drives: using institutional analysis and development to frame research needs and governance in a systems context
13790J. Kuzma, F. Gould, Z. Brown, J. Collins, J. Delborne, E. Frow, K. Esvelt, D. Guston, C. Leitschuh, K. Oye and S. Stauffer, Journal of Responsible Innovation, 5:S13-S39. 2018-01-24 15:34:37.
This paper reports on a workshop held in February 2016 to explore the complex intersection of political, economic, ethical, and ecological risk issues associated with gene drives. Workshop participants were encouraged to use systems thinking and mapping to describe the connections among social, policy, economic, and ecological variables as they intersect within governance systems. In this paper, we analyze the workshop transcripts and maps using the Institutional Analysis and Development (IAD) framework to categorize variables associated with gene drive governance and account for the complexities of socio-ecological systems.
Mapping research and governance needs for gene drives
13788J. Delborne, J. Kuzma, F. Gould, E. Frow, C. Leitschuh and J. Sudweeks, Journal of Responsible Innovation, 5:S4-S12. 2018-01-24 15:28:09.
This special issue represents both deep and broad thinking about gene drives. The papers were first drafted nearly two years ago, and since then have been reviewed and revised to flesh out key arguments and take account of ongoing developments in the field. This field has moved very fast indeed! Technical research publications have increased in number; NASEM released a major report in June 2016; and workshops have proliferated.
Gene drives and the expanding horizon of governance
13786E. Fisher, Journal of Responsible Innovation, 5:S1-S3. 2018-01-24 15:23:59.
Like other areas of emerging science and technology that trigger prolonged public debate over their transformative prospects, gene drives simultaneously generate prospects for new knowledge, hoped-for benefits, and formidable concerns. Their ability to bias inheritance of and in theory spread a genetic trait throughout an entire population of organisms—even to the point of extinction—is driving home the need for their responsible governance. Significantly, it is also driving home the need to develop capacities for such governance.
A Framework for the risk assessment and management of gene drive technology in contained use
4023van der Vlugt, CJBB, David D.; Lehmann, Kathleen; Leunda, Amaya; Willemarck, Nicolas, Applied Biosafety, 23:25-31. 2018-01-21 00:00:00.
The utilisation of the CRISPR/Cas9 technology has sparked a renewed interest in gene drive mechanisms. These mechanisms of biased inheritance may yield promising applications in the fields of vector control and nature conservation. However, the same properties that will enable these applications may also pose a risk if organisms that are equipped with gene drive cassettes are unintentionally released into the environment. Although several groups of scientists and regulators have started to address these safety concerns, there are currently no dedicated guidelines published on the required risk assessment and minimal control measures applicable to gene drive organisms in contained use. To fill this gap, this paper describes a fundamental approach to assessing the risks of these organisms while handled in a contained laboratory environment. Based on the likelihood that an adverse effect will arise from the handling of a gene drive organism and the severity of this effect, three risk classes for contained use activities are presented. Finally, specific minimum requirements regarding physical measures and working practices are proposed according to the presented risk classes and tailored to activities with rodents, insects, and fungi, which are most likely to be used for gene drive applications in the near future.
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.
The roles of ethics in gene drive research and governance
4019Thompson, PB, Journal of Responsible Innovation, 5:S159-S179. 2018-01-17 00:00:00.
Ethics research queries the norms and values that shape the goals and justification for gene drive projects, and that might lead to issue or opposition to such projects. A framework for organizing ethics research is offered. In addition to basic research ethics and risk assessment, gene drives will give rise to questions about the fiduciary responsibilities of scientists, democratizing technology, and the links between epistemology and social power relations. A final category of ethical issues covers the way in which research on norms and values is organized, funded and integrated into other aspects of a gene drive project.
Identifying knowledge gaps for gene drive research to control invasive animal species: The next CRISPR step
3998Moro, DB, Margaret; Kennedy, Malcolm; Campbell, Susan; Tizard, Mark, Global Ecology and Conservation, 13:e00363. 2018-01-16 00:00:00.
Invasive animals have been linked to the extinctions of native wildlife, and to significant agricultural financial losses or impacts. Current approaches to control invasive species require ongoing resources and management over large geographic scales, and often result in the short-term suppression of populations. New and innovative approaches are warranted. Recently, the RNA guided gene drive system based on CRISPR/Cas9 is being proposed as a potential gene editing tool that could be used by wildlife managers as a nonlethal addition or alternative to help reduce pest animal populations. While regulatory control and social acceptance are crucial issues that must be addressed, there is an opportunity now to identify the knowledge and research gaps that exist for some important invasive species. Here we systematically determine the knowledge gaps for pest species for which gene drives could potentially be applied. We apply a conceptual ecological risk framework within the gene drive context within an Australian environment to identify key requirements for undertaking work on seven exemplar invasive species in Australia. This framework allows an evaluation of the potential research on an invasive species of interest and within a gene drive and risk context. We consider the currently available biological, genetic and ecological information for the house mouse, European red fox, feral cat, European rabbit, cane toad, black rat and European starling to evaluate knowledge gaps and identify candidate species for future research. We discuss these findings in the context of future thematic areas of research worth pursuing in preparation for a more formal assessment of the use of gene drives as a novel strategy for the control of these and other invasive species.
Origin, composition, and structure of the supernumerary B chromosome of Drosophila melanogaster
3978Hanlon, SLM, Danny E.; Eche, Salam; Hawley, R. Scott, Genetics, 210:1197. 2018-01-16 00:00:00.
The number of chromosomes carried by an individual species is one of its defining characteristics. Some species, however, can also carry supernumerary chromosomes referred to as B chromosomes. B chromosomes were recently identified in a laboratory stock of Drosophila melanogaster—an established model organism with a wealth of genetic and genomic resources—enabling us to subject them to extensive molecular analysis. We isolated the B chromosomes by pulsed-field gel electrophoresis and determined their composition through next-generation sequencing. Although these B chromosomes carry no known euchromatic sequence, they are rich in transposable elements and long arrays of short nucleotide repeats, the most abundant being the uncharacterized AAGAT satellite repeat. Fluorescent in situ hybridization on metaphase chromosome spreads revealed this repeat is located on chromosome 4, strongly suggesting the origin of the B chromosomes is chromosome 4. Cytological and quantitative comparisons of signal intensity between chromosome 4 and the B chromosomes supports the hypothesis that the structure of the B chromosome is an isochromosome. We also report the identification of a new B chromosome variant in a related laboratory stock. This B chromosome has a similar repeat signature as the original but is smaller and much less prevalent. We examined additional stocks with similar genotypes and did not find B chromosomes, but did find these stocks lacked the AAGAT satellite repeat. Our molecular characterization of D. melanogaster B chromosomes is the first step toward understanding how supernumerary chromosomes arise from essential chromosomes and what may be necessary for their stable inheritance.
Public engagement and communication: who is in charge?
3958Boëte, C, EMBO reports, 19:1. 2018-01-16 00:00:00.
The discovery of CRISPR has led to the development of gene drive systems that could be used to spread desired traits in a target species or to exterminate a population within a few generations. It is no surprise then that such a controversial and disruptive technology has raised hopes and fears regarding its application for public health, conservation, or agriculture. It has even prompted a call for a moratorium on genetically engineered gene drive last year that was signed by about 160 organizations (http://www.synbiowatch.org/gene-drives/gene-drives-moratorium/). In reaction to this call, an open letter was addressed to the Parties to the 13th meeting on the Convention on Biological Diversity (CBD) in December 2016 in Mexico and the Cartagena Protocol on Biosafety, requesting support on gene drive research. Interestingly, this call was presented on the website of Target Malaria (http://targetmalaria.org/open-letter/), a consortium that is developing a gene drive approach to suppress the populations of mosquito malaria vectors. About 80 scientists, most of whom are involved in insect research and malaria control, have signed this open letter. At the end, the call for a …
Switchable genome editing via genetic code expansion
4018Suzuki, TA, Maki; Patel, Sanjay G.; Luk, Louis Y. P.; Tsai, Yu-Hsuan; Perry, Anthony C. F., Scientific Reports, 8:10051. 2018-01-16 00:00:00.
Multiple applications of genome editing by CRISPR-Cas9 necessitate stringent regulation and Cas9 variants have accordingly been generated whose activity responds to small ligands, temperature or light. However, these approaches are often impracticable, for example in clinical therapeutic genome editing in situ or gene drives in which environmentally-compatible control is paramount. With this in mind, we have developed heritable Cas9-mediated mammalian genome editing that is acutely controlled by the cheap lysine derivative, Lys(Boc) (BOC). Genetic code expansion permitted non-physiological BOC incorporation such that Cas9 (Cas9BOC) was expressed in a full-length, active form in cultured somatic cells only after BOC exposure. Stringently BOC-dependent, heritable editing of transgenic and native genomic loci occurred when Cas9BOC was expressed at the onset of mouse embryonic development from cRNA or Cas9BOC transgenic females. The tightly controlled Cas9 editing system reported here promises to have broad applications and is a first step towards purposed, spatiotemporal gene drive regulation over large geographical ranges.
Economic issues to consider for gene drives
3997Mitchell, PDB, Z.; McRoberts, N., Journal of Responsible Innovation, 5:S180-S202. 2018-01-15 00:00:00.
We examine four economic issues regarding gene drive applications made possible by gene editing technologies. First, whether gene drives are self-sustaining or self-limiting will largely determine which types of organizations have incentives to develop and deploy gene drives and greatly influence their governance and regulation. Social factors will also play key roles, particularly public perceptions, with these perceptions co-determined with regulation and governance. Second, gene drive applications will generate unintended negative social impacts that will partially offset benefits. Third, economic surplus, the traditional measure of economic benefits, incompletely captures the welfare impacts of gene drive applications. Fourth, gene drives imply dynamic nonlinearities that make identifying economic equilibria and general policy recommendations challenging. The potentially substantial benefits, coupled with the technical, social, and economic uncertainties surrounding gene drives, suggest that a responsible course of action is to move forward while maintaining regulatory flexibility and conducting research to resolve key uncertainties.
Gene drive inhibition by the anti-CRISPR proteins AcrIIA2 and AcrIIA4 in Saccharomyces cerevisiae
3957Basgall, EMG, S. C.; Goeckel, M. E.; Giersch, R. M.; Roggenkamp, E.; Schrock, M. N.; Halloran, M.; Finnigan, G. C., Microbiology-Sgm, 164:464-474. 2018-01-15 00:00:00.
Given the widespread use and application of the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas gene editing system across many fields, a major focus has been the development, engineering and discovery of molecular means to precisely control and regulate the enzymatic function of the Cas9 nuclease. To date, a variety of Cas9 variants and fusion assemblies have been proposed to provide temporally inducible and spatially controlled editing functions. The discovery of a new class of 'anti-CRISPR' proteins, evolved from bacteriophage in response to the prokaryotic nuclease-based immune system, provides a new platform for control over genomic editing. One Cas9-based application of interest to the field of population control is that of the 'gene drive'. Here, we demonstrate use of the AcrIIA2 and AcrIIA4 proteins to inhibit active gene drive systems in budding yeast. Furthermore, an unbiased mutational scan reveals that titration of Cas9 inhibition may be possible by modification of the anti-CRISPR primary sequence.
Improved CRISPR-based suppression gene drives mitigate resistance and impose a large reproductive load on laboratory-contained mosquito populations
3977Hammond, AMK, Kyros; Gribble, Matthew; Karlsson, Xenia; Morianou, Ioanna; Galizi, Roberto; Beaghton, Andrea; Crisanti, Andrea; Nolan, Tony, bioRxiv, 360339:1-16. 2018-01-15 00:00:00.
CRISPR-based genes drives bias their own inheritance and can be used to modify entire populations of insect vectors of disease as a novel form of sustainable disease control. Gene drives designed to interfere with female fertility can suppress populations of the mosquito vector of malaria, however laboratory demonstrations showed strong unintended fitness costs and high levels of resistant mutations that limited the potential of the first generation of gene drives to spread. We describe three new gene drives designed to restrict spatio-temporal nuclease expression by using novel regulatory sequences. Two of the three new designs dramatically improve fitness and mitigate the creation and selection of resistance. We dissect the relative contributions of germline CRISPR activity versus embryonic CRISPR activity resulting from parental deposition, showing that the improved performance of the new designs is due to tighter germline restriction of the nuclease activity and significantly lower rates of end-joining repair in the embryo. Moreover, we demonstrate in laboratory-contained population experiments that these gene drives show remarkably improved invasion dynamics compared to the first generation drives, resulting in greater than 90% suppression of the reproductive output and a delay in the emergence of target site resistance, even at a loosely constrained target sequence. These results illustrate important considerations for gene drive design and will help expedite the development of gene drives designed to control malaria transmission in Africa.
Kinetic basis for DNA target specificity of CRISPR-Cas12a
4017Strohkendl, IS, Fatema A.; Rybarski, James R.; Finkelstein, Ilya J.; Russell, Rick, Molecular Cell, 71:816-824. 2018-01-15 00:00:00.
Summary Class 2 CRISPR-Cas nucleases are programmable genome editing tools with promising applications in human health and disease. However, DNA cleavage at off-target sites that resemble the target sequence is a pervasive problem that remains poorly understood mechanistically. Here, we use quantitative kinetics to dissect the reaction steps of DNA targeting by Acidaminococcus sp Cas12a (also known as Cpf1). We show that Cas12a binds DNA tightly in two kinetically separable steps. Protospacer-adjacent motif (PAM) recognition is followed by rate-limiting R-loop propagation, leading to inevitable DNA cleavage of both strands. Despite functionally irreversible binding, Cas12a discriminates strongly against mismatches along most of the DNA target sequence. This result implies substantial reversibility during R-loop formation—a late transition state—and defies common descriptions of a “seed” region. Our results provide a quantitative basis for the DNA cleavage patterns measured in vivo and observations of greater reported target specificity for Cas12a than for the Cas9 nuclease.
Anticipating complexity in the deployment of gene drive insects in agriculture
3956Baltzegar, JCB, Jessica; Elsensohn, Johanna E.; Gutzmann, Nicole; Jones, Michael S.; King, Sheron; Sudweeks, Jayce, Journal of Responsible Innovation, 5:S81-S97. 2018-01-14 00:00:00.
Insects cause substantial losses to agricultural crops each yearand require intensive management approaches. Genetic pestmanagement has emerged as a viable, non-chemical alternative formanaging insect pests. The development of engineered genedrives for agricultural use is promising, though unproven, and hasthe potential to impact farmers as well as broader socio-ecologicalsystems in several ways. Drawing on lessons from the deploymentof other pest control technologies, this paper considers howinsects containing gene drives could intersect with some of thecomplexities that characterize agricultural systems. Gene drives arebeing developed in a landscape of pest management shaped bypast and current approaches, experiences, regulations, publicopinion, and pest invasions. Because gene drive insects may spreadwell beyond their release area, stakeholder groups at differentspatial scales need to be engaged in decisions about theirdeployment. This new paradigm both complicates and offers greatpromise for future pest management efforts
Genetics and genomics of an unusual selfish sex ratio distortion in an insect
3976Hamilton, PTH, C. N.; Curtis, C. I.; Perlman, S. J., Current Biology, 28:3864-3870. 2018-01-14 00:00:00.
Diverse selfish genetic elements have evolved the ability to manipulate reproduction to increase their transmission, and this can result in highly distorted sex ratios [1]. Indeed, one of the major explanations for why sex determination systems are so dynamic is because they are shaped by ongoing coevolutionary arms races between sex-ratio-distorting elements and the rest of the genome [2]. Here, we use genetic crosses and genome analysis to describe an unusual sex ratio distortion with striking consequences on genome organization in a booklouse species, Liposcelis sp. (Insecta: Psocodea), in which two types of females coexist. Distorter females never produce sons but must mate with males (the sons of nondistorting females) to reproduce [3]. Although they are diploid and express the genes inherited from their fathers in somatic tissues, distorter females only ever transmit genes inherited from their mothers. As a result, distorter females have unusual chimeric genomes, with distorter-restricted chromosomes diverging from their nondistorting counterparts and exhibiting features of a giant non-recombining sex chromosome. The distorter-restricted genome has also acquired a gene from the bacterium Wolbachia, a well-known insect reproductive manipulator; we found that this gene has independently colonized the genomes of two other insect species with unusual reproductive systems, suggesting possible roles in sex ratio distortion in this remarkable genetic system.
Harnessing gene drive
3996Min, JS, Andrea L.; Najjar, Devora; Esvelt, Kevin M., Journal of Responsible Innovation, 5:S40-S65. 2018-01-14 00:00:00.
When scientists alter the genome of an organism, we typically reduce its ability to reproduce in the wild. This limitation has prevented researchers from rendering wild insects unable to spread disease, programing pests to ignore our crops, using genetics to precisely remove environmentally damaging invasive species, and much more. Gene drive occurs when a vertically transmitted genetic element reliably spreads through a population over generations despite providing no reproductive advantage to each host organism. Until recently, scientific efforts to take advantage of this natural phenomenon achieved only limited success. The advent of CRISPR genome editing has dramatically accelerated efforts to harness gene drive. Small groups of scientists may now be capable of unilaterally altering entire wild populations, and through them, the shared environment. Determining whether, when, and how to develop gene drive interventions responsibly will be a defining challenge of our time. Here we describe capabilities, safeguards, applications, and opportunities relevant to gene drive technologies.
Satellite DNAs unveil clues about the ancestry and composition of B chromosomes in three grasshopper species
3995Milani, DB, Vanessa; Ferretti, Ana; Palacios-Gimenez, Octavio; Melo, Adriana; Moura, Rita; Loreto, Vilma; Song, Hojun; Cabral-de-Mello, Diogo, Genes, 9:e523. 2018-01-13 00:00:00.
Supernumerary (B) chromosomes are dispensable genomic elements occurring frequently among grasshoppers. Most B chromosomes are enriched with repetitive DNAs, including satellite DNAs (satDNAs) that could be implicated in their evolution. Although studied in some species, the specific ancestry of B chromosomes is difficult to ascertain and it was determined in only a few examples. Here we used bioinformatics and cytogenetics to characterize the composition and putative ancestry of B chromosomes in three grasshopper species, Rhammatocerus brasiliensis, Schistocerca rubiginosa, and Xyleus discoideus angulatus. Using the RepeatExplorer pipeline we searched for the most abundant satDNAs in Illumina sequenced reads, and then we generated probes used in fluorescent in situ hybridization (FISH) to determine chromosomal position. We used this information to infer ancestry and the events that likely occurred at the origin of B chromosomes. We found twelve, nine, and eighteen satDNA families in the genomes of R. brasiliensis, S. rubiginosa, and X. d. angulatus, respectively. Some satDNAs revealed clustered organization on A and B chromosomes varying in number of sites and position along chromosomes. We did not find specific satDNA occurring in the B chromosome. The satDNAs shared among A and B chromosomes support the idea of putative intraspecific ancestry from small autosomes in the three species, i.e., pair S11 in R. brasiliensis, pair S9 in S. rubiginosa, and pair S10 in X. d. angulatus. The possibility of involvement of other chromosomal pairs in B chromosome origin is also hypothesized. Finally, we discussed particular aspects in composition, origin, and evolution of the B chromosome for each species.
Selfish genetic elements
3955Agren, JAC, A. G., PLOS Genetics, 14:20. 2018-01-13 00:00:00.
Selfish genetic elements (historically also referred to as selfish genes, ultra-selfish genes, selfish DNA, parasitic DNA, genomic outlaws) are genetic segments that can enhance their own transmission at the expense of other genes in the genome, even if this has no or a negative effect on organismal fitness. [1-6] Genomes have traditionally been viewed as cohesive units, with genes acting together to improve the fitness of the organism. However, when genes have some control over their own transmission, the rules can change, and so just like all social groups, genomes are vulnerable to selfish behaviour by their parts. Early observations of selfish genetic elements were made almost a century ago, but the topic did not get widespread attention until several decades later. Inspired by the gene-centred views of evolution popularized by George Williams[7] and Richard Dawkins,[8] two papers were published back-to-back in Nature in 1980-by Leslie Orgel and Francis Crick[9] and Ford Doolittle and Carmen Sapienza[10] respectively-introducing the concept of selfish genetic elements (at the time called "selfish DNA") to the wider scientific community. Both papers emphasized that genes can spread in a population regardless of their effect on organismal fitness as long as they have a transmission advantage. Selfish genetic elements have now been described in most groups of organisms, and they demonstrate a remarkable diversity in the ways by which they promote their own transmission.[11] Though long dismissed as genetic curiosities, with little relevance for evolution, they are now recognized to affect a wide swath of biological processes, ranging from genome size and architecture to speciation.[12]
Strengthening regulatory capacity for gene drives in Africa: leveraging NEPAD’s experience in establishing regulatory systems for medicines and GM crops in Africa
3975Glover, BA, Olalekan; Savadogo, Moussa; Timpo, Samuel; Lemgo, Godwin; Sinebo, Woldeyesus; Akile, Sunday; Obukosia, Silas; Ouedraogo, Jeremy; Ndomondo-Sigonda, Margareth; Koch, Muffy; Makinde, Diran; Ambali, Aggrey, BMC Proceedings, 12:1-10. 2018-01-13 00:00:00.
The New Partnership for Africa’s Development (NEPAD) Agency recognizes that Africa is in a period of transition and that this demands exploring and harnessing safe advances made in science-based innovations including modern biotechnology. To advance the science of biotechnology in Africa effectively, while at the same time safeguarding human health and the environment, the African Union (AU) adopted a High-Level Panel report on modern biotechnology entitled, Freedom to Innovate, which advocated for a coevolutionary approach where technology development goes hand in hand with regulation. Furthermore, most AU member states are Parties to the Cartagena Protocol on Biosafety (CPB), a legally binding international agreement negotiated, concluded and adopted within the framework of the Convention on Biological Diversity. This seeks to guide Parties in developing systems for the environmentally sound management of modern biotechnology applications. Currently, 49 AU Member States have signed and ratified the CPB, of which 12 have passed biosafety laws. African Union (AU) member states are at different stages in the development of regulatory frameworks for applications of modern biotechnology, which include genetically modified (GM) products and other emerging technologies. Biosafety regulatory frameworks comprise: biotechnology and/or biosafety policy; laws, regulations and guidelines; administrative systems; decision-making systems; and mechanisms for public engagement. To assist Member States to implement functional regulatory frameworks for both agriculture and health applications, the NEPAD Agency established the African Biosafety Network of Expertise (ABNE) and the African Medicines Regulatory Harmonization (AMRH). Currently, transgenic insects and GM crops are regulated by Competent National Authorities whose mandate derives from national biosafety laws. For GM crops, a lot of research has been conducted up to the confined field trial (CFT) and multi-location trials stages in a number of African countries. Burkina Faso has fully functional containment facilities for transgenic mosquitoes while Mali and Uganda are developing theirs. The Burkina Faso regulatory agency has granted permits and has already received sets of sterile mosquito eggs for trials in the contained facility. It is instructive to note that both ABNE and AMRH have worked with national and regional regulatory bodies in Africa to enhance their technical capacities for informed decision making, adoption of best practices, and compliance with international standards. It is against the backdrop of a rich blend of on-the-ground knowledge, experience, expertise, and insight into the context and political sensitivities of member states that the NEPAD Agency seeks to expand existing support. This would include capacity strengthening in the regulation of emerging technologies, such as the application of gene drives in the development of transgenic mosquito for the control of malaria transmission.
To reduce the global burden of human schistosomiasis, use ‘old fashioned’ snail control
4015Sokolow, SHW, Chelsea L.; Jones, Isabel J.; Lafferty, Kevin D.; Kuris, Armand; Hsieh, Michael H.; De Leo, Giulio A., Trends in Parasitology, 34:23-40. 2018-01-13 00:00:00.
Control strategies to reduce human schistosomiasis have evolved from ‘snail picking’ campaigns, a century ago, to modern wide-scale human treatment campaigns, or preventive chemotherapy. Unfortunately, despite the rise in preventive chemotherapy campaigns, just as many people suffer from schistosomiasis today as they did 50 years ago. Snail control can complement preventive chemotherapy by reducing the risk of transmission from snails to humans. Here, we present ideas for modernizing and scaling up snail control, including spatiotemporal targeting, environmental diagnostics, better molluscicides, new technologies (e.g., gene drive), and ‘outside the box’ strategies such as natural enemies, traps, and repellants. We conclude that, to achieve the World Health Assembly’s stated goal to eliminate schistosomiasis, it is time to give snail control another look.
Gene flow mediates the role of sex chromosome meiotic drive during complex speciation
3994Meiklejohn, CDL, Emily L.; Gordon, Kathleen E.; Rzatkiewicz, Thomas; Kingan, Sarah B.; Geneva, Anthony J.; Vedanayagam, Jeffrey P.; Muirhead, Christina A.; Garrigan, Daniel; Stern, David L.; Presgraves, Daven C., eLife, 7:e35468. 2018-01-12 00:00:00.
During speciation, sex chromosomes often accumulate interspecific genetic incompatibilities faster than the rest of the genome. The drive theory posits that sex chromosomes are susceptible to recurrent bouts of meiotic drive and suppression, causing the evolutionary build-up of divergent cryptic sex-linked drive systems and, incidentally, genetic incompatibilities. To assess the role of drive during speciation, we combine high-resolution genetic mapping of X-linked hybrid male sterility with population genomics analyses of divergence and recent gene flow between the fruitfly species, Drosophila mauritiana and D. simulans. Our findings reveal a high density of genetic incompatibilities and a corresponding dearth of gene flow on the X chromosome. Surprisingly, we find that a known drive element recently migrated between species and, rather than contributing to interspecific divergence, caused a strong reduction in local sequence divergence, undermining the evolution of hybrid sterility. Gene flow can therefore mediate the effects of selfish genetic elements during speciation.
Population dynamics of engineered underdominance and killer-rescue gene drives in the control of disease vectors
3974Edgington, MPA, Luke S., PLOS Computational Biology, 14:e1006059. 2018-01-12 00:00:00.
Vector-borne diseases represent a severe burden to both human and animal health worldwide. The methods currently being used to control a range of these diseases do not appear sufficient to address the issues at hand. As such, alternate methods for the control of vector-borne diseases are currently being investigated. Among the promising techniques currently being considered are a range of genetic control methods known as gene drive systems. These allow desirable genetic traits (such as a much reduced capacity for vectors to transmit viruses) to be spread through a target population; taking advantage of natural mate seeking behaviour to locate vector sub-populations that can be extremely difficult for humans to locate and reach. Here we use mathematical models (parameterised to consider mosquito populations) to demonstrate the robustness of the engineered underdominance and killer-rescue classes of gene drive to different ecological factors including birth and death rates; the number and quality of breeding sites (i.e. carrying capacity); and the strength of density-dependent competition during the larval development phase. We then go on to explore the range of potential outcomes that may result from the migration of individuals between two neighbouring populations.
Synthetic gene drive: between continuity and novelty: Crucial differences between gene drive and genetically modified organisms require an adapted risk assessment for their use
4014Simon, SO, Mathias; Engelhard, Margret, EMBO Reports, 19:e45760. 2018-01-12 00:00:00.
Gene drive organisms differ from “classical” genetically modified organisms in several crucial aspects. It would require new approaches for risk assessment to gauge their potential impact on the environment. While some argue that current risk assessment frameworks can accommodate synthetic gene drives, others call for a moratorium owing to gene drives’ potentially detrimental impact on wildlife
A CRISPR–Cas9-based gene drive platform for genetic interaction analysis in Candida albicans
4013Shapiro, RSC, Alejandro; Porter, Caroline B. M.; Hamblin, Meagan; Kaas, Christian S.; DiCarlo, James E.; Zeng, Guisheng; Xu, Xiaoli; Revtovich, Alexey V.; Kirienko, Natalia V.; Wang, Yue; Church, George M.; Collins, James J., Nature Microbiology, 3:73-82. 2018-01-11 00:00:00.
Candida albicans is the leading cause of fungal infections; yet, complex genetic interaction analysis remains cumbersome in this diploid pathogen. Here, we developed a CRISPR–Cas9-based ‘gene drive array’ platform to facilitate efficient genetic analysis in C. albicans. In our system, a modified DNA donor molecule acts as a selfish genetic element, replaces the targeted site and propagates to replace additional wild-type loci. Using mating-competent C. albicans haploids, each carrying a different gene drive disabling a gene of interest, we are able to create diploid strains that are homozygous double-deletion mutants. We generate double-gene deletion libraries to demonstrate this technology, targeting antifungal efflux and biofilm adhesion factors. We screen these libraries to identify virulence regulators and determine how genetic networks shift under diverse conditions. This platform transforms our ability to perform genetic interaction analysis in C. albicans and is readily extended to other fungal pathogens.
