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.
Disclaimer>
Does the U.S. public support using gene drives in agriculture? And what do they want to know?
3922Jones, MSD, Jason A.; Elsensohn, Johanna; Mitchell, Paul D.; Brown, Zachary S., Science Advances, 5:eaau8462. 2019-01-20 00:00:00.
Gene drive development is progressing more rapidly than our understanding of public values toward these technologies. We analyze a statistically representative survey (n = 1018) of U.S. adult attitudes toward agricultural gene drives. When informed about potential risks, benefits, and two previously researched applications, respondents’ support/opposition depends heavily (+22%/?19%) on whether spread of drives can be limited, non-native versus native species are targeted (+12%/?9%), or the drive replaces versus suppresses target species (±2%). The one-fifth of respondents seeking out non–GMO–labeled food are more likely to oppose drives, although their support exceeds opposition for limited applications. Over 62% trust U.S. universities and the Department of Agriculture to research gene drives, with the private sector and Department of Defense viewed as more untrustworthy. Uncertain human health and ecological effects are the public’s most important concerns to resolve. These findings can inform responsible innovation in gene drive development and risk assessment.
On the road to a gene drive in mammals
3902Conklin, BR, Nature, 566:43-45. 2019-01-20 00:00:00.
A method for making a version of a gene more likely to be inherited than normal, generating what is called a gene drive, might be used to control insect populations. It has now been reported to work in mammals, too.
Transmission ratio distortion is frequent in Arabidopsis thaliana controlled crosses
3942Seymour, DKC, E.; Arioz, B. I.; Koenig, D.; Weigel, D., Heredity, 122:294-304. 2019-01-20 00:00:00.
The equal probability of transmission of alleles from either parent during sexual reproduction is a central tenet of genetics and evolutionary biology. Yet, there are many cases where this rule is violated. The preferential transmission of alleles or genotypes is termed transmission ratio distortion (TRD). Examples of TRD have been identified in many species, implying that they are universal, but the resolution of species-wide studies of TRD are limited. We have performed a species-wide screen for TRD in over 500 segregating F-2 populations of Arabidopsis thaliana using pooled reduced-representation genome sequencing. TRD was evident in up to a quarter of surveyed populations. Most populations exhibited distortion at only one genomic region, with some regions being repeatedly affected in multiple populations. Our results begin to elucidate the species-level architecture of biased transmission of genetic material in A. thaliana, and serve as a springboard for future studies into the biological basis of TRD in this species.
CRISPR gene drive efficiency and resistance rate is highly heritable with no common genetic loci of large effect
3901Champer, JW, Z. X.; Luthra, A.; Reeves, R.; Chung, J.; Liu, C.; Lee, Y. L.; Liu, J. X.; Yang, E.; Messer, P. W.; Clark, A. G., Genetics, 212:333-341. 2019-01-19 00:00:00.
Gene drives could allow for control of vector-borne diseases by directly suppressing vector populations or spreading genetic payloads designed to reduce pathogen transmission. Clustered regularly interspaced short palindromic repeat (CRISPR) homing gene drives work by cleaving wild-type alleles, which are then converted to drive alleles by homology-directed repair, increasing the frequency of the drive in a population over time. However, resistance alleles can form when end-joining repair takes place in lieu of homology-directed repair. Such alleles cannot be converted to drive alleles, which would eventually halt the spread of a drive through a population. To investigate the effects of natural genetic variation on resistance formation, we developed a CRISPR homing gene drive in Drosophila melanogaster and crossed it into the genetically diverse Drosophila Genetic Reference Panel (DGRP) lines, measuring several performance parameters. Most strikingly, resistance allele formation postfertilization in the early embryo ranged from 7 to 79% among lines and averaged 42 +/- 18%. We performed a genome-wide association study using our results in the DGRP lines, and found that the resistance and conversion rates were not explained by common alleles of large effect, but instead there were several genetic polymorphisms showing weak association. RNA interference knockdown of several genes containing these polymorphisms confirmed their effect, but the small effect sizes imply that their manipulation would likely yield only modest improvements to the efficacy of gene drives.
Killing two bugs with one stone: a perspective for targeting multiple pest species by incorporating reproductive interference into sterile insect technique
3921Honma, AK, N.; Noriyuki, S., Pest Management Science, 75:571-577. 2019-01-19 00:00:00.
The sterile insect technique is an environmentally friendly method to control and even eradicate agricultural and veterinary insect pests without using chemical pesticides in excess. However, the continuous production and release of sterile insects is economically costly and eradication programs using sterile insects have not always been successful owing to the incomplete mating ability of the sterile insects. Here we focus on the theory and empirical findings of interspecific negative mating interaction, known as reproductive interference, to develop a more cost-effective and value-added pest management program. We suggest that sterile insects can be used for simultaneous control of both wild-type conspecifics and closely related pest species by taking advantage of the fact that, when species recognition abilities are incomplete, courtship and mating are often misdirected toward heterospecies. This new approach might help mitigate economic damage and human health crises caused by pest insects. (c) 2018 Society of Chemical Industry
MGDrivE: A modular simulation framework for the spread of gene drives through spatially-explicit mosquito populations
3941Sánchez C, HMW, Sean L.; Bennett, Jared B.; Marshall, John M., Methods in Ecology and Evolution, 10:1-24. 2019-01-19 00:00:00.
Malaria, dengue, Zika, and other mosquito-borne diseases continue to pose a major global health burden through much of the world, despite the widespread distribution of insecticide-based tools and antimalarial drugs. The advent of CRISPR/Cas9-based gene editing and its demonstrated ability to streamline the development of gene drive systems has reignited interest in the application of this technology to the control of mosquitoes and the diseases they transmit. The versatility of this technology has enabled a wide range of gene drive architectures to be realized, creating a need for their population-level and spatial dynamics to be explored. 2.We present MGDrivE (Mosquito Gene Drive Explorer): a simulation framework designed to investigate the population dynamics of a variety of gene drive architectures and their spread through spatially-explicit mosquito populations. A key strength of the MGDrivE framework is its modularity: a) a genetic inheritance module accommodates the dynamics of gene drive systems displaying userdefined inheritance patterns, b) a population dynamic module accommodates the life history of a variety of mosquito disease vectors and insect agricultural pests, and c) a landscape module generates the metapopulation model by which insect populations are connected via migration over space. 3.Example MGDrivE simulations are presented to demonstrate the application of the framework to CRISPR/Cas9-based homing gene drive for: a) driving a disease-refractory gene into a population (i.e. population replacement), and b) disrupting a gene required for female fertility (i.e. population suppression), incorporating homing-resistant alleles in both cases. Further documentation and use examples are provided at the project's Github repository. 4.MGDrivE is an open-source R package freely available on CRAN. We intend the package to provide a flexible tool capable of modeling novel inheritance-modifying constructs as they are proposed and become available. The field of gene drive is moving very quickly, and we welcome suggestions for future development.
Arthropod containment guidelines, version 3.2
3920American Committee of Medical Entomology, American Society of Tropical Medicine and Hygiene Vector-Borne and Zoonotic Diseases, 19:3:152-173. 2019-01-18 00:00:00.
In 2003, just a few months after I became editor of Vector-; Borne and Zoonotic Diseases, we published the Arthropod; Containment Guidelines, likely our first of what would become; known as an Open Access publication. The concept to; produce the guidelines resulted from a discussion with staff; from the National Institutes of Health that had been involved; in supporting efforts to develop the capacity to genetically; engineer mosquitoes. What followed was more than a 2-year; effort by members of the American Committee for Medical; Entomology (ACME)—a subgroup of the American Society; of Tropical Medicine and Hygiene (ASTMH). Drafts of the; document were widely circulated among researchers and; vector biologists, and revised several times until a consensus; document was finalized. The guidelines were rapidly embraced; by the international community as the ‘‘go-to’’ reference; document for those working with arthropod vectors in; laboratories, and administrators on committees that oversee; these facilities.
Molecular safeguarding of CRISPR gene drive experiments
3900Champer, JC, Joan; Lee, Yoo Lim; Liu, Chen; Yang, Emily; Wen, Zhaoxin; Clark, Andrew G.; Messer, Philipp W., eLife, 8:e41439. 2019-01-18 00:00:00.
CRISPR-based homing gene drives have sparked both enthusiasm and deep concerns due to their potential for genetically altering entire species. This raises the question about our ability to prevent the unintended spread of such drives from the laboratory into a natural population. Here, we experimentally demonstrate the suitability of synthetic target site drives as well as split drives as flexible safeguarding strategies for gene drive experiments by showing that their performance closely resembles that of standard homing drives in Drosophila melanogaster. Using our split drive system, we further find that maternal deposition of both Cas9 and gRNA is required to form resistance alleles in the early embryo and that maternally-deposited Cas9 alone can power germline drive conversion in individuals that lack a genomic source of Cas9.
Population management using gene drive: molecular design, models ofspread dynamics and assessment of ecological risks
3940Rode, NOE, A.; Bourguet, D.; Courtier-Orgogozo, V.; Debarre, F., Conservation Genetics, 20:671-690. 2019-01-18 00:00:00.
CRISPR gene drive has recently been proposed as a promising technology for population management, including in conservation genetics. The technique would consist in releasing genetically engineered individuals that are designed to rapidly propagate a desired mutation or transgene into wild populations. Potential applications in conservation biology include the control of invasive pest populations that threaten biodiversity (eradication and suppression drives), or the introduction of beneficial mutations in endangered populations (rescue drives). The propagation of a gene drive is affected by different factors that depend on the drive construct (e.g. its fitness effect and timing of expression) or on the target species (e.g. its mating system and population structure). We review potential applications of the different types of gene drives for conservation. We examine the challenges posed by the evolution of resistance to gene drives and review the various molecular and environmental risks associated with gene drives (e.g. propagation to non target populations or species and unintended detrimental ecosystem impacts). We provide some guidelines for future gene drive research and discuss ethical, biosafety and regulation issues.
Gene drives as a response to infection and resistance
3919Hayirli, TCM, P.F., Infection and Drug Resistance, 12:229-234. 2019-01-17 00:00:00.
Vector-borne infectious diseases continue to be a major threat to public health. Although some prevention and treatment modalities exist for these diseases, resistance to such modalities, exacerbated by global climate change, remains a fundamental challenge. Developments in genomic engineering technologies present a new front in battling vector-borne illnesses; however, there is a lack of consensus over the scope and consequences of these approaches. In this article, we use malaria as a case study to address the developments and controversies surrounding gene drives, a novel genomic engineering technology. We draw attention to the themes of infection control, resistance, and reversibility using a science and technology studies framework. Unlike other current prevention and treatment modalities, gene drives have the capacity to alter not only single organisms but also entire species and ecologies. Therefore, broader public and scientific engagement is needed to inform a more inclusive discussion between clinicians, researchers, policy makers, and society.
Male competition and the evolution of mating and ire-history traits in experimental populations of Aedes aegypti
3939Qureshi, AA, A.; Hollis, B.; Ponlawat, A.; Cator, L. J., Proceedings of the Royal Society B-Biological Sciences, 286:20190591. 2019-01-17 00:00:00.
Aedes aegypti is an important disease vector and a major target of reproductive control efforts. We manipulated the opportunity for sexual selection in populations of Ae. aegypti by controlling the number of males competing for a single female. Populations exposed to higher levels of male competition rapidly evolved higher male competitive mating success relative to populations evolved in the absence of competition, with an evolutionary response visible atter only five generations. We also detected correlated evolution in other important mating and life-history traits, such as acoustic signalling, fecundity and body size. Our results indicate that there is ample segregating variation for determinants of male mating competitiveness in wild populations and that increased male mating success trades-off with other important life-history traits. The mating conditions imposed on laboratory-reared mosquitoes are likely a significant determinant of male mating success in populations destined for release.
Variability in the durability of CRISPR-Cas immunity
3899Chabas, HN, A.; Meaden, S.; Westra, E. R.; Tremblay, D. M.; Pradier, L.; Lion, S.; Moineau, S.; Gandon, S., Philosophical Transactions of the Royal Society B-Biological Sciences, 374:1-9. 2019-01-17 00:00:00.
The durability of host resistance is challenged by the ability of pathogens to escape the defence of their hosts. Understanding the variability in the durability of host resistance is of paramount importance for designing more effective control strategies against infectious diseases. Here, we study the durability of various clustered regularly interspaced short palindromic repeats-Cas (CRISPR-Cas) alleles of the bacteria Streptococcus thermophilus against lytic phages. We found substantial variability in durability among different resistant bacteria. Since the escape of the phage is driven by a mutation in the phage sequence targeted by CRISPR-Cas, we explored the fitness costs associated with these escape mutations. We found that, on average, escape mutations decrease the fitness of the phage. Yet, the magnitude of this fitness cost does not predict the durability of CRISPR-Cas immunity. We contend that this variability in the durability of resistance may be because of variations in phage mutation rate or in the proportion of lethal mutations across the phage genome. These results have important implications on the coevolutionary dynamics between bacteria and phages and for the optimal deployment of resistance strategies against pathogens and pests. Understanding the durability of CRISPR-Cas immunity may also help develop more effective gene-drive strategies based on CRISPR-Cas9 technology. This article is part of a discussion meeting issue 'The ecology and evolution of prokaryotic CRISPR-Cas adaptive immune systems'.
A Y-chromosome shredding gene drive for controlling pest vertebrate populations
3938Prowse, TAAA, F.; Cassey, P.; Thomas, P.; Ross, J. V., eLife, 8:19. 2019-01-16 00:00:00.
Self-replicating gene drives that modify sex ratios or infer a fitness cost could be used to control populations of invasive alien species. The targeted deletion of Y sex chromosomes using CRISPR technology offers a new approach for sex bias that could be incorporated within gene-drive designs. We introduce a novel gene-drive strategy termed Y-CHromosome deletion using Orthogonal Programmable Endonucleases (Y-CHOPE), incorporating a programmable endonuclease that 'shreds' the Y chromosome, thereby converting XY males into fertile XO females. Firstly, we demonstrate that the CRISPR/Cas12a system can eliminate the Y chromosome in embryonic stem cells with high efficiency (c. 90%). Next, using stochastic, individual-based models of a pest mouse population, we show that a Y-shredding drive that progressively depletes the pool of XY males could effect population eradication through mate limitation. Our molecular and modeling data suggest that a Y-CHOPE gene drive could be a viable tool for vertebrate pest control.
Gene drive gone wild: exploring deliberative possibilities by developing One Health ethics
3898Capps, B, Law, Innovation and Technology, 11:231-256. 2019-01-16 00:00:00.
Gene editing may be used to engineer organisms that are better or worse adapted to survival. Coupled with gene drives ? molecular genetic strategies that perpetuate specific phenotypes in a target species ? it would now be possible to edit wild animal populations that impact on public health. It is generally agreed that community engagement should guide prospective gene drive field trials. However, the analysis in this article reveals that there is a tension between publics and the public interest: it is contentious to allow communities to decide policy when doing so will have consequences beyond their own interests, as surely gene drives will; conversely, it goes against ideal deliberation for the state to impose policy without this democratic condition. The gene drive controversy creates further dichotomies illustrative of this tension: giving effect to weighted decisions that discriminate between culture and nature, local and global, private and public, and present and future interests. In this article, an emerging concept of One Health ethics (OH) is employed to strengthen ethical engagement on the policy roadmap used to navigate the gene drive controversy. OH in practice has been shown to provide insightful solutions at the interface between animal and human health; and, in this article, that advantage is extended to the public good and public interest. In so doing, OH ethics ? as spelled out here ? is coextensive with public health ethics.
Knowledge engagement in gene drive research for malaria control
3918Hartley, ST, D.; Ledingham, K.; Coulibaly, M.; Diabate, A.; Dicko, B.; Diop, S.; Kayondo, J.; Namukwaya, A.; Nourou, B.; Toe, L. P., PLOS Neglected Tropical Diseases, 13:e0007233. 2019-01-16 00:00:00.
Scientists and funding bodies have made repeated calls for public engagement in gene drive. In 2016, the National Academies of Sciences, Engineering, and Medicine (NASEM) published its report, Gene Drives on the Horizon: Advancing Science, Navigating Uncertainty, and Aligning Research with Public Values. The report identified public engagement as a key area of responsible science, defining engagement as “seeking and facilitating the sharing and exchange of knowledge, perspectives, and preferences between or among groups who often have differences in expertise, power, and values”. Researchers are asked to participate in two-way engagement with publics (defined as stakeholders, communities, and the public) to allow their knowledge to contribute to technology development and align the technology with public values. In this viewpoint, we share our initial research findings in this area and propose a conceptual tool that contributes to the debate at this critical juncture.
Predicting the spatial dynamics of Wolbachia infections in Aedes aegypti arbovirus vector populations in heterogeneous landscapes
3917Hancock, PAR, S. A.; Koenraadt, C. J. M.; Scott, T. W.; Hoffmann, A. A.; Godfray, H. C. J., Journal of Applied Ecology, 56:1674-1686. 2019-01-15 00:00:00.
A promising strategy for reducing the transmission of dengue and other arboviral human diseases by Aedes aegypti mosquito vector populations involves field introductions of the endosymbiotic bacteria Wolbachia. Wolbachia infections inhibit viral transmission by the mosquito, and can spread between mosquito hosts to reach high frequencies in the vector population. Wolbachia spreads by maternal transmission, and spread dynamics can be variable and highly dependent on natural mosquito population dynamics, population structure and fitness components. We develop a mathematical model of an A. aegypti metapopulation that incorporates empirically validated relationships describing density-dependent mosquito fitness components. We assume that density dependent relationships differ across subpopulations, and construct heterogeneous landscapes for which model-predicted patterns of variation in mosquito abundance and demography approximate those observed in field populations. We then simulate Wolbachia release strategies similar to that used in field trials. We show that our model can produce rates of spatial spread of Wolbachia similar to those observed following field releases. We then investigate how different types of spatio-temporal variation in mosquito habitat, as well as different fitness costs incurred by Wolbachia on the mosquito host, influence predicted spread rates. We find that fitness costs reduce spread rates more strongly when the habitat landscape varies temporally due to stochastic and seasonal processes. Synthesis and applications: Our empirically based modelling approach represents effects of environmental heterogeneity on the spatial spread of Wolbachia. The models can assist in interpreting observed spread patterns following field releases and in designing suitable release strategies for targeting spatially heterogeneous vector populations.
Safe CRISPR: Challenges and Possible Solutions
3937Pineda, ML, A.; Collins, J. P.; Kiani, S., Trends in Biotechnology, 37:389-401. 2019-01-15 00:00:00.
Applications of CRISPR in human health and in gene drives are at the forefront of biological research as tools. This technology will affect humankind and our environment, so as this technology pushes forward, the design and implementation of safety measures is imperative. Novel technologies and forethought in various applications of CRISPR are essential for using this technology safely. Here, we review environmental and health-related safety concerns associated with using CRISPR and ways proposed to minimize risk.
The ethical landscape of gene drive research
3897Callies, DE, Bioethics, 33:1091-1097. 2019-01-15 00:00:00.
Gene drive technology has immense potential. The ability to bypass the laws of Mendelian inheritance and almost ensure the transmission of specific genetic material to future generations creates boundless possibilities. But alongside these boundless possibilities are major social and ethical issues. This article aims to introduce gene drive technology, some of its potential applications, and some of the social and ethical issues that arise during research into the technology. For example, is investigation into gene drives hubristic? Would applications of gene drives count as technological fixes? Or does research into such a technology sit on a slippery slope or lock us in to its full-scale use? Are there perverse effects of engaging in research, and, most importantly, who ought to be included in the decision-making process regarding research and field trials? Understanding the basic ethical landscape of this technology will prove invaluable to the public, scientists, and policy-makers as research moves forward.
Design, execution, and analysis of CRISPR-Cas9-based deletions and genetic interaction networks in the fungal pathogen Candida albicans
3916Halder, VP, C. B. M.; Chavez, A.; Shapiro, R. S., Nature Protocols, 14:955-975. 2019-01-14 00:00:00.
The study of fungal pathogens is of immediate importance, yet progress is hindered by the technical challenges of genetic manipulation. For Candida species, their inability to maintain plasmids, unusual codon usage, and inefficient homologous recombination are among the obstacles limiting efficient genetic manipulation. New advances in genomic biotechnologies -particularly CRISPR-based tools-have revolutionized genome editing for many fungal species. Here, we present a protocol for CRISPR-Cas9-based manipulation in Candida albicans using a modified gene-drive-based strategy that takes similar to 1 month to complete. We detail the generation of Candida-optimized Cas9-based plasmids for gene deletion, an efficient transformation protocol using C. albicans haploids, and an optimized mating strategy to generate homozygous single- and double-gene diploid mutants. We further describe protocols for quantifying cell growth and analysis pipelines to calculate fitness and genetic interaction scores for genetic mutants. This protocol overcomes previous limitations associated with genetic manipulation in C. albicans and advances researchers' ability to perform genetic analysis in this pathogen; the protocol also has broad applicability to other mating-competent microorganisms.
Population genetics of Anopheles funestus, the African malaria vector, Kenya
3936Ogola, EOO, J. O.; Mwangangi, J. M.; Masiga, D. K.; Tchouassi, D. P., Parasites & Vectors, 12:15. 2019-01-14 00:00:00.
Anopheles funestus is among the major malaria vectors in Kenya and sub-Saharan Africa and has been recently implicated in persistent malaria transmission. However, its ecology and genetic diversity remain poorly understood in Kenya.MethodsUsing 16 microsatellite loci, we examined the genetic structure of An. funestus sampled from 11 locations (n = 426 individuals) across a wide geographical range in Kenya spanning coastal, western and Rift Valley areas.ResultsKenyan An. funestus resolved as three genetically distinct clusters. The largest cluster (FUN1) broadly included samples from western and Rift Valley areas of Kenya with two clusters identified from coastal Kenya (FUN2 and FUN3), not previously reported. Geographical distance had no effect on population differentiation of An. funestus. We found a significant variation in the mean Plasmodium infectivity between the clusters ((2) = 12.1, df = 2, P = 0.002) and proportional to the malaria prevalence in the different risk zones of Kenya. Notably, there was variation in estimated effective population sizes between the clusters, suggesting possible differential impact of anti-vector interventions in represented areas.ConclusionsHeterogeneity among Kenyan populations of An. funestus will impact malaria vector control with practical implications for the development of gene-drive technologies. The difference in Plasmodium infectivity and effective population size between the clusters could suggest potential variation in phenotypic characteristics relating to competence or insecticide resistance. This is worth examining in future studies.
Contact Us
Alex Sullivan
Foundation for the
National Institutes of Health
geneconvenevi@fnih.org