Scholarly Literature

This is a database of scholarly literature that concentrates currently on natural and engineered selfish genetic elements (gene drives).  The latest are shown here.
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CRISPR/Cas9 -mediated gene knockout of Anopheles gambiae FREP1 suppresses malaria parasite infection

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Dong, YS, Maria L.; Marois, Eric; Dimopoulos, George,  PLOS Pathogens,  14:e1006898. 2018-01-11 00:00:00.
The causative agent of malaria, Plasmodium, has to complete a complex infection cycle in the Anopheles gambiae mosquito vector in order to reach the salivary gland from where it can be transmitted to a human host. The parasite’s development in the mosquito relies on numerous host factors (agonists), and their inhibition or inactivation can thereby result in suppression of infection and consequently malaria transmission. The recently developed CRISPR/Cas9-based genome editing tools for Anopheles mosquitoes provide new and promising opportunities to delete (inactivate) Plasmodium agonists to better understand their function and for blocking malaria transmission. Here we have established a modified CRISPR/Cas9 genome editing technique for malaria vector A. gambiae mosquitoes. Through this approach we have inactivated the fibrinogen-related protein 1 (FREP1) gene, via CRISPR/Cas9 genome editing, and the impact of this manipulation on the mosquito’s susceptibility to Plasmodium and on mosquito fitness. FREP1 knockout mutants showed a profound suppression of infection with both human and rodent malaria parasites, while it also resulted in fitness costs: a significantly lower blood-feeding propensity, fecundity and egg hatching rate, and a retarded larval development and pupation time, and reduced longevity after a blood meal.

Genetically engineered mosquitoes, Zika and other arboviruses, community engagement, costs, and patents: Ethical issues

3993
Meghani, ZB, Christophe,  PLOS Neglected Tropical Diseases,  12:e0006501. 2018-01-11 00:00:00.
We discuss here key ethical questions raised by the use of GE insects, with the aim of fostering discussion between the public, researchers, policy makers, healthcare organizations, and regulatory agencies at the local, national, and international levels. We affect that goal by outlining a procedural approach to decision-making about the use of the biotechnology that goes beyond community engagement. The protocol we advocate for entails informed deliberations and decision-making at the community level. It is designed to ensure that the voices of the marginalized and vulnerable groups that would be disproportionately affected by the decision are heard during the community-wide discussions. Moreover, we make the case that the values embedded in the risk assessment should be identified so that the community can make an informed decision about the use of GE insects. In addition, we advocate for the involvement of a variety of actors whose responsibility would be to ensure that the community has the opportunity to make an informed decision based on deliberations about the use of the biotechnology.

Carrying a selfish genetic element predicts increased migration propensity in free-living wild house mice

4012
Runge, J-NL, Anna K.,  Proceedings of the Royal Society B: Biological Sciences,  285:20181333. 2018-01-10 00:00:00.
Life is built on cooperation between genes, which makes it vulnerable to parasitism. Selfish genetic elements that exploit this cooperation can achieve large fitness gains by increasing their transmission relative to the rest of the genome. This leads to counter-adaptations that generate unique selection pressures on the selfish genetic element. This arms race is similar to host–parasite coevolution, as some multi-host parasites alter the host’s behaviour to increase the chance of transmission to the next host. Here, we ask if, similarly to these parasites, a selfish genetic element in house mice, the t haplotype, also manipulates host behaviour, specifically the host’s migration propensity. Variants of the t that manipulate migration propensity could increase in fitness in a meta-population. We show that juvenile mice carrying the t haplotype were more likely to emigrate from and were more often found as migrants within a long-term free-living house mouse population. This result may have applied relevance as the t has been proposed as a basis for artificial gene drive systems for use in population control.

CRISPR-based gene drives for pest control

3992
McFarlane, GRW, C. Bruce A.; Lillico, Simon G.,  Trends in Biotechnology,  36:130-133. 2018-01-10 00:00:00.
Clustered regularly interspaced short palindromic repeats (CRISPR)-based gene drives (GDs) could be used to spread desirable genetic elements through wild populations. With the imminent development of this technology in vertebrates, we believe that it is timely to highlight two forms of sex-ratio distorting GDs that show potential as pest management tools.

Invasion and migration of spatially self-limiting gene drives: A comparative analysis

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Dhole, S.; Vella, M. R; Lloyd, A. L.; Gould, F.,  Evolutionary Applications,  11:794-808. 2018-01-10 00:00:00.
Recent advances in research on gene drives have produced genetic constructs that could theoretically spread a desired gene (payload) into all populations of a species, with a single release in one place. This attribute has advantages, but also comes with risks and ethical concerns. There has been a call for research on gene drive systems that are spatially and/or temporally self?limiting. Here, we use a population genetics model to compare the expected characteristics of three spatially self?limiting gene drive systems: one?locus underdominance, two?locus underdominance and daisy?chain drives. We find large differences between these gene drives in the minimum release size required for successfully driving a payload into a population. The daisy?chain system is the most efficient, requiring the smallest release, followed by the two?locus underdominance system, and then the one?locus underdominance system. However, when the target population exchanges migrants with a nontarget population, the gene drives requiring smaller releases suffer from higher risks of unintended spread. For payloads that incur relatively low fitness costs (up to 30%), a simple daisy?chain drive is practically incapable of remaining localized, even with migration rates as low as 0.5% per generation. The two?locus underdominance system can achieve localized spread under a broader range of migration rates and of payload fitness costs, while the one?locus underdominance system largely remains localized. We also find differences in the extent of population alteration and in the permanence of the alteration achieved by the three gene drives. The two?locus underdominance system does not always spread the payload to fixation, even after successful drive, while the daisy?chain system can, for a small set of parameter values, achieve a temporally limited spread of the payload. These differences could affect the suitability of each gene drive for specific applications.

Can CRISPR-based gene drive be confined in the Wild? A question for molecular and population biology

3991
Marshall, JMA, Omar S.,  ACS Chemical Biology,  13:424-430. 2018-01-09 00:00:00.
The recent discovery of CRISPR and its application as a gene editing tool has enabled a range of gene drive systems to be engineered with greater ease. In order for the benefits of this technology to be realized, in some circumstances drive systems should be developed that are capable of both spreading into populations to achieve their desired impact and being recalled in the event of unwanted consequences or public disfavor. We review the performance of three broad categories of drive systems at achieving these goals: threshold-dependent drives, homing-based drive and remediation systems, and temporally self-limiting systems such as daisy-chain drives.

Gene drives in our future: challenges of and opportunities for using a self-sustaining technology in pest and vector management

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Collins, JP,  BMC Proceedings,  12:9. 2018-01-09 00:00:00.
Gene drives are systems of biased inheritance that enhance the likelihood a sequence of DNA passes between generations through sexual reproduction and potentially throughout a local population and ultimately all connected populations of a species. Gaps in our knowledge of gene drive systems prompted the US National Institutes of Health (NIH) and the Foundation for the NIH to ask the US National Academies of Sciences, Engineering, and Medicine (NASEM) to convene an expert panel to provide an independent, objective examination of what we know about gene drive systems. The report, “Gene drives on the horizon: Advancing science, navigating uncertainty, and aligning research with public values,” outlines our understanding of the science, ethics, public engagement, governance, and risk assessment pertaining to gene drive research.

Gene drive gets safety features limiting risk for a tool that could alter entire species

Collins, CH,  Scientific American,  319:37-38. 2018-01-08 00:00:00.
Research into a genetic engineering technology that can permanently change the traits of a population or even an entire species is progressing rapidly. The approach uses gene drives—genetic elements that pass from parents to unusually high numbers of their offspring, thereby spreading through populations rather quickly. Gene drives occur naturally but can also be engineered, and doing so could be a boon to humanity in many ways. The technology has the potential to stop insects from transmitting malaria and other terrible infections, enhance crop yields by altering pests that attack plants, render corals resistant to environmental stress, and keep invasive plants and animals from destroying ecosystems. Yet investigators are deeply aware that altering or even eliminating a species could have profound consequences. In response, they are developing rules to govern the transfer of gene drives from the laboratory into future field tests and wider use.

Unexpected patterns of segregation distortion at a selfish supergene in the fire ant Solenopsis invicta

4010
Ross, KGS, DeWayne,  BMC Genetics,  19:101. 2018-01-08 00:00:00.
The Sb supergene in the fire ant Solenopsis invicta determines the form of colony social organization, with colonies whose inhabitants bear the element containing multiple reproductive queens and colonies lacking it containing only a single queen. Several features of this supergene — including suppressed recombination, presence of deleterious mutations, association with a large centromere, and “green-beard” behavior — suggest that it may be a selfish genetic element that engages in transmission ratio distortion (TRD), defined as significant departures in progeny allele frequencies from Mendelian inheritance ratios. We tested this possibility by surveying segregation ratios in embryo progenies of 101 queens of the “polygyne” social form (3512 embryos) using three supergene-linked markers and twelve markers outside the supergene.

Veni, vidi, vici: the success of wtf meiotic drivers in fission yeast

3990
López Hernández, JFZ, Sarah E.,  Yeast,  35:447-453. 2018-01-08 00:00:00.
Meiotic drivers are selfish DNA loci that can bias their own transmission into gametes. Owing to their transmission advantages, meiotic drivers can spread in populations even if the drivers or linked variants decrease organismal fitness. Meiotic drive was first formally described in the 1950s and is thought to be a powerful force shaping eukaryotic genomes. Classic genetic analyses have detected the action of meiotic drivers in plants, filamentous fungi, insects and vertebrates. Several of these drive systems have limited experimental tractability and relatively little is known about the molecular mechanisms of meiotic drive. Recently, however, meiotic drivers were discovered in a yeast species. The Schizosaccharomyces pombe wtf gene family contains several active meiotic drive genes. This review summarizes what is known about the wtf family and highlights its potential as a highly tractable experimental model for molecular and evolutionary characterization of meiotic drive.

Development of a multi-locus CRISPR gene drive system in budding yeast

4029
Yan, YF, Gregory C.,  Scientific reports,  8:17277-17277. 2018-01-07 00:00:00.
The discovery of CRISPR/Cas gene editing has allowed for major advances in many biomedical disciplines and basic research. One arrangement of this biotechnology, a nuclease-based gene drive, can rapidly deliver a genetic element through a given population and studies in fungi and metazoans have demonstrated the success of such a system. This methodology has the potential to control biological populations and contribute to eradication of insect-borne diseases, agricultural pests, and invasive species. However, there remain challenges in the design, optimization, and implementation of gene drives including concerns regarding biosafety, containment, and control/inhibition. Given the numerous gene drive arrangements possible, there is a growing need for more advanced designs. In this study, we use budding yeast to develop an artificial multi-locus gene drive system. Our minimal setup requires only a single copy of S. pyogenes Cas9 and three guide RNAs to propagate three gene drives. We demonstrate how this system could be used for targeted allele replacement of native genes and to suppress NHEJ repair systems by modifying DNA Ligase IV. A multi-locus gene drive configuration provides an expanded suite of options for complex attributes including pathway redundancy, combatting evolved resistance, and safeguards for control, inhibition, or reversal of drive action.

Population dynamics of underdominance gene drive systems in continuous space

3969
Champer, JZ, Joanna; Champer, Sam; Liu, Jingxian; Messer, Philipp W.,  bioRxiv,  449355:1-23. 2018-01-07 00:00:00.
Underdominance gene drive systems promise a mechanism for rapidly spreading payload alleles through a local population while otherwise remaining confined, unable to spread into neighboring populations due to their frequency-dependent dynamics. Such systems could provide a new tool in the fight against vector-borne diseases by disseminating transgenic payloads through vector populations. If local confinement can indeed be achieved, the decision-making process for the release of such constructs would likely be considerably simpler compared to other gene drive mechanisms such as CRISPR homing drives. So far, the confinement ability of underdominance systems has only been demonstrated in models of panmictic populations linked by migration. How such systems would behave in realistic populations where individuals move over continuous space remains largely unknown. Here, we study several underdominance systems in continuous-space population models and show that their dynamics are drastically altered from those in panmictic populations. Specifically, we find that all underdominance systems we studied can fail to persist in such environments, even after successful local establishment. At the same time, we find that a two-locus two-toxin-antitoxin system can still successfully invade neighboring populations in many scenarios even under weak migration. This suggests that the parameter space for underdominance systems to both establish in a given region and remain confined to that region would likely be highly limited. Overall, these results indicate that spatial context must be considered when assessing strategies for the deployment of underdominance systems.

Recent advances in threshold-dependent gene drives for mosquitoes

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Leftwich, PTE, Matthew P.; Harvey-Samuel, Tim; Carabajal Paladino, Leonela Z.; Norman, Victoria C.; Alphey, Luke,  Biochemical Society Transactions,  46:1203-1212. 2018-01-07 00:00:00.
Mosquito-borne diseases, such as malaria, dengue and chikungunya, cause morbidity and mortality around the world. Recent advances in gene drives have produced control methods that could theoretically modify all populations of a disease vector, from a single release, making whole species less able to transmit pathogens. This ability has caused both excitement, at the prospect of global eradication of mosquito-borne diseases, and concern around safeguards. Drive mechanisms that require individuals to be released at high frequency before genes will spread can therefore be desirable as they are potentially localised and reversible. These include underdominance-based strategies and use of the reproductive parasite Wolbachia. Here, we review recent advances in practical applications and mathematical analyses of these threshold-dependent gene drives with a focus on implementation in Aedes aegypti, highlighting their mechanisms and the role of fitness costs on introduction frequencies. Drawing on the parallels between these systems offers useful insights into practical, controlled application of localised drives, and allows us to assess the requirements needed for gene drive reversal.CI, cytoplasmic incompatibility; UD, underdominance; UDMEL, maternal-effect lethal underdominance

Tuning CRISPR-Cas9 gene grives in Saccharomyces cerevisiae

4009
Roggenkamp, EG, Rachael M.; Schrock, Madison N.; Turnquist, Emily; Halloran, Megan; Finnigan, Gregory C.,  G3-Genes Genomes Genetics,  8:999. 2018-01-07 00:00:00.
Control of biological populations is an ongoing challenge in many fields, including agriculture, biodiversity, ecological preservation, pest control, and the spread of disease. In some cases, such as insects that harbor human pathogens (e.g., malaria), elimination or reduction of a small number of species would have a dramatic impact across the globe. Given the recent discovery and development of the CRISPR-Cas9 gene editing technology, a unique arrangement of this system, a nuclease-based “gene drive,” allows for the super-Mendelian spread and forced propagation of a genetic element through a population. Recent studies have demonstrated the ability of a gene drive to rapidly spread within and nearly eliminate insect populations in a laboratory setting. While there are still ongoing technical challenges to design of a more optimal gene drive to be used in wild populations, there are still serious ecological and ethical concerns surrounding the nature of this powerful biological agent. Here, we use budding yeast as a safe and fully contained model system to explore mechanisms that might allow for programmed regulation of gene drive activity. We describe four conserved features of all CRISPR-based drives and demonstrate the ability of each drive component—Cas9 protein level, sgRNA identity, Cas9 nucleocytoplasmic shuttling, and novel Cas9-Cas9 tandem fusions—to modulate drive activity within a population.

Reducing resistance allele formation in CRISPR gene drive

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Champer, JL, Jingxian; Oh, Suh Yeon; Reeves, Riona; Luthra, Anisha; Oakes, Nathan; Clark, Andrew G.; Messer, Philipp W.,  Proceedings of the National Academy of Sciences of the United States of America,  115:5522-5527. 2018-01-06 00:00:00.
A functioning gene drive mechanism could fundamentally change our strategies for the control of vector-borne diseases, such as malaria, dengue, and Zika. CRISPR homing gene drive promises such a mechanism, which could be used to rapidly spread genetic modifications among the mosquitoes that transmit these diseases. However, recent studies have shown that current drives would likely be unable to spread in insect populations due to the high rate at which resistance will evolve. In this study, we provide an experimental demonstration that guide RNA multiplexing can successfully reduce resistance rates but also find that such an approach would still need to be combined with additional strategies to create drives that are efficient enough for use in wild populations.CRISPR homing gene drives can convert heterozygous cells with one copy of the drive allele into homozygotes, thereby enabling super-Mendelian inheritance. Such a mechanism could be used, for example, to rapidly disseminate a genetic payload in a population, promising effective strategies for the control of vector-borne diseases. However, all CRISPR homing gene drives studied in insects thus far have produced significant quantities of resistance alleles that would limit their spread. In this study, we provide an experimental demonstration that multiplexing of guide RNAs can both significantly increase the drive conversion efficiency and reduce germline resistance rates of a CRISPR homing gene drive in Drosophila melanogaster. We further show that an autosomal drive can achieve drive conversion in the male germline, with no subsequent formation of resistance alleles in embryos through paternal carryover of Cas9. Finally, we find that the nanos promoter significantly lowers somatic Cas9 expression compared with the vasa promoter, suggesting that nanos provides a superior choice in drive strategies where gene disruption in somatic cells could have fitness costs. Comparison of drive parameters among the different constructs developed in this study and a previous study suggests that, while drive conversion and germline resistance rates are similar between different genomic targets, embryo resistance rates can vary significantly. Taken together, our results mark an important step toward developing effective gene drives capable of functioning in natural populations and provide several possible avenues for further control of resistance rates.

RPM-Drive: A robust, safe, and reversible gene drive system that remains functional after 200+ generations

4008
Reed, FAA-M, Todd G.; Costantini, Maria S.; Láruson, Áki J.; Sutton, Jolene T.,  arXiv,  1806.05304:1-19. 2018-01-06 00:00:00.
Despite the advent of several novel, synthetic gene drive mechanisms and their potential to one-day control a number of devastating diseases, among other applications, practical use of these systems remains contentious and risky. In particular, there is little in the way of empirical evidence of the long-term robustness of these synthetic systems against mutational breakdown. Rather, most existing systems are either known or predicted to be susceptible to rapid inactivation, though methodological designs continue to be refined. Here we evaluate a currently existing synthetic, underdominance-based gene drive system 200+ generations after it was first established in a laboratory colony of Drosophila melanogaster. Not only do we find that the system is still functioning as designed, we also show evidence that disruptions to the genetic construct are highly likely to be removed by natural selection, contributing to the system's robust, long-term stability. This stability appears to be a result of a fundamental relationship between ribosomal proteins (a novel target of the system) and natural cellular defenses that protect against cancer development. As far as we are aware, this is the longest continually functioning synthetic gene drive system thus verified, making it highly appropriate for additional research into its eventual suitability for field trials. Due to inherent properties of this gene drive, it is also likely to be adaptable for use in many different species. The insect lines established and used to test this system have been deposited at a Drosophila stock center, and are available to labs for further, independent testing.

The use of driving endonuclease genes to suppress mosquito vectors of malaria in temporally variable environments

3988
Lambert, BN, Ace; Burt, Austin; Godfray, H. Charles J.,  Malaria Journal,  17:154. 2018-01-06 00:00:00.
The use of gene drive systems to manipulate populations of malaria vectors is currently being investigated as a method of malaria control. One potential system uses driving endonuclease genes (DEGs) to spread genes that impose a genetic load. Previously, models have shown that the introduction of DEG-bearing mosquitoes could suppress or even extinguish vector populations in spatially-heterogeneous environments which were constant over time. In this study, a stochastic spatially-explicit model of mosquito ecology is combined with a rainfall model which enables the generation of a variety of daily precipitation patterns. The model is then used to investigate how releases of a DEG that cause a bias in population sex ratios towards males are affected by seasonal or random rainfall patterns. The parameters of the rainfall model are then fitted using data from Bamako, Mali, and Mbita, Kenya, to evaluate release strategies in similar climatic conditions.

A CRISPR–Cas9 gene drive targeting doublesex causes complete population suppression in caged Anopheles gambiae mosquitoes

3987
Kyrou, KH, Andrew M.; Galizi, Roberto; Kranjc, Nace; Burt, Austin; Beaghton, Andrea K.; Nolan, Tony; Crisanti, Andrea,  Nature Biotechnology,  36:1062–1066. 2018-01-05 00:00:00.
In the human malaria vector Anopheles gambiae, the gene doublesex (Agdsx) encodes two alternatively spliced transcripts, dsx-female (AgdsxF) and dsx-male (AgdsxM), that control differentiation of the two sexes. The female transcript, unlike the male, contains an exon (exon 5) whose sequence is highly conserved in all Anopheles mosquitoes so far analyzed. We found that CRISPR–Cas9-targeted disruption of the intron 4–exon 5 boundary aimed at blocking the formation of functional AgdsxF did not affect male development or fertility, whereas females homozygous for the disrupted allele showed an intersex phenotype and complete sterility. A CRISPR–Cas9 gene drive construct targeting this same sequence spread rapidly in caged mosquitoes, reaching 100% prevalence within 7–11 generations while progressively reducing egg production to the point of total population collapse. Owing to functional constraint of the target sequence, no selection of alleles resistant to the gene drive occurred in these laboratory experiments. Cas9-resistant variants arose in each generation at the target site but did not block the spread of the drive.

Catch me if you can: A spatial model for a brake-driven gene drive reversal

3967
Calvez, V,,Debarre, F., Girardin, Leo,  arXiv,  1812.06641:1-30. 2018-01-05 00:00:00.
We successfully prove that, whenever the drive fitness is at most 50% of the wild-type one while the brake fitness is close to the wild-type one, co-extinction of the brake and the drive occurs in the long run.

Correction to ‘Dodging silver bullets: good CRISPR gene-drive design is critical for eradicating exotic vertebrates’

4007
Prowse, TAAC, Phillip; Ross, Joshua V.; Pfitzner, Chandran; Wittmann, Talia; Thomas, Paul,  Proceedings of the Royal Society B: Biological Sciences,  285:1-2. 2018-01-05 00:00:00.
Proc. R. Soc. B 284, 20170799. (Published Online 9 August 2017). (doi:10.1098/rspb.2017.0799)We recently found an error in our calculation of the probability of a wild-type allele moving from s to j susceptible sites (), and acquiring the gene drive (), during gene-drive homing, under the assumption that multiplexed gRNAs are expressed simultaneously. In the R code provided (function GeneDriveSimRec, appendix S1), these probabilities are calculated recursively and the multiplier was missing (from line 11), where j is the number of cut target sites along an inter-site NHEJ-mediated deletion at which NHEJ …

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