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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Hybrid mosquitoes? Evidence from rural Tanzania on how local communities conceptualize and respond to modified mosquitoes as a tool for malaria control

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M. F. Finda, F. O. Okumu, E. Minja, R. Njalambaha, W. Mponzi, B. B. Tarimo, P. Chaki, J. Lezaun, A. H. Kelly and N. Christofides,  Malaria Journal,  20:134. 2021-03-06 14:11:52.
Different forms of mosquito modifications are being considered as potential high-impact and low-cost tools for future malaria control in Africa. Although still under evaluation, the eventual success of these technologies will require high-level public acceptance. Understanding prevailing community perceptions of mosquito modification is, therefore, crucial for effective design and implementation of these interventions. This study investigated community perceptions regarding genetically-modified mosquitoes (GMMs) and their potential for malaria control in Tanzanian villages where no research or campaign for such technologies has yet been undertaken.

A confinable home and rescue gene drive for population modification

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N. P. Kandul, J. Liu, J. B. Bennett, J. M. Marshall and O. S. Akbari,  eLife,  10:e65939. 2021-03-05 16:30:16.
Homing based gene drives, engineered using CRISPR/Cas9, have been proposed to spread desirable genes throughout populations. However, invasion of such drives can be hindered by the accumulation of resistant alleles. To limit this obstacle, we engineer a confinable population modification Home-and-Rescue (HomeR) drive in Drosophila targeting an essential gene. In our experiments, resistant alleles that disrupt the target gene function were recessive lethal, and therefore disadvantaged. We demonstrate that HomeR can achieve an increase in frequency in population cage experiments, but that fitness costs due to the Cas9 insertion limit drive efficacy.

Engineered expression of the invertebrate-specific scorpion toxin AaHIT reduces adult longevity and female fecundity in the diamondback moth Plutella xylostella

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T. Harvey-Samuel, X. Xu, E. Lovett, T. Dafa'alla, A. Walker, V. C. Norman, R. Carter, J. Teal, L. Akilan, P. T. Leftwich, C. M. Reitmayer, H. A. Siddiqui and L. Alphey,  Pest Management Science,  2021-03-04 17:21:00.
To increase the flexibility of future genetic pest management systems in the diamondback moth, we aimed to assess the use of a non-cell-autonomous, invertebrate-specific, neurotoxic effector ? the scorpion toxin AaHIT. This AaHIT effector was designed to be secreted by expressing cells, potentially leading to effects on distant cells, specifically neuromuscular junctions. We demonstrated the feasibility of using non-cell-autonomous effectors within a GPM context for the first time in Lepidoptera, one of the most economically damaging orders of insects. These findings provide a framework for extending this system to other pest Lepidoptera and to other secreted effectors.

Quantifying the risk of vector-borne disease transmission attributable to genetically modified vectors

16530
G. R. Hosack, A. Ickowicz and K. R. Hayes,  Royal Society Open Science,  8:201525. 2021-03-03 18:28:51.
The relative risk of disease transmission caused by the potential release of transgenic vectors, such as through sterile insect technique or gene drive systems, is assessed with comparison with wild-type vectors. The probabilistic risk framework is demonstrated with an assessment of the relative risk of lymphatic filariasis, malaria and o'nyong'nyong arbovirus transmission by mosquito vectors to human hosts given a released transgenic strain of Anopheles coluzzii carrying a dominant sterile male gene construct. Harm is quantified by a logarithmic loss function that depends on the causal risk ratio, which is a quotient of basic reproduction numbers derived from mathematical models of disease transmission. The basic reproduction numbers are predicted to depend on the number of generations in an insectary colony and the number of backcrosses between the transgenic and wild-type lineages. Analogous causal risk ratios for short-term exposure to a single cohort release are also derived. These causal risk ratios were parametrized by probabilistic elicitations, and updated with experimental data for adult vector mortality. For the wild-type, high numbers of insectary generations were predicted to reduce the number of infectious human cases compared with uncolonized wild-type. Transgenic strains were predicted to produce fewer infectious cases compared with the uncolonized wild-type.

Developing GDi-CRISPR System for Multi-copy Integration in Saccharomyces cerevisiae

16544
Z.-X. Zhang, Y.-Z. Wang, Y.-S. Xu, X.-M. Sun and H. Huang,  Applied Biochemistry and Biotechnology,  2021-03-03 16:12:03.
This study aims to develop a low-cost and easy-to-use multi-copy integration tool in S. cerevisiae. Firstly, twenty-one Cas proteins from different microorganisms were tested in S. cerevisiae to find the functional Cas proteins with optimal cleavage ability. Results showed that eight Cas proteins can complete gene editing. However, most of the transformants have low copy numbers, which may be caused by high cutting efficiency exceeding the repair rate. Therefore, the effect of donor translocation order was further investigated. Results showed that 4 copies were obtained by donor first translocation. Then, the gene drive delta site integration system by the CRISPR system (GDi-CRISPR) was developed by combining gene drive principle and CRISPR system. To be clear, the gRNA was put into donor fragments. Then, both of them were integrated into the genome, which can drive further cutting and repair due to increasing number of gRNA. Instead of high-throughput screening or resistance pressure, 6 copies were obtained in only 5–6 days using the GDi-CRISPR system. It is expected to further advance the development of S. cerevisiae multi-copy integration tools.

Knowledge, Attitude, and Practices Survey in Greece before the Implementation of Sterile Insect Technique against Aedes albopictus

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A. Stefopoulou, S. L. LaDeau, N. Syrigou, G. Balatsos, V. Karras, I. Lytra, E. Boukouvala, D. P. Papachristos, P. G. Milonas, A. Kapranas, P. Vahamidis and A. Michaelakis,  Insects,  12. 2021-03-02 13:52:16.
A KAP tool was used to shed light on the knowledge, practices, and attitudes of local community members in order to better prepare and motivate participation in household mosquito control and to assess current understanding of SIT. Each household also received specific information about mosquito source habitat in their own yards at the time of the initial KAP survey. These household data were complemented by standardized mosquito trapping in the municipality. Our findings indicate that citizens’ attitude toward SIT ranged from indecisive to fully supportive, while 77.5% of the respondents agreed that the SIT has many advantages over chemical control methods. Furthermore, the results demonstrate that using the door-to-door campaign as an intervention and prerelease method before SIT can suppress the initial mosquito population and potentially improve its efficacy. Lastly, we show that the presence of local municipality officials during door-to-door visits was associated with increased willingness from the residents to participate in the intervention.

Demographic and psychographic drivers of public acceptance of novel invasive pest control technologies

17086
F. Eppink, P. J. Walsh and E. MacDonald,  Ecology and Society,  26. 2021-03-01 15:15:26.
Invasive mammals are a primary threat to New Zealand's endemic species. In remote areas, aerial delivery of poison is the preferred method of pest management, although it faces some public backlash. Novel pest control technologies are currently being investigated as alternatives but may face similar concerns. To investigate potential social and demographic determinants of public perceptions of new methods for pest control, we conducted a national choice experiment, focused on several novel technologies: gene drives, Trojan females, and species-specific poisons. We found that preferences strongly depend on the type of technology, with Trojan female technology strictly preferred to the other two. Although several characteristics affected preferences in predictable ways education, trust in science, and liberal political leaning increased acceptance ;the same did not hold with preferences for aerial delivery. Our results are useful for targeting future engagement campaigns and leveraging existing efforts.

Meiotic drive does not cause condition-dependent reduction of the sexual ornament in stalk-eyed flies

17034
S. R. Finnegan, M. Mondani, K. Fowler and A. Pomiankowski,  Journal of Evolutionary Biology,  11. 2021-02-28 11:18:46.
Meiotic drive systems are associated with low-frequency chromosomal inversions. These are expected to accumulate deleterious mutations due to reduced recombination and low effective population size. We test this prediction using the 'sex-ratio' (SR) meiotic drive system of the Malaysian stalk-eyed fly Teleopsis dalmanni. SR is associated with a large inversion (or inversions) on the X chromosome. In particular, we study eyespan in males carrying the SR chromosome, as this trait is a highly exaggerated, sexually dimorphic trait, known to have heightened condition-dependent expression. Larvae were raised in low and high larval food stress environments. SR males showed reduced eyespan under the low and high stress treatments, but there was no evidence of a condition-dependent decrease in eyespan under high stress. Similar but more complex patterns were observed for female eyespan, with evidence of additivity under low stress and heterosis under high stress. These results do not support the hypothesis that reduced sexual ornament size in meiotic drive males is due to a condition-dependent response to the putative increase in mutation load. Instead, reduced eyespan likely reflects compensatory resource allocation to different traits in response to drive-mediated destruction of sperm.

Designing gene drives to limit spillover to non-target populations

16516
G. Greenbaum, M. W. Feldman, N. A. Rosenberg and J. Kim,  PLOS Genetics,  17:e1009278. 2021-02-25 15:02:27.
We develop mathematical models of gene-drive dynamics that incorporate migration between a target and non-target populations to investigate the possibility of effectively applying a gene drive in the target population while limiting its spillovers to the non-target population (‘differential targeting’). We observe that the feasibility of differential targeting depends on the gene-drive design specification, as well as on the migration rates between the populations. Even when differential targeting is possible, as migration increases, the possibility for differential targeting disappears. We find that differential targeting can be effective for low migration rates, and that it is sensitive to the design of the gene drive under high migration rates. We suggest that differential targeting could be used, in combination with other mitigation measures, as an additional safeguard to limit gene drive spillovers.

Sterile Insect Technique: Lessons From the Past

18706
M. Q. Benedict,  Journal of Medical Entomology,  58:1974-1979. 2021-02-25 13:35:08.
When E.F. Knipling conceived of the release of sexually sterile insects to suppress wild populations, he laid down several fundamental qualities that characterized suitable target species—some of which mosquitoes generally violate—including high reproductive rates and large population numbers. Regardless of this, their global importance in public health has led numerous research teams to attempt to use the mosquito sterile insect technique against several species. Because of the degree of financial commitment required for suppression programs, most releases have consisted of preliminary investigations of male performance, population characteristics, and production methods. Those that have accomplished suppression provide important insights regarding the challenges of production, dispersal, and immigration. Insights gained from these studies remain relevant today, regardless of the genetic control technology being applied. In this article, I highlight studies that were notable for the insights that were gained, the intrinsic difficulties that mosquitoes present, and synthesize these into recommendations for successful applications of the sterile insect technique and newer technologies to mosquitoes.

Sterile Insect Technique (SIT) against Aedes Species Mosquitoes: A Roadmap and Good Practice Framework for Designing, Implementing and Evaluating Pilot Field Trials

16659
C. F. Oliva, M. Q. Benedict, C. M. Collins, T. Baldet, R. Bellini, H. Bossin, J. Bouyer, V. Corbel, L. Facchinelli, F. Fouque, M. Geier, A. Michaelakis, D. Roiz, F. Simard, C. Tur and L.-C. Gouagna,  Insects,  12. 2021-02-24 13:44:35.
We offer here a pragmatic and accessible ‘roadmap’ for the pre-pilot and pilot phases to guide any interested party. This will support stakeholders, non-specialist scientists, implementers, and decision-makers. Applying these concepts will ensure, given adequate resources, a sound basis for local field trialing and for developing experience with the technique in readiness for potential operational deployment. This synthesis is based on the available literature, in addition to the experience and current knowledge of the expert contributing authors in this field. We describe a typical path to successful pilot testing, with the four concurrent development streams of Laboratory, Field, Stakeholder Relations, and the Business and Compliance Case. We provide a graphic framework with criteria that must be met in order to proceed.

Population genomics of invasive rodents on islands: Genetic consequences of colonization and prospects for localized synthetic gene drive

16657
K. P. Oh, A. B. Shiels, L. Shiels, D. V. Blondel, K. J. Campbell, J. R. Saah, A. L. Lloyd, P. Q. Thomas, F. Gould, Z. Abdo, J. R. Godwin and A. J. Piaggio,  Evolutionary Applications,  2021-02-22 17:41:41.
Here we used pooled whole-genome sequencing of invasive mouse (Mus musculus) populations on four islands along with paired putative source populations to test genetic predictions of island colonization and characterize locally fixed Cas9 genomic targets. Patterns of variation across the genome reflected marked reductions in allelic diversity in island populations and moderate to high degrees of differentiation from nearby source populations despite relatively recent colonization. Locally fixed Cas9 sites in female fertility genes were observed in all island populations, including a small number with multiplexing potential. In practice, rigorous sampling of presumptive LFA will be essential to fully assess risk of resistance alleles. These results should serve to guide development of improved, spatially limited gene drive design in future applications.

Modeling impact and cost-effectiveness of gene drives for malaria elimination in the Democratic Republic of the Congo

16477
N. Metchanun, C. Borgemeister, G. Amzati, J. von Braun, M. Nikolov, P. Selvaraj and J. Gerardin,  medRxiv,  2020.06.29.20142760. 2021-02-22 13:51:04.
Using a spatially explicit, agent-based model of malaria transmission in eight representative provinces of the Democratic Republic of the Congo, we predict the impact and cost-effectiveness of integrating driving-Y gene drive mosquitoes in malaria elimination strategies that include existing interventions such as insecticide-treated nets and case management of symptomatic malaria. Gene drive mosquitoes could eliminate malaria and were the most cost-effective intervention overall if the drive component was highly effective with at least 95% X-shredding and associated cost of deployment below 7.17 $int per person per year. Suppression gene drive could be a cost-effective supplemental intervention for malaria elimination, but tight constraints on drive effectiveness and cost ceilings may limit its feasibility.

Holocentric Chromosomes Probably Do Not Prevent Centromere Drive in Cyperaceae

16676
M. Kratka, J. Smerda, K. Lojdova, P. Bures and F. Zedek,  Frontiers in Plant Science,  12:9. 2021-02-19 14:30:42.
In response to these selfish centromeres, the histone protein CenH3, which recruits kinetochore components, adaptively evolves to restore chromosomal parity and counter the detrimental effects of centromere drive. Holocentric chromosomes, whose kinetochores are assembled along entire chromosomes, have been hypothesized to prevent expanded centromeres from acquiring a selective advantage and initiating centromere drive. In such a case, CenH3 would be subjected to less frequent or no adaptive evolution. Using codon substitution models, we analyzed 36 CenH3 sequences from 35 species of the holocentric family Cyperaceae. We found 10 positively selected codons in the CenH3 gene [six codons in the N-terminus and four in the histone fold domain (HFD)] and six branches of its phylogeny along which the positive selection occurred. One of the positively selected codons was found in the centromere targeting domain (CATD) that directly interacts with DNA and its mutations may be important in centromere drive suppression. The frequency of these positive selection events was comparable to the frequency of positive selection in monocentric clades with asymmetric female meiosis. Taken together, these results suggest that preventing centromere drive is not the primary adaptive role of holocentric chromosomes, and their ability to suppress it likely depends on their kinetochore structure in meiosis.

Split versions of Cleave and Rescue selfish genetic elements for measured self limiting gene drive

16426
G. Oberhofer, T. Ivy and B. A. Hay,  PLoS genetics,  17:e1009385. 2021-02-18 20:00:28.
Self-sustaining Cleave and Rescue (ClvR) elements include a DNA sequence-modifying enzyme such as Cas9/gRNAs that disrupts endogenous versions of an essential gene, a tightly linked recoded version of the essential gene resistant to cleavage (the Rescue), and a Cargo. ClvR spreads by creating loss-of-function (LOF) conditions in which those without ClvR die because they lack functional copies of the essential gene. We use modeling to show that when the Rescue-Cargo and one or both components required for LOF allele creation (Cas9 and gRNA) reside at different locations (split ClvR), drive of Rescue-Cargo is self-limiting due to a progressive decrease in Cas9 frequency, and thus opportunities for creation of LOF alleles, as spread occurs. Importantly, drive strength and duration can be extended in a measured manner-which is still self-limiting-by moving the two components close enough to each other that they experience some degree of linkage. With linkage, Cas9 transiently experiences drive by hitchhiking with Rescue-Cargo until linkage disequilibrium between the two disappears, a function of recombination frequency and number of generations, creating a novel point of control. We implement split ClvR in Drosophila, with key elements on different chromosomes. Cargo/Rescue/gRNAs spreads to high frequency in a Cas9-dependent manner, while the frequency of Cas9 decreases.

Emergent challenges for CRISPR: biosafety, biosecurity, patenting, and regulatory issues

19398
Braddick, D. , and Ramarohetra, R. F.,  Genome Engineering Via Crispr-Cas9 System,  2021-02-18 17:46:33.
The recent advancements of CRISPR-Cas technologies have transformed this simple and efficient gene editing technique into an extraordinarily powerful tool. The most anticipated applications could create novel therapeutics against mankind's most serious afflictions and help eradicate vector-based diseases. However, with these desired benefits come new ethical questions and potential threats. CRISPR technologies are not yet fully developed toward delivering all of their promises, and suffer from biosafety problems in human products and biosecurity threats arising from its potential dual use and errant gene drives. Furthermore, the future innovations of CRISPR technologies may encounter non-scientific challenges in patentability and unclear legal regulations at the national and international levels. This chapter will discuss these issues, and where possible, will highlight the currently proposed solutions that could mitigate the threats, and could address the problems that hold back CRISPR's full potential.

Scientifically framed gene drive communication perceived as credible but riskier

16406
E. A. MacDonald, E. D. Edwards, J. Balanovic and F. Medvecky,  People and Nature,  2021-02-17 18:23:29.
Framing is a communication technique in which certain beliefs or values are emphasized that resonate with the target audience. Framing may increase how much people objectively think about new information and update their opinions; framing may mitigate emo

ReMOT Control Delivery of CRISPR-Cas9 Ribonucleoprotein Complex to Induce Germline Mutagenesis in the Disease Vector Mosquitoes Culex pipiens pallens (Diptera: Culicidae)

17482
X. X. Li, Y. Xu, H. B. Zhang, H. T. Yin, D. Zhou, Y. Sun, L. Ma, B. Shen and C. L. Zhu,  Journal of Medical Entomology,  58. 2021-02-16 14:57:35.
The wide distribution of Culex (Cx.) pipiens complex mosquitoes makes it difficult to prevent the transmission of mosquito-borne diseases in humans. Gene editing using CRISPR/Cas9 is an effective technique with the potential to solve the growing problem of mosquito-borne diseases. This study uses the ReMOT Control technique in Culex pipiens pallens (L.) to produce genetically modified mosquitoes. A microinjection system was established by injecting 60 adult female mosquitoes-14 mu l injection mixture was required, and no precipitation occurred with <= 1 mu l of endosomal release reagents (chloroquine or saponin). The efficiency of delivery of the P2C-enhanced green fluorescent protein-Cas9 (P2C-EGFP-Cas9) ribonucleoprotein complex into the ovary was 100% when injected at 24 h post-bloodmeal (the peak of vitellogenesis). Using this method for KMO knockout, we found that gene editing in the ovary could also occur when P2C-Cas9 RNP complex was injected into the hemolymph of adult Cx. pipiens pallens by ReMOT Control. In the chloroquine group, of the 2,251 G(0) progeny screened, 9 individuals showed with white and mosaic eye phenotypes. In the saponin group, of the 2,462 G(0) progeny screened, 8 mutant individuals were observed. Sequencing results showed 13 bp deletions, further confirming the fact that gene editing occurred. In conclusion, the successful application of ReMOT Control in Cx. pipiens pallens not only provides the basic parameters (injection parameters and injection time) for this method but also facilitates the study of mosquito biology and control.

Operational Parameters for the Aerial Release of Sterile Codling Moths Using an Uncrewed Aircraft System

17762
E. D. Esch, R. M. Horner, D. C. Krompetz, N. Moses-Gonzales, M. R. Tesche and D. M. Suckling,  Insects,  12:2/13/2021. 2021-02-13 14:52:13.
The codling moth is a serious pest of apples in most regions of the world where this fruit is produced. The sterile insect technique is one strategy used to control this pest and is employed as part of an area-wide integrated pest management program for the codling moth in British Columbia, Canada. Modified fixed wing aircraft are the most common method for the release of sterile insects in large area-wide pest management programs. However, aerial release with a full-size aircraft can be prohibitively expensive. We evaluated the use of small, uncrewed aircraft systems (UASs) for the release of sterile codling moths. Sterile codling moths released from greater altitudes were more broadly distributed and drifted more in strong winds, compared to those released from lower altitudes. Most of the released insects were recaptured in a 50 m wide swath under the release route. Recapture rates for aerially released insects were 40–70% higher compared to those released from the ground. UASs provide a promising alternative to ground release and conventional aircraft for the release of sterile codling moths.

Optimized CRISPR tools and site-directed transgenesis in Culex quinquefasciatus mosquitoes for gene drive development

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X. Feng, V. Lopez Del Amo, E. Mameli, M. Lee, A. L. Bishop, N. Perrimon and V. M. Gantz,  bioRxiv,  2021.02.10.430702. 2021-02-11 20:33:00.
Here, we developed a Culex-specific Cas9/gRNA expression toolkit and used site-directed homology-based transgenesis to generate and validate a Culex quinquefasciatus Cas9-expressing line. We showed that gRNA scaffold variants improve transgenesis efficiency in both Culex and Drosophila and boost gene-drive performance in the fruit fly. These findings support future technology development to control Culex mosquitoes and provide valuable insight for improving these tools in other species.

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