35 results found
Hammond A, Karlsson X, Morianou I, et al., 2021, Regulating the expression of gene drives is key to increasing their invasive potential and the mitigation of resistance, PLOS GENETICS, Vol: 17, ISSN: 1553-7404
Simoni A, Hammond AM, Beaghton AK, et al., 2020, A male-biased sex-distorter gene drive for the human malaria vector Anopheles gambiae, Nature Biotechnology, Vol: 38, Pages: 1054-1060, ISSN: 1087-0156
Only female insects transmit diseases such as malaria, dengue and Zika; therefore, control methods that bias the sex ratio of insect offspring have long been sought. Genetic elements such as sex-chromosome drives can distort sex ratios to produce unisex populations that eventually collapse, but the underlying molecular mechanisms are unknown. We report a male-biased sex-distorter gene drive (SDGD) in the human malaria vector Anopheles gambiae. We induced super-Mendelian inheritance of the X-chromosome-shredding I-PpoI nuclease by coupling this to a CRISPR-based gene drive inserted into a conserved sequence of the doublesex (dsx) gene. In modeling of invasion dynamics, SDGD was predicted to have a quicker impact on female mosquito populations than previously developed gene drives targeting female fertility. The SDGD at the dsx locus led to a male-only population from a 2.5% starting allelic frequency in 10-14 generations, with population collapse and no selection for resistance. Our results support the use of SDGD for malaria vector control.
Simoni A, Hammond AM, Beaghton AK, et al., 2020, A male-biased sex-distorter gene drive for the human malaria vector Anopheles gambiae (vol 14, pg 931, 2020), NATURE BIOTECHNOLOGY, Vol: 38, Pages: 1097-1097, ISSN: 1087-0156
Beaghton AK, Hammond A, Nolan T, et al., 2019, Gene drive for population genetic control: non-functional resistance and parental effects, Proceedings of the Royal Society B: Biological Sciences, Vol: 286, Pages: 1-8, ISSN: 0962-8452
Gene drive is a natural process of biased inheritance that, in principle, could be used to control pest and vector populations. As with any form of pest control, attention should be paid to the possibility of resistance evolving. For nuclease-based gene drive aimed at suppressing a population, resistance could arise by changes in the target sequence that maintain function, and various strategies have been proposed to reduce the likelihood that such alleles arise. Even if these strategies are successful, it is almost inevitable that alleles will arise at the target site that are resistant to the drive but do not restore function, and the impact of such sequences on the dynamics of control has been little studied. We use population genetic modelling of a strategy targeting a female fertility gene to demonstrate that such alleles may be expected to accumulate, and thereby reduce the reproductive load on the population, if nuclease expression per se causes substantial heterozygote fitness effects or if parental (especially paternal) deposition of nuclease either reduces offspring fitness or affects the genotype of their germline. All these phenomena have been observed in synthetic drive constructs. It will, therefore, be important to allow for non-functional resistance alleles in predicting the dynamics of constructs in cage populations and the impacts of any field release.
A first generation of CRISPR-based gene drives has now been tested in the laboratory in a number of organisms, including malaria vector mosquitoes. Challenges for their use in the area-wide genetic control of vector-borne disease have been identified, including the development of target site resistance, their long-term efficacy in the field, their molecular complexity, and practical and legal limitations for field testing of both gene drive and coupled anti-pathogen traits. We have evaluated theoretically the concept of integral gene drive (IGD) as an alternative paradigm for population replacement. IGDs incorporate a minimal set of molecular components, including drive and anti-pathogen effector elements directly embedded within endogenous genes – an arrangement that in theory allows targeting functionally conserved coding sequences without disrupting their function. Autonomous and non-autonomous IGD strains could be generated, optimized, regulated and imported independently. We performed quantitative modeling comparing IGDs with classical replacement drives and show that selection for the function of the hijacked host gene can significantly reduce the establishment of resistant alleles in the population, while drive occurring at multiple genomic loci prolongs the duration of transmission blockage in the face of pre-existing target site variation. IGD thus has potential as a more durable and flexible population replacement strategy.
Kyrou K, Hammond AM, Galizi R, et al., 2018, A CRISPR-Cas9 gene drive targeting doublesex causes complete population suppression in caged Anopheles gambiae mosquitoes, Nature Biotechnology, Vol: 36, Pages: 1062-1066, ISSN: 1087-0156
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.
Nikolov M, Ouedraogo A, Beaghton A, et al., 2018, POPULATION SEASONALITY AND RELEASE TIMING SIGNIFICANTLY AFFECT THE PROBABILITY OF ESTABLISHMENT FOR SMALL RELEASES OF GENE DRIVE MOSQUITOES, 67th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTHM), Publisher: AMER SOC TROP MED & HYGIENE, Pages: 367-367, ISSN: 0002-9637
Beaghton AK, Beaghton PJ, Burt A, 2017, Vector control with driving Y chromosomes: modelling the evolution of resistance, Malaria Journal, Vol: 16, ISSN: 1475-2875
BackgroundThe introduction of new malaria control interventions has often led to the evolution of resistance, both of the parasite to new drugs and of the mosquito vector to new insecticides, compromising the efficacy of the interventions. Recent progress in molecular and population biology raises the possibility of new genetic-based interventions, and the potential for resistance to evolve against these should be considered. Here, population modelling is used to determine the main factors affecting the likelihood that resistance will evolve against a synthetic, nuclease-based driving Y chromosome that produces a male-biased sex ratio. MethodsA combination of deterministic differential equation models and stochastic analyses involving branching processes and Gillespie simulations is utilized to assess the probability that resistance evolves against a driving Y that otherwise is strong enough to eliminate the target population. The model considers resistance due to changes at the target site such that they are no longer cleaved by the nuclease, and due to trans-acting autosomal suppressor alleles. ResultsThe probability that resistance evolves increases with the mutation rate and the intrinsic rate of increase of the population, and decreases with the strength of drive and any pleiotropic fitness costs of the resistant allele. In seasonally varying environments, the time of release can also affect the probability of resistance evolving. Trans-acting suppressor alleles are more likely to suffer stochastic loss at low frequencies than target site resistant alleles. ConclusionsAs with any other intervention, there is a risk that resistance will evolve to new genetic approaches to vector control, and steps should be taken to minimize this probability. Two design features that should help in this regard are to reduce the rate at which resistant mutations arise, and to target sequences such that if they do arise, they impose a significant fitness cost on the mosquito.
Beaghton A, Hammond A, Nolan T, et al., 2017, Requirements for Driving Antipathogen Effector Genes into Populations of Disease Vectors by Homing, Genetics, Vol: 205, Pages: 1587-1596
Beaghton A, Beaghton PJ, Burt A, 2016, Gene drive through a landscape: Reaction–diffusion models of population suppression and elimination by a sex ratio distorter, Theoretical Population Biology, Vol: 108, Pages: 51-69, ISSN: 1096-0325
Some genes or gene complexes are transmitted from parents to offspring at a greater-than-Mendelian rate, and can spread and persist in populations even if they cause some harm to the individuals carrying them. Such genes may be useful for controlling populations or species that are harmful. Driving-Y chromosomes may be particularly potent in this regard, as they produce a male-biased sex ratio that, if sufficiently extreme, can lead to population elimination. To better understand the potential of such genes to spread over a landscape, we have developed a series of reaction–diffusion models of a driving-Y chromosome in 1-D and radially-symmetric 2-D unbounded domains. The wild-type system at carrying capacity is found to be unstable to the introduction of driving-Y males for all models investigated. Numerical solutions exhibit travelling wave pulses and fronts, and analytical and semi-analytical solutions for the asymptotic wave speed under bounded initial conditions are derived. The driving-Y male invades the wild-type equilibrium state at the front of the wave and completely replaces the wild-type males, leaving behind, at the tail of the wave, a reduced- or zero-population state of females and driving-Y males only. In our simplest model of a population with one life stage and density-dependent mortality, wave speed depends on the strength of drive and the diffusion rate of Y-drive males, and is independent of the population dynamic consequences (suppression or elimination). Incorporating an immobile juvenile stage of fixed duration into the model reduces wave speed approximately in proportion to the relative time spent as a juvenile. If females mate just once in their life, storing sperm for subsequent reproduction, then wave speed depends on the movement of mated females as well as Y-drive males, and may be faster or slower than in the multiple-mating model, depending on the relative duration of juvenile and adult life stages. Numerical solutions are shown
Beaghton AK, 2016, The Many Faces of Javert in Anglophone Adaptation, Les Misérables and Its Afterlives Between Page, Stage, and Screen, Editors: Grossman, Stephens, Publisher: Routledge, Pages: 143-158, ISBN: 9781317105695
Exploring the enduring popularity of Victor Hugo’s Les Misérables, this collection offers analysis of both the novel itself and its adaptations.
Beaghton AK, Myers AL, 2014, The Moon Tilt Illusion, KoG, Vol: 18, Pages: 53-59, ISSN: 1331-1611
The moon tilt illusion is the startling discrepancy between the direction of the light beam illuminating the moon and the direction of the sun. The illusion arises because the observer erroneously expects a light ray between sun and moon to appear as a line of constant slope according to the positions of the sun and the moon in the sky. Thisexpectation does not correspond to the reality that observation by direct vision or a camera is according to perspective projection, for which the observed slope of a straight line in three-dimensional space changes according to the direction of observation. Comparing the observed and expected directions of incoming light at the moon, we derive a quantitative expression for the magnitude of the moon tilt illusion that can be applied to all conﬁgurations of sun and moon in the sky.
Beaghton A, 2010, HUGO AND SAND IN MORSE CODE, French Studies Bulletin, Vol: 31, Pages: 21-24, ISSN: 0262-2750
MYERSBEAGHTON AK, VVEDENSKY DD, 1991, STEP DYNAMICS ON VICINAL SI(001) DURING EPITAXIAL-GROWTH, APPLIED PHYSICS LETTERS, Vol: 59, Pages: 2013-2015, ISSN: 0003-6951
MYERSBEAGHTON AK, VVEDENSKY DD, 1991, GENERALIZED BURTON-CABRERA-FRANK THEORY FOR GROWTH AND EQUILIBRATION ON STEPPED SURFACES, PHYSICAL REVIEW A, Vol: 44, Pages: 2457-2468, ISSN: 1050-2947
MYERSBEAGHTON AK, TAYLOR JPG, VVEDENSKY DD, et al., 1991, GROWTH-KINETICS AND ELECTRONIC CHARACTERISTICS OF QUANTUM WIRES, 6TH INTERNATIONAL CONF ON MOLECULAR BEAM EPITAXY, Publisher: ELSEVIER SCIENCE BV, Pages: 328-332, ISSN: 0022-0248
MYERSBEAGHTON AK, WILBY MR, 1991, THE DYNAMIC VARIATIONS OF TERRACE LENGTH DURING GROWTH ON STEPPED SURFACES, JOURNAL OF PHYSICS A-MATHEMATICAL AND GENERAL, Vol: 24, Pages: L35-L41, ISSN: 0305-4470
MYERSBEAGHTON AK, 1991, 2-DIMENSIONAL KINEMATIC DIFFRACTION PATTERNS FROM SIMULATIONS OF EPITAXIAL-GROWTH, SURFACE SCIENCE, Vol: 241, Pages: 439-453, ISSN: 0039-6028
Myersbeaghton AK, Vvedensky DD, 1991, Nonlinear diffusion equation for epitaxial-growth and recovery on vicinal surfaces, Journal of Crystal Growth, Vol: 111, Pages: 162-167, ISSN: 0022-0248
Joyce BA, Zhang J, Foxon CT, et al., 1991, Growth dynamics of lattice-matched and strained layer III-V compounds in molecular beam epitaxy
Recent experimental and theoretical results on cation incorporation dynamics in the MBE growth of 111-V materials will be presented. The measurement techniques were reflection high energy electron diffraction and modulated beam relaxation spectroscopy supported theoretically by Monte Carlo simulation. The concept of surface accumulation of cations (especially indium) during conventional MBE growth is introduced and adatom migration and attachment kinetics are considered in detail.
JOYCE BA, NEAVE JH, ZHANG J, et al., 1990, GROWTH OF III-V COMPOUNDS ON VICINAL PLANES BY MOLECULAR-BEAM EPITAXY, SEMICONDUCTOR SCIENCE AND TECHNOLOGY, Vol: 5, Pages: 1147-1154, ISSN: 0268-1242
MYERSBEAGHTON AK, VVEDENSKY DD, 1990, NONLINEAR-THEORY FOR EPITAXIAL-GROWTH OF SEMICONDUCTOR ALLOYS ON VICINAL SURFACES, SURFACE SCIENCE, Vol: 240, Pages: L599-L603, ISSN: 0039-6028
MYERSBEAGHTON AK, VVEDENSKY DD, 1990, NONLINEAR MODEL FOR TEMPORAL EVOLUTION OF STEPPED SURFACES DURING MOLECULAR-BEAM EPITAXY, PHYSICAL REVIEW B, Vol: 42, Pages: 9720-9723, ISSN: 0163-1829
MYERSBEAGHTON AK, VVEDENSKY DD, 1990, NONLINEAR DIFFUSION EQUATION FOR CRYSTAL-GROWTH ON STEPPED SURFACES, JOURNAL OF PHYSICS A-MATHEMATICAL AND GENERAL, Vol: 23, Pages: L995-L1001, ISSN: 0305-4470
MYERSBEAGHTON AK, VVEDENSKY DD, 1990, NONLINEAR EQUATION FOR DIFFUSION AND ADATOM INTERACTIONS DURING EPITAXIAL-GROWTH ON VICINAL SURFACES, PHYSICAL REVIEW B, Vol: 42, Pages: 5544-5554, ISSN: 0163-1829
MYERSBEAGHTON AK, VVEDENSKY DD, 1990, NONEQUILIBRIUM LATTICE MODELS OF EPITAXIAL-GROWTH, SURFACE SCIENCE, Vol: 232, Pages: 161-184, ISSN: 0039-6028
Vvedensky DD, Clarke S, Hugill KJ, et al., 1990, Growth Kinetics on Vicinal (001) Surfaces: The Solid-on-Solid Model of Molecular-Beam Epitaxy, Kinetics of Ordering and Growth at Surfaces, Editors: Lagally, Publisher: Springer US, Pages: 297-311, ISBN: 978-1-4613-0653-5
Growth kinetics during molecular-beam epitaxy (MBE) on vicinal surfaces are simulated with a kinetic solid-on-solid model. Comparison is made between the simulated step-density and the specular intensity of reflection high-energy electron-diffraction (RHEED) measurements. In addition to identifying the kinetic mechanisms giving rise to observed phenomena, this similarity provides considerable insight into the sensitivity of specular RHEED to specific features of morphological sensitivity involving two-point surface correlations. Applications of the model encompass both III-V and group-IV semiconductors. Examples for GaAs(001) MBE include: (i) a discussion of growth modes on vicinal surfaces as a function of substrate temperature, with (ii) a direct determination of model parameters from a comparison of step-density and RHEED evolutions; and (iii) the fabrication of quantum wires. For growth on Si(001) surfaces, we discuss (iv) the role of monatomic and biatomic steps and the dimer reconstruction in determining the mode of growth, and (v) the coverage of 2 × 1 and 1 × 2 domains during growth and after recovery.
MYERSBEAGHTON AK, VVEDENSKY DD, 1989, CHAPMAN-KOLMOGOROV EQUATION FOR MARKOV-MODELS OF EPITAXIAL-GROWTH, JOURNAL OF PHYSICS A-MATHEMATICAL AND GENERAL, Vol: 22, Pages: L467-L475, ISSN: 0305-4470
Myers AK, Benziger JB, 1989, Effect of substituent groups on the interaction of benzene with nickel(111), Langmuir, Vol: 5, Pages: 1270-1288
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.