scholarly journals Spatial structure undermines parasite suppression by gene drive cargo

2019 ◽  
Author(s):  
James J Bull ◽  
Christopher H Remien ◽  
Richard Gomulkiewicz ◽  
Stephen M Krone
Keyword(s):  
Spatial Structure ◽  
The Other ◽  
Gene Drive ◽  
High Coverage ◽  
Disease Eradication ◽  
Vector Population ◽  
Evolution Of Resistance ◽  
Disease Agent ◽  
Gene Drives ◽  
Simple Models

ABSTRACTGene drives may be used in two ways to curtail vectored diseases. Both involve engineering the drive to spread in the vector population. One approach uses the drive to directly depress vector numbers, possibly to extinction. The other approach leaves intact the vector population but suppresses the disease agent during its interaction with the vector. This second application may use a drive engineered to carry a genetic cargo that blocks the disease agent. An advantage of the second application is that it is far less likely to select vector resistance to block the drive, but the disease agent may instead evolve resistance to the inhibitory cargo. However, some gene drives are expected to spread so fast and attain such high coverage in the vector population that, if the disease agent can evolve resistance only gradually, disease eradication may be feasible. Here we use simple models to show that spatial structure in the vector population can greatly facilitate persistence and evolution of resistance by the disease agent. We suggest simple approaches to avoid some types of spatial structure, but others may be intrinsic to the populations being challenged and difficult to overcome.

scholarly journals Spatial structure undermines parasite suppression by gene drive cargo

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e7921 ◽  
Author(s):  
James J. Bull ◽  
Christopher H. Remien ◽  
Richard Gomulkiewicz ◽  
Stephen M. Krone
Keyword(s):  
Spatial Structure ◽  
The Other ◽  
Gene Drive ◽  
High Coverage ◽  
Disease Eradication ◽  
Vector Population ◽  
Evolution Of Resistance ◽  
Disease Agent ◽  
Gene Drives ◽  
Simple Models

Gene drives may be used in two ways to curtail vectored diseases. Both involve engineering the drive to spread in the vector population. One approach uses the drive to directly depress vector numbers, possibly to extinction. The other approach leaves intact the vector population but suppresses the disease agent during its interaction with the vector. This second application may use a drive engineered to carry a genetic cargo that blocks the disease agent. An advantage of the second application is that it is far less likely to select vector resistance to block the drive, but the disease agent may instead evolve resistance to the inhibitory cargo. However, some gene drives are expected to spread so fast and attain such high coverage in the vector population that, if the disease agent can evolve resistance only gradually, disease eradication may be feasible. Here we use simple models to show that spatial structure in the vector population can greatly facilitate persistence and evolution of resistance by the disease agent. We suggest simple approaches to avoid some types of spatial structure, but others may be intrinsic to the populations being challenged and difficult to overcome.

scholarly journals Targeting conserved sequences circumvents the evolution of resistance in a viral gene drive against human cytomegalovirus

2021 ◽  
Author(s):  
Marius Walter ◽  
Rosalba Perrone ◽  
Eric Verdin
Keyword(s):  
Cell Culture ◽  
Human Cytomegalovirus ◽  
Viral Population ◽  
Viral Gene ◽  
Gene Drive ◽  
Conserved Sequences ◽  
Evolution Of Resistance ◽  
Gene Drives ◽  
Over Time

Gene drives are genetic systems designed to efficiently spread a modification through a population. They have been designed almost exclusively in eukaryotic species, and especially in insects. We recently developed a CRISPR-based gene drive system in herpesviruses that relies on similar mechanisms and could efficiently spread into a population of wildtype viruses. A common consequence of gene drives in insects is the appearance and selection of drive-resistant sequences that are no longer recognized by CRISPR-Cas9. Here, we analyze in cell culture experiments the evolution of resistance in a viral gene drive against human cytomegalovirus. We report that, after an initial invasion of the wildtype population, a drive-resistant population is positively selected over time and outcompetes gene drive viruses. However, we show that targeting evolutionary conserved sequences ensures that drive-resistant viruses acquire long-lasting mutations and are durably attenuated. As a consequence, and even though engineered viruses do not stably persist in the viral population, remaining viruses have a replication defect, leading to a long-term reduction of viral levels. This marks an important step toward developing effective gene drives in herpesviruses, especially for therapeutic applications. Importance The use of defective viruses that interfere with the replication of their infectious parent after co-infecting the same cells – a therapeutic strategy known as viral interference – has recently generated a lot of interest. The CRISPR-based system that we recently reported in herpesviruses represents a novel interfering strategy that causes the conversion of wildtype viruses into new recombinant viruses and drives the native viral population to extinction. In this report, we analyzed how targeted viruses evolved resistance against the technology. Through numerical simulations and cell culture experiments with human cytomegalovirus, we show that, after the initial propagation, a resistant viral population is positively selected and outcompetes engineered viruses over time. We show however that targeting evolutionary conserved sequences ensures that resistant viruses are mutated and attenuated, which leads to a long-term reduction of viral levels. This marks an important step toward the development of novel therapeutic strategies against herpesviruses.

scholarly journals Targeting evolutionary conserved sequences circumvents the evolution of resistance in a viral gene drive against human cytomegalovirus

2021 ◽  
Author(s):  
Marius Walter ◽  
Rosalba Perrone ◽  
Eric Verdin
Keyword(s):  
Human Cytomegalovirus ◽  
Viral Gene ◽  
Gene Drive ◽  
Eukaryotic Species ◽  
Resistant Population ◽  
Evolution Of Resistance ◽  
Gene Drives ◽  
Over Time ◽  
Selection Of

Gene drives are genetic systems designed to efficiently spread a modification through a population. Most engineered gene drives rely on CRISPR-Cas9 and were designed in insects or other eukaryotic species. We recently developed a viral gene drive in herpesviruses that efficiently spread into a population of wildtype viruses. A common consequence of gene drives is the appearance and selection of drive-resistant sequences that are no longer recognized by CRISPR-Cas9. Here, we analyze in cell culture experiments the evolution of resistance in a gene drive against human cytomegalovirus. We report that after an initial invasion of the wildtype population, a drive-resistant population is positively selected over time and outcompetes gene drive viruses. However, we show that targeting evolutionary conserved regions ensures that drive-resistant viruses have a replication defect, leading to a long-term reduction of viral levels. This marks an important step toward developing effective gene drives in viruses, especially for therapeutic applications.

scholarly journals Modeling the mutation and reversal of engineered underdominance gene drives

2018 ◽  
Author(s):  
Matthew P. Edgington ◽  
Luke S. Alphey
Keyword(s):  
Genetic Material ◽  
Theoretical Work ◽  
The Other ◽  
Lethal Gene ◽  
Gene Drive ◽  
Loss Of Function ◽  
Wild Type ◽  
Type Population ◽  
Drive Systems ◽  
Gene Drives

AbstractA range of gene drive systems have been proposed that are predicted to increase their frequency and that of associated desirable genetic material even if they confer a fitness cost on individuals carrying them. Engineered underdominance (UD) is such a system and, in one version, is based on the introduction of two independently segregating transgenic constructs each carrying a lethal gene, a suppressor for the lethal at the other locus and a desirable genetic “cargo”. Under this system individuals carrying at least one copy of each construct (or no copies of either) are viable whilst those that possess just one of the transgenic constructs are non-viable. Previous theoretical work has explored various properties of these systems, concluding that they should persist indefinitely in absence of resistance or mutation. Here we study a population genetics model of UD gene drive that relaxes past assumptions by allowing for loss-of-function mutations in each introduced gene. We demonstrate that mutations are likely to cause UD systems to break down, eventually resulting in the elimination of introduced transgenes. We then go on to investigate the potential of releasing “free suppressor” carrying individuals as a new method for reversing UD gene drives and compare this to the release of wild-types; the only previously proposed reversal strategy for UD. This reveals that while free suppressor carrying individuals may represent an inexpensive reversal strategy due to extremely small release requirements, they are not able to return a fully wild-type population as rapidly as the release of wild-types.

scholarly journals Propagation of seminal toxins through binary expression gene drives can suppress polyandrous populations

2021 ◽  
Author(s):  
Juan Hurtado ◽  
Santiago Revale ◽  
Luciano M Matzkin
Keyword(s):  
Expression System ◽  
Target Population ◽  
The Other ◽  
Gene Drive ◽  
High Frequencies ◽  
Dominant Lethal ◽  
System Components ◽  
Fertility Gene ◽  
Highly Effective ◽  
Gene Drives

Gene drives can be highly effective in controlling a target population by disrupting a female fertility gene. To spread across a population, these drives require that disrupted alleles be largely recessive so as not to impose too high of a fitness penalty. We argue that this restriction may be relaxed by using a double gene drive design to spread a split binary expression system. One drive carries a dominant lethal/toxic effector alone and the other a transactivator factor, without which the effector will not act. Only after the drives reach sufficiently high frequencies would individuals have the chance to inherit both system components and the effector be expressed. We explore through mathematical modeling the potential of this design to spread dominant lethal/toxic alleles and suppress populations. We show that this system could be implemented to spread engineered seminal proteins designed to kill females, making it highly effective against polyandrous populations.

scholarly journals Novel combination of CRISPR-based gene drives eliminates resistance and localises spread

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nicky R. Faber ◽  
Gus R. McFarlane ◽  
R. Chris Gaynor ◽  
Ivan Pocrnic ◽  
C. Bruce A. Whitelaw ◽  
...  
Keyword(s):  
Driving Forces ◽  
Spatial Models ◽  
Cost Effective ◽  
Biodiversity Loss ◽  
Invasive Pest ◽  
Economic Losses ◽  
Sciurus Carolinensis ◽  
Gene Drive ◽  
Grey Squirrel ◽  
Gene Drives

AbstractInvasive species are among the major driving forces behind biodiversity loss. Gene drive technology may offer a humane, efficient and cost-effective method of control. For safe and effective deployment it is vital that a gene drive is both self-limiting and can overcome evolutionary resistance. We present HD-ClvR in this modelling study, a novel combination of CRISPR-based gene drives that eliminates resistance and localises spread. As a case study, we model HD-ClvR in the grey squirrel (Sciurus carolinensis), which is an invasive pest in the UK and responsible for both biodiversity and economic losses. HD-ClvR combats resistance allele formation by combining a homing gene drive with a cleave-and-rescue gene drive. The inclusion of a self-limiting daisyfield gene drive allows for controllable localisation based on animal supplementation. We use both randomly mating and spatial models to simulate this strategy. Our findings show that HD-ClvR could effectively control a targeted grey squirrel population, with little risk to other populations. HD-ClvR offers an efficient, self-limiting and controllable gene drive for managing invasive pests.

scholarly journals Żywiołowe rozprzestrzenianie się Poznania: profil morfologiczny i mikroekonomiczny

2020 ◽  
pp. 81-99
Author(s):  
Piotr Lityński
Keyword(s):  
Spatial Structure ◽  
Urban Sprawl ◽  
The Other ◽  
Moderate Degree ◽  
Financial Situation ◽  
Housing Preferences ◽  
Household Budget ◽  
High Degree ◽  
Financial Losses ◽  
Morphological Assessment

The aim of the article is to assess Poznań’s urban sprawl from the perspective of the morphology of space and financial situation of suburban households. The morphological assessment uses a method based on two grids of squares with a side: 1 km, 500 m; and data on the location of buildings from CCGCD. On the other hand, the assessment of households was carried out on the basis of the CSO Household Budget database. The results of the research indicate that the analyzed communes in the Poznań area are characterized by a moderate degree of disorder in the spatial structure. There are no communes with a completely compact specificity, there are also no communes with an absolutely high degree of spatial disorder. Households causing urban sprawl in Poznań are entities that incur moderate financial losses in order to maximize their housing preferences.

Towards CRISPR/Cas9-based gene drive in the diamondback moth Plutella xylostella

2021 ◽  
Author(s):  
Xuejiao Xu ◽  
Tim Harvey-Samuel ◽  
Hamid Anees Siddiqui ◽  
Joshua Ang ◽  
Michelle E Anderson ◽  
...  
Keyword(s):  
Genetic Control ◽  
Plutella Xylostella ◽  
Control Strategies ◽  
Diamondback Moth ◽  
Regulatory Elements ◽  
Strategy Development ◽  
Gene Drive ◽  
Global Agriculture ◽  
High Level ◽  
Gene Drives

Promising to provide powerful genetic control tools, gene drives have been constructed in multiple dipterans, yeast and mice, for the purposes of population elimination or modification. However, it remains unclear whether these techniques can be applied to lepidopterans. Here, we used endogenous regulatory elements to drive Cas9 and sgRNA expression in the diamondback moth, (Plutella xylostella), and test the first split-drive system in a lepidopteran. The diamondback moth is an economically important global agriculture pest of cruciferous crops and has developed severe resistance to various insecticides, making it a prime candidate for such novel control strategy development. A very high level of somatic editing was observed in Cas9/sgRNA transheterozygotes, although no significant homing was revealed in the subsequent generation. Although heritable, Cas9-medated germline cleavage, as well as maternal and paternal Cas9 deposition was observed, rates were far lower than for somatic cleavage events, indicating robust somatic but limited germline activity of Cas9/sgRNA under the control of selected regulatory elements. Our results provide valuable experience, paving the way for future construction of gene drive-based genetic control strategies in DBM or other lepidopterans.

Containment strategies for synthetic gene drive organisms and impacts on gene flow.

2021 ◽  
pp. 137-152
Author(s):  
Lei Pei ◽  
Markus Schmidt
Keyword(s):  
Gene Flow ◽  
Fungal Infections ◽  
Basic Research ◽  
Fruit Fly ◽  
Mitigation Strategies ◽  
Synthetic Gene ◽  
Model Organisms ◽  
Gene Drive ◽  
Comprehensive Overview ◽  
Gene Drives

Abstract Gene drives, particularly synthetic gene drives, may help to address some important challenges, by efficiently altering specific sections of DNA in entire populations of wild organisms. Here we review the current development of the synthetic gene drives, especially those RNA-guided synthetic gene drives based on the CRISPR nuclease Cas. Particular focuses are on their possible applications in agriculture (e.g. disease resistance, weed control management), ecosystem conservation (e.g. evasion species control), health (e.g. to combat insect-borne and fungal infections), and for basic research in model organisms (e.g. Saccharomyces, fruit fly, and zebra fish). The physical, chemical, biological, and ecological containment strategies that might help to confine these gene drive-modified organisms are then explored. The gene flow issues, those from gene drive-derived organisms to the environment, are discussed, while possible mitigation strategies for gene drive research are explored. Last but not least, the regulatory context and opinions from key stakeholders (regulators, scientists, and concerned organizations) are reviewed, aiming to provide a more comprehensive overview of the field.

Energy in Thermal Physics

2021 ◽  
pp. 1-48
Author(s):  
Daniel V. Schroeder
Keyword(s):  
Low Temperature ◽  
Molecular Level ◽  
The Other ◽  
Thermal Physics ◽  
Other Hand ◽  
Energy Flows ◽  
Basic Concepts ◽  
Simple Models

The behavior of energy in bulk-matter systems is subtle. We observe that energy flows spontaneously from high to low temperature; we refer to this flowing energy as heat; and we distinguish heat from work, the transfer of energy through mechanical or other means unrelated to temperature. On the other hand, simple models of gases and solids strongly suggest that at the molecular level all energy is purely mechanical. This introductory chapter surveys these basic concepts of thermal physics, illustrates them with a wide variety of familiar examples, and sets the stage for developing a deeper understanding.

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