scholarly journals Daisy-chain gene drives for the alteration of local populations

2016 ◽  
Author(s):  
Charleston Noble ◽  
John Min ◽  
Jason Olejarz ◽  
Joanna Buchthal ◽  
Alejandro Chavez ◽  
...  
Keyword(s):  
Local Level ◽  
Field Trials ◽  
Local Communities ◽  
Chain Gene ◽  
Gene Drive ◽  
Guide Rna ◽  
Local Populations ◽  
Wide Range ◽  
Global Spread ◽  
Drive Systems

AbstractRNA-guided gene drive elements could address many ecological problems by altering the traits of wild organisms, but the likelihood of global spread tremendously complicates ethical development and use. Here we detail a localized form of CRISPR-based gene drive composed of genetic elements arranged in a daisy-chain such that each element drives the next. “Daisy drive” systems can duplicate any effect achievable using an equivalent global drive system, but their capacity to spread is limited by the successive loss of non-driving elements from the base of the chain. Releasing daisy drive organisms constituting a small fraction of the local wild population can drive a useful genetic element to local fixation for a wide range of fitness parameters without resulting in global spread. We additionally report numerous highly active guide RNA sequences sharing minimal homology that may enable evolutionary stable daisy drive as well as global CRISPR-based gene drive. Daisy drives could simplify decision-making and promote ethical use by enabling local communities to decide whether, when, and how to alter local ecosystems.Author’s Summary‘Global’ gene drive systems based on CRISPR are likely to spread to every population of the target species, hampering safe and ethical use. ‘Daisy drive’ systems offer a way to alter the traits of only local populations in a temporary manner. Because they can exactly duplicate the activity of any global CRISPR-based drive at a local level, daisy drives may enable safe field trials and empower local communities to make decisions concerning their own shared environments.For more details and an animation intended for a general audience, see the summary at Sculpting Evolution.

scholarly journals Daisy-chain gene drives for the alteration of local populations

2019 ◽  
Vol 116 (17) ◽  
pp. 8275-8282 ◽  
Author(s):  
Charleston Noble ◽  
John Min ◽  
Jason Olejarz ◽  
Joanna Buchthal ◽  
Alejandro Chavez ◽  
...  
Keyword(s):  
Drive System ◽  
Chain Gene ◽  
Gene Drive ◽  
Rna Sequences ◽  
Guide Rna ◽  
Highly Active ◽  
Wide Range ◽  
Fitness Parameters ◽  
Drive Systems ◽  
Gene Drives

If they are able to spread in wild populations, CRISPR-based gene-drive elements would provide new ways to address ecological problems by altering the traits of wild organisms, but the potential for uncontrolled spread tremendously complicates ethical development and use. Here, we detail a self-exhausting form of CRISPR-based drive system comprising genetic elements arranged in a daisy chain such that each drives the next. “Daisy-drive” systems can locally duplicate any effect achievable by using an equivalent self-propagating drive system, but their capacity to spread is limited by the successive loss of nondriving elements from one end of the chain. Releasing daisy-drive organisms constituting a small fraction of the local wild population can drive a useful genetic element nearly to local fixation for a wide range of fitness parameters without self-propagating spread. We additionally report numerous highly active guide RNA sequences sharing minimal homology that may enable evolutionarily stable daisy drive as well as self-propagating CRISPR-based gene drive. Especially when combined with threshold dependence, daisy drives could simplify decision-making and promote ethical use by enabling local communities to decide whether, when, and how to alter local ecosystems.

scholarly journals Modeling confinement and reversibility of threshold-dependent gene drive systems in spatially-explicit Aedes aegypti populations

2019 ◽  
Author(s):  
Héctor M. Sánchez C. ◽  
Jared B. Bennett ◽  
Sean L. Wu ◽  
Gordana Rašić ◽  
Omar S. Akbari ◽  
...  
Keyword(s):  
Aedes Aegypti ◽  
Disease Transmission ◽  
Release Site ◽  
Field Trials ◽  
Mosquito Vector ◽  
Gene Drive ◽  
Isolated Populations ◽  
Dependent Behavior ◽  
Wide Scale ◽  
Drive Systems

AbstractBackgroundThe discovery of CRISPR-based gene editing and its application to homing-based gene drive systems has been greeted with excitement, for its potential to control mosquito-borne diseases on a wide scale, and concern, for the invasiveness and potential irreversibility of a release. Gene drive systems that display threshold-dependent behavior could potentially be used during the trial phase of this technology, or when localized control is otherwise desired, as simple models predict them to spread into partially isolated populations in a confineable manner, and to be reversible through releases of wild-type organisms. Here, we model hypothetical releases of two recently-engineered threshold-dependent gene drive systems - reciprocal chromosomal translocations and a form of toxin-antidote-based underdominance known as UDMEL - to explore their ability to be confined and remediated.ResultsWe simulate releases of Aedes aegypti, the mosquito vector of dengue, Zika and other arboviruses, in Yorkeys Knob, a suburb of Cairns, Australia, where previous biological control interventions have been undertaken on this species. We monitor spread to the neighboring suburb of Trinity Park to assess confinement. Results suggest that translocations could be introduced on a suburban scale, and remediated through releases of non-disease-transmitting male mosquitoes with release sizes on the scale of what has been previously implemented. UDMEL requires fewer releases to introduce, but more releases to remediate, including of females capable of disease transmission. Both systems are expected to be confineable to the release site; however, spillover of translocations into neighboring populations is less likely.ConclusionsOur analysis supports the use of translocations as a threshold-dependent drive system capable of spreading disease-refractory genes into Ae. aegypti populations in a confineable and reversible manner. It also highlights increased release requirements when incorporating life history and population structure into models. As the technology nears implementation, further ecological work will be essential to enhance model predictions in preparation for field trials.

scholarly journals MGDrivE: A modular simulation framework for the spread of gene drives through spatially-explicit mosquito populations

2018 ◽  
Author(s):  
Héctor M. Sánchez C. ◽  
Sean L. Wu ◽  
Jared B. Bennett ◽  
John M. Marshall
Keyword(s):  
Spatial Dynamics ◽  
Population Level ◽  
Spatially Explicit ◽  
Pest Species ◽  
Gene Drive ◽  
Simulation Framework ◽  
Population Replacement ◽  
Wide Range ◽  
Drive Systems ◽  
Genetic Simulation

AbstractMalaria, 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 also enabled a wide range of gene drive architectures to be realized, creating a need for their population-level and spatial dynamics to be explored. To this end, 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 user-defined inheritance patterns, b) a population dynamic module accommodates the life history of a variety of mosquito disease vectors and insect agricultural pest species, and c) a landscape module accommodates the distribution of insect metapopulations connected by migration in space. 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. We compare MGDrivE with other genetic simulation packages, and conclude with a discussion of future directions in gene drive modeling.

scholarly journals Retargeting: an unrecognized consideration in endonuclease-based gene drive biology

2016 ◽  
Author(s):  
Andrew M. Scharenberg ◽  
Barry L Stoddard ◽  
Raymond J Monnat ◽  
Anthony Nolan
Keyword(s):  
Gene Editing ◽  
Insect Pests ◽  
Field Testing ◽  
Nuclease Activity ◽  
Genome Replication ◽  
Gene Drive ◽  
Regulatory Issues ◽  
Guide Rna ◽  
Insect Populations ◽  
Drive Systems

AbstractThere is intense interest surrounding the use of gene editing nucleases in gene drive systems to control agricultural insect pests and insect vectors of infectious diseases such as malaria, dengue and Zika virus. While gene drive systems offer immense promise for the beneficial modification of deleterious insect populations, their unique mechanism of action also raises novel safety concerns and regulatory issues. A recent US National Academies of Science report provides a list of potential regulatory issues associated with implementation of homologous recombination (HR)-mediated gene drive systems, based on the premise that all such systems would exhibit similar biological behaviors. Here we examine how HR-mediated gene drive systems based on different gene editing nuclease platforms could be affected by mutations that occur during host cell transcription, genome replication, and, in conjunction with gene editing nuclease activity, during HR-mediated gene drive. Our analysis suggests that the same feature that makes RNA-guided nucleases such attractive research tools—their ease of reprogramming by alterations to their guide RNA components—might also contribute to increased rates of retargeting that could influence the long term behavior of RNA-guided gene drive systems. Predictability of behavior over time is an issue that should be addressed by in-depth risk assessment before field testing of organisms incorporating nuclease-mediated gene drives.

scholarly journals Modeling CRISPR gene drives for suppression of invasive rodents

2020 ◽  
Author(s):  
Samuel E. Champer ◽  
Nathan Oakes ◽  
Ronin Sharma ◽  
Pablo García-Díaz ◽  
Jackson Champer ◽  
...  
Keyword(s):  
Machine Learning ◽  
Population Model ◽  
Supervised Machine Learning ◽  
Sensitivity Analyses ◽  
Island Population ◽  
Gene Drive ◽  
Wide Range ◽  
Outcome Space ◽  
Drive Systems ◽  
Invasive Rodents

ABSTRACTInvasive rodent populations pose a threat to biodiversity across the globe. When confronted with these new invaders, native species that evolved independently are often defenseless. CRISPR gene drive systems could provide a solution to this problem by spreading transgenes among invaders that induce population collapse. Such systems might be deployed even where traditional control methods are impractical or prohibitively expensive. Here, we develop a high-fidelity model of an island population of invasive rodents that includes three types of suppression gene drive systems. The individual-based model is spatially explicit and allows for overlapping generations and a fluctuating population size. Our model includes variables for drive fitness, efficiency, resistance allele formation rate, as well as a variety of ecological parameters. The computational burden of evaluating a model with such a high number of parameters presents a substantial barrier to a comprehensive understanding of its outcome space. We therefore accompany our population model with a meta-model that utilizes supervised machine learning to approximate the outcome space of the underlying model with a high degree of accuracy. This enables us to conduct an exhaustive inquiry of the population model, including variance-based sensitivity analyses using tens of millions of evaluations. Our results suggest that sufficiently capable gene drive systems have the potential to eliminate island populations of rodents under a wide range of demographic assumptions, but only if resistance can be kept to a minimal level. This study highlights the power of supervised machine learning for identifying the key parameters and processes that determine the population dynamics of a complex evolutionary system.

scholarly journals Genetic conversion of a split-drive into a full-drive element

2021 ◽  
Author(s):  
Gerard Terradas ◽  
Jared B. Bennett ◽  
Zhiqian Li ◽  
John M. Marshall ◽  
Ethan Bier
Keyword(s):  
Gene Drive ◽  
Fitness Costs ◽  
Experimental Proof ◽  
Guide Rna ◽  
Split Gene ◽  
Core Components ◽  
Beneficial Traits ◽  
Drive Systems ◽  
Genetic Conversion ◽  
Gene Drives

AbstractGene-drive systems offer an important new avenue for spreading beneficial traits into wild populations. Their core components, Cas9 and guide RNA (gRNA), can either be linked within a single cassette (full gene drive, fGD) or provided in two separate elements (split gene drive, sGD) wherein the gRNA-bearing element drives in the presence of an independent static source of Cas9. We previously designed a system engineered to turn split into full gene drives. Here, we provide experimental proof-of-principle for such a convertible system inserted at the spo11 locus, which is recoded to restore gene function. In multigenerational cage studies, the reconstituted spo11 fGD cassette initially drives with slower kinetics than the unlinked sGD element (using the same Mendelian vasa-Cas9 source), but eventually reaches a similar level of final introgression. Different kinetic behaviors may result from transient fitness costs associated with individuals co-inheriting Cas9 and gRNA transgenes during the drive process.

scholarly journals Daisyfield gene drive systems harness repeated genomic elements as a generational clock to limit spread

2017 ◽  
Author(s):  
John Min ◽  
Charleston Noble ◽  
Devora Najjar ◽  
Kevin M. Esvelt
Keyword(s):  
Single Copy ◽  
Drive System ◽  
Gene Drive ◽  
Wild Type ◽  
Wild Populations ◽  
Guide Rna ◽  
Guide Rnas ◽  
Multiple Copies ◽  
Rna Elements ◽  
Drive Systems

AbstractMethods of altering wild populations are most useful when inherently limited to local geographic areas. Here we describe a novel form of gene drive based on the introduction of multiple copies of an engineered ‘daisy’ sequence into repeated elements of the genome. Each introduced copy encodes guide RNAs that target one or more engineered loci carrying the CRISPR nuclease gene and the desired traits. When organisms encoding a drive system are released into the environment, each generation of mating with wild-type organisms will reduce the average number of the guide RNA elements per ‘daisyfield’ organism by half, serving as a generational clock. The loci encoding the nuclease and payload will exhibit drive only as long as a single copy remains, placing an inherent limit on the extent of spread.

scholarly journals Modeling CRISPR gene drives for suppression of invasive rodents using a supervised machine learning framework

2021 ◽  
Vol 17 (12) ◽  
pp. e1009660
Author(s):  
Samuel E. Champer ◽  
Nathan Oakes ◽  
Ronin Sharma ◽  
Pablo García-Díaz ◽  
Jackson Champer ◽  
...  
Keyword(s):  
Machine Learning ◽  
Population Model ◽  
Supervised Machine Learning ◽  
Sensitivity Analyses ◽  
Island Population ◽  
Gene Drive ◽  
Wide Range ◽  
Outcome Space ◽  
Drive Systems ◽  
Invasive Rodents

Invasive rodent populations pose a threat to biodiversity across the globe. When confronted with these invaders, native species that evolved independently are often defenseless. CRISPR gene drive systems could provide a solution to this problem by spreading transgenes among invaders that induce population collapse, and could be deployed even where traditional control methods are impractical or prohibitively expensive. Here, we develop a high-fidelity model of an island population of invasive rodents that includes three types of suppression gene drive systems. The individual-based model is spatially explicit, allows for overlapping generations and a fluctuating population size, and includes variables for drive fitness, efficiency, resistance allele formation rate, as well as a variety of ecological parameters. The computational burden of evaluating a model with such a high number of parameters presents a substantial barrier to a comprehensive understanding of its outcome space. We therefore accompany our population model with a meta-model that utilizes supervised machine learning to approximate the outcome space of the underlying model with a high degree of accuracy. This enables us to conduct an exhaustive inquiry of the population model, including variance-based sensitivity analyses using tens of millions of evaluations. Our results suggest that sufficiently capable gene drive systems have the potential to eliminate island populations of rodents under a wide range of demographic assumptions, though only if resistance can be kept to a minimal level. This study highlights the power of supervised machine learning to identify the key parameters and processes that determine the population dynamics of a complex evolutionary system.

scholarly journals Design and analysis of CRISPR-based underdominance toxin-antidote gene drives

2019 ◽  
Author(s):  
Jackson Champer ◽  
Samuel E. Champer ◽  
Isabel Kim ◽  
Andrew G. Clark ◽  
Philipp W. Messer
Keyword(s):  
Critical Frequency ◽  
Essential Gene ◽  
Geographic Location ◽  
Early Embryo ◽  
Gene Drive ◽  
Wide Range ◽  
Vector Borne ◽  
Drive Systems ◽  
Invasion Threshold ◽  
Gene Drives

ABSTRACTCRISPR gene drive systems offer a mechanism for transmitting a desirable transgene throughout a population for purposes ranging from vector-borne disease control to invasive species suppression. In this simulation study, we assess the performance of several CRISPR-based underdominance gene drive constructs employing toxin-antidote principles. These drives disrupt the wild-type version of an essential gene using a CRISPR nuclease (the toxin) while simultaneously carrying a recoded version of the gene (the antidote). Drives of this nature allow for releases that could be potentially confined to a desired geographic location. This is because such drives have a nonzero invasion threshold frequency, referring to the critical frequency required for the drive to spread through the population. We model drives which target essential genes that are either haplosufficient or haplolethal, using nuclease promoters with expression restricted to the germline, promoters that additionally result in cleavage activity in the early embryo from maternal deposition, and promoters that have ubiquitous somatic expression. We also study several possible drive architectures, considering both “same-site” and “distant-site” systems, as well as several reciprocally targeting drives. Together, these drive variants provide a wide range of invasion threshold frequencies and options for both population modification and suppression. Our results suggest that CRISPR toxin-antidote underdominance drive systems could allow for the design of highly flexible and potentially confinable gene drive strategies.

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