scholarly journals Daisy quorum drives for the genetic restoration of wild populations

2017 ◽  
Author(s):  
John Min ◽  
Charleston Noble ◽  
Devora Najjar ◽  
Kevin M. Esvelt
Keyword(s):  
Local Population ◽  
Ecological Engineering ◽  
Local Area ◽  
Drive System ◽  
Shared Environment ◽  
Gene Drive ◽  
Wild Type ◽  
Wild Populations ◽  
Quorum Systems ◽  
Drive Systems

AbstractAn ideal gene drive system to alter wild populations would 1) exclusively affect organisms within the political boundaries of consenting communities, and 2) be capable of restoring any engineered population to its original genetic state. Here we describe ‘daisy quorum’ drive systems that meet these criteria by combining daisy drive with underdominance. A daisy quorum drive system is predicted to spread through a population until all of its daisy elements have been lost, at which point its fitness becomes frequency-dependent: mostly altered populations become fixed for the desired change, while engineered genes at low frequency are swiftly eliminated by natural selection. The result is an engineered population surrounded by wild-type organisms with limited mixing at the boundary. Releasing large numbers of wild-type organisms or a few bearing a population suppression element can reduce the engineered population below the quorum, triggering elimination of all engineered sequences. In principle, the technology can restore any drive-amenable population carrying engineered genes to wild-type genetics. Daisy quorum systems may enable efficient, community-supported, and genetically reversible ecological engineering.SummaryLocal communities should be able to control their own environments without forcing those choices on others. Ideally, each community could reversibly alter local wild organisms in ways that cannot spread beyond their own boundaries, and any engineered population could be restored to its original genetic state. We've invented a 'daisy quorum' drive system that appears to meet these criteria.“Daisy” refers to a daisy drive, which typically uses a daisy-chain of linked genes to spread a change through a local population while losing links every generation until it stops spreading. “Quorum” reflects the system's ability to “vote” on whether a local population should be altered or not: once all daisy elements are lost, it favors replication by the altered version or the original depending on which is more abundant in the local area. Put together, they result in a change that first spreads through a local population, then either becomes locally prevalent is eliminating, inhibiting mixing at the boundary. All organisms in the target population are altered, but changes are unable to spread much beyond that area due to being greatly outnumbered by wild-type organisms and consequently less able to replicate.We haven't yet performed any experiments involving daisy quorum systems. Rather, we’re describing what we intend to do, including the safeguards we will use and our assessment of risks, in the hope that others will evaluate our plans and tell us if there's anything wrong that we missed. We hope that all researchers working on gene drive systems - and other technologies that could impact the shared environment - will similarly pre-register their plans. Sharing plans can reduce needless duplication, accelerate progress, and make the proposed work safer for everyone.

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 Current CRISPR gene drive systems are likely to be highly invasive in wild populations

2017 ◽  
Author(s):  
Charleston Noble ◽  
Ben Adlam ◽  
George M. Church ◽  
Kevin M. Esvelt ◽  
Martin A. Nowak
Keyword(s):  
Local Population ◽  
Gene Drive ◽  
Host Organism ◽  
Wild Populations ◽  
Flow Rates ◽  
Standing Variation ◽  
Large Populations ◽  
Mitigating Factors ◽  
Drive Systems ◽  
Gene Drives

AbstractRecent reports have suggested that CRISPR-based gene drives are unlikely to invade wild populations due to drive-resistant alleles that prevent cutting. Here we develop mathematical models based on existing empirical data to explicitly test this assumption. We show that although resistance prevents drive systems from spreading to fixation in large populations, even the least effective systems reported to date are highly invasive. Releasing a small number of organisms often causes invasion of the local population, followed by invasion of additional populations connected by very low gene flow rates. Examining the effects of mitigating factors including standing variation, inbreeding, and family size revealed that none of these prevent invasion in realistic scenarios. Highly effective drive systems are predicted to be even more invasive. Contrary to the National Academies report on gene drive, our results suggest that standard drive systems should not be developed nor field-tested in regions harboring the host organism.

scholarly journals Gene Drives Across Engineered Fitness Valleys: Modeling a Design to Prevent Drive Spillover

2020 ◽  
Author(s):  
Frederik J.H. de Haas ◽  
Sarah P. Otto
Keyword(s):  
Local Population ◽  
Target Population ◽  
Drive System ◽  
High Threshold ◽  
Gene Drive ◽  
Time Model ◽  
Population Replacement ◽  
Low Threshold ◽  
Drive Systems ◽  
Gene Drives

1AbstractEngineered gene drive techniques for population replacement and/or suppression have potential for tackling complex challenges, including reducing the spread of diseases and invasive species. Unfortunately, the self-propelled behavior of drives can lead to the spread of transgenic elements beyond the target population, which is concerning. Gene drive systems with a low threshold frequency for invasion, such as homing-based gene drive systems, require initially few transgenic individuals to spread and are therefore easy to implement. However their ease of spread presents a double-edged sword; their low threshold makes these drives much more susceptible to spread outside of the target population (spillover). We model a proposed drive system that transitions in time from a low threshold drive system (homing-based gene drive) to a high threshold drive system (underdominance) using daisy chain technology. This combination leads to a spatially restricted drive strategy, while maintaining an attainable release threshold. We develop and analyze a discrete-time model as proof of concept and find that this technique effectively generates stable local population suppression, while preventing the spread of transgenic elements beyond the target population under biologically realistic parameters.

scholarly journals Current CRISPR gene drive systems are likely to be highly invasive in wild populations

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Charleston Noble ◽  
Ben Adlam ◽  
George M Church ◽  
Kevin M Esvelt ◽  
Martin A Nowak
Keyword(s):  
Gene Flow ◽  
Empirical Data ◽  
Local Population ◽  
Malaria Prevention ◽  
Field Trials ◽  
Gene Drive ◽  
Wild Populations ◽  
Target Species ◽  
Large Populations ◽  
Drive Systems

Recent reports have suggested that self-propagating CRISPR-based gene drive systems are unlikely to efficiently invade wild populations due to drive-resistant alleles that prevent cutting. Here we develop mathematical models based on existing empirical data to explicitly test this assumption for population alteration drives. Our models show that although resistance prevents spread to fixation in large populations, even the least effective drive systems reported to date are likely to be highly invasive. Releasing a small number of organisms will often cause invasion of the local population, followed by invasion of additional populations connected by very low rates of gene flow. Hence, initiating contained field trials as tentatively endorsed by the National Academies report on gene drive could potentially result in unintended spread to additional populations. Our mathematical results suggest that self-propagating gene drive is best suited to applications such as malaria prevention that seek to affect all wild populations of the target species.

scholarly journals Experiments confirm a dispersive phenotype associated with a natural gene drive system

2021 ◽  
Vol 8 (5) ◽  
Author(s):  
Jan-Niklas Runge ◽  
Anna K. Lindholm
Keyword(s):  
Sperm Competition ◽  
Local Density ◽  
House Mice ◽  
Gene Drive ◽  
Wild Type ◽  
Fitness Costs ◽  
Oestrus Cycle ◽  
Drive Systems ◽  
Average Body ◽  
Average Body Weight

Meiotic drivers are genetic entities that increase their own probability of being transmitted to offspring, usually to the detriment of the rest of the organism, thus ‘selfishly’ increasing their fitness. In many meiotic drive systems, driver-carrying males are less successful in sperm competition, which occurs when females mate with multiple males in one oestrus cycle (polyandry). How do drivers respond to this selection? An observational study found that house mice carrying the t haplotype, a meiotic driver, are more likely to disperse from dense populations. This could help the t avoid detrimental sperm competition, because density is associated with the frequency of polyandry. However, no controlled experiments have been conducted to test these findings. Here, we confirm that carriers of the t haplotype are more dispersive, but we do not find this to depend on the local density. t -carriers with above-average body weight were particularly more likely to disperse than wild-type mice. t -carrying mice were also more explorative but not more active than wild-type mice. These results add experimental support to the previous observational finding that the t haplotype affects the dispersal phenotype in house mice, which supports the hypothesis that dispersal reduces the fitness costs of the t .

scholarly journals Evolutionary dynamics of CRISPR gene drives

2016 ◽  
Author(s):  
Charleston Noble ◽  
Jason Olejarz ◽  
Kevin M. Esvelt ◽  
George M. Church ◽  
Martin A. Nowak
Keyword(s):  
Evolutionary Dynamics ◽  
Evolutionary Stability ◽  
Clear Understanding ◽  
Gene Drive ◽  
Host Organism ◽  
Wild Populations ◽  
Selfish Genetic Elements ◽  
Real World Applications ◽  
Drive Systems ◽  
Gene Drives

AbstractThe alteration of wild populations has been discussed as a solution to a number of humanity’s most pressing ecological and public health concerns. Enabled by the recent revolution in genome editing, CRISPR gene drives, selfish genetic elements which can spread through populations even if they confer no advantage to their host organism, are rapidly emerging as the most promising approach. But before real-world applications are considered, it is imperative to develop a clear understanding of the outcomes of drive release in nature. Toward this aim, we mathematically study the evolutionary dynamics of CRISPR gene drives. We demonstrate that the emergence of drive-resistant alleles presents a major challenge to previously reported constructs, and we show that an alternative design which selects against resistant alleles greatly improves evolutionary stability. We discuss all results in the context of CRISPR technology and provide insights which inform the engineering of practical gene drive systems.

scholarly journals Author response: Current CRISPR gene drive systems are likely to be highly invasive in wild populations

2018 ◽  
Author(s):  
Charleston Noble ◽  
Ben Adlam ◽  
George M Church ◽  
Kevin M Esvelt ◽  
Martin A Nowak
Keyword(s):  
Author Response ◽  
Gene Drive ◽  
Wild Populations ◽  
Drive Systems ◽  
Response Current

scholarly journals Mice Against Ticks: an experimental community-guided effort to prevent tick-borne disease by altering the shared environment

2019 ◽  
Vol 374 (1772) ◽  
pp. 20180105 ◽  
Author(s):  
Joanna Buchthal ◽  
Sam Weiss Evans ◽  
Jeantine Lunshof ◽  
Sam R. Telford ◽  
Kevin M. Esvelt
Keyword(s):  
Disease Transmission ◽  
Technology Development ◽  
Ecological Engineering ◽  
Shared Environment ◽  
Gene Drive ◽  
Community Members ◽  
Engineering Project ◽  
Mouse Population ◽  
Transmission Cycle ◽  
Tick Borne Disease

Mice Against Ticks is a community-guided ecological engineering project that aims to prevent tick-borne disease by using CRISPR-based genome editing to heritably immunize the white-footed mice ( Peromyscus leucopus ) responsible for infecting many ticks in eastern North America. Introducing antibody-encoding resistance alleles into the local mouse population is anticipated to disrupt the disease transmission cycle for decades. Technology development is shaped by engagement with community members and visitors to the islands of Nantucket and Martha's Vineyard, including decisions at project inception about which types of disease resistance to pursue. This engagement process has prompted the researchers to use only white-footed mouse DNA if possible, meaning the current project will not involve gene drive. Instead, engineered mice would be released in the spring when the natural population is low, a plan unlikely to increase total numbers above the normal maximum in autumn. Community members are continually asked to share their suggestions and concerns, a process that has already identified potential ecological consequences unanticipated by the research team that will likely affect implementation. As an early example of CRISPR-based ecological engineering, Mice Against Ticks aims to start small and simple by working with island communities whose mouse populations can be lastingly immunized without gene drive. This article is part of a discussion meeting issue ‘The ecology and evolution of prokaryotic CRISPR-Cas adaptive immune systems’.

scholarly journals Population dynamics of underdominance gene drive systems in continuous space

2018 ◽  
Author(s):  
Jackson Champer ◽  
Joanna Zhao ◽  
Joanna Zhao ◽  
Samuel E. Champer ◽  
Jingxian Liu ◽  
...  
Keyword(s):  
Decision Making ◽  
Population Dynamics ◽  
Local Population ◽  
Spatial Context ◽  
Decision Making Process ◽  
Gene Drive ◽  
Continuous Space ◽  
Vector Borne Diseases ◽  
Vector Borne ◽  
Drive Systems

ABSTRACTUnderdominance 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.

scholarly journals RNA-guided gene drives can efficiently and reversibly bias inheritance in wild yeast

2015 ◽  
Author(s):  
James E DiCarlo ◽  
Alejandro Chavez ◽  
Sven L Dietz ◽  
Kevin M Esvelt ◽  
George M Church
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Gene Drive ◽  
Wild Type ◽  
Wild Populations ◽  
Yeast Saccharomyces Cerevisiae ◽  
Wild Yeast ◽  
Successive Generations ◽  
Gene Drives ◽  
General Method ◽  
Made In

Inheritance-biasing “gene drives” may be capable of spreading genomic alterations made in laboratory organisms through wild populations. We previously considered the potential for RNA-guided gene drives based on the versatile CRISPR/Cas9 genome editing system to serve as a general method of altering populations. Here we report molecularly contained gene drive constructs in the yeast Saccharomyces cerevisiae that are typically copied at rates above 99% when mated to wild yeast. We successfully targeted both non-essential and essential genes, showed that the inheritance of an unrelated “cargo” gene could be biased by an adjacent drive, and constructed a drive capable of overwriting and reversing changes made by a previous drive. Our results demonstrate that RNA-guided gene drives are capable of efficiently biasing inheritance when mated to wild-type organisms over successive generations.

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