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 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 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 Weakly deleterious natural genetic variation amplifies probability of resistance in multiplexed gene drive systems

2021 ◽  
Author(s):  
Bhavin S Khatri ◽  
Austin Burt
Keyword(s):  
De Novo ◽  
Large Population ◽  
Stochastic Simulations ◽  
Gene Drive ◽  
End Joining ◽  
Single Nucleotide ◽  
Major Barrier ◽  
Standing Variation ◽  
Large Populations ◽  
Drive Systems

Evolution of resistance is a major barrier to successful deployment of gene drive systems to suppress natural populations. Multiplexed guide RNAs that require resistance mutations in all target cut sites is a promising strategy to overcome resistance. Using novel stochastic simulations that accurately model evolution at very large population sizes, we explore the probability of resistance due to three important mechanisms: 1) non-homologous end-joining mutations, 2) single nucleotide mutants arising de novo or, 3) single nucleotide polymorphisms pre-existing as standing variation. If the fraction of functional end-joining mutants is rare, we show that standing variation dominates, via a qualitatively new phenomenon where weakly deleterious variants significantly amplify the probability of multi-site resistance. This means resistance can be probable even with many target sites in not very large populations. This result has broad application to resistance arising in multi-site evolutionary scenarios including the evolution of vaccine escape mutations in large populations.

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 The effect of mating complexity on gene drive dynamics

2021 ◽  
Author(s):  
Prateek Verma ◽  
R. Guy Reeves ◽  
Samson Simon ◽  
Mathias Otto ◽  
Chaitanya S. Gokhale
Keyword(s):  
Mate Choice ◽  
Mating Systems ◽  
Population Level ◽  
Gene Drive ◽  
Wild Populations ◽  
Transgenic Organisms ◽  
Drive Systems ◽  
The Impact ◽  
Gene Drives ◽  
Drive Dynamics

AbstractGene drive technology is being presented as a means to deliver on some of the global challenges humanity faces today in healthcare, agriculture and conservation. However, there is a limited understanding of the consequences of releasing self-perpetuating transgenic organisms into the wild populations under complex ecological conditions. In this study, we analyze the impact of three factors, mate-choice, mating systems and spatial mating network, on the population dynamics for two distinct classes of modification gene drive systems; distortion and viability-based ones. All three factors had a high impact on the modelling outcome. First, we demonstrate that distortion based gene drives appear to be more robust against the mate-choice than viability-based gene drives. Second, we find that gene drive spread is much faster for higher degrees of polygamy. With fitness cost, speed is the highest for intermediate levels of polygamy. Finally, the spread of gene drive is faster and more effective when the individuals have fewer connections in a spatial mating network. Our results highlight the need to include mating complexities while modelling the population-level spread of gene drives. This will enable a more confident prediction of release thresholds, timescales and consequences of gene drive in populations.

scholarly journals Experimental demonstration of tethered gene drive systems for confined population modification or suppression

2021 ◽  
Author(s):  
Matthew Metzloff ◽  
Emily Yang ◽  
Sumit Dhole ◽  
Andrew G. Clark ◽  
Philipp W. Messer ◽  
...  
Keyword(s):  
Population Control ◽  
Local Population ◽  
Natural Populations ◽  
Great Promise ◽  
Gene Drive ◽  
Native Range ◽  
Target Populations ◽  
Experimental Cage ◽  
Drive Systems ◽  
Gene Drives

Homing gene drives hold great promise for the genetic control of natural populations. However, current homing systems are capable of spreading uncontrollably between populations connected by even marginal levels of migration. This could represent a substantial sociopolitical barrier to the testing or deployment of such drives and may generally be undesirable when the objective is only local population control, such as suppression of an invasive species outside of its native range. Tethered drive systems, in which a locally confined gene drive provides the CRISPR nuclease needed for a homing drive, could provide a solution to this problem, offering the power of a homing drive and confinement of the supporting drive. Here, we demonstrate the engineering of a tethered drive system in Drosophila, using a TARE drive to support modification and suppression homing drives. Each drive was able to bias inheritance in its favor, and the TARE drive was shown to spread only when released above a threshold frequency in experimental cage populations. After the TARE drive had established in the population, it facilitated the spread of a subsequently released split homing modification drive (to all individuals in the cage) and of a homing suppression drive (to its equilibrium frequency). Our results show that the tethered drive strategy is a viable and easily engineered option for providing confinement of homing drives to target populations. 

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 CRISPR gene-drive systems based on Cas9 nickases promote super-Mendelian inheritance in Drosophila

2021 ◽  
Author(s):  
Víctor López Del Amo ◽  
Sara Sanz Juste ◽  
Valentino M. Gantz
Keyword(s):  
Dna Repair ◽  
Mendelian Inheritance ◽  
Essential Genes ◽  
Gene Products ◽  
Gene Drive ◽  
Repair Pathway ◽  
Wild Populations ◽  
Drive Systems ◽  
Gene Drives ◽  
Wildtype Allele

ABSTRACTCRISPR-based gene drive systems can be used to modify entire wild populations due to their ability to bias their own inheritance towards super-Mendelian rates (>100%). Current gene drives contain a Cas9 and a gRNA gene inserted at the location targeted by the gRNA. These gene products are able to cut the opposing wildtype allele, and lead to its replacement with a copy of the gene drive through the homology-directed DNA repair pathway. When this allelic conversion occurs in the germline it leads to the preferential inheritance of the engineered allele — a property that has been proposed to disseminate engineered traits for managing disease-transmitting mosquito populations. Here, we report a novel gene-drive strategy relying on Cas9 nickases which operates by generating staggered paired-nicks in the DNA to promote propagation of the gene drive allele. We show that only when 5’ overhangs are generated, the system efficiently leads to allelic conversion. Further, the nickase gene-drive arrangement produces large stereotyped deletions, providing potential advantages for targeting essential genes. Indeed, the nickase-gene-drive design should expand the options available for gene drive designs aimed at applications in mosquitoes and beyond.

scholarly journals Invasion and migration of spatially self-limiting gene drives: a comparative analysis

2017 ◽  
Author(s):  
Sumit Dhole ◽  
Michael R. Vella ◽  
Alun L. Loyd ◽  
Fred Gould
Keyword(s):  
Target Population ◽  
Gene Drive ◽  
Fitness Costs ◽  
Invasion And Migration ◽  
Migration Rates ◽  
Chain System ◽  
Drive Systems ◽  
And Migration ◽  
The One ◽  
Gene Drives

AbstractRecent advances in research on gene drives have produced genetic constructs that could theoretically spread a desired gene (payload) into all populations of a species, with a single release in one place. This attribute has advantages, but also comes with risks and ethical concerns. There has been a call for research on gene drive systems that are spatially and/or temporally self-limiting. Here we use a population genetics model to compare the expected characteristics of three spatially self-limiting gene drive systems: one-locus underdominance, two-locus underdominance, and daisy-chain drives. We find large differences between these gene drives in the minimum release size required for successfully driving a payload into a population. The daisy-chain system is the most efficient, requiring the smallest release, followed by the two-locus underdominance system, and then the one-locus underdominance system. However, when the target population exchanges migrants with a non-target population, the gene drives requiring smaller releases suffer from higher risks of unintended spread. For payloads that incur relatively low fitness costs (up to 30%), a simple daisy-chain drive is practically incapable of remaining localized, even with migration rates as low as 0.5% per generation. The two-locus underdominance system can achieve localized spread under a broader range of migration rates and of payload fitness costs, while the one-locus underdominance system largely remains localized. We also find differences in the extent of population alteration and in the permanence of the alteration achieved by the three gene drives. The two-locus underdominance system does not always spread the payload to fixation, even after successful drive, while the daisy-chain system can, for a small set of parameter values, achieve a temporally-limited spread of the payload. These differences could affect the suitability of each gene drive for specific applications.Note:This manuscript has been accepted for publication in the journal Evolutionary Applications and is pending publication. We suggest that any reference to or quotation of this article should be made with this recognition.

scholarly journals Modulating CRISPR gene drive activity through nucleocytoplasmic localization of Cas9 in S. cerevisiae

2018 ◽  
Author(s):  
Megan E. Goeckel ◽  
Erianna M. Basgall ◽  
Isabel C. Lewis ◽  
Samantha C. Goetting ◽  
Yao Yan ◽  
...  
Keyword(s):  
Nuclease Activity ◽  
Gene Drive ◽  
Wild Populations ◽  
Vector Borne Diseases ◽  
Vector Borne ◽  
Mendelian Laws ◽  
Artificial Gene ◽  
Nuclear Localization Sequences ◽  
Gene Drives

ABSTRACTThe bacterial CRISPR/Cas genome editing system has provided a major breakthrough in molecular biology. One use of this technology is within a nuclease-based gene drive. This type of system can install a genetic element within a population at unnatural rates. Combatting of vector-borne diseases carried by metazoans could benefit from a delivery system that bypasses traditional Mendelian laws of segregation. Recently, laboratory studies in fungi, insects, and even mice, have demonstrated successful propagation of CRISPR gene drives and the potential utility of this type of mechanism. However, current gene drives still face challenges including evolved resistance, containment, and the consequences of application in wild populations. In this study, we use an artificial gene drive system in budding yeast to explore mechanisms to modulate nuclease activity of Cas9 through its nucleocytoplasmic localization. We examine non-native nuclear localization sequences on Cas9 fusion proteins in vivo and demonstrate that appended signals can titrate gene drive activity and serve as a potential molecular safeguard.

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