Cheating evolution: engineering gene drives to manipulate the fate of wild populations

Gene drives may be capable of addressing ecological problems by altering entire populations of wild organisms, but their use has remained largely theoretical due to technical constraints. Here we consider the potential for RNA-guided gene drives based on the CRISPR nuclease Cas9 to serve as a general method for spreading altered traits through wild populations over many generations. We detail likely capabilities, discuss limitations, and provide novel precautionary strategies to control the spread of gene drives and reverse genomic changes. The ability to edit populations of sexual species would offer substantial benefits to humanity and the environment. For example, RNA-guided gene drives could potentially prevent the spread of disease, support agriculture by reversing pesticide and herbicide resistance in insects and weeds, and control damaging invasive species. However, the possibility of unwanted ecological effects and near-certainty of spread across political borders demand careful assessment of each potential application. We call for thoughtful, inclusive, and well-informed public discussions to explore the responsible use of this currently theoretical technology.

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

10.1101/408369 ◽

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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Engineering multiple species-like genetic incompatibilities in insects

10.1101/2020.04.03.024588 ◽

2020 ◽

Cited By ~ 1

Author(s):

Maciej Maselko ◽

Nathan Feltman ◽

Ambuj Upadhyay ◽

Amanda Hayward ◽

Siba Das ◽

...

Keyword(s):

Life Stages ◽

Agricultural Pests ◽

Wild Type ◽

Recessive Resistance ◽

Wild Populations ◽

Hybrid Lethality ◽

Multiple Species ◽

Type Strains ◽

Gene Drives ◽

New Strategies

AbstractSpeciation constrains the flow of genetic information between populations of sexually reproducing organisms. Gaining control over mechanisms of speciation would enable new strategies to manage wild populations of disease vectors, agricultural pests, and invasive species. Additionally, such control would provide safe biocontainment of transgenes and gene drives. Natural speciation can be driven by pre-zygotic barriers that prevent fertilization or by post-zygotic genetic incompatibilities that render the hybrid progeny inviable or sterile. Here we demonstrate a general approach to create engineered genetic incompatibilities (EGIs) in the model insect Drosophila melanogaster. Our system couples a dominant lethal transgene with a recessive resistance allele. EGI strains that are homozygous for both elements are fertile and fecund when they mate with similarly engineered strains, but incompatible with wild-type strains that lack resistant alleles. We show that EGI genotypes can be tuned to cause hybrid lethality at different developmental life-stages. Further, we demonstrate that multiple orthogonal EGI strains of D. melanogaster can be engineered to be mutually incompatible with wild-type and with each other. Our approach to create EGI organisms is simple, robust, and functional in multiple sexually reproducing organisms.

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Evolutionary dynamics of CRISPR gene drives

10.1101/057281 ◽

2016 ◽

Cited By ~ 10

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.

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

10.1101/013896 ◽

2015 ◽

Cited By ~ 7

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

10.1101/219022 ◽

2017 ◽

Cited By ~ 10

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.

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A confinable home and rescue gene drive for population modification

eLife ◽

10.7554/elife.65939 ◽

2021 ◽

Vol 10 ◽

Author(s):

Nikolay P Kandul ◽

Junru Liu ◽

Jared B Bennett ◽

John M Marshall ◽

Omar S Akbari

Keyword(s):

Mathematical Modeling ◽

Target Gene ◽

Essential Gene ◽

Gene Drive ◽

Wild Populations ◽

Fitness Costs ◽

Recessive Lethal ◽

Transmission Rates ◽

Population Cage ◽

Gene Drives

Homing based gene drives, engineered using CRISPR/Cas9, have been proposed to spread desirable genes throughout populations. However, invasion of such drives can be hindered by the accumulation of resistant alleles. To limit this obstacle, we engineer a confinable population modification Home-and-Rescue (HomeR) drive in Drosophila targeting an essential gene. In our experiments, resistant alleles that disrupt the target gene function were recessive lethal, and therefore disadvantaged. We demonstrate that HomeR can achieve an increase in frequency in population cage experiments, but that fitness costs due to the Cas9 insertion limit drive efficacy. Finally, we conduct mathematical modeling comparing HomeR to contemporary gene drive architectures for population modification over wide ranges of fitness costs, transmission rates, and release regimens. HomeR could potentially be adapted to other species, as a means for safe, confinable, modification of wild populations.

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The effect of mating complexity on gene drive dynamics

10.1101/2021.09.16.460618 ◽

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.

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Concerning RNA-Guided Gene Drives for the Alteration of Wild Populations

10.1101/007203 ◽

2014 ◽

Cited By ~ 21

Author(s):

Kevin M Esvelt ◽

Andrea L Smidler ◽

Flaminia Catteruccia ◽

George M Church

Keyword(s):

Invasive Species ◽

Herbicide Resistance ◽

Wild Populations ◽

Genomic Changes ◽

Ecological Problems ◽

Political Borders ◽

And Control ◽

Gene Drives ◽

Careful Assessment ◽

General Method

Gene drives may be capable of addressing ecological problems by altering entire populations of wild organisms, but their use has remained largely theoretical due to technical constraints. Here we consider the potential for RNA-guided gene drives based on the CRISPR nuclease Cas9 to serve as a general method for spreading altered traits through wild populations over many generations. We detail likely capabilities, discuss limitations, and provide novel precautionary strategies to control the spread of gene drives and reverse genomic changes. The ability to edit populations of sexual species would offer substantial benefits to humanity and the environment. For example, RNA-guided gene drives could potentially prevent the spread of disease, support agriculture by reversing pesticide and herbicide resistance in insects and weeds, and control damaging invasive species. However, the possibility of unwanted ecological effects and near-certainty of spread across political borders demand careful assessment of each potential application. We call for thoughtful, inclusive, and well-informed public discussions to explore the responsible use of this currently theoretical technology.

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Author response: Concerning RNA-guided gene drives for the alteration of wild populations

10.7554/elife.03401.019 ◽

2014 ◽

Cited By ~ 5

Author(s):

Kevin M Esvelt ◽

Andrea L Smidler ◽

Flaminia Catteruccia ◽

George M Church

Keyword(s):

Author Response ◽

Wild Populations ◽

Gene Drives

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