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

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.

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Designing gene drives to limit spillover to non-target populations

10.1101/680744 ◽

2019 ◽

Cited By ~ 2

Author(s):

Gili Greenbaum ◽

Marcus W. Feldman ◽

Noah A. Rosenberg ◽

Jaehee Kim

Keyword(s):

Target Population ◽

Unintended Effects ◽

Gene Drive ◽

Migration Rates ◽

Target Populations ◽

Disease Vector ◽

Narrow Region ◽

Natural Settings ◽

Gene Drives ◽

High Migration

AbstractThe prospect of utilizing CRISPR-based gene-drive technology for controlling populations, such as invasive and disease-vector species, has generated much excitement. However, the potential for spillovers of gene drive alleles from the target population to non-target populations — events that may be ecologically catastrophic — has raised concerns. Here, using two-population mathematical models, we investigate the possibility of limiting spillovers and impact on non-target populations by designing differential-targeting gene drives, in which the expected equilibrium gene drive allele frequencies are high in the target population but low in the non-target population. We find that achieving differential targeting is possible with certain configurations of gene drive parameters. Most of these configurations ensure differential targeting only under relatively low migration rates between target and non-target populations. Under high migration, differential targeting is possible only in a narrow region of the parameter space. When migration is increased, differential-targeting states can sharply transition to states of global fixation or global loss of the gene drive. Because fixation of the gene drive in the non-target population could severely disrupt ecosystems, we outline possible ways to avoid this outcome. Our results emphasize that, although gene drive technology is promising, understanding the potential consequences for populations other than the targets requires detailed analysis of gene-drive spillovers, and that ways to limit the unintended effects of gene drives to non-target populations should be explored prior to the application of gene drives in natural settings.

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

10.1101/2020.10.29.360404 ◽

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.

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Designing gene drives to limit spillover to non-target populations

PLoS Genetics ◽

10.1371/journal.pgen.1009278 ◽

2021 ◽

Vol 17 (2) ◽

pp. e1009278

Author(s):

Gili Greenbaum ◽

Marcus W. Feldman ◽

Noah A. Rosenberg ◽

Jaehee Kim

Keyword(s):

Target Population ◽

Field Trials ◽

Gene Drive ◽

Migration Rates ◽

Target Populations ◽

Narrow Region ◽

Theoretical Predictions ◽

Potential Applications ◽

And Control ◽

Gene Drives

The prospect of utilizing CRISPR-based gene-drive technology for controlling populations has generated much excitement. However, the potential for spillovers of gene-drive alleles from the target population to non-target populations has raised concerns. Here, using mathematical models, we investigate the possibility of limiting spillovers to non-target populations by designing differential-targeting gene drives, in which the expected equilibrium gene-drive allele frequencies are high in the target population but low in the non-target population. We find that achieving differential targeting is possible with certain configurations of gene-drive parameters, but, in most cases, only under relatively low migration rates between populations. Under high migration, differential targeting is possible only in a narrow region of the parameter space. Because fixation of the gene drive in the non-target population could severely disrupt ecosystems, we outline possible ways to avoid this outcome. We apply our model to two potential applications of gene drives—field trials for malaria-vector gene drives and control of invasive species on islands. We discuss theoretical predictions of key requirements for differential targeting and their practical implications.

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

10.1101/2021.12.05.471291 ◽

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.

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

Royal Society Open Science ◽

10.1098/rsos.202050 ◽

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 .

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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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CircRNA circPDSS1 promotes bladder cancer by down-regulating miR-16

Bioscience Reports ◽

10.1042/bsr20191961 ◽

2020 ◽

Vol 40 (1) ◽

Cited By ~ 4

Author(s):

Qinnan Yu ◽

Pei Liu ◽

Guangye Han ◽

Xiangdong Xue ◽

Derong Ma

Keyword(s):

Cell Proliferation ◽

Bladder Cancer ◽

Circular Rna ◽

Migration And Invasion ◽

Expression Levels ◽

Invasion And Migration ◽

Migration Rates ◽

Urothelial Bladder ◽

And Migration

Abstract Background: Circular RNA (circRNA) circPDSS1 is a recently identified oncogene in gastric cancer, while its roles in other types of cancer are unknown. We investigated the functions of circPDSS1 in urothelial bladder cancer (UBC). Materials and methods: Seventy-two patients (50 males and 22 females, age 38–69 years, mean: 52.3 ± 6.3 years) with UBC were enrolled in Gansu Provincial People’s Hospital from August 2015 to August 2018. RT-qPCR was used to measure gene expression levels in both biopsies from UBC patients and in vitro cultivated HT-1197 and UMUC3 cells. Cell transfections were performed to analyze gene interactions. Cell proliferation, transwell migration and invasion assays were performed to analyze the effects of transfections on HT-1197 and UMUC3 cell proliferation, migration and invasion, respectively. Results: We found that circPDSS1 was up-regulated in UBC. Expression levels of circPDSS1 were increased with increase in clinical stages. MiR-16 was down-regulated and correlated with circPDSS1 in UBC. Overexpression of circPDSS1 led to down-regulation of miR-16, while miR-16 overexpression failed to significantly affect circPDSS1. Overexpression of circPDSS1 led to increased proliferation, invasion and migration rates of UBC cells. Overexpression of miR-16 not only led to inhibited proliferation, invasion and migration of UBC cells, but also attenuated the effects of circPDSS1 overexpression. Conclusion: Therefore, circRNA circPDSS1 may promote UBC by down-regulating miR-16.

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Engineered reciprocal chromosome translocations drive high threshold, reversible population replacement in Drosophila

10.1101/088393 ◽

2016 ◽

Cited By ~ 8

Author(s):

Anna B. Buchman ◽

Tobin Ivy ◽

John M. Marshall ◽

Omar S. Akbari ◽

Bruce A. Hay

Keyword(s):

High Threshold ◽

Gene Drive ◽

Chromosomal Breakage ◽

Population Replacement ◽

Migration Rates ◽

Chromosome Translocations ◽

Laboratory Populations ◽

Insect Populations ◽

And Migration ◽

Global Population

AbstractReplacement of wild insect populations with transgene-bearing individuals unable to transmit disease or survive under specific environmental conditions provides self-perpetuating methods of disease prevention and population suppression, respectively. Gene drive mechanisms that require the gene drive element and linked cargo exceed a high threshold frequency to spread are attractive because they offer several points of control: they bring about local, but not global population replacement; and transgenes can be eliminated by reintroducing wildtypes into the population so as to drive the frequency of transgenes below the threshold required for drive. It has long been recognized that reciprocal chromosome translocations could, in principal, be used to bring about high threshold gene drive through a form of underdominance. However, translocations able to drive population replacement have not been reported, leaving it unclear if translocation-bearing strains fit enough to mediate gene drive can easily be generated. Here we use modeling to identify a range of conditions under which translocations should spread, and the equilibrium frequencies achieved, given specific introduction frequencies, fitness costs and migration rates. We also report the creation of engineered translocation-bearing strains of Drosophila melanogaster, generated through targeted chromosomal breakage and homologous recombination. By several measures translocation-bearing strains are fit, and drive high threshold, reversible population replacement in laboratory populations. These observations, together with the generality of the tools used to generate translocations, suggest that engineered translocations may be useful for controlled population replacement in many species.

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Does the U.S. public support using gene drives in agriculture? And what do they want to know?

Science Advances ◽

10.1126/sciadv.aau8462 ◽

2019 ◽

Vol 5 (9) ◽

pp. eaau8462 ◽

Cited By ~ 9

Author(s):

Michael S. Jones ◽

Jason A. Delborne ◽

Johanna Elsensohn ◽

Paul D. Mitchell ◽

Zachary S. Brown

Keyword(s):

Department Of Defense ◽

Native Species ◽

Public Support ◽

Responsible Innovation ◽

Gene Drive ◽

Target Species ◽

Department Of Agriculture ◽

Potential Risks ◽

The One ◽

Gene Drives

Gene drive development is progressing more rapidly than our understanding of public values toward these technologies. We analyze a statistically representative survey (n = 1018) of U.S. adult attitudes toward agricultural gene drives. When informed about potential risks, benefits, and two previously researched applications, respondents’ support/opposition depends heavily (+22%/−19%) on whether spread of drives can be limited, non-native versus native species are targeted (+12%/−9%), or the drive replaces versus suppresses target species (±2%). The one-fifth of respondents seeking out non–GMO–labeled food are more likely to oppose drives, although their support exceeds opposition for limited applications. Over 62% trust U.S. universities and the Department of Agriculture to research gene drives, with the private sector and Department of Defense viewed as more untrustworthy. Uncertain human health and ecological effects are the public’s most important concerns to resolve. These findings can inform responsible innovation in gene drive development and risk assessment.

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