Invasive species pose a major threat to biodiversity on islands. While successes have been achieved using traditional removal methods, such as toxicants aimed at rodents, these approaches have limitations and various off-target effects on island ecosystems. Gene drive technologies designed to eliminate a population provide an alternative approach, but the potential for drive-bearing individuals to escape from the target release area and impact populations elsewhere is a major concern. Here we propose the “Locally Fixed Alleles” approach as a novel means for localizing elimination by a drive to an island population that exhibits significant genetic isolation from neighboring populations. Our approach is based on the assumption that in small island populations of rodents, genetic drift will lead to alleles at multiple genomic loci becoming fixed. In contrast, multiple alleles are likely to be maintained in larger populations on mainlands. Utilizing the high degree of genetic specificity achievable using homing drives, for example based on the CRISPR/Cas9 system, our approach aims at employing one or more locally fixed alleles as the target for a gene drive on a particular island. Using mathematical modeling, we explore the feasibility of this approach and the degree of localization that can be achieved. We show that across a wide range of parameter values, escape of the drive to a neighboring population in which the target allele is not fixed will at most lead to modest transient suppression of the non-target population. While the main focus of this paper is on elimination of a rodent pest from an island, we also discuss the utility of the locally fixed allele approach for the goals of population suppression or population replacement. Our analysis also provides a threshold condition for the ability of a gene drive to invade a partially resistant population.
Optimism regarding potential epidemiological and conservation applications of modern gene drives is tempered by concern about the possibility of unintended spread of engineered organisms beyond the target population. In response, several novel gene drive approaches have been proposed that can, under certain conditions, locally alter characteristics of a population. One challenge for these gene drives is the difficulty of achieving high levels of localized population suppression without very large releases in the face of gene flow. We present a new gene drive system, tethered homing (TH), with improved capacity for both localization and population suppression. The TH drive is based on driving a payload gene using a homing construct that is anchored to a spatially restricted gene drive. We use a proof‐of‐concept mathematical model to show the dynamics of a TH drive that uses engineered underdominance as an anchor. This system is composed of a split homing drive and a two‐locus engineered underdominance drive linked to one part of the split drive (the Cas endonuclease). We use simple population genetic simulations to show that the tethered homing technique can offer improved localized spread of costly transgenic payload genes. Additionally, the TH system offers the ability to gradually adjust the genetic load in a population after the initial alteration, with minimal additional release effort. We discuss potential solutions for improving localization and the feasibility of creating TH drive systems. Further research with models that include additional biological details will be needed to better understand how TH drives would behave in natural populations, but the preliminary results shown here suggest that tethered homing drives can be a useful addition to the repertoire of localized gene drives.
more » « less- NSF-PAR ID:
- 10461229
- Publisher / Repository:
- Wiley-Blackwell
- Date Published:
- Journal Name:
- Evolutionary Applications
- Volume:
- 12
- Issue:
- 8
- ISSN:
- 1752-4571
- Format(s):
- Medium: X Size: p. 1688-1702
- Size(s):
- ["p. 1688-1702"]
- Sponsoring Org:
- National Science Foundation
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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.
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Abstract Gene drive technology could allow the intentional spread of a desired gene throughout an entire wild population in relatively few generations. However, there are major concerns that gene drives could either fail to spread or spread without restraint beyond the targeted population. One potential solution is to use more localized threshold-dependent drives, which only spread when they are released in a population above a critical frequency. However, under certain conditions, small changes in gene drive fitness could lead to divergent outcomes in spreading behavior. In the face of ecological uncertainty, the inability to estimate gene drive fitness in a real-world context could prove problematic because gene drives designed to be localized could spread to fixation in neighboring populations if ecological conditions unexpectedly favor the gene drive. This perspective offers guidance to developers and managers because navigating gene drive spread and controllability could be risky without detailed knowledge of ecological contexts.
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Rinaldi, Gabriel (Ed.)CRISPR gene drives could revolutionize the control of infectious diseases by accelerating the spread of engineered traits that limit parasite transmission in wild populations. Gene drive technology in mollusks has received little attention despite the role of freshwater snails as hosts of parasitic flukes causing 200 million annual cases of schistosomiasis. A successful drive in snails must overcome self-fertilization, a common feature of host snails which could prevents a drive’s spread. Here we developed a novel population genetic model accounting for snails’ mixed mating and population dynamics, susceptibility to parasite infection regulated by multiple alleles, fitness differences between genotypes, and a range of drive characteristics. We integrated this model with an epidemiological model of schistosomiasis transmission to show that a snail population modification drive targeting immunity to infection can be hindered by a variety of biological and ecological factors; yet under a range of conditions, disease reduction achieved by chemotherapy treatment of the human population can be maintained with a drive. Alone a drive modifying snail immunity could achieve significant disease reduction in humans several years after release. These results indicate that gene drives, in coordination with existing public health measures, may become a useful tool to reduce schistosomiasis burden in selected transmission settings with effective CRISPR construct design and evaluation of the genetic and ecological landscape.more » « less
