North American red fox rabies immunity gene drive for safer (sub)urban rewilding – ScienceOpen
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      North American red fox rabies immunity gene drive for safer (sub)urban rewilding

      Research Ideas and Outcomes
      Pensoft Publishers

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          Abstract

          Animal-transmitted diseases such as rabies represent a barrier to successful rewilding and threaten continued human-wildlife co-existence. In North America, population growth and human settlement expansion lead to encounters with wild mammals which have the potential to transmit rabies to domestic dogs and humans. The recent development of gene drives mediated by CRISPR-Cas9 allows for ecosystem engineering at unprecedented scales given the potential to spread new traits through wild populations with biased inheritance exceeding the pattern of classical Mendelian dominant genes. This study of a possible red fox rabies immunity gene drive project contributes a novel proposal to the existing academic conversation about suitable applications of gene drive technology in wild animal populations, such as projects to fight malaria and Lyme disease. Noting the unique characteristics of rabies, such as the dire mortality rate in humans once symptoms arise, as well as the tendency for rabid wild animals to lose their fear of humans, it appears to be a suitable target for eventual eradication via gene drive to spread immunity through wild mammal reservoir populations. Introducing heritable rabies immunity into North American red fox populations through gene drive represents a strategy to both battle rabies and adjust the ecology of (sub)urban environments. Given this review of the project's possible implementation and expected outcomes, providing inherited rabies immunity to wild red fox populations in North America via gene drive appears both feasible and sensible. Similar projects may be used to eradicate comparable infectious diseases from other wild animal populations, with likely benefits to human patients, wildlife and ecosystems.

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          Most cited references35

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          Concerning RNA-guided gene drives for the alteration 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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            Reducing resistance allele formation in CRISPR gene drive

            A functioning gene drive mechanism could fundamentally change our strategies for the control of vector-borne diseases, such as malaria, dengue, and Zika. CRISPR homing gene drive promises such a mechanism, which could be used to rapidly spread genetic modifications among the mosquitoes that transmit these diseases. However, recent studies have shown that current drives would likely be unable to spread in insect populations due to the high rate at which resistance will evolve. In this study, we provide an experimental demonstration that guide RNA multiplexing can successfully reduce resistance rates but also find that such an approach would still need to be combined with additional strategies to create drives that are efficient enough for use in wild populations. CRISPR homing gene drives can convert heterozygous cells with one copy of the drive allele into homozygotes, thereby enabling super-Mendelian inheritance. Such a mechanism could be used, for example, to rapidly disseminate a genetic payload in a population, promising effective strategies for the control of vector-borne diseases. However, all CRISPR homing gene drives studied in insects thus far have produced significant quantities of resistance alleles that would limit their spread. In this study, we provide an experimental demonstration that multiplexing of guide RNAs can both significantly increase the drive conversion efficiency and reduce germline resistance rates of a CRISPR homing gene drive in Drosophila melanogaster . We further show that an autosomal drive can achieve drive conversion in the male germline, with no subsequent formation of resistance alleles in embryos through paternal carryover of Cas9. Finally, we find that the nanos promoter significantly lowers somatic Cas9 expression compared with the vasa promoter, suggesting that nanos provides a superior choice in drive strategies where gene disruption in somatic cells could have fitness costs. Comparison of drive parameters among the different constructs developed in this study and a previous study suggests that, while drive conversion and germline resistance rates are similar between different genomic targets, embryo resistance rates can vary significantly. Taken together, our results mark an important step toward developing effective gene drives capable of functioning in natural populations and provide several possible avenues for further control of resistance rates.
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              Germline transmission of donor haplotype following spermatogonial transplantation.

              Spermatogenesis is a complex, highly organized, very efficient process that is based upon the capacity of stem cell spermatogonia simultaneously to undergo self-renewal and to provide progeny that differentiate into mature spermatozoa. We report here that testis-derived cells transplanted into the testis of an infertile mouse will colonize seminiferous tubules and initiate spermatogenesis in > 70% of recipients. Testis-derived cells from newborn mice were less effective in colonizing recipient testes than cells from 5- to 15- or 21- to 28-day-old mice. Increasing the number of Sertoli cells in the donor cell population did not increase the efficiency of colonization. Unmodified embryonic stem cells were not able to substitute for testis-derived cells in colonizing testes but instead formed tumors in syngeneic as well as nonsyngeneic hosts. Finally, with recipients that maintained endogenous spermatogenesis, testis cell transplantation yielded mice in which up to 80% of progeny were sired by donor-derived spermatozoa. The technique of spermatogonial cell transplantation should provide a means to generate germline modifications in a variety of species following development of spermatogonial culture techniques and should have additional applications in biology, medicine, and agriculture.
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                Author and article information

                Contributors
                (View ORCID Profile)
                Journal
                Research Ideas and Outcomes
                RIO
                Pensoft Publishers
                2367-7163
                December 19 2024
                December 19 2024
                : 10
                Article
                10.3897/rio.10.e134189
                63a97d30-67ba-44d6-b433-a5e20b282891
                © 2024

                http://creativecommons.org/licenses/by/4.0/

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