Development of strategies for invasive rodent population control through modification of naturally-occurring meiotic drive systems
Date
2024
Authors
Gierus, Luke Jackson
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Abstract
Invasive alien species are responsible for significant biodiversity and economic consequences. They have been associated with 60% of global extinctions and are estimated to cost more than $400 billion annually. The current management of invasive rodents, one of the most impactful invasive alien pests, relies on trapping and non-specific anticoagulant rodenticides. These methods are costly, labour-intensive, have restricted applicability on islands, and are not always successful in effective eradication. New tools are therefore required to control invasive rodents, and thereby preserve global biodiversity, and mitigate their economic impact. Genetic biocontrol strategies have shown promise in invertebrates but have proven difficult to translate effectively to vertebrate species. This thesis investigates a novel gene drive strategy, termed tCRISPR, in which a naturally-occurring gene drive found exclusively in mice, known as the t haplotype, is modified to spread a recessive mutation that causes female infertility. The strategy involved the generation of transgenic split drive mice (where gene drive components are on different chromosomes) and in vivo testing. Results from these experiments, combined with individual-based in silico modelling, suggest that this new genetic biocontrol strategy can achieve eradication of invasive mouse populations on islands. This represents the first viable proof-of-concept gene drive strategy targeting vertebrates. To ensure the safety and controllability of tCRISPR, the development of a precision tCRISPR gene drive was explored. This mechanism aims to spatially restrict tCRISPR by targeting a single nucleotide polymorphism fixed in mice on a target island, but not neighbouring populations. This approach, which is broadly applicable to other gene drive strategies, was designed as an all-in-one system. However, the generation of this mouse has thus far been unsuccessful. Alternative options are being investigated, posing a challenge that must be overcome for the successful creation of any all-in-one tCRISPR gene drive. The biassed transmission mechanism of the t haplotype, particularly the role of the Sperm motility kinase 2 (Smok2) family, was also investigated. A comprehensive understanding of the t haplotype mechanism will provide insight into the evolution of this system and may enable the development of novel gene drive strategies inspired by the t haplotype. The Smok2 family, comprised of Smok2a and Smok2b, was knocked out in mice using CRISPR-Cas9. Surprisingly, the loss of Smok2 genes had no impact on sperm motility or transmission in wild-type and t haplotype backgrounds, indicating the potential redundant role of these genes. Preliminary investigations into the rescue mechanism and role of SmokTCR revealed novel Smok genes and a potential neomorphic mutation in SmokTCR. These experiments demonstrated that the t haplotype distortion mechanism, proposed to target SMOK2, and the rescue mechanism, mediated by SMOKTCR, are more complex than previously thought. This thesis has made significant progress towards generating a safe and controllable gene drive to suppress invasive mouse populations while shedding light on the complexities of the t haplotype mechanism.
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Thesis (Ph.D.) -- University of Adelaide, School of ENTER SCHOOL, YEAR
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