Dissertation Title: Towards Rodent Genetic Biocontrol

Abstract:
Invasive rodents impose a substantial economic burden globally through agricultural losses while serving as disease vectors presenting critical public health risks. Conventional control methods, particularly anticoagulant rodenticides, raise ethical and environmental concerns through secondary poisoning and resistance evolution. This dissertation investigates CRISPR-based genetic biocontrol strategies as species-specific solutions for rodent population management. First, we examined public attitudes toward genetic biocontrol; finding general support for genome engineering approaches with prioritization of ecosystem disruption and community consultation before implementation. Second, we developed Y-linked editor systems targeting; Xist for daughterless phenotypes, Acsl4 for female subfertility, and androgen receptor for female masculinization. While technical challenges prevented achievement of intended phenotypes, population modeling demonstrated that Acsl4-targeting could achieve substantial suppression. Finally, we investigated a purifying gene drive system targeting haploinsufficient spermatogenesis gene KLHL10 to overcome low homing rates in mammals by exploiting selection against non-homologous end joining repair outcomes. Frameshift mutations were strongly selected against in male reproduction, with coding sequence cassettes effectively rescuing gene function. Unexpectedly, we observed purifying selection in female reproduction, suggesting previously unknown KLHL10 functions in oocyte development. This work establishes foundational principles for mammalian genetic biocontrol while emphasizing transparent research practices and responsible innovation frameworks.

Committee members:
Kevin Esvelt, Associate Professor of Media Arts and Sciences, MIT
Katie Galloway, Assistant Professor of Chemical Engineering, MIT
David Page, Professor of Biology, MIT. Investigatior, HHMI