Developing Y chromosome-linked genome editors as a self-limiting strategy for population control of the malaria vector Anopheles gambiae
File(s)
Author(s)
Tolosana Labarta, Ignacio
Type
Thesis
Abstract
Anopheles gambiae mosquitoes are the major vector of malaria in Africa, the most affected region by this disease that causes more than 600,000 deaths annually. In the last decades, important reductions in malaria incidence and mortality have been achieved, primarily driven by vector control programmes based on the use of insecticides and bed nets. Nevertheless, the decrease in malaria cases has recently come to a standstill and there is a consensus that new technologies will be needed to achieve malaria eradication. Genetic control strategies to suppress mosquito populations arise as very promising tools due to their species-specificity and versatility. While effective self-sustaining strategies have been developed in Anopheles mosquitoes, the development of an efficient technology that is geographically and/or temporally restricted would present advantages that include a higher prospect for control and regulatory approval. This thesis describes the generation of such technology: a Y chromosome-linked genome editor (YLE), only present in males, that transmits a female-specific sterility-causing dominant mutation to over 90% of the offspring. The YLE is a Cas9-based system that is always inherited by all the males and targets the female isoform of the doublesex gene, involved in sex determination. It is the first reported genetic control strategy linked to the Y chromosome in Anopheles. Alternative target genes to induce female lethality in the offspring of YLE males were explored by attempting to validate putative haplo-insufficient genes located in the X chromosome. A different YLE strategy approach might be based on depositing female-specific toxins in the embryos. Transcripts present in the early Anopheles embryos that had been potentially contributed from the male progenitor were identified. Future studies on the regulatory sequences of these transcripts will determine whether they can be used to induce paternal deposition of a female-specific toxin in the form of mRNA or snRNA.
Version
Open Access
Date Issued
2023-08-04
Date Awarded
01/12/2023
License URL
Advisor
Crisanti, Andrea
Nolan, Tony
Sponsor
Bill and Melinda Gates Foundation
Open Philanthropy Project
Publisher Department
Department of Life Sciences
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)