The role of the doublesex gene in tissue dimorphisms in Anopheles Gambian
File(s)
Author(s)
Page, Nicole
Type
Thesis
Abstract
Genetic control has become a popular strategy for suppressing mosquito vectors of disease. Gene drives are synthetic genetic elements that are able to increase the inheritance of a desired allele to surpass mendelian levels. Gene drives targeting female fertility genes have been successfully used in the laboratory for population suppression of the African malaria mosquito Anopheles gambiae. The doublesex gene (dsx) is currently the best candidate for this form of gene drive. In A. gambiae, the dsx gene has two sex-specific isoforms which are important for sex determination and development. Disruption of the female isoform causes complete sterility in A. gambiae females which makes it an effective target for vector control strategies.
When disrupting an endogenous gene it is important that there are no unsolicited consequences of this modification. In this case, when dealing with a vector of the malaria parasite, it is important to ensure that targeting Agdsx will not increase the vectorial capability of the female mosquitoes in any way. This can be achieved by thorough investigation into the role of the dsx gene, particularly in the tissues involved in parasite transmission in the mosquito. I used transgenic mosquitoes that carried either a complete knockout or a tissue-specific knockdown of the dsx female isoform (dsxF) to better understand gene function and the effects on vector capability.
Disruption of dsxF in the midgut can induce a significant reduction in Plasmodium infection intensity as well as minor female fertility costs. It is therefore likely that Agdsx plays a significant role in the regulation of midgut genes important for fertility and infection which could reveal new targets for vector control. While creating a targeted gene knockout, I characterised a novel putative midgut promoter, Chitinase 8 (Cht8), showing high levels of tissue-specific expression which could have widespread applications in vector biology.
When disrupting an endogenous gene it is important that there are no unsolicited consequences of this modification. In this case, when dealing with a vector of the malaria parasite, it is important to ensure that targeting Agdsx will not increase the vectorial capability of the female mosquitoes in any way. This can be achieved by thorough investigation into the role of the dsx gene, particularly in the tissues involved in parasite transmission in the mosquito. I used transgenic mosquitoes that carried either a complete knockout or a tissue-specific knockdown of the dsx female isoform (dsxF) to better understand gene function and the effects on vector capability.
Disruption of dsxF in the midgut can induce a significant reduction in Plasmodium infection intensity as well as minor female fertility costs. It is therefore likely that Agdsx plays a significant role in the regulation of midgut genes important for fertility and infection which could reveal new targets for vector control. While creating a targeted gene knockout, I characterised a novel putative midgut promoter, Chitinase 8 (Cht8), showing high levels of tissue-specific expression which could have widespread applications in vector biology.
Version
Open Access
Date Issued
2022-11-23
Date Awarded
01/07/2023
License URL
Advisor
Crisanti, Andrea
Fasulo, Barbara
Sponsor
Bill and Melinda Gates Foundation
Publisher Department
Life Sciences
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)