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| |  The inability to ensure that newly introduced genes will become established within regional mosquito populations has been a major roadblock to the advancement of genetic strategies for vector control.
Dr. Burt and his colleagues are investigating homing endonuclease genes (HEGs), so-called "parasitic" genes that can spread rapidly through mosquito populations even if they harm the host insect. This gives HEGs the potential to move newly introduced traits, such as sterility or inability to transmit disease, through a population quickly. The project's ultimate goal is to develop HEGs as a flexible, robust, powerful, and safe system to drive useful traits through populations of mosquitoes that transmit malaria.
The team will continue to refine the combination of HEGs and Anopheles targets to test various strategies for population depletion. Investigators are beginning to develop an implementation strategy based on a staged approach of increasing complexity, with appropriate monitoring at each stage. |
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| | | Analyze HEG activity in a Drosophila model system and in Anopheles gambiae, the primary vector for malaria in Africa, using defined crosses and then in cage experiments to assess the dynamics of HEG spread through populations. | | | | | Identify suitable target sequences and promoters, first by searching for candidates in Drosophila and then finding homologs in Anopheles. These studies focus particularly on targets for population depletion, such as female sterility, lethality, and X chromosome disruption. | | | | | Engineer HEGs to recognize and cleave critical Anopheles targets and test their efficiency in defined crosses and population cage experiments. | | | | | Conduct modeling studies to predict HEG spread through natural mosquito populations and how this might affect malaria transmission. | | | | | Use this information to develop a step-by-step proposal for release of HEG-bearing mosquitoes into natural conditions and monitoring results. Actual field release is not part of the project. | | |
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| | | To investigate homing in a Drosophila model system, investigators have designed donor and recipient constructs and have constructed transgenic strains. They have demonstrated that a particular HEG, I-SceI, can be expressed in the male germline, and that it cuts its chromosomal recognition system at a high frequency. They have demonstrated homing for the first time in an animal, and are currently investigating the use of alternative promoters to increase the frequency. | | | | | To assess the potential for homing in Anopheles, investigators have performed assays in cultured cells and in embryos. These demonstrated expression and activity of two different HEGs in the mosquito. In addition, the rDNA repeats in Anopheles are restricted to the X chromosome, and so is an attractive target for sex ratio distortion strategy which relies on shredding the X-chromosome. The team has demonstrated that the HEG I-PpoI recognizes and cleaves chromosomal rDNA, and are now constructing transgenic strains to test the in vivo effect. | | | | | Using literature and homology searches, investigators have generated lists of candidate target genes, including both essential genes and female fertility genes. | | | | | Using a combination of computational and experimental approaches, investigators have developed a system to modify the recognition sequence of a homing endonuclease by one base pair. They are using the system for evolving enzymes with new specificities, and are now using this and the computational approach to attempt a more ambitious approaches. | | | | | Investigators have constructed models to predict the spread of various HEG-based constructs through a population, and have constructed a stage-structured model of Anopheles population dynamics and infection rates. | | |
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| | | Fred Hutchinson Cancer Research Center, Washington, United States - US | | | | | University of Washington, Washington, United States - US | | | | | Cambridge University, United Kingdom - GB | | |
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