The proposed work is to engineer multiple independent invasive gene drive systems in the Dengue mosquito, Aedes aegypti, a major vector of human insect-borne disease known to annually infect 50-100 million people worldwide, killing millions. The current approaches used for Dengue disease prevention, including vector suppression by environmental modification, insecticides and anti-pathogen drugs are simply insufficient. The replacement of wild mosquito populations with genetically modified individuals that are engineered to be disease resistant in theory should provide a sustainable long-term method for disease prevention. However, the transgenes that mediate the disease refractoriness are unlikely to confer an overall fitness benefit on insects that carry them. Additionally, wild populations are large, partially reproductively isolated, and dispersed over wide areas. Therefore, population replacement requires a gene drive mechanism in order to spread linked cargo genes mediating disease refractoriness through wild populations. I have previously developed multiple synthetic selfish genetic elements including Maternal-Effect-Dominant-Embryonic-Arrest (Medea) and recently a threshold dependent underdominance system (UDmel) in insects that can rapidly spread through populations, even in the presence of a linked cargo refractory gene that may impose a large increase in fitness cost. Here I propose to simply transfer these synthetic systems into an insect that vectors disease, Aedes aegypti. Therefore, the major aims of this proposal are to develop three systems: 1) Medea, 2) Threshold dependent underdominance (UDmel), and 3) a selfish genetic element the can rapidly spread and crash a population, all in the Dengue vector, Aedes aegypti. Each of these gene drive systems have several attractive features important for social and scientific acceptance for wild transgene releases: the systems are species specific and horizontal spread with other species is limited; minimal ecological impact in contrast to insecticides; relatively robust and unbreakable with a tight linkage of the selfish genetic element with its cargo; transgene recall (for Medea) and complete transgene removal (underdominance) can be carried out if desired. In summary, the overall goal of this proposal is to develop multiple population control technologies in the mosquito that can be applied successfully and safely to fight human disease.

Public Health Relevance

The overall goal of this proposal is to develop alternative and sustainable methods for human vector borne disease control. I propose to engineer multiple invasive gene drive systems in the mosquito that will be capable of either rapidly replacing wild populations with disease resistant individuals or eradicating the pest altogether.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Career Transition Award (K22)
Project #
5K22AI113060-02
Application #
9124726
Study Section
Microbiology and Infectious Diseases B Subcommittee (MID)
Program Officer
Costero-Saint Denis, Adriana
Project Start
2015-08-11
Project End
2017-07-31
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of California Riverside
Department
Zoology
Type
Earth Sciences/Resources
DUNS #
627797426
City
Riverside
State
CA
Country
United States
Zip Code
92521
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Gantz, Valentino M; Akbari, Omar S (2018) Gene editing technologies and applications for insects. Curr Opin Insect Sci 28:66-72
Marshall, John M; Akbari, Omar S (2018) Can CRISPR-Based Gene Drive Be Confined in the Wild? A Question for Molecular and Population Biology. ACS Chem Biol 13:424-430
Li, Ming; Bui, Michelle; Yang, Ting et al. (2017) Germline Cas9 expression yields highly efficient genome engineering in a major worldwide disease vector, Aedes aegypti. Proc Natl Acad Sci U S A 114:E10540-E10549
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