Malaria is a devastating global killer, with human-to-human disease transmission necessarily proceeding through a handful of competent vector mosquito species. Mosquitoes mount a vigorous immune defense against malaria parasites present in an infected bloodmeal. This typically results in high, but incomplete, parasite mortality. Wild mosquito populations segregate for considerable genetic variation in the ability to suppress parasite development, such that some individuals are completely refractory to transmission while others are highly susceptible. Mosquitoes suffer measurable fitness costs as a result of malaria infection, suggesting a potential selective advantage to efficacious immune defense. Under this proposal, we will explore the genetic basis for natural resistance to malaria in Anopheles gambiae, the most common and destructive vector of human malaria. This will be done with a genotype-phenotype association study, testing statistical correlation between polymorphism in 60 malaria responsive candidate genes and phenotypic measures of parasite suppression. Twenty of the candidate genes will be further examined with in-depth population genetic analyses in multiple Anopheles species. The focal Anopheles species will be chosen as distinct vector/non-vector pairs, where the non-vectors are phylogenetically nested within the vectors. The data collected will result in a basic population genetic characterization of the species, none of which have been adequately described from a population genetic perspective, and will allow tests for adaptation driven by natural selection. The phylogenetic structure of the species examined will allow powerful molecular evolutionary tests for natural selection specifically associated with exposure to human malaria. Integration of the three aims of this proposal will yield a comprehensive view of coevolution between Anopheles species and malaria parasites, and will highlight points of coevolutionary "tension" between host and parasite where targeted human intervention could tip the balance to disrupt disease transmission. The genetic basis of resistance to malaria in wild mosquitoes will be explored. Evolutionary patterns in mosquito defense genes will be used to identify proteins that coevolve with malaria parasites. This work may suggest genetic targets that could be manipulated to limit malaria transmission.