We are studying the molecular genetics of Anopheles gambiae in order to understand the biological basis of its status as the world's most successful vector of human malaria and to develop new methods of controlling malaria parasites by interfering with their sporogonic development. Collaborative efforts are underway to map and eventually clone several naturally occurring malaria refractoriness genes causing melanotic encapsulation of oocysts. We found that a gene involved in encapsulation of Plasmodium cynomolgi Ceylon, differing from all genes known to be required for encapsulation of P. cynomolgi B, is linked to a cluster of functionally related genes including Diphenol oxidase-A2 and Dopa decarboxylase, both of which are necessary for melanin production. We are mapping this gene more precisely using QTL analysis. We are also studying Dox-A2 and Ddc expression in malaria infected and uninfected, susceptible and refractory mosquitoes. A second major project in the lab involves characterization of the regulation of transcription of Vitellogenin genes when adult females take a blood meal. These sequences might be exploited to drive appropriate expression of a malaria toxin gene in transgenic mosquitoes. Since Vg gene transcript abundance is reduced by about 33% when malaria parasites are developing in A. gambiae females, a phenomenon known as parasite-induced fecundity reduction, we are also beginning to study whether malaria parasites are the direct cause, and, if so, whether they exert this effect through down-regulation of initiation of transcription of Vg genes, through decreasing Vg mRNA stability or both.