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General Description The overall research focus of the lab is the population and molecular genetics of insect vectors of human disease. We have developed a program that pursues knowledge that may be applied to the control of vectorborne diseases but at the same time addresses critical issues in basic evolutionary genetics. An additional goal is the application of cutting edge molecular biological methods to problems at the level of populations. Research efforts involve both field and laboratory based research. Over the past several years we have conducted extensive fieldwork in Mali, Cameroon, Brazil, Costa Rica and Nicaragua. The Laboratory of Vector Genetics is directed by UC Davis medical entomologist Gregory Lanzaro, a professor in the Department of Pathology, MIcrobiology and Immunology (PMI) of the School of Veterinary Medicine, University of California, Davis. He also directs the statewide UC Mosquito Research Program, a statewide program of the UC Division of Agriculture and Natural Resources and the UC Mosquito Research Program affiliate, the UC Malaria Research and Control Group. Laboratory specialist: Claudio Meneses Research Anopheles gambiae Population Genetics
Malaria is one of the most important infectious diseases of humans with more than 300 million clinical cases and 2-3 million deaths per year, most of these in Africa. Anopheles gambiae is one of the most potent malaria vectors known. This species has a broad geographic distribution, occurring throughout sub-Saharan Africa [Figure 2]. An. gambiae has three pairs of chromosomes, including two autosomes and X/Y sex chromosomes. Like Drosophila the chromosomes in some tissues exist as large polytene chromosomes with distinctive patterns of bands [Figure 3]. Cytogenetic studies based on microscopic examination of the polytene chromosomes have revealed extensive polymorphism in the form of chromosome inversions [Figure 4]. Earlier work describing the distribution of inversions suggested the existence of subpopulations, identified as “chromosomal forms,” among which gene flow is severely restricted [Figure 5]. Our research on populations of An. gambiae in Africa is centered on understanding their complex genetic structure. This work is conducted both at field sites in Africa and in our lab located on the 6th floor of Storer Hall at UC Davis. Our fieldwork in Africa includes sites in both Mali and Cameroon [Figure 6]. Using microsatellite DNA markers [Figure 7] we have been able to show that levels of divergence (gene flow) among the chromosomal forms is not uniformly distributed over the genome, being significantly higher at loci within inversions compared to elsewhere in the genome [Figure 8]. These results are important because (1) they suggest selection on loci contained within inversions and (2) that subpopulations may not be maintained by assortative mating alone. By analyzing DNA from sperm recovered from mated females [Figure 9] collected in the field we were able to demonstrate strong assortative mating with respect to chromosomal form, but that reproductive isolation is far from complete. Our current efforts include the development of methods for mapping the spatial boundaries of An. gambiae demes in Mali and Cameroon by incorporating genetic data into GIS maps (in collaboration with Dr. Charles Taylor, Biology Department and Dr. Xong-Kang Xue, Department of Geography both at UCLA). This effort involves extensive field work to obtain field collected mosquitoes from many locations in Mali and Cameroon [Figure 10]. Sand Flies and Leishmaniasis
This research project deals with understanding the complex interactions between insect vectors, pathogens and vertebrate hosts. We use sand flies and leishmaniasis as our model system, and are focusing on how these interactions may be understood at the molecular level by studying salivary proteins and the genes that encode them. The saliva of blood feeding insects contains a fascinating array of proteins that have potent anti-hemostatic activities. Hemostasis describes a collection of complex biochemical pathways that act to inhibit blood loss due to trauma. Hemostasis includes blood clotting, coagulation and vasoconstriction. In addition to their role as anti-hemostatic agents many of these substances are immunomodulators, that is they inhibit the host immune system. We work with one small protein, known as maxadilan (MAX) [Figure 11] that occurs in the saliva of the sand fly, Lutzomyia longipalpis [Figure 12]. This sand fly is the vector of the parasite, Lesihmania chagasi, causative agent of visceral leishmaniasis in Latin America [Figure 13]. MAX is a potent vasodilator (in fact the most potent vasodilator known). In addition, MAX inhibits macrophage function. It has been shown that MAX is important in the pathogenesis of L. chagasi [Figure 14] and that animals immunized with MAX are protected from L. chagasi infection [Figure 15]. It has therefore been proposed that MAX may be developed as an effective vaccine for leishmaniasis [Figure 16]. We have conducted a series of experiments in which we have shown that specific anti-MAX antibodies are produced by animals and humans exposed to Lu. longipalpis bites [Figure 17] and that these antibodies neutralize the vasodilatory activity of MAX [Figure 18]. Consequently flies feeding on animals with MAX antibodies take smaller bloodmeals [Figure 19] and lay fewer eggs than those feeding on naive animals [Figure 20]. We reasoned that flies in nature have likely evolved some means of avoiding the host immune system. We have demonstrated that MAX is hypervariable in natural fly populations [Figure 21] and that this variation represents antigenic variation [Figure 22] that has evolved in response to the challenge imposed by host antibodies. This is the first description of antigenic variation in a bloodfeeding arthropod. Lutzomyia longipalpis Population Genetics Our work on the population genetics of Lu. longipalpis was conducted in conjunction with the MAX work. We have described the genetic structure of Lu. longipalpis at over 20 sites throughout its range (from northern Argentina to southern Mexico) [Figure 23]. This work was based on isozymes and mitochondrial DNA [Figure 24]. We have shown that at least four distinct population groups occur in nature and that these probably represent species. The species status has been confirmed by experimental hybridization, which culminated in the production of sterile hybrid males [Figure 25]. In addition, close examination has revealed morphological features that are diagnostic for at least some of our putative species.
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