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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI062995-03
Application #
7480233
Study Section
Genetic Variation and Evolution Study Section (GVE)
Program Officer
Costero, Adriana
Project Start
2006-08-01
Project End
2011-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
3
Fiscal Year
2008
Total Cost
$358,691
Indirect Cost
Name
Cornell University
Department
Zoology
Type
Schools of Earth Sciences/Natur
DUNS #
872612445
City
Ithaca
State
NY
Country
United States
Zip Code
14850
Crawford, Jacob E; Riehle, Michelle M; Markianos, Kyriacos et al. (2016) Evolution of GOUNDRY, a cryptic subgroup of Anopheles gambiae s.l., and its impact on susceptibility to Plasmodium infection. Mol Ecol 25:1494-510
Crawford, Jacob E; Riehle, Michelle M; Guelbeogo, Wamdaogo M et al. (2015) Reticulate Speciation and Barriers to Introgression in the Anopheles gambiae Species Complex. Genome Biol Evol 7:3116-31
Rottschaefer, Susan M; Crawford, Jacob E; Riehle, Michelle M et al. (2015) Population genetics of Anopheles coluzzii immune pathways and genes. G3 (Bethesda) 5:329-39
Crawford, Jacob E; Rottschaefer, Susan M; Coulibaly, Boubacar et al. (2013) No evidence for positive selection at two potential targets for malaria transmission-blocking vaccines in Anopheles gambiae s.s. Infect Genet Evol 16:87-92
Crawford, Jacob E; Bischoff, Emmanuel; Garnier, Thierry et al. (2012) Evidence for population-specific positive selection on immune genes of Anopheles gambiae. G3 (Bethesda) 2:1505-19
Mitri, Christian; Vernick, Kenneth D (2012) Anopheles gambiae pathogen susceptibility: the intersection of genetics, immunity and ecology. Curr Opin Microbiol 15:285-91
Crawford, Jacob E; Lazzaro, Brian P (2012) Assessing the accuracy and power of population genetic inference from low-pass next-generation sequencing data. Front Genet 3:66
Rottschaefer, Susan M; Riehle, Michelle M; Coulibaly, Boubacar et al. (2011) Exceptional diversity, maintenance of polymorphism, and recent directional selection on the APL1 malaria resistance genes of Anopheles gambiae. PLoS Biol 9:e1000600
Fellous, Simon; Lazzaro, Brian P (2011) Potential for evolutionary coupling and decoupling of larval and adult immune gene expression. Mol Ecol 20:1558-67
Fellous, Simon; Lazzaro, Brian P (2010) Larval food quality affects adult (but not larval) immune gene expression independent of effects on general condition. Mol Ecol 19:1462-8

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