Evolutionary Genomics of Anti-Malaria Genes in Mosquito

描述（由申请人提供）：疟疾是一种毁灭性的全球杀手，人与人之间的疾病传播必然通过少数有能力的媒介蚊子进行。蚊子对存在于被感染血液中的疟疾寄生虫形成强有力的免疫防御。这通常会导致寄生虫高但不完全的死亡率。野生蚊子种群在抑制寄生虫发育的能力上存在相当大的遗传变异，因此一些个体对传播完全不敏感，而另一些个体则高度敏感。由于疟疾感染，蚊子承受了可测量的健康成本，这表明有效的免疫防御具有潜在的选择优势。根据这一建议，我们将探索冈比亚按蚊（Anopheles gambiae）对疟疾自然抗性的遗传基础，冈比亚按蚊是人类疟疾最常见和最具破坏性的媒介。这将通过基因型-表型关联研究来完成，测试60个疟疾应答候选基因多态性与寄生虫抑制表型测量之间的统计相关性。其中20个候选基因将在多个按蚊物种中进行深入的种群遗传分析。焦点按蚊种将被选择为不同的媒介/非媒介对，其中非媒介在系统发育上嵌套在媒介中。收集到的数据将得出该物种的基本种群遗传特征，这些特征都没有从种群遗传角度得到充分描述，并将允许对自然选择驱动的适应进行测试。所检查的物种的系统发育结构将允许对与暴露于人类疟疾有关的自然选择进行强有力的分子进化测试。这一提议的三个目标的整合将产生一个关于按蚊物种和疟疾寄生虫之间共同进化的全面观点，并将突出宿主和寄生虫之间共同进化“紧张”的要点，在这些要点上，有针对性的人类干预可能打破平衡，破坏疾病传播。

DESCRIPTION (provided by applicant): 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.