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物种进行。蚊子对存在于被感染的血液中的疟疾寄生虫进行了强有力的免疫防御。这通常导致高但不完全的寄生虫死亡率。野生蚊子种群在抑制寄生虫发育的能力方面因相当大的遗传变异而分离，使得一些个体对传播完全难治，而另一些个体高度易感。蚊子遭受可测量的健身成本作为疟疾感染的结果，这表明有效的免疫防御的潜在选择优势。根据这项建议，我们将探索冈比亚按蚊对疟疾的天然抵抗力的遗传基础，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中的多态性与寄生虫抑制的表型测量之间的统计相关性。20个候选基因将在多个按蚊物种中进行深入的群体遗传分析。将选择重点按蚊种属作为不同的载体/非载体对，其中非载体在载体内进行遗传嵌套。收集的数据将导致物种的基本群体遗传特征，其中没有一个从群体遗传角度得到充分描述，并将允许测试自然选择驱动的适应性。物种的系统发育结构检查将允许强大的分子进化测试自然选择，特别是与人类疟疾的接触。这一建议的三个目标的整合将产生一个全面的观点按蚊物种和疟疾寄生虫之间的共同进化，并将突出点的共同进化的“张力”之间的主机和寄生虫，有针对性的人类干预可能会打破平衡，破坏疾病的传播。 将探索野生蚊子对疟疾的抗性的遗传基础。蚊子防御基因的进化模式将被用来识别与疟原虫共同进化的蛋白质。这项工作可能表明可以操纵基因靶点来限制疟疾传播。

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.