Doctoral Dissertation Research: Signatures of past selection for identification of pathogen-related loci

人类的人口历史是由许多因素塑造的，包括病原体的经验。 这个博士论文项目调查了过去自然选择事件的基因组特征，以确定导致当前对蚊子传播的病原体的易感性和抗性的潜在遗传因素。该项目的人类学遗传学和进化医学方法将促进对人类人口历史，古病理学和古流行病学的了解，并为日益威胁包括美国在内的地区的蚊媒病原体的临床研究和政策提供信息。该项目还将支持培训和指导来自STEM领域代表性不足的群体的学生，国际研究合作以及公共科学和健康教育和外展。 登革热病毒是一种蚊子传播的RNA病原体，与黄热病和西尼罗河病毒有关。它在亚热带和热带环境中广泛传播，估计每年感染人数高达3.9亿，导致2.5万人死亡。研究人员的目标是通过调查过去在中美洲人（n=360）基因组中留下自然选择签名的进化事件，确定玛雅/拉迪诺人群中导致登革热病毒易感性和抗性的宿主遗传因素。该项目的目标是确定：1）登革热感染的宿主遗传风险因素; 2）疾病进展的宿主遗传风险因素; 3）通过两种分子（细胞因子和生长因子）测量有助于免疫反应的遗传变异。对于遗传分析，将检测384种遗传变异与感染状态、疾病进展和免疫反应的相关性。这项研究的结果将为其他有兴趣使用进化观点研究现代传染病的研究人员提供一个框架。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Human population history has been shaped by many factors, including pathogen experience. This doctoral dissertation project investigates genomic signatures of past natural selection events to identify potential genetic factors contributing to current susceptibility and resistance to a mosquito-borne pathogen. The project's anthropological genetics and evolutionary medicine approaches will advance knowledge about human population history, paleopathology, and paleoepidemiology, and inform clinical research and policy on mosquito-borne pathogens that increasingly threaten regions including the United States. The project will also support training and mentoring of students from groups underrepresented in STEM fields, international research collaborations, and public science and health education and outreach. Dengue virus is a mosquito-borne RNA pathogen related to yellow-fever and West Nile virus. It is widespread in sub-tropic and tropic environments, with estimates as high as 390 million infections annually, resulting in 25,000 deaths. The investigators aim to identify host genetic factors contributing to dengue virus susceptibility and resistance in a Maya/Ladino population, by investigating past evolutionary events that left signatures of natural selection in the genomes of Mesoamericans (n=360). The project goals are to identify: 1) host genetic risk factors for dengue infection; 2) host genetic risk factors for disease progression; and 3) genetic variants contributing to immune response measured via two molecules, cytokines and growth factors. For genetic analysis, 384 genetic variants will be tested for associations with infection status, disease progression, and immune response. The results from this study will provide a framework for other researchers interested in studying modern infectious diseases using evolutionary perspectives.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.