Next generation sequencing of East African trypanosomes to expand the molecular e

描述（由申请人提供）：非洲人类锥虫病，又称昏睡病，是一种影响撒哈拉以南非洲成千上万人的人畜共患疾病，周期性流行病造成了重大的社会和经济破坏。导致昏睡病的锥虫在形态上与在动物中发现的密切相关的寄生虫难以区分，导致人们对人类疾病暴发的起源感到困惑。该项目旨在改进现有的工具，以了解这种被忽视疾病的流行病学。当前的目标是开发一套可靠和广泛适用的遗传标记，并在乌干达的一项试点研究中验证这些标记，乌干达是一个目前正在经历严重流行病的疾病流行国家。本项目将采用多个锥虫基因组的下一代测序，选择包括在初步研究中观察到的锥虫之间复杂的进化关系。将评估从基因组比较中鉴定出的遗传多态性，以确定它们在乌干达疾病焦点中精细规模种群结构和区分人类感染寄生虫和动物限制寄生虫的能力。从长期来看，本项目开发的标记将为以下方面提供基础：对自然界中锥虫的全部多样性进行编目，确定与人类疾病最相关的锥虫库，以及描述分布在东非各地的锥虫种群之间的关系。此外，比较动物限制性锥虫和引起人类疾病的锥虫的基因组将有助于深入了解赋予人类传染性的功能遗传差异。

DESCRIPTION (provided by applicant): Human African trypanosomiasis, also known as sleeping sickness, is a zoonotic disease affecting thousands of people across sub-Saharan Africa and periodic epidemics have caused significant social and economic disruption. The trypanosome responsible for sleeping sickness is morphologically indistinguishable from closely related parasites found in animals, leading to confusion regarding the origins of human disease outbreaks. This project seeks to improve the tools available for understanding the epidemiology of this neglected disease. The immediate aims are to develop a robust and broadly applicable panel of genetic markers and to validate these in a pilot study in Uganda, a disease-endemic country currently experiencing a severe epidemic. This project will employ next-generation sequencing of multiple trypanosome genomes, selected to encompass the complicated evolutionary relationships observed among trypanosomes in preliminary studies. The genetic polymorphisms identified from genome comparisons will be evaluated for their ability to resolve fine scale population structure and to distinguish between human-infective and animal-restricted parasites in the Ugandan disease focus. In the longer term, the markers developed in this project will provide a foundation for cataloguing the full diversity of trypanosomes in nature, for identifying the pool of trypanosomes that are most relevant for human disease, and for characterizing the relationships among trypanosome populations distributed across eastern Africa. In addition, comparisons among the genomes of animal-restricted and human-disease causing trypanosomes will provide insight into the functional genetic differences conferring human infectivity. PUBLIC HEALTH RELEVANCE: This project, which seeks to develop new molecular markers for understanding human sleeping sickness in eastern sub-Saharan Africa, will provide a universal diagnostic platform for monitoring parasites found in animal reservoirs with respect to important traits such as human infectivity, disease severity and drug resistance. In addition, this project will enable future population genetic studies aimed at identifying major social, evolutionary and ecological forces influencing disease transmission. This information will help to identify optimal methods for preventing and controlling disease outbreaks.