Chagas Disease in the ancient Americas: Investigating past to present human parasitism through the molecular and archaeological record

社会、行为和经济科学理事会提供博士后研究金，为最近的博士毕业生提供获得额外培训的机会，在知名科学家的赞助下获得研究经验，并在本科和研究生培训之外拓宽他们的科学视野。博士后奖学金还旨在帮助新的科学家指导他们的研究工作，跨越传统的学科领域，并利用独特的研究资源，地点和设施，包括在国外的地点。这个博士后奖学金培养了一个跨学科的科学家，探索与美洲恰加斯病出现相关的进化和人为过程。恰加斯病（CD）是由一种新世界寄生虫引起的，自从我们最早的移民到美洲以来，这种寄生虫就感染了人类。一万五千年前。今天，病原体克氏锥虫感染了数百万人，主要是在拉丁美洲。CD提出了一个新的全球挑战，因为它在气候变化和人类活动的推动下持续传播，威胁到非流行国家，仅在美国就造成30万例感染。虽然急性感染可以治疗，但慢性感染可能导致心脏和消化器官衰竭。早在9,000年前，南美洲的考古人类遗骸就已经认识到了这种临床表现。尽管可用的遗传数据增加，T。cruzi和恰加斯病出现的时间仍然没有解决。该项目应用新的古基因组学方法靶向T。在前哥伦布时期的南美洲发现的人类遗骸中发现了cruzi，以测试关于人类适应谱系的起源，时间和传播的假设。对当代社会更重要的是，研究小组还探讨了与美洲CD的出现和持续相关的人为（即人类行为，景观使用，社会结构，生存）和自然（即气候变化）因素。生命科学和社会科学（包括计算生物学）的跨学科合作和培训对于成功至关重要。研究期间产生的所有序列数据将存放在公共数据库中，学生，临床研究人员和更大的科学界可以广泛访问。结果将在同行评审的期刊上，在专业会议上，以及在课堂和社区内传播，为研究员提供更多的机会，继续参与促进年轻女性参与科学的推广和教育计划。通过提供对过去人类感染的遗传特征的直接访问，我们促进了对当代地方和全球健康问题的“深时间”方法。cruzi和照亮的进化和人类活动的过程与美洲锥虫病的出现。虽然以前的古遗传学分析CD提供有限的遗传和系统发育信息，完整的古代病原体基因组的分析能够解决提出的问题，现在可能的应用DNA富集和高通量测序考古或历史样本。该项目代表了第一个古CD的基因组规模研究。在UCSC人类古基因组学实验室的专用洁净室中，“下一代”方法被应用于前哥伦布时期南美洲考古人类遗骸的广泛，良好的背景收集，包括鉴定出CD临床症状的样本。对于每个个体，在从骨骼、牙齿或组织提取DNA后立即构建独特的DNA测序文库。图书馆建设的过程有效地将样本转化为可再生资源;“不朽”的图书馆可以永远被重新放大，从而重新用于新的实验，并与其他研究人员共享。病原体DNA通常代表文库中不到0.1%的内源性分子;富集方法用于靶向和仅捕获感兴趣的序列，从根本上提高了回收T的可能性。克鲁兹基因研究团队使用最新的计算方法，能够面对来自高度受损、降解的DNA的下一代数据，这些数据充满了测序错误，帮助我们建立真实性，并产生高质量的输出用于进化分析。通过从时间戳序列数据中获得的校准点，他们可以估计突变率，重建与公开可用的现代T。cruzi DNA的方法，整合异源数据，和日期分歧事件用于测试目前的假设，关于人类适应T。克鲁兹随着新世界过去几千年的古生态记录和考古背景的增加，该研究员的目标是在不断变化的文化和环境条件下，对CD的古流行病学模式提供一个历时性的视角。

The Directorate of Social, Behavioral and Economic Sciences offers postdoctoral research fellowships to provide opportunities for recent doctoral graduates to obtain additional training, to gain research experience under the sponsorship of established scientists, and to broaden their scientific horizons beyond their undergraduate and graduate training. Postdoctoral fellowships are further designed to assist new scientists to direct their research efforts across traditional disciplinary lines and to avail themselves of unique research resources, sites, and facilities, including at foreign locations. This postdoctoral fellowship trains an interdisciplinary scientist exploring the evolutionary and anthropogenic processes associated with the emergence of Chagas Disease in the Americas.Chagas Disease (CD) is caused by a New World parasite that has infected humans since our earliest migrations into the Americas c. 15,000 years ago. Today the causative agent, Trypanosoma cruzi, infects millions of people, primarily in Latin America. CD presents a new global challenge as its continual spread, facilitated by climate change and human activity, threatens non-endemic countries, causing 300,000 infections in the US alone. While treatment is available for acute infections, the chronic form can result in cardiac and digestive organ failure. The clinical manifestations have been recognized in archaeological human remains from South America as early as 9,000 years ago. Despite the increase of available genetic data, the evolutionary history of T. cruzi and the timing of the emergence of Chagas Disease remain unresolved. This project applies novel paleogenomic methods to target T. cruzi in human remains found in pre-Columbian South America to test hypotheses regarding the origins, timing and dispersal of human-adapted lineages. More critical for contemporary society, the research team also explores the anthropogenic (i.e. human behavior, landscape use, social structure, subsistence) and natural (i.e. climate change) factors associated with the emergence and persistence of CD in the Americas. Interdisciplinary collaboration and training from both life and social sciences, including computational biology, is critical for success. All sequence data generated during the research will be deposited on public databases, broadly accessible to students, clinical researchers and the greater scientific community. Results will be disseminated in peer-reviewed journals, at professional meetings, and within the classroom and community, providing the fellow with additional opportunities to continue her participation in outreach and educational programs that promote young women in science. By providing direct access to the genetic signatures of past human infection, we promote a "deep-time" approach to contemporary issues of local and global health.The proposed project synthesizes bioarchaeological, molecular and ecological evidence to examine the origins and dispersal of T. cruzi and illuminate the evolutionary and anthropogenic processes associated with the emergence of Chagas Disease in the Americas. While previous paleogenetic analyses of CD offer limited genetic and phylogenetic information, analyses of complete ancient pathogen genomes capable of addressing the proposed questions are now possible following the application of DNA enrichment and high-throughput sequencing to archaeological or historic samples. This project represents the first genome-scale study of ancient CD. In the dedicated cleanroom at the UCSC Human Paleogenomics Lab, "next-gen" methods are applied to an extensive, well-contextualized collection of archaeological human remains from pre-Columbian South America, including samples identified with clinical signs of CD. For each individual, a unique DNA sequencing library is constructed immediately following DNA extraction from the bone, tooth or tissue. The process of library construction effectively transforms samples into renewable resources; "immortalized" libraries can perpetually be re-amplified and thus repurposed for new experiments and shared with other researchers. Pathogen DNA often represents less than 0.1% of endogenous molecules in a library; enrichment methods are employed to target and capture only sequences of interest, radically improving the likelihood of recovering T. cruzi DNA. The research team uses the latest computational methods capable of confronting next-generation data from highly damaged, degraded DNA fraught with sequencing errors, helping us to establish authenticity, and producing high quality output to use in evolutionary analyses. With calibration points derived from the time-stamped sequence data, they can estimate mutation rates, reconstruct phylogenies alongside publicly available modern T. cruzi DNA with methods that integrate heterochronous data, and date divergence events used to test current hypotheses regarding the evolution of human-adapted T. cruzi. With the addition of paleoecological records and the archaeological context of the past several millennia in the New World, the Fellow aims to provide a diachronic perspective on the paleoepidemiological patterns of CD in the face of changing cultural and environmental conditions.