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

社会、行为和经济科学司提供博士后研究奖学金，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，并扩大他们在本科和研究生训练之外的科学视野。博士后奖学金的进一步设计是为了帮助新科学家指导他们跨越传统学科线的研究工作，并利用他们自己独特的研究资源、地点和设施，包括在国外的研究地点。该博士后奖学金培养一名跨学科科学家，探索与美洲恰加斯病出现有关的进化和人为过程。恰加斯病（Chagas Disease， CD）是由一种新世界的寄生虫引起的，自从人类最早在1.5万年前迁徙到美洲以来，这种寄生虫就一直感染着人类。今天，病原体克氏锥虫感染了数百万人，主要是在拉丁美洲。由于气候变化和人类活动的推动，乳糜泻不断蔓延，威胁到非流行国家，仅在美国就造成30万人感染，这给全球带来了新的挑战。虽然急性感染可以治疗，但慢性感染会导致心脏和消化器官衰竭。早在9000年前的南美洲考古人类遗骸中就发现了这种临床表现。尽管现有的遗传数据有所增加，但克氏锥虫的进化史和恰加斯病的出现时间仍未得到解决。该项目采用新颖的古基因组学方法，以在南美前哥伦布时代发现的人类遗骸中的克氏锥虫为目标，测试有关人类适应谱系的起源、时间和分布的假设。对当代社会更为重要的是，研究小组还探讨了与美洲CD出现和持续相关的人为因素（即人类行为、景观利用、社会结构、生存）和自然因素（即气候变化）。来自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成功至关重要。研究过程中产生的所有序列数据将存储在公共数据库中，供学生、临床研究人员和更大的科学界广泛访问。研究结果将在同行评议的期刊上、专业会议上、课堂上和社区内发表，为研究人员提供额外的机会，继续参与推广和教育项目，促进年轻女性在科学领域的发展。通过提供对过去人类感染的遗传特征的直接访问，我们促进对当地和全球健康的当代问题采取“深度时间”方法。拟议的项目综合了生物考古、分子和生态证据，以审查克氏锥虫的起源和传播，并阐明与美洲恰加斯病出现有关的进化和人为过程。虽然以前的古成因分析提供了有限的遗传和系统发育信息，但随着DNA富集和高通量测序在考古或历史样本中的应用，能够解决所提出问题的完整古代病原体基因组分析现在成为可能。该项目代表了古代CD的第一个基因组规模研究。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考古人类遗骸的广泛，背景良好的收集，包括鉴定出CD临床症状的样本。对于每个个体，从骨骼，牙齿或组织中提取DNA后，立即构建独特的DNA测序库。图书馆建设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通常在文库中只占不到0.1%的内源性分子；富集方法用于靶向和捕获感兴趣的序列，从根本上提高了恢复克氏T. DNA的可能性。研究团队使用最新的计算方法，能够处理来自高度受损、降解、充满测序错误的DNA的下一代数据，帮助我们建立真实性，并产生用于进化分析的高质量输出。利用从带有时间戳的序列数据中获得的校准点，他们可以估计突变率，利用整合异时数据的方法，与公开可用的现代克氏锥虫DNA一起重建系统发育，并确定用于测试有关人类适应克氏锥虫进化的当前假设的分歧事件的日期。通过对新大陆过去几千年的古生态记录和考古背景的研究，该研究员旨在为面对不断变化的文化和环境条件下的CD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.