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

古代美洲的恰加斯病：通过分子和考古记录调查过去和现在的人类寄生

• 批准号: 1513501
• 负责人: Lars Fehren-Schmitz
• 金额: $ 21.76万
• 依托单位: University of California-Santa Cruz
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1513501&HistoricalAwards=false
• 关键词: Chagas; Disease; ancient; Americas; Investigating

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.

社会，行为和经济科学局提供了博士后研究奖学金，为最近的博士毕业生提供了获得额外培训的机会，以在既定科学家的赞助下获得研究经验，并将其科学视野扩大到本科生和研究生培训之外。博士后奖学金的进一步旨在帮助新科学家在传统的纪律线上指导他们的研究工作，并利用独特的研究资源，站点和设施，包括在外国地点。这项博士后奖学金训练跨学科的科学家探索与美洲木马疾病出现相关的进化和人为过程。查加斯病（CD）是由一种新世界寄生虫引起的，该寄生虫自我们最早进入美洲以来一直感染了人类。 15，000年前。如今，由于克鲁兹锥虫锥虫锥虫的原因，主要在拉丁美洲感染了数百万人。 CD提出了一项新的全球挑战，因为它的持续传播是由于气候变化和人类活动的促进，威胁着非流行国家，仅在美国就引起了300,000次感染。尽管可用于急性感染的治疗，但慢性形式可能导致心脏和消化器官衰竭。早在9，000年前，南美考古人类遗体就已经认可了临床表现。尽管可用的遗传数据增加了，但克鲁兹的进化史和夏加斯疾病出现的时机仍未解决。该项目将新颖的古生物学方法应用于哥伦布省南美人类遗体中的t. cruzi靶标，以测试有关人适应谱系的起源，时机和分散的假设。对于当代社会而言，研究小组还探索了与美国CD在美洲CD的出现和持久性相关的自然因素（即气候变化）因素（即气候变化）因素（即气候变化）因素。生活和社会科学（包括计算生物学）的跨学科合作和培训对于成功至关重要。研究期间生成的所有序列数据都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都可以广泛访问。结果将在经过同行评审的期刊，专业会议上以及在课堂和社区中传播，从而为研究员提供了更多机会，以继续她参与促进科学中年轻女性的外展和教育计划。通过直接获取过去人类感染的遗传学特征，我们为当代和全球健康的当代问题促进了一种“深度”方法。拟议的项目合成了生物结构，分子和生态证据，以研究Cruzi的起源和分散，并阐明了与奇加斯（Chagas）相关的Chagas sepences of Chagas seaus in nimence of Chagas se Animence of Chagas in nimence of Chagas seaus in eapervence of ChagaS seaps a at emaps eaperce semaps eaperce shimen s。虽然以前对CD的古发明分析提供了有限的遗传和系统发育信息，但在将DNA富集和高通量测序应用于考古或历史样本中后，现在可以解决能够解决提出问题的完全古代病原体基因组的分析。该项目代表了古代CD的第一个基因组规模研究。在UCSC人类古生物学实验室的专用洁净室中，“下一代”方法应用于哥伦比亚前南美前南美的广泛，良好的考古人类遗体集合，其中包括带有CD临床迹象的样品。对于每个人，在从骨骼，牙齿或组织中提取DNA之后，立即构建了独特的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；可以将“永生”的图书馆永久重新扩增，从而重新用于新实验并与其他研究人员共享。病原体DNA通常代表文库中内源性分子的0.1％。富集方法用于靶向和仅捕获感兴趣的序列，从根本上改善了恢复t. cruzi DNA的可能性。研究团队使用了能够与高度受损，降解的DNA充满测序误差的最新计算方法，可与下一代数据，帮助我们建立真实性，并产生高质量的输出以在进化分析中使用。通过从时间stamp的序列数据得出的校准点，它们可以估计突变速率，将系统发育与公开可用的现代T. cruzi DNA以及整合杂体数据的方法以及用于测试有关人类适应性T. Cruzi的演化的当前假设的日期差异事件的方法。随着新世界几千年中过去几千年的古学记录和考古记录的增加，该研究员的目的是在面对文化和环境状况的变化时就CD的古ePidemiologicy模式提供历时性观点。