Ancient American tuberculosis: origin(s), spread, and replacement

人类和其他动物之间的病原体交换由来已久，最近的例子包括艾滋病毒、SARS、流感病毒和鼠疫耶尔森氏菌(导致鼠疫)。今天，特别是在发展中国家，人类及其驯养的动物继续侵占野生动物的栖息地，随着接触的增加，跨物种传播(或“溢出”)的机会越来越大。该项目将深入了解病原体适应新宿主的过程以及过去人类迁徙和相互作用对病原体传播的影响。特别是，该项目将使用古代DNA和骨骼分析来调查人类迁徙事件和结核分枝杆菌毒力的可能变化如何在人类进化史上促进结核病的传播，并对结核病可能如何从动物传播到人类以及从东半球传播到美洲提出具体的假设。更好地了解分枝杆菌的进化史，如那些导致结核病和麻风的分枝杆菌，可以为其他有兴趣开发临床治疗方法的研究人员提供见解。由于人类结核病(及其后代)对其他物种产生了深远的影响，因此也是一个保护问题。在这个项目中，本科生和研究生都将接受分子技术和数据分析方面的培训。生成的数据将存储在公共数据库中，如GenBank，数据分析的结果将以学术文章和公众可访问的格式发表。该项目将识别、记录和采样285具结核病特征的骨骼病变的遗骸，这些遗骸可以追溯到欧洲在美洲接触之前和之后。然后，将使用新开发的方法从这些样本中提取DNA，并对古代病原体基因组进行靶标和测序。我们已经组建了一个由古代DNA、生物考古学、生物信息学和种群遗传学方面的专家组成的团队，以解决两个具体目标。第一个是研究美洲致病分枝杆菌，特别是结核分枝杆菌复合体(MTBC)的地理模式。具体地说，我们将测试秘鲁和南美的史前结核病是否是Pinnipedii进入人类的一次跳跃的结果，如果北美的史前结核病是由与古代南美洲发现的M.pinnipedii菌株关系最密切的MTBC菌株引起的，以及在接触前墨西哥的非典型骨骼病理标本中发现的菌株是否是M.lepromatsis(一种新发现的导致非典型麻风的分枝杆菌菌株)。第二个目标是通过时间辨别分枝杆菌适应人类的信号。为此，我们将检验以下假设：1)在南美洲“跳入”人类的人畜共患病的Pinnipedii菌株(S)显示出表明适应这种新宿主的选择迹象，以及2)美洲当地的分枝杆菌菌株在相对较短的时间内被更强的毒力菌株所取代(例如：在接触后/在新大陆的贸易增加)。从古代样本中获得的基因组数据以及从现代菌株中获得的比较数据将被用于构建这些病原体的系统发育图，评估美洲各地(以及整个时间)的多样性模式，并测试选择的信号。MTBC和其他分枝杆菌随着时间的推移在人类体内的适应模式是令人感兴趣的，因为它有助于理解这些生物的成功及其未来可能的轨迹。

The exchange of pathogens between humans and other animals has been longstanding, and recent examples include HIV, SARS, flu viruses, and Yersinia pestis (which causes the plague). Today, especially in the developing world, humans and their domesticated animals continue to encroach upon wild animal habitats, with opportunities for cross-species transmission (or "spillover") expanding as exposure increases. This project will provide insight into the process by which pathogens adapt to new hosts and the impact of human migration and interaction on the spread of pathogens in the past. In particular, the project will use ancient DNA and skeletal analyses to investigate how human migration events and possible changes in virulence of M. tuberculosis strains have facilitated the spread of tuberculosis (TB) during human evolutionary history, with specific hypotheses about how tuberculosis may have been transmitted from animals to humans, and from the Old World to the Americas. A better understanding of the evolutionary history of mycobacteria such as those causing TB and leprosy can provide insights for other researchers interested in developing clinical treatments. Because human TB (and its descendants) has had a profound impact on other species, it is thus also a conservation concern. During this project, both undergraduate and graduate students will be trained in molecular techniques and data analysis. The data generated will be deposited in public databases such as GenBank, and the results of data analyses will be published in scholarly articles as well as in formats accessible to the general public.This project will identify, document, and sample 285 remains with skeletal lesions characteristic of TB that date to before and after European contact in the Americas. Newly developed methods will then be used to extract DNA from these samples, as well as to target and sequence the ancient pathogen genomes. We have assembled a team of experts in ancient DNA, bioarchaeology, bioinformatics, and population genetics to address two specific aims. The first is to examine the geographic patterning of pathogenic mycobacteria, particularly M. tuberculosis complex (MTBC), in the Americas through time. Specifically, we will test whether prehistoric TB in Peru and South America were the result of a single jump of M. pinnipedii into humans, if prehistoric TB in North America was caused by MTBC strains that are most closely related to M. pinnipedii strains found in ancient South Americans, and whether strains found in specimens with atypical skeletal pathologies from pre-contact Mexico are M. lepromatosis (a newly discovered strain of mycobacteria that causes atypical leprosy). The second aim is to discern signatures of adaptation to humans by mycobacteria through time. For this aim, we will test the hypotheses that 1) the zoonotic M. pinnipedii strain(s) that "jumped" into humans in South America shows signs of selection that indicate adaptation to this new host and 2) local mycobacterial strains in the Americas were replaced by more virulent strains at contact over a relatively short time period (ex: following contact/increased trade in the New World). The genome data obtained from the ancient samples along with comparative data from modern strains will be used to construct phylogenies of these pathogens, to assess patterns of diversity across the Americas (and through time), and to test for signals of selection. The pattern of adaptation of the MTBC and other mycobacteria in humans over time is of interest since it helps understand the success of these organisms and their possible future trajectories.