Doctoral Dissertation Research: Genetic Adaptation to Disease: Tuberculosis Susceptibility in Native South Americans

生物人类学家长期以来一直对疾病易感性的人口差异问题感兴趣，但美洲原住民社区历来在宿主-病原体共同进化的研究中代表性不足。鉴于古病理学中关于新世界结核病起源的长期未决争议，纳入这些群体对于了解这种疾病的演变及其对土著社区的历史和当前影响至关重要。美洲原住民人口中的结核病发病率自欧洲接触以来一直很高，美洲原住民的极端易感性传统上被认为是前哥伦布时期结核病的证据，但最近的研究证实了在欧洲接触之前新大陆存在这种疾病。因此，美洲原住民群体的易感性必须作为对其他环境因素的潜在适应机制进行研究。对世界其他人群进行的研究提供的越来越多的证据表明，宿主遗传学和环境的复杂相互作用在决定结核病易感性方面发挥着重要作用。例如，在迄今为止研究的亚洲、非洲和欧洲人群中，多个基因涉及易感性，并且这些基因因人群而异。本文探讨了宿主遗传学和环境因素在结核病易感性在巴拉圭的Ache的作用。将分析其他人群中与结核病相关的候选基因（维生素D受体、天然耐药相关巨噬细胞蛋白和甘露糖结合凝集素）与结核病的联系。该项目的科学价值在于，它是第一个对美洲原住民进行的大规模研究，纳入了广泛的谱系、人口统计和流行病学数据，以研究结核病易感性的遗传和环境原因。纵向性质的数据集将允许检查潜在的遗传原因的高案件率在美洲原住民人口相对于欧洲的。在更广泛的层面上，这个项目可以作为一个模型，检查结核病的易感性，在其他美洲土著群体，类似的基因座可能涉及。通过在一个尚未被研究的美洲原住民群体中确定与结核病易感性有关的基因座，这里提出的研究可以增加关于人类群体及其病原体共同进化的越来越多的信息。在个人层面，将培训一名研究生和一名本科生助理。在人口水平上，可能会对Ache和其他南美土著社区产生健康和经济后果，这些社区在这类研究中的代表性不足。土著社区的疾病易感性不仅仅是一个生物学问题：高发病率导致社会混乱和经济生产力的损失。关于疾病易感性的遗传与环境原因的信息可能是未来公共卫生战略的关键。

Biological anthropologists have long been interested in the question of population differences in disease susceptibility, but Native American communities have historically been underrepresented in research on host-pathogen co-evolution. Given that a longstanding, unresolved controversy in paleopathology concerns the origin of New World tuberculosis, inclusion of these groups is of utmost importance to the understanding of the evolution of this disease and its historical and current impact on native communities. Tuberculosis incidence in Native American populations since European contact has been high, and extreme susceptibility of Native Americans was traditionally considered evidence against pre-Columbian tuberculosis, but recent studies confirm presence of the disease in the New World prior to European contact. Thus, susceptibility of Native American groups must be examined as a potential adaptive mechanism to other environmental factors. Mounting evidence from research performed on other world populations indicates that a complex interplay of host genetics and the environment play an important role in determining tuberculosis susceptibility. In Asian, African and European populations studied to date, for example multiple genes are involved in susceptibility, and these genes differ by population. This dissertation examines the role of host genetics and environmental factors in tuberculosis susceptibility in the Ache of Paraguay. Candidate genes associated with tuberculosis in other populations (vitamin D receptor, natural resistance-associated macrophage protein, and mannose binding lectin) will be analyzed for linkage to tuberculosis. The scientific merit of this project is that it is the first large-scale study of Native Americans to incorporate extensive pedigree, demographic and epidemiological data to examine genetic and environmental causes of tuberculosis susceptibility. The longitudinal nature of the data set will allow examination of the underlying genetic causes of the high case rates in Native American populations relative to European ones. At a broader level, this project can serve as a model for examining susceptibility to TB in other Native American groups in that similar loci may be involved. The research proposed here can add to the growing body of information on the co-evolution of human populations and their pathogens by identifying loci that are involved in TB susceptibility in an as yet unexamined Native American group.The broader impact of this research can be divided into two stages. At an individual level, a graduate student, and an undergraduate assistant will be trained. At the level of the population, there may be health and economic consequences for Ache and perhaps other native South American communities, who have been underrepresented in this type of research. Disease susceptibility in native communities is more than a biological question: high rates of disease lead to social disruption and loss of economic productivity. Information about genetic vs. environmental causes of disease susceptibility may be key for future public health strategies.