Doctoral Dissertation Improvement: Identifying Adaptations to Pathogens and the Environments of the Americas via Native American Paleogenomic Diversity

在人类生物学的理解中，最重要的是了解新的和快速变化的环境如何影响人类。 作为这种环境变化的主要假设影响的一个例子，美洲原住民对特定传染病的遗传易感性长期以来一直被认为是欧洲殖民化后疾病相关死亡率的主要因素，其中发病率达到90%以上。然而，以前的研究只研究了活着的美洲原住民的DNA变异，未能捕捉到欧洲人接触之前土著人口的遗传多样性。这使得很难检查遗传学在多大程度上促成了这种假定的易感性，因为必须完全依赖统计假设。通过直接分析生活在欧洲接触之前的古代美洲原住民的全基因组数据，本论文研究项目可以显着有助于了解人类如何在新的和快速变化的环境中与病原体相互作用，同时解决有关遗传对人类易感性/抵抗传染病的基本问题。尖端的DNA测序方法将应用于从生活在太平洋西北部的美洲原住民以及生活在欧洲接触之前的古代祖先的遗骸中收集的样本。 这种DNA测序技术的最新进展提供了成本有效地分析编码蛋白质的人类基因组的整个区域（即，外显子组）;据估计，80%的人类疾病变异预计来自这些基因组区域。 通过统计研究古代美洲原住民的相关遗传差异，该研究将允许检测自然选择特征，并最终测试美洲存在特定病原体景观的假设-其他地理区域不存在的景观。由于人类遗传适应可能在一种生态情景中被证明是有益的，但在另一种生态情景中是有害的，在这种情景中，特定的病原体能够利用特定的免疫结构，随着时间的推移观察到的变化可能有助于解释土著人民与欧洲传播的病原体的历史经验的各个方面。此外，通过本研究中使用的方法产生的数据允许测试有关基因组适应美洲其他古代环境变量（如饮食）的假设。因此，这项研究阐明了人类适应新环境的动态，在隔离和人口快速融合的背景下，同时强调了病原体在人类在地球仪扩张时所发挥的关键作用。 最后，该项目有助于提高对基因组研究的认识，并有助于培养代表性不足的少数民族对科学事业的兴趣，因为美洲原住民研究人员和学生都将参与研究和相关活动。

Of major importance in the understanding of human biology is appreciation for how novel and rapidly changing environments can impact human populations. As an example of a major presumed impact of such environmental change, the genetic susceptibility of Native Americans to specific infectious diseases has long been postulated as a major factor for disease-related mortality after European colonization, where morbidity rates reached upwards of 90%. Previous research, however, has only examined DNA variation of living Native Americans, failing to capture the genetic diversity of indigenous populations before European contact. This makes it difficult to examine the extent to which genetics contributed to this presumed susceptibility, as there must be reliance solely on statistical assumptions. By directly analyzing genome-wide data of ancient Native Americans that lived prior to European contact, this dissertation research project can significantly contribute to the understanding of how humans interact with pathogens in novel and rapidly changing environments, while addressing fundamental questions about the genetic contribution to human susceptibility/resistance to infectious disease. Cutting-edge DNA sequencing methods will be applied to samples collected from living Pacific Northwest Native Americans, as well as from the remains of their ancient ancestors who lived previous to European contact. Recent advances in such DNA sequencing techniques provide the ability to cost-effectively analyze entire regions of the human genome that code for proteins (i.e., the exome) in ancient peoples; it is these genomic areas from which an estimated 80% of human disease variation is expected to derive. By statistically examining relevant genetic differences in ancient Native Americans, the research will allow for detection of natural selection signatures and ultimately test the hypothesis that a specific pathogen landscape existed in the Americas - a landscape that was not present in other geographic regions. As human genetic adaptations may have proven beneficial in one ecological scenario but deleterious in another, where specific pathogens were capable of exploiting particular immune configurations, observed changes over time may help explain aspects of the historical experience of Native peoples with European-borne pathogens. Furthermore, the data generated through the methodology utilized in this research allows for the testing of hypotheses concerning genomic adaptations to other ancient environmental variables in the Americas, such as diet. This research, therefore, illuminates the dynamics of human adaptation to new environments, in both the context of isolation and rapid merging of populations, while emphasizing the key role played by pathogens as humans expanded throughout the globe. And finally, this project facilitates awareness of genomic research and helps foster interest in the pursuit of careers in the sciences on the part of underrepresented minorities, as both Native American researchers and students will be involved in the research and associated activities.