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

博士论文改进：通过美洲原住民古基因组多样性识别美洲病原体和环境的适应

• 批准号: 1413551
• 负责人: Ripan Malhi
• 金额: $ 3.12万
• 依托单位: University of Illinois at Urbana-Champaign
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1413551&HistoricalAwards=false
• 关键词: Doctoral; Dissertation; Improvement; Identifying; Adaptations

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.

对人类生物学的理解至关重要的是对新颖和迅速变化的环境如何影响人群如何影响人群的主要意见。 作为这种环境变化的主要推测影响的一个例子，长期以来，美洲原住民对特定传染病的遗传敏感性一直被认为是欧洲殖民后与疾病相关的死亡率的主要因素，在欧洲殖民地殖民后，发病率达到90％以上。然而，先前的研究仅检查了活美洲原住民的DNA变化，未能捕获欧洲接触之前的土著人口的遗传多样性。这使得很难检查遗传学对这种假定易感性的贡献的程度，因为必须仅依赖统计假设。通过直接分析在欧洲接触之前居住的古代原住民的全基因组数据，该论文研究项目可以显着有助于理解人类在新颖和快速变化的环境中如何与病原体相互作用，同时解决有关人类对人类对感染疾病的遗传敏感性/抵抗的基本问题。尖端的DNA测序方法将应用于从太平洋西北部的原住民美洲原住民那里收集的样品，以及从欧洲接触之前居住的古代祖先的遗体。 这种DNA测序技术的最新进展提供了能够成本效益分析人类基因组的整个区域，以使蛋白质代码（即外显子组）在古代民族中；正是这些基因组区域估计有80％的人类疾病变异得出。 通过统计检查古代原住民的遗传差异，该研究将允许检测自然选择签名，并最终检验以下假设：美洲存在特定的病原体景观 - 在其他地理区域中不存在的景观。由于人类的遗传适应可能在一种生态场景中被证明是有益的，但在另一种生态场景中，特定的病原体能够利用特定的免疫构型，因此观察到的变化随着时间的流逝可能有助于解释具有欧洲传播病原体的本土民族历史经验的方面。此外，这项研究中使用的方法产生的数据允许测试有关对美洲其他古老环境变量（例如饮食）基因组适应的假设。因此，这项研究阐明了人类对新环境的适应动力，在隔离和快速融合人群的背景下，同时强调了随着人类在全球范围内扩展的病原体所起的关键作用。 最后，该项目促进了对基因组研究的认识，并有助于促进对科学领域的职业兴趣，因为代表人数不足，美国原住民研究人员和学生都将参与研究和相关活动。