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

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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.