Prioritization of Evolutionary Events for Immune Response Studies: Introgression, Selection, and Infectious Disease Among Indigenous Americans

Abstract

A history of exposure to infectious diseases has influenced the biology of Mesoamericans. From the urbanization of Mesoamerican communities to colonial contact in the 15th century, immune response to various pathogens have shaped the available diversity at various genomic loci providing immunological resistance to pathogens. This dissertation explores the population history of Mesoamerican populations as it relates to exposures to and immunity against infectious diseases. I use an evolutionary lens to look at three time scales: 1) archaic introgression in immune response pathways that took place thousands of years prior to the peopling of the Americas 30,000 years ago, 2) signatures of natural selection in immune response genes from the establishment of city-states to colonial contact, shaped 10,000 years ago to the 15th century, 3) epidemiological risk factors for dengue-infection in Guatemala between the years 2018 and 2019. I use publicly available DNA sequences from Indigenous Americans, SNP array genotype data, and ethnographic surveys to answer the following questions: 1) Are the detectable regions of archaic introgression in modern Mesoamericans related to immunity? 2) Are we able to detect signatures of natural selection in Mesoamericans at immune response loci? 3) What risk factors contribute to dengue-infection in Mesoamerican populations today? The introgression analysis in an indigenous American population from Mexico finds that multiple genes lying in the TGF-β signaling pathway were introgressed by Neanderthals. Similarly, various genes associated with cytoplasm and exosomes, part of the innate immune system, were introgressed by Denisovans. The presence of those segments in important immune response pathways and responses highlights that variants deep in evolutionary history may continue to be relevant today. Similarly, our natural selection scan in a Mesoamerican cohort demonstrated that the Major Histocompatibility Complex (MHC) and the peroxisome proliferator-activated receptor gamma (PPAR-γ) signaling pathway showed signatures of positive selection. This demonstrates that in the more recent past, various pathogens including smallpox exerted strong evolutionary pressure on the human genome, thus shaping host responses to infection. Our epidemiological survey demonstrated various risk factors for dengue infection in Guatemalan populations of Mesoamerican ancestry. We found that factors related to water accumulation including water security, water storage, and nearby trash increased the risk for dengue-infection likely by providing additional breeding grounds for mosquito. This study suggests where the Ministry of Public Health should focus their efforts for dengue prevention. Furthermore, it identifies the epidemiological risk-factors that future studies of dengue infection should account for in Guatemala. This dissertation highlights the importance of adaptation on immunity among Mesoamerican populations whether deep in our evolutionary past, as recent as colonial contact, or even continuously shaped by more recent infectious diseases like dengue. Furthermore, it demonstrates how to prioritize candidate genomic regions influencing host susceptibility or resistance to modern infectious disease using an evolutionary approach. This emphasis on compiling outlying genes will be particularly beneficial to studies conducted on smaller sample sizes as it provides greater statistical power given that these outlying genes have greater effects physiologically more so than other genomic regions.