The Role of Gene Regulation in Infectious Disease in the Ugandan Red Colobus Monkey (Piliocolobus tephrosceles)
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Date
2018-09-06
Authors
Simons, Noah
Journal Title
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Publisher
University of Oregon
Abstract
Infectious diseases, and their etiological pathogens, have been among the strongest selective pressures throughout primate evolution. As a result, the study of the nonhuman primate immune system has contributed substantially to our understanding of the causes and consequences of pathogenic infection for human health. In this work, I study a population of Ugandan red colobus as a naturalistic model to investigate the role of gene expression in explaining variation in host control of infection and progression to disease, which may have indirect benefits to human public health in the event of future zoonotic transmissions.
In this work, I identify genetic variants in the gene regulatory region of an important immune gene, MHC-DQA1, that are associated with whipworm infection in the Ugandan red colobus. I then functionally validate the ability of those infection-associated variants to drive differences in gene expression, a prerequisite for visibility to natural selection. As both variants were able to causally change gene expression in vitro, I also provide evidence that balancing selection has maintained those variants over time.
In this work, I also describe the sequencing and de novo assembly of a new Ugandan red colobus reference genome, which will be of utility to the research community at large, particularly for inclusion in studies of primate genome evolution. I then used this reference genome for an analysis of genome-wide patterns of gene expression associated with SIV infection in the Ugandan red colobus. I present evidence that patterns of gene expression characteristic of nonpathogenic SIV infection in other Old World monkeys are also present in the Ugandan red colobus, supporting the hypothesis that SIV infection is also nonpathogenic in the Ugandan red colobus. This hypothesis is further supported by evidence that estimates of T cell abundances inferred by gene expression deconvolution do not differ between SIV-infected and uninfected individuals. Finally, I provide evidence for a shared pattern of upregulation of immunosuppressive gene expression in natural SIV hosts, with species-specific patterns of individual immunosuppressive genes.
This dissertation includes previously published and unpublished coauthored
material.