Evolutionary and functional analyses of primate genes reveal critical host-virus interactions

dc.contributor.advisorSawyer, Sara L.en
dc.contributor.committeeMemberKrug, Robert Men
dc.contributor.committeeMemberDudley, Jaquelin Pen
dc.contributor.committeeMemberBull, James Jen
dc.contributor.committeeMemberEhrlich, Lauren IRen
dc.creatorMeyerson, Nicholas Ryanen
dc.date.submittedDecember 2014
dc.description.abstractViruses exert a tremendous evolutionary pressure on their hosts. By hijacking cellular machinery and resources, viruses have been wildly successful at infecting and propagating throughout all domains of life. In the following dissertation, the interactions between primates and some of the viruses that infect them are examined through an evolutionary lens. I begin by introducing the long-standing battle between mammals and viruses that has raged on for hundreds of millions of years. I propose a theoretical framework to understand how slowly evolving mammals are able to keep pace with rapidly evolving viruses, and how we might use this framework to monitor future virus outbreaks. The core of my analyses stems from an evolutionary concept known as the host-virus arms race. This tug-of-war for survival between hosts and viruses leaves an imprint in the DNA of each organism involved that can be detected using statistical analyses. In Chapter 2, I describe these analyses in great detail and perform many tests to ensure that they are being used and applied appropriately. The remainder of my studies focuses on detecting novel signatures of positive selection in primate genes that are likely caused by ancient host-virus arms races. I characterize the evolutionary history of several primate genes that have been implicated in viral life cycles and provide functional evidence that viruses drove their rapid divergence. In doing so I make three important discoveries. First, I characterize a genetic variant of CD4, the cellular receptor for HIV-1, in an owl monkey species that could make them a viable HIV-1 model system. Second, I show that gorilla-specific mutations in RANBP2, a gatekeeper of the cell nucleus, can inhibit HIV-1 infection. And finally, evolutionary signatures in TRIM25, a component of the innate immune system, revealed its ability to inhibit influenza A virus replication by binding incoming viral ribonucleoproteins.en
dc.subjectMolecular evolutionen
dc.subjectArms raceen
dc.subjectInnate immunityen
dc.titleEvolutionary and functional analyses of primate genes reveal critical host-virus interactionsen