Date of Degree

2-2016

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biology

Advisor(s)

Stéphane Boissinot

Cathy Savage-Dunn

Committee Members

Cathy Savage-Dunn

Susan Rotenberg

Shaneen Singh

Margaret MacDonald

Subject Categories

Evolution | Molecular Biology | Molecular Genetics

Keywords

OAS1, Oligoadenylate Synthetase 1, antiviral sensor, innate immunity, immune evolution

Abstract

Animals produce an array of sensors patrolling the intracellular environment poised to detect and respond to viral infection. The oligoadenylate synthetase family of enzymes comprises a crucial part of this innate immune response, directly signaling endonuclease activity responsible for inhibiting viral replication. Oligoadenylate synthetase 1 plays a vital role in animal susceptibility to pathogens including flaviviruses such as dengue, West Nile, and hepatitis c virus. This thesis includes a population level analysis of OAS1 diversity within macaque and baboon species followed by a broader survey of the gene in nineteen Old World monkeys. My research found that at the species level, macaques exhibit extremely high diversity with intriguing similarities to that previously found in chimpanzees. Across Old World monkeys, I identified commonly shared patterns of positive selection. Detailed structural analysis of OAS1 variation indicates sites of accelerated evolution at the host-virus interface and at sites of possible viral antagonism, both signifying a history of virus-driven evolution. Finally, I have analyzed the cetartiodactyl OAS1 gene family which includes two, and in some lineages, three copies of OAS1. This analysis identifies some of the same regions under evolutionary pressure as found in primates and also highlights others suggesting neofunctionalization of paralogous genes.

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