Learning from the past: Searching for novel TRIM, CypA, and TRIMCyp antiviral factors in primates

Abstract

The evolutionary history and genetic composition of mammals has been strongly influenced by viruses. This is reflected by evolved mechanisms of host defense mediated by restriction factors that are in an arms race to win over recurrent viral pressure. Restriction factors demonstrate genetic innovation, observed in forms such as positive selection and recurrent births of novel antiviral genes, that serves as a beacon to signify and study this arms race. In this dissertation, I explore these signals of genetic innovation to identify new restriction factors and extrapolate from them insights into the history of host-virus interactions. I first describe an ancient antiviral <italic>TRIM5-CyclophilinA</italic> gene fusion, termed <italic>TRIMCypA3</italic>, which likely protected primate ancestors 43 million years ago, but has since decayed. I then present an analysis of the primate <italic>TRIM</italic> multigene family and highlight members displaying signatures of positive selection, which represent novel restriction factor candidates. Amongst these, I focus on <italic>TRIM52</italic> that demonstrates a unique genetic innovation in the RING domain, suggesting a novel recognition domain. Finally, I present an additional analysis of primate genomes designed to catalogue <italic>CypA</italic> retrogenes and explore their evolutionary history, given that a pilot exploration of <italic>CypA</italic> retrogenes led to the discovery of <italic>TRIMCypA3</italic>. A systematic examination has highlighted several other retrogene copies with diverse evolutionary histories suggesting both preservation and innovation. The genetic innovation explored in this dissertation has highlighted several restriction factor candidates amongst the <italic>TRIM</italic> gene family and numerous <italic>CypA</italic> retrogenes encoded within primate genomes that has set a foundation to discover novel antiviral genes.