The evolutionary history and activity of a gain-of-function polymorphism in a human antiviral gene

Thesis (Ph.D.)--University of Washington, 2016-07Humans express seven human APOBEC3 proteins, which can inhibit viruses and endogenous retroelements through cytidine deaminase activity. The seven paralogs differ in the potency of their antiviral effects, as well as in their antiviral targets. One APOBEC3, APOBEC3C, is exceptional as it had previously been found to only weakly block viruses and endogenous retroelements compared to other APOBEC3s. However, our positive selection analyses suggested that APOBEC3C has played a role in pathogen defense during primate evolution. Here, I describe a single nucleotide polymorphism in human APOBEC3C, a change from serine to isoleucine at position 188 (I188) that confers potent antiviral activity against HIV-1. The gain-of-function APOBEC3C SNP results in increased enzymatic activity and hypermutation of target sequences when tested in vitro, and correlates with increased dimerization of the protein. Furthermore, I show, using a fully-dimerizing point mutant as well as a synthetic dimer of APOBEC3C, that dimerization correlates with potent antiviral activity. The I188 is widely distributed in human African populations, and is the ancestral primate allele, but is not found in chimpanzees or gorillas. Thus, while other hominids have lost activity of this antiviral gene, it has been maintained, or re-acquired, as a more active antiviral gene in a subset of humans. Taken together, my results suggest that APOBEC3C is in fact involved in protecting hosts from lentiviruses