Ancient Adaptive Evolution of the Primate Antiviral DNA-Editing Enzyme APOBEC3G

Abstract

Host genomes have adopted several strategies to curb the proliferation of transposable elements and viruses. A recently discovered novel primate defense against retroviral infection involves a single-stranded DNA-editing enzyme, APOBEC3G, that causes hypermutation of HIV. The HIV-encoded virion infectivity factor (Vif) protein targets APOBEC3G for destruction, setting up a genetic conflict between the APOBEC3G and Vif genes. This kind of conflict leads to rapid fixation of mutations that alter amino acids at the protein–protein interface, referred to as positive selection. We show that the APOBEC3G gene has been subject to strong positive selection throughout the history of primate evolution. Unexpectedly, this selection appears more ancient than, and is likely only partially caused by, modern lentiviruses. Furthermore, five additional APOBEC genes in the human genome appear to be engaged in similar genetic conflicts, displaying some of the highest signals for positive selection in the human genome. Despite being only recently discovered, editing of RNA and DNA may thus represent an ancient form of host defense in primate genomes.

The Retroviral Hypermutation Specificity of APOBEC3F and APOBEC3G Is Governed by the C-terminal DNA Cytosine Deaminase Domain

“…The A3GϩF chimera decreased retroviral infectivity nearly 10-fold. This effect was smaller than that attributable to equivalent amounts of APOBEC3F or -3G, but this slight decline in chimera efficacy is perhaps not surprising given that these proteins are at least several million years diverged (chimpanzees also express both APOBEC3F and -3G (8,24,33,34)). …”

The evolutionary history of the CD209 (DC-SIGN) family in humans and non-human primates

“…13 Comparative analysis of the genes that encode APO-BEC3G and TRIM5a has revealed the intensity of the selective pressures resulting from the long-standing conflict between retroviruses and their hosts. 14,15 These two genes/proteins constitute a paradigm of pathogendriven positive selection pressure, not only because of their global elevated K A /K S values, but also by the identification of precise residues and domains under strong positive selection. Analysis of APOBEC3G across primate species reveals many residues in the aminoterminal cytidine deaminase domain that are under positive selection, which coincide indeed with the proposed region of interaction with the human immunodeficiency virus-1 Vif protein.…”

Large-scale DNA editing of retrotransposons accelerates mammalian genome evolution

“…In primates, as in rodents, retrotransposons occupy nearly half of the genome, including some recently, or even currently, active elements 2 . The APOBEC3 gene family expanded in primates and underwent particularly strong positive selection [24][25][26] . We thus expected to find that editing has had a significant role also in primate genome evolution.…”