title: APOBEC3 has not left an evolutionary footprint on the HIV-1 genome.
abstract: It is known that the human immune proteins APOBEC3G and -F (hA3G/F) can inhibit Vif-deficient HIV by G-to-A mutation; however, the roles of these enzymes in the evolution of HIV are debated. We argue that if evolutionary pressure from hA3G/F exists there should be evidence of their imprint on the HIV genome in the form of (i) underrepresentation of hA3G/F target motifs (e.g., TGGG [targeted position is underlined]) and overrepresentation of product motifs (e.g., TAGG) and/or (ii) an increase in the ratio of nonsynonymous to synonymous (NS/S) G-to-A changes among hA3G/F target motifs and a decrease of NS/S A-to-G changes among hA3G/F product motifs. To test the first hypothesis, we studied the representation of hA3G/F target and product motifs in 1,932 complete HIV-1 genomes using Markov models. We found that the highly targeted motifs are not underrepresented and their product motifs are not overrepresented. To test the second hypothesis, we determined the NS/S G↔A changes among the hA3G/F target and product motifs in 1,540 complete sets of nine HIV-1 genes. The NS/S changes did not show an increasing/decreasing trend within the target/product motifs, but the NS/S changes within the motif AG was exceptionally low. We observed the same pattern by analyzing 740 human genes. Given that hA3G/F do not act on the human genome, this suggests a small NS/S change within AG has arisen by other mechanisms. We therefore find no evidence of an evolutionary footprint of hA3G/F. We postulate several mechanisms to explain why the HIV-1 genome does not contain the hA3G/F footprint.
authors.affiliation: Centre for Vascular Research, Faculty of Medicine, University of New South Wales, Sydney 2052, Australia.
authors.forename: Diako
authors.initials: D
authors.lastname: Ebrahimi
authors.forename: Firoz
authors.initials: F
authors.lastname: Anwar
authors.forename: Miles P
authors.initials: MP
authors.lastname: Davenport
mesh_terms: D000071478:APOBEC Deaminases; D019295:Computational Biology / Q000379:methods; D003564:Cytidine Deaminase; D043525:Cytosine Deaminase / Q000276:immunology*; D019143:Evolution, Molecular; D016679:Genome, Viral; D015658:HIV Infections / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D012367:RNA, Viral / Q000235:genetics*; D012641:Selection, Genetic
chemical_list: D012367:RNA, Viral; D043525:Cytosine Deaminase; D000071478:APOBEC Deaminases; C502889:APOBEC3 proteins, human; D003564:Cytidine Deaminase