|Smith, Timothy - Tim|
Submitted to: BioMed Central (BMC) Molecular Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/18/2008
Publication Date: 11/18/2008
Citation: Larue, R.S., Jonsson, S.R., Silverstein, K.A., Lajoie, M., Bertrand, D., El-Mabrouk, N., Hotzel, I., Andresdottir, V., Smith, T.P., Harris, R. 2008. The artiodactyl APOBEC3 innate immune repertoire shows evidence for a multi-functional domain organization that existed in the ancestor of placental mammals. BioMed Central (BMC) Molecular Biology. 9:104.
Interpretive Summary: Mammalian cells produce proteins capable of defending against invasion by a class of disease-causing viruses known as retrovirus. The A3 group of proteins produced by APOBEC3 genes are a prominent example of these anti-viral proteins, acting to inactivate the viral DNA and preventing it from replicating (making copies of itself). There is only one A3 gene in mice, but seven in humans, and this study was intended to examine the evolutionary history and activity of A3 genes among species to help understand the relationship between the variety of A3 genes and their activity against particular retroviruses. The A3 genes in sheep, cattle and pigs were sequenced to determine their number and structure, which showed that sheep and cattle both have three A3 genes, whereas pigs have only two. Analysis of the data indicated that the ancient common ancestor in swine also had three A3 genes but one has been lost during evolution. The data indicate that a remarkable series of eight recombination events are needed to explain the expanded repertoire of human A3 proteins and suggest a selective pressure on primates to expand or diversify their response to a potentially wider range of retroviral pathogens.
Technical Abstract: Background: APOBEC3 (A3) proteins deaminate DNA cytosines and block the replication of retroviruses and retrotransposons. Each A3 gene encodes a protein with one or two conserved zinc-coordinating motifs (Z1, Z2 or Z3). The presence of one A3 gene in mice (Z2-Z3) and seven in humans, A3A-H (Z1a, Z2a-Z1b, Z2b, Z2c-Z2d, Z2e-Z2f, Z2g-Z1c, Z3), suggests extraordinary evolutionary flexibility. To gain insights into the mechanism and timing of A3 gene expansion and into the functional modularity of these genes, we analyzed the genomic sequences, expressed cDNAs and activities of the full A3 repertoire of three artiodactyl lineages: sheep, cattle and pigs. Results: Sheep and cattle have three A3 genes, A3Z1, A3Z2 and A3Z3, whereas pigs only have two, A3Z2 and A3Z3. A comparison between domestic and wild pigs indicated that A3Z1 was deleted in the pig lineage. In all three species, read-through transcription and alternative splicing also produced a catalytically active double domain A3Z2-Z3 protein that had a distinct cytoplasmic localization. Thus, the three A3 genes of sheep and cattle encode four conserved and active proteins. These data, together with phylogenetic analyses, indicated that a similar, functionally modular A3 repertoire existed in the common ancestor of artiodactyls and primates (i.e., the ancestor of placental mammals). This mammalian ancestor therefore possessed the minimal A3 gene set, Z1-Z2-Z3, required to evolve through a remarkable series of eight recombination events into the present day eleven Z domain human repertoire. Conclusions: The dynamic recombination-filled history of the mammalian A3 genes is consistent with the modular nature of the locus and a model in which most of these events (especially the expansions) were selected by ancient pathogenic retrovirus infections.