The artiodactyl APOBEC3 innate immune repertoire shows evidence for a multi-functional domain organization that existed in the ancestor of placental mammals.
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.
LaRue
Rebecca S
RS
Department of Biochemistry, Molecular Biology and Biophysics, Institute for Molecular Virology, Beckman Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota 55455, USA. rsh@umn.edu
Jónsson
Stefán R
SR
Silverstein
Kevin A T
KA
Lajoie
Mathieu
M
Bertrand
Denis
D
El-Mabrouk
Nadia
N
Hötzel
Isidro
I
Andrésdóttir
Valgerdur
V
Smith
Timothy P L
TP
Harris
Reuben S
RS
D000071478:APOBEC Deaminases; D000818:Animals; D001188:Artiodactyla / Q000235:genetics* / Q000276:immunology*; D001483:Base Sequence; D002384:Catalysis; D002417:Cattle; D017124:Conserved Sequence; D003564:Cytidine Deaminase; D043525:Cytosine Deaminase / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020440:Gene Duplication; D016678:Genome / Q000235:genetics; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D008957:Models, Genetic; D008969:Molecular Sequence Data; D010802:Phylogeny; D010920:Placenta / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011995:Recombination, Genetic / Q000235:genetics; D012641:Selection, Genetic; D034561:Sheep, Domestic; D013552:Swine
D012333:RNA, Messenger; D043525:Cytosine Deaminase; D000071478:APOBEC Deaminases; C502889:APOBEC3 proteins, human; D003564:Cytidine Deaminase