title: The artiodactyl APOBEC3 innate immune repertoire shows evidence for a multi-functional domain organization that existed in the ancestor of placental mammals.
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.
authors.affiliation: 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
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: LaRue
authors.forename: Stefán R
authors.initials: SR
authors.lastname: Jónsson
authors.forename: Kevin A T
authors.initials: KA
authors.lastname: Silverstein
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lajoie
authors.forename: Denis
authors.initials: D
authors.lastname: Bertrand
authors.forename: Nadia
authors.initials: N
authors.lastname: El-Mabrouk
authors.forename: Isidro
authors.initials: I
authors.lastname: Hötzel
authors.forename: Valgerdur
authors.initials: V
authors.lastname: Andrésdóttir
authors.forename: Timothy P L
authors.initials: TP
authors.lastname: Smith
authors.forename: Reuben S
authors.initials: RS
authors.lastname: Harris
mesh_terms: 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
chemical_list: D012333:RNA, Messenger; D043525:Cytosine Deaminase; D000071478:APOBEC Deaminases; C502889:APOBEC3 proteins, human; D003564:Cytidine Deaminase