title: Comparative genomic analysis of mammalian NKG2D ligand family genes provides insights into their origin and evolution.
abstract: NKG2D is a major activating receptor of natural killer cells. Its ligands are major histocompatibility complex (MHC) class I-like molecules whose expression is induced by cellular stresses such as infections and tumorigenesis. Humans have two families of NKG2D ligands (NKG2DL): MHC class I-related chains (MIC) encoded in the MHC and UL16-binding proteins (ULBP) encoded outside the MHC. By contrast, mice have only the latter family of ligands; instead, they have non-MHC-encoded MILL molecules that are closely related to MIC, but do not function as NKG2DL. To gain insights into the origin and evolution of MIC, ULBP, and MILL gene families, we conducted comparative genomic analysis of NKG2DL family genes in five mammalian species. In the opossum MHC, we identified a ULBP-like gene adjacent to a previously described MIC-like gene, suggesting that ULBP genes were originally encoded in the MHC. The opossum genome also contained a transcribed MILL-like gene in a region syntenic to the rodent regions encoding MILL molecules. These observations indicate that MIC-, ULBP-, and MILL-like genes emerged before the divergence of placental and marsupial mammals. Comparison of the human, cattle, rat, mouse, and opossum genomes indicates that after emigration from the MHC, ULBP genes underwent extensive duplications in each species. In mice, some of the ULBP genes appear to have been translocated telomerically on the same chromosome, forming a major cluster of existent NKG2DL genes.
authors.affiliation: Department of Pathology, Hokkaido University Graduate School of Medicine, North-15 West-7, Sapporo, 060-8638, Japan.
authors.forename: Mizuho
authors.initials: M
authors.lastname: Kondo
authors.forename: Takako
authors.initials: T
authors.lastname: Maruoka
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Otsuka
authors.forename: Jun
authors.initials: J
authors.lastname: Kasamatsu
authors.forename: Kazunori
authors.initials: K
authors.lastname: Fugo
authors.forename: Naoto
authors.initials: N
authors.lastname: Hanzawa
authors.forename: Masanori
authors.initials: M
authors.lastname: Kasahara
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D019295:Computational Biology; D019143:Evolution, Molecular; D058851:GPI-Linked Proteins; D016678:Genome; D055436:Growth Differentiation Factor 15 / Q000235:genetics; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008024:Ligands; D008322:Mammals / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D051920:NK Cell Lectin-Like Receptor Subfamily D / Q000235:genetics*; D009893:Opossums / Q000235:genetics; D010802:Phylogeny; D051381:Rats
chemical_list: C526140:GDF15 protein, human; D058851:GPI-Linked Proteins; D055436:Growth Differentiation Factor 15; D015395:Histocompatibility Antigens Class I; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C532300:Mill1 protein, mouse; D051920:NK Cell Lectin-Like Receptor Subfamily D; C423231:ULBP1 protein, human