title: Evolutionary analysis of two complement C4 genes: Ancient duplication and conservation during jawed vertebrate evolution.
abstract: The complement C4 is a thioester-containing protein, and a histidine (H) residue catalyzes the cleavage of the thioester to allow covalent binding to carbohydrates on target cells. Some mammalian and teleost species possess an additional isotype where the catalytic H is replaced by an aspartic acid (D), which binds preferentially to proteins. We found the two C4 isotypes in many other jawed vertebrates, including sharks and birds/reptiles. Phylogenetic analysis suggested that C4 gene duplication occurred in the early days of the jawed vertebrate evolution. The D-type C4 of bony fish except for mammals formed a cluster, termed D-lineage. The D-lineage genes were located in a syntenic region outside MHC, and evolved conservatively. Mammals lost the D-lineage before speciation, but D-type C4 was regenerated by recent gene duplication in some mammalian species or groups. Dual C4 molecules with different substrate specificities would have contributed to development of the antibody-dependent classical pathway.
authors.affiliation: Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan. Electronic address: nmayumi@bs.s.u-tokyo.ac.jp.
authors.forename: Mayumi I
authors.initials: MI
authors.lastname: Nonaka
authors.affiliation: Department of Molecular Genetics in Medicine, Shiga University of Medical Science, Shiga, Japan.
authors.forename: Tokio
authors.initials: T
authors.lastname: Terado
authors.affiliation: Department of Molecular Genetics in Medicine, Shiga University of Medical Science, Shiga, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kimura
authors.affiliation: Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Nonaka
mesh_terms: D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity; D005075:Biological Evolution; D001717:Birds / Q000276:immunology*; D020134:Catalytic Domain / Q000235:genetics; D003181:Complement C4 / Q000235:genetics*; D017124:Conserved Sequence / Q000235:genetics; D019143:Evolution, Molecular; D020440:Gene Duplication; D008322:Mammals / Q000235:genetics / Q000276:immunology; D005810:Multigene Family / Q000235:genetics; D012104:Reptiles / Q000276:immunology*; D012754:Sharks / Q000235:genetics / Q000276:immunology*; D013045:Species Specificity; D013379:Substrate Specificity
chemical_list: D003181:Complement C4
keywords: Classical pathway; Complement C4; Evolution; Gene duplication; Isotype; Shark