title: Genomic organization and evolution of the CX3CR1/CCR8 chemokine receptor locus.
abstract: The chemokine receptors CCR8 and CX3CR1 are key players in adaptive immunity and are co-receptors for human immunodeficiency virus. We describe here the genomic organization and evolutionary history of both of these genes. CX3CR1 has three promoters that transcribe three separate exons that are spliced with a fourth exon containing the coding region. CCR8 has two promoters. One promoter produces a transcript of two spliced exons, and the other promoter transcribes an exon containing the coding region and lacks introns. We analyzed these promoters in the context of a luciferase reporter and identified several positive and negative regulatory elements. Identification of the genomic organization of these genes in mouse demonstrates a similar organization for CCR8, but mouse CX3CR1 lacks two of the human promoters and has an additional mouse-specific promoter that transcribes only the exon containing the coding region and therefore resembles the organization of the human and mouse CCR8 genes. We also identify two nontranscribed regions that are highly conserved between human and mouse CX3CR1 containing possible regulatory elements. Examination of the CX3CR1 and CCR8 genes and surrounding genomic regions indicates that these genes are the result of the duplication of an ancestral gene prior to the divergence of teleost fish. We characterize single nucleotide polymorphisms in the promoters of human CCR8 and CX3CR1 and establish linkage relationships between CX3CR1 promoter polymorphisms and two previously described CX3CR1 coding polymorphisms associated with human immunodeficiency virus disease progression and arteriosclerosis susceptibility.
authors.affiliation: Division of Experimental Therapeutics, and Department of Immunology, University of Toronto, University Health Network, Toronto General Research Institute, Toronto General Hospital, Toronto, Ontario M5G 2C4, Canada.
authors.forename: Mark E
authors.initials: ME
authors.lastname: DeVries
authors.forename: Henian
authors.initials: H
authors.lastname: Cao
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Luoling
authors.initials: L
authors.lastname: Xu
authors.forename: Alyson A
authors.initials: AA
authors.lastname: Kelvin
authors.forename: Longsi
authors.initials: L
authors.lastname: Ran
authors.forename: Luan A
authors.initials: LA
authors.lastname: Chau
authors.forename: Joaquin
authors.initials: J
authors.lastname: Madrenas
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hegele
authors.forename: David J
authors.initials: DJ
authors.lastname: Kelvin
mesh_terms: D000818:Animals; D001483:Base Sequence; D000073883:CX3C Chemokine Receptor 1; D002893:Chromosomes, Human, Pair 3; D017124:Conserved Sequence; D019143:Evolution, Molecular; D020440:Gene Duplication; D016678:Genome; D006801:Humans; D008565:Membrane Proteins; D051379:Mice; D008969:Molecular Sequence Data; D005810:Multigene Family / Q000235:genetics; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D019713:Receptors, CCR5 / Q000235:genetics; D054401:Receptors, CCR8; D019707:Receptors, Chemokine / Q000235:genetics*; D023741:Takifugu
chemical_list: C103330:CCR8 protein, human; D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; D008565:Membrane Proteins; D019713:Receptors, CCR5; D054401:Receptors, CCR8; D019707:Receptors, Chemokine