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J. Biol. Chem., Vol. 278, Issue 14, 11985-11994, April 4, 2003

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Genomic Organization and Evolution of the CX3CR1/CCR8 Chemokine Receptor Locus^*

Mark E. DeVries^§¶, Henian Cao^**, Jian Wang^**, Luoling Xu, Alyson A. Kelvin, Longsi Ran, Luan A. Chau^**, Joaquin Madrenas^§**, Robert A. Hegele^**, and David J. Kelvin^§

From the  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, the Departments of ^§ Microbiology and Immunology and of  Biochemistry, University of Western Ontario, London, Ontario N6A 5C1, Canada, and ^** Robarts Research Institute, London, Ontario N6G 2V4, Canada

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.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY016370.

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