Dating the origin of the CCR5-Delta32 AIDS-resistance allele by the coalescence of haplotypes. |
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| Authors: | J C Stephens D E Reich D B Goldstein H D Shin M W Smith M Carrington C Winkler G A Huttley R Allikmets L Schriml B Gerrard M Malasky M D Ramos S Morlot M Tzetis C Oddoux F S di Giovine G Nasioulas D Chandler M Aseev M Hanson L Kalaydjieva D Glavac P Gasparini E Kanavakis M Claustres M Kambouris H Ostrer G Duff V Baranov H Sibul A Metspalu D Goldman N Martin D Duffy J Schmidtke X Estivill S J O'Brien and M Dean |
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| Affiliation: | 1Laboratory of Genomic Diversity, and;2Intramural Research Support Program, Science Applications International Corporation–Frederick, National Cancer Institute, Frederick, MD;;3Molecular Genetics Department, Hospital Duran i Reynals (IRO), Barcelona;;4Institut fur Humangenetik, Medizinische Hochschule, Hannover;;5First Department of Pediatrics, Athens University, St. Sophia's Children's Hospital, and;6Department of Hygiene and Epidemiology, University of Athens School of Medicine, National Retrovirus Reference Center, Athens;;7Human Genetics Program, Department of Pediatrics, New York University Medical Center, New York;;8Department of Molecular and Genetic Medicine, University of Sheffield, Sheffield;;9Centre for Human Genetics, Edith Cowan University, Perth;;10Institute of Obstetrics and Gynecology, Russian Academy of Medical Sciences, St. Petersburg;;11Laboratory of Molecular Pathology, University of Ljubljana, Ljubljana;;12National Medical Genetics Service, IRCCS-CSS Hospital, San Giovanni Rotondo, Italy;;13Laboratoire de Biochimie Genetique, CNRS UPR 9008, Montpellier;;14King Faisal Specialist Hospital and Research Center, Riyadh;;15Estonian Biocentre and Children's Hospital, University of Tartu, Tartu, Estonia;;16Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, Rockville;;17Department of Zoology, University of Oxford, Oxford; and;18Queensland Institute of Medical Research, Royal Brisband Hospital, Herston, Australia |
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| Abstract: | The CCR5-Delta32 deletion obliterates the CCR5 chemokine and the human immunodeficiency virus (HIV)-1 coreceptor on lymphoid cells, leading to strong resistance against HIV-1 infection and AIDS. A genotype survey of 4,166 individuals revealed a cline of CCR5-Delta32 allele frequencies of 0%-14% across Eurasia, whereas the variant is absent among native African, American Indian, and East Asian ethnic groups. Haplotype analysis of 192 Caucasian chromosomes revealed strong linkage disequilibrium between CCR5 and two microsatellite loci. By use of coalescence theory to interpret modern haplotype genealogy, we estimate the origin of the CCR5-Delta32-containing ancestral haplotype to be approximately 700 years ago, with an estimated range of 275-1,875 years. The geographic cline of CCR5-Delta32 frequencies and its recent emergence are consistent with a historic strong selective event (e.g. , an epidemic of a pathogen that, like HIV-1, utilizes CCR5), driving its frequency upward in ancestral Caucasian populations. |
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| Keywords: | Author Keywords: Coalescence of haplotypes AIDS resistance Phylogenetic analysis Ancestral haplotype Short tandem-repeat polymorphism |
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