Dating the Origin of the CCR5-Δ32 AIDS-Resistance Allele by the Coalescence of Haplotypes
Open accessAbstract
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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From an observed level of LD, allele age is estimated by solving for t.
“From an observed level of LD, allele age is estimate by solving for t (REFS 95,102).”
From Linkage disequilibrium--understanding the evolutionary past and mapping the medical future. (2008) · cites this paper as [95]
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“This method considers the chromosomal haplotypes defined by STRP loci in linkage disequilibrium with CCR5-D32 as indicators of derivative events for which we can estimate the frequency on the basis of mutation and recombination rates (see Kaplan et al. 1994; Risch et al. 1995; Tishkoff et al. 1996).”
MethodTHE AGE OF A NEUTRAL MUTANT PERSISTING IN A FINITE POPULATION
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- Authors
- Stephens, J. C., Reich, D. E., Goldstein, D. B., Shin, H. D., Smith, M. W., Carrington, M., Winkler, C., Huttley, G. A., Allikmets, R., Schriml, L., Gerrard, B., Malasky, M., Ramos, M. D., Morlot, S., Tzetis, M., Oddoux, C., di Giovine, F. S., Nasioulas, G., Chandler, D., Aseev, M., Hanson, M., Kalaydjieva, L., Glavac, D., Gasparini, P., Kanavakis, E., Claustres, M., Kambouris, M., Ostrer, H., Duff, G., Baranov, V., Sibul, H., Metspalu, A., Goldman, D., Martin, N., Duffy, D., Schmidtke, J., Estivill, X., O'Brien, S. J., & Dean, M.
- Affiliations
- National Cancer Institute (US)
- University of Oxford (GB)
- Medizinische Hochschule Hannover (DE)
- National and Kapodistrian University of Athens (GR)
- NYU Langone Health (US)
- Edith Cowan University (AU)
- Research Institute of Obstetrics and Gynecology named after D.O. Ott (RU)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Centre National de la Recherche Scientifique (FR)
- King Faisal Specialist Hospital & Research Centre (SA)
- University of Sheffield (GB)
- Estonian Biocentre (EE)
- National Institute on Alcohol Abuse and Alcoholism (US)
- QIMR Berghofer Medical Research Institute (AU)
- Duran i Reynals Hospital (ES)
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 1998-06
- Volume
- 62
- Issue
- 6
- Pages
- 1507-1515
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC1377146
- OpenAlex
- W2142992633
- Cited by
- 520
- References
- 2
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 7 · 2023: 13 · 2022: 12 · 2021: 15 · 2020: 6 · 2019: 13 · 2018: 13 · 2017: 17 · 2016: 12 · 2015: 10 · 2014: 20 · 2013: 22 · 2012: 24
- FWCI
- 7.59
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- NSUWorks (Nova Southeastern University) (submittedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Forensic and Genetic Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Keywords
- CCR5Δ32, HIV-1 resistance, CCR5 gene, linkage disequilibrium, microsatellite markers, allele frequency clines, natural selection, Caucasian population, chemokine coreceptors
- MeSH terms
- Acquired Immunodeficiency Syndrome, Alleles, Gene Frequency, Haplotypes, Humans, Hybrid Cells, Immunity, Innate, Gene Deletion, Evolution, Molecular, Receptors, CCR5
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