Dating the Origin of the CCR5-Δ32 AIDS-Resistance Allele by the Coalescence of Haplotypes

Stephens, Jonathan; Reich, David; Goldstein, David B.; Shin, Hyoung Doo; Smith, Michael W.; Carrington, Mary; Winkler, Cheryl A.; Huttley, Gavin A.; Allikmets, Rando; Schriml, Lynn M.; Gerrard, Bernard; Malasky, Michael; Ramos, María Dolores Burguete; Morlot, Susanne; Tzetis, Maria; Oddoux, Carole; Giovine, F. S. Di; Nasioulas, Georgios; Chandler, David; Aseev, Michael; Hanson, Matthew; Kalaydjieva, Luba; Glavač, Damjan; Gasparini, Paolo; Kanavakis, Emmanouel; Claustres, Mireille; Kambouris, Marios; Ostrer, Harry; Duff, Gordon W.; Baranov, V. S.; Sibul, Hiljar; Metspalu, Andres; Goldman, David; Martin, Nicholas G.; Duffy, David L.; Schmidtke, Jörg; Estivill, Xavier; O’Brien, Stephen J.; Dean, Michael

doi:10.1086/301867

Cited by 479 publications

(441 citation statements)

References 57 publications

(67 reference statements)

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“…It has been argued extensively that the elevated frequency of this allele in Northern Europe compared with the south represents a signature of natural selection acting on CCR5-D32, in response to either bubonic plague during the 1300s AD, 43 or as a more recent theory proposes, in response to prolonged exposure to smallpox virus. 44 Notably, disease models suggest that certain KIR/HLA combinations that favor NK cell activation improve resistance/clearance of viral infections, for example, 3DS1 and Bw4-80I are associated with delayed progression of human immunodeficiency virus infection in patients.…”

Section: Discussionmentioning

confidence: 99%

Receptor systems controlling natural killer cell function are genetically stratified in Europe

et al. 2009

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Natural killer (NK) cells are components of the innate immune system that function in identifying and destroying aberrant or pathogen-infected cells. These functions are largely controlled by killer cell immunoglobulin-like receptors (KIRs). KIRs inhibit and activate NK cell functions through interactions with their ligands, epitopes encoded by human leukocyte antigen (HLA) class I genes (HLA-C1, C2 and Bw4). Genes that encode KIR and their HLA ligands vary in frequency across human populations. Here, we characterize two Irish populations for KIR and HLA and determine the spatial distribution of functionally important KIR:HLA systems in Europe, a region known for its considerable underlying genetic stratification. We find that Southern Europe is a region characterized by higher frequencies of activatory KIR and strong inhibitory HLA ligand systems (2DL1:HLA-C2 and 3DL1:Bw4). A lower frequency of activatory KIR and the predominance of a comparatively weaker inhibitory ligand system (2DL3:HLA-C1) are observed northwards. Despite contrasting KIR:HLA systems in Northern and Southern Europe, there is a clear balance between inhibitory and activatory repertoires, and their ligands in both regions. These findings show 'functional stratification' of the epistatic KIR:HLA receptor system in Europe, the presence of which will likely affect NK cell-mediated immunity across different populations.

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Section: Discussionmentioning

confidence: 99%

Receptor systems controlling natural killer cell function are genetically stratified in Europe

et al. 2009

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“…The well-known geographic variation of CCR5-⌬32 frequencies in Europe and Eurasia, with highest frequencies in Northern Europe, 18,19 together with preferential migration of certain European populations to certain US cities or states could influence regional frequencies of CCR5, particularly among US whites. Unfortunately, the questionnaire administered to the participants of this study did not collect information on the geographic origin of their ancestors.…”

Section: Genes and Immunitymentioning

confidence: 99%

Regional variation in CCR5-Δ32 gene distribution among women from the US HIV Epidemiology Research Study (HERS)

et al. 2002

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“…[1][2][3] In retrospective analyses, the homozygous ⌬32/⌬32 genotype has been associated with protection against HIV-R5 infection, [4][5][6] while the heterozygous wt/⌬32 genotype was associated with a slower rate of progression to AIDS. 5,6 Recent data [7][8][9][10][11] suggests an allelic frequency of 9-18% for the CCR5-⌬32 deletion among Caucasians in northern Europe and North America compared to only 3-6% among Mediterranean populations and 0% among Africans. 6 The highest allelic frequency (20.9%) in this survey was observed 7 among a small number (n = 43) of Ashkenazi Jews.…”

Section: Introductionmentioning

confidence: 99%

Evidence for recent selection of the CCR5-Δ32 deletion from differences in its frequency between Ashkenazi and Sephardi Jews

Maayan¹,

Zhang

Shinar³

et al. 2000

Genes Immun

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Recent studies have shown higher frequencies of the CCR5-⌬32 allele and the CCR5-⌬32/⌬32 genotype, which confers protection against HIV infection, in northern Europe as compared to Mediterranean countries. Here, we analyse the prevalence of CCR5-⌬32 in 922 HIV seronegative blood donors in Israel to verify its frequency in Jews of Ashkenazi and Sephardi origin. A significant difference (P Ͻ 0.001) was found between the CCR5-⌬32 allele frequency in Ashkenazi (13.8%) vs (4.9%) Jews. In contrast, no significant difference was observed in the frequency of the CCR2-64I mutation between Ashkenazi (9.2%) and Sephardi (13.4%) Jews. Using the Island model we calculate that a minimal genetic migration rate of 3% per generation would have been necessary if the higher CCR5-⌬32 prevalence in Ashkenazi is to be fully explained by mixing with the indigenous north-European populations. This putative migration rate is 20-fold higher than that currently estimated from other genes, and would correspond to a non-realistic minimal current admixture of 80%. Thus, our results suggest that a positive selection process for CCR5-⌬32 should have occurred in northern Europe at most a 1000 years ago, after the Ashkenazi Jews separated from their Sephardi kin and moved to north Europe. Genes and Immunity (2000) 1, 358-361.

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Dating the Origin of the CCR5-Δ32 AIDS-Resistance Allele by the Coalescence of Haplotypes

Cited by 479 publications

References 57 publications

Receptor systems controlling natural killer cell function are genetically stratified in Europe

Receptor systems controlling natural killer cell function are genetically stratified in Europe

Regional variation in CCR5-Δ32 gene distribution among women from the US HIV Epidemiology Research Study (HERS)

Evidence for recent selection of the CCR5-Δ32 deletion from differences in its frequency between Ashkenazi and Sephardi Jews

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