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The Geographic Spread of the CCR5 Δ32 HIV-Resistance Allele

The Δ32 mutation at the CCR5 locus is a well-studied example of natural selection acting in humans. The mutation is found principally in Europe and western Asia, with higher frequencies generally in the north. Homozygous carriers of the Δ32 mutation are resistant to HIV-1 infection because the mutat...

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Autores principales: Novembre, John, Galvani, Alison P, Slatkin, Montgomery
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2005
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1255740/
https://www.ncbi.nlm.nih.gov/pubmed/16216086
http://dx.doi.org/10.1371/journal.pbio.0030339
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author Novembre, John
Galvani, Alison P
Slatkin, Montgomery
author_facet Novembre, John
Galvani, Alison P
Slatkin, Montgomery
author_sort Novembre, John
collection PubMed
description The Δ32 mutation at the CCR5 locus is a well-studied example of natural selection acting in humans. The mutation is found principally in Europe and western Asia, with higher frequencies generally in the north. Homozygous carriers of the Δ32 mutation are resistant to HIV-1 infection because the mutation prevents functional expression of the CCR5 chemokine receptor normally used by HIV-1 to enter CD4+ T cells. HIV has emerged only recently, but population genetic data strongly suggest Δ32 has been under intense selection for much of its evolutionary history. To understand how selection and dispersal have interacted during the history of the Δ32 allele, we implemented a spatially explicit model of the spread of Δ32. The model includes the effects of sampling, which we show can give rise to local peaks in observed allele frequencies. In addition, we show that with modest gradients in selection intensity, the origin of the Δ32 allele may be relatively far from the current areas of highest allele frequency. The geographic distribution of the Δ32 allele is consistent with previous reports of a strong selective advantage (>10%) for Δ32 carriers and of dispersal over relatively long distances (>100 km/generation). When selection is assumed to be uniform across Europe and western Asia, we find support for a northern European origin and long-range dispersal consistent with the Viking-mediated dispersal of Δ32 proposed by G. Lucotte and G. Mercier. However, when we allow for gradients in selection intensity, we estimate the origin to be outside of northern Europe and selection intensities to be strongest in the northwest. Our results describe the evolutionary history of the Δ32 allele and establish a general methodology for studying the geographic distribution of selected alleles.
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spelling pubmed-12557402005-10-18 The Geographic Spread of the CCR5 Δ32 HIV-Resistance Allele Novembre, John Galvani, Alison P Slatkin, Montgomery PLoS Biol Research Article The Δ32 mutation at the CCR5 locus is a well-studied example of natural selection acting in humans. The mutation is found principally in Europe and western Asia, with higher frequencies generally in the north. Homozygous carriers of the Δ32 mutation are resistant to HIV-1 infection because the mutation prevents functional expression of the CCR5 chemokine receptor normally used by HIV-1 to enter CD4+ T cells. HIV has emerged only recently, but population genetic data strongly suggest Δ32 has been under intense selection for much of its evolutionary history. To understand how selection and dispersal have interacted during the history of the Δ32 allele, we implemented a spatially explicit model of the spread of Δ32. The model includes the effects of sampling, which we show can give rise to local peaks in observed allele frequencies. In addition, we show that with modest gradients in selection intensity, the origin of the Δ32 allele may be relatively far from the current areas of highest allele frequency. The geographic distribution of the Δ32 allele is consistent with previous reports of a strong selective advantage (>10%) for Δ32 carriers and of dispersal over relatively long distances (>100 km/generation). When selection is assumed to be uniform across Europe and western Asia, we find support for a northern European origin and long-range dispersal consistent with the Viking-mediated dispersal of Δ32 proposed by G. Lucotte and G. Mercier. However, when we allow for gradients in selection intensity, we estimate the origin to be outside of northern Europe and selection intensities to be strongest in the northwest. Our results describe the evolutionary history of the Δ32 allele and establish a general methodology for studying the geographic distribution of selected alleles. Public Library of Science 2005-11 2005-10-18 /pmc/articles/PMC1255740/ /pubmed/16216086 http://dx.doi.org/10.1371/journal.pbio.0030339 Text en Copyright: © 2005 Novembre et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Novembre, John
Galvani, Alison P
Slatkin, Montgomery
The Geographic Spread of the CCR5 Δ32 HIV-Resistance Allele
title The Geographic Spread of the CCR5 Δ32 HIV-Resistance Allele
title_full The Geographic Spread of the CCR5 Δ32 HIV-Resistance Allele
title_fullStr The Geographic Spread of the CCR5 Δ32 HIV-Resistance Allele
title_full_unstemmed The Geographic Spread of the CCR5 Δ32 HIV-Resistance Allele
title_short The Geographic Spread of the CCR5 Δ32 HIV-Resistance Allele
title_sort geographic spread of the ccr5 δ32 hiv-resistance allele
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1255740/
https://www.ncbi.nlm.nih.gov/pubmed/16216086
http://dx.doi.org/10.1371/journal.pbio.0030339
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