the geographic spread of the ccr5 δ32 hiv-resistance allele的地理传播ccr5δ32 hiv-resistance等位基因.pdfVIP

Open access, freely available online PLoS BIOLOGY The Geographic Spread of the CCR5 D32 HIV-Resistance Allele * John Novembre , Alison P. Galvani, Montgomery Slatkin Department of Integrative Biology, University of California, Berkeley, California, United States of America The D32 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 D32 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 CD4þ T cells. HIV has emerged only recently, but population genetic data strongly suggest D32 has been under intense selection for much of its evolutionary history. To understand how selection and dispersal have interacted during the history of the D32 allele, we implemented a spatially explicit model of the spread of D32. 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 D32 allele may be relatively far from the current areas of highest allele frequency. The geographic distribution of the D32 allele is consistent with previous reports of a strong selective advantage (.10%) for D32 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 D32 proposed by G. Lucotte and G. Mercier. However, when we allow for gradients in selection intensity, we estimate t