The geographic spread of the CCR5 Delta32 HIV-resistance allele.
The Delta32 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 Delta32 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 Delta32 has been under intense selection for much of its evolutionary history. To understand how selection and dispersal have interacted during the history of the Delta32 allele, we implemented a spatially explicit model of the spread of Delta32. 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 Delta32 allele may be relatively far from the current areas of highest allele frequency. The geographic distribution of the Delta32 allele is consistent with previous reports of a strong selective advantage (>10%) for Delta32 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 Delta32 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 Delta32 allele and establish a general methodology for studying the geographic distribution of selected alleles.
Novembre
John
J
Department of Integrative Biology, University of California, Berkeley, California, United States of America. novembre@berkeley.edu
Galvani
Alison P
AP
Slatkin
Montgomery
M
D000483:Alleles; D004351:Drug Resistance; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005828:Genetics, Population; D005843:Geography; D006678:HIV / Q000235:genetics*; D006801:Humans; D007055:Iceland; D016013:Likelihood Functions; D008962:Models, Theoretical; D009154:Mutation; D019713:Receptors, CCR5 / Q000235:genetics*; D012641:Selection, Genetic; D012984:Software
D019713:Receptors, CCR5