Detection of the signature of natural selection in humans: Evidence from the Duffy blood group locus

The Duffy blood group locus, which encodes a chemokine receptor, is charact erized by three alleles-FY*A, FY*B, and FY*O. The frequency of the FY*O all ele, which corresponds to the absence of Fy antigen on red blood cells, is at or near fixation in most sub-Saharan African populations but is very rar e outside Africa. The F-ST value for the FY*O allele is the highest observe d for any allele in humans, providing strong evidence for the action of nat ural selection at this locus. Homozygosity for the FY*O allele confers comp lete resistance to vivax malaria, suggesting that this allele has been the target of selection by Plasmodium vivax or some other infectious agent. To characterize the signature of directional selection at this locus, we surve yed DNA sequence variation, both in a 1.9-kb region centered on the FY*O mu tation site and in a 1-kb region 5-6 kb away from it, in 17 Italians and in a total of 24 individuals from five sub-Saharan African populations. The l evel of variation across both regions is two- to threefold lower in the Afr icans than in the Italians. As a result, the pooled African sample shows a significant departure from the neutral expectation for the number of segreg ating sites, whereas the Italian sample does not. The FY*O allele occurs on two major haplotypes in three of the five African populations. This findin g could be due to recombination, recurrent mutation, population structure, and/or mutation accumulation and drift. Although we are unable to distingui sh among these alternative hypotheses, it is likely that the two major hapl otypes originated prior to selection on the FY*O mutation.