Haplotype Diversity and Linkage Disequilibrium at Human G6PD: Recent Origin of Alleles That

The frequencies of low-activity alleles of glucose-6-phosphate dehydrogenase in humans are highly correlated with the prevalence of malaria. These ÒdeÞ-ciencyÓ alleles are thought to provide reduced risk from infection by the Plasmodium parasite and are maintained at high frequency despite the hemo-pathologies that they cause. Haplotype analysis of ÒA2Ó and ÓMedÒ mutations at this locus indicates that they have evolved independently and have increased in frequency at a rate that is too rapid to be explained by random genetic drift. Statistical modeling indicates that the A2 allele arose within the past 3840 to 11,760 years and the Med allele arose within the past 1600 to 6640 years. These results support the hypothesis that malaria has had a major impact on humans only since the introduction of agriculture within the past 10,000 years and provide a striking example of the signature of selection on the human genome. Malaria, resulting from infection by the Plas-modium falciparum, P. vivax, P. malariae, or P. ovale parasites, is the leading cause o