The Extent of Linkage Disequilibrium Caused by Selection on G6PD in Humans

The gene coding for glucose-6-phosphate dehydrogenase (G6PD) is subject to positive selection by malaria in some human populations. The G6PD A- allele, which is common in sub-Saharan Africa, is associated with deficient enzyme activity and protection from severe malaria. To delimit the impact of selection on patterns of linkage disequilibrium (LD) and nucleotide diversity, we resequenced 5.1 kb at G6PD and approximately 2-3 kb at each of eight loci in a 2.5-Mb region roughly centered on G6PD in a diverse sub-Saharan African panel of 51 unrelated men (including 20 G6PD A-, 11 G6PD A+, and 20 G6PD B chromosomes). The signature of selection is evident in the absence of genetic variation at G6PD and at three neighboring loci within 0.9 Mb from G6PD among all individuals bearing G6PD A- alleles. A genomic region of approximately 1.6 Mb around G6PD was characterized by long-range LD associated with the A- alleles. These patterns of nucleotide variability and LD suggest that G6PD A- is younger than previous age estimates and has increased in frequency in sub-Saharan Africa due to strong selection (0.1 < s < 0.2). These results also show that selection can lead to nonrandom associations among SNPs over great physical and genetic distances, even in African populations.