Polymorphic sites in the African population detected by sequence analysis of the glucose-6-phosphate dehydrogenase gene outline the evolution of the variants A and A-.

Abstract

The human X chromosome-linked, gene encoding glucose-6-phosphate dehydrogenase (G6PD; EC 1.1.1.49) is known to be highly polymorphic from the biochemical characterization of enzyme variants. The variant A (with enzyme activity in the normal range) and the variant A-(associated with enzyme deficiency) each have a frequency of about 0.2 in several African populations. Two restriction fragment length polymorphisms have also been found in people of African descent, but not in other populations, whereas a silent mutation has been shown to be polymorphic in Mediterranean, Middle Eastern, African, and Indian populations. We report now on two additional polymorphisms that we have detected by sequence analysis, one in intron 7 and one in intron 8. The analysis of 54 African male subjects for the seven polymorphic sites, clustered within 3 kilobases of the G6PD gene, has revealed only 7 of the 128 possible haplotypes, indicating marked linkage disequilibrium. These data have enabled us to suggest an evolutionary pathway for the different mutations, with only a single ambiguity. The, mutation underlying the A variant is the most ancient and the mutation underlying the A-variant is the most recent. Since it seems reasonable that the A-allele is subject to positive selection by malaria, whereas the other alleles are neutral, G6PD may lend itself to the analysis of the role of random genetic drift and selection in determining allele frequencies within a single genetic locus in human populations.

Glucose-6-phosphate Dehydrogenase Deficiency in Portugal: Biochemical and Mutational Profiles, Heterogeneity, and Haplotype Association

“…Xu et al in the population of the Canary Island (29) and Medina et al in Mexico (31), detected the NlaIII (ϩ) associated with the FokI (ϩ), haplotype VIa. Our results are in accordance with Vulliamy et al (12) and Xu et al (29) and Medina et al (31). Accordingly, the NlaIII polymorphism is more recent than the Betica and Santa Maria mutations.…”

“…We were able to expand, with the introduction of the NlaIII allele, the haplotype profile described by Vulliamy et al (12), and Nafa et al (13), now designated by haplotype Ia, IVa, VIa and VIIa with the information of the intron 11 NlaIII restriction enzyme site-NlaIII (ϩ)-and the absence of the restriction site, haplotypes I, IV, VI and VII-NlaIII (Ϫ). Table 8 shows that the polymorphisms FokI (ϩ) and PvuII (ϩ) that are not present in the control population are present in the affected population with frequencies of 75.7 and 48.6%, respectively.…”

“…The haplotype-associated G6PD A 376 A 3 G origin mutations IV and VI, here designated as IVa and VIa with the gain of the Intron 11 NlaIII site, were described by Vulliamy et al (12). Among these, the Betica mutation was described in Spain (15,16) and the Santa Maria mutation in Costa Rica (17,18) and in Algeria (13).…”

Chronic hemolytic anemia is associated with a new glucose-6-phosphate dehydrogenase in-frame deletion in an older woman

“…The G6PD coding exons 2-13 were amplified by polymerase chain reaction (PCR) and tested for the common G6PD deficient variants, as previously described [25][26][27]. The amplicons were subjected to single strand conformation polymorphism (SSCP) analysis and to direct sequencing by dideoxy chain termination reaction, using the ABI Prism 310 genetic analyser (Applied Biosystems).…”

Mutations and haplotype diversity in 70 Portuguese G6PD-deficient individuals: an overview on the origin and evolution of mutated alleles

“…G6PD gene exons 2 to 13 PCR amplification and mutation screening were carried out using primers and strategies previously reported. [5][6][7] Haplotype patterns in patients and in 66 unrelated normal individuals (41 males and 25 females) from Central Portugal were established with 6 intragenic RFLPs (Tables 1 and 2) and a (CTT)n microsatellite using primers and conditions previously reported. [5][6][7] Linkage phase from female diploid data was performed by analysis of the father's sample or by statistical inference.…”