Beta-globin gene haplotypes and selected Malaria-associated variants among black Southern African populations

Abstract

Partial carrier-resistance to Plasmodium falciparum malaria conferred by the sickle cell (HbS) mutation has resulted in the local amplification and positive selection of sickle cell disease (SCD) in malaria-endemic regions and particularly in sub-Saharan Africa (SSA). The present study investigated the β-globin gene haplotypes, and selected malaria-associated variants among three cohorts of Bantu-speaking individuals from Malawi, Zimbabwe and South Africa compared with reports with data from others SSA populations. The data suggest a south-ward frequency decrease of malaria-associated variants in SSA linked to the evolutionary dynamics of various African populations' genomes through selective pressure of malaria. These selected genomics differences, positive selection of SCD in malaria-endemic regions among 'Bantus' from various part of Africa emphasise the evidence of the dissociation between genetics, anthropology and culture. The present study also showed a relatively prevalent Benin haplotype, which is mostly found in West Africa, among Southern African Blacks and very low Bantu haplotype, which could suggest a major migration route, of Southern Africa Bantu, along the African west coast, post-occurrence of the Sickle cell mutation, which date remain to be fully elucidated.

Keywords: Southern Africa; malaria resistance; sickle cell disease; β-globin haplotypes.

Fig. 1.

Population frequencies of all haplotypes for the study cohorts (South Africa, Zimbabwe and Malawi), versus frequencies conditional on being homozygous for HbS in the other population's groups across the continent. (with adaptation of previously reported from [16]).

Fig. 2.

Minor frequencies of malaria-restriction SNPs amongst southern African populations and three populations from the 1000Genomes Project within the malaria-endemic central Africa. A: rs8176703; B: rs372091; C: rs2334880.

Fig. 3.

Distribution of frequency differentiation of targeted SNPs rs8176703; rs372091 and rs2334880 across various African populations. When comparing the measure of frequency differentiation among the genotyped SNPs and the corresponding frequencies of these SNPs in the 1000Genomes data, the frequency of the genotyped SNPs were highest among the Southern African populations and the African populations (Esan, Luhya, Yoruba, Mende and Mandinka) (Fig. 3). The frequencies were lowest between American, Asian and European populations. * Populations studied in from the current paper (South Africa, Zimbabwe and Malawi); other data were extracted from the 1000G project. The values provided are F-statistics calculated between each MAF for the three SNPs (rs8176703; rs372091 and rs2334880) and colored coded grey (genetically proximal) to red (genetically distal). Populations with less genetic distance have lower F-st and shown in grey whereas populations with greater genetic distance have higher F-st and are shown in red.

Fig. 4.

Haplotype bifurcation diagrams. The root of each diagram is a core haplotype at the variant rs334, identified by a white circle. The diagram is bi-directional, portraying both proximal and distal LD for derived (each top) and ancestral allele (each bottom). The breakdown of LD on the core haplotype background is portrayed at progressively longer distances, depending on whether the allele is present or not. The thickness of the lines corresponds to the number of samples with the indicated long-distance haplotype. (A) ESN (B) YRI (C) GWD (D) MSL and (E) LWK.

Fig. 5.

Pattern of linkage disequilibrium. A linkage disequilibrium (LD) block of polymorphisms in a tight region around rs334. (A) ESN (B) YRI (C) GWD (D) MSL and (E) LWK.