Figure 2.

HBB-β^S origin in Africa, population migration dynamics, and evolving research questions. Current data support a single origin of the HBB-β^S variant in central-west Africa in the vicinity of present day Cameroon ~7300 years ago (1), or ~22 000 years ago (14) (A); the precise date of occurrence still remains to be determined. This is supported by the following lines of evidence; First, P. falciparum diverged from its common ancestor with P. praefalciparum 40 000–60 000 years ago in gorillas found around Cameroon (86); the absence of Plasmodium infection in eastern gorillas (B) further supported this observation. Subterranean malaria pressure probably led to the emergence of HBB-β^S on a CAM HBB haplotype background (a) as recently reported (1). It is therefore possible that the occurrence of the HBB-β^S variant is much older than the current estimates. A genetic bottleneck ~5000–6000 years ago and selection of more virulent strains of P. falciparum, as a consequence, with a rapid parasite expansion then occurred (38,40), possibly triggering at least one of the waves of the Bantu expansion (C). With Bantu expansion, and populations settling in various parts of Africa, it is likely that genomic recombination events within the HBB-like genes cluster have generated the other classical HBB haplotypes (Fig. 1B), and the regional distributions of these haplotypes have been subsequently shaped by intra African back and forth migratory events, whose sequences and dates are still to be determined (D). The distribution of the HBB-β^S variant from Africa into the Mediterranean, the Middle East, and the Indian sub-continent, where the Benin and Indian-Arab haplotype are the most prevalent, could reflect a much recent historical regional migration out of Africa as well as population admixtures, which still need to be properly investigated (E). The high prevalence of HbC in West Africa, even though HbS associated genotypes are known to demonstrate excess of average fitness higher than HbC associated genotypes, indicate that HBB-β^S is recent in this West African region (F); This needs to be properly investigated from an evolutionary genetic point of view. Lastly, from the time HBB-β^S attained equilibrium in populations [currently estimated at 5000 years ago (1)], it is likely that the pressure because of SCA on the human genome could have contributed to the enrichment of additional adaptive signatures, that still need to be investigated, as suggested by the enrichment of recurrent variants in numerous genes that are relevant to pathophysiology of SCD among patients in Africa (57).