Haemoglobin S and haemoglobin C: ‘quick but costly’ versus ‘slow but gratis’ genetic adaptations to Plasmodium falciparum malaria

Abstract

Haemoglobin S (HbS; β6Glu→Val) and HbC (β6Glu→Lys) strongly protect against clinical Plasmodium falciparum malaria. HbS, which is lethal in homozygosity, has a multi-foci origin and a widespread geographic distribution in sub-Saharan Africa and Asia whereas HbC, which has no obvious CC segregational load, occurs only in a small area of central West-Africa. To address this apparent paradox, we adopted two partially independent haplotypic approaches in the Mossi population of Burkina Faso where both the local S (S^Benin) and the C alleles are common (0.05 and 0.13). Here we show that: both C and S^Benin are monophyletic; C has accumulated a 4-fold higher recombinational and DNA slippage haplotypic variability than the S^Benin allele (P = 0.003) implying higher antiquity; for a long initial lag period, the C alleles did apparently remain very few. These results, consistent with epidemiological evidences, imply that the C allele has been accumulated mainly through a recessive rather than a semidominant mechanism of selection. This evidence explains the apparent paradox of the uni-epicentric geographic distribution of HbC, representing a ‘slow but gratis’ genetic adaptation to malaria through a transient polymorphism, compared to the polycentric ‘quick but costly’ adaptation through balanced polymorphism of HbS.