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

Abstract

Haemoglobin S (HbS; beta6Glu-->Val) and HbC (beta6Glu-->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.

Haplotype Analyses of Haemoglobin C and Haemoglobin S and the Dynamics of the Evolutionary Response to Malaria in Kassena-Nankana District of Ghana

“…This low HbS allele frequency has been observed in malaria endemic regions where HbC [3], [4], [5] or HbE [24], [29] occur at high frequency. As per the suggestion of Modiano and colleagues, [4] and their subsequent age estimates for the two HBB variants [30], HbC may be older than HbS. Indeed our haplotype patterns agree with this observation.…”

Effect of red blood cell variants on childhood malaria in Mali: a prospective cohort study

“…7, 11 This increased risk may sufficiently impair fitness in malaria-endemic areas to account for the very limited geographic distribution of HbC, despite the clear protection it affords to homozygotes, the mild clinical sequelae associated with it, and the greater age of HbC compared with HbS alleles. 12 The molecular pathology of HbAC on RBCs is minimal, manifesting as slightly reduced RBC lifespan, mild anaemia (with normal reticulocytaemia), 13 and increased mean corpuscular haemoglobin concentration. 14 In-vitro experiments indicate that HbAC RBCs support normal invasion and parasite maturation 15, 16 but reduce the expression of parasite cytoadherence proteins on the RBC surface; 17 this latter finding, also present in HbAS RBCs, 18 suggests a common mechanism of protection where in these β-globin variants attenuate cytoadherence and modulate innate immune activation.…”

Methodological challenges of genome-wide association analysis in Africa

“…For example, there are two distinct variants of the HBB gene that confer resistance to malaria in West Africa: one encodes HbS (a valine substitution at codon 6) and the other encodes HbC (a lysine substitution, also at codon 6). HbS is relatively widespread, whereas HbC has a more localized distribution – for example, among the Dogon people of Mali, who have a low frequency of HbS [95, 96, 97]. This example is well understood because haemoglobin has been intensively studied by geneticists for many years, but allelic heterogeneity of this sort might be extremely difficult to dissect by GWA analysis, unless it is based on genome sequencing.…”