Haldane's Hemoglobin Hypothesis

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Science  18 Dec 2009:
Vol. 326, Issue 5960, pp. 1590
DOI: 10.1126/science.326.5960.1590-a

Malaria parasites invade and feed within human red blood cells and can cause high rates of mortality if untreated. Consequently, and as hypothesized by Haldane, in recent human history malaria has selected for several hemoglobin mutations with distinctive patterns of global distribution, which hinder the parasite to different degrees. Penman et al. have investigated the population genetics of the contrasting distributions of hemoglobin mutations associated with thalassemias (which exhibit quantitative deficiencies in α- and β-globin synthesis that can provide up to 60% protection against malaria) in the Mediterranean, and those of sickle-cell anemia (a structural defect in β-globin that confers in excess of 90% malaria protection) in sub-Saharan Africa. The authors suggest that the distinct geographies reflect an active exclusion of the sickle-cell mutation from Mediterranean populations as a result of intracellular interactions between the α- and β-globin variants. The pathophysiology of the thalassemias is caused by an imbalance in the globin subunits; several mutations coexist, and if an individual inherits two different thalassemia mutations, the imbalance may be ameliorated without any loss of the malariaprotective effect. In contrast, co-inheritance of an α thalassemia with sickle cell anemia ablates any malaria-protective effect and transmits a double whammy of hemoglobinopathy and malaria risk to the afflicted individual.

Proc. Natl. Acad. Sci. U.S.A. 10.1073/pnas.0910840106 (2009).

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