Journey of the sickle cell gene Open Access

The origin and age of the sickle cell allele (hemoglobin S [HbS] or β-globin [β^S]) have been major research questions. This is because of its importance in understanding human migration and its link to various diseases and conditions, such as malaria, glucose-6-phosphate dehydrogenase deficiency, and APOL1-induced kidney disease. There is currently no consensus on the age of β^S. In this issue of Blood Global Hematology, Pendharkar and Nirmal¹, in their review, drew on geography and migration history to argue that the sickle cell gene emerged in Africa ∼50 000 years ago owing to malaria selection.

The malaria hypothesis, which proposes that survival advantage is conferred by β^S in the heterozygote state (known as sickle cell trait) against malaria, was first stated about 80 years ago and is based on the fact that the sickle cell trait is highly prevalent (15%-40%) in malaria-endemic regions in Africa, the Mediterranean, the Middle East, and India.^2-4 However, the homozygote state (β^Sβ^S, known as sickle cell anemia [HbSS]) is devastating because of the polymerization of HbS under low O₂ tension, which leads to the occlusion of blood vessels, hemolytic anemia, and multiorgan damage in the affected individuals.

Sickle cell anemia severely impedes the quality of life of the affected persons and accounts for early childhood mortality in sub-Saharan Africa. Although a monogenic disease, its clinical manifestations are highly diverse and complex and are influenced by the background variation surrounding the mutation (haplotypes) and genetic modifiers of fetal hemoglobin (HbF). The 5 typical sickle haplotypes, named after where they were first identified, namely Arab-Indian, Bantu (Central Africa Republic), Benin, Cameroon, and Senegal, have been associated with HbF levels and clinical severity of HbSS. The Arab-Indian and Senegal haplotypes are known for their association with elevated HbF levels because of the presence of the Xmn1 restriction site in the HBG2 promoter region. These haplotypes correlate with milder complications of HbSS.⁵ In contrast, the Bantu haplotype is characterized by the lowest HbF levels and is associated with a more severe form of HbSS. These 5 haplotypes are essential for investigating the evolution and origin of β^S.

A single origin of β^S has been proposed based on population-genetic data.⁶ These data suggest that it arose between ∼7000 years ago, during the wet phase Holocene, and ∼22 000 years ago, in the late Pleistocene, in West Central Africa (present-day Cameroon).^6,7 From this origin, β^S spread through migrations at different times, particularly during the Bantu expansion, to other parts of Africa, the Mediterranean, the Middle East, and India.⁸ Others propose a multicentric origin and have identified at least 3 separate origins in Benin, Senegal, and the Central African Republic.^9,10 The single origin theory of Hb β^S is favored because of the low probability of multiple identical mutations arising independently and occurring at the observed high frequency in populations. This suggests a shared ancestral lineage of the β^S-globin haplotypes rather than several independent origins.⁸ 

The 50 000-year β^S dating¹ seems to be poorly supported, and a better substantiated estimate would require a high-resolution haplotype network, allele sharing statistics, and demographic modeling that compares alternative evolutionary routes and timelines. Pendharkar and Nirmal mentioned that β^S spread with early modern humans along a southern coastal route through the Arabian Peninsula into India. Their review highlights the predominance of an Arab-Indian genetic background in parts of India, Oman, Yemen, and Saudi Arabia, supporting the idea of a 50 000-year coastal migration. They emphasized several factors, including (1) the overlap between malaria-endemic regions and the high frequencies of the sickle allele, (2) the dominance of the Arab-Indian haplotype, and (3) the high frequencies of hemoglobin β^S in central Indian tribal groups that practice endogamy. They interpret these observations as evidence that support an "Out-of-Africa" theory for the dispersal of the allele that coincided with early human migration. This allele persisted in malaria-endemic areas because of natural selection. However, they do not dismiss the possibility that later movements, such as Holocene expansions and historic gene flow across the Arabian Sea, could also have contributed to this pattern.

Pendharkar and Nirmal mentioned the zoonotic origins of Plasmodium falciparum tens of thousands of years ago and imply long-standing strong selection since ∼50 000 years ago. However, malaria selection intensity likely rose markedly during the Holocene, coinciding with the rise of agriculture, higher population density, and ecologic change, an important historical context that is missing in their review. A quantitative selection analysis in multiple populations, coupled with demography, would help to reconcile the timing claims with the observed haplotype lengths and frequencies.

Conflict-of-interest disclosure: The authors declare no competing financial interests.