The sickle cell trait heterozygote advantage

According to eastern Nigerian mythology, an Ogbanje is a child who dies within a few months or years of birth and returns to a mythical land, only to re-enter the womb of his or her mother and be born again.  Chinua Achebe’s novel Things Fall Apart describes an ogbanje that was reborn nine times to an Igbo woman, and whose comings and goings devastated her mother.  The Yoruba, another population group within the borders of present-day Nigeria, but separated from the Igbos by the Niger River and considerable land mass, have a similar ancient myth referring to “Abiku”, who in a poem by Nobel laureate Wole Soyinka is “calling for the first and repeated time”.

While the Yorubas, Igbos and other West African subpopulations with similar myths are not connected genetically, they all are subject to strong selective pressure from Falciparum malaria. The P.  falciparum parasite, which causes malaria, and its Anopheles gambiae vector are most concentrated across Africa’s equatorial belt.  The high frequency of malaria in this area and the balancing selection that maintains the HbS allele in the population may underlie the origins of the ogbanje myths.  A recent socio-medical study confirmed that 70 of 80 reputed ogbanjes had sickle cell anemia.

How exactly are heterozygotes protected?  It was first thought that sickled red blood cells might be less able to be infected by Plasmodium falciparum parasites, but this was later shown to be untrue.  Indeed, HbA homozygotes and heterozygote children are equally likely to be infected with Falciparum malaria.  The advantage stems from what happens next.  A significant proportion of young children who are infected with Plasmodium falciparum will suffer a syndrome known as severe malaria, which is caused by the parasite making its host’s red blood cells knobbed and sticky, so that they clump together.  The knobbed cells stick to each other and to the lining of blood vessels in the brain, causing a type of stroke that is very often fatal.  They also stick to vessels in the placenta, placing pregnant women and their unborn children at risk of death. The cell aggregation allows the parasite to sequester large clumps of red blood cells and increase its opportunities to replicate.

The parasite is unable to produce as many knobs in sickled cells, and the knob protein that is produced is aberrantly distributed on the surface of the infected sickled cells.  (This knobbing defect is also seen in other hemaglobinopathies such as HbC and α-thalassemia, which also protect from severe malaria).  The end result is that heterozygotes are less likely than HbA homozygotes to progress to or die of severe malaria, while HbS homozygotes generally do not reach adulthood without medical intervention.  Thus, in places where Plasmodium falciparum is endemic, and in the absence of treatments for malaria or sickle cell anemia, heterozygotes are more likely to survive to reproductive age and reproduce successfully than either HbS or HbA homozygotes: they are fitter. 

Sickle cell heterozygotes are generally healthy but are more likely to be oxygen-deprived at high altitudes or during extremely vigorous exercise.  Therefore the HbS allele only provides a fitness advantage where malaria is endemic.  However, the result of centuries of selective pressure from malaria in equatorial Africa, and a subsequent Founder Effect, explains why African Americans, whose ancestors were forcibly brought from malaria-endemic Africa to the now malaria-free North America, continue to carry the HbS allele at a high frequency.