In particular, Allison linked the global distribution of sickle-cell trait to regions most affected by falciparum malaria, a parasitic disease that primarily affects RBCs. He reasoned that possession of a single mutant gene must confer a survival advantage and be positively selected at the population level. Anthony Allison, an internist and epidemiologist working in Kenya, wondered how this mutant gene, which causes a deadly disease when present in two copies, could have reached such high levels in certain populations while being nearly nonexistent in other African populations (Allison, 1954). Subsequent global epidemiological studies established that SCA and sickle-cell trait are present at high levels in parts of sub-Saharan Africa, the Saudi Arabian peninsula, central India, and certain parts of Southern Europe (Figure 2). This leads to leads to anemia, as well as congestion and fibrosis of the spleen at an early age.Įarly investigators noted that SCA patients in the United States were almost always of African origin (Diggs et al., 1933). The cells' sickle shape and associated fragility result in rapid RBC destruction by a patient's own body. The abnormally shaped cells can build up in capillaries and veins, obstructing (occluding) blood flow and leading to severe pain and tissue damage in almost any organ of the body. In the deoxygenated environment of tissue capillary beds, the misshapen RBCs are the cause of all the problems associated with SCA. Over time, however, these transitions lead to irreversible distortions of the RBC membrane into a sickle shape (Figure 1) (Lux et al., 1976). Amazingly, the distorted RBCs resume a normal shape in the lungs when oxygen once again binds to hemoglobin. This rapidly leads to stacking of the hemoglobin into long polymers that deform the cell membrane into its characteristic sickle shape. Specifically, the deoxygenated hemoglobin molecule changes conformation such that the exposed valine sticks to a hydrophobic patch on a neighboring hemoglobin molecule. ![]() In vivo, the consequences of this amino acid substitution only become apparent when oxygen dissociates from hemoglobin.
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