PP[A]P: The Idea Behind Sickle-Cell Heterozygote Advantage
Sorry not sorry for the title. That was a beautiful reference. But I digress.
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Sickle cell anemia is a homozygous recessive condition characterized by sickle-shaped blood cells due to a single amino acid substitution mutation (Glu→Val) resulting in the production of HbS (sickle) instead of the normal HbA. This disease is devastating in the homozygous recessive condition due to frequent bouts of pain and fatigue that result from having this condition. However, although this condition reduces evolutionary fitness (not all patients survive to reproductive age, thereby decreasing the proportion of alleles passed to the next generation) this condition persists due to the phenomenon of heterozygote advantage, or overdominance.
The physiological basis of this advantage revolves around the pentose phosphate pathway (PPP), which oxidizes sugars to form nucleotides. Because this process is oxidative, it needs an accompanying reduction to prevent free electrons from buzzing about. Removed electrons are added to NADP+, which is reduced into NADPH. Because NADPH has an electron, it is reducing, and can alleviate oxidative stress. Thus, this pathway has served a double function in our evolution: it produced nucleotides for us, and helped organisms transition from a low-to-high oxygen environment during the Oxygen Revolution.
The first enzyme of this pathway, glucose-6-phosphate dehydrogenase (G6PD), is faulty in sickle cell anemia. Thus, the pentose phosphate pathway is severely compromised and oxidative stress is not adequately reduced. Reactive oxygen species (ROS) can damage cell membranes, causing release of Hb into the blood (hemolytic anemia), resulting in jaundice.
However, in the case of sickle cell heterozygotes, G6PD is only partially faulty. Thus, oxidative stress is prevented to such a degree that the organism is somewhat protected and has enough nucleotides, but a malarial parasite (genus Plasmodium) would not be protected in the body. This is like having an inbuilt medication for malaria. This is the sickle cell heterozygote advantage. Antimalarial drugs often target Plasmodium’s intolerance of oxidative stress as well; sulfa antibiotics and primaquine are common drugs for malaria that induce oxidative stress to fight malaria.
Further resources!
https://www.youtube.com/watch?v=9-gvnQfbrIA - This source explains favism, which is characterized by an intolerance to fava beans. These beans contain oxidative substances, so those with a G6PD deficiency (the defining trait of favism) will experience oxidative stress (and therefore hemolytic anemia) upon consumption of these beans.
