|MadSci Network: Cell Biology|
The following answer is adapted from two web sites listed at the bottom and from Stryer's Biochemistry.
Sickle cell disease is an inherited blood disorder in which there is a substitutive formation of hemoglobin in the red blood cells, producing a distinctive disease process. This disease was first scientifically recorded in 1910 by Dr. James Herrick. While examining the blood of a young West Indian student, he observed that many of the red blood cells were elongated with a curved shape instead of the normal round configuration. It was after similar repeated observations by other investigators that the descriptive term "sickle cell anemia" was used to describe this disease.
In sickle cell anemia, there is an alteration in the arrangement of the hemoglobin molecular structure. At the sixth position in each beta chain where the amino acid, glutamate should normally be incorporated, it is replaced by another amino acid, valine. This small change in the molecule results in great changes in its physical and chemical characteristics, so that in certain stressful conditions when the body is deprived of oxygen, the red cells then assume a crescent, banana, or sickle shape. This particular shape of the red cells makes its travel through the smaller blood vessels extremely difficult, producing an obstruction by creating a "log-jam", which may result in tissue and ultimately organ damage. Because of the abnormal hemoglobin and the shape of the red cells, they are quickly destroyed. This, combined with an inability of the body to produce sufficient numbers of new cells, produces a state of anemia. The term sickle cell disease refers to all the clinically significant sickling disorders, since the degree of anemia may be variable and many potentially dangerous episodes can occur without an increase in the severity of the anemia.
Hemoglobin S (the mutated hemoglobin with the valine substitution) occurs with greatest prevalence in tropical Africa; the heterozygote frequency is usually about 20 percent, but in some areas it reaches 40 percent. The sickle cell trait has a frequency of about 8 percent in African Americans. High prevalence of sickle cell trait in areas of the world where malaria has been common has strongly suggested that persons with sickle cell trait have a selective advantage over individuals with only normal hemoglobin A. This advantage seems to be restricted to those infected with Plasmodium falciparum malaria. While readily infected, the parasite count remains low. When a red cell containing P. falciparum undergoes the sickling process, the parasite dies. It has also been suggested that the infected red cell sickles and is destroyed, probably in the vascular system, liver or spleen. Whatever the mechanism, the result is that the infection is of short duration and the incidence of cerebral malaria and death is low in the heterozygote population.
Sickle Cell and Malaria
Plasmodium metabolism causes sickle cell hemoglobin to form the fibers that results in red blood cell sickling. The parasite significantly lowers cytoplasm pH (increases acidity) causing hemoglobin to release oxygen which results in more sickling since low oxygen promotes the process. "Knobs" form on the cell wall of infected RBCs (Red blood cells) slowing transit through capillaries. The result is an increase of sickling to about 40% of the RBCs in AS (heterozygotes who have the mutated S and normal A alleles) individuals.
The development of the Plasmodium is disrupted by the sickling of the red blood cells. Sickling depletes cell reserves of potassium which is required for the parasite to grow. Plasmodium quickly dies in potassium depleted cells. Additionally, infected sickled cells may be prematurely removed by the spleen. Sickling of a significant proportion of infected cells increases malaria resistance, even if not all parasites die. The subsequent reduction in the rate of multiplication of Plasmodium gives the immune system time to mount a serious counterattack.
In summary, in areas where malaria is common, people who have one A and one S hemoglobin have a higher fitness because they are protected against malaria. Those homozygous for A are not afforded this protection and those who are homozygous S are very sick. Thus there is a selective pressure for the heterozygous genotype but only in those areas where malaria is present.
Stryer, L Bochemistry 3rd Edition
hope this helps,
gabriel vargas md/phd
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