Sickle Cell and its Genes
Sickle cell anemia (sickle cell disease) is a disorder of the blood caused by inherited abnormal hemoglobin (the oxygen-carrying protein within the red blood cells). The sickled red blood cells are fragile and prone to rupture. When the number of red blood cells decreases from rupture (hemolysis), anemia is the result. The major features and symptoms of sickle cell anemia include: Fatigue and anemia, Pain crises, Dactylitis (swelling and inflammation of the hands and/or feet) and arthritis, Bacterial infections, Sudden pooling of blood in the spleen and liver congestion, Lung and heart injury, Leg ulcers, Aseptic necrosis and bone infarcts (death of portions of bone), Eye damage
Sickle cell anaemia is also genetic disease due to the homozygosity of an allele “SS”. This allele usually acts as a recessive lethal. This disease is characterized by anaemia, enlarged spleen, heart, kidney and brain damage. Homozygote for the sickling usually dies as adolescents or young adults. Sickle cell anaemia is a blood disease which occurs in the haemoglobin of the red blood cell.There are various haemoglobin in man. The first that is formed during development is foetal haemoglobin, HbF. This is replaced four months later by the normal adult form, HbA. This normal adult haemoglobin is round or disc-shaped.
The mutant form of the normal adult form is the abnormal sickle-cell haemoglobin, HbS. These red blood cells are crescent or sickle-shaped.
Sickle-shaped cells can clump and block blood vessels in various parts of the body leading to malfunctions of the organs as mentioned. These defective corpuscles also have lower oxygen-carrying capacity and are easily destroyed by the liver leading to anaemia.
The genes producing the normal haemoglobin is HbA while the mutant allele which produces the abnormal or sickle-shaped red blood cells is HbS. If an afflicted individual (HbS/HbS) marries a Homozygous normal individual (HbA/HbA) all their children will be heterozygote or carriers (HbA/HbS).
Heterozygotes are not sufferers but they are symptomatic because they are carriers of the disease. However, if two heterozygote marries, there is a 1:4 chances of them having a child with the disease as sufferer(HbS/HbS) and 50:50 chances of having a child who is a carrier themselves(HbA/HbS)
The HbS Haemoglobin even in small dose possessed by the heterozygote (HbA/HbS) confers a powerful resistance to malaria (caused by plasmodium falciparium). This gives them a great advantage refered to as heterozygote Advantage or superiority in regions where malaria is prevalent.
The sickle-cell haemoglobin (HbS) differs from the normal haemoglobin (HbA) because of a mutation in the gene for the 6th amino acid of a β-chain of the haemoglobin molecule. This mutation causes valine to replace glutamic acid in that position. When the availability of oxygen is reduced, the erythrocytes containing sickle-cell haemoglobin changes from round or disc-shaped to crescent or sickle-shaped cells. This is referred to as SICKLING.
The sickling of these cells has two major consequences. First, the liver destroys the sickled cells and this causes anaemia. The phenotypic effects of this anaemia include physical weakness, slow development and hypertrophy of the bone marrow. Second, the sickled cells clump and block blood capillaries cutting off oxygen supply to the cells thereby damaging major organs of the body.
Sickled cell red blood blocking the capillaries
This condition not only reduces fitness but the sickle-cell homozygote(HbS/HbS) almost never become parents as they almost always die of anaemia. In other words, almost every time one sickling allele encounters another in a homozygous offspring (HbS/HbS) usually from a marriage between two heterozygote(HbA/HbS × HbA/HbS), two sickling alleles are removed from the population by death.
This situation of reduced or zero fitness and eventually death of the afflicted would ordinarily lead one to expect that the sickle-cell allele would become extinct or rare with time in all populations. But this is not the case as the disease is common in Africa, India and Asia where malaria is endemic.
As earlier indicated, the sickle-cell homozygote (HbS/HbS) usually dies of anaemia, the heterozygote(HbA/HbS) is only slightly anaemic and has resistance to malaria. The normal homozygote (HbA/HbA) is no anaemic and has no resistance to malaria. Thus, as far as the sickle-cell disease is concerned, in areas where malaria is common, there is loss of human life due to either anaemia (for HbS/HbS) or malaria (for HbA/HbA). The sickle-cell heterozygote(HbA/HbS) is the most fit genotype of the three because it has resistance to malaria, and no or only minor anaemia. This is heterozygous superiority or advantage. Moreover, for reasons that are not yet known, women who carry heterozygous sickling allele are more fertile. These features confer the superiority or advantage of the heterozygote.
This conclusion regarding the superiority of the heterozygote is supported by the fact that when a population from a malarial area moves to a non-malarial area, there is chance in allelic frequencies. This is because, the normal homozygote(HbA/HbA) is no longer at risk for malaria, the heterozygotes(HbA/HbS) still maintains its advantage even though it perpetuates the sickle-cell allele in the progeny, selection therefore acts mainly on the sickle-cell homozygote(HbS/HbS). Consequently, the sickle cell haemoglobin allele(HbS) is reduced. This is the case with Africa Americans.