Human Genetic Variation
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Sickle Cell Disease

Description

Sickle cell disease is a genetic disorder that affects approximately 1 out of every 625 African Americans in the United States. It is caused by a single amino acid change in a protein called hemoglobin.

Hemoglobin is the major protein inside red blood cells. Its primary function is to transport oxygen. When the oxygen concentration in the blood decreases, the defective hemoglobin molecule forms long crystals inside the red blood cell. These crystals cause the red blood cells to elongate and assume a "sickle" shape. The crystallized hemoglobin also damages the cell membrane so that the cells become very fragile.

Sickle Cell Disease - Incidence (Africa)

Map of the world portraying Sickle Cell Occurence - 0.25% African-Americans and 4.0% of Africans In some parts of Africa, about 4 percent of black Africans have sickle cell disease.

Why does sickle cell disease occur more frequently among black Africans than among African-Americans? Scientists believe that this difference is related to the threat of a fatal form of malaria that occurs in many parts of Africa. Studies reveal that people who are homozygous for the normal allele for hemoglobin (Hb A/Hb A) often die of malaria. However, people with sickle cell trait (people who are heterozygous, Hb A/Hb S), do not contract the fatal form of malaria. Thus, more heterozygotes live than do people who are homozygous for the normal allele, and these people often pass the sickle cell allele on to their children. This phenomenon keeps the incidence of the sickle cell allele in the population higher than it would be if there were no threat of malaria.

Sickle Cell Disease - Incidence (United States)

About one-quarter of 1 percent (0.25 percent) of African Americans are homozygous for the sickle cell hemoglobin allele and have sickle cell disease.

Why is the incidence of sickle-cell disease in the United States so low? It is low because people with sickle cell disease often die in childhood or early adulthood, before they have had children. Thus, may people with sickle cell disease do not pass this allele on to children. Instead, most inheritance of the allele is from a parent who is heterozygous for the allele to one or more of his or her children.

2 people, both with the HbS hemoglobin.  The combination gives rise to sickle cell disease. 2 people, one with the HbS hemoglobin and one with the HbA hemoglobin.  The combination gives rise to sickle cell trait.

Sickle Cell Disease - Inheritance

Sickle cell disease results when a person inherits an allele for sickle-cell hemoglobin from each of his or her parents. This inheritance pattern means that the person is homozygous for sickle-cell hemoglobin and that his or her body does not produce any normal hemoglobin, but only sickle cell hemoglobin.

Geneticists show the inheritance pattern of sickle-cell disease by using symbols to represent the allele for normal hemoglobin (Hb A) and the allele for sickle-cell hemoglobin (HB S). A person with normal hemoglobin has inherited one allele for normal hemoglobin from each parent and so has the genotype Hb A/Hb A. In contrast, a person who has sickle disease has inherited one sickle-cell allele from each parent and has the genotype Hb S/Hb S.

But what about a person who inherits an allele for normal hemoglobin from one parent and an allele for sickle-cell hemoglobin from the other parent? This person has the genotype Hb A/Hb S, and is said to have sickle-cell trait. Although some of the hemoglobin in this person's body is sickle-cell hemoglobin, the rest of the hemoglobin is normal, and the person usually exhibits no symptoms of the disease.

Amino Acid Sequence in hemoglobin: valine, histidine, leucine, threonine, proline, valine (in red), glutamic acid, and lysine.Sickle Cell Disease - Structure of Altered Hemoglobin

The hemoglobin that is made in the bodies of people with sickle cell disease (Hb S) differs from normal hemoglobin (Hb A) in just one amino acid. In normal hemoglobin, this amino acid is glutamic acid. In sickle-cell hemoglobin, it is a valine.

Sickle Cell Disease - Symptoms

People with sickle cell disease may experience symptoms such as severe pain, fever, and even death. These symptoms occur when the misshapen red blood cells that form under conditions of low oxygen concentration clog blood vessels and burst.

Such patients frequently experience a vicious cycle of events called a "sickle cell disease crisis" in which low oxygen concentration causes sickling, which causes ruptured red blood cells, which in turn, causes even lower oxygen concentrations in the body and still more sickling and red blood cell destruction. This process leads to a serious loss of red blood cells within a few hours and can cause death.

Sickle Cell Disease - Testing

Normal hemoglobin (Hb A) and sickle cell hemoglobin (Hb S) differ in just one amino acid. Hb S has valine in the position where Hb A has glutamic acid. This difference results from a difference between the DNA sequence of the allele that codes for normal hemoglobin and the sequence of the allele that codes for sickle cell hemoglobin.

The difference in one amino acid between Hb A and Hb S causes a difference in the electrical charge of the two forms of hemoglobin. Hb A has a greater negative charge than Hb S. This difference can be used to distinguish Hb A and Hb S in a process called electrophoresis. Hemoglobin from individuals suspected of having sickle cell disease or sickle cell trait is placed on a gelatinous slab (gel) beside standards of Hb A and Hb S. An electrical charge is applied across the gel and the proteins move through the gel toward the positive end of the electrical field at a rate based on their size and charge. Because Hb A has a greater negative charge than Hb S, it will move further through the gel. After electrophoresis, the gel is removed and stained with a solution that adheres to proteins, revealing "bands" of stain at the positions to which the hemoglobin has migrated.

Doctors diagnose sickle cell disease by comparing the banding position of the hemoglobin from an individual with the banding positions of Hb A and Hb S standards. An individual who is homozygous for Hb A will have only one protein band on the gel, at the same position as the Hb A standard, whereas an individual who is homozygous for Hb S (and has sickle cell disease) will also have one protein band on the gel, but at the same position as the Hb S standard. A heterozygous individual will have two protein bands, one at each position.

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