Sickle Cell Anemia: Genotypic and Phenotypic Expressions

Introduction to Sickle Cell Anemia

Sickle cell anemia is an inherited blood disorder in which hemoglobin is defective. After hemoglobin molecules give up their oxygen, some cluster together and form long, rod-like structures. These structures cause red blood cells to become stiff and assume a sickle shape, making it difficult for them to squeeze through small blood vessels. As a result, they stack up and cause blockages that deprive organs and tissues of oxygen-carrying blood.

Sickle cell anemia affects millions worldwide. It is most common among people whose ancestors come from sub-Saharan Africa; Spanish-speaking regions (South America, Cuba, and Central America); Saudi Arabia; India; and Mediterranean countries such as Turkey, Greece, and Italy. In the United States, it affects around 72,000 people, most of whose ancestors come from Africa. The disease occurs in approximately one in every 500 African-American births and one in every 1,000 to 1,400 Hispanic-American births. About two million Americans — or one in twelve African-Americans — carry the sickle cell trait.

Genotypic Expressions

People have twenty-two identical chromosome pairs, with one of each pair inherited from the father and one from the mother. Mutation involving gene alteration in the exchange between a parent and child occurs only rarely. Most likely, sickle cell disease depends on inherited genes from parents; the disease cannot be caught, acquired, or otherwise transmitted. It is caused by a change in a single amino acid in the beta chain of hemoglobin.

Individuals with two copies of the sickle form of the gene have sickle cell anemia. Heterozygotes — individuals with one normal and one mutant copy of the sickle gene — appear normal and do not manifest the disease except under very stressful conditions. However, these individuals are carriers of the sickle cell trait. Approximately ten percent of African-Americans are carriers. In Africa and India, the frequencies of the disease and carriers are even higher, due to the protection against malaria that the sickle cell trait confers, as discussed further below.

Beta-globin is a major component of adult hemoglobin, and its gene is located on chromosome 11, with more than 475 allelic variants (Ashley-Koch, Yang, and Olney, 2000). One of these variants, sickle hemoglobin (Hb S), is responsible for sickle cell disease. The most influential risk factor for disease severity is genotype. Individuals who are homozygous for the sickle beta-globin gene (b^S) have sickle cell anemia (SS disease). Individuals with sickle beta thalassemia carry both a b^S gene and a gene for beta thalassemia. If no beta-globin is produced by the beta thalassemia gene, the individual has Sb^o thalassemia. If some normal beta-globin is produced by the thalassemia gene, the individual has Sb⁺ thalassemia. In the case of SC disease, the individual has two abnormal beta-globin genes — b^S and b^C — and produces two abnormal hemoglobins, Hb S and Hb C.

Phenotypic Expressions

There are several phenotypes associated with the homozygous sickle genotype. Sickle cell anemia refers to a recessive gene condition in which a person has inherited two genes for hemoglobin S, one from each parent. If two carrier parents have a child, there is a one-in-four chance of the child developing the illness and a one-in-two chance of the child being a carrier. Children who receive one abnormal gene and one normal gene usually have no symptoms and are said to have sickle cell trait.

The next two phenotypes — blood cell sickling and altered beta-globin electrophoretic mobility — involve partially dominant genes when both the dominant and recessive alleles are present in the genotype. For example, in the case of sickle beta thalassemia, the individual has inherited a gene for hemoglobin S from one parent and a gene for beta thalassemia from the other. In the instance of SC disease, the individual has inherited a gene for hemoglobin S from one parent and a gene for hemoglobin C from the other.

The sickle cell trait in heterozygous carriers confers resistance to malaria, a phenotype characterized by a dominant gene. Because people with sickle trait were more likely to survive malaria outbreaks in Africa than those with normal hemoglobin, sickle hemoglobin is believed to have evolved as a protection against malaria.

Conclusion and Implications

Phenotype is equivalent to a genotype plus its development in a given environment. In only a narrow genetic sense does the genotype define the phenotype. Selection acts on phenotypes because differential reproduction and survivorship depend on phenotype. If the phenotype affecting reproduction or survivorship is genetically based, then selection can eliminate genotypes indirectly by eliminating unfavorable phenotypes.

Because malaria is prevalent in Africa and India, heterozygotes can maintain the sickle allele in balance with the normal allele. However, in the United States, where malaria is rare, carriers possess no such advantage and may even face a small selective disadvantage. Therefore, due to the strong selection acting against those with sickle cell anemia, the frequency of the disease should decline in the United States over time, provided that malaria outbreaks do not occur. Furthermore, reducing malaria worldwide should carry the same positive implications for reducing the prevalence of sickle cell disease globally.

Bibliography

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