Sickle Cell Anaemia-The Facts
Christina Apthorp | 27 March 2017

Sickle cell anaemia is an inherited blood disorder where red blood cells, which carry oxygen around the body, develop abnormally. Sickle-cell disease is associated with a number of acute and chronic health problems such as lethargy (a lack of energy), tiredness and breathlessness (particularly after exercise), as well as severe infections, attacks of severe pain ("sickle-cell crisis"), and an increased risk of death. Almost 300,000 children are born with a form of sickle-cell disease every year.

 

The condition was first described in the medical literature by the American physician James B. Herrick in 1910, and in 1949 contributions by Nobel prize-winner Linus Pauling made it the first human disease where the exact genetic and molecular defect was successfully understood.

 

A genetic mutation in the gene producing haemoglobin causes Sickle-cell anaemia. This is due to the DNA molecules that produces some amino acid chains in haemoglobin. The change is due to the nucleotide base adenine substituted by the nucleotide base thymine. The normal DNA triplet on the template strand is changed from CTC to CAC. Therefore the mRNA produced has a different code and codes for a different amino acid, forming polypeptides with different characteristics. Normal red blood cells are flexible and disc-shaped, but in Sickle-cell anaemia they can can become rigid and shaped like a crescent (or sickle). The sickle-shaped cells contain defective haemoglobin (the iron-rich protein that enables red blood cells to carry oxygen from your lungs to the rest of the body). The abnormal cells are also unable to move around as easily as normal shaped cells and can block blood vessels, resulting in tissue and organ damage and episodes of severe pain. Such episodes are known as a sickle cell crisis or a vaso-occlusive crisis. They can last from a few minutes to several months, although on average most last five to seven days. The abnormal blood cells also have a shorter lifespan and aren't replaced as quickly as normal blood cells. This leads to a shortage of red blood cells, known as anaemia. The changed mRNA codes for the amino acid valine rather than for glutamic acid. This minor difference produces a molecule of haemoglobin (called haemoglobin S) that has a 'sticky patch'. When the haemoglobin molecules are not carrying oxygen (i.e. at low oxygen concentrations) they tend to adhere to one another by their sticky patch and become insoluble, forming long fibres within the red blood cells. These fibres distort the red blood cells, making them inflexible and sickle (crescent) shaped. These sickle cells are unable to carry oxygen and may block small capillaries because their diameter is greater than that of capillaries.

 

Sickle-cell anaemia is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs or symptoms of the condition. As Sickle-cell anaemia is the result of a gene that has two codominant alleles (conditions in which both alleles for one gene in a heterozygous organism contribute to the phenotype), HbA (normal) and Hbs (sickled). This gives three different possible genotypes combinations of these two alleles:

 

Homozygous for haemoglobin S (Hbs Hbs) individuals suffer from sickle-cell anaemia and are likely to die young if they do not receive medical attention. The complications of sickle-cell disease can be prevented to a large extent with vaccination, preventative antibiotics, blood transfusion, and the drug hydroxyurea (a small proportion requires a transplant of bone marrow cells). They rarely live long enough to pass their genes on to the next generation. Their anaemia is so severe it outweighs the advantages of being resistant to one form of malaria. So individuals are always selected against.

 

Homozygous for haemoglobin A (HbA HbA) individuals lead normal healthy lives, but are susceptible to malaria in areas of the world where the disease is endemic and they are therefore selected against only in these regions.

 

Heterozygous for haemoglobin (HbA Hbs) individuals are said to have sickle-cell traits, but are not badly affected, except when they oxygen concentration of their blood is low (e.g. exercising muscles). Sufferers may therefore become tired more easily but, in general, the condition is symptomless. They do, however, have resistance to malaria and this advantage outweighs the disadvantages of tiredness in areas of the world where malaria occurs. Heterozygous individuals are therefore selected against in areas without malaria, but selected for in areas where malaria is common.

 

Sickle-cell conditions have an autosomal recessive pattern of inheritance from parents. The types of haemoglobin a person makes in the red blood cells depend on what haemoglobin genes are inherited from their parents. Sickle-cell gene mutation probably arose spontaneously in different geographic areas, as suggested by restriction endonuclease analysis.

 

Different crosses:

 

 

  • homozygous for haemoglobin A (normal) and homozygous for haemoglobin S (sickle-cell anemia)

 

 

 

HbA

HbA

Hbs

HbA Hbs

HbA Hbs

Hbs

HbA Hbs

HbA Hbs

 

This would cause a 100% frequency of genotype HbA Hbs, heterozygous, individuals who have sickle-cell traits, but are not badly affected. However are resistance to malaria.

 

 

  • homozygous for haemoglobin A (have sickle-cell anemia but not badly infected) and heterozygous for haemoglobin (have sickle-cell anemia but not badly infected)

 

 

 

HbA

HbA

HbA

HbA HbA

HbA HbA

Hbs

HbA Hbs

HbA Hbs

 

This would cause a 50% frequency of genotype HbA HbA, homozygous for haemoglobin A, individuals lead normal healthy lives, but are susceptible to malaria. As well as 50% frequency of genotype HbA Hbs, heterozygous, individuals who have sickle-cell traits, but are not badly affected. However are resistance to malaria.

 

(They same 50:50 ratio would be given mating homozygous for haemoglobin S and heterozygous, however it would be for Hbs Hbs and HbA Hbs)

 

 

  • Heterozygous for haemoglobin (normal) and heterozygous for haemoglobin (have Sickle-cell anemia but not badly infected)

 

 

 

HbA

Hbs

HbA

HbA HbA

HbA Hbs

Hbs

HbA Hbs

Hbs Hbs

 

This would cause a 25% frequency of genotype HbA HbA, homozygous for haemoglobin A, individuals lead normal healthy lives, but are susceptible to malaria. A 50% frequency of genotype HbA Hbs, heterozygous, individuals who have sickle-cell traits, but are not badly affected. However are resistance to malaria. As well as 25% frequency of genotype Hbs Hbs, homozygous for haemoglobin S, individuals suffer from Sickle-cell anaemia.

 

 

  • homozygous for haemoglobin A (normal) and homozygous for haemoglobin A (normal) would produce 100% frequency homozygous for haemoglobin A

 

 

  • homozygous for haemoglobin S (Sickle-cell anaemia) and homozygous for haemoglobin S (Sickle-cell anaemia) would produce 100% frequency homozygous for haemoglobin S

 

 

The highest frequency of Sickle-cell disease is found in tropical regions, particularly sub-Saharan Africa, India and the Middle-East. Migration of substantial populations from these high prevalence areas to low prevalence countries in Europe has dramatically increased in recent decades and in some European countries Sickle-cell disease has now overtaken more familiar genetic conditions such as Haemophilia and Cystic Fibrosis. In 2010, there were about 29,000 deaths attributed to Sickle-cell disease globally. Sickle-cell disease occurs more commonly among people whose ancestors lived in tropical and sub-tropical sub-Saharan regions where malaria is or was common. Where malaria is common, carrying a single Sickle-cell allele (heterozygous) gave a selective advantage. Specifically, humans with one of the two alleles of Sickle-cell disease show less severe symptoms when infected with malaria. Three quarters of sickle-cell cases occur in Africa. The malarial parasite, Plasmodium, is unable to exist in sickle red blood cells. The disorder mainly affects people of African, Caribbean, Middle Eastern, Eastern Mediterranean and Asian origin.

 

In England, about 250,000 people are thought to have the sickle cell trait (far less than in Africa) , with those of African-Caribbean origin primarily affected. In the Europe, Sickle-cell disorders are most commonly seen in African and Caribbean people. This is because there is little risk of malaria. So by having resistance to malaria doesn't outweigh the disadvantages of tiredness in areas of the world where little to no malaria occurs. Therefore individuals with the trait are not selected. Sickle-cell anaemia is far less common in Europe compared to Africa.

 

Sickle-cell anaemia is a codominate genetic disease which causes red blood cells to develop abnormally, with it being most present in African countries due to natural selection.

 

Reference:

1. AQA Biology A2 Textbook page 273-274 - Nelson Thornes

2. NHS website - http://www.nhs.uk/Conditions/sickle-cell-anaemia/Pages/introduction.aspx

3. Wikipedia - http://en.wikipedia.org/wiki/Sickle-cell_disease

4. National Heart, Lunch and Blood Institute - http://www.nhlbi.nih.gov/health/health-topics/topics/sca/

5. Genetic Home Reference - http://ghr.nlm.nih.gov/condition/sickle-cell-disease

6. Mayo Clinic - http://www.mayoclinic.org/diseases-conditions/sickle-cell- anemia/basics/definition/con-20019348

7. Medicin Net - http://www.medicinenet.com/sickle_cell/article.htm

James Routledge 2016