Normal haemoglobin is called hemoglobin A but people with sickle cell disease have only hemoglobin S which turns normal, round red blood cells into abnormally curved (sickle) shapes. Normally, a person inherits two, copies of the gene that produces beta globin, a protein needed to produce normal hemoglobin (hemoglobin A, genotype AA). A person with sickle cell trait inherits one normal gene and one abnormal gene encoding hemoglobin S (hemoglobin genotype AS).
Independent Origins of the Sickle Cell Gene.
Two mutations found in non transcribed sequences of DNA adjacent to the B-globin gene are so close to each other that the likelihood of crossover is very small. Restriction endonuclease digests of the B-globin gene cluster have shown five distinct patterns associated with sickle cell (CAG-GTG) mutation (Almeida and Roberts, 2005).
Four are observed in Africa, the Bantu, Benin, Sengal and Cameroon types and a fifth type is found in the Indian subcontinent and Arabia. The cited authors repot that haplotype analysis in the B-globin region shows strong linkage disequilibrium over the distance indicated which shows that Hbs mutation occurred independently at least five times. The high level of AS in parts of Africa and India presumably resulted from independent selection occurring in different populations living in malarious environments.
The demonstration that sickle cell heterozygoten have some degree of protection against P. falciparum was the first example of genetically controlled innate resistance to human malaria as recognized by experts on inherited factors affecting human infectious diseases (Alcais, et al, 2009). It was also the first demonstration of Darwinian selection in humans as recognized by evolutionary biologists (carrol, 2009).
Distribution of the Sickle Cell Gene
Since sickle cell homozygotes are at a strong selective disadvantage, while protection against malaria favours the heterozygotes, it would be expected that high frequencies of the Hbs gene would be found only in populations living in regions where malaria transmission is intense. Frequencies of sickle cell heterozygotes are 20-49% in malarious areas, whereas they are very low in the highlands of Kenya, Uganda and Tanzania. (Allison, 2009).
High frequencies of the Hbs gene are confined to a broad belt across central Africa, but excluding most of Ethiopia and the East African highlands, this corresponds closely to areas of malaria transmission. Sickle cell heterozygote frequencies up to 20% also occur in pockets of India and Greece that were formerly high Malarious. Thousands of individuals have been studied, and high frequencies of abnormal hemoglobins have not been found in any population that was malaria free (Piel, et al, 2010).