Genetics

The genetic basis of sickle cell anemia is central to the history of medical genetics. The disease was first described by Herrick (1910), a cardiologist, who observed sickle-shaped red cells (Figure 14.3) in the blood of a medical student from Grenada, who suffered from chronic hemolytic anemia. James V. Neel was the first to suggest that sickle cell anemia was a homozygous state and sickle trait (the asymptomatic carrier state) was a heterozygous state of a genetic character that had not yet been defined. Linus Pauling proposed that the sickling represented an abnormality of the hemoglobin molecule, based on the observation of the medical student that sickle cells, induced by deoxygenation, were birefringent. Birefringence indicated to Pauling that some type of molecular alignment or orientation existed inside these red cells, and since hemoglobin predominates overwhelmingly it had to be this particular protein which was involved in the pathology. Electrophoretic studies confirmed this interpretation and the concept of molecular disease was born.

The biochemical definition of Hb S was achieved by Vernon Ingram, who developed a technique capable of probing the primary sequence of a protein, and revealed that sickle hemoglobin differed from normal hemoglobin by a single peptide, which was later found to have a single amino acid change in position 6 of the P chain, in which a glutamic acid was replaced by a valine. At the gene level the change was A^ T in the middle nucleotide of codon 6 of the P chain.

The globin genes were among the first to be located in the human genome, the P and P-like globin genes mapping to chromosome 11. Using 11 polymorphic sites located in the P

Fig. 14.3 Sickled cell

This is an Hb S-homozygous (SS) red cell that has been deoxygenated. Notice the digitations stemming in all directions. These digitations are the product of the presence of fascicles of fibers, which are the polymerized form of deoxyHb S.

Fig. 14.3 Sickled cell

This is an Hb S-homozygous (SS) red cell that has been deoxygenated. Notice the digitations stemming in all directions. These digitations are the product of the presence of fascicles of fibers, which are the polymerized form of deoxyHb S.

gene cluster, it has been established that the PS gene is associated with three distinctly different chromosomal haplotypes in Africa, identifiable by their specific array of DNA polymorphic sites (haplotypes), each one exclusively present in three separate geographical areas in Africa (Figure 14.4). Finally, a rather small ethnic group in southern Cameroon, the Eton people, have their own haplotype linked to the sickle gene.

The sickle gene has arisen around the world on at least five separate occasions, but the present-day gene frequencies demonstrate that the heterozygote is favored, compensating for the lower fitness of the homozygous state (balanced polymorphism). The selective pressure involved is the protective effect of Hb S in sickle carriers against Plasmodium falciparum malaria.

The multicentric origin of the sickle gene in the world expanded when a different haplotype was found to be associated with this gene in the eastern oasis of Saudi Arabia and among the 'tribals' of India. This Indo-European sickle mutation has been proposed to have originated in the Harappa of the

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