Index >> Phenotypic Expression of Genes (Biochemical genetics) >> Human Haemoglobin Genetics

	Human Haemoglobin Genetics The respiratory pigment, haemoglobin (Hb) of human red blood cells, chemically is a conjugated protein which is composed of four separate polypeptide chains and four iron containing ring compounds (heme groups). In general, globin protein of haemoglobin may be composed of four different kinds of polypeptide chains called alpha (α), beta (β), gamma (γ) and delta (δ). Each kind of polypeptide chain differs with each other in number and arrangement of amino acids. 98 percent haemoglobin of normal adult people (HbA) consists of two α -polypeptide chains (each of 141AA) and two β -chains (each of 146AA), so that the molecule can be written as αA αA βA βA (574AA, M. Xt. 67,000). HbA is thus a protein made up of more than one kind of polypeptide and is therefore called a hetero-polymeric protein.
A. (Haemoglobin A2 Hb-A2 ( α1 α2 δ1 δ2) B. Hb-A(Haemoglobin A)( α1 α2 β1β2) C. Hb-F(Haemoglobin A)( α1 α2 γ1γ2)   The rest 2 per cent haemoglobin of normal adult human blood contains two delta (δ) polypeptide chains instead of beta chains, such haemoglobin (HbA2) can be symbolized as αA αA δA δA. The haemoglobin of foetal blood has two gamma (γ) polypeptide chains instead of β -polypeptide chains, such haemoglobin (HbF) can be symbolized as αA αA γF γF. From these variants of haemoglobin [viz., αA αA βA βA (HbA), αA αA δA δA (HbA2), and αA αA γF γF (HbF)] it becomes evident that αA polypeptide chains are controlled by a single gene, while,  β, γ, δ polypeptide chains are controlled by different forms (alleles) of another single gene or some closely linked genes.
In 1949 Pauling and his coworkers reported that the formation of an abnormal haemoglobin (haemoglobin S, HbS) which differed in its electrophoretic mobility from normal haemoglobin (HbA) was the cause of hereditary disease the sickle-cell anemia in man. A.Normal Erythrocytes B. Erythrocytes from venous blood of a pateint with sickle-cell anemia
	The red blood cells of individuals suffering from this fatal form of hemolytic anemia undergo a reversible alteration in shape when the oxygen tension of the plasma falls slightly, and they assume elongate, filamentous, and sickle-like forms. Such red cells show a greatly shortened life span, since they tend to clump together and often causing vascular obstruction and are rapidly destroyed. The individuals with sickle-cell anemia have been found to be homozygous for an abnormal gene (HS). The blood cells of normal individuals (of genotypes HA/HA) never sickle, but the blood cells of perfectly healthy heterozygotes (HA/HA) can be caused to sickle provided the oxygen concentration is drastically reduced. Shortly after the discovery of haemoglobin S (HbS) the study of certain families which showed as aberrant system of inheritance of sickle-cell anemia led to the identification of a second abnormal haemologlobin C (HbC). HbC is also have a tendency of sickle-cell anemia.

The Hb^S and Hb^C traits, later on found to be controlled by two alleles of a single gene. The heme moieties of the different haemoglobin are identical, and it was suggested, therefore, that the differences in the net electric charge of Hb^A, Hb^S, and Hb^C,might result from modification in the amino acid sequence. Ingram (1957) showed subsequently that the difference between haemoglobins A, S, and C (i.e., Hb^A, Hb^S and Hb^C) resulted from amino acid substitutions.Each, β-chain of haemoglobin has 146 positions, each occupied by a specific amino acid. Position six is occupied by a negatively charged glutamic acid in Hb^A; whereas neutral valine and positively charged lysine are substituted at this position, in case of Hb^S and Hb^C, respectively, as illustrated in following manner:
Hb^A: val-his-Ieu-thr-pro-glu-glu-Iys … ..
Hb^S: val -his-leu-thr-pro-val-glu-Iys … ..
Hb^C: val-his-leu-thr-pro-lys-glu-Iys ... ..
These amino acids substitutions result in HbS and HbC molecules Dearing a net charge relative to Hb^A of 2+ and 4+. Such charge differences account for the observed differences in the electrophoretic points of the three molecules.

A. Normal	B. Sickle cell trait
C. Sickle cell anaemia

The available informations, therefore, indicates that in the case of haemoglobin at least two chromosomal genes are concerned with the formation of a single protein and that at each locus there occur a variety of alleles. The genetics of haemoglobin also gives the evidence in support of gene's relation with molecular structure of proteins (i.e., arrangement of amino acids in the polypeptide chains of a protein).