IX. GENETICS AND HUMAN HEMOGLOBIN CHEMISTRY 457 



the ^ genes during adult life or the y genes during fetal life produce 

 (3.i and y-z dimers in excess over the available an dimers. A similar situa- 

 tion is not observed in conditions involving a decrease in /? chains 

 production (as in ft thalassemia). No abnormal aggregation of a.. 

 dimers is observed in this disease and no evidence of an accumulation 

 of these dimers has been reported. The a gene seem thus to have a non- 

 autonomous regulation. The amount of a chains produced seems to be 

 dependent on the amount of y or /? chains available; if not enough (3 or 

 y chains are made, the production of a chains seems to be lowered in a 

 parallel and corresponding way. It is not known how this control is 

 achieved; one can guess that steric hindrance factors, prohibiting the 

 polymerization of a chains, are of importance, if the solubility of the 

 dimers or of the single chains is low in physiological conditions. One 

 can visualize an equilibrium between a peptide chains sitting on or in 

 the proximity of the ribosomal templates, dimerization of the a chains, 

 and release of the a-^ dimers upon combination with /J-, ys, or 82 dimers. 

 The answer to these questions may possibly come from experiments on 

 hemoglobin synthesis in reticulocytes or in cell-free systems (Dintzis, 

 1961) (see Schweet and Bishop, Chapter VIII). 



Within the hemoglobin peptide chains there are extreme variations 

 in the rate of synthesis. Hb-Ao (uo''" 82"^=) represents approximately only 

 2.5% of the hemoglobin in normal adults. For eveiy 40 ft-'' chains only 

 one 8-^- chain is synthesized. This ratio is quite constant, within the 

 limits of random variability, and is only found to be altered in favor of 

 the 8 chains when ft chains are produced with lower efficiency, as in 

 ft thalassemia. One wonders how this constant ratio is maintained and 

 why the 8 chains, which are extremely similar to the ft chains from a 

 chemical point of view, are produced with so much lower an efficiency. 

 The existence of controlling genetic elements has been postulated by 

 sevei'al authors (see Neel, 1961); in their view the synthesis of the 8 

 chains is repressed by a specific regulator gene or, vice versa, the syn- 

 thesis of ft chains is activated to a higher extent by a specific regulator 

 gene. Thalassemia may then correspond to a mutation of a regulator 

 gene, rather than of a stmctural gene (Ingram and Stretton, 1959b). 

 No clear-cut genetic or chemical evidence has so far been presented in 

 support of this hypothesis. 



2. The Rate of Synthesis of Abnormal Peptide Chains 



The finding of Pauling et al. (1949) that an abnormal hemoglobin 

 is present in lower amounts than Hb-A has been confirmed for all the 

 abnormal hemoglobins discovered. The only possible exception to this 

 rule reported in the literature is Hb-J (Thorup et al., 1956). 



