IX. GENETICS AND HUMAN HEMOGLOBIN CHEMISTRY 453 



of the amino acid sequence, for instance, are j^robably not revealed by 

 the fingerprinting analysis or by the analysis of the amino acid com- 

 position of peptides; the only conclusive chemical evidence is the deter- 

 mination of the entire primary sequence of the "Hb-A" from a thalas- 

 semic. To reach this goal may require years of hard work. 



Moreover, very little is known about the effect of a change in the 

 genetic information of a structural gene on the primary sequence of the 

 corresponding peptide chain. Some mutations may not result in an altera- 

 tion of the primary structure of a peptide chain, but only in a difficult 

 "reading" of the genetic code: i.e., ambiguity in the genetic information 

 may cause the production of a large proportion of senseless peptide 

 chains unable to fold, or a difficulty in translating the genetic code may 

 slow down the synthesis of a peptide chain. An alternative hypothesis 

 has been advanced by Ingram and Stretton (1959b), based on Freese's 

 (1958) idea of "connecting units" alternating in linear arrangement with 

 structural genes. If these connecting units serve to induce or repress 

 structural genes, then thalassemia may be the consequence of a change 

 of these regulators. How^ever, thalassemia is not likely to be a mutation 

 of an ''i" type gene, in the teniiinology of Jacob and Monod (1961); 

 mutations of these genes exhibit a ti'ans effect, which is not observed 

 in thalassemia. Only the synthesis of the a or /? peptide chain in cis 

 with the thalassemic mutation is repressed. The validity of a comparison 

 between the function of the genes of a bacterial chromosome with the 

 genes of higher organisms' chromosomes is, however, questionable. The 

 complexity of chromosomal structures in higher organisms and the 

 larger dimensions of the genetic material may limit the diffusion of 

 repressor or inducer molecules to neighboring groups of genes and mimic 

 in this way a cis effect. 



H. ABNORMAL HEMOGLOBINS FROM ALTERED AGGREGATION OF 

 PEPTIDE CHAINS 



Under this denomination are classified abnormal hemoglobins which 

 are not properly described as variants of the normal hemoglobins. 



1. Hb-H 



Rigas et al. (1955) and Gouttas et al. (1955) described this electro- 

 phoretically fast moving hemoglobin, characterized by instability and 

 denaturation on storage. Hb-H is precipitated in the erythrocytes as 

 inclusion bodies on incubation with cresyl blue. 



Jones et al. (1959a) have shown that Hb-H is made up of four /3-^ 

 chains. Motulsky (1956) pointed out the close association between Hb-H 

 and thalassemia; Hb-H carriers usually pi-esent the blood picture char- 



