GENETIC CONTROL 11 



tions originating from Nigeria, is characterized by an anomalous behaviour 

 of the red blood cells: when the oxygen tension is low, the blood cells 

 become twisted and under the microscope they look somewhat like sickles. 

 In 1949, Neel established that the disease is inherited in a mendelian 

 manner. Pauling et al. (1949) showed that the blood cells of individuals 

 carrying the sickle cell trait contain a haemoglobin which can be separated 

 from normal haemoglobin by electrophoresis. Sickle cell haemoglobin is a 

 little less negatively charged, and it is less soluble at low oxygen pressures 

 than normal haemoglobin; this lower solubility explains gelation and 

 sickling of the cells (Harris, 1950). 



Mutant individuals containing the sickle cell gene make a slightly abnor- 

 mal haemoglobin, just as some tryptophan-less mutants of Neurospora 

 make a slightly abnormal protein which has lost the catalytic properties of 

 tryptophan synthetase. Sickle cell anaemia manifests itself in the individ- 

 uals who are homozygous for the sickle cell gene; these make only sickle 

 cell haemoglobin, no normal haemoglobin. The disease is the consequence 

 of an inborn defect in haemoglobin, one of the best known of all proteins. 

 The molecule of haemoglobin is made of two identical halves (Perutz et al., 

 1951, 1960), each half containing two different polypeptide chains a and jS. 

 The complete amino acids sequence in haemoglobin is not known. Never- 

 theless, Ingram (1956, 1957) has been able to compare amino acid sequences 

 of haemoglobin S (sickle cell) and haemoglobin A (normal adult haemo- 

 globin). Haemoglobin is split by trypsin into 26 different peptides, and a 

 resistant core is left which can in turn be split into about as many peptides 

 by chymotrypsin. The peptides can be separated by paper chromatography 

 and the chromatograms display a pattern of spots which is sufficiently 

 constant and reproducible to be considered characteristic of the protein. 

 The 'finger prints' of haemoglobin A and S are nearly identical : no differ- 

 ence can be detected in the chymotrypsin digest of the trypsin resistant core 

 (Hunt and Ingram, 1958, 1959). Among the peptides produced by trypsin 

 hydrolysis, all except one are identical (Ingram, 1958) in both haemo- 

 globins. In the one peptide which differs between the two haemoglobins, 

 the only difference is the replacement of one glutamic residue by a valine 

 residue in S haemoglobin. 



More than 20 varieties of abnormal haemoglobins are known at present 

 (Itano, 1957; Ager et al., 1958) and many of them have been shown to be 

 genetically determined (Benzer et al., 1958). The finger print procedure 

 again revealed a great similarity of structure between these variants and 

 normal haemoglobin; in all the cases analysed so far, each haemoglobin 

 differs from the others by the substitution of one amino acid for another 

 one, as shown in Fig. 11. 



These remarkable studies clearly show that mutation of a gene can result 

 in the replacement of one amino acid by another in the protein, without any 



