MECHANISMS OF GENE ACTION 283 



no recombination between the factor determining sickle cell disease and 

 that determining the particular anemia in which HhC is produced. 



Thus gene mutation at a particular site in the DNA has resulted in 

 single amino acid substitutions at a particular site in the protein. These 

 findings support the view of a very precise relationship between muta- 

 tional!) altered DNA and altered protein. It should be noted, however, 

 that the genetic data, coming from human pedigrees, are far less precise 

 than are the chemical data. 



Additional forms of hemoglobin are being reported at an accelerating 

 rate, as improved methods for their detection become available. A 

 number of them are listed in Table 10.2. Most of them were detected 

 initially by altered electrophoretic mobility resulting from a charge 

 difference. If one uncharged amino acid is substituted for another un- 

 charged one, the altered protein may not be detected. Consequently, 

 there may be many more forms of hemoglobin than are now known, and 

 their recognition will depend upon a different principle of separation. 

 The same problem applies to the detection of other altered proteins. 



The dramatic clarity of the hemoglobin story supports the optimistic 

 view that gene action may be a simple process in which genes determine 

 amino acid sequence, and sequence in turn determines the folded, bio- 

 logically active configuration of the protein. This view proposes the 

 simplest possible solution to two outstandingly complex problems: gene 

 action, and the relation of sequence to folding in protein structure. The 

 very simplicity of this view recommends it. There are, however, numer- 

 ous observations which do not fit well with this hypothesis. Before dis- 

 cussing them, we shall digress briefly to re\iew some current concepts 

 in the field of protein structure which are directly pertinent to our 

 problem. 



SOME CONCEPTS OF PROTEIN STRUCTURE 



Proteins are large polymers built of approximately 20 different amino 

 acids, held together by covalent peptide bonds. From the chemical 

 point of view, there is essentially equal probability that any amino acid 

 will be peptide-bonded with any other and, consequently, in a polymer 

 of 100 amino acids, 20^°*^ different arrangements are possible. Since 

 cells contain only several thousand different proteins, it is evident that 

 a very small group has been selected for biological activity from an al- 

 most infinite number of chemically possible molecules. 



Many cellular proteins are very large, containing thousands of amino 

 acids, and in their extended form encompassing lengths of several 



