GENETIC CONTROL 19 



(b) Difficulties in the use of the cistron concept. Further studies on cases 

 of complementation in heterocaryons between mutants deficient in the 

 same enzyme showed that the apphcation of the cistron concept as the unit 

 of function of genetic material in enzyme synthesis can lead to absurdity. 



Thus Giles et al. (1957) studied several mutants of the locus responsible 

 for adenylosuccinase synthesis. Certain associations of two such mutants in 

 a heterocaryon gave complementation, others did not. The puzzling situa- 

 tion which follows was observed: mutants A and B gave no complementa- 

 tion, which means that they were in the same cistron, by definition. In the 

 same way, mutants B and C were also found to be in the same cistron. 

 However, A and C gave complementation and — by definition — were not 

 in the same cistron. These three conclusions are obviously incompatible. 



Similarly, Pateman and Fincham (1958) found that out of eleven 

 mutants in the glutamic dehydrogenase locus of Neurospora crassa, only 

 two pairwise combinations produced enzyme activity in heterocaryons, 

 whereas all the others gave no complementation. Again some pairs of 

 mutants were therefore in the same cistron, according to certain experi- 

 ments, and in different cistrons according to other experiments. In such 

 cases, the notion of cistron breaks down. The reason is most probably that 

 the operational definition of the cistron by the cis-trans test rests on the 

 common sense idea that adding two bad things together does not make a 

 good one. This assumption is not entirely justified. Fincham (1960) has 

 shown that the functional glutamic dehydrogenases produced by com- 

 plementation are not identical to the normal enzyme: they diff"er from the 

 wild type dehydrogenase and from each other in their thermostability, and 

 they have abnormal Michaelis constants. The co-operation of the genomes 

 of these mutants therefore has not reconstituted the normal protein, it has 

 produced doubly abnormal proteins. But these happen to have an enzymic 

 activity sufficiently similar to that of the normal enzyme to be functional. 

 The molecule of glutamic dehydrogenase results of the association of 

 several identical polypeptide chains. It is conceivable that polypeptides 

 with lesions in different places might be able to cover each other's deficien- 

 cies and to form an almost correctly folded protein structure with almost 

 normal enzyme activity (Fincham, 1960; Catcheside, 1960). 



Fincham's observations are of great interest for protein synthesis. They 

 are compatible with the idea that the genetic locus strictly controls the 

 primary structure of the polypeptide chains (the amino acid sequence), and 

 they call attention to the fact that the appearance of the specific catalytic or 

 serological properties associated with the protein produced is an epiphe- 

 nomenon. This depends on eventual association of the polypeptide chains, 

 on their folding into helices, and on the manner parts of helices twist 

 around each other, thus bringing together the elements which constitute 

 the active centre of the enzyme, or the particular surface of the antigen. 



