126 MUTATIONS 



found particularly fascinating, right from the beginning of my work 

 with chemical mutagens. The possibility was raised already whether 

 chemical mutagens may act more specifically than radiation, whether 

 certain loci respond to certain mutagens better than to others. 



There is no doubt that this is true in an operational sense. There 

 have been many instances now where the pattern of response to a 

 variety of mutagens differs between loci. What I want to discuss and 

 also want to study myself is at what level of the mutagenic process this 

 specificity happens. 



Dr. Zamenhof has stressed again and again the fact that mutation 

 is a complex process, a process with many steps, and I want to discuss 

 each of them separately to show that what is observed as mutagen 

 specificity may occur at any one of these steps. 



I want to say one thing beforehand, for those who are interested 

 only in the decoding. In using chemical mutagens as a means for 

 decoding the DNA there is, of course, no interest in mutagen specificity 

 at any level except that of the DNA. All other specificities are just 

 obstacles, and so the kind of work which I am going to discuss now, 

 the kind of approach, will have only negative value because it removes 

 red herrings. But if one is interested in the whole process of mutagenesis 

 in the cell, at the cellular level, I find that chemical mutagens and 

 their specific effects may be very useful tools for unraveling what 

 happens at these other steps. 



If we have a nonmutated gene in a nonmutated cell, the mutagen 

 has to reach the gene. It has to penetrate to the gene and also, pre- 

 sumably, will interact with the cytoplasm. I think in higher organisms 

 one should not forget that it also has to interact in some way with 

 the protein with which the gene is associated. 



After this comes a step which leads to — I forget what Witkin calls 

 it — the premutated gene. This state certainly occurs after UV and pos- 

 sibly also after other mutagens. In this state the gene still has, so to 

 speak, a choice. It may recover and go back to the original condition or 

 it may go on to the actual mutated state. After this, we have a mutated 

 gene in a nonmutated cell; this mutated gene now has to change the 

 biochemical pattern of the cell, which it has to do in the face of com- 

 petition from other cells in the same environment, and it has to over- 

 come obstacles there which as I shall show with some examples, 

 may lead to specificity. Finally, then, we end up with the mutated 

 gene in the mutated cell. 



I want to illustrate this by a few examples. Mutagen specificities in 

 macroorganisms are complicated to analyze because it is so difficult to 



