Chapter 31 



THE MOLECULAR BASIS 

 OF MUTATION 



T 



|he spontaneous mutation fre- 

 quency is influenced by natu- 

 rally-occurring physical muta- 

 gens such as ultraviolet light and ionizing 

 radiations (Chapter 13) and probably by nat- 

 urally-occurring chemical mutagens (Chap- 

 ter 14); mutability is also under consid- 

 erable genetic control (Chapter 30). The 

 correlation found betwen mutagenicity and 

 the wavelength of ultraviolet light suggests 

 that nucleic acids are involved in the muta- 

 tion process (p. 261). What, then, is the 

 detailed molecular basis of spontaneous and 

 induced mutation? 



Mutagens and Antimutagens 



In E. coli auxotrophic for tryptophan, the 

 spontaneous mutation rate from sensitivity to 

 resistance to infection by 4>T5 or ^>T6 is 

 found to depend upon whichever component 

 of the nutrient medium is made the limiting 

 factor for growth. 1 The highest rate is ob- 

 tained when the growth-controlling factor in 

 the medium is tryptophan; the lowest rate is 

 obtained when the growth-controlling factor 

 is lactate. 



This result indicates that the spontaneous 

 mutation rate depends upon the physiological 

 or biochemical state of the organism — a view 

 also supported by the effect of temperature 

 changes upon the spontaneous mutation rate 

 (p. 192) — and suggests that chemical sub- 

 stances added to a culture of E. coli growing 



1 Based upon work of A. Novick and L. Szilard 

 (1951). 



391 



in a medium limited in one essential nutrient 

 would have a pronounced mutagenic effect. 



By testing various substances in concen- 

 trations that produce no appreciable killing 

 of tryptophan-limited bacteria, many purines 

 and purine derivatives are found to be muta- 

 genic. The most mutagenic is caffeine; 

 theophylline is nearly as effective; azaguanine 

 is mutagenic, and — to a lesser degree — ade- 

 nine. In contrast, no pyrimidines or their 

 derivatives are mutagenic under the same 

 conditions. If purine ribosides such as aden- 

 osine or guanosine are added to the medium 

 containing any one of several purine muta- 

 gens, the mutagenic activity is completely 

 suppressed.- Thus, for example, adenosine 

 completely suppresses the mutagenicity of 

 adenine or caffeine. Clearly the purine ribo- 

 sides are acting as antimutagens — just as an- 

 oxia or catalase are antimutagens so far as 

 chromosomal breakage (p. 182) or point 

 mutations (p. 192) produced by X rays are 

 concerned — and are not acting as selective 

 agents against induced mutants. On the 

 other hand, pyrimidine ribosides, deoxyaden- 

 osine, and deoxyguanosine either are not 

 at all antimutagenic to purines and their 

 derivatives, or they are much less efficient 

 than the purine ribosides. 



Theophylline is mutagenic under aerobic 

 but not anaerobic conditions. Adenosine, 

 however, is present in significant concentra- 

 tions in bacteria growing anaerobically but 

 not detectable in bacteria growing aerobically. 

 Under anaerobic conditions, adenosine is ap- 

 parently a normally-present antimutagen that 

 counteracts the effect of purines added in the 

 medium. Note that anacrobiosis has no 

 effect on the ultraviolet-induced mutation 

 rate and makes gamma radiation less effec- 

 tive only because of the reduction in oxygen; 

 such a result is consistent with the finding 

 that extra adenosine has no antimutagenic 

 effect on either ultraviolet or gamma radia- 

 tion mutagens. 



-See A. Novick (1956). 



