MUTATION AS A CHEMICAL PROCESS 217 



quency than does the base it replaced; it would therefore reduce the 

 chance of mutation and make the gene more, rather than less, stable. 



Although there is still much to be learned, we no longer need conceive 

 of mutant alleles as existing in different thermodynamic energy troughs 

 for completely unspecified reasons. Watson and Crick, in originally 

 proposing their model, noted that the bases may sometimes be in a rare 

 tautomeric state. Adenine, for example, oscillates between the two 

 states shown in Figure 8.8. In the first, or common, state it is capable 

 of fitting opposite thymine in the double helix, but in the second, or 

 rare, state it is compatible only with cytosine, of the four bases. If it 

 were in this rare state at the moment of duplication, it would be likely 

 to choose cytosine as its mate, and this base would be incorporated in 

 the new polynucleotide strand. At the next replication, guanine would 

 pair with cytosine and a transitional change in base order would have 

 been accomplished. In comparable ways, molecular mechanisms must be 

 envisaged for mutations that occur by transversion. 



POINT MUTATIONS VERSUS GROSSER CHANGES IN THE GENE 



The mechanisms of point mutation discussed above have all presumed 

 that the molecular event was at the level of nucleotide pairs and involved 

 a base substitution. Since many mutations can be localized well within 

 the extent of the functional gene, this presumption seems a valid one. 

 Nonetheless we must leave open the possibility that mutations may be of 

 many kinds. Some may involve breaks in the backbone of the poly- 

 nucleotide strands. Such breaks can be induced by ionizing radiations 

 and by radiomimetic alkylating agents, such as the sulphur and nitrogen 

 mustards and the epoxides. Double breaks at the same level, one in 

 each complementary strand, would not heal with a switching between the 

 two strands because of the polarity of structure which runs in an oppo- 

 site direction in each polynucleotide chain of the DNA double helix. If 

 they did not heal to restore the original continuity, they would cause 

 a fragmentation of the DNA molecule. But breaks in different positions 

 in the two strands and breaks in the same strand would not immediately 

 cause degradation of the DNA because the fragmented strands would 

 remain attached to each other by hydrogen bonds, and the breaks 

 would remain cryptic until these bonds were parted. Urea will separate 

 the twin strands of DNA, and it has been shown to reveal breaks 

 induced by treatment with X-rays or alkylating agents (Figure 8.9). 

 One consequence of double breaks in the same strand might be a dele- 

 tion, yielding defects which would occupy loci including one or more 



