398 



< IIU'TFR 31 



figure 31—5. One postulated sequence of 

 events leading to transition or transversion. 



mutagens, and low pH may ultimately cause 

 base substitution. Replacement of one pu- 

 rine by another purine (A«-»G) or one 

 pyrimidine by another pyrimidine (T<-»C) 

 is called transition; replacement of a purine 

 by a pyrimidine or the reverse (for example 

 A«-*C or TeG) is called transversion. 14 

 Both kinds of substitution should be possible 

 at the nucleotide and subnucleotide level. 



What is the sequence of events involved 

 in a transition or transversion? A particular 

 base pair, T:A, exposed to a mutagen may 

 become T:A' (Figure 31—5). For exam- 

 ple, suppose that at the time of strand sep- 

 aration, A' specifies C (instead of T), and 

 at the next division C acts normally to spec- 

 ify G. The net result is that the original A 

 strand eventually produces a second-genera- 

 tion strand carrying G; this is a transition. 

 (Or, given the original pair G-C, a mutagen 

 may produce C' which specifies A instead 

 of G which, in turn, specifics T. The net 

 change from C to T in this example is also 

 a transition.) If A:T becomes A:T', T' 

 specifies C, and C specifies G, the overall 

 result is that T is replaced by G, and a trans- 

 version occurred. 



Another possible mechanism for intranu- 



14 Following the terminology of E. Freese. 



cleotide base changes requires the members 

 of a base pair to undergo rotational substi- 

 tution by breaking their bonds to sugar, ro- 

 tating 180 . and rejoining. 1 Thus, after 

 rotational substitution, which may be a fre- 

 quent consequence of ion action, C-G be- 

 comes GjC, the resultant double transver- 

 sion being mutant. Note that in all the 

 mechanisms mentioned for producing base 

 changes, the transitions and transversions 

 were initiated by a change in the old base. 



Base changes in new genes. Base analogs 

 are incorporated into DNA in vitro when 

 they are present as deoxyriboside 5'-triphos- 

 phates (p. 284). For example, uracil (U), 

 5-bromo uracil (BU), or 5-fiuoro uracil 

 (FU) can be substituted for T only; 5- 

 mcthyl, 5-bromo, or 5-fluoro cytosine can 

 be substituted for C only; hypoxanthine can 

 be substituted for G only. BU, 5-chloro 

 uracil, and 5-iodo uracil can replace some 

 of the T in DNA of bacteria, phages, and 

 human cell lines and are also highly muta- 

 genic. 5-Bromo deoxyuridine (BUdR) is a 

 more efficient mutagen than BU, probably 

 because it is more readily converted to the 

 triphosphate condition and interferes less 

 with the formation of U or C. 



Consider the kinds of mistakes which may 

 occur involving BU. Since the usual tauto- 

 mer of BU (like T) is in the keto state, this 

 tautomer is usually incorporated as the com- 

 plement of A. The rare enol tautomer of 

 BU (like T), however, can pair with G, 

 forming BU;G. Consequently, two kinds 

 of mistakes of incorporation of BU are pos- 

 sible: formation of the A:BU and the 

 GjBU pairs. Once part of a DNA strand, 

 the BU of an A:BU pair can continue to 

 specify A. so that no mistakes in replication 

 occur. If, however, such a BU assumes its 

 rare enol state and accepts G as its comple- 

 ment, the grandparental A will be replaced 



'•"'See H. J. Muller, E. Carlson, and A. Schalet 

 ( 1961 ). 



