Forward and Back Mutations

Although the rates of spontaneous mutation are low, they can be greatly increased by mutagenic chemicals (Chapter 27) or by irradiation. It is perfectly practical to measure the rates of both forward and back mutation. When this was done, it was found that certain chemicals, e.g., acridine dyes, induce mutations that undergo reverse mutation at a very much lower frequency than normal. It was eventually shown that these mutations resulted either from deletions of one or more nucleotides from the chain or from insertions of extra nucleotides. Deletion and insertion mutations often result from errors during genetic recombination and repair at times when the DNA chain is broken. 

In a study using cultured L5178Y mouse lymphoma cells, Rogers and Back (1981) reported that both 1,1-dimethylhydrazine and 1,2-dimethylhydrazine induced forward mutations at the thymidine kinase level in the absence of an extraneous metabolic activation system. The investigators also noted that the two dimethylhydrazines appeared to have different modes of action under these conditions. 

From the observed rate of appearance of point mutations (one mutation per 106 gene duplications), we can estimate that one mutation occurs per 109 replications at a single nucleotide site. Point mutants tend to "back mutate," often at almost the same rate as is observed for the forward mutation. That is, one in 109 times a mutation of the same nucleotide will take place to return the code to its original form. The phenomenon is easy to understand. For example, if T should be replaced by C because the latter formed a minor tautomer and paired with A, the mutation would appear in progeny duplexes as a GC pair. When this pair was replicated, there would be a finite probability that the C of the parental DNA strand would again assume the minor tautomeric structure and pair with A instead of G, leading to a back mutation. 

---