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Induction of Specific Mutations with 5-Bromouracil

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  • Caltech Library Services
  • Chemistry
  • Medicine
  • Physics


The hereditary characteristics of an organism occasionally undergo abrupt changes (mutations), and genetic techniques have traced these to alterations at definite locations in the genetic structure. Recently, the fineness of this genetic mapping has been extended to the level where the finite molecular units (nucleotides) of the hereditary material limit further subdivision. At this level, local details of the hereditary material should exert their influence; the frequency of mutation at a particular point should depend upon the local molecular configuration. It is therefore feasible to try to correlate genetic observations with precise molecular models, such as the one proposed by Watson and Crick [1] for the structure of DNA. In a fine-structure study of spontaneous mutations in phage T4, the mutability at different points in the genetic structure was, in fact, found to be strikingly varied [2]. To relate mutability to actual chemical structure, it would seem promising to employ mutagenic agents of specific types, to act selectively on particular configurations. Since the initial discovery by Muller [3] and Stadler [4] on induct on of mutations with X-rays and the discovery of chemical mutagenesis by Auerbach and Robson [5] and by Oehlkers [6], many physical agents and chemical substances have been found to be mutagenic in many organisms. Some mutagens act selectively; in particular the induced reversion from biochemically dependent to independent strains has been shown to depend upon the mutant and the mutagen used. (For chemical mutagens in bacteria see Demerec [7].) A recent comprehensive review of this subject has been published by Westergaard [8]. Mutagens in some cases produce gross chromosomal aberrations; in others the alterations are so small as to be beyond the limited resolving power of genetic techniques for the organism used. The absence of this limitation makes phage a suitable organism for our purposes. There have been reports of induction of mutations in phage by ultraviolet light [9,10] nitrogen mustard [11], streptomycin [12], and proflavine [13]. A very provocative discovery is that analogues of the normal bases may be built into DNA in place of the usual ones and also raise the mutation rate. In particular, one such analogue, 5-bromouracil, has been proven by Dunn and Smith [14] to be incorporated into the DNA of phage (in place of thymine), and Litman and Pardee [15] have shown that it greatly increases the frequency with which phage mutants of various types arise. In the present work, this possibility of directly affecting the DNA structure is combined with a genetic analysis of high resolving power, to make a fine-structure study of mutagenesis. Our attention will be restricted to the rII region of the genome of phage T4. The mutational alterations arising by 5-bromouracil induction are compared to, and shown to differ from, those which occur spontaneously.

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