Genetic Aspects of Drug Resistance 51 



change occurs it is transmitted to the offspring of the variant 

 bacteria and behaves as a heritable characteristic. Observa- 

 tions of changes from sensitivity to resistance (Newcombe and 

 Hawirko, 1949; Demerec, 1951) have indicated that they 

 occur at a predictable rate (about 1 X 10"^ to 1 X lO-^^ pej. 

 bacterium per division) as is expected of changes due to gene 

 mutations. Reverse changes from streptomycin dependence 

 to non-dependence also occur spontaneously with a certain 

 frequency, characteristic in each strain; and the frequency 

 of occurrence can be increased by treatment with any agent 

 that has been proved capable of inducing gene mutations in 

 bacteria (Demerec, 1951; Demerec, Bertani and Flint, 1951). 

 The frequency of occurrence of changes from dependence to 

 non-dependence varies considerably among different depen- 

 dent strains of separate origin. Similar variation has been 

 detected w ith regard to the frequency of occurrence of changes 

 from sensitivity to resistance and dependence among sensitive 

 strains derived from dependent strains by isolation of sensi- 

 tive variants (Demerec, 1950). These patterns of behaviour 

 are analogous to those observed in genetic analyses of spon- 

 taneous and induced mutability in several genes concerned 

 with biochemical reaction in Esch. coli (Demerec, 1953), 

 Salmonella typhimurium (Hartman, 1956) and Neurospora 

 crassa (Giles, 1951), which studies have shown that each gene 

 as well as each allele of a gene has its own characteristic 

 mutation rate. 



Another way in which the determinant of streptomycin 

 resistance acts like a gene is evidenced by studies of a mutator 

 factor in Esch. coli (Treffers, Spinelli and Belser, 1954 ; 

 Treffers et al., 1956). This factor, whose location on the 

 chromosome has been determined (Skaar, 1956), affects the 

 stability of the genome by increasing the rates of mutation 

 of individual genes. Similar factors have been identified in 

 Drosophila (Demerec, 1937; Plough and Holthausen, 1937), 

 and in maize (McClintock, 1951). It has been found that this 

 mutator factor in Esch. coli has the same general effect on the 

 determinant of streptomycin resistance as on the other 



