414 RADIATION BIOLOGY 



mutation rate. In apparent accord with this principle, later work has 

 given evidence that under the influence of either abnormally high (Muller, 

 1928d; Plough and Ives, 1932; Buchmann and Timofeeff-Ressovsky, 

 1935, 1936) or abnormally low (Birkina, 1938; Kerkis, 1939) tempera- 

 tures, and possibly also under that of violent changes in temperature even 

 when the temperatures would, if constant, have lain in the normal range 

 (Zuitin, 1939), the mutation frequency of Drosophila is considerably 

 increased. Similarly, Stubbe and Doring (1938) have found malnutri- 

 tion, caused by an undersupply of any one of several elements, to raise the 

 mutation frequency in Antirrhinum two or more fold. 



Meanwhile, long before the findings on abnormal temperatures, a 

 second series of results on the so-called "spontaneous" mutation fre- 

 quency in Drosophila, obtained by the present writer, had shown that it is 

 a highly variable quantity, often differing from one experiment to 

 another by a factor of 10 or more, and that at least one cause of this 

 variability is probably the genetic composition (Muller, 1928c). Later, 

 the existence of definite genes (doubtless themselves mutant) which 

 increase the general mutation frequency of Drosophila to this extent was 

 proved in several different investigations by Demerec (1937), Plough 

 and Holthausen (1937), Neel (1942), and Ives and Andrews (1946). 

 Such genes are now known as mutator genes. A gene of this kind in 

 maize, called "sticky " from its effect on the chromosomes, in which it also 

 caused a high frequency of breakage and structural change, has been 

 reported by Beadle (1932). It is such mutations, affecting mutation 

 frequency itself, but, in the main, those decreasing mutation frequency, 

 which must have furnished most of the material for natural selection to 

 work with, whereby the natural or "spontaneous" mutation frequency 

 has been brought within such limits as are on the whole advantageous to 

 the species in its survival and evolution. In addition, the more stable 

 alleles of each individual gene must also have been selected. 



The existence of marked variations in mutation frequency and, more 

 specifically, of those caused by abnormal temperature influences, by mal- 

 nutrition, and by mutator genes, pointed clearly to the conclusion that 

 differences in chemical conditions must affect the occurrence of the muta- 

 tions which are called spontaneous. It was therefore to be expected that 

 mutagenic chemicals could be found, and that even the natural differ- 

 ences in cellular biochemistry associated with different stages of develop- 

 ment, types of cell, and modes of metabolism might to some extent 

 influence the occurrence of mutations. Nevertheless, tests of various sub- 

 stances, even in highly detrimental amounts, for a long time failed to give 

 evidence of any marked production of mutations in Drosophila. It is 

 true that results bordering on the significant, and indicating something 

 on the order of a doubling of the mutation frequency, were occasionally 

 reported (for example, in tests of iodine, of copper sulfate, and of ammo- 



