STADLER 



below the level at which the experi- 

 mental study of individual cases is 

 possible, we might still be constructing 

 more and more refined models of the 

 gene on this pattern. As the predic- 

 tions made from the model were con- 

 tradicted by experimental results, we 

 would change the various numerical 

 values, or introduce additional vari- 

 ables, or perhaps, if necessary, even 

 create additional hypothetical units. 

 But the model would remain essen- 

 tially an imaginary construct inferred 

 from mere numbers of mutations, for 

 we would have no possibility of con- 

 tradicting the plausible assumption 

 that one mutation is as good as an- 

 other. 



WH.'^T IS A GENE? 



The early studies of gene mutation 

 were concerned mainly with problems 

 of technique arising from the extreme 

 rarity of the phenomenon. Although 

 the mutations of OeJiothera, on which 

 the mutation theory was based, had 

 proved illusory, it soon became evident 

 that mutant alterations do occur that 

 are inherited as if they were due to 

 changes in individual genes. The com- 

 prehensive genetic analysis of Dro- 

 sophila by Morgan and his coworkers 

 showed numerous cases of this sort— in 

 fact, almost all the loci shown on the 

 gene-map represented the mutant oc- 

 currence of visible alterations which, 

 on subsequent tests, proved to be in- 

 herited in typical Mendelian fashion. 

 These were assumed to be due, in each 

 case, to a change of the wild-type gene 

 to an alternative form, producing a 

 recognizably different phenorv^pic ef- 

 fect. The frequency of these muta- 

 tions, however, seemed far too low to 

 permit experimental investigation of 

 the conditions affecting their occur- 

 rence. 



Muller {4) pointed out in 1917 that 

 gene mutations resulting in inviability 



247 



("lethals") are probably more fre- 

 quent than mutations permitting sur- 

 vival with modified phenotype ("visi- 

 bles"). In experiments extending over 

 the next 10 years (5), he developed 

 various special techniques by which it 

 was possible to determine the total 

 number of lethal mutations for all loci 

 within a given chromosome or region. 

 These total frequencies proved to be 

 high enough to permit significant ex- 

 perimental comparison of mutation 

 frequencies under different tempera- 

 tures. The loci yielding lethal muta- 

 tions were distributed over the chro- 

 mosomes approximately as expected 

 from the distribution of loci for visible 

 mutants, and it was concluded that the 

 lethal mutations might legitimately be 

 used as an index of gene mutations in 

 general. 



Meanwhile, many attempts to in- 

 crease the frequency of genetic altera- 

 tions by external treatments had been 

 made, including studies with various 

 chemical, radiological, and serological 

 treatments, and studies in which vari- 

 ous plant and animal forms were used. 

 None of these experiments gave con- 

 clusive proof of an effect of any ex- 

 perimental treatment on the frequency 

 of mutation, although in several of the 

 experiments there wxre genetic altera- 

 tions that may have been induced by 

 the treatment. The failure of proof 

 was due to two difficulties: (i) that of 

 proving that the genetic alterations ob- 

 served in the progeny of treated in- 

 dividuals were in fact due to the treat- 

 ment rather than to some genetic 

 irregularity present in the treated 

 strains, and (ii) that of showing sta- 

 tistically convincing increases in the 

 frequency of mutations in the treated 

 group. What was needed was a genetic 

 technique suitable for the detection of 

 mutations in adequate numbers in an 

 organism in which the gene-deter- 

 mined inheritance of the mutant char- 



