MANNER OF PRODUCTION OF MUTATIONS 481 



of these cases, however, the data were insufficient or actually indicated a 

 nonlinear relation. In other cases the structural changes investigated 

 belonged to a special class of translocations involving the small fourth 

 chromosome of Drosophila, which were detected by means of a phenotypic 

 position effect, cubitus interruptus, produced by them. The manifestation 

 of this effect is very sensitive to differences in cultural conditions, which 

 may not have been controlled with sufficient rigor. Carefully controlled 

 studies on translocations of this kind (Muller, Makki, and Sidky, 1939; 

 Muller, 1940) showed that these translocations, like other gross struc- 

 tural changes, follow the %-power rule in their frequency-dosage relation. 

 Moreover, all dosage work on the production of gross structural changes 

 by irradiation of Drosophila spermatozoa carried out during the last 

 thirteen years (e.g., Timofeeff-Ressovsky, 1939; Catsch, Radu, and 

 Kanellis, 1943; Catsch et at., 1944; Catsch, 1948; Muller and Valencia, 

 unpublished data) has served to confirm the ^2-po^'^'er rule for the doses 

 ordinarily used. 



Additional evidence for the point that breakage occurs before union in 

 Drosophila was seen, in the light of a discussion by Muller (1932) in 

 which the bearing that such evidence would have on this question had 

 been pointed out, in the finding of structural alterations involving the 

 rotational exchange of six or more broken ends, derived from multiple 

 breakage (Muller, 1936a, 1940; Kossikov and Muller, 1935; also Dubinin 

 and Khvostova, 1935, who, however, did not regard the evidence in this 

 light). It was also seen in the finding by Sidky (1940) of a case of 

 exchange between the broken ends of a chromosome irradiated in the 

 spermatozoon stage and those of a chromosome derived from the egg 

 which that spermatozoon had later fertilized. Finally, the finding that 

 offspring are frequently mosaic for structural changes showed that the 

 two chromatids of an irradiated spermatozoan chromosome do not always 

 undergo union of their broken ends in the same way, even though the 

 nonmosaic nature of most of the gene mutations produced by irradiating 

 spermatozoa indicated that the chromosomes had been undivided in the 

 spermatozoon stage. From this evidence too it was therefore inferred 

 (Muller, 1940) that union occurs subsequently to breakage. 



This evidence led also to the conclusion that in some cases single 

 breaks of chromosomes could later be followed by union between sister 

 pieces, which would give dicentric and acentric isochromosomes unable 

 to continue. The frequency of losses of individual X chromosomes 

 derived from irradiated spermatozoa was therefore determined by means 

 of special genetic methods, and it was found that this frequency, unlike 

 that of all the other gross chromosome aberrations which had been 

 studied in Drosophila, varies in simple linear manner with the dose 

 (Muller, 1939a, 1940; Bauer, 1939a, b, 1942; Pontecorvo, 1941, 1942). 

 This provided evidence from another angle for the conclusion that the 



