GENETICS OF NEOPLASIA 257 



brown, and we have demonstrated linkage with agouti. 562 Strong 1294 observed linkage 

 between gastric tumors and brown. MacDowell 835 found linkage between dilution and 

 leukemia, and Law 768 demonstrated linkage between flexed tail and leukemia. In our 

 laboratory, linkage has been demonstrated between pulmonary tumors and 8 

 specific genes on 6 different chromosomes. 260 - 556, 1347 These include hr in group I, 

 A y in group V, vt, sh-2, and wa-2 in group VII, Fu in group IX, ob in group XI, and/ 

 in group XIV. Burdette 144 also demonstrated linkage between pulmonary tumors 

 and sh-2 and wa-2. The pulmonary tumor linkages were first demonstrated with 

 induced tumors, the quantitative measure of response in terms of nodule number offer- 

 ing advantages over incidence data in showing the differences to be real although not 

 great. However, in all cases where the tests were repeated for spontaneous tumors, 

 linkage was confirmed. 



What is termed linkage here is an association, and in many cases it is not possible 

 to ascertain whether this association is true linkage or a pleiotropic effect of the gene 

 tested. Lethal yellow offers an advantage in that the test can be made in the F 1 

 animals which segregate at this locus since the inbred YBR strain has forced heterozy- 

 gosis here owing to the lethal effect of the gene when homozygous. There is strong 

 evidence then that any effect noted in the occurrence of tumors is due to this gene itself 

 rather than true linkage. 



There is a suggestion in the response of the normal overlaps that the effect of 

 flexed tail is also a pleiotropic effect. The occurrence of pulmonary tumors in pheno- 

 typically flexed mice was significantly lower than in the genotypically normals. How- 

 ever, that in the genotypically flexed but phenotypically normal was comparable with 

 that in the genotypically normal mice. 



Identification of effects associated with specific genes offers opportunities for more 

 precise studies on paths of genie action which will be discussed more fully later. There 

 is evidence that the effects of lethal yellow and flexed tail on pulmonary tumors may be 

 associated with their effects on normal growth. A number of studies are suggested 

 here, some of which could carry the problem to the biochemical level. The association 

 between flexed tail and increased occurrence of leukemia may be related to the effect of 

 this gene on the hematopoietic system. Flexed-tailed animals are born with a transitory 

 anemia. Other genes associated with anemia should also be tested for linkage with 

 leukemia. 



Correlation of these linkage tests with carcinogenic tests can yield interesting 

 information. Lethal yellow increased pulmonary tumors when they arose spon- 

 taneously or were induced with urethan, nitrogen mustard, or methylcholanthrene, but 

 had no effect on pulmonary tumors induced with dibenz[#, h] anthracene. The same 

 was observed in the linkage studies on flexed tail. This suggests that the mechanism of 

 carcinogenesis with dibenz[a, h] anthracene is in some way unique. On the other 

 hand some of the other genes were associated with occurrence of pulmonary tumors 

 induced with dibenz[a, A]anthracene suggesting that, as would be expected, not all 

 genes are affecting occurrence of pulmonary tumors through the same mechanism. 



