Susceptibility to Fibrosarcomas in 2NHO Mice *

In the highly inbred Strong A strain of mice, an attempt to produce divergent sub-strains with regard to age distribution of spontaneous mammary adenocarcinomas by means of selective breeding proved ineffectual.' It was concluded that this result was an exemplification of Johannsen's genetic principle that pure lines are not amenable to selection. Conversely, Kreyberg8 succeeded in selecting divergent strains of mice with regard to susceptibility to tar-induced tumors; his original mice were not from pure lines. Kreyberg did not use age distribution as his criterion, but percentage incidence at comparable ages. In the establishment of the NHO stock,6 the object was to obtain many heterozygous gene pairs by strain crossing, so that a broad field for selective breeding would be opened. At the same time, however, a new problem was introduced, namely, heterosis. Although this may not affect susceptibility to tumors directly, heterosis may well affect it indirectly through its effects on disease resistance, reproduction, longevity, and associated physiology. The NHO stock was produced by hybridizing three pure strains, JK, CBA, and N, each different from the others by independent descent. They differ also in several color genes.' The subsequent generations of the NHO stock, inbred brother-sister, and uniformly tested as to tumor induction with methylcholanthrene, have shown some remarkable changes. Selection toward resistance to tumor induction (increased latent period) was started in F4 and continued to F30. Selection in all sublines (Br, BrS, pBr, Brpb, and pBrpb) was temporarily effective in increasing the latent period for all types of tumors (total number). However, with continuing selection a contrary trend appeared, counter to selection, of lower and lower average latent periods.7"0 We have then a paradoxical effect: the final generations of inbreeding show similar resistance to that of the first generations (heterotic). In this paper data on the effect of selection toward resistance to methylcholanthrene-induced tumors are presented, beginning with the F1 generation of a new NHO subline and continuing to the F20. This is the period of biological variability by reducing the potential number of heterozygous pairs of genes.2 Heterosis was also being reduced, since no attempt was made to pick out the healthiest mice in each generation.