Gamma-ray-induced dominant mutations that cause skeletal abnormalities in mice I. Plan,summary of results and discussion

Male mice were exposed to 100 R + 500 R γ-rays (60 R/min) with a 24-h fractionation interval. Skeletons of F₁ sons were examined for abnormalities, and, if any were found, the skeletons of their descendants were also examined. Of 2646 sons from treated spermatogonia, 37, or 1.4%, were diagnosed as carriers of autosomal dominant mutations affecting the skeleton, 31 by breeding tests, and six by other criteria for identifying mutations in F₁'s having no progeny. Earlier experiments by U.H. Ehling on dominant skeletal mutations indicated the spontaneous mutation frequency to be small relative to the induced frequencies from radiation doses similar to that used in this experiment. The mutation rate of 1.4% now reported probably includes some spontaneous mutations; however, any error in overestimating the induced rate made by taking all mutations as induced is probably more than counterbalanced by some mutations not being scored, mainly because of incomplete penetrance or poor viability.Many mutations caused a large number of anomalies in different regions of the skeleton. Most regions of the skeleton were affected by at least one mutation, and the mutations had incomplete penetrance for some or all of their effects. Three of the mutations affected skeletal size only.If certain assumptions are made, these skeletal data can be used to derive an estimate of induced genetic damage from dominant mutations affecting all parts of the body. When this is applied to man, the resultant risk estimate is not inconsistent with that made for dominant and irregularly inherited disease by the BEIR Committee, by use of the doubling-dose method. Since most of the mutations can be characterized as models of irregularly inherited conditions in man, the data directly relate to the controversy over the relative importance of mutation pressure and balanced selection in maintaining man's large burden of irregularly inherited disease. Contrary to a recent hypothesis by H.B. Newcombe that man's large burden of irregularly inherited disease is maintained almost exclusively by balanced selection, these results suggest that at least an important fraction of the irregularly inherited conditions are maintained by mutation pressure. Therefore, this finding does not support the major changes in the estimate of genetic hazard to man that would be required on the basis of Newcombe's hypothesis.