Major impacts of gonadal mosaicism on hereditary risk estimation, origin of hereditary diseases, and evolution

Abstract

The specific-locus test in mice is by far the most extensively applied method for precisely defining gene mutation frequencies in mammals. Computer simulations of control experiments involving 57.4 million offspring, based on vast amounts of historical data, show that because of gonadal mosaicism, the total frequency of spontaneous mutations per generation is much higher than has been thought. The estimated combined spontaneous mutation frequency for both sexes for the seven genes tested in specific-locus experiments is 39.6 x 10-5 mutation/gamete. Division of this frequency by the combined induced mutation frequencies in parents of both sexes results in an estimate of the doubling-dose (DD) of from 5.4 to 7.7 Gy. For decades, the DD has been thought to be about 1 Gy. As the DD increases, estimates of hereditary risk that are based upon it decrease. Thus, one important ramification of this new understanding is that estimates of the hereditary risk to humans from radiation, commonly made by the doubling-dose (DD) approach, are probably at least five times too high. It also appears that gonadal mosaicism is likely to play a much more important role both in evolution and the origin of hereditary diseases than has been appreciated in the past.