SPONTANEOUS MUTATION DURING FETAL DEVELOPMENT AND POSTNATAL-GROWTH

Somatic mutations seem to accumulate slowly with age during adult life in both mice and men. There is, however, a substantial mutant frequen cy at birth, suggesting that the rate of accumulation is much higher b efore birth. This suggests that DNA replication plays an important rol e in the generation of spontaneous mutations. Since most cell division and accompanying DNA replication occurs early in development, more mu tations would arise during growth and development. Indeed, if the muta tions are genetically neutral, the mutant frequency would rise very ra pidly during early fetal growth, more slowly during later fetal growth and development and still more slowly after birth. To test this hypot hesis, we have assayed the mutant frequencies from before birth to 28 days after birth, by which time most growth has occurred. We have used the F-1 mice generated by crossing SWR females and Muta(TM)Mouse male s. The Muta(TM)Mouse has a rescuable lacZ/lambda shuttle vector that c an be assayed for an in vivo mutation in an in vitro system. Up to and including birth we assayed the entire animal for mutants; at 14 and 2 8 days after birth we assayed the small intestine. The data show that, as expected, many mutations arise early in development, by 12.5 days after conception, and confirms the non-linearity of mutation with age. In these mice, about one third of mutations arise before birth, about one third during growth to adulthood and the remaining during the res t of the animal's life, although this depends somewhat on the tissue.