Spontaneous mutation during fetal development and post-natal growth

Area of Science:

• Genetics
• Developmental Biology
• Molecular Biology

Background:

• Somatic mutations accumulate with age, but a high frequency at birth suggests rapid prenatal accumulation.
• DNA replication during early development is a likely source of spontaneous mutations.
• Mutation accumulation is hypothesized to be non-linear, increasing rapidly during fetal growth.

Purpose of the Study:

• To investigate the rate of somatic mutation accumulation from before birth to adulthood in mice.
• To test the hypothesis that mutation rates are higher during early development compared to later life.
• To quantify the proportion of mutations arising during different life stages.

Main Methods:

• Utilized F1 mice from SWR and MutaMouse crosses, with MutaMouse containing a rescuable lacZ/lambda shuttle vector for in vivo mutation assays.
• Assayed mutant frequencies in the entire animal up to birth and in the small intestine at 14 and 28 days postpartum.
• Employed an in vitro system to analyze mutations within the shuttle vector.

Main Results:

• Confirmed a high frequency of mutations by 12.5 days of gestation, supporting non-linear accumulation with age.
• Demonstrated that approximately one-third of mutations arise before birth.
• Observed that another third of mutations accumulate during postnatal growth to adulthood, with the remainder occurring later in life.

Conclusions:

• Somatic mutation accumulation is significantly non-linear, with a substantial proportion occurring during prenatal development.
• DNA replication during early development is a critical period for the generation of spontaneous mutations.
• The timing of mutation acquisition varies, with roughly equal thirds occurring prenatally, during growth, and in adult life, though tissue-specific differences exist.