The Ups and Downs of Mutation Frequencies during Aging Can Account for the Apert Syndrome Paternal Age Effect

Abstract

Apert syndrome is almost always caused by a spontaneous mutation of paternal origin in one of two nucleotides in the fibroblast growth factor receptor 2 gene (FGFR2). The incidence of this disease increases with the age of the father (paternal age effect), and this increase is greater than what would be expected based on the greater number of germ-line divisions in older men. We use a highly sensitive PCR assay to measure the frequencies of the two causal mutations in the sperm of over 300 normal donors with a wide range of ages. The mutation frequencies increase with the age of the sperm donors, and this increase is consistent with the increase in the incidence rate. In both the sperm data and the birth data, the increase is non-monotonic. Further, after normalizing for age, the two Apert syndrome mutation frequencies are correlated within individual sperm donors. We consider a mathematical model for germ-line mutation which reproduces many of the attributes of the data. This model, with other evidence, suggests that part of the increase in both the sperm data and the birth data is due to selection for mutated premeiotic cells. It is likely that a number of other genetic diseases have similar features.

Author Summary

Epidemiological studies show that the incidence of some genetic diseases increases with the age of the father. This “paternal age effect” is traditionally explained by the fact that, as men age, the male germ-line cells continue to divide, and each division presents an additional chance for mutation. Apert syndrome is an example of such a disease; virtually all cases are caused by spontaneous base substitution mutations of paternal origin at either one of just two sites. In this paper, we measure the frequencies of these two mutations in the sperm of unaffected men of different ages and find a frequency increase with age similar to what has been found in the data on Apert syndrome births. We also find (1) the increase in mutation frequency is not strictly monotonic, featuring a decrease followed by an increase in middle age, and (2) after normalizing for age, the two mutation frequencies are correlated within individual donors. The mutation frequency increase we observed is greater than expected based just on the number of male germ-line divisions. Along with other evidence, our data supports a novel explanation for the paternal age effect whereby Apert syndrome mutations, though harmful to the child, confer an advantage to premeiotic cells in the male germ-line that carry such a mutation. A number of other genetic diseases may exhibit similar features.