The ups and downs of mutation frequencies during aging can account for the apert syndrome paternal age effect

: PLoS Genet. 2009 Jul;5(7):e1000558. Epub 2009 Jul 10.
The ups and downs of mutation frequencies during aging can account for the apert syndrome paternal age effect.Yoon SR, Qin J, Glaser RL, Wang Jabs E, Wexler NS, Sokol R, Arnheim N, Calabrese P.
Molecular and Computational Biology Program, University of Southern California, Los Angeles, California, United States of America.

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.

PMID: 19593369 [PubMed - in process]

Related articles
The paternal-age effect in Apert syndrome is due, in part, to the increased frequency of mutations in sperm. Am J Hum Genet. 2003 Oct; 73(4):939-47. Epub 2003 Jul 31.
[Am J Hum Genet. 2003]
A germ-line-selective advantage rather than an increased mutation rate can explain some unexpectedly common human disease mutations. Proc Natl Acad Sci U S A. 2008 Jul 22; 105(29):10143-8. Epub 2008 Jul 16.
[Proc Natl Acad Sci U S A. 2008]
Paternal origin of FGFR2 mutations in sporadic cases of Crouzon syndrome and Pfeiffer syndrome. Am J Hum Genet. 2000 Mar; 66(3):768-77.
[Am J Hum Genet. 2000]
ReviewThe high spontaneous mutation rate: is it a health risk? Proc Natl Acad Sci U S A. 1997 Aug 5; 94(16):8380-6.
[Proc Natl Acad Sci U S A. 1997]
ReviewIonizing radiation and genetic risks IX. Estimates of the frequencies of mendelian diseases and spontaneous mutation rates in human populations: a 1998 perspective. Mutat Res. 1998 Sep; 411(2):129-78.
[Mutat Res. 1998]
» See reviews... | » See all...