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Higher Mutations in older men

FWF Stand-alone Projects P25525


Project duration: 2013-2017

There are certain disease-causing de novo mutations in the germline with rates per generation orders of magnitude higher than the genome average. Moreover, these mutations occur exclusively in the male germ line, and older men have a higher probability of having an affected child than younger ones, known as the paternal age-effect (PAE). One of the best known PAE mutations is achondroplasia, caused by a single nucleotide substitution in FGFR3. The mechanisms propagating these mutations are not well understood but in the last decade it was shown that for other spontaneous congenital disorders following a PAE, such as Apert syndrome and multiple endocrine neoplasia type 2b (MEN2B), mutations confer a selective advantage to spermatogonial stem cells. It also has been suggested that the selective advantage is the result of changes in the growth factor receptor-RAS signaling pathways caused by the mutant protein. Yet, there are still many open questions on how and to what extent mutations change germline stem-cell behavior, if all PAE mutations are driven by similar mechanisms, and whether other mechanisms such as apoptosis or cell-death counterbalance oncogenic expansions of mutant germline cells.

The aim of this projectis to get a deeper understanding of the mutation mechanisms behind the paternal age effect in FGFR3. Specifically, we will focus on the two achondroplasia mutationsand the thanatophoric displasia II mutation. These mutations have different mutation rates and show differences in signaling dysregulation of mutant FGFR3 presenting a unique opportunity to assess these properties as effectors in the biology of the paternal age effect. The frequency of these three mutations will be analyzed at different stages of spermatogenesis, specifically in spermatogonia, sperm from ejaculates and sperm with the highest motility in donors of different ages. We have developed a highly sensitive technique based on bead-emulsion amplification that can for the first time measure these mutations. With this project we can elucidate for the first time the very important relationship between mutation, selection, and cell-death at different developmental stages of spermatogenesis and how these factors contribute to the paternal age effect.