The activation of FGFR3 signalling has different consequences in the transmission of mutations the male germline

Description

The majority of new mutations originate in the male germline. However, to date we lack information on a unique type of mutagenesis—expansion of driver mutations in the male germline. These are associated with congenital disorders, occur at thousand-fold higher frequencies than other mutations, and drastically increase with paternal-age. To date, the mechanisms propagating these germline driver mutations are not completely understood. Here we examined the origin and expansion of four driver mutations in sperm and a dissected testis differing in mutation rates and the strength of dysregulation of the mutant FGFR3 receptor: c.1138G>A, c.1138G>C both causing achondroplasia (ACH), c.1948A>G associated with thanatophoric displasia II (TDII), and c.1948A>C causing hypochondroplasia (HCH). Only two out of four mutations (c.1138G>A and c.1948A>G) showed that mutant DNA concentrated within different clusters of the old donor’s testis, resulting from the growth advantage of mutant stem cells caused by the activation of FGFR3. Interestingly, no measurable clustering was observed for the ACH mutation with the lower mutation frequency (c.1138G>C). We also observed that mutations with a stronger effect on FGFR3 signaling (TDII) showed a reduced transmission into sperm. In contrast, mildly activating mutations (HCH) were measured at a very high frequency in sperm of old donors by ultra-sensitive sequencing. Thus, there are important regulatory mechanisms at different developmental stages of spermatogenesis that affect the downstream transmission of driver mutations. Our analysis forms a basis for understanding this type of mutagenesis and the associated risks of delayed parenthood in our society. Funded by: LIT213201001 and FWFP25525000

Period	18 Jun 2018
Event title	European Society of Human Genetics
Event type	Conference
Location	ItalyShow on map