Väterlicher Alterseffect auf das Spermien-Epigenom und die resultierenden Nachkommen.
Zusammenfassung der Projektergebnisse
Several epidemiological studies reported evidence linking paternal age at conception to diseases and complications in the offspring. It is well-known that the genomes of children of older males harbor more genetic mutations. Similarly, older males might have a higher epimutation rate in their germ cells which might play a role in offspring disease pathogenesis. To explore this possibility, purified sperm samples from young and old males were studied using deep bisulfite sequencing (DBS) on the GS Junior. To detect rare epimutations and subtle methylation changes, we first analyzed the promoter methylation of several candidate genes: the maternally imprinted genes LIT1 and MEST, the tumour suppressor genes BRCA1, PTEN, NF1 and RAD51C, in addition to genes associated with disorders showing a “paternal age effect”, SHANK3, PSEN1 and FGFR3. A highly significant difference (P-value < 0.0001) was observed in the tumor suppressor gene NF1 and in SHANK3, a gene associated with autism spectrum disorders. Sperm of older males exhibited a higher NF1 and a lower SHANK3 methylation when compared to their younger counterparts. Currently, genes reported as differentially methylated by Jenkins et al. are being confirmed in a cohort of > 250 sperm samples and in cord blood from their respective offspring. Our aim is to provide a link between epigenetic aberrations in germ cells of aged males and increased disease susceptibility in their children. Furthermore, the “selfish spermatogonial stem cell” hypothesis will be studied by analyzing differentially methylated regions in testis of young and old males.
