Paternal age effects on sperm epigenome and the resultant offspring.

• Applicant: Nady El Hajj, Ph.D.
• Subject Area: Reproductive Medicine, Urology
• Term: from 2013 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 240711082

Epidemiological studies provide evidence for an influence of paternal age on the prevalence of certain diseases in the offspring, including autism and cancer. Genome-wide sequencing techniques revealed that the offspring of older men carry more genetic mutations. It is well known that the number of germ cell divisions in males increase with age; therefore, the higher de novo mutation rate in the offspring of older fathers may have originated in sperm. We speculate that in addition to an increased number of genetic mutations, the sperm of older males contain more epigenetic perturbations when compared to their younger counterparts. The inheritance of spermspecific epimutations may contribute to the etiology of disorders showing a “paternal age effect”. To explore this possibility we will perform genome-wide methylation (Illumina 450K arrays) analysis with sperm samples of old versus young males. The methylation of well selected candidate genes will be additionally measured via deep bisulfite sequencing to detect rare epimutations. As a followup, we will analyze the fetal cord blood methylome of the resultant offspring to assess whether paternal age has an epigenetic influence on the next generation. The aim of this project is to provide insight on the epigenetic effect of paternal aging on sperm and on the onset of certain disorders in the offspring of older fathers.

• DFG Programme: Research Grants