PROJECT SUMMARY / ABSTRACT Male infertility impacts up to 7% of all men and has been shown to be associated with poor somatic health and elevated individual and familial cancer risk. Significant epidemiological data links male infertility to poorer somatic health compared with fertile men, manifesting as increased individual risks for prostate cancer, testis cancer, colon cancer, cardiovascular disease and reduced life span. Recent work by our group has also demonstrated that family members of infertile men are at higher risk of testis cancer and both major congenital anomalies and pediatric cancer. Specifically, much of this work found different associations in men with severe oligozoospermia (reduced sperm counts) compared with those with azoospermia, suggesting that their etiologies are fundamentally different. In a follow up study that mined age and cause of death information from the Utah Population Database (UPDB), we found that individuals with the highest quartile of age-adjusted germline mutation rates live for five fewer years than those in the lowest quartile. This project aims to study a unique population to measure mutations in the testis, mature sperm, and somatic tissue to test the hypotheses that genomic instability underlies reduced fertility, and that genome instability in one’s germline is connected to increased somatic mutation and mosaicism. We will test this through two aims. 1.) Assessment of whether subfertile men have higher germline mutation rates than fertile men by examining complex pedigree data to identify familial associations between male infertility and cancer risk and determine mutation rates in the germline and somatic cells of 20 oligozoospermic men and 20 hyperzoospermic men. 2.) We will test whether higher germline mutation rates are predictive of elevated somatic mutation rates and lower sperm counts by using cadaveric organ donor tissue from testis, sperm, prostate, blood and colon to assess mutation rates. These two aims will provide foundational datasets for the field and will be able to answer whether higher de-novo mutation rates are the mechanistic link underlying both male infertility and poor somatic health.

PROJECT NARRATIVE Male infertility is a devastating problem that impacts 7% of all men and has been shown to significantly impact somatic health, particularly risk for both individual and familial cancer. Despite this association, the mechanism driving it remains unknown. We seek to perform a study examining complex pedigree data to assess how infertility can impact familial cancer risk among high risk pedigrees and then use high depth and coverage DNA sequencing to determine if elevated de novo mutation rates in both the germline and somatic tissue are what drive the association between male infertility and poor somatic health.