Project Summary/Abstract
Male infertility is a highly prevalent condition, impacting ~7% of men. However, clinical management is complex,
as roughly half of male infertility cases are idiopathic. Furthermore, a diagnosis of male infertility has health
ramifications even beyond an affected individual’s reproductive health. Epidemiologic studies associate infertile
men and their families with poor somatic health, including increased risks for testicular cancer, prostate cancer,
cardiovascular disease, congenital abnormalities, and reduced lifespans.
To explain these associations, my Co-Sponsor, Dr. Aston, found significant overlap in DNA repair genes involved
in male infertility and human cancers. Additionally, our lab found that fertile men in the top quartile of age-adjusted
germline mutation rates died five years earlier than men in the lowest quartile. When translating these findings
to infertile men, mutation accumulation in the germline may be connected to deleterious somatic mutagenesis in
the same infertile male, potentially resulting in reduced fertility and poor somatic health, respectively.
Currently, the exact mechanisms underlying impaired spermatogenesis in infertile men are poorly understood.
For example, while DNA fragmentation and aneuploidy rates have extensively been studied in the sperm of fertile
and infertile men, the relationship between male infertility and germline de novo mutagenesis, or the
accumulation of spontaneous single nucleotide alterations in a male’s spermatogonial stem cell (SSC) lineage,
has been ignored. Additionally, it is unknown whether reduced sperm production in infertile men is related to an
abnormal SSC composition or distribution of SSC states. Given these knowledge gaps, there exists a critical
need to comprehensively characterize the mutational landscape directly in the sperm of fertile and infertile men,
as such analyses may illuminate key biological and mutagenic processes involved in male infertility.
This project will use duplex sequencing to explore connections between genome hypermutation, male infertility,
and poor health. Specifically, I will investigate whether infertile, oligozoospermic men harbor elevated degrees
of germline and somatic mutagenesis relative to fertile, normozoospermic men. Aim 1 will examine germline
mutation rates from the bulk sperm of normozoospermic men, including samples collected from the same
individual spanning multiple decades. Aim 2 will determine if infertile men exhibit increased rates of germline
mutagenesis compared to age-matched normozoospermic men. Finally, Aim 3 will test whether oligozoospermic
men harbor elevated somatic mutation rates compared to fertile controls. Completing these aims will establish
germline and somatic mutagenesis as hallmark genetic features of male infertility. Furthermore, novel insights
gained from this analysis will inform future investigations into upstream biological and cellular processes
contributing to genome hypermutation, impaired spermatogenesis, and associated somatic comorbidities.
