Male infertility is associated with elevated rates of aneuploidy and DNA breaks in spermatozoa and germline precursors. This common condition is not well understood and is associated with poor individual and familial somatic health relative to fertile men. To further understand the extent and source of genome instability, we used error-corrected duplex DNA sequencing to test whether the impaired spermatogenesis and relatively poorer health of oligozoospermic men are linked to elevated single nucleotide de novo mutation frequencies in their sperm and blood, respectively. We observed a significant 1.34 to 2.01-fold increase in age-adjusted sperm mutation frequencies in infertile, oligozoospermic men. Conversely, consistently elevated mutation frequencies in the blood of oligozoospermic men were not found. Gain-of-function mutations linked to clonal spermatogenesis and Mendelian disorders accumulate with age at a similar rate in normozoospermic and oligozoospermic men. These results implicate germline hypermutation as a hallmark feature of oligozoospermia and point to age-independent processes affecting spermatogonial stem cell biology that may underlie spermatogenic impairment before and after puberty. Our findings also underscore the importance of investigating tissue-specific mechanisms driving the association between reduced reproductive and somatic health in infertile men.

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organization for the submitted work; JMH has a financial relationship with Paterna Biosciences; no other relationships or activities that could appear to have influenced the submitted work.

This study was funded by the NICHD R01HD106112 and NICHD F31HD115390.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This study received ethical approval by the University of Utah Institutional Review Board (IRB_00063950).

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All data produced and code are available online at https://github.com/quinlan-lab/normo-vs-oligo-manuscript or in the supplementary material. In the interest of patient privacy, we are unable to provide precise donor ages in our publicly available dataset but are able to provide such data upon reasonable request.

https://github.com/quinlan-lab/normo-vs-oligo-manuscript