Temporal stability of human sperm mosaic mutations results in life-long threat of transmission to offspring

Every newborn harbors scores of new single nucleotide variants (SNVs) that may impact health and disease[1][1]–[4][2]; the majority of these are contributed by the paternal germ cells[5][3]. In some cases, these mutations are identifiable in a subset of the parents’ cells—a phenomenon called mosaicism, which is capable of producing disease recurrence[6][4]–[8][5]. Here, we provide a comprehensive analysis of male gonadal mosaic mutations, employing 300× whole genome sequencing (WGS) of blood and sperm in 17 healthy individuals, including assessment across multiple samples and age groups. Approximately 1 in 15 healthy males is predicted to harbor a transmissible, likely pathogenic exonic variant that is mosaic in his sperm. In general, only a third of sperm mosaic mutations were detectable in blood cells, all were remarkably stable over the course of months to years, and 23% were present in 5% or more of sperm cells. There was no evidence of age-dependent clonal expansion or collapse, as seen in hematopoiesis. Thus, despite the observed increase of mutations in offspring of men with advanced paternal age, detectable sperm mosaicism remains stable, represents a life-long transmission risk to offspring, and suggests a testis stem cell niche that prevents widespread clonality. ### Competing Interest Statement M.W.B., D.A., K.N.J., J.S., and J.G.G. are inventors on a patent (PCT/US2018/024878, WO2018183525A1) filed by UC, San Diego that is titled 'Methods for assessing risk of or diagnosing genetic defects by identifying de novo mutations or somatic mosaic variants in sperm or somatic tissues'. [1]: #ref-1 [2]: #ref-4 [3]: #ref-5 [4]: #ref-6 [5]: #ref-8