Cell. 2021 Sep 2;184(18):4772-4783.e15. doi: 10.1016/j.cell.2021.07.024. | PubMed

Xiaoxu Yang¹, Martin W Breuss¹, Xin Xu¹, Danny Antaki¹, Kiely N James¹, Valentina Stanley¹, Laurel L Ball¹, Renee D George¹, Sara A Wirth¹, Beibei Cao¹, An Nguyen¹, Jennifer McEvoy-Venneri¹, Guoliang Chai¹, Shareef Nahas², Lucitia Van Der Kraan², Yan Ding², Jonathan Sebat³, Joseph G Gleeson⁴

1. Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA; Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
2. Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
3. Beyster Center for Genomics of Psychiatric Diseases, University of California, San Diego, La Jolla, CA 92093, USA; Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
4. Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA; Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA. Electronic address: jogleeson@health.ucsd.edu.

Abstract

Throughout development and aging, human cells accumulate mutations resulting in genomic mosaicism and genetic diversity at the cellular level. Mosaic mutations present in the gonads can affect both the individual and the offspring and subsequent generations. Here, we explore patterns and temporal stability of clonal mosaic mutations in male gonads by sequencing ejaculated sperm. Through 300× whole-genome sequencing of blood and sperm from healthy men, we find each ejaculate carries on average 33.3 ± 12.1 (mean ± SD) clonal mosaic variants, nearly all of which are detected in serial sampling, with the majority absent from sampled somal tissues. Their temporal stability and mutational signature suggest origins during embryonic development from a largely immutable stem cell niche. Clonal mosaicism likely contributes a transmissible, predicted pathogenic exonic variant for 1 in 15 men, representing a life-long threat of transmission for these individuals and a significant burden on human population health.

Presented By Xiaoxu Yang and Martin W. Breuss