Developmental and temporal characteristics of clonal sperm mosaicism

Cell. 2021 Sep 2;184(18):4772-4783.e15. doi: 10.1016/j.cell.2021.07.024. Epub 2021 Aug 12.


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.

Keywords: autism spectrum disorder; clonal mosaicism; congenital disorders; de novo mutation; embryogenesis; mutational signature; somatic; sperm; transmission risk.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Aging / blood
  • Alleles
  • Clone Cells
  • Cohort Studies
  • Growth and Development*
  • Humans
  • Male
  • Models, Biological
  • Mosaicism*
  • Mutation / genetics
  • Risk Factors
  • Spermatozoa / metabolism*
  • Time Factors
  • Young Adult