Mutation timing, accumulation, and selection in the male germline shape inheritance risk for developmental disorders.

Paternal de novo mutation risk for developmental disorders is mainly influenced by age-related mutation accumulation and selection, with early mosaicism contributing to about 8% of cases.

• Why it matters: Understanding how mutation timing, paternal age, and spermatogonial selection influence transmissible risk is crucial for assessing developmental disorder inheritance, yet these factors' joint effects are not well understood.
• What they did: The study combined trio whole-genome sequencing of 167 families with deep NanoSeq profiling of sperm from 127 fathers, analyzing mutation burden, spectra, and selection landscapes, and identifying early mosaic variants.
• The result: Findings show that most paternal de novo mutation risk is driven by universal age-related mutation and selection processes, while early mosaicism, present in about 8% of pathogenic cases, creates rare but high-risk individuals.