Genomic instability is common in human embryos, but the underlying causes are largely unknown. Here, we
examined the consequences of sperm DNA damage on the embryonic genome by single-cell whole-genome
sequencing of individual blastomeres from bovine embryos produced with sperm damaged by ?-radiation. Sperm
DNA damage primarily leads to fragmentation of the paternal chromosomes followed by random distribution of
the chromosomal fragments over the two sister cells in the first cell division. An unexpected secondary effect of
sperm DNA damage is the induction of direct unequal cleavages, which include the poorly understood heterogoneic
cell divisions. As a result, chaotic mosaicism is common in embryos derived from fertilizations with damaged
sperm. The mosaic aneuploidies, uniparental disomies, and de novo structural variation induced by sperm DNA
damage may compromise fertility and lead to rare congenital disorders when embryos escape developmental arrest.