Sperm DNA damage causes genomic instability in early embryonic development

Abstract

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 γ-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.

Molecular Contribution to Embryonic Aneuploidy and Genotypic Complexity During Initial Cleavage Divisions of Mammalian Development

“…2H ). These results helped explain previous findings of blastomeres with uniparental origins and those that completely lacked nuclear DNA when assessed by SNP genotyping and/or NGS (Daughtry et al, 2019; Destouni et al, 2016; Middelkamp et al, 2020).…”

“…Unlike mouse embryos, which exhibit spatial separation of parental genomes by dual-spindle formation (Mayer, Smith, Fundele, & Haaf, 2000; Reichmann et al, 2018), bovine embryos normally undergo syngamy at the zygote stage (Yao et al, 2018). By avoiding syngamy and undergoing multipolar cytokinesis, zygotes differentially segregate entire parental genomes to daughter cells, helping to explain previous findings of heterogoneic divisions and the production of blastomeres with uniparental origins in both cattle and primates (Daughtry et al, 2019; Destouni et al, 2016; Middelkamp et al, 2020). Examination of micronuclei fate in subsequent divisions revealed an equal incidence of unilateral inheritance and fusion back with the primary nucleus, with a smaller percentage of embryos exhibiting a chromatin bridge between blastomeres following micronuclei formation ( Fig.…”

Interspecific ICSI for the Assessment of Sperm DNA Damage: Technology Report

“…In general, heavy sperm DNA damage leads to embryo development arrest. When sperm DNA is less damaged, embryo development is impaired, embryos show genomic instability, and if offspring are born, they may exhibit certain abnormalities such as altered adiposity and regulation of glucose in females [ 20 , 21 ].…”

Genome diversity and instability in human germ cells and preimplantation embryos

“…Second, low genome-wide recombination rates are associated with elevated aneuploidy risk, especially of the XY chromosomes. Finally, sperm also transmit a disproportionate number of de novo single nucleotide variants to the embryo compared to eggs [113] .…”

“…Loss of REC114 function leads to decrease in double strand break formation during oogenesis and spermatogenesis [149] , [150] . A few studies show that sperm DNA fragmentation is a contributing factor of embryonic failure and genome instability, though its causes remain unclear [113] , [151] , [152] . However, a recent study concludes that sperm DNA fragmentation does not affect fertilization, blastulation, aneuploidy, or pregnancy outcomes after in-vitro fertilization and intra cytoplasmic sperm injection [153] .…”