Sperm DNA damage causes genomic instability in early embryonic development

Abstract

<jats:title>Abstract</jats:title><jats:p>Genomic instability is common in early embryo development, but the underlying causes are largely unknown. Here we examined the consequences of sperm DNA damage on the embryonic genome by single-cell genome sequencing of individual blastomeres from bovine embryos produced with sperm damaged by radiation. Sperm DNA damage caused fragmentation of chromosomes and segregation errors such as heterogoneic cell divisions yielding a broad spectrum of genomic aberrations that are similar to those frequently found in human embryos. The mosaic aneuploidies, mixoploidy, uniparental disomies and <jats:italic>de novo</jats:italic> structural variation induced upon sperm DNA damage may compromise health and lead to rare genomic disorders when embryos escape developmental arrest.</jats:p><jats:sec><jats:title>One Sentence Summary</jats:title><jats:p>DNA damage in sperm cells leads to genomic defects in embryos</jats:p></jats:sec>

Parental genomes segregate into different blastomeres during multipolar zygotic divisions leading to mixoploid and chimeric blastocysts

“…The co-existence of diploid, triploid and uniparental cell lineages was discovered in bovine and nonhuman primate pre-implantation embryos (39)(40)(41)(42). Here, we demonstrate this occurs in human embryos as well.…”

“…normal, and dispermic fertilizations. The existence of mixoploidy and chimerism was subsequently confirmed in other bovine (41), and nonhuman primate (42) in vitro fertilized (IVF) cleavage-stage embryos. Since all cells originate from a single zygote, we hypothesize mixoploidy and chimerism to arise from the segregation of parental genomes into different daughter cells during the zygotic division.…”

A developmentally programmed splicing failure contributes to DNA damage response attenuation during mammalian zygotic genome activation

“…DDR and DNA repair pathways operate during the early stages of mammalian development (31)(32)(33). However, several studies in different mammalian species indicate that cleavage stage embryos are particularly resistant to certain DNA damage-inducing agents (34)(35)(36)(37)(38), suggesting that at least some DDR pathways may not be fully functional during ZGA. To gain further insights into DDR regulation at this stage, we first treated mouse embryos with the topoisomerase inhibitor etoposide at different developmental points: before, during, and after the major ZGA wave (1C, late 2C, and 8C-16C stages, respectively).…”

Sperm DNA integrity and male infertility: a narrative review and guide for the reproductive physicians

“…During the early divisions of embryonic development, fragmented male genome is unequally distributed between daughter cells, leading to a phenomenon called chaotic mosaicism; meaning cells of the developing embryo do not contain an identical and balanced genotype. This has been attributed as a major cause of miscarriage resulting in a reduced live birth rate following ART, as well as repeated miscarriage incidents with RPL (74). If the pregnancy progresses to live birth, damaged sperm leading to chromosomal abnormalities may lead to congenital anomalies in the offspring (74).…”