Safeguarding the development of offspring: the role of genetic integrity of the maternal germline.

Maternal DNA repair safeguards genome stability during the oocyte-to-embryo transition.

De novo mutations are a major source of genetic variation and disease risk, yet the developmental timing and mechanisms underlying their origin require further investigation. While germ cells have traditionally been considered the primary source of these mutations, increasing evidence suggests that a substantial fraction arise after fertilization. Here, we investigated the role of maternal DNA repair in shaping mutagenesis during this critical window by using a mouse model with oocyte-specific disruption of the homologous recombination factor RAD51 and a combination of cellular and molecular analyses. Loss of maternal RAD51 led to the accumulation of DNA double-strand breaks in oocytes without impairing their growth, meiotic maturation, or fertilization competence. In contrast, embryos derived from RAD51-deficient oocytes exhibited increased DNA damage and developmental delay during early cleavage stages. Whole-genome sequencing revealed a significant increase in de novo variants in offspring, the majority displaying intermediate allele frequencies consistent with post-zygotic mosaic mutations. These findings confirm that maternal DNA repair safeguards genome stability across the oocyte-to-embryo transition and identify early embryogenesis as a major source of de novo mutations, with implications for reproductive biology and the origins of genetic diseases.

Maternal age as a driver of genome instability: mechanisms linking aneuploidy, mutagenesis and mitochondrial dysfunction.

Epigenetic Reprogramming and Zygotic Genome Activation in Human Preimplantation Development: Mechanisms, Models, and Translational Prospects

ABSTRACT Purpose Early human embryogenesis unfolds through a tightly coupled sequence of events—clearance of maternal transcripts, remodeling of parental chromatin, zygotic genome activation (ZGA), lineage segregation, implantation, and post‐implantation patterning—accompanied by epigenetic reprogramming, including X‐chromosome dosage compensation around the time of implantation. This review aims to synthesize recent advances in understanding this developmental program and to consider their implications for reproductive medicine. Methods I review recent literature on human early embryogenesis, with particular emphasis on findings enabled by single‐cell genomics and stem‐cell‐based embryo modeling, and integrate these insights to identify human‐specific features of early development. Results These approaches have made previously inaccessible aspects of human early embryogenesis experimentally tractable, revealing molecular and epigenetic features that distinguish human development from that of model organisms, including species‐specific dynamics of ZGA, maternal transcript clearance, chromatin reprogramming, and X‐chromosome dosage compensation. Conclusions Advances in single‐cell genomics and embryo modeling are transforming our understanding of human early embryogenesis. Building on these insights, while recognizing their current limitations, I propose a vision for improving reproductive medicine, including the potential for next‐generation embryo selection strategies.

Rethinking evidence for epigenetic inheritance in human research.

In multicellular organisms, epigenetic inheritance is a process by which traits induced by life experiences or environmental factors in a parent are passed to offspring without involving changes in the DNA sequence, but rather in the epigenome. While epigenetic inheritance is evident in many species, from plants to rodents, it remains unproven in humans because of biological barriers, methodological complexity, and the difficulty of disentangling environmental from social and genetic factors. The unique human context of prolonged parental care, as well as cross-generational cultural and societal effects, compounds these difficulties and highlights the need for clear criteria to assess epigenetic inheritance claims. This article aims to help the field move from cataloging biological markers to conducting rigorous human research by clarifying key concepts and defining testable criteria as a guiding framework.

Extrachromosomal Circular DNA Function as Mobile Elements to Alter the Mammalian Germline Genome

The viability of any species including the human requires that the germline genome is kept stable as it is transmitted across generations by the germ cells. Failure to safeguard the genome integrity and stability would lead to inherited diseases and infertility. Thus, a better understanding of the mechanisms that alter the germline genome is crucial to ensure human health and our continuation as a species. Here, we show that the extrachromosomal circular DNA (eccDNA) in the mouse and human male germline represents a new mechanism in altering the mammalian germline genome. To enable the tracking of germline eccDNA in vivo, we established a novel mouse model that allows the generation of a reporter eccDNA in a cell type- specific manner. Using this mouse model, we showed that eccDNA formed in the developing male germ cells can integrate into the germline genome. Using eccDNA-containing sperm for in vitro fertilization led to the eccDNA sequence being inherited by the embryos. By analyzing a large cohort of long-read whole genome sequencing data, we showed that eccDNA-mediated germline genome insertions represent an important source of human genome structural variations. Finally, by leveraging human sperm samples, we found that diabetes induces an increase in sperm eccDNA quantity, which is mediated at least in part through poly (ADP-ribose) polymerases. Together, our results provide new insights into how the mammalian germline genome can be altered, with important implications for human health and genome evolution.

Non-invasive Ultra-early in Utero Detection and Precision CRISPR-mediated Correction of Monogenic Embryonic Mutations: A Critical Appraisal of a Hypothetical Therapeutic Framework

Whether that proposition that a pathogenic single-gene variant might be identified non-invasively at the earliest stage of pregnancy and corrected in situ before irreversible pathology develops is presently coherent as a therapeutic framework is examined.