Recent advances in assisted reproductive technologies (ART) have revolutionized human reproduction, offering hope to millions of couples facing infertility issues. At the same time, concerns persist regarding the potential impact of ART on the genomic integrity of offspring conceived through these techniques. Specifically, questions abound about the effects of these techniques on the incidence of de novo mutations (DNMs), which are genetic alterations that arise spontaneously in the germline or during early embryonic development and are implicated in various human diseases. The extent to which ART directly affects the rate of de novo mutations has been the subject of ongoing debate. This review explores recent studies that have investigated the relationship between ART and DNMs. It underscores the necessity for further research to clarify the clinical implications and long-term consequences of ART.

Background and Clinical Significance: The oocyte zona pellucida (ZP) is an extracellular glycoprotein matrix with essential roles in oogenesis, fertilization, and early embryonic development. Abnormal ZP morphology is associated with female infertility and adverse outcomes after assisted reproductive technology (ART), but its molecular basis remains incompletely understood. Case Presentation: We present three patients with female infertility, abnormal oocyte ZP morphology, and adverse embryological outcomes, including fertilization failure and early developmental arrest. Whole-genome sequencing identified an extremely rare heterozygous missense variant in the ZP4 gene (rs1254095560) in one patient, resulting in the p.Leu342Pro substitution at a conserved amino acid position within the functionally important ZP-C subdomain of the protein. In silico modeling showed that the p.Leu342Pro substitution may alter the spatial folding of the ZP4 protein. Conclusions: These results and the known role of ZP4 in the organization of the zona pellucida allow this variant to be considered a candidate genetic factor potentially associated with disruption of the zona pellucida structure. The absence of comparable, apparently pathogenic coding variants in ZP genes in two other patients with a similar zona pellucida phenotype suggests genetic heterogeneity of this phenotype.

An extended female post-reproductive lifespan (PRLS) represents an evolutionary paradox and a rare life-history adaptation in mammals. The molecular mechanisms and genetic changes underlying this trait remain poorly understood. In toothed whales, extended PRLS has been documented in multiple lineages, providing an opportunity to search for candidate genomic regions associated with this life-history phenotype in a comparative framework. Here, we identify accelerated regions (ARs) in three toothed whale species with documented extended PRLS: killer whale, narwhal, and beluga whale. We used closely related toothed whale species without evidence of this phenotype as a comparison and found more than one million conserved autosomal regions, as well as thousands of lineage-specific ARs in each focal species. Across the three species, accelerated regions overlapped 12 unique human noncoding candidate cis-regulatory elements (cCREs) and 300 annotated genes, and exonic regions in 20 genes. Shared AR-associated genes showed enrichment for developmental and neurobiological functions, including neurogenesis, synaptic organization, and neuronal projections, and included candidates previously linked to aging, longevity, and reproductive aging. Thus, we identified candidate regions whose accelerated evolution is putatively associated with extended PRLS in toothed whales.