Revealing de novo Age-related Genetic Alterations in Mouse Oocytes through Single-cell Exome Sequencing

In our study, scWES was employed on oocytes from female mice with different reproductive ages. We also performed whole exome sequencing on bluk blood samples in trios to detect de novo germline variations in oocytes. Both natural aging and accelerated reproductive aging were involved. We demonstrated that genetic alterations, including base variants and structural variations, occurred in mouse oocytes during aging. Genes harboring natural aging or accelerated aging-related de novo germline variants (DNGVs) were almost involved in Ugt1a, V2R, and Mucin gene families. A copy number variant (CNV) associated with chromatin modeling were detected in natural aging oocytes. More importantly, we shortlisted various critical biological functions, like calcium binding pathway and p53 pathways, affected by these aging-related genetic alterations. Our work is the first study to identify genetic alterations in mouse oocytes with in vivo aging and offers a new direction of dissecting the aging mechanisms in oocytes and clarifying genetic causes of lower fertility at advanced maternal age.