Allele Frequency Selection and No Age-Related Increase in Human Oocyte Mitochondrial Mutations

Mitochondrial dysfunction can cause a multitude of systemic diseases, and thus, the origin of such dysfunction is of great interest to many clinicians and researchers. Part of mitochondrial dysfunction can be explained by mutations in mitochondrial DNA (mtDNA), which can be measured both in somatic and germline cells. As the average maternal age continues to increase, determining if mutations in mtDNA increase with age is an important aspect of reproductive health care. This study was designed to assess the frequency of de novo mutations in mtDNA in oocytes based on age, compared with the frequency of mutations in somatic cells. This study used high-quality, full-length mtDNA sequences for 22 individuals between the ages of 20 and 42, obtaining samples from blood, saliva, and oocytes. Duplex sequencing was used to identify variants in mtDNA; median mtDNA enrichment was 85.4%, 0.7%, and 4.0% and a median duplex consensus sequence (DCS) depth of 1440X, 78X, and 158X for oocytes, blood, and saliva, respectively. There were 3525 high-confidence variants identified across all samples. Across age groups and geographic regions, there were significantly fewer mutations in oocytes compared with blood and saliva. When predicting the probability of a mutation in mtDNA as a function of age, there were significant increases in mutation frequency in blood and saliva, but not in oocytes (P