Endometriosis-associated germline mutagenesis

Endometriosis is a benign gynecological disorder that is characterized by the presence of endometrial tissue (stroma or glands) outside the uterine cavity, leading to a chronic inflammatory reaction. It is one of the most widespread gynecological diseases affecting about 510% of women of reproductive age, rising to 2550% in patients with infertility. By causing pelvic pain and infertility, endometriosis affects the quality of life and constitutes a considerable threat to the physical, psychological, and social integrity of many women. Furthermore, endometriosis was suggested to also affect the offspring of mothers suffering from endometriosis: In addition to a compromised oocyte quality in endometriosis patients that is possibly connected with observed alterations in mitochondria (which are also referred to as the powerhouse of the cell), an increased risk for various birth defects and other diseases in offspring of mothers affected by endometriosis was shown. These are potentially associated with genetic causes, however, to date, an endometriosis-associated germline mutagenicity has not yet been studied. In the project titled Endometriosis-associated germline mutagenesis, we therefore aim to study the role of endometriosis in mitochondrial DNA (mtDNA) mutagenicity in oocytes. We will use the highly accurate duplex sequencing approach to measure new mutations in mtDNA of human oocytes. By sequencing both DNA strands separately, duplex sequencing can reliably measure true DNA variants. Mutations in oocytes originating from endometriosis patients will be compared to those measured in oocytes originating from healthy donors. With this project, we can for the first time elucidate the potential role of endometriosis in mtDNA germline mutagenesis. Increased mutation frequencies might have long-term effects on the sequence of the human genome, with potential health effects. Given the high incidence of endometriosis, and with up to 50% of all women undergoing in vitro fertilization treatment being endometriosis patients, it is important to better understand potential consequences of the disease on the offspring - many children who would not live without intervention. The results will allow considerations e.g. if alternative methods such as oocyte donation could be beneficial, or e.g. if having children or storing oocytes at a younger age might be advantageous to minimize the time oocytes spend in the inflammatory environment.