Molecular origin of non-disjunction in human meiotic and early mitotic divisions (360G-Wellcome-215625_Z_19_Z)

In humans, pregnancy with the wrong number of chromosomes (aneuploidy) is common and the risk increases with maternal age, rising from ~2% for women under the age of 25, to around 35% for women over 40. Aneuploidy is a leading cause of early miscarriage, whilst affected full term births exhibit severe medical problems. Most aneuploidies arise from chromosome segregation errors that occur during the meiotic divisions of the oocyte or early mitotic divisions of the embryo. The next challenges are to determine the mechanisms of chromosome segregation in oocytes, to understand how high fidelity is ensured and to identify the origin of aneuploidies found in early human embryos. Work on model systems has identified adaptations to the kinetochore which direct and monitor specialized pathways of chromosome segregation during meiosis. However, the extent to which similar mechanisms function in human oocytes is unknown. Indeed, our recent work revealed unexpected properties of kinetochores in human oocytes, potentially contributing to the high error rate. We will perform a detailed examination of kinetochore behaviour in human oocytes and early embryos to gain the first insights into chromosome segregation at the start of life and uncover potential sources of error.