title: Unique geometry of sister kinetochores in human oocytes during meiosis I may explain maternal age-associated increases in chromosomal abnormalities.
abstract: The first meiotic division in human oocytes is highly error-prone and contributes to the uniquely high incidence of aneuploidy observed in human pregnancies. A successful meiosis I (MI) division entails separation of homologous chromosome pairs and co-segregation of sister chromatids. For this to happen, sister kinetochores must form attachments to spindle kinetochore-fibres emanating from the same pole. In mouse and budding yeast, sister kinetochores remain closely associated with each other during MI, enabling them to act as a single unified structure. However, whether this arrangement also applies in human meiosis I oocytes was unclear. In this study, we perform high-resolution imaging of over 1900 kinetochores in human oocytes, to examine the geometry and architecture of the human meiotic kinetochore. We reveal that sister kinetochores in MI are not physically fused, and instead individual kinetochores within a pair are capable of forming independent attachments to spindle k-fibres. Notably, with increasing female age, the separation between kinetochores increases, suggesting a degradation of centromeric cohesion and/or changes in kinetochore architecture. Our data suggest that the differential arrangement of sister kinetochores and dual k-fibre attachments may explain the high proportion of unstable attachments that form in MI and thus indicate why human oocytes are prone to aneuploidy, particularly with increasing maternal age.
authors.affiliation: Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK.
authors.forename: Jessica
authors.initials: J
authors.lastname: Patel
authors.affiliation: Department of Obstetrics and Gynecology, McGill University, Montreal, Quebec H3A 1A1, Canada.
authors.forename: Seang Lin
authors.initials: SL
authors.lastname: Tan
authors.affiliation: Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK.
authors.forename: Geraldine M
authors.initials: GM
authors.lastname: Hartshorne
authors.affiliation: Centre for Mechanochemical Cell Biology, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK a.d.mcainsh@warwick.ac.uk.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: McAinsh
keywords: Aneuploidy; Chromosome segregation; Human; Kinetochore; Meiosis; Oocyte