title: Sister kinetochore splitting and precocious disintegration of bivalents could explain the maternal age effect.
abstract: Aneuploidy in human eggs is the leading cause of pregnancy loss and Down's syndrome. Aneuploid eggs result from chromosome segregation errors when an egg develops from a progenitor cell, called an oocyte. The mechanisms that lead to an increase in aneuploidy with advanced maternal age are largely unclear. Here, we show that many sister kinetochores in human oocytes are separated and do not behave as a single functional unit during the first meiotic division. Having separated sister kinetochores allowed bivalents to rotate by 90 degrees on the spindle and increased the risk of merotelic kinetochore-microtubule attachments. Advanced maternal age led to an increase in sister kinetochore separation, rotated bivalents and merotelic attachments. Chromosome arm cohesion was weakened, and the fraction of bivalents that precociously dissociated into univalents was increased. Together, our data reveal multiple age-related changes in chromosome architecture that could explain why oocyte aneuploidy increases with advanced maternal age.
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom.
authors.forename: Agata P
authors.initials: AP
authors.lastname: Zielinska
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Holubcova
authors.affiliation: Bourn Hall Clinic, Cambridge, United Kingdom.
authors.forename: Martyn
authors.initials: M
authors.lastname: Blayney
authors.affiliation: Bourn Hall Clinic, Cambridge, United Kingdom.
authors.forename: Kay
authors.initials: K
authors.lastname: Elder
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom.|Max Planck Institute for Biophysical Chemistry, Goettingen, Germany.
authors.forename: Melina
authors.initials: M
authors.lastname: Schuh
mesh_terms: D000782:Aneuploidy; D020090:Chromosome Segregation; D006801:Humans; D018386:Kinetochores / Q000378:metabolism*; D008423:Maternal Age; D008540:Meiosis; D009865:Oocytes / Q000502:physiology*
keywords: aneuploidy; cell biology; chromosomes; genes; human; human oocytes; kinetochores; maternal age effect; meiosis; mouse