Sister kinetochore splitting and precocious disintegration of bivalents could explain the maternal age effect

  1. Agata P Zielinska
  2. Zuzana Holubcova
  3. Martyn Blayney
  4. Kay Elder
  5. Melina Schuh  Is a corresponding author
  1. Medical Research Council, United Kingdom
  2. Bourn Hall Clinic, United Kingdom

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.

Article and author information

Author details

  1. Agata P Zielinska

    Laboratory of Molecular Biology, Medical Research Council, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Zuzana Holubcova

    Laboratory of Molecular Biology, Medical Research Council, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Martyn Blayney

    Bourn Hall Clinic, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Kay Elder

    Bourn Hall Clinic, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Melina Schuh

    Laboratory of Molecular Biology, Medical Research Council, Cambridge, United Kingdom
    For correspondence
    mschuh@mrc-lmb.cam.ac.uk
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Andrea Musacchio, Max Planck Institute of Molecular Physiology, Germany

Ethics

Human subjects: The use of immature unfertilized human oocytes in this study has been approved by the UK's National Research Ethics Service under the REC reference 11/EE/0346; IRAS Project ID 84952. Immature unfertilized oocytes were donated by women receiving assisted reproduction treatment at Bourn Hall Clinic (Cambridge, UK).

Version history

  1. Received: September 4, 2015
  2. Accepted: December 9, 2015
  3. Accepted Manuscript published: December 15, 2015 (version 1)
  4. Accepted Manuscript updated: December 16, 2015 (version 2)
  5. Version of Record published: February 2, 2016 (version 3)

Copyright

© 2015, Zielinska et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Agata P Zielinska
  2. Zuzana Holubcova
  3. Martyn Blayney
  4. Kay Elder
  5. Melina Schuh
(2015)
Sister kinetochore splitting and precocious disintegration of bivalents could explain the maternal age effect
eLife 4:e11389.
https://doi.org/10.7554/eLife.11389

Share this article

https://doi.org/10.7554/eLife.11389

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