1. Cell Biology
  2. Chromosomes and Gene Expression
Download icon

Chromosome Segregation: Freewheeling sisters cause problems

  1. Takashi Akera
  2. Michael A Lampson  Is a corresponding author
  1. University of Pennsylvania, United States
  • Cited 1
  • Views 617
  • Annotations
Cite this article as: eLife 2016;5:e13788 doi: 10.7554/eLife.13788


The factors that lead to errors in chromosome segregation during the production of egg cells in humans are becoming clearer.

Main text

Chromosomes must be accurately segregated during the production of sex cells to ensure that the next generation inherits an intact copy of the genome. However, this process is particularly error-prone in women and gets worse as they get older (Hassold and Hunt, 2001). Errors in chromosome segregation produce egg cells with the wrong number of chromosomes, which can lead to infertility and Down syndrome (Herbert et al., 2015).

New eggs develop from immature egg cells (or oocytes) via meiosis: this process involves the original cell’s DNA being replicated once before it divides twice to produce four new cells, each with half the original number of chromosomes. Most errors in the number of chromosomes in human eggs come from mistakes made when the oocyte divides for the first time in a process commonly called meiosis I. Multiple factors can contribute to these errors, but it is not clear which are most significant in human oocytes (Holubcova et al., 2015; Nagaoka et al., 2012).

Human oocytes start with 23 pairs of homologous chromosomes, which are split during the anaphase stage of meiosis I so that the egg contains one from each pair. There are two main requirements that must be met during meiosis I. First, each pair of homologous chromosomes must be physically connected to form a “bivalent”. Second, the two sister kinetochores on each chromosome must be functionally fused together so that both sisters connect to the same spindle pole (Figure 1). Now, in eLife, Melina Schuh and colleagues at the MRC Laboratory of Molecular Biology, the Max Planck Institute for Biophysical Chemistry and the Bourn Hall Clinic show that these two requirements are both compromised in human oocytes. This provides a plausible mechanism to explain the errors often seen in meiosis I in women (Zielinska et al., 2015).

Normal and abnormal meiosis I in human oocytes.

Before meiosis, the 46 chromosomes are duplicated such that each consists of two sister chromatids. During meiosis I, the homologous chromosomes then partner up into 23 pairs. A single pair of homologous chromosomes is shown (top), and the two chromosomes are connected via crossovers called “chiasmata”. The kinetochores (shown as black semi-circles) on sister chromatids are fused together and become attached to microtubules (shown in green) emanating from the same pole of the spindle (not shown). This geometry helps the kinetochores of pairs of homologous chromosomes to be captured by microtubules from opposite spindle poles, and pulled to opposite sides of the cell. Zielinska et al. occasionally observed abnormal configurations of chromosomes in human oocytes. Often the sister kinetochores were split and ended up attached to spindle microtubules from different spindle poles (bottom left). This allowed the pair of homologous chromosomes (or "bivalent”) to rotate. Also, the connections between homologous chromosomes were commonly compromised, which sometimes led to premature separation of the bivalent (bottom right).

Schuh and colleagues – who include Agata Zielinska as first author – used optical microscopy to investigate the geometry of kinetochores in oocytes from women of various ages. They observed that sister kinetochores that should have been fused during meiosis I were often disconnected (Figure 1). This splitting of sister kinetochores has typically not been observed in mice and yeast (Kim et al., 2015). Older women also had more split kinetochores than younger women, which is consistent with the findings of previous studies involving mice and humans (Lister et al., 2010; Chiang et al., 2010; Sakakibara et al., 2015).

Zielinska et al. also found that split kinetochores did not attach properly to the spindle that pulls the chromosomes apart during meiosis, which allowed the bivalent to twist or rotate (Figure 1). Rotating bivalents could lead to errors in segregation of the chromosomes, such as replicated copies of each chromosome separating too soon. However, it is still unclear whether these rotated bivalents contribute to cells having the wrong number of chromosomes (a phenomenon known as aneuploidy). An important next step in this research is to investigate how rotated bivalents segregate during anaphase.

A previous study showed that segregation errors in oocytes from older mice occur when a bivalent separates prematurely (Sakakibara et al., 2015). Zielinska et al. show that this also occurs in human oocytes, including oocytes from younger women (Figure 1). This finding may explain why human oocytes are highly error-prone, even at an earlier age, compared to other species (Hassold and Hunt, 2001).

Finally, Zielienska et al. also show that human oocytes proceed to anaphase even if their chromosomes are not aligned correctly. During mitotic cell division, a surveillance system called the spindle assembly checkpoint (SAC) prevents the start of anaphase until all the kinetochores are attached to the spindle: this helps to ensure that the chromosomes are segregated correctly. The work of Zielinska et al. indicates at least two, not mutually exclusive, possibilities for how the SAC works during meiosis in humans. First, it is possible that the SAC does not respond to attachment defects that are associated with the chromosomes not being aligned correctly. Second, the kinetochores may be attached to the spindle, even on the misaligned chromosomes, and therefore do not activate the SAC.

Zielinska et al. suggest that the splitting of sister kinetochores and the premature separation of a bivalent in human oocytes could lead to aneuploidy in the resulting eggs. Complexes containing a cohesion protein called Rec8 are essential for both sister kinetochore fusion and bivalent formation (Watanabe, 2012), and Meikin family proteins work through Rec8 to fuse sister kinetochores (Kim et al., 2015). Thus, it would be interesting to study the Meikin-Rec8 pathway in human oocytes. Rec8 is found along the length of each chromosome (because it connects the homologous chromosomes), as well as near the kinetochore, so examining where Rec8 is localized on the chromosome axis in human oocytes might help us understand why bivalents separate prematurely. Furthermore, the increased separation of sister kinetochores and bivalents that occurs with age may also be explained by defects in Rec8’s function, because previous studies reported that less Rec8 cohesin was associated with chromosomes in older mice (Lister et al., 2010; Chiang et al., 2010).

Last year Schuh and co-workers reported that defects in the formation of the spindle contribute to problems with chromosome segregation in human oocytes (Holubcova et al., 2015). Thus, multiple features of meiosis in human oocytes have been described recently, and further work may identify the major factor, or factors, that contribute to aneuploidy.


  1. 1
  2. 2
  3. 3
  4. 4
  5. 5
  6. 6
  7. 7
  8. 8
  9. 9
  10. 10

Article and author information

Author details

  1. Takashi Akera

    Department of Biology, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8406-9333
  2. Michael A Lampson

    Department of Biology, University of Pennsylvania, Philadelphia, United States
    For correspondence
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2825-1894

Publication history

  1. Version of Record published: February 2, 2016 (version 1)


© 2016, Akera et al.

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


  • 617
    Page views
  • 176
  • 1

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Biochemistry and Chemical Biology
    2. Cell Biology
    Mikel Garcia-Marcos et al.
    Tools and Resources Updated

    Heterotrimeric G-proteins are signal transducers involved in mediating the action of many natural extracellular stimuli and many therapeutic agents. Non-invasive approaches to manipulate the activity of G-proteins with high precision are crucial to understand their regulation in space and time. Here, we developed LOV2GIVe, an engineered modular protein that allows the activation of heterotrimeric G-proteins with blue light. This optogenetic construct relies on a versatile design that differs from tools previously developed for similar purposes, that is metazoan opsins, which are light-activated G-protein-coupled receptors (GPCRs). Instead, LOV2GIVe consists of the fusion of a G-protein activating peptide derived from a non-GPCR regulator of G-proteins to a small plant protein domain, such that light uncages the G-protein activating module. Targeting LOV2GIVe to cell membranes allowed for light-dependent activation of Gi proteins in different experimental systems. In summary, LOV2GIVe expands the armamentarium and versatility of tools available to manipulate heterotrimeric G-protein activity.

    1. Cell Biology
    2. Plant Biology
    Madlen Stephani et al.
    Research Article Updated

    Eukaryotes have evolved various quality control mechanisms to promote proteostasis in the endoplasmic reticulum (ER). Selective removal of certain ER domains via autophagy (termed as ER-phagy) has emerged as a major quality control mechanism. However, the degree to which ER-phagy is employed by other branches of ER-quality control remains largely elusive. Here, we identify a cytosolic protein, C53, that is specifically recruited to autophagosomes during ER-stress, in both plant and mammalian cells. C53 interacts with ATG8 via a distinct binding epitope, featuring a shuffled ATG8 interacting motif (sAIM). C53 senses proteotoxic stress in the ER lumen by forming a tripartite receptor complex with the ER-associated ufmylation ligase UFL1 and its membrane adaptor DDRGK1. The C53/UFL1/DDRGK1 receptor complex is activated by stalled ribosomes and induces the degradation of internal or passenger proteins in the ER. Consistently, the C53 receptor complex and ufmylation mutants are highly susceptible to ER stress. Thus, C53 forms an ancient quality control pathway that bridges selective autophagy with ribosome-associated quality control in the ER.