Accurate chromosome segregation by probabilistic self-organisation.
BACKGROUND
For faithful chromosome segregation during cell division, correct attachments must be established between sister chromosomes and microtubules from opposite spindle poles through kinetochores (chromosome bi-orientation). Incorrect attachments of kinetochore microtubules (kMTs) lead to chromosome mis-segregation and aneuploidy, which is often associated with developmental abnormalities such as Down syndrome and diseases including cancer. The interaction between kinetochores and microtubules is highly dynamic with frequent attachments and detachments. However, it remains unclear how chromosome bi-orientation is achieved with such accuracy in such a dynamic process.


RESULTS
To gain new insight into this essential process, we have developed a simple mathematical model of kinetochore-microtubule interactions during cell division in general, i.e. both mitosis and meiosis. Firstly, the model reveals that the balance between attachment and detachment probabilities of kMTs is crucial for correct chromosome bi-orientation. With the right balance, incorrect attachments are resolved spontaneously into correct bi-oriented conformations while an imbalance leads to persistent errors. In addition, the model explains why errors are more commonly found in the first meiotic division (meiosis I) than in mitosis and how a faulty conformation can evade the spindle assembly checkpoint, which may lead to a chromosome loss.


CONCLUSIONS
The proposed model, despite its simplicity, helps us understand one of the primary causes of chromosomal instability-aberrant kinetochore-microtubule interactions. The model reveals that chromosome bi-orientation is a probabilistic self-organisation, rather than a sophisticated process of error detection and correction.
Institute of Medical Sciences, School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK. y.saka@abdn.ac.uk.
Yasushi
Y
Saka
Institute of Medical Sciences, School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK. v.c.giuraniuc@abdn.ac.uk.
Claudiu V
CV
Giuraniuc
Wellcome Trust Centre for Cell Biology, University of Edinburgh, Michael Swann Building, Max Born Crescent, Edinburgh, EH9 3BF, UK. h.ohkura@ed.ac.uk.
Hiroyuki
H
Ohkura
D020090:Chromosome Segregation; D006801:Humans; D018386:Kinetochores / Q000378:metabolism*; D008540:Meiosis; D008870:Microtubules / Q000378:metabolism*; D008938:Mitosis; D008954:Models, Biological; D015233:Models, Statistical; D008941:Spindle Apparatus / Q000378:metabolism