Accurate chromosome segregation by probabilistic self-organization

TL;DR

This paper presents a simple mathematical model demonstrating that chromosome bi-orientation during cell division is achieved through probabilistic self-organization, explaining how errors are spontaneously corrected or persist based on attachment dynamics.

Contribution

The study introduces a novel probabilistic model of kinetochore-microtubule interactions, highlighting the importance of attachment-detachment balance for accurate chromosome segregation.

Findings

Correct attachment balance leads to spontaneous error correction.

Errors are more common in meiosis I than in mitosis.

Faulty conformations can evade the spindle checkpoint, causing chromosome loss.

Abstract

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-organization, rather than a sophisticated process of error detection and correction.