Computer simulation of merotelic kinetochore-microtubule attachments: corona size is more important than other cell parameters.

Abstract

The even chromosome segregation between daughter cells during mitosis is crucial for genome integrity and is mostly regulated by proper attachments of spindle microtubules to kinetochores. Abnormalities in this process can lead to chromosome mis-segregation and potentially result in severe developmental disorders such as aneuploidy and cancer. Merotelic attachments when tubulin microtubules captured by the kinetochore of one chromatid originate from both spindle poles are considered as one of the key molecular processes that cause such abnormalities. In this paper, we use computer modeling and the Monte Carlo approach to reveal the reasons for retaining merotelic attachments at the end of metaphase. To this end, we varied, in small increments, the basic cell parameters within ensembles of 100, 500, and 1000 virtual cells. The analysis of configurations that ensure the preservation of the largest fraction of merotelic attachments enabled us to conclude that only a change in the size of the kinetochore corona can significantly increase the number of merotelic attachments and the angle between the centromere axis and the spindle axis. The effect of the other changes in model parameters, if any, was steadily suppressed by the end of metaphase. In addition, our computer model was validated by successfully reproducing the results of third-party theoretical studies as well as some experimental observations. We also found that the orientation of chromosomes and the number of merotelic attachments do not have an explicit correlation with each other and within some limits can change independently.