Abstract
The presence of extra centrioles, termed centrosome amplification, is a hallmark of cancer. The distribution of centriole numbers within a cancer cell population appears to be at an equilibrium maintained by centriole overproduction and selection, reminiscent of mutation-selection balance. It is unknown to date if the interaction between centriole overproduction and selection can quantitatively explain the intra- and inter-population heterogeneity in centriole numbers. Here, we define mutation-selection-like models and employ a model selection approach to infer patterns of centriole overproduction and selection in a diverse panel of human cell lines. Surprisingly, we infer strong and uniform selection against any number of extra centrioles in most cell lines. Finally we assess the accuracy and precision of our inference method and find that it increases non-linearly as a function of the number of sampled cells. We discuss the biological implications of our results and how our methodology can inform future experiments.
Highlights
Centrioles are microtubule-based structures that organise the centrosome and thereby orchestrate microtubule nucleation in vertebrate cells [1, 2]
It is thought that these cells arise from centriole overproduction and are subsequently eliminated by selection, such that their frequency is stable in the population
We model the cell population dynamics of abnormal centriole numbers inspired by classical evolutionary theory, and infer overproduction and selection parameters from a panel of 67 human cell lines
Summary
Centrioles are microtubule-based structures that organise the centrosome and thereby orchestrate microtubule nucleation in vertebrate cells [1, 2]. Centriole number abnormalities are a source of phenotypic heterogeneity in cancer cells. To the best of our knowledge, there exists no quantitative description of how centriole numbers are distributed in cancer cells. In a proliferating cell population, cells start the cell cycle with two centrioles, which duplicate once and only once during S-phase. After cytokinesis, both daughter cells inherit two centrioles each. Both daughter cells inherit two centrioles each This centriole duplication and segregation cycle ensures that centriole number is kept constant across generations [3, 6, 7]
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