Patterns of selection against centrosome amplification in human cell lines

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. Author summary Human cells possess small structures called centrioles, which need to be duplicated and properly segregated to ensure cell viability. Paradoxically, cells with a variable number of excess centrioles are commonly found in cancer. 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. However, it is not known if this overproduction-selection balance is sufficient to explain the observed intra- and inter-population variation in centriole numbers. In this study, 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. Surprisingly, our results indicate that the observed variability in most cell lines can be best explained by models assuming a single penalty against extra centrioles, regardless of their number, and complex overproduction rules, where multiple centrioles can be gained in a single event. Furthermore, we estimate that selection against extra centrioles is generally very strong. Our work presents a novel quantitative approach to analyse centriole number variation and to further our understanding of the role of centriole number abnormalities in cancer development.

Automated summary

This study investigates the phenomenon of centrosome amplification in cancer cells, where excess centrioles are common. Surprisingly, the study finds that the variability in centriole numbers in most cell lines can be best explained by models assuming a single penalty against extra centrioles, regardless of their number. Furthermore, the study estimates that selection against extra centrioles is generally very strong.