Statistical method for comparing the level of intracellular organization between cells

Abstract

Systems level approaches to analyzing complex emergent behavior require quantitative characterization of alterations of behavior on both the microscale and macroscale. Here we consider the problem of cellular organization and describe a statistical methodology for quantitative comparison of the internal organization between different populations of similar physical objects, such as cells. This comparison is achieved with several steps of analysis. Starting with three-dimensional or two-dimensional images of cells, images are segmented to identify individual cells. Locations of internal points of interest, such as organelles or proteins, are recorded. To define the configuration of internal points in each cell, the individual cells are subjected to bounded Voronoi tessellation: subdividing the bounded volume or area of the cell into subvolumes determined by the locations of the internal points of interest. A statistical methodology is applied to yield a metric for similarity in degree of organization between populations. We applied this methodology to test whether centrioles play a role in global cellular organization, using mutants of the green alga Chlamydomonas reinhardtii with known alterations in centriole number, structure, and position as a model system. Comparing mutant populations and wild-type populations revealed a dramatic difference in the degree of organization in the mutant strains. These computational and experimental results provide statistical support for prior observational studies and support the idea that centrioles play a role in generating or maintaining global cellular organization. Our results confirm that this method can be used to sensitively compare the extent and type of organization within cells.cell shape | image analysis | microscopy | cytoskeleton A major outstanding problem in basic biology is how cells generate and regulate their 3D geometry on the molecular level (1). In addition to being an interesting fundamental science question, there are clinical implications involved. In development, differentiation of stem cells into distinct functional cell types is accompanied by characteristic changes in cellular organization (2). The disruption of cellular organization (dysplasia) is a major hallmark of cancer and the basis of cytopathology (3). The biochemistry canon presupposes cell organization is mechanistically generated from molecular networks and molecular self-assembly (4). Although entire genomes have been sequenced and genome-wide molecular-interaction maps exist for model organisms (5), it remains unclear which molecules regulate the intracellular organization or how they do it (1, 6, 7).Traditionally, cell organization has been investigated visually by identifying mutants or perturbations that cause gross changes in cell appearance. However, such an approach will only identify the most dramatic phenotypes, and it is likely that many mutations may exist that play more subtle roles in cell organization and that are only distinguishable statistically by considering large num...

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