Functional defects resulting from deleterious mutations can often be restored during evolution by compensatory mutations. Importantly, this process can generate the genetic diversity seen in networks regulating the same biological function in different species. How the options for compensatory evolution depend on the molecular interactions underlying these functions is currently unclear. We investigate how gene deletions compensating for a defect in the polarity pathway of Saccharomyces cerevisiae impact the fitness landscape. Using a transposon mutagenesis screen, we demonstrate that gene disruption tolerance has changed on a genome-wide scale in the compensated strain. An analysis of the functional associations between the affected genes reveals that compensation impacts cellular processes that have no clear connection to cell polarity. Moreover, genes belonging to the same process tend to show the same direction of tolerance change, indicating that compensation rewires the fitness contribution of cellular processes rather than of individual genes. In conclusion, our results strongly suggest that functional overlap between modules and the interconnectedness of the molecular interaction network play major roles in mediating compensatory evolution.

Research in molecular cell biology has typically been focused on identifying specific genes and proteins responsible for cellular phenomena. However, it is increasingly recognized that the function of many biomolecules is variable and context dependent, raising the question if specific components can adequately explain cellular mechanisms. Philosophers of biology have proposed an alternative perspective known as process ontology, posing that not objects or molecules, but processes are the fundamental units of living systems. Process ontology is gaining popularity in biological theory, but remains challenging to integrate into scientific practice. Here, we assess the applicability of the process perspective in the context of a concrete biological system, namely polarization in budding yeast. We identify relevant processes in yeast polarization at different timescales and examine how these processes affect our understanding of polarity. Using this case study, we demonstrate how the processual perspective evokes new kinds of scientific questions and provide concrete pointers for incorporating processual thought into cell biological research.

In this Perspective, Journal of Cell Science invited researchers working on cell and tissue polarity to share their thoughts on unique, emerging or open questions relating to their field. The goal of this article is to feature 'voices' from scientists around the world and at various career stages, to bring attention to innovative and thought-provoking topics of interest to the cell biology community. These voices discuss intriguing questions that consider polarity across scales, evolution, development and disease. What can yeast and protists tell us about the evolution of cell and tissue polarity in animals? How are cell fate and development influenced by emerging dynamics in cell polarity? What can we learn from atypical and extreme polarity systems? How can we arrive at a more unified biophysical understanding of polarity? Taken together, these pieces demonstrate the broad relevance of the fascinating phenomenon of cell polarization to diverse fundamental biological questions.

Cellular life exhibits order and complexity, which typically increase over the course of evolution. Cell polarization is a well-studied example of an ordering process that breaks the internal symmetry of a cell by establishing a preferential axis. Like many cellular processes, polarization is driven by self-organization, meaning that the macroscopic pattern emerges as a consequence of microscopic molecular interactions at the biophysical level. However, the role of self-organization in the evolution of complex protein networks remains obscure. In this Review, we provide an overview of the evolution of polarization as a self-organizing process, focusing on the model species Saccharomyces cerevisiae and its fungal relatives. Moreover, we use this model system to discuss how self-organization might relate to evolutionary change, offering a shift in perspective on evolution at the microscopic scale.