A bottom-up route towards predicting evolution relies on a deep understanding of the complex network that proteins form inside cells. In a rapidly expanding panorama of experimental possibilities, the most difficult question is how to conceptually approach the disentangling of such complex networks. These can exhibit varying degrees of hierarchy and modularity, which obfuscate certain protein functions that may prove pivotal for adaptation. Using the well-established polarity network in budding yeast as a case study, we first organize current literature to highlight protein entrenchments inside polarity. Following three examples, we see how alternating between experimental novelties and subsequent emerging design strategies can construct a layered understanding, potent enough to reveal evolutionary targets. We show that if you want to understand a cell’s evolutionary capacity, such as possible future evolutionary paths, seemingly unimportant proteins need to be mapped and studied. Finally, we generalize this research structure to be applicable to other systems of interest.
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