Principles of studying a cell - a non-boastful paper for all molecular biologists

Studies of a cell rely on either observational approaches or perturbational/genetic approaches to define the contribution of a gene to specific cellular traits. It is unclear, however, under what circumstances each of the two approaches can be most successful and when they are doomed to fail. By analyzing over 500 complex traits of the yeast Saccharomyces cerevisiae we show that the trait relatedness to fitness determines the performance of observational approaches. Specifically, in traits subject to strong natural selection, genes identified using observational approaches are often highly coordinated in expression, such that the gene-trait associations are readily recognizable; in sharp contrast, the lack of such coordination in traits subject to weak selection leads to no detectable activity-trait associations for any individual genes and thus the failure of observational approaches. We further show that genetic approaches can be successful when the genes responsible for coordinating the target genes of observational approaches are perturbed. However, because the system-level cellular responses to a random mutation affect more or less every gene and consequently every trait, most genetic effects convey no trait-specific functional information for understanding the traits, which is particularly true for traits subject to weak selection.\n\nSignificance statementCell research is nearly exclusively based on empirical data obtained through either observational approaches or perturbational/genetic approaches. It is, however, increasingly clear that an analytical framework able to guide the empirical strategies is necessary to drive the field further ahead. This study analyzes ~500 complex traits of the yeast Saccharomyces cerevisiae and reveals the organizing principles of a cell. Specifically, a cell can be viewed as a factory, with each trait being the product of a production line operated directly by workers who are supervised by managers. For a cellular trait produced by many workers, the coordination level of the workers determines the performance of observational approaches. Meanwhile, the coordination of workers is realized by managers that are recruited and/or maintained by natural selection. Thus, observational approaches are expected to fail for traits subject to little selection, and genetic approaches can be successful only when the managers of fitness-tightly-coupled traits are perturbed. The manager-worker architecture built by natural selection explains well the origins of global epistasis and ubiquitous genetic effects, two major issues confusing current genetics and molecular and cellular biology, providing a clear guideline on how to study a cell.