The genotype-phenotype relationships in the light of natural selection.

Although any genotype-phenotype relationships are a result of evolution, little is known about how natural selection and neutral drift, two distinct driving forces of evolution, operate to shape the relationships. By analysing ∼500 yeast quantitative traits we reveal a basic "supervisor-worker" gene architecture underlying a trait. Supervisors are often identified by "perturbational" approaches (such as gene deletion), while workers, which usually show small and statistically insignificant deletion effects, are tracked primarily by "observational" approaches that examine the correlation between gene activity and trait value across a number of conditions. Accordingly, supervisors provide most of the genetic understandings of the trait while workers provide rich mechanistic understandings. Further analyses suggest that most observed supervisor-worker interactions may evolve largely neutrally, resulting in pervasive between-worker epistasis that suppresses the tractability of workers. In contrast, a fraction of supervisors are recruited/maintained by natural selection to build worker co-expression, boosting the tractability of workers. Thus, by revealing a supervisor-worker gene architecture underlying complex traits, the opposite roles of natural selection versus neutral drift in shaping the gene architecture, and the complementary strengths of the perturbational and observational research strategies in characterizing the gene architecture, this study may lay a new conceptual foundation for understanding the molecular basis of complex traits.