Natural selection defines the cellular complexity

Current biology is perplexed by the lack of a theoretical framework for understanding the organization principles of the molecular system within a cell. Here we first studied growth rate, one of the seemingly most complex cellular traits, using functional data of yeast single-gene deletion mutants. We observed nearly one thousand e xpression i nformative g enes (EIGs) whose expression levels are linearly correlated to the trait within an unprecedentedly large functional space. A simple model considering six EIG-formed protein modules revealed a variety of novel mechanistic insights, and also explained ∼50% of the variance of cell growth rates measured by Bar-seq technique for over 400 yeast mutants (Pearson’s R = 0.69), a performance comparable to the microarray-based ( R = 0.77) or colony-size-based ( R = 0.66) experimental approach. We then applied the same strategy to 501 morphological traits of the yeast and achieved successes in most fitness-coupled traits each with hundreds of trait-specific EIGs. Surprisingly, there is no any EIG found for most fitness-uncoupled traits, indicating that they are controlled by super-complex epistases that allow no simple expression-trait correlation. Thus, EIGs are recruited exclusively by natural selection, which builds a rather simple functional architecture for fitness-coupled traits, and the endless complexity of a cell lies primarily in its fitness-uncoupled features.