Understanding Cell Reprogramming By Adaptive Regulatory Mutations As a Guide for Cell Design

Adaptive regulatory mutations are common genetic variants in evolutionary experiments. These mutations shift gene expression at a global scale to switch functions between different cellular states. In this work Escherichia coli RNA Polymerase mutants were analyzed to understand the implications of such evolutionary mechanisms in synthetic biology . Using multi-omic data, key environmental controls and a genome scale model of metabolism and gene expression it was possible to unravel the system reprogramming by single amino acid changes in the RNAP. The regulatory effect of the mutations results in a perturbed cellular state that increase growth and cell yield by reducing non-growth related protein expression. Transcriptional regulatory network analysis show the mechanism of cellular function shift. Econometric analysis reveal the resource allocation constraints that organisms face. Detailed phenotypic assays show consistent fitness benefits and detriments in specific environments. Our results advance in the understanding of the multi-scale relationship between a genetic variation and the mechanism of phenotypic change. Thus they should be able to guide synthetic biology efforts and provide a basis for the design of synthetic cell phenotypes.