A Systems Biology Definition of the Core Proteome of Metabolism and Expression Is Consistent with High-Throughput Data

Finding the minimal set of gene functions needed to sustain life is of both fundamental and practical importance. Minimal gene lists have been proposed using comparative genomics-based core proteome definitions. A definition of a core proteome that is supported by empirical data, is understood at the systems level, and provides a basis for computing essential cell functions is lacking. Here, we use a systems biology-based genome-scale model of metabolism and expression to define a functional core proteome consisting of 356 gene products, accounting for 44% of the Escherichia coli proteome by mass based on proteomics data. This systems biology core proteome includes nearly 200 genes not found in previous comparative genomics-based core proteome definitions, accounts for 65% of known essential genes in E. coli, and has functional overlap with minimal genomes (Buchnera aphidicola and Mycoplasma genitalium) (AUC = 0.78). Based on transcriptomics data across growth conditions and genetic backgrounds, the systems biology core proteome is significantly enriched in non-differentially expressed genes, and depleted in differentially expressed genes. Compared to the non-core, core gene expression levels are also similar across genetic backgrounds. Furthermore, core genes exhibit significantly more complex transcriptional and post-transcriptional regulatory features (40% more transcription start sites per gene, >20% longer 5’UTR). Thus, genome-scale systems biology approaches rigorously identify a functional core proteome needed to support growth. This framework, discerned and validated using high-throughput datasets, facilitates a mechanistic understanding of systems-level core proteome function through in silico models; it de facto defines a paleome.