A Diverse Genetic Basis for Metabolic Reactions is Revealed Through Pangenome analysis

Sequenced genomes for thousands of strains of a bacterial species allow for a comprehensive analysis of its pangenome. We present a pangenome study of Escherichia colis metabolism by formulating gene-to-protein-to-reaction associations (GPRs) for about 2,700 metabolic reactions in 2,377 fully sequenced strains. On one hand, these GPRs reconstruct strain-specific networks that allow computational predictions (and experimental validation) of metabolic phenotypes, while on the other hand, they give the genetic basis for a given metabolic reaction in every strain. A pangenome-wide analysis of GPRs shows that: 1) We can reveal the genetic basis for a specific metabolic property at the species level; 2) The genetic basis for many metabolic reactions is diverse; 3) Many rare genes show variation in the genes genomic neighborhood which often contain genes from transposable elements, 4) Many rare genes show large-scale fragmentation and horizontal gene transfer (>11,000 rare genes in 2,377 strains); and 5) The aromatic amino acids and branched chain amino acids pathways are enriched with rare genes, with Acetolactate synthase having 29 distinct genes. Thus, analysis of GPRs across the pangenome reveals a complex dynamic evolutionary history of metabolism, revealing the role of conserved, fragmented, and horizontally transferred metabolic genes.