Genomic coordination of nucleotide skews and gene strand distribution driven by GC‐content in prokaryotes

Abstract Understanding how prokaryotic genomes coordinate nucleotide composition and gene distribution is a central yet unresolved question in genome evolution. Across different genomes, GC‐content, nucleotide asymmetries, and biased gene distribution between replication strands are tightly associated, but existing explanations typically address only individual components and lack a unified causal framework. Here, by analyzing 4012 complete sequences, we show that the variation in GC‐content, together with intrinsic constraints imposed by the genetic code and selection, can account for the coordinated evolution of GC‐skew, AT‐skew, and gene strand bias (GS‐bias). We show that decreasing GC‐content inevitably influences both synonymous codon usage and amino acid usage, thereby enforcing stronger GC‐ and AT‐skews in coding genes and driving a shift between “typical” (GC‐skew > 0, AT‐skew < 0, and GS‐bias > 0 in the leading strand) and “atypical” (GC‐skew > 0, AT‐skew > 0, and GS‐bias > 0) modes of organization. Grounded in first principles, we propose an evolutionary framework that integrates previously proposed hypotheses. This framework explains why atypical organization emerges primarily in low‐GC genomes, reveals that mutational biases likely evolved to accommodate the skew requirements of coding genes, and highlights the importance of internal constraints on prokaryotic genome evolution.