Abstract We report the discovery of a fundamental organizational principle in complex genomes: structural risk and evolutionary selection operate as orthogonal (independent) forces in humans (r = -0.0041, p < 10^-294), while remaining strongly coupled in simple organisms like E. coli (r = -0.550, p < 10^-159). This 'Orthogonality Principle,' discovered through the HexaGene™ Framework, represents a previously unknown law of genomic organization that distinguishes complex from simple life forms. Analysis of 6,187,367 structural windows across the complete human genome (hg38) confirms this principle holds universally across all chromosomes. Additionally, we identify powerful resilience mechanisms (r = -0.9904) that buffer structural vulnerabilities in complex organisms. These findings suggest that the evolution of complexity required the decoupling of structural and selective constraints, enabling the sophisticated regulatory architecture of higher organisms. The HexaGene Framework integrates multiple computational laws to analyze genomic structure beyond traditional protein-centric models. While we detail the Orthogonality Principle (Law 9) herein as a fundamental biological discovery, the complete framework encompasses nine interrelated laws that will be reported as intellectual property protection is finalized. Keywords: genomic organization, structural biology, evolutionary constraints, orthogonality principle, complexity evolution

Chromosomal fragile sites are specific genomic loci that exhibit spontaneous breaks, gaps, or rearrangements under conditions of mild replication stress. Over 100 common fragile sites have been mapped in the human genome, and their locations frequently coincide with cancer-associated translocation breakpoints and oncogene disruption sites. Despite decades of research, the molecular mechanisms underlying CFS vulnerability remain incompletely understood. Current models emphasize sequence-level vulnerability factors: AT-richness (weak hydrogen bonding), homopolymer runs (impaired replication processivity), and specific secondary structure motifs (hairpins, triplexes). However, predictive models incorporating these features typically achieve only modest discriminative performance (AUC 0.60–0.72), suggesting that additional organizational principles—currently uncharacterized—govern structural stability