A relational architecture of the human genome
Journal:
bioRxiv
Published Date:
Oct 16, 2026
Abstract
Complex systems exhibit organization not only through their components but also via their interdependencies. Local nucleotide dependencies underpin regulatory motifs and RNA structures, yet principles governing a higher-order organization across the human genome remain unknown. Here we systematically perturbed every position of the com- plete telomere-to-telomere human genome using Nucleotide Transformer v3 with an ex- ascale compute cluster, generating nucleotide-resolution dependency maps that reveal a directed, weighted network of position-to-position genomic relationships. This network recapitulates known biological features and uncovers recurrent, directional architec- tures termed 'relons', spanning coding, non-coding, and unannotated regions. These re- lational modules reflect evolutionary and functional constraints and associate with hu- man genetic variation and pathogenic variants. Our findings suggest a higher-order rela- tional layer of genome organization, providing a framework to interpret DNA as a complex system of dependencies beyond linear and 3D structure, with implications for under- standing genetic variation and disease.
