Human mutation patterns show mostly balanced biases with some irreversible trends
Human mutation field reveals an equilibrium-like structure with irreversible circulation
Artificial Intelligence
Summary
DNA changes in humans happen in ways that can be thought of like moving through an energy landscape, where some changes are more likely than others. The authors studied mutations and found most follow this balanced pattern, but a small part breaks this balance, showing a direction or 'circulation' in how some mutations happen. This leftover imbalance is linked to specific DNA features and chemical changes. Their work helps separate normal mutation tendencies from special mutational mechanisms.
What this means in practice
- •For genomic data analysts: Improve mutation models in human genome analyses by incorporating balanced and directional mutation biases revealed by the study.
- •For bioinformatics software developers: Develop more accurate mutation prediction tools using energy-based modeling of mutation probabilities including non-equilibrium circulation effects.
Authors
Isabella Caranzano, Daniel Maria Busiello, Stefano Priorelli, Amos Maritan, Piero Fariselli
Abstract
The evolution of DNA sequences can be viewed as stochastic dynamics on a high-dimensional discrete space, but it is unclear when empirical transition biases reduce to an effective energy landscape versus retain irreducible non-equilibrium circulation. Human context-dependent mutation probabilities offer a direct test: every single-nucleotide substitution in a local context has a reverse substitution, so the logarithm of the forward-to-reverse probability ratio defines an antisymmetric field-the human mutation field. We show this field has a dominant gradient component and a smaller but reproducible curl component. Using seven-base human germline substitution probabilities, we infer an effective mutational landscape with a Siamese neural network constrained to predict only energy differences. This model predicts forward-to-reverse log-ratios for held-out mutations with a correlation of about 0.93, close to both an unconstrained predictive reference (0.948) and the empirical reversible ceiling from Hodge projection (about 0.96). Although trained only on mutation probabilities, the inferred landscape largely recovers short-word genomic composition and Chargaff reverse-complement symmetry for sequences up to length four. Deviations from equilibrium structure reveal a small but detectable nonequilibrium component: a residual irreversible circulation violating the Kolmogorov cycle condition for detailed balance, reproducible across African, Asian, and European populations, and strongest in CpG-linked cycles and CpG-transition edges, consistent with methylcytosine deamination. These results give a thermodynamic decomposition of the human mutation field: most mutation bias is organized by a local equilibrium-like energy landscape aligned with genome composition, while the residual circulation points to specific directional mutational mechanisms.