Year: 2026
Type: preprint
Abstract: DNA replication achieves error rates as low as 10 −9 -10 −11 per base pair through the combined contribution of base selection, exonuclease proofreading, and mismatch repair. Among those processes, base selection determines the initial level of accuracy and is strongly modulated by local sequence context. Existing models address this dependence either by fitting individual rate constants for each sequence context or by invoking the global template properties, neither of which derives sequence dependence from the underlying thermodynamics and kinetics of base pair formation. Here we present a mechanism for sequence-dependent base selection fidelity, built from two physical properties: nearest-neighbor stacking thermodynamics and directional kinetic asymmetry. The model fits the experimentally observed mutation spectra from three mismatch repair-deficient organisms well (r=0.74, 0.70, and 0.58), and predicts that base-selection accuracy varies non-monotonically with temperature in a sequence-dependent manner. Our model, therefore, provides a framework that connects sequence-dependent thermodynamic and kinetic effects during nucleotide incorporation to experimentally observed mutation rates. Statement of significance The accuracy with which correct nucleotides are selected during DNA replication is dependent on the local sequence context, yet it remains poorly understood. Here we present a theoretical model in which the intrinsic base-selection error ratios emerge from the combined effect of nearest-neighbor base-stacking thermodynamics and a directional asymmetry in cooperativity between adjacent base pairs on the growing strand. We found that sequence-dependent error ratios calculated by the model exhibit correlations of r=0.74, 0.70, and 0.58 with mutation rates measured in mismatch-repair-deficient strains of three organisms. The model also predicts a non-monotonic dependence of base-selection accuracy on temperature. This work provides a theoretical framework, grounded in base-stacking energetics and asymmetric kinetics, for interpreting sequence-dependent base-selection error rates.
Institution: National Institute of Technology Durgapur
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7172342062