# The template-specific fidelity of DNA replication with high-order neighbor effects: a first-passage approach

## TL;DR

This paper introduces a first-passage analytical approach to quantify DNA replication fidelity, revealing how high-order neighbor effects influence positional accuracy and demonstrating the dominance of nearest-neighbor sequences in fidelity determination.

## Contribution

It develops a novel first-passage method to analyze template-specific replication fidelity considering high-order neighbor effects, providing analytical expressions under biologically relevant conditions.

## Key findings

- Fidelity is mainly determined by nearest-neighbor sequences.
- Analytical expressions link kinetic pathways to high fidelity and velocity.
- Replication mutations are randomly distributed across the genome.

## Abstract

DNA replication fidelity is a critical issue in molecular biology. Biochemical experiments have provided key insights on the mechanism of fidelity control by DNAP in the past decades, whereas systematic theoretical studies on this issue began only recently. Because of the underlying difficulties of mathematical treatment, comprehensive surveys on the template-specific replication kinetics are still rare. Here we proposed a first-passage approach to address this problem, in particular the positional fidelity, for complicated processes with high-order neighbor effects. Under biologically-relevant conditions, we derived approximate analytical expressions of the positional fidelity which shows intuitively how some key kinetic pathways are coordinated to guarantee the high fidelity, as well as the high velocity, of the replication processes. It was also shown that the fidelity at any template position is dominantly determined by the nearest-neighbor template sequences, which is consistent with the idea that replication mutations are randomly distributed in the genome.