Mechanisms of DNA repair have evolved to minimise the probability of nonsense mutations

Abstract

ABSTRACTVariation in sequence mutability has important implications for evolutionary models and predicting disease occurrence, and is driven in part by evolutionary divergence in mechanisms of DNA repair. The aim of this study was twofold: first, to assess the effect of local sequence context on substitution rates in the mouse lineage; second, to investigate the relationship between sequence mutability and selection. We show that the 7-mer context (i.e three bases either side of the base of interest) explains more variation in substitution rates between chromosomes in the mouse lineage than either the 3-mer, 5-mer, or 9-mer contexts. Furthermore, we also show that 7-mer substitutions with the potential to cause nonsense mutations when they occur in translated sequences occur at a lower rate across the genome than 7-mer substitutions with the potential to cause synonymous mutations. We propose that mechanisms of DNA repair have evolved to prioritise substitutions that are more likely to be deleterious to fitness.