Mutation bias shapes gene evolution inArabidopsis thaliana

Classical evolutionary theory maintains that mutation rate variation between genes should be random with respect to fitness^1–4and evolutionary optimization of genic mutation rates remains controversial^3,5. However, it has now become known that cytogenetic (DNA sequence + epigenomic) features influence local mutation probabilities⁶, which is predicted by more recent theory to be a prerequisite for beneficial mutation rates between different classes of genes to readily evolve⁷. To test this possibility, we used de novo mutations in Arabidopsis thaliana to create a high resolution predictive model of mutation rates as a function of cytogenetic features across the genome. As expected, mutation rates are significantly predicted by features such as GC content, histone modifications, and chromatin accessibility. Deeper analyses of predicted mutation rates reveal effects of introns and untranslated exon regions in distancing coding sequences from mutational hotspots at the start and end of transcribed regions in A. thaliana. Finally, predicted coding region mutation rates are significantly lower in genes where mutations are more likely to be deleterious, supported by numerous estimates of evolutionary and functional constraint. These findings contradict neutral expectations that mutation probabilities are independent of fitness consequences. Instead they are consistent with the evolution of lower mutation rates in functionally constrained loci due to cytogenetic features, with important implications for evolutionary biology⁸.