How mutation rate evolves: Gene expression shapes genome-wide mutation rates in Drosophila melanogaster and Caenorhabditis elegans
Mutation rates vary across the genome, linked to biochemical properties of local DNA sequences. However, mutation rate variation also associates with functional genomic features, raising the possibility that intragenomic mutation rate variation is shaped by adaptive evolution. In particular, recent studies in the model plant Arabidopsis thaliana suggested that highly conserved genes under strong purifying selection also have reduced de novo mutation rates, suggesting that natural selection may have acted to reduce mutation rate specifically at important genes. However, whether this is true for wider taxa, including animals, remains unknown. Here we repurposed published mutation accumulation datasets from Drosophila melanogaster and Caenorhabditis elegans to investigate the determinants of de novo single nucleotide variant (DNV) rates genome-wide under minimal selection. Loci under stronger purifying selection accumulated fewer mutations, including intronic and synonymous mutations. Various sequence-specific (i.e. GC content) and regulatory features (e.g. chromatin modifications) were strongly correlated with mutation rate, but gene expression best explained the depletion of mutations within strongly conserved loci, even after accounting for correlations amongst variables. Using excision repair (XR)-sequencing data we determined that higher levels of transcription- coupled repair (TCR) were associated with reduced mutation rates, strongly suggesting that TCR lowers mutation rate of highly conserved genes. Furthermore, by comparing orthologs between C. elegans and its close relative Pristionchus pacificus, we found that altered gene expression across evolutionary time correlated with altered mutation rate. These findings support a model whereby developmental transcription modulates local mutation rates through TCR. A corollary is that adaptive mutation bias may emerge indirectly, downstream of gene regulation evolution, providing a mechanistic framework that reconciles non-random local mutation rate variation with established evolutionary theory.