Relationship between biased mutagenesis and H3K4me1-targeted DNA repair in plants

Mutation is the ultimate source of genetic variation. Mutation rate variability has been observed within plant genomes, but the underlying mechanisms have been unclear. We previously found that mutations occur less often in functionally constrained regions of the genome in Arabidopsis thaliana and that this mutation rate reduction is predicted by H3K4me1, a histone modification found in the gene bodies of actively expressed and evolutionarily conserved genes in plants. We reanalyzed de novo germline single base substitutions in fast neutron irradiated mutation accumulation lines in Kitaake rice (Oryza sativa) and found the same reduction in mutations associated with H3K4me1, gene bodies, and constrained genes as in A. thaliana, suggesting conserved mechanisms for mutation reduction in plants. Here, we characterize a model of targeted DNA repair to explain these observations; PDS5C and MSH6 DNA repair-related proteins target H3K4me1 through their Tudor domains, resulting in nearby DNA experiencing elevated repair. Experimental data and in-silico modeling support the high affinity of the Tudor domain for H3K4me1 in both proteins, and that this affinity is conserved between plant species. ChIP-seq data from PDS5C confirms its localization to conserved and low mutation rate genome regions. Somatic and germline mutations observed by deep sequencing of wild-type and MSH6 knockout lines confirm that MSH6 preferentially repairs gene bodies and H3K4me1-enriched regions. These findings inspire further research to characterize the origins of mechanisms of targeted DNA repair in eukaryotes and their consequences on tuning the evolutionary trajectories of genomes.