The effects of chromatin organization on variation in mutation rates in the genome

Key Points Regional variation in mutation rates is an important phenomenon that affects genome evolution. It is determined by features of genomic landscape, with chromatin having an important influence. Pairwise studies have revealed the complexity of correlation between chromatin and mutation rates. Some studies support a link between open chromatin and repressed mutations, whereas some argue for a link between closed chromatin and decreased mutation rates. Other studies highlight patterns that are base-specific, depend on epigenomic modifications in a genomic region, or are shaped by selection. As features characterizing chromatin states are correlated with each other and with other genomic landscape features, multivariate segmentation analyses (using hidden Markov models) are providing a more nuanced depiction of the relationship between chromatin and germline mutation rates. Specifically, a prevalent genomic state with moderately high substitution and deletion rates is located in regions with closed chromatin, whereas a less abundant state with very high substitution, insertion and deletion rates is located in regions with open chromatin. Several recent studies indicate a positive association between increased somatic mutation rates and closed chromatin in cancer genomes. In several types of cancer, driver mutations are located in genes that regulate chromatin, leading to the hypothesis that consequent global or local chromatin remodelling results in malignancy. Transcription of genes is influenced by chromatin state and leads to a biased substitution pattern that is probably due to transcription-coupled repair. The evolution of genes is influenced by regional variation in mutation rates (RViMR). Chromatin organization affects RViMR, although the correlation between chromatin state and mutation types and rates is complex. This Review describes recent research on RViMR and chromatin organization, and the emerging findings from investigations of both germline and somatic mutations. The variation in local rates of mutations can affect both the evolution of genes and their function in normal and cancer cells. Deciphering the molecular determinants of this variation will be aided by the elucidation of distinct types of mutations, as they differ in regional preferences and in associations with genomic features. Chromatin organization contributes to regional variation in mutation rates, but its contribution differs among mutation types. In both germline and s