Differential DNA Mismatch Repair Causes Genome-Wide Mutation Rate Variation

Analysis of cancer genome sequencing studies indicates that somatic mutations occur less frequently in regions of early replicating euchromatin and are more frequent in late replicating heterochromatin. However, the mechanisms underlying this variation in mutation rate across the genome remain poorly understood. Supek and Lehner analyzed the regional single-nucleotide variant (SNV) densities in 652 fully sequenced human tumor genomes derived from 16 different tissues. Principal component analysis revealed that mutation densities were relatively stable across tumor types and that tissue-specific differences in mutation rates closely paralleled changes in the timing of DNA replication and average gene expression levels. However, this analysis identified a group of outlier samples derived from colorectal, stomach, and uterine cancers, which often exhibit inactivation of the DNA mismatch repair (MMR) pathway, resulting in microsatellite instability (MSI) and an increased SNV load. Indeed, these outlier cancers were almost uniformly characterized as MSI-high tumors and exhibited decreased variability in regional mutation rate across much of the genome. Importantly, MSI-high cancers displayed a more homogenous mutation rate compared with ultramutated microsatellite-stable tumors with DNA polymerase ϵ inactivation, suggesting that differential MMR, rather than increased mutation supply, contributes to mutation rate variation. Using deconvolution of mutational signatures, the authors found that the distribution of mutations across the genome, including both mutation signatures characteristic of MMR deficiency and non–MSI-associated signatures, became less variable with increasing time spent in an MMR-deficient state. Furthermore, mutations that arose after MMR inactivation were no longer increased in late replicating heterochromatin as compared with early replicating euchromatin. In sum, these data demonstrate that differences in DNA MMR result in somatic mutation rate variation and suggest that enhanced MMR activity prevents mutation accumulation in regions of early replicating euchromatin.

Supek F, Lehner B. Differential DNA mismatch repair underlies mutation rate variation across the human genome. Nature 2015 Feb 23 [Epub ahead of print].