The clock-like accumulation of germline and somatic mutations can arise from the interplay of DNA damage and repair

作者：Natanael Spisak, Marc de Manuel, William Milligan, Guy Sella, Molly Przeworski · 发表于：PLoS Biology · 年份：2024 · DOI：10.1371/journal.pbio.3002678 · 被引用次数：43 · 研究领域：Cancer Genomics and Diagnostics、DNA Repair Mechanisms、Genomics and Rare Diseases

The rates at which mutations accumulate across human cell types vary. To identify causes of this variation, mutations are often decomposed into a combination of the single-base substitution (SBS) "signatures" observed in germline, soma, and tumors, with the idea that each signature corresponds to one or a small number of underlying mutagenic processes. Two such signatures turn out to be ubiquitous across cell types: SBS signature 1, which consists primarily of transitions at methylated CpG sites thought to be caused by spontaneous deamination, and the more diffuse SBS signature 5, which is of unknown etiology. In cancers, the number of mutations attributed to these 2 signatures accumulates linearly with age of diagnosis, and thus the signatures have been termed "clock-like." To better understand this clock-like behavior, we develop a mathematical model that includes DNA replication errors, unrepaired damage, and damage repaired incorrectly. We show that mutational signatures can exhibit clock-like behavior because cell divisions occur at a constant rate and/or because damage rates remain constant over time, and that these distinct sources can be teased apart by comparing cell lineages that divide at different rates. With this goal in mind, we analyze the rate of accumulation of mutations in multiple cell types, including soma as well as male and female germline. We find no detectable increase in SBS signature 1 mutations in neurons and only a very weak increase in mutations a...