Disentangling sources of clock-like mutations in germline and soma

Abstract

The rates of mutations vary across cell types. 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 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 two signatures accumulates linearly with age of diagnosis, and thus the signatures have been termed “clock-like.” To better understand this clocklike behavior, we develop a mathematical model that includes DNA replication errors, unrepaired damage, and damage repaired incorrectly. We show that mutational signatures can exhibit clocklike 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 assigned to the female germline, but a significant increase with time in rapidly-dividing cells, suggesting that SBS signature 1 is driven by rounds of DNA replication occurring at a relatively fixed rate. In contrast, SBS signature 5 increases with time in all cell types, including post-mitotic ones, indicating that it accumulates independently of cell divisions; this observation points to errors in DNA repair as the key underlying mechanism. Thus, the two “clock-like” signatures observed across cell types likely have distinct origins, one set by rates of cell division, the other by damage rates.

Population size interacts with reproductive longevity to shape the germline mutation rate

“…About 90% of human germline mutations have been attributed to a process known as SBS5 in the Catalog of Somatic Mutations in Cancer (COSMIC) database, while the remaining 10% are mostly attributed to a process known as SBS1 (38, 39). Both SBS1 and SBS5 have been classified as “clocklike” mutational signatures based on the correlation of their exposures with age in tumor data, though they are not clocklike with respect to the same time unit.…”

“…In contrast, SBS1 is dominated by CpG>TpG transitions caused by deamination of methylcytosine. While SBS1 was once thought to accumulate at a constant rate per year based on phylogenetic substitution data (41), de novo mutation data have since suggested that the load of SBS1 actually scales with the number of cell divisions, with little to no activity in post-mitotic cells but commensurately high activity in cells that are rapidly dividing (39, 40). The clocklike nature of these processes explains the mutagenic effect of generation time within species, since longer generations tend to span both more time and more cell divisions than shorter generations, leaving more time for SBS1 and SBS5 to accumulate.…”

Optimizing clinical genomic analysis of FFPE specimens for enhanced data quality, reduced artefacts, and ensured reliability

“…Among the 409 variants detected in 6 samples (2 each by 3 different fragmentation methods -no fragmentation, enzyme, and ultrasonication), nine mutation signatures, namely single base substitutions (SBS) SBS1, SBS3, SBS5, SBS7a, SBS10b, SBS30, SBS51, SBS58 and SBS87, were detected. Signatures SBS1 and SBS5 are recognized as being linked to the cell division/mitotic clock in most cancers 28,29 and were reported as the prevalent signatures across the various cancers 30,31 . Intriguingly, SBS30 was most prominently observed in the non-shared mutations, particularly evident in cases of enzyme fragmentation (Fig.…”

The impact of ancestral, environmental and genetic influences on germlinede novomutation rates and spectra

“…Tobacco smoke is known to affect the accumulation of de novo micro/minisatellites 6 , but its effects on de novo point mutations, the best-characterised form of genetic variation, have not yet been studied. Genetic factors may also influence germline mutation rate 7 . Rare variants in DNA repair genes are well-known modifiers of somatic mutation rates and spectra 8–10 , and have been shown to contribute to elevated rates of germline mutation 4,10 .…”