The etiology of clonal mosaicism in human aging and disease

Massaar, Sanne; Sanders, Mathijs A.

doi:10.1002/aac2.12061

Cited by 4 publications

(3 citation statements)

References 176 publications

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“…The idea that somatic mutations can drive clonal expansion has stimulated renewed interest in the mutational theory of aging. This represents a new mechanism by which mutations can lead to aging phenotypes [8, 9] and is distinct from earlier proposals which treated absolute mutation burden as a sufficient cause for organismal aging [10]. Given its importance as a driver of aging, it would seem that somatic evolution could form the basis for a new type of aging timer.…”

Section: Introductionmentioning

confidence: 98%

Cell Tree Rings: the structure of somatic evolution as a human aging timer

Csordás

Sipos²,

Kurucová

et al. 2022

Preprint

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Biological age is typically estimated using biomarkers whose states have been observed to correlate with chronological age. A persistent limitation of such aging clocks is that it is difficult to establish how the biomarker states are related to the mechanisms of aging. Somatic mutations could potentially form the basis for a more fundamental aging clock since the mutations are both markers and drivers of aging and have a natural timescale. Such a timer has been impractical thus far, however, because detection of somatic variants in single cells presents a significant technological challenge. Cell lineage trees built out of these mutations are phylogenetic structures that can help quantify somatic evolution. The central conjecture behind our aging timer approach is that the shape, that is the combination of branch lengths and branching patterns, of cell lineage trees is predictive of the aging status of the body. Here we show that somatic mutations detected using single-cell RNA sequencing (scRNA-seq) from hundreds or thousands of cells can be used to construct a cell lineage tree whose shape correlates with chronological age. Single-nucleotide variants (SNVs) are detected de novo in human peripheral blood mononuclear cells using a modified protocol. Penalized multiple regression is used to select from over 30 possible metrics characterizing the shape of the phylogenetic tree resulting in a Pearson correlation of 0.8 between predicted and chronological age and a median absolute error of ~6 years. The geometry of the cell lineage tree records the structure of somatic evolution in the individual and represents a new modality for aging timers. In addition to providing an estimate for biological age, it unveils a temporal history of the aging process, revealing how clonal structure evolves over lifespan. Cell Tree Rings as a foundational component and integrative framework of combined clocks might mitigate the current uncertainty in the assessment of geroprotective trials.

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Section: Introductionmentioning

confidence: 98%

Cell Tree Rings: the structure of somatic evolution as a human aging timer

Csordás

Sipos²,

Kurucová

et al. 2022

Preprint

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show abstract

“…In contrast, SBS5 has a more diffuse distribution among the 96 SBS types. Its ubiquity across cell types, cancerous and healthy, has led to the suggestion that the signature reflects “background” endogenous cellular damage to DNA [ 19 , 20 ]. However, the number of SBS5 mutations is also affected by the presence of at least one exogenous mutagen, tobacco smoke [ 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

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

Spisak,

de Manuel,

Milligan

et al. 2024

PLoS Biol

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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 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 postmitotic 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.

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“…In contrast, SBS5 has a more diffuse distribution among the 96 SBS types. Its ubiquity across cell types, cancerous and healthy, has led to the suggestion that the signature reflects “background” endogenous cellular damage to DNA [20, 21]. However, the number of SBS5 mutations is also affected by the presence of at least one exogenous mutagen, tobacco smoke [22, 23].…”

Section: Introductionmentioning

confidence: 99%

Disentangling sources of clock-like mutations in germline and soma

Spisak,

de Manuel,

Milligan

et al. 2023

Preprint

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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.

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The etiology of clonal mosaicism in human aging and disease

Cited by 4 publications

References 176 publications

Cell Tree Rings: the structure of somatic evolution as a human aging timer

Cell Tree Rings: the structure of somatic evolution as a human aging timer

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

Disentangling sources of clock-like mutations in germline and soma

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