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Disentangling sources of clock-like mutations in germline and soma

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 u...

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Autores principales: Spisak, Natanael, de Manuel, Marc, Milligan, William, Sella, Guy, Przeworski, Molly
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10515775/
https://www.ncbi.nlm.nih.gov/pubmed/37745549
http://dx.doi.org/10.1101/2023.09.07.556720
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author Spisak, Natanael
de Manuel, Marc
Milligan, William
Sella, Guy
Przeworski, Molly
author_facet Spisak, Natanael
de Manuel, Marc
Milligan, William
Sella, Guy
Przeworski, Molly
author_sort Spisak, Natanael
collection PubMed
description 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 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 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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spelling pubmed-105157752023-09-23 Disentangling sources of clock-like mutations in germline and soma Spisak, Natanael de Manuel, Marc Milligan, William Sella, Guy Przeworski, Molly bioRxiv Article 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 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 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. Cold Spring Harbor Laboratory 2023-09-12 /pmc/articles/PMC10515775/ /pubmed/37745549 http://dx.doi.org/10.1101/2023.09.07.556720 Text en https://creativecommons.org/licenses/by-nd/4.0/This work is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, and only so long as attribution is given to the creator. The license allows for commercial use.
spellingShingle Article
Spisak, Natanael
de Manuel, Marc
Milligan, William
Sella, Guy
Przeworski, Molly
Disentangling sources of clock-like mutations in germline and soma
title Disentangling sources of clock-like mutations in germline and soma
title_full Disentangling sources of clock-like mutations in germline and soma
title_fullStr Disentangling sources of clock-like mutations in germline and soma
title_full_unstemmed Disentangling sources of clock-like mutations in germline and soma
title_short Disentangling sources of clock-like mutations in germline and soma
title_sort disentangling sources of clock-like mutations in germline and soma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10515775/
https://www.ncbi.nlm.nih.gov/pubmed/37745549
http://dx.doi.org/10.1101/2023.09.07.556720
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