Intrinsic base substitution patterns in diverse species reveal links to cancer and metabolism

Gelova, Suzana P; Doherty, Kassidy N; Alasmar, Salma; Chan, Kin

doi:10.1093/genetics/iyac144

Cited by 10 publications

(9 citation statements)

References 74 publications

(18 reference statements)

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“…In the case of SBS5 and SBS40, the causes for both damage and repair are less clear. Recent experimental evidence suggests that one of the possible causes of SBS5 damage may be protonation of single-stranded DNA (ssDNA) [49, 50], while the formation of ssDNA is known to be increased in acute hypoxia [51]. Notably, these experimental studies also found that the source of the damaging protons may be glycolytic sugar metabolisation, which is strongly upregulated under hypoxic conditions [52].…”

Section: Resultsmentioning

confidence: 99%

“…This revealed novel associations between epigenetic states and mutational signature activities and allowed us to investigate the origins of SBS3, SBS5 and SBS40, focusing on the links to POL θ . The generation of point mutations by POL θ has been proposed to be related to its translesion synthesis activity during ssDNA gap filling [89, 78, 79], although other translesion polymerases may also play a role [91, 49, 92, 79]. The increased importance of POL θ in both replication-associated and DSB repair in cancer tumours coincides with the increase in replication stress caused by oncogenes [93].…”

Section: Discussionmentioning

confidence: 99%

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Mutational signature decomposition with deep neural networks reveals origins of clock-like processes and hypoxia dependencies

Serrano Colome,

Canal Anton,

Seplyarskiy

et al. 2023

Preprint

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DNA mutational processes generate patterns of somatic and germline mutations. A multitude of such mutational processes has been identified and linked to biochemical mechanisms of DNA damage and repair. Cancer genomics relies on these so-called mutational signatures to classify tumours into subtypes, navigate treatment, determine exposure to mutagens, and characterise the origin of individual mutations. Yet, state-of-the-art methods to quantify the contributions of different mutational signatures to a tumour sample frequently fail to detect certain mutational signatures, work well only for a relatively high number of mutations, and do not provide comprehensive error estimates of signature contributions. Here, we present a novel approach to signature decomposition using artificial neural networks that addresses these problems. We show that our approach, SigNet, outperforms existing methods by learning the prior frequencies of signatures and their correlations present in real data. Unlike any other method we tested, SigNet achieves high prediction accuracy even with few mutations. We used this to generate estimates of signature weights for more than 7500 tumours for which only whole-exome sequencing data are available. We then identified systematic differences in signature activity both as a function of epigenetic covariates and over the course of tumour evolution. This allowed us to decipher the origins of signatures SBS3, SBS5 and SBS40. We further discovered novel associations of mutational signatures with hypoxia, including strong positive correlations with the activities of clock-like and defective DNA repair mutational processes. These results provide new insights into the interplay between tumour biology and mutational processes and demonstrate the utility of our novel approach to mutational signature decomposition, a crucial part of cancer genomics studies.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mutational signature decomposition with deep neural networks reveals origins of clock-like processes and hypoxia dependencies

Serrano Colome,

Canal Anton,

Seplyarskiy

et al. 2023

Preprint

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“…51 Interestingly, SBS5 seems to be the signature that explains most of the intrinsic genetic variation in many different species. 61 SBS5 and SBS1 were also among the three most common signatures in another study in sperm where DS was used to sequence the FGFR3 gene coding region. 25 The proportions of the two signatures in sperm in our study (88% SBS5 and 12% SBS1) are also consistent with a study in seminiferous tubules 51 and a study on DNMs in more than 20,000 families 12 , both of which reported 85% of SBS5/40 and 15% of SBS1.…”

Section: Discussionmentioning

confidence: 95%

“…We note that SBS40, the most common SBS in the blood of our men, is highly similar to SBS5. 50,51 SBS40 (like SBS5 61 ) has an unknown etiology but is related to age. 50 If we combined SBS40 and SBS5 into a single signature, as previously done by others to account for their similarity, 51 then SBS5/40 and SBS1 were the most common signatures in both blood and sperm (Figure 6), with SBS5/40 being the most frequent.…”

Section: Discussionmentioning

confidence: 99%

Frequency and spectrum of mutations in human sperm measured using duplex sequencing correlate with trio-basedde novomutation analyses

Axelsson,

LeBlanc,

Shojaeisaadi

et al. 2024

Preprint

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De novo mutations (DNMs) are drivers of genetic disorders. However, the study of DNMs is hampered by technological limitations preventing accurate quantification of ultra-rare mutations. Duplex Sequencing (DS) theoretically has < 1 error/billion base-pairs (bp). To determine the utility of DS to quantify and characterize DNMs, we analyzed DNA from blood and spermatozoa from six healthy, 18-year-old Swedish men using the TwinStrand DS mutagenesis panel (48 kb spanning 20 genic and intergenic loci). The mean single nucleotide variant mutation frequency (MF) was 1.2 x 10-7 per bp in blood and 2.5 x 10-8 per bp in sperm, with the most common base substitution being C>T. Blood MF and substitution spectrum were similar to those reported in blood cells with an orthogonal method. The sperm MF was in the same order of magnitude and had a strikingly similar spectrum to DNMs from publicly available whole genome sequencing data from human pedigrees (1.2 x 10-8 per bp). DS revealed much larger numbers of insertions and deletions in sperm over blood, driven by an abundance of putative extra-chromosomal circular DNAs. The study indicates the strong potential of DS to characterize human DNMs to inform factors that contribute to disease susceptibility and heritable genetic risks.

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“…Our analyses further confirm the importance of damage as a source not only of somatic mutations, but also for germline mutations [51, 58, 59]: over two-thirds of germline mutations are assigned to SBS1 and SBS5, signatures that arise from damage that is either not repaired or repaired incorrectly. The source of such DNA damage is most likely endogenous cellular processes, accounting for the omnipresence of these two signatures across cell types [2] and species [60], as well as their characteristic clock-like behavior under most conditions [42].…”

Section: Discussionmentioning

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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Intrinsic base substitution patterns in diverse species reveal links to cancer and metabolism

Cited by 10 publications

References 74 publications

Mutational signature decomposition with deep neural networks reveals origins of clock-like processes and hypoxia dependencies

Mutational signature decomposition with deep neural networks reveals origins of clock-like processes and hypoxia dependencies

Frequency and spectrum of mutations in human sperm measured using duplex sequencing correlate with trio-basedde novomutation analyses

Disentangling sources of clock-like mutations in germline and soma

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