Population sequencing data reveal a compendium of mutational processes in the human germ line

Biological mechanisms underlying human germline mutations remain largely unknown. We statistically decompose variation in the rate and spectra of mutations along the genome using volume-regularized nonnegative matrix factorization. The analysis of a sequencing dataset (TOPMed) reveals nine processes that explain the variation in mutation properties between loci. We provide a biological interpretation for seven of these processes. We associate one process with bulky DNA lesions that resolve asymmetrically with respect to transcription and replication. Two processes track direction of replication fork and replication timing, respectively. We identify a mutagenic effect of active demethylation primarily acting in regulatory regions and a mutagenic effect of LINE repeats. We localize a mutagenic process specific to oocytes from population sequencing data. This process appears transcriptionally asymmetric.

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Population sequencing data reveal a compendium of mutational processes in human germline

10.1101/2020.01.10.893024 ◽

2020 ◽

Author(s):

Vladimir B. Seplyarskiy ◽

Ruslan A. Soldatov ◽

Ryan J. McGinty ◽

Jakob M. Goldmann ◽

Ryan Hernandez ◽

...

Keyword(s):

Large Scale ◽

Replication Timing ◽

Mutagenic Effect ◽

Dna Lesions ◽

Sequencing Data ◽

Biological Interpretation ◽

Mutagenic Process ◽

Mutational Processes ◽

Transcription And Replication

Mechanistic processes underlying human germline mutations remain largely unknown. Variation in mutation rate and spectra along the genome is informative about the biological mechanisms. We statistically decompose this variation into separate processes using a blind source separation technique. The analysis of a large-scale whole genome sequencing dataset (TOPMed) reveals nine processes that explain the variation in mutation properties between loci. Seven of these processes lend themselves to a biological interpretation. One process is driven by bulky DNA lesions that resolve asymmetrically with respect to transcription and replication. Two processes independently track direction of replication fork and replication timing. We identify a mutagenic effect of active demethylation primarily acting in regulatory regions. We also demonstrate that a recently discovered mutagenic process specific to oocytes can be localized solely from population sequencing data. This process is spread across all chromosomes and is highly asymmetric with respect to the direction of transcription, suggesting a major role of DNA damage.

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Bioinformatics Methods and Biological Interpretation for Next-Generation Sequencing Data

BioMed Research International ◽

10.1155/2015/690873 ◽

2015 ◽

Vol 2015 ◽

pp. 1-2

Author(s):

Guohua Wang ◽

Yunlong Liu ◽

Dongxiao Zhu ◽

Gunnar W. Klau ◽

Weixing Feng

Keyword(s):

Next Generation Sequencing ◽

Next Generation Sequencing Data ◽

Next Generation ◽

Sequencing Data ◽

Biological Interpretation ◽

Generation Sequencing

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Novel Role of mfd: Effects on Stationary-Phase Mutagenesis in Bacillus subtilis

Journal of Bacteriology ◽

10.1128/jb.00980-06 ◽

2006 ◽

Vol 188 (21) ◽

pp. 7512-7520 ◽

Cited By ~ 44

Author(s):

Christian Ross ◽

Christine Pybus ◽

Mario Pedraza-Reyes ◽

Huang-Mo Sung ◽

Ronald E. Yasbin ◽

...

Keyword(s):

Bacillus Subtilis ◽

Rna Polymerase ◽

Stationary Phase ◽

Coupling Factor ◽

Dna Lesions ◽

Adaptive Mutagenesis ◽

Associated Proteins ◽

Mutagenic Process ◽

Protein Transcription

ABSTRACT Previously, using a chromosomal reversion assay system, we established that an adaptive mutagenic process occurs in nongrowing Bacillus subtilis cells under stress, and we demonstrated that multiple mechanisms are involved in generating these mutations (41, 43). In an attempt to delineate how these mutations are generated, we began an investigation into whether or not transcription and transcription-associated proteins influence adaptive mutagenesis. In B. subtilis, the Mfd protein (transcription repair coupling factor) facilitates removal of RNA polymerase stalled at transcriptional blockages and recruitment of repair proteins to DNA lesions on the transcribed strand. Here we demonstrate that the loss of Mfd has a depressive effect on stationary-phase mutagenesis. An association between Mfd mutagenesis and aspects of transcription is discussed.

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Structure and expression of a gene encoding a putative GTP-binding protein identified by provirus integration in a transgenic mouse strain.

Molecular and Cellular Biology ◽

10.1128/mcb.11.2.886 ◽

1991 ◽

Vol 11 (2) ◽

pp. 886-893 ◽

Cited By ~ 25

Author(s):

K Mooslehner ◽

U Müller ◽

U Karls ◽

L Hamann ◽

K Harbers

Keyword(s):

Mouse Strain ◽

Embryonal Carcinoma ◽

Germ Line ◽

Leukemia Virus ◽

Embryonic Stem ◽

Mutagenic Effect ◽

Cell Types ◽

Transcription Unit ◽

Preimplantation Embryos ◽

Gtp Binding

The Mov-10 mouse strain was derived by infection of preimplantation embryos with the Moloney murine leukemia virus and carries one copy of the provirus in its germ line. Here we show that the provirus has integrated into an evolutionarily conserved gene that can code for a protein of 110 kDa containing the three consensus elements characteristic for GTP-binding proteins. The Mov-10 locus was expressed in a variety of cell types, including embryonal carcinoma and embryonic stem cells. Transcription of the gene was down-regulated about 10-fold when F9 embryonal carcinoma cells are differentiated into parietal endodermlike cells and about 2-fold when they are differentiated into visceral endodermlike cells. High levels of Mov-10 transcripts were also found at different stages of embryonal development and in the testes and thymus of adult animals. Expression was cell cycle controlled, with steady-state RNA levels significantly higher in growth-arrested than in growth-stimulated cells. The results suggest that the Mov-10 locus has an important function in development and/or control of cell proliferation. The provirus was shown to have integrated into intron 1 of the gene without disrupting expression, indicating that integration into intronic sequences of a transcription unit does not necessarily affect transcription. This result together with previous results from the Mov-13 mouse strain suggested that proviruses exert their mutagenic effect only by integration in specific sites, such as cis-regulatory DNA elements.

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Biological Interpretation of Next-Generation Sequencing Data

10.6019/tae.biointngs.2013.00001.1 ◽

2014 ◽

Keyword(s):

Next Generation Sequencing ◽

Next Generation Sequencing Data ◽

Next Generation ◽

Sequencing Data ◽

Biological Interpretation ◽

Generation Sequencing

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Genome-wide DNA replication profile for Drosophila melanogaster: a link between transcription and replication timing

Nature Genetics ◽

10.1038/ng1005 ◽

2002 ◽

Vol 32 (3) ◽

pp. 438-442 ◽

Cited By ~ 211

Author(s):

Dirk Schübeler ◽

David Scalzo ◽

Charles Kooperberg ◽

Bas van Steensel ◽

Jeffrey Delrow ◽

...

Keyword(s):

Drosophila Melanogaster ◽

Dna Replication ◽

Replication Timing ◽

Genome Wide ◽

Transcription And Replication

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MutationalPatterns: The one stop shop for the analysis of mutational processes

10.1101/2021.11.01.466730 ◽

2021 ◽

Author(s):

Freek Manders ◽

Arianne M. Brandsma ◽

Jurrian de Kanter ◽

Mark Verheul ◽

Rurika Oka ◽

...

Keyword(s):

Protein Function ◽

Mutational Analysis ◽

Cancer Diagnostics ◽

Sequencing Data ◽

Strand Asymmetry ◽

A Genome ◽

A Cell ◽

The One ◽

Double Base ◽

Mutational Processes

Background: The collective of somatic mutations in a genome represents a record of mutational processes that have been operative in a cell. These processes can be investigated by extracting relevant mutational patterns from sequencing data. Results: Here, we present the next version of MutationalPatterns, an R/Bioconductor package, which allows in-depth mutational analysis of catalogues of single and double base substitutions as well as small insertions and deletions. Major features of the package include the possibility to perform regional mutation spectra analyses and the possibility to detect strand asymmetry phenomena, such as lesion segregation. On top of this, the package also contains functions to determine how likely it is that a signature can cause damaging mutations (i.e., mutations that affect protein function). This updated package supports stricter signature refitting on known signatures in order to prevent overfitting. Using simulated mutation matrices containing varied signature contributions, we showed that reliable refitting can be achieved even when only 50 mutations are present per signature. Additionally, we incorporated bootstrapped signature refitting to assess the robustness of the signature analyses. Finally, we applied the package on genome mutation data of cell lines in which we deleted specific DNA repair processes and on large cancer datasets, to show how the package can be used to generate novel biological insights. Conclusions: This novel version of MutationalPatterns allows for more comprehensive analyses and visualization of mutational patterns in order to study the underlying processes. Ultimately, in-depth mutational analyses may contribute to improved biological insights in mechanisms of mutation accumulation as well as aid cancer diagnostics. MutationalPatterns is freely available at http://bioconductor.org/packages/MutationalPatterns.

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Great ape mutation spectra vary across the phylogeny and the genome due to distinct mutational processes that evolve at different rates

10.1101/805598 ◽

2019 ◽

Cited By ~ 1

Author(s):

Michael E. Goldberg ◽

Kelley Harris

Keyword(s):

Replication Timing ◽

Mutation Rates ◽

Great Ape ◽

Mutational Signatures ◽

Clock Model ◽

Cis Acting ◽

Molecular Clock Model ◽

Species Specific ◽

Mutation Spectra ◽

Mutational Processes

ABSTRACTRecent studies of hominoid variation have shown that mutation rates and spectra can evolve rapidly, contradicting the fixed molecular clock model. The relative mutation rates of three-base-pair motifs differ significantly among great ape species, suggesting the action of unknown modifiers of DNA replication fidelity. To illuminate the footprints of these hypothetical mutators, we measured mutation spectra of several functional compartments (such as late-replicating regions) that are likely targeted by localized mutational processes. Using genetic diversity from 88 great apes, we find that compartment-specific mutational signatures appear largely conserved between species. These signatures layer with species-specific signatures to create rich mutational portraits: for example, late-replicating regions in gorillas contain an identifiable mixture of a replication timing signature and a gorilla-specific signature. Our results suggest that cis-acting mutational modifiers are highly conserved between species and transacting modifiers are driving rapid mutation spectrum evolution.

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DNA lesions proximity modulates damage tolerance pathways inEscherichia coli

10.1101/210237 ◽

2017 ◽

Author(s):

Élodie Chrabaszcz ◽

Luisa Laureti ◽

Vincent Pagès

Keyword(s):

Homologous Recombination ◽

Damage Tolerance ◽

Genome Instability ◽

Mutagenic Effect ◽

Genotoxic Stress ◽

Dna Lesions ◽

Strong Increase ◽

Dna Damages ◽

Dna Lesion ◽

Local Inhibition

ABSTRACTThe genome of all organisms is constantly threatened by numerous agents that cause DNA damages. When the replication fork encounters an unrepaired DNA lesion, two DNA damage tolerance pathways are possible: error-prone translesion synthesis (TLS) that requires specialized DNA polymerases, and error-free Damage Avoidance (DA) that relies on homologous recombination. The balance between these two mechanisms is essential since it defines the level of mutagenesis during lesion bypass, allowing genetic variability and adaptation to the environment, but also introducing the risk of generating genome instability. Here we report that the mere proximity of replication-blocking lesions that arise inEscherichia coli’s genome during a genotoxic stress, leads to a strong increase in the use of the error-prone TLS. We show that this increase is caused by the local inhibition of homologous recombination due to the overlapping of single-stranded DNA regions generated downstream the lesions. This increase in TLS is independent of SOS activation, but its mutagenic effect is additive with the one of SOS. Hence, the combination of SOS induction and lesions proximity leads to a strong increase in TLS that becomes the main lesion tolerance pathway used by the cell during a genotoxic stress.

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The effects of mutational processes and selection on driver mutations across cancer types

10.1101/149096 ◽

2017 ◽

Cited By ~ 2

Author(s):

Daniel Temko ◽

Ian PM Tomlinson ◽

Simone Severini ◽

Benjamin Schuster-Böckler ◽

Trevor A Graham

Keyword(s):

Driver Mutations ◽

Sequencing Data ◽

Epidemiological Evidence ◽

Dna Mismatch ◽

Cancer Types ◽

Key Driver ◽

Independent Effects ◽

Mutational Processes ◽

Mutation And Selection

ABSTRACTEpidemiological evidence has long associated environmental mutagens with increased cancer risk. However, links between specific mutation-causing processes and the acquisition of individual driver mutations have remained obscure. Here we have used public cancer sequencing data to infer the independent effects of mutation and selection on driver mutation complement. First, we detect associations between a range of mutational processes, including those linked to smoking, ageing, APOBEC and DNA mismatch repair (MMR) and the presence of key driver mutations across cancer types. Second, we quantify differential selection between well-known alternative driver mutations, including differences in selection between distinct mutant residues in the same gene. These results show that while mutational processes play a large role in determining which driver mutations are present in a cancer, the role of selection frequently dominates.

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