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

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.

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

Science ◽  
2021 ◽  
pp. eaba7408
Author(s):  
Vladimir B. Seplyarskiy ◽  
Ruslan A. Soldatov ◽  
Evan Koch ◽  
Ryan J. McGinty ◽  
Jakob M. Goldmann ◽  
...  
Keyword(s):  
Germ Line ◽  
Nonnegative Matrix ◽  
Replication Timing ◽  
Mutagenic Effect ◽  
Dna Lesions ◽  
Sequencing Data ◽  
Biological Interpretation ◽  
Mutagenic Process ◽  
Mutational Processes ◽  
Transcription And Replication

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.

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

2006 ◽  
Vol 188 (21) ◽  
pp. 7512-7520 ◽  
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.

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

2017 ◽  
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.

scholarly journals SomaticSignatures: Inferring Mutational Signatures from Single Nucleotide Variants

2014 ◽  
Author(s):  
Julian S. Gehring ◽  
Bernd Fischer ◽  
Michael Lawrence ◽  
Wolfgang Huber
Keyword(s):  
Large Scale ◽  
R Package ◽  
Sequencing Data ◽  
Single Nucleotide Variants ◽  
Mutational Signatures ◽  
Single Nucleotide ◽  
Pattern Decomposition ◽  
Bioconductor Project ◽  
Mutational Processes

Mutational signatures are patterns in the occurrence of somatic single nucleotide variants (SNVs) that can reflect underlying mutational processes. The SomaticSignatures package provides flexible, interoperable, and easy-to-use tools that identify such signatures in cancer sequencing data. It facilitates large-scale, cross-dataset estimation of mutational signatures, implements existing methods for pattern decomposition, supports extension through user-defined methods and integrates with Bioconductor workflows. The R package SomaticSignatures is available as part of the Bioconductor project (R Core Team, 2014; Gentleman et al., 2004). Its documentation provides additional details on the methodology and demonstrates applications to biological datasets.

scholarly journals Analysis of gene expression and mutation data points on contribution of transcription to the mutagenesis by APOBEC enzymes

NAR Cancer ◽  
2021 ◽  
Vol 3 (3) ◽  
Author(s):  
Almira Chervova ◽  
Bulat Fatykhov ◽  
Alexander Koblov ◽  
Evgeny Shvarov ◽  
Julia Preobrazhenskaya ◽  
...  
Keyword(s):  
Gene Expression ◽  
Whole Genome Sequencing Data ◽  
Sequencing Data ◽  
Induced Mutations ◽  
Cellular Processes ◽  
Human Cancers ◽  
Sense Strand ◽  
Data Points ◽  
Transcription And Replication

Abstract Since the discovery of the role of the APOBEC enzymes in human cancers, the mechanisms of this type of mutagenesis remain little understood. Theoretically, targeting of single-stranded DNA by the APOBEC enzymes could occur during cellular processes leading to the unwinding of DNA double-stranded structure. Some evidence points to the importance of replication in the APOBEC mutagenesis, while the role of transcription is still underexplored. Here, we analyzed gene expression and whole genome sequencing data from five types of human cancers with substantial APOBEC activity to estimate the involvement of transcription in the APOBEC mutagenesis and compare its impact with that of replication. Using the TCN motif as the mutation signature of the APOBEC enzymes, we observed a correlation of active APOBEC mutagenesis with gene expression, confirmed the increase of APOBEC-induced mutations in early-replicating regions and estimated the relative impact of transcription and replication on the APOBEC mutagenesis. We also found that the known effect of higher density of APOBEC-induced mutations on the lagging strand was highest in middle-replicating regions and observed higher APOBEC mutation density on the sense strand, the latter bias positively correlated with the gene expression level.

scholarly journals Analysis of gene expression and mutation data points on contribution of transcription to the mutagenesis by APOBEC enzymes

2021 ◽  
Author(s):  
Almira Chervova ◽  
Bulat Fatykhov ◽  
Alexander Koblov ◽  
Evgeny Shvarov ◽  
Julia Preobrazhenskaya ◽  
...  
Keyword(s):  
Gene Expression ◽  
Whole Genome Sequencing Data ◽  
Sequencing Data ◽  
Induced Mutations ◽  
Cellular Processes ◽  
Human Cancers ◽  
Sense Strand ◽  
Data Points ◽  
Transcription And Replication

Since the discovery of the role of the APOBEC enzymes in human cancers, the mechanisms of this type of mutagenesis remain little understood. Theoretically, targeting of single-stranded DNA by the APOBEC enzymes could occur during cellular processes leading to the unwinding of DNA double-stranded structure. Some evidence points to the importance of replication in the APOBEC mutagenesis, while the role of transcription is still underexplored. Here, we analyzed gene expression and whole genome sequencing data from five types of human cancers with substantial APOBEC activity to estimate the involvement of transcription in the APOBEC mutagenesis and compare its impact with that of replication. Using the TCN motif as the mutation signature of the APOBEC enzymes, we observed a correlation of active APOBEC mutagenesis with gene expression, confirmed the increase of APOBEC-induced mutations in early-replicating regions, and estimated the relative impact of transcription and replication on the APOBEC mutagenesis, which turned out to be approximately equal in transcribed regions. We also found that the known effect of higher density of APOBEC-induced mutations on the lagging strand was highest in middle-replicating regions, and observed higher APOBEC mutation density on the sense strand, the latter bias positively correlated with the gene expression level.

scholarly journals Assessment of LIN28A variants in Parkinson’s disease

2020 ◽  
Author(s):  
Monica Diez-Fairen ◽  
Mary B. Makarious ◽  
Sara Bandres-Ciga ◽  
Cornelis Blauwendraat
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Large Scale ◽  
Disease Risk ◽  
Age At Onset ◽  
European Ancestry ◽  
Whole Genome Sequencing Data ◽  
Sequencing Data ◽  
Common Genetic Variants

AbstractParkinson’s disease (PD) is a complex neurodegenerative disease with a strong genetic component in which both rare and common genetic variants contribute to disease risk, onset and progression. Despite that several genes have been associated with familial forms of disease, validation of novel genes associated with PD remains extremely challenging. Recently, a heterozygous loss-of-function variant in LIN28A was associated with PD pathogenesis in the Asian population. Here, we comprehensively assess the role of LIN28A variants in PD susceptibility using individual-level genotyping data from 14,671 PD cases and 17,667 controls, as well as whole-genome sequencing data from 1,647 PD patients and 1,050 controls. Additionally, we further assessed the summary statistics from the most recent GWAS meta-analyses to date for PD risk and age at onset. After evaluating these data, we did not find evidence to support a role for LIN28A as a major causal gene for PD. However, additional large-scale familial and case-control studies in non-European ancestry populations are necessary to further evaluate the role of LIN28A in PD etiology.

The Role of Sense of Direction and Other Factors During Navigation in a Large-Scale, Unconstrained Environment

2013 ◽  
Author(s):  
Elisabeth J. Ploran ◽  
Ericka Rovira ◽  
James C. Thompson ◽  
Raja Parasuraman
Keyword(s):  
Large Scale ◽  
Sense Of Direction

Magnetic Properties of xCeO2•(50 − x) PbO•50B2O3 Glasses and Glass Ceramics

2017 ◽  
Vol 13 (1) ◽  
pp. 4486-4494 ◽  
Author(s):  
G.El Damrawi ◽  
F. Gharghar
Keyword(s):  
Magnetic Properties ◽  
Large Scale ◽  
Glass Ceramics ◽  
Magnetic Behavior ◽  
Crystal Formation ◽  
Dual Roles ◽  
Effective Agent ◽  
Ordered Structures ◽  
Essential Change

Cerium oxide in borate glasses of composition xCeO2·(50 − x)PbO·50B2O3 plays an important role in changing both microstructure and magnetic behaviors of the system. The structural role of CeO2 as an effective agent for cluster and crystal formation in borate network is clearly evidenced by XRD technique. Both structure and size of well-formed cerium separated clusters have an effective influence on the structural properties. The cluster aggregations are documented to be found in different range ordered structures, intermediate and long range orders are the most structures in which cerium phases are involved. The nano-sized crystallized cerium species in lead borate phase are evidenced to have magnetic behavior.  The criteria of building new specific borate phase enriched with cerium as ferrimagnetism has been found to keep the magnetization in large scale even at extremely high temperature. Treating the glass thermally or exposing it to an effective dose of ionized radiation is evidenced to have an essential change in magnetic properties. Thermal heat treatment for some of investigated materials is observed to play dual roles in the glass matrix. It can not only enhance alignment processes of the magnetic moment but also increases the capacity of the crystallite species in the magnetic phases. On the other hand, reverse processes are remarked under the effect of irradiation. The magnetization was found to be lowered, since several types of the trap centers which are regarded as defective states can be produced by effect of ionized radiation. 

The Impact of Quantitative Easing on Emerging Markets – Literature Review

e-Finanse ◽  
2018 ◽  
Vol 14 (4) ◽  
pp. 67-76
Author(s):  
Piotr Bartkiewicz
Keyword(s):  
Emerging Markets ◽  
Large Scale ◽  
Empirical Literature ◽  
Quantitative Easing ◽  
Methodological Choices ◽  
The Subject ◽  
Methodological Approaches ◽  
The Impact ◽  
Sufficient Precision

AbstractThe article presents the results of the review of the empirical literature regarding the impact of quantitative easing (QE) on emerging markets (EMs). The subject is of interest to policymakers and researchers due to the increasingly larger role of EMs in the world economy and the large-scale capital flows occurring after 2009. The review is conducted in a systematic manner and takes into consideration different methodological choices, samples and measurement issues. The paper puts the summarized results in the context of transmission channels identified in the literature. There are few distinct methodological approaches present in the literature. While there is a consensus regarding the direction of the impact of QE on EMs, its size and durability have not yet been assessed with sufficient precision. In addition, there are clear gaps in the empirical findings, not least related to relative underrepresentation of the CEE region (in particular, Poland).

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