scholarly journals Sequence dependencies and mutation rates of localized mutational processes in cancer

2021 ◽  
Author(s):  
Gustav Alexander Poulsgaard ◽  
Simon Grund Sørensen ◽  
Randi Istrup Juul ◽  
Morten Muhlig Nielsen ◽  
Jakob Skou Pedersen
Keyword(s):  
Mutation Rate ◽  
Genomic Sequence ◽  
Mutation Rates ◽  
Unknown Etiology ◽  
Mutational Signatures ◽  
Data Set ◽  
Recurrent Mutations ◽  
Mutational Hotspots ◽  
Pan Cancer ◽  
Mutational Processes

Background: Cancer mutations accumulate through replication errors and DNA damage coupled with incomplete repair. Individual mutational processes often show strong sequence and regional preferences. As a result, some sequence contexts mutate at much higher rates than others. Mutational hotspots, with recurrent mutations across cancer samples, represent genomic positions with elevated mutation rates, often caused by highly localized mutational processes. Results: We analyze the mutation rates of all 11-mer genomic sequence contexts using the PCAWG set of 2,583 pan-cancer whole genomes. We further associate individual mutations and contexts to mutational signatures and estimate their relative mutation rates. We show that hotspots generally identify highly mutable sequence contexts. Using these, we show that some mutational signatures are enriched in hotspot sequence contexts, corresponding to well-defined sequence preferences for the underlying localized mutational processes. This includes signature 17b (of unknown etiology) and signatures 62 (POLE), 7a (UV), and 72 (linked to lymphomas). In some cases, the mutation rate increases further when focusing on certain genomic regions, such as signature 62 in poised promoters, where the mutation is increased several thousand folds over the overall data set average. Conclusion: We summarize our findings in a catalog of localized mutational processes, their sequence preferences, and their estimated mutation rates. Keywords: pan-cancer, mutational processes, hotspots, mutation rate

scholarly journals Viral Mutation Rates

2010 ◽  
Vol 84 (19) ◽  
pp. 9733-9748 ◽  
Author(s):  
Rafael Sanjuán ◽  
Miguel R. Nebot ◽  
Nicola Chirico ◽  
Louis M. Mansky ◽  
Robert Belshaw
Keyword(s):  
Mutation Rate ◽  
Rna Viruses ◽  
Experimental Testing ◽  
Mutation Rates ◽  
Cell Infection ◽  
Nucleotide Substitutions ◽  
Data Set ◽  
Dna Viruses ◽  
Double Stranded Dna ◽  
Viral Mutation

ABSTRACT Accurate estimates of virus mutation rates are important to understand the evolution of the viruses and to combat them. However, methods of estimation are varied and often complex. Here, we critically review over 40 original studies and establish criteria to facilitate comparative analyses. The mutation rates of 23 viruses are presented as substitutions per nucleotide per cell infection (s/n/c) and corrected for selection bias where necessary, using a new statistical method. The resulting rates range from 10−8 to10−6 s/n/c for DNA viruses and from 10−6 to 10−4 s/n/c for RNA viruses. Similar to what has been shown previously for DNA viruses, there appears to be a negative correlation between mutation rate and genome size among RNA viruses, but this result requires further experimental testing. Contrary to some suggestions, the mutation rate of retroviruses is not lower than that of other RNA viruses. We also show that nucleotide substitutions are on average four times more common than insertions/deletions (indels). Finally, we provide estimates of the mutation rate per nucleotide per strand copying, which tends to be lower than that per cell infection because some viruses undergo several rounds of copying per cell, particularly double-stranded DNA viruses. A regularly updated virus mutation rate data set will be available at www.uv.es/rsanjuan/virmut .

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

2019 ◽  
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.

Mutational signatures and heterogeneous host response revealed via large-scale characterization of SARS-CoV-2 genomic diversity

2020 ◽  
Author(s):  
Alex Graudenzi ◽  
Davide Maspero ◽  
Fabrizio Angaroni ◽  
Rocco Piazza ◽  
Daniele Ramazzotti
Keyword(s):  
Large Scale ◽  
Purifying Selection ◽  
Genomic Diversity ◽  
Nucleotide Substitutions ◽  
Mutational Signatures ◽  
Mutational Hotspots ◽  
Scale Characterization ◽  
Definition Of ◽  
Mutational Processes

AbstractTo dissect the mechanisms underlying the inflation of variants in the SARS-CoV-2 genome, we present one of the largest up-to-date analyses of intra-host genomic diversity, which reveals that most samples present heterogeneous genomic architectures, due to the interplay between host-related mutational processes and transmission dynamics.The deconvolution of the set of intra-host minor variants unveils the existence of non overlapping mutational signatures related to specific nucleotide substitutions, which prove that distinct hosts respond differently to SARS-CoV-2 infections, and which are likely ruled by APOBEC, Reactive Oxygen Species (ROS) and ADAR.Thanks to a corrected-for-signatures dN/dS analysis we demonstrate that the mutational processes underlying such signatures are affected by purifying selection, with important exceptions. In fact, several mutations linked to low-rate mutational processes appear to transit to clonality in the population, eventually leading to the definition of new clonal genotypes and to a statistically significant increase of overall genomic diversity.Importantly, the analysis of the phylogenetic model shows the presence of multiple homoplasies, due to mutational hotspots, phantom mutations or positive selection, and supports the hypothesis of transmission of minor variants during infections. Overall, the results of this study pave the way for the integrated characterization of intra-host genomic diversity and clinical outcome of SARS-CoV-2 hosts.

scholarly journals A test of the hypothesis that variable mutation rates create signals that have previously been interpreted as evidence of archaic introgression into humans

2020 ◽  
Author(s):  
William Amos
Keyword(s):  
Mutation Rate ◽  
Alternative Model ◽  
Mutation Rates ◽  
Human Populations ◽  
Common Cause ◽  
Coalescent Simulations ◽  
Recurrent Mutations ◽  
Archaic Introgression ◽  
Excess Base ◽  
Human Specific

AbstractIt is widely accepted that non-African humans carry 1-2% Neanderthal DNA due to historical inter-breeding. However, inferences about introgression rely on a critical assumption that mutation rate is constant and that back-mutations are too rare to be important. Both these assumptions have been challenged, and recent evidence points towards an alternative model where signals interpreted as introgression are driven mainly by higher mutation rates in Africa. In this model, non-Africans appear closer to archaics not because they harbour introgressed fragments but because Africans have diverged more. Here I test this idea by using the density of rare, human-specific variants (RHSVs) as a proxy for recent mutation rate. I find that sites that contribute most to the signal interpreted as introgression tend to occur in tightly defined regions spanning only a few hundred bases in which mutation rate differs greatly between the two human populations being compared. Mutation rate is invariably higher in the population into which introgression is not inferred. I confirmed that RHSV density reflects mutation rate by conducting a parallel analysis looking at the density of RHSVs around sites with three alleles, an independent class of site that also requires recurrent mutations to form. Near-identical peaks in RHSV density are found, suggesting a common cause. Similarly, coalescent simulations confirm that, with constant mutation rate, introgressed fragments do not occur preferentially in regions with a high density of rare, human-specific variants. Together, these observations are difficult to reconcile with a model where excess base-sharing is driven by archaic legacies but instead provide support for a higher mutation rate inside Africa driving increased divergence from the ancestral human state.

scholarly journals Dynamic and Heterogeneous Mutations to Fluconazole Resistance in Cryptococcus neoformans

2001 ◽  
Vol 45 (2) ◽  
pp. 420-427 ◽  
Author(s):  
Jianping Xu ◽  
Chiatogu Onyewu ◽  
Heather J. Yoell ◽  
Rabia Y. Ali ◽  
Rytas J. Vilgalys ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Mutation Rate ◽  
Antifungal Agent ◽  
Basidiomycetous Yeast ◽  
Mutation Rates ◽  
Significant Heterogeneity ◽  
Random Set ◽  
Fluconazole Resistance ◽  
Mutational Processes

ABSTRACT Infections with the human pathogenic basidiomycetous yeastCryptococcus neoformans are often treated with fluconazole. Resistance to this antifungal agent has been reported. This study investigated the patterns of mutation to fluconazole resistance inC. neoformans in vitro. The MIC of fluconazole was measured for 21 strains of C. neoformans. The MICs for these 21 strains differed (0.25 to 4.0 μg/ml), but the strains were selected for this study because they exhibited no growth on plates of yeast morphology agar (YMA) containing 8 μg of fluconazole per ml. To determine their mutation rates, six independent cultures from a single original colony were established for each of the 21 strains. Each culture was then spread densely on a YMA plate with 8 μg of fluconazole per ml. A random set of putative mutants was subcultured, and the MIC of fluconazole was determined for each mutant. The 21 strains evinced significant heterogeneity in their mutation rates. The MICs of the putative mutants ranged widely, from their original MIC to 64 μg of fluconazole per ml. However, for this set of 21 strains, there was no significant correlation between the original MIC for a strain and the mutation rate of that strain; the MIC for the mutant could not be predicted from the original MIC. These results suggest that dynamic and heterogeneous mutational processes are involved in generating fluconazole resistance in C. neoformans.

scholarly journals Contributory role of SARS-CoV-2 genomic variations and life expectancy in COVID-19 transmission and low fatality rate in Africa

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Olabode E. Omotoso
Keyword(s):  
Mutational Analysis ◽  
Health Care Systems ◽  
Selective Advantage ◽  
African Population ◽  
Young Generation ◽  
Regulatory Policies ◽  
Recurrent Mutations ◽  
Mutational Hotspots ◽  
Care Systems ◽  
Novel Coronavirus

Abstract Background The novel coronavirus disease (COVID-19) has claimed lots of lives, posing a dire threat to global health. It was predicted that the coronavirus outbreak in the African population would be very lethal and result to economic devastation owing to the prevalence of immune-compromised population, poverty, low lifespan, fragile health care systems, poor economy, and lifestyle factors. Accumulation of mutations gives virus selective advantage for host invasion and adaptation, higher transmissibility of more virulent strains, and drug resistance. The present study determined the severe acute respiratory syndrome-2 (SARS-CoV-2) genomic variability and the contributory factors to the low COVID-19 fatality in Africa. To assess the SARS-CoV-2 mutational landscape, 924 viral sequences from the Africa region with their sociobiological characteristics mined from the Global Initiative on Sharing All Influenza Data (GISAID) database were analyzed. Results Mutational analysis of the SARS-CoV-2 sequences revealed highly recurrent mutations in the SARS-CoV-2 spike glycoprotein D614G (97.2%), concurrent R203K, and G204R (65.2%) in the nucleocapsid phosphoprotein, and P4715L (97.2%) in the RNA-dependent RNA polymerase flagging these regions as SARS-CoV-2 mutational hotspots in the African population. COVID-19 is more severe in older people (> 65 years); Africa has a low percentage of people within this age group (4.36%). The average age of the infected patients observed in this study is 46 years with only 47 infected patients (5.1%) above 65 years in Africa in comparison to 13.12% in countries in other continents with the highest prevalence of COVID-19. Conclusions Africa’s young generation, the late incidence of the disease, and adherence to public health guidelines are important indicators that may have contributed to the observed low COVID-19 deaths in Africa. However, with the easing of lockdown and regulatory policies, daily increasing incidence in most countries, and low testing and sequencing rate, the epidemiology and the true impact of the pandemic in Africa remain to be unraveled.

scholarly journals Mutation rate analysis via parent–progeny sequencing of the perennial peach. II. No evidence for recombination-associated mutation

2016 ◽  
Vol 283 (1841) ◽  
pp. 20161785 ◽  
Author(s):  
Long Wang ◽  
Yanchun Zhang ◽  
Chao Qin ◽  
Dacheng Tian ◽  
Sihai Yang ◽  
...  
Keyword(s):  
Mutation Rate ◽  
Recombination Rate ◽  
Mutation Rates ◽  
Recombination Rates ◽  
Rate Analysis ◽  
A Genome ◽  
Break Points ◽  
New Mutations

Mutation rates and recombination rates vary between species and between regions within a genome. What are the determinants of these forms of variation? Prior evidence has suggested that the recombination might be mutagenic with an excess of new mutations in the vicinity of recombination break points. As it is conjectured that domesticated taxa have higher recombination rates than wild ones, we expect domesticated taxa to have raised mutation rates. Here, we use parent–offspring sequencing in domesticated and wild peach to ask (i) whether recombination is mutagenic, and (ii) whether domesticated peach has a higher recombination rate than wild peach. We find no evidence that domesticated peach has an increased recombination rate, nor an increased mutation rate near recombination events. If recombination is mutagenic in this taxa, the effect is too weak to be detected by our analysis. While an absence of recombination-associated mutation might explain an absence of a recombination–heterozygozity correlation in peach, we caution against such an interpretation.

Evolution of mutation rate and virulence among human retroviruses

1994 ◽  
Vol 346 (1317) ◽  
pp. 333-343 ◽  
Keyword(s):  
Immune System ◽  
Mutation Rate ◽  
Hiv Infections ◽  
Molecular Data ◽  
Mutation Rates ◽  
Rapid Progression ◽  
Human T Cell ◽  
Large Numbers ◽  
The Individual ◽  
Multicellular Organisms

High mutation rates are generally considered to be detrimental to the fitness of multicellular organisms because mutations untune finely tuned biological machinery. However, high mutation rates may be favoured by a need to evade an immune system that has been strongly stimulated to recognize those variants that reproduced earlier during the infection, hiv infections conform to this situation because they are characterized by large numbers of viruses that are continually breaking latency and large numbers that are actively replicating throughout a long period of infection. To be transmitted, HIVS are thus generally exposed to an immune system that has been activated to destroy them in response to prior viral replication in the individual. Increases in sexual contact should contribute to this predicament by favouring evolution toward relatively high rates of replication early during infection. Because rapid replication and high mutation rate probably contribute to rapid progression of infections to aids, the interplay of sexual activity, replication rate, and mutation rate helps explain why HIV-1 has only recently caused a lethal pandemic, even though molecular data suggest that it may have been present in humans for more than a century. This interplay also offers an explanation for geographic differences in progression to cancer found among infections due to the other major group of human retroviruses, human T-cell lymphotropic viruses (HTLV). Finally, it suggests ways in which we can use natural selection as a tool to control the aids pandemic and prevent similar pandemics from arising in the future.

scholarly journals Transfer RNA genes experience exceptionally elevated mutation rates

2018 ◽  
Vol 115 (36) ◽  
pp. 8996-9001 ◽  
Author(s):  
Bryan P. Thornlow ◽  
Josh Hough ◽  
Jacquelyn M. Roger ◽  
Henry Gong ◽  
Todd M. Lowe ◽  
...  
Keyword(s):  
Mutation Rate ◽  
Trna Gene ◽  
Gene Evolution ◽  
Purifying Selection ◽  
Mutation Rates ◽  
Model Organisms ◽  
Biological Synthesis ◽  
Human Populations ◽  
Trna Genes ◽  
Simple Method

Transfer RNAs (tRNAs) are a central component for the biological synthesis of proteins, and they are among the most highly conserved and frequently transcribed genes in all living things. Despite their clear significance for fundamental cellular processes, the forces governing tRNA evolution are poorly understood. We present evidence that transcription-associated mutagenesis and strong purifying selection are key determinants of patterns of sequence variation within and surrounding tRNA genes in humans and diverse model organisms. Remarkably, the mutation rate at broadly expressed cytosolic tRNA loci is likely between 7 and 10 times greater than the nuclear genome average. Furthermore, evolutionary analyses provide strong evidence that tRNA genes, but not their flanking sequences, experience strong purifying selection acting against this elevated mutation rate. We also find a strong correlation between tRNA expression levels and the mutation rates in their immediate flanking regions, suggesting a simple method for estimating individual tRNA gene activity. Collectively, this study illuminates the extreme competing forces in tRNA gene evolution and indicates that mutations at tRNA loci contribute disproportionately to mutational load and have unexplored fitness consequences in human populations.

Y-chromosomal microsatellite mutation rates: Differences in mutation rate between and within loci

2004 ◽  
Vol 23 (2) ◽  
pp. 117-124 ◽  
Author(s):  
B. Myhre Dupuy ◽  
M. Stenersen ◽  
T. Egeland ◽  
B. Olaisen
Keyword(s):  
Mutation Rate ◽  
Mutation Rates ◽  
Microsatellite Mutation
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