DNA local structure decreases mutation rates

ABSTRACTBackgroundMutation rates vary across the genome. Whereas manytransfactors that influence mutation rates have been identified, as have specific sequence motifs at the 1-7 bp scale,ciselements remain poorly characterized. The lack of understanding why different sequences have different mutation rates hampers our ability to identify positive selection in evolution and to identify driver mutations in tumorigenesis.ResultsHere we show, using a combination of synthetic genes and sequencing of thousands of isolated yeast colonies, that intrinsic DNA curvature is the majorcisdeterminant of mutation rate. Mutation rate negatively correlates with DNA curvature within genes, and a 10% decrease in curvature results in a 70% increase in mutation rate. Consistently, both yeast cells and human tumors accumulate mutations in regions with small curvature. We further show that this effect is due to differences in the intrinsic mutation rate, likely due to differences in mutagen sensitivity, and not due to differences in the local activity of DNA repair.ConclusionsOur study establishes a framework in understanding thecisproperties of DNA sequence in modulating the local mutation rate and identifies a novel causal source of non-uniform mutation rates across the genome.

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Rapid evolution of the human mutation spectrum

10.1101/084343 ◽

2016 ◽

Cited By ~ 5

Author(s):

Kelley Harris ◽

Jonathan K. Pritchard

Keyword(s):

Mutation Rate ◽

Genetic Modifier ◽

Rapid Evolution ◽

Biological Information ◽

Mutation Rates ◽

Specific Sequence ◽

Mutational Spectra ◽

Damage Repair ◽

Human Mutation ◽

System Selection

AbstractDNA is a remarkably precise medium for copying and storing biological information. This high fidelity results from the action of hundreds of genes involved in replication, proofreading, and damage repair. Evolutionary theory suggests that in such a system, selection has limited ability to remove genetic variants that change mutation rates by small amounts or in specific sequence contexts. Consistent with this, using SNV variation as a proxy for mutational input, we report here that mutational spectra differ substantially among species, human continental groups and even some closely-related populations. Close examination of one signal, an increased TCC→TTC mutation rate in Europeans, indicates a burst of mutations from about 15,000 to 2,000 years ago, perhaps due to the appearance, drift, and ultimate elimination of a genetic modifier of mutation rate. Our results suggest that mutation rates can evolve markedly over short evolutionary timescales and suggest the possibility of mapping mutational modifiers.

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Distinct evolutionary trajectories in asexual populations through an interplay of their size, resource availability and mutation rates

10.1101/2020.08.27.269829 ◽

2020 ◽

Author(s):

Bhaskar Kumawat ◽

Ramray Bhat

Keyword(s):

Mutation Rate ◽

Single Cells ◽

Maximum Size ◽

Mutation Rates ◽

Genome Replication ◽

Sequence Motifs ◽

Complex Picture ◽

Distinct Sequence ◽

Resource Levels ◽

Asexual Populations

AbstractAsexually reproducing populations of single cells evolve through mutation, natural selection, and genetic drift to enhance their reproductive fitness. The environment provides the contexts that allow and regulate their fitness dynamics. In this work, we used Avida - a digital evolution framework - to uncover the effect of mutation rates, maximum size of the population, and the relative abundance of resources, on evolutionary outcomes in asexually reproducing populations of digital organisms. We observed that over extended simulations, the population evolved predominantly to one of several discrete fitness classes, each with distinct sequence motifs and/or phenotypes. For a low mutation rate, the organisms acquired either of four fitness values through an enhancement in the rate of genomic replication. Evolution at a relatively higher mutation rate presented a more complex picture. While the highest fitness values at a high mutation rate were achieved through enhanced genome replication rates, a suboptimal one was achieved through organisms sharing information relevant to metabolic tasks with each other. The information sharing capacity was vital to fitness acquisition and frequency of the genotype associated with it increased with greater resource levels and maximum population size. In addition, populations optimizing their fitness through such means exhibited a greater degree of genotypic heterogeneity and metabolic activity than those that improved replication rates. Our results reveal a minimal set of conditions for the emergence of interdependence within evolving populations with significant implications for biological systems in appropriate environmental contexts.

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Sequence, Chromatin and Evolution of Satellite DNA

International Journal of Molecular Sciences ◽

10.3390/ijms22094309 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4309

Author(s):

Jitendra Thakur ◽

Jenika Packiaraj ◽

Steven Henikoff

Keyword(s):

Dna Sequences ◽

Satellite Dna ◽

Tandem Repeats ◽

Large Fraction ◽

Dna Curvature ◽

Sequence Motifs ◽

Specific Sequence ◽

Satellite Dnas ◽

Dna Repeat ◽

Species Specific

Satellite DNA consists of abundant tandem repeats that play important roles in cellular processes, including chromosome segregation, genome organization and chromosome end protection. Most satellite DNA repeat units are either of nucleosomal length or 5–10 bp long and occupy centromeric, pericentromeric or telomeric regions. Due to high repetitiveness, satellite DNA sequences have largely been absent from genome assemblies. Although few conserved satellite-specific sequence motifs have been identified, DNA curvature, dyad symmetries and inverted repeats are features of various satellite DNAs in several organisms. Satellite DNA sequences are either embedded in highly compact gene-poor heterochromatin or specialized chromatin that is distinct from euchromatin. Nevertheless, some satellite DNAs are transcribed into non-coding RNAs that may play important roles in satellite DNA function. Intriguingly, satellite DNAs are among the most rapidly evolving genomic elements, such that a large fraction is species-specific in most organisms. Here we describe the different classes of satellite DNA sequences, their satellite-specific chromatin features, and how these features may contribute to satellite DNA biology and evolution. We also discuss how the evolution of functional satellite DNA classes may contribute to speciation in plants and animals.

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Rapid evolution of the human mutation spectrum

eLife ◽

10.7554/elife.24284 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 59

Author(s):

Kelley Harris ◽

Jonathan K Pritchard

Keyword(s):

Mutation Rate ◽

Genetic Modifier ◽

Rapid Evolution ◽

Biological Information ◽

Mutation Rates ◽

Specific Sequence ◽

Mutational Spectra ◽

Damage Repair ◽

Human Mutation ◽

System Selection

DNA is a remarkably precise medium for copying and storing biological information. This high fidelity results from the action of hundreds of genes involved in replication, proofreading, and damage repair. Evolutionary theory suggests that in such a system, selection has limited ability to remove genetic variants that change mutation rates by small amounts or in specific sequence contexts. Consistent with this, using SNV variation as a proxy for mutational input, we report here that mutational spectra differ substantially among species, human continental groups and even some closely related populations. Close examination of one signal, an increased TCC→TTC mutation rate in Europeans, indicates a burst of mutations from about 15,000 to 2000 years ago, perhaps due to the appearance, drift, and ultimate elimination of a genetic modifier of mutation rate. Our results suggest that mutation rates can evolve markedly over short evolutionary timescales and suggest the possibility of mapping mutational modifiers.

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Analysis of the Genetic Variability of Virulence-Related Loci in Epidemic Clones of Methicillin-Resistant Staphylococcus aureus

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.49.1.366-379.2005 ◽

2005 ◽

Vol 49 (1) ◽

pp. 366-379 ◽

Cited By ~ 41

Author(s):

A. R. Gomes ◽

S. Vinga ◽

M. Zavolan ◽

H. de Lencastre

Keyword(s):

Staphylococcus Aureus ◽

Genetic Variability ◽

Amino Acid Level ◽

Point Of View ◽

Sequence Motifs ◽

Related Factors ◽

Specific Sequence ◽

Methicillin Resistant ◽

Sequence Types ◽

R Domain

ABSTRACT Methicillin-resistant Staphylococcus aureus (MRSA) isolates have previously been classified into major epidemic clonal types by pulsed-field gel electrophoresis in combination with multilocus sequence typing (MLST) and staphylococcal cassette chromosome mec typing. We aimed to investigate whether genetic variability in potentially polymorphic domains of virulence-related factors could provide another level of differentiation in a diverse collection of epidemic MRSA clones. The target regions of strains representative of epidemic clones and genetically related methicillin-susceptible S. aureus isolates from the 1960s that were sequenced included the R domains of clfA and clfB; the D, W, and M regions of fnbA and fnbB; and three regions in the agr operon. Sequence variation ranged from very conserved regions, such as those for RNAIII and the agr interpromoter region, to the highly polymorphic R regions of the clf genes. The sequences of the clf R domains could be grouped into six major sequence types on the basis of the sequences in their 3′ regions. Six sequence types were also observed for the fnb sequences at the amino acid level. From an evolutionary point of view, it was interesting that a small DNA stretch at the 3′ clf R-domain sequence and the fnb sequences agreed with the results of MLST for this set of strains. In particular, clfB R-domain sequences, which had a high discriminatory capacity and with which the types distinguished were congruent with those obtained by other molecular typing methods, have potential for use for the typing of S. aureus. Clone- and strain-specific sequence motifs in the clf and fnb genes may represent useful additions to a typing methodology with a DNA array.

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Structural and mechanistic basis for translation inhibition by macrolide and ketolide antibiotics

Nature Communications ◽

10.1038/s41467-021-24674-9 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Bertrand Beckert ◽

Elodie C. Leroy ◽

Shanmugapriya Sothiselvam ◽

Lars V. Bock ◽

Maxim S. Svetlov ◽

...

Keyword(s):

Antibiotic Resistance Genes ◽

Structural Basis ◽

Sequence Motifs ◽

Specific Sequence ◽

Bacterial Ribosome ◽

Translational Arrest ◽

Exit Tunnel ◽

Mechanistic Basis ◽

Dynamics Simulations ◽

Context Specific

AbstractMacrolides and ketolides comprise a family of clinically important antibiotics that inhibit protein synthesis by binding within the exit tunnel of the bacterial ribosome. While these antibiotics are known to interrupt translation at specific sequence motifs, with ketolides predominantly stalling at Arg/Lys-X-Arg/Lys motifs and macrolides displaying a broader specificity, a structural basis for their context-specific action has been lacking. Here, we present structures of ribosomes arrested during the synthesis of an Arg-Leu-Arg sequence by the macrolide erythromycin (ERY) and the ketolide telithromycin (TEL). Together with deep mutagenesis and molecular dynamics simulations, the structures reveal how ERY and TEL interplay with the Arg-Leu-Arg motif to induce translational arrest and illuminate the basis for the less stringent sequence-specific action of ERY over TEL. Because programmed stalling at the Arg/Lys-X-Arg/Lys motifs is used to activate expression of antibiotic resistance genes, our study also provides important insights for future development of improved macrolide antibiotics.

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

Proceedings of The Royal Society B Biological Sciences ◽

10.1098/rspb.2016.1785 ◽

2016 ◽

Vol 283 (1841) ◽

pp. 20161785 ◽

Cited By ~ 4

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.

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Evolution of mutation rate and virulence among human retroviruses

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.1994.0150 ◽

1994 ◽

Vol 346 (1317) ◽

pp. 333-343 ◽

Cited By ~ 14

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.

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Transfer RNA genes experience exceptionally elevated mutation rates

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1801240115 ◽

2018 ◽

Vol 115 (36) ◽

pp. 8996-9001 ◽

Cited By ~ 12

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.

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