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

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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Mutational signatures efficiently identify different mutational processes underlying cancers with similar somatic mutation spectra

Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis ◽

10.1016/j.mrfmmm.2017.07.004 ◽

2017 ◽

Vol 806 ◽

pp. 27-30 ◽

Cited By ~ 2

Author(s):

Nan Zhou ◽

Yuan Yuan ◽

Xin Long ◽

Chuanfang Wu ◽

Jinku Bao

Keyword(s):

Somatic Mutation ◽

Mutational Signatures ◽

Mutation Spectra ◽

Mutational Processes

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A modified fluctuation assay reveals a natural mutator phenotype that drives mutation spectrum variation within Saccharomyces cerevisiae

10.1101/2021.01.11.425955 ◽

2021 ◽

Author(s):

Pengyao Jiang ◽

Anja R. Ollodart ◽

Vidha Sudhesh ◽

Alan J. Herr ◽

Maitreya J. Dunham ◽

...

Keyword(s):

Saccharomyces Cerevisiae ◽

Rare Variants ◽

De Novo ◽

Major Axis ◽

Mutation Spectrum ◽

Mutation Rates ◽

Rate Variation ◽

Naturally Occurring ◽

Mutation Spectra ◽

Mutational Processes

AbstractMutations are the source of genetic variation and a prerequisite for evolution. Despite their fundamental importance, however, their rarity makes them expensive and difficult to detect, which has limited our ability to measure the extent to which mutational processes vary within and between species. Here, we use the 1011 Saccharomyces cerevisiae collection to measure variation of mutation rates and spectra among strains isolated from a variety of natural and human-related environments. The mutation spectra of variants segregating in different S. cerevisiae populations exhibit differences in the relative numbers of specific transition and transversion types, a pattern reminiscent of previously observed mutation spectrum differences between populations of humans, great apes, and mice. Such natural variation is thought to reveal historical differences in the activity of particular mutational processes, but is also potentially complicated by other forces such as admixture, genetic drift, and selection. In order to directly test how much of the observed mutation spectrum variation is caused by heritable differences between extant strains of S. cerevisiae, we developed an experimental pipeline to assay de novo mutation rates and spectra of individual strains, using the reporter gene CAN1. We found a 10-fold range of mutation rate variation among 16 haploid strains surveyed. While many strains exhibit similar mutation spectra, two related strains from the panel’s “Mosaic beer” clade, known as AEQ and AAR, share a distinctive mutation spectrum enrichment for C>A mutations. This C>A enrichment found through our experimental pipeline mirrors an enrichment of C>A mutations in rare variants segregating throughout the genomes of AEQ and AAR as well as additional Mosaic beer strains. We deduce that a major axis of S. cerevisiae mutation spectrum variation is likely driven by one or more naturally occurring mutator alleles whose action is measurable in a controlled laboratory environment.

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Sequence dependencies and mutation rates of localized mutational processes in cancer

10.1101/2021.10.27.465848 ◽

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

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Faculty Opinions recommendation of Mutation rates across budding yeast chromosome VI are correlated with replication timing.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13335957.14702055 ◽

2011 ◽

Author(s):

Nicolas Galtier ◽

Julien Dutheil

Keyword(s):

Budding Yeast ◽

Replication Timing ◽

Mutation Rates ◽

Yeast Chromosome

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ASAR15, A cis-Acting Locus that Controls Chromosome-Wide Replication Timing and Stability of Human Chromosome 15

PLoS Genetics ◽

10.1371/journal.pgen.1004923 ◽

2015 ◽

Vol 11 (1) ◽

pp. e1004923 ◽

Cited By ~ 23

Author(s):

Nathan Donley ◽

Leslie Smith ◽

Mathew J. Thayer

Keyword(s):

Human Chromosome ◽

Replication Timing ◽

Chromosome 15 ◽

Cis Acting

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Loss of Heterozygosity and Base Mutation Rates Vary Among Saccharomyces cerevisiae Hybrid Strains

G3 Genes|Genome|Genetics ◽

10.1534/g3.120.401551 ◽

2020 ◽

Vol 10 (9) ◽

pp. 3309-3319 ◽

Cited By ~ 2

Author(s):

Ajith V Pankajam ◽

Suman Dash ◽

Asma Saifudeen ◽

Abhishek Dutta ◽

Koodali T Nishant

Keyword(s):

Saccharomyces Cerevisiae ◽

Loss Of Heterozygosity ◽

Mutation Rates ◽

Single Nucleotide ◽

Single Nucleotide Mutation ◽

Genome Wide ◽

Nucleotide Mutation ◽

Specific Variation ◽

Chromosomal Changes ◽

Species Specific

Abstract A growing body of evidence suggests that mutation rates exhibit intra-species specific variation. We estimated genome-wide loss of heterozygosity (LOH), gross chromosomal changes, and single nucleotide mutation rates to determine intra-species specific differences in hybrid and homozygous strains of Saccharomyces cerevisiae. The mutation accumulation lines of the S. cerevisiae hybrid backgrounds - S288c/YJM789 (S/Y) and S288c/RM11-1a (S/R) were analyzed along with the homozygous diploids RM11, S288c, and YJM145. LOH was extensive in both S/Y and S/R hybrid backgrounds. The S/Y background also showed longer LOH tracts, gross chromosomal changes, and aneuploidy. Short copy number aberrations were observed in the S/R background. LOH data from the S/Y and S/R hybrids were used to construct a LOH map for S288c to identify hotspots. Further, we observe up to a sixfold difference in single nucleotide mutation rates among the S. cerevisiae S/Y and S/R genetic backgrounds. Our results demonstrate LOH is common during mitotic divisions in S. cerevisiae hybrids and also highlight genome-wide differences in LOH patterns and rates of single nucleotide mutations between commonly used S. cerevisiae hybrid genetic backgrounds.

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Mutational signatures are jointly shaped by DNA damage and repair

10.1101/686295 ◽

2019 ◽

Cited By ~ 2

Author(s):

Nadezda V Volkova ◽

Bettina Meier ◽

Víctor González-Huici ◽

Simone Bertolini ◽

Santiago Gonzalez ◽

...

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Excision Repair ◽

Dna Lesions ◽

Single Nucleotide Variants ◽

Mutational Signatures ◽

Experimental Conditions ◽

Repair Deficiency ◽

Dna Repair Deficiency ◽

Mutation Spectra

AbstractMutations arise when DNA lesions escape DNA repair. To delineate the contributions of DNA damage and DNA repair deficiency to mutagenesis we sequenced 2,717 genomes of wild-type and 53 DNA repair defective C. elegans strains propagated through several generations or exposed to 11 genotoxins at multiple doses. Combining genotoxin exposure and DNA repair deficiency alters mutation rates or leads to unexpected mutation spectra in nearly 40% of all experimental conditions involving 9/11 of genotoxins tested and 32/53 genotypes. For 8/11 genotoxins, signatures change in response to more than one DNA repair deficiency, indicating that multiple genes and pathways are involved in repairing DNA lesions induced by one genotoxin. For many genotoxins, the majority of observed single nucleotide variants results from error-prone translesion synthesis, rather than primary mutagenicity of altered nucleotides. Nucleotide excision repair mends the vast majority of genotoxic lesions, preventing up to 99% of mutations. Analogous mutagenic DNA damage-repair interactions can also be found in cancers, but, except for rare cases, effects are weak owing to the unknown histories of genotoxic exposures and DNA repair status. Overall, our data underscore that mutation spectra are joint products of DNA damage and DNA repair and imply that mutational signatures computationally derived from cancer genomes are more variable than currently anticipated.

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Periodic variation of mutation rates in bacterial genomes associated with replication timing

10.1101/195818 ◽

2017 ◽

Author(s):

Marcus M. Dillon ◽

Way Sung ◽

Michael Lynch ◽

Vaughn S. Cooper

Keyword(s):

Vibrio Fischeri ◽

Bacterial Species ◽

Replication Timing ◽

Small Chromosome ◽

Burkholderia Cenocepacia ◽

Mutation Rates ◽

Base Substitution ◽

Large Chromosome ◽

Bacterial Genomes ◽

Substitution Mutation

ABSTRACTThe causes and consequences of spatiotemporal variation in mutation rates remains to be explored in nearly all organisms. Here we examine relationships between local mutation rates and replication timing in three bacterial species whose genomes have multiple chromosomes:Vibrio fischeri, Vibrio cholerae, andBurkholderia cenocepacia. Following five evolution experiments with these bacteria conducted in the near-absence of natural selection, the genomes of clones from each lineage were sequenced and analyzed to identify variation in mutation rates and spectra. In lineages lacking mismatch repair, base-substitution mutation rates vary in a mirrored wave-like pattern on opposing replichores of the large chromosome ofV. fischeriandV. cholerae, where concurrently replicated regions experience similar base-substitution mutation rates. The base-substitution mutation rates on the small chromosome are less variable in both species but occur at similar rates as the concurrently replicated regions of the large chromosome. Neither nucleotide composition nor frequency of nucleotide motifs differed among regions experiencing high and low base-substitution rates, which along with the inferred ~800 Kb wave period suggests that the source of the periodicity is not sequence-specific but rather a systematic process related to the cell cycle. These results support the notion that base-substitution mutation rates are likely to vary systematically across many bacterial genomes, which exposes certain genes to elevated deleterious mutational load.

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

Science ◽

10.1126/science.aba7408 ◽

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.

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