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Molecular Systems Biology Jan 2024The sparsity of mutations observed across tumours hinders our ability to study mutation rate variability at nucleotide resolution. To circumvent this, here we...
The sparsity of mutations observed across tumours hinders our ability to study mutation rate variability at nucleotide resolution. To circumvent this, here we investigated the propensity of mutational processes to form mutational hotspots as a readout of their mutation rate variability at single base resolution. Mutational signatures 1 and 17 have the highest hotspot propensity (5-78 times higher than other processes). After accounting for trinucleotide mutational probabilities, sequence composition and mutational heterogeneity at 10 Kbp, most (94-95%) signature 17 hotspots remain unexplained, suggesting a significant role of local genomic features. For signature 1, the inclusion of genome-wide distribution of methylated CpG sites into models can explain most (80-100%) of the hotspot propensity. There is an increased hotspot propensity of signature 1 in normal tissues and de novo germline mutations. We demonstrate that hotspot propensity is a useful readout to assess the accuracy of mutation rate models at nucleotide resolution. This new approach and the findings derived from it open up new avenues for a range of somatic and germline studies investigating and modelling mutagenesis.
Topics: Humans; Mutation; Mutation Rate; Neoplasms; Base Sequence; Nucleotides
PubMed: 38177930
DOI: 10.1038/s44320-023-00001-w -
G3 (Bethesda, Md.) Jan 2022DNA mismatch repair (MMR), an evolutionarily conserved repair pathway shared by prokaryotic and eukaryotic species alike, influences molecular evolution by detecting and...
Mutation rate and spectrum in obligately outcrossing Caenorhabditis elegans mutation accumulation lines subjected to RNAi-induced knockdown of the mismatch repair gene msh-2.
DNA mismatch repair (MMR), an evolutionarily conserved repair pathway shared by prokaryotic and eukaryotic species alike, influences molecular evolution by detecting and correcting mismatches, thereby protecting genetic fidelity, reducing the mutational load, and preventing lethality. Herein we conduct the first genome-wide evaluation of the alterations to the mutation rate and spectrum under impaired activity of the MutSα homolog, msh-2, in Caenorhabditis elegans male-female fog-2(lf) lines. We performed mutation accumulation (MA) under RNAi-induced knockdown of msh-2 for up to 50 generations, followed by next-generation sequencing of 19 MA lines and the ancestral control. msh-2 impairment in the male-female background substantially increased the frequency of nuclear base substitutions (∼23×) and small indels (∼328×) relative to wildtype hermaphrodites. However, we observed no increase in the mutation rates of mtDNA, and copy-number changes of single-copy genes. There was a marked increase in copy-number variation of rDNA genes under MMR impairment. In C. elegans, msh-2 repairs transitions more efficiently than transversions and increases the AT mutational bias relative to wildtype. The local sequence context, including sequence complexity, G + C-content, and flanking bases influenced the mutation rate. The X chromosome exhibited lower substitution and higher indel rates than autosomes, which can either result from sex-specific mutation rates or a nonrandom distribution of mutable sites between chromosomes. Provided the observed difference in mutational pattern is mostly due to MMR impairment, our results indicate that the specificity of MMR varies between taxa, and is more efficient in detecting and repairing small indels in eukaryotes relative to prokaryotes.
Topics: Animals; Caenorhabditis elegans; DNA Mismatch Repair; Female; Male; Mutation; Mutation Accumulation; Mutation Rate; RNA Interference
PubMed: 34849777
DOI: 10.1093/g3journal/jkab364 -
Genome Research Jan 2021Mutations are the source of both genetic diversity and mutational load. However, the effects of increasing environmental temperature on plant mutation rates and relative...
Mutations are the source of both genetic diversity and mutational load. However, the effects of increasing environmental temperature on plant mutation rates and relative impact on specific mutational classes (e.g., insertion/deletion [indel] vs. single nucleotide variant [SNV]) are unknown. This topic is important because of the poorly defined effects of anthropogenic global temperature rise on biological systems. Here, we show the impact of temperature increase on mutation, studying whole genome profiles of mutation accumulation (MA) lineages grown for 11 successive generations at 29°C. Whereas growth of at standard temperature (ST; 23°C) is associated with a mutation rate of 7 × 10 base substitutions per site per generation, growth at stressful high temperature (HT; 29°C) is highly mutagenic, increasing the mutation rate to 12 × 10 SNV frequency is approximately two- to threefold higher at HT than at ST, and HT-growth causes an ∼19- to 23-fold increase in indel frequency, resulting in a disproportionate increase in indels (vs. SNVs). Most HT-induced indels are 1-2 bp in size and particularly affect homopolymeric or dinucleotide A or T stretch regions of the genome. HT-induced indels occur disproportionately in nucleosome-free regions, suggesting that much HT-induced mutational damage occurs during cell-cycle phases when genomic DNA is packaged into nucleosomes. We conclude that stressful experimental temperature increases accelerate plant mutation rates and particularly accelerate the rate of indel mutation. Increasing environmental temperatures are thus likely to have significant mutagenic consequences for plants growing in the wild and may, in particular, add detrimentally to mutational load.
Topics: Arabidopsis; Biodiversity; Mutation; Mutation Rate; Temperature
PubMed: 33334733
DOI: 10.1101/gr.259853.119 -
Trends in Genetics : TIG Aug 2021Stochastic gains and losses of DNA methylation at CG dinucleotides are a frequent occurrence in plants. These spontaneous 'epimutations' occur at a rate that is... (Review)
Review
Stochastic gains and losses of DNA methylation at CG dinucleotides are a frequent occurrence in plants. These spontaneous 'epimutations' occur at a rate that is 100 000 times higher than the genetic mutation rate, are effectively neutral at the genome-wide scale, and are stably inherited across mitotic and meiotic cell divisions. Mathematical models have been extraordinarily successful at describing how epimutations accumulate in plant genomes over time, making this process one of the most predictable epigenetic phenomena to date. Here, we propose that their high rate and effective neutrality make epimutations a powerful new molecular clock for timing evolutionary events of the recent past and for age dating of long-lived perennials such as trees.
Topics: DNA Methylation; Epigenesis, Genetic; Genome, Plant; Models, Theoretical; Mutation Rate; Plants; Selection, Genetic
PubMed: 34016450
DOI: 10.1016/j.tig.2021.04.010 -
Scientific Reports Jan 2022Using high-depth whole genome sequencing of F0 mating pairs and multiple individual F1 offspring, we estimated the nuclear mutation rate per generation in the malaria...
Using high-depth whole genome sequencing of F0 mating pairs and multiple individual F1 offspring, we estimated the nuclear mutation rate per generation in the malaria vectors Anopheles coluzzii and Anopheles stephensi by detecting de novo genetic mutations. A purpose-built computer program was employed to filter actual mutations from a deep background of superficially similar artifacts resulting from read misalignment. Performance of filtering parameters was determined using software-simulated mutations, and the resulting estimate of false negative rate was used to correct final mutation rate estimates. Spontaneous mutation rates by base substitution were estimated at 1.00 × 10 (95% confidence interval, 2.06 × 10-2.91 × 10) and 1.36 × 10 (95% confidence interval, 4.42 × 10-3.18 × 10) per site per generation in A. coluzzii and A. stephensi respectively. Although similar studies have been performed on other insect species including dipterans, this is the first study to empirically measure mutation rates in the important genus Anopheles, and thus provides an estimate of µ that will be of utility for comparative evolutionary genomics, as well as for population genetic analysis of malaria vector mosquito species.
Topics: Animals; Anopheles; Female; Humans; Insect Proteins; Malaria; Male; Mosquito Vectors; Mutation Rate; Whole Genome Sequencing
PubMed: 34996998
DOI: 10.1038/s41598-021-03943-z -
Journal of AAPOS : the Official... Oct 2023To investigate the population-based incidence and de novo mutation rate of Marfan syndrome and risk of ectopia lentis.
PURPOSE
To investigate the population-based incidence and de novo mutation rate of Marfan syndrome and risk of ectopia lentis.
METHODS
Patients newly diagnosed with Marfan syndrome in Olmsted County, Minnesota, from January 1, 1976, through December 31, 2005, were identified through medical records review. Outcome measures were Marfan incidence, de novo mutation rate, risk of ectopia lentis.
RESULTS
Marfan syndrome was identified in 17 patients during the 30-year period, yielding an incidence of 0.52 per 100,000 people/year (95% CI, 0.27-0.77). Mean age at diagnosis was 24.4 years (range, 1.7 year to 51.3 years). Nine patients (53%) were female. Of the 17, 5 (29%) were new mutations, with a calculated mutation rate of 3.8 ± 1.7 × 10. Four (24%) were diagnosed with ectopia lentis, including 3 at the time of their Marfan diagnosis. Of the 14 patients at risk for developing ectopia lentis after being diagnosed with Marfan syndrome, 1 (7%) developed it during a mean follow-up of 9 years (range, 0-6.4). Twelve (71%) were diagnosed with dilated ascending aorta during a mean follow-up of 13.2 years (range, 6.7 months to 28.9 years).
CONCLUSIONS
Incidence and de novo mutation rate of Marfan syndrome in this population-based cohort was higher than prior reports. Ectopia lentis, whose prevalence in North America has not been reported previously, occurred in approximately one-fourth of study patients and more commonly around the time of initial Marfan diagnosis.
Topics: Humans; Female; Infant; Male; Ectopia Lentis; Marfan Syndrome; Mutation Rate; Incidence; Mutation
PubMed: 37716433
DOI: 10.1016/j.jaapos.2023.07.006 -
Genome Biology and Evolution Dec 2021Mutation rates and spectra vary between species and among populations. Hybridization can contribute to this variation, but its role remains poorly understood. Estimating...
Mutation rates and spectra vary between species and among populations. Hybridization can contribute to this variation, but its role remains poorly understood. Estimating mutation rates requires controlled conditions where the effect of natural selection can be minimized. One way to achieve this is through mutation accumulation experiments coupled with genome sequencing. Here, we investigate 400 mutation accumulation lines initiated from 11 genotypes spanning intralineage, interlineage, and interspecific crosses of the yeasts Saccharomyces paradoxus and S. cerevisiae and propagated for 770 generations. We find significant differences in mutation rates and spectra among crosses, which are not related to the level of divergence of parental strains but are specific to some genotype combinations. Differences in number of generations and departures from neutrality play a minor role, whereas polyploidy and loss of heterozygosity impact mutation rates in some of the hybrid crosses in an opposite way.
Topics: Genotype; Hybridization, Genetic; Mutation Rate; Saccharomyces; Saccharomyces cerevisiae; Selection, Genetic
PubMed: 34908117
DOI: 10.1093/gbe/evab282 -
Molecular Cell Aug 2019Mutation rates affect both a population's present fitness and its capacity to adapt to future environmental changes. When the available genetic variability limits... (Review)
Review
Mutation rates affect both a population's present fitness and its capacity to adapt to future environmental changes. When the available genetic variability limits adaptation to environmental change, natural selection favors high mutations rates. However, constitutively high mutation rates compromise the fitness of a population in stable environments. This problem may be resolved if an increase in mutation rates is limited to times of stress, restricted to some genomic regions, and occurs only in a subpopulation of cells. Such within-population heterogeneity of mutation rates can result from genetic, environmental, and stochastic effects. The presence of subpopulations of transient mutator cells does not jeopardize the overall fitness of a population under stable environmental conditions. However, they can increase the odds of survival in changing environments because they represent reservoirs of increased genetic variability. This article presents evidence that such heterogeneity of mutation rates is more the norm than the exception.
Topics: Adaptation, Physiological; DNA Damage; DNA Repair; Drug Resistance, Bacterial; Gene-Environment Interaction; Genetic Fitness; Genetic Heterogeneity; Genetics, Population; Humans; Mutation Rate; Neoplasms
PubMed: 31398322
DOI: 10.1016/j.molcel.2019.06.029 -
Nature Communications Jun 2021What determines the rate (μ) and molecular spectrum of mutation is a fundamental question. The prevailing hypothesis asserts that natural selection against deleterious...
What determines the rate (μ) and molecular spectrum of mutation is a fundamental question. The prevailing hypothesis asserts that natural selection against deleterious mutations has pushed μ to the minimum achievable in the presence of genetic drift, or the drift barrier. Here we show that, contrasting this hypothesis, μ substantially exceeds the drift barrier in diverse organisms. Random mutation accumulation (MA) in yeast frequently reduces μ, and deleting the newly discovered mutator gene PSP2 nearly halves μ. These results, along with a comparison between the MA and natural yeast strains, demonstrate that μ is maintained above the drift barrier by stabilizing selection. Similar comparisons show that the mutation spectrum such as the universal AT mutational bias is not intrinsic but has been selectively preserved. These findings blur the separation of mutation from selection as distinct evolutionary forces but open the door to alleviating mutagenesis in various organisms by genome editing.
Topics: Genetic Drift; Models, Genetic; Mutation Accumulation; Mutation Rate; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Selection, Genetic; Whole Genome Sequencing
PubMed: 34193872
DOI: 10.1038/s41467-021-24364-6 -
Mutation Research 2023The fluctuation assay remains an important tool for analyzing the levels of mutagenesis in microbial populations. The mutant counts originating from some average number...
The fluctuation assay remains an important tool for analyzing the levels of mutagenesis in microbial populations. The mutant counts originating from some average number of mutations are usually assumed to obey the Luria-Delbrück distribution. While several tools for estimating mutation rates are available, they sometimes lack accuracy or versatility under non-standard conditions. In this work, extensions to the Luria-Delbrück protocol to account for phenotypic lag and cellular death with either perfect or partial plating were developed. Hence, the novel MLE MUtation Rate calculator, or mlemur, is the first tool that provides a user-friendly graphical interface allowing the researchers to model their data with consideration for partial plating, differential growth of mutants and non-mutants, phenotypic lag, cellular death, variability of the final number of cells, post-exponential-phase mutations, and the size of the inoculum. Additionally, mlemur allows the users to incorporate most of these special conditions at the same time to obtain highly accurate estimates of mutation rates and P values, confidence intervals for an arbitrary function of data (such as fold), and perform power analysis and sample size determination for the likelihood ratio test. The accuracy of point and interval estimates produced by mlemur against historical and simulated fluctuation experiments are assessed. Both mlemur and the analyses in this work might be of great help when evaluating fluctuation experiments and increase the awareness of the limitations of the widely-used Lea-Coulson formulation of the Luria-Delbrück distribution in the more realistic biological contexts.
Topics: Mutation Rate; Mutation; Mutagenesis; Likelihood Functions; Data Analysis; Models, Genetic
PubMed: 37104996
DOI: 10.1016/j.mrfmmm.2023.111816