scholarly journals Genome wide estimates of mutation rates and spectrum in Schizosaccharomyces pombe indicate CpG sites are highly mutagenic despite the absence of DNA methylation

2015 ◽  
Author(s):  
Megan G Behringer ◽  
David W Hall
Keyword(s):  
Schizosaccharomyces Pombe ◽  
Mutation Rate ◽  
Life Histories ◽  
Mutation Rates ◽  
Effective Population ◽  
Additional Mechanism ◽  
Yeast Saccharomyces Cerevisiae ◽  
Ascomycetous Yeast ◽  
Cpg Dinucleotides ◽  
Genome Wide

We accumulated mutations for 1952 generations in 79 initially identical, haploid lines of the fission yeast Schizosaccharomyces pombe and then performed whole-genome sequencing to determine the mutation rates and spectrum. We captured 696 spontaneous mutations across the 79 mutation accumulation lines. We compared the mutation spectrum and rate to another model ascomycetous yeast, the budding yeast Saccharomyces cerevisiae. While the two organisms are approximately 600 million years diverged from each other, they share similar life histories, genome size and genomic G/C content. We found that Sc. pombe and S. cerevisiae have similar mutation rates, contrary to what was expected given Sc. pombe’s smaller reported effective population size. Sc. pombe’s also exhibits a strong insertion bias in comparison to S. cerevisiae,. Intriguingly, we observed an increased mutation rate at cytosine nucleotides, specifically CpG nucleotides, which is also seen in S. cerevisiae. However, the absence of methylation in Sc. pombe and the pattern of mutation at these sites, primarily C→ A as opposed to C→T, strongly suggest that the increased mutation rate is not caused by deamination of methylated cytosines. This result implies that the high mutability of CpG dinucleotides in other species may be caused in part by an additional mechanism than methylation.

scholarly journals Death and population dynamics affect mutation rate estimates and evolvability under stress in bacteria

2017 ◽  
Author(s):  
Antoine Frénoy ◽  
Sebastian Bonhoeffer
Keyword(s):  
Population Dynamics ◽  
Mutation Rate ◽  
Death Rate ◽  
Mutation Rates ◽  
Resistance Mutations ◽  
Bacterial Populations ◽  
Plasmid Segregation ◽  
Genome Wide ◽  
Response To Stress ◽  
Induced Mutagenesis

AbstractThe stress-induced mutagenesis paradigm postulates that in response to stress, bacteria increase their genome-wide mutation rate, in turn increasing the chances that a descendant is able to withstand the stress. This has implications for antibiotic treatment: exposure to sub-inhibitory doses of antibiotics has been reported to increase bacterial mutation rates, and thus probably the rate at which resistance mutations appear and lead to treatment failure.Measuring mutation rates under stress, however, is problematic, because existing methods assume there is no death. Yet sub-inhibitory stress levels may induce a substantial death rate. Death events need to be compensated by extra replication to reach a given population size, thus giving more opportunities to acquire mutations. We show that ignoring death leads to a systematic overestimation of mutation rates under stress.We developed a system using plasmid segregation to measure death and growth rates simultaneously in bacterial populations. We use it to replicate classical experiments reporting antibiotic-induced mutagenesis. We found that a substantial death rate occurs at the tested sub-inhibitory concentrations, and taking this death into account lowers and sometimes removes the signal for stress-induced mutagenesis. Moreover even when antibiotics increase mutation rate, sub-inhibitory treatments do not increase genetic diversity and evolvability, again because of effects of the antibiotics on population dynamics.Beside showing that population dynamic is a crucial but neglected parameter affecting evolvability, we provide better experimental and computational tools to study evolvability under stress, leading to a re-assessment of the magnitude and significance of the stress-induced mutagenesis paradigm.

scholarly journals Epigenetic modifications affect the rate of spontaneous mutations in a pathogenic fungus

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Michael Habig ◽  
Cecile Lorrain ◽  
Alice Feurtey ◽  
Jovan Komluski ◽  
Eva H. Stukenbrock
Keyword(s):  
Temperature Stress ◽  
Mutation Rate ◽  
Cytosine Methylation ◽  
Pathogenic Fungus ◽  
Epigenetic Modifications ◽  
Mutation Rates ◽  
Adaptive Mutation ◽  
Spontaneous Mutations ◽  
Evolutionary Trajectory ◽  
Genome Wide

AbstractMutations are the source of genetic variation and the substrate for evolution. Genome-wide mutation rates appear to be affected by selection and are probably adaptive. Mutation rates are also known to vary along genomes, possibly in response to epigenetic modifications, but causality is only assumed. In this study we determine the direct impact of epigenetic modifications and temperature stress on mitotic mutation rates in a fungal pathogen using a mutation accumulation approach. Deletion mutants lacking epigenetic modifications confirm that histone mark H3K27me3 increases whereas H3K9me3 decreases the mutation rate. Furthermore, cytosine methylation in transposable elements (TE) increases the mutation rate 15-fold resulting in significantly less TE mobilization. Also accessory chromosomes have significantly higher mutation rates. Finally, we find that temperature stress substantially elevates the mutation rate. Taken together, we find that epigenetic modifications and environmental conditions modify the rate and the location of spontaneous mutations in the genome and alter its evolutionary trajectory.

scholarly journals De novo mutations across 1,465 diverse genomes reveal novel mutational insights and reductions in the Amish founder population

2019 ◽  
Author(s):  
Michael D. Kessler ◽  
Douglas P. Loesch ◽  
James A. Perry ◽  
Nancy L. Heard-Costa ◽  
Brian E. Cade ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Mutation Rate ◽  
De Novo ◽  
Population Level ◽  
Mutation Rates ◽  
Founder Population ◽  
Single Nucleotide ◽  
Genome Wide ◽  
Nucleotide Mutation ◽  
Rare Genetic Variation

Abstractde novo Mutations (DNMs), or mutations that appear in an individual despite not being seen in their parents, are an important source of genetic variation whose impact is relevant to studies of human evolution, genetics, and disease. Utilizing high-coverage whole genome sequencing data as part of the Trans-Omics for Precision Medicine (TOPMed) program, we directly estimate and analyze DNM counts, rates, and spectra from 1,465 trios across an array of diverse human populations. Using the resulting call set of 86,865 single nucleotide DNMs, we find a significant positive correlation between local recombination rate and local DNM rate, which together can explain up to 35.5% of the genome-wide variation in population level rare genetic variation from 41K unrelated TOPMed samples. While genome-wide heterozygosity does correlate weakly with DNM count, we do not find significant differences in DNM rate between individuals of European, African, and Latino ancestry, nor across ancestrally distinct segments within admixed individuals. However, interestingly, we do find significantly fewer DNMs in Amish individuals compared with other Europeans, even after accounting for parental age and sequencing center. Specifically, we find significant reductions in the number of T→C mutations in the Amish, which seems to underpin their overall reduction in DNMs. Finally, we calculate near-zero estimates of narrow sense heritability (h2), which suggest that variation in DNM rate is significantly shaped by non-additive genetic effects and/or the environment, and that a less mutagenic environment may be responsible for the reduced DNM rate in the Amish.SignificanceHere we provide one of the largest and most diverse human de novo mutation (DNM) call sets to date, and use it to quantify the genome-wide relationship between local mutation rate and population-level rare genetic variation. While we demonstrate that the human single nucleotide mutation rate is similar across numerous human ancestries and populations, we also discover a reduced mutation rate in the Amish founder population, which shows that mutation rates can shift rapidly. Finally, we find that variation in mutation rates is not heritable, which suggests that the environment may influence mutation rates more significantly than previously realized.

scholarly journals A deep learning-based framework for estimating fine-scale germline mutation rates

2021 ◽  
Author(s):  
Yiyuan Fang ◽  
Shuyi Deng ◽  
Cai Li
Keyword(s):  
Deep Learning ◽  
Mutation Rate ◽  
Germline Mutation ◽  
Homo Sapiens ◽  
Predictive Performance ◽  
Training Data ◽  
Mutation Rates ◽  
Fine Scale ◽  
Current State ◽  
Genome Wide

Germline mutation rates are essential for genetic and evolutionary analyses. Yet, estimating accurate fine-scale mutation rates across the genome is a great challenge, due to relatively few observed mutations and intricate relationships between predictors and mutation rates. Here we present MuRaL (Mutation Rate Learner), a deep learning-based framework to predict fine-scale mutation rates using only genomic sequences as input. Harnessing human germline variants for comprehensive assessment, we show that MuRaL achieves better predictive performance than current state-of-the-art methods. Moreover, MuRaL can build models with relatively few training mutations and a moderate number of sequenced individuals. It can leverage transfer learning to build models with further less training data and time. We apply MuRaL to produce genome-wide mutation rate profiles for four species - Homo sapiens, Macaca mulatta, Arabidopsis thaliana and Drosophila melanogaster, demonstrating its high applicability. The generated mutation rate profiles and open source software can greatly facilitate related research.

scholarly journals Low genetic variation is associated with low mutation rate in the giant duckweed

2018 ◽  
Author(s):  
Shuqing Xu ◽  
Jessica Stapley ◽  
Saskia Gablenz ◽  
Justin Boyer ◽  
Klaus J. Appenroth ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Population Size ◽  
Mutation Rate ◽  
Spontaneous Mutation ◽  
Effective Population ◽  
Spontaneous Mutation Rate ◽  
Low Genetic Diversity ◽  
Genome Wide ◽  
Census Population Size

AbstractMutation rate and effective population size (Ne) jointly determine intraspecific genetic diversity, but the role of mutation rate is often ignored. We investigate genetic diversity, spontaneous mutation rate andNein the giant duckweed (Spirodela polyrhiza). Despite its large census population size, whole-genome sequencing of 68 globally sampled individuals revealed extremely low within-species genetic diversity. Assessed under natural conditions, the genome-wide spontaneous mutation rate is at least seven times lower than estimates made for other multicellular eukaryotes, whereasNeis large. These results demonstrate that low genetic diversity can be associated with large-Nespecies, where selection can reduce mutation rates to very low levels, and accurate estimates of mutation rate can help to explain seemingly counterintuitive patterns of genome-wide variation.One Sentence SummaryThe low-down on a tiny plant: extremely low genetic diversity in an aquatic plant is associated with its exceptionally low mutation rate.

scholarly journals Joint inference of demography and mutation rates from polymorphism data and pedigrees

2016 ◽  
Author(s):  
Florence Parat ◽  
Sándor Miklós Szilágyi ◽  
Daniel Wegmann ◽  
Aurélien Tellier
Keyword(s):  
Mutation Rate ◽  
Overlapping Generations ◽  
Genetic Data ◽  
Mutation Rates ◽  
Pedigree Information ◽  
Pedigree Data ◽  
Computationally Efficient ◽  
Effective Population ◽  
Joint Inference ◽  
Major Interest

ABSTRACTInference of demography and mutation rates is of major interest but difficult because genetic data is only informative about the population mutation rate, the product of the effective population size times the mutation rate, and not about these quantities individually. Here we show that this limitation can be overcome by combining genetic data with pedigree information. To successfully use pedigree data, however, important aspects of real populations such as the presence of two sexes, unbalanced sex ratios and overlapping generations have to be taken into account. We present here an extension of the classic Wright-Fisher model accounting for these effects and show that the coalescent process under this model reduces to the classic Kingman coalescent with specific scaling parameters. We further derive the probability of a pedigree under that model and show how pedigree data can thus be used to infer demographic parameters. Finally, we present a computationally efficient inference approach combining pedigree information and genetic data summarized by the site frequency spectrum (SFS) that allows for the joint inference of the mutation rate, sex-specific population sizes and the fraction of overlapping generations. Using simulations we then show that these parameters can be accurately inferred from pedigrees spanning just a few generations, as are available for many species. We finally discuss future possible extensions of the model and inference framework necessary for applications to wild and domesticated species, namely the account for more complex demographies and the uncertainty in assigning pedigree individuals to specific generations.

scholarly journals Effects of mutation on selection limits in finite populations with multiple alleles.

Genetics ◽  
1989 ◽  
Vol 122 (4) ◽  
pp. 977-984
Author(s):  
Z B Zeng ◽  
H Tachida ◽  
C C Cockerham
Keyword(s):  
Mutation Rate ◽  
Present Model ◽  
Substantial Effect ◽  
Mutation Rates ◽  
Additive Effects ◽  
Selection Coefficient ◽  
Effective Population ◽  
Weak Selection ◽  
Multiple Alleles ◽  
Selection Limit

Abstract The ultimate response to directional selection (i.e., the selection limit) under recurrent mutation is analyzed by a diffusion approximation for a population in which there are k possible alleles at a locus. The limit mainly depends on two scaled parameters S (= 4Ns sigma a) and theta (= 4Nu) and k, the number of alleles, where N is the effective population size, u is the mutation rate, s is the selection coefficient, and sigma 2a is the variance of allelic effects. When the selection pressure is weak (S less than or equal to 0.5), the limit is given approximately by 2S sigma a[1 - (1 + c2)/k]/(theta + 1) for additive effects of alleles, where c is the coefficient of variation of the mutation rates among alleles. For strong selection, other approximations are devised to analyze the limit in different parameter regions. The effect of mutation on selection limits largely relies on the potential of mutation to introduce new and better alleles into the population. This effect is, however, bounded under the present model. Unequal mutation rates among alleles tend to reduce the selection limit, and can have a substantial effect only for small numbers of alleles and weak selection. The selection limit decreases as the mutation rate increases.

scholarly journals Background selection theory overestimates effective population size for high mutation rates

2022 ◽  
Author(s):  
Joseph D Matheson ◽  
Joanna Masel
Keyword(s):  
Population Size ◽  
Effective Population Size ◽  
Deleterious Mutation ◽  
Neutral Theory ◽  
Mutation Rates ◽  
Background Selection ◽  
Effective Population ◽  
Selection Theory ◽  
Linkage Disequilibria ◽  
Genome Wide

Simple models from the neutral theory of molecular evolution are claimed to be flexible enough to incorporate the complex effects of background selection against linked deleterious mutations. Complexities are collapsed into an "effective" population size that specifies neutral genetic diversity. To achieve this, current background selection theory assumes linkage equilibrium among deleterious variants. Data do not support this assumption, nor do theoretical considerations when the genome-wide deleterious mutation is realistically high. We simulate genomes evolving under background selection, allowing the emergence of linkage disequilibria. With realistically high deleterious mutation rates, neutral diversity is much lower than predicted from previous analytical theory.

scholarly journals Cross-sectional genomic perspective of epidemic waves of SARS-CoV-2: a pan India study

2021 ◽  
Author(s):  
Sanjeet Kumar ◽  
Kanika Bansal
Keyword(s):  
Mutation Rate ◽  
Large Scale ◽  
Mutational Analysis ◽  
Silent Mutation ◽  
Mutation Rates ◽  
Rna Dependent Rna Polymerase ◽  
Cross Sectional ◽  
Genome Wide ◽  
Sectional Analysis ◽  
Second Wave

COVID-19 has posed unforeseen circumstances and throttled major economies worldwide. India has witnessed two waves affecting around 31 million people representing 16% of the cases globally. To date, the epidemic waves have not been comprehensively investigated to understand pandemic progress in India. In the present study, we aim for a cross-sectional analysis since its first incidence up to 26th July 2021. We have performed the pan Indian evolutionary study using 20,086 high-quality complete genomes of SARS-CoV-2. Based on the number of cases reported and mutation rates, we could divide the Indian epidemic into seven different phases. First, three phases constituting the pre-first wave had a very less average mutation rate (<11), which increased in the first wave to 17 and then doubled in the second wave (~34). In accordance with the mutation rate, variants of concern (alpha, beta, gamma and delta) and interest (eta and kappa) also started appearing in the first wave (1.5% of the genomes), which dominated the second (~96% of genomes) and post-second wave (100% of genomes) phases. Whole genome-based phylogeny could demarcate the post-first wave isolates from previous ones by the point of diversification leading to incidences of VOCs and VOIs in India. Nation-wide mutational analysis depicted more than 0.5 million events with four major mutations in ~97% of the total 20,086 genomes in the study. These included two mutations in coding (spike (D614G) and NSP 12b (P314L) of RNA dependent RNA polymerase), one silent mutation (NSP3 F106F) and one extragenic mutation (5 UTR 241). Large scale genome-wide mutational analysis is crucial in expanding knowledge on evolution of deadly variants of SARS-CoV-2 and timely management of the pandemic.

scholarly journals De novo mutation rates at the single-mutation resolution in a human HBB gene-region associated with adaptation and genetic disease

2022 ◽  
pp. gr.276103.121
Author(s):  
Daniel Melamed ◽  
Yuval Nov ◽  
Assaf Malik ◽  
Michael B Yakass ◽  
Evgeni Bolotin ◽  
...  
Keyword(s):  
Mutation Rate ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Region Of Interest ◽  
De Novo Mutation ◽  
Mutation Rates ◽  
Single Mutation ◽  
Random Mutation ◽  
Genome Wide ◽  
Specific Manner

While it is known that the mutation rate varies across the genome, previous estimates were based on averaging across various numbers of positions. Here we describe a method to measure the origination rates of target mutations at target base positions and apply it to a 6-bp region in the human hemoglobin subunit beta (HBB) gene and to the identical, paralogous hemoglobin subunit delta (HBD) region in sperm cells from both African and European donors. The HBB region of interest (ROI) includes the site of the hemoglobin S (HbS) mutation, which protects against malaria, is common in Africa and has served as a classic example of adaptation by random mutation and natural selection. We found a significant correspondence between de novo mutation rates and past observations of alleles in carriers, showing that mutation rates vary substantially in a mutation-specific manner that contributes to the site frequency spectrum. We also found that the overall point mutation rate is significantly higher in Africans than in Europeans in the HBB region studied. Finally, the rate of the 20A→T mutation, called the 'HbS mutation' when it appears in HBB, is significantly higher than expected from the genome-wide average for this mutation type. Nine instances were observed in the African HBB ROI, where it is of adaptive significance, representing at least three independent originations; no instances were observed elsewhere. Further studies will be needed to examine mutation rates at the single-mutation resolution across these and other loci and organisms and to uncover the molecular mechanisms responsible.

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