High and Highly Variable Spontaneous Mutation Rates in Daphnia

Abstract The rate and spectrum of spontaneous mutations are critical parameters in basic and applied biology because they dictate the pace and character of genetic variation introduced into populations, which is a prerequisite for evolution. We use a mutation–accumulation approach to estimate mutation parameters from whole-genome sequence data from multiple genotypes from multiple populations of Daphnia magna, an ecological and evolutionary model system. We report extremely high base substitution mutation rates (µ-n,bs = 8.96 × 10−9/bp/generation [95% CI: 6.66–11.97 × 10−9/bp/generation] in the nuclear genome and µ-m,bs = 8.7 × 10−7/bp/generation [95% CI: 4.40–15.12 × 10−7/bp/generation] in the mtDNA), the highest of any eukaryote examined using this approach. Levels of intraspecific variation based on the range of estimates from the nine genotypes collected from three populations (Finland, Germany, and Israel) span 1 and 3 orders of magnitude, respectively, resulting in up to a ∼300-fold difference in rates among genomic partitions within the same lineage. In contrast, mutation spectra exhibit very consistent patterns across genotypes and populations, suggesting the mechanisms underlying the mutational process may be similar, even when the rates at which they occur differ. We discuss the implications of high levels of intraspecific variation in rates, the importance of estimating gene conversion rates using a mutation–accumulation approach, and the interacting factors influencing the evolution of mutation parameters. Our findings deepen our knowledge about mutation and provide both challenges to and support for current theories aimed at explaining the evolution of the mutation rate, as a trait, across taxa.

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First Estimation of the Spontaneous Mutation Rate in Diatoms

Genome Biology and Evolution ◽

10.1093/gbe/evz130 ◽

2019 ◽

Vol 11 (7) ◽

pp. 1829-1837 ◽

Cited By ~ 11

Author(s):

Marc Krasovec ◽

Sophie Sanchez-Brosseau ◽

Gwenael Piganeau

Keyword(s):

Mutation Rate ◽

Spontaneous Mutation ◽

Mutation Accumulation ◽

Mutation Rates ◽

Model Organisms ◽

Base Substitution ◽

Unicellular Eukaryote ◽

Fundamental Parameter ◽

Secondary Endosymbiosis ◽

Spontaneous Mutation Rate

Abstract Mutations are the origin of genetic diversity, and the mutation rate is a fundamental parameter to understand all aspects of molecular evolution. The combination of mutation–accumulation experiments and high-throughput sequencing enabled the estimation of mutation rates in most model organisms, but several major eukaryotic lineages remain unexplored. Here, we report the first estimation of the spontaneous mutation rate in a model unicellular eukaryote from the Stramenopile kingdom, the diatom Phaeodactylum tricornutum (strain RCC2967). We sequenced 36 mutation accumulation lines for an average of 181 generations per line and identified 156 de novo mutations. The base substitution mutation rate per site per generation is μbs = 4.77 × 10−10 and the insertion–deletion mutation rate is μid = 1.58 × 10−11. The mutation rate varies as a function of the nucleotide context and is biased toward an excess of mutations from GC to AT, consistent with previous observations in other species. Interestingly, the mutation rates between the genomes of organelles and the nucleus differ, with a significantly higher mutation rate in the mitochondria. This confirms previous claims based on indirect estimations of the mutation rate in mitochondria of photosynthetic eukaryotes that acquired their plastid through a secondary endosymbiosis. This novel estimate enables us to infer the effective population size of P. tricornutum to be Ne∼8.72 × 106.

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Nature of Deleterious Mutation Load in Drosophila

Genetics ◽

10.1093/genetics/144.4.1993 ◽

1996 ◽

Vol 144 (4) ◽

pp. 1993-1999 ◽

Cited By ~ 5

Author(s):

Peter D Keightley

Keyword(s):

Deleterious Mutation ◽

Spontaneous Mutation ◽

Mutation Accumulation ◽

Mutation Rates ◽

Mutation Load ◽

Spontaneous Mutation Rate ◽

A Minor ◽

Chromosome I ◽

Balancer Chromosomes ◽

Balancer Chromosome

Much population genetics and evolution theory depends on knowledge of genomic mutation rates and distributions of mutation effects for fitness, but most information comes from a few mutation accumulation experiments in Drosophila in which replicated chromosomes are sheltered from natural selection by a balancer chromosome. I show here that data from these experiments imply the existence of a large class of minor viability mutations with approximately equivalent effects. However, analysis of the distribution of viabilities of chromosomes exposed to EMS mutagenesis reveals a qualitatively different distribution of effects lacking such a minor effects class. A possible explanation for this difference is that transposable element insertions, a common class of spontaneous mutation event in Drosophila, frequently generate minor viability effects. This explanation would imply that current estimates of deleterious mutation rates are not generally applicable in evolutionary models, as transposition rates vary widely. Alternatively, much of the apparent decline in viability under spontaneous mutation accumulation could have been nonmutational, perhaps due to selective improvement of balancer chromosomes. This explanation accords well with the data and implies a spontaneous mutation rate for viability two orders of magnitude lower than previously assumed, with most mutation load attributable to major effects.

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Base-substitution mutation rate across the nuclear genome of Alpheus snapping shrimp and the timing of isolation by the Isthmus of Panama

10.1101/2020.11.25.396556 ◽

2020 ◽

Author(s):

Katherine Silliman ◽

Jane L. Indorf ◽

Nancy Knowlton ◽

William E. Browne ◽

Carla Hurt

Keyword(s):

Mutation Rate ◽

Sequence Data ◽

Nuclear Genome ◽

Base Substitution ◽

Snapping Shrimp ◽

Isthmus Of Panama ◽

Species Pairs ◽

Genotype By Sequencing ◽

Independent Calibration ◽

Taxonomic Groups

AbstractThe formation of the Isthmus of Panama and final closure of the Central American Seaway (CAS) provides an independent calibration point for examining the rate of DNA substitutions. This vicariant event has been widely used to estimate the substitution rate across mitochondrial genomes and to date evolutionary events in other taxonomic groups. Nuclear sequence data is increasingly being used to complement mitochondrial datasets for phylogenetic and evolutionary investigations; these studies would benefit from information regarding the rate and pattern of DNA substitutions derived from the nuclear genome. To estimate this genomewide neutral mutation rate (μ), genotype-by-sequencing (GBS) datasets were generated for three transisthmian species pairs in Alpheus snapping shrimp. Using a Bayesian coalescent approach (G-PhoCS) applied to 44,960 GBS loci, we estimated μ to be 2.64E-9 substitutions/site/year, when calibrated with the closure of the CAS at 3 Ma. This estimate is remarkably similar to experimentally derived mutation rates in model arthropod systems, strengthening the argument for a recent closure of the CAS. To our knowledge this is the first use of transisthmian species pairs to calibrate the rate of molecular evolution from GBS data.

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Spontaneous mutation rate estimates for the principal malaria vectors Anopheles coluzzii and Anopheles stephensi

Scientific Reports ◽

10.1038/s41598-021-03943-z ◽

2022 ◽

Vol 12 (1) ◽

Author(s):

Iliyas Rashid ◽

Melina Campos ◽

Travis Collier ◽

Marc Crepeau ◽

Allison Weakley ◽

...

Keyword(s):

Confidence Interval ◽

Mutation Rate ◽

Anopheles Stephensi ◽

Spontaneous Mutation ◽

False Negative ◽

False Negative Rate ◽

Mutation Rates ◽

Malaria Vectors ◽

Base Substitution ◽

Anopheles Coluzzii

AbstractUsing 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 × 10−9 (95% confidence interval, 2.06 × 10−10—2.91 × 10−9) and 1.36 × 10−9 (95% confidence interval, 4.42 × 10−10—3.18 × 10−9) 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.

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Variable Spontaneous Mutation and Loss of Heterozygosity among Heterozygous Genomes in Yeast

Molecular Biology and Evolution ◽

10.1093/molbev/msaa150 ◽

2020 ◽

Vol 37 (11) ◽

pp. 3118-3130 ◽

Cited By ~ 2

Author(s):

Duong T Nguyen ◽

Baojun Wu ◽

Hongan Long ◽

Nan Zhang ◽

Caitlyn Patterson ◽

...

Keyword(s):

Genetic Variation ◽

Yeast Species ◽

Spontaneous Mutation ◽

Mutation Accumulation ◽

Primary Sources ◽

Mutation Rates ◽

Substantial Variation ◽

Heterozygous Site ◽

Genome Wide ◽

Mutation Spectra

Abstract Mutation and recombination are the primary sources of genetic variation. To better understand the evolution of genetic variation, it is crucial to comprehensively investigate the processes involving mutation accumulation and recombination. In this study, we performed mutation accumulation experiments on four heterozygous diploid yeast species in the Saccharomycodaceae family to determine spontaneous mutation rates, mutation spectra, and losses of heterozygosity (LOH). We observed substantial variation in mutation rates and mutation spectra. We also observed high LOH rates (1.65–11.07×10−6 events per heterozygous site per cell division). Biases in spontaneous mutation and LOH together with selection ultimately shape the variable genome-wide nucleotide landscape in yeast species.

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Whole genome sequence-based haplotypes reveal a single origin of the 1393 bp HBB deletion

Journal of Medical Genetics ◽

10.1136/jmedgenet-2019-106698 ◽

2020 ◽

Vol 57 (8) ◽

pp. 567-570 ◽

Cited By ~ 1

Author(s):

Xunde Wang ◽

Julia Z Xu ◽

Anna Conrey ◽

Laurel Mendelsohn ◽

Daniel Shriner ◽

...

Keyword(s):

Genome Sequence ◽

Sequence Data ◽

Point Mutations ◽

Pairwise Comparison ◽

Large Deletion ◽

Whole Genome Sequence ◽

Base Substitution ◽

Whole Genome ◽

Single Origin ◽

Haemoglobin Disorders

BackgroundMutations of HBB give rise to two prevalent haemoglobin disorders—sickle cell disease (SCD) and β-thalassaemia. While SCD is caused by a single base substitution, nearly 300 mutations that downregulate expression of HBB have been described. The vast majority of β-thalassaemia alleles are point mutations or small insertion/deletions within the HBB gene; deletions causing β-thalassaemia are very rare. We have identified three individuals with haemoglobin Sβ0-thalassaemia in which the β0-thalassaemia mutation is caused by a large deletion.ObjectiveTo use whole genome sequence data to determine whether these deletions arose from a single origin.MethodsWe used two approaches to confirm unrelatedness: pairwise comparison of SNPs and identity by descent analysis. Eagle, V.2.4, was used to generate phased haplotypes for the 683 individuals. The Neighbor-Net method implemented in SplitsTree V.4.13.1 was used to construct the network of haplotypes.ResultsAll three deletions involved 1393 bp, encompassing the β-promoter, exons 1 and 2, and part of intron 2, with identical breakpoints. The cases were confirmed to be unrelated. Haplotypes based on 29 SNPs in the HBB cluster showed that the three individuals harboured different βS haplotypes. In contrast, the haplotype harbouring the 1393 bp deletion was the same in all three individuals.ConclusionWe suggest that all the reported cases of the 1393 bp HBB deletion, including the three cases here, are likely to be of the same ancestral origin.

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Stability across the Whole Nuclear Genome in the Presence and Absence of DNA Mismatch Repair

Cells ◽

10.3390/cells10051224 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1224

Author(s):

Scott Alexander Lujan ◽

Thomas A. Kunkel

Keyword(s):

Cell Division ◽

Cell Line ◽

Mismatch Repair ◽

Dna Mismatch Repair ◽

Nuclear Genome ◽

Mutation Accumulation ◽

Mutation Rates ◽

Wild Type ◽

Dna Mismatch ◽

Chicken Cell

We describe the contribution of DNA mismatch repair (MMR) to the stability of the eukaryotic nuclear genome as determined by whole-genome sequencing. To date, wild-type nuclear genome mutation rates are known for over 40 eukaryotic species, while measurements in mismatch repair-defective organisms are fewer in number and are concentrated on Saccharomyces cerevisiae and human tumors. Well-studied organisms include Drosophila melanogaster and Mus musculus, while less genetically tractable species include great apes and long-lived trees. A variety of techniques have been developed to gather mutation rates, either per generation or per cell division. Generational rates are described through whole-organism mutation accumulation experiments and through offspring–parent sequencing, or they have been identified by descent. Rates per somatic cell division have been estimated from cell line mutation accumulation experiments, from systemic variant allele frequencies, and from widely spaced samples with known cell divisions per unit of tissue growth. The latter methods are also used to estimate generational mutation rates for large organisms that lack dedicated germlines, such as trees and hyphal fungi. Mechanistic studies involving genetic manipulation of MMR genes prior to mutation rate determination are thus far confined to yeast, Arabidopsis thaliana, Caenorhabditis elegans, and one chicken cell line. A great deal of work in wild-type organisms has begun to establish a sound baseline, but far more work is needed to uncover the variety of MMR across eukaryotes. Nonetheless, the few MMR studies reported to date indicate that MMR contributes 100-fold or more to genome stability, and they have uncovered insights that would have been impossible to obtain using reporter gene assays.

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Early Phylogenetic Diversification of SARS-CoV-2: Determination of Variants and the Effect on Epidemiology, Immunology, and Diagnostics

Journal of Clinical Medicine ◽

10.3390/jcm9061615 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1615 ◽

Cited By ~ 2

Author(s):

Rene Kaden

Keyword(s):

Sequence Data ◽

Gene Prediction ◽

Herd Immunity ◽

Diagnostic Methods ◽

Whole Genome Sequence ◽

Primer Binding Site ◽

Base Substitution ◽

Phylogenetic Clustering ◽

Source Tracing ◽

Globally Distributed

The phylogenetic clustering of 95 SARS-CoV-2 sequences from the first 3 months of the pandemic reveals insights into the early evolution of the virus and gives first indications of how the variants are globally distributed. Variants might become a challenge in terms of diagnostics, immunology, and effectiveness of drugs. All available whole genome sequence data from the NCBI database (March 16, 2020) were phylogenetically analyzed, and gene prediction as well as analysis of selected variants were performed. Antigenic regions and the secondary protein structure were predicted for selected variants. While some clusters are presenting the same variant with 100% identical bases, other SARS-CoV-2 lineages show a beginning diversification and phylogenetic clustering due to base substitutions and deletions in the genomes. First molecular epidemiological investigations are possible with the results by adding metadata as travelling history to the presented data. The advantage of variants in source tracing can be a challenge in terms of virulence, immune response, and immunological memory. Variants of viruses often show differences in virulence or antigenicity. This must also be considered in decisions like herd immunity. Diagnostic methods might not work if the variations or deletions are in target regions for the detection of the pathogen. One base substitution was detected in a primer binding site.

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Mutability of mononucleotide repeats, not oxidative stress, explains the discrepancy between laboratory-accumulated mutations and the natural allele-frequency spectrum in C. elegans

10.1101/2021.02.09.430480 ◽

2021 ◽

Author(s):

Moein Rajaei ◽

Ayush Shekhar Saxena ◽

Lindsay M. Johnson ◽

Michael C. Snyder ◽

Timothy A. Crombie ◽

...

Keyword(s):

Oxidative Stress ◽

Sequence Data ◽

Wild Strain ◽

Whole Genome Sequence ◽

Base Substitution ◽

Wild Type ◽

Deletion Mutations ◽

C Elegans ◽

Mutational Spectra ◽

Mutational Process

AbstractImportant clues about natural selection can be gleaned from discrepancies between the properties of segregating genetic variants and of mutations accumulated experimentally under minimal selection, provided the mutational process is the same in the lab as in nature. The ratio of transitions to transversions (Ts/Tv) is consistently lower in C. elegans mutation accumulation (MA) experiments than in nature, which has been argued to be in part due to increased oxidative stress in the lab environment. Using whole-genome sequence data from a set of C. elegans MA lines carrying a mutation (mev-1) that increases the cellular titer of reactive oxygen species (ROS), leading to increased endogenous oxidative stress, we find that the base-substitution spectrum is similar between mev-1 lines, its wild-type progenitor (N2), and another set of MA lines derived from a different wild strain (PB306). By contrast, the rate of short insertions is greater in the mev-1 lines, consistent with studies in other organisms in which environmental stress led to an increase in the rate of insertion-deletion mutations. Further, the mutational properties of mononucleotide repeats in all strains are qualitatively different from those of non-mononucleotide sequence, both for indels and base-substitutions, and whereas the non-mononucleotide spectra are fairly similar between MA lines and wild isolates, the mononucleotide spectra are very different. The discrepancy in mutational spectra between lab MA experiments and natural variation is likely due to a consistent (but unknown) effect of the lab environment that manifests itself via different modes of mutability and/or repair at mononucleotide loci.

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Paternal age in rhesus macaques is positively associated with germline mutation accumulation but not with measures of offspring sociability

10.1101/706705 ◽

2019 ◽

Cited By ~ 3

Author(s):

Richard J. Wang ◽

Gregg W.C. Thomas ◽

Muthuswamy Raveendran ◽

R. Alan Harris ◽

Harshavardhan Doddapaneni ◽

...

Keyword(s):

Mutation Rate ◽

Neurodevelopmental Disorders ◽

Complex Disease ◽

De Novo ◽

Sequence Data ◽

Mutation Accumulation ◽

Paternal Age ◽

Whole Genome Sequence ◽

Whole Genome ◽

Increased Risk

AbstractMutation is the ultimate source of all genetic novelty and the cause of heritable genetic disorders. Mutational burden has been linked to complex disease, including neurodevelopmental disorders such as schizophrenia and autism. The rate of mutation is a fundamental genomic parameter and direct estimates of this parameter have been enabled by accurate comparisons of whole-genome sequences between parents and offspring. Studies in humans have revealed that the paternal age at conception explains most of the variation in mutation rate: each additional year of paternal age in humans leads to approximately 1.5 additional mutations inherited by the child. Here, we present an estimate of the de novo mutation rate in the rhesus macaque (Macaca mulatta) using whole-genome sequence data from 32 individuals in four large pedigrees. We estimated an average mutation rate of 0.58 × 10-8 per base pair per generation (at an average parental age of 7.5 years), much lower than found in direct estimates from great apes (including human, chimpanzee, and gorilla). As in humans, older macaque fathers transmit more mutations to their offspring, approximately 1.5 extra mutations per year in our probands. Mutations at CpG sites accounted for 24% of all observed point mutations. We found that the rate of mutation accumulation after puberty is similar between macaques and humans, but that a smaller number of mutations accumulate before puberty in macaques. We additionally investigated the role of paternal age on offspring sociability, a proxy for normal neurodevelopment. In 203 male macaques studied in large social groups, we found no relationship between paternal age and multiple measures of social function. Our findings are consistent with the hypothesis that the increased risk of neurodevelopmental disorders with paternal age in primates is not primarily due to de novo mutations.

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