Mutation rate of SARS-CoV-2 and emergence of mutators during experimental evolution

"How predictable is evolution?" is a key question in evolutionary biology. Experimental evolution has shown that the evolutionary path of microbes can be extraordinarily reproducible. Here, using experimental evolution in two circulating SARS-CoV-2, we estimate its mutation rate and demonstrate the repeatability of its evolution when facing a new cell type but no immune or drug pressures. We estimate a genomic mutation rate of 3.7x10^-6 nt^-1 cycle^-1 for a lineage of SARS-CoV-2 with the originally described spike protein (CoV-2-D) and of 2.9x10^-6 nt^-1 cycle-1 for a lineage carrying the D614G mutation that has spread worldwide (CoV-2-G). We further show that mutation accumulation is heterogeneous along the genome, with the spike gene accumulating mutations at a mean rate 16x10^-6 nt^-1 per infection cycle across backgrounds, five-fold higher than the genomic average. We observe the emergence of mutators in the CoV-2-G background, likely linked to mutations in the RNA-dependent RNA polymerase and/or in the error-correcting exonuclease protein. Despite strong bottlenecks, several de novo mutations spread to high frequencies by selection and considerable convergent evolution in spike occurs. These results demonstrate the high adaptive potential of SARS-CoV-2 during the first stages of cell infection in the absence of immune surveillance.

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Extensivede novomutation rate variation between individuals and across the genome ofChlamydomonas reinhardtii

10.1101/015693 ◽

2015 ◽

Cited By ~ 1

Author(s):

Rob W Ness ◽

Andrew D Morgan ◽

Radhakrishnan B Vasanthakrishnan ◽

Nick Colegrave ◽

Peter D Keightley

Keyword(s):

Mutation Rate ◽

Evolutionary Biology ◽

De Novo ◽

Spontaneous Mutation ◽

Gc Content ◽

Rate Variation ◽

De Novo Mutations ◽

Local Sequence ◽

Wild Strains ◽

Genomic Regions

Describing the process of spontaneous mutation is fundamental for understanding the genetic basis of disease, the threat posed by declining population size in conservation biology, and in much evolutionary biology. However, directly studying spontaneous mutation is difficult because of the rarity of de novo mutations. Mutation accumulation (MA) experiments overcome this by allowing mutations to build up over many generations in the near absence of natural selection. In this study, we sequenced the genomes of 85 MA lines derived from six genetically diverse wild strains of the green algaChlamydomonas reinhardtii. We identified 6,843 spontaneous mutations, more than any other study of spontaneous mutation. We observed seven-fold variation in the mutation rate among strains and that mutator genotypes arose, increasing the mutation rate dramatically in some replicates. We also found evidence for fine-scale heterogeneity in the mutation rate, driven largely by the sequence flanking mutated sites, and by clusters of multiple mutations at closely linked sites. There was little evidence, however, for mutation rate heterogeneity between chromosomes or over large genomic regions of 200Kbp. Using logistic regression, we generated a predictive model of the mutability of sites based on their genomic properties, including local GC content, gene expression level and local sequence context. Our model accurately predicted the average mutation rate and natural levels of genetic diversity of sites across the genome. Notably, trinucleotides vary 17-fold in rate between the most mutable and least mutable sites. Our results uncover a rich heterogeneity in the process of spontaneous mutation both among individuals and across the genome.

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Spontaneous rate of clonal mutations in Daphnia galeata

10.1101/2020.08.31.275495 ◽

2020 ◽

Author(s):

Markus Pfenninger ◽

Halina Binde Doria ◽

Jana Nickel ◽

Anne Thielsch ◽

Klaus Schwenk ◽

...

Keyword(s):

Mutation Rate ◽

De Novo ◽

Mutation Accumulation ◽

Parental Genotype ◽

De Novo Mutations ◽

Daphnia Galeata ◽

Short Term ◽

Heritable Variation ◽

Nucleotide Mutation ◽

Ultimate Source

AbstractMutations are the ultimate source of heritable variation and therefore the fuel for evolution, but direct estimates exist only for few species. We estimated the spontaneous nucleotide mutation rate among clonal generations in the waterflea Daphnia galeata with a short term mutation accumulation approach. Individuals from eighteen mutation accumulation lines over five generations were deep genome sequenced to count de novo mutations that were not present in a pool of F1 individuals, representing the parental genotype. We identified 12 new nucleotide mutations in 90 clonal generational passages. This resulted in an estimated haploid mutation rate of 0.745 x 10-9 (95% c.f. 0.39 x 10-9 − 1.26 x 10-9), which is slightly lower than recent estimates for other Daphnia species. We discuss the implications for the population genetics of Cladocerans.

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Empirical investigation of mutation rate for herbicide resistance

Weed Science ◽

10.1017/wsc.2019.19 ◽

2019 ◽

Vol 67 (4) ◽

pp. 361-368 ◽

Cited By ~ 4

Author(s):

Federico A. Casale ◽

Darci A. Giacomini ◽

Patrick J. Tranel

Keyword(s):

Mutation Rate ◽

Herbicide Resistance ◽

De Novo ◽

Selection Process ◽

Theoretical Calculations ◽

Acetolactate Synthase ◽

De Novo Mutation ◽

De Novo Mutations ◽

Sources Of Resistance ◽

Resistant Mutants

AbstractIn a predictable natural selection process, herbicides select for adaptive alleles that allow weed populations to survive. These resistance alleles may be available immediately from the standing genetic variation within the population or may arise from immigration via pollen or seeds from other populations. Moreover, because all populations are constantly generating new mutant genotypes by de novo mutations, resistant mutants may arise spontaneously in any herbicide-sensitive weed population. Recognizing that the relative contribution of each of these three sources of resistance alleles influences what strategies should be applied to counteract herbicide-resistance evolution, we aimed to add experimental information to the resistance evolutionary framework. Specifically, the objectives of this experiment were to determine the de novo mutation rate conferring herbicide resistance in a natural plant population and to test the hypothesis that the mutation rate increases when plants are stressed by sublethal herbicide exposure. We used grain amaranth (Amaranthus hypochondriacus L.) and resistance to acetolactate synthase (ALS)-inhibiting herbicides as a model system to discover spontaneous herbicide-resistant mutants. After screening 70.8 million plants, however, we detected no spontaneous resistant genotypes, indicating the probability of finding a spontaneous ALS-resistant mutant in a given sensitive population is lower than 1.4 × 10−8. This empirically determined upper limit is lower than expected from theoretical calculations based on previous studies. We found no evidence that herbicide stress increased the mutation rate, but were not able to robustly test this hypothesis. The results found in this study indicate that de novo mutations conferring herbicide resistance might occur at lower frequencies than previously expected.

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A direct multi-generational estimate of the human mutation rate from autozygous segments seen in thousands of parentally related individuals

10.1101/059436 ◽

2016 ◽

Cited By ~ 12

Author(s):

Vagheesh M Narasimhan ◽

Raheleh Rahbari ◽

Aylwyn Scally ◽

Arthur Wuster ◽

Dan Mason ◽

...

Keyword(s):

Mutation Rate ◽

Base Pair ◽

De Novo ◽

Recent Common Ancestor ◽

Human Populations ◽

De Novo Mutations ◽

Pakistani Population ◽

Human Mutation ◽

C To T Mutations ◽

Mutational Processes

AbstractHeterozygous mutations within homozygous sequences descended from a recent common ancestor offer a way to ascertain de novo mutations (DNMs) across multiple generations. Using exome sequences from 3,222 British-Pakistani individuals with high parental relatedness, we estimate a mutation rate of 1. 45 ± 0.05 × 10−8 per base pair per generation in autosomal coding sequence, with a corresponding noncrossover gene conversion rate of 8.75 ± 0.05 × 10−6 per base pair per generation. This is at the lower end of exome mutation rates previously estimated in parent-offspring trios, suggesting that post-zygotic mutations contribute little to the human germline mutation rate. We found frequent recurrence of mutations at polymorphic CpG sites, and an increase in C to T mutations in a 5’ CCG 3’ → 5’ CTG 3’ context in the Pakistani population compared to Europeans, suggesting that mutational processes have evolved rapidly between human populations.

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Higher Germline Mutagenesis of Genes with Stronger Testis Expressions Refutes the Transcriptional Scanning Hypothesis

Molecular Biology and Evolution ◽

10.1093/molbev/msaa168 ◽

2020 ◽

Vol 37 (11) ◽

pp. 3225-3231

Author(s):

Haoxuan Liu ◽

Jianzhi Zhang

Keyword(s):

Mutation Rate ◽

Germline Mutation ◽

De Novo ◽

Expression Level ◽

Human Testis ◽

Confounding Factors ◽

De Novo Mutations ◽

Gene Expressions ◽

Specific Manner ◽

Mammalian Testis

Abstract Why are more genes expressed in the testis than in any other organ in mammals? The recently proposed transcriptional scanning hypothesis posits that transcription alleviates mutagenesis through transcription-coupled repair so has been selected in the testis to modulate the germline mutation rate in a gene-specific manner. Here, we show that this hypothesis is theoretically untenable because the selection would be too weak to have an effect in mammals. Furthermore, the analysis purported to support the hypothesis did not control known confounding factors and inappropriately excluded genes with no observed de novo mutations. After remedying these problems, we find the human germline mutation rate of a gene to rise with its testis expression level. This trend also exists for inferred coding strand-originated mutations, suggesting that it arises from transcription-associated mutagenesis. Furthermore, the testis expression level of a gene robustly correlates with its overall expression in other organs, nullifying the need to explain the testis silencing of a minority of genes by adaptive germline mutagenesis. Taken together, our results demonstrate that human testis transcription increases the germline mutation rate, rejecting the transcriptional scanning hypothesis of extensive gene expressions in the mammalian testis.

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Rapid Accumulation of Mutations in Growing Mycelia of a Hypervariable Fungus Schizophyllum commune

Molecular Biology and Evolution ◽

10.1093/molbev/msaa083 ◽

2020 ◽

Vol 37 (8) ◽

pp. 2279-2286

Author(s):

Aleksandra V Bezmenova ◽

Elena A Zvyagina ◽

Anna V Fedotova ◽

Artem S Kasianov ◽

Tatiana V Neretina ◽

...

Keyword(s):

Cell Division ◽

Mutation Rate ◽

De Novo ◽

Schizophyllum Commune ◽

Natural Populations ◽

De Novo Mutations ◽

Rapid Accumulation ◽

Living Organisms ◽

Very High ◽

Rate Of Accumulation

Abstract The basidiomycete Schizophyllum commune has the highest level of genetic polymorphism known among living organisms. In a previous study, it was also found to have a moderately high per-generation mutation rate of 2×10−8, likely contributing to its high polymorphism. However, this rate has been measured only in an experiment on Petri dishes, and it is unclear how it translates to natural populations. Here, we used an experimental design that measures the rate of accumulation of de novo mutations in a linearly growing mycelium. We show that S. commune accumulates mutations at a rate of 1.24×10−7 substitutions per nucleotide per meter of growth, or ∼2.04×10−11 per nucleotide per cell division. In contrast to what has been observed in a number of species with extensive vegetative growth, this rate does not decline in the course of propagation of a mycelium. As a result, even a moderate per-cell-division mutation rate in S. commune can translate into a very high per-generation mutation rate when the number of cell divisions between consecutive meiosis is large.

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Calibrating the Human Mutation Rate via Ancestral Recombination Density in Diploid Genomes

10.1101/015560 ◽

2015 ◽

Cited By ~ 3

Author(s):

Mark Lipson ◽

Po-Ru Loh ◽

Sriram Sankararaman ◽

Nick Patterson ◽

Bonnie Berger ◽

...

Keyword(s):

Mutation Rate ◽

De Novo ◽

Sequence Divergence ◽

Great Apes ◽

Human Populations ◽

De Novo Mutations ◽

Essential Parameter ◽

Human Mutation ◽

Rate Of Accumulation

The human mutation rate is an essential parameter for studying the evolution of our species, interpreting present-day genetic variation, and understanding the incidence of genetic disease. Nevertheless, our current estimates of the rate are uncertain. Most notably, recent approaches based on counting de novo mutations in family pedigrees have yielded significantly smaller values than classical methods based on sequence divergence. Here, we propose a new method that uses the fine-scale human recombination map to calibrate the rate of accumulation of mutations. By comparing local heterozygosity levels in diploid genomes to the genetic distance scale over which these levels change, we are able to estimate a long-term mutation rate averaged over hundreds or thousands of generations. We infer a rate of 1.61 +/- 0.13 x 10^(-8) mutations per base per generation, which falls in between phylogenetic and pedigree-based estimates, and we suggest possible mechanisms to reconcile our estimate with previous studies. Our results support intermediate-age divergences among human populations and between humans and other great apes.

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Mutation rates and the evolution of germline structure

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2015.0137 ◽

2016 ◽

Vol 371 (1699) ◽

pp. 20150137 ◽

Cited By ~ 30

Author(s):

Aylwyn Scally

Keyword(s):

Mutation Rate ◽

De Novo ◽

Active Role ◽

Paternal Age ◽

State Transitions ◽

De Novo Mutations ◽

Evolutionary Changes ◽

Sequencing Studies ◽

Paternal Age Effect ◽

Stem Cell State

Genome sequencing studies of de novo mutations in humans have revealed surprising incongruities in our understanding of human germline mutation. In particular, the mutation rate observed in modern humans is substantially lower than that estimated from calibration against the fossil record, and the paternal age effect in mutations transmitted to offspring is much weaker than expected from our long-standing model of spermatogenesis. I consider possible explanations for these discrepancies, including evolutionary changes in life-history parameters such as generation time and the age of puberty, a possible contribution from undetected post-zygotic mutations early in embryo development, and changes in cellular mutation processes at different stages of the germline. I suggest a revised model of stem-cell state transitions during spermatogenesis, in which ‘dark’ gonial stem cells play a more active role than hitherto envisaged, with a long cycle time undetected in experimental observations. More generally, I argue that the mutation rate and its evolution depend intimately on the structure of the germline in humans and other primates. This article is part of the themed issue ‘Dating species divergences using rocks and clocks'.

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De novo mutations in domestic cat are consistent with an effect of reproductive longevity on both the rate and spectrum of mutations

10.1101/2021.04.06.438608 ◽

2021 ◽

Author(s):

Richard J Wang ◽

Muthuswamy Raveendran ◽

R Alan Harris ◽

William J Murphy ◽

Leslie A Lyons ◽

...

Keyword(s):

Mutation Rate ◽

Sexual Maturity ◽

De Novo ◽

Age Effect ◽

Domestic Cat ◽

Reproductive Age ◽

Paternal Age ◽

De Novo Mutations ◽

The Difference ◽

Paternal Age Effect

The mutation rate is a fundamental evolutionary parameter with direct and appreciable effects on the health and function of individuals. Here, we examine this important parameter in the domestic cat, a beloved companion animal as well as a valuable biomedical model. We estimate a mutation rate of 0.86 × 10-8 per bp per generation for the domestic cat (at an average age of 3.8 years). We find evidence for a strong paternal age effect, with more mutations transmitted by older sires. Our analyses suggest that the cat and the human have accrued similar numbers of mutations in the germline before reaching sexual maturity. The per-generation mutation rate in the cat is slightly lower than what has been observed in humans, but consistent with the shorter generation time in the cat. Using a model of reproductive longevity, which takes into account differences in the reproductive age and time to sexual maturity, we are able to explain much of the difference in per-generation rates between species. We further apply our reproductive longevity model in a novel analysis of mutation spectra and find that the spectrum for the cat resembles the human mutation spectrum at a younger age of reproduction. Together, these results implicate changes in life-history as a driver of mutation rate evolution between species. As the first direct observation of the paternal age effect outside of primates, our results also suggest a phenomenon that may be universal among mammals.

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Mutation spectrum of EXT1 and EXT2 in the Saudi patients with hereditary multiple exostoses

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-021-01738-z ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Zayed Al-Zayed ◽

Roua A. Al-Rijjal ◽

Lamya Al-Ghofaili ◽

Huda A. BinEssa ◽

Rajeev Pant ◽

...

Keyword(s):

Mutation Rate ◽

De Novo ◽

Mutation Spectrum ◽

Sequencing Analysis ◽

De Novo Mutations ◽

Novel Mutations ◽

Hereditary Multiple Exostoses ◽

Multiple Osteochondromas ◽

Multiple Exostoses ◽

Saudi Patients

Abstract Background Hereditary Multiple Exostoses (HME), also known as Multiple Osteochondromas (MO) is a rare genetic disorder characterized by multiple benign cartilaginous bone tumors, which are caused by mutations in the genes for exostosin glycosyltransferase 1 (EXT1) and exostosin glycosyltransferase 2 (EXT2). The genetic defects have not been studied in the Saudi patients. Aim of study We investigated mutation spectrum of EXT1 and EXT2 in 22 patients from 17 unrelated families. Methods Genomic DNA was extracted from peripheral leucocytes. The coding regions and intron–exon boundaries of both EXT1 and EXT2 genes were screened for mutations by PCR-sequencing analysis. Gross deletions were analyzed by MLPA analysis. Results EXT1 mutations were detected in 6 families (35%) and 3 were novel mutations: c.739G > T (p. E247*), c.1319delG (p.R440Lfs*4), and c.1786delA (p.S596Afs*25). EXT2 mutations were detected in 7 families (41%) and 3 were novel mutations: c.541delG (p.D181Ifs*89), c.583delG (p.G195Vfs*75), and a gross deletion of approximately 10 kb including promoter and exon 1. Five patients from different families had no family history and carried de novo mutations (29%, 5/17). No EXT1 and EXT2 mutations were found in the remaining four families. In total, EXT1 and EXT2 mutations were found in 77% (13/17) of Saudi HME patients. Conclusion EXT1 and EXT2 mutations contribute significantly to the pathogenesis of HME in the Saudi population. In contrast to high mutation rate in EXT 1 (65%) and low mutation rate in EXT2 (25%) in other populations, the frequency of EXT2 mutations are much higher (41%) and comparable to that of EXT1 among Saudi patients. De novo mutations are also common and the six novel EXT1/EXT2 mutations further expands the mutation spectrum of HME.

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