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

2015 ◽  
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.

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

2016 ◽  
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.

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

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.

scholarly journals Spontaneous rate of clonal mutations in Daphnia galeata

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.

Empirical investigation of mutation rate for herbicide resistance

Weed Science ◽  
2019 ◽  
Vol 67 (4) ◽  
pp. 361-368 ◽  
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.

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

2015 ◽  
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.

scholarly journals Parallel evolution of influenza across multiple spatiotemporal scales

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Katherine S Xue ◽  
Terry Stevens-Ayers ◽  
Angela P Campbell ◽  
Janet A Englund ◽  
Steven A Pergam ◽  
...  
Keyword(s):  
Evolutionary Dynamics ◽  
De Novo ◽  
Parallel Evolution ◽  
Global Scale ◽  
De Novo Mutations ◽  
Small Set ◽  
Spatiotemporal Scales ◽  
H3n2 Influenza ◽  
Multiple Patients

Viral variants that arise in the global influenza population begin as de novo mutations in single infected hosts, but the evolutionary dynamics that transform within-host variation to global genetic diversity are poorly understood. Here, we demonstrate that influenza evolution within infected humans recapitulates many evolutionary dynamics observed at the global scale. We deep-sequence longitudinal samples from four immunocompromised patients with long-term H3N2 influenza infections. We find parallel evolution across three scales: within individual patients, in different patients in our study, and in the global influenza population. In hemagglutinin, a small set of mutations arises independently in multiple patients. These same mutations emerge repeatedly within single patients and compete with one another, providing a vivid clinical example of clonal interference. Many of these recurrent within-host mutations also reach a high global frequency in the decade following the patient infections. Our results demonstrate surprising concordance in evolutionary dynamics across multiple spatiotemporal scales.

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

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.

scholarly journals Antibiotic treatment enhances the genome-wide mutation rate of target cells

2016 ◽  
Vol 113 (18) ◽  
pp. E2498-E2505 ◽  
Author(s):  
Hongan Long ◽  
Samuel F. Miller ◽  
Chloe Strauss ◽  
Chaoxian Zhao ◽  
Lei Cheng ◽  
...  
Keyword(s):  
Mutation Rate ◽  
De Novo ◽  
De Novo Mutation ◽  
Target Cells ◽  
Invasive Pathogens ◽  
Dna Mismatch ◽  
Damage Repair ◽  
Genome Wide ◽  
Enhanced Expression

Although it is well known that microbial populations can respond adaptively to challenges from antibiotics, empirical difficulties in distinguishing the roles of de novo mutation and natural selection have left several issues unresolved. Here, we explore the mutational properties ofEscherichia coliexposed to long-term sublethal levels of the antibiotic norfloxacin, using a mutation accumulation design combined with whole-genome sequencing of replicate lines. The genome-wide mutation rate significantly increases with norfloxacin concentration. This response is associated with enhanced expression of error-prone DNA polymerases and may also involve indirect effects of norfloxacin on DNA mismatch and oxidative-damage repair. Moreover, we find that acquisition of antibiotic resistance can be enhanced solely by accelerated mutagenesis, i.e., without direct involvement of selection. Our results suggest that antibiotics may generally enhance the mutation rates of target cells, thereby accelerating the rate of adaptation not only to the antibiotic itself but to additional challenges faced by invasive pathogens.

scholarly journals Mutation rates and the evolution of germline structure

2016 ◽  
Vol 371 (1699) ◽  
pp. 20150137 ◽  
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'.

scholarly journals Drastic mutations can be hidden in short-read mapping: thousands of mutation clusters in human genome are explained by short-range template switching

2021 ◽  
Author(s):  
Ari Löytynoja
Keyword(s):  
Human Genome ◽  
De Novo ◽  
Human Populations ◽  
Template Switching ◽  
Sequencing Data ◽  
De Novo Mutations ◽  
Sequence Comparisons ◽  
Short Read ◽  
Short Read Sequencing ◽  
Template Switch

Variation within human genomes is distributed unevenly and variants show spatial clustering. DNA-replication related template switching is a poorly known mutational mechanism capable of causing major chromosomal rearrangements as well as creating short inverted sequence copies that appear as local mutation clusters in sequence comparisons. We reanalyzed haplotype-resolved genome assemblies representing 25 human populations and multinucleotide variants aggregated from 140,000 human sequencing experiments. We found local template switching to explain thousands of complex mutation clusters across the human genome, the loci segregating within and between populations with a small number appearing as de novo mutations. We developed computational tools for genotyping candidate template switch loci using short-read sequencing data and for identification of template switch events using both short-read data and genotype data. These tools will enable building a catalogue of affected loci and studying the cellular mechanisms behind template switching both in healthy organisms and in disease. Strikingly, we noticed that widely-used analysis pipelines for short-read sequencing data - capable of identifying single nucleotide changes - may miss TSM-origin inversions of tens of base pairs, potentially invalidating medical genetic studies searching for causative alleles behind genetic diseases.

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