Extensive de novo mutation rate variation between individuals and across the genome ofChlamydomonas reinhardtii

AbstractUnderstanding the patterns and genesis of germline de novo mutations is important for studying genome evolution and human diseases. Nucleosome organization is suggested to be a contributing factor to mutation rate variation across the genome. However, the small number of published de novo mutations and the low resolution of earlier nucleosome maps limited our understanding of how nucleosome organization affects germline mutation rates in the human genome. Here, we systematically investigated the relationship between nucleosome organization and fine-scale mutation rate variation by analyzing >300,000 de novo mutations from whole-genome trio sequencing and high-resolution nucleosome maps in human. We found that de novo mutation rates are elevated around strong, translationally stable nucleosomes, a previously under-appreciated aspect. We confirmed this observation having controlled for local sequence context and other potential confounding factors. Analysis of the underlying mutational processes suggests that the increased mutation rates around strong nucleosomes are shaped by a combination of low-fidelity replication, frequent DNA damage and insufficient/error-prone repair in these regions. Interestingly, strong nucleosomes are preferentially located in young SINE/LINE elements, implying frequent nucleosome re-positioning (i.e. shifting of dyad position) and their contribution to hypermutation at new retrotransposons during evolution. These findings provide novel insights into how chromatin organization affects germline mutation rates and have important implications in human genetics and genome evolution.

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Direct estimate of the spontaneous mutation rate uncovers the effects of drift and recombination in theChlamydomonas reinhardtiiplastid genome

10.1101/031898 ◽

2015 ◽

Author(s):

Rob W Ness ◽

Susanne A Kraemer ◽

Nick Colegrave ◽

Peter D Keightley

Keyword(s):

Mutation Rate ◽

Genetic Drift ◽

Plastid Genome ◽

De Novo ◽

Spontaneous Mutation ◽

Genome Structure ◽

Nuclear Genome ◽

De Novo Mutation ◽

Direct Estimate ◽

Plastid Genomes

Plastids perform crucial cellular functions, including photosynthesis, across a wide variety of eukaryotes. Since endosymbiosis, plastids have maintained independent genomes that now display a wide diversity of gene content, genome structure, gene regulation mechanisms, and transmission modes. The evolution of plastid genomes depends on an input ofde novomutation, but our knowledge of mutation in the plastid is limited to indirect inference from patterns of DNA divergence between species. Here, we use a mutation accumulation experiment, where selection acting on mutations is rendered ineffective, combined with whole-plastid genome sequencing to directly characterize de novo mutation inChlamydomonas reinhardtii. We show that the mutation rates of the plastid and nuclear genomes are similar, but that the base spectra of mutations differ significantly. We integrate our measure of the mutation rate with a population genomic dataset of 20 individuals, and show that the plastid genome is subject to substantially stronger genetic drift than the nuclear genome. We also show that high levels of linkage disequilibrium in the plastid genome are not due to restricted recombination, but are instead a consequence of increased genetic drift. One likely explanation for increased drift in the plastid genome is that there are stronger effects of genetic hitchhiking. The presence of recombination in the plastid is consistent with laboratory studies inC. reinhardtiiand demonstrates that although the plastid genome is thought to be uniparentally inherited, it recombines in nature at a rate similar to the nuclear genome.

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Nucleosome positioning stability is a modulator of germline mutation rate variation across the human genome

Nature Communications ◽

10.1038/s41467-020-15185-0 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Cai Li ◽

Nicholas M. Luscombe

Keyword(s):

Human Genome ◽

Mutation Rate ◽

Germline Mutation ◽

Nucleosome Positioning ◽

Rate Variation ◽

Mutation Rate Variation

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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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Minisatellite mutation rate variation associated with a flanking DNA sequence polymorphism

Nature Genetics ◽

10.1038/ng1094-162 ◽

1994 ◽

Vol 8 (2) ◽

pp. 162-170 ◽

Cited By ~ 62

Author(s):

Darren G. Monckton ◽

Rita Neumann ◽

Tara Guram ◽

Neale Fretwell ◽

Keiji Tamaki ◽

...

Keyword(s):

Dna Sequence ◽

Mutation Rate ◽

Sequence Polymorphism ◽

Rate Variation ◽

Dna Sequence Polymorphism ◽

Mutation Rate Variation

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Mutation Biases and Mutation Rate Variation Around Very Short Human Microsatellites Revealed by Human–Chimpanzee–Orangutan Genomic Sequence Alignments

Journal of Molecular Evolution ◽

10.1007/s00239-010-9377-4 ◽

2010 ◽

Vol 71 (3) ◽

pp. 192-201 ◽

Cited By ~ 14

Author(s):

William Amos

Keyword(s):

Mutation Rate ◽

Genomic Sequence ◽

Rate Variation ◽

Sequence Alignments ◽

Mutation Rate Variation

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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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