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

2018 ◽  
Author(s):  
Cai Li ◽  
Nicholas M. Luscombe
Keyword(s):  
Human Genome ◽  
Genome Evolution ◽  
Mutation Rate ◽  
Germline Mutation ◽  
De Novo ◽  
Mutation Rates ◽  
Rate Variation ◽  
Nucleosome Organization ◽  
Local Sequence ◽  
Mutation Rate Variation

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.

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 Highly accelerated rates of heritable large-scale mutations under prolonged exposure to a metal mixture of copper and nickel

2018 ◽  
Author(s):  
Frédéric J.J. Chain ◽  
Jullien M. Flynn ◽  
James K. Bull ◽  
Melania E. Cristescu
Keyword(s):  
Mutation Rate ◽  
Large Scale ◽  
Prolonged Exposure ◽  
De Novo ◽  
Multiple Stressors ◽  
Copy Number Variations ◽  
Environmental Stressors ◽  
Mutation Rates ◽  
Rate Variation ◽  
Mutational Load

AbstractMutation rate variation has been under intense investigation for decades. Despite these efforts, little is known about the extent to which environmental stressors accelerate mutation rates and influence the genetic load of populations. Moreover, most studies have focused on point mutations rather than large-scale deletions and duplications (copy number variations or “CNVs”). We estimated mutation rates inDaphnia pulexexposed to low levels of environmental stressors as well as the effect of selection onde novomutations. We conducted a mutation accumulation (MA) experiment in which selection was minimized, coupled with an experiment in which a population was propagated under competitive conditions in a benign environment. After an average of 103 generations of MA propagation, we sequenced 60 genomes and found significantly accelerated rates of deletions and duplications in MA lines exposed to ecologically relevant concentrations of metals. Whereas control lines had gene deletion and duplication rates comparable to other multicellular eukaryotes (1.8 × 10−6per gene per generation), a mixture of nickel and copper increased rates fourfold. The realized mutation rate under selection was reduced to 0.4x that of control MA lines, providing evidence that CNVs contribute to mutational load. Our CNV breakpoint analysis revealed that nonhomologous recombination associated with regions of DNA fragility is the primary source of CNVs, plausibly linking metal-induced DNA strand breaks with higher CNV rates. Our findings suggest that environmental stress, in particular multiple stressors, can have profound effects on large-scale mutation rates and mutational load of populations.

scholarly journals Signals of variation in human mutation rate at multiple levels of sequence context

2018 ◽  
Author(s):  
Rachael C. Aikens ◽  
Kelsey E. Johnson ◽  
Benjamin F. Voight
Keyword(s):  
Mutation Rate ◽  
Rate Variation ◽  
Evolutionary Models ◽  
Base Pairs ◽  
Sequence Context ◽  
Local Sequence ◽  
Multiple Levels ◽  
Human Mutation ◽  
Genetic Context ◽  
Mutation Rate Variation

ABSTRACTOur understanding of mutation rate helps us build evolutionary models and make sense of genetic variation. Recent work indicates that the frequencies of specific mutation types have been elevated in Europe, and that many more, subtler signatures of global polymorphism variation may yet remain unidentified. Here, we present an analysis of the 1,000 Genomes Project (phase 3), suggesting additional putative signatures of mutation rate variation across populations and the extent to which they are shaped by local sequence context. First, we compiled a list of the most significantly variable polymorphism types in a cross-continental statistical test. Clustering polymorphisms together, we observed four sets of substitution types that showed similar trends of relative mutation rate across populations, and describe the patterns of these mutational clusters among continental groups. For the majority of these signatures, we found that a single flanking base pair of sequence context was sufficient to determine the majority of enrichment or depletion of a mutation type. However, local genetic context up to 2-3 base pairs away contributes additional variability, and helps to interpret a previously noted enrichment of certain polymorphism types in some East Asian groups. Building our understanding of mutation rate in this way can help us to construct more accurate evolutionary models and better understand the mechanisms that underlie genetic change.

scholarly journals Extremely rare variants reveal patterns of germline mutation rate heterogeneity in humans

2017 ◽  
Author(s):  
Jedidiah Carlson ◽  
Adam E Locke ◽  
Matthew Flickinger ◽  
Matthew Zawistowski ◽  
Shawn Levy ◽  
...  
Keyword(s):  
Mutation Rate ◽  
Germline Mutation ◽  
De Novo ◽  
Gc Content ◽  
Mutation Rates ◽  
Rate Heterogeneity ◽  
Genomic Features ◽  
Genome Wide ◽  
Wide Variability ◽  
Nucleotide Context

AbstractA detailed understanding of the genome-wide variability of single-nucleotide germline mutation rates is essential to studying human genome evolution. Here we use ∼36 million singleton variants from 3,560 whole-genome sequences to infer fine-scale patterns of mutation rate heterogeneity. Mutability is jointly affected by adjacent nucleotide context and diverse genomic features of the surrounding region, including histone modifications, replication timing, and recombination rate, sometimes suggesting specific mutagenic mechanisms. Remarkably, GC content, DNase hypersensitivity, CpG islands, and H3K36 trimethylation are associated with both increased and decreased mutation rates depending on nucleotide context. We validate these estimated effects in an independent dataset of ∼46,000 de novo mutations, and confirm our estimates are more accurate than previously published estimates based on ancestrally older variants without considering genomic features. Our results thus provide the most refined portrait to date of the factors contributing to genome-wide variability of the human germline mutation rate.

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

2015 ◽  
Vol 25 (11) ◽  
pp. 1739-1749 ◽  
Author(s):  
Rob W. Ness ◽  
Andrew D. Morgan ◽  
Radhakrishnan B. Vasanthakrishnan ◽  
Nick Colegrave ◽  
Peter D. Keightley
Keyword(s):  
Mutation Rate ◽  
De Novo ◽  
De Novo Mutation ◽  
Rate Variation ◽  
Mutation Rate Variation

scholarly journals Mutation rate variation shapes genome-wide diversity in Drosophila melanogaster

2021 ◽  
Author(s):  
Gustavo Valadares Barroso ◽  
Julien Y Dutheil
Keyword(s):  
Drosophila Melanogaster ◽  
Molecular Evolution ◽  
Mutation Rate ◽  
Nucleotide Diversity ◽  
Population Genomics ◽  
Genomic Variation ◽  
Mutation Rates ◽  
Rate Variation ◽  
Evolutionary Forces ◽  
Mutation Rate Variation

What shapes the distribution of nucleotide diversity along the genome? Attempts to answer this question have sparked debate about the roles of neutral stochastic processes and natural selection in molecular evolution. However, the mechanisms of evolution do not act in isolation, and integrative models that simultaneously consider the influence of multiple factors on diversity are lacking; without them, confounding factors lurk in the estimates. Here we present a new statistical method that jointly infers the genomic landscapes of genealogies, recombination rates and mutation rates. In doing so, our model captures the effects of genetic drift, linked selection and local mutation rates on patterns of genomic variation. Guided by our causal model, we use linear regression to estimate the individual contributions of these micro-evolutionary forces to levels of nucleotide diversity. Our analyses reveal the signature of selection in Drosophila melanogaster, but we estimate that the mutation landscape is the major driver of the distribution of diversity in this species. Furthermore, our simulation study suggests that in many evolutionary scenarios the mutation landscape will be a crucial force shaping diversity, depending notably on the genomic window size used in the analysis. We argue that incorporating mutation rate variation into the null model of molecular evolution will lead to more realistic inference in population genomics.

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