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

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.

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

10.1101/494914 ◽

2018 ◽

Cited By ~ 3

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.

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The Genomic Architecture of a Rapid Island Radiation: Recombination Rate Variation, Chromosome Structure, and Genome Assembly of the Hawaiian Cricket Laupala

10.1101/160952 ◽

2017 ◽

Cited By ~ 1

Author(s):

Thomas Blankers ◽

Kevin P. Oh ◽

Aureliano Bombarely ◽

Kerry L. Shaw

Keyword(s):

Large Scale ◽

De Novo ◽

Chromosomal Rearrangements ◽

Evolutionary Genetics ◽

Rate Variation ◽

Linkage Maps ◽

Recombination Rates ◽

Behavioral Isolation ◽

Genomic Architecture ◽

Suppressed Recombination

ABSTRACTPhenotypic evolution and speciation depend on recombination in many ways. Within populations, recombination can promote adaptation by bringing together favorable mutations and decoupling beneficial and deleterious alleles. As populations diverge, cross-over can give rise to maladapted recombinants and impede or reverse diversification. Suppressed recombination due to genomic rearrangements, modifier alleles, and intrinsic chromosomal properties may offer a shield against maladaptive gene flow eroding co-adapted gene complexes. Both theoretical and empirical results support this relationship. However, little is known about this relationship in the context of behavioral isolation, where co-evolving signals and preferences are the major hybridization barrier. Here we examine the genomic architecture of recently diverged, sexually isolated Hawaiian swordtail crickets (Laupala). We assemble a de novo genome and generate three dense linkage maps from interspecies crosses. In line with expectations based on the species’ recent divergence and successful interbreeding in the lab, the linkage maps are highly collinear and show no evidence for large-scale chromosomal rearrangements. The maps were then used to anchor the assembly to pseudomolecules and estimate recombination rates across the genome. We tested the hypothesis that loci involved in behavioral isolation (song and preference divergence) are in regions of low interspecific recombination. Contrary to our expectations, a genomic region where a male song QTL co-localizes with a female preference QTL was not associated with particularly low recombination rates. This study provides important novel genomic resources for an emerging evolutionary genetics model system and suggests that trait-preference co-evolution is not necessarily facilitated by locally suppressed recombination.

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Comprehensive Transcriptome Analysis Reveals Insights into Phylogeny and Positively Selected Genes of Sillago Species

Animals ◽

10.3390/ani10040633 ◽

2020 ◽

Vol 10 (4) ◽

pp. 633

Author(s):

Fangrui Lou ◽

Yuan Zhang ◽

Na Song ◽

Dongping Ji ◽

Tianxiang Gao

Keyword(s):

Amino Acid ◽

Energy Metabolism ◽

De Novo ◽

Multiple Stressors ◽

Oxygen Depletion ◽

Environmental Stressors ◽

Biological Processes ◽

Species Relationships ◽

Phylogenetic Structure ◽

High Turbidity

Sillago species lives in the demersal environments and face multiple stressors, such as localized oxygen depletion, sulfide accumulation, and high turbidity. In this study, we performed transcriptome analyses of seven Sillago species to provide insights into the phylogeny and positively selected genes of this species. After de novo assembly, 82,024, 58,102, 63,807, 85,990, 102,185, 69,748, and 102,903 unigenes were generated from S. japonica, S. aeolus, S. sp.1, S. sihama, S. sp.2, S. parvisquamis, and S. sinica, respectively. Furthermore, 140 shared orthologous exon markers were identified and then applied to reconstruct the phylogenetic relationships of the seven Sillago species. The reconstructed phylogenetic structure was significantly congruent with the prevailing morphological and molecular biological view of Sillago species relationships. In addition, a total of 44 genes were identified to be positively selected, and these genes were potential participants in the stress response, material (carbohydrate, amino acid and lipid) and energy metabolism, growth and differentiation, embryogenesis, visual sense, and other biological processes. We suspected that these genes possibly allowed Sillago species to increase their ecological adaptation to multiple environmental stressors.

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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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De novo mutations across 1,465 diverse genomes reveal novel mutational insights and reductions in the Amish founder population

10.1101/553214 ◽

2019 ◽

Author(s):

Michael D. Kessler ◽

Douglas P. Loesch ◽

James A. Perry ◽

Nancy L. Heard-Costa ◽

Brian E. Cade ◽

...

Keyword(s):

Genetic Variation ◽

Mutation Rate ◽

De Novo ◽

Population Level ◽

Mutation Rates ◽

Founder Population ◽

Single Nucleotide ◽

Genome Wide ◽

Nucleotide Mutation ◽

Rare Genetic Variation

Abstractde novo Mutations (DNMs), or mutations that appear in an individual despite not being seen in their parents, are an important source of genetic variation whose impact is relevant to studies of human evolution, genetics, and disease. Utilizing high-coverage whole genome sequencing data as part of the Trans-Omics for Precision Medicine (TOPMed) program, we directly estimate and analyze DNM counts, rates, and spectra from 1,465 trios across an array of diverse human populations. Using the resulting call set of 86,865 single nucleotide DNMs, we find a significant positive correlation between local recombination rate and local DNM rate, which together can explain up to 35.5% of the genome-wide variation in population level rare genetic variation from 41K unrelated TOPMed samples. While genome-wide heterozygosity does correlate weakly with DNM count, we do not find significant differences in DNM rate between individuals of European, African, and Latino ancestry, nor across ancestrally distinct segments within admixed individuals. However, interestingly, we do find significantly fewer DNMs in Amish individuals compared with other Europeans, even after accounting for parental age and sequencing center. Specifically, we find significant reductions in the number of T→C mutations in the Amish, which seems to underpin their overall reduction in DNMs. Finally, we calculate near-zero estimates of narrow sense heritability (h2), which suggest that variation in DNM rate is significantly shaped by non-additive genetic effects and/or the environment, and that a less mutagenic environment may be responsible for the reduced DNM rate in the Amish.SignificanceHere we provide one of the largest and most diverse human de novo mutation (DNM) call sets to date, and use it to quantify the genome-wide relationship between local mutation rate and population-level rare genetic variation. While we demonstrate that the human single nucleotide mutation rate is similar across numerous human ancestries and populations, we also discover a reduced mutation rate in the Amish founder population, which shows that mutation rates can shift rapidly. Finally, we find that variation in mutation rates is not heritable, which suggests that the environment may influence mutation rates more significantly than previously realized.

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Transfer RNA genes experience exceptionally elevated mutation rates

10.1101/229906 ◽

2017 ◽

Cited By ~ 1

Author(s):

Bryan P. Thornlow ◽

Josh Hough ◽

Jacquelyn M. Roger ◽

Henry Gong ◽

Todd M. Lowe ◽

...

Keyword(s):

Mutation Rate ◽

Sequence Variation ◽

Trna Gene ◽

Purifying Selection ◽

Transfer Rna ◽

Mutation Rates ◽

Biological Synthesis ◽

Human Populations ◽

Trna Genes ◽

Mutational Load

AbstractTransfer RNAs (tRNAs) are a central component for the biological synthesis of proteins, and they are among the most highly conserved and frequently transcribed genes in all living things. Despite their clear significance for fundamental cellular processes, the forces governing tRNA evolution are poorly understood. We present evidence that transcription-associated mutagenesis and strong purifying selection are key determinants of patterns of sequence variation within and surrounding tRNA genes in humans and diverse model organisms. Remarkably, the mutation rate at broadly expressed cytosolic tRNA loci is likely between seven and ten times greater than the nuclear genome average. Furthermore, evolutionary analyses provide strong evidence that tRNA genes, but not their flanking sequences, experience strong purifying selection, acting against this elevated mutation rate. We also find a strong correlation between tRNA expression levels and the mutation rates in their immediate flanking regions, suggesting a simple new method for estimating individual tRNA gene activity. Collectively, this study illuminates the extreme competing forces in tRNA gene evolution, and implies that mutations at tRNA loci contribute disproportionately to mutational load and have unexplored fitness consequences in human populations.Significance StatementWhile transcription-associated mutagenesis (TAM) has been demonstrated for protein coding genes, its implications in shaping genome structure at transfer RNA (tRNA) loci in metazoans have not been fully appreciated. We show that cytosolic tRNAs are a striking example of TAM because of their variable rates of transcription, well-defined boundaries and internal promoter sequences. tRNA loci have a mutation rate approximately seven-to tenfold greater than the genome-wide average, and these mutations are consistent with signatures of TAM. These observations indicate that tRNA loci are disproportionately large contributors to mutational load in the human genome. Furthermore, the correlations between tRNA locus variation and transcription implicate that prediction of tRNA gene expression based on sequence variation data is possible.

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Mutation bias shapes gene evolution in Arabidopsis thaliana

10.1101/2020.06.17.156752 ◽

2020 ◽

Cited By ~ 1

Author(s):

J. Grey Monroe ◽

Thanvi Srikant ◽

Pablo Carbonell-Bejerano ◽

Moises Exposito-Alonso ◽

Mao-Lun Weng ◽

...

Keyword(s):

Arabidopsis Thaliana ◽

De Novo ◽

Gene Evolution ◽

Gc Content ◽

Mutation Rates ◽

Rate Variation ◽

Recent Theory ◽

De Novo Mutations ◽

Coding Region ◽

Mutational Hotspots

Classical evolutionary theory maintains that mutation rate variation between genes should be random with respect to fitness 1–4 and evolutionary optimization of genic mutation rates remains controversial 3,5. However, it has now become known that cytogenetic (DNA sequence + epigenomic) features influence local mutation probabilities 6, which is predicted by more recent theory to be a prerequisite for beneficial mutation rates between different classes of genes to readily evolve 7. To test this possibility, we used de novo mutations in Arabidopsis thaliana to create a high resolution predictive model of mutation rates as a function of cytogenetic features across the genome. As expected, mutation rates are significantly predicted by features such as GC content, histone modifications, and chromatin accessibility. Deeper analyses of predicted mutation rates reveal effects of introns and untranslated exon regions in distancing coding sequences from mutational hotspots at the start and end of transcribed regions in A. thaliana. Finally, predicted coding region mutation rates are significantly lower in genes where mutations are more likely to be deleterious, supported by numerous estimates of evolutionary and functional constraint. These findings contradict neutral expectations that mutation probabilities are independent of fitness consequences. Instead they are consistent with the evolution of lower mutation rates in functionally constrained loci due to cytogenetic features, with important implications for evolutionary biology8.

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A modified fluctuation assay reveals a natural mutator phenotype that drives mutation spectrum variation within Saccharomyces cerevisiae

10.1101/2021.01.11.425955 ◽

2021 ◽

Author(s):

Pengyao Jiang ◽

Anja R. Ollodart ◽

Vidha Sudhesh ◽

Alan J. Herr ◽

Maitreya J. Dunham ◽

...

Keyword(s):

Saccharomyces Cerevisiae ◽

Rare Variants ◽

De Novo ◽

Major Axis ◽

Mutation Spectrum ◽

Mutation Rates ◽

Rate Variation ◽

Naturally Occurring ◽

Mutation Spectra ◽

Mutational Processes

AbstractMutations are the source of genetic variation and a prerequisite for evolution. Despite their fundamental importance, however, their rarity makes them expensive and difficult to detect, which has limited our ability to measure the extent to which mutational processes vary within and between species. Here, we use the 1011 Saccharomyces cerevisiae collection to measure variation of mutation rates and spectra among strains isolated from a variety of natural and human-related environments. The mutation spectra of variants segregating in different S. cerevisiae populations exhibit differences in the relative numbers of specific transition and transversion types, a pattern reminiscent of previously observed mutation spectrum differences between populations of humans, great apes, and mice. Such natural variation is thought to reveal historical differences in the activity of particular mutational processes, but is also potentially complicated by other forces such as admixture, genetic drift, and selection. In order to directly test how much of the observed mutation spectrum variation is caused by heritable differences between extant strains of S. cerevisiae, we developed an experimental pipeline to assay de novo mutation rates and spectra of individual strains, using the reporter gene CAN1. We found a 10-fold range of mutation rate variation among 16 haploid strains surveyed. While many strains exhibit similar mutation spectra, two related strains from the panel’s “Mosaic beer” clade, known as AEQ and AAR, share a distinctive mutation spectrum enrichment for C>A mutations. This C>A enrichment found through our experimental pipeline mirrors an enrichment of C>A mutations in rare variants segregating throughout the genomes of AEQ and AAR as well as additional Mosaic beer strains. We deduce that a major axis of S. cerevisiae mutation spectrum variation is likely driven by one or more naturally occurring mutator alleles whose action is measurable in a controlled laboratory environment.

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A Global Analysis of Mutations Accompanying Microevolution in the Heterozygous Diploid Pathogen Candida albicans

10.1101/288597 ◽

2018 ◽

Author(s):

Iuliana V. Ene ◽

Rhys A. Farrer ◽

Matthew P. Hirakawa ◽

Kennedy Agwamba ◽

Christina A. Cuomo ◽

...

Keyword(s):

Candida Albicans ◽

Large Scale ◽

De Novo ◽

Global Analysis ◽

Purifying Selection ◽

Opportunistic Pathogen ◽

Mutation Rates ◽

Colonization Model ◽

Chromosomal Changes ◽

Host Infection

AbstractCandida albicans is a heterozygous diploid yeast that is a commensal of the human gastrointestinal (GI) tract and a prevalent opportunistic pathogen. Here, whole-genome sequencing was performed on multiple C. albicans isolates passaged in different niches to characterize the complete spectrum of mutations arising during microevolution. We reveal that evolution during short time-scales (<600 generations) is driven by both de novo base substitutions and short-tract loss of heterozygosity (LOH) events. In contrast, large-scale chromosomal changes are relatively rare, although chromosome 7 trisomies repeatedly emerged during passaging in one GI colonization model. Both strain background and chromosomal features affected mutational patterns, with mutation rates being greatly elevated in regions adjacent to emergent LOH tracts. Mutation rates were also elevated during host infection where genomes showed strong evidence of purifying selection. These results establish the genetic events driving C. albicans evolution and that this heterozygous diploid is extensively shaped by purifying selection.

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Estimation of the SNP mutation rate in two vegetatively propagating species of duckweed

10.1101/2020.06.26.173039 ◽

2020 ◽

Author(s):

George Sandler ◽

Magdalena Bartkowska ◽

Aneil F. Agrawal ◽

Stephen I. Wright

Keyword(s):

Salt Stress ◽

Mutation Rate ◽

Mutation Detection ◽

De Novo ◽

Lemna Minor ◽

Tree Of Life ◽

Mutation Rates ◽

Spirodela Polyrhiza ◽

Cell Lineages ◽

Multiple Cell

AbstractMutation rate estimates for vegetatively reproducing organisms are rare, despite their frequent occurrence across the tree of life. Here we report mutation rate estimates in two vegetatively reproducing duckweed species, Lemna minor and Spirodela polyrhiza. We use a modified approach to estimating mutation rates by taking into account the reduction in mutation detection power that occurs when new individuals are produced from multiple cell lineages. We estimate an extremely low per generation mutation rate in both species of duckweed and note that allelic coverage at de novo mutation sites is very skewed. We also find no substantial difference in mutation rate between mutation accumulation lines propagated under benign conditions and those grown under salt stress. Finally, we discuss the implications of interpreting mutation rate estimates in vegetatively propagating organisms.

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