Mutation bias shapes gene evolution in Arabidopsis thaliana

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

10.1101/349563 ◽

2018 ◽

Cited By ~ 1

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.

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Contrasting determinants of mutation rates in germline and soma

10.1101/117325 ◽

2017 ◽

Cited By ~ 1

Author(s):

Chen Chen ◽

Hongjian Qi ◽

Yufeng Shen ◽

Joseph Pickrell ◽

Molly Przeworski

Keyword(s):

Somatic Mutations ◽

Gc Content ◽

Replication Timing ◽

Germline Mutations ◽

Mutation Rates ◽

Coding Region ◽

Expression Levels ◽

Strand Asymmetry ◽

Number Of Factors ◽

Somatic Tissues

AbstractRecent studies of somatic and germline mutations have led to the identification of a number of factors that influence point mutation rates, including CpG methylation, expression levels, replication timing and GC content. Intriguingly, some of the effects appear to differ between soma and germline: in particular, whereas mutation rates have been reported to decrease with expression levels in tumors, no clear effect has been detected in the germline. Distinct approaches were taken to analyze the data, however, so it is hard to know whether these apparent differences are real. To enable a cleaner comparison, we considered a statistical model in which the mutation rate of a coding region is predicted by GC content, expression levels, replication timing, and two histone repressive marks. We applied this model to both a set of germline mutations identified in exomes and to exonic somatic mutations in four types of tumors. Germline and soma share most determinants of mutations; notably, we detected an effect of expression levels on germline mutations as well as on somatic ones. However, whereas in somatic tissues, increased expression levels are associated with greater strand asymmetry and decreased mutation rates, in ovaries and testes, increased expression leads to greater strand asymmetry but increased mutation rates. This contrast points to differences in damage or repair rates during transcription in soma and germline.

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Germline and somatic mutations in STXBP1 with diverse neurodevelopmental phenotypes

Neurology Genetics ◽

10.1212/nxg.0000000000000199 ◽

2017 ◽

Vol 3 (6) ◽

pp. e199 ◽

Cited By ~ 22

Author(s):

Mohammed Uddin ◽

Marc Woodbury-Smith ◽

Ada Chan ◽

Ledia Brunga ◽

Sylvia Lamoureux ◽

...

Keyword(s):

Brain Tissue ◽

De Novo ◽

Focal Cortical Dysplasia ◽

Autism Spectrum ◽

Epileptic Encephalopathy ◽

De Novo Mutation ◽

Chromosomal Microarray ◽

Published Data ◽

De Novo Mutations ◽

Coding Region

Objective:To expand the clinical phenotype associated with STXBP1 gene mutations and to understand the effect of STXBP1 mutations in the pathogenesis of focal cortical dysplasia (FCD).Methods:Patients with STXBP1 mutations were identified in various ways: as part of a retrospective cohort study of epileptic encephalopathy; through clinical referrals of individuals (10,619) with developmental delay (DD) for chromosomal microarray; and from a collection of 5,205 individuals with autism spectrum disorder (ASD) examined by whole-genome sequencing.Results:Seven patients with heterozygous de novo mutations affecting the coding region of STXBP1 were newly identified. Three cases had radiologic evidence suggestive of FCD. One male patient with early infantile epileptic encephalopathy, DD, and ASD achieved complete seizure remission following resection of dysplastic brain tissue. Examination of excised brain tissue identified mosaicism for STXBP1, providing evidence for a somatic mechanism. Cell-type expression analysis suggested neuron-specific expression. A comprehensive analysis of the published data revealed that 3.1% of severe epilepsy cases carry a pathogenic de novo mutation within STXBP1. By contrast, ASD was rarely associated with mutations in this gene in our large cohorts.Conclusions:STXBP1 mutations are an important cause of epilepsy and are also rarely associated with ASD. In a case with histologically proven FCD, an STXBP1 somatic mutation was identified, suggesting a role in its etiology. Removing such tissue may be curative for STXBP1-related epilepsy.

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Selection On synonymous Mutations Revealed by 1135 Genomes of Arabidopsis thaliana

Evolutionary Bioinformatics ◽

10.1177/1176934320916794 ◽

2020 ◽

Vol 16 ◽

pp. 117693432091679 ◽

Cited By ~ 4

Author(s):

Lai Wei

Keyword(s):

Arabidopsis Thaliana ◽

Synonymous Codon ◽

Natural Populations ◽

Gc Content ◽

Synonymous Codon Usage ◽

Genome Project ◽

Allele Frequencies ◽

Coding Region ◽

Synonymous Mutations ◽

Snp Data

Synonymous mutations do not change the amino acid but do change the synonymous codon usage. In genomes of different organisms, the gene conversion process is biased toward GC, which is irrespective of mutation bias. In the coding region, this trend is especially obvious and it is possibly caused by the preference on G/C-ending codons over the A/T-ending ones. If the G/C-ending codons are advantageous, then the synonymous mutations that change A/T to G/C would be “optimal” compared to the opposite ones. In theory, one should observe signals of positive selection on these optimal synonymous mutations. The recently released single-nucleotide polymorphism (SNP) data from the 1001 genome project of Arabidopsis thaliana provided researchers with an unprecedented opportunity to verify this assumption. I fully take advantage of the SNP data from 1,135 A thaliana lines and came to the conclusion that synonymous mutations in natural populations are not strictly neutral: the synonymous mutations that increase GC content (from A/T to G/C) tend to have higher derived allele frequencies (DAFs) and, therefore, are likely to be positively selected. My current study broadens our knowledge of the selection patterns of synonymous mutations and should be appealing to evolutionary biologists. One sentence summary: In 1135 genomes of Arabidopsis thaliana, the synonymous mutations that increase the GC content tend to have higher derived allele frequencies (DAFs) and are likely to be positively selected.

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

10.1101/108290 ◽

2017 ◽

Cited By ~ 10

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.

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High Mutation Frequency and Significant Population Differentiation in Papaya Ringspot Virus-W Isolates

Pathogens ◽

10.3390/pathogens10101278 ◽

2021 ◽

Vol 10 (10) ◽

pp. 1278

Author(s):

Vivek Khanal ◽

Akhtar Ali

Keyword(s):

Geographical Location ◽

Gc Content ◽

Purifying Selection ◽

Ringspot Virus ◽

Papaya Ringspot Virus ◽

Coding Region ◽

Minimal Impact ◽

High Mutation Frequency ◽

Cp Gene ◽

Mutational Hotspots

A total of 101 papaya ringspot virus-W (PRSV-W) isolates were collected from five different cucurbit hosts in six counties of Oklahoma during the 2016–2018 growing seasons. The coat protein (CP) coding region of these isolates was amplified by reverse transcription-polymerase chain reaction, and 370 clones (3–5 clones/isolate) were sequenced. Phylogenetic analysis revealed three phylogroups while host, location, and collection time of isolates had minimal impact on grouping pattern. When CP gene sequences of these isolates were compared with sequences of published PRSV isolates (both P and W strains), they clustered into four phylogroups based on geographical location. Oklahoman PRSV-W isolates formed one of the four distinct major phylogroups. The permutation-based tests, including Ks, Ks *, Z *, Snn, and neutrality tests, indicated significant genetic differentiation and polymorphisms among PRSV-W populations in Oklahoma. The selection analysis confirmed that the CP gene is undergoing purifying selection. The mutation frequencies among all PRSV-W isolates were within the range of 1 × 10−3. The substitution mutations in 370 clones of PRSV-W isolates showed a high proportion of transition mutations, which gave rise to higher GC content. The N-terminal region of the CP gene mostly contained the variable sites with numerous mutational hotspots, while the core region was highly conserved.

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De novo mutations in TOMM70, a receptor of the mitochondrial import translocase, cause neurological impairment

Human Molecular Genetics ◽

10.1093/hmg/ddaa081 ◽

2020 ◽

Vol 29 (9) ◽

pp. 1568-1579 ◽

Cited By ~ 1

Author(s):

Debdeep Dutta ◽

Lauren C Briere ◽

Oguz Kanca ◽

Paul C Marcogliese ◽

Melissa A Walker ◽

...

Keyword(s):

White Matter ◽

Protein Import ◽

De Novo ◽

Mitochondrial Protein ◽

Neurological Impairment ◽

Loss Of Function ◽

De Novo Mutations ◽

Coding Region ◽

Mitochondrial Protein Import ◽

Mitochondrial Proteome

Abstract The translocase of outer mitochondrial membrane (TOMM) complex is the entry gate for virtually all mitochondrial proteins and is essential to build the mitochondrial proteome. TOMM70 is a receptor that assists mainly in mitochondrial protein import. Here, we report two individuals with de novo variants in the C-terminal region of TOMM70. While both individuals exhibited shared symptoms including hypotonia, hyper-reflexia, ataxia, dystonia and significant white matter abnormalities, there were differences between the two individuals, most prominently the age of symptom onset. Both individuals were undiagnosed despite extensive genetics workups. Individual 1 was found to have a p.Thr607Ile variant while Individual 2 was found to have a p.Ile554Phe variant in TOMM70. To functionally assess both TOMM70 variants, we replaced the Drosophila Tom70 coding region with a Kozak-mini-GAL4 transgene using CRISPR-Cas9. Homozygous mutant animals die as pupae, but lethality is rescued by the mini-GAL4-driven expression of human UAS-TOMM70 cDNA. Both modeled variants lead to significantly less rescue indicating that they are loss-of-function alleles. Similarly, RNAi-mediated knockdown of Tom70 in the developing eye causes roughening and synaptic transmission defect, common findings in neurodegenerative and mitochondrial disorders. These phenotypes were rescued by the reference, but not the variants, of TOMM70. Altogether, our data indicate that de novo loss-of-function variants in TOMM70 result in variable white matter disease and neurological phenotypes in affected individuals.

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