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DNA Repair Sep 2019Cancer genome sequencing has revealed that somatic mutation rates vary substantially across the human genome and at scales from megabase-sized domains to individual... (Review)
Review
Cancer genome sequencing has revealed that somatic mutation rates vary substantially across the human genome and at scales from megabase-sized domains to individual nucleotides. Here we review recent work that has both revealed the major mutation biases that operate across the genome and the molecular mechanisms that cause them. The default mutation rate landscape in mammalian genomes results in active genes having low mutation rates because of a combination of factors that increase DNA repair: early DNA replication, transcription, active chromatin modifications and accessible chromatin. Therefore, either an increase in the global mutation rate or a redistribution of mutations from inactive to active DNA can increase the rate at which consequential mutations are acquired in active genes. Several environmental carcinogens and intrinsic mechanisms operating in tumor cells likely cause cancer by this second mechanism: by specifically increasing the mutation rate in active regions of the genome.
Topics: Chromatin; DNA; DNA Repair; Genome, Human; Humans; Mutation Rate; Neoplasms
PubMed: 31307927
DOI: 10.1016/j.dnarep.2019.102647 -
The New Phytologist Mar 2023Genetic mutations provide the heritable material for plant adaptation to their environments. At the same time, the environment can affect the mutation rate across plant... (Review)
Review
Genetic mutations provide the heritable material for plant adaptation to their environments. At the same time, the environment can affect the mutation rate across plant genomes. However, the extent to which environmental plasticity in mutation rates can facilitate or hinder adaptation remains a longstanding and unresolved question. Emerging discoveries of mechanisms affecting mutation rate variability provide opportunities to consider this question in a new light. Links between chromatin states, transposable elements, and DNA repair suggest cases of adaptive mutation rate plasticity could occur. Yet, numerous evolutionary and biological forces are expected to limit the impact of any such mutation rate plasticity on adaptive evolution. Persistent uncertainty about the significance of mutation rate plasticity on adaptation motivates new experimental and theoretical research relevant to understanding plant responses in changing environments.
Topics: Mutation Rate; Biological Evolution; Adaptation, Physiological; Mutation; Genome, Plant; Plants
PubMed: 36444532
DOI: 10.1111/nph.18640 -
Genes Mar 2023Mutation rate is a crucial parameter in evolutionary genetics. However, the mutation rate of most species as well as the extent to which the environment can alter the...
Mutation rate is a crucial parameter in evolutionary genetics. However, the mutation rate of most species as well as the extent to which the environment can alter the genome of multicellular organisms remain poorly understood. Here, we used parents-progeny sequencing to investigate the mutation rate and spectrum of the domestic silkworm () among normal and two temperature stress conditions (32 °C and 0 °C). The rate of single-nucleotide mutations in the normal temperature rearing condition was 0.41 × 10 (95% confidence interval, 0.33 × 10-0.49 × 10) per site per generation, which was up to 1.5-fold higher than in four previously studied insects. Moreover, the mutation rates of the silkworm under the stresses are significantly higher than in normal conditions. Furthermore, the mutation rate varies less in gene regions under normal and temperature stresses. Together, these findings expand the known diversity of the mutation rate among eukaryotes but also have implications for evolutionary analysis that assumes a constant mutation rate among species and environments.
Topics: Animals; Bombyx; Temperature; Mutation Rate; Insecta; Genome
PubMed: 36980921
DOI: 10.3390/genes14030649 -
Journal of Molecular Evolution Jun 2023Loss of heterozygosity (LOH) is a mitotic recombination event that converts heterozygous loci to homozygous loci. This mutation event is widespread in organisms that... (Review)
Review
Loss of heterozygosity (LOH) is a mitotic recombination event that converts heterozygous loci to homozygous loci. This mutation event is widespread in organisms that have asexual reproduction like budding yeasts, and is also an important and frequent mutation event in tumorigenesis. Mutation accumulation studies have demonstrated that LOH occurs at a rate higher than the point mutation rate, and can impact large portions of the genome. Laboratory evolution experiments of heterozygous yeasts have revealed that LOH often unmasks beneficial recessive alleles that can confer large fitness advantages. Here, I highlight advances in understanding dominance, fitness, and phenotypes in laboratory evolved heterozygous yeast strains. I discuss best practices for detecting LOH in intraspecific and interspecific evolved clones and populations. Utilizing heterozygous strain backgrounds in laboratory evolution experiments offers an opportunity to advance our understanding of this important mutation type in shaping adaptation and genome evolution in wild, domesticated, and clinical populations.
Topics: Saccharomyces cerevisiae; Mutation; Loss of Heterozygosity; Mutation Rate; Genome
PubMed: 36752826
DOI: 10.1007/s00239-022-10088-8 -
Current Genetics Aug 2016Over the last decade, mutation studies have grown in popularity due to the affordability and accessibility of whole genome sequencing. As the number of species in which... (Review)
Review
Over the last decade, mutation studies have grown in popularity due to the affordability and accessibility of whole genome sequencing. As the number of species in which spontaneous mutation has been directly estimated approaches 20 across two domains of life, questions arise over the repeatability of results in such experiments. Five species were identified in which duplicate mutation studies have been performed. Across these studies the difference in estimated spontaneous mutation rate is at most, weakly significant (p < 0.01). However, a highly significant (p < 10(-5)), threefold difference in the rate of insertions/deletions (indels) exists between two recent studies in Schizosaccharomyces pombe. Upon investigation of the ancestral genome sequence for both studies, a possible anti-mutator allele was identified. The observed variation in indel rate may imply that the use of indel markers, such as microsatellites, for the investigation of genetic diversity within and among populations may be inappropriate because of the assumption of uniform mutation rate within a species.
Topics: Evolution, Molecular; Genome, Fungal; Genomics; INDEL Mutation; Microsatellite Repeats; Mutation; Mutation Rate; Polymorphism, Single Nucleotide; Reproducibility of Results; Yeasts
PubMed: 26919990
DOI: 10.1007/s00294-016-0573-7 -
Nature Communications Aug 2022Ecological and demographic factors can significantly shape the evolution of microbial populations both directly and indirectly, as when changes in the effective...
Ecological and demographic factors can significantly shape the evolution of microbial populations both directly and indirectly, as when changes in the effective population size affect the efficiency of natural selection on the mutation rate. However, it remains unclear how rapidly the mutation-rate responds evolutionarily to the entanglement of ecological and population-genetic factors over time. Here, we directly assess the mutation rate and spectrum of Escherichia coli clones isolated from populations evolving in response to 1000 days of different transfer volumes and resource-replenishment intervals. The evolution of mutation rates proceeded rapidly in response to demographic and/or environmental changes, with substantial bidirectional shifts observed as early as 59 generations. These results highlight the remarkable rapidity by which mutation rates are shaped in asexual lineages in response to environmental and population-genetic forces, and are broadly consistent with the drift-barrier hypothesis for the evolution of mutation rates, while also highlighting situations in which mutator genotypes may be promoted by positive selection.
Topics: Escherichia coli; Genetics, Population; Genotype; Mutation Rate; Selection, Genetic
PubMed: 35963846
DOI: 10.1038/s41467-022-32353-6 -
Cells Jan 2024Driver mutations are considered the cornerstone of cancer initiation. They are defined as mutations that convey a competitive fitness advantage, and hence, their... (Review)
Review
Driver mutations are considered the cornerstone of cancer initiation. They are defined as mutations that convey a competitive fitness advantage, and hence, their mutation frequency in premalignant tissue is expected to exceed the basal mutation rate. In old terms, that translates to "the survival of the fittest" and implies that a selective process underlies the frequency of cancer driver mutations. In that sense, each tissue is its own niche that creates a molecular selective pressure that may favor the propagation of a mutation or not. At the heart of this stands one of the biggest riddles in cancer biology: the tissue-predisposition to cancer driver mutations. The frequency of cancer driver mutations among tissues is non-uniform: for instance, mutations in are particularly frequent in colorectal cancer, and 99% of chronic myeloid leukemia patients harbor the driver fusion mutation, which is rarely found in solid tumors. Here, we provide a mechanistic framework that aims to explain how tissue-specific features, ranging from epigenetic underpinnings to the expression of viral transposable elements, establish a molecular basis for selecting cancer driver mutations in a tissue-specific manner.
Topics: Humans; Precancerous Conditions; Disease Susceptibility; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mutation; Mutation Rate
PubMed: 38247798
DOI: 10.3390/cells13020106 -
PLoS Genetics Jun 2022Mutation rates are of key importance for understanding evolutionary processes and predicting their outcomes. Empirical mutation rate estimates are available for a number...
Mutation rates are of key importance for understanding evolutionary processes and predicting their outcomes. Empirical mutation rate estimates are available for a number of RNA viruses, but few are available for DNA viruses, which tend to have larger genomes. Whilst some viruses have very high mutation rates, lower mutation rates are expected for viruses with large genomes to ensure genome integrity. Alphabaculoviruses are insect viruses with large genomes and often have high levels of polymorphism, suggesting high mutation rates despite evidence of proofreading activity by the replication machinery. Here, we report an empirical estimate of the mutation rate per base per strand copying (s/n/r) of Autographa californica multiple nucleopolyhedrovirus (AcMNPV). To avoid biases due to selection, we analyzed mutations that occurred in a stable, non-functional genomic insert after five serial passages in Spodoptera exigua larvae. Our results highlight that viral demography and the stringency of mutation calling affect mutation rate estimates, and that using a population genetic simulation model to make inferences can mitigate the impact of these processes on estimates of mutation rate. We estimated a mutation rate of μ = 1×10-7 s/n/r when applying the most stringent criteria for mutation calling, and estimates of up to μ = 5×10-7 s/n/r when relaxing these criteria. The rates at which different classes of mutations accumulate provide good evidence for neutrality of mutations occurring within the inserted region. We therefore present a robust approach for mutation rate estimation for viruses with stable genomes, and strong evidence of a much lower alphabaculovirus mutation rate than supposed based on the high levels of polymorphism observed.
Topics: Animals; Mutation; Mutation Rate; Nucleopolyhedroviruses; Spodoptera
PubMed: 35666722
DOI: 10.1371/journal.pgen.1009806 -
Annual Review of Plant Biology May 2023Mutation is the source of all heritable diversity, the essential material of evolution and breeding. While mutation rates are often regarded as constant, variability in... (Review)
Review
Mutation is the source of all heritable diversity, the essential material of evolution and breeding. While mutation rates are often regarded as constant, variability in mutation rates has been observed at nearly every level-varying across mutation types, genome locations, gene functions, epigenomic contexts, environmental conditions, genotypes, and species. This mutation rate variation arises from differential rates of DNA damage, repair, and transposable element activation and insertion that together produce what is measured by DNA mutation rates. We review historical and recent investigations into the causes and consequences of mutation rate variability in plants by focusing on the mechanisms shaping this variation. Emerging mechanistic models point to the evolvability of mutation rate variation across genomes via mechanisms that target DNA repair, shaping the diversification of plants at phenotypic and genomic scales.
Topics: Mutation Rate; Plant Breeding; Mutation; Genome, Plant; Plants; DNA Transposable Elements; Evolution, Molecular
PubMed: 36889008
DOI: 10.1146/annurev-arplant-070522-054109 -
Molecular Biology and Evolution Apr 2023SARS-CoV-2 evolves rapidly in part because of its high mutation rate. Here, we examine whether this mutational process itself has changed during viral evolution. To do...
SARS-CoV-2 evolves rapidly in part because of its high mutation rate. Here, we examine whether this mutational process itself has changed during viral evolution. To do this, we quantify the relative rates of different types of single-nucleotide mutations at 4-fold degenerate sites in the viral genome across millions of human SARS-CoV-2 sequences. We find clear shifts in the relative rates of several types of mutations during SARS-CoV-2 evolution. The most striking trend is a roughly 2-fold decrease in the relative rate of G→T mutations in Omicron versus early clades, as was recently noted by Ruis et al. (2022. Mutational spectra distinguish SARS-CoV-2 replication niches. bioRxiv, doi:10.1101/2022.09.27.509649). There is also a decrease in the relative rate of C→T mutations in Delta, and other subtle changes in the mutation spectrum along the phylogeny. We speculate that these changes in the mutation spectrum could arise from viral mutations that affect genome replication, packaging, and antagonization of host innate-immune factors, although environmental factors could also play a role. Interestingly, the mutation spectrum of Omicron is more similar than that of earlier SARS-CoV-2 clades to the spectrum that shaped the long-term evolution of sarbecoviruses. Overall, our work shows that the mutation process is itself a dynamic variable during SARS-CoV-2 evolution and suggests that human SARS-CoV-2 may be trending toward a mutation spectrum more similar to that of other animal sarbecoviruses.
Topics: Animals; Humans; SARS-CoV-2; COVID-19; Mutation; Mutation Rate; Severe acute respiratory syndrome-related coronavirus; Genome, Viral
PubMed: 37039557
DOI: 10.1093/molbev/msad085