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Nature Feb 2022Clustered somatic mutations are common in cancer genomes and previous analyses reveal several types of clustered single-base substitutions, which include doublet- and...
Clustered somatic mutations are common in cancer genomes and previous analyses reveal several types of clustered single-base substitutions, which include doublet- and multi-base substitutions, diffuse hypermutation termed omikli, and longer strand-coordinated events termed kataegis. Here we provide a comprehensive characterization of clustered substitutions and clustered small insertions and deletions (indels) across 2,583 whole-genome-sequenced cancers from 30 types of cancer. Clustered mutations were highly enriched in driver genes and associated with differential gene expression and changes in overall survival. Several distinct mutational processes gave rise to clustered indels, including signatures that were enriched in tobacco smokers and homologous-recombination-deficient cancers. Doublet-base substitutions were caused by at least 12 mutational processes, whereas most multi-base substitutions were generated by either tobacco smoking or exposure to ultraviolet light. Omikli events, which have previously been attributed to APOBEC3 activity, accounted for a large proportion of clustered substitutions; however, only 16.2% of omikli matched APOBEC3 patterns. Kataegis was generated by multiple mutational processes, and 76.1% of all kataegic events exhibited mutational patterns that are associated with the activation-induced deaminase (AID) and APOBEC3 family of deaminases. Co-occurrence of APOBEC3 kataegis and extrachromosomal DNA (ecDNA), termed kyklonas (Greek for cyclone), was found in 31% of samples with ecDNA. Multiple distinct kyklonic events were observed on most mutated ecDNA. ecDNA containing known cancer genes exhibited both positive selection and kyklonic hypermutation. Our results reveal the diversity of clustered mutational processes in human cancer and the role of APOBEC3 in recurrently mutating and fuelling the evolution of ecDNA.
Topics: APOBEC Deaminases; Genome; Humans; INDEL Mutation; Mutagenesis; Mutation; Neoplasms
PubMed: 35140399
DOI: 10.1038/s41586-022-04398-6 -
Scientific Reports Nov 2017Mutations are induced by not only intrinsic factors such as inherent molecular errors but also by extrinsic mutagenic factors such as UV radiation. Therefore,...
Mutations are induced by not only intrinsic factors such as inherent molecular errors but also by extrinsic mutagenic factors such as UV radiation. Therefore, identifying the mutational properties for both factors is necessary to achieve a comprehensive understanding of evolutionary processes both in nature and in artificial situations. Although there have been extensive studies on intrinsic factors, the mutational profiles of extrinsic factors are poorly understood on a genomic scale. Here, we explored the mutation profiles of UV radiation, a ubiquitous mutagen, in Escherichia coli on the genomic scale. We performed an evolution experiment under periodic UV radiation for 28 days. The accumulation speed of the mutations was found to increase so that it exceeded that of a typical mutator strain with deficient mismatch repair processes. The huge contribution of the extrinsic factors to all mutations consequently increased the risk of the destruction of inherent error correction systems. The spectrum of the UV-induced mutations was broader than that of the spontaneous mutations in the mutator. The broad spectrum and high upper limit of the frequency of occurrence suggested ubiquitous roles for UV radiation in accelerating the evolutionary process.
Topics: Escherichia coli; Mutation; Mutation Accumulation; Ultraviolet Rays
PubMed: 29109412
DOI: 10.1038/s41598-017-15008-1 -
Molecular Ecology Sep 2002Homoplasy has recently attracted the attention of population geneticists, as a consequence of the popularity of highly variable stepwise mutating markers such as... (Review)
Review
Homoplasy has recently attracted the attention of population geneticists, as a consequence of the popularity of highly variable stepwise mutating markers such as microsatellites. Microsatellite alleles generally refer to DNA fragments of different size (electromorphs). Electromorphs are identical in state (i.e. have identical size), but are not necessarily identical by descent due to convergent mutation(s). Homoplasy occurring at microsatellites is thus referred to as size homoplasy. Using new analytical developments and computer simulations, we first evaluate the effect of the mutation rate, the mutation model, the effective population size and the time of divergence between populations on size homoplasy at the within and between population levels. We then review the few experimental studies that used various molecular techniques to detect size homoplasious events at some microsatellite loci. The relationship between this molecularly accessible size homoplasy size and the actual amount of size homoplasy is not trivial, the former being considerably influenced by the molecular structure of microsatellite core sequences. In a third section, we show that homoplasy at microsatellite electromorphs does not represent a significant problem for many types of population genetics analyses realized by molecular ecologists, the large amount of variability at microsatellite loci often compensating for their homoplasious evolution. The situations where size homoplasy may be more problematic involve high mutation rates and large population sizes together with strong allele size constraints.
Topics: Biological Evolution; Genetic Markers; Genetics, Population; Microsatellite Repeats; Models, Genetic; Molecular Biology; Mutation
PubMed: 12207711
DOI: 10.1046/j.1365-294x.2002.01576.x -
Annual Review of Immunology Apr 2022Vertebrate immune systems suppress viral infection using both innate restriction factors and adaptive immunity. Viruses mutate to escape these defenses, driving hosts to... (Review)
Review
Vertebrate immune systems suppress viral infection using both innate restriction factors and adaptive immunity. Viruses mutate to escape these defenses, driving hosts to counterevolve to regain fitness. This cycle recurs repeatedly, resulting in an evolutionary arms race whose outcome depends on the pace and likelihood of adaptation by host and viral genes. Although viruses evolve faster than their vertebrate hosts, their proteins are subject to numerous functional constraints that impact the probability of adaptation. These constraints are globally defined by evolutionary landscapes, which describe the fitness and adaptive potential of all possible mutations. We review deep mutational scanning experiments mapping the evolutionary landscapes of both host and viral proteins engaged in arms races. For restriction factors and some broadly neutralizing antibodies, landscapes favor the host, which may help to level the evolutionary playing field against rapidly evolving viruses. We discuss the biophysical underpinnings of these landscapes and their therapeutic implications.
Topics: Animals; Biological Evolution; Humans; Mutation; Viral Proteins; Virus Diseases; Viruses
PubMed: 35080919
DOI: 10.1146/annurev-immunol-072621-084422 -
Experimental & Molecular Medicine Jul 2022Mutation signature analysis has been used to infer the contributions of various DNA mutagenic-repair events in individual cancer genomes. Here, we build a statistical...
Mutation signature analysis has been used to infer the contributions of various DNA mutagenic-repair events in individual cancer genomes. Here, we build a statistical framework using a multinomial distribution to assign individual mutations to their cognate mutation signatures. We applied it to 47 million somatic mutations in 1925 publicly available cancer genomes to obtain a mutation signature map at the resolution of individual somatic mutations. Based on mutation signature-level genetic-epigenetic correlative analyses, mutations with transcriptional and replicative strand asymmetries show different enrichment patterns across genomes, and "transcribed" chromatin states and gene boundaries are particularly vulnerable to transcription-coupled repair activities. While causative processes of cancer-driving mutations can be diverse, as shown for converging effects of multiple mutational processes on TP53 mutations, the substantial fraction of recurrently mutated amino acids points to specific mutational processes, e.g., age-related C-to-T transition for KRAS p.G12 mutations. Our investigation of evolutionary trajectories with respect to mutation signatures further revealed that candidate pairs of early- vs. late-operative mutation processes in cancer genomes represent evolutionary dynamics of multiple mutational processes in the shaping of cancer genomes. We also observed that the local mutation clusters of kataegis often include mutations arising from multiple mutational processes, suggestive of a locally synchronous impact of multiple mutational processes on cancer genomes. Taken together, our examination of the genome-wide landscape of mutation signatures at the resolution of individual somatic mutations shows the spatially and temporally distinct mutagenesis-repair-replication histories of various mutational processes and their effects on shaping cancer genomes.
Topics: DNA Repair; Genome, Human; Humans; Mutagenesis; Mutation; Neoplasms
PubMed: 35902761
DOI: 10.1038/s12276-022-00808-x -
BMC Evolutionary Biology Aug 2019Organisms are expected to respond to changing environmental conditions through local adaptation, range shift or local extinction. The process of local adaptation can...
BACKGROUND
Organisms are expected to respond to changing environmental conditions through local adaptation, range shift or local extinction. The process of local adaptation can occur by genetic changes or phenotypic plasticity, and becomes especially relevant when dispersal abilities or possibilities are somehow constrained. For genetic changes to occur, mutations are the ultimate source of variation and the mutation rate in terms of a mutator locus can be subject to evolutionary change. Recent findings suggest that the evolution of the mutation rate in a sexual species can advance invasion speed and promote adaptation to novel environmental conditions. Following this idea, this work uses an individual-based model approach to investigate if the mutation rate can also evolve in a sexual species experiencing different conditions of directional climate change, under different scenarios of colored stochastic environmental noise, probability of recombination and of beneficial mutations. The color of the noise mimicked investigating the evolutionary dynamics of the mutation rate in different habitats.
RESULTS
The results suggest that the mutation rate in a sexual species experiencing directional climate change scenarios can evolve and reach relatively high values mainly under conditions of complete linkage of the mutator locus and the adaptation locus. In contrast, when they are unlinked, the mutation rate can slightly increase only under scenarios where at least 50% of arising mutations are beneficial and the rate of environmental change is relatively fast. This result is robust under different scenarios of stochastic environmental noise, which supports the observation of no systematic variation in the mutation rate among organisms experiencing different habitats.
CONCLUSIONS
Given that 50% beneficial mutations may be an unrealistic assumption, and that recombination is ubiquitous in sexual species, the evolution of an elevated mutation rate in a sexual species experiencing directional climate change might be rather unlikely. Furthermore, when the percentage of beneficial mutations and the population size are small, sexual species (especially multicellular ones) producing few offspring may be expected to react to changing environments not by adaptive genetic change, but mainly through plasticity. Without the ability for a plastic response, such species may become - at least locally - extinct.
Topics: Adaptation, Physiological; Biological Evolution; Climate Change; Computer Simulation; Ecosystem; Extinction, Biological; Mutation; Mutation Rate; Population Density; Reproduction
PubMed: 31462290
DOI: 10.1186/s12862-019-1494-0 -
Genetics Dec 2017Different factors can influence the evolution of the mutation rate of a species: costs associated with DNA replication fidelity, indirect selection caused by the...
Different factors can influence the evolution of the mutation rate of a species: costs associated with DNA replication fidelity, indirect selection caused by the mutations produced (that should generally favor lower mutation rates, given that most mutations affecting fitness are deleterious), and genetic drift, which may render selection acting on weak mutators inefficient. In this paper, we use a two-locus model to compute the strength of indirect selection acting on a modifier locus that affects the mutation rate toward a deleterious allele at a second, linked, locus, in a population undergoing partial selfing or partial clonality. The results show that uniparental reproduction increases the effect of indirect selection for lower mutation rates. Extrapolating to the case of a whole genome with many deleterious alleles, and introducing a direct cost to DNA replication fidelity, the results can be used to compute the evolutionarily stable mutation rate, In the absence of mutational bias toward higher , the analytical prediction fits well with individual-based, multilocus simulation results. When such a bias is added into the simulations, however, genetic drift may lead to the maintenance of higher mutation rates, and this effect may be amplified in highly selfing or highly clonal populations due to their reduced effective population size.
Topics: Alleles; DNA Replication; Evolution, Molecular; Genetic Drift; Genetics, Population; Models, Genetic; Mutation; Mutation Rate; Reproduction, Asexual; Selection, Genetic
PubMed: 28971958
DOI: 10.1534/genetics.117.300346 -
Genomics Jan 2009The availability of the human genome sequence and progress in sequencing and bioinformatic technologies have enabled genome-wide investigation of somatic mutations in... (Review)
Review
The availability of the human genome sequence and progress in sequencing and bioinformatic technologies have enabled genome-wide investigation of somatic mutations in human cancers. This article briefly reviews challenges arising in the statistical analysis of mutational data of this kind. A first challenge is that of designing studies that efficiently allocate sequencing resources. We show that this can be addressed by two-stage designs and demonstrate via simulations that even relatively small studies can produce lists of candidate cancer genes that are highly informative for future research efforts. A second challenge is to distinguish mutated genes that are selected for by cancer (drivers) from mutated genes that have no role in the development of cancer and simply happened to mutate (passengers). We suggest that this question is best approached as a classification problem and discuss some of the difficulties of more traditional testing-based approaches. A third challenge is to identify biologic processes affected by the driver genes. This can be pursued by gene set analyses. These can reliably identify functional groups and pathways that are enriched for mutated genes even when the individual genes involved in those pathways or sets are not mutated at sufficient frequencies to provide conclusive evidence as drivers.
Topics: DNA Mutational Analysis; Genes, Neoplasm; Genome, Human; Genomics; Humans; Mutation; Neoplasm Proteins; Neoplasms
PubMed: 18692126
DOI: 10.1016/j.ygeno.2008.07.005 -
G3 (Bethesda, Md.) Aug 2020The mutation rate and mutations' effects on fitness are crucial to evolution. Mutation rates are under selection due to linkage between mutation rate modifiers and...
The mutation rate and mutations' effects on fitness are crucial to evolution. Mutation rates are under selection due to linkage between mutation rate modifiers and mutations' effects on fitness. The linkage between a higher mutation rate and more beneficial mutations selects for higher mutation rates, while the linkage between a higher mutation rate and more deleterious mutations selects for lower mutation rates. The net direction of selection on mutations rates depends on the fitness landscape, and a great deal of work has elucidated the fitness landscapes of mutations. However, tests of the effect of varying a mutation rate on evolution in a single organism in a single environment have been difficult. This has been studied using strains of antimutators and mutators, but these strains may differ in additional ways and typically do not allow for continuous variation of the mutation rate. To help investigate the effects of the mutation rate on evolution, we have genetically engineered a strain of with a point mutation rate that can be smoothly varied over two orders of magnitude. We did this by engineering a strain with inducible control of the mismatch repair proteins MutH and MutL. We used this strain in an approximately 350 generation evolution experiment with controlled variation of the mutation rate. We confirmed the construct and the mutation rate were stable over this time. Sequencing evolved strains revealed a higher number of single nucleotide polymorphisms at higher mutations rates, likely due to either the beneficial effects of these mutations or their linkage to beneficial mutations.
Topics: Escherichia coli; Escherichia coli Proteins; Mutation; Mutation Rate; Point Mutation; Selection, Genetic
PubMed: 32503807
DOI: 10.1534/g3.120.401124 -
Nature Communications Jun 2021What determines the rate (μ) and molecular spectrum of mutation is a fundamental question. The prevailing hypothesis asserts that natural selection against deleterious...
What determines the rate (μ) and molecular spectrum of mutation is a fundamental question. The prevailing hypothesis asserts that natural selection against deleterious mutations has pushed μ to the minimum achievable in the presence of genetic drift, or the drift barrier. Here we show that, contrasting this hypothesis, μ substantially exceeds the drift barrier in diverse organisms. Random mutation accumulation (MA) in yeast frequently reduces μ, and deleting the newly discovered mutator gene PSP2 nearly halves μ. These results, along with a comparison between the MA and natural yeast strains, demonstrate that μ is maintained above the drift barrier by stabilizing selection. Similar comparisons show that the mutation spectrum such as the universal AT mutational bias is not intrinsic but has been selectively preserved. These findings blur the separation of mutation from selection as distinct evolutionary forces but open the door to alleviating mutagenesis in various organisms by genome editing.
Topics: Genetic Drift; Models, Genetic; Mutation Accumulation; Mutation Rate; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Selection, Genetic; Whole Genome Sequencing
PubMed: 34193872
DOI: 10.1038/s41467-021-24364-6