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Cellular and Molecular Life Sciences :... Dec 2016The remarkable capacity of some viruses to adapt to new hosts and environments is highly dependent on their ability to generate de novo diversity in a short period of... (Review)
Review
The remarkable capacity of some viruses to adapt to new hosts and environments is highly dependent on their ability to generate de novo diversity in a short period of time. Rates of spontaneous mutation vary amply among viruses. RNA viruses mutate faster than DNA viruses, single-stranded viruses mutate faster than double-strand virus, and genome size appears to correlate negatively with mutation rate. Viral mutation rates are modulated at different levels, including polymerase fidelity, sequence context, template secondary structure, cellular microenvironment, replication mechanisms, proofreading, and access to post-replicative repair. Additionally, massive numbers of mutations can be introduced by some virus-encoded diversity-generating elements, as well as by host-encoded cytidine/adenine deaminases. Our current knowledge of viral mutation rates indicates that viral genetic diversity is determined by multiple virus- and host-dependent processes, and that viral mutation rates can evolve in response to specific selective pressures.
Topics: Genome, Viral; Mutation; Mutation Rate; Recombination, Genetic; Virus Replication; Viruses
PubMed: 27392606
DOI: 10.1007/s00018-016-2299-6 -
Cell Nov 2017Cancer develops as a result of somatic mutation and clonal selection, but quantitative measures of selection in cancer evolution are lacking. We adapted methods from...
Cancer develops as a result of somatic mutation and clonal selection, but quantitative measures of selection in cancer evolution are lacking. We adapted methods from molecular evolution and applied them to 7,664 tumors across 29 cancer types. Unlike species evolution, positive selection outweighs negative selection during cancer development. On average, <1 coding base substitution/tumor is lost through negative selection, with purifying selection almost absent outside homozygous loss of essential genes. This allows exome-wide enumeration of all driver coding mutations, including outside known cancer genes. On average, tumors carry ∼4 coding substitutions under positive selection, ranging from <1/tumor in thyroid and testicular cancers to >10/tumor in endometrial and colorectal cancers. Half of driver substitutions occur in yet-to-be-discovered cancer genes. With increasing mutation burden, numbers of driver mutations increase, but not linearly. We systematically catalog cancer genes and show that genes vary extensively in what proportion of mutations are drivers versus passengers.
Topics: Humans; INDEL Mutation; Microsatellite Instability; Models, Genetic; Mutation Rate; Neoplasms; Point Mutation; Polymorphism, Single Nucleotide; Selection, Genetic
PubMed: 29056346
DOI: 10.1016/j.cell.2017.09.042 -
PLoS Genetics Oct 2019Viral quasispecies refers to a population structure that consists of extremely large numbers of variant genomes, termed mutant spectra, mutant swarms or mutant clouds....
Viral quasispecies refers to a population structure that consists of extremely large numbers of variant genomes, termed mutant spectra, mutant swarms or mutant clouds. Fueled by high mutation rates, mutants arise continually, and they change in relative frequency as viral replication proceeds. The term quasispecies was adopted from a theory of the origin of life in which primitive replicons) consisted of mutant distributions, as found experimentally with present day RNA viruses. The theory provided a new definition of wild type, and a conceptual framework for the interpretation of the adaptive potential of RNA viruses that contrasted with classical studies based on consensus sequences. Standard clonal analyses and deep sequencing methodologies have confirmed the presence of myriads of mutant genomes in viral populations, and their participation in adaptive processes. The quasispecies concept applies to any biological entity, but its impact is more evident when the genome size is limited and the mutation rate is high. This is the case of the RNA viruses, ubiquitous in our biosphere, and that comprise many important pathogens. In virology, quasispecies are defined as complex distributions of closely related variant genomes subjected to genetic variation, competition and selection, and that may act as a unit of selection. Despite being an integral part of their replication, high mutation rates have an upper limit compatible with inheritable information. Crossing such a limit leads to RNA virus extinction, a transition that is the basis of an antiviral design termed lethal mutagenesis.
Topics: Evolution, Molecular; High-Throughput Nucleotide Sequencing; Mutation Rate; Origin of Life; Quasispecies; RNA Viruses; Viral Vaccines; Virus Replication
PubMed: 31622336
DOI: 10.1371/journal.pgen.1008271 -
Genome Research Nov 2018Numerous large-scale genomic studies of matched tumor-normal samples have established the somatic landscapes of most cancer types. However, the downstream analysis of...
Numerous large-scale genomic studies of matched tumor-normal samples have established the somatic landscapes of most cancer types. However, the downstream analysis of data from somatic mutations entails a number of computational and statistical approaches, requiring usage of independent software and numerous tools. Here, we describe an R Bioconductor package, Maftools, which offers a multitude of analysis and visualization modules that are commonly used in cancer genomic studies, including driver gene identification, pathway, signature, enrichment, and association analyses. Maftools only requires somatic variants in Mutation Annotation Format (MAF) and is independent of larger alignment files. With the implementation of well-established statistical and computational methods, Maftools facilitates data-driven research and comparative analysis to discover novel results from publicly available data sets. In the present study, using three of the well-annotated cohorts from The Cancer Genome Atlas (TCGA), we describe the application of Maftools to reproduce known results. More importantly, we show that Maftools can also be used to uncover novel findings through integrative analysis.
Topics: Clonal Evolution; Humans; Mutation Rate; Neoplasms; Sequence Analysis, DNA; Software
PubMed: 30341162
DOI: 10.1101/gr.239244.118 -
The New Phytologist Feb 2019Contents Summary 1253 I. Introduction 1253 II. What is the rate and molecular spectrum of spontaneous epimutations? 1254 III. Do spontaneous epimutations have phenotypic... (Review)
Review
Contents Summary 1253 I. Introduction 1253 II. What is the rate and molecular spectrum of spontaneous epimutations? 1254 III. Do spontaneous epimutations have phenotypic consequences? 1257 IV. Conclusion and discussion 1258 Acknowledgements 1258 References 1258 SUMMARY: Heritable gains or losses of cytosine methylation can arise stochastically in plant genomes independently of DNA sequence changes. These so-called 'spontaneous epimutations' appear to be a byproduct of imperfect DNA methylation maintenance and epigenome reinforcement events that occur in specialized cell types. There is continued interest in the plant epigenetics community in trying to understand the broader implications of these stochastic events, as some have been shown to induce heritable gene expression changes, shape patterns of methylation diversity within and among plant populations, and appear to be responsive to multi-generational environmental stressors. In this paper we synthesized our current knowledge of the molecular basis and functional consequences of spontaneous epimutations in plants, discuss technical and conceptual challenges, and highlight emerging research directions.
Topics: Epigenesis, Genetic; Genetic Loci; Mutation; Mutation Rate; Phenotype; Plants
PubMed: 30216456
DOI: 10.1111/nph.15434 -
Signal Transduction and Targeted Therapy Aug 2022
Topics: Longevity; Mutation Rate
PubMed: 35961971
DOI: 10.1038/s41392-022-01122-8 -
Current Opinion in Genetics &... Jun 2020Germline mutations are the source of all heritable variation. In the past few years, whole genome sequencing has allowed direct and comprehensive surveys of mutation... (Review)
Review
Germline mutations are the source of all heritable variation. In the past few years, whole genome sequencing has allowed direct and comprehensive surveys of mutation patterns in humans and other species. These studies have documented substantial variation in both mutation rates and spectra across primates, the causes of which remain unclear. Here, we review what is currently known about mutation rates in primates, highlight the factors proposed to explain the variation across species, and discuss some implications of these findings on our understanding of the chronology of primate evolution and the process of mutagenesis.
Topics: Animals; Biological Evolution; Genome; Genomics; Mutation; Mutation Rate; Primates
PubMed: 32634682
DOI: 10.1016/j.gde.2020.05.028 -
Journal of Virology Jul 2018Many viruses evolve rapidly. This is due, in part, to their high mutation rates. Mutation rate estimates for over 25 viruses are currently available. Here, we review the... (Review)
Review
Many viruses evolve rapidly. This is due, in part, to their high mutation rates. Mutation rate estimates for over 25 viruses are currently available. Here, we review the population genetics of virus mutation rates. We specifically cover the topics of mutation rate estimation, the forces that drive the evolution of mutation rates, and how the optimal mutation rate can be context-dependent.
Topics: Evolution, Molecular; Humans; Mutation; Mutation Rate; Virus Replication; Viruses
PubMed: 29720522
DOI: 10.1128/JVI.01031-17 -
Journal of Theoretical Biology Sep 2023The cost of germline maintenance gives rise to a trade-off between lowering the deleterious mutation rate and investing in life history functions. Therefore, life...
The cost of germline maintenance gives rise to a trade-off between lowering the deleterious mutation rate and investing in life history functions. Therefore, life history and the mutation rate coevolve, but this coevolution is not well understood. We develop a mathematical model to analyse the evolution of resource allocation traits, which simultaneously affect life history and the deleterious mutation rate. First, we show that the invasion fitness of such resource allocation traits can be approximated by the basic reproductive number of the least-loaded class; the expected lifetime production of offspring without deleterious mutations born to individuals without deleterious mutations. Second, we apply the model to investigate (i) the coevolution of reproductive effort and germline maintenance and (ii) the coevolution of age-at-maturity and germline maintenance. This analysis provides two resource allocation predictions when exposure to environmental mutagens is higher. First, selection favours higher allocation to germline maintenance, even if it comes at the expense of life history functions, and leads to a shift in allocation towards reproduction rather than survival. Second, life histories tend to be faster, characterised by individuals with shorter lifespans and smaller body sizes at maturity. Our results suggest that mutation accumulation via the cost of germline maintenance can be a major force shaping life-history traits.
Topics: Humans; Mutation Rate; Basic Reproduction Number; Body Size; Life History Traits; Mutation Accumulation
PubMed: 37598761
DOI: 10.1016/j.jtbi.2023.111598 -
Molecular Biology and Evolution Aug 2021De novo mutations are central for evolution, since they provide the raw material for natural selection by regenerating genetic variation. However, studying de novo...
De novo mutations are central for evolution, since they provide the raw material for natural selection by regenerating genetic variation. However, studying de novo mutations is challenging and is generally restricted to model species, so we have a limited understanding of the evolution of the mutation rate and spectrum between closely related species. Here, we present a mutation accumulation (MA) experiment to study de novo mutation in the unicellular green alga Chlamydomonas incerta and perform comparative analyses with its closest known relative, Chlamydomonas reinhardtii. Using whole-genome sequencing data, we estimate that the median single nucleotide mutation (SNM) rate in C. incerta is μ = 7.6 × 10-10, and is highly variable between MA lines, ranging from μ = 0.35 × 10-10 to μ = 131.7 × 10-10. The SNM rate is strongly positively correlated with the mutation rate for insertions and deletions between lines (r > 0.97). We infer that the genomic factors associated with variation in the mutation rate are similar to those in C. reinhardtii, allowing for cross-prediction between species. Among these genomic factors, sequence context and complexity are more important than GC content. With the exception of a remarkably high C→T bias, the SNM spectrum differs markedly between the two Chlamydomonas species. Our results suggest that similar genomic and biological characteristics may result in a similar mutation rate in the two species, whereas the SNM spectrum has more freedom to diverge.
Topics: Base Composition; Chlamydomonas; Chlamydomonas reinhardtii; Mutation; Mutation Accumulation; Mutation Rate
PubMed: 33950243
DOI: 10.1093/molbev/msab140