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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 -
Nature Genetics Oct 2023Mosaic chromosomal alterations (mCAs) are common in cancers and can arise decades before diagnosis. A quantitative understanding of the rate at which these events occur,...
Mosaic chromosomal alterations (mCAs) are common in cancers and can arise decades before diagnosis. A quantitative understanding of the rate at which these events occur, and their functional consequences, could improve cancer risk prediction and our understanding of somatic evolution. Using mCA clone size estimates from the blood of approximately 500,000 UK Biobank participants, we estimate mutation rates and fitness consequences of acquired gain, loss and copy-neutral loss of heterozygosity events. Most mCAs have moderate to high fitness effects but occur at a low rate, being more than tenfold less common than equivalently fit single-nucleotide variants. Notable exceptions are mosaic loss of X and Y, which we estimate have roughly 1,000-fold higher mutation rates than autosomal mCAs. Although the way in which most mCAs increase in prevalence with age is consistent with constant growth rates, some mCAs exhibit different behavior, suggesting that their fitness may depend on inherited variants, extrinsic factors or distributions of fitness effects.
Topics: Humans; Male; Mutation Rate; Chromosomes, Human, Y; Mosaicism; Chromosomes; Neoplasms; Mutation
PubMed: 37697102
DOI: 10.1038/s41588-023-01490-z -
Heredity Nov 2014Because genes that affect mutation rates are themselves subject to mutation, mutation rates can be influenced by natural selection and other evolutionary forces. The... (Review)
Review
Because genes that affect mutation rates are themselves subject to mutation, mutation rates can be influenced by natural selection and other evolutionary forces. The population genetics of mutation rate modifier alleles has been a subject of theoretical interest for many decades. Here, we review experimental contributions to our understanding of mutation rate modifier dynamics. Numerous evolution experiments have shown that mutator alleles (modifiers that elevate the genomic mutation rate) can readily rise to high frequencies via genetic hitchhiking in non-recombining microbial populations. Whereas these results certainly provide an explanatory framework for observations of sporadically high mutation rates in pathogenic microbes and in cancer lineages, it is nonetheless true that most natural populations have very low mutation rates. This raises the interesting question of how mutator hitchhiking is suppressed or its phenotypic effect reversed in natural populations. Very little experimental work has addressed this question; with this in mind, we identify some promising areas for future experimental investigation.
Topics: Alleles; Escherichia coli; Evolution, Molecular; Genetics, Population; Models, Genetic; Mutation Rate
PubMed: 24849169
DOI: 10.1038/hdy.2014.49 -
Molecular Ecology Jun 2021A key step in understanding the genetic basis of different evolutionary outcomes (e.g., adaptation) is to determine the roles played by different mutation types (e.g.,... (Review)
Review
A key step in understanding the genetic basis of different evolutionary outcomes (e.g., adaptation) is to determine the roles played by different mutation types (e.g., SNPs, translocations and inversions). To do this we must simultaneously consider different mutation types in an evolutionary framework. Here, we propose a research framework that directly utilizes the most important characteristics of mutations, their population genetic effects, to determine their relative evolutionary significance in a given scenario. We review known population genetic effects of different mutation types and show how these may be connected to different evolutionary outcomes. We provide examples of how to implement this framework and pinpoint areas where more data, theory and synthesis are needed. Linking experimental and theoretical approaches to examine different mutation types simultaneously is a critical step towards understanding their evolutionary significance.
Topics: Adaptation, Physiological; Biological Evolution; Chromosome Inversion; Genetics, Population; Models, Genetic; Mutation; Mutation Rate; Population Density; Selection, Genetic
PubMed: 33955064
DOI: 10.1111/mec.15936 -
Current Biology : CB Oct 2018Mutation rate variation is often explained by varying optimal rates, or through effective population sizes determining the effectiveness of selection. But a rate... (Review)
Review
Mutation rate variation is often explained by varying optimal rates, or through effective population sizes determining the effectiveness of selection. But a rate difference between humans and owl monkeys is now explained mechanistically as a consequence of differing reproductive longevities.
Topics: Animals; Aotidae; Genetic Fitness; Humans; Longevity; Mutation; Mutation Rate; Population Density
PubMed: 30300601
DOI: 10.1016/j.cub.2018.07.067 -
Annual Review of Genetics Nov 2023The ciliate genus served as one of the first model systems in microbial eukaryotic genetics, contributing much to the early understanding of phenomena as diverse as... (Review)
Review
The ciliate genus served as one of the first model systems in microbial eukaryotic genetics, contributing much to the early understanding of phenomena as diverse as genome rearrangement, cryptic speciation, cytoplasmic inheritance, and endosymbiosis, as well as more recently to the evolution of mating types, introns, and roles of small RNAs in DNA processing. Substantial progress has recently been made in the area of comparative and population genomics. species combine some of the lowest known mutation rates with some of the largest known effective populations, along with likely very high recombination rates, thereby harboring a population-genetic environment that promotes an exceptionally efficient capacity for selection. As a consequence, the genomes are extraordinarily streamlined, with very small intergenic regions combined with small numbers of tiny introns. The subject of the bulk of research, the ancient species complex, is descended from two whole-genome duplication events that retain high degrees of synteny, thereby providing an exceptional platform for studying the fates of duplicate genes. Despite having a common ancestor dating to several hundred million years ago, the known descendant species are morphologically indistinguishable, raising significant questions about the common view that gene duplications lead to the origins of evolutionary novelties.
Topics: Paramecium; Evolution, Molecular; Genomics; Genome; Mutation Rate
PubMed: 38012024
DOI: 10.1146/annurev-genet-071819-104035 -
EMBO Reports Oct 2023Owing to advances in genome sequencing, genome stability has become one of the most scrutinized cellular traits across the Tree of Life. Despite its centrality to all... (Review)
Review
Owing to advances in genome sequencing, genome stability has become one of the most scrutinized cellular traits across the Tree of Life. Despite its centrality to all things biological, the mutation rate (per nucleotide site per generation) ranges over three orders of magnitude among species and several-fold within individual phylogenetic lineages. Within all major organismal groups, mutation rates scale negatively with the effective population size of a species and with the amount of functional DNA in the genome. This relationship is most parsimoniously explained by the drift-barrier hypothesis, which postulates that natural selection typically operates to reduce mutation rates until further improvement is thwarted by the power of random genetic drift. Despite this constraint, the molecular mechanisms underlying DNA replication fidelity and repair are free to wander, provided the performance of the entire system is maintained at the prevailing level. The evolutionary flexibility of the mutation rate bears on the resolution of several prior conundrums in phylogenetic and population-genetic analysis and raises challenges for future applications in these areas.
Topics: Mutation Rate; Phylogeny; Genetic Drift; Biological Evolution; Selection, Genetic; Mutation; Evolution, Molecular
PubMed: 37615267
DOI: 10.15252/embr.202357561 -
Genome Biology and Evolution Nov 2023Germline mutations are the ultimate source of genetic variation and the raw material for organismal evolution. Despite their significance, the frequency and genomic...
Germline mutations are the ultimate source of genetic variation and the raw material for organismal evolution. Despite their significance, the frequency and genomic locations of mutations, as well as potential sex bias, are yet to be widely investigated in most species. To address these gaps, we conducted whole-genome sequencing of 12 great reed warblers (Acrocephalus arundinaceus) in a pedigree spanning 3 generations to identify single-nucleotide de novo mutations (DNMs) and estimate the germline mutation rate. We detected 82 DNMs within the pedigree, primarily enriched at CpG sites but otherwise randomly located along the chromosomes. Furthermore, we observed a pronounced sex bias in DNM occurrence, with male warblers exhibiting three times more mutations than females. After correction for false negatives and adjusting for callable sites, we obtained a mutation rate of 7.16 × 10-9 mutations per site per generation (m/s/g) for the autosomes and 5.10 × 10-9 m/s/g for the Z chromosome. To demonstrate the utility of species-specific mutation rates, we applied our autosomal mutation rate in models reconstructing the demographic history of the great reed warbler. We uncovered signs of drastic population size reductions predating the last glacial period (LGP) and reduced gene flow between western and eastern populations during the LGP. In conclusion, our results provide one of the few direct estimates of the mutation rate in wild songbirds and evidence for male-driven mutations in accordance with theoretical expectations.
Topics: Animals; Female; Male; Songbirds; Germ-Line Mutation; Genome; Sex Chromosomes; Mutation; Mutation Rate
PubMed: 37793164
DOI: 10.1093/gbe/evad180 -
BMC Systems Biology Nov 2018Cancer is one of the leading causes for the morbidity and mortality worldwide. Although substantial studies have been conducted theoretically and experimentally in...
BACKGROUND
Cancer is one of the leading causes for the morbidity and mortality worldwide. Although substantial studies have been conducted theoretically and experimentally in recent years, it is still a challenge to explore the mechanisms of cancer initiation and progression. The investigation for these problems is very important for the diagnosis of cancer diseases and development of treatment schemes.
RESULTS
To accurately describe the process of cancer initiation, we propose a new concept of gene initial mutation rate based on our recently designed mathematical model using the non-constant mutation rate. Unlike the widely-used average gene mutation rate that depends on the number of mutations, the gene initial mutation rate can be used to describe the initiation process of a single patient. In addition, we propose the instantaneous tumour doubling time that is a continuous function of time based on the non-constant mutation rate. Our proposed concepts are supported by the clinic data of seven patients with advanced pancreatic cancer. The regression results suggest that, compared with the average mutation rate, the estimated initial mutation rate has a larger value of correlation coefficient with the patient survival time. We also provide the estimated tumour size of these seven patients over time.
CONCLUSIONS
The proposed concepts can be used to describe the cancer initiation and progression for different patients more accurately. Since a quantitative understanding of cancer progression is important for clinical treatment, our proposed model and calculated results may provide insights into the development of treatment schemes and also have other clinic implications.
Topics: Carcinogenesis; Cell Proliferation; Disease Progression; Humans; Models, Biological; Mutation Rate; Neoplasm Metastasis
PubMed: 30463617
DOI: 10.1186/s12918-018-0629-z -
Genetics Apr 2022The statistical associations between mutations, collectively known as linkage disequilibrium, encode important information about the evolutionary forces acting within a...
The statistical associations between mutations, collectively known as linkage disequilibrium, encode important information about the evolutionary forces acting within a population. Yet in contrast to single-site analogues like the site frequency spectrum, our theoretical understanding of linkage disequilibrium remains limited. In particular, little is currently known about how mutations with different ages and fitness costs contribute to expected patterns of linkage disequilibrium, even in simple settings where recombination and genetic drift are the major evolutionary forces. Here, I introduce a forward-time framework for predicting linkage disequilibrium between pairs of neutral and deleterious mutations as a function of their present-day frequencies. I show that the dynamics of linkage disequilibrium become much simpler in the limit that mutations are rare, where they admit a simple heuristic picture based on the trajectories of the underlying lineages. I use this approach to derive analytical expressions for a family of frequency-weighted linkage disequilibrium statistics as a function of the recombination rate, the frequency scale, and the additive and epistatic fitness costs of the mutations. I find that the frequency scale can have a dramatic impact on the shapes of the resulting linkage disequilibrium curves, reflecting the broad range of time scales over which these correlations arise. I also show that the differences between neutral and deleterious linkage disequilibrium are not purely driven by differences in their mutation frequencies and can instead display qualitative features that are reminiscent of epistasis. I conclude by discussing the implications of these results for recent linkage disequilibrium measurements in bacteria. This forward-time approach may provide a useful framework for predicting linkage disequilibrium across a range of evolutionary scenarios.
Topics: Biological Evolution; Genetic Drift; Linkage Disequilibrium; Models, Genetic; Mutation; Mutation Rate; Selection, Genetic
PubMed: 35100407
DOI: 10.1093/genetics/iyac004