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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 Opinion in Genetics &... Dec 2016The germline mutation rate has long been a major source of uncertainty in human evolutionary and demographic analyses based on genetic data, but estimates have improved... (Review)
Review
The germline mutation rate has long been a major source of uncertainty in human evolutionary and demographic analyses based on genetic data, but estimates have improved substantially in recent years. I discuss our current knowledge of the mutation rate in humans and the underlying biological factors affecting it, which include generation time, parental age and other developmental and reproductive timescales. There is good evidence for a slowdown in mean mutation rate during great ape evolution, but not for a more recent change within the timescale of human genetic diversity. Hence, pending evidence to the contrary, it is reasonable to use a present-day rate of approximately 0.5×10bpyear in all human or hominin demographic analyses.
Topics: Animals; Demography; Evolution, Molecular; Genetic Variation; Germ-Line Mutation; Hominidae; Humans; Mutation Rate
PubMed: 27589081
DOI: 10.1016/j.gde.2016.07.008 -
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 -
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 -
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 -
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 -
Molecular Biology and Evolution Sep 2023Mutation rate is a fundamental parameter in population genetics. Apart from being an important scaling parameter for demographic and phylogenetic inference, it allows...
Mutation rate is a fundamental parameter in population genetics. Apart from being an important scaling parameter for demographic and phylogenetic inference, it allows one to understand at what rate new genetic diversity is generated and what the expected level of genetic diversity is in a population at equilibrium. However, except for well-established model organisms, accurate estimates of de novo mutation rates are available for a very limited number of organisms from the wild. We estimated mutation rates (µ) in two marine populations of the nine-spined stickleback (Pungitius pungitius) with the aid of several 2- and 3-generational family pedigrees, deep (>50×) whole-genome resequences and a high-quality reference genome. After stringent filtering, we discovered 308 germline mutations in 106 offspring translating to µ = 4.83 × 10-9 and µ = 4.29 × 10-9 per base per generation in the two populations, respectively. Up to 20% of the mutations were shared by full-sibs showing that the level of parental mosaicism was relatively high. Since the estimated µ was 3.1 times smaller than the commonly used substitution rate, recalibration with µ led to substantial increase in estimated divergence times between different stickleback species. Our estimates of the de novo mutation rate should provide a useful resource for research focused on fish population genetics and that of sticklebacks in particular.
Topics: Animals; Smegmamorpha; Mutation Rate; Phylogeny; Mutation; Germ-Line Mutation
PubMed: 37648662
DOI: 10.1093/molbev/msad192 -
The American Naturalist Oct 2023AbstractThe joint distribution of selection coefficients and mutation rates is a key determinant of the genetic architecture of molecular adaptation. Three different...
AbstractThe joint distribution of selection coefficients and mutation rates is a key determinant of the genetic architecture of molecular adaptation. Three different distributions are of immediate interest: (1) the "nominal" distribution of possible changes, prior to mutation or selection; (2) the "de novo" distribution of realized mutations; and (3) the "fixed" distribution of selectively established mutations. Here, we formally characterize the relationships between these joint distributions under the strong-selection/weak-mutation (SSWM) regime. The de novo distribution is enriched relative to the nominal distribution for the highest rate mutations, and the fixed distribution is further enriched for the most highly beneficial mutations. Whereas mutation rates and selection coefficients are often assumed to be uncorrelated, we show that even with no correlation in the nominal distribution, the resulting de novo and fixed distributions can have correlations with any combination of signs. Nonetheless, we suggest that natural systems with a finite number of beneficial mutations will frequently have the kind of nominal distribution that induces negative correlations in the fixed distribution. We apply our mathematical framework, along with population simulations, to explore joint distributions of selection coefficients and mutation rates from deep mutational scanning and cancer informatics. Finally, we consider the evolutionary implications of these joint distributions together with two additional joint distributions relevant to parallelism and the rate of adaptation.
Topics: Mutation Rate; Selection, Genetic; Models, Genetic; Mutation; Biological Evolution; Evolution, Molecular
PubMed: 37792926
DOI: 10.1086/726014 -
BioEssays : News and Reviews in... Feb 2024Although random mutation is central to models of evolutionary change, a lack of clarity remains regarding the conceptual possibilities for thinking about the nature and...
Although random mutation is central to models of evolutionary change, a lack of clarity remains regarding the conceptual possibilities for thinking about the nature and role of mutation in evolution. We distinguish several claims at the intersection of mutation, evolution, and directionality and then characterize a previously unrecognized category: complex conditioned mutation. Empirical evidence in support of this category suggests that the historically famous fluctuation test should be revisited, and new experiments should be undertaken with emerging experimental techniques to facilitate detecting mutation rates within specific loci at an ultra-high, individual base pair resolution.
Topics: Mutation; Mutation Rate; Research Design
PubMed: 38254311
DOI: 10.1002/bies.202300025 -
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