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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 -
Viruses Feb 2022Although variola virus (VARV) has been eradicated through widespread vaccination, other pathogenic for humans circulate in nature. Recently, new , including some able...
Although variola virus (VARV) has been eradicated through widespread vaccination, other pathogenic for humans circulate in nature. Recently, new , including some able to infect humans, have been found and their complete genomes have been sequenced. Questions about the mutation rate and the emergence of new threats to humankind as a result of the evolution of circulating remain open. Based on contemporary data on ancient VARV DNA and DNA of new species, an analysis of the molecular evolution of was carried out and the timescale of their emergence was estimated. It was calculated that the of the Old and New Worlds separated approximately 40,000 years ago; the recently discovered Akhmeta virus and Alaskapox virus separated from other approximately 10,000-20,000 years ago; the rest of modern orthopoxvirus species originated from 1700 to 6000 years ago, with the exception of VARV, which emerged in approximately 300 AD. Later, there was a separation of genetic variants of some species, so the monkeypox virus West African subtype originated approximately 600 years ago, and the VARV minor alastrim subtype emerged approximately 300 years ago.
Topics: Animals; Databases, Genetic; Evolution, Molecular; Mutation Rate; Orthopoxvirus; Phylogeny; Poxviridae Infections
PubMed: 35215981
DOI: 10.3390/v14020388 -
Genome Research Sep 2021Mutation is the source of genetic variation and the fundament of evolution. Temperature has long been suggested to have a direct impact on realized spontaneous mutation...
Mutation is the source of genetic variation and the fundament of evolution. Temperature has long been suggested to have a direct impact on realized spontaneous mutation rates. If mutation rates vary in response to environmental conditions, such as the variation of the ambient temperature through space and time, they should no longer be described as species-specific constants. By combining mutation accumulation with whole-genome sequencing in a multicellular organism, we provide empirical support to reject the null hypothesis of a constant, temperature-independent mutation rate. Instead, mutation rates depended on temperature in a U-shaped manner with increasing rates toward both temperature extremes. This relation has important implications for mutation-dependent processes in molecular evolution, processes shaping the evolution of mutation rates, and even the evolution of biodiversity as such.
Topics: Evolution, Molecular; Mutation; Mutation Accumulation; Mutation Rate; Temperature
PubMed: 34301628
DOI: 10.1101/gr.275168.120 -
Viruses Sep 2021The error rate displayed during template copying to produce viral RNA progeny is a biologically relevant parameter of the replication complexes of viruses. It has... (Review)
Review
The error rate displayed during template copying to produce viral RNA progeny is a biologically relevant parameter of the replication complexes of viruses. It has consequences for virus-host interactions, and it represents the first step in the diversification of viruses in nature. Measurements during infections and with purified viral polymerases indicate that mutation rates for RNA viruses are in the range of 10 to 10 copying errors per nucleotide incorporated into the nascent RNA product. Although viruses are thought to exploit high error rates for adaptation to changing environments, some of them possess misincorporation correcting activities. One of them is a proofreading-repair 3' to 5' exonuclease present in coronaviruses that may decrease the error rate during replication. Here we review experimental evidence and models of information maintenance that explain why elevated mutation rates have been preserved during the evolution of RNA (and some DNA) viruses. The models also offer an interpretation of why error correction mechanisms have evolved to maintain the stability of genetic information carried out by large viral RNA genomes such as the coronaviruses.
Topics: Animals; Biological Evolution; Coronavirus; Exonucleases; Genetic Variation; Genome, Viral; Humans; Mutation; Mutation Rate; RNA Virus Infections; RNA Viruses; RNA, Viral; Virus Replication
PubMed: 34578463
DOI: 10.3390/v13091882 -
Evolution; International Journal of... Mar 2022Mutation accumulation (MA) experiments, in which de novo mutations are sampled and subsequently characterized, are an essential tool in understanding the processes...
Mutation accumulation (MA) experiments, in which de novo mutations are sampled and subsequently characterized, are an essential tool in understanding the processes underlying evolution. In microbial populations, MA protocols typically involve a period of population growth between severe bottlenecks, such that a single individual can form a visible colony. While it has long been appreciated that the action of positive selection during this growth phase cannot be eliminated, it is typically assumed to be negligible. Here, we quantify the effect of both positive and negative selection in MA studies, demonstrating that selective effects can substantially bias the distribution of fitness effects (DFE) and mutation rates estimated from typical MA protocols in microbes. We then present a simple correction for this bias that applies to both beneficial and deleterious mutations, and can be used to correct the observed DFE in multiple environments. We use simulated MA experiments to illustrate the extent to which the MA-inferred DFE differs from the underlying true DFE, and demonstrate that the proposed correction accurately reconstructs the true DFE over a wide range of scenarios; we also provide an example of these corrections applied to experimental data. These results highlight that positive selection during microbial MA experiments is in fact not negligible, but can be corrected to gain a more accurate understanding of fundamental evolutionary parameters.
Topics: Genetic Fitness; Mutation; Mutation Accumulation; Mutation Rate; Selection Bias; Selection, Genetic
PubMed: 34989408
DOI: 10.1111/evo.14430 -
DNA Repair Sep 2019
Topics: Animals; Bacteria; DNA Repair; Eukaryota; Genomic Instability; Humans; Mutagenesis; Mutation Rate
PubMed: 31427173
DOI: 10.1016/j.dnarep.2019.102677 -
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 -
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 -
PLoS Computational Biology Jul 2023Stochastic models of sequential mutation acquisition are widely used to quantify cancer and bacterial evolution. Across manifold scenarios, recurrent research questions...
Stochastic models of sequential mutation acquisition are widely used to quantify cancer and bacterial evolution. Across manifold scenarios, recurrent research questions are: how many cells are there with n alterations, and how long will it take for these cells to appear. For exponentially growing populations, these questions have been tackled only in special cases so far. Here, within a multitype branching process framework, we consider a general mutational path where mutations may be advantageous, neutral or deleterious. In the biologically relevant limiting regimes of large times and small mutation rates, we derive probability distributions for the number, and arrival time, of cells with n mutations. Surprisingly, the two quantities respectively follow Mittag-Leffler and logistic distributions regardless of n or the mutations' selective effects. Our results provide a rapid method to assess how altering the fundamental division, death, and mutation rates impacts the arrival time, and number, of mutant cells. We highlight consequences for mutation rate inference in fluctuation assays.
Topics: Humans; Mutation; Mutation Rate; Neoplasms; Probability; Bacteria; Models, Genetic
PubMed: 37428805
DOI: 10.1371/journal.pcbi.1011289 -
Trends in Genetics : TIG Nov 2020Molecular data have been used to date species divergences ever since they were described as documents of evolutionary history in the 1960s. Yet, an inadequate fossil... (Review)
Review
Molecular data have been used to date species divergences ever since they were described as documents of evolutionary history in the 1960s. Yet, an inadequate fossil record and discordance between gene trees and species trees are persistently problematic. We examine how, by accommodating gene tree discordance and by scaling branch lengths to absolute time using mutation rate and generation time, multispecies coalescent (MSC) methods can potentially overcome these challenges. We find that time estimates can differ - in some cases, substantially - depending on whether MSC methods or traditional phylogenetic methods that apply concatenation are used, and whether the tree is calibrated with pedigree-based mutation rates or with fossils. We discuss the advantages and shortcomings of both approaches and provide practical guidance for data analysis when using these methods.
Topics: Animals; Biological Evolution; Fossils; Gene Flow; Mammals; Models, Genetic; Models, Theoretical; Mutation Rate; Phylogeny
PubMed: 32709458
DOI: 10.1016/j.tig.2020.06.002