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Christopher G Knight - One of the best experts on this subject based on the ideXlab platform.
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opposing effects of final population density and stress on escherichia coli Mutation Rate
The ISME Journal, 2018Co-Authors: Rok Krasovec, Elizabeth Aston, Huw Richards, Danna R Gifford, Roman V Belavkin, Alastair Channon, Andrew J Mcbain, Christopher G KnightAbstract:Evolution depends on Mutations. For an individual genotype, the Rate at which Mutations arise is known to increase with various stressors (stress-induced mutagenesis—SIM) and decrease at high final population density (density-associated Mutation-Rate plasticity—DAMP). We hypothesised that these two forms of Mutation-Rate plasticity would have opposing effects across a nutrient gradient. Here we test this hypothesis, culturing Escherichia coli in increasingly rich media. We distinguish an increase in Mutation Rate with added nutrients through SIM (dependent on error-prone polymerases Pol IV and Pol V) and an opposing effect of DAMP (dependent on MutT, which removes oxidised G nucleotides). The combination of DAMP and SIM results in a Mutation Rate minimum at intermediate nutrient levels (which can support 7 × 108 cells ml−1). These findings demonstRate a strikingly close and nuanced relationship of ecological factors—stress and population density—with Mutation, the fuel of all evolution.
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spontaneous Mutation Rate is a plastic trait associated with population density across domains of life
PLOS Biology, 2017Co-Authors: Rok Krasovec, Elizabeth Aston, Huw Richards, Danna R Gifford, Charlie Hatcher, Katy J Faulkner, Roman V Belavkin, Alastair Channon, Andrew J Mcbain, Christopher G KnightAbstract:Rates of random, spontaneous Mutation can vary plastically, dependent upon the environment. Such plasticity affects evolutionary trajectories and may be adaptive. We recently identified an inverse plastic association between Mutation Rate and population density at 1 locus in 1 species of bacterium. It is unknown how widespread this association is, whether it varies among organisms, and what molecular mechanisms of mutagenesis or repair are required for this Mutation-Rate plasticity. Here, we address all 3 questions. We identify a strong negative association between Mutation Rate and population density across 70 years of published literature, comprising hundreds of Mutation Rates estimated using phenotypic markers of Mutation (fluctuation tests) from all domains of life and viruses. We test this relationship experimentally, determining that there is indeed density-associated Mutation-Rate plasticity (DAMP) at multiple loci in both eukaryotes and bacteria, with up to 23-fold lower Mutation Rates at higher population densities. We find that the degree of plasticity varies, even among closely related organisms. Nonetheless, in each domain tested, DAMP requires proteins scavenging the mutagenic oxidised nucleotide 8-oxo-dGTP. This implies that phenotypic markers give a more precise view of Mutation Rate than previously believed: having accounted for other known factors affecting Mutation Rate, controlling for population density can reduce variation in Mutation-Rate estimates by 93%. Widespread DAMP, which we manipulate genetically in dispaRate organisms, also provides a novel trait to use in the fight against the evolution of antimicrobial resistance. Such a prevalent environmental association and conserved mechanism suggest that Mutation has varied plastically with population density since the early origins of life.
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Monotonicity of fitness landscapes and Mutation Rate control
Journal of Mathematical Biology, 2016Co-Authors: Roman V Belavkin, Elizabeth Aston, Rok Krasovec, Alastair Channon, John A. D. Aston, Christopher G KnightAbstract:A common view in evolutionary biology is that Mutation Rates are minimised. However, studies in combinatorial optimisation and search have shown a clear advantage of using variable Mutation Rates as a control parameter to optimise the performance of evolutionary algorithms. Much biological theory in this area is based on Ronald Fisher’s work, who used Euclidean geometry to study the relation between Mutation size and expected fitness of the offspring in infinite phenotypic spaces. Here we reconsider this theory based on the alternative geometry of discrete and finite spaces of DNA sequences. First, we consider the geometric case of fitness being isomorphic to distance from an optimum, and show how problems of optimal Mutation Rate control can be solved exactly or approximately depending on additional constraints of the problem. Then we consider the general case of fitness communicating only partial information about the distance. We define weak monotonicity of fitness landscapes and prove that this property holds in all landscapes that are continuous and open at the optimum. This theoretical result motivates our hypothesis that optimal Mutation Rate functions in such landscapes will increase when fitness decreases in some neighbourhood of an optimum, resembling the control functions derived in the geometric case. We test this hypothesis experimentally by analysing approximately optimal Mutation Rate control functions in 115 complete landscapes of binding scores between DNA sequences and transcription factors. Our findings support the hypothesis and find that the increase of Mutation Rate is more rapid in landscapes that are less monotonic (more rugged). We discuss the relevance of these findings to living organisms.
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Mutation Rate plasticity in rifampicin resistance depends on escherichia coli cell cell interactions
Nature Communications, 2014Co-Authors: Rok Krasovec, Elizabeth Aston, Roman V Belavkin, Alastair Channon, John A. D. Aston, Bharat M Rash, Manikandan Kadirvel, Sarah Forbes, Christopher G KnightAbstract:Variation of Mutation Rate at a particular site in a particular genotype, in other words Mutation Rate plasticity (MRP), can be caused by stress or ageing. However, Mutation Rate control by other factors is less well characterized. Here we show that in wild-type Escherichia coli (K-12 and B strains), the Mutation Rate to rifampicin resistance is plastic and inversely related to population density: lowering density can increase Mutation Rates at least threefold. This MRP is genetically switchable, dependent on the quorum-sensing gene luxS—specifically its role in the activated methyl cycle—and is socially mediated via cell–cell interactions. Although we identify an inverse association of Mutation Rate with fitness under some circumstances, we find no functional link with stress-induced mutagenesis. Our experimental manipulation of Mutation Rates via the social environment raises the possibility that such manipulation occurs in nature and could be exploited medically.
Peter D Keightley - One of the best experts on this subject based on the ideXlab platform.
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extensive de novo Mutation Rate variation between individuals and across the genome of chlamydomonas reinhardtii
Genome Research, 2015Co-Authors: Rob W Ness, Andrew D Morgan, Nick Colegrave, Radhakrishnan B Vasanthakrishnan, Peter D KeightleyAbstract:Describing the process of spontaneous Mutation is fundamental for understanding the genetic basis of disease, the threat posed by declining population size in conservation biology, and much of evolutionary biology. Directly studying spontaneous Mutation has been difficult, however, because new Mutations are rare. Mutation accumulation (MA) experiments overcome this by allowing Mutations to build up over many generations in the near absence of natural selection. Here, we sequenced the genomes of 85 MA lines derived from six genetically diverse strains of the green alga Chlamydomonas reinhardtii. We identified 6843 new Mutations, more than any other study of spontaneous Mutation. We observed sevenfold variation in the Mutation Rate among strains and that mutator genotypes arose, increasing the Mutation Rate approximately eightfold in some replicates. We also found evidence for fine-scale heterogeneity in the Mutation Rate, with certain sequence motifs mutating at much higher Rates, and clusters of multiple Mutations occurring at closely linked sites. There was little evidence, however, for Mutation Rate heterogeneity between chromosomes or over large genomic regions of 200 kbp. We geneRated a predictive model of the mutability of sites based on their genomic properties, including local GC content, gene expression level, and local sequence context. Our model accuRately predicted the average Mutation Rate and natural levels of genetic diversity of sites across the genome. Notably, trinucleotides vary 17-fold in Rate between the most and least mutable sites. Our results uncover a rich heterogeneity in the process of spontaneous Mutation both among individuals and across the genome.
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extensive de novo Mutation Rate variation between individuals and across the genome of chlamydomonas reinhardtii
bioRxiv, 2015Co-Authors: Rob W Ness, Andrew D Morgan, Nick Colegrave, Radhakrishnan B Vasanthakrishnan, Peter D KeightleyAbstract:Describing the process of spontaneous Mutation is fundamental for understanding the genetic basis of disease, the threat posed by declining population size in conservation biology, and in much evolutionary biology. However, directly studying spontaneous Mutation is difficult because of the rarity of de novo Mutations. Mutation accumulation (MA) experiments overcome this by allowing Mutations to build up over many generations in the near absence of natural selection. In this study, we sequenced the genomes of 85 MA lines derived from six genetically diverse wild strains of the green alga Chlamydomonas reinhardtii. We identified 6,843 spontaneous Mutations, more than any other study of spontaneous Mutation. We observed seven-fold variation in the Mutation Rate among strains and that mutator genotypes arose, increasing the Mutation Rate dramatically in some replicates. We also found evidence for fine-scale heterogeneity in the Mutation Rate, driven largely by the sequence flanking mutated sites, and by clusters of multiple Mutations at closely linked sites. There was little evidence, however, for Mutation Rate heterogeneity between chromosomes or over large genomic regions of 200Kbp. Using logistic regression, we geneRated a predictive model of the mutability of sites based on their genomic properties, including local GC content, gene expression level and local sequence context. Our model accuRately predicted the average Mutation Rate and natural levels of genetic diversity of sites across the genome. Notably, trinucleotides vary 17-fold in Rate between the most mutable and least mutable sites. Our results uncover a rich heterogeneity in the process of spontaneous Mutation both among individuals and across the genome.
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estimation of the spontaneous Mutation Rate in heliconius melpomene
Molecular Biology and Evolution, 2015Co-Authors: Peter D Keightley, Ana Pinharanda, Rob W Ness, Fraser Simpson, Kanchon K Dasmahapatra, John W Davey, James Mallet, Chris D JigginsAbstract:We estimated the spontaneous Mutation Rate in Heliconius melpomene by genome sequencing of a pair of parents and 30 of their offspring, based on the ratio of number of de novo heterozygotes to the number of callable site-individuals. We detected nine new Mutations, each one affecting a single site in a single offspring. This yields an estimated Mutation Rate of 2.9 × 10−9 (95% confidence interval, 1.3 × 10−9–5.5 × 10−9), which is similar to recent estimates in Drosophila melanogaster, the only other insect species in which the Mutation Rate has been directly estimated. We infer that recent effective population size of H. melpomene is about 2 million, a substantially lower value than its census size, suggesting a role for natural selection reducing diversity. We estimate that H. melpomene diverged from its Mullerian comimic H. erato about 6 Ma, a somewhat later date than estimates based on a local molecular clock.
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estimate of the spontaneous Mutation Rate in chlamydomonas reinhardtii
Genetics, 2012Co-Authors: Rob W Ness, Andrew D Morgan, Nick Colegrave, Peter D KeightleyAbstract:The nature of spontaneous Mutations, including their Rate, distribution across the genome, and fitness consequences, is of central importance to biology. However, the low Rate of Mutation has made it difficult to study spontaneous mutagenesis, and few studies have directly addressed these questions. Here, we present a direct estimate of the Mutation Rate and a description of the properties of new spontaneous Mutations in the unicellular green alga Chlamydomonas reinhardtii. We conducted a Mutation accumulation experiment for ∼350 generations followed by whole-genome resequencing of two replicate lines. Our analysis identified a total of 14 Mutations, including 5 short indels and 9 single base Mutations, and no evidence of larger structural Mutations. From this, we estimate a total Mutation Rate of 3.23 × 10−10/site/generation (95% C.I. 1.82 × 10−10 to 5.23 × 10−10) and a single base Mutation Rate of 2.08 × 10−10/site/generation (95% C.I., 1.09 × 10−10 to 3.74 × 10−10). We observed no Mutations from A/T → G/C, suggesting a strong Mutational bias toward A/T, although paradoxically, the GC content of the C. reinhardtii genome is very high. Our estimate is only the second direct estimate of the Mutation Rate from plants and among the lowest spontaneous base-substitution Rates known in eukaryotes.
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direct estimation of the mitochondrial dna Mutation Rate in drosophila melanogaster
PLOS Biology, 2008Co-Authors: Cathy Haagliautard, Michael Lynch, Nicole Coffey, David Houle, Brian Charlesworth, Peter D KeightleyAbstract:Mitochondrial DNA (mtDNA) variants are widely used in evolutionary genetics as markers for population history and to estimate divergence times among taxa. Inferences of species history are generally based on phylogenetic comparisons, which assume that molecular evolution is clock-like. Between-species comparisons have also been used to estimate the Mutation Rate, using sites that are thought to evolve neutrally. We directly estimated the mtDNA Mutation Rate by scanning the mitochondrial genome of Drosophila melanogaster lines that had undergone approximately 200 generations of spontaneous Mutation accumulation (MA). We detected a total of 28 point Mutations and eight insertion-deletion (indel) Mutations, yielding an estimate for the single-nucleotide Mutation Rate of 6.2 310 � 8 per site per fly generation. Most Mutations were heteroplasmic within a line, and their frequency distribution suggests that the effective number of mitochondrial genomes transmitted per female per generation is about 30. We observed repeated occurrences of some indel Mutations, suggesting that indel Mutational hotspots are common. Among the point Mutations, there is a large excess of G!A Mutations on the major strand (the sense strand for the majority of mitochondrial genes). These Mutations tend to occur at nonsynonymous sites of protein-coding genes, and they are expected to be deleterious, so do not become fixed between species. The overall mtDNA Mutation Rate per base pair per fly generation in Drosophila is estimated to be about 103 higher than the nuclear Mutation Rate, but the mitochondrial major strand G!A Mutation Rate is about 703higher than the nuclear Rate. Silent sites are substantially more strongly biased towards A and T than nonsynonymous sites, consistent with the extreme Mutation bias towards AþT. Strand-asymmetric Mutation bias, coupled with selection to maintain specific nonsynonymous bases, therefore provides an explanation for the extreme base composition of the mitochondrial genome of Drosophila.
Rok Krasovec - One of the best experts on this subject based on the ideXlab platform.
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opposing effects of final population density and stress on escherichia coli Mutation Rate
The ISME Journal, 2018Co-Authors: Rok Krasovec, Elizabeth Aston, Huw Richards, Danna R Gifford, Roman V Belavkin, Alastair Channon, Andrew J Mcbain, Christopher G KnightAbstract:Evolution depends on Mutations. For an individual genotype, the Rate at which Mutations arise is known to increase with various stressors (stress-induced mutagenesis—SIM) and decrease at high final population density (density-associated Mutation-Rate plasticity—DAMP). We hypothesised that these two forms of Mutation-Rate plasticity would have opposing effects across a nutrient gradient. Here we test this hypothesis, culturing Escherichia coli in increasingly rich media. We distinguish an increase in Mutation Rate with added nutrients through SIM (dependent on error-prone polymerases Pol IV and Pol V) and an opposing effect of DAMP (dependent on MutT, which removes oxidised G nucleotides). The combination of DAMP and SIM results in a Mutation Rate minimum at intermediate nutrient levels (which can support 7 × 108 cells ml−1). These findings demonstRate a strikingly close and nuanced relationship of ecological factors—stress and population density—with Mutation, the fuel of all evolution.
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spontaneous Mutation Rate is a plastic trait associated with population density across domains of life
PLOS Biology, 2017Co-Authors: Rok Krasovec, Elizabeth Aston, Huw Richards, Danna R Gifford, Charlie Hatcher, Katy J Faulkner, Roman V Belavkin, Alastair Channon, Andrew J Mcbain, Christopher G KnightAbstract:Rates of random, spontaneous Mutation can vary plastically, dependent upon the environment. Such plasticity affects evolutionary trajectories and may be adaptive. We recently identified an inverse plastic association between Mutation Rate and population density at 1 locus in 1 species of bacterium. It is unknown how widespread this association is, whether it varies among organisms, and what molecular mechanisms of mutagenesis or repair are required for this Mutation-Rate plasticity. Here, we address all 3 questions. We identify a strong negative association between Mutation Rate and population density across 70 years of published literature, comprising hundreds of Mutation Rates estimated using phenotypic markers of Mutation (fluctuation tests) from all domains of life and viruses. We test this relationship experimentally, determining that there is indeed density-associated Mutation-Rate plasticity (DAMP) at multiple loci in both eukaryotes and bacteria, with up to 23-fold lower Mutation Rates at higher population densities. We find that the degree of plasticity varies, even among closely related organisms. Nonetheless, in each domain tested, DAMP requires proteins scavenging the mutagenic oxidised nucleotide 8-oxo-dGTP. This implies that phenotypic markers give a more precise view of Mutation Rate than previously believed: having accounted for other known factors affecting Mutation Rate, controlling for population density can reduce variation in Mutation-Rate estimates by 93%. Widespread DAMP, which we manipulate genetically in dispaRate organisms, also provides a novel trait to use in the fight against the evolution of antimicrobial resistance. Such a prevalent environmental association and conserved mechanism suggest that Mutation has varied plastically with population density since the early origins of life.
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Monotonicity of fitness landscapes and Mutation Rate control
Journal of Mathematical Biology, 2016Co-Authors: Roman V Belavkin, Elizabeth Aston, Rok Krasovec, Alastair Channon, John A. D. Aston, Christopher G KnightAbstract:A common view in evolutionary biology is that Mutation Rates are minimised. However, studies in combinatorial optimisation and search have shown a clear advantage of using variable Mutation Rates as a control parameter to optimise the performance of evolutionary algorithms. Much biological theory in this area is based on Ronald Fisher’s work, who used Euclidean geometry to study the relation between Mutation size and expected fitness of the offspring in infinite phenotypic spaces. Here we reconsider this theory based on the alternative geometry of discrete and finite spaces of DNA sequences. First, we consider the geometric case of fitness being isomorphic to distance from an optimum, and show how problems of optimal Mutation Rate control can be solved exactly or approximately depending on additional constraints of the problem. Then we consider the general case of fitness communicating only partial information about the distance. We define weak monotonicity of fitness landscapes and prove that this property holds in all landscapes that are continuous and open at the optimum. This theoretical result motivates our hypothesis that optimal Mutation Rate functions in such landscapes will increase when fitness decreases in some neighbourhood of an optimum, resembling the control functions derived in the geometric case. We test this hypothesis experimentally by analysing approximately optimal Mutation Rate control functions in 115 complete landscapes of binding scores between DNA sequences and transcription factors. Our findings support the hypothesis and find that the increase of Mutation Rate is more rapid in landscapes that are less monotonic (more rugged). We discuss the relevance of these findings to living organisms.
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Mutation Rate plasticity in rifampicin resistance depends on escherichia coli cell cell interactions
Nature Communications, 2014Co-Authors: Rok Krasovec, Elizabeth Aston, Roman V Belavkin, Alastair Channon, John A. D. Aston, Bharat M Rash, Manikandan Kadirvel, Sarah Forbes, Christopher G KnightAbstract:Variation of Mutation Rate at a particular site in a particular genotype, in other words Mutation Rate plasticity (MRP), can be caused by stress or ageing. However, Mutation Rate control by other factors is less well characterized. Here we show that in wild-type Escherichia coli (K-12 and B strains), the Mutation Rate to rifampicin resistance is plastic and inversely related to population density: lowering density can increase Mutation Rates at least threefold. This MRP is genetically switchable, dependent on the quorum-sensing gene luxS—specifically its role in the activated methyl cycle—and is socially mediated via cell–cell interactions. Although we identify an inverse association of Mutation Rate with fitness under some circumstances, we find no functional link with stress-induced mutagenesis. Our experimental manipulation of Mutation Rates via the social environment raises the possibility that such manipulation occurs in nature and could be exploited medically.
Richard Durbin - One of the best experts on this subject based on the ideXlab platform.
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revising the human Mutation Rate implications for understanding human evolution
Nature Reviews Genetics, 2012Co-Authors: Aylwyn Scally, Richard DurbinAbstract:It is now possible to make direct measurements of the Mutation Rate in modern humans using next-generation sequencing. These measurements reveal a value that is approximately half of that previously derived from fossil calibration, and this has implications for our understanding of demographic events in human evolution and other aspects of population genetics. Here, we discuss the implications of a lower-than-expected Mutation Rate in relation to the timescale of human evolution.
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Revising the human Mutation Rate: Implications for understand ing human evolution
Nature Reviews Genetics, 2012Co-Authors: Aylwyn Scally, Richard DurbinAbstract:It is now possible to make direct measurements of the Mutation Rate in modern humans using next-generation sequencing. These measurements reveal a value that is approximately half of that previously derived from fossil calibration, and this has implications for our understanding of demographic events in human evolution and other aspects of population genetics. Here, we discuss the implications of a lower-than-expected Mutation Rate in relation to the timescale of human evolution.
Agnar Helgason - One of the best experts on this subject based on the ideXlab platform.
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the y chromosome point Mutation Rate in humans
Nature Genetics, 2015Co-Authors: Axel W Einarsson, Valdis B Guðmundsdottir, Asgeir Sigurðsson, Ellen Gunnarsdottir, Anuradha Jagadeesan, Agnar Helgason, Sunna S EbenesersdottirAbstract:Agnar Helgason and colleagues report the point Mutation Rate for the male-specific euchromatic sequence of the Y chromosome based on 753 Icelandic males. They find that the non-recombining portions of the Y chromosome mutate at a faster Rate than palindromic regions, suggesting that gene conversion acts to correct Mutations in palindromic sequences.
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the Mutation Rate in the human mtdna control region
American Journal of Human Genetics, 2000Co-Authors: Sigrun Sigurðardottir, Agnar Helgason, Jeffrey R Gulcher, Kari Stefansson, Peter DonnellyAbstract:The Mutation Rate of the mitochondrial control region has been widely used to calibRate human population history. However, estimates of the Mutation Rate in this region have spanned two orders of magnitude. To readdress this Rate, we sequenced the mtDNA control region in 272 individuals, who were related by a total of 705 mtDNA transmission events, from 26 large Icelandic pedigrees. Three base substitutions were observed, and the Mutation Rate across the two hypervariable regions was estimated to be 3/705 =.0043 per generation (95% confidence interval [CI].00088-.013), or.32/site/1 million years (95% CI.065-.97). This study is substantially larger than others published, which have directly assessed mtDNA Mutation Rates on the basis of pedigrees, and the estimated Mutation Rate is intermediate among those derived from pedigree-based studies. Our estimated Rate remains higher than those based on phylogenetic comparisons. We discuss possible reasons for-and consequences of-this discrepancy. The present study also provides information on Rates of insertion/deletion Mutations, Rates of heteroplasmy, and the reliability of maternal links in the Icelandic genealogy database.
