The Experts below are selected from a list of 42594 Experts worldwide ranked by ideXlab platform
Peter D. Keightley - One of the best experts on this subject based on the ideXlab platform.
-
Fitness decline under osmotic stress in Caenorhabditis elegans populations subjected to spontaneous Mutation Accumulation at varying population sizes.
Evolution; international journal of organic evolution, 2018Co-Authors: Vaishali Katju, Lucille B Packard, Peter D. KeightleyAbstract:The consequences of Mutations for population fitness depends on their individual selection coefficients and the effective population size. An earlier study of Caenorhabditis elegans spontaneous Mutation Accumulation lines evolved for 409 generations at three population sizes found that Ne = 1 populations declined significantly in fitness whereas the fitness of larger populations (Ne = 5, 50) was indistinguishable from the ancestral control under benign conditions. To test if larger MA populations harbor a load of cryptic deleterious Mutations that are obscured under benign laboratory conditions, we measured fitness under osmotic stress via exposure to hypersaline conditions. The fitness of Ne = 1 lines exhibited a further decline under osmotic stress compared to benign conditions. However, the fitness of larger populations remained indistinguishable from that of the ancestral control. The average effects of deleterious Mutations in Ne = 1 lines were estimated to be 22% for productivity and 14% for survivorship, exceeding values previously detected under benign conditions. Our results suggest that fitness decline is due to large effect Mutations that are rapidly removed via selection even in small populations, with implications for conservation practices. Genetic stochasticity may not be as potent and immediate a threat to the persistence of small populations as other demographic and environmental stochastic factors.
-
fitness change in relation to Mutation number in spontaneous Mutation Accumulation lines of chlamydomonas reinhardtii
Evolution, 2017Co-Authors: Susanne A Kraemer, Peter D. Keightley, Rob W Ness, Katharina B Bondel, Nick ColegraveAbstract:: Although all genetic variation ultimately stems from Mutations, their properties are difficult to study directly. Here, we used multiple Mutation Accumulation (MA) lines derived from five genetic backgrounds of the green algae Chlamydomonas reinhardtii that have been previously subjected to whole genome sequencing to investigate the relationship between the number of spontaneous Mutations and change in fitness from a nonevolved ancestor. MA lines were on average less fit than their ancestors and we detected a significantly negative correlation between the change in fitness and the total number of accumulated Mutations in the genome. Likewise, the number of Mutations located within coding regions significantly and negatively impacted MA line fitness. We used the fitness data to parameterize a maximum likelihood model to estimate discrete categories of Mutational effects, and found that models containing one to two Mutational effect categories (one neutral and one deleterious category) fitted the data best. However, the best-fitting Mutational effects models were highly dependent on the genetic background of the ancestral strain.
-
mitochondrial Mutation rate spectrum and heteroplasmy in caenorhabditis elegans spontaneous Mutation Accumulation lines of differing population size
Molecular Biology and Evolution, 2017Co-Authors: Anke Konrad, Owen Thompson, Donald G Moerman, Ulfar Bergthorsson, Robert H Waterston, Peter D. Keightley, Vaishali KatjuAbstract:: Mitochondrial genomes of metazoans, given their elevated rates of evolution, have served as pivotal markers for phylogeographic studies and recent phylogenetic events. In order to determine the dynamics of spontaneous mitochondrial Mutations in small populations in the absence and presence of selection, we evolved Mutation Accumulation (MA) lines of Caenorhabditis elegans in parallel over 409 consecutive generations at three varying population sizes of N = 1, 10, and 100 hermaphrodites. The N =1 populations should have a minimal influence of natural selection to provide the spontaneous Mutation rate and the expected rate of neutral evolution, whereas larger population sizes should experience increasing intensity of selection. New Mutations were identified by Illumina paired-end sequencing of 86 mtDNA genomes across 35 experimental lines and compared with published genomes of natural isolates. The spontaneous mitochondrial Mutation rate was estimated at 1.05 × 10-7/site/generation. A strong G/C→A/T Mutational bias was observed in both the MA lines and the natural isolates. This suggests that the low G + C content at synonymous sites is the product of Mutation bias rather than selection as previously proposed. The mitochondrial effective population size per worm generation was estimated to be 62. Although it was previously concluded that heteroplasmy was rare in C. elegans, the vast majority of Mutations in this study were heteroplasmic despite an experimental regime exceeding 400 generations. The frequencies of frameshift and nonsynonymous Mutations were negatively correlated with population size, which suggests their deleterious effects on fitness and a potent role for selection in their eradication.
-
fitness decline in spontaneous Mutation Accumulation lines of caenorhabditis elegans with varying effective population sizes
Evolution, 2015Co-Authors: Vaishali Katju, Peter D. Keightley, Lucille B Packard, Lijing Bu, Ulfar BergthorssonAbstract:The rate and fitness effects of new Mutations have been investigated by Mutation Accumulation (MA) experiments in which organisms are maintained at a constant minimal population size to facilitate the Accumulation of Mutations with minimal efficacy of selection. We evolved 35 MA lines of Caenorhabditis elegans in parallel for 409 generations at three population sizes (N = 1, 10, and 100), representing the first spontaneous long-term MA experiment at varying population sizes with corresponding differences in the efficacy of selection. Productivity and survivorship in the N = 1 lines declined by 44% and 12%, respectively. The average effects of deleterious Mutations in N = 1 lines are estimated to be 16.4% for productivity and 11.8% for survivorship. Larger populations (N = 10 and 100) did not suffer a significant decline in fitness traits despite a lengthy and sustained regime of consecutive bottlenecks exceeding 400 generations. Together, these results suggest that fitness decline in very small populations is dominated by Mutations with large deleterious effects. It is possible that the MA lines at larger population sizes contain a load of cryptic deleterious Mutations of small to moderate effects that would be revealed in more challenging environments.
-
spontaneous Mutation Accumulation in multiple strains of the green alga chlamydomonas reinhardtii
Evolution, 2014Co-Authors: Andrew D Morgan, Peter D. Keightley, Rob W Ness, Nick ColegraveAbstract:Estimates of Mutational parameters, such as the average fitness effect of a new Mutation and the rate at which new genetic variation for fitness is created by Mutation, are important for the understanding of many biological processes. However, the causes of interspecific variation in Mutational parameters and the extent to which they vary within species remain largely unknown. We maintained multiple strains of the unicellular eukaryote Chlamydomonas reinhardtii, for approximately 1000 generations under relaxed selection by transferring a single cell every ∼10 generations. Mean fitness of the lines tended to decline with generations of Mutation Accumulation whereas Mutational variance increased. We did not find any evidence for differences among strains in any of the Mutational parameters estimated. The overall change in mean fitness per cell division and rate of input of Mutational variance per cell division were more similar to values observed in multicellular organisms than to those in other single-celled microbes. However, after taking into account differences in genome size among species, estimates from multicellular organisms and microbes, including our new estimates from C. reinhardtii, become substantially more similar. Thus, we suggest that variation in genome size is an important determinant of interspecific variation in Mutational parameters.
John A. Corbett - One of the best experts on this subject based on the ideXlab platform.
-
Selective mtDNA Mutation Accumulation results in β-cell apoptosis and diabetes development
American journal of physiology. Endocrinology and metabolism, 2009Co-Authors: Kenneth G. Bensch, Justin L. Mott, Shin Wen Chang, Polly A. Hansen, Michael A. Moxley, Kari T. Chambers, Wieke De Graaf, H. Peter Zassenhaus, John A. CorbettAbstract:To test the hypothesis that somatic mitochondrial (mt)DNA Mutation Accumulation predisposes mice to β-cell loss and diabetes development, transgenic mice expressing a proofreading-deficient mtDNA polymerase-γ under the control of the rat insulin-1 promoter were generated. At 6 wk of age, mtDNA Mutations reached 0.01% (1.05 Mutations/10,000 bp) in islets isolated from transgenic mice. This Mutational burden is associated with impaired glucose tolerance and a diabetes prevalence of 52% in male transgenic mice. Female transgenic mice maintain slightly elevated fasting glucose levels, mild glucose intolerance, and a diabetes prevalence of 14%. Diabetes in transgenic animals is associated with insulin insufficiency that results from a significant reduction in β-cell mass. Importantly, apoptosis of β-cells is increased 7-fold in female and 11-fold in male transgenic mice compared with littermate controls. These results are consistent with a causative role of somatic mtDNA Mutation Accumulation in the loss of β-cell mass and diabetes development.
-
A transgenic model to study the pathogenesis of somatic mtDNA Mutation Accumulation in β-cells
Diabetes Obesity and Metabolism, 2007Co-Authors: Kenneth G. Bensch, W. Degraaf, P. A. Hansen, H. P. Zassenhaus, John A. CorbettAbstract:Low levels of somatic Mutations accumulate in mitochondrial DNA (mtDNA) as we age; however, the pathogenic nature of these Mutations is unknown. In contrast, Mutational loads of >30% of mtDNA are associated with electron transport chain defects that result in mitochondrial diseases such as mitochondrial encephalopathy lactic acidosis and stroke-like episodes. Pancreatic β-cells may be extremely sensitive to the Accumulation of mtDNA Mutations, as insulin secretion requires the mitochondrial oxidation of glucose to CO2. Type 2 diabetes arises when β-cells fail to compensate for the increased demand for insulin, and many type 2 diabetics progress to insulin dependence because of a loss of β-cell function or β-cell death. This loss of β-cell function/β-cell death has been attributed to the toxic effects of elevated levels of lipids and glucose resulting in the enhanced production of free radicals in β-cells. mtDNA, localized in close proximity to one of the major cellular sites of free radical production, comprises more than 95% coding sequences such that Mutations result in changes in the coding sequence. It has long been known that mtDNA Mutations accumulate with age; however, only recently have studies examined the influence of somatic mtDNA Mutation Accumulation on disease pathogenesis. This article will focus on the effects of low-level somatic mtDNA Mutation Accumulation on ageing, cardiovascular disease and diabetes.
Vaishali Katju - One of the best experts on this subject based on the ideXlab platform.
-
Fitness decline under osmotic stress in Caenorhabditis elegans populations subjected to spontaneous Mutation Accumulation at varying population sizes.
Evolution; international journal of organic evolution, 2018Co-Authors: Vaishali Katju, Lucille B Packard, Peter D. KeightleyAbstract:The consequences of Mutations for population fitness depends on their individual selection coefficients and the effective population size. An earlier study of Caenorhabditis elegans spontaneous Mutation Accumulation lines evolved for 409 generations at three population sizes found that Ne = 1 populations declined significantly in fitness whereas the fitness of larger populations (Ne = 5, 50) was indistinguishable from the ancestral control under benign conditions. To test if larger MA populations harbor a load of cryptic deleterious Mutations that are obscured under benign laboratory conditions, we measured fitness under osmotic stress via exposure to hypersaline conditions. The fitness of Ne = 1 lines exhibited a further decline under osmotic stress compared to benign conditions. However, the fitness of larger populations remained indistinguishable from that of the ancestral control. The average effects of deleterious Mutations in Ne = 1 lines were estimated to be 22% for productivity and 14% for survivorship, exceeding values previously detected under benign conditions. Our results suggest that fitness decline is due to large effect Mutations that are rapidly removed via selection even in small populations, with implications for conservation practices. Genetic stochasticity may not be as potent and immediate a threat to the persistence of small populations as other demographic and environmental stochastic factors.
-
mitochondrial Mutation rate spectrum and heteroplasmy in caenorhabditis elegans spontaneous Mutation Accumulation lines of differing population size
Molecular Biology and Evolution, 2017Co-Authors: Anke Konrad, Owen Thompson, Donald G Moerman, Ulfar Bergthorsson, Robert H Waterston, Peter D. Keightley, Vaishali KatjuAbstract:: Mitochondrial genomes of metazoans, given their elevated rates of evolution, have served as pivotal markers for phylogeographic studies and recent phylogenetic events. In order to determine the dynamics of spontaneous mitochondrial Mutations in small populations in the absence and presence of selection, we evolved Mutation Accumulation (MA) lines of Caenorhabditis elegans in parallel over 409 consecutive generations at three varying population sizes of N = 1, 10, and 100 hermaphrodites. The N =1 populations should have a minimal influence of natural selection to provide the spontaneous Mutation rate and the expected rate of neutral evolution, whereas larger population sizes should experience increasing intensity of selection. New Mutations were identified by Illumina paired-end sequencing of 86 mtDNA genomes across 35 experimental lines and compared with published genomes of natural isolates. The spontaneous mitochondrial Mutation rate was estimated at 1.05 × 10-7/site/generation. A strong G/C→A/T Mutational bias was observed in both the MA lines and the natural isolates. This suggests that the low G + C content at synonymous sites is the product of Mutation bias rather than selection as previously proposed. The mitochondrial effective population size per worm generation was estimated to be 62. Although it was previously concluded that heteroplasmy was rare in C. elegans, the vast majority of Mutations in this study were heteroplasmic despite an experimental regime exceeding 400 generations. The frequencies of frameshift and nonsynonymous Mutations were negatively correlated with population size, which suggests their deleterious effects on fitness and a potent role for selection in their eradication.
-
fitness decline in spontaneous Mutation Accumulation lines of caenorhabditis elegans with varying effective population sizes
Evolution, 2015Co-Authors: Vaishali Katju, Peter D. Keightley, Lucille B Packard, Lijing Bu, Ulfar BergthorssonAbstract:The rate and fitness effects of new Mutations have been investigated by Mutation Accumulation (MA) experiments in which organisms are maintained at a constant minimal population size to facilitate the Accumulation of Mutations with minimal efficacy of selection. We evolved 35 MA lines of Caenorhabditis elegans in parallel for 409 generations at three population sizes (N = 1, 10, and 100), representing the first spontaneous long-term MA experiment at varying population sizes with corresponding differences in the efficacy of selection. Productivity and survivorship in the N = 1 lines declined by 44% and 12%, respectively. The average effects of deleterious Mutations in N = 1 lines are estimated to be 16.4% for productivity and 11.8% for survivorship. Larger populations (N = 10 and 100) did not suffer a significant decline in fitness traits despite a lengthy and sustained regime of consecutive bottlenecks exceeding 400 generations. Together, these results suggest that fitness decline in very small populations is dominated by Mutations with large deleterious effects. It is possible that the MA lines at larger population sizes contain a load of cryptic deleterious Mutations of small to moderate effects that would be revealed in more challenging environments.
Aneil F Agrawal - One of the best experts on this subject based on the ideXlab platform.
-
Mutation Accumulation in selfing populations under fluctuating selection
Evolution, 2018Co-Authors: Eddie K H Ho, Aneil F AgrawalAbstract:: Selfing species are prone to extinction, possibly because highly selfing populations can suffer from a continuous Accumulation of deleterious Mutations, a process analogous to Muller's ratchet in asexual populations. However, current theory provides little insight into which types of genes are most likely to accumulate deleterious alleles and what environmental circumstances may accelerate genomic degradation. Here, we investigate temporal changes in the environment that cause fluctuations in the strength of purifying selection. We simulate selfing populations with genomes containing a mixture of loci experiencing constant selection and loci experiencing selection that fluctuates in strength (but not direction). Even when both types of loci experience the same average strength of selection, loci under fluctuating selection contribute disproportionately more to deleterious Mutation Accumulation. Moreover, the presence of loci experiencing fluctuating selection in the genome increases the deleterious fixation rate at loci under constant selection; under most realistic scenarios, this effect of linked selection can be attributed to a reduction in Ne . Fluctuating selection is particularly injurious when selective environments are strongly autocorrelated over time and when selection is concentrated into rare bouts of strong selection. These results imply that loci under fluctuating selection are likely important drivers of extinction in selfing species.
-
Mutation Accumulation in populations of varying size: large effect Mutations cause most Mutational decline in the rotifer Brachionus calyciflorus under UV-C radiation.
Journal of evolutionary biology, 2018Co-Authors: Pepijn Luijckx, Andrijana Stanic, Aneil F AgrawalAbstract:Theory predicts that fitness decline via Mutation Accumulation will depend on population size, but there are only a few direct tests of this key idea. To gain a qualitative understanding of the fitness effect of new Mutations, we performed a Mutation Accumulation experiment with the facultative sexual rotifer Brachionus calyciflorus at six different population sizes under UV-C radiation. Lifetime reproduction assays conducted after ten and sixteen UV-C radiations showed that while small populations lost fitness, fitness losses diminished rapidly with increasing population size. Populations kept as low as 10 individuals were able to maintain fitness close to the nonmutagenized populations throughout the experiment indicating that selection was able to remove the majority of large effect Mutations in small populations. Although our results also seem to imply that small populations are effectively immune to Mutational decay, we caution against this interpretation. Given sufficient time, populations of moderate to large size can experience declines in fitness from accumulating weakly deleterious Mutations as demonstrated by fitness estimates from simulations and, tentatively, from a long-term experiment with populations of moderate size. There is mounting evidence to suggest that Mutational distributions contain a heavier tail of large effects. Our results suggest that this is also true when the Mutational spectrum is altered by UV radiation.
-
Mutation Accumulation in selfing populations under fluctuating selection
bioRxiv, 2017Co-Authors: Eddie K H Ho, Aneil F AgrawalAbstract:Selfing species tend to be prone to extinction and this may be because selfing reduces the efficacy of selection acting to establish beneficial Mutations and remove deleterious Mutations from the population. Past theory shows that highly selfing populations can suffer from a continuous Accumulation of deleterious Mutations, a process analogous to Mullers ratchet in asexual populations. However, current theory provides little insight into which types of genes are most likely to accumulate deleterious alleles and what environmental circumstances may accelerate genomic degradation. Here we investigate temporal changes in the environment that cause fluctuations in the strength of purifying selection acting on some genes. We simulate highly selfing populations with genomes containing a mixture of loci experiencing time constant selection and loci experiencing selection that fluctuates in strength over time (but not in direction). Even when both types of loci experience the same average strength of selection over time, loci under fluctuating selection contribute disproportionately more to deleterious Mutation Accumulation. Moreover, the presence of loci experiencing fluctuating selection in the genome increases the fixation rate of deleterious alleles at loci that are under constant selection; under most realistic scenarios this effect of linked selection can be attributed to a reduction in Ne. Fluctuating selection is particularly injurious to highly selfing populations when selective environments are strongly autocorrelated over time and when selection is concentrated into temporally rare environments in which selection is strong. From these results, we suggest that loci under fluctuating selection are likely to be important drivers of extinction in selfing species.
Kenneth G. Bensch - One of the best experts on this subject based on the ideXlab platform.
-
Selective mtDNA Mutation Accumulation results in β-cell apoptosis and diabetes development
American journal of physiology. Endocrinology and metabolism, 2009Co-Authors: Kenneth G. Bensch, Justin L. Mott, Shin Wen Chang, Polly A. Hansen, Michael A. Moxley, Kari T. Chambers, Wieke De Graaf, H. Peter Zassenhaus, John A. CorbettAbstract:To test the hypothesis that somatic mitochondrial (mt)DNA Mutation Accumulation predisposes mice to β-cell loss and diabetes development, transgenic mice expressing a proofreading-deficient mtDNA polymerase-γ under the control of the rat insulin-1 promoter were generated. At 6 wk of age, mtDNA Mutations reached 0.01% (1.05 Mutations/10,000 bp) in islets isolated from transgenic mice. This Mutational burden is associated with impaired glucose tolerance and a diabetes prevalence of 52% in male transgenic mice. Female transgenic mice maintain slightly elevated fasting glucose levels, mild glucose intolerance, and a diabetes prevalence of 14%. Diabetes in transgenic animals is associated with insulin insufficiency that results from a significant reduction in β-cell mass. Importantly, apoptosis of β-cells is increased 7-fold in female and 11-fold in male transgenic mice compared with littermate controls. These results are consistent with a causative role of somatic mtDNA Mutation Accumulation in the loss of β-cell mass and diabetes development.
-
A transgenic model to study the pathogenesis of somatic mtDNA Mutation Accumulation in β-cells
Diabetes Obesity and Metabolism, 2007Co-Authors: Kenneth G. Bensch, W. Degraaf, P. A. Hansen, H. P. Zassenhaus, John A. CorbettAbstract:Low levels of somatic Mutations accumulate in mitochondrial DNA (mtDNA) as we age; however, the pathogenic nature of these Mutations is unknown. In contrast, Mutational loads of >30% of mtDNA are associated with electron transport chain defects that result in mitochondrial diseases such as mitochondrial encephalopathy lactic acidosis and stroke-like episodes. Pancreatic β-cells may be extremely sensitive to the Accumulation of mtDNA Mutations, as insulin secretion requires the mitochondrial oxidation of glucose to CO2. Type 2 diabetes arises when β-cells fail to compensate for the increased demand for insulin, and many type 2 diabetics progress to insulin dependence because of a loss of β-cell function or β-cell death. This loss of β-cell function/β-cell death has been attributed to the toxic effects of elevated levels of lipids and glucose resulting in the enhanced production of free radicals in β-cells. mtDNA, localized in close proximity to one of the major cellular sites of free radical production, comprises more than 95% coding sequences such that Mutations result in changes in the coding sequence. It has long been known that mtDNA Mutations accumulate with age; however, only recently have studies examined the influence of somatic mtDNA Mutation Accumulation on disease pathogenesis. This article will focus on the effects of low-level somatic mtDNA Mutation Accumulation on ageing, cardiovascular disease and diabetes.
