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1.
Linda Partridge 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2010,365(1537):147-154
Human life expectancy in developed countries has increased steadily for over 150 years, through improvements in public health and lifestyle. More people are hence living long enough to suffer age-related loss of function and disease, and there is a need to improve the health of older people. Ageing is a complex process of damage accumulation, and has been viewed as experimentally and medically intractable. This view has been reinforced by the realization that ageing is a disadvantageous trait that evolves as a side effect of mutation accumulation or a benefit to the young, because of the decline in the force of natural selection at later ages. However, important recent discoveries are that mutations in single genes can extend lifespan of laboratory model organisms and that the mechanisms involved are conserved across large evolutionary distances, including to mammals. These mutations keep the animals functional and pathology-free to later ages, and they can protect against specific ageing-related diseases, including neurodegenerative disease and cancer. Preliminary indications suggest that these new findings from the laboratory may well also apply to humans. Translating these discoveries into medical treatments poses new challenges, including changing clinical thinking towards broad-spectrum, preventative medicine and finding novel routes to drug development. 相似文献
2.
Is senescence the adaptive result of tradeoffs between younger and older ages or the nonadaptive burden of deleterious mutations that act at older ages? To shed new light on this unresolved question we combine adaptive and nonadaptive processes in a single model. Our model uses Penna''s bit-strings to capture different age-specific mutational patterns. Each pattern represents a genotype and for each genotype we find the life history strategy that maximizes fitness. Genotypes compete with each other and are subject to selection and to new mutations over generations until equilibrium in gene-frequencies is reached. The mutation-selection equilibrium provides information about mutational load and the differential effects of mutations on a life history trait - the optimal age at maturity. We find that mutations accumulate only at ages with negligible impact on fitness and that mutation accumulation has very little effect on the optimal age at maturity. These results suggest that life histories are largely determined by adaptive processes. The non-adaptive process of mutation accumulation seems to be unimportant at evolutionarily relevant ages. 相似文献
3.
Biljana Stojković Mirko Đorđević Jelena Janković Uroš Savković Nikola Tucić 《Insect Science》2015,22(2):295-309
We tested mutation accumulation hypothesis for the evolution of senescence using short‐lived and long‐lived populations of the seed‐feeding beetle, Acanthoscelides obtectus (Say), obtained by selection on early‐ and late‐life for many generations. The expected consequence of the mutation accumulation hypothesis is that in short‐lived populations, where the force of natural selection is the strongest early in life, the late‐life fitness traits should decline due to genetic drift which increases the frequency of mutations with deleterious effects in later adult stages. Since it is unlikely that identical deleterious mutations will increase in several independent populations, hybrid vigor for late‐life fitness is expected in offspring obtained in crosses among populations selected for early‐life fitness traits. We tested longevity of both sexes, female fecundity and male reproductive behavior for hybrid vigor by comparing hybrid and nonhybrid short‐lived populations. Hybrid vigor was confirmed for male virility, mating speed and copulation duration, and longevity of both sexes at late ages. In contrast to males, the results on female fecundity in short‐lived populations did not support mutation accumulation as a genetic mechanism for the evolution of this trait. Contrary to the prediction of this hypothesis, male mating ability indices and female fecundity in long‐lived populations exhibited hybrid vigor at all assayed age classes. We demonstrate that nonhybrid long‐lived populations diverged randomly regarding female and male reproductive fitness, indicating that sexually antagonistic selection, when accompanied with genetic drift for female fecundity and male virility, might be responsible for overriding natural selection in the independently evolving long‐lived populations. 相似文献
4.
The ageing mitochondrial genome 总被引:2,自引:0,他引:2
The population of elderly individuals has increased significantly over the past century and is predicted to rise even more rapidly in the future. Ageing is a major risk factor for many diseases such as neurodegenerative disease, diabetes and cancer. This highlights the importance of understanding the mechanisms involved in the ageing process. One plausible mechanism for ageing is accumulation of mutations in the mitochondrial genome. In this review, we discuss some of the most convincing data surrounding age-related mtDNA mutations and the evidence that these mutations contribute to the ageing process. 相似文献
5.
Mitochondrial DNA (mtDNA) is essential for the ability of mammalian cells to generate a functional oxidative phosphorylation system. Mutations in mtDNA occur in human disease and also during ageing. Here, we address three questions concerning the occurrence and accumulation of mtDNA mutations during the lifespan of the mammalian cell. What sort of mutations accumulate with age in humans and other mammals? How is the female germ line spared from the accumulation of such mutations as occurs in many somatic tissues, so that neonates normally start life with a ‘clean sheet'? Is the occurrence of mtDNA mutations associated with the functional decline of cells and tissues during ageing? We argue that mtDNA mutations in somatic cells do not just reflect a passive imprint of ageing, but they are causally associated with the loss of bioenergetic function during the ageing process. 相似文献
6.
Sexual selection on spontaneous mutations strengthens the between‐sex genetic correlation for fitness
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Scott L. Allen Katrina McGuigan Tim Connallon Mark W. Blows Stephen F. Chenoweth 《Evolution; international journal of organic evolution》2017,71(10):2398-2409
A proposed benefit to sexual selection is that it promotes purging of deleterious mutations from populations. For this benefit to be realized, sexual selection, which is usually stronger on males, must purge mutations deleterious to both sexes. Here, we experimentally test the hypothesis that sexual selection on males purges deleterious mutations that affect both male and female fitness. We measured male and female fitness in two panels of spontaneous mutation‐accumulation lines of the fly, Drosophila serrata, each established from a common ancestor. One panel of mutation accumulation lines limited both natural and sexual selection (LS lines), whereas the other panel limited natural selection, but allowed sexual selection to operate (SS lines). Although mutation accumulation caused a significant reduction in male and female fitness in both the LS and SS lines, sexual selection had no detectable effect on the extent of the fitness reduction. Similarly, despite evidence of mutational variance for fitness in males and females of both treatments, sexual selection had no significant impact on the amount of mutational genetic variance for fitness. However, sexual selection did reshape the between‐sex correlation for fitness: significantly strengthening it in the SS lines. After 25 generations, the between‐sex correlation for fitness was positive but considerably less than one in the LS lines, suggesting that, although most mutations had sexually concordant fitness effects, sex‐limited, and/or sex‐biased mutations contributed substantially to the mutational variance. In the SS lines this correlation was strong and could not be distinguished from unity. Individual‐based simulations that mimick the experimental setup reveal two conditions that may drive our results: (1) a modest‐to‐large fraction of mutations have sex‐limited (or highly sex‐biased) fitness effects, and (2) the average fitness effect of sex‐limited mutations is larger than the average fitness effect of mutations that affect both sexes similarly. 相似文献
7.
G. Engström L. -E. Liljedahl T. Björklund 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》1992,85(1):26-32
Summary A selection experiment with Drosophila melanogaster was carried out to test some theories of ageing by calculating genetic parameters for a reproductive fitness trait at different ages. Successful selection for increased lifespan showed that longevity is a trait under genetic control. Positive genetic correlations between early and late fitness were found. These results do not support the pleiotropy theory of ageing which predicts a negative genetic correlation. Both environmental and additive genetic variation clearly increased with age. Increased environmental variation probably reflects the individuals' difficulties in coping with environmental stress. The increase in additive genetic variation supports the mutation accumulation theory of ageing, as well as other theories that postulate increased additive genetic variation with age. 相似文献
8.
Theories of Life-History Evolution 总被引:1,自引:0,他引:1
In order to assess current scientific understanding of life-historyevolution, the alternative fundamental theories are formulatedin a refutable form and compared with the available empiricalevidence. The hypothesis that life-history does not evolve isrejected on the grounds that life-history can be readily modifiedby artifical selection. The hypothesis that life-history evolvesaccording to mechanisms other than natural selection actingon genetic variation is shown to have no sound experimentalbasis. The hypothesis that life-history evolution depends primarilyon group selection is undermined by the absence of the predictedgroup adaptations. The hypothesis that life-history is a unitarycharacter which evolves in the same fashion as fitness is rejectedbecause of the disparity between life-history genetics and basictheory concerning the evolution of fitness. The hypothesis thatlife-history is composed of a set of autonomous characters whichare subject to mutation accumulation at later ages is refutedby the lack of any detectable increase in genetic variabilitywith age and the evidence for the interdependence of life-historycharacters. It is concluded that the hypothesis of antagonisticinteractions between life-history characters, generalized totake genetic variability into account, is the most satisfactorytheory of life-history evolution available. 相似文献
9.
Matthew T. Rutter Frank H. Shaw Charles B. Fenster 《Evolution; international journal of organic evolution》2010,64(6):1825-1835
Mutations are the ultimate source of genetic diversity and their contributions to evolutionary process depend critically on their rate and their effects on traits, notably fitness. Mutation rate and mutation effect can be measured simultaneously through the use of mutation accumulation lines, and previous mutation accumulation studies measuring these parameters have been performed in laboratory conditions. However, estimation of mutation parameters for fitness in wild populations requires assays in environments where mutations are exposed to natural selection and natural environmental variation. Here we quantify mutation parameters in both the wild and greenhouse environments using 100 25th generation Arabidopsis thaliana mutation accumulation lines. We found significantly greater mutational variance and a higher mutation rate for fitness under field conditions relative to greenhouse conditions. However, our field estimates were low when scaled to natural environmental variation. Many of the mutation accumulation lines have increased fitness, counter to the expectation that nearly all mutations decrease fitness. A high mutation rate and a low mutational contribution to phenotypic variation may explain observed levels of natural genetic variation. Our findings indicate that mutation parameters are not fixed, but are variables whose values may reflect the specific environment in which mutations are tested. 相似文献
10.
The accumulation of deleterious mutations is driven by rare fluctuations that lead to the loss of all mutation free individuals, a process known as Muller's ratchet. Even though Muller's ratchet is a paradigmatic process in population genetics, a quantitative understanding of its rate is still lacking. The difficulty lies in the nontrivial nature of fluctuations in the fitness distribution, which control the rate of extinction of the fittest genotype. We address this problem using the simple but classic model of mutation selection balance with deleterious mutations all having the same effect on fitness. We show analytically how fluctuations among the fittest individuals propagate to individuals of lower fitness and have dramatically amplified effects on the bulk of the population at a later time. If a reduction in the size of the fittest class reduces the mean fitness only after a delay, selection opposing this reduction is also delayed. This delayed restoring force speeds up Muller's ratchet. We show how the delayed response can be accounted for using a path-integral formulation of the stochastic dynamics and provide an expression for the rate of the ratchet that is accurate across a broad range of parameters. 相似文献
11.
Iron, brain ageing and neurodegenerative disorders 总被引:1,自引:0,他引:1
There is increasing evidence that iron is involved in the mechanisms that underlie many neurodegenerative diseases. Conditions such as neuroferritinopathy and Friedreich ataxia are associated with mutations in genes that encode proteins that are involved in iron metabolism, and as the brain ages, iron accumulates in regions that are affected by Alzheimer's disease and Parkinson's disease. High concentrations of reactive iron can increase oxidative-stress induced neuronal vulnerability, and iron accumulation might increase the toxicity of environmental or endogenous toxins. By studying the accumulation and cellular distribution of iron during ageing, we should be able to increase our understanding of these neurodegenerative disorders and develop new therapeutic strategies. 相似文献
12.
D. K. DOWLING A. A. MAKLAKOV U. FRIBERG F. HAILER 《Journal of evolutionary biology》2009,22(4):818-827
Two genetic models exist to explain the evolution of ageing – mutation accumulation (MA) and antagonistic pleiotropy (AP). Under MA, a reduced intensity of selection with age results in accumulation of late‐acting deleterious mutations. Under AP, late‐acting deleterious mutations accumulate because they confer beneficial effects early in life. Recent studies suggest that the mitochondrial genome is a major player in ageing. It therefore seems plausible that the MA and AP models will be relevant to genomes within the cytoplasm. This possibility has not been considered previously. We explore whether patterns of covariation between fitness and ageing across 25 cytoplasmic lines, sampled from a population of Drosophila melanogaster, are consistent with the genetic associations predicted under MA or AP. We find negative covariation for fitness and the rate of ageing, and positive covariation for fitness and lifespan. Notably, the direction of these associations is opposite to that typically predicted under AP. 相似文献
13.
Arthur E. Weis Susana M. Wadgymar Michael Sekor Steven J. Franks 《Evolutionary ecology》2014,28(5):885-904
Selection gradient analysis examines the strength and direction of phenotypic selection as well as the curvature of fitness functions, allowing predictions on and insights into the process of evolution in natural populations. However, traditional linear and quadratic selection analyses are not capable of detecting other features of fitness functions, such as asymmetry or thresholds, which may be relevant for understanding key aspects of selection on many traits. In these cases, additional analyses are needed to test specific hypotheses about fitness functions. In this study we used several approaches to analyze selection on a major life-history trait—flowering time—in the annual plant Brassica rapa subjected to experimentally abbreviated and lengthened growing seasons. We used a model that incorporated a tradeoff between the time allocated to growth versus the time allocated to reproduction in order to predict fitness function shape. The model predicted that optimal flowering time shifts to earlier and later dates as the growing season contracts and expands. It also showed the flowering time fitness function to be asymmetrical: reproductive output increases modestly between the earliest and the optimal flowering date, but then falls sharply with later dates, truncating in a ‘tail of zeros’. Our experimental results strongly supported selection for early flowering in short season and selection for late flowering in long season conditions. We also found support for the predicted asymmetry of the flowering time fitness function, including a ‘tail of zeros’ at later flowering dates. The form of the fitness function revealed here has implications for interpreting estimates of selection on flowering time in natural populations and for refining predictions on evolutionary response to climate change. More generally, this study illustrates the value of diverse statistical approaches to understanding mechanisms of natural selection. 相似文献
14.
McGuigan K Petfield D Blows MW 《Evolution; international journal of organic evolution》2011,65(10):2816-2829
Mutation load is a key parameter in evolutionary theories, but relatively little empirical information exists on the mutation load of populations, or the elimination of this load through selection. We manipulated the opportunity for sexual selection within a mutation accumulation divergence experiment to determine how sexual selection on males affected the accumulation of mutations contributing to sexual and nonsexual fitness. Sexual selection prevented the accumulation of mutations affecting male mating success, the target trait, as well as reducing mutation load on productivity, a nonsexual fitness component. Mutational correlations between mating success and productivity (estimated in the absence of sexual selection) were positive. Sexual selection significantly reduced these fitness component correlations. Male mating success significantly diverged between sexual selection treatments, consistent with the fixation of genetic differences. However, the rank of the treatments was not consistent across assays, indicating that the mutational effects on mating success were conditional on biotic and abiotic context. Our experiment suggests that greater insight into the genetic targets of natural and sexual selection can be gained by focusing on mutational rather than standing genetic variation, and on the behavior of trait variances rather than means. 相似文献
15.
Ageing is the greatest risk factor of late-onset neurodegenerative diseases. In the realm of sporadic tauopathies, modelling the process of biological ageing in experimental animals forms the foundation of searching for the molecular origin of pathogenic tau and developing potential therapeutic interventions. Although prior research into transgenic tau models offers valuable lessons for studying how tau mutations and overexpression can drive tau pathologies, the underlying mechanisms by which ageing leads to abnormal tau accumulation remains poorly understood. Mutations associated with human progeroid syndromes have been proposed to be able to mimic an aged environment in animal models. Here, we summarise recent attempts in modelling ageing in relation to tauopathies using animal models that carry mutations associated with human progeroid syndromes, or genetic elements unrelated to human progeroid syndromes, or have exceptional natural lifespans, or a remarkable resistance to ageing-related disorders. 相似文献
16.
Aging or senescence is an age-dependent decline in physiological function, demographically manifest as decreased survival and fecundity with increasing age. Since aging is disadvantageous it should not evolve by natural selection. So why do organisms age and die? In the 1940s and 1950s evolutionary geneticists resolved this paradox by positing that aging evolves because selection is inefficient at maintaining function late in life. By the 1980s and 1990s this evolutionary theory of aging had received firm empirical support, but little was known about the mechanisms of aging. Around the same time biologists began to apply the tools of molecular genetics to aging and successfully identified mutations that affect longevity. Today, the molecular genetics of aging is a burgeoning field, but progress in evolutionary genetics of aging has largely stalled. Here we argue that some of the most exciting and unresolved questions about aging require an integration of molecular and evolutionary approaches. Is aging a universal process? Why do species age at different rates? Are the mechanisms of aging conserved or lineage-specific? Are longevity genes identified in the laboratory under selection in natural populations? What is the genetic basis of plasticity in aging in response to environmental cues and is this plasticity adaptive? What are the mechanisms underlying trade-offs between early fitness traits and life span? To answer these questions evolutionary biologists must adopt the tools of molecular biology, while molecular biologists must put their experiments into an evolutionary framework. The time is ripe for a synthesis of molecular biogerontology and the evolutionary biology of aging. 相似文献
17.
The mitochondrial genome is considered generally to be an innocent bystander in adaptive evolution; however, there is increasing evidence that mitochondrial DNA (mtDNA) is an important contributor to viability and fecundity. Some of this evidence is now well documented, with mtDNA mutations having been shown to play a causal role in degenerative diseases, ageing, and cancer. However, most research on mtDNA has ignored the possibility that other instances exist where mtDNA mutations could have profound fitness consequences. Recent work in humans and other species now indicates that mtDNA mutations play an important role in sperm function, male fertility, and male fitness. Ironically, deleterious mtDNA mutations that affect only males, such as those that impair sperm function, will not be subject to natural selection because mitochondria are generally maternally inherited and could reach high frequencies in populations if the mutations are not disadvantageous in females. Here, we review how such mtDNA mutations might affect the viability of natural populations. We consider factors that increase or decrease the strength of the effect of mtDNA mutations on population viability and discuss what mechanisms exist to mitigate deleterious mtDNA effects. 相似文献
18.
In spatially heterogeneous environments, natural selection for maintenance of adaptation to habitats that contribute little to the population's reproduction is weak. In this paper we model a mechanism that can result in loss of fitness in such marginal habitats, and thus lead to specialisation on the main habitat. It involves accumulation of mutations that are deleterious in the marginal habitat but neutral or nearly so in the main habitat (mutations deleterious in the main habitat and neutral in the marginal habitat have a negligible influence). If the contribution of the marginal habitat to total reproduction in the absence of the mutations is less than a threshold value, selection is too weak to counter accumulation of such mutations. A positive feedback then results in loss of fitness in the marginal habitat. This mechanism does not require antagonistic pleiotropy in adaptation to different habitats, although antagonistic pleiotropy facilitates the mutational collapse of fitness in the marginal habitat. We suggest that deleterious mutations with habitat-specific expression may play a role in the evolution of ecological specialisation and promote evolutionary conservatism of ecological niches. 相似文献
19.
Our understanding of the evolutionary consequences of mutation relies heavily on estimates of the rate and fitness effect of spontaneous mutations generated by mutation accumulation (MA) experiments. We performed a classic MA experiment in which frequent sampling of MA lines was combined with whole genome resequencing to develop a high-resolution picture of the effect of spontaneous mutations in a hypermutator (ΔmutS) strain of the bacterium Pseudomonas aeruginosa. After ∼644 generations of mutation accumulation, MA lines had accumulated an average of 118 mutations, and we found that average fitness across all lines decayed linearly over time. Detailed analyses of the dynamics of fitness change in individual lines revealed that a large fraction of the total decay in fitness (42.3%) was attributable to the fixation of rare, highly deleterious mutations (comprising only 0.5% of fixed mutations). Furthermore, we found that at least 0.64% of mutations were beneficial and probably fixed due to positive selection. The majority of mutations that fixed (82.4%) were base substitutions and we failed to find any signatures of selection on nonsynonymous or intergenic mutations. Short indels made up a much smaller fraction of the mutations that were fixed (17.4%), but we found evidence of strong selection against indels that caused frameshift mutations in coding regions. These results help to quantify the amount of natural selection present in microbial MA experiments and demonstrate that changes in fitness are strongly influenced by rare mutations of large effect. 相似文献
20.
Asexual species accumulate deleterious mutations through an irreversible process known as Muller's ratchet. Attempts to quantify the rate of the ratchet have ignored the role of temporal environmental heterogeneity even though it is common in nature and has the potential to affect overall ratchet rate. Here we examine Muller's ratchet in the context of conditional neutrality (i.e., mutations that are deleterious in some environmental conditions but neutral in others) as well as more subtle changes in the strength (but not sign) of selection. We find that temporal variation increases the rate of the ratchet (mutation accumulation) and the rate of fitness decline over that of populations experiencing constant selection of equivalent average strength. Temporal autocorrelation magnifies the effects of temporal heterogeneity and can allow the ratchet to operate at large population sizes in which it would be halted under constant selection. Classic studies of Muller's ratchet show that the rate of fitness decline is maximized when selection is of a low but intermediate strength. This relationship changes quantitatively with all forms of temporal heterogeneity studied and changes qualitatively when there is temporal autocorrelation in selection. In particular, the rate of fitness decline can increase indefinitely with the strength of selection with some forms of temporal heterogeneity. Our finding that temporal autocorrelation in selection dramatically increases ratchet rate and rate of fitness decline may help to explain the paucity of asexual taxa. 相似文献