An analysis of selection at two loci in fluctuating populations of Microtus.
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Animals↗
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The cost of fluctuating inbreeding depression.
We present a phenotypic model for the evolution of self-fertilization in an infinite population of annual hermaphrodites for the case in which fitness and inbreeding depression vary among generations (e.g., due to fluctuations in the environment from year to year). Conditions for the evolution of selfing, mixed mating, and outcrossing are derived and are compared with results from numerical calculations that assume a normal distribution of inbreeding depression. In contrast to the situation in which inbreeding depression does not vary, when inbreeding depression fluctuates in a stochastic manner among generations with a mean less than 0.5, selfing is not necessarily selected. Thus, fluctuating inbreeding depression can be viewed as an additional cost of selfing that may stabilize mixed mating systems. These results emphasize the need to take into account fluctuating inbreeding depression in empirical studies aimed at understanding mating system evolution in annuals.
Biological Evolution↗
Analysis of Eigen's equations for selection of biological molecules with fluctuating mutation rates.
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Biological Evolution↗
Theoretical study of near neutrality. II. Effect of subdivided population structure with local extinction and recolonization.
There are several unsolved problems concerning the model of nearly neutral mutations. One is the interaction of subdivided population structure and weak selection that spatially fluctuates. The model of nearly neutral mutations whose selection coefficient spatially fluctuates has been studied by adopting the island model with periodic extinction-recolonization. Both the number of colonies and the migration rate play significant roles in determining mutants' behavior, and selection is ineffective when the extinction-recolonization is frequent with low migration rate. In summary, the number of mutant substitutions decreases and the polymorphism increases by increasing the total population size, and/or decreasing the extinction-recolonization rate. However, by increasing the total size of the population, the mutant substitution rate does not become as low when compared with that in panmictic populations, because of the extinction-recolonization, especially when the migration rate is limited. It is also found that the model satisfactorily explains the contrasting patterns of molecular polymorphisms observed in sibling species of Drosophila, including heterozygosity, proportion of polymorphism and fixation index.
Animals↗
Convergent evolution of Darwin's finches caused by introgressive hybridization and selection.
Between 1973 and 2003 mean morphological features of the cactus finch, Geospiza scandens, and the medium ground finch, G. fortis, populations on the Galápagos island of Daphne Major were subject to fluctuating directional selection. An increase in bluntness or robustness in the beak of G. scandens after 1990 can only partly be explained by selection. We use 16 microsatellite loci to test predictions of the previously proposed hypothesis that introgressive hybridization contributed to the trend, resulting in genes flowing predominantly from G. fortis to G. scandens. To identify F1 hybrids and backcrosses we use pedigrees where known, supplemented by the results of assignment tests based on 14 autosomal loci when parents were not known. We analyze changes in morphology and allelic composition in the two populations over a period of 15-20 years. With samples that included F1 hybrids and backcrosses, the G. scandens population became more similar to the G. fortis population both genetically and morphologically. Gene flow between species was estimated to be three times greater from G. fortis to G. scandens than in the opposite direction, resulting in a 20% reduction in the genetic difference between the species. Nevertheless, removing identified F1 hybrids and backcrosses from the total sample and reanalyzing the traits did not eliminate the convergence. The two species also converged in beak shape by 22.2% and in body size by 45.5%. A combination of introgressive hybridization and selection jointly provide the best explanation of convergence in morphology and genetic constitution under the changed ecological conditions following a major El Niño event in 1983. The study illustrates how species without postmating barriers to gene exchange can alternate between convergence and divergence when environmental conditions oscillate.
Animals↗
[Persistence of the control of the fluctuations of heart rate in the anesthetized and pithed adult rat. Effect of enteraminergic drugs].
Spontaneous fluctuations in heart rate were analyzed by spectral analysis in the ether anesthetized and pithed adult rat. In order to investigate the changes in the spectral pattern of the fluctuations, the selective 5HT-2 and -3 isoreceptor blockers ritanserin and BRL 43694A were used. In both the experimental conditions, ritanserin blockade led to dose-dependent increased fluctuations in HR low and high frequencies. In both the anesthetized and pithed rats, the low frequency range HR fluctuations were drastically reduced by BRL 43694A.
Anesthesia↗
Drug treatment of Parkinson's disease in the 1990s. Achievements and future possibilities.
Advances in the medical treatment of Parkinson's disease have improved the disability related to complications of long term levodopa therapy, including motor fluctuations, dyskinesias and neuropsychiatric toxicity. A range of new dopamine agonists are in various stages of preclinical and clinical development. Cabergoline appears to be effective in improving moderate motor fluctuations, and a number of dopamine partial agonists that can act as either agonists or antagonists depending on the degree of denervation and receptor sensitivity are being investigated. Apomorphine represents a significant advance in the treatment of well developed motor fluctuations in selected patients who are able to master the technique of subcutaneous administration. The catecholamine-O-methyl transferase inhibitors are proving useful in phase III studies in the management of patients with moderate motor fluctuations. A role for glutamate antagonists is supported by animal and early clinical data, although the poor therapeutic index associated with the currently available nonselective, noncompetitive glutamate antagonists has prompted a search for more selective antagonists with less toxicity. The management of levodopa-induced dyskinesias remains a major therapeutic challenge. Some reports of dopamine partial agonists, selective D2 receptor antagonists and atypical antipsychotics being useful await confirmation. Neuropsychiatric toxicity probably remains the major dose-limiting adverse effect of levodopa and is a major reason for parkinsonian patients being admitted to nursing homes. The development of new atypical antipsychotics with improved therapeutic indices, along with the possible use of serotonergic antagonists, may improve management of this difficult problem. The challenge will be to fit these new forms of treatment into our present range of available drugs and to assess their relative role within the emerging framework of functional neurosurgery for parkinsonian disability.
Antiparkinson Agents↗
Directional selection and developmental stability: evidence from fluctuating asymmetry of morphometric characters in rats.
Developmental stability was assessed among lines of rats selected for increased (up lines), decreased (down lines), and no body weight gain (controls) by the measurement of fluctuating asymmetry (FA) in 11 bilateral osteometric characters. This was done primarily to test the hypothesis that developmental stability should be lower (and thus FA higher) in both selection lines compared to the control line. FA values were obtained for all characters in each sex, line, and replicate (two each) within lines. Expressed as a proportion of the total variance, the FA values ranged from about 2% to over 50%, the average being 23%. FA for 3 of the 11 characters showed statistically significant differences among the lines, and in a multivariate analysis of variance, lines (but not sex or replicates) also showed overall significance (P less than 0.05). For the pooled sexes and replicates, seven of 11 FA values in the high line were greater than the comparable values in the control line (especially that for femur length), this conforming with theoretical expectations. Only one FA value in the down line was greater than that of the controls, however, and it was hypothesized that this was a consequence of the action of natural selection opposing artificial selection for decreased body weight gain.
Animals↗
Density-dependent selection on horn phenotype in Soay sheep.
In the naturally regulated population of Soay sheep (Ovis aries L.) on Hirta (St Kilda), 12% of males and 24% of females have scurred horns. This trait reduces the competitive ability of males in the mating season but is associated with higher overwinter survival rates in both sexes (Moorcroft et al. 1996). In this paper, we show that scurred females also show higher conception rates and weaning rates than non-scurred ones, and that these differences are associated with heavier maternal body weight as well as higher birth weights of offspring. Selection pressures favouring scurredness in females vary with population density and are generally more pronounced among younger animals than adults. We discuss these results with reference to recent suggestions that temporal fluctuation in selection pressures may help to maintain genetic diversity within populations. We suggest that selection against scurredness operating through male mating success is opposed by selection favouring this trait, operating through the breeding success of females and the survival of both sexes.
Age Factors↗
Evaluation of cancer chemopreventive agents using clones derived from a human prostate cancer cell line.
BACKGROUND: The successful use of clonal selection through fluctuation analysis of human cancer cells as a means for studying tumor progression has been previously reported. MATERIALS AND METHODS: Three clones derived from a parental population of human prostate cancer (LNCaP) cells were selected based on proliferation, hormone sensitivity and anchorage-independent growth. The effects of five potential cancer preventive agents were evaluated using cell proliferation, anchorage-independent growth and apoptosis as end-points. RESULTS: Clone 21 cells, which represent a presumptive normal phenotype, were generally more sensitive than Clone 17 and Clone 6 cells, which represent a more malignant phenotype, to fluasterone, 7beta-HF, L-selenomethionine and troglitazone in assays for proliferation and/or apoptosis. CONCLUSION: The results confirm the efficacy of the above agents as cancer chemopreventive agents and support our contention that clonal selection of established human cancer cells provides a model to study the efficacy of chemopreventive agents.
Anticarcinogenic Agents↗
Dynamics of genome change in the E2/NS1 region of hepatitis C virus in vivo.
To substantiate and extend the quasispecies model of hepatitis C virus (HCV), we made a pairwise comparison in the nucleotide and deduced amino acid sequences for multiple recombinant clones of the E2/NS1 region, which derived from each blood sample taken from five patients of subtype II or subtype III infection at different stages. Sequence heterogeneity among the clones was generally high. The heterogeneity, however, changed temporally and appeared to be significantly lowered after interferon therapy. The temporal fluctuation involved selection of particular amino acids at particular positions, which had represented only a minor fraction or had been absent in the previous clones. Evolution of defective viruses was featured by most of the cases, the proportion of which also fluctuated temporally and was extremely high at a certain stage in one of the patients. A comparison was also made among the clones from different stages of each patient and revealed highly divergent clones. An extreme case of subtype III infection showed sequence differences well beyond those among chronologically and geographically different isolates of subtype I or subtype II, which were defined by the same calculation of available sequence data. These features of HCV genome suggest that the virus could circulate as an extremely heterogeneous population including defective viruses and that this heterogeneity lends itself to selection pressures including interferon therapy and host immune response. Our results also indicate an absolute need of population based approach in HCV genetics.
Aged↗
Constraints on adaptive mutations in the codling moth Cydia pomonella (L.): measuring fitness trade-offs and natural selection.
Adaptive changes in populations encountering a new environment are often constrained by deleterious pleiotropic interactions with ancestral physiological functions. Evolutionary responses of populations can thus be limited by natural selection under fluctuating environmental conditions, if the adaptive mutations are associated with pleiotropic fitness costs. In this context, we have followed the evolution of the frequencies of insecticide-resistant mutants of Cydia pomonella when reintroduced into an untreated environment. The novel set of selective forces after removal of insecticide pressure led to the decline of the frequencies of resistant phenotypes over time, suggesting that the insecticide-adapted genetic variants were selected against the absence of insecticide (with a selective coefficient estimated at 0.11). The selective coefficients were also estimated for both the major cytochrome P450-dependent monooxygenase (MFO) and the minor glutathione S-transferase (GST) systems (0.17 and negligible, respectively), which have been previously shown to be involved in resistance. The involvement of metabolic systems acting both through xenobiotic detoxification and biosynthetic pathways of endogenous compounds may be central to explaining the deleterious physiological consequences resulting from pleiotropy of adaptive changes. The estimation of the magnitude of the fitness cost associated with insecticide resistance in C. pomonella suggests that resistance management strategies exclusively based on insecticide alternations would be unlikely to delay such a selection process.
Animals↗
Orientation selectivity in visual cortex by fluctuation-controlled criticality.
Within a large-scale neuronal network model of macaque primary visual cortex, we examined how intrinsic dynamic fluctuations in synaptic currents modify the effect of strong recurrent excitation on orientation selectivity. Previously, we showed that, using a strong network inhibition countered by feedforward and recurrent excitation, the cortical model reproduced many observed properties of simple and complex cells. However, that network's complex cells were poorly selective for orientation, and increasing cortical self-excitation led to network instabilities and unrealistically high firing rates. Here, we show that a sparsity of connections in the network produces large, intrinsic fluctuations in the cortico-cortical conductances that can stabilize the network and that there is a critical level of fluctuations (controllable by sparsity) that allows strong cortical gain and the emergence of orientation-selective complex cells. The resultant sparse network also shows near contrast invariance in its selectivity and, in agreement with recent experiments, has extracellular tuning properties that are similar in pinwheel center and iso-orientation regions, whereas intracellular conductances show positional dependencies. Varying the strength of synaptic fluctuations by adjusting the sparsity of network connectivity, we identified a transition between the dynamics of bistability and without bistability. In a network with strong recurrent excitation, this transition is characterized by a near hysteretic behavior and a rapid rise of network firing rates as the synaptic drive or stimulus input is increased. We discuss the connection between this transition and orientation selectivity in our model of primary visual cortex.
Animals↗
A microbial modified prisoner's dilemma game: how frequency-dependent selection can lead to random phase variation.
Random phase variation (RPV) is a control strategy in which the expression of a cell state or phenotype randomly alternates between discrete 'on' and 'off' states. Though this mode of control is common for bacterial virulence factors like pili and toxins, precise conditions under which RPV confers an advantage have not been well defined. In Part I of this study, we predicted that fluctuating environments select for RPV if transitions between different selective environments cannot be reliably sensed (J. Theor. Biol. (2005)). However, selective forces both inside and outside of human hosts are also likely to be frequency dependent in the sense that the fitnesses of some bacterial states are greatest when rare. Here we show that RPV at slow rates can provide a survival advantage in such a frequency-dependent environment by generating population heterogeneity, essentially mimicking a polymorphism. More surprisingly, RPV at a faster 'optimal' rate can shift the population composition toward an optimal growth rate that exceeds that possible for polymorphic populations, but this optimal strategy is not evolutionarily stable. The population would be most fit if all cells randomly phase varied at the optimal rate, but individual cells have a growth-rate incentive to defect (mutate) to other switching rates or non-phase variable phenotype expression, leading to an overall loss of fitness of the individual and the population. This scenario describes a modified Prisoner's Dilemma game (Evolution and the Theory of Games, Cambridge University Press, Cambridge, New York, 1982, viii, 224pp.; Nature 398 (6726) (1999) 367), with random phase variation at optimal switching rates serving as the cooperation strategy.
Bacteria↗
[Development of an automatic analytical tool for quantitative cerebral blood flow measurement using 99mTc-ECD, and verification of clinical examples].
The following process conventionally has been followed to develop quantitative images of cerebral blood flow: (1) mean cerebral blood flow (mCBF) is calculated by the Patlak plot method; (2) a SPECT slice that includes the basal ganglia is selected; and (3) based on the value of mCBF calculated by the Patlak plot method, the SPECT slice is corrected by the Lassen method and developed into a SPECT image of quantitative regional cerebral blood flow. However, this process is complicated, and the values of rCBF have been reported to fluctuate because selection of the SPECT slice and the ROI setting are in the hands of the operator. We have developed new software that automates this analysis. This software enables automatic processing simply by inputting the value of mCBF in the normal hemisphere. Since there is no need for manual operations such as setting the ROI, reproducibility is improved as well. Regional cerebral blood flow as determined by this software is quite similar to that calculated by the conventional method, so the existing clinical evaluation does not need to be changed. This software is considered to be useful.
Adult↗
Unpredictable evolution in a 30-year study of Darwin's finches.
Evolution can be predicted in the short term from a knowledge of selection and inheritance. However, in the long term evolution is unpredictable because environments, which determine the directions and magnitudes of selection coefficients, fluctuate unpredictably. These two features of evolution, the predictable and unpredictable, are demonstrated in a study of two populations of Darwin's finches on the Galápagos island of Daphne Major. From 1972 to 2001, Geospiza fortis (medium ground finch) and Geospiza scandens (cactus finch) changed several times in body size and two beak traits. Natural selection occurred frequently in both species and varied from unidirectional to oscillating, episodic to gradual. Hybridization occurred repeatedly though rarely, resulting in elevated phenotypic variances in G. scandens and a change in beak shape. The phenotypic states of both species at the end of the 30-year study could not have been predicted at the beginning. Continuous, long-term studies are needed to detect and interpret rare but important events and nonuniform evolutionary change.
Animals↗
Environmental fluctuations and the maintenance of genetic diversity in age or stage-structured populations.
The ability of random fluctuations in selection to maintain genetic diversity is greatly increased when generations overlap. This result has been derived previously using genetic models with very special assumptions about the population age structure. Here we explore its robustness in more realistic population models, with very general age structure or physiological structure. For a range of genetic models (haploid, diploid, single and multi-locus) we find that the condition for maintaining genetic diversity generalizes almost without change. Genetic diversity is maintained by selection if a product of the form (generation overlap) x (selection intensity) x (variability in the selection regime) is sufficiently large, where the generation overlap is measured in units of Fisher's reproductive value. This conclusion is based on a local evolutionary stability analysis, which differs from the standard "protected polymorphism" criterion for the maintenance of genetic diversity. Simulation results match the predictions from the local stability analysis, but not those from the protected polymorphism criterion. The condition obtained here for maintaining genetic diversity requires fitness fluctuations that are substantial but well within the range observed in many studies of natural populations.
Aging↗
Variations of synaptotagmin I, synaptotagmin IV, and synaptophysin mRNA levels in rat hippocampus during the estrous cycle.
Periodic changes in ovarian steroid levels during fertility cycles affect learning both in humans and in rats in parallel with electrophysiological and morphological fluctuations in selective neuronal populations. In particular, during the estrous cycle of the female rat, hippocampal CA1 region undergoes cyclic modifications in synaptic density. To investigate the molecular mechanisms involved in synaptic remodeling during the estrous cycle, we analyzed the expression of three presynaptic markers, synaptotagmin I, synaptotagmin IV, and synaptophysin, in the female adult rat brain by in situ hybridization. Relative abundance in mRNA for these three markers was quantified at four phases of the estrous cycle: diestrus, proestrus (AM and PM), and estrus. mRNA levels for syt1 exhibited cyclic variations in pyramidal neurons of the CA3 region of hippocampus during the estrous cycle, while mRNA levels for syt4 and SYN were relatively invariant in this or other regions of the hippocampus. Because CA3 pyramidal neurons make synaptic contacts in CA1, modulation of syt1 expression in CA3 may participate in the changes in synaptic density observed in CA1 during the estrous cycle. Furthermore, both syt1 and SYN mRNA varied cyclically in layer II, but not in layer III of entorhinal cortex, while syt4 remained unchanged throughout the cycle. These data suggest that regular variations in steroid hormone levels during fertility cycles may alter the properties of several networks involved in information processing and learning and memory through altered levels of presynaptic proteins.
Animals↗