Haploid selection, sex ratio bias, and transitions between sex-determining systems

Sex determination is remarkably dynamic; many taxa display shifts in the location of sex-determining loci or the evolution of entirely new sex-determining systems. Predominant theories for why we observe such transitions generally conclude that novel sex-determining systems are favoured by selection if they equalise the sex ratio or increase linkage with a locus that experiences different selection in males versus females. We use population genetic models to extend these theories in two ways: (1) We consider the dynamics of loci very tightly linked to the ancestral sex-determining loci, e.g., within the nonrecombining region of the ancestral sex chromosomes. Variation at such loci can favour the spread of new sex-determining systems in which the heterogametic sex changes (XY to ZW or ZW to XY) and the new sex-determining region is less closely linked (or even unlinked) to the locus under selection. (2) We consider selection upon haploid genotypes either during gametic competition (e.g., pollen competition) or meiosis (i.e., nonmendelian segregation), which can cause the zygotic sex ratio to become biased. Haploid selection can drive transitions between sex-determining systems without requiring selection to act differently in diploid males versus females. With haploid selection, we find that transitions between male and female heterogamety can evolve so that linkage with the sex-determining locus is either strengthened or weakened. Furthermore, we find that sex ratio biases may increase or decrease with the spread of new sex chromosomes, which implies that transitions between sex-determining systems cannot be simply predicted by selection to equalise the sex ratio. In fact, under many conditions, we find that transitions in sex determination are favoured equally strongly in cases in which the sex ratio bias increases or decreases. Overall, our models predict that sex determination systems should be highly dynamic, particularly when haploid selection is present, consistent with the evolutionary lability of this trait in many taxa

Red Queen Dynamics with Non-Standard Fitness Interactions

Antagonistic coevolution between hosts and parasites can involve rapid fluctuations of genotype frequencies that are known as Red Queen dynamics. Under such dynamics, recombination in the hosts may be advantageous because genetic shuffling can quickly produce disproportionately fit offspring (the Red Queen hypothesis). Previous models investigating these dynamics have assumed rather simple models of genetic interactions between hosts and parasites. Here, we assess the robustness of earlier theoretical predictions about the Red Queen with respect to the underlying host-parasite interactions. To this end, we created large numbers of random interaction matrices, analysed the resulting dynamics through simulation, and ascertained whether recombination was favoured or disfavoured. We observed Red Queen dynamics in many of our simulations provided the interaction matrices exhibited sufficient ‘antagonicity’. In agreement with previous studies, strong selection on either hosts or parasites favours selection for increased recombination. However, fast changes in the sign of linkage disequilibrium or epistasis were only infrequently observed and do not appear to be a necessary condition for the Red Queen hypothesis to work. Indeed, recombination was often favoured even though the linkage disequilibrium remained of constant sign throughout the simulations. We conclude that Red Queen-type dynamics involving persistent fluctuations in host and parasite genotype frequencies appear to not be an artefact of specific assumptions about host-parasite fitness interactions, but emerge readily with the general interactions studied here. Our results also indicate that although recombination is often favoured, some of the factors previously thought to be important in this process such as linkage disequilibrium fluctuations need to be reassessed when fitness interactions between hosts and parasites are complex

Predicting the Evolution of Sex on Complex Fitness Landscapes

Most population genetic theories on the evolution of sex or recombination are based on fairly restrictive assumptions about the nature of the underlying fitness landscapes. Here we use computer simulations to study the evolution of sex on fitness landscapes with different degrees of complexity and epistasis. We evaluate predictors of the evolution of sex, which are derived from the conditions established in the population genetic literature for the evolution of sex on simpler fitness landscapes. These predictors are based on quantities such as the variance of Hamming distance, mean fitness, additive genetic variance, and epistasis. We show that for complex fitness landscapes all the predictors generally perform poorly. Interestingly, while the simplest predictor, ΔVarHD, also suffers from a lack of accuracy, it turns out to be the most robust across different types of fitness landscapes. ΔVarHD is based on the change in Hamming distance variance induced by recombination and thus does not require individual fitness measurements. The presence of loci that are not under selection can, however, severely diminish predictor accuracy. Our study thus highlights the difficulty of establishing reliable criteria for the evolution of sex on complex fitness landscapes and illustrates the challenge for both theoretical and experimental research on the origin and maintenance of sexual reproduction

Effects of Transdermal Fentanyl Treatment on Acute Pain and Inflammation in Rats with Adjuvant-induced Monoarthritis

Eliminating unnecessary pain is an important requirement of performing animal experimentation, including reducing and controlling pain of animals used in pain research. The goal of this study was to refine an adjuvant-induced monoarthritis model in rats by providing analgesia with a transdermal fentanyl solution (TFS). Male and female Sprague-Dawley rats, single- or pair-housed, were injected with 20 μL of complete Freund adjuvant (CFA) into the left ankle joint. CFA-injected rats treated with a single dose of transdermal fentanyl solution (0.33 or 1 mg/kg) were compared with an untreated CFA-injected group and sham groups that received either no treatment or TFS treatment (1 mg/kg) during 72 h. At the tested doses, TFS reduced mechanical hyperalgesia and improved the mobility, stance, rearing, and lameness scores at 6 h after CFA injection. Joint circumferences were not reduced by TFS treatment, and no significant differences were detected between the 2 doses of TFS, or between single- and pair-housed rats. Treatment with TFS did not appear to interfere with model development and characteristics. However, overall, the analgesic effect was transient, and several opioid-related side effects were observed

The evolution o constitutive and induced defences to infectious disease

In response to infectious disease, hosts typically mount both constitutive and induced defences. Constitutive defence prevents infection in the first place, while induced defence typically shortens the infectious period. The two routes to defence, therefore, have very different implications not only to individuals but also to the epidemiology of the disease. Moreover, the costs of constitutive defences are likely to be paid even in the absence of disease, while induced defences are likely to incur the most substantial costs when they are used in response to infection. We examine theoretically the evolutionary implications of these fundamental differences. A key result is that high virulence in the parasite typically selects for higher induced defences even if they result in immunopathology leading to very high disease mortality. Disease impacts on fecundity are critical to the relative investment in constitutive and induced defence with important differences found when parasites castrate their hosts. The trade-off between constitutive and induced defence has been cited as a cause of the diversity in defence, but we show that the trade-off alone is unlikely to lead to diversity. Our models provide a framework to examine relative investment in different defence components both experimentally and in the field

Spirometry reference equations for central European populations from school age to old age.

Spirometry reference values are important for the interpretation of spirometry results. Reference values should be updated regularly, derived from a population as similar to the population for which they are to be used and span across all ages. Such spirometry reference equations are currently lacking for central European populations. To develop spirometry reference equations for central European populations between 8 and 90 years of age. We used data collected between January 1993 and December 2010 from a central European population. The data was modelled using "Generalized Additive Models for Location, Scale and Shape" (GAMLSS). The spirometry reference equations were derived from 118'891 individuals consisting of 60'624 (51%) females and 58'267 (49%) males. Altogether, there were 18'211 (15.3%) children under the age of 18 years. We developed spirometry reference equations for a central European population between 8 and 90 years of age that can be implemented in a wide range of clinical settings

Distributions of epistasis in microbes fit predictions from a fitness landscape model.

How do the fitness effects of several mutations combine? Despite its simplicity, this question is central to the understanding of multilocus evolution. Epistasis (the interaction between alleles at different loci), especially epistasis for fitness traits such as reproduction and survival, influences evolutionary predictions "almost whenever multilocus genetics matters". Yet very few models have sought to predict epistasis, and none has been empirically tested. Here we show that the distribution of epistasis can be predicted from the distribution of single mutation effects, based on a simple fitness landscape model. We show that this prediction closely matches the empirical measures of epistasis that have been obtained for Escherichia coli and the RNA virus vesicular stomatitis virus. Our results suggest that a simple fitness landscape model may be sufficient to quantitatively capture the complex nature of gene interactions. This model may offer a simple and widely applicable alternative to complex metabolic network models, in particular for making evolutionary predictions

Anti-nausea effects and pharmacokinetics of ondansetron, maropitant and metoclopramide in a low-dose cisplatin model of nausea and vomiting in the dog: a blinded crossover study

Nausea is a subjective sensation which is difficult to measure in non-verbal species. The aims of this study were to determine the efficacy of three classes of antiemetic drugs in a novel low dose cisplatin model of nausea and vomiting and measure change in potential nausea biomarkers arginine vasopressin (AVP) and cortisol. A four period cross-over blinded study was conducted in eight healthy beagle dogs of both genders. Dogs were administered 18 mg/m2 cisplatin intravenously, followed 45 min later by a 15 min infusion of either placebo (saline) or antiemetic treatment with ondansetron (0.5 mg/kg; 5-HT3 antagonist), maropitant (1 mg/kg; NK1 antagonist) or metoclopramide (0.5 mg/kg; D2 antagonist). The number of vomits and nausea associated behaviours, scored on a visual analogue scale, were recorded every 15 min for 8 h following cisplatin administration. Plasma samples were collected to measure AVP, cortisol and antiemetic drug concentrations

Epistasis for Growth Rate and Total Metabolic Flux in Yeast

Studies of interactions between gene deletions repeatedly show that the effect of epistasis on the growth of yeast cells is roughly null or barely positive. These observations relate generally to the pace of growth, its costs in terms of required metabolites and energy are unknown. We measured the maximum rate at which yeast cultures grow and amounts of glucose they consume per synthesized biomass for strains with none, single, or double gene deletions. Because all strains were maintained under a fermentative mode of growth and thus shared a common pattern of metabolic processes, we used the rate of glucose uptake as a proxy for the total flux of metabolites and energy. In the tested sample, the double deletions showed null or slightly positive epistasis both for the mean growth and mean flux. This concordance is explained by the fact that average efficiency of converting glucose into biomass was nearly constant, that is, it did not change with the strength of growth effect. Individual changes in the efficiency caused by gene deletions did have a genetic basis as they were consistent over several environments and transmitted between single and double deletion strains indicating that the efficiency of growth, although independent of its rate, was appreciably heritable. Together, our results suggest that data on the rate of growth can be used as a proxy for the rate of total metabolism when the goal is to find strong individual interactions or estimate the mean epistatic effect. However, it may be necessary to assay both growth and flux in order to detect smaller individual effects of epistasis

Fitness Ranking of Individual Mutants Drives Patterns of Epistatic Interactions in HIV-1

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