Genotype-by-environment interactions and sexual selection

Genotype-by-environment interactions (G x Es) describe genetic variation for phenotypic plasticity, such that the relative performance of genotypes varies across environments. These interactions have been studied in the context of natural selection for decades, but research interest in the evolutionary consequences of G x Es in sexual traits is more recent. Theory suggests that G x Es in sexual traits could be of fundamental importance to the operation of sexual selection across heterogeneous environments, but empirical research lags behind the theory. In this thesis, I review the current literature on the role of G x Es in sexual selection and identify areas for further research. Using cuticular hydrocarbons (CHCs) in the fruit fly Drosophila simulans as a model system for sexual selection, I examine G x Es in trait expression and quantify the effect of these G x Es in terms of sexual signal reliability and the coevolution of male and female sexual traits. To do so, I use a combination of quantitative genetics and laboratory environmental manipulations. First, I demonstrate that male CHC profile is subject to sexual selection through female mate choice and find some variation in patterns of mate choice across diets and temperatures (Chapter 3). Next, I identify G x Es in male and female CHC expression across diets and temperatures, although G x Es in male CHC profile across temperatures are weak (Chapter 4). I find that G x Es in male CHC expression can cause sexual signal unreliability, as predicted by theory, since male CHCs do not reliably signal heritable aspects of male attractiveness across diets and temperatures (Chapter 5). I also find G x Es in some aspects of female mate choice across temperatures (Chapter 6). In spite of the evidence for signal unreliability and variation in female mate choice across environments, I show that the overall outcome of mate choice is unaffected by G x Es, such that the same male genotypes are attractive across diets and temperatures (Chapters 5 and 6). From my results, it seems likely that females assess male attractiveness based on multiple male sexual signals, so that whilst male CHCs influence mate choice, CHC profile does not necessarily correlate well with overall male attractiveness. I discuss the implications of these results for the evolution of sexual traits and the genetic covariance between male and female sexual traits across environments. The research in this thesis highlights the importance of multivariate studies of sexual selection across environments for a more complete understanding of the evolution of sexual traits.ES

Sexual dimorphism in the Drosophila melanogaster (Diptera: Drosophilidae) metabolome increases throughout development

The expression of sexually dimorphic phenotypes from a shared genome between males and females is a longstanding puzzle in evolutionary biology. Increasingly, research has made use of transcriptomic technology to examine the molecular basis of sexual dimorphism through gene expression studies, but even this level of detail misses the metabolic processes that ultimately link gene expression with the whole organism phenotype. We use metabolic profiling in Drosophila melanogaster to complete this missing step, with a view to examining variation in male and female metabolic profiles, or metabolomes, throughout development. We show that the metabolome varies considerably throughout larval, pupal and adult stages. We also find significant sexual dimorphism in the metabolome, although only in pupae and adults, and the extent of dimorphism increases throughout development. We compare this to transcriptomic data from the same population and find that the general pattern of increasing sex differences throughout development is mirrored in RNA expression. We discuss our results in terms of the usefulness of metabolic profiling in linking genotype and phenotype to more fully understand the basis of sexually dimorphic phenotypes

Detecting differential gene expression in blastocysts following pronuclear transfer.

Nuclear transfer techniques (a.k.a. mitochondrial replacement therapies) are currently under development to provide a route to eliminating particular instances of mitochondrial disease from the germline. Before these kinds of techniques are implemented clinically it is of primary concern that their safety and efficacy is established. In a recent paper, Hyslop et al. (Nature 534:383-386, 2016. doi: 10.1038/nature18303 ) utilized a specific version of pronuclear transfer to investigate the consequences for gene expression in the developing embryo, which may indicate whether or not developmental pathways have been perturbed. However, the study was only able to include a small number of blastocysts within each treatment group, although a larger number of single cell expression profiles from each blastocyst were acquired. Using simulated datasets we show that the size and experimental design of this study cannot provide conclusive evidence that expression profiles of manipulated or control samples are indistinguishable from one another due to low power. These simulations also illustrate why visual inspections of principle component analyses used in the study cannot replace statistical modeling of treatment effects

Are deprivation-specific cancer survival patterns similar according to individual- and area-based measures? A cohort study of patients diagnosed with five malignancies in England & Wales, 2008-2016

Objective: To investigate if measured inequalities in cancer survival differ when using individual- (‘person’) compared to area- (‘place’) based measures of deprivation for three socio-economic dimensions: income, deprivation and occupation Design: Cohort studySetting: Data from the Office for National Statistics (ONS) Longitudinal Study of England and Wales, UK, linked to the National Cancer Registration DatabaseParticipants: Patients diagnosed with cancers of the colorectum, breast, prostate, bladder or with Non-Hodgkin Lymphoma (NHL) during the period 2008-2016Primary and secondary outcome measures: Differentials in net survival between groups defined by individual wage, occupation and education compared to those obtained from corresponding area-level metrics using the English and Welsh Indices of Multiple Deprivation (IMD).Results: Survival was negatively associated with area-based deprivation irrespective of the type analysed, although a trend from least to most deprived was not always observed. Socio-economic differences were present according to individually-measured socio-economic groups although there was an absence of a consistent ‘gradient’ in survival. The magnitude of differentials was similar for area-based and individually-derived measures of deprivation, which was unexpected.Conclusion: These unique data suggest that the socio-economic influence of ‘person’ is different to that of ‘place’ with respect to cancer outcomes. This has implications for health policy aimed at reducing inequalities. Further research could further consider the separate and additional influence of area-based deprivation over individual-level characteristics (contextual effects) as well as investigate the geographic, socio-economic and healthcare related characteristics of areas with poor outcomes in order to inform policy intervention

Assessment of the concordance between individual- and area-level measures of socio-economic deprivation in a cancer patient cohort in England and Wales

ObjectivesMost research on health inequalities uses aggregated deprivation scores assigned to the small area where the patient lives; however, the concordance between aggregate area-level deprivation measures and personal deprivation experienced by individuals living in the area is poorly understood. Our objective was to examine the agreement between individual and ecological deprivation. We tested the concordance between metrics of income, occupation and education at individual and area levels, and assessed the reliability of area-based deprivation measures to predict individual deprivation circumstances.SettingEngland and WalesParticipantsA cancer patient cohort of 9,547 individuals extracted from the ONS Longitudinal Study.OutcomesWe quantified the concordance between measures of income, occupation and education at individual and area level. In addition, we used ROC curves and the area under the curve (AUC) to assess the reliability of area-based deprivation measures to predict individual deprivation circumstances.ResultsWe found low concordance between individual and area-level indicators of deprivation (Cramer’s V statistics range between 0.07 and 0.20). The most commonly used indicator in health inequalities research, area-based income deprivation, was a poor predictor of individual income status (AUC between 0.56 and 0.59), whereas education and occupation were slightly better predictors (AUC between 0.62 and 0.65). The results were consistent across sexes and across six major cancer types.ConclusionsOur results indicate that ecological deprivation measures capture only part of the relationship between deprivation and health outcomes, especially with respect to income measurement. This has important implications for our understanding of the relationship between deprivation and health, and, as a consequence, healthcare policy. The results have a wide-reaching impact for the way in which we measure and monitor inequalities, and in turn, fund and organise current UK healthcare policy aimed at reducing them

An investigation of cancer survival inequalities associated with individual-level socio-economic status, area-level deprivation, and contextual effects, in a cancer patient cohort in England and Wales

BackgroundPeople living in more deprived areas of high-income countries have lower cancer survival than those in less deprived areas. However, associations between individual-level socio-economic circumstances and cancer survival are relatively poorly understood. Moreover, few studies have addressed contextual effects, where associations between individual-level socio-economic status and cancer survival vary depending on area-based deprivation. MethodsUsing 9,276 individual-level observations from a longitudinal study in England and Wales, we examined the association with cancer survival of area-level deprivation and individual-level occupation, education, and income, for colorectal, prostate and breast cancer patients aged 20-99 at diagnosis. With flexible parametric excess hazard models, we estimated excess mortality across individual-level and area-level socio-economic variables and investigated contextual effects. ResultsFor colorectal cancers, we found evidence of an association between education and cancer survival in men with Excess Hazard Ratio EHR=0.80, 95% CI [0.60;1.08] comparing “degree-level qualification and higher” to “no qualification” and EHR=0.74 [0.56;0.97] comparing “apprenticeships and vocational qualification” to “no qualification”, adjusted on occupation and income; and between occupation and cancer survival for women with EHR=0.77 [0.54;1.10] comparing “managerial/professional occupations” to “manual/technical,” and EHR=0.81 [0.63;1.06] comparing “intermediate” to “manual/technical”, adjusted on education and income. For breast cancer in women, we found evidence of an association with income (EHR=0.52 [0.29;0.95] for the highest income quintile compared to the lowest, adjusted on education and occupation), while for prostate cancer, all three individual-level socio-economic variables were associated to some extent with cancer survival. We found contextual effects of area-level deprivation on survival inequalities between occupation types for breast and prostate cancers, suggesting wider individual-level inequalities in more deprived areas compared to least deprived areas. Individual-level income inequalities for breast cancer were more evident than an area-level differential, suggesting that area-level deprivation might not be the most effective measure of inequality for this cancer. For colorectal cancer in both sexes, we found evidence suggesting area- and individual-level inequalities, but no evidence of contextual effects. ConclusionsFindings highlight that both individual and contextual effects contribute to inequalities in cancer outcomes. These insights provide potential avenues for more effective policy and practice

Causes of male sexual trait divergence in introduced populations of guppies

Males from different populations of the same species often differ in their sexually selected traits. Variation in sexually selected traits can be attributed to sexual selection if phenotypic divergence matches the direction of sexual selection gradients among populations. However, phenotypic divergence of sexually selected traits may also be influenced by other factors, such as natural selection and genetic constraints. Here, we document differences in male sexual traits among six introduced Australian populations of guppies and untangle the forces driving divergence in these sexually selected traits. Using an experimental approach, we found that male size, area of orange coloration, number of sperm per ejaculate and linear sexual selection gradients for male traits differed among populations. Within populations, a large mismatch between the direction of selection and male traits suggests that constraints may be important in preventing male traits from evolving in the direction of selection. Among populations, however, variation in sexual selection explained more than half of the differences in trait variation, suggesting that, despite within-population constraints, sexual selection has contributed to population divergence of male traits. Differences in sexual traits were also associated with predation risk and neutral genetic distance. Our study highlights the importance of sexual selection in trait divergence in introduced populations, despite the presence of constraining factors such as predation risk and evolutionary history

Addition of abiraterone to first-line long-term hormone therapy in prostate cancer (STAMPEDE): Model to estimate long-term survival, quality-adjusted survival, and cost-effectiveness

Background: Results from randomised trials show adding abiraterone acetate plus prednisolone (AAP) to standard of care (SOC) improves disease-free and overall survival in men with prostate cancer (PC) starting long-term hormone therapy for first time. Formal assessment is required of whether funding AAP here shows appropriate use of resources. This cost-effectiveness decision model tests if giving AAP to these patients is cost-effective using costs from English National Health Service, the largest nation where STAMPEDE recruited. / Methods: Health outcomes and costs were modelled using patient data from AAP comparison of STAMPEDE (recruitment 2011-14). This included 1917 men with high-risk, locally advanced metastatic or recurrent PC starting 1st-line hormone therapy. SOC was hormone therapy for ≥2 years with radiotherapy in pre-selected patients. If allocated to research group, AAP (AA 1000mg/day, P 5mg/day) was added to SOC. The model makes lifetime predictions of survival, costs and quality-adjusted lifeyears (QALYs), with costs and QALYs discounted at 3.5% annually. Sensitivity analyses were performed. / Results: The model predicted AAP would extend survival (discounted quality-adjusted survival) by 2.68y (1.46 QALYs) for metastatic patients and 0.30y (0.29 QALYs) for non-metastatic. The cost of AAP means it is not currently cost-effective in this setting, including with Patient Access Scheme costs for AAP and enzalutamide and similar reductions for cabazitaxel and Ra. If AAP’s price reduces after patent expiry as expected (90% reduction on BNF cost), it would be cost-effective in both patient groups, with incremental cost-effectiveness ratios below £10,000 (US$12,665) per QALY. AAP could also dominate in non-metastatic patients (i.e. lower costs and higher QALYs than SOC alone). / Conclusions: AAP could be cost-effective for patients with non-metastatic and metastatic disease with expected future pricing and may be cost-saving in the former. Policymakers should encourage license submissions and generic price reductions to facilitate use of AAP given cost-saving potential in addition to improving survival. / Clinical trial information: NCT00268476

Genome-wide sexually antagonistic variants reveal long-standing constraints on sexual dimorphism in fruit flies.

The evolution of sexual dimorphism is constrained by a shared genome, leading to 'sexual antagonism', in which different alleles at given loci are favoured by selection in males and females. Despite its wide taxonomic incidence, we know little about the identity, genomic location, and evolutionary dynamics of antagonistic genetic variants. To address these deficits, we use sex-specific fitness data from 202 fully sequenced hemiclonal Drosophila melanogaster fly lines to perform a genome-wide association study (GWAS) of sexual antagonism. We identify approximately 230 chromosomal clusters of candidate antagonistic single nucleotide polymorphisms (SNPs). In contradiction to classic theory, we find no clear evidence that the X chromosome is a hot spot for sexually antagonistic variation. Characterising antagonistic SNPs functionally, we find a large excess of missense variants but little enrichment in terms of gene function. We also assess the evolutionary persistence of antagonistic variants by examining extant polymorphism in wild D. melanogaster populations and closely related species. Remarkably, antagonistic variants are associated with multiple signatures of balancing selection across the D. melanogaster distribution range and in their sister species D. simulans, indicating widespread and evolutionarily persistent (about 1 million years) genomic constraints on the evolution of sexual dimorphism. Based on our results, we propose that antagonistic variation accumulates because of constraints on the resolution of sexual conflict over protein coding sequences, thus contributing to the long-term maintenance of heritable fitness variation

Cost-utility analysis of adding abiraterone acetate plus prednisone/prednisolone to long-term hormone therapy in newly diagnosed advanced prostate cancer in England: Lifetime decision model based on STAMPEDE trial data

Adding abiraterone acetate (AA) plus prednisolone (P) to standard of care (SOC) improves survival in newly diagnosed advanced prostate cancer (PC) patients starting hormone therapy. Our objective was to determine the value for money to the English National Health Service (NHS) of adding AAP to SOC. We used a decision analytic model to evaluate cost-effectiveness of providing AAP in the English NHS. Between 2011-2014, the STAMPEDE trial recruited 1917 men with high-risk localised, locally advanced, recurrent or metastatic PC starting first-line androgen-deprivation therapy (ADT), and they were randomised to receive SOC plus AAP, or SOC alone. Lifetime costs and quality-adjusted life-years (QALYs) were estimated using STAMPEDE trial data supplemented with literature data where necessary, adjusting for baseline patient and disease characteristics. British National Formulary (BNF) prices (£98/day) were applied for AAP. Costs and outcomes were discounted at 3.5%/year. AAP was not cost-effective. The incremental cost-effectiveness ratio (ICER) was £149,748/QALY gained in the non-metastatic (M0) subgroup, with 2.4% probability of being cost-effective at NICE's £30,000/QALY threshold; and the metastatic (M1) subgroup had an ICER of £47,503/QALY gained, with 12.0% probability of being cost-effective. Scenario analysis suggested AAP could be cost-effective in M1 patients if priced below £62/day, or below £28/day in the M0 subgroup. AAP could dominate SOC in the M0 subgroup with price below £11/day. AAP is effective for non-metastatic and metastatic disease but is not cost-effective when using the BNF price. AAP currently only has UK approval for use in a subset of M1 patients. The actual price currently paid by the English NHS for abiraterone acetate is unknown. Broadening AAP's indication and having a daily cost below the thresholds described above is recommended, given AAP improves survival in both subgroups and its cost-saving potential in M0 subgroup