Evolutionary genetics: Dissecting a sexually antagonistic polymorphism

Males and females experience divergent selection on many shared traits, which can lead to 'sexual antagonism' - opposing fitness effects of genetic variants in each sex. A new study in the fly Drosophila serrata links sexually antagonistic selection on cuticular hydrocarbons to a single major-effect gene

The genetics and evolutionary dynamics of sexually antagonistic polymorphisms in Drosophila melanogaster

The evolution of sexual dimorphism is constrained by a shared genome between males and females. This constraint can lead to ‘sexual antagonism’ where segregating alleles at given genetic loci have opposing fitness effects in each sex. Despite its wide taxonomic incidence, little is known about the identity, genomic location and evolutionary dynamics of sexually antagonistic polymorphisms. This is a major knowledge gap, since a better understanding of antagonistic polymorphisms can shed light on two fundamental questions: (i) how does the genome evolve to accommodate divergent and often contradictory selective pressures, and (ii) what evolutionary forces maintain genetic variation for fitness? In this thesis, I describe the genetics and evolutionary dynamics of sexually antagonistic polymorphisms. I first highlight the limitations of previous genetic studies of sexual antagonism (Chapter 2). Specifically, I re-analyse a prominent study of antagonistic gene expression and show that inferences of antagonistic selection were driven by non-random population structure in the sample of genomes considered, rendering previous conclusions unreliable. I then present the first genome-wide association study of sex-specific fitness and sexual antagonism in a laboratory-adapted population of D. melanogaster (Chapter 3). I show that antagonistic variation disproportionately accumulates in coding regions but not on the X chromosome. I proceed to test whether sexually antagonistic selection maintains population genetic variation (Chapter 4), as has long been proposed but never tested. Consistent with this hypothesis, I find multiple signatures of balancing selection associated with antagonistic loci across populations of D. melanogaster separated over 10,000 years, and possibly across species boundaries. Finally, I present experimental work testing whether a specific candidate gene—fruitless—is under antagonistic selection (Chapter 5). The results presented are consistent with balancing but not antagonistic selection. Overall, this thesis underscores the fundamental difficulty of evolving genetic mechanisms that accommodate the divergent evolutionary interests of each sex

Ultrasonic monitoring to assess the impacts of forest conversion on Solomon Island bats

Paleotropical islands are experiencing extensive land-use change, yet little is known about how such changes are impacting wildlife in these biodiversity hotspots. To address this knowledge gap, we characterized bat responses to forest conversion in a biodiverse, human-threatened coastal rainforest habitat on Makira, Solomon Islands. We analysed ~200hrs of acoustic recordings from echolocating bats in the four dominant types of land-use on Makira: intact forest, secondary forest, food gardens and cacao plantations. Bat calls were identified to the species level using a supervised classification model (where labelled data are used to train the system). We examined relative activity levels and morphological traits across habitats. Relative activity levels were highest in intermediately disturbed habitats and lowest in the most heavily disturbed habitat, although these differences were not significant. There were significant differences in the mean forearm length of bat assemblages across habitats, with the highest mean forearm length found in the most open habitat (Cacao). Overall, our study constitutes the first detailed exploration of anthropogenic effects on mammalian diversity in the Solomon Islands and includes the first acoustic and morphological information for many bat species in Melanesia. We use our experience to discuss the challenges of acoustic monitoring in such a remote and poorly studied region.Publisher PDFPeer reviewe

Polygenic signals of sex differences in selection in humans from the UK Biobank

Sex differences in the fitness effects of genetic variants can influence the rate of adaptation and the maintenance of genetic variation. For example, “sexually antagonistic” (SA) variants, which are beneficial for one sex and harmful for the other, can both constrain adaptation and increase genetic variability for fitness components such as survival, fertility, and disease susceptibility. However, detecting variants with sex-differential fitness effects is difficult, requiring genome sequences and fitness measurements from large numbers of individuals. Here, we develop new theory for studying sex-differential selection across a complete life cycle and test our models with genotypic and reproductive success data from approximately 250,000 UK Biobank individuals. We uncover polygenic signals of sex-differential selection affecting survival, reproductive success, and overall fitness, with signals of sex-differential reproductive selection reflecting a combination of SA polymorphisms and sexually concordant polymorphisms in which the strength of selection differs between the sexes. Moreover, these signals hold up to rigorous controls that minimise the contributions of potential confounders, including sequence mapping errors, population structure, and ascertainment bias. Functional analyses reveal that sex-differentiated sites are enriched in phenotype-altering genomic regions, including coding regions and loci affecting a range of quantitative traits. Population genetic analyses show that sex-differentiated sites exhibit evolutionary histories dominated by genetic drift and/or transient balancing selection, but not long-term balancing selection, which is consistent with theoretical predictions of effectively weak SA balancing selection in historically small populations. Overall, our results are consistent with polygenic sex-differential—including SA—selection in humans. Evidence for sex-differential selection is particularly strong for variants affecting reproductive success, in which the potential contributions of nonrandom sampling to signals of sex differentiation can be excluded

Pro-inflammatory and neurotrophic factor responses of cells derived from degenerative human intervertebral discs to the opportunistic pathogen Cutibacterium acnes

Previously, we proposed the hypothesis that similarities in the inflammatory response observed in acne vulgaris and degenerative disc disease (DDD), especially the central role of interleukin (IL)-1β, may be further evidence of the role of the anaerobic bacterium Cutibacterium (previously Propionibacterium) acnes in the underlying aetiology of disc degeneration. To investigate this, we examined the upregulation of IL-1β, and other known IL-1β-induced inflammatory markers and neurotrophic factors, from nucleus-pulposus-derived disc cells infected in vitro with C. acnes for up to 48 h. Upon infection, significant upregulation of IL-1β, alongside IL-6, IL-8, chemokine (C-C motif) ligand 3 (CCL3), chemokine (C-C motif) ligand 4 (CCL4), nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), was observed with cells isolated from the degenerative discs of eight patients versus non-infected controls. Expression levels did, however, depend on gene target, multiplicity and period of infection and, notably, donor response. Pre-treatment of cells with clindamycin prior to infection significantly reduced the production of pro-inflammatory mediators. This study confirms that C. acnes can stimulate the expression of IL-1β and other host molecules previously associated with pathological changes in disc tissue, including neo-innervation. While still controversial, the role of C. acnes in DDD remains biologically credible, and its ability to cause disease likely reflects a combination of factors, particularly individualised response to infection

Importance of Propionibacterium acnes hemolytic activity in human intervertebral discs:A microbiological study

Most patients with chronic lower back pain (CLBP) exhibit degenerative disc disease. Disc specimens obtained during initial therapeutic discectomies are often infected/colonized with Propionibacterium acnes, a Gram-positive commensal of the human skin. Although pain associated with infection is typically ascribed to the body's inflammatory response, the Gram-positive bacterium Staphylococcus aureus was recently observed to directly activate nociceptors by secreting pore-forming α-hemolysins that disrupt neuronal cell membranes. The hemolytic activity of P. acnes in cultured disc specimens obtained during routine therapeutic discectomies was assessed through incubation on sheep-blood agar. The β-hemolysis pattern displayed by P. acnes on sheep-blood agar was variable and phylogroup-dependent. Their molecular phylogroups were correlated with their hemolytic patterns. Our findings raise the possibility that pore-forming proteins contribute to the pathogenesis and/or symptomology of chronic P. acnes disc infections and CLBP, at least in a subset of cases

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

Prevalence of Propionibacterium acnes in Intervertebral Discs of Patients Undergoing Lumbar Microdiscectomy: A Prospective Cross-Sectional Study

Background The relationship between intervertebral disc degeneration and chronic infection by Propionibacterium acnes is controversial with contradictory evidence available in the literature. Previous studies investigating these relationships were under-powered and fraught with methodical differences;moreover, they have not taken into consideration P. acnes' ability to form biofilms or attempted to quantitate the bioburden with regard to determining bacterial counts/genome equivalents as criteria to differentiate true infection from contamination. The aim of this prospective cross-sectional study was to determine the prevalence of P. acnes in patients undergoing lumbar disc microdiscectomy. Methods and Findings The sample consisted of 290 adult patients undergoing lumbar microdiscectomy for symptomatic lumbar disc herniation. An intraoperative biopsy and pre-operative clinical data were taken in all cases. One biopsy fragment was homogenized and used for quantitative anaerobic culture and a second was frozen and used for real-time PCR-based quantification of P. acnes genomes. P. acnes was identified in 115 cases (40%), coagulase-negative staphylococci in 31 cases (11%) and alpha-hemolytic streptococci in 8 cases (3%). P. acnes counts ranged from 100 to 9000 CFU/ml with a median of 400 CFU/ml. The prevalence of intervertebral discs with abundant P. acnes (>= 1x10(3) CFU/ml) was 11% (39 cases). There was significant correlation between the bacterial counts obtained by culture and the number of P. acnes genomes detected by real-time PCR (r = 0.4363, p<0.0001). Conclusions In a large series of patients, the prevalence of discs with abundant P. acnes was 11%. We believe, disc tissue homogenization releases P. acnes from the biofilm so that they can then potentially be cultured, reducing the rate of false-negative cultures. Further, quantification study revealing significant bioburden based on both culture and real-time PCR minimize the likelihood that observed findings are due to contamination and supports the hypothesis P. acnes acts as a pathogen in these cases of degenerative disc disease