Biology subjects

Reuter, M.

Publications and source records attributed to Reuter, M..

28 records · Page 2Linked to original sources

bioRxiv2020

Resting state brain signal complexity of young healthy adults reflects genetic risk for developing Alzheimer Disease

The e4 allele of the APOE gene is strongly associated with impaired brain functionality and cognitive decline in humans at older age. It is controversial whether and how the APOE e4 allele is affecting brain activity among young healthy individuals and how such effects may contribute to individual differences in cognitive performance. Signal complexity is a critical aspect of brain activity that has been shown to be associated with brain function. In this study, we analyzed multiscale entropy (MSE) of EEG signals among young healthy adults as an indicator of brain signal complexity and investigated how MSE is predicted by APOE genotype groups. Furthermore, by means of structural equation modeling, we investigated whether MSE predicts fluid intelligence. Results indicate larger MSE in young healthy e4 carriers across all time scales. Moreover, better fluid intelligence (gf) is associated with smaller MSE at low time scales and larger MSE at higher scales. However, MSE does not account for better cognitive performance among APOE e4 carriers by mediating the APOE genotype effect on fluid intelligence. The present results shed further light on the neural mechanisms underlying gene-behavior association relevant for Alzheimers Disease risk.

neuroscience↗

bioRxiv2020

Mother's curse is pervasive across a large mito-nuclear Drosophila panel

The maternal inheritance of mitochondrial genomes entails a sex-specific selective sieve, whereby mutations in mitochondrial DNA can only respond to selection acting directly on females. In theory, this enables male-harming mutations to accumulate in mitochondrial genomes if they are neutral, beneficial, or only slightly deleterious to females. Ultimately, this bias could drive the evolution of male-specific mitochondrial mutation loads, an idea known as mothers curse. Earlier work on this hypothesis has mainly used small Drosophila panels, in which naturally-sourced mitochondrial genomes were coupled to an isogenic nuclear background. However, the lack of nuclear genetic variation has precluded robust generalization. Here we test the predictions of mothers curse using a large Drosophila mito-nuclear genetic panel, comprising 9 isogenic nuclear genomes coupled to 9 mitochondrial haplotypes, giving a total of 81 different mito-nuclear genotypes. This enables systematic testing of both mito-nuclear interactions and mitochondrial genetic variance. Following a predictive framework, we performed a screen for wing centroid size, as this trait is highly sexually dimorphic and depends on metabolic function. We confirmed that the trait is sexually dimorphic, and show high levels of mito-nuclear epistasis. Importantly, we report that mitochondrial genetic variance has a greater impact on male versus female Drosophila, in 8 out of the 9 nuclear genetic backgrounds. These results demonstrate that the maternal inheritance of mitochondrial DNA does indeed modulate male life-history traits in a more generalisable way than previously envisaged.

evolutionary biology↗

bioRxiv2020

The molecular basis of socially-mediated phenotypic plasticity in a eusocial paper wasp

Phenotypic plasticity, the ability to produce multiple phenotypes from a single genotype, represents an excellent model with which to examine the relationship between gene expression and phenotypes. Despite this, analyses of the molecular bases of plasticity have been limited by the challenges of linking individual phenotypes with individual-level gene expression profiles, especially in the case of complex social phenotypes. Here, we tackle this challenge by analysing the individual-level gene expression profiles of Polistes dominula paper wasps following the loss of a queen, a perturbation that induces some individuals to undergo a significant phenotypic shift and become replacement reproductives. Using a machine learning approach, we find a strong response of caste-associated gene expression to queen loss, wherein individuals expression profiles become intermediate between queen and worker states. Importantly, this change occurs even in individuals that appear phenotypically unaffected. Part of this response is explained by individual attributes, most prominently age. These results demonstrate that large changes in gene expression may occur in the absence of detectable phenotypic changes, resulting here in a socially mediated de-differentiation of individuals at the transcriptomic but not the phenotypic level. Our findings also highlight the complexity of the relationship between gene expression and phenotype, where transcriptomes are neither a direct reflection of the genotype nor a proxy for the molecular underpinnings of the external phenotype.

bioinformatics↗

bioRxiv2019

Sex-specific transcriptomic responses to changes in the nutritional environment

Males and females typically pursue divergent reproductive strategies and accordingly require different dietary compositions to maximise their fitness. Here we move from identifying sex-specific optimal diets to understanding the molecular mechanisms that underlie male and female responses to dietary variation. We examine male and female gene expression on male-optimal (carbohydrate-rich) and female-optimal (protein-rich) diets. We find that the sexes share a large core of metabolic genes that are concordantly regulated in response to dietary composition. However, we also observe smaller sets of genes with divergent and opposing regulation, most notably in reproductive genes which are over-expressed on each sexs optimal diet. Our results suggest that nutrient sensing output emanating from a shared metabolic machinery are reversed in males and females, leading to opposing diet-dependent regulation of reproduction in males and females. Further analysis and experiments suggest that this reverse regulation occurs within the IIS/TOR network.

evolutionary biology↗

bioRxiv2018

Sexual antagonism drives the displacement of polymorphism across gene regulatory cascades

Males and females have different reproductive roles and are often subject to contrasting selection pressures. This sexual antagonism can lead, at a given locus, to different alleles being favoured in each sex and, consequently, to genetic variation being maintained in a population. Although the presence of antagonistic polymorphisms has been documented across a range of species, their evolutionary dynamics remain poorly understood. Here we study antagonistic selection on gene expression, which is fundamental to sexual dimorphism, via the evolution of regulatory binding sites. We show that for sites longer than 1 nucleotide, polymorphism is maintained only when intermediate expression levels are deleterious to both sexes. We then show that, in a regulatory cascade, polymorphism tends to become displaced over evolutionary time from the target of antagonistic selection to upstream regulators. Our results have consequences for understanding the evolution of sexual dimorphism, and provide specific empirical predictions for the regulatory architecture of genes under antagonistic selection

evolutionary biology↗

bioRxiv2018

Chemotactic motility and biofilm formation in Campylobacter jejuni are coordinated by the CheAYWVX system

Flagellar motility plays a central role in the bacterial foodborne pathogen Campylobacter jejuni, as flagellar motility is required for reaching the intestinal epithelium and subsequent colonisation or disease. Flagellar proteins also contribute strongly to biofilm formation during transmission. Chemotaxis is the process directing flagellar motility in response to attractant and repellent stimuli, but its role in biofilm formation of C. jejuni is not well understood. Here we show that inactivation of the core chemotaxis genes cheVAWY in C. jejuni strain NCTC 11168 affects both chemotactic motility and biofilm formation. Inactivation of any of the core chemotaxis genes (cheA, cheY, cheV or cheW) impaired chemotactic motility but did not affect flagellar assembly or growth. The {Delta}cheY mutant swam in clockwise loops, while complementation restored normal motility. Inactivation of the core chemotaxis genes interfered with the ability to form a discrete biofilm at the air-media interface, and the {Delta}cheY mutant displayed reduced dispersal/shedding of bacteria into the planktonic fraction. This suggests that while the chemotaxis system is not required for biofilm formation per se, it is necessary for organized biofilm formation. Hence interference with the Campylobacter chemotaxis system at any level disrupts optimal chemotactic motility and transmission modes such as biofilm formation.

microbiology↗

bioRxiv2018

HSF2BP Negatively Regulates Homologous Recombination in DNA Interstrand Crosslink Repair in Human Cells by Direct Interaction With BRCA2

The tumor suppressor BRCA2 is essential for homologous recombination, replication fork stability and DNA interstrand crosslink (ICL) repair in vertebrates. We show that a functionally uncharacterized protein, HSF2BP, is involved in a novel, direct and highly evolutionarily conserved interaction with BRCA2. Although HSF2BP was previously described as testis-specific, we find it is expressed in mouse ES cells, in human cancer cell lines, and in tumor samples. Elevated levels of HSF2BP sensitize human cells to ICL-inducing agents (mitomycin C and cisplatin) and PARP inhibitors, resulting in a phenotype characteristic of cells from Fanconi anemia (FA) patients. We biochemically recapitulate the suppression of ICL repair and establish that excess HSF2BP specifically compromises homologous recombination by preventing BRCA2 and RAD51 loading at the ICL. As increased ectopic expression of HSF2BP occurs naturally, we suggest that it can be considered as a causative agent in FA and a source of cancer-promoting genomic instability.

molecular biology↗

bioRxiv2017

Sex- and genotype-effects on nutrient-dependent fitness landscapes in Drosophila melanogaster

The sexes perform different reproductive roles and have evolved sometimes strikingly different phenotypes. One focal point of adaptive divergence occurs in the context of diet and metabolism, and males and females of a range of species have been shown to require different nutrients to maximise their fitness. Biochemical analyses in Drosophila melanogaster have confirmed that dimorphism in dietary requirements is associated with molecular sex-differences in metabolite titres. In addition, they also showed significant within-sex genetic variation in the metabolome. To date however, it is unknown whether this metabolic variation translates into differences in reproductive fitness. The answer to this question is crucial to establish whether genetic variation is selectively neutral or indicative of constraints on sex-specific physiological adaptation and optimisation. Here we assay genetic variation in consumption and metabolic fitness effects by screening male and female fitness of thirty D. melanogaster genotypes across four protein-to-carbohydrate ratios. In addition to confirming sexual dimorphism in consumption and fitness, we find significant genetic variation in male and female dietary requirements. Importantly, these differences are not explained by feeding responses and most likely reflect metabolic variation that, in turn, suggest the presence of genetic constraints on metabolic dimorphism.

evolutionary biology↗

bioRxiv2017

Sexual antagonism exerts evolutionarily persistent genomic constraints on sexual differentiation in Drosophila melanogaster

The evolution of sexual dimorphism is constrained by a shared genome, leading to sexual antagonism where 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 D. melanogaster fly lines to perform a genome-wide association study of sexual antagonism. We identify ~230 chromosomal clusters of candidate antagonistic SNPs. In contradiction to classic theory, we find no clear evidence that the X chromosome is a hotspot 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. Remarkably, antagonistic variants are associated with multiple signatures of balancing selection across the D. melanogaster distribution range, indicating widespread and evolutionarily persistent (>10,000 years) genomic constraints. Based on our results, we propose that antagonistic variation accumulates due to constraints on the resolution of sexual conflict over protein coding sequences, thus contributing to the long-term maintenance of heritable fitness variation.

evolutionary biology↗

bioRxiv2016

Mindboggling morphometry of human brains

Mindboggle (http://mindboggle.info) is an open source brain morphometry platform that takes in preprocessed T1-weighted MRI data and outputs volume, surface, and tabular data containing label, feature, and shape information for further analysis. In this article, we document the software and demonstrate its use in studies of shape variation in healthy and diseased humans. The number of different shape measures and the size of the populations make this the largest and most detailed shape analysis of human brains every conducted. Brain image morphometry shows great potential for providing much-needed biological markers for diagnosing, tracking, and predicting progression of mental health disorders. Very few software algorithms provide more than measures of volume and cortical thickness, and more subtle shape measures may provide more sensitive and specific biomarkers. Mindboggle computes a variety of (primarily surface-based) shapes: area, volume, thickness, curvature, depth, Laplace-Beltrami spectra, Zernike moments, etc. We evaluate Mindboggles algorithms using the largest set of manually labeled, publicly available brain images in the world and compare them against state-of-the-art algorithms where they exist. All data, code, and results of these evaluations are publicly available.\n\nAuthor SummaryBrains vary in many ways, including their shape. Analysing differences in shape between brains or changes in brain shape over time has been used to characterize morphology of diseased brains, but these analyses conventionally rely on simple volumetric shape measures. We believe that access to a greater variety of shape measures could provide greater sensitivity and specificity to morphological disturbances, and could aid in diagnosis, tracking, and prediction of the progression of mental health disorders. Mindboggle is open source software that provides neuroscientists (and indeed, anyone interested in computing shapes) tools for computing a variety of shape measures, including area, volume, thickness, curvature, geodesic depth, travel depth, Laplace-Beltrami spectra, and Zernike moments. In addition to algorithmic contributions, we conducted evaluations and applied Mindboggle to conduct the most detailed shape analysis of human brains.

neuroscience↗