Suchergebnisse

AbstractPneumonia is a respiratory condition with complex etiology. Host genetic variation is thought to contribute to individual differences in susceptibility and symptom manifestation. Here, we analyze pneumonia data from the UK Biobank (14,780 cases and 439,096 controls) and FinnGen (9980 cases and 86,519 controls) and perform a genomewide association study meta-analysis. We use gene-based tests, colocalization, genetic correlation, latent causal variable (LCV) and polygenic prediction in an independent Australian sample (N = 5595) to draw insights into the etiology of pneumonia risk. We identify two independent loci on chromosome 15 (lead single-nucleotide polymorphisms rs2009746 and rs76474922) to be associated with pneumonia (p < 5e−8). Gene-based tests revealed 18 genes in chromosomes 15, 16 and 9, including IL127, PBX3, ApoB receptor (APOBR) and smoking related genes CHRNA3/5, statistically associated with pneumonia. We observed genetic correlations between pneumonia and cardiorespiratory, psychiatric and inflammatory related traits. LCV analysis suggests a strong genetic causal relationship with cardiovascular health phenotypes. Polygenic risk scores for pneumonia significantly predicted self-reported pneumonia in an independent sample, albeit with a small effect size (OR = 1.11 95% CI [1.04, 1.19], p < .05). Sensitivity analyses suggested the associations in chromosome 15 are mediated by smoking history, but the associations in chromosomes 16 and 9, and polygenic prediction were robust to adjustment for smoking. Altogether, our results highlight common genetic variants, genes and potential pathways that contribute to individual differences in susceptibility to pneumonia, and advance our understanding of the genetic factors underlying heterogeneity in respiratory medical outcomes.

scRNA-seq data for this project has been deposited in ArrayExpress under the accession numbers E-MTAB-6072 and E-MTAB-7311. Processed data can be found in https://figshare.com/projects/Treg_scRNA-seq/38864, and analysis notebooks can be found in https://github.com/tomasgomes/Treg_analysis. ; Non-lymphoid tissues (NLTs) harbor a pool of adaptive immune cells with largely unexplored phenotype and development. We used single-cell RNA-seq to characterize 35,000 CD4+ regulatory (Treg) and memory (Tmem) T cells in mouse skin and colon, their respective draining lymph nodes (LNs) and spleen. In these tissues, we identified Treg cell subpopulations with distinct degrees of NLT phenotype. Subpopulation pseudotime ordering and gene kinetics were consistent in recruitment to skin and colon, yet the initial NLT-priming in LNs and the final stages of NLT functional adaptation reflected tissue-specific differences. Predicted kinetics were recapitulated using an in vivo melanoma-induction model, validating key regulators and receptors. Finally, we profiled human blood and NLT Treg and Tmem cells, and identified cross-mammalian conserved tissue signatures. In summary, we describe the relationship between Treg cell heterogeneity and recruitment to NLTs through the combined use of computational prediction and in vivo validation. ; Wethank V. Proserpio, M. Stubbington, T. Hagai, F.V. Braga, V. Svensson, and J. Henriksson for helpful discussions and advice; T. Hagai, R. Vento-Tormo, K. Meyer, and J. Park for critical reading of the manuscript; and B. Koppelman for editorial support. We thank WSI Single-cell Genomic Core Facility, WSI Sequencing Facility, WSI Flow Cytometry facilities, K. Polanski, and the Kennedy Institute Flow Cytometry Facility for expert technical advice and assistance. R.J.M. was supported by a PhD Fellowship from the Fundação para a Ciência e Tecnologia, Portugal (SFRH/BD/51950/2012) and T.G. by the European Union's H2020 research and innovation program ''ENLIGHT-TEN'' under the Marie Sklodowska-Curie grant ...

30 p.-7 fig. ; Genetic analyses in atypical hemolytic uremic syndrome (aHUS) and C3-glomerulopathy (C3G) patients have provided an excellent understanding of the genetic component of the disease and informed genotype-phenotype correlations supporting an individualized approach to patient management and treatment. In this context, a correct categorization of the disease-associated gene variants is critical to avoid detrimental consequences for patients and their relatives. Here we describe a comprehensive procedure to measure levels and functional activity of complement regulator factor H (FH) encoded by CFH, the commonest genetic factor associated with aHUS and C3G, and present the results of the analysis of 28 uncharacterized, disease-associated, FH variants. Sixteen variants were not expressed in plasma and eight had significantly reduced functional activities that impact on complement regulation. In total, 24 of 28 CFH variants were unambiguously categorized as pathogenic and the nature of the pathogenicity fully documented for each. The data also reinforce the genotype-phenotype correlations that associate specific FH functional alterations with either aHUS or C3G and illustrate important drawbacks of the prediction algorithms dealing with variants located in FH functional regions. We also report that the novel aHUS-associated M823T variant is functionally impaired. This was unexpected and uncovered the important contribution of regions outside the N-terminal and C-terminal functional domains to FH regulatory activities on surfaces. Thus, our work significantly advances knowledge towards a complete functional understanding of the CFH genetic variability and highlights the importance of functional analysis of the disease-associated CFH variants. ; SRdeC is supported by the Spanish Ministerio de Economía y Competitividad/FEDER (grant number SAF2015-66287-R), the Seventh Framework Programme European Union Project EURenOmics (grantnumber 305608), and the Autonomous Region of Madrid (grantnumber S2010/BMD-2316). ; Peer reviewed

<i>Objectives:</i> To compare the overall birth prevalence of diagnosed glycogen storage disease type II (GSD II) with the predicted frequency based on mutation screening, in order to determine whether GSD II is an underdiagnosed condition, and to analyze which medical disciplines recognize GSD II. <i>Methods:</i> Retrospective data on all enzymatic diagnoses of GSD II were collected from diagnostic labs throughout the Netherlands, covering the period from January 1, 1972 to December 31, 1996. Age-specific diagnostic incidence rates were calculated for the entire study period. By adding together the diagnostic incidences for all age groups, we calculated the birth prevalence of diagnosed GSD II and compared these figures with the predicted frequency based on mutation screening in a random sample from the general population. The medical specialization of the referring clinicians was also recorded. <i>Results:</i> GSD II was diagnosed in 154 individuals, including 11 prenatal diagnoses. The birth prevalences of the various phenotypes were 1/101,000 (infantile form), 1/720,000 (juvenile form) and 1/53,000 (adult form). The birth prevalence of the adult and infantile phenotype together was 1/35,000. Eighty-two percent of the patients were diagnosed in university hospitals. Of the patients with infantile GSD II, 71% were diagnosed by a pediatrician, whereas most patients with adult GSD II were diagnosed by a neurologist (80%). <i>Conclusions:</i> There is no evidence for the underdiagnosis of GSD II in the Netherlands, as the calculated birth prevalences of the disease are consistent with previous predictions based on mutation screening in a random sample of newborns. The worldwide birth prevalence of the disease may well be higher than 1 in 100,000. GSD II is mainly diagnosed in university hospitals.

AbstractBiological age captures a person's age-related risk of unfavorable outcomes using biophysiological information. Multivariate biological age measures include frailty scores and molecular biomarkers. These measures are often studied in isolation, but here we present a large-scale study comparing them. In 2 prospective cohorts (n = 3 222), we compared epigenetic (DNAm Horvath, DNAm Hannum, DNAm Lin, DNAm epiTOC, DNAm PhenoAge, DNAm DunedinPoAm, DNAm GrimAge, and DNAm Zhang) and metabolomic-based (MetaboAge and MetaboHealth) biomarkers in reflection of biological age, as represented by 5 frailty measures and overall mortality. Biomarkers trained on outcomes with biophysiological and/or mortality information outperformed age-trained biomarkers in frailty reflection and mortality prediction. DNAm GrimAge and MetaboHealth, trained on mortality, showed the strongest association with these outcomes. The associations of DNAm GrimAge and MetaboHealth with frailty and mortality were independent of each other and of the frailty score mimicking clinical geriatric assessment. Epigenetic, metabolomic, and clinical biological age markers seem to capture different aspects of aging. These findings suggest that mortality-trained molecular markers may provide novel phenotype reflecting biological age and strengthen current clinical geriatric health and well-being assessment.

Although transport and slaughter of cattle during the last 10% of the gestation period is prohibited in the European Union, such cattle are sometimes sent for slaughter. The late term pregnancy is usually not recognized by the authorities until the uterus is inspected after slaughter and a near term fetus is observed. Accurate post mortem determination of age of bovine fetuses is therefore of major importance as evidence for the subsequent prosecution of the owner. Fetometric measurements such as crown-rump length (CRL) have been used, but these existing estimators have often been established based on insufficiently described study populations or phenotypes that may have changed in the past decades. Morphological characteristics are also used, but few data are available on the correlation between fetal age and the development of these characteristics. The objectives of this study were to investigate the correlation between fetal age and morphological features of bovine Holstein fetuses and to evaluate the use of these features alone and in combination with fetometric measurements to predict fetal age. We collected fetuses from 274 pregnant Holstein cows with recorded insemination dates slaughtered at a Danish abattoir. Gender, teeth development, occurrence of pigmentation, coat, tactile hair and other morphological features were recorded along with CRL, head width, head length and body weight (BW). The gestational length was calculated based on recorded insemination and slaughter dates, and coefficients of variation (R2) were determined for all recorded variables. Notably, the highest R2 was recorded for head length (0.985) followed by CRL (0.979) and head width (0.974). The categorical (morphological) variables were less informative. When used in multivariable models, they did offer statistically significance, but for practical purposes, limited additional information. A multivariable model including the fetometric variables head length and width in combination with CRL resulted in R2 = 0.99 with predictions that were roughly within +/- 11-12 days in 95% of cases. We conclude that the model based on the fetometric variables only provided the most precise predictions, while combination with morphological features such as eruption of teeth, pigmentation and coat mostly increased the width of the prediction intervals.

AbstractThis article outlines the over‐pruning hypothesis of autism. The hypothesis originates in a neurocomputational model of the regressive sub‐type (Thomas, Knowland & Karmiloff‐Smith, 2011a, 2011b). Here we develop a more general version of the over‐pruning hypothesis to address heterogeneity in the timing of manifestation of ASD, including new computer simulations which reconcile the different observed developmental trajectories (early onset, late onset, regression) via a single underlying atypical mechanism; and which show how unaffected siblings of individuals with ASD may differ from controls either by inheriting a milder version of the pathological mechanism or by co‐inheriting the risk factors without the pathological mechanism. The proposed atypical mechanism involves overly aggressive synaptic pruning in infancy and early childhood, an exaggeration of a normal phase of brain development. We show how the hypothesis generates novel predictions that differ from existing theories of ASD including that (1) the first few months of development in ASD will be indistinguishable from typical, and (2) the earliest atypicalities in ASD will be sensory and motor rather than social. Both predictions gain cautious support from emerging longitudinal studies of infants at‐risk of ASD. We review evidence consistent with the over‐pruning hypothesis, its relation to other current theories (including C. Frith's under‐pruning proposal; C. Frith, 2003, 2004), as well as inconsistent data and current limitations. The hypothesis situates causal accounts of ASD within a framework of protective and risk factors (Newschaffer et al., 2012); clarifies different versions of the broader autism phenotype (i.e. the implication of observed similarities between individuals with autism and their family members); and integrates data from multiple disciplines, including behavioural studies, neuroscience studies, genetics, and intervention studies.

Background: Mental disorders and individual characteristics such as intelligence and personality are complex traits sharing a largely unknown neuronal basis. Their genetic architectures are highly polygenic and overlapping, which is supported by heterogeneous phenotypic expression and substantial clinical overlap. Brain network analysis provides a non-invasive means of dissecting biological heterogeneity yet its sensitivity, specificity and validity in assessing individual characteristics relevant for brain function and mental health and their genetic underpinnings in clinical applications remains a challenge. Methods: In a machine learning approach, we predicted individual scores for educational attainment, fluid intelligence and dimensional measures of depression, anxiety and neuroticism using fMRI-based static and dynamic temporal synchronization between large-scale brain network nodes in 10,343 healthy individuals from the UK Biobank. In addition to age and sex to serve as our reference point, we also predicted individual polygenic scores for related phenotypes, and 13 different neuroticism traits and schizophrenia. Results: Beyond high accuracy for age and sex, supporting the biological sensitivity of the connectome-based features, permutation tests revealed above chance-level prediction accuracy for trait-level educational attainment and fluid intelligence. Educational attainment and fluid intelligence were mainly negatively associated with static brain connectivity in frontal and default mode networks, whereas age showed positive correlations with a more widespread pattern. In contrast, prediction accuracy was at chance level for depression, anxiety, neuroticism and polygenic scores across traits. Conclusion: These novel findings provide a benchmark for future studies linking the genetic architecture of individual and mental health traits with fMRI-based brain connectomics. ; The authors were funded by the Research Council of Norway (213837, 223723, 229129, 204966, 249795), the South-Eastern Norway Regional Health Authority (2014097, 2015073, 2016083, 2017112), the European Research Council under the European Union's Horizon 2020 research and innovation program (ERC StG, Grant 802998), the Department of Psychology, University of Oslo and the KG Jebsen Stiftelsen. ; acceptedVersion

Intralocus sexual conflict (IASC) prevents males and females from reaching their disparate phenotypic optima and is widespread, but little is known about its genetic underpinnings. In Rhizoglyphus robini, a mite species with alternative male morphs, elevated sexual dimorphism of the armoured fighter males (compared to more feminized scramblers males) was previously reported to be associated with increased IASC. Because IASC persists if gene expression patterns are correlated between sexes, we compared gene expression patterns of males and females from the replicate lines selected for increased proportion of fighter or scrambler males (F- and S-lines, respectively). Specifically, we tested the prediction that selection for fighter morph caused correlated changes in gene expression patterns in females. We identified 532 differentially expressed genes (FDR < 0.05) between the F-line and S-line males. Consistent with the prediction, expression levels of these genes also differed between females from respective lines. Thus, significant proportion of genes differentially expressed between sexually selected male phenotypes showed correlated expression levels in females, likely contributing to elevated IASC in F-lines reported in a previous study. ; This work was supported by the Foundation for Polish Science, International PhD Projects Programme co-financed by the European Regional Development Fund within the project MPD/2009-3/5, "Environmental stress, population viability and adaptation", KNOW RNA Research Centre in Poznań 01/KNOW2/2014, and the Jagiellonian University (DS/WBiNoZ/INoS/762/14). The bulb mite genome analyses were supported by HHMI International Early Career Scientist Program (55007424), the MINECO (BFU2012-31329 and BFU2015-68723-P), Spanish Ministry of Economy and Competitiveness Centro de Excelencia Severo Ochoa 2013-2017 grant (SEV-2012-0208), Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement de la Generalitat's AGAUR program (2014 SGR 0974), and the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013, ERC grant agreement (335980_EinME).

Introduction. Borderline Personality Disorder (BPD) is characterised, among other features, by increased impulsivity and aggression, both directed toward the self and others. These clinical signs most likely arise from complex gene-environment interactions. In our study, we sought to elucidate the role of prenatal testosterone exposure in female patients with BPD. Materials and Methods. In a sample of 42 patients and 50 controls matched for age and biological sex, we measured the ratio of the second to the fourth digit of both hands (2D:4D ratio), which is established as a reliable correlate of prenatal testosterone levels in the foetus. In addition, we used several self-rating scales to determine personality dimensions, impulsivity, aggressiveness and risk-taking behaviour. Results. No differences between the groups emerged with regard to 2D:4D ratio of both hands. In ad-dition, there were almost no correlations between psychological measures and the 2D:4D ratio in the entire sample. Conclusions. Contrary to predictions, female patients with BPD did not differ from controls in 2D:4D ratio bimanually, suggesting no abnormal intrauterine (prenatal) exposure to testosterone in this clinical group. As expected, differences between patients and controls in personality traits, impulsivity, aggressiveness and risk-taking were highly significant and in concordance with the existing body of knowledge. Since BPD features are highly heterogeneous, it could be interesting to study subgroups of BPD patients, rather than the broader phenotype according to DSM-5 criteria.

Insects show remarkable phenotypic plasticity in response to changing environmental conditions. The abiotic factors that determine their phenotypes often vary in time and space, and oceanic islands harbour ideal environments for testing predictions on this matter. The ubiquitous beetle Pimelia laevigata costipennis Wollaston, 1864 (Tenebrionidae) is distributed over the entire altitudinal gradient of the island El Hierro (Canary archipelago), from 0 to 1501 m above sea level. Here, we examine how environmental factors (i.e., rainfall and temperature), associated with the altitudinal gradient, affect the body size, reproductive phenology, clutch size and egg volume, and population dynamics of this ectothermic flightless insect. Pimelia l. costipennis populations inhabiting upland localities, typified by lower temperatures, and greater precipitation and vegetation cover, were larger in body size and laid larger clutches with smaller eggs than those in the lowlands. Moreover, reproduction occurred earlier in the year at lower sites and later at higher sites, whereas activity density was highest in the uplands where it increases with temperature. This study first explores the changes in life history patterns along a whole insular altitudinal gradient, and finds interpopulation plasticity. It confirms that environmental factors associated with species spatial distribution act additively as drivers of phenological and phenotypic expression. ; The Spanish National Research Council (CSIC) financed the contract of HL and the Gobierno de Canarias (ACIISI) funded this project (ProID20100258), partially supported by FEDER funds from the European Union. ; Peer reviewed

Abstract
Hypertrophic cardiomyopathy (HCM) is an inherited disorder often caused by mutations to sarcomeric genes. Many different HCM-associated TPM1 mutations have been identified but they vary in their degrees of severity, prevalence, and rate of disease progression. The pathogenicity of many TPM1 variants detected in the clinical population remains unknown. Our objective was to employ a computational modeling pipeline to assess pathogenicity of one such variant of unknown significance, TPM1 S215L, and validate predictions using experimental methods. Molecular dynamic simulations of tropomyosin on actin suggest that the S215L significantly destabilizes the blocked regulatory state while increasing flexibility of the tropomyosin chain. These changes were quantitatively represented in a Markov model of thin-filament activation to infer the impacts of S215L on myofilament function. Simulations of in vitro motility and isometric twitch force predicted that the mutation would increase Ca2+ sensitivity and twitch force while slowing twitch relaxation. In vitro motility experiments with thin filaments containing TPM1 S215L revealed higher Ca2+ sensitivity compared with wild type. Three-dimensional genetically engineered heart tissues expressing TPM1 S215L exhibited hypercontractility, upregulation of hypertrophic gene markers, and diastolic dysfunction. These data form a mechanistic description of TPM1 S215L pathogenicity that starts with disruption of the mechanical and regulatory properties of tropomyosin, leading thereafter to hypercontractility and finally induction of a hypertrophic phenotype. These simulations and experiments support the classification of S215L as a pathogenic mutation and support the hypothesis that an inability to adequately inhibit actomyosin interactions is the mechanism whereby thin-filament mutations cause HCM.

Behavioral genetics and cultural evolution have both revolutionized our understanding of human behavior-largely independent of each other. Here we reconcile these two fields under a dual inheritance framework, offering a more nuanced understanding of the interaction between genes and culture. Going beyond typical analyses of gene-environment interactions, we describe the cultural dynamics that shape these interactions by shaping the environment and population structure. A cultural evolutionary approach can explain, for example, how factors such as rates of innovation and diffusion, density of cultural sub-groups, and tolerance for behavioral diversity impact heritability estimates, thus yielding predictions for different social contexts. Moreover, when cumulative culture functionally overlaps with genes, genetic effects become masked, unmasked, or even reversed, and the causal effects of an identified gene become confounded with features of the cultural environment. The manner of confounding is specific to a particular society at a particular time, but a WEIRD (Western, educated, industrialized, rich, democratic) sampling problem obscures this boundedness. Cultural evolutionary dynamics are typically missing from models of gene-to-phenotype causality, hindering generalizability of genetic effects across societies and across time. We lay out a reconciled framework and use it to predict the ways in which heritability should differ between societies, between socioeconomic levels and other groupings within some societies but not others, and over the life course. An integrated cultural evolutionary behavioral genetic approach cuts through the nature-nurture debate and helps resolve controversies in topics such as IQ.

The composition of a cell in terms of macromolecular building blocks and other organic molecules underlies the metabolic needs and capabilities of a species. Although some core biomass components such as nucleic acids and proteins are evident for most species, the essentiality of the pool of other organic molecules, especially cofactors and prosthetic groups, is yet unclear. Here we integrate biomass compositions from 71 manually curated genome-scale models, 33 large-scale gene essentiality datasets, enzyme-cofactor association data and a vast array of publications, revealing universally essential cofactors for prokaryotic metabolism and also others that are specific for phylogenetic branches or metabolic modes. Our results revise predictions of essential genes in Klebsiella pneumoniae and identify missing biosynthetic pathways in models of Mycobacterium tuberculosis. This work provides fundamental insights into the essentiality of organic cofactors and has implications for minimal cell studies as well as for modeling genotype-phenotype relations in prokaryotic metabolic networks. ; J.C.X. was sponsored by Fundação para a Ciência e Tecnologia, Portugal [Grant SFRH/BD/81626/2011]. This study was supported by the European Molecular Biology Laboratory, the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/BIO/04469/2013 unit, COMPETE 2020 (POCI-01–0145-FEDER-006684) and BioTecNorte operation (NORTE-01–0145-FEDER-000004) funded by European Regional Development Fund under the scope of Norte2020 - Programa Operacional Regional do Norte. This project has received funding from the European Union's Horizon 2020 research and innovation programme under Grant agreement no ...

How genes contribute to cognition is a perennial question for psychologists and geneticists. In the early 21st century, familial studies, including twin studies, supported the theory that genetic variations contribute to differences in cognition, but have been of little practical use to clinical and educational practitioners as no individual predictions can be made using such data; heritability cannot predict the impact of environmental factors or intervention programs. With the sequencing of animal genomes and the development of molecular genetics, new methodologies have been developed: gene targeting (replacing a functional gene with a neutral gene by homologous recombination), transgenesis (overexpressing one gene or a set of genes from one species in another species), and genome-wide scans and quantitative trait loci mapping (a strategy for identifying chromosomal regions involved in complex traits). Association studies can be performed to find associations between allelic forms and variations in IQ. Genes linked to "normal" variations in cognition have been detected but for the moment such discoveries have had no direct applications in a clinical setting; the number of genes identified as being linked to intellectual impairment has increased rapidly. Links have been reported between chromosomal deletions and triplications and behavioral phenotypes. The identification of mechanisms involved in genetic diseases should have long-term consequences on educational and/or psychological support programs as well as on health care. Psychologists need to keep up to date on advances in research establishing relationships between genetics and intellectual disability and will thus be able to refer children with cognitive impairments to specialized care services.