Human and mouse essentiality screens as a resource for disease gene discovery

The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery. Discovery of causal variants for monogenic disorders has been facilitated by whole exome and genome sequencing, but does not provide a diagnosis for all patients. Here, the authors propose a Full Spectrum of Intolerance to Loss-of-Function (FUSIL) categorization that integrates gene essentiality information to aid disease gene discovery

A genome-wide association study of anorexia nervosa suggests a risk locus implicated in dysregulated leptin signaling

J. Kaprio, A. Palotie, A. Raevuori-Helkamaa ja S. Ripatti ovat työryhmän Eating Disorders Working Group of the Psychiatric Genomics Consortium jäseniä. Erratum in: Sci Rep. 2017 Aug 21;7(1):8379, doi: 10.1038/s41598-017-06409-3We conducted a genome-wide association study (GWAS) of anorexia nervosa (AN) using a stringently defined phenotype. Analysis of phenotypic variability led to the identification of a specific genetic risk factor that approached genome-wide significance (rs929626 in EBF1 (Early B-Cell Factor 1); P = 2.04 x 10(-7); OR = 0.7; 95% confidence interval (CI) = 0.61-0.8) with independent replication (P = 0.04), suggesting a variant-mediated dysregulation of leptin signaling may play a role in AN. Multiple SNPs in LD with the variant support the nominal association. This demonstrates that although the clinical and etiologic heterogeneity of AN is universally recognized, further careful sub-typing of cases may provide more precise genomic signals. In this study, through a refinement of the phenotype spectrum of AN, we present a replicable GWAS signal that is nominally associated with AN, highlighting a potentially important candidate locus for further investigation.Peer reviewe

A genome-wide association study of anorexia nervosa

Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2,907 cases with AN from 14 countries (15 sites) and 14,860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery datasets. Seventy-six (72 independent) SNPs were taken forward for in silico (two datasets) or de novo (13 datasets) replication genotyping in 2,677 independent AN cases and 8,629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication datasets comprised 5,551 AN cases and 21,080 controls. AN subtype analyses (1,606 AN restricting; 1,445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01×10−7) in SOX2OT and rs17030795 (P=5.84×10−6) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76×10−6) between CUL3 and FAM124B and rs1886797 (P=8.05×10−6) near SPATA13. Comparing discovery to replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P= 4×10−6), strongly suggesting that true findings exist but that our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field

Aportaciones de las Humanidades Digitales a los estudios sobre teatro: una revisión sistemática (2001-2020)

The article aims at displaying the current panorama of the contribution of digital studies to the interpretation of dramatic Works, as well as to point out the main lines of interest and possible areas of Development around this field of study. This systematic review includes 31 peer reviewed original articles, in Spanish and English, published during the last two decades (2001-2020) in journals indexed in Scopus and SCImago. The information is collected through systematic research based on eleven international databases such as Web of Science, Scopus, Science Direct, Mendeley-Elsevier, Dialnet, SciELO, Google Scholar, Jstor, ERIC, Zenodo and Humanities Commons. It is concluded that most of the technological research focuses on quantitative data analysis, digital processing of texts and digital critical editions. It is evidenced a shortage of works dedicated to virtual reconstruction of theater spaces in 3D, and propaedeutic sense of the theatrical action in the didactic field.El presente artículo se propone mostrar el panorama actual de las aportaciones de los estudios digitales a la interpretación de obras dramáticas, así como señalar las principales líneas de interés y posibles áreas de desarrollo en torno a este campo de estudio. La revisión sistemática abarca 31 artículos originales revisados por pares, en español y en inglés, publicados durante las últimas dos décadas (2001-2020) en revistas indexadas en Scopus y SCImago. La búsqueda sistemática se ha realizado en once bases de datos internacionales: Web of Science, Scopus, Science Direct, Mendeley-Elsevier, Dialnet, SciELO, Google Scholar, Jstor, ERIC, Zenodo y Humanities Commons. Se concluye que la mayor parte de la investigación tecnológica se centra en análisis cuantitativos, tratamiento digital de textos y ediciones críticas digitales. Se evidencia la escasez de estudios dedicados a la reconstrucción virtual de espacios teatrales en 3D y al sentido propedéutico de la acción teatral en ámbito didáctico.

Aportaciones de las Humanidades Digitales a los estudios sobre teatro: una revisión sistemática (2001-2020)

The article aims at displaying the current panorama of the contribution of digital studies to the interpretation of dramatic Works, as well as to point out the main lines of interest and possible areas of Development around this field of study. This systematic review includes 31 peer reviewed original articles, in Spanish and English, published during the last two decades (2001-2020) in journals indexed in Scopus and SCImago. The information is collected through systematic research based on eleven international databases such as Web of Science, Scopus, Science Direct, Mendeley-Elsevier, Dialnet, SciELO, Google Scholar, Jstor, ERIC, Zenodo and Humanities Commons. It is concluded that most of the technological research focuses on quantitative data analysis, digital processing of texts and digital critical editions. It is evidenced a shortage of works dedicated to virtual reconstruction of theater spaces in 3D, and propaedeutic sense of the theatrical action in the didactic field.El presente artículo se propone mostrar el panorama actual de las aportaciones de los estudios digitales a la interpretación de obras dramáticas, así como señalar las principales líneas de interés y posibles áreas de desarrollo en torno a este campo de estudio. La revisión sistemática abarca 31 artículos originales revisados por pares, en español y en inglés, publicados durante las últimas dos décadas (2001-2020) en revistas indexadas en Scopus y SCImago. La búsqueda sistemática se ha realizado en once bases de datos internacionales: Web of Science, Scopus, Science Direct, Mendeley-Elsevier, Dialnet, SciELO, Google Scholar, Jstor, ERIC, Zenodo y Humanities Commons. Se concluye que la mayor parte de la investigación tecnológica se centra en análisis cuantitativos, tratamiento digital de textos y ediciones críticas digitales. Se evidencia la escasez de estudios dedicados a la reconstrucción virtual de espacios teatrales en 3D y al sentido propedéutico de la acción teatral en ámbito didáctico.

Spatially resolved multiomics of human cardiac niches

The function of a cell is defined by its intrinsic characteristics and its niche: the tissue microenvironment in which it dwells. Here we combine single-cell and spatial transcriptomics data to discover cellular niches within eight regions of the human heart. We map cells to microanatomical locations and integrate knowledge-based and unsupervised structural annotations. We also profile the cells of the human cardiac conduction system1. The results revealed their distinctive repertoire of ion channels, G-protein-coupled receptors (GPCRs) and regulatory networks, and implicated FOXP2 in the pacemaker phenotype. We show that the sinoatrial node is compartmentalized, with a core of pacemaker cells, fibroblasts and glial cells supporting glutamatergic signalling. Using a custom CellPhoneDB.org module, we identify trans-synaptic pacemaker cell interactions with glia. We introduce a druggable target prediction tool, drug2cell, which leverages single-cell profiles and drug–target interactions to provide mechanistic insights into the chronotropic effects of drugs, including GLP-1 analogues. In the epicardium, we show enrichment of both IgG+ and IgA+ plasma cells forming immune niches that may contribute to infection defence. Overall, we provide new clarity to cardiac electro-anatomy and immunology, and our suite of computational approaches can be applied to other tissues and organs

Spatially resolved multiomics of human cardiac niches

The function of a cell is defined by its intrinsic characteristics and its niche: the tissue microenvironment in which it dwells. Here we combine single-cell and spatial transcriptomics data to discover cellular niches within eight regions of the human heart. We map cells to microanatomical locations and integrate knowledge-based and unsupervised structural annotations. We also profile the cells of the human cardiac conduction system1. The results revealed their distinctive repertoire of ion channels, G-protein-coupled receptors (GPCRs) and regulatory networks, and implicated FOXP2 in the pacemaker phenotype. We show that the sinoatrial node is compartmentalized, with a core of pacemaker cells, fibroblasts and glial cells supporting glutamatergic signalling. Using a custom CellPhoneDB.org module, we identify trans-synaptic pacemaker cell interactions with glia. We introduce a druggable target prediction tool, drug2cell, which leverages single-cell profiles and drug–target interactions to provide mechanistic insights into the chronotropic effects of drugs, including GLP-1 analogues. In the epicardium, we show enrichment of both IgG+ and IgA+ plasma cells forming immune niches that may contribute to infection defence. Overall, we provide new clarity to cardiac electro-anatomy and immunology, and our suite of computational approaches can be applied to other tissues and organs

A human fetal lung cell atlas uncovers proximal-distal gradients of differentiation and key regulators of epithelial fates

We present a multiomic cell atlas of human lung development that combines single-cell RNA and ATAC sequencing, high-throughput spatial transcriptomics, and single-cell imaging. Coupling single-cell methods with spatial analysis has allowed a comprehensive cellular survey of the epithelial, mesenchymal, endothelial, and erythrocyte/leukocyte compartments from 5-22 post-conception weeks. We identify previously uncharacterized cell states in all compartments. These include developmental-specific secretory progenitors and a subtype of neuroendocrine cell related to human small cell lung cancer. Our datasets are available through our web interface (https://lungcellatlas.org). To illustrate its general utility, we use our cell atlas to generate predictions about cell-cell signaling and transcription factor hierarchies which we rigorously test using organoid models

A human fetal lung cell atlas uncovers proximal-distal gradients of differentiation and key regulators of epithelial fates.

We present a multiomic cell atlas of human lung development that combines single-cell RNA and ATAC sequencing, high-throughput spatial transcriptomics, and single-cell imaging. Coupling single-cell methods with spatial analysis has allowed a comprehensive cellular survey of the epithelial, mesenchymal, endothelial, and erythrocyte/leukocyte compartments from 5-22 post-conception weeks. We identify previously uncharacterized cell states in all compartments. These include developmental-specific secretory progenitors and a subtype of neuroendocrine cell related to human small cell lung cancer. Our datasets are available through our web interface (https://lungcellatlas.org). To illustrate its general utility, we use our cell atlas to generate predictions about cell-cell signaling and transcription factor hierarchies which we rigorously test using organoid models