RESUMO
Harmonizing cell types across the single-cell community and assembling them into a common framework is central to building a standardized Human Cell Atlas. Here, we present CellHint, a predictive clustering tree-based tool to resolve cell-type differences in annotation resolution and technical biases across datasets. CellHint accurately quantifies cell-cell transcriptomic similarities and places cell types into a relationship graph that hierarchically defines shared and unique cell subtypes. Application to multiple immune datasets recapitulates expert-curated annotations. CellHint also reveals underexplored relationships between healthy and diseased lung cell states in eight diseases. Furthermore, we present a workflow for fast cross-dataset integration guided by harmonized cell types and cell hierarchy, which uncovers underappreciated cell types in adult human hippocampus. Finally, we apply CellHint to 12 tissues from 38 datasets, providing a deeply curated cross-tissue database with â¼3.7 million cells and various machine learning models for automatic cell annotation across human tissues.
Assuntos
Perfilação da Expressão Gênica , Transcriptoma , Humanos , Bases de Dados Factuais , Análise de Célula ÚnicaRESUMO
Severe obesity is a rapidly growing global health threat. Although often attributed to unhealthy lifestyle choices or environmental factors, obesity is known to be heritable and highly polygenic; the majority of inherited susceptibility is related to the cumulative effect of many common DNA variants. Here we derive and validate a new polygenic predictor comprised of 2.1 million common variants to quantify this susceptibility and test this predictor in more than 300,000 individuals ranging from middle age to birth. Among middle-aged adults, we observe a 13-kg gradient in weight and a 25-fold gradient in risk of severe obesity across polygenic score deciles. In a longitudinal birth cohort, we note minimal differences in birthweight across score deciles, but a significant gradient emerged in early childhood and reached 12 kg by 18 years of age. This new approach to quantify inherited susceptibility to obesity affords new opportunities for clinical prevention and mechanistic assessment.
Assuntos
Peso Corporal , Herança Multifatorial/genética , Obesidade/patologia , Adolescente , Índice de Massa Corporal , Criança , Bases de Dados Factuais , Feminino , Estudo de Associação Genômica Ampla , Humanos , Recém-Nascido , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Obesidade/genética , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
The melanocortin 4 receptor (MC4R) is a G protein-coupled receptor whose disruption causes obesity. We functionally characterized 61 MC4R variants identified in 0.5 million people from UK Biobank and examined their associations with body mass index (BMI) and obesity-related cardiometabolic diseases. We found that the maximal efficacy of ß-arrestin recruitment to MC4R, rather than canonical Gαs-mediated cyclic adenosine-monophosphate production, explained 88% of the variance in the association of MC4R variants with BMI. While most MC4R variants caused loss of function, a subset caused gain of function; these variants were associated with significantly lower BMI and lower odds of obesity, type 2 diabetes, and coronary artery disease. Protective associations were driven by MC4R variants exhibiting signaling bias toward ß-arrestin recruitment and increased mitogen-activated protein kinase pathway activation. Harnessing ß-arrestin-biased MC4R signaling may represent an effective strategy for weight loss and the treatment of obesity-related cardiometabolic diseases.
Assuntos
Mutação com Ganho de Função/genética , Obesidade/patologia , Receptor Tipo 4 de Melanocortina/genética , Transdução de Sinais , Adulto , Idoso , Índice de Massa Corporal , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/patologia , AMP Cíclico/metabolismo , Bases de Dados Factuais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Feminino , Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/metabolismo , Polimorfismo de Nucleotídeo Único , Receptor Tipo 4 de Melanocortina/química , Receptor Tipo 4 de Melanocortina/metabolismo , beta-Arrestinas/metabolismoRESUMO
Machine learning, a collection of data-analytical techniques aimed at building predictive models from multi-dimensional datasets, is becoming integral to modern biological research. By enabling one to generate models that learn from large datasets and make predictions on likely outcomes, machine learning can be used to study complex cellular systems such as biological networks. Here, we provide a primer on machine learning for life scientists, including an introduction to deep learning. We discuss opportunities and challenges at the intersection of machine learning and network biology, which could impact disease biology, drug discovery, microbiome research, and synthetic biology.
Assuntos
Biologia Computacional/métodos , Aprendizado de Máquina , Algoritmos , Bases de Dados Factuais , Descoberta de Drogas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Microbiota , Redes Neurais de ComputaçãoRESUMO
Heritability is essential for understanding the biological causes of disease but requires laborious patient recruitment and phenotype ascertainment. Electronic health records (EHRs) passively capture a wide range of clinically relevant data and provide a resource for studying the heritability of traits that are not typically accessible. EHRs contain next-of-kin information collected via patient emergency contact forms, but until now, these data have gone unused in research. We mined emergency contact data at three academic medical centers and identified 7.4 million familial relationships while maintaining patient privacy. Identified relationships were consistent with genetically derived relatedness. We used EHR data to compute heritability estimates for 500 disease phenotypes. Overall, estimates were consistent with the literature and between sites. Inconsistencies were indicative of limitations and opportunities unique to EHR research. These analyses provide a validation of the use of EHRs for genetics and disease research.
Assuntos
Registros Eletrônicos de Saúde , Doenças Genéticas Inatas/genética , Algoritmos , Bases de Dados Factuais , Relações Familiares , Doenças Genéticas Inatas/patologia , Genótipo , Humanos , Linhagem , Fenótipo , Característica Quantitativa HerdávelRESUMO
We conducted comprehensive integrative molecular analyses of the complete set of tumors in The Cancer Genome Atlas (TCGA), consisting of approximately 10,000 specimens and representing 33 types of cancer. We performed molecular clustering using data on chromosome-arm-level aneuploidy, DNA hypermethylation, mRNA, and miRNA expression levels and reverse-phase protein arrays, of which all, except for aneuploidy, revealed clustering primarily organized by histology, tissue type, or anatomic origin. The influence of cell type was evident in DNA-methylation-based clustering, even after excluding sites with known preexisting tissue-type-specific methylation. Integrative clustering further emphasized the dominant role of cell-of-origin patterns. Molecular similarities among histologically or anatomically related cancer types provide a basis for focused pan-cancer analyses, such as pan-gastrointestinal, pan-gynecological, pan-kidney, and pan-squamous cancers, and those related by stemness features, which in turn may inform strategies for future therapeutic development.
Assuntos
Neoplasias/patologia , Aneuploidia , Cromossomos/genética , Análise por Conglomerados , Ilhas de CpG , Metilação de DNA , Bases de Dados Factuais , Humanos , MicroRNAs/metabolismo , Mutação , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias/genética , RNA Mensageiro/metabolismoRESUMO
Two recent studies exploited ultra-fast structural aligners and deep-learning approaches to cluster the protein structure space in the AlphaFold Database. Barrio-Hernandez et al.1 and Durairaj et al.2 uncovered fascinating new protein functions and structural features previously unknown.
Assuntos
Análise por Conglomerados , Bases de Dados FactuaisRESUMO
Threatened species are by definition species that are in need of assistance. In the absence of suitable conservation interventions, they are likely to disappear soon1. There is limited understanding of how and where conservation interventions are applied globally, or how well they work2,3. Here, using information from the International Union for Conservation of Nature Red List and other global databases, we find that for species at risk from three of the biggest drivers of biodiversity loss-habitat loss, overexploitation for international trade and invasive species4-many appear to lack the appropriate types of conservation interventions. Indeed, although there has been substantial recent expansion of the protected area network, we still find that 91% of threatened species have insufficient representation of their habitats within protected areas. Conservation interventions are not implemented uniformly across different taxa and regions and, even when present, have infrequently led to substantial improvements in the status of species. For 58% of the world's threatened terrestrial species, we find conservation interventions to be notably insufficient or absent. We cannot determine whether such species are truly neglected, or whether efforts to recover them are not included in major conservation databases. If they are indeed neglected, the outlook for many of the world's threatened species is grim without more and better targeted action.
Assuntos
Biodiversidade , Conservação dos Recursos Naturais , Espécies em Perigo de Extinção , Internacionalidade , Animais , Conservação dos Recursos Naturais/métodos , Conservação dos Recursos Naturais/estatística & dados numéricos , Bases de Dados Factuais , Espécies em Perigo de Extinção/estatística & dados numéricos , Extinção Biológica , Espécies Introduzidas/estatística & dados numéricosRESUMO
Understanding how and why menopause has evolved is a long-standing challenge across disciplines. Females can typically maximize their reproductive success by reproducing for the whole of their adult life. In humans, however, women cease reproduction several decades before the end of their natural lifespan1,2. Although progress has been made in understanding the adaptive value of menopause in humans3,4, the generality of these findings remains unclear. Toothed whales are the only mammal taxon in which menopause has evolved several times5, providing a unique opportunity to test the theories of how and why menopause evolves in a comparative context. Here, we assemble and analyse a comparative database to test competing evolutionary hypotheses. We find that menopause evolved in toothed whales by females extending their lifespan without increasing their reproductive lifespan, as predicted by the 'live-long' hypotheses. We further show that menopause results in females increasing their opportunity for intergenerational help by increasing their lifespan overlap with their grandoffspring and offspring without increasing their reproductive overlap with their daughters. Our results provide an informative comparison for the evolution of human life history and demonstrate that the same pathway that led to menopause in humans can also explain the evolution of menopause in toothed whales.
Assuntos
Evolução Biológica , Menopausa , Modelos Biológicos , Baleias , Animais , Feminino , Bases de Dados Factuais , Longevidade/fisiologia , Menopausa/fisiologia , Reprodução/fisiologia , Baleias/classificação , Baleias/fisiologia , HumanosRESUMO
Increasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health1. This is compounded by the limited efficacy of available treatments1 and high failure rates during drug development2, highlighting an urgent need to better understand disease mechanisms. Here we show how functional genomics could address this challenge. By investigating an intergenic haplotype on chr21q22-which has been independently linked to inflammatory bowel disease, ankylosing spondylitis, primary sclerosing cholangitis and Takayasu's arteritis3-6-we identify that the causal gene, ETS2, is a central regulator of human inflammatory macrophages and delineate the shared disease mechanism that amplifies ETS2 expression. Genes regulated by ETS2 were prominently expressed in diseased tissues and more enriched for inflammatory bowel disease GWAS hits than most previously described pathways. Overexpressing ETS2 in resting macrophages reproduced the inflammatory state observed in chr21q22-associated diseases, with upregulation of multiple drug targets, including TNF and IL-23. Using a database of cellular signatures7, we identified drugs that might modulate this pathway and validated the potent anti-inflammatory activity of one class of small molecules in vitro and ex vivo. Together, this illustrates the power of functional genomics, applied directly in primary human cells, to identify immune-mediated disease mechanisms and potential therapeutic opportunities.
Assuntos
Inflamação , Macrófagos , Proteína Proto-Oncogênica c-ets-2 , Feminino , Humanos , Masculino , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Células Cultivadas , Cromossomos Humanos Par 21/genética , Bases de Dados Factuais , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Genômica , Haplótipos/genética , Inflamação/genética , Doenças Inflamatórias Intestinais/genética , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Proteína Proto-Oncogênica c-ets-2/genética , Proteína Proto-Oncogênica c-ets-2/metabolismo , Reprodutibilidade dos Testes , Fatores de Necrose Tumoral/metabolismo , Interleucina-23/metabolismoRESUMO
Regular exercise promotes whole-body health and prevents disease, but the underlying molecular mechanisms are incompletely understood1-3. Here, the Molecular Transducers of Physical Activity Consortium4 profiled the temporal transcriptome, proteome, metabolome, lipidome, phosphoproteome, acetylproteome, ubiquitylproteome, epigenome and immunome in whole blood, plasma and 18 solid tissues in male and female Rattus norvegicus over eight weeks of endurance exercise training. The resulting data compendium encompasses 9,466 assays across 19 tissues, 25 molecular platforms and 4 training time points. Thousands of shared and tissue-specific molecular alterations were identified, with sex differences found in multiple tissues. Temporal multi-omic and multi-tissue analyses revealed expansive biological insights into the adaptive responses to endurance training, including widespread regulation of immune, metabolic, stress response and mitochondrial pathways. Many changes were relevant to human health, including non-alcoholic fatty liver disease, inflammatory bowel disease, cardiovascular health and tissue injury and recovery. The data and analyses presented in this study will serve as valuable resources for understanding and exploring the multi-tissue molecular effects of endurance training and are provided in a public repository ( https://motrpac-data.org/ ).
Assuntos
Treino Aeróbico , Multiômica , Condicionamento Físico Animal , Resistência Física , Animais , Feminino , Humanos , Masculino , Ratos , Acetilação , Sangue/imunologia , Sangue/metabolismo , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/metabolismo , Bases de Dados Factuais , Epigenoma , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/metabolismo , Internet , Lipidômica , Metaboloma , Mitocôndrias/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/imunologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Especificidade de Órgãos/genética , Especificidade de Órgãos/imunologia , Especificidade de Órgãos/fisiologia , Fosforilação , Condicionamento Físico Animal/fisiologia , Resistência Física/genética , Resistência Física/fisiologia , Proteoma/metabolismo , Proteômica , Fatores de Tempo , Transcriptoma/genética , Ubiquitinação , Ferimentos e Lesões/genética , Ferimentos e Lesões/imunologia , Ferimentos e Lesões/metabolismoRESUMO
There are two main life cycles in plants-annual and perennial1,2. These life cycles are associated with different traits that determine ecosystem function3,4. Although life cycles are textbook examples of plant adaptation to different environments, we lack comprehensive knowledge regarding their global distributional patterns. Here we assembled an extensive database of plant life cycle assignments of 235,000 plant species coupled with millions of georeferenced datapoints to map the worldwide biogeography of these plant species. We found that annual plants are half as common as initially thought5-8, accounting for only 6% of plant species. Our analyses indicate that annuals are favoured in hot and dry regions. However, a more accurate model shows that the prevalence of annual species is driven by temperature and precipitation in the driest quarter (rather than yearly means), explaining, for example, why some Mediterranean systems have more annuals than desert systems. Furthermore, this pattern remains consistent among different families, indicating convergent evolution. Finally, we demonstrate that increasing climate variability and anthropogenic disturbance increase annual favourability. Considering future climate change, we predict an increase in annual prevalence for 69% of the world's ecoregions by 2060. Overall, our analyses raise concerns for ecosystem services provided by perennial plants, as ongoing changes are leading to a higher proportion of annual plants globally.
Assuntos
Ecossistema , Mapeamento Geográfico , Filogeografia , Fenômenos Fisiológicos Vegetais , Plantas , Aclimatação , Evolução Biológica , Mudança Climática/estatística & dados numéricos , Bases de Dados Factuais , Clima Desértico , Atividades Humanas , Região do Mediterrâneo , Plantas/classificação , Chuva , TemperaturaRESUMO
Increasing gold and mineral mining activity in rivers across the global tropics has degraded ecosystems and threatened human health1,2. Such river mineral mining involves intensive excavation and sediment processing in river corridors, altering river form and releasing excess sediment downstream2. Increased suspended sediment loads can reduce water clarity and cause siltation to levels that may result in disease and mortality in fish3,4, poor water quality5 and damage to human infrastructure6. Although river mining has been investigated at local scales, no global synthesis of its physical footprint and impacts on hydrologic systems exists, leaving its full environmental consequences unknown. We assemble and analyse a 37-year satellite database showing pervasive, increasing river mineral mining worldwide. We identify 396 mining districts in 49 countries, concentrated in tropical waterways that are almost universally altered by mining-derived sediment. Of 173 mining-affected rivers, 80% have suspended sediment concentrations (SSCs) more than double pre-mining levels. In 30 countries in which mining affects large (>50 m wide) rivers, 23 ± 19% of large river length is altered by mining-derived sediment, a globe-spanning effect representing 35,000 river kilometres, 6% (±1% s.e.) of all large tropical river reaches. Our findings highlight the ubiquity and intensity of mining-associated degradation in tropical river systems.
Assuntos
Ecossistema , Sedimentos Geológicos , Mineração , Rios , Clima Tropical , Animais , Humanos , Bases de Dados Factuais , Ouro , Hidrologia , Mineração/estatística & dados numéricos , Mineração/tendências , Peixes , Sedimentos Geológicos/análiseRESUMO
Determining the drivers of non-native plant invasions is critical for managing native ecosystems and limiting the spread of invasive species1,2. Tree invasions in particular have been relatively overlooked, even though they have the potential to transform ecosystems and economies3,4. Here, leveraging global tree databases5-7, we explore how the phylogenetic and functional diversity of native tree communities, human pressure and the environment influence the establishment of non-native tree species and the subsequent invasion severity. We find that anthropogenic factors are key to predicting whether a location is invaded, but that invasion severity is underpinned by native diversity, with higher diversity predicting lower invasion severity. Temperature and precipitation emerge as strong predictors of invasion strategy, with non-native species invading successfully when they are similar to the native community in cold or dry extremes. Yet, despite the influence of these ecological forces in determining invasion strategy, we find evidence that these patterns can be obscured by human activity, with lower ecological signal in areas with higher proximity to shipping ports. Our global perspective of non-native tree invasion highlights that human drivers influence non-native tree presence, and that native phylogenetic and functional diversity have a critical role in the establishment and spread of subsequent invasions.
Assuntos
Biodiversidade , Meio Ambiente , Espécies Introduzidas , Árvores , Bases de Dados Factuais , Atividades Humanas , Espécies Introduzidas/estatística & dados numéricos , Espécies Introduzidas/tendências , Filogenia , Chuva , Temperatura , Árvores/classificação , Árvores/fisiologiaRESUMO
The distribution of dryland trees and their density, cover, size, mass and carbon content are not well known at sub-continental to continental scales1-14. This information is important for ecological protection, carbon accounting, climate mitigation and restoration efforts of dryland ecosystems15-18. We assessed more than 9.9 billion trees derived from more than 300,000 satellite images, covering semi-arid sub-Saharan Africa north of the Equator. We attributed wood, foliage and root carbon to every tree in the 0-1,000 mm year-1 rainfall zone by coupling field data19, machine learning20-22, satellite data and high-performance computing. Average carbon stocks of individual trees ranged from 0.54 Mg C ha-1 and 63 kg C tree-1 in the arid zone to 3.7 Mg C ha-1 and 98 kg tree-1 in the sub-humid zone. Overall, we estimated the total carbon for our study area to be 0.84 (±19.8%) Pg C. Comparisons with 14 previous TRENDY numerical simulation studies23 for our area found that the density and carbon stocks of scattered trees have been underestimated by three models and overestimated by 11 models, respectively. This benchmarking can help understand the carbon cycle and address concerns about land degradation24-29. We make available a linked database of wood mass, foliage mass, root mass and carbon stock of each tree for scientists, policymakers, dryland-restoration practitioners and farmers, who can use it to estimate farmland tree carbon stocks from tablets or laptops.
Assuntos
Carbono , Clima Desértico , Ecossistema , Árvores , Carbono/análise , Carbono/metabolismo , Árvores/anatomia & histologia , Árvores/química , Árvores/metabolismo , Dessecação , Imagens de Satélites , África Subsaariana , Aprendizado de Máquina , Madeira/análise , Raízes de Plantas , Agricultura , Recuperação e Remediação Ambiental , Bases de Dados Factuais , Biomassa , ComputadoresRESUMO
Integrating human genomics and proteomics can help elucidate disease mechanisms, identify clinical biomarkers and discover drug targets1-4. Because previous proteogenomic studies have focused on common variation via genome-wide association studies, the contribution of rare variants to the plasma proteome remains largely unknown. Here we identify associations between rare protein-coding variants and 2,923 plasma protein abundances measured in 49,736 UK Biobank individuals. Our variant-level exome-wide association study identified 5,433 rare genotype-protein associations, of which 81% were undetected in a previous genome-wide association study of the same cohort5. We then looked at aggregate signals using gene-level collapsing analysis, which revealed 1,962 gene-protein associations. Of the 691 gene-level signals from protein-truncating variants, 99.4% were associated with decreased protein levels. STAB1 and STAB2, encoding scavenger receptors involved in plasma protein clearance, emerged as pleiotropic loci, with 77 and 41 protein associations, respectively. We demonstrate the utility of our publicly accessible resource through several applications. These include detailing an allelic series in NLRC4, identifying potential biomarkers for a fatty liver disease-associated variant in HSD17B13 and bolstering phenome-wide association studies by integrating protein quantitative trait loci with protein-truncating variants in collapsing analyses. Finally, we uncover distinct proteomic consequences of clonal haematopoiesis (CH), including an association between TET2-CH and increased FLT3 levels. Our results highlight a considerable role for rare variation in plasma protein abundance and the value of proteogenomics in therapeutic discovery.
Assuntos
Bancos de Espécimes Biológicos , Proteínas Sanguíneas , Estudos de Associação Genética , Genômica , Proteômica , Humanos , Alelos , Biomarcadores/sangue , Proteínas Sanguíneas/análise , Proteínas Sanguíneas/genética , Bases de Dados Factuais , Exoma/genética , Hematopoese , Mutação , Plasma/química , Reino UnidoRESUMO
The use of omic modalities to dissect the molecular underpinnings of common diseases and traits is becoming increasingly common. But multi-omic traits can be genetically predicted, which enables highly cost-effective and powerful analyses for studies that do not have multi-omics1. Here we examine a large cohort (the INTERVAL study2; n = 50,000 participants) with extensive multi-omic data for plasma proteomics (SomaScan, n = 3,175; Olink, n = 4,822), plasma metabolomics (Metabolon HD4, n = 8,153), serum metabolomics (Nightingale, n = 37,359) and whole-blood Illumina RNA sequencing (n = 4,136), and use machine learning to train genetic scores for 17,227 molecular traits, including 10,521 that reach Bonferroni-adjusted significance. We evaluate the performance of genetic scores through external validation across cohorts of individuals of European, Asian and African American ancestries. In addition, we show the utility of these multi-omic genetic scores by quantifying the genetic control of biological pathways and by generating a synthetic multi-omic dataset of the UK Biobank3 to identify disease associations using a phenome-wide scan. We highlight a series of biological insights with regard to genetic mechanisms in metabolism and canonical pathway associations with disease; for example, JAK-STAT signalling and coronary atherosclerosis. Finally, we develop a portal ( https://www.omicspred.org/ ) to facilitate public access to all genetic scores and validation results, as well as to serve as a platform for future extensions and enhancements of multi-omic genetic scores.
Assuntos
Doença da Artéria Coronariana , Multiômica , Humanos , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/metabolismo , Metabolômica/métodos , Fenótipo , Proteômica/métodos , Aprendizado de Máquina , Negro ou Afro-Americano/genética , Asiático/genética , População Europeia/genética , Reino Unido , Conjuntos de Dados como Assunto , Internet , Reprodutibilidade dos Testes , Estudos de Coortes , Proteoma/análise , Proteoma/metabolismo , Metaboloma , Plasma/metabolismo , Bases de Dados FactuaisRESUMO
Illegal harvesting and trading of wildlife have become major threats to global biodiversity and public health1-3. Although China is widely recognized as an important destination for wildlife illegally obtained abroad4, little attention has been given to illegal hunting within its borders. Here we extracted 9,256 convictions for illegal hunting from a nationwide database of trial verdicts in China spanning January 2014 to March 2020. These convictions involved illegal hunting of 21% (n = 673) of China's amphibian, reptile, bird and mammal species, including 25% of imperilled species in these groups. Sample-based extrapolation indicates that many more species were taken illegally during this period. Larger body mass and range size (for all groups), and proximity to urban markets (for amphibians and birds) increase the probability of a species appearing in the convictions database. Convictions pertained overwhelmingly to illegal hunting for commercial purposes and involved all major habitats across China. A small number of convictions represented most of the animals taken, indicating the existence of large commercial poaching operations. Prefectures closer to urban markets show higher densities of convictions and more individual animals taken. Our results suggest that illegal hunting is a major, overlooked threat to biodiversity throughout China.
Assuntos
Animais Selvagens , Biodiversidade , Caça , Animais , Anfíbios , Aves , China , Bases de Dados Factuais , Espécies em Perigo de Extinção/economia , Espécies em Perigo de Extinção/legislação & jurisprudência , Espécies em Perigo de Extinção/estatística & dados numéricos , Caça/economia , Caça/legislação & jurisprudência , Caça/estatística & dados numéricos , Mamíferos , RépteisRESUMO
Cellular functions are mediated by protein-protein interactions, and mapping the interactome provides fundamental insights into biological systems. Affinity purification coupled to mass spectrometry is an ideal tool for such mapping, but it has been difficult to identify low copy number complexes, membrane complexes and complexes that are disrupted by protein tagging. As a result, our current knowledge of the interactome is far from complete, and assessing the reliability of reported interactions is challenging. Here we develop a sensitive high-throughput method using highly reproducible affinity enrichment coupled to mass spectrometry combined with a quantitative two-dimensional analysis strategy to comprehensively map the interactome of Saccharomyces cerevisiae. Thousand-fold reduced volumes in 96-well format enabled replicate analysis of the endogenous GFP-tagged library covering the entire expressed yeast proteome1. The 4,159 pull-downs generated a highly structured network of 3,927 proteins connected by 31,004 interactions, doubling the number of proteins and tripling the number of reliable interactions compared with existing interactome maps2. This includes very-low-abundance epigenetic complexes, organellar membrane complexes and non-taggable complexes inferred by abundance correlation. This nearly saturated interactome reveals that the vast majority of yeast proteins are highly connected, with an average of 16 interactors. Similar to social networks between humans, the average shortest distance between proteins is 4.2 interactions. AlphaFold-Multimer provided novel insights into the functional roles of previously uncharacterized proteins in complexes. Our web portal ( www.yeast-interactome.org ) enables extensive exploration of the interactome dataset.
Assuntos
Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas , Proteoma , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Espectrometria de Massas , Mapeamento de Interação de Proteínas/métodos , Proteoma/química , Proteoma/metabolismo , Reprodutibilidade dos Testes , Saccharomyces cerevisiae/química , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/metabolismo , Epigênese Genética , Bases de Dados FactuaisRESUMO
The Pharma Proteomics Project is a precompetitive biopharmaceutical consortium characterizing the plasma proteomic profiles of 54,219 UK Biobank participants. Here we provide a detailed summary of this initiative, including technical and biological validations, insights into proteomic disease signatures, and prediction modelling for various demographic and health indicators. We present comprehensive protein quantitative trait locus (pQTL) mapping of 2,923 proteins that identifies 14,287 primary genetic associations, of which 81% are previously undescribed, alongside ancestry-specific pQTL mapping in non-European individuals. The study provides an updated characterization of the genetic architecture of the plasma proteome, contextualized with projected pQTL discovery rates as sample sizes and proteomic assay coverages increase over time. We offer extensive insights into trans pQTLs across multiple biological domains, highlight genetic influences on ligand-receptor interactions and pathway perturbations across a diverse collection of cytokines and complement networks, and illustrate long-range epistatic effects of ABO blood group and FUT2 secretor status on proteins with gastrointestinal tissue-enriched expression. We demonstrate the utility of these data for drug discovery by extending the genetic proxied effects of protein targets, such as PCSK9, on additional endpoints, and disentangle specific genes and proteins perturbed at loci associated with COVID-19 susceptibility. This public-private partnership provides the scientific community with an open-access proteomics resource of considerable breadth and depth to help to elucidate the biological mechanisms underlying proteo-genomic discoveries and accelerate the development of biomarkers, predictive models and therapeutics1.