Morales AE, Dong Y, Brown T
… +31 more, Baid K, Kontopoulos D-, Gonzalez V, Huang Z, Ahmed AW, Bhuinya A, Hilgers L, Winkler S, Hughes G, Li X, Lu P, Yang Y, Kirilenko BM, Devanna P, Lama TM, Nissan Y, Pippel M, Dávalos LM, Vernes SC, Puechmaille SJ, Rossiter SJ, Yovel Y, Prescott JB, Kurth A, Ray DA, Lim BK, Myers E, Teeling EC, Banerjee A, Irving AT, Hiller M
Zoonoses are infectious diseases transmitted from animals to humans. Bats have been suggested to harbour more zoonotic viruses than any other mammalian order. Infections in bats are largely asymptomatic, indicating limit...Zoonoses are infectious diseases transmitted from animals to humans. Bats have been suggested to harbour more zoonotic viruses than any other mammalian order. Infections in bats are largely asymptomatic, indicating limited tissue-damaging inflammation and immunopathology. To investigate the genomic basis of disease resistance, the Bat1K project generated reference-quality genomes of ten bat species, including potential viral reservoirs. Here we describe a systematic analysis covering 115 mammalian genomes that revealed that signatures of selection in immune genes are more prevalent in bats than in other mammalian orders. We found an excess of immune gene adaptations in the ancestral chiropteran branch and in many descending bat lineages, highlighting viral entry and detection factors, and regulators of antiviral and inflammatory responses. ISG15, which is an antiviral gene contributing to hyperinflammation during COVID-19 (refs. ), exhibits key residue changes in rhinolophid and hipposiderid bats. Cellular infection experiments show species-specific antiviral differences and an essential role of protein conjugation in antiviral function of bat ISG15, separate from its role in secretion and inflammation in humans. Furthermore, in contrast to humans, ISG15 in most rhinolophid and hipposiderid bats has strong anti-SARS-CoV-2 activity. Our work reveals molecular mechanisms that contribute to viral tolerance and disease resistance in bats.
Bipolar disorder is a leading contributor to the global burden of disease. Despite high heritability (60-80%), the majority of the underlying genetic determinants remain unknown. We analysed data from participants of Eur...Bipolar disorder is a leading contributor to the global burden of disease. Despite high heritability (60-80%), the majority of the underlying genetic determinants remain unknown. We analysed data from participants of European, East Asian, African American and Latino ancestries (n = 158,036 cases with bipolar disorder, 2.8 million controls), combining clinical, community and self-reported samples. We identified 298 genome-wide significant loci in the multi-ancestry meta-analysis, a fourfold increase over previous findings, and identified an ancestry-specific association in the East Asian cohort. Integrating results from fine-mapping and other variant-to-gene mapping approaches identified 36 credible genes in the aetiology of bipolar disorder. Genes prioritized through fine-mapping were enriched for ultra-rare damaging missense and protein-truncating variations in cases with bipolar disorder, highlighting convergence of common and rare variant signals. We report differences in the genetic architecture of bipolar disorder depending on the source of patient ascertainment and on bipolar disorder subtype (type I or type II). Several analyses implicate specific cell types in the pathophysiology of bipolar disorder, including GABAergic interneurons and medium spiny neurons. Together, these analyses provide additional insights into the genetic architecture and biological underpinnings of bipolar disorder.
Cheng L, Wang N, Bao Z
… +21 more, Zhou Q, Guarracino A, Yang Y, Wang P, Zhang Z, Tang D, Zhang P, Wu Y, Zhou Y, Zheng Y, Hu Y, Lian Q, Ma Z, Lassois L, Zhang C, Lucas WJ, Garrison E, Stein N, Städler T, Zhou Y, Huang S
The tetraploid genome and clonal propagation of the cultivated potato (Solanum tuberosum L.) dictate a slow, non-accumulative breeding mode of the most important tuber crop. Transitioning potato breeding to a seed-propag...The tetraploid genome and clonal propagation of the cultivated potato (Solanum tuberosum L.) dictate a slow, non-accumulative breeding mode of the most important tuber crop. Transitioning potato breeding to a seed-propagated hybrid system based on diploid inbred lines has the potential to greatly accelerate its improvement. Crucially, the development of inbred lines is impeded by manifold deleterious variants; explaining their nature and finding ways to eliminate them is the current focus of hybrid potato research. However, most published diploid potato genomes are unphased, concealing crucial information on haplotype diversity and heterozygosity. Here we develop a phased potato pangenome graph of 60 haplotypes from cultivated diploids and the ancestral wild species, and find evidence for the prevalence of transposable elements in generating structural variants. Compared with the linear reference, the graph pangenome represents a broader diversity (3,076 Mb versus 742 Mb). Notably, we observe enhanced heterozygosity in cultivated diploids compared with wild ones (14.0% versus 9.5%), indicating extensive hybridization during potato domestication. Using conservative criteria, we identify 19,625 putatively deleterious structural variants (dSVs) and reveal a biased accumulation of deleterious single nucleotide polymorphisms (dSNPs) around dSVs in coupling phase. Based on the graph pangenome, we computationally design ideal potato haplotypes with minimal dSNPs and dSVs. These advances provide critical insights into the genomic basis of clonal propagation and will guide breeders to develop a suite of promising inbred lines.
Klein D, Palla G, Lange M
… +17 more, Klein M, Piran Z, Gander M, Meng-Papaxanthos L, Sterr M, Saber L, Jing C, Bastidas-Ponce A, Cota P, Tarquis-Medina M, Parikh S, Gold I, Lickert H, Bakhti M, Nitzan M, Cuturi M, Theis FJ
Single-cell genomic technologies enable the multimodal profiling of millions of cells across temporal and spatial dimensions. However, experimental limitations hinder the comprehensive measurement of cells under native t...Single-cell genomic technologies enable the multimodal profiling of millions of cells across temporal and spatial dimensions. However, experimental limitations hinder the comprehensive measurement of cells under native temporal dynamics and in their native spatial tissue niche. Optimal transport has emerged as a powerful tool to address these constraints and has facilitated the recovery of the original cellular context. Yet, most optimal transport applications are unable to incorporate multimodal information or scale to single-cell atlases. Here we introduce multi-omics single-cell optimal transport (moscot), a scalable framework for optimal transport in single-cell genomics that supports multimodality across all applications. We demonstrate the capability of moscot to efficiently reconstruct developmental trajectories of 1.7 million cells from mouse embryos across 20 time points. To illustrate the capability of moscot in space, we enrich spatial transcriptomic datasets by mapping multimodal information from single-cell profiles in a mouse liver sample and align multiple coronal sections of the mouse brain. We present moscot.spatiotemporal, an approach that leverages gene-expression data across both spatial and temporal dimensions to uncover the spatiotemporal dynamics of mouse embryogenesis. We also resolve endocrine-lineage relationships of delta and epsilon cells in a previously unpublished mouse, time-resolved pancreas development dataset using paired measurements of gene expression and chromatin accessibility. Our findings are confirmed through experimental validation of NEUROD2 as a regulator of epsilon progenitor cells in a model of human induced pluripotent stem cell islet cell differentiation. Moscot is available as open-source software, accompanied by extensive documentation.
Type A GABA (γ-aminobutyric acid) receptors (GABA receptors) mediate most fast inhibitory signalling in the brain and are targets for drugs that treat epilepsy, anxiety, depression and insomnia and for anaesthetics. Thes...Type A GABA (γ-aminobutyric acid) receptors (GABA receptors) mediate most fast inhibitory signalling in the brain and are targets for drugs that treat epilepsy, anxiety, depression and insomnia and for anaesthetics. These receptors comprise a complex array of 19 related subunits, which form pentameric ligand-gated ion channels. The composition and structure of native GABA receptors in the human brain have been inferred from subunit localization in tissue, functional measurements and structural analysis from recombinant expression and in mice. However, the arrangements of subunits that co-assemble physiologically in native human GABA receptors remain unknown. Here we isolated α1 subunit-containing GABA receptors from human patients with epilepsy. Using cryo-electron microscopy, we defined a set of 12 native subunit assemblies and their 3D structures. We address inconsistencies between previous native and recombinant approaches, and reveal details of previously undefined subunit interfaces. Drug-like densities in a subset of these interfaces led us to uncover unexpected activity on the GABA receptor of antiepileptic drugs and resulted in localization of one of these drugs to the benzodiazepine-binding site. Proteomics and further structural analysis suggest interactions with the auxiliary subunits neuroligin 2 and GARLH4, which localize and modulate GABA receptors at inhibitory synapses. This work provides a structural foundation for understanding GABA receptor signalling and targeted pharmacology in the human brain.
Many human diseases are the result of early developmental defects. As most paediatric diseases and disorders are rare, children are critically underrepresented in research. Functional genomics studies primarily rely on a...Many human diseases are the result of early developmental defects. As most paediatric diseases and disorders are rare, children are critically underrepresented in research. Functional genomics studies primarily rely on adult tissues and lack critical cell states in specific developmental windows. In parallel, little is known about the conservation of developmental programmes across non-human primate (NHP) species, with implications for human evolution. Here we introduce the developmental Genotype-Tissue Expression (dGTEx) projects, which span humans and NHPs and aim to integrate gene expression, regulation and genetics data across development and species. The dGTEx cohort will consist of 74 tissue sites across 120 human donors from birth to adulthood, and developmentally matched NHP age groups, with additional prenatal and adult animals, with 126 rhesus macaques (Macaca mulatta) and 72 common marmosets (Callithrix jacchus). The data will comprise whole-genome sequencing, extensive bulk, single-cell and spatial gene expression profiles, and chromatin accessibility data across tissues and development. Through community engagement and donor diversity, the human dGTEx study seeks to address disparities in genomic research. Thus, dGTEx will provide a reference human and NHP dataset and tissue bank, enabling research into developmental changes in expression and gene regulation, childhood disorders and the effect of genetic variation on development.
Polygenic genome editing in human embryos and germ cells is predicted to become feasible in the next three decades. Several recent books and academic papers have outlined the ethical concerns raised by germline genome ed...Polygenic genome editing in human embryos and germ cells is predicted to become feasible in the next three decades. Several recent books and academic papers have outlined the ethical concerns raised by germline genome editing and the opportunities that it may present. To date, no attempts have been made to predict the consequences of altering specific variants associated with polygenic diseases. In this Analysis, we show that polygenic genome editing could theoretically yield extreme reductions in disease susceptibility. For example, editing a relatively small number of genomic variants could make a substantial difference to an individual's risk of developing coronary artery disease, Alzheimer's disease, major depressive disorder, diabetes and schizophrenia. Similarly, large changes in risk factors, such as low-density lipoprotein cholesterol and blood pressure, could, in theory, be achieved by polygenic editing. Although heritable polygenic editing (HPE) is still speculative, we completed calculations to discuss the underlying ethical issues. Our modelling demonstrates how the putatively positive consequences of gene editing at an individual level may deepen health inequalities. Further, as single or multiple gene variants can increase the risk of some diseases while decreasing that of others, HPE raises ethical challenges related to pleiotropy and genetic diversity. We conclude by arguing for a collectivist perspective on the ethical issues raised by HPE, which accounts for its effects on individuals, their families, communities and society.
Many known and unknown historical events have remained below detection thresholds of genetic studies because subtle ancestry changes are challenging to reconstruct. Methods based on shared haplotypes and rare variants im...Many known and unknown historical events have remained below detection thresholds of genetic studies because subtle ancestry changes are challenging to reconstruct. Methods based on shared haplotypes and rare variants improve power but are not explicitly temporal and have not been possible to adopt in unbiased ancestry models. Here we develop Twigstats, an approach of time-stratified ancestry analysis that can improve statistical power by an order of magnitude by focusing on coalescences in recent times, while remaining unbiased by population-specific drift. We apply this framework to 1,556 available ancient whole genomes from Europe in the historical period. We are able to model individual-level ancestry using preceding genomes to provide high resolution. During the first half of the first millennium CE, we observe at least two different streams of Scandinavian-related ancestry expanding across western, central and eastern Europe. By contrast, during the second half of the first millennium CE, ancestry patterns suggest the regional disappearance or substantial admixture of these ancestries. In Scandinavia, we document a major ancestry influx by approximately 800 CE, when a large proportion of Viking Age individuals carried ancestry from groups related to central Europe not seen in individuals from the early Iron Age. Our findings suggest that time-stratified ancestry analysis can provide a higher-resolution lens for genetic history.
Reproduction, development and homeostasis depend on motile cilia, whose rhythmic beating is powered by a microtubule-based molecular machine called the axoneme. Although an atomic model of the axoneme is available for th...Reproduction, development and homeostasis depend on motile cilia, whose rhythmic beating is powered by a microtubule-based molecular machine called the axoneme. Although an atomic model of the axoneme is available for the alga Chlamydomonas reinhardtii, structures of mammalian axonemes are incomplete. Furthermore, we do not fully understand how molecular structures of axonemes vary across motile-ciliated cell types in the body. Here we use cryoelectron microscopy, cryoelectron tomography and proteomics to resolve the 96-nm modular repeat of axonemal doublet microtubules (DMTs) from both sperm flagella and epithelial cilia of the oviduct, brain ventricles and respiratory tract. We find that sperm DMTs are the most specialized, with epithelial cilia having only minor differences across tissues. We build a model of the mammalian sperm DMT, defining the positions and interactions of 181 proteins including 34 newly identified proteins. We elucidate the composition of radial spoke 3 and uncover binding sites of kinases associated with regeneration of ATP and regulation of ciliary motility. We discover a sperm-specific, axoneme-tethered T-complex protein ring complex (TRiC) chaperone that may contribute to construction or maintenance of the long flagella of mammalian sperm. We resolve axonemal dyneins in their prestroke states, illuminating conformational changes that occur during ciliary movement. Our results illustrate how elements of chemical and mechanical regulation are embedded within the axoneme, providing valuable resources for understanding the aetiology of ciliopathy and infertility, and exemplifying the discovery power of modern structural biology.
The rapid melting of mountain glaciers and the vanishing of their streams is emblematic of climate change. Glacier-fed streams (GFSs) are cold, oligotrophic and unstable ecosystems in which life is dominated by microbial...The rapid melting of mountain glaciers and the vanishing of their streams is emblematic of climate change. Glacier-fed streams (GFSs) are cold, oligotrophic and unstable ecosystems in which life is dominated by microbial biofilms. However, current knowledge on the GFS microbiome is scarce, precluding an understanding of its response to glacier shrinkage. Here, by leveraging metabarcoding and metagenomics, we provide a comprehensive survey of bacteria in the benthic microbiome across 152 GFSs draining the Earth's major mountain ranges. We find that the GFS bacterial microbiome is taxonomically and functionally distinct from other cryospheric microbiomes. GFS bacteria are diverse, with more than half being specific to a given mountain range, some unique to single GFSs and a few cosmopolitan and abundant. We show how geographic isolation and environmental selection shape their biogeography, which is characterized by distinct compositional patterns between mountain ranges and hemispheres. Phylogenetic analyses furthermore uncovered microdiverse clades resulting from environmental selection, probably promoting functional resilience and contributing to GFS bacterial biodiversity and biogeography. Climate-induced glacier shrinkage puts this unique microbiome at risk. Our study provides a global reference for future climate-change microbiology studies on the vanishing GFS ecosystem.
Qu Q, Chen Y, Wang Y
… +24 more, Long S, Wang W, Yang HY, Li M, Tian X, Wei X, Liu YH, Xu S, Zhang C, Zhu M, Lam SM, Wu J, Yun C, Chen J, Xue S, Zhang B, Zheng ZZ, Piao HL, Jiang C, Guo H, Shui G, Deng X, Zhang CS, Lin SC
Calorie restriction (CR) is a dietary intervention used to promote health and longevity. CR causes various metabolic changes in both the production and the circulation of metabolites; however, it remains unclear which al...Calorie restriction (CR) is a dietary intervention used to promote health and longevity. CR causes various metabolic changes in both the production and the circulation of metabolites; however, it remains unclear which altered metabolites account for the physiological benefits of CR. Here we use metabolomics to analyse metabolites that exhibit changes in abundance during CR and perform subsequent functional validation. We show that lithocholic acid (LCA) is one of the metabolites that alone can recapitulate the effects of CR in mice. These effects include activation of AMP-activated protein kinase (AMPK), enhancement of muscle regeneration and rejuvenation of grip strength and running capacity. LCA also activates AMPK and induces life-extending and health-extending effects in Caenorhabditis elegans and Drosophila melanogaster. As C. elegans and D. melanogaster are not able to synthesize LCA, these results indicate that these animals are able to transmit the signalling effects of LCA once administered. Knockout of AMPK abrogates LCA-induced phenotypes in all the three animal models. Together, we identify that administration of the CR-mediated upregulated metabolite LCA alone can confer anti-ageing benefits to metazoans in an AMPK-dependent manner.
Modern humans arrived in Europe more than 45,000 years ago, overlapping at least 5,000 years with Neanderthals. Limited genomic data from these early modern humans have shown that at least two genetically distinct groups...Modern humans arrived in Europe more than 45,000 years ago, overlapping at least 5,000 years with Neanderthals. Limited genomic data from these early modern humans have shown that at least two genetically distinct groups inhabited Europe, represented by Zlatý kůň, Czechia and Bacho Kiro, Bulgaria. Here we deepen our understanding of early modern humans by analysing one high-coverage genome and five low-coverage genomes from approximately 45,000-year-old remains from Ilsenhöhle in Ranis, Germany, and a further high-coverage genome from Zlatý kůň. We show that distant familial relationships link the Ranis and Zlatý kůň individuals and that they were part of the same small, isolated population that represents the deepest known split from the Out-of-Africa lineage. Ranis genomes harbour Neanderthal segments that originate from a single admixture event shared with all non-Africans that we date to approximately 45,000-49,000 years ago. This implies that ancestors of all non-Africans sequenced so far resided in a common population at this time, and further suggests that modern human remains older than 50,000 years from outside Africa represent different non-African populations.
He F, Aebersold R, Baker MS
… +99 more, Bian X, Bo X, Chan DW, Chang C, Chen L, Chen X, Chen YJ, Cheng H, Collins BC, Corrales F, Cox J, E W, Van Eyk JE, Fan J, Faridi P, Figeys D, Gao GF, Gao W, Gao ZH, Goda K, Goh WWB, Gu D, Guo C, Guo T, He Y, Heck AJR, Hermjakob H, Hunter T, Iyer NG, Jiang Y, Jimenez CR, Joshi L, Kelleher NL, Li M, Li Y, Lin Q, Liu CH, Liu F, Liu GH, Liu Y, Liu Z, Low TY, Lu B, Mann M, Meng A, Moritz RL, Nice E, Ning G, Omenn GS, Overall CM, Palmisano G, Peng Y, Pineau C, Poon TCW, Purcell AW, Qiao J, Reddel RR, Robinson PJ, Roncada P, Sander C, Sha J, Song E, Srivastava S, Sun A, Sze SK, Tang C, Tang L, Tian R, Vizcaíno JA, Wang C, Wang C, Wang X, Wang X, Wang Y, Weiss T, Wilhelm M, Winkler R, Wollscheid B, Wong L, Xie L, Xie W, Xu T, Xu T, Yan L, Yang J, Yang X, Yates J, Yun T, Zhai Q, Zhang B, Zhang H, Zhang L, Zhang L, Zhang P, Zhang Y, Zheng YZ, Zhong Q, Zhu Y, π-HuB Consortium
The human body contains trillions of cells, classified into specific cell types, with diverse morphologies and functions. In addition, cells of the same type can assume different states within an individual's body during...The human body contains trillions of cells, classified into specific cell types, with diverse morphologies and functions. In addition, cells of the same type can assume different states within an individual's body during their lifetime. Understanding the complexities of the proteome in the context of a human organism and its many potential states is a necessary requirement to understanding human biology, but these complexities can neither be predicted from the genome, nor have they been systematically measurable with available technologies. Recent advances in proteomic technology and computational sciences now provide opportunities to investigate the intricate biology of the human body at unprecedented resolution and scale. Here we introduce a big-science endeavour called π-HuB (proteomic navigator of the human body). The aim of the π-HuB project is to (1) generate and harness multimodality proteomic datasets to enhance our understanding of human biology; (2) facilitate disease risk assessment and diagnosis; (3) uncover new drug targets; (4) optimize appropriate therapeutic strategies; and (5) enable intelligent healthcare, thereby ushering in a new era of proteomics-driven phronesis medicine. This ambitious mission will be implemented by an international collaborative force of multidisciplinary research teams worldwide across academic, industrial and government sectors.
Jiao C, Xie X, Hao C
… +20 more, Chen L, Xie Y, Garg V, Zhao L, Wang Z, Zhang Y, Li T, Fu J, Chitikineni A, Hou J, Liu H, Dwivedi G, Liu X, Jia J, Mao L, Wang X, Appels R, Varshney RK, Guo W, Zhang X
Wheat is the second largest food crop with a very good breeding system and pedigree record in China. Investigating the genomic footprints of wheat cultivars will unveil potential avenues for future breeding efforts. Here...Wheat is the second largest food crop with a very good breeding system and pedigree record in China. Investigating the genomic footprints of wheat cultivars will unveil potential avenues for future breeding efforts. Here we report chromosome-level genome assemblies of 17 wheat cultivars that chronicle the breeding history of China. Comparative genomic analysis uncovered a wealth of structural rearrangements, identifying 249,976 structural variations with 49.03% (122,567) longer than 5 kb. Cultivars developed in 1980s displayed significant accumulations of structural variations, a pattern linked to the extensive incorporation of European and American varieties into breeding programmes of that era. We further proved that structural variations in the centromere-proximal regions are associated with a reduction of crossover events. We showed that common wheat evolved from spring to winter types via mutations and duplications of the VRN-A1 gene as an adaptation strategy to a changing environment. We confirmed shifts in wheat cultivars linked to dietary preferences, migration and cultural integration in Northwest China. We identified large presence or absence variations of pSc200 tandem repeats on the 1RS terminal, suggesting its own rapid evolution in the wheat genome. The high-quality genome assemblies of 17 representatives developed and their good complementarity to the 10+ pan-genomes offer a robust platform for future genomics-assisted breeding in wheat.
Despite the fundamental role of bacterial strain variation in gut microbiota function, the number of unique strains of a species that can stably colonize the human intestine is still unknown for almost all species. Here...Despite the fundamental role of bacterial strain variation in gut microbiota function, the number of unique strains of a species that can stably colonize the human intestine is still unknown for almost all species. Here we determine the strain richness (SR) of common gut species using thousands of sequenced bacterial isolates with paired metagenomes. We show that SR varies across species, is transferable by faecal microbiota transplantation, and is uniquely low in the gut compared with soil and lake environments. Active therapeutic administration of supraphysiologic numbers of strains per species increases recipient SR, which then converges back to the population average after dosing is ceased. Stratifying engraftment outcomes by high or low SR shows that SR predicts microbial addition or replacement in faecal transplants. Together, these results indicate that properties of the gut ecosystem govern the number of strains of each species colonizing the gut and thereby influence strain addition and replacement in faecal microbiota transplantation and defined live biotherapeutic products.
Knight CG, Nicolitch O, Griffiths RI
… +19 more, Goodall T, Jones B, Weser C, Langridge H, Davison J, Dellavalle A, Eisenhauer N, Gongalsky KB, Hector A, Jardine E, Kardol P, Maestre FT, Schädler M, Semchenko M, Stevens C, Tsiafouli MΑ, Vilhelmsson O, Wanek W, de Vries FT
Increasing extreme climatic events threaten the functioning of terrestrial ecosystems. Because soil microbes govern key biogeochemical processes, understanding their response to climate extremes is crucial in predicting...Increasing extreme climatic events threaten the functioning of terrestrial ecosystems. Because soil microbes govern key biogeochemical processes, understanding their response to climate extremes is crucial in predicting the consequences for ecosystem functioning. Here we subjected soils from 30 grasslands across Europe to four contrasting extreme climatic events under common controlled conditions (drought, flood, freezing and heat), and compared the response of soil microbial communities and their functioning with those of undisturbed soils. Soil microbiomes exhibited a small, but highly consistent and phylogenetically conserved, response under the imposed extreme events. Heat treatment most strongly impacted soil microbiomes, enhancing dormancy and sporulation genes and decreasing metabolic versatility. Microbiome response to heat in particular could be predicted by local climatic conditions and soil properties, with soils that do not normally experience the extreme conditions being imposed being most vulnerable. Our results suggest that soil microbiomes from different climates share unified responses to extreme climatic events, but that predicting the extent of community change may require knowledge of the local microbiome. These findings advance our understanding of soil microbial responses to extreme events, and provide a first step for making general predictions about the impact of extreme climatic events on soil functioning.
To K, Fei L, Pett JP
… +34 more, Roberts K, Blain R, Polański K, Li T, Yayon N, He P, Xu C, Cranley J, Moy M, Li R, Kanemaru K, Huang N, Megas S, Richardson L, Kapuge R, Perera S, Tuck E, Wilbrey-Clark A, Mulas I, Memi F, Cakir B, Predeus AV, Horsfall D, Murray S, Prete M, Mazin P, He X, Meyer KB, Haniffa M, Barker RA, Bayraktar O, Chédotal A, Buckley CD, Teichmann SA
Human embryonic bone and joint formation is determined by coordinated differentiation of progenitors in the nascent skeleton. The cell states, epigenetic processes and key regulatory factors that underlie lineage commitm...Human embryonic bone and joint formation is determined by coordinated differentiation of progenitors in the nascent skeleton. The cell states, epigenetic processes and key regulatory factors that underlie lineage commitment of these cells remain elusive. Here we applied paired transcriptional and epigenetic profiling of approximately 336,000 nucleus droplets and spatial transcriptomics to establish a multi-omic atlas of human embryonic joint and cranium development between 5 and 11 weeks after conception. Using combined modelling of transcriptional and epigenetic data, we characterized regionally distinct limb and cranial osteoprogenitor trajectories across the embryonic skeleton and further described regulatory networks that govern intramembranous and endochondral ossification. Spatial localization of cell clusters in our in situ sequencing data using a new tool, ISS-Patcher, revealed mechanisms of progenitor zonation during bone and joint formation. Through trajectory analysis, we predicted potential non-canonical cellular origins for human chondrocytes from Schwann cells. We also introduce SNP2Cell, a tool to link cell-type-specific regulatory networks to polygenic traits such as osteoarthritis. Using osteolineage trajectories characterized here, we simulated in silico perturbations of genes that cause monogenic craniosynostosis and implicate potential cell states and disease mechanisms. This work forms a detailed and dynamic regulatory atlas of bone and cartilage maturation and advances our fundamental understanding of cell-fate determination in human skeletal development.
Predicting elemental cycles and maintaining water quality under increasing anthropogenic influence requires knowledge of the spatial drivers of river microbiomes. However, understanding of the core microbial processes go...Predicting elemental cycles and maintaining water quality under increasing anthropogenic influence requires knowledge of the spatial drivers of river microbiomes. However, understanding of the core microbial processes governing river biogeochemistry is hindered by a lack of genome-resolved functional insights and sampling across multiple rivers. Here we used a community science effort to accelerate the sampling, sequencing and genome-resolved analyses of river microbiomes to create the Genome Resolved Open Watersheds database (GROWdb). GROWdb profiles the identity, distribution, function and expression of microbial genomes across river surface waters covering 90% of United States watersheds. Specifically, GROWdb encompasses microbial lineages from 27 phyla, including novel members from 10 families and 128 genera, and defines the core river microbiome at the genome level. GROWdb analyses coupled to extensive geospatial information reveals local and regional drivers of microbial community structuring, while also presenting foundational hypotheses about ecosystem function. Building on the previously conceived River Continuum Concept, we layer on microbial functional trait expression, which suggests that the structure and function of river microbiomes is predictable. We make GROWdb available through various collaborative cyberinfrastructures, so that it can be widely accessed across disciplines for watershed predictive modelling and microbiome-based management practices.
Piraner DI, Abedi MH, Duran Gonzalez MJ
… +12 more, Chazin-Gray A, Lin A, Zhu I, Ravindran PT, Schlichthaerle T, Huang B, Bearchild TH, Lee D, Wyman S, Jun YW, Baker D, Roybal KT
Despite recent advances in mammalian synthetic biology, there remains a lack of modular synthetic receptors that can robustly respond to soluble ligands and, in turn, activate bespoke cellular functions. Such receptors w...Despite recent advances in mammalian synthetic biology, there remains a lack of modular synthetic receptors that can robustly respond to soluble ligands and, in turn, activate bespoke cellular functions. Such receptors would have extensive clinical potential to regulate the activity of engineered therapeutic cells, but so far only receptors against cell-surface targets have approached clinical translation. To address this gap, here we adapt a receptor architecture called the synthetic intramembrane proteolysis receptor (SNIPR) for activation by soluble ligands. Our SNIPR platform can be activated by both natural and synthetic soluble factors, with notably low baseline activity and high fold activation, through an endocytic, pH-dependent cleavage mechanism. We demonstrate the therapeutic capabilities of the receptor platform by localizing the activity of chimeric antigen receptor (CAR) T cells to solid tumours in which soluble disease-associated factors are expressed, bypassing the major hurdle of on-target off-tumour toxicity in bystander organs. We further apply the SNIPR platform to engineer fully synthetic signalling networks between cells orthogonal to natural signalling pathways, expanding the scope of synthetic biology. Our design framework enables cellular communication and environmental interactions, extending the capabilities of synthetic cellular networking in clinical and research contexts.
Pancreatic ductal adenocarcinoma (PDAC) has an atypical, highly stromal tumour microenvironment (TME) that profoundly contributes to its poor prognosis. Here, to better understand the intercellular signalling between can...Pancreatic ductal adenocarcinoma (PDAC) has an atypical, highly stromal tumour microenvironment (TME) that profoundly contributes to its poor prognosis. Here, to better understand the intercellular signalling between cancer and stromal cells directly in PDAC tumours, we developed a multidimensional proteomic strategy called TMEPro. We applied TMEPro to profile the glycosylated secreted and plasma membrane proteome of 100 human pancreatic tissue samples to a great depth, define cell type origins and identify potential paracrine cross-talk, especially that mediated through tyrosine phosphorylation. Temporal dynamics during pancreatic tumour progression were investigated in a genetically engineered PDAC mouse model. Functionally, we revealed reciprocal signalling between stromal cells and cancer cells mediated by the stromal PDGFR-PTPN11-FOS signalling axis. Furthermore, we examined the generic shedding mechanism of plasma membrane proteins in PDAC tumours and revealed that matrix-metalloprotease-mediated shedding of the AXL receptor tyrosine kinase ectodomain provides an additional dimension of intercellular signalling regulation in the PDAC TME. Importantly, the level of shed AXL has a potential correlation with lymph node metastasis, and inhibition of AXL shedding and its kinase activity showed a substantial synergistic effect in inhibiting cancer cell growth. In summary, we provide TMEPro, a generically applicable clinical functional proteomic strategy, and a comprehensive resource for better understanding the PDAC TME and facilitating the discovery of new diagnostic and therapeutic targets.