Chen J, Jia Y, Sun Y
… +49 more, Liu K, Zhou C, Liu C, Li D, Liu G, Zhang C, Yang T, Huang L, Zhuang Y, Wang D, Xu D, Zhong Q, Guo Y, Li A, Seim I, Jiang L, Wang L, Lee SMY, Liu Y, Wang D, Zhang G, Liu S, Wei X, Yue Z, Zheng S, Shen X, Wang S, Qi C, Chen J, Ye C, Zhao F, Wang J, Fan J, Li B, Sun J, Jia X, Xia Z, Zhang H, Liu J, Zheng Y, Liu X, Wang J, Yang H, Kristiansen K, Xu X, Mock T, Li S, Zhang W, Fan G
The past two decades has witnessed a remarkable increase in the number of microbial genomes retrieved from marine systems. However, it has remained challenging to translate this marine genomic diversity into biotechnolog...The past two decades has witnessed a remarkable increase in the number of microbial genomes retrieved from marine systems. However, it has remained challenging to translate this marine genomic diversity into biotechnological and biomedical applications. Here we recovered 43,191 bacterial and archaeal genomes from publicly available marine metagenomes, encompassing a wide range of diversity with 138 distinct phyla, redefining the upper limit of marine bacterial genome size and revealing complex trade-offs between the occurrence of CRISPR-Cas systems and antibiotic resistance genes. In silico bioprospecting of these marine genomes led to the discovery of a novel CRISPR-Cas9 system, ten antimicrobial peptides, and three enzymes that degrade polyethylene terephthalate. In vitro experiments confirmed their effectiveness and efficacy. This work provides evidence that global-scale sequencing initiatives advance our understanding of how microbial diversity has evolved in the oceans and is maintained, and demonstrates how such initiatives can be sustainably exploited to advance biotechnology and biomedicine.
Our genomes influence nearly every aspect of human biology-from molecular and cellular functions to phenotypes in health and disease. Studying the differences in DNA sequence between individuals (genomic variation) could...Our genomes influence nearly every aspect of human biology-from molecular and cellular functions to phenotypes in health and disease. Studying the differences in DNA sequence between individuals (genomic variation) could reveal previously unknown mechanisms of human biology, uncover the basis of genetic predispositions to diseases, and guide the development of new diagnostic tools and therapeutic agents. Yet, understanding how genomic variation alters genome function to influence phenotype has proved challenging. To unlock these insights, we need a systematic and comprehensive catalogue of genome function and the molecular and cellular effects of genomic variants. Towards this goal, the Impact of Genomic Variation on Function (IGVF) Consortium will combine approaches in single-cell mapping, genomic perturbations and predictive modelling to investigate the relationships among genomic variation, genome function and phenotypes. IGVF will create maps across hundreds of cell types and states describing how coding variants alter protein activity, how noncoding variants change the regulation of gene expression, and how such effects connect through gene-regulatory and protein-interaction networks. These experimental data, computational predictions and accompanying standards and pipelines will be integrated into an open resource that will catalyse community efforts to explore how our genomes influence biology and disease across populations.
Green GS, Fujita M, Yang HS
… +15 more, Taga M, Cain A, McCabe C, Comandante-Lou N, White CC, Schmidtner AK, Zeng L, Sigalov A, Wang Y, Regev A, Klein HU, Menon V, Bennett DA, Habib N, De Jager PL
Alzheimer's disease (AD) has recently been associated with diverse cell states, yet when and how these states affect the onset of AD remains unclear. Here we used a data-driven approach to reconstruct the dynamics of the...Alzheimer's disease (AD) has recently been associated with diverse cell states, yet when and how these states affect the onset of AD remains unclear. Here we used a data-driven approach to reconstruct the dynamics of the brain's cellular environment and identified a trajectory leading to AD that is distinct from other ageing-related effects. First, we built a comprehensive cell atlas of the aged prefrontal cortex from 1.65 million single-nucleus RNA-sequencing profiles sampled from 437 older individuals, and identified specific glial and neuronal subpopulations associated with AD-related traits. Causal modelling then prioritized two distinct lipid-associated microglial subpopulations-one drives amyloid-β proteinopathy while the other mediates the effect of amyloid-β on tau proteinopathy-as well as an astrocyte subpopulation that mediates the effect of tau on cognitive decline. To model the dynamics of cellular environments, we devised the BEYOND methodology, which identified two distinct trajectories of brain ageing, each defined by coordinated progressive changes in certain cellular communities that lead to (1) AD dementia or (2) alternative brain ageing. Thus, we provide a cellular foundation for a new perspective on AD pathophysiology that informs personalized therapeutic development, targeting different cellular communities for individuals on the path to AD or to alternative brain ageing.
The nitrogen isotopic composition of sedimentary rocks (δN) can trace redox-dependent biological pathways and early Earth oxygenation. However, there is no substantial change in the sedimentary δN record across the Great...The nitrogen isotopic composition of sedimentary rocks (δN) can trace redox-dependent biological pathways and early Earth oxygenation. However, there is no substantial change in the sedimentary δN record across the Great Oxidation Event about 2.45 billion years ago (Ga), a prominent redox change. This argues for a temporal decoupling between the emergence of the first oxygen-based oxidative pathways of the nitrogen cycle and the accumulation of atmospheric oxygen after 2.45 Ga (ref. ). The transition between both states shows strongly positive δN values (10-50‰) in rocks deposited between 2.8 Ga and 2.6 Ga, but their origin and spatial extent remain uncertain. Here we report strongly positive δN values (>30‰) in the 2.68-Gyr-old shallow to deep marine sedimentary deposit of the Serra Sul Formation, Amazonian Craton, Brazil. Our findings are best explained by regionally variable extents of ammonium oxidation to N or NO tied to a cryptic oxygen cycle, implying that oxygenic photosynthesis was operating at 2.7 Ga. Molecular oxygen production probably shifted the redox potential so that an intermediate N cycle based on ammonium oxidation developed before nitrate accumulation in surface waters. We propose to name this period, when strongly positive nitrogen isotopic compositions are superimposed on the usual range of Precambrian δN values, the Nitrogen Isotope Event. We suggest that it marks the earliest steps of the biogeochemical reorganizations that led to the Great Oxidation Event.
Conservation, restoration and land management are increasingly implemented at landscape scales. However, because species interaction data are typically habitat- and/or guild-specific, exactly how those interactions conne...Conservation, restoration and land management are increasingly implemented at landscape scales. However, because species interaction data are typically habitat- and/or guild-specific, exactly how those interactions connect habitats and affect the stability and function of communities at landscape scales remains poorly understood. We combine multi-guild species interaction data (plant-pollinator and three plant-herbivore-parasitoid communities, collected from landscapes with one, two or three habitats), a field experiment and a modelling approach to show that multi-habitat landscapes support higher species and interaction evenness, more complementary species interactions and more consistent robustness to species loss. These emergent network properties drive improved pollination success in landscapes with more habitats and are not explained by simply summing component habitat webs. Linking landscape composition, through community structure, to ecosystem function, highlights mechanisms by which several contiguous habitats can support landscape-scale ecosystem services.
Pölönen P, Di Giacomo D, Seffernick AE
… +56 more, Elsayed A, Kimura S, Benini F, Montefiori LE, Wood BL, Xu J, Chen C, Cheng Z, Newman H, Myers J, Iacobucci I, Li E, Sussman J, Hedges D, Hui Y, Diorio C, Uppuluri L, Frank D, Fan Y, Chang Y, Meshinchi S, Ries R, Shraim R, Li A, Bernt KM, Devidas M, Winter SS, Dunsmore KP, Inaba H, Carroll WL, Ramirez NC, Phillips AH, Kriwacki RW, Yang JJ, Vincent TL, Zhao Y, Ghate PS, Wang J, Reilly C, Zhou X, Sanders MA, Takita J, Kato M, Takasugi N, Chang BH, Press RD, Loh M, Rampersaud E, Raetz E, Hunger SP, Tan K, Chang TC, Wu G, Pounds SB, Mullighan CG, Teachey DT
T-lineage acute lymphoblastic leukaemia (T-ALL) is a high-risk tumour that has eluded comprehensive genomic characterization, which is partly due to the high frequency of noncoding genomic alterations that result in onco...T-lineage acute lymphoblastic leukaemia (T-ALL) is a high-risk tumour that has eluded comprehensive genomic characterization, which is partly due to the high frequency of noncoding genomic alterations that result in oncogene deregulation. Here we report an integrated analysis of genome and transcriptome sequencing of tumour and remission samples from more than 1,300 uniformly treated children with T-ALL, coupled with epigenomic and single-cell analyses of malignant and normal T cell precursors. This approach identified 15 subtypes with distinct genomic drivers, gene expression patterns, developmental states and outcomes. Analyses of chromatin topology revealed multiple mechanisms of enhancer deregulation that involve enhancers and genes in a subtype-specific manner, thereby demonstrating widespread involvement of the noncoding genome. We show that the immunophenotypically described, high-risk entity of early T cell precursor ALL is superseded by a broader category of 'early T cell precursor-like' leukaemia. This category has a variable immunophenotype and diverse genomic alterations of a core set of genes that encode regulators of hematopoietic stem cell development. Using multivariable outcome models, we show that genetic subtypes, driver and concomitant genetic alterations independently predict treatment failure and survival. These findings provide a roadmap for the classification, risk stratification and mechanistic understanding of this disease.
Guanidine is a chemically stable nitrogen compound that is excreted in human urine and is widely used in manufacturing of plastics, as a flame retardant and as a component of propellants, and is well known as a protein d...Guanidine is a chemically stable nitrogen compound that is excreted in human urine and is widely used in manufacturing of plastics, as a flame retardant and as a component of propellants, and is well known as a protein denaturant in biochemistry. Guanidine occurs widely in nature and is used by several microorganisms as a nitrogen source, but microorganisms growing on guanidine as the only substrate have not yet been identified. Here we show that the complete ammonia oxidizer (comammox) Nitrospira inopinata and probably most other comammox microorganisms can grow on guanidine as the sole source of energy, reductant and nitrogen. Proteomics, enzyme kinetics and the crystal structure of a N. inopinata guanidinase homologue demonstrated that it is a bona fide guanidinase. Incubation experiments with comammox-containing agricultural soil and wastewater treatment plant microbiomes suggested that guanidine serves as substrate for nitrification in the environment. The identification of guanidine as a growth substrate for comammox shows an unexpected niche of these globally important nitrifiers and offers opportunities for their isolation.
Harnik Y, Yakubovsky O, Hoefflin R
… +19 more, Novoselsky R, Bahar Halpern K, Barkai T, Korem Kohanim Y, Egozi A, Golani O, Addadi Y, Kedmi M, Keidar Haran T, Levin Y, Savidor A, Keren-Shaul H, Mayer C, Pencovich N, Pery R, Shouval DS, Tirosh I, Nachmany I, Itzkovitz S
The mouse small intestine shows profound variability in gene expression along the crypt-villus axis. Whether similar spatial heterogeneity exists in the adult human gut remains unclear. Here we use spatial transcriptomic...The mouse small intestine shows profound variability in gene expression along the crypt-villus axis. Whether similar spatial heterogeneity exists in the adult human gut remains unclear. Here we use spatial transcriptomics, spatial proteomics and single-molecule fluorescence in situ hybridization to reconstruct a comprehensive spatial expression atlas of the adult human proximal small intestine. We describe zonated expression and cell type representation for epithelial, mesenchymal and immune cell types. We find that migrating enterocytes switch from lipid droplet assembly and iron uptake at the villus bottom to chylomicron biosynthesis and iron release at the tip. Villus tip cells are pro-immunogenic, recruiting γδ T cells and macrophages to the tip, in contrast to their immunosuppressive roles in mouse. We also show that the human small intestine contains abundant serrated and branched villi that are enriched at the tops of circular folds. Our study presents a detailed resource for understanding the biology of the adult human small intestine.
Cornish AJ, Gruber AJ, Kinnersley B
… +33 more, Chubb D, Frangou A, Caravagna G, Noyvert B, Lakatos E, Wood HM, Thorn S, Culliford R, Arnedo-Pac C, Househam J, Cross W, Sud A, Law P, Leathlobhair MN, Hawari A, Woolley C, Sherwood K, Feeley N, Gül G, Fernandez-Tajes J, Zapata L, Alexandrov LB, Murugaesu N, Sosinsky A, Mitchell J, Lopez-Bigas N, Quirke P, Church DN, Tomlinson IPM, Sottoriva A, Graham TA, Wedge DC, Houlston RS
Colorectal carcinoma (CRC) is a common cause of mortality, but a comprehensive description of its genomic landscape is lacking. Here we perform whole-genome sequencing of 2,023 CRC samples from participants in the UK 100...Colorectal carcinoma (CRC) is a common cause of mortality, but a comprehensive description of its genomic landscape is lacking. Here we perform whole-genome sequencing of 2,023 CRC samples from participants in the UK 100,000 Genomes Project, thereby providing a highly detailed somatic mutational landscape of this cancer. Integrated analyses identify more than 250 putative CRC driver genes, many not previously implicated in CRC or other cancers, including several recurrent changes outside the coding genome. We extend the molecular pathways involved in CRC development, define four new common subgroups of microsatellite-stable CRC based on genomic features and show that these groups have independent prognostic associations. We also characterize several rare molecular CRC subgroups, some with potential clinical relevance, including cancers with both microsatellite and chromosomal instability. We demonstrate a spectrum of mutational profiles across the colorectum, which reflect aetiological differences. These include the role of Escherichia coli colibactin in rectal cancers and the importance of the SBS93 signature, which suggests that diet or smoking is a risk factor. Immune-escape driver mutations are near-ubiquitous in hypermutant tumours and occur in about half of microsatellite-stable CRCs, often in the form of HLA copy number changes. Many driver mutations are actionable, including those associated with rare subgroups (for example, BRCA1 and IDH1), highlighting the role of whole-genome sequencing in optimizing patient care.
Soula M, Unlu G, Welch R
… +13 more, Chudnovskiy A, Uygur B, Shah V, Alwaseem H, Bunk P, Subramanyam V, Yeh HW, Khan A, Heissel S, Goodarzi H, Victora GD, Beyaz S, Birsoy K
Cancer cells frequently alter their lipids to grow and adapt to their environment. Despite the critical functions of lipid metabolism in membrane physiology, signalling and energy production, how specific lipids contribu...Cancer cells frequently alter their lipids to grow and adapt to their environment. Despite the critical functions of lipid metabolism in membrane physiology, signalling and energy production, how specific lipids contribute to tumorigenesis remains incompletely understood. Here, using functional genomics and lipidomic approaches, we identified de novo sphingolipid synthesis as an essential pathway for cancer immune evasion. Synthesis of sphingolipids is surprisingly dispensable for cancer cell proliferation in culture or in immunodeficient mice but required for tumour growth in multiple syngeneic models. Blocking sphingolipid production in cancer cells enhances the anti-proliferative effects of natural killer and CD8 T cells partly via interferon-γ (IFNγ) signalling. Mechanistically, depletion of glycosphingolipids increases surface levels of IFNγ receptor subunit 1 (IFNGR1), which mediates IFNγ-induced growth arrest and pro-inflammatory signalling. Finally, pharmacological inhibition of glycosphingolipid synthesis synergizes with checkpoint blockade therapy to enhance anti-tumour immune response. Altogether, our work identifies glycosphingolipids as necessary and limiting metabolites for cancer immune evasion.
Biomolecular condensates enable cell compartmentalization by acting as membraneless organelles. How cells control the interactions of condensates with other cellular structures such as membranes to drive morphological tr...Biomolecular condensates enable cell compartmentalization by acting as membraneless organelles. How cells control the interactions of condensates with other cellular structures such as membranes to drive morphological transitions remains poorly understood. We discovered that formation of a tight-junction belt, which is essential for sealing epithelial tissues, is driven by a wetting phenomenon that promotes the growth of a condensed ZO-1 layer around the apical membrane interface. Using temporal proximity proteomics in combination with imaging and thermodynamic theory, we found that the polarity protein PATJ mediates a transition of ZO-1 into a condensed surface layer that elongates around the apical interface. In line with the experimental observations, our theory of condensate growth shows that the speed of elongation depends on the binding affinity of ZO-1 to the apical interface and is constant. Here, using PATJ mutations, we show that ZO-1 interface binding is necessary and sufficient for tight-junction belt formation. Our results demonstrate how cells exploit the collective biophysical properties of protein condensates at membrane interfaces to shape mesoscale structures.
The global retreat of glaciers is dramatically altering mountain and high-latitude landscapes, with new ecosystems developing from apparently barren substrates. The study of these emerging ecosystems is critical to under...The global retreat of glaciers is dramatically altering mountain and high-latitude landscapes, with new ecosystems developing from apparently barren substrates. The study of these emerging ecosystems is critical to understanding how climate change interacts with microhabitat and biotic communities and determines the future of ice-free terrains. Here, using a comprehensive characterization of ecosystems (soil properties, microclimate, productivity and biodiversity by environmental DNA metabarcoding) across 46 proglacial landscapes worldwide, we found that all the environmental properties change with time since glaciers retreated, and that temperature modulates the accumulation of soil nutrients. The richness of bacteria, fungi, plants and animals increases with time since deglaciation, but their temporal patterns differ. Microorganisms colonized most rapidly in the first decades after glacier retreat, whereas most macroorganisms took longer. Increased habitat suitability, growing complexity of biotic interactions and temporal colonization all contribute to the increase in biodiversity over time. These processes also modify community composition for all the groups of organisms. Plant communities show positive links with all other biodiversity components and have a key role in ecosystem development. These unifying patterns provide new insights into the early dynamics of deglaciated terrains and highlight the need for integrated surveillance of their multiple environmental properties.
Genetic variation that influences gene expression and splicing is a key source of phenotypic diversity. Although invaluable, studies investigating these links in humans have been strongly biased towards participants of E...Genetic variation that influences gene expression and splicing is a key source of phenotypic diversity. Although invaluable, studies investigating these links in humans have been strongly biased towards participants of European ancestries, which constrains generalizability and hinders evolutionary research. Here to address these limitations, we developed MAGE, an open-access RNA sequencing dataset of lymphoblastoid cell lines from 731 individuals from the 1000 Genomes Project, spread across 5 continental groups and 26 populations. Most variation in gene expression (92%) and splicing (95%) was distributed within versus between populations, which mirrored the variation in DNA sequence. We mapped associations between genetic variants and expression and splicing of nearby genes (cis-expression quantitative trait loci (eQTLs) and cis-splicing QTLs (sQTLs), respectively). We identified more than 15,000 putatively causal eQTLs and more than 16,000 putatively causal sQTLs that are enriched for relevant epigenomic signatures. These include 1,310 eQTLs and 1,657 sQTLs that are largely private to underrepresented populations. Our data further indicate that the magnitude and direction of causal eQTL effects are highly consistent across populations. Moreover, the apparent 'population-specific' effects observed in previous studies were largely driven by low resolution or additional independent eQTLs of the same genes that were not detected. Together, our study expands our understanding of human gene expression diversity and provides an inclusive resource for studying the evolution and function of human genomes.
Chen W, Choi J, Li X
… +13 more, Nathans JF, Martin B, Yang W, Hamazaki N, Qiu C, Lalanne JB, Regalado S, Kim H, Agarwal V, Nichols E, Leith A, Lee C, Shendure J
Measurements of gene expression or signal transduction activity are conventionally performed using methods that require either the destruction or live imaging of a biological sample within the timeframe of interest. Here...Measurements of gene expression or signal transduction activity are conventionally performed using methods that require either the destruction or live imaging of a biological sample within the timeframe of interest. Here we demonstrate an alternative paradigm in which such biological activities are stably recorded to the genome. Enhancer-driven genomic recording of transcriptional activity in multiplex (ENGRAM) is based on the signal-dependent production of prime editing guide RNAs that mediate the insertion of signal-specific barcodes (symbols) into a genomically encoded recording unit. We show how this strategy can be used for multiplex recording of the cell-type-specific activities of dozens to hundreds of cis-regulatory elements with high fidelity, sensitivity and reproducibility. Leveraging signal transduction pathway-responsive cis-regulatory elements, we also demonstrate time- and concentration-dependent genomic recording of WNT, NF-κB and Tet-On activities. By coupling ENGRAM to sequential genome editing via DNA Typewriter, we stably record information about the temporal dynamics of two orthogonal signalling pathways to genomic DNA. Finally we apply ENGRAM to integratively record the transient activity of nearly 100 transcription factor consensus motifs across daily windows spanning the differentiation of mouse embryonic stem cells into gastruloids, an in vitro model of early mammalian development. Although these are proof-of-concept experiments and much work remains to fully realize the possibilities, the symbolic recording of biological signals or states within cells, to the genome and over time, has broad potential to complement contemporary paradigms for how we make measurements in biological systems.