Showing papers by "Howard Hughes Medical Institute published in 2014"
TL;DR: Pfam as discussed by the authors is a widely used database of protein families, containing 14 831 manually curated entries in the current version, version 27.0, and has been updated several times since 2012.
Abstract: Pfam, available via servers in the UK (http://pfam.sanger.ac.uk/) and the USA (http://pfam.janelia.org/), is a widely used database of protein families, containing 14 831 manually curated entries in the current release, version 27.0. Since the last update article 2 years ago, we have generated 1182 new families and maintained sequence coverage of the UniProt Knowledgebase (UniProtKB) at nearly 80%, despite a 50% increase in the size of the underlying sequence database. Since our 2012 article describing Pfam, we have also undertaken a comprehensive review of the features that are provided by Pfam over and above the basic family data. For each feature, we determined the relevance, computational burden, usage statistics and the functionality of the feature in a website context. As a consequence of this review, we have removed some features, enhanced others and developed new ones to meet the changing demands of computational biology. Here, we describe the changes to Pfam content. Notably, we now provide family alignments based on four different representative proteome sequence data sets and a new interactive DNA search interface. We also discuss the mapping between Pfam and known 3D structures.
9,415 citations
Howard Hughes Medical Institute1, Johns Hopkins University2, Swim Across America3, Boston University4, University of Turin5, Life Technologies6, Indiana University Health7, Indiana University8, Ludwig Institute for Cancer Research9, University of Pennsylvania10, University of Ulsan11, University of São Paulo12, Amgen13, Karolinska Institutet14, University of Colorado Boulder15, Memorial Sloan Kettering Cancer Center16, Indiana University – Purdue University Indianapolis17
TL;DR: The ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types was evaluated and suggested that ctDNA is a broadly applicable, sensitive, and specific biomarker that can be used for a variety of clinical and research purposes.
Abstract: The development of noninvasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital polymerase chain reaction-based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. We found that ctDNA was detectable in >75% of patients with advanced pancreatic, ovarian, colorectal, bladder, gastroesophageal, breast, melanoma, hepatocellular, and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. In patients with localized tumors, ctDNA was detected in 73, 57, 48, and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. ctDNA was often present in patients without detectable circulating tumor cells, suggesting that these two biomarkers are distinct entities. In a separate panel of 206 patients with metastatic colorectal cancers, we showed that the sensitivity of ctDNA for detection of clinically relevant KRAS gene mutations was 87.2% and its specificity was 99.2%. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor blockade in 24 patients who objectively responded to therapy but subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase pathway. Together, these data suggest that ctDNA is a broadly applicable, sensitive, and specific biomarker that can be used for a variety of clinical and research purposes in patients with multiple different types of cancer.
3,533 citations
TL;DR: The genome sequence of single cells isolated from brain glioblastomas was examined, which revealed shared chromosomal changes but also extensive transcription variation, including genes related to signaling, which represent potential therapeutic targets.
Abstract: Human cancers are complex ecosystems composed of cells with distinct phenotypes, genotypes, and epigenetic states, but current models do not adequately reflect tumor composition in patients. We used single-cell RNA sequencing (RNA-seq) to profile 430 cells from five primary glioblastomas, which we found to be inherently variable in their expression of diverse transcriptional programs related to oncogenic signaling, proliferation, complement/immune response, and hypoxia. We also observed a continuum of stemness-related expression states that enabled us to identify putative regulators of stemness in vivo. Finally, we show that established glioblastoma subtype classifiers are variably expressed across individual cells within a tumor and demonstrate the potential prognostic implications of such intratumoral heterogeneity. Thus, we reveal previously unappreciated heterogeneity in diverse regulatory programs central to glioblastoma biology, prognosis, and therapy.
3,475 citations
TL;DR: It is found that large-scale genomic analysis can identify nearly all known cancer genes in these cancer types and 33 genes that were not previously known to be significantly mutated in cancer, including genes related to proliferation, apoptosis, genome stability, chromatin regulation, immune evasion, RNA processing and protein homeostasis.
Abstract: Although a few cancer genes are mutated in a high proportion of tumours of a given type (.20%), most are mutated at intermediate frequencies (2–20%). To explore the feasibility of creating a comprehensive catalogue of cancer genes, we analysed somatic point mutations in exome sequences from 4,742 human cancers and their matched normal-tissue samples across 21 cancer types. We found that large-scale genomic analysis can identify nearly all known cancer genes in these tumour types. Our analysis also identified 33 genes that were not previously known to be significantly mutated in cancer, including genes related to proliferation, apoptosis, genome stability, chromatin regulation, immune evasion, RNA processing and protein homeostasis. Down-sampling analysis indicates that larger sample sizes will reveal many more genes mutated at clinically important frequencies. We estimate that near-saturation may be achieved with 600– 5,000 samples per tumour type, depending on background mutation frequency. The results may help to guide the next stage of cancer genomics. Comprehensive knowledge of the genes underlying human cancers is a critical foundation for cancer diagnostics, therapeutics, clinical-trial design and selection of rational combination therapies. It is now possible to use genomic analysis to identify cancer genes in an unbiased fashion, based on the presence of somatic mutations at a rate significantly higher than the expected background level. Systematic studies have revealed many new cancer genes, as well as new classes of cancer genes 1,2 . They have also made clear that, although some cancer genes are mutated at high frequencies, most cancer genes in most patients occur at intermediate frequencies (2–20%) or lower. Accordingly, a complete catalogue of mutations in this frequency class will be essential for recognizing dysregulated pathways and optimal targets for therapeutic intervention. However, recent work suggests major gaps in our knowledge of cancer genes of intermediate frequency. For example, a study of 183 lung adenocarcinomas 3 found that 15% of patients lacked even a single mutation affecting any of the 10 known hallmarks of cancer, and 38% had 3 or fewer such mutations. In this paper, we analysed somatic point mutations (substitutions and small insertion and deletions) in nearly 5,000 human cancers and their matched normal-tissue samples (‘tumour–normal pairs’) across 21 tumour types. The questions that we examine here are: first, whether large-scale genomic analysis across tumour types can reliably identify all known cancer genes; second, whether it will reveal many new candidate cancer genes; and third, how far we are from having a complete catalogue of cancer genes (at least those of intermediate frequency). We used rigorous statistical methods to enumerate candidate cancer genes and then carefully inspected each gene to identify those with strong biological connections to cancer and mutational patterns consistent with the expected function. The analysis reveals nearly all known cancer genes and revealed 33 novel candidates, including genes related to proliferation, apoptosis, genome stability, chromatin regulation, immune evasion, RNA processing and protein homeostasis. Importantly, the data show that the
2,565 citations
Broad Institute1, Emory University2, Cincinnati Children's Hospital Medical Center3, University of Colorado Boulder4, Harvard University5, University of Minnesota6, University of Toronto7, Women & Children's Hospital of Buffalo8, Boston Children's Hospital9, Mayo Clinic10, University of California, San Francisco11, Long Island Jewish Medical Center12, Children's Hospital of Philadelphia13, Children's Hospital of Eastern Ontario14, Nationwide Children's Hospital15, Howard Hughes Medical Institute16
TL;DR: Comparing the microbial signatures between the ileum, the rectum, and fecal samples indicates that at this early stage of disease, assessing the rectal mucosal-associated microbiome offers unique potential for convenient and early diagnosis of CD.
2,410 citations
TL;DR: Compared microbiotas across >1,000 fecal samples obtained from the TwinsUK population, many microbial taxa whose abundances were influenced by host genetics were identified.
2,310 citations
TL;DR: It is estimated that LGD mutation in about 400 genes can contribute to the joint class of affected females and males of lower IQ, with an overlapping and similar number of genes vulnerable to contributory missense mutation.
Abstract: Whole exome sequencing has proven to be a powerful tool for understanding the genetic architecture of human disease. Here we apply it to more than 2,500 simplex families, each having a child with an autistic spectrum disorder. By comparing affected to unaffected siblings, we show that 13% of de novo missense mutations and 43% of de novo likely gene-disrupting (LGD) mutations contribute to 12% and 9% of diagnoses, respectively. Including copy number variants, coding de novo mutations contribute to about 30% of all simplex and 45% of female diagnoses. Almost all LGD mutations occur opposite wild-type alleles. LGD targets in affected females significantly overlap the targets in males of lower intelligence quotient (IQ), but neither overlaps significantly with targets in males of higher IQ. We estimate that LGD mutation in about 400 genes can contribute to the joint class of affected females and males of lower IQ, with an overlapping and similar number of genes vulnerable to contributory missense mutation. LGD targets in the joint class overlap with published targets for intellectual disability and schizophrenia, and are enriched for chromatin modifiers, FMRP-associated genes and embryonically expressed genes. Most of the significance for the latter comes from affected females.
2,124 citations
TL;DR: Using mouse models with tagged mammary tumors, it is demonstrated that CTC clusters arise from oligoclonal tumor cell groupings and not from intravascular aggregation events, and though rare in the circulation, they greatly contribute to the metastatic spread of cancer.
1,884 citations
TL;DR: The pathway of ncRNA research is described, where every established "rule" seems destined to be overturned.
1,875 citations
TL;DR: It is demonstrated that ferroptosis is a pervasive and dynamic form of cell death, which, when impeded, promises substantial cytoprotection.
Abstract: Ferroptosis is a non-apoptotic form of cell death induced by small molecules in specific tumour types, and in engineered cells overexpressing oncogenic RAS. Yet, its relevance in non-transformed cells and tissues is unexplored and remains enigmatic. Here, we provide direct genetic evidence that the knockout of glutathione peroxidase 4 (Gpx4) causes cell death in a pathologically relevant form of ferroptosis. Using inducible Gpx4(-/-) mice, we elucidate an essential role for the glutathione/Gpx4 axis in preventing lipid-oxidation-induced acute renal failure and associated death. We furthermore systematically evaluated a library of small molecules for possible ferroptosis inhibitors, leading to the discovery of a potent spiroquinoxalinamine derivative called Liproxstatin-1, which is able to suppress ferroptosis in cells, in Gpx4(-/-) mice, and in a pre-clinical model of ischaemia/reperfusion-induced hepatic damage. In sum, we demonstrate that ferroptosis is a pervasive and dynamic form of cell death, which, when impeded, promises substantial cytoprotection.
1,875 citations
TL;DR: Two channelrhodopsins, Chronos and Chrimson, are described, discovered through sequencing and physiological characterization of opsins from over 100 species of alga, that enable two-color activation of neural spiking and downstream synaptic transmission in independent neural populations without detectable cross-talk in mouse brain slice.
Abstract: Optogenetic tools enable examination of how specific cell types contribute to brain circuit functions. A long-standing question is whether it is possible to independently activate two distinct neural populations in mammalian brain tissue. Such a capability would enable the study of how different synapses or pathways interact to encode information in the brain. Here we describe two channelrhodopsins, Chronos and Chrimson, discovered through sequencing and physiological characterization of opsins from over 100 species of alga. Chrimson's excitation spectrum is red shifted by 45 nm relative to previous channelrhodopsins and can enable experiments in which red light is preferred. We show minimal visual system-mediated behavioral interference when using Chrimson in neurobehavioral studies in Drosophila melanogaster. Chronos has faster kinetics than previous channelrhodopsins yet is effectively more light sensitive. Together these two reagents enable two-color activation of neural spiking and downstream synaptic transmission in independent neural populations without detectable cross-talk in mouse brain slice.
Max Planck Society1, University of California, Berkeley2, Broad Institute3, Harvard University4, University of Washington5, National Institutes of Health6, University of California, Santa Cruz7, Ludwig Maximilian University of Munich8, Emory University9, Fondation Jean Dausset Centre d'Etude du Polymorphisme Humain10, Allen Institute for Brain Science11, Russian Academy of Sciences12, Howard Hughes Medical Institute13
TL;DR: It is shown that interbreeding, albeit of low magnitude, occurred among many hominin groups in the Late Pleistocene and a definitive list of substitutions that became fixed in modern humans after their separation from the ancestors of Neanderthals and Denisovans is established.
Abstract: We present a high-quality genome sequence of a Neanderthal woman from Siberia. We show that her parents were related at the level of half-siblings and that mating among close relatives was common among her recent ancestors. We also sequenced the genome of a Neanderthal from the Caucasus to low coverage. An analysis of the relationships and population history of available archaic genomes and 25 present-day human genomes shows that several gene flow events occurred among Neanderthals, Denisovans and early modern humans, possibly including gene flow into Denisovans from an unknown archaic group. Thus, interbreeding, albeit of low magnitude, occurred among many hominin groups in the Late Pleistocene. In addition, the high-quality Neanderthal genome allows us to establish a definitive list of substitutions that became fixed in modern humans after their separation from the ancestors of Neanderthals and Denisovans.
TL;DR: It is shown that both binding and cleavage of DNA by Cas9–RNA require recognition of a short trinucleotide protospacer adjacent motif (PAM) and that PAM interactions trigger Cas9 catalytic activity.
Abstract: The clustered regularly interspaced short palindromic repeats (CRISPR)-associated enzyme Cas9 is an RNA-guided endonuclease that uses RNA-DNA base-pairing to target foreign DNA in bacteria. Cas9-guide RNA complexes are also effective genome engineering agents in animals and plants. Here we use single-molecule and bulk biochemical experiments to determine how Cas9-RNA interrogates DNA to find specific cleavage sites. We show that both binding and cleavage of DNA by Cas9-RNA require recognition of a short trinucleotide protospacer adjacent motif (PAM). Non-target DNA binding affinity scales with PAM density, and sequences fully complementary to the guide RNA but lacking a nearby PAM are ignored by Cas9-RNA. Competition assays provide evidence that DNA strand separation and RNA-DNA heteroduplex formation initiate at the PAM and proceed directionally towards the distal end of the target sequence. Furthermore, PAM interactions trigger Cas9 catalytic activity. These results reveal how Cas9 uses PAM recognition to quickly identify potential target sites while scanning large DNA molecules, and to regulate scission of double-stranded DNA.
Howard Hughes Medical Institute1, Florida State University2, University of the Sciences3, National Institutes of Health4, University of Minnesota5, University of Cambridge6, University of California, San Francisco7, University of Tennessee8, Max Planck Society9, Johns Hopkins University10, Duke University11
TL;DR: A new microscope using ultrathin light sheets derived from two-dimensional optical lattices is developed, demonstrating the performance advantages of lattice light-sheet microscopy compared with previous techniques and highlighted phenomena that, when seen at increased spatiotemporal detail, may hint at previously unknown biological mechanisms.
Abstract: Although fluorescence microscopy provides a crucial window into the physiology of living specimens, many biological processes are too fragile, are too small, or occur too rapidly to see clearly with existing tools. We crafted ultrathin light sheets from two-dimensional optical lattices that allowed us to image three-dimensional (3D) dynamics for hundreds of volumes, often at subsecond intervals, at the diffraction limit and beyond. We applied this to systems spanning four orders of magnitude in space and time, including the diffusion of single transcription factor molecules in stem cell spheroids, the dynamic instability of mitotic microtubules, the immunological synapse, neutrophil motility in a 3D matrix, and embryogenesis in Caenorhabditis elegans and Drosophila melanogaster. The results provide a visceral reminder of the beauty and the complexity of living systems.
TL;DR: The different roles of iron in triggering cell death, targets of iron-dependent ROS that mediate cell death and a new form ofIron-dependent cell death termed ferroptosis are described to suggest new therapeutic avenues to treat cancer, organ damage and degenerative disease.
Abstract: The transition metal iron is essential for life, yet potentially toxic iron-catalyzed reactive oxygen species (ROS) are unavoidable in an oxygen-rich environment. Iron and ROS are increasingly recognized as important initiators and mediators of cell death in a variety of organisms and pathological situations. Here, we review recent discoveries regarding the mechanism by which iron and ROS participate in cell death. We describe the different roles of iron in triggering cell death, targets of iron-dependent ROS that mediate cell death and a new form of iron-dependent cell death termed ferroptosis. Recent advances in understanding the role of iron and ROS in cell death offer unexpected surprises and suggest new therapeutic avenues to treat cancer, organ damage and degenerative disease.
TL;DR: This work presents a census of 1,542 manually curated RBPs that are analysed for their interactions with different classes of RNA, their evolutionary conservation, their abundance and their tissue-specific expression, a critical step towards the comprehensive characterization of proteins involved in human RNA metabolism.
Abstract: Post-transcriptional gene regulation (PTGR) concerns processes involved in the maturation, transport, stability and translation of coding and non-coding RNAs. RNA-binding proteins (RBPs) and ribonucleoproteins coordinate RNA processing and PTGR. The introduction of large-scale quantitative methods, such as next-generation sequencing and modern protein mass spectrometry, has renewed interest in the investigation of PTGR and the protein factors involved at a systems-biology level. Here, we present a census of 1,542 manually curated RBPs that we have analysed for their interactions with different classes of RNA, their evolutionary conservation, their abundance and their tissue-specific expression. Our analysis is a critical step towards the comprehensive characterization of proteins involved in human RNA metabolism.
Kansas State University1, University of Bristol2, United States Department of Agriculture3, University of Bologna4, Consiglio per la ricerca e la sperimentazione in agricoltura5, Norwegian University of Life Sciences6, University of Adelaide7, Murdoch University8, University of Haifa9, Bayer10, Blaise Pascal University11, University of Udine12, University of Saskatchewan13, University of California, Berkeley14, Howard Hughes Medical Institute15, Illumina16
TL;DR: The developed array and cluster identification algorithms provide an opportunity to infer detailed haplotype structure in polyploid wheat and will serve as an invaluable resource for diversity studies and investigating the genetic basis of trait variation in wheat.
Abstract: High-density single nucleotide polymorphism (SNP) genotyping arrays are a powerful tool for studying genomic patterns of diversity, inferring ancestral relationships between individuals in populations and studying marker-trait associations in mapping experiments. We developed a genotyping array including about 90,000 gene-associated SNPs and used it to characterize genetic variation in allohexaploid and allotetraploid wheat populations. The array includes a significant fraction of common genome-wide distributed SNPs that are represented in populations of diverse geographical origin. We used density-based spatial clustering algorithms to enable high-throughput genotype calling in complex data sets obtained for polyploid wheat. We show that these model-free clustering algorithms provide accurate genotype calling in the presence of multiple clusters including clusters with low signal intensity resulting from significant sequence divergence at the target SNP site or gene deletions. Assays that detect low-intensity clusters can provide insight into the distribution of presence-absence variation (PAV) in wheat populations. A total of 46 977 SNPs from the wheat 90K array were genetically mapped using a combination of eight mapping populations. The developed array and cluster identification algorithms provide an opportunity to infer detailed haplotype structure in polyploid wheat and will serve as an invaluable resource for diversity studies and investigating the genetic basis of trait variation in wheat.
TL;DR: A computational pipeline to identifycircRNAs and quantify their relative abundance from RNA-seq data is developed, providing a new framework for future investigation of this intriguing topological isoform while raising doubts regarding a biological function of most circRNAs.
Abstract: Background: The recent reports of two circular RNAs (circRNAs) with strong potential to act as microRNA (miRNA) sponges suggest that circRNAs might play important roles in regulating gene expression. However, the global properties of circRNAs are not well understood. Results: We developed a computational pipeline to identify circRNAs and quantify their relative abundance from RNA-seq data. Applying this pipeline to a large set of non-poly(A)-selected RNA-seq data from the ENCODE project, we annotated 7,112 human circRNAs that were estimated to comprise at least 10% of the transcripts accumulating from their loci. Most circRNAs are expressed in only a few cell types and at low abundance, but they are no more cell-type-specific than are mRNAs with similar overall expression levels. Although most circRNAs overlap protein-coding sequences, ribosome profiling provides no evidence for their translation. We also annotated 635 mouse circRNAs, and although 20% of them are orthologous to human circRNAs, the sequence conservation of these circRNA orthologs is no higher than that of their neighboring linear exons. The previously proposed miR-7 sponge, CDR1as, is one of only two circRNAs with more miRNA sites than expected by chance, with the next best miRNA-sponge candidate deriving from a gene encoding a primate-specific zinc-finger protein, ZNF91. Conclusions: Our results provide a new framework for future investigation of this intriguing topological isoform while raising doubts regarding a biological function of most circRNAs.
TL;DR: Developing efficient algorithms for approximate inference of the model underlying the STRUCTURE program using a variational Bayesian framework and proposing useful heuristic scores to identify the number of populations represented in a data set and a new hierarchical prior to detect weak population structure in the data.
Abstract: Tools for estimating population structure from genetic data are now used in a wide variety of applications in population genetics. However, inferring population structure in large modern data sets imposes severe computational challenges. Here, we develop efficient algorithms for approximate inference of the model underlying the STRUCTURE program using a variational Bayesian framework. Variational methods pose the problem of computing relevant posterior distributions as an optimization problem, allowing us to build on recent advances in optimization theory to develop fast inference tools. In addition, we propose useful heuristic scores to identify the number of populations represented in a data set and a new hierarchical prior to detect weak population structure in the data. We test the variational algorithms on simulated data and illustrate using genotype data from the CEPH-Human Genome Diversity Panel. The variational algorithms are almost two orders of magnitude faster than STRUCTURE and achieve accuracies comparable to those of ADMIXTURE. Furthermore, our results show that the heuristic scores for choosing model complexity provide a reasonable range of values for the number of populations represented in the data, with minimal bias toward detecting structure when it is very weak. Our algorithm, fastSTRUCTURE, is freely available online at http://pritchardlab.stanford.edu/structure.html.
01 Feb 2014
TL;DR: Chronos and Chrimson as mentioned in this paper have been shown to enable two-color activation of neural spiking and downstream synaptic transmission in independent neural populations without detectable cross-talk in mouse brain slice.
Abstract: Optogenetic tools enable examination of how specific cell types contribute to brain circuit functions. A long-standing question is whether it is possible to independently activate two distinct neural populations in mammalian brain tissue. Such a capability would enable the study of how different synapses or pathways interact to encode information in the brain. Here we describe two channelrhodopsins, Chronos and Chrimson, discovered through sequencing and physiological characterization of opsins from over 100 species of alga. Chrimson's excitation spectrum is red shifted by 45 nm relative to previous channelrhodopsins and can enable experiments in which red light is preferred. We show minimal visual system-mediated behavioral interference when using Chrimson in neurobehavioral studies in Drosophila melanogaster. Chronos has faster kinetics than previous channelrhodopsins yet is effectively more light sensitive. Together these two reagents enable two-color activation of neural spiking and downstream synaptic transmission in independent neural populations without detectable cross-talk in mouse brain slice.
TL;DR: It is shown that lenalidomide-bound cereblon acquires the ability to target for proteasomal degradation two specific B cell transcription factors, Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3).
Abstract: Thalidomide-like drugs such as lenalidomide are clinically important treatments for multiple myeloma and show promise for other B cell malignancies. The biochemical mechanisms underlying their antitumor activity are unknown. Thalidomide was recently shown to bind to, and inhibit, the cereblon ubiquitin ligase. Cereblon loss in zebrafish causes fin defects reminiscent of the limb defects seen in children exposed to thalidomide in utero. Here we show that lenalidomide-bound cereblon acquires the ability to target for proteasomal degradation two specific B cell transcription factors, Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3). Analysis of myeloma cell lines revealed that loss of IKZF1 and IKZF3 is both necessary and sufficient for lenalidomide’s therapeutic effect, suggesting that the antitumor and teratogenic activities of thalidomide-like drugs are dissociable.
TL;DR: Using a 3D organoid system, this paper reported success in long-term culture of prostate cancer from biopsy specimens and circulating tumor cells, including TMPRSS2-ERG fusion, SPOP mutation, SPINK1 overexpression, and CHD1 loss.
Broad Institute1, Harvard University2, University of Tübingen3, Max Planck Society4, University of Mainz5, University of Washington6, University of California, Berkeley7, Massachusetts Institute of Technology8, Stockholm University9, University of Adelaide10, The Heritage Foundation11, National Museum of Natural History12, University of Edinburgh13, Sultan Qaboos University14, University of Costa Rica15, University of Antioquia16, Rambam Health Care Campus17, University of Pécs18, Al Akhawayn University19, Catholic University of the Sacred Heart20, University of Oxford21, Belgorod State University22, University of Toronto23, University of Buenos Aires24, University of Bern25, Russian Academy of Sciences26, Paul Sabatier University27, North-Eastern Federal University28, University of Chicago29, University of Arizona30, Stony Brook University31, University of Bergen32, Illumina33, Sofia Medical University34, Bashkir State University35, University of Cambridge36, Vilnius University37, Estonian Biocentre38, University of Strasbourg39, University College London40, Amgen41, Gladstone Institutes42, University of Tartu43, University of Oulu44, Muhimbili University of Health and Allied Sciences45, University of Palermo46, University of Chile47, University of Tarapacá48, Academy of Sciences of Uzbekistan49, Armenian National Academy of Sciences50, University of North Texas51, University of Santiago de Compostela52, University of Kharkiv53, Higher University of San Andrés54, Novosibirsk State University55, Leidos56, Lebanese American University57, University of Split58, University of Pennsylvania59, Banaras Hindu University60, Centre for Cellular and Molecular Biology61, Estonian Academy of Sciences62, Pompeu Fabra University63, Howard Hughes Medical Institute64
TL;DR: It is shown that most present-day Europeans derive from at least three highly differentiated populations: west European hunter-gatherers, who contributed ancestry to all Europeans but not to Near Easterners; ancient north Eurasians related to Upper Palaeolithic Siberians; and early European farmers, who were mainly of Near Eastern origin but also harboured west Europeanhunter-gatherer related ancestry.
Abstract: We sequenced the genomes of a ∼7,000-year-old farmer from Germany and eight ∼8,000-year-old hunter-gatherers from Luxembourg and Sweden. We analysed these and other ancient genomes with 2,345 contemporary humans to show that most present-day Europeans derive from at least three highly differentiated populations: west European hunter-gatherers, who contributed ancestry to all Europeans but not to Near Easterners; ancient north Eurasians related to Upper Palaeolithic Siberians, who contributed to both Europeans and Near Easterners; and early European farmers, who were mainly of Near Eastern origin but also harboured west European hunter-gatherer related ancestry. We model these populations' deep relationships and show that early European farmers had ∼44% ancestry from a 'basal Eurasian' population that split before the diversification of other non-African lineages.
TL;DR: Fiber photometry was developed and applied to optically record natural neural activity in genetically and connectivity-defined projections to elucidate the real-time role of specified pathways in mammalian behavior and captures a fundamental and previously inaccessible dimension of mammalian circuit dynamics.
TL;DR: F Fate-mapping showed that LepR(+) cells arose postnatally and gave rise to most bone and adipocytes formed in adult bone marrow, including bone regenerated after irradiation or fracture.
TL;DR: The breadth of circular RNAs, their biogenesis and metabolism, and their known and anticipated functions are reviewed.
Abstract: It is now clear that there is a diversity of circular RNAs in biological systems. Circular RNAs can be produced by the direct ligation of 5′ and 3′ ends of linear RNAs, as intermediates in RNA processing reactions, or by “backsplicing,” wherein a downstream 5′ splice site (splice donor) is joined to an upstream 3′ splice site (splice acceptor). Circular RNAs have unique properties including the potential for rolling circle amplification of RNA, the ability to rearrange the order of genomic information, protection from exonucleases, and constraints on RNA folding. Circular RNAs can function as templates for viroid and viral replication, as intermediates in RNA processing reactions, as regulators of transcription in cis, as snoRNAs, and as miRNA sponges. Herein, we review the breadth of circular RNAs, their biogenesis and metabolism, and their known and anticipated functions.
TL;DR: It is demonstrated that distinct soil types harbour distinct resistomes, and that the addition of nitrogen fertilizer strongly influenced soil ARG content, challenging previous hypotheses that horizontal gene transfer effectively decouples resistomes from phylogeny.
Abstract: Ancient and diverse antibiotic resistance genes (ARGs) have previously been identified from soil, including genes identical to those in human pathogens. Despite the apparent overlap between soil and clinical resistomes, factors influencing ARG composition in soil and their movement between genomes and habitats remain largely unknown. General metagenome functions often correlate with the underlying structure of bacterial communities. However, ARGs are proposed to be highly mobile, prompting speculation that resistomes may not correlate with phylogenetic signatures or ecological divisions. To investigate these relationships, we performed functional metagenomic selections for resistance to 18 antibiotics from 18 agricultural and grassland soils. The 2,895 ARGs we discovered were mostly new, and represent all major resistance mechanisms. We demonstrate that distinct soil types harbour distinct resistomes, and that the addition of nitrogen fertilizer strongly influenced soil ARG content. Resistome composition also correlated with microbial phylogenetic and taxonomic structure, both across and within soil types. Consistent with this strong correlation, mobility elements (genes responsible for horizontal gene transfer between bacteria such as transposases and integrases) syntenic with ARGs were rare in soil by comparison with sequenced pathogens, suggesting that ARGs may not transfer between soil bacteria as readily as is observed between human pathogens. Together, our results indicate that bacterial community composition is the primary determinant of soil ARG content, challenging previous hypotheses that horizontal gene transfer effectively decouples resistomes from phylogeny.
TL;DR: A dense network of proteins interacting with METTL3, a component of the methyltransferase complex, is identified, and it is shown that three of them (WTAP, METTL14, and KIAA1429) are required for methylation.
TL;DR: It is concluded that stem cells possess mechanical memory - with YAP/TAZ acting as an intracellular mechanical rheostat - that stores information from past physical environments and influences the cells’ fate.
Abstract: Mechanical cues from the local cellular microenvironment can direct cell fate. Now, experiments with human mesenchymal stem cells cultured on phototunable soft poly(ethylene glycol) hydrogels show that the cells remember past physical environments—with the transcriptional co-activators YAP and TAZ acting as a mechanical rheostat—and therefore that appropriate doses of mechanical cues can be used to manipulate the cells’ fate.
TL;DR: In this paper, the authors used flow-cytometry-based bacterial cell sorting and 16S sequencing to characterize taxa-specific coating of the intestinal microbiota with immunoglobulin A (IgA-SEQ) and show that high IgA coating uniquely identifies colitogenic intestinal bacteria in a mouse model of microbiota-driven colitis.