| 1. |
|
|
| 2. |
- Sungnak, W., et al.
(författare)
-
SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes
- 2020
-
Ingår i: Nature Medicine. - : Nature Research. - 1078-8956 .- 1546-170X. ; 26:5, s. 681-687
-
Tidskriftsartikel (refereegranskat)abstract
- We investigated SARS-CoV-2 potential tropism by surveying expression of viral entry-associated genes in single-cell RNA-sequencing data from multiple tissues from healthy human donors. We co-detected these transcripts in specific respiratory, corneal and intestinal epithelial cells, potentially explaining the high efficiency of SARS-CoV-2 transmission. These genes are co-expressed in nasal epithelial cells with genes involved in innate immunity, highlighting the cells’ potential role in initial viral infection, spread and clearance. The study offers a useful resource for further lines of inquiry with valuable clinical samples from COVID-19 patients and we provide our data in a comprehensive, open and user-friendly fashion at www.covid19cellatlas.org.
|
|
| 3. |
- Callaway, EM, et al.
(författare)
-
A multimodal cell census and atlas of the mammalian primary motor cortex
- 2021
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 598:7879, s. 86-102
-
Tidskriftsartikel (refereegranskat)abstract
- Here we report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties and cellular resolution input–output mapping, integrated through cross-modal computational analysis. Our results advance the collective knowledge and understanding of brain cell-type organization1–5. First, our study reveals a unified molecular genetic landscape of cortical cell types that integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a consensus taxonomy of transcriptomic types and their hierarchical organization that is conserved from mouse to marmoset and human. Third, in situ single-cell transcriptomics provides a spatially resolved cell-type atlas of the motor cortex. Fourth, cross-modal analysis provides compelling evidence for the transcriptomic, epigenomic and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types. We further present an extensive genetic toolset for targeting glutamatergic neuron types towards linking their molecular and developmental identity to their circuit function. Together, our results establish a unifying and mechanistic framework of neuronal cell-type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties.
|
|
| 4. |
|
|
| 5. |
- Bakken, TE, et al.
(författare)
-
Comparative cellular analysis of motor cortex in human, marmoset and mouse
- 2021
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 598:7879, s. 111-
-
Tidskriftsartikel (refereegranskat)abstract
- The primary motor cortex (M1) is essential for voluntary fine-motor control and is functionally conserved across mammals1. Here, using high-throughput transcriptomic and epigenomic profiling of more than 450,000 single nuclei in humans, marmoset monkeys and mice, we demonstrate a broadly conserved cellular makeup of this region, with similarities that mirror evolutionary distance and are consistent between the transcriptome and epigenome. The core conserved molecular identities of neuronal and non-neuronal cell types allow us to generate a cross-species consensus classification of cell types, and to infer conserved properties of cell types across species. Despite the overall conservation, however, many species-dependent specializations are apparent, including differences in cell-type proportions, gene expression, DNA methylation and chromatin state. Few cell-type marker genes are conserved across species, revealing a short list of candidate genes and regulatory mechanisms that are responsible for conserved features of homologous cell types, such as the GABAergic chandelier cells. This consensus transcriptomic classification allows us to use patch–seq (a combination of whole-cell patch-clamp recordings, RNA sequencing and morphological characterization) to identify corticospinal Betz cells from layer 5 in non-human primates and humans, and to characterize their highly specialized physiology and anatomy. These findings highlight the robust molecular underpinnings of cell-type diversity in M1 across mammals, and point to the genes and regulatory pathways responsible for the functional identity of cell types and their species-specific adaptations.
|
|
| 6. |
- Regev, A, et al.
(författare)
-
The Human Cell Atlas
- 2017
-
Ingår i: eLife. - : ELIFE SCIENCES PUBLICATIONS LTD. - 2050-084X. ; 6
-
Tidskriftsartikel (refereegranskat)
|
|
| 7. |
|
|
| 8. |
- Rhind, Nicholas, et al.
(författare)
-
Comparative Functional Genomics of the Fission Yeasts
- 2011
-
Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 332:6032, s. 930-936
-
Tidskriftsartikel (refereegranskat)abstract
- The fission yeast clade-comprising Schizosaccharomyces pombe, S. octosporus, S. cryophilus, and S. japonicus-occupies the basal branch of Ascomycete fungi and is an important model of eukaryote biology. A comparative annotation of these genomes identified a near extinction of transposons and the associated innovation of transposon-free centromeres. Expression analysis established that meiotic genes are subject to antisense transcription during vegetative growth, which suggests a mechanism for their tight regulation. In addition, trans-acting regulators control new genes within the context of expanded functional modules for meiosis and stress response. Differences in gene content and regulation also explain why, unlike the budding yeast of Saccharomycotina, fission yeasts cannot use ethanol as a primary carbon source. These analyses elucidate the genome structure and gene regulation of fission yeast and provide tools for investigation across the Schizosaccharomyces clade.
|
|
| 9. |
|
|
| 10. |
- Ma, Li-Jun, et al.
(författare)
-
Comparative genomics reveals mobile pathogenicity chromosomes in Fusarium.
- 2010
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 464:7287, s. 367-73
-
Tidskriftsartikel (refereegranskat)abstract
- Fusarium species are among the most important phytopathogenic and toxigenic fungi. To understand the molecular underpinnings of pathogenicity in the genus Fusarium, we compared the genomes of three phenotypically diverse species: Fusarium graminearum, Fusarium verticillioides and Fusarium oxysporum f. sp. lycopersici. Our analysis revealed lineage-specific (LS) genomic regions in F. oxysporum that include four entire chromosomes and account for more than one-quarter of the genome. LS regions are rich in transposons and genes with distinct evolutionary profiles but related to pathogenicity, indicative of horizontal acquisition. Experimentally, we demonstrate the transfer of two LS chromosomes between strains of F. oxysporum, converting a non-pathogenic strain into a pathogen. Transfer of LS chromosomes between otherwise genetically isolated strains explains the polyphyletic origin of host specificity and the emergence of new pathogenic lineages in F. oxysporum. These findings put the evolution of fungal pathogenicity into a new perspective.
|
|
| 11. |
|
|
| 12. |
|
|
| 13. |
- Bonfiglio, Ferdinando, et al.
(författare)
-
GWAS of stool frequency provides insights into gastrointestinal motility and irritable bowel syndrome
- 2021
-
Ingår i: Cell Genomics. - Cambridge, MA, United States : Elsevier. - 2666-979X. ; 1:3
-
Tidskriftsartikel (refereegranskat)abstract
- Gut dysmotility is associated with constipation, diarrhea, and functional gastrointestinal disorders like irritable bowel syndrome (IBS), although its molecular underpinnings are poorly characterized. We studied stool frequency (defined by the number of bowel movements per day, based on questionnaire data) as a proxy for gut motility in a GWAS meta-analysis including 167,875 individuals from UK Biobank and four smaller population-based cohorts. We identify 14 loci associated with stool frequency (p ≤ 5.0 × 10-8). Gene set and pathway analyses detected enrichment for genes involved in neurotransmitter/neuropeptide signaling and preferentially expressed in enteric motor neurons controlling peristalsis. PheWAS identified pleiotropic associations with dysmotility syndromes and the response to their pharmacological treatment. The genetic architecture of stool frequency correlates with that of IBS, and UK Biobank participants from the top 1% of stool frequency polygenic score distribution were associated with 5× higher risk of IBS with diarrhea. These findings pave the way for the identification of actionable pathological mechanisms in IBS and the dysmotility syndromes.
|
|
| 14. |
- Haniffa, Muzlifah, et al.
(författare)
-
A roadmap for the Human Developmental Cell Atlas
- 2021
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 597:7875, s. 196-205
-
Tidskriftsartikel (refereegranskat)abstract
- This Perspective outlines the Human Developmental Cell Atlas initiative, which uses state-of-the-art technologies to map and model human development across gestation, and discusses the early milestones that have been achieved. The Human Developmental Cell Atlas (HDCA) initiative, which is part of the Human Cell Atlas, aims to create a comprehensive reference map of cells during development. This will be critical to understanding normal organogenesis, the effect of mutations, environmental factors and infectious agents on human development, congenital and childhood disorders, and the cellular basis of ageing, cancer and regenerative medicine. Here we outline the HDCA initiative and the challenges of mapping and modelling human development using state-of-the-art technologies to create a reference atlas across gestation. Similar to the Human Genome Project, the HDCA will integrate the output from a growing community of scientists who are mapping human development into a unified atlas. We describe the early milestones that have been achieved and the use of human stem-cell-derived cultures, organoids and animal models to inform the HDCA, especially for prenatal tissues that are hard to acquire. Finally, we provide a roadmap towards a complete atlas of human development.
|
|
| 15. |
- Rozenblatt-Rosen, O., et al.
(författare)
-
Building a high-quality Human Cell Atlas
- 2021
-
Ingår i: Nature Biotechnology. - : Nature Research. - 1087-0156 .- 1546-1696. ; 39:2, s. 149-153
-
Tidskriftsartikel (refereegranskat)
|
|
| 16. |
- Vickovic, Sanja, et al.
(författare)
-
SM-Omics is an automated platform for high-throughput spatial multi-omics
- 2022
-
Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 13:1
-
Tidskriftsartikel (refereegranskat)abstract
- The spatial organization of cells and molecules plays a key role in tissue function in homeostasis and disease. Spatial transcriptomics has recently emerged as a key technique to capture and positionally barcode RNAs directly in tissues. Here, we advance the application of spatial transcriptomics at scale, by presenting Spatial Multi-Omics (SM-Omics) as a fully automated, high-throughput all-sequencing based platform for combined and spatially resolved transcriptomics and antibody-based protein measurements. SM-Omics uses DNA-barcoded antibodies, immunofluorescence or a combination thereof, to scale and combine spatial transcriptomics and spatial antibody-based multiplex protein detection. SM-Omics allows processing of up to 64 in situ spatial reactions or up to 96 sequencing-ready libraries, of high complexity, in a similar to 2 days process. We demonstrate SM-Omics in the mouse brain, spleen and colorectal cancer model, showing its broad utility as a high-throughput platform for spatial multi-omics.
|
|
| 17. |
- Wegmann, A., et al.
(författare)
-
Augmenting the Zachman enterprise architecture Framework with a systemic conceptualization
- 2008
-
Ingår i: Proc. - IEEE Int. Enterp. Distrib. Object Comput. Conf., EDOC. - 9780769533735 ; , s. 3-13
-
Konferensbidrag (refereegranskat)abstract
- The Zachman Framework offers a classification of the models created in an enterprise architecture project. These models form a holistic representation of the organization. Despite the prominent position of the Framework, there is little information publicly available to help designers create exact models that fit each other. In this paper, we propose a conceptualization based on General Systems Thinking. Our conceptualization provides concrete guidelines for creating the models required by the Framework. The proposed conceptualization establishes a better understanding of the models and of their relationships. This facilitates the creation and interpretation of the models. It also improves the traceability between them. We illustrate our approach with the results of a case study.
|
|
| 18. |
- Baker, Ethan A. G., et al.
(författare)
-
In silico tissue generation and power analysis for spatial omics
- 2023
-
Ingår i: Nature Methods. - : Springer Nature. - 1548-7091 .- 1548-7105. ; 20:3, s. 424-
-
Tidskriftsartikel (refereegranskat)abstract
- As spatially resolved multiplex profiling of RNA and proteins becomes more prominent, it is increasingly important to understand the statistical power available to test specific hypotheses when designing and interpreting such experiments. Ideally, it would be possible to create an oracle that predicts sampling requirements for generalized spatial experiments. However, the unknown number of relevant spatial features and the complexity of spatial data analysis make this challenging. Here, we enumerate multiple parameters of interest that should be considered in the design of a properly powered spatial omics study. We introduce a method for tunable in silico tissue (IST) generation and use it with spatial profiling data sets to construct an exploratory computational framework for spatial power analysis. Finally, we demonstrate that our framework can be applied across diverse spatial data modalities and tissues of interest. While we demonstrate ISTs in the context of spatial power analysis, these simulated tissues have other potential use cases, including spatial method benchmarking and optimization. This paper presents a statistical framework for power analysis of spatial omics studies, facilitated by an in silico tissue-generation method.
|
|
| 19. |
- Bao, Erik L, et al.
(författare)
-
Inherited myeloproliferative neoplasm risk affects haematopoietic stem cells
- 2020
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 586:7831, s. 769-775
-
Tidskriftsartikel (refereegranskat)abstract
- Myeloproliferative neoplasms (MPNs) are blood cancers that are characterized by the excessive production of mature myeloid cells and arise from the acquisition of somatic driver mutations in haematopoietic stem cells (HSCs). Epidemiological studies indicate a substantial heritable component of MPNs that is among the highest known for cancers1. However, only a limited number of genetic risk loci have been identified, and the underlying biological mechanisms that lead to the acquisition of MPNs remain unclear. Here, by conducting a large-scale genome-wide association study (3,797 cases and 1,152,977 controls), we identify 17 MPN risk loci (P < 5.0 × 10-8), 7 of which have not been previously reported. We find that there is a shared genetic architecture between MPN risk and several haematopoietic traits from distinct lineages; that there is an enrichment for MPN risk variants within accessible chromatin of HSCs; and that increased MPN risk is associated with longer telomere length in leukocytes and other clonal haematopoietic states-collectively suggesting that MPN risk is associated with the function and self-renewal of HSCs. We use gene mapping to identify modulators of HSC biology linked to MPN risk, and show through targeted variant-to-function assays that CHEK2 and GFI1B have roles in altering the function of HSCs to confer disease risk. Overall, our results reveal a previously unappreciated mechanism for inherited MPN risk through the modulation of HSC function.
|
|
| 20. |
- Grabherr, Manfred G, et al.
(författare)
-
Full-length transcriptome assembly from RNA-Seq data without a reference genome
- 2011
-
Ingår i: Nature Biotechnology. - : Springer Science and Business Media LLC. - 1087-0156 .- 1546-1696. ; 29:7, s. 644-652
-
Tidskriftsartikel (refereegranskat)abstract
- Massively parallel sequencing of cDNA has enabled deep and efficient probing of transcriptomes. Current approaches for transcript reconstruction from such data often rely on aligning reads to a reference genome, and are thus unsuitable for samples with a partial or missing reference genome. Here we present the Trinity method for de novo assembly of full-length transcripts and evaluate it on samples from fission yeast, mouse and whitefly, whose reference genome is not yet available. By efficiently constructing and analyzing sets of de Bruijn graphs, Trinity fully reconstructs a large fraction of transcripts, including alternatively spliced isoforms and transcripts from recently duplicated genes. Compared with other de novo transcriptome assemblers, Trinity recovers more full-length transcripts across a broad range of expression levels, with a sensitivity similar to methods that rely on genome alignments. Our approach provides a unified solution for transcriptome reconstruction in any sample, especially in the absence of a reference genome.
|
|
| 21. |
|
|
| 22. |
|
|
| 23. |
- Zattelman, Lilach, et al.
(författare)
-
N-terminal splicing extensions of the human MYO1C gene fine-tune the kinetics of the three full-length myosin IC isoforms
- 2017
-
Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 292:43, s. 17804-17818
-
Tidskriftsartikel (refereegranskat)abstract
- The MYO1C gene produces three alternatively spliced isoforms, differing only in their N-terminal regions (NTRs). These isoforms, which exhibit both specific and overlapping nuclear and cytoplasmic functions, have different expression levels and nuclear–cytoplasmic partitioning. To investigate the effect of NTR extensions on the enzymatic behavior of individual isoforms, we overexpressed and purified the three full-length human isoforms from suspension-adapted HEK cells. MYO1CC favored the actomyosin closed state (AMC), MYO1C16 populated the actomyosin open state (AMO) and AMC equally, and MYO1C35 favored the AMO state. Moreover, the full-length constructs isomerized before ADP release, which has not been observed previously in truncated MYO1CC constructs. Furthermore, global numerical simulation analysis predicted that MYO1C35 populated the actomyosin·ADP closed state (AMDC) 5-fold more than the actomyosin·ADP open state (AMDO) and to a greater degree than MYO1CC and MYO1C16 (4- and 2-fold, respectively). On the basis of a homology model of the 35-amino acid NTR of MYO1C35 (NTR35) docked to the X-ray structure of MYO1CC, we predicted that MYO1C35 NTR residue Arg-21 would engage in a specific interaction with post-relay helix residue Glu-469, which affects the mechanics of the myosin power stroke. In addition, we found that adding the NTR35 peptide to MYO1CC yielded a protein that transiently mimics MYO1C35 kinetic behavior. By contrast, NTR35, which harbors the R21G mutation, was unable to confer MYO1C35-like kinetic behavior. Thus, the NTRs affect the specific nucleotide-binding properties of MYO1C isoforms, adding to their kinetic diversity. We propose that this level of fine-tuning within MYO1C broadens its adaptability within cells.
|
|
