| 1. |
- Ameur, Adam, et al.
(författare)
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SweGen : a whole-genome data resource of genetic variability in a cross-section of the Swedish population
- 2017
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Ingår i: European Journal of Human Genetics. - : NATURE PUBLISHING GROUP. - 1018-4813 .- 1476-5438. ; 25:11, s. 1253-1260
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Tidskriftsartikel (refereegranskat)abstract
- Here we describe the SweGen data set, a comprehensive map of genetic variation in the Swedish population. These data represent a basic resource for clinical genetics laboratories as well as for sequencing-based association studies by providing information on genetic variant frequencies in a cohort that is well matched to national patient cohorts. To select samples for this study, we first examined the genetic structure of the Swedish population using high-density SNP-array data from a nation-wide cohort of over 10 000 Swedish-born individuals included in the Swedish Twin Registry. A total of 1000 individuals, reflecting a cross-section of the population and capturing the main genetic structure, were selected for whole-genome sequencing. Analysis pipelines were developed for automated alignment, variant calling and quality control of the sequencing data. This resulted in a genome-wide collection of aggregated variant frequencies in the Swedish population that we have made available to the scientific community through the website https://swefreq.nbis.se. A total of 29.2 million single-nucleotide variants and 3.8 million indels were detected in the 1000 samples, with 9.9 million of these variants not present in current databases. Each sample contributed with an average of 7199 individual-specific variants. In addition, an average of 8645 larger structural variants (SVs) were detected per individual, and we demonstrate that the population frequencies of these SVs can be used for efficient filtering analyses. Finally, our results show that the genetic diversity within Sweden is substantial compared with the diversity among continental European populations, underscoring the relevance of establishing a local reference data set.
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| 2. |
- Asp, Michaela, et al.
(författare)
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A Spatiotemporal Organ-Wide Gene Expression and Cell Atlas of the Developing Human Heart
- 2019
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Ingår i: Cell. - : CELL PRESS. - 0092-8674 .- 1097-4172. ; 179:7, s. 1647-
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Tidskriftsartikel (refereegranskat)abstract
- The process of cardiac morphogenesis in humans is incompletely understood. Its full characterization requires a deep exploration of the organ-wide orchestration of gene expression with a single-cell spatial resolution. Here, we present a molecular approach that reveals the comprehensive transcriptional landscape of cell types populating the embryonic heart at three developmental stages and that maps cell-type-specific gene expression to specific anatomical domains. Spatial transcriptomics identified unique gene profiles that correspond to distinct anatomical regions in each developmental stage. Human embryonic cardiac cell types identified by single-cell RNA sequencing confirmed and enriched the spatial annotation of embryonic cardiac gene expression. In situ sequencing was then used to refine these results and create a spatial subcellular map for the three developmental phases. Finally, we generated a publicly available web resource of the human developing heart to facilitate future studies on human cardiogenesis.
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| 3. |
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| 4. |
- De Jonghe, Joachim, et al.
(författare)
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A community effort to track commercial single-cell and spatial 'omic technologies and business trends
- 2024
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Ingår i: Nature Biotechnology. - : Springer Nature. - 1087-0156 .- 1546-1696. ; 42:7, s. 1017-1023
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Tidskriftsartikel (refereegranskat)abstract
- There is an ever-growing choice of single-cell and spatial 'omics platforms for industry and academia. The scTrends Consortium provides a brief historical overview of the established platforms and companies, revealing market trends and presenting possible angles for how technologies may differentiate themselves.
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| 5. |
- Firsova, Alexandra, et al.
(författare)
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Topographic atlas of cell states identifies regional gene expression in the adult human lung
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Single cell mRNA sequencing of the whole organ has become a popular technique to reveal rare types and subtypes of previously characterized cells as well as to distinguish and characterize gene expression of previously unknown cell types. Unsupervised clustering can reveal tens or even hundreds of variable genes that characterize cell types. Variation in gene expression is often observed within one cell type, and sometimes cannot be biologically explained without mapping of mRNA on tissue. In this study we aim to (i) map the majority of cell types of human lung, (ii) describe variability in their gene expression and (iii) relate this gene expression to cellular location and neighborhoods. Using three different spatial transcriptomics approaches, we mapped epithelial cell states of airways and submucosal gland, and defined cell type-unrelated gene expression variability along proximo-distal axis, including potential regulators and co-regulators of such cell states in the mesenchymal and immune cell niches. In addition, we mapped rare cell types, such as subtypes of neuroendocrine cells, ionocytes and tuft (brush) cells, revealing tracheal preference for ionocytes, and distal airways for GHRL-positive neuroendocrine cells. Finally, we used the created map as a reference for the diseased tissue from patients with stage II COPD and revealed perturbed cell states and COPD-specific imbalance of cell types, affecting immune and AT0 clusters.
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| 6. |
- Haniffa, Muzlifah, et al.
(författare)
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A roadmap for the Human Developmental Cell Atlas
- 2021
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 597:7875, s. 196-205
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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.
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| 7. |
- Käller, Max, 1976-
(författare)
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Arrayed identification of DNA signatures
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In this thesis techniques are presented that aim to determine individual DNA signatures by controlled synthesis of nucleic acid multimers. Allele-specific extension reactions with an improved specificity were applied for several genomic purposes. Since DNA polymerases extend some mismatched 3’-end primers, an improved specificity is a concern. This has been possible by exploiting the faster extension of matched primers and applying the enzymes apyrase or Proteinase K. The findings were applied to methods for resequencing and viral and single nucleotide polymorphism (SNP) genotyping. P53 mutation is the most frequent event in human cancers. Here, a model system for resequencing of 15 bps in p53 based on apyrase-mediated allele-specific extension (AMASE) is described, investigated and evaluated (Paper I). A microarray format with fluorescence detection was used. On each array, four oligonucleotides were printed for each base to resequence. Target PCR products were hybridized and an AMASE-reaction performed in situ to distinguish which of the printed oligonucleotides matched the target. The results showed that without the inclusion of apyrase, the resulting sequence was unreadable. The results open the possibilities for developing large-scale resequencing tools. The presence of certain types of human papillomaviruses (HPV) transforms normal cells into cervical cancer cells. Thus, HPV type determination is clinically important. Also, multiple HPV infections are common but difficult to distinguish. Therefore, a genotyping platform based on competitive hybridization and AMASE is described, used on clinical sample material and evaluated by comparison to Sanger DNA sequencing (Papers II and III). A flexible tag-microarray was used for detection and the two levels of discrimination gave a high level of specificity. Easy identification of multiple infections was possible which provides new opportunities to investigate the importance of multiply infected samples. To achieve highly multiplexed allele-specific extension reactions, large numbers of primers will be employed and lead to spurious hybridizations. Papers IV to VI focus on an alternative approach to control oligomerization by using protease mediated allele-specific extension (PrASE). In order to maintain stringency at higher temperatures, Proteinase K, was used instead of apyrase, leading to DNA polymerase degradation and preventing unspecific extensions. An automated assay with tag-array detection for SNP genotyping was established. First PrASE was introduced and characterized (Paper IV), then used for genotyping of 10 SNPs in 442 samples (Paper V). A 99.8 % concordance to pyrosequencing was found. PrASE is a flexible tool for association studies and the results indicate an improved assay conversion rate as compared to plain allele-specific extension. The highly polymorphic melanocortin-1 receptor gene (MC1R) is involved in melanogenesis. Twenty-one MC1R variants were genotyped with PrASE since variants in the gene have been associated to an increased risk of developing melanoma. A pilot study was performed to establish the assay (Paper VI) and subsequently a larger study was executed to investigate allele frequencies in the Swedish population (Paper VII). The case and control groups consisted of 1001 and 721 samples respectively. A two to sevenfold increased risk of developing melanoma was observed for carriers of variants.
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| 8. |
- Lázár, Enikő, et al.
(författare)
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Spatial Dynamics of the Developing Human Heart
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Heart development relies on a topologically defined interplay between a diverse array of cardiac cells. We finely curated spatial and single-cell measurements with subcellular imaging-based transcriptomics validation to explore spatial dynamics during early human cardiogenesis. Analyzing almost 80,000 individual cells and 70,000 spatially barcoded tissue regions between the 5.5th and 14th postconceptional weeks, we identified 31 coarse- and 72 fine-grained cell states and mapped them to highly resolved cardiac cellular niches. We provide novel insight into the development of the cardiac pacemaker-conduction system, heart valves, and atrial septum, and decipher heterogeneity of the hitherto elusive cardiac fibroblast population. Furthermore, we describe the formation of cardiac autonomic innervation and present the first spatial account of chromaffin cells in the fetal human heart. In summary, our study delineates the cellular and molecular landscape of the developing heart’s architecture, offering links to genetic causes of heart disease.
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| 9. |
- Li, Xiaofei, et al.
(författare)
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Profiling spatiotemporal gene expression of the developing human spinal cord and implications for ependymoma origin
- 2023
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Ingår i: Nature Neuroscience. - : Springer Nature. - 1097-6256 .- 1546-1726. ; 26:5, s. 891-901
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Tidskriftsartikel (refereegranskat)abstract
- The authors created a comprehensive developmental cell atlas for spatiotemporal gene expression of the human spinal cord, revealed species-specific regulation during development and used the atlas to infer novel markers for pediatric ependymomas. The spatiotemporal regulation of cell fate specification in the human developing spinal cord remains largely unknown. In this study, by performing integrated analysis of single-cell and spatial multi-omics data, we used 16 prenatal human samples to create a comprehensive developmental cell atlas of the spinal cord during post-conceptional weeks 5-12. This revealed how the cell fate commitment of neural progenitor cells and their spatial positioning are spatiotemporally regulated by specific gene sets. We identified unique events in human spinal cord development relative to rodents, including earlier quiescence of active neural stem cells, differential regulation of cell differentiation and distinct spatiotemporal genetic regulation of cell fate choices. In addition, by integrating our atlas with pediatric ependymomas data, we identified specific molecular signatures and lineage-specific genes of cancer stem cells during progression. Thus, we delineate spatiotemporal genetic regulation of human spinal cord development and leverage these data to gain disease insight.
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| 10. |
- Li Zweifel, Ulla, et al.
(författare)
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God havsmiljö 2020 : Marin strategi för Nordsjön och Östersjön Del 2: God miljöstatus och miljökvalitetsnormer
- 2012
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Havsmiljöförordningens övergripande mål är att upprätthålla eller uppnå en god miljöstatus i de svenska förvaltningsområdena Nordsjön och Östersjön till år 2020. En av uppgifterna i den första förvaltningsperioden är att bestämma vad som kännetecknar god miljöstatus i respektive förvaltningsområde samt att ta fram miljökvalitetsnormer. God miljöstatus baseras på ett ramverk av så kallade deskriptorer som anges i havsmiljödirektivet, det vill säga det EU-direktiv som i Sverige genomförs genom havsmiljöförordningen. Deskriptorerna beskriver god miljöstatus på en övergripande nivå för 11 temaområden. Till varje deskriptor hör en rad kriterier som anger vad som ska ingå i en bedömning av miljöstatus. I Sverige har god miljöstatus formulerats för samtliga 29 kriterier som ska beaktas enligt direktivet. Dessa kvalitativa beskrivningar anger vad som kännetecknar god miljöstatus i Nordsjön och Östersjön. För att praktiskt bedöma om god miljöstatus har uppnåtts föreslås 37 nationella indikatorer. En uppsättning av indikatorer omfattar miljöns tillstånd och avspeglar ekosystemets komponenter i form av nyckelarter, samhällen, och livsmiljöer. En utgångspunkt vid val av indikatorer för miljöns tillstånd har varit koppling till de belastningar som i den inledande bedömningen av miljötillståndet i Nordsjön och Östersjön bedömts ha stor negativ påverkan på ekosystemet. En annan uppsättning indikatorer berör påverkan och belastning på miljön i form av tillförsel av näringsämnen och farliga ämnen, samt biologisk och fysisk störning av miljön. Tillsammans utgör indikatorerna ett verktyg för att följa utvecklingen av miljötillståndet och effekter av åtgärder i havsmiljön. Vid val av indikatorer har arbetet delvis utgått från existerande miljöövervakning och redan utvecklade indikatorer. Med denna utgångspunkt uppfylls en rad av havsmiljödirektivets krav, bland annat en god uppföljning av effekter av tillförsel av näringsämnen. Funktionella indikatorer, det vill säga indikatorer som utvärderats och för vilka god miljöstatus har definierats, saknas dock för tio av havsmiljödirektivets 29 kriterier. För uppföljning av biologisk mångfald saknas bland annat miljöövervakning och metoder för att bedöma livsmiljöers tillstånd. För att kunna bedöma fysiska skador på havsbotten saknas en övergripande sammanställning av information om aktiviteter som påverkar havsbottnar samt metodik för att bedöma effekterna. Det saknas också utvecklade indikatorer för det kriterium som berör uppföljning av storleks- och åldersstruktur hos fiskar. Brist på kunskap gör också att inga förslag på svenska indikatorer kan ges för effekter på levande organismer från marint avfall, undervattensbuller, och främmande arter samt att endast ett begränsat antal indikatorer tagits fram som speglar effekter av farliga ämnen. De indikatorer som fastställs i juli 2012 utgör således inte en slutlig lista för att följa upp havsmiljödirektivet. Bristerna kommer att beaktas i det fortsatta genomförandet av havsmiljöförordningen där nästa steg är att anpassa miljöövervakningsprogrammen till uppföljning av miljötillståndet med valda indikatorer senast år 2014 samt att ta fram åtgärdsprogram till år 2015. God miljöstatus ska uppnås genom tillämpning av miljökvalitetsnormer det vill säga rättsligt bindande regler som avspeglar den lägsta godtagbara miljökvaliteten i Nordsjön och Östersjön. För att nå god miljöstatus har elva svenska miljökvalitetsnormer formulerats. Dessa miljökvalitetsnormer omfattar belastning i form av näringsämnen, farliga ämnen, främmande arter, uttag av arter, fysisk påverkan på havsbottnar och avfall i havsmiljön. Målsättningen har varit att utforma miljökvalitetsnormer som motsvarar alla de belastningar som i den inledande bedömningen har identifierats ha en stor påverkan på miljön.
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