22951 results for "ega"

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• Diagnosis of multisystem inflammatory syndrome in children by a whole-blood transcriptional signature

  To identify a diagnostic blood transcriptomic signature that distinguishes multisystem inflammatory syndrome in children (MIS-C) from Kawasaki Disease (KD), bacterial infections and viral infections. Children presenting with MIS-C to participating hospitals in the United Kingdom and the European Union between April 2020-April 2021 were prospectively recruited. Whole blood RNA Sequencing was performed, contrasting the transcriptomes of children with MIS-C to those from children with KD, definite bacterial and viral infections. Data deposited here comprises samples from patients recruited into the DIAMONDS study.

  Study EGAS00001007409

• Whole Genome sequencing of Angolan and Mozambican individuals

  To support the continued discovery and cataloguing of genomic variation in human populations and to further our understanding of the Bantu Expansion, we sequenced the genomes of 291 individuals from Cabinda, a northern exclave of Angola, and 49 individuals from Maputo, the capital of Mozambique. Utilising the power and flexibility of these whole-genome sequencing datasets, we discover rare variation, fine-scale population structure, and perform analyses using haplotype-based inference tools and our own model-based simulation framework to reconstruct complex dispersals of Bantu speak-ing populations across sub-Saharan Africa.

  Study EGAS00001007458

• AfricanNeo aDNA Study

  With the largest genomic dataset to date of Bantu-speaking populations, including newly generated data of modern-day and ancient DNA from previously unsampled regions in Africa, we shed fresh light on the expansion of peoples speaking Bantu languages that started ~4000 years ago in western Africa. We have generated whole-genome sequences from 12 Late Iron Age individuals. Our comprehensive genetic analysis of the expansion of people speaking Bantu languages reveals a complex history of serial founder events, variable levels of contact with local groups, and spread-over-spread events.

  Study EGAS00001007519

• Korea4K: whole genome sequences of 4,157 Koreans with 107 phenotypes derived from extensive health check-ups

  Here, we present 4,157 whole-genome sequences (Korea4K) coupled with 107 health check-up parameters as the largest genomic resource of the Korean Genome Project. Collectively, Korea4K provides not only the largest Korean genome data but also corresponding health check-up parameters and novel genome-phenome associations. The large-scale pathological whole-genome-wide omics data will become a powerful set for genome-phenome level association studies to discover causal markers for the prediction and diagnosis of health conditions in future studies.

  Study EGAS00001007580

• NEOPREDICT-Lung: longitudinal whole exome sequencing of non-small cell lung cancers under immunotherapy

  In 43 patients pretreatment tumor biopsies, resected tumors and normal tissue of sufficient quality and quantity were obtained to longitudinally explore the mutational profiles of a comprehensive set of cancer-related genes. For tumor samples, one to four FFPE sections (10 µm thickness, number depending on sample size) were lysed for genomic DNA isolation. Isolation was performed semi-automatically on the Maxwell purification system (Maxwell RSC DNA FFPE Kit, AS1450, Promega) as specified by the manufacturer. DNA was eluted in 50 µl RNase-free water and quantified fluorescently for library preparation using a Qubit 2.0 fluorometer (Life Technology) with its appertaining DNA broad-range assay. Corresponding normal DNA was isolated from blood or PBMCs using routinely available QIAGEN technology. DNA was stored at -20°C before use. Whole-exome sequencing (WES) was performed using the Twist Human Core + RefSeq + Mitochondrial Panel (Twist Bioscience), and 2 x 100 bp fragment sizes were sequenced using a NovaSeq6000 (Illumina). Demultiplexing of sequenced reads was achieved using bcl2fastq (version 2.2).

  Dataset EGAD00001015362

• Selection of somatic escape variants in SERPINA1 in liver tissue of patients with alpha-1 anti-trypsin deficiency - WGS

  Somatic variants accumulate in non-malignant tissues with age. Functional variants leading to clonal advantage of hepatocytes accumulate in the liver from patients with acquired chronic liver disease (CLD). Whether somatic variants are common to CLD from differing aetiologies is unknown. We analysed liver somatic variants in patients with genetic CLD from alpha-1 anti-trypsin (A1AT) deficiency or haemochromatosis. We show that somatic variants in SERPINA1, the gene encoding A1AT, are strongly selected for in A1AT deficiency, with evidence of convergent evolution. Acquired SERPINA1 variants are clustered leading to truncation or coding change at the C-terminus of A1AT. In vitro and in vivo, C-terminal truncation variants reduce disease-associated Z-A1AT polymer accumulation and disruption of the endoplasmic reticulum, supporting the C-terminal domain swap mechanism. Therefore, somatic escape variants from a deleterious germline variant are selected for in A1AT deficiency, suggesting functional somatic variants are disease-specific in CLD and point to disease-associated mechanisms.

  Dataset EGAD00001015430

• Somatic mutation in edited cholangiocyte organoids

  Primary human cells cultured in organoid format have great promise as potential regenerative cellular therapies. However, their immunogenicity and mutagenic profile remain unresolved, impeding effective long-term translation to the clinic. In this study we report, for the first time, the generation of human leukocyte antigen (HLA)-I and HLA-II knock-out human expandable primary cholangiocyte organoids (PCOs) using CRISPR-Cas9 as a potential ‘universal’ low-immunogenic therapy for bile duct disorders. HLA-edited PCOs (ePCOs) displayed the same phenotypic and functional characteristics as parental unedited PCOs. Despite minimal off-target edits, duplex sequencing approaches demonstrated that ePCOs and PCOs acquire mutations in culture at similar rates, but without evident selection for cancer-driver mutations. ePCOs induced reduced T cell-mediated immunity and donor-dependent NK cell cytotoxicity in vitro and evaded cytotoxic responses with increased graft survival in humanized mice in vivo. Our findings have important implications for assessment of safety and immunogenicity of primary cell-derived organoid cellular therapies.

  Dataset EGAD00001015455

• WGS dataset of Characterization of UV DNA damage in B-cell precursor acute lymphoblastic leukemia

  We characterized B-cell precursor acute lymphoblastic leukemia (BCP-ALL) patients that present with the mutational signature SBS7a. We found clear subtype specificity, but presence of SBS7a did not seem linked to heterogeneity within subtypes. To further distinguish the incidence of SBS7a in pediatric cancer we analyzed a pan-cancer WGS cohort and identified frequent SBS7a in anaplastic large cell lymphomas. As SBS7a is commonly found in skin cancers and has been linked to UV-light induced DNA damage, we compared the features of UV-light induced DNA damage in skin cancer and SBS7a in ALL, and found high similarity. We found no defects in UV damage response pathways in SBS7a-positive samples, indicating no additional UV vulnerability. Additionally, transcriptomic data showed no differences between samples with and without SBS7a. Finally we looked into the moment of exposure to the source of SBS7a by deep sequencing of diagnosis-relapse pairs and single cell whole genome sequencing of diagnosis samples with high SBS7a.

  Dataset EGAD00001015600

• Genomic Advances in Sepsis (GAinS) genotyping

  This cohort comprises a subset of patients enrolled in the Genomic Advances in Sepsis (GAinS) study, an established biobank of adult sepsis patients. Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Patients with sepsis due to community acquired pneumonia or faecal peritonitis were recruited from 35 hospitals across the UK from 2005-2018, with samples for functional genomics and detailed clinical information collected over the first five days of ICU admission to investigate how host genetics affects the individual repsonse to sepsis. DNA was extracted from buffy coat or whole blood samples using the Qiagen DNA extraction protocol, the automated Maxwell Blood purification kit (Promega), or the QIAamp Blood Midi kit protocol (Qiagen). Genotyping data were generated using the Illumina HumanOmniExpress BeadChip (295 patients), the Infinium CoreExome BeadChip (655 patients), and the Infinium Global Screening Array BeadChip (307 patients). Genotyping QC and imputation into the Haplotype Reference Consortium was perfomed within each batch. The datasets were combined and following post-imputation filtering data were available on 1168 samples.

  Dataset EGAD00001015369

• Understanding the development of resident memory T cells (Trm) in the human small intestine using integrative multiomic approaches: Adult RNA (2025-10-14)

  Animal studies have demonstrated that resident memory T (Trm) cells provide enhanced protective responses to a broad array of tissue-tropic pathogens, thus making Trm cells promising targets for novel vaccination strategies. However, the biological pathways that enable the long-term survival of Trm cells are poorly understood in humans. Here, we will employ a unique human intestinal transplantation setting that allows us to study the retention of persistent T cells in the grafts and the temporal development of resident T-cell populations from recruited recipient T cells. We will integrate high resolution transcriptomics, epigenetics, proteomics and immune repertoire single-cell data from purified intestinal T cells. These single-cell multiomics approaches will uncover the diversity and differentiation of the T cell populations in the human intestine, allowing us to temporally resolve the generation and maintenance of gut resident T cells. . This dataset contains all the data available for this study on 2025-10-14.

  Dataset EGAD00001015739

• The ALT pathway generates telomere fusions that can be detected in the blood of cancer patients

  Telomere fusions (TFs) can trigger the accumulation of oncogenic alterations leading to malignant transformation and drug resistance. Despite their relevance in tumour evolution, our understanding of the patterns and consequences of TFs in human cancers remains limited. Here, we characterize the rates and spectrum of somatic TFs across >30 cancer types using whole-genome sequencing data. TFs are pervasive in human tumours with rates varying markedly across and within cancer types. In addition to end-to-end fusions, we find novel patterns of TFs that we mechanistically link to the activity of the alternative lengthening of telomeres (ALT) pathway. We show that TFs can be detected in the blood of cancer patients, which enables cancer detection with high specificity and sensitivity even for early-stage tumours and cancers of high unmet clinical need. Overall, we report a novel genomic footprint that enables characterization of the telomere maintenance mechanism of tumours and liquid biopsy analysis.

  Dataset EGAD00001012101

• WGS dataset of Mutational Mechanisms in Multiply Relapsed Pediatric Acute Lymphoblastic Leukemia

  Pediatric acute lymphoblastic leukemia (ALL) is marked by low mutational load at initial diagnosis, which increases at relapse. The elevated mutational load at relapse can partly be explained by at least two therapy-related effects and a combination of therapy and underlying mismatch repair deficiency. However, our understanding of the type and timing of mutational mechanisms in relapsed ALL is limited, and it is unclear to what extent mutational processes contribute to disease progression. We collected a cohort of 29 Dutch ALL patients across multiple treatment protocols who had multiple relapses. Using whole genome sequencing of the sequential tumor samples of each patient we were able to distinguish the mutational processes active in relapsed ALL and could track the activity of mutational processes over time. This allowed us to investigate whether subtype-specific mutational processes at diagnosis can continue in relapse or emerge at relapse if absent in initial diagnosis. Furthermore, we assessed whether the activity of mutational processes contributed to disease development and relapse.

  Dataset EGAD00001015401

• A developmental cell atlas of the human thyroid gland - WGS

  The thyroid gland produces hormones essential for health from embryogenesis to adulthood. Thyroid disorders, including congenital hypothyroidism and thyroid carcinoma, are prevalent and pose significant health challenges. Congenital hypothyroidism often results from thyroid dysgenesis or impaired hormone synthesis, is particularly prevalent in trisomy 21 (T21), while thyroid carcinoma is the most frequent endocrine malignancy, affecting both paediatric and adult populations. Understanding the molecular basis of these conditions requires deeper insights into fetal thyroid development. We generated a spatiotemporal atlas of the human thyroid during early pregnancy, revealing key cell types, including hormone-producing thyrocytes. Thyroid follicular cells are heterogeneous, with two functional cell states (fTFC1, fTFC2) that persist into adulthood, with fTFC2 characterised by elevated PAX8 expression. We demonstrated that T21 thyroids displayed dysgenesis with disrupted follicular morphology, and altered extracellular matrix interactions, and that the fTFC2 signature was enriched in paediatric papillary thyroid cancer compared to adults. These findings uncover thyrocyte heterogeneity across the lifespan, advancing understanding of thyroid development and disease.

  Dataset EGAD00001015447

• A developmental cell atlas of the human thyroid gland - RNA

  The thyroid gland produces hormones essential for health from embryogenesis to adulthood. Thyroid disorders, including congenital hypothyroidism and thyroid carcinoma, are prevalent and pose significant health challenges. Congenital hypothyroidism often results from thyroid dysgenesis or impaired hormone synthesis, is particularly prevalent in trisomy 21 (T21), while thyroid carcinoma is the most frequent endocrine malignancy, affecting both paediatric and adult populations. Understanding the molecular basis of these conditions requires deeper insights into fetal thyroid development. We generated a spatiotemporal atlas of the human thyroid during early pregnancy, revealing key cell types, including hormone-producing thyrocytes. Thyroid follicular cells are heterogeneous, with two functional cell states (fTFC1, fTFC2) that persist into adulthood, with fTFC2 characterised by elevated PAX8 expression. We demonstrated that T21 thyroids displayed dysgenesis with disrupted follicular morphology, and altered extracellular matrix interactions, and that the fTFC2 signature was enriched in paediatric papillary thyroid cancer compared to adults. These findings uncover thyrocyte heterogeneity across the lifespan, advancing understanding of thyroid development and disease.

  Dataset EGAD00001015448

• DERMATLAS: Hidradenoma papilliferum_RNAseq

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible.For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previously, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles.

  Dataset EGAD00001015480

• Transcriptional consequences of SETBP1 variants in developmental disorders and malignancies

  The SETBP1 gene encodes a DNA-binding nuclear protein that regulates gene expression across multiple tissues. Precise control of SETBP1 dosage is essential for normal cellular function, as both loss- and gain-of-function variants of SETBP1 can lead to severe phenotypic consequences. De novo germline gain-of-function point mutations that prolong SETBP1 half-life result in Schinzel-Giedion syndrome (SGS), an ultra-rare and severe congenital disorder associated with extensive developmental abnormalities and health complications. These SGS-associated variants cluster within a hotspot in the SKI-homology domain of SETBP1, overlapping with somatic mutations recurrently observed in myeloid leukaemia with poor prognosis. Thus far, the precise mechanisms by which these SETBP1 mutations drive disease remain largely unclear. Here, through single-cell and single-nucleus mRNA sequencing of a rare collection of primary patient samples with SGS and myeloid leukaemia, we examined the transcriptional consequences of SETBP1 gain-of-function variants in haematopoietic cells, comparing their impacts when acquired in the germline and somatically in malignancies.

  Dataset EGAD00001015482

• DNMT3A-R882 mutations intrinsically drive dysfunctional neutropoiesis from human haematopoietic stem cells

  Clonal haematopoiesis (CH) arises from the expansion of hematopoietic stem cells (HSCs) carrying leukaemia-associated somatic mutations. CH is linked to pathological immune dysregulation and a greater risk of age-related inflammatory diseases. Yet, how CH mutations impact HSC differentiation into immune effector cells remains understudied. Here, we report a single-cell resolution functional and multi-omic investigation of HSC clonal and differentiation dynamics in individuals with DNMT3A-R882 CH. DNMT3A-R882 reshapes the clonal architecture of haematopoiesis towards an aged phylogenetic structure. Functionally, DNMT3A-R882 HSCs produce decreased monocytic output but more abundant and mature neutrophil progeny compared to WT HSCs in the same individual. Whereas DNMT3A-R882 myeloid progenitors display attenuated inflammatory transcriptional programmes, DNMT3A-R882 mature neutrophils acquire proinflammatory and immunomodulatory features typical of maladaptive immunity and CH co-morbidities. Our findings, validated in humanised mice, identify aberrant DNMT3A-R882 HSC-driven neutropoiesis as a key link between CH, immune dysregulation and risk of inflammatory disease.

  Dataset EGAD00001015750

• Somatic mutation in edited cholangiocyte organoids

  Primary human cells cultured in organoid format have great promise as potential regenerative cellular therapies. However, their immunogenicity and mutagenic profile remain unresolved, impeding effective long-term translation to the clinic. In this study we report, for the first time, the generation of human leukocyte antigen (HLA)-I and HLA-II knock-out human expandable primary cholangiocyte organoids (PCOs) using CRISPR-Cas9 as a potential ‘universal’ low-immunogenic therapy for bile duct disorders. HLA-edited PCOs (ePCOs) displayed the same phenotypic and functional characteristics as parental unedited PCOs. Despite minimal off-target edits, duplex sequencing approaches demonstrated that ePCOs and PCOs acquire mutations in culture at similar rates, but without evident selection for cancer-driver mutations. ePCOs induced reduced T cell-mediated immunity and donor-dependent NK cell cytotoxicity in vitro and evaded cytotoxic responses with increased graft survival in humanized mice in vivo. Our findings have important implications for assessment of safety and immunogenicity of primary cell-derived organoid cellular therapies.

  Dataset EGAD00001015457

• DERMATLAS: Hidradenoma papilliferum_WES

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible.For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previously, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles.

  Dataset EGAD00001015481

• A non-canonical lymphoblast in refractory childhood T-cell leukaemia

  Refractory cancers may arise either through the acquisition of resistance mechanisms or represent distinct disease states. The origin of childhood T-cell acute lymphoblastic leukaemia (T-ALL) that does not respond to initial treatment, i.e. refractory disease, is unknown. Refractory T-ALL carries a poor prognosis and cannot be predicted at diagnosis. Here, we perform single cell mRNA sequencing of T-ALL from 58 children (84 samples) who did, or did not respond to initial treatment. We identify a transcriptionally distinctive blast population, exhibiting features of innate-like lymphocytes, as the major source of refractory disease. Evidence of such blasts at diagnosis heralds refractory disease across independent datasets and is associated with survival in a large, contemporary trial cohort. Our findings portray refractory T-ALL as a distinct disease with the potential for immediate clinical utility. This dataset contains 56 single-cell RNA sequencing data files with corresponding single-cell T cell receptor sequencing data files. The data here form the validation cohort in our paper.

  Dataset EGAD00001015673

• Single cell transcriptional evolution of myeloid leukaemia of Down syndrome – WGS

  Abstract: Children with Down syndrome have a 150-fold increased risk of developing myeloid leukaemia (ML-DS). Unusually for a childhood leukaemia, ML-DS arises from a preleukaemic state, termed transient abnormal myelopoiesis (TAM), and via a conserved sequence of mutations. Here, we examined the relationship between the genetic and transcriptional evolution of ML-DS from a rich collection of primary patient samples through single cell mRNA sequencing, complemented by phylogenetic analyses in progressive disease. We distilled the transcriptional consequence of each genetic step in the evolution of ML-DS, showing that TAM-defining GATA1 mutations account for most of the ML-DS transcriptome, including those of progressive disease. This transcriptional backbone may thus represent a common vulnerability in ML-DS. We extracted the transcriptional difference between TAM and ML-DS which, unexpectedly, reflected features shared across childhood leukaemia. Our approach delineates the transcriptional evolution of ML-DS and provides an analytical blueprint for distilling consequences of mutations directly from patient samples.

  Dataset EGAD00001015453

• Gene expression QTL mapping in stimulated iPSC-derived macrophages

  Immune cells sense and respond to external stimuli, initiating an inflammatory response, with genetic variants potentially altering these responses. Traditional QTL mapping often uses naïve cells, missing condition-specific variants detectable post-stimulation. Our study uses a high-throughput platform to map eQTLs across 24 conditions using iPSC-derived macrophages, identifying that 76% of eQTLs in stimulated conditions were also present in naïve cells. We found response eQTLs (reQTLs) vary widely across conditions, with rare single-condition reQTLs being overrepresented among disease-colocalizing eQTLs. This study nominates 21.7% more disease effector genes at GWAS loci through reQTL colocalization, with 38.6% not found in the GTEx catalogue, highlighting the importance of condition-specific regulatory variation in understanding disease risk alleles. Our findings underscore the value of condition-specific studies in elucidating the genetic mechanisms underlying complex diseases. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Dataset EGAD00001015380

• Selection of somatic escape variants in SERPINA1 in liver tissue of patients with alpha-1 anti-trypsin deficiency - Exome

  Somatic variants accumulate in non-malignant tissues with age. Functional variants leading to clonal advantage of hepatocytes accumulate in the liver from patients with acquired chronic liver disease (CLD). Whether somatic variants are common to CLD from differing aetiologies is unknown. We analysed liver somatic variants in patients with genetic CLD from alpha-1 anti-trypsin (A1AT) deficiency or haemochromatosis. We show that somatic variants in SERPINA1, the gene encoding A1AT, are strongly selected for in A1AT deficiency, with evidence of convergent evolution. Acquired SERPINA1 variants are clustered leading to truncation or coding change at the C-terminus of A1AT. In vitro and in vivo, C-terminal truncation variants reduce disease-associated Z-A1AT polymer accumulation and disruption of the endoplasmic reticulum, supporting the C-terminal domain swap mechanism. Therefore, somatic escape variants from a deleterious germline variant are selected for in A1AT deficiency, suggesting functional somatic variants are disease-specific in CLD and point to disease-associated mechanisms.

  Dataset EGAD00001015431

• Somatic mutation in edited cholangiocyte organoids

  Primary human cells cultured in organoid format have great promise as potential regenerative cellular therapies. However, their immunogenicity and mutagenic profile remain unresolved, impeding effective long-term translation to the clinic. In this study we report, for the first time, the generation of human leukocyte antigen (HLA)-I and HLA-II knock-out human expandable primary cholangiocyte organoids (PCOs) using CRISPR-Cas9 as a potential ‘universal’ low-immunogenic therapy for bile duct disorders. HLA-edited PCOs (ePCOs) displayed the same phenotypic and functional characteristics as parental unedited PCOs. Despite minimal off-target edits, duplex sequencing approaches demonstrated that ePCOs and PCOs acquire mutations in culture at similar rates, but without evident selection for cancer-driver mutations. ePCOs induced reduced T cell-mediated immunity and donor-dependent NK cell cytotoxicity in vitro and evaded cytotoxic responses with increased graft survival in humanized mice in vivo. Our findings have important implications for assessment of safety and immunogenicity of primary cell-derived organoid cellular therapies.

  Dataset EGAD00001015456

• Mapping genetic variants that underlie gene regulation in intestinal cell types to identify novel, validated, Crohn’s disease drug targets

  Biopsies from the terminal ileum and rectum of healthy individuals and terminal ileum and blood from Crohns disease patients are collected and processed single cells and processed for single-cell RNA-sequencing using 10X Genomics 3' v3 and v3.1 and Illumina sequencing. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001003647