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• Characterization of DLBCL with a PMBL gene expression signature

  Primary mediastinal large B-cell lymphoma (PMBL) is a type of aggressive B-cell lymphoma that typicallyaffects young adults, characterized by presence of a bulky anterior mediastinal mass. Lymphomas withgene expression features of PMBL have been described in non-mediastinal sites, raising questions abouthow these tumors should be classified.Here, we investigated whether these "non-mediastinal PMBLs" are indeed PMBLs or instead represent adistinct group within DLBCL. From a cohort of 325 de novo DLBCL cases, we identified tumors frompatients without evidence of anterior mediastinal involvement that expressed a PMBL expression signature(nm-PMBLsig-pos, n=16, 5%). The majority of these tumors expressed MAL and CD23 – proteins typicallyobserved in bona fide PMBL (bf-PMBL). Evaluation of clinical features of nm-PMBLsig-pos cases revealedclose associations with DLBCL, and the majority displayed a germinal center B-cell-like cell-of-origin(GCB). In contrast to bf-PMBL, nm-PMBLsig-pos patients presented at an older age, did not show pleuraldisease, and bone/bone marrow involvement was observed in three cases. However, while clinicallydistinct from bf-PMBL, nm-PMBL-sig-pos tumors resembled bf-PMBL at the molecular level with upregulationof immune response, JAK-STAT, and NF-kB signatures. Mutational analysis revealed frequent somatic genemutations in SOCS1, IL4R, ITPKB and STAT6, as well as CD83 and BIRC3, with the latter genes beingsignificantly more frequently affected than in GCB-DLBCL and bf-PMBL.Our data establish nm-PMBLsig-pos lymphomas as a group of DLBCL with distinct phenotypic and geneticfeatures, and potential implications for gene expression- and mutation-based subtyping of aggressive Bcell lymphoma and related targeted therapies.

  Study EGAS00001005057

• Biallelic variants in the non-protein coding minor spliceosome components RNU6ATAC and RNU6ATAC cause syndromic monogenic autoimmune diabetes

  Non-protein coding genes are emerging as critical contributors to the aetiology of rare diseases, providing key insights into human biology and uncovering novel disease mechanisms. We identified 7 individuals from 4 families with early-onset diabetes (diagnosed <5 years) and immune dysregulatory features caused by biallelic variants in RNU6ATAC. RNU6ATAC encodes a small nuclear RNA (snRNA) acting as a catalytic component of the minor spliceosome, a protein-RNA complex mediating splicing of ~700 genes containing U12/minor-type introns. Variant screening of the other 64 minor spliceosome genes in 276 infants with diabetes identified 12 unrelated individuals with biallelic disease-causing variants in RNU4ATAC. Biallelic pathogenic RNU4ATAC variants are known to cause a variable spectrum of clinical features, which until now did not include diabetes. Clinically, 12/19 RNU6ATAC/RNU4ATAC patients had additional immune dysregulatory features, and 50% of patients tested were islet-autoantibody positive, strongly supporting an autoimmune aetiology for their diabetes. RNA-seq in 3 individuals with biallelic RNU6ATAC variants showed a pattern of intron retention in U12 intron-containing genes similar to that seen in RNU4ATAC-individuals (n=3), supporting a shared disease mechanism. Analysis of patients’ transcriptomic, methylation and immune data revealed impaired B cell development and maturation. We conclude that biallelic RNU6ATAC variants cause a novel syndrome of early-onset autoimmune diabetes and immune dysregulation. We further show that infancy-onset diabetes is a previously unrecognised feature of RNU4ATACopathy. Our work highlights the important role of two snRNAs critical to minor spliceosome function in immune system regulation, providing novel insights into the pathogenesis of autoimmune diabetes.

  Study EGAS50000001565

• Liverpool Preterm Birth Biomarker Study

  Preterm birth is a multifactorial condition defined as birth less than 37 weeks of gestation. This study aimed to identify early pregnancy biomarkers from maternal genome-wide and transcriptome-wide data of women experiencing two types of spontaneous PTB (sPTB): spontaneous preterm birth (SPTB) and preterm premature rupture of membranes (PPROM). Whole blood samples were obtained from women with singleton pregnancies (N=567) recruited at the Liverpool Women’s Hospital at 16 and 20 weeks of gestation. Women with a previous history of sPTB pregnancies &lt;34 weeks were categorised on their index pregnancy outcome as spontaneous preterm birth (SPTB) and preterm premature rupture of membranes (PPROM) or high-risk term control (HTERM, ≥37 weeks). Women with no history of SPTB/PPROM and delivered at term were LTERM (≥39 weeks of gestation). DNA was genotyped on the UK Biobank Axiom™ array (Applied Biosystems™, Thermo Fisher Scientific) and RNA who processed using the Clariom™ D Human assay (Thermo Fisher Scientific). Genome-wide association analysis, differential expression analysis and expression quantitative trait loci (eQTL) were completed.

  Study EGAS00001005076

• Neural Systems, Inhibitory Control, and Methamphetamine Dependence

  The Neural Systems, Inhibitory Control, and Methamphetamine Dependence study started in 2011 and is currently finishing data collection for its last participants. The study included methamphetamine abusing individuals and healthy control participants aged 18-55 years. Participants who qualified over the telephone were scheduled to visit the London Laboratory at the UCLA Semel Institute for Neuroscience and Human Behavior for the In-Person Screening Phase. The screening procedures, usually scheduled over two visits, determined if participants were eligible to complete the subsequent study visits. Both groups completed identical screening procedures, with the exception of more in-depth drug use questions for the methamphetamine users. After providing written consent, participants completed questionnaires about their mood, medical, psychiatric and drug use history, personality and life experiences. They also provided a urine sample to determine what drugs they recently used and a breath sample to determine the carbon monoxide levels in their system. The drug screen tested for recent methamphetamine, cocaine, opiates/opioids, benzodiazepines, THC and other amphetamines. Methamphetamine participants needed to test positive for methamphetamine at admission. If methamphetamine participants tested positive for any drugs other than methamphetamine or marijuana, and if healthy control participants tested positive for any drugs other than marijuana, they were excluded from the study. Additionally, the urine samples of female participants were tested for pregnancy; pregnant females were also excluded. If no exclusionary criteria were met during the first screening visit, participants completed a second screening visit to ensure they were mentally and physically healthy enough to participate. The second screening visit included a psychiatric diagnostic interview (DSM-IV (SCID-I) for first 500 participants and the MINI International Neuropsychiatric Interview M.I.N.I for the last 50 participants). Additionally, laboratory tests and procedures were completed by the UCLA General Clinical Research Center and interpreted by a study physician. Laboratory tests included vital signs (heart rate--BPM, blood pressure, and respirations), an electrocardiogram (ECG) to record the electrical activity of the heart, and an 18-cc blood sample to perform laboratory tests which included a complete chemistry and metabolic panel, hepatic panel, Hepatitis-C tests, and HIV test. The laboratory tests from this blood sample ensured that participants&#39; liver and kidneys were functioning normally, and that their standard blood counts (red cell, white cell, and salts) were also normal. If a Hepatitis-C (HCV) or HIV test was positive, participants were not allowed to continue in the study and their results were reported to the California State Health Department. Participants deemed eligible to continue in the methamphetamine group participated on an outpatient basis or were admitted to the UCLA Medical Center to participate on an inpatient basis for up to 10 days. Typically, detectable levels of methamphetamine in urinalysis remain for 2-3 days, therefore inpatient days 0-3 served as a "washout period" and the methamphetamine abusing inpatient participants provided daily urine samples to test for recent drug use and pregnancy (female participants only). Outpatient participants were also required to remain abstinent from all drugs except nicotine and marijuana for at least 4 days prior to study sessions. Self-reported abstinence for outpatients was verified by urine toxicology and saliva screening at every visit to UCLA before completion of study procedures. Neurocognitive assessments, about three hours each, typically took place on two separate days. The purpose of the neurocognitive sessions were to assess participants&#39; intellectual and neurocognitive functioning. On either the same day as the neurocognitive testing or on separate days, both methamphetamine abusers and healthy controls were administered a structural MRI to collect information on brain structure.

  Study phs001197

• A Case-Controlled Study for Genotype-Phenotype Associations in Multiple Sclerosis (MS)

  This is a multi-centre, case-controlled study to develop a dataset containing 1000 MS cases and 1000 matched controls and to associate DNA sequence (allelic) variations with MS phenotypes. Study subjects were enrolled through a prospective effort initiated in 2003. Three MS clinical centres were involved in subject recruitment and biological specimen collection using identical inclusion/exclusion criteria, two in Europe (Vrije Universiteit Medical Center, Amsterdam; and University Hospital Basel) and one in the US (University of California San Francisco). This study recruited subjects of northern-European ancestry with a diagnosis of MS (McDonald et al., 2001), with dissemination in time and space. Patients with Clinically Isolated Syndromes (CIS) were also included if they fulfilled 3 of the 4 Barkhof criteria for dissemination in space as per application of the McDonald criteria (McDonald et al., 2001). While recruitment predominantly included subjects with a relapsing onset of MS, individuals with all clinical subtypes of the disease participated, including clinically isolated syndrome (CIS), relapsing remitting MS (RRMS), secondary progressive MS (SPMS), primary progressive MS (PPMS), and progressive relapsing MS (PRMS). The control group consisted of unrelated individuals, primarily spouses/partners, friends, and other volunteers. Control subjects were of northern-European ancestry and matched as a group, proportionally with cases according to age (&#177;5 years) and gender. A familial history or current diagnosis of MS as well as a relation to another case or control subject were considered exclusionary for this group. Protocols were approved by the Committees on Human Research at all Institutions and informed consent was obtained from all participants prior to participation in the study. Primary Study Objective:To identify DNA sequence variations (genotype) and flanking sequences that are associated with clinical factors (phenotype) which differ between study subjects with and without MS. Secondary Study Objectives: To develop a clinical dataset including quantitative measures of 1000 well-characterized cases with MS, and 1000 ethnically matched controls. To identify other genotype-phenotype associations in MS study subjects such as magnetic resonance imaging (MRI) measures of disease burden and/or severity. To identify or confirm candidate surrogate markers of neurodegeneration using a variety of techniques including biochemical assays, blood transcriptome analysis, plasma proteomics and MRI*. GenotypingGenotyping of the complete dataset was performed at the Illumina facilities using the Sentrix&#174; HumanHap550 BeadChip. *MRI results are not available on dbGaP.

  Study phs000171

• miRNA

  The purpose is to perform miRNA analysis on FACS sorted target immune cell populations to uncover novel potential miRNA diagnostic markers biomarkers predictive of therapy response but also possibly identify perturbed signaling pathways or miRNA targets of intervention with the use of agomirs/antagomirs.

  Dataset EGAD50000002025

• Single nuclei sequencing of early, late-term, and early-onset pre-eclamptic decidua and villi.

  Hypertensive disorders in pregnancy, of which the multisystem syndrome pre-eclampsia is the most severe, leading to preterm delivery, maternal mortality, and life-long complications. To elucidate early disease dynamics, we present the first spatio-temporal study comparing single-nuclei transcriptomes of human preterm pre-eclamptic placentae and healthy controls, contextualizing this in a comprehensive study including early and late gestational placentae. This study includes early placentae samples from the fetal part (villi; n=10), maternal part (Decidua; n=3), late placentae samples from healthy pregnancies, villi (n=6), decidua (n=4), and late placentae samples from early-onset preeclamptic pregnancies, villi (n=5) and decidua (n=5).

  Dataset EGAD00001008273

• MutWP4__CRUK_Grand_Challenge_Mutographs_of_Cancer__Mutagen_treated_organoids

  The Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Different patterns of somatic mutation are generated by the different environmental, lifestyle and genetic factors that cause cancer, many of them are still unknown. Within Mutographs, Kings College London will characterise the mutational signatures induced by putative human carcinogens in order to identify the origins of mutational signatures found in human cancers. To achieve this human organoid cell cultures will be exposed to a representative catalogue of known or suspected human carcinogens and mutagens and, using whole genome sequencing, the patterns of mutations induced by them will be determined. Somatic mutational signatures will be subsequently extracted by non-negative matrix factorisation methods and correlated with exposure data. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development.

  Study EGAS00001004873

• MutWP4__CRUK_Grand_Challenge_Mutographs_of_Cancer__organoid_control_WGS

  The Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Different patterns of somatic mutation are generated by the different environmental, lifestyle and genetic factors that cause cancer, many of them are still unknown. Within Mutographs, Kings College London will characterise the mutational signatures induced by putative human carcinogens in order to identify the origins of mutational signatures found in human cancers. To achieve this human organoid cell cultures will be exposed to a representative catalogue of known or suspected human carcinogens and mutagens and, using whole genome sequencing, the patterns of mutations induced by them will be determined. Somatic mutational signatures will be subsequently extracted by non-negative matrix factorisation methods and correlated with exposure data. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development.

  Study EGAS00001005449

• MutWP4__CRUK_Grand_Challenge_Mutographs_of_Cancer__Gastric_Organoids

  The Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Different patterns of somatic mutation are generated by the different environmental, lifestyle and genetic factors that cause cancer, many of them are still unknown. Within Mutographs, Kings College London will characterise the mutational signatures induced by putative human carcinogens in order to identify the origins of mutational signatures found in human cancers. To achieve this human organoid cell cultures will be exposed to a representative catalogue of known or suspected human carcinogens and mutagens and, using whole genome sequencing, the patterns of mutations induced by them will be determined. Somatic mutational signatures will be subsequently extracted by non-negative matrix factorisation methods and correlated with exposure data. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development.

  Study EGAS00001003151

• MutWP4__CRUK_Grand_Challenge_Mutographs_of_Cancer__Pancreatic_Organoids

  The Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Different patterns of somatic mutation are generated by the different environmental, lifestyle and genetic factors that cause cancer, many of them are still unknown. Within Mutographs, Kings College London will characterise the mutational signatures induced by putative human carcinogens in order to identify the origins of mutational signatures found in human cancers. To achieve this human organoid cell cultures will be exposed to a representative catalogue of known or suspected human carcinogens and mutagens and, using whole genome sequencing, the patterns of mutations induced by them will be determined. Somatic mutational signatures will be subsequently extracted by non-negative matrix factorisation methods and correlated with exposure data. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development.

  Study EGAS00001003520

• Immunophenotyping in a COVID-19 Cohort (IMPACC) Transcriptomics and Genotyping Assays

  IMPACC (IMmunoPhenotyping Assessment in a COVID-19 Cohort) is a prospective longitudinal cohort study (NCT04378777) launched in May 2020 in response to the worldwide pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It was funded by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institute of Health (NIH). Patient enrollment and sample analysis involved 20 hospitals associated with 15 U.S. biomedical research centers and 11 centralized Core immunoassay laboratories.The study aimed to enable the identification of potential biomarkers and inform future therapeutic interventions using a longitudinal approach encompassing the whole disease course for a comprehensive understanding of the contributions of the pathogen and host immune response in modulating the manifestations, severity, and post-acute sequelae of the infection. IMPACC enrolled close to 1200 adult symptomatic, molecularly confirmed hospitalized COVID-19 patients in the study within 48 hours of their hospital admission. Clinical data and biological samples (blood, mid-turbinate nasal swabs, and esophageal aspirant) were collected according to minimal risk guidelines at enrollment and on days 4, 7, 14, 21, and 28. Biological samples were collected at 3-month intervals up to 12 months after hospital discharge to assess functional and immunologic recovery measures. Sample collection, processing, and storage procedures were standardized across sites, and samples were transported to centralized assay-specific core laboratories (Core Labs) in batches for testing and analysis. The description of outcome severity was not limited to survival versus death but encompassed a clinical trajectory approach using 5 groups leveraging longitudinal data based on time in the hospital, disease severity by ordinal scale based on the degree of respiratory illness, and presence or absence of limitations at discharge. Disease severity was assessed based on the degree of respiratory illness using a 7-point ordinal scale adapted from the World Health Organization COVID-19 and NIAID disease ordinal severity scales. DNA for genetic analyses was collected from whole blood at a single time point. To identify any genomic determinants of severe COVID-19 disease, single-nucleotide polymorphism (SNP) genotyping and exome sequencing were conducted to assess genetic variants associated with individual susceptibility to severe disease. In addition, IMPACC included bulk transcriptomic analysis of upper airway (nasal swaps) samples, lower airway (esophageal aspirant) samples, and peripheral blood mononuclear cells (PBMCs) to evaluate dynamic changes in cellular composition and cellular response during the course of the disease. Reads were aligned to the GRCh38 human reference genome. Additional information for the IMPACC study has been submitted to The Immunology Database and Analysis Portal (ImmPort) under study accession SDY1760. Further information and requests for resources and reagents should be directed to and will be fulfilled by the Lead Contact, Dr. Steven Kleinstein (steven.kleinstein@yale.edu).

  Study phs002686

• Strand-specific RNA Sequencing of initial and recurrent gliomas

  Four RNA-sequencing datasets from two patients with initial low-grade glioma and copy number alteration at IDH1 upon recurrence. Data is provided as bam files.

  Dataset EGAD00001003764

• Somatic mutations, clonal architecture and genomic evolution in multiple myeloma

  Multiple myeloma is an incurable plasma cell malignancy whose molecular pathogenesis is incompletely understood. We used whole exome sequencing, copy number profiling and cytogenetic to analyses 84 samples from 67 patients with myeloma. In addition to known myeloma genes, we identify new candidate genes, including truncations of SP140, ROBO1 and FAT3 and clustered missense mutations in EGR1. We find oncogenic mutations in cancer genes not previously implicated in myeloma, including SF3B1, PI3KCA and PTEN. We define diverse processes contributing to the mutational repertoire, including kataegis and somatic hypermutation. Most cases have at least one cluster of subclonal variants, including subclonal driver mutations, implying on-going tumor evolution. Serial samples revealed diverse patterns of clonal evolution, including linear evolution, differential clonal response and branching evolution. Our findings reveal the myeloma genome to be heterogeneous across patients and, within individual patients, to exhibit diversity in clonal admixture and dynamics in response to therapy.

  Dataset EGAD00001000339

• UMCU Molpheno Closed

  This dataset contains Whole Genome Sequencing and, if available, RNA-sequencing and/or ATAC-sequencing data obtained from PBMCs derived from blood samples of two patients with intellectual disability and/or multiple congenital anomalies and eight parents included in the University Medical Center Utrecht (The Netherlands). Data access is closed.

  Dataset EGAD00001004864

• Prognostic factors in prostate cancer: deep sequencing pilot project TAPG

  This is a pilot project to determine whether the TAPG FFPE DNA's are suitable for deep sequencing. If successful an investigation of SNP distribution in a larger cohort will follow.

  Dataset EGAD00001001237

• RNA sequencing of untreated head and neck cancer patient-derived xenografts (PDXs) and matched patient tumor tissue.

  RNA sequencing was performed on untreated patient tumor tissue and matched patient-derived xenograft (PDX) models of primary head and neck squamous cell carcinoma (HNSCC). The aim of this analysis was to characterize the transcriptional landscape of the tumors in the in vivo setting. 117 total samples were sequenced with paired reads on 10 lanes from different flowcells. They were loaded as 2400 separate files to maintain the data as it was received from BGI - each sample is therefore composed of 5 separate EGAN with 4 files each, adding a 0.1 - .. - 0.5 to each BioSample ID to generate sample aliases. All R1 (and R2, separately) files referring to a BioSample ID should be concatenated to obtain fastq files corresponding to single patients or PDXs.

  Dataset EGAD50000002278

• Whole Genome Sequencing of Liver Cancers

  Genomic alterations driving tumorigenesis result from the interaction of environmental exposures and endogeneous cellular processes. With a diversity of risk factors including viral infection, carcinogenic exposures and metabolic diseases, liver cancer is an ideal model to study these interactions. Whole genome sequencing of liver tumors identified 10 mutational signatures showing distinct relationships with environmental exposures, replication and transcription. Transcription-coupled damage was specifically associated with the liver-specific signature 16 and alcohol intake. Flood of indels were identified in very highly expressed hepato-specific genes, likely resulting from replication-transcription collisions. Reconstruction of sub-clonal architecture revealed mutational signature evolution during tumor development exemplified by the vanishing of aflatoxin-B1 signature in African migrants. These findings shed new light on the natural history of liver cancers.

  Dataset EGAD00001003281

• An MTOR mutation hitchhikes through renal embryogenesis, driving multifocal, multiphenotypic tumours - WGS

  Embryogenesis is a vulnerable time. Mutations in developmental cells can result in the seeding of cells predisposed to disease within mature organs, creating a field effect. We characterise an embryonic cancer mutation that drives multifocal, multiphenotypic renal tumours in a 14-year-old girl. Their shared MTOR mutation, absent from normal tissues, increases protein flexibility which enables a FAT domain hinge to dramatically increase mTORC1 activity. Developmental mutations, not usually detected in traditional genetic screening, have vital clinical importance in guiding prognosis, targeted treatment, and family screening decisions for paediatric tumours.

  Dataset EGAD00001011645

• An MTOR mutation hitchhikes through renal embryogenesis, driving multifocal, multiphenotypic tumours - RNA

  Embryogenesis is a vulnerable time. Mutations in developmental cells can result in the seeding of cells predisposed to disease within mature organs, creating a field effect. We characterise an embryonic cancer mutation that drives multifocal, multiphenotypic renal tumours in a 14-year-old girl. Their shared MTOR mutation, absent from normal tissues, increases protein flexibility which enables a FAT domain hinge to dramatically increase mTORC1 activity. Developmental mutations, not usually detected in traditional genetic screening, have vital clinical importance in guiding prognosis, targeted treatment, and family screening decisions for paediatric tumours.

  Dataset EGAD00001011646

• An MTOR mutation hitchhikes through renal embryogenesis, driving multifocal, multiphenotypic tumours - scRNA

  Embryogenesis is a vulnerable time. Mutations in developmental cells can result in the seeding of cells predisposed to disease within mature organs, creating a field effect. We characterise an embryonic cancer mutation that drives multifocal, multiphenotypic renal tumours in a 14-year-old girl. Their shared MTOR mutation, absent from normal tissues, increases protein flexibility which enables a FAT domain hinge to dramatically increase mTORC1 activity. Developmental mutations, not usually detected in traditional genetic screening, have vital clinical importance in guiding prognosis, targeted treatment, and family screening decisions for paediatric tumours.

  Dataset EGAD00001011647

• Functional single-cell characterization of immune aplastic anemia shows convergence of NK and NK-like CD8+ T cells with disease-associated TCR signature

  Immune aplastic anemia (AA) is a life-threatening bone marrow (BM) failure disorder driven by an autoimmune T cell attack against the hematopoietic stem and progenitor cells (HSPCs). However, the autoantigen targets and the role of other immune cells are unknown. Here, by analyzing an international cohort of 156 AA patients with scRNA+TCRαβ-seq, TCRβ-seq, flow cytometry, and plasma cytokine profiling with comparisons to healthy controls and patients with other hematological disorders, we identify NK cells and CD8+ TEMRA cells expressing NK receptors with AA-associated TCRβ-seq motifs as the most dysregulated immune cell populations in AA BM. Functional co-culture experiments with scRNA-TCRαβ-seq readout utilizing primary HSPCs and immune cells provide evidence that NK cellscannot kill HSPCs alone, but sensitize them to CD8+ T cell-mediated killing. Furthermore, HSPCs induce strong activation of T cell clones with CD8+ TEMRA NK-like phenotype and AA-associated TCR motifs. Our results reveal the convergent evolution of innate and adaptive immune cells in AA, where NK cells support CD8+ T cell-mediated autoimmunity.

  Study EGAS00001007602

• Functional single-cell characterization of immune aplastic anemia shows convergence of NK and NK-like CD8+ T cells with disease-associated TCR signature

  Immune aplastic anemia (AA) is a life-threatening bone marrow (BM) failure disorder driven by an autoimmune T cell attack against the hematopoietic stem and progenitor cells (HSPCs). However, the autoantigen targets and the role of other immune cells are unknown. Here, by analyzing an international cohort of 156 AA patients with scRNA+TCRαβ-seq, TCRβ-seq, flow cytometry, and plasma cytokine profiling with comparisons to healthy controls and patients with other hematological disorders, we identify NK cells and CD8+ TEMRA cells expressing NK receptors with AA-associated TCRβ-seq motifs as the most dysregulated immune cell populations in AA BM. Functional co-culture experiments with scRNA-TCRαβ-seq readout utilizing primary HSPCs and immune cells provide evidence that NK cellscannot kill HSPCs alone, but sensitize them to CD8+ T cell-mediated killing. Furthermore, HSPCs induce strong activation of T cell clones with CD8+ TEMRA NK-like phenotype and AA-associated TCR motifs. Our results reveal the convergent evolution of innate and adaptive immune cells in AA, where NK cells support CD8+ T cell-mediated autoimmunity.

  Study EGAS00001007604

• Spatial transcriptomics elucidates medulla niche supporting germinal center response in myasthenia gravis thymoma

  Myasthenia gravis (MG) is known to be epidemiologically associated with abnormalities of the thymus, an organ that maintains central tolerance. However, due to the complexity of the thymus, specific characteristics related to the pathogenesis of MG remain elusive. In our study, we attempted to narrow down the features associated with MG using spatial transcriptome analysis of thymoma and thymic hyperplasia samples. We found that the majority of thymomas were constituted by the cortical region, whereas the medullary region was localized in comparatively restricted areas. Moreover, the medullary region contained polygenic enrichment, MG-specific germinal center structures, and a supporting immune microenvironment. Additionally, neuromuscular medullary thymic epithelial cells (nmTECs), previously identified as MG-specific autoantigen-producing cells, were situated at the cortico-medullary junction. The immune microenvironment in the medulla was characterized by a specific chemokine pattern and specific immune cells, such as CCR7+ migratory dendritic cells (migDCs) and effector regulatory T (Treg) cells. Furthermore, similar germinal center structures and immune microenvironments were observed in the medulla during thymic hyperplasia. This study indicates that the medulla and junction areas are related to the pathology of MG, suggesting that these areas should be the focus of future studies on MG pathogenesis and drug targeting.

  Study JGAS000672

• Low T cell diversity is associated with poor outcome in bladder cancer - Bulk TCRseq data

  T cells are crucial effector cells in the endogenous defense against cancer, yet the clinical impact of their quantity, diversity, and dynamics remains underexplored. In this study we performed bulk TCRseq on tumor and serial blood samples from patients with muscle invasive (n patients = 119) or non-muscle invasive bladder cancer (n patients = 30). The goal was to investigate the clinical relevance of the blood and tumor TCR repertoire in patients with bladder cancer.

  Study EGAS50000000940

• Multi-omic and functional analysis for classification and treatment of sarcomas with FUS-TFCP2 or EWSR1-TFCP2 fusions(H021/INF)

  Many rare cancers are not well understood, and pathogenesis-directed therapies are often lacking, resulting in poor patient outcomes. Leveraging two (inter)national precision oncology trials that enroll large numbers of rare cancers, we investigated the clinical, histopathologic, molecular, and functional characteristics of rhabdomyosarcoma (RMS) with fusions of FUS or EWSR1 to the TFCP2 transcription factor, a recently discovered ultra-rare entity whose classification, pathogenesis, and optimal treatment are unclear. Unusually for fusion-driven sarcomas, most cases had highly rearranged genomes, including chromothripsis, and signs of defective homologous recombination DNA repair. All tumors showed extreme expression of a truncated TERT variant and the ALK receptor tyrosine kinase, which was additionally affected by intragenic deletions and aberrant splicing, resulting in the expression of shortened variants in 58% of cases. Three ALK variants were oncogenic in immortalized cells, and patient-derived tumor cells expressing two variants responded to certain ALK inhibitors. Other recurrent alterations included CDKN2A/MTAP co-deletions and mutations in PAPPA2, encoding an IGFBP5-specific proteinase, in 67% and 25% of cases, respectively. DNA methylation analysis, along with 19 other soft-tissue sarcoma classes, revealed a close relationship with undifferentiated sarcoma but not other RMS subtypes, suggesting that TFCP2-rearranged RMS is a separate entity, possibly arising from a distinct cell of origin. Expression of TFCP2 fusions in immortalized human cells blocked late myogenic differentiation and significantly induced genes that were also highly expressed in patient tumors, including ALK, TERT, and two known regulators of skeletal muscle cells, IGFBP5 and PTH1R. Genome-wide chromatin profiling demonstrated direct binding of FUS-TFCP2 to the ALK and TERT loci outside their regular promoters, which correlated with the expression of alternative transcript variants. Finally, FUS-TFCP2 inhibited the repair of DNA double-strand breaks in immortalized cells, rendering them sensitive to treatment with cisplatin. This study provides insight into the pathogenesis and therapeutic vulnerabilities of a new RMS subtype and illustrates the value of linking comprehensive molecular diagnostics and functional annotation within multicenter consortia to improve the understanding and clinical management of rare cancers.

  Study EGAS00001006939

• Comprehensive Genomic Profiling of a National Cohort of Pediatric Papillary Thyroid Carcinoma in Hungary

  Pediatric papillary thyroid carcinoma (PTC) is a rare childhood malignancy with increasing incidence and distinct clinicopathological features, including high rate of locoregional metastases and different molecular background compared to adult cases. Traditional treatments (surgery, radioactive iodine) are effective but pose long-term risks, prompting the exploration of targeted therapies. We performed comprehensive genomic profiling on 21 pediatric PTC patients applying Illumina TruSight Oncology 500 platform and detected mutations, gene fusions, copy number variations and revealed tumor mutational burden.

  Dataset EGAD50000002659

• Paediatric glioma cell line WGS

  Whole genome sequencing of 5 paediatric glioma cells lines - KNS42, SF188, UW479, RES186 and RES259. Illumina paired end sequencing is provided as 5 BAM files aligned to hg19 with bwa.

  Dataset EGAD00001004123

• Tumor Profiler Project - OV scRNA data additional samples

  The dataset contains 10x Chromium single-cell transcriptomics data from 6 samples from 4 different patients with ovarian cancer. 3 samples were collected from the tumor, 3 samples from ascites. Sequencing was performed in paired-end mode and sequencing data is provided in fastq format. This dataset contains additional samples from patients not classified as having high-grade serous adenocarcinoma.

  Dataset EGAD50000001293

• microRNA-seq of human serum from a longitudinal study of 66 women with no history of cancer

  This dataset includes microRNA sequencing data from 198 human serum samples, representing a subset of 66 women with no history of cancer who participated in the UKCTOCS study and with serum samples collected at three timepoints over a period of up to 5 years. Small RNA libraries prepared from the serum samples were sequenced with 50-bp single end reads on an Illumina HiSeq 2000 instrument. Data is provided as FASTQ files.

  Dataset EGAD00001004348

• Ultra-deep sequencing of cell-free DNA derived from reference materials and a patient with asymmetric overgrowth

  This dataset contains: Ultra-deep sequencing data using the Duplex sequencing technology of: 1.) SeraSeq cfDNA reference materials with spike-in variants with allele frequencies from 0% to 5% 2.) One cfDNA sample from a CRC patient 3.) One cfDNA sample from a patient with asymmetric overgrowth Paired-end sequencing was performed with 2x151 bp reads on the NextSeq 500 system. Data is provided as mapped .bam files (aligned to GRCh38/hg38).

  Dataset EGAD00001009784

• Heart Failure Network: Functional Impact of GLP-1 for Heart Failure Treatment (HFN FIGHT-BioLINCC)

  Objectives To test whether therapy with a GLP-1 agonist improves clinical stability following hospitalization for acute heart failure. Background Heart failure was the leading cause of hospitalization in the United States with more than 4 million admissions per year from 2003&#8211;2009. Abnormal cardiac metabolism contributes to the pathophysiology of advanced heart failure with reduced left ventricular ejection fraction (LVEF). As heart failure progresses, these abnormalities become more pronounced and are observed in both patients with and without type 2 diabetes. At this time of this study, there was no heart failure therapy that targeted these metabolic abnormalities; however, in earlier clinical studies, glucagon-like peptide 1 (GLP-1) agonists showed cardioprotective effects in patients with advanced heart failure, irrespective of type 2 diabetes status. Glucagon-like peptide 1 is an endogenous incretin hormone that improves insulin sensitivity with minimal risk of hypoglycemia. This study was created to determine if use of GLP-1 agonists improved clinical stability in recently hospitalized patients with acute heart failure and reduced LVEF. Participants There were 300 participants. Design Participants were identified by hospital admission records and were enrolled during either the last 24 hours of his or her hospitalization for heart failure or the 2-week interval after the hospitalization. Baseline evaluations were conducted, which included echocardiographic measures, the 6-minute walk test, the Kansas City Cardiomyopathy Questionnaire (KCCQ), and blood tests. After the baseline evaluation, patients were randomized in a 1:1 ratio to receive either the GLP-1 agonist liraglutide or placebo as a daily subcutaneous injection. The protocol involved titration of study drug dosage as tolerated every 14 days from 0.6 mg/d to 1.2 mg/d to 1.8 mg/d during the first 30 days of the trial (as tolerated). Follow-up testing was performed at 30-, 90-, and 180-day study visits. The primary end point was a global rank score in which all participants, regardless of treatment assignment, were ranked across 3 hierarchical tiers: time to death, time to rehospitalization for heart failure, and time-averaged proportional change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) level from baseline to 180 days. Conclusions The GLP-1 agonist liraglutide did not improve post-hospitalization clinical stability in patients with advanced heart failure and reduced LVEF. There was no significant between-group difference in the global rank scores and furthermore, there were no significant differences detected in any of the secondary endpoints.

  Study phs003542

• Repression of CADM1 transcription by HPV type 18 is mediated by three-dimensional rearrangement of promoter-enhancer interactions

  'Repression of CADM1 transcription by HPV type 18 is mediated by three-dimensional rearrangement of promoter-enhancer interactions

  Dataset EGAD50000001135

• Single-Cell DNA Methylation Profiling with sciMETv2

  In this study we developed a high-throughput single-cell DNA methylation analysis technology, sciMETv2. This technique is rapid, cost-effective, and robust, enabling large-scale single-cell methylome dataset generation. We demonstrate this technology on human middle frontal gyrus, where we identified major cell types. We additionally performed target enrichment using sciMET-cap to enable a reduction in sequencing costs per cell while achieving comparable cell type identification.

  Study phs003091

• A single-cell atlas of the early COPD lung - Nanopore long-read

  Single cell atlas of the human airways from 10 patients suffering of early stage Chronic Obstructive Pulmonary Disease and 12 healthy age matched volunteers. This dataset was sequenced by 10X Genomics 3’ RNA-seq profiling. It is composed of more than 400 000 cells coming from 119 samples total. Sampling was performed by brushings and biopsies from the nose to the 6 th division of the airways. 14 samples were also sequenced using Nanopore long-read sequencing.

  Dataset EGAD50000001002

• Detecting PKD1 variants in Polycystic Kidney Disease patients by single-molecule long-read sequencing

  A genetic diagnosis of autosomal dominant polycystic kidney disease (ADPKD) is challenging. However, long-read single-molecule sequencing has been shown to be a reliable alternative strategy that could overcome PKD1 complexities. Using long-read sequencing to characterize a cohort of 19 patients with ADPKD, we developed an approach that provided high sensitivity in identifying PKD1 pathogenic variants, with a diagnostic yield of 94.7%. Reliable screening of ADPKD patients in a single test without interference of PKD1 homologous sequences is now possible.

  Study EGAS00001002106

• DAC of the STIC project

  Ovarian high-grade serous carcinoma (HGSC) originates in the fallopian tube, with secretory cells carrying a TP53 mutation, known as ‘p53 signatures’, identified as potential precursors. p53 signatures evolve into serous tubal intraepithelial carcinomas (STIC) lesions, which, in turn, progress into invasive HGSC that readily spread to the ovary and disseminate around the peritoneal cavity. We recently investigated the genomic landscape of early- and late-stage HGSC and found higher ploidy in late-stage (median 3.1) than early-stage (median 2.0) samples. Here, to explore whether the high ploidy and possible whole genome duplication observed in late-stage disease are determined early in the evolution of HGSC, we analysed archival formalin-fixed paraffin-embedded samples (FFPE) from five HGSC patients. p53 signatures and STIC lesions were laser-capture microdissected and sequenced using shallow whole genome sequencing (sWGS), while invasive ovarian/fallopian tube and metastatic carcinoma samples underwent macrodissection and were profiled using both sWGS and targeted next generation sequencing. Results showed highly similar patterns of global copy number change between STIC lesions and invasive carcinoma samples within each patient. Ploidy changes were evident in STIC lesions, but not p53 signatures, and there was strong correlation between ploidy in STIC lesions and invasive ovarian/fallopian tube and metastatic samples in each patient. The reconstruction of sample phylogeny for each patient from relative copy number indicated that high ploidy, when present, occurred early in the evolution of HGSC, which was further validated by copy number signatures in ovarian and metastatic tumours. These findings suggest that aberrant ploidy, suggestive of whole genome duplication, arises early in HGSC, and is detected in STIC lesions, implying that the trajectory of HGSC may be determined at the earliest stages of tumour development.

  Dac EGAC50000000227

• Systematic dissection of tumor-normal single-cell ecosystems across a thousand tumors of 30 cancer types

  The complexity of the tumor microenvironment poses significant challenges in cancer therapy. Here, to comprehensively investigate the tumor-normal ecosystems, we perform an integrative analysis of 4.9 million single-cell transcriptomes from 1,070 tumor and 493 normal samples in combination with pan-cancer 137 spatial transcriptomics, 8,887 TCGA, and 1,261 checkpoint inhibitor-treated bulk tumors. We define a myriad of cell states constituting the tumor-normal ecosystems and also identify hallmark gene signatures across different cell types and organs. Our atlas characterizes distinctions between inflammatory fibroblasts marked by AKR1C1 or WNT5A in terms of cellular interactions and spatial co-localization patterns. Co-occurrence analysis reveals interferon-enriched community states including tertiary lymphoid structure (TLS) components, which exhibit differential rewiring between tumor, adjacent normal, and healthy normal tissues. The favorable response of interferon-enriched community states to immunotherapy is validated using immunotherapy-treated cancers (n=1,261) including our lung cancer cohort (n=497). Deconvolution of spatial transcriptomes discriminates TLS-enriched from non-enriched cell types among immunotherapy-favorable components. Our systematic dissection of tumor-normal ecosystems provides a deeper understanding of inter- and intra-tumoral heterogeneity.

  Study EGAS50000000324

• Exome sequencing in HIV+ Viremic Non-Progressors (VNPs) and HIV+ Progressors

  This dataset contains 184 paired fastq files sequences with Illumina NovaSeq600 from 38 participants. Relevant clinical and demographical data is also included.

  Dataset EGAD50000000111

• Germline mutations in the transcription factor IKZF5 cause thrombocytopenia.

  To identify novel causes of hereditary thrombocytopenia, we performed a genetic association analysis of whole-genome sequencing data from 13,037 individuals enrolled in the NIHR BioResource, including 233 cases with isolated thrombocytopenia. We found an association between rare variants in the transcription factor encoding gene IKZF5 and thrombocytopenia. We report five causal missense variants in or near IKZF5 zinc fingers (Znfs), of which two occurred de novo and three co-segregated in three pedigrees. A canonical DNA-Znf binding model predicts that three of the variants alter DNA recognition. Expression studies showed that chromatin binding was disrupted in mutant compared to wild-type (WT) IKZF5 and electron microscopy revealed a reduced quantity of alpha granules in normally sized platelets. Proplatelet formation (PPF) was reduced in megakaryocytes (MKs) from seven cases relative to six controls. Comparison of RNA-seq data from platelets, monocytes, neutrophils and CD4 T-cells from three cases and 14 healthy controls showed 1,194 differentially expressed genes in platelets but only four DEGs in each of the other blood cell types. In conclusion, IKZF5 is a novel transcriptional regulator of megakaryopoiesis and the eighth transcription factor associated with dominant thrombocytopenia in humans.

  Study EGAS00001003736

• TRACERx Renal 100

  Evolutionary dynamics of clear cell renal cell carcinoma (ccRCC) have not been studied prospectively or across all disease stages. Through the multi-centre prospective cohort study, Renal TRACERx Renal, we analysed 1209 primary tumour regions from 101 patients with ccRCC. We detect up to 30 driver events in a single tumour, and show that subclonal diversification is associated with known clinical parameters. Defining driver event co-occurrence, mutual exclusivity and timing at clone level, we reveal deterministic patterns of clonal evolution and disease progression. We find that ccRCC can be grouped into seven distinct evolutionary subtypes, ranging from tumours characterised by early fixation of multiple mutational and copy number driver events that can disseminate widely and rapidly; to highly branched tumours with &gt;10 subclonal drivers and extensive parallel evolution presenting with oligometastatic disease. We identify either heterogeneity or chromosome instability, or both, as determinants of patient outcome. Our insights reconcile the variable clinical behaviour of ccRCC and the benefit of surgical intervention in early and late-stage disease; and offer potential biomarker opportunities to maximise the benefit of both surgery and active surveillance.

  Study EGAS00001002793

• Multi-omics integration reveals only minor long-term molecular and functional sequelae in immune cells of individuals recovered from COVID-19

  The majority of COVID-19 patients experience mild to moderate disease course and recover within a few weeks. An increasing number of studies characterized the long-term changes in the specific anti-SARS-CoV-2 immune responses, but how COVID-19 shapes the innate and heterologous adaptive immune system after recovery is less well known. To comprehensively investigate the post-SARS-CoV-2 infection sequelae on the immune system, we performed a multi-omics study by integrating single-cell RNA-sequencing, single-cell ATAC-sequencing, genome-wide DNA methylation profiling, and functional validation experiments in convalescent COVID-19 and healthy individuals. We showed that immune responses generally recover without major sequelae after COVID-19. However, subtle differences persist at the transcriptomic level in monocytes, with downregulation of the interferon pathway, while DNA methylation also displays moderate changes in convalescent COVID-19 individuals. However, these differences did not affect the cytokine production capacity of PBMCs upon different bacterial, viral, and fungal stimuli, although baseline release of IL-1RA and IFN?? was higher in convalescent individuals. In conclusion, despite minor differences in epigenetic and transcriptional programs, the immune system of convalescent COVID-19 patients largely recovers to the homeostatic level of healthy individuals.

  Study EGAS00001005529

• RNASeq of bone marrow endothelial cells upon regeneration, (fetal) niche formation, and steady-state.

  Comprehensive transcriptional characterization of bone marrow endothelial cells by RNA sequencing was performed to determine the molecular properties/signatures of endothelium during bone marrow recovery and niche formation. Regenerative bone marrow endothelium was FACS-isolated from bone marrow aspirates of Acute Myeloid Leukemia patients 17 days after receiving chemotherapy (n=3). Niche-forming endothelial cells were FACS-isolated from fetal bones (gestational age 15-20 weeks) (n=3). Healthy adult bone marrow endothelial cells (n=7) were used as steady-state controls. cDNA was prepared using the SMARTer procedure (SMARTer Ultra Low RNA Kit, Clonetech). The provided file type is FASTQ.

  Dataset EGAD00001003904

• Genomic signatures define three subtypes of EGFR-mutant stage II-III non-small-cell lung cancer with distinct adjuvant therapy outcomes

  This dataset contains targeted sequencing data of 204 surgical samples from resected NSCLC. Genomic profiling identifies five predictive biomarkers, which is then integrated into the Multiple-gene INdex to Evaluate the Relative benefit of Various Adjuvant therapies (MINERVA) score. The MINERVA score categorizes patients into three subgroups with relative disease-free survival and overall survival benefits from either adjuvant gefitinib or chemotherapy. This study demonstrates that predictive genomic signatures could potentially stratify resected EGFR-mutant NSCLC patients and provide precise guidance towards future personalized adjuvant therapy.

  Dataset EGAD00001008157

• Transcriptomic hallmarks and RNA isoform diversity in human neurodegenerative disease

  Single-cell RNA-sequencing (scRNA-seq) has enabled high-throughput RNA analysis at an unprecedented resolution. One staple analysis in scRNA-seq is identifying differentially expressed genes (DEGs) between two populations. However, the mRNA isoforms have often been overlooked in these transcriptomic analyses due to technical limitations. In order to investigate the mRNA isoforms at the single-cell level, we used a targeted single-nucleus long-read RNA-sequencing method combining single-nucleus short-read RNA-seq (snRNA-seq), target gene enrichment, and Iso-Seq. We performed snRNA-seq and targeted single-nucleus Iso-Seq (snIso-Seq) on 25 human frontal cortices from individuals with AD, DLB, or PD, and age-matched controls. Our short-read transcriptome analysis revealed that DLB samples had more overlapping DEGs with AD than PD despite sharing pathological hallmarks with PD. We observed vast RNA isoform diversity in the 50 genes targeted, including genes that were not differentially expressed in our short-read data. We also identified several novel isoforms that are not included in the reference annotation. Our data collectively characterize the transcriptome of various neurodegenerative diseases and illuminate the mRNA isoform diversity.

  Study EGAS50000000132

• Clinical Resistance to Crenolanib in Acute Myeloid Leukemia Due to Diverse Molecular Mechanisms

  FLT3 mutations are commonly detected in Acute Myeloid Leukemia (AML) patients and are associated with poor prognosis. Crenolanib, a potent type I pan-FLT3 (GeneID:2322) inhibitor, is effective against both internal tandem duplications (ITD) and resistance-conferring tyrosine kinase domain (TKD) mutations. While crenolanib monotherapy has demonstrated significant clinical benefit in heavily pretreated relapsed/refractory AML patients, responses are transient and relapse eventually occurs. To investigate the mechanisms of crenolanib resistance, we performed whole exome sequencing of AML patient samples before and after crenolanib treatment (122 samples from 59 patients). Unlike other FLT3 inhibitors, crenolanib did not induce FLT3 activation loop mutations, and mutations of the FLT3 &#34;gatekeeper&#34; residue were infrequent. Instead, mutations of NRAS (GeneID:4893) and IDH2 (GeneID:3418) arose, mostly as FLT3-independent subclones, while TET2 (GeneID:54790) and IDH1 (GeneID:3417) predominantly co-occurred with the FLT3-mutant clone and were enriched in crenolanib poor-responders. The remaining patients exhibited post-crenolanib expansion of mutations associated with epigenetic regulators, transcription factors, and cohesion factors, suggesting diverse non-FLT3 genetic/epigenetic mechanisms of crenolanib resistance. Drug combinations in experimental models restored crenolanib sensitivity.

  Study phs001628

• Genomic Evolution of Breast Cancer Metastasis and Relapse

  Recurrent breast cancer is almost universally fatal. We characterize 170 patients locally relapsed or distant metastatic cancers using massively parallel sequencing. We identify that the relapse-seeding clone disseminates late from the primary tumor. TP53 and AKT1 appear to be enriched in ER-positive cancers predisposed to relapse. Mutation acquisition continues at relapse as the same mutation signatures continue to operate and new signatures, such as that caused by radiotherapy appear de novo. In 49% of cases we identify drivers mutations private to the relapse and these are sampled from a wider range of cancer genes, including SWI-SNF complex and JAK-STAT signaling.

  Dataset EGAD00001002696

• GDAP - Genome Diversity in Africa Project (2021-02-12)

  The Genomic Diversity in Africa Project (GDAP) started with the plan to develop a genomic resource from African populations, characterise genomic diversity and population history, and facilitate clinical studies in Africa. Currently, 25 individuals from 24 ethnolinguistic groups have been whole-genome sequenced at high depth totalling 585 individuals. An additional 41 individuals have been sequenced with 10X Genomics libraries. At this stage, the initial curation of this dataset has been finished and we are performing the analysis in coordination with our collaborators. The current state of the GDAP represents a very diverse panel of African populations that maximizes geographical and ethnic variation and represents a great starting point to achieve the aforementioned goals. However, southern sub-Saharan countries, Bantu speakers and hunter gatherer groups are currently underrepresented, despite being crucial to understand the evolutionary history of the continent. After extensive effort to collate studies documentation, we finally have the opportunity to sequence 600 new individuals from these groups, including countries as Gabon, Rwanda and Zambia, and address these deficiencies. We aim to proceed with the same strategy: to sequence at high depth 25 individuals with standard PCR free libraries, with 2 additional individuals with 10X Genomics Chromium libraries per ethnolinguistic group. The former allows a good representation of variants down to low frequency in any given population, and the latter allows accurate phasing and the analysis of structural variation. By including these new populations, we want to investigate three crucial questions in African history in addition to the initial objectives: the Bantu expansion, the evolutionary history of hunter gatherers and the transatlantic slave trade. Additionally, the expanded dataset will help us better discover the genetic variation present in Africa and characterize the African pangenome. 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/ . This dataset contains all the data available for this study on 2021-02-12.

  Dataset EGAD00001006965

• Identification of the Global miR-130a Targetome Reveals a Novel Role for TBL1XR1 in Hematopoietic Stem Cell Self-Renewal and t(8;21) AML

  In this study, we identified miR-130a as a regulator of HSC self-renewal and differentiation. To characterize gene expression changes following enforced expression of miR-130a OE, we performed RNA-seq in CD34+ cord blood (CB) cells transduced with control and miR-130a OE lentiviruses. To capture miRNA targets in an unbiased, transcriptome-wide manner, we perfomed enhanced CLIPseq procol in 2 replicates of CD34+ CB cells and Kasumi-1 cell line, which represent a model system for t(8;21) AML. We chose this cell line, as we found miR-130a to be highly expressed in this AML subtype where it is critical for maintaining the oncogenic molecular program mediated by AML1-ETO. Chimeric Ago2 eCLIPseq in CD34+ CB cells combined with Mass Spectrometry data analysis identified TBL1XR1 as a principal target of miR-130a. To elucidate gene expression changes associated with TBL1XR1 loss of function, we performed RNA-seq in CD34+CD38- CB cells transduced with control and shRNA targeted against TBL1XR1. To determine the functional significance of high miR-130a expression levels in Kasumi-1 cells on the molecular network controlled by AML1-ETO, we performed CUT&amp;RUN assay and RNA-seq in Kasumi-1 cells following miR-130a knock-down (KD). Collectively, our findings reveal a unique role of miR-130a in regulating normal hematopoietic stem cell self-renewal and how elevated levels of miR-130a in t(8;21) AML contribute to the leukemogenesis of this AML subtype.

  Dataset EGAD00001008412

• IG-MYC ALL - DNA and RNA sequencing

  The dataset is composed by the raw RNA sequencing (n=6), targeted DNA sequencing (n=18) and whole exome sequencing (n=17) from 19 patients with IG-MYC-rearrangements.

  Dataset EGAD00001008705