3901 results for "*geneti*"

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• Host pathogen interaction long read transcriptome

  Our incomplete knowledge of the human transcriptome impairs the detection of disease-causing variants, in particular in transcripts only expressed under certain conditions. These transcripts are often lacking from reference transcript sets, such as Ensembl/GENCODE and RefSeq, and could be relevant for establishing genetic diagnoses. We present SUsPECT (Solving Unsolved Patient Exomes/gEnomes using Custom Transcriptomes), a pipeline based on the Ensembl Variant Effect Predictor (VEP) to predict variant impact on custom transcript sets, such as those generated by long-read RNA-sequencing, for downstream prioritization. Our pipeline predicts the functional consequence and likely deleteriousness scores for missense variants in the context of novel open reading frames predicted from any transcriptome. We demonstrate the utility of SUsPECT by uncovering potential mutational mechanisms of pathogenic variants in ClinVar that are predicted to be benign using the reference transcript annotation. In further support of SUsPECT’s utility, we identified an enrichment of immune-related variants predicted to have a more severe molecular consequence when annotating with a newly generated transcriptome from stimulated immune cells instead of the reference transcriptome. Our pipeline outputs crucial information for further prioritization of potentially disease-causing variants for any disease and will become increasingly useful as more long-read RNA sequencing datasets become available.

  Study EGAS00001006779

• Genomic_characterisation_of_MGUS__

  he hematological malignancy multiple myeloma (MM), also called Kahler’s disease or plasma cell (PC) myeloma, is characterized by a clonal expansion of PCs originating in the bone marrow (BM). The expansion of these cells leads to an overproduction of antibodies and results in typical symptoms such as anemia, renal failure and bone lesions. All cases of MM are preceded by the asymptomatic, non-malignant pre-stage monoclonal gammopathy of undetermined significance (MGUS). Of all MGUS patients, only 1% per year will progress to MM. Despite efforts to elucidate the molecular mechanisms underlying the MGUS-to-MM progression, its pathogenesis still remains largely unknown. Additionally, the genetic profiles of MGUS patients have only been limitedly investigated due to the only incidental finding of MGUS, the difficulties in BM sampling and isolating a sufficient number of aberrant PCs from the BM aspirates of MGUS patients. Consequently, reliable biomarkers to individually predict which MGUS patients will progress to MM and which will not, are lacking. Therefore, it is highly required to study the molecular pathogenesis of MGUS and the role of genetic events in relation to the malignant transformation to MM.

  Study EGAS00001004124

• DNA methylation-based classification of sinonasal tumors [Proteomics data]

  The diagnosis of sinonasal tumors is challenging due to a heterogeneous spectrum of various differential diagnoses as well as poorly defined, disputed entities such as sinonasal undifferentiated carcinomas (SNUCs). In this study, we apply a machine learning algorithm based on DNA methylation patterns to classify sinonasal tumors with clinical-grade reliability. We further show that sinonasal tumors with SNUC morphology are not as undifferentiated as their current terminology suggests but rather reassigned to four distinct molecular classes defined by epigenetic, mutational and proteomic profiles. This includes two classes with neuroendocrine differentiation, characterized by IDH2 or SMARCA4/ARID1A mutations with an overall favorable clinical course, one class composed of highly aggressive SMARCB1-deficient carcinomas and another class with tumors that represent previously misclassified adenoid cystic carcinomas. The repository includes the raw mass spectrometry-based proteomics data

  Study EGAS00001006712

• High-throughput telomere length measurement at nucleotide resolution using the PacBio high fidelity sequencing platform, P49-P104 and run1 replicates

  Telomeres are specialized nucleoprotein structures at the ends of linear chromosomes that are essential for the stability as well as the complete replication of the human genome. The progressive shortening of steady-state telomere length in normal human somatic cells is a promising biomarker for age-associated diseases. However, there remain substantial challenges in quantifying telomere length in clinics and research laboratories due to the lack of accurate and high-throughput telomere length measurement method. Here, we describe a novel workflow to capture and analyze telomeres accurately at the single-nucleotide resolution. By using newly designed telobaits that are complementary to the single-stranded G-rich 3’ telomeric overhangs, we can specifically and efficiently capture full-length telomeres and subject them to single-molecule real-time (SMRT) sequencing. We show that the telomere length can be measured at nucleotide resolution using the PacBio high fidelity (HiFi) sequencing platform, which provides the necessary accuracy and throughput to uncover the steady-state telomere length distribution in human culture cell lines as well as clinical patient samples. This new method is a valuable tool not only in population-wide epidemiology studies but also for the longitudinal assessment of telomere attrition in individuals. Our results also reveal the extreme heterogeneity of telomeric variant sequences (TVSs) that is dispersed throughout the telomere repeat region. Importantly, the unique distribution pattern and sequence of TVSs in individuals may be used as a fingerprint for sample identification. In addition, the presence of TVSs disrupts the continuity of the canonical (5’-TTAGGG-3’)n telomere repeats, which could affect the binding of shelterin complexes at the chromosomal ends. Therefore, TVSs may act as a form of genetic polymorphisms that impairs telomere protection. Together with the absolute telomere length in each individual, TVSs may have profound implications in human aging and diseases.

  Study EGAS00001006595

• single-stranded DNA study

  A ssDNA library protocol was applied to cfDNA from plasma samples obtained from different DNA extraction methods and revealed significant differences in DNA fragmentation patterns in comparison to dsDNA-based protocols. In particular, a specific combination of methods revealed a population of ultrashort fragments, organized at ~50 bp. We observed significant differences in the relative abundance of these ultrashort DNA fragments in plasma from healthy individuals and cancer patients. Through shallow whole genome sequencing (sWGS, <0.5-fold coverage) and the analysis of somatic copy number aberrations (SCNA), we determined the landscape of genetic alterations in this newly identified population of cfDNA fragments. In addition, we studied their potential link with regulatory regions by investigating the genome-wide coverage patterns at transcription start sites (TSS). Furthermore, we demonstrated that the ultrashort cfDNA fragments map to regions associated with secondary DNA structures, G-quadruplexes (G4s).

  Study EGAS00001005093

• Whole exome sequencing identifies clinically relevant mutational signatures in resected hepatocellular carcinoma

  We conducted a multicentre pilot study on patients with localized HCC following complete radiological response to surgical resection. Patients received 250 mg oral gefitinib once daily as adjuvant therapy, up to a maximum of 6 months. The clinical endpoints included recurrence-free survival (RFS) and overall survival (OS), and correlative genetic analyses were conducted from whole exome sequencing data (n=33). All statistical analyses were carried out on an intention-to-treat basis. The study is registered with ClinicalTrials.gov (NCT00282100).

  Study EGAS00001004371

• Long-read sequencing of diagnosis and post-therapy medulloblastoma reveals complex rearrangement patterns and epigenetic signatures (Hipo_021)

  Cancer genomes harbor a broad spectrum of structural variants (SV) driving tumorigenesis, a relevant subset of which escape discovery using short-read sequencing. We employed Oxford Nanopore Technologies (ONT) long-read sequencing in a paired diagnostic and post- therapy medulloblastoma to unravel the haplotype-resolved somatic genetic and epigenetic landscape. We assemble complex rearrangements and such associated with telomeric sequences, including a 1.55 Megabasepair chromothripsis event. We uncover a complex SV pattern termed ‘templated insertion thread’ (TI thread), characterized by short (mostly <1kb) insertions showing prevalent self-concatenation into highly amplified structures of up to 50kbp in size. TI threads occur in 3% of cancers, with a prevalence ranging to 74% in liposarcoma, and frequent colocalization with chromothripsis. We also perform long-read based methylome profiling and discover allele-specific methylation (ASM) effects, complex rearrangements exhibiting differential methylation, and differential promoter methylation in cancer-driver genes. Our study shows the advantage of long-read sequencing in the discovery and characterization of complex somatic rearrangements.

  Study EGAS00001006629

• The Genetic Landscape of Ocular Adnexa MALT Lymphoma Reveals Frequent Aberrations in NFAT and MEF2B Signaling Pathways

  A comprehensive constellation of somatic non-silent mutations and copy number (CN) variations in ocular adnexa marginal zone lymphoma (OAMZL) is unknown. By utilizing whole-exome sequencing in 69 tumors we define the genetic landscape of OAMZL. Mutations and CN changes in CABIN1 (30%), RHOA (26%), TBL1XR1 (22%), and CREBBP (17%) and inactivation of TNFAIP3 (26%) were among the most common aberrations. Candidate cancer driver genes cluster in the B-cell receptor (BCR), NFkB, NOTCH and NFAT signaling pathways. One of the most commonly altered genes is CABIN1, a calcineurin inhibitor acting as a negative regulator of the NFAT and MEF2B transcriptional activity. CABIN1 deletions enhance BCR-stimulated NFAT and MEF2B transcriptional activity, while CABIN1 mutations enhance only MEF2B transcriptional activity by impairing binding of mSin3a to CABIN1. Our data provide an unbiased identification of genetically altered genes that may play a role in the molecular pathogenesis of OAMZL and serve as therapeutic targets.

  Study EGAS00001006631

• Search for genetic variants influencing gestational weight gain in type 1 diabetes patients by genome wide association method

  Clinical data suggest that BMI and gestational weight gain (GWG) are strongly interconnected phenotypes, however the genetic basis of the latter is rather unclear. Here we aim to investigate the genetic factors associated with GWG from the perspective of the genetics of obesity.

  Study EGAS00001004408

• Nasal epithelial cells of PCD and non-PCD patients grown at air-liquid interface for RNAseq analysis

  Raw RNAseq data files of genetically unsolved PCD patients used for transcriptomic analysis aming to uplift the diagnostic rate. The non-PCD patients were used as a clinical comparator to the PCD patients. Majority of the nasal epithelial cells used for RNAseq were cultured at an air-liquid interface for 21 days, unless the data file name indicates a different air-liquid-culture time-point.

  Study EGAS00001006632

• H3Africa - Trauma And Neurobiology: Maternal stress and transgenerational impact. Search for Epigenetic Markers

  This project aims to characterize the transgenerational genomic impact of genocide exposure and post-traumatic stress disorder (PTSD) in women survivors of the Rwandan genocide and their offspring.

  Study EGAS00001006645

• Gene copy number variation in pediatric mental illness in a general population

  We assessed the relationship of gene copy number variation (CNV) in mental health/neurodevelopmental traits and diagnoses, physical health, and cognitive biomarkers in a community sample of 7,100 unrelated European, and East Asian children and youth (Spit for Science). Diagnoses of mental health disorders were found in 17.5% of participants and 27.6% scored in the highest 10% on either or both ADHD and OCD trait measures. Clinically relevant CNVs were present in 3.9% of participants and were associated with elevated scores on a continuous measure of ADHD (p=5.0×10-3), on a cognitive biomarker of mental health (response inhibition (p=1.0×10-2)), and on prevalence of mental disorders (p=1.9×10-6, odds ratio: 3.09). With a rise of mental illness, our data establishes a baseline for delineating genetic contributors in paediatric-onset conditions.

  Study EGAS00001006659

• DNA methylation landscape of prostate cancer

  Metastases from primary prostate cancers to rare locations, such as the brain, are becoming more common due to longer life expectancy thanks to improved treatments. Epigenetic dysregulation is a feature of primary prostate cancer, and distinct DNA methylation profiles are associated with the mutually exclusive SPOP mutant or TMPRSS2-ERG fusion genetic backgrounds. Using a cohort of 42 patients with prostate cancer brain metastases (PCBM), with matched primary samples available for 17 patients, we carried out DNA methylation analysis using Illumina EPIC array. We examined the epigenetic distinction between primary PCa and PCBM, the association between epigenetic alterations and mutational background, and particular epigenetic alterations that may be associated with PCBM in particular. Multiregion sampling of PCBM revealed epigenetic heterogeneity in metastases. We found aberrant methylation in PCBM is associated with mutational background, PRC2 complex activity and upregulation of EZH2, an effect that is particularly pronounced in SPOP mutant PCBM. While we detected a hypermethylator phenotype in PCBM, we also observed hypomethylation occurring at the promoters of genes involved in neuroactive ligand-receptor interactions or the calcium signalling pathway, such as GABRB3 and GRM5, a change not observed in non-brain prostate cancer metastases.

  Study EGAS00001006670

• Follicular lymphoma at diagnosis, treated in first line with immunochemotherapy

  We performed targeted NGS in Follicular lymphoma samples at diagnosis. Explored clinico-genetic correlations and assessed four clinical or clinicogenetic risk models (FLIPI, FLIPI-2, PRIMA-IP or m7-FLIPI-molecular score) in patients with symptomatic FL who received frontline immunochemotherapy. Out of 191 patients with FL grade 1-3a, 109 were successfully genotyped. Treatment consisted on rituximab (R) plus CVP/CHOP (72.5%) or R-bendamustine (R-B) (27.5%).

  Study EGAS00001006674

• DERMATLAS__Tubular_adenoma_RNAseq

  IVirtually 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 previoulsy, 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. The cases in this cohort are tubular adenomas.

  Study EGAS00001006685

• Pre-neoplastic liver colonization by 11p15.5 altered mosaic cells in young children with hepatoblastoma

  In children, liver tumors are a heterogeneous group representing 1-2% of all cancers with the most common diagnosis being hepatoblastoma (HB). While HBs are predominantly sporadic, around 15% of cases develop as part of predisposition syndromes such as familial adenomatous polyposis (APC mutation) or Beckwith-Wiedemann (BWS; 11p15.5 locus altered). Here, we identified a mosaic genetic alteration of 11p15.5 locus in the liver in 17% of HB patients without a clinical diagnosis of BWS syndrome. These mosaic 11p15.5 alterations were never found in children with other types of liver tumor (hepatocellular carcinoma or adenoma, fibrolamellar carcinoma). Bulk transcriptomic analysis revealed the abundance of extracellular matrix, angiogenesis, and progenitor gene signatures in mosaic livers. In situ hybridization assay RNAscope allowed for the detection of 11p15.5 altered hepatocytes mosaicism in liver FFPE sections of HB patients presenting IGF2 overexpression and H19 downregulation together with an alteration of the zonal architecture of the liver. Spatial transcriptomics analysis revealed an overexpression of the IGF2 pathway, lipogenesis, and platelet activation in 11p15.5 altered hepatocytes. These data provide insights for 11p15.5 mosaicism detection as well as functional consequences of these alterations during the early steps of carcinogenesis.

  Study EGAS00001006692

• Hexanucleotide repeat expansions in C9orf72 alter microglial responses and prevent a coordinated glial reaction in ALS

  Neuroinflammation is an important hallmark in amyotrophic lateral sclerosis (ALS). Experimental evidence has highlighted a role of microglia in the modulation of motor neuron degeneration. However, the exact contribution of microglia to both sporadic and genetic forms of ALS is still unclear. We generated single nuclei profiles of spinal cord and motor cortex from sporadic and C9orf72 ALS patients, as well as controls. We particularly focused on the transcriptomic responses of both microglia and astrocytes. We confirmed that C9orf72 is highly expressed in microglia and shows a diminished expression in carriers of the hexanucleotide repeat expansion (HRE). This resulted in an impaired response to disease, with specific deficits in phagocytic and lysosomal transcriptional pathways. Astrocytes also displayed a dysregulated response in C9orf72 ALS patients, remaining in a homeostatic state. This suggests that C9orf72 HRE alters a coordinated glial response, which ultimately would increase the risk for developing ALS. Our results indicate that C9orf72 HRE results in a selective microglial loss-of-function, likely impairing microglial-astrocyte communication and preventing a global glial response. This is relevant as it indicates that sporadic and familial forms of ALS may present a different cellular substrate, which is of great importance for patient stratification and treatment.

  Study EGAS00001006711

• DNA methylation-based classification of sinonasal tumors [DNA sequencing]

  The diagnosis of sinonasal tumors is challenging due to a heterogeneous spectrum of various differential diagnoses as well as poorly defined, disputed entities such as sinonasal undifferentiated carcinomas (SNUCs). In this study, we apply a machine learning algorithm based on DNA methylation patterns to classify sinonasal tumors with clinical-grade reliability. We further show that sinonasal tumors with SNUC morphology are not as undifferentiated as their current terminology suggests but rather reassigned to four distinct molecular classes defined by epigenetic, mutational and proteomic profiles. This includes two classes with neuroendocrine differentiation, characterized by IDH2 or SMARCA4/ARID1A mutations with an overall favorable clinical course, one class composed of highly aggressive SMARCB1-deficient carcinomas and another class with tumors that represent previously misclassified adenoid cystic carcinomas. This repository includes the results from DNA sequencing and mass spectrometry-based proteomics.

  Study EGAS00001006713

• Chromatin landscape of medulloblastoma reveals context dependent driver

  In this study, we defined subgroup specific chromatin landscape (H3K27ac, H3K27me3, RNA-Seq, 27ac hichip, WGS) of medulloblastoma to identify pathogenic epigenetic alterations that regulate expression of a context dependent driver gene.

  Study EGAS00001006741

• The Iberian Roma genetic variant server

  The Roma are the most numerous ethnic minority in Europe. The Iberian Roma arrived in the Iberian Peninsula five centuries ago and still today, they keep a strong group identity. Demographic and cultural reasons lie behind a high rate of Mendelian disease often related to founder variants. We have analysed exome data from 119 Iberian Roma individuals collected from 2018 to 2020. A database of variant frequency has been implemented (IRPVS) and made available online. We have analysed the carrier rate of founder private alleles as well as pathogenic variants present in the general population. Significant enrichment in structural variants involving gene clusters related to keratinization and epidermal growth suggest that evolutive mechanisms have developed towards climate and environmental adaptation. IRPVS can be accessed at http://irpvs.clinbioinfosspa.es/

  Study EGAS00001006758

• Erythroid/megakaryocytic differentiation confers BCL-XL dependency and venetoclax resistance in acute myeloid leukemia

  Myeloid neoplasms with erythroid or megakaryocytic differentiation include pure erythroid leukemia (PEL), myelodysplastic syndrome (MDS) with erythroid features, and acute megakaryoblastic leukemia (FAB M7) and are characterized by poor prognosis and limited treatment options. Here, we investigate the drug sensitivity landscape of these rare malignancies. We show that acute myeloid leukemia (AML) cells with erythroid or megakaryocytic differentiation depend on the anti-apoptotic protein BCL-XL, rather than BCL-2, using combined ex vivo drug sensitivity testing, genetic perturbation, and transcriptomic profiling. Single-cell and bulk transcriptomics of patient samples with erythroid and megakaryoblastic leukemias identified high BCL2L1 expression compared to other subtypes of AML and other hematological malignancies, where BCL2 and MCL1 were more prominent. Our results suggest targeting BCL-XL as a potential therapy option in erythroid/megakaryoblastic leukemias and highlight an AML subgroup with potentially reduced sensitivity to venetoclax-based treatments.

  Study EGAS00001006819

• Molecular heterogeneity and commonalities in pancreatic cancer precursors with gastric and intestinal phenotype

  Due to the limited number of modifiable risk factors, secondary prevention strategies based on early diagnosis represent the preferred route to improve the prognosis of pancreatic ductal adenocarcinoma (PDAC). Here, we provide a comparative morphogenetic analysis of PDAC precursors aiming at dissecting the process of carcinogenesis and tackling the heterogeneity of preinvasive lesions.

  Study EGAS00001006793

• Exome sequencing of HCV+ lymphoma

  The present retrospective study aimed to explore the genetic landscape of a well-characterized series of 34 HCV-associated B-cell lymphomas from the observational multicentric ANRS HC-13 Lympho-C Study using tumor and matched germline whole exome sequencing (WES). It reported the first series of VHC-positive lymphoma patients analyzed by WES. Our results provide an overview of the genetic landscape associated to HCV-related B-cell lymphomas and highlight some novel putative candidate genes.

  Study EGAS00001006860

• Atypical teratoid/rhabdoid tumoroids reveal subgroup-specific drug vulnerabilities WGS

  Atypical teratoid/rhabdoid tumors (ATRTs) represent a rare, but aggressive pediatric brain tumor entity. They are genetically uniquely defined by alterations in the SWI/SNF chromatin remodeling complex members SMARCB1 or SMARCA4. ATRTs can be further classified in different molecular subgroups based on their epigenetic profiles. Although recent studies suggest that the different subgroups have distinct clinical features, subgroup-specific treatment regimens have not been developed thus far. This is hampered by the lack of pre-clinical in vitro models representative of the different molecular subgroups. Here, we describe the establishment of ATRT tumoroid models from the ATRT-MYC and ATRT-SHH subgroups. We demonstrate that ATRT tumoroids retain subgroup-specific epigenetic and gene expression profiles. High throughput drug screens on our ATRT tumoroids revealed distinct drug sensitivities between and within ATRT-MYC and ATRT-SHH subgroups. Whereas ATRT-MYC universally displayed high sensitivity to multi-targeted tyrosine kinase inhibitors, ATRT-SHH showed a more heterogeneous response with a subset showing high sensitivity to Notch inhibitors, which corresponded to high expression of Notch receptors. Our ATRT tumoroids represent the first pediatric brain tumor organoid model, providing a representative pre-clinical model which enables the development of subgroup-specific therapies.

  Study EGAS00001006865

• Atypical teratoid/rhabdoid tumoroids reveal subgroup-specific drug vulnerabilities RNA-Seq

  Atypical teratoid/rhabdoid tumors (ATRTs) represent a rare, but aggressive pediatric brain tumor entity. They are genetically uniquely defined by alterations in the SWI/SNF chromatin remodeling complex members SMARCB1 or SMARCA4. ATRTs can be further classified in different molecular subgroups based on their epigenetic profiles. Although recent studies suggest that the different subgroups have distinct clinical features, subgroup-specific treatment regimens have not been developed thus far. This is hampered by the lack of pre-clinical in vitro models representative of the different molecular subgroups. Here, we describe the establishment of ATRT tumoroid models from the ATRT-MYC and ATRT-SHH subgroups. We demonstrate that ATRT tumoroids retain subgroup-specific epigenetic and gene expression profiles. High throughput drug screens on our ATRT tumoroids revealed distinct drug sensitivities between and within ATRT-MYC and ATRT-SHH subgroups. Whereas ATRT-MYC universally displayed high sensitivity to multi-targeted tyrosine kinase inhibitors, ATRT-SHH showed a more heterogeneous response with a subset showing high sensitivity to Notch inhibitors, which corresponded to high expression of Notch receptors. Our ATRT tumoroids represent the first pediatric brain tumor organoid model, providing a representative pre-clinical model which enables the development of subgroup-specific therapies.

  Study EGAS00001006866

• Population_based_analysis_of_POT1_variants_in_a_cutaneous_melanoma_case_control_cohort

  Pathogenic germline variants in the protection of telomeres 1 gene (POT1) have been associated with predisposition to a range of tumor types, including melanoma, glioma, leukemia and cardioangiosarcoma. We sequenced all coding exons of the POT1 gene in 2,929 European-descent melanoma cases and 3,298 controls, identifying 43 protein-changing genetic variants. We performed functional studies on each of these variants and explored their possible contribution to disease risk.

  Study EGAS00001006870

• Atypical teratoid/rhabdoid tumoroids reveal subgroup-specific drug vulnerabilities DNA-Methylation

  Atypical teratoid/rhabdoid tumors (ATRTs) represent a rare, but aggressive pediatric brain tumor entity. They are genetically uniquely defined by alterations in the SWI/SNF chromatin remodeling complex members SMARCB1 or SMARCA4. ATRTs can be further classified in different molecular subgroups based on their epigenetic profiles. Although recent studies suggest that the different subgroups have distinct clinical features, subgroup-specific treatment regimens have not been developed thus far. This is hampered by the lack of pre-clinical in vitro models representative of the different molecular subgroups. Here, we describe the establishment of ATRT tumoroid models from the ATRT-MYC and ATRT-SHH subgroups. We demonstrate that ATRT tumoroids retain subgroup-specific epigenetic and gene expression profiles. High throughput drug screens on our ATRT tumoroids revealed distinct drug sensitivities between and within ATRT-MYC and ATRT-SHH subgroups. Whereas ATRT-MYC universally displayed high sensitivity to multi-targeted tyrosine kinase inhibitors, ATRT-SHH showed a more heterogeneous response with a subset showing high sensitivity to Notch inhibitors, which corresponded to high expression of Notch receptors. Our ATRT tumoroids represent the first pediatric brain tumor organoid model, providing a representative pre-clinical model which enables the development of subgroup-specific therapies.

  Study EGAS00001006881

• Separation of chronic myeloid leukemia stem cells from normal hematopoietic stem cells at single-cell resolution

  Chronic myeloid leukemia (CML) is a clonal disease, initiated and sustained by a subpopulation of CML stem cells (CML-SC) containing the BCR::ABL1 oncogene. Genetic markers that enrich for CML-SC have been identified, including CD26 being most specific. Genome sequencing analysis remain yet to be performed at single cell level in order to determine differences and heterogeneity in the genetic profile of CML-SC versus normal hematopoietic stem cells (HSC). Here we show that CD26 and CD33 separate CML-SC from normal HSC in freshly isolated bone marrow samples from newly diagnosed CML patients. DNA sequencing confirms that single CML-SC derived colonies are positive for BCR::ABL1 and harbor a recurrent set of patient-specific clonal somatic mutations across different CML-SC derived colonies. In contrast, marker-negative (CD26-CD33-) HSC from the same patients are negative for the BCR::ABL1 oncogene and do not carry recurrent, clonal mutation across different colonies. These results support the concept that CD26/CD33 expression separates genetically defined, clonal mutant CML-SC from normal HSC that carry individual sets of random mutations in CML patients. We provide whole exome DNA sequencing data for 23 clinical samples of CML-SC plus two buccal swipes derived normal samples. CML samples are comprised of 4 to 8 replicates from two patients, at diagnosis and after treatment. Single CML stem cells before treatment and single non-transformed HSC at remission were selected from bone marrow samples by FACS, according to genetic markers CD33+CD26+ at diagnosis and CD33+CD26-/CD33-CD26- at remission. WES libraries of colony forming assays derived CML-SC and HSC populations were prepared using Agilent SureSelect Human All Exon V6 kit and sequenced running 150 cycles (2x 75bp paired-end) on an Illumina NextSeq 500 platform. Following GATK best practices for somatic mutation calling, novel CML variants and random mutation events during remission phase were obtained.

  Study EGAS00001006904

• Multiome_HB

  Hepatoblastoma (HB) cells display strong phenotypic heterogeneity with a major impact on drug response, but the underlying mechanisms are poorly understood. Here, we use a single-cell multi-omic strategy to unravel the molecular determinants of this plasticity. HB display a continuum of single-cell states between hepatocytic (scH), liver progenitor (scLP) and mesenchymal (scM) differentiation poles, with an intermediate scH/LP population bordering scLP and scH areas in spatial transcriptomics. Chromatin accessibility landscapes reveal the gene regulatory networks of each differentiation pole, and the sequence of transcription factor activation underlying cell state transitions. Single-cell mapping of somatic alterations reveals the clonal architecture of each tumor, showing that each genetic subclone displays its own range of cellular plasticity across differentiation poles. The most scLP subclones, overexpressing stem cell and DNA repair genes, proliferate faster after neo-adjuvant chemotherapy. These results highlight how the interplay of clonal evolution and epigenetic plasticity shapes the potential of HB subclones to respond to chemotherapy.

  Study EGAS00001006932

• CYP2C19 long-read sequencing

  Inter-individual differences in drug response based on genetic variations can lead to drug toxicity and treatment inefficacy. A large part of this variability is caused by genetic variants in pharmacogenes. Unfortunately, the Single Nucleotide Variant (SNV) panels currently used in clinical pharmacogenomic (PGx) testing are unable to detect all genetic variability in these genes. Long-read sequencing, on the other hand, has been shown to be able to resolve complex (pharmaco)genes. In this study we have assessed the added value of long-read sequencing for PGx focusing on the clinically important and highly polymorphic CYP2C19 gene. With a capture-based long-read sequencing panel we were able to characterize the entire region and assign variants to their allele of origin (phasing), resulting in the identification of 813 unique variants in 37 samples. To assess the clinical utility of this data we have compared the performance of three different *-allele tools (Aldy, PharmCat and PharmaKU) which are specifically designed to assign clinical haplotypes to pharmacogenes based on all input variants. We conclude that long-read sequencing can improve our ability to characterize the CYP2C19 locus, help to identify novel haplotypes and that *-allele tools are an useful asset in phenotype prediction. Ultimately, this approach could help to better predict an individual’s drug response and improve therapy outcomes.

  Study EGAS00001006929

• Feasibility of Ultra-Rapid Exome Sequencing in Critically Ill Infants and Children With Suspected Monogenic Conditions in the Australian Public Health Care System

  Critically ill infants and children with suspected monogenic conditions underwent ultra-rapid whole exome genetic testing. A molecular diagnosis was established in 51% of the patients. This study suggests feasibility of ultra-rapid genomic testing in critically ill pediatric patients.

  Study EGAS00001005430

• Genotype data from 'Dense sampling of ethnic groups within African countries reveals fine-scale genetic structure and extensive historical admixture.'

  Previous studies have highlighted how African genomes have been shaped by a complex series of historical events. Despite this, genome-wide data has only been obtained from a small proportion of present-day ethnolinguistic groups. By analysing new autosomal genetic variation data of 1333 individuals from over 150 ethnic groups from Cameroon, Republic of the Congo, Ghana, Nigeria and Sudan, we demonstrate a previously underappreciated fine-scale level of genetic structure within these countries, for example correlating with historical polities in western Cameroon. By comparing genetic variation patterns among populations, we infer that many northern Cameroonian and Sudanese groups share genetic links with multiple geographically disparate populations, likely resulting from long-distance migrations. In Ghana and Nigeria, we infer signatures of intermixing dated to over 2000 years ago, corresponding to reports of environmental transformations possibly related to climate change. We also infer recent intermixing signals in multiple African populations, including Congolese, that likely relates to the expansions of Bantu language-speaking peoples.

  Study EGAS00001006944

• Comprehensive epigenomic profiling reveals the extent of disease-specific chromatin states and informs drug target discovery in ankylosing spondylitis

  Ankylosing spondylitis (AS) is a common, highly heritable inflammatory arthritis characterised by enthesitis of the spine and sacroiliac joints. Genome-wide association studies have revealed >100 genetic associations but their functional effects remain largely unresolved. Here, we present a comprehensive transcriptomic and epigenomic map of disease-relevant blood immune cell subsets from AS patients and healthy controls. We report differential disease signatures for specific genomic regions from individual -omic modalities and multi-omic integration, showing enrichment at genetically associated loci and evidence for altered monocyte function in AS. We link putative functional SNPs with cognate genes using high-resolution Capture-C at 10 loci, including PTGER4 and ETS1. We also show how disease-specific functional genomic data can be integrated with GWAS evidence to enhance therapeutic target discovery. This study combines multiple epigenetic and transcriptional analysis with GWAS to identify cell types, candidate drug target genes and transcriptional regulation of likely pathogenic relevance.

  Study EGAS00001006945

• The multifaceted genomic history of Ashaninka from Amazonian Peru

  Genome-wide profiles of Ashaninkas from Peruvian Amazonia reveal two genetic subgroups. Ashaninka ancestors derived from a south-north migration from southeastern South America. The Ashaninka1 subgroup testifies to an Arawakan-Caribbean genetic link in the Early Ceramic Age. The Ashaninka2 subgroup had recent interactions with Andean and Pacific Indigenous populations.

  Study EGAS00001006958

• HSP90 inhibitor resistant cell line

  Genetic analysis of K562 cell which are resistant against HSP90 inhibitors.

  Study EGAS00001006381

• After the completion of CINECA, EUCANCan, and euCanSHare. What's next?

  CINECA, EUCANCan, and euCanSHare were part of the EUCAN Cluster, made up of six projects that received funding under the same Horizon 2020 call. All EUCAN projects (CINECA, EUCANCan, EUCAN-Connect, euCanSHare, Receptor Plus, and ReCoDID) were aimed at facilitating data reuse and knowledge discovery by enhancing data exchange and long-term collaboration in the health field. Here are some highlights about EGA’s contribution to these projects. CINECA: advances in Federated discovery and infrastructure for cohorts CINECA (Common Infrastructure for National Cohorts in Europe, Canada, and Africa) developed a federated cloud-based infrastructure for making genomic and biomolecular data accessible. The project has assembled a virtual cohort of 1.4 million individuals from sources such as the EGA, CanDIG and H3Africa. The EGA–CRG co-leaded a work package Work Package 1 on Federated Data Discovery and Querying. Beacon v2, championed by Jordi Rambla and Lauren Fromont, has been one of the central elements for the discovery of human genetic and phenotypic data. The EGA-CRG contributed to the development of a model for cohort discovery inside the Beacon v2 model. The team also delivered a Discovery Portal was implemented to explore cohorts and individuals of synthetic data. It is a UI that gathers a network of Beacons, a service for query expansion, and a visualisation tool. Have a look at the Discovery Portal UI, gathering a network of Beacons. You will find entities such as the Barcelona Supercomputing Center (BSC), BioData.pt and the European Genomic Data Infrastructure (GDI), among others. euCanSHare: facilitation of data access management This joint EU-Canada project aimed to build a European and Canadian FAIR platform for cardiovascular data sharing and analysis. The EGA’s tasks contributed to the development of the data management plan and data flows, main web-portal and interoperability protocols. An important part of the EuCanShare platform is the data access manager, a tool for the data owners to control the access to their sensitive datasets. We built a user-friendly interface for data access committees (data owners) to easily manage their data requests and access credentials. The data access portal facilitates the creation and internal organization of the data access committees as well as the linkage of data usage conditions to specific datasets. The interface includes filters for browsing requests and page to visualize the request history helping with the handling of data access requests. EUCANCan: toward a federation of clinical institutions in oncology The EUropean-CAnadian CANcer Network worked towards building a federated network to advance personalized medicine in oncology, by promoting the standard analysis, management and sharing of harmonized genomic and phenotypic data. The EGA led tasks on defining data flows and preparing an adapted infrastructure for long-term data storage and sharing. One of the key contributions was the conception of the EGA communities, offering standard and interoperable solutions for data discovery, processing, and sharing to projects and institutions that would like to manage and share data in the context of the EGA ecosystem. What's Next? The participation in projects such as CINECA, EUCANCan, and euCanSHare provide us with experience for future projects. We are happy to enhance data sharing and reuse, vital for advancing clinical and genomic research. The Discovery Portal is a wonderful proof of concept for the Beacon network. Next, we will finalise both the network and the user interface, and make sure it can be applied to more clinically-centred settings like hospitals. Most data hosted at the EGA are about cancer research. Currently, we contribute to building tools and infrastructure to empower oncology research in several European projects such as EUCAIM, EUCANIMAGE and EOSC4Cancer. We also do not lose sight of initiatives in the field such as the International Cancer Genome Consortium (ICGC) with the project ARGO, whose data model was adopted in EUCanCan.

  Blog cineca-eucancan-and-eucanshare-were-concluded-in-june

• The EGA at the International Congress of Human Genetics

  Today is the start of the International Congress of Human Genetics (ICHG). This event, hosted by the African Society of Human Genetics (AfSHG) and the Southern African Society for Human Genetics (SASHG), will reunite international experts to highlight how genomic technologies are being managed to address challenges generated by the current status of Human Health and Genomics. The European Genome-phenome Archive (EGA) will be at the Congress participating in workshops, meetings and talks where topics such as data access and discovery as well as the Federated EGA will be present. Data access and discovery In the context of the “Federated data analysis workshop“ that will be held the 26ᵗʰ, managed in the context of the CINECA project, a hands-on-session on Beacon v2 Discovery will be led by Mauricio Moldes. Another session on authorisation and data access will be presented by Mallory Freeberg and Coline Thomas, with and introduction by Thomas Keane. During the workshop, an end-to-end federated data analysis use case will be presented. Data access and discovery In the context of the “ Federated data analysis workshop“ that will be held the 26ᵗʰ, managed in the context of the CINECA project, a hands-on-session on Beacon v2 Discovery will be led by Mauricio Moldes. Another session on authorisation and data access will be presented by Mallory Freeberg and Coline Thomas, with and introduction by Thomas Keane. During the workshop, an end-to-end federated data analysis use case will be presented. During the last four years, CINECA has been identifying gaps in data sharing between Africa, Canada and Europe in order to build a federated solution for data access. Thomas Keane will present the project within the sessions happening the 24ᵗʰ. The Federated EGA at the ICHG A Federated EGA poster will be shown during the Poster Session 1 that will take place the 23ʳᵈ. The objective is to bring awareness of the European Genome-phenome Archive as a resource for permanent archive and secure data sharing. In this context, the network generated by the Federated EGA is key for cases where research data cannot be shared outside local jurisdictions. The Federated EGA was officially launched on 2022 with research institutes from five countries becoming the first nodes of this network. Nowadays, with more than 20 nodes preparing to join, it aims to become the largest human omics data sharing initiative towards understanding human health and disease. The H3Africa Initiative and the African research represented in the EGA 1.1% of the EGA studies include samples from African populations. Countries such as South Africa, Kenya, Uganda or Egypt, among others, are present in the 72.577 samples from African individuals archived at the EGA. 23 EGA datasets are managed by the Human Heredity and Health in Africa Initiative (H3Africa). This Initiative will celebrate its Consortium Meeting the 27ᵗʰ and 28ᵗʰ, back-to-back with the ICHG. H3ABioNet, the Pan African Bioinformatics Network for the H3Africa consortium, will also take this context to celebrate its 10-Year Symposium during the Congress. Members of the EGA team will attend both of them, as the H3ABioNet works in conjunction with H3Africa projects, to submit data to the European Genome-Phenome Archive.

  Blog the-ega-at-the-international-congress-of-human-genetics

• Shedding light over COVID-19 susceptibility and severity

  “One of the most remarkable features of SARS-CoV-2 infection is the variation in consequence ranging from asymptomatic to life-threatening” state the authors of the majestic Nature paper released in accelerated pre-view on July 2021. This variation in consequences represent not only an issue of burning medical relevance, but also a scientific and intellectual challenge for scientists around the globe. Researchers are known to be easily triggered by a challenge, and they recently demonstrated to be even better at double their efforts to focus on an urgent societal need. In this work led and coordinated by the COVID-19 Host Genetics Initiative (COVID-19 HGI), researchers gathered data from 49,562 cases and two million controls from 46 studies performed worldwide. The majority of the data has been deposited at the EGA, where 29 datasets have been collected under the study number EGAS00001005304. Data gathered from diverse sources conferred a huge robustness to the results. Genetic data from different ancestry origin were included in the analyses, even though data from patients with European origin was highly predominant (approx. 75%). Separated analysis of the different ancestries gave rise to relevant differences in the results, highlighting how important it is to take this aspect in consideration for future studies. Data from the individual studies was compiled into three categories according to COVID-19 severity for a meta-analysis: (a) critically ill cases (b) moderate or severe cases (c) all cases. They were paired with non-COVID-19-reported controls. All three analysis resulted in a total of 13 genetic loci associated with COVID-19 severity. Out of those, 9 loci associated specifically with critical illness, while 6 (a few overlapped) associated with moderated illness. Some genomic position matched previous findings. Interestingly, working with such an enormous amount of data allowed the depth to discriminate association with disease susceptibility vs severity, an issue of large medical relevance. Several loci mapped into biological relevant genes, like TYK2, PPP1R15A and FOXP4, previously implicated in immune response and/or lung functions. Researchers participating in the COVID-19 Host Genetics Initiative have worked in an unprecedented time-tight collaboration, prioritizing data sharing and collective results to tackle the pandemic affecting the world. The scientific community won’t miss any of the lessons to learn from this, and the EGA is ready to keep working to enable safe data sharing and fruitful collaborations.

  Blog covid-19-susceptibility-and-severity

• GCAT | Genomes for life

  The GCAT project is a prospective cohort study that was designed to recruit the general population of Catalonia, the north-east region of Spain. This study is a long-term genomic, environmental and lifestyle cohort project that aims to evaluate and track multiple pathologies as well as biologically related traits. By the end of 2017, the GCAT Study had recruited a total of 20 000 participants aged 40–65 years. Participants who agreed to take part in the study completed a self-administered computer-driven questionnaire, and underwent blood pressure, cardiac frequency and anthropometry measurements. For each participant, blood plasma, blood serum and white blood cells are collected at baseline. The GCAT Study has access to the electronic health records of the Catalan Public Healthcare System. Participants are followed biannually for/during, at least, 20 years after recruitment. Therefore, the GCAT Study offers a unique opportunity to integrate diverse data to allow the identification of novel relations among different biomarkers and conditions. Results may lead to the development of new genetic, genomic, epigenomic and proteomic diagnoses and screening tests, as well as new public health recommendations. The only currently available population-based prospective cohort study in Spain to the date, including more than 4899 genotyped participants and 800 whole genome sequences is now stored in the EGA archive under accession id EGAS00001003018.

  Blog gcat-genomes-for-life

• Providing access to COVID-19 data: one year later

  response efforts On 11 March 2020 the World Health Organization declared the novel coronavirus outbreak a global pandemic. Four months later, the European Genome-phenome Archive (EGA) released its first COVID-19 dataset. This dataset – single cell RNA and VDJ sequencing of B cells from 60 COVID-19 patients – showed that neutralizing antibodies could be identified by high-throughput sequencing in response to SARS-CoV-2 infection. That was one year ago. Today, the EGA provides access to fifteen COVID-19 datasets from researchers across seven countries in Asia, Europe, and North America. These studies represent almost 17,000 individuals and have resulted in at least sixteen publications and preprints. Researchers deposit controlled access COVID-19 data at EGA The global research community has come together rapidly to investigate the SARS-CoV-2 coronavirus and better understand the related disease, COVID-19. These research efforts generate valuable genetic and phenotypic data from patients and research participants that can be shared with approved researchers. The EGA enables sharing of this research data by providing a service for archiving and controlled distribution of sensitive data. Over the past year, the EGA has worked with researchers to archive and distribute COVID-19 data from high-throughput sequencing experiments, genotyping studies, and phenotypic information. These datasets investigate the immune system, blood, and cells and tissues of the lung, which are relevant for studying a contagious respiratory illness caused by a viral infection. *Study Spotlight. In January 2021, Ancestry.com demonstrated the utility of deep phenotyping based on self-reported outcomes from a large population of mild and asymptomatic COVID-19 cases. They identified genetic associations with eight COVID-19 phenotypes and showed distinct patterns of association, most notably related to the chr3/SLC6A20/LZTFL1 and chr9/ABO regions. The supporting data is available at the EGA to approved researchers and includes both genotype and phenotype data for 15,000 individuals. EGA collaborates with global COVID-19 community Since the coronavirus outbreak, the EGA has collaborated with other life science resources to support discovery and access to COVID-19 datasets. COVID-19 Host Genetics Initiative. With the NHGRI’s Genomic Data Science Analysis, Visualization, and Informatics Lab-space (AnVIL) platform, the EGA enables sharing of individual-level genetic and phenotypic data from the COVID-19 Host Genetics Initiative (HGI). This initiative aims to generate, share, and analyze data from COVID-19 host genetics research projects to better understand the genetic determinants of COVID-19 susceptibility, severity, and outcomes. In response to COVID-19, the EGA actively supports COVID-19 data submissions and integration of data access and flow into the COVID-19-HGI analysis platform. *Study Spotlight. The COVID-19 HGI has combined individual-level data for 13,868 COVID-19 positive patients (N=7,167 hospitalized) from 17 cohorts in nine countries. The data were used to assess the association of the major common COVID-19 genetic risk factor (chromosome 3 locus tagged by rs10490770) with mortality, COVID-19-related complications, and laboratory values. The genotype and phenotype data for 10 of these cohorts is available at the EGA to approved researchers under accession EGAS00001005304. Fig 1: EGA COVID-19 studies are searchable in the European COVID-19 Data Portal alongside other COVID-19 and SARS-CoV-2 public datasets. European COVID-19 Data Portal. EGA-archived COVID-19 data are discoverable via the European COVID-19 Data Portal (Fig. 1), which brings together public and controlled access data to accelerate coronavirus research for the international community. By indexing all COVID-19-related data in one place, researchers can more easily discover relevant datasets of interest, thus increasing the “FAIRness” (Findability, Accessibility, Interoperability, Reusability) of this valuable data. Fig 2: SARS-CoV-2 viral sequences are imported from ENA and analysed in Galaxy to detect variants. Results are accessible to researchers through the COVID-19 Viral Beacon. COVID-19 Viral Beacon. The COVID-19 Viral Beacon tool was developed in collaboration with the European Nucleotide Archive and Galaxy to enable near real-time browsing of SARS-CoV-2 variability at genomic, amino acid, and motif levels (Fig. 2). The COVID-19 Viral Beacon allows researchers to (i) perform detailed searches about genomic variants, (ii) filter queries and find unique cases, (iii) filter data based on strain-specific variants, and (iv) explore associated metadata. It uses the Global Alliance for Genomics and Health (GA4GH) Beacon standard including new Beacon v2 features. With this tool, researchers can study intra-host mutations on genomic regions of interest, or trace any variant frequency over time using raw read data. More than 200,000 SARS-CoV-2 analysed genomic data files are now available to researchers for further exploration. Ongoing COVID-19 efforts at EGA Addressing the COVID-19 pandemic is a global effort. Federated resources are necessary to support transnational deposition, access, and analysis of sensitive COVID-19 host genetics and other related data. At the same time, many countries now have emerging personalized medicine programmes which are generating data from national or regional healthcare initiatives. These data are subject to more stringent information governance than research data and often must comply with national data protection legislation. To address this need, the Federated EGA was established to serve as the primary global resource for discovery and access of sensitive human omics and associated data consented for secondary use. The Federated EGA will comprise a network of national human data repositories and will implement community standards and common interfaces. Launching Federated EGA promises to accelerate not only global research efforts to understand, diagnose, and treat COVID-19, but also to foster data reuse, enable reproducibility, and accelerate biomedical and disease research to ultimately improve human health.

  Blog providing-access-to-covid-19

• The last addition to the list of clonal evolution studies in the EGA

  Tumours of different types may arise from a single cell with at least one malignant mutation. Accumulation of subsequent hits generates lineages of cells with different cancer transformation power; thus, every clone follows an autonomous evolution, and several clones may co-exist into the same solid or liquid tumour. Clonal evolution studies are not new: the conceptual power of this approach has been recognized since the early ’80, especially in leukaemia patients. Nonetheless, these studies greatly benefit from recent technological improvements -machineries and protocols-, which enable ever-increasing sequencing depth, allowing the detection of low frequency variants and consequently more tumour clones. Note: the figure belongs to the original paper and is owned by the authors. Researchers at the University of Kyoto in Japan, have indeed used state of the art knowledge to investigate the clonal evolution of chronic myeloid leukemia (CML) in a large panel of patients. CML progresses from a majoritarian benign chronic phase into an often fatal blast crisis phase. It is nowadays known that blast crisis are triggered by genetic instability and disrupted DNA repair, which lead to accumulation of DNA mutations. The use of thyrosine kinase inhibitors targeting the Philadelphia chromosome have enormously improved the treatment of blast crisis, nonetheless resistant patients are still a medical challenge. Yotaro Ochi and collegues used Whole Exome Sequencing of paired chronic phase and blast crisis samples to depict the genetic landscape of progression from the first to the second stage of the disease (as illustrated in their figure). Their results were published in Nature Communication on this May 2021. They used a dataset previously deposited at the EGA (EGAS00001003071) and their new generated data have been made available under accession number EGAS00001005075. Their analysis of the occurring mutations contribute to understanding the mechanisms of CML evolution and therefore develop a protocol for early management of patients with a TKI resistance signature. Up to date, the EGA hosts 99 clonal evolution studies, developed in several cancer types, including myeloma, renal carcinomas and ovarian cancer, in addition to various leukaemia subtypes, where this approach has been more widely applied and produced important results and seminal papers. From a pan-cancer point of view, the definition of tumour architecture through clonal evolution studies is instrumental to unravel the mechanisms of disease progression and treatment-resistance insource. At the EGA, we are honoured to contribute to exciting and important science advances with our service!

  Blog the-last-addition-to-the-list-of-clonal-evolution-studies-in-the-ega

• The Federated EGA network

  In the last 10 years, most human omics data has been generated in the context of research consortia while recently there has been an emergence of large cohorts of human data generated by healthcare initiatives. Many countries in Europe now have nascent personalised medicine programmes. Thus, human genomics is shifting from being predominantly research-driven to being funded through healthcare systems. Genetic data generated in a healthcare context is subject to more stringent information governance than research data and nonetheless all data must adhere to national data protections laws. In this context, EGA identified the need for the development of a federated network to enable secure sharing of data whilst enabling genetic data to remain within the jurisdiction in which it was generated. The Federated EGA is designed to support national data management requirements for genomic and clinical data collected from citizens as part of healthcare or biomedical research projects. It includes a secure authorised access mechanism to support research use of these data across Europe and worldwide. We have engaged with over 14 ELIXIR countries to develop the federation model. The EGA federated configuration is composed of Central EGA, Federated EGA nodes and Community EGA nodes: Central EGA offers international submissions and helpdesk support, currently EGA co-managed by EMBL-EBI and CRG, Federated EGA nodes offer EGA services to researchers within their national jurisdiction, Community EGA nodes are individual institutions or initiatives with human genetic data intended to be shared with the research community. Key services available in the Federated EGA structure are: Central EGA Federated EGA node Community EGA nodes Data submission Offers international submissions service Offers submission service in a particular jurisdiction Does not offer an external submissions service Helpdesk support Provides external international helpdesk Provides helpdesk support for submitters in its jurisdiction and for approved users of data managed at its facilities Provides helpdesk support only for approved users of data managed at its facilities Data distribution Manages worldwide distribution for data hosted at Central EGA Manages worldwide distribution for data hosted at Federated EGA node Distribution for data hosted at Community EGA node EMBL-EBI and CRG have prepared a series of documents describing the overall governance and coordination framework. These describe the Federated EGA structure, the rights and responsibilities of the different parties and governing committees, and node operation guidelines. The federation governance proposal is under review by the first countries invited to join as Federated nodes, with further interested countries likely to join in the coming years. The Central EGA team has been working closely with many ELIXIR partners, including ELIXIR Finland, Luxembourg, Germany, Norway, Spain and Sweden.

  Blog the-federated-ega-network

• Data upcycling, powered by EGA

  In 2012 a collaborative effort headed by the teams of Carlos Caldas in Cambridge, UK and Samuel Aparicio, Canada, produced a pivotal study aimed at defining the mutational landscape of breast cancer. They gathered a collection of over 2000 breast cancer samples (METABRIC) associated with long-term clinical follow-up. They delineated an array of inherited and somatically acquired genetic variants and associated them to gene expression. This led to the identification of putative cancer-driving events and improved stratification of breast cancer patients. The study elicited huge attention and was tackled as herculean effort by fellow researchers. Cristina Curtis and her colleagues deposited the data in the EGA archive (EGAS00000000083). What they probably could not foresee is that their data would be reused more than 100 times, becoming one of the most downloaded datasets at EGA. In 2015, Frederik S. Varn and colleagues accessed the above-mentioned data from the New Hampshire, USA, to correlate it to transcriptional programs of hematopoietic cells infiltrated in breast tumours and found that those can influence patients' prognosis. Their findings, published in Nature Communications, improved the understanding of the interplay between immune system and cancer. Again, in 2017 the dataset was downloaded by an Italian/Polish collaboration and used to corroborate their mechanistic study that demonstrate how a long non-coding RNA (lncRNA) is aberrantly localized into the chromatin, where it modulates oncogenic isoforms expression, thus contributing to breast cancer. To date, the METABRIC dataset has been reused to contribute to 147 publications. Its impact on breast cancer research is incalculable, and it even spread beyond that, with recent contributions to the understanding of pan-cancer mechanisms and features. Some of the publications are translating into improvements in diagnosis and treatment of different types of breast cancer. This is just an example of how data upcycling can amplify the potential of any dataset, well past the scope of its creation, the imagination of its owners and any geographical border. At EGA, we are proud to empower such fruitful worldwide cycles of knowledge, providing a platform that enables safe sharing of sensitive genetic data.

  Blog data-upcycling-powered-by-ega

• Youth-GEMs, the project using data to define the mental health trajectories of young people

  Mental health trajectories are shaped by genetic, cognitive, social, and environmental factors that are particularly influential during human development. How exactly the interplay between these factors is impacting mental health, however, is yet unknown. The project “Gene Environment interactions in Mental health trajectories of Youth (Youth-GEMs)”, funded by the European Commission under the Horizon Europe programme, aims to help reducing mental suffering among European youth. How do Youth-GEMs contribute to bettering mental health in young people? Youth-GEMs aims to identify specific neurological, (epi)genetic and environmental drivers on mental health trajectories of young people. To do so, the project is working on a public knowledge base on functional genomics of the developing human brain, between birth and 24 years old. Reliable predictive models for trajectories of onset and course of mental illness in young people of the general population in Europe will be developed. Additionally, a secure and FAIR data infrastructure in mental health is being produced. Engaging and empowering young people Youth-GEMs is also working on the engagement of young people in the scientific field of Psychiatry. For that, the project is developing initiatives such as Science Café, intended to create a learning community where ideas and stories are shared. The 10th Science Café will take place today, with the participation of Lauren Fromont from the EGA. How do the EGA contribute to Youth-GEMs? The contributions require careful data management and harmonisation: we are dealing with an extraordinary amount of data types, sources, and time points (since the studies are longitudinal). To analyse them together and to determine which factors and interactions are truly key to account for mental health trajectories, the variables need to be transformed in a common “language”, i.e., harmonised under a common data model. Further, to guarantee FAIRness of data storage and sharing for future projects that will further advance our knowledge in the mental health field, we are ensuring that data are processed securely but can also be discovered easily. Find out more information about the project in the Youth-GEMs website.

  Blog youth-gems-mental-health

• From research to data sharing: exploring EGA user's experiences

  The Cell Plasticity and Regeneration Group at the Bellvitge Biomedical Research Institute-IDIBELL focuses on the process of recruitment of macrophages that takes place in the small intestine during injury and healing. They recently published a paper titled “Mucosal Macrophages Govern Intestinal Regeneration in Response to Injury" in Gastroenterology Journal. As part of the research, some experiments were conducted using human intestinal organoid lines. These cells were processed for RNA sequencing, and the sequencing data were deposited at the EGA to be made available to the scientific community. When dealing with human genomic information, repositories must ensure the availability of the datasets while ensuring data protection. In this context, the European Genome-phenome Archive stands as a service for secure archiving and sharing of genetic, phenotypic and clinical data resulting from biomedical research. Following the recent publication of their paper, we took the opportunity to talk to Ilias Moraitis, first author, and Jordi Guiu, group leader, to find out about their experience with data sharing. Could you explain the focus of your research? In the lab, we study intestinal regeneration and how immune cells participate in this process. We use several techniques: engineered mouse models, image tracing, as well as mouse and human cells intestinal organoids. What challenges do you face regarding data management? We didn’t have a lot of problems. Always the informatic part, the data analysis, can give problems. But everything was smooth and working. We think it’s very important to deposit the data in repositories. For the mouse data it is very straightforward, but for us it was the first time depositing human data, which is sensitive because it comes from patients, and this is legally regulated. That’s why we thought about the EGA, and it was our first time. Why do you think it is important to submit data to repositories such as EGA? Because we think data is important for the science. Nowadays, we are sequencing a lot everywhere worldwide and having these resources shared with the scientific community it’s not only good for science, but it is also saving money and reducing costs. And there is so much data in there that can be used for other projects and for other questions. And it saves time! How was the process of submitting the data to the EGA? The communication worked very well but it was slower than we would like. But I think this is something we learn on the way. People usually wait until the last minute to do this before publication but if you know it in advance, you can start the process earlier. If you had to repeat the process, would you do anything differently? It’s like everything, isn’t it? For the first time you don’t know, you aren’t sure, but for the second time you know the steps, you know what to do and it’s faster. Of course, we would to do it earlier. Also, there were some things related to the control access that we didn’t know how to manage, but it was something more internal to us. Who is going to receive the communications and when, is our ethical committee going to evaluate this? All these technicalities that we didn’t know before starting this process, so we had to think about all these things. Next time it will be faster on our side. Do you have any suggestions for us to improve the submission process? Maybe we’ll need to ask our bioinformatician who did it! He was in charge of this part. Besides that, we think if the process were faster, it would be better for everyone. Also, in science a lot of times you have to do a lot of things at the very last minute, because of the nature of the experiments, or the need to accomplish for submitting a paper. Being faster in the process would be a plus. On your side, we went through the process and were able to find some information, but there were aspects we weren't aware of and weren't sure how to handle. I'm not sure if other institutes have different protocols for managing data requests or how they handle these internally. We believe the main issue lies in how the forms are filled out. Do you have any recommendations for other submitters? The main advice is to do this with enough time. Submit the data when you have the sequences, and don’t wait until the last minute. And then it can be under embargo, so you don’t need to make it public at that moment. As soon as you sequence, upload it and then it will be there for whenever you need to publish. How do you think we could encourage other researchers to submit their data? There are different layers here. One is that it is mandatory. You have to do this. The other is that we belong to a research community, to the same community and sharing this is making our research community stronger and more efficient. And then, also because this gives you visibility. The data is there, other people can analyse your data, and this also will bring citations to your papers. It has many advantages.

  Blog from-research-to-data-sharing

• Integrated single-cell profiling dissects cell-state-specific enhancer landscapes of human tumor infiltrating T cells.

  Study EGAS00001006141

• Full AfricanNeo ModernDNA 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 genotyped 1,763 participants, including 1,487 Bantu speakers from 143 populations across 14 African countries. 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 EGAS50000000006

• Genome-wide SNP data of Fulani populations from the Sahel belt

  This project seeks to uncover the genetic structure and ancestry of the Fulani populations across the Sahel/Savannah Belt. The study includes two datasets (''WGA_Fulani_Database'' and ''Saliva_Fulani_Ddatabase''), and SNP-genotyping data was generated using the Illumina Infinium H3Africa Consortium array (BeadChip type: H3Africa_2019_20037295_B1) in two genotyping batches (TE-2559_201029 and TE-2559_201020). In total, 419 were genotyped for this study and the key results were presented in Fortes-Lima et al. 2024 (doi: 10.1101/2024.06.22.600206).

  Study EGAS50000000451

• Association studies using the Metabochip array - Samples analysed by the WTCCC (1958 British Birth Cohort (58BC), Hypertension cohort (HT), Type 2 Diabetes Cohort (T2D) and Coronary Artery Disease (CAD) cohort)

  Genomewide association studies (GWAS) have proven a powerful hypothesis-free method to identify common disease-associated variants. Even quite large GWAS, however, have only at best identified moderate proportions of the genetic variants contributing to disease heritability. To provide cost-effective genotyping of common and rare variants to map the remaining heritability and to fine-map established loci, the Metabochip Consortium has developed a 200,000 SNP chip that has been produced in very large numbers for a fraction of the cost of GWAS chips. This chip provides a powerful tool for genetic studies of metabolic, cardiovascular and anthropometric traits (Voight et al., in press PLoS Genetics).

  Study EGAS00000000115

• Deregulation of FOXF1/FENDRR from t(14;16)(q32;q24) defines a subtype of high risk lineage ambiguous leukemia

  Despite great progress in understanding the genomic basis of immature T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma (T-ALL) and acute leukemias of ambiguous lineage (ALAL), there are still cases that lack defining genetic markers, complicating risk stratification and limiting targeted therapeutic options. Here, we describe a subtype of leukemia defined by the t(14;16)(q32;q24) translocation, which places the FOXF1 gene and its antisense long noncoding RNA gene FENDRR under the regulatory control of the BCL11B enhancer, leading to their ectopic transcriptional activation. Analysis of different high-throughput sequencing data, including WGS, RNA-seq, scDNA-seq, scRNA-seq, ChIP-seq, ATAC-seq, and HiChIP-seq, identified BCL11B-enhancer mediated deregulation of FOXF1/FENDRR as a hallmark of a subtype of high-risk lineage ambiguous leukemia that is potentially amenable to targeted therapeutic intervention.

  Study EGAS50000001255