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• CSER: Evaluating Utility and Improving Implementation of Genomic Sequencing for Pediatric Cancer Patients in the Diverse Population and Healthcare Settings of Texas: The KidsCanSeq Study

  Through this Clinical Sequencing Evidence-Generating Research (CSER) with Enhanced Diversity project we are completing a clinical study (The Texas KidsCanSeq Study) comparing the results of targeted cancer panel sequencing versus genome-scale testing in pediatric cancer patients across diverse clinical settings. We will compare the targeted pediatric cancer panel to germline whole exome sequencing (WES) of unselected childhood cancer patients. We will also compare an RNA/DNA targeted pediatric cancer panel versus WES, transcriptome sequencing and copy number array of FFPE tumor samples for the subset of patients with high-risk tumors. Exome sequencing is performed from a blood or saliva sample of the pediatric age (0-18) patient. We are building on our success completing the CSER program BASIC3 exome sequencing trial (which included 60% Hispanic and African-American patients from a single large academic center) in this large multi-institutional study of an even more diverse patient population from six pediatric oncology healthcare settings across Texas. Data from the Texas KidsCanSeq study will be submitted through the CSER Data Coordinating Center for access in NIH-supported databases.

  Study phs002378

• Biallelic loss of function PAX4 variants are a Novel Cause of Transient Neonatal Diabetes

  The identification of genes in which loss of function (LoF) variants cause neonatal diabetes mellitus (NDM) can provide unique insights into the development and function of human pancreatic beta cells. We describe the identification of biallelic PAX4 LoF variants in 2 unrelated individuals with transient NDM: one due to a homozygous p.(Arg126*) PAX4 stop gain variant and a second due to a homozygous c.-352_104del 2.65kb deletion affecting the first 4 exons and promoter of the PAX4 Matched Annotation from NCBI and EMBL-EBI select transcript. We confirmed reduced transcript expression due to nonsense mediated decay for the e p.(Arg126*) variant in CRISPR-edited iPSC-derived pancreatic endoderm cells. Analysis of PAX4 binding through integration of CUT&RUN and RNA-sequencing in PAX4 depleted endocrine cells identified genes directly regulated by PAX4 involved in both pancreatic islet development and glucose-sensitive insulin secretion. The remitting and relapsing diabetes in both probands demonstrates that in contrast to mice PAX4 is not essential for the development of pancreatic beta-cells and supports differences in the requirements of functional beta-cell mass across the life-course.

  Study EGAS50000000857

• Final results and ctDNA analyses from the randomized phase 3 IMpassion031 trial evaluating peri-operative atezolizumab for early-stage triple-negative breast cancer

  In IMpassion031, adding atezolizumab to neoadjuvant chemotherapy significantly improved pathologic complete response (pCR) rate (primary endpoint) for stage II/III triple-negative breast cancer (TNBC). Patients with stage II/III TNBC were randomized 1:1 to neoadjuvant chemotherapy plus peri-operative atezolizumab or pre-operative placebo. Descriptive secondary endpoints included event-free, disease-free, and overall survival. Long-term outcomes favored the atezolizumab group (event-free survival HR 0.76, 95% CI: 0.47–1.21). Among patients without pCR, 14/70 (20%) atezolizumab-treated and 33/99 (33%) placebo-treated patients received additional adjuvant therapy, frequently capecitabine. In exploratory analyses, pCR was prognostic for long-term outcome. Patients with baseline ctDNA-negative status (6%) had excellent long-term outcomes. Most patients (87%) had cleared ctDNA at surgery. ctDNA-positive status at surgery identified a subset of non-pCR patients with poorest prognosis. Long-term safety was consistent with primary results. Adding atezolizumab to chemotherapy for stage II/III TNBC is associated with more favorable long-term outcomes. ctDNA dynamics provide prognostic value beyond pCR. ClinicalTrials.gov identifier: NCT03197935

  Study EGAS50000000974

• DynaTag for efficient profiling of transcription factors in small samples and single cells

  Systematic discovery of transcription factor (TF) landscapes in low-input samples and at single cell level is a major challenge in the fields of molecular biology, genetics, and epigenetics. To address this, we present here cleavage under Dynamic targets and Tagmentation (DynaTag), which allows robust mapping of specific TF-DNA interactions via the use of a physiological salt solution during sample preparation. Using this method, we revealed occupancy alterations for 15 different TFs in stem cell and cancer tissue models. Of note, we showcased for NANOG, MYC, and OCT4 differentially occupied genomic loci during stem cell differentiation, both in bulk and at single-cell resolution. DynaTag demonstrated superior signal-to-background ratio and occupancy resolution in comparison to CUT&RUN and ChIP-seq. In addition, a model for small cell lung cancer chemotherapy treatment in vivo showed increased chromatin occupancies of the gain-of-function mutant P53 p.R248Q, FOXA1, and MYC at altered gene pathways, such as epithelial-mesenchymal-transition. Altogether, these results highlight the technical advancement of DynaTag to uncover TF landscapes in cell models and in tissues of a complex disease model.

  Study EGAS50000001074

• Chicago Infant Mortality Study

  The Chicago Infant Mortality Study (CIMS) was a population-based, prospective, case-control study conducted in metropolitan Chicago, Cook County, Illinois, to examine the risk factors for sudden infant death syndrome (SIDS) among a primarily Black population. Eligible case infants were aged birth to one year where the cause of death was determined to be SIDS while eligible control infants were aged one month to one year who died of other sudden unexpected infant death (SUID) causes. Recruitment occurred between November 1993 and April 1996. The goal of this ancillary multiomics study was to evaluate possible genetic and epigenetic determinates of SIDS and together with metabolomic profiles, identify novel clinical diagnostic tools to enable molecular autopsies and biomarkers to proactively identify and intervene in infants at greater risk of death from SIDS. The multiomics data was generated from medical examiner autopsy specimens and includes: whole exome sequencing genotypes; RNA-seq transcriptome and methylome profiles from autopsy heart tissue; and serum metabolomics profiles. The sample size available varies with the modality of the omics assay, but the total number of unique infants included is about 400.

  Study phs003790

• Non-neuronal TGF-β–mediated extracellular matrix remodeling drives neurodegeneration in a PSP-Richardson syndrome model

  Progressive supranuclear palsy-Richardson syndrome (PSP-RS) is a devastating neurodegenerative disorder marked by rapid motor decline, cognitive impairment, and widespread accumulation of pathological tau. Yet, the molecular triggers of sporadic PSP-RS remain elusive. In this study, we combined patient-derived midbrain organoids with integrative multi-omics to uncover a previously unrecognized pathological cascade. At the core lies an early and aberrant activation of TGF-β signaling, which initiates profound extracellular matrix (ECM) remodeling and aberrant integrin-mediated focal adhesion. This cascade leads to persistent hyperactivation of PI3K/AKT and MAPK/ERK pathways, disrupting cytoskeletal integrity, impairing autophagy, promoting pathological tau phosphorylation and mislocalization, and ultimately driving synaptic degeneration. Single-cell RNA sequencing revealed an ectopic expansion of vascular leptomeningeal-like cells (VLMCs), a collagen-producing population, accompanied by a broad ECM gene dysregulation unique to PSP-RS. Remarkably, pharmacological blockade of TGF-β, AKT, ERK, or mTOR signaling reversed tau pathology and restored synaptic integrity. These findings position TGF-β-driven ECM remodeling as a master regulator of neurodegeneration in sporadic PSP-RS and unveil multiple actionable therapeutic targets for this currently untreatable disease.

  Study EGAS50000001236

• NCI COVID-19 in Cancer Patients Study (NCCAPS): A Longitudinal Natural History Study

  NCCAPS is a longitudinal prospective cohort study designed to assess patient, disease and treatment factors associated with short- and long-term outcomes in patients with cancer who develop COVID-19. We also aimed to describe COVID-19 symptoms and treatments, and to describe disruptions in cancer treatment due to COVID-19. The study enrolled patients with cancer on active treatment or with a history of stem cell transplant or CAR-T cell therapy with new, active COVID-19, defined as being within 14 days of their first positive SARS-CoV-2 test. The study found that receipt of chemotherapy and baseline history of stroke, atrial fibrillation or pulmonary embolism were associated with a higher risk of hospitalization for COVID-19. Vaccination for SARS-CoV-2 was associated with a lower risk of hospitalization. Death due to COVID-19 was highest in patients with lymphoma, intermediate in those with acute leukemia and lung cancer, and lowest in those with other solid tumors and other hematologic cancers. Disruptions of cancer treatment were frequent in the first 30 days after SARS-CoV-2 infection.

  Study phs004178

• Effective screening strategy for deafness using a new-genetation sequencing platform: a consecutive analysis

  The diagnosis of the genetic etiology of deafness contributes to the clinical management of patients. We performed the following four genetic tests in three stages for 52 consecutive deafness subjects in one facility. We used the Invade assay and Sanger sequencing for the GJB2 gene or SLC26A4 gene in the first stage test, TaqMan genotyping assay in second stage test, and targeted exon sequencing using the massively parallel DNA sequencing in third stage test. Overall, we identified the genetic cause in 40% (21/52) of patients. The diagnostic rates of the first-, second- and third-stage genetic testing were 17%(9/52), 9%(4/43) and 21% (8/39), respectively. The combination approach using these genetic tests appears to be useful as a diagnostic tool for deafness patients. We recommended that genetic testing for the screening of common mutations in deafness genes using the Invader assay or TaqMan genotyping assay be performed as the initial evaluation. For the remaining undiagnosed cases, targeted exon sequencing using MPS is clinically and economically beneficial. This data set was MPS reads data (fastq) for 39 sensorineural hearing loss patients.

  Study JGAS000032

• Investigation of molecular diagnosis by molecular biological analysis using next-generation sequencer for actionable endocrine diseases (including neoplastic diseases)

  Fructose-1,6-bisphosphatase (FBPase) deficiency, caused by an FBP1 mutation, is an autosomal recessive disorder characterized by hypoglycemic lactic acidosis. Due to the rarity of FBPase deficiency, the mechanism by which the mutations cause enzyme activity loss still remains unclear. Here we identify compound heterozygous missense mutations of FBP1, c.491G>A (p.G164D) and c.581T>C (p.F194S), in an adult patient with hypoglycemic lactic acidosis. The G164D and F194S FBP1 mutants exhibit decreased FBP1 protein expression and a loss of FBPase enzyme activity. The biochemical phenotypes of all previously reported FBP1 missense mutations in addition to G164D and F194S are classified into three functional categories. Type 1 mutations are located at pivotal residues in enzyme activity motifs and have no effects on protein expression. Type 2 mutations structurally cluster around the substrate binding pocket and are associated with decreased protein expression due to protein misfolding. Type 3 mutations are likely nonpathogenic. These findings demonstrate a key role of protein misfolding in mediating the pathogenesis of FBPase deficiency, particularly for Type 2 mutations. This study provides important insights that certain patients with Type 2 mutations may respond to chaperone molecules.

  Study JGAS000625

• Induction of fetal meiotic oocytes from embryonic stem cells in cynomolgus monkeys

  Human in vitro oogenesis provides a framework for clarifying the mechanism of human oogenesis. To create its benchmark, it is vital to promote in vitro oogenesis using a model physiologically close to humans. Here, we establish a foundation for in vitro oogenesis in cynomolgus (cy) monkeys: cy female embryonic stem cells harboring one active and one inactive X chromosome (Xa and Xi, respectively) differentiate robustly into primordial germ cell-like cells, which in xenogeneic reconstituted ovaries develop efficiently into oogonia and, remarkably, further into meiotic oocytes at the zygotene stage. This differentiation entails a comprehensive epigenetic reprogramming, including Xi reprogramming, yet, as partly observed in vivo, Xa and Xi remain epigenetically asymmetric with incomplete Xi reactivation. In humans and monkeys, the Xi epigenome in pluripotent stem cells functions as an Xi-reprogramming determinant. We further show that developmental-pathway over-activations with suboptimal up-regulation of relevant meiotic genes impede in vitro meiotic progression. Cy in vitro oogenesis exhibits critical homology with the human system, including with respect to bottlenecks, providing a salient model for advancing human in vitro oogenesis.

  Study JGAS000573

• MATISSE WES and bulk RNA-sequencing data

  High-risk cutaneous squamous cell carcinoma is frequently seen in frail, elderly patients and often requires mutilating surgical treatment and adjuvant radiotherapy (RT). The MATISSE trial (NCT04620200) was conducted to improve clinical prospects in CSCC patients eligible for extensive curative surgery, and evaluated early treatment response and immune dynamics following ultra-short neoadjuvant immunotherapy prior to standard of care surgery with or without radiotherapy. Fifty patients were randomized to receive two courses of nivolumab 3 mg/kg (NIVO, weeks 0&2) or nivolumab 3 mg/kg (weeks 0&2) and one course of ipilimumab 1 mg/kg (week 0 only, NIVO/IPI before surgery at week 4, with the primary objective being histopathological response based on residual viable tumor cells in the surgical specimen. Ten patients choose not to undergo surgery, of whom nine reached a clinical complete response during follow up, and were disease-free at median 34 months follow up. Serial tumor and blood samples at baseline, week 1, week 2 and week 4, enabled to investigate dynamical changes through bulk WES and RNA sequencing to potentially aid future de-escalation trials.

  Study EGAS50000001003

• Proteomic predictors of individualized nutrient-specific insulin secretion in health and disease

  Population level variation and molecular mechanisms behind insulin secretion in response to carbohydrate, protein, and fat remain uncharacterized despite ramifications for personalized nutrition. We now define prototypical insulin secretion dynamics in response to the three macronutrients in islets from 140 cadaveric donors, including those diagnosed with type 2 diabetes. We leverage the insulin response heterogeneity and use transcriptomics and proteomics to identify molecular pathways of specific nutrient responsiveness. Surprisingly, we find robust insulin secretion to fatty acid stimulus in ~8% of donors, challenging the idea that fat has negligible effects on insulin release. Distinct islet proteomes with differences in metabolic signalling networks convey this hyper-responsiveness to fat relative to carbohydrate. By comparing human islets to human embryonic stem cell-derived islet clusters, we show that, unlike glucose-responsiveness, fat hyper-responsiveness is equivalent and may be a hallmark of functionally immature cells. Our study represents the first comparison of dynamic responses to nutrients and multi-omics analysis in human insulin secreting cells. Responses of different people’s islets to carbohydrate, protein, and fat lay the groundwork for personalized nutrition.

  Study EGAS00001007241

• Context-specific regulatory genetic variation in MTOR dampens neutrophil-T cell crosstalk in pneumonia-associated sepsis, modulating disease

  Sepsis is a heterogeneous clinical syndrome with a high mortality, requiring personalised stratification strategies. Here, we characterise genetic variation that modulates MTOR, a critical regulator of metabolism and immune responses in sepsis. The effects are highly context specific, involving a regulatory element that affects MTOR expression in activated T cells with opposite direction of effect in neutrophils. We show that the G-allele of the lead variant, rs4845987, associated with decreased risk of T2D, reduces MTOR expression in T cells and improves survival in sepsis due to pneumonia, with effects specific to sepsis endotype. Using ex vivo models, we demonstrate that activated T cells promote immunosuppressive sepsis neutrophils through released cytokines, a process dampened by hypoxia and the mTOR inhibitor rapamycin. Our work demonstrates a novel epigenetic mechanism that fine-tunes MTOR transcription and T cell activity via the variant-containing regulatory element, which further exhibits an allelic effect upon vitamin C treatment. These findings reveal how genetic variation interacts with disease state to modulate immune cell-cell communication, providing a patient stratification strategy to inform more effective sepsis treatment.

  Study EGAS50000000894

• A Single-Cell and Spatial Atlas of Early Human Olfactory Development

  The human nasal region is a complex anatomical structure comprising neural crest- and placode-derived lineages, yet its developmental dynamics in humans remain poorly understood due to limited access to fetal tissue and challenges in resolving its spatial and cellular complexity. We built a single-cell and spatial transcriptomic atlas of the human fetal nasal region from 10 fetuses spanning post-conceptional weeks 7 to 12. Using snRNA-seq, we identify 34 cell types in the fetal nasal region and reconstruct lineage trajectories in the olfactory epithelium (OE). Spatial analyses uncover regionalized OE organization, dorsoventral gradients of olfactory receptors (ORs) and high-resolution OR expression. Combining snRNAseq and MERFISH, we reveal early onset of OR gene expression, with most olfactory sensory neurons (OSNs) following the one neuron-one receptor rule already during the first trimester. This work provides the first integrated molecular and spatial framework of early human nasal region and it provides an unprecedented molecular blueprint of the human olfactory system development. In addition, this study offers a foundational resource for embryologists and developmental biologists investigating sensory neurogenesis, epithelial patterning, and congenital diseases.

  Study EGAS50000001203

• Non-canonical NF-κB signaling skews B cells away from germinal center to low-affinity effector fate

  The non-canonical (NC) NF-κB pathway is a central regulator of B-cell development and survival, yet its role during B-cell mediated adaptive responses remains uncharted. Here, we uncover an unanticipated regulatory function for NC NF-κB in shaping humoral immunity. High-resolution mapping of NC NF-kB status in B cells from human lymphoid tissues revealed low activity in germinal center B-cells (GCB) than effector subsets, suggesting a selective attenuation. Consistently, mice model harboring B-cells with enforced NC NF-κB activation revealed near- complete loss of GCB and high-affinity antibodies, following vaccination. GCB loss was not driven by intrinsic defects in formation or expansion, but by an immune-niche dysregulation marked by regulatory T-cell expansion. Mechanistically, NC NF-κB activation promoted B-cell- derived IL-10, and blocking this axis normalize the niche and rescue GCB. Concurrently, NC NF- κB signaling boosted low-affinity antibody responses by transcriptionally priming follicular B- cells for plasmacytic differentiation. Together, these findings position NC NF-κB as a tunable rheostat linking B-cell signaling to immune-niche control and humoral immunity.

  Study EGAS50000001646

• Submitters and requesters Statistics

  EGA Statistics Bibliography Growth Community Archive Distribution Catalogue Here, we show the amount and global distribution of submitters and requesters Requester accounts created by country The below figure represents the number of requester accounts by country. In most of the cases cases, country was inferred from the requester email domain. Those requesters whose email domain could not be assigned to a country such as @gmail.com, are not included. Note that a requester is a user that has had a granted permission at some point in time. Requester Accounts Created by Country Download as PNG Download as JPG Download as WEBP Download as CSV map pie mapChart('requester-country', 'https://stats.ega-archive.org/requester/country') pieChart('requester-country-pie-chart', 'https://stats.ega-archive.org/requester/country','Requester accounts created by country') Requester accounts created by year The below figure represents the number of requester accounts by year. Note that a requester is a user that has had a granted permission at some point in time. Requester Accounts Created by Year Download as PNG Download as JPG Download as WEBP Download as CSV barChart('requester-year', 'https://stats.ega-archive.org/requester/year', ['Requester Accounts', 'Years'], true) Industry requester accounts The below figure represents the top 15 industry requesting companies. Industry Requester Accounts Download as PNG Download as JPG Download as WEBP Download as CSV pieChart('industry-requester-accounts', 'https://stats.ega-archive.org/industry/requester/accounts', 'Industry Requester Accounts') Submitter accounts created by country The below figure represents the number of submitter accounts by country. Location was infered from the requester email domain. Submitter Accounts Created by Country Download as PNG Download as JPG Download as WEBP Download as CSV map pie mapChart('submitter-accounts', 'https://stats.ega-archive.org/submitter/accounts/country') pieChart('submitter-accounts-pie-chart', 'https://stats.ega-archive.org/submitter/accounts/country','Submitter accounts created by country') Submitter accounts created by year The below figure represents the number of submitter accounts by year. Submitter Accounts Created by Year Download as PNG Download as JPG Download as WEBP Download as CSV barChart('submitter-users-year', 'https://stats.ega-archive.org/submitter/users/year', ['Submitter Accounts', 'Years'], true) DAC Members by Country The below figure represents the number of DAC members by country. DAC Members by Country Download as PNG Download as JPG Download as WEBP Download as CSV map pie mapChart('dac-members-by-country', 'https://stats.ega-archive.org/dac_member/country') pieChart('dac-members-by-country-pie-chart', 'https://stats.ega-archive.org/dac_member/country','DAC members by country')

  Documentation about/statistics/community

• Adaptive Therapy Exploits Fitness Deficits in Chemotherapy-Resistant Ovarian Cancer to Achieve Long-Term Tumor Control Open Access

  Drug resistance results in poor outcomes for cancer patients. Adaptive therapy is a potential strategy to address drug resistance that exploits competitive interactions between sensitive and resistant subclones. Here, we showed that adapting carboplatin dose according to tumor response (adaptive therapy) significantly prolonged survival of murine ovarian cancer models compared to standard carboplatin dosing, without increasing mean daily drug dose or toxicity. Platinum resistant ovarian cancer cells exhibited diminished fitness when drug was absent in vitro and in vivo, which caused selective decline of resistant populations due to reduced proliferation and increased apoptosis. Conversely fitter, sensitive cells re-grew when drug was withdrawn. Using a bioinformatics pipeline that exploits copy number changes to quantify the emergence of treatment resistance, analysis of cell‐free DNA obtained longitudinally from ovarian cancer patients during treatment showed subclonal selection through therapy, and measurements of resistant population growth correlated strongly with disease burden. These preclinical findings pave the way for future clinical testing of personalized adaptive therapy regimens tailored to the evolution of carboplatin resistance in individual ovarian cancer patients.

  Study EGAS50000001142

• Whole Genome Sequencing of Neuroblastoma

  Neuroblastoma is a childhood tumour of the peripheral sympathetic nervous system. The pathogenesis has for a long time been quite enigmatic, as only very few gene defects were identified in this often lethal tumour1. Frequently detected gene alterations are limited to MYCN amplification (20%) and ALK activations (7%)2-5. Here we present a whole genome sequence analysis of 87 neuroblastoma of all stages. Only few recurrent amino-acid changing mutations were found. In contrast, analysis of structural defects identified in 18% of high stage neuroblastoma a local shredding of chromosomes, known as chromothripsis6. These tumours are associated with a poor outcome. Structural alterations recurrently affected ODZ3, PTPRD and CSMD1, which are involved in neuronal growth cone stabilization7-9. In addition, ATRX, TIAM1 and a series of regulators of the Rac Rho pathway were mutated, further implicating defects in neuritogenesis in neuroblastoma. Most tumors with defects in these genes were aggressive high stage neuroblastoma, but did not carry MYCN amplifications. The genomic landscape of neuroblastoma therefore reveals two novel molecular defects, chromotripsis and neuritogenesis gene alterations, which frequently occur in high risk tumors.

  Study EGAS00001000222

• WTCCC2 Visceral Leishmaniasis (VL) samples

  A WTCCC2 project genome-wide association study for visceral leishmaniasis (VL) in individuals from India, Brazil and Sudan, genotyped on the custom Illumina 670k array. The WTCCC2 analysis of the Brazilian and Indian samples is described in Fakiola et al. [Nat Genet. 2013 Feb;45(2):208-13].It should be noted that due to expected family structure in the data, normal analyses of these data should include an estimation of the relatedness between the samples. For more details about sample collection for the project please refer to the Methods section of the paper above. The samples from India were all collected from Bihar state in northeastern India. The Brazilian samples were collected from a wide area of northern Brazil, and managed at two laboratories in Natal and Belem. For more details on the geographic distribution of the Brazil samples please see Jamieson et al. [Genes Immun. 2007 Jan;8(1):84-90]. We have not generated qc_passed or info files for the Sudanese data, a preliminary scan of the data indicated that there may be DNA quality issues with these samples.

  Study EGAS00001000773

• Transcriptomes of human CD4+ T lymphocytes - Metabolic project

  Human CD4+ T cells are essential mediators of immune responses. By altering the mitochondrial and metabolic states, we defined metabolic requirements of human CD4+ T cells for in vitro activation, expansion, and effector function. T cell activation and proliferation were reduced by inhibiting oxidative phosphorylation, while early cytokine production was maintained by either OXPHOS or glycolytic activity. Glucose deprivation in the presence of mild mitochondrial stress markedly reduced all three T cell functions, contrasting the exposure to resveratrol, an antioxidant and sirtuin-1 activator, which specifically inhibited cytokine production and T cell proliferation, but not T cell activation. Conditions that inhibited T cell activation were associated with the downregulation of 2′,5′-oligoadenylate synthetase genes via interferon response pathways. Our findings indicate that T cell function is grossly impaired by stressors combined with nutrient deprivation, suggesting that correcting nutrient availability, metabolic stress and/or the function of T cells in these conditions will improve the efficacy of T cell-based therapies.

  Study EGAS00001005565

• Single-nucleus transcriptomic profiling of aging Down Syndrome brains

  Down syndrome (DS) – trisomy of human chromosome 21 (HSA21) – is characterized by lifelong cognitive impairments and development of neuropathological hallmarks of Alzheimer’s disease (AD). The cellular and molecular modifications responsible for these effects are not understood. Here we performed single-nucleus RNA-sequencing (snRNA-seq) employing both short (Illumina) and long-read (Pacific Biosciences) sequencing technologies on a total of 29 DS and non-DS control prefrontal cortex samples. In DS, the ratio of inhibitory-to-excitatory neurons was significantly increased, which was not observed in previous reports examining sporadic AD. DS microglial transcriptomes displayed AD-related aging and activation signatures in advance of AD neuropathology, with increased microglial expression of C1q complement genes (associated with dendritic pruning) and the HSA21 transcription factor gene RUNX1. Long-read sequencing detected vast RNA isoform diversity within and amongst specific cell types including numerous novel sequences that differed between DS and normal brains. Notably, over 8,000 genes produced RNAs containing intra-exonic junctions (IEJs), including APP that had previously been associated with somatic gene recombination. These and related results illuminate large-scale cellular and transcriptomic alterations as novel features of the aging DS brain.

  Study EGAS00001005691

• Duplexseq_of_the_interstrand_crosslinks_WGS

  One of the most dangerous forms of DNA damage are interstrand crosslinks (ICLs), which covalently crosslink the two strands of the DNA double helix. The repair of these lesions is crucial for cellular survival due to their ability to block transcription and DNA replication. Initially, the major pathway that has been described in ICL repair involves a network of 22 genes that are mutated in a severe human genetic disease known as Fanconi Anemia (FA). Using synthetic lethality screens in the near-haploid human HAP1 cell line, we recently identified two potentially novel regulators of ICL repair, C1orf112 and THAP12. Loss of C1orf112 and THAP12 causes hypersensitivity to ICL-inducing DNA damaging agents, such as Mitomycin C (MMC). Additionally, C1orf112-depleted cells show elevated levels of micronuclei and accumulation of DNA damage in S-phase. To better understand how C1orf112 and THAP12 mediate the repair of ICLs, we want to perform mutational signature analysis, using the BotSeq method. Therefore, WT, C1orf112 and THAP12 knockout cells were cultured in vehicle or MMC treated conditions for 10 days and the genomic DNA was isolated. FANCA and FANCD2 knockout cells are taken along as controls in this experimental setting.

  Study EGAS00001006545

• Spatial multi-omic map of human myocardial infarction

  Myocardial infarction is a leading cause of mortality worldwide 1 . While advances have been made in acute treatment, an incomplete understanding of remodelling processes has limited the effectiveness of therapies to reduce late-stage mortality 2 . Here, we generate an integrative high- resolution map of human cardiac remodelling after myocardial infarction using single-cell gene expression, chromatin accessibility, and spatial transcriptomic profiling of multiple physiological zones at distinct time points in myocardium from myocardial infarction and control patients. Multimodal data integration allowed us to evaluate cardiac cell-type compositions at increased resolution, yielding insights into changes of the cardiac transcriptome and epigenome through the identification of distinct tissue structures of injury, repair and remodelling. We identified and validated disease-specific cardiac cell-states of major cell-types and analysed them in their spatial context, evaluating their dependency on other cell-types. Our data elucidates molecular principles of human myocardial tissue organisation, recapitulating a gradual cardiomyocyte and myeloid continuum following ischemic injury. In total, our study provides an integrative molecular map of human myocardial infarction and represents an essential reference for the field and paves the way for advanced mechanistic and therapeutic studies of cardiac disease.

  Study EGAS00001006330

• Distinct portrayal of lesions in synchronous multifocal lung adenocarcinoma revealed by genome sequencing

  Distinguishing multiple primary lung cancers in the synchronous multifocal intrapulmonary lesions has important significance on clinical staging and therapeutic decision. To investigate genomic aberration profiles, we applied whole genome and whole exome sequencing, and microarray-based comparative genomic hybridization on 15 intrapulmonary tumors derived from six patients with synchronous multifocal lung cancers having similar histological diagnosis. Any pair of intrapulmonary tumors in a single patient, which shared the identical genetic background and environment, showed an extinctive heterogeneity between each other. Phylogenetic relationship analysis indicated an independently branched evolution among all the tumors, suggesting they were multiple primary lung cancers. EGFR or KRAS mutations were found in 7 or 3 out of the 15 tumors, from 3 or 2 patients, respectively. Somatic mutational heterogeneity of these two genes in a single patient was also observed. Our analysis indicates genomic aberration profiling is valuable for identification of multiple primary lung cancer, especially when high histopathological concordance was observed between lesions. We also suggest a thoroughly molecular diagnosis against therapeutic target genes should be taken for each accessible nodule before making a plan for adjuvant therapy.

  Study EGAS00001001572

• Study on the proliferation history of colorectal adenomas

  Mismatch repair (MMR) deficient colorectal adenomas are composed of transformed cells that descend from a common founder and progressively accumulate genomic alterations but their proliferation history is still largely unknown. Here we rebuilt the proliferation history of four MMR deficient colorectal adenomas from male individuals by deep sequencing the X chromosome and mapping the somatic mutations that were progressively acquired during tumor growth. We developed a novel method to call high and low frequency mutations, to cluster them according to their frequencies and rebuild the proliferation trees directly from these mutation clusters using a recursive algorithm. The trees of all four lesions were formed of a dominant subclone that coexisted with other genetically heterogeneous subpopulations of cells. Despite this similar hierarchical organization, however, the growth dynamics varied among and within tumors, likely depending on a combination of tumor-specific genetic and environmental factors. Our study provides insights into the biological properties of individual MMR deficient colorectal adenomas that may influence their growth and also the response to therapy. Extended to other solid tumors, our approach could inform on the mechanisms of cancer progression, thus providing insight into the best choice of cancer treatment methods.

  Study EGAS00001000883