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• Transcriptomic Analysis of Pluripotent Stem Cell-Based Model of Human Amniogenesis

  The amniotic epithelium is the innermost layer of the amniochorionic membrane that physically divides the maternal and fetal environments. Amniogenesis is initiated during implantation in humans. In implanting blastocysts, the pluripotent epiblast cells undergo apical-basal polarization to form a cyst with a central lumen, the future amniotic cavity. This event is followed by the fate transition of pluripotent epiblast cells at the uterine-proximal pole of the cyst to squamous amniotic ectoderm, forming a sharp boundary between amnion and pluripotent epiblast portions of the cyst. To enable mechanistic investigations into amnion fate progression, several in vitro models based on human pluripotent stem cells were recently developed. In this study, transcriptomic features of human pluripotent stem cell-derived amniogenesis models were examined.

  Study phs002184

• MAP Kinase-Mutant Hematologic Malignancies and Their Therapeutic Resistance

  The Mitogen-Activated Protein Kinase (MAPK) signaling pathway has been critically important in understanding pathology and developing targeted therapy for many cancers, but high frequency mutations in this pathway in hematopoietic malignancies were unknown until a series of sequencing studies from our group and others revealed a high frequency of activating mutations in BRAF (GeneID:673), MAP2K1 (GeneID:5604), and other key components of the MAPK pathway in two groups of rare and poorly studied blood cancers: hairy cell leukemia (HCL) and the systemic histiocytoses (SH). Although HCL and the SH both share common gene mutations in BRAF (BRAFV600E) and MAP2K1, these are distinct blood cancers with different clinical behaviors; however, their actual developmental cellular origins, genomic, and pathogenic differences are poorly understood, which led to our project goal of determining how BRAFV600E, MAP2K1, and other MAPK pathway mutations contribute to the pathogenesis of distinct blood cancers and affect their clinical responses to MAPK pathway inhibitors. This study proposal seeks to advance our understanding of the actual cells of origin of cancer-causing MAPK mutations in HCL and the SH, to determine why BRAFV600E and MAP2K1 mutations can cause two distinct blood cancers, and to understand how these mutations in HCL and SH influence responses to MAPK pathway inhibitor drugs and other receptor tyrosine kinase (RTK) inhibitors such as RET and ALK inhibitors that could potentially become effective therapy for these poorly understood blood cancers.

  Study phs001864

• Case Report: Rare IKZF1 gene fusions identified in neonate with congenital KMT2A-rearranged Acute Lymphoblastic Leukemia

  Here we describe a rare case of congenital KMT2Ar ALL presenting with co-occurring IKZF1 gene fusions and a predictably aggressive disease trajectory. We report for the first time, the novel IKZF1::TUT1 and KDM2A::IKZF1 gene fusions. Rearrangements in-volving KMT2A are commonly retained in relapsed infant ALL, however, in this case the KMT2A::AFF1 gene fusion did not appear to be the lesion driving leukemic relapse. Instead, our data suggest that relapse was driven by IKZF1::TUT1. This gene fusion remained in all samples investigated, including the on-blinatumomab therapy sample taken immediately prior to relapse. Conversely, the KMT2A::AFF1 gene fusion was only detected in the diagnosis and refractory post-induction samples highlighting a key role for IKZF1::TUT1 in disease pathogenesis. Intriguingly, both IKZF1 gene fusions are predicted to be out-of-frame, however, our data demonstrate the IKZF1 gene is still expressed. This is not unprecedented and it has previously been observed that out-of-frame fusions can cause transcriptional activation/repression of genes involved in the fusions leading to increases or decreases of their expression and the as-sociated functional outcomes.

  Study EGAS00001006947

• Lipomatous tumors with 12q amplification

  The project concerns whole genome sequencing (short-read and long-read) and RNA-sequencing of lipomatous tumors with 12q-amplification. A subset of lipomatous tumors is driven by amplification of genes mapping to chromosome arm 12q, including the MDM2 gene. The goals of the study were to compare expression levels of genes mapping to 12q in tumors with amplification in rod-shaped or circularized chromosomes as well as to assess and compare the structural variants in those tumors. In total, 20 samples were analyzed, and the data were correlated with genomic data on bulk and single cell DNA from the same tumors. The fastq files from the tumors were uploaded to EGA.

  Dataset EGAD50000000087

• NHLBI TOPMed: Pathways to Immunologically Mediated Asthma (PIMA)

  Study designed to further our understanding of the pathogenesis of asthma exacerbations in children. Children enrolled in the study (n=217) were all asthmatic and primarily Hispanic white. The children were followed for 18 months until they experienced an asthma exacerbation or completed the follow-up without an exacerbation. The time to the first asthma exacerbation was considered the outcome. The acute and convalescent immune phenotype of each asthma exacerbation was documented.

  Study phs001727

• Genetic Association Studies in the Solomon Islanders

  The goal of this study was to determine the genetics underlying blond hair in the Solomon Islands, which has the highest prevalence of blondism outside of Europe. Participants in the study were of self-reported Solomon Islands ancestry and were 6-36 years of age at enrollment. Individuals with blond (N = 43) and dark hair (N = 42) were selected, approximately matched for age, sex and local geography, and spectrophometric measurements of hair pigmentation were made as a single measurement taken from hair at the crown. Individuals with gray, white, thin, bleached or artificially colored hair were excluded from analysis. All 85 participants were evaluated in a genome-wide scan to detected association to hair pigmentation in the Solomon Islands.

  Study phs000493

• 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.

  Dataset EGAD50000000519

• Post_Mortem_Tissue_COVID19_RNA

  Single cell analysis of post mortem tissue samples from SARS-CoV2-infected patients We aim to directly identify the human cell types infected by SARS-CoV-2 and measure the cellular response to COVID19 infection across 20 different tissues from infected patient autopsies. We have examined the expression pattern of viral entry receptors across healthy human tissues to predict several candidate target cell types across the airway and heart. In addition, high prevalence of cardiac failure and abnormal renal function in COVID19 patients implicates heart and kidney involvement, but the pathogenesis of organ specific damage - whether via a direct cytopathic mechanism or an indirect inflammatory response - remains unknown . Currently, we lack confirmation of target cell types and cellular processes in infected tissues as autopsies are discouraged in most countries due to health and safety risks. Our collaborators Drs Michael Osborn and Brian Hanley (Imperial College) have outlined guidelines to perform post-mortem in COVID19 patients (Hanley et al., 2020) and have established a programme of autopsies for research to be performed in a high-risk facility at Westminster Public Mortuary. Here, we propose to identify infected cell types and aberrant molecular pathologies in this precious tissue resource using single cell and spatial genomics. We will prioritise three organ systems: the human airway, heart and the kidney. We will directly examine the cellular identities of SARS-CoV-2 infected cell types and identify the cellular responses to infection across these organs. This fundamental knowledge will help guide future treatment choices for COVID19. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001004442

• Post_Mortem_Tissue_COVID19_spatial

  Single cell analysis of post mortem tissue samples from SARS-CoV2-infected patients We aim to directly identify the human cell types infected by SARS-CoV-2 and measure the cellular response to COVID19 infection across 20 different tissues from infected patient autopsies. We have examined the expression pattern of viral entry receptors across healthy human tissues to predict several candidate target cell types across the airway and heart. In addition, high prevalence of cardiac failure and abnormal renal function in COVID19 patients implicates heart and kidney involvement, but the pathogenesis of organ specific damage - whether via a direct cytopathic mechanism or an indirect inflammatory response - remains unknown . Currently, we lack confirmation of target cell types and cellular processes in infected tissues as autopsies are discouraged in most countries due to health and safety risks. Our collaborators Drs Michael Osborn and Brian Hanley (Imperial College) have outlined guidelines to perform post-mortem in COVID19 patients (Hanley et al., 2020) and have established a programme of autopsies for research to be performed in a high-risk facility at Westminster Public Mortuary. Here, we propose to identify infected cell types and aberrant molecular pathologies in this precious tissue resource using single cell and spatial genomics. We will prioritise three organ systems: the human airway, heart and the kidney. We will directly examine the cellular identities of SARS-CoV-2 infected cell types and identify the cellular responses to infection across these organs. This fundamental knowledge will help guide future treatment choices for COVID19. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001004441

• Small Genomic Insertions Form Enhancers that Misregulate Oncogenes

  ChIP-Seq data from 102 cell lines were processed to identify insertions relative to the human reference genome. To confirm the ability of a computational pipeline to identify insertions that are actually present in these genomes, we PCR-amplified and deeply sequenced regions where insertions were predicted to exist in MOLT4 T-cell acute lymphoblastic leukemia cells. The current study release makes available sequences of amplicons from a tumor cell genome (MOLT4) where a computational pipeline predicted small insertions from orthogonal data.

  Study phs001242