3901 results for "*geneti*"

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• Identification of 19 novel loci reveals gene regulatory mechanisms determining susceptibility to testicular germ cell tumour

  Testicular germ cell tumour (TGCT) is the most common cancer in young men1,2, and is characterised by strong inherited genetic risk factors3. Here we have undertaken large-scale genome wide association study (GWAS) for TGCT, encompassing ~7,500 cases and ~23,000 controls, through the Oncoarray consortium. We identified 19 novel loci, approximately doubling the number of known TGCT risk loci to 44 (P<5x10-8)4-14 and conduct deep, high-throughput functional annotation of all risk loci. We establish a network of physical interactions for all risk SNPs to candidate casual genes in 3D space, using high-throughput chromosome conformation capture techniques (HiC) in TGCT cells. Firstly, functional evidence reveals widespread disruption of developmental transcriptional regulators, consistent with failed primordial germ cell differentiation as an initiating step in TGCT oncogenesis15. We secondly observe multiple risk loci associated with defective microtubule assembly, compatible with the high level of aneuploidy observed in TGCTs, suggesting gross chromosomal instability. Finally KIT-MAPK signalling features as a recurrently dysregulated pathway. In summary our findings substantially increase the number of known TGCT risk alleles, and provides a functional basis for disease susceptibility.

  Study EGAS00001001836

• Genomewide detection of cytosine methylation by single molecule real-time sequencing

  5-methylcytosine (5mC) is an important type of epigenetic modification. In this study, we enhanced 5mC detection using SMRT sequencing by holistically analyzing kinetic signals of a DNA polymerase and sequence context for every base within a measurement window. We employed a convolutional neural network to train a methylation classification model. This methodology has provided a system for simultaneous genome-wide genetic and epigenetic analyses. 

  Study EGAS00001004642

• Mutated H3 Histones Drive Human Pre-Leukemic Hematopoietic Stem Cell Expansion And Promote Leukemic Aggressiveness

  Leukemogenesis is a stepwise progression from mutated, pre-neoplastic hematopoietic stem cells (HSCs) to full-blown leukemia. Our ability to prevent or treat acute myeloid leukemia (AML) is limited by our incomplete understanding of the epigenetic disruption that is central to this process, including improper histone methylation. Comprehensive analysis of 16 histone H3 genes in 434 primary AML samples identified Q69H, A26P, R2Q, R8H and K27M/I mutations (1.6%), and a higher incidence in secondary AML (s-AML) (9%). We establish that these mutations are important early events in leukemogenesis. They occur in pre-leukemic HSCs, increase the frequency of functional human HSCs, and alter differentiation. The mutations are present in the major leukemic clones in primary samples, and the mutant histones amplify leukemic aggressiveness with increased proliferation, expansion of leukemic progenitor and blast cells, and superior competitiveness in vivo. These effects are dependent on the specific mutation. Genome-wide analysis of K27 mutants revealed increased expression of genes involved in erythrocyte and myeloid differentiation with a corresponding decrease in histone H3 K27 tri-methylation and increase in K27 acetylation. The functional impact of histone mutations is independent of RUNX1 mutations, although they can co-occur. These data establish the involvement of H3 mutations as initial drivers of pre-cancerous stem cell expansion and leukemogenesis.

  Study EGAS00001003288

• Chromosome Y Philogeny in Sardinia

  Genetic variation within the male specific portion of the Y chromosome (MSY) can clarify the origins of contemporary populations, but previous studies were hampered by partial genetic information. Population sequencing of 1,204 Sardinian males identified 11,763 MSY single nucleotide polymorphisms (SNPs), of which 6,751 have not previously been observed. We constructed a MSY phylogenetic tree containing all main haplogroups found in Europe along with many Sardinian-specific lineage clusters within each haplogroup. The tree was calibrated with archaeological data from the initial expansion of the Sardinian population ~7,700 years ago. The ages of nodes highlight different genetic strata in Sardinia and reveal presumptive timing of coalescence with other human populations. We calculate a putative age for coalescence of ~180-200,000 years ago, consistent with previous mitochondrial DNA (mtDNA) based estimates.

  Study EGAS00001000532

• Genome-wide quantification of rare somatic mutations in normal human tissues using massively parallel sequencing

  We present Bottleneck Sequencing System (BotSeqS), a nextgeneration sequencing method that simultaneously quantifies rare somatic point mutations across the mitochondrial and nuclear genomes. BotSeqS combines molecular barcoding with a simple dilution step immediately prior to library amplification. We use BotSeqS to show age and tissue-dependent accumulations of rare mutations and demonstrate that somatic mutational burden in normal tissues can vary by several orders of magnitude, depending on biologic and environmental factors. We further show major differences between the mutational patterns of the mitochondrial and nuclear genomes in normal tissues. Lastly, the mutation spectra of normal tissues were different from each other, but similar to those of the cancers that arose in them. This technology can provide insights into the number and nature of genetic alterations in normal tissues and can be used to address a variety of fundamental questions about the genomes of diseased tissues.

  Study EGAS00001001838

• Tumor suppressor miR-133a modulates the prostate cancer epigenome by repressing BAZ2A

  Our study revealed a new subgroup of prostate tumors defined by the expression of a novel prognostic marker, BAZ2A, and the first time to show the establishment of CIMP via an microRNA-epigenetic interaction in prostate tumors.

  Study EGAS00001000568

• From matrimonial practices to genetic diversity in Southeast Asian populations: the signature of the matrilineal puzzle

  This project aims at revisiting the "matrilineal puzzle" from a population genetics' point of view. The dataset consists of 719 individuals from 12 populations sampled in continental Southeast Asia and genotyped at 598764 loci. This dataset can only be accessed and used for non-commercial research purposes with a finality complying with the informed consent provided by donors. For accessing the data, please provide: 1. An explicit title for the project you wish to use the data for. 2. A detailed institutional affiliation of all recipients and users of the data. 3. A summary (500 words) of the research project, with emphasis on its scientific and societal finality, and predicted outputs. If access is granted by the DAC, data cannot be shared with a third party not initially involved in the project, without the third party officially applying for accessing the data.

  Study EGAS00001003727

• Using_genetics_to_identify_cell_types_and_mechanisms_underlying_susceptibility_to_primary_sclerosing_cholangitis

  Primary sclerosing cholangitis (PSC) is a T-cell mediated, chronic inflammatory condition of the biliary tree that is strongly associated with inflammatory bowel disease. Genome-wide association studies have identified 22 non-HLA genetic risk variants associated PSC. Identifying the genes impacted by these variants has proven difficult as the majority lie in non-coding regions of the genome. Knowledge of the genes and biological pathways these non-coding variants are perturbing is vital to understanding the disease biology. One means of assessing the impact of non-coding variants within disease associated loci upon genes is via colocalisation with eQTL. Many eQTL are cell-type specific, requiring the analysis of disease relevant cell types to detect colocalisation. We have collected PSC-relevant T-cell-subtypes from the peripheral blood of PSC patients via fluorescence activated cell sorting in preparation for RNA sequencing and mapping of eQTL. Samples were collected at the Norfolk and Norwich University Hopital, for which local ethical approval has been granted. Lysed cell samples will be transferred to WTSI and DNA/RNA will be extracted from lysed cell samples by T143 before genotyping (DNA) and custom library preparation and sequencing (RNA). 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 EGAS00001002642

• DNA Methylation loss coupled with mitotic cell division promotes immune evasion of tumours with high mutation load

  Mitotic cell division increases tumour mutation burden and copy number load with a positive and inverse correlation, respectively, with the clinical benefit of immunotherapy. Markers of cell division correlate also with genomic demethylation involving methylation loss in late-replicating partial methylation domains. Here we find that immunomodulatory pathway genes are concentrated in these domains and transcriptionally repressed in demethylated tumours with CpG island promoter hypermethylation. Global methylation loss correlated with immune evasion signatures independently of mutation burden and aneuploidy. Methylome data of our cohort (n = 60) and a published cohort (n = 81) in lung cancer and a melanoma cohort (n = 40) consistently demonstrated that genomic methylation alterations counteract the contribution of high mutation burden and increase immunotherapeutic resistance. Higher predictive power was observed for methylation loss than mutation burden. We also found that genomic hypomethylation correlates with the immune escape signatures of aneuploid tumours. Hence, DNA methylation alterations implicate epigenetic modulation as a combination regimens for precision immunotherapy.

  Study EGAS00001003731

• A system-wide approach to monitor responses to synergistic BRAF and EGFR inhibition in colorectal cancer cells

  Molecular heterogeneity of tumors, epigenetic changes and a diverse range of molecular mechanisms are main contributors to drug resistance, which represents one of the great challenges in cancer treatment. A deeper understanding of the molecular biology of cancer has resulted in better targeted therapies, where one or multiple drugs are adopted in novel therapies to tackle resistance. This beneficial effect of using combination treatments has to some extent also been observed in colorectal cancer (CRC) patients harboring the BRAF(V600E) mutation, whereby dual inhibition of BRAF(V600E) and EGFR increases antitumor activity. Notwithstanding this success, it is not clear whether this combination treatment is the only or most effective treatment to block resistance. Here, we investigate molecular responses upon single and multi-target treatments, over time, using BRAF(V600E) mutant CRC cells as a well-define model system. Through integration of transcriptomic, proteomic and phosphoproteomics data we obtain a comprehensive overview, revealing both well-known and novel responses. We primarily observe widespread upregulation of tyrosine kinases (RTKs) and and metabolic pathways. This points to by which the treated cells switch energy sources as a defensive response entering a quiescent like state, while activating signalling to re-activate the MAPK pathway.

  Study EGAS00001002654

• FinHer_Breast_Cancer_Study

  The purpose of this study is to sequence 500 known cancer genes in 960 newly diagnosed high risk breast cancer patients treated with current standard of care therapies and trastuzumab, for somatic alteration and copy number changes. We will be using next gen sequencing technology to determine the prognostic relevance of these somatic genetic alterations and of teh low frequency events to determine if they are associated with trastuzumab benefit or HER2 positive breast cancer, i.e. treatment interaction. The samples will be analysed adn correlated with clinical variables including outcome.

  Study EGAS00001000648

• Clonal expansion and epigenetic reprogramming following deletion or amplification of mutant IDH1

  IDH1 mutation is the earliest genetic alteration in low-grade gliomas (LGGs), but its role in tumor recurrence is unclear. Mutant IDH1 drives overproduction of the oncometabolite D-2-hydroxyglutarate (2HG) and a CpG island (CGI) hypermethylation phenotype (G-CIMP). To investigate the role of mutant IDH1 at recurrence, we performed a longitudinal analysis of 50 IDH1 mutant LGGs. We discovered six cases with copy number alterations (CNAs) at the IDH1 locus at recurrence. Deletion or amplification of IDH1 was followed by clonal expansion and recurrence at a higher grade. Successful cultures derived from IDH1 mutant, but not IDH1 wild-type, gliomas systematically deleted IDH1 in vitro and in vivo, further suggestive of selection against the heterozygous mutant state as tumors progress. Tumors and cultures with IDH1 CNA had decreased 2HG, maintenance of G-CIMP, and DNA methylation reprogramming outside CGI. Thus, while IDH1 mutation initiates gliomagenesis, in some patients, mutant IDH1 and 2HG are not required for later clonal expansions.

  Study EGAS00001001854

• Genetic subclone heterogeneity of tumor-initiating cells in human colorectal cancer

  A subset of tumor-initiating cells (TIC) drives colorectal cancer (CRC) progression in serial mouse xenografts. The TIC compartment itself is heterogeneous and comprises hierarchically organized long-term TIC, tumor transient amplifying cells, and delayed contributing TIC. To address the genomic heterogeneity of the CRC TIC compartment, genome-wide high-coverage whole genome sequencing was performed on patient tumors (n=3), corresponding serially passaged TIC-enriched spheres, and serial xenografts.HIPO P002

  Study EGAS00001001857

• Whole transcriptome and exome sequencing of childhood ALL

  Gene fusion is a major class of genomic abnormalities in childhood acute lymphoblastic leukemia (ALL) and sentinel chromosomal rearrangements involving EP300 and CREBBP may cause global epigenetic deregulation during leukemogenesis with potentials for therapeutic targeting. This dataset includes whole transcriptome sequencing of 231 children with acute lymphoblastic leukemia from a Singapore-Malaysia frontline clinical treatment protocol.

  Study EGAS00001001858

• Next-Generation Sequencing of AV Nodal Reentry Tachycardia patients

  Atrioventricular nodal reentry tachycardia (AVNRT) is the most common form of regular paroxysmal supraventricular tachycardia. This arrhythmia affects women twice as frequently as men, and is often diagnosed in patients below 40 years of age. Familial clustering, early onset of symptoms, and lack of structural anomaly indicate involvement of genetic factors in AVNRT pathophysiology. We hypothesized that AVNRT patients have a high prevalence of variants in genes that are highly expressed in the atrioventricular conduction axis of the heart and potentially involved in arrhythmic diseases. Next-generation sequencing of 67 genes was applied to the DNA profile of 298 AVNRT patients and 10 AVNRT family members using HaloPlex Target Enrichment System.In total, we identified 229 variants in 60 genes; 215 missenses, four frame shifts, four codon deletions, three missense and splice sites, two stop-gain variants, and one start-lost variant. Sixty-five of these were not present in the Exome Aggregation Consortium (ExAC) database. Furthermore, we report two AVNRT families with co-segregating variants. Seventy-five of 284 AVNRT patients (26.4%) and three family members to different AVNRT probands had one or more variants in genes affecting the sodium handling. Fifty-four out of 284 AVNRT patients (19.0%) had variants in genes affecting the calcium handling of the heart. We furthermore find a large proportion of variants in the HCN1-4 genes. We did not detect a significant enrichment of rare variants in the tested genes.This could be an indication that AVNRT might be an electrical arrhythmic disease with abnormal sodium and calcium handling.

  Study EGAS00001002745

• Glioblastoma initiating cells are sensitive to histone demethylase inhibition due to epigenetic deregulation

  Tumor-initiating cells are a subpopulation of cells that have self-renewal capacity to regenerate a tumor. Here, we identify stem cell-like chromatin features in human glioblastoma initiating cells (GICs) and link them to a loss of the repressive histone H3 lysine 9 trimethylation (H3K9me3) mark. Increasing H3K9me3 levels by histone demethylase inhibition led to cell death in GICs but not in their differentiated counterparts. The induction of apoptosis was accompanied by a loss of the activating H3 lysine 9 acetylation (H3K9ac) modification and accumulation of DNA damage and downregulation of DDR genes. Upon knockdown of histone demethylases KDM4C and KDM7A both differentiation and DNA damage was induced. Thus, the H3K9me3-H3K9ac equilibrium is crucial for GIC viability and represents a chromatin feature that can be exploited to specifically target this tumor subpopulation.

  Study EGAS00001003750

• DIPG RNA and exome sequencing

  DIPG is a paediatric high-grade glioma that diffusely infiltrates the brainstem and is the leading cause of paediatric brain tumour death. Here we performed RNA and whole exome sequencing on DIPG and control samples to analyse transcriptomic and genetic alterations associated with this devastating disease, and to understand the relationship between them.

  Study EGAS00001004749

• Variation in the Glucose Transporter gene SLC2A2 is associated with glycaemic response to metformin

  Metformin is the first-line antidiabetic drug with over 100 million users worldwide, yet its mechanism of action remains unclear1. Here the Metformin Genetics (MetGen) Consortium reports a three-stage genome wide association study (GWAS), consisting of 13,123 participants of different ancestries. The C-allele of rs8192675 in the intron of SLC2A2, which encodes the facilitated glucose transporter GLUT2, was associated with a 0.17% (p=6.6x10-14) greater metformin induced HbA1c reduction in 10,577 participants of European ancestry. rs8192675 is the top cis-eQTL for SLC2A2 in 1,226 human liver samples, suggesting a key role for hepatic GLUT2 in regulation of metformin action. In obese individuals C-allele homozygotes at rs8192675 had a 0.33% (3.6mmol/mol) greater absolute HbA1c reduction than T-allele homozygotes.This is about half the effect seen with the addition of a DPP-4 inhibitor, and equates to a dose difference of 550mg of metformin, suggesting rs8192675 as a potential biomarker for stratified medicine.

  Study EGAS00001001875

• Growth Hormone (GH) -secreting Pituitary Adenoma

  We profiled the somatic landscape of 21 growth hormone (GH) -secreting pituitary adenomas using somatic copy-number alteration (SCNA), whole-genome sequencing (WGS), bisulfate sequencing, and transcriptome approaches. See details in Valimaki et al. Genetic and epigenetic characterization of growth hormone (GH) - secreting pituitary tumors. Manuscript in preparation, 2019.

  Study EGAS00001003488

• Kibbutzim Family study

  The Kibbutzim Family Study (KFS) was established in 1992 to investigate the environmental and genetic determinants of cardiometabolic risk factors and their change over time. The participants belong to large families living in close-knit communities, called “Kibbutzim”, in Northern Israel. The Kibbutz has been a communal settlement, which has created a relatively homogeneous environment for its members. Kibbutz members are mostly of Ashkenazi Jewish ancestry, with the remaining members belonging to other Jewish subgroups. Participants were recruited in two phases from six Kibbutzim. In the first recruitment phase of the study (1992–1993) 500 individuals from 80 extended families (range 2 to 43) were examined. During the second phase (1999–2000), all participants from the first phase were invited for repeat examinations (80% response rate) and additional new participants were recruited, giving a total of 922 individuals from 150 extended families (range 2 to 55). Families were invited to participate if they consisted of at least four individuals who (i) lived in the Kibbutz, (ii) spanned at least two generations, and (iii) were at least 15 years old. Families were retained if at least two family members consented to participate in the study. Overall, 1033 participants were recruited; 111 were examined only in the first phase, 533 only in the second phase, and 389 were included in both. 901 individuals were successfully genotyped using Illumina HumanCoreExome BeadChip.

  Study EGAS00001002782

• The_contribution_of_POT1_variants_to_sporadic_melanoma_development

  A case-control series of melanoma cases from Leeds, UK have been sequenced in the Fluidigm platform to identify genetic variants associated with sporadic melanoma development. Samples in which potentially contributing variants have been detected are being sequenced in an orthogonal platform for variant confirmation.

  Study EGAS00001001964

• Second hit rare genetic variants in families with seemingly GBA gene associated Parkinson’s disease

  Study EGAS00001004777

• Genetic control of the transcriptomic response of monocytes to bacterial and viral stimuli assessed by RNA-seq in Africans and Europeans

  Humans differ in the outcome that follows exposure to life-threatening pathogens, yet the extent of population differences in immune responses, and their genetic and evolutionary determinants, remain undefined. Here, we characterized, using RNA-sequencing, the transcriptional response of primary monocytes from Africans and Europeans to bacterial and viral stimuli - ligands activating Toll-like receptors pathways (TLR1/2, TLR4 and TLR7/8) and influenza virus - and mapped expression quantitative trait loci (eQTL). We identify multiple cis- and trans-eQTL that contribute to the marked differences in immune responses detected within and between populations, including a TLR1 master regulator that decreases expression of pro-inflammatory genes in Europeans only. We show that regulatory variants have been privileged targets of natural selection, uncovering evolutionarily advantageous mechanisms, such as attenuated inflammation. Finally, we demonstrate that admixture with Neandertals introduced regulatory variants into European genomes, affecting preferentially responses to viral challenges, and identify archaic haplotypes that contributed to population genetic adaptation.

  Study EGAS00001001895

• Methylation analysis for plasma DNA of patients with organ transplantation

  We developed Genetic-Epigenetic Tissue Mapping (GETMap) to determine the tissue composition of plasma DNA carrying genetic variants not present in the constitutional genome through comparing their methylation profiles with relevant tissues. We validated this approach by showing that, in pregnant women, circulating DNA carrying fetal-specific alleles was entirely placenta-derived.

  Study EGAS00001004788

• Knee_OA_Functional_Genomics

  The aim of this work is to apply an integrated systems approach to understand the biological underpinnings of knee osteoarthritis that culminates in the need for total joint replacement (TJR). This study is a feasibility pilot that integrates functional genomics data from diseased and non-diseased tissues of OA patients who have undergone TJR. For each tissue, we characterised epigenetic marks (methylation), gene transcription (RNASeq) and expression (quantitative proteomics). We also generated genotype data on the HumanCoreExome array for each individual.

  Study EGAS00001001899

• Familial psychosis associated with a missense mutation at MACF1 gene combined with the rare duplications DUP3p26.3 and DUP16p23.3, affecting the CNTN6 and CDH13 genes

  Psychosis is a highly heritable and heterogeneous psychiatric condition. Its genetic architecture is thought to be the result of the joint effect of common and rare variants. Families with high prevalence are an interesting approach to shed light on the rare variant's contribution without the need of collecting large cohorts. To unravel the genomic architecture of a family enriched for psychosis, with four affected individuals, we applied a system genomic approach based on karyotyping, genotyping by whole-exome sequencing to search for rare single nucleotide polymorphisms (SNPs) and SNP array to search for copy-number variants (CNVs). We identified a rare non-synonymous variant, g.39914279 C>G, in the MACF1 gene, segregating with psychosis. Rare variants in the MACF1 gene have been previously detected in SCZ patients. Besides, two rare CNVs, DUP3p26.3 and DUP16p23.3, were also identified in the family affecting relevant genes (CNTN6 and CDH13, respectively). We hypothesize that the co-segregation of these duplications with the rare variant g.39914279 C>G of MACF1 gene precipitated with schizophrenia and schizoaffective disorder.

  Study EGAS00001004791

• Primary prostate Hi-C

  Prostate cancer is a heterogeneous disease whose progression is linked to genome instability. Despite large-scale tumour sequencing efforts, the impact of mutations on the genetic architecture in cancer remains ill-defined due to limited integration of genomics data across dimensions. We addressed this limitation by assessing the impact of structural variants on the chromatin states and the three-dimensional organization across benign and malignant primary prostate genomes. We find high concordance in the three-dimensional genome organization between malignant and benign prostate tissues, arguing for constraints to the three-dimensional genome of prostate tumours. Moreover, we identify structural variants as effectors of changes to focal chromatin interactions, guiding cis-regulatory element hijacking that imposes opposing expression changes on genes found at antipodes of a rearrangement. This leads to the repression of tumour suppressor gene expression and up-regulation of oncogenes, such as at the TMPRSS2-ERG and PMEPA1-ZNF156 loci. Collectively, our results argue that cis-regulatory element hijacking by structural variants overshadows large-scale topological changes to alter gene regulation and promote oncogenesis.

  Study EGAS00001005014

• Genomics analysis of mucinous tumours of the ovary and related neoplasms

  To perform genetic and gene expression analyses on mucinous ovarian tumours to determine a progression model, cell of origin and novel therapeutic targets.

  Study EGAS00001003545

• Comprehensive Genomic and Transcriptomic Analysis of Rare Cancers for Guiding of Therapy (H021)

  Here we analyzed the molecular profiles and clinical outcomes of 1,310 patients (proportion of rare cancers, 75%) enrolled in a prospective observational study by the German Cancer Consortium that applies whole-genome/exome and RNA sequencing to inform the care of adults with incurable cancers. Based on 472 single and six composite biomarkers, a cross-institutional molecular tumor board provided evidence-based management recommendations, including diagnostic reevaluation, genetic counseling, and experimental treatment, in 88% of cases. Recommended therapies were administered in 362 of 1,138 patients (31.8%) and resulted in significantly improved response and disease control rates (23.9% and 55.3%, respectively) compared to previous therapies, translating into a progression-free survival ratio >1.3 in 35.7% of patients.

  Study EGAS00001004813

• Summary statistics of meta-analysis using two genome-wide association study of inflammatory bowel disease in Koreans.

  Inflammatory bowel disease (IBD), a chronic inflammatory disorder of the gastrointestinal tract, is thought to develop due to dysregulated mucosal immune responses to gut flora in genetically susceptible individuals. Crohn’s disease (CD) and ulcerative colitis (UC) are the two major subtypes of IBD. To identify additional susceptibility loci for IBD in Asians, we performed meta-analyses using two genome-wide association studies.

  Study EGAS00001005026

• Genetics and transcriptomes of pediatric B cell precursor leukemia with gain of chromosome 21

  Down syndrome (DS, constitutive trisomy 21) children have a 27-fold increased risk of developing B-ALL (DS-ALL), face a worse outcome due to treatment-related morbidities, and an increased rate of relapses compared to other children. This highlights the need to better understand the mechanisms of DS-associated leukemogenesis to develop more adapted treatment. In this study, we characterized the genetic and transcriptomic landscapes of DS-ALL and found a high incidence of somatic mutations leading to RAS/MAPK pathway activation in DS-ALL, as seen in other pediatric B-ALL presenting somatic gains of the chromosome 21 (B-ALL+21).

  Study EGAS00001003760

• BLUEPRINT ChIP-seq of Epigenetic programming during monocyte to macrophage differentiation and trained innate immunity

  Monocyte differentiation into macrophages represents a cornerstone process for host defense. Concomitantly, immunological imprinting of either tolerance or trained immunity determines the functional fate of macrophages and susceptibility to secondary infections. Transcriptomes and epigenomes in four primary cell types: monocytes, in vitro differentiated naïve, tolerized and trained macrophages were characterized. Inflammatory and metabolic pathways were modulated in macrophages, including decreased inflammasome activation, and pathways functionally implicated in trained immunity were identified. Strikingly, β-glucan training elicits an exclusive epigenetic signature, revealing a complex network of enhancers and promoters. Analysis of transcription factor motifs in DNase I hypersensitive sites at cell-type specific epigenetic loci unveiled differentiation and treatment specific repertoires. Altogether, this study provides a resource to understand the epigenetic changes that underlie innate immunity in humans.

  Study EGAS00001000951

• HipSci___Whole_Exome_sequencing___Battens

  The HipSci project brings together diverse constituents in genomics, proteomics, cell biology and clinical genetics to create a UK national iPS cell resource and use it to carry out cellular genetic studies. In this sub-study we perform whole exome sequencing using Agilent whole exome pulldown method on iPS cells generated from skin biopsies or blood samples from rare disease patients diagnosed with Battens disease

  Study EGAS00001001975

• Mapping_genetic_variants_underlying_gene_regulation_in_inflammed_intestinal_cell_types_to_identify_novel_IBD_drug_targets

  Biopsies from the terminal ileum and rectum of individuals with Crohn's disease are digested on ice to single cells and processed for single-cell RNA-sequencing (10X Genomics and Illumina) 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 EGAS00001003770

• Physiological and genetic adaptations to diving in Sea Nomads

  Understanding the physiology and genetics of human hypoxia tolerance has important medical implications, but this phenomenon has thus far only been investigated in high-altitude human populations. Another system, yet to be explored, is humans who engage in breath-hold diving. The indigenous Bajau people (“Sea Nomads”) of Southeast Asia live a subsistence lifestyle based on breath-hold diving and are renowned for their extraordinary breath holding abilities. However, it is unknown whether this has a genetic basis. Using a comparative genomic study, we show that natural selection on genetic variants in the PDE10A gene have increased spleen size in the Bajau, providing them with a larger reservoir of oxygenated red blood cells. We also find evidence of strong natural selection specific to the Bajau on BDKRB2, a gene affecting the human diving reflex. Thus, the Bajau, and possibly other natural diving populations, provide a new opportunity to study human adaptation to hypoxia tolerance.

  Study EGAS00001002823

• HipSci___Whole_Exome_sequencing___Macular_dystrophy

  The HipSci project brings together diverse constituents in genomics, proteomics, cell biology and clinical genetics to create a UK national iPS cell resource and use it to carry out cellular genetic studies. In this sub-study we perform whole exome sequencing using Agilent whole exome pulldown method on iPS cells generated from skin biopsies or blood samples from rare disease patients diagnosed with Macular dystrophy

  Study EGAS00001001982

• HipSci___Whole_Exome_sequencing___PID

  The HipSci project brings together diverse constituents in genomics, proteomics, cell biology and clinical genetics to create a UK national iPS cell resource and use it to carry out cellular genetic studies. In this sub-study we perform whole exome sequencing using Agilent whole exome pulldown method on iPS cells generated from skin biopsies or blood samples from rare disease patients diagnosed with blood and platelet disorders

  Study EGAS00001001983

• HipSci HumanExome BeadChip analysis - Hereditary Spastic Paraplegia

  The HipSci project brings together diverse constituents in genomics, proteomics, cell biology and clinical genetics to create a UK national iPS cell resource and use it to carry out cellular genetic studies. In this sub-study we performed Genotyping analysis using the Infinium HumanExome BeadChip on iPS cells generated from skin biopsies or blood samples from rare disease patients diagnosed with Hereditary Spastic Paraplegia.

  Study EGAS00001002006

• HipSci HumanExome BeadChip analysis - Congenital Hyperinsulinia

  The HipSci project brings together diverse constituents in genomics, proteomics, cell biology and clinical genetics to create a UK national iPS cell resource and use it to carry out cellular genetic studies. In this sub-study we performed Genotyping analysis using the Infinium HumanExome BeadChip on iPS cells generated from skin biopsies or blood samples from rare disease patients diagnosed with Congenital Hyperinsulinia.

  Study EGAS00001002010

• HipSci HumanExome BeadChip analysis - Hypertrophic Cardiomyopathy

  The HipSci project brings together diverse constituents in genomics, proteomics, cell biology and clinical genetics to create a UK national iPS cell resource and use it to carry out cellular genetic studies. In this sub-study we performed Genotyping analysis using the Infinium HumanExome BeadChip on iPS cells generated from skin biopsies or blood samples from rare disease patients diagnosed with Hypertrophic Cardiomyopathy.

  Study EGAS00001002011

• HipSci HumanExome BeadChip analysis - Battens disease

  The HipSci project brings together diverse constituents in genomics, proteomics, cell biology and clinical genetics to create a UK national iPS cell resource and use it to carry out cellular genetic studies. In this sub-study we performed Genotyping analysis using the Infinium HumanExome BeadChip on iPS cells generated from skin biopsies or blood samples from rare disease patients diagnosed with Battens disease.

  Study EGAS00001002016

• HipSci HumanHT 12 Expression BeadChip analysis - Alport syndrome

  The HipSci project brings together diverse constituents in genomics, proteomics, cell biology and clinical genetics to create a UK national iPS cell resource and use it to carry out cellular genetic studies. In this sub-study we performed Expression analysis using the Illumina HumanHT -12 Expression BeadChip on iPS cells generated from skin biopsies or blood samples from rare disease patients diagnosed with Alport syndrome.

  Study EGAS00001002024

• HipSci HumanHT 12 Expression BeadChip analysis - Hypertrophic Cardiomyopathy

  The HipSci project brings together diverse constituents in genomics, proteomics, cell biology and clinical genetics to create a UK national iPS cell resource and use it to carry out cellular genetic studies. In this sub-study we performed Expression analysis using the Illumina HumanHT -12 Expression BeadChip on iPS cells generated from skin biopsies or blood samples from rare disease patients diagnosed with Hypertrophic Cardiomyopathy.

  Study EGAS00001002026

• HipSci HumanHT 12 Expression BeadChip analysis - Primary immune deficiency

  The HipSci project brings together diverse constituents in genomics, proteomics, cell biology and clinical genetics to create a UK national iPS cell resource and use it to carry out cellular genetic studies. In this sub-study we performed Expression analysis using the Illumina HumanHT -12 Expression BeadChip on iPS cells generated from skin biopsies or blood samples from rare disease patients diagnosed with Primary immune deficiency.

  Study EGAS00001002027

• HipSci HumanHT 12 Expression BeadChip analysis - Bleeding and Platelet disorders

  The HipSci project brings together diverse constituents in genomics, proteomics, cell biology and clinical genetics to create a UK national iPS cell resource and use it to carry out cellular genetic studies. In this sub-study we performed Expression analysis using the Illumina HumanHT -12 Expression BeadChip on iPS cells generated from skin biopsies or blood samples from rare disease patients diagnosed with Bleeding and Platelet disorders.

  Study EGAS00001002028

• HipSci HumanHT 12 Expression BeadChip analysis - Macular Dystrophy

  The HipSci project brings together diverse constituents in genomics, proteomics, cell biology and clinical genetics to create a UK national iPS cell resource and use it to carry out cellular genetic studies. In this sub-study we performed Expression analysis using the Illumina HumanHT -12 Expression BeadChip on iPS cells generated from skin biopsies or blood samples from rare disease patients diagnosed with Macular Dystrophy.

  Study EGAS00001002029

• HipSci HumanHT 12 Expression BeadChip analysis - Battens disease

  The HipSci project brings together diverse constituents in genomics, proteomics, cell biology and clinical genetics to create a UK national iPS cell resource and use it to carry out cellular genetic studies. In this sub-study we performed Expression analysis using the Illumina HumanHT -12 Expression BeadChip on iPS cells generated from skin biopsies or blood samples from rare disease patients diagnosed with Battens disease.

  Study EGAS00001002031

• Extreme phenotypes define epigenetic and metabolic signatures in cardiovascular diseases.

  Improving the understanding of cardiometabolic syndrome pathophysiology and its relationship with thrombosis are ongoing healthcare challenges. Using plasma biomarkers analysis coupled with the transcriptional and epigenetic characterisation of cell types involved in thrombosis, obtained from two extreme phenotype groups (obese and lipodystrophy) and comparing these to lean individuals and blood donors, the present study identifies the molecular mechanisms at play, highlighting patterns of abnormal activation in innate immune phagocytic cells and shows that extreme phenotype groups could be distinguished from lean individuals, and from each other, across all data layers. The characterisation of the same obese group, six months after bariatric surgery shows the loss of the patterns of abnormal activation of innate immune cells previously observed. However, rather than reverting to the gene expression landscape of lean individuals, this occurs via the establishment of novel gene expression landscapes. Netosis and its control mechanisms emerge amongst the pathways that show an improvement after surgical intervention. Taken together, by integrating across data layers, the observed molecular and metabolic differences form a disease signature that is able to discriminate, amongst the blood donors, those individuals with a higher likelihood of having cardiometabolic syndrome, even when not presenting with the classic features.

  Study EGAS00001003780

• Characterization_of_genomic_landscape_of_Peripheral_T_cell_Lymphomas__not_otherwise_specified__PTCL_NOS_

  Peripheral T-cell lymphomas not otherwise specified (PTCL-NOS) represent a heterogeneous group of nodal and extra-nodal mature T-cell lymphomas, with a low prevalence in Western countries. PTCL-NOSs account for about 25% of all PTCLs and are currently diagnosed based on exclusion criteria, as this lymphomas lack unifying morphological, phenotypic and genomic features. Cytogenetic and FISH analysis of PTCL-NOS samples have not revealed recurrent pathogenetic abnormalities, while gene expression profiling has shown only partial ability to segregate cases representing homogeneous clinic-pathological entities. This underscores the need to look at PTCL-NOS with innovative and high-throughput approaches to identify recurrent genetic lesions that could further our understanding of the biology of this heterogeneous group of diseases, provide better diagnostic tools and perhaps new targets for innovative treatments. Our aim is to study ~15 patients affected by PTCL-NOS. Out study will be funded by a private, non-profit Italian cancer research fund (Associazione Italiana per la Ricerca sul Cancro, www.airc.it) based on a grant owned by Anna Dodero and Cristiana Carniti, hematologists at INT. Samples will be analysed by whole genome sequencing using Illumina X10 machines, on a 150bp-PE protocol. Data will be analysed using the pipeline available in Team 78, under the supervision of Peter Campbell, the WTSI faculty who will oversee the project, and by Francesco Maura, visiting scientist at the WTSI.

  Study EGAS00001002057

• Genetic analysis of HLA and immune escape genes in Diffuse Large B-cell Lymphoma

  Fifty percent of diffuse large B-cell lymphoma (DLBCL) cases lack cell-surface expression of the class-I major histocompatibility complex (MHC-I), thereby escaping immune recognition by cytotoxic T cells. In order to comprehensively identify the mechanisms involved in MHC-I loss, we first performed immunophenotypic analysis of both MHC class-I and -II in 657 cases across the spectrum of B-NHL, revealing that loss of MHC-I, but not MHC-II, is preferentially restricted to DLBCL. We then used whole exome and targeted deep-sequencing to examine genes involved in MHC-I expression in 74 DLBCL samples representative of MHC-I positive and negative cases. We show here that somatic biallelic or monoallelic inactivation of B2M and/or HLA-I is present in 80.9% (34/42) of MHC-I negative tumors. Furthermore, 68.8% (22/32) of MHC-I positive DLBCLs also harbored monoallelic HLA-I genetic alterations (MHC-I positivemono) that lead to allelic imbalance, suggesting allele-specific inactivation. Both MHC-I negative and MHC-I positivemono cases showed a significantly higher mutational burden as well as a higher number of inferred neo-antigens, suggesting co-selection of HLA-I loss and sustained neo-antigen production. Interestingly, the analysis of > 500.000 individuals in two databases revealed homozygosity of germline HLA-I genes in 26-38% of DLBCL patients, a frequency significantly higher than that observed in any other cancer type. In mice, germinal-center B cells lacking HLA-I expression did not progress to lymphoma and were counterselected in the context of oncogene-driven lymphomagenesis, suggesting that additional events are needed to license immune evasion. These results suggest a multi-step process of HLA-I loss including both germ-line and somatic events in DLBCL development, and have direct implications for the pathogenesis and immunotherapeutic targeting of this disease.

  Study EGAS00001005054