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• Whole genome sequencing

  This dataset contains whole genome sequencing data from 22 samples of FACS-purified bone marrow CD34+ haematopoietic stem and progenitor cells and matched hair follicle controls collected from individuals undergoing hip replacement surgery. Additionally, it contains whole genome sequencing data from unseparated bone marrow mononuclear cells, CD3-CD34- bone marrow mononuclear cells, and peripheral blood granulocytes of the same 14 samples. Haematopoietic samples were sequenced to a target coverage of 90-120x; 19 of them were re-sequenced to a total target coverage of 270x. Hair follicle controls were sequenced to a target coverage of 30x.

  Dataset EGAD00001015178

• Chordoma Sequencing Project RNAseq

  This is a continuation of the Chordoma Sequencing Project. All cancers arise due to somatically acquired abnormalities in DNA sequence. Systematic sequencing of cancer genomes allows acquisition of complete catalogues of all classes of somatic mutation present in cancer. These mutation catalogues will allow identification of the somatically mutated cancer genes that are operative and characterise patterns of somatic mutation that may reflect previous exogenous and endogenous mutagenic exposures. In this application, we aim to perform whole genome sequencing on 10 chordoma matched genome pairs. RNA Sequencing/Methylation and SNP6 and an additional sequencing of three cancer cell lines will be added to this work.

  Dataset EGAD00001000653

• Transcriptomics of human olfactory mucosa

  The olfactory gene repertoire is largely species-specific, shaped by the nature and necessity of chemosensory information for survival in each species' niche. We are intrigued by this interspecific variation and started to investigate the olfactory transcriptome in primates for evidence of selection at the level of receptor gene choice. Having collected this data from two primates, we now wish to extend the analysis to humans. 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/

  Dataset EGAD00001003213

• IBD Whole Genome Sequencing Phase 1 (2018-08-03)

  We will sequence at 15X coverage the genomes of 960 IBD patients. These samples are currently onsite at Sanger and made available for sequencing via our collaboration with the UK IBD Genetics consortium. During the next quinquennium we intend to sequence the genomes of many thousand IBD patients and these 960 represent the first stage of this effort. Ultimately we will perform association tests comparing these genomes to similar numbers of control genomes to identify rare and low-frequency variants underlying IBD. . This dataset contains all the data available for this study on 2018-08-03.

  Dataset EGAD00001004272

• Congenital anosmia 1

  Congenital anosmias can be complete (the lack of a sense of smell) or specific (the inability to detect specific smells). To date, only a single recessive gene underlying complete anosmia has been identified. Here we sequenced the exomes of 10 individuals from a single family, including three with complete anosmia, across three generations to identify the genetic basis of congenital anosmia in this family. 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/

  Dataset EGAD00001002210

• Gene expression profile of mesothelial-derived carcinoma-associated fibroblasts

  RNA-sequencing was carried out on ascetic fluid-isolated mesothelial cells from low-grade serous ovarian cancer patients, high-grade serous ovarian cancer patients, chemotherapy-treated high-grade serous ovarian cancer patients and control mesothelial cells obtained from non-oncologic patients to identify differentially expressed genes associated to mesothelial-to-mesenchymal transition process. The dataset contains 18 samples: - Control mesothelial cells: 4 samples - Group 1, high-grade serous ovarian cancer patients: 3 samples - Group 2, chemotherapy-treated high-grade serous ovarian cancer patients: 5 samples - Group 3, low-grade serous ovarian cancer patients: 6 samples

  Dataset EGAD00001005133

• RNA sequencing of CD8 T cells from melanoma patients prior to and during checkpoint immunotherapy and untreated healthy controls

  We are interested in inter-individual variation in transcriptional response to immune checkpoint blockade. We have analysed poly A purified RNA expression from CD8 T cells (297 transcriptomes in total) isolated from metastatic melanoma patients (n=106) prior to and during treatment with either single agent (Pembrolizumab) or combination (Ipilimumab/ Nivolumab) immune checkpoint blockade. We compare expression at different stages of treatment and additionally contrast this with that from healthy controls (n=68).

  Dataset EGAD00001005973

• Application of short-RNA-seq in post-mortem human hippocampi from the Calgary Brain Bank (CBB) to assess transcriptome-wide deregulation in processing of SINE Alu RNAs in Alzheimer’s disease

  Here, we investigate through short-RNA_seq in human hippocampi from the Calgary Brain Bank (CBB) whether Alu RNAs are processed in human brains, and whether their processing ratio is deregulated in brains of AD patients compared to healthy aging individuals.

  Study EGAS00001004973

• Whole Exome Sequencing and RNA-Seq to Characterize the Somatic Breast Cancer Landscape Among Latinas in California

  Somatic mutational profiles are increasingly being used to guide treatment. However, there is a dearth of data from non-European populations. To address this gap, we conducted paired tumor/normal whole exome paired-end sequencing and tumor RNA-Seq on 146 breast tumors from 140 Hispanic/Latina (H/L) women with breast cancer. We characterized somatic mutations, copy number alterations, tumor subtypes [Prediction Analysis of Microarray 50 (PAM50)], Catalogue Of Somatic Mutations In Cancer (COSMIC) mutation signatures and expression profiles, and compared them to breast tumors from non-Hispanic White (White) women in The Cancer Genome Atlas (TCGA). Using MutSigCV, we found that the most commonly mutated genes, including TP53, RUNX1, PTEN, PIK3CA, MAP3K1, GATA3, CDH1 and CBFB, were similar to those in breast tumors from non-Hispanic white women. Novel findings were that outliers of BLTP2 (aka KIAA0100) over-expression and COSMIC mutational signature 16 were more common in tumors from H/L women than White women. We also identified that the known germline APOBEC3A/B deletion variant was significantly more common in H/L women and was associated with indigenous American ancestry. Data available through dbGaP will be whole-exome sequencing (WES) and RNA sequencing (RNA-Seq) data, as well as phenotypic data, including estrogen receptor, progesterone receptor, and HER2 receptor status, tumor histology, stage, and grade, and age at diagnosis.

  Study phs003218

• Novel CNV contribution to schizophrenia from a genome wide study of 41,321 subjects

  Genomic copy number variants (CNVs) have been strongly implicated in the etiology schizophrenia (SCZ). However, apart from a small number of risk variants, elucidation of the CNV contribution to risk has been difficult due to the very low frequencies of risk alleles, all occurring in less than 1% of patients. We sought to address this obstacle through a collaborative effort unprecedented in psychiatry in which we applied a centralized analysis pipeline to a large SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden is observed in SCZ patients (OR=1.11, P=5.7e-15), and persists after excluding loci implicated in previous studies (OR=1.07, P=1.7e-6). CNV Burden is also enriched for genes associated with synaptic function (OR = 1.68, P = 2.8e-11) and neurobehavioral phenotypes in mouse (OR = 1.18, P= 7.3e-05). While only previously implicated loci surpass strict genome-wide testing correction, we identify “novel” CNVs (BH-FDR < 0.05) that confer both protective and risk effects on SCZ and are predominantly mediated by non-allelic homologous recombination (NAHR). Our combined data find genome-wide significant support for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2.

  Study EGAS00001001960

• Resistance to anti-EGFR therapy in colorectal cancer

  Monoclonal antibodies targeting the Epidermal Growth Factor Receptor (EGFR), such as cetuximab and panitumumab, have evolved to important therapeutic options in metastatic colorectal cancer (CRC). However, almost all patients with clinical response to anti-EGFR therapies show disease progression within a few months and little is known about mechanism and timing of resistance evolution. Here we performed whole genome sequencing of plasma DNA (plasma-Seq) from patients treated with anti-EGFR therapy. We demonstrate that development of resistance to anti-EGFR therapies is frequently associated with focal amplifications of KRAS, MET, and ERBB2. However, we also show that focal KRAS amplifications can be acquired in tumor genomes of patients under cytotoxic chemotherapy. Furthermore, we provide evidence that specific chromosomal polysomies, such as overrepresentations of 12p and 7p, harboring KRAS and EGFR, respectively, determine responsiveness to anti-EGFR therapy. In contrast, employing ultra-sensitive deep sequencing of genes associated with anti-EGFR resistance, such as KRAS, BRAF, PIK3CA, and EGFR, we did not observe the occurrence of novel, acquired mutations. Overall, whole-genome plasma DNA sequencing represents a non-invasive blood-based surrogate measure of changes in tumors. As such, plasma-Seq enables the identification of novel mutant clones and may therefore facilitate early adjustments of therapies that may delay or prevent disease progression.

  Study EGAS00001000582

• Polyclonal selection of immune checkpoint mutations in thyroid autoimmunity - ExomeNanoSeq

  Our immune system contains multiple tolerance checkpoints to prevent the activation of self-reactive lymphocytes. How some lymphocytes escape these constraints to cause autoimmune disease remains poorly understood. A long-standing hypothesis in autoimmunity posits that somatic mutations in immune regulatory genes may enable self-reactive lymphocytes to bypass tolerance checkpoints. However, testing this hypothesis has proved challenging due to technical limitations in detecting somatic mutations in polyclonal cell populations. Here, we use deep whole-exome and targeted NanoSeq, a highly accurate single-molecule DNA sequencing protocol, to comprehensively search for driver mutations in autoimmune thyroid disease. This revealed a remarkably high number of B cell clones convergently acquiring loss-of-function somatic mutations in key immune checkpoint genes TNFRSF14 (also known as HVEM) and CD274 (encoding PD-L1), as well as less frequent driver mutations in a diversity of other immune genes. In highly inflamed biopsies, we detected tens to hundreds of independent immune-checkpoint mutant clones. Laser capture microdissection, methylation sequencing, spatial transcriptomics, immunohistochemistry and single-nucleus DNA sequencing localised these mutations to non-naive B cells and revealed frequent co-occurrence of drivers in single cells. We found widespread TNFRSF14 biallelic loss in mutant B cells, and several clones with as many as 4-6 driver mutations. Whilst each clone accounts for a small proportion of cells (typically <1%), the myriad mutant clones in each donor collectively amounted to a substantial fraction of B cells harbouring one or more driver mutations. Our results support the hypothesis that somatic mutations in autoimmune lymphocytes may allow them to escape tolerance constraints through a polyclonal cascade of somatic evolution. These findings provide new insights into the molecular basis of autoimmune disease and suggest novel diagnostic and therapeutic avenues.

  Dataset EGAD00001016058

• Polyclonal selection of immune checkpoint mutations in thyroid autoimmunity - TargetedNanoSeq

  Our immune system contains multiple tolerance checkpoints to prevent the activation of self-reactive lymphocytes. How some lymphocytes escape these constraints to cause autoimmune disease remains poorly understood. A long-standing hypothesis in autoimmunity posits that somatic mutations in immune regulatory genes may enable self-reactive lymphocytes to bypass tolerance checkpoints. However, testing this hypothesis has proved challenging due to technical limitations in detecting somatic mutations in polyclonal cell populations. Here, we use deep whole-exome and targeted NanoSeq, a highly accurate single-molecule DNA sequencing protocol, to comprehensively search for driver mutations in autoimmune thyroid disease. This revealed a remarkably high number of B cell clones convergently acquiring loss-of-function somatic mutations in key immune checkpoint genes TNFRSF14 (also known as HVEM) and CD274 (encoding PD-L1), as well as less frequent driver mutations in a diversity of other immune genes. In highly inflamed biopsies, we detected tens to hundreds of independent immune-checkpoint mutant clones. Laser capture microdissection, methylation sequencing, spatial transcriptomics, immunohistochemistry and single-nucleus DNA sequencing localised these mutations to non-naive B cells and revealed frequent co-occurrence of drivers in single cells. We found widespread TNFRSF14 biallelic loss in mutant B cells, and several clones with as many as 4-6 driver mutations. Whilst each clone accounts for a small proportion of cells (typically <1%), the myriad mutant clones in each donor collectively amounted to a substantial fraction of B cells harbouring one or more driver mutations. Our results support the hypothesis that somatic mutations in autoimmune lymphocytes may allow them to escape tolerance constraints through a polyclonal cascade of somatic evolution. These findings provide new insights into the molecular basis of autoimmune disease and suggest novel diagnostic and therapeutic avenues.

  Dataset EGAD00001016059

• Polyclonal selection of immune checkpoint mutations in thyroid autoimmunity - TargetedEMSeq

  Our immune system contains multiple tolerance checkpoints to prevent the activation of self-reactive lymphocytes. How some lymphocytes escape these constraints to cause autoimmune disease remains poorly understood. A long-standing hypothesis in autoimmunity posits that somatic mutations in immune regulatory genes may enable self-reactive lymphocytes to bypass tolerance checkpoints. However, testing this hypothesis has proved challenging due to technical limitations in detecting somatic mutations in polyclonal cell populations. Here, we use deep whole-exome and targeted NanoSeq, a highly accurate single-molecule DNA sequencing protocol, to comprehensively search for driver mutations in autoimmune thyroid disease. This revealed a remarkably high number of B cell clones convergently acquiring loss-of-function somatic mutations in key immune checkpoint genes TNFRSF14 (also known as HVEM) and CD274 (encoding PD-L1), as well as less frequent driver mutations in a diversity of other immune genes. In highly inflamed biopsies, we detected tens to hundreds of independent immune-checkpoint mutant clones. Laser capture microdissection, methylation sequencing, spatial transcriptomics, immunohistochemistry and single-nucleus DNA sequencing localised these mutations to non-naive B cells and revealed frequent co-occurrence of drivers in single cells. We found widespread TNFRSF14 biallelic loss in mutant B cells, and several clones with as many as 4-6 driver mutations. Whilst each clone accounts for a small proportion of cells (typically <1%), the myriad mutant clones in each donor collectively amounted to a substantial fraction of B cells harbouring one or more driver mutations. Our results support the hypothesis that somatic mutations in autoimmune lymphocytes may allow them to escape tolerance constraints through a polyclonal cascade of somatic evolution. These findings provide new insights into the molecular basis of autoimmune disease and suggest novel diagnostic and therapeutic avenues.

  Dataset EGAD00001016060

• Polyclonal selection of immune checkpoint mutations in thyroid autoimmunity - PTA_WGS

  Our immune system contains multiple tolerance checkpoints to prevent the activation of self-reactive lymphocytes. How some lymphocytes escape these constraints to cause autoimmune disease remains poorly understood. A long-standing hypothesis in autoimmunity posits that somatic mutations in immune regulatory genes may enable self-reactive lymphocytes to bypass tolerance checkpoints. However, testing this hypothesis has proved challenging due to technical limitations in detecting somatic mutations in polyclonal cell populations. Here, we use deep whole-exome and targeted NanoSeq, a highly accurate single-molecule DNA sequencing protocol, to comprehensively search for driver mutations in autoimmune thyroid disease. This revealed a remarkably high number of B cell clones convergently acquiring loss-of-function somatic mutations in key immune checkpoint genes TNFRSF14 (also known as HVEM) and CD274 (encoding PD-L1), as well as less frequent driver mutations in a diversity of other immune genes. In highly inflamed biopsies, we detected tens to hundreds of independent immune-checkpoint mutant clones. Laser capture microdissection, methylation sequencing, spatial transcriptomics, immunohistochemistry and single-nucleus DNA sequencing localised these mutations to non-naive B cells and revealed frequent co-occurrence of drivers in single cells. We found widespread TNFRSF14 biallelic loss in mutant B cells, and several clones with as many as 4-6 driver mutations. Whilst each clone accounts for a small proportion of cells (typically <1%), the myriad mutant clones in each donor collectively amounted to a substantial fraction of B cells harbouring one or more driver mutations. Our results support the hypothesis that somatic mutations in autoimmune lymphocytes may allow them to escape tolerance constraints through a polyclonal cascade of somatic evolution. These findings provide new insights into the molecular basis of autoimmune disease and suggest novel diagnostic and therapeutic avenues.

  Dataset EGAD00001016061

• Polyclonal selection of immune checkpoint mutations in thyroid autoimmunity - PTA_DNAHyb

  Our immune system contains multiple tolerance checkpoints to prevent the activation of self-reactive lymphocytes. How some lymphocytes escape these constraints to cause autoimmune disease remains poorly understood. A long-standing hypothesis in autoimmunity posits that somatic mutations in immune regulatory genes may enable self-reactive lymphocytes to bypass tolerance checkpoints. However, testing this hypothesis has proved challenging due to technical limitations in detecting somatic mutations in polyclonal cell populations. Here, we use deep whole-exome and targeted NanoSeq, a highly accurate single-molecule DNA sequencing protocol, to comprehensively search for driver mutations in autoimmune thyroid disease. This revealed a remarkably high number of B cell clones convergently acquiring loss-of-function somatic mutations in key immune checkpoint genes TNFRSF14 (also known as HVEM) and CD274 (encoding PD-L1), as well as less frequent driver mutations in a diversity of other immune genes. In highly inflamed biopsies, we detected tens to hundreds of independent immune-checkpoint mutant clones. Laser capture microdissection, methylation sequencing, spatial transcriptomics, immunohistochemistry and single-nucleus DNA sequencing localised these mutations to non-naive B cells and revealed frequent co-occurrence of drivers in single cells. We found widespread TNFRSF14 biallelic loss in mutant B cells, and several clones with as many as 4-6 driver mutations. Whilst each clone accounts for a small proportion of cells (typically <1%), the myriad mutant clones in each donor collectively amounted to a substantial fraction of B cells harbouring one or more driver mutations. Our results support the hypothesis that somatic mutations in autoimmune lymphocytes may allow them to escape tolerance constraints through a polyclonal cascade of somatic evolution. These findings provide new insights into the molecular basis of autoimmune disease and suggest novel diagnostic and therapeutic avenues.

  Dataset EGAD00001016062

• Polyclonal selection of immune checkpoint mutations in thyroid autoimmunity - PTA_RNA

  Our immune system contains multiple tolerance checkpoints to prevent the activation of self-reactive lymphocytes. How some lymphocytes escape these constraints to cause autoimmune disease remains poorly understood. A long-standing hypothesis in autoimmunity posits that somatic mutations in immune regulatory genes may enable self-reactive lymphocytes to bypass tolerance checkpoints. However, testing this hypothesis has proved challenging due to technical limitations in detecting somatic mutations in polyclonal cell populations. Here, we use deep whole-exome and targeted NanoSeq, a highly accurate single-molecule DNA sequencing protocol, to comprehensively search for driver mutations in autoimmune thyroid disease. This revealed a remarkably high number of B cell clones convergently acquiring loss-of-function somatic mutations in key immune checkpoint genes TNFRSF14 (also known as HVEM) and CD274 (encoding PD-L1), as well as less frequent driver mutations in a diversity of other immune genes. In highly inflamed biopsies, we detected tens to hundreds of independent immune-checkpoint mutant clones. Laser capture microdissection, methylation sequencing, spatial transcriptomics, immunohistochemistry and single-nucleus DNA sequencing localised these mutations to non-naive B cells and revealed frequent co-occurrence of drivers in single cells. We found widespread TNFRSF14 biallelic loss in mutant B cells, and several clones with as many as 4-6 driver mutations. Whilst each clone accounts for a small proportion of cells (typically <1%), the myriad mutant clones in each donor collectively amounted to a substantial fraction of B cells harbouring one or more driver mutations. Our results support the hypothesis that somatic mutations in autoimmune lymphocytes may allow them to escape tolerance constraints through a polyclonal cascade of somatic evolution. These findings provide new insights into the molecular basis of autoimmune disease and suggest novel diagnostic and therapeutic avenues.

  Dataset EGAD00001016063

• Polyclonal selection of immune checkpoint mutations in thyroid autoimmunity - LCMB_WGS

  Our immune system contains multiple tolerance checkpoints to prevent the activation of self-reactive lymphocytes. How some lymphocytes escape these constraints to cause autoimmune disease remains poorly understood. A long-standing hypothesis in autoimmunity posits that somatic mutations in immune regulatory genes may enable self-reactive lymphocytes to bypass tolerance checkpoints. However, testing this hypothesis has proved challenging due to technical limitations in detecting somatic mutations in polyclonal cell populations. Here, we use deep whole-exome and targeted NanoSeq, a highly accurate single-molecule DNA sequencing protocol, to comprehensively search for driver mutations in autoimmune thyroid disease. This revealed a remarkably high number of B cell clones convergently acquiring loss-of-function somatic mutations in key immune checkpoint genes TNFRSF14 (also known as HVEM) and CD274 (encoding PD-L1), as well as less frequent driver mutations in a diversity of other immune genes. In highly inflamed biopsies, we detected tens to hundreds of independent immune-checkpoint mutant clones. Laser capture microdissection, methylation sequencing, spatial transcriptomics, immunohistochemistry and single-nucleus DNA sequencing localised these mutations to non-naive B cells and revealed frequent co-occurrence of drivers in single cells. We found widespread TNFRSF14 biallelic loss in mutant B cells, and several clones with as many as 4-6 driver mutations. Whilst each clone accounts for a small proportion of cells (typically <1%), the myriad mutant clones in each donor collectively amounted to a substantial fraction of B cells harbouring one or more driver mutations. Our results support the hypothesis that somatic mutations in autoimmune lymphocytes may allow them to escape tolerance constraints through a polyclonal cascade of somatic evolution. These findings provide new insights into the molecular basis of autoimmune disease and suggest novel diagnostic and therapeutic avenues.

  Dataset EGAD00001016064

• Polyclonal selection of immune checkpoint mutations in thyroid autoimmunity - LCMB_WES

  Our immune system contains multiple tolerance checkpoints to prevent the activation of self-reactive lymphocytes. How some lymphocytes escape these constraints to cause autoimmune disease remains poorly understood. A long-standing hypothesis in autoimmunity posits that somatic mutations in immune regulatory genes may enable self-reactive lymphocytes to bypass tolerance checkpoints. However, testing this hypothesis has proved challenging due to technical limitations in detecting somatic mutations in polyclonal cell populations. Here, we use deep whole-exome and targeted NanoSeq, a highly accurate single-molecule DNA sequencing protocol, to comprehensively search for driver mutations in autoimmune thyroid disease. This revealed a remarkably high number of B cell clones convergently acquiring loss-of-function somatic mutations in key immune checkpoint genes TNFRSF14 (also known as HVEM) and CD274 (encoding PD-L1), as well as less frequent driver mutations in a diversity of other immune genes. In highly inflamed biopsies, we detected tens to hundreds of independent immune-checkpoint mutant clones. Laser capture microdissection, methylation sequencing, spatial transcriptomics, immunohistochemistry and single-nucleus DNA sequencing localised these mutations to non-naive B cells and revealed frequent co-occurrence of drivers in single cells. We found widespread TNFRSF14 biallelic loss in mutant B cells, and several clones with as many as 4-6 driver mutations. Whilst each clone accounts for a small proportion of cells (typically <1%), the myriad mutant clones in each donor collectively amounted to a substantial fraction of B cells harbouring one or more driver mutations. Our results support the hypothesis that somatic mutations in autoimmune lymphocytes may allow them to escape tolerance constraints through a polyclonal cascade of somatic evolution. These findings provide new insights into the molecular basis of autoimmune disease and suggest novel diagnostic and therapeutic avenues.

  Dataset EGAD00001016065

• The double-hit signature identifies double-hit diffuse large B-cell lymphoma with genetic events cryptic to FISH​

  High-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/THs) include a group of diffuse large B-cell lymphomas (DLBCLs) with inferior outcomes after standard chemoimmunotherapy. We recently described a gene expression signature that identifies 27% of germinal center B-cell DLBCLs (GCB-DLBCLs) as having a double-hit-like expression pattern (DHITsig) and inferior outcomes; however, only half of these cases have both MYC and BCL2 translocations identifiable using standard breakapart fluorescence in situ hybridization (FISH). Here, 20 DHITsig+ GCB-DLBCLs apparently lacking MYC and/or BCL2 rearrangements underwent whole-genome sequencing. This revealed 6 tumors with MYC or BCL2 rearrangements that were cryptic to breakapart FISH. Copy-number analysis identified 3 tumors with MYC and 6 tumors with MIR17HG gains or amplifications, both of which may contribute to dysregulation of MYC and its downstream pathways. Focal deletions of the PVT1 promoter were observed exclusively among DHITsig+ tumors lacking MYC translocations; this may also contribute to MYC overexpression. These results highlight that FISH fails to identify all HGBL-DH/THs, while revealing a range of other genetic mechanisms potentially underlying MYC dysregulation in DHITsig+ DLBCL, suggesting that gene expression profiling is more sensitive for identifying the biology underlying poor outcomes in GCB-DLBCL.

  Study EGAS00001004285

• ATAC-seq of a selected group of AML cases

  ATAC-seq data were generated for a number of selected patients to investigate changes in enhancer and promoter regions. ATAC-seq was essentially carried out as described in31. Briefly, prior to transposition the viability of the cells was assessed and 1 × 106 cells were treated in culture medium with DNase I (Sigma) at a final concentration of 200 U ml−1 for 30 minutes at 37 °C. After Dnase I treatment, cells were washed twice with ice-cold PBS, and cell viability and the corresponding cell count were assessed. 5 × 104 cells were aliquoted into a new tube and spun down at 500 × g for 5 minutes at 4 °C, before the supernatant was discarded completely. The cell pellet was resuspended in 50 µl of ATAC-RSB buffer (10 mM Tris-HCl pH 7.4, 10 mM NaCl, 3 mM MgCl2) containing 0.1% NP-40, 0.1% Tween-20, and 1% Digitonin (Promega), and was incubated on ice for 3 minutes to lyse the cells. Lysis was washed out with 1 ml of ATAC-RSB buffer containing 0.1% Tween-20. Nuclei were pelleted at 500 × g for 10 minutes at 4 °C. The supernatant was discarded carefully and the cell pellet was resuspended in 50 µl of transposition mixture (25 µl 2× tagment DNA buffer, 2.5 µl transposase (100 nM final; Illumina), 16.5 µl PBS, 0.5 µl 1% digitonin, 0.5 µl 10% Tween-20, 5 µl H2O) by pipetting up and down six times. The reaction was incubated at 37 °C for 30 minutes with mixing before the DNA was purified using the Monarch PCR & DNA Cleanup Kit (NEB) according to the manufacturer’s instructions. Purified DNA was eluted in 20 µl elution buffer (EB) and 10 µl purified sample was objected to a ten-cycle PCR amplification using Nextera i7- and i5-index primers (Illumina). Purification and size selection of the amplified DNA were carried out with Agencourt AMPure XP beads. For purification the ratio of sample to beads was set to 1:1.8, whereas for size selection the ratio was set to 1:0.55. Purified samples were eluted in 15 µl of EB. Quality and concentration of the generated ATAC libraries were analyzed using the High Sensitivity D1000 ScreenTape Kit (Agilent) and libraries were sequenced paired-end on a NovaSeq (Illumina). ATAC-seq reads were aligned to the human reference genome build hg19 with bowtie2

  Dataset EGAD00001007583

• Field Studies of Human Immunity to Amebiasis in Bangladesh (NIH Birth Cohort) and Exploration of the Biologic Basis for Underperformance of Oral Polio and Rotavirus Vaccines in Bangladesh (PROVIDE)

  NIH birth cohort study Amebiasis is a common cause of diarrhea and is associated with malnutrition in grade-school aged children in an urban slum of Dhaka, Bangladesh. Field Studies of Human Immunity to Amebiasis in Bangladesh was designed to determine the contribution of amebiasis to illness in the first 2 years of life when most deaths due to diarrhea occur, and understand the immunologic and genetic factors that protect children from amebiasis. The hypothesis underlying the study is that susceptibility to amebiasis is determined by host innate and acquired immune responses that vary between individuals in part due to: human genetic polymorphisms; environmental influences including malnutrition and concurrent geohelminth infection; and virulence differences among Entamoeba histolytica genotypes. Specific aims proposed in the design of the study were to: a) Measure the incidence of amebiasis and correlate it with human and parasite genetic polymorphisms, immune responses, and environmental factors such as geohelminth infection and malnutrition; b) Test the hypothesis that protective immunity is mediated both by innate immune responses initiated via TLR stimulation as well as by mucosal IgA against the Gal/GalNAc lectin and systemic IFN-γ; c) Test for the association of common genetic polymorphisms in host innate and acquired immune genes with incidence of amebiasis. 629 newborn babies were enrolled and followed regularly through bi-weekly surveillance for diarrheal episodes, anthropometry at 3-month interval until 60 months of age. The infants that were consented for GWAS analysis were genotyped in 3 separate batches at different times, on 3 different arrays. Quality control was performed on the 3 separate data sets and then jointly after merging. Genetic data available on 447 infants together with their phenotype data is made available in this submission PROVIDE (Performance of Rotavirus and Oral Polio Vaccines in Developing Countries) Study Oral polio and rotavirus vaccines are significantly less effective in children living in the developing world. Environmental enteropathy, which is associated with intestinal inflammation, decreased absorption and increased permeability, may contribute substantially to oral vaccine failure in developing country settings. The primary objective of the study was to determine the association of environmental enteropathy with the efficacy of oral polio and rotavirus vaccines in children in Bangladesh. Secondary and exploratory objectives were designed to address other possible causes of oral vaccine underperformance including malnutrition, interference with maternal or breastmilk antibodies, changes in gut microbiota, and genetic susceptibility. The PROVIDE study was structured as a 2x2 clinical trial with a prospective birth cohort enrollment of 700 infants and their mothers in the urban slum of Mirpur, Dhaka, Bangladesh. All children received the full series of Bangladesh's Expanded Program on Immunization vaccines, including oral polio vaccine (OPV) and followed for their first 2 years of life. Half the children were randomized to receive an inactivated polio vaccine (IPV) for their 4th dose at 39 weeks instead of the standard OPV dose. In the other trial, half the infants received the 2-dose rotavirus vaccine (Rotarix) with delayed dosing at 10 and 17 weeks of age. A detailed description of the study design and procedures can be obtained from PROVIDE methods publication: Kirkpatrick B.D., Colgate R.E., Mychaleckyj J.C., Haque R., Dorothy D.M., Carmolli M.P., et al. (2015) Am J Trop Med Hyg 92, 744-751 The Poliovirus trial and results are described in Mychaleckyj et al, Vaccine 2016 The Rotavirus trial and results are described in Colgate et al, Clin Infect Dis 2016 The PROVIDE infants were genotyped on a custom Affymetrix Axiom array (30K SNPs) at the University of Virginia Center for Public Health Genomics; and on a pre-production version of the Illumina MEGA v2 chip at the Wellcome Trust Sanger Institute, UK. The latter genotyping was performed under the auspices of the VaccGene Consortium. Analyses are ongoing to identify variants associated with the included phenotypes. A manuscript describing the genotyping methods and analysis is in preparation for the initial phenotypes. The Infection Malnutrition Bangladesh Cohort is utilized in the following dbGaP sub-studies. To view genotypes, other molecular data, and derived variables collected in these sub-studies, please click on the following sub-studies below or in the "Sub-studies" box located on the right hand side of this top-level study page phs001475 Infection Malnutrition Bangladesh Cohort. phs001476 Amebiasis Immunity phs001478 Polio Rotavirus Vaccines phs001665 Cryptosporidiosis Enteropathogens

  Study phs001475

• Whole Exome Sequencing for Colorectal Cancer

  This project was designed to use next generation sequencing technology to screen the protein coding regions of the genome for low frequency variants in a panel of high-risk colorectal adenocarcinoma cases. Blood and cell-line DNA for colorectal cancer patients and a subset of quality control samples that had existing whole exome sequence data were analyzed using Illumina HiSeq sequencers. Samples from this project were from participants in the Women's Health Initiative (WHI) and the Diet, Activity, and Lifestyle Study (DALS).

  Study phs000410

• The Mexican-American Coronary Artery Disease Study (MACAD)

  The MACAD Study, funded by NHLBI, was designed to explore genetic contributions to coronary artery disease and glucose homeostasis traits among Hispanics using a family-based design. The baseline examination of the cohort included the euglycemic hyperinsulinemic clamp test from which the two key phenotypes were obtained: insulin sensitivity (M) and metabolic clearance rate of insulin (MCRI). Genome-wide genotyping was obtained under separate funding by NIDDK as a part of the GUARDIAN (Genetics Underlying Diabetes in Hispanics) Consortium.

  Study phs001397

• NHLBI TOPMed: Partners HealthCare Biobank

  The Atrial Fibrillation Genetics Consortium (AFGen) was organized to identify common and rare genetic variation associated with atrial fibrillation risk. In the current study, we have performed whole genome sequencing in cases with early-onset atrial fibrillation. Samples in this study were enrolled as a part of the Partners HealthCare Biobank. Cases with early-onset atrial fibrillation were identified from the Biobank (defined as atrial fibrillation onset prior to 61 years and in the absence of structural heart disease).

  Study phs001024