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• A whole-genome sequencing study for evolutionary history of Tibetans and their genetic adaptations to high altitude

  Due to a unique adaptation to high altitude, the Tibetan Plateau population has been the subject of much research interest. In this study, we conducted whole genome sequencing of 27 Tibetan individuals. Through our analysis, we inferred a detailed history of demography and revealed the natural selection of Tibetan population. We provided evidence of genetic separation between the two subpopulations of Han and Tibetans as early as 44 to 58 thousand years ago, replicated previously reported high altitude adaptation genes, including EPAS1 and EGLN1, and reported three new candidate genes, including PTGIS, VDR, and KCTD12.

  Study phs001338

• Alloreactive T-cell receptor (TCR) repertoire in kidney transplantation

  We analyzed the T-cell receptor (TCR) repertoires from twelve kidney transplant recipients. Six out of the twelve kidney transplant recipients experienced a cellular rejection after kidney transplantation. TCR repertoires of CD4+ and CD8+ positive T-cells were assessed prior to transplantation and after transplantation at time of allograft biopsy using RNA based T-cell receptor beta next generation sequencing (NGS). In addition, the pre-formed alloreactive TCR repertoire for each kidney transplant recipient was identified using mixed lymphocyte reaction and donor reactive T-cells were subjected to TCR beta sequencing. In two out of the six patients with cellular rejection the TCR repertoire of graft infiltrating T-cells was additionally captured. This dataset comprises a total of 98 samples. NGS TCR beta libraries of all samples were sequenced on an Illumina NextSeq 500 and raw sequencing data (in the form of fastq files) as well assembled clonotypes and their counts (in the form of clonotype tables) are provided.

  Dataset EGAD00001007695

• Myeloid cell programming in patients with non-medullary thyroid carcinoma

  This dataset contains single-cell RNA sequencing data from patients with thyroid cancer (n=7), multinodal Goiter (n=3) and healthy individuals (n=5). Mononuclear cells were taken from both the peripheral blood and the bone marrow compartments. We used a pooled single-cell design where multiple individuals were pooled in a single sample for sequencing (NextSeq 500-V2) and later demultiplexed using their genotype data. Associated metadata contains information on the phenotypes per individual, the pooling design and the linkage between the supplied files and sequenced pools. Due to limitations from EGA in uploading single-cell data, the raw fastq files were processed as follows: (i) I1/I2/R1/R2 fast files were concatenated over the different lanes. (ii) Concatenated I1 and I2 files were interleaved, as were the concatenated R1 and R2 files to generate two fastq files per pool containing all the information. To interleave the fastq files, the BBmap tool bbmap/reformat.sh was used, which can also be used to de-interleave the files.

  Dataset EGAD00001008108

• Transcriptome analysis for intrahepatic cholangiocarcinoma

  Intrahepatic cholangiocarcinomas (iCCs) are characterized by their rarity, difficulty in diagnosis, and overall poor prognosis. We performed comprehensive transcriptomic characterization of treatment-naive iCC. Whole transcriptome analyses identified two prognostic subtypes, concordant with previous reports.The findings could assist in patient stratification with iCCs and in developing rational therapeutic strategies.

  Dataset EGAD00001008544

• Organoid Derivation Project: WGS (2023-06-22)

  Sequencing of tissue samples and their derived organoids from oesophageal, pancreatic and colorectal cancer patients. . This dataset contains all the data available for this study on 2023-06-22.

  Dataset EGAD00001011090

• T-cell reconstitution after reduced dose ATLG induction in kidney transplant patients

  We analyzed the T-cell receptor (TCR) repertoires from ten kidney transplant recipients. Five out of the ten kidney transplant recipients received ATLG while the other five recipients received basiliximab as induction therapy. TCR repertoires of CD4+ and CD8+ positive T-cells were assessed prior to transplantation and within the first month after transplantation as well as at three- and 12-months post-transplant. In addition, the pre-formed alloreactive TCR repertoire for each kidney transplant recipient was identified using mixed lymphocyte reaction and donor reactive T-cells were subjected to TCR beta sequencing. This dataset comprises a total of 106 samples. NGS TCR beta libraries of all samples were sequenced on an Illumina NextSeq 500 and raw sequencing data (in the form of fastq files) as well assembled clonotypes and their counts (in the form of clonotype tables) are provided.

  Dataset EGAD00001008478

• Molecular features of adenomas predicting metachronous colorectal cancer: a nested-case control study

  "Background & Aims: Current morphological features defining advanced adenomas (size ≥10 mm, high grade dysplasia or >25% villous component) cannot optimally distinguish individuals at high-risk or low-risk of metachronous colorectal cancer (me-CRC), which may result in suboptimal surveillance. Certain DNA copy number alterations are associated with adenoma-to-carcinoma progression (cancer-associated events; CAEs). We aimed to evaluate whether CAEs can better predict an individual’s risk of me-CRC than the morphological advanced adenoma features. Methods: In this nested case-control study, 529 individuals with a single adenoma at their first colonoscopy were selected from a Norwegian adenoma cohort. DNA copy number profiles were determined, by means of low-coverage whole genome sequencing. We assessed the prevalence of CAEs in advanced and non-advanced adenomas and its association with me-CRC. For the latter, cases (with CRC) were matched to controls (without CRC), with the same follow-up period as cases, as well as age and sex. Subsequently, odds ratios (OR) for the association of the presence of an advanced adenoma or a molecularly-defined high-risk adenoma with me-CRC were calculated. Results: Molecular high-risk features were observed in 85/267 (32%) of advanced adenomas and in 27/262 (10%) of non-advanced adenomas. Me-CRC was more strongly associated with advanced adenomas (OR 3.58; 95% CI 2.27-5.72) than with molecular high-risk adenomas (OR 1.90; 95% CI 1.14–3.16). After adjusting for other variables, only advanced adenoma remained significantly associated with me-CRC (OR 3.39; 95% CI 2.10–5.55). Conclusion: Molecularly-defined high-risk adenomas were associated with me-CRC, but the association of advanced adenoma with me-CRC was stronger. " Project goal: Evaluate the value of DNA copy numbers alterations detected in a baseline adenoma, in the prediction of risk of metachronous CRC

  Study EGAS00001007039

• scRNAseq for patients with immunodeficiency and HCs

  The NFAT family of transcription factors plays central roles in adaptive immunity in murine models, however, their contribution to human immune homeostasis remains poorly defined. In a multigenerational pedigree, we identified three patients carrying germline biallelic missense variants in NFATC1, presenting with recurrent infections, hypogammaglobulinemia and decreased antibody responses. The compound heterozygous NFATC1 variants identified in the patients caused decreased stability and reduced binding of DNA and interacting proteins. We observed defects in early activation and proliferation of T and B cells from these patients, amenable to reconstitution upon genetic rescue. Following stimulation, T-cell activation and proliferation were impaired, reaching that of healthy controls with delay indicative of an adaptive capacity of the cells. Assessment of the metabolic capacity of patient T cells, revealed that NFATc1-dysfunction rendered T cells unable to engage in glycolysis following stimulation, although oxidative metabolic processes were intact. We hypothesized that NFATc1-mutant T cells could compensate for the energy deficit due to defective glycolysis by enhanced lipid metabolism as an adaptation, leading to a delayed, but not lost activation responses. Indeed, we observed increased 13C-labelled palmitate incorporation into citrate indicating higher fatty acid oxidation and we demonstrated that metformin and rosiglitazone improved patient T-cell effector functions. Collectively, enabled by our molecular dissection of NFATC1 mutations and extending the role of NFATc1 in human immunity beyond receptor signaling, and reveal evidence of metabolic plasticity in the context of impaired glycolysis observed in patient T cells to remedy delayed effector responses.

  Study EGAS00001007271

• DAC for Genomic landscapes of endometrioid and mucinous ovarian cancers and morphologically similar tumor types

  While endometrioid and mucinous ovarian cancers represent nearly a quarter of ovarian cancers, their molecular characteristics and pathologic origins are poorly understood. To characterize the genomic and epigenomic alterations of these ovarian cancer subtypes and evaluate links to morphologically similar tumors from other sites, we performed sequence, copy number, mutation signature, rearrangement, and methylation analyses from tumor samples and matched normal tissues of 133 patients. These analyses included patients with ovarian endometrioid (n=44), ovarian mucinous (n=43), uterine endometrial (n=15), and gastrointestinal mucinous cancers (n=31). In addition to identifying genes previously known to be involved in these tumors, we identified alterations in RAD51C, NOTCH4, SMARCA1/4 and JAK1 in ovarian endometrioid, ESR1 in uterine endometrioid, and SMARCA4 in ovarian mucinous cancers. Whole genome sequencing revealed rearrangements involving PTEN, NF1, and NF2 in ovarian endometrioid tumors, and NF1 and MED1 in ovarian mucinous cancers. The number of alterations and affected genes in ovarian and uterine endometrioid cancers were similar as were genome-wide methylation profiles, suggesting that these tumors may have a similar tissue of origin. By contrast, methylation patterns in ovarian mucinous cancers were more similar to other gastrointestinal mucinous cancers, including mucinous cancers of the stomach, colon, and pancreas. These analyses provide insights into the genomic landscapes and origins of mucinous and endometrioid ovarian carcinomas, providing new avenues for early clinical intervention and management of patients with these cancers.

  Dac EGAC50000000341

• Table of gene-level RNA counts from newborn screening dried blood spot samples

  Table of gene-level RNA counts from 21 newborn screening dried blood spot (DBS) samples. These DBS samples were obtained from extremely low gestional age newborns, where 10 of them were affected by a fetal inflammatory response (FIR) before birth, and 11 were unaffected. Total RNA was sequenced using an Illumina NextSeq-500 instrument. The sample preparation protocol included the depletion of rRNA and globin mRNA using the Globin Zero Gold rRNA Removal Kit from Illumina. Libraries were prepared using the NebNext Ultra TM II Directionl RNA LIbrary Prep Kit (New England Biolabs). Rows correspond to genes and columns to samples, where there is an additional column (BS13sub), corresponding to sample BS13, which was downsampled to 1/4 of its original depth.

  Dataset EGAD00010001707