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• Whole genome sequencing delineates regulatory, structural, and cryptic splice variants in early onset cardiomyopathy

  Cardiomyopathy (CMP) is a heritable disorder. Over 50% cases are gene-elusive on clinical gene panel testing. The contribution of variants in non-coding DNA elements that result in cryptic splicing and regulate gene expression has not been explored. We analyzed whole genome sequencing (WGS) data in a discovery cohort of 209 pediatric CMP patients and 1,953 independent replication genomes and exomes. We searched for protein-coding variants, and non-coding variants predicted to affect the function or expression of genes. Thirty-nine % cases harbored pathogenic coding variants in known CMP genes, and 5% harbored high-risk loss-of-function (LoF) variants in additional candidate CMP genes. Fifteen % harbored high-risk regulatory variants in promoters and enhancers of CMP genes (Odds ratio 2.25, p=6.70×10-7 versus controls). Genes involved in α-dystroglycan glycosylation (FKTN, DTNA) and desmosomal signaling (DSC2, DSG2) were most highly enriched for regulatory variants (Odds ratio 6.7-58.1). Functional effects were confirmed in patient myocardium and reporter assays in human cardiomyocytes, and in zebrafish CRISPR knockouts. We provide strong evidence for the genomic contribution of functionally active variants in new genes and in regulatory elements of known CMP genes to early-onset CMP.

  Study EGAS00001004929

• Significant and pervasive effects of RNA degradation on Nanopore direct RNA sequencing

  Abstract Oxford Nanopore direct RNA sequencing (DRS) is capable of sequencing complete RNA molecules and accurately measuring gene and isoform expression. However, as DRS is designed to profile intact RNA, expression quantification may be more heavily dependent upon RNA integrity than alternate RNA-seq methodologies. It is currently unclear how RNA degradation impacts DRS or if it can be corrected for. To assess the impact of RNA integrity on DRS we performed a degradation time-series using SH-SY5Y neuroblastoma cells. Our results demonstrate that degradation is a significant and pervasive factor that can bias DRS measurements, including a reduction in library complexity resulting in an overrepresentation of short genes and isoforms. Degradation also biases differential expression analyses; however, we find explicit correction can almost fully recover meaningful biological signal. In addition, DRS provided less biased profiling of partially degraded samples than nanopore cDNA-PCR sequencing. Overall, we find samples with RIN > 9.5 can be treated as undegraded and samples with RIN > 7 can be utilised for DRS with appropriate correction. These results establish the suitability of DRS for a wide range of samples, including partially degraded in-vivo clinical and post-mortem samples, whilst limiting the confounding effect of degradation on expression quantification.

  Study EGAS00001006542

• Hexanucleotide repeat expansions in C9orf72 alter microglial responses and prevent a coordinated glial reaction in ALS

  Neuroinflammation is an important hallmark in amyotrophic lateral sclerosis (ALS). Experimental evidence has highlighted a role of microglia in the modulation of motor neuron degeneration. However, the exact contribution of microglia to both sporadic and genetic forms of ALS is still unclear. We generated single nuclei profiles of spinal cord and motor cortex from sporadic and C9orf72 ALS patients, as well as controls. We particularly focused on the transcriptomic responses of both microglia and astrocytes. We confirmed that C9orf72 is highly expressed in microglia and shows a diminished expression in carriers of the hexanucleotide repeat expansion (HRE). This resulted in an impaired response to disease, with specific deficits in phagocytic and lysosomal transcriptional pathways. Astrocytes also displayed a dysregulated response in C9orf72 ALS patients, remaining in a homeostatic state. This suggests that C9orf72 HRE alters a coordinated glial response, which ultimately would increase the risk for developing ALS. Our results indicate that C9orf72 HRE results in a selective microglial loss-of-function, likely impairing microglial-astrocyte communication and preventing a global glial response. This is relevant as it indicates that sporadic and familial forms of ALS may present a different cellular substrate, which is of great importance for patient stratification and treatment.

  Study EGAS00001006711

• T cell landscape definition by multi-omics identifies galectin-9 as novel immunotherapy target in chronic lymphocytic leukemia (CLL)

  Failure of immunotherapy after applying checkpoint inhibitors or CAR-T cells is linked to T cell exhaustion. Here, we explored the T cell landscape in chronic lymphocytic leukemia (CLL) by single-cell omics analyses of blood, bone marrow and lymph node samples of patients and spleen samples of a CLL mouse model. By single-cell RNA- sequencing, mass cytometry (CyTOF), and multiplex image analysis of tissue microarrays, we defined the spectrum of phenotypes and transcriptional programs of T cells and and their differentiation state trajectories. We identified disease-specific accumulation of distinct regulatory T cell subsets and T cells harboring an exhausted phenotype exclusively in the CLL lymph node tissue. Integration of TCR data revealed a clonal expansion of CD8+ precursor exhausted T cells, suggesting their reactivity for CLL cells. Interactome analyses identified the TIM3 ligand Galectin-9 as novel immunoregulatory molecule in CLL. Blocking of Galectin-9 in CLL-bearing mice slowed down disease development and reduced the number of TIM3 expressing T cells. Galectin-9 expression correlated with shorter survival of CLL patients. Thus, Galectin-9 contributes to immune escape in CLL and represents a novel target for immunotherapy.

  Study EGAS00001006864

• FASTQ files of total RNA-Seq data from the POPS PET (pre-eclamptic) samples

  All the samples were obtained from the Pregnancy Outcome Prediction–a prospective cohort study of nulliparous women attending the Rosie Hospital, Cambridge (UK) for their dating ultrasound scan between January 14, 2008, and July 31, 2012. Ethical approval for the study was given by the Cambridgeshire 2 Research Ethics Committee (reference number 07/H0308/163) and all participants provided written informed consent. Cases of preeclampsia (PET) were defined on the basis of the 2013 ACOG criteria and cases of small for gestational age (SGA)infants were confined to severe SGA, i.e. a customized birth weight <5th percentile. Chorionic villi from the corresponding placentas (free from decidua, visible infarction, calcification, hematoma, or damage) were collected and processed within 30 minutes of separation from the uterus. After repeated washes in chilled phosphate buffered saline, the samples were placed in RNA later (Applied Biosystems) and stored at -80°C. Total placental RNA was extracted using mirVana Isolation Kit (Ambion). For each placenta, approximately 5 mg of tissue were homogenized in the Lysis/Binding solution for 20 sec at 6 m/s using a bead beater (FastPrep24) and Lysing Matrix D Tubes (MP Biomedicals). The samples were then spun at 13,000 rpm for 5 min at 4°C and the supernatants recovered. Afterwards, the manufacturer's instructions were followed. Immediately after the RNA extraction, placental RNA samples were DNase-treated using DNA-free DNA Removal Kit (Ambion), aliquoted, and stored in -80°C. Quantity and quality of the RNA samples were assessed using the Agilent 2100 Bioanalyzer, the Agilent RNA 6000 Nano Kit (Agilent Technologies), and Qubit fluorometer. Libraries were prepared starting with 300-500 ng of good quality total RNA (RIN ≥7.5) using the TruSeq Stranded Total RNA Library Prep Kit with Ribo-Zero Human/Mouse/Rat (Illumina), according to the manufacturer's instructions. The kit contains 96 uniquely indexed adapter combinations in order to allow pooling of multiple samples prior to sequencing. After determining their size (with the Agilent 2100 Bioanalyzer and the Agilent High Sensitivity DNA Kit by Agilent Technologies) and concentration (by qPCR with the KAPA Illumina ABI Prism Library Quantification Kit, Kapa Biosystems), libraries have been pooled and sequenced (single-end, 125 bp) using a Single End V4 Cluster Kit and an Illumina HiSeq2500 or HiSeq4000 instrument.

  Dataset EGAD00001003508

• FASTQ files of total RNA-Seq data from the POPS SGA (Small for Gestational Age) samples

  All the samples were obtained from the Pregnancy Outcome Prediction–a prospective cohort study of nulliparous women attending the Rosie Hospital, Cambridge (UK) for their dating ultrasound scan between January 14, 2008, and July 31, 2012. Ethical approval for the study was given by the Cambridgeshire 2 Research Ethics Committee (reference number 07/H0308/163) and all participants provided written informed consent. Cases of preeclampsia (PET) were defined on the basis of the 2013 ACOG criteria and cases of small for gestational age (SGA)infants were confined to severe SGA, i.e. a customized birth weight <5th percentile. Chorionic villi from the corresponding placentas (free from decidua, visible infarction, calcification, hematoma, or damage) were collected and processed within 30 minutes of separation from the uterus. After repeated washes in chilled phosphate buffered saline, the samples were placed in RNA later (Applied Biosystems) and stored at -80°C. Total placental RNA was extracted using mirVana Isolation Kit (Ambion). For each placenta, approximately 5 mg of tissue were homogenized in the Lysis/Binding solution for 20 sec at 6 m/s using a bead beater (FastPrep24) and Lysing Matrix D Tubes (MP Biomedicals). The samples were then spun at 13,000 rpm for 5 min at 4°C and the supernatants recovered. Afterwards, the manufacturer's instructions were followed. Immediately after the RNA extraction, placental RNA samples were DNase-treated using DNA-free DNA Removal Kit (Ambion), aliquoted, and stored in -80°C. Quantity and quality of the RNA samples were assessed using the Agilent 2100 Bioanalyzer, the Agilent RNA 6000 Nano Kit (Agilent Technologies), and Qubit fluorometer. Libraries were prepared starting with 300-500 ng of good quality total RNA (RIN ≥7.5) using the TruSeq Stranded Total RNA Library Prep Kit with Ribo-Zero Human/Mouse/Rat (Illumina), according to the manufacturer's instructions. The kit contains 96 uniquely indexed adapter combinations in order to allow pooling of multiple samples prior to sequencing. After determining their size (with the Agilent 2100 Bioanalyzer and the Agilent High Sensitivity DNA Kit by Agilent Technologies) and concentration (by qPCR with the KAPA Illumina ABI Prism Library Quantification Kit, Kapa Biosystems), libraries have been pooled and sequenced (single-end, 125 bp) using a Single End V4 Cluster Kit and an Illumina HiSeq2500 or HiSeq4000 instrument.

  Dataset EGAD00001003507

• LITS

  Difference in gene expression values between case and control, log2 values. Blood transcriptome from women participating in the Norwegian Women and Cancer study (NOWAC) Post-genome Cohort taken up to eight years before brest cancer diagnosis. Illumina HumanWG-6 version 3 or Illumina HumanHT-12 expression bead chip, combined on identical nucleotide universal identifiers.

  Dataset EGAD00010001400

• usgwas-QC_imputed_update

  Understanding Society GWAS, samples that passed quality control, imputed to UK10K + 1000 Genomes combined reference panel

  Dataset EGAD00010000918

• A novel orthotopic patient-derived xenograft model of radiation-induced glioma following medulloblastoma

  DNA methylation arrays were performed to molecularly subtype these samples based on Capper D, Jones DTW, Sill M, et al. DNA methylation-based classification of central nervous system tumours. Nature. 2018;555(7697):469-474. doi:10.1038/nature26000

  Dataset EGAD00010002017

• HGSC lines: ATACseq and RNAseq, pre- vs post-treatment with HKMTi-1-005

  Formation of a DAC to support the deposition of RNAseq and ATACseq data, from pre- vs post-treatment high-grade serous ovarian carcinoma cell lines. The lines include PEO1, PEO4, PEA2, OVCAR5, OVCAR8, and the treatment includes use of a novel epigenetic drug called HKMTi-1-005.

  Dac EGAC50000000034