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• Recurrent intra-tumour heterogeneity is a hallmark of metastatic prostate cancer

  The evolution of cancers from low grade to metastatic disease is a major determinant of cancer mortality. Cancer evolution involves a complex interplay between cell intrinsic genetics and transcriptional alterations and the extrinsic microenvironment. To define the key mechanisms underpinning metastatic development, we focused on the most lethal form of prostate cancer, metastatic castration-resistant prostate cancer, and employed single-cell multi-omics and whole-genome sequencing to deeply profile 34 metastatic lesions from 9 patients obtained from rapid autopsy. We found that intra-tumour heterogeneity is an indicator of key evolutionary processes, characterised by recurrent tumour populations acting as critical functional components of the tumour ecosystem, irrespective of clonal and microenvironmental backgrounds. Unexpectedly, microenvironments across metastatic sites played a limited role while clonal evolution primarily promoted transcriptional noise. Intra-patient functional convergence of tumour ecosystems was observed across metastatic sites, pointing towards system-level selection pressures that drive the heterogeneity landscape of mCRPC. Our findings reveal functional evolutionary convergence of metastatic disease into units of intra-tumour heterogeneity identifying critical determinants of metastatic progression for therapeutic targeting. Note: matched WGS for some tumour single-cell experiments, as well as germline WGS for patients CA0027, CA0034, CA0035, CA0043, and CA0076, can be found in EGAS00001006598.

  Study EGAS50000001312

• Exome_trios_in_patients_with_gastroschisis

  Gastroschisis (MIM 230750) is a herniation of the intestines through a defect of the abdominal wall lateral to the umbilicus (usually on the right side), and it is not covered by a membrane [Ledbetter, 2012]. Gastroschisis is a congenital anomaly with increasing incidence, easy prenatal diagnosis and extremely variable postnatal outcomes. On the basis of clinical manifestations, epidemiologic charateristics, and the presence and type of additional malformations, gastroschisis could be considered a heterogeneous condition with no gene/s discovered yet. This congenital anomaly affects approximately 1-3 infancts per 10,000 live births [Calzolari et al.1995;Parker et al.,2010] Current knowledge about causative mutations/variants. To date, no single gene has been linked to gastroschisis. Some publications have tried to link this malformation to variants in genes (such as AEBP1 (adipocyte enhancer binding protein) gene [Feldkamp et al,. 2012] or the VEGF-NOS3 pathway [Lammer et al., 2008]. Previously, a Scribble mutant mouse model (circletail) was reported to exhibit gastroschisis, however recent studies demonstrated that the Scribble knockout fetus exhibits exomphalos phenotype of gastroschisis [Carnagham et al., 2013]. 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 EGAS00001002664

• Genome-wide DNA-methylation assessment by MethylCap-seq and Infinium HumanMethylation450 BeadChips: an independent large-scale comparison

  DNA-methylation is an important epigenetic feature in health and disease. Two cost-efficient genome-scale methodologies to assess DNA-methylation are MethylCap-seq and Illumina's Infinium HumanMethylation450 BeadChips (HM450). However, objective information regarding the best-suited methodology for a specific research question is scant. Therefore, we performed a large-scale evaluation on a set of 70 brain tissue samples obtained from 65 glioblastoma and 5 non-tumoral brain tissues, using a gold standard free Bayesian modeling procedure. While conditional specificity was adequate for both approaches, conditional sensitivity was systematically higher for HM450. Also the genome-wide characteristics were compared, revealing that the HM450 probes assess less than 10% of the regions identified as methylated by MethylCap-seq. Hence the latter method may detect more potentially relevant DNA-methylation, defined by either functional location or previously reported differentially methylated candidate regions. Our results therefore indicate that – at least for the tissue under study - both methodologies are complementary, with a higher sensitivity for HM450, but a far larger genome-wide coverage for MethylCap-seq. Note that here only the relevant MethylCap-seq data is deposited, for the HM450 data we refer to GEO (GSE60274).

  Study EGAS00001001191

• Developmental_Dysplasia_of_the_Hip__DDH_

  The National Joint Registry for England and Wales (NJR) has become established as one of the largest repositories of clinical information about patients undergoing hip and knee replacement. The primary aim of this proposal is to examine the feasibility of adding value to that clinical information by partnering it with a DNA dataset to allow its use to be extended to the study of the underlying pathogenesis of diseases of the hip and knee, and the complications of their treatment. We will do this 1) by establishing a mechanism for accessing and linking pseudo-anonymised demographic and phenotype data between the NJR database and the proposed DNA Biobank; 2) by validating the collection of postal DNA samples from consenting NJR patients; and 3) by genotyping genome-wide 900 patients with the condition developmental dysplasia of the hip (DDH) to find variants that play a role in this heritable condition. The successful demonstration that the NJR can be used to establish a DNA Biobank will provide a powerful platform to examine the genetic basis for a wide range of joint diseases, and the complications of their treatment. This proposal is to carry out the genotyping portion of this project on the current CoreExome array

  Study EGAS00001000916

• Variation and transmission of the human gut microbiota across generations - shotgun data

  Although composition and functional potential of the human gut microbiota evolve over lifespan, kinship has been identified as a key covariate of microbial community diversification. To date, sharing of microbiota features within families has however mostly been assessed between parents and their direct offspring. Here, we investigate potential transmission and persistence of familial microbiome patterns and microbial genotypes in a family cohort (N=102) spanning three to five generations over the same female bloodline. We observe microbiome community composition to be associated with kinship, with seven (low-abundant) genera displaying familial distribution patterns. While kinship and current cohabitation emerged as closely entangled variables, our explorative analyses of microbial genotype distribution and transmission estimates point at the latter as a key covariate of strain dissemination. Highest potential transmission rates are estimated between sisters and mother-daughter pairs, decreasing with increasing daughter’s age, and being higher among cohabiting pairs than those living apart. Although rare, we do detect potential transmission events spanning three and four generations, primarily involving species of the genera Alistipes and Bacteroides. Overall, while our analyses confirm the existence of family-bound microbiome community profiles, transmission or co-acquisition of bacterial strains appears to be strongly linked to cohabitation.

  Study EGAS00001005649

• Variation and transmission of the human gut microbiota across generations - 16S data

  Although composition and functional potential of the human gut microbiota evolve over lifespan, kinship has been identified as a key covariate of microbial community diversification. To date, sharing of microbiota features within families has however mostly been assessed between parents and their direct offspring. Here, we investigate potential transmission and persistence of familial microbiome patterns and microbial genotypes in a family cohort (N=102) spanning three to five generations over the same female bloodline. We observe microbiome community composition to be associated with kinship, with seven (low-abundant) genera displaying familial distribution patterns. While kinship and current cohabitation emerged as closely entangled variables, our explorative analyses of microbial genotype distribution and transmission estimates point at the latter as a key covariate of strain dissemination. Highest potential transmission rates are estimated between sisters and mother-daughter pairs, decreasing with increasing daughter’s age, and being higher among cohabiting pairs than those living apart. Although rare, we do detect potential transmission events spanning three and four generations, primarily involving species of the genera Alistipes and Bacteroides. Overall, while our analyses confirm the existence of family-bound microbiome community profiles, transmission or co-acquisition of bacterial strains appears to be strongly linked to cohabitation.

  Study EGAS00001005651

• RNA-seq study of human long-term and short-term hematopoietic stem cells from umblical cord blood with lentiviral overexpression of S1PR3

  To investigate the molecular and biological pathways altered by S1PR3OE in human hematopoietic stem cells (HSC), we performed RNA-sequencing (RNA-seq) of LT- and ST-HSC 3 days after transduction with control or S1PR3 overexpression (OE) lentiviral vectors. LT-HSC and ST-HSC from 3 pool of CB lin- were FACS-purified, cells were prestimulated for 4 hours and transduced with lentiviral vectors. At day 3, 2000-5300 BFP+ cells were FACS-purified for RNA isolation with a PicoPure kit. We were able to isolate only 1600-1800 BFP+ cells from LT-HSC control samples as opposed to 4000-5400 BFP+ cells from S1PR3OE samples. Thus, we pooled all control BFP+ LT-HSC cells into one sample for RNA-seq analysis. BFP- LT-HSC from control vector transduction were purified from CB1 as an additional LT-HSC control. Nextera libraries generated from 10 ng RNA from 5 LT-HSC samples (2 controls, 3 S1PR3OE) and 6 ST-HSC samples (3 controls, 3 S1PR3OE) were subjected to 125 bp, paired-end RNA-sequencing on the Illumina HiSeq 2500 with an average of 50 million reads/sample at the Center for Applied Genomics, Sick Kids Hospital.

  Study EGAS00001004798

• Targeted sequencing of diffuse large B-cell lymphoma tumour samples from the UK's Haematological Malignancy Research Network

  Targeted sequencing was applied to an unselected population-based diffuse large B-cell lymphoma cohort (n=928) diagnosed in the UK's Haematological Malignancy Research Network catchment population of ~4 million (14 centres). DNA extracted from tumour samples was sequenced with a 293-gene panel using the Illumina HiSeq 2500. All data are provided in the CRAM format.

  Dataset EGAD00001008616

• Pooled scRNA-seq of iPSC-derived neural stem cells from ADHD and control individuals

  This dataset comprises paired-end FASTQ files from single-cell RNA sequencing (scRNA-seq) of neural stem cells (NSCs) derived from induced pluripotent stem cells (iPSCs). The iPSCs were reprogrammed from somatic cells (keratinocytes, PBMCs, or lymphoblastoid cell lines) collected from individuals diagnosed with attention-deficit hyperactivity disorder (ADHD) and age-matched healthy controls (ages 6–18 years). Reprogramming was carried out using the non-integrative Sendai virus system (CytoTune-iPS 2.0, Thermo Fisher Scientific), introducing OCT3/4, SOX2, KLF4, and cMYC. iPSCs were cultured in Essential 8 medium on vitronectin and underwent rigorous quality control including immunocytochemistry, qRT-PCR, mycoplasma testing, and SNP genotyping (Illumina Global Screening Array). NSCs were generated using a standardized neural induction protocol and validated via qRT-PCR and immunostaining for markers including PAX6, SOX2, NESTIN, TUJ1, and FOXG1. Two independent scRNA-seq multiplexed experiments were performed: Experiment 1 (ADHD: n = 7; Control: n = 6) and Experiment 2 (ADHD: n = 9; Control: n = 7). Samples were pooled and demultiplexed using the Ensemblex algorithm, incorporating prior genotype data. After quality control filtering (>500 unique RNA molecules per cell), 30,433 single-cell transcriptomes were retained. Differential gene expression analysis was conducted to identify transcriptional signatures associated with ADHD compared to controls.

  Study EGAS00001008169

• Fetal Chorioamniotic Membranes Show Molecular Changes in Placenta Previa and Placenta Accreta Spectrum

  Placenta previa and the placenta accreta spectrum (PAS) are understudied pregnancy disorders with serious consequences for both mother and infant. To better understand the molecular and cellular etiologies of these diseases, we performed 3SEQ of formalin-fixed paraffin-embedded (FFPE) fetal chorioamniotic membrane samples from PAS, previa, and gestationally age-matched spontaneous pre-term birth samples to identify molecule signatures of these diseases. These samples were subsequently validated using a second validation cohort of previa, PAS, and control patients. FFPE archival samples provide opportunities for retrospective molecular investigation of many diseases.

  Study phs002075