3413 results for "*geneti*"

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• HipSci_RNASEQ_Retinitis_Pigmentosa

  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 RNAseq on iPS lines from Retinitis Pigmentosa patients

  Study EGAS00001001996

• Succession Of Transiently Active Tumour-Initiating Cell Clones inHuman Pancreatic Cancer

  To elucidate whether newly acquired genetic alterations during serial transplantation of patient derived primary pancreatic cancer cultures contribute to the observed clonal dynamics in vivo, all coding genes of two patient derived primary cultures and derived genetically marked serial xenografts (1°/2°/3°) were sequenced.

  Study EGAS00001000882

• The identification of genetic vulnerabilities in head and neck cancers for the development of novel treatments.

  The global cancer burden is expected to double by the year 2030 and this will disproportionately affect the Asian continent. Head and neck squamous cell carcinoma (HNSCC) is endemic in Asia. It is the sixth most common cancer worldwide and the second most common in Malaysia, with approximately 600,000 new cases per year globally. Longterm survival remains less than 50%, underscoring the need for better therapeutic strategies. In this proposal we aim to bring new technological advancements in the identification of critical genes in HNSCC and the identification of compounds for the development of new therapies in HNSCC. We propose to genomically characterise 16 unique Asian H&N cancer cell lines, to classify sub groups where identification of essential genes that can be targeted for tumor control can be applied in a more rational way. Further, we propose to use zebrafish, an established drug discovery platform to identify promising pathway-specific compounds that could be further studied using CRISPR/Cas9 lethality screens and biological models to better identify novel therapeutic strategies to combat this major health problem in Asia.

  Study EGAS00001002682

• Metastatic_Breast_Cancer_Whole_Genome

  We propose to definitively characterise the somatic genetics of Metastatic breast cancer through generation of comprehensive catalogues of somatic mutations in Metastatic breast cancer cases by high coverage genome sequencing coupled with integrated transcriptomic and methylation analyses.

  Study EGAS00001000902

• Somatic_mutation_and_clonal_evolution_in_premalignant_lung_disease___WGS

  Cancer is a genetic disease caused by an accumulations of mutations, however many of these mutations have been identified in pathologically normal tissue. We aim to use laser-capture microscopy (LCM) to sample individual clones from the lung tissue of individuals with a variety of lung diseases (COPD, UIP, IPF, Emphysema, pulmonary hypertension). This will allow us to identify whether cancer-associated mutations appear in this normal tissue, assess the mutational burden present, and identify the mutational processes causing these mutations. Smoking is a large risk factor for developing many of these lung diseases so we are particularly keen to determining whether there is evidence of a smoking signature in these patients.

  Study EGAS00001002747

• Mechanisms_of_patient_response_to_Dabrafenib_in_Melanoma

  Samples will be from the BRF113683 (BREAK-3) study which is a Phase III Randomized, Open-label Study Comparing GSK2118436 to Dacarbazine (DTIC) in Previously Untreated Subjects With BRAF Mutation Positive Advanced (Stage III) or Metastatic (Stage IV) Melanoma (n=250 enrolled)•NGS [Agilent capture (Sanger V2 panel): 360 genes and 20 gene fusions; Illumina HiSEQ Sequencing]•CNV: [via NGS or Affy SNP 6.0 or Illumina Omni (TBD)]Bioinformatics: Analysis will be performed using core Sanger informatics pipelines similar to those previously described (Papaemmanuil E et al. (2013) Blood. 22:3616 -3627). Briefly, copy number analysis will be performed using the ASCAT algorithm, and base substitutions, small insertions and deletions using the CAVEMAN and Pindel algorithms, respectively. Statistical approaches including generalized linear models will be used to predict clinical variables such as maximum clinical response and duration of response using genetic data. Sanger and EBI to conduct analysis; Raw data and correlation with clinical endpoints to be analyzed by both EBI/Sanger and GSK (unique pipeline analyses to increase call confidence)

  Study EGAS00001000946

• MutWP1__CRUK_Grand_Challenge_Mutographs_of_Cancer__pancreas

  The Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Different patterns of somatic mutation are generated by the different environmental, lifestyle and genetic factors that cause cancer, many of them are still unknown. Within Mutographs, the International Agency for Research on Cancer is coordinating the recruitment of 5000 individuals with cancer (colorectal, renal, pancreatic, oesophageal adenocarcinoma or oesophageal squamous cancers) across 5 continents to explore whether different mutational signatures explain marked variation in incidence. In brief, through an international network of collaborators around the world, biological materials are collected, along with demographic, histological, clinical and questionnaire data. Whole genome sequences of tumour-germline DNA pairs are generated at the Wellcome Trust Sanger Institute (Illumina HiSeqX, 40X and 20X depth respectively). Somatic mutational signatures are subsequently extracted by non-negative matrix factorisation methods and correlated with risk factors data. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development.

  Study EGAS00001002726

• Himalayan_population_genetic_study

  We genotyped 770 individuals belonging to 49 populations from Nepal, Bhutan, North India or Tibet at over 500,000 SNPs genomewide to investigate the demographic history of the region and the genetic adaptations to the harsh environment. 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 EGAS00001002731

• The_British_Autozygosity_Populations_BioResource

  This data set contains whole exome sequences of individuals with self-stated parental relatedness from the East London Genes & Health cohort. Rare frequency functional variants in these healthy individuals will be studied with respect to the genetic health of the participants and loss-of-function analysis of human genes. 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 EGAS00001002742

• DKFZ-HIPO Project H021/NCT MASTER

  Clinical genome and transcriptome sequencing in younger adults with advanced-stage cancer across all histologies: DKFZ-HIPO Project H021 (http://www.hipo-heidelberg.org/hipo2/index.php/menu-item-2/32-021-prospective-genetic-characterization-of-tumors-from-individual-patients-of-special-interest) / NCT MASTER (http://www.nct-heidelberg.de/forschung/nct-master.html)

  Study EGAS00001000948

• Fetal hemoglobin in sickle cell disease patients from Tanzania

  Levels of fetal hemoglobin have been associated with differences in severity and outcome of sickle cell disease (SCD). While some genetic associations have been reported between SNPs and HbF level, little of the variance in the trait is explained, and most studies have focused on African American, rather than African samples. We have carried out a GWAS in a collection of SCD patients from Dar es Salaam, Tanzania. This sample represents a diverse, metropolitan collection of individuals from East Africa. Omni 2.5M genotypes and HbF levels (measured after 5 years of age) are available.

  Study EGAS00001000990

• Genomic analysis Nasopharyngeal cancer through whole exome sequencing and whole genomic sequencing.

  Nasopharyngeal carcinoma (NPC) is a squamous-cell carcinoma and has remarkable ethnic and geographic distribution, with a high prevalence in southern China, southeast Asia, northern Africa and Alaska. Although there are previous studies implicated NF-κB pathway play an important role in NPC. Newer research also found several important cellular processes and pathways in NPC, including chromatin modification, ERBB-PI3K signaling and autophagy machinery. Put these studies together, although, NPC is still poorly understood at the genetic level. Here we determined the mutational landscape of 553 cases with NPC using whole-genomic and whole-exome sequencing. These approaches revealed a distinct mutational signature and significantly mutated genes.

  Study EGAS00001002788

• DNA hypermethylation and differential gene expression associated with Klinefelter syndrome

  The molecular basis for the phenotypic traits and morbidity in Klinefelter syndrome (KS) are not clarified. As DNA methylation affect gene expression and thereby play a role in disease susceptibility, we performed genome-wide DNA methylation profiling of leucocytes from peripheral blood samples from 67 KS patients, 67 male controls and 33 female controls, in addition to genome-wide RNA-sequencing profiling in a subset of 9 KS patients, 9 control males and 13 female controls. Characterization of the methylome as well as the transcriptome of both coding and non-coding genes identified a unique epigenetic and genetic landscape of both autosomal chromosomes as well as the X chromosome in KS. A subset of genes show significant correlation between methylation values and expression values. Gene set enrichment analysis of differentially methylated positions yielded terms associated with well-known comorbidities seen in KS. In addition, differentially expressed genes revealed enrichment for genes involved in the immune system, wnt-signaling pathway and neuron development. Based on our data we point towards many new candidate genes (AKAP17A, AMOT, APOB, DACT1, DDX58, DOCK7, EIF2S3, FIGNL1, G3BP1, HENMT1, HERC5, IFI44, IFI44L, IFIT1, IFIT3, ISG15, KANK1, LGALS1, NSD1, PEX10, PLSCR1, RSAD2, SHROOM2, SLC25A6, SPEG, SPON2, TXLNG), which may be implicated in the phenotype and further point towards non-coding genes (RP13-216E22.4, RP13-36G14.4, G087825, G088512), which may be involved in X chromosome inactivation in KS and in the regulation of escape genes.

  Study EGAS00001002797

• 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/

  Study EGAS00001001124

• Somatic_mutation_and_clonal_evolution_normal_breast_tissue_WGS

  Cancer is a genetic disease caused by an accumulation of mutations, however many of these mutations have been identified in pathologically normal tissue. We aim to use laser-capture microscopy (LCM) to sample individual clones from breast tissue to identify whether cancer-associated mutations appear in this normal tissue, assess the mutational burden present, and identify the mutational processes causing these mutations. We will sample from a wide age range of individuals (<20 to >70 years old) to determine whether these processes differ in pre- and post-menopausal women. We will also be comparing the tissue from healthy individuals (samples from breast reduction surgery) to those at elevated risk of breast cancer (mastectomy from BRCA1/2 patients) and those who have breast cancer (adjacent normal, distal normal, and tumour tissue from mastectomy). This will allow us to determine how these processes are different between these groups of individuals, and gain insight into the earliest stages of tumour development.

  Study EGAS00001002857

• Somatic_mutation_and_clonal_evolution_normal_breast_tissue_TGS

  Cancer is a genetic disease caused by an accumulation of mutations, however many of these mutations have been identified in pathologically normal tissue. We aim to use laser-capture microscopy (LCM) to sample individual clones from breast tissue to identify whether cancer-associated mutations appear in this normal tissue, assess the mutational burden present, and identify the mutational processes causing these mutations. We will sample from a wide age range of individuals (<20 to >70 years old) to determine whether these processes differ in pre- and post-menopausal women. We will also be comparing the tissue from healthy individuals (samples from breast reduction surgery) to those at elevated risk of breast cancer (mastectomy from BRCA1/2 patients) and those who have breast cancer (adjacent normal, distal normal, and tumour tissue from mastectomy). This will allow us to determine how these processes are different between these groups of individuals, and gain insight into the earliest stages of tumour development.

  Study EGAS00001002858

• Genetic_profiling_of_mucosal_melanoma

  Primary mucosal melanomas (MMs) arise from melanocytes located in mucosal membranes lining the respiratory, gastrointestinal and urogenital tracts. MMs frequently present late and have a poor prognosis; the 5-year survival rate is only 14%. MM makes up only ~1.4% of all melanomas and it is this rarity that makes knowledge of the genetic changes that contribute to its pathogenesis limited to a small number of exome/genome studies and other targeted studies. Thus to investigate the somatic alterations and mutation spectra in MM genomes, we have extracted genomic DNA from formalin-fixed, paraffin-embedded (FFPE) human MMs, and subjected them to whole exome sequencing. Given the propensity of MM to metastasize, we will also be sequencing metastatic MM lesions; primary and metastatic lesions from the same individual represent an excellent opportunity to identify potential drivers of metastasis in MM. Finally we will sequence ‘normal’ DNA from the same individual, where possible, to exclude germline variations.

  Study EGAS00001001115

• ESGI___Whole_Genome_Sequencing_of_samples_from_the_INGI_Val_Borbera_genetic_isolate__X10_

  Whole genome sequencing of sampels from an isolated population from the Val Borbera valley in Italy. The samples are sequenced using the Illumina HiSeq X Ten system.

  Study EGAS00001001123

• DPY30_ChIP_seq

  H9 human embryonic stem cells (hESCs) were cultured in feeder-free chemically-defined conditions in medium containing 10ng/ml Activin A and 12ng/ml FGF2 (Vallier L. 2011, Methods in Molecular Biology, 690: 57–66). Chromatin immunoprecipitation was performed as described in Brown S. et al. 2011. Stem Cells 29: 1176–85 by using 5ug of anti-DPY30 antibody (Sigma, cat. number HPA043761). This protocol was performed in control hESCs (expressing a scrambled shRNA) and in hESCs stably expressing an shRNA against DPY30 (Sigma, clone n. TRCN0000131112).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 EGAS00001001132

• HipSci___Whole_Exome_sequencing___Monogenic_Diabetes

  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 Monogenic Diabetes.

  Study EGAS00001001140

• HipSci_RNASEQ_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 RNAseq on iPS lines from Macular Dystrophy patients

  Study EGAS00001001995

• A whole genome analysis of single fetal human stem cells from the liver and the intestine

  Mutations of embryonic and fetal origin have the potential to affect a large proportion of adult cells and may alter cancer predisposition or lead to genetic disease syndromes. We have recently shown that human adult-stem cells progressively acquire approximately 40 novel tissue-specific mutations per year throughout postnatal life. Prenatal mutation rates are as yet unknown. Here we determined genome-wide mutation patterns of single stem cells in human development by sequencing of clonally expanded intestinal and liver organoid cultures of 2nd trimester human foetuses. Our results show that mutation rates in fetal stem cells are significantly higher than in adult stem cells.

  Study EGAS00001002886

• Genome_Diversity_in_Africa_Project___ancient_samples___standard_libraries

  Given the central importance of Africa to studies of human origins, genetic diversity and disease susceptibility, large-scale and representative characterisation of genetic diversity in Africa is needed. Analyses of ancient DNA from Africa would complement sequencing of modern African populations and provide unique opportunities to transform our understanding of the pre-history of the region. This approach would greatly refine our understanding of population structure and gene flow in Africa and globally, including genetic signatures of ancient admixture. This low coverage sequencing experiment will allow us to test and refine our pipeline for ancient DNA sequencing.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 EGAS00001001182

• G&T-seq: parallel sequencing of the genomes and transcriptomes of single cells

  The ability to simultaneously sequence the genome and transcriptome of the same single cell offersa powerful means to dissect functional genetic heterogeneity at the cellular level. Here we describeG&T-seq, a method for separating and sequencing genomic DNA and full-length mRNA from singlecells. By applying G&T-seq to over 220 single cells we reveal cellular properties that cannot beinferred from DNA or RNA sequencing alone, including associations between DNA copy numbervariation and gene expression dosage. We further demonstrate the detection of coding interchromosomalfusions and single nucleotide variants in both the genomes and transcriptomes ofindividual cells. G&T-seq enables the study of genotype-phenotype associations in single cells, andthe investigation of DNA cell lineage trees of healthy and diseased tissues with transcriptome inferredcell types and states.

  Study EGAS00001001204

• Institut Curie Neuroblastoma Whole Genome Sequencing Diagnosis Relapse

  Neuroblastoma, a clinically heterogeneous pediatric cancer, is characterized by distinct genomic profiles but few recurrent mutations. As neuroblastoma is expected to have high degree of genetic heterogeneity, study of neuroblastoma's clonal evolution with deep coverage whole-genome sequencing of diagnosis and relapse samples will lead to a better understanding of the molecular events associated with relapse. Samples were included in this study if sufficient DNA from constitutional, diagnosis and relapse tumors was available for WGS. Whole genome sequencing was performed on trios (constitutional, diagnose and relapse DNA) from eight patients using Illumina Hi-seq2500 leading to paired-ends (PE) 90x90 for 6 of them and 100x100 for two. Expected coverage for sample NB0175 100x100bp was 30X for tumor and constitutional samples. For the seven other patients expected coverage was 80X for tumor samples with PE 100x100, 100X in the other tumor samples and 50X for all constitutional samples (see table 1). Following alignment with BWA (Li et al., Oxford J, 2009 Jul) allowing up to 4% of mismatches, bam files were cleaned up according to the Genome Analysis Toolkit (GATK) recommendations (Van der Auwera et al., Current Protocols in Bioinformatics, 2013, picard-1.45, GenomeAnalysisTK-2.2-16). Variant calling was performed in parallel using 3 variant callers: GenomeAnalysisTK-2.2-16, Samtools-0.1.18 and MuTect-1.1.4 (McKenna et al., Genome Res, 2010; Li et al., Oxford J, 2009 Aug; Cibulskis et al., Nature, 2013). Annovar-v2012-10-23 with cosmic-v64 and dbsnp-v137 were used for the annotation and RefSeq for the structural annotation. For GATK and Samtools, single nucleotide variants (SNVs) with a quality under 30, a depth of coverage under 6 or with less than 2 reads supporting the variant were filter out. MuTect with parameters following GATK and Samtools thresholds have been used to filter our irrelevant variants. .SNVs within and around exons of coding genes overlapping splice sites.. Then,variants reported in more than 1% of the population in the 1000 genomes (1000gAprl_2012) or Exome Sequencing Project (ESP6500) have been discarded in order to filter polymorphisms. Finally, synonymous variants were filtered out. MuTect focuses on somatic by filtering with constitutional sample. Mpileup comparison between constitutional and somatic DNAs allowed us to focus also on tumor specific SNVs with GATK and Samtools. Finally, every SNV called by our pipeline and also supported in any constitutional samples were filtered our in order to prevent putative constitutional DNA coverage deficiency. Then we analyzed CNVs (copy number variants) with HMMcopy-v0.1.1 (Gavin et al., Genome Res, 2012) and control-FREEC-v6.7 (Boeva et al., Bioinformatics 2011) with a respective window of 2000bp and 1000 bp, and auto-correction of normal contamination of tumor samples for Control-FREEC. Finally we explored Structural variants (SVs) including deletions, inversions, tandem duplications and translocations using DELLY-v0.5.5 with standard parameters (Rausch et al., Oxford J, 2012). In tumors, at least 10 supporting reads were required to make a call and 5 supporting reads for the sample NB0175 with a coverage of only 40X (see table 2). To predict SVs in constitutional samples for subsequent somatic filtering, only 2 supporting reads were required in order not to miss one. To identify somatic events, all the SVs in each normal sample were first flanked by 500 bp in both directions and any SVs called in a tumor sample which was in the combined flanked regions of respective normal sample was removed (see graph 1). Deletions with more than 5 genes impacted or larger than 1Mb and inversions or tandem duplications covering more than 4 genes, were removed. We focused on exonic and splicing events for deletions, inversions, and tandem duplications. For translocation, we keep all SVs that occurred in intronic, exonic, 5'UTR, upstream or splicing regions. Bioinformatics detection of variations with Deep sequencing approach Once PE reads merged and adaptors trimmed by SeqPrep with default parameters, merged reads were aligned via the BWA (Li H. and Durbin R. 2009 PMID 19451168) allowing up to 1 differences in the 22-base-long seeds and reporting only unique alignments. Only reads having a mapping quality 20 or more have been further analysed. Variant calling software was not used, since we aimed to predict variations at low frequencies, observed in less than 1% of reads. Such variants require a custom approach. Using DepthOfCoverage functions of the Genome Analysis Toolkit (GATK) v2.13.2 (McKenna A, et al., 2010 Genome Research PMID: 20644199), we focused on high quality coverage of bases A, C, G and T at the targeted variant position. Depth of coverage of each base following a mapping quality higher than 20 and a base quality higher than 10 have been taken into account in order to focus only on high quality data. Aiming to determine the background level of variability at the studied regions, 10 control samples were included in the analysis. The same approach and filtering criteria have been applied as introduced above over the entire amplicons. In order to highlight variants, for each sample the frequencies of each bases at each amplicon position were then compared to those observed in the set of controls. Statistical analyses were performed with the R statistical software (http://www.R-project.org). Fisher’s exact two-sided tests with a Bonferroni correction were performed to compare percentages of bases between the data sets, i.e. for a given base between a case and the controls. Finally, significant variations were filtered-in once (i) a significant increase in the percentage of avariant base and (ii) a significant decrease in the percentage of it's reference base following our p.values criteria was observed (p.val < 0.05).

  Study EGAS00001001184

• Illumina HumanCoreExome genotyping data from the British Society for Surgery of the Hand Genetics of Dupuytren’s Disease consortium (BSSH-GODD consortium) collection

  Dupuytren's Disease (DD - OMIM126900) is the most common heritable disorder of connective tissue. It is a fibroproliferative disorder of the palmer fascia, causing flexion contractures of affected digits. DD affects men more commonly than women. DD is an archetypal complex disease, with multiple genetic and environmental factors affecting the final expression of the disease phenotype. The incidence increases with age, and the prevalence of DD is therefore increasing as the UK population ages. Half of all patients present before age 60. DD causes significant functional impairment, and severe contractures can lead to permanent disability. The mainstay of current treatment is surgery, but recurrence and complications are both high. For severe contractures, the only suitable treatment option is amputation. The direct costs to the NHS are high, and underestimate the true economic costs to society. We collected salivary samples from adults in the UK who have had surgery for DD. We have genotyped these samples using the Illumina HumanCoreExome Beadchips. https://research.ndorms.ox.ac.uk/public/dupuytrens/what-is-dupuytrens-disease/

  Study EGAS00001001206

• PSCP_bisulphite_analysis_in_hESCs

  Many studies over the past 10 years, culminating in the recent report of the International Stem Cell Initiative (ISCI, 2011) have shown that hPSC acquire genetic and epigenetic changes during their time in culture. Many of the genetic changes are non-random and recurrent, probably because they provide a selective growth advantage to the undifferentiated cells. Some are shared by embryonal carcinoma cells, the malignant counterparts of ES cells. The origins of these growth advantages are poorly understood, but may come from altered cell cycle dynamics, resistance to apoptosis or altered patterns of differentiation. Less is known about the nature and consequences of epigenetic changes, but it is likely that these similarly affect hPSC behaviour; e.g., enhanced expression of DLK1, an imprinted gene, is associated with altered hPSC growth (Enver et al 2005). Inevitably, these genetic and epigenetic changes will impact on our ability to use hPSC for regenerative medicine, either because malignant transformation of the undifferentiated cells or their differentiated derivatives to be used for transplantation compromises safety, or because they impede the function of those differentiated derivatives, or because they affect the efficiency with which the undifferentiated cells can be expanded and differentiated into desired cell types. Focusing initially upon the existing clinical grade hESC lines, later moving to iPSC, we will Consolidate and extend knowledge of the rate, type and functional impact of the genetic variations that occur during hPSC culture. We will use whole genome and exome sequencing as well as SNP arrays, together with clonal analysis and other cytogenetics techniques. Common changes will be compared with those found in the normal human population, at low frequency in the original cell population or observed during iPSC generation in the HIPSCI project currently based at the WTSI. These studies will provide a better understanding of the range of genetic changes that occur in hPSC beyond the CNVs already identified. In conjunction with cancer genome resources and expertise at WTSI, bioinformatic analyses of these hPSC data will allow us to assess potential impact on hPSC behaviour pertinent to applications in regenerative medicine, notably the likelihood that specific changes arising in undifferentiated PSC cultures may be associated with potential malignant transformation of differentiated progeny. 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 EGAS00001001625

• HipSci Illumina 450K Methylation analysis-Rare_BBS

  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 Methylation analysis using the Infinium HumanMethylation450 BeadChip on iPS cells generated from skin biopsies or blood samples from rare disease patients diagnosed with Bardet-Biedl syndrome.

  Study EGAS00001001274

• WES_of_adult_intellectual_disabilities_with_co_morbid_psychiatric_disorders

  ost adults with intellectual disabilities (ID) do not undergo genetic diagnostic investigation as part of their clinical care and have 'missed the boat' with regard to the WES and WGS genetic testing that is now being provided for children with ID. There is a dramatically increased risk of psychistric disorders in adults with ID, e.g. the risk of psychoses is 10X higher than in the general population. It remains an open question as to how much of adult ID is genetic in origin and how similar the genetic forms of adult ID are to those being diagnosed in children, in part due to survivor bias. There is also the opportunity to identify adults with treatable forms of ID, of which over 80 have been described, thus improving their clinical management. Furthermore, analysis of medical records of adults with genetic forms of ID can help to characterise the 'natural history' of individual disorders, resulting in more accurate prognoses for diagnosed children and identifying opportunities for improved management and possibly therapeutic intervention (e.g. optimal anti-epileptic therapy). Here we propose to exome sequence (to ~50X coverage) 200 adults with ID and co-morbid psychiatric disorders. This cohort has previously been assayed with chromosomal microarrays (Wolfe et al 2017 EJHG, 25, 66–72) identifying a diagnostic yield of ~11% which is comparable to the CNV diagnostic yield in various child ID cohorts (10-15%). The authors observed no substantive biases in diagnostic yield between different psychiatric diagnostic classes. The WES data will be analysed using the diagnostic workflows developed in the DDD study to ensure comparability between child and adult ID datasets. This study is intended as a pilot study to demonstrate the value of WES in adults with ID. 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 EGAS00001002962

• Identification of Therapeutic Targets in Rhabdomyosarcoma Through Integrated Genomic, Epigenomic, and Proteomic Analyses

  Personalized cancer therapy based on the somatic mutations identified in patient tumors is becoming an increasingly emphasized approach to improve outcomes of patients with cancer. There are also examples of therapeutic vulnerabilities in cancer that result from changes in gene expression that are a direct or indirect result of tumor specific epigenetic perturbations. These genomic and epigenomic changes are ultimately manifest in the tumor proteome and phosphoproteome. In this study, we integrated genomic, epigenomic and proteomic data for rhabdomyosarcoma (RMS) to identify therapeutic vulnerabilities. RMS was selected for this analysis because RAS pathway mutations in rhabdomyosarcoma (RMS) are the most common potentially actionable lesions across pediatric solid tumors. The epigenomic data was useful for identifying deregulated developmental pathways in RMS including the WNT, HH, BMP, adenyl cyclase, p38/MAPK and PI3K pathways. Perturbations in those 6 myogenic signal transduction pathways were also evident in the proteome and phosphoteome data. In addition, the proteomic/phosphoproteomic data revealed that the cell cycle checkpoint, unfolded protein response and RB/E2F pathways were deregulated in RMS relative to normal muscle. Recent success targeting CDK4/6 and MEK in adult cancers with RAS mutations led us to test the value of these targets in RMS tumors. We also targeted the unfolded protein response pathway and cell cycle checkpoint pathway using molecular targeted therapeutics in orthotopic patient derived xenografts. Taken together, these data demonstrate the value of integrating epigenomic and proteomic data to identify tumor vulnerabilities that extend beyond somatic mutations identified in the genome.

  Study EGAS00001002967

• Genetic_screening__of_GPI_anchor_protein_synthesis__

  This study will analyse the guide sequence which were used for making mutations in the Cas9-expressing cells. We used GeCKO v2 library which were released by Feng Zhang, 2014. 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 EGAS00001001256

• HipSci_RNASEQ_Kabuki

  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 RNAseq on iPS lines from kabuki patients

  Study EGAS00001001989

• HipSci HumanHT 12v4 Expression BeadChip analysis-Rare_BBS

  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 Bardet-Biedl syndrome.

  Study EGAS00001001276

• HipSci HumanHT 12v4 Expression BeadChip analysis - monogenic diabetes

  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 monogenic diabetes.

  Study EGAS00001001277

• Somatic_Genetics_of_lesions_from_a_POT1_patient

  In this project we will use exome sequencing to identify somatic mutations in lesions from a patient with a germline mutation in the protection of telomeres 1 gene (POT1).

  Study EGAS00001001343

• HipSci - Human Induced Pluripotent Stem Cells Initiative

  Human induced pluripotent stem (iPS) cells can be generated from adult tissues and differentiated into a range of specific cell types (Yamanaka and Blau, 2010). They therefore provide unprecedented opportunities for investigating disease mechanisms and understanding the phenotypic consequences of genetic variation within the normal population. HipSci brings together diverse constitutents 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. Between 2013 and 2016 we aim to generate iPS cells from over 500 healthy individuals and 500 individuals with genetic disease. We will then use these cells to discover how genomic variation impacts on cellular phenotype and identify new disease mechanisms. Strong links with NHS investigators will ensure that studies on the disease-associated cell lines will be linked to extensive clinical information. Further key features of the project are an open access model of data sharing; engagement of the wider clinical genetics community in selecting patient samples; and provision of dedicated laboratory space for collaborative cell phenotyping and differentiation.

  Study EGAS00001001465

• Genetic landscape of relapsed DLBCL

  Diffuse large B-cell lymphoma is a heterogenous malignancy that can arise de novo or can result from histologic transformation from indolent lymphomas. Considerable sequencing effort has been placed on determining the mutations that are common at the time of diagnosis in DLBCL but little is known about the nature of relapsed disease. We have sequenced tumour and matched normal exomes of 38 rrDLBCL patients including 25 de novo DLBCLs and 13 transformed lymphomas to identify somatic mutations and copy number alterations associated with relapse.

  Study EGAS00001001553

• The_British_Autozygosity_Populations_BioResource

  This data set contains whole exome sequences of 500 individuals with self-stated parental relatedness from the East London Genes & Health cohort. Rare frequency functional variants in these healthy individuals will be studied with respect to the genetic health of the participants and loss-of-function analysis of human genes.

  Study EGAS00001001565

• PSCP_mutation_analysis_in_hESCs

  Many studies over the past 10 years, culminating in the recent report of the International Stem Cell Initiative (ISCI, 2011) have shown that hPSC acquire genetic and epigenetic changes during their time in culture. Many of the genetic changes are non-random and recurrent, probably because they provide a selective growth advantage to the undifferentiated cells. Some are shared by embryonal carcinoma cells, the malignant counterparts of ES cells. The origins of these growth advantages are poorly understood, but may come from altered cell cycle dynamics, resistance to apoptosis or altered patterns of differentiation. Less is known about the nature and consequences of epigenetic changes, but it is likely that these similarly affect hPSC behaviour; e.g., enhanced expression of DLK1, an imprinted gene, is associated with altered hPSC growth (Enver et al 2005). Inevitably, these genetic and epigenetic changes will impact on our ability to use hPSC for regenerative medicine, either because malignant transformation of the undifferentiated cells or their differentiated derivatives to be used for transplantation compromises safety, or because they impede the function of those differentiated derivatives, or because they affect the efficiency with which the undifferentiated cells can be expanded and differentiated into desired cell types. Focusing initially upon the existing clinical grade hESC lines, later moving to iPSC, we will Consolidate and extend knowledge of the rate, type and functional impact of the genetic variations that occur during hPSC culture. We will use whole genome and exome sequencing as well as SNP arrays, together with clonal analysis and other cytogenetics techniques. Common changes will be compared with those found in the normal human population, at low frequency in the original cell population or observed during iPSC generation in the HIPSCI project currently based at the WTSI. These studies will provide a better understanding of the range of genetic changes that occur in hPSC beyond the CNVs already identified. In conjunction with cancer genome resources and expertise at WTSI, bioinformatic analyses of these hPSC data will allow us to assess potential impact on hPSC behaviour pertinent to applications in regenerative medicine, notably the likelihood that specific changes arising in undifferentiated PSC cultures may be associated with potential malignant transformation of differentiated progeny. This data is part of a pre-publication release. For information on the proper use of pre-publication data shred by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001001561

• RNA_seq_analysis_of_transcriptome_variation_with_human_ESC_subclones

  Many studies over the past 10 years, culminating in the recent report of the International Stem Cell Initiative (ISCI, 2011) have shown that hPSC acquire genetic and epigenetic changes during their time in culture. Many of the genetic changes are non-random and recurrent, probably because they provide a selective growth advantage to the undifferentiated cells. Some are shared by embryonal carcinoma cells, the malignant counterparts of ES cells. The origins of these growth advantages are poorly understood, but may come from altered cell cycle dynamics, resistance to apoptosis or altered patterns of differentiation. Less is known about the nature and consequences of epigenetic changes, but it is likely that these similarly affect hPSC behaviour; e.g., enhanced expression of DLK1, an imprinted gene, is associated with altered hPSC growth (Enver et al 2005). Inevitably, these genetic and epigenetic changes will impact on our ability to use hPSC for regenerative medicine, either because malignant transformation of the undifferentiated cells or their differentiated derivatives to be used for transplantation compromises safety, or because they impede the function of those differentiated derivatives, or because they affect the efficiency with which the undifferentiated cells can be expanded and differentiated into desired cell types. Focusing initially upon the existing clinical grade hESC lines, later moving to iPSC, we will Consolidate and extend knowledge of the rate, type and functional impact of the genetic variations that occur during hPSC culture. We will use whole genome and exome sequencing as well as SNP arrays, together with clonal analysis and other cytogenetics techniques. Common changes will be compared with those found in the normal human population, at low frequency in the original cell population or observed during iPSC generation in the HIPSCI project currently based at the WTSI. These studies will provide a better understanding of the range of genetic changes that occur in hPSC beyond the CNVs already identified. In conjunction with cancer genome resources and expertise at WTSI, bioinformatic analyses of these hPSC data will allow us to assess potential impact on hPSC behaviour pertinent to applications in regenerative medicine, notably the likelihood that specific changes arising in undifferentiated PSC cultures may be associated with potential malignant transformation of differentiated progenyThis 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 EGAS00001001655

• Single Cell ATAC-Seq on human cord-blood derived HSPC.

  Study EGAS00001004740

• Genomic and epigenomic characterization of juvenile myelomonocytic leukemia (JMML)

  Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative disorder of early childhood. While some cases show spontaneous remission, allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative treatment option for the majority of patients, however, the 5-year event-free survival reaches only about 50%. Hyperactive RAS signaling is assumed to be the main driving event in JMML. It is caused by genetic alterations in CBL, KRAS, NF1, NRAS, or PTPN11 in about 90% of patients. So far, there is no clear understanding of how RAS pathway mutations relate to the heterogeneous disease biology and variable clinical outcome seen in JMML patients. As a consequence, established clinical and genetic markers fail to fully represent the observed disease heterogeneity. We hypothesized that DNA methylation profiling, either alone or in combination with genetic alterations, might provide a molecular basis for disease classification. Genome wide DNA methylation analysis using the HumanMethylation450 Bead Chip array was performed in a discovery cohort of 20 patients (19 JMML, 1 Noonan syndrome). The clinical relevance of our findings was assessed in an unselected sample set consisting of 147 consecutive patients with JMML (n=129) or Noonan syndrome (n=18) associated myeloproliferative disorder (n=18) registered in the EWOG-MDS 1998 & 2006 trials. Data integration was performed in a subset of patients with available exome sequencing (n=50) and expression profiling (n=15) data. This integrated approach identified three JMML subgroups characterized by distinct clinical and biological features. This analysis further suggested a molecular mechanism by which additional genetic events, presumably further activating the RAS-RAF-MEK-ERK pathway, mediate DNA hypermethylation via up-regulation of DNMTs in more aggressive JMML cases.

  Study EGAS00001002511

• Investigating_the_genetics_of_immunity_against_Salmonella_in_humans

  This study entails whole genome sequencing of an interleukin (IL)-12 b-1 receptor-deficient individual who presented with a chronic systemic Salmonella Enteritidis infection that did not resolve with standard IFNg and antibiotic treatment. Whole genome sequencing of the patient’s parents are also included.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 EGAS00001001664

• Exome sequencing of advanced hepatocellular carcinoma

  The aim of our project is to decipher the genomic of advanced hepatocellular carcinoma using whole exome sequencing. To this purpose, we aim to compare genetic landscape of advanced hepatocellular carcinoma with early tumor in order to understand the mechanisms of tumor progression. This work will also help to identify new therapeutic targets potentially useful to treat patients at advanced stage. This study contain whole exome sequencing aligned reads for 41 tumor with matched normal samples

  Study EGAS00001003130

• Non-coding mutations reveal cancer driver cistromes in luminal breast cancer

  Whole-genome sequencing of primary breast tumors enabled the identification of cancer driver genes and non-coding cancer driver plexuses from somatic mutations. However, differentiating between driver and passenger events among non-coding genetic variants remains a challenge to understand the etiology of cancer and inform the delivery of personalized cancer medicine. Herein, we reveal enrichment of non-coding mutations in cis-regulatory elements that cover a subset of transcription factors linked to tumor progression in luminal breast cancers. Using a cohort of 26 primary luminal ER+PR+ breast tumors, we compiled a catalogue of ~100,000 unique cis-regulatory elements from ATAC-seq data. Integrating this catalogue with somatic mutations from 350 publicly available breast tumor whole genomes, we identified four recurrently mutated individual cis-regulatory elements. By then partitioning the non-coding genome into cistromes, defined as the sum of binding sites for a transcription factor, we uncovered cancer driver cistromes for ten transcription factors, namely CTCF, ELF1, ESR1, FOSL2, FOXA1, FOXM1 GATA3, JUND, TFAP2A, and TFAP2C in luminal breast cancer. Nine of these ten transcription factors were shown to be essential for growth in breast cancer, with four exclusive to the luminal subtype. Collectively, we present a strategy to find cancer driver cistromes relying on quantifying the enrichment of non-coding mutations over cis-regulatory elements concatenated into a functional unit drawn from an accessible chromatin catalogue derived from primary cancer tissues.

  Study EGAS00001005235

• Open_Targets_020_Epigenomes_of_Cell_Lines

  There is currently a drive to establish cell based assay systems of greater human biological and disease relevance through the use of well characterised transformed cell lines, primary cells and complex cellular models (e.g. co-culture, 3D models). However, although the field is gaining valuable experience in running more non-standard & complex cell assays for target validation and compound pharmacology studies, there is the lack of a systematic approach to determine if this expansion in cell assay models is reflected in increased human biological and disease relevance. The increasing wealth of publically available transcriptomic, and epigenome (ENCODE and Epigenome Roadmap) data represents an ideal reference mechanism for determining the relationship between cell types used for target & compound studies to primary human cells and tissues from both healthy volunteers & patients. The CTTV020 epigenomes of cell line project aims to generate epigenetic and transcriptomic profiles of cell lines and compare these with existing and newly generated reference data sets from human tissue and cell types. The aim is to identify assay systems which will provide greater confidence in translating target biology and compound pharmacology to patients. Multiple cell types commonly used within research have been grouped according to biology. Examples include erythroid, lung epithelial, hepatocyte cell types and immortalised models of monocyte / macrophage biology. 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 EGAS00001003136

• HipSci RNA sequencing for embryonic stem cell control lines

  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 RNA sequencing on commercially available embryonic stem cell lines as control samples against which to compare HipSci's iPS cell lines.

  Study EGAS00001001727

• HipSci expression microarray for embryonic stem cell control lines

  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 use commercially available embryonic stem cell lines as control samples against which to compare HipSci's iPS cell lines. We performed expression analysis using the Illumina HumanHT -12 Expression BeadChip.

  Study EGAS00001001729

• PAGE: Prenatal Assessment of Genomes and Exomes

  The Prenatal Assessment of Genomes and Exomes (PAGE) study is a multicentre prospective trial, performing exome sequence analysis on samples from 1000 families with structural anomalies in prenatal ultrasound screening but normal aneuploidy results. The data will enable discovery of novel genetic disorders and increase the diagnostic yield. Where appropriate, results will be reported back to the families at the end of the pregnancy, after thorough clinical review. Ultimately, the translation of the acquired know-how into cost-effective prenatal diagnostic sequencing will improve genetics-derived prognoses and allow more informed parental counselling as well as management of pregnancy and childbirth.

  Study EGAS00001001713

• ENU_CCK_81_cetuximab_pilot_project

  Cetuximab is a targeted monoclonal antibody against the epidermal growth factor receptor (EGFR) which is used therapeutically for the treatment of KRAS wild-type colorectal cancer (CRC). The Cetuximab sensitive KRAS wild-type CRC cell line NCI-H508 has been treated with a fixed concentration of ENU for 24 hours and then selected with Cetuximab until drug resistant clones were ready to be picked and grown up as sub-clones of the parental cell line. These will have genes causally implicated in cancer sequenced to identify common point mutations in multiple independently derived drug resistant clones as a forward genetic screen for mechanisms of resistance to Cetuximab in CRC.

  Study EGAS00001001743