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• Systemic mutagen exposures reported by normal kidney cell genomes - matched normal samples (whole-genome sequencing)

  Lifestyle, environmental and other exposures to exogenous mutagens generate somatic mutations in normal human cells in vivo and increase cancer risk. However, the global repertoire of exogenous mutagen exposures is uncertain. Using single-molecule duplex sequencing of normal kidney (n=319) and blood (n=272) samples from 10 countries, we show that kidney proximal tubule cells exhibit higher mutation rates than most normal cell types despite low cell division rates. Compared to cells from kidney glomeruli, medulla, distal tubules, or peripheral blood, proximal tubule cells show marked enrichment of mutational signatures due to the exogenous carcinogenic mutagens, aristolochic acids, and of several signatures of unknown causes. The results suggest the existence of multiple, common, systemically circulated mutagens affecting human populations and indicate that the genomes of kidney proximal tubule cells report such exposures with high sensitivity.

  Dataset EGAD00001015828

• Transcriptional consequences of SETBP1 variants in developmental disorders and malignancies

  The SETBP1 gene encodes a DNA-binding nuclear protein that regulates gene expression across multiple tissues. Precise control of SETBP1 dosage is essential for normal cellular function, as both loss- and gain-of-function variants of SETBP1 can lead to severe phenotypic consequences. De novo germline gain-of-function point mutations that prolong SETBP1 half-life result in Schinzel-Giedion syndrome (SGS), an ultra-rare and severe congenital disorder associated with extensive developmental abnormalities and health complications. These SGS-associated variants cluster within a hotspot in the SKI-homology domain of SETBP1, overlapping with somatic mutations recurrently observed in myeloid leukaemia with poor prognosis. Thus far, the precise mechanisms by which these SETBP1 mutations drive disease remain largely unclear. Here, through single-cell and single-nucleus mRNA sequencing of a rare collection of primary patient samples with SGS and myeloid leukaemia, we examined the transcriptional consequences of SETBP1 gain-of-function variants in haematopoietic cells, comparing their impacts when acquired in the germline and somatically in malignancies.

  Dataset EGAD00001015482

• DNMT3A-R882 mutations intrinsically drive dysfunctional neutropoiesis from human haematopoietic stem cells

  Clonal haematopoiesis (CH) arises from the expansion of hematopoietic stem cells (HSCs) carrying leukaemia-associated somatic mutations. CH is linked to pathological immune dysregulation and a greater risk of age-related inflammatory diseases. Yet, how CH mutations impact HSC differentiation into immune effector cells remains understudied. Here, we report a single-cell resolution functional and multi-omic investigation of HSC clonal and differentiation dynamics in individuals with DNMT3A-R882 CH. DNMT3A-R882 reshapes the clonal architecture of haematopoiesis towards an aged phylogenetic structure. Functionally, DNMT3A-R882 HSCs produce decreased monocytic output but more abundant and mature neutrophil progeny compared to WT HSCs in the same individual. Whereas DNMT3A-R882 myeloid progenitors display attenuated inflammatory transcriptional programmes, DNMT3A-R882 mature neutrophils acquire proinflammatory and immunomodulatory features typical of maladaptive immunity and CH co-morbidities. Our findings, validated in humanised mice, identify aberrant DNMT3A-R882 HSC-driven neutropoiesis as a key link between CH, immune dysregulation and risk of inflammatory disease.

  Dataset EGAD00001015750

• Genomic evolution and natural history of myeloproliferative neoplasms on therapy - SCC_CALRmutated ET

  Philadelphia-negative myeloproliferative neoplasms are chronic blood neoplasms. Treatments control blood counts but disease can progress to myelofibrosis or acute myeloid leukaemia. We performed longitudinal whole-genome and targeted sequencing in 30 patients, integrating clonal dynamics with 7,986 blood counts and clinical histories. Distinct evolutionary patterns distinguished stable from progressive disease, with leukaemic transformation arising via TP53 loss, stepwise driver mutation acquisition within complex clones, or emergence of independent leukaemic clones. In contrast, stable disease showed long-term clonal equilibrium without new drivers. Phylogenetic analysis using 203 whole-genomes of haematopoietic colonies revealed age-appropriate polyclonal haematopoiesis in triple-negative essential thrombocythaemia and germline predisposition to thrombocytosis, supporting non-neoplastic origins. Therapy-associated mutagenesis was observed, including C>G mutations following azacitidine and characteristic T>A/T>G after hydroxycarbamide exposure in blood cells, although not in skin where UV damage predominated. These findings demonstrate progression is genomically encoded years in advance and support serial monitoring and further study of treatment-related mutagenesis.

  Dataset EGAD00001016068

• Genomic evolution and natural history of myeloproliferative neoplasms on therapy - triple-negative-ET

  Philadelphia-negative myeloproliferative neoplasms are chronic blood neoplasms. Treatments control blood counts but disease can progress to myelofibrosis or acute myeloid leukaemia. We performed longitudinal whole-genome and targeted sequencing in 30 patients, integrating clonal dynamics with 7,986 blood counts and clinical histories. Distinct evolutionary patterns distinguished stable from progressive disease, with leukaemic transformation arising via TP53 loss, stepwise driver mutation acquisition within complex clones, or emergence of independent leukaemic clones. In contrast, stable disease showed long-term clonal equilibrium without new drivers. Phylogenetic analysis using 203 whole-genomes of haematopoietic colonies revealed age-appropriate polyclonal haematopoiesis in triple-negative essential thrombocythaemia and germline predisposition to thrombocytosis, supporting non-neoplastic origins. Therapy-associated mutagenesis was observed, including C>G mutations following azacitidine and characteristic T>A/T>G after hydroxycarbamide exposure in blood cells, although not in skin where UV damage predominated. These findings demonstrate progression is genomically encoded years in advance and support serial monitoring and further study of treatment-related mutagenesis.

  Dataset EGAD00001016066

• A practical guide for mutational signature analysis in hematological malignancies

  Analysis of mutational signatures is becoming routine in cancer genomics, with implications for pathogenesis, classification, prognosis, and even treatment decisions. However, the field lacks a consensus on analysis and result interpretation. Using whole-genome sequencing of multiple myeloma (MM), chronic lymphocytic leukemia (CLL) and acute myeloid leukemia, we compare the performance of public signature analysis tools. We describe caveats and pitfalls of de novo signature extraction and fitting approaches, reporting on common inaccuracies: erroneous signature assignment, identification of localized hyper-mutational processes, overcalling of signatures. We provide reproducible solutions to solve these issues and use orthogonal approaches to validate our results. We show how a comprehensive mutational signature analysis may provide relevant biological insights, reporting evidence of c-AID activity among unmutated CLL cases or the absence of BRCA1/BRCA2-mediated homologous recombination deficiency in a MM cohort. Finally, we propose a general analysis framework to ensure production of accurate and reproducible mutational signature data.

  Dataset EGAD00001005028

• DERMATLAS: Hidradenoma papilliferum_WES

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible.For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previously, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles.

  Dataset EGAD00001015481

• Gene expression QTL mapping in stimulated iPSC-derived macrophages

  Immune cells sense and respond to external stimuli, initiating an inflammatory response, with genetic variants potentially altering these responses. Traditional QTL mapping often uses naïve cells, missing condition-specific variants detectable post-stimulation. Our study uses a high-throughput platform to map eQTLs across 24 conditions using iPSC-derived macrophages, identifying that 76% of eQTLs in stimulated conditions were also present in naïve cells. We found response eQTLs (reQTLs) vary widely across conditions, with rare single-condition reQTLs being overrepresented among disease-colocalizing eQTLs. This study nominates 21.7% more disease effector genes at GWAS loci through reQTL colocalization, with 38.6% not found in the GTEx catalogue, highlighting the importance of condition-specific regulatory variation in understanding disease risk alleles. Our findings underscore the value of condition-specific studies in elucidating the genetic mechanisms underlying complex diseases. 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 EGAD00001015380

• Selection of somatic escape variants in SERPINA1 in liver tissue of patients with alpha-1 anti-trypsin deficiency - Exome

  Somatic variants accumulate in non-malignant tissues with age. Functional variants leading to clonal advantage of hepatocytes accumulate in the liver from patients with acquired chronic liver disease (CLD). Whether somatic variants are common to CLD from differing aetiologies is unknown. We analysed liver somatic variants in patients with genetic CLD from alpha-1 anti-trypsin (A1AT) deficiency or haemochromatosis. We show that somatic variants in SERPINA1, the gene encoding A1AT, are strongly selected for in A1AT deficiency, with evidence of convergent evolution. Acquired SERPINA1 variants are clustered leading to truncation or coding change at the C-terminus of A1AT. In vitro and in vivo, C-terminal truncation variants reduce disease-associated Z-A1AT polymer accumulation and disruption of the endoplasmic reticulum, supporting the C-terminal domain swap mechanism. Therefore, somatic escape variants from a deleterious germline variant are selected for in A1AT deficiency, suggesting functional somatic variants are disease-specific in CLD and point to disease-associated mechanisms.

  Dataset EGAD00001015431

• GoNL release 5 haplotype panel

  The samples in this panel come from 250 families: 248 parents-child trios and 2 parent-child duos. As the children do not provide additional haplotypes or population information, they were excluded from the panel. The samples present in the release are composed of 248 couples, 2 single individuals and 1 sample composed from the 2 haplotypes from the duo's children transmitted by their missing parent. The composed sample is named gonl-220c_223c.The files contain a total of 18.9M SNVs and 1.1M INDELs in autosomal chromosomes. They were generated by phasing/imputing the SNVs (a) and INDELs (b) using MVNCall. Only sites passing filters are reported. Sites filtered as part of the GoNL inaccessible genome were kept (but flagged as filtered) and still may contain true positive calls but should be used with care as they are located in parts of the genome that are less well captured (systematic under or over-covered or low-mapping quality)

  Dataset EGAD00001000744