Nature genetics最新文献

{"title":"Enhancer adoption by an LTR retrotransposon generates viral-like particles, causing developmental limb phenotypes","authors":"Juliane Glaser, Giulia Cova, Beatrix Fauler, Cesar A. Prada-Medina, Virginie Stanislas, Mai H. Q. Phan, Robert Schöpflin, Yasmin Aktas, Martin Franke, Guillaume Andrey, Natalia Bartzoka, Christina Paliou, Verena Laupert, Wing-Lee Chan, Lars Wittler, Thorsten Mielke, Stefan Mundlos","doi":"10.1038/s41588-025-02248-5","DOIUrl":"10.1038/s41588-025-02248-5","url":null,"abstract":"Transposable elements (TEs) are scattered across mammalian genomes. Silencing of TEs prevents harmful effects caused by either global activation leading to genome instability or insertional mutations disturbing gene transcription. However, whether the activation of a TE can cause disease without directly affecting gene expression is largely unknown. Here we show that a TE insertion can adopt nearby regulatory activity, resulting in the production of cell-type-specific viral-like particles (VLPs) that affect embryo formation. Failure to silence an LTR retrotransposon inserted upstream of the Fgf8 gene results in their co-expression during mouse development. VLP assembly in the Fgf8-expressing cells of the developing limb triggers apoptotic cell death, resulting in a limb malformation resembling human ectrodactyly. The phenotype can be rescued by mutating the retrotransposon coding sequence, thus preventing its full endogenous retroviral cycle. Our findings illustrate that TE insertions can be incorporated into the local genomic regulatory landscape and that VLP production in post-implantation embryos can cause developmental defects. Activation of an LTR retrotransposon inserted upstream of the Fgf8 gene produces viral-like particles in the mouse developing limb, triggering apoptosis and causing limb malformation. This phenotype can be rescued by mutations in the retrotransposon coding sequence.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 7","pages":"1766-1776"},"PeriodicalIF":31.7,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-025-02248-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144586647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A retrotransposon caught red-handed in a curious case of missing digits","authors":"Youjia Guo, Andrew J. Modzelewski","doi":"10.1038/s41588-025-02147-9","DOIUrl":"10.1038/s41588-025-02147-9","url":null,"abstract":"A newly uncovered mechanism shows how a single transposable element of retroviral origin can adopt the expression pattern of a neighboring gene. This leads to the production of viral-like particles that disrupt organ formation when epigenetic silencing is compromised.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 7","pages":"1571-1573"},"PeriodicalIF":31.7,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144586504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decomposition of phenotypic heterogeneity in autism reveals underlying genetic programs","authors":"Aviya Litman, Natalie Sauerwald, LeeAnne Green Snyder, Jennifer Foss-Feig, Christopher Y. Park, Yun Hao, Ilan Dinstein, Chandra L. Theesfeld, Olga G. Troyanskaya","doi":"10.1038/s41588-025-02224-z","DOIUrl":"10.1038/s41588-025-02224-z","url":null,"abstract":"Unraveling the phenotypic and genetic complexity of autism is extremely challenging yet critical for understanding the biology, inheritance, trajectory and clinical manifestations of the many forms of the condition. Using a generative mixture modeling approach, we leverage broad phenotypic data from a large cohort with matched genetics to identify robust, clinically relevant classes of autism and their patterns of core, associated and co-occurring traits, which we further validate and replicate in an independent cohort. We demonstrate that phenotypic and clinical outcomes correspond to genetic and molecular programs of common, de novo and inherited variation and further characterize distinct pathways disrupted by the sets of mutations in each class. Remarkably, we discover that class-specific differences in the developmental timing of affected genes align with clinical outcome differences. These analyses demonstrate the phenotypic complexity of children with autism, identify genetic programs underlying their heterogeneity, and suggest specific biological dysregulation patterns and mechanistic hypotheses. Classes of autism are uncovered with a generative mixture modeling approach leveraging matched phenotypic and genetic data from a large cohort, revealing different genetic programs underlying their phenotypic and clinical traits.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 7","pages":"1611-1619"},"PeriodicalIF":31.7,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-025-02224-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144586558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The synthetic lethal interaction between CDS1 and CDS2 is a vulnerability in uveal melanoma and across multiple tumor types","authors":"Pui Ying Chan, Diana Alexander, Ishan Mehta, Larissa Satiko Alcantara Sekimoto Matsuyama, Victoria Harle, Rebeca Olvera-León, Jun Sung Park, Fernanda G. Arriaga-González, Louise van der Weyden, Saamin Cheema, Vivek Iyer, Victoria Offord, David Barneda, Phillip T. Hawkins, Len Stephens, Zuza Kozik, Michael Woods, Kim Wong, Gabriel Balmus, Alessandro Vinceti, Nicola A. Thompson, Martin Del Castillo Velasco-Herrera, Lodewyk Wessels, Joris van de Haar, Emanuel Gonçalves, Sanju Sinha, Martha Estefania Vázquez-Cruz, Luisa Bisceglia, Francesco Raimondi, Jyoti Choudhary, Sumeet Patiyal, Anjan Venkatesh, Francesco Iorio, Colm J. Ryan, David J. Adams","doi":"10.1038/s41588-025-02222-1","DOIUrl":"10.1038/s41588-025-02222-1","url":null,"abstract":"Metastatic uveal melanoma is an aggressive disease with limited effective therapeutic options. To comprehensively map monogenic and digenic dependencies, we performed CRISPR–Cas9 screening in ten extensively profiled human uveal melanoma cell line models. Analysis involved genome-wide single-gene and combinatorial paired-gene CRISPR libraries. Among our 76 uveal melanoma-specific essential genes and 105 synthetic lethal gene pairs, we identified and validated the CDP-diacylglycerol synthase 2 gene (CDS2) as a genetic dependency in the context of low CDP-diacylglycerol synthase 1 gene (CDS1) expression. We further demonstrate that CDS1/CDS2 forms a synthetic lethal interaction in vivo and reveal that CDS2 knockout results in the disruption of phosphoinositide synthesis and increased cellular apoptosis and that re-expression of CDS1 rescues this cell fitness defect. We extend our analysis using pan-cancer data, confirming increased CDS2 essentiality in diverse tumor types with low CDS1 expression. Thus, the CDS1/CDS2 axis is a therapeutic target across a range of cancers. This study employs a functional genomic approach to identify a synthetic lethal interaction between CDS1 and CDS2 in uveal melanoma and other cancers, which may represent a potential therapeutic target.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 7","pages":"1672-1683"},"PeriodicalIF":31.7,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-025-02222-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cytidine diphosphate diacylglycerol synthase 2 is a synthetic lethal target in mesenchymal-like cancers","authors":"Tim Arnoldus, Alex van Vliet, Onno B. Bleijerveld, Adriaan F. H. de Groot, Qinglin Piao, Niek Blomberg, Désirée Schatton, Jing Dong, Susan E. van Hal-van Veen, Rolf Harkes, Anita E. Grootemaat, Natalie Proost, Birol Cabukusta, Christian Frezza, Marieke van de Ven, Nicole N. van der Wel, Martin Giera, Maarten Altelaar, Daniel S. Peeper","doi":"10.1038/s41588-025-02221-2","DOIUrl":"10.1038/s41588-025-02221-2","url":null,"abstract":"Synthetic lethal interactions (SLIs) based on genomic alterations in cancer have been therapeutically explored. We investigated the SLI space as a function of differential RNA expression in cancer and normal tissue. Computational analyses of functional genomic and gene expression resources uncovered a cancer-specific SLI between the paralogs cytidine diphosphate diacylglycerol synthase 1 (CDS1) and CDS2. The essentiality of CDS2 for cell survival is observed for mesenchymal-like cancers, which have low or absent CDS1 expression and account for roughly half of all cancers. Mechanistically, the CDS1–2 SLI is accompanied by disruption of lipid homeostasis, including accumulation of cholesterol esters and triglycerides, and apoptosis. Genome-wide CRISPR–Cas9 knockout screens in CDS1-negative cancer cells identify no common escape mechanism of death caused by CDS2 ablation, indicating the robustness of the SLI. Synthetic lethality is driven by CDS2 dosage and depends on catalytic activity. Thus, CDS2 may serve as a pharmacologically tractable target in mesenchymal-like cancers. The paralogs cytidine diphosphate diacylglycerol synthase 1 and 2 form a potentially targetable synthetic lethal relationship in mesenchymal-like cancers that involves disruption of lipid metabolism.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 7","pages":"1659-1671"},"PeriodicalIF":31.7,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-025-02221-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Detecting and quantifying clonal selection in somatic stem cells","authors":"Verena Körber, Niels Asger Jakobsen, Naser Ansari-Pour, Rachel Moore, Nina Claudino, Marlen Metzner, Eva Thielecke, Franziska Esau, Batchimeg Usukhbayar, Mirian Angulo Salazar, Simon Newman, Benjamin J. L. Kendrick, Adrian H. Taylor, Rasheed Afinowi-Luitz, Roger Gundle, Bridget Watkins, Kim Wheway, Debra Beazley, Stephanie G. Dakin, Antony Palmer, Andrew J. Carr, Paresh Vyas, Thomas Höfer","doi":"10.1038/s41588-025-02217-y","DOIUrl":"10.1038/s41588-025-02217-y","url":null,"abstract":"As DNA variants accumulate in somatic stem cells, become selected or evolve neutrally, they may ultimately alter tissue function. When, and how, selection occurs in homeostatic tissues is incompletely understood. Here, we introduce SCIFER, a scalable method that identifies selection in an individual tissue, without requiring knowledge of the driver event. SCIFER also infers self-renewal and mutation dynamics of the tissue’s stem cells, and the size and age of selected clones. Probing bulk whole-genome sequencing data of nonmalignant human bone marrow and brain, we detected pervasive selection in both tissues. Selected clones in hematopoiesis, with or without known drivers, were initiated uniformly across life. In the brain, we found pre-malignant clones with glioma-initiating mutations and clones without known drivers. In contrast to hematopoiesis, selected clones in the brain originated preferentially from childhood to young adulthood. SCIFER is broadly applicable to renewing somatic tissues to detect and quantify selection. SCIFER detects clonal selection in whole-genome sequencing data using a population genetics model. Applied to a range of somatic tissues, SCIFER quantifies stem cell dynamics and infers clonal ages and sizes without requiring knowledge of driver events.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 7","pages":"1718-1729"},"PeriodicalIF":31.7,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-025-02217-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144546935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial organization of chromatin restricts activation of poised alternative promoters in LTRs","authors":"","doi":"10.1038/s41588-025-02238-7","DOIUrl":"10.1038/s41588-025-02238-7","url":null,"abstract":"Transposable elements (TEs) are important in the evolution of genomic functions but the mechanisms of their precise role in cancer pathogenesis is unclear. Alternative promoters at the TE subclass long terminal repeats (LTRs) are activated when topologically associating domain (TAD) hierarchy maintained by NIPBL is lost, potentially leading to aberrant transcription of oncogenes.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 7","pages":"1576-1577"},"PeriodicalIF":31.7,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144546933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell Micro-C profiles 3D genome structures at high resolution and characterizes multi-enhancer hubs","authors":"Honggui Wu, Jiankun Zhang, Longzhi Tan, Xiaoliang Sunney Xie","doi":"10.1038/s41588-025-02247-6","DOIUrl":"10.1038/s41588-025-02247-6","url":null,"abstract":"In animal genomes, regulatory DNA elements called enhancers govern precise spatiotemporal gene expression patterns in specific cell types. However, the spatial organization of enhancers within the nucleus to regulate target genes remains poorly understood. Here we report single-cell Micro-C (scMicro-C), a micrococcal nuclease-based three-dimensional (3D) genome mapping technique with an improved spatial resolution of 5 kb, and identified a specialized 3D enhancer structure termed ‘promoter–enhancer stripes (PESs)’, connecting a gene’s promoter to multiple enhancers. PES are formed by cohesin-mediated loop extrusion, which potentially brings multiple enhancers to the promoter. Further, we observed the prevalence of multi-enhancer hubs on genes with PES within single-cell 3D genome structures, wherein multiple enhancers form a spatial cluster in association with the gene promoter. Through its improved resolution, scMicro-C elucidates how enhancers are spatially coordinated to control genes. scMicro-C is a new method that provides high-resolution maps of the 3D genome. scMicro-C identifies structures called ‘promoter stripes’, which link a gene promoter to multiple downstream enhancers.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 7","pages":"1777-1786"},"PeriodicalIF":31.7,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-025-02247-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The long-term effects of chemotherapy on normal blood cells","authors":"Emily Mitchell, My H. Pham, Anna Clay, Rashesh Sanghvi, Nicholas Williams, Sandra Pietsch, Joanne I. Hsu, Hyunchul Jung, Aditi Vedi, Sarah Moody, Jingwei Wang, Daniel Leonganmornlert, Michael Spencer Chapman, Ellie Dunstone, Anna Santarsieri, Alex Cagan, Heather E. Machado, E. Joanna Baxter, George Follows, Daniel J. Hodson, Ultan McDermott, Gary J. Doherty, Inigo Martincorena, Laura Humphreys, Krishnaa Mahbubani, Kourosh Saeb Parsy, Koichi Takahashi, Margaret A. Goodell, David Kent, Elisa Laurenti, Peter J. Campbell, Raheleh Rahbari, Jyoti Nangalia, Michael R. Stratton","doi":"10.1038/s41588-025-02234-x","DOIUrl":"10.1038/s41588-025-02234-x","url":null,"abstract":"Several chemotherapeutic agents act by increasing DNA damage in cancer cells, triggering cell death. However, there is limited understanding of the extent and long-term consequences of collateral DNA damage in normal tissues. To investigate the impact of chemotherapy on mutation burdens and the cell population structure of normal tissue, we sequenced blood cell genomes from 23 individuals aged 3–80 years who were treated with a range of chemotherapy regimens. Substantial additional somatic mutation loads with characteristic mutational signatures were imposed by some chemotherapeutic agents, but the effects were dependent on the drug and blood cell types. Chemotherapy induced premature changes in the cell population structure of normal blood, similar to those caused by normal aging. The results show the long-term biological consequences of cytotoxic agents to which a substantial fraction of the population is exposed as part of disease management, raising mechanistic questions and highlighting opportunities for the mitigation of adverse effects. Mutational signature analysis of blood cells isolated from 23 chemotherapy-exposed samples and 9 nonexposed controls characterizes the effects of various drugs on mutational burden, signature exposure and cell types.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 7","pages":"1684-1694"},"PeriodicalIF":31.7,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-025-02234-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144520413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clonal evolution of hematopoietic stem cells after autologous stem cell transplantation","authors":"Hidetaka Uryu, Koichi Saeki, Hiroshi Haeno, Chiraag Deepak Kapadia, Ken Furudate, Jyoti Nangalia, Michael Spencer Chapman, Li Zhao, Joanne I. Hsu, Chong Zhao, Shujuan Chen, Tomoyuki Tanaka, Zongrui Li, Satoko Ogata, Sarah Hanache, Hui Yang, Courtney DiNardo, Naval Daver, Naveen Pemmaraju, Nitin Jain, Farhad Ravandi, Jianhua Zhang, Xingzhi Song, Erika Thompson, Hongli Tang, Latasha Little, Curtis Gumbs, Robert Z. Orlowski, Muzaffar Qazilbash, Kapil Bhalla, Simona Colla, Hagop Kantarjian, Rashmi Kanagal-Shamanna, Carlos Bueso-Ramos, Daisuke Nakada, Gheath Al-Atrash, Jeffery Molldrem, P. Andrew Futreal, Elizabeth Shpall, Margaret Goodell, Guillermo Garcia-Manero, Koichi Takahashi","doi":"10.1038/s41588-025-02235-w","DOIUrl":"10.1038/s41588-025-02235-w","url":null,"abstract":"The impact of exogenous stressors, such as cancer chemotherapies, on the genomic integrity and clonal dynamics of normal hematopoiesis is not well defined. We conducted whole-genome sequencing on 1,276 single-cell-derived hematopoietic stem and progenitor cell (HSPC) colonies from ten patients with multiple myeloma treated with chemotherapies and six normal donors. Melphalan treatment significantly increased the mutational burden, producing a distinctive mutation signature, whereas other chemotherapeutic agents had minimal effects. Consequently, the clonal diversity and architecture of post-treatment HSPCs resemble those observed in normal elderly individuals, particularly through the progression of oligoclonal hematopoiesis, thereby suggesting that chemotherapy accelerates clonal aging. Integrated phylogenetic analysis of matched therapy-related myeloid neoplasm samples traced their clonal origin to a single-HSPC clone among multiple competing clones, supporting a model of oligoclonal to monoclonal transformation. These findings underscore the need for further systematic research on the long-term hematological consequences of cancer chemotherapy. Analysis of whole-genome sequencing data from hematopoietic stem and progenitor cells taken from patients with myeloma shows how treatment shapes clonal architecture and sheds light on the evolution of treatment-related myeloid neoplasms.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 7","pages":"1695-1707"},"PeriodicalIF":31.7,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-025-02235-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144520459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}