Nature genetics最新文献

{"title":"Enhancer mutational screen in vivo","authors":"Tiago Faial","doi":"10.1038/s41588-025-02277-0","DOIUrl":"10.1038/s41588-025-02277-0","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 7","pages":"1565-1565"},"PeriodicalIF":31.7,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144611078","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":"Expanding in situ genome sequencing","authors":"Petra Gross","doi":"10.1038/s41588-025-02278-z","DOIUrl":"10.1038/s41588-025-02278-z","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 7","pages":"1565-1565"},"PeriodicalIF":31.7,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144611079","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":"Y chromosome loss in cancer","authors":"Safia Danovi","doi":"10.1038/s41588-025-02276-1","DOIUrl":"10.1038/s41588-025-02276-1","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 7","pages":"1565-1565"},"PeriodicalIF":31.7,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144611080","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":"Perturb-Multimodal pooled screening in intact tissues","authors":"Wei Li","doi":"10.1038/s41588-025-02279-y","DOIUrl":"10.1038/s41588-025-02279-y","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 7","pages":"1565-1565"},"PeriodicalIF":31.7,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144611202","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":"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}