Nature genetics最新文献

{"title":"GGC repeat expansions within new open reading frames are translated into toxic polyglycine proteins in oculopharyngodistal myopathy","authors":"Manon Boivin, Jiaxi Yu, Nobuyuki Eura, Léa Schmitt, David Pietri, Erwan Grandgirard, Patrice Goetz-Reiner, Damien Plassard, Chadia Nahy, Anne Maglott, Bastien Morlet, Chao Gao, Elise Lefebvre, Muriel Philipps, Pascal Eberling, Angélique Pichot, Paola Rossolillo, Christelle Thibault, Mustapha Oulad-Abdelghani, Ichizo Nishino, Kang Yang, Ning Wang, Zhaoxia Wang, Jianwen Deng, Nicolas Charlet-Berguerand","doi":"10.1038/s41588-026-02507-z","DOIUrl":"10.1038/s41588-026-02507-z","url":null,"abstract":"A total of 3–6% human genome is composed of microsatellite sequences, which are short DNA elements composed of two to six nucleotide motifs repeated in tandem. Expansion of a subset of these microsatellites is the leading cause of >60 diseases. However, most of these mutations are located in sequences annotated as noncoding, which raises questions about their pathogenicity. Here we found that GGC repeat expansions causing oculopharyngodistal myopathy with or without oculopharyngeal myopathy leukoencephalopathy are located within previously unrecognized open reading frames (ORFs), resulting in their translation into new polyglycine-containing proteins. Antibodies developed against these proteins stain the p62-positive inclusions typical of these diseases. Moreover, expression of these polyglycine proteins causes locomotor and skeletal muscle alterations associated with neurodegeneration in cell, fly and mouse models. Finally, we identified a compound, the cationic porphyrin TMPyP4, targeting the expression of these polyglycine proteins, raising hope to develop a therapy for these disorders. Overall, this work highlights the complexity and richness of the human genome and the importance of mutations in yet-unrecognized small ORFs. GGC repeat expansions causing oculopharyngeal myopathy with or without leukoencephalopathy are located in small open reading frames and translated into polyglycine proteins that form cellular aggregates, driving neuronal and muscle cell dysfunction.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 3","pages":"517-529"},"PeriodicalIF":29.0,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-026-02507-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146205026","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":"Modeling the evolutionary dynamics of clonal hematopoiesis","authors":"Sadegh Marzban, Thomas Stiehl, Zhuoer Xie, Morten Andersen, Jordan Snyder, Johanne Gudmand-Høyer, Johnny T. Ottesen, Nathaniel V. Mon Père, Benjamin Werner, Weini Huang, Amy E. DeZern, Mikkael A. Sekeres, Matthew J. Walter, Eric Padron, Nancy Gillis, Jeffrey West","doi":"10.1038/s41588-026-02504-2","DOIUrl":"10.1038/s41588-026-02504-2","url":null,"abstract":"Clonal hematopoiesis (CH) results from the acquisition and expansion of somatic mutations in hematopoietic stem and progenitor cells and is associated with age-related clinical sequelae, including an increased risk for cardiovascular disease, myeloid neoplasms and complications related to cancer therapy. Chemotherapy and radiation can accelerate CH expansion and further elevate the risk of adverse events, including cardiotoxicity and therapy-related myeloid neoplasms. Although CH is increasingly recognized as a clinically relevant precursor state and predictive biomarker, the long-term dynamics of CH expansion in humans remain poorly understood. Longitudinal data are often collected but not integrated with mathematical prediction. Mathematical modeling is essential for characterizing CH evolution, estimating clone fitness, inferring stem cell pool dynamics and enabling patient-level predictions. This study summarizes the current evidence on CH dynamics in humans, compares mathematical models used to predict CH progression, assesses the validity of model assumptions and discusses the implications for clinical management of individuals with these precursor conditions. This Perspective discusses current evidence on clonal hematopoiesis dynamics in humans and compares mathematical models used to predict CH progression, highlighting their implications for the clinical management of individuals with precursor states.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 3","pages":"481-491"},"PeriodicalIF":29.0,"publicationDate":"2026-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146205028","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":"Acute NIPBL depletion reveals in vivo dynamics of loop extrusion and its role in transcription activation","authors":"Tessa M. Popay, Ami Pant, Femke Munting, Melodi Tastemel, Morgan E. Black, Nicholas Haghani, Jesse R. Dixon","doi":"10.1038/s41588-026-02516-y","DOIUrl":"10.1038/s41588-026-02516-y","url":null,"abstract":"The organization of the genome in three-dimensional space is highly dynamic, yet how these dynamics are regulated and the role they play in genome function is poorly understood. Here we utilized acute depletion of NIPBL to characterize cohesin-mediated loop extrusion in vivo. We find that many chromatin loops are rapidly diminished upon loss of NIBPL, but some cohesin-dependent chromatin loops persist for multiple hours. These persistent loops required NIPBL for their establishment during mitotic exit, were associated with distinct chromatin states and were preferentially dependent on STAG1 for their persistence. Furthermore, by depleting NIPBL from multiple cell types, we find that NIPBL specifically regulates cell identity genes by supporting a unique local genome conformation defined by greater spatial proximity to nearby super-enhancers and weaker transcription start site insulation of genomic contacts. Overall, we show that NIPBL-mediated loop extrusion is critical to genome organization and transcription regulation in vivo. Acute depletion of NIPBL reveals a class of chromatin loops that are independent of NIPBL for their maintenance but not their establishment and that NIPBL is necessary for the expression of lineage-defining genes.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 4","pages":"869-880"},"PeriodicalIF":29.0,"publicationDate":"2026-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-026-02516-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146205029","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":"Author Correction: Genotyping sequence-resolved copy number variation using pangenomes reveals paralog-specific global diversity and expression divergence of duplicated genes","authors":"Walfred Ma, Mark J. P. Chaisson","doi":"10.1038/s41588-026-02518-w","DOIUrl":"10.1038/s41588-026-02518-w","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 3","pages":"673-673"},"PeriodicalIF":29.0,"publicationDate":"2026-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-026-02518-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146205027","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":"Comprehensive repertoire of the chromosomal alteration and mutational signatures across 16 cancer types","authors":"Andrew Everall, Avraam Tapinos, Aliah Hawari, Alex J. Cornish, Amit Sud, Daniel Chubb, Ben Kinnersley, Anna Frangou, Miguel Barquin, Josephine Jung, David N. Church, Ludmil B. Alexandrov, Richard S. Houlston, Andreas J. Gruber, David C. Wedge","doi":"10.1038/s41588-025-02474-x","DOIUrl":"10.1038/s41588-025-02474-x","url":null,"abstract":"Whole-genome sequencing (WGS) enables exploration of the full spectrum of oncogenic processes that generate characteristic patterns of mutations. Mutational signatures provide clues to tumor etiology and highlight potentially targetable pathway defects. Here alongside single-base substitution, doublet-base substitution, small insertion and deletion and copy number aberration signatures previously covered by the Catalogue of Somatic Mutations in Cancer (COSMIC), we report signatures from an additional mutation type, structural variations (SVs), extracted de novo from WGS in 10,983 patients across 16 tumor types recruited to the 100,000 Genomes Project. Across the five mutation classes, we report 134 signatures, 26 of which are new to COSMIC, including an SV signature reference set. By relating signatures to genomic features and clinical phenotypes, we provide further insights into mutagenic processes and the application of signature analysis to precision oncology. This study analyses whole-genome sequencing data of cancer samples from 10,983 patients and explores relationships among mutational signatures, various biomarkers and clinical outcomes.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 3","pages":"570-581"},"PeriodicalIF":29.0,"publicationDate":"2026-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-025-02474-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146195028","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 HUNT study identifies host genetic factors reproducibly associated with human gut microbiota composition","authors":"Marta Riise Moksnes, Eivind Coward, Maria Nethander, Koen Dekkers, Louise Grahnemo, Anna E. Törnqvist, Lei Li, Per Lundmark, Kamalita Pertiwi, Gabriel Baldanzi, Robin Mjelle, Janne Marie Moll, Aron Charles Eklund, Henrik Bjørn Nielsen, Johan Svensson, Arnulf Langhammer, Guro F. Giskeødegård, Ben Brumpton, Rebecka Hjort, Eivind Ness-Jensen, Gunnar Engström, Thaher Pelaseyed, Karl Michaëlsson, Marju Orho-Melander, Tove Fall, Kristian Hveem, Claes Ohlsson","doi":"10.1038/s41588-026-02502-4","DOIUrl":"10.1038/s41588-026-02502-4","url":null,"abstract":"The gut microbiota is associated with human health and disease. Here we conducted a genome-wide association study of host genetic factors influencing gut microbiota composition in 12,652 individuals from the Trøndelag Health Study (HUNT), with replication in Nordic cohorts (n = 16,017–21,976). We identified 12 reproducible SNP–species associations across six genomic loci, including known (LCT, ABO) and novel (HLA-DQB1, MUC12, SLC37A2, FUT2) regions. Additionally, we detected genetic signals associated with gut microbiota functional modules at three loci (LCT, ABO, FUT2). Follow-up analyses suggest that these host–microbiota associations are linked to the pathogenesis of celiac disease and hemorrhoidal disease. Mendelian randomization analyses provided evidence supporting a causal effect of body mass index on gut microbiota composition. These findings highlight the interplay between host genetics and gut microbiota for human health and disease. Genome-wide analyses in the Norwegian HUNT study with replication in Swedish and Finnish cohorts identify host genetic variants associated with gut microbiome features and provide evidence of a causal effect of body mass index on gut microbiota composition.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 3","pages":"530-539"},"PeriodicalIF":29.0,"publicationDate":"2026-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-026-02502-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146195121","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":"Genome-wide association analyses highlight the role of the intestinal molecular environment in human gut microbiota variation","authors":"Koen F. Dekkers, Kamalita Pertiwi, Gabriel Baldanzi, Per Lundmark, Ulf Hammar, Marta Riise Moksnes, Eivind Coward, Maria Nethander, Ghassan Ali Salih, Mariam Miari, Diem Nguyen, Sergi Sayols-Baixeras, Aron C. Eklund, Jacob Bak Holm, H. Bjørn Nielsen, Camila Gazolla Volpiano, Guillaume Méric, Manonanthini Thangam, Liisa Hakaste, Tiinamaija Tuomi, Emma Ahlqvist, Christopher A. Smith, Marie Allen, Frank Reimann, Fiona M. Gribble, Claes Ohlsson, Kristian Hveem, Olle Melander, Peter M. Nilsson, Gunnar Engström, J. Gustav Smith, Karl Michaëlsson, Johan Ärnlöv, Marju Orho-Melander, Tove Fall","doi":"10.1038/s41588-026-02512-2","DOIUrl":"10.1038/s41588-026-02512-2","url":null,"abstract":"Despite the importance of the gut microbiome to health, the role of human genetic variation in shaping its composition remains poorly understood. Here we report genome-wide association analyses of harmonized metagenomic data from 16,017 adults in four Swedish population-based studies, with replication in 12,652 people from the Norwegian HUNT study. We identified variants in the OR51E1–OR51E2 locus, encoding sensors for microbiome-derived fatty acids, associated with microbial richness. We further identified 15 study-wide significant genetic associations (P < 5.4 × 10−11) involving eight loci and 14 common bacterial species, of which 11 associations at six loci were replicated. The results confirm previously reported associations at LCT, ABO and FUT2, and provide evidence for new loci MUC12, CORO7–HMOX2, SLC5A11, FOXP1 and FUT3–FUT6, with supporting data from metabolomics and gene expression analyses. Our findings link gut microbial variation genetically to gastrointestinal functions, including enteroendocrine fatty acid sensing, bile composition and mucosal layer composition. Population-based studies from Sweden with replication in Norway identify associations between host genetic variants and gut microbial composition and implicate short-chain fatty acid chemosensors as modulators of gut microbial richness.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 3","pages":"540-549"},"PeriodicalIF":29.0,"publicationDate":"2026-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-026-02512-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146195075","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 West African Genetic Medicine Center as a model to address the challenge of genetic disorders in Africa","authors":"Solomon F. Ofori-Acquah, Melissa Nuno, Judith A. Osae-Larbi, Kalinka Tavares, Annabella Osei-Tutu, Dorcas A. Barkers Ansah, Esther Y. Brobbey, Frederick Akuffo, Joseph Honny, Isaiah Buertey, Yvonne Dei-Adomakoh, Lorna Renner, Lily Paemka, Amma Benneh-Akwasi Kuma, William Kudzi, Kofi A. Anie","doi":"10.1038/s41588-026-02509-x","DOIUrl":"10.1038/s41588-026-02509-x","url":null,"abstract":"Here we describe the establishment of the West African Genetic Medicine Centre in Ghana to help the country implement a World Health Assembly resolution to guide capacity building to address sickle-cell disease and other genetic disorders in Africa.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 3","pages":"467-471"},"PeriodicalIF":29.0,"publicationDate":"2026-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146181129","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":"Functional dissection of m6A in cancer","authors":"Petra Gross","doi":"10.1038/s41588-026-02528-8","DOIUrl":"10.1038/s41588-026-02528-8","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 2","pages":"240-240"},"PeriodicalIF":29.0,"publicationDate":"2026-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146162896","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":"A tRNA-targeting CRISPR defense","authors":"Hui Hua","doi":"10.1038/s41588-026-02529-7","DOIUrl":"10.1038/s41588-026-02529-7","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 2","pages":"240-240"},"PeriodicalIF":29.0,"publicationDate":"2026-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146162911","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}