Nature genetics最新文献

{"title":"How and when organisms edit their own genomes","authors":"Vincent C. T. Hanlon, Alex Cagan, Sebastian Eves-van den Akker","doi":"10.1038/s41588-025-02230-1","DOIUrl":"https://doi.org/10.1038/s41588-025-02230-1","url":null,"abstract":"<p>Mutations are often thought of as untargeted and non-adaptive, but in rare cases, organisms perform programmed, targeted and adaptive rearrangements of their own DNA sequences. Notable examples include the somatic diversification of immunoglobulin genes, which is the foundation of the vertebrate immune system, and natural CRISPR spacer arrays in bacteria, which recognize and cleave foreign DNA. These systems, along with a dozen known analogs scattered across the tree of life, often underlie critical biological functions, particularly in host–pathogen conflicts. In this Review, we compare the mechanisms by which organisms edit their own genomes. We show that superficially dissimilar editing systems often rely on surprisingly similar genetic mechanisms, regardless of function or taxon. Finally, we argue that the recurrence of editing in host–pathogen conflicts and the bias to a handful of well-studied organisms strongly suggest that new editing systems will be found in understudied pathogens and their hosts.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"16 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144500404","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":"Spatial and temporal dynamics in progressive gallbladder cancer","authors":"Colm J. O’Rourke, Jesper B. Andersen","doi":"10.1038/s41588-025-02232-z","DOIUrl":"https://doi.org/10.1038/s41588-025-02232-z","url":null,"abstract":"How primary gallbladder tumors evolve to acquire immunosuppressive and pro-metastatic capabilities remains unclear. A study using single-cell RNA sequencing coupled with spatial profiling and functional experiments has pinpointed mechanisms of immune-mediated tumor cell reprogramming, fostering disease progression.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"102 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144488382","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":"Multi-omic analysis of gallbladder cancer identifies distinct tumor microenvironments associated with disease progression","authors":"Tao Zhou, Yanhong Wu, Shuai Li, Xinyao Qiu, Erdong Liu, Zhihua Xie, Xuebing Shi, Yani Zhang, Guosheng Ma, Wenbo Guo, Xiang Wang, Kaiting Wang, Xiaomeng Yao, Ji Hu, Siyun Shen, Shuai Yang, Xiaoqing Jiang, Jing Fu, Hongyang Wang, Jin Gu, Lei Chen","doi":"10.1038/s41588-025-02236-9","DOIUrl":"https://doi.org/10.1038/s41588-025-02236-9","url":null,"abstract":"<p>Gallbladder carcinoma (GBC) is the most aggressive biliary tract cancer and is associated with a high mortality rate. Treatment of GBC faces therapeutic challenges owing to the elusive nature of in situ drivers within the local tumor microenvironment that drive its progression. Here, we created a single-cell atlas of 1,117,245 cells and a mutational landscape from 102 patients, which unveiled spatial–temporal characterizations of cellular constitutions, spatial interplays and molecular functions, and generalized five local ecosystems stratifying clinical outcomes. An integrated epithelial program, AI-EPI, combined with spatial transcriptome analysis, revealed the concurrent localization of a highly malignant tumor subtype (GM16) and AREG^<i>+</i> T cell, B cell, dendritic cell and macrophage subtypes within the pro-metastatic niche of primary adenocarcinomas. In vitro and in vivo experiments suggest that in addition to promoting metastasis, AREG facilitates CXCL5 expression in tumor cells through EGFR–pERK–EGR1 signaling, leading to increased neutrophil infiltration and impeding the effectiveness of immunotherapy. Our study provides a spatial–temporal landscape of the GBC microenvironment and sheds light on potential strategies for preventing immunotherapy resistance.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"20 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144488428","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 and spatial transcriptomics of stricturing Crohn’s disease highlights a fibrosis-associated network","authors":"Lingjia Kong, Sathish Subramanian, Åsa Segerstolpe, Vy Tran, Angela R. Shih, Grace T. Carter, Hiroko Kunitake, Shaina W. Twardus, Jasmine Li, Shivam Gandhi, Marco E. Kaper, Christy Cauley, Eric J. Chen, Caroline B. M. Porter, Toni M. Delorey, Liliana Bordeianou, Rocco Ricciardi, Ashwin N. Ananthakrishnan, Helena Lau, Daniel B. Graham, Richard Hodin, Jacques Deguine, Christopher S. Smillie, Ramnik J. Xavier","doi":"10.1038/s41588-025-02225-y","DOIUrl":"https://doi.org/10.1038/s41588-025-02225-y","url":null,"abstract":"<p>Fibrosis is a major complication of Crohn’s disease (CD) marked by excess deposition of extracellular matrix, leading to stricturing and functional impairment. As mechanistic characterization and therapeutic options are lacking, we paired single-cell and spatial transcriptomics in 61 samples from 21 patients with CD and 10 patients without inflammatory bowel disease (IBD). Intestinal strictures were characterized by increased immune cells, including IgG⁺ plasma cells, <i>CCR7</i>-hi CD4⁺ T cells and inflammatory fibroblasts. Spatial transcriptomics showed that key subsets colocalize within diseased tissues and identified additional populations such as interstitial cells of Cajal and enteric neurons. Furthermore, we mapped gene expression onto intestinal biogeography, finding that known genetic risk loci are enriched within discrete spatial modules, defined by the presence of inflammatory fibroblasts and lymphoid follicles. Altogether, our datasets chart the key transcriptomic and cellular networks in stricturing CD and highlight the spatial organization of multicellular genetic risk factors.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"61 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144478989","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 eQTL analysis identifies genetic variation underlying metabolic dysfunction-associated steatohepatitis","authors":"Sung Eun Hong, Seon Ju Mun, Young Joo Lee, Taekyeong Yoo, Kyung-Suk Suh, Keon Wook Kang, Myung Jin Son, Won Kim, Murim Choi","doi":"10.1038/s41588-025-02237-8","DOIUrl":"https://doi.org/10.1038/s41588-025-02237-8","url":null,"abstract":"<p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized for its medical and socioeconomic impacts, driven by diverse genetic and environmental factors. Here, to address the urgent need for individually tailored therapies, we show results from single-cell expression quantitative trait locus (sc-eQTL) analysis on liver biopsies from 25 patients with MASLD and 23 controls. This approach identified over 3,500 sc-eQTLs across major liver cell types and cell-state-interacting eQTLs (ieQTLs) with significant enrichment for disease heritability (for MASLD trait, ieQTL enrichment odds ratio 10.27). We integrated transcription factors as upstream regulators of ieQTLs, revealing 601 functional units (‘quartets’) composed of transcription factors, cell states, SNP components of ieQTL (ieSNPs) and Gene component of ieQTL (ieGenes). From these results, we pinpoint the loss of an eQTL in <i>EFHD1</i> during hepatocyte maladaptation associated with genotype-specific regulation by FOXO1, further contributing to the risk of MASLD. Our approach underscores the role of eQTL analysis in capturing crucial genetic variations that influence gene expression and clinical outcomes in complex diseases.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"193 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144478990","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":"Author Correction: Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings","authors":"Axel Schmidt, Magdalena Danyel, Kathrin Grundmann, Theresa Brunet, Hannah Klinkhammer, Tzung-Chien Hsieh, Hartmut Engels, Sophia Peters, Alexej Knaus, Shahida Moosa, Luisa Averdunk, Felix Boschann, Henrike Lisa Sczakiel, Sarina Schwartzmann, Martin Atta Mensah, Jean Tori Pantel, Manuel Holtgrewe, Annemarie Bösch, Claudia Weiß, Natalie Weinhold, Aude-Annick Suter, Corinna Stoltenburg, Julia Neugebauer, Tillmann Kallinich, Angela M. Kaindl, Susanne Holzhauer, Christoph Bührer, Philip Bufler, Uwe Kornak, Claus-Eric Ott, Markus Schülke, Hoa Huu Phuc Nguyen, Sabine Hoffjan, Corinna Grasemann, Tobias Rothoeft, Folke Brinkmann, Nora Matar, Sugirthan Sivalingam, Claudia Perne, Elisabeth Mangold, Martina Kreiss, Kirsten Cremer, Regina C. Betz, Martin Mücke, Lorenz Grigull, Thomas Klockgether, Isabel Spier, André Heimbach, Tim Bender, Fabian Brand, Christiane Stieber, Alexandra Marzena Morawiec, Pantelis Karakostas, Valentin S. Schäfer, Sarah Bernsen, Patrick Weydt, Sergio Castro-Gomez, Ahmad Aziz, Marcus Grobe-Einsler, Okka Kimmich, Xenia Kobeleva, Demet Önder, Hellen Lesmann, Sheetal Kumar, Pawel Tacik, Meghna Ahuja Bhasin, Pietro Incardona, Min Ae Lee-Kirsch, Reinhard Berner, Catharina Schuetz, Julia Körholz, Tanita Kretschmer, Nataliya Di Donato, Evelin Schröck, André Heinen, Ulrike Reuner, Amalia-Mihaela Hanßke, Frank J. Kaiser, Eva Manka, Martin Munteanu, Alma Kuechler, Kiewert Cordula, Raphael Hirtz, Elena Schlapakow, Christian Schlein, Jasmin Lisfeld, Christian Kubisch, Theresia Herget, Maja Hempel, Christina Weiler-Normann, Kurt Ullrich, Christoph Schramm, Cornelia Rudolph, Franziska Rillig, Maximilian Groffmann, Ania Muntau, Alexandra Tibelius, Eva M. C. Schwaibold, Christian P. Schaaf, Michal Zawada, Lilian Kaufmann, Katrin Hinderhofer, Pamela M. Okun, Urania Kotzaeridou, Georg F. Hoffmann, Daniela Choukair, Markus Bettendorf, Malte Spielmann, Annekatrin Ripke, Martje Pauly, Alexander Münchau, Katja Lohmann, Irina Hüning, Britta Hanker, Tobias Bäumer, Rebecca Herzog, Yorck Hellenbroich, Dominik S. Westphal, Tim Strom, Reka Kovacs, Korbinian M. Riedhammer, Katharina Mayerhanser, Elisabeth Graf, Melanie Brugger, Julia Hoefele, Konrad Oexle, Nazanin Mirza-Schreiber, Riccardo Berutti, Ulrich Schatz, Martin Krenn, Christine Makowski, Heike Weigand, Sebastian Schröder, Meino Rohlfs, Katharina Vill, Fabian Hauck, Ingo Borggraefe, Wolfgang Müller-Felber, Ingo Kurth, Miriam Elbracht, Cordula Knopp, Matthias Begemann, Florian Kraft, Johannes R. Lemke, Julia Hentschel, Konrad Platzer, Vincent Strehlow, Rami Abou Jamra, Martin Kehrer, German Demidov, Stefanie Beck-Wödl, Holm Graessner, Marc Sturm, Lena Zeltner, Ludger J. Schöls, Janine Magg, Andrea Bevot, Christiane Kehrer, Nadja Kaiser, Ernest Turro, Denise Horn, Annette Grüters-Kieslich, Christoph Klein, Stefan Mundlos, Markus Nöthen, Olaf Riess, Thomas Meitinger, Heiko Krude, Peter M. Krawitz, Tobias Haack, Nadja Ehmke, Matias Wagner","doi":"10.1038/s41588-025-02271-6","DOIUrl":"https://doi.org/10.1038/s41588-025-02271-6","url":null,"abstract":"<p>Correction to: <i>Nature Genetics</i> https://doi.org/10.1038/s41588-024-01836-1, published online 22 July 2024.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"7 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144371175","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":"Empowering African GWAS with a map of blood regulatory variation","authors":"","doi":"10.1038/s41588-025-02228-9","DOIUrl":"https://doi.org/10.1038/s41588-025-02228-9","url":null,"abstract":"We created a population-scale functional genomic dataset that maps whole blood regulatory variation in three South African groups. This resource supports the interpretation of genome-wide association studies in African-ancestry individuals, enabling translation to actionable discoveries.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"9 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144371174","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":"Publisher Correction: Analysis of R-loop forming regions identifies RNU2-2 and RNU5B-1 as neurodevelopmental disorder genes","authors":"Adam Jackson, Nishi Thaker, Alexander Blakes, Gillian Rice, Sam Griffiths-Jones, Meena Balasubramanian, Jennifer Campbell, Nora Shannon, Jungmin Choi, Juhyeon Hong, David Hunt, Anna de Burca, Soo Yeon Kim, Taekeun Kim, Seungbok Lee, Melody Redman, Rocio Rius, Cas Simons, Tiong Yang Tan, Jamie Ellingford, Raymond T. O’Keefe, Jong Hee Chae, Siddharth Banka","doi":"10.1038/s41588-025-02274-3","DOIUrl":"https://doi.org/10.1038/s41588-025-02274-3","url":null,"abstract":"<p>Correction to: <i>Nature Genetics</i> https://doi.org/10.1038/s41588-025-02209-y, published online 29 May 2025.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144371173","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":"Predicting resistance to chemotherapy using chromosomal instability signatures","authors":"Joe Sneath Thompson, Laura Madrid, Barbara Hernando, Carolin M. Sauer, Maria Vias, Maria Escobar-Rey, Wing-Kit Leung, Diego Garcia-Lopez, Jamie Huckstep, Magdalena Sekowska, Karen Hosking, Mercedes Jimenez-Linan, Marika A. V. Reinius, Abhipsa Roy, Omar Abdulle, Justina Pangonyte, Harry Dobson, Amy E. Cullen, Dilrini De Silva, David Gómez-Sánchez, Marina Torres, Ángel Fernández-Sanromán, Deborah Sanders, Filipe Correia Martins, Ionut-Gabriel Funingana, Giovanni Codacci-Pisanelli, Miguel Quintela-Fandino, Florian Markowetz, Jason Yip, James D. Brenton, Anna M. Piskorz, Geoff Macintyre","doi":"10.1038/s41588-025-02233-y","DOIUrl":"https://doi.org/10.1038/s41588-025-02233-y","url":null,"abstract":"<p>Chemotherapies are often given without precision biomarkers, exposing patients to toxic side effects without guaranteed benefit. Here we present chromosomal instability signature biomarkers that identify resistance to platinum-, taxane- and anthracycline-based treatments using a single genomic test. In retrospectively emulated randomized-control biomarker clinical trials using real-world cohorts (<i>n</i> = 840), predicted resistant patients had elevated treatment failure risk for taxane (hazard ratio (HR) of 7.44) and anthracycline (HR of 1.88) in ovarian, taxane (HR of 3.98) and anthracycline (HR of 3.69) in metastatic breast and taxane (HR of 5.46) in metastatic prostate. Nonrandomized emulations showed predictive capacity for platinum resistance in ovarian (HR of 1.46) and anthracycline in sarcoma (HR of 3.59). We demonstrate feasibility using whole-genome sequencing, capture-panel sequencing and cell-free DNA. Our findings highlight the clinical value of chromosomal instability signatures in predicting resistance to chemotherapies across multiple cancer types, with the potential to transform the one-size-fits-all chemotherapy approach into precise, tailored treatment.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"147 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340981","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":"Using large-scale population-based data to improve disease risk assessment of clinical variants","authors":"Iain S. Forrest, Kuan-Lin Huang, Julie M. Eggington, Wendy K. Chung, Daniel M. Jordan, Ron Do","doi":"10.1038/s41588-025-02212-3","DOIUrl":"https://doi.org/10.1038/s41588-025-02212-3","url":null,"abstract":"<p>Understanding the disease risk of genetic variants is fundamental to precision medicine. Estimates of penetrance—the probability of disease for individuals with a variant allele—rely on disease-specific cohorts, clinical testing and emerging electronic health record (EHR)-linked biobanks. These data sources, while valuable, each have limitations in quality, representativeness and analyzability. Here, we provide a historical account of the currently accepted pathogenicity classification system and data available in ClinVar, a public archive that aggregates variant interpretations but lacks detailed data for accurate penetrance assessment, highlighting its oversimplification of disease risk. We propose an integrative Bayesian framework that unifies pathogenicity and penetrance, leveraging both functional and real-world evidence to refine risk predictions. In addition, we advocate for enhancing ClinVar with the inclusion of high-priority phenotypes, age-stratified data and population-based cohorts linked to EHRs. We suggest developing a community repository of population-based penetrance estimates to support the clinical application of genetic data.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"16 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340982","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}