Nature genetics最新文献

{"title":"Developmental and MAPK-responsive transcription factors regulate distinct malignant cell states and associated genetic dependencies in pancreatic cancer","authors":"Pasquale Laise, Mikko Turunen, Alvaro Curiel-Garcia, Lorenzo Tomassoni, H. Carlo Maurer, Ela Elyada, Bernhard Schmierer, Jeremy Worley, Jordan Kesner, Xiangtian Tan, Ester Calvo Fernandez, Yuanqing Xue, Yining Chen, Kelly Wong, Urszula N. Wasko, Somnath Tagore, Alexander L. E. Wang, Sabrina Ge, Alina C. Iuga, Aaron T. Griffin, Winston Wong, Gulam A. Manji, Mariano J. Alvarez, Faiyaz Notta, David A. Tuveson, Kenneth P. Olive, Andrea Califano","doi":"10.1038/s41588-026-02714-8","DOIUrl":"10.1038/s41588-026-02714-8","url":null,"abstract":"There is broad consensus that the malignant epithelial cells of human pancreatic ductal adenocarcinoma (PDA) comprise multiple, molecularly distinct states. Yet precise characterization of how these are regulated—including their mechanistic determinants, dependencies, plasticity and functional properties—remains elusive. Single-cell master regulator (MR) analysis of multiple PDA cohorts identified malignant cells in three co-existing, molecularly distinct developmental lineage states, with distinct histopathological morphologies and spatial architecture. These include a poorly differentiated lineage driven by epithelial–mesenchymal-transition-related MRs and two well-differentiated states driven by gastrointestinal epithelial development and pancreatic development MRs, respectively. Furthermore, each state comprises two epigenetically distinct substates with low versus high MAPK signaling activity. Barcode-based lineage tracing confirmed both spontaneous and treatment-dependent cross-state plasticity. Furthermore, loss-of-function studies confirmed state-specific MR essentiality, while their ectopic expression effectively reprogrammed cell state, in vitro and in vivo, thus providing a mechanism-based foundation for PDA heterogeneity and a roadmap for pharmacological targeting. The authors apply ARACNe and metaVIPER to published scRNA-seq datasets to characterize pancreatic cancer subtypes, identifying six distinct cell states as well as their mechanistic determinants. Functional experiments in vivo and in vitro demonstrate how these inferred states display plasticity and associate with functional dependencies.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 9","pages":"2226-2239"},"PeriodicalIF":25.5,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-026-02714-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148830743","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":"Prediction of human missense variant effects from functional evidence","authors":"Barış Kayaalp, Kerem Çil, Clément Conil, Aurélie Cobat, Meltem Ece Kars, Yuval Itan, Jean-Laurent Casanova, Tayfun Özçelik","doi":"10.1038/s41588-026-02727-3","DOIUrl":"10.1038/s41588-026-02727-3","url":null,"abstract":"Prediction of missense variant effects remains a critical bottleneck in both research and diagnostic genetics. Current predictors typically rely on clinical outcomes or population patterns rather than direct measures of functional impact, leading to limited generalizability and data circularity. Here we present FuncVEP, a family of variant effect predictors trained on diverse functional data to predict the functional impact of missense variants. FuncVEP generalizes across datasets and outperforms 48 existing predictors across a wide range of benchmarks, improving accuracy from 78.8% to 84.6% on functional benchmarks and from 90.1% to 92.4% on clinical benchmarks. From a discovery perspective, we identified 210 new gene–phenotype associations involving 494 genes linked to inborn errors of immunity in the UK Biobank and the Mount Sinai Million Health Discoveries Program. FuncVEP substantially improved the discovery rate relative to state-of-the-art predictors. Overall, FuncVEP provides a robust, scalable solution for variant interpretation, advancing both diagnostic precision and gene discovery. This study presents FuncVEP, a tool trained on functional data to improve missense variant interpretation and identify new gene–phenotype associations in population cohorts.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 9","pages":"2350-2360"},"PeriodicalIF":25.5,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148830681","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":"Pancreatic adenocarcinoma comprises six universally coexisting cell states","authors":"","doi":"10.1038/s41588-026-02715-7","DOIUrl":"10.1038/s41588-026-02715-7","url":null,"abstract":"This study shows that virtually every pancreatic adenocarcinoma, regardless of specific genetic alterations, comprises six molecularly distinct cell states whose spontaneous and drug-mediated plasticity support rapid adaptation to monotherapy. The mechanistic determinants of these states were remarkably conserved, suggesting that effective, highly universal combination therapies targeting these cell states might be designed.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 9","pages":"2083-2084"},"PeriodicalIF":25.5,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148830678","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":"Predictive design of tissue-specific mammalian enhancers that function in the mouse embryo","authors":"Shenzhi Chen, Vincent Loubiere, Ethan W. Hollingsworth, Ken Murakami, Nikolaus Mandlburger, Sandra H. Jacinto, Atrin Dizehchi, Jacob Schreiber, Evgeny Z. Kvon, Alexander Stark","doi":"10.1038/s41588-026-02729-1","DOIUrl":"10.1038/s41588-026-02729-1","url":null,"abstract":"Enhancers control tissue-specific gene expression across animals1. Although deep learning2,3 has enabled enhancer prediction and design in mammalian cell lines and non-mammalian model organisms4–10 (reviewed in a previous publication11), it remains unclear whether such approaches can operate within the regulatory complexity of mammalian genomes and tissues in vivo. Here we present a general strategy for designing tissue-specific enhancers that function reliably in mice. We use deep learning to train compact convolutional neural networks on curated chromatin accessibility data and fine-tune them by transfer learning on validated human and mouse enhancers. Guided by these models, we design 15 synthetic enhancers for the heart, limb and central nervous system in mouse embryos, all of which are active in their intended target tissue. These results demonstrate that mammalian enhancer function can be reliably inferred from DNA sequence alone, enabling the predictive de novo design of tissue-specific synthetic enhancers from modest training sets. This work establishes a generalizable framework for programmable control of mammalian gene expression in vivo, opening new avenues in functional genomics, synthetic biology and gene therapy. Researchers used AI to design synthetic transcriptional enhancers that are active in specific tissues in mammals and validated their function in mice. This type of approach could enable advanced gene expression control in synthetic biology and gene therapy.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 9","pages":"2129-2133"},"PeriodicalIF":25.5,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-026-02729-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148818907","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":"Improved spike-in normalization clarifies the relationship between active histone modifications and transcription","authors":"Lauren Patel, Yuwei Cao, Tianyao Xu, Eduardo Modolo, Tamar Dishon, Lingzhi Zhang, Eric Mendenhall, Sven Heinz, Itamar Simon, Christopher Benner, Alon Goren","doi":"10.1038/s41588-026-02728-2","DOIUrl":"10.1038/s41588-026-02728-2","url":null,"abstract":"Spike-in normalization enables quantitative analysis of chromatin immunoprecipitation sequencing (ChIP-seq) signal. Here we introduce a robust dual spike-in normalization approach for ChIP-seq (ChIP-wrangler), optimize parameters and verify its accuracy in quantifying changes in ChIP-seq signal and detecting technical artifacts. We use ChIP-wrangler to revisit recent claims that active histone marks depend on transcription. We show that acute depletion of RNA polymerase II (RNAPII) has a modest impact on H3K27ac levels, with only 6% of peaks significantly changing after RNAPII depletion, indicating that histone acetylation maintenance is not entirely dependent on ongoing transcription. Promoters and enhancers are differentially affected, with 82% of decreasing acetylation peaks located at promoter-distal elements with enhancer-related motifs. ChIP-wrangler provides increased rigor and ‘guardrails’ for successful spike-in normalization and, as applied here, refines the understanding of crosstalk between RNAPII activity and transcription-associated histone marks. ChIP-wrangler is a normalization method that improves ChIP-seq accuracy and unmasks technical errors by using dual-species spike-ins. This study concludes that histone acetylation is mostly independent of active transcription, refuting previous reports.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 9","pages":"2389-2397"},"PeriodicalIF":25.5,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148818815","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":"Toward the clinical application of long-read sequencing in repeat-expansion disorders","authors":"Louise Benarroch, Jovan Pešović, Marzia Rossato, Zhongbo Chen, Morghan C. Lucas, Guillaume Cogan, Indhu-Shree Rajan-Babu, Vitus Prokosch, Christina Zarouchlioti, Marco Carlomagno, Ida Höijer, Mayra Sauer, Ismail Jamail, Shota Shibata, Glen Lester Sequiera, Benjamin P. Kleinstiver, Sonia Lameiras, Ricardo Mouro Pinto, Giuseppe Novelli, Davina Hensman Moss, Natalia Dominik, Mathieu Barbier, Isabelle Le Ber, Guillaume Bassez, Denis Furling, Massimo Delledonne, Karen Usdin, Sylvain Baulande, Geneviève Gourdon, Birgitt Schüle, Dušanka Savić-Pavićević, Annalisa Botta, Alice E. Davidson, Adam Ameur, Vincent Dion, Stéphanie Tomé, on behalf of LRS-RED Consortium","doi":"10.1038/s41588-026-02694-9","DOIUrl":"10.1038/s41588-026-02694-9","url":null,"abstract":"Repeat-expansion disorders (REDs) are a mechanistically and clinically well-defined subgroup of rare diseases caused by the expansion of short tandem repeats (STRs). These expansions can exceed several kilobases and show complex features, such as noncanonical secondary structures, somatic instability, repeat interruptions and allele-specific methylation. These characteristics are highly relevant for understanding disease mechanisms, clinical variability, prognosis and potentially therapeutic decision-making, but cannot be fully resolved using traditional diagnostic methods or short-read sequencing technologies. By contrast, long-read sequencing (LRS) enables accurate investigation of STR complexity in a single assay, facilitates the discovery of new pathogenic repeat expansions and drives advances in diagnostics, clinical and basic research, which may allow for better patient stratification in future clinical trials. This Perspective discusses recent LRS-driven discoveries, methodological and bioinformatic advances, and emerging diagnostic applications to illustrate the potential of LRS in reshaping both research and clinical practice. This Perspective by the LRS-RED consortium discusses methodological, bioinformatic and diagnostic advances in long-read sequencing (LRS) for repeat-expansion disorders, highlighting the potential of LRS to reshape research and clinical practice.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 9","pages":"2087-2103"},"PeriodicalIF":25.5,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148795638","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":"Distinguishing different psychiatric disorders using DDx-PRS","authors":"Wouter J. Peyrot, Georgia Panagiotaropoulou, Loes M. Olde Loohuis, Mark J. Adams, Ole A. Andreassen, Swapnil Awasthi, Andreas J. Forstner, Tian Ge, Andrew M. McIntosh, Brittany L. Mitchell, Niamh Mullins, Kevin S. O’Connell, Brenda W.J.H. Penninx, Danielle Posthuma, Stephan Ripke, Douglas M. Ruderfer, Emil Uffelmann, Bjarni J. Vilhjalmsson, Zhihong Zhu, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Jordan W. Smoller, Alkes L. Price","doi":"10.1038/s41588-026-02684-x","DOIUrl":"10.1038/s41588-026-02684-x","url":null,"abstract":"Despite great progress on case–control polygenic prediction, an unmet need remains for a method that genetically distinguishes clinically related disorders (e.g., schizophrenia (SCZ) versus bipolar disorder (BIP) versus major depressive disorder (MDD) versus controls). We introduce differential diagnosis–polygenic risk score (DDx-PRS), which jointly estimates the posterior probabilities of each diagnostic category (e.g., SCZ = 50%, BIP = 25%, MDD = 15%, control = 10%) by modeling variance–covariance structure across disorders, leveraging case–control polygenic risk scores and prior clinical probabilities for each diagnostic category. We applied DDx-PRS to Psychiatric Genomics Consortium SCZ, BIP, MDD and control data, including summary-level training data from three case–control genome-wide association studies (n = 41,917–173,140 cases; total n = 1,048,683) and held-out test data from different cohorts with equal numbers for each diagnostic category (total n = 11,460). DDx-PRS was well calibrated and well powered (consistent with simulations) and produced comparable results to methods that require tuning data. True diagnosis probabilities in the top deciles of predicted diagnosis probabilities were considerably larger than prior baseline probabilities, implying appreciable potential for clinical utility in certain settings. Differential diagnosis–polygenic risk score (DDx-PRS) is a method to distinguish related psychiatric disorders from each other and from controls by modeling the variance–covariance structure of disorder liabilities and polygenic risk scores.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 9","pages":"2371-2380"},"PeriodicalIF":25.5,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148769324","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":"RNA-binding protein guides polymerase recruitment during gene activation","authors":"","doi":"10.1038/s41588-026-02711-x","DOIUrl":"10.1038/s41588-026-02711-x","url":null,"abstract":"Enhancers activate genes through long-range chromatin looping, but how these regulatory elements communicate with gene promoters and trigger transcription has remained unclear. We show that the RNA-binding protein hnRNPK acts as a molecular bridge that connects enhancer–promoter communication with recruitment of RNA polymerase II.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 9","pages":"2085-2086"},"PeriodicalIF":25.5,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148795656","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":"Adaptive evolution of polyploid crops","authors":"Peilin Wang, Chenhui Li, Dongjiao Wang, Tingting Sun, Qibin Wu, Jonathan F. Wendel, Youxiong Que","doi":"10.1038/s41588-026-02707-7","DOIUrl":"10.1038/s41588-026-02707-7","url":null,"abstract":"Crop evolution represents a fundamental biological process through which plants respond to selection in different environments. This encompasses mechanisms operating at multiple scales of biological organization, including genetic and epigenetic regulation and higher-order interactions among molecular complexes. This Review synthesizes how polyploidy shapes crop evolution by generating duplicated genes, driving genome reorganization, altering dosage relationships and promoting regulatory divergence, which together influence crop metabolism, physiology, development and environmental responses. We focus mainly on the mechanisms underlying adaptation in polyploid crops, including the consequences of gene and genome duplication, genome reorganization and subfunctionalization. We also examine how hybridization, phenotypic plasticity and crop–microbiome interactions intersect with polyploidy to expand or constrain adaptive potential. Together, these processes affect crop survival, fitness and breeding value under changing environments. We suggest that future research connect polyploid genome architecture with experimentally validated signatures of selection and field performance to make better use of polyploidy-derived variation in crop improvement. This Review discusses how polyploidy shapes crop evolution and environmental adaptation by genome duplication, phenotypic plasticity and stress responses, and proposes how these insights can accelerate climate-resilient crop breeding.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 9","pages":"2118-2128"},"PeriodicalIF":25.5,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148795661","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: Translating genomic data into healthcare practice with the Singapore National Precision Medicine program","authors":"Shih Wee Seow, Theresia Mina, Maxime Hebrard, Nilanjana Sadhu, Claire Bellis, Bitong Clarabelle Alexandrine Lin, Pritesh Jain, Pierre Vincent-Goy, Xiaoyan Wang, Pin Yan Low, Tavintharan Subramaniam, Sharon Pek, Hwee Lin Wee, Joanne Ngeow, Ken Redekop, Alec Morton, Kar Hui Ng, David Matchar, Yi Wang, Mikael Hartman, Jingmei Li, Elaine Ah Gi Lo, Charlie Guan Yi Lim, Jiali Yao, Wei Ting Huang, PRECISE-SG100K Consortium, PRECISE-CIP Consortium, Eleanor Wong, Kriti Sethi, Doreen Low, Irenaeus Paul Chia, Yasmin Bylstra, Weng Khong Lim, Saumya Jamuar, Ruifen Weng, Marthe Smedinga, Tamra Lysaght, Weiling Zheng, Mingshi Koh, Jimmy Lee, Sabrina Wong, Khung Keong Yeo, Ching-Yu Cheng, Charumathi Sabanayagam, Xueling Sim, Boon Cher Goh, Chiea Chuen Khor, Nicolas Bertin, Ee Shien Tan, Max Lam, E. Shyong Tai, John Chambers, Patrick Tan","doi":"10.1038/s41588-026-02742-4","DOIUrl":"10.1038/s41588-026-02742-4","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 9","pages":"2411-2411"},"PeriodicalIF":25.5,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-026-02742-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148795696","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}