Nature genetics最新文献

{"title":"AI identifies promoter variants that alter gene expression","authors":"Tiago Faial","doi":"10.1038/s41588-025-02340-w","DOIUrl":"10.1038/s41588-025-02340-w","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 9","pages":"2083-2083"},"PeriodicalIF":29.0,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032179","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":"Non-CG DNA methylation in animal genomes","authors":"Thirsa Brethouwer, Alex de Mendoza, Ozren Bogdanovic","doi":"10.1038/s41588-025-02303-1","DOIUrl":"https://doi.org/10.1038/s41588-025-02303-1","url":null,"abstract":"<p>Cytosine DNA methylation is widespread in animal genomes and occurs predominantly at CG dinucleotides (mCG). While the roles of mCG, such as in genomic imprinting and genome stability, are well established, non-CG DNA methylation (mCH) remains poorly understood. In most vertebrate tissues, roughly 80% of CGs are methylated, whereas mCH levels are generally low, typically ranging from 1% to 3%. In vertebrates, mCH is most prevalent in neural tissue, oocytes and embryonic stem cells and has been linked to neurodevelopmental disorders. Moreover, mCH appears to have a conserved role in regulating vertebrate neural genomes, and recent studies suggest that it has functions in the embryogenesis of teleost fish. Overall, mCH represents an intriguing emerging aspect of gene regulation with potential implications for cellular identity, repeat silencing and neural function. In this Review, we provide a critical overview of the patterning, mechanisms and functional implications of mCH in animals.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"35 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032193","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":"DNA methylation cooperates with genomic alterations during non-small cell lung cancer evolution","authors":"Francisco Gimeno-Valiente,&nbsp;Carla Castignani,&nbsp;Elizabeth Larose Cadieux,&nbsp;Nana E. Mensah,&nbsp;Xiaohong Liu,&nbsp;Kezhong Chen,&nbsp;Olga Chervova,&nbsp;Takahiro Karasaki,&nbsp;Clare E. Weeden,&nbsp;Corentin Richard,&nbsp;Siqi Lai,&nbsp;Carlos Martínez-Ruiz,&nbsp;Emilia L. Lim,&nbsp;Alexander M. Frankell,&nbsp;Thomas B. K. Watkins,&nbsp;Georgia Stavrou,&nbsp;Ieva Usaite,&nbsp;Wei-Ting Lu,&nbsp;Daniele Marinelli,&nbsp;Sadegh Saghafinia,&nbsp;Gareth A. Wilson,&nbsp;Pawan Dhami,&nbsp;Heli Vaikkinen,&nbsp;Jonathan Steif,&nbsp;Selvaraju Veeriah,&nbsp;Robert E. Hynds,&nbsp;Martin Hirst,&nbsp;Crispin Hiley,&nbsp;Andrew Feber,&nbsp;Özgen Deniz,&nbsp;Mariam Jamal-Hanjani,&nbsp;Nicholas McGranahan,&nbsp;TRACERx Consortium,&nbsp;Stephan Beck,&nbsp;Jonas Demeulemeester,&nbsp;Miljana Tanić,&nbsp;Charles Swanton,&nbsp;Peter Van Loo,&nbsp;Nnennaya Kanu","doi":"10.1038/s41588-025-02307-x","DOIUrl":"10.1038/s41588-025-02307-x","url":null,"abstract":"Aberrant DNA methylation has been described in nearly all human cancers, yet its interplay with genomic alterations during tumor evolution is poorly understood. To explore this, we performed reduced representation bisulfite sequencing on 217 tumor and matched normal regions from 59 patients with non-small cell lung cancer from the TRACERx study to deconvolve tumor methylation. We developed two metrics for integrative evolutionary analysis with DNA and RNA sequencing data. Intratumoral methylation distance quantifies intratumor DNA methylation heterogeneity. MR/MN classifies genes based on the rate of hypermethylation at regulatory (MR) versus nonregulatory (MN) CpGs to identify driver genes exhibiting recurrent functional hypermethylation. We identified DNA methylation-linked dosage compensation of essential genes co-amplified with neighboring oncogenes. We propose two complementary mechanisms that converge for copy number alteration-affected chromatin to undergo the epigenetic equivalent of an allosteric activity transition. Hypermethylated driver genes under positive selection may open avenues for therapeutic stratification of patients. Integrated multi-omic analyses using samples from the TRACERx study highlight cross-talk between DNA hypermethylation and genomic lesions in non-small cell lung cancer.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 9","pages":"2226-2237"},"PeriodicalIF":29.0,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-025-02307-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025749","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: Why genomic diversity should not be framed by census alone","authors":"Manuel Corpas, Heinner Guio, Catalina Lopez-Correa, Segun Fatumo","doi":"10.1038/s41588-025-02357-1","DOIUrl":"https://doi.org/10.1038/s41588-025-02357-1","url":null,"abstract":"<p>Correction to: <i>Nature Genetics</i> https://doi.org/10.1038/s41588-025-02272-5, published online 29 July 2025.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"67 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025282","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":"The Solve-RD Solvathons as a pan-European interdisciplinary collaboration to diagnose patients with rare disease","authors":"Vicente A. Yépez, German Demidov, Kornelia Ellwanger, Steven Laurie, Rebeka Luknárová, Midhuna Immaculate Joseph Maran, Thomas Hentrich, Lydia Sagath, Bart van der Sanden, Galuh Astuti, Kornelia Neveling, Laura Batlle-Masó, Danique Beijer, Felix Brechtmann, Andrés Caballero-Oteyza, Marc Dabad, Anne-Sophie Denommé-Pichon, Cenna Doornbos, Zakaria Eddafir, Berta Estévez-Arias, Ozge Aksel Kilicarslan, Ingrid H. M. Kolen, Leon Kraß, Katja Lohmann, Shubhankar Londhe, Estrella López-Martín, Kars Maassen, William Macken, Beatriz Martínez-Delgado, Davide Mei, Christian Mertes, Raffaella Minardi, Heba Morsy, Juliane S. Mueller, Daniel Natera-de Benito, Isabelle Nelson, Machteld M. Oud, Ida Paramonov, Daniel Picó, Davide Piscia, Kiran Polavarapu, Emanuele Raineri, Marco Savarese, Noor Smal, Marloes Steehouwer, Wouter Steyaert, Morris A. Swertz, Mirja Thomsen, Ana Töpf, Liedewei Van de Vondel, Gerben van der Vries, Antonio Vitobello, Carlo Wilke, Birte Zurek, Peter-Bram t’ Hoen, Leslie Matalonga, Lisenka E. L. M. Vissers, Christian Gilissen, Julia Schulze-Hentrich, Sergi Beltran, Anna Esteve-Codina, Alexander Hoischen, Julien Gagneur, Holm Graessner","doi":"10.1038/s41588-025-02290-3","DOIUrl":"https://doi.org/10.1038/s41588-025-02290-3","url":null,"abstract":"<p>Despite advances in genomic diagnostics, the majority of individuals with rare diseases remain without a confirmed genetic diagnosis. The rapid emergence of advanced omics technologies, such as long-read genome sequencing, optical genome mapping and multiomic profiling, has improved diagnostic yield but also substantially increased analytical and interpretational complexity. Addressing this complexity requires systematic multidisciplinary collaboration, as recently demonstrated by targeted diagnostic workshops. Here, we highlight the experience of the Solve-RD consortium, a pan-European initiative, in implementing four structured workshops, termed ‘Solvathons’, as a regular and effective component of its operational workflow. We provide actionable insights, best practices and lessons learned for successful data integration, expert training and scalable collaborative diagnostics within large research consortia.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"35 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145017501","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":"Robust and accurate Bayesian inference of genome-wide genealogies for hundreds of genomes","authors":"Yun Deng,&nbsp;Rasmus Nielsen,&nbsp;Yun S. Song","doi":"10.1038/s41588-025-02317-9","DOIUrl":"10.1038/s41588-025-02317-9","url":null,"abstract":"The Ancestral Recombination Graph (ARG), which describes the genealogical history of a sample of genomes, is a vital tool in population genomics and biomedical research. Recent advancements have substantially increased ARG reconstruction scalability, but they rely on approximations that can reduce accuracy, especially under model misspecification. Moreover, they reconstruct only a single ARG topology and cannot quantify the considerable uncertainty associated with ARG inferences. Here, to address these challenges, we introduce SINGER (sampling and inferring of genealogies with recombination), a method that accelerates ARG sampling from the posterior distribution by two orders of magnitude, enabling accurate inference and uncertainty quantification for hundreds of whole-genome sequences. Through extensive simulations, we demonstrate SINGER’s enhanced accuracy and robustness to model misspecification compared to existing methods. We demonstrate the utility of SINGER by applying it to individuals of British and African descent within the 1000 Genomes Project, identifying signals of population differentiation, archaic introgression and strong support for ancient polymorphism in the human leukocyte antigen region shared across primates. SINGER is a method for creating ancestral recombination graphs to understand the genealogical history of genomes. The method has increased speed, and thus scalability, without sacrificing accuracy.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 9","pages":"2124-2135"},"PeriodicalIF":29.0,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-025-02317-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145009054","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: The genomic landscape of gene-level structural variations in Japanese and global soybean Glycine max cultivars","authors":"Ryoichi Yano, Feng Li, Susumu Hiraga, Ryoma Takeshima, Michie Kobayashi, Kyoko Toda, Yosuke Umehara, Hiromi Kajiya-Kanegae, Hiroyoshi Iwata, Akito Kaga, Masao Ishimoto","doi":"10.1038/s41588-025-02356-2","DOIUrl":"https://doi.org/10.1038/s41588-025-02356-2","url":null,"abstract":"<p>Correction to: <i>Nature Genetics</i> https://doi.org/10.1038/s41588-025-02113-5, published online 3 March 2025.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"125 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145009496","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":"Multiancestry brain pQTL fine-mapping and integration with genome-wide association studies of 21 neurologic and psychiatric conditions","authors":"Aliza P. Wingo,&nbsp;Yue Liu,&nbsp;Selina M. Vattathil,&nbsp;Ekaterina S. Gerasimov,&nbsp;Zhen Mei,&nbsp;Suda Parimala Ravindran,&nbsp;Jiaqi Liu,&nbsp;Ananth Shantaraman,&nbsp;Fatemeh Seifar,&nbsp;Erming Wang,&nbsp;Bin Zhang,&nbsp;Joseph Reddy,&nbsp;Mariet Allen,&nbsp;Nilüfer Ertekin-Taner,&nbsp;Philip L. De Jager,&nbsp;Edward J. Fox,&nbsp;Duc M. Duong,&nbsp;Michael P. Epstein,&nbsp;David J. Cutler,&nbsp;Allan I. Levey,&nbsp;David A. Bennett,&nbsp;Nicholas T. Seyfried,&nbsp;Thomas S. Wingo","doi":"10.1038/s41588-025-02291-2","DOIUrl":"10.1038/s41588-025-02291-2","url":null,"abstract":"To understand shared and ancestry-specific genetic control of brain protein expression and its ramifications for disease, we mapped protein quantitative trait loci (pQTLs) in 1,362 brain proteomes from African American, Hispanic/Latin American and non-Hispanic white donors. Among the pQTLs that multiancestry fine-mapping MESuSiE confidently assigned as putative causal pQTLs in a specific population, most were shared across the three studied populations and are referred to as multiancestry causal pQTLs. These multiancestry causal pQTLs were enriched for exonic and promoter regions. To investigate their effects on disease, we modeled the 858 multiancestry causal pQTLs as instrumental variables using Mendelian randomization and genome-wide association study results for neurologic and psychiatric conditions (21 traits in participants with European ancestry, 10 in those with African ancestry and 4 in Hispanic participants). We identified 119 multiancestry pQTL–protein pairs consistent with a causal role in these conditions. Remarkably, 29% of the multiancestry pQTLs in these pairs were coding variants. These results lay an important foundation for the creation of new molecular models of neurologic and psychiatric conditions that are likely to be relevant to individuals across different genetic ancestries. Multiancestry fine-mapping of brain protein quantitative trait loci coupled with Mendelian randomization analyses identifies protein–trait pairs consistent with causal effects across neurological and psychiatric conditions.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 9","pages":"2156-2165"},"PeriodicalIF":29.0,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-025-02291-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145009055","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":"Improving broad-spectrum resistance to clubroot disease with one gene","authors":"","doi":"10.1038/s41588-025-02304-0","DOIUrl":"10.1038/s41588-025-02304-0","url":null,"abstract":"GSL5, a glucan synthase, acts as a suppressor of jasmonic acid-mediated immunity in cruciferous plants. Inactivation of GSL5 by genome editing confers high-level and broad-spectrum resistance to pathogens that cause clubroot disease in four cruciferous species.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 9","pages":"2086-2087"},"PeriodicalIF":29.0,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144995784","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":"Genetic variants affecting RNA stability influence complex traits and disease risk","authors":"Elaine Huang, Ting Fu, Ling Zhang, Guanao Yan, Ryo Yamamoto, Sari Terrazas, Thuy Linh Nguyen, Carlos Gonzalez-Figueroa, Armen Khanbabaei, Jae Hoon Bahn, Rajagopal Varada, Kofi Amoah, Jonatan Hervoso, Michelle T. Paulsen, Brian Magnuson, Mats Ljungman, Jingyi Jessica Li, Xinshu Xiao","doi":"10.1038/s41588-025-02326-8","DOIUrl":"https://doi.org/10.1038/s41588-025-02326-8","url":null,"abstract":"<p>Gene expression is modulated jointly by transcriptional regulation and messenger RNA stability, yet the latter is often overlooked in studies on genetic variants. Here, leveraging metabolic labeling data (Bru/BruChase-seq) and a new computational pipeline, RNAtracker, we categorize genes as allele-specific RNA stability (asRS) or allele-specific RNA transcription events. We identify more than 5,000 asRS variants among 665 genes across a panel of 11 human cell lines. These variants directly overlap conserved microRNA target regions and allele-specific RNA-binding protein sites, illuminating mechanisms through which stability is mediated. Furthermore, we identified causal asRS variants using a massively parallel screen (MapUTR) for variants that affect post-transcriptional mRNA abundance, as well as through CRISPR prime editing approaches. Notably, asRS genes were enriched significantly among a multitude of immune-related pathways and contribute to the risk of several immune system diseases. This work highlights RNA stability as a critical, yet understudied mechanism linking genetic variation and disease.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"39 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144995747","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}