Nature genetics最新文献

{"title":"Meta-analysis of genome-wide associations and polygenic risk prediction for atrial fibrillation in more than 180,000 cases","authors":"Carolina Roselli, Ida Surakka, Morten S. Olesen, Gardar Sveinbjornsson, Nicholas A. Marston, Seung Hoan Choi, Hilma Holm, Mark Chaffin, Daniel Gudbjartsson, Matthew C. Hill, Hildur Aegisdottir, Christine M. Albert, Alvaro Alonso, Christopher D. Anderson, Dan E. Arking, David O. Arnar, John Barnard, Emelia J. Benjamin, Eugene Braunwald, Ben Brumpton, Archie Campbell, Nathalie Chami, Daniel I. Chasman, Kelly Cho, Eue-Keun Choi, Ingrid E. Christophersen, Mina K. Chung, David Conen, Harry J. Crijns, Michael J. Cutler, Tomasz Czuba, Scott M. Damrauer, Martin Dichgans, Marcus Dörr, Elton Dudink, ThuyVy Duong, Christian Erikstrup, Tõnu Esko, Diane Fatkin, Jessica D. Faul, Manuel Ferreira, Daniel F. Freitag, Santhi K. Ganesh, J. Michael Gaziano, Bastiaan Geelhoed, Jonas Ghouse, Christian Gieger, Franco Giulianini, Sarah E. Graham, Vilmundur Gudnason, Xiuqing Guo, Christopher Haggerty, Caroline Hayward, Susan R. Heckbert, Kristian Hveem, Kaoru Ito, Renee Johnson, J. Wouter Jukema, Sean J. Jurgens, Stefan Kääb, John P. Kane, Shinwan Kany, Sharon L. R. Kardia, Maryam Kavousi, Shaan Khurshid, Frederick K. Kamanu, Paulus Kirchhof, Marcus E. Kleber, Stacey Knight, Issei Komuro, Jose E. Krieger, Lenore J. Launer, Dadong Li, Honghuang Lin, Henry J. Lin, Ruth J. F. Loos, Luca Lotta, Steven A. Lubitz, Kathryn L. Lunetta, Peter W. Macfarlane, Patrik K. E. Magnusson, Rainer Malik, Helene Mantineo, Gregory M. Marcus, Winfried März, David D. McManus, Olle Melander, Giorgio E. M. Melloni, Pascal B. Meyre, Kazuo Miyazawa, Sanghamitra Mohanty, Laia M. Monfort, Martina Müller-Nurasyid, Navid A. Nafissi, Andrea Natale, Saman Nazarian, Sisse R. Ostrowski, Hui-Nam Pak, Shichao Pang, Ole B. Pedersen, Nancy L. Pedersen, Alexandre C. Pereira, James P. Pirruccello, Michael Preuss, Bruce M. Psaty, Clive R. Pullinger, Daniel J. Rader, Joel T. Rämö, Paul M. Ridker, Michiel Rienstra, Lorenz Risch, Dan M. Roden, Jerome I. Rotter, Marc S. Sabatine, Heribert Schunkert, Svati H. Shah, Jaemin Shim, M. Benjamin Shoemaker, Bridget Simonson, Moritz F. Sinner, Roelof A. J. Smit, Jennifer A. Smith, Nicholas L. Smith, J. Gustav Smith, Elsayed Z. Soliman, Erik Sørensen, Nona Sotoodehnia, Daniel Strbian, Bruno H. Stricker, Maris Teder-Laving, Yan V. Sun, Sébastien Thériault, Rosa B. Thorolfsdottir, Unnur Thorsteinsdottir, Arnljot Tveit, Pim van der Harst, Joyce van Meurs, Biqi Wang, Stefan Weiss, Quinn S. Wells, Lu-Chen Weng, Peter W. Wilson, Ling Xiao, Pil-Sung Yang, Jie Yao, Zachary T. Yoneda, Tanja Zeller, Lingyao Zeng, Wei Zhao, Xiang Zhou, Sebastian Zöllner, The BioBank Japan Project, Regeneron Genetics Center, DBDS Genomic Consortium, Christian T. Ruff, Henning Bundgaard, Cristen Willer, Kari Stefansson, Patrick T. Ellinor","doi":"10.1038/s41588-024-02072-3","DOIUrl":"10.1038/s41588-024-02072-3","url":null,"abstract":"Atrial fibrillation (AF) is the most common heart rhythm abnormality and is a leading cause of heart failure and stroke. This large-scale meta-analysis of genome-wide association studies increased the power to detect single-nucleotide variant associations and found more than 350 AF-associated genetic loci. We identified candidate genes related to muscle contractility, cardiac muscle development and cell–cell communication at 139 loci. Furthermore, we assayed chromatin accessibility using assay for transposase-accessible chromatin with sequencing and histone H3 lysine 4 trimethylation in stem cell-derived atrial cardiomyocytes. We observed a marked increase in chromatin accessibility for our sentinel variants and prioritized genes in atrial cardiomyocytes. Finally, a polygenic risk score (PRS) based on our updated effect estimates improved AF risk prediction compared to the CHARGE-AF clinical risk score and a previously reported PRS for AF. The doubling of known risk loci will facilitate a greater understanding of the pathways underlying AF. Genome-wide association meta-analyses identify more than 350 loci associated with atrial fibrillation. A polygenic score derived from these results improves atrial fibrillation risk prediction compared to published clinical and polygenic scores.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 3","pages":"539-547"},"PeriodicalIF":31.7,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143560635","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":"Origin and de novo domestication of sweet orange","authors":"Shengjun Liu, Yuantao Xu, Kun Yang, Yue Huang, Zhihao Lu, Shulin Chen, Xiang Gao, Gongao Xiao, Peng Chen, Xiuli Zeng, Lun Wang, Weikang Zheng, Zishuang Liu, Guanglian Liao, Fa He, Junjie Liu, Pengfei Wan, Fang Ding, Junli Ye, Wenbiao Jiao, Lijun Chai, Zhiyong Pan, Fei Zhang, Zongcheng Lin, Yanjun Zan, Wenwu Guo, Robert M. Larkin, Zongzhou Xie, Xia Wang, Xiuxin Deng, Qiang Xu","doi":"10.1038/s41588-025-02122-4","DOIUrl":"10.1038/s41588-025-02122-4","url":null,"abstract":"Sweet orange is cultivated worldwide but suffers from various devastating diseases because of its monogenetic background. The elucidation of the origin of a crop facilitates the domestication of new crops that may better cope with new challenges. Here we collected and sequenced 226 citrus accessions and assembled telomere-to-telomere phased diploid genomes of sweet orange and sour orange. On the basis of a high-resolution haplotype-resolved genome analysis, we inferred that sweet orange originated from a sour orange × mandarin cross and confirmed this model using artificial hybridization experiments. We identified defense-related metabolites that potently inhibited the growth of multiple industrially important pathogenic bacteria. We introduced diversity to sweet orange, which showed wide segregation in fruit flavor and disease resistance and produced canker-resistant sweet orange by selecting defense-related metabolites. Our findings elucidate the origin of sweet orange and de novo domesticated disease-resistant sweet oranges, illuminating a strategy for the rapid domestication of perennial crops. Genomic analyses of Citrus species including haplotype-resolved genomes of Citrus sinensis and Citrus aurantium highlight the origin of sweet orange and provide a strategy for de novo domestication of perennial crops.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 3","pages":"754-762"},"PeriodicalIF":31.7,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-025-02122-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143546574","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 study meta-analysis provides insights into the etiology of heart failure and its subtypes","authors":"Albert Henry, Xiaodong Mo, Chris Finan, Mark D. Chaffin, Doug Speed, Hanane Issa, Spiros Denaxas, James S. Ware, Sean L. Zheng, Anders Malarstig, Jasmine Gratton, Isabelle Bond, Carolina Roselli, David Miller, Sandesh Chopade, A. Floriaan Schmidt, Erik Abner, Lance Adams, Charlotte Andersson, Krishna G. Aragam, Johan Ärnlöv, Geraldine Asselin, Anna Axelsson Raja, Joshua D. Backman, Traci M. Bartz, Kiran J. Biddinger, Mary L. Biggs, Heather L. Bloom, Eric Boersma, Jeffrey Brandimarto, Michael R. Brown, Søren Brunak, Mie Topholm Bruun, Leonard Buckbinder, Henning Bundgaard, David J. Carey, Daniel I. Chasman, Xing Chen, James P. Cook, Tomasz Czuba, Simon de Denus, Abbas Dehghan, Graciela E. Delgado, Alexander S. Doney, Marcus Dörr, Joseph Dowsett, Samuel C. Dudley, Gunnar Engström, Christian Erikstrup, Tõnu Esko, Eric H. Farber-Eger, Stephan B. Felix, Sarah Finer, Ian Ford, Mohsen Ghanbari, Sahar Ghasemi, Jonas Ghouse, Vilmantas Giedraitis, Franco Giulianini, John S. Gottdiener, Stefan Gross, Daníel F. Guðbjartsson, Hongsheng Gui, Rebecca Gutmann, Sara Hägg, Christopher M. Haggerty, Åsa K. Hedman, Anna Helgadottir, Harry Hemingway, Hans Hillege, Craig L. Hyde, Bitten Aagaard Jensen, J. Wouter Jukema, Isabella Kardys, Ravi Karra, Maryam Kavousi, Jorge R. Kizer, Marcus E. Kleber, Lars Køber, Andrea Koekemoer, Karoline Kuchenbaecker, Yi-Pin Lai, David Lanfear, Claudia Langenberg, Honghuang Lin, Lars Lind, Cecilia M. Lindgren, Peter P. Liu, Barry London, Brandon D. Lowery, Jian’an Luan, Steven A. Lubitz, Patrik Magnusson, Kenneth B. Margulies, Nicholas A. Marston, Hilary Martin, Winfried März, Olle Melander, Ify R. Mordi, Michael P. Morley, Andrew P. Morris, Alanna C. Morrison, Lori Morton, Michael W. Nagle, Christopher P. Nelson, Alexander Niessner, Teemu Niiranen, Raymond Noordam, Christoph Nowak, Michelle L. O’Donoghue, Sisse Rye Ostrowski, Anjali T. Owens, Colin N. A. Palmer, Guillaume Paré, Ole Birger Pedersen, Markus Perola, Marie Pigeyre, Bruce M. Psaty, Kenneth M. Rice, Paul M. Ridker, Simon P. R. Romaine, Jerome I. Rotter, Christian T. Ruff, Marc S. Sabatine, Neneh Sallah, Veikko Salomaa, Naveed Sattar, Alaa A. Shalaby, Akshay Shekhar, Diane T. Smelser, Nicholas L. Smith, Erik Sørensen, Sundararajan Srinivasan, Kari Stefansson, Garðar Sveinbjörnsson, Per Svensson, Mari-Liis Tammesoo, Jean-Claude Tardif, Maris Teder-Laving, Alexander Teumer, Guðmundur Thorgeirsson, Unnur Thorsteinsdottir, Christian Torp-Pedersen, Vinicius Tragante, Stella Trompet, Andre G. Uitterlinden, Henrik Ullum, Pim van der Harst, David van Heel, Jessica van Setten, Marion van Vugt, Abirami Veluchamy, Monique Verschuuren, Niek Verweij, Christoffer Rasmus Vissing, Uwe Völker, Adriaan A. Voors, Lars Wallentin, Yunzhang Wang, Peter E. Weeke, Kerri L. Wiggins, L. Keoki Williams, Yifan Yang, Bing Yu, Faiez Zannad, Chaoqun Zheng, Genes & Health Research Team, Estonian Biobank Research Team, DBDS Genomic Consortium, Folkert W. Asselbergs, Thomas P. Cappola, Marie-Pierre Dubé, Michael E. Dunn, Chim C. Lang, Nilesh J. Samani, Svati Shah, Ramachandran S. Vasan, J. Gustav Smith, Hilma Holm, Sonia Shah, Patrick T. Ellinor, Aroon D. Hingorani, Quinn Wells, R. Thomas Lumbers, HERMES Consortium","doi":"10.1038/s41588-024-02064-3","DOIUrl":"10.1038/s41588-024-02064-3","url":null,"abstract":"Heart failure (HF) is a major contributor to global morbidity and mortality. While distinct clinical subtypes, defined by etiology and left ventricular ejection fraction, are well recognized, their genetic determinants remain inadequately understood. In this study, we report a genome-wide association study of HF and its subtypes in a sample of 1.9 million individuals. A total of 153,174 individuals had HF, of whom 44,012 had a nonischemic etiology (ni-HF). A subset of patients with ni-HF were stratified based on left ventricular systolic function, where data were available, identifying 5,406 individuals with reduced ejection fraction and 3,841 with preserved ejection fraction. We identify 66 genetic loci associated with HF and its subtypes, 37 of which have not previously been reported. Using functionally informed gene prioritization methods, we predict effector genes for each identified locus, and map these to etiologic disease clusters through phenome-wide association analysis, network analysis and colocalization. Through heritability enrichment analysis, we highlight the role of extracardiac tissues in disease etiology. We then examine the differential associations of upstream risk factors with HF subtypes using Mendelian randomization. These findings extend our understanding of the mechanisms underlying HF etiology and may inform future approaches to prevention and treatment. Genome-wide association analyses identify new risk loci for heart failure and its subtypes, extending understanding of the underlying biological pathways and disease mechanisms.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 4","pages":"815-828"},"PeriodicalIF":31.7,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-02064-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538304","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 contribution of genetic determinants of blood gene expression and splicing to molecular phenotypes and health outcomes","authors":"Alex Tokolyi, Elodie Persyn, Artika P. Nath, Katie L. Burnham, Jonathan Marten, Thomas Vanderstichele, Manuel Tardaguila, David Stacey, Ben Farr, Vivek Iyer, Xilin Jiang, Samuel A. Lambert, Guillaume Noell, Michael A. Quail, Diana Rajan, Scott C. Ritchie, Benjamin B. Sun, Scott A. J. Thurston, Yu Xu, Christopher D. Whelan, Heiko Runz, Slavé Petrovski, Daniel J. Gaffney, David J. Roberts, Emanuele Di Angelantonio, James E. Peters, Nicole Soranzo, John Danesh, Adam S. Butterworth, Michael Inouye, Emma E. Davenport, Dirk S. Paul","doi":"10.1038/s41588-025-02096-3","DOIUrl":"10.1038/s41588-025-02096-3","url":null,"abstract":"The biological mechanisms through which most nonprotein-coding genetic variants affect disease risk are unknown. To investigate gene-regulatory mechanisms, we mapped blood gene expression and splicing quantitative trait loci (QTLs) through bulk RNA sequencing in 4,732 participants and integrated protein, metabolite and lipid data from the same individuals. We identified cis-QTLs for the expression of 17,233 genes and 29,514 splicing events (in 6,853 genes). Colocalization analyses revealed 3,430 proteomic and metabolomic traits with a shared association signal with either gene expression or splicing. We quantified the relative contribution of the genetic effects at loci with shared etiology, observing 222 molecular phenotypes significantly mediated by gene expression or splicing. We uncovered gene-regulatory mechanisms at disease loci with therapeutic implications, such as WARS1 in hypertension, IL7R in dermatitis and IFNAR2 in COVID-19. Our study provides an open-access resource on the shared genetic etiology across transcriptional phenotypes, molecular traits and health outcomes in humans ( https://IntervalRNA.org.uk ). Integrative analyses of whole-blood gene expression and splicing QTLs with protein, metabolite and lipid QTLs from the same individuals shed light on the shared genetic architecture of molecular traits and health outcomes.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 3","pages":"616-625"},"PeriodicalIF":31.7,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-025-02096-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538305","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 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/s41588-025-02113-5","DOIUrl":"10.1038/s41588-025-02113-5","url":null,"abstract":"Japanese soybeans are traditionally bred to produce soy foods such as tofu, miso and boiled soybeans. Here, to investigate their distinctive genomic features, including genomic structural variations (SVs), we constructed 11 nanopore-based genome references for Japanese and other soybean lines. Our assembly-based comparative method, designated ‘Asm2sv’, identified gene-level SVs comprehensively, enabling pangenome analysis of 462 worldwide cultivars and varieties. Based on these, we identified selective sweeps between Japanese and US soybeans, one of which was the pod-shattering resistance gene PDH1. Genome-wide association studies further identified several quantitative trait loci that accounted for large-seed phenotypes of Japanese soybean lines, some of which were also close to regions of the selective sweeps, including PDH1. Notably, specific combinations of alleles, including SVs, were found to increase the seed size of some Japanese landraces. In addition to the differences in cultivation environments, distinct food processing usages might result in changes in Japanese soybean genomes. Long-read genome assemblies for seven Japanese, three North American and one primitive Glycine max cultivars highlight gene-level structural variation underlying distinct seed morphology phenotypes.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 4","pages":"973-985"},"PeriodicalIF":31.7,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-025-02113-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532304","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 Federated European Genome–Phenome Archive as a global network for sharing human genomics data","authors":"Teresa D’Altri, Mallory Ann Freeberg, Amy J. Curwin, Ana Alonso, Ana T. Freitas, Salvador Capella-Gutierrez, Luiz Gadelha, Anna Hagwall, Eivind Hovig, Giselle Kerry, Koray Kirli, Krzysztof Kochel, Oliver Kohlbacher, Jan O. Korbel, Jaakko Leinonen, Blazej Marciniak, Jorge S. Oliveira, Kjell Petersen, Mário J. Silva, Oliver Stegle, Alfonso Valencia, Johan Viklund, Roderic Guigo, Helen Parkinson, Arcadi Navarro, Jordi Rambla, Thomas M. Keane","doi":"10.1038/s41588-025-02101-9","DOIUrl":"10.1038/s41588-025-02101-9","url":null,"abstract":"In this era of rapidly expanding human genomics in research and healthcare, efficient data reuse is essential to maximize benefits for society. In response, the Federated European Genome–Phenome Archive (FEGA) was launched in 2022, and as of 2024, the FEGA network was composed of seven national nodes. Here we describe the complexities, challenges and achievements of FEGA, unravelling the dynamic interplay of regulatory frameworks, technical challenges and the shared vision of advancing genomic research.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 3","pages":"481-485"},"PeriodicalIF":31.7,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532313","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 transcriptomic architecture of common cancers reflects synthetic lethal interactions","authors":"Syed Haider, Rachel Brough, Santiago Madera, Jacopo Iacovacci, Aditi Gulati, Andrew Wicks, John Alexander, Stephen J. Pettitt, Andrew N. J. Tutt, Christopher J. Lord","doi":"10.1038/s41588-025-02108-2","DOIUrl":"10.1038/s41588-025-02108-2","url":null,"abstract":"To maintain cell fitness, deleterious genetic alterations are buffered by compensatory changes in additional genes. In cancer, buffering processes could be targeted by synthetic lethality. However, despite the large-scale identification of synthetic lethal effects in preclinical models, evidence that these operate clinically is limited. This impedes the application of synthetic lethal approaches. By integrating molecular profiling data from >9,000 cancers with synthetic lethal screens, we show that transcriptomic buffering of tumor suppressor gene (TSG) loss by hyperexpression of synthetic lethal partners is a common phenomenon, extending to multiple TSGs and histotypes. Transcriptomic buffering is also notable in cancers that phenocopy TSG loss, such as BRCAness cancers, where expression of BRCA1/2 synthetic lethal genes correlates with clinical outcome. Synthetic lethal genes that exhibit transcriptomic buffering also represent more robust synthetic lethal effects. These observations have implications for understanding how tumor cells tolerate TSG loss, in part explain transcriptomic architectures in cancer and provide insight into target selection. Tumor cells upregulate compensatory buffering genes following tumor suppressor loss. These genes may represent new synthetic lethal partners that could be harnessed therapeutically.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 3","pages":"522-529"},"PeriodicalIF":31.7,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-025-02108-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532302","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":"Long-read RNA sequencing atlas of human microglia isoforms elucidates disease-associated genetic regulation of splicing","authors":"Jack Humphrey, Erica Brophy, Roman Kosoy, Biao Zeng, Elena Coccia, Daniele Mattei, Ashvin Ravi, Tatsuhiko Naito, Anastasia G. Efthymiou, Elisa Navarro, Claudia De Sanctis, Victoria Flores-Almazan, Benjamin Z. Muller, Gijsje J. L. J. Snijders, Amanda Allan, Alexandra Münch, Reta Birhanu Kitata, Steven P. Kleopoulos, Stathis Argyriou, Periklis Malakates, Konstantina Psychogyiou, Zhiping Shao, Nancy Francoeur, Chia-Feng Tsai, Marina A. Gritsenko, Matthew E. Monroe, Vanessa L. Paurus, Karl K. Weitz, Tujin Shi, Robert Sebra, Tao Liu, Lot D. de Witte, Alison M. Goate, David A. Bennett, Vahram Haroutunian, Gabriel E. Hoffman, John F. Fullard, Panos Roussos, Towfique Raj","doi":"10.1038/s41588-025-02099-0","DOIUrl":"10.1038/s41588-025-02099-0","url":null,"abstract":"Microglia, the innate immune cells of the central nervous system, have been genetically implicated in multiple neurodegenerative diseases. Mapping the genetics of gene expression in human microglia has identified several loci associated with disease-associated genetic variants in microglia-specific regulatory elements. However, identifying genetic effects on splicing is challenging because of the use of short sequencing reads. Here, we present the isoform-centric microglia genomic atlas (isoMiGA), which leverages long-read RNA sequencing to identify 35,879 novel microglia isoforms. We show that these isoforms are involved in stimulation response and brain region specificity. We then quantified the expression of both known and novel isoforms in a multi-ancestry meta-analysis of 555 human microglia short-read RNA sequencing samples from 391 donors, and found associations with genetic risk loci in Alzheimer’s and Parkinson’s disease. We nominate several loci that may act through complex changes in isoform and splice-site usage. This isoform-centric microglia genomic atlas includes 35,879 novel human microglia isoforms identified by long-read RNA sequencing. A multi-ancestry quantitative trait locus meta-analysis of known and novel isoforms in 555 samples from 391 donors finds associations with genetic risk loci in Alzheimer’s and Parkinson’s diseases.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 3","pages":"604-615"},"PeriodicalIF":31.7,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532306","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":"Post-polyploidization centromere evolution in cotton","authors":"Hu Yan, Jinlei Han, Shangkun Jin, Zegang Han, Zhanfeng Si, Sunyi Yan, Lisha Xuan, Guangrun Yu, Xueying Guan, Lei Fang, Kai Wang, Tianzhen Zhang","doi":"10.1038/s41588-025-02115-3","DOIUrl":"10.1038/s41588-025-02115-3","url":null,"abstract":"Upland cotton (Gossypium hirsutum) accounts for more than 90% of the world’s cotton production and, as an allotetraploid, is a model plant for polyploid crop domestication. In the present study, we reported a complete telomere-to-telomere (T2T) genome assembly of Upland cotton accession Texas Marker-1 (T2T-TM-1), which has a total size of 2,299.6 Mb, and annotated 79,642 genes. Based on T2T-TM-1, interspecific centromere divergence was detected between the A- and D-subgenomes and their corresponding diploid progenitors. Centromere-associated repetitive sequences (CRCs) were found to be enriched for Gypsy-like retroelements. Centromere size expansion, repositioning and structure variations occurred post-polyploidization. It is interesting that CRC homologs were transferred from the diploid D-genome progenitor to the D-subgenome, invaded the A-subgenome and then underwent post-tetraploidization proliferation. This suggests an evolutionary advantage for the CRCs of the D-genome progenitor, presents a D-genome-adopted inheritance of centromere repeats after polyploidization and shapes the dynamic centromeric landscape during polyploidization in polyploid species. A telomere-to-telomere genome assembly of Upland cotton (Gossypium hirsutum) accession TM-1 including a set of complete centromeres provides insights into centromere evolution following polyploidization.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 4","pages":"1021-1030"},"PeriodicalIF":31.7,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532420","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":"Super pangenome of Vitis empowers identification of downy mildew resistance genes for grapevine improvement","authors":"Li Guo, Xiangfeng Wang, Dilay Hazal Ayhan, Mohammad Saidur Rhaman, Ming Yan, Jianfu Jiang, Dongyue Wang, Wei Zheng, Junjie Mei, Wei Ji, Jian Jiao, Shaoying Chen, Jie Sun, Shu Yi, Dian Meng, Jing Wang, Mohammad Nasim Bhuiyan, Guochen Qin, Linling Guo, Qingxian Yang, Xuenan Zhang, Haisheng Sun, Chonghuai Liu, Xing Wang Deng, Wenxiu Ye","doi":"10.1038/s41588-025-02111-7","DOIUrl":"10.1038/s41588-025-02111-7","url":null,"abstract":"Grapevine (Vitis) is one of the oldest domesticated fruit crops with great cultural and economic importance. Here we assembled and annotated haplotype-resolved genomes of 72 global Vitis accessions including 25 wild and 47 cultivated grapevines, among which genomes for 60 grapevines are newly released. Haplotype-aware phylogenomics disentangled the mysterious hybridization history of grapevines, revealing the enormous genetic diversity of the Vitis genus. Pangenomic analysis reveals that European cultivars, more susceptible to the destructive disease downy mildew (DM), have a smaller repertoire of resistance genes in the NLR family encoding the TIR-NBARC-LRR domain. Through extensive structural variation (SV) characterization, phenotyping, DM-infection transcriptome profiling of 113 Vitis accessions, and SV–expression quantitative trait loci analysis, we have identified over 63 SVs and their relevant genes significantly associated with DM resistance, exemplified by a lysine histidine transporter, VvLHT8. This haplotype-resolved super pangenome of the Vitis genus will accelerate breeding and enrich our understanding of the evolution and biology of grapevines. Super pangenome of the Vitis genus assembled from haplotype-resolved genomes of 72 global Vitis accessions characterizes the landscape of structural variants (SVs) and identifies SV–expression quantitative trait loci for downy mildew resistance.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 3","pages":"741-753"},"PeriodicalIF":31.7,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143495325","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}