Nature genetics最新文献

{"title":"Author Correction: Pangenome graphs and their applications in biodiversity genomics","authors":"Simona Secomandi, Guido Roberto Gallo, Riccardo Rossi, Carlos Rodríguez Fernandes, Erich D. Jarvis, Andrea Bonisoli-Alquati, Luca Gianfranceschi, Giulio Formenti","doi":"10.1038/s41588-025-02132-2","DOIUrl":"https://doi.org/10.1038/s41588-025-02132-2","url":null,"abstract":"<p>Correction to: <i>Nature Genetics</i> https://doi.org/10.1038/s41588-024-02029-6, published online 8 January 2025.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"4 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143462170","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":"Safeguard repressor locks hepatocyte identity and blocks liver cancer","authors":"","doi":"10.1038/s41588-025-02082-9","DOIUrl":"https://doi.org/10.1038/s41588-025-02082-9","url":null,"abstract":"PROX1 acts as a molecular ‘cell fate guardian’ in hepatocytes, preserving liver cell identity throughout life by actively repressing unwanted plasticity. PROX1 loss impairs liver regeneration and fuels tumor formation, whereas PROX1 activation halts cancer formation and progression, revealing unexpected therapeutic potential.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"2 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143443446","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":"Mass spectrometry-based mapping of plasma protein QTLs in children and adolescents","authors":"Yansheng Liu","doi":"10.1038/s41588-025-02088-3","DOIUrl":"https://doi.org/10.1038/s41588-025-02088-3","url":null,"abstract":"Mass spectrometry-based proteomics demonstrated its increasing analytical power and unique strengths in measuring genome-wide plasma proteomes and identifying protein quantitative trait loci (pQTLs), as reported in a study of over 3,000 Danish children and adolescents.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"85 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143443326","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":"Plasma proteome variation and its genetic determinants in children and adolescents","authors":"Lili Niu, Sara Elizabeth Stinson, Louise Aas Holm, Morten Asp Vonsild Lund, Cilius Esmann Fonvig, Leonardo Cobuccio, Jonas Meisner, Helene Bæk Juel, Joao Fadista, Maja Thiele, Aleksander Krag, Jens-Christian Holm, Simon Rasmussen, Torben Hansen, Matthias Mann","doi":"10.1038/s41588-025-02089-2","DOIUrl":"https://doi.org/10.1038/s41588-025-02089-2","url":null,"abstract":"<p>Our current understanding of the determinants of plasma proteome variation during pediatric development remains incomplete. Here, we show that genetic variants, age, sex and body mass index significantly influence this variation. Using a streamlined and highly quantitative mass spectrometry-based proteomics workflow, we analyzed plasma from 2,147 children and adolescents, identifying 1,216 proteins after quality control. Notably, the levels of 70% of these were associated with at least one of the aforementioned factors, with protein levels also being predictive. Quantitative trait loci (QTLs) regulated at least one-third of the proteins; between a few percent and up to 30-fold. Together with excellent replication in an additional 1,000 children and 558 adults, this reveals substantial genetic effects on plasma protein levels, persisting from childhood into adulthood. Through Mendelian randomization and colocalization analyses, we identified 41 causal genes for 33 cardiometabolic traits, emphasizing the value of protein QTLs in drug target identification and disease understanding.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"13 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143443448","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":"Evaluation of polygenic scores for hypertrophic cardiomyopathy in the general population and across clinical settings","authors":"Sean L. Zheng, Sean J. Jurgens, Kathryn A. McGurk, Xiao Xu, Chris Grace, Pantazis I. Theotokis, Rachel J. Buchan, Catherine Francis, Antonio de Marvao, Lara Curran, Wenjia Bai, Chee Jian Pua, Hak Chiaw Tang, Paloma Jorda, Marjon A. van Slegtenhorst, Judith M. A. Verhagen, Andrew R. Harper, Elizabeth Ormondroyd, Calvin W. L. Chin, Antonis Pantazis, John Baksi, Brian P. Halliday, Paul Matthews, Yigal M. Pinto, Roddy Walsh, Ahmad S. Amin, Arthur A. M. Wilde, Stuart A. Cook, Sanjay K. Prasad, Paul J. R. Barton, Declan P. O’Regan, R. T. Lumbers, Anuj Goel, Rafik Tadros, Michelle Michels, Hugh Watkins, Connie R. Bezzina, James S. Ware","doi":"10.1038/s41588-025-02094-5","DOIUrl":"https://doi.org/10.1038/s41588-025-02094-5","url":null,"abstract":"<p>Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality, with pathogenic variants found in about a third of cases. Large-scale genome-wide association studies (GWAS) demonstrate that common genetic variation contributes to HCM risk. Here we derive polygenic scores (PGS) from HCM GWAS and genetically correlated traits and test their performance in the UK Biobank, 100,000 Genomes Project, and clinical cohorts. We show that higher PGS significantly increases the risk of HCM in the general population, particularly among pathogenic variant carriers, where HCM penetrance differs 10-fold between those in the highest and lowest PGS quintiles. Among relatives of HCM probands, PGS stratifies risks of developing HCM and adverse outcomes. Finally, among HCM cases, PGS strongly predicts the risk of adverse outcomes and death. These findings support the broad utility of PGS across clinical settings, enabling tailored screening and surveillance and stratification of risk of adverse outcomes.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"16 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435024","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":"ImmuneLENS characterizes systemic immune dysregulation in aging and cancer","authors":"Robert Bentham, Thomas P. Jones, James R. M. Black, Carlos Martinez-Ruiz, Michelle Dietzen, Maria Litovchenko, Kerstin Thol, Thomas B. K. Watkins, Chris Bailey, Oriol Pich, Zhihui Zhang, Peter Van Loo, Charles Swanton, Nicholas McGranahan","doi":"10.1038/s41588-025-02086-5","DOIUrl":"https://doi.org/10.1038/s41588-025-02086-5","url":null,"abstract":"<p>Recognition and elimination of pathogens and cancer cells depend on the adaptive immune system. Thus, accurate quantification of immune subsets is vital for precision medicine. We present immune lymphocyte estimation from nucleotide sequencing (ImmuneLENS), which estimates T cell and B cell fractions, class switching and clonotype diversity from whole-genome sequencing data at depths as low as 5× coverage. By applying ImmuneLENS to the 100,000 Genomes Project, we identify genes enriched with somatic mutations in T cell-rich tumors, significant sex-based differences in circulating T cell fraction and demonstrated that the circulating T cell fraction in patients with cancer is significantly lower than in healthy individuals. Low circulating B cell fraction was linked to increased cancer incidence. Finally, circulating T cell abundance was more prognostic of 5-year cancer survival than infiltrating T cells.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"4 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435022","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":"Large-scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy","authors":"Rafik Tadros, Sean L. Zheng, Christopher Grace, Paloma Jordà, Catherine Francis, Dominique M. West, Sean J. Jurgens, Kate L. Thomson, Andrew R. Harper, Elizabeth Ormondroyd, Xiao Xu, Pantazis I. Theotokis, Rachel J. Buchan, Kathryn A. McGurk, Francesco Mazzarotto, Beatrice Boschi, Elisabetta Pelo, Michael Lee, Michela Noseda, Amanda Varnava, Alexa M. C. Vermeer, Roddy Walsh, Ahmad S. Amin, Marjon A. van Slegtenhorst, Nicole M. Roslin, Lisa J. Strug, Erika Salvi, Chiara Lanzani, Antonio de Marvao, Jason D. Roberts, Maxime Tremblay-Gravel, Genevieve Giraldeau, Julia Cadrin-Tourigny, Philippe L. L’Allier, Patrick Garceau, Mario Talajic, Sarah A. Gagliano Taliun, Yigal M. Pinto, Harry Rakowski, Antonis Pantazis, Wenjia Bai, John Baksi, Brian P. Halliday, Sanjay K. Prasad, Paul J. R. Barton, Declan P. O’Regan, Stuart A. Cook, Rudolf A. de Boer, Imke Christiaans, Michelle Michels, Christopher M. Kramer, Carolyn Y. Ho, Stefan Neubauer, Paul M. Matthews, Arthur A. M. Wilde, Jean-Claude Tardif, Iacopo Olivotto, Arnon Adler, Anuj Goel, James S. Ware, Connie R. Bezzina, Hugh Watkins","doi":"10.1038/s41588-025-02087-4","DOIUrl":"https://doi.org/10.1038/s41588-025-02087-4","url":null,"abstract":"<p>Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality with both monogenic and polygenic components. Here, we report results from a large genome-wide association study and multitrait analysis including 5,900 HCM cases, 68,359 controls and 36,083 UK Biobank participants with cardiac magnetic resonance imaging. We identified 70 loci (50 novel) associated with HCM and 62 loci (20 novel) associated with relevant left ventricular traits. Among the prioritized genes in the HCM loci, we identify a novel HCM disease gene, <i>SVIL</i>, which encodes the actin-binding protein supervillin, showing that rare truncating <i>SVIL</i> variants confer a roughly tenfold increased risk of HCM. Mendelian randomization analyses support a causal role of increased left ventricular contractility in both obstructive and nonobstructive forms of HCM, suggesting common disease mechanisms and anticipating shared response to therapy. Taken together, these findings increase our understanding of the genetic basis of HCM, with potential implications for disease management.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"1 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435023","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":"Polyguanine microsatellites are robust replication clocks in cancer","authors":"Ron S. Gejman, Benjamin Izar","doi":"10.1038/s41588-025-02098-1","DOIUrl":"https://doi.org/10.1038/s41588-025-02098-1","url":null,"abstract":"Cancer phylogenetic trees describe the evolutionary relationship between primary tumors and metastatic sites. A study now shows that mutations in guanine homopolymer microsatellites represent accurate molecular clocks, revealing the number of cell divisions that have occurred during cancer development and progression.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"80 4 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143427024","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":"Multiomic single-cell profiling identifies critical regulators of postnatal brain","authors":"Tereza Clarence, Jaroslav Bendl, Xuan Cao, Xinyi Wang, Shiwei Zheng, Gabriel E. Hoffman, Alexey Kozlenkov, Aram Hong, Marina Iskhakova, Manoj K. Jaiswal, Sarah Murphy, Alexander Yu, Vahram Haroutunian, Stella Dracheva, Schahram Akbarian, John F. Fullard, Guo-Cheng Yuan, Donghoon Lee, Panos Roussos","doi":"10.1038/s41588-025-02083-8","DOIUrl":"https://doi.org/10.1038/s41588-025-02083-8","url":null,"abstract":"<p>Human brain development spans from embryogenesis to adulthood, with dynamic gene expression controlled by cell-type-specific <i>cis</i>-regulatory element activity and three-dimensional genome organization. To advance our understanding of postnatal brain development, we simultaneously profiled gene expression and chromatin accessibility in 101,924 single nuclei from four brain regions across ten donors, covering five key postnatal stages from infancy to late adulthood. Using this dataset and chromosome conformation capture data, we constructed enhancer-based gene regulatory networks to identify cell-type-specific regulators of brain development and interpret genome-wide association study loci for ten main brain disorders. Our analysis connected 2,318 cell-specific loci to 1,149 unique genes, representing 41% of loci linked to the investigated traits, and highlighted 55 genes influencing several disease phenotypes. Pseudotime analysis revealed distinct stages of postnatal oligodendrogenesis and their regulatory programs. These findings provide a comprehensive dataset of cell-type-specific gene regulation at critical timepoints in postnatal brain development.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"6 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143427025","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 Marchantia polymorpha pangenome reveals ancient mechanisms of plant adaptation to the environment","authors":"Chloé Beaulieu, Cyril Libourel, Duchesse Lacourt Mbadinga Zamar, Karima El Mahboubi, David J. Hoey, George R. L. Greiff, Jean Keller, Camille Girou, Helene San Clemente, Issa Diop, Emilie Amblard, Baptiste Castel, Anthony Théron, Stéphane Cauet, Nathalie Rodde, Sabine Zachgo, Wiebke Halpape, Anja Meierhenrich, Bianca Laker, Andrea Bräutigam, Peter Szovenyi, Shifeng Cheng, Yasuhiro Tanizawa, Simon Aziz, James H. Leebens-Mack, Jeremy Schmutz, Jenell Webber, Jane Grimwood, Christophe Jacquet, Christophe Dunand, Jessica M. Nelson, Fabrice Roux, Hervé Philippe, Sebastian Schornack, Maxime Bonhomme, Pierre-Marc Delaux","doi":"10.1038/s41588-024-02071-4","DOIUrl":"https://doi.org/10.1038/s41588-024-02071-4","url":null,"abstract":"<p>Plant adaptation to terrestrial life started 450 million years ago and has played a major role in the evolution of life on Earth. The genetic mechanisms allowing this adaptation to a diversity of terrestrial constraints have been mostly studied by focusing on flowering plants. Here, we gathered a collection of 133 accessions of the model bryophyte <i>Marchantia polymorpha</i> and studied its intraspecific diversity using selection signature analyses, a genome–environment association study and a pangenome. We identified adaptive features, such as peroxidases or nucleotide-binding and leucine-rich repeats (NLRs), also observed in flowering plants, likely inherited from the first land plants. The <i>M. polymorpha</i> pangenome also harbors lineage-specific accessory genes absent from seed plants. We conclude that different land plant lineages still share many elements from the genetic toolkit evolved by their most recent common ancestor to adapt to the terrestrial habitat, refined by lineage-specific polymorphisms and gene family evolution.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"23 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143427026","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}