Nature genetics最新文献_第4页

Polyguanine microsatellites are robust replication clocks in cancer

IF 30.8 1区生物学

Nature genetics Pub Date : 2025-02-17 DOI: 10.1038/s41588-025-02098-1

Ron S. Gejman, Benjamin Izar

引用次数: 0

Multiomic single-cell profiling identifies critical regulators of postnatal brain 多组学单细胞图谱确定出生后大脑的关键调控因子

IF 30.8 1区生物学

Nature genetics Pub Date : 2025-02-17 DOI: 10.1038/s41588-025-02083-8

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

{"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":"Human brain development spans from embryogenesis to adulthood, with dynamic gene expression controlled by cell-type-specific cis-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.","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}

引用次数: 0

The Marchantia polymorpha pangenome reveals ancient mechanisms of plant adaptation to the environment Marchantia polymorpha 泛基因组揭示了植物适应环境的古老机制

IF 30.8 1区生物学

Nature genetics Pub Date : 2025-02-17 DOI: 10.1038/s41588-024-02071-4

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

{"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":"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 Marchantia polymorpha 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 M. polymorpha 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.","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}

引用次数: 0

Functional analysis of cancer-associated germline risk variants

IF 30.8 1区生物学

Nature genetics Pub Date : 2025-02-17 DOI: 10.1038/s41588-024-02070-5

Laura N. Kellman, Poornima H. Neela, Suhas Srinivasan, Zurab Siprashvili, Ronald L. Shanderson, Audrey W. Hong, Deepti Rao, Douglas F. Porter, David L. Reynolds, Robin M. Meyers, Margaret G. Guo, Xue Yang, Yang Zhao, Glenn G. Wozniak, Laura K. H. Donohue, Rajani Shenoy, Lisa A. Ko, Duy T. Nguyen, Smarajit Mondal, Omar S. Garcia, Lara E. Elcavage, Ibtihal Elfaki, Nathan S. Abell, Shiying Tao, Christopher M. Lopez, Stephen B. Montgomery, Paul A. Khavari

{"title":"Functional analysis of cancer-associated germline risk variants","authors":"Laura N. Kellman, Poornima H. Neela, Suhas Srinivasan, Zurab Siprashvili, Ronald L. Shanderson, Audrey W. Hong, Deepti Rao, Douglas F. Porter, David L. Reynolds, Robin M. Meyers, Margaret G. Guo, Xue Yang, Yang Zhao, Glenn G. Wozniak, Laura K. H. Donohue, Rajani Shenoy, Lisa A. Ko, Duy T. Nguyen, Smarajit Mondal, Omar S. Garcia, Lara E. Elcavage, Ibtihal Elfaki, Nathan S. Abell, Shiying Tao, Christopher M. Lopez, Stephen B. Montgomery, Paul A. Khavari","doi":"10.1038/s41588-024-02070-5","DOIUrl":"https://doi.org/10.1038/s41588-024-02070-5","url":null,"abstract":"Single-nucleotide variants (SNVs) in regulatory DNA are linked to inherited cancer risk. Massively parallel reporter assays of 4,041 SNVs linked to 13 neoplasms comprising >90% of human malignancies were performed in pertinent primary human cell types and then integrated with matching chromatin accessibility, DNA looping and expression quantitative trait loci data to nominate 380 potentially regulatory SNVs and their putative target genes. The latter highlighted specific protein networks in lifetime cancer risk, including mitochondrial translation, DNA damage repair and Rho GTPase activity. A CRISPR knockout screen demonstrated that a subset of germline putative risk genes also enables the growth of established cancers. Editing one SNV, rs10411210, showed that its risk allele increases rhophilin RHPN2 expression and stimulus-responsive RhoA activation, indicating that individual SNVs may upregulate cancer-linked pathways. These functional data are a resource for variant prioritization efforts and further interrogation of the mechanisms underlying inherited risk for cancer.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"11 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143427030","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}

引用次数: 0

Comparative analysis of the Mexico City Prospective Study and the UK Biobank identifies ancestry-specific effects on clonal hematopoiesis

IF 30.8 1区生物学

Nature genetics Pub Date : 2025-02-13 DOI: 10.1038/s41588-025-02085-6

Sean Wen, Pablo Kuri-Morales, Fengyuan Hu, Abhishek Nag, Ioanna Tachmazidou, Sri V. V. Deevi, Haeyam Taiy, Katherine R. Smith, Douglas P. Loesch, Oliver S. Burren, Ryan S. Dhindsa, Sebastian Wasilewski, Jesus Alegre-Díaz, Jaime Berumen, Jonathan Emberson, Jason M. Torres, Rory Collins, Keren Carss, Quanli Wang, Slavé Petrovski, Roberto Tapia-Conyer, Margarete A. Fabre, Andrew R. Harper, George S. Vassiliou, Jonathan Mitchell

{"title":"Comparative analysis of the Mexico City Prospective Study and the UK Biobank identifies ancestry-specific effects on clonal hematopoiesis","authors":"Sean Wen, Pablo Kuri-Morales, Fengyuan Hu, Abhishek Nag, Ioanna Tachmazidou, Sri V. V. Deevi, Haeyam Taiy, Katherine R. Smith, Douglas P. Loesch, Oliver S. Burren, Ryan S. Dhindsa, Sebastian Wasilewski, Jesus Alegre-Díaz, Jaime Berumen, Jonathan Emberson, Jason M. Torres, Rory Collins, Keren Carss, Quanli Wang, Slavé Petrovski, Roberto Tapia-Conyer, Margarete A. Fabre, Andrew R. Harper, George S. Vassiliou, Jonathan Mitchell","doi":"10.1038/s41588-025-02085-6","DOIUrl":"https://doi.org/10.1038/s41588-025-02085-6","url":null,"abstract":"The impact of genetic ancestry on the development of clonal hematopoiesis (CH) remains largely unexplored. Here, we compared CH in 136,401 participants from the Mexico City Prospective Study (MCPS) to 416,118 individuals from the UK Biobank (UKB) and observed CH to be significantly less common in MCPS compared to UKB (adjusted odds ratio = 0.59, 95% confidence interval (CI) = [0.57, 0.61], P = 7.31 × 10−185). Among MCPS participants, CH frequency was positively correlated with the percentage of European ancestry (adjusted beta = 0.84, 95% CI = [0.66, 1.03], P = 7.35 × 10−19). Genome-wide and exome-wide association analyses in MCPS identified ancestry-specific variants in the TCL1B locus with opposing effects on DNMT3A-CH versus non-DNMT3A-CH. Meta-analysis of MCPS and UKB identified five novel loci associated with CH, including polymorphisms at PARP11/CCND2, MEIS1 and MYCN. Our CH study, the largest in a non-European population to date, demonstrates the power of cross-ancestry comparisons to derive novel insights into CH pathogenesis.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"63 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401366","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}

引用次数: 0

Active repression of cell fate plasticity by PROX1 safeguards hepatocyte identity and prevents liver tumorigenesis

IF 30.8 1区生物学

Nature genetics Pub Date : 2025-02-13 DOI: 10.1038/s41588-025-02081-w

Bryce Lim, Aryan Kamal, Borja Gomez Ramos, Juan M. Adrian Segarra, Ignacio L. Ibarra, Lennart Dignas, Tim Kindinger, Kai Volz, Mohammad Rahbari, Nuh Rahbari, Eric Poisel, Kanela Kafetzopoulou, Lio Böse, Marco Breinig, Danijela Heide, Suchira Gallage, Jose E. Barragan Avila, Hendrik Wiethoff, Ivan Berest, Sarah Schnabellehner, Martin Schneider, Jonas Becker, Dominic Helm, Dirk Grimm, Taija Mäkinen, Darjus F. Tschaharganeh, Mathias Heikenwalder, Judith B. Zaugg, Moritz Mall

{"title":"Active repression of cell fate plasticity by PROX1 safeguards hepatocyte identity and prevents liver tumorigenesis","authors":"Bryce Lim, Aryan Kamal, Borja Gomez Ramos, Juan M. Adrian Segarra, Ignacio L. Ibarra, Lennart Dignas, Tim Kindinger, Kai Volz, Mohammad Rahbari, Nuh Rahbari, Eric Poisel, Kanela Kafetzopoulou, Lio Böse, Marco Breinig, Danijela Heide, Suchira Gallage, Jose E. Barragan Avila, Hendrik Wiethoff, Ivan Berest, Sarah Schnabellehner, Martin Schneider, Jonas Becker, Dominic Helm, Dirk Grimm, Taija Mäkinen, Darjus F. Tschaharganeh, Mathias Heikenwalder, Judith B. Zaugg, Moritz Mall","doi":"10.1038/s41588-025-02081-w","DOIUrl":"https://doi.org/10.1038/s41588-025-02081-w","url":null,"abstract":"Cell fate plasticity enables development, yet unlocked plasticity is a cancer hallmark. While transcription master regulators induce lineage-specific genes to restrict plasticity, it remains unclear whether plasticity is actively suppressed by lineage-specific repressors. Here we computationally predict so-called safeguard repressors for 18 cell types that block phenotypic plasticity lifelong. We validated hepatocyte-specific candidates using reprogramming, revealing that prospero homeobox protein 1 (PROX1) enhanced hepatocyte identity by direct repression of alternative fate master regulators. In mice, Prox1 was required for efficient hepatocyte regeneration after injury and was sufficient to prevent liver tumorigenesis. In line with patient data, Prox1 depletion caused hepatocyte fate loss in vivo and enabled the transition of hepatocellular carcinoma to cholangiocarcinoma. Conversely, overexpression promoted cholangiocarcinoma to hepatocellular carcinoma transdifferentiation. Our findings provide evidence for PROX1 as a hepatocyte-specific safeguard and support a model where cell-type-specific repressors actively suppress plasticity throughout life to safeguard lineage identity and thus prevent disease.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"7 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401365","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}

引用次数: 0

DNA loop extrusion is asymmetric but can switch direction

IF 31.7 1区生物学

Nature genetics Pub Date : 2025-02-12 DOI: 10.1038/s41588-025-02102-8

Chiara Anania

引用次数: 0

Engineering extrachromosomal DNA

IF 31.7 1区生物学

Nature genetics Pub Date : 2025-02-12 DOI: 10.1038/s41588-025-02103-7

Safia Danovi

引用次数: 0

Germline mutations increasing pediatric cancer risk