Nature genetics最新文献

{"title":"CHOIR improves significance-based detection of cell types and states from single-cell data","authors":"Cathrine Sant, Lennart Mucke, M. Ryan Corces","doi":"10.1038/s41588-025-02148-8","DOIUrl":"https://doi.org/10.1038/s41588-025-02148-8","url":null,"abstract":"<p>Clustering is a critical step in the analysis of single-cell data, enabling the discovery and characterization of cell types and states. However, most popular clustering tools do not subject results to statistical inference testing, leading to risks of overclustering or underclustering data and often resulting in ineffective identification of cell types with widely differing prevalence. To address these challenges, we present CHOIR (<u>c</u>luster <u>h</u>ierarchy <u>o</u>ptimization by <u>i</u>terative <u>r</u>andom forests), which applies a framework of random forest classifiers and permutation tests across a hierarchical clustering tree to statistically determine clusters representing distinct populations. We demonstrate the performance of CHOIR through extensive benchmarking against 15 existing clustering methods across 230 simulated and five real single-cell RNA sequencing, assay for transposase-accessible chromatin sequencing, spatial transcriptomic and multi-omic datasets. CHOIR can be applied to any single-cell data type and provides a flexible, scalable and robust solution to the challenge of identifying biologically relevant cell groupings within heterogeneous single-cell data.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"59 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143789730","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":"An eRNA transcription checkpoint for diverse signal-dependent enhancer activation programs","authors":"Lishuan Wang,&nbsp;Wei Yuan,&nbsp;Amir Gamliel,&nbsp;Wubin Ma,&nbsp;Seowon Lee,&nbsp;Yuliang Tan,&nbsp;Zeyu Chen,&nbsp;Havilah Taylor,&nbsp;Kenneth Ohgi,&nbsp;Soohwan Oh,&nbsp;Aneel K. Aggarwal,&nbsp;Michael G. Rosenfeld","doi":"10.1038/s41588-025-02138-w","DOIUrl":"10.1038/s41588-025-02138-w","url":null,"abstract":"The evidence that signal- and ligand-dependent pathways function by activating regulatory enhancer programs suggests that a ‘checkpoint’ strategy may underline activation of many diversely regulated enhancers. Here we report a molecular mechanism common to several acute signal- and ligand-dependent enhancer activation programs based on release of a shared enhancer RNA (eRNA) transcription checkpoint. It requires recruitment of a DNA-dependent protein kinase catalytic subunit (DNA-PKcs)-phosphorylated RING finger repressor (Krüppel-associated box)-associated protein 1 (KAP1) as a modulator, inhibiting its association with 7SK and E3 small ubiquitin-like modifier (SUMO) ligase activity on the CDK9 subunit of positive transcription elongation factor b (P-TEFb). This facilitates formation of an activated P-TEFb complex, licensing eRNA elongation. Overcoming this checkpoint for signal-dependent enhancer activation occurs in diverse pathways, including estrogen receptor-α, NF-κB-regulated proinflammatory stimulation, androgen receptor and neuronal depolarization. Therefore, a specific strategy required to convert a basal state enhancer P-TEFb complex to an active state to release a conserved checkpoint is apparently employed by several functionally important signal-regulated regulatory enhancers to implement the instructions of the endocrine and paracrine system. Phosphorylation of KAP1 by DNA-PKcs at enhancers regulated by diverse stimuli prevents association with 7SK small nuclear RNPs and CDK9 SUMOylation, thereby activating the P-TEFb complex and promoting enhancer RNA transcription.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 4","pages":"962-972"},"PeriodicalIF":31.7,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143775357","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":"A conserved checkpoint for ligand-dependent enhancer activation","authors":"","doi":"10.1038/s41588-025-02146-w","DOIUrl":"10.1038/s41588-025-02146-w","url":null,"abstract":"We identify that signal-dependent and ligand-dependent enhancer activation programs require release of a shared enhancer RNA (eRNA) transcription checkpoint. Further mechanistic evidence reveals signal-dependent activation of P-TEFb on enhancers, which licenses the enhancer transcriptional program by overcoming pausing of transcription and promoting eRNA elongation.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 4","pages":"782-783"},"PeriodicalIF":31.7,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143775320","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":"Psychiatric genetics in the diverse landscape of Latin American populations","authors":"Estela M. Bruxel, Diego L. Rovaris, Sintia I. Belangero, Gabriela Chavarría-Soley, Alfredo B. Cuellar-Barboza, José J. Martínez-Magaña, Sheila T. Nagamatsu, Caroline M. Nievergelt, Diana L. Núñez-Ríos, Vanessa K. Ota, Roseann E. Peterson, Laura G. Sloofman, Amy M. Adams, Elinette Albino, Angel T. Alvarado, Diego Andrade-Brito, Paola Y. Arguello-Pascualli, Cibele E. Bandeira, Claiton H. D. Bau, Cynthia M. Bulik, Joseph D. Buxbaum, Carolina Cappi, Nadia S. Corral-Frias, Alejo Corrales, Fabiana Corsi-Zuelli, James J. Crowley, Renata B. Cupertino, Bruna S. da Silva, Suzannah S. De Almeida, Juan F. De la Hoz, Diego A. Forero, Gabriel R. Fries, Joel Gelernter, Yeimy González-Giraldo, Eugenio H. Grevet, Dorothy E. Grice, Adriana Hernández-Garayua, John M. Hettema, Agustín Ibáñez, Iuliana Ionita-Laza, Maria Claudia Lattig, Yago C. Lima, Yi-Sian Lin, Sandra López-León, Camila M. Loureiro, Verónica Martínez-Cerdeño, Gabriela A. Martínez-Levy, Kyle Melin, Daniel Moreno-De-Luca, Carolina Muniz Carvalho, Ana Maria Olivares, Victor F. Oliveira, Rafaella Ormond, Abraham A. Palmer, Alana C. Panzenhagen, Maria Rita Passos-Bueno, Qian Peng, Eduardo Pérez-Palma, Miguel L. Prieto, Panos Roussos, Sandra Sanchez-Roige, Hernando Santamaría-García, Flávio M. Shansis, Rachel R. Sharp, Eric A. Storch, Maria Eduarda A. Tavares, Grace E. Tietz, Bianca A. Torres-Hernández, Luciana Tovo-Rodrigues, Pilar Trelles, Eva M. Trujillo-ChiVacuan, Maria M. Velásquez, Fernando Vera-Urbina, Georgios Voloudakis, Talia Wegman-Ostrosky, Jenny Zhen-Duan, Hang Zhou, Marcos L. Santoro, Humberto Nicolini, Elizabeth G. Atkinson, Paola Giusti-Rodríguez, Janitza L. Montalvo-Ortiz","doi":"10.1038/s41588-025-02127-z","DOIUrl":"https://doi.org/10.1038/s41588-025-02127-z","url":null,"abstract":"<p>Psychiatric disorders are highly heritable and polygenic, influenced by environmental factors and often comorbid. Large-scale genome-wide association studies (GWASs) through consortium efforts have identified genetic risk loci and revealed the underlying biology of psychiatric disorders and traits. However, over 85% of psychiatric GWAS participants are of European ancestry, limiting the applicability of these findings to non-European populations. Latin America and the Caribbean, regions marked by diverse genetic admixture, distinct environments and healthcare disparities, remain critically understudied in psychiatric genomics. This threatens access to precision psychiatry, where diversity is crucial for innovation and equity. This Review evaluates the current state and advancements in psychiatric genomics within Latin America and the Caribbean, discusses the prevalence and burden of psychiatric disorders, explores contributions to psychiatric GWASs from these regions and highlights methods that account for genetic diversity. We also identify existing gaps and challenges and propose recommendations to promote equity in psychiatric genomics.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"37 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143758409","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 interplay between germline and somatic variants in alpha-1 anti-trypsin deficiency liver disease","authors":"Sílvia Vilarinho","doi":"10.1038/s41588-025-02151-z","DOIUrl":"10.1038/s41588-025-02151-z","url":null,"abstract":"The biological significance of somatic mutations in rare genetic liver diseases has remained elusive. A study using genomic sequencing paired with experimental cell-based assays has shed light on the selective advantage and accumulation of somatic variants in SERPINA1 found in liver explants from patients with alpha-1 anti-trypsin deficiency.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 4","pages":"775-776"},"PeriodicalIF":31.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744699","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":"Quantitative characterization of tissue states using multiomics and ecological spatial analysis","authors":"Daisy Yi Ding,&nbsp;Zeyu Tang,&nbsp;Bokai Zhu,&nbsp;Hongyu Ren,&nbsp;Alex K. Shalek,&nbsp;Robert Tibshirani,&nbsp;Garry P. Nolan","doi":"10.1038/s41588-025-02119-z","DOIUrl":"10.1038/s41588-025-02119-z","url":null,"abstract":"The spatial organization of cells in tissues underlies biological function, and recent advances in spatial profiling technologies have enhanced our ability to analyze such arrangements to study biological processes and disease progression. We propose MESA (multiomics and ecological spatial analysis), a framework drawing inspiration from ecological concepts to delineate functional and spatial shifts across tissue states. MESA introduces metrics to systematically quantify spatial diversity and identify hot spots, linking spatial patterns to phenotypic outcomes, including disease progression. Furthermore, MESA integrates spatial and single-cell multiomics data to facilitate an in-depth, molecular understanding of cellular neighborhoods and their spatial interactions within tissue microenvironments. Applying MESA to diverse datasets demonstrates additional insights it brings over prior methods, including newly identified spatial structures and key cell populations linked to disease states. Available as a Python package, MESA offers a versatile framework for quantitative decoding of tissue architectures in spatial omics across health and disease. Multiomics and ecological spatial analysis (MESA) calculates ecodiversity-inspired metrics in spatially resolved omics integrated with single-cell data, enabling the quantitative comparison of tissue states across a range of conditions.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 4","pages":"910-921"},"PeriodicalIF":31.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-025-02119-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744725","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":"Borzoi decodes the complex DNA signals governing gene regulation","authors":"Sandra T. Cooper","doi":"10.1038/s41588-025-02154-w","DOIUrl":"10.1038/s41588-025-02154-w","url":null,"abstract":"Borzoi is a deep learning model that predicts RNA sequencing coverage across each exon of every human gene, across different cells and tissues, based on DNA sequence alone.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 4","pages":"777-779"},"PeriodicalIF":31.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744698","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":"Spatially resolved transcriptomic analysis of the adult human prostate","authors":"Junyi Hu,&nbsp;Fei Liu,&nbsp;Jing Zhang,&nbsp;Lei Yin,&nbsp;Wanli Cao,&nbsp;Weidong Xu,&nbsp;Yifan Chang,&nbsp;Ye Wang,&nbsp;Jian Wang,&nbsp;Yaxin Hou,&nbsp;Lilong Liu,&nbsp;Sujun Chen,&nbsp;Guanghui Zhu,&nbsp;Junhui Jiang,&nbsp;Zixian Wang,&nbsp;Gong-Hong Wei,&nbsp;Housheng Hansen He,&nbsp;Di Gu,&nbsp;Ke Chen,&nbsp;Shancheng Ren","doi":"10.1038/s41588-025-02139-9","DOIUrl":"10.1038/s41588-025-02139-9","url":null,"abstract":"The prostate is an organ characterized by significant spatial heterogeneity. To better understand its intricate structure and cellular composition, we constructed a comprehensive single-cell atlas of the adult human prostate. Our high-resolution mapping effort identified 253,381 single cells and 34,876 nuclei sampled from 11 patients who underwent radical resection of bladder cancer, which were categorized into 126 unique subpopulations. This work revealed various new cell types in the human prostate and their specific spatial localization. Notably, we discovered four distinct acini, two of which were tightly associated with E-twenty-six transcription factor family (ETS)-fusion-negative prostate cancer. Through the integration of spatial, single-cell and bulk-seq analyses, we propose that two specific luminal cell types could serve as the common origins of prostate cancer. Additionally, our findings suggest that zone-specific fibroblasts may contribute to the observed heterogeneity among luminal cells. This atlas will serve as a valuable reference for studying prostate biology and diseases such as prostate cancer. Multi-omic analysis of the adult human prostate identifies spatially resolved cell populations with potential links to prostate carcinogenesis.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 4","pages":"922-933"},"PeriodicalIF":31.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744703","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":"Collaborative genome-wide association analysis with cryptography","authors":"","doi":"10.1038/s41588-025-02110-8","DOIUrl":"10.1038/s41588-025-02110-8","url":null,"abstract":"Modern genome-wide association study (GWAS) datasets are biobank scale and are distributed across isolated repositories, owing to privacy concerns and regulations. Secure federated GWAS leverages cryptographic tools to enable joint analysis of these siloed datasets, thereby enhancing a range of common analyses while providing formal guarantees of data privacy.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 4","pages":"780-781"},"PeriodicalIF":31.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744700","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 complexity of tobacco smoke-induced mutagenesis in head and neck cancer","authors":"Laura Torrens,&nbsp;Sarah Moody,&nbsp;Ana Carolina de Carvalho,&nbsp;Mariya Kazachkova,&nbsp;Behnoush Abedi-Ardekani,&nbsp;Saamin Cheema,&nbsp;Sergey Senkin,&nbsp;Thomas Cattiaux,&nbsp;Ricardo Cortez Cardoso Penha,&nbsp;Joshua R. Atkins,&nbsp;Valérie Gaborieau,&nbsp;Priscilia Chopard,&nbsp;Christine Carreira,&nbsp;Ammal Abbasi,&nbsp;Erik N. Bergstrom,&nbsp;Raviteja Vangara,&nbsp;Jingwei Wang,&nbsp;Stephen Fitzgerald,&nbsp;Calli Latimer,&nbsp;Marcos Diaz-Gay,&nbsp;David Jones,&nbsp;Jon Teague,&nbsp;Felipe Ribeiro Pinto,&nbsp;Luiz Paulo Kowalski,&nbsp;Jerry Polesel,&nbsp;Fabiola Giudici,&nbsp;José Carlos de Oliveira,&nbsp;Pagona Lagiou,&nbsp;Areti Lagiou,&nbsp;Marta Vilensky,&nbsp;Dana Mates,&nbsp;Ioan N. Mates,&nbsp;Lidia M. Arantes,&nbsp;Rui Reis,&nbsp;Jose Roberto V. Podesta,&nbsp;Sandra V. von Zeidler,&nbsp;Ivana Holcatova,&nbsp;Maria Paula Curado,&nbsp;Cristina Canova,&nbsp;Elenora Fabianova,&nbsp;Paula A. Rodríguez-Urrego,&nbsp;Laura Humphreys,&nbsp;Ludmil B. Alexandrov,&nbsp;Paul Brennan,&nbsp;Michael R. Stratton,&nbsp;Sandra Perdomo","doi":"10.1038/s41588-025-02134-0","DOIUrl":"10.1038/s41588-025-02134-0","url":null,"abstract":"Tobacco smoke, alone or combined with alcohol, is the predominant cause of head and neck cancer (HNC). We explore how tobacco exposure contributes to cancer development by mutational signature analysis of 265 whole-genome sequenced HNC samples from eight countries. Six tobacco-associated mutational signatures were detected, including some not previously reported. Differences in HNC incidence between countries corresponded with differences in mutation burdens of tobacco-associated signatures, consistent with the dominant role of tobacco in HNC causation. Differences were found in the burden of tobacco-associated signatures between anatomical subsites, suggesting that tissue-specific factors modulate mutagenesis. We identified an association between tobacco smoking and alcohol-related signatures, indicating a combined effect of these exposures. Tobacco smoking was associated with differences in the mutational spectra, repertoire of driver mutations in cancer genes and patterns of copy number change. Our results demonstrate the multiple pathways by which tobacco smoke can influence the evolution of cancer cell clones. Whole-genome sequencing and mutational signature analysis of 265 head and neck cancer samples collected from eight different countries provide insight into the vital contribution of tobacco smoke in disease etiology.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 4","pages":"884-896"},"PeriodicalIF":31.7,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-025-02134-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143736573","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}