Nature genetics最新文献

{"title":"ArchMap is a web-based platform for reference-based analysis of single-cell datasets","authors":"Mohammad Lotfollahi, Chelsea Bright, Ronald Skorobogat, Mohammad Moghareh Dehkordi, Xavier George, Simon Richter, Vladimir A. Shitov, Aleksandra Topalova, Helena Melcher, Noah Nussbaumer, Annika Fomm, Malte D. Luecken, Fabian J. Theis","doi":"10.1038/s41588-026-02756-y","DOIUrl":"10.1038/s41588-026-02756-y","url":null,"abstract":"Leveraging single-cell reference atlases to analyze new data has brought about a paradigm shift in single-cell data science akin to the first reference genome in genomics. However, methods for performing this mapping require computational expertise and, oftentimes, considerable compute power, limiting access for researchers who may benefit the most. Here ArchMap, a no-code query-to-reference mapping tool, removes this barrier by providing all-in-one automated mapping, cell-type annotation and collaborative features to analyze single-cell datasets from a wide range of integrated, often published, reference atlases and allows the extension of atlases with the growing Human Cell Atlas and related efforts. This paves the way for a democratization of reference mapping capabilities. Existing software for mapping single-cell datasets onto reference atlases often requires coding expertise or a license. ArchMap is a free no-code query-to-reference mapping web tool compatible with Python-based mapping methods.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 10","pages":"2469-2473"},"PeriodicalIF":25.5,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-026-02756-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149087597","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":"Lineage identity governs oncogene dependence in mouse NSCLC models of KRAS inhibitor resistance","authors":"Nicolas Mathey-Andrews, Carrie L. Rodriguez, Bing Shui, Agata L. Patriotis, William M. Rideout III, Victor Z. Chen, Ileana Murazzi, Phaedra Ghazi, Milton R. Cornwall-Brady, Manyuan Liu, Morgan G. Heileman, Marianna Trakala, Carla P. Concepcion-Crisol, Dian Yang, Tyler Jacks","doi":"10.1038/s41588-026-02768-8","DOIUrl":"10.1038/s41588-026-02768-8","url":null,"abstract":"Primary and acquired resistance to targeted therapy represent significant challenges to durable treatment responses in oncology. In lung adenocarcinoma, KRAS inhibitors are hampered by incomplete clinical responses and acquired resistance. Here we treated genetically engineered mouse models of Kras-driven lung adenocarcinoma with KRAS inhibitors to model these conditions. Initial treatment response was rapid but incomplete, with residual tumor burden transcriptionally resembling alveolar epithelial cells. With continued treatment, we invariably observed genetic Kras amplification as a resistance mechanism. To model oncogene-independent resistance, we used functional CRISPR approaches to promote squamous lineage transformation. We found that ∆Np63 was sufficient to transform alveolar organoids to a squamous state in vitro, conferring insensitivity to KRAS inhibition. In vivo, Nkx2-1 loss and/or ectopic Sox2 expression poised tumors for squamous lineage commitment. Squamous-transformed tumors did not exhibit evidence of KRAS/MAPK reactivation, underscoring the role for lineage transcription factors and histologic transformation in mediating KRAS independence. KRAS-mutant lung cancers frequently develop resistance to targeted inhibition. This study demonstrates that lineage plasticity shapes oncogene dependence during response and resistance to KRAS inhibition, establishing new models of histologic transformation.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 10","pages":"2605-2618"},"PeriodicalIF":25.5,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149087596","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":"Defining pathogenic macrophages in the fibrotic niche of human chronic liver disease","authors":"","doi":"10.1038/s41588-026-02778-6","DOIUrl":"10.1038/s41588-026-02778-6","url":null,"abstract":"Monocyte-derived macrophages are central in liver fibrosis pathogenesis, but the specific phenotype of the pro-fibrotic subpopulation is unknown. Using a liver single-cell atlas from 77 patients with chronic liver disease, we resolve 2 subpopulations of TREM2+ scar-associated macrophages and identify OLR1 as a candidate therapeutic target to selectively modulate pro-fibrotic macrophage functions and thereby attenuate liver fibrosis.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 10","pages":"2427-2428"},"PeriodicalIF":25.5,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149081503","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":"Genetics and treatment history influence clonal hematopoiesis risk after PARP inhibitor therapy","authors":"","doi":"10.1038/s41588-026-02749-x","DOIUrl":"10.1038/s41588-026-02749-x","url":null,"abstract":"PARP inhibitors and platinum chemotherapy both promote expansion of blood stem cell clones carrying leukemia-associated mutations, but inherited defects in homologous recombination limit this process. These findings reveal that therapy-related leukemia risk may depend on an interaction between treatment history and inherited genetics.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 10","pages":"2431-2432"},"PeriodicalIF":25.5,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149081507","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":"CCNB1IP1 regulatory evolution underlies gradual increases in cortical size and folding in primates","authors":"Ting Hu, Pengcheng Ma, Yifan Kong, Yulian Tan, Xuelian Sun, Jianhong Wang, Kun Xiang, Bingyu Mao, Qingfeng Wu, Soojin V. Yi, Lei Shi","doi":"10.1038/s41588-026-02773-x","DOIUrl":"10.1038/s41588-026-02773-x","url":null,"abstract":"The gradual expansion and folding of the cortex are key factors in human cognitive evolution, yet their molecular underpinnings remain not well understood. Here we identify cyclin B1 interacting protein 1 (CCNB1IP1) gene as a key regulator of human brain evolution using tree shrew as an outgroup. In primates, CCNB1IP1 acquired brain expression and gradually increased its expression during evolution, mirroring the increase of cortical size and folding. Comparative analysis of cis-regulatory elements reveals evolutionary changes underlying the increase of CCNB1IP1 expression. Overexpression of CCNB1IP1 affects the cell cycle, increasing the abundance of basal progenitors and neurons. Mechanistically, we demonstrated that CCNB1IP1 represses the transcription factor E2F1 through the ubiquitin-mediated degradation pathway. Moreover, CCNB1IP1 knock-in can develop cortical folding in otherwise smooth mouse brains. These findings reveal that evolutionary changes in CCNB1IP1 expression have contributed to the enlargement and folding of the primate cortex. The authors use tree shrews in multispecies comparisons to identify evolutionary changes in CCNB1IP1 expression associated with primate cortical expansion and folding, and investigate the cis-regulatory and molecular mechanisms through which CCNB1IP1 may influence these processes.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 10","pages":"2630-2644"},"PeriodicalIF":25.5,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149081474","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 human single-cell atlas identifies OLR1+ scar-associated macrophages as a potential therapeutic target for chronic liver disease","authors":"Eleni Papachristoforou, Kexin Kong, Fabio Colella, Jacky Tam, Juliet Luft, Ravi Parhar, Yingxin Liang, Ailish McCafferty-Brown, George Finney, Keshav Rao, Jayamary Divya Ravichandar, Elena F. Sutherland, Stefan Veizades, Malgorzata Grzelka, Pak Kwan Qiu, Ayma Asif, Ines Battle, Max Hammer, Theresa Kuschnereit, Raktaprabal Kashyap, Sebastian J. Wallace, John R. Wilson-Kanamori, Ginerva Pistocchi, Tabitha Turner-Stokes, Alvile Kasarinaite, Josepmaria Argemi, Elisa Pose, Ramon Bataller, David Lopez, Anna Zagorska, Grant Budas, Gareth-Rhys Jones, Calum C. Bain, Catalina A. Vallejos, Ashis Mukhopadhya, Neil C. Henderson, David C. Hay, James C. Lee, Laura J. Pallett, Volker M. Lauschke, Timothy J. Kendall, Jonathan A. Fallowfield, Prakash Ramachandran","doi":"10.1038/s41588-026-02774-w","DOIUrl":"10.1038/s41588-026-02774-w","url":null,"abstract":"Chronic liver disease (CLD) results in liver fibrosis, leading to adverse clinical outcomes. Macrophages regulate fibrosis and represent an attractive therapeutic target. However, the specific macrophage subpopulation that drives fibrosis in CLD remains unclear. Here we generate a liver single-cell atlas comprising 649,295 cells from 42 healthy and 35 CLD patients, identifying 125 transcriptionally distinct cellular states. We resolve two types of disease-expanded TREM2+ scar-associated macrophages (SAMac), including a pro-inflammatory subpopulation that expresses the scavenger receptor OLR1 and spatially accumulates in the CLD fibrotic niche. High hepatic OLR1 expression was associated with increased fibrosis across multiple CLD etiologies and adverse patient outcomes in metabolic dysfunction-associated steatotic liver disease. Corollary pro-inflammatory OLR1+ SAMac expanded in mouse CLD, while targeting of macrophage OLR1 attenuated fibrogenic activity in human coculture and multilineage spheroid models. Overall, our atlas provides a reference to study disease-associated cell states in CLD and identifies OLR1 as a potential therapeutic target to attenuate liver fibrosis. This study provides a single-cell RNA-sequencing atlas of 77 healthy and chronic liver disease livers and identifies a subpopulation of pro-inflammatory scar-associated macrophages enriched for OLR1 expression with therapeutic potential.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 10","pages":"2550-2565"},"PeriodicalIF":25.5,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-026-02774-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075501","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":"Germline homologous recombination deficiency influences TP53-mutant clonal hematopoiesis fitness during platinum and PARP inhibitor treatment","authors":"Jeremy T. Baeten, Irenaeus C. C. Chan, Lea Moukarzel, Giulia E. M. Petrone, Jie Liu, Duc Tran, Jacob Tabs, Imene Tabet, Sumedha Agashe, Elaheh Nasrollahzadeh, Ankush Vasireddy, Amber Carter, Minal Patel, Konrad H. Stopsack, Philip W. Kantoff, Weiyin Zhou, Armel L. Batchi-Bouyou, J. Scott Beeler, Griffen Mustion, Paul Pharoah, James Brenton, Kenneth Offit, Ethan Barnett, Bob Li, Wassim Abida, Alison M. Schram, Britta Weigelt, David Mutch, Alessandro Vindigni, Mary Mullen, Carlos Cruchaga, Howard Scher, Ross Levine, Elli Papaemmanuil, Mitchell J. Machiela, Karen Cadoo, Daniel C. Link, Kelly L. Bolton","doi":"10.1038/s41588-026-02752-2","DOIUrl":"10.1038/s41588-026-02752-2","url":null,"abstract":"Poly(ADP-ribose) polymerase inhibitors (PARPi) are commonly used in tumors with homologous recombination deficiency (HRD) but are associated with an increased risk of therapy-related myeloid neoplasms (tMN). Clonal hematopoiesis (CH) driven by DNA damage response (DDR) mutations is the origin of most tMN. Here, to better understand the causes of tMN following PARPi therapy, we studied the relationship between PARPi use and CH. We observed a high frequency of DDR CH following PARPi therapy, largely explained by prior carboplatin exposure. Among patients with serial blood sampling, DDR CH expanded during carboplatin and to a lesser extent, during PARPi treatment. Surprisingly, this expansion was largely reduced in patients with germline HRD. We validated these findings in a mouse model of Trp53-mutated CH. Our findings suggest that the increased risk of tMN following PARPi is largely influenced by prior oncologic therapies, including carboplatin, and may vary by germline HRD status. The authors show that platinum is a greater driver of DNA damage response gene-mutant clonal hematopoiesis than poly(ADP-ribose) polymerase inhibitors and that the presence of germline mutations conferring homologous recombination deficiency reduces the rate of expansion of these clones.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 10","pages":"2579-2589"},"PeriodicalIF":25.5,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-026-02752-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075456","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":"Euchromatin forms condensed domains with short active regions on the surface","authors":"Joseph M. Paggi, Lawrence Y. Long, Bin Zhang","doi":"10.1038/s41588-026-02775-9","DOIUrl":"10.1038/s41588-026-02775-9","url":null,"abstract":"The three-dimensional organization of enhancers and promoters at nucleosome resolution remains poorly resolved, limiting our understanding of the structural basis of transcriptional regulation. Here, we developed a simulation framework that leverages region-capture micro-C contact maps to infer conformational ensembles of megabase-scale regions at nucleosome resolution. A key component of this framework is a micro-C balancing strategy that identifies variation in contact density. The simulations reproduce pairwise distance distributions measured by chromatin tracing and contain packing domains and nucleosome clutches, as observed in imaging studies. The inferred structures reveal a striking departure from the classical view of euchromatin as uniformly open. Instead, euchromatin generally forms condensed domains with comparable densities but smaller sizes than heterochromatin domains. Kilobase-scale regions at promoters and enhancers often protrude from these condensed domains and become highly accessible. This arrangement effectively compartmentalizes regulatory elements from the surrounding chromatin, facilitating protein binding and enhancer–promoter communication. Simulations integrating micro-C and imaging data provide a coherent view of chromatin organization from nucleosomes to clutches to domains, revealing that most regions form compact domains but short regulatory elements are highly exposed.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 10","pages":"2673-2683"},"PeriodicalIF":25.5,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149049510","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":"Genome-wide mapping of common and rare variant effects on adiposity across childhood","authors":"Katherine A. Kentistou,Jonas Sundfjord,Roya Karimi,Lena R. Kaisinger,Robin J. Hofmeister,Nicolas Fragoso-Bargas,Adina E. Lupu,Yajie Zhao,John A. Tadross,Lukas Steuernagel,Georgina K. C. Dowsett,Sam Lockhart,Jens C. Brüning,Jimmy Liu,Adrian Cortes,Yancy Lo,Jonathan Davitte,Lieven Clement,Alexandra Havdahl,Ole A. Andreassen,Eirik Bratland,Brian Y. H. Lam,Stephen O’Rahilly,Giles S. H. Yeo,Pål R. Njølstad,Zoltán Kutalik,Felix R. Day,Marc Vaudel,John R. B. Perry,Ken K. Ong,Stefan Johansson","doi":"10.1038/s41588-026-02772-y","DOIUrl":"https://doi.org/10.1038/s41588-026-02772-y","url":null,"abstract":"Abstract Our understanding of the genetic architecture of obesity is primarily based on studies of adults, with sparser data from childhood. Here, we conducted age-stratified genetic association studies against objectively measured ( n  = 62,276) or recalled childhood adiposity-related traits ( n eff  = 599,924), identifying 624 common variants associated with childhood adiposity, with one-third having no concordant association with adult body mass index. Signals linked to the leptin–melanocortin pathway ( BSX , GNAS , LEPR and PCSK1 ) and incretin signaling ( GIPR and GLP1R ) showed childhood-specific effects on adiposity. Single-nucleus RNA sequencing data identified childhood-specific adiposity-regulating cell populations in the arcuate nucleus and mammillary bodies, indicating neurocircuits that regulate adiposity specifically during childhood. Finally, sequencing in 479,615 individuals uncovered rare protein-coding variation in ADCY3 , CALCR , MC4R , MRAP2 , POMC and MYH13 , exhibiting stronger associations in childhood than in adults. Our findings suggest that childhood provides a more sensitive window for the study of key endocrine and neuropeptide pathways that regulate energy balance.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149049511","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":"Single-cell analysis of chromatin accessibility in the human intestine identifies regulatory programs and clarifies genetic associations in Crohn’s disease","authors":"Yu Zhao, Ran Zhou, Zepeng Mu, Peter Carbonetto, Xiaoyuan Zhong, Bingqing Xie, Kaixuan Luo, Zhiwei Jiang, Jianqiao Liu, Candace M. Cham, Jason Koval, Xin He, Andrew W. Dahl, Xuanyao Liu, Eugene B. Chang, Anindita Basu, Sebastian Pott","doi":"10.1038/s41588-026-02755-z","DOIUrl":"10.1038/s41588-026-02755-z","url":null,"abstract":"Crohn’s disease is a complex inflammatory bowel disease resulting from an interplay of genetic, microbial and environmental factors. Cell-type-specific contributions to Crohn’s disease etiology and genetic risk are incompletely understood. Here we built a comprehensive atlas of cell-type-resolved chromatin accessibility comprising 557,310 candidate cis-regulatory elements (cCREs) in terminal ileum and ascending colon from 23 patients with active and inactive Crohn’s disease and 16 healthy controls. We identified cell-type-specific, anatomical location-specific and context-specific cCREs and characterized the regulatory programs underlying inflammatory responses in the intestinal mucosa of patients with Crohn’s disease. These cell-type-resolved data confirmed that Crohn’s disease heritability is primarily enriched in adaptive immune cells, in particular T cells, and in innate immune cells, including neutrophils. Using fine-mapped, noncoding Crohn’s disease variants, we identified 30 variants located within cCREs. Our atlas provides a comprehensive resource to study gene-regulatory effects in Crohn’s disease and health and highlights the cellular complexity underlying Crohn’s disease risk. This study uses single-cell ATAC–seq to map chromatin accessibility in the intestinal mucosa from patients with Crohn’s disease and healthy controls to characterize regulatory programs associated with inflammation and genetic effects.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 10","pages":"2535-2549"},"PeriodicalIF":25.5,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-026-02755-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149050056","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}