CellPub Date : 2026-10-19DOI: 10.1016/j.cell.2026.09.015
Eric I. Elliott,Tomomi M. Yoshida,Susana C.B.R. Nakandakari,Scott Pope,Cuiling Zhang,Timothy Nottoli,Jae Jin Chae,Daniel L. Kastner,Richard A. Flavell,Vishwa Deep Dixit,Vijay A. Rathinam,Fayyaz S. Sutterwala,Andrew Wang
{"title":"The pyrin inflammasome senses OCTN2-mediated uptake of extracellular ʟ-carnitine from muscle injury or ingestion","authors":"Eric I. Elliott,Tomomi M. Yoshida,Susana C.B.R. Nakandakari,Scott Pope,Cuiling Zhang,Timothy Nottoli,Jae Jin Chae,Daniel L. Kastner,Richard A. Flavell,Vishwa Deep Dixit,Vijay A. Rathinam,Fayyaz S. Sutterwala,Andrew Wang","doi":"10.1016/j.cell.2026.09.015","DOIUrl":"https://doi.org/10.1016/j.cell.2026.09.015","url":null,"abstract":"Red-meat-containing diets are epidemiologically associated with diseases of chronic inflammation, while diets that restrict red meat improve health. Yet, it is uncertain how red meat incites inflammation. Here, we discover that ʟ-carnitine, an amino acid highly concentrated in skeletal muscle myocytes, drives inflammasome activation in lipopolysaccharide (LPS)-challenged mice and LPS-primed murine and human macrophages. We find that extracellular ʟ-carnitine represses mevalonate synthesis, thereby triggering activation of the pyrin inflammasome, downstream of cellular import by the high-affinity ʟ-carnitine transporter OCTN2. We find that the inflammatory response to skeletal muscle injury also requires pyrin and OCTN2. Thus, in summary, we identify macrophages as sentinels of exogenous and endogenous extracellular ʟ-carnitine that serve as a proxy for skeletal myocyte damage, and we open the field to examine the mechanistic basis for how excess dietary intake of carnitine-rich food drives inflammatory disease.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"4 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218249","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 microbiome-bile acid axis mediates protection from chronic liver disease in females","authors":"Mengci Li,Junliang Kuang,Tianlu Chen,Keke Ding,Yuanyuan Chen,Fuxin Jiao,Yang Li,Peiyang Luo,Linyu Xia,Huiheng Zhang,Jieyi Wang,Dan Zheng,Mingliang Zhao,Tao Sun,Xiaowen Chao,Yuhuai Guo,Min Zhu,Yimin Sun,Xixi Xia,Kun Ge,Chun Qu,Changliang Yao,Guoxiang Xie,Kejun Zhou,Panayiotis Louca,Cristina Menni,Aihua Zhao,Qihao Guo,Xinjian Wan,Lu Zhang,Guang Ji,Jian Zhou,Cheng Hu,Weiping Jia,Xiaojiao Zheng,Wei Jia","doi":"10.1016/j.cell.2026.09.048","DOIUrl":"https://doi.org/10.1016/j.cell.2026.09.048","url":null,"abstract":"Sex-based differences in chronic liver disease (CLD) incidence and progression are well documented, yet the mechanistic basis of this sexual disparity remains elusive. Here, leveraging a large-scale metabolomics database comprising 9,254 individuals, we identify the endogenous bile acid, isoursodeoxycholic acid (isoUDCA), as a candidate mediator of female-associated hepatoprotection. We trace the origin of isoUDCA to a bacterial consortium, which is selectively enriched by estrogen through shaping a specialized intestinal microenvironment. Mechanistically, isoUDCA promotes the nuclear accumulation of SREBP2. This upregulates the intracellular transporter STARD4 and its functionally coupled downstream enzyme CYP7B1, thereby facilitating intracellular cholesterol handling and metabolic conversion. Collectively, our findings support a microbiome-bile acid-liver axis that may contribute to sex differences in CLD susceptibility and support further evaluation of isoUDCA as a potential therapeutic intervention.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"1 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218170","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 Oryza orphan gene confers trans-species drought tolerance.","authors":"Haifu Tu, Qian Liu, Tiantian Ye, Ying Ye, Xinhua Feng, Lishi Shen, Shuang Li, Siqi Bai, Xiao Liu, Xin Liu, Huaijun Wang, Xiaokai Li, Junlong Lin, Hao Wang, Yu Chen, Zhiyue Feng, Boming Ji, Jihua Ding, Wei Li, Jianwei Zhang, Mingqiu Dai, Faming Dong, Honghong Hu, Ning Tang, Xuelei Lai, Haiyan Xiong, Lizhong Xiong","doi":"10.1016/j.cell.2026.07.005","DOIUrl":"10.1016/j.cell.2026.07.005","url":null,"abstract":"<p><p>Drought threatens crop productivity, yet enhancing tolerance often compromises yield. Abscisic acid (ABA) signaling is central to drought response, but its deep conservation can constrain adaptive flexibility. Here, we identify ROAD1 (rice orphan gene adapted for drought 1), an Oryza-specific orphan gene that confers robust drought tolerance without obvious growth defects under normal conditions. ROAD1 originated from Oryza meridionalis, and its functional allele, ROAD1<sup>C</sup>, was selected during japonica domestication. In field trials, elite rice lines carrying ROAD1<sup>C</sup> exhibited up to 34.75% higher grain yield than corresponding controls under drought. Mechanistically, ROAD1 bypasses the canonical ABA receptor-ligand complex by binding the phosphatase OsPP2C68, preventing sucrose non-fermenting 1-related protein kinases 2 (SnRK2) dephosphorylation and activating downstream responses. ROAD1 also interacts with protein phosphatase 2C (PP2C) orthologs from maize, wheat, and Arabidopsis, and heterologous expression of ROAD1<sup>C</sup> enhances drought tolerance in Arabidopsis, rapeseed, maize, wheat, and poplar. These findings reveal that an Oryza-specific orphan gene can co-opt conserved signaling for potential trans-species drought tolerance.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":"6865-6881.e8"},"PeriodicalIF":45.1,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148576956","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}
CellPub Date : 2026-10-15Epub Date: 2026-07-29DOI: 10.1016/j.cell.2026.07.016
Alex C Y Chen, Keely Y Ji, Cansu Yerinde, Nelson H Knudsen, Kevin Bi, Shumeng Hao, Vasyl Zhabotynsky, Daniela Martinez, Thomas J Carmona-LaSalle, Kazuhiro Taguchi, Katherine H Xu, Elizabeth M Seider, Marc A Schwartz, Maria Zschummel, Linda T Nieman, Kathleen B Yates, Francesca S Gazzaniga, Brian C Miller, Thorsten R Mempel, Robert T Manguso, Nir Hacohen, Debattama R Sen
{"title":"CRISPR screens identify targets to rescue age-related T cell dysfunction in cancer.","authors":"Alex C Y Chen, Keely Y Ji, Cansu Yerinde, Nelson H Knudsen, Kevin Bi, Shumeng Hao, Vasyl Zhabotynsky, Daniela Martinez, Thomas J Carmona-LaSalle, Kazuhiro Taguchi, Katherine H Xu, Elizabeth M Seider, Marc A Schwartz, Maria Zschummel, Linda T Nieman, Kathleen B Yates, Francesca S Gazzaniga, Brian C Miller, Thorsten R Mempel, Robert T Manguso, Nir Hacohen, Debattama R Sen","doi":"10.1016/j.cell.2026.07.016","DOIUrl":"10.1016/j.cell.2026.07.016","url":null,"abstract":"<p><p>Immune aging impairs T cell-mediated tumor control as well as cancer immunotherapy outcomes. The most important drivers of T cell dysfunction in aged tumors remain unknown. We performed single-cell CRISPR screens to identify Dusp5 and Zfp219 as key regulators of CD8<sup>+</sup> T cell persistence and effector differentiation within aged tumors. Loss of Dusp5 increased extracellular signal-regulated kinase (ERK) phosphorylation and globally enhanced T cell proliferation. Conversely, Zfp219 deletion induced epigenetic reprogramming and increased expression of cytotoxic molecules, enhancing antitumor immunity specifically in aging. Levels of the human ortholog ZNF219 were higher within intratumoral CD8<sup>+</sup> T cells from older cancer patients, which correlates with worse survival following immunotherapy. Zfp219 ablation synergized with immune checkpoint inhibitors to expand effector-like CD8<sup>+</sup> T cells, leading to tumor clearance in aged mice. Our findings highlight Dusp5 and Zfp219 as critical drivers of age-related T cell dysfunction that can be targeted to rejuvenate antitumor immunity in older cancer patients.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":"6738-6751.e7"},"PeriodicalIF":45.1,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148618466","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}
CellPub Date : 2026-10-15DOI: 10.1016/j.cell.2026.09.042
Luca Posa,Giovanna R. Romano,Xiang Ji,Saif Khan,Antonina L. Nazarova,Sheida Sharghi Moshtaghin,Bruno Paz,Gye Won Han,Anisul Arefin,Alberto J. Gonzalez-Hernandez,Ipsit Srivastava,Saheem A. Zaidi,Kenny Calderon-Godinez,Zixin Zhang,Aaliyah S. Tyson,Mohsen Ranjbar,Kristen E. Pleil,Kanupriya Pande,Vsevolod Katritch,Cornelius Gati,Dirk Trauner,Joshua Levitz
{"title":"An opioid efficacy switch for reversible optical control of analgesia","authors":"Luca Posa,Giovanna R. Romano,Xiang Ji,Saif Khan,Antonina L. Nazarova,Sheida Sharghi Moshtaghin,Bruno Paz,Gye Won Han,Anisul Arefin,Alberto J. Gonzalez-Hernandez,Ipsit Srivastava,Saheem A. Zaidi,Kenny Calderon-Godinez,Zixin Zhang,Aaliyah S. Tyson,Mohsen Ranjbar,Kristen E. Pleil,Kanupriya Pande,Vsevolod Katritch,Cornelius Gati,Dirk Trauner,Joshua Levitz","doi":"10.1016/j.cell.2026.09.042","DOIUrl":"https://doi.org/10.1016/j.cell.2026.09.042","url":null,"abstract":"The mu-opioid receptor (MOR) is a major target for pain treatment, but its effectiveness is limited by dangerous side effects. However, the systemic administration of opioids makes it difficult both to decipher their underlying mechanisms of action and to limit drug action to specific receptor subpopulations to isolate therapeutic effects from adverse effects. Here, we develop a reversibly photoswitchable morphinan agonist termed “azo-morphine-3” (AM-3) that interconverts from low to high efficacy in response to light to enable optical control of MOR signaling. Structural analysis of the low (“trans”) and high (“cis”) efficacy states of AM-3 bound to the MOR reveals distinct binding modes, with each state driving unique ligand, receptor, and G protein dynamics. In mice, AM-3 drives reversible and repeatable optical control of antinociception across pain models with a reduced side effect profile owing to its limited brain accumulation and its ability to be locally activated.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"13 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149173081","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":"Spatiotemporal co-transcriptomics uncovers coordinated rhizobia-legume stress programs supporting nitrogen fixation in Medicago","authors":"Wenwen Shao,Xiaobao Shi,Xing Guo,Sunhuan Xiang,Yubin Xiao,Xuanmin Guang,Dongming Fang,Xinghua Lian,Li Luo,Yali Sun,Peng Xu,Yaxin Zhuang,Lihua Chen,Xinhang Chen,Jialin Wen,Meng Yan,Yi Wang,Pingli Xie,Yilin Mao,Chuxing Tang,Jiaying Wu,Changfu Tian,Yayu Wang,Liyuan Zhong,Caiyao Zhao,Yang Zhao,Xiaowei Zhang,Tong Wei,Ying Gu,Jun Yang,Huan Liu,Xun Xu,Ertao Wang","doi":"10.1016/j.cell.2026.07.033","DOIUrl":"https://doi.org/10.1016/j.cell.2026.07.033","url":null,"abstract":"Rhizobial nitrogen fixation in legume nodules requires precise spatial and temporal coordination between host and bacterial gene expression. Here, we applied spatial enhanced resolution omics sequencing (Stereo-seq) to profile Medicago nodules across five developmental stages, generating a co-transcriptomic atlas of nodule development. Using a mixed-probe capture strategy, we simultaneously detected host and rhizobial transcripts within the same tissue sections, enabling analysis of host-microbe transcriptional coordination during symbiosis. We identified dynamic changes in host cell composition and developmental trajectories and uncovered two transcription factors, MtERF82 and MtDOF53, required for maintenance of the indeterminate nodule meristem. Rhizobial and host genes exhibited stage- and zone-specific expression patterns along the nodule apex-to-base axis. Notably, reactive oxygen species (ROS)-associated stress responses in both host cells and rhizobia were linked to symbiotic nitrogen fixation. Functional analyses further showed that MtERF71 and MtCBF1 promote nitrogen fixation by regulating ROS homeostasis and activating key symbiotic genes, highlighting stress signaling as an integral component of mutualistic symbiosis.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"11 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149173085","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}
CellPub Date : 2026-10-15DOI: 10.1016/j.cell.2026.09.034
Mitchell R. Vollger,Elliott G. Swanson,Shane J. Neph,Benjamin J. Mallory,Danilo Dubocanin,Ching-Huang Ho,Yong-Han Hank Cheng,Jane Ranchalis,Katherine M. Munson,Adriana E. Sedeno-Cortes,Devaraja G. Mudeppa,William E. Fondrie,Stephanie C. Bohaczuk,Maxwell A. Dippel,Yizi Mao,Nancy L. Parmalee,William T. Harvey,Youngjun Kwon,Gage H. Garcia,Kendra Hoekzema,Jeffrey G. Meyer,Mine Cicek,Evan E. Eichler,William S. Noble,Daniela M. Witten,James T. Bennett,John P. Ray,Andrew B. Stergachis
{"title":"Somatic epimutations cap genetic determinism in the human diploid chromatin epigenome","authors":"Mitchell R. Vollger,Elliott G. Swanson,Shane J. Neph,Benjamin J. Mallory,Danilo Dubocanin,Ching-Huang Ho,Yong-Han Hank Cheng,Jane Ranchalis,Katherine M. Munson,Adriana E. Sedeno-Cortes,Devaraja G. Mudeppa,William E. Fondrie,Stephanie C. Bohaczuk,Maxwell A. Dippel,Yizi Mao,Nancy L. Parmalee,William T. Harvey,Youngjun Kwon,Gage H. Garcia,Kendra Hoekzema,Jeffrey G. Meyer,Mine Cicek,Evan E. Eichler,William S. Noble,Daniela M. Witten,James T. Bennett,John P. Ray,Andrew B. Stergachis","doi":"10.1016/j.cell.2026.09.034","DOIUrl":"https://doi.org/10.1016/j.cell.2026.09.034","url":null,"abstract":"Diploid human cells contain two non-identical genomes, and differences in their regulation underlie human development and disease. We present Fiber-seq inferred regulatory elements (FIRE) and show that FIRE provides a more comprehensive and quantitative snapshot of the accessible chromatin landscape across the 6 Gbp diploid human genome, overcoming previously unrecognized biases in existing regulatory element catalogs. FIRE enables comprehensive detection of haplotype-selective chromatin accessibility (HSCA), exposing imprinted elements lacking underlying parent-of-origin differences in DNA methylation and gene regulatory modules that permit genes to escape X chromosome inactivation. We uncover that the human leukocyte antigen (HLA) locus harbors the most HSCA in immune cells, where we resolve specific transcription factor (TF) binding events disrupted by disease-associated variants. Finally, we demonstrate that the regulatory landscape of a cell is littered with autosomal somatic chromatin epimutations that are propagated by clonal expansions to create mitotically stable and non-genetically deterministic chromatin alterations.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"13 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149173087","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}
CellPub Date : 2026-10-15Epub Date: 2026-09-01DOI: 10.1016/j.cell.2026.08.009
Melissa A Gray, Katelyn L Randal, Jennifer A Co, Michelle T Tang, Athena Z Xue, Sophia W Chen, Hlib Razumkov, Qusay Q Omran, David E Solow-Cordero, Jeonghye Yu, Stephanie A Robinson, Cara A Starnbach, Nathanael S Gray, Steven M Corsello, Steven M Banik
{"title":"Ratiometric transcriptional activation by protein degradation.","authors":"Melissa A Gray, Katelyn L Randal, Jennifer A Co, Michelle T Tang, Athena Z Xue, Sophia W Chen, Hlib Razumkov, Qusay Q Omran, David E Solow-Cordero, Jeonghye Yu, Stephanie A Robinson, Cara A Starnbach, Nathanael S Gray, Steven M Corsello, Steven M Banik","doi":"10.1016/j.cell.2026.08.009","DOIUrl":"10.1016/j.cell.2026.08.009","url":null,"abstract":"<p><p>Cells can respond to alterations in the abundances of specific proteins through transcriptional outputs. Synthetic approaches inspired by native post-transcriptional circuits that convert protein abundance changes into programmable gene expression would be transformative. Here, we discover and describe design principles that effectively convert protein degradation into transcriptional outputs in live cells. We define ratiometric transcriptional activation, where control over the ratio between a transcription factor and a protein of interest fused to its inhibitor enables detection of abundance changes with high sensitivity at scale. We show that ratiometric transcriptional activation can be implemented in single cells using triply orthogonal circuits or in multicellular pools, operating independently of the mechanism of protein downregulation and enabling simultaneous detection of multiple protein downregulation events through outputs such as cell survival, fluorescent protein expression, or barcode sequencing. These circuits can be applied to oncogenic targets and enable discovery of new molecular glue degraders.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":"6666-6683.e9"},"PeriodicalIF":45.1,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148872748","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}
CellPub Date : 2026-10-15DOI: 10.1016/j.cell.2026.09.035
Santosh S. Atanur,Fengyuan Hu,Haiyi Lou,Xiaoyin Li,Xueqing Zoe Zou,Sean O’Dell,Sri V.V. Deevi,Paula Sawczuk,Karyn Megy,Zammy Fairhurst-Hunter,Amanda O’Neill,AstraZeneca Genomics Initiative,Lifeng Tian,Keren Carss,Jonathan Mitchell,Stewart MacArthur,Sebastian Wasilewski,Ryan S. Dhindsa,Quanli Wang,Katherine R. Smith,Oliver S. Burren,Slavé Petrovski
{"title":"A phenome-wide structural variant map from 467,152 UK Biobank genomes","authors":"Santosh S. Atanur,Fengyuan Hu,Haiyi Lou,Xiaoyin Li,Xueqing Zoe Zou,Sean O’Dell,Sri V.V. Deevi,Paula Sawczuk,Karyn Megy,Zammy Fairhurst-Hunter,Amanda O’Neill,AstraZeneca Genomics Initiative,Lifeng Tian,Keren Carss,Jonathan Mitchell,Stewart MacArthur,Sebastian Wasilewski,Ryan S. Dhindsa,Quanli Wang,Katherine R. Smith,Oliver S. Burren,Slavé Petrovski","doi":"10.1016/j.cell.2026.09.035","DOIUrl":"https://doi.org/10.1016/j.cell.2026.09.035","url":null,"abstract":"Structural variants (SVs) are large (>50 base pairs) genomic rearrangements that can significantly influence human phenotypes, yet their contribution to health and disease remains undercharacterized. We conducted a phenome-wide association study (PheWAS) of 1.6 million SVs identified in whole-genome sequencing data from 467,152 UK Biobank participants, across 13,322 binary, 2,018 quantitative, and 2,923 plasma protein traits. Of these, 82.25% of SVs were outside the detectable range of prior copy-number variant studies. Protein quantitative trait loci analysis linked 3,467 SVs to 1,690 proteins, with effects dependent on SV type and location. In SV-PheWAS, we detected 28,184 associations with human health outcomes. Notably, we uncovered rare SVs with strong phenotypic effects. Furthermore, we show that at known genome-wide association study loci, 32.21% of associated SVs overlapped functional genomic regions. This study underscores the underestimated role of SVs in human genetics and their potential to advance understanding of human biology and drug discovery.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"36 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149173084","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}
CellPub Date : 2026-10-15DOI: 10.1016/j.cell.2026.09.037
The Somatic Mosaicism across Human Tissues Network
{"title":"Comprehensive benchmarking of somatic mutation detection by the SMaHT Network","authors":"The Somatic Mosaicism across Human Tissues Network","doi":"10.1016/j.cell.2026.09.037","DOIUrl":"https://doi.org/10.1016/j.cell.2026.09.037","url":null,"abstract":"Somatic mosaicism is increasingly recognized as a fundamental feature of human biology, yet the detection of somatic mutations remains challenging. The Somatic Mosaicism across Human Tissues (SMaHT) Network conducted large-scale benchmarking experiments involving cell lines and donor tissues to evaluate sequencing technologies, experimental approaches, and computational methods for detecting different types of somatic mutations, generating community resources with >1,000× short-read and 100–400× long-read data for nine analyzed samples. We determined effective strategies for utilizing short- and long-read sequencing for mutation detection and demonstrated that using donor-specific and pangenome-inferred diploid assemblies improved calling, extending mutation catalogs to challenging genomic regions. We benchmarked six duplex technologies and showed that single-cell sequencing resolves cell-type-specific mutational patterns and heterogeneity. Our results indicate that bulk, single-cell, and duplex analyses are complementary and that leveraging all three provides comprehensive characterization of mosaicism within tissues. Together, these findings provide the scientific and clinical communities with a roadmap for accurate genome-wide somatic mutation analysis.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"31 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149173088","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}
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