Nature genetics最新文献

{"title":"Publisher Correction: Genomic landscape of the human vaginal microbiome is linked to host genetics and population of origin","authors":"Zhuye Jie, Weiting Liang, Qiuxia Ding, Xiaomin Liu, Yunhong Zhang, Na Chen, Shenghui Li, Xin Tong, Hongqin Gao, Ruike Lu, Xincheng Huang, Ruochun Guo, Junhong Chen, Jie Zhu, Zhe Zhang, Na Liu, Zhangwei Xie, Xiaman Wang, Le Qi, Yumei Li, Liang Xiao, Shaoqiao Zhang, Xin Jin, Xun Xu, Huanming Yang, Jian Wang, Fangqing Zhao, Huijue Jia, Karsten Kristiansen, Tao Zhang, Lilan Hao, Lan Zhu, Chen Chen","doi":"10.1038/s41588-026-02788-4","DOIUrl":"10.1038/s41588-026-02788-4","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 10","pages":"2717-2717"},"PeriodicalIF":25.5,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-026-02788-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149002373","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":"Crop legacies as genetic targets for sustainable farming systems","authors":"Shanice Van Haeften, Stephanie M. Brunner, Ben J. Hayes, Michael Udvardi, Lee T. Hickey, Millicent R. Smith","doi":"10.1038/s41588-026-02744-2","DOIUrl":"10.1038/s41588-026-02744-2","url":null,"abstract":"Food production must rise while its environmental footprint falls, an imperative sharpened by pressure to use fewer external inputs. Meeting this challenge requires gains from aspects that crop breeding has so far overlooked. One such source is the soil, because every crop transforms the environment in which it grows, shaping the conditions experienced by the next crop. We propose that these legacy effects, expressed through altered soil nutrients, water, structure and microbial communities, could offer new breeding targets. Many traits that modulate these effects vary within major crop species, and this variation is heritable and therefore selectable. We advocate breeding for farming systems to exploit this untapped genetic dimension. We outline the mechanisms underpinning this relationship, the frameworks needed to quantify it and the practical challenges of integrating legacy-aware selection into breeding pipelines. Every crop leaves a legacy, and understanding this provides a pathway to a more sustainable agricultural future. Crops leave a legacy in the soil that shapes the next season’s harvest, and the size of that legacy depends on the variety’s genetics. This Perspective proposes breeding for entire rotations rather than single crops to build more sustainable farms.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 10","pages":"2448-2456"},"PeriodicalIF":25.5,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148983210","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":"Type 1 interferon perturbates clonal competition by reshaping human blood development.","authors":"Chhiring Lama, Danielle Isakov, Shira Rosenberg, Miguel Quijada-Álamo, Mirca S Saurty-Seerunghen, Sara Moein, Mathis Nozais, Tsega-Ab Abera, Olivia Sakaguchi, Mansi Totwani, Grace Freed, Leila Zaydon, Chi-Lam Poon, Neelang Parghi, Andrea Kubas-Meyer, Amy X Xie, Mohamed Omar, Daniel Choi, Franco Castillo-Tokumori, Ghaith Abu-Zeinah, Alicia Dillard, Saravanan Ganesan, Nathaniel D Omans, Neville Dusaj, Paulina Chamely, Eleni Mimitou, Peter Smibert, Heidi E Kosiorek, Amylou C Dueck, Rona Weinberg, Ronan Chaligne, Bridget Marcellino, Luigi Marchionni, Sanjay Patel, Paul Simonson, Dan A Landau, Elvin Wagenblast, Ronald Hoffman, Anna S Nam","doi":"10.1038/s41588-026-02751-3","DOIUrl":"10.1038/s41588-026-02751-3","url":null,"abstract":"<p><p>Inflammation accelerates evolutionary dynamics of hematopoietic stem cells (HSCs) in clonal hematopoiesis and myeloid neoplasms. We studied HSCs, progenitors and immune cells from patients with myeloproliferative neoplasms at baseline and following interferon-α (IFNα) treatment, the only therapy to deplete mutated stem cells. We deployed single-cell multiomics methods that distinguish the IFNα effects on mutated stem cells from the admixed wild-type HSCs, with respect to their differentiation, transcriptomes, immunophenotypes and chromatin accessibility. IFNα simultaneously activated HSCs into two polarized states: a lymphoid progenitor expansion associated with an anti-inflammatory state and an inflammatory myeloid progenitor state derived from HSCs. The augmented lymphoid differentiation balanced the typical myeloproliferative-neoplasm-induced myeloid bias, associated with normalized blood counts. Somatic mutations modified the effects of IFNα on HSC differentiation and cell cycle entry rates. Clonal fitness upon IFNα exposure was due to resistance of CALR- or JAK2-mutated stem cells to differentiate into inflammatory myeloid progenitors.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":" ","pages":""},"PeriodicalIF":25.5,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148977303","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":"Pierre Chambon (1931–2026)","authors":"Christophe O. Benoist,&nbsp;Diane Mathis,&nbsp;Patrick Schultz,&nbsp;László Tora","doi":"10.1038/s41588-026-02771-z","DOIUrl":"10.1038/s41588-026-02771-z","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 10","pages":"2422-2423"},"PeriodicalIF":25.5,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-026-02771-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149125996","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":"Pan-genome-based resequencing of 2,320 accessions reveals structural variations and accelerates breeding advances in cultivated peanut","authors":"Yiyang Liu,&nbsp;Weitao Li,&nbsp;Rongchong Li,&nbsp;Manish K. Pandey,&nbsp;Bo Bai,&nbsp;Yan Han,&nbsp;Guiying Tang,&nbsp;Lei Zhang,&nbsp;Annapurna Chitkineni,&nbsp;Yanjiao Li,&nbsp;Libing Li,&nbsp;Shulong Li,&nbsp;Vanika Garg,&nbsp;Fengping Du,&nbsp;Feng Cui,&nbsp;Liangqiong He,&nbsp;Lei Shan,&nbsp;Fangji Xu,&nbsp;Pingli Xu,&nbsp;Ronghua Tang,&nbsp;Reyazul R. Mir,&nbsp;Feng Guo,&nbsp;Xinguo Li,&nbsp;Jialei Zhang,&nbsp;Zheng Zhang,&nbsp;Kuldeep Singh,&nbsp;Qiang He,&nbsp;Guowei Li,&nbsp;Xinyou Zhang,&nbsp;Rajeev K. Varshney,&nbsp;Shubo Wan","doi":"10.1038/s41588-026-02765-x","DOIUrl":"10.1038/s41588-026-02765-x","url":null,"abstract":"The cultivated peanut is a crucial global legume crop that is essential for food security and nutrition, particularly in developing regions. However, its limited genetic variation hampers breeding progress and yield improvement. Here we constructed a graph-based pan-genome for peanut, incorporating 14 genomes that represent all 6 peanut varieties. Using this pan-genome, we genotyped 2,320 accessions, covering 88.03% of ICRISAT and 59.21% of USDA core germplasm, enriching valuable resources for genomic studies and breeding. We cataloged genomic structural variations and investigated the role of homoeologous exchanges in population divergence. Through our pan-genome approach, we overcame the challenges of genotyping posed by homoeologous exchanges and identified key genes associated with flowering and dwarfism in peanut. By integrating superior haplotypes and germplasm resources guided by the pan-genome, we further developed high-yield dwarf lines. This work provides essential genomic resources to accelerate functional gene discovery and modern peanut breeding. Pan-genome analyses of cultivated peanut using 10 newly assembled genomes, along with whole-genome resequencing of 2,320 germplasm accessions, highlight structural variations and loci associated with agronomic traits such as flowering and dwarfism.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 10","pages":"2706-2716"},"PeriodicalIF":25.5,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148977282","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":"APOE-stratified genome-wide association analyses provide insights into the genetic etiology of Alzheimers’s disease","authors":"Jesper Qvist Thomassen,&nbsp;Hampton Leonard,&nbsp;Brittany Ulms,&nbsp;Benjamin Grenier-Boley,&nbsp;Sami Heikkinen,&nbsp;Pablo Garcia-González,&nbsp;Atahualapa Castillo-Morales,&nbsp;Masataka Kikuchi,&nbsp;Jungsoo Gim,&nbsp;Han Cao,&nbsp;Fahri Küçükali,&nbsp;Najaf Amin,&nbsp;Dabin Yoon,&nbsp;Itziar de Rojas,&nbsp;Pilar Alvarez Jerez,&nbsp;Victoria Alvarez,&nbsp;Beatrice Arosio,&nbsp;Céline Bellenguez,&nbsp;Sverre Bergh,&nbsp;Kimberley Billingsley,&nbsp;Cornelis Blauwendraat,&nbsp;Merce Boada,&nbsp;Barbara Borroni,&nbsp;Paola Bossù,&nbsp;María J. Bullido,&nbsp;Antonio Daniele,&nbsp;Ángel Carracedo,&nbsp;Alexandre de Mendonça,&nbsp;Mark Cookson,&nbsp;Jürgen Deckert,&nbsp;Martin Dichgans,&nbsp;Srdjan Djurovic,&nbsp;Oriol Dols-Icardo,&nbsp;Carole Dufouil,&nbsp;Emrah Düzel,&nbsp;Valentina Escott-Price,&nbsp;Tormod Fladby,&nbsp;Laura Fratiglioni,&nbsp;Amy K. Y. Fu,&nbsp;Daniela Galimberti,&nbsp;Jose Maria García-Alberca,&nbsp;Vilmantas Giedraitis,&nbsp;Guillermo Garcia-Ribas,&nbsp;Caroline Graff,&nbsp;Timo Grimmer,&nbsp;Edna Grünblatt,&nbsp;Olivier Hanon,&nbsp;Lucrezia Hausner,&nbsp;Stefanie Heilmann-Heimbach,&nbsp;Jakub Hort,&nbsp;Frank Jessen,&nbsp;Kendall Jensen,&nbsp;Caroline Jonson,&nbsp;Yoontae Kim,&nbsp;Nicole Kuznetsov,&nbsp;Ville Leinonen,&nbsp;Anssi Lipponen,&nbsp;Jiao Luo,&nbsp;Mary Makarious,&nbsp;Henna Martiskainen,&nbsp;Carlo Masullo,&nbsp;Patrizia Mecocci,&nbsp;Shima Mehrabian,&nbsp;Pablo Mir,&nbsp;Akinori Miyashita,&nbsp;Susanne Moebus,&nbsp;Kin Y. Mok,&nbsp;Laura Molina Porcel,&nbsp;Fermin Moreno,&nbsp;Benedetta Nacmias,&nbsp;Lucilla Parnetti,&nbsp;Pau Pastor,&nbsp;Jordi Pérez-Tur,&nbsp;Oliver Peters,&nbsp;Yolande A. L. Pijnenburg,&nbsp;Gerard Piñol-Ripoll,&nbsp;Julius Popp,&nbsp;Innocenzo Rainero,&nbsp;Luis M. Real,&nbsp;Steffi Riedel-Heller,&nbsp;Eloy Rodriguez-Rodriguez,&nbsp;Arvid Rongve,&nbsp;Giacomina Rossi,&nbsp;Jose Luis Royo,&nbsp;Dan Rujescu,&nbsp;Ingvild Saltvedt,&nbsp;María Eugenia Sáez,&nbsp;Raquel Sánchez-Valle,&nbsp;Florentino Sanchez-Garcia,&nbsp;Nicolai Sandau,&nbsp;Nikolaos Scarmeas,&nbsp;Katja Scheffler,&nbsp;Norbert Scherbaum,&nbsp;Anja Schneider,&nbsp;Geir Selbæk,&nbsp;Davide Seripa,&nbsp;Vincenzo Solfrizzi,&nbsp;Marco Spallazzi,&nbsp;Alessio Squassina,&nbsp;Eystein Stordal,&nbsp;Niccoló Tesi,&nbsp;Lucio Tremolizzo,&nbsp;Kumar P. Tripathi,&nbsp;Wiesje M. van der Flier,&nbsp;Julie Williams,&nbsp;Jens Wiltfang,&nbsp;Dag Aarsland,&nbsp;Andrew B. Singleton,&nbsp;Philippe Amouyel,&nbsp;Stéphanie Debette,&nbsp;Magda Tsolaki,&nbsp;Gael Nicolas,&nbsp;Sven van der Lee,&nbsp;Henne Holstege,&nbsp;Maria Victoria Fernandez,&nbsp;Patrick Gavin Kehoe,&nbsp;Kristel Sleegers,&nbsp;Martin Ingelsson,&nbsp;Roberta Ghidoni,&nbsp;Ole A. Andreassen,&nbsp;Peter A. Holmans,&nbsp;Pascual Sánchez-Juan,&nbsp;Rebecca Sims,&nbsp;Nancy Y. Ip,&nbsp;Kun Ho Lee,&nbsp;Takeshi Ikeuchi,&nbsp;Alfredo Ramirez,&nbsp;Agustin Ruiz,&nbsp;Mikko Hiltunen,&nbsp;Jean-Charles Lambert,&nbsp;Cornelia van Duijn,&nbsp;Mike Nalls,&nbsp;Ruth Frikke-Schmidt","doi":"10.1038/s41588-026-02713-9","DOIUrl":"10.1038/s41588-026-02713-9","url":null,"abstract":"Among the more than 90 identified genetic risk loci for late-onset Alzheimer’s disease (AD) and related dementias, the apolipoprotein E (APOE) gene ɛ2/ɛ3/ɛ4 polymorphisms remain the longstanding benchmark for genetic disease risk with a consistently large effect across studies1–10. Despite this massive signal, the exact mechanisms by which ɛ4 increases and ɛ2 decreases dementia risk remain poorly understood. Notably, recent trials of anti-amyloid therapies suggest less efficacy and higher risks of severe side effects in ε4 carriers11–13, hampering the treatment of those with the highest unmet need. To improve our understanding of the genetic architecture of AD in the context of its main genetic driver, we performed genome-wide association studies (GWASs) stratified by ε4 and ε2 carrier status. HP1BP3, SLC50A1, PTPRC, NPAS3, DDHD1, CHST9, SMYD2, PRAMEF1 and GFRA1 emerged as new genomic signals for AD risk, appearing only when stratified by APOE carrier status. DDHD1 appeared especially promising, showing protective effects in ε4 carriers, being identified as an expression quantitative trait locus and being involved in rare neuronal diseases. Such APOE-stratified insights may help understand and overcome side effects, inform clinical trial enrollment strategies, and create the scientific basis for targeted, mechanism-driven therapies in neurodegenerative diseases. Genome-wide association analyses of Alzheimer’s disease stratified by APOE carrier status identify variants whose effects are attenuated or augmented by the ε4 risk allele.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 10","pages":"2474-2484"},"PeriodicalIF":25.5,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-026-02713-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148970084","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":"All of Us diversity and scale yield context-dependent improvements in polygenic prediction","authors":"Kristin Tsuo,&nbsp;Zhuozheng Shi,&nbsp;Tian Ge,&nbsp;Ravi Mandla,&nbsp;Kangcheng Hou,&nbsp;Yi Ding,&nbsp;Bogdan Pasaniuc,&nbsp;Ying Wang,&nbsp;Alicia R. Martin","doi":"10.1038/s41588-026-02734-4","DOIUrl":"10.1038/s41588-026-02734-4","url":null,"abstract":"Polygenic risk scores (PRSs) trained on multiancestry data can improve prediction in under-represented groups, but large linked genetic and health datasets capturing broad human diversity remain limited. Using 245,388 whole-genome sequences from the All of Us research program (AoU) together with UK Biobank data, we developed multiancestry PRSs for 32 traits and diseases. We evaluated how ancestry, methodology and genetic architecture influenced PRS performance across ancestrally diverse AoU participants. Increased diversity in the AoU improved PRS accuracy for several traits, especially in under-represented populations. However, maximizing sample size by meta-analyzing AoU and UK Biobank was not universally optimal: for less polygenic traits, AoU-only training performed best in African ancestry participants, consistent with ancestry-enriched effects. Individual PRS accuracy declined linearly with increasing ancestry divergence from the discovery GWAS, but this decay was attenuated using multiancestry training data. These findings underscore the value of more representative biobanks for equitable PRS performance. Leveraging multiancestry and multi-biobank data from the All of Us Research Program and the UK Biobank improves polygenic prediction models for complex traits and diseases, especially for under-represented populations.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 10","pages":"2485-2493"},"PeriodicalIF":25.5,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148970027","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":"Recommendations for return of secondary genomic findings in observational cohort studies","authors":"Iftikhar J. Kullo,&nbsp;Carol R. Horowitz,&nbsp;Lisa Bastarache,&nbsp;Benjamin Berkman,&nbsp;Leslie Biesecker,&nbsp;Kyle Brothers,&nbsp;April P. Carson,&nbsp;Keith Diaz,&nbsp;Richard A. Gibbs,&nbsp;Robert C. Green,&nbsp;Heather Hampel,&nbsp;Candace Henley,&nbsp;Jodell E. Linder,&nbsp;Gail P. Jarvik,&nbsp;Sadiya S. Khan,&nbsp;Barry Make,&nbsp;Samuli Ripatti,&nbsp;Mimsie Robinson,&nbsp;Juliann M. Savatt,&nbsp;Gabriel Q. Shaibi,&nbsp;Stephen Olufemi Sodeke,&nbsp;Colin Wise,&nbsp;Yuling Hong,&nbsp;Ye Yan,&nbsp;Ronit I. Yarden","doi":"10.1038/s41588-026-02724-6","DOIUrl":"10.1038/s41588-026-02724-6","url":null,"abstract":"The return of secondary genomic findings (ROSF) to participants in observational cohort studies has evolved from a topic of debate to an accepted standard. This Perspective synthesizes the proceedings of a 2024 National Heart, Lung and Blood Institute-sponsored workshop and the broader literature to provide updated guidance for ROSF. Building on the 2010 National Heart, Lung and Blood Institute Working Group recommendations and the 2014 Clinical Sequencing Exploratory Research/Electronic Medical Records and Genomics ‘floor and ceiling’ framework, we address four areas: an integrated ethical framework for observational cohort settings; the emerging challenge of returning novel result types beyond monogenic variants, including polygenic risk scores, somatic mosaicism and pharmacogenomic findings; health equity and community engagement as structural prerequisites for ethical ROSF; and scalability challenges, including technology-assisted disclosure. Drawing on implementation experience from large-scale sequencing programs, we offer recommendations that balance researcher obligations with participant autonomy and equitable access to the benefits of genomic research. This Perspective presents an integrated ethical framework for the return of secondary findings from observational cohort studies, including polygenic risk scores, somatic mosaicism and pharmacogenomic results, for which prior guidance is limited.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 10","pages":"2437-2447"},"PeriodicalIF":25.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148932673","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":"Cancer treatment alters mutant selection in normal esophagus","authors":"Joanna C. Fowler,&nbsp;Giuseppina Arbore,&nbsp;Roshan K. Sood,&nbsp;Irina Abnizova,&nbsp;Luca Albarello,&nbsp;Oliver Pickering,&nbsp;Kasumi Murai,&nbsp;Ujjwal Banerjee,&nbsp;Salomé Brunon,&nbsp;Swee Hoe Ong,&nbsp;Andrea Cossu,&nbsp;Ugo Elmore,&nbsp;Francesco Puccetti,&nbsp;David Fernandez-Antoran,&nbsp;Giovanni Tonon,&nbsp;Paolo Dellabona,&nbsp;Riccardo Rosati,&nbsp;Samuel Luke Hill,&nbsp;Tim Underwood,&nbsp;Benjamin A. Hall,&nbsp;David Shorthouse,&nbsp;Philip H. Jones","doi":"10.1038/s41588-026-02738-0","DOIUrl":"10.1038/s41588-026-02738-0","url":null,"abstract":"Aging epithelial tissues, including the esophagus, are colonized by somatic mutant clones under strong competitive selection. The effect of cancer treatment on mutant selection in normal epithelium is unknown. We hypothesized that some mutant clones may be selectively expanded during treatment. To test this, we sequenced normal esophageal epithelium removed from 70 patients after therapy for esophageal cancer. Patients received either no treatment, combination chemotherapy (FLOT, ECX or EOX) or chemotherapy and radiation therapy (CROSS). Mutant TP53 and PPM1D clones were expanded in patients undergoing CROSS. In the group undergoing FLOT, there was increased selection for RAC1, NFE2L2 and MTOR mutations consistent with these mutants conferring 5-fluorouracil resilience in normal epithelium. Sequencing normal epithelia reveals treatment-specific selection of mutations and may identify genes implicated in cellular responses to therapy. Cancer treatment alters the selection of preexisting somatic mutations in the normal esophagus, including druggable mutants that confer treatment resilience to normal cells.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 10","pages":"2566-2578"},"PeriodicalIF":25.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-026-02738-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148932675","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":"Cancer treatment alters the selection of pre-existing somatic mutations in normal esophagus","authors":"","doi":"10.1038/s41588-026-02740-6","DOIUrl":"10.1038/s41588-026-02740-6","url":null,"abstract":"Short duration chemotherapy and/or radiation therapy before surgery selected mutations in DNA damage response, human leukocyte antigen and kinase genes in normal esophageal epithelium, despite leaving no detectable mutational signatures in the tissue. Thus, sequencing normal tissue from treated patients with cancer could identify genes and pathways conferring resistance to treatment.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 10","pages":"2429-2430"},"PeriodicalIF":25.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148955721","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}