Pub Date : 2025-12-04DOI: 10.1038/s41588-025-02423-8
Jonathan E. LoTempio Jr, Christopher R. Donohue, Jonathan D. Moreno, Ana Santos Rutschman, Joshua Sarnoff, Michael S. Sinha, Thomas Stoeger, Jorge L. Contreras
The bankruptcy of 23andMe was an inflection point for the direct-to-consumer genetics market. Although the privacy of consumer data has been highlighted by many as a concern, we discuss another key tension in this case: the corporate enclosure of scientific data that has considerable potential value for biomedical research and public health.
{"title":"Impact of the 23andMe bankruptcy on preserving the public benefit of scientific data","authors":"Jonathan E. LoTempio Jr, Christopher R. Donohue, Jonathan D. Moreno, Ana Santos Rutschman, Joshua Sarnoff, Michael S. Sinha, Thomas Stoeger, Jorge L. Contreras","doi":"10.1038/s41588-025-02423-8","DOIUrl":"10.1038/s41588-025-02423-8","url":null,"abstract":"The bankruptcy of 23andMe was an inflection point for the direct-to-consumer genetics market. Although the privacy of consumer data has been highlighted by many as a concern, we discuss another key tension in this case: the corporate enclosure of scientific data that has considerable potential value for biomedical research and public health.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 12","pages":"2933-2936"},"PeriodicalIF":29.0,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664519","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}
Pub Date : 2025-12-03DOI: 10.1038/s41588-025-02430-9
Tao Sun, Qin Li, Jonathan M. Geisinger, Shi-Bin Hu, Boming Fan, Shichen Su, Waitang Tsui, Hongchao Guo, Jinbiao Ma, Jin Billy Li
Endogenous long double-stranded RNAs (dsRNAs), which are not edited by the RNA editing enzyme ADAR1, may activate the antiviral dsRNA receptor MDA5 to trigger interferon-mediated immune responses. Among the large number of endogenous long dsRNAs, the key substrates that activate MDA5—termed as immunogenic dsRNAs—remain largely unidentified. Here we reveal that human immunogenic dsRNAs constitute a surprisingly small fraction of all cellular dsRNAs. We found that these immunogenic dsRNAs were highly enriched in mRNAs and depleted of introns, consistent with their role as cytosolic MDA5 substrates. We validated the MDA5-dependent immunogenicity of these dsRNAs, which was dampened following ADAR1-mediated RNA editing. Notably, immunogenic dsRNAs were enriched at genetic susceptibility loci associated with common inflammatory diseases, implying their functional importance. We anticipate that a focused analysis of immunogenic dsRNAs will enhance our understanding and treatment of cancer and inflammatory diseases, where the roles of dsRNA editing and sensing are increasingly recognized. The authors show that only a small subset of cytosolic double-stranded RNAs (dsRNAs) requires ADAR1-mediated RNA editing to evade an MDA5-dependent immune response. These immunogenic dsRNAs are enriched in mRNAs and overlap with GWAS signals for common inflammatory diseases.
{"title":"ADAR1 editing is necessary for only a small subset of cytosolic dsRNAs to evade MDA5-mediated autoimmunity","authors":"Tao Sun, Qin Li, Jonathan M. Geisinger, Shi-Bin Hu, Boming Fan, Shichen Su, Waitang Tsui, Hongchao Guo, Jinbiao Ma, Jin Billy Li","doi":"10.1038/s41588-025-02430-9","DOIUrl":"10.1038/s41588-025-02430-9","url":null,"abstract":"Endogenous long double-stranded RNAs (dsRNAs), which are not edited by the RNA editing enzyme ADAR1, may activate the antiviral dsRNA receptor MDA5 to trigger interferon-mediated immune responses. Among the large number of endogenous long dsRNAs, the key substrates that activate MDA5—termed as immunogenic dsRNAs—remain largely unidentified. Here we reveal that human immunogenic dsRNAs constitute a surprisingly small fraction of all cellular dsRNAs. We found that these immunogenic dsRNAs were highly enriched in mRNAs and depleted of introns, consistent with their role as cytosolic MDA5 substrates. We validated the MDA5-dependent immunogenicity of these dsRNAs, which was dampened following ADAR1-mediated RNA editing. Notably, immunogenic dsRNAs were enriched at genetic susceptibility loci associated with common inflammatory diseases, implying their functional importance. We anticipate that a focused analysis of immunogenic dsRNAs will enhance our understanding and treatment of cancer and inflammatory diseases, where the roles of dsRNA editing and sensing are increasingly recognized. The authors show that only a small subset of cytosolic double-stranded RNAs (dsRNAs) requires ADAR1-mediated RNA editing to evade an MDA5-dependent immune response. These immunogenic dsRNAs are enriched in mRNAs and overlap with GWAS signals for common inflammatory diseases.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 12","pages":"3101-3111"},"PeriodicalIF":29.0,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-025-02430-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664346","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}
Pub Date : 2025-11-28DOI: 10.1038/s41588-025-02464-z
David S. M. Lee, Kathleen M. Cardone, David Y. Zhang, Noah L. Tsao, Sarah Abramowitz, Pranav Sharma, John S. DePaolo, Mitchell Conery, Krishna G. Aragam, Kiran Biddinger, Ozan Dikilitas, Lily Hoffman-Andrews, Renae L. Judy, Atlas Khan, Iftikhar J. Kullo, Megan J. Puckelwartz, Nosheen Reza, Benjamin A. Satterfield, Pankhuri Singhal, Penn Medicine Biobank, Zoltan Arany, Thomas P. Cappola, Eric D. Carruth, Sharlene M. Day, Ron Do, Christopher M. Haggerty, Jacob Joseph, Elizabeth M. McNally, Girish Nadkarni, Anjali T. Owens, Daniel J. Rader, Marylyn D. Ritchie, Yan V. Sun, Benjamin F. Voight, Michael G. Levin, Scott M. Damrauer
{"title":"Author Correction: Common-variant and rare-variant genetic architecture of heart failure across the allele-frequency spectrum","authors":"David S. M. Lee, Kathleen M. Cardone, David Y. Zhang, Noah L. Tsao, Sarah Abramowitz, Pranav Sharma, John S. DePaolo, Mitchell Conery, Krishna G. Aragam, Kiran Biddinger, Ozan Dikilitas, Lily Hoffman-Andrews, Renae L. Judy, Atlas Khan, Iftikhar J. Kullo, Megan J. Puckelwartz, Nosheen Reza, Benjamin A. Satterfield, Pankhuri Singhal, Penn Medicine Biobank, Zoltan Arany, Thomas P. Cappola, Eric D. Carruth, Sharlene M. Day, Ron Do, Christopher M. Haggerty, Jacob Joseph, Elizabeth M. McNally, Girish Nadkarni, Anjali T. Owens, Daniel J. Rader, Marylyn D. Ritchie, Yan V. Sun, Benjamin F. Voight, Michael G. Levin, Scott M. Damrauer","doi":"10.1038/s41588-025-02464-z","DOIUrl":"10.1038/s41588-025-02464-z","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 12","pages":"3201-3201"},"PeriodicalIF":29.0,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-025-02464-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145635672","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}
Pub Date : 2025-11-27DOI: 10.1038/s41588-025-02418-5
Sukanya Panja, Padmaja Mantri, Kofi Ennu Johnson, Juan Sebastian Andrade-Martinez, Soo-Ryum Yang, Aditya Deshpande, Huasong Tian, Shaham Beg, Kentaro Ohara, Alessandro Leal, Joel Rosiene, Marlon Stoeckius, Peter Smibert, William D. Travis, Juan Miguel Mosquera, Paz Polak, Marcin Imieliński
DNA damage is preferentially repaired in expressed genes; thus, genome-wide correlations between somatic mutation patterns and normal cell transcription may reflect tumor cell origins. Accordingly, we found that aggregate lung adenocarcinoma (LUAD) and squamous cancer (LUSC) somatic mutation density associated most strongly with distal (alveolar) and proximal (basal) lung cell-type-specific gene expression, respectively, consistent with presumed LUAD and LUSC cell origins. Analyzing individual genomes, 21% of LUADs bore mutational footprints of proximal airway origins, with 38% classified as ambiguous. Distal origin LUADs, enriched for KRAS and STK11 drivers, occurred mainly in smokers; proximal origin LUADs, enriched for EGFR drivers, were more common in never-smokers. Ambiguous origin LUADs showed APOBEC signatures and SMARCA4 alterations. TP53 mutant LUADs with non-distal cell origins preferentially exhibited non-distal transcriptional identity. Our study reveals a complex interplay between lineage and identity in LUAD evolution and offers a scalable strategy to infer tumor origins in human cancers. This study shows how the links between somatic passenger mutations in tumors and normal cell transcriptomes can be used to infer cell-of-origin in lung adenocarcinoma.
{"title":"Passenger mutations link cellular origin and transcriptional identity in human lung adenocarcinomas","authors":"Sukanya Panja, Padmaja Mantri, Kofi Ennu Johnson, Juan Sebastian Andrade-Martinez, Soo-Ryum Yang, Aditya Deshpande, Huasong Tian, Shaham Beg, Kentaro Ohara, Alessandro Leal, Joel Rosiene, Marlon Stoeckius, Peter Smibert, William D. Travis, Juan Miguel Mosquera, Paz Polak, Marcin Imieliński","doi":"10.1038/s41588-025-02418-5","DOIUrl":"10.1038/s41588-025-02418-5","url":null,"abstract":"DNA damage is preferentially repaired in expressed genes; thus, genome-wide correlations between somatic mutation patterns and normal cell transcription may reflect tumor cell origins. Accordingly, we found that aggregate lung adenocarcinoma (LUAD) and squamous cancer (LUSC) somatic mutation density associated most strongly with distal (alveolar) and proximal (basal) lung cell-type-specific gene expression, respectively, consistent with presumed LUAD and LUSC cell origins. Analyzing individual genomes, 21% of LUADs bore mutational footprints of proximal airway origins, with 38% classified as ambiguous. Distal origin LUADs, enriched for KRAS and STK11 drivers, occurred mainly in smokers; proximal origin LUADs, enriched for EGFR drivers, were more common in never-smokers. Ambiguous origin LUADs showed APOBEC signatures and SMARCA4 alterations. TP53 mutant LUADs with non-distal cell origins preferentially exhibited non-distal transcriptional identity. Our study reveals a complex interplay between lineage and identity in LUAD evolution and offers a scalable strategy to infer tumor origins in human cancers. This study shows how the links between somatic passenger mutations in tumors and normal cell transcriptomes can be used to infer cell-of-origin in lung adenocarcinoma.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 12","pages":"3066-3074"},"PeriodicalIF":29.0,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145609476","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}
Pub Date : 2025-11-27DOI: 10.1038/s41588-025-02414-9
Guido Barzaghi, Aristotelis Tsirigos
A study using single-cell 3D genome mapping reveals phenotypic convergence during mouse Kras-driven lung adenocarcinoma progression and prioritizes clinically actionable driver genes. This highlights the importance of cell-to-cell variation in chromatin architecture as a determinant of cancer evolution.
{"title":"Single-cell 3D architecture maps the drivers of lung adenocarcinoma","authors":"Guido Barzaghi, Aristotelis Tsirigos","doi":"10.1038/s41588-025-02414-9","DOIUrl":"10.1038/s41588-025-02414-9","url":null,"abstract":"A study using single-cell 3D genome mapping reveals phenotypic convergence during mouse Kras-driven lung adenocarcinoma progression and prioritizes clinically actionable driver genes. This highlights the importance of cell-to-cell variation in chromatin architecture as a determinant of cancer evolution.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 12","pages":"2948-2949"},"PeriodicalIF":29.0,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145609477","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}
Pub Date : 2025-11-27DOI: 10.1038/s41588-025-02413-w
Karsten Suhre, Qingwen Chen, Anna Halama, Kevin Mendez, Amber Dahlin, Nisha Stephan, Gaurav Thareja, Hina Sarwath, Harendra Guturu, Varun B. Dwaraka, Ryan Smith, Serafim Batzoglou, Frank Schmidt, Jessica A. Lasky-Su
Most studies to date of protein quantitative trait loci (pQTLs) have relied on affinity proteomics platforms, which provide only limited information about the targeted protein isoforms and may be affected by genetic variation in their epitope binding. Here we show that mass spectrometry (MS)-based proteomics can complement these studies and provide insights into the role of specific protein isoform and epitope-altering variants. Using the Seer Proteograph nanoparticle enrichment MS platform, we identified and replicated new pQTLs in a genome-wide association study of proteins in blood plasma samples from two cohorts and evaluated previously reported pQTLs from affinity proteomics platforms. We found that >30% of the evaluated pQTLs were confirmed by MS proteomics to be consistent with the hypothesis that genetic variants induce changes in protein abundance, whereas another 30% could not be replicated and are possibly due to epitope effects, although alternative explanations for nonreplication need to be considered on a case-by-case basis. Genome-wide association analyses of blood plasma samples using a mass spectrometry-based platform illustrate the complementarity of different proteomics approaches for identifying protein quantitative trait loci.
{"title":"A genome-wide association study of mass spectrometry proteomics using a nanoparticle enrichment platform","authors":"Karsten Suhre, Qingwen Chen, Anna Halama, Kevin Mendez, Amber Dahlin, Nisha Stephan, Gaurav Thareja, Hina Sarwath, Harendra Guturu, Varun B. Dwaraka, Ryan Smith, Serafim Batzoglou, Frank Schmidt, Jessica A. Lasky-Su","doi":"10.1038/s41588-025-02413-w","DOIUrl":"10.1038/s41588-025-02413-w","url":null,"abstract":"Most studies to date of protein quantitative trait loci (pQTLs) have relied on affinity proteomics platforms, which provide only limited information about the targeted protein isoforms and may be affected by genetic variation in their epitope binding. Here we show that mass spectrometry (MS)-based proteomics can complement these studies and provide insights into the role of specific protein isoform and epitope-altering variants. Using the Seer Proteograph nanoparticle enrichment MS platform, we identified and replicated new pQTLs in a genome-wide association study of proteins in blood plasma samples from two cohorts and evaluated previously reported pQTLs from affinity proteomics platforms. We found that >30% of the evaluated pQTLs were confirmed by MS proteomics to be consistent with the hypothesis that genetic variants induce changes in protein abundance, whereas another 30% could not be replicated and are possibly due to epitope effects, although alternative explanations for nonreplication need to be considered on a case-by-case basis. Genome-wide association analyses of blood plasma samples using a mass spectrometry-based platform illustrate the complementarity of different proteomics approaches for identifying protein quantitative trait loci.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 12","pages":"2987-2996"},"PeriodicalIF":29.0,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-025-02413-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145609479","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}
Pub Date : 2025-11-25DOI: 10.1038/s41588-025-02452-3
Vincent J. Straub, Stefania Benonisdottir, Augustine Kong, Melinda C. Mills
{"title":"Publisher Correction: Realizing the full potential of Our Future Health through data linkage and trans-biobank efforts","authors":"Vincent J. Straub, Stefania Benonisdottir, Augustine Kong, Melinda C. Mills","doi":"10.1038/s41588-025-02452-3","DOIUrl":"10.1038/s41588-025-02452-3","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 12","pages":"3201-3201"},"PeriodicalIF":29.0,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-025-02452-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145593501","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}
Pub Date : 2025-11-25DOI: 10.1038/s41588-025-02427-4
Robbee Wedow
Creative use of informed statistical genetics methods combined with large-scale genomic data has delivered insights about sorting into educational fields. This study has wide-ranging implications for geneticists, sociogenomicists and social scientists for what can be learned about society within genetic data.
{"title":"Exploring educational field sorting using genetics","authors":"Robbee Wedow","doi":"10.1038/s41588-025-02427-4","DOIUrl":"10.1038/s41588-025-02427-4","url":null,"abstract":"Creative use of informed statistical genetics methods combined with large-scale genomic data has delivered insights about sorting into educational fields. This study has wide-ranging implications for geneticists, sociogenomicists and social scientists for what can be learned about society within genetic data.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 12","pages":"2946-2947"},"PeriodicalIF":29.0,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145593500","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}
Pub Date : 2025-11-25DOI: 10.1038/s41588-025-02425-6
The long-term contribution of human hematopoietic stem cell (HSC) clones to different blood lineages needs to be assessed under steady-state conditions over time. Using retrospective phylogenetic analysis and prospective clonal mutational tracing of all major blood lineages, we show that some HSC clones contribute stably to all lineages, while others show stable, intrinsically programmed lineage restriction.
{"title":"Stable, intrinsically programmed lineage restriction of human hematopoietic stem cells","authors":"","doi":"10.1038/s41588-025-02425-6","DOIUrl":"10.1038/s41588-025-02425-6","url":null,"abstract":"The long-term contribution of human hematopoietic stem cell (HSC) clones to different blood lineages needs to be assessed under steady-state conditions over time. Using retrospective phylogenetic analysis and prospective clonal mutational tracing of all major blood lineages, we show that some HSC clones contribute stably to all lineages, while others show stable, intrinsically programmed lineage restriction.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 12","pages":"2958-2959"},"PeriodicalIF":29.0,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145599448","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}
Pub Date : 2025-11-24DOI: 10.1038/s41588-025-02428-3
Ariella Angelini Stewart, Rebecca C. Ahrens-Nicklas, Shengdar Q. Tsai, Kiran Musunuru, Petros Giannikopoulos, Claire D. Clelland
CRISPR genetic therapies are revolutionizing the landscape of preclinical research and clinical studies, providing new potential routes for curative intervention for a range of previously untreatable diseases. As with any therapy, the therapeutic benefits and risks must be weighed against consideration of the disease threat. Genome-related adverse events are an inherent risk of CRISPR genetic therapies, including off-target edits. The perception that CRISPR therapies ought to have near-zero off-targets belies clinical medicine, therapy development and biology, which demonstrate that ‘perfect’ therapeutics do not exist. Given that not all genomic off-target events are equal, we provide a practical framework to evaluate and assess off-target safety based on the tools available today and ones that will be developed in the future. With the comprehensive information and assessment gathered using these guidelines, we aim to streamline the transition of CRISPR therapeutics from bench to bedside. This Perspective provides a practical and clinically relevant framework rooted in benefit–risk analyses to evaluate genomic CRISPR off-targets. Such an approach is applicable to currently available as well as future technologies.
{"title":"Measurement and clinical interpretation of CRISPR off-targets","authors":"Ariella Angelini Stewart, Rebecca C. Ahrens-Nicklas, Shengdar Q. Tsai, Kiran Musunuru, Petros Giannikopoulos, Claire D. Clelland","doi":"10.1038/s41588-025-02428-3","DOIUrl":"10.1038/s41588-025-02428-3","url":null,"abstract":"CRISPR genetic therapies are revolutionizing the landscape of preclinical research and clinical studies, providing new potential routes for curative intervention for a range of previously untreatable diseases. As with any therapy, the therapeutic benefits and risks must be weighed against consideration of the disease threat. Genome-related adverse events are an inherent risk of CRISPR genetic therapies, including off-target edits. The perception that CRISPR therapies ought to have near-zero off-targets belies clinical medicine, therapy development and biology, which demonstrate that ‘perfect’ therapeutics do not exist. Given that not all genomic off-target events are equal, we provide a practical framework to evaluate and assess off-target safety based on the tools available today and ones that will be developed in the future. With the comprehensive information and assessment gathered using these guidelines, we aim to streamline the transition of CRISPR therapeutics from bench to bedside. This Perspective provides a practical and clinically relevant framework rooted in benefit–risk analyses to evaluate genomic CRISPR off-targets. Such an approach is applicable to currently available as well as future technologies.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 1","pages":"20-27"},"PeriodicalIF":29.0,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145583024","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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