Pub Date : 2026-03-13DOI: 10.1038/s41588-026-02557-3
Safia Danovi
{"title":"Mutations and selection in normal tissues after cancer treatment","authors":"Safia Danovi","doi":"10.1038/s41588-026-02557-3","DOIUrl":"10.1038/s41588-026-02557-3","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 3","pages":"472-472"},"PeriodicalIF":29.0,"publicationDate":"2026-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147441955","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}
Although nitrogen fertilizer use has boosted crop yields, excessive application diminishes crop nitrogen use efficiency (NUE) and causes environmental problems. Therefore, increasing crop NUE is urgently needed for agricultural sustainability. Through a genome-wide association study, we identified a locus, NCR1 (Nitrate Concentration Regulator 1), that correlates with nitrate concentrations in maize root xylem. NCR1 encodes a MYB transcription factor that positively regulates the transcription of nitrate transporter NRT2.3 expressed predominantly in root xylem parenchyma cells. The NCR1–NRT2.3 transcription module responds to external nitrogen and controls nitrate translocation from roots to shoots. The superior NCR1−In allele with a 123-bp promoter deletion has decreased in frequency as nitrogen fertilizer use in China has increased. Overexpression of NCR1 or NRT2.3, or introgression of NCR1−In, increases grain yield and nitrogen content in the shoot and seed. This study uncovers a crucial genetic module for improving grain yield and NUE in maize. NCR1 (nitrate concentration regulator 1) promotes root-to-shoot nitrate transport by regulating the transcription of nitrate transporter NRT2.3, thereby contributing to grain yield in maize.
{"title":"A genetic module boosts grain yield and nitrogen use efficiency by improving nitrate transport in maize","authors":"Meiling Zhang, Ziqi Wu, Liangliang Huang, Xiaomeng Shen, Kangqi Wang, Yingying Hu, Burebiyanmu Wubulikasimu, Yizhou Qin, Junzheng Fu, Ziwei Luo, Bo Yang, Xiaoming Zhao, Xiqing Wang, Feng Qin, Chao Bian, Haiming Zhao, Jian Chen, Weibin Song, Yi Wang, Jinsheng Lai","doi":"10.1038/s41588-026-02532-y","DOIUrl":"10.1038/s41588-026-02532-y","url":null,"abstract":"Although nitrogen fertilizer use has boosted crop yields, excessive application diminishes crop nitrogen use efficiency (NUE) and causes environmental problems. Therefore, increasing crop NUE is urgently needed for agricultural sustainability. Through a genome-wide association study, we identified a locus, NCR1 (Nitrate Concentration Regulator 1), that correlates with nitrate concentrations in maize root xylem. NCR1 encodes a MYB transcription factor that positively regulates the transcription of nitrate transporter NRT2.3 expressed predominantly in root xylem parenchyma cells. The NCR1–NRT2.3 transcription module responds to external nitrogen and controls nitrate translocation from roots to shoots. The superior NCR1−In allele with a 123-bp promoter deletion has decreased in frequency as nitrogen fertilizer use in China has increased. Overexpression of NCR1 or NRT2.3, or introgression of NCR1−In, increases grain yield and nitrogen content in the shoot and seed. This study uncovers a crucial genetic module for improving grain yield and NUE in maize. NCR1 (nitrate concentration regulator 1) promotes root-to-shoot nitrate transport by regulating the transcription of nitrate transporter NRT2.3, thereby contributing to grain yield in maize.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 3","pages":"618-629"},"PeriodicalIF":29.0,"publicationDate":"2026-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147441951","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 : 2026-03-12DOI: 10.1038/s41588-026-02537-7
Wouter De Coster, Marleen Van den Broeck, Matt Baker, Nikhil B. Ghayal, Sarah Wynants, Anthony Batzler, Cyril Pottier, Sara Alidadiani, Fahri Küçükali, Gregory D. Jenkins, Rafaela Policarpo, Marka van Blitterswijk, Mariely DeJesus-Hernandez, Alexandra I. Soto-Beasley, Júlia Faura, Elise Coopman, Saskia Hutten, Merel O. Mol, David Wallon, Anne Sieben, Elizabeth C. Finger, Melissa E. Murray, Shelley L. Forrest, Maria C. Tartaglia, Claire Troakes, Jeroen G. J. van Rooij, Aivi T. Nguyen, R. Ross Reichard, Natalie L. Woodman, Alissa L. Nana, Sandra Weintraub, Tamar Gefen, Bart De Vil, Istvan Bodi, Oscar L. Lopez, Susana Boluda, Serge Belliard, Florence Lebert, Florent Marguet, Qinwen Mao, Marsel M. Mesulam, Adam L. Boxer, Mathieu Vandenbulcke, EunRan Suh, Jolien Schaeverbeke, Jean-Charles Lambert, Sonja W. Scholz, Clifton L. Dalgard, Bryan J. Traynor, Raphael J. Gibbs, Gerard D. Schellenberg
Atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions (aFTLD-U) is neuropathologically characterized by aggregation of the FET family of proteins and clinically manifests as sporadic young-onset frontotemporal dementia. Here we describe a major risk locus on chr15q14 identified through a genome-wide association study in 59 pathologically confirmed aFTLD-U cases and 3,153 controls (lead single nucleotide polymorphism rs549846383, P = 5.85 × 10−21, odds ratio 26.7). When combined with data from 28 additional aFTLD-U cases, 3,712 controls and 3,215 individuals with other neurodegenerative diseases and by leveraging in-house and public long-read genome sequencing data from 1,715 individuals, we identified a tandem repeat expansion on the associated haplotypes in an intron of GOLGA8A. We found variation in repeat length, motif length, and motif sequence, with long CT-dimer expansions strongly associated with aFTLD-U. Although the functional consequence of this repeat remains unknown, its presence in nearly 60% of aFTLD-U cases points to a fundamental role in disease pathogenesis.
非典型额颞叶变性伴泛素阳性包涵体（aFTLD-U）是一种以FET家族蛋白聚集为神经病理学特征的疾病，临床表现为散发性年轻发病额颞叶痴呆。通过对59例病理证实的aFTLD-U病例和3153例对照进行全基因组关联研究，我们描述了chr15q14上的一个主要风险位点（先导单核苷酸多态性rs549846383， P = 5.85 × 10−21，优势比26.7）。结合另外28例aFTLD-U病例、3,712例对照和3,215例其他神经退行性疾病患者的数据，并利用内部和公开的1,715例个体的长读基因组测序数据，我们确定了GOLGA8A内含子中相关单倍型的串联重复扩增。我们发现重复长度、基序长度和基序序列存在差异，长ct二聚体扩增与aFTLD-U密切相关。虽然这种重复的功能后果尚不清楚，但它在近60%的aFTLD-U病例中存在，表明它在疾病发病机制中起着根本作用。
{"title":"A repeat expansion in GOLGA8A is a major risk factor for atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions","authors":"Wouter De Coster, Marleen Van den Broeck, Matt Baker, Nikhil B. Ghayal, Sarah Wynants, Anthony Batzler, Cyril Pottier, Sara Alidadiani, Fahri Küçükali, Gregory D. Jenkins, Rafaela Policarpo, Marka van Blitterswijk, Mariely DeJesus-Hernandez, Alexandra I. Soto-Beasley, Júlia Faura, Elise Coopman, Saskia Hutten, Merel O. Mol, David Wallon, Anne Sieben, Elizabeth C. Finger, Melissa E. Murray, Shelley L. Forrest, Maria C. Tartaglia, Claire Troakes, Jeroen G. J. van Rooij, Aivi T. Nguyen, R. Ross Reichard, Natalie L. Woodman, Alissa L. Nana, Sandra Weintraub, Tamar Gefen, Bart De Vil, Istvan Bodi, Oscar L. Lopez, Susana Boluda, Serge Belliard, Florence Lebert, Florent Marguet, Qinwen Mao, Marsel M. Mesulam, Adam L. Boxer, Mathieu Vandenbulcke, EunRan Suh, Jolien Schaeverbeke, Jean-Charles Lambert, Sonja W. Scholz, Clifton L. Dalgard, Bryan J. Traynor, Raphael J. Gibbs, Gerard D. Schellenberg","doi":"10.1038/s41588-026-02537-7","DOIUrl":"https://doi.org/10.1038/s41588-026-02537-7","url":null,"abstract":"Atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions (aFTLD-U) is neuropathologically characterized by aggregation of the FET family of proteins and clinically manifests as sporadic young-onset frontotemporal dementia. Here we describe a major risk locus on chr15q14 identified through a genome-wide association study in 59 pathologically confirmed aFTLD-U cases and 3,153 controls (lead single nucleotide polymorphism rs549846383, P = 5.85 × 10−21, odds ratio 26.7). When combined with data from 28 additional aFTLD-U cases, 3,712 controls and 3,215 individuals with other neurodegenerative diseases and by leveraging in-house and public long-read genome sequencing data from 1,715 individuals, we identified a tandem repeat expansion on the associated haplotypes in an intron of GOLGA8A. We found variation in repeat length, motif length, and motif sequence, with long CT-dimer expansions strongly associated with aFTLD-U. Although the functional consequence of this repeat remains unknown, its presence in nearly 60% of aFTLD-U cases points to a fundamental role in disease pathogenesis.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"1 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2026-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147394047","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 : 2026-03-11DOI: 10.1038/s41588-026-02526-w
Irenaeus C. C. Chan, Pu Zhang, Xiangyu Pan, Cynthia Castro, Nina Fox, Alexander M. Lewis, Kenyon Weis, Adriana Cuibus, Steven Tittley, Giulia Petrone, J. Scott Beeler, Duc Tran, Griffen Mustion, Catrina Fronick, Konrad H. Stopsack, Carlos Cruchaga, Omar Abdel-Wahab, Kelly L. Bolton
Therapy-related myeloid neoplasm (tMN) is a fatal consequence of exposure to cytotoxic therapy administered in the treatment of cancer. Individuals with pre-existing TP53 clonal hematopoiesis (CH) are at high risk of tMN, with avoidance of therapy being the only strategy to reduce tMN risk. Here, in four randomized clinical trials, we show that the CDK4/6 inhibitor trilaciclib, given in conjunction with a variety of chemotherapeutic regimens and across diverse populations of patients with cancer, mitigates chemotherapy-related expansion of CH clones with mutations in DNA damage response genes, including TP53. This finding was also observed in a syngeneic mouse model of TP53-mutant CH, demonstrating that CDK4/6 inhibition blocks platinum-induced TP53 competitive repopulation through promoting hematopoietic stem and progenitor quiescence and decreasing the stemness advantage of TP53-mutant clones. This represents a proof of concept for a potential pharmacologic strategy to block chemotherapy-induced expansion of preleukemic TP53-mutant clones. Analysis of clinical trial data suggests that CDK4/6 inhibitors prevent the expansion of TP53-mutant clones in the blood, potentially mitigating the risk of secondary myeloid neoplasms in patients treated with cytotoxic drugs.
{"title":"CDK4/6 inhibition mitigates chemotherapy-induced expansion of TP53-mutant clonal hematopoiesis","authors":"Irenaeus C. C. Chan, Pu Zhang, Xiangyu Pan, Cynthia Castro, Nina Fox, Alexander M. Lewis, Kenyon Weis, Adriana Cuibus, Steven Tittley, Giulia Petrone, J. Scott Beeler, Duc Tran, Griffen Mustion, Catrina Fronick, Konrad H. Stopsack, Carlos Cruchaga, Omar Abdel-Wahab, Kelly L. Bolton","doi":"10.1038/s41588-026-02526-w","DOIUrl":"10.1038/s41588-026-02526-w","url":null,"abstract":"Therapy-related myeloid neoplasm (tMN) is a fatal consequence of exposure to cytotoxic therapy administered in the treatment of cancer. Individuals with pre-existing TP53 clonal hematopoiesis (CH) are at high risk of tMN, with avoidance of therapy being the only strategy to reduce tMN risk. Here, in four randomized clinical trials, we show that the CDK4/6 inhibitor trilaciclib, given in conjunction with a variety of chemotherapeutic regimens and across diverse populations of patients with cancer, mitigates chemotherapy-related expansion of CH clones with mutations in DNA damage response genes, including TP53. This finding was also observed in a syngeneic mouse model of TP53-mutant CH, demonstrating that CDK4/6 inhibition blocks platinum-induced TP53 competitive repopulation through promoting hematopoietic stem and progenitor quiescence and decreasing the stemness advantage of TP53-mutant clones. This represents a proof of concept for a potential pharmacologic strategy to block chemotherapy-induced expansion of preleukemic TP53-mutant clones. Analysis of clinical trial data suggests that CDK4/6 inhibitors prevent the expansion of TP53-mutant clones in the blood, potentially mitigating the risk of secondary myeloid neoplasms in patients treated with cytotoxic drugs.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 3","pages":"582-592"},"PeriodicalIF":29.0,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-026-02526-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147393748","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 : 2026-03-11DOI: 10.1038/s41588-026-02525-x
The development of therapy-related myeloid neoplasms is a dangerous complication of cancer-directed therapy and is driven by the selection of hematopoietic cells with mutations in genes involved in the DNA damage response pathway. We show that short-term CDK4/6 inhibition mitigates clonal expansion of TP53-mutant hematopoietic cells during cytotoxic chemotherapy.
{"title":"Curbing the risk of therapy-related myeloid neoplasms","authors":"","doi":"10.1038/s41588-026-02525-x","DOIUrl":"10.1038/s41588-026-02525-x","url":null,"abstract":"The development of therapy-related myeloid neoplasms is a dangerous complication of cancer-directed therapy and is driven by the selection of hematopoietic cells with mutations in genes involved in the DNA damage response pathway. We show that short-term CDK4/6 inhibition mitigates clonal expansion of TP53-mutant hematopoietic cells during cytotoxic chemotherapy.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 3","pages":"477-478"},"PeriodicalIF":29.0,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147393749","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 : 2026-03-11DOI: 10.1038/s41588-026-02536-8
Martin Fischer, Steve Hoffmann
The transcriptional interference model suggests that RNA polymerases elongating through overlapping transcription units mutually inhibit transcription and disrupt associated cis-regulatory elements. As a longstanding fundamental concept of gene regulation, the idea of reciprocal inhibition between sense and antisense transcription has been supported by a significant body of research. However, despite the model's biophysical plausibility and historical significance, evidence from large-scale transcriptome studies raises questions about its universal applicability. In particular, the new data indicate that a measurable influence of transcriptional interference is absent from the majority of loci with overlapping transcription. Here we highlight key aspects of overlapping transcription and propose potential solutions to this emerging puzzle. Gaining a better understanding of the molecular mechanisms that render loci sensitive or resistant to interference could lead to groundbreaking insights into the biology of gene regulation.
{"title":"Transcriptional interference revisited.","authors":"Martin Fischer, Steve Hoffmann","doi":"10.1038/s41588-026-02536-8","DOIUrl":"https://doi.org/10.1038/s41588-026-02536-8","url":null,"abstract":"<p><p>The transcriptional interference model suggests that RNA polymerases elongating through overlapping transcription units mutually inhibit transcription and disrupt associated cis-regulatory elements. As a longstanding fundamental concept of gene regulation, the idea of reciprocal inhibition between sense and antisense transcription has been supported by a significant body of research. However, despite the model's biophysical plausibility and historical significance, evidence from large-scale transcriptome studies raises questions about its universal applicability. In particular, the new data indicate that a measurable influence of transcriptional interference is absent from the majority of loci with overlapping transcription. Here we highlight key aspects of overlapping transcription and propose potential solutions to this emerging puzzle. Gaining a better understanding of the molecular mechanisms that render loci sensitive or resistant to interference could lead to groundbreaking insights into the biology of gene regulation.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":" ","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147434389","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 : 2026-03-10DOI: 10.1038/s41588-026-02538-6
Songbo Wang, Tun Xu, Pengyu Zhang, Kai Ye
Population-level structural variant (SV) profiling is crucial in the era of pangenomes. However, identifying SVs from genome assemblies and pangenome graphs remains a substantial challenge. Here we present Swave, a sequence-to-image, deep learning-based method that accurately resolves both simple and complex SVs, along with their population characteristics, from assembly-derived pangenome graphs. Swave introduces ‘projection waves’ to summarize the dotplot images that capture mapping patterns between reference and SV-indicating alleles in the pangenome. Then, a recurrent neural network distinguishes true SV signals from background noise introduced by genomic repeats. Swave demonstrates superior performance in both SV-type classification and genotyping compared with existing methods. When applied to healthy cohorts and rare-disease cohorts, Swave reveals complex and polymorphic SV patterns across human populations and identifies potentially pathogenic SVs. These advancements will facilitate the creation of comprehensive population-level SV catalogs, deepening our understanding of SVs in genetic diversity and disease associations. Swave is a method to call structural variants from pangenome graphs using a recurrent neural network to identify structural variant patterns, including complex structural variants.
{"title":"Population-level structural variant characterization using pangenome graphs","authors":"Songbo Wang, Tun Xu, Pengyu Zhang, Kai Ye","doi":"10.1038/s41588-026-02538-6","DOIUrl":"10.1038/s41588-026-02538-6","url":null,"abstract":"Population-level structural variant (SV) profiling is crucial in the era of pangenomes. However, identifying SVs from genome assemblies and pangenome graphs remains a substantial challenge. Here we present Swave, a sequence-to-image, deep learning-based method that accurately resolves both simple and complex SVs, along with their population characteristics, from assembly-derived pangenome graphs. Swave introduces ‘projection waves’ to summarize the dotplot images that capture mapping patterns between reference and SV-indicating alleles in the pangenome. Then, a recurrent neural network distinguishes true SV signals from background noise introduced by genomic repeats. Swave demonstrates superior performance in both SV-type classification and genotyping compared with existing methods. When applied to healthy cohorts and rare-disease cohorts, Swave reveals complex and polymorphic SV patterns across human populations and identifies potentially pathogenic SVs. These advancements will facilitate the creation of comprehensive population-level SV catalogs, deepening our understanding of SVs in genetic diversity and disease associations. Swave is a method to call structural variants from pangenome graphs using a recurrent neural network to identify structural variant patterns, including complex structural variants.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 3","pages":"664-672"},"PeriodicalIF":29.0,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147381753","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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