Nature geneticsPub Date : 2025-08-06DOI: 10.1038/s41588-025-02288-x
Diogo M. Ribeiro, Robin J. Hofmeister, Simone Rubinacci, Olivier Delaneau
{"title":"Noncoding rare variant associations with blood traits in 166,740 UK Biobank genomes","authors":"Diogo M. Ribeiro, Robin J. Hofmeister, Simone Rubinacci, Olivier Delaneau","doi":"10.1038/s41588-025-02288-x","DOIUrl":"10.1038/s41588-025-02288-x","url":null,"abstract":"Large biobanks with whole-genome sequencing (WGS) now enable the association of noncoding rare variants with complex human traits. Given that >98% of the genome is available for exploration, the selection of noncoding variants remains a critical yet unresolved challenge in these analyses. Here we leverage knowledge of blood gene regulation and deleteriousness scores to select noncoding variants pertinent for association with blood-related traits. Integrating WGS and 42 blood cell count and biomarker measurements for 166,740 UK Biobank samples, we perform variant collapsing tests, identifying hundreds of gene–trait associations involving noncoding variants. However, we demonstrate that most of these noncoding rare variant associations (1) reproduce associations known from previous studies and (2) are driven by linkage disequilibrium between nearby common and rare variants. This study underscores the prevailing challenges in rare variant analysis and the need for caution when interpreting noncoding rare variant association results. Noncoding rare variant analyses using whole-genome sequencing data from the UK Biobank identify gene–trait associations for 42 blood cell traits but find that most signals are driven by linkage disequilibrium between common and rare variants.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 9","pages":"2146-2155"},"PeriodicalIF":29.0,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144786806","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}
Nature geneticsPub Date : 2025-08-06DOI: 10.1038/s41588-025-02284-1
Kaden M. Southard, Rico C. Ardy, Anran Tang, Deirdre D. O’Sullivan, Eli Metzner, Karthik Guruvayurappan, Thomas M. Norman
{"title":"Comprehensive transcription factor perturbations recapitulate fibroblast transcriptional states","authors":"Kaden M. Southard, Rico C. Ardy, Anran Tang, Deirdre D. O’Sullivan, Eli Metzner, Karthik Guruvayurappan, Thomas M. Norman","doi":"10.1038/s41588-025-02284-1","DOIUrl":"10.1038/s41588-025-02284-1","url":null,"abstract":"Cell atlas projects have revealed that common cell types often comprise distinct, recurrent transcriptional states, but the function and regulation of these states remain poorly understood. Here, we show that systematic activation of transcription factors can recreate such states in vitro, providing tractable models for mechanistic and functional studies. Using a scalable CRISPR activation (CRISPRa) Perturb-seq platform, we activated 1,836 transcription factors in two cell types. CRISPRa induced gene expression within physiological ranges, with chromatin features predicting responsiveness. Comparisons with atlas datasets showed that transcription factor perturbations recapitulated key fibroblast states and identified their regulators, including KLF2 and KLF4 for a universal state present in many tissues, and PLAGL1 for a disease-associated inflammatory state. Inducing the universal state suppressed the inflammatory state, suggesting therapeutic potential. These findings position CRISPRa as a nuanced tool for perturbing differentiated cells and establish a general strategy for studying clinically relevant transcriptional states ex vivo. CRISPR activation of 1,836 human transcription factors recapitulates fibroblast transcriptional states observed in vivo and identifies regulators that can revert inflammatory states.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 9","pages":"2323-2334"},"PeriodicalIF":29.0,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144786744","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}
Nature geneticsPub Date : 2025-08-06DOI: 10.1038/s41588-025-02273-4
Manyi Sun, Beibei Cao, Kui Li, Jiaming Li, Jun Liu, Cheng Xue, Kaidi Gu, Shaozhuo Xu, Yuanjun Li, Qingyu Li, Meina Qu, Mingyue Zhang, Runze Wang, Yueyuan Liu, Chenjie Yao, Hang He, Jun Wu
{"title":"Haplotype-resolved, gap-free genome assemblies provide insights into the divergence between Asian and European pears","authors":"Manyi Sun, Beibei Cao, Kui Li, Jiaming Li, Jun Liu, Cheng Xue, Kaidi Gu, Shaozhuo Xu, Yuanjun Li, Qingyu Li, Meina Qu, Mingyue Zhang, Runze Wang, Yueyuan Liu, Chenjie Yao, Hang He, Jun Wu","doi":"10.1038/s41588-025-02273-4","DOIUrl":"10.1038/s41588-025-02273-4","url":null,"abstract":"Pears (Pyrus spp.) are self-incompatible crops with broad genetic diversity. High heterozygosity and technical limitations result in gaps within reference genomes. Our study presents the telomere-to-telomere, haplotype-resolved genomes of a representative Asian pear ‘Dangshansuli’ (Pyrus bretschneideri) and a European pear ‘Max Red Bartlett’ (Pyrus communis). Haplotype-specific genes exhibited notable differences from biallelic genes regarding transposable content, methylation patterns and expression levels. Allele-specific expression analysis suggested that the dominance effect is vital in the formation of fruit quality of pears. Population analysis of 362 accessions revealed that interspecific introgression increased pear diversity. We constructed a graph-based genome and identified structural variations associated with agronomic traits. A 286-bp insertion in the promoter region, along with differential expression of PyACS1, was identified between Asian and European pears, which exhibit distinct fruit-softening characteristics. Further experiments demonstrated the role of PyACS1 in fruit softening. Overall, this study provided insights into genetic variation and will facilitate pear improvement. Haplotype-resolved, gap-free genome assemblies for a representative Asian pear (Pyrus bretschneideri, ‘Dangshansuli’) and a European pear (Pyrus communis, ‘Max Red Bartlett’) provide insights into genome evolution and interspecies variation in Pyrus species.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 8","pages":"2040-2051"},"PeriodicalIF":29.0,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-025-02273-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144786606","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}
Nature geneticsPub Date : 2025-08-05DOI: 10.1038/s41588-025-02249-4
Anjali Chawla, Doruk Cakmakci, Laura M. Fiori, Wenmin Zang, Malosree Maitra, Jennie Yang, Dariusz Żurawek, Gabriella Frosi, Reza Rahimian, Haruka Mitsuhashi, Maria Antonietta Davoli, Ryan Denniston, Gary Gang Chen, Volodymyr Yerko, Deborah Mash, Kiran Girdhar, Schahram Akbarian, Naguib Mechawar, Matthew Suderman, Yue Li, Corina Nagy, Gustavo Turecki
{"title":"Single-nucleus chromatin accessibility profiling identifies cell types and functional variants contributing to major depression","authors":"Anjali Chawla, Doruk Cakmakci, Laura M. Fiori, Wenmin Zang, Malosree Maitra, Jennie Yang, Dariusz Żurawek, Gabriella Frosi, Reza Rahimian, Haruka Mitsuhashi, Maria Antonietta Davoli, Ryan Denniston, Gary Gang Chen, Volodymyr Yerko, Deborah Mash, Kiran Girdhar, Schahram Akbarian, Naguib Mechawar, Matthew Suderman, Yue Li, Corina Nagy, Gustavo Turecki","doi":"10.1038/s41588-025-02249-4","DOIUrl":"10.1038/s41588-025-02249-4","url":null,"abstract":"Genetic variants associated with major depressive disorder (MDD) are enriched in the regulatory genome. Here, we investigate gene-regulatory mechanisms underlying MDD compared to neurotypical controls by combining single-cell chromatin accessibility with gene expression in over 200,000 cells from the dorsolateral prefrontal cortex of 84 individuals. MDD-associated alterations in chromatin accessibility were prominent in deep-layer excitatory neurons characterized by transcription factor (TF) motif accessibility and binding of NR4A2, an activity-dependent TF reactive to stress. The same neurons were enriched for MDD-associated genetic variants, disrupting TF binding sites linked to genes that likely affect synaptic communication. Furthermore, a gray matter microglia cluster exhibited decreased accessibility in individuals with MDD at binding sites bound by TFs known to regulate immune homeostasis. Finally, we identified gene-regulatory effects of MDD-risk variants using sequence-based accessibility predictions, donor-specific genotypes and cell-based assays. These findings shed light on the cell types and regulatory mechanisms through which genetic variation may increase the risk of MDD. Integration of snATAC-seq and snRNA-seq data from brains of individuals with major depressive disorder identifies chromatin accessibility alterations and functional enrichment of risk variants in deep-layer excitatory neurons. Gray matter microglia in these individuals show decreased accessibility at sites bound by regulators of immune homeostasis.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 8","pages":"1890-1904"},"PeriodicalIF":29.0,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144778612","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}
Nature geneticsPub Date : 2025-08-05DOI: 10.1038/s41588-025-02320-0
Gunes Gundem, Max F. Levine, Stephen S. Roberts, Irene Y. Cheung, Juan S. Medina-Martínez, Yi Feng, Juan E. Arango-Ossa, Loic Chadoutaud, Mathieu Rita, Georgios Asimomitis, Joe Zhou, Daoqi You, Nancy Bouvier, Barbara Spitzer, David B. Solit, Filemon Dela Cruz, Michael P. LaQuaglia, Brian H. Kushner, Shakeel Modak, Neerav Shukla, Christine A. Iacobuzio-Donahue, Andrew L. Kung, Nai-Kong V. Cheung, Elli Papaemmanuil
{"title":"Author Correction: Clonal evolution during metastatic spread in high-risk neuroblastoma","authors":"Gunes Gundem, Max F. Levine, Stephen S. Roberts, Irene Y. Cheung, Juan S. Medina-Martínez, Yi Feng, Juan E. Arango-Ossa, Loic Chadoutaud, Mathieu Rita, Georgios Asimomitis, Joe Zhou, Daoqi You, Nancy Bouvier, Barbara Spitzer, David B. Solit, Filemon Dela Cruz, Michael P. LaQuaglia, Brian H. Kushner, Shakeel Modak, Neerav Shukla, Christine A. Iacobuzio-Donahue, Andrew L. Kung, Nai-Kong V. Cheung, Elli Papaemmanuil","doi":"10.1038/s41588-025-02320-0","DOIUrl":"10.1038/s41588-025-02320-0","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 9","pages":"2338-2338"},"PeriodicalIF":29.0,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-025-02320-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144778383","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}
Nature geneticsPub Date : 2025-08-04DOI: 10.1038/s41588-025-02282-3
{"title":"SBRR1-R variant regulates sheath blight resistance in rice","authors":"","doi":"10.1038/s41588-025-02282-3","DOIUrl":"10.1038/s41588-025-02282-3","url":null,"abstract":"Rice sheath blight is a major fungal disease caused by the necrotrophic pathogen Rhizoctonia solani. We identified a natural SBRR1-R allele that is activated by the bHLH57 transcription factor, leading to increased expression of chitinase antifungal protein genes that confer resistance to sheath blight.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 8","pages":"1800-1801"},"PeriodicalIF":29.0,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144777773","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}
Nature geneticsPub Date : 2025-08-04DOI: 10.1038/s41588-025-02264-5
Yarong Wu, Chao Yang, Kai Mu, Yan Guo, Yajun Song, Ruifu Yang, Yujun Cui
{"title":"Insights into Yersinia pestis evolution through rearrangement analysis of 242 complete genomes","authors":"Yarong Wu, Chao Yang, Kai Mu, Yan Guo, Yajun Song, Ruifu Yang, Yujun Cui","doi":"10.1038/s41588-025-02264-5","DOIUrl":"10.1038/s41588-025-02264-5","url":null,"abstract":"Yersinia pestis, the bacterium that causes the plague, has a dynamic genome with highly conserved fragments prone to rearrangement, influencing gene function and evolution. However, understanding these patterns is limited by few complete genomes and analytical methods. We developed a dual-validation strategy to analyze 242 complete genomes of Y. pestis natural isolates from diverse phylogroups. We detected 459 rearrangements, which enhanced phylogenetic resolution and resolved the third pandemic’s polytomy. Rearrangements are primarily mediated by four common insertion sequences, with IS1661 and IS100 showing the highest activity. These rearrangements are under strong positive selection, evidenced by 43 hotspots and convergent evolution in the rpsO-pnp operon, whose disruptions and reconnections altered gene expressions and temperature stress responses. We also identified unique structural alterations in human avirulent phylogroups, inactivating three genes and reordering 17 intergenic regions, some affecting virulence-related genes. This study provides a fresh perspective on Y. pestis evolution, revealing experimental targets and establishing a methodology for microbes with frequent rearrangements. Analysis of synteny blocks and genomic rearrangement patterns of 178 newly sequenced and 64 publicly available complete genomes of Yersinia pestis highlights the impact of key variations on genes involved in adaptation and virulence.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 8","pages":"1994-2003"},"PeriodicalIF":29.0,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144769897","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}
Nature geneticsPub Date : 2025-08-04DOI: 10.1038/s41588-025-02269-0
Isabelle F. Foote, Jonny P. Flint, Anna E. Fürtjes, Jeremy M. Lawrence, Donncha S. Mullin, John D. Fisk, Tobias K. Karakach, Andrew Rutenberg, Nicholas G. Martin, Michelle K. Lupton, David J. Llewellyn, Janice M. Ranson, Simon R. Cox, Michelle Luciano, Kenneth Rockwood, Andrew D. Grotzinger
{"title":"Uncovering the multivariate genetic architecture of frailty with genomic structural equation modeling","authors":"Isabelle F. Foote, Jonny P. Flint, Anna E. Fürtjes, Jeremy M. Lawrence, Donncha S. Mullin, John D. Fisk, Tobias K. Karakach, Andrew Rutenberg, Nicholas G. Martin, Michelle K. Lupton, David J. Llewellyn, Janice M. Ranson, Simon R. Cox, Michelle Luciano, Kenneth Rockwood, Andrew D. Grotzinger","doi":"10.1038/s41588-025-02269-0","DOIUrl":"10.1038/s41588-025-02269-0","url":null,"abstract":"Frailty is a multifaceted clinical state associated with accelerated aging and adverse health outcomes. Informed etiological models of frailty hold promise for producing widespread health improvements across the aging population. Frailty is currently measured using aggregate scores, which obscure etiological pathways that are only relevant to subcomponents of frailty. Here we perform a multivariate genome-wide association study of the latent genetic architecture between 30 frailty deficits, which identifies 408 genomic risk loci. Our model includes a general factor of genetic overlap across all deficits, plus six new factors indexing a shared genetic signal across specific groups of deficits. We demonstrate the added clinical and etiological value of the six factors, including predicting frailty in external datasets, highlighting divergent genetic correlations with clinically relevant outcomes and uncovering unique underlying biology linked to aging. We show that nuanced models of frailty are key to understanding its causes and how it relates to worse health. Multivariate genome-wide association analyses of the latent genetic architecture of frailty identify one general factor of genetic overlap across all frailty deficits and six factors indexing a shared genetic signal across specific groups of deficits.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 8","pages":"1848-1859"},"PeriodicalIF":29.0,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144769895","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}
Nature geneticsPub Date : 2025-08-01DOI: 10.1038/s41588-025-02287-y
{"title":"G-quadruplexes define promoter identity in mammals","authors":"","doi":"10.1038/s41588-025-02287-y","DOIUrl":"10.1038/s41588-025-02287-y","url":null,"abstract":"We show that alternative DNA structures, called G-quadruplexes, behave as elements of eukaryotic promoters. Our data suggest that they function to support intrinsic nucleosome exclusion and to facilitate transcriptional pause release by RNA polymerase II.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 8","pages":"1798-1799"},"PeriodicalIF":29.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144756385","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}
Nature geneticsPub Date : 2025-07-31DOI: 10.1038/s41588-025-02315-x
Emily Mitchell, My H. Pham, Anna Clay, Rashesh Sanghvi, Nicholas Williams, Sandra Pietsch, Joanne I. Hsu, Nina Friesgaard Øbro, Hyunchul Jung, Aditi Vedi, Sarah Moody, Jingwei Wang, Daniel Leonganmornlert, Michael Spencer Chapman, Ellie Dunstone, Anna Santarsieri, Alex Cagan, Heather E. Machado, E. Joanna Baxter, George Follows, Daniel J. Hodson, Ultan McDermott, Gary J. Doherty, Inigo Martincorena, Laura Humphreys, Krishnaa Mahbubani, Kourosh Saeb Parsy, Koichi Takahashi, Margaret A. Goodell, David Kent, Elisa Laurenti, Peter J. Campbell, Raheleh Rahbari, Jyoti Nangalia, Michael R. Stratton
{"title":"Author Correction: The long-term effects of chemotherapy on normal blood cells","authors":"Emily Mitchell, My H. Pham, Anna Clay, Rashesh Sanghvi, Nicholas Williams, Sandra Pietsch, Joanne I. Hsu, Nina Friesgaard Øbro, Hyunchul Jung, Aditi Vedi, Sarah Moody, Jingwei Wang, Daniel Leonganmornlert, Michael Spencer Chapman, Ellie Dunstone, Anna Santarsieri, Alex Cagan, Heather E. Machado, E. Joanna Baxter, George Follows, Daniel J. Hodson, Ultan McDermott, Gary J. Doherty, Inigo Martincorena, Laura Humphreys, Krishnaa Mahbubani, Kourosh Saeb Parsy, Koichi Takahashi, Margaret A. Goodell, David Kent, Elisa Laurenti, Peter J. Campbell, Raheleh Rahbari, Jyoti Nangalia, Michael R. Stratton","doi":"10.1038/s41588-025-02315-x","DOIUrl":"10.1038/s41588-025-02315-x","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 8","pages":"2075-2075"},"PeriodicalIF":29.0,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-025-02315-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144747439","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}
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