Nature genetics最新文献

{"title":"Atlas of cell types and regulatory elements underlying human facial diversity","authors":"Alek G. Erickson, Yaakov Gershtein, Rozalina Galimullina, Felix Waern, Tonyak Riba, Markéta Kaiser, Daniela Schnyder, Lei Li, Nikita Vaulin, Saga Samuelsson, Aliia Murtazina, Sergey Isaev, Thibault Bouderlique, Viktoria Parobkova, Hugo Zeberg, Tomáš Zikmund, Jozef Kaiser, Kaj Fried, Elena I. Shagimardanova, Leyla Shigapova, Guzel R. Gazizova, Ivan V. Reva, Ruslan Deviatiiarov, Kateřina Vymazalová, Seppe Goovaerts, Yuk Kit Lor, Gonçalo Castelo-Branco, Peter Claes, Xiaofei Li, Oleg Gusev, Andrei S. Chagin, Erik Sundström, Peter V. Kharchenko, Igor Adameyko","doi":"10.1038/s41588-026-02748-y","DOIUrl":"10.1038/s41588-026-02748-y","url":null,"abstract":"Human genetic diversity generates an astonishing variety of facial shapes, and craniofacial anomalies rank among the most common birth defects. Identifying the cellular mechanisms that mediate the genome’s influence on facial variation remains a challenge. Here we created a multimodal facial atlas across embryonic weeks 6–11, providing single-cell transcriptomics, chromatin accessibility and spatial transcriptomics, all at single-cell resolution. We characterized 56 cell states, mapping mesenchymal subtypes and their gene–enhancer cis-regulatory landscapes in space and time. Gene expression associations with facial traits were strongest in early mesenchymal progenitor cells, gradually becoming more region restricted. Autocorrelation analysis revealed patterning genes that define spatial neighborhoods of mesenchyme, potentially explaining trait specificity of their nearby variants. Enhancers of key pathology-related genes were found to be likely vehicles for generating facial variation in modern human populations. One such enhancer, linked to PAX1 expression, appears to be important for normal skeletal development in mice. Finally, facial effects inferred from the genome-wide association study, cell signaling interaction analysis and validation in mice revealed that peripheral nerves fine-tune maxilla shape during embryonic development. Together, these data offer new insights into the mechanisms underlying human phenotypic individuality and yield a multimodal atlas useful for studying craniofacial development and abnormalities. Single-cell transcriptomics, spatial transcriptomics and chromatin accessibility maps of the human craniofacial region in developing embryos provide insights into the mechanisms underlying facial variation and pathology.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 10","pages":"2645-2659"},"PeriodicalIF":25.5,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-026-02748-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149040019","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":"Human facial development atlas illuminates enhancer-based control of facial individuality","authors":"","doi":"10.1038/s41588-026-02746-0","DOIUrl":"10.1038/s41588-026-02746-0","url":null,"abstract":"The facial skeleton is essential for eating, breathing, kissing, speech and personal identity. Our spatiotemporally resolved cell atlas of human embryonic craniofacial development will facilitate a deeper understanding of how genetics influences appearance and might help to identify the causes of rare congenital craniofacial anomalies.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 10","pages":"2435-2436"},"PeriodicalIF":25.5,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149040000","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":"Divergent medulloblastoma chromatin states disclose KDM2B as a selective dependency","authors":"Ran Tao, Serap Erkek-Ozhan, Beisi Xu, Yurika Matsui, Priya Mittal, Kyle S. Smith, Yiran Li, David Filipovic, Ruijie Xu, Qingsong Gao, Emily Darrow, Rahul Kumar, Nadhir Djekidel, Richa Bajpai, Jennifer Hadley, Melissa Batts, Sara A. Lewis, Taha Soliman, Colleen Reilly, Natarajan V. Bhanu, Leena Paul, Hong Lin, Brian Gudenas, Kim Lowe, Marc Zapatka, Laura Sieber, David T. W. Jones, Marcel Kool, Sebastian M. Waszak, Volker Hovestadt, Ivo Buchhalter, Marina Ryzhova, Andrey Korshunov, Peter Lichter, Lukas Chavez, Lena M. Kutscher, Benjamin A. Garcia, Shondra M. Pruett-Miller, Xin Zhou, Brent A. Orr, Giles W. Robinson, Gang Wu, Jan O. Korbel, Jamy C. Peng, Stefan M. Pfister, Paul A. Northcott","doi":"10.1038/s41588-026-02745-1","DOIUrl":"10.1038/s41588-026-02745-1","url":null,"abstract":"Medulloblastoma is a biologically heterogeneous childhood cerebellar tumor harboring frequent chromatin-modifying gene alterations. How these alterations promote transcriptional programs governing malignancy remains poorly defined. To address this knowledge gap, we evaluated chromatin states across medulloblastoma subgroups by multi-modal integration of histone modifications with mutational, DNA methylation and transcriptomic profiles. A bivalent/poised enhancer (EnhBiv) state was specifically enriched at the promoters of neurodevelopmental genes in Group 3/4 medulloblastoma. Integrative bioinformatics coupled with chromatin occupancy studies identified aberrant KDM2B binding at EnhBiv-enriched promoters. CRISPR-mediated knockout or acute protein degradation of KDM2B selectively suppressed the growth of medulloblastoma models in vitro and in vivo. Mechanistically, KDM2B promotes sequential recruitment of Polycomb repressive complexes (PRC1/PRC2) and EnhBiv chromatin, thereby repressing neuronal differentiation programs. Collectively, we provide foundational insights into an epigenetic basis of medulloblastoma, nominating KDM2B as a selective dependency in high-risk subgroups that warrants consideration as a candidate therapeutic target. Epigenomic analyses of medulloblastoma identify a bivalent/poised enhancer (EnhBiv) chromatin signature enriched for KDM2B binding in Group 3 and Group 4 tumors. Functional work suggests a selective dependency of these subtypes on KDM2B.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 10","pages":"2590-2604"},"PeriodicalIF":25.5,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-026-02745-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149039991","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":"Gb3 encodes a unique kinase fusion protein conferring greenbug resistance in wheat","authors":"Dhondup Lhamo, Jianqiang Shen, Genqiao Li, Toni Mohr, Roger Thilmony, Prakitchai Chotewutmontri, Han-Chang Chang, Honglian Ye, Mingcheng Luo, Shuyu Liu, Guihua Bai, Jackie Rudd, Brett F. Carver, Yong Q. Gu, Xiangyang Xu, Steven S. Xu","doi":"10.1038/s41588-026-02754-0","DOIUrl":"10.1038/s41588-026-02754-0","url":null,"abstract":"Understanding plant resistance to insects has lagged owing to a scarcity of cloned resistance genes. Here we report cloning of the greenbug resistance gene Gb3 in wheat (Triticum aestivum L.), initially introgressed into cultivars such as ‘TAM112’ from Aegilops tauschii. Gb3 encodes an intracellular kinase–pseudokinase protein, featuring a unique MAP3K-like domain. This gene probably originated through fusion, duplication and indel events in the Triticeae tribe, retaining its functionality in several Aegilops species. Transgenic Gb3 expression in the susceptible Fielder wheat enhanced resistance to multiple biotypes, while the Gb3 knockout in TAM112 resulted in susceptibility. Comprehensive analyses indicate that greenbugs preferentially feed on susceptible plants, inducing a prolonged oxidative stress response. Conversely, resistant plants expressing Gb3 mediate greenbug resistance by producing oxylipins and other defensive compounds. Our findings lay the groundwork for investigating plant–insect interactions and provide a crucial genetic resource for developing sustainable aphid resistance in cereal crops. Gb3 encodes an intracellular kinase–pseudokinase protein with a unique MAP3K-like domain that confers resistance to multiple greenbug biotypes in wheat.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 10","pages":"2696-2705"},"PeriodicalIF":25.5,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-026-02754-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149021187","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":"Genetic factor analysis for characterizing phenome-wide patterns of genetic pleiotropy","authors":"Jean Morrison, Jason Willwerscheid, Dhajanae Sylvertooth, Xin He, Matthew Stephens","doi":"10.1038/s41588-026-02753-1","DOIUrl":"10.1038/s41588-026-02753-1","url":null,"abstract":"Genetic associations shared by multiple traits provide evidence about the biological role of disease associated variants. Here we propose genetic factor analysis (GFA), a multiphenotype analysis method that identifies common patterns of cross-trait associations, the signatures of shared biological processes. GFA overcomes limitations of alternative methods by automatically selecting the number of factors, accounting for sample overlap and allowing factors to be non-orthogonal. We apply GFA to analysis of 22 common risk factors for coronary artery disease and type 2 diabetes to partition the heritability of these traits into 15 pleiotropic components. In addition, we use GFA to obtain a biologically meaningful decomposition of a large set of blood cell composition phenotypes and use these results to increase precision in multivariable Mendelian randomization. In this application, we find that accounting for overlapping samples is critical to obtaining biologically interpretable results. Genetic factor analysis uses genome-wide association summary statistics to identify shared polygenic factors underlying patterns of cross-trait genetic associations, while automatically determining the number of factors and accounting for sample overlap.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 10","pages":"2494-2501"},"PeriodicalIF":25.5,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149022465","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":"Balancing phenotyping depth and representativeness in psychiatric genomics","authors":"Woojae Myung,Jisun Ryu,Hong-Hee Won","doi":"10.1038/s41588-026-02777-7","DOIUrl":"https://doi.org/10.1038/s41588-026-02777-7","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"2 3-4 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149021186","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":"Single-nucleus atlas of cell-type specific genetic regulation in the human brain","authors":"Biao Zeng, Hui Yang, Prashant N. M, Sanan Venkatesh, Deepika Mathur, Pavan Auluck, David A. Bennett, Stefano Marenco, Vahram Haroutunian, PsychAD Consortium, Georgios Voloudakis, Donghoon Lee, John F. Fullard, Jaroslav Bendl, Kiran Girdhar, Gabriel E. Hoffman, Panos Roussos","doi":"10.1038/s41588-026-02733-5","DOIUrl":"10.1038/s41588-026-02733-5","url":null,"abstract":"Genetic risk variants for common diseases are predominantly located in non-coding regulatory regions and modulate gene expression. Although bulk tissue studies have elucidated shared mechanisms of regulatory and disease-associated genetics, the cellular specificity of these mechanisms remains largely unexplored. Here we present a comprehensive, single-nucleus multi-ancestry atlas of genetic regulation of gene expression in the human prefrontal cortex, comprising 5.6 million nuclei from 1,384 donors of diverse ancestries. Through multi-resolution analyses spanning eight major cell classes and 27 subclasses, we identify genetic regulation for 14,258 genes, with 981 showing cell type-specific regulatory effects at the class level and 857 at the subclass level. Colocalization of genetic variants associated with gene regulation and disease traits uncovers novel cell type-specific genes implicated in Alzheimer’s disease, schizophrenia and other disorders that were not detectable in bulk tissue analyses. Analysis of dynamic genetic regulation at the single-nucleus level identifies 2,073 genes with regulatory effects that vary across developmental trajectories, inferred from a broad age range of donors. We also uncover 1,655 genes with trans-regulatory effects, revealing distal regulation of gene expression. This high-resolution atlas provides insight into the cell type-specific regulatory architecture of the human brain, and offers novel mechanistic targets for understanding the genetic basis of neuropsychiatric and neurodegenerative diseases. Multi-resolution genetic regulatory atlas of the human brain from single-nucleus transcriptomics of 1,384 donors of diverse ancestries reveals cell type-specific regulation underlying genetic risk of neuropsychiatric and neurodegenerative diseases.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 10","pages":"2525-2534"},"PeriodicalIF":25.5,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-026-02733-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149021188","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":"Interpreting human genetic variation at atomic resolution.","authors":"Michael T Zimmermann, Raul Urrutia","doi":"10.1038/s41588-026-02763-z","DOIUrl":"https://doi.org/10.1038/s41588-026-02763-z","url":null,"abstract":"<p><p>The widespread adoption of clinical sequencing and large-scale national and international genomics initiatives has transformed genomic medicine. These efforts have enabled new diagnostic tests and computational tools for processing sequencing-derived information, yet interpretation of many variants remains limited. In parallel, over the last two decades, computational structural genomics (CSG) has emerged as a complementary approach that shifts from static genetic annotation to dynamic, mechanistic interpretation by leveraging models of gene products and their organization within biomolecular complexes of protein, DNA, RNA and small molecules. In this Perspective, we highlight how CSG has resulted in a comprehensive and mechanistic understanding of how interindividual genetic variants function, by integrating sequence information, motifs, domains, molecular structures, molecular dynamics simulations, multi-omics data annotations and artificial intelligence-driven tools. These advanced technologies enable prediction of variant effects at atomic resolution and support simultaneous classification according to their mechanisms of dysfunction.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":" ","pages":""},"PeriodicalIF":25.5,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149017530","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":"Protein interactions reveal the hidden wiring of the genome","authors":"Jing Hou,&nbsp;Joseph Schacherer","doi":"10.1038/s41588-026-02757-x","DOIUrl":"10.1038/s41588-026-02757-x","url":null,"abstract":"A large-scale genetic screen in yeast identifies protein interaction quantitative trait loci (piQTLs), demonstrating that natural genetic variation acts extensively through protein interaction networks rather than solely through changes in gene expression.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 10","pages":"2425-2426"},"PeriodicalIF":25.5,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149017581","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":"Genetic landscape of an in vivo protein interactome","authors":"Savandara Besse,&nbsp;Tatsuya Sakaguchi,&nbsp;Louis Gauthier,&nbsp;Zahra Sahaf,&nbsp;Rini Ravindran,&nbsp;Lidice Gonzalez,&nbsp;Xavier Castellanos-Girouard,&nbsp;Cassandre Clermont,&nbsp;Nazli Koçatug,&nbsp;Olivier Péloquin,&nbsp;Chloé Matta,&nbsp;Julie G. Hussin,&nbsp;Stephen W. Michnick,&nbsp;Adrian W. R. Serohijos","doi":"10.1038/s41588-026-02747-z","DOIUrl":"10.1038/s41588-026-02747-z","url":null,"abstract":"Protein–protein interaction (PPI) networks accurately map environmental perturbations to their molecular consequences in cells, yet the effects of natural genetic variation on PPIs remain poorly understood. Here we measured 61 reporter PPIs across inbred strains of Saccharomyces cerevisiae harboring ~12,000 single-nucleotide polymorphisms and identified protein-interaction quantitative trait loci (piQTLs) linking genomic variation to in vivo PPI strength. trans-acting piQTLs were significantly enriched and exhibited stronger per-variant effect sizes than cis-acting piQTLs. Consistent with the small-world architecture of PPI networks, trans-piQTLs often mapped to genes encoding proteins in close network proximity to reporter PPIs. We identified and validated piQTLs in poorly annotated regions, including noncoding RNAs and 3′UTRs, with effects comparable to coding single-nucleotide polymorphisms. piQTLs also overlapped more with protein abundance QTLs than expression QTLs, highlighting how PPI networks capture post-transcriptional and proteome-level regulation. This study provides a roadmap for dissecting complex traits through PPI network analysis. This study uses budding yeast as a model system to link genetic variants with quantitative changes in protein–protein interaction strength under different environmental perturbations by leveraging a protein-fragment complementation assay targeting 61 pairs of interacting proteins.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 10","pages":"2684-2695"},"PeriodicalIF":25.5,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149010503","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}