Nature genetics最新文献

{"title":"Analysis of R-loop forming regions identifies RNU2-2 and RNU5B-1 as neurodevelopmental disorder genes","authors":"Adam Jackson, Nishi Thaker, Alexander Blakes, Gillian Rice, Sam Griffiths-Jones, Meena Balasubramanian, Jennifer Campbell, Nora Shannon, Jungmin Choi, Juhyeon Hong, David Hunt, Anna de Burca, Soo Yeon Kim, Taekeun Kim, Seungbok Lee, Melody Redman, Rocio Rius, Cas Simons, Tiong Yang Tan, Jamie Ellingford, Raymond T. O’Keefe, Jong Hee Chae, Siddharth Banka","doi":"10.1038/s41588-025-02209-y","DOIUrl":"10.1038/s41588-025-02209-y","url":null,"abstract":"R-loops are DNA–RNA hybrid structures that may promote mutagenesis. However, their contribution to human Mendelian disorders is unexplored. Here we show excess de novo variants in genomic regions that form R-loops (henceforth, ‘R-loop regions’) and demonstrate enrichment of R-loop region variants (RRVs) in ribozyme, snoRNA and snRNA genes, specifically in rare disease cohorts. Using this insight, we report neurodevelopmental disorders (NDDs) caused by rare variants in two major spliceosomal RNA encoding genes, RNU2-2 and RNU5B-1. These, along with the recently described RNU4-2-related ReNU syndrome, provide a genetic explanation for a substantial proportion of individuals with NDDs. Genomic analyses focused on regions that form R-loops identify rare mutations in RNU2-2 and RNU5B-1 in individuals with neurodevelopmental disorders.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 6","pages":"1362-1366"},"PeriodicalIF":31.7,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-025-02209-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144165359","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":"Author Correction: Distinct dynamics and functions of H2AK119ub1 and H3K27me3 in mouse preimplantation embryos","authors":"Zhiyuan Chen, Mohamed Nadhir Djekidel, Yi Zhang","doi":"10.1038/s41588-025-02211-4","DOIUrl":"10.1038/s41588-025-02211-4","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 6","pages":"1564-1564"},"PeriodicalIF":31.7,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-025-02211-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144153384","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":"Genome synteny reveals hidden enhancer conservation","authors":"Alex de Mendoza","doi":"10.1038/s41588-025-02194-2","DOIUrl":"10.1038/s41588-025-02194-2","url":null,"abstract":"Enhancer sequences evolve rapidly, which has led to the prevailing view that most are not functionally conserved across species. A study now challenges this assumption by leveraging interspecies point projection — a method that uses genome synteny to uncover hidden enhancer conservation.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 6","pages":"1328-1329"},"PeriodicalIF":31.7,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144145595","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":"Conservation of regulatory elements with highly diverged sequences across large evolutionary distances","authors":"Mai H. Q. Phan, Tobias Zehnder, Fiona Puntieri, Andreas Magg, Blanka Majchrzycka, Milan Antonović, Hannah Wieler, Bai-Wei Lo, Damir Baranasic, Boris Lenhard, Ferenc Müller, Martin Vingron, Daniel M. Ibrahim","doi":"10.1038/s41588-025-02202-5","DOIUrl":"10.1038/s41588-025-02202-5","url":null,"abstract":"Developmental gene expression is a remarkably conserved process, yet most cis-regulatory elements (CREs) lack sequence conservation, especially at larger evolutionary distances. Some evidence suggests that CREs at the same genomic position remain functionally conserved independent of sequence conservation. However, the extent of such positional conservation remains unclear. Here, we profiled the regulatory genome in mouse and chicken embryonic hearts at equivalent developmental stages and found that most CREs lack sequence conservation. To identify positionally conserved CREs, we introduced the synteny-based algorithm interspecies point projection, which identifies up to fivefold more orthologs than alignment-based approaches. We termed positionally conserved orthologs ‘indirectly conserved’ and showed that they exhibited chromatin signatures and sequence composition similar to sequence-conserved CREs but greater shuffling of transcription factor binding sites between orthologs. Finally, we validated indirectly conserved chicken enhancers using in vivo reporter assays in mouse. By overcoming alignment-based limitations, we revealed widespread functional conservation of sequence-divergent CREs. Combining functional genomic data from mouse and chicken with a synteny-based strategy identifies positionally conserved cis-regulatory elements in the absence of direct sequence conservation.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 6","pages":"1524-1534"},"PeriodicalIF":31.7,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-025-02202-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144145594","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":"Base editing of trinucleotide repeats that cause Huntington’s disease and Friedreich’s ataxia reduces somatic repeat expansions in patient cells and in mice","authors":"Zaneta Matuszek, Mandana Arbab, Maheswaran Kesavan, Alvin Hsu, Jennie C. L. Roy, Jing Zhao, Tian Yu, Ben Weisburd, Gregory A. Newby, Neil J. Doherty, Muzhou Wu, Shota Shibata, Ana Cristian, Y. Allen Tao, Liam G. Fearnley, Melanie Bahlo, Heidi L. Rehm, Jun Xie, Guangping Gao, Ricardo Mouro Pinto, David R. Liu","doi":"10.1038/s41588-025-02172-8","DOIUrl":"10.1038/s41588-025-02172-8","url":null,"abstract":"Trinucleotide repeat (TNR) diseases are neurological disorders caused by expanded genomic TNRs that become unstable in a length-dependent manner. The CAG•CTG sequence is found in approximately one-third of pathogenic TNR loci, including the HTT gene that causes Huntington’s disease. Friedreich’s ataxia, the most prevalent hereditary ataxia, results from GAA repeat expansion at the FXN gene. Here we used cytosine and adenine base editing to reduce the repetitiveness of TNRs in patient cells and in mice. Base editors introduced G•C>A•T and A•T>G•C interruptions at CAG and GAA repeats, mimicking stable, nonpathogenic alleles that naturally occur in people. AAV9 delivery of optimized base editors in Htt.Q111 Huntington’s disease and YG8s Friedreich’s ataxia mice resulted in efficient editing in transduced tissues, and significantly reduced repeat expansion in the central nervous system. These findings demonstrate that introducing interruptions in pathogenic TNRs can mitigate a key neurological feature of TNR diseases in vivo. Base editing of the pathogenic trinucleotide repeat expansions underlying Huntington’s disease and Friedreich’s ataxia introduces repeat interruptions that reduce somatic expansion in patient cells and mice.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 6","pages":"1437-1451"},"PeriodicalIF":31.7,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-025-02172-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144137161","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":"Base editing as a therapeutic strategy for somatic repeat expansion diseases","authors":"Krishanu Saha","doi":"10.1038/s41588-025-02201-6","DOIUrl":"10.1038/s41588-025-02201-6","url":null,"abstract":"CRISPR–Cas base editing of trinucleotide repeats shows promise in reducing somatic repeat expansions in Huntington’s disease and Friedreich’s ataxia, offering a potential new therapeutic strategy.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 6","pages":"1326-1327"},"PeriodicalIF":31.7,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144137158","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":"Genome-wide association study of long COVID","authors":"Vilma Lammi, Tomoko Nakanishi, Samuel E. Jones, Shea J. Andrews, Juha Karjalainen, Beatriz Cortés, Heath E. O’Brien, Ana Ochoa-Guzman, Brian E. Fulton-Howard, Martin Broberg, Hele H. Haapaniemi, Masahiro Kanai, Matti Pirinen, Axel Schmidt, Ruth E. Mitchell, Abdou Mousas, Massimo Mangino, Alicia Huerta-Chagoya, Nasa Sinnott-Armstrong, Elizabeth T. Cirulli, Marc Vaudel, Alex S. F. Kwong, Amit K. Maiti, Minttu M. Marttila, Daniel C. Posner, Alexis A. Rodriguez, Chiara Batini, Francesca Minnai, Anna R. Dearman, C. A. Robert Warmerdam, Celia B. Sequeros, Thomas W. Winkler, Daniel M. Jordan, Raimonds Rešcenko, Lorenzo Miano, Jacqueline M. Lane, Ryan K. Chung, Beatriz Guillen-Guio, Olivia C. Leavy, Laura Carvajal-Silva, Kevin Aguilar-Valdés, Erika Frangione, Lindsay Guare, Ekaterina Vergasova, Eirini Marouli, Pasquale Striano, Ummu Afeera Zainulabid, Ashutosh Kumar, Hajar Fauzan Ahmad, Ryuya Edahiro, Shuhei Azekawa, Long COVID Host Genetics Initiative, FinnGen, VA Million Veteran Program, MexGen-COVID Initiative, DBDS Genomic Consortium, GEN-COVID Multicenter Study, PHOSP-COVID Collaborative Group, GENCOV Study, Estonian Biobank Research Team, Shiuh-Wen Luoh, Christian Erikstrup, Ole B. V. Pedersen, Jordan Lerner-Ellis, Alicia Colombo, Joseph J. Grzymski, Makoto Ishii, Yukinori Okada, Noam D. Beckmann, Meena Kumari, Ralf Wagner, Iris M. Heid, Catherine John, Patrick J. Short, Per Magnus, Laura Ansone, Luca V. C. Valenti, Sulggi A. Lee, Louise V. Wain, Ricardo A. Verdugo, Karina Banasik, Frank Geller, Lude H. Franke, Alexander Rakitko, Emma L. Duncan, Alessandra Renieri, Konstantinos K. Tsilidis, Rafael de Cid, Ahmadreza Niavarani, Erik Abner, Teresa Tusié-Luna, Shefali S. Verma, George Davey Smith, Nicholas J. Timpson, Ravi K. Madduri, Kelly Cho, Mark J. Daly, Andrea Ganna, Eva C. Schulte, J. Brent Richards, Kerstin U. Ludwig, Michael Marks-Hultström, Hugo Zeberg, Hanna M. Ollila","doi":"10.1038/s41588-025-02100-w","DOIUrl":"10.1038/s41588-025-02100-w","url":null,"abstract":"Infections can lead to persistent symptoms and diseases such as shingles after varicella zoster or rheumatic fever after streptococcal infections. Similarly, severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) infection can result in long coronavirus disease (COVID), typically manifesting as fatigue, pulmonary symptoms and cognitive dysfunction. The biological mechanisms behind long COVID remain unclear. We performed a genome-wide association study for long COVID including up to 6,450 long COVID cases and 1,093,995 population controls from 24 studies across 16 countries. We discovered an association of FOXP4 with long COVID, independent of its previously identified association with severe COVID-19. The signal was replicated in 9,500 long COVID cases and 798,835 population controls. Given the transcription factor FOXP4’s role in lung physiology and pathology, our findings highlight the importance of lung function in the pathophysiology of long COVID. A genome-wide study by the Long COVID Host Genetics Initiative identifies an association between the FOXP4 locus and long COVID, implicating altered lung function in its pathophysiology.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 6","pages":"1402-1417"},"PeriodicalIF":31.7,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-025-02100-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144113741","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":"Genomic landscape of multiple myeloma and its precursor conditions","authors":"Jean-Baptiste Alberge, Ankit K. Dutta, Andrea Poletti, Tim H. H. Coorens, Elizabeth D. Lightbody, Rosa Toenges, Xavi Loinaz, Sofia Wallin, Andrew Dunford, Oliver Priebe, Johnathan Dagan, Cody J. Boehner, Erica Horowitz, Nang K. Su, Hadley Barr, Laura Hevenor, Katherine Towle, Rashmika Beesam, Jenna B. Beckwith, Jacqueline Perry, David M. Cordas dos Santos, Luca Bertamini, Patricia T. Greipp, Kirsten Kübler, Peter F. Arndt, Carolina Terragna, Elena Zamagni, Eileen M. Boyle, Kwee Yong, Gareth Morgan, Brian A. Walker, Meletios Athanasios Dimopoulos, Efstathios Kastritis, Julian Hess, Romanos Sklavenitis-Pistofidis, Chip Stewart, Gad Getz, Irene M. Ghobrial","doi":"10.1038/s41588-025-02196-0","DOIUrl":"10.1038/s41588-025-02196-0","url":null,"abstract":"Reliable strategies to capture patients at risk of progression from precursor stages of multiple myeloma (MM) to overt disease are still missing. We assembled a comprehensive collection of MM genomic data comprising 1,030 patients (218 with precursor conditions) that we used to identify recurrent coding and non-coding candidate drivers as well as significant hotspots of structural variation. We used those drivers to define and validate a simple ‘MM-like’ score, which we could use to place patients’ tumors on a gradual axis of progression toward active disease. Our MM precursor genomic map provides insights into the time of initiation and cell-of-origin of the disease, order of acquisition of genomic alterations and mutational processes found across the stages of transformation. Taken together, we highlight here the potential of genome sequencing to better inform risk assessment and monitoring of MM precursor conditions. The genomic features of precursor conditions of multiple myeloma provide multiple biological insights into disease origins and evolution, together with opportunities to identify those at highest risk of progression.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 6","pages":"1493-1503"},"PeriodicalIF":31.7,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-025-02196-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144103987","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":"The contribution of gametic phase disequilibrium to the heritability of complex traits","authors":"Yuanxiang Zhang, Saori Sakaue, Sam Morris, Mariaelisa Graff, The Biobank Japan Project, Kenichi Yamamoto, Zhengming Chen, Liming Li, Matthew C. Keller, Michael E. Goddard, Robin G. Walters, Yukinori Okada, Peter M. Visscher, Loic Yengo","doi":"10.1038/s41588-025-02192-4","DOIUrl":"10.1038/s41588-025-02192-4","url":null,"abstract":"Nonrandom mating induces genome-wide correlations between unlinked genetic variants, known as gametic phase disequilibrium (GPD), whose contribution to heritability remains uncharacterized. Here we introduce the disequilibrium genome-based restricted maximum likelihood (DGREML) method to simultaneously quantify the additive contribution of SNPs to heritability and that of their directional covariances. We applied DGREML to 26 phenotypes of 550,000 individuals from diverse biobanks and found that cross-autosome GPD contributes 10–27% of the SNP-based heritability of height, educational attainment, intelligence, income, self-rated health status and sedentary behaviors. We observed a differential contribution of GPD to the heritability of height between the UK, Chinese and Japanese populations. Finally, bivariate DGREML analyses of educational attainment and height show that cross-autosome GPD contributes at least 32% of their genetic correlation. Altogether, our versatile and powerful method reveals understudied features of the genetic architecture of complex traits and informs potential mechanisms generating these features. Disequilibrium genome-based restricted maximum likelihood (DGREML) simultaneously quantifies the contribution of SNPs and their directional covariances to trait heritability and shows that cross-autosomal correlations contribute substantially to SNP-based heritability for many complex traits.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 6","pages":"1418-1425"},"PeriodicalIF":31.7,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144088143","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":"APOBEC3 mutagenesis drives therapy resistance in breast cancer","authors":"Avantika Gupta, Andrea Gazzo, Pier Selenica, Anton Safonov, Fresia Pareja, Edaise M. da Silva, David N. Brown, Hong Shao, Yingjie Zhu, Juber Patel, Juan Blanco-Heredia, Bojana Stefanovska, Michael A. Carpenter, Yanjun Chen, Isabella Vegas, Xin Pei, Denise Frosina, Achim A. Jungbluth, Marc Ladanyi, Giuseppe Curigliano, Britta Weigelt, Nadeem Riaz, Simon N. Powell, Pedram Razavi, Reuben S. Harris, Jorge S. Reis-Filho, Antonio Marra, Sarat Chandarlapaty","doi":"10.1038/s41588-025-02187-1","DOIUrl":"10.1038/s41588-025-02187-1","url":null,"abstract":"Acquired genetic alterations drive resistance to endocrine and targeted therapies in metastatic breast cancer; however, the underlying processes engendering these alterations are largely uncharacterized. To identify the underlying mutational processes, we utilized a clinically annotated cohort of 3,880 patient samples with tumor-normal sequencing. Mutational signatures associated with apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) enzymes were prevalent and enriched in post-treatment hormone receptor-positive cancers. These signatures correlated with shorter progression-free survival on antiestrogen plus CDK4/6 inhibitor therapy in hormone receptor-positive metastatic breast cancer. Whole-genome sequencing of breast cancer models and paired primary-metastatic samples demonstrated that active APOBEC3 mutagenesis promoted therapy resistance through characteristic alterations such as RB1 loss. Evidence of APOBEC3 activity in pretreatment samples illustrated its pervasive role in breast cancer evolution. These studies reveal APOBEC3 mutagenesis to be a frequent mediator of therapy resistance in breast cancer and highlight its potential as a biomarker and target for overcoming resistance. Analysis of a large cohort of metastatic breast cancer samples shows that APOBEC mutational signatures are enriched in post-treatment samples. APOBEC activity was also associated with mutations known to drive drug resistance.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 6","pages":"1452-1462"},"PeriodicalIF":31.7,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-025-02187-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144065982","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}