Nature genetics最新文献

{"title":"A model of heritable genome editing for complex traits","authors":"Michael Fletcher","doi":"10.1038/s41588-025-02105-5","DOIUrl":"10.1038/s41588-025-02105-5","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 2","pages":"280-280"},"PeriodicalIF":31.7,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397433","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":"Oncofetal reprogramming drives phenotypic plasticity in WNT-dependent colorectal cancer","authors":"Slim Mzoughi, Megan Schwarz, Xuedi Wang, Deniz Demircioglu, Gulay Ulukaya, Kevin Mohammed, Habiba Zorgati, Denis Torre, Lewis E. Tomalin, Federico Di Tullio, Carlos Company, Yuliia Dramaretska, Marc Leushacke, Bruno Giotti, Tamsin RM Lannagan, Daniel Lozano-Ojalvo, Panagiotis Karras, Peter B. Vermeulen, Dan Hasson, Robert Sebra, Alexander M. Tsankov, Owen J. Sansom, Jean-Christophe Marine, Nick Barker, Gaetano Gargiulo, Ernesto Guccione","doi":"10.1038/s41588-024-02058-1","DOIUrl":"10.1038/s41588-024-02058-1","url":null,"abstract":"Targeting cancer stem cells (CSCs) is crucial for effective cancer treatment, yet resistance mechanisms to LGR5+ CSC depletion in WNT-driven colorectal cancer (CRC) remain elusive. In the present study, we revealed that mutant intestinal stem cells (SCs) depart from their canonical identity, traversing a dynamic phenotypic spectrum. This enhanced plasticity is initiated by oncofetal (OnF) reprogramming, driven by YAP and AP-1, with subsequent AP-1 hyperactivation promoting lineage infidelity. The retinoid X receptor serves as a gatekeeper of OnF reprogramming and its deregulation after adenomatous polyposis coli (APC) loss of function establishes an OnF ‘memory’ sustained by YAP and AP-1. Notably, the clinical significance of OnF and LGR5+ states in isolation is constrained by their functional redundancy. Although the canonical LGR5+ state is sensitive to the FOLFIRI regimen, an active OnF program correlates with resistance, supporting its role in driving drug-tolerant states. Targeting this program in combination with the current standard of care is pivotal for achieving effective and durable CRC treatment. Oncofetal (OnF) reprogramming, driven by YAP and AP-1, induces phenotypic plasticity and therapy resistance in WNT-dependent colorectal cancer (CRC). Targeting the OnF state in combination with chemotherapy substantially attenuates tumor growth in mouse models and patient-derived CRC tumoroids.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 2","pages":"402-412"},"PeriodicalIF":31.7,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-02058-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143375432","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 African Animal Breeding Network as a pathway towards genetic improvement of livestock","authors":"Appolinaire Djikeng, Victor E. Olori, Isidore Houaga, Samuel E. Aggrey, Okeyo Mwai, Eveline M. Ibeagha-Awemu, Raphael Mrode, Mizeck G. G. Chagunda, Christian K. Tiambo, Romdhane Rekaya, Oyenkanmi Nash, Zabron Nziku, Oluyinka Opoola, Mapholi Ntanganedzeni, Chinyere Ekine-Dzivenu, Alexander Kahi, Tobias Okeno, John M. Hickey, Negussie Enyew, Edward J. O. Rege","doi":"10.1038/s41588-025-02079-4","DOIUrl":"10.1038/s41588-025-02079-4","url":null,"abstract":"Transforming Africa’s agricultural production and food systems is an imperative to achieve the United Nations Sustainable Development Goals and deliver on the Africa Union’s 2063 vision, ‘the Africa we want’. Transforming livestock systems through genetic improvement will sustainably increase productivity and proffer an inclusive socioeconomic development of farming communities. The African Animal Breeding Network (AABNet) is a platform of highly knowledgeable geneticists, animal breeders and professionals willing to provide information, training, advice and support across the continent. It will leverage available human resources among its members, facilitate partnerships and investment and develop infrastructure for innovative livestock genetic improvement in Africa. This Perspective introduces the African Animal Breeding Network as a platform to develop infrastructure for innovative livestock genetic improvement in Africa and discusses the challenges in implementing successful animal breeding programs.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 3","pages":"498-504"},"PeriodicalIF":31.7,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143375431","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":"Prioritizing effector genes at trait-associated loci using multimodal evidence","authors":"Marijn Schipper, Christiaan A. de Leeuw, Bernardo A. P. C. Maciel, Douglas P. Wightman, Nikki Hubers, Dorret I. Boomsma, Michael C. O’Donovan, Danielle Posthuma","doi":"10.1038/s41588-025-02084-7","DOIUrl":"10.1038/s41588-025-02084-7","url":null,"abstract":"Genome-wide association studies (GWAS) yield large numbers of genetic loci associated with traits and diseases. Predicting the effector genes that mediate these locus-trait associations remains challenging. Here we present the FLAMES (fine-mapped locus assessment model of effector genes) framework, which predicts the most likely effector gene in a locus. FLAMES creates machine learning predictions from biological data linking single-nucleotide polymorphisms to genes, and then evaluates these scores together with gene-centric evidence of convergence of the GWAS signal in functional networks. We benchmark FLAMES on gene-locus pairs derived by expert curation, rare variant implication and domain knowledge of molecular traits. We demonstrate that combining single-nucleotide-polymorphism-based and convergence-based modalities outperforms prioritization strategies using a single line of evidence. Applying FLAMES, we resolve the FSHB locus in the GWAS for dizygotic twinning and further leverage this framework to find schizophrenia risk genes that converge with rare coding evidence and are relevant in different stages of life. FLAMES is a machine learning approach combining variant fine-mapping, SNP-to-gene annotations and convergence-based gene prioritization scores to identify candidate effector genes at genome-wide associated loci with high accuracy.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 2","pages":"323-333"},"PeriodicalIF":31.7,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143375433","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 prostate-specific antigen levels in 392,522 men identifies new loci and improves prediction across ancestry groups","authors":"Thomas J. Hoffmann, Rebecca E. Graff, Ravi K. Madduri, Alex A. Rodriguez, Clinton L. Cario, Karen Feng, Yu Jiang, Anqi Wang, Robert J. Klein, Brandon L. Pierce, Scott Eggener, Lin Tong, William Blot, Jirong Long, Louisa B. Goss, Burcu F. Darst, Timothy Rebbeck, Joseph Lachance, Caroline Andrews, Akindele O. Adebiyi, Ben Adusei, Oseremen I. Aisuodionoe-Shadrach, Pedro W. Fernandez, Mohamed Jalloh, Rohini Janivara, Wenlong C. Chen, James E. Mensah, Ilir Agalliu, Sonja I. Berndt, John P. Shelley, Kerry Schaffer, Mitchell J. Machiela, Neal D. Freedman, Wen-Yi Huang, Shengchao A. Li, Phyllis J. Goodman, Cathee Till, Ian Thompson, Hans Lilja, Dilrini K. Ranatunga, Joseph Presti, Stephen K. Van Den Eeden, Stephen J. Chanock, Jonathan D. Mosley, David V. Conti, Christopher A. Haiman, Amy C. Justice, Linda Kachuri, John S. Witte","doi":"10.1038/s41588-024-02068-z","DOIUrl":"10.1038/s41588-024-02068-z","url":null,"abstract":"We conducted a multiancestry genome-wide association study of prostate-specific antigen (PSA) levels in 296,754 men (211,342 European ancestry, 58,236 African ancestry, 23,546 Hispanic/Latino and 3,630 Asian ancestry; 96.5% of participants were from the Million Veteran Program). We identified 318 independent genome-wide significant (P ≤ 5 × 10−8) variants, 184 of which were novel. Most demonstrated evidence of replication in an independent cohort (n = 95,768). Meta-analyzing discovery and replication (n = 392,522) identified 447 variants, of which a further 111 were novel. Out-of-sample variance in PSA explained by our genome-wide polygenic risk scores ranged from 11.6% to 16.6% for European ancestry, 5.5% to 9.5% for African ancestry, 13.5% to 18.2% for Hispanic/Latino and 8.6% to 15.3% for Asian ancestry and decreased with increasing age. Midlife genetically adjusted PSA levels were more strongly associated with overall and aggressive prostate cancer than unadjusted PSA levels. Our study highlights how including proportionally more participants from underrepresented populations improves genetic prediction of PSA levels, offering potential to personalize prostate cancer screening. This study shows how including different ancestry groups in a genome-wide association study for prostate-specific antigen levels can improve prostate cancer risk prediction, with implications for population screening.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 2","pages":"334-344"},"PeriodicalIF":31.7,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-02068-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143375462","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":"Publisher Correction: Functional innovation through new genes as a general evolutionary process","authors":"Shengqian Xia, Jianhai Chen, Deanna Arsala, J. J. Emerson, Manyuan Long","doi":"10.1038/s41588-025-02116-2","DOIUrl":"10.1038/s41588-025-02116-2","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 3","pages":"764-764"},"PeriodicalIF":31.7,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-025-02116-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143367405","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":"Unveiling heterogeneity in rare cells by combining RNA-based sorting and scRNA-seq","authors":"Madison Wahlsten, Sydney M. Shaffer","doi":"10.1038/s41588-024-02073-2","DOIUrl":"10.1038/s41588-024-02073-2","url":null,"abstract":"A study describes the development of PERFF-seq, a method to ‘FISH’ out rare cells using RNA markers, helping to solve the challenge in single-cell biology of studying cells that make up less than 1% of a sample.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 2","pages":"283-284"},"PeriodicalIF":31.7,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143257835","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":"Oncofetal reprogramming induces phenotypic heterogeneity in colorectal cancer","authors":"","doi":"10.1038/s41588-025-02092-7","DOIUrl":"10.1038/s41588-025-02092-7","url":null,"abstract":"Phenotypic plasticity of cancer cells is increasingly recognized as a mechanism of tumor escape from targeted therapies. Yet, the phenotypic heterogeneity of colorectal cancer remains poorly explored. Our study identifies oncofetal reprogramming of neoplastic stem cells, driven by the transcription factors YAP and AP-1, as a critical driver of phenotypic heterogeneity, lineage plasticity and therapy resistance. Targeting the oncofetal program enhances the efficacy and durability of current treatments.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 2","pages":"285-286"},"PeriodicalIF":31.7,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143367404","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":"Quantifying cell divisions along evolutionary lineages in cancer","authors":"Martin Blohmer, David M. Cheek, Wei-Ting Hung, Maria Kessler, Foivos Chatzidimitriou, Jiahe Wang, William Hung, I-Hsiu Lee, Alexander N. Gorelick, Emma CE Wassenaar, Ching-Yeuh Yang, Yi-Chen Yeh, Hsiang-Ling Ho, Dorothee Speiser, Maria M. Karsten, Michael Lanuti, Sara I. Pai, Onno Kranenburg, Jochen K. Lennerz, Teh-Ying Chou, Matthias Kloor, Kamila Naxerova","doi":"10.1038/s41588-025-02078-5","DOIUrl":"10.1038/s41588-025-02078-5","url":null,"abstract":"Cell division drives somatic evolution but is challenging to quantify. We developed a framework to count cell divisions with DNA replication-related mutations in polyguanine homopolymers. Analyzing 505 samples from 37 patients, we studied the milestones of colorectal cancer evolution. Primary tumors diversify at ~250 divisions from the founder cell, while distant metastasis divergence occurs significantly later, at ~500 divisions. Notably, distant but not lymph node metastases originate from primary tumor regions that have undergone surplus divisions, tying subclonal expansion to metastatic capacity. Then, we analyzed a cohort of 73 multifocal lung cancers and showed that the cell division burden of the tumors’ common ancestor distinguishes independent primary tumors from intrapulmonary metastases and correlates with patient survival. In lung cancer too, metastatic capacity is tied to more extensive proliferation. The cell division history of human cancers is easily accessible using our simple framework and contains valuable biological and clinical information. This work presents a framework for estimating cell division numbers using DNA replication-associated polyguanine tract mutations, with applications for understanding tumor natural histories and origins.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 3","pages":"706-717"},"PeriodicalIF":31.7,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143083418","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":"A barley pan-transcriptome reveals layers of genotype-dependent transcriptional complexity","authors":"Wenbin Guo, Miriam Schreiber, Vanda B. Marosi, Paolo Bagnaresi, Morten Egevang Jørgensen, Katarzyna B. Braune, Ken Chalmers, Brett Chapman, Viet Dang, Christoph Dockter, Anne Fiebig, Geoffrey B. Fincher, Agostino Fricano, John Fuller, Allison Haaning, Georg Haberer, Axel Himmelbach, Murukarthick Jayakodi, Yong Jia, Nadia Kamal, Peter Langridge, Chengdao Li, Qiongxian Lu, Thomas Lux, Martin Mascher, Klaus F. X. Mayer, Nicola McCallum, Linda Milne, Gary J. Muehlbauer, Martin T. S. Nielsen, Sudharsan Padmarasu, Pai Rosager Pedas, Klaus Pillen, Curtis Pozniak, Magnus W. Rasmussen, Kazuhiro Sato, Thomas Schmutzer, Uwe Scholz, Danuta Schüler, Hana Šimková, Birgitte Skadhauge, Nils Stein, Nina W. Thomsen, Cynthia Voss, Penghao Wang, Ronja Wonneberger, Xiao-Qi Zhang, Guoping Zhang, Luigi Cattivelli, Manuel Spannagl, Micha Bayer, Craig Simpson, Runxuan Zhang, Robbie Waugh","doi":"10.1038/s41588-024-02069-y","DOIUrl":"10.1038/s41588-024-02069-y","url":null,"abstract":"A pan-transcriptome describes the transcriptional and post-transcriptional consequences of genome diversity from multiple individuals within a species. We developed a barley pan-transcriptome using 20 inbred genotypes representing domesticated barley diversity by generating and analyzing short- and long-read RNA-sequencing datasets from multiple tissues. To overcome single reference bias in transcript quantification, we constructed genotype-specific reference transcript datasets (RTDs) and integrated these into a linear pan-genome framework to create a pan-RTD, allowing transcript categorization as core, shell or cloud. Focusing on the core (expressed in all genotypes), we observed significant transcript abundance variation among tissues and between genotypes driven partly by RNA processing, gene copy number, structural rearrangements and conservation of promotor motifs. Network analyses revealed conserved co-expression module::tissue correlations and frequent functional diversification. To complement the pan-transcriptome, we constructed a comprehensive cultivar (cv.) Morex gene-expression atlas and illustrate how these combined datasets can be used to guide biological inquiry. A long- and short-read barley pan-transcriptome assembled from 20 diverse barley genotypes offers insights into genotype- and tissue-dependent gene expression and function.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 2","pages":"441-450"},"PeriodicalIF":31.7,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-02069-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143077198","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}