Nature genetics最新文献_第2页

Functional analysis of cancer-associated germline risk variants

IF 30.8 1区生物学

Nature genetics Pub Date : 2025-02-17 DOI: 10.1038/s41588-024-02070-5

Laura N. Kellman, Poornima H. Neela, Suhas Srinivasan, Zurab Siprashvili, Ronald L. Shanderson, Audrey W. Hong, Deepti Rao, Douglas F. Porter, David L. Reynolds, Robin M. Meyers, Margaret G. Guo, Xue Yang, Yang Zhao, Glenn G. Wozniak, Laura K. H. Donohue, Rajani Shenoy, Lisa A. Ko, Duy T. Nguyen, Smarajit Mondal, Omar S. Garcia, Lara E. Elcavage, Ibtihal Elfaki, Nathan S. Abell, Shiying Tao, Christopher M. Lopez, Stephen B. Montgomery, Paul A. Khavari

{"title":"Functional analysis of cancer-associated germline risk variants","authors":"Laura N. Kellman, Poornima H. Neela, Suhas Srinivasan, Zurab Siprashvili, Ronald L. Shanderson, Audrey W. Hong, Deepti Rao, Douglas F. Porter, David L. Reynolds, Robin M. Meyers, Margaret G. Guo, Xue Yang, Yang Zhao, Glenn G. Wozniak, Laura K. H. Donohue, Rajani Shenoy, Lisa A. Ko, Duy T. Nguyen, Smarajit Mondal, Omar S. Garcia, Lara E. Elcavage, Ibtihal Elfaki, Nathan S. Abell, Shiying Tao, Christopher M. Lopez, Stephen B. Montgomery, Paul A. Khavari","doi":"10.1038/s41588-024-02070-5","DOIUrl":"https://doi.org/10.1038/s41588-024-02070-5","url":null,"abstract":"Single-nucleotide variants (SNVs) in regulatory DNA are linked to inherited cancer risk. Massively parallel reporter assays of 4,041 SNVs linked to 13 neoplasms comprising >90% of human malignancies were performed in pertinent primary human cell types and then integrated with matching chromatin accessibility, DNA looping and expression quantitative trait loci data to nominate 380 potentially regulatory SNVs and their putative target genes. The latter highlighted specific protein networks in lifetime cancer risk, including mitochondrial translation, DNA damage repair and Rho GTPase activity. A CRISPR knockout screen demonstrated that a subset of germline putative risk genes also enables the growth of established cancers. Editing one SNV, rs10411210, showed that its risk allele increases rhophilin RHPN2 expression and stimulus-responsive RhoA activation, indicating that individual SNVs may upregulate cancer-linked pathways. These functional data are a resource for variant prioritization efforts and further interrogation of the mechanisms underlying inherited risk for cancer.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"11 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143427030","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}

引用次数: 0

Comparative analysis of the Mexico City Prospective Study and the UK Biobank identifies ancestry-specific effects on clonal hematopoiesis

IF 30.8 1区生物学

Nature genetics Pub Date : 2025-02-13 DOI: 10.1038/s41588-025-02085-6

Sean Wen, Pablo Kuri-Morales, Fengyuan Hu, Abhishek Nag, Ioanna Tachmazidou, Sri V. V. Deevi, Haeyam Taiy, Katherine R. Smith, Douglas P. Loesch, Oliver S. Burren, Ryan S. Dhindsa, Sebastian Wasilewski, Jesus Alegre-Díaz, Jaime Berumen, Jonathan Emberson, Jason M. Torres, Rory Collins, Keren Carss, Quanli Wang, Slavé Petrovski, Roberto Tapia-Conyer, Margarete A. Fabre, Andrew R. Harper, George S. Vassiliou, Jonathan Mitchell

{"title":"Comparative analysis of the Mexico City Prospective Study and the UK Biobank identifies ancestry-specific effects on clonal hematopoiesis","authors":"Sean Wen, Pablo Kuri-Morales, Fengyuan Hu, Abhishek Nag, Ioanna Tachmazidou, Sri V. V. Deevi, Haeyam Taiy, Katherine R. Smith, Douglas P. Loesch, Oliver S. Burren, Ryan S. Dhindsa, Sebastian Wasilewski, Jesus Alegre-Díaz, Jaime Berumen, Jonathan Emberson, Jason M. Torres, Rory Collins, Keren Carss, Quanli Wang, Slavé Petrovski, Roberto Tapia-Conyer, Margarete A. Fabre, Andrew R. Harper, George S. Vassiliou, Jonathan Mitchell","doi":"10.1038/s41588-025-02085-6","DOIUrl":"https://doi.org/10.1038/s41588-025-02085-6","url":null,"abstract":"The impact of genetic ancestry on the development of clonal hematopoiesis (CH) remains largely unexplored. Here, we compared CH in 136,401 participants from the Mexico City Prospective Study (MCPS) to 416,118 individuals from the UK Biobank (UKB) and observed CH to be significantly less common in MCPS compared to UKB (adjusted odds ratio = 0.59, 95% confidence interval (CI) = [0.57, 0.61], P = 7.31 × 10−185). Among MCPS participants, CH frequency was positively correlated with the percentage of European ancestry (adjusted beta = 0.84, 95% CI = [0.66, 1.03], P = 7.35 × 10−19). Genome-wide and exome-wide association analyses in MCPS identified ancestry-specific variants in the TCL1B locus with opposing effects on DNMT3A-CH versus non-DNMT3A-CH. Meta-analysis of MCPS and UKB identified five novel loci associated with CH, including polymorphisms at PARP11/CCND2, MEIS1 and MYCN. Our CH study, the largest in a non-European population to date, demonstrates the power of cross-ancestry comparisons to derive novel insights into CH pathogenesis.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"63 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401366","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}

引用次数: 0

Active repression of cell fate plasticity by PROX1 safeguards hepatocyte identity and prevents liver tumorigenesis

IF 30.8 1区生物学

Nature genetics Pub Date : 2025-02-13 DOI: 10.1038/s41588-025-02081-w

Bryce Lim, Aryan Kamal, Borja Gomez Ramos, Juan M. Adrian Segarra, Ignacio L. Ibarra, Lennart Dignas, Tim Kindinger, Kai Volz, Mohammad Rahbari, Nuh Rahbari, Eric Poisel, Kanela Kafetzopoulou, Lio Böse, Marco Breinig, Danijela Heide, Suchira Gallage, Jose E. Barragan Avila, Hendrik Wiethoff, Ivan Berest, Sarah Schnabellehner, Martin Schneider, Jonas Becker, Dominic Helm, Dirk Grimm, Taija Mäkinen, Darjus F. Tschaharganeh, Mathias Heikenwalder, Judith B. Zaugg, Moritz Mall

{"title":"Active repression of cell fate plasticity by PROX1 safeguards hepatocyte identity and prevents liver tumorigenesis","authors":"Bryce Lim, Aryan Kamal, Borja Gomez Ramos, Juan M. Adrian Segarra, Ignacio L. Ibarra, Lennart Dignas, Tim Kindinger, Kai Volz, Mohammad Rahbari, Nuh Rahbari, Eric Poisel, Kanela Kafetzopoulou, Lio Böse, Marco Breinig, Danijela Heide, Suchira Gallage, Jose E. Barragan Avila, Hendrik Wiethoff, Ivan Berest, Sarah Schnabellehner, Martin Schneider, Jonas Becker, Dominic Helm, Dirk Grimm, Taija Mäkinen, Darjus F. Tschaharganeh, Mathias Heikenwalder, Judith B. Zaugg, Moritz Mall","doi":"10.1038/s41588-025-02081-w","DOIUrl":"https://doi.org/10.1038/s41588-025-02081-w","url":null,"abstract":"Cell fate plasticity enables development, yet unlocked plasticity is a cancer hallmark. While transcription master regulators induce lineage-specific genes to restrict plasticity, it remains unclear whether plasticity is actively suppressed by lineage-specific repressors. Here we computationally predict so-called safeguard repressors for 18 cell types that block phenotypic plasticity lifelong. We validated hepatocyte-specific candidates using reprogramming, revealing that prospero homeobox protein 1 (PROX1) enhanced hepatocyte identity by direct repression of alternative fate master regulators. In mice, Prox1 was required for efficient hepatocyte regeneration after injury and was sufficient to prevent liver tumorigenesis. In line with patient data, Prox1 depletion caused hepatocyte fate loss in vivo and enabled the transition of hepatocellular carcinoma to cholangiocarcinoma. Conversely, overexpression promoted cholangiocarcinoma to hepatocellular carcinoma transdifferentiation. Our findings provide evidence for PROX1 as a hepatocyte-specific safeguard and support a model where cell-type-specific repressors actively suppress plasticity throughout life to safeguard lineage identity and thus prevent disease.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"7 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401365","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}

引用次数: 0

DNA loop extrusion is asymmetric but can switch direction

IF 31.7 1区生物学

Nature genetics Pub Date : 2025-02-12 DOI: 10.1038/s41588-025-02102-8

Chiara Anania

引用次数: 0

Engineering extrachromosomal DNA

IF 31.7 1区生物学

Nature genetics Pub Date : 2025-02-12 DOI: 10.1038/s41588-025-02103-7

Safia Danovi

引用次数: 0

Germline mutations increasing pediatric cancer risk

IF 31.7 1区生物学

Nature genetics Pub Date : 2025-02-12 DOI: 10.1038/s41588-025-02104-6

Tiago Faial

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A model of heritable genome editing for complex traits

IF 31.7 1区生物学

Nature genetics Pub Date : 2025-02-12 DOI: 10.1038/s41588-025-02105-5

Michael Fletcher

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Oncofetal reprogramming drives phenotypic plasticity in WNT-dependent colorectal cancer

IF 31.7 1区生物学

Nature genetics Pub Date : 2025-02-10 DOI: 10.1038/s41588-024-02058-1

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

{"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}

引用次数: 0

The African Animal Breeding Network as a pathway towards genetic improvement of livestock

IF 30.8 1区生物学

Nature genetics Pub Date : 2025-02-10 DOI: 10.1038/s41588-025-02079-4

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

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Prioritizing effector genes at trait-associated loci using multimodal evidence

IF 31.7 1区生物学

Nature genetics Pub Date : 2025-02-10 DOI: 10.1038/s41588-025-02084-7

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

{"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}

引用次数: 0