Nature genetics最新文献

{"title":"Spatial mapping of Alzheimer’s disease across genetic subtypes","authors":"Alexi Nott, Inge R. Holtman","doi":"10.1038/s41588-024-01895-4","DOIUrl":"10.1038/s41588-024-01895-4","url":null,"abstract":"Alzheimer’s disease is a complex, heterogeneous disorder with multiple genetic subtypes. Spatial and single-cell gene expression analyses of these subtypes have provided new insights into general and subtype-specific cellular and molecular mechanisms of Alzheimer’s disease.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 12","pages":"2592-2593"},"PeriodicalIF":31.7,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142696620","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":"ChIP-DIP maps binding of hundreds of proteins to DNA simultaneously and identifies diverse gene regulatory elements","authors":"Andrew A. Perez, Isabel N. Goronzy, Mario R. Blanco, Benjamin T. Yeh, Jimmy K. Guo, Carolina S. Lopes, Olivia Ettlin, Alex Burr, Mitchell Guttman","doi":"10.1038/s41588-024-02000-5","DOIUrl":"10.1038/s41588-024-02000-5","url":null,"abstract":"Gene expression is controlled by dynamic localization of thousands of regulatory proteins to precise genomic regions. Understanding this cell type-specific process has been a longstanding goal yet remains challenging because DNA–protein mapping methods generally study one protein at a time. Here, to address this, we developed chromatin immunoprecipitation done in parallel (ChIP-DIP) to generate genome-wide maps of hundreds of diverse regulatory proteins in a single experiment. ChIP-DIP produces highly accurate maps within large pools (>160 proteins) for all classes of DNA-associated proteins, including modified histones, chromatin regulators and transcription factors and across multiple conditions simultaneously. First, we used ChIP-DIP to measure temporal chromatin dynamics in primary dendritic cells following LPS stimulation. Next, we explored quantitative combinations of histone modifications that define distinct classes of regulatory elements and characterized their functional activity in human and mouse cell lines. Overall, ChIP-DIP generates context-specific protein localization maps at consortium scale within any molecular biology laboratory and experimental system. ChIP-DIP (ChIP done in parallel) is a highly multiplex assay for protein–DNA binding, scalable to hundreds of proteins including modified histones, chromatin regulators and transcription factors, offering a refined view of the cis-regulatory code.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 12","pages":"2827-2841"},"PeriodicalIF":31.7,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142696621","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":"Split-pool barcoding serves up an epigenomic smorgasbord","authors":"Vijay Ramani","doi":"10.1038/s41588-024-01980-8","DOIUrl":"10.1038/s41588-024-01980-8","url":null,"abstract":"Perez, Goronzy et al. present ChIP-DIP, which enables multiplex genomic mapping of hundreds of epitopes from a single sample. The authors apply ChIP-DIP to localize modified histones, transcription factors and other chromatin-interacting proteins at scale, in both cell lines and primary cells.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 12","pages":"2596-2597"},"PeriodicalIF":31.7,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142696619","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-cell multiomics analysis reveals dynamic clonal evolution and targetable phenotypes in acute myeloid leukemia with complex karyotype","authors":"Aino-Maija Leppä, Karen Grimes, Hyobin Jeong, Frank Y. Huang, Alvaro Andrades, Alexander Waclawiczek, Tobias Boch, Anna Jauch, Simon Renders, Patrick Stelmach, Carsten Müller-Tidow, Darja Karpova, Markus Sohn, Florian Grünschläger, Patrick Hasenfeld, Eva Benito Garagorri, Vera Thiel, Anna Dolnik, Bernardo Rodriguez-Martin, Lars Bullinger, Krzysztof Mrózek, Ann-Kathrin Eisfeld, Alwin Krämer, Ashley D. Sanders, Jan O. Korbel, Andreas Trumpp","doi":"10.1038/s41588-024-01999-x","DOIUrl":"10.1038/s41588-024-01999-x","url":null,"abstract":"Chromosomal instability is a major driver of intratumoral heterogeneity (ITH), promoting tumor progression. In the present study, we combined structural variant discovery and nucleosome occupancy profiling with transcriptomic and immunophenotypic changes in single cells to study ITH in complex karyotype acute myeloid leukemia (CK-AML). We observed complex structural variant landscapes within individual cells of patients with CK-AML characterized by linear and circular breakage–fusion–bridge cycles and chromothripsis. We identified three clonal evolution patterns in diagnosis or salvage CK-AML (monoclonal, linear and branched polyclonal), with 75% harboring multiple subclones that frequently displayed ongoing karyotype remodeling. Using patient-derived xenografts, we demonstrated varied clonal evolution of leukemic stem cells (LSCs) and further dissected subclone-specific drug–response profiles to identify LSC-targeting therapies, including BCL-xL inhibition. In paired longitudinal patient samples, we further revealed genetic evolution and cell-type plasticity as mechanisms of disease progression. By dissecting dynamic genomic, phenotypic and functional complexity of CK-AML, our findings offer clinically relevant avenues for characterizing and targeting disease-driving LSCs. An integrated single-cell multiomic analysis of complex karyotype acute myeloid leukemia characterizes intratumoral heterogeneity and highlights links to therapeutic sensitivities.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 12","pages":"2790-2803"},"PeriodicalIF":31.7,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01999-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142696622","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":"Spatial and single-nucleus transcriptomic analysis of genetic and sporadic forms of Alzheimer’s disease","authors":"Emily Miyoshi, Samuel Morabito, Caden M. Henningfield, Sudeshna Das, Negin Rahimzadeh, Sepideh Kiani Shabestari, Neethu Michael, Nora Emerson, Fairlie Reese, Zechuan Shi, Zhenkun Cao, Shushrruth Sai Srinivasan, Vanessa M. Scarfone, Miguel A. Arreola, Jackie Lu, Sierra Wright, Justine Silva, Kelsey Leavy, Ira T. Lott, Eric Doran, William H. Yong, Saba Shahin, Mari Perez-Rosendahl, Alzheimer’s Biomarkers Consortium–Down Syndrome (ABC–DS), Elizabeth Head, Kim N. Green, Vivek Swarup","doi":"10.1038/s41588-024-01961-x","DOIUrl":"10.1038/s41588-024-01961-x","url":null,"abstract":"The pathogenesis of Alzheimer’s disease (AD) depends on environmental and heritable factors, with its molecular etiology still unclear. Here we present a spatial transcriptomic (ST) and single-nucleus transcriptomic survey of late-onset sporadic AD and AD in Down syndrome (DSAD). Studying DSAD provides an opportunity to enhance our understanding of the AD transcriptome, potentially bridging the gap between genetic mouse models and sporadic AD. We identified transcriptomic changes that may underlie cortical layer-preferential pathology accumulation. Spatial co-expression network analyses revealed transient and regionally restricted disease processes, including a glial inflammatory program dysregulated in upper cortical layers and implicated in AD genetic risk and amyloid-associated processes. Cell–cell communication analysis further contextualized this gene program in dysregulated signaling networks. Finally, we generated ST data from an amyloid AD mouse model to identify cross-species amyloid-proximal transcriptomic changes with conformational context. Spatial and single-nucleus analyses in human postmortem Alzheimer’s disease (AD) brain tissues at early and late stages from individuals with and without Down syndrome, as well as in AD mouse models, show sex and species-specific phenotypic changes.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 12","pages":"2704-2717"},"PeriodicalIF":31.7,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01961-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142684268","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":"Elucidating the genomic basis of rare pediatric neurological diseases in Central Asia and Transcaucasia","authors":"Rauan Kaiyrzhanov, Nazira Zharkinbekova, Ulviyya Guliyeva, Manizha Ganieva, Zaruhi Tavadyan, Tamar Gachechiladze, Kamran Salayev, Sughra Guliyeva, Mariam Isayan, Mariam Kekenadze, Biayna Sukhudyan, Ani Gevorgyan, Artsruni Hakobyan, Rima Ibadova, Nazi Tabatadze, Ekaterina Kurua, Teona Shatirishvili, Nigara Yerkhojayeva, Kairgali Koneev, Dauren Zhumakhanov, Askhat Mukushev, Altynshash Jaxybayeva, Alissa Nauryzbayeva, Maksudjon Isrofilov, Saadat Badalova, Naila Zeyniyeva, Ilaha Hajiyeva, Leyla Alakbarov, Aynur Zeynalova, Viorica Chelban, Jana Vandrovcova, Valentina Turchetti, David Murphy, Stephanie Efthymiou, Shahryar Alavi, Rahema Mohammad, Tinatin Tkemaladze, Chingiz Shashkin, Nana Nino Tatishvili, Maia Beridze, Samson G. Khachatryan, Gia Melikishvili, John Hardy, Reza Maroofian, Henry Houlden","doi":"10.1038/s41588-024-02016-x","DOIUrl":"10.1038/s41588-024-02016-x","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 12","pages":"2582-2584"},"PeriodicalIF":31.7,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142684248","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 lifesaving revolution delayed","authors":"Susan Weiss Liebman","doi":"10.1038/s41588-024-02013-0","DOIUrl":"10.1038/s41588-024-02013-0","url":null,"abstract":"A family tragedy revealed a hidden genetic mutation and transformed my work as a geneticist into a mission to increase awareness of the critical importance of genetic testing.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 12","pages":"2579-2579"},"PeriodicalIF":31.7,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142684247","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 analysis provides insights into the molecular etiology of dilated cardiomyopathy","authors":"Sean L. Zheng, Albert Henry, Douglas Cannie, Michael Lee, David Miller, Kathryn A. McGurk, Isabelle Bond, Xiao Xu, Hanane Issa, Catherine Francis, Antonio De Marvao, Pantazis I. Theotokis, Rachel J. Buchan, Doug Speed, Erik Abner, Lance Adams, Krishna G. Aragam, Johan Ärnlöv, Anna Axelsson Raja, Joshua D. Backman, John Baksi, Paul J. R. Barton, Kiran J. Biddinger, Eric Boersma, Jeffrey Brandimarto, Søren Brunak, Henning Bundgaard, David J. Carey, Philippe Charron, James P. Cook, Stuart A. Cook, Spiros Denaxas, Jean-François Deleuze, Alexander S. Doney, Perry Elliott, Christian Erikstrup, Tõnu Esko, Eric H. Farber-Eger, Chris Finan, Sophie Garnier, Jonas Ghouse, Vilmantas Giedraitis, Daniel F. Guðbjartsson, Christopher M. Haggerty, Brian P. Halliday, Anna Helgadottir, Harry Hemingway, Hans L. Hillege, Isabella Kardys, Lars Lind, Cecilia M. Lindgren, Brandon D. Lowery, Charlotte Manisty, Kenneth B. Margulies, James C. Moon, Ify R. Mordi, Michael P. Morley, Andrew D. Morris, Andrew P. Morris, Lori Morton, Mahdad Noursadeghi, Sisse R. Ostrowski, Anjali T. Owens, Colin N. A. Palmer, Antonis Pantazis, Ole B. V. Pedersen, Sanjay K. Prasad, Akshay Shekhar, Diane T. Smelser, Sundararajan Srinivasan, Kari Stefansson, Garðar Sveinbjörnsson, Petros Syrris, Mari-Liis Tammesoo, Upasana Tayal, Maris Teder-Laving, Guðmundur Thorgeirsson, Unnur Thorsteinsdottir, Vinicius Tragante, David-Alexandre Trégouët, Thomas A. Treibel, Henrik Ullum, Ana M. Valdes, Jessica van Setten, Marion van Vugt, Abirami Veluchamy, W. M. Monique Verschuren, Eric Villard, Yifan Yang, COVIDsortium, DBDS Genomic Consortium, Estonian Biobank Research Team, HERMES Consortium, Folkert W. Asselbergs, Thomas P. Cappola, Marie-Pierre Dube, Michael E. Dunn, Patrick T. Ellinor, Aroon D. Hingorani, Chim C. Lang, Nilesh J. Samani, Svati H. Shah, J. Gustav Smith, Ramachandran S. Vasan, Declan P. O’Regan, Hilma Holm, Michela Noseda, Quinn Wells, James S. Ware, R. Thomas Lumbers","doi":"10.1038/s41588-024-01952-y","DOIUrl":"10.1038/s41588-024-01952-y","url":null,"abstract":"Dilated cardiomyopathy (DCM) is a leading cause of heart failure and cardiac transplantation. We report a genome-wide association study and multi-trait analysis of DCM (14,256 cases) and three left ventricular traits (36,203 UK Biobank participants). We identified 80 genomic risk loci and prioritized 62 putative effector genes, including several with rare variant DCM associations (MAP3K7, NEDD4L and SSPN). Using single-nucleus transcriptomics, we identify cellular states, biological pathways, and intracellular communications that drive pathogenesis. We demonstrate that polygenic scores predict DCM in the general population and modify penetrance in carriers of rare DCM variants. Our findings may inform the design of genetic testing strategies that incorporate polygenic background. They also provide insights into the molecular etiology of DCM that may facilitate the development of targeted therapeutics. Genome-wide association analyses comprising 14,256 cases and 1,199,156 controls and incorporating correlated cardiac magnetic resonance imaging traits provide insights into the molecular etiology of dilated cardiomyopathy.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 12","pages":"2646-2658"},"PeriodicalIF":31.7,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01952-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142678340","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-wide association study reveals mechanisms underlying dilated cardiomyopathy and myocardial resilience","authors":"Sean J. Jurgens, Joel T. Rämö, Daria R. Kramarenko, Leonoor F. J. M. Wijdeveld, Jan Haas, Mark D. Chaffin, Sophie Garnier, Liam Gaziano, Lu-Chen Weng, Alex Lipov, Sean L. Zheng, Albert Henry, Jennifer E. Huffman, Saketh Challa, Frank Rühle, Carmen Diaz Verdugo, Christian Krijger Juárez, Shinwan Kany, Constance A. van Orsouw, Kiran Biddinger, Edwin Poel, Amanda L. Elliott, Xin Wang, Catherine Francis, Richard Ruan, Satoshi Koyama, Leander Beekman, Dominic S. Zimmerman, Jean-François Deleuze, Eric Villard, David-Alexandre Trégouët, Richard Isnard, FinnGen, VA Million Veteran Program, HERMES Consortium, Dorret I. Boomsma, Eco J. C. de Geus, Rafik Tadros, Yigal M. Pinto, Arthur A. M. Wilde, Jouke-Jan Hottenga, Juha Sinisalo, Teemu Niiranen, Roddy Walsh, Amand F. Schmidt, Seung Hoan Choi, Kyong-Mi Chang, Philip S. Tsao, Paul M. Matthews, James S. Ware, R. Thomas Lumbers, Saskia van der Crabben, Jari Laukkanen, Aarno Palotie, Ahmad S. Amin, Philippe Charron, Benjamin Meder, Patrick T. Ellinor, Mark Daly, Krishna G. Aragam, Connie R. Bezzina","doi":"10.1038/s41588-024-01975-5","DOIUrl":"10.1038/s41588-024-01975-5","url":null,"abstract":"Dilated cardiomyopathy (DCM) is a heart muscle disease that represents an important cause of morbidity and mortality, yet causal mechanisms remain largely elusive. Here, we perform a large-scale genome-wide association study and multitrait analysis for DCM using 9,365 cases and 946,368 controls. We identify 70 genome-wide significant loci, which show broad replication in independent samples and map to 63 prioritized genes. Tissue, cell type and pathway enrichment analyses highlight the central role of the cardiomyocyte and contractile apparatus in DCM pathogenesis. Polygenic risk scores constructed from our genome-wide association study predict DCM across different ancestry groups, show differing contributions to DCM depending on rare pathogenic variant status and associate with systolic heart failure across various clinical settings. Mendelian randomization analyses reveal actionable potential causes of DCM, including higher bodyweight and higher systolic blood pressure. Our findings provide insights into the genetic architecture and mechanisms underlying DCM and myocardial function more broadly. Genome-wide association and multitrait analyses for dilated cardiomyopathy (DCM) using 9,365 cases and 946,368 controls provide insights into the mechanisms underlying DCM and myocardial resilience","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 12","pages":"2636-2645"},"PeriodicalIF":31.7,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01975-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142678341","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":"Epigenetic scars of Brca1 loss point toward breast cancer cell of origin","authors":"Steven M. Lewis, Camila dos Santos","doi":"10.1038/s41588-024-02021-0","DOIUrl":"10.1038/s41588-024-02021-0","url":null,"abstract":"The two-hit hypothesis suggests that a second mutation is necessary for cancer development in cells with a defective tumor-suppressor gene, such as BRCA1. However, a study now shows that the loss of just one Brca1 allele in mice can pre-program cells for cancer-promoting changes, indicating cancer may progress earlier than previously thought.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 12","pages":"2594-2595"},"PeriodicalIF":31.7,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673218","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}