Pub Date : 2025-01-08DOI: 10.1038/s41588-024-02036-7
Tsion Abay, Robert R. Stickels, Meril T. Takizawa, Benan N. Nalbant, Yu-Hsin Hsieh, Sidney Hwang, Catherine Snopkowski, Kenny Kwok Hei Yu, Zaki Abou-Mrad, Viviane Tabar, Brooke E. Howitt, Leif S. Ludwig, Ronan Chaligné, Ansuman T. Satpathy, Caleb A. Lareau
Single-cell genomics technologies have accelerated our understanding of cell-state heterogeneity in diverse contexts. Although single-cell RNA sequencing identifies rare populations that express specific marker transcript combinations, traditional flow sorting requires cell surface markers with high-fidelity antibodies, limiting our ability to interrogate these populations. In addition, many single-cell studies require the isolation of nuclei from tissue, eliminating the ability to enrich learned rare cell states based on extranuclear protein markers. In the present report, we addressed these limitations by developing Programmable Enrichment via RNA FlowFISH by sequencing (PERFF-seq), a scalable assay that enables scRNA-seq profiling of subpopulations defined by the abundance of specific RNA transcripts. Across immune populations (n = 184,126 cells) and fresh-frozen and formalin-fixed, paraffin-embedded brain tissue (n = 33,145 nuclei), we demonstrated that programmable sorting logic via RNA-based cytometry can isolate rare cell populations and uncover phenotypic heterogeneity via downstream, high-throughput, single-cell genomics analyses. Programmable Enrichment via RNA FlowFISH by sequencing (PERFF-seq) isolates rare cells based on RNA marker transcripts for single-cell RNA sequencing profiling of complex tissues, with applicability to a broad variety of samples and cell types.
{"title":"Transcript-specific enrichment enables profiling of rare cell states via single-cell RNA sequencing","authors":"Tsion Abay, Robert R. Stickels, Meril T. Takizawa, Benan N. Nalbant, Yu-Hsin Hsieh, Sidney Hwang, Catherine Snopkowski, Kenny Kwok Hei Yu, Zaki Abou-Mrad, Viviane Tabar, Brooke E. Howitt, Leif S. Ludwig, Ronan Chaligné, Ansuman T. Satpathy, Caleb A. Lareau","doi":"10.1038/s41588-024-02036-7","DOIUrl":"10.1038/s41588-024-02036-7","url":null,"abstract":"Single-cell genomics technologies have accelerated our understanding of cell-state heterogeneity in diverse contexts. Although single-cell RNA sequencing identifies rare populations that express specific marker transcript combinations, traditional flow sorting requires cell surface markers with high-fidelity antibodies, limiting our ability to interrogate these populations. In addition, many single-cell studies require the isolation of nuclei from tissue, eliminating the ability to enrich learned rare cell states based on extranuclear protein markers. In the present report, we addressed these limitations by developing Programmable Enrichment via RNA FlowFISH by sequencing (PERFF-seq), a scalable assay that enables scRNA-seq profiling of subpopulations defined by the abundance of specific RNA transcripts. Across immune populations (n = 184,126 cells) and fresh-frozen and formalin-fixed, paraffin-embedded brain tissue (n = 33,145 nuclei), we demonstrated that programmable sorting logic via RNA-based cytometry can isolate rare cell populations and uncover phenotypic heterogeneity via downstream, high-throughput, single-cell genomics analyses. Programmable Enrichment via RNA FlowFISH by sequencing (PERFF-seq) isolates rare cells based on RNA marker transcripts for single-cell RNA sequencing profiling of complex tissues, with applicability to a broad variety of samples and cell types.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 2","pages":"451-460"},"PeriodicalIF":31.7,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936099","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}
Pub Date : 2025-01-07DOI: 10.1038/s41588-024-02039-4
Julianne S. Funk, Maria Klimovich, Daniel Drangenstein, Ole Pielhoop, Pascal Hunold, Anna Borowek, Maxim Noeparast, Evangelos Pavlakis, Michelle Neumann, Dimitrios-Ilias Balourdas, Katharina Kochhan, Nastasja Merle, Imke Bullwinkel, Michael Wanzel, Sabrina Elmshäuser, Julia Teply-Szymanski, Andrea Nist, Tara Procida, Marek Bartkuhn, Katharina Humpert, Marco Mernberger, Rajkumar Savai, Thierry Soussi, Andreas C. Joerger, Thorsten Stiewe
The mutational landscape of TP53, a tumor suppressor mutated in about half of all cancers, includes over 2,000 known missense mutations. To fully leverage TP53 mutation status for personalized medicine, a thorough understanding of the functional diversity of these mutations is essential. We conducted a deep mutational scan using saturation genome editing with CRISPR-mediated homology-directed repair to engineer 9,225 TP53 variants in cancer cells. This high-resolution approach, covering 94.5% of all cancer-associated TP53 missense mutations, precisely mapped the impact of individual mutations on tumor cell fitness, surpassing previous deep mutational scan studies in distinguishing benign from pathogenic variants. Our results revealed even subtle loss-of-function phenotypes and identified promising mutants for pharmacological reactivation. Moreover, we uncovered the roles of splicing alterations and nonsense-mediated messenger RNA decay in mutation-driven TP53 dysfunction. These findings underscore the power of saturation genome editing in advancing clinical TP53 variant interpretation for genetic counseling and personalized cancer therapy. A large-scale CRISPR-mediated deep mutational scanning approach is used to interrogate the function of mutations in the endogenous locus of TP53 mapping to the DNA-binding domain.
{"title":"Deep CRISPR mutagenesis characterizes the functional diversity of TP53 mutations","authors":"Julianne S. Funk, Maria Klimovich, Daniel Drangenstein, Ole Pielhoop, Pascal Hunold, Anna Borowek, Maxim Noeparast, Evangelos Pavlakis, Michelle Neumann, Dimitrios-Ilias Balourdas, Katharina Kochhan, Nastasja Merle, Imke Bullwinkel, Michael Wanzel, Sabrina Elmshäuser, Julia Teply-Szymanski, Andrea Nist, Tara Procida, Marek Bartkuhn, Katharina Humpert, Marco Mernberger, Rajkumar Savai, Thierry Soussi, Andreas C. Joerger, Thorsten Stiewe","doi":"10.1038/s41588-024-02039-4","DOIUrl":"10.1038/s41588-024-02039-4","url":null,"abstract":"The mutational landscape of TP53, a tumor suppressor mutated in about half of all cancers, includes over 2,000 known missense mutations. To fully leverage TP53 mutation status for personalized medicine, a thorough understanding of the functional diversity of these mutations is essential. We conducted a deep mutational scan using saturation genome editing with CRISPR-mediated homology-directed repair to engineer 9,225 TP53 variants in cancer cells. This high-resolution approach, covering 94.5% of all cancer-associated TP53 missense mutations, precisely mapped the impact of individual mutations on tumor cell fitness, surpassing previous deep mutational scan studies in distinguishing benign from pathogenic variants. Our results revealed even subtle loss-of-function phenotypes and identified promising mutants for pharmacological reactivation. Moreover, we uncovered the roles of splicing alterations and nonsense-mediated messenger RNA decay in mutation-driven TP53 dysfunction. These findings underscore the power of saturation genome editing in advancing clinical TP53 variant interpretation for genetic counseling and personalized cancer therapy. A large-scale CRISPR-mediated deep mutational scanning approach is used to interrogate the function of mutations in the endogenous locus of TP53 mapping to the DNA-binding domain.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 1","pages":"140-153"},"PeriodicalIF":31.7,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-02039-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142934766","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}
Pub Date : 2025-01-06DOI: 10.1038/s41588-024-02025-w
Elina Wiechens, Flavia Vigliotti, Kanstantsin Siniuk, Robert Schwarz, Katjana Schwab, Konstantin Riege, Alena van Bömmel, Ivonne Görlich, Martin Bens, Arne Sahm, Marco Groth, Morgan A. Sammons, Alexander Loewer, Steve Hoffmann, Martin Fischer
Convergent transcription, that is, the collision of sense and antisense transcription, is ubiquitous in mammalian genomes and believed to diminish RNA expression. Recently, antisense transcription downstream of promoters was found to be surprisingly prevalent. However, functional characteristics of affected promoters are poorly investigated. Here we show that convergent transcription marks an unexpected positively co-regulated promoter constellation. By assessing transcriptional dynamic systems, we identified co-regulated constituent promoters connected through a distinct chromatin structure. Within these cis-regulatory domains, transcription factors can regulate both constituting promoters by binding to only one of them. Convergent promoters comprise about a quarter of all active transcript start sites and initiate 5′-overlapping antisense RNAs—an RNA class believed previously to be rare. Visualization of nascent RNA molecules reveals convergent cotranscription at these loci. Together, our results demonstrate that co-regulated convergent promoters substantially expand the cis-regulatory repertoire, reveal limitations of the transcription interference model and call for adjusting the promoter concept. Genome-wide analysis and genetic manipulation at loci regulated by p53, E2F4 and RFX7 show that convergent promoters with similar epigenetic features can be co-regulated and simultaneously expressed in the same direction.
{"title":"Gene regulation by convergent promoters","authors":"Elina Wiechens, Flavia Vigliotti, Kanstantsin Siniuk, Robert Schwarz, Katjana Schwab, Konstantin Riege, Alena van Bömmel, Ivonne Görlich, Martin Bens, Arne Sahm, Marco Groth, Morgan A. Sammons, Alexander Loewer, Steve Hoffmann, Martin Fischer","doi":"10.1038/s41588-024-02025-w","DOIUrl":"10.1038/s41588-024-02025-w","url":null,"abstract":"Convergent transcription, that is, the collision of sense and antisense transcription, is ubiquitous in mammalian genomes and believed to diminish RNA expression. Recently, antisense transcription downstream of promoters was found to be surprisingly prevalent. However, functional characteristics of affected promoters are poorly investigated. Here we show that convergent transcription marks an unexpected positively co-regulated promoter constellation. By assessing transcriptional dynamic systems, we identified co-regulated constituent promoters connected through a distinct chromatin structure. Within these cis-regulatory domains, transcription factors can regulate both constituting promoters by binding to only one of them. Convergent promoters comprise about a quarter of all active transcript start sites and initiate 5′-overlapping antisense RNAs—an RNA class believed previously to be rare. Visualization of nascent RNA molecules reveals convergent cotranscription at these loci. Together, our results demonstrate that co-regulated convergent promoters substantially expand the cis-regulatory repertoire, reveal limitations of the transcription interference model and call for adjusting the promoter concept. Genome-wide analysis and genetic manipulation at loci regulated by p53, E2F4 and RFX7 show that convergent promoters with similar epigenetic features can be co-regulated and simultaneously expressed in the same direction.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 1","pages":"206-217"},"PeriodicalIF":31.7,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-02025-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142937083","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}
Pub Date : 2025-01-03DOI: 10.1038/s41588-024-02030-z
Frederik Prip, Philippe Lamy, Sia Viborg Lindskrog, Trine Strandgaard, Iver Nordentoft, Karin Birkenkamp-Demtröder, Nicolai Juul Birkbak, Nanna Kristjánsdóttir, Asbjørn Kjær, Tine G. Andreasen, Johanne Ahrenfeldt, Jakob Skou Pedersen, Asta Mannstaedt Rasmussen, Gregers G. Hermann, Karin Mogensen, Astrid C. Petersen, Arndt Hartmann, Marc-Oliver Grimm, Marcus Horstmann, Roman Nawroth, Ulrika Segersten, Danijel Sikic, Kim E. M. van Kessel, Ellen C. Zwarthoff, Tobias Maurer, Tatjana Simic, Per-Uno Malmström, Núria Malats, Jørgen Bjerggaard Jensen, UROMOL Consortium, Francisco X. Real, Lars Dyrskjøt
Understanding the molecular landscape of nonmuscle-invasive bladder cancer (NMIBC) is essential to improve risk assessment and treatment regimens. We performed a comprehensive genomic analysis of patients with NMIBC using whole-exome sequencing (n = 438), shallow whole-genome sequencing (n = 362) and total RNA sequencing (n = 414). A large genomic variation within NMIBC was observed and correlated with different molecular subtypes. Frequent loss of heterozygosity in FGFR3 and 17p (affecting TP53) was found in tumors with mutations in FGFR3 and TP53, respectively. Whole-genome doubling (WGD) was observed in 15% of the tumors and was associated with worse outcomes. Tumors with WGD were genomically unstable, with alterations in cell-cycle-related genes and an altered immune composition. Finally, integrative clustering of multi-omics data highlighted the important role of genomic instability and immune cell exhaustion in disease aggressiveness. These findings advance our understanding of genomic differences associated with disease aggressiveness in NMIBC and may ultimately improve patient stratification. A genomic and transcriptomic analysis of nonmuscle-invasive bladder cancer identifies four molecular subtypes, and associates whole-genome duplication and immune exhaustion with tumor progression.
{"title":"Comprehensive genomic characterization of early-stage bladder cancer","authors":"Frederik Prip, Philippe Lamy, Sia Viborg Lindskrog, Trine Strandgaard, Iver Nordentoft, Karin Birkenkamp-Demtröder, Nicolai Juul Birkbak, Nanna Kristjánsdóttir, Asbjørn Kjær, Tine G. Andreasen, Johanne Ahrenfeldt, Jakob Skou Pedersen, Asta Mannstaedt Rasmussen, Gregers G. Hermann, Karin Mogensen, Astrid C. Petersen, Arndt Hartmann, Marc-Oliver Grimm, Marcus Horstmann, Roman Nawroth, Ulrika Segersten, Danijel Sikic, Kim E. M. van Kessel, Ellen C. Zwarthoff, Tobias Maurer, Tatjana Simic, Per-Uno Malmström, Núria Malats, Jørgen Bjerggaard Jensen, UROMOL Consortium, Francisco X. Real, Lars Dyrskjøt","doi":"10.1038/s41588-024-02030-z","DOIUrl":"10.1038/s41588-024-02030-z","url":null,"abstract":"Understanding the molecular landscape of nonmuscle-invasive bladder cancer (NMIBC) is essential to improve risk assessment and treatment regimens. We performed a comprehensive genomic analysis of patients with NMIBC using whole-exome sequencing (n = 438), shallow whole-genome sequencing (n = 362) and total RNA sequencing (n = 414). A large genomic variation within NMIBC was observed and correlated with different molecular subtypes. Frequent loss of heterozygosity in FGFR3 and 17p (affecting TP53) was found in tumors with mutations in FGFR3 and TP53, respectively. Whole-genome doubling (WGD) was observed in 15% of the tumors and was associated with worse outcomes. Tumors with WGD were genomically unstable, with alterations in cell-cycle-related genes and an altered immune composition. Finally, integrative clustering of multi-omics data highlighted the important role of genomic instability and immune cell exhaustion in disease aggressiveness. These findings advance our understanding of genomic differences associated with disease aggressiveness in NMIBC and may ultimately improve patient stratification. A genomic and transcriptomic analysis of nonmuscle-invasive bladder cancer identifies four molecular subtypes, and associates whole-genome duplication and immune exhaustion with tumor progression.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 1","pages":"115-125"},"PeriodicalIF":31.7,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-02030-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142917043","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}
Pub Date : 2025-01-03DOI: 10.1038/s41588-024-02014-z
John J. Y. Lee, Ran Tao, Zhen You, Parthiv Haldipur, Anders W. Erickson, Hamza Farooq, Liam D. Hendriske, Namal Abeysundara, Cory M. Richman, Evan Y. Wang, Neha Das Gupta, Jennifer Hadley, Melissa Batts, Christopher W. Mount, Xiaochong Wu, Alex Rasnitsyn, Swneke Bailey, Florence M. G. Cavalli, Sorana Morrissy, Livia Garzia, Kulandaimanuvel Antony Michealraj, Abhi Visvanathan, Vernon Fong, Jonelle Palotta, Raul Suarez, Bryn G. Livingston, Miao Liu, Betty Luu, Craig Daniels, James Loukides, Anne Bendel, Pim J. French, Johan M. Kros, Andrey Korshunov, Marcel Kool, Fernando Chico Ponce de León, Mario Perezpeña-Diazconti, Boleslaw Lach, Sheila K. Singh, Sarah E. S. Leary, Byung-Kyu Cho, Seung-Ki Kim, Kyu-Chang Wang, Ji-Yeoun Lee, Teiji Tominaga, William A. Weiss, Joanna J. Phillips, Shizhong Dai, Gelareh Zadeh, Ali G. Saad, László Bognár, Almos Klekner, Ian F. Pollack, Ronald L. Hamilton, Young-shin Ra, Wieslawa A. Grajkowska, Marta Perek-Polnik, Reid C. Thompson, Anna M. Kenney, Michael K. Cooper, Stephen C. Mack, Nada Jabado, Mathieu Lupien, Marco Gallo, Vijay Ramaswamy, Mario L. Suva, Hiromichi Suzuki, Kathleen J. Millen, L. Frank Huang, Paul A. Northcott, Michael D. Taylor
Transcription factors are frequent cancer driver genes, exhibiting noted specificity based on the precise cell of origin. We demonstrate that ZIC1 exhibits loss-of-function (LOF) somatic events in group 4 (G4) medulloblastoma through recurrent point mutations, subchromosomal deletions and mono-allelic epigenetic repression (60% of G4 medulloblastoma). In contrast, highly similar SHH medulloblastoma exhibits distinct and diametrically opposed gain-of-function mutations and copy number gains (20% of SHH medulloblastoma). Overexpression of ZIC1 suppresses the growth of group 3 medulloblastoma models, whereas it promotes the proliferation of SHH medulloblastoma precursor cells. SHH medulloblastoma ZIC1 mutants show increased activity versus wild-type ZIC1, whereas G4 medulloblastoma ZIC1 mutants exhibit LOF phenotypes. Distinct ZIC1 mutations affect cells of the rhombic lip in diametrically opposed ways, suggesting that ZIC1 is a critical developmental transcriptional regulator in both the normal and transformed rhombic lip and identifying ZIC1 as an exquisitely context-dependent driver gene in medulloblastoma. Analysis of medulloblastomas in humans and mice shows that the functional consequences of ZIC1 mutations are exquisitely dependent on the cells of origin that give rise to different subgroups of medulloblastoma.
{"title":"ZIC1 is a context-dependent medulloblastoma driver in the rhombic lip","authors":"John J. Y. Lee, Ran Tao, Zhen You, Parthiv Haldipur, Anders W. Erickson, Hamza Farooq, Liam D. Hendriske, Namal Abeysundara, Cory M. Richman, Evan Y. Wang, Neha Das Gupta, Jennifer Hadley, Melissa Batts, Christopher W. Mount, Xiaochong Wu, Alex Rasnitsyn, Swneke Bailey, Florence M. G. Cavalli, Sorana Morrissy, Livia Garzia, Kulandaimanuvel Antony Michealraj, Abhi Visvanathan, Vernon Fong, Jonelle Palotta, Raul Suarez, Bryn G. Livingston, Miao Liu, Betty Luu, Craig Daniels, James Loukides, Anne Bendel, Pim J. French, Johan M. Kros, Andrey Korshunov, Marcel Kool, Fernando Chico Ponce de León, Mario Perezpeña-Diazconti, Boleslaw Lach, Sheila K. Singh, Sarah E. S. Leary, Byung-Kyu Cho, Seung-Ki Kim, Kyu-Chang Wang, Ji-Yeoun Lee, Teiji Tominaga, William A. Weiss, Joanna J. Phillips, Shizhong Dai, Gelareh Zadeh, Ali G. Saad, László Bognár, Almos Klekner, Ian F. Pollack, Ronald L. Hamilton, Young-shin Ra, Wieslawa A. Grajkowska, Marta Perek-Polnik, Reid C. Thompson, Anna M. Kenney, Michael K. Cooper, Stephen C. Mack, Nada Jabado, Mathieu Lupien, Marco Gallo, Vijay Ramaswamy, Mario L. Suva, Hiromichi Suzuki, Kathleen J. Millen, L. Frank Huang, Paul A. Northcott, Michael D. Taylor","doi":"10.1038/s41588-024-02014-z","DOIUrl":"10.1038/s41588-024-02014-z","url":null,"abstract":"Transcription factors are frequent cancer driver genes, exhibiting noted specificity based on the precise cell of origin. We demonstrate that ZIC1 exhibits loss-of-function (LOF) somatic events in group 4 (G4) medulloblastoma through recurrent point mutations, subchromosomal deletions and mono-allelic epigenetic repression (60% of G4 medulloblastoma). In contrast, highly similar SHH medulloblastoma exhibits distinct and diametrically opposed gain-of-function mutations and copy number gains (20% of SHH medulloblastoma). Overexpression of ZIC1 suppresses the growth of group 3 medulloblastoma models, whereas it promotes the proliferation of SHH medulloblastoma precursor cells. SHH medulloblastoma ZIC1 mutants show increased activity versus wild-type ZIC1, whereas G4 medulloblastoma ZIC1 mutants exhibit LOF phenotypes. Distinct ZIC1 mutations affect cells of the rhombic lip in diametrically opposed ways, suggesting that ZIC1 is a critical developmental transcriptional regulator in both the normal and transformed rhombic lip and identifying ZIC1 as an exquisitely context-dependent driver gene in medulloblastoma. Analysis of medulloblastomas in humans and mice shows that the functional consequences of ZIC1 mutations are exquisitely dependent on the cells of origin that give rise to different subgroups of medulloblastoma.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 1","pages":"88-102"},"PeriodicalIF":31.7,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-02014-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142917044","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}
Modern sugarcane, a highly allo-autopolyploid organism, has a very complex genome. In the present study, the karyotype and genome architecture of modern sugarcane were investigated, resulting in a genome assembly of 97 chromosomes (8.84 Gb). The allopolyploid genome was divided into subgenomes from Saccharum officinarum (Soh) and S. spontaneum (Ssh), with Soh dominance in the Saccharum hybrid (S. hybrid). Genome shock affected transcriptome dynamics during allopolyploidization. Analysis of an inbreeding population with 192 individuals revealed the underlying genetic basis of transgressive segregation. Population genomics of 310 Saccharum accessions clarified the breeding history of modern sugarcane. Using the haplotype-resolved S. hybrid genome as a reference, genome-wide association studies identified a potential candidate gene for sugar content from S. spontaneum. These findings illuminate the complex genome evolution of allopolyploids, offering opportunities for genomic enhancements and innovative breeding strategies for sugarcane. A haplotype-resolved genome of hybrid sugarcane cultivar XTT22 and population analyses of Saccharum accessions highlight the genome evolution of allopolyploids and provide opportunities for sugarcane breeding.
{"title":"The highly allo-autopolyploid modern sugarcane genome and very recent allopolyploidization in Saccharum","authors":"Jisen Zhang, Yiying Qi, Xiuting Hua, Yongjun Wang, Baiyu Wang, Yongwen Qi, Yumin Huang, Zehuai Yu, Ruiting Gao, Yixing Zhang, Tianyou Wang, Yuhao Wang, Jing Mei, Qing Zhang, Gang Wang, Haoran Pan, Zhen Li, Shuangyu Li, Jia Liu, Nameng Qi, Xiaoxi Feng, Mingxing Wu, Shuqi Chen, Cuicui Du, Yihan Li, Yi Xu, Yaxue Fang, Panpan Ma, Qingyun Li, Yuanchang Sun, Xiaomin Feng, Wei Yao, Muqing Zhang, Baoshan Chen, Xinlong Liu, Ray Ming, Jianping Wang, Zuhu Deng, Haibao Tang","doi":"10.1038/s41588-024-02033-w","DOIUrl":"10.1038/s41588-024-02033-w","url":null,"abstract":"Modern sugarcane, a highly allo-autopolyploid organism, has a very complex genome. In the present study, the karyotype and genome architecture of modern sugarcane were investigated, resulting in a genome assembly of 97 chromosomes (8.84 Gb). The allopolyploid genome was divided into subgenomes from Saccharum officinarum (Soh) and S. spontaneum (Ssh), with Soh dominance in the Saccharum hybrid (S. hybrid). Genome shock affected transcriptome dynamics during allopolyploidization. Analysis of an inbreeding population with 192 individuals revealed the underlying genetic basis of transgressive segregation. Population genomics of 310 Saccharum accessions clarified the breeding history of modern sugarcane. Using the haplotype-resolved S. hybrid genome as a reference, genome-wide association studies identified a potential candidate gene for sugar content from S. spontaneum. These findings illuminate the complex genome evolution of allopolyploids, offering opportunities for genomic enhancements and innovative breeding strategies for sugarcane. A haplotype-resolved genome of hybrid sugarcane cultivar XTT22 and population analyses of Saccharum accessions highlight the genome evolution of allopolyploids and provide opportunities for sugarcane breeding.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 1","pages":"242-253"},"PeriodicalIF":31.7,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142917045","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}
Pub Date : 2025-01-03DOI: 10.1038/s41588-024-02031-y
Guochong Jia, Zhishan Chen, Jie Ping, Qiuyin Cai, Ran Tao, Chao Li, Joshua A. Bauer, Yuhan Xie, Stefan Ambs, Mollie E. Barnard, Yu Chen, Ji-Yeob Choi, Yu-Tang Gao, Montserrat Garcia-Closas, Jian Gu, Jennifer J. Hu, Motoki Iwasaki, Esther M. John, Sun-Seog Kweon, Christopher I. Li, Koichi Matsuda, Keitaro Matsuo, Katherine L. Nathanson, Barbara Nemesure, Olufunmilayo I. Olopade, Tuya Pal, Sue K. Park, Boyoung Park, Michael F. Press, Maureen Sanderson, Dale P. Sandler, Chen-Yang Shen, Melissa A. Troester, Song Yao, Ying Zheng, Thomas Ahearn, Abenaa M. Brewster, Adeyinka Falusi, Anselm J. M. Hennis, Hidemi Ito, Michiaki Kubo, Eun-Sook Lee, Timothy Makumbi, Paul Ndom, Dong-Young Noh, Katie M. O’Brien, Oladosu Ojengbede, Andrew F. Olshan, Min-Ho Park, Sonya Reid, Taiki Yamaji, Gary Zirpoli, Ebonee N. Butler, Maosheng Huang, Siew-Kee Low, John Obafunwa, Clarice R. Weinberg, Haoyu Zhang, Hongyu Zhao, Michelle L. Cote, Christine B. Ambrosone, Dezheng Huo, Bingshan Li, Daehee Kang, Julie R. Palmer, Xiao-Ou Shu, Christopher A. Haiman, Xingyi Guo, Jirong Long, Wei Zheng
Genome-wide association studies have identified approximately 200 genetic risk loci for breast cancer, but the causal variants and target genes are mostly unknown. We sought to fine-map all known breast cancer risk loci using genome-wide association study data from 172,737 female breast cancer cases and 242,009 controls of African, Asian and European ancestry. We identified 332 independent association signals for breast cancer risk, including 131 signals not reported previously, and for 50 of them, we narrowed the credible causal variants down to a single variant. Analyses integrating functional genomics data identified 195 putative susceptibility genes, enriched in PI3K/AKT, TNF/NF-κB, p53 and Wnt/β-catenin pathways. Single-cell RNA sequencing or in vitro experiment data provided additional functional evidence for 105 genes. Our study uncovered large numbers of association signals and candidate susceptibility genes for breast cancer, uncovered breast cancer genetics and biology, and supported the value of including multi-ancestry data in fine-mapping analyses. Multi-ancestry fine-mapping of breast cancer susceptibility regions identifies candidate causal variants and prioritizes likely effector genes supported by functional genomic evidence.
{"title":"Refining breast cancer genetic risk and biology through multi-ancestry fine-mapping analyses of 192 risk regions","authors":"Guochong Jia, Zhishan Chen, Jie Ping, Qiuyin Cai, Ran Tao, Chao Li, Joshua A. Bauer, Yuhan Xie, Stefan Ambs, Mollie E. Barnard, Yu Chen, Ji-Yeob Choi, Yu-Tang Gao, Montserrat Garcia-Closas, Jian Gu, Jennifer J. Hu, Motoki Iwasaki, Esther M. John, Sun-Seog Kweon, Christopher I. Li, Koichi Matsuda, Keitaro Matsuo, Katherine L. Nathanson, Barbara Nemesure, Olufunmilayo I. Olopade, Tuya Pal, Sue K. Park, Boyoung Park, Michael F. Press, Maureen Sanderson, Dale P. Sandler, Chen-Yang Shen, Melissa A. Troester, Song Yao, Ying Zheng, Thomas Ahearn, Abenaa M. Brewster, Adeyinka Falusi, Anselm J. M. Hennis, Hidemi Ito, Michiaki Kubo, Eun-Sook Lee, Timothy Makumbi, Paul Ndom, Dong-Young Noh, Katie M. O’Brien, Oladosu Ojengbede, Andrew F. Olshan, Min-Ho Park, Sonya Reid, Taiki Yamaji, Gary Zirpoli, Ebonee N. Butler, Maosheng Huang, Siew-Kee Low, John Obafunwa, Clarice R. Weinberg, Haoyu Zhang, Hongyu Zhao, Michelle L. Cote, Christine B. Ambrosone, Dezheng Huo, Bingshan Li, Daehee Kang, Julie R. Palmer, Xiao-Ou Shu, Christopher A. Haiman, Xingyi Guo, Jirong Long, Wei Zheng","doi":"10.1038/s41588-024-02031-y","DOIUrl":"10.1038/s41588-024-02031-y","url":null,"abstract":"Genome-wide association studies have identified approximately 200 genetic risk loci for breast cancer, but the causal variants and target genes are mostly unknown. We sought to fine-map all known breast cancer risk loci using genome-wide association study data from 172,737 female breast cancer cases and 242,009 controls of African, Asian and European ancestry. We identified 332 independent association signals for breast cancer risk, including 131 signals not reported previously, and for 50 of them, we narrowed the credible causal variants down to a single variant. Analyses integrating functional genomics data identified 195 putative susceptibility genes, enriched in PI3K/AKT, TNF/NF-κB, p53 and Wnt/β-catenin pathways. Single-cell RNA sequencing or in vitro experiment data provided additional functional evidence for 105 genes. Our study uncovered large numbers of association signals and candidate susceptibility genes for breast cancer, uncovered breast cancer genetics and biology, and supported the value of including multi-ancestry data in fine-mapping analyses. Multi-ancestry fine-mapping of breast cancer susceptibility regions identifies candidate causal variants and prioritizes likely effector genes supported by functional genomic evidence.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 1","pages":"80-87"},"PeriodicalIF":31.7,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142917047","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}
Aberrant immune responses to viral pathogens contribute to pathogenesis, but our understanding of pathological immune responses caused by viruses within the human virome, especially at a population scale, remains limited. We analyzed whole-genome sequencing datasets of 6,321 Japanese individuals, including patients with autoimmune diseases (psoriasis vulgaris, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), pulmonary alveolar proteinosis (PAP) or multiple sclerosis) and coronavirus disease 2019 (COVID-19), or healthy controls. We systematically quantified two constituents of the blood DNA virome, endogenous HHV-6 (eHHV-6) and anellovirus. Participants with eHHV-6B had higher risks of SLE and PAP; the former was validated in All of Us. eHHV-6B-positivity and high SLE disease activity index scores had strong correlations. Genome-wide association study and long-read sequencing mapped the integration of the HHV-6B genome to a locus on chromosome 22q. Epitope mapping and single-cell RNA sequencing revealed distinctive immune induction by eHHV-6B in patients with SLE. In addition, high anellovirus load correlated strongly with SLE, RA and COVID-19 status. Our analyses unveil relationships between the human virome and autoimmune and infectious diseases. Analysis of the blood DNA virome in patients with COVID-19 and autoimmune disease associates endogenous HHV-6 (eHHV-6) and high anellovirus load with increased disease risk, most notably for systemic lupus erythematosus. eHHV-6 carriers show a distinct immune response.
{"title":"Blood DNA virome associates with autoimmune diseases and COVID-19","authors":"Noah Sasa, Shohei Kojima, Rie Koide, Takanori Hasegawa, Ho Namkoong, Tomomitsu Hirota, Rei Watanabe, Yuumi Nakamura, Eri Oguro-Igashira, Kotaro Ogawa, Tomohiro Yata, Kyuto Sonehara, Kenichi Yamamoto, Toshihiro Kishikawa, Saori Sakaue, Ryuya Edahiro, Yuya Shirai, Yuichi Maeda, Takuro Nii, Shotaro Chubachi, Hiromu Tanaka, Haruka Yabukami, Akari Suzuki, Kimiko Nakajima, Noriko Arase, Takashi Okamoto, Rika Nishikawa, Shinichi Namba, Tatsuhiko Naito, Ippei Miyagawa, Hiroaki Tanaka, Masanobu Ueno, Yosuke Ishitsuka, Junichi Furuta, Kayo Kunimoto, Ikko Kajihara, Satoshi Fukushima, Hideaki Miyachi, Hiroyuki Matsue, Masahiro Kamata, Mami Momose, Toshinori Bito, Hiroshi Nagai, Tetsuya Ikeda, Tatsuya Horikawa, Atsuko Adachi, Tsukasa Matsubara, Kyoko Ikumi, Emi Nishida, Ikuma Nakagawa, Mayu Yagita-Sakamaki, Maiko Yoshimura, Shiro Ohshima, Makoto Kinoshita, Satoru Ito, Toru Arai, Masaki Hirose, Yoshinori Tanino, Takefumi Nikaido, Toshio Ichiwata, Shinya Ohkouchi, Taizou Hirano, Toshinori Takada, Ryushi Tazawa, Konosuke Morimoto, Masahiro Takaki, Satoshi Konno, Masaru Suzuki, Keisuke Tomii, Atsushi Nakagawa, Tomohiro Handa, Kiminobu Tanizawa, Haruyuki Ishii, Manabu Ishida, Toshiyuki Kato, Naoya Takeda, Koshi Yokomura, Takashi Matsui, Akifumi Uchida, Hiromasa Inoue, Kazuyoshi Imaizumi, Yasuhiro Goto, Hiroshi Kida, Tomoyuki Fujisawa, Takafumi Suda, Takashi Yamada, Yasuomi Satake, Hidenori Ibata, Mika Saigusa, Toshihiro Shirai, Nobuyuki Hizawa, Koh Nakata, Japan COVID-19 Task Force, Shinichi Imafuku, Yayoi Tada, Yoshihide Asano, Shinichi Sato, Chikako Nishigori, Masatoshi Jinnin, Hironobu Ihn, Akihiko Asahina, Hidehisa Saeki, Tatsuyoshi Kawamura, Shinji Shimada, Ichiro Katayama, Hannah M. Poisner, Taralynn M. Mack, Alexander G. Bick, Koichiro Higasa, Tatsusada Okuno, Hideki Mochizuki, Makoto Ishii, Ryuji Koike, Akinori Kimura, Emiko Noguchi, Shigetoshi Sano, Hidenori Inohara, Manabu Fujimoto, Yoshikazu Inoue, Etsuro Yamaguchi, Seishi Ogawa, Takanori Kanai, Akimichi Morita, Fumihiko Matsuda, Mayumi Tamari, Atsushi Kumanogoh, Yoshiya Tanaka, Koichiro Ohmura, Koichi Fukunaga, Seiya Imoto, Satoru Miyano, Nicholas F. Parrish, Yukinori Okada","doi":"10.1038/s41588-024-02022-z","DOIUrl":"10.1038/s41588-024-02022-z","url":null,"abstract":"Aberrant immune responses to viral pathogens contribute to pathogenesis, but our understanding of pathological immune responses caused by viruses within the human virome, especially at a population scale, remains limited. We analyzed whole-genome sequencing datasets of 6,321 Japanese individuals, including patients with autoimmune diseases (psoriasis vulgaris, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), pulmonary alveolar proteinosis (PAP) or multiple sclerosis) and coronavirus disease 2019 (COVID-19), or healthy controls. We systematically quantified two constituents of the blood DNA virome, endogenous HHV-6 (eHHV-6) and anellovirus. Participants with eHHV-6B had higher risks of SLE and PAP; the former was validated in All of Us. eHHV-6B-positivity and high SLE disease activity index scores had strong correlations. Genome-wide association study and long-read sequencing mapped the integration of the HHV-6B genome to a locus on chromosome 22q. Epitope mapping and single-cell RNA sequencing revealed distinctive immune induction by eHHV-6B in patients with SLE. In addition, high anellovirus load correlated strongly with SLE, RA and COVID-19 status. Our analyses unveil relationships between the human virome and autoimmune and infectious diseases. Analysis of the blood DNA virome in patients with COVID-19 and autoimmune disease associates endogenous HHV-6 (eHHV-6) and high anellovirus load with increased disease risk, most notably for systemic lupus erythematosus. eHHV-6 carriers show a distinct immune response.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 1","pages":"65-79"},"PeriodicalIF":31.7,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-02022-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142917049","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}
Pub Date : 2025-01-03DOI: 10.1038/s41588-024-01996-0
Constantin Ahlmann-Eltze, Wolfgang Huber
Identifying gene expression differences in heterogeneous tissues across conditions is a fundamental biological task, enabled by multi-condition single-cell RNA sequencing (RNA-seq). Current data analysis approaches divide the constituent cells into clusters meant to represent cell types, but such discrete categorization tends to be an unsatisfactory model of the underlying biology. Here, we introduce latent embedding multivariate regression (LEMUR), a model that operates without, or before, commitment to discrete categorization. LEMUR (1) integrates data from different conditions, (2) predicts each cell’s gene expression changes as a function of the conditions and its position in latent space and (3) for each gene, identifies a compact neighborhood of cells with consistent differential expression. We apply LEMUR to cancer, zebrafish development and spatial gradients in Alzheimer’s disease, demonstrating its broad applicability.
{"title":"Analysis of multi-condition single-cell data with latent embedding multivariate regression","authors":"Constantin Ahlmann-Eltze, Wolfgang Huber","doi":"10.1038/s41588-024-01996-0","DOIUrl":"https://doi.org/10.1038/s41588-024-01996-0","url":null,"abstract":"<p>Identifying gene expression differences in heterogeneous tissues across conditions is a fundamental biological task, enabled by multi-condition single-cell RNA sequencing (RNA-seq). Current data analysis approaches divide the constituent cells into clusters meant to represent cell types, but such discrete categorization tends to be an unsatisfactory model of the underlying biology. Here, we introduce latent embedding multivariate regression (LEMUR), a model that operates without, or before, commitment to discrete categorization. LEMUR (1) integrates data from different conditions, (2) predicts each cell’s gene expression changes as a function of the conditions and its position in latent space and (3) for each gene, identifies a compact neighborhood of cells with consistent differential expression. We apply LEMUR to cancer, zebrafish development and spatial gradients in Alzheimer’s disease, demonstrating its broad applicability.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"1 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142917048","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}
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