Pub Date : 2025-01-15DOI: 10.1038/s41588-024-02060-7
Safia Danovi
{"title":"Mutations in healthy breast tissue","authors":"Safia Danovi","doi":"10.1038/s41588-024-02060-7","DOIUrl":"10.1038/s41588-024-02060-7","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 1","pages":"2-2"},"PeriodicalIF":31.7,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142986745","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 : 2025-01-14DOI: 10.1038/s41588-024-02057-2
Ya Cui, Frederick J. Arnold, Jason Sheng Li, Jie Wu, Dan Wang, Julien Philippe, Michael R. Colwin, Sebastian Michels, Chaorong Chen, Tamer Sallam, Leslie M. Thompson, Albert R. La Spada, Wei Li
Tandem repeat (TR) size variation is implicated in ~50 neurological disorders, yet its impact on gene regulation in the human brain remains largely unknown. In the present study, we quantified the impact of TR size variation on brain gene regulation across distinct molecular phenotypes, based on 4,412 multi-omics samples from 1,597 donors, including 1,586 newly sequenced ones. We identified ~2.2 million TR molecular quantitative trait loci (TR-xQTLs), linking ~139,000 unique TRs to nearby molecular phenotypes, including many known disease-risk TRs, such as the G2C4 expansion in C9orf72 associated with amyotrophic lateral sclerosis. Fine-mapping revealed ~18,700 TRs as potential causal variants. Our in vitro experiments further confirmed the causal and independent regulatory effects of three TRs. Additional colocalization analysis indicated the potential causal role of TR variation in brain-related phenotypes, highlighted by a 3ʹ-UTR TR in NUDT14 linked to cortical surface area and a TG repeat in PLEKHA1, associated with Alzheimer’s disease. Mapping of multi-omic molecular quantitative trait loci associated with tandem repeat size variation in up to 4,412 human brain samples from 1,597 donors offers insights into how these variants affect gene regulation and mediate disease risk.
{"title":"Multi-omic quantitative trait loci link tandem repeat size variation to gene regulation in human brain","authors":"Ya Cui, Frederick J. Arnold, Jason Sheng Li, Jie Wu, Dan Wang, Julien Philippe, Michael R. Colwin, Sebastian Michels, Chaorong Chen, Tamer Sallam, Leslie M. Thompson, Albert R. La Spada, Wei Li","doi":"10.1038/s41588-024-02057-2","DOIUrl":"10.1038/s41588-024-02057-2","url":null,"abstract":"Tandem repeat (TR) size variation is implicated in ~50 neurological disorders, yet its impact on gene regulation in the human brain remains largely unknown. In the present study, we quantified the impact of TR size variation on brain gene regulation across distinct molecular phenotypes, based on 4,412 multi-omics samples from 1,597 donors, including 1,586 newly sequenced ones. We identified ~2.2 million TR molecular quantitative trait loci (TR-xQTLs), linking ~139,000 unique TRs to nearby molecular phenotypes, including many known disease-risk TRs, such as the G2C4 expansion in C9orf72 associated with amyotrophic lateral sclerosis. Fine-mapping revealed ~18,700 TRs as potential causal variants. Our in vitro experiments further confirmed the causal and independent regulatory effects of three TRs. Additional colocalization analysis indicated the potential causal role of TR variation in brain-related phenotypes, highlighted by a 3ʹ-UTR TR in NUDT14 linked to cortical surface area and a TG repeat in PLEKHA1, associated with Alzheimer’s disease. Mapping of multi-omic molecular quantitative trait loci associated with tandem repeat size variation in up to 4,412 human brain samples from 1,597 donors offers insights into how these variants affect gene regulation and mediate disease risk.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 2","pages":"369-378"},"PeriodicalIF":31.7,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142974575","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}
Rice production is facing substantial threats from global warming associated with extreme temperatures. Here we report that modifying a heat stress-induced negative regulator, a negative regulator of thermotolerance 1 (NAT1), increases wax deposition and enhances thermotolerance in rice. We demonstrated that the C2H2 family transcription factor NAT1 directly inhibits bHLH110 expression, and bHLH110 directly promotes the expression of wax biosynthetic genes CER1/CER1L under heat stress conditions. In situ hybridization revealed that both NAT1 and bHLH110 are predominantly expressed in epidermal layers. By using gene-editing technology, we successfully mutated NAT1 to eliminate its inhibitory effects on wax biosynthesis and improved thermotolerance without yield penalty under normal temperature conditions. Field trials further confirmed the potential of NAT1-edited rice to increase seed-setting rate and grain yield. Therefore, our findings shed light on the regulatory mechanisms governing wax biosynthesis under heat stress conditions in rice and provide a strategy to enhance heat resilience through the modification of NAT1. Negative regulator of thermotolerance 1 (NAT1) is identified as a negative regulator of thermotolerance in rice through the NAT1–bHLH110–CER1/CER1L module. Modifying NAT1 by targeted gene editing increases wax deposition and enhances thermotolerance in rice.
水稻生产正面临着与极端温度相关的全球变暖的重大威胁。本文报道了对热胁迫诱导的负调节因子——耐热性负调节因子NAT1 （negative regulator of thermotolerance 1, NAT1）进行修饰，可以增加水稻的蜡沉积，增强其耐热性。我们证明了C2H2家族转录因子NAT1直接抑制bHLH110的表达，bHLH110在热应激条件下直接促进蜡质生物合成基因CER1/CER1L的表达。原位杂交结果显示，NAT1和bHLH110主要表达于表皮层。通过基因编辑技术，我们成功突变了NAT1，消除了其对蜡生物合成的抑制作用，提高了常温条件下的耐热性，且产量不受影响。田间试验进一步证实了nat1编辑水稻在提高结实率和籽粒产量方面的潜力。因此，我们的研究结果揭示了水稻在热胁迫条件下蜡质生物合成的调控机制，并提供了通过修饰NAT1来增强耐热性的策略。
{"title":"The NAT1–bHLH110–CER1/CER1L module regulates heat stress tolerance in rice","authors":"Hai-Ping Lu, Xue-Huan Liu, Mei-Jing Wang, Qiao-Yun Zhu, Yu-Shu Lyu, Jian-Hang Xu, Jian-Xiang Liu","doi":"10.1038/s41588-024-02065-2","DOIUrl":"10.1038/s41588-024-02065-2","url":null,"abstract":"Rice production is facing substantial threats from global warming associated with extreme temperatures. Here we report that modifying a heat stress-induced negative regulator, a negative regulator of thermotolerance 1 (NAT1), increases wax deposition and enhances thermotolerance in rice. We demonstrated that the C2H2 family transcription factor NAT1 directly inhibits bHLH110 expression, and bHLH110 directly promotes the expression of wax biosynthetic genes CER1/CER1L under heat stress conditions. In situ hybridization revealed that both NAT1 and bHLH110 are predominantly expressed in epidermal layers. By using gene-editing technology, we successfully mutated NAT1 to eliminate its inhibitory effects on wax biosynthesis and improved thermotolerance without yield penalty under normal temperature conditions. Field trials further confirmed the potential of NAT1-edited rice to increase seed-setting rate and grain yield. Therefore, our findings shed light on the regulatory mechanisms governing wax biosynthesis under heat stress conditions in rice and provide a strategy to enhance heat resilience through the modification of NAT1. Negative regulator of thermotolerance 1 (NAT1) is identified as a negative regulator of thermotolerance in rice through the NAT1–bHLH110–CER1/CER1L module. Modifying NAT1 by targeted gene editing increases wax deposition and enhances thermotolerance in rice.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 2","pages":"427-440"},"PeriodicalIF":31.7,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142975171","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 : 2025-01-14DOI: 10.1038/s41588-024-02056-3
Jinxing Shi, Zhongxin Kong, Jinkun Zhong, Xiaoqiu Zhang, Xianmin Luo, Heyu Wang, Boyang Xu, Xin Wang, Rui Cheng, Yang Yuan, Na Li, Quan Xie, Guoqiang Li, Haiyan Jia, Zhengqiang Ma
Ambiguity about whether the histidine-rich calcium-binding protein-coding gene (HisR) or the pore-forming toxin-like gene (PFT) or both are responsible for Fusarium head blight (FHB) resistance conferred by the Fhb1 quantitative trait locus hinders progress toward elucidating Fhb1 resistance mechanisms. Here, with a series of developed lines with or without PFT but all possessing HisR and five HisR-carrying PFT mutant lines created via gene editing, we show that PFT does not confer FHB resistance and that the HisR resistance effect does not require PFT in the tested conditions. We also show that PFT mutations are not associated with morphological and phenological characteristics that often affect FHB severity. Analysis of wheat lines generated through introgression or gene editing provides evidence that Fhb1-mediated resistance to Fusarium head blight is independent of the pore-forming toxin gene PFT.
{"title":"Mutagenesis and analysis of contrasting wheat lines do not support a role for PFT in Fusarium head blight resistance","authors":"Jinxing Shi, Zhongxin Kong, Jinkun Zhong, Xiaoqiu Zhang, Xianmin Luo, Heyu Wang, Boyang Xu, Xin Wang, Rui Cheng, Yang Yuan, Na Li, Quan Xie, Guoqiang Li, Haiyan Jia, Zhengqiang Ma","doi":"10.1038/s41588-024-02056-3","DOIUrl":"10.1038/s41588-024-02056-3","url":null,"abstract":"Ambiguity about whether the histidine-rich calcium-binding protein-coding gene (HisR) or the pore-forming toxin-like gene (PFT) or both are responsible for Fusarium head blight (FHB) resistance conferred by the Fhb1 quantitative trait locus hinders progress toward elucidating Fhb1 resistance mechanisms. Here, with a series of developed lines with or without PFT but all possessing HisR and five HisR-carrying PFT mutant lines created via gene editing, we show that PFT does not confer FHB resistance and that the HisR resistance effect does not require PFT in the tested conditions. We also show that PFT mutations are not associated with morphological and phenological characteristics that often affect FHB severity. Analysis of wheat lines generated through introgression or gene editing provides evidence that Fhb1-mediated resistance to Fusarium head blight is independent of the pore-forming toxin gene PFT.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 2","pages":"310-313"},"PeriodicalIF":31.7,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142974574","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 : 2025-01-13DOI: 10.1038/s41588-024-02015-y
Naitao Wang, Mohini R. Pachai, Dan Li, Cindy J. Lee, Sarah Warda, Makhzuna N. Khudoynazarova, Woo Hyun Cho, Guojia Xie, Sagar R. Shah, Li Yao, Cheng Qian, Elissa W. P. Wong, Juan Yan, Fanny V. Tomas, Wenhuo Hu, Fengshen Kuo, Sizhi P. Gao, Jiaqian Luo, Alison E. Smith, Ming Han, Dong Gao, Kai Ge, Haiyuan Yu, Sarat Chandarlapaty, Gopakumar V. Iyer, Jonathan E. Rosenberg, David B. Solit, Hikmat A. Al-Ahmadie, Ping Chi, Yu Chen
Members of the KMT2C/D–KDM6A complex are recurrently mutated in urothelial carcinoma and in histologically normal urothelium. Here, using genetically engineered mouse models, we demonstrate that Kmt2c/d knockout in the urothelium led to impaired differentiation, augmented responses to growth and inflammatory stimuli and sensitization to oncogenic transformation by carcinogen and oncogenes. Mechanistically, KMT2D localized to active enhancers and CpG-poor promoters that preferentially regulate the urothelial lineage program and Kmt2c/d knockout led to diminished H3K4me1, H3K27ac and nascent RNA transcription at these sites, which leads to impaired differentiation. Kmt2c/d knockout further led to KMT2A–menin redistribution from KMT2D localized enhancers to CpG-high and bivalent promoters, resulting in derepression of signal-induced immediate early genes. Therapeutically, Kmt2c/d knockout upregulated epidermal growth factor receptor signaling and conferred vulnerability to epidermal growth factor receptor inhibitors. Together, our data posit that functional loss of Kmt2c/d licenses a molecular ‘field effect’ priming histologically normal urothelium for oncogenic transformation and presents therapeutic vulnerabilities. Loss of Kmt2c or Kmt2d in mice drives the redeployment of KMT2A–menin to bivalent promoters, leading to changes in gene expression. This primes cells for transformation and elicits sensitivity to EGFR inhibitors.
{"title":"Loss of Kmt2c or Kmt2d primes urothelium for tumorigenesis and redistributes KMT2A–menin to bivalent promoters","authors":"Naitao Wang, Mohini R. Pachai, Dan Li, Cindy J. Lee, Sarah Warda, Makhzuna N. Khudoynazarova, Woo Hyun Cho, Guojia Xie, Sagar R. Shah, Li Yao, Cheng Qian, Elissa W. P. Wong, Juan Yan, Fanny V. Tomas, Wenhuo Hu, Fengshen Kuo, Sizhi P. Gao, Jiaqian Luo, Alison E. Smith, Ming Han, Dong Gao, Kai Ge, Haiyuan Yu, Sarat Chandarlapaty, Gopakumar V. Iyer, Jonathan E. Rosenberg, David B. Solit, Hikmat A. Al-Ahmadie, Ping Chi, Yu Chen","doi":"10.1038/s41588-024-02015-y","DOIUrl":"10.1038/s41588-024-02015-y","url":null,"abstract":"Members of the KMT2C/D–KDM6A complex are recurrently mutated in urothelial carcinoma and in histologically normal urothelium. Here, using genetically engineered mouse models, we demonstrate that Kmt2c/d knockout in the urothelium led to impaired differentiation, augmented responses to growth and inflammatory stimuli and sensitization to oncogenic transformation by carcinogen and oncogenes. Mechanistically, KMT2D localized to active enhancers and CpG-poor promoters that preferentially regulate the urothelial lineage program and Kmt2c/d knockout led to diminished H3K4me1, H3K27ac and nascent RNA transcription at these sites, which leads to impaired differentiation. Kmt2c/d knockout further led to KMT2A–menin redistribution from KMT2D localized enhancers to CpG-high and bivalent promoters, resulting in derepression of signal-induced immediate early genes. Therapeutically, Kmt2c/d knockout upregulated epidermal growth factor receptor signaling and conferred vulnerability to epidermal growth factor receptor inhibitors. Together, our data posit that functional loss of Kmt2c/d licenses a molecular ‘field effect’ priming histologically normal urothelium for oncogenic transformation and presents therapeutic vulnerabilities. Loss of Kmt2c or Kmt2d in mice drives the redeployment of KMT2A–menin to bivalent promoters, leading to changes in gene expression. This primes cells for transformation and elicits sensitivity to EGFR inhibitors.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 1","pages":"165-179"},"PeriodicalIF":31.7,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-02015-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968265","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 : 2025-01-10DOI: 10.1038/s41588-024-02050-9
Alexander Haglund, Verena Zuber, Maya Abouzeid, Yifei Yang, Jeong Hun Ko, Liv Wiemann, Maria Otero-Jimenez, Louwai Muhammed, Rahel Feleke, Alexi Nott, James D. Mills, Liisi Laaniste, Djordje O. Gveric, Daniel Clode, Ann C. Babtie, Susanna Pagni, Ravishankara Bellampalli, Alyma Somani, Karina McDade, Jasper J. Anink, Lucia Mesarosova, Nurun Fancy, Nanet Willumsen, Amy Smith, Johanna Jackson, Javier Alegre-Abarrategui, Eleonora Aronica, Paul M. Matthews, Maria Thom, Sanjay M. Sisodiya, Prashant K. Srivastava, Dheeraj Malhotra, Julien Bryois, Leonardo Bottolo, Michael R. Johnson
Gene expression quantitative trait loci are widely used to infer relationships between genes and central nervous system (CNS) phenotypes; however, the effect of brain disease on these inferences is unclear. Using 2,348,438 single-nuclei profiles from 391 disease-case and control brains, we report 13,939 genes whose expression correlated with genetic variation, of which 16.7–40.8% (depending on cell type) showed disease-dependent allelic effects. Across 501 colocalizations for 30 CNS traits, 23.6% had a disease dependency, even after adjusting for disease status. To estimate the unconfounded effect of genes on outcomes, we repeated the analysis using nondiseased brains (n = 183) and reported an additional 91 colocalizations not present in the larger mixed disease and control dataset, demonstrating enhanced interpretation of disease-associated variants. Principled implementation of single-cell Mendelian randomization in control-only brains identified 140 putatively causal gene–trait associations, of which 11 were replicated in the UK Biobank, prioritizing candidate peripheral biomarkers predictive of CNS outcomes. Analysis of single nuclei RNA-sequencing data across eight major brain cell types identifies putative causal associations between cell-type-specific expression and brain phenotypes.
{"title":"Cell state-dependent allelic effects and contextual Mendelian randomization analysis for human brain phenotypes","authors":"Alexander Haglund, Verena Zuber, Maya Abouzeid, Yifei Yang, Jeong Hun Ko, Liv Wiemann, Maria Otero-Jimenez, Louwai Muhammed, Rahel Feleke, Alexi Nott, James D. Mills, Liisi Laaniste, Djordje O. Gveric, Daniel Clode, Ann C. Babtie, Susanna Pagni, Ravishankara Bellampalli, Alyma Somani, Karina McDade, Jasper J. Anink, Lucia Mesarosova, Nurun Fancy, Nanet Willumsen, Amy Smith, Johanna Jackson, Javier Alegre-Abarrategui, Eleonora Aronica, Paul M. Matthews, Maria Thom, Sanjay M. Sisodiya, Prashant K. Srivastava, Dheeraj Malhotra, Julien Bryois, Leonardo Bottolo, Michael R. Johnson","doi":"10.1038/s41588-024-02050-9","DOIUrl":"10.1038/s41588-024-02050-9","url":null,"abstract":"Gene expression quantitative trait loci are widely used to infer relationships between genes and central nervous system (CNS) phenotypes; however, the effect of brain disease on these inferences is unclear. Using 2,348,438 single-nuclei profiles from 391 disease-case and control brains, we report 13,939 genes whose expression correlated with genetic variation, of which 16.7–40.8% (depending on cell type) showed disease-dependent allelic effects. Across 501 colocalizations for 30 CNS traits, 23.6% had a disease dependency, even after adjusting for disease status. To estimate the unconfounded effect of genes on outcomes, we repeated the analysis using nondiseased brains (n = 183) and reported an additional 91 colocalizations not present in the larger mixed disease and control dataset, demonstrating enhanced interpretation of disease-associated variants. Principled implementation of single-cell Mendelian randomization in control-only brains identified 140 putatively causal gene–trait associations, of which 11 were replicated in the UK Biobank, prioritizing candidate peripheral biomarkers predictive of CNS outcomes. Analysis of single nuclei RNA-sequencing data across eight major brain cell types identifies putative causal associations between cell-type-specific expression and brain phenotypes.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 2","pages":"358-368"},"PeriodicalIF":31.7,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-02050-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142961338","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 : 2025-01-09DOI: 10.1038/s41588-024-02044-7
Hrushikesh Loya, Georgios Kalantzis, Fergus Cooper, Pier Francesco Palamara
The rapid growth of modern biobanks is creating new opportunities for large-scale genome-wide association studies (GWASs) and the analysis of complex traits. However, performing GWASs on millions of samples often leads to trade-offs between computational efficiency and statistical power, reducing the benefits of large-scale data collection efforts. We developed Quickdraws, a method that increases association power in quantitative and binary traits without sacrificing computational efficiency, leveraging a spike-and-slab prior on variant effects, stochastic variational inference and graphics processing unit acceleration. We applied Quickdraws to 79 quantitative and 50 binary traits in 405,088 UK Biobank samples, identifying 4.97% and 3.25% more associations than REGENIE and 22.71% and 7.07% more than FastGWA. Quickdraws had costs comparable to REGENIE, FastGWA and SAIGE on the UK Biobank Research Analysis Platform service, while being substantially faster than BOLT-LMM. These results highlight the promise of leveraging machine learning techniques for scalable GWASs without sacrificing power or robustness. Quickdraws is a mixed-model association tool with a noninfinitesimal prior for analyzing binary and quantitative traits, using a scalable variational inference that allows analysis of biobank-scale cohorts.
{"title":"A scalable variational inference approach for increased mixed-model association power","authors":"Hrushikesh Loya, Georgios Kalantzis, Fergus Cooper, Pier Francesco Palamara","doi":"10.1038/s41588-024-02044-7","DOIUrl":"10.1038/s41588-024-02044-7","url":null,"abstract":"The rapid growth of modern biobanks is creating new opportunities for large-scale genome-wide association studies (GWASs) and the analysis of complex traits. However, performing GWASs on millions of samples often leads to trade-offs between computational efficiency and statistical power, reducing the benefits of large-scale data collection efforts. We developed Quickdraws, a method that increases association power in quantitative and binary traits without sacrificing computational efficiency, leveraging a spike-and-slab prior on variant effects, stochastic variational inference and graphics processing unit acceleration. We applied Quickdraws to 79 quantitative and 50 binary traits in 405,088 UK Biobank samples, identifying 4.97% and 3.25% more associations than REGENIE and 22.71% and 7.07% more than FastGWA. Quickdraws had costs comparable to REGENIE, FastGWA and SAIGE on the UK Biobank Research Analysis Platform service, while being substantially faster than BOLT-LMM. These results highlight the promise of leveraging machine learning techniques for scalable GWASs without sacrificing power or robustness. Quickdraws is a mixed-model association tool with a noninfinitesimal prior for analyzing binary and quantitative traits, using a scalable variational inference that allows analysis of biobank-scale cohorts.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 2","pages":"461-468"},"PeriodicalIF":31.7,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-02044-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142937081","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 : 2025-01-08DOI: 10.1038/s41588-024-02029-6
Simona Secomandi, Guido Roberto Gallo, Riccardo Rossi, Carlos Rodríguez Fernandes, Erich D. Jarvis, Andrea Bonisoli-Alquati, Luca Gianfranceschi, Giulio Formenti
Complete datasets of genetic variants are key to biodiversity genomic studies. Long-read sequencing technologies allow the routine assembly of highly contiguous, haplotype-resolved reference genomes. However, even when complete, reference genomes from a single individual may bias downstream analyses and fail to adequately represent genetic diversity within a population or species. Pangenome graphs assembled from aligned collections of high-quality genomes can overcome representation bias by integrating sequence information from multiple genomes from the same population, species or genus into a single reference. Here, we review the available tools and data structures to build, visualize and manipulate pangenome graphs while providing practical examples and discussing their applications in biodiversity and conservation genomics across the tree of life. Pangenomes integrate multiple genomes to mitigate reference bias. This Review presents tools to build, visualize and manipulate pangenome graphs and also highlights pangenome applications in biodiversity and conservation genomics.
{"title":"Pangenome graphs and their applications in biodiversity genomics","authors":"Simona Secomandi, Guido Roberto Gallo, Riccardo Rossi, Carlos Rodríguez Fernandes, Erich D. Jarvis, Andrea Bonisoli-Alquati, Luca Gianfranceschi, Giulio Formenti","doi":"10.1038/s41588-024-02029-6","DOIUrl":"10.1038/s41588-024-02029-6","url":null,"abstract":"Complete datasets of genetic variants are key to biodiversity genomic studies. Long-read sequencing technologies allow the routine assembly of highly contiguous, haplotype-resolved reference genomes. However, even when complete, reference genomes from a single individual may bias downstream analyses and fail to adequately represent genetic diversity within a population or species. Pangenome graphs assembled from aligned collections of high-quality genomes can overcome representation bias by integrating sequence information from multiple genomes from the same population, species or genus into a single reference. Here, we review the available tools and data structures to build, visualize and manipulate pangenome graphs while providing practical examples and discussing their applications in biodiversity and conservation genomics across the tree of life. Pangenomes integrate multiple genomes to mitigate reference bias. This Review presents tools to build, visualize and manipulate pangenome graphs and also highlights pangenome applications in biodiversity and conservation genomics.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 1","pages":"13-26"},"PeriodicalIF":31.7,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936062","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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