Nature genetics最新文献

Empirically determined baseline masking strategies and other considerations for gene-level burden tests. 经验确定的基线掩盖策略和基因水平负担测试的其他考虑因素。

IF 29 1区生物学

Nature genetics Pub Date : 2026-05-08 DOI: 10.1038/s41588-026-02597-9

Trang Nguyen, Ryan Koesterer, Poeya Haydarlou, Peter Dornbos, Satoshi Yoshiji, Alex Llamas, Dongkeun Jang, Patrick Smadbeck, Annie Moriondo, Quy Hoang, Oliver Ruebenacker, Connie R Bezzina, Patrick Ellinor, Sean J Jurgens, Noël P Burtt, Jason Flannick

{"title":"Empirically determined baseline masking strategies and other considerations for gene-level burden tests.","authors":"Trang Nguyen, Ryan Koesterer, Poeya Haydarlou, Peter Dornbos, Satoshi Yoshiji, Alex Llamas, Dongkeun Jang, Patrick Smadbeck, Annie Moriondo, Quy Hoang, Oliver Ruebenacker, Connie R Bezzina, Patrick Ellinor, Sean J Jurgens, Noël P Burtt, Jason Flannick","doi":"10.1038/s41588-026-02597-9","DOIUrl":"https://doi.org/10.1038/s41588-026-02597-9","url":null,"abstract":"Rare-variant association studies typically perform gene-level tests in which coding variants are filtered (or 'masked') and aggregated based on functional annotation and allele frequency. Through a systematic literature review, we cataloged 664 masks used across 234 studies and found that masking strategies (that is, sets of masks) rarely repeat across studies and are rarely justified. To quantify their impact on association results, we applied all previously employed strategies to 54 traits within 189,947 UK Biobank exomes. Here we find that the number of significant associations greatly depends on the masking strategy (ranging from 58 to 2,523 associations), which is a key reason for the modest overlap (<30%) of associations between separate published analyses of this dataset. We empirically determine masking strategies with high discovery power for low-frequency and rare variant gene-level associations across numerous datasets and traits, and we use these to explore the impact of other factors on burden test results. These findings offer a baseline strategy in burden tests to increase study power and replicability, addressing one source of inconsistency in previous studies.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":" ","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856881","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

Alterations of chromatin state at transposable elements rewire stemness in acute myeloid leukemia. 急性髓系白血病转座因子染色质状态的改变。

IF 29 1区生物学

Nature genetics Pub Date : 2026-05-07 DOI: 10.1038/s41588-026-02599-7

引用次数: 0

Population-level super-pangenome reveals genome evolution and empowers precision breeding in watermelon. 群体水平的超级泛基因组揭示了西瓜的基因组进化和精确育种。

IF 29 1区生物学

Nature genetics Pub Date : 2026-05-05 DOI: 10.1038/s41588-026-02598-8

Honghe Sun, Jie Zhang, Shengjin Liao, Shaogui Guo, Zhe Zhou, Xuebo Zhao, Shan Wu, Jiantao Zhao, Guoyi Gong, Jinfang Wang, Maoying Li, Yongtao Yu, Yi Ren, Shouwei Tian, Shaofang Li, Haiying Zhang, Sue A Hammar, Cecilia McGregor, Robert Jarret, Patrick Wechter, Sandra E Branham, Chandrasekar Kousik, Amnon Levi, Rebecca Grumet, Zhangjun Fei, Yong Xu

{"title":"Population-level super-pangenome reveals genome evolution and empowers precision breeding in watermelon.","authors":"Honghe Sun, Jie Zhang, Shengjin Liao, Shaogui Guo, Zhe Zhou, Xuebo Zhao, Shan Wu, Jiantao Zhao, Guoyi Gong, Jinfang Wang, Maoying Li, Yongtao Yu, Yi Ren, Shouwei Tian, Shaofang Li, Haiying Zhang, Sue A Hammar, Cecilia McGregor, Robert Jarret, Patrick Wechter, Sandra E Branham, Chandrasekar Kousik, Amnon Levi, Rebecca Grumet, Zhangjun Fei, Yong Xu","doi":"10.1038/s41588-026-02598-8","DOIUrl":"https://doi.org/10.1038/s41588-026-02598-8","url":null,"abstract":"Pangenomes are increasingly important for harnessing crop genetic diversity, yet their resolution and utility are often limited by insufficient sampling of high-quality genome assemblies. Here we present a population-level watermelon super-pangenome constructed from 138 reference-grade assemblies, including 135 newly generated genomes representing all seven species. This super-pangenome captures approximately 1 million structural variants (SVs), enabling accurate variant genotyping across 914 accessions. Broader sampling within the pangenome provides insights into watermelon genome evolution and the origin of cultivated watermelon. Incorporating SVs into genome-wide association studies improves mapping resolution and reveals a copy number variant upstream of ClFCI1 that regulates flesh color intensity in a dosage-dependent manner. Leveraging this comprehensive variation map, we developed high-accuracy genomic prediction models for 18 agronomic traits. Together, these findings and genomic resources establish a foundation for dissecting complex traits and accelerating precision breeding in watermelon, while offering a valuable model for SV-resolved pangenomics in crops.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":" ","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840360","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

The Single Cell Notebooks for inclusive and accessible training in single-cell and spatial omics. 单细胞笔记本的单细胞和空间组学的包容性和可访问的培训。

IF 29 1区生物学

Nature genetics Pub Date : 2026-05-05 DOI: 10.1038/s41588-026-02584-0

Adolfo Rojas-Hidalgo, Raúl Arias-Carrasco, Joyce Karoline Silva, Erick Armingol, Sebastián Urquiza-Zurich, Bruno Vinagre, Cesar A Prada-Medina, Sergio Triana, Daniela D Russo, Diego Pérez-Stuardo, Emiliano Vicencio, Gerardo Muñoz, Cristóvão Antunes de Lanna, Leandro Santos, Gabriela Rapozo, Natalia Tavares, Andrés Moreno-Estrada, John Randell, Patricia Severino, Ricardo Khouri, Orr Ashenberg, Alex K Shalek, Mariana Boroni, Yesid Cuesta-Astroz, Benilton S Carvalho, Vinicius Maracaja-Coutinho

引用次数: 0

Age distinguishes selection from causation in cancer genomes. 年龄将癌症基因组中的选择与因果区分开来。

IF 29 1区生物学

Nature genetics Pub Date : 2026-05-05 DOI: 10.1038/s41588-026-02593-z

David Cheek, Martin Blohmer, Martin A Nowak, Tibor Antal, Kamila Naxerova

引用次数: 0

Transposable elements shape stemness in normal and leukemic hematopoiesis. 转座因子在正常和白血病造血中形成干细胞。

IF 29 1区生物学

Nature genetics Pub Date : 2026-05-04 DOI: 10.1038/s41588-026-02585-z

Giacomo Grillo, Bettina Nadorp, Aditi Qamra, Bryce Drylie, Amanda Mitchell, Christopher Arlidge, Ankita Nand, Naoya Takayama, Alex Murison, Seyed Ali Madani Tonekaboni, Komaldeep Kaur Kang, Andrea Arruda, Jean C Y Wang, Mark D Minden, Özgen Deniz, Héléna Boutzen, John E Dick, Mathieu Lupien

{"title":"Transposable elements shape stemness in normal and leukemic hematopoiesis.","authors":"Giacomo Grillo, Bettina Nadorp, Aditi Qamra, Bryce Drylie, Amanda Mitchell, Christopher Arlidge, Ankita Nand, Naoya Takayama, Alex Murison, Seyed Ali Madani Tonekaboni, Komaldeep Kaur Kang, Andrea Arruda, Jean C Y Wang, Mark D Minden, Özgen Deniz, Héléna Boutzen, John E Dick, Mathieu Lupien","doi":"10.1038/s41588-026-02585-z","DOIUrl":"https://doi.org/10.1038/s41588-026-02585-z","url":null,"abstract":"Despite most acute myeloid leukemia (AML) patients achieving complete remission after induction chemotherapy, two-thirds relapse within 5 years. AML follows a cellular hierarchy sustained by leukemia stem cells (LSCs), which drive tumor progression and relapse. Little is known about the genetic determinants driving LSCs stemness properties. By identifying chromatin variants from accessibility measurements across LSCs, hematopoietic stem cells and downstream progeny, we identified transposable elements (TEs) as genetic determinants of primitive versus mature populations. Accessibility at 121 TE subfamilies distinguished LSCs from mature leukemic cells and stratified AML patients by stemness and survival. Functional assays revealed that these TE subfamilies serve as docking sites for genome topology regulators or lineage-specific transcription factors, including LYL1 in LSCs. Chromatin editing established the necessity of accessibility at LTR12C elements to maintain LSC stemness. Thus, TEs regulate primitive versus mature cell states, with distinct subfamilies underlying stemness in normal versus leukemic stem cells.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":" ","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840413","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

High-resolution single-cell mapping of clonal hematopoiesis and structural variation in aplastic anemia. 再生障碍性贫血克隆造血和结构变异的高分辨率单细胞图谱。

IF 29 1区生物学

Nature genetics Pub Date : 2026-05-01 DOI: 10.1038/s41588-026-02587-x

Masanori Yoshida, Sushree S Sahoo, Paula Y Arnold, Carmelo Gurnari, Anaïs J C N van Leeuwen, Limeng Pu, Markus J van Roosmalen, Ti-Cheng Chang, Charnise Goodings, Rashid Mehmood, Lucca L M Derks, Nathan Gray, Michelle Boals, Sara Lewis, Lili Kotmayer, Cristyn N Branstetter, Swapna Thota, Joshua Leow, Wenchao Zhang, Yichao Li, Melanie R Loyd, Granger Ridout, Emily V Walker, Christy W LaFlamme, Heather C Mefford, Zachary Brady, Yash B Shah, Rheanna G Congdon, Miriam Erlacher, Brigitte Strahm, Ayami Yoshimi, Shinsuke Hirabayashi, Helen D Reed, Akiko Shimamura, Guolian Kang, Xiang Chen, Jinghui Zhang, Charlotte M Niemeyer, Joseph H Oved, Timothy S Olson, Ruben van Boxtel, Jaroslaw P Maciejewski, Daria V Babushok, Marcin W Wlodarski

{"title":"High-resolution single-cell mapping of clonal hematopoiesis and structural variation in aplastic anemia.","authors":"Masanori Yoshida, Sushree S Sahoo, Paula Y Arnold, Carmelo Gurnari, Anaïs J C N van Leeuwen, Limeng Pu, Markus J van Roosmalen, Ti-Cheng Chang, Charnise Goodings, Rashid Mehmood, Lucca L M Derks, Nathan Gray, Michelle Boals, Sara Lewis, Lili Kotmayer, Cristyn N Branstetter, Swapna Thota, Joshua Leow, Wenchao Zhang, Yichao Li, Melanie R Loyd, Granger Ridout, Emily V Walker, Christy W LaFlamme, Heather C Mefford, Zachary Brady, Yash B Shah, Rheanna G Congdon, Miriam Erlacher, Brigitte Strahm, Ayami Yoshimi, Shinsuke Hirabayashi, Helen D Reed, Akiko Shimamura, Guolian Kang, Xiang Chen, Jinghui Zhang, Charlotte M Niemeyer, Joseph H Oved, Timothy S Olson, Ruben van Boxtel, Jaroslaw P Maciejewski, Daria V Babushok, Marcin W Wlodarski","doi":"10.1038/s41588-026-02587-x","DOIUrl":"https://doi.org/10.1038/s41588-026-02587-x","url":null,"abstract":"Aplastic anemia (AA) results from T-cell-mediated destruction of hematopoietic stem and progenitor cells (HSPCs), driving clonal hematopoiesis via loss of human leukocyte antigen (HLA) risk alleles (HLA loss-of-function mutations or uniparental disomy 6p, UPD6p), paroxysmal nocturnal hemoglobinuria and clonal hematopoiesis of indeterminate potential (CHIP) mutations. Here genomic profiling of 619 patients with AA revealed clonal hematopoiesis in 69% of cases, with ASXL1, BCOR and BCORL1 identified as the most frequent CHIP mutations in pediatric cases. Single-cell multi-omics analysis of 304,902 cells from 48 samples uncovered complex branching clonal architecture, with a median of three HLA loss events per patient, converging to inactivate HLA risk alleles. Single-cell whole-genome sequencing (WGS) resolved up to 15 HLA loss clones per patient and phylogenetic reconstruction indicated that these clones originated years before diagnosis. Long-read WGS precisely mapped UPD6p breakpoints and HLA methylation. HLA loss conferred a protective effect against CHIP, evidenced by their near-absent co-occurrence. Longitudinal single-cell analysis demonstrated that long-lived clones were enriched in the CD34+ HSPC compartment. These findings reveal parallel evolutionary pathways used by hematopoietic cells to evade immune attack.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":" ","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147817800","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

Machine learning in prediction and classification of type 1 diabetes. 机器学习在1型糖尿病预测和分类中的应用。

IF 29 1区生物学

Nature genetics Pub Date : 2026-04-30 DOI: 10.1038/s41588-026-02571-5

Yangxi Li, Constantin Polychronakos

引用次数: 0

Genetic association and machine learning improve the prediction of type 1 diabetes risk. 遗传关联和机器学习提高了1型糖尿病风险的预测。

IF 29 1区生物学

Nature genetics Pub Date : 2026-04-30 DOI: 10.1038/s41588-026-02578-y

Carolyn McGrail, Timothy J Sears, Emily N Griffin, Alexandra L Ghaben, Patrick Smadbeck, Jason Flannick, Parul Kudtarkar, Hannah Carter, Kyle Gaulton

{"title":"Genetic association and machine learning improve the prediction of type 1 diabetes risk.","authors":"Carolyn McGrail, Timothy J Sears, Emily N Griffin, Alexandra L Ghaben, Patrick Smadbeck, Jason Flannick, Parul Kudtarkar, Hannah Carter, Kyle Gaulton","doi":"10.1038/s41588-026-02578-y","DOIUrl":"10.1038/s41588-026-02578-y","url":null,"abstract":"Type 1 diabetes (T1D) has a large genetic component, and expanded genetic studies of T1D can enhance biological and therapeutic discovery and improve risk prediction. Here we performed genome-wide genetic association and fine-mapping analyses in 20,355 T1D and 797,363 nondiabetic individuals of European ancestry and in 10,107 T1D and 19,639 nondiabetic individuals at the MHC locus, which identified 160 risk signals. We trained a machine learning model, T1GRS, to predict T1D using genetic risk, which improved classification in Europeans and performed similarly in African Americans, compared to previous scores. T1GRS particularly improved prediction in T1D, with fewer high-risk HLA haplotypes and more complex risk profiles, and revealed 154 nonlinear interactions between MHC and non-MHC loci. Finally, we identified four genetic subclusters based on T1GRS features with significant differences in age of onset and diabetic complications. Overall, improved genetic discovery and prediction will have wide clinical, therapeutic and research applications for T1D.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":" ","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147817774","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

Multi-ancestry genome-wide association and integrated multi-omics analyses of endometriosis and its clinical manifestations. 子宫内膜异位症及其临床表现的多祖先全基因组关联及综合多组学分析。

IF 29 1区生物学

Nature genetics Pub Date : 2026-04-29 DOI: 10.1038/s41588-026-02582-2

Dora Koller, Jun He, Solveig Løkhammer, Selena Aranda, Dan Qiu, David Davtian, Qianyu Chen, Ziang Xu, Zhongzheng Mao, Eleni Friligkou, Sefayet Karaca, Bru Cormand, Idhaliz Flores, Signe Altmäe, Marina Mitjans, Brenda Cabrera-Mendoza, Renato Polimanti

{"title":"Multi-ancestry genome-wide association and integrated multi-omics analyses of endometriosis and its clinical manifestations.","authors":"Dora Koller, Jun He, Solveig Løkhammer, Selena Aranda, Dan Qiu, David Davtian, Qianyu Chen, Ziang Xu, Zhongzheng Mao, Eleni Friligkou, Sefayet Karaca, Bru Cormand, Idhaliz Flores, Signe Altmäe, Marina Mitjans, Brenda Cabrera-Mendoza, Renato Polimanti","doi":"10.1038/s41588-026-02582-2","DOIUrl":"10.1038/s41588-026-02582-2","url":null,"abstract":"Endometriosis is a chronic systemic disease affecting ~10% of women, yet its genetic basis and molecular mechanisms remain poorly understood. Hence, here we conducted a genome-wide association study of endometriosis and adenomyosis in ~1.4 million women, including 105,869 cases, aiming to expand loci discovery across ancestries, dissect symptom-specific effects and integrate multi-omic data. We identified 80 genomic regions associated with endometriosis risk, including 37 new loci, of which 5 are also associated with adenomyosis. We identified putative causal variants underlying over 50 of these associations. Transcriptomic, epigenetic and proteomic analyses across tissues linked endometriosis risk to pathways involved in cell differentiation, immune and hormonal regulation, tissue remodeling and inflammation. Drug-repurposing analyses highlighted potential treatments currently used for breast cancer, contraception and preterm birth prevention. Endometriosis polygenic risk interacted with abdominal pain, anxiety, migraine and nausea. This study advances understanding of genetic risk factors for endometriosis and provides molecular support for several hypotheses on its pathogenesis.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":" ","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147776393","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