Nature genetics最新文献_第3页

Systematic design of combination therapy by targeting master regulators of coexisting diffuse midline glioma cell states. 针对共存的弥漫性中线胶质瘤细胞状态的主要调节因子进行联合治疗的系统设计。

IF 30.8 1区生物学

Nature genetics Pub Date : 2026-04-22 DOI: 10.1038/s41588-026-02550-w

Ester Calvo Fernández,Lorenzo Tomassoni,Xu Zhang,Junqiang Wang,Aleksandar Obradovic,Pasquale Laise,Aaron T Griffin,Lukas Vlahos,Hanna E Minns,Diana V Morales,Christian Simmons,Matthew Gallitto,Hong-Jian Wei,Timothy J Martins,Pamela S Becker,John R Crawford,Theophilos Tzaridis,Robert J Wechsler-Reya,James Garvin,Robyn D Gartrell,Luca Szalontay,Stergios Zacharoulis,Cheng-Chia Wu,Zhiguo Zhang,Andrea Califano,Jovana Pavisic

{"title":"Systematic design of combination therapy by targeting master regulators of coexisting diffuse midline glioma cell states.","authors":"Ester Calvo Fernández,Lorenzo Tomassoni,Xu Zhang,Junqiang Wang,Aleksandar Obradovic,Pasquale Laise,Aaron T Griffin,Lukas Vlahos,Hanna E Minns,Diana V Morales,Christian Simmons,Matthew Gallitto,Hong-Jian Wei,Timothy J Martins,Pamela S Becker,John R Crawford,Theophilos Tzaridis,Robert J Wechsler-Reya,James Garvin,Robyn D Gartrell,Luca Szalontay,Stergios Zacharoulis,Cheng-Chia Wu,Zhiguo Zhang,Andrea Califano,Jovana Pavisic","doi":"10.1038/s41588-026-02550-w","DOIUrl":"https://doi.org/10.1038/s41588-026-02550-w","url":null,"abstract":"Intratumor heterogeneity fundamentally challenges cancer treatment, as coexisting, molecularly distinct cell states with non-overlapping drug sensitivities can drive therapeutic resistance. We establish and validate a generalizable, network-based framework to systematically identify combination therapies targeting complementary tumor cell states. Applied to diffuse midline glioma (DMG)-a universally fatal pediatric malignancy-this approach identified master regulator protein dependencies in seven coexisting cell states, confirmed by pooled CRISPR-Cas9 assays. Perturbational transcriptional profiles for 372 clinically relevant drugs prioritized candidates predicted to invert state-specific master regulator activity. State-selective drug sensitivity was validated for eight out of nine (89%) drugs in vivo, including avapritinib, ruxolitinib and larotrectinib. Compared with monotherapy, co-administering drugs targeting complementary states significantly prolonged survival across virtually all combinations, with avapritinib plus ruxolitinib extending median survival nearly threefold versus vehicle and 1.5-fold versus avapritinib alone. These findings establish clinically actionable DMG combinations and a tumor-agnostic and mutation-agnostic framework for rational combination therapy design.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"96 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147733979","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

k-mer-based approaches to unlock genebank genomics for targeted crop improvement. 基于k-mer的方法解锁基因库基因组学，用于靶向作物改良。

IF 30.8 1区生物学

Nature genetics Pub Date : 2026-04-21 DOI: 10.1038/s41588-026-02568-0

Anna Elisabeth Backhaus,Jesus Quiroz-Chavez,Susanne Dreisigacker,Emile Cavalet-Giorsa,Cristobal Uauy,Simon G Krattinger

引用次数: 0

Multi-ancestry genome-wide association analyses of refractive error augment genetic discovery and polygenic prediction. 屈光不正的多祖先全基因组关联分析增强了遗传发现和多基因预测。

IF 30.8 1区生物学

Nature genetics Pub Date : 2026-04-20 DOI: 10.1038/s41588-026-02576-0

Fei-Fei Cheng,Xiaoxi Liu,Hao Mi,Lizhong Wang,Ruilei Ma,Yazhou Guo,Julia Sidorenko,Chen Jiang,Tania Islam,Akira Meguro,Keiko Hikino,Yuki Ishikawa,Senwei Tang,Teng Li,Ruoyan Chen,Likun Wang,Reedik Mägi,Andres Metspalu, ,Masaki Takeuchi,Nobuhisa Mizuki,Hélène Choquet,Zi-Bing Jin,Gang Chen,Kun Zhou,Chikashi Terao,Jian Zeng,Jian Yang

{"title":"Multi-ancestry genome-wide association analyses of refractive error augment genetic discovery and polygenic prediction.","authors":"Fei-Fei Cheng,Xiaoxi Liu,Hao Mi,Lizhong Wang,Ruilei Ma,Yazhou Guo,Julia Sidorenko,Chen Jiang,Tania Islam,Akira Meguro,Keiko Hikino,Yuki Ishikawa,Senwei Tang,Teng Li,Ruoyan Chen,Likun Wang,Reedik Mägi,Andres Metspalu, ,Masaki Takeuchi,Nobuhisa Mizuki,Hélène Choquet,Zi-Bing Jin,Gang Chen,Kun Zhou,Chikashi Terao,Jian Zeng,Jian Yang","doi":"10.1038/s41588-026-02576-0","DOIUrl":"https://doi.org/10.1038/s41588-026-02576-0","url":null,"abstract":"Refractive errors (REs) affect over half of the global population, with consequences ranging from blurred vision to blindness. Here we conducted ancestry-stratified and cross-ancestry meta-analyses of genome-wide association studies for RE in people of European (n = 1,495,159), East Asian (n = 121,172) and African (n = 144,737) ancestries. The cross-ancestry meta-analysis identified 932 RE-associated variants, including 241 previously unknown associations, four East Asian-specific associations and one African-specific association. Statistical fine-mapping pinpointed 16 high-confidence putative causal variants, and gene prioritization analyses highlighted 23 genes involved in eye development. We constructed an enhanced polygenic predictor incorporating functional annotations that explained 21.4% of RE variation, effectively stratified the onset, progression and severity of myopia, and achieved an area under the receiver operating characteristic curve of 0.806 for predicting high myopia. Our multi-ancestry genome-wide association study expands substantially the catalog of genetic variants for RE and demonstrates the potential clinical utility of polygenic prediction in identifying high-risk people across diverse populations.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"24 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147726210","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

Pangenomic analyses of rose uncover widespread structure variation and empower genomics-directed breeding. 玫瑰的全基因组分析揭示了广泛的结构变异和授权基因组定向育种。

IF 30.8 1区生物学

Nature genetics Pub Date : 2026-04-16 DOI: 10.1038/s41588-026-02569-z

Xiaoni Zhang,Lan Lan,Yingxue Yang,Huilin Guan,Dan Peng,Heling Jiang,Quanshu Wu,Rui Huang,Xuezhu Liao,Shengnan Lin,Desheng Gong,Bingyao Huang,Clement Bellot,Judit Szécsi,Manzhu Bao,Mohammed Bendahmane,Xiaopeng Fu,Zhiqiang Wu,Weihua Pan

{"title":"Pangenomic analyses of rose uncover widespread structure variation and empower genomics-directed breeding.","authors":"Xiaoni Zhang,Lan Lan,Yingxue Yang,Huilin Guan,Dan Peng,Heling Jiang,Quanshu Wu,Rui Huang,Xuezhu Liao,Shengnan Lin,Desheng Gong,Bingyao Huang,Clement Bellot,Judit Szécsi,Manzhu Bao,Mohammed Bendahmane,Xiaopeng Fu,Zhiqiang Wu,Weihua Pan","doi":"10.1038/s41588-026-02569-z","DOIUrl":"https://doi.org/10.1038/s41588-026-02569-z","url":null,"abstract":"Roses are economically important ornamental plants, with widespread applications in the cut flowers, garden and cosmetics industries. The genomic evolution and diversity of the subgenus Rosa remain understudied, limiting exploitation of its diversity in breeding. Here we assembled genomes of 23 accessions, comprising 51 haplotypes that capture the subgenus's high genetic diversity. Extensive introgression across accessions from different sections highlights crossbreeding potential. Pangenome analysis revealed 1,801,537 structural variations, providing insights into the genetic basis and key regulators controlling key traits such as continuous flowering, petal number and discoloration. A key finding was the identification of a CCD4 homolog as the main regulator of petal discoloration. Additional subgenomic analysis of the allopolyploid Rosa gallica and the triploid Rosa hybrida 'La France', two important breeding materials of modern roses, revealed their hybrid origins. Overall, this study advances understanding of rose genomics and provides valuable resources for future breeding and trait improvement.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"22 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147695192","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

Mapping cancer evolution with the mouse cell line atlas 利用小鼠细胞系图谱绘制癌症进化图谱

IF 29 1区生物学

Nature genetics Pub Date : 2026-04-15 DOI: 10.1038/s41588-026-02589-9

Cong Zhao

引用次数: 0

Whole-embryo spatial transcriptomics 全胚胎空间转录组学

IF 29 1区生物学

Nature genetics Pub Date : 2026-04-15 DOI: 10.1038/s41588-026-02591-1

Petra Gross

引用次数: 0

Challenges and future directions for Mendelian randomization. 孟德尔随机化的挑战和未来方向。

IF 30.8 1区生物学

Nature genetics Pub Date : 2026-04-15 DOI: 10.1038/s41588-026-02546-6

Eleanor Sanderson,Michael G Levin,Venexia Walker,Shuai Yuan,Isabella Badini,Julia Dolce,Karina J Mahida,Ju-Woo Nho,J B Pingault,Scott M Damrauer,Gibran Hemani,Neil M Davies

引用次数: 0

Koalas rebounding from population bottleneck 考拉从种群瓶颈中反弹

IF 29 1区生物学

Nature genetics Pub Date : 2026-04-15 DOI: 10.1038/s41588-026-02588-w

Margot Brandt

引用次数: 0

Chromatin remodeling during brain aging 脑老化过程中的染色质重塑

IF 29 1区生物学

Nature genetics Pub Date : 2026-04-15 DOI: 10.1038/s41588-026-02590-2

Tiago Faial

引用次数: 0

Somatic mosaicism in ALS and FTD identifies focal mutations associated with widespread degeneration. 肌萎缩侧索硬化症和FTD的体细胞嵌合体鉴定了与广泛变性相关的局灶突变。

IF 30.8 1区生物学

Nature genetics Pub Date : 2026-04-15 DOI: 10.1038/s41588-026-02570-6

Zinan Zhou,Junho Kim,August Yue Huang,Matthew Nolan,Junseok Park,Ryan Doan,Taehwan Shin,Michael B Miller,Mingyun Bae,Boxun Zhao,Jinhyeong Kim,Brian Chhouk,Katherine Morillo,Rebecca C Yeh,Connor Kenny,Jennifer E Neil,Chao-Zong Lee,Takuya Ohkubo,John Ravits,Olaf Ansorge,Lyle W Ostrow,Clotilde Lagier-Tourenne,Eunjung Alice Lee,Christopher A Walsh

{"title":"Somatic mosaicism in ALS and FTD identifies focal mutations associated with widespread degeneration.","authors":"Zinan Zhou,Junho Kim,August Yue Huang,Matthew Nolan,Junseok Park,Ryan Doan,Taehwan Shin,Michael B Miller,Mingyun Bae,Boxun Zhao,Jinhyeong Kim,Brian Chhouk,Katherine Morillo,Rebecca C Yeh,Connor Kenny,Jennifer E Neil,Chao-Zong Lee,Takuya Ohkubo,John Ravits,Olaf Ansorge,Lyle W Ostrow,Clotilde Lagier-Tourenne,Eunjung Alice Lee,Christopher A Walsh","doi":"10.1038/s41588-026-02570-6","DOIUrl":"https://doi.org/10.1038/s41588-026-02570-6","url":null,"abstract":"Although mutations in many genes cause familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), most cases are sporadic (sALS and sFTD) with unclear etiology. Here we tested whether somatic mutations contribute to sALS and sFTD by deep targeted sequencing of 88 neurodegeneration-related genes in postmortem brain and spinal cord samples from 399 sporadic cases and 144 controls. Predicted deleterious somatic variants in ALS/FTD genes were observed in 2.1% of sporadic cases lacking deleterious germline variants. These variants occurred at very low allele fractions (typically <2%) and were often focal and enriched in disease-affected regions. Analysis of bulk RNA-sequencing data from an additional cohort identified deleterious somatic variants in DYNC1H1 and LMNA, genes associated with pediatric motor neuron degeneration. Targeted long-read sequencing further identified one sFTD case with de novo somatic C9orf72 repeat expansions. Together, these findings suggest that rare, focal somatic variants can contribute to sALS and sFTD and drive widespread neurodegeneration.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"29 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147685102","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