Nature genetics最新文献

Therapeutic strategies for fragile X syndrome and implications for other gene-silencing disorders 脆性X综合征的治疗策略及其对其他基因沉默疾病的影响

IF 30.8 1区生物学

Nature genetics Pub Date : 2025-07-17 DOI: 10.1038/s41588-025-02255-6

Aseel Gadban, Keith M. Gunapala, Verdon Taylor, Nissim Benvenisty

引用次数: 0

Toward improving multiomic research in understudied cereals 改进未充分研究谷物的多组学研究

IF 30.8 1区生物学

Nature genetics Pub Date : 2025-07-16 DOI: 10.1038/s41588-025-02245-8

Fanjing Yang, Xiaojiao Gong, Pan Zhao, Lingtong Cheng, Yujie Zhang, Yingting Luo, Qian-Hao Zhu, Chu-Yu Ye

引用次数: 0

Germline genetic variation impacts clonal hematopoiesis landscape and progression to malignancy 种系遗传变异影响克隆造血景观和恶性肿瘤的进展

IF 30.8 1区生物学

Nature genetics Pub Date : 2025-07-15 DOI: 10.1038/s41588-025-02250-x

Jie Liu, Duc Tran, Liying Xue, Brian J. Wiley, Caitlyn Vlasschaert, Caroline J. Watson, Hamish A. J. MacGregor, Xiaoyu Zong, Irenaeus C. C. Chan, Indraniel Das, Md Mesbah Uddin, Abhishek Niroula, Gabriel Griffin, Benjamin L. Ebert, Taralynn Mack, Yash Pershad, Brian Sharber, Michael Berger, Ahmet Zehir, Ryan Ptashkin, Ross L. Levine, Elli Papaemmanuil, Vijai Joseph, Teng Gao, Yelena Kemel, Diana Mandelker, Konrad H. Stopsack, Paul D. P. Pharoah, Semanti Mukherjee, Li Ding, Yin Cao, Matthew J. Walter, Jamie R. Blundell, Nilanjan Chatterjee, Kenneth Offit, Lucy A. Godley, Daniel C. Link, Zsofia K. Stadler, Alexander G. Bick, Pradeep Natarajan, Kelly L. Bolton

{"title":"Germline genetic variation impacts clonal hematopoiesis landscape and progression to malignancy","authors":"Jie Liu, Duc Tran, Liying Xue, Brian J. Wiley, Caitlyn Vlasschaert, Caroline J. Watson, Hamish A. J. MacGregor, Xiaoyu Zong, Irenaeus C. C. Chan, Indraniel Das, Md Mesbah Uddin, Abhishek Niroula, Gabriel Griffin, Benjamin L. Ebert, Taralynn Mack, Yash Pershad, Brian Sharber, Michael Berger, Ahmet Zehir, Ryan Ptashkin, Ross L. Levine, Elli Papaemmanuil, Vijai Joseph, Teng Gao, Yelena Kemel, Diana Mandelker, Konrad H. Stopsack, Paul D. P. Pharoah, Semanti Mukherjee, Li Ding, Yin Cao, Matthew J. Walter, Jamie R. Blundell, Nilanjan Chatterjee, Kenneth Offit, Lucy A. Godley, Daniel C. Link, Zsofia K. Stadler, Alexander G. Bick, Pradeep Natarajan, Kelly L. Bolton","doi":"10.1038/s41588-025-02250-x","DOIUrl":"https://doi.org/10.1038/s41588-025-02250-x","url":null,"abstract":"With age, clonal expansions occur pervasively across normal tissues yet only in rare instances lead to cancer, despite being driven by well-established cancer drivers. Characterization of the factors that influence clonal progression is needed to inform interventional approaches. Germline genetic variation influences cancer risk and shapes tumor mutational profile, but its influence on the mutational landscape of normal tissues is not well known. Here we studied the impact of germline genetic variation on clonal hematopoiesis (CH) in 731,835 individuals. We identified 22 new CH-predisposition genes, most of which predispose to CH driven by specific mutational events. CH-predisposition genes contribute to unique somatic landscapes, reflecting the influence of germline genetic backdrop on gene-specific CH fitness. Correspondingly, somatic–germline interactions influence the risk of CH progression to hematologic malignancies. These results demonstrate that germline genetic variation influences somatic evolution in the blood, findings that likely extend to other tissues.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"23 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144629584","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

Enhancer mutational screen in vivo 体内增强子突变筛选

IF 30.8 1区生物学

Nature genetics Pub Date : 2025-07-11 DOI: 10.1038/s41588-025-02277-0

Tiago Faial

{"title":"Enhancer mutational screen in vivo","authors":"Tiago Faial","doi":"10.1038/s41588-025-02277-0","DOIUrl":"https://doi.org/10.1038/s41588-025-02277-0","url":null,"abstract":"Transcriptional enhancers are key to dynamic gene regulation, but current knowledge on which sequences and motifs are essential for proper enhancer function is still incomplete. This limits our ability to interpret the relevance of enhancer mutations for disease risk. Kosicki et al. decided to mutate human developmental enhancers and investigate their functional sensitivity in vivo. Specifically, they selected seven enhancers, which are active in embryonic brain, heart, limb and face, and derived around 1,700 transgenic mice carrying 260 human enhancer alleles. The mutagenesis approach involved altering 12-bp blocks in each enhancer. This large-scale experiment showed that 69% of all tested blocks are essential for enhancer activity. As expected, most mutations led to a loss of function (60%), whereas only 9% created gain-of-function alleles. In addition, the authors used machine learning to predict the identity of crucial nucleotides at enhancers. Most of the predicted motifs or sites (88%) agreed with the experimental data. Indeed, the model demonstrated good sensitivity and identified 59% of functional blocks. The scale of this in vivo study is impressive and it clearly highlights the degree to which human developmental enhancers are sensitive to perturbation. This analysis contributes substantially to our growing understanding of enhancer structure and function.Original reference: Nature https://doi.org/10.1038/s41586-025-09182-w (2025)","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"12 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144611078","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

Expanding in situ genome sequencing 扩展原位基因组测序

IF 30.8 1区生物学

Nature genetics Pub Date : 2025-07-11 DOI: 10.1038/s41588-025-02278-z

Petra Gross

{"title":"Expanding in situ genome sequencing","authors":"Petra Gross","doi":"10.1038/s41588-025-02278-z","DOIUrl":"https://doi.org/10.1038/s41588-025-02278-z","url":null,"abstract":"Despite recent advances in measuring the transcriptome at cellular resolution, direct approaches to link genome organization to changes in nuclear structure are lacking. Labade et al. expand on a previous in situ genome sequencing approach by combining it with expansion microscopy (ExIGS) to simultaneously sequence genomic DNA and image nuclear features at nanoscale resolution. To validate the method, they use fibroblasts derived from patients with progeria to directly link morphological changes in nuclear structure to chromatin organization within individual cells. In progeria fibroblasts, chromosomes more closely follow the contours of the inner lamina topology, which is characterized by lamina thickening and invaginations that reach into the nuclear interior, compared with the uniform lamina layer found in control cells. Interestingly, chromatin organization is disrupted in local hotspots of lamina abnormalities, which are associated with aberrant gene silencing, thus potentially disrupting gene programs important for cell identity. Together, this work demonstrates the potential of combining genomic readout with super-resolution imaging to obtain enhanced spatial information future studies are needed to determine whether the observations are generalizable across diverse cellular and aging contexts.Original reference: Science https://doi.org/10.1126/science.adt2781 (2025)","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"694 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144611079","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

Y chromosome loss in cancer Y染色体在癌症中的丢失

IF 30.8 1区生物学

Nature genetics Pub Date : 2025-07-11 DOI: 10.1038/s41588-025-02276-1

Safia Danovi

{"title":"Y chromosome loss in cancer","authors":"Safia Danovi","doi":"10.1038/s41588-025-02276-1","DOIUrl":"https://doi.org/10.1038/s41588-025-02276-1","url":null,"abstract":"Loss of the Y chromosome (LOY) in male patients with cancer is associated with poor prognosis but the reason for this is unclear. Using a combination of mouse models and single-cell RNA sequencing analysis of human tumors, Chen et al. make the intriguing observation that epithelial tumors with LOY often occur in microenvironments where infiltrating, non-transformed immune cells — particularly CD4+ and CD8+ T cells — had also lost their copy of the Y chromosome. Tumor-infiltrating T cells with LOY showed features normally associated with a muted anti-tumor activity. Together, these data suggest that concomitant LOY in malignant cells and proximal immune cells creates an immunosuppressive milieu that favors aggressive tumor growth and poor outcomes for patients. Perhaps one of the most fascinating questions emanating from the study is how coordinated LOY occurs. Another is how LOY alters immune cell activity given that the function of the small gene-poor Y chromosome has traditionally been thought to be restricted to male development. These questions will need to be answered, but for now, the study provides a fascinating example of the way crosstalk between malignant and immune cells can affect disease outcomes.Original reference: Nature https://doi.org/10.1038/s41586-025-09071-2 (2025)","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"47 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144611080","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

Perturb-Multimodal pooled screening in intact tissues 在完整组织中进行多模态混合筛选

IF 30.8 1区生物学

Nature genetics Pub Date : 2025-07-11 DOI: 10.1038/s41588-025-02279-y

Wei Li

{"title":"Perturb-Multimodal pooled screening in intact tissues","authors":"Wei Li","doi":"10.1038/s41588-025-02279-y","DOIUrl":"https://doi.org/10.1038/s41588-025-02279-y","url":null,"abstract":"Imaging-based pooled genetic screening has been adopted to study genotype–phenotype relationships and expanded to multimodal measurements. Saunders et al. introduce an integrated approach known as Perturb-Multimodal (Perturb-Multi), which combines imaging and single-cell RNA sequencing for pooled genetic screens in intact tissues with multimodal phenotypic readouts. Perturb-Multi benefits from technological innovations to capture RNA–protein phenotypes and intact transcriptomes for in vivo screens. The unique feature is paired sequencing and imaging analysis of genetic perturbations in the same tissue, which enables the effects on both gene expression and subcellular morphology to be measured simultaneously, providing the potential to study genetic regulation of organ function at scale and in vivo. Applying Perturb-Multi to the mouse liver led to a systematic view of diverse gene perturbation effects on transcriptional state and tissue organization, and importantly, the identification of candidate genetic regulators of liver physiology related to hepatocyte zonation, cellular stress response and steatosis. Perturb-Multi provides training data for machine learning models, and may be expanded to other organs for functional genomics studies at the cellular and tissue levels under different physiological conditions.Original reference: Cell https://doi.org/10.1016/j.cell.2025.05.022 (2025)","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"11 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144611202","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

Enhancer adoption by an LTR retrotransposon generates viral-like particles, causing developmental limb phenotypes LTR逆转录转座子采用增强子产生病毒样颗粒，导致发育肢体表型

IF 30.8 1区生物学

Nature genetics Pub Date : 2025-07-09 DOI: 10.1038/s41588-025-02248-5

Juliane Glaser, Giulia Cova, Beatrix Fauler, Cesar A. Prada-Medina, Virginie Stanislas, Mai H. Q. Phan, Robert Schöpflin, Yasmin Aktas, Martin Franke, Guillaume Andrey, Natalia Bartzoka, Christina Paliou, Verena Laupert, Wing-Lee Chan, Lars Wittler, Thorsten Mielke, Stefan Mundlos

{"title":"Enhancer adoption by an LTR retrotransposon generates viral-like particles, causing developmental limb phenotypes","authors":"Juliane Glaser, Giulia Cova, Beatrix Fauler, Cesar A. Prada-Medina, Virginie Stanislas, Mai H. Q. Phan, Robert Schöpflin, Yasmin Aktas, Martin Franke, Guillaume Andrey, Natalia Bartzoka, Christina Paliou, Verena Laupert, Wing-Lee Chan, Lars Wittler, Thorsten Mielke, Stefan Mundlos","doi":"10.1038/s41588-025-02248-5","DOIUrl":"https://doi.org/10.1038/s41588-025-02248-5","url":null,"abstract":"Transposable elements (TEs) are scattered across mammalian genomes. Silencing of TEs prevents harmful effects caused by either global activation leading to genome instability or insertional mutations disturbing gene transcription. However, whether the activation of a TE can cause disease without directly affecting gene expression is largely unknown. Here we show that a TE insertion can adopt nearby regulatory activity, resulting in the production of cell-type-specific viral-like particles (VLPs) that affect embryo formation. Failure to silence an LTR retrotransposon inserted upstream of the Fgf8 gene results in their co-expression during mouse development. VLP assembly in the Fgf8-expressing cells of the developing limb triggers apoptotic cell death, resulting in a limb malformation resembling human ectrodactyly. The phenotype can be rescued by mutating the retrotransposon coding sequence, thus preventing its full endogenous retroviral cycle. Our findings illustrate that TE insertions can be incorporated into the local genomic regulatory landscape and that VLP production in post-implantation embryos can cause developmental defects.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"28 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144586647","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

A retrotransposon caught red-handed in a curious case of missing digits 一个反转录转座子在一个奇怪的数字丢失案例中被当场抓获

IF 30.8 1区生物学

Nature genetics Pub Date : 2025-07-09 DOI: 10.1038/s41588-025-02147-9

Youjia Guo, Andrew J. Modzelewski

引用次数: 0

Decomposition of phenotypic heterogeneity in autism reveals underlying genetic programs 自闭症表型异质性的分解揭示了潜在的遗传程序

IF 30.8 1区生物学

Nature genetics Pub Date : 2025-07-09 DOI: 10.1038/s41588-025-02224-z

Aviya Litman, Natalie Sauerwald, LeeAnne Green Snyder, Jennifer Foss-Feig, Christopher Y. Park, Yun Hao, Ilan Dinstein, Chandra L. Theesfeld, Olga G. Troyanskaya

{"title":"Decomposition of phenotypic heterogeneity in autism reveals underlying genetic programs","authors":"Aviya Litman, Natalie Sauerwald, LeeAnne Green Snyder, Jennifer Foss-Feig, Christopher Y. Park, Yun Hao, Ilan Dinstein, Chandra L. Theesfeld, Olga G. Troyanskaya","doi":"10.1038/s41588-025-02224-z","DOIUrl":"https://doi.org/10.1038/s41588-025-02224-z","url":null,"abstract":"Unraveling the phenotypic and genetic complexity of autism is extremely challenging yet critical for understanding the biology, inheritance, trajectory and clinical manifestations of the many forms of the condition. Using a generative mixture modeling approach, we leverage broad phenotypic data from a large cohort with matched genetics to identify robust, clinically relevant classes of autism and their patterns of core, associated and co-occurring traits, which we further validate and replicate in an independent cohort. We demonstrate that phenotypic and clinical outcomes correspond to genetic and molecular programs of common, de novo and inherited variation and further characterize distinct pathways disrupted by the sets of mutations in each class. Remarkably, we discover that class-specific differences in the developmental timing of affected genes align with clinical outcome differences. These analyses demonstrate the phenotypic complexity of children with autism, identify genetic programs underlying their heterogeneity, and suggest specific biological dysregulation patterns and mechanistic hypotheses.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"135 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144586558","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