Nature genetics最新文献

{"title":"Causal machine learning for single-cell genomics","authors":"Alejandro Tejada-Lapuerta, Paul Bertin, Stefan Bauer, Hananeh Aliee, Yoshua Bengio, Fabian J. Theis","doi":"10.1038/s41588-025-02124-2","DOIUrl":"10.1038/s41588-025-02124-2","url":null,"abstract":"Advances in single-cell ''-omics'' allow unprecedented insights into the transcriptional profiles of individual cells and, when combined with large-scale perturbation screens, enable measuring of the effect of targeted perturbations on the whole transcriptome. These advances provide an opportunity to better understand the causative role of genes in complex biological processes. In this Perspective, we delineate the application of causal machine learning to single-cell genomics and its associated challenges. We first present the causal model that is most commonly applied to single-cell biology and then identify and discuss potential approaches to three open problems: the lack of generalization of models to novel experimental conditions, the complexity of interpreting learned models, and the difficulty of learning cell dynamics. This Perspective explores causal machine learning in single-cell genomics, addressing challenges such as generalization, interpretability and cell dynamics, while highlighting advances and the potential to uncover new insights into cellular mechanisms.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 4","pages":"797-808"},"PeriodicalIF":31.7,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143736570","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}

{"title":"The genome and GeneBank genomics of allotetraploid Nicotiana tabacum provide insights into genome evolution and complex trait regulation","authors":"Yanjun Zan, Shuai Chen, Min Ren, Guoxiang Liu, Yutong Liu, Yu Han, Yang Dong, Yao Zhang, Huan Si, Zhengwen Liu, Dan Liu, Xingwei Zhang, Ying Tong, Yuan Li, Caihong Jiang, Liuying Wen, Zhiliang Xiao, Yangyang Sun, Ruimei Geng, Yan Ji, Quanfu Feng, Yuanying Wang, Guoyou Ye, Lingzhao Fang, Yong Chen, Lirui Cheng, Aiguo Yang","doi":"10.1038/s41588-025-02126-0","DOIUrl":"10.1038/s41588-025-02126-0","url":null,"abstract":"Nicotiana tabacum is an allotetraploid hybrid of Nicotiana sylvestris and Nicotiana tomentosiformis and a model organism in genetics. However, features of subgenome evolution, expression coordination, genetic diversity and complex traits regulation of N. tabacum remain unresolved. Here we present chromosome-scale assemblies for all three species, and genotype and phenotypic data for 5,196 N. tabacum germplasms. Chromosome rearrangements and epigenetic modifications are associated with genome evolution and expression coordination following polyploidization. Two subgenomes and genes biased toward one subgenome contributed unevenly to complex trait variation. Using 178 marker–trait associations, a reference genotype-to-phenotype map was built for 39 morphological, developmental and disease resistance traits, and a novel gene regulating leaf width was validated. Signatures of positive and polygenic selection during the process of selective breeding were detected. Our study provides insights into genome evolution, complex traits regulation in allotetraploid N. tabacum and the use of GeneBank-scale resources for advancing genetic and genomic research. Chromosome-level genome assemblies of allotetraploid Nicotiana tabacum and its ancestors, along with their transcriptomes, epigenomes and genotype and phenotype data for 5,196 N. tabacum germplasms, provide insights into genome evolution and complex trait regulation.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 4","pages":"986-996"},"PeriodicalIF":31.7,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-025-02126-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143703243","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}

{"title":"Rare loss-of-function variants in HECTD2 and AKAP11 confer risk of bipolar disorder","authors":"Thorgeir E. Thorgeirsson, Vinicius Tragante, Gardar Sveinbjornsson, Gudrun A. Jonsdottir, G. Bragi Walters, Erna V. Ivarsdottir, Gudny A. Arnadottir, Arni Sturluson, Brynjar O. Jensson, Run Fridriksdottir, Astros Th. Skuladottir, Gudmundur Einarsson, Gyda Bjornsdottir, Arni F. Gunnarsson, Rosa S. Gisladottir, Asgeir Sigurdsson, Asmundur Oddsson, Hakon Jonsson, Olafur Th. Magnusson, Hannes Helgason, Gudmundur Norddahl, Gudmar Thorleifsson, Magnus Haraldsson, Engilbert Sigurdsson, Hilma Holm, Gisli Masson, Daniel F. Gudbjartsson, Hreinn Stefansson, Patrick Sulem, Kari Stefansson","doi":"10.1038/s41588-025-02141-1","DOIUrl":"10.1038/s41588-025-02141-1","url":null,"abstract":"Bipolar disorder is a highly heritable psychiatric disorder; genome-wide association studies of bipolar disorder have yielded over 60 risk loci harboring common variants. To harness the information contained in rare loss-of-function (LOF) variants, holding promise for informing on the underlying biology, we performed a variant burden analysis for bipolar disorder using gene-based aggregation of LOF variants in whole-genome sequencing data from Iceland (4,197 cases, more than 200,000 controls) and the UK Biobank (1,881 cases, 426,622 controls). We found that HECTD2 was associated with bipolar disorder and confirmed it using the Bipolar Exome dataset. Meta-analysis with Bipolar Exome also revealed that LOF variants in AKAP11 were associated with bipolar disorder. Both associations with bipolar disorder are new, but AKAP11 has previously been associated with psychosis and schizophrenia. The products of AKAP11 and HECTD2 interact with GSK3β, a protein inhibited by lithium, the most effective mood stabilizer available to treat bipolar disorder. Analysis of whole-genome sequencing data from Iceland and the UK Biobank identifies an excess burden of rare loss-of-function variants in HECTD2 and AKAP11 in individuals diagnosed with bipolar disorder.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 4","pages":"851-855"},"PeriodicalIF":31.7,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-025-02141-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143695630","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}

{"title":"Author Correction: Origin and de novo domestication of sweet orange","authors":"Shengjun Liu, Yuantao Xu, Kun Yang, Yue Huang, Zhihao Lu, Shulin Chen, Xiang Gao, Gongao Xiao, Peng Chen, Xiuli Zeng, Lun Wang, Weikang Zheng, Zishuang Liu, Guanglian Liao, Fa He, Junjie Liu, Pengfei Wan, Fang Ding, Junli Ye, Wenbiao Jiao, Lijun Chai, Zhiyong Pan, Fei Zhang, Zongcheng Lin, Yanjun Zan, Wenwu Guo, Robert M. Larkin, Zongzhou Xie, Xia Wang, Xiuxin Deng, Qiang Xu","doi":"10.1038/s41588-025-02165-7","DOIUrl":"10.1038/s41588-025-02165-7","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 4","pages":"1059-1059"},"PeriodicalIF":31.7,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-025-02165-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143695631","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}

{"title":"Author Correction: Rare variant analyses in 51,256 type 2 diabetes cases and 370,487 controls reveal the pathogenicity spectrum of monogenic diabetes genes","authors":"Alicia Huerta-Chagoya, Philip Schroeder, Ravi Mandla, Jiang Li, Lowri Morris, Maheak Vora, Ahmed Alkanaq, Dorka Nagy, Lukasz Szczerbinski, Jesper G. S. Madsen, Silvia Bonàs-Guarch, Fanny Mollandin, Joanne B. Cole, Bianca Porneala, Kenneth Westerman, Josephine H. Li, Toni I. Pollin, Jose C. Florez, Anna L. Gloyn, David J. Carey, Inês Cebola, Uyenlinh L. Mirshahi, Alisa K. Manning, Aaron Leong, Miriam Udler, Josep M. Mercader","doi":"10.1038/s41588-025-02175-5","DOIUrl":"10.1038/s41588-025-02175-5","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 4","pages":"1060-1060"},"PeriodicalIF":31.7,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-025-02175-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143695618","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}

{"title":"The landscape of N6-methyladenosine in localized primary prostate cancer","authors":"Xin Xu, Helen Zhu, Rupert Hugh-White, Julie Livingstone, Stefan Eng, Nicole Zeltser, Yujuan Wang, Kinga Pajdzik, Sujun Chen, Kathleen E. Houlahan, Wenqin Luo, Shun Liu, Xi Xu, Minzhi Sheng, Wang Yuan Guo, Jaron Arbet, Yuxi Song, Miranda Wang, Yong Zeng, Shiyan Wang, Guanghui Zhu, Tingxiao Gao, Wei Chen, Xinpei Ci, Wenjie Xu, Kexin Xu, Michele Orain, Valerie Picard, Helene Hovington, Alain Bergeron, Louis Lacombe, Bernard Têtu, Yves Fradet, Mathieu Lupien, Gong-Hong Wei, Marianne Koritzinsky, Robert G. Bristow, Neil E. Fleshner, Xue Wu, Yang Shao, Chuan He, Alejandro Berlin, Theodorus van der Kwast, Hon Leong, Paul C. Boutros, Housheng Hansen He","doi":"10.1038/s41588-025-02128-y","DOIUrl":"10.1038/s41588-025-02128-y","url":null,"abstract":"N6-methyladenosine (m6A), the most abundant internal RNA modification in humans, regulates most aspects of RNA processing. Prostate cancer is characterized by widespread transcriptomic dysregulation; therefore, we characterized the m6A landscape of 162 localized prostate tumors with matched DNA, RNA and protein profiling. m6A abundance varied dramatically across tumors, with global patterns emerging via complex germline–somatic cooperative regulation. Individual germline polymorphisms regulated m6A abundance, cooperating with somatic mutation of cancer driver genes and m6A regulators. The resulting complex patterns were associated with prognostic clinical features and established the biomarker potential of global and locus-specific m6A patterns. Tumor hypoxia dysregulates m6A profiles, bridging prior genomic and proteomic observations. Specific m6A sites, such as those in VCAN, drive disease aggression, associating with poor outcomes, tumor growth and metastasis. m6A dysregulation is thus associated with key events in the natural history of prostate cancer: germline risk, microenvironmental dysregulation, somatic mutation and metastasis. Transcriptome-wide m6A RNA methylation profile in 162 primary prostate tumors identifies m6A association with prognostic clinical features and disease aggression.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 4","pages":"934-948"},"PeriodicalIF":31.7,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-025-02128-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677657","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}

{"title":"Reply to: An alternative model for maternal mtDNA inheritance","authors":"William Lee, Angelica Zamudio-Ochoa, Gina Buchel, Petar Podlesniy, Nuria Marti Gutierrez, Aleksei Mikhalchenko, Ramon Trullas, Shoukhrat Mitalipov, Dmitry Temiakov","doi":"10.1038/s41588-025-02150-0","DOIUrl":"https://doi.org/10.1038/s41588-025-02150-0","url":null,"abstract":"<p><span>replying to</span> M. Alexeyev &amp; Y. Bai <b><i>Nature Genetics</i></b> https://doi.org/10.1038/s41588-025-02149-7 (2025)</p><p>The dogma of uniparental inheritance of mitochondrial DNA (mtDNA) represents a fascinating aspect of genetics and the evolution of all living organisms. The processes underlying this trait involve molecular mechanisms that act before and after oocyte fertilization. The former involves elimination of mtDNA during spermatogenesis, the process of sperm cell maturation^1,2,3. Post-fertilization mechanisms include removal of sperm mitochondria through autophagy and ubiquitin-mediated proteolysis after the cell penetrates an oocyte^4,5.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"91 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143660365","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}

{"title":"An alternative model for maternal mtDNA inheritance","authors":"Mikhail Alexeyev, Yidong Bai","doi":"10.1038/s41588-025-02149-7","DOIUrl":"https://doi.org/10.1038/s41588-025-02149-7","url":null,"abstract":"<p><span>arising from</span> W. Lee et al. <i>Nature Genetics</i> https://doi.org/10.1038/s41588-023-01505-9 (2023)</p><p>The exact mechanism preventing paternal mitochondrial DNA (mtDNA) inheritance in humans remains unresolved. In their recent report, ‘Molecular basis for maternal inheritance of human mitochondrial DNA’, Lee et al. propose that this process is controlled by phosphorylation of the mitochondrial transcription factor A (TFAM) on two serine residues located in the matrix targeting sequence (MTS), which blocks this protein’s mitochondrial import, thus uncoating mtDNA and exposing it to attack and destruction by unspecified mitochondrial nuclease(s), which prevents paternal mtDNA from entering the oocyte during fertilization. We argue that the experimental evidence presented in the article is inconclusive and also supports an alternative possibility: that mtDNA turnover following the loss of expression of key mtDNA replication proteins might be responsible. Therefore, additional experimentation is needed to resolve the two competing mechanisms that align with the experimental data presented by Lee et al.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"124 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143661030","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}

{"title":"A likelihood-based framework for demographic inference from genealogical trees","authors":"Caoqi Fan,&nbsp;Jordan L. Cahoon,&nbsp;Bryan L. Dinh,&nbsp;Diego Ortega-Del Vecchyo,&nbsp;Christian D. Huber,&nbsp;Michael D. Edge,&nbsp;Nicholas Mancuso,&nbsp;Charleston W. K. Chiang","doi":"10.1038/s41588-025-02129-x","DOIUrl":"10.1038/s41588-025-02129-x","url":null,"abstract":"The demographic history of a population underlies patterns of genetic variation and is encoded in the gene-genealogical trees of the sampled haplotypes. Here we propose a demographic inference framework called the genealogical likelihood (gLike). Our method uses a graph-based structure to summarize the relationships among all lineages in a gene-genealogical tree with all possible trajectories of population memberships through time and derives the full likelihood across trees under a parameterized demographic model. We show through simulations and empirical applications that for populations that have experienced multiple admixtures, gLike can accurately estimate dozens of demographic parameters, including ancestral population sizes, admixture timing and admixture proportions, and it outperforms conventional demographic inference methods using the site frequency spectrum. Taken together, our proposed gLike framework harnesses underused genealogical information to offer high sensitivity and accuracy in inferring complex demographies for humans and other species. gLike infers population demographic histories with a variety of complex admixture events by analysis of graphs of states, which conceptualize the relationships of all lineages found in trees encoded in the ancestral recombination graph.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 4","pages":"865-874"},"PeriodicalIF":31.7,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143660367","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}

{"title":"A structured coalescent model reveals deep ancestral structure shared by all modern humans","authors":"Trevor Cousins,&nbsp;Aylwyn Scally,&nbsp;Richard Durbin","doi":"10.1038/s41588-025-02117-1","DOIUrl":"10.1038/s41588-025-02117-1","url":null,"abstract":"Understanding the history of admixture events and population size changes leading to modern humans is central to human evolutionary genetics. Here we introduce a coalescence-based hidden Markov model, cobraa, that explicitly represents an ancestral population split and rejoin, and demonstrate its application on simulated and real data across multiple species. Using cobraa, we present evidence for an extended period of structure in the history of all modern humans, in which two ancestral populations that diverged ~1.5 million years ago came together in an admixture event ~300 thousand years ago, in a ratio of ~80:20%. Immediately after their divergence, we detect a strong bottleneck in the major ancestral population. We inferred regions of the present-day genome derived from each ancestral population, finding that material from the minority correlates strongly with distance to coding sequence, suggesting it was deleterious against the majority background. Moreover, we found a strong correlation between regions of majority ancestry and human–Neanderthal or human–Denisovan divergence, suggesting the majority population was also ancestral to those archaic humans. The cobraa model extends the pairwise sequentially Markovian coalescent to identify structured population history by examination of the model transition matrix. Applied to human polymorphism data, cobraa identifies an ancient admixture event ancestral to all modern humans.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 4","pages":"856-864"},"PeriodicalIF":31.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-025-02117-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143640502","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}