Nature geneticsPub Date : 2025-08-12DOI: 10.1038/s41588-025-02283-2
{"title":"Recreating fibroblast diversity in vitro by activating transcription factors","authors":"","doi":"10.1038/s41588-025-02283-2","DOIUrl":"10.1038/s41588-025-02283-2","url":null,"abstract":"We combined CRISPR activation of all 1,836 known human transcription factors with high-throughput Perturb-seq to recreate the diverse transcriptional states occupied by fibroblasts in vivo. Our study revealed regulators of key states and showed that inducing normal states can, in some cases, suppress those linked to disease.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 9","pages":"2088-2089"},"PeriodicalIF":29.0,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144824934","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}
Nature geneticsPub Date : 2025-08-11DOI: 10.1038/s41588-025-02246-7
Julia Engelhorn, Samantha J. Snodgrass, Amelie Kok, Arun S. Seetharam, Michael Schneider, Tatjana Kiwit, Ayush Singh, Michael Banf, Duong Thi Hai Doan, Merritt Khaipho-Burch, Daniel E. Runcie, Victor A. Sánchez-Camargo, Rechien Bader, J. Vladimir Torres-Rodriguez, Guangchao Sun, Maike Stam, Fabio Fiorani, Sebastian Beier, James C. Schnable, Hank W. Bass, Matthew B. Hufford, Benjamin Stich, Wolf B. Frommer, Jeffrey Ross-Ibarra, Thomas Hartwig
{"title":"Genetic variation at transcription factor binding sites largely explains phenotypic heritability in maize","authors":"Julia Engelhorn, Samantha J. Snodgrass, Amelie Kok, Arun S. Seetharam, Michael Schneider, Tatjana Kiwit, Ayush Singh, Michael Banf, Duong Thi Hai Doan, Merritt Khaipho-Burch, Daniel E. Runcie, Victor A. Sánchez-Camargo, Rechien Bader, J. Vladimir Torres-Rodriguez, Guangchao Sun, Maike Stam, Fabio Fiorani, Sebastian Beier, James C. Schnable, Hank W. Bass, Matthew B. Hufford, Benjamin Stich, Wolf B. Frommer, Jeffrey Ross-Ibarra, Thomas Hartwig","doi":"10.1038/s41588-025-02246-7","DOIUrl":"10.1038/s41588-025-02246-7","url":null,"abstract":"Comprehensive maps of functional variation at transcription factor (TF) binding sites (cis-elements) are crucial for elucidating how genotype shapes phenotype. Here, we report the construction of a pan-cistrome of the maize leaf under well-watered and drought conditions. We quantified haplotype-specific TF footprints across a pan-genome of 25 maize hybrids and mapped over 200,000 variants, genetic, epigenetic, or both (termed binding quantitative trait loci (bQTL)), linked to cis-element occupancy. Three lines of evidence support the functional significance of bQTL: (1) coincidence with causative loci that regulate traits, including vgt1, ZmTRE1 and the MITE transposon near ZmNAC111 under drought; (2) bQTL allelic bias is shared between inbred parents and matches chromatin immunoprecipitation sequencing results; and (3) partitioning genetic variation across genomic regions demonstrates that bQTL capture the majority of heritable trait variation across ~72% of 143 phenotypes. Our study provides an auspicious approach to make functional cis-variation accessible at scale for genetic studies and targeted engineering of complex traits. Pan-cistrome of the maize leaf under well-watered and drought conditions profiled by haplotype-specific MOA-seq highlights the relevance of transcription factor binding QTLs for understanding phenotypic diversity in maize.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 9","pages":"2313-2322"},"PeriodicalIF":29.0,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-025-02246-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812928","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}
Nature geneticsPub Date : 2025-08-11DOI: 10.1038/s41588-025-02286-z
Jasper P. Hof, Doug Speed
{"title":"LDAK-KVIK performs fast and powerful mixed-model association analysis of quantitative and binary phenotypes","authors":"Jasper P. Hof, Doug Speed","doi":"10.1038/s41588-025-02286-z","DOIUrl":"10.1038/s41588-025-02286-z","url":null,"abstract":"Mixed-model association analysis (MMAA) is the preferred tool for performing genome-wide association studies. However, existing MMAA tools often have long runtimes and high memory requirements. Here we present LDAK-KVIK, an MMAA tool for analysis of quantitative and binary phenotypes. LDAK-KVIK is computationally efficient, requiring less than 10 CPU hours and 5 Gb memory to analyze genome-wide data for 350,000 individuals. Using simulated phenotypes, we show that LDAK-KVIK produces well-calibrated test statistics for both homogeneous and heterogeneous datasets. When applied to real phenotypes, LDAK-KVIK has the highest power among all tools considered. For example, across 40 quantitative UK Biobank phenotypes (average sample size 349,000), LDAK-KVIK finds 16% more independent, genome-wide significant loci than classical linear regression, whereas BOLT-LMM and REGENIE find 15% and 11% more, respectively. LDAK-KVIK can also be used to perform gene-based tests; across the 40 quantitative UK Biobank phenotypes, LDAK-KVIK finds 18% more significant genes than the leading existing tool. Last, LDAK-KVIK produces state-of-the-art polygenic scores. LDAK-KVIK is a mixed-model association method for genome-wide studies that optimizes computational performance and power. LDAK-KVIK can also perform gene-based tests and produces state-of-the-art polygenic scores.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 9","pages":"2116-2123"},"PeriodicalIF":29.0,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812924","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}
Nature geneticsPub Date : 2025-08-08DOI: 10.1038/s41588-025-02309-9
Margot Brandt
{"title":"Turning gene expression up and down","authors":"Margot Brandt","doi":"10.1038/s41588-025-02309-9","DOIUrl":"10.1038/s41588-025-02309-9","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 8","pages":"1795-1795"},"PeriodicalIF":29.0,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144802620","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}
Nature geneticsPub Date : 2025-08-07DOI: 10.1038/s41588-025-02285-0
Konstantin A. Klötzer, Amin Abedini, Shen Li, Michael S. Balzer, Xiujie Liang, Jonathan Levinsohn, Eunji Ha, Bernhard Dumoulin, Jonathan J. Hogan, Ghazal Quinn, Roy D. Bloom, Max Schuller, Kathrin Eller, Balazs Halmos, Nancy R. Zhang, Katalin Susztak
{"title":"Analysis of individual patient pathway coordination in a cross-species single-cell kidney atlas","authors":"Konstantin A. Klötzer, Amin Abedini, Shen Li, Michael S. Balzer, Xiujie Liang, Jonathan Levinsohn, Eunji Ha, Bernhard Dumoulin, Jonathan J. Hogan, Ghazal Quinn, Roy D. Bloom, Max Schuller, Kathrin Eller, Balazs Halmos, Nancy R. Zhang, Katalin Susztak","doi":"10.1038/s41588-025-02285-0","DOIUrl":"10.1038/s41588-025-02285-0","url":null,"abstract":"The use of single-cell RNA sequencing in clinical and translational research is limited by the challenge of identifying cell-type-specific, targetable molecular changes in individual patients and cross-species differences. Here we created an integrated single-cell kidney atlas including over 1 million cells from 140 samples, defining more than 70 conserved cell states in human and rodent models. We developed CellSpectra, a computational tool that quantifies changes in gene expression coordination across cellular functions, which we applied to kidney and lung cancer data. This tool powers our patient-level single-cell functional profiling report, which highlights cell-type-specific changes in the coordination of pathway gene expression in individuals. Our cross-species atlas facilitates the selection of a rodent model that closely reflects the cellular and pathway-level signatures observed in patient samples, advancing the application of single-cell methodologies in clinical precision medicine. Finally, using experimental models, we demonstrate how our informatics approach can be applied for the potential selection of suitable therapeutics. CellSpectra identifies functionally relevant changes in cellular pathways when analyzing single samples in comparison to a reference atlas, here applied to rodent models and patient samples of kidney disease.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 8","pages":"1922-1934"},"PeriodicalIF":29.0,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144792841","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}
Nature geneticsPub Date : 2025-08-06DOI: 10.1038/s41588-025-02252-9
Liang Yu, Ruohan Feng, Youhai Sun, Yaojin Peng
{"title":"Governance of cross-border genomic data sharing through a human rights approach","authors":"Liang Yu, Ruohan Feng, Youhai Sun, Yaojin Peng","doi":"10.1038/s41588-025-02252-9","DOIUrl":"10.1038/s41588-025-02252-9","url":null,"abstract":"Cross-border genomic data sharing is crucial for advancing research progress, understanding of genetic diversity and international public health. However, this practice also leads to concerns regarding biosecurity, individual privacy and regulatory conflicts. Scientific communities often advocate data sovereignty approaches to address these challenges, yet related frameworks are often inadequate in their ability to address such challenges and have an overemphasis on national control and protectionism. They also may not fully consider the inherently transnational nature of genomic data and the need for a governance system that reflects the shared human heritage of the data and global interconnectivity. Instead, we propose here a human rights-based approach that surpasses territorial boundaries to promote shared responsibility and equitable research practices. A balanced governance framework that incorporates extraterritorial obligations and aligns data policy with human rights principles can safeguard individual privacy and biosecurity, encourage international collaboration and support ethically responsible genomic research. This Perspective proposes a human rights-based governance framework for cross-border genomic data sharing, addressing limitations of data sovereignty approaches while balancing privacy, security and global research collaboration.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 9","pages":"2090-2098"},"PeriodicalIF":29.0,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144786805","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}
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
