Pub Date : 2025-09-16DOI: 10.1038/s41576-025-00885-4
Sushant Kumar, Mark Gerstein
Large-scale annotation efforts over the past two decades have identified regulatory regions and networks through functional genomics and evolutionary analyses. The challenge now will be to incorporate the many ‘heterogeneities’ of gene regulation — across cell types, developmental stages and individuals — into regulatory annotation based on new experimental and computational approaches. After more than two decades of large-scale efforts to annotate the regulatory genome, Sushant Kumar and Mark Gerstein forecast how new technologies and experimental approaches will pave the way in mapping regulatory elements across cell types, developmental stages and genetically diverse individuals.
{"title":"Regulatory genome annotation","authors":"Sushant Kumar, Mark Gerstein","doi":"10.1038/s41576-025-00885-4","DOIUrl":"10.1038/s41576-025-00885-4","url":null,"abstract":"Large-scale annotation efforts over the past two decades have identified regulatory regions and networks through functional genomics and evolutionary analyses. The challenge now will be to incorporate the many ‘heterogeneities’ of gene regulation — across cell types, developmental stages and individuals — into regulatory annotation based on new experimental and computational approaches. After more than two decades of large-scale efforts to annotate the regulatory genome, Sushant Kumar and Mark Gerstein forecast how new technologies and experimental approaches will pave the way in mapping regulatory elements across cell types, developmental stages and genetically diverse individuals.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"26 10","pages":"661-662"},"PeriodicalIF":52.0,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145067700","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}
Pub Date : 2025-09-16DOI: 10.1038/s41576-025-00879-2
Stephen B. Montgomery
Biobank-scale studies of gene expression and proteomics are providing new opportunities to study gene regulation and its effect on traits and diseases. Moving from small cohorts to studies of thousands of people with regulatory genomics data will accelerate the use of gene regulation and non-coding variation in precision health. Studies of human regulatory genomics are being performed at biobank scales, with data from tens of thousands of individuals. Stephen Montgomery describes how these datasets will advance our understanding of how variation in gene regulation shapes human traits and disease.
{"title":"Regulatory genomics at biobank scales","authors":"Stephen B. Montgomery","doi":"10.1038/s41576-025-00879-2","DOIUrl":"10.1038/s41576-025-00879-2","url":null,"abstract":"Biobank-scale studies of gene expression and proteomics are providing new opportunities to study gene regulation and its effect on traits and diseases. Moving from small cohorts to studies of thousands of people with regulatory genomics data will accelerate the use of gene regulation and non-coding variation in precision health. Studies of human regulatory genomics are being performed at biobank scales, with data from tens of thousands of individuals. Stephen Montgomery describes how these datasets will advance our understanding of how variation in gene regulation shapes human traits and disease.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"26 10","pages":"657-658"},"PeriodicalIF":52.0,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145067756","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}
Pub Date : 2025-09-16DOI: 10.1038/s41576-025-00880-9
Wendy A. Bickmore
The idea that the regulation of our genome is influenced by its three-dimensional (3D) organization dates to early cytological studies of heterochromatin and euchromatin within the nucleus. However, advances in the ability to analyse and perturb 3D genome organization now enable the functional relationship between gene regulation and 3D organization to be explored at unparalleled spatial and genomic resolution. In this Comment, Wendy Bickmore discusses mechanistic models of how 3D genome organization facilitates communication between distant enhancers and their target promoters to regulate gene expression.
{"title":"Is enhancer-driven gene regulation all wrapped up?","authors":"Wendy A. Bickmore","doi":"10.1038/s41576-025-00880-9","DOIUrl":"10.1038/s41576-025-00880-9","url":null,"abstract":"The idea that the regulation of our genome is influenced by its three-dimensional (3D) organization dates to early cytological studies of heterochromatin and euchromatin within the nucleus. However, advances in the ability to analyse and perturb 3D genome organization now enable the functional relationship between gene regulation and 3D organization to be explored at unparalleled spatial and genomic resolution. In this Comment, Wendy Bickmore discusses mechanistic models of how 3D genome organization facilitates communication between distant enhancers and their target promoters to regulate gene expression.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"26 10","pages":"655-656"},"PeriodicalIF":52.0,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145067701","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}
Pub Date : 2025-09-16DOI: 10.1038/s41576-025-00894-3
For the 25th anniversary of Nature Reviews Genetics, we reflect on exciting progress towards decoding the regulatory genome and its mechanisms, a central goal in genetics that must be solved with interdisciplinary research to yield widespread insights into evolution, development and disease.
{"title":"Making sense of the regulatory genome","authors":"","doi":"10.1038/s41576-025-00894-3","DOIUrl":"10.1038/s41576-025-00894-3","url":null,"abstract":"For the 25th anniversary of Nature Reviews Genetics, we reflect on exciting progress towards decoding the regulatory genome and its mechanisms, a central goal in genetics that must be solved with interdisciplinary research to yield widespread insights into evolution, development and disease.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"26 10","pages":"651-652"},"PeriodicalIF":52.0,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41576-025-00894-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145067698","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}
Pub Date : 2025-09-15DOI: 10.1038/s41576-025-00888-1
Gitta Szabó, Emiley A. Eloe-Fadrosh, Jennifer Pett-Ridge, Tanja Woyke
Microorganisms are essential to all life on Earth through critical roles in key biological processes and diverse interactions with other organisms that shape ecosystems, drive biogeochemical cycles and influence both human health and environmental health. High-throughput sequencing from environmental samples has revolutionized the understanding of microbial diversity and functions. With vast amounts of genomes now available across Earth’s biomes, these data provide a blueprint of microbial life that can be harnessed for a more holistic understanding of microbiome structure and function across the various ecosystems on Earth. Here we review the application of genome-centric approaches, including recent advances in single-cell sequencing and functional profiling, to survey microbial and viral diversity. We highlight some of the most impactful evolutionary and functional discoveries, explore the spatial diversity and temporal dynamics of microorganisms across diverse environments, and discuss genome-enabled insights into host-associated microorganisms. Genome-wide approaches have uncovered the vast microbial and viral diversity across ecosystems. This Review explores advances in metagenomics, single-cell sequencing and functional profiling to elucidate the evolution, biogeography and ecological dynamics of Earth’s microbiomes.
{"title":"A genomic view of Earth’s biomes","authors":"Gitta Szabó, Emiley A. Eloe-Fadrosh, Jennifer Pett-Ridge, Tanja Woyke","doi":"10.1038/s41576-025-00888-1","DOIUrl":"10.1038/s41576-025-00888-1","url":null,"abstract":"Microorganisms are essential to all life on Earth through critical roles in key biological processes and diverse interactions with other organisms that shape ecosystems, drive biogeochemical cycles and influence both human health and environmental health. High-throughput sequencing from environmental samples has revolutionized the understanding of microbial diversity and functions. With vast amounts of genomes now available across Earth’s biomes, these data provide a blueprint of microbial life that can be harnessed for a more holistic understanding of microbiome structure and function across the various ecosystems on Earth. Here we review the application of genome-centric approaches, including recent advances in single-cell sequencing and functional profiling, to survey microbial and viral diversity. We highlight some of the most impactful evolutionary and functional discoveries, explore the spatial diversity and temporal dynamics of microorganisms across diverse environments, and discuss genome-enabled insights into host-associated microorganisms. Genome-wide approaches have uncovered the vast microbial and viral diversity across ecosystems. This Review explores advances in metagenomics, single-cell sequencing and functional profiling to elucidate the evolution, biogeography and ecological dynamics of Earth’s microbiomes.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"27 1","pages":"13-31"},"PeriodicalIF":52.0,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145059287","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}
Pub Date : 2025-09-11DOI: 10.1038/s41576-025-00897-0
Paul Meller, Peter Kilroy, Helen Sims, Helena R. R. Wells, Michael Dunn
The importance of ethics and inclusivity in genomics is widely recognized. Less explored is the huge potential for transdisciplinary collaboration at the intersection of genomics, the humanities and social sciences, and wider societal stakeholders to drive research innovation and discovery. Transdisciplinary collaboration fuels innovation and discovery. Meller et al. call for broader collaboration at the intersection of genomics, the humanities and social sciences, and wider societal stakeholders, to test new ways of working across disciplines and co-develop future research agendas.
{"title":"Collaborating at the nexus of genomics, humanities, social science and stakeholders","authors":"Paul Meller, Peter Kilroy, Helen Sims, Helena R. R. Wells, Michael Dunn","doi":"10.1038/s41576-025-00897-0","DOIUrl":"10.1038/s41576-025-00897-0","url":null,"abstract":"The importance of ethics and inclusivity in genomics is widely recognized. Less explored is the huge potential for transdisciplinary collaboration at the intersection of genomics, the humanities and social sciences, and wider societal stakeholders to drive research innovation and discovery. Transdisciplinary collaboration fuels innovation and discovery. Meller et al. call for broader collaboration at the intersection of genomics, the humanities and social sciences, and wider societal stakeholders, to test new ways of working across disciplines and co-develop future research agendas.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"26 11","pages":"737-738"},"PeriodicalIF":52.0,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031924","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}
Pub Date : 2025-09-05DOI: 10.1038/s41576-025-00893-4
Jian Zeng, Peter M. Visscher
Polygenic scores (PGS) have shown promise in predicting complex traits and disease risk, but their accuracy remains limited and poorly transferable across ancestries. Integrating functional annotations with whole-genome sequencing data can improve prediction by prioritizing likely causal variants shared across populations and by assigning greater weight to variants in biologically relevant regions. The accuracy of polygenic scores (PGS) remains limited and poorly transferable across ancestries. In this Comment, Zeng and Visscher discuss how integrating functional annotations with whole-genome sequencing data can improve PGS by prioritizing likely causal variants shared across populations and by assigning greater weight to variants in biologically relevant regions.
{"title":"Harnessing functional annotation to improve the accuracy and transferability of polygenic scores","authors":"Jian Zeng, Peter M. Visscher","doi":"10.1038/s41576-025-00893-4","DOIUrl":"10.1038/s41576-025-00893-4","url":null,"abstract":"Polygenic scores (PGS) have shown promise in predicting complex traits and disease risk, but their accuracy remains limited and poorly transferable across ancestries. Integrating functional annotations with whole-genome sequencing data can improve prediction by prioritizing likely causal variants shared across populations and by assigning greater weight to variants in biologically relevant regions. The accuracy of polygenic scores (PGS) remains limited and poorly transferable across ancestries. In this Comment, Zeng and Visscher discuss how integrating functional annotations with whole-genome sequencing data can improve PGS by prioritizing likely causal variants shared across populations and by assigning greater weight to variants in biologically relevant regions.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"26 12","pages":"805-806"},"PeriodicalIF":52.0,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144995189","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}
Pub Date : 2025-08-21DOI: 10.1038/s41576-025-00891-6
Kellie Wise, Anna Pascual-Reguant
In this Tools of the Trade article, Kellie Wise and Anna Pascual-Reguant introduce STAMP (single-cell transcriptomics analysis and multimodal profiling), which harnesses imaging to measure RNA and/or protein expression in fixed cells or nuclei.
{"title":"Imaging-based multimodal profiling of single cells with STAMP","authors":"Kellie Wise, Anna Pascual-Reguant","doi":"10.1038/s41576-025-00891-6","DOIUrl":"10.1038/s41576-025-00891-6","url":null,"abstract":"In this Tools of the Trade article, Kellie Wise and Anna Pascual-Reguant introduce STAMP (single-cell transcriptomics analysis and multimodal profiling), which harnesses imaging to measure RNA and/or protein expression in fixed cells or nuclei.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"26 12","pages":"809-809"},"PeriodicalIF":52.0,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144898381","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}
Pub Date : 2025-08-20DOI: 10.1038/s41576-025-00890-7
Daudi Jjingo
Daudi Jjingo highlights a recent publication by Chu et al., who performed an integrative single-cell analysis of human colorectal cancer to characterize the tumour microenvironment (TME) and stratify patients according to their heterogeneous TMEs, which exploit different immune evasion mechanisms.
{"title":"Prospects for personalized cancer treatment in the era of single-cell sequencing","authors":"Daudi Jjingo","doi":"10.1038/s41576-025-00890-7","DOIUrl":"10.1038/s41576-025-00890-7","url":null,"abstract":"Daudi Jjingo highlights a recent publication by Chu et al., who performed an integrative single-cell analysis of human colorectal cancer to characterize the tumour microenvironment (TME) and stratify patients according to their heterogeneous TMEs, which exploit different immune evasion mechanisms.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"26 11","pages":"741-741"},"PeriodicalIF":52.0,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144898189","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}
Pub Date : 2025-08-15DOI: 10.1038/s41576-025-00884-5
Elaine R. Mardis, Richard K. Wilson
Accelerated discovery in biomedical science is typically punctuated by technological advances, and the past decade has been exemplary regarding breakthroughs in our genomic understanding of human biology in health and disease. This phenomenon was facilitated by the availability of a human genome reference sequence and the development and continuous improvement of next-generation and single-molecule sequencing technologies, accompanied by advances in computational analytics. These fundamental tools have driven the emergence of innovative methods that capture different aspects of human cell biology, with exquisite detail genome wide, in a sequence-based readout. The resulting expansion of knowledge has poised these approaches for clinical adoption, fulfilling the original intention of decoding the human genome and ushering in the era of genomic medicine. Extraordinary advances in genomic science have defined the twenty-first century, transforming our understanding of human biology in both health and disease. This timeline Perspective charts two decades of genomic innovation since the human genome reference sequence became available, highlighting the evolution of sequencing technologies and how they, combined with computational advances, paved the way for genomic medicine.
{"title":"Tracing the evolution of sequencing into the era of genomic medicine","authors":"Elaine R. Mardis, Richard K. Wilson","doi":"10.1038/s41576-025-00884-5","DOIUrl":"10.1038/s41576-025-00884-5","url":null,"abstract":"Accelerated discovery in biomedical science is typically punctuated by technological advances, and the past decade has been exemplary regarding breakthroughs in our genomic understanding of human biology in health and disease. This phenomenon was facilitated by the availability of a human genome reference sequence and the development and continuous improvement of next-generation and single-molecule sequencing technologies, accompanied by advances in computational analytics. These fundamental tools have driven the emergence of innovative methods that capture different aspects of human cell biology, with exquisite detail genome wide, in a sequence-based readout. The resulting expansion of knowledge has poised these approaches for clinical adoption, fulfilling the original intention of decoding the human genome and ushering in the era of genomic medicine. Extraordinary advances in genomic science have defined the twenty-first century, transforming our understanding of human biology in both health and disease. This timeline Perspective charts two decades of genomic innovation since the human genome reference sequence became available, highlighting the evolution of sequencing technologies and how they, combined with computational advances, paved the way for genomic medicine.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"26 10","pages":"719-734"},"PeriodicalIF":52.0,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144851398","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}
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