Pub Date : 2026-03-25DOI: 10.1038/s41588-026-02548-4
Vincent C. T. Hanlon, Peter M. Lansdorp
{"title":"Strand-seq and the future of personalized genomics","authors":"Vincent C. T. Hanlon, Peter M. Lansdorp","doi":"10.1038/s41588-026-02548-4","DOIUrl":"https://doi.org/10.1038/s41588-026-02548-4","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"14 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147506814","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 : 2026-03-23DOI: 10.1038/s41588-026-02555-5
Maria Luiza Lopes De Oliveira,Piotr Konieczny
{"title":"A refined blueprint for human skin.","authors":"Maria Luiza Lopes De Oliveira,Piotr Konieczny","doi":"10.1038/s41588-026-02555-5","DOIUrl":"https://doi.org/10.1038/s41588-026-02555-5","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"11 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147502241","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 : 2026-03-23DOI: 10.1038/s41588-026-02552-8
Paula Restrepo, Alexis Wilder, Aubrey Houser, Harkirat Singh Sandhu, Angie Ramirez, M. Grace Hren, Raman Gill, Abiha Kazmi, Larry Chen, Alexandra Nigro, Ichiro Imanishi, Deniz Demircioglu, Dan Hasson, Alan Soto, Stephanie McQuillan, Edgar Gonzalez-Kozlova, Rachel Brody, Benjamin Ungar, Maria Kasper, Catherine P. Lu, Philip Torina, Jesse M. Lewin, Sacha Gnjatic, Sai Ma, Andrew L. Ji
The skin is the largest human organ and a site of substantial disease burden, yet its cellular and molecular organization across the body is largely undefined. Here we construct an organ-wide single-cell spatial atlas of ~1.2 million cells from normal adult human skin, resolving the location of 45 cell types across 114 samples encompassing 15 anatomic sites. We uncover site-specific stereotypic cell-type composition and their organization into ten multicellular neighborhoods, most notably a perivascular neighborhood reminiscent of skin-associated lymphoid tissue. Within this neighborhood, ligand–receptor (L–R) analyses identify a central role for tumor necrosis factor in maintaining CCL19+ perivascular fibroblasts, highlighting homeostatic immune–stromal crosstalk. Finally, comparing neighborhood dynamics in spatial transcriptomics of skin disease, we find pan-disease immune alterations in this perivascular neighborhood, suggesting spatial compartmentalization of pathogenic activity. Thus, multicellular neighborhoods underlie the skin’s multiscale molecular to macroanatomic organization, orchestrate cell–cell interactions and anatomic site specialization and exhibit architectural disruption in disease.
{"title":"Single-cell spatial transcriptomic analysis of human skin anatomy","authors":"Paula Restrepo, Alexis Wilder, Aubrey Houser, Harkirat Singh Sandhu, Angie Ramirez, M. Grace Hren, Raman Gill, Abiha Kazmi, Larry Chen, Alexandra Nigro, Ichiro Imanishi, Deniz Demircioglu, Dan Hasson, Alan Soto, Stephanie McQuillan, Edgar Gonzalez-Kozlova, Rachel Brody, Benjamin Ungar, Maria Kasper, Catherine P. Lu, Philip Torina, Jesse M. Lewin, Sacha Gnjatic, Sai Ma, Andrew L. Ji","doi":"10.1038/s41588-026-02552-8","DOIUrl":"https://doi.org/10.1038/s41588-026-02552-8","url":null,"abstract":"The skin is the largest human organ and a site of substantial disease burden, yet its cellular and molecular organization across the body is largely undefined. Here we construct an organ-wide single-cell spatial atlas of ~1.2 million cells from normal adult human skin, resolving the location of 45 cell types across 114 samples encompassing 15 anatomic sites. We uncover site-specific stereotypic cell-type composition and their organization into ten multicellular neighborhoods, most notably a perivascular neighborhood reminiscent of skin-associated lymphoid tissue. Within this neighborhood, ligand–receptor (L–R) analyses identify a central role for tumor necrosis factor in maintaining CCL19+ perivascular fibroblasts, highlighting homeostatic immune–stromal crosstalk. Finally, comparing neighborhood dynamics in spatial transcriptomics of skin disease, we find pan-disease immune alterations in this perivascular neighborhood, suggesting spatial compartmentalization of pathogenic activity. Thus, multicellular neighborhoods underlie the skin’s multiscale molecular to macroanatomic organization, orchestrate cell–cell interactions and anatomic site specialization and exhibit architectural disruption in disease.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"51 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147496841","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 : 2026-03-23DOI: 10.1038/s41588-026-02574-2
Hailin Zhang, Alex Windhorst, Elesandro Bornhofen, Zuzana Tulpova, Petr Novak, Jiri Macas, Hana Simkova, Marcin Nadzieja, Jung Min Kim, Dustin Cram, Yongguo Cao, David J F Konkin, Olaf Sass, Gregor Welna, Axel Himmelbach, Martin Mascher, Wolfgang Link, Soon-Jae Kwon, Tae-Jin Yang, Stig Uggerhøj Andersen, Murukarthick Jayakodi
{"title":"Author Correction: Allelic variation at a single locus distinguishes spring and winter faba beans.","authors":"Hailin Zhang, Alex Windhorst, Elesandro Bornhofen, Zuzana Tulpova, Petr Novak, Jiri Macas, Hana Simkova, Marcin Nadzieja, Jung Min Kim, Dustin Cram, Yongguo Cao, David J F Konkin, Olaf Sass, Gregor Welna, Axel Himmelbach, Martin Mascher, Wolfgang Link, Soon-Jae Kwon, Tae-Jin Yang, Stig Uggerhøj Andersen, Murukarthick Jayakodi","doi":"10.1038/s41588-026-02574-2","DOIUrl":"https://doi.org/10.1038/s41588-026-02574-2","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":" ","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147504423","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}
Limited pangenome and ambiguous genomic architecture constrain comprehensive genetic variation discovery and cotton improvement. Here we assembled a telomere-to-telomere (T2T) genome for elite cultivar NDM13 and near-T2T genomes for 27 additional representatives of Gossypium hirsutum over the recent century, with transcriptomic profiling of 15 distinct tissues from each. We uncovered 51,551 one-to-one conserved orthologs across all genomes and landscapes of telomere, centromere, 45S rDNA, segmental duplication and copy number variant. We revealed hotspots of structural variation (SV) and impacts of SV, segmental duplication and copy number variant on gene expression or content alteration, as well as adversity resistances. We identified thousands of divergent SVs and genes implicated in modern breeding evolution. Combining T2T-reference-based pangenome construction and 761,536 SVs identified across 1,671 worldwide accessions with phenotypic data from 22 environments, we captured a number of hidden SVs that potentially influence critical breeding traits. These will boost genetic study and biotechnological improvement of the crop.
{"title":"A pangenome reference and population studies link structural variants with breeding traits in Gossypium hirsutum.","authors":"Yan Zhang,Zhengwen Sun,Shilin Tian,Liqiang Wu,Qishen Gu,Huifeng Ke,Guiyin Zhang,Bin Chen,Zhicheng Wang,Jin Zhang,Xinyu Zhang,Ziming Li,Jun Yang,Xiangkong Li,Yafei Jiang,Kaijian Zhang,Jinhua Wu,Guoning Wang,Dongmei Zhang,Xingyi Wang,Chengsheng Meng,Yanbin Li,Zixu Zhang,Weiyi Chen,Mengjia Jiao,Hao Jia,Jing Li,Haonan Zuo,Yan Wang,Man Gu,Meixia Xie,Lizhu Wu,Zhikun Li,Yuanyuan Yan,Yanru Cui,Jie Liu,Xingfen Wang,Zhiying Ma","doi":"10.1038/s41588-026-02523-z","DOIUrl":"https://doi.org/10.1038/s41588-026-02523-z","url":null,"abstract":"Limited pangenome and ambiguous genomic architecture constrain comprehensive genetic variation discovery and cotton improvement. Here we assembled a telomere-to-telomere (T2T) genome for elite cultivar NDM13 and near-T2T genomes for 27 additional representatives of Gossypium hirsutum over the recent century, with transcriptomic profiling of 15 distinct tissues from each. We uncovered 51,551 one-to-one conserved orthologs across all genomes and landscapes of telomere, centromere, 45S rDNA, segmental duplication and copy number variant. We revealed hotspots of structural variation (SV) and impacts of SV, segmental duplication and copy number variant on gene expression or content alteration, as well as adversity resistances. We identified thousands of divergent SVs and genes implicated in modern breeding evolution. Combining T2T-reference-based pangenome construction and 761,536 SVs identified across 1,671 worldwide accessions with phenotypic data from 22 environments, we captured a number of hidden SVs that potentially influence critical breeding traits. These will boost genetic study and biotechnological improvement of the crop.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"14 4 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147490138","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 : 2026-03-19DOI: 10.1038/s41588-026-02541-x
Beomjin Jang,Kailash Bp,Alex Tokolyi,Winston H Dredge,Ashvin Ravi,Sang-Hyuk Jung,Tatsuhiko Naito,Beomsu Kim,Min Seo Kim,Minyoung Cho,Mi-So Park,Mikaela Rosen,Joel Blanchard,Jack Humphrey,David A Knowles,Hong-Hee Won,Towfique Raj
Most genetic risk variants for neurological diseases are located in noncoding regulatory regions, where they often act as expression quantitative trait loci (eQTLs), modulating gene expression and influencing disease susceptibility. However, eQTL studies in bulk brain tissue or cell lines fail to capture the brain's cellular diversity. Single-nucleus RNA sequencing (snRNA-seq) allows high-resolution mapping of eQTLs across diverse brain cell types. Here we performed a meta-analysis by integrating snRNA-seq and genotype data from four cohorts, totaling 5.8 million nuclei from 983 individuals of European ancestry. We mapped cis-eQTLs and trans-eQTLs across major brain cell types and subtypes, including disease-specific and sex-specific eQTLs, and applied colocalization and Mendelian randomization to identify genes that mediate neurological disease risk. We observed up to tenfold more cis-eQTLs and uncovered cell-type-specific genes linked to neurological disease. SingleBrain is a comprehensive single-cell eQTL resource that provides insights into the genetic mechanism of brain disorders.
{"title":"A meta-analysis of single-nucleus expression quantitative trait loci linking genetic risk to brain disorders.","authors":"Beomjin Jang,Kailash Bp,Alex Tokolyi,Winston H Dredge,Ashvin Ravi,Sang-Hyuk Jung,Tatsuhiko Naito,Beomsu Kim,Min Seo Kim,Minyoung Cho,Mi-So Park,Mikaela Rosen,Joel Blanchard,Jack Humphrey,David A Knowles,Hong-Hee Won,Towfique Raj","doi":"10.1038/s41588-026-02541-x","DOIUrl":"https://doi.org/10.1038/s41588-026-02541-x","url":null,"abstract":"Most genetic risk variants for neurological diseases are located in noncoding regulatory regions, where they often act as expression quantitative trait loci (eQTLs), modulating gene expression and influencing disease susceptibility. However, eQTL studies in bulk brain tissue or cell lines fail to capture the brain's cellular diversity. Single-nucleus RNA sequencing (snRNA-seq) allows high-resolution mapping of eQTLs across diverse brain cell types. Here we performed a meta-analysis by integrating snRNA-seq and genotype data from four cohorts, totaling 5.8 million nuclei from 983 individuals of European ancestry. We mapped cis-eQTLs and trans-eQTLs across major brain cell types and subtypes, including disease-specific and sex-specific eQTLs, and applied colocalization and Mendelian randomization to identify genes that mediate neurological disease risk. We observed up to tenfold more cis-eQTLs and uncovered cell-type-specific genes linked to neurological disease. SingleBrain is a comprehensive single-cell eQTL resource that provides insights into the genetic mechanism of brain disorders.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147483667","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 : 2026-03-19DOI: 10.1038/s41588-026-02544-8
Charles-Etienne Castonguay,Farah Aboasali,Miranda Medeiros,Paria Alipour,Kate Bornais,Théodore Becret,Zoe Schmilovich,Anouar Khayachi,Alex Rajput,Patrick A Dion,Guy A Rouleau
Essential tremor, a movement disorder characterized by an upper-limb postural and action tremor, is among the most common neurological disorders, affecting 1% of the population worldwide. Despite strong evidence for genetic factors driving the etiology of essential tremor, the underlying pathophysiology remains poorly understood. To understand the effects of genetic risk factors in essential tremor on the cerebellum, the brain region suspected to be affected by the disease, we built a population-scale single-cell atlas of the human cerebellar cortex comprising more than 1 million cells from 109 individuals. Here, using single-cell expression quantitative trait loci and Mendelian randomization, we show that essential-tremor-associated variants in the BACE2 locus are causally linked to its downregulation in cerebellar oligodendrocytes. We highlight a genetically vulnerable population of BACE2-expressing immature oligodendrocytes, suggestive of demyelination. We also identify dysfunctional processes affecting interactions between neuronal populations and oligodendrocytes in essential tremor. Our findings suggest a crucial role for cerebellar oligodendrocytes in the pathogenesis of essential tremor.
{"title":"Single-cell expression QTL analyses of the human cerebellum reveal vulnerability of oligodendrocytes in essential tremor.","authors":"Charles-Etienne Castonguay,Farah Aboasali,Miranda Medeiros,Paria Alipour,Kate Bornais,Théodore Becret,Zoe Schmilovich,Anouar Khayachi,Alex Rajput,Patrick A Dion,Guy A Rouleau","doi":"10.1038/s41588-026-02544-8","DOIUrl":"https://doi.org/10.1038/s41588-026-02544-8","url":null,"abstract":"Essential tremor, a movement disorder characterized by an upper-limb postural and action tremor, is among the most common neurological disorders, affecting 1% of the population worldwide. Despite strong evidence for genetic factors driving the etiology of essential tremor, the underlying pathophysiology remains poorly understood. To understand the effects of genetic risk factors in essential tremor on the cerebellum, the brain region suspected to be affected by the disease, we built a population-scale single-cell atlas of the human cerebellar cortex comprising more than 1 million cells from 109 individuals. Here, using single-cell expression quantitative trait loci and Mendelian randomization, we show that essential-tremor-associated variants in the BACE2 locus are causally linked to its downregulation in cerebellar oligodendrocytes. We highlight a genetically vulnerable population of BACE2-expressing immature oligodendrocytes, suggestive of demyelination. We also identify dysfunctional processes affecting interactions between neuronal populations and oligodendrocytes in essential tremor. Our findings suggest a crucial role for cerebellar oligodendrocytes in the pathogenesis of essential tremor.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"16 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147483668","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}
Breeding ideotype maize for high-density planting is crucial for increasing yield but is hindered by a limited understanding of plant architecture regulation. Here we uncover a prominent role for the accumulation of homozygous favorable alleles in genes regulating four principal shoot traits constituting a maize ideotype, and we identify and functionally validate eight architecture-regulating genes. Guided by genomics, we selected the elite hybrid Yufeng303 as a chassis to develop five improved parental lines by pyramiding favorable alleles of these eight genes together with genome-wide loci associated with these traits. These improved parental lines led to the creation of four new hybrids better suited for high-density planting, achieving 4.1–9.2% higher plot yields than Yufeng303 across eight environments. This study exemplifies the power of genomics-guided breeding of ideotype maize for high densities and serves as a template for informed hybrid improvement of other appropriate crops.
{"title":"Breeding ideotype maize with enhanced yield through genomics-guided pyramiding of favorable alleles","authors":"Wen Yao, Lixia Ku, Baobao Wang, Zhenzhen Ren, Huihui Su, Chengwei Li, Huafeng Liu, Haixia Zeng, Zhixue Liu, Dongling Zhang, Yazhou Wang, Xinle Zhu, Qiannan Zhao, Xiaomeng Hu, Chongyu Sun, Shengbo Han, Jiafa Chen, Miaomiao Bao, Tianyi Li, Haiyang Wang, Yanhui Chen","doi":"10.1038/s41588-026-02522-0","DOIUrl":"https://doi.org/10.1038/s41588-026-02522-0","url":null,"abstract":"Breeding ideotype maize for high-density planting is crucial for increasing yield but is hindered by a limited understanding of plant architecture regulation. Here we uncover a prominent role for the accumulation of homozygous favorable alleles in genes regulating four principal shoot traits constituting a maize ideotype, and we identify and functionally validate eight architecture-regulating genes. Guided by genomics, we selected the elite hybrid Yufeng303 as a chassis to develop five improved parental lines by pyramiding favorable alleles of these eight genes together with genome-wide loci associated with these traits. These improved parental lines led to the creation of four new hybrids better suited for high-density planting, achieving 4.1–9.2% higher plot yields than Yufeng303 across eight environments. This study exemplifies the power of genomics-guided breeding of ideotype maize for high densities and serves as a template for informed hybrid improvement of other appropriate crops.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"1 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147465335","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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