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Differential regulation of mesoscale chromosome conformations in osteoblasts and osteosarcoma 成骨细胞和骨肉瘤中尺度染色体构象的差异调控
IF 12.3 1区 生物学
Genome Biology Pub Date : 2025-09-26 DOI: 10.1186/s13059-025-03785-2
Madhoolika Bisht, Yu-Chieh Chung, Siou-Luan He, Sydney Willey, Benjamin D. Sunkel, Meng Wang, Benjamin Z. Stanton, Li-Chun Tu
{"title":"Differential regulation of mesoscale chromosome conformations in osteoblasts and osteosarcoma","authors":"Madhoolika Bisht, Yu-Chieh Chung, Siou-Luan He, Sydney Willey, Benjamin D. Sunkel, Meng Wang, Benjamin Z. Stanton, Li-Chun Tu","doi":"10.1186/s13059-025-03785-2","DOIUrl":"https://doi.org/10.1186/s13059-025-03785-2","url":null,"abstract":"Chromosome conformation within the nucleus is essential for genome function. These have primarily been studied at the scale of loops and compartments, or at lower spatial resolution using traditional in situ hybridization in chemically fixed samples. However, the mesoscale organization of single chromosomes in vivo, shaped by the interplay between chromatin architectural proteins and histone modifications, remains partially understood. In this study, we interrogated the mesoscale conformations of interphase chromosomes in live human osteoblasts and transformed osteosarcoma cells, focusing on chromosome 19. Chromosome conformations were quantified by the aspect ratio of the principal axes of gyration tensors. In osteoblasts, approximately 81% of chromosome 19 are observed to consist of regions characterized by highly extended organizations, with aspect ratios approximately four times greater than those of spheres. In contrast, in osteosarcoma cells, the chromosome displays an extensively collapsed conformation, with aspect ratios more closely approximately that of a sphere. In both cell types, the chromosome’s conformation is bimodal and the balance between these two modes differs very significantly between the two cell types. While the mesoscopic conformation is considerably stable, it is superimposed on dynamic, smaller scale regions. Additional results reveal that this significant conformational shift is independent of the cell cycle but co-regulated by CTCF, cohesion, and H3K27 modifications. Our findings provide new insights into the coordinated complex regulatory mechanisms governing mesoscale chromosome organization in normal and transformed osteogenic tissues.\u0000","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"2 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145141409","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
Interaction of plant-derived metabolites and rhizobiome functions enhances drought stress tolerance 植物代谢物与根瘤菌功能的相互作用增强了植物对干旱胁迫的耐受性
IF 12.3 1区 生物学
Genome Biology Pub Date : 2025-09-26 DOI: 10.1186/s13059-025-03778-1
Anna Kazarina, Soumyadev Sarkar, Bryttan Adams, Brooke Vogt, Leslie Rodela, Sophia Pogranichny, Summer Powell, Hallie Wiechman, Leah Heeren, Nicholas Reese, Darcy Thompson, Qinghong Ran, Eli Hartung, Alina Akhunova, Eduard Akhunov, Loretta Johnson, Ari Jumpponen, Sonny T.M. Lee
{"title":"Interaction of plant-derived metabolites and rhizobiome functions enhances drought stress tolerance","authors":"Anna Kazarina, Soumyadev Sarkar, Bryttan Adams, Brooke Vogt, Leslie Rodela, Sophia Pogranichny, Summer Powell, Hallie Wiechman, Leah Heeren, Nicholas Reese, Darcy Thompson, Qinghong Ran, Eli Hartung, Alina Akhunova, Eduard Akhunov, Loretta Johnson, Ari Jumpponen, Sonny T.M. Lee","doi":"10.1186/s13059-025-03778-1","DOIUrl":"https://doi.org/10.1186/s13059-025-03778-1","url":null,"abstract":"Plants have evolved alongside microbes, enabling plants to better cope with abiotic and biotic stress. Interactions between plant roots and local soil microbes are critical for environmental adaptation and plant health. Plants actively regulate the microbial community composition in their rhizospheres to recruit specific microorganisms that enhance their fitness in the ecosystem they inhabit. This study builds on prior research suggesting that plants exhibit a “home field advantage” by preferentially recruiting microbes unique to their native environments, likely through mutual recognition and selective recruitment mechanisms. Using gene- and genome-centric approaches, we assess the functional potential of root-associated microbes and profile their host metabolites to uncover the metabolic outputs potentially regulating host‒microbe interactions in Andropogon gerardii. We find that plants adapted to drier environments experience less stress, producing fewer stress-related metabolites and impacting the recruitment of microbes with genes linked to stress relief pathways. In particular, plant-derived trimethyllysine is highly associated with microbial populations capable of improving nutrient uptake, producing plant growth-promoting compounds, and modulating stress responses. This study highlights the critical interplay between host exudates and microbial substrate uptake as the primary mechanism of rhizosphere assembly. We demonstrate that plants actively produce metabolites to recruit microbial populations with the functional potential to enhance their ability to thrive in stressful environments. This research provides insights into the mechanisms of plant–microbe communication, rhizosphere recruitment, and the complex interplay of plant–microbe interactions. Furthermore, it highlights promising avenues for manipulating rhizosphere microbiomes to support conservation agriculture when coping with climate change.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"17 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145141466","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
Single-nucleus transcriptomics revealed auxin-driven mechanisms of wood plasticity to enhance severe drought tolerance in poplar 单核转录组学揭示了生长素驱动的木材可塑性增强杨树抗旱性的机制
IF 12.3 1区 生物学
Genome Biology Pub Date : 2025-09-26 DOI: 10.1186/s13059-025-03794-1
Daniela Gómez-Soto, Wendell J. Pereira, Alejandro Piedrabuena-Díaz, Christopher Dervinis, Matias Kirst, Isabel Allona, Mariano Perales, Daniel Conde
{"title":"Single-nucleus transcriptomics revealed auxin-driven mechanisms of wood plasticity to enhance severe drought tolerance in poplar","authors":"Daniela Gómez-Soto, Wendell J. Pereira, Alejandro Piedrabuena-Díaz, Christopher Dervinis, Matias Kirst, Isabel Allona, Mariano Perales, Daniel Conde","doi":"10.1186/s13059-025-03794-1","DOIUrl":"https://doi.org/10.1186/s13059-025-03794-1","url":null,"abstract":"Drought significantly affects forests and woody crops by limiting their growth, increasing their susceptibility to diseases, and reducing productivity. Wood anatomical plasticity is a crucial adaptive mechanism that enables trees to cope with fluctuations in water availability. During severe drought, trees develop more and narrower vessels, enhancing hydraulic safety and reducing the risk of embolism. However, the molecular regulation of vessel formation is still not well understood. Using single-nucleus transcriptomics, we have generated a cell type-specific gene expression map of the mature poplar stem under well-watered and drought conditions. Our findings reveal extensive gene expression reprogramming in xylem-forming cells, with changes in auxin homeostasis identified as a key mechanism for anatomical adaptation. Specifically, we show that poplar WAT1-like genes control vessel spatial patterning. Additionally, the downregulation of WAT1-like gene expression in the dividing cells of the vascular cambium and the upregulation of MP-like gene expression in cells undergoing early vessel differentiation facilitate the formation of secondary xylem with narrower and more numerous vessels under drought. Furthermore, the wat2 mutant exhibits greater drought tolerance than wild-type trees, underscoring its potential for developing drought-resilient tree varieties. This study provides the first single-nucleus transcriptomic map of hybrid poplar stems under severe drought, uncovering auxin-driven hormonal networks that regulate xylem plasticity and enhance drought tolerance. These insights provide valuable targets for improving resilience in poplar and other woody species.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"2 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145141471","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
Genome of the green-head ant, Rhytidoponera metallica, reveals mechanisms of toxin evolution in a genetically hyper-diverse eusocial species 绿头蚁(Rhytidoponera metallica)的基因组揭示了一个遗传高度多样化的真社会物种的毒素进化机制
IF 12.3 1区 生物学
Genome Biology Pub Date : 2025-09-26 DOI: 10.1186/s13059-025-03777-2
Anders Isaksen, Pedro G. Nachtigall, Robin A. Araya, Jia Hao Beh, Samuel D. Robinson, Thomas F. Hansen, Eivind A. B. Undheim
{"title":"Genome of the green-head ant, Rhytidoponera metallica, reveals mechanisms of toxin evolution in a genetically hyper-diverse eusocial species","authors":"Anders Isaksen, Pedro G. Nachtigall, Robin A. Araya, Jia Hao Beh, Samuel D. Robinson, Thomas F. Hansen, Eivind A. B. Undheim","doi":"10.1186/s13059-025-03777-2","DOIUrl":"https://doi.org/10.1186/s13059-025-03777-2","url":null,"abstract":"While ants are textbook examples of eusocial animals in which altruistic behavior is maintained through kin selection, several ants form genetically diverse colonies that challenge this concept. One example is the Australian green-head ant (Rhytidoponera metallica) whose colonies harbor such extreme genetic variation that they have been speculated to represent an unstable form of eusociality. Yet, R. metallica is among the most successful ants on the Australian subcontinent. This success has been hypothesized to be partly due to the diverse venoms harbored within each colony. However, the genomic basis and evolutionary scenarios that maintain this toxin diversity remain unknown. To examine toxin genomic architecture, quantify individual-level genetic variation, and identify both proximate and ultimate mechanisms that have facilitated the toxin diversity in R. metallica, we generate a high-quality draft genome from a single worker. Most ectatotoxin genes are in clusters that contain evidence of multiple, complex gene-family expansions, some of which are likely explained by the presence of transposable elements. We also show that toxin regions of the genome exhibit elevated genetic variation despite being under strong selection and that this variation can translate to phenotypic diversity through toxin alleles with different functional properties. Taken together, our results point to classical gene duplication and diversification as the main evolutionary mechanism by which the main toxin family in ant venoms evolves, suggest toxin-gene functional diversification under frequency-dependent selection maintains colony-level venom hypervariability in R. metallica, and provide new insight into the role of multi-level selection in eusocial animals.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"62 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145141386","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
Deciphering functional landscapes of rumen microbiota unveils the role of Prevotella bryantii in milk fat synthesis in goats 破译瘤胃微生物群的功能景观揭示了布氏普氏菌在山羊乳脂合成中的作用
IF 12.3 1区 生物学
Genome Biology Pub Date : 2025-09-26 DOI: 10.1186/s13059-025-03788-z
Yu Lei, Yining Zheng, Yiting Yan, Kai Zhang, Xuyang Sun, Bo Yang, Lan Ge, Zhongming Meng, Xi Cao, Xiumin Zhang, Xiaoting Yan, Yangbin Xu, Ting Zhang, Jinping Shi, Shiwei Chen, Qiang Qiu, Yulin Chen, Lu Deng, Zhipeng Li, Xiaolong Wang, Ke Zhang
{"title":"Deciphering functional landscapes of rumen microbiota unveils the role of Prevotella bryantii in milk fat synthesis in goats","authors":"Yu Lei, Yining Zheng, Yiting Yan, Kai Zhang, Xuyang Sun, Bo Yang, Lan Ge, Zhongming Meng, Xi Cao, Xiumin Zhang, Xiaoting Yan, Yangbin Xu, Ting Zhang, Jinping Shi, Shiwei Chen, Qiang Qiu, Yulin Chen, Lu Deng, Zhipeng Li, Xiaolong Wang, Ke Zhang","doi":"10.1186/s13059-025-03788-z","DOIUrl":"https://doi.org/10.1186/s13059-025-03788-z","url":null,"abstract":"The rumen microbiome is critical for regulating milk synthesis in dairy livestock, yet the molecular mechanisms linking microbial functions to host lipid metabolism remain poorly understood. While host genetics and microbial composition have been studied, integrative analyses of the rumen-blood-mammary gland axis remain lacking. Here, we present the goat rumen microbial reference gene catalog and 5514 metagenome-assembled genomes (MAGs) from 160 multi-breed rumen samples. Integrating this resource with lactation data from 177 Saanen dairy goats, we identify Prevotella spp. as keystone taxa driving concurrent increases in milk yield and fat percentage. Functional and metabolomic profiling reveals that Prevotella bryantii B14 synthesizes nicotinate, which is converted to nicotinamide in circulation. Using in vitro and in vivo models, we demonstrate that nicotinamide activates the mTORC1 pathway in mammary epithelial cells via GPR109A, which upregulates transcription factors SREBP and PPAR-γ and the downstream lipogenic genes FASN, ACCα, and SCD1 to promote milk fat synthesis. In contrast, the relative deficiency of P. bryantii B14 and the associated reduction in nicotinamide levels in the rumen of poor lactating dairy goats may represent a significant contributor to impaired lactation performance. Additionally, the enhanced hydrogenotrophic methanogenesis activity may also adversely affect their lactation phenotype. Our study establishes a causal link between rumen microbial metabolism and mammary lipid synthesis mediated by nicotinamide-mTORC1 signaling and identifies Prevotella abundance as a biomarker for precision breeding. These findings advance the understanding of microbiome-host crosstalk in lactation and provide actionable strategies for enhancing dairy productivity through microbiota-targeted interventions.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"18 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145141384","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
SNPmanifold: detecting single-cell clonality and lineages from single-nucleotide variants using binomial variational autoencoder SNPmanifold:检测单细胞克隆和谱系从单核苷酸变异使用二项变分自编码器
IF 12.3 1区 生物学
Genome Biology Pub Date : 2025-09-26 DOI: 10.1186/s13059-025-03803-3
Hoi Man Chung, Yuanhua Huang
{"title":"SNPmanifold: detecting single-cell clonality and lineages from single-nucleotide variants using binomial variational autoencoder","authors":"Hoi Man Chung, Yuanhua Huang","doi":"10.1186/s13059-025-03803-3","DOIUrl":"https://doi.org/10.1186/s13059-025-03803-3","url":null,"abstract":"Single-nucleotide-variant (SNV) clone assignment of high-covariance single-cell lineage tracing data remains a challenge due to hierarchical mutation structure and many missing signals. We develop SNPmanifold, a Python package that learns an SNV embedding manifold using a binomial variational autoencoder to give an efficient and interpretable cell-cell distance metric. We demonstrate that SNPmanifold is a suitable tool for analysis of complex, single-cell SNV mutation data, such as in the context of demultiplexing a large number of donors and somatic lineage tracing via mitochondrial SNV data and can reveal insights into single-cell clonality and lineages more accurately and comprehensively than existing methods.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"73 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145141465","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
Land plant-specific H3K27 methyltransferases ATXR5 and ATXR6 control plant development and stress responses 陆地植物特异性H3K27甲基转移酶ATXR5和ATXR6控制植物发育和胁迫反应
IF 12.3 1区 生物学
Genome Biology Pub Date : 2025-09-25 DOI: 10.1186/s13059-025-03801-5
Xiaoyi Li, Jie Pan, Qian Liu, Huairen Zhang, Hui Li, Danhua Jiang
{"title":"Land plant-specific H3K27 methyltransferases ATXR5 and ATXR6 control plant development and stress responses","authors":"Xiaoyi Li, Jie Pan, Qian Liu, Huairen Zhang, Hui Li, Danhua Jiang","doi":"10.1186/s13059-025-03801-5","DOIUrl":"https://doi.org/10.1186/s13059-025-03801-5","url":null,"abstract":"Histone modifications are critical for transcriptional regulation. A notable genetic innovation in land plants is the emergence of histone lysine methyltransferases ATXR5/6, which specifically catalyze the repressive histone H3 lysine 27 monomethylation (H3K27me1). Current knowledge of ATXR5/6 function is largely based on Arabidopsis studies using a weak atxr5;atxr6 hypomorphic mutant, in which ATXR6 is still partially expressed and defects are primarily observed in heterochromatin. However, the significance for land plants to evolve these enzymes remains unclear. In this study, we generate strong atxr5;atxr6 mutants with further reduced ATXR6 expression in Arabidopsis to explore the broader roles of ATXR5/6. Our results show that ATXR5/6 are essential for plant reproductive development and play a critical role in supporting normal plant growth by repressing the transcription of stress responsive genes. In addition, ATXR5/6 are necessary for maintaining H3K27 trimethylation (H3K27me3), likely by providing H3K27me1 as a substrate for further methylation. We also demonstrate that the function of ATXR5/6 in regulating development and responsive genes is conserved in the monocot rice. Our findings suggest that land plants evolved ATXR5/6 not only to maintain heterochromatin, but also to regulate development and environmental responses, providing new insights into the functional significance of ATXR5/6 in land plants.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"17 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145133445","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
Antagonistic effects of selection on alleles associated with seed size and seed dormancy in wheat 小麦种子大小和种子休眠相关等位基因的选择拮抗作用
IF 12.3 1区 生物学
Genome Biology Pub Date : 2025-09-25 DOI: 10.1186/s13059-025-03770-9
Feilong Guo, Changbin Yin, Tian Li, Sitong Liu, Jiayu Dong, Hao Jiang, Yu Fang, Jun Wei, Yi Han, Yu Li, Hong Cao, Yuting Ning, Galal Khamis, Xin Deng, Ke Wang, Jirui Wang, Cuijun Zhang, Fei Lu, Yongxiu Liu
{"title":"Antagonistic effects of selection on alleles associated with seed size and seed dormancy in wheat","authors":"Feilong Guo, Changbin Yin, Tian Li, Sitong Liu, Jiayu Dong, Hao Jiang, Yu Fang, Jun Wei, Yi Han, Yu Li, Hong Cao, Yuting Ning, Galal Khamis, Xin Deng, Ke Wang, Jirui Wang, Cuijun Zhang, Fei Lu, Yongxiu Liu","doi":"10.1186/s13059-025-03770-9","DOIUrl":"https://doi.org/10.1186/s13059-025-03770-9","url":null,"abstract":"Seed dormancy and size are two crucial traits influencing crop yield, and they have undergone strong selection during cereal domestication and improvement. However, the genetic basis underlying the antagonistic effects between seed dormancy and seed size remains poorly understood. Based on genome-wide association study, we perform a comprehensive comparative analysis of 545 global wheat accessions to dissect the genetic architecture of these two traits during wheat improvement. We detect a strong negative correlation between the accumulation of favorable alleles for seed dormancy and the accumulation of favorable alleles for seed size. At the wheat genome level, a set of SNPs harboring antagonistic alleles explain up to 26.56% and 47.21% of the phenotypic variation for seed dormancy and seed size, respectively. In contrast, a set of SNPs with synergistic alleles account for only 0.54% and 1.12% of the variation in both traits. During wheat breeding improvement, favorable alleles associated with increased seed size are preferentially selected, resulting in a compromise in seed dormancy. Under different climate conditions, the frequencies of haplotypes of the pleiotropic genes with antagonistic effects and synergistic loci collectively shape wheat diversity through balancing seed dormancy and seed size. Our findings reveal the genetic architecture underlying the observed weakening of seed dormancy as seed size increases during wheat improvement, enabling further genome-informed cultivar breeding to balance and improve seed dormancy and seed size traits.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"57 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145133444","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
Dissecting the genetic architecture of circadian rhythms in human tissues using a quantitative circadian deviation score 使用定量昼夜节律偏差评分剖析人体组织中昼夜节律的遗传结构
IF 12.3 1区 生物学
Genome Biology Pub Date : 2025-09-25 DOI: 10.1186/s13059-025-03767-4
Zheyu Li, Liang Chen
{"title":"Dissecting the genetic architecture of circadian rhythms in human tissues using a quantitative circadian deviation score","authors":"Zheyu Li, Liang Chen","doi":"10.1186/s13059-025-03767-4","DOIUrl":"https://doi.org/10.1186/s13059-025-03767-4","url":null,"abstract":"Circadian rhythms influence various physiological and behavioral processes, including sleep, metabolism, and immune response. Although key regulatory factors of biological clocks have been identified and genome-wide association studies have pinpointed some genetic variants linked to sleep traits, the genetic architecture underlying circadian rhythms remains incompletely understood. Here, we introduce the circadian deviation score, a novel quantitative trait that measures circadian disruption at the molecular level. Derived from gene expression levels of thousands of circadian genes across Human tissues, this score helps identify tissue-specific genetic influences on circadian rhythms. Our analysis reveals 654 SNPs, which we named Circ-SNPs, associated with global circadian disruption at the expression level. These include previously known SNPs Linked to insomnia, chronotype, and circadian rhythm, as well as new SNPs that enhance understanding of circadian regulation. Most Circ-SNPs exhibit significant associations with the circadian deviation score in the small intestine and adrenal gland, with about 19.4% situated on the X chromosome, highlighting sex-specific differences in circadian disorders. Circ-SNPs often reside near the 3′ end of transcripts, indicating their potential regulatory roles, particularly in post-transcriptional processes. The genes harboring Circ-SNPs, which we named Circ-regulators, are enriched for known circadian traits. DrugBank analysis shows 18 of 122 protein-coding Circ-regulators are targetable by 163 existing drugs, including six approved for sleep disorders. Our findings highlight the potential for repurposing existing drugs to treat circadian-related disorders and provide a deeper understanding of the genetic components of circadian rhythms and sleep disorders.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"96 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145133499","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
Determinants of de novo mutations in extended pedigrees of 43 dog breeds 43个犬种扩展谱系中新生突变的决定因素
IF 12.3 1区 生物学
Genome Biology Pub Date : 2025-09-25 DOI: 10.1186/s13059-025-03804-2
Shao-Jie Zhang, Jilong Ma, Meritxell Riera, Søren Besenbacher, Julia E. Niskanen, Noora Salokorpi, Sruthi Hundi, Marjo K. Hytönen, Tong Zhou, Gui-Mei Li, Elaine A. Ostrander, Mikkel Heide Schierup, Hannes Lohi, Guo-Dong Wang
{"title":"Determinants of de novo mutations in extended pedigrees of 43 dog breeds","authors":"Shao-Jie Zhang, Jilong Ma, Meritxell Riera, Søren Besenbacher, Julia E. Niskanen, Noora Salokorpi, Sruthi Hundi, Marjo K. Hytönen, Tong Zhou, Gui-Mei Li, Elaine A. Ostrander, Mikkel Heide Schierup, Hannes Lohi, Guo-Dong Wang","doi":"10.1186/s13059-025-03804-2","DOIUrl":"https://doi.org/10.1186/s13059-025-03804-2","url":null,"abstract":"Understanding the determinants of de novo mutation is critical for elucidating evolutionary processes and genetic disease susceptibility. But the interplay between life history, genomic architecture, and recombination remains poorly understood in non-model species. Domestic dogs, lacking the recombination regulator PRDM9 and subject to intense artificial selection, offer a unique system for dissecting factors that jointly influence mutation accumulation. Here, we leverage large-scale trio sequencing to unravel the determinants of de novo mutations across diverse dog breeds. By analyzing 390 trios from 43 breeds, we estimate a germline mutation rate of 4.89 × 10−9 per base pair per generation. Parental age, especially paternal age, strongly influences mutation rates, with a 1.5-fold greater paternal age effect in dogs compared to humans. Larger breeds exhibit elevated early-life mutations, aligning with accelerated developmental trajectories. Strikingly, CpG Islands in dogs exhibit a 2.6-fold higher mutation rate than the genomic average, unlike humans where no such increase occurs. We also find a tenfold hypermutated dog and suggest a unique maternal mechanism of MLH1-mediated germline instability during gametogenesis. The unique mutational landscape in canids is determined by paternal age, body size, and CpG Islands recombination. Despite extensive breeding, germline mutation rates in dogs remain stable across breeds. The elevated mutation rate in CpG Islands due to recombination in the absence of PRDM9 underscores a distinct evolutionary mechanism in canids. These findings enhance our understanding of mutation dynamics, with implications for canine genetic diversity, disease susceptibility, and broader genomic studies in species lacking PRDM9.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"40 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145133443","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
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