Genome Biology最新文献

{"title":"Whole genome sequence analysis of low-density lipoprotein cholesterol across 246 K individuals","authors":"Margaret Sunitha Selvaraj, Xihao Li, Zilin Li, Eric Van Buren, Sara Haidermota, Darina Postupaka, Whitney Hornsby, Joshua C. Bis, Jennifer A. Brody, Brian E. Cade, Ren-Hua Chung, Joanne E. Curran, Scott M. Damrauer, Lisa de las Fuentes, Paul S. de Vries, Ravindranath Duggirala, Barry I. Freedman, MariaElisa Graff, Xiuqing Guo, Bertha A. Hidalgo, Lifang Hou, Ryan Irvin, Renae Judy, Rita R. Kalyani, Tanika N. Kelly, Iain R. Konigsberg, Brian G. Kral, Lydia Coulter Kwee, Daniel Levy, Changwei Li, Ani W. Manichaikul, Lisa Warsinger Martin, May E. Montasser, Alanna C. Morrison, Take Naseri, Kari E. North, Jeffrey R. O’Connell, Nicholette D. Palmer, Patricia A. Peyser, Alex P. Reiner, Svati H. Shah, Roelof A. J. Smit, Jennifer A. Smith, Kent D. Taylor, Hemant Tiwari, Michael Y. Tsai, Satupa‘itea Viali, Zhe Wang, Yuxuan Wang, Wei Zhao, Donna K. Arnett, John Blangero, Eric Boerwinkle, Donald W. Bowden, Jenna C. Carlson, Yii-Der Ida Chen, Patrick T. Ellinor, Myriam Fornage, Jiang He, ..","doi":"10.1186/s13059-025-03698-0","DOIUrl":"https://doi.org/10.1186/s13059-025-03698-0","url":null,"abstract":"Rare genetic variation provided by whole genome sequence datasets has been relatively less explored for its contributions to human traits. Meta-analysis of sequencing data offers advantages by integrating larger sample sizes from diverse cohorts, thereby increasing the likelihood of discovering novel insights into complex traits. Furthermore, emerging methods in genome-wide rare variant association testing further improve power and interpretability. Here, we conduct the largest meta-analysis of whole genome sequencing for low-density lipoprotein cholesterol (LDL-C), a therapeutic target for coronary artery disease, analyzing data from 246 K participants and integrating 1.23B variants from the UK Biobank and the Trans-Omics for Precision Medicine (TOPMed) program. We identify numerous rare coding and non-coding gene associations related to LDL-C, with replication across 86 K participants in All of Us. Our findings are based on single-variant analyses, rare coding and non-coding variant aggregation tests, and sliding window approaches. Through this comprehensive analysis, we identify 704 novel single-variant associations, 25 novel rare coding variant aggregates, 28 novel rare non-coding variant aggregates, and one novel sliding window aggregate. This study provides a meta-analysis framework for large-scale whole genome sequence association analyses from diverse population groups, yielding novel rare non-coding variant associations.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"53 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145017492","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":"DNA G-quadruplex profiling in skeletal muscle stem cells reveals functional and mechanistic insights","authors":"Xiaona Chen, Feng Yang, Suyang Zhang, Xiaofan Guo, Jieyu Zhao, Yulong Qiao, Liangqiang He, Yang Li, Qin Zhou, Michael Tim-Yun Ong, Chun Kit Kwok, Hao Sun, Huating Wang","doi":"10.1186/s13059-025-03753-w","DOIUrl":"https://doi.org/10.1186/s13059-025-03753-w","url":null,"abstract":"DNA G-quadruplexes (G4s) are non-canonical secondary structures formed in guanine-rich DNA sequences and play important roles in modulating biological processes through a variety of gene regulatory mechanisms. Emerging G4 profiling allows global mapping of endogenous G4 formation. Here in this study, we map the G4 landscapes in adult skeletal muscle stem cells (MuSCs), which are essential for injury-induced muscle regeneration. Throughout the myogenic lineage progression of MuSCs, we uncover dynamic endogenous G4 formation with a pronounced G4 induction when MuSCs become activated and proliferating. We further demonstrate that the G4 induction promotes MuSC activation thus the regeneration process. Mechanistically, we found that promoter-associated G4s regulate gene transcription through facilitating chromatin looping. Furthermore, we found that G4 sites are enriched for transcription factor (TF) binding events in activated MuSCs; MAX binds to G4 structures to synergistically facilitate chromatin looping and gene transcription, thus promoting MuSC activation and regeneration. The above uncovered global regulatory functions/mechanisms are further dissected on the paradigm of Ccne1 promoter, demonstrating that Ccne1 is a bona fide G4/MAX regulatory target in activated MuSCs. Altogether, our findings for the first time demonstrate the prevalent and dynamic formation of G4s in adult MuSCs and the mechanistic role of G4s in modulating gene expression and MuSC activation/proliferation.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"62 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144995702","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":"Artemisinin alleviates Parkinson’s disease by targeting Adcy5-Gch1 axis to trigger a cascade generation of BH4 and dopamine in rats","authors":"Xin-xing Yang, Guo-qing Wang, Qian Wen, Yu-jia Zhao, Dai-di Li, Feng Zhang","doi":"10.1186/s13059-025-03712-5","DOIUrl":"https://doi.org/10.1186/s13059-025-03712-5","url":null,"abstract":"Parkinson’s disease is a highly prevalent neurodegenerative disorder. Hyposecretion of dopamine (DA) is the end result in the pathology of Parkinson’s disease. Unfortunately, safe and efficient therapeutic drugs are deficient. Tyrosine hydroxylase is the rate-limiting enzyme for DA synthesis, could hydroxylate tyrosine and generate levodopa with tetrahydrobiopterin (BH4) as an indispensable coenzyme. Furthermore, BH4 was confirmed to confer neuroprotection against Parkinson’s disease. Thus, regulation of BH4 synthesis was verified to become a promising therapeutic strategy for Parkinson’s disease. We demonstrate that artemisinin effectively produced neuroprotection against Parkinson’s disease in rats. Integrated analysis of midbrain proteomics and non-targeted metabolomics suggests that artemisinin might target adenylate cyclase 5 (Adcy5) to increase GTP cyclohydrolase 1 (Gch1, BH4 synthetase) expression to further boost BH4 synthesis. To verify this hypothesis, molecular docking experiments demonstrate that ART could directly bind to Adcy5. Artemisinin increases Adcy5 and Gch1 expressions and BH4 production both in vivo and in vitro. Further rescue experiments demonstrate that artemisinin-generated DA neuroprotection and hypersecretion of DA and BH4 disappears after inhibition of Adcy5 or Gch1 in vitro. Additionally, suppression of Adcy5 aggravates Parkinson’s disease manifestation, decreases midbrain DA and BH4 production and down-regulated Gch1 expression in vivo. Artemisinin mediates neuroprotection against Parkinson’s disease via regulation of Adcy5-Gch1-BH4 axis in rats. These findings present a beneficial potential for future application of artemisinin on Parkinson’s disease treatment. ","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"21 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144987591","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":"RoAM: computational reconstruction of ancient methylomes and identification of differentially methylated regions","authors":"Yoav Mathov, Naomi Rosen, Chen Leibson, Eran Meshorer, Benjamin Yakir, Liran Carmel","doi":"10.1186/s13059-025-03702-7","DOIUrl":"https://doi.org/10.1186/s13059-025-03702-7","url":null,"abstract":"We present a new and considerably improved version of RoAM (Reconstruction of Ancient Methylation), a flexible tool for reconstructing ancient methylomes and identifying differentially methylated regions (DMRs) between populations. Through a series of filtering and quality control steps, RoAM produces highly reliable DNA methylation maps, making it a valuable tool for paleoepigenomics studies. We apply RoAM to pre-and post-Neolithic transition Balkan samples, and uncover DMRs in genes related to sugar metabolism. Notably, we observe post-Neolithic hypermethylation of PTPRN2, a regulator of insulin secretion. These results are compatible with hypoinsulinism in pre-Neolithic hunter-gatherers.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"61 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144987592","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":"Evolutionary diversification of ancestral genes across vertebrates and insects","authors":"Federica Mantica, Manuel Irimia","doi":"10.1186/s13059-025-03699-z","DOIUrl":"https://doi.org/10.1186/s13059-025-03699-z","url":null,"abstract":"Vertebrates and insects diverged approximately 700 million years ago, and yet they retain a large core of conserved genes from their last common ancestor. These ancient genes present strong evolutionary constraints, which limit their overall sequence and expression divergence. However, these constraints can greatly vary across ancestral gene families and, in at least some cases, sequence and expression changes can have functional consequences. Importantly, overall patterns of sequence and expression divergence and their potential functional outcomes have never been explored in a genome-wide manner across large animal evolutionary distances. We focus on approximately 7000 highly conserved genes shared between vertebrates and insects, and we investigate global patterns of molecular diversification driven by changes in sequence and gene expression. We identify molecular features generally linked to higher or lower diversification rates, together with gene groups with similar diversification profiles in both clades. Moreover, we discover that specific sets of genes underwent differential diversification during vertebrate and insect evolution, potentially contributing to the emergence of unique phenotypes in each clade. We generate a comprehensive dataset of measures of sequence and expression divergence across vertebrates and insects, which reveals a continuous spectrum of evolutionary constraints among highly conserved genes. These constraints are normally consistent between these two clades and are associated with specific molecular features, but in some cases we also identify instances of lineage-specific diversification likely linked to functional evolution.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"71 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144987694","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":"Comparative benchmarking of single-cell clustering algorithms for transcriptomic and proteomic data","authors":"Yu-Hang Yin, Fang Wang, Wei Li, Qiaoming Liu, Shengming Zhou, Murong Zhou, Zhongjun Jiang, Dong-Jun Yu, Guohua Wang","doi":"10.1186/s13059-025-03719-y","DOIUrl":"https://doi.org/10.1186/s13059-025-03719-y","url":null,"abstract":"Differences in data distribution, feature dimensions, and quality between different single-cell modalities pose challenges for clustering. Although clustering algorithms have been developed for single-cell transcriptomic or proteomic data, their performance across different omics data types and integration scenarios remains poorly investigated, which limits the selection of methods and future method development. In this study, we conduct a systematic and comparative benchmark analysis of 28 computational algorithms on 10 paired transcriptomic and proteomic datasets, evaluating their performance across various metrics in terms of clustering, peak memory, and running time. We also discuss the impact of highly variable genes (HVGs) and cell type granularity on clustering performance. Additionally, the robustness of these clustering methods on two kinds of omics is evaluating by using 30 simulated datasets. Furthermore, to explore the benefits of integrating omics information for clustering tasks, we integrate single-cell transcriptomic and proteomic data using 7 state-of-the-art integration methods and assess the performance of existing single-omics clustering schemes on the integrated features. Our findings reveal modality-specific strengths and limitations, highlight the complementary nature of existing methods, and provide actionable insights to guide the selection of appropriate clustering approaches for specific scenarios. Overall, for top performance across two omics, consider scAIDE, scDCC, and FlowSOM, with FlowSOM also offering excellent robustness. For users prioritizing memory efficiency scDCC and scDeepCluster are recommended, while TSCAN, SHARP, and MarkovHC are recommended for users who prioritize time efficiency, and community detection-based methods offer a balance.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"28 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144930475","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":"Ancient genomes provide evidence of demographic shift to Slavic-associated groups in Moravia","authors":"Ilektra Schulz, Denisa Zlámalová, Carlos S Reyna-Blanco, Sam Morris, Guido Alberto Gnecchi-Ruscone, Raphael Eckel, Renáta Přichystalová, Pavlína Ingrová, Petr Dresler, Luca Traverso, Garrett Hellenthal, Jiří Macháček, Daniel Wegmann, Zuzana Hofmanová","doi":"10.1186/s13059-025-03700-9","DOIUrl":"https://doi.org/10.1186/s13059-025-03700-9","url":null,"abstract":"The Slavs are a major ethnolinguistic group of Europe, yet the process that led to their formation remains disputed. As of the sixth century CE, people supposedly belonging to the Slavs populated the space between the Avar Khaganate in the Carpathian Basin, the Merovingian Frankish Empire to the West and the Balkan Peninsula to the South. Proposed theories to explain those events are, however, conceptually incompatible, as some invoke major population movements while others stress the continuity of local populations. We report high-quality genomic data of 18 individuals from two nearby burial sites in South Moravia that span from the fifth to the tenth century CE, during which the region became the core of the ninth century Slavic principality. In contrast to existing data, the individuals reported here can be directly connected to an Early-Slavic-associated culture and include the earliest known inhumation associated with any such culture. The data indicates a strong genetic shift incompatible with local continuity between the fifth and seventh century, supporting the notion that the Slavic expansion in South Moravia was driven by population movement.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"62 1","pages":"259"},"PeriodicalIF":12.3,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144987691","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":"Imbalanced chromatin distribution in cellular senescence specifies paraspeckle dynamics","authors":"Joonwoo Lee, Jinmi Choi, Jeongeun Park, Seonduk Lee, Eun-Jung Cho, Youngdae Gwon","doi":"10.1186/s13059-025-03757-6","DOIUrl":"https://doi.org/10.1186/s13059-025-03757-6","url":null,"abstract":"Cellular senescence is accompanied by extensive genomic reorganization, such as senescence-associated heterochromatin foci and expanded interchromatin compartments, to ultimately affect gene expression. Here, we demonstrate that chromatin structural changes in senescent cells drive significant alterations in the phase behavior and motility of paraspeckles, a type of interchromatin compartment condensate. We observe increased numbers, size, and elongation of paraspeckles harboring NONO and NEAT1_2, driven by elevated levels of those components, consistent with the micellization model of longitudinal growth rather than condensate coalescence. Enhanced paraspeckle motility is associated with HP1α-mediated heterochromatin condensation and interchromatin expansion found in cellular senescence.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"14 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144927854","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":"CLDN10-driven lineage decision in an amnion and primordial germ cell progenitor at the amnion-epiblast boundary in primates","authors":"Nikola Sekulovski, Amber E. Carleton, Anusha Rengarajan, Chien-Wei Lin, Maliha Kabir, Lauren N. Juga, Allison E. Whorton, Lauren E. Elberfeld, Jenna C. Wettstein, Jenna K. Schmidt, Thaddeus G. Golos, Kenichiro Taniguchi","doi":"10.1186/s13059-025-03751-y","DOIUrl":"https://doi.org/10.1186/s13059-025-03751-y","url":null,"abstract":"A growing body of evidence from primate embryos as well as in vitro systems supports the notion that amnion and primordial germ cell (PGC) lineage progressing cells share a common precursor. To gain comprehensive transcriptomic insights into this critical but poorly understood precursor and its progeny, we examine the evolving transcriptome of a developing human pluripotent stem cell-derived model of amnion and PGC formation at the single cell level. This analysis reveals several continuous amniotic fate progressing states with state-specific markers. Additionally, a progenitor-like cell, that displays bi-potential characteristics for amnion and PGC-like cell lineages and is marked by CLDN10, is identified. Strikingly, we find that expression of CLDN10 is restricted to the amnion-epiblast boundary region in our human post-implantation amniotic sac model as well as in peri-gastrula cynomolgus macaque embryos; moreover, this boundary region presents amnion and PGC progenitor-like transcriptional characteristics. Furthermore, our loss of function analysis shows that CLDN10 promotes amniotic but suppresses PGC-like fate. Overall, based on the single cell transcriptomic resource in this study, we identify a CLDN10+ amnion and PGC progenitor-like population at the amnion-epiblast boundary of the primate peri-gastrula, and present additional molecular clues as to how amnion and PGC may be formed at the amnion-epiblast boundary in human peri-gastrula. ","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"16 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144928301","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":"Mammalian conservation of endogenous G-quadruplex reveals their associations with complex traits","authors":"Ze-Hao Zhang, Zi-Yan Wang, Cong-Hui Li, Sheng Hu Qian, Wen Zhang, Zhen-Xia Chen","doi":"10.1186/s13059-025-03750-z","DOIUrl":"https://doi.org/10.1186/s13059-025-03750-z","url":null,"abstract":"DNA G-quadruplexes (G4s) are four-stranded DNA structures. Endogenous G-quadruplexes (eG4s) have been identified as pivotal regulatory elements for gene expression in the human genome. The measurement of evolutionary conservation can be employed to ascertain the functional relevance of putative regulatory elements. However, the evolutionary profiles of human eG4s remain largely unknown. Here, we construct mammalian evolutionary profiles of human eG4s based on a comprehensive reference annotation of human eG4s from the integration of the eG4 database EndoQuad covering 41 human cell lines and our home-made G4 CUT&Tag data covering seven cell lines. We find that transposable elements contribute substantially to the evolutionary spread of primate-specific eG4s. A total of 92,910 highly conserved human eG4s were identified under mammalian constraint. By developing and utilizing the eG4 prediction tool eG4finder, which is based on a large language model, we verify the high structural conservation of highly conserved eG4s. The enrichment of highly conserved eG4s in developmental and aging pathways highlights their potential significance in key biological processes. Notably, highly conserved eG4s exhibit higher regulatory potential, regulatory activity and affinity for transcription factors. We demonstrate that highly conserved eG4s are the most powerful transcriptional activation elements in the total eG4 collection. Meanwhile, trait-associated variants and variants affecting the expression of high phenotypic severity genes are most enriched in highly conserved eG4s. Our study highlights the important regulatory functions and close association with complex human traits of human eG4s that are highly conserved in the mammalian lineage.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"30 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144923883","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}