Genome Medicine最新文献

{"title":"Bi-allelic variants in BRF2 are associated with perinatal death and craniofacial anomalies.","authors":"Francesca Mattioli, Rún Friðriksdóttir, Anne Hebert, Sissy Bassani, Nazia Ibrahim, Shagufta Naz, Jacqueline Chrast, Clara Pailler-Pradeau, Ásmundur Oddsson, Patrick Sulem, Gisli H Halldorsson, Páll Melsted, Daníel F Guðbjartsson, Flavia Palombo, Tommaso Pippucci, Nayereh Nouri, Marco Seri, Emily G Farrow, Carol J Saunders, Nicolas Guex, Muhammad Ansar, Kari Stefansson, Alexandre Reymond","doi":"10.1186/s13073-025-01463-3","DOIUrl":"https://doi.org/10.1186/s13073-025-01463-3","url":null,"abstract":"<p><strong>Background: </strong>Variants in genes encoding multiple subunits of the RNA Polymerase III complex which synthesizes rRNAs, tRNAs, and other small RNAs were previously associated with neurological disorders, such as syndromic hypomyelination leukodystrophies, pontocerebellar hypoplasia, and cerebellofaciodental syndrome. One new such candidate is BRF2, which encodes a TFIIB-like factor that recruits the RNA polymerase III complex to type 3 promoters to initiate transcription of U6, RnaseP, and 7SK RNAs.</p><p><strong>Methods: </strong>We combined sequencing with functional analyses to investigate the effects of BRF2 variants.</p><p><strong>Results: </strong>We observe that a previously reported significant underrepresentation of double transmission of a splice variant results in recessive lethality in three large Icelandic families with multiple perinatal losses. Using data aggregation, we identified an additional seven individuals worldwide from three unrelated families carrying biallelic variants in BRF2. Affected individuals present a variable phenotype ranging from severe craniofacial anomalies with early death to intellectual disability with motor and speech development. In silico 3D modelling and functional analyses showed functional impairment of the identified variants, e.g., differences in target loci occupancy. Zebrafish knocked down for the orthologous brf2 presented with abnormal escape response, reduced swimming velocity and head size, and craniofacial malformations. These defects were complemented by the human wild-type but not mutated BRF2 mRNA further demonstrating their deleteriousness.</p><p><strong>Conclusions: </strong>Overall, our results support the association of biallelic BRF2 variants with a novel neurodevelopmental disease and provide an additional link between RNA polymerase III, its targets and craniofacial anomalies.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"38"},"PeriodicalIF":10.4,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11995667/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143997008","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}

{"title":"Epigenetic timing effects on child developmental outcomes: a longitudinal meta-regression of findings from the Pregnancy And Childhood Epigenetics Consortium.","authors":"Alexander Neumann, Sara Sammallahti, Marta Cosin-Tomas, Sarah E Reese, Matthew Suderman, Silvia Alemany, Catarina Almqvist, Sandra Andrusaityte, Syed H Arshad, Marian J Bakermans-Kranenburg, Lawrence Beilin, Carrie Breton, Mariona Bustamante, Darina Czamara, Dana Dabelea, Celeste Eng, Brenda Eskenazi, Bernard F Fuemmeler, Frank D Gilliland, Regina Grazuleviciene, Siri E Håberg, Gunda Herberth, Nina Holland, Amy Hough, Donglei Hu, Karen Huen, Anke Hüls, Marjo-Riitta Jarvelin, Jianping Jin, Jordi Julvez, Berthold V Koletzko, Gerard H Koppelman, Inger Kull, Xueling Lu, Léa Maitre, Dan Mason, Erik Melén, Simon K Merid, Peter L Molloy, Trevor A Mori, Rosa H Mulder, Christian M Page, Rebecca C Richmond, Stefan Röder, Jason P Ross, Laura Schellhas, Sylvain Sebert, Dean Sheppard, Harold Snieder, Anne P Starling, Dan J Stein, Gwen Tindula, Marinus H van IJzendoorn, Judith Vonk, Esther Walton, Jonathan Witonsky, Cheng-Jian Xu, Ivana V Yang, Paul D Yousefi, Heather J Zar, Ana C Zenclussen, Hongmei Zhang, Henning Tiemeier, Stephanie J London, Janine F Felix, Charlotte Cecil","doi":"10.1186/s13073-025-01451-7","DOIUrl":"10.1186/s13073-025-01451-7","url":null,"abstract":"<p><strong>Background: </strong>DNA methylation (DNAm) is a developmentally dynamic epigenetic process; yet, most epigenome-wide association studies (EWAS) have examined DNAm at only one timepoint or without systematic comparisons between timepoints. Thus, it is unclear whether DNAm alterations during certain developmental periods are more informative than others for health outcomes, how persistent epigenetic signals are across time, and whether epigenetic timing effects differ by outcome.</p><p><strong>Methods: </strong>We applied longitudinal meta-regression models to published meta-analyses from the PACE consortium that examined DNAm at two timepoints-prospectively at birth and cross-sectionally in childhood-in relation to the same child outcome (ADHD symptoms, general psychopathology, sleep duration, BMI, asthma). These models allowed systematic comparisons of effect sizes and statistical significance between timepoints. Furthermore, we tested correlations between DNAm regression coefficients to assess the consistency of epigenetic signals across time and outcomes. Finally, we performed robustness checks, estimated between-study heterogeneity, and tested pathway enrichment.</p><p><strong>Results: </strong>Our findings reveal three new insights: (i) across outcomes, DNAm effect sizes are consistently larger in childhood cross-sectional analyses compared to prospective analyses at birth; (ii) higher effect sizes do not necessarily translate into more significant findings, as associations also become noisier in childhood for most outcomes (showing larger standard errors in cross-sectional vs prospective analyses); and (iii) DNAm signals are highly time-specific, while also showing evidence of shared associations across health outcomes (ADHD symptoms, general psychopathology, and asthma). Notably, these observations could not be explained by sample size differences and only partly to differential study-heterogeneity. DNAm sites changing associations were enriched for neural pathways.</p><p><strong>Conclusions: </strong>Our results highlight developmentally-specific associations between DNAm and child health outcomes, when assessing DNAm at birth vs childhood. This implies that EWAS results from one timepoint are unlikely to generalize to another. Longitudinal studies with repeated epigenetic assessments are direly needed to shed light on the dynamic relationship between DNAm, development and health, as well as to enable the creation of more reliable and generalizable epigenetic biomarkers. More broadly, this study underscores the importance of considering the time-varying nature of DNAm in epigenetic research and supports the potential existence of epigenetic \"timing effects\" on child health.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"39"},"PeriodicalIF":10.4,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11995515/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143988276","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}

{"title":"A single-cell atlas of Schwannoma across genetic backgrounds and anatomic locations.","authors":"L Nicolas Gonzalez Castro, Avishai Gavish, Lillian Bussema, Christopher W Mount, Cyril Neftel, Masashi Nomura, E Antonio Chiocca, Wenya Linda Bi, Omar Arnaout, Fred G Barker, Justin M Brown, Justin T Jordan, Tracy T Batchelor, Anat Stemmer-Rachamimov, Scott R Plotkin, Itay Tirosh, Mario L Suvà","doi":"10.1186/s13073-025-01462-4","DOIUrl":"https://doi.org/10.1186/s13073-025-01462-4","url":null,"abstract":"<p><strong>Background: </strong>Schwannomas are nerve sheath tumors arising at cranial and peripheral nerves, either sporadically or in patients with a schwannomatosis-predisposition syndrome. There is limited understanding of the transcriptional heterogeneity of schwannomas across genetic backgrounds and anatomic locations.</p><p><strong>Methods: </strong>Here, we prospectively profile by single-cell full-length transcriptomics tumors from 22 patients with NF2-related schwannomatosis, non-NF2-related schwannomatosis, and sporadic schwannomas, resected from cranial and peripheral nerves. We profiled 11,373 cells (after QC), including neoplastic cells, fibroblasts, T cells, endothelial cells, myeloid cells, and pericytes.</p><p><strong>Results: </strong>We characterize the intra-tumoral genetic and transcriptional heterogeneity of schwannoma, identifying six distinct transcriptional metaprograms, with gene signatures related to stress, myelin production, antigen presentation, interferon signaling, glycolysis, and extracellular matrix. We demonstrate the robustness of our findings with analysis of an independent cohort.</p><p><strong>Conclusions: </strong>Overall, our atlas describes the spectrum of gene expression across schwannoma entities at the single-cell level and will serve as an important resource for the community.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"37"},"PeriodicalIF":10.4,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11992879/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143997370","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}

{"title":"Integration of functional genomics and statistical fine-mapping systematically characterizes adult-onset and childhood-onset asthma genetic associations.","authors":"Xiaoyuan Zhong, Robert Mitchell, Christine Billstrand, Emma E Thompson, Noboru J Sakabe, Ivy Aneas, Isabella M Salamone, Jing Gu, Anne I Sperling, Nathan Schoettler, Marcelo A Nóbrega, Xin He, Carole Ober","doi":"10.1186/s13073-025-01459-z","DOIUrl":"10.1186/s13073-025-01459-z","url":null,"abstract":"<p><strong>Background: </strong>Genome-wide association studies (GWAS) have identified hundreds of loci underlying adult-onset asthma (AOA) and childhood-onset asthma (COA). However, the causal variants, regulatory elements, and effector genes at these loci are largely unknown.</p><p><strong>Methods: </strong>We performed heritability enrichment analysis to determine relevant cell types for AOA and COA, respectively. Next, we fine-mapped putative causal variants at AOA and COA loci. To improve the resolution of fine-mapping, we integrated ATAC-seq data in blood and lung cell types to annotate variants in candidate cis-regulatory elements (CREs). We then computationally prioritized candidate CREs underlying asthma risk, experimentally assessed their enhancer activity by massively parallel reporter assay (MPRA) in bronchial epithelial cells (BECs) and further validated a subset by luciferase assays. Combining chromatin interaction data and expression quantitative trait loci, we nominated genes targeted by candidate CREs and prioritized effector genes for AOA and COA.</p><p><strong>Results: </strong>Heritability enrichment analysis suggested a shared role of immune cells in the development of both AOA and COA while highlighting the distinct contribution of lung structural cells in COA. Functional fine-mapping uncovered 21 and 67 credible sets for AOA and COA, respectively, with only 16% shared between the two. Notably, one-third of the loci contained multiple credible sets. Our CRE prioritization strategy nominated 62 and 169 candidate CREs for AOA and COA, respectively. Over 60% of these candidate CREs showed open chromatin in multiple cell lineages, suggesting their potential pleiotropic effects in different cell types. Furthermore, COA candidate CREs were enriched for enhancers experimentally validated by MPRA in BECs. The prioritized effector genes included many genes involved in immune and inflammatory responses. Notably, multiple genes, including TNFSF4, a drug target undergoing clinical trials, were supported by two independent GWAS signals, indicating widespread allelic heterogeneity. Four out of six selected candidate CREs demonstrated allele-specific regulatory properties in luciferase assays in BECs.</p><p><strong>Conclusions: </strong>We present a comprehensive characterization of causal variants, regulatory elements, and effector genes underlying AOA and COA genetics. Our results supported a distinct genetic basis between AOA and COA and highlighted regulatory complexity at many GWAS loci marked by both extensive pleiotropy and allelic heterogeneity.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"35"},"PeriodicalIF":10.4,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11983851/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144002315","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}

{"title":"Genomic and functional analysis of rmp locus variants in Klebsiella pneumoniae.","authors":"Margaret M C Lam, Stephen M Salisbury, Logan P Treat, Ryan R Wick, Louise M Judd, Kelly L Wyres, Sylvain Brisse, Kimberly A Walker, Virginia L Miller, Kathryn E Holt","doi":"10.1186/s13073-025-01461-5","DOIUrl":"10.1186/s13073-025-01461-5","url":null,"abstract":"<p><strong>Background: </strong>Klebsiella pneumoniae is an opportunistic pathogen and a leading cause of healthcare-associated infections in hospitals, which are frequently antimicrobial resistant (AMR). Exacerbating the public health threat posed by K. pneumoniae, some strains also harbour additional hypervirulence determinants typically acquired via mobile genetic elements such as the well-characterised large virulence plasmid KpVP-1. The rmpADC locus is considered a key virulence feature of K. pneumoniae and is associated with upregulated capsule expression and the hypermucoid phenotype, which can enhance virulence by contributing to serum resistance. Typically such strains have been susceptible to all antimicrobials besides ampicillin; however, the recent emergence of AMR hypermucoid strains is concerning.</p><p><strong>Methods: </strong>Here, we investigate the genetic diversity, evolution, mobilisation and prevalence of rmpADC, in a dataset of 14,000 genomes from isolates of the Klebsiella pneumoniae species complex, and describe the RmST virulence typing scheme for tracking rmpADC variants for the purposes of genomic surveillance. Additionally, we examine the functionality of representatives for variants of rmpADC introduced into a mutant strain lacking its native rmpADC locus.</p><p><strong>Results: </strong>The rmpADC locus was detected in 7% of the dataset, mostly from genomes of K. pneumoniae and a very small number of K. variicola and K. quasipneumoniae. Sequence variants of rmpADC grouped into five distinct lineages (rmp1, rmp2, rmp2A, rmp3 and rmp4) that corresponded to unique mobile elements, and were differentially distributed across different populations (i.e. clonal groups) of K. pneumoniae. All variants were demonstrated to produce enhanced capsule production and hypermucoviscosity.</p><p><strong>Conclusions: </strong>These results provide an overview of the diversity and evolution of a prominent K. pneumoniae virulence factor and support the idea that screening for rmpADC in K. pneumoniae isolates and genomes is valuable to monitor the emergence and spread of hypermucoid K. pneumoniae, including AMR strains.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"36"},"PeriodicalIF":10.4,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11984045/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144005636","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}

{"title":"Cell-type-specific subtyping of epigenomes improves prognostic stratification of cancer.","authors":"Qi Luo, Andrew E Teschendorff","doi":"10.1186/s13073-025-01453-5","DOIUrl":"10.1186/s13073-025-01453-5","url":null,"abstract":"<p><strong>Background: </strong>Most molecular classifications of cancer are based on bulk-tissue profiles that measure an average over many distinct cell types. As such, cancer subtypes inferred from transcriptomic or epigenetic data are strongly influenced by cell-type composition and do not necessarily reflect subtypes defined by cell-type-specific cancer-associated alterations, which could lead to suboptimal cancer classifications.</p><p><strong>Methods: </strong>To address this problem, we here propose the novel concept of cell-type-specific combinatorial clustering (CELTYC), which aims to group cancer samples by the molecular alterations they display in specific cell types. We illustrate this concept in the context of DNA methylation data of liver and kidney cancer, deriving in each case novel cancer subtypes and assessing their prognostic relevance against current state-of-the-art prognostic models.</p><p><strong>Results: </strong>In both liver and kidney cancer, we reveal improved cell-type-specific prognostic models, not discoverable using standard methods. In the case of kidney cancer, we show how combinatorial indexing of epithelial and immune-cell clusters define improved prognostic models driven by synergy of high mitotic age and altered cytokine signaling. We validate the improved prognostic models in independent datasets and identify underlying cytokine-immune-cell signatures driving poor outcome.</p><p><strong>Conclusions: </strong>In summary, cell-type-specific combinatorial clustering is a valuable strategy to help dissect and improve current prognostic classifications of cancer in terms of the underlying cell-type-specific epigenetic and transcriptomic alterations.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"34"},"PeriodicalIF":10.4,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11967111/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779480","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}

{"title":"STopover captures spatial colocalization and interaction in the tumor microenvironment using topological analysis in spatial transcriptomics data.","authors":"Sungwoo Bae, Hyekyoung Lee, Kwon Joong Na, Dong Soo Lee, Hongyoon Choi, Young Tae Kim","doi":"10.1186/s13073-025-01457-1","DOIUrl":"10.1186/s13073-025-01457-1","url":null,"abstract":"<p><p>Unraveling the spatial configuration of the tumor microenvironment (TME) is crucial for elucidating tumor-immune interactions based on immuno-oncology. We present STopover, a novel approach utilizing spatially resolved transcriptomics (SRT) data and topological analysis to investigate the TME. By gradually lowering the feature threshold, connected components (CCs) are extracted based on spatial distance and persistence, with Jaccard indices quantifying their spatial overlap, and transcriptomic profiles are permutated to assess statistical significance. Applied to lung and breast cancer SRT, STopover revealed immune and stromal cell infiltration patterns, predicted key cell-cell communication, and identified relevant regions, shedding light on cancer pathophysiology (URL: https://github.com/bsungwoo/STopover ).</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"33"},"PeriodicalIF":10.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11963362/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763690","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}

{"title":"DNA methylation memory of pancreatic acinar-ductal metaplasia transition state altering Kras-downstream PI3K and Rho GTPase signaling in the absence of Kras mutation.","authors":"Emily K W Lo, Adrian Idrizi, Rakel Tryggvadottir, Weiqiang Zhou, Wenpin Hou, Hongkai Ji, Patrick Cahan, Andrew P Feinberg","doi":"10.1186/s13073-025-01452-6","DOIUrl":"10.1186/s13073-025-01452-6","url":null,"abstract":"<p><strong>Background: </strong>A critical area of recent cancer research is the emergence of transition states between normal and cancer that exhibit increased cell plasticity which underlies tumor cell heterogeneity. Pancreatic ductal adenocarcinoma (PDAC) can arise from the combination of a transition state termed acinar-to-ductal metaplasia (ADM) and a gain-of-function mutation in the proto-oncogene KRAS. During ADM, digestive enzyme-producing acinar cells acquire a transient ductal epithelium-like phenotype while maintaining their geographical acinar organization. One route of ADM initiation is the overexpression of the Krüppel-like factor 4 gene (KLF4) in the absence of oncogenic driver mutations. Here, we asked to what extent cells acquire and retain an epigenetic memory of the ADM transition state in the absence of oncogene mutation.</p><p><strong>Methods: </strong>We profiled the DNA methylome and transcriptome of KLF4-induced ADM in transgenic mice at various timepoints during and after recovery from ADM. We validated the identified DNA methylation and transcriptomic signatures in the widely used caerulein model of inducible pancreatitis.</p><p><strong>Results: </strong>We identified differential DNA methylation at Kras-downstream PI3K and Rho/Rac/Cdc42 GTPase pathway genes during ADM, as well as a corresponding gene expression increase in these pathways. Importantly, differential methylation persisted after gene expression returned to normal. Caerulein exposure, which induces widespread digestive system changes in addition to ADM, showed similar changes in DNA methylation in ADM cells. Regions of differential methylation were enriched for motifs of KLF and AP-1 family transcription factors, as were those of human pancreatic intraepithelial neoplasia (PanIN) samples, demonstrating the relevance of this epigenetic transition state memory in human carcinogenesis. Finally, single-cell spatial transcriptomics revealed that these ADM transition cells were enriched for PI3K pathway and AP1 family members.</p><p><strong>Conclusions: </strong>Our comprehensive study of DNA methylation in the acinar-ductal metaplasia transition state links epigenetic memory to cancer-related cell plasticity even in the absence of oncogenic mutation.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"32"},"PeriodicalIF":10.4,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11951614/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742771","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}

{"title":"The Chinese gut virus catalogue reveals gut virome diversity and disease-related viral signatures.","authors":"Qiulong Yan, Liansha Huang, Shenghui Li, Yue Zhang, Ruochun Guo, Pan Zhang, Zhixin Lei, Qingbo Lv, Fang Chen, Zhiming Li, Jinxin Meng, Jing Li, Guangyang Wang, Changming Chen, Hayan Ullah, Lin Cheng, Shao Fan, Wei You, Yan Zhang, Jie Ma, Shanshan Sha, Wen Sun","doi":"10.1186/s13073-025-01460-6","DOIUrl":"10.1186/s13073-025-01460-6","url":null,"abstract":"<p><strong>Background: </strong>The gut viral community has been increasingly recognized for its role in human physiology and health; however, our understanding of its genetic makeup, functional potential, and disease associations remains incomplete.</p><p><strong>Methods: </strong>In this study, we collected 11,286 bulk or viral metagenomes from fecal samples across large-scale Chinese populations to establish a Chinese Gut Virus Catalogue (cnGVC) using a de novo virus identification approach. We then examined the diversity and compositional patterns of the gut virome in relation to common diseases by analyzing 6311 bulk metagenomes representing 28 disease or unhealthy states.</p><p><strong>Results: </strong>The cnGVC contains 93,462 nonredundant viral genomes, with over 70% of these being novel viruses not included in existing gut viral databases. This resource enabled us to characterize the functional diversity and specificity of the gut virome. Using cnGVC, we profiled the gut virome in large-scale populations, assessed sex- and age-related variations, and identified 4238 universal viral signatures of diseases. A random forest classifier based on these signatures achieved high accuracy in distinguishing diseased individuals from controls (AUC = 0.698) and high-risk patients from controls (AUC = 0.761), and its predictive ability was also validated in external cohorts.</p><p><strong>Conclusions: </strong>Our resources and findings significantly expand the current understanding of the human gut virome and provide a comprehensive view of the associations between gut viruses and common diseases. This will pave the way for novel strategies in the treatment and prevention of these diseases.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"30"},"PeriodicalIF":10.4,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11938785/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718151","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}

{"title":"STRchive: a dynamic resource detailing population-level and locus-specific insights at tandem repeat disease loci.","authors":"Laurel Hiatt, Ben Weisburd, Egor Dolzhenko, Vincent Rubinetti, Akshay K Avvaru, Grace E VanNoy, Nehir Edibe Kurtas, Heidi L Rehm, Aaron R Quinlan, Harriet Dashnow","doi":"10.1186/s13073-025-01454-4","DOIUrl":"10.1186/s13073-025-01454-4","url":null,"abstract":"<p><p>Approximately 8% of the human genome consists of repetitive elements called tandem repeats (TRs): short tandem repeats (STRs) of 1-6 bp motifs and variable number tandem repeats (VNTRs) of 7 + bp motifs. TR variants contribute to several dozen monogenic diseases but remain understudied and enigmatic. It remains comparatively challenging to interpret the clinical significance of TR variants, particularly relative to single nucleotide variants. We present STRchive ( http://strchive.org/ ), a dynamic resource consolidating information on TR disease loci from the research literature, up-to-date clinical resources, and large-scale genomic databases, streamlining TR variant interpretation at disease-associated loci.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"29"},"PeriodicalIF":10.4,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11938676/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718148","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}