Genome Medicine最新文献

{"title":"Modelling ischaemic AKI in human kidney organoids reveals injury-associated epithelial states and macrophage-epithelial crosstalk.","authors":"Ana B Nunez-Nescolarde, Yang Liao, Laura Perlaza-Jiménez, Mehran Piran, Zhengqi Cheng, Chris K Barlow, Joel R Steele, Deanna Deveson, Julie L M Moreau, Han-Chung Lee, Jinhua Li, Ralf B Schittenhelm, Christine A Wells, Wei Shi, David J Nikolic-Paterson, Alexander N Combes","doi":"10.1186/s13073-026-01712-z","DOIUrl":"https://doi.org/10.1186/s13073-026-01712-z","url":null,"abstract":"<p><strong>Background: </strong>Acute kidney injury (AKI) is a common clinical syndrome associated with high morbidity and progression to chronic kidney disease. Ischaemia is a leading cause of AKI, driving cellular stress, metabolic reprogramming, and injury-associated epithelial states. Scalable human models that enable controlled investigation of ischaemic injury, repair, and therapeutic targets in AKI remain limited. We therefore assessed the extent to which induced pluripotent stem cell (iPSC)-derived human kidney organoids recapitulate key features of ischaemic AKI.</p><p><strong>Methods: </strong>Kidney organoids were subjected to hypoxic injury (1% O₂, 48 h) followed by normoxic recovery. Transcriptomic, proteomic, metabolomic, single-cell, and spatial profiling were performed across acute injury and recovery phases. iPSC-derived macrophages were integrated into organoids and analysed following hypoxic injury.</p><p><strong>Results: </strong>Hypoxia induced acute stress responses, including hypoxia-inducible factor activation, glycolytic reprogramming, cell cycle arrest, and induction of injury markers. Following recovery, organoids exhibited sustained inflammatory signalling and persistent metabolic dysregulation. Single-cell analysis revealed loss of cell type-specific markers and key functional genes across nephron segments. After return to normoxia, podocyte and distal tubule markers were largely restored, whereas proximal tubule markers showed only partial recovery. Injury-associated and inflammatory programs persisted across all nephron cell types, including upregulation of GDF15, MMP7, SPP1, CXCL2, and ICAM1, with enrichment of complement, TNF-NFκB, and lipid-associated inflammatory pathways. Injured proximal tubules were enriched for adaptive/maladaptive repair signatures derived from human kidney biopsies and displayed heterogeneous recovery. While some cells restored canonical identity, others retained dedifferentiated injury-associated states, including focal expression of CDKN1A and VCAM1. Integrated macrophages transitioned from homeostatic, resident-like profiles to activated phenotypes following injury, exhibiting spatially localised interactions with injured tubules and increased expression of cytokines, chemokines, and matrix-remodelling factors.</p><p><strong>Conclusions: </strong>Human kidney organoids recapitulate key epithelial features of hypoxic injury, including segment-specific vulnerability, persistent inflammatory signalling, and heterogeneous recovery, with integrated macrophages adopting activated inflammatory states following injury. While constrained by developmental immaturity, this system provides a tractable human platform to investigate injury-associated epithelial states and macrophage-epithelial crosstalk in AKI.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"18 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13487967/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148792073","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 multi-ancestry polygenic risk score for body mass index predicts longitudinal weight change.","authors":"Tianyuan Lu, Lily N Stalter, Kate V Lauer, Bret M Hanlon, Wenmin Zhang, Luke M Funk","doi":"10.1186/s13073-026-01741-8","DOIUrl":"10.1186/s13073-026-01741-8","url":null,"abstract":"<p><strong>Background: </strong>Identifying individuals at risk for future weight gain is challenging, partly because associations with traditional clinical risk factors may be biased by confounding and reverse causation. Polygenic risk scores (PRS) provide a stable, lifelong measure of genetic predisposition to obesity. However, existing PRS have not been evaluated for their association with longitudinal weight change in adulthood and often lack generalizability across diverse genetic ancestry groups.</p><p><strong>Methods: </strong>We conducted ancestry-specific genome-wide association study meta-analyses of body mass index (BMI) in populations of European, African or African American, Admixed American, East Asian, and South Asian ancestries and developed ancestry-specific PRS. A multi-ancestry polygenic risk score (MAPRS) was trained using ancestry-specific PRS in a model selection dataset (N = 39,685) from the All of Us Research Program (AoU). We evaluated the MAPRS in an independent AoU model evaluation dataset (N = 158,743) for BMI prediction and in a separate AoU test dataset (N = 78,219) with repeated measurements over 1.5-2.5 years for weight change prediction. The outcomes included change in BMI and ≥ 10% or ≥ 5% total body weight (TBW) gain. We further examined the relationship between MAPRS and 12 clinical risk factors commonly comorbid with obesity in relation to weight change.</p><p><strong>Results: </strong>The MAPRS captured 7.05% of the variance in measured BMI in the AoU model evaluation dataset and demonstrated improved generalizability across all non-European genetic ancestry groups. In the AoU test dataset, conditioned on baseline BMI at the second-to-last measurement, a one SD increase in MAPRS was associated with a 0.16 kg/m² increase in future BMI (standard error = 0.012 kg/m²; p-value = 2.2 × 10^-39), 1.27-fold increased odds of experiencing ≥ 10% TBW gain (95% CI: 1.24-1.31; p-value = 1.4 × 10^-55), and 1.15-fold increased odds of experiencing ≥ 5% TBW gain (95% CI: 1.13-1.18; p-value = 2.8 × 10^-39). These associations were observed across all genetic ancestry groups and remained highly consistent after adjustment for any clinical risk factor. In contrast, most clinical risk factors demonstrated inconsistent or weaker associations with weight change outcomes.</p><p><strong>Conclusions: </strong>We developed an MAPRS for BMI that represents a robust and generalizable risk factor for longitudinal weight gain in adulthood, providing a foundation for genetically informed risk stratification and earlier, more targeted obesity prevention strategies.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"18 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13543510/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887171","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":"Transcriptome signatures for the identification of bevacizumab responders in ovarian cancer.","authors":"Olga Zolotareva, Karen Legler, Olga Tsoy, Anna Esteve, Alexey Sergushichev, Vladimir Sukhov, Jan Baumbach, Kathrin Eylmann, Minyue Qi, Malik Alawi, Stefan Kommoss, Barbara Schmalfeldt, Leticia Oliveira-Ferrer","doi":"10.1186/s13073-026-01727-6","DOIUrl":"10.1186/s13073-026-01727-6","url":null,"abstract":"<p><strong>Background: </strong>Bevacizumab is widely used as an anti-angiogenic maintenance therapy in ovarian cancer; however, there are currently no validated clinical criteria to guide patient selection for its use.</p><p><strong>Methods: </strong>To satisfy the urgent need for bevacizumab response biomarkers, we created a novel RNA-seq dataset (n = 244) and applied unsupervised and supervised machine learning to identify expression signatures associated with benefit from adding bevacizumab to standard treatment and validated our findings using a previously published microarray dataset (n = 377). Additionally, we validated the existence of the discovered signatures using RNA-seq data from the TCGA-OV cohort (n = 426) and performed public expression data mining to provide a biological interpretation of the prioritized signature.</p><p><strong>Results: </strong>Among expression signatures reproducibly detected in independent datasets, one was prioritized as a potential predictive biomarker for bevacizumab benefit. Further stratified analysis revealed that over-expression of this signature was associated with improved overall survival in patients who received bevacizumab in addition to standard chemotherapy in both novel (HR = 0.41, 95% CI: (0.23-0.74), adj.p-value = 0.008) and previously published cohorts (HR = 0.51, 95% CI: (0.34-0.75), adj.p-value = 0.003), while no significant survival benefit from bevacizumab was observed in patients negative for this signature. We hypothesize that this signature may be associated with stemness-like features, possibly driven by CTCFL. In addition, we identified several other signatures reproducible in independent datasets and not related to known molecular subtypes of ovarian cancer, which may also represent biomarker candidates and require further validation in additional RNA-seq data.</p><p><strong>Conclusions: </strong>We identified a previously undescribed expression signature with potential predictive value for bevacizumab benefit, and revealed transcriptional heterogeneity of ovarian cancer that extends beyond current molecular classifications. Given the high heterogeneity of ovarian cancer and that the novel signature only partially explains variation in survival outcomes under bevacizumab treatment, larger RNA-seq datasets are required to further improve predictive models.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"18 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13455466/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148706320","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":"Comprehensive genomic characterization of extraintestinal pathogenic Escherichia coli isolated from neonates: multiple center insights into virulence, resistance, and transmission dynamics.","authors":"Dongmiao Zhang, Yijun Ding, Wenqing Kang, Xueping Zhu, Zheng Cao, Yangfang Li, Jidong Lai, Jinxing Feng, Xiaoyun Wang, Guoqiang Hou, Yanyan Wang, Xianghong Li, Yang Wang, Xiao Liang, Linhui Hao, Peicen Zou, Juntao Li, Ruiqi Xiao, Hengliang Wang, Chao Pan, Yajuan Wang","doi":"10.1186/s13073-026-01717-8","DOIUrl":"10.1186/s13073-026-01717-8","url":null,"abstract":"<p><strong>Background: </strong>Neonatal extraintestinal pathogenic Escherichia coli (ExPEC), which can cause severe long-term sequelae by systemic infections, is gradually becoming the primary pathogen threatening neonatal health. The lack of large-scale genomic epidemiological investigation hinders further understanding of neonatal ExPEC. We conducted this nationwide multicenter study to support further strategies for improving neonatal ExPEC management.</p><p><strong>Methods: </strong>The neonatal ExPEC strains and clinical information, including antimicrobial resistance phenotype, were collected from nine centers within 7 provinces across China between 2018 and 2023. Whole-genome sequencing was performed. Sequence types (ST) and serotypes were acquired to characterize the strains. Phylogenetic analysis and pan-genomic analysis were conducted to identify the population structure. Bioinformatics analysis associated with virulence factors, antimicrobial resistance genes, and mobile genetic elements were conducted. To characterize the situation of horizontal gene transfer, we developed a computational tool for identifying horizontal evolutionary patterns from large-scale genomic draft assemblies. Co-occurrence and co-localization metrics were used to describe the synergistic effects and transmission mechanism of genes.</p><p><strong>Results: </strong>A total of 411 neonatal ExPEC strains were included. ST1193 (18·0%) was the main ST, while O75 (15·8%) was the most common serotype. Virulence factors and antimicrobial resistance genes were widely distributed across various STs, provinces, years, and isolation sites. Co-occurrence analysis revealed multiple clusters of virulence factors and antimicrobial resistance genes, suggesting co-transmission or co-evolution. Multiple kinds of mobile genetic elements were widely distributed throughout the country. The predicted plasmid-derived contig, genome islands, prophages, and transposons carry different pathogenic genes, respectively. Multiple pathogenic genes exhibited co-occurrence with a specific plasmid replicon, suggesting the critical role of plasmids in the evolution of ExPEC.</p><p><strong>Conclusions: </strong>Our findings indicate that neonatal ExPEC had a shared phylogenetic spectrum with adult ExPEC isolates, but distinct dominant subtypes. Multiple virulence factors and drug resistance genes form a complex network that enhances pathogenicity. The formation of these gene clusters is associated with both the inherent genetic factors of ExPEC and the involvement of complex mobile genetic elements. These data accelerate the understanding of neonatal ExPEC, revealing the distribution of STs, serotypes, pathogenic genes, and transmission dynamics.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"18 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13440116/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148678305","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":"Multifeature sequencing-based liquid biopsy for cancer diagnosis and monitoring.","authors":"Mariano A Molina, Martina De Simoni, Norbert Moldovan, Florent Mouliere, Daniel W Hagey","doi":"10.1186/s13073-026-01739-2","DOIUrl":"10.1186/s13073-026-01739-2","url":null,"abstract":"<p><p>Liquid biopsy has emerged as a transformative development in oncology, enabling the minimally invasive detection and monitoring of cancer through the analysis of tumor-derived material in blood. Moving beyond single-variable analysis, multifeature sequencing-based liquid biopsy (MSLB) integrates diverse classes of data from a single blood sample to provide deep multifactorial insight into tumor biology. In this review, MSLB is defined as the extraction of multiple biological signals from a single sequencing dataset and is put in the context of other layers of multimodal diagnostics. We focus on how recent advances in patient-, and potentially microbe-derived, cell-free nucleic acid analysis expand the biological information that can be extracted from a single blood sample. MSLB enables this by allowing the concurrent assessment of, for example, DNA methylation, copy number, fragmentation, and, in exploratory workflows, microbe-associated signals. This provides a broader view of tumor, immune, and microenvironment states. When combined with emerging bioinformatic and machine-learning frameworks, these complementary signals may improve early detection, disease monitoring, and treatment selection. Addressing challenges in standardization, validation, and regulatory alignment will be essential to determine how MSLB can be integrated into routine oncologic practice.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"18 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13430740/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148669263","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":"Single-cell analysis of the progeria arterial wall reveals progerin-induced progressive, cell type-specific dysfunction and somatic mutation accumulation.","authors":"Lara G Merino, Gwladys Revêchon, Santhilal Subhash, Fabiana Stefani, Daniel Whisenant, Marianna Skipitari, Quentin Giraud, Lars Muhl, Giuseppe Mocci, Johan Björkegren, Piotr Machtel, Liqun He, Christer Betsholtz, Maria Eriksson","doi":"10.1186/s13073-026-01719-6","DOIUrl":"10.1186/s13073-026-01719-6","url":null,"abstract":"<p><strong>Background: </strong>The premature aging disorder Hutchinson-Gilford Progeria Syndrome (HGPS) is caused by de novo LMNA mutations producing the aberrant Lamin A isoform progerin. HGPS patients die from cardiovascular disease, with their arteries showing extensive cellular and structural remodeling, but the mechanisms driving vascular dysfunction are not fully understood.</p><p><strong>Methods: </strong>To define molecular processes underlying progressive vascular degeneration in HGPS, we performed single-cell RNA-sequencing (scRNA-seq) of aortic arch cells from Lmna^G609G/G609G mice without atheroprone stimuli. These mice carry the murine equivalent of the most common HGPS-causing mutation and faithfully recapitulate the vascular phenotype. Sequencing was performed at multiple ages to capture disease-related and time-dependent transcriptional changes. We used Smart-seq2 for sequencing, due to its high sensitivity and full-length transcript coverage. Histology, immunostaining and in situ hybridization were used for arterial characterization.</p><p><strong>Results: </strong>The aortic arch of Lmna^G609G/G609G mice exhibited a gradual age-dependent vascular smooth muscle cell (VSMC) loss, accompanied by a transient proliferation surge, and ultimately by increased apoptosis. scRNA-seq identified transcriptionally distinct cell populations with unique features that evolved during disease progression. Disease-enriched VSMCs at early stages were characterized by elevated endoplasmic reticulum (ER) stress. With disease development, these VSMCs further underwent phenotypic switching toward a fibroblast-like state, which was predicted to expand through non-cell-autonomous mechanisms. At later stages, disease-enriched VSMCs upregulated apoptotic gene expression, partially coinciding with sustained ER stress. Furthermore, progeria VSMCs showed an increase in both DNA damage and somatic SNVs, with the increased number of SNVs correlating with high expression of ER stress, ROS and p53-related genes. In contrast, progeria-enriched fibroblasts either became activated or increased their cartilage production and showed a delayed accumulation of somatic SNVs compared to VSMCs, highlighting both a cell-type-specific progerin response and differences in somatic mutation susceptibility.</p><p><strong>Conclusions: </strong>Our study shows that progerin leads to somatic mutation accumulation particularly in VSMCs, highlighting the need for early, cell-type-specific therapeutic intervention in HGPS to prevent permanent vascular tissue damage. In addition, the cell-type-specific molecular dynamics of the aortic arch VSMCs and fibroblasts during HGPS disease progression are provided in a user-friendly searchable scRNA-seq database available for preclinical research targeting vascular aging.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"18 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13425876/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148648497","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":"Circulating tumor DNA precision oncology enables effective and sensitive molecular diagnostics and actionable target detection in pediatric solid tumors - the INFORM experience.","authors":"Kendra K Maass, Pitithat Puranachot, Stefanie Volz, Paulina S Schad, Agnes M E Finster, Tom T Fischer, Barbara C Jones, Kathrin Schramm, Sophie C Henneken, Nike Simon, Sophia H Montigel, Tatjana Wedig, Nathalie Schwarz, Cecilia Zuliani, Petra Fiesel, Christopher Previti, Gnanaprakash Balasubramanian, Florian Iser, Jochen Meyer, Cornelis M van Tilburg, Till Milde, Olaf Witt, Corinne Rossi, Monika Sparber-Sauer, Stefanie Zimmermann, Thomas Lehrnbecher, Melchior Lauten, Martin Sill, Natalie Jäger, Robert J Autry, Paul A Northcott, Felix Sahm, David T W Jones, Stefan M Pfister, Benedikt Brors, Kristian W Pajtler","doi":"10.1186/s13073-026-01737-4","DOIUrl":"10.1186/s13073-026-01737-4","url":null,"abstract":"<p><strong>Background: </strong>Pediatric solid high-risk malignancies mostly lack established molecular biomarkers for early detection, minimal residual disease assessment, or treatment monitoring. Challenges include small patient numbers, limited sample volumes, low tumor mutational burden, and few recurrent alterations.</p><p><strong>Methods: </strong>Within the multicenter pediatric precision oncology program INFORM, we prospectively collected liquid biopsies from 130 pediatric patients and optimized cell-free DNA isolation and analysis. Whole-genome, whole-exome, and targeted panel sequencing were performed using liquid biopsy-adapted protocols.</p><p><strong>Results: </strong>Integrating tissue-derived molecular profiles and orthogonal validation revealed that low-coverage whole-genome sequencing reliably detects circulating tumor DNA. An in silico ctDNA estimation score, combining fragment length and genome segment alterations, improved sensitivity and specificity to 95%, enabling plasma-based tumor detection in 93% of patients. Whole-exome and panel sequencing effectively identified clinically relevant, potentially druggable molecular targets. However, their utility varied substantially across different tumor entities, underscoring the need for entity-specific considerations in the interpretation and application of these methodologies. In-depth analyses demonstrated liquid biopsy's potential to track tumor evolution, identifying common tumor ancestors and refining patient stratification.</p><p><strong>Conclusions: </strong>This study advances liquid biopsy methodologies in pediatric oncology and provides a rationale that, as SNVs are more sensitively captured by panel sequencing and WES, while CNVs are better represented by lcWGS and WES. The underlying tumor genomic profile should guide the selection of liquid biopsy assays to optimize clinical decision-making. Systematic liquid biopsy analyses within the pediatric precision oncology INFORM registry enabled a real-world, multicenter comparison of sequencing approaches across high-risk malignancies. By optimizing preanalytical and bioinformatic tools for pediatric settings, we improved plasma-based cancer detection, molecular tumor characterization, and identification of targetable alterations, laying the groundwork for integration into personalized medicine programs and clinical trials.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"18 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13411563/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148601877","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":"Exome-wide association study reveals common and rare coding variants shaping chronic pain in 327,642 UK biobank participants.","authors":"Xiang Ao, Goodarz Kolifarhood, Marc Parisien, Andrey Bortsov, Audrey V Grant, Luda Diatchenko","doi":"10.1186/s13073-026-01732-9","DOIUrl":"https://doi.org/10.1186/s13073-026-01732-9","url":null,"abstract":"<p><strong>Background: </strong>Chronic pain is a major global health burden with a substantial but incompletely understood genetic basis. Although genome-wide association studies have identified multiple common-variant loci for pain-related traits, the contribution of rare coding variants to chronic pain susceptibility, biological mechanisms, and shared architecture across pain phenotypes remains unclear.</p><p><strong>Methods: </strong>We performed an exome-wide association study across ten chronic pain phenotypes using whole-exome sequencing data from 327,642 European participants in the UK Biobank. Variant-level and gene-level association analyses were conducted to identify common and rare coding signals. Downstream analyses included conditional analysis, statistical fine-mapping, validation in non-European populations, replication in independent cohorts, cross-trait meta-analysis, colocalization, pathway and tissue enrichment, single-cell enrichment, summary-data-based Mendelian randomization, and estimation of heritability and genetic correlation from common and rare variants.</p><p><strong>Results: </strong>We identified 286 significant variant-level associations arising from 235 unique variants mapped to 117 genes, including 13 novel lead variants and 44 independent lead signals. Gene-level analyses identified ten significant genes driven predominantly by rare functional variants: ADAMTSL5, ANKRD12, ARID5A, DPP7, GMCL1, HCK, KIF20B, SLC13A1, UBR2, and ZNF558. Functional analyses implicated pathways related to nervous system development, axonogenesis, and synaptic organization, with enrichment in brain tissues and hTRPM8-expressing dorsal root ganglion neurons. Mendelian randomization analyses highlighted convergent regulatory effects across neural and immune-related tissues. Heritability analyses showed that rare coding variants explained a modest proportion of variance relative to common variants but exhibited larger average effects in the most damaging functional classes, particularly high-confidence loss-of-function variants. Genetic correlation analyses revealed shared genetic components among chronic pain conditions and positive correlations with selected psychiatric and nervous system disorders.</p><p><strong>Conclusions: </strong>These findings provide a comprehensive map of coding variation underlying chronic pain and show that both common and rare coding variants contribute to its genetic architecture. Rare coding variants explain only a limited fraction of heritability but offer strong mechanistic insight by implicating discrete genes and pathways related to neuronal development, neuroimmune signaling, and tissue homeostasis. This work advances understanding of chronic pain biology and provides a foundation for future multi-ancestry studies and functional validation.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"18 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149224040","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":"Cumulative cgMLST provides increased discrimination of nested phylogenetic groups.","authors":"Armen Ovsepian, Jose F Delgado-Blas, Martin Rethoret-Pasty, Melissa J Martin, François Lebreton, Sylvain Brisse","doi":"10.1186/s13073-026-01720-z","DOIUrl":"https://doi.org/10.1186/s13073-026-01720-z","url":null,"abstract":"<p><strong>Background: </strong>Core genome multilocus sequence typing (cgMLST) is a powerful method for bacterial strain genotyping. However, the size of the core genome decreases as the phylogenetic breadth of the target group increases, reducing discriminatory power. To overcome this discrimination/applicability tradeoff, here we developed a cumulative cgMLST approach, where sets of core loci conserved within nested phylogenetic entities are added. We illustrate this approach using the Klebsiella pneumoniae species complex (KpSC), for which a widely used cgMLST scheme (KpSC-cgMLST) comprises only 629 genes.</p><p><strong>Methods: </strong>We created non-redundant cgMLST schemes for the individual species K. pneumoniae sensu stricto (Kpn-cgMLST scheme), and its multidrug resistant sublineages (SLs) SL147 and SL307. To extract core genes, we used 37,874 genome assemblies originating from over 80 countries worldwide. A methodology was set to filter redundant loci before importing them into the genotyping tool BIGSdb, where they were combined into schemes together with preexisting loci conserved at higher phylogenetic levels. The performance of the cumulative cgMLST schemes was evaluated on previously published datasets and on novel data from an inter-hospital outbreak of SL307.</p><p><strong>Results: </strong>The Kpn-cgMLST, SL147 and SL307 schemes comprise 2752, 852, and 947 additional loci, respectively. The mean allele call rate of the novel loci was > 99% in the validation datasets. Compared to the KpSC scheme used alone, pairwise allelic distances among isolates increased on average 5.6-fold using the Kpn scheme, and further by 1.2-fold and 1.3-fold using the SL147 and SL307 schemes, respectively. We demonstrated the added value of this increased discriminatory power for epidemiological analyses and observed a level of discrimination that approaches that of whole-genome single nucleotide polymorphism analysis.</p><p><strong>Conclusions: </strong>The cumulative cgMLST strategy combines broad phylogenetic applicability and nearly complete genotyping resolution, expanding the utility of this harmonized approach for genomic epidemiology.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"18 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149223973","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":"CRISPR integration of an FLT3 CAR into the TRAC locus generates CAR T cells for AML.","authors":"Maya G Noer, Kimmie B Christensen, Nanna S Mikkelsen, Sigrid Fu Skjelbostad, Frederik H Rothemejer, Thomas Wittenborn, Simon Fammé, Kasper Mikkelsen, Torben Barington, Martin K Thomsen, Mike B Barnkob, Bjarne K Møller, Rasmus O Bak","doi":"10.1186/s13073-026-01718-7","DOIUrl":"10.1186/s13073-026-01718-7","url":null,"abstract":"<p><strong>Background: </strong>Acute myeloid leukemia (AML) remains a therapeutically challenging hematological malignancy with high relapse rates, especially in patients harboring mutations in the FMS-like tyrosine kinase 3 (FLT3) gene. FLT3, a receptor tyrosine kinase involved in hematopoietic cell proliferation and survival, is frequently mutated or overexpressed in AML, contributing to leukemic proliferation and poor prognosis. Although FLT3 inhibitors have demonstrated clinical benefit, resistance often develops, underscoring the need for alternative treatment strategies.</p><p><strong>Methods: </strong>In this study, we developed and evaluated allogeneic anti-FLT3 CAR T cells engineered by CRISPR/Cas9-mediated targeted integration into the T cell receptor α constant (TRAC) locus (TRAC-CAR T). This approach enables CAR expression under the endogenous TRAC promoter while simultaneously disrupting native TCR expression, thereby allowing the use of allogeneic T cells with reduced risk of graft-versus-host disease.</p><p><strong>Results: </strong>TRAC-CAR T cells demonstrated efficient disruption of TCRαβ expression, robust surface CAR expression, and superior integration efficiency compared to safe harbor AAVS1-targeted and lentivirally transduced CAR T cells (LV-CAR T). Functionally, TRAC-CAR T cells exhibited potent and selective cytotoxicity against FLT3-positive AML cell lines in vitro, achieving comparable killing relative to LV-CAR T cells. In a xenograft AML mouse model, TRAC-CAR T cells effectively reduced leukemia burden and prolonged mouse survival, with efficacy matching that of LV-CAR T cells. Notably, TRAC-CAR T cells exhibited reduced exhaustion marker expression.</p><p><strong>Conclusions: </strong>Together, these results highlight TRAC-integrated anti-FLT3 CAR T cells as a promising off-the-shelf immunotherapy candidate, combining precise gene editing, efficient manufacturing, and potent anti-leukemic activity.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"18 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13660038/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149167596","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}