Genome Medicine最新文献

{"title":"MGCL-ST: multi-view graph contrastive learning for spatial transcriptomics imputation.","authors":"Jiazhou Chen, Weitian Huang, Xiaojia Chen, Siqi Ding, Yi Liao, Shangyan Cai, Hongmin Cai","doi":"10.1186/s13073-026-01683-1","DOIUrl":"10.1186/s13073-026-01683-1","url":null,"abstract":"<p><p>High-resolution, continuous spatial gene expression profiling is critical for dissecting complex tissue microenvironments, yet current spatial transcriptomics (ST) platforms suffer from spatial gaps and insufficient resolution. Here, we present MGCL-ST, a multi-view graph contrastive learning method for super-resolution ST imputation. By jointly modeling local and global spatial graphs with histological features derived from a pathology foundation model, MGCL-ST accurately imputes unmeasured gene expression across the tissue space. Evaluated across three diverse platforms, MGCL-ST outperforms state-of-the-art methods in imputation accuracy and spatial clustering, significantly enhancing biological interpretability and enabling the precise mapping of tumor microenvironments. MGCL-ST is available at https://github.com/guxin2002/MGCL-ST .</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":" ","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13450143/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148155675","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":"Health benefits of a five-day at-home modified fasting program: a randomised controlled trial.","authors":"Franziska Grundler, Quinten R Ducarmon, Alfred Holley, Marie Knufinke, Selina Strathmeyer, Steffen Heelemann, Roland Geyer, Borja Martínez-Téllez, Michael R MacArthur, Georg Zeller, Françoise Wilhelmi de Toledo, Robin Mesnage","doi":"10.1186/s13073-026-01681-3","DOIUrl":"10.1186/s13073-026-01681-3","url":null,"abstract":"<p><strong>Background: </strong>Fasting is one of the most cost-effective methods to improve cardiometabolic health. We tested a 5-day hypocaloric (~ 600 kcal/day) and ketogenic, modified fasting program (MFP) in a two-arm randomised controlled trial, where sixty-four healthy subjects were randomised to MFP or control group.</p><p><strong>Methods: </strong>We randomly assigned 64 participants to a group receiving the MFP or to a group of participants who were told to continue with their usual eating behaviour and lifestyle (control group). The changes in blood pressure and body weight were considered as primary endpoints. Secondary outcomes included ketosis, glucose and lipid metabolism, inflammatory markers, antioxidant capacity and well-being. Biological pathways and metabolic processes were explored with nuclear magnetic resonance blood metabolomics and gut metagenomics analyses. Outcomes were assessed at baseline, end of the MFP, after food reintroduction, and one month later.</p><p><strong>Results: </strong>MFP participants (n = 32) experienced weight loss compared to controls (- 0.52 ± 0.03 kg vs. - 0.03 ± 0.02 kg, p < 0.001). Changes in blood pressure caused by the MFP were non-significant at the end of the fasting period. However, blood pressure was significantly reduced following food reintroduction (systolic: -0.56 ± 0.12 mmHg vs. - 0.16 ± 0.12 mmHg, p < 0.05 and diastolic: -0.36 ± 0.08 mmHg vs. - 0.01 ± 0.08 mmHg, p < 0.01). Serum biochemistry showed the MFP reduced glucose levels and coagulation factors. The MFP also significantly increased physical well-being. Blood metabolomics revealed a significant decrease in chronic inflammation markers. Shotgun metagenomics of the gut microbiome showed significant changes in relative abundance of 11 bacterial species and in the genomic repertoire of 52 carbohydrate-active enzymes (CAZymes), reflecting an increase in families metabolising host-derived glycan substrates. None of these differences in gut microbiome and blood metabolome were shown to be statistically different from the control group one month after the intervention. Comparing MFP effects with a previous cohort's 5-day prolonged fasting showed similar metabolic changes.</p><p><strong>Conclusions: </strong>This MFP is safe and transiently improves cardiometabolic health and physical well-being in healthy individuals.</p><p><strong>Clinical trial registration: </strong>This trial was prospectively registered at ClinicalTrials.gov (NCT05821660) on 6 April 2023 prior to the start of patient recruitment.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"18 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13227866/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148143142","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":"Dynamics of tumor ecosystems and microbiome in response to neoadjuvant ABFOLFOX treatment in patients with unresectable colorectal cancer with liver metastasis.","authors":"Wonkyung Kim, Jeong Eun Kim, Yong Sang Hong, Dae Wook Hwang, Jihun Kim, Ji Sung Lee, Jin Ho Shin, Tae Won Kim, Deepti Nagarkar, Allyson Byrd, Chang Ohk Sung, Sun Young Kim","doi":"10.1186/s13073-026-01680-4","DOIUrl":"10.1186/s13073-026-01680-4","url":null,"abstract":"<p><strong>Background: </strong>This study aims to explore the effects of neoadjuvant atezolizumab, bevacizumab, leucovorin, 5-fluorouracil, and oxaliplatin (ABFOLFOX) in patients with unresectable colorectal liver metastases (CRLM), focusing on the molecular dynamics of tumor ecosystems (TE) of CRLM and their impact on treatment outcomes.</p><p><strong>Methods: </strong>The study comprises two cohorts with CRLM tissue samples analyzed with RNA sequencing and immunohistochemical staining: cross-sectional cohort A (n = 60, CRLM treated with or without neoadjuvant chemotherapy) and prospectively registered cohort B (n = 20 with serial sampling and treated with ABFOLFOX). Shotgun metagenomic sequencing was performed for stool samples from cohort B.</p><p><strong>Results: </strong>Durable disease control (PFS ≥ 24 months) was observed in 35% (7/20) of patients receiving ABFOLFOX. Analysis revealed a progressive increase in the immunogenic microenvironment within CRLM tissues upon the addition of therapeutic agents, specifically bevacizumab, and the most significant TE changes in CRLM were observed in those treated with ABFOLFOX in cohort B. The monocyte lineage was significantly associated with benefit from ABFOLFOX. Good responders exhibited improved immune response and notable activation of the SP140 transcription factor regulon. Moreover, microbiome analysis revealed that high abundance of Prevotella was positively correlated with good response and enhanced immune environment within the tumor. Causal mediation analysis suggested that the gut microbiome partially links the ABFOLFOX treatment response to the tumor microenvironment.</p><p><strong>Conclusions: </strong>ABFOLFOX enhances the TE immune profile of CRLM, which is further augmented by the gut-liver axis characterized by Prevotella abundance, and can induce durable disease control in a subgroup of patients.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov, NCT03698461. May 08, 2019 (prospectively registered).</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":" ","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13439765/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148101385","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":"Systemic multi-omics analysis reveals interferon response heterogeneity and links lipid metabolism to immune alterations in severe COVID-19.","authors":"Ronaldo Lira-Junior, Anoop T Ambikan, Axel Cederholm, Sefanit Rezene, Flora Mikaeloff, Sara Svensson Akusjärvi, Ahmet Yalcinkaya, Xi Chen, Maike Sperk, Maribel Aranda-Guillén, Hampus Nordqvist, Carl Johan Treutiger, Nils Landegren, Ujjwal Neogi, Soham Gupta","doi":"10.1186/s13073-026-01677-z","DOIUrl":"10.1186/s13073-026-01677-z","url":null,"abstract":"<p><strong>Background: </strong>Interferons play a central role in antiviral defense, but their dysregulation contributes to inflammation and immune dysfunction in respiratory viral infections, including COVID-19. While interferon-stimulated genes (ISGs) are essential effectors of this response, their expression patterns in patients are heterogeneous and not always predictive of disease severity. The immunometabolic consequences of this heterogeneity remain poorly understood.</p><p><strong>Methods: </strong>We analyzed hospitalized COVID-19 patients (n = 37) and uninfected controls (n = 31) using whole-blood transcriptomics, immune cell deconvolution, plasma proteomics, and standardized plasma metabolomics from a previously generated dataset within this cohort. Patients were stratified into low (LIS), moderate (MIS), and high (HIS) ISG score clusters. Plasma innate immune activation markers were measured by ELISA. Interferon-directed antibody reactivity was analyzed by multiplex bead-based assays measuring antigen reactivity. Functional immune responses were assessed via ex vivo stimulation of healthy donor immune cells with patient plasma, and correlations were performed between metabolites and immune activation markers.</p><p><strong>Results: </strong>HIS patients exhibited increased inflammatory mediators and innate immune cell expansion compared with LIS and MIS groups. However, within the HIS group, severe cases displayed distinct metabolic and immune dysregulation. Specifically, severe HIS cases showed reductions in phospholipids, sphingolipids, and tricarboxylic acid cycle intermediates, suggestive of disrupted mitochondrial and lipid metabolism. Plasma from severe HIS patients tended to impair neutrophil and monocyte activation, indicating functional attenuation of innate immune activation within a shared high-ISG background. Correlation analysis revealed that branched-chain lipids, tryptophan-derived metabolites, and a branched-chain dicarboxylic acid were positively associated with immune activation markers. Although type-I interferon neutralization was detected in a subset of patients with IFN antigen reactivity, these samples did not fully account for the observed ISG heterogeneity or disease severity.</p><p><strong>Conclusions: </strong>High ISG expression in COVID-19 defines a transcriptional endotype associated with systemic inflammation and innate immune activation. However, severe cases within this group exhibit metabolic constraints and reduced innate immune responsiveness, supporting an immune-metabolic axis in which inflammatory mediators and altered lipid/energy metabolism intersect with innate immune function. These findings motivate future studies to determine whether interferon-associated immune-metabolic states during acute infection relate to persistent inflammation or post-acute sequelae in selected patient subsets.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"18 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13220500/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148053919","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":"PAX4 R192H variant impairs β cell function by disrupting β cell identity and compensatory capacity in response to metabolic stress.","authors":"Jungsun Park, Kyun Hoo Kim, Hyunsuk Lee, Joon Ho Moon, Soo Heon Kwak, Jong Il Kim, Hail Kim, Kyong Soo Park","doi":"10.1186/s13073-026-01669-z","DOIUrl":"10.1186/s13073-026-01669-z","url":null,"abstract":"<p><strong>Background: </strong>Type 2 diabetes is characterized by progressive β cell dysfunction, yet the mechanisms by which genetic susceptibility contributes to β cell area and function remain poorly understood. PAX4 is a transcription factor critical for β cell development, and a nonsynonymous variant resulting in an arginine-to-histidine substitution at position 192 (R192H) has been associated with increased type 2 diabetes risk and identified only in individuals of East Asian ancestry.</p><p><strong>Methods: </strong>Here, we generated PAX4 R192H knock-in (Pax4^R192H/R192H) mouse and integrated metabolic phenotyping, bulk and single cell transcriptomics, and human cohort analyses to investigate how PAX4 R192H mutation increases the risk of type 2 diabetes.</p><p><strong>Results: </strong>Homozygote knock-in mice (Pax4 R192H) exhibited normal pancreatic endocrine development but developed glucose intolerance and impaired insulin secretion when fed a high-fat diet. Bulk and single-cell RNA-seq of islets from Pax4 R192H mice fed high-fat diet revealed impaired β cell adaptation to metabolic stress characterized by enhanced endoplasmic reticulum stress and impaired β cell maturity, with upregulation of dedifferentiation and α cell markers and downregulation of β cell identity genes. Pax4 deletion in β cells resulted in similar phenotypic and transcriptomic profiles to Pax4 R192H mice. In humans, the trajectories of β cell function were evaluated over a 14-year period using biennial oral glucose tolerance tests from 4,242 participants, where PAX4 R192H carriers showed 1.4-fold accelerated decline in disposition index, with increasing body mass index further exacerbating their type 2 diabetes risk.</p><p><strong>Conclusions: </strong>Overall, PAX4 is essential for maintaining β cell identity and compensatory function under metabolic stress, and the R192H variant predisposes to type 2 diabetes by impairing this adaptive capacity.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":" ","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13403659/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148053786","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 indicators of body mass predict survival outcomes in colorectal cancer patients: patient cohort analysis.","authors":"Tanwei Yuan, Marko Mandic, Xianzhe Li, Melanie Bewerunge-Hudler, Hermann Brenner, Michael Hoffmeister","doi":"10.1186/s13073-026-01678-y","DOIUrl":"10.1186/s13073-026-01678-y","url":null,"abstract":"<p><strong>Background: </strong>The prognostic relevance of body mass index (BMI) in colorectal cancer (CRC) remains controversial, partly due to disease-related weight loss. DNA methylation (DNAm)-based BMI scores may be a more stable prognostic indicator than a single BMI measurement. This study evaluated the associations between blood-derived DNAm-BMI scores and mortality in CRC patients, compared with self-reported BMI.</p><p><strong>Methods: </strong>We analyzed data from 2,126 newly diagnosed CRC patients (41.2% women, median age 69) in the German DACHS study. Self-reported BMI at diagnosis and up to 14 years earlier and pre-diagnostic weight loss was recorded. Five externally developed and validated DNAm-BMI scores were calculated from blood DNAm. Outcomes included all-cause, CRC-specific, and non-CRC-specific mortality. Associations were estimated using Cox proportional hazards models adjusted for demographic, lifestyle, clinical, and treatment factors.</p><p><strong>Results: </strong>All DNAm-BMI scores showed consistent correlations with self-reported BMI at CRC diagnosis and up to14 years prior (Spearman r = 0.15-0.41). Underweight at diagnosis was linked to increased all-cause mortality (adjusted hazard ratio [aHR]: 1.42, 95% confidence interval [CI]: 1.07-1.88), whereas obesity was associated with decreased risk (0.83, 95%CI: 0.70-0.99). In contrast, four of the five DNAm-BMI scores (mBMI-135, mBMI-379, mBMI-435, mBMI-1109) showed consistent, positive linear associations with mortality risk. The 135-CpG score was most predictive (1.57, 95%CI: 1.23-1.99). Most of these associations were confined to the subgroup with blood samples collected before chemo-/radiotherapy.</p><p><strong>Conclusions: </strong>Blood-based DNAm-BMI scores, reflecting the biological effects of adiposity exposure, were positively associated with CRC mortality, and might be useful to improve risk stratification beyond self-reported BMI.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"18 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13218036/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148053973","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":"Preservation and clonal behavior of extrachromosomal DNA in patient-derived xenograft models of childhood cancers.","authors":"Rishaan Kenkre, Owen S Chapman, Eugene Yui-Ching Chow, Jens Luebeck, Yan Yuen Lo, Megan Paul, Wenshu Zhang, Jill Mesirov, Vineet Bafna, Kevin Yip, Jon D Larson, Robert J Wechsler-Reya, Lukas Chavez","doi":"10.1186/s13073-026-01676-0","DOIUrl":"10.1186/s13073-026-01676-0","url":null,"abstract":"<p><strong>Background: </strong>Extrachromosomal DNA (ecDNA) is a structural variant linked to poor prognosis in pediatric cancers. Patient-derived xenograft (PDX) models are crucial tools for cancer research, as they are believed to recapitulate the molecular features and intratumoral heterogeneity in patient tumors. However, ecDNA demonstrates unique evolutionary dynamics under selective pressure, and its behavior during PDX development remains largely uncharacterized. This study investigates the fidelity of PDX models in representing ecDNA from primary tumors. By analyzing ecDNA sequence composition and copy number conservation across pediatric solid cancers, we assess how well PDX models recapitulate the ecDNA landscape observed in human tumors.</p><p><strong>Methods: </strong>AmpliconArchitect was used to analyze whole-genome sequencing (WGS) of 338 PDX models and 127 corresponding primary tumors. ecDNA status, sequence, copy number, and associated genes were compared between PDX models and their matched human tumors. Additionally, multiome RNA and ATAC single-cell sequencing of a PDX tumor enabled comparison of ecDNA intratumoral heterogeneity relative to similar data from the primary tumor.</p><p><strong>Results: </strong>ecDNA in PDX models largely recapitulated oncogene amplifications observed in human tumors, with MYCN being the most frequently amplified. ecDNA status remained unchanged for a majority of the PDX models (105/127, 83%) compared to primary tumors, with 20% of previously ecDNA-negative cases acquiring ecDNA during PDX development. Consequently, ecDNA was more prevalent in the PDX models than in their corresponding human tumors (McNemar's test, p = 0.00086). Detailed examination of ecDNA sequences in tumor-PDX pairs showed substantial conservation (67% with > 90% sequence overlap) but variable breakpoint concordance. Single-cell analysis demonstrated that rare ecDNA-positive cells from the primary tumor preferentially drive PDX tumor development.</p><p><strong>Conclusion: </strong>This study highlights the prevalence, oncogenic content, and conservation of ecDNA in PDX models relative to pediatric patient tumors. We observed that ecDNA frequently recapitulates oncogene amplifications found in human cancers, is generally preserved during PDX establishment, and reflects subtype-specific patterns across tumor types. These findings support the utility of PDX models in studying ecDNA biology in pediatric cancer progression and therapy. Longitudinal sampling during PDX tumor growth and under therapeutic pressure could provide insights into molecular evolution, clonal selection, and ecDNA-driven therapy resistance.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":" ","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13403850/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148053837","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":"Genome-wide association study reveals a novel tuberculosis susceptibility locus in multiple East Asian and European populations.","authors":"Xuling Chang, Zheng Li, Phan Vuong Khac Thai, Dang Thi Minh Ha, Nguyen Thuy Thuong Thuong, Denise Wee, Alya Sufiyah Binte Mohamed Subhan, Matthew Silcocks, Cynthia Bin Eng Chee, Nguyen Thi Quynh Nhu, Chew-Kiat Heng, Yik Ying Teo, Amit Singhal, Stefan H Oehlers, Jian-Min Yuan, Woon-Puay Koh, Maxine Caws, Chiea Chuen Khor, Rajkumar Dorajoo, Sarah J Dunstan","doi":"10.1186/s13073-026-01670-6","DOIUrl":"10.1186/s13073-026-01670-6","url":null,"abstract":"<p><strong>Background: </strong>Tuberculosis (TB) continues to be a leading cause of morbidity and mortality worldwide. Although numerous genome-wide association studies (GWAS) have explored TB susceptibility across various ethnic groups, multi-population replication of findings has been very limited, particularly outside the HLA region, and a significant portion of TB heritability remains unexplained.</p><p><strong>Methods: </strong>We conducted GWAS in the Singapore Chinese and Vietnamese, followed by a comprehensive meta-analysis incorporating 4 independent East Asian datasets (N = 11,841 cases; N = 197,373 controls). The transferability of any identified association was assessed using summary statistics from independent European populations. Potential candidate genes were prioritized using gene-based association testing and integrative bioinformatic database mining, followed by functional validation through assessment of Mycobacterium marinum (M.marinum) infection burden in CRISPR-Cas9-edited zebrafish embryos.</p><p><strong>Results: </strong>We identified a novel susceptibility locus for pulmonary TB (PTB) at 22q12.2 in East Asians [rs6006426, OR (95%Cl) = 1.097(1.066, 1.130), P_meta=3.31 × 10^- 10]. The association was further validated in Europeans [OR (95%Cl) = 1.101(1.002, 1.211), P = 0.046] and was strengthened in the combined meta-analysis including a total of 12,736 PTB cases and 673,864 controls [OR (95%Cl) = 1.098 (1.068, 1.129); P_meta=4.33 × 10^- 11]. Gene-based association test identified Oncostatin M (OSM) to be significantly associated with PTB (ZSTAT = 5.013; P = 2.68 × 10^- 7; P_adj=0.005). The lead SNP rs6006426 affected Splicing factor 3a subunit 1 (SF3A1) expression in various immune cells (P from 0.003 to 6.17 × 10^- 18) and OSM expression in monocytes post lipopolysaccharide stimulation (P = 5.57 × 10^- 4) as reported in the eQTL Catalogue. CRISPR-Cas9 edited zebrafish embryos with osm depletion resulted in decreased burden of M.marinum in infected embryos (P = 0.047).</p><p><strong>Conclusions: </strong>Our findings offer novel insights into the genetic factors underlying TB and reveals new avenues for understanding its etiology.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"18 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13214086/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148029281","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":"High-fidelity genome and prime editing enabled by the AI-designed openCRISPR-1.","authors":"Hye-Yeon Hwang, Hwalin Yi, Yuju Gwon, Eunju Jeon, Daesik Kim","doi":"10.1186/s13073-026-01682-2","DOIUrl":"10.1186/s13073-026-01682-2","url":null,"abstract":"<p><strong>Background: </strong>RNA-guided nucleases such as CRISPR-Cas9 systems have revolutionized genome engineering by enabling programmable DNA modifications. Although structure-guided and evolution-derived high-fidelity Cas9 variants improve target specificity, they often compromise on-target activity or constrain guide RNA (gRNA) design.</p><p><strong>Methods: </strong>We performed head-to-head comparisons of OpenCRISPR-1 and Cas9 in human cells using amplicon sequencing, multiplex Digenome-seq, and off-target validation by targeted sequencing. Editing activity was assessed across 28 endogenous loci in HEK293T cells and further evaluated in human induced pluripotent stem cells (iPSCs) and MRC-5 fibroblasts. To test clinically relevant delivery, Cas9 and OpenCRISPR-1 ribonucleoproteins were delivered using engineered virus-like particles (eVLPs). We also generated OpenCRISPR-based prime editors, OpenCRISPR-PE2 and OpenCRISPR-PE7, and compared them with PE2max and PE7 using pegRNAs and engineered epegRNAs.</p><p><strong>Results: </strong>Here, we show that OpenCRISPR-1, an AI-designed, Cas9-like nuclease, retains Cas9-level editing efficiency across multiple genomic loci while significantly reducing off-target mutations. Using multiplex Digenome-seq and targeted deep sequencing, OpenCRISPR-1 exhibits up to a 553-fold reduction in off-target mutations compared to Cas9 and achieves off-target indices that match or surpass those of high-fidelity Cas9 variants. OpenCRISPR-1 also sustains robust editing across diverse gRNA formats (GX₁₉, gX₁₉, and gX₂₀), highlighting its enhanced versatility. Furthermore, converting OpenCRISPR-1 into a prime editor yields comparable editing efficiencies while lowering the relative specificity ratio by up to 97%.</p><p><strong>Conclusions: </strong>These findings establish generative AI-guided protein design as a powerful strategy to overcome the specificity-efficiency trade-off, expanding the genome editing toolkit for both research and therapeutic use, and ushering in a new era of rational protein design.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":" ","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13393691/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148029347","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":"Enhanced measures of neoantigenicity capture unique tumor-immune interactions across primary melanoma subtypes.","authors":"Eva R Shteinman, Grace H Attrill, Nigel G Maher, Kiran Gnana, Venkateswar Addala, Yizhe Mao, Umaimainthan Palendira, Jordan W Conway, Andrew J Colebatch, Nicola Waddell, Nicholas K Hayward, John V Pearson, Georgina V Long, Richard A Scolyer, James S Wilmott, Ismael A Vergara","doi":"10.1186/s13073-026-01673-3","DOIUrl":"10.1186/s13073-026-01673-3","url":null,"abstract":"<p><strong>Background: </strong>As immune checkpoint inhibitor therapies move toward treatment of clinically high-risk localized primary melanoma, there is an increasing need for clear understanding of the tumor-immune interaction across primary melanoma subtypes. Tumor genomic properties play a crucial role in the interaction with the immune system and have been widely explored in metastatic melanoma, but are less understood in the primary context across melanoma subtypes. Persistent tumor mutational burden (pTMB) has been proposed as an enhanced proxy of neoantigenicity in metastatic melanoma compared to standard TMB, but its role in primary disease is not known.</p><p><strong>Methods: </strong>This study utilised a cohort of 178 predominantly primary melanomas (cutaneous non-acral: n = 69, acral: n = 36, mucosal: n = 73) with available whole-genome sequencing (WGS, n = 127) to measure TMB, pTMB, aneuploidy and loss of heterozygosity, as well as multiplexed immunohistochemistry (mIHC, n = 140) to identify intratumoral T cells (CD3 + , CD8 + , CD45RO + & CD103 +), B cells (CD20 +), dendritic cells (CD11c +), macrophages (CD68 +) and PD-L1 + cells.</p><p><strong>Results: </strong>Whilst pTMB is mostly contributed by mutations present in multiple copies across primary melanoma subtypes, distinct families of clonal pTMB capture relationships with CD8 + T cells and CD8 + CD103 + T cells across subtypes not captured by clonal standard TMB. Clonal single-copy pTMB was positively associated with elevated CD8 + T cell (p = 0.003) and CD8 + CD103 + T cell infiltration (p = 0.008) in cutaneous melanomas. In contrast, clonal multiple-copy pTMB was positively associated with elevated CD8 + CD103 + T cell infiltration in acral (p = 0.048) and mucosal (p = 0.049) melanomas. Cutaneous primary melanomas had greater proportions of CD8 + T cells (p = 0.009) and CD8 + CD103 + T cells (p = 0.0002) compared to mucosal melanomas. In turn, CD8 + T cell infiltration was associated with absence of lymphatic invasion (p = 0.003), and negatively associated with tumor mitotic rate (p = 0.049) in cutaneous melanomas, indicative of less aggressive disease.</p><p><strong>Conclusions: </strong>Primary melanoma subtypes present significant differences in their immune and genomic landscapes, as well as their interactions. Distinct measures of pTMB carry added value compared to standard TMB for identification of tumour-immune associations across primary melanoma subtypes. Our findings indicate that pTMB is a relevant neoantigenicity marker in primary melanoma with the potential to modulate immune infiltration, leading to more aggressive disease.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":" ","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13390141/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148014804","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}