Genome Medicine最新文献

{"title":"Advantages of updated WHO mutation catalog combined with existing whole-genome sequencing-based approaches for Mycobacterium tuberculosis resistance prediction.","authors":"Yiwang Chen, Xuecong Zhang, Jialei Liang, Qi Jiang, Mijiti Peierdun, Peng Xu, Howard E Takiff, Qian Gao","doi":"10.1186/s13073-025-01458-0","DOIUrl":"10.1186/s13073-025-01458-0","url":null,"abstract":"<p><strong>Background: </strong>The WHO recently released a second edition of the mutation catalog for predicting drug resistance in Mycobacterium tuberculosis (MTB). This study evaluated its effectiveness compared to existing whole-genome sequencing (WGS)-based prediction methods and proposes a novel approach for its optimization.</p><p><strong>Methods: </strong>We tested the accuracy of five tools-the WHO catalog, TB Profiler, SAM-TB, GenTB, and MD-CNN-for predicting drug susceptibility on a global dataset of 36,385 MTB isolates with high-quality phenotypic drug susceptibility testing (DST) and WGS data. By integrating the genotypic DST predictions of these five tools in an ensemble machine learning framework, we developed an improved computational model for MTB drug susceptibility prediction. We then validated the ensemble model on 860 MTB isolates with phenotypic and WGS data collected in Shenzhen, China (2013-2019) and Valencia, Spain (2014-2016).</p><p><strong>Results: </strong>Among the five genotypic DST tools for predicting susceptibility to ten drugs, MD-CNN exhibited the highest overall performance (AUC 92.1%; 95% CI 89.8-94.4%). The WHO catalog demonstrated the highest specificity of 97.3% (95% CI 95.8-98.4%), while TB Profiler had the best sensitivity at 79.5% (95% CI 71.8-86.2%). The ensemble machine learning model (AUC 93.4%; 95% CI 91.4-95.4%) outperformed all of the five individual tools, with a specificity of 95.4% (95% CI 93.0-97.6%) and a sensitivity of 84.1% (95% CI 78.8-88.8%), principally due to considerable improvements in second-line drug resistance predictions (AUC 91.8%; 95% CI 89.6-94.0%).</p><p><strong>Conclusions: </strong>The second edition of the WHO MTB mutation catalog does not, by itself, perform better than existing tools for predicting MTB drug resistance. An integrative approach combining the WHO catalog with other genotypic DST methods significantly enhances prediction accuracy.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"31"},"PeriodicalIF":10.4,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11938600/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718586","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":"Metronidazole response profiles of Gardnerella species are congruent with phylogenetic and comparative genomic analyses.","authors":"Katherine A Innamorati, Joshua P Earl, Shirley C Barrera, Rachel L Ehrlich, Josephine Aiyeku, Ari Gordon, Evan Powell, Adam C Retchless, Azad Ahmed, Bhaswati Sen, Sergey Balashov, Joshua Chang Mell, Sharon L Hillier, Garth D Ehrlich","doi":"10.1186/s13073-025-01446-4","DOIUrl":"10.1186/s13073-025-01446-4","url":null,"abstract":"<p><strong>Background: </strong>Bacterial vaginosis (BV) affects 20-50% of reproductive-age female patients annually, arising when opportunistic pathogens outcompete healthy vaginal flora. Many patients fail to resolve symptoms with a course of metronidazole, the current first-line treatment for BV. Our study was designed to identify genomic variation associated with metronidazole resistance among strains of Gardnerella vaginalis spp. (GV), a genus of biogenic-amine-producing bacteria closely associated with BV pathogenesis, for the development of a companion molecular diagnostic.</p><p><strong>Methods: </strong>Whole-genome sequencing and comparative genomic metrics, including average nucleotide identity and GC content, were performed on a diverse set of 129 GV genomes to generate data for detailed taxonomic analyses. Pangenomic analyses were employed to construct a phylogenetic tree and cluster highly related strains within genospecies. G. vaginalis spp. clinical isolates within our collection were subjected to plate-based minimum inhibitory concentration (MIC) testing of metronidazole (n = 60) and clindamycin (n = 63). DECIPHER and MAFFT were used to identify genospecies-specific primers associated with antibiotic-resistance phenotypes. PCR-based analyses with these primers were used to confirm their specificity for the relevant genospecies.</p><p><strong>Results: </strong>Eleven distinct genospecies based on standard ANI criteria were identified among the GV strains in our collection. Metronidazole MIC testing revealed six genospecies within a closely related phylogenetic clade contained only highly metronidazole-resistant strains (MIC ≥ 32 µg/mL) and suggested at least two mechanisms of metronidazole resistance within the eleven GV genospecies. All strains within the six highly metronidazole-resistant genospecies displayed susceptibility to clinically relevant clindamycin concentrations (MIC ≤ 2 µg/mL). A PCR-based molecular diagnostic assay was developed to distinguish between members of the metronidazole-resistant and mixed-response genospecies, which should be useful for determining the clade membership of various GV strains and could assist in the selection of appropriate antibiotic therapies for BV cases.</p><p><strong>Conclusions: </strong>This study provides comparative genomic and phylogenetic evidence for eleven distinct genospecies within the genus Gardnerella vaginalis spp., and identifies genospecies-specific responses to metronidazole, the first-line treatment for BV. A companion molecular diagnostic assay was developed that is capable of identifying essentially all highly metronidazole-resistant strains that phylogenetically cluster together within the GV genospecies, which is informative for antibiotic treatment options.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"28"},"PeriodicalIF":10.4,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11934483/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708153","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":"Rare damaging CCR2 variants are associated with lower lifetime cardiovascular risk.","authors":"Marios K Georgakis, Rainer Malik, Omar El Bounkari, Natalie R Hasbani, Jiang Li, Jennifer E Huffman, Gabrielle Shakt, Reinier W P Tack, Tamara N Kimball, Yaw Asare, Alanna C Morrison, Noah L Tsao, Renae Judy, Braxton D Mitchell, Huichun Xu, May E Montasser, Ron Do, Eimear E Kenny, Ruth J F Loos, James G Terry, John Jeffrey Carr, Joshua C Bis, Bruce M Psaty, W T Longstreth, Kendra A Young, Sharon M Lutz, Michael H Cho, Jai Broome, Alyna T Khan, Fei Fei Wang, Nancy Heard-Costa, Sudha Seshadri, Ramachandran S Vasan, Nicholette D Palmer, Barry I Freedman, Donald W Bowden, Lisa R Yanek, Brian G Kral, Lewis C Becker, Patricia A Peyser, Lawrence F Bielak, Farah Ammous, April P Carson, Michael E Hall, Laura M Raffield, Stephen S Rich, Wendy S Post, Russel P Tracy, Kent D Taylor, Xiuqing Guo, Michael C Mahaney, Joanne E Curran, John Blangero, Shoa L Clarke, Jeffrey W Haessler, Yao Hu, Themistocles L Assimes, Charles Kooperberg, Jürgen Bernhagen, Christopher D Anderson, Scott M Damrauer, Ramin Zand, Jerome I Rotter, Paul S de Vries, Martin Dichgans","doi":"10.1186/s13073-025-01456-2","DOIUrl":"10.1186/s13073-025-01456-2","url":null,"abstract":"<p><strong>Background: </strong>Previous work has shown a role of CCL2, a key chemokine governing monocyte trafficking, in atherosclerosis. However, it remains unknown whether targeting CCR2, the cognate receptor of CCL2, provides protection against human atherosclerotic cardiovascular disease.</p><p><strong>Methods: </strong>Computationally predicted damaging or loss-of-function (REVEL > 0.5) variants within CCR2 were detected in whole-exome-sequencing data from 454,775 UK Biobank participants and tested for association with cardiovascular endpoints in gene-burden tests. Given the key role of CCR2 in monocyte mobilization, variants associated with lower monocyte count were prioritized for experimental validation. The response to CCL2 of human cells transfected with these variants was tested in migration and cAMP assays. Validated damaging variants were tested for association with cardiovascular endpoints, atherosclerosis burden, and vascular risk factors. Significant associations were replicated in six independent datasets (n = 1,062,595).</p><p><strong>Results: </strong>Carriers of 45 predicted damaging or loss-of-function CCR2 variants (n = 787 individuals) were at lower risk of myocardial infarction and coronary artery disease. One of these variants (M249K, n = 585, 0.15% of European ancestry individuals) was associated with lower monocyte count and with both decreased downstream signaling and chemoattraction in response to CCL2. While M249K showed no association with conventional vascular risk factors, it was consistently associated with a lower risk of myocardial infarction (odds ratio [OR]: 0.66, 95% confidence interval [CI]: 0.54-0.81, p = 6.1 × 10^-5) and coronary artery disease (OR: 0.74, 95%CI: 0.63-0.87, p = 2.9 × 10^-4) in the UK Biobank and in six replication cohorts. In a phenome-wide association study, there was no evidence of a higher risk of infections among M249K carriers.</p><p><strong>Conclusions: </strong>Carriers of an experimentally confirmed damaging CCR2 variant are at a lower lifetime risk of myocardial infarction and coronary artery disease without carrying a higher risk of infections. Our findings provide genetic support for the translational potential of CCR2-targeting as an atheroprotective approach.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"27"},"PeriodicalIF":10.4,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11929344/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143676886","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":"Long-read sequencing identifies copy-specific markers of SMN gene conversion in spinal muscular atrophy.","authors":"M M Zwartkruis, M G Elferink, D Gommers, I Signoria, L Blasco-Pérez, M Costa-Roger, J van der Sel, I J Renkens, J W Green, J V Kortooms, C Vermeulen, R Straver, H W M van Deutekom, J H Veldink, F Asselman, E F Tizzano, R I Wadman, W L van der Pol, G W van Haaften, E J N Groen","doi":"10.1186/s13073-025-01448-2","DOIUrl":"10.1186/s13073-025-01448-2","url":null,"abstract":"<p><strong>Background: </strong>The complex 2 Mb survival motor neuron (SMN) locus on chromosome 5q13, including the spinal muscular atrophy (SMA)-causing gene SMN1 and modifier SMN2, remains incompletely resolved due to numerous segmental duplications. Variation in SMN2 copy number, presumably influenced by SMN1 to SMN2 gene conversion, affects disease severity, though SMN2 copy number alone has insufficient prognostic value due to limited genotype-phenotype correlations. With advancements in newborn screening and SMN-targeted therapies, identifying genetic markers to predict disease progression and treatment response is crucial. Progress has thus far been limited by methodological constraints.</p><p><strong>Methods: </strong>To address this, we developed HapSMA, a method to perform polyploid phasing of the SMN locus to enable copy-specific analysis of SMN and its surrounding genes. We used HapSMA on publicly available Oxford Nanopore Technologies (ONT) sequencing data of 29 healthy controls and performed long-read, targeted ONT sequencing of the SMN locus of 31 patients with SMA.</p><p><strong>Results: </strong>In healthy controls, we identified single nucleotide variants (SNVs) specific to SMN1 and SMN2 haplotypes that could serve as gene conversion markers. Broad phasing including the NAIP gene allowed for a more complete view of SMN locus variation. Genetic variation in SMN2 haplotypes was larger in SMA patients. Forty-two percent of SMN2 haplotypes of SMA patients showed varying SMN1 to SMN2 gene conversion breakpoints, serving as direct evidence of gene conversion as a common genetic characteristic in SMA and highlighting the importance of inclusion of SMA patients when investigating the SMN locus.</p><p><strong>Conclusions: </strong>Our findings illustrate that both methodological advances and the analysis of patient samples are required to advance our understanding of complex genetic loci and address critical clinical challenges.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"26"},"PeriodicalIF":10.4,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11927269/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143676883","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":"Predicting MHC-I ligands across alleles and species: how far can we go?","authors":"Daniel M Tadros, Julien Racle, David Gfeller","doi":"10.1186/s13073-025-01450-8","DOIUrl":"10.1186/s13073-025-01450-8","url":null,"abstract":"<p><strong>Background: </strong>CD8⁺ T-cell activation is initiated by the recognition of epitopes presented on class I major histocompatibility complex (MHC-I) molecules. Identifying such epitopes is useful for molecular understanding of cellular immune responses and can guide the development of personalized vaccines for various diseases including cancer. For a few hundred common human and mouse MHC-I alleles, large datasets of ligands are available and machine learning MHC-I ligand predictors trained on such data reach high prediction accuracy. However, for the vast majority of other MHC-I alleles, no ligand is known.</p><p><strong>Methods: </strong>We capitalize on an expanded architecture of our MHC-I ligand predictor (MixMHCpred3.0) to systematically assess the extent to which predictions of MHC-I ligands can be applied to MHC-I alleles that currently lack known ligand data.</p><p><strong>Results: </strong>Our results reveal high prediction accuracy for most MHC-I alleles in human and in laboratory mouse strains, but significantly lower accuracy in other species. Our work further outlines some of the molecular determinants of MHC-I ligand prediction accuracy across alleles and species. Robust benchmarking on external data shows that our MHC-I ligand predictor demonstrates competitive performance relative to other state-of-the-art MHC-I ligand predictors and can be used for CD8⁺ T-cell epitope predictions.</p><p><strong>Conclusions: </strong>Our work provides a valuable tool for predicting antigen presentation across all human and mouse MHC-I alleles. MixMHCpred3.0 tool is available at https://github.com/GfellerLab/MixMHCpred .</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"25"},"PeriodicalIF":10.4,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11927126/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143669522","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":"Whole genome sequencing of 378 prostate cancer metastases reveals tissue selectivity for mismatch deficiency with potential therapeutic implications.","authors":"Daniel J Vis, Sander A L Palit, Marie Corradi, Edwin Cuppen, Niven Mehra, Martijn P Lolkema, Lodewyk F A Wessels, Michiel S van der Heijden, Wilbert Zwart, Andries M Bergman","doi":"10.1186/s13073-025-01445-5","DOIUrl":"10.1186/s13073-025-01445-5","url":null,"abstract":"<p><strong>Background: </strong>Survival of patients with metastatic castration-resistant prostate cancer (mCRPC) depends on the site of metastatic dissemination.</p><p><strong>Methods: </strong>Patients with mCRPC were prospectively included in the CPCT-02 metastatic site biopsy study. We evaluated whole genome sequencing (WGS) of 378 mCRPC metastases to understand the genetic traits that affect metastatic site distribution.</p><p><strong>Results: </strong>Our findings revealed that RB1, PIK3CA, JAK1, RNF43, and TP53 mutations are the most frequent genetic determinants associated with site selectivity for metastatic outgrowth. Furthermore, we explored mutations in the non-coding genome and found that androgen receptor (AR) chromatin binding sites implicated in metastatic prostate cancer differ in mutation frequencies between metastatic sites, converging on pathways that impact DNA repair. Notably, liver and visceral metastases have a higher tumor mutational load (TML) than bone and lymph node metastases, independent of genetic traits associated with neuroendocrine differentiation. We found that TML is strongly associated with DNA mismatch repair (MMR)-deficiency features in these organs.</p><p><strong>Conclusions: </strong>Our results revealed gene mutations that are significantly associated with metastatic site selectivity and that frequencies of non-coding mutations at AR chromatin binding sites differ between metastatic sites. Immunotherapeutics are thus far unsuccessful in unselected mCRPC patients. We found a higher TML in liver and visceral metastases compared to bone and lymph node metastases. As immunotherapeutics response is associated with mutational burden, these findings may assist in selecting mCRPC patients for immunotherapy treatment based on organs affected by metastatic disease.</p><p><strong>Trial registration number: </strong>NCT01855477.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"24"},"PeriodicalIF":10.4,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11927350/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143669540","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 polygenic score for height identifies an unmeasured genetic predisposition among pediatric patients with idiopathic short stature.","authors":"John P Shelley, Mingjian Shi, Josh F Peterson, Sara L Van Driest, Jill H Simmons, Jonathan D Mosley","doi":"10.1186/s13073-025-01455-3","DOIUrl":"10.1186/s13073-025-01455-3","url":null,"abstract":"<p><strong>Background: </strong>A subset of children with short stature do not have an identified clinical explanation after extensive diagnostic evaluation. We hypothesized that a polygenic score for height (PGS_height) could identify children with non-familial idiopathic short stature (ISS-NF) who carry a polygenic predisposition to shorter height that is not accounted for by existing measures.</p><p><strong>Methods: </strong>We studied 534 pediatric participants in an electronic health record (EHR)-linked DNA biobank (BioVU) who had been evaluated for short stature by an endocrinologist. Participants were classified as having one of five short stature subtypes: primary growth disorders, secondary growth disorders, idiopathic short stature (ISS), which was sub-classified into familial (ISS-F) and non-familial (ISS-NF), and constitutional delay of puberty (ISS-DP). Differences in polygenic predisposition between subtypes were analyzed using a validated PGS_height which was standardized to a standard deviation score (SDS). Adult height predictions were generated using the PGS_height and mid-parental height (MPH). Within-child differences in height predictions were compared across subtypes. Logistic regression models and AUC analyses were used to test the ability of the PGS_height to differentiate ISS-NF from growth disorders. The incremental improvement (ΔAUC) of adding the PGS_height to prediction models with MPH was also estimated.</p><p><strong>Results: </strong>Among the 534 participants, 29.0% had secondary growth disorders, 24.9% had ISS-F, 20.2% had ISS-NF, 17.2% had ISS-DP, and 8.6% had primary growth disorders. Participants with ISS-NF had similar PGS_height values to those with ISS-F (difference [Δ] in PGS_height SDS [95% CI] = 0.19 [- 0.31 to 0.70], p = 0.75). Predicted heights generated by the PGS_height were lower than the MPH estimate for children with ISS-NF (Δ[PGS_height - MPH] =  - 0.37 SDS; p = 3.2 × 10^-9) but not for children with ISS-F (Δ =  - 0.07; p = 0.56). Children with ISS-NF also had lower PGS_height than children with primary growth disorders (ΔPGS_height =  - 0.53 [- 1.03 to - 0.04], p = 0.03) and secondary growth disorders (Δ =  - 0.45 [- 0.80 to - 0.10], p = 0.005). The PGS_height improved model discrimination between ISS-NF and children with primary (ΔAUC, + 0.07 [95% CI, 0.02 to 0.17]) and secondary growth disorders (ΔAUC, + 0.03 [95% CI, 0.01 to 0.10]).</p><p><strong>Conclusions: </strong>Some children with ISS-NF have an unrecognized polygenic predisposition to shorter height, similar to children with ISS-F and greater than those with growth disorders. A PGS_height could aid clinicians in identifying children with a benign, polygenic predisposition to shorter height.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"23"},"PeriodicalIF":10.4,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11924680/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662670","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":"Metatranscriptomic profiling reveals pathogen and host response signatures of pediatric acute sinusitis and upper respiratory infection.","authors":"Andrew C Doxey, Nooran Abu Mazen, Max Homm, Vivian Chu, Manjot Hunjan, Briallen Lobb, Sojin Lee, Marcia Kurs-Lasky, John V Williams, William MacDonald, Monika Johnson, Jeremy A Hirota, Nader Shaikh","doi":"10.1186/s13073-025-01447-3","DOIUrl":"10.1186/s13073-025-01447-3","url":null,"abstract":"<p><strong>Background: </strong>Acute sinusitis (AS) is a frequent cause of antibiotic prescriptions in children. Distinguishing bacterial AS from common viral upper respiratory infections (URIs) is crucial to prevent unnecessary antibiotic use but is challenging with current diagnostic methods. Despite its speed and cost, untargeted RNA sequencing of clinical samples from children with suspected AS has the potential to overcome several limitations of other methods. In addition, RNA-seq may reveal novel host-response biomarkers for development of future diagnostic assays that distinguish bacterial from viral infections. There are however no available RNA-seq datasets of pediatric AS that provide a comprehensive view of both pathogen etiology and host immune response.</p><p><strong>Methods: </strong>Here, we performed untargeted RNA-seq (metatranscriptomics) of nasopharyngeal samples from 221 children with AS and performed a comprehensive analysis of pathogen etiology and the impact of bacterial and viral infections on host immune responses. Accuracy of RNA-seq-based pathogen detection was evaluated by comparison with culture tests for three common bacterial pathogens and qRT-PCR tests for 12 respiratory viruses. Host gene expression patterns were explored to identify potential host responses that distinguish bacterial from viral infections.</p><p><strong>Results: </strong>RNA-seq-based pathogen detection showed high concordance with culture or qRT-PCR, showing 87%/81% sensitivity (sens) / specificity (spec) for detecting three AS-associated bacterial pathogens, and 86%/92% (sens/spec) for detecting 12 URI-associated viruses, respectively. RNA-seq also detected an additional 22 pathogens not tested for clinically and identified plausible pathogens in 11/19 (58%) of cases where no organism was detected by culture or qRT-PCR. We reconstructed genomes of 196 viruses across the samples including novel strains of coronaviruses, respiratory syncytial virus, and enterovirus D68, which provide useful genomic data for ongoing pathogen surveillance programs. By analyzing host gene expression, we identified host-response signatures that differentiate bacterial and viral infections, revealing hundreds of candidate gene biomarkers for future diagnostic assays.</p><p><strong>Conclusions: </strong>Our study provides a one-of-kind dataset that profiles the interplay between pathogen infection and host responses in pediatric AS and URI. It reveals bacterial and viral-specific host responses that could enable new diagnostic approaches and demonstrates the potential of untargeted RNA-seq in diagnostic analysis of AS and URI.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"22"},"PeriodicalIF":10.4,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11912616/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143648274","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":"MuCST: restoring and integrating heterogeneous morphology images and spatial transcriptomics data with contrastive learning.","authors":"Yu Wang, Zaiyi Liu, Xiaoke Ma","doi":"10.1186/s13073-025-01449-1","DOIUrl":"10.1186/s13073-025-01449-1","url":null,"abstract":"<p><p>Spatially resolved transcriptomics (SRT) simultaneously measure spatial location, histology images, and transcriptional profiles of cells or regions in undissociated tissues. Integrative analysis of multi-modal SRT data holds immense potential for understanding biological mechanisms. Here, we present a flexible multi-modal contrastive learning for the integration of SRT data (MuCST), which joins denoising, heterogeneity elimination, and compatible feature learning. MuCST accurately identifies spatial domains and is applicable to diverse datasets platforms. Overall, MuCST provides an alternative for integrative analysis of multi-modal SRT data ( https://github.com/xkmaxidian/MuCST ).</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"21"},"PeriodicalIF":10.4,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11907906/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624377","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 insights into the plasmidome of non-tuberculous mycobacteria.","authors":"Margo Diricks, Florian P Maurer, Viola Dreyer, Ivan Barilar, Christian Utpatel, Matthias Merker, Nils Wetzstein, Stefan Niemann","doi":"10.1186/s13073-025-01443-7","DOIUrl":"10.1186/s13073-025-01443-7","url":null,"abstract":"<p><strong>Background: </strong>Non-tuberculous mycobacteria (NTM) are a diverse group of environmental bacteria that are increasingly associated with human infections and difficult to treat. Plasmids, which might carry resistance and virulence factors, remain largely unexplored in NTM.</p><p><strong>Methods: </strong>We used publicly available complete genome sequence data of 328 NTM isolates belonging to 125 species to study gene content, genomic diversity, and clusters of 196 annotated NTM plasmids. Furthermore, we analyzed 3755 draft genome assemblies from over 200 NTM species and 5415 short-read sequence datasets from six clinically relevant NTM species or complexes including M. abscessus, M. avium complex, M. ulcerans complex and M. kansasii complex, for the presence of these plasmids.</p><p><strong>Results: </strong>Between one and five plasmids were present in approximately one-third of the complete NTM genomes. The annotated plasmids varied widely in length (most between 10 and 400 kbp) and gene content, with many genes having an unknown function. Predicted gene functions primarily involved plasmid replication, segregation, maintenance, and mobility. Only a few plasmids contained predicted genes that are known to confer resistance to antibiotics commonly used to treat NTM infections. Out of 196 annotated plasmid sequences, 116 could be grouped into 31 clusters of closely related sequences, and about one-third were found across multiple NTM species. Among clinically relevant NTM, the presence of NTM plasmids showed significant variation between species, within (sub)species, and even among strains within (sub)lineages, such as dominant circulating clones of Mycobacterium abscessus.</p><p><strong>Conclusions: </strong>Our analysis demonstrates that plasmids are a diverse and heterogeneously distributed feature in NTM bacteria. The frequent occurrence of closely related putative plasmid sequences across different NTM species suggests they may play a significant role in NTM evolution through horizontal gene transfer at least in some groups of NTM. However, further in vitro investigations and access to more complete genomes are necessary to validate our findings, elucidate gene functions, identify novel plasmids, and comprehensively assess the role of plasmids in NTM.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"17 1","pages":"19"},"PeriodicalIF":10.4,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11877719/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556626","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}