Genome Medicine最新文献

{"title":"Decoding coupled epigenetic-fragmentomic signals in circulating cell-free DNA for interpretable cancer diagnosis.","authors":"Yunze Wang, Yuying Hou, Xinyu Liu, Qingjiao Li, Wen Zhang, Xionghui Zhou","doi":"10.1186/s13073-026-01793-w","DOIUrl":"10.1186/s13073-026-01793-w","url":null,"abstract":"<p><strong>Background: </strong>Plasma cell-free DNA (cfDNA) whole-genome methylation sequencing enables simultaneous characterization of DNA methylation and fragmentomic features for cancer detection. However, it remains unclear whether methylation library preparation faithfully preserves fragmentomic signals, how methylation and fragmentation are biologically coupled, and how these two modalities can be systematically integrated.</p><p><strong>Methods: </strong>We systematically evaluated the preservation of cfDNA fragmentomic features in whole-genome bisulfite sequencing (WGBS) and enzymatic methyl sequencing (EM-seq) relative to conventional whole-genome sequencing (WGS). We next investigated the biological relationship between methylation and fragmentation and delineated methylation haplotype blocks (MHBs) directly from plasma cfDNA as biologically interpretable units for organizing multimodal cfDNA signals. Guided by these findings, we developed multimodal diagnostic models integrating complementary methylation and fragmentomic features.</p><p><strong>Results: </strong>Canonical cfDNA fragmentomic patterns were partially preserved across methylation sequencing protocols, although the degree of preservation varied among individual features. DNA methylation levels were associated with characteristic fragment length and end-motif patterns. Plasma-derived MHBs exhibited tissue-associated regulatory features and distinct patterns of chromatin accessibility, repeat enrichment, and methylation heterogeneity, providing biologically interpretable units for integrated cfDNA analysis. Within these regions, methylation and fragmentomic signals exhibited coordinated yet complementary patterns. Leveraging this framework, we developed Fragmentomics And Methylation Ensemble (FAME), an interpretable multimodal model integrating MHB-centered methylation and fragmentomic features for cancer detection and tissue-of-origin prediction, and further extended it with complementary genome-wide methylation and fragmentomic features to generate a genome-wide-augmented FAME model (FAME-GW). Across cross-validation, independent validation, and comparisons with THEMIS (THorough Epigenetic Marker Integration Solution), SPOT-MAS (screening for the presence of tumor by methylation and size), and DELFI (DNA evaluation of fragments for early interception), FAME-based models achieved robust diagnostic performance, with FAME providing a compact and interpretable representation and FAME-GW delivering the strongest overall predictive performance.</p><p><strong>Conclusions: </strong>Our study demonstrates that cfDNA whole-genome methylation sequencing partially preserves informative fragmentomic signals and establishes plasma-derived MHBs as biologically interpretable units for organizing and integrating complementary methylation and fragmentomic information. This framework provides insight into the coupling of epigenetic and fragmentomic information and an effective strategy for ","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"18 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13675978/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149206795","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 nationwide prospective randomized trial for diagnosing developmental disorders demonstrates genome sequencing outperforms standard of care.","authors":"Mathilde Geysens, Erika Souche, Maria Chiara Baroni, Valérie Benoit, Tessi Beyltjens, Wouter Bossuyt, Vincent Bours, Marian Crabbé, Didier Croes, Matthias De Smet, Julie Désir, Koenraad Devriendt, Annelies Dheedene, Boyan Ivanov Dimitrov, Katrien Janssens, Candy Kumps, Aimé Lumaka, Björn Menten, Marije Meuwissen, Olivier Monestier, Geert Mortier, Catharina Olsen, Leonor Palmeira, Hilde Peeters, Laura Pölsler, Nicole Revencu, Dominique Roland, Julie Soblet, Yves Sznajer, Sylvia Taziaux, Hilde Van Esch, Geert Vandeweyer, Elise Vantroys, Catherline Vilain, Elsa Wiame, Kris Van Den Bogaert, Joris Robert Vermeesch","doi":"10.1186/s13073-026-01771-2","DOIUrl":"https://doi.org/10.1186/s13073-026-01771-2","url":null,"abstract":"<p><strong>Background: </strong>Exome (ES) or genome (GS) sequencing are recommended as first- or second-tier molecular tests for patients with developmental disorders (DD), but the clinical utility of GS continues to be debated.</p><p><strong>Methods: </strong>This prospective randomized trial involving all Belgian human genetics centers compared the standard of care (SoC) - combining ES and chromosomal microarray analysis or shallow GS - with GS for 567 individuals with unexplained DD. The study was retrospectively registered.</p><p><strong>Results: </strong>The diagnostic yield of GS was 39.8% (113/284) vs. 30% for SoC (85/283) (p = 0.015), mainly due to an increased detection of single nucleotide variants and indels (+ 8.7%). GS also enabled the detection of three non-coding (potential) pathogenic variants. Across both study arms, the diagnostic yield was higher for females (45.5%, 97/213) compared to males (28.5%, 101/354) (p < 0.001). Upon correction for the sex distribution and analytical differences between the study arms, the diagnostic yield difference between GS and SoC was reduced to 7.3% (p = 0.069). De novo variants were found for 23.6% of patients. Analysis of inherited variants in genes associated with autosomal dominant phenotypes contributed more to the diagnostic yield (3.9%) than X-linked variants (1.9%), and to a similar extent as autosomal recessive variants (4.1%).</p><p><strong>Conclusions: </strong>This nationwide study indicates GS outperforms SoC for the diagnosis of patients with DD in a decentralized hospital setting and well-characterized cohort. The results also highlight the importance of evaluating autosomal dominant inherited variants in genomics analyses for DD.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov (NCT07051213, 03-07-2025).</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"18 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13637178/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149108567","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":"Blood cell composition reveals distinct biological interpretation of DNA methylation age and age acceleration.","authors":"Thomas H Jonkman, Anne Richmond, Riccardo E Marioni, Erik W van Zwet, Bastiaan T Heijmans","doi":"10.1186/s13073-026-01751-6","DOIUrl":"https://doi.org/10.1186/s13073-026-01751-6","url":null,"abstract":"<p><strong>Background: </strong>Epigenetic clocks are widely applied biomarkers of biological age, but their biological underpinnings remain unclear. We previously showed that epigenetic clocks are affected by naïve and memory T cell proportions, suggesting blood cell composition as a potential driver. However, analysis of cell composition is complicated by collinearity between cell fractions.</p><p><strong>Methods: </strong>We first develop a principal component analysis (PCA) method that is robust to collinearity of blood cell counts and show that this approach provides biologically meaningful insights. Next, we quantify the contribution of cell composition to DNA methylation age and age acceleration estimated by six 1st - or 2nd -generation epigenetic clocks in an analysis of 4,058 samples. Finally, we test the influence of cell composition on the association between age acceleration and 176 incident health outcomes using a study of 18,859 individuals.</p><p><strong>Results: </strong>We find that up to 53% of the variation in DNA methylation age can be attributed to cell counts, with a particularly strong contribution of the balance between naïve and memory T cells. Associations between age acceleration and cell counts are weaker (up to 21% variance explained) and, for 2nd -generation clocks, primarily involve neutrophils. We validate the contribution of cell counts to epigenetic clocks using artificial cell mixtures. Interestingly, cell composition significantly attenuates the association of age acceleration investigated with 176 incident health outcomes, although this effect remains modest.</p><p><strong>Conclusions: </strong>DNAmAge and AgeAccel are markedly different in their associations with cell composition, indicating that they - at least in part - reflect different biological processes. Surprisingly, the variation in age acceleration that can be attributed to blood cell composition only has a minor contribution to its association with mortality and incident disease outcomes.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"18 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13632308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149107800","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":"Migration and tuberculosis transmission in Hamburg, Germany: insights from 25 years of molecular epidemiology.","authors":"Nicole Ullrich, Roland Diel, Karen Meywald-Walter, Christian Schwarzbach, Matthias I Gröschel, Martin Kuhns, Inna Friesen, Stefan Niemann, Viola Dreyer","doi":"10.1186/s13073-026-01750-7","DOIUrl":"10.1186/s13073-026-01750-7","url":null,"abstract":"<p><strong>Background: </strong>Tuberculosis (TB) epidemiology in low-incidence settings is increasingly influenced by the importation of Mycobacterium tuberculosis complex (Mtbc) strains from high-incidence regions. Globally, more virulent \"generalist\" lineages such as Lineage 2 (L2) and Lineage 4 (L4) contrast with geographically restricted \"specialist\" lineages (L1, L3, L5-L9), reflecting differences in transmissibility and adaptation. The introduction of strains of diverse lineages can alter local transmission dynamics and drug susceptibility patterns, underscoring the need for high-resolution genomic surveillance.</p><p><strong>Methods: </strong>We performed whole genome sequencing (WGS) on 3,131 Mtbc strains collected from patients with TB in Hamburg, Germany, over 25 years (1997-2021). We analysed population structure and transmission dynamics in relation to patients' self-reported geographical origins.</p><p><strong>Results: </strong>Strains from major Mtbc lineages L1-L6 and M. bovis were detected, with L4 strains being most prevalent (74.6%, n = 2,337). Lineage distribution shifted over time: L4 strains decreased from 83.5% in the first five years to 63.0% in the last five years, while L3 strains increased from 4.8% to 18.1%. These changes correlated with an increasing number of foreign-born patients rather than enhanced transmission of strains of specific lineages. L4 strains accounted for most clusters (81%, 218/269). In-depth analyses revealed heterogeneity in transmission potential among L4 sublineages, underscoring the importance of sublineage-level resolution. Strains of sublineages L4.1.2.1, L4.8, and L4.3 were detected in patients born in over 15 regions each, with >57% of cases from Europe, supporting their representation as globally successful generalist lineages.</p><p><strong>Conclusions: </strong>Migration substantially increased the genetic diversity of the Mtbc population in Hamburg but did not fundamentally alter local transmission dynamics. Transmission remained lineage-specific and was predominantly driven by established L4 strains, suggesting that successful transmission is mediated by locally adapted sublineages. Predominant L4.1.2.1 and L4.8 sublineages occurred in individuals from a wide range of countries, supporting the generalist-specialist hypothesis at the sublineage level. These findings highlight the interplay between pathogen characteristics and host demographics in shaping transmission and the value of integrating genomic, demographic, and epidemiological data to distinguish imported cases from sustained local transmission in low-incidence settings.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"18 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13595784/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149016809","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":"Uncovering pan-cancer signatures of chemoresistance.","authors":"Mohammed Inayatullah, Engin Demirdizen, Zachery Keepers, Catarina Mendes Correia, Seyyed Morteza Hashemi, Kaushlendra Tripathi, Souren Sadhukhan, Ishita Bardhan, Arun Mahesh, Feyruz V Rassool, Mikkel Green Terp, Hem D Shukla, Vijay K Tiwari","doi":"10.1186/s13073-026-01763-2","DOIUrl":"10.1186/s13073-026-01763-2","url":null,"abstract":"<p><strong>Background: </strong>Chemotherapy resistance remains a formidable challenge in cancer treatment, driving high mortality rates worldwide. Despite significant advancements, it remains unclear whether conserved molecular programs underpin therapy resistance across cancer types.</p><p><strong>Methods: </strong>Here, we integrate single-cell RNA sequencing, spatial transcriptomics, regulatory network modeling, transcription factor binding data, and pharmacologic perturbation across multiple cancer types to define a conserved, proliferative chemoresistant tumor state.</p><p><strong>Results: </strong>Contrary to the prevailing notion that resistance arises from quiescent or EMT-like phenotypes, we find that resistant tumor cells display elevated G2/M and S-phase activity, enriched expression of E2F and MYC target genes, and activation of DNA repair and PI3K/AKT signaling pathways. We identify the transcription factor MYC as a central regulator of the resistant state, with progressive activation along the resistance trajectory and focal expression in resistant epithelial niches. A novel MYC target, SRM (Spermidine Synthase), emerges as a conserved effector of resistance, promoting polyamine biosynthesis critical for chromatin stability and metabolic resilience. SRM expression correlates with MYC binding and predicts poor patient survival. Functional validation in cell lines, patient-derived organoids and mouse models demonstrate that pharmacologic inhibition of MYC, SRM, or WNT signalling restores chemotherapy sensitivity, suppresses resistance-associated pathways, and reactivates apoptosis. Spatial and survival analyses confirm the clinical relevance of the MYC-SRM axis, establishing it as a druggable module in treatment-refractory cancers.</p><p><strong>Conclusions: </strong>To our knowledge, this is the first comprehensive study that redefines chemoresistance as a proliferative, MYC-driven state and uncover SRM as a tractable vulnerability, offering new avenues for therapeutic intervention across diverse epithelial malignancies.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"18 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13625386/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149080583","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":"Machine learning identifies microbiome and clinical predictors of sustained weight loss following prolonged fasting.","authors":"Gelsomina Kaufhold, Theda U P Bartolomaeus, Kristin Schütte, Till Schütte, Sakshi Kamboj, Ulrike Löber, Gabriele Rahn, Victoria McParland, Lena Braun, Lajos Markó, Matanat Mammadli, Alexander Krannich, Lina S Bahr, Friederike Gutmann, Friedemann Paul, Quinten R Ducarmon, Georg Zeller, Robin Mesnage, Nicola Wilck, Alma Zernecke, Peter J Oefner, Wolfram Gronwald, Dominik N Müller, Sofia K Forslund-Startceva, Sylvia Bähring, Hendrik Bartolomaeus, Nadja Siebert","doi":"10.1186/s13073-026-01765-0","DOIUrl":"10.1186/s13073-026-01765-0","url":null,"abstract":"<p><strong>Background: </strong>Prolonged fasting may improve metabolic health, but controlled data in healthy adults with longer follow-up and multi-omics profiling are limited. We investigated the immediate and 12-week follow-up effects of a 5-day fasting intervention on body composition, gut microbiome, and circulating and fecal metabolites, and assessed whether baseline characteristics predict individual weight-loss response.</p><p><strong>Methods: </strong>In a randomized, waitlist-controlled trial, 38 healthy adults completed a 5-day fasting intervention with 12-week follow-up (LEANER study). Outcomes included body mass index and body composition, gut microbiome composition, and plasma and fecal metabolites. Changes over time and between groups were evaluated using regression-based models and paired non-parametric tests, as appropriate. Additionally, permutation-based multivariate testing was performed on microbiome and metabolome data. Twelve-week body weight response was predicted using data-driven machine learning with cross-validation, followed by external validation in three independent cohorts undergoing prolonged fasting protocols.</p><p><strong>Results: </strong>Fasting reduced body mass index acutely, predominantly driven by loss of fat mass, and these improvements partially persisted at 12 weeks. Fasting induced marked shifts in gut microbiome composition and in plasma and fecal metabolites. Post-fasting and longer-term changes in microbial diversity were associated with baseline microbiome diversity. A model combining baseline microbiome and clinical variables predicted body mass index response at 12 weeks; prominent predictors included an unclassified Faecalibacterium species, Oscillibacter sp. 50_27, low-density lipoprotein cholesterol, and systolic blood pressure. The model generalized to three independent cohorts, including individuals with metabolic syndrome, patients with multiple sclerosis exposed to repeated fasting, and healthy volunteers fasting for 6-12 days.</p><p><strong>Conclusions: </strong>In healthy adults, a 5-day prolonged fasting intervention produces robust short-term metabolic changes with partial persistence and consistent remodeling of the gut microbiome and metabolite profiles. Baseline microbiome and clinical characteristics can help stratify expected longer-term responses, supporting the development of individualized fasting-based interventions.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov, NCT04452916. Prospectively registered on June 29, 2020.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"18 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13587497/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148989337","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":"Accurate characterization of CRISPR-Cas9 genome editing outcomes and mosaicism with near-perfect long reads.","authors":"Ida Höijer, Robin van Schendel, Anastasia Emmanouilidou, Rebecka Östlund, Ignas Bunikis, Marcel Tijsterman, Marcel den Hoed, Adam Ameur","doi":"10.1186/s13073-026-01772-1","DOIUrl":"10.1186/s13073-026-01772-1","url":null,"abstract":"<p><strong>Background: </strong>Genetic mosaicism is a well-recognized consequence of CRISPR-Cas9 genome editing, yet its characterization remains challenging, especially when it involves low-frequency structural variants. A comprehensive analysis of mosaicism requires deep and unbiased sequencing of the target loci, with accurate single-molecule reads.</p><p><strong>Methods: </strong>We performed amplification-free PureTarget PacBio sequencing to investigate CRISPR-Cas9 outcomes at on-target and off-target sites in genome edited zebrafish and their offspring. CRISPR-Cas9 genome editing was performed by micro-injection in fertilized eggs at the single-cell stage.</p><p><strong>Results: </strong>Thirty samples from pooled larvae and individual zebrafish were successfully sequenced, resulting in > 1100x average target coverage. The PacBio reads reached an exceptional accuracy (QV39) over the target regions, with every read originating from a unique DNA molecule. The two haplotypes of the target loci displayed a balanced depth of coverage, while long-range PCR of the same samples resulted in skewed data. Further analysis of the PureTarget data revealed widespread genetic mosaicism in individual founder (F0) fish, with up to 18 distinct on-target events and 11 off-target events present in a single adult founder. Several CRISPR-Cas9 editing outcomes, including large structural variants and off-target mutations, were inherited to the F1 generation. Notably, as many as seven unique editing events were found among sibling F1 juvenile offspring derived from a single founder pair, thereby confirming the presence of genetic mosaicism in germ cells of founder zebrafish. This implies that some consequences of CRISPR-Cas9 editing may emerge only in the second generation. We also analyzed DNA methylation signals in the PureTarget data but did not observe altered 5mC CpG levels in genome edited samples.</p><p><strong>Conclusions: </strong>PureTarget enables efficient, accurate, and unbiased profiling of genetic mosaicism and DNA methylation at pre-defined genomic regions. Our results show that CRISPR-Cas9-induced mosaicism is widespread and represents an important factor to consider in genome editing experiments.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"18 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13587479/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148988945","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 reusable model of pangenome selection informs optimal surveillance strategies over vaccine introductions.","authors":"Leonie J Lorenz, Joel Hellewell, Samuel T Horsfield, Matthew J Russell, Shrijana Shrestha, Andrew J Pollard, Stephen D Bentley, Stephanie W Lo, Caroline Colijn, Nicholas J Croucher, John A Lees","doi":"10.1186/s13073-026-01672-4","DOIUrl":"10.1186/s13073-026-01672-4","url":null,"abstract":"<p><strong>Background: </strong>The human pathogen Streptococcus pneumoniae is a major cause of disease, including pneumonia and meningitis. The introduction of Pneumococcal Conjugate Vaccines (PCVs) initially reduced the burden of disease through a reduction of colonisation by vaccine-targeted serotypes. However, since PCVs only target a proportion of pneumococcal serotypes, they shift intraspecific competition, eventually allowing non-targeted types to 'replace' vaccine types. Understanding the host and pathogen factors causing replacement is important for future vaccine development. Mechanistic understanding of vaccine replacement dynamics is crucial for forecasting and optimisation of genomic surveillance strategies to evaluate realised vaccine effectiveness.</p><p><strong>Methods: </strong>We developed a mathematical model of the genomic and demographic factors which explain vaccine replacement, used this model to replicate serotype-frequency changes, and investigated cost-effective genomic surveillance strategies. We extended a forward-time model based on the Wright-Fisher model, developing a user-friendly model framework that describes the post-vaccine dynamics of S. pneumoniae populations. Our model describes vaccine replacement as a function of vaccine impact, immigration of new strains, and negative frequency-dependent selection (NFDS) on the accessory genome content.</p><p><strong>Results: </strong>We used our model to study vaccine replacement in newly sequenced genomic surveillance data from Kathmandu (Nepal), and existing data from Massachusetts (US) and Southampton (UK), with distinct surveillance strategies. We showed that the model with NFDS better replicates replacement dynamics than a null model without NFDS, and that NFDS likely only acts on part of the S. pneumoniae accessory genome. We found consistent estimates for vaccination effectiveness across the different study locations and region-specific genes under NFDS, highlighting the importance of conducting genomic surveillance in each country of interest. By simulating data from the model, we showed that an optimal surveillance strategy prioritises per-sampling sample size over sampling frequency for small sampling budgets.</p><p><strong>Conclusions: </strong>Our model can be used to predict vaccine replacement dynamics after PCV introduction, and can be easily reapplied to analyse new data from vaccine introductions or new regions. Our model is available in the R package Stubentiger (Studying Balancing Evolution (NFDS) To Investigate Genome Replacement) on GitHub https://github.com/bacpop/Stubentiger .</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"18 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13551875/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148906091","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":"Pangenomes aid accurate detection of large insertions and deletions from targeted sequencing: the case of cardiomyopathies.","authors":"Francesco Mazzarotto, Özem Kalay, Elif Arslan, Valeria Cinquina, Rachel J Buchan, Valeria Bertini, Esmé Cavanagh, Deniz Turgut, Mona Allouba, Alaa Afify, Sarah Halawa, Pantazis Theotokis, Gungor Budak, Francesca Girolami, Alessia Azzu, Petra Peldova, Nik Matthews, Dudley J Pennell, Jiri Bonaventura, Iacopo Olivotto, Elisabetta Pelo, Marina Colombi, Milan Macek, Paul J R Barton, Yasmine Aguib, Magdi Yacoub, Marco Ritelli, Massimo Gennarelli, H Serhat Tetikol, Roddy Walsh, James S Ware, Amit Jain","doi":"10.1186/s13073-026-01749-0","DOIUrl":"10.1186/s13073-026-01749-0","url":null,"abstract":"<p><strong>Background: </strong>Gene panels represent a widely used strategy for genetic testing in a vast range of Mendelian disorders. While this approach aids reliable bioinformatic detection of short coding variants, it often fails to detect many larger variants. Recent studies have recommended the adoption of pangenome references (as opposed to linear reference genomes like GRCh38) to augment detection of large variants from targeted sequencing, potentially providing diagnostic laboratories with the possibility to streamline diagnostic work-ups and reduce costs.</p><p><strong>Methods: </strong>Here, we analyze 1969 cardiomyopathy cases and 1805 controls sequenced with the Illumina Trusight Cardio panel using a pangenome-based workflow (GRAF) and five conventional orthogonal methodologies (GATK HaplotypeCaller, GATK-gCNV, ExomeDepth, Manta and Lumpy-SV) to detect variants ≥ 20 bp in size.</p><p><strong>Results: </strong>Following lab-based variant validation by means of PCR and Sanger sequencing, we show that GRAF conjugates higher precision and recall (F1 score 0.86) compared with other methods (F1 0-0.57) in detecting potentially pathogenic variants ≥ 20 bp from short-read panel data. Results were complemented by a comparison of the tools' performance in detecting ground truth variants on reference sample HG002 from Genome In A Bottle, which confirmed GRAF to outperform other tools also on exome sequencing (F1 0.97 vs. 0-0.94). Notably, in the HG002 benchmark dataset, GRAF also showed slightly improved performance compared to GATK HaplotypeCaller in the identification of small variants (1-19 bp; F1 0.975 vs. 0.968).</p><p><strong>Conclusions: </strong>Our results indicate that pangenome-based workflows aid improved detection of large variants from targeted sequencing data in the clinical context and suggest that they may contribute to more unified variant detection frameworks for all-size genetic variants in the future.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"18 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13563831/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148929711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The clinical and molecular spectrum of AGO2-associated Lessel-Kreienkamp neurodevelopmental syndrome.","authors":"Debora Tibbe, Christina Kiel, Olena Ielesicheva, Kerstin Robles de Maruri, Helia Mahboobi, Joschka Züghart, Hans-Hinrich Hönck, Christoph Meier, Fabiola Biasella, Marcela Legüe, María Francisca Lopez Avaria, Edward Blair, Tracy Lester, Benito Banos-Pinero, Jose S Pulido, Adele Schneider, Rebecca Procopio, Chloe Quelin, Bailey J Leal, Julian A Martinez-Agosto, Stephanie A Bottomley, Ágnes Till, Kinga Hadzsiev, Renata Szalai, Kathryn Nicole Weaver, Joel Fluss, Henri Margot, Berta Almoguera, Isabel Lorda-Sánchez, Lucía López-López, J Austin Hamm, Himanshu Goel, Yasemin Alanay, Ozlem Akgun Doğan, Gulşah Şebnem Ozkose-Iyigel, Genevieve Baujat, Marion Lesieur-Sebellin, Sophie Rondeau, Katherine Schon, Joseph Christopher, Bertrand Isidor, Benjamin Cogne, Neena S Agrawal, Ryan Dahlhauser, Yutaka Furuta, Rachel Rabin, John Pappas, Chirag Patel, Irma Järvelä, Merja Rauhala, Isabelle Schrauwen, Suzanne M Leal, Siddharth Banka, Riya Tharakan, Céline Pebrel-Richard, Fanny Laffargue, Nelly Durand, Tristan Celse, Maja Hempel, Ilia Valentin, Andrea Gregorova, Lenka Noskova, Sara Baumgartner, Christa Überbacher, Kai Muru, Ülle Murumets, Stella Lilles, Katharina Steindl, Anita Rauch, Federica Ruscitti, Alain Verloes, Jonathan Levy, Joohyun Park, Tobias B Haack, Ingrid Bader, Sophie Julia, Guillaume Banneau, Alison M Muir, Davor Lessel, Hans-Jürgen Kreienkamp","doi":"10.1186/s13073-026-01745-4","DOIUrl":"10.1186/s13073-026-01745-4","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Pathogenic variants in AGO2, encoding a central component of the RNA-induced silencing complex (RISC), cause the neurodevelopmental disorder Lessel-Kreienkamp syndrome (LESKRES). The variant spectrum and associated molecular mechanisms underlying phenotypic variability and disease severity remain incompletely understood.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We investigated 45 newly identified individuals carrying 33 distinct AGO2 variants, 30 of which were previously unreported. Phenotypic data from these and previously reported cases (n = 70) were integrated to delineate the LESKRES-associated clinical spectrum and genotype-phenotype correlations. Functional studies included shRNA-based silencing, co-immunoprecipitation, subcellular localization, and sequencing of AGO2-bound miRNAs.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;All individuals presented with a neurodevelopmental disorder of variable severity. Delayed speech and language development (97%), intellectual disability (97%), and motor delay (93%) were the most consistent features, frequently accompanied by muscular hypotonia, autistic traits, attention deficit hyperactivity disorder, visual impairment and structural brain anomalies. Systemic manifestations, including skeletal, craniofacial, cardiac, and male urogenital anomalies were common, underscoring AGO2's multisystemic role. Moreover, we report occurrence of gonadal mosaicism and reveal the presence of interfamilial and variant-specific clinical heterogeneity. Variants clustered in defined regions of AGO2, including the L1 loop, helix-7, and multiple loops of the PIWI domain, highlight structural hotspots critical for RISC activity. Not all pathogenic variants impaired shRNA-mediated silencing; this was restricted to p.(Arg714Trp) and p.(Asn729His). Biochemical analyses revealed that p.(Asp619Asn) impaired GW182 binding and P-body assembly. Variants p.(Arg506Gln), p.(Glu531Gln) p.(Gly604Arg) and p.(Asp619Asn), reduced C-terminal phosphorylation, implicating defective AGO2 recycling. AGO2-miRNA co-immunoprecipitation and sequencing demonstrated variant-specific perturbations in miRNA association, strand selectivity, and isomiR generation. Variants near the hinge of the helix-7 region, especially p.(Phe182del), induced extensive changes in miRNA association and 3'-end modification, suggesting impaired anchoring within the miRNA-binding pocket.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Our findings substantially broaden the clinical and molecular landscape of LESKRES, establishing AGO2 as a pivotal regulator of neurodevelopment whose structural integrity is essential for precise miRNA-mediated gene regulation. Pathogenic variants disrupt distinct interconnected processes: P-body association, phosphorylation-dependent turnover, and miRNA interactions, culminating in dysregulated post-transcriptional gene silencing. These mechanistic insights link specific structural perturbations in AGO2 to graded clinical outcomes and unders","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"18 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13501643/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148812917","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}