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PubMed2026

Strategies for mosaic variant calling in brain disorders.

The human brain is a genomic mosaic, where postzygotic mutations arising from embryogenesis to senescence drive diverse neurodevelopmental and neurodegenerative diseases. Because of numerous sequencing artifacts at ultralow variant allele frequencies (VAFs), detecting these variants remains a significant analytical challenge. This review focuses on single-nucleotide variants and small indels, summarizing current strategies for aligning sampling methods, including bulk, laser capture microdissection, and single-cell genomics, with the expected clonal architecture of the brain. It emphasizes that mosaic detection sensitivity is fundamentally constrained by sequencing depth, since even the most advanced algorithms cannot identify variants not physically represented in the sequencing library. The review further recommends the selection of variant calling algorithms based on validated VAF detection performance, matching tools like MuTect2 and MosaicForecast to their optimal performance ranges. Furthermore, we discuss how multitissue sampling, as emphasized by the SMaHT project, addresses the matched-control dilemma and supports accurate variant classification via cross-tissue VAF gradients. Integrating these established pipelines with multiomics modalities, including transcriptomic and epigenetic data, could advance the field toward a functional understanding of how the somatic genome impacts human brain health and disease.

Humans↗
PubMed2026

Safe and Stable Germline Transmission of MSTN Mutations in Cattle.

With the global population expected to reach 10 billion by 2050, sustainable livestock production is critical. Gene editing of the myostatin (MSTN) gene represents a promising strategy to enhance muscle growth in cattle. In this study, MSTN-mutated founder (F0) cows were used to generate F1 offspring via ovum pick-up, in vitro fertilization, and embryo transfer. Four F1 calves were born, all confirmed to be heterozygous for the MSTN mutation. Long-term monitoring showed normal growth and no visible health abnormalities. Whole-genome sequencing identified SNPs, INDELs, and structural variants, most with minimal predicted functional effects. Proteomic profiling of Longissimus dorsi muscle quantified 2947 proteins, revealing only subtle expression differences between MSTN-mutated and wild-type cattle. These results demonstrate stable inheritance and confirm that MSTN editing does not disrupt genome integrity or protein expression. Overall, our findings support the safety and utility of MSTN gene editing to improve livestock productivity for future food security.

Animals↗
PubMed2026

Somatic mutations: recent advances in brain aging and neurodegeneration.

Somatic mutations are genetic variants that occur after the single-cell phase of development and have been implicated in disease pathogenesis. While most DNA lesions are detected and repaired, examination of healthy tissue has revealed that some lesions escape repair, leading to somatic mutations that accumulate at a consistent rate, including in human brain tissue and postmitotic neurons. Emerging methodological and analytical advances have revealed the presence of persistent mutagenic mechanisms during healthy brain aging as well as mutational pattern shifts in the context of neurodegenerative diseases. Here, we highlight recent methodological advances, summarize our current understanding of somatic mutagenesis in neurotypical brain aging, and examine the role of somatic mutations in neurodegenerative diseases.

Humans↗
PubMed2026

O'nyong-nyong virus adaptive mutations in non-structural protein 1 and 3 enhance RNA replication and overcome FHL1 requirement.

Arthritogenic alphaviruses, like o'nyong-nyong virus (ONNV), cause debilitating musculoskeletal diseases and are geographically expanding. To predict their emergence, we seek to better understand evolutionary mechanisms that enable changes in virus tropism. Here, we identify adaptive mutations in the ONNV non-structural proteins (nsPs) that arose during cellular serial passaging and enabled ONNV to infect non-permissive Lunet cells. Using shotgun proteomics, we show that this human hepatoma cell line lacks the four-and-a-half-LIM domain protein 1 (FHL1), an essential host factor in ONNV RNA replication. Individual single nucleotide mutations in the nsP1 ring-aperture membrane-binding and oligomerization domain, the nsP3 macrodomain, and the nsP3 opal stop codon overcome FHL1 deficiency in Lunet cells by enhanced RNA replication. These findings demonstrate how subtle genomic changes in nsPs can profoundly influence alphavirus replication and tropism.

LIM Domain Proteins↗
PubMed2026

Seventeen-year follow-up of hypophosphatasia diagnosed in middle-aged siblings harboring a novel intronic and a rare missense ALPL gene mutation.

Hypophosphatasia (HPP) is the rare inborn-error-of-metabolism that features impaired mineralization of the skeleton and teeth due to a deactivating mutation or mutations of the gene ALPL which encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). We report 17-year follow-up of twin sisters and a brother referred in middle-age for painful proximal femoral "stress fractures" and then diagnosed with HPP. They reported generalized muscle and bone pain, metatarsal fractures, arthropathy and, since childhood, tooth loss. Their concordant findings were explained by compound heterozygosity in ALPL for a rare maternal missense mutation (c.1403C > T, p.Ala468Val) in exon 12, together with a novel presumably paternal change (c.863-14G > A) predicting a cryptic mRNA splice site in intron 8. Fractures continued during follow-up until one sister received a three-and-one-half-year course of hydroxyapatite-targeted TNSALP supplementation therapy (asfotase alfa) during which substantial improvement occurred in her clinical, biochemical, and functional parameters as well as quality of life. Following subsequent unplanned treatment cessation she suffered significant clinical deterioration, including new fractures and loss of mobility. Her bone histopathology documented osteomalacia. Treatment resumption restored its benefits. Among ten asymptomatic family members evaluated in this four-generation kindred, eight were carriers heterozygous for either ALPL mutation. Those harboring the maternal missense defect manifested mild hypophosphatasemia, suggesting a dominant-negative mutation effect. This experience underscores the importance of in-depth phenotyping and then clinical follow-up to characterize ALPL variant combinations, and for maintaining effective asfotase alfa treatment.

Humans↗
PubMed2026

Frequent mutations in the BIRC3 gene promote metastatic potential of nasopharyngeal carcinoma cells through the TRAF2-NF-κB pathway.

Nasopharyngeal carcinoma (NPC) is a head and neck cancer characterized by highly locoregionally invasive behavior attributable to the latent infection with Epstein-Barr virus (EBV) and genomic instability. It is well established that EBV-encoded oncogenic molecules actively contribute to the malignant behavior of NPC cells. However, the mechanism by which aberrant genomic alterations enable NPC cells to become aggressive remains largely unknown. In the present study, whole-exome sequencing (WES) revealed that the gene encoding the baculoviral IAP repeat-containing 3 (BIRC3) protein was frequently mutated in circulating tumor cells (CTCs) but not in paired primary tumor cells from patients with metastatic NPC. A minigene assay indicated that the c.637 A > G mutation disrupted normal mRNA splicing, resulting in the partial deletion of Exons 2 and 3 and altered stability of BIRC3 mRNA. In vitro experiments demonstrated that ectopic expression of the BIRC3c.637A>G mutant enhanced NPC cell invasive properties, including proliferation, resistance to apoptosis, migration, and invasion. Furthermore, overexpression of wild-type BIRC3 promoted invasive characteristics in NPC cells through the TRAF2-NF-κB signaling axis. In summary, BIRC3 acts as a regulator of the malignant features of NPC cells. Frequent BIRC3 mutations in CTCs, such as the c.637 A > G mutation, further enhance the metastatic potential of disseminated NPC cells by inducing aberrant alternative splicing. These findings suggest the therapeutic feasibility of targeting the BIRC3/TRAF2/NF-κB axis in the treatment of NPC.

Humans↗
PubMed2026

Molecular Landscape and Advanced Diagnostic Technologies for BRAF Mutations in Cancer: From Quantitative PCR and ddPCR to CRISPR-Based Platforms.

BRAF mutations are key oncogenic alterations across multiple malignancies, including melanoma, thyroid carcinoma, colorectal cancer, non-small cell lung cancer, glioma, and hairy cell leukemia. The most prevalent variant, BRAF-V600E, induces constitutive activation of the MAPK signaling pathway, promoting tumor progression and influencing therapeutic responsiveness. Accurate detection of BRAF alterations is therefore essential for molecular classification, prognostic assessment, treatment selection, and resistance surveillance. This review summarizes the molecular heterogeneity of BRAF mutations and critically evaluates current diagnostic methodologies. Conventional approaches such as allele-specific PCR and Sanger sequencing are compared with advanced quantitative platforms, including high-resolution melting analysis, droplet digital PCR, and next-generation sequencing, with emphasis on analytical sensitivity, mutation coverage, and clinical applicability. Emerging technologies such as CRISPR-based assays, rolling circle amplification systems, and nanoparticle-based biosensors and point-of-care diagnostic platforms are also discussed for their potential to enhance ultra-sensitive detection, particularly in liquid biopsy settings. These emerging tools are highlighted for their potential to enable ultra-sensitive, rapid, and decentralized mutation detection, particularly in liquid biopsy settings. Key challenges, including intratumoral heterogeneity, low allele-frequency variants, FFPE-associated artifacts, and clonal evolution under therapeutic pressure, are examined within a translational framework. In addition, we examine critical barriers to clinical implementation, including standardization, cost, and global accessibility of molecular diagnostics, and outline potential solutions through scalable technologies and decentralized testing strategies. We propose that optimal BRAF testing requires a mutation subclass-informed and clinically integrated strategy combining comprehensive baseline profiling with longitudinal molecular monitoring. Future diagnostic paradigms will likely integrate multi-omics data and artificial intelligence (AI)-assisted interpretation to refine precision oncology implementation. Looking forward, we propose that optimal BRAF testing will require integration of multi-omics profiling with AI-assisted interpretation, enabling automated variant classification, real-time clinical decision support, and improved prediction of therapeutic response and resistance.

Humans↗
PubMed2026

Temporal shifts in gyrA mutation types and sublineage replacement in ST11 Salmonella enterica serovar Enteritidis over a decade (2014-2023): A genomic epidemiological study in Guangxi, China.

The overuse or abuse of antibiotics drives the global health threat of antimicrobial resistance. Although bans on certain veterinary antibiotics, such as colistin, have proven effective, the impact of fluoroquinolone stewardship on the evolution of the foodborne pathogen Salmonella enterica serovar Enteritidis (S. Enteritidis) remains unclear. Here, we conducted a decade-long (2014-2023) retrospective longitudinal genomic epidemiological analysis of 441 ST11 S. Enteritidis isolates from Guangxi, China, alongside a global reference dataset of 4297 genomes. Our aim was to elucidate the effect of real-world antibiotic stewardship on the shift of gyrA point mutations and lineage distribution. Surveillance identified three global epidemic clade sublineages (GEC-L2, L3, L4), with the multidrug-resistant GEC-L4 (i.e., GC-c or MMC2), characterized by the gyrA mutation with amino acid substitution D87Y, being domestically dominant (70.07%, 309/441). Following China's 2016 ban on the veterinary use of critical fluoroquinolones, the proportion of the highly resistant GEC-L4 sublineage decreased continuously (from 86.84% in 2017 to 56.00% in 2023), while the less resistant GEC-L3 sublineage (i.e., GC-b or MMC1), mainly characterized by gyrA D87G, increased simultaneously (from 13.16% to 44.00%). This phenomenon might be attributed to the fact that the GEC-L4 sublineage exhibited a higher fitness cost compared with the GEC-L3 sublineage, as confirmed by the competition assay. A Random Forest Model validated that the gyrA mutation with amino acid substitution D87Y was the paramount feature for these sublineages' identification. In contrast, global data showed a continuous increase in gyrA mutations (from 8.63% in 2006 to 68.85% in 2024), primarily D87Y (from 1.44% to 31.15%) and D87N (from 4.32% to 22.95%), correlating with rising average fluoroquinolone consumption. This study provides direct genomic evidence that national-level antibiotic stewardship can drive the replacement of highly resistant sublineages with moderately resistant ones. These findings offer crucial scientific evidence for evaluating the impact of antibiotic management policies and inform strategies for the rational use of antimicrobials.

China↗
PubMed2026

Targeted sequencing reveals a distinct genetic alteration landscape in oral multiple primary squamous cell carcinomas.

OBJECTIVE: Oral multiple primary cancers (MPCs) are associated with poor clinical outcomes, yet their genomic characteristics remain insufficiently understood. DESIGN: Fifty-four formalin-fixed paraffin-embedded (FFPE) tumor samples from 30 patients with oral MPCs were analyzed using high-depth targeted sequencing of a customized 14-gene panel derived from prior whole-exome sequencing data. Detected alterations were analyzed after removal of synonymous mutations. RESULTS: Non-silent genomic alterations were identified in 59.3% (32/54) of samples, involving 19 patients. A total of 70 variant loci across 13 genes were detected. AKAP13 was the most frequently mutated gene at both the sample (22.2%, 12/54), with recurrent mutations observed across multiple patients. In contrast, TP53 mutations occurred at a substantially lower frequency (11.1%, 6/54). Marked inter- and intra-patient mutational heterogeneity was observed. CONCLUSIONS: FFPE-based targeted sequencing enabled an initial characterization of genomic alterations in oral MPCs. Recurrent alterations in AKAP13, GLI2, JMJD1C, and DNAH8, together with the relatively low frequency of TP53 alterations, identify candidate genomic features for further investigation and provide a basis for future studies of the molecular basis of oral MPCs.

Humans↗
PubMed2026

Azithromycin-resistant Salmonella enterica Typhi with AcrB R717L/Q mutations in the United States.

BACKGROUND AND OBJECTIVES: Azithromycin is a critical oral treatment for typhoid fever caused by Salmonella enterica serovar Typhi (Salmonella Typhi), since XDR has rendered other first-line treatment options ineffective. Azithromycin resistance conferred by amino acid changes in AcrB, an AcrAB-TolC efflux pump component, represents an emerging public health concern. Leveraging phenotypic and genotypic data from U.S. Salmonella Typhi surveillance systems, this study describes the prevalence, phenotype and genomic epidemiology of Salmonella Typhi with AcrB mutations in U.S. patients since the first detection in 2015. METHODS: AST and WGS data of >3000 Salmonella Typhi isolates were used to identify all cases with an AcrB mutation in the United States (2015-2025). We calculated annual prevalence and MIC ranges. Phylogenetic analysis was used to contextualize U.S. cases of Salmonella Typhi with an AcrB mutation within all globally reported cases. RESULTS: While the prevalence of AcrB mutations in the United States is low (1.5%), it has risen significantly in recent years, from 0.2% in 2016-2022 to 2.2% in 2023-2025. This increase is predominantly driven by clonal expansion of existing strains circulating in South Asia. AcrB mutations do not reliably confer resistance to azithromycin (MIC ≥ 32 mg/L), complicating clinical interpretation. CONCLUSIONS: The prevalence of AcrB mutations in Salmonella Typhi is increasing in the United States, and likely globally, given that U.S. data function as an informal proxy for regions without routine surveillance infrastructure. Clinical outcomes data are needed to inform Salmonella Typhi treatment guidelines and potentially amend clinical breakpoints for azithromycin.

Journal Article↗
PubMed2026

Clinical and genetic features of Ph-negative myeloproliferative neoplasms with dual-driver gene positivity.

OBJECTIVES: To investigate the clinical laboratory characteristics and gene mutation features of dual-driver gene positivity in patients with Philadelphia chromosome-negative myeloproliferative neoplasm (Ph-negative MPN). METHODS: We conducted a retrospective analysis of clinical data and genetic test results from 203 newly diagnosed patients with Ph-negative MPN. Of these, 194 had single-driver gene positivity and 9 had dual-driver gene positivity. High-throughput sequencing was used to detect mutations in JAK2, CALR, and MPL. Clinical characteristics and gene mutation profiles were compared between the two patient groups. RESULTS: The incidence of dual-driver gene positivity was 4.4% (9/203), with the most common combinations being JAK2 with CALR (4 patients) and JAK2 with MPL (4 patients). Compared with the single-driver group, the dual-driver group had a significantly higher risk of bleeding [4.1% (8/194) vs. 33.3% (3/9), P = 0.008] and a higher proportion of uncommon mutations [3.6% (7/194) vs. 33.3% (3/9), P = 0.006]. No statistically significant differences were observed between the two groups regarding age, thrombosis incidence, splenomegaly, or routine blood test indicators. During follow-up, 1 patient in the dual-driver group died from cerebrovascular disease. No leukaemia transformation or disease-related deaths occurred among the remaining patients. DISCUSSION: The increased bleeding risk in dual-driver patients may be related to a higher proportion of CALR mutations, elevated platelet counts, and higher variant allele frequencies, though these findings require validation in larger cohorts due to the small sample size. The higher prevalence of uncommon mutations suggests a more complex mutational landscape in this subgroup. CONCLUSION: Patients with Ph-negative MPN and dual-driver gene positivity may have a higher risk of bleeding and a more complex gene mutation profile.

Humans↗
PubMed2026

Osimertinib With or Without Chemotherapy in Advanced Non-Small Cell Lung Cancer With EGFR and Concurrent TP53 Mutations: A Randomized Clinical Trial.

IMPORTANCE: Combination therapy has emerged as a promising therapeutic approach for patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, its clinical benefit-risk profile remains a focus of ongoing debate. Identifying patients most likely to derive benefit from such regimens remains an unmet clinical need. OBJECTIVE: To prospectively compare the efficacy and safety of first-line osimertinib plus chemotherapy with osimertinib monotherapy for patients with EGFR-mutated advanced NSCLC harboring concurrent TP53 mutations. DESIGN, SETTING, AND PARTICIPANTS: A multicenter, randomized, open-label, phase 3 study conducted at 17 sites in China. Between March 25, 2021, and July 11, 2024, a total of 294 eligible patients with treatment-naive, stage IV or recurrent nonsquamous NSCLC harboring concurrent TP53 and EGFR-sensitizing mutations were enrolled. INTERVENTIONS: Patients were randomized (1:1) to receive osimertinib plus chemotherapy (pemetrexed and carboplatin every 3 weeks for 4 cycles, followed by maintenance therapy of osimertinib plus pemetrexed; n&#x2009;=&#x2009;146) or osimertinib monotherapy (n&#x2009;=&#x2009;148). MAIN OUTCOMES AND MEASURES: The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, response, safety, and quality of life. RESULTS: Among 294 enrolled patients, the median age was 57 years (range, 26-79 years), and 159 (54.1%) were female. The data cutoff date was November 11, 2025. At a median follow-up of 25.1 months for the osimertinib-chemotherapy group and 26.1 months for the osimertinib monotherapy group, median progression-free survival was significantly longer with osimertinib plus chemotherapy than with osimertinib monotherapy (34.0 vs 15.6 months; difference, 18.4 months [95% CI, 9.9-22.3]; hazard ratio, 0.44 [95% CI, 0.32-0.60]; P&#x2009;<&#x2009;.001). This benefit was consistent across prespecified subgroups, including those with brain metastases and L858R mutations. The overall survival data remained immature (30.6% maturity); however, a trend toward overall survival benefit with combination therapy was observed. The incidence of grade 3 or higher treatment-related adverse events was higher in the combination group, with no new safety signal identified. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, osimertinib plus chemotherapy significantly increased progression-free survival among patients with EGFR-mutated advanced NSCLC harboring concurrent TP53 mutations. These findings provided a clinical rationale for individualized combination strategies in the management of patients with EGFR-mutated NSCLC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04695925.

Adult↗
PubMed2026

Systematic review of the mutations in the active antigenic site &#xd8; of the prefusion F protein of the Respiratory Syncytial Virus (RSV) following the implementation of monoclonal antibody prophylaxis.

BACKGROUND: Monoclonal antibody (mAb) nirsevimab, which targets the antigenic site &#xd8; of the prefusion F protein (pre-F) of RSV, was introduced for RSV prophylaxis in several countries. METHODS: A systematic search was conducted between January 1, 2022, and July 31, 2026 for studies analyzing substitutions within the epitope of pre-F RSV protein, which is the target of nirsevimab, after the implementation of the mAb. We searched across PubMed, Scopus, Web of Science and ClinicalTrial.gov for studies involving children with confirmed RSV infection, that conducted genomic analysis. RESULTS: Seven studies (five observational and two randomized controlled trials) including 2156 RSV-positive samples (RSV-A: 1347, RSV-B: 809) were analyzed. RSV-A strains showed limited variability within antigenic site &#xd8;, with K65R being the most common substitution and K209E being the only intermediate-resistance RSV-A substitution. RSV-B strains demonstrated substantially higher substitution frequencies, particularly involving I206M, Q209R, and S211N. Most identified substitutions appeared to represent naturally occurring polymorphisms and retained susceptibility to nirsevimab, while multiple RSV-B substitutions and combinations involving residues 64-68 and 204-208 demonstrated reduced susceptibility or high-level resistance. Resistance-associated variants were detected in 28 of 2156 (1.3%) RSV-positive samples and exclusively among nirsevimab breakthrough infections. In a sub-analysis restricted to nirsevimab-treated individuals, resistance-associated variants were significantly more frequent among RSV-B than RSV-A (9.8% vs 0.5%; p&#xa0;<&#xa0;0.001). CONCLUSION: Most substitutions that were detected within the nirsevimab antigenic site reflect ongoing natural RSV evolution and do not significantly affect nirsevimab susceptibility. However, detection of resistance-associated variants highlights the importance of continuous genomic and phenotypic surveillance.

Humans↗
PubMed2026

Gene-environment interaction between perinatal oxytocin exposure and Pten mutation shapes epigenetic reprogramming of oxytocin signaling and behavior in mice.

Synthetic oxytocin (Pitocin) is the most commonly used pharmacologic agent for induction and augmentation of labor. Beyond its uterotonic effects, oxytocin plays a critical role in neurodevelopment and social behavior. Dysregulated oxytocin signaling has been implicated in autism spectrum disorder (ASD), raising concern that perinatal exposure to exogenous oxytocin may have lasting neurodevelopmental consequences. This study aimed to determine whether offspring harboring a genetic predisposition for ASD are differentially impacted by perinatal oxytocin exposures, with a focus on long-term oxytocin signaling and autism-like behavior. Pregnant mice carrying offspring with heterozygous mutations in phosphatase and tensin homolog deleted on chromosome ten (Pten), a well-established monogenic risk factor for ASD, received continuous oxytocin versus phosphate-buffered saline (PBS) control via micro-osmotic pumps during late gestation. Wild-type (WT) offspring exposed to each treatment served as a secondary control. Adult offspring were assessed for oxytocin receptor (Oxtr) methylation in the frontal cortex and hippocampus, oxytocin expression in the hypothalamus, serum oxytocin levels, and were subject to a battery of social and anxiety-related behavior tests. Perinatal oxytocin exposure produced genotype-dependent effects in offspring. Epigenetic analyses revealed bidirectional remodeling of Oxtr methylation in the frontal cortex and hippocampus, with increased exon 1 methylation in WT mice and decreased methylation in Pten-mutant mice, resulting in significant genotype-treatment interactions. Hypothalamic oxytocin expression increased following treatment regardless of genotype, though baseline levels were higher in Pten-mutant mice. Neither oxytocin treatment nor genotype impacted long-term serum oxytocin levels. Behavioral outcomes were modest but context-specific: repetitive behaviors and cognition performance were unchanged, but oxytocin-treated Pten-mutant mice exhibited increased anxiety-like behavior alongside improved social memory. In contrast, oxytocin-treated WT mice showed reduced social novelty preference. Exploratory analyses suggested potential sex-dependent trends. Our findings support a model in which genetic susceptibility shapes the epigenetic encoding of early-life hormonal signals, thereby recalibrating oxytocin system function and downstream behavioral outcomes. Together, these data highlight the context-dependent effects of perinatal oxytocin exposure and argue against uniformly beneficial or detrimental effects, emphasizing the importance of gene-environment interactions in neurodevelopmental trajectories.

Animals↗
PubMed2026

Whole genome sequencing of unusual Hepatitis C virus subtypes and drug resistance analysis during direct-acting antiviral therapy in India.

INTRODUCTION AND OBJECTIVES: Pangenotypic direct-acting antivirals (DAA) are effective against highly prevalent Hepatitis C virus (HCV) subtypes, but have been clinically validated almost exclusively in high-income countries. Unusual HCV subtypes may carry natural polymorphisms, potentially impacting DAA susceptibility. We conducted full-genome characterization and resistance analysis of unusual HCV subtypes in patients receiving DAA treatment. PATIENTS AND METHODS: In this prospective hospital-based study, eligible patients were screened for anti-HCV antibodies and active infection was confirmed by diagnostic 5'NCR-based HCV RNA detection. Genotyping was performed by core region sequencing, and viral load quantified by real-time PCR. For whole genome sequencing, multiplex primers were designed using alignments of global reference sequences. Sequencing was carried out using the Oxford Nanopore Technology platform. Phylogenetic analysis used multiple sequence alignment and the HCV-GLUE resource for resistance-associated substitution (RAS) analysis. RESULTS: Predominant genotype was genotype 3 in 64.3% (n = 45); genotype 6 in 21.4% (n = 15); and genotype 1 in 14.2% (n = 10). Unusual HCV subtype 6xa was detected in two patients and showed no NS5A resistance mutations. One genotype 3b patient relapsed at 24 weeks post-DAA treatment completion and carried NS5A resistance-associated substitutions 30 K and 31 M both at baseline and at relapse, conferring high-level resistance to NS5A inhibitors. CONCLUSION: This is the first report from India of whole genome sequencing of HCV subtype 6xa. The identification of NS5A resistance mutations in the 3b relapse case underscores challenges for global HCV elimination strategies.

Humans↗
PubMed2026

Origins and timing of somatic variants in the brain.

Somatic variants accumulate in human brain cells throughout the lifespan. Variant allele fraction has traditionally been used as a proxy for both the developmental timing of somatic variants and their functional effect, based on the assumption that earlier mutations are shared by larger cell populations and therefore have greater potential for severe phenotypes. However, recent discoveries challenge this simplified model. Variables such as developmental bottlenecks, lineage restriction, and cellular and molecular context play critical roles in shaping the distribution and functional impact of somatic variants in the brain. These insights support a shift toward a context-dependent framework for interpreting somatic mosaicism.

Humans↗