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PubMed2026

Evaluation of the SLC11A1 non-synonymous variant rs17235409 and tuberculosis susceptibility in a multi-ethnic population from southwestern China.

Tuberculosis (TB) remains a major infectious disease burden, and inter-individual heterogeneity in progression from exposure to active disease suggests contributions from host genetic factors. SLC11A1 (formerly NRAMP1) encodes a phagosomal divalent cation transporter implicated in macrophage-mediated antimicrobial defense; the non-synonymous rs17235409 polymorphism (D543N) has been evaluated in multiple populations with inconsistent results. We conducted a retrospective matched case-control study in Qiandongnan, Guizhou Province, China, including 50 patients diagnosed with TB (2022-2023) and 50 healthy controls frequency-matched by ethnicity and selected demographics. Participants were drawn from Miao, Dong, and other minority groups. Among TB cases, the frequencies of the GG, GA, and AA genotypes were 80.0%, 20.0%, and 0%, respectively, compared with 74.0%, 18.0%, and 8.0% among controls. The overall genotype distribution did not differ significantly between the 2 groups (P = .124). Under the dominant model, no significant association was observed between rs17235409 and TB susceptibility (OR = 0.71, 95% CI: 0.28-1.82; P = .635). Allelic analysis showed that the frequency of the A allele was lower in cases than in controls (10.0% vs 17.0%), but this difference was not statistically significant (OR = 0.54, 95% CI: 0.24-1.25; P = .214). Ethnicity-stratified analyses similarly showed no statistically detectable associations in Miao, Dong, or other groups. The minor allele frequency was 0.095, lower than the Han Chinese reference from 1000 Genomes. In this pilot study of multi-ethnic populations from southwestern China, no statistically significant association was identified between the SLC11A1 rs17235409 polymorphism and tuberculosis susceptibility. Although the A allele appeared less frequent among cases, the limited sample size and statistical power preclude definitive conclusions regarding modest or ethnic-specific effects. These findings provide preliminary genetic data from underrepresented ethnic minority populations and warrant validation in larger multicenter studies.

Adult↗

PubMed2026

INPP5K-related muscular dystrophy caused by a novel synonymous splicing variant in a Chinese patient: a case report.

Congenital muscular dystrophies (CMDs) are a genetically heterogeneous group of disorders. Variants in the INPP5K gene, which encodes a phosphoinositide phosphatase, are a rare cause of CMD. The condition is commonly associated with muscle weakness, early-onset cataracts, and intellectual disability, and prior reports have primarily identified missense, frameshift, or deletion variants. We describe the first Chinese case of INPP5K-related muscular dystrophy in a 28-year-old male with a mild phenotype, notably lacking intellectual disability. His presentation included bilateral cataracts at age 5 and adolescent onset limb girdle weakness. Muscle magnetic resonance imaging (MRI) revealed a characteristic pattern of selective fatty infiltration, with severe involvement of gluteal and thigh muscles and striking sparing of the rectus femoris, sartorius, and gracilis. Genetic analysis identified compound heterozygous novel INPP5K variants: a missense c.274C>T, p.(Arg92Cys) and a synonymous c.261G>A, p.(Lys87=) change. Functional studies confirmed the synonymous variant causes aberrant splicing (exon 3 skipping), leading to a frameshift and premature termination p.(Leu52SerfsTer49). According to American College of Medical Genetics and Genomics guidelines, the c.274C>T and c.261G>A variants were classified as likely pathogenic and pathogenic, respectively. This first report of a Chinese patient with INPP5K-related muscular dystrophy broadens both the genetic and clinical spectrum of the disorder. We identify the first disease-causing synonymous variant (via aberrant splicing) and a novel hypomorphic missense variant p.(Arg92Cys), the combination of which explains the attenuated phenotype lacking intellectual disability. Our case highlights the critical role of RNA analysis in diagnosing non-canonical variants and confirms the universal diagnostic relevance of the characteristic muscle MRI pattern.

Adult↗

PubMed2026

A synonymous NPR2 variant causes acromesomelic dysplasia through aberrant pre-mRNA splicing.

Precise regulation of pre-mRNA splicing is essential for normal development, and its disruption represents an important but frequently underrecognized mechanism of human disease. The C-type natriuretic peptide (CNP) receptor NPR2 is a critical regulator of growth plate chondrocyte proliferation and differentiation, and loss-of-function variants in NPR2 cause acromesomelic dysplasia, Maroteaux type (AMDM). Here, we identify a homozygous synonymous NPR2 variant (NM_003995.4:c.2484C > T) in an individual with AMDM and demonstrate its pathogenic mechanism at the RNA level. Although predicted to be silent at the protein level, in silico analysis suggested splice donor gain. Functional analysis using patient-derived leukocyte RNA revealed aberrant splicing leading to partial exon truncation, frameshift, and premature termination of NPR2 which is predicted to trigger nonsense-mediated mRNA decay given its position upstream of multiple downstream exon-exon junctions. Heterozygous family members expressed both normal and aberrant transcripts, whereas the affected individual showed exclusive expression of the aberrant isoform, consistent with a dosage-dependent loss-of-function mechanism. These findings establish aberrant splicing induced by a synonymous variant as a disease-causing mechanism affecting a core developmental signaling pathway. Our study highlights the importance of transcript-level functional analysis in the interpretation of rare variants and underscores the central role of precise RNA processing in skeletal development and human disease.

Humans↗

PubMed2026

Hurdles to horizontal gene transfer: species-specific effects of synonymous variation and plasmid copy number determine antibiotic resistance phenotype.

Could codon composition condition the immediate success and the orientation of horizontal gene transfer? Horizontal gene transfer represents a change in the genome of expression of the transferred gene, and experimental evidence has accumulated indicating that the codon composition of a sequence is an important determinant of its compatibility with the translation machinery of the genome in which it is expressed. This suggests that codon composition influences the phenotype and the fitness conferred by a transferred gene and thus the immediate success of the transfer. To directly test this hypothesis, we characterized the resistance conferred by synonymous variants of a gentamicin resistance gene in three bacterial species: Escherichia coli, Acinetobacter baylyi and Pseudomonas aeruginosa. The strongest determinant of the resistance level conferred was the species in which the resistance gene was transferred, very likely because of important differences in the copy number of the plasmid carrying the gene. Significant differences in resistance were also found between synonymous variants within each of the three species, but more importantly, there was a strong interaction between species and variant: variants conferring high resistance in one species confer low resistance in another. However, the similarity in codon usage between the synonymous variants and the host genome only explained part of the phenotypic differences between variants in one species, P. aeruginosa. Further investigation of alternative explanations did not reveal common universal mechanisms across our three bacterial species. We conclude that codon composition can be a determinant of post-horizontal gene transfer success. However, there are multiple paths leading from synonymous sequence to phenotype, and sensitivity to these different paths is species-specific.

Gene Transfer, Horizontal↗

PubMed2025

Epstein-Barr Virus Sequence Variations Among the Understudied Nasopharyngeal Carcinoma Patients of Diverse Ancestries in Southeast Asia.

Epstein-Barr virus (EBV) is associated with cancers, including lymphomas and nasopharyngeal carcinoma (NPC). To date, risk variants for NPC were mainly identified from Chinese populations, which dominated the world's total number of cases. Although Southeast Asia (SEA) countries have among the world's top yet intriguingly diverse NPC age-standardized incidence rates across subpopulations, data on EBV from SEA remains scarce. In this study, we examined 83 NPC patients of different ancestries for the presence of risk haplotypes associated with the Southern Chinese NPC and generated and analyzed 67 EBV sequences (from tissue, patient-derived xenografts and lymphoblastoid cell lines of 60 NPC patients) together with 838 published EBV genomes. Our study revealed that NPC patients of non-Chinese ancestry had fewer risk variants and haplotypes that are associated with Southern Chinese NPC and clustered distinctly from lymphomas, Southern Chinese NPC, and non-cancer controls. The distribution of non-synonymous variants was similar among NPC patients of Chinese ancestry, irrespective of geographical location. Meanwhile, non-synonymous variants in genes related to packaging, latency, and structural proteins such as BPLF1, LF3, and LMP1 varied across different ancestries. Our findings suggest possibilities of EBV adaptation to host genetics for NPC pathogenesis and warrant further research for the understudied NPC subpopulations.

Adult↗

PubMed2026

A Combination of Alleles in LMOD2 and a lncRNA is Strongly Associated With Myxomatous Mitral Valve Disease in Cavalier King Charles Spaniels.

A previous genome-wide association study identified regions on canine chromosome (cfa) 13 and 14 associated with early onset myxomatous mitral valve disease (MMVD) in Cavalier King Charles Spaniels (CKCS). In the present study, whole genome sequencing (WGS) of 9 CKCS cases (mitral regurgitation (MR) before 4.5 years or congestive heart failure (CHF) at any age due to MMVD) and 10 CKCS controls (no or mild MR after 8 years of age) identified > 2000 genetic variants in the MMVD associated cfa13 and cfa14 regions. Ensembl Variant Effect Predictor (VEP) identified a possible functional impact of 18 variants. These were genotyped in 250 CKCS; 117 cases and 133 controls. The most significantly associated variants were a splice-site variant in a long noncoding RNA (lncRNA) on cfa13, a nonsynonymous variant in HYAL4, a 39 base-pair insertion in LMOD2 and a synonymous variant in ENSCAFG00000024436 (p-values from 2.03E-08 to 4.20E-06). Concomitant homozygosity for risk alleles in LMOD2 and the lncRNA gave an odds-ratio for MMVD of 52.5 compared to homozygosity for the nonrisk alleles (p = 0.00034, 95% CI: 8.8-1023.8). Upon validation of our results in an independent cohort, this gene variant combination in CKCS is expected to enable targeted breeding programs to reduce MMVD prevalence in CKCS.

Animals↗

PubMed2026

Genome-Wide and Rare Variant Association Studies of Amblyopia in Admixed American and African Ancestry Groups.

OBJECTIVE: To identify genetic variants associated with amblyopia in African (AFR) and Admixed American (AMR) ancestry groups, expanding on previous studies conducted in European ancestry. DESIGN: Retrospective ancestry-stratified genome-wide association study (GWAS) and gene-level rare variant association study (RVAS). PARTICIPANTS: Participants in the All of Us Research Program from AFR and AMR ancestry groups who had whole-genome sequencing available. Cases and controls were distinguished based on the presence of International Classification of Diseases 9/10/SNOMED diagnosis codes for amblyopia in electronic health records. This yielded ancestry-stratified subsets of 269 cases and 71 585 controls of AMR ancestry and 366 cases and 79 460 controls of AFR ancestry. METHODS: Stratified logistic regression models were adjusted for age, biological sex, and the top 10 principal components of genomic ancestry. GWAS was limited to common variants (minor allele frequency ≥1%), and RVAS was limited to rare variants with coding sequence-altering effects (minor allele frequency >1%, exonic only, excluding synonymous variants) aggregated at the gene level using the SKAT algorithm. Downstream analyses of the significant variants were performed using KEGG and GO pathway analysis and STRING database queries for protein-protein interactions and gene-gene interactions. MAIN OUTCOME MEASURES: Single-nucleotide polymorphisms were determined to have genome-wide significance if P < 5e-8 in the GWAS, and genes were determined to have significant association with amblyopia in the RVAS if P < 8.0 × 10-4. RESULTS: In the AMR GWAS, 245 unique single-nucleotide polymorphisms mapping to 97 distinct loci were identified, notably within neurodevelopmental and axonal guidance genes, including ROBO1, SEMA4B, PTPRD, NRXN1, and CAMK2D. The AFR GWAS identified 11 significant variants corresponding to 6 loci mapping primarily to long noncoding RNAs and pseudogenes. The AMR RVAS identified 15 genes, including axonal transport genes (KIF1B and KIF7) and growth factor signaling genes (EGF, ERBIN, and AKAP17A). The AFR RVAS identified a single gene, DLG2, which encodes the postsynaptic protein PSD-93, which promotes the closure of the sensitive period of neuroplasticity for vision in early childhood. CONCLUSIONS: Genetic risk architectures for amblyopia differ across ancestries but fundamentally converge on neurodevelopmental signaling, cortical synapse assembly, and sensitive period plasticity rather than ocular structural dynamics. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.

Amblyopia↗

PubMed2024

Genetic and functional analyses of CTBP2 in anorexia nervosa and body weight regulation.

The C-terminal binding protein 2 (CTBP2) gene (translational isoforms: CTBP2-L/S, RIBEYE) had been identified by a cross-trait analysis of genome-wide association studies for anorexia nervosa (AN) and body mass index (BMI). Here, we did a mutation analysis in CTBP2 by performing polymerase chain reactions with subsequent Sanger-sequencing to identify variants relevant for AN and body weight regulation and ensued functional studies. Analysis of the coding regions of CTBP2 in 462 female patients with AN (acute or recovered), 490 children and adolescents with severe obesity, 445 healthy-lean adult individuals and 168 healthy adult individuals with normal body weight detected 24 variants located in the specific exon of RIBEYE. In the initial analysis, three of these were rare non-synonymous variants (NSVs) detected heterozygously in patients with AN (p.Arg72Trp - rs146900874; p.Val289Met -rs375685611 and p.Gly362Arg - rs202010294). Four NSVs and one heterozygous frameshift variant were exclusively detected in children and adolescents with severe obesity (p.Pro53Ser - rs150867595; p.Gln175ArgfsTer45 - rs141864737; p.Leu310Val - rs769811964; p.Pro397Ala - rs76134089 and p.Pro402Ser - rs113477585). Ribeye mRNA was detected in mouse hypothalamus. No effect of fasting or overfeeding on murine hypothalamic Ribeye expression was determined. Yet, increased Ribeye expression was detected in hypothalami of leptin-treated Lepob/ob mice. This increase was not related to reduced food intake and leptin-induced weight loss. We detected rare and frequent variants in the RIBEYE specific exon in both patients with AN and in children and adolescents with severe obesity. Our data suggest RIBEYE as a relevant gene for weight regulation.

Humans↗

PubMed2026

'Truthsets' for clinical validation of large-scale functional assays: Practice recommendations from Cancer Variant Interpretation Group UK (CanVIG-UK).

BACKGROUND: Large-scale functional assays, including multiplex assays of variant effect, have substantial potential to resolve variants of uncertain significance (VUS), particularly for rare missense variants where clinical and population evidence are limited. The ClinGen assay-level clinical validation framework described by Brnich et al provided baseline guidance for the use of functional data for variant classification. However, clear consensus regarding construction of variant 'truthsets' by which to clinically validate functional data remains lacking. METHODS: CanVIG-UK developed consensus recommendations for truthset construction through an iterative national consultation process involving the CanVIG Steering Advisory Group (CStAG), wider CanVIG-UK membership, and engagement with international functional genomics experts. Consultation was based on previous analyses of 2,120 truthset constructions examining the impact of truthset composition on evidence point allocation within the ClinGen assay-level clinical validation framework. RESULTS: Across several consultations, CanVIG-UK established nine guiding principles and seven best-practice recommendations for assay-level clinical validation, using the assumed context of an assay for a cancer susceptibility gene where loss-of-function is the mechanism of pathogenicity. The principal recommendation stipulates, where assays are intended for use in interpretation of largely missense variants, the truthset used to validate should comprise only missense variants. Rather than mixtures of different variant types which may serve to over-estimate assay performance. Additional recommendations support option for relaxation of truthset stringency to improve power, augmentation of benign missense truthsets with systematically derived 'proxy-clinical' benign variants, independent clinical validation separate from assayist-defined validation, and careful evaluation of missense score distributions against that of protein-truncating and synonymous variants. Guidance is also provided for scenarios with limited pathogenic truthset availability and for assays reporting multiple deleterious zones or readouts. CONCLUSIONS: The CanVIG-UK principles and recommendations for truthset construction upon the ClinGen assay-level clinical validation framework, while aiming to form a baseline for future discussion regarding other functional and disease contexts and helping to address the gap between publication of new data and routine clinical implementation.

Journal Article↗

PubMed2025

Rare pathogenic NR2F2 (COUP-TFII) variants as potential etiological causes in pediatric patients with congenital heart diseases (CHDs).

OBJECTIVES: Congenital heart diseases (CHDs) are complex genetic disorders, and their genetic basis is not yet fully understood. Nuclear receptor subfamily 2 group F member 2 (NR2F2 or COUP-TFII) encodes a transcription factor which is expressed at high levels during mammalian development. Few studies have identified heterozygous and rare variants in the NR2F2 gene in individuals with CHD. This study aimed to evaluate the association between pathogenic genetic alterations in NR2F2 with CHD risk. METHODS: A case-control study was conducted on a group of 135 patients (83 boys and 52 girls) with various types of non-hereditary, isolated CHD who were undergoing open-heart surgery. Additionally, 95 matched healthy children without syndromic or isolated heart abnormalities were selected. RESULTS: Using Sanger sequencing, we identified 5 heterozygous single nucleotide variants in exons 2 and 3 of the NR2F2 gene. These variations were novel and not present in any genomic variation databases. Four of the variations were missense mutations (p.Pro159Arg, p.Ser329Phe, p.Qln338Pro, and p.Tyr348Ser) and one was a synonymous variant (p.G361 = ) in the coding region. Importantly, in silico results indicated that the missense variants had pathogenic effects on protein function. Additionally, the missense variants substantially altered the predicted structure of COUP-TFII. CONCLUSION: The results we obtained not only validate the correlation between NR2F2 mutations and CHDs but also have significant potential for guiding new preventive and therapeutic strategies. This could contribute to the advancement of medical interventions in the fields of cardiology and genetics.

Humans↗

PubMed2024

A novel splice-altering TNC variant (c.5247A > T, p.Gly1749Gly) in an Chinese family with autosomal dominant non-syndromic hearing loss.

BACKGROUND: This study aims to analyze the pathogenic gene in a Chinese family with non-syndromic hearing loss and identify a novel mutation site in the TNC gene. METHODS: A five-generation Chinese family from Anhui Province, presenting with autosomal dominant non-syndromic hearing loss, was recruited for this study. By analyzing the family history, conducting clinical examinations, and performing genetic analysis, we have thoroughly investigated potential pathogenic factors in this family. The peripheral blood samples were obtained from 20 family members, and the pathogenic genes were identified through whole exome sequencing. Subsequently, the mutation of gene locus was confirmed using Sanger sequencing. The conservation of TNC mutation sites was assessed using Clustal Omega software. We utilized functional prediction software including dbscSNV_AdaBoost, dbscSNV_RandomForest, NNSplice, NetGene2, and Mutation Taster to accurately predict the pathogenicity of these mutations. Furthermore, exon deletions were validated through RT-PCR analysis. RESULTS: The family exhibited autosomal dominant, progressive, post-lingual, non-syndromic hearing loss. A novel synonymous variant (c.5247A > T, p.Gly1749Gly) in TNC was identified in affected members. This variant is situated at the exon-intron junction boundary towards the end of exon 18. Notably, glycine residue at position 1749 is highly conserved across various species. Bioinformatics analysis indicates that this synonymous mutation leads to the disruption of the 5' end donor splicing site in the 18th intron of the TNC gene. Meanwhile, verification experiments have demonstrated that this synonymous mutation disrupts the splicing process of exon 18, leading to complete exon 18 skipping and direct splicing between exons 17 and 19. CONCLUSION: This novel splice-altering variant (c.5247A > T, p.Gly1749Gly) in exon 18 of the TNC gene disrupts normal gene splicing and causes hearing loss among HBD families.

Adult↗

PubMed2026

RBM20 Truncating Variants and Human Cardiomyopathy.

IMPORTANCE: Genetic diagnosis has become increasingly important to guide clinical decision-making for patients with dilated cardiomyopathy (DCM). Pathogenic or likely pathogenic (P/LP) missense variants in the gene RBM20 cause a highly penetrant arrhythmogenic DCM, but the role of RBM20 truncating variants (RBM20tvs) is unclear. OBJECTIVE: To assess the contribution of RBM20 variants to arrhythmogenic DCM. DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, participants in the genome-first UK Biobank (UKB) and All of Us populations were evaluated to assess the etiologic fraction, natural history and penetrance of RBM20 variants. Retrospective data were collected from an international cohort of patients with DCM and RBM20 variants identified at centers of excellence for genetic heart disease and compared based on time to event. Study dates are not disclosed because the institutional review board did not authorize the sharing of this information. EXPOSURES: RBM20 variants were compared to known P/LP variants and variants of uncertain significance in RBM20 as well as titin truncating variants (TTNtvs). MAIN OUTCOMES AND MEASURES: Major ventricular arrhythmias, end-stage heart failure, and heart failure hospitalization as measured by medical record review (retrospective cohort) and diagnostic codes (UKB). RESULTS: Two main cohorts were studied for this project. In UK Biobank, a cohort of participants with RBM20tvs, RBM20 synonymous variants, and TTNtvs was studied. Of these 4249 participants, 1869 (44%) were male. The mean (SD) age at enrollment was 56 (8.2) years. In the RBM20 registry, of 179 patients, 105 (58.6%) were male, and the mean (SD) age at enrollment was 43.8 (19.1) years. A validation cohort from the All of Us biobank was also used. This consisted of 7002 participants, 4342 of whom (62.0%) were male, and the mean (SD) age was 52.7 (16.7) years. The etiologic fraction of RBM20 variants in arrhythmogenic DCM was 0.53 (95% CI, 0.32-0.67; P < .001). In genome-first biobanks, lifetime incidence of cardiomyopathy, heart failure, or major ventricular arrhythmia diagnosis was lower in participants with RBM20 variants than in those with TTNtvs (hazard ratio, 0.55; 95% CI, 0.36-0.84; P < .001). Patients with RBM20tvs and DCM presented to referral centers later in life than those with P/LP RBM20 and DCM (mean [SD], 53 [10] vs 34 [18] years; P < .001) and were less likely to have a family history of sudden cardiac arrest (2 of 10 [20%] vs 11 of 17 [65%]; P = .046) or cardiomyopathy (2 of 10 [20%] vs 14 of 18 [78%]; P < .001). There was no significant difference in age- and sex-adjusted incident major heart failure or arrhythmia events between patients with RBM20tv and DCM or those with P/LP RBM20 and DCM, though sex-adjusted lifetime hazard was reduced in those with RBM20tv and DCM (hazard ratio, 0.13; 95% CI, 0.03-0.56; P = .01). CONCLUSIONS AND RELEVANCE: This study found that RBM20 variants contributed to arrhythmogenic DCM phenotypes but conferred reduced lifetime disease penetrance compared to TTNtvs and milder disease severity alone than P/LP RBM20 variants. Their potential for additive interactions with other damaging variants should be considered in patients with DCM and their families.

Humans↗

PubMed2025

Translation of the downstream ORF from bicistronic mRNAs by human cells: Impact of codon usage and splicing in the upstream ORF.

Biochemistry textbooks describe eukaryotic mRNAs as monocistronic. However, increasing evidence reveals the widespread presence and translation of upstream open reading frames preceding the "main" ORF. DNA and RNA viruses infecting eukaryotes often produce polycistronic mRNAs and viruses have evolved multiple ways of manipulating the host's translation machinery. Here, we introduce an experimental model to study gene expression regulation from virus-like bicistronic mRNAs in human cells. The model consists of a short upstream ORF and a reporter downstream ORF encoding a fluorescent protein. We have engineered synonymous variants of the upstream ORF to explore large parameter space, including codon usage preferences, mRNA folding features, and splicing propensity. We show that human translation machinery can translate the downstream ORF from bicistronic mRNAs, albeit reporter protein levels are thousand times lower than those from the upstream ORF. Furthermore, synonymous recoding of the upstream ORF exclusively during elongation significantly influences its own translation efficiency, reveals cryptic splice signals, and modulates the probability of downstream ORF translation. Our results are consistent with a leaky scanning mechanism facilitating downstream ORF translation from bicistronic mRNAs in human cells, offering new insights into the role of upstream ORFs in translation regulation.

Humans↗

PubMed2026

No receptor-binding domain adaptation detected in within-host H5N1 surveillance of 4,559 US dairy outbreak sequences.

BACKGROUND: The 2024-2026 US H5N1 clade 2.3.4.4b dairy cattle outbreak has been characterised primarily through consensus-level phylogenetics. Whether mammalian-adaptation variants are emerging at sub-consensus frequencies within infected hosts, particularly at the haemagglutinin receptor-binding domain (RBD), remains unknown because no systematic within-host variant analysis of the public sequencing corpus has been performed. METHODS: We conducted a pre-registered, corpus-wide intrahost single-nucleotide variant (iSNV) analysis of all publicly available H5N1 cattle, feline-spillover, and retail-milk sequences on the NCBI Sequence Read Archive (4559 samples across 7 BioProjects). A dual-caller concordance pipeline (iVar + LoFreq) with empirically determined allele frequency (AF) threshold (3%, set via four-criterion validation including synthetic spike-in controls) was applied to an 11-site Tier 1 mammalian-adaptation panel spanning the polymerase complex, haemagglutinin RBD, and accessory proteins. Within-host nucleotide diversity was compared across host categories. RESULTS: The HA RBD sites Q226L and G228S (H3 numbering) showed zero detections across >4300 adequately sequenced samples at all AF thresholds tested (1-5%), despite the pipeline detecting other non-synonymous variants at these exact codon positions (upper 95% CI for prevalence: 0.08%). Seven of eleven adaptation sites carried statistically significant iSNV signals after Bonferroni correction (corrected α = 0.00417), though all at low prevalence (≤2.95%). Genotype stratification showed that most polymerase-site detections reflected genotype structure rather than within-host emergence: the apparent PB2 631 L→M "reversion" was largely the ancestral avian state of the D1.1 genotype (20 of 23 detections), which never acquired the 631L mammalian adaptation, with only two genuine sub-consensus events in the B3.13 background, while consensus-level PB2 701N was a fixed feature of the D1.1 genotype (10 of 14 detections) rather than independent sub-consensus emergence. Cattle exhibited significantly higher within-host nucleotide diversity than feline-spillover samples (π = 1.59 × 10-4 vs 6.11 × 10-5; Kruskal-Wallis p = 6.6 × 10-15), a finding that persisted after depth-matching (p = 4.6 × 10-5); this may reflect prolonged mammary-gland infection, though sampling differences and host biology cannot be excluded. CONCLUSIONS: We did not detect HA receptor-switching adaptation (the acquisition of human-type α2,6 receptor binding via Q226L/G228S) at any tested allele frequency in the US dairy H5N1 outbreak. Sub-consensus mammalian-adaptation signals exist at polymerase-complex sites but at low prevalence, are genotype-structured rather than independently recurrent, and require functional characterisation before informing risk assessment.

Dairy cattle↗

PubMed2026

Evolution of virulence of a plant RNA virus in developmental stage-structured host populations.

Natural host populations are age-structured, and developmental stages differ in susceptibility and within-host pathogen dynamics, potentially imposing distinct selective pressures on viruses. However, the evolutionary consequences of host age structure remain poorly understood. We experimentally evolved turnip mosaic potyvirus for 5 passages in Arabidopsis thaliana populations spanning 7 demographic regimes, from juvenile- to mature-dominated cohorts. We quantified disease progression, symptom severity, and viral load, cross-inoculated evolved lineages across host stages to construct infection matrices, and performed whole-population sequencing at passages 1 and 5. Disease traits changed markedly with passage, demography, and their interaction. Disease progression evolved faster in older populations, whereas symptom severity was independent of median age, indicating demographic reweighting of virulence components. Viral load increased across passages and positively correlated with severity, linking within-host fitness to symptoms. Cross-inoculation assays revealed a modular infection network: juvenile-evolved lineages specialized on juvenile hosts, whereas lineages from intermediate and older populations were more generalist. Genomically, we detected both parallel and demography-specific adaptations, including recurrent changes in the viral protein VPg (involved in translation, replication, and host interactions) as well as synonymous variants showing consistent or opposing selection across host population stage structures. Overall, host age structure emerges as a major ecological driver of virulence evolution, shaping tradeoffs between disease progression and severity and determining specialization versus generalism. These results integrate phenotypic and genomic responses and suggest that manipulating crop age structure could steer virus evolution toward less damaging outcomes.

Virulence↗

PubMed1991

Latent Semantic Indexing of medical diagnoses using UMLS semantic structures.

The relational files within the UMLS Metathesaurus contain rich semantic associations to main concepts. We invoked the technique of Latent Semantic Indexing to generate information matrices based on these relationships and created "semantic vectors" using singular value decomposition. Evaluations were made on the complete set and subsets of Metathesaurus main concepts with the semantic type "Disease or Syndrome." Real number matrices were created with main concepts, lexical variants, synonyms, and associated expressions. Ancestors, children, siblings, and related terms were added to alternative matrices, preserving the hierarchical direction of the relation as the imaginary component of a complex number. Preliminary evaluation suggests that this technique is robust. A major advantage is the exploitation of semantic features which derive from a statistical decomposition of UMLS structures, possibly reducing dependence on the tedious construction of semantic frames by humans.

Abstracting and Indexing↗

PubMed2025

In silico prediction of the impact of genomic variations in the small conductance calcium activated potassium channel SK3 structure and function.

The small-conductance calcium-activated potassium channel SK3, encoded by the KCNN3 gene, plays a critical role in regulating dopaminergic neuron (DN) firing patterns by modulating after hyperpolarization currents. SK3 dysfunction has been implicated in neuropsychiatric and neurodegenerative disorders. We analyzed structural and functional consequences of KCNN3 splicing and genetic variation. Alternative splicing variants of the KCNN3 gene were retrieved from the Ensembl database and aligned using T-Coffee, manually inspected and curated. Protein domains were identified with Pfam 35.0, SMART 9.0, and InterPro 98.0, and visualized. An AlphaFold2 model of SK3 full-length protein (UniProt: Q9UGI6) used as reference and structural models of its splicing variants were predicted with ColabFold. Functional domains (S1-S6 transmembrane helices, H5 pore loop, and calmodulin-binding) were defined and superimposed onto the AlphaFold2 reference. Domain integrity was assessed based on completeness of all expected residue indices within each functional region. SNPs and CNVs across all coding KCNN3 splicing variants were analyzed, classified, and filtered to isolate pathogenic variants prioritizing non-synonymous amino acid substitutions. Differential variant impacts across splicing isoforms were assessed by mapping variant positions to individual transcript protein sequences and used to predict functional consequences. Two long and two short splicing variants are known. Short variants lack the motif required for potassium channels. Pathogenic variants result from missense mutations resulting in amino acid substitutions. In all cases, the consequential effects depend on the specific location and role of the amino acid being changed.

SK3 channels↗

PubMed2026

Tackling non-canonical splicing in arrhythmogenic cardiomyopathy to reduce the uncertain significance variants burden.

BACKGROUND: Splice-altering variants (SAVs), particularly those outside canonical splice sites, are an underappreciated contributor to inherited cardiovascular diseases. In arrhythmogenic cardiomyopathy (ACM), these variants frequently remain classified as of uncertain significance (VUS) due to limited predictive power and lack of transcript-level evidence, constraining genetic yield and clinical management. Our study aimed to determine the functional impact of SAVs in ACM genes and refine their classification using ACMG/AMP and ClinGen SVI criteria. METHODS: SAVs identified in 200 ACM probands underwent SpliceAI prediction, GTEx cardiac exon-usage annotation, and functional assessment using pSPL3-based minigene assays. Aberrant transcripts were quantified using Percent Splicing Alteration (PSA). Segregation data and ACMG/AMP criteria refined by ClinGen SVI were applied to integrate functional and clinical evidence for classification. RESULTS: Aberrant splicing was confirmed in 9/20 variants (45%), including synonymous, missense, and non-canonical intronic changes. SpliceAI scores correlated strongly with PSA values (R²=0.86). Case-control burden testing revealed significant enrichment of splice-altering variants in DSP, DSG2, DSC2 and FLNC. Integrating predictive algorithms with experimental validation and segregation analysis markedly enhances reclassification of 16/20 variants (80%). CONCLUSION: Splicing defects beyond canonical sites significantly shape ACM genetic landscape. Integrating predictive models with experimental validation clarifies uncertain variants bridging the gap between genomic uncertainty and clinical decision-making.

Humans↗