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Whole genome characterisation of Australian and New Zealand OsHV-1 'μVar' like variants over time.

Ostreid herpesvirus 1 (OsHV-1) is a major pathogen of Pacific oysters (Magallana gigas), linked to mass mortality events worldwide and presents a substantial threat to global aquaculture. Since 2010, mortality events have been occurring in Pacific oysters within Australia with the cause being an OsHV-1 microvariant highly similar to OsHV-1 μVar first detected in France, 2008. In this study, fifteen OsHV-1 whole genomes were assembled from Australian and New Zealand mortality events, including twelve newly sequenced genomes and three assembled from public datasets. Whole-genome phylogenetic analyses indicate that Australian and New Zealand OsHV-1 isolates form a distinct clade, separate from European and East Asian genomes, and with moderate regional and temporal divergence across the past 14 years. Across the dataset, multiple biologically relevant mutations were observed in genes of known function, including DNA polymerase, ribonucleotide reductase subunits, and apoptosis-related proteins, though most mutations occurred in uncharacterised genes. These findings highlight the limitations of single-gene typing and support the need for whole-genome approaches in understanding OsHV-1 evolution. Critically, the lack of recent whole-genome data, particularly from East and Southeast Asia, restricts the ability to trace viral origins and detect novel variants, underscoring the need for expanded global OsHV-1 genomic surveillance.

Australia

A Case Report of Infantile Dopa-Responsive Dystonia Onset With Sleep Disorder Complicated With Autism Spectrum Disorder.

AIMS/BACKGROUND: Dopa-responsive dystonia (DRD) is a rare genetic disorder with complex and diverse clinical manifestations, resulting in a high rate of misdiagnosis. This case report describes an infantile case of DRD complicated by autism spectrum disorder (ASD), initially presenting with a sleep disorder. We aim to summarize its clinical manifestations, diagnostic process, treatment, and follow-up outcomes in order to improve clinical understanding of this disease. CASE PRESENTATION: A retrospective analysis was performed on a male infant who was treated at Jinhua Maternal and Child Health Care Hospital in 2020. The patient presented at one month of age with sleep disturbances, delayed motor development, and intermittent upward deviation of the eyes. Genetic testing identified two heterozygous pathogenic variants in the tyrosine hydroxylase (TH) gene. Among them, the c.738-2A>G variant was not recorded in the Exome Aggregation Consortium (ExAC), Genome Aggregation Database (gnomAD), or 1000 Genomes Asian population databases. During follow-up, the patient was also found to have comorbid ASD. RESULTS: Genetic testing confirmed biallelic TH mutations, establishing the diagnosis of infantile DRD. The patient exhibited marked clinical response to levodopa/benserazide, though dose titration was required with growth. CONCLUSION: For infants with unexplained sleep disorder accompanied by delayed motor development, genetic testing should be performed as early as possible to facilitate the identification of the root cause and implement timely treatment. In addition, close follow-up should be conducted to detect comorbid neurodevelopmental disorders.

Humans

De novo genome assemblies of threatened Asian hornbills (Bucerotidae) reveal declining population trajectories during the late Pleistocene.

BACKGROUND: Asian hornbills are flagship species of the wet tropics that face significant threats from hunting, habitat loss, and fragmentation. Despite being conservation flagships, whole genome information is available for only two of the 32 Asian hornbill species. In this study, we provide the first de novo genome assemblies for four hornbill species (Bucerotidae) in Asia. METHODS: We used a combination of long-read and short-read sequencing data to assemble and annotate de novo hybrid genomes of four species of hornbills. We also assembled and compared mitochondrial genomes of these species. Using a comparative genomics approach, we performed orthology assignment and gene evolution analyses to identify unique gene families in Asian hornbills, gene families that showed significant expansion, their functions and structural variation. Furthermore, using the Pairwise Sequentially Markov Coalescent (PSMC) method, we reconstructed demographic histories of hornbill species to examine changes in their population trajectories in the past. RESULTS: We present hybrid genome assemblies for Great Hornbill (B. bicornis - GH), Rufous-necked Hornbill (A. nipalensis- RNH), Malabar Pied Hornbill (A. coronatus- MPH) and Wreathed Hornbill (R. undulatus- WH). The genome sizes of these hornbills range from 1.1 Gb to 1.3 Gb, with over 95.9% completeness and gene prediction BUSCO. We reported 10,525 orthogroups shared among four Asian hornbill species and identified significant expansion in gene families associated with structural keratin development in Asian hornbills compared to their ancestors. We also provide annotated mitogenomes for each of these species. Furthermore, we found that the WH, a more abundant, widely distributed, and migratory species, showed a higher Ne than the other three hornbill species. However, an overall decline in Ne for all species was recorded during the Pleistocene climatic fluctuations. CONCLUSIONS: We present the first-ever, high-quality reference genomes for the threatened hornbill species from Asia. Hornbills have shown significant expansion in genes involved in structural keratin development. Our results indicate that Pleistocene climatic fluctuations have led to dramatic population declines in all four species. We believe that this study provides robust genomic resources to support future comparative and conservation genomics efforts for hornbills.

Animals

Assessment of Genetic Correlations Between Tobacco or Alcohol Use and Neurodegenerative Diseases Using East Asian Genetic Ancestry Genome-Wide Association Study Results.

Alzheimer's disease (AD) and Parkinson's disease (PD) are the most prevalent late-onset neurodegenerative diseases worldwide. Both are influenced in part by genetic factors and are currently incurable. Tobacco and alcohol, the two most common substances used among the general adult population, are potential AD/PD risk factors and are also heritable. Although important progress has been made, most existing research on the genetics of AD and PD has been carried out in individuals of European genetic ancestry. Investigations in a broad range of groups are crucial to understand disease mechanisms. Given the current availability of ancestry-specific tobacco and alcohol use as well as AD and PD genome-wide association study summary statistics, we performed global and local genetic correlation analyses using East Asian datasets. Genes within the correlated genetic regions were subsequently used to identify potentially enriched biological pathways between substance use and neurodegenerative diseases. We identified a global genetic correlation between smoking cessation and PD, which we confirmed in complementary European genetic ancestry data. Gene set enrichment analyses highlighted potentially shared genetic mechanisms between breast cancer and AD, which warrants further exploration. This work aims to promote further analyses across genetic ancestry groups.

Female

Prevalence of pharmacogenomically implicated prescriptions in multi-ethnic populations in Singapore.

AIM: To assess the potential impact of implementing pre-emptive pharmacogenomic (PGx) testing in Singapore, focusing on prevalence and genetic actionability of PGx prescriptions. METHODS: Electronic Health Records from 2014 to 2021 were obtained from the National University Hospital (NUH), a tertiary medical centre serving approximately 6% of Singapore's population, which were filtered for pharmacogenomically implicated medicines (CPIC Level A or A/B), defined as PGx medications. Coupling this with published data of whole-genome sequencing of 9051 Singaporeans, we estimated the proportion of patients whose prescriptions might have been modified based on pre-emptive PGx at population level. RESULTS: From 2014 to 2021, a total of 1 157 359 unique patients were seen at NUH, with 38.1% to 43.0% of patients with prescriptions receiving at least one PGx medication annually, exhibiting minimal variance over year of prescription, sex or race/ethnicity. The most frequently prescribed PGx medications were omeprazole, statins and tramadol, while the most implicated pharmacogenes were CYP2C19, CYP2D6 and SLCO1B1. The age-dependent increase in PGx medication exposure varied significantly by sex, with males prescribed these medications earlier in life than females. Similarly, Indians and Malays were more likely to be prescribed these medicines at a younger age than Chinese. Based on frequency of PGx variants in Singaporeans, we estimate that 18.4% of patients could have their prescriptions modified from pre-emptive PGx testing. DISCUSSION: Pharmacogenomically implicated medication prescriptions are common in Singapore and are particularly prevalent in elderly populations. Strategic investments in infrastructure and policy development will be pivotal to the successful integration of pre-emptive PGx into clinical practice.

Asian genomes

Genomic diversity and selection signatures in Asian Zebu Cattle: insights into adaptation and genetic erosion.

Indigenous cattle breeds in Asia are highly adapted to their local environments providing essential commodities such as meat, milk and draught power while also playing a key role in traditional ceremonies, and sports. Despite ongoing efforts to characterize and conserve these breeds, the increasing trend of indiscriminate crossbreeding of Zebu cattle with high-yielding taurine breeds, threatens their genetic diversity. This study investigates the population structure, inbreeding levels, effective population size, gene flow and identification of selection footprints of Asian Zebu (Bos indicus) cattle. Using an Axiom 60 K SNP chip, we analyzed genotypes from 1303 cattle across 36 populations in nine countries, including seven taurine outgroups and 29 Zebu populations from Bangladesh, Cambodia, India, Myanmar, Pakistan, and Sri Lanka. Zebu populations demonstrated moderate genetic diversity, with heterozygosity levels averaging 0.356, inbreeding coefficients ranging from 0.026 to 0.074 and genetic differentiation (FST) varied between 0.01 and 0.11. Breed clusters aligned closely with their geographic locations except for Achai (Pakistan) and Baru Harak (Sri Lanka) breeds that appeared in both Zebu and taurine clusters indicating evidence of taurine admixture. Genomic analyses identified regions under selection using extended haplotype homozygosity (EHH) and fixation index (FST) methods. Candidate genes associated with key biological functions related to environmental responsiveness, including heat tolerance (HSP90AA1), immunity (RIPK3), metabolism and fertility (REC8, CLIC4, TSSK4), were identified, reflecting adaptive traits critical for Zebu survival and utility across diverse environments. These findings provide valuable insights for conservation and management strategies aimed at preserving the unique genetic diversity of Asian Bos indicus breeds.

Animals

A genome-wide association study identifies a novel East Asian-specific locus for dementia with Lewy bodies in Japanese subjects.

BACKGROUND: Dementia with Lewy bodies (DLB) is the second most common type of degenerative dementia in older patients. As with other multifactorial diseases, the pathogenesis results from interactions of environmental and genetic factors. The genetic basis of DLB is not yet fully understood. Recent genomic analyses of DLB in Caucasian cohorts identified genetic susceptibility loci for DLB, but the comprehensive genomic analysis in Asians was still not performed. METHODS: We conducted a genome-wide association study (GWAS) in Japanese subjects (211 DLB cases and 6113 controls) to clarify the genetic architecture of DLB pathogenesis. RESULTS: We identified the East Asian-specific DHTKD1 locus (rs138587229) on chromosome 10 with genome-wide significance (GWS; P&#x2009;=&#x2009;3.2710-8) and the ICOS/PARD3B locus on chromosome 2 with suggestive significance (P&#x2009;=&#x2009;3.9510-7) as novel DLB genetic risk loci. We also confirmed the APOE locus (rs429358, P&#x2009;<&#x2009;5.0&#x2009;&#xd7;&#x2009;10-8), a known risk locus for DLB and Alzheimer's disease in Caucasians. The DHTKD1 locus was associated with the gene expression of SEC61A2 and showed a causal relationship with cholinesterase levels. In a trans-ethnic meta-analysis that included Japanese, UK Biobank, and other Caucasian GWAS, we confirmed the risk for DLB at APOE and SNCA loci with GWS. Transcriptome-wide association analysis identified ZNF155 and ZNF284 in the brain cortex and GPRIN3 in the substantia nigra as putative causal genes for DLB. CONCLUSIONS: This is the first GWAS for DLB in East Asians, and our findings provide new biological and clinical insights into the pathogenesis of DLB.

Aged

A genome-wide association study of stroke risk in Asian statin users: evidence from KoGES and UK Biobank.

BACKGROUND: Despite proven efficacy of statins in stroke prevention, genetic factors may influence individual stroke risk among statin users. With increasing precision medicine approaches and growing evidence of population-specific genetic variations, identifying genetic markers that predict stroke risk in statin-treated Asian populations has become critically important for personalized cardiovascular prevention strategies. METHODS: We conducted a genome-wide association study of 1,678 participants using lipid-lowering agents in the Korean Genome and Epidemiology Study (KoGES) cohort. Significant findings were replicated in 2,170 Asian participants on statins from the UK Biobank using an additive genetic model adjusted for relevant covariates. RESULTS: In the discovery analysis, 83 single nucleotide polymorphisms were suggestively associated with stroke (p&#x2009;<1.0&#x2009;&#xd7;&#x2009;10-5). Among these, 21 SNPs in the CDH13 gene were associated with increased stroke risk. The lead SNP, rs7201829, was significantly replicated in the UK Biobank (odds ratio: 2.29, p&#x2009;=&#x2009;2.39&#x2009;&#xd7;&#x2009;10-5). CONCLUSIONS: This study identified CDH13 as a significant genetic marker associated with stroke risk among Asian statin users. These findings provide the first genome-wide evidence for genetic determinants of stroke susceptibility during statin therapy, supporting the development of personalized prevention strategies in Asian populations.

Aged

Paired genomic profiling of primary tumor and lymph-node metastases identifies candidate prognostic features in penile squamous cell carcinoma.

BACKGROUND: Penile squamous cell carcinoma (PSCC) is a rare malignancy with limited genomic data in Asian populations. Lymph node metastasis heavily dictates prognosis, yet molecular determinants of progression remain poorly understood. We aimed to characterize the genomic landscape and explore candidate prognostic genomic features using paired primary and metastatic PSCC tumors. PATIENTS AND METHODS: Targeted next-generation sequencing (437 cancer-related genes) was performed on primary tumors and matched lymph node metastases from 20 Chinese patients. Somatic alterations, intralesional heterogeneity, and tumor mutation burden (TMB) were analyzed and correlated with disease-free survival (DFS) and overall survival (OS). RESULTS: The most frequent primary tumor mutations included TP53 (45%) and TERT (40%). Notably, CCND1/FGF19 co-amplification (20% of cases) was associated with inferior DFS (P&#x2009;=&#x2009;.027) and showed a trend toward shorter OS (P&#x2009;=&#x2009;.050). Conversely, T-cell receptor (TCR) pathway alterations correlated with markedly improved survival. Comparing paired lesions revealed 59.8% shared alterations. Elevated TMB in metastases relative to matched primary tumors was significantly associated with poorer DFS (P&#x2009;=&#x2009;.008), while higher intralesional heterogeneity showed a trend toward worse OS. CONCLUSION: Paired profiling revealed broadly conserved genomic features together with lesion-specific divergence in PSCC. Recurrent CCND1/FGF19-containing 11q13 amplification, TCR pathway alterations, and elevated metastatic TMB warrant evaluation as potential prognostic features in larger, independently validated cohorts with integrated HPV and immune profiling.

Humans

Whole genome sequencing of Yersinia pestis isolates from Central Asian natural plague foci revealed the role of adaptation to different hosts and environmental conditions in shaping specific genotypes.

The genetic diversity and biovar classification of Yersinia isolates from Central Asia were investigated using whole-genome sequencing. In total, 98 isolates from natural plague foci were sequenced using the MiSeq platform. Computational pipelines were developed for accurate assembly of Y. pestis replicons, including small cryptic plasmids, and for identifying genetic polymorphisms. A panel of 99 diagnostic polymorphisms was established, enabling the distinction of dominant Medievalis isolates derived from desert and upland regions. Evidence of convergent evolution was observed in polymorphic allele distributions across genetically distinct Y. pestis biovars, Y. pseudotuberculosis, and other Y. pestis strains, likely driven by adaptation to similar environmental conditions. Genetic polymorphisms in the napA, araC, ssuA, and rhaS genes, along with transposon and CRISPR-Cas insertion patterns, were confirmed as suitable tools for identifying Y. pestis biovars, although their homoplasy suggests limited utility for phylogenetic inference. Notably, a novel cryptic plasmid, pCKF, previously associated with the strain of the population 2.MED0 from the Central-Caucasus high-altitude autonomous plague focus, was detected in a genetically distinct isolate of 2.MED1 population from the Ural-Embi region, indicating potential plasmid transfer across the 2.MED lineage. These findings emphasize the need for ongoing genomic surveillance to monitor the spread of virulence-associated genetic elements and to improve our understanding of Y. pestis evolution and ecology.

Yersinia pestis

Validation of a genome-wide polygenic score for body mass index in South Asians.

Obesity is a complex disorder, manifested by the interaction of inherited and environmental factors and modulated by a person's lifestyle habits. India has witnessed more than a two-fold increase in the number of overweight adults in the last 30 years. The polygenic risk score (PRS) quantitatively measures an individual's risk for common diseases. The PRS for obesity have been validated in the Caucasian population but not in the South Asian (SAS) population. In this study, we benchmarked and validated the existing genome-wide PRS model of obesity with 2.1 million variants in the SAS population. We analyzed a total of 14,263 individuals from three different South Asian cohorts. We compared the risk score with the body mass index (BMI) categories (underweight, normal weight, overweight, and obese) in all three cohorts. High PRS was associated with increased BMI in all the three cohorts. This study also compared validation results from another population-specific PRS model for the BMI. We conclude that high PRS is associated with high BMI in South Asians. Our study suggests that the PRS score can perhaps be an early predictor of overweight and obesity in the South Asian population.

South Asian

Genomic characteristics and prognostic correlations in Chinese multiple myeloma patients.

BACKGROUND: Multiple myeloma (MM) is a hematologic malignancy characterized by the proliferation of abnormal clonal plasma cells in the bone marrow. The heterogeneity in Chinese MM populations remains underexplored. METHODS: We conducted whole-exome sequencing (WES) on 241 tumor samples, complemented by RNA sequencing (RNA-seq) on 131 samples from 212 Chinese MM patients. RESULTS: We identified a novel mutational signature and analyzed molecular differences between newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM) patients. NFKBIA mutations were notably more frequent in NDMM patients compared to the MMRF-COMMPASS cohort (4/50 vs 22/937, p&#x2009;=&#x2009;0.048), with additional recurrent mutations in several genes like TTN, IGLL5 and SYNE1. In RRMM patients, UBR5 mutations were more prevalent (4/24 vs 0/50, p&#x2009;=&#x2009;0.01), alongside frequent mutations in OBSCN, CACNA1H, and HSPG2. Clonal evolution was assessed through multiple time points and locations, identifying genes potentially linked to circulating plasma cell formation. Cox regression analysis revealed that age and mutations in OBSCN and RB1 were significant predictors of progression-free survival (PFS) in NDMM patients. Additionally, albumin, &#x3b2;2-microglobulin, and RB1 mutations were correlated with overall survival (OS). CONCLUSIONS: In summary, we characterized the genomic landscape of MM in diverse Chinese populations, confirmed clonal evolution, and identified prognostic genes.

Adult

Idiopathic pulmonary fibrosis risk loci in East Asian populations mirror those of European populations.

RATIONALE: Common and rare variants that are associated with the risk of developing idiopathic pulmonary fibrosis (IPF) have been identified predominantly in European ancestry populations. OBJECTIVES: To better understand the genetic variants that contribute to IPF in individuals with Asian ancestry, we conducted a genome-wide association study of IPF in East Asian populations. METHODS: We included 1026 patients with IPF and compared them to 1723 unaffected controls of Japanese and Korean ancestry. Genome-wide association analysis was conducted in the Japanese and Korean ancestry cohorts separately and combined using meta-analysis. Restricted maximum likelihood was used to estimate the SNP-based heritability and local ancestry of chromosome 11 was inferred for each subject. MEASUREMENTS AND MAIN RESULTS: We identified loci on chromosomes 4 (FAM13A; rs7690839), 5 (TERT; rs7734992), 6 (DSP; rs2076295), and 11 (MUC5B; rs35705950) that were significantly associated with risk of IPF. Importantly, the sentinel variants in each of these loci are the same as, or in strong linkage disequilibrium with, the risk variants that have been observed in studies of European ancestry populations. In aggregate, common variants (not including the MUC5B promoter variant) account for approximately 25% of the risk of developing IPF in these East Asian ancestry cohorts. Moreover, local ancestry analysis indicates that the presence of MUC5B promoter variant in the East Asian population is not a result of admixture with European ancestry populations. CONCLUSIONS: We conclude that the IPF risk loci in East Asian populations are shared with those of European ancestry populations, although their risk allele frequencies and effect sizes differ. These findings indicate shared genetic risk factors of IPF across ancestries.

Aged

Genomic reconstruction of the Pakistani Roma reveals dual South Asian ancestry, medieval bottlenecks, and the early dispersal routes of the Romani people.

The Roma people represent one of the largest and most historically enigmatic diasporas in Eurasia, illuminating human migration patterns and cultural resilience across continents. Despite extensive research on European Roma as the diaspora endpoint, the genetic legacy of their putative South Asian source populations remains critically underexplored, leaving fundamental gaps in understanding the pre-diaspora demographic structure and early dispersal dynamics. This study uniquely positions Pakistani Roma as a potential ancestral reservoir, offering a rare window into the pre-migration phase distinct from derived European Roma populations shaped by centuries of post-dispersal admixture. We analyze 82 Pakistani Roma from Punjab using high-resolution genome-wide SNP data and comprehensive mitochondrial haplogroup profiling to reconstruct their genetic origins, population structure, and historical trajectory. Analyses reveal a dual ancestry profile comprising 50-82% Indus Valley related, 20-30% Onge related, and up to 26% Steppe derived components, with three distinct subgroups exhibiting varying affinities along a South Asian to Central Western Eurasian continuum reflecting jati-like endogamy. A severe demographic bottleneck ~800&#xa0;years ago coincides with medieval socio-political upheavals, while major Eurasian admixture is dated to ~660&#xa0;years ago. Mitochondrial haplogroups H (45.12%) and M (26.83%) underscore dual maternal influences from West and South Eurasia. Pakistani Roma retain substantially higher South Asian ancestry than their European counterparts, establishing them as a genetically distinct population preserving the ancestral pre-diaspora state. These findings redefine the Romani origin narrative and underscore the critical value of understudied South Asian minorities in reconstructing complex human migration pathways and diaspora formation mechanisms.

Humans

An Integrative Morphological and Genomic Analysis With a Refined Fluorescence In Situ Hybridization (FISH) Threshold and Novel Kinase Fusions in a Large Asian Cohort of Spitzoid Neoplasms.

Differentiating atypical Spitz tumors (ASTs) from true Spitz melanomas (SMs) and conventional melanomas with spitzoid features (MSFs) remains a formidable diagnostic challenge. Because current molecular epidemiological data are overwhelmingly derived from Caucasian cohorts, the genomic landscape of Asian populations remains largely unexplored. To elucidate the molecular progression landscape and refine the diagnostic criteria, we performed a comprehensive multimodal analysis-integrating histomorphology, immunohistochemistry, multiprobe fluorescence in situ hybridization (FISH), and targeted RNA/DNA-based next-generation sequencing (NGS)-on a cohort of 140 spitzoid neoplasms. This cohort, comprising 126 ASTs, 8 SMs, and 6 MSFs, represents the largest Asian cohort to date. Malignant phenotype strongly correlated with lesional asymmetry, deep atypical mitoses, a sheet-like growth pattern, diffuse preferentially expressed antigen of melanoma positivity, and significant loss of p16 expression (64.3% in SM/MSF vs 9.5% in ASTs; P < .0001). Building upon the established melanoma FISH criteria, we optimized a prognostic threshold of &#x2265;2 FISH abnormalities specifically tailored for spitzoid neoplasms. We demonstrated that isolated single chromosomal aberrations (particularly MYB loss) are relatively stable events that are frequent in indolent ASTs, whereas our refined &#x2265;2 threshold yielded 100% sensitivity and 92.5% specificity for predicting regional lymph node metastasis/local recurrence. Molecularly, NGS identified mutually exclusive initiating driver alterations (comprising kinase fusions and HRAS mutations) in 89.9% of true Spitz neoplasms, a remarkably high prevalence suggesting a distinct genetic background in Asian populations. We also characterized 5 entirely novel kinase fusions (ZNF24::ROS1, PCBP1::ROS1, NUMA1::RET, CBWD1::ALK, and TPR::NTRK1). Furthermore, NGS definitively segregated true Spitz neoplasms from morphological mimics (MSF), which lacked fusions and were driven by canonical genomic alterations of the conventional melanoma pathway. Integrating these genomic landscapes validated a stepwise progression model. Although isolated kinase fusions drove indolent ASTs, malignant SM invariably harbored concurrent pathogenic secondary alterations, demonstrating a profound reliance on CDKN2A/B, TP53, and CDK4 aberrations. Ultimately, we propose an integrated diagnostic algorithm combining morphological evaluation, the refined FISH threshold, and comprehensive NGS profiling, providing a precise, evidence-based framework for pathway classification and clinical management of spitzoid neoplasms.

fluorescence in situ hybridization

Integrated Genomic and Immune Profiling of Early Onset Lung Cancer in East Asians Reveals a Distinct Molecular Architecture.

BACKGROUND: The age cut-off for early-onset lung cancer (EOLC) varies across studies (40-50 years). Here, we define EOLC as diagnosis at &#x2264; 40 years, a threshold identifying a subgroup with distinct clinical characteristics. However, whether EOLC differs fundamentally from late-onset lung cancer (LOLC) at the molecular level and represents a distinct subtype requiring different management remains unclear. METHODS: This integrated analysis included genomic and immune profiling data from 8,021 lung cancer patients, comprising 302 EOLC and 7,719 LOLC cases. Using targeted sequencing, we assessed somatic and germline alterations, mutational signatures, and immune biomarkers including tumor mutational burden (TMB), MSI status, and PD-L1 expression. RESULTS: EOLC patients were more often female, had adenocarcinoma, and earlier-stage disease. Molecular profiling revealed significant enrichment of ERBB2 mutations in EOLC, while KRAS, TP53, and MET mutations were more common in LOLC. Mutational signature analysis indicated tobacco-related signatures predominated in LOLC, whereas endogenous processes contributed more substantially in EOLC. Germline analysis showed a higher burden of pathogenic variants in EOLC (14.57% vs. 8.93%, P < .01), with TP53 and BRCA1 being particularly prominent. Immunologically, LOLC tumors exhibited higher TMB and PD-L1 positivity. CONCLUSION: Integrated profiling establishes EOLC as a distinct molecular subtype, defined by a unique triad: an ERBB2-driven somatic profile, germline susceptibility in DNA damage response pathways, and an endogenous mutagenic process within a low-TMB microenvironment. The findings are specific to the selected threshold and should be interpreted accordingly, while elucidating EOLC pathogenesis and supporting age-specific management strategies.

Humans

Biochemical and Genomic Underpinnings of Carotenoid Colour Variation Across a Hybrid Zone Between South Asian Flameback Woodpeckers.

Colouration and patterning have been implicated in lineage diversification across various taxa, as colour traits are heavily influenced by sexual and natural selection. Investigating the biochemical and genomic foundations of these traits therefore provides deeper insights into the interplay between genetics, ecology and social interactions in shaping the diversity of life. In this study, we assessed the pigment chemistries and genomic underpinnings of carotenoid colour variation in naturally hybridising Dinopium flamebacks in tropical South Asia. We employed reflectance spectrometric analysis to quantify species-specific plumage colouration, High-Performance Liquid Chromatography (HPLC) to elucidate the feather carotenoids of flamebacks across the hybrid zone, and Genome-Wide Association Study (GWAS) using next-generation sequencing data to uncover the genetic factors underlying carotenoid colour variation in flamebacks. Our analysis revealed that the red mantle feathers of D. psarodes primarily contained astaxanthin, with small amounts of other 4-keto-carotenoids. In contrast, the yellow mantle feathers of D. benghalense predominantly contained lutein and 3'-dehydro-lutein, alongside minor amounts of zeaxanthin, &#x3b2;-cryptoxanthin and canary-xanthophylls A and B. Hybrids with an intermediate, orange colouration deposited all of these pigments in their mantle feathers, with notably higher concentrations of carotenoids with &#x3b5;-end rings. The GWAS analysis identified the CYP2J2 gene, which plays a role in carotenoid ketolation, as associated with the expression of carotenoid colouration. Read depth data suggested variation in copy number of this gene in flamebacks. These findings contribute to the growing knowledge of avian carotenoid metabolism and highlight how genomic architecture can influence phenotypic diversity.

Animals

Whole-exome characterization of host genetic variation in HIV-associated genes across the high-prevalence Mizo population, Northeast India.

BACKGROUND: The Mizoram state of Northeast India has one of the highest HIV prevalence rates in Asia, yet the host genetic factors influencing HIV susceptibility in this Tibeto-Burman population remain uncharacterised. METHODS: We performed whole-exome sequencing using Illumina NovaSeq 6000, mean coverage 100X on 76 HIV-negative Mizo individuals. Variants were called using GATK HaplotypeCaller v4.3 against GRCh38p14, annotated with ANNOVAR, and filtered using hard-quality thresholds (QD&#xa0;&#x2265;&#xa0;2, SOR&#xa0;&#x2264;&#xa0;3, MQ&#xa0;&#x2265;&#xa0;40, DP&#xa0;&#x2265;&#xa0;10, GQ&#xa0;&#x2265;&#xa0;20). The allele frequencies were compared against gnomAD v2.1.1 population databases. Hardy-Weinberg equilibrium was assessed using the Wigginton exact test with Bonferroni correction. RESULTS: Post-quality filtering resulted in 12,011 sample-variants across 2,821 unique positions from 36 HIV-associated loci (33 protein-coding genes, 2 chemokine ligands, and 3 lncRNA targets). Of these, 784 observations (51 unique positions) were high-impact nonsynonymous or loss-of-function variants. ADAR rs2229857 (p.K384R, NM_015840) was the most frequently observed variant (Mizo carrier frequency&#xa0;=&#xa0;0.895; 95% CI: 0.806-0.946). CXCR1 rs16858808 (p.R335C) showed the greatest population enrichment (Mizo carrier frequency&#xa0;=&#xa0;0.197; 95% CI: 0.123-0.300; 7.65-fold carrier-frequency enrichment versus gnomAD South Asian; CADD&#xa0;=&#xa0;15.60). Sixteen of 20 tested variants deviated from Hardy-Weinberg equilibrium after Bonferroni correction (p&#xa0;<&#xa0;0.0025), predominantly showing excess homozygosity consistent with the endogamous Mizo population. The protective variant CCR5-&#x394;32 was absent in all the 76 individuals tested. CONCLUSION: This first whole-exome characterization of HIV host genes in the Mizo population identifies CXCR1 rs16858808 as the most population-enriched functional variant and reveals a pervasive endogamy signature. These findings provide a population-specific genetic framework for future HIV susceptibility studies and ART pharmacogenomics research.

Humans