SEARCH · Search PubMed

Results for “Relative copy number variation”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources

PubMed2024

Whole exome sequencing analysis of 167 men with primary infertility.

BACKGROUND: Spermatogenic failure is one of the leading causes of male infertility and its genetic etiology has not yet been fully understood. METHODS: The study screened a cohort of patients (n = 167) with primary male infertility in contrast to 210 normally fertile men using whole exome sequencing (WES). The expression analysis of the candidate genes based on public single cell sequencing data was performed using the R language Seurat package. RESULTS: No pathogenic copy number variations (CNVs) related to male infertility were identified using the the GATK-gCNV tool. Accordingly, variants of 17 known causative (five X-linked and twelve autosomal) genes, including ACTRT1, ADAD2, AR, BCORL1, CFAP47, CFAP54, DNAH17, DNAH6, DNAH7, DNAH8, DNAH9, FSIP2, MSH4, SLC9C1, TDRD9, TTC21A, and WNK3, were identified in 23 patients. Variants of 12 candidate (seven X-linked and five autosomal) genes were identified, among which CHTF18, DDB1, DNAH12, FANCB, GALNT3, OPHN1, SCML2, UPF3A, and ZMYM3 had altered fertility and semen characteristics in previously described knockout mouse models, whereas MAGEC1,RBMXL3, and ZNF185 were recurrently detected in patients with male factor infertility. The human testis single cell-sequencing database reveals that CHTF18, DDB1 and MAGEC1 are preferentially expressed in spermatogonial stem cells. DNAH12 and GALNT3 are found primarily in spermatocytes and early spermatids. UPF3A is present at a high level throughout spermatogenesis except in elongating spermatids. The testicular expression profiles of these candidate genes underlie their potential roles in spermatogenesis and the pathogenesis of male infertility. CONCLUSION: WES is an effective tool in the genetic diagnosis of primary male infertility. Our findings provide useful information on precise treatment, genetic counseling, and birth defect prevention for male factor infertility.

Humans↗

PubMed2026

"Tissue-specific mitochondrial dysfunction in keratoconus: An integrated structural, genomic, and functional analysis".

PURPOSE: Keratoconus (KC) is a progressive corneal ectasia characterized by stromal thinning, conical protrusion, and irregular astigmatism, leading to visual impairment. Although oxidative stress is implicated in KC, the role of mitochondrial dysfunction remains unclear. We evaluated mitochondrial structural, genomic, and functional abnormalities in corneal tissues and blood from KC patients. METHODS: This prospective study enrolled 110 KC patients and 55 controls. Transmission electron microscopy (TEM) and immunohistochemistry (IHC) were performed on epithelial and stromal tissues from 10 KC to 5 control corneas assessing mitochondrial morphology, oxidative phosphorylation (OXPHOS) complexes and pro-apoptotic protein NOXA. Whole mitochondrial DNA (mtDNA) sequencing and relative mtDNA copy number analysis were performed on paired blood and corneal tissues from 50 KC patients and 35 controls including both epithelial and stromal samples. Gene expression of mitochondrial biogenesis and oxidative stress-related genes was analysed by qRT-PCR in corneal epithelium from independent 50 KC patients and 15 controls. RESULTS: TEM revealed cristolysis, membrane disruption, and reduced mitochondrial density in KC corneas. IHC showed reduced expression of OXPHOS complexes and increased NOXA expression (p < 0.05). Sequencing identified 1107 mtDNA variants, with more variants in corneal tissues than matched blood (929 vs. 576; p = 0.0002). Recurrent likely pathogenic variants were enriched in complex I-encoding genes (ND4, ND5). KC corneas showed reduced mtDNA copy number, downregulated POLRMT, upregulated NOX4, and significant downregulation of multiple antioxidant genes (p < 0.0001). CONCLUSION: KC patients exhibit tissue-specific mitochondrial abnormalities and impaired oxidative stress regulation, supporting a role for mitochondrial dysfunction in disease pathogenesis and highlighting potential therapeutic targets.

Corneal pathology↗

PubMed2025

Genetic and phenotypic diversity of wine-associated Hanseniaspora species.

The genus Hanseniaspora includes apiculate yeasts commonly found in fruit- and fermentation-associated environments. Their genetic diversity and evolutionary adaptations remain largely unexplored despite their ecological and oenological significance. This study investigated the phylogenetic relationships, genome structure, selection patterns, and phenotypic diversity of Hanseniaspora species isolated primarily from Australian wine environments, focusing on Hanseniaspora uvarum, the most abundant non-Saccharomyces yeast in wine fermentation. A total of 151 isolates were sequenced, including long-read genomes for representatives of the main phylogenetic clades. Comparative genomics revealed ancestral chromosomal rearrangements between the slow-evolving lineage (SEL) and fast-evolving lineage (FEL) that could have contributed to their evolutionary split, as well as significant loss of genes associated with mRNA splicing, chromatid segregation and signal recognition particle protein targeting in the FEL. Pangenome analysis within H. uvarum identified extensive copy number variation, particularly in genes related to xenobiotic tolerance and nutrient transport. Investigation into the selective landscape following the FEL/SEL divergence identified diversifying selection in 229 genes in the FEL, with significant enrichment in genes within the lysine biosynthetic pathway. Furthermore, phenotypic screening of 116 isolates revealed substantial intraspecific diversity, with specific species exhibiting enhanced ethanol, osmotic, copper, SO₂, and cold tolerance.

Wine↗

PubMed2026

Graph-based pan-genome reveals structural and functional diversity across oil palm domestication gradients.

BACKGROUND: Oil palm (Elaeis guineensis Jacq.), the world's most land-efficient oil crop, underpins global vegetable oil supply yet faces mounting constraints from limited expansion, climate stress, and disease pressure. These challenges highlight the urgent need for genomic resources that capture species-wide diversity to support sustainable improvement. While recent reference assemblies have advanced trait discovery, single linear genomes fail to represent the full spectrum of structural and gene-content variation, limiting resolution of agronomic alleles. RESULTS: Here, we constructed a graph-based pan-genome from 30 diverse oil palm assemblies representing wild, semi-domesticated, and commercial accessions. We characterized structural variants, gene presence-absence variation, and copy-number gains, with focusing on functional stratification and resistance gene dynamics. The graph-based pan-genome revealed extensive structural and gene-content variation, including a large conserved core, complemented by shell and unique fractions enriched or biased toward regulatory, stress-responsive, and defense-related functions. Structural variation and duplication-derived copy-number gains contributed substantially to gene-content diversity, with semi-domesticated accessions exhibiting the greatest variability. Resistance gene repertoires showed contrasting patterns: receptor-like kinases remained comparatively stable, whereas the CNL subclass of NLR genes contributed disproportionately to shell-genome variation and duplication-associated turnover. CONCLUSIONS: This graph-based pan-genome provides a curated multi-assembly reference and comparative framework for oil palm genomics. By capturing structural variants, gene-content variations, copy-number gains, and resistance gene dynamics across domestication gradients, it establishes a foundation for future pan-GWAS analysis, functional genomics, and molecular breeding strategies aimed at improving resilience and productivity in this globally important crop.

Arecaceae↗

PubMed2025

Genomic and Transcriptomic Landscape of Epstein-Barr Virus-Positive Inflammatory Follicular Dendritic Cell Sarcoma: A Multicenter Study.

Epstein-Barr virus (EBV)-positive inflammatory follicular dendritic cell sarcoma (EBV+ IFDCS) is a rare indolent malignant neoplasm, which occurs almost exclusively in the liver or spleen and may arise from a common EBV-infected mesenchymal cell that differentiates along the follicular or fibroblastic dendritic cell pathway. Despite its rarity, it presents a pressing need for an improved understanding of its genetic underpinnings and potential treatment strategies for recurrent or disseminated cases. To address this, we conducted comprehensive whole-exome sequencing and transcriptome sequencing (mRNA-seq) analyses on 31 and 6 cases of EBV+ IFDCS, respectively, collected from multiple centers in China. We also compared the genetic features of EBV+ IFDCS with those of other EBV-associated malignancies. Our analyses revealed a relatively high somatic mutation rate and widespread copy number variations affecting the major histocompatibility complex-I/II in EBV+ IFDCS. Integrated mutational profiling identified key signaling pathways involved in epigenetic regulation, NF-κB signaling, RTK/RAS/PI(3)K, and the Hippo pathway. Furthermore, we identified several frequently altered genes that could serve as potential therapeutic targets in EBV+ IFDCS. Transcriptomic analysis unveiled significant upregulation of pathways related to virus infection, immune responses, and multiple immune checkpoint genes in EBV+ IFDCS. Comparative analysis demonstrated clear genetic distinctions between EBV+ IFDCS and other EBV-associated tumors. In conclusion, our study provides comprehensive insights into the unique genomic and transcriptomic landscape of EBV+ IFDCS. We have identified multiple genetic alterations that likely contribute to the development and progression of this malignancy. Our results suggest that targeted therapy and immune checkpoint inhibitors may hold promise as potential therapeutic approaches for patients with recurrent or disseminated EBV+ IFDCS.

Humans↗

PubMed2025

Quinoxaline-based anti-schistosomal compounds have potent anti-plasmodial activity.

The human pathogens Plasmodium and Schistosoma are each responsible for over 200 million infections annually, especially in low- and middle-income countries. There is a pressing need for new drug targets for these diseases, driven by emergence of drug-resistance in Plasmodium and an overall dearth of drug targets against Schistosoma. Here, we explored the opportunity for pathogen-hopping by evaluating a series of quinoxaline-based anti-schistosomal compounds for their activity against P. falciparum. We identified compounds with low nanomolar potency against 3D7 and multidrug-resistant strains. In vitro resistance selections using wildtype and mutator P. falciparum lines revealed a low propensity for resistance. Only one of the series, compound 22, yielded resistance mutations, including point mutations in a non-essential putative hydrolase pfqrp1, as well as copy number amplification of a phospholipid-translocating ATPase, pfatp2, a potential target. Notably, independently generated CRISPR-edited mutants in pfqrp1 also showed resistance to compound 22 and a related analogue. Moreover, previous lines with pfatp2 copy number variations were similarly less susceptible to challenge with the new compounds. Finally, we examined whether the predicted hydrolase activity of PfQRP1 underlies its mechanism of resistance, showing that both mutation of the putative catalytic triad and a more severe loss of function mutation elicited resistance. Collectively, we describe a compound series with potent activity against two important pathogens and their potential target in P. falciparum.

Quinoxalines↗

PubMed2026

Integrated pan-cancer profiling highlights OSR2 as a prognostic indicator and immune-associated biomarker.

BACKGROUND: Odd-skipped-related 2 (OSR2), encoded by the OSR2 gene, has been reported to function as a checkpoint associated with CD8⁺ T-cell exhaustion in the tumor microenvironment of solid malignancies, suggesting its potential as a therapeutic target to improve immunotherapeutic responses. Nevertheless, the molecular and clinical significance of OSR2 across diverse cancer types has not yet been systematically investigated, and its pan-cancer expression profile, prognostic implications, and associations with tumor immunity remain to be fully elucidated. METHODS: In this study, we integrated datasets from The Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression (GTEx) portal, and the Human Protein Atlas to construct a systematic pan-cancer profile of OSR2. The prognostic value of OSR2 was comprehensively assessed using univariate Cox regression, survival analysis, and receiver operating characteristic (ROC) curve analysis. In addition, we performed an in-depth analysis of the relationships between OSR2 and multiple molecular and immunological features, including copy number variation (CNV), DNA methylation, tumor mutational burden (TMB), microsatellite instability (MSI), immune-related gene expression, immune cell infiltration, and drug sensitivity, with the aim of exploring its potential immunological associations with the tumor microenvironment. RESULTS: OSR2 expression was significantly upregulated or downregulated in the majority of tumor tissues relative to normal counterparts and exhibited distinct cancer-type-specific patterns across clinical stages. CNV alterations and aberrant DNA methylation were closely associated with abnormal OSR2 mRNA expression in multiple cancers. Prognostic analyses indicated that OSR2 expression was significantly associated with overall survival, disease-specific survival, disease-free interval, and progression-free interval across multiple cancer types, showing either risk-associated or protective associations in a tumor-context-dependent manner. Furthermore, OSR2 expression showed strong associations with immune cell infiltration, particularly T-cell subsets, and was significantly correlated with the expression of multiple immune checkpoint-related genes across diverse malignancies. OSR2 expression was also closely associated with TMB, MSI, and sensitivity to multiple anticancer agents. CONCLUSION: Taken together, these findings suggest that OSR2 is associated with prognosis and immune-related features across multiple cancer types. OSR2 may be linked to features of the tumor immune microenvironment through its relationships with immune cell infiltration, immune checkpoint gene expression, and genomic instability, and thus may serve as a candidate biomarker for further investigation in cancer immunotherapy.

CD8⁺ T-cell↗

PubMed2026

Genomic profiling of digestion related enzymes in Anopheles aquasalis a major coastal neotropical malaria vector.

Digestive genes are fundamental for the development and survival of mosquitoes and can serve as a target for the development of strategies for mosquito control or vector-borne disease prevention. Genes related to digestion were identified in the genome of the neotropical malaria vector Anopheles aquasalis by similarity. We used reciprocal BLAST with annotated digestion proteins for Anopheles gambiae. Orthology and evolutionary analyses were performed using MEGA with a bootstrapped phylogenetic tree constructed by the neighbor-joining method, and copy number variation was measured by the standard deviation of the average copy number in each gene family. We identified 241 genes related to digestion in An. aquasalis: 56 genes related to carbohydrate digestion, 51 genes for lipid digestion, and 134 genes for protein digestion. Phylogenetic relationships with other anophelines show that An. aquasalis genes are closely related to those of neotropical mosquitoes Anopheles darlingi and Anopheles albimanus. Orthologous gene clusters are conserved in important families of all four species. Some of these conserved genes are of interest for studies on controlling mosquito vectors, such as larvicidal toxin receptor genes, alpha-amylase, alpha-glucosidase, and maltase; important target genes for transmission-blocking vaccines, such as aminopeptidase N1 and carboxypeptidase B; and the major intestinal serine proteases, such as trypsins and chymotrypsins, which can positively or negatively affect Plasmodium development in the midgut. These data provide a better understanding of digestion-related genes in American anopheline mosquitoes and may support further fundamental and applied studies aimed at malaria control.

Animals↗

PubMed2025

The MTORC1 signaling pathway related gene POLR3G serves as a potential prognostic biomarker in Hepatocellular Carcinoma.

This study aims to investigate the prognostic significance and potential biological functions of the MTORC1 signaling pathway-associated gene POLR3G in Hepatocellular carcinoma (HCC). A prognostic risk model for HCC was developed by integrating HCC-related datasets and associated clinical data obtained from The Cancer Genome Atlas (TCGA) database. The GSVA website was employed to analyze the model genes across pan-cancer datasets, focusing on copy number variations (CNV), single nucleotide variations (SNV), methylation differences, drug sensitivity and immune cell infiltration profiles. Subsequently, we examined the expression levels and prognostic significance of POLR3G in HCC. Utilizing Spearman correlation analysis, we identified genes associated with POLR3G. Furthermore, Gene Set Enrichment Analysis (GSEA) was employed to elucidate the potential signaling pathways in which POLR3G may be involved. The relationship between POLR3G expression and immune cell abundance in HCC samples was assessed using the ssGSEA algorithm. Finally, the impact of POLR3G on HCC cell proliferation was validated through CCK-8 and EDU cell proliferation assays. Through univariate Cox regression analysis and LASSO regression analysis, we established a prognostic risk model for HCC comprising 13 genes. The analysis revealed that individuals categorized in the low-risk group had a markedly improved overall survival probability relative to those in the high-risk group. POLR3G exhibited a markedly elevated expression in HCC tissues when compared to adjacent normal tissues. The expression of POLR3G was correlated with tumor grade, and elevated POLR3G expression was associated with poor prognosis in HCC patients. Furthermore, the expression level of POLR3G was found to be correlated with the level of immune cell infiltration. Knockdown of POLR3G significantly inhibited the proliferative capacity of hepatocellular carcinoma cells. The findings suggest that POLR3G may serve as a potential biomarker influencing the prognosis of hepatocellular carcinoma patients by modulating the tumor immune microenvironment.

Humans↗

PubMed2024

Comparative genomic landscape of lower-grade glioma and glioblastoma.

Biomarkers for classifying and grading gliomas have been extensively explored, whereas populations in public databases were mostly Western/European. Based on public databases cannot accurately represent Chinese population. To identify molecular characteristics associated with clinical outcomes of lower-grade glioma (LGG) and glioblastoma (GBM) in the Chinese population, we performed whole-exome sequencing (WES) in 16 LGG and 35 GBM tumor tissues. TP53 (36/51), TERT (31/51), ATRX (16/51), EFGLAM (14/51), and IDH1 (13/51) were the most common genes harboring mutations. IDH1 mutation (c.G395A; p.R132H) was significantly enriched in LGG, whereas PCDHGA10 mutation (c.A265G; p.I89V) in GBM. IDH1-wildtype and PCDHGA10 mutation were significantly related to poor prognosis. IDH1 is an important biomarker in gliomas, whereas PCDHGA10 mutation has not been reported to correlate with gliomas. Different copy number variations (CNVs) and oncogenic signaling pathways were identified between LGG and GBM. Differential genomic landscapes between LGG and GBM were revealed in the Chinese population, and PCDHGA10, for the first time, was identified as the prognostic factor of gliomas. Our results might provide a basis for molecular classification and identification of diagnostic biomarkers and even potential therapeutic targets for gliomas.

Humans↗

PubMed2026

Unveiling the power of TIIC: A prognostic tool for esophageal adenocarcinoma.

BACKGROUND: Esophageal adenocarcinoma (EAC) remains a lethal malignancy with limited prognostic tools for guiding immunotherapy. Tumor-infiltrating immune cells (TIICs) play a critical role in EAC prognosis and treatment response. METHODS: We integrated single-cell RNA sequencing and bulk transcriptome data from TCGA and GEO databases. TIIC-specific RNAs were identified via tissue specificity index calculation combined with machine learning feature selection. Twenty machine learning algorithms were benchmarked to construct an optimal TIIC signature score (TIIC-Score) based on the comprehensive C-index. Immunotherapy response, genomic mutation, and copy number variation were analyzed. Summary-data-based Mendelian randomization (SMR) and two-sample Mendelian randomization (MR) were performed to explore genetic associations. Core prognostic TIIC-related genes were functionally validated in esophageal cancer cell lines through loss-of-function assays. RESULTS: The TIIC-Score demonstrated robust prognostic value for 1-, 2-, and 3-year overall survival across multiple cohorts, outperforming 22 published models. High TIIC-Score was associated with poor survival and increased chromosomal instability. Mutation profiling revealed high frequencies of TP53 (78.2%), TTN (48.7%), and SYNE1 (30.8%). MR analysis identified a significant association between gastro-oesophageal reflux and EAC risk at SNP rs8130507. Functionally, CCNI was upregulated in esophageal cancer cells, and its knockdown suppressed malignant phenotypes while promoting apoptosis, supporting its pro-tumorigenic role. CONCLUSION: The TIIC-Score provides a novel prognostic framework for EAC that effectively stratifies patient risk and may help identify individuals most likely to benefit from immunotherapy.

Esophageal adenocarcinoma↗

PubMed2025

Absolute copy number aware CNV calling of sub-megabase segments in ultra-low coverage single-cell DNA sequencing data.

Recent advances in ultra-low coverage whole-genome sequencing (WGS) of single cells have enabled detailed analysis of copy number variation at a throughput approaching that of single-cell RNA sequencing. However, downstream computational methods have not seen comparable advances and are largely adaptations of deep sequencing methodology with reduced precision. Here, we present ASCENT, a computational method built to take full advantage of modern direct tagmentation-based WGS at ultra-low depth. Using joint segmentation with high-resolution bins, we accurately detect small segments, achieving accurate copy number profiles even at 100 000 reads per cell. ASCENT implements true absolute copy state inference for single cells, based on statistical modeling of coverage rather than comparison to a reference, while taking variable segment copy state into account. Further, ASCENT implements per-segment copy-neutral loss of heterozygosity (LOH) calling without the need for non-tumor or bulk WGS reference. When applied to a pediatric B-ALL sample, ASCENT finds copy-neutral LOH in a small segment and a minor subclone defined by breakpoints missed in bulk WGS. Thus, by applying appropriate computational methods, single-cell WGS provides clear advantages over bulk, even at a relatively low cell number and sequencing depth.

DNA Copy Number Variations↗

PubMed2026

Unraveling the genomic blueprint of the Indian black soldier fly: From genome assembly to evolutionary insights.

The black soldier fly (BSF) (Hermetia illucens) has been renowned for its sustainable bioconversion capabilities, resulting in smart protein production with wide applications in animal feed, bioenergy, and biofertilizer. However, the genetic mechanisms underlying efficient bioconversion and productivity remain poorly understood. To advance strain-specific applications and strengthen genetic resource availability, we present the whole genome sequencing (WGS) data for an Indian isolate of black soldier fly. The assembled genome was 1.46 Gb with a scaffold N50 of 172.7 Mb, and a GC content of 42.6%. Furthermore, 64.17% of genomic sequences were masked as repeated, and 14,317 protein-coding sequences were identified. Variant analysis against the reference genome identified 34.44 million variants (∼33.25 million SNPs and ∼ 1.18 million INDELs), with the majority (99.3%) classified as MODIFIER, 0.54% as LOW impact, 0.14% as MODERATE, and only 0.003% as HIGH impact. Comparative genomic analysis with other related species revealed expansions of gene families in BSF associated with Immune effector (Antimicrobial peptides (AMPs), Lysozymes, and Peptidoglycan Recognition Protein (PGRP) and Detoxification (cytochrome P450 enzymes). Notably, AMPs in the Indian isolate showed enhanced copy number variation in defensin (27) and PGRP (40) compared to reference BSF, suggesting potential regional adaptations to pathogen exposure. Collectively, this genomic data provides an improved resource for evolutionary studies, functional genomics, and targeted genetic improvement of BSF for sustainable bioconversion applications.

Comparative genomics↗

PubMed2026

Using cancer profiles to identify synthetic lethal therapeutic targets and predictive biomarkers in cancer gene dependency data.

MOTIVATION: Large scale loss-of-function screens utilising CRISPR or siRNA can provide profound insights into the importance of individual genes for the survival of a cancer cell and can drive the identification of therapeutic targets and biomarkers, and the development of targeted drugs. However, the analysis of these data and the substantial bodies of metadata that relate to them, is technically challenging and typically requires substantial expertise in data science and computer coding. RESULTS: To facilitate the analysis of cancer gene dependency data by cancer biologists and clinical scientists, we have developed DepMine-a computational toolkit providing a powerful system for framing complex queries relating cancer gene dependency to the underlying genetic changes that occur in cancer cells. DepMine identifies synthetic lethal relationships between putative target genes and complex 'cancer profiles' built from user-specified combinations of mutations, copy-number variation, and expression levels, and can refine these to optimal biomarker definitions for target dependency. AVAILABILITY: The Python implementation of DepMine and associated data files can be obtained at https://github.com/UOSbioinformaticslab/depmine and is free to academics and Not-For-Profit organisations. The DepMine release referenced in this paper is archived as DOI: 10.5281/zenodo.19570601.

Humans↗

PubMed2024

Contribution of copy number variations to education, socioeconomic status and cognition from a genome-wide study of 305,401 subjects.

Educational attainment (EA), socioeconomic status (SES) and cognition are phenotypically and genetically linked to health outcomes. However, the role of copy number variations (CNVs) in influencing EA/SES/cognition remains unclear. Using a large-scale (n = 305,401) genome-wide CNV-level association analysis, we discovered 33 CNV loci significantly associated with EA/SES/cognition, 20 of which were novel (deletions at 2p22.2, 2p16.2, 2p12, 3p25.3, 4p15.2, 5p15.33, 5q21.1, 8p21.3, 9p21.1, 11p14.3, 13q12.13, 17q21.31, and 20q13.33, as well as duplications at 3q12.2, 3q23, 7p22.3, 8p23.1, 8p23.2, 17q12 (105 kb), and 19q13.32). The genes identified in gene-level tests were enriched in biological pathways such as neurodegeneration, telomere maintenance and axon guidance. Phenome-wide association studies further identified novel associations of EA/SES/cognition-associated CNVs with mental and physical diseases, such as 6q27 duplication with upper respiratory disease and 17q12 (105 kb) duplication with mood disorders. Our findings provide a genome-wide CNV profile for EA/SES/cognition and bridge their connections to health. The expanded candidate CNVs database and the residing genes would be a valuable resource for future studies aimed at uncovering the biological mechanisms underlying cognitive function and related clinical phenotypes.

Humans↗

PubMed2026

Genomic Profiling of Anophthalmia/Microphthalmia-Associated CNVs Reveals Complex Genotype-Phenotype Correlations and Incomplete Penetrance.

BACKGROUND: Anophthalmia/microphthalmia (A/M) is a severe congenital ocular malformation characterized by the complete absence or small size of the eye bulb. Interpreting copy number variations (CNVs) in A/M is challenged by variable genotype-phenotype correlations and reduced penetrance. This study investigated the genetic etiology of A/M-associated CNVs. METHODS: Genomic profiling was performed on four unrelated families presenting with ocular anomalies or harboring A/M-susceptible CNVs. Variants were evaluated by integrating American College of Medical Genetics and Genomics (ACMG) guidelines with clinical phenotypes and familial segregation. RESULTS: An inherited 8.13 Mb deletion (8p23.3p23.1) in Patient 1 was excluded due to genotype-phenotype mismatch. Patients 2 and 3 harbored de novo pathogenic deletions involving OTX2 (14q22.3) and SOX2 (3q26.33), causing typical A/M. Case 4 revealed a 14q22.2q23.1 deletion encompassing OTX2 in a fetus and mother without ocular anomalies, consistent with the incomplete penetrance of OTX2-related microphthalmia. Thus, CNV-induced haploinsufficiency causes A/M with high phenotypic variability. CONCLUSION: Accurate CNV interpretation requires robust genotype-phenotype correlation and careful assessment of incomplete penetrance to prevent diagnostic pitfalls and improve genetic counseling.

Female↗

PubMed2025

LYCEUM: learning to call copy number variants on low-coverage ancient genomes.

MOTIVATION: Copy number variants (CNVs) are pivotal in driving phenotypic variation that facilitates species adaptation. They are significant contributors to various disorders, making ancient genomes crucial for uncovering the genetic origins of disease susceptibility across populations. However, detecting CNVs in ancient DNA (aDNA) samples poses substantial challenges due to several factors: (i) aDNA is often highly degraded; (ii) contamination from microbial DNA and DNA from closely related species introduces additional noise into sequencing data; and finally, (iii) the typically low-coverage of aDNA renders accurate CNV detection particularly difficult. Conventional CNV calling algorithms, which are optimized for high-coverage read-depth signals, underperform under such conditions. RESULTS: To address these limitations, we introduce LYCEUM, the first machine learning-based CNV caller for aDNA. To overcome challenges related to data quality and scarcity, we employ a two-step training strategy. First, the model is pre-trained on whole genome sequencing data from the 1000 Genomes Project, teaching it CNV-calling capabilities similar to conventional methods. Next, the model is fine-tuned using high-confidence CNV calls derived from only a few existing high-coverage aDNA samples. During this stage, the model adapts to making CNV calls based on the downsampled read depth signals of the same aDNA samples. LYCEUM achieves accurate detection of CNVs even in typically low-coverage ancient genomes. We also observe that the segmental deletion calls made by LYCEUM show correlation with the demographic history of the samples and exhibit patterns of negative selection inline with natural selection. AVAILABILITY AND IMPLEMENTATION: LYCEUM is available at https://github.com/ciceklab/LYCEUM.

DNA Copy Number Variations↗

PubMed2025

Epstein-Barr Virus-Associated Gastric Cancer: A Histopathologic Study With Comprehensive Molecular Profiling.

A subset of gastric cancers (GCs) is linked to Epstein-Barr virus (EBV) infection. This study aims to characterize the histopathological and molecular features of EBV-associated GCs (EBVaGCs), focusing on predictive biomarkers and genomic and transcriptomic analysis. A total of 35 primary EBVaGCs were considered. The presence of EBV was confirmed with in situ hybridization. Immunohistochemical analyses for HER2, PD-L1, claudin 18.2, and mismatch repair proteins were performed. Genomic and transcriptomic profiles were assessed using AmoyDx Master Panel, which can identify single-nucleotide variants, InDels, and copy number variations on 571 hot genes, as well as microsatellite status, tumor molecular burden, and homologous recombination deficiency at the DNA level; however, at the RNA level, it identifies rearrangements/fusions in 45 genes and also quantifies the expression of 2396 cancer-related transcripts. The following histotypes were identified: carcinoma with lymphoid stroma (CLS; 69%), tubular (20%), and mixed (11%). Most cases were associated with atrophic gastritis (71%), and only 11% with dysplasia. The vast majority (94%) of EBVaGCs expressed EBV-encoded RNA in all tumor cells. Mismatch repair deficiency and HER2 overexpression were each observed in 6% of cases, whereas all tumors had a PD-L1-combined positive score ≥10. Sixty-six percent of cases showed moderate/strong claudin 18.2 expression in ≥75% of cancer cells. The most frequently altered genes were PIK3CA (41%) and ARID1A (17%). Transcriptomic analysis revealed substantial differential gene expression between EBVaGCs and EBV-negative controls, with upregulation of genes involved in antigen presentation, natural killer cell-mediated cytotoxicity, and cytokine-cytokine receptor interaction in EBVaGCs. Within EBVaGC, CLS showed higher expression of immune-related transcripts and higher PD-L1 expression than other histotypes. This study establishes EBVaGC as a distinct molecular class, with a distinctive profile of genomic alterations and expression of predictive biomarkers, and also with a unique immune microenvironment with enhanced cytotoxic activity. The findings highlight EBV's role in early tumor development and EBVaG-CLS as a distinct subgroup within EBVaGC, characterized by unique morphologic features and a pronounced immune activation profile.

Humans↗