Mol. Genet. Genomics [JOURNAL]
Sun
200 papers
Reliable estimates of Japanese encephalitis virus evolutionary rate supported by a formal test of temporal signal.
Ukraintceva P, Bondaryuk A, Sakhabeev R
Mol Genet Genomics · 2025 Nov · PMID 41222823 · Publisher ↗
The single-stranded RNA viruses exhibit stupendously high evolutionary rate spanned several orders of magnitude. The accurate and reliable estimates of the virus evolutionary rate are of importance for the robust interpr...
The single-stranded RNA viruses exhibit stupendously high evolutionary rate spanned several orders of magnitude. The accurate and reliable estimates of the virus evolutionary rate are of importance for the robust interpretation of outbreak investigations and are critical for understanding short-term virus transmission patterns. In the previous studies, the substitution rate of the Japanese encephalitis virus (JEV) and time to the most recent common ancestor (MRCA) were reported, however, the estimates are substantially different between some of the studies. Importantly, temporal signal in data was not evaluated by a formal test. The purpose of our study is to estimate the substitution rate and the age of the JEV common clade (GI-GV) and of two JEV genotypes (GI and GIII) supported by a formal Bayesian analysis of temporal signal in the open reading frame (ORF) nucleotide data. Additionally, we assessed temporal signal in the data from the previous work to explain the observed discrepancy between the reported JEV evolutionary rate estimates. Results showed that the mean substitution rate of the JEV GI-GV was 2.41 × 10 nucleotide substitution per site per year (s/s/y) with 95% highest posterior density (HPD) interval of 1.67 × 10-3.14 × 10 or approximately 2.5 nucleotide substitutions per ORF (10,296 nucleotides) per year. That is one of the lowest substitution rates among the species closely related to JEV and other well-studied members of mosquito-borne flaviviruses. The mean substitution rate of GI and GIII was evaluated to be 4.13 × 10 s/s/y (95% HPD interval, 3.45 × 10- 4.82 × 10) and 6.17 × 10 s/s/y (95% HPD interval 3.84 × 10-8.62 × 10), accordingly, with the ages of clades of 153 (95% HPD, 87-237) and 216 (95% HPD, 139-317), respectively. The mean root height of JEV is 1234 years (95% HPD, 407-2333).
Cloning and characterization of soybean gene Fg4 encoding a novel flavonol 3-O-glucoside/galactoside rhamnosyltransferase.
Di S, Rodas FR, Murai Y … +2 more , Yan F, Takahashi R
Mol Genet Genomics · 2025 Nov · PMID 41222750 · Publisher ↗
The glycosylation patterns of flavonol glycosides (FGs) in soybean leaves are associated with productivity and insect resistance. The structure of FGs is conditioned by four flavonoid glycoside glycosyltransferase (FGG)...
The glycosylation patterns of flavonol glycosides (FGs) in soybean leaves are associated with productivity and insect resistance. The structure of FGs is conditioned by four flavonoid glycoside glycosyltransferase (FGG) genes, Fg1 (6"-glucoside present), Fg2 (6"-rhamnoside present), Fg3 (2"-glucoside present), and Fg4 (2"-rhamnoside present). We previously cloned and characterized the Fg1 to Fg3 genes. This study was conducted to comprehensively identify FGG genes by isolating the Fg4 gene. Leaves of the cultivar, Clark (Fg4 allele), contained FGs with rhamnose at the 4"-position, whereas those of the cultivar A.K. (fg4 allele), were devoid of 4"-rhamnoside. Their F population segregated in three Clark-type: 1 A.K.-type ratios, suggesting that a single gene controlled the existence of 4"-rhamnoside. Based on genetic mapping, we cloned a candidate gene, Glyma.06G235000, with three amino acid substitutions between cultivars. Recombinant protein of Clark acted on kaempferol 3-O-rhamnosyl-(1→6)-galactoside and generated a product with a similar retention time to kaempferol 3-O-rhamnosyl-(1→4)-[rhamnosyl-(1→6)-glalactoside]. Furthermore, it acted on kaempferol 3-O-glucoside/galactoside and generated products with similar retention times to kaempferol 3-O-rhamnosyl-(1→2)-glucoside/galactoside. The A.K. protein did not function presumably due to G293R mutation. The cleaved amplified polymorphic sequence (CAPS) marker to detect the mutation co-segregated with FG composition. These results suggest that Glyma.06G235000 corresponds to the Fg4 gene and that the protein attaches rhamnose to the 2"- or 4"-position, depending on the substrates. Information of all FGG genes may be useful for developing cultivars with the desired FGG composition.
Klebsiella quasipneumoniae: a novel sequence type 1699 by whole genome sequence analysis from food fish in India.
Sabu J, Sahadevan S, Hamza MK … +8 more , Ojha R, Shome BR, Raisen C, Elsadek MFKK, Alshehri EH, Dara PK, Holmes MA, Sivaraman GK
Mol Genet Genomics · 2025 Oct · PMID 41137939 · Publisher ↗
Klebsiella quasipneumoniae, an emerging member of the Klebsiella genus, has recently garnered attention as a clinically significant pathogen capable of causing severe human infections. Despite its pathogenic potential, i...
Klebsiella quasipneumoniae, an emerging member of the Klebsiella genus, has recently garnered attention as a clinically significant pathogen capable of causing severe human infections. Despite its pathogenic potential, it is frequently misidentified as Klebsiella pneumoniae due to their close genetic and phenotypic similarities, leading to diagnostic challenges and potential implications for treatment and epidemiological surveillance. This study addresses a critical gap in our understanding of K. quasipneumoniae by applying high-resolution genomic tools to distinguish it from its more well-characterized K. pneumoniae, assessed their AMR profiles and evaluate the limitation of conventional identification methods. Whole genome of a gram-negative K. quasipneumoniae (Klebsiella ST1699) bacterium found in an edible fish bought from a retail market in Assam, India. Whole Genome Sequencing (WGS) using the Illumina sequencing and species identification by Mash Screen confirmed the authenticity of K. quasipneumoniae. We assembled the 5.21 Mb complete genome of Klebsiella ST1699 and harboured several Antimicrobial Resistance Genes (ARGs) viz., blaLAP-2, blaOKP-B-1, fosA, tet(A), Sul2, dfrA14. OqxA and OqxB, and identified as a novel sequence type 1699 K. quasipneumoniae (ST 1699) from the edible fish in the retail market, Assam, India. We also performed comparative genome analysis with 6 other strains of K. quasipneumoniae genome sequences in the NCBI database. K. quasipneumoniae represents a clinically relevant and underrecognized pathogen with significant antimicrobial resistance. Improved molecular diagnostics are essential for accurate identification and effective infection control. Misidentification may contribute to underreporting and inappropriate therapeutic strategies, underscoring the need for heightened awareness and surveillance. Our findings have implications for diagnostic accuracy, resistance surveillance, and the development of targeted therapeutic strategies.
Characterization of the complete mitogenomes of Synodontis decorus and Synodontis petricola (Teleostei: Mochokidae) with a phylogenetic analysis of the Mochokidae family.
Sun CH, Li XR, Zhan YJ … +1 more , Lu CH
Mol Genet Genomics · 2025 Oct · PMID 41137929 · Publisher ↗
Synodontis, of great edible and ornamental value, is the most species-rich genus of the catfish family Mochokidae, but comparative studies based on its mitogenome data are still lacking. Therefore, we sequenced and analy...
Synodontis, of great edible and ornamental value, is the most species-rich genus of the catfish family Mochokidae, but comparative studies based on its mitogenome data are still lacking. Therefore, we sequenced and analyzed the complete mitogenomes of Synodontis decorus and Synodontis petricola and compared them with those of other Mochokidae or Synodontis species; these were determined to be 16,574 and 16,529 bp, respectively. A phylogenetic analysis further confirmed the position of Synodontis in Mochokidae and showed that the genus Synodontis is polyphyletic. These results are beneficial to a further understanding of the phylogenetic evolution of the Mochokidae family and Synodontis genus and provide a basis for species identification and conservation genetics.
Regulation of melanin synthesis in goat hair follicles by melatonin through the Wnt/β-catenin pathway.
Yu F, Liu K, Wang Z … +5 more , Wang S, Li H, Zhao J, Gao X, He J
Mol Genet Genomics · 2025 Oct · PMID 41137864 · Publisher ↗
To investigate the mechanism by which melatonin influences melanin production in goat melanocytes, and to provide a theoretical foundation for the genetic principles underlying animal hair color formation, dorsal skin ti...
To investigate the mechanism by which melatonin influences melanin production in goat melanocytes, and to provide a theoretical foundation for the genetic principles underlying animal hair color formation, dorsal skin tissues were collected approximately 5 cm behind the shoulder of 4-day-old Jiaohe black goats. Melanocytes were localized using immunohistochemistry and immunofluorescence techniques, isolated from hair follicle tissues through enzyme digestion, and treated with different concentrations of melatonin. Cell viability, proliferation, apoptosis, and melanin synthesis were assessed using CCK8, EdU, flow cytometry, and melanin content assays, respectively. Melanocytes were subjected to transcriptome sequencing, differential gene screening, and functional enrichment analyses. The expression of relevant genes and proteins was verified using real-time quantitative PCR and western blotting, respectively. Melanocytes were determined to be located above the hair follicle papilla and in the outer root sheath, and were successfully isolated and cultured. Melatonin inhibited melanocyte proliferation, promoted apoptosis, and inhibited melanin synthesis. After RNA sequencing, 952 and 1300 differentially expressed genes (DEGs) were screened by comparing the two groups respectively, which were mainly enriched in Melanogenesis and the Wnt signaling pathway. Validation experiments confirmed that melatonin inhibited the expression of genes and proteins related to the Wnt/β-catenin signaling pathway. Notably, treatment with an agonist of the Wnt/β-catenin pathway attenuated the inhibitory effect of melatonin. This study reveals that melatonin can reduce melanocyte viability, inhibit proliferation, promote apoptosis, reduce melanogenesis, and affect melanin synthesis through the Wnt/β-catenin signaling pathway. This study provides a theoretical basis for understanding the regulatory role of melatonin in hair color formation in animals.
Making sense of carbonic anhydrase function in zebrafish using antisense morpholinos.
Aspatwar A
Mol Genet Genomics · 2025 Oct · PMID 41107628 · Full text
Understanding gene function in vertebrate development requires tools that allow precise and timely manipulation of gene expression. Zebrafish (Danio rerio), with its transparent embryos and rapid development, offers an i...
Understanding gene function in vertebrate development requires tools that allow precise and timely manipulation of gene expression. Zebrafish (Danio rerio), with its transparent embryos and rapid development, offers an ideal model to study vertebrate biology. This review explores how morpholino oligonucleotides (MOs), a widely used tool for transient gene knockdown, have been employed to investigate the roles of carbonic anhydrases (CAs) and carbonic anhydrase-related proteins (CARPs) in zebrafish. CAs are metalloenzymes, while CARPs are inactive isozymes that play critical roles in pH regulation, ion transport, CO₂ metabolism, and protein interactions influencing diverse biological functions. Many of the MO knockdown studies presented here have been extensively conducted in our laboratory over the past decade, revealing novel roles for CAs in neural development, reproduction, and swim bladder formation. These studies also confirm roles previously reported in humans, such as pigmentation, acid-base homeostasis, neural development, and motor coordination. We discuss technical aspects of MO design, delivery, and validation, and address common challenges such as off-target effects, transient gene silencing, and the necessity of rescue experiments. In addition, the review includes a comparative analysis of MOs versus CRISPR/Cas9-based genome editing, underscoring their respective advantages and limitations for functional genomics. In conclusion, this review provides not only a methodological guide but also biological insights into CA function in zebrafish, highlighting how antisense technology continues to inform vertebrate development and disease modeling. The lessons learned here may inform the study of other gene families and support translational research in carbonic anhydrase-related human disorders.
Comparative evaluation of MG-RAST, MEGAN6 and Kraken2 for whole metagenome analysis of saffron corms for bacterial community structure and function.
Sharma N, Verma A, Ambardar S … +2 more , Raj S, Vakhlu J
Mol Genet Genomics · 2025 Oct · PMID 41085703 · Publisher ↗
Taxonomic and functional analysis outcomes are greatly influenced by the algorithms and databases used by different software. The present study evaluated three widely used software; MG-RAST, MEGAN6 and Kraken2 for the an...
Taxonomic and functional analysis outcomes are greatly influenced by the algorithms and databases used by different software. The present study evaluated three widely used software; MG-RAST, MEGAN6 and Kraken2 for the analysis of the shotgun metagenomic data of saffron cormosphere. Kraken2 outperformed other two for taxonomy. It gave significantly higher alpha diversity values, indicating greater taxonomic diversity and evenness compared to MG-RAST and MEGAN6. The limitation of the Kraken2 is that it does not support functional analysis which both MG-RAST and MEGAN6 can do in addition to taxonomical analysis. Additionally, they can analyse sequence data generated by different sequencing methods such as Sanger, Illumina and PacBio. MG-RAST is comparatively easy to use and integrates large number of databases than MEGAN6, however data processing is relatively slow. Additionally, MEGAN6 has a feature of extraction of genes automatically, that allows user to study sub set of specific genes, though in MG-RAST, it can be done manually and the process is cumbersome. The difference in the outcome of these three software can be attributed to differences in the databases, algorithms, and parameters used by the three software. A combined approach using the results from more than one software can be considered to create a more comprehensive taxonomy and functional profile until a factotum software is developed.
AL137246.1 inhibits esophageal squamous cell carcinoma cisplatin resistance by suppressing the transcriptional activity of GLI2 on ABCC1.
Song L, Zhuang L, Ke B … +1 more , Wang L
Mol Genet Genomics · 2025 Oct · PMID 41085663 · Publisher ↗
Esophageal squamous cell carcinoma (ESCC) is a malignant cancer. At present, platinum-based chemotherapy drugs are mainly used to treat ESCC patients. However, certain patients have developed significant resistance to ci...
Esophageal squamous cell carcinoma (ESCC) is a malignant cancer. At present, platinum-based chemotherapy drugs are mainly used to treat ESCC patients. However, certain patients have developed significant resistance to cisplatin, which greatly limits the effectiveness of treatment. Hence, it is urgent to probe the mechanism of cisplatin chemotherapy resistance in ESCC. To clarify the association between AL137246.1 level and cisplatin resistance in ESCC patients, a total of 30 pairs of cisplatin-sensitive and cisplatin-resistant ESCC tissues were collected, and 30 non-cancerous tissues were used as controls. Survival analysis was used to detect the relationship between AL137246.1 level and ESCC prognosis. Then, Eca109 and Kyse70 cells were treated with cisplatin to induce the ESCC cisplatin resistance model. For understanding the detailed molecular process involving AL137246.1 in the development of cisplatin resistance in ESCC, the binding relationship between GLI2 and ABCC1 promoter was determined by dual luciferase and ChIP assays. RIP was applied to test the interaction between AL137246.1 and GLI2. Cell viability and proliferation were detected by CCK8 and Edu assays, respectively. Cell apoptosis was detected by flow cytometry. The results indicated that AL137246.1 level was reduced in ESCC and indicated a poor prognosis of ESCC. AL137246.1 overexpression was associated with increased sensitivity to cisplatin in ESCC cells, which was reversed by ABCC1 upregulation. Mechanistically, GLI2 led to the transcriptional activation of ABCC1 in ESCC. In conclusion, AL137246.1 inhibited the expression of ABCC1 by binding to GLI2, thereby enhancing the sensitivity of ESCC to cisplatin. This study suggested that AL137246.1, as a potential molecular target, has important application prospects in improving the sensitivity of ESCC to cisplatin chemotherapy.
The crucial role of immune factors in susceptibility to SARS-CoV-2 infection and severity of COVID-19.
Yu XH, Cao RR, Yang YQ … +3 more , Cao HW, Deng FY, Lei SF
Mol Genet Genomics · 2025 Oct · PMID 41085581 · Publisher ↗
Susceptibility to SARS-CoV-2 infection and severity of COVID-19 have high heterogeneity, but the underlying factors for such heterogeneity were largely unknown. This study aimed to investigate whether genetically determi...
Susceptibility to SARS-CoV-2 infection and severity of COVID-19 have high heterogeneity, but the underlying factors for such heterogeneity were largely unknown. This study aimed to investigate whether genetically determined immune phenotypes contribute to the variability in COVID-19 outcomes, by integrating large-scale GWAS data to assess genetic correlations, causal associations, and pleiotropic gene functions. Based on the summary statistics from GWAS analyses for immune phenotypes and COVID-19 outcomes, comprehensive analyses were performed to elucidate the associations between immune phenotypes and COVID-19 pairs. The genetic correlations between COVID-19 outcomes and immune phenotypes were commonly observed, and 60 immune phenotypes were significantly correlated with four COVID-19 outcomes (64 pairs) (FDR < 0.05). Treg T cell panel and B cell panel have relatively more significant pairs in number. Pairwise gene-based analyses identified numerous pleiotropic genes for significant pairs identified. The gene set enrichment analysis revealed the involvement of the identified pleiotropic genes in complex immune processes. We observed significant causal effects of six immune phenotypes from 4 trait panels on any one of the two COVID-19 outcomes, and of which CD19 on naïve-mature B cell was the only significant immune phenotype shared by the two COVID-19 outcomes. The findings greatly improved our understanding of the interaction between immune response and COVID-19 outcome, and also contribute to the detection of susceptible individuals and the design of therapeutic strategies from the perspectives of immunology. In conclusion, our study provides genetic evidence that immune phenotypes, particularly B cell and Treg traits, play a causal role in susceptibility to SARS-CoV-2 infection and progression to severe COVID-19.
Comprehensive study of W06A7.4 and TMEM144 mediated pathways in aging: insights from Caenorhabditis elegans to human.
Wang LF, Liu X, Li S … +4 more , Li R, Li R, Yan F, Jing X
Mol Genet Genomics · 2025 Sep · PMID 41026247 · Publisher ↗
Aging is a major biological process underlying increased risk of chronic and neurodegenerative diseases, yet its molecular mechanisms remain incompletely defined. Our study systematically investigates the conserved funct...
Aging is a major biological process underlying increased risk of chronic and neurodegenerative diseases, yet its molecular mechanisms remain incompletely defined. Our study systematically investigates the conserved functions and pathways of W06A7.4 in Caenorhabditis elegans and its human homolog TMEM144 in the regulation of aging, combining genetic manipulation in model organisms, analysis of human clinical samples, and functional assays in cell lines. The results demonstrate that W06A7.4 promotes longevity in C. elegans through synergistic effects with dietary restriction, reduction of oxidative damage, modulation of IIS and mTOR signaling, and maintenance of mitochondrial membrane potential. In human samples and cellular models, TMEM144 expression increases with age and in Alzheimer's disease. Our results suggest that TMEM144 may be involved in the regulation of glucose transport and mitochondrial respiration via the downstream protein TIMMDC1. These findings advance our understanding of evolutionarily conserved aging pathways and identify W06A7.4/TMEM144 as promising molecular targets for anti-aging and neurodegenerative disease interventions.
Unravelling mutation patterns in Extended-Spectrum β-Lactamases for precision drug design against AMR in Enterobacteriaceae.
Bano N, Raza K
Mol Genet Genomics · 2025 Sep · PMID 41021041 · Publisher ↗
Antimicrobial resistance (AMR) presents a critical global challenge, causing over 1.27 million deaths annually, with projections reaching 10 million by 2050. Among the most concerning contributors are Enterobacteriaceae,...
Antimicrobial resistance (AMR) presents a critical global challenge, causing over 1.27 million deaths annually, with projections reaching 10 million by 2050. Among the most concerning contributors are Enterobacteriaceae, particularly Escherichia coli and Klebsiella pneumoniae, which harbour Extended-Spectrum β-Lactamase (ESBL) genes-enzymes that hydrolyse β-lactam antibiotics and confer resistance-such as bla-CTX-M, bla-SHV, and bla-TEM. These genes confer resistance to β-lactam antibiotics, including penicillins and cephalosporins, limiting treatment options for urinary tract infections, bloodstream infections, and pneumonia. The World Health Organisation has classified these pathogens as critical targets for new drug development. In this study, we comprehensively analysed all known variants of bla-CTX-M, bla-SHV, and bla-TEM genes along with their wild-type sequences. Using a multi-step computational approach, we assessed guanine-cytosine (GC) content, single nucleotide polymorphisms (SNPs; single-base changes in DNA), insertion and deletion (InDel) variants (mutations involving nucleotide addition or removal), codon usage patterns, transcription factor binding sites (TFBS; DNA regions regulating gene expression), amino acid composition, protein stability, mutational hotspots, nucleotide and amino acid mutation frequencies, hydrophobicity, isoelectric point, aromaticity, aliphatic index, and molecular flexibility. The integrated dataset maps conserved regions and identifies residues frequently associated with resistance phenotypes. Our findings provide a framework for predicting resistance-associated mutation patterns and identifying genomic regions suitable for resistance-free drug targeting. These insights support prioritising drug target sites, optimising screening libraries, and generating high-quality datasets for machine learning-based precision drug design.
A de novo nonsense variant in RPS10 causes Diamond-Blackfan anaemia in an Indian patient: clinical and functional evidence.
Kamble P, Saptarshi A, Mudaliar S … +2 more , Kanvinde P, Kedar PS
Mol Genet Genomics · 2025 Sep · PMID 40960598 · Publisher ↗
Diamond-Blackfan anaemia (DBA) is a rare inherited disorder marked by early-onset macrocytic anaemia and erythroid hypoplasia, resulting from mutations in ribosomal protein genes. Despite growing genetic insights, data o...
Diamond-Blackfan anaemia (DBA) is a rare inherited disorder marked by early-onset macrocytic anaemia and erythroid hypoplasia, resulting from mutations in ribosomal protein genes. Despite growing genetic insights, data on functional validation remain limited in India; here we report a novel RPS10 mutation with functional validation and provide genotype-phenotype correlation by integrating our findings with all previously reported RPS10 variants. A clinically suspected Diamond-Blackfan anaemia (DBA) case was evaluated through haematological profiling, bone marrow examination, and erythrocyte adenosine deaminase (eADA) activity measurement. Whole exome sequencing (WES) was followed by Sanger sequencing to identify and validate a novel pathogenic variant. Gene expression of ribosomal and regulatory genes was analysed by quantitative RT-PCR, and rRNA processing analysis was carried out to assess functional impact. The proband presented with severe macrocytic anaemia, reticulocytopenia, and erythroid hypoplasia consistent with Diamond-Blackfan anaemia (DBA). Whole exome sequencing identified a novel heterozygous nonsense variant in RPS10 (c.206G > A; p.Trp69Ter), and Sanger sequencing confirmed the variant as de novo. Gene expression analysis revealed significant upregulation of TP53 and downregulation of RPS10 and GATA1, indicating ribosomal dysfunction and activation of the p53 pathway. Additionally, the rRNA processing defect validated the pathogenicity of the novel RPS10 variant. This study identifies a novel de novo nonsense variant in RPS10 associated with Diamond-Blackfan anaemia, with supporting functional evidence of haploinsufficiency and p53 pathway activation. These findings expand the mutational spectrum of RPS10 and underscore the diagnostic value of integrating genomic and functional analyses in rare haematological disorders, while also contributing to ongoing efforts to delineate genotype-phenotype correlations in DBA.
Performance comparison of germline variant calling tools in sporadic disease cohorts.
Song Q, Zhai J, Chen C … +4 more , Li H, Cao A, Yuan B, An Y
Mol Genet Genomics · 2025 Sep · PMID 40913732 · Publisher ↗
Accurate variant calling is essential for next-generation sequencing (NGS)-based diagnosis of rare diseases, yet most benchmarking studies have focused on standard cell lines or trio-based samples, with limited relevance...
Accurate variant calling is essential for next-generation sequencing (NGS)-based diagnosis of rare diseases, yet most benchmarking studies have focused on standard cell lines or trio-based samples, with limited relevance to sporadic cases. Here, we systematically compared the performance of DeepVariant and GATK HaplotypeCaller in two Chinese cohorts of patients with sporadic epilepsy (EP) and autism spectrum disorder (ASD). DeepVariant exhibited higher precision and sensitivity in detecting single nucleotide variants (SNVs), while GATK showed a distinct advantage in identifying rare variants, which are often key to understanding the genetic basis of rare diseases. Comparative analyses based on disease-related gene panels further highlighted differences in the identification of potentially deleterious variants. These findings reveal important trade-offs between variant callers and emphasize the need to tailor variant-calling strategies to specific research and clinical contexts. Our study provides practical vision for optimizing germline variant detection pipelines in sporadic neurodevelopmental disorders, offering broader insights for precision medicine applications.
Rare phenotypes of white coat color in Simmental calves: genetic causes of syndromic forms of albinism and depigmentation.
Jacinto JGP, Leuenberger T, Hauser M … +4 more , Häfliger IM, Seefried FR, Letko A, Drögemüller C
Mol Genet Genomics · 2025 Sep · PMID 40913728 · Full text
The aim of this study was to investigate three unrelated Simmental calves with atypical white coat color, identify potential genetic causes using a trio-based whole-genome sequencing approach, and assess the prevalence o...
The aim of this study was to investigate three unrelated Simmental calves with atypical white coat color, identify potential genetic causes using a trio-based whole-genome sequencing approach, and assess the prevalence of the identified variants in the breed. Several inherited alleles affecting coat color, ranging from fawn to red spotted and white-headed, have been described in Simmental cattle originating from Switzerland. However, no genetic variant has yet been associated with an almost completely white coat in this breed. Clinical examination revealed different syndromic disorders of white coat color in Simmental in all three cases, and pedigree records indicated recessive inheritance. Filtering for rare protein-changing variants revealed an independent homozygous variant that could be the cause in each case: a likely pathogenic missense variant in TYR (NP_851344.1:p.Pro428Leu) in case 1 with oculocutaneous albinism type 1, a likely pathogenic missense variant in GRID1 (XP_024842694.1:p.Pro489His) in case 2 with short stature-auditory depigmentation syndrome, and a frameshift variant of uncertain significance in RAD54B (NP_001179884.1:p.Ala722_Gly724delinsAsnLeuIlePheCys*) in case 3 with a multisystem depigmentation syndrome. Validation by Sanger sequencing confirmed the variant genotypes, and parental heterozygosity supported recessive inheritance. These variants were almost entirely absent from other breeds, and the allele frequency of the three candidate causal variants was less than 1% in the current Swiss Simmental population. This study identified three novel recessive alleles associated with syndromic forms of albinism or depigmentation, revealing unexpected heterogeneity. The investigation did not reveal any indications of possible dominant de novo mutations impacting protein coding genes including known candidate genes for depigmentation phenotypes. These findings possibly expand the list of pigmentation related genes in mammals, but further investigation is needed. We also highlight the biomedical relevance of investigating rare congenital disorders in livestock.
Computational identification of membrane proteins for vaccine design against drug-resistant Moraxella catarrhalis.
Arshad F, Pervaiz R, Sarfraz A … +7 more , Ejaz H, Alotaibi A, Ullah R, Nishan U, Ali A, Khan MU, Shah M
Mol Genet Genomics · 2025 Sep · PMID 40913648 · Publisher ↗
Moraxella catarrhalis is a Gram-negative diplococcus bacterium and a common respiratory pathogen, implicated in 15-20% of otitis media (OM) cases in children and chronic obstructive pulmonary disease (COPD) in adults. Th...
Moraxella catarrhalis is a Gram-negative diplococcus bacterium and a common respiratory pathogen, implicated in 15-20% of otitis media (OM) cases in children and chronic obstructive pulmonary disease (COPD) in adults. The rise of drug-resistant Moraxella catarrhalis has highlighted the urgent need for the potent vaccine strategies to reduce its clinical burden. Despite a mortality rate of 13%, there is no FDA-approved vaccine for this pathogen. The aim of this study was to computationally identify novel antigens and design a multi-epitope peptide-based vaccine candidate against M. catarrhalis using an immunoinformatics-driven subtractive proteomics and reverse vaccinology approaches. The core proteome of 12 M. catarrhalis genomes were analyzed, identifying 360 host non-homologous proteins. Subsequent screening revealed 30 metabolic pathway-dependent and 7 independent drug targets, along with 7 membrane and extracellular proteins as potential vaccine candidates. A prioritized protein target (WP_081569984.1) was selected for vaccine design. The predicted B-cell, MHC-I, and MHC-II epitopes were linked using adjuvants and linkers to construct four vaccine candidates (V1-V4). These constructs were assessed for physicochemical properties, allergenicity, antigenicity, secondary structures, and immune receptor interactions. As a result, V1 emerged as the most promising candidate. Molecular docking and molecular dynamics (MD) simulations evaluated the interactions of V1 with human toll-like receptors (TLR2 and TLR3). MD trajectories including RMSD, RMSF, Radius of gyration (Rg), SASA, binding free energy (MM-PBSA), PCA, free energy landscapes, and DCCM, showed a strong interaction of vaccine with the TLR recptors. Immune simulations predicted significant immune responses against the proposed vaccine. Additionally, the vaccine construct was in-silico tested in an E. coli plasmid vector (pET-28a(+) for its cloning potential. These findings highlight the potential of the proposed multi-epitope vaccine V1 as a safe and effective preventive strategy against M. catarrhalis-associated infections, and additionally laid the groundwork for future in vitro, in vivo, and clinical studies to validate its immunogenicity and protective efficacy.
Testis-specific serine/threonine kinase 3 regulates the size of sperm reservoir in Anopheles stephensi.
Meghwanshi KK, Choudhary C, Rohilla P … +3 more , Dixit R, Saxena V, Shukla JN
Mol Genet Genomics · 2025 Sep · PMID 40913647 · Publisher ↗
Mosquito reproductive biology is an underexplored area with potential for developing novel vector control strategies. In this study, we investigated the role of the testis-specific serine/threonine-protein kinase (tssk)...
Mosquito reproductive biology is an underexplored area with potential for developing novel vector control strategies. In this study, we investigated the role of the testis-specific serine/threonine-protein kinase (tssk) family, an essential regulator of spermiogenesis in mammals, in mosquitoes. We identified tssk homologues, As_tssk3 and Aea_tssk1, in Anopheles stephensi and Aedes aegypti, respectively and analyzed their expression across different developmental stages. Functional characterization of As_tssk3 was performed by RNAi mediated gene silencing in An. stephensi. The efficiency of As_tssk3 knockdown was analyzed using qRT-PCR, and the testes of knockdown and control males were compared for phenotypic changes. Additionally, the effect of As_tssk3 knockdown on the reproductive potential of male mosquitoes was analyzed via mating analysis. Further, in-silico studies were conducted to identify interactions between As_TSSK3 and the homologues of known Drosophila TSSK targets involved in the process of spermatogenesis, in Anopheles. As_tssk3 and Aea_tssk1 were found to express in a male-specific manner throughout development. Efficient knockdown in the expression of As_tssk3 gene was observed upon feeding An. stephensi larvae with target dsRNA. The knockdown of As_tssk3 led to a reduced sperm reservoir in adult males. As_TSSK3 was found to interact with the Nucleosome Assembly Protein1 like-4 (NAP1like-4), a putative transcription factor in our in-silico analysis. We hypothesize that As_TSSK3 might regulate the transcription of the protamine gene via the NAP protein. The study presented here is the first report of the characterization of tssk homologues in mosquitoes' and demonstrates a possible role of As_tssk3 in maintaining sperm stores.
Exome sequencing in a Pakistani male infertility cohort: perspective on molecular diagnosis, genetic heterogeneity, and diagnostic yield.
Zhou D, Fatima A, Ahmed A … +11 more , Afridi TUK, Khan HN, Ashraf M, Naeem M, Jamal SB, Hassan I, Davis EE, Zhang F, Rehman R, Liu C, Khan TN
Mol Genet Genomics · 2025 Sep · PMID 40906241 · Publisher ↗
Male infertility affects a significant number of couples worldwide, yet the precise causes and genetic mechanisms underlying this condition remain largely unknown. To investigate the monogenic causes of primary male infe...
Male infertility affects a significant number of couples worldwide, yet the precise causes and genetic mechanisms underlying this condition remain largely unknown. To investigate the monogenic causes of primary male infertility, we performed exome sequencing (ES) in a cohort of 100 unrelated Pakistani male patients with non-obstructive, non-syndromic primary infertility. ES identified potential causal variants in established infertility-associated genes in 17/100 patients, resulting in a diagnostic yield of 17%. This highlights the effectiveness of next-generation sequencing technologies, particularly the ES approach, in unraveling the genetic basis of male infertility. Overall, this study provides valuable insights into the genetic underpinnings of male infertility. Our findings explore the diagnostic potential of ES and expand the spectrum of causal variants underlying male infertility.
Transfer RNA Aspartic Acid Methyltransferase 1 (TRDMT1/DNMT2) Regulates Plant Development and Gene Expression in the Moss Physcomitrium patens.
Sharma H, Yadav R, Singh D … +4 more , Goel B, Seshadri V, Kapoor S, Kapoor M
Mol Genet Genomics · 2025 Sep · PMID 40905999 · Publisher ↗
TRDMT1/DNMT2 is a unique 5-methylcytosine methyltransferase that utilizes the catalytic mechanism of a typical DNA methyltransferase to methylate cytosines in tRNAs. It is known to be involved in diverse physiological re...
TRDMT1/DNMT2 is a unique 5-methylcytosine methyltransferase that utilizes the catalytic mechanism of a typical DNA methyltransferase to methylate cytosines in tRNAs. It is known to be involved in diverse physiological regulatory processes such as protein synthesis, immune response, stress and gene expression regulation. While its biological roles have been well studied in animal systems, its cellular functions in land plants have been poorly understood. This study aims to gain deeper insight into regulatory roles of TRDMT1/DNMT2 in the moss Physcomitrium patens. We previously reported that TRDMT1/DNMT2 plays a crucial role in stress tolerance in P. patens. In the present study we generated TRDMT1/DNMT2-disruptant lines (ppdnmt2fl) by deleting the catalytic motifs I to VII encoding genomic region. Phenotypic characterization showed developmental transitions to be affected in ppdnmt2fl. RNA bisulphite sequencing revealed C38 methylation in tRNAAsp(GTC) to be affected similar to Arabidopsis and non-plant species. Interestingly, methylation at additional sites (C48, C49) in tRNAAsp(GTC) were also observed to be affected in P. patens. Polysome profiling and genome-wide proteome analysis showed reduced association of translatable mRNAs with polysomes and differential protein accumulation in ppdnmt2fl. Transcriptome analysis and integration of the omics data (proteome and transcriptome) showed expression of housekeeping genes to be deregulated at transcript and protein levels. The work presented in this study highlights the role of TRDMT1/DNMT2 in maintaining physiological and biochemical homeostasis in P. patens. This molecular attribute underlies stress resilience of this early land plant and possibly contributed in its adaptation to terrestrial habitats during plant evolution.
Variant classification of hereditary cancer genes is affected by genomic underrepresentation of admixed populations.
Bianco BCF, Planello AC
Mol Genet Genomics · 2025 Sep · PMID 40900392 · Publisher ↗
Variant classification in genetic testing often culminates in "uncertain" calls, known as variants of uncertain significance (VUS), which remain a major clinical challenge. Among the established criteria for variant clas...
Variant classification in genetic testing often culminates in "uncertain" calls, known as variants of uncertain significance (VUS), which remain a major clinical challenge. Among the established criteria for variant classification, population allele frequency (AF) is fundamental, yet under-representation of non-European groups hinders accurate interpretation. In this study, we evaluated the impact of population-specific AF on the reclassification of VUS and conflicting variants in hereditary cancer genes. From ClinVar, we curated 487 variants present in both the Brazilian cohort ABraOM and gnomAD v4.1 databases. Comparative population analysis revealed that 43% of shared variants showed significantly different AFs (q ≤ 0.01), with 113 (23%) exhibiting large effect sizes (OR ≥ 4), including 39 VUS. Among these, 20 VUS had higher AF in the Brazilian cohort and exceeded benignity thresholds (BS1), while remaining rare in other populations. Functional prediction tools such as REVEL and CADD failed to distinguish these variants from globally rare VUS. Integrating Brazilian‑specific AF with ClinGen VCEP rules downgraded 15% (3/20) of candidate VUS and resolved five conflicting calls. These findings argue for routine incorporation of regional reference datasets in diagnostic curation to reduce uncertainty and avoid inappropriate clinical management in diverse populations.
CRIF counteracts oncogenic Ras and regulates heterochromatin.
Lim SJ, Li J, Li WX
Mol Genet Genomics · 2025 Sep · PMID 40892326 · Publisher ↗
Oncogenic Ras mutations are prevalent in human cancers, yet the mechanisms by which Ras promotes tumorigenesis remain incompletely understood. In Drosophila, oncogenic Ras (Ras) induces tissue overgrowth and metastasis,...
Oncogenic Ras mutations are prevalent in human cancers, yet the mechanisms by which Ras promotes tumorigenesis remain incompletely understood. In Drosophila, oncogenic Ras (Ras) induces tissue overgrowth and metastasis, but the cellular restraints it must overcome are unclear. We have identified Drosophila CRIF, the homolog of mammalian CR6-interacting factor 1 (CRIF1), as a modifier of Ras-induced lethality and Ras-induced overgrowth and cell proliferation. Knockdown of CRIF exacerbated Ras phenotypes, while CRIF overexpression ameliorated them. Further, we found that CRIF was also required for heterochromatin formation, as loss of CRIF suppressed position-effect variegation (PEV) and reduced the levels of Heterochromatin Proteins 1 (HP1) and Histone H3 Lysine 9 trimethylation (H3K9me3). CRIF physically interacted with HP1, suggesting a role in recruiting HP1 to heterochromatin. Notably, CRIF did not regulate HP1 transcription or total protein levels but influenced HP1 localization. Our findings demonstrate that CRIF functions as a tumor suppressor by negatively regulating cell proliferation and maintaining heterochromatin stability. CRIF's interaction with HP1 and its role in heterochromatin regulation suggest a novel mechanism linking heterochromatin to tumor suppression in Ras-driven cancers. These results highlight CRIF as a potential therapeutic target and provide new insights into the interplay between chromatin regulation and oncogenic signaling.
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