Across the tree of life, DNA damage response (DDR) proteins play a pivotal, yet dichotomous role in organismal development and evolution. Here, we present a comprehensive analysis of 432 DDR proteins encoded by 68 genomes, including that of Nucleospora cyclopteri, an intranuclear microsporidia sequenced in this study. We compared the DDR proteins encoded by these genomes to those of humans to uncover the DNA repair-ome across phylogenetically distant eukaryotes. We also performed further analyses to understand if organismal complexity and lifestyle play a role in the evolution of DDR protein length and conserved domain architecture. We observed that the genomes of extreme parasites such as Paramicrocytos, Giardia, Spironucleus, and certain microsporidian lineages encode the smallest eukaryotic repertoire of DDR proteins and that pathways involved in modulation of nucleotide pools and nucleotide excision repair are the most preserved DDR pathways in the eukaryotic genomes analysed here. We found that DDR and DNA repair proteins are consistently longer than housekeeping and metabolic proteins. This is likely due to the higher number of physical protein-protein interactions which DDR proteins are involved. We find that although DNA repair proteins are generally longer than housekeeping proteins, their functional domains occupy a relatively smaller footprint. Notably, this pattern holds true across diverse organisms and shows no dependence on either lifestyle or mitochondrial status. Finally, we observed that unicellular organisms harbour proteins that are tenfold longer than their human homologues, with the extra amino acids forming interdomain regions with a clearly novel albeit undetermined function.
- MeSH
- Eukaryota * genetics MeSH
- Phylogeny MeSH
- Humans MeSH
- Microsporidia genetics MeSH
- Evolution, Molecular * MeSH
- DNA Repair * MeSH
- DNA Damage * MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Alzheimer's disease (AD), a leading cause of dementia worldwide, is a multifactorial neurodegenerative disorder characterized by amyloid-beta plaques, tauopathy, neuronal loss, neuro-inflammation, brain atrophy, and cognitive deficits. AD manifests as familial early-onset (FAD) with specific gene mutations or sporadic late-onset (LOAD) caused by various genetic and environmental factors. Numerous transgenic rodent models have been developed to understand AD pathology development and progression. The TgF344-AD rat model is a double transgenic model that carries two human gene mutations: APP with the Swedish mutation and PSEN-1 with delta exon 9 mutations. This model exhibits a complete repertoire of AD pathology in an age-dependent manner. This review summarizes multidisciplinary research insights gained from studying TgF344-AD rats in the context of AD pathology. We explore neuropathological findings; electrophysiological assessments revealing disrupted synaptic transmission, reduced spatial coding, network-level dysfunctions, and altered sleep architecture; behavioral studies highlighting impaired spatial memory; alterations in excitatory-inhibitory systems; and molecular and physiological changes in TgF344-AD rats emphasizing their age-related effects. Additionally, the impact of various interventions studied in the model is compiled, underscoring their role in bridging gaps in understanding AD pathogenesis. The TgF344-AD rat model offers significant potential in identifying biomarkers for early detection and therapeutic interventions, providing a robust platform for advancing translational AD research. Key words Alzheimer's disease, Transgenic AD models, TgF344-AD rats, Spatial coding.
- MeSH
- Alzheimer Disease * genetics pathology metabolism MeSH
- Amyloid beta-Protein Precursor genetics metabolism MeSH
- Rats MeSH
- Humans MeSH
- Disease Models, Animal * MeSH
- Brain pathology metabolism MeSH
- Rats, Inbred F344 MeSH
- Rats, Transgenic * MeSH
- Presenilin-1 genetics MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Dystonia is a movement disorder characterized by genetic and clinical heterogeneity. A recurring p.(Glu303del)-deletion in TOR1A is a well-established cause for DYT-TOR1A (DYT1), an autosomal dominant early-onset isolated dystonia. TOR1A encodes TorsinA, an AAA + ATPase located in the nuclear envelope. By whole exome analyses of a family with a novel dystonia-hemichorea-/hemiballism phenotype, we identified a TOR1AIP2 NM_001199260.2 c.1234A > G p.(Arg412Gly) variant. The variant is very rare in databases and was absent from whole exome data from >1000 dystonia patients. TOR1AIP2 encodes LULL1, a transmembrane protein that activates TorsinA, and correct interaction between TorsinA and LULL1 is essential for proper nuclear envelope architecture. The p.(Arg412Gly) variant disrupts the binding interface between TorsinA and LULL1 around p.Arg412; this same interface is also impaired in DYT1. Functional analyses via a co-purification assay revealed that interaction between TorsinA-LULL1Arg412Gly is weaker than the wild-type interaction, and that it resembles the situation in DYT1 (TorsinAΔE303-LULL1). A second family with milder dystonia, hemichorea, and stereotypic leg flexion during gait and a TOR1AIP2 p.(Gln338His) variant was identified. The clinical phenotype of both families shared proximal arm movements, and flutter in facial musculature. Expressivity of the movement disorder symptoms was variable. Several proteins in the nuclear envelope have been implicated in various forms of neurodevelopmental disorders with dystonia. Taken together, our findings suggest TOR1AIP2 as a new candidate gene implicated in a complex hereditary movement disorder with dystonia and hemichorea/hemiballism.
- MeSH
- Chorea * genetics MeSH
- Adult MeSH
- Dyskinesias * genetics MeSH
- Dystonic Disorders * genetics MeSH
- Dystonia * genetics MeSH
- Middle Aged MeSH
- Humans MeSH
- Molecular Chaperones * genetics MeSH
- Pedigree MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Diet, stress, genetics, and a sedentary lifestyle may all contribute to heart disease rates. Although recent studies propose comprehensive automated diagnostic systems, these systems tend to focus on one aspect, such as feature selection, prioritization, or predictive accuracy. A more complete approach that considers all of these factors can improve the efficiency of a cardiac prediction system. This study uses an appropriate strategy to overcome potential network design problems, design challenges, overfitting, and lack of robustness that can interfere with system performance. The research introduces an ideally designed deep trust network called ID-DTN to improve system performance. The Ruzzo-Tompa method is used to eliminate noncontributory features. The Seagull Optimization Algorithm (SOA) is introduced to optimize the trust depth network to achieve optimal network design. The study scrutinizes the deep trust network (ID-DTN) and the restricted Boltzmann machine (RBM) and sheds light on the system's operation. This proposal can optimize both network architecture and feature selection, which is the main novelty. The proposed method is analyzed using the below-mentioned metrics: Matthew's correlation coefficient, F1 score, accuracy, sensitivity, specificity, and accuracy. ID-DTN performs well compared to other state-of-the-art methods. The validation results confirm that the proposed method improves the prediction accuracy to 97.11% and provides reliable recommendations for patients with cardiovascular disease.
- MeSH
- Algorithms * MeSH
- Humans MeSH
- Heart Diseases * diagnosis MeSH
- Neural Networks, Computer MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
OBJECTIVE: Idiopathic inflammatory myopathies (IIMs, myositis) are rare systemic autoimmune disorders that lead to muscle inflammation, weakness, and extramuscular manifestations, with a strong genetic component influencing disease development and progression. Previous genome-wide association studies identified loci associated with IIMs. In this study, we imputed data from two prior genome-wide myositis studies and analyzed the largest myositis data set to date to identify novel risk loci and susceptibility genes associated with IIMs and its clinical subtypes. METHODS: We performed association analyses on 14,903 individuals (3,206 patients and 11,697 controls) with genotypes and imputed data from the Trans-Omics for Precision Medicine reference panel. Fine-mapping and expression quantitative trait locus colocalization analyses in myositis-relevant tissues indicated potential causal variants. Functional annotation and network analyses using the random walk with restart (RWR) algorithm explored underlying genetic networks and drug repurposing opportunities. RESULTS: Our analyses identified novel risk loci and susceptibility genes, such as FCRLA, NFKB1, IRF4, DCAKD, and ATXN2 in overall IIMs; NEMP2 in polymyositis; ACBC11 in dermatomyositis; and PSD3 in myositis with anti-histidyl-transfer RNA synthetase autoantibodies (anti-Jo-1). We also characterized effects of HLA region variants and the role of C4. Colocalization analyses suggested putative causal variants in DCAKD in skin and muscle, HCP5 in lung, and IRF4 in Epstein-Barr virus (EBV)-transformed lymphocytes, lung, and whole blood. RWR further prioritized additional candidate genes, including APP, CD74, CIITA, NR1H4, and TXNIP, for future investigation. CONCLUSION: Our study uncovers novel genetic regions contributing to IIMs, advancing our understanding of myositis pathogenesis and offering new insights for future research.
Bipolar disorder is a leading contributor to the global burden of disease1. Despite high heritability (60-80%), the majority of the underlying genetic determinants remain unknown2. We analysed data from participants of European, East Asian, African American and Latino ancestries (n = 158,036 cases with bipolar disorder, 2.8 million controls), combining clinical, community and self-reported samples. We identified 298 genome-wide significant loci in the multi-ancestry meta-analysis, a fourfold increase over previous findings3, and identified an ancestry-specific association in the East Asian cohort. Integrating results from fine-mapping and other variant-to-gene mapping approaches identified 36 credible genes in the aetiology of bipolar disorder. Genes prioritized through fine-mapping were enriched for ultra-rare damaging missense and protein-truncating variations in cases with bipolar disorder4, highlighting convergence of common and rare variant signals. We report differences in the genetic architecture of bipolar disorder depending on the source of patient ascertainment and on bipolar disorder subtype (type I or type II). Several analyses implicate specific cell types in the pathophysiology of bipolar disorder, including GABAergic interneurons and medium spiny neurons. Together, these analyses provide additional insights into the genetic architecture and biological underpinnings of bipolar disorder.
- MeSH
- Asian People genetics MeSH
- White MeSH
- White People genetics MeSH
- Bipolar Disorder * genetics MeSH
- Genome-Wide Association Study * MeSH
- Black or African American genetics MeSH
- Phenotype * MeSH
- GABAergic Neurons metabolism MeSH
- Genetic Predisposition to Disease MeSH
- Genomics * MeSH
- Hispanic or Latino genetics MeSH
- Humans MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Background/Objectives: Health and social care systems around the globe are currently undergoing a transformation towards personalized, preventive, predictive, participative precision medicine (5PM), considering the individual health status, conditions, genetic and genomic dispositions, etc., in personal, social, occupational, environmental, and behavioral contexts. This transformation is strongly supported by technologies such as micro- and nanotechnologies, advanced computing, artificial intelligence, edge computing, etc. Methods: To enable communication and cooperation between actors from different domains using different methodologies, languages, and ontologies based on different education, experiences, etc., we have to understand the transformed health ecosystem and all its components in terms of structure, function and relationships in the necessary detail, ranging from elementary particles up to the universe. In this way, we advance design and management of the complex and highly dynamic ecosystem from data to knowledge level. The challenge is the consistent, correct, and formalized representation of the transformed health ecosystem from the perspectives of all domains involved, representing and managing them based on related ontologies. The resulting business viewpoint of the real-world ecosystem must be interrelated using the ISO/IEC 21838 Top Level Ontologies standard. Thereafter, the outcome can be transformed into implementable solutions using the ISO/IEC 10746 Open Distributed Processing Reference Model. Results: The model and framework for this system-oriented, architecture-centric, ontology-based, policy-driven approach have been developed by the first author and meanwhile standardized as ISO 23903 Interoperability and Integration Reference Architecture. The formal representation of any ecosystem and its development process including examples of practical deployment of the approach, are presented in detail. This includes correct systems and standards integration and interoperability solutions. A special issue newly addressed in the paper is the correct and consistent formal representation Conclusions: of all components in the development process, enabling interoperability between and integration of any existing representational artifacts such as models, work products, as well as used terminologies and ontologies. The provided solution is meanwhile mandatory at ISOTC215, CEN/TC251 and many other standards developing organization in health informatics for all projects covering more than just one domain.
- Publication type
- Journal Article MeSH
Satellite DNAs (satDNAs) are abundant components of eukaryotic genomes, playing pivotal roles in chromosomal organization, genome stability, and evolution. Here, we combined cytogenetic and genomic methods to characterize the satDNAs in the genomes of Leptidea butterflies. Leptidea is characterized by the presence of a high heterochromatin content, large genomes, and extensive chromosomal reshuffling as well as the occurrence of cryptic species. We show that, in contrast to other Lepidoptera, satDNAs constitute a considerable proportion of Leptidea genomes, ranging between 4.11% and 11.05%. This amplification of satDNAs, together with the hyperactivity of transposable elements, contributes to the substantial genome expansion in Leptidea. Using chromosomal mapping, we show that, particularly LepSat01-100 and LepSat03-167 satDNAs, are preferentially localized in heterochromatin exhibiting variable distribution that may have contributed to the highly diverse karyotypes within the genus. The satDNAs also exhibit W-chromosome accumulation, suggesting their involvement in sex chromosome evolution. Our results provide insights into the dynamics of satDNAs in Lepidoptera genomes and highlight their role in genome expansion and chromosomal organization, which could influence the speciation process. The high proportion of repetitive DNAs in the genomes of Leptidea underscores the complex evolutionary dynamics revealing the interplay between repetitive DNAs and genomic architecture in the genus.
- MeSH
- Phylogeny MeSH
- Genome, Insect * MeSH
- Heterochromatin genetics MeSH
- Karyotype * MeSH
- Chromosome Mapping MeSH
- Evolution, Molecular * MeSH
- Butterflies * genetics MeSH
- DNA, Satellite * genetics MeSH
- DNA Transposable Elements MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
We report a very unusual case of melanocytic neoplasm appearing clinically as a 0.5-cm dome-shaped pigmented papule on the chest of a 63-year-old man. Microscopically, it was an asymmetric, entirely dermally based neoplasm characterized by a multinodular, vaguely plexiform architecture composed of moderately pleomorphic spindled melanocytes with ample, dusty pigmented cytoplasm and scattered multinucleated cells. The tumor cells were strongly positive for Melan-A, HMB45, S100, and PRAME, whereas p16 showed diffuse nuclear loss. β-catenin presented a strong and diffuse cytoplasmic staining, while nuclei were negative. Despite an increased cellularity, mitotic count was low (1/mm 2 ). Fluorescence in situ hybridization revealed no copy number alteration in melanoma-related genes ( CDKN2A, MYB, MYC, CCND1 and RREB1 ). DNA and RNA sequencing identified KIT c.2458G>T and APC c.6709C>T mutations. No further genetic alteration was detected including TERT-promoter (TERT-p ) hot-spot mutation. A re-excision was performed. A sentinel lymph node biopsy was negative. Clinical investigations revealed no extracutaneous involvement. The patient is disease-free after a follow-up period of 8 months. Given the peculiar morphologic and molecular findings, we hypothesize the lesion may represent a novel subtype of an intermediate grade melanocytic tumor (melanocytoma).
- MeSH
- Antigens, Neoplasm MeSH
- Sentinel Lymph Node Biopsy MeSH
- In Situ Hybridization, Fluorescence MeSH
- Middle Aged MeSH
- Humans MeSH
- Melanocytes pathology MeSH
- Melanoma * pathology MeSH
- Mutation MeSH
- Skin Neoplasms * pathology MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Publication type
- Journal Article MeSH
- Case Reports MeSH
BACKGROUND: Genetic factors are involved in the pathogenesis of familial and sporadic amyotrophic lateral sclerosis (ALS) and constitute a link to its association with frontotemporal dementia (FTD). Gene-targeted therapies for some forms of ALS (C9orf72, SOD1) have recently gained momentum. Genetic architecture in Czech ALS patients has not been comprehensively assessed so far. OBJECTIVE: We aimed to deliver pilot data on the genetic landscape of ALS in our country. METHODS: A cohort of patients with ALS (n = 88), recruited from two Czech Neuromuscular Centers, was assessed for hexanucleotide repeat expansion (HRE) in C9orf72 and also for genetic variations in other 36 ALS-linked genes via next-generation sequencing (NGS). Nine patients (10.1%) had a familial ALS. Further, we analyzed two subgroups of sporadic patients - with concomitant FTD (n = 7) and with young-onset of the disease (n = 22). RESULTS: We detected the pathogenic HRE in C9orf72 in 12 patients (13.5%) and three other pathogenic variants in FUS, TARDBP and TBK1, each in one patient. Additional 7 novel and 9 rare known variants with uncertain causal significance have been detected in 15 patients. Three sporadic patients with FTD (42.9%) were harbouring a pathogenic variant (all HRE in C9orf72). Surprisingly, none of the young-onset sporadic patients harboured a pathogenic variant and we detected no pathogenic SOD1 variant in our cohort. CONCLUSION: Our findings resemble those from other European populations, with the highest prevalence of HRE in the C9orf72 gene. Further, our findings suggest a possibility of a missing genetic variability among young-onset patients.
- MeSH
- Amyotrophic Lateral Sclerosis * genetics MeSH
- DNA-Binding Proteins genetics MeSH
- Adult MeSH
- DNA Repeat Expansion * MeSH
- Frontotemporal Dementia * genetics MeSH
- Genetic Predisposition to Disease MeSH
- Cohort Studies MeSH
- Middle Aged MeSH
- Humans MeSH
- C9orf72 Protein * genetics MeSH
- RNA-Binding Protein FUS genetics MeSH
- Protein Serine-Threonine Kinases genetics MeSH
- Aged MeSH
- Age of Onset MeSH
- High-Throughput Nucleotide Sequencing MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Czech Republic MeSH
