Infrequent and rare genetic variants in the human population vastly outnumber common ones. Although they may contribute significantly to the genetic basis of a disease, these seldom-encountered variants may also be miss-identified as pathogenic if no correct references are available. Somatic and germline TP53 variants are associated with multiple neoplastic diseases, and thus have come to serve as a paradigm for genetic analyses in this setting. We searched 14 independent, globally distributed datasets and recovered TP53 SNPs from 202,767 cancer-free individuals. In our analyses, 19 new missense TP53 SNPs, including five novel variants specific to the Asian population, were recurrently identified in multiple datasets. Using a combination of in silico, functional, structural, and genetic approaches, we showed that none of these variants displayed loss of function compared to the normal TP53 gene. In addition, classification using ACMG criteria suggested that they are all benign. Considered together, our data reveal that the TP53 coding region shows far more polymorphism than previously thought and present high ethnic diversity. They furthermore underline the importance of correctly assessing novel variants in all variant-calling pipelines associated with genetic diagnoses for cancer.
Individuals reared in captivity are exposed to distinct selection pressures and evolutionary processes causing genetic and phenotypic divergence from wild populations. Consequently, restocking with farmed individuals may represent a considerable risk for the fitness of free-living populations. Supportive breeding on a massive scale has been established in many European countries to increase hunting opportunities for the most common duck species, the mallard (Anas platyrhynchos). It has previously been shown that mallards from breeding facilities differ genetically from wild populations and there is some indication of morphological differences. Using a common-garden experiment, we tested for differences in growth parameters between free-living populations and individuals from breeding facilities during the first 20 days of post-hatching development, a critical phase for survival in free-living populations. In addition, we compared their immune function by assessing two haematological parameters, H/L ratio and immature erythrocyte frequency, and plasma complement activity. Our data show that farmed ducklings exhibit larger morphological parameters, a higher growth rates, and higher complement activity. In haematological parameters, we observed high dynamic changes in duckling ontogeny in relation to their morphological parameters. In conclusion, our data demonstrate pronounced phenotype divergence between farmed and wild mallard populations that can be genetically determined. We argue that this divergence can directly or indirectly affect fitness of farmed individuals introduced to the breeding population as well as fitness of farmed x wild hybrids.
- MeSH
- chov MeSH
- divoká zvířata růst a vývoj imunologie MeSH
- farmy MeSH
- fenotyp MeSH
- kachny růst a vývoj imunologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
Although histone acetylation is one of the most widely studied epigenetic modifications, there is still a lack of information regarding how the acetylome is regulated during brain development and pathophysiological processes. We demonstrate that the embryonic brain (E15) is characterized by an increase in H3K9 acetylation as well as decreases in the levels of HDAC1 and HDAC3. Moreover, experimental induction of H3K9 hyperacetylation led to the overexpression of NCAM in the embryonic cortex and depletion of Sox2 in the subventricular ependyma, which mimicked the differentiation processes. Inducing differentiation in HDAC1-deficient mouse ESCs resulted in early H3K9 deacetylation, Sox2 downregulation, and enhanced astrogliogenesis, whereas neuro-differentiation was almost suppressed. Neuro-differentiation of (wt) ESCs was characterized by H3K9 hyperacetylation that was associated with HDAC1 and HDAC3 depletion. Conversely, the hippocampi of schizophrenia-like animals showed H3K9 deacetylation that was regulated by an increase in both HDAC1 and HDAC3. The hippocampi of schizophrenia-like brains that were treated with the cannabinoid receptor-1 inverse antagonist AM251 expressed H3K9ac at the level observed in normal brains. Together, the results indicate that co-regulation of H3K9ac by HDAC1 and HDAC3 is important to both embryonic brain development and neuro-differentiation as well as the pathophysiology of a schizophrenia-like phenotype.
- MeSH
- acetylace MeSH
- antagonisté kanabinoidních receptorů farmakologie MeSH
- antipsychotika farmakologie MeSH
- časové faktory MeSH
- epigeneze genetická MeSH
- gestační stáří MeSH
- histondeacetylasa 1 antagonisté a inhibitory genetika metabolismus MeSH
- histondeacetylasy genetika metabolismus MeSH
- histony metabolismus MeSH
- inhibitory histondeacetylas farmakologie MeSH
- methylazoxymethanolacetát MeSH
- modely nemocí na zvířatech MeSH
- molekuly buněčné adheze nervové genetika metabolismus MeSH
- mozek účinky léků embryologie enzymologie patologie MeSH
- myši inbrední C57BL MeSH
- neurogeneze * účinky léků MeSH
- neurony účinky léků enzymologie patologie MeSH
- posttranslační úpravy proteinů MeSH
- potkani Sprague-Dawley MeSH
- receptor kanabinoidní CB1 antagonisté a inhibitory metabolismus MeSH
- schizofrenie chemicky indukované farmakoterapie enzymologie genetika MeSH
- signální transdukce MeSH
- transkripční faktory SOXB1 genetika metabolismus MeSH
- vývojová regulace genové exprese MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Owing to the complex nature of vector-borne diseases (VBDs), whereby monitoring of human case patients does not suffice, public health authorities experience challenges in surveillance and control of VBDs. Knowledge on the presence and distribution of vectors and the pathogens that they transmit is vital to the risk assessment process to permit effective early warning, surveillance, and control of VBDs. Upon accepting this reality, public health authorities face an ever-increasing range of possible surveillance targets and an associated prioritization process. Here, we propose a comprehensive approach that integrates three surveillance strategies: population-based surveillance, disease-based surveillance, and context-based surveillance for EU member states to tailor the best surveillance strategy for control of VBDs in their geographic region. By classifying the surveillance structure into five different contexts, we hope to provide guidance in optimizing surveillance efforts. Contextual surveillance strategies for VBDs entail combining organization and data collection approaches that result in disease intelligence rather than a preset static structure.
- Publikační typ
- časopisecké články MeSH
