Mechanism Of Inheritance Research Articles

Learning and Memory in Drosophila Larvae.

The Drosophila larva has become an attractive model system for studying fundamental questions in neuroscience. Although the focus was initially on topics such as the structure of genes, mechanisms of inheritance, genetic regulation of development, and the function and physiology of ion channels, today it is often on the cellular and molecular principles of naive and learned behavior. Drosophila larvae have developed different mechanisms, often widespread in similar manifestations in the animal kingdom, to orient themselves toward olfactory, gustatory, mechanosensory, thermal, and visual stimuli to coordinate their locomotion appropriately. To adapt to changes in the environment, larvae are able to learn to categorize some of these sensory impressions as "good" or "bad." Depending on their relevance and reliability, the larva learns them and constantly updates these memories. Laboratory experiments allow us to parametrically study and describe many of these processes (e.g., olfactory appetitive and aversive memory or visual appetitive and aversive memory). Combining behavioral tests with various neurogenetic techniques allows us to thermally or optogenetically activate or inhibit individual cells during learning, memory consolidation, and memory retrieval. The molecular and genetic bases of larval learning can be analyzed by using specific mutants. The CRISPR-Cas method has established extensive new directions in this area, in addition to the already wide-ranging traditional approaches, like the GAL4/UAS system. The combination of these genetic methods with the simplicity and cost-effectiveness of the introduced behavioral assay provides a platform for discovering the fundamental mechanisms underlying learning and memory formation in the rather simple larval brain.

Integrative analysis of GWAS and transcriptome reveals p53 signaling pathway mediates resistance to visceral white-nodules disease in large yellow croaker

Visceral white-nodules disease (VWND), caused by Pseudomonas plecoglossicida, is one of the primary causes of morbidity and mortality in large yellow croaker aquaculture. Host disease resistance is a heritable trait that involves complex regulatory processes. However, the regulatory mechanism of bacterial resistance in large yellow croaker is still unclear. This study attempted to systematically evaluate the major genetic loci and transcriptional regulatory mechanisms associated with the resistance to VWND in large yellow croaker by crossover method studies. A large population of large yellow croaker was challenged with P. plecoglossicida, with survival time recorded and samples were taken for genotyping. Meanwhile, spleen samples that were used for RNA-seq to compare their transcriptomic profiles before and after infection were taken from resistant populations (RS) and susceptible control populations (CS) bred using the genomic selection (GS) technique. Genome-wide association analyses using 46 K imputed SNP genotypes highlighted that resistance is a polygenic trait. The integrative analysis results show the co-localization of the cd82a gene between disease resistance-related genetic loci and comparative transcriptional analysis. And functional enrichment analysis showed differential enrichment of the p53 signaling pathway in RS and CS groups, suggesting that there may be cd82a-mediated p53 signaling pathway activation for VWND resistance. This large-scale study provides further evidence for the heritability and transcriptional regulatory mechanisms of host inheritance of VWND resistance.

Progress on molecular composition and genetic mechanism of plant B chromosomes.

In addition to the standard set of chromosomes (A chromosomes, As), so-called supernumerary B chromosomes (Bs) have been found causing a numerical chromosome variation. Bs have been considered to be genetically inert elements without any functional genes for a long period, because of the limited experimental methods and its dispensable property. More recently, sequencing of dissected Bs from several organisms has revealed the DNA composition, a vast number of protein-coding genes have been found with the effects on the transcripts and protein expression of the host. In this review, we summarize current understanding of B chromosomes carrying plants including rye (Secale cereale L.), maize (Zea mays L.) and Aegilops (Aegilops speltoides Tausch.), with the emphasis on Bs phenotypic effects, the inheritance mechanism of Bs, the molecular composition of Bs, the effects on host transcription regulation and protein expression upon the presence of Bs. Besides, we discuss the current study state and potential application of B chromosomes, aim to provide a new venue for chromosome engineering and breeding research.

Going Back to Fundamentals: Three Marriageable Actions for Thalassemia and Carrier Population Management

We investigated the impact of three marriageable actions: normal-to-carrier, carrier-to-normal, and carrier-to-carrier marriages on thalassemia and carrier populations. The well-known strategy is limiting the carrier-to-carrier marriage to reduce the thalassemia population. Thus, the other two marriageable actions were often ignored. Other than a simple explanation of their genetic consequences, their important aspect in the thalassemia inheritance mechanism has never been studied at the population level. Moreover, there is no mathematical model investigating problem of interest for blood disorders at the population level. Hence, we developed a mathematical model to examine the possibility of eradication/reduction of thalassemia and carrier populations through each of the three marriageable actions in the long-term. We conducted computer simulations with the demographic data of the United Arab Emirates in which high thalassemia carrier prevalence is identified. We found that promoting more carrier-to-normal marriage will eventually have the same effects on marriage reconsideration for carrier-carrier couples, contributing to the reduction of the carrier population in the long-term. Interestingly, the normal-to-carrier marriage does not necessarily have a similar effect on thalassemia and carrier populations as that of the carrier-to-normal marriage. Thus, the two marriageable actions should be distinguished and also seriously considered in education and public awareness campaigns for thalassemia.

Inheritance of cultural asset of the family: educational and professional paths of generations, biographical approach

The article analyzes the cultural capital of the family, as well as the ways of its transmission to the younger generations. The relevance of the problem is due to the need to develop human resources, especially educational and professional ones. The research questions were the types of cultural family capital and the peculiarities of its transmission, the influence of the teacher's profession in the field of preschool education on personal and intergenerational social mobility, the passage of educational and professional path by representatives of several family generations, the relevance of the biographical method. The project studied biographical interviews of parents of students of top-rated Russian schools. The collected empirical arrays allowed us to draw conclusions about three generations of the informants' family. In addition to the intergenerational analysis, a study of existing sociological projects was conducted that examined in detail the activities of teachers in the field of preschool and school education. The author presents the substantiation of several significant mechanisms of inheritance of cultural capital by the middle and younger generations of the family. The study of biographical materials was carried out using the domestic computer program Diskant. It is established that the profession of a kindergarten teacher has a positive effect on personal and generational social mobility. The main way of transferring family capital is the inheritance of value orientations for education and obtaining a profession in the field of highly qualified labor. An additional mechanism for the transmission of cultural resources can be considered a visit to cultural events and clubs. The relevance of the biographical approach in application to the problems of research is substantiated. The method provides extensive empirical material with the opportunity to delve into the understanding of texts. The limitation in using the biographical approach was the complexity of digital processing of primary sociological information.

Simultaneous single-cell genome and transcriptome sequencing in nanoliter droplet with digital microfluidics identifying essential driving genes

Single-cell genome and transcriptome sequencing investigates how genotype influences the phenotype of single cells, so as to comprehensively interpret biological inheritance and explain functional heterogeneity at the single-cell level. Current sample preparation technologies for simultaneous DNA and RNA sequencing of the same cell are cumbersome, expensive, and suffer from cross-contamination and limited sensitivity. Herein we describe DMF-DR-seq, a nanoliter-scale single-cell multi-omics sample preparation platform based on digital microfluidics. DMF-DR-seq integrates the major steps of single-cell isolation, DNA/RNA separation, and nucleic acid amplification in situ. The results confirm the enhanced ability of DMF-DR-seq relative to current state-of-the-art technology, with lower amplification bias, higher genome-wide coverage in DNA sequencing and better gene detection ability in RNA sequencing results. By using DMF-DR-seq, we identified the genome variation-induced abnormal transcriptome expression of single circulating tumor cells (CTCs) and cancer cells from multiple myeloma patients. The results identified potentially essential genes, known as transporters associated with antigen presentation (TAP1 and TAP2), that participate in the pathologic progress. The unique flexibility, sensitivity, and accuracy of DMF-DR-seq suggest its potential utility in deeper multi-omics analysis for inheritance mechanism study in single-cell biology.

Modern physiology vindicates Darwin's dream.

New Findings What is the topic of this review? Revisiting the 2013 article ‘Physiology is rocking the foundations of evolutionary biology’. What advances does it highlight? The discovery that the genome is not isolated from the soma and the environment, and that there is no barrier preventing somatic characteristics being transmitted to the germline, means that Darwin's pangenetic ideas become relevant again. Charles Darwin spent the last decade of his life collaborating with physiologists in search of the biological processes of evolution. He viewed physiology as the way forward in answering fundamental questions about inheritance, acquired characteristics, and the mechanisms by which organisms could achieve their ends and survival. He collaborated with 19th century physiologists, notably John Burdon‐Sanderson and George Romanes, in his search for the mechanisms of transgenerational inheritance. The discovery that the genome is not isolated from the soma and the environment, and that there is no barrier preventing somatic characteristics being transmitted to the germline, means that Darwin's pangenetic ideas become relevant again. It is time for 21st century physiology to come to the rescue of evolutionary biology. This article outlines research lines by which this could be achieved.

Modulators of CFTR protein function in the treatment of cystic fibrosis - a literature review

Cystic fibrosis (CF) is a multi-system genetic disease with an autosomal recessive inheritance mechanism. The breakthroughs in the therapy of patients with CF turned out to be modulators of CFTR protein function. These small-molecule substances, influencing the basic pathogenetic defect, became a model example of precise targeted therapy, thus showing a significant advantage over symptomatic treatment. For modulators of CFTR protein function, numerous therapeutic benefits have been demonstrated with an acceptable safety profile - improved lung function and reduced frequency of pulmonary exacerbations, reduced hospitalization rate, and disease-related improvement in quality of life. The use of these drugs changes the perception of CF from a fatal pediatric disease significantly shortening the life expectancy of patients into a chronic disease in young adults. The subject of further research interest is the development of alternative therapeutic strategies based on new modulators and gene therapy. The publication is a review of the literature and summarizes the current scientific reports on the effectiveness of the use of modulators of CFTR protein function in the treatment of cystic fibrosis.

Negative evidence on the transgenerational inheritance of defense priming in Arabidopsis thaliana

Defense priming allows plants to enhance their immune responses to subsequent pathogen challenges. Recent reports suggested that acquired resistances in parental generation can be inherited into descendants. Although epigenetic mechanisms are plausible tools enabling the transmission of information or phenotypic traits induced by environmental cues across generations, the mechanism for the transgenerational inheritance of defense priming in plants has yet to be elucidated. With the initial aim to elucidate an epigenetic mechanism for the defense priming in plants, we reassessed the transgenerational inheritance of plant defense, however, could not observe any evidence supporting it. By using the same dipping method with previous reports, Arabidopsis was exposed repeatedly to Pseudomonas syringae pv tomato DC3000 (Pst DC3000) during vegetative or reproductive stages. Irrespective of the developmental stages of parental plants that received pathogen infection, the descendants did not exhibit primed resistance phenotypes, defense marker gene (PR1) expression, or elevated histone acetylation within PR1 chromatin. In assays using the pressure-infiltration method for infection, we obtained the same results as above. Thus, our results suggest that the previous observations on the transgenerational inheritance of defense priming in plants should be more extensively and carefully reassessed.

Mechanisms of chromatin-based epigenetic inheritance.

Multi-cellular organisms such as humans contain hundreds of cell types that share the same genetic information (DNA sequences), and yet have different cellular traits and functions. While how genetic information is passed through generations has been extensively characterized, it remains largely obscure how epigenetic information encoded by chromatin regulates the passage of certain traits, gene expression states and cell identity during mitotic cell divisions, and even through meiosis. In this review, we will summarize the recent advances on molecular mechanisms of epigenetic inheritance, discuss the potential impacts of epigenetic inheritance during normal development and in some disease conditions, and outline future research directions for this challenging, but exciting field.

Autoinflammatory disease syndrome of hyperimmunoglobulinemia D

Objective: present a clinical case of a rare autoinflammatory disease. Materials and methods: an analysis of a clinical case of mevalonate kinase deficiency syndrome in an 8-year-old girl was carried out. Results: mevalonate kinase deficiency syndrome (SDMC) is a rare autoinflammatory disease with an autosomal recessive inheritance mechanism. The severity of the disease correlates with the residual activity of the enzyme mevalonate kinase, which is involved in the biosynthesis of cholesterol and isoprenoids, which is necessary for the conversion of mevalonate into the final product. As a result, the body accumulates mevalonic acid, especially high levels of it are found in the urine. A relatively mild SDMC phenotype is distinguished: hyperimmunoglobulinemia syndrome D (first described as HIDS in 1984) and a severe variant – mevalonic aciduria. A little more than 300 patients with SDMC have been described in the world. The disease is manifested by intermittent fever, arthralgia, pharyngitis, cervical lymphadenitis, urticarial rash resembling urticaria, less often vasculitis-like manifestations in the form of petechial-purple elements. Diagnosis is based on the activity of the mevalonate kinase enzyme in the blood or skin cells, biochemical analysis of urine (high numbers of mevalonic acid), as well as genetic confirmation of a mutation in the mevalonate kinase gene. The main principles of therapy for autoinflammatory diseases are the control of clinical symptoms and inflammation in general, as well as the prevention of amyloidosis. Conclusion: if an autoinflammatory process in the body is suspected, it is necessary to conduct a genetic study for timely diagnosis and the appointment of pathogenetic therapy to improve the quality of life and prevent complications.

Abstract SY03-02: Extrachromosomal DNA (ecDNA): Cancer's dynamic circular genome

Abstract Human genes are arranged on 23 pairs of chromosomes, but in cancer, tumor-promoting genes and regulatory elements can free themselves from chromosomes and relocate to circular, extrachromosomal pieces of DNA (ecDNA). ecDNA poses one of the greatest challenges for cancer patients, affecting children and adults and women and men, with a wide variety of cancer types. Although ecDNA was first observed more than 50 years ago, its critical importance has only recently come to light. ecDNA, because of its non-chromosomal inheritance, drives high-copy number oncogene amplification and enables tumors to evolve their genomes rapidly, contributing to treatment resistance and shorter survival for patients. Furthermore, the circular ecDNA architecture fundamentally alters gene regulation and transcription. In this talk, I will discuss recent collaborative discoveries that highlight how the higher order, spatial organization of ecDNA, and its mechanism of inheritance, contributes to aggressive tumorigenesis, accelerated evolution, and treatment resistance. Citation Format: Paul S. Mischel. Extrachromosomal DNA (ecDNA): Cancer's dynamic circular genome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY03-02.

Live analysis of position-effect variegation in Drosophila reveals different modes of action for HP1a and Su(var)3-9

Position-effect variegation (PEV) results from the juxtaposition of euchromatic and heterochromatic components of eukaryotic genomes, silencing genes near the new euchromatin/heterochromatin junctions. Silencing is itself heritable through S phase, giving rise to distinctive random patterns of cell clones expressing the genes intermixed with clones in which the genes are silenced. Much of what we know about epigenetic inheritance in the soma stems from work on PEV aimed at identifying the components of the silencing machinery and its mechanism of inheritance. The roles of two central gene activities-the Su(var)3-9-encoded histone H3-lysine-9 methyltransferase and the Su(var)205-encoded methyl-H3-lysine-9 binding protein heterochromatin protein 1 (HP1a)-have been inferred from terminal phenotypes, leaving considerable gaps in understanding of how PEV behaves through development. Here, we investigate the PEV phenotypes of Su(var)3-9 and Su(var)205 mutations in live developing tissues. We discovered that mutation in Su(var)205 compromises the initial establishment of PEV in early embryogenesis. Later gains of heterochromatin-induced gene silencing are possible but are unstable and lost rapidly. In contrast, a strain with mutation in Su(var)3-9 exhibits robust silencing early in development but fails to maintain it through subsequent cell divisions. Our analyses show that, while the terminal phenotypes of these mutations may appear identical, they have arrived at them through different developmental trajectories. We discuss how our findings expand and clarify existing models for epigenetic inheritance of heterochromatin-induced gene silencing.

Assessment of parental benzo[a]pyrene exposure-induced cross-generational neurotoxicity and changes in offspring sperm DNA methylome in medaka fish.

Previous studies have revealed that DNA methylation changes could serve as potential genomic markers for environmental benzo[a]pyrene (BaP) exposure and intergenerational inheritance of various physiological impairments (e.g. obesity and reproductive pathologies). As a typical aromatic hydrocarbon pollutant, direct BaP exposure has been shown to induce neurotoxicity. To unravel the inheritance mechanisms of the BaP-induced bone phenotype in freshwater medaka, we conducted whole-genome bisulfite sequencing of F1 sperm and identified 776 differentially methylated genes (DMGs). Ingenuity pathway analysis revealed that DMGs were significantly enriched in pathways associated with neuronal development and function. Therefore, it was hypothesized that parental BaP exposure (1 μg/l, 21 days) causes offspring neurotoxicity. Furthermore, the possibility for sperm methylation as an indicator for a neurotoxic phenotype was investigated. The F0 adult brains and F1 larvae were analyzed for BaP-induced direct and inherited toxicity. Acetylcholinesterase activity was significantly reduced in the larvae, together with decreased swimming velocity. Molecular analysis revealed that the marker genes associated with neuron development and growth (alpha1-tubulin, mbp, syn2a, shh, and gap43) as well as brain development (dlx2, otx2, and krox-20) were universally downregulated in the F1 larvae (3 days post-hatching). While parental BaP exposure at an environmentally relevant concentration could induce neurotoxicity in the developing larvae, the brain function of the exposed F0 adults was unaffected. This indicates that developmental neurotoxicity in larvae may result from impaired neuronal development and differentiation, causing delayed brain growth. The present study demonstrates that the possible adverse health effects of BaP in the environment are more extensive than currently understood. Thus, the possibility of multigenerational BaP toxicity should be included in environmental risk assessments.

Molecular cardiology: from decoding the genetic nature and mechanisms of the diseases development to the introduction into the clinic

In recent decades, advances in molecular biology have led to a change in understanding the inheritance mechanisms and development of cardiological diseases of predominantly genetic origin, such as hypertrophic and dilated cardiomyopathies, familial hypercholesterolemia, etc. This knowledge made it possible to develop fundamentally new drug interventions. Programs for detecting cardiac diseases of predominantly genetic origin have been created, including genetic counseling and testing. Competence in this area is becoming a necessary part of a cardiologist's job.

The transcription factor Atf1 lowers the transition barrier for nucleosome-mediated establishment of heterochromatin.

Transcription factors can exert opposite effects depending on the chromosomal context. The fission yeast transcription factor Atf1 both activates numerous genes in response to stresses and mediates heterochromatic gene silencing in the mating-type region. Investigating this context dependency, we report here that the establishment of silent heterochromatin in the mating-type region occurs at a reduced rate in the absence of Atf1 binding. Quantitative modeling accounts for the observed establishment profiles by a combinatorial recruitment of histone-modifying enzymes: locally by Atf1 at two binding sites and over the whole region by dynamically appearing heterochromatic nucleosomes, a source of which is the RNAi-dependent cenH element. In the absence of Atf1 binding, the synergy is lost, resulting in a slow rate of heterochromatin formation. The system shows how DNA-binding proteins can influence local nucleosome states and thereby potentiate long-range positive feedback on histone-modification reactions to enable heterochromatin formation over large regions in a context-dependent manner.

Flexible and Efficient QoS Provisioning in AXI4-Based Network-on-Chip Architecture

We propose a network-on-chip (NoC)-based whole system design, whose communication architecture is compatible with the advanced microcontroller bus architecture advanced extensible interface 4 (AXI4) protocol and supports high-performance multiple quality-of-service (QoS) schemes. In our system, the network interface (NI) between the NoC and the master/slave node is proposed to make the NoC architecture independent from the AXI4 protocol via message format conversion between the AXI4 signal format and the packet format, offering high flexibility to the NoC design. Besides, a QoS inheritance mechanism is applied in the slave-side NI to support QoS during packets’ round-trip transfer in the NoC. The NoC system contains time-division multiplexing (TDM) and virtual channel (VC) subnetworks to apply multiple QoS schemes to AXI4 signals with different QoS tags, and the NI is responsible for signals distribution between two subnetworks. Besides, a traffic converter is proposed in each NI to balance the traffic between the two subnetworks when necessary. The experimental results show that our proposed architecture ensures a high-throughput and low-latency NoC system. By applying the traffic converter, the packet latency can be improved.

Testicular "Inherited Metabolic Memory" of Ancestral High-Fat Diet Is Associated with Sperm sncRNA Content.

Excessive adiposity caused by high-fat diets (HFDs) is associated with testicular metabolic and functional abnormalities up to grand-offspring, but the mechanisms of this epigenetic inheritance are unclear. Here we describe an association of sperm small non-coding RNA (sncRNA) with testicular “inherited metabolic memory” of ancestral HFD, using a transgenerational rodent model. Male founders were fed a standard chow for 200 days (CTRL), HFD for 200 days (HFD), or standard chow for 60 days followed by HFD for 140 days (HFDt). The male offspring and grand-offspring were fed standard chow for 200 days. The sncRNA sequencing from epidydimal spermatozoa revealed signatures associated with testicular metabolic plasticity in HFD-exposed mice and in the unexposed progeny. Sperm tRNA-derived RNA (tsRNA) and repeat-derived small RNA (repRNA) content were specially affected by HFDt and in the offspring of HFD and HFDt mice. The grand-offspring of HFD and HFDt mice showed lower sperm counts than CTRL descendants, whereas the sperm miRNA content was affected. Although the causality between sperm sncRNAs content and transgenerational epigenetic inheritance of HFD-related traits remains elusive, our results suggest that sperm sncRNA content is influenced by ancestral exposure to HFD, contributing to the sperm epigenome up to the grand-offspring.

The prevention of hereditary breast cancer in Italy: towards the implementation of the national prevention plan in the Italian regions

Breast cancer is the malignant cancer with highest incidence in females, representing 29% of all cancers, followed by colorectal cancer (13%), lung cancer (6%), thyroid cancer (5%), and uterine body cancer (5%). It has been estimated that in Italy almost 48,000 women were be affected in 2015 [1]. The majority of breast cancers shows a multifactorial pathogenesis, however 5-7% shows a strong hereditary component, namely genetic factors that follow mendelian inheritance mechanisms. In fact, among affected woman, almost 2% of breast cancers is determined by genetic variants of BRCA1 and BRCA2 (“BRCA genes”), that show an high penetrance pattern of hereditary predisposition. Nevertheless, when considering only affected women younger than 40 years, the percentage of carriers of pathogenic variants BRCA genes rises up to 10%. The prevalence of pathogenic variants of BRCA genes in the Caucasians is around 1/400 [2]. When applying this frequency to the whole Italian resident population in 2015, it can be estimated that in our country almost 152,000 people are carriers of these variants, and can therefore be at higher risk to develop breast cancer. In fact, the median estimate of cumulative risk of breast cancer in 70 years-old women is 57% for carriers of BRCA1 variants and 49% for BRCA2 [1]. Moreover, carriers of pathogenic variants show a tendency to develop breast cancer at earlier age, and are also at increased risk of ovarian cancer (lifetime risk is 40% and 18% for carriers of BRCA1 and BRCA2 variants, respectively [1]).

Adaptive Multifactorial Evolutionary Optimization for Multitask Reinforcement Learning

Evolutionary computation has largely exhibited its potential to complement conventional learning algorithms in a variety of machine learning tasks, especially those related to unsupervised (clustering) and supervised learning. It has not been until lately when the computational efficiency of evolutionary solvers has been put in prospective for training reinforcement learning models. However, most studies framed so far within this context have considered environments and tasks conceived in isolation, without any exchange of knowledge among related tasks. In this manuscript we present A-MFEA-RL, an adaptive version of the well-known MFEA algorithm whose search and inheritance operators are tailored for multitask reinforcement learning environments. Specifically, our approach includes crossover and inheritance mechanisms for refining the exchange of genetic material, which rely on the multilayered structure of modern deep-learning-based reinforcement learning models. In order to assess the performance of the proposed approach, we design an extensive experimental setup comprising multiple reinforcement learning environments of varying levels of complexity, over which the performance of A-MFEA-RL is compared to that furnished by alternative nonevolutionary multitask reinforcement learning approaches. As concluded from the discussion of the obtained results, A-MFEA-RL not only achieves competitive success rates over the simultaneously addressed tasks, but also fosters the exchange of knowledge among tasks that could be intuitively expected to keep a degree of synergistic relationship.