scholarly journals Histone 4 Lysine 20 Methylation: A Case for Neurodevelopmental Disease

Biology ◽  
2019 ◽  
Vol 8 (1) ◽  
pp. 11 ◽  
Author(s):  
Rochelle Wickramasekara ◽  
Holly Stessman
Keyword(s):  
Large Scale ◽  
Developmental Process ◽  
Current Knowledge ◽  
Fine Tuning ◽  
Future Research ◽  
Sequencing Data ◽  
Neurodevelopmental Disease ◽  
Kleefstra Syndrome ◽  
Sequencing Studies ◽  
Methyltransferase Gene

Neurogenesis is an elegantly coordinated developmental process that must maintain a careful balance of proliferation and differentiation programs to be compatible with life. Due to the fine-tuning required for these processes, epigenetic mechanisms (e.g., DNA methylation and histone modifications) are employed, in addition to changes in mRNA transcription, to regulate gene expression. The purpose of this review is to highlight what we currently know about histone 4 lysine 20 (H4K20) methylation and its role in the developing brain. Utilizing publicly-available RNA-Sequencing data and published literature, we highlight the versatility of H4K20 methyl modifications in mediating diverse cellular events from gene silencing/chromatin compaction to DNA double-stranded break repair. From large-scale human DNA sequencing studies, we further propose that the lysine methyltransferase gene, KMT5B (OMIM: 610881), may fit into a category of epigenetic modifier genes that are critical for typical neurodevelopment, such as EHMT1 and ARID1B, which are associated with Kleefstra syndrome (OMIM: 610253) and Coffin-Siris syndrome (OMIM: 135900), respectively. Based on our current knowledge of the H4K20 methyl modification, we discuss emerging themes and interesting questions on how this histone modification, and particularly KMT5B expression, might impact neurodevelopment along with current challenges and potential avenues for future research.

scholarly journals Detecting cancer vulnerabilities through gene networks under purifying selection in 4,700 cancer genomes

2017 ◽  
Author(s):  
Anika Gupta ◽  
Heiko Horn ◽  
Parisa Razaz ◽  
April Kim ◽  
Michael Lawrence ◽  
...  
Keyword(s):  
Gene Networks ◽  
Large Scale ◽  
Significant Proportion ◽  
Low Frequency ◽  
Interaction Network ◽  
Purifying Selection ◽  
Sequencing Data ◽  
Gene Sets ◽  
Sequencing Studies ◽  
Significant Enrichment

ABSTRACTLarge-scale cancer sequencing studies have uncovered dozens of mutations critical to cancer initiation and progression. However, a significant proportion of genes linked to tumor propagation remain hidden, often due to noise in sequencing data confounding low frequency alterations. Further, genes in networks under purifying selection (NPS), or those that are mutated in cancers less frequently than would be expected by chance, may play crucial roles in sustaining cancers but have largely been overlooked. We describe here a statistical framework that identifies genes that have a first order protein interaction network significantly depleted for mutations, to elucidate key genetic contributors to cancers. Not reliant on and thus, unbiased by, the gene of interest’s mutation rate, our approach has identified 685 putative genes linked to cancer development. Comparative analysis indicates statistically significant enrichment of NPS genes in previously validated cancer vulnerability gene sets, while further identifying novel cancer-specific candidate gene targets. As more tumor genomes are sequenced, integrating systems level mutation data through this network approach should become increasingly useful in pinpointing gene targets for cancer diagnosis and treatment.

Genetic contributions to anxiety disorders: where we are and where we are heading

2021 ◽  
pp. 1-16
Author(s):  
Helga Ask ◽  
Rosa Cheesman ◽  
Eshim S. Jami ◽  
Daniel F. Levey ◽  
Kirstin L. Purves ◽  
...  
Keyword(s):  
Anxiety Disorders ◽  
Psychiatric Disorders ◽  
Large Scale ◽  
Current Knowledge ◽  
Association Studies ◽  
Twin Studies ◽  
Future Research ◽  
Specific Gene ◽  
Genome Wide Association Studies ◽  
Genome Wide

Abstract Anxiety disorders are among the most common psychiatric disorders worldwide. They often onset early in life, with symptoms and consequences that can persist for decades. This makes anxiety disorders some of the most debilitating and costly disorders of our time. Although much is known about the synaptic and circuit mechanisms of fear and anxiety, research on the underlying genetics has lagged behind that of other psychiatric disorders. However, alongside the formation of the Psychiatric Genomic Consortium Anxiety workgroup, progress is rapidly advancing, offering opportunities for future research. Here we review current knowledge about the genetics of anxiety across the lifespan from genetically informative designs (i.e. twin studies and molecular genetics). We include studies of specific anxiety disorders (e.g. panic disorder, generalised anxiety disorder) as well as those using dimensional measures of trait anxiety. We particularly address findings from large-scale genome-wide association studies and show how such discoveries may provide opportunities for translation into improved or new therapeutics for affected individuals. Finally, we describe how discoveries in anxiety genetics open the door to numerous new research possibilities, such as the investigation of specific gene–environment interactions and the disentangling of causal associations with related traits and disorders. We discuss how the field of anxiety genetics is expected to move forward. In addition to the obvious need for larger sample sizes in genome-wide studies, we highlight the need for studies among young people, focusing on specific underlying dimensional traits or components of anxiety.

scholarly journals A framework for annotation of antigen specificities in high-throughput T-cell repertoire sequencing studies

2019 ◽  
Author(s):  
Mikhail V Pogorelyy ◽  
Mikhail Shugay
Keyword(s):  
T Cell ◽  
Large Scale ◽  
Cell Receptor ◽  
Specific Response ◽  
Clustering Methods ◽  
Sequencing Data ◽  
Antigen Specificity ◽  
Cell Repertoire ◽  
Sequencing Studies ◽  
Repertoire Sequencing

AbstractRecently developed molecular methods allow large-scale profiling of T-cell receptor (TCR) sequences that encode for antigen specificity and immunological memory of these cells. However, it is well known, that the even unperturbed TCR repertoire structure is extremely complex due to the high diversity of TCR rearrangements and multiple biases imprinted by VDJ rearrangement process. The latter gives rise to the phenomenon of “public” TCR clonotypes that can be shared across multiple individuals and non-trivial structure of the TCR similarity network. Here we outline a framework for TCR sequencing data analysis that can control for these biases in order to infer TCRs that are involved in response to antigens of interest. Using an example dataset of donors with known HLA haplotype and CMV status we demonstrate that by applying HLA restriction rules and matching against a database of TCRs with known antigen specificity it is possible to robustly detect motifs of an epitope-specific responses in individual repertoires. We also highlight potential shortcomings of TCR clustering methods and demonstrate that highly expanded TCRs should be individually assessed to get the full picture of antigen-specific response.

scholarly journals Novel σ B regulation modules of Gram-positive bacteria involve the use of complex hybrid histidine kinases

Microbiology ◽  
2011 ◽  
Vol 157 (1) ◽  
pp. 3-12 ◽  
Author(s):  
Mark de Been ◽  
Christof Francke ◽  
Roland J. Siezen ◽  
Tjakko Abee
Keyword(s):  
Sigma Factor ◽  
Current Knowledge ◽  
Bacterial Species ◽  
Fine Tuning ◽  
Activation Mechanism ◽  
Future Research ◽  
Control Mechanisms ◽  
Gram Positive ◽  
Gram Positive Bacteria ◽  
Genome Context

A common bacterial strategy to cope with stressful conditions is the activation of alternative sigma factors that control specific regulons enabling targeted responses. In the human pathogen Bacillus cereus, activation of the major stress-responsive sigma factor σ B is controlled by a signalling route that involves the multi-sensor hybrid histidine kinase RsbK. RsbK-type kinases are not restricted to the B. cereus group, but occur in a wide variety of other bacterial species, including members of the the low-GC Gram-positive genera Geobacillus and Paenibacillus as well as the high-GC actinobacteria. Genome context and protein sequence analyses of 118 RsbK homologues revealed extreme variability in N-terminal sensory as well as C-terminal regulatory domains and suggested that RsbK-type kinases are subject to complex fine-tuning systems, including sensitization and desensitization via methylation and demethylation within the helical domain preceding the H-box. The RsbK-mediated stress-responsive sigma factor activation mechanism that has evolved in B. cereus and the other species differs markedly from the extensively studied and highly conserved RsbRST-mediated σ B activation route found in Bacillus subtilis and other low-GC Gram-positive bacteria. Implications for future research on sigma factor control mechanisms are presented and current knowledge gaps are briefly discussed.

scholarly journals Multi-platform discovery of haplotype-resolved structural variation in human genomes

2017 ◽  
Author(s):  
Mark J.P. Chaisson ◽  
Ashley D. Sanders ◽  
Xuefang Zhao ◽  
Ankit Malhotra ◽  
David Porubsky ◽  
...  
Keyword(s):  
Genome Sequencing ◽  
Large Scale ◽  
Structural Variation ◽  
High Throughput Sequencing ◽  
Whole Genome Sequencing Data ◽  
Sequencing Data ◽  
Full Spectrum ◽  
Variant Discovery ◽  
Sequencing Technologies ◽  
Sequencing Studies

ABSTRACTThe incomplete identification of structural variants (SVs) from whole-genome sequencing data limits studies of human genetic diversity and disease association. Here, we apply a suite of long-read, short-read, and strand-specific sequencing technologies, optical mapping, and variant discovery algorithms to comprehensively analyze three human parent–child trios to define the full spectrum of human genetic variation in a haplotype-resolved manner. We identify 818,054 indel variants (<50 bp) and 27,622 SVs (≥50 bp) per human genome. We also discover 156 inversions per genome—most of which previously escaped detection. Fifty-eight of the inversions we discovered intersect with the critical regions of recurrent microdeletion and microduplication syndromes. Taken together, our SV callsets represent a sevenfold increase in SV detection compared to most standard high-throughput sequencing studies, including those from the 1000 Genomes Project. The method and the dataset serve as a gold standard for the scientific community and we make specific recommendations for maximizing structural variation sensitivity for future large-scale genome sequencing studies.

scholarly journals CDKL5 variants

2017 ◽  
Vol 3 (6) ◽  
pp. e200 ◽  
Author(s):  
Ralph D. Hector ◽  
Vera M. Kalscheuer ◽  
Friederike Hennig ◽  
Helen Leonard ◽  
Jenny Downs ◽  
...  
Keyword(s):  
Large Scale ◽  
Catalytic Domain ◽  
Genetic Diagnosis ◽  
Missense Variant ◽  
Functional Domain ◽  
Sequencing Data ◽  
Missense Variants ◽  
Combining Data ◽  
Sequencing Studies ◽  
Scale Population

Objective:To provide new insights into the interpretation of genetic variants in a rare neurologic disorder, CDKL5 deficiency, in the contexts of population sequencing data and an updated characterization of the CDKL5 gene.Methods:We analyzed all known potentially pathogenic CDKL5 variants by combining data from large-scale population sequencing studies with CDKL5 variants from new and all available clinical cohorts and combined this with computational methods to predict pathogenicity.Results:The study has identified several variants that can be reclassified as benign or likely benign. With the addition of novel CDKL5 variants, we confirm that pathogenic missense variants cluster in the catalytic domain of CDKL5 and reclassify a purported missense variant as having a splicing consequence. We provide further evidence that missense variants in the final 3 exons are likely to be benign and not important to disease pathology. We also describe benign splicing and nonsense variants within these exons, suggesting that isoform hCDKL5_5 is likely to have little or no neurologic significance. We also use the available data to make a preliminary estimate of minimum incidence of CDKL5 deficiency.Conclusions:These findings have implications for genetic diagnosis, providing evidence for the reclassification of specific variants previously thought to result in CDKL5 deficiency. Together, these analyses support the view that the predominant brain isoform in humans (hCDKL5_1) is crucial for normal neurodevelopment and that the catalytic domain is the primary functional domain.

Cryptic species in plant-parasitic nematodes

Nematology ◽  
2014 ◽  
Vol 16 (10) ◽  
pp. 1105-1118 ◽  
Author(s):  
Juan E. Palomares-Rius ◽  
Carolina Cantalapiedra-Navarrete ◽  
Pablo Castillo
Keyword(s):  
Cryptic Species ◽  
Large Scale ◽  
Current Knowledge ◽  
Species Conservation ◽  
Future Research ◽  
Parasitic Nematodes ◽  
Plant Parasitic Nematodes ◽  
The Many ◽  
Diverse Groups ◽  
Plant Parasitic

This paper summarises the current knowledge concerning cryptic species of plant-parasitic nematode and briefly reviews the different methods available for their detection and characterisation. Cryptic species represent an important component of biodiversity, such speciation being common among plant-parasitic nematodes and occurring in diverse groups with different life history traits, including the spiral, virus vector, root-lesion and false root-knot nematodes. Cryptic species are important for a number of reasons, including food security, quarantine, non-chemical management technologies and species conservation, and should not be ignored. The magnitude of the phenomenon is largely unknown, but the available data on plant-parasitic nematodes demonstrate that reliance on morphology alone for species delimitation seriously underestimates the total number of taxa. Future research should focus on appropriately designed case studies using combined approaches, including large-scale, whole sample analyses by next-generation sequencing or proteomics in order to be able to answer the many questions that still remain.

scholarly journals scBERT: a Large-scale Pretrained Deep Langurage Model for Cell Type Annotation of Single-cell RNA-seq Data

2021 ◽  
Author(s):  
Wenchuan Wang ◽  
Fan Yang ◽  
Yuan Fang ◽  
Duyu Tang ◽  
Junzhou Huang ◽  
...  
Keyword(s):  
Single Cell ◽  
Large Scale ◽  
Marker Gene ◽  
Gene Interaction ◽  
Fine Tuning ◽  
Superior Performance ◽  
Cell Type ◽  
Sequencing Data ◽  
Downstream Analysis ◽  
Fine Tune

AbstractReliable cell type annotation is a prerequisite for downstream analysis of single-cell RNA sequencing data. Existing annotation algorithms typically suffer from improper handling of batch effect, lack of curated marker gene lists, or difficulty in leveraging the latent gene-gene interaction information. Inspired by large scale pretrained langurage models, we present a pretrained deep neural network-based model scBERT (single-cell Bidirectional Encoder Representations from Transformers) to overcome the above challenges. scBERT follows the state-of-the-art paradigm of pre-train and fine-tune in the deep learning field. In the first phase of scBERT, it obtains a general understanding of gene-gene interaction by being pre-trained on huge amounts of unlabeled scRNA-seq data. The pre-trained scBERT can then be used for the cell annotation task of unseen and user-specific scRNA-seq data through supervised fine-tuning. Extensive and rigorous benchmark studies validate the superior performance of scBERT on various tasks, including cell type annotation, novel cell type discovery, as well as investigation of gene-gene interactions. Thus, scBERT enjoys the advantages of improved generalization and interpretability than existing annotation tools.

scholarly journals Insights Into Development and Progression of Idiopathic Pulmonary Fibrosis From Single Cell RNA Studies

2020 ◽  
Vol 7 ◽  
Author(s):  
Julia Nemeth ◽  
Annika Schundner ◽  
Manfred Frick
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Single Cell ◽  
Large Scale ◽  
Current Knowledge ◽  
Current Model ◽  
Alveolar Epithelium ◽  
Mesenchymal Cell ◽  
Alveolar Type ◽  
Sequencing Studies

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with limited therapeutic options. The current model suggests that chronic or repetitive “micro-injuries” of the alveolar epithelium lead to activation and proliferation of fibroblasts and excessive extracellular matrix (ECM) deposition. Disruption of alveolar type II (ATII) epithelial cell homeostasis and the characteristics of mesenchymal cell populations in IPF have received particular attention in recent years. Emerging data from single cell RNA sequencing (scRNAseq) analysis shed novel light on alterations in ATII cell progenitor dysfunction and the diversity of mesenchymal cells within the fibrotic lung. Within this minireview, we summarize the data from most recent human scRNAseq studies. We aim to collate the current knowledge on cellular plasticity and heterogeneity in the development and progression of IPF, effects of drug treatment on transcriptional changes. Finally, we provide a brief outlook on future challenges and promises for large scale sequencing studies in the development of novel therapeutics for IPF.

Canine Hemangiosarcoma: A Certainly Less Than Ideal, Very Ugly Cancer

2020 ◽  
Author(s):  
Ashley Tinsley
Keyword(s):  
Large Scale ◽  
Current Knowledge ◽  
Treatment Plan ◽  
The Body ◽  
Future Research ◽  
Survival Times ◽  
Cell Structures ◽  
Hemorrhagic Events ◽  
Client Communication ◽  
Future Direction

Canine Hemangiosarcoma (HSA) is a devastating cancer affecting blood vessels in numerous sites within the body that is primarily seen in middle to older aged dogs. It is marked by its rapid aggressive metastatic pathology that often results in a lack of apparent symptoms in early stages. In most cases, disease becomes apparent due to hemorrhagic events following the rupture of the malignant vascular cell structures that can capture and pool blood cells, resulting in necrosis of the affected tissues. The poor survival times in affected patients cause a hindrance to the ability to carry out large scale studies, leaving numerous knowledge gaps to be filled in future research. The pathologic similarities between this and human angiosarcoma (HA) provides the potential for translatable research to be carried out that would improve outcomes across species. Here, current knowledge is outlined in order to improve understanding HSA holistically and suggest future direction. Emphasis is placed on the potential to improve veterinary practices in ways that will improve the ability to quickly and accurately diagnose patients in order to establish better client communication and provide clarity in collaborating to create the best informed treatment plan possible.

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