scholarly journals The Genomic Physics of COVID-19 Pathogenesis and Spread

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 80
Author(s):  
Ang Dong ◽  
Jingshuai Zhao ◽  
Christopher Griffin ◽  
Rongling Wu
Keyword(s):  
Statistical Physics ◽  
Molecular Mechanisms ◽  
Close Contact ◽  
Mitigation Strategies ◽  
Viral Genomes ◽  
Genome Wide ◽  
A Genome ◽  
Genetic Mechanisms ◽  
Physics Model ◽  
Main Effects

Coronavirus disease (COVID-19) spreads mainly through close contact of infected persons, but the molecular mechanisms underlying its pathogenesis and transmission remain unknown. Here, we propose a statistical physics model to coalesce all molecular entities into a cohesive network in which the roadmap of how each entity mediates the disease can be characterized. We argue that the process of how a transmitter transforms the virus into a recipient constitutes a triad unit that propagates COVID-19 along reticulate paths. Intrinsically, person-to-person transmissibility may be mediated by how genes interact transversely across transmitter, recipient, and viral genomes. We integrate quantitative genetic theory into hypergraph theory to code the main effects of the three genomes as nodes, pairwise cross-genome epistasis as edges, and high-order cross-genome epistasis as hyperedges in a series of mobile hypergraphs. Charting a genome-wide atlas of horizontally epistatic hypergraphs can facilitate the systematic characterization of the community genetic mechanisms underlying COVID-19 spread. This atlas can typically help design effective containment and mitigation strategies and screen and triage those more susceptible persons and those asymptomatic carriers who are incubation virus transmitters.

scholarly journals Stable DNMT3L overexpression in SH-SY5Y neurons recreates a facet of the genome-wide Down syndrome DNA methylation signature

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Benjamin I. Laufer ◽  
J. Antonio Gomez ◽  
Julia M. Jianu ◽  
Janine M. LaSalle
Keyword(s):  
Dna Methylation ◽  
Down Syndrome ◽  
Neuronal Differentiation ◽  
Molecular Mechanisms ◽  
Cpg Island ◽  
Differential Methylation ◽  
Chromosome 21 ◽  
Pairwise Comparisons ◽  
Genome Wide ◽  
A Genome

Abstract Background Down syndrome (DS) is characterized by a genome-wide profile of differential DNA methylation that is skewed towards hypermethylation in most tissues, including brain, and includes pan-tissue differential methylation. The molecular mechanisms involve the overexpression of genes related to DNA methylation on chromosome 21. Here, we stably overexpressed the chromosome 21 gene DNA methyltransferase 3L (DNMT3L) in the human SH-SY5Y neuroblastoma cell line and assayed DNA methylation at over 26 million CpGs by whole genome bisulfite sequencing (WGBS) at three different developmental phases (undifferentiated, differentiating, and differentiated). Results DNMT3L overexpression resulted in global CpG and CpG island hypermethylation as well as thousands of differentially methylated regions (DMRs). The DNMT3L DMRs were skewed towards hypermethylation and mapped to genes involved in neurodevelopment, cellular signaling, and gene regulation. Consensus DNMT3L DMRs showed that cell lines clustered by genotype and then differentiation phase, demonstrating sets of common genes affected across neuronal differentiation. The hypermethylated DNMT3L DMRs from all pairwise comparisons were enriched for regions of bivalent chromatin marked by H3K4me3 as well as differentially methylated sites from previous DS studies of diverse tissues. In contrast, the hypomethylated DNMT3L DMRs from all pairwise comparisons displayed a tissue-specific profile enriched for regions of heterochromatin marked by H3K9me3 during embryonic development. Conclusions Taken together, these results support a mechanism whereby regions of bivalent chromatin that lose H3K4me3 during neuronal differentiation are targeted by excess DNMT3L and become hypermethylated. Overall, these findings demonstrate that DNMT3L overexpression during neurodevelopment recreates a facet of the genome-wide DS DNA methylation signature by targeting known genes and gene clusters that display pan-tissue differential methylation in DS.

Abstract 12192: MBNL1 Directly Regulates the Alternative Splicing of mRNAs That Promote Myofibroblast Differentiation

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Jennifer Davis ◽  
Michelle Sargent ◽  
Jianjian Shi ◽  
Lei Wei ◽  
Maurice S Swanson ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Transforming Growth Factor ◽  
Ventricular Remodeling ◽  
Cardiac Injury ◽  
Myofibroblast Differentiation ◽  
Genome Wide ◽  
A Genome

Rationale: During the cardiac injury response fibroblasts differentiate into myofibroblasts, a cell type that enhances extracellular matrix production and facilitates ventricular remodeling. To better understand the molecular mechanisms whereby myofibroblasts are generated in the heart we performed a genome-wide screen with 18,000 cDNAs, which identified the RNA-binding protein muscleblind-like splicing regulator 1 (MBNL1), suggesting a novel association between mRNA alternative splicing and the regulation of myofibroblast differentiation. Objective: To determine the mechanism whereby MBNL1 regulates myofibroblast differentiation and the cardiac fibrotic response. Methods and Results: Confirming the results from our genome wide screen, adenoviral-mediated overexpression of MBNL1 promoted transformation of rat cardiac fibroblasts and mouse embryonic fibroblasts (MEFs) into myofibroblasts, similar to the level of conversion obtained by the profibrotic agonist transforming growth factor β (TGFβ). Antithetically, Mbnl1 -/- MEFs were refractory to TGFβ-induced myofibroblast differentiation. MBNL1 expression is induced in transforming fibroblasts in response to TGFβ and angiotensin II. These results were extended in vivo by analysis of dermal wound healing, a process dependent on myofibroblast differentiation and their proper activity. By day 6 control mice had achieved 82% skin wound closure compared with only 40% in Mbnl1 -/- mice. Moreover, Mbnl1 -/- mice had reduced survival following myocardial infarction injury due to defective fibrotic scar formation and healing. High throughput RNA sequencing (RNAseq) and RNA immunoprecipitation revealed that MBNL1 directly regulates the alternative splicing of transcripts for myofibroblast signaling factors and cytoskeletal-assembly elements. Functional analysis of these factors as mediators of MBNL1 activity is also described here. Conclusions: Collectively, our data suggest that MBNL1 coordinates myofibroblast transformation by directly mediating the alternative splicing of an array of mRNAs encoding differentiation-specific signaling transcripts, which then alter the fibroblast proteome for myofibroblast structure and function.

scholarly journals Comparative transcriptome analysis of mule uncovered several heterosis-related genes for improving muscular endurance and cognition

2019 ◽  
Author(s):  
Shan Gao
Keyword(s):  
Alternative Splicing ◽  
Molecular Genetic ◽  
Hybrid Vigor ◽  
Neuronal System ◽  
Future Studies ◽  
Genome Wide ◽  
A Genome ◽  
Genetic Mechanisms ◽  
Productive Traits ◽  
Genome Wide Gene Expression

AbstractHeterosis has been widely exploited in animal and plant breeding to enhance the productive traits of hybrid progeny of two breeds or two species. Although, there were multiple models for explaining the hybrid vigor, such as dominance and over-dominance hypothesis, its underlying molecular genetic mechanisms remain equivocal. The aim of this study is through comparing the different expression genes (DEGs) and different alternative splicing (DAS) genes to explore the mechanism of heterosis. Here, we performed a genome-wide gene expression and alternative splicing analysis of two heterotic crosses between donkey and horse in three tissues. The results showed that the DAS genes influenced the heterosis-related phenotypes in a unique than DEGs and about 10% DEGs are DAS genes. In addition, over 69.7% DEGs and 87.2% DAS genes showed over-dominance or dominance, respectively. Furthermore, the “Muscle Contraction” and “Neuronal System” pathways were significantly enriched both for the DEGs and DAS genes in muscle. TNNC2 and RYR1 genes may contribute to mule’s great endurance while GRIA2 and GRIN1 genes may be related with mule’s cognition. Together, these DEGs and DAS genes provide the candidates for future studies of the genetic and molecular mechanism of heterosis in mule.

scholarly journals Common genetic risk variants identified in the SPARK cohort implicate DDHD2 as a novel autism risk gene

2020 ◽  
Author(s):  
Nana Matoba ◽  
Dan Liang ◽  
Huaigu Sun ◽  
Nil Aygün ◽  
Jessica C. McAfee ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Association Study ◽  
Genetic Risk ◽  
Molecular Mechanisms ◽  
Autism Spectrum ◽  
Risk Variants ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
A Genome ◽  
Gene Regulatory

AbstractBackgroundAutism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder. Large genetically informative cohorts of individuals with ASD have led to the identification of three common genome-wide significant (GWS) risk loci to date. However, many more common genetic variants are expected to contribute to ASD risk given the high heritability. Here, we performed a genome-wide association study (GWAS) using the Simons Foundation Powering Autism Research for Knowledge (SPARK) dataset to identify additional common genetic risk factors and molecular mechanisms underlying risk for ASD.MethodsWe performed an association study on 6,222 case-pseudocontrol pairs from SPARK and meta-analyzed with a previous GWAS. We integrated gene regulatory annotations to map non-coding risk variants to their regulated genes. Further, we performed a massively parallel reporter assay (MPRA) to identify causal variant(s) within a novel risk locus.ResultsWe identified one novel GWS locus from the SPARK GWAS. The meta-analysis identified four significant loci, including an additional novel locus. We observed significant enrichment of ASD heritability within regulatory regions of the developing cortex, indicating that disruption of gene regulation during neurodevelopment is critical for ASD risk. The MPRA identified one variant at the novel locus with strong impacts on gene regulation (rs7001340), and expression quantitative trait loci data demonstrated an association between the risk allele and decreased expression of DDHD2 (DDHD domain containing 2) in both adult and pre-natal brains.ConclusionsBy integrating genetic association data with multi-omic gene regulatory annotations and experimental validation, we fine-mapped a causal risk variant and demonstrated that DDHD2 is a novel gene associated with ASD risk.

scholarly journals Patterns of genome-wide allele-specific expression in hybrid rice and the implications on the genetic basis of heterosis

2019 ◽  
Vol 116 (12) ◽  
pp. 5653-5658 ◽  
Author(s):  
Lin Shao ◽  
Feng Xing ◽  
Conghao Xu ◽  
Qinghua Zhang ◽  
Jian Che ◽  
...  
Keyword(s):  
Genetic Basis ◽  
Molecular Mechanisms ◽  
Sequencing Data ◽  
Specific Expression ◽  
Allele Specific Expression ◽  
Parental Allele ◽  
Genetic Components ◽  
Genome Wide ◽  
A Genome ◽  
Allele Specific

Utilization of heterosis has greatly increased the productivity of many crops worldwide. Although tremendous progress has been made in characterizing the genetic basis of heterosis using genomic technologies, molecular mechanisms underlying the genetic components are much less understood. Allele-specific expression (ASE), or imbalance between the expression levels of two parental alleles in the hybrid, has been suggested as a mechanism of heterosis. Here, we performed a genome-wide analysis of ASE by comparing the read ratios of the parental alleles in RNA-sequencing data of an elite rice hybrid and its parents using three tissues from plants grown under four conditions. The analysis identified a total of 3,270 genes showing ASE (ASEGs) in various ways, which can be classified into two patterns: consistent ASEGs such that the ASE was biased toward one parental allele in all tissues/conditions, and inconsistent ASEGs such that ASE was found in some but not all tissues/conditions, including direction-shifting ASEGs in which the ASE was biased toward one parental allele in some tissues/conditions while toward the other parental allele in other tissues/conditions. The results suggested that these patterns may have distinct implications in the genetic basis of heterosis: The consistent ASEGs may cause partial to full dominance effects on the traits that they regulate, and direction-shifting ASEGs may cause overdominance. We also showed that ASEGs were significantly enriched in genomic regions that were differentially selected during rice breeding. These ASEGs provide an index of the genes for future pursuit of the genetic and molecular mechanism of heterosis.

scholarly journals A genome-wide genetic pleiotropy approach identified shared loci between multiple system atrophy and inflammatory bowel disease

2019 ◽  
Author(s):  
Alexey A Shadrin ◽  
Sören Mucha ◽  
David Ellinghaus ◽  
Mary B Makarious ◽  
Cornelis Blauwendraat ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Multiple System Atrophy ◽  
Bowel Disease ◽  
Molecular Mechanisms ◽  
Gut Dysfunction ◽  
Genome Wide ◽  
A Genome ◽  
Genetic Overlap ◽  
Inflammatory Bowel ◽  
Shared Genetic

ABSTRACTWe aimed to identify shared genetic background between multiple system atrophy (MSA) and autoimmune diseases by using the conjFDR approach. Our study showed significant genetic overlap between MSA and inflammatory bowel disease and identified DENND1B, C7, and RSP04 loci, which are linked to significant changes in methylation or expression levels of adjacent genes. We obtained evidence of enriched heritability involving immune/digestive categories. Finally, an MSA mouse model showed dysregulation of the C7 gene in the degenerating midbrain compared to wildtype mice. The results identify novel molecular mechanisms and implicate immune and gut dysfunction in MSA pathophysiology.

scholarly journals Identification of Genes Regulating Cell Death inStaphylococcus aureus

2019 ◽  
Author(s):  
Rebecca Yee ◽  
Jie Feng ◽  
Jiou Wang ◽  
Jiazhen Chen ◽  
Ying Zhang
Keyword(s):  
Cell Death ◽  
Acetic Acid ◽  
Drug Targets ◽  
Opportunistic Pathogen ◽  
Infection Model ◽  
Chronic Infections ◽  
Bacterial Cell Death ◽  
Genome Wide ◽  
A Genome ◽  
Genetic Mechanisms

AbstractStaphylococcus aureusis an opportunistic pathogen that causes acute and chronic infections. Due toS. aureus’ s highly resistant and persistent nature, it is paramount to identify better drug targets in order to eradicateS. aureusinfections. Despite the efforts in understanding bacterial cell death, the genes and pathways ofS. aureuscell death remain elusive. Here, we performed a genome-wide screen using a transposon mutant library to study the genetic mechanisms involved inS. aureuscell death. Using a precisely controlled heat-ramp and acetic acid exposure assays, mutations in 27 core genes (hsdR1, hslO, nsaS, sspA, folD, mfd, vraF, kdpB, USA300HOU_2684, 0868, 0369, 0420, 1154, 0142, 0930, 2590, 0997, 2559, 0044, 2004, 1209, 0152, 2455, 0154, 2386, 0232, 0350 involved in transporters, transcription, metabolism, peptidases, kinases, transferases, SOS response, nucleic acid and protein synthesis) caused the bacteria to be more death-resistant. In addition, we identified mutations in core 10 genes (capA, gltT, mnhG1,USA300HOU_1780, 2496, 0200, 2029, 0336, 0329, 2386, involved in transporters, metabolism, transcription, cell wall synthesis) from heat-ramp and acetic acid that caused the bacteria to be more death-sensitive or with defect in persistence. Interestingly, death-resistant mutants were more virulent than the parental strain USA300 and caused increased mortality in aCaenorhabditis elegansinfection model. Conversely, death-sensitive mutants were less persistent and formed less persister cells upon exposure to different classes of antibiotics. These findings provide new insights into the mechanisms ofS. aureuscell death and offer new therapeutic targets for developing more effective treatments caused byS. aureus.

scholarly journals The Potential Role of Genetic Assimilation during Maize Domestication

2017 ◽  
Author(s):  
Anne Lorant ◽  
Sarah Pedersen ◽  
Irene Holst ◽  
Matthew B. Hufford ◽  
Klaus Winter ◽  
...  
Keyword(s):  
Gene Expression ◽  
Zea Mays ◽  
Potential Role ◽  
Expression Patterns ◽  
Genetic Assimilation ◽  
Genome Wide ◽  
A Genome ◽  
Genetic Mechanisms ◽  
Maize Domestication

ABSTRACTDomestication research has largely focused on identification of morphological and genetic differences between extant populations of crops and their wild relatives. Little attention has been paid to the potential effects of environment despite substantial known changes in climate from the time of domestication to modern day. Recent research, in which maize and teosinte (i.e., wild maize) were exposed to environments similar to the time of domestication, resulted in a plastic induction of domesticated phenotypes in teosinte and little response to environment in maize. These results suggest that early agriculturalists may have selected for genetic mechanisms that cemented domestication phenotypes initially induced by a plastic response of teosinte to environment, a process known as genetic assimilation. To better understand this phenomenon and the potential role of environment in maize domestication, we examined differential gene expression in maize (Zea mays ssp. mays) and teosinte (Zea mays ssp. parviglumis) between past and present conditions. We identified a gene set of over 2000 loci showing a change in expression across environmental conditions in teosinte and invariance in maize. In fact, overall we observed both greater plasticity in gene expression and more substantial re-wiring of expression networks in teosinte across environments when compared to maize. While these results suggest genetic assimilation played at least some role in domestication, genes showing expression patterns consistent with assimilation are not significantly enriched for previously identified domestication candidates, indicating assimilation did not have a genome-wide effect.

scholarly journals Genome-Wide Association Study of H/L Traits in Chicken

Animals ◽  
2019 ◽  
Vol 9 (5) ◽  
pp. 260 ◽  
Author(s):  
Bo Zhu ◽  
Qinghe Li ◽  
Ranran Liu ◽  
Maiqing Zheng ◽  
Jie Wen ◽  
...  
Keyword(s):  
Disease Resistance ◽  
Association Study ◽  
Genetic Basis ◽  
Molecular Mechanisms ◽  
Genome Wide Association Study ◽  
Gene Annotation ◽  
Immune Defense ◽  
Genome Wide Association ◽  
Genome Wide ◽  
A Genome

Presently, the heterophil-to-lymphocyte (H/L) ratio is being studied extensively as a disease resistance trait. Through intricate mechanisms to identify and destroy pathogenic microorganisms, heterophils play a pivotal role in the immune defense systems of avian species. To reveal the genetic basis and molecular mechanisms affecting the H/L ratio, phenotypic and H/L data from 1650 white feather chicken broilers were used in performing a genome-wide association study. A self-developed, chicken-specific 55K chip was used for heterophils, lymphocytes, and H/L classification, according to individual genomic DNA profiles. We identified five significant single nucleotide polymorphisms (SNPs) when the genome-wide significance threshold was set to 5% (p < 2.42 × 10−6). A total of 15 SNPs obtained seemingly significant levels (p < 4.84 × 10−5). Gene annotation indicated that CARD11 (Caspase recruitment domain family member 11), BRIX1 (Biogenesis of ribosomes BRX1), and BANP (BTG3 associated nuclear protein) play a role in H/L-associated cell regulation and potentially constitute candidate gene regions for cellular functions dependent on H/L ratios. These results lay the foundation for revealing the genetic basis of disease resistance and future marker-assisted selection for disease resistance.

A genome-wide association study of hexanal content related to soymilk off-flavours in seed of soybean (Glycine max)

2020 ◽  
Vol 71 (6) ◽  
pp. 552 ◽  
Author(s):  
Zhikun Wang ◽  
Gege Bao ◽  
Chao Yang ◽  
Mingming Yang ◽  
Xue Zhao ◽  
...  
Keyword(s):  
Glycine Max ◽  
Candidate Genes ◽  
Quantitative Trait ◽  
Molecular Mechanisms ◽  
Fatty Acid Content ◽  
Soybean Seed ◽  
Genome Wide Association ◽  
Genome Wide ◽  
A Genome ◽  
Hexanal Content

Flavour is an essential quality characteristic of soymilk; however, it contains volatile compounds unacceptable to consumers. Hexanal is the most important flavour compound that gives a sensory beany, grassy flavour in the soymilk. An effective way to reduce hexanal content in soymilk is to screen for and utilise cultivars of soybean (Glycine max (L.) Merr.) with lower hexanal content. The objective of the present study was to dissect the genetic basis of hexanal content in soybean seed by using genome-wide association analysis (GWAS), thereby providing guidance for the selection and breeding of soybean varieties with low hexanal content. We used 24651 single-nucleotide polymorphisms (SNPs) and screened seeds from 111 cultivated soybean accessions to identify quantitative trait nucleotides (QTNs) affecting hexanal content. We discovered 14 novel QTNs located on five different chromosomes that are significantly associated with hexanal content in soybean seed. Among these, 11 QTNs co-localised with quantitative trait loci previously found in linkage or association mapping studies related to protein, oil and/or fatty acid content in soybean seed. We also identified some candidate genes involved in amino acid metabolism, protein content, lipid metabolism and hormone metabolism. Six cultivars with low hexanal content were identified by screening. This is the first GWAS study on hexanal content in soybean seed, and a number of QTNs and candidate genes were identified. Some of these may be useful to breeders for the improvement of marker-assisted breeding efficiency for low hexanal content and may be useful for exploring possible molecular mechanisms underlying hexanal content in soybean seed.

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