scholarly journals Changes in gene expression shift and switch genetic interactions

2019 ◽  
Author(s):  
Xianghua Li ◽  
Jasna Lalic ◽  
Pablo Baeza-Centurion ◽  
Riddhiman Dhar ◽  
Ben Lehner
Keyword(s):  
Gene Expression ◽  
Mathematical Model ◽  
Protein Folding ◽  
Minimal System ◽  
Genetic Interactions ◽  
Mechanistic Models ◽  
List Type ◽  
Cellular Phenotype ◽  
Lambda Repressor ◽  
Intermediate Phenotypes

SummaryAn important goal in disease genetics and evolutionary biology is to understand how mutations combine to alter phenotypes and fitness. Non-additive interactions between mutations occur extensively and change across conditions, cell types, and species, making genetic prediction a difficult challenge. To understand the reasons for this, we reduced the problem to a minimal system where we combined mutations in a single protein performing a single function (a transcriptional repressor inhibiting a target gene). Even in this minimal system, a change in gene expression altered both the strength and type of genetic interactions. These seemingly complicated changes could, however, be predicted by a mathematical model that propagates the effects of mutations on protein folding to the cellular phenotype. We show that similar changes will be observed for many genes. These results provide fundamental insights into genotype-phenotype maps and illustrate how changes in genetic interactions can be predicted using hierarchical mechanistic models.One sentence SummaryDeep mutagenesis of the lambda repressor reveals that changes in gene expression will alter the strength and direction of genetic interactions between mutations in many genes.HighlightsDeep mutagenesis of the lambda repressor at two expression levels reveals extensive changes in mutational effects and genetic interactionsGenetic interactions can switch from positive (suppressive) to negative (enhancing) as the expression of a gene changesA mathematical model that propagates the effects of mutations on protein folding to the cellular phenotype accurately predicts changes in mutational effects and interactionsChanges in expression will alter mutational effects and interactions for many genesFor some genes, perfect mechanistic models will never be able to predict how mutations of known effect combine without measurements of intermediate phenotypes

HealthTwiSt: The Berlin Twin Registry for Health Research

2012 ◽  
Vol 16 (1) ◽  
pp. 163-166 ◽  
Author(s):  
Andreas Busjahn
Keyword(s):  
Gene Expression ◽  
Health Research ◽  
Media Coverage ◽  
Collaborative Research ◽  
Twin Studies ◽  
Research Topics ◽  
Private Company ◽  
Intermediate Phenotypes ◽  
Twin Registry ◽  
Scientific Results

The Berlin Twin Registry has its focus on health research. It is operated as a private company, making twin studies available to academic institutions as well as commercial partners in the area of biotechnology and nutrition. Recruitment is based on invitation in the context of mass media coverage of scientific results. Phenotyping in the unselected twin subjects is directed toward intermediate phenotypes that can bear on common diseases. These phenotypes include proteomic approaches and gene expression. Some results are briefly described to give an impression of the range of research topics and related opportunities for retrospective and prospective collaborative research.

Abstract 5953: Flow Pulsation Affect Distal Pulmonary Artery Endothelial Cell mRNA Expression

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Min Li ◽  
Kurt Stenmark ◽  
Robin Shandas ◽  
Wei Tan
Keyword(s):  
Gene Expression ◽  
Pulmonary Artery ◽  
Pulsatile Flow ◽  
Static Condition ◽  
Flow Chamber ◽  
Physical Characteristics ◽  
List Type ◽  
Flow Pulsation ◽  
Individual Gene ◽  
Speed Flow

Background: Due to the development of pulmonary arterial hypertension (PAH), distal pulmonary artery endothelial cells (dPAEC) are exposed to wall shear stress (SS) that is different in physical characteristics compared to normal condition. The effect of individual components of SS on PAEC biology has not been thoroughly examined. Thus the current study was designed to examine how dPAEC respond to different component of SS in regarding to gene expression including adhesion molecules: ICAM, VCAM, E-selectin; chemokine: MCP-1 and growth factors:VEGF, Flt-1. Methods: Bovine dPAEC were cultured and placed on fibronectin-coated slides till confluent. Cells were then exposed to SS with different frequency (1Hz, 2Hz), pulsation (low, medium and high with an average SS of 14 dynes/cm 2 ) and time (1hr or 6hrs). The flow studies were carried out using a flow chamber connected to a variable speed flow pump. All data was represented as fold change relative to static condition. Results: As shown in table below, The effect of flow frequency on gene expression depends on individual gene. There was no difference of ICAM expression between 1Hz and 2Hz. Frequency of 2Hz significantly increased VCAM and MCP-1 expression compared to frequency of 1Hz. Compared to static condition, steady flow increased all gene expression. One hour pulsatile flow further increased ICAM, VCAM, E-selectin and MCP-1 but not VEGF or Flt-1 expression as pulsation increased. 3) Prolonged pulsatile flow further increased all gene expression. Conclusion: Physical characteristics of flow, especially flow pulsation stimulate dPAEC gene expression which can contribute to the development of PAH.

scholarly journals Genetic effect in leaf and xylem transcriptome variations among Eucalyptus urophylla x grandis hybrids in field conditions

2018 ◽  
Vol 67 (1) ◽  
pp. 57-65
Author(s):  
Alexandre Vaillant ◽  
Astrid Honvault ◽  
Stéphanie Bocs ◽  
Maryline Summo ◽  
Garel Makouanzi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Variance Components ◽  
Genetic Effect ◽  
Field Conditions ◽  
Eucalyptus Urophylla ◽  
Rna Seq ◽  
Intermediate Phenotypes ◽  
False Discovery ◽  
Hybrid Clones ◽  
Selection Of

Abstract To assess the genetic and environmental components of gene-expression variation among trees we used RNA-seq technology and Eucalyptus urophylla x grandis hybrid clones tested in field conditions. Leaf and xylem transcriptomes of three 20 month old clones differing in terms of growth, repeated in two blocks, were investigated. Transcriptomes were very similar between ramets. The number of expressed genes was significantly (P<0.05) higher in leaf (25,665±634) than in xylem (23,637±1,241). A pairwise clone comparisons approach showed that 4.5 to 14 % of the genes were diffe­rentially expressed (false discovery rate [FDR]<0.05) in leaf and 7.1 to 16 % in xylem. An assessment of among clone variance components revealed significant results in leaf and xylem in 3431 (248) genes (at FDR<0.2) and 160 (3) (at FDR<0.05), respectively. These two complementary approa­ches displayed correlated results. A focus on the phenylpro­panoid, cellulose and xylan pathways revealed a large majo­rity of low expressed genes and a few highly expressed ones, with RPKM values ranging from nearly 0 to 600 in leaf and 10,000 in xylem. Out of the 115 genes of these pathways, 45 showed differential expression for at least one pair of geno­type, five of which displaying also clone variance compo­nents. These preliminary results are promising in evaluating whether gene expression can serve as possible ‘intermediate phenotypes’ that could improve the accuracy of selection of grossly observable traits.

scholarly journals 77 Prevalence of secondary immunotherapeutic targets in the absence of established immune biomarkers in solid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A86-A86
Author(s):  
Paul DePietro ◽  
Mary Nesline ◽  
Yong Hee Lee ◽  
RJ Seager ◽  
Erik Van Roey ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Reference Population ◽  
List Type ◽  
Tumor Type ◽  
Genomic Profiling ◽  
Rna Seq ◽  
Immune Biomarkers ◽  
Cancer Types ◽  
Immune Related Genes

BackgroundImmune checkpoint inhibitor-based therapies have achieved impressive success in the treatment of several cancer types. Predictive immune biomarkers, including PD-L1, MSI and TMB are well established as surrogate markers for immune evasion and tumor-specific neoantigens across many tumors. Positive detection across cancer types varies, but overall ~50% of patients test negative for these primary immune markers.1 In this study, we investigated the prevalence of secondary immune biomarkers outside of PD-L1, TMB and MSI.MethodsComprehensive genomic and immune profiling, including PD-L1 IHC, TMB, MSI and gene expression of 395 immune related genes was performed on 6078 FFPE tumors representing 34 cancer types, predominantly composed of lung cancer (36.7%), colorectal cancer (11.9%) and breast cancer (8.5%). Expression levels by RNA-seq of 36 genes targeted by immunotherapies in solid tumor clinical trials, identified as secondary immune biomarkers, were ranked against a reference population. Genes with a rank value ≥75th percentile were considered high and values were associated with PD-L1 (positive ≥1%), MSI (MSI-H or MSS) and TMB (high ≥10 Mut/Mb) status. Additionally, secondary immune biomarker status was segmented by tumor type and cancer immune cycle roles.ResultsIn total, 41.0% of cases were PD-L1+, 6.4% TMB+, and 0.1% MSI-H. 12.6% of cases were positive for >2 of these markers while 39.9% were triple negative (PD-L1-/TMB-/MSS). Of the PD-L1-/TMB-/MSS cases, 89.1% were high for at least one secondary immune biomarker, with 69.3% having ≥3 markers. PD-L1-/TMB-/MSS tumor types with ≥50% prevalence of high secondary immune biomarkers included brain, prostate, kidney, sarcoma, gallbladder, breast, colorectal, and liver cancer. High expression of cancer testis antigen secondary immune biomarkers (e.g., NY-ESO-1, LAGE-1A, MAGE-A4) was most commonly observed in bladder, ovarian, sarcoma, liver, and prostate cancer (≥15%). Tumors demonstrating T-cell priming (e.g., CD40, OX40, CD137), trafficking (e.g., TGFB1, TLR9, TNF) and/or recognition (e.g., CTLA4, LAG3, TIGIT) secondary immune biomarkers were most represented by kidney, gallbladder, and sarcoma (≥40%), with melanoma, esophageal, head & neck, cervical, stomach, and lung cancer least represented (≥15%).ConclusionsOur studies show comprehensive tumor profiling that includes gene expression can detect secondary immune biomarkers targeted by investigational therapies in ~90% of PD-L1-/TMB-/MSS cases. While genomic profiling could also provide therapeutic choices for a percentage of these patients, detection of secondary immune biomarkers by RNA-seq provides additional options for patients without a clear therapeutic path as determined by PD-L1 testing and genomic profiling alone.ReferenceHuang R S P, Haberberger J, Severson E, et al. A pan-cancer analysis of PD-L1 immunohistochemistry and gene amplification, tumor mutation burden and microsatellite instability in 48,782 cases. Mod Pathol 2021;34: 252–263.

scholarly journals A comprehensive analysis of vomeronasal organ transcriptome reveals variable gene expression depending on age and function in rabbits

2020 ◽  
Author(s):  
PR Villamayor ◽  
D Robledo ◽  
C Fernández ◽  
J Gullón ◽  
L Quintela ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transient Receptor Potential ◽  
Expression Patterns ◽  
Vomeronasal Organ ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
List Type ◽  
Gene Repertoire ◽  
Behavioural Responses ◽  
Transient Receptor

ABSTRACTThe vomeronasal organ (VNO) is a chemosensory organ specialized in the detection of pheromones and consequently the regulation of behavioural responses mostly related to reproduction. VNO shows a broad variation on its organization, functionality and gene expression in vertebrates, and although the species analyzed to date have shown very specific features, its expression patterns have only been well-characterized in mice. Despite rabbits represent a model of chemocommunication, unfortunately no genomic studies have been performed on VNO of this species to date. The capacity of VNO to detect a great variety of different stimuli suggests a large number of genes with complex organization to support this function. Here we provide the first comprehensive gene expression analysis of the rabbit VNO through RNA-seq across different sexual maturation stages. We characterized the VNO transcriptome, updating the number of the two main vomeronasal receptor (VR) families, 129 V1R and 70 V2R. Among others, the expression of transient receptor potential channel 2 (TRPC2), a crucial cation channel generating electrical responses to sensory stimulation in vomeronasal neurons, along with the specific expression of some fomyl-peptide receptors and H2-Mv genes, both known to have specific roles in the VNO, revealed a the particular gene expression repertoire of this organ, but also its singularity in rabbits. Moreover, juvenile and adult VNO transcriptome showed consistent differences, which may indicate that these receptors are tuned to fulfill specific functions depending on maturation age. We also identified VNO-specific genes, including most VR and TRPC2, thus confirming their functional association with the VNO. Overall, these results represent the genomic baseline for future investigations which seek to understand the genetic basis of behavioural responses canalized through the VNO.HIGHLIGHTSFirst description of the rabbit vomeronasal organ (VNO) transcriptomeVNO contains a unique gene repertoire depending on the speciesHigh fluctuation of the VNO gene expression reveals changes dependent on age and specific functionsMost vomeronasal-receptors (VR) and transient receptor potential channel 2 (TRPC2) genes are VNO-specificReproduction-related genes shows a wide expression pattern

scholarly journals Digital signaling decouples activation probability and population heterogeneity

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Ryan A Kellogg ◽  
Chengzhe Tian ◽  
Tomasz Lipniacki ◽  
Stephen R Quake ◽  
Savaş Tay
Keyword(s):  
Gene Expression ◽  
Single Cell ◽  
Cell Activation ◽  
Population Heterogeneity ◽  
Cellular Phenotype ◽  
Noisy Environments ◽  
Gene Expression Phenotype ◽  
Weak Stimulation ◽  
Cell To Cell Variability ◽  
Activation Probability

Digital signaling enhances robustness of cellular decisions in noisy environments, but it is unclear how digital systems transmit temporal information about a stimulus. To understand how temporal input information is encoded and decoded by the NF-κB system, we studied transcription factor dynamics and gene regulation under dose- and duration-modulated inflammatory inputs. Mathematical modeling predicted and microfluidic single-cell experiments confirmed that integral of the stimulus (or area, concentration × duration) controls the fraction of cells that activate NF-κB in the population. However, stimulus temporal profile determined NF-κB dynamics, cell-to-cell variability, and gene expression phenotype. A sustained, weak stimulation lead to heterogeneous activation and delayed timing that is transmitted to gene expression. In contrast, a transient, strong stimulus with the same area caused rapid and uniform dynamics. These results show that digital NF-κB signaling enables multidimensional control of cellular phenotype via input profile, allowing parallel and independent control of single-cell activation probability and population heterogeneity.

scholarly journals The Strassen invariance principle for certain non-stationary Markov–Feller chains

2020 ◽  
Vol 121 (1) ◽  
pp. 1-34 ◽  
Author(s):  
Dawid Czapla ◽  
Katarzyna Horbacz ◽  
Hanna Wojewódka-Ściążko
Keyword(s):  
Gene Expression ◽  
Mathematical Model ◽  
Population Dynamics ◽  
Invariance Principle ◽  
Probability Function ◽  
Stochastic Dynamics ◽  
Transition Probability ◽  
Type Condition ◽  
Iterated Logarithm ◽  
Transition Probability Function

We propose certain conditions implying the functional law of the iterated logarithm (the Strassen invariance principle) for some general class of non-stationary Markov–Feller chains. This class may be briefly specified by the following two properties: firstly, the transition operator of the chain under consideration enjoys a non-linear Lyapunov-type condition, and secondly, there exists an appropriate Markovian coupling whose transition probability function can be decomposed into two parts, one of which is contractive and dominant in some sense. Our criterion may serve as a useful tool in verifying the functional law of the iterated logarithm for certain random dynamical systems, developed e.g. in biology and population dynamics. In the final part of the paper we present an example application of our main theorem to a mathematical model describing stochastic dynamics of gene expression.

Method for inferring and extracting reliable genetic interactions from time-series profile of gene expression

2008 ◽  
Vol 215 (1) ◽  
pp. 105-114 ◽  
Author(s):  
Masahiko Nakatsui ◽  
Takanori Ueda ◽  
Yukihiro Maki ◽  
Isao Ono ◽  
Masahiro Okamoto
Keyword(s):  
Gene Expression ◽  
Time Series ◽  
Genetic Interactions
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