scholarly journals Extrinsic noise and heavy-tailed laws in gene expression

2019 ◽  
Author(s):  
Lucy Ham ◽  
Rowan D. Brackston ◽  
Michael P.H. Stumpf
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Extrinsic Noise ◽  
Individual Gene ◽  
Copy Numbers ◽  
Heavy Tailed Distributions ◽  
Heavy Tailed ◽  
Intrinsic Stochasticity ◽  
The Individual ◽  
Noise In Gene Expression

AbstractNoise in gene expression is one of the hallmarks of life at the molecular scale. Here we derive analytical solutions to a set of models describing the molecular mechanisms underlying transcription of DNA into RNA. Our Ansatz allows us to incorporate the effects of extrinsic noise – encompassing factors external to the transcription of the individual gene – and discuss the ramifications for heterogeneity in gene product abundance that has been widely observed in single cell data. Crucially, we are able to show that heavy-tailed distributions of RNA copy numbers cannot result from the intrinsic stochasticity in gene expression alone, but must instead reflect extrinsic sources of variability.

scholarly journals Single-cell RNA sequencing reveals the mesangial identity and species diversity of glomerular cell transcriptomes

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Bing He ◽  
Ping Chen ◽  
Sonia Zambrano ◽  
Dina Dabaghie ◽  
Yizhou Hu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Human Kidney ◽  
Cell Types ◽  
Model Organisms ◽  
Mural Cell ◽  
Glomerular Cell ◽  
Individual Gene ◽  
The Individual

AbstractMolecular characterization of the individual cell types in human kidney as well as model organisms are critical in defining organ function and understanding translational aspects of biomedical research. Previous studies have uncovered gene expression profiles of several kidney glomerular cell types, however, important cells, including mesangial (MCs) and glomerular parietal epithelial cells (PECs), are missing or incompletely described, and a systematic comparison between mouse and human kidney is lacking. To this end, we use Smart-seq2 to profile 4332 individual glomerulus-associated cells isolated from human living donor renal biopsies and mouse kidney. The analysis reveals genetic programs for all four glomerular cell types (podocytes, glomerular endothelial cells, MCs and PECs) as well as rare glomerulus-associated macula densa cells. Importantly, we detect heterogeneity in glomerulus-associated Pdgfrb-expressing cells, including bona fide intraglomerular MCs with the functionally active phagocytic molecular machinery, as well as a unique mural cell type located in the central stalk region of the glomerulus tuft. Furthermore, we observe remarkable species differences in the individual gene expression profiles of defined glomerular cell types that highlight translational challenges in the field and provide a guide to design translational studies.

scholarly journals Technical considerations when designing a gene expression panel for renal transplant diagnosis

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
F. Toulza ◽  
K. Dominy ◽  
T. Cook ◽  
J. Galliford ◽  
J. Beadle ◽  
...  
Keyword(s):  
Gene Expression ◽  
Renal Transplant ◽  
Biological Significance ◽  
Tissue Sampling ◽  
Individual Gene ◽  
Antibody Mediated Rejection ◽  
Gene Level ◽  
Diagnostic Panel ◽  
The Individual ◽  
Gene Panels

Abstract Gene expression analysis is emerging as a new diagnostic tool in transplant pathology, in particular for the diagnosis of antibody-mediated rejection. Diagnostic gene expression panels are defined on the basis of their pathophysiological relevance, but also need to be tested for their robustness across different preservatives and analysis platforms. The aim of this study is the investigate the effect of tissue sampling and preservation on candidate genes included in a renal transplant diagnostic panel. Using the NanoString platform, we compared the expression of 219 genes in 51 samples, split for formalin-fixation and paraffin-embedding (FFPE) and RNAlater preservation (RNAlater). We found that overall, gene expression significantly correlated between FFPE and RNAlater samples. However, at the individual gene level, 46 of the 219 genes did not correlate across the 51 matched FFPE and RNAlater samples. Comparing gene expression results using NanoString and qRT-PCR for 18 genes in the same pool of RNA (RNAlater), we found a significant correlation in 17/18 genes. Our study indicates that, in samples from the same routine diagnostic renal transplant biopsy procedure split for FFPE and RNAlater, 21% of 219 genes of potential biological significance do not correlate in expression. Whether this is due to fixatives or tissue sampling, selection of gene panels for routine diagnosis should take this information into consideration.

scholarly journals Contribution of RNA Degradation to Intrinsic and Extrinsic Noise in Gene Expression

Cell Reports ◽  
2019 ◽  
Vol 26 (13) ◽  
pp. 3752-3761.e5 ◽  
Author(s):  
Antoine Baudrimont ◽  
Vincent Jaquet ◽  
Sandrine Wallerich ◽  
Sylvia Voegeli ◽  
Attila Becskei
Keyword(s):  
Gene Expression ◽  
Rna Degradation ◽  
Extrinsic Noise ◽  
Noise In Gene Expression ◽  
Intrinsic And Extrinsic Noise

scholarly journals Maxima of Sums of Heavy-Tailed Random Variables

2002 ◽  
Vol 32 (1) ◽  
pp. 43-55 ◽  
Author(s):  
K.W. Ng ◽  
Q.H. Tang ◽  
H. Yang
Keyword(s):  
Asymptotic Properties ◽  
Random Variables ◽  
Independent Random Variables ◽  
Partial Sums ◽  
Tail Probabilities ◽  
Large Classes ◽  
Heavy Tailed Distributions ◽  
Heavy Tailed ◽  
The Individual ◽  
Risk Processes

AbstractIn this paper, we investigate asymptotic properties of the tail probabilities of the maxima of partial sums of independent random variables. For some large classes of heavy-tailed distributions, we show that the tail probabilities of the maxima of the partial sums asymptotically equal to the sum of the tail probabilities of the individual random variables. Then we partially extend the result to the case of random sums. Applications to some commonly used risk processes are proposed. All heavy-tailed distributions involved in this paper are supposed on the whole real line.

scholarly journals Exactly solvable models of stochastic gene expression

2020 ◽  
Author(s):  
Lucy Ham ◽  
David Schnoerr ◽  
Rowan D. Brackston ◽  
Michael P. H. Stumpf
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Power Series Expansion ◽  
Transcript Abundance ◽  
Multistate Models ◽  
Extrinsic Noise ◽  
Cell Fate Decisions ◽  
Fresh Perspective ◽  
Heavy Tailed ◽  
Eukaryotic Organisms

Stochastic models are key to understanding the intricate dynamics of gene expression. But the simplest models which only account for e.g. active and inactive states of a gene fail to capture common observations in both prokaryotic and eukaryotic organisms. Here we consider multistate models of gene expression which generalise the canonical Telegraph process, and are capable of capturing the joint effects of e.g. transcription factors, heterochromatin state and DNA accessibility (or, in prokaryotes, Sigma-factor activity) on transcript abundance. We propose two approaches for solving classes of these generalised systems. The first approach offers a fresh perspective on a general class of multistate models, and allows us to “decompose” more complicated systems into simpler processes, each of which can be solved analytically. This enables us to obtain a solution of any model from this class. We further show that these models cannot have a heavy-tailed distribution in the absence of extrinsic noise. Next, we develop an approximation method based on a power series expansion of the stationary distribution for an even broader class of multistate models of gene transcription. The combination of analytical and computational solutions for these realistic gene expression models also holds the potential to design synthetic systems, and control the behaviour of naturally evolved gene expression systems, e.g. in guiding cell-fate decisions.

scholarly journals Retinal Genomic Fabrics Remodeling after Optic Nerve Injury

2021 ◽  
Author(s):  
Pedro Henrique Victorino ◽  
Camila Marra ◽  
Dumitru Andrei Iacobas ◽  
Sanda Iacobas ◽  
David C Spray ◽  
...  
Keyword(s):  
Gene Expression ◽  
Optic Nerve ◽  
Notch Signaling ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Notch Signaling Pathway ◽  
Complement Cascade ◽  
Gene Expressions ◽  
Nerve Crush ◽  
Individual Gene

Glaucoma is a multifactorial neurodegenerative disease, characterized by degeneration of the retinal ganglion cells (RGCs). There has been little progress in developing efficient strategies for neuroprotection in glaucoma. We profiled the retina transcriptome of Lister Hooded rats at 2 weeks after optic nerve crush (ONC) and analyzed the data from the Genomic Fabric Paradigm (GFP) to bring additional insights into the molecular mechanisms of the retinal remodeling after induction of RGC degeneration. GFP considers for the expression of each gene 3 independent characteristics: level, variability and correlation with each other gene. Thus, the 17,657 quantified genes our study generated a total of 155,911,310 values to analyze. This represents 8,830x more data per condition than a traditional transcriptomic analysis. ONC led to a 57% reduction in RGC numbers as detected by retrograde labeling with DiI. We observed a higher Relative Expression Variability after ONC. Gene expression stability was used as a measure of transcription control and disclosed a robust reduction in the number of very stably expressed genes. Predicted Protein-Protein interaction (PPI) analysis with STRING revealed axon and neuron projection as mostly decreased processes, consistent with RGC degeneration. Conversely, immune response PPIs were found among up-regulated genes. Enrichment analysis showed that Complement Cascade and Notch Signaling Pathway, as well as Oxidative Stress and Kit Receptor Pathway were affected after ONC. To expand our studies of altered molecular pathways, we examined the pair-wise coordination of gene expressions within each pathway and within the entire transcriptome using Pearson correlations. ONC increased the number of synergistically coordinated pairs of genes and the number of similar profiles mainly in Complement Cascade and Notch Signaling Pathway. This deep bioinformatic study provides novel insights beyond the regulation of individual gene expression and discloses changes in the control of expression of Complement Cascade and Notch Signaling functional pathways that may be relevant for both RGC degeneration and remodeling of the retinal tissue after ONC.

scholarly journals An interaction-based model for neuropsychiatric features of copy-number variants

2018 ◽  
Author(s):  
Matthew Jensen ◽  
Santhosh Girirajan
Keyword(s):  
Gene Expression ◽  
Copy Number ◽  
Copy Number Variants ◽  
Model Organisms ◽  
Expression Data ◽  
Individual Gene ◽  
Functional Assays ◽  
Genetic Complexity ◽  
The Individual ◽  
Lines Of Evidence

ABSTRACTVariably expressive copy-number variants (CNVs) are characterized by extensive phenotypic heterogeneity of neuropsychiatric phenotypes. Approaches to identify single causative genes for these phenotypes within each CNV have not been successful. Here, we posit using multiple lines of evidence, including pathogenicity metrics, functional assays of model organisms, and gene expression data, that multiple genes within each CNV region are likely responsible for the observed phenotypes. We propose that candidate genes within each region likely interact with each other through shared pathways to modulate the individual gene phenotypes, emphasizing the genetic complexity of CNV-associated neuropsychiatric features.

scholarly journals Screening for Copy Number Variations of the 15q13.3 Hotspot in CHRNA7 Gene and Expression in Patients with Migraines

2021 ◽  
Vol 43 (2) ◽  
pp. 1090-1113
Author(s):  
Mehmet Fatih Özaltun ◽  
Sırma Geyik ◽  
Şenay Görücü Yılmaz
Keyword(s):  
Gene Expression ◽  
Copy Number ◽  
Molecular Mechanisms ◽  
Cholinergic Receptor ◽  
Copy Number Variations ◽  
Healthy Controls ◽  
Standard Curve ◽  
Copy Numbers ◽  
Significant Difference ◽  
Alpha 7

Background: a migraine is a neurological disease. Copy number variation (CNV) is a phenomenon in which parts of the genome are repeated. We investigated the effects of the CNV and gene expression at the location 15q13.3 in the Cholinergic Receptor Nicotinic Alpha 7 Subunit (CHRNA7) gene, which we believe to be effective in the migraine clinic. Methods: we evaluated changes in CHRNA7 gene expression levels and CNV of 15q13.3 in patients with migraine (n = 102, with aura, n = 43; without aura, n = 59) according to healthy controls (n = 120) by q-PCR. The data obtained were analyzed against the reference telomerase reverse transcriptase (TERT) gene with the double copy number by standard curve analysis. Copy numbers were graded as a normal copy (2), gain (2>), and loss (<2). Results: we analyzed using the 2−ΔΔCT calculation method. The CHRNA7 gene was significantly downregulated in patients (p < 0.05). The analysis of CNV in the CHRNA7 gene was statistically significant in the patient group, according to healthy controls (p < 0.05). A decreased copy number indicates a dosage loss. However, no significant difference was observed among gain, normal, and loss copy numbers and expression values in patients (p > 0.05). The change in CNV was not associated with the downregulation of the CHRNA7 gene. Conclusion: Downregulation of the CHRNA7 gene may contribute to the formation of migraine by inactivation of the alpha-7 nicotinic receptor (α7nAChR). The association of CNV gains and losses with migraines will lead to better understanding of the molecular mechanisms and pathogenesis, to better define the disease, to be used as a treatment target.

scholarly journals Extrinsic Noise and Heavy-Tailed Laws in Gene Expression

2020 ◽  
Vol 124 (10) ◽  
Author(s):  
Lucy Ham ◽  
Rowan D. Brackston ◽  
Michael P. H. Stumpf
Keyword(s):  
Gene Expression ◽  
Extrinsic Noise ◽  
Heavy Tailed
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