MeSCoT: The tool for quantitative trait simulation through the mechanistic modelling of genes’ regulatory interactions

Abstract This work represents a novel mechanistic approach to simulate and study genomic networks with accompanying regulatory interactions and complex mechanisms of quantitative trait formation. The approach implemented in MeSCoT software is conceptually based on the omnigenic genetic model of quantitative (complex) trait, and closely imitates the basic in vivo mechanisms of quantitative trait realization. The software provides a framework to study molecular mechanisms of gene-by-gene and gene-by-environment interactions underlying quantitative trait’s realization and allows detailed mechanistic studies of impact of genetic and phenotypic variance on gene regulation. MeSCoT performs a detailed simulation of genes’ regulatory interactions for variable genomic architectures, and generates complete set of transcriptional and translational data together with simulated quantitative trait values. Such data provide opportunities to study, for example, verification of novel statistical methods aiming to integrate intermediate phenotypes together with final phenotype in quantitative genetic analyses, or to investigate novel approaches for exploiting gene-by-gene and gene-by-environment interactions.

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Caenorhabditis elegans as an in vivo Model to Assess Amphetamine Tolerance

Brain Behavior and Evolution ◽

10.1159/000514858 ◽

2021 ◽

pp. 1-9

Author(s):

Dayana Torres Valladares ◽

Sirisha Kudumala ◽

Murad Hossain ◽

Lucia Carvelli

Keyword(s):

Caenorhabditis Elegans ◽

Molecular Mechanisms ◽

Drugs Of Abuse ◽

Genetic Model ◽

In Vivo Model ◽

C Elegans ◽

Hyperactivity Disorder ◽

In Vitro Data

Amphetamine is a potent psychostimulant also used to treat attention deficit/hyperactivity disorder and narcolepsy. In vivo and in vitro data have demonstrated that amphetamine increases the amount of extra synaptic dopamine by both inhibiting reuptake and promoting efflux of dopamine through the dopamine transporter. Previous studies have shown that chronic use of amphetamine causes tolerance to the drug. Thus, since the molecular mechanisms underlying tolerance to amphetamine are still unknown, an animal model to identify the neurochemical mechanisms associated with drug tolerance is greatly needed. Here we took advantage of a unique behavior caused by amphetamine in <i>Caenorhabditis elegans</i> to investigate whether this simple, but powerful, genetic model develops tolerance following repeated exposure to amphetamine. We found that at least 3 treatments with 0.5 mM amphetamine were necessary to see a reduction in the amphetamine-induced behavior and, thus, to promote tolerance. Moreover, we found that, after intervals of 60/90 minutes between treatments, animals were more likely to exhibit tolerance than animals that underwent 10-minute intervals between treatments. Taken together, our results show that <i>C. elegans</i> is a suitable system to study tolerance to drugs of abuse such as amphetamines.

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Analytical strategies to include the X-chromosome in variance heterogeneity analyses: evidence for trait-specific polygenic variance structure

10.1101/306654 ◽

2018 ◽

Author(s):

Wei Q. Deng ◽

Shihong Mao ◽

Anette Kalnapenkis ◽

Tõnu Esko ◽

Reedik Mägi ◽

...

Keyword(s):

Sexual Dimorphism ◽

X Chromosome ◽

Quantitative Trait ◽

Specific Effect ◽

Enrichment Analysis ◽

Complex Trait ◽

Conclusive Evidence ◽

Phenotypic Variance ◽

Variance Heterogeneity ◽

Analytical Strategies

AbstractGenotype-stratified variance of a quantitative trait could differ in the presence of gene-gene or gene-environment interactions. Genetic markers associated with phenotypic variance are thus considered promising candidates for follow-up interaction or joint location-scale analyses. However, as in studies of main effects, the X-chromosome is routinely excluded from ‘whole-genome’ scans due to analytical challenges. Specifically, as males carry only one copy of the X-chromosome, the inherent sex-genotype dependency could bias the trait-genotype association, through sexual dimorphism in quantitative traits with sex-specific means or variances. Here we investigate phenotypic variance heterogeneity associated with X-chromosome SNPs and propose valid and powerful strategies. Among those, a generalized Levene’s test has adequate power and remains robust to sexual dimorphism. An alternative approach is sex-stratified analysis but at the cost of slightly reduced power and modeling flexibility. We applied both methods to an Estonian study of gene expression quantitative trait loci (eQTL; n=841), and two complex trait studies of height, hip and waist circumferences, and body mass index from multi-ethnic study of atherosclerosis (MESA; n=2,073) and UK Biobank (UKB; n=327,393). Consistent with previous eQTL findings on mean, we found some but no conclusive evidence for cis regulators being enriched for variance association. SNP rs2681646 is associated with variance of waist circumference (p=9.5E-07) at X-chromosome-wide significance in UKB, with a suggestive female-specific effect in MESA (p=0.048). Collectively, an enrichment analysis using permutated UKB (p<1/10) and MESA (p<1/100) datasets, suggests a possible polygenic structure for the variance of human height.

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Retinitis Pigmentosa Results in Neurodegeneration Concomitant With Neuroinflammation, Extracellular Matrix Disorganization and the Upregulation of Neuroprotective Pathways in Glial Cells and Neurons

10.21203/rs.3.rs-101559/v1 ◽

2020 ◽

Author(s):

Christina B. Bielmeier ◽

Saskia Roth ◽

Sabrina I. Schmitt ◽

Stefaniya K. Boneva ◽

Anja Schlecht ◽

...

Keyword(s):

Extracellular Matrix ◽

Retinitis Pigmentosa ◽

Retinal Degeneration ◽

Molecular Mechanisms ◽

Genetic Model ◽

Immunofluorescent Staining ◽

System Response ◽

Photoreceptor Degeneration ◽

The Impact

Abstract BackgroundHereditary retinal degenerations like retinitis pigmentosa (RP) are amongst the leading causes of blindness in younger patients. To enable in vivo investigation of cellular and molecular mechanisms responsible for photoreceptor cell death and to allow testing of therapeutic strategies that could prevent retinal degeneration, animal models have been created. Here, we in-depth characterized the transgenic VPP mouse model, a genetic model for autosomal dominant RP. MethodsWe examined the degree of photoreceptor degeneration and studied the impact of the VPP transgene-induced retinal degeneration on the transcriptome level of the retina using next generation RNA sequencing (RNASeq) analyses followed by weighted correlation network analysis (WGCNA). We furthermore identified cellular subpopulations responsible for some of the observed dysregulations using in situ hybridizations, immunofluorescent staining and 3D reconstruction. ResultsOne month-old VPP mice showed a significantly higher number of apoptotic photoreceptor cells that resulted in a significantly thinner ONL in three months-old VPP mice, concomitant with an increase in reactivity of microglia and Müller cells. By RNASeq analysis we identified 9,256 dysregulated genes and six significantly associated gene modules in the subsequently performed WGCNA. Gene ontology enrichment showed, amongst others, dysregulation of TGF-β regulated extracellular matrix organization, factors of the (ocular) immune system/response and apoptosis. ConclusionThe predominant effect pointed towards induction of neuroinflammation and the upregulation of neuroprotective pathways like TGF-β, G-protein activated and VEGF signaling that were significantly associated with the VPP transgene-induced photoreceptor degeneration. Thus, modulation of these processes might represent new therapeutic options to delay the degeneration of photoreceptors in diseases like RP.

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A Haplotype Block Model for Fine Mapping of Quantitative Trait Loci Regulating HIV-1 Pathogenesis

Journal of Theoretical Medicine ◽

10.1080/10273660412331319486 ◽

2003 ◽

Vol 5 (3-4) ◽

pp. 227-234 ◽

Cited By ~ 1

Author(s):

Yun Zhu ◽

Wei Hou ◽

Rongling Wu

Keyword(s):

Quantitative Trait Loci ◽

Quantitative Trait ◽

Positional Cloning ◽

Haplotype Block ◽

Environmental Changes ◽

Dynamic Change ◽

Complex Trait ◽

Trait Loci ◽

Hiv 1

The dynamic change of human immunodeficiency virus type-1 (HIV-1) particles that cause AIDS displays considerable variation from patients to patients. It is likely that such variation in HIV-1 pathogenesis is correlated with the genetic architecture of hosts. Traditional genetic analysis of HIV-1 infection is based on various biochemical approaches, but it has been little successful because HIV-1 dynamics, as a complex trait, is under polygenic control and sensitive to environmental changes. Here, we present a novel model for integrating mathematical functions for HIV-1 dynamics that have been well constructed into a multivariate mixture model for genetic mapping. This integrative mapping model on the foundation of linkage disequilibrium (LD)-based haplotype block analysis provides unique power to precisely detect human quantitative trait loci (QTL) determining HIV-1 dynamics and facilitates positional cloning of target QTL. The model allows for a number of hypothesis tests for the effects of the dynamic QTL on the virion clearance rate, the infected cell life-span and the average viral generation timein vivo, all of which provide theoretical principles to guide the development of efficient gene therapy strategies.

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Construction of a high-density genetic map and identification of quantitative trait loci for nitrite tolerance in the Pacific white shrimp (Litopenaeus vannamei)

10.21203/rs.2.18940/v1 ◽

2019 ◽

Cited By ~ 1

Author(s):

Digang Zeng ◽

Xiuli Chen ◽

Weilin Zhu ◽

Min Peng ◽

Chunling Yang ◽

...

Keyword(s):

Quantitative Trait Loci ◽

Genetic Map ◽

Quantitative Trait ◽

Molecular Mechanisms ◽

Average Distance ◽

Pacific White Shrimp ◽

High Density ◽

White Shrimp ◽

Phenotypic Variance ◽

Trait Loci

Abstract BackgroundNitrite is a major environmental toxin in aquaculture systems disrupting multiple physiological functions in aquatic animals. Although nitrite tolerance in shrimp is closely related to successful industrial production, few genetic studies of this trait are available. ResultsIn this study, we constructed a high-density genetic map of L. vannamei with 17,242 single nucleotide polymorphism markers spanning 6,828.06 centimorgans (cM) and an average distance of 0.4 cM between adjacent markers on 44 linkage groups (LGs). Using this genetic map, we identified 2 quantitative trait loci (QTLs) involved in nitrite tolerance on two LGs explaining 8.42–10.31% of the phenotypic variance. We then sequenced the transcriptomes of the most nitrite-tolerant and the most nitrite-sensitive individuals from each of four genetically distinct L. vannamei families and found 2,002, 1,983, 1,954, and 1,867 differentially expressed genes in the four families, respectively. By integrating QTL and transcriptomics analyses, we identified a candidate gene associated with nitrite tolerance. This gene was annotated as solute carrier family 26 member 6 (SLC26A6). RNA interference (RNAi) analysis demonstrated that SLC26A6 was critical for nitrite tolerance in L. vannamei. ConclusionsThe present study increases our understanding of the molecular mechanisms underlying nitrite tolerance in shrimp, and provides a basis for molecular-marker-assisted shrimp breeding.

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Two-Way Development of the Genetic Model for Endometrial Tumorigenesis in Mice: Current and Future Perspectives

Frontiers in Genetics ◽

10.3389/fgene.2021.798628 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yoshiaki Maru ◽

Yoshitaka Hippo

Keyword(s):

Genetic Engineering ◽

Molecular Mechanisms ◽

Genetic Model ◽

Ex Vivo ◽

Hybrid Approach ◽

Genetic Alterations ◽

Female Reproductive Tract ◽

Current Status ◽

Specific Gene

Endometrial cancer (EC) is the most common malignancy of the female reproductive tract worldwide. Although comprehensive genomic analyses of EC have already uncovered many recurrent genetic alterations and deregulated signaling pathways, its disease model has been limited in quantity and quality. Here, we review the current status of genetic models for EC in mice, which have been developed in two distinct ways at the level of organisms and cells. Accordingly, we first describe the in vivo model using genetic engineering. This approach has been applied to only a subset of genes, with a primary focus on Pten inactivation, given that PTEN is the most frequently altered gene in human EC. In these models, the tissue specificity in genetic engineering determined by the Cre transgenic line has been insufficient. Consequently, the molecular mechanisms underlying EC development remain poorly understood, and preclinical models are still limited in number. Recently, refined Cre transgenic mice have been created to address this issue. With highly specific gene recombination in the endometrial cell lineage, acceptable in vivo modeling of EC development is warranted using these Cre lines. Second, we illustrate an emerging cell-based model. This hybrid approach comprises ex vivo genetic engineering of organoids and in vivo tumor development in immunocompromised mice. Although only a few successful cases have been reported as proof of concept, this approach allows quick and comprehensive analysis, ensuring a high potential for reconstituting carcinogenesis. Hence, ex vivo/in vivo hybrid modeling of EC development and its comparison with corresponding in vivo models may dramatically accelerate EC research. Finally, we provide perspectives on future directions of EC modeling.

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