scholarly journals Genome-wide association mapping of ethanol sensitivity in the Diversity Outbred mouse population

2021 ◽  
Author(s):  
Clarissa C. Parker ◽  
Vivek M. Philip ◽  
Daniel M. Gatti ◽  
Steven Kasparek ◽  
Andrew M. Kreuzman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Strong Predictor ◽  
Therapeutic Interventions ◽  
Ethanol Sensitivity ◽  
Mouse Population ◽  
Positional Candidate ◽  
Righting Response ◽  
Efficient Gene ◽  
Diversity Outbred ◽  
Gene Expression Trait

AbstractBackgroundA strong predictor for the development of alcohol use disorders (AUDs) is altered sensitivity to the intoxicating effects of alcohol. Individual differences in the initial sensitivity to alcohol are controlled in part by genetic factors. Mice offer a powerful tool for elucidating the genetic basis of behavioral and physiological traits relevant to AUDs; but conventional experimental crosses have only been able to identify large chromosomal regions rather than specific genes. Genetically diverse, highly recombinant mouse populations allow for the opportunity to observe a wider range of phenotypic variation, offer greater mapping precision, and thus increase the potential for efficient gene identification.MethodsWe have taken advantage of the Diversity Outbred (DO) mouse population to identify and precisely map quantitative trait loci (QTL) associated with ethanol sensitivity. We phenotyped 798 male J:DO mice for three measures of ethanol sensitivity: ataxia, hypothermia, and loss of the righting response. We used high density MEGAMuga and GIGAMuga arrays to obtain genotypes ranging from 77,808 – 143,259 SNPs. In addition, we performed RNA sequencing in striatum to map expression QTLs and to identify gene expression-trait correlations.ResultsWe then applied a systems genetic strategy to identify narrow QTLs and construct the network of correlations that exist between DNA sequence, gene expression values and ethanol-related phenotypes to prioritize our list of positional candidate genes.ConclusionsOur results can be used to identify alleles that contribute to AUDs in humans, elucidate causative biological mechanisms, or assist in the development of novel therapeutic interventions.

scholarly journals Inflammatory monocyte gene expression: trait or state marker in bipolar disorder?

2015 ◽  
Vol 3 (1) ◽  
Author(s):  
K. Becking ◽  
B. C. M. Haarman ◽  
R. F. Riemersma van der Lek ◽  
L. Grosse ◽  
W. A. Nolen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bipolar Disorder ◽  
Expression Trait ◽  
Inflammatory Monocyte ◽  
Gene Expression Trait ◽  
State Marker

scholarly journals The Functional False Discovery Rate with Applications to Genomics

2017 ◽  
Author(s):  
Xiongzhi Chen ◽  
David G. Robinson ◽  
John D. Storey
Keyword(s):  
Gene Expression ◽  
False Discovery Rate ◽  
Genetic Marker ◽  
Read Depth ◽  
False Discovery Rates ◽  
Additional Information ◽  
False Discovery ◽  
Gene Expression Trait ◽  
Genetics Of Gene Expression ◽  
False Discoveries

AbstractThe false discovery rate measures the proportion of false discoveries among a set of hypothesis tests called significant. This quantity is typically estimated based on p-values or test statistics. In some scenarios, there is additional information available that may be used to more accurately estimate the false discovery rate. We develop a new framework for formulating and estimating false discovery rates and q-values when an additional piece of information, which we call an “informative variable”, is available. For a given test, the informative variable provides information about the prior probability a null hypothesis is true or the power of that particular test. The false discovery rate is then treated as a function of this informative variable. We consider two applications in genomics. Our first is a genetics of gene expression (eQTL) experiment in yeast where every genetic marker and gene expression trait pair are tested for associations. The informative variable in this case is the distance between each genetic marker and gene. Our second application is to detect differentially expressed genes in an RNA-seq study carried out in mice. The informative variable in this study is the per-gene read depth. The framework we develop is quite general, and it should be useful in a broad range of scientific applications.

Baculoviruses Mediate Efficient Gene Expression in a Wide Range of Vertebrate Cells

2011 ◽  
pp. 279-301 ◽  
Author(s):  
Kari J. Airenne ◽  
Kaisa-Emilia Makkonen ◽  
Anssi J. Mähönen ◽  
Seppo Ylä-Herttuala
Keyword(s):  
Gene Expression ◽  
Efficient Gene ◽  
Wide Range

scholarly journals Nitrosative Stress and Lipid Homeostasis as a Mechanism for Zileuton Hepatotoxicity and Resistance in Genetically Sensitive Mice

2020 ◽  
Vol 175 (2) ◽  
pp. 220-235 ◽  
Author(s):  
Dahea You ◽  
Lascelles E Lyn-Cook ◽  
Daniel M Gatti ◽  
Natalie Bell ◽  
Philip R Mayeux ◽  
...  
Keyword(s):  
Liver Injury ◽  
Nitrosative Stress ◽  
Farnesoid X Receptor ◽  
Therapeutic Interventions ◽  
Mechanistic Study ◽  
Acid Oxidation ◽  
Fatty Change ◽  
Active Inhibitor ◽  
Mouse Population ◽  
Mechanisms Of Toxicity

Abstract Zileuton is an orally active inhibitor of leukotriene synthesis for maintenance treatment of asthma, for which clinical usage has been associated with idiosyncratic liver injury. Mechanistic understanding of zileuton toxicity is hampered by the rarity of the cases and lack of an animal model. A promising model for mechanistic study of rare liver injury is the Diversity Outbred (J:DO) mouse population, with genetic variation similar to that found in humans. In this study, female DO mice were administered zileuton or vehicle daily for 7 days (i.g.). Serum liver enzymes were elevated in the zileuton group, with marked interindividual variability in response. Zileuton exposure-induced findings in susceptible DO mice included microvesicular fatty change, hepatocellular mitosis, and hepatocellular necrosis. Inducible nitric oxide synthase and nitrotyrosine abundance were increased in livers of animals with necrosis and those with fatty change, implicating nitrosative stress as a possible injury mechanism. Conversely, DO mice lacking adverse liver pathology following zileuton exposure experienced decreased hepatic concentrations of resistin and increased concentrations of insulin and leptin, providing potential clues into mechanisms of toxicity resistance. Transcriptome pathway analysis highlighted mitochondrial dysfunction and altered fatty acid oxidation as key molecular perturbations associated with zileuton exposure, and suggested that interindividual differences in cytochrome P450 metabolism, glutathione-mediated detoxification, and farnesoid X receptor signaling may contribute to zileuton-induced liver injury (ZILI). Taken together, DO mice provided a platform for investigating mechanisms of toxicity and resistance in context of ZILI which may lead to targeted therapeutic interventions.

scholarly journals Physiological Consequences of Coronary Arteriolar Dysfunction and Its Influence on Cardiovascular Disease

Physiology ◽  
2018 ◽  
Vol 33 (5) ◽  
pp. 338-347 ◽  
Author(s):  
Hassan Allaqaband ◽  
David D. Gutterman ◽  
Andrew O. Kadlec
Keyword(s):  
Strong Predictor ◽  
Therapeutic Interventions ◽  
Major Focus ◽  
Microcirculatory Dysfunction ◽  
Prognostic Implications ◽  
Artery Disease ◽  
Diagnostic Modalities ◽  
Microcirculatory Function ◽  
In Vivo Diagnosis

To date, the major focus of diagnostic modalities and interventions to treat coronary artery disease has been the large epicardial vessels. Despite substantial data showing that microcirculatory dysfunction is a strong predictor of future adverse cardiovascular events, very little research has gone into developing techniques for in vivo diagnosis and therapeutic interventions to improve microcirculatory function. In this review, we will discuss the pathophysiology of coronary arteriolar dysfunction, define its prognostic implications, evaluate the diagnostic modalities available, and provide speculation on current and potential therapeutic opportunities.

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