Biology subjects

Chesler, E.

Publications and source records attributed to Chesler, E..

7 recordsLinked to original sources

bioRxiv2026

Identification of Genomic Loci Associated with Cellular Rhythms in Diversity Outbred Mice

Inter-individual variation in human molecular and behavioral circadian rhythms motivates genetic dissection in model systems with human-like diversity. We quantified cellular clock phenotypes from primary skin fibroblasts of several hundred Diversity Outbred (DO) mice-each carrying a unique mosaic of eight founder genomes-by longitudinal bioluminescence recordings of a Bmal1-luciferase reporter (LumiCycle). Canonical rhythm parameters (period, phase, amplitude, damping) were extracted and exhibited broad variability (heritability {approx}13-35%), exceeding the ranges of founder strains. We performed genome-wide QTL mapping with R/qtl2 (linear mixed models with sex and experimental group covariates, kinship control, permutation-based significance, 1.5-LOD support intervals). A suggestive QTL for amplitude localized to chromosome 12 (LOD 6.9; [~]7.5-12.0 Mb), with founder effects indicating higher amplitude for C57BL/6J and lower for PWK/PhJ. Among 21 protein-coding genes in this interval, Apob (apolipoprotein B), a clock-regulated determinant of lipoprotein assembly, emerged as a strong candidate for amplitude control. A phase QTL mapped to chromosome 1 (support interval [~]1.36 Mb) with divergent founder effects (C57BL/6J, NOD/ShiLtJ, WSB/EiJ: delayed; PWK/PhJ, CAST/EiJ: advanced) and prioritized candidates including Epha4 (an Eph receptor tyrosine kinase implicated in photic entrainment) and Acsl3. Integrative analysis in GeneWeaver connected QTL gene sets to prior loci for voluntary alcohol consumption and circadian period on proximal chromosome 12, and highlighted overlaps with GWAS signals for adolescent idiopathic scoliosis and schizophrenia, suggesting shared pathways between circadian regulation, metabolism, and neurobehavioral traits. Together, these findings define reproducible genomic loci for cellular clock phenotypes in a highly recombinant population, nominate tractable candidate genes (Apob, Epha4/Acsl3) for mechanistic follow-up, and illustrate how high-diversity mouse genetics bridges cellular circadian variation with complex disease biology.

genetics↗

bioRxiv2023

DISCOVERY AND VALIDATION OF GENES DRIVING DRUG-INTAKE AND RELATED BEHAVIORAL TRAITS IN MICE

Substance use disorders (SUDs) are heritable disorders characterized by compulsive drug use, but the biological mechanisms driving addiction remain largely unknown. Genetic correlations reveal that predisposing drug-naive phenotypes, including anxiety, depression, novelty preference, and sensation seeking, are predictive of drug-use phenotypes, implicating shared genetic mechanisms. Because of this relationship, high-throughput behavioral screening of predictive phenotypes in knockout (KO) mice allows efficient discovery of genes likely to be involved in drug use. We used this strategy in two rounds of screening in which we identified 33 drug-use candidate genes and ultimately validated the perturbation of 22 of these genes as causal drivers of substance intake. In our initial round of screening, we employed the two-bottle-choice paradigms to assess alcohol, methamphetamine, and nicotine intake. We identified 19 KO strains that were extreme responders on at least one predictive phenotype. Thirteen of the 19 gene deletions (68%) significantly affected alcohol use three methamphetamine use, and two both. In the second round of screening, we employed a multivariate approach to identify outliers and performed validation using methamphetamine two-bottle choice and ethanol drinking-in-the-dark protocols. We identified 15 KO strains that were extreme responders across the predisposing drug-naive phenotypes. Eight of the 15 gene deletions (53%) significantly affected intake or preference for three alcohol, eight methamphetamine or three both (3). We observed multiple relations between predisposing behaviors and drug intake, revealing many distinct biobehavioral processes underlying these relationships. The set of mouse models identified in this study can be used to characterize these addiction-related processes further.

genetics↗

bioRxiv2022

The Collaborative Cross strains and their founders vary widely in cocaine-induced behavioral sensitization

Cocaine use and overdose deaths attributed to cocaine have increased significantly in the United States in the last 10 years. Despite the prevalence of cocaine use disorder (CUD) and the personal and societal problems it presents, there are currently no approved pharmaceutical treatments. The absence of treatment options is due, in part, to our lack of knowledge about the etiology of CUDs. There is ample evidence that genetics plays a role in increasing CUD risk but thus far, very few risk genes have been identified in human studies. Genetic studies in mice have been extremely useful for identifying genetic loci and genes, but have been limited to very few genetic backgrounds, leaving substantial phenotypic and genetic diversity unexplored. Herein we report the measurement of cocaine-induced behavioral sensitization using a 19-day protocol that captures baseline locomotor activity, acute locomotor response to cocaine and locomotor sensitization across 5 exposures to the drug. These behaviors were measured in 51 genetically diverse yet tractable Collaborative Cross (CC) strains along with their inbred founder strains. The CC was generated by crossing 8 genetically diverse inbred strains such that each inbred CC strain has genetic contributions from each of the founder strains. Inbred CC mice are infinitely reproducible and provide a stable, yet diverse genetic platform on which to study the genetic architecture and genetic correlations among phenotypes. We have identified significant differences in cocaine locomotor sensitivity and behavioral sensitization across the panel of CC strains and their founders. We have established relationships among cocaine sensitization behaviors and identified extreme responding strains that can be used in future studies aimed at understanding the genetic, biological and pharmacological mechanisms that drive addiction-related behaviors. Finally, we have determined that these behaviors exhibit relatively robust heritability making them amenable to future genetic mapping studies to identify addiction risk genes and genetic pathways that can be studied as potential targets for the development of novel therapeutics.

genetics↗

bioRxiv2021

Improving replicability using interaction with laboratories: a multi-lab experimental assessment

Experimentation with mouse and rat models has become a central strategy for discovering mammalian gene function, and for preclinical testing of pharmacological treatments, yet the utility of any findings critically depends on their replicability in other laboratories. In previous publications we proposed a statistical approach for estimating the inter-laboratory replicability of novel discoveries made in a single laboratory. We demonstrated that previous phenotyping results from multi-lab databases can be used to derive a Genotype-by-Lab (GxL) adjustment factor to greatly enhance the replicability of the single-lab findings, for similarly measured phenotypes, even before making the effort of replicating these finding in additional laboratories. This demonstration, however, still raised several important questions that could only be answered by an additional large-scale prospective experiment: 1) Does GxL-adjustment work in single-lab experiments that were not intended to be standardized across laboratories, and with genotypes that were not included in the previous experiments? And 2) Can it be used to adjust the results of pharmacological experiments? We investigated these questions by attempting to replicate, across three laboratories, results from five single-lab studies in the Mouse Phenome Database (MPD), offering 212 comparisons, including 60 involving a pharmacological treatment: 18 mg/kg/day fluoxetine. In addition, we define and use a dimensionless GxL factor, by dividing the GxL variance by the standard deviation between animals within groups, as a more robust vehicle to transfer the adjustment from the multi-lab analysis to very different labs and genotypes. For genotype comparisons, GxL-adjustment reduced the rate of non-replicable discoveries from 60% to 12%, for the price of reducing the power to make replicable discoveries from 87% to 66%. In absolute numbers, the adjustment prevented 23 non-replicable discoveries for the price of missing only three replicated ones. Tools and data needed for deployment of this method across other mouse experiments are publicly available in MPD. Our results further point at some phenotypes as more prone to produce non-replicable results, while others, known to be more difficult to measure, are as likely to produce replicable results (once adjusted) such as the physiological measure, body weight.

animal behavior and cognition↗

bioRxiv2021

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

BackgroundA 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.

genetics↗

bioRxiv2019

Cross-Species Integration of Transcriptomic Effects of Tobacco and Nicotine Exposure Helps to Prioritize Genetic Effects on Human Tobacco Consumption

Computational advances have fostered the development of new methods and tools to integrate gene expression and functional evidence into human-genetic association analyses. Integrative functional genomics analysis for altered response to alcohol in mice provided the first evidence that multi-species analysis tools, such as GeneWeaver, can identify or confirm novel alcohol-related loci. The present study describes an integrative framework to investigate how highly-connected genes linked by their association to tobacco-related behaviors, contribute to individual differences in tobacco consumption. Data from individuals of European ancestry in the UKBiobank (N=139,043) were used to examine the relative contribution of orthologs of a set of genes that are transcriptionally co-regulated by tobacco or nicotine exposure in model organism experiments to human tobacco consumption. Multi-component mixed linear models using genotyped and imputed single nucleotide variants indicated that: (1) variation within human orthologs of these genes accounted for 2-5% of the observed heritability (meta h2SNP-Total=0.08 [95% CI: 0.07, 0.09]) of tobacco/nicotine consumption across three independent folds of unrelated individuals (enrichment ranging from 0.85 - 2.98), and (2) variation around (5, 10, 15, 25, and 50 Kb regions) the set of co-transcriptionally regulated genes accounted for 5-36% of the observed SNP-heritability (enrichment ranging from 1.60 - 31.45). Notably, the effects of variants in co-transcriptionally regulated genes were enriched in tobacco GWAS. These findings highlight the advantages of using multiple species evidence to isolate genetic factors to better understand the etiological complexity of tobacco and other nicotine consumption.

genetics↗

bioRxiv2019

Tmod2 is a regulator of cocaine responses through control of striatal and cortical excitability, and drug-induced plasticity

Drugs of abuse induce neuroadaptations, including synaptic plasticity, that are critical for transition to addiction, and genes and pathways that regulate these neuroadaptations are potential therapeutic targets. Tropomodulin 2 (Tmod2) is an actin-regulating gene that plays an important role in synapse maturation and dendritic arborization and has been implicated in substance-abuse and intellectual disability in humans. Here we mine the KOMP2 data and find that Tmod2 knockout mice show emotionality phenotypes that are predictive of addiction vulnerability. Detailed addiction phenotyping showed that Tmod2 deletion does not affect the acute locomotor response to cocaine administration. However, sensitized locomotor responses are highly attenuated in these knockouts, indicating perturbed drug-induced plasticity. In addition, Tmod2 mutant animals do not self-administer cocaine indicating lack of hedonic responses to cocaine. Whole brain MR imaging shows differences in brain volume across multiple regions although transcriptomic experiments did not reveal perturbations in gene co-expression networks. Detailed electrophysiological characterization of Tmod2 KO neurons, showed increased spontaneous firing rate of early postnatal and adult cortical and striatal neurons. Cocaine-induced synaptic plasticity that is critical for sensitization is either missing or reciprocal in Tmod2 KO nucleus accumbens shell medium spiny neurons, providing a mechanistic explanation of the cocaine response phenotypes. Combined, these data provide compelling evidence that Tmod2 is a major regulator of plasticity in the mesolimbic system and regulates the reinforcing and addictive properties of cocaine.\n\nSignificance statementWe identify, characterize, and establish tropomodulin 2 (Tmod2), an actin-regulating gene exclusively expressed in neurons, as an important regulator of addiction-related phenotypes. We show that Tmod2, knockout mice (Tmod2 KO) exhibit phenotypes that are predictive of addiction. In detailed addiction phenotyping, we find the Tmod2 regulates cocaine sensitization and self-administration. We explore anatomical, transcriptional, electrophysiological mechanisms of this regulation. Combined these studies provide compelling evidence that Tmod2 is critical for synaptic plasticity necessary for transition to addiction.

neuroscience↗