Biology subjects

Tatom, Z.

Publications and source records attributed to Tatom, Z..

3 recordsLinked to original sources

bioRxiv2025

Genetic Mapping in Diversity Outbred Mice Identifies Novel Loci and Candidate Genes for Anxiety-Like Behavior and Genetic Subgroups Predictive of Ethanol Consumption

Anxiety disorders are the most common class of psychiatric disorder. Risk for anxiety disorders is thought to be influenced by many genes, each contributing a small effect. The light-dark box behavioral assay was designed to measure anxiety-like behavior in rodents. Diversity Outbred (DO) mice were designed for high-resolution quantitative trait loci (QTL) mapping on a genetically-diverse background. Here, we studied a population of 518 male DO mice for anxiety-like and locomotor behaviors from a light-dark box assay. Multivariate analysis of behavioral data identified two major subgroups of animals differing in basal anxiety behavior and subsequent ethanol consumption patterns. Behavioral QTL analysis identified a significant locus on Chromosome 14 associated with 3 anxiety-like behavioral phenotypes. Haplotype analysis revealed an effect of C57BL/6J alleles at this locus, with mice carrying those alleles exhibiting more anxiety-like behavior. An additional 9 suggestive loci were identified. Genes located within the confidence intervals for the Chromosome 14 locus were analyzed for coding sequence polymorphisms, prefrontal cortex expression QTLs, human GWAS data, and additional data sets related to psychiatric conditions including substance use. Results prioritized two candidate genes, Tbc1d4 and Lmo7, for further study. These results represent the highest-resolution genetic mapping of light-dark box behaviors in mice to date, revealing insights into the complex biology of anxiety disorders. Additionally the studies identify striking subgroups of animals where basal anxiety-like behavior predicts eventual ethanol consumption phenotypes.

animal behavior and cognition↗

bioRxiv2023

Identification of Genetic and Genomic Influences on Progressive Ethanol Consumption in Diversity Outbred Mice

Genetic factors play a significant role in the risk for development of alcohol use disorder (AUD). Using 3-bottle choice intermittent access ethanol (IEA), we have employed the Diversity Outbred (DO) mouse panel as a model of alcohol use disorder in a genetically diverse population. Through use of gene expression network analysis techniques, in combination with expression quantitative trait loci (eQTL) mapping, we have completed an extensive analysis of the influence of genetic background on gene expression changes in the prefrontal cortex (PFC). This approach revealed that, in DO mice, genes whose expression was significantly disrupted by intermittent ethanol in the PFC also tended to be those whose expression correlated to intake. This finding is in contrast to previous studies of both mice and nonhuman primates. Importantly, these analyses identified genes involved in myelination in the PFC as significantly disrupted by IEA, correlated to ethanol intake, and having significant eQTLs. Genes that code for canonical components of the myelin sheath, such as Mbp, also emerged as key drivers of the gene expression response to intermittent ethanol drinking. Several regulators of myelination were also key drivers of gene expression, and had significant QTLs, indicating that genetic background may play an important role in regulation of brain myelination. These findings underscore the importance of disruption of normal myelination in the PFC in response to prolonged ethanol exposure, that genetic variation plays an important role in this response, and that this interaction between genetics and myelin disruption in the presence of ethanol may underlie previously observed behavioral changes under intermittent access ethanol drinking such as escalation of consumption.

genomics↗

bioRxiv2022

Genetic Mapping of Progressive Ethanol Consumption in the Diversity Outbred Mouse

Traditional genetic mapping studies using inbred crosses are a powerful tool for identifying chromosomal regions associated with ethanol-related traits, but typically have very large confidence intervals which make identification of specific and potentially causal candidate genes difficult. Diversity Outbred (DO) mice offer the ability to map quantitative trait loci (QTLs) associated with ethanol-drinking behaviors at a high resolution that allows for easier identification of candidate genes. Here, we exposed a population of 636 male DO mice to four weeks of intermittent ethanol access via a three-bottle choice paradigm, identifying 3 significant (Chrs 3, 4, and 12) and 12 suggestive loci for ethanol-drinking behaviors. The confidence intervals for these loci were narrow (1-4 Mbp for significant QTLs). We then further analyzed positional candidate genes using transcriptomics data from prefrontal cortex samples taken from 220 of these animals, as well as human GWAS data and prior gene set data for ethanol or other drugs of abuse. These results represent the highest-resolution genetic mapping of ethanol consumption behaviors in mice to date, providing for the identification of novel loci and candidate genes for progressive ethanol consumption, including Car8 --the lone gene with a significant cis-eQTL in strong linkage disequilibrium with our QTL for last week ethanol consumption on Chr 4.

genetics↗