Reciprocal Congenics Defining Individual Quantitative Trait Loci for Sedative/Hypnotic Sensitivity to Ethanol

Bennett, Barry; Beeson, Mary; Gordon, Lena; Johnson, T. E.

doi:10.1097/00000374-200202000-00001

Cited by 17 publications

(61 citation statements)

References 16 publications

(21 reference statements)

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“…Rodent models offer a way to tightly control both environmental and genetic sources of variation and are widely used to study the genetic basis of differences in response to stress and ethanol. For example, the LXS [13], [14], [15] and BXD [16] families of recombinant inbred (RI) strains of mice have been used to discover several quantitative trait loci (QTLs) and candidate genes that control ethanol responses [17], [18], [19], [20].…”

Section: Introductionmentioning

confidence: 99%

Treatment- and Population-Dependent Activity Patterns of Behavioral and Expression QTLs

et al. 2012

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Genetic control of gene expression and higher-order phenotypes is almost invariably dependent on environment and experimental conditions. We use two families of recombinant inbred strains of mice (LXS and BXD) to study treatment- and genotype-dependent control of hippocampal gene expression and behavioral phenotypes. We analyzed responses to all combinations of two experimental perturbations, ethanol and restraint stress, in both families, allowing for comparisons across 8 combinations of treatment and population. We introduce the concept of QTL activity patterns to characterize how associations between genomic loci and traits vary across treatments. We identified several significant behavioral QTLs and many expression QTLs (eQTLs). The behavioral QTLs are highly dependent on treatment and population. We classified eQTLs into three groups: cis-eQTLs (expression variation that maps to within 5 Mb of the cognate gene), syntenic trans-eQTLs (the gene and the QTL are on the same chromosome but not within 5 Mb), and non-syntenic trans-eQTLs (the gene and the QTL are on different chromosomes). We found that most non-syntenic trans-eQTLs were treatment-specific whereas both classes of syntenic eQTLs were more conserved across treatments. We also found there was a correlation between regions along the genome enriched for eQTLs and SNPs that were conserved across the LXS and BXD families. Genes with eQTLs that co-localized with the behavioral QTLs and displayed similar QTL activity patterns were identified as potential candidate genes associated with the phenotypes, yielding identification of novel genes as well as genes that have been previously associated with responses to ethanol.

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Section: Introductionmentioning

confidence: 99%

Treatment- and Population-Dependent Activity Patterns of Behavioral and Expression QTLs

et al. 2012

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“…Ten minutes later animals were injected ip with ethanol, 2.5 g/kg for ILS mice and 4.1 g/kg for ISS mice, and LORE was measured as described above. We administered 2.5 g/kg ethanol to ILS instead of 4.1 g/kg because the 2.5 g/kg dose gives a mean LORE duration similar to that of ISS at 4.1 g/kg [29]. The 2.5 g/kg dose is routinely used in our laboratory to test ILS mice or congenic mice on an ILS background.…”

Section: Methodsmentioning

confidence: 99%

The metabotropic glutamate receptor subtype 5 mediates sensitivity to the sedative properties of ethanol

Downing

Marks

Larson

et al. 2010

Pharmacogenetics and Genomics

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Objective-Inbred Long-Sleep and Short-Sleep mice (ILS and ISS) were selectively bred for differential sensitivity to the sedative effects of ethanol. Lines of mice derived from these progenitors have been used to identify several Quantitative Trait Loci (QTLs) mediating Loss Of the Righting reflex due to Ethanol (LORE). The present study investigated mGluR5 as a candidate gene underlying Lore7, a QTL mediating differential LORE sensitivity.Methods-We used knockout mice, a quantitative complementation test, pharmacological antagonism of mGluR5, real-time quantitative PCR, radioligand binding, DNA sequencing and bioinformatics to examine the role of mGluR5 in ethanol-induced sedation.Results-mGluR5 knockout mice had a significantly longer LORE duration than wild-type controls. Administration of the mGluR5 antagonist 2-methyl-6-(phenylethyl)-pyridine (MPEP) had differential effects on LORE in ILS and ISS mice. A quantitative complementation test also supported mGluR5 mediating LORE. Two intronic single-nucleotide polymorphisms in mGluR5 were highly correlated with LORE in recombinant inbred mice derived from a cross between ILS and ISS (LXS RIs). Differences in mGluR5 mRNA level and receptor density were observed between ILS and ISS in distinct brain regions. Finally, data from WebQTL showed that mGluR5 expression was highly correlated with several LORE phenotypes in the LXS RIs.Conclusions-Taken together, this data provides convincing evidence that mGluR5 mediates differential sensitivity to the sedative effects of ethanol. Studies from the human literature have also identified MGLUR5 as a potential candidate gene for ethanol sensitivity.

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“…Briefly, these strains trace their descent from a genetically heterogeneous stock (HS;McClearn et al, 1970) derived from an 8-way cross of inbred strains maintained at that time by the Cancer Research Genetics Laboratory at the University of California at Berkeley (A, AKR, BALB/c, C3H/2, C57BL, DBA/2, Is/Bi, and RIII). Selection in the HS for differential sensitivity to the sedative effect of ethanol produced the LS and SS selected lines (McClearn and Kakihana, 1981), which were subsequently inbred to produce ILS and ISS (Bennett et al, 2002). To generate the LÂS RI strains, ILS and ISS mice were reciprocally intercrossed to produce 125 mating pairs in the F 2 generation.…”

Section: Animalsmentioning

confidence: 99%

Quantitative Trait Locus Mapping for Acute Functional Tolerance to Ethanol in the L × S Recombinant Inbred Panel

Bennett

Downing

Carosone-Link

et al. 2007

Alcoholism Clin & Exp Res

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Both SS and ISS developed greater AFT, assessed by both methods, than LS and ILS; this difference was significant in virtually all sex by strain comparisons. In the L x S RI, there was no correlation between initial sensitivity, measured by BEC at initial loss of balance, and either measure of AFT, on a stationary dowel. These results indicate that in this model system, initial sensitivity does not predict tolerance. Several QTLs for tolerance were identified; candidates in the narrowed chromosome 12 region, which has been reported in 2 other mapping studies, merit additional study.

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Reciprocal Congenics Defining Individual Quantitative Trait Loci for Sedative/Hypnotic Sensitivity to Ethanol

Cited by 17 publications

References 16 publications

Treatment- and Population-Dependent Activity Patterns of Behavioral and Expression QTLs

Treatment- and Population-Dependent Activity Patterns of Behavioral and Expression QTLs

The metabotropic glutamate receptor subtype 5 mediates sensitivity to the sedative properties of ethanol

Quantitative Trait Locus Mapping for Acute Functional Tolerance to Ethanol in the L × S Recombinant Inbred Panel

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