Mapping a locus for alcohol physical dependence and associated withdrawal to a 1.1 Mb interval of mouse chromosome 1 syntenic with human chromosome

Department of Veterans Affairs Medical Center, Portland, OR, USA.
Genes Brain and Behavior (Impact Factor: 3.66). 08/2008; 7(5):560-7. DOI: 10.1111/j.1601-183X.2008.00391.x
Source: PubMed


Physiological dependence and associated withdrawal episodes are thought to constitute a motivational force perpetuating continued alcohol use/abuse. Although no animal model duplicates alcoholism, models for specific factors, like the withdrawal syndrome, are useful to identify potential determinants of liability in humans. We previously detected quantitative trait loci (QTLs) with large effects on predisposition to physical dependence and associated withdrawal following chronic or acute alcohol exposure to a large region of chromosome 1 in mice (Alcdp1 and Alcw1, respectively). Here, we provide the first confirmation of Alcw1 in a congenic strain, and, using interval-specific congenic strains, narrow its position to a minimal 1.1 Mb (maximal 1.7 Mb) interval syntenic with human chromosome 1q23.2-23.3. We also report the development of a small donor segment congenic that confirms capture of a gene(s) affecting physical dependence after chronic alcohol exposure within this small interval. This congenic will be invaluable for determining whether this interval harbors a gene(s) involved in additional alcohol responses for which QTLs have been detected on distal chromosome 1, including alcohol consumption, alcohol-conditioned aversion and -induced ataxia. The possibility that this QTL plays an important role in such diverse responses to alcohol makes it an important target. Moreover, human studies have identified markers on chromosome 1q associated with alcoholism, although this association is still suggestive and mapped to a large region. Thus, the fine mapping of this QTL and analyses of the genes within the QTL interval can inform developing models for genetic determinants of alcohol dependence in humans.

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Available from: Laura B Kozell, Oct 03, 2014
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    • "Additional studies using the interval-specific congenic mice carrying short segments of DBA/2J DNA in a background of C57BL/6J DNA detected, confirmed, and finely mapped a second QTL on mouse chromosome 1 with large effects on the predisposition to withdrawal following chronic and acute alcohol exposure (Kozell et al. 2008). This QTL maps to a 1.1-Mb interval syntenic with human 1q23.2–23.3. "
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    ABSTRACT: The genetic determinants of alcoholism still are largely unknown, hindering effective treatment and prevention. Systematic approaches to gene discovery are critical if novel genes and mechanisms involved in alcohol dependence are to be identified. Although no animal model can duplicate all aspects of alcoholism in humans, robust animal models for specific alcohol-related traits, including physiological alcohol dependence and associated withdrawal, have been invaluable resources. Using a variety of genetic animal models, the identification of regions of chromosomal DNA that contain a gene or genes which affect a complex phenotype (i.e., quantitative trait loci [QTLs]) has allowed unbiased searches for candidate genes. Several QTLs with large effects on alcohol withdrawal severity in mice have been detected, and fine mapping of these QTLs has placed them in small intervals on mouse chromosomes 1 and 4 (which correspond to certain regions on human chromosomes 1 and 9). Subsequent work led to the identification of underlying quantitative trait genes (QTGs) (e.g., Mpdz) and high-quality QTG candidates (e.g., Kcnj9 and genes involved in mitochondrial respiration and oxidative stress) and their plausible mechanisms of action. Human association studies provide supporting evidence that these QTLs and QTGs may be directly relevant to alcohol risk factors in clinical populations.
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    • "Fine-mapping has delineated two QTLs (B and C with 1.7 Mb and 0.44 Mb QTL intervals, respectively) within the starting QTL region . The more proximal QTL (B) affects ethanol withdrawal, but not pentobarbital or zolpidem withdrawal (Kozell et al., 2008), while the more distal QTL (C) affects ethanol, pentobarbital, and zolpidem withdrawal (Kozell et al., 2009). Both QTLs are syntenic to human chromosome 1q23.2-1q23.3. "
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    ABSTRACT: Evidence for genetic linkage to alcohol and other substance dependence phenotypes in areas of the human and mouse genome have now been reported with some consistency across studies. However, the question remains as to whether the genes that underlie the alcohol-related behaviors seen in mice are the same as those that underlie the behaviors observed in human alcoholics. The aims of the current set of analyses were to identify a small set of alcohol-related phenotypes in human and in mouse by which to compare quantitative trait locus (QTL) data between the species using syntenic mapping. These analyses identified that QTLs for alcohol consumption and acute and chronic alcohol withdrawal on distal mouse chromosome 1 are syntenic to a region on human chromosome 1q where a number of studies have identified QTLs for alcohol-related phenotypes. Additionally, a QTL on human chromosome 15 for alcohol dependence severity/withdrawal identified in two human studies was found to be largely syntenic with a region on mouse chromosome 9, where two groups have found QTLs for alcohol preference. In both of these cases, while the QTLs were found to be syntenic, the exact phenotypes between humans and mice did not necessarily overlap. These studies demonstrate how this technique might be useful in the search for genes underlying alcohol-related phenotypes in multiple species. However, these findings also suggest that trying to match exact phenotypes in humans and mice may not be necessary or even optimal for determining whether similar genes influence a range of alcohol-related behaviors between the two species.
    Full-text · Article · Apr 2010 · Addiction Biology
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    • "Quantitative trait loci for ethanol physical dependence and associated withdrawal are detected on distal mouse chromosome 1 in several mapping populations derived from the B6 and D2 progenitor strains and underlie $25% of the genetic variability displayed in acute (Alcw1) and chronic (Alcdp1) withdrawal severity (Buck et al. 1997, 2002). In the accompanying paper (Kozell et al. 2008), we mapped Alcw1 and Alcdp1 to the same 1.1 Mb minimal interval. Here, we report a detailed molecular analysis identifying 17 genes as promising candidates to underlie these QTLs' effects on alcohol withdrawal. "
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    ABSTRACT: We recently mapped quantitative trait loci (QTLs) with large effects on predisposition to physical dependence and associated withdrawal severity following chronic and acute alcohol exposure (Alcdp1/Alcw1) to a 1.1-Mb interval of mouse chromosome 1 syntenic with human chromosome 1q23.2-23.3. Here, we provide a detailed analysis of the genes within this interval and show that it contains 40 coding genes, 17 of which show validated genotype-dependent transcript expression and/or non-synonymous coding sequence variation that may underlie the influence of Alcdp1/Alcw1 on ethanol dependence and associated withdrawal. These high priority candidates are involved in diverse cellular functions including intracellular trafficking, oxidative homeostasis, mitochondrial respiration, and extracellular matrix dynamics, and indicate both established and novel aspects of the neurobiological response to ethanol. This work represents a substantial advancement toward identification of the gene(s) that underlies the phenotypic effects of Alcdp1/Alcw1. Additionally, a multitude of QTLs for a variety of complex traits, including diverse behavioral responses to ethanol, have been mapped in the vicinity of Alcdp1/Alcw1, and as many as four QTLs on human chromosome 1q have been implicated in human mapping studies for alcoholism and associated endophenotypes. Thus, our results will be primary to further efforts to identify genes involved in a wide variety of behavioral responses to alcohol and may directly facilitate progress in human alcoholism genetics.
    Preview · Article · Aug 2008 · Genes Brain and Behavior
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