Mapping a locus for alcohol physical dependence and associated withdrawal to a 1.1 Mb interval of mouse chromosome 1 syntenic with human chromosome 1q23.2-23.3.
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.
Kozell
L
L
Department of Veterans Affairs Medical Center, Portland, OR, USA.
Belknap
J K
JK
Hofstetter
J R
JR
Mayeda
A
A
Buck
K J
KJ
D000208:Acute Disease; D020270:Alcohol Withdrawal Seizures / Q000235:genetics*; D000437:Alcoholism / Q000235:genetics*; D000818:Animals; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian; D018757:GABA Modulators / Q000494:pharmacology; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010424:Pentobarbital / Q000494:pharmacology; D010641:Phenotype; D040641:Quantitative Trait Loci; D013375:Substance Withdrawal Syndrome / Q000235:genetics
D018757:GABA Modulators; D010424:Pentobarbital