Common genetic determinants of the ataxic and hypothermic effects of ethanol in BXD/Ty recombinant inbred mice: genetic correlations and quantitative trait loci.
Sensitivity and tolerance to ethanol-induced ataxia and hypothermia are determined in part by genetic factors; some genes that affect one of these traits may affect others as well. To test this general hypothesis, we examined hypothermia and two tests of ataxia in the C57BL/6J and DBA/2J inbred mouse stains and in 18 to 25 of their recombinant inbred strains. Genetic correlations among strain mean responses revealed strong positive associations of genetic origin between sensitivity and tolerance for each of the three responses. Furthermore, tolerance to grid test ataxia and tolerance to hypothermia were positively associated. Sensitivity scores across the three responses were uncorrelated. The second method employed to assess genetic correlation was to examine the pattern of genetic locations of quantitative trait loci (QTLs) provisionally identified using genetic mapping procedures. This method identified 3 to 14 QTLs associated with each trait. Within each response, a number of these associations were in common for measures of sensitivity and tolerance; this suggests the existence of several specific genes that exert pleiotropic effects on sensitivity and tolerance. In a result consistent with the analyses of genetic correlations, there was modest evidence for QTLs associated across measures. Some QTLs associated with multiple traits mapped to chromosomal regions where candidate genes (e.g., genes for neurotransmitter receptors) have been mapped. In summary, the analyses presented suggest modest commonality of genetic influence on tolerance to some measures of ataxia and hypothermia, and they strongly support previous data indicating that sensitivity and tolerance to specific effects of ethanol share common genetic determinants.
Crabbe
J C
JC
Department of Veterans Affairs Medical Center, Portland, Oregon, USA.
Phillips
T J
TJ
Gallaher
E J
EJ
Crawshaw
L I
LI
Mitchell
S R
SR
D000818:Animals; D001259:Ataxia / Q000139:chemically induced*; D001831:Body Temperature / Q000187:drug effects*; D002874:Chromosome Mapping; D003434:Crossing Over, Genetic; D004361:Drug Tolerance / Q000235:genetics; D000431:Ethanol / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA
D000431:Ethanol