IDENTIFICATION OF A GENETIC REGION IN MICE THAT SPECIFIES SENSITIVITYTO PROPOFOL

Background: Long-sleep (LS) and short-sleep (SS) mice, initially selec ted for differential sensitivity to ethanol, also exhibit differential sensitivity to propofol By interbreeding LS and SS mice to obtain pro geny whose chromosomes are a patchwork of the IS and SS chromosomes, t he authors determined whether differential propofol sensitivity cosegr egates with any particular chromosomal region(s). Such cosegregation i s the essence of genetic linkage mapping and a first step toward isola ting a gene that can modulate propofol sensitivity in mammals. A gene underlying a quantitative trait such as anesthetic sensitivity is comm only called a quantitative trait locus (QTL). Methods: The propofol do se was 20 mg/kg injected retroorbitally. Sensitivity was measured as t he duration of the loss of righting reflex (LORR). The LORR and propof ol brain levels at awakening were determined for 24 LSXSS recombinant- inbred CRI) strains, derived by intercrossing LS and SS for two genera tions followed by >20 generations of inbreeding. A genetic linkage bet ween LORR and an albino mutation on chromosome 7 was investigated furt her using 164 second-generation progeny (F(2)s) from intercrossing inb red LS and inbred SS mice, similar to the ISXSS RIs except F(2)s are n ot inbred The linkage between propofol sensitivity and the albino locu s also was investigated using additional genetic markers on chromosome 7. Statistical significance was assessed by interval mapping using a regression method for RIs and Mapmaker/QTL (Whitehead Institute, Cambr idge, MA) for F(2)s. Results: Genetic mapping in the LSXSS RIs reveale d a QTL tightly linked to the Tyr (albino) locus that accounts for nea rly all of the genetic difference in propofol sensitivity between LS a nd SS mice. Analysis of propofol brain levels at awakening indicated t hat this QTL results from differential neurosensitivity. Mapping in F( 2)s confirmed the genetic linkage to Tyr. Mice (ISS c/c x C57BL/6 c(2J )/C) that differed only by an albino mutation at Tyr mere not differen tially sensitive to propofol. Conclusions: A single QTL, called Lorp1, underlies most of the genetic difference in propofol neurosensitivity between LS and SS mice. Although this QTL is tightly linked to Tyr, p ropofol sensitivity is not modulated by albinism. For mapping this QTL , the LSXSS ms proved to be an especially powerful resource, localizin g the candidate-gene region to a 99% confidence interval of only 2.5 c entimorgans.