Inheritance of hypoxic exercise tolerance in mice

All mammals tested, when exposed acutely to a degree of hypoxia above some threshold, exhibit a reduced capacity to perform work. Chronic hypoxic exposure is usually associated with some degree of acclimation resulting in partial recovery of the preexposure work capacity. The present study reports that, among mice, interindividual variability in recovery of ability to tolerate a standardized hypoxic exercise [t(et); time elapsed in treadmill exercise in hypoxia until 4-s failure to avoid a grid configured to deliver a mild aversive current (0.15 MA)], after 8 weeks' exposure to half-atmospheric pressure, is influenced predominantly by two unlinked genes of major effect. Two approaches were taken toward genetic characterization. In one, a maximum-likelihood procedure was applied to 11 models of genetic determinacy in the t(et) distributions of BALB/cBy (C) and C57BL/6By (B6) parental inbred strains, their F-1 hybrid, and the backcross (BC) generations. Breeding tests of the resulting candidate ''best-fit'' major locus inheritance models involved repeated cycles of selecting, as the progenitor of a new BC generation, the male with the highest value of the test variable in the previous BC generation, and breeding him to C females. Mice from each of four distinct phenotypes appearing in BC3 were bred to C mice, producing distributions expected from two-locus segregation. The second approach was based upon CXB/By RI strain distribution pattern and derivative breeding tests to reveal phenotypic distributions consistent with two-locus inheritance of t(et). Melding these results with a positional cloning strategy may permit relating a behavioral difference to specific heritable elements and identifying their products as the (partial) physiological substrata of the behavior.