Genetic determinants of acute hypoxic ventilation: Patterns of inheritance in mice

Acutely lowering ambient O₂ tension increases ventilation in many mammalian species, including humans and mice. Inheritance patterns among kinships and between mouse strains suggest that a robust genetic influence determines individual hypoxic ventilatory responses (HVR). Here, we tested specific genetic hypotheses to describe the inheritance patterns of HVR phenotypes among two inbred mouse strains and their segregant and nonsegregant progeny. Using whole body plethysmography, we assessed the magnitude and pattern of ventilation in C3H/HeJ (C3) and C57BL/6J (B6) progenitor strains at baseline and during acute (3-5 min) hypoxic [mild hypercapnic hypoxia, inspired O₂ fraction (FI(O₂)) = 0.10] and normoxic (mild hypercapnic normoxia, FI(O₂) = 0.21) inspirate challenges in mild hypercapnia (inspired CO₂ fraction = 0.03). First- and second-filial generations and two backcross progeny were also studied to assess response distributions of HVR phenotypes relative to the parental strains. Although the minute ventilation (V̇E) during hypoxia was comparable between the parental strains, breathing frequency (f) and tidal volume were significantly different; C3 mice demonstrated a slow, deep HVR relative to a rapid, shallow phenotype of B6 mice. The HVR profile in B6C3F₁/J mice suggested that this offspring class represented a third phenotype, distinguishable from the parental strains. The distribution of HVR among backcross and intercross offspring suggested that the inheritance patterns for f and V̇E during mild hypercapnic hypoxia are consistent with models that incorporate two genetic determinants. These results further suggest that the quantitative genetic expression of alleles derived from C3 and B6 parental strains interact to significantly attenuate individual HVR in the first- and second-filial generations. In conclusion, the genetic control of HVR in this model was shown to exhibit a relatively simple genetic basis in terms of respiratory timing characteristics.