Selected contribution: variation in acute hypoxic ventilatory response is linked to mouse chromosome 9

Genetic determinants confer variation among inbred mouse strains with respect to the magnitude and pattern of breathing during acute hypoxic challenge. Specifically, inheritance patterns derived from C3H/HeJ (C3) and C57BL/6J (B6) parental strains suggest that differences in hypoxic ventilatory response (HVR) are controlled by as few as two genes. The present study demonstrates that at least one genetic determinant is located on mouse chromosome 9. This genotype-phenotype association was established by phenotyping 52 B6C3F2 (F2) offspring for HVR characteristics. A genome-wide screen was performed using microsatellite DNA markers (n = 176) polymorphic between C3 and B6 mice. By computing log-likelihood values (LOD scores), linkage analysis compared marker genotypes with minute ventilation (&Vdot;E), tidal volume (VT), and mean inspiratory flow (VT/TI, where TI is inspiratory time) during acute hypoxic challenge (inspired O2 fraction = 0.10, inspired CO2 fraction = 0.03 in N2). A putative quantitative trait locus (QTL) positioned in the vicinity of D9Mit207 was significantly associated with hypoxic VE (LOD = 4.5), VT (LOD = 4.0), and VT/TI (LOD = 5.1). For each of the three HVR characteristics, the putative QTL explained more than 30% of the phenotypic variation among F(2) offspring. In conclusion, this genetic model of differential HVR characteristics demonstrates that a locus approximately 33 centimorgans from the centromere on mouse chromosome 9 confers a substantial proportion of the variance in VE, VT, and VT/TI during acute hypoxic challenge.