Physiological and Genomic Consequences of Intermittent Hypoxia: Selected Contribution: Variation in acute hypoxic ventilatory response is linked to mouse chromosome 9

Genetic determinants confervariation among inbred mouse strains with respect to the magnitude andpattern 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 ventilatoryresponse (HVR) are controlled by as few as two genes. The present studydemonstrates that at least one genetic determinant is located on mousechromosome 9. This genotype-phenotype association was established byphenotyping 52 B6C3F₂ (F₂) offspring for HVRcharacteristics. A genome-wide screen was performed usingmicrosatellite DNA markers (n = 176) polymorphicbetween C3 and B6 mice. By computing log-likelihood values (LODscores), linkage analysis compared marker genotypes with minuteventilation (E), tidal volume (VT), andmean inspiratory flow (VT/TI, whereTI is inspiratory time) during acute hypoxic challenge(inspired O₂ fraction = 0.10, inspired CO₂fraction = 0.03 in N₂). A putative quantitative traitlocus (QTL) positioned in the vicinity of D9Mit207 wassignificantly associated with hypoxic E (LOD = 4.5), VT (LOD = 4.0), andVT/TI (LOD = 5.1). For each of the threeHVR characteristics, the putative QTL explained more than 30% of thephenotypic variation among F₂ offspring. In conclusion,this genetic model of differential HVR characteristics demonstratesthat a locus ~33 centimorgans from the centromere on mouse chromosome9 confers a substantial proportion of the variance inE, VT, and VT/TIduring acute hypoxic challenge.