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Interactions in hypoxic and hypercapnic breathing are genetically linked to mouse chromosomes 1 and 5

Departments of ¹Environmental Health Sciences and ²Biostatistics, The Johns Hopkins University, Bloomberg School of Public Health, Baltimore, Maryland 21205

Submitted 10 October 2003 ; accepted in final form 16 February 2004

The genetic basis for differences in the regulation of breathing is certainly multigenic. The present paper builds on a well-established genetic model of differences in breathing using inbred mouse strains. We tested the interactive effects of hypoxia and hypercapnia in two strains of mice known for variation in hypercapnic ventilatory sensitivity (HCVS); i.e., high gain in C57BL/6J (B6) and low gain in C3H/HeJ (C3) mice. Strain differences in the magnitude and pattern of breathing were measured during normoxia [inspired O₂ fraction (FI_O2) = 0.21] and hypoxia (FI_O2 = 0.10) with mild or severe hypercapnia (inspired CO₂ fraction = 0.03 or 0.08) using whole body plethysmography. At each level of FI_O2, the change in minute ventilation (E) from 3 to 8% CO₂ was computed, and the strain differences between B6 and C3 mice in HCVS were maintained. Inheritance patterns showed potentiation effects of hypoxia on HCVS (i.e., CO₂ potentiation) unique to the B6C3F1/J offspring of B6 and C3 progenitors; i.e., the change in E from 3 to 8% CO₂ was significantly greater (P < 0.01) with hypoxia relative to normoxia in F1 mice. Linkage analysis using intercross progeny (F2; n = 52) of B6 and C3 progenitors revealed two significant quantitative trait loci associated with variable HCVS phenotypes. After normalization for body weight, variation in E responses during 8% CO₂ in hypoxia was linked to mouse chromosome 1 (logarithm of the odds ratio = 4.4) in an interval between 68 and 89 cM (i.e., between D1Mit14 and D1Mit291). The second quantitative trait loci linked differences in CO₂ potentiation to mouse chromosome 5 (logarithm of the odds ratio = 3.7) in a region between 7 and 29 cM (i.e., centered at D5Mit66). In conclusion, these results support the hypothesis that a minimum of two significant genes modulate the interactive effects of hypoxia and hypercapnia in this genetic model.

C3H/HeJ; C57BL/6J; carbon dioxide potentiation; control of breathing; linkage analysis

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