Tankersley Clarke G, Broman Karl W
Department of Environmental Health Sciences, The Johns Hopkins University, Baltimore, MD 21205, USA.
J Appl Physiol (1985). 2004 Jul;97(1):77-84. doi: 10.1152/japplphysiol.01102.2003. Epub 2004 Feb 20.
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 O(2) fraction (Fi(O(2))) = 0.21] and hypoxia (Fi(O(2)) = 0.10) with mild or severe hypercapnia (inspired CO(2) fraction = 0.03 or 0.08) using whole body plethysmography. At each level of Fi(O(2)), the change in minute ventilation (Ve) from 3 to 8% CO(2) 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., CO(2) potentiation) unique to the B6C3F1/J offspring of B6 and C3 progenitors; i.e., the change in Ve from 3 to 8% CO(2) 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 Ve responses during 8% CO(2) 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 CO(2) 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.
呼吸调节差异的遗传基础无疑是多基因的。本文基于一个成熟的利用近交系小鼠品系研究呼吸差异的遗传模型展开。我们在两种以高碳酸通气敏感性（HCVS）存在差异而闻名的小鼠品系中测试了低氧和高碳酸血症的交互作用；即C57BL/6J（B6）小鼠的HCVS高增益和C3H/HeJ（C3）小鼠的HCVS低增益。使用全身体积描记法，在常氧[吸入氧分数（Fi(O₂)）= 0.21]和低氧（Fi(O₂)= 0.10）条件下，分别在轻度或重度高碳酸血症（吸入二氧化碳分数 = 0.03或0.08）时测量呼吸幅度和模式的品系差异。在每个Fi(O₂)水平下，计算从3%到8%二氧化碳时分钟通气量（Ve）的变化，并且B6和C3小鼠在HCVS方面的品系差异得以维持。遗传模式显示低氧对HCVS具有增强作用（即二氧化碳增强作用），这在B6和C3祖代的B6C3F1/J后代中是独特的；也就是说，在F1小鼠中，相对于常氧，低氧时从3%到8%二氧化碳的Ve变化显著更大（P < 0.01）。使用B6和C3祖代的杂交后代（F2；n = 52）进行连锁分析，发现了两个与可变HCVS表型相关的显著数量性状基因座。在对体重进行标准化后，低氧时8%二氧化碳条件下Ve反应的变化与小鼠1号染色体（优势对数比 = 4.4）在68至89 cM之间的区间（即D1Mit14和D1Mit291之间）相关。第二个数量性状基因座将二氧化碳增强作用的差异与小鼠5号染色体（优势对数比 = 3.7）在7至29 cM之间的区域（即以D5Mit66为中心）联系起来。总之，这些结果支持了这样一个假设，即在这个遗传模型中，至少有两个重要基因调节低氧和高碳酸血症的交互作用。
