1, 40 (A/J ? C3H/HeJ) F1, 104 (A/J ? C3H/HeJ) Fdos intercross, and 369 [(A/J ? C3H/HeJ)F1? C3H/HeJ] backcross mice; the values forRL, expressed as a percentage of baseline for the 330 and 1,000 ?g/kg doses, are shown in Table 1 along with the log ED150RLvalues. A scatterplot ofRL values for the 330 ?g/kg dose (expressed as a percentage of baseline) from individual parental, F1, F2, and backcross mice is presented in 1 and as the log ED150RLvalues in 2. Analysis of the distribution of airway responsiveness phenotypes in the A/J and C3H/HeJ parental strains confirmed the original observations that A/J mice are more responsive to challenge with cholinergic bronchoconstrictors than C3H/HeJ mice (8, 11).
F1-153 n = 365. RL, pulmonary resistance; log ED150RL, log-transformed dose required for a 1.50-fold increase inRL; ACF1, A/J female mated with C3H/HeJ male F1 hybrid strain; backcross, [(A/J ? C3H/HeJ)F1 ? C3H/HeJ] mice.
1.Scatterplot of pulmonary resistance (R ACF1, A/J female mated with CeH/HeJ male F1 hybrid; CAF1, C3H/HeJ female mated with A/J male F1 hybrid; backcross, [(A/J ? C3H/HeJ)F1? C3H/HeJ]; n, no. of mice. * Significantly different from C3H/HeJ mice,P < 0.05.
2.Scatterplot of RLvalues for log-transformed dose required for 1.50-fold increase inRL (log ED150RL) for parental and hybrid mice. Distribution of airway responsiveness phenotypes and therefore genetically informative progeny in F2 intercross group is narrower than range of responses to 330 ?g/kg dose (expressed as a percentage of baseline). n, No. of mice.
Analysis of the distribution of individual animals demonstrates that the mode of inheritance does not follow a simple Mendelian or complex genetic pattern. TheRL values for the 330 ?g/kg dose, expressed as a percentage of baseline, are presented in 1. Analysis of F1 mice derived from reciprocal crosses [A/J females mated with C3H/HeJ males (ACF1) and C3H/HeJ females with A/J males (CAF1)] revealed significant differences in airway responsiveness. Both F1 hybrids had a phenotype that was intermediate between the A/J and C3H/HeJ strains but was skewed more toward the A/J strain (Table 1). However, significantly greater responses were observed in the ACF1 hybrid strain than in the CAF1 strain (P < 0.0047; Table 1, 1). Airway responses were broadly distributed to encompass the range of values observed in the C3H/HeJ, F1, and A/J groups ( 1) in F2 mice derived from ACF1 mice. A similar analysis of the log ED150RLvalues for the parental and hybrid crosses revealed a narrower distribution of airway responses ( 2) than that in response to 330 ?g/kg of methacholine alone. Airway responsiveness in F2 mice, ascertained with theRL response to 330 or 1,000 ?g/kg of methacholine or log ED150RLvalues, was not normally distributed (P < 0.0001 by Shapiro-WilkW-test for normality). Analysis of airway responses for the 330 ?g/kg dose in the F2 intercross and CAF1 mice indicated that 48% of the total variance in the intercross was genetic. The CAF1 group was used to calculate the genetic component of the variance because the variability in airway responses in this F1 group was significantly less compared with that in the ACF1 cross.
Because airway hyperresponsiveness appeared to be intermediate in the ACF1 mice but skewed toward the A/J phenotype, they were backcrossed to the hyporesponsive C3H/HeJ parental strain [(A/J ? C3H/HeJ) F1 ? C3H/HeJ]. Airway responsiveness in 369 backcross best Nottingham hookup site progeny ( 1) was not normally distributed (P < 0.0001), a finding similar to that for the F2 progeny (3).
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3.Estimated distribution of methacholine response and normal quantile plot of backcross (A) and F2 intercross (B) mice studied in terms ofRL values for 330 ?g/kg dose. n, No. of mice. Neither F2 intercross progeny nor backcross progeny were normally distributed.