RESUMEN
Genetic control of differential inspiratory timing (TI) at baseline has been previously demonstrated among inbred mouse strains. The inheritance pattern for TI between C3H/HeJ (C3; 188 +/- 3 ms) and C57BL/6J (B6; 111 +/- 2 ms) progenitors was consistent with a two-gene model. By using the strain distribution pattern for recombinant inbred strains derived from C3 and B6 progenitors, 100% concordance was established between TI phenotypes and DNA markers on mouse chromosome 3. This genotype-phenotype hypothesis was tested by typing 52 B6C3F2 (F2) progeny by using simple sequence repeat DNA markers (n = 21) polymorphic between C3 and B6 strains on mouse chromosome 3. Linkage analysis compared marker genotypes to baseline ventilatory phenotypes by computing log-likelihood values. A putative quantitative trait locus located in proximity to D3Mit119 was significantly associated with baseline TI phenotypes. At the peak (log-likelihood = 3.3), the putative quantitative trait locus determined 25% of the phenotypic variance in TI among F2 progeny. In conclusion, this genetic model of ventilatory characteristics demonstrated an important linkage between differential baseline TI and a candidate genomic region on mouse chromosome 3.
Asunto(s)
Cromosomas/genética , Cromosomas/fisiología , Mecánica Respiratoria/genética , Mecánica Respiratoria/fisiología , Animales , ADN/genética , ADN/aislamiento & purificación , Femenino , Ligamiento Genético/genética , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Fenotipo , Reacción en Cadena de la Polimerasa , Carácter Cuantitativo HeredableRESUMEN
A genetic predisposition to nonspecific airway hyperresponsiveness (AHR) can be demonstrated in humans and in many animal models. The goal of the current study was to gain insight into the molecular mechanisms that determine AHR by mapping the genes that control this phenotype. We describe genetic studies in a mouse model of differential sensitivity to acetylcholine (ACh)-induced AHR. This model was used to ascertain the number, magnitude of effect, and chromosomal location of quantitative trait loci (QTL) providing susceptibility to ACh-induced AHR. Segregation analyses indicated that a major locus acting additively with a polygenic effect segregates with the airway pressure-time index (APTI) in the progeny of hyperresponsive A/J and hyporesponsive C3H/HeJ mice. Additionally, four loci segregate with respiratory system resistance (Rrs). Examination of the genome for markers linked to these phenotypes indicated that a QTL on chromosome 6 was common to both traits. QTL analysis in the [(C3H/HeJ x A/J)F1 x A/J] backcross generation revealed significant linkage for ACh-induced AHR within the interval spanning the chromosome 6 deoxyribonucleic acid (DNA) markers D6Mit16 and D6Mit13. A/J alleles in this interval were associated with significantly greater airway responsiveness than were C3H/HeJ alleles. Several important candidate genes map to this region, including the locus for the interleukin-5 (IL-5) receptor. This mapping information in the mouse may relate to human studies in which bronchial hyperresponsiveness links to the chromosomal region containing the gene for IL-5 (1).