RESUMEN
Airway hyperresponsiveness is a key characteristic of human asthma and a marker for asthma-like conditions in animals. F1 mice derived from A/J and C57BL/6J display a phenotype which resembles the asthma-like phenotype of the A/J mice. Since airway responsiveness failed to segregate as a mendelian trait, we show significant linkage at two loci, Bhr1 (lod = 3.0) and Bhr2 (lod = 3.7) on chromosomes 2 and 15. A third locus, Bhr3 (lod = 2.83), maps to chromosome 17. Each of these loci maps near candidate loci implicated in the pathobiology of asthma. Our study represents the first linkages established through a genome-wide survey of airway hyperresponsiveness in any mammal.
Asunto(s)
Asma/genética , Asma/fisiopatología , Mapeo Cromosómico , Pulmón/fisiología , Pruebas de Función Respiratoria , Análisis de Varianza , Animales , Cruzamientos Genéticos , ADN/análisis , ADN/aislamiento & purificación , Femenino , Ligamiento Genético , Genotipo , Humanos , Riñón/metabolismo , Escala de Lod , Pulmón/efectos de los fármacos , Masculino , Mamíferos , Cloruro de Metacolina/farmacología , Ratones , Ratones Endogámicos A , Ratones Endogámicos C57BL , Parasimpaticomiméticos/farmacología , Fenotipo , Pletismografía , Reacción en Cadena de la PolimerasaRESUMEN
A powerful approach for identifying mammalian primary (gonadal) sex determination genes is the molecular genetic analyses of sex reversal conditions (that is, XX individuals with testicular tissue and XY individuals with ovarian tissue). Here we determined the number and chromosomal location of autosomal and X-linked genes that cause sex reversal in C57BL/6J (B6) mice carrying a Y chromosome of Mus domesticus poschiavinus origin (YPOS). B6 XYPOS mice develop either as females with exclusively ovarian tissue or as true hermaphrodites with ovarian and testicular tissue. In contrast, the YPOS chromosome is fully masculinizing on most other inbred strain backgrounds. B6-YPOS sex reversal appears to result from the incompatibility of the Sry (sex determining region, Y chromosome) allele carried on the YPOS chromosome with B6-derived autosomal or X-linked loci. We found strong evidence for the location of one gene, designated tda1 (testis-determining, autosomal 1), at the distal end of Chromosome (Chr) 4 and a second gene, tda2, in the central region of Chr 2. A third gene, tda3, on Chr 5 is implicated, but the evidence here is not as strong. We suggest that B6 alleles at these loci predispose XYPOS fetuses to ovarian tissue development, but no single locus or combination of loci is necessary and sufficient to cause sex reversal. The TDA proteins may regulate Sry expression or form complexes with the SRY protein to regulate other genes, or the tda genes may be activated or repressed by the SRY protein.
Asunto(s)
Trastornos del Desarrollo Sexual , Genes/genética , Ligamiento Genético , Proteínas Nucleares , Diferenciación Sexual/genética , Factores de Transcripción , Animales , Mapeo Cromosómico , Cruzamientos Genéticos , Proteínas de Unión al ADN/genética , Trastornos del Desarrollo Sexual/genética , Femenino , Genotipo , Gónadas/embriología , Masculino , Ratones , Ratones Endogámicos C57BL , Muridae , Proteína de la Región Y Determinante del Sexo , Cromosoma X/genética , Cromosoma Y/genéticaRESUMEN
We have constructed a genetic map of the mouse genome containing 4,006 simple sequence length polymorphisms (SSLPs). The map provides an average spacing of 0.35 centiMorgans (cM) between markers, corresponding to about 750 kb. Approximately 90% of the genome lies within 1.1 cM of a marker and 99% lies within 2.2 cM. The markers have an average polymorphism rate of 50% in crosses between laboratory strains. The markers are distributed in a relatively uniform fashion across the genome, although some deviations from randomness can be detected. In particular, there is a significant underrepresentation of markers on the X chromosome. This map represents the two-thirds point toward our goal of developing a mouse genetic map containing 6,000 SSLPs.