Genome screen for asthma and related phenotypes in the French EGEA study.

A genome-wide search was conducted in 107 nuclear families with at least two siblings with asthma, as part of the French EGEA study. A two-stage analysis strategy was applied to the 107 families divided into two independent subsets of 46 and 61 families, where all regions detected in the first set of families were tested for replication in the second set. In addition, all regions reported by published genome scans in different populations were examined in the total sample. A total of 254 markers were typed in the first set of families and 70% of them in the second set. Linkage was investigated by model-free methods for asthma and four asthma-related phenotypes: bronchial responsiveness (BR), skin test response, total immunoglobulin E (IgE) levels, and eosinophil count. The two-stage analysis led to the detection of three regions: 11p13 for IgE, 12q24 for eosinophils, and 17q12-21 for asthma and skin tests. Among the regions reported by published genome screens, seven were found in the 107 French EGEA families: three being already detected by the two-stage analysis, 11p13 (p = 0.005), 12q24 (p = 0.0008), and 17q12-21 (p = 0.001), and four additional ones, 1p31 (p = 0.005) for asthma, 11q13 (p = 0.006) for IgE, 13q31 (p = 0.001) for eosinophils, and 19q13 (p = 0.02) for BR.

Complete genome searches for quantitative trait loci controlling blood pressure and related traits in four segregating populations derived from Dahl hypertensive rats.

The Dahl salt-sensitive rat is one of the principal animal models of hereditary hypertension. Genome-wide searches were undertaken to detect quantitative trait loci (QTLs) that influence blood pressure, cardiac mass, and body weight in four F2 populations derived from Dahl salt-sensitive rats and different inbred normotensive control strains of rat. We detected three QTLs associated with one or more of the phenotypes, using a stringent statistical criterion for linkage (p < 0.00003). These included a novel QTL linked to blood pressure on rat Chromosome (Chr) 12, and another QTL on rat Chr 3 linked to body weight. A QTL on rat Chr 10 for which linkage to blood pressure has been described in other crosses was found to be a principal determinant of blood pressure and cardiac mass in some but not all of the crosses examined here. Three other regions showed evidence of linkage to these phenotypes with a less stringent statistical criterion of linkage at QTLs previously reported in other studies. As part of our study, microsatellite markers have been developed for three candidate genes for investigation in hypertension, and the genes have been localized by linkage mapping. These are: the rat Gs alpha subunit (Gnas) gene, the alpha-1B adrenergic receptor (Adra1b), and the Na+, K+-ATPase beta2 subunit (Atp1b2) gene.

Practicable approaches to targeted comparative mapping of rat chromosome regions: linkage mapping of five genes on rat chromosome 13.

We demonstrate feasible approaches to comparative mapping between the region near the renin locus on rat chromosome 13 and human chromosome 1q by assigning five additional genes as anchor loci. Base-substitution polymorphisms were sought in the 3'- and/or 5'-untranslated regions for subsequent development of PCR-amplified markers, which, in turn, could be used for either restriction fragment analysis or allele-specific PCR.

A linkage map of the rat genome derived from three F2 crosses.

We report the construction of a dense linkage map of the rat genome integrating 767 simple sequence length polymorphism markers, combined over three crosses with high rates of polymorphism. F2 populations from WKY x S (n = 159), BN x S (n = 91), and BN x GK (n = 139) were selected and genotyped for combinations of microsatellite markers. The loci define 21 linkage groups corresponding to the 20 rat autosomal chromosomes and the X chromosome. The map spans a genetic length of 1998 cM. This combined linkage map should facilitate the advancement of genetic studies for a wide variety of rat models characterized for complex phenotypes.

A gene-based genetic linkage and comparative map of the rat X chromosome.

We have constructed a gene-based genetic linkage map of the rat X chromosome. Fifteen polymorphic microsatellite markers associated with 13 different X chromosome genes have been isolated and genotyped on F2 progency from five different intercrosses. These markers have been integrated with 23 further rat X chromosome markers, resulting in a single linkage group for the X chromosome containing 38 microsatellite markers associated with 21 different genes and spanning a genetic distance of 88 cM. Fluorescence in situ hybridization was used to confirm the gene order obtained for the new markers and also placed 2 further genes, Hprt and Fmr1, on the map. Comparisons of gene order among rat, mouse, and human indicate homologous regions of conserved synteny and regions where evolutionary breakpoints have occurred. The genes from human Xq are conserved in order on the rat X chromosome, whereas those from human Xp have been rearranged into at least four conserved segments. The polymorphic markers and comparative map will be useful in studies on rat models of genetic disease.