Genes for Difference in Eosinophilic Phenotype between MES and BN.MES-Cyba(mes) Rats Are on Chromosomes 9, 5, and 1

The Matsumoto Eosinophilia Shinshu (MES) rat strain develops hereditary blood eosinophilia due to the mutant Cybames gene. In contrast, BN.MES-Cybames congenic rats, in which the mutant Cybames gene introduced into the background of the BN strain, have a normal blood eosinophil level despite showing robust proliferation of eosinophils in the bone marrow. However, the congenic rats manifest focal necrosis with eosinophilic infiltration in the liver, a phenotype rarely observed in the original MES rat strain. To elucidate the genetic basis for the strain differences, (MES × BN.MES-Cybames)F2 rats were bred, and genetic analyses of phenotypes for eosinophilia were performed. Blood and bone marrow eosinophil levels in the F2 rats showed broad distributions, suggesting that the traits were under the influence of multiple genes. Genetic association studies revealed that BN-derived marker loci on chromosomes 9 and 5 were responsible for the increase in eosinophil level in the bone marrow, decrease in blood eosinophil level, and the induction of focal necrosis with eosinophilic infiltration in the liver. The BN-derived allele of the marker gene on chromosome 1 was responsible for the decrease of both bone marrow and blood eosinophil levels. These data suggest the existence of genes characterizing/distinguishing the eosinophilic phenotypes of MES and BN.MES-Cybames on these chromosomes, and form the basis for positional cloning studies of the genes. These studies will advance the understanding of the mechanisms involved in eosinophil mobilization from the bone marrow and recruitment to the organs.