Expression and linkage of genes for X-linked hemophilias A and B in the dog.

The linkage distance on the X chromosome between the genes for hemophilia A (classic hemophilia) and B (PTC deficiency, Christmas disease) was estimated directly by breeding two strains of dogs, each segregating for a different type of hemophilia. Gene expression was determined by bioassays of plasma factor VIII (antihemophilic factor) and factor IX (PTC, Christmas factor). Double heterozygotes in repulsion for both hemophilia A and B could be readily identified by intermediate plasma levels of both procoagulants. There was no evidence of a tendency toward preferential inactivation of the paternally derived X chromosome, and the procoagulant levels showed that random inactivation had occurred at both loci. When double heterozygotes were bred against normal males or males with hemophilia A and B, the progeny that resulted indicated that the genes recombined freely. Thus, the genes are at least 50 map units apart. The phenotypes of five new hemophilic genotypes are described as a result of the various crossbreedings, including males with double hemophilia AB. When both hemophilia genes are in the coupling phase, there is evidence of increased intrauterine or neonatal lethality in males. The data from this study, along with that on gene linkage of human hemophilia A and B, provide support for the thesis of homology of the X chromosome during speciation.