COMPARATIVE MAPPING OF CANINE AND HUMAN PROXIMAL XQ AND GENETIC-ANALYSIS OF CANINE X-LINKED SEVERE COMBINED IMMUNODEFICIENCY

Parallel genetic analysis of animal and human genetic diseases can fac ilitate the identification and characterization of the causative gene defects. For example, canine X-linked severe combined immunodeficiency (SCID) is characterized by clinical, pathological, and immunological manifestations similar to the most common form of human SCID. To deriv e a canine syntenic map including genes that in humans are located in proximal Xq, near human X-linked SCID, poly(TG) polymorphisms were ide ntified at the canine phosphoglycerate kinase (PGK) and choroideremia (CHM) loci. These plus a polymorphic poly(CAG) sequence in exon 1 of t he canine androgen receptor gene (AR) were used to genotype members of the colony informative for X-linked SCID. No recombinations among SCI DX1, AR, PGK, or CHM were observed. Fluorescence in situ hybridization localized PGK and CHM to proximal Xq in the dog, in the same chromoso mal location occupied by the human genes. Somatic cell hybrid analysis and methylation differences at AR demonstrated that female dogs carry ing X-linked SCID have the same lymphocyte-limited skewed X-chromosome inactivation patterns as human carriers. These genetic and phenotypic findings provide evidence that mutations in the same gene, now identi fied as the gamma chain of the IL-2 receptor, cause canine and human X -linked SCID. This approach is an efficient method for comparative gen e mapping and disease identification. (C) 1994 Academic Press, Inc.