New approaches to localization and characterization of specific genes have generated the following results: 1. Denaturing gradient gel electrophoresis (DGGE) of amplified gene fragments identified mutations of the gene for the alpha-subunit of G(s) protein in Albright's Hereditary Osteodystrophy (AHO); silent mutations of this gene identified by the same methods were used in linkage mapping of this gene on CEPH pedigrees to the end of the long arm of chromosome 20. 2. Two closely linked adrenergic receptor genes on chromosome 10 (alpha2-adrenergic receptor and beta1-adrenergic receptor) have been shown to be on the same 250 kb SfiI fragment by pulse field gel electrophoresis (PFGE), confirming earlier results and suggesting evolutionary duplication of a several gene fragment. 3. Rapid chromosomal localization of genes by analysis of somatic cell (human * rodent hybrids using polymerase chain reaction (PCR) localized the following genes: the protease cathepsin B to chromosome 8 (sublocalized to 8p22), and the protease inhibitors stefin A (cystatin A) and kininogen to chromosome 3. Sublocalization of stefin A is to 3cen-q2l and kininogen to 3q26-ter. New clinical developments include the following: 1. Multipoint linkage analysis of manic-depressive illness to markers of the X-chromosome q27-q28 region exclude linkage in the entire region. 2. New collaborations to generate large pedigree series that may detect linkage in the presence of heterogeneity. These include the NIMH Genetics Initiative, collaboration in Mediterranean countries on X-linkage, and collaborations generated through our yearly course on diagnostic and pedigree methods in psychiatric genetics.
