The purpose of this project is to locate the genes for a number of different human genetic disorders, and to study their function once they have been successfully identified. Using the techniques of positional cloning, we are currently closing in on the gene for familial early onset breast cancer (BRCA1), which has been narrowed to an approximately 1 Mb interval of chromosome 17. A total of 28 candidate genes are being investigated for potential mutations in the germline of individuals from linked families, and it is anticipated that the correct gene will be identified in the near future. Other disease genes which are being sought by similar methods include the Long QT syndrome on chromosome 11, the Bloom's Syndrome gene on chromosome 15, the familial Mediterranean fever gene on chromosome 16, the ataxia telangiectasia gene on chromome 11, and the multiple endocrine neoplasia type I gene on chromosome 10. Many of these efforts are being carried out in collaboration with other investigators both inside and outside the NIH. A new and ambitious effort is to identify the major loci predisposing to adult onset diabetes. For this purpose we have established a collaboration with investigators in Finland to study 400 affected sib pairs, with intent of surveying the netire genome to look for contributing loci. Disease genes which have previously been found by our group, and which are currently being studied to understand the mechanism by which mutations cause disease, include the common inversion 16 seen in the M4 type of adult leukemia, in which a transcription factor gene on 16q is connected to a myosin heavy chain on 16p, producing a transforming protein. We are also studying the Huntington's disease gene on chromosome 4, in which an expansion of a CAG trinucleotide repeat results in neurodegenerative disease. Reconstruction of a full length cDNA is nearly complete and should enable an analysis of the normal function of the protein, which remains elusive. Two significant efforts are also underway to improve the technology of gene identification and analysis of function. These include a novel method of identifying genes encoded within human DNA cloned into yeast artificial chromosomes, using homologous recombination and 3' exon trapping. An ambitious effort is also underway to construct human artificial chromosomes, by putting together centromere, origin of replication, and telomere functions, with the hopes of producing a mitotically stable vector for transfer to human cells.
