It is the ultimate goal of this research to understand the mechanisms by which chromosomal imbalances, duplications, deletions and rearrangements lead to phenotypic abnormalities and to identify the genes and basic mechanisms that produce inherited disorders in mouse and man. It is anticipated that genes causing, or predisposing to, inherited disorders will be mapped to chromosomes in increasing numbers due to the availability of highly polymorphic, closely spaced markers on the linkage map. The next step, to isolate them by positional cloning, is very laborious and can be abbreviated by the accurate placement of candidate genes. To this end, genes of known function that have been cloned and sequenced will be assigned to chromosomal map positions. The project will concentrate on genes that are involved in growth control and tumorigenesis, in transcriptional regulation and developmental steps, and/or are specifically expressed in brain, muscle, hematopoietic or endocrine organs and that could conceivably be involved in recognizable phenotypic alterations when mutated. The mapping information generated will be used to formulate testable hypotheses regarding involvement of specific genes in (a) germ-line Mendelian mutations that lead to phenotypic abnormalities as suggested by mapping of a candidate gene to the site of a known mutation in human or mouse; b) the pathogenesis of malformation syndromes associated with duplications and/or deletions of defined chromosomal regions; c) nonrandom chromosome rearrangements in malignant cells as suggested by mapping of candidate genes to sites of translocation breakpoints; d) somatic mutations leading to cancer by mapping genes to regions of frequent loss of heterozygosity in tumors; e) the establishment and precise delineation of regions of conserved synteny on human and mouse chromosomes which in turn lead to predictions of gene localization in the other species, to insights into chromosome evolution and to testable hypotheses regarding disease models in both species. A step-wise approach of increasing resolution is proposed: Newly cloned genes or gene families will be assigned to human and mouse chromosomes by PCR screening or Southern hybridization of somatic cell hybrid mapping panels. For further sublocalization on human chromosomes, hybrid cell panels with defined regions of the chromosome of interest retained, deletion mapping, and fluorescent in situ hybridization to metaphase chromosomes and, subsequently, multicolor FISH with other gene probes from the same region will be employed to establish physical order. In the mouse, recombinant inbred strain and interspecific backcross mapping will place the loci on the linkage map. As YAC contigs of chromosome regions and whole chromosomes become available, these will be screened in order to place the gene on the STS map. This will provide anchor points that connect the various maps and facilitate their integration.
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