Molecular and somatic cell genetic research is proposed to continue extensive gene mapping studies for characterizing the physical and genetic maps of the human. We will concentrate on understanding the chromosomal location and organization of growth control genes and the extent of their involvement and that of DNA segments in chromosomal rearrangements associated with cancer. The markers for mapping on human chromosomes include large numbers of (1) genes associated with metabolic disease and fatal disorders, (2) DNA segments assigned to highly specific chromosomal regions associated with Wilms' tumor (chromosome 11p13 deletion), small cell carcinoma of the lung (chromosome 3p14-23 deletion), Down's syndrome (chromosome 21q22), and breakpoints associated with non-random chromosomal rearrangement observed in specific cancers (11q13, 11q23, 3p13, 3p14, 3p21, 21q22), (3) genes associated with transformation that are induced in human cells by growth factors, epidermal growth factor and transforming growth factor-Alpha, which compete for the same receptor--the cellular homolog of the oncogene v-erb B, and (5) genes whose transcription is enhanced in leukemic cells. The gene markers will be chromosomally assigned by specific site in situ mapping and chromosome and regional mapping panels of somatic cell hybrids. DNA probes that map at a chromosome breakpoint or in a deletion associated with cancer will be characterized to determine sequences at break sites and adjacent probes to study these regions will be isolated by chromosome walking. All gene probes studied will be utilized to identify DNA polymorphisms (RFLPs) for linkage relationships, linear organization of the genome, and genetic counseling. The inherited nature of these DNA polymorphisms will be determined in 3 generation families. Genes associated with inherited disorders, abnormal growth and cancer will be mapped in the mouse using mouse-Chinese hamster cell hybrids to determine and predict human disease, evolution and chromosome assignment. Studies will be conducted to generate human-mouse cell hybrids that retain a single human chromosome for rapid gene mapping purposes. This research is designed to locate human genes associated with molecular disease and cancer to specific chromosomal sites for genetically understanding human disease, gene organization and control, and for genetic diagnosis and counseling.
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