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UBC Theses and Dissertations

Refinement of the physical and genetic maps of the MEN2A region in pericentromeric chromosome 10 Miller, Diane L.


The gene responsible for multiple endocrine neoplasia type 2A (MEN2A) has been localized to the pericentromeric region of chromosome 10.Several markers which fail to recombine with MEN2A have been identified including D10Z1, D10S94 , RET, D10S97, and D1OS102. Meiotic mapping in the MEN2A region is limited by a paucity of critical crossovers, attributable in part to reduced rates of recombination in the region, particularly in male meioses. Additional approaches for mapping loci in the pericentromeric region of chromosome 10 are required. The work described in this thesis involves the use of radiation reduced somatic cell hybrids to generate a detailed physical map, along with cloning and mapping of new DNA markers in the pericentromeric region of chromosome 10. The radiation reduced hybrids used for mapping studies all retain small subchromosomal fragments which include both D10S94 and D10Z1. One hybrid, pp11A, was chosen as the source of DNA for molecular cloning experiments. 106 human recombinant clones were isolated from lambda libraries made with pp11A DNA. Of these, 23 clones have been regionally localized using the radiation hybrid mapping panel. Eight markers have been identified which, when taken together with previously meiotically mapped markers, define eight radiation hybrid map intervals between D10S34 and RBP3. The predicted order of markers is the same using both the radiation hybrid mapping panel and a meiotic mapping panel. This combination cloning and mapping approach facilitates the precise positioning of new markers in pericentromeric chromosome 10 and aids in further refinement of the localization of MEN2A. Two new markers (D10S253 and D10S252) were assigned to the interval between D10S94 and RBP3 in 10q11.2 based on radiation hybrid mapping. Both were demonstrated to recombine with MEN2A. They flankMEN2A more closely than RBP3 and refine the interval to which the disease gene is assigned. The identification of these new flanking markers is of practical importance to DNA diagnostic programs for MEN 2A families and in efforts to clone the disease gene based on its chromosomal localization.

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