Our long range goal continues to be the elucidation of chromosomal organization, with emphasis on 10 chromosome fine structure and 2) three-dimensional chromosome positions in normal and abnormal interphase nuclei. We have refined and expanded non-isotopic in-situ hybridization methods toward these ends. More specifically, nucleic acids have been tagged with different ligands for simultaneous discrimination of different sequences, high resolution (ultrastructural) details have been preserved, and conditions that faithfully label single chromosome domains, or entire single chromosomes have been developed. These methods have wide application, and can be used to clarify pathogenic mechanisms in neoplastic, cytogenetic, and functionally altered human specimen. We request the opportunity to solidify and expand on our previous biological findings. Thus we will attempt 1) to further define chromosomal bands in terms of their molecular structure (e.g. SINE, Line, and other repeated DNA subsets), DNA lengths, replication patterns and structural orientation, 2) to further exploit our ability to rapidly detect complex numerical and structural aberrations in neuroectodermal tumors, and 3) to continue three-dimensional analyses of interphase chromosome position and structure in differentiating and adult CNS cells. Data from our laboratory indicates that there can be substantial and specific chromosome rearrangements in post-mitotic interphase neurons during differentiation and in pathological states (e.g. uncontrolled seizures). We suggest that such movements underlie or modulate the expression of ordered sets of genes.
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