Molecular Basis of Robertsonian Translocation Formation

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DESCRIPTION (provided by applicant): Despite the high frequency at which chromosomal abnormalities occur in humans, the molecular mechanisms underlying their occurrence are poorly understood. Robertsoman translocations (ROB), whole arm exchanges between the acrocentric chromosomes 13, 14, 15, 21, and 22, are the most common chromosomal rearrangements in humans. These rearrangements contribute greatly to fetal wastage, mental retardation, and birth defects. The formation of de novo ROB occurs at an exceptionally high rate. We have postulated that ROB form through two distinct mechanisms; a directive process resulting in the common rob(13q14q) and rob(14q21q), and a more random process resulting in the remaining eight rarer classes. To elucidate the mechanisms involved, we propose to identify the region containing the breakpoints in the two most common classes of Robertsonian translocations, rob (13q14q) and rob(14q21q) and clone the sequence(s) involved in the translocation formation. This will allow for the elucidation of the mechanism(s) of Robertsonian translocation formation and evolution of these regions on the acrocentnc chromosomes through the following specific aims: (1) Develop physical maps of the breakpoint regions in the proximal short arms of chromosomes 13, 14, and 21. (2) Determine the sequences at the rob(13q14q) and rob(14q21q) breakpoints and implicate them in ROB formation. (3) Identify factors that predispose to ROB formation through determining the mechanism through which satellite ifi DNA makes the acrocentric short arms susceptible to rearrangement. (4) Examine the spatial relationship between the acrocenthc chromosomes in oocytes and compare the frequency of meiotic exchange foci between acrocentric short arms within oocytes and between oocytes and spermatocytes. (5) Determine the evolutionary conservation of subfamilies of satellite III DNA among primates. The study of this common class of structural rearrangements has broader implications to understanding constitutional and acquired translocation formation in other regions of the genome, providing insight into recombination differences between the sexes within highly repetitive DNA, and facilitating our understanding of nondisjunction of the acrocentric chromosomes. Additionally, the cloning and mapping of sequences on the acrocentric short arms will give insight into the concerted evolution of these sequences among these chromosomes and contribute to the general understanding of chromosome evolution in mammals, and specifically in primates. Finally, this research is exploring a region of our genome that has been largely ignored by the effort of the Human Genome Project. The reagents produced in this research will contribute to the overall understanding of the organization of the human chromosome and may lead to an understanding of the role satellite DNA plays in chromosome structure, organization and function.