MOLECULAR BASIS OF ROBERTSONIAN TRANSLOCATION FORMATION

尽管染色体异常发生的频率， 人类，其发生的分子机制很差 明白 罗伯逊易位（ROB），全臂交换 近端着丝粒染色体13、14、15、21和22之间， 常见的，周期性的染色体重排 ROB有 异常高的从头形成率。我们假设， ROB通过两种不同的机制形成： 在常见的rob（13 q14 q）和rob（14 q21 q）中， 导致剩下的八个更稀有的类。 阐明本 ROB形成所涉及的机制，我们建议识别该区域 包含两个最常见类别中的断点，rob（13 q14 q） 和rob（14 q21 q），并克隆参与易位的序列 阵 待检验的假设是，特定序列是 在非同源染色体13，14和21之间共享， 适当定向以促进配对和重组， 易位形成 这一假设得到了 观察到不成比例的大量rob（13 q14 q）和 rob（14 q21 q）与罕见的 发生，其余类别的ROB具有高度可变的断点。 本提案的具体目标是：1）进一步描述和 缩小染色体13、14和21上的断裂点区域，以及2）测试 现有的卫星III亚科从我们的实验室，以阐明 可能参与ROB形成。 如果上述卫星三号 序列似乎不参与易位交换 然后，我们将3）确定短臂上的新序列， ROB断裂点周围的13、14和21号染色体;以及4）测试这些 序列，以阐明其在ROB形成中的潜在作用。 研究 这类常见的结构重排具有更广泛的 对理解体质和后天易位的影响 形成，染色质交换的基本机制，重组 性别之间的差异和人类的不分离。

Despite the frequency at which chromosomal abnormalities occur in humans, the molecular mechanisms underlying their occurrence are poorly understood. Robertsonian translocations (ROB), whole arm exchanges between the acrocentric chromosomes 13, 14, 15, 21, and 22, are the most common, recurrent, chromosomal rearrangements in humans. ROBs have exceptionally high rates of de novo formation. We have postulated that ROBs 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 in ROB formation, we propose to identify the region containing the breakpoints in the two most common classes, rob(13q14q) and rob(14q21q), and clone the sequence(s) involved in the translocation formation. The hypothesis to be tested is that specific sequences are shared between the nonhomologous chromosomes 13, 14, and 21 that are properly oriented as to facilitate pairing and recombination leading to translocation formation. This hypothesis is supported by the observations of disproportionately large numbers of rob(13q14q) and rob(14q21q) with consistent breakpoints as compared to the rarely occurring, remaining classes of ROB with highly variable breakpoints. The specific aims of this proposal are to 1) further characterize and narrow the breakpoint regions on chromosomes 13, 14, and 21 and 2) test existing satellite III subfamilies from our laboratory to elucidate potential involvement in ROB formation. If the above satellite III sequences do not appear to be involved in the translocation exchanges we will then 3) identify novel sequences on the short arms of chromosomes 13, 14, and 21 around the ROB breakpoints; and 4) test these sequences to elucidate their potential role in ROB formation. The study of this common class of structural rearrangements has broader implications to understanding constitutional and acquired translocation formation, basic mechanisms for chromatin exchange, recombination differences between the sexes and nondisjunction in humans.