MOLECULAR BASIS OF ROBERTSONIAN TRANSLOCATION FORMATION

罗伯逊易位形成的分子基础

• 批准号: 2857328
• 负责人: LISA SHAFFER
• 金额: $ 23.06万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2001-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2857328
• 关键词: chromosome disorders; chromosome translocation; clinical research; family genetics; fluorescent in situ hybridization; genetic mapping; genetic recombination; human genetic material tag; human subject; molecular cloning; molecular genetics; nucleic acid sequence; pulsed field gel electrophoresis

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.

尽管染色体异常发生的频率在 人类，其发生的分子机制很差 明白了。罗伯逊易位(ROB)，全臂交换 在13、14、15、21和22号端着丝粒染色体之间， 人类常见的、重复的、染色体重排。罗伯斯有 极高的新形成率。我们假设过 抢劫通过两种不同的机制形成；一个指导性的过程导致 在常见的ROB(13q14q)和ROB(14q21q)以及更随机的过程中 导致剩下的八个班级更加稀有。为了澄清 涉及ROB形成的机制，我们建议确定该区域 包含两个最常见的类中的断点，Rob(13q14q) 和Rob(14q21q)，克隆与易位有关的序列(S 队形。要检验的假设是特定的序列是 在非同源染色体13、14和21之间共享，这些染色体 适当定向，以促进配对和重组导致 易位形成。这一假设得到了 观察到数量不成比例的罗布(13q14q)和 ROB(14q21q)具有一致的断点，而不是很少 发生的、剩余的具有高度可变断点的ROB类。 这项建议的具体目的是1)进一步描述和 缩小13、14和21号染色体上的断裂点区域，并进行测试 来自我们实验室的现有卫星III亚家族来阐明 可能参与了Rob的形成。如果上面的卫星三号 序列似乎不参与易位交换 然后，我们将在短臂上鉴定新的序列 位于Rob断裂点附近的13、14和21号染色体；以及4)测试这些 序列以阐明它们在ROB形成中的潜在作用。这项研究 这种常见的结构调整类别中有更广泛的 对理解生理性和获得性易位的影响 染色质交换、重组的形成、基本机制 人类的性别差异和不分离。