Molecular Basis of Robertsonian Translocation Formation

罗伯逊易位形成的分子基础

• 批准号: 6792166
• 负责人: LISA SHAFFER
• 金额: $ 29.36万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 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 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6792166
• 关键词: chromosome disorders; chromosome translocation; clinical research; cytogenetics; family genetics; fluorescent in situ hybridization; gene rearrangement; genetic mapping; genetic recombination; human genetic material tag; human subject; molecular cloning; molecular genetics; nucleic acid sequence; oogenesis; polymerase chain reaction; pulsed field gel electrophoresis; spermatogenesis

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.

描述（由申请人提供）：尽管人类染色体异常发生频率很高，但对其发生的分子机制知之甚少。Robertsoman易位（ROB），即13、14、15、21和22号近端着丝粒染色体之间的全臂交换，是人类最常见的染色体重排。这些重排极大地导致了胎儿浪费、智力低下和出生缺陷。新生ROB的形成以异常高的速率发生。我们假设ROB通过两种不同的机制形成：一种是导致共同rob（13q14q）和rob（14q21q）的定向过程，另一种是导致剩余8个稀有类的随机过程。为了阐明所涉及的机制，我们建议确定两种最常见的罗伯逊易位，rob（13q14q）和rob（14q21q）中包含断点的区域，并克隆易位形成中涉及的序列。这将允许通过以下特定目的阐明罗伯逊易位形成的机制和近端染色体上这些区域的进化： (1)绘制13、14和21号染色体近端短臂断裂点区域的物理图谱。 (2)确定rob（13q14q）和rob（14q21q）断点处的序列，并将其与ROB形成联系起来。 (3)通过确定卫星ifi DNA使近端着丝粒短臂易于重排的机制，确定易于形成ROB的因素。 (4)检查卵母细胞中近端着丝粒染色体之间的空间关系，并比较卵母细胞内近端着丝粒短臂之间以及卵母细胞与精母细胞之间减数分裂交换灶的频率。 (5)确定灵长类动物中卫星III DNA亚家族的进化保守性。这类常见的结构重排的研究有更广泛的意义，了解宪法和获得性易位形成在基因组的其他区域，提供洞察性别之间的重组差异在高度重复的DNA，并促进我们的理解不分离的近端着丝粒染色体。此外，近端着丝粒短臂上序列的克隆和作图将深入了解这些染色体之间这些序列的协同进化，并有助于对哺乳动物，特别是灵长类动物染色体进化的一般理解。最后，这项研究正在探索我们基因组中的一个区域，该区域在很大程度上被人类基因组计划所忽视。在这项研究中产生的试剂将有助于对人类染色体组织的全面了解，并可能导致对卫星DNA在染色体结构，组织和功能中所起作用的理解。