MECHANISMS OF HUMAN CHROMOSOME ABNORMALITIES

染色体结构或数目的异常是最常见的 已识别的导致智力低下和/或遗传缺陷的类别 其他发育异常。染色体缺陷出现在大约1 在160个活产婴儿中，大多数有显著的身体或智力 异常现象。本计划的长期目标是了解 人类染色体异常的分子基础，与 这种异常的原因和具体性质与表型和 阐明染色体结构和功能的一般特征 与遗传病的病因学有关的。 虽然广泛的群体细胞遗传学研究已经确定了 各类染色体异常发生率较低 已知数字或结构染色体的原因 缺陷。在此修订后的应用程序中，我们建议组合使用 分子和细胞遗传学方法研究最常见的和 这些疾病的临床意义。在对21三体的研究中，我们 将利用我们建立的超过1000个唐氏综合症的良好登记 个人调查21号染色体非功能障碍的起源， 我们将使用一种新的基因作图方法来识别与 该综合征的特定表型成分。在父权关系的研究中- 衍生的非整倍体，我们将使用荧光原位杂交和 用单精子聚合酶链式反应直接分析雄配子，研究 21三体和21三体儿童父性非功能障碍的发生率和病因 Klinefelter综合征在罗伯逊易位的研究中，大多数 人类常见的结构染色体异常，我们将结合 分子和细胞遗传学技术在减数分裂形成研究中的应用 这些重排的行为。最后，在X染色体的研究中 异常，我们将确定异常的分子性质 在Turner综合征及其变异体中检测到的染色体 有智力低下和严重发育影响的人，分析 不同着丝粒结构对有丝分裂染色体的影响 隔离，并测试一种新的机制，在严重的 与这些染色体的子集相关的表型。

Abnormalities of chromosome structure or number are the most common identified class of genetic defect leading to mental retardation and/or other developmental anomalies. Chromosome defects are present in about 1 in 160 livebirths, most with significant physical or intellectual abnormalities. The longterm goal of this Program is to understand the molecular basis for chromosome abnormalities in humans, to relate the causes and specific nature of such abnormalities to phenotype, and to elucidate general features of chromosome structure and function that are relevant to the etiology of genetic disease. While extensive population cytogenetic studies have determined the incidence of various classes of chromosome abnormality, relatively little is known about the causes of either numerical or structural chromosome defects. In this revised application, we propose to use a combination of molecular and cytogenetic approaches to study the most common and clinically significant of these disorders. In studies of trisomy 21, we will utilize our well-established registry of over 1000 Down syndrome individuals to investigate the genesis of non-disfunction of chromosome 21, and we will use a novel gene mapping approach to identify genes involved in specific phenotype components of the syndrome. In studies of paternally- derived aneuploidy, we will use fluorescence in situ hybridization and single sperm PCR to analyze directly the male gametes, to study the incidence and etiology of paternal non-disfunction in trisomy 21 and in Klinefelter syndrome. In studies of Robertsonian translocations, the most common structural chromosome abnormality in humans, we will combine molecular and cytogenetic techniques to study the formation and meiotic behavior of these rearrangements. Finally, in studies of X chromosome abnormalities, we will determine the molecular nature of abnormal chromosomes detected in Turner syndrome and in variants of Turner syndrome with mental retardation and severe developmental effects, analyze the effect of different pericentromeric structures on mitotic chromosome segregation, and test a novel mechanism potentially important in the severe phenotypes seen associated with a subset of such chromosomes.