MECHANISMS OF HUMAN CHROMOSOME ABNORMALITIES

染色体结构或数目的异常是最常见的 已确定的导致精神发育迟滞的遗传缺陷类别和/或 其他发育异常。 染色体缺陷存在于约1 在160例活产婴儿中，大多数具有显著的身体或智力 异常 该计划的长期目标是了解 人类染色体异常的分子基础， 表型异常的原因和具体性质，以及 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。 虽然广泛的群体细胞遗传学研究已经确定， 各类染色体异常的发生率相对较少 关于数量染色体或结构染色体的原因， 缺陷 在本修订申请中，我们建议使用以下组合 分子和细胞遗传学的方法来研究最常见的， 这些疾病的临床意义。 在21三体的研究中，我们 将利用我们完善的登记超过1000唐氏综合症 研究21号染色体非功能障碍的起源， 我们将使用一种新的基因定位方法来识别参与 综合征的特定表型成分。 在对父亲的研究中- 衍生的非整倍体，我们将使用荧光原位杂交， 单精子PCR直接分析雄配子， 21-三体和21-三体中父亲非功能障碍发生率和病因 克氏综合征。 在罗伯逊易位的研究中， 人类常见的染色体结构异常，我们将联合收割机 分子和细胞遗传学技术研究的形成和减数分裂 这些重组的行为。 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 在特纳综合征和特纳综合征变体中检测到的染色体 精神发育迟滞和严重的发展影响，分析 不同着丝粒周围结构对有丝分裂染色体影响 分离，并测试一种新的机制，在严重的 与这些染色体的子集有关的表现型。

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.