Genomic Approaches to Aneuploidy

非整倍体的基因组方法

• 批准号: 8066268
• 负责人: Roger H Reeves
• 金额: $ 16.21万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-10 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8066268
• 关键词: Accounting; Adult; Affect; Aneuploidy; Animal Model; Award; Birth; Brain region; Candidate Disease Gene; Cells; Chromosomes; Chromosomes, Human, Pair 16; Chromosomes, Human, Pair 21; Communities; Complex; Conflict (Psychology); Development; Dimensions; Discipline; Disease; Down Syndrome; Engineering; Epidemiologic Studies; Etiology; Event; Face; First Pharyngeal Arch; Frequencies; Gene Dosage; Gene Expression Profile; Genes; Genetic; Genetic Models; Genomics; Genotype; Hereditary Disease; Hippocampus (Brain); Human Chromosomes; Incidence; Individual; Intestinal Neoplasms; Knowledge; Link; Measures; Mental Retardation; Modeling; Molecular; Molecular Biology; Mus; Neural Crest; Neural Crest Cell; Orthologous Gene; Phenotype; Population; Predisposition; Reporting; Research; Research Personnel; Resistance; Scientist; Skeleton; Solid Neoplasm; Source; Staging; Techniques; Testing; Tissues; Trisomy; Work; base; behavior test; craniofacial; dosage; granule cell; insight; leukemia; mortality; mouse Ts1Rhr; mouse Ts65Dn; mouse model; prenatal; programs; protective effect; research study

DESCRIPTION (provided by applicant): Down syndrome (DS) is caused by trisomy for human chromosome 21 (HSA21). The Down syndrome critical region hypothesis suggests that most DS features result from one or a few dosage sensitive genes located in critical regions on the chromosome. We performed the first direct test of this hypothesis by creating mice with a duplication or deletion of a critical region associated with a variety of DS facial features. Our analysis shows that genes from the critical region are not sufficient and are largely unnecessary to produce these complex features in mice, thus refuting the DSCR hypothesis. Molecular level studies remain important for DS, but explanations of the etiology of DS phenotypes must include the critical dimensions of where and when genes are expressed in development, and a realization that trisomy-induced events in one cells may initiate a cascade of changes in other cells, independent of additional gene dosage effects. Animal models are essential to these further studies, but existing mouse models for DS are inadequate. They do not represent the complete genetic insult and range of phenotypes in DS. Further, they are difficult to use, discouraging consideration of DS by the wider scientific community, something that is critical in dealing with a problem as complicated as trisomy 21. We will use chromosome engineering techniques optimized in the previous award period to build three new mouse models for DS that together contain three copies of all mouse orthologs of HSA21 genes. We will characterize them for additional, quantifiable features with parallels to DS. These more complete genetic models will simplify both husbandry and typing of trisomic mice, making them accessible to a much larger community, and will greatly facilitate developmental studies that are an essential to understanding and finally ameliorating the effects of trisomy. In the last award period, we made a second fundamental discovery by showing that the trisomic transcriptome is characterized by small changes in a large percentage of disomic genes. These changes are for the most part not individually significant, but collectively, they robustly distinguish trisomic and euploid transcriptomes. This finding that hundreds of disomic genes are expressed differently in trisomic vs. euploid cells has been confirmed in a purified population of cultured granule cell precursors. In addition, we provided direct evidence to prove the observation from epidemiological studies that individuals with trisomy 21 have a significantly lower than expected incidence of solid tumors, and narrowed from 350 to 33 the number of candidate resistance genes that are sufficient to provide protection. We will use new models to determine the genetic basis for this resistance.

描述（申请人提供）：唐氏综合征（DS）是由人类21号染色体三体（HSA 21）引起的。唐氏综合征关键区域假说表明，大多数DS特征来自位于染色体关键区域的一个或几个剂量敏感基因。我们通过创建与各种DS面部特征相关的关键区域重复或缺失的小鼠，对这一假设进行了第一次直接测试。我们的分析表明，来自关键区域的基因是不够的，在很大程度上是不必要的，以产生这些复杂的功能在小鼠中，从而驳斥了DSCR假说。分子水平的研究仍然是重要的DS，但解释的病因DS表型必须包括关键尺寸的基因表达的发展，并认识到三体诱导的事件在一个细胞可能会引发级联的变化在其他细胞，独立于额外的基因剂量效应。 动物模型对这些进一步的研究是必不可少的，但现有的DS小鼠模型是不够的。它们不代表DS中的完整遗传损伤和表型范围。此外，它们难以使用，阻碍了更广泛的科学界对DS的考虑，这对于处理像21三体这样复杂的问题至关重要。我们将使用在上一个奖励期优化的染色体工程技术来构建三种新的DS小鼠模型，这些小鼠模型共同包含三个HSA21基因的所有小鼠直系同源物的拷贝。我们将描述他们的额外的，可量化的功能与DS相似。这些更完整的遗传模型将简化三体小鼠的饲养和分型，使它们能够进入更大的社区，并将大大促进发育研究，这对理解和最终改善三体的影响至关重要。 在上一个奖项期间，我们通过显示三体转录组的特点是大比例的二体基因的小变化，取得了第二个基本发现。这些变化在很大程度上不是单独显著的，但总体上，它们有力地区分了三体和整倍体转录组。在培养的颗粒细胞前体的纯化群体中，已经证实了数百个二体基因在三体细胞与整倍体细胞中不同地表达的这一发现。 此外，我们提供了直接证据来证明流行病学研究的观察结果，即21三体个体的实体瘤发病率显著低于预期，并将足以提供保护的候选耐药基因数量从350减少到33。我们将使用新的模型来确定这种抗性的遗传基础。