A Program of Research in Population Cytogenetics

群体细胞遗传学研究计划

基本信息

批准号：
9144186
负责人：
TERRY J HASSOLD
金额：
$ 59.45万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9144186
关键词：
Address Adult Affect Aneuploidy Animal Model Attention Back Caenorhabditis elegans Cell division Chromatin Chromatin Structure Chromosome Pairing Chromosome Segregation Chromosome abnormality Chromosomes Clinical Congenital Abnormality Cytogenetics DNA Sequence Data Defect Development Drosophila genus Engineering Etiology Event Failure Female Genetic Nondisjunction Genetic Recombination Germ Cells Homologous Gene Human Human Chromosomes In Vitro Infertility Lead Link Maternal Age Mechanics Meiosis Meiotic Recombination Methodology Modeling Molecular Mosaicism Mus Mutation Nature Oocytes Oogenesis Pathway interactions Pattern Population Procedures Process Prophase Research Research Personnel Role Spermatocytes Spontaneous abortion Staging Synapses System Systems Development Testing Tissues Translating Trisomy Variant Yeasts age related base egg fetal human female human male insight interest male offspring older women preference prevent programs sex sperm cell therapeutic development

项目摘要

ABSTRACT Despite the importance of maternal meiotic errors to the etiology of human chromosome abnormalities, we know very little about chromosome dynamics during human female meiosis, and remain ignorant of the reasons why the process is so error-prone. Further, we have little understanding of the basis of the sex-specific differences in meiotic error rate or recombination patterns in our species. The studies that comprise this renewal application will directly examine meiosis in human oocytes and spermatocytes. By combining this approach with molecular and quantitative methodologies, we will answer fundamental questions about meiosis in humans. We will examine and compare the way in which homologous chromosomes find and synapse with one another during meiotic prophase in the human female and male and ask how synaptic patterns influence the formation of crossovers. In addition, because the placement of crossovers established during the fetal stages of oogenesis affects chromosome segregation in the adult female, we will combine the data obtained from human studies with studies in the mouse to test different models proposed to explain the relationship between recombination and nondisjunction. Finally, we will examine the contribution of chromatin structure and interference to sex-specific differences in recombination rates. The clinical implications of the basic information obtained from these studies are considerable: Aneuploidy is the most common cause of miscarriage and birth defects in our species. Understanding the mechanics of the meiotic process in humans and sex-specific differences not only provides a crucial first step in the development of therapeutic approaches to prevent or at least minimize errors, but also critical information for the development of systems for producing gametes in vitro to treat human infertility.

抽象的尽管母体减数分裂错误对于人类染色体异常的病因学很重要，我们对人类女性减数分裂期间的染色体动力学知之甚少，并且仍然对该过程如此容易出错的原因。此外，我们对性别特异性的基础知之甚少。我们物种减数分裂错误率或重组模式的差异。包含此内容的研究更新应用程序将直接检查人类卵母细胞和精母细胞的减数分裂。通过结合这个通过分子和定量方法，我们将回答有关减数分裂的基本问题在人类中。我们将检查并比较同源染色体发现和突触的方式在人类女性和男性的减数分裂前期彼此进行研究，并询问突触模式如何影响交叉的形成。此外，由于交叉的放置是在胎儿时期建立的卵子发生阶段影响成年女性的染色体分离，我们将结合获得的数据根据人类研究和小鼠研究来测试为解释这种关系而提出的不同模型重组与不分离之间。最后，我们将检查染色质结构的贡献以及对重组率中性别特异性差异的干扰。从这些研究中获得的基本信息的临床意义是相当大的：非整倍体是我们物种流产和出生缺陷的最常见原因。了解人类减数分裂过程的机制和性别特异性差异不仅提供了关键的第一步在开发治疗方法以防止或至少尽量减少错误的过程中，但也至关重要有关开发体外生产配子以治疗人类不育症的系统的信息。