A Program of Research in Population Cytogenetics

群体细胞遗传学研究计划

• 批准号: 8831210
• 负责人: TERRY J HASSOLD
• 金额: $ 62.44万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 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/8831210
• 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

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.

摘要 尽管母体减数分裂错误对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过程中的染色体动力学知之甚少， 这就是为什么这个过程如此容易出错。此外，我们对性别特异性的基础知之甚少。 减数分裂错误率或重组模式的差异。这些研究包括 更新申请将直接检查人类卵母细胞和精母细胞的减数分裂。通过组合该 方法与分子和定量方法，我们将回答有关减数分裂的基本问题 在人类身上。我们将检查和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， 跨界车的形成。此外，由于在胎儿期建立的交叉点的位置 卵子发生的各个阶段影响成年雌性的染色体分离，我们将联合收割机获得的数据 从人类研究到小鼠研究，以测试不同的模型来解释这种关系 重组和不分离之间的区别最后，我们将研究染色质结构的贡献 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， 在治疗方法的发展，以防止或至少最大限度地减少错误，但也至关重要 信息的发展系统生产配子在体外治疗人类不育症。