A new system for modeling supernumerary chromosome dynamics and formation during meiosis.

一种用于模拟减数分裂期间多余染色体动力学和形成的新系统。

• 批准号: 9805440
• 负责人: STACEY L HANLON
• 金额: $ 10.42万
• 依托单位: STOWERS INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-21 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9805440
• 关键词: Affect; Animal Model; Architecture; Area; Behavior; Biological Models; Biology; Birth; Centromere; Chemicals; Chromatin Fiber; Chromosome Markers; Chromosome Pairing; Chromosome Segregation; Chromosome abnormality; Chromosomes; Chromosomes, Human, 13-15; Chromosomes, Human, 4-5; Chromosomes, Human, Pair 4; Complement; Complex; Conceptions; Crowding; Cytogenetics; Cytology; Data; Development; Developmental Process; Etiology; Exposure to; Female; Foundations; Frequencies; Gametogenesis; Genes; Genetic; Genetic Screening; Genomics; Germ Cells; Growth and Development function; Health; Human; Human Cell Line; Imagery; Individual; Infertility; Inherited; Intellectual functioning disability; Investigation; Knowledge; Length; Link; Malnutrition; Maternal Age; Measures; Mechanics; Meiosis; Modeling; Molecular; Monitor; Mothers; Mus; Oocytes; Organism; Patients; Pattern; Positioning Attribute; Property; Reproduction; Research; Research Personnel; Research Training; Resolution; Sampling; Sex Differences; Spontaneous abortion; Structural defect; Structure; System; Testing; Work; arm; base; chromosome missegregation; fetal loss; genetic analysis; genetic approach; genomic tools; insight; novel; novel marker; segregation; transmission process

PROJECT SUMMARY The normal growth, development, and reproduction of an organism relies on a defined set of essential chromosomes. At conception, the gain or loss of whole chromosomes is generally lethal and is thought to be the leading cause of spontaneous abortions in humans. Though the presence of a whole chromosome can be lethal, the gain of only part of a chromosome can be viable. Small supernumerary marker chromosomes (sSMCs) are structurally abnormal chromosomes that are present in ~1/2300 births and have been linked to infertility, fetal loss, and intellectual and developmental disabilities. Despite their clear impact on human health, very little is understood about important aspects of sSMC biology. Patient studies and human cell lines have been instrumental in determining the composition and frequency of existing sSMCs, but these systems are unable to model sSMC dynamics and formation during complex developmental processes. To close this knowledge gap, I will use the supernumerary B chromosomes recently found in D. melanogaster as a tractable model system to gain fundamental insight into supernumerary chromosome biology during female meiosis. Similar to some sSMCs described in humans, the B chromosomes can disrupt meiotic chromosome segregation, are subject to sex-specific differences in transmission frequency to progeny, and were formed from an essential chromosome. I will determine how B chromosomes disrupt the segregation of essential chromosomes during female meiosis using a genetic approach to monitor chromosome missegregation relative to a wide-ranging number of B chromosomes. I will then complement this genetic analysis with the visualization of live female meioses to gain a comprehensive view of meiotic supernumerary chromosome dynamics. To elucidate how B chromosomes are preferentially transmitted during female meiosis, I will identify differences in the centromeres of the B chromosomes and the essential chromosomes with high resolution by measuring the centromeric domains on chromatin fibers and conducting long-read sequencing and assembly of centromeric regions. Finally, I will determine the mechanism of supernumerary chromosome formation by strategically marking one of the essential chromosomes so that I can easily identify the formation of a new supernumerary chromosome. Based on the unique arrangement of markers this new supernumerary chromosome carries, I will deduce the mechanism by which it formed. Together, this work will allow me to gain research training in several areas that are essential for the continued investigation of supernumerary chromosome dynamics and formation, providing a foundation for my future research as an independent investigator examining how supernumerary chromosomes promote infertility, reduce gamete quality, and form de novo during meiosis.

项目摘要 生物体的正常生长、发育和繁殖依赖于一套确定的基本的 染色体在受孕时，整个染色体的获得或丢失通常是致命的， 人类自然流产的主要原因虽然整个染色体的存在可能是 致命的，只有部分染色体的获得才能存活。小额外标记染色体 （sSMCs）是结构异常的染色体，存在于约1/2300的出生中，并已与 不孕不育、胎儿丢失以及智力和发育障碍。尽管它们对人类有明显的影响 健康，对sSMC生物学的重要方面了解甚少。患者研究和人类细胞系 已经在确定现有sSMC的组成和频率方面发挥了作用，但是这些系统 无法模拟sSMC动力学和复杂的发育过程中的形成。要关闭此 为了填补知识空白，我将使用最近在D中发现的多余B染色体。黑腹菌作为一种易处理的 模型系统，以获得在女性减数分裂期间额外染色体生物学的基本见解。 类似于人类中描述的一些sSMC，B染色体可以破坏减数分裂染色体 分离，受到性别特异性差异的传播频率，以后代，并形成 从一个基本的染色体。我将确定B染色体是如何破坏 使用遗传方法监测染色体错误分离相对于雌性减数分裂期间的染色体 到大量的B染色体。然后，我将补充这一遗传分析与 可视化活的雌性减数分裂，以获得减数分裂额外染色体的全面视图 动力学为了阐明B染色体是如何在女性减数分裂中优先传递的，我将确定 B染色体和基本染色体的着丝粒差异， 测量染色质纤维上的着丝粒结构域并进行长读序测序和组装 着丝粒区域的。最后，我将确定额外染色体形成的机制， 战略性地标记一个重要的染色体，这样我就可以很容易地识别一个新的 额外染色体基于标记的独特排列， 染色体携带，我将推导出它形成的机制。我们一起合作，这项工作将使我获得 在几个领域的研究培训，这是必要的继续调查编外 染色体动力学和形成，为我未来的研究提供了一个独立的基础， 研究额外染色体如何促进不育，降低配子质量， 在减数分裂过程中从头开始