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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。

基本信息

批准号：
10583533
负责人：
STACEY L HANLON
金额：
$ 22.82万
依托单位：
UNIVERSITY OF CONNECTICUT STORRS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-21 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10583533
关键词：
Affect Architecture Area Behavior Biological Models Biology Birth Centromere Chemicals Chromatin Fiber Chromosome 4 Chromosome Markers Chromosome Pairing Chromosome Segregation Chromosome abnormality Chromosomes Chromosomes, Human, 13-15 Chromosomes, Human, 4-5 Complement Complex Conceptions Crowding Cytogenetics Data Development Developmental Process Etiology Exposure to Female Foundations Frequencies Gametogenesis Genes Genetic Genetic Screening Genomics Germ Cells Growth Health Human Human Cell Line 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 Postdoctoral Fellow Property Reproduction Research Research Personnel Research Training Resolution Sampling Sex Differences Spontaneous abortion Structural defect Structure System Testing Visualization Work arm chromosome missegregation fetal loss genetic analysis genetic approach genomic tools insight model organism novel novel marker segregation transmission process

项目摘要

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.

项目总结生物体的正常生长、发育和繁殖依赖于一套确定的必要的染色体。在受孕时，整个染色体的获得或丢失通常是致命的，被认为是是导致人类自然流产的主要原因。尽管整个染色体的存在可能是致命的是，只获得一部分染色体就可以存活。小额外标记染色体 (SSMC)是一种结构异常的染色体，存在于约1/2300名新生儿中，并与不孕不育、胎儿丧失、智力和发育障碍。尽管它们对人类产生了明显的影响健康方面，人们对SSMC生物学的重要方面知之甚少。患者研究和人类细胞系在确定现有SSMC的组成和频率方面发挥了重要作用，但这些系统无法模拟复杂发育过程中SSMC的动态和形成。要结束这件事知识鸿沟，我会用最近在黑腹小卷蛾身上发现的多余的B染色体作为一个容易驯服的模型系统，以获得对雌性减数分裂过程中额外染色体生物学的基本见解。与人类中描述的一些sSMCs类似，B染色体可以破坏减数分裂染色体分离，是受性别差异传播给后代的频率的差异，并形成从一个重要的染色体上。我将确定B染色体如何破坏必需基因的分离用遗传学方法监测雌性减数分裂过程中的染色体错配大量的B染色体。然后我会用这个基因分析来补充对活的雌性减数分裂进行可视化，以获得减数分裂额外染色体的全貌动力学。为了阐明B染色体如何在雌性减数分裂过程中优先传递，我将确定 B染色体和基本染色体着丝粒的高分辨率差异测量染色质纤维上的着丝粒结构域并进行长读测序和组装着丝粒区域。最后，我将通过以下方式确定额外染色体的形成机制战略性地标记一条重要的染色体，这样我就可以很容易地识别出新的额外的染色体。基于标记的独特排列，这一新的编外染色体携带，我将推断它形成的机制。总而言之，这项工作将使我获得对继续调查编外人员至关重要的几个领域的研究培训染色体的动力学和形成，为我作为一个独立的研究多余染色体如何促进不育症、降低配子质量和形成的研究者在减数分裂过程中从头开始。