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:10313087
- 负责人:
- 金额:$ 24.9万
- 依托单位:
- 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 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAnimal ModelArchitectureAreaBehaviorBiological ModelsBiologyBirthCentromereChemicalsChromatin FiberChromosome 4Chromosome MarkersChromosome PairingChromosome SegregationChromosome abnormalityChromosomesChromosomes, Human, 13-15Chromosomes, Human, 4-5ComplementComplexConceptionsCrowdingCytogeneticsCytologyDataDevelopmentDevelopmental ProcessEtiologyExposure toFemaleFoundationsFrequenciesGametogenesisGenesGeneticGenetic ScreeningGenomicsGerm CellsGrowth and Development functionHealthHumanHuman Cell LineIndividualInfertilityInheritedIntellectual functioning disabilityInvestigationKnowledgeLengthLinkMalnutritionMaternal AgeMeasuresMechanicsMeiosisModelingMolecularMonitorMothersMusOocytesOrganismPatientsPatternPositioning AttributePropertyReproductionResearchResearch PersonnelResearch TrainingResolutionSamplingSex DifferencesSpontaneous abortionStructural defectStructureSystemTestingVisualizationWorkarmbasechromosome missegregationfetal lossgenetic analysisgenetic approachgenomic toolsinsightnovelnovel markersegregationtransmission 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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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STACEY L HANLON其他文献
STACEY L HANLON的其他文献
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{{ truncateString('STACEY L HANLON', 18)}}的其他基金
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:
10327742 - 财政年份:2019
- 资助金额:
$ 24.9万 - 项目类别:
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 - 财政年份:2019
- 资助金额:
$ 24.9万 - 项目类别:
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:
10000194 - 财政年份:2019
- 资助金额:
$ 24.9万 - 项目类别:
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:
10583533 - 财政年份:2019
- 资助金额:
$ 24.9万 - 项目类别:
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