Cell biological mechanisms of centromere drive

着丝粒驱动的细胞生物学机制

• 批准号: 9892184
• 负责人: Michael Lampson
• 金额: $ 4.49万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9892184
• 关键词: Address; Alleles; Binding; Binding Proteins; Biological; Cell division; Cells; Cellular biology; Centromere; Chromosome Segregation; Chromosome abnormality; Chromosomes; Conflict (Psychology); DNA; DNA Sequence; Defect; Development; Ensure; Epigenetic Process; Eukaryota; Evolution; Family; Female; Fertility; Genetic; Genetic Materials; Genome; Goals; Hybrids; Individual; Inherited; Kinetochores; Laws; Lead; Meiosis; Modeling; Molecular Abnormality; Natural Selections; Organism; Outcome; Population; Pregnancy loss; Process; Proteins; Regulation; Repetitive Sequence; Reproductive Biology; System; cost; egg; experimental study; fascinate; insight; male; mouse model; next generation; pressure; reproductive; reproductive fitness; segregation; sperm cell

The centromere drive hypothesis invokes genetic conflict to explain the paradox that both centromere DNA sequences and centromere-binding proteins have evolved rapidly, despite highly conserved centromere function across eukaryotes. Genetic conflict at centromeres is grounded in the asymmetry inherent in female meiosis I (MI). In this reductionist cell division, one chromosome from each homologous pair remains in the egg and can be transmitted to the next generation, while the other is degraded in the polar body. Natural selection strongly favors any allele that can increase its chance of remaining in the egg, in violation of Mendel's First Law (Law of Segregation). Such biased chromosome segregation in meiosis does occur and is a form of meiotic drive. The first part of the centromere drive hypothesis is that rapid evolution of centromere DNA is driven by competition to orient towards the spindle pole that will remain in the egg. The model is that expansion of repetitive sequences at a centromere leads to formation of a larger kinetochore and preferential retention in the egg. The second part of the hypothesis explains the evolution of centromere proteins through conflict between individual centromeres, which expand to gain a reproductive advantage, and the reproductive fitness of the organism. If differences between centromeres of homologous chromosomes cause defects in male meiosis, this fertility cost provides selective pressure favoring alleles of centromere-binding proteins that equalize centromeres and suppress drive by binding independent of sequence. The centromere drive hypothesis has had a major impact on the centromere field because it provides a conceptual framework for understanding the evolution of centromere DNA and centromere proteins, but the underlying cell biological mechanisms are unknown. This proposal addresses three major gaps in our understanding of centromere drive. First, how does centromere DNA sequence influence centromere function? Centromeres are defined epigenetically in most organisms, and the contribution of sequence has long been unclear. Second, how is biased segregation in MI achieved? The mechanism by which one centromere preferentially remains in the egg is unknown. Third, is there a fertility cost in male meiosis? Direct evidence for this crucial component of the drive hypothesis is scant. If there is a cost, what is the mechanistic basis? To address these questions, we have established an experimental system in which we observe drive, using a hybrid mouse model created by crossing two strains with different centromeres. Genetic conflict has shaped many aspects of our genomes, and centromeres are a particularly fascinating case because of the implications for non-Mendelian inheritance. The outcomes of our experiments will provide the first mechanistic insight into the cell biology underlying centromere drive. With broad consequences for reproductive biology and chromosome evolution, this project represents a unique contribution to the field of evolutionary cell biology.

Centromere驱动假说引起了遗传冲突，以解释两个Centromere DNA的悖论 尽管高度保守的中心粒 跨真核生物的功能。 centromeres的遗传冲突基于女性固有的不对称性 减数分裂I（MI）。在这种还原主义的细胞分裂中，每个同源对中的一个染色体保留在 鸡蛋可以传输到下一代，而另一个则降解在极体中。自然的 选择强烈利用任何可以增加其在鸡蛋中留在鸡蛋中的机会的等位基因，违反了门德尔的 第一法（隔离法）。确实发生了减数分裂中的这种偏见的染色体分离 减数分裂驱动。 Centromere驱动假设的第一部分是Centromere DNA的快速演变为 在竞争的驱动下，将留在鸡蛋中的主轴杆方向。该模型是扩展 丝粒处的重复序列的形成较大的动物学，并优先保留 鸡蛋。假设的第二部分解释了通过冲突通过冲突的中心粒蛋白的演变 在各个中心粒之间扩展以获得生殖优势和生殖健康 有机体。如果同源染色体的centromeres之间的差异导致男性缺陷 减数分裂，这种生育成本提供了有选择的压力，有利于共粒结合蛋白的等位基因 通过与序列无关的结合来均衡中心粒并抑制驱动。 Centromere驱动器 假设对Centromere领域产生了重大影响，因为它为 了解Centromere DNA和Centromere蛋白的演变，但潜在的细胞生物学 机制是未知的。该提案解决了我们对Centromere的理解的三个主要差距 驾驶。首先，CentRomere DNA序列如何影响Centromere的功能？定义了中心粒 在大多数生物体中，表观遗传学，序列的贡献一直尚不清楚。第二，怎么了 MI中有偏见的隔离？一个丝粒优先保留在鸡蛋中的机制 是未知的。第三，男性减数分裂成本有生育能力吗？直接证据证明了这一关键组成部分 驱动假设很少。如果有成本，机械基础是什么？为了解决这些问题，我们 已经建立了一个实验系统，我们使用由由混合鼠标模型创建的混合鼠标模型来观察驱动器 与不同的丝粒跨越两个菌株。遗传冲突塑造了我们基因组的许多方面， 由于对非孟德尔继承的意义，Centromeres是一个特别令人着迷的案例。 我们实验的结果将提供对细胞生物学基础的首次机械洞察力 Centromere驱动器。该项目对生殖生物学和染色体进化产生了广泛的影响， 代表对进化细胞生物学领域的独特贡献。