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.

着丝粒驱动假说援引遗传冲突来解释着丝粒DNA 尽管着丝粒高度保守，但序列和着丝粒结合蛋白仍迅速进化 在真核生物中发挥作用。着丝粒的遗传冲突是基于女性固有的不对称性 减数分裂I（MI）。在这种还原论的细胞分裂中，来自每一对同源染色体的一条染色体保留在染色体中。 卵中的一种可以传递给下一代，而另一种则在极体中降解。自然 选择强烈倾向于任何可以增加其留在卵子中的机会的等位基因，这违反了孟德尔的理论。 第一法（隔离法）。在减数分裂中，这种偏向性的染色体分离确实发生，并且是一种形式。 减数分裂驱动着丝粒驱动假说的第一部分是着丝粒DNA的快速进化是 在竞争的驱使下朝向留在蛋中的纺锤杆。这个模型是， 在着丝粒上的重复序列导致形成更大的动粒，并优先保留在 鸡蛋假说的第二部分解释了着丝粒蛋白通过冲突的进化 个体的着丝粒，扩张以获得生殖优势，和生殖适合度之间的关系， 生物体。如果同源染色体的着丝粒之间的差异导致男性的缺陷， 在减数分裂中，这种育性代价提供了选择压力，有利于着丝粒结合蛋白的等位基因， 通过独立于序列的结合来均衡着丝粒和抑制驱动。着丝粒驱动 这一假设对着丝粒场产生了重大影响，因为它为以下方面提供了概念框架 了解着丝粒DNA和着丝粒蛋白质的进化，但潜在的细胞生物学 机制不明。这个提议解决了我们对着丝粒理解的三个主要空白 驱动首先，着丝粒DNA序列如何影响着丝粒功能？着丝粒被定义为 在大多数生物体中，表观遗传学上，序列的贡献长期以来一直不清楚。第二，如何 是否实现MI中的偏倚隔离？一个着丝粒优先保留在卵中的机制 不明第三，男性减数分裂是否有生育成本？直接证据表明， 驱力假说是缺乏的。如果有成本的话，其机制基础是什么？为了解决这些问题，我们 我已经建立了一个实验系统，我们观察驱动器，使用杂交小鼠模型， 将两个具有不同着丝粒的菌株杂交。遗传冲突塑造了我们基因组的许多方面， 而着丝粒是一个特别吸引人的例子，因为它暗示了非孟德尔遗传。 我们的实验结果将提供对细胞生物学基础的第一个机械见解 着丝粒驱动该项目对生殖生物学和染色体进化产生了广泛的影响， 代表了对进化细胞生物学领域的独特贡献。