Cell biological mechanisms of centromere drive

着丝粒驱动的细胞生物学机制

• 批准号: 9795484
• 负责人: Michael Lampson
• 金额: $ 1.73万
• 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/9795484
• 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两个着丝粒 DNA 的悖论 尽管着丝粒高度保守，序列和着丝粒结合蛋白仍然迅速进化 跨真核生物的功能。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)。在这种还原性细胞分裂中，每个同源对中的一条染色体保留在 卵子可以遗传给下一代，而另一部分则在极体中降解。自然的 选择强烈偏爱任何可以增加其留在鸡蛋中的机会的等位基因，这违反了孟德尔定律 第一定律（隔离定律）。减数分裂中这种偏向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 在竞争的驱动下，它们会朝着留在鸡蛋中的纺锤体杆方向移动。该模型是扩展 着丝粒处的重复序列导致形成更大的动粒并优先保留 鸡蛋。假设的第二部分解释了着丝粒蛋白通过冲突的进化 个体着丝粒之间，通过扩展以获得生殖优势和生殖适应性 有机体的。如果同源染色体着丝粒之间的差异导致男性缺陷 减数分裂时，这种生育成本提供了有利于着丝粒结合蛋白等位基因的选择压力， 通过与序列无关的结合平衡着丝粒并抑制驱动。着丝粒驱动 假说对着丝粒领域产生了重大影响，因为它提供了一个概念框架 了解着丝粒 DNA 和着丝粒蛋白的进化，但潜在的细胞生物学 机制尚不清楚。该提案解决了我们对着丝粒理解的三个主要差距 驾驶。首先，着丝粒DNA序列如何影响着丝粒功能？着丝粒的定义 在大多数生物体中都存在表观遗传，而序列的贡献长期以来一直不清楚。二、怎么样 MI 中的偏向隔离实现了吗？一个着丝粒优先保留在卵子中的机制 未知。第三，男性减数分裂是否会产生生育成本？这一关键组成部分的直接证据 驱动力假设很少。如果有成本，其机制依据是什么？为了解答这些问题，我们 建立了一个实验系统，我们使用由 使具有不同着丝粒的两种菌株杂交。遗传冲突塑造了我们基因组的许多方面， 由于对非孟德尔遗传的影响，着丝粒是一个特别令人着迷的案例。 我们的实验结果将为细胞生物学提供第一个机制洞察 着丝粒驱动。该项目对生殖生物学和染色体进化具有广泛的影响 代表了对进化细胞生物学领域的独特贡献。