Cell biological mechanisms of centromere drive

着丝粒驱动假说援引遗传冲突来解释着丝粒DNA 序列和着丝粒结合蛋白进化迅速，尽管着丝粒高度保守 在真核生物中发挥作用。着丝粒上的遗传冲突植根于女性固有的不对称性 减数分裂I(MI)。在这种简化论的细胞分裂中，每对同源细胞中的一条染色体保留在 卵可以传给下一代，而另一种则在极体中降解。天然 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 第一定律(隔离法)。在减数分裂中确实会发生这种有偏见的染色体分离，这是一种 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 在竞争的推动下，向着仍将留在鸡蛋中的纺锤杆定向。其模式就是扩张 着丝粒上的重复序列导致更大的着丝粒的形成和优先保留 鸡蛋。该假说的第二部分解释了着丝粒蛋白在冲突中的进化。 在个体着丝粒和生殖适合度之间，着丝粒扩张以获得生殖优势 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，这种生育成本提供了选择压力，有利于着丝粒结合蛋白的等位基因 平衡着丝粒，通过独立于序列的结合抑制驱动。着丝粒驱动力 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。这项建议解决了我们对着丝粒的理解中的三个主要差距 驾驶。第一，着丝粒DNA序列如何影响着丝粒功能？着丝粒的定义 在大多数生物中是表观遗传学的，而序列的作用长期以来一直不清楚。第二，情况如何？ 在MI中实现了有偏见的隔离？着丝粒优先留在卵子中的机制 是未知的。第三，男性减数分裂是否有生育成本？这一关键组成部分的直接证据 驱动力假说很少。如果有成本，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，在其中我们观察驱动器，使用由 用两个不同着丝粒的菌株杂交。基因冲突塑造了我们基因组的许多方面， 着丝粒是一个特别吸引人的案例，因为它意味着非孟德尔式的遗传。 我们的实验结果将提供对细胞生物学基础的第一个机械洞察力。 着丝粒驱动。对生殖生物学和染色体进化产生广泛影响的这个项目 代表着对进化细胞生物学领域的独特贡献。

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.