Cell biology of meiotic drive in mammals

描述（由申请人提供）：当减数分裂中同源染色体的分离是非随机的时，违反孟德尔第一定律，称为减数分裂驱动，其适用于雌性减数分裂，因为其固有的不对称性：只有分离到卵子的染色体进入配子。因此，任何偏离随机分离的偏向都处于强正选择之下，并对着丝粒和核型进化以及物种形成具有重要影响。这种现象的机械基础尚不清楚。罗伯逊（Rb）融合的非随机分离，发生在两个近端着丝粒染色体（着丝粒在一端）之间，形成一个中间着丝粒（着丝粒在中间），可以决定一个物种是否具有近端着丝粒或中间着丝粒核型。此外，优先分离的方向可以逆转并驱动核型和物种形成的变化。这个提议的总体目标是确定着丝粒和减数分裂纺锤体不对称性之间的功能差异如何导致非随机染色体分离，以及驱动方向如何确定。Rb融合体与两条同源的近端着丝粒染色体配对，在减数分裂I中形成“三价体”。减数分裂驱动需要三价体在不对称纺锤体上的优先取向和不对称细胞分裂，使得一个纺锤体极优先进入极体。小鼠卵母细胞提供了一个理想的系统，以解决潜在的机制，这是不理解的，因为它是公认的，融合优先分离到极体在大多数菌株。基于我们的初步结果，我们建议，融合着丝粒优先捕获微管从极有更多的星形微管，这决定了三价的方向。目标1将区分 两个模型之间的差异，在着丝粒强度。目的2将测试的假设，在不对称的纺锤体极的差异微管行为驱动三价取向和纺锤体取向。目标3将解决如何决定减数分裂驱动的方向。多个Rb融合体已经在Zalibri小鼠品系中固定，表明驱动方向相对于常见的实验室品系几乎可以肯定是相反的，这提供了一个理想的实验系统。我们将测试两种可能性：纺锤体相对于皮质的取向或纺锤体上的三价取向都可以逆转（但不能同时逆转）。拟议的实验结果将提供第一次深入了解动物减数分裂驱动的机制，并建立个体细胞染色体分离的基本细胞生物学与核型进化和种群物种形成之间的联系。此外，该提议与人类健康有关，因为Rb融合是人类最常见的染色体异常，发生在约0.1%的减数分裂中，并与不育有关。Rb融合基因优先分离到人类的卵子中，这意味着异常在携带它们的家庭中持续存在。

DESCRIPTION (provided by applicant): Violations of Mendel's First law occur when segregation of homologous chromosomes in meiosis is nonrandom, termed meiotic drive, which applies to female meiosis because of its inherent asymmetry: only chromosomes that segregate to the egg go into a gamete. Any bias away from random segregation is therefore under strong positive selection and has significant consequences for centromere and karyotype evolution and speciation. The mechanistic basis for the phenomenon is unknown. Nonrandom segregation of Robertsonian (Rb) fusions, which occur between two acrocentric chromosomes (centromere at one end) to form a metacentric (centromere in the middle), can determine whether a species has an acrocentric or metacentric karyotype. Moreover, the direction of the preferential segregation can reverse and drive changes in karyotype and speciation. The overall goal of this proposal is to determine how functional differences between centromeres and meiotic spindle asymmetry lead to nonrandom chromosome segregation, and how the direction of drive is determined. Rb fusions pair with the two homologous acrocentric chromosomes to create a "trivalent" in meiosis I. Meiotic drive requires preferential orientation of the trivalent on an asymmetric spindle and an asymmetric cell division such that one spindle pole preferentially enters the polar body. Mouse oocytes provide an ideal system to address the underlying mechanisms, which are not understood, because it is well established that the fusion preferentially segregates to the polar body in most strains. Based on our preliminary results, we propose that the fusion centromere preferentially captures microtubules from the pole that has more astral microtubules, which determines the orientation of the trivalent. Aim 1 will distinguish between two models for differences in centromere strength. Aim 2 will test the hypothesis that differential microtubule behavior at asymmetric spindle poles drives trivalent orientation and spindle orientation. Aim 3 will address how the direction of meiotic drive is determined. Multiple Rb fusions have become fixed in the Zalende mouse strain, indicating that the direction of drive is almost certainly reversed relative to common lab strains, which provides an ideal experimental system. We will test two possibilities: either spindle orientation relative to the cortex or trivalent orientation on the spindle could reverse (but not both). The results of the proposed experiments will provide the first insight into mechanisms underlying meiotic drive in animals and establish a link between the basic cell biology of chromosome segregation in individual cells and karyotype evolution and speciation in populations. Moreover, the proposal is relevant to human health because Rb fusions are the most common chromosomal abnormality in humans, occurring in ~ 0.1% of meiotic divisions, and are associated with infertility. Rb fusions preferentially segregate to the egg in humans, which means that the abnormalities persist in families that carry them.