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，就会发生违反孟德尔第一定律的情况，称为减数分裂驱动，这适用于女性减数分裂，因为其固有的不对称性：只有染色体分离到卵子进入配子。因此，任何偏离随机分离的偏差都处于强正选择之下，并对着丝粒和核型进化和物种形成产生重大影响。这种现象的机制基础尚不清楚。罗伯逊（Rb）融合的非随机分离，发生在两个中心染色体（着丝粒在一端）之间，形成一个中心染色体（着丝粒在中间），可以确定一个物种是否具有中心或中心核型。此外，优先分离的方向可以逆转和驱动核型和物种形成的变化。本提案的总体目标是确定着丝粒和减数分裂纺锤体不对称之间的功能差异如何导致非随机染色体分离，以及驱动方向是如何确定的。在减数分裂i中，Rb与两条同源的单中心染色体融合形成“三价”染色体。减数分裂驱动需要三价染色体在不对称纺锤体上的优先定向和不对称细胞分裂，这样一个纺锤体极点优先进入极体。小鼠卵母细胞提供了一个理想的系统来解决潜在的机制，这些机制尚不清楚，因为在大多数菌株中，融合优先分离到极体。基于我们的初步结果，我们提出融合着丝粒优先从具有更多星状微管的极点捕获微管，这决定了三价的取向。目标1将区分

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.