Cell biology of meiotic drive in mammals

哺乳动物减数分裂驱动的细胞生物学

• 批准号: 8725709
• 负责人: Michael Lampson
• 金额: $ 30.67万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8725709
• 关键词: Address; Alleles; Animals; Behavior; Binding; Binding Proteins; Binding Sites; Biology; Cell division; Cells; Cellular biology; Centromere; Chromosome Segregation; Chromosome abnormality; Chromosomes; DNA Sequence; Disputes; Educational process of instructing; Equilibrium; Evolution; Family; Female; Genetic; Germ Cells; Goals; Health; Human; Individual; Infertility; Inherited; Karyotype; Kinetochores; Laws; Lead; Link; Mammals; Meiosis; Microtubules; Modeling; Mouse Strains; Mus; Oocytes; Population; Process; Proteins; Regulation; Relative (related person); System; Testing; aurora B kinase; base; density; egg; high school; insight; public health relevance; reproductive; research study; segregation

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.

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（称为减数分裂驱动）时，就会违反孟德尔第一定律，它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才会进入配子。因此，任何偏离随机分离的偏差都会受到强烈的正选择的影响，并对着丝粒和核型进化和物种形成产生重大影响。该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条近端着丝粒染色体（一端着丝粒）之间形成中着丝粒（着丝粒位于中间），可以确定一个物种是否具有近端着丝粒或中着丝粒核型。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。该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，以及如何确定驱动方向。 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 中产生“三价”。减数分裂驱动需要三价在不对称纺锤体上的优先取向和不对称细胞分裂，以便一个纺锤体杆优先进入极体。小鼠卵母细胞提供了一个理想的系统来解决目前尚不清楚的潜在机制，因为众所周知，在大多数品系中融合优先分离到极体。根据我们的初步结果，我们提出融合着丝粒优先捕获具有更多星体微管的极点的微管，这决定了三价的方向。目标1将区分 两个模型之间着丝粒强度的差异。目标 2 将检验以下假设：不对称纺锤体极处的差异微管行为驱动三价取向和纺锤体取向。目标 3 将解决如何确定减数分裂驱动的方向。 Zalende 小鼠品系中的多个 Rb 融合已被固定，这表明相对于常见的实验室品系，驱动方向几乎肯定是相反的，这提供了一个理想的实验系统。我们将测试两种可能性：纺锤体相对于皮层的方向或纺锤体上的三价方向可以反转（但不能同时反转）。拟议实验的结果将首次深入了解动物减数分裂驱动的机制，并在个体细胞中染色体分离的基本细胞生物学与群体中核型进化和物种形成之间建立联系。此外，该提议与人类健康相关，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，并且与不育有关。在人类中，Rb 融合体优先分离到卵子中，这意味着携带它们的家族中仍然存在这种异常。