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隔离为非随机，称为减数分裂驱动时，违反了Mendel的第一定律，该染色体被称为女性减数分裂，因为其固有的不对称性：只有染色体将其隔离到鸡蛋中。因此，远离随机分离的任何偏见都处于强烈的积极选择之下，并且对中心粒和核型的演化和物种产生重大影响。该现象的机械基础尚不清楚。罗伯逊（RB）融合的非随机隔离，这些融合发生在两个杂技染色体（一端的Centromere）之间，形成一个元中心（中间的Centromere），可以确定该物种是否具有杂型中心或元中型核心型。此外，优先隔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丝粒和减数分裂纺锤体不对称之间的功能差异导致非随机染色体分离，以及如何确定驱动方向。 RB融合与两个同源性杂技染色体配对，以在减数分裂驱动器中创建“三价”，这需要在非对称纺锤体上的三价和不对称的细胞分裂的优先取向，以使一个主轴极优先进入极性体。小鼠卵母细胞提供了一个理想的系统来解决尚不清楚的基本机制，因为融合在大多数菌株中优先将融合分离为极体。基于我们的初步结果，我们建议融合中心丝粒优先捕获来自具有更多星体微管的极点，这决定了三价的方向。 AIM 1将区分 在两种模型之间，有丝粒强度的差异。 AIM 2将检验以下假设：不对称纺锤杆处的微管行为驱动三价方向和主轴取向。 AIM 3将如何确定减数分裂驱动的方向。多个RB融合已在Zalende小鼠应变中固定，表明驱动方向几乎可以肯定相对于普通实验室菌株逆转，这提供了理想的实验系统。我们将测试两种可能性：主轴方向相对于皮层，或者主轴上的三价方向可以逆转（但不能同时）。提出的实验的结果将提供对动物减数分裂驱动的机制的首次见解，并在单个细胞中染色体分离的基本细胞生物学与种群中的核型进化和物种形成之间建立联系。此外，该提案与人类健康有关，因为RB融合是人类中最常见的染色体异常，发生在约0.1％的减数分裂分裂，并且与不孕有关。 RB融合优先将人类的鸡蛋分离为卵，这意味着携带它们的家庭中的异常持续存在。