Genetic conflict shapes centromeres and heterochromatin

描述(申请人提供)：染色体分离缺陷可导致不孕、出生缺陷和癌症。着丝粒是有丝分裂纺锤体和减数分裂纺锤体与DNA的连接点，并调节所有真核染色体的忠实分离。着丝粒DMA发展迅速，其大小和复杂性可达几个数量级。传统的研究着丝粒的尝试没有解释这种复杂性和快速进化背后的原因。我们的方法是研究决定着丝粒特性的表观遗传学蛋白质，而不是直接研究着丝粒DNA序列。我们发现，果蝇着丝粒组蛋白(CenH3)Cid在正向选择下不断进化，表明它参与了经常性的遗传冲突。我们的假设是，“着丝粒驱动”是这场冲突的根源。在这种模式下，着丝粒通过微管连接在动植物雌性减数分裂中竞争优先传递，因为4个减数分裂产物中只有1个成为卵子。这种竞争为染色体提供了一种自私的优势，可以制造更多的微管连接，并可能导致着丝粒卫星的失控扩张。虽然有益于驱动染色体，但这些扩张可能会对有机体和物种的适合性产生有害影响。例如，在人类群体中，罗伯逊融合(在0.12%的人口中发现着丝粒上的染色体融合)优先通过女性传播，但罗伯逊融合的男性携带者可能部分或完全不育。我们认为CenH3s和其他异染色质蛋白可能处于正选择状态，以抑制着丝粒驱动的有害后果，恢复减数分裂的奇偶性。我们计划通过以下具体目标来验证我们的假说：(1)我们将测试最近在黑腹果蝇中的卫星扩张是否在雌性减数分裂中具有传递优势；(2)我们将通过用来自密切相关物种或假想祖先的“未适应”的内源基因替换“适应的”内源基因来检验Cid和其他异染色质蛋白在果蝇中的正向选择的影响；(3)我们将分析不对称的雌性减数分裂对着丝粒进化的影响，在缺乏雌雄减数分裂的酵母和四膜虫中，以及完全缺乏减数分裂的Bdelloid轮虫中。

DESCRIPTION (provided by applicant): Defects in chromosome segregation can lead to infertility, to birth defects and to cancer. Centromeres serve as attachment points of mitotic and meiotic spindles to DMA, and mediate the faithful segregation of all eukaryotic chromosomes. Centromeric DMA evolves rapidly, and can range in size and complexity over several orders of magnitude. Traditional attempts at studying centromeres have left unexplained the causes underlying this complexity and rapid evolution. Our approach is to study the proteins that epigenetically determine centromere identity, instead of directly studying centromeric DNA sequence. We have discovered that the Drosophila centromeric histone (CenH3), Cid, has constantly evolved under positive selection, suggesting its involvement in recurrent genetic conflict. Our hypothesis is that 'centromere-drive' is the source of this conflict. Under this model, centromeres compete via microtubule attachments for preferential transmission in female meiosis in animals and plants, since only 1 of 4 meiotic products becomes the egg. This competition confers a selfish advantage to chromosomes that can make more microtubule attachments, and can result in runaway expansions of centromeric satellites. While beneficial to the 'driving' chromosome, these expansions can have deleterious effects on the fitness of an organism and of the species. For instance, in human populations, Robertsonian fusions (chromosome fusions at centromeres found in 0.12% of the population) are preferentially transmitted through females but male carriers of Robertsonian fusions can be partially or completely sterile. We propose that CenH3s as well as other heterochromatin proteins may be under positive selection to suppress the deleterious consequences of 'centromere-drive' and to restore meiotic parity. We plan to test our hypothesis with the following specific aims: (1) We will test whether recent satellite expansions in D. melanogaster have a transmission advantage in female meiosis, (2) We will examine the effects of the positive selection of Cid and other heterochromatin proteins in Drosophila by replacing 'adapted' endogenous genes with 'unadapted' versions from closely related species or hypothetical ancestors, and (3) We will assay the effects of asymmetric female meiosis on centromere evolution, in yeast and Tetrahymena that lack female and male meiosis, and bdelloid rotifers that lack meiosis altogether.