Genetic conflict shapes centromeres and heterochromatin

遗传冲突塑造着丝粒和异染色质

• 批准号: 7251925
• 负责人: HARMIT S MALIK
• 金额: $ 32.06万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7251925
• 关键词: Accounting; Aneuploidy; Animals; Automobile Driving; Binding Proteins; Biological Assay; Cellular biology; Centromere; Chromosome Segregation; Chromosomes; Code; Conflict (Psychology); Congenital Abnormality; DNA Sequence; Defect; Down Syndrome; Drosophila genus; Drosophila inturned protein; Eukaryota; Eukaryotic Cell; Evolution; Female; Foundations; Functional RNA; Future; Genes; Genetic; Genome; Heterochromatin; Histones; Human; Infertility; Lead; Left; Length; Localized; Malignant Neoplasms; Mediating; Meiosis; Microtubules; Mitosis; Mitotic; Modeling; Molecular Evolution; Nature; Organism; Plants; Population; Population Genetics; Proteins; Range; Recurrence; Research Personnel; Runaway; Shapes; Source; Sterility; Taxon; Testing; Tetrahymena; Trisomy; Validation; Yeasts; egg; fitness; male; novel; parity; pressure; programs; research study; segregation; size; transmission process

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.

描述（由申请人提供）：染色体分离缺陷可能导致不孕、出生缺陷和癌症。着丝粒作为有丝分裂和减数分裂纺锤体与 DMA 的附着点，并介导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到几个数量级。研究着丝粒的传统尝试未能解释这种复杂性和快速进化背后的原因。我们的方法是研究通过表观遗传学决定着丝粒身份的蛋白质，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 在正选择下不断进化，表明它参与了反复发生的遗传冲突。我们的假设是“着丝粒驱动”是这种冲突的根源。在这种模型下，着丝粒通过微管附着物竞争动物和植物雌性减数分裂中的优先传递，因为 4 种减数分裂产物中只有 1 种成为卵。这种竞争赋予染色体一种自私的优势，可以产生更多的微管附着，并可能导致着丝粒卫星的失控扩张。虽然这些扩展对“驱动”染色体有益，但可能对生物体和物种的健康产生有害影响。例如，在人类群体中，罗伯逊融合体（在 0.12% 的人口中发现着丝粒的染色体融合）优先通过女性传播，但罗伯逊融合体的男性携带者可能部分或完全不育。我们提出，CenH3s 以及其他异染色质蛋白可能处于正选择之下，以抑制“着丝粒驱动”的有害后果并恢复减数分裂奇偶性。我们计划通过以下具体目标来检验我们的假设：（1）我们将测试黑腹果蝇最近的卫星扩张是否在雌性减数分裂中具有传播优势，（2）我们将通过用来自密切相关物种或假设祖先的“未适应”版本替换“适应”内源基因来检查果蝇中 Cid 和其他异染色质蛋白正选择的影响，以及（3）我们将 测定缺乏雌性和雄性减数分裂的酵母和四膜虫以及完全缺乏减数分裂的蛭形轮虫中不对称雌性减数分裂对着丝粒进化的影响。