Conflict-driven aneuploidy and genomic instability caused by meiotic proteins

项目摘要/摘要 染色体分离可能失败，并产生染色体过多或过少的细胞，这是一种情况 这被称为非整倍体。非整倍体是癌症进展的驱动力，大多数癌症表现出 异常核型。非整倍体也是不孕不育和先天性出生缺陷的主要原因，例如 唐氏综合症。由于非整倍体在癌症和不孕不育中的普遍存在，它对 了解染色体分离不准确的原因。染色体的某些组成部分 分离机制是基因组中进化最快的基因之一。这种快速的演变是 自相矛盾的，因为染色体分离的过程是必要的，并且在很大程度上是保守的。据认为， 在真核生物中发现的由遗传寄生虫引起的冲突可能是这种快速进化的原因之一。 减数分裂驱动因素是这样一种类型的基因组内寄生虫，它们自私地促进自己的传播到 配子。这项提案的总体目标是确定导致非整倍体和不孕不育的机制。这个 提出的目标将解决三个重要的问题：1)什么是分子机制，利用 减数分裂驱动因素？2)减数分裂驱动因素是否促进非整倍体配子的形成？3)是什么导致了 染色体分离？我最近的工作发现，分裂酵母wtf基因是一种易于处理的模型系统 用来研究减数分裂驱动的。在我的论文(目标1)中，我将测试由这些基因引起的遗传冲突 减数分裂驱动因素可能影响染色体分离机制，从而影响非整倍体的频率。 配子。此外，我将测试人群中高频率的减数分裂驱动因素是否会促进 低保真染色体分离的进化。在我的博士后研究期间(目标2)，我将应用 在我的论文研究中获得的见解，以解决染色体分离的减数分裂成分 机器可能会导致人类有丝分裂染色体分离的错误。此外，我将测试是否 减数分裂基因的不及时表达导致了癌细胞中的非整倍体。要实现这些目标 目标，我将使用跨学科的方法，如遗传学、理论进化、共聚焦显微镜和 细胞遗传学。这些目标的实现将扩大我们对非整倍体原因的理解和 不孕症，以及遗传冲突对基因组完整性的影响。拟议的研究 代表了对染色体分离和癌症研究领域的独特贡献。

PROJECT SUMMARY/ ABSTRACT Chromosome segregation can fail and generate cells with too many or too few chromosomes, a condition known as aneuploidy. Aneuploidy is a driving force in cancer progression and most cancers exhibit an abnormal karyotype. Aneuploidy is also the leading cause of infertility and congenital birth defects, such as Down syndrome. Because of the prevalence of aneuploidy in cancer and infertility, it is paramount to understand the causes of inaccurate chromosome segregation. Some components of the chromosome segregation machinery are among the fastest evolving genes in the genome. This rapid evolution is paradoxical as the process of chromosome segregation is essential and largely conserved. It is thought that conflicts caused by genetic parasites, found throughout eukaryotes, could be one cause of this rapid evolution. Meiotic drivers are one such type of intragenomic parasites that selfishly promote their own transmission into gametes. The overall goal of this proposal is to identify mechanisms that cause aneuploidy and infertility. The proposed aims will address three important questions: 1) What are the molecular mechanisms utilized by meiotic drivers? 2) Do meiotic drivers promote the formation of aneuploid gametes? 3) What causes errors in chromosome segregation? My work recently identified fission yeast wtf genes as a tractable model system in which to study meiotic drive. For my thesis dissertation (Aim 1), I will test if the genetic conflict caused by these meiotic drivers could affect the chromosome segregation machinery and thus the frequency of aneuploid gametes. Additionally, I will test if a high frequency of meiotic drivers in a population could promote the evolution of low fidelity chromosome segregation. During my postdoctoral research (Aim 2), I will apply the insights gained in my thesis research to address if the meiotic components of the chromosome segregation machinery can contribute to errors in mitotic chromosome segregation in humans. In addition, I will test if the untimely expression of meiotic genes contributes to the aneuploidy seen in cancer cells. To achieve these goals, I will use interdisciplinary approaches such as genetics, theoretical evolution, confocal microscopy, and cytogenetics. The completion of these aims will expand our understanding of the causes of aneuploidy and infertility, as well as the impact that genetic conflict has on genome integrity. The proposed research represents a unique contribution to the field of chromosome segregation and cancer research.