Evolutionary innovation to preserve zygotic genome integrity

染色体异常，特别是非整倍体，在早期细胞周期中普遍存在。 植入人类胚胎。有丝分裂错误的高发生率令人困惑--稳定的染色体 遗传是一种基本的过程，表面上看是由自然选择磨练出来的。然而，许多 潜在的蛋白质，包括指导染色体分离的着丝粒蛋白质和端粒蛋白质 保存染色体末端的物种，在正向选择下快速进化。守恒细胞的悖论 由不保守的机器支持的过程意味着反复的创新。一项提议的，但主要是 这一悖论的未经检验的解决方案是，重复DNA的快速进化推动了蛋白质的进化，这种蛋白质 把这个DNA打包。在这种共同进化模式下，不断变化的重复dna损害了生存能力。 和/或生育，刺激染色体蛋白质的适应，以保持基因组的稳定性。数据来自非 哺乳动物模式生物蕴含着最早的胚胎周期。在这里，我们认为不同的 精子沉积的DNA带来的挑战，它进入高度致密和惰性的卵子并被转化 通过母体蛋白质进入有能力的染色体。我们假设母体沉积的蛋白质会进化 在不断进化的父亲重复DNA上快速重塑和建立着丝粒和端粒。vbl.使用 小鼠作为哺乳动物模型系统，我们利用了MUS着丝粒和端粒的自然变异 肌肉分枝杆菌近缘种重复DNA含量和母体差异蛋白的细胞生物学研究 父方重复DNA和母方提供的蛋白质“不匹配”的后果。我们的假设 预测母体提供的蛋白质在一个物种中适应重复的DNA将不起作用 当面对另一个物种的父亲不同的着丝粒和端粒时，最好的选择是。我们的特定 目的是(1)建立体外受精(IVF)方案，系统地改变父亲的DNA和(2) 用来自相关物种的不同版本取代快速进化的母体蛋白。在每种情况下，我们都会 确定着丝粒和端粒包装以及胚胎基因组稳定性的后果。这 创新的、以进化为导向的功能方法揭示了其他看不见的遗传和表观遗传 早期胚胎存活的决定因素。我们的总体目标是建立一个完整的实验系统 这使得我们能够用不同重复的父系基因组来挑战分化的、母体提供的蛋白质 数字和序列，为未来研究受精卵如何恢复的R01提供关键支持 在母体和母体之间存在遗传差异的基本染色体座位之间的表观遗传对称性 父亲的基因组。在动态进化界面上定义着丝粒和端粒因子 同源重复DNA将暴露植入前被低估的共同进化过程 胚胎。在这种模式下，父系和母系基因组中经常被忽视的重复DNA组成 危及基因组的稳定和传播，这是人类试管受精失败和早孕丢失的标志。

Chromosomal abnormalities, particularly aneuploidies, are prevalent during the earliest cell cycles in pre- implantation human embryos. The high incidence of mitotic errors is puzzling – stable chromosome transmission represents a fundamental process ostensibly honed by natural selection. However, many of the underlying proteins, including centromere proteins that direct chromosome segregation and telomere proteins that preserve chromosome ends, evolve rapidly under positive selection. This paradox of conserved cellular processes supported by unconserved machinery suggests recurrent innovation. A proposed but largely untested resolution to this paradox is that rapid evolution of repetitive DNA drives the evolution of proteins that package this DNA. Under this co-evolution model, constantly changing repetitive DNA compromises viability and/or fertility, spurring adaptation at chromosomal proteins that preserve genome stability. Data from non- mammalian model organisms implicates the very earliest embryonic cycles. Here we consider the distinct challenges posed by sperm-deposited DNA, which enters the egg highly compact and inert and is transformed into competent chromosomes by maternal proteins. We hypothesize that maternally-deposited proteins evolve rapidly to remodel and establish centromeres and telomeres on ever-evolving paternal repetitive DNA. Using mouse as a mammalian model system, we exploit both natural variation in Mus centromeric and telomeric repetitive DNA content and divergent maternal proteins from M. musculus relatives to study the cell biological consequences of ‘mismatched’ paternal repetitive DNA and maternally provisioned proteins. Our hypothesis predicts that maternally-provisioned proteins adapted to repetitive DNA in one species will not function optimally when confronted with divergent paternal centromeres and telomeres of another species. Our specific aims are to (1) establish an in vitro fertilization (IVF) scheme to systematically vary the paternal DNA and (2) replace rapidly-evolving maternal proteins with diverged versions from related species. In each case, we will determine the consequences for centromere and telomere packaging and embryonic genome stability. This innovative, evolution-guided functional approach reveals otherwise invisible genetic and epigenetic determinants of early embryonic viability. Our overall goal is to establish an integrated experimental system that allows us to challenge diverged, maternally provisioned proteins with paternal genomes of varying repeat number and sequence, providing crucial support for a future R01 that investigates how the zygote restores epigenetic symmetry between essential chromosomal loci that diverge genetically between the maternal and paternal genomes. Defining the centromere and telomere factors at the interface of dynamic evolution with cognate repetitive DNA will expose an underappreciated co-evolutionary process in the pre-implantation embryo. Under this model, the often ignored repetitive DNA composition of paternal and maternal genomes imperils genome stability and transmission, a hallmark of failed human IVF and early pregnancy loss.