Evolutionary innovation to preserve zygotic genome integrity

保持合子基因组完整性的进化创新

• 批准号: 10040108
• 负责人: Michael Lampson
• 金额: $ 24.3万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10040108
• 关键词: Aneuploidy; Animal Model; Biological; Biological Assay; Biological Models; Biological Process; Cell Cycle; Cell physiology; Cells; Centromere; Chromosome Segregation; Chromosome abnormality; Chromosomes; DNA; Data; Defect; Deposition; Development; Embryo; Epigenetic Process; Evolution; Exhibits; Fertility; Fertilization in Vitro; Future; Genetic; Genome; Genome Stability; Goals; Human; Hybrids; Immunofluorescence Immunologic; Incidence; Maternal Age; Mitosis; Mitotic; Modeling; Molecular; Molecular Evolution; Mus; Natural Selections; Ploidies; Process; Proteins; Recurrence; Resolution; Risk; Scheme; System; TINF2 gene; Technology; Testing; Untranslated RNA; Variant; base; blastocyst; blastomere structure; chromosome loss; chromosome missegregation; conditional knockout; developmental disease; dynamical evolution; early pregnancy loss; egg; genome editing; genome integrity; innovation; lens; multiple myeloma M Protein; preimplantation; preservation; sperm cell; telomere; transmission process; zygote

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.

染色体异常，特别是非整倍体，在早期细胞周期中普遍存在。 植入人类胚胎时，有丝分裂错误的高发生率令人费解——稳定的染色体。 传播代表了一个表面上由自然选择磨练出来的基本过程，然而，其中的许多过程。 基础蛋白质，包括指导染色体分离的着丝粒蛋白和端粒蛋白 保留染色体末端的细胞在正选择下迅速进化。 由不保守的机器支持的过程表明了一项拟议的但主要是创新。 对于这一悖论，未经检验的解决方案是重复 DNA 的快速进化驱动了蛋白质的进化， 在这种共同进化模型下，不断变化的重复 DNA 会损害生存能力。 和/或生育力，刺激染色体蛋白的适应，从而保持基因组的稳定性。 哺乳动物模式生物涉及最早的胚胎周期。在这里我们考虑不同的胚胎周期。 精子沉积的 DNA 所带来的挑战，该 DNA 进入卵子时高度紧凑且惰性，并发生转化 我们帮助母体沉积的蛋白质进化成有能力的染色体。 使用不断进化的父系重复DNA快速重塑和建立着丝粒和端粒。 小鼠作为哺乳动物模型系统，我们利用小鼠着丝粒和端粒的自然变异 利用来自小家鼠近缘种的重复 DNA 含量和不同的母体蛋白来研究细胞生物学 我们的假设是父系重复DNA和母系提供的蛋白质“不匹配”的后果。 预测母体提供的适应某一物种重复 DNA 的蛋白质将无法发挥作用 当面对另一个物种的不同父系着丝粒和端粒时，效果最佳。 目标是 (1) 建立体外受精 (IVF) 方案以系统地改变父本 DNA 以及 (2) 在每种情况下，我们都会用来自相关物种的不同版本替换快速进化的母体蛋白质。 确定对着丝粒和端粒包装以及胚胎基因组稳定性的影响。 创新的、进化引导的功能方法揭示了原本看不见的遗传和表观遗传 我们的总体目标是建立一个综合的实验系统。 这使我们能够用不同重复的父本基因组来挑战不同的、母本提供的蛋白质 编号和序列，为未来研究受精卵如何恢复的 R01 提供重要支持 母体和母体之间遗传差异的重要染色体位点之间的表观遗传对称性 定义动态进化界面的着丝粒和端粒因子。 同源重复DNA将暴露植入前未被充分认识的共同进化过程 在这种模型下，父本和母本基因组的重复DNA组成经常被忽视。 危及基因组稳定性和传播，这是人类体外受精失败和早期妊娠流产的标志。