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，特别是非整倍性，在早期的细胞周期中是普遍存在的。 植入人类胚胎有丝分裂错误的高发生率令人困惑-稳定染色体 传播代表了一个表面上由自然选择磨练的基本过程。然而，许多 基础蛋白，包括指导染色体分离的着丝粒蛋白和端粒蛋白 在正向选择下进化迅速。这种保守的细胞 由不保守的机制支持的过程表明经常性的创新。一个提议，但主要是 这个悖论的一个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， 包装这个DNA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，以保持基因组的稳定性。数据来自非 哺乳动物模式生物暗示了最早的胚胎周期。在这里，我们考虑不同的 精子沉积的DNA所带来的挑战，它进入卵子高度紧凑和惰性， 转化为感受态染色体。我们假设母体沉积的蛋白质 在不断进化的父系重复DNA上迅速重塑和建立着丝粒和端粒。使用 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 重复DNA含量和不同的母体蛋白质。肌亲属研究细胞生物学 “错配”的父亲重复DNA和母亲提供的蛋白质的后果。我们的假设 预测，在一个物种中，母体提供的适应重复DNA的蛋白质将不起作用， 最佳的情况是当面对不同的父亲着丝粒和另一个物种的端粒。我们的具体 目的是（1）建立一个体外受精（IVF）方案，系统地改变父亲的DNA和（2） 用相关物种的分化版本取代快速进化的母体蛋白。在每种情况下，我们将 确定着丝粒和端粒包装和胚胎基因组稳定性的后果。这 创新，进化引导功能方法揭示了不可见的遗传和表观遗传 早期胚胎生存能力的决定因素。我们的总体目标是建立一个综合的实验体系 这使我们能够挑战具有不同重复序列的父系基因组的分歧的母系提供的蛋白质， 数字和序列，为未来研究合子如何恢复的R 01提供关键支持 表观遗传对称性之间的基本染色体位点，分歧遗传之间的母亲和 父亲的基因组在动态进化的界面定义着丝粒和端粒因子， 同源重复DNA将揭示植入前的共同进化过程， 胚胎在这种模式下，经常被忽视的父方和母方基因组的重复DNA组成， 危及基因组的稳定性和传播，这是人类体外受精失败和早孕失败的标志。