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: 10216317
• 负责人: Michael Lampson
• 金额: $ 20.31万
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216317
• 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，尤其是非整倍性，在前最早的细胞周期中很普遍 植入人类胚胎。高丝分裂错误的高事件令人困惑 - 稳定的染色体 传输代表了表面上以自然选择尊重的基本过程。但是，许多 潜在蛋白质，包括直接染色体分离和端粒蛋白的丝粒蛋白 保留染色体结束，在阳性选择下迅速发展。保守细胞的悖论 未经保守的机械支持的过程提出了经常创新。提议但在很大程度上 未经测试的该悖论的分辨率是，重复性DNA的快速演变驱动蛋白质的演变， 包装此DNA。在这个共同进化模型下，不断变化的重复DNA损害了生存能力 和/或生育力，刺激了保持基因组稳定性的染色体蛋白的适应性。来自非 - 的数据 哺乳动物模型有机体实现了早期的胚胎周期。在这里，我们考虑了独特的 精子沉积的DNA提出的挑战，该DNA进入高度紧凑和惰性的鸡蛋，并转化 通过母体蛋白质成染色体。我们假设母体沉积的蛋白质进化 迅速以对不断发展的父亲重复DNA进行重塑并建立centromeres和端粒。使用 小鼠作为哺乳动物模型系统，我们利用了centromeric和远程仪的自然变化 重复的DNA含量和来自肌肉菌群的发散蛋白质研究细胞生物学 “不匹配”父亲重复DNA和母体提供的蛋白质的后果。我们的假设 预测，在一个物种中，主要配置为重复DNA的蛋白质将不起作用 当面对另一种物种的父亲centromeres和端粒时，最好。我们的具体 目的是（1）建立一个体外受精（IVF）方案，以系统地改变父亲DNA和（2） 用相关物种的分歧版本代替快速发展的母体蛋白质。在每种情况下，我们都会 确定对丝粒和端粒包装以及胚胎基因组稳定性的后果。这 创新的，进化引导的功能方法揭示了看不见的遗传和表观遗传学 早期胚胎生存力的决定因素。我们的总体目标是建立一个集成的实验系统 这使我们能够挑战分化的，母亲为蛋白质提供不同重复的父亲基因组 数字和序列，为未来的R01提供关键支持，该R01研究了合子如何修复 基本染色体基因座之间的表观遗传对称性，通常在母体和孕妇之间发散 父亲基因组。在动态演化的界面上定义中心仪和端粒因子 同源重复的DNA将在植入前揭示未经认可的共同进化过程 胚胎。在此模型下，父亲和母体基因组的重复性DNA组成通常被忽略 损害基因组稳定性和传播，这是人IVF失败和早期妊娠丧失的标志。