Causes and functional consequences of chromatin evolution

染色质进化的原因和功能后果

• 批准号: 9976537
• 负责人: Mia Tauna Levine
• 金额: $ 39.21万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-11 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9976537
• 关键词: Aging; Amino Acids; Biological; Biology; Blood; CRISPR/Cas technology; Cell physiology; Cellular biology; Chromatin; Chromosome Segregation; Complex; Conflict (Psychology); Congenital Abnormality; DNA; DNA Packaging; DNA Sequence; Developmental Process; Disease; Drosophila melanogaster; Elements; Engineering; Evolution; Genes; Genetic; Genome; Genomic Instability; Genomics; Heterochromatin; Infertility; Left; Malignant Neoplasms; Mediating; Molecular; Mutation; Proteins; Race; Recurrence; Research; Selfish Genes; Sex Chromosomes; Shapes; Testing; Testis; Time; Transgenic Organisms; Trisomy; X Chromosome; Y Chromosome; arm; cancer type; chromatin protein; genetic approach; genetic information; genome integrity; innovation; insight; pressure; programs; telomere; transmission process; tumor; virtual

PROJECT SUMMARY DNA packaging into chromatin mediates chromosome segregation, telomere protection, genome integrity, and other essential, conserved cellular processes. However, many chromatin proteins are strikingly unconserved— domains and residues evolve rapidly between even closely related species. This paradox of conserved, chromatin-dependent functions supported by fast-evolving chromatin proteins suggests that maintaining essential cellular processes requires recurrent innovation. The biological significance of this innovation is virtually unexplored. With few exceptions, we understand neither the evolutionary forces that shape contemporary chromatin proteins nor the chromatin-dependent functions modified by recent adaptation. Nevertheless, aberrant chromatin packaging is the hallmark of many blood and tumor cancers, chromosomal birth defects, and aging. My lab integrates evolutionary genomics, transgenics, cell biology, and classical genetics to identify the evolutionary pressures that drive recurrent DNA packaging innovation and the consequences for fundamental, chromatin-dependent cellular and developmental processes. We utilize the classic evolutionary framework of a “molecular arms race” between a host genome and its selfish genetic elements to gain new insights into the causes and functional consequences of DNA packaging evolution. We focus specifically on adaptively evolving chromatin proteins that package the gene-poor, repeat-rich, and fast- evolving “heterochromatic” DNA sequence enriched at telomeres and along the sex chromosomes. We hypothesize that selfish genetic elements, which thrive in heterochromatin, antagonize sex chromosome and telomere packaging proteins. Consistent with this hypothesis, these heterochromatin proteins harbor the distinct DNA signature left behind by intra-genomic conflict—the rapid accumulation of amino acid-changing mutations over evolutionary time (i.e., positive selection). To empirically test the hypothesis that recurrent bouts of selfish element evasion and heterochromatin protein suppression drive these signatures of adaptation, we engineer “evolutionary mismatches” between contemporary Drosophila melanogaster selfish elements and “resurrected” versions of fast-evolving host proteins. Specifically, we leverage CRISPR/Cas9-mediated editing to delete or to swap in an ancestrally reconstructed host gene. Our preliminary results indicate that “mal- adapted” telomere proteins de-repress telomere-embedded selfish elements. Similarly, deleting young, testis- restricted heterochromatin proteins unleashes a selfish X chromosome that sabotages Y chromosome transmission. Our “reverse evolutionary genetics” approach offers us the unique opportunity to (1) identify selfish elements and their targets and (2) elucidate the mechanisms by which selfish elements gain a transmission advantage and by which chromatin proteins suppress them. By identifying the biological causes and consequences of heterochromatin protein innovation, our research program provides new insights into how rapid evolution renders our genome vulnerable to chromatin-mediated disease and infertility.

项目摘要 DNA包装到染色质中介导染色体分离，端粒保护，基因组完整性和 其他必不可少的蜂窝过程。但是，许多染色质蛋白质均未得到明显的保守 - 域并在密切相关的物种之间迅速保留进化。构成的悖论， 由快速发展的染色质蛋白支持的染色质依赖性功能表明，保持 必需的细胞过程需要经常创新。这项创新的生物学是 几乎是出乎意料的。除少数例外，我们既不了解塑造的进化力 当代染色质蛋白或通过近期适应所改变的染色质依赖性功能。 然而，异常染色质包装是许多血液和肿瘤癌，染色体的标志 出生缺陷和衰老。我的实验室整合了进化基因组学，转化，细胞生物学和经典 遗传学以识别驱动复发性DNA包装创新的进化压力和 基本，染色质依赖性细胞和发育过程的后果。我们利用 宿主基因组与其自私遗传之间的“分子武器竞赛”的经典进化框架 元素以获得对DNA包装演化的原因和功能后果的新见解。我们 专门关注适应性发展的染色质蛋白，这些蛋白质包装基因贫乏，重复富含和快速的染色质蛋白 富含端粒和性染色体富含的“异质” DNA序列。我们 假设自私的遗传元素在异染色质中壮成长，拮抗性染色体和 端粒包装蛋白。与这一假设一致，这些异染色质蛋白具有 基因组内冲突留下的独特的DNA签名 - 氨基酸改变的快速积累 进化时间的突变（即阳性选择）。凭经验检验复发的假设 自私的元素进化和异染色质蛋白抑制的回合驱动着这些适应性的签名， 我们设计了当代果蝇的自私元素和 快速发展的宿主蛋白的“复活​​”版本。具体而言，我们利用CRISPR/CAS9介导的编辑 删除或交换祖先重建的宿主基因。我们的初步结果表明“ 改编的”端粒蛋白去抑制端粒脱粒的自私元素。同样，删除了年轻，睾丸 - 受限的异染色质蛋白释放出破坏y染色体的自私X染色体 传播。我们的“反向进化遗传学”方法为我们提供了独特的机会（1）确定 自私的要素及其目标，（2）阐明了自私元素获得的机制 传输优势以及染色质蛋白抑制它们。通过识别生物学原因 和异染色质蛋白创新的后果，我们的研究计划提供了新的见解 进化的速度如何使我们的基因组容易受到染色质介导的疾病和不育的影响。