Evolutionary and functional diversification of chromatin proteins

染色质蛋白的进化和功能多样化

• 批准号: 8567656
• 负责人: Mia Tauna Levine
• 金额: $ 9万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-09 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8567656
• 关键词: Alleles; Amino Acids; Antitoxins; Automobile Driving; Biological; Biological Process; Biology; Birth; Blood; Cell physiology; Cellular biology; Centromere; Cessation of life; Chromatin; Chromosome Segregation; Chromosomes; Complement; Complex; Conflict (Psychology); Congenital Abnormality; DNA; DNA biosynthesis; Data; Disease; Drosophila genome; Drosophila genus; Elements; Epigenetic Process; Event; Evolution; Family; Female; Fertility; Functional disorder; Gene Family; Genes; Genetic; Genome; Genome Stability; Genomic Instability; Heterochromatin; Homeostasis; Infertility; Length; Link; Liquid substance; Malignant Neoplasms; Mediating; Meiosis; Modeling; Molecular; Mutation; Pattern; Phenotype; Phylogenetic Analysis; Phylogeny; Primates; Process; Proteins; Pseudogenes; Race; Recurrence; Research; Shapes; Structure; System; Testing; Tissues; Toxin; Trisomy; Y Chromosome; arm; base; cancer type; chromatin protein; cost; fitness; gene replacement; genetic element; heterochromatin-specific nonhistone chromosomal protein HP-1; innovation; insight; like heterochromatin protein 1; male; novel; prevent; public health relevance; segregation; sperm cell; telomere; tumor

DESCRIPTION (provided by applicant): Eukaryotic DNA is packaged into distinct chromatin compartments that mediate the expression, stability, and faithful inheritance of genetic information. These chromatin compartments support essential, highly conserved functions yet the chromatin proteins that define them are strikingly unconserved--domains and residues evolve rapidly even between closely related species. Although chromatin dysfunction is directly implicated in the initiation and progression of numerous cancers, the biological causes and functional consequences of this evolutionary innovation at chromatin proteins are virtually unknown. This proposal utilizes the classic evolutionary framework of a "molecular arms race" between a host genome and its selfish genetic elements to gain new insights into essential chromatin-dependent cellular processes. Telomeric chromatin proteins prevent catastrophic chromosome fusions and support telomere length homeostasis yet they evolve rapidly. The first aim posits that this evolution reflects recurrent innovation to suppress the fitness costs of selfih telomeres that "cheat" female meiosis via non-Mendelian segregation. This hypothesis is tested by transgenically introducing into D. melanogaster "mal-adapted" alleles of essential telomeric proteins that effectively reverse the amino acid evolution driven by genetic conflict over millions of years. The functional consequences of resurrecting the ancestral allele on genome instability phenotypes are quantified. In addition to rapid turnover of residues, wholesale turnover of chromatin protein repertoires between closely related species is common. The applicant's recent phylogenomic analysis of the Drosophila Heterochromatin Protein 1 (HP1) gene family discovered abundant gene birth and death across a 40 million year snapshot. Nevertheless, HP1 gene number per species is remarkably uniform, consistent with a "revolving door" of gene replacement. Based on a combination of functional and phylogenetic data, the second aim tests the hypothesis that a Y chromosome-linked toxin-antitoxin system drives this revolving door of chromatin proteins that support a persistent male fertility function. Finally, the HP1 gene family in higher primates harbors over 25 currently unannotated retrogenes. The Drosophila HP1 family diversification suggests that many of these primate retrogenes encode functional proteins that support fertility and genome stability. The final aim expands and characterizes primate HP1 retrogenes, elucidating their tissue-specific expression patterns, cytological localization and evolutionary signatures to delineate the biological processes driving a potential "revolving door" in primate HP1s. By identifying the biological causes and consequences of chromatin protein innovation, these studies will provide novel insights into how rapid evolution renders our genome vulnerable to epigenetic disease and infertility.

描述（由申请人提供）：真核DNA包装在不同的染色质区室中，介导遗传信息的表达、稳定性和忠实遗传。这些染色质区室支持基本的，高度保守的功能，但定义它们的染色质蛋白是惊人的不保守-结构域和残基进化迅速，即使在密切相关的物种之间。虽然染色质功能障碍直接涉及许多癌症的发生和发展，但染色质蛋白质的这种进化创新的生物学原因和功能后果几乎是未知的。这一建议利用了经典的进化框架的“分子军备竞赛”之间的主机基因组和它的自私的遗传因素，以获得新的见解基本染色质依赖的细胞过程。端粒染色质蛋白防止灾难性的染色体融合，并支持端粒长度的稳态，但它们进化迅速。第一个目标假定，这种演变反映了经常性的创新，以抑制自我端粒的健身成本，“欺骗”女性减数分裂通过非孟德尔分离。通过转基因导入D.黑腹果蝇“不适应”的基本端粒蛋白等位基因，有效地逆转了数百万人的遗传冲突所驱动的氨基酸进化。 年.对基因组不稳定性表型上的祖先等位基因的复活的功能后果进行量化。除了残基的快速周转，密切相关的物种之间的染色质蛋白库的批发周转是常见的。申请人最近对果蝇异染色质蛋白质1（HP 1）基因家族的基因组分析发现了跨越4000万年快照的丰富的基因出生和死亡。然而，每个物种的HP 1基因数量是非常均匀的，与基因替换的“旋转门”一致。基于功能和系统发育数据的组合，第二个目标测试的假设，Y染色体连锁的毒素-抗毒素系统驱动这个旋转门的染色质蛋白，支持持久的男性生育功能。最后，在高等灵长类动物的HP 1基因家族窝藏超过25个目前未注释的逆转录基因。果蝇HP 1家族的多样性表明，许多灵长类动物的逆转录基因编码的功能蛋白，支持生育力和基因组的稳定性。最终目标是扩展和表征灵长类动物HP 1逆转录基因，阐明其组织特异性表达模式、细胞学定位和进化特征，以描绘驱动灵长类动物HP 1潜在“旋转门”的生物学过程。通过确定染色质蛋白质创新的生物学原因和后果，这些研究将为快速进化如何使我们的基因组容易受到表观遗传疾病和不育症的影响提供新的见解。