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）：将真核DNA包装到不同的染色质室中，这些染色质室介导遗传信息的表达，稳定性和忠实的遗传。这些染色质区室支持必需的高度保守功能，但定义它们的染色质蛋白却是明显的未经保守的 - 植物和残基甚至在密切相关的物种之间迅速发展。尽管染色质功能障碍直接与众多癌症的起始和进展有关，但这种进化创新在染色质蛋白上的生物学原因和功能后果实际上是未知的。该建议利用宿主基因组及其自私遗传元素之间“分子武器竞赛”的经典进化框架来获得对必需染色质依赖性细胞过程的新见解。端粒染色质蛋白可以预防灾难性的染色体融合并支持端粒长度稳态，但它们迅速发展。第一个目的表明，这种进化反映了反复的创新，以抑制通过非孟德尔种族隔离“作弊”女性减数分裂的自我端粒的健身成本。该假设是通过转基因引入基本端粒蛋白的“癌变”等位基因的D. melanogaster检验 几年。量化了祖先等位基因对基因组不稳定性表型的功能后果。除残留物的快速周转外，密切相关物种之间染色质蛋白质库的批发周转很常见。申请人最近对果蝇异染色质蛋白1（HP1）基因家族的系统基因分析发现了4000万年的快照中的大量基因出生和死亡。然而，每个物种的HP1基因数非常均匀，与基因替代的“旋转门”一致。基于功能和系统发育数据的组合，第二个目标检验了以下假设：Y染色体连接的毒素 - 抗抗毒素系统驱动了支持持续性男性生育功能的染色质蛋白的这种旋转门。最后，高级灵长类动物中的HP1基因家族在当前未注释的后退25个以上。果蝇HP1家族多样化表明，这些灵长类动物的重新基因编码支持生育能力和基因组稳定性的功能蛋白。最终目标扩展并表征了灵长类动物HP1反培养基，阐明了其组织特异性表达模式，细胞学定位和进化特征，以描绘出灵长类动物HP1中潜在“旋转门”的生物学过程。通过鉴定染色质蛋白创新的生物学原因和后果，这些研究将为我们的基因组如何易受表观遗传疾病和不育的影响提供新的见解。