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Evolutionary and functional diversification of chromatin proteins

染色质蛋白的进化和功能多样化

基本信息

批准号：
8730205
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
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-09 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8730205
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

项目摘要

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被包装成不同的染色质区室，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却惊人地不保守——即使在密切相关的物种之间，结构域和残基也会迅速进化。尽管染色质功能障碍与许多癌症的发生和发展直接相关，但染色质蛋白进化创新的生物学原因和功能后果实际上是未知的。这一建议利用宿主基因组及其自私遗传元素之间的“分子军备竞赛”的经典进化框架，以获得对基本染色质依赖的细胞过程的新见解。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，但它们的进化速度很快。第一个目标假设，这种进化反映了反复的创新，以抑制通过非孟德尔分离“欺骗”女性减数分裂的自利端粒的适应成本。这一假设通过转基因方式引入黑腹d.m anogaster必需端粒蛋白的“错误适应”等位基因得到验证，这些等位基因有效地逆转了由数百万遗传冲突驱动的氨基酸进化